Thomas Montine, MD

Abstract

Assay for Transposase Accessible Chromatin by sequencing (ATAC-seq) accurately depicts the chromatin regulatory state and altered mechanisms guiding gene expression in disease. However, bulk sequencing entangles information from different cell types and obscures cellular heterogeneity. To address this, we developed Cellformer, a deep learning method that deconvolutes bulk ATAC-seq into cell type-specific expression across the whole genome. Cellformer enables cost-effective cell type-specific open chromatin profiling in large cohorts. Applied to 191 bulk samples from 3 brain regions, Cellformer identifies cell type-specific gene regulatory mechanisms involved in resilience to Alzheimer's disease, an uncommon group of cognitively healthy individuals that harbor a high pathological load of Alzheimer's disease. Cell type-resolved chromatin profiling unveils cell type-specific pathways and nominates potential epigenetic mediators underlying resilience that may illuminate therapeutic opportunities to limit the cognitive impact of the disease. Cellformer is freely available to facilitate future investigations using high-throughput bulk ATAC-seq data.

View details for DOI 10.1038/s41467-023-40611-4

View details for PubMedID 37587197

View details for PubMedCentralID 6071637

Abstract

BACKGROUND: Decedents with late-life dementia are often found at autopsy to have vascular pathology, cortical Lewy bodies, hippocampal sclerosis, and/or TDP-43 encephalopathy alone or with concurrent Alzheimer's disease (AD) lesions. Nonetheless, it is commonly believed that AD neuropathologic changes (NC) are the dominant or exclusive drivers of late-life dementia.OBJECTIVE: Assess associations of end-of-life cognitive impairment with any one or any combination of five distinct NC. Assess impairment prevalence among subjects having natural resistance to each type of NC.METHODS: Brains from 1,040 autopsied participants of the Honolulu-Asia Study, the Nun Study, and the 90+Study were examined for NC of AD, Lewy body dementia, microvascular brain injury, hippocampal sclerosis, and limbic predominate TDP-43 encephalopathy. Associations with impairment were assessed for each NC and for NC polymorbidity (variable combinations of 2-5 concurrent NC).RESULTS: Among 387 autopsied decedents with severe cognitive impairment, 20.4% had only AD lesions (ADNC), 25.3% had ADNC plus 1 other NC, 11.1% had ADNC plus 2 or more other NC, 28.7% had no ADNC but 1-4 other NC, and 14.5% had no/negligible NC. Combinations of any two, three, or four NC were highly frequent among the impaired. Natural resistance to ADNC or any other single NC had a modest impact on overall cohort impairment levels.CONCLUSION: Polymorbidity involving 1-5 types of concurrent NC is a dominant neuropathologic feature of AD and related dementias. This represents a daunting challenge to future prevention and could explain failures of prior preventive intervention trials and of efforts to identify risk factors.

View details for DOI 10.3233/JAD-230331

View details for PubMedID 37522210

Abstract

Hippocampal sclerosis of aging (HS-A) is a common age-related neuropathological lesion characterized by neuronal loss and astrogliosis in subiculum and CA1 subfield of hippocampus. HS-A is associated with cognitive decline that mimics Alzheimer's disease. Pathological diagnosis of HS-A is traditionally binary based on presence/absence of the lesion. We compared this traditional measure against our novel quantitative measure for studying the relationship between HS-A and other neuropathologies and cognitive impairment. We included 409 participants from The 90+ study with neuropathological examination and longitudinal neuropsychological assessments. In those with HS-A, we examined digitized H&E and LFB stained hippocampal slides. The length of HS-A in each subfield of hippocampus and subiculum, each further divided into three subregions, was measured using Aperio eSlide Manager. For each subregion, the proportion affected by HS-A was calculated. Using regression models, both traditional/binary and quantitative measures were used to study the relationship between HS-A and other neuropathological changes and cognitive outcomes. HS-A was present in 48 (12%) of participants and was always focal, primarily affecting CA1 (73%), followed by subiculum (9%); overlapping pathology (subiculum and CA1) affected 18% of individuals. HS-A was more common in the left (82%) than the right (25%) hemisphere and was bilateral in 7% of participants. HS-A traditional/binary assessment was associated with limbic-predominant age-related TDP-43 encephalopathy (LATE-NC; OR=3.45, p<0.001) and aging-related tau astrogliopathy (ARTAG; OR=2.72, p=0.008). In contrast, our quantitative approach showed associations between the proportion of HS-A (CA1/subiculum/combined) and LATE-NC (p=0.001) and arteriolosclerosis (p=0.005). While traditional binary assessment of HS-A was associated with impaired memory (OR=2.60, p=0.007), calculations (OR=2.16, p=0.027), and orientation (OR=3.56, p<0.001), our quantitative approach revealed additional associations with impairments in language (OR=1.33, p=0.018) and visuospatial domains (OR=1.37, p=0.006). Our novel quantitative method revealed associations between HS-A and vascular pathologies and impairment in cognitive domains that were not detected using traditional/binary measures.

View details for DOI 10.1007/s00401-023-02606-9

View details for PubMedID 37382680

View details for PubMedCentralID 2677204

Abstract

Clonal hematopoiesis of indeterminate potential (CHIP) is a premalignant expansion of mutated hematopoietic stem cells. As CHIP-associated mutations are known to alter the development and function of myeloid cells, we hypothesized that CHIP may also be associated with the risk of Alzheimer's disease (AD), a disease in which brain-resident myeloid cells are thought to have a major role. To perform association tests between CHIP and AD dementia, we analyzed blood DNA sequencing data from 1,362 individuals with AD and 4,368 individuals without AD. Individuals with CHIP had a lower risk of AD dementia (meta-analysis odds ratio (OR)=0.64, P=3.810-5), and Mendelian randomization analyses supported a potential causal association. We observed that the same mutations found in blood were also detected in microglia-enriched fraction of the brain in seven of eight CHIP carriers. Single-nucleus chromatin accessibility profiling of brain-derived nuclei in six CHIP carriers revealed that the mutated cells comprised a large proportion of the microglial pool in the samples examined. While additional studies are required to validate the mechanistic findings, these results suggest that CHIP may have a role in attenuating the risk of AD.

View details for DOI 10.1038/s41591-023-02397-2

View details for PubMedID 37322115

View details for PubMedCentralID 4306669

Abstract

BACKGROUND: APOE genotype is associated with Alzheimer disease. Thus, the concentration of apolipoprotein E (apoE) isoforms in cerebrospinal fluid (CSF) could be altered in dementia. However, conflicting results have been obtained in different studies. Carefully validated and standardized assays could improve the interpretation of research findings, allow their replication in other laboratories, and generalize their application.METHODS: To evaluate this hypothesis, we aimed to develop, validate, and standardize a new measurement procedure using LC-MS/MS. Purified recombinant apoE protein standards (E2, E3, E4) were thoroughly characterized and used to assign the concentration of a matrix-matched calibration material that contained each apoE isoform, which ensured the metrological traceability of results.RESULTS: The assay of each isoform in human CSF was precise (11%CV) and of moderate throughput (approximately 80 samples per day). It demonstrated good linearity and parallelism for lumbar CSF, ventricular CSF, and bovine CSF. The use of an SI-traceable matrix-matched calibrator enabled precise and accurate measurements. There was no association observed between total apoE concentration and the number of 4 alleles in a cohort of 322 participants. However, the concentration of each isoform was significantly different in heterozygotes, with E4 > E3 > E2. Isoform concentrations were associated with cognitive and motor symptoms but contributed negligibly to a predictive model of cognitive impairment that included established CSF biomarkers.CONCLUSIONS: Our method simultaneously measures each apoE isoform in human CSF with excellent precision and accuracy. A secondary matrix-matched material has been developed and is available to other laboratories to improve interlaboratory agreement.

View details for DOI 10.1093/clinchem/hvad056

View details for PubMedID 37279935

Abstract

Resilience to Alzheimer's disease is an uncommon combination of high disease burden without dementia that offers valuable insights into limiting clinical impact. Here we assessed 43 research participants meeting stringent criteria, 11 healthy controls, 12 resilience to Alzheimer's disease and 20 Alzheimer's disease with dementia and analyzed matched isocortical regions, hippocampus, and caudate nucleus by mass spectrometry-based proteomics. Of 7115 differentially expressed soluble proteins, lower isocortical and hippocampal soluble A levels is a significant feature of resilience when compared to healthy control and Alzheimer's disease dementia groups. Protein co-expression analysis reveals 181 densely-interacting proteins significantly associated with resilience that were enriched for actin filament-based processes, cellular detoxification, and wound healing in isocortex and hippocampus, further supported by four validation cohorts. Our results suggest that lowering soluble A concentration may suppress severe cognitive impairment along the Alzheimer's disease continuum. The molecular basis of resilience likely holds important therapeutic insights.

View details for DOI 10.1038/s41467-023-38376-x

View details for PubMedID 37173305

View details for PubMedCentralID 3266529

Abstract

Presence of lymph node metastasis (LNM) influences prognosis and clinical decision-making in colorectal cancer. However, detection of LNM is variable and depends on a number of external factors. Deep learning has shown success in computational pathology, but has struggled to boost performance when combined with known predictors.Machine-learned features are created by clustering deep learning embeddings of small patches of tumor in colorectal cancer via k-means, and then selecting the top clusters that add predictive value to a logistic regression model when combined with known baseline clinicopathological variables. We then analyze performance of logistic regression models trained with and without these machine-learned features in combination with the baseline variables.The machine-learned extracted features provide independent signal for the presence of LNM (AUROC: 0.638, 95% CI: [0.590, 0.683]). Furthermore, the machine-learned features add predictive value to the set of 6 clinicopathologic variables in an external validation set (likelihood ratio test, p<0.00032; AUROC: 0.740, 95% CI: [0.701, 0.780]). A model incorporating these features can also further risk-stratify patients with and without identified metastasis (p<0.001 for both stage II and stage III).This work demonstrates an effective approach to combine deep learning with established clinicopathologic factors in order to identify independently informative features associated with LNM. Further work building on these specific results may have important impact in prognostication and therapeutic decision making for LNM. Additionally, this general computational approach may prove useful in other contexts.

View details for DOI 10.1038/s43856-023-00282-0

View details for PubMedID 37095223

View details for PubMedCentralID 5069274

Abstract

Alzheimer's disease (AD) is a looming public health disaster with limited interventions. Alzheimer's is a complex disease that can present with or without causative mutations and can be accompanied by a range of age-related comorbidities. This diverse presentation makes it difficult to study molecular changes specific to AD. To better understand the molecular signatures of disease we constructed a unique human brain sample cohort inclusive of autosomal dominant AD dementia (ADD), sporadic ADD, and those without dementia but with high AD histopathologic burden, and cognitively normal individuals with no/minimal AD histopathologic burden. All samples are clinically well characterized, and brain tissue was preserved postmortem by rapid autopsy. Samples from four brain regions were processed and analyzed by data-independent acquisition LC-MS/MS. Here we present a high-quality quantitative dataset at the peptide and protein level for each brain region. Multiple internal and external control strategies were included in this experiment to ensure data quality. All data are deposited in the ProteomeXchange repositories and available from each step of our processing.

View details for DOI 10.1038/s41597-023-02057-7

View details for PubMedID 37059743

View details for PubMedCentralID PMC10104800

Abstract

Some oldest-old individuals can maintain superior cognition despite advanced age. Little is known about the neuropathological changes in the brains of oldest-old superior cognitive performers.Our objective was to examine the associations between Alzheimer's disease (AD) and non-AD neuropathologic features in relation to superior cognitive performance in oldest-old individuals.We analyzed brain autopsy data from 102 participants with normal cognition from The 90+ Study. Superior global cognitive performers (SGCP) were defined as having Mini-Mental State Examination (MMSE) score 28 in the last visit 12 to 2 months before death. To examine the associations between individual and multiple comorbid neuropathologic features with SGCP status we used multiple logistic regression models adjusting for age, sex, and education.Alzheimer's disease neuropathological change (ADNC) and low levels of vascular pathologic change were not associated with superior cognition. In contrast, participants with limbic (OR=8.37; 95% CI: 1.48-47.44) and neocortical (OR=10.80;95% CI: 1.03-113.82) Lewy body disease (LBD), or with hippocampal sclerosis (HS) (OR=5.28; 95% CI: 1.10-25.47) were more likely to be non-SGCP. High total burden of multiple comorbid neuropathologic features was associated with a lower likelihood of being SGCP.Oldest-old superior cognitive performers were resilient to ADNC and low levels of vascular pathologic change and were resistant to non-AD neurodegenerative changes and multiple comorbid neuropathologic features. Understanding the factors underlying the ability of superior cognitive performers to resist these changes might provide useful insights on maintenance of superior cognition despite advanced age.

View details for DOI 10.3233/JAD-221062

View details for PubMedID 37066908

View details for DOI 10.5858/arpa.2021-0438-OA)

View details for Web of Science ID 000958483400012

Abstract

The association between neuropathological changes and dementia among centenarians and nonagenarians remains unclear.We examined brain tissue from 100 centenarians and 297 nonagenarians from The 90+ Study, a community-based longitudinal study of aging. We determined the prevalence of 10 neuropathological changes and compared their associations with dementia and cognitive performance between centenarians and nonagenarians.A total of 59% of centenarians and 47% of nonagenarians had at least four neuropathological changes. In centenarians, neuropathological changes were associated with higher odds of dementia and, compared to nonagenarians, the odds were not attenuated. For each additional neuropathological change, the Mini-Mental State Examination score was lower by 2 points for both groups.Neuropathological changes continue to be strongly related to dementia in centenarians, highlighting the importance of slowing or preventing the development of multiple neuropathological changes in the aging brain to maintain cognitive health.Individual and multiple neuropathological changes are frequent in centenarians. These neuropathological changes are strongly associatedwith dementia. There is no attenuation of this association with age.

View details for DOI 10.1002/alz.12981

View details for PubMedID 36795955

View details for DOI 10.1002/ana.26574

View details for Web of Science ID 000925056000001

View details for Web of Science ID 000936803500050

Abstract

Post-mortem analysis provides definitive diagnoses of neurodegenerative diseases; however, only a few can be diagnosed during life.This study employed statistical tools and machine learning to predict 17 neuropathologic lesions from a cohort of 6518 individuals using 381 clinical features (Table S1). The multisite data allowed validation of the model's robustness by splitting train/test sets by clinical sites. A similar study was performed for predicting Alzheimer's disease (AD) neuropathologic change without specific comorbidities.Prediction results show high performance for certain lesions that match or exceed that of research annotation. Neurodegenerative comorbidities in addition to AD neuropathologic change resulted in compounded, but disproportionate, effects across cognitive domains as the comorbidity number increased.Certain clinical features could be strongly associated with multiple neurodegenerative diseases, others were lesion-specific, and some were divergent between lesions. Our approach could benefit clinical research, and genetic and biomarker research by enriching cohorts for desired lesions.

View details for DOI 10.1002/alz.12921

View details for PubMedID 36681388

Abstract

Background: Gait and balance impairments are among the most troublesome and heterogeneous in Parkinson's disease (PD). This heterogeneity may, in part, reflect genetic variation. The apolipoprotein E (APOE) gene has three major allelic variants (epsilon2, epsilon3 and epsilon4). Previous work has demonstrated that older adult (OA) APOE epsilon4 carriers demonstrate gait deficits. This study compared gait and balance measures between APOE epsilon4 carriers and non-carriers in both OA and PD.Methods: 334 people with PD (81 APOE epsilon4 carriers and 253 non-carriers) and 144 OA (41 carriers and 103 non-carriers) were recruited. Gait and balance were assessed using body-worn inertial sensors. Two-way analyses of covariance (ANCOVA) compared gait and balance characteristics between APOE epsilon4 carriers and non-carriers in people with PD and OA, controlling for age, gender, and testing site.Results: Gait and balance were worse in people with PD compared to OA. However, there were no differences between APOE epsilon4 carriers and non-carriers in either the OA or PD group. In addition, there were no significant group (OA/PD) by APOE epsilon4 status (carrier/non-carrier) interaction effects for any measures of gait or balance.Conclusions: Although we found expected impairments in gait and balance in PD compared to OA, gait and balance characteristics did not differ between APOE epsilon4 carriers and non-carriers in either group. While APOE status did not impact gait and balance in this cross-sectional study, future work is needed to determine whether progression of gait and balance deficits is faster in PD APOE 4 carriers.

View details for DOI 10.1016/j.prdoa.2023.100201

View details for PubMedID 37252677

Abstract

Alzheimer's disease (AD) is the most common cause of dementia. AD neuropathologic change (ADNC) likely begins decades before clinical manifestations. One mechanism implicated in AD is oxidative stress. We explored the potential association of ADNC with antioxidant vitamin supplements taken about 30 years before death.The 264 brain-autopsied participants were part of The 90+ Study, a longitudinal study of aging among people aged 90+ years, and originally members of the Leisure World Cohort Study, a population-based health study established in the 1980s. Intake of supplemental vitamins A, C, and E was collected by the Leisure World Cohort Study about 30 years before ADNC assessment. Odds ratios of ADNC (intermediate/high vs. none/low) for vitamin intake were estimated using logistic regression.The adjusted odds ratio (95% CI) of ADNC was 0.52 (0.29-0.92) for vitamin E supplements and 0.51 (0.27-0.93) for vitamin C supplements. Supplemental vitamin E intake was the first variable, after education, to enter the stepwise model. Intake of vitamin A or C did not improve the model fit.The observed association of ADNC and supplemental vitamin E intake decades earlier suggests a beneficial effect and supports further investigation into a nutritional approach to preventing AD with vitamin supplementation.

View details for DOI 10.1097/WAD.0000000000000551

View details for Web of Science ID 001006680100001

View details for PubMedID 36821174

View details for PubMedCentralID PMC9976331

Abstract

Limbic-predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC) is a recently described neuropathological construct associated with dementia. This study aimed to investigate in an autopsy study, LATE-NC and its associations with potential estrogen-related risk factors collected about 30years before death. Participants were part of The 90+ Study and had, as part of the Leisure World Cohort Study, provided information on menstrual and reproductive variables and details of use of estrogen replacement therapy (ERT). No menstrual and reproductive variable showed an association with LATE-NC. Use of ERT, especially long-term use (15+ years) and more recent use (within 1 year of completing the questionnaire), was associated with reduced risk. The odds were significantly lower for long-term (0.39, 95% confidence interval [CI]: 0.16-0.95) and recent use (0.39, 95% CI: 0.16-0.91) compared with no use. In conclusion, we found that women who reported long-term ERT in their 50s and 60s had a significantly reduced odds of harboring LATE-NC when they died in the 10th and 11th decades of their lives. Our study adds to the existing literature reporting seemingly protective effect of peri- and postmenopausal ERT against neurodegenerative dementia.

View details for DOI 10.1093/jnen/nlac119

View details for PubMedID 36562637

Abstract

An international consensus report in 2019 recommended a classification system for limbic-predominant age-related TDP-43 encephalopathy neuropathologic changes (LATE-NC). The suggested neuropathologic staging system and nomenclature have proven useful for autopsy practice and dementia research. However, some issues remain unresolved, such as cases with unusual features that do not fit with current diagnostic categories. The goal of this report is to update the neuropathologic criteria for the diagnosis and staging of LATE-NC, based primarily on published data. We provide practical suggestions about how to integrate available genetic information and comorbid pathologies [e.g., Alzheimer's disease neuropathologic changes (ADNC) and Lewy body disease]. We also describe recent research findings that have enabled more precise guidance on how to differentiate LATE-NC from other subtypes of TDP-43 pathology [e.g., frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS)], and how to render diagnoses in unusual situations in which TDP-43 pathology does not follow the staging scheme proposed in 2019. Specific recommendations are also made on when not to apply this diagnostic term based on current knowledge. Neuroanatomical regions of interest in LATE-NC are described in detail and the implications for TDP-43 immunohistochemical results are specified more precisely. We also highlight questions that remain unresolved and areas needing additional study. In summary, the current work lays out a number of recommendations to improve the precision of LATE-NC staging based on published reports and diagnostic experience.

View details for DOI 10.1007/s00401-022-02524-2

View details for PubMedID 36512061

Abstract

Alzheimer's disease (AD) is the most common cause of dementia with advancing age as its strongest risk factor. AD neuropathologic change (ADNC) is known to be associated with numerous DNA methylation changes in the human brain, but the oldest old (>90years) have so far been underrepresented in epigenetic studies of ADNC. Our study participants were individuals aged over 90years (n=47) from The 90+Study. We analyzed DNA methylation from bulk samples in eight precisely dissected regions of the human brain: middle frontal gyrus, cingulate gyrus, entorhinal cortex, dentate gyrus, CA1, substantia nigra, locus coeruleus and cerebellar cortex. We deconvolved our bulk data into cell-type-specific (CTS) signals using computational methods. CTS methylation differences were analyzed across different levels of ADNC. The highest amount of ADNC related methylation differences was found in the dentate gyrus, a region that has so far been underrepresented in large scale multi-omic studies. In neurons of the dentate gyrus, DNA methylation significantly differed with increased burden of amyloid beta (A) plaques at 5897 promoter regions of protein-coding genes. Amongst these, higher A plaque burden was associated with promoter hypomethylation of the Presenilin enhancer 2 (PEN-2) gene, one of the rate limiting genes in the formation of gamma-secretase, a multicomponent complex that is responsible in part for the endoproteolytic cleavage of amyloid precursor protein into A peptides. In addition to novel ADNC related DNA methylation changes, we present the most detailed array-based methylation survey of the old aged human brain to date. Our open-sourced dataset can serve as a brain region reference panel for future studies and help advance research in aging and neurodegenerative diseases.

View details for DOI 10.1186/s40478-022-01470-0

View details for PubMedID 36447297

View details for PubMedCentralID PMC9710143

Abstract

BACKGROUND: The recent promise of disease-modifying therapies for Alzheimer's disease (AD) has reinforced the need for accurate biomarkers for early disease detection, diagnosis and treatment monitoring. Advances in the development of novel blood-based biomarkers for AD have revealed that plasma levels of tau phosphorylated at various residues are specific and sensitive to AD dementia. However, the currently available tests have shortcomings in access, throughput, and scalability that limit widespread implementation.METHODS: We evaluated the diagnostic and prognostic performance of a high-throughput and fully-automated Lumipulse plasma p-tau181 assay for the detection of AD. Plasma from older clinically unimpaired individuals (CU, n = 463) and patients with mild cognitive impairment (MCI, n = 107) or AD dementia (n = 78) were obtained from the longitudinal Stanford University Alzheimer's Disease Research Center (ADRC) and the Stanford Aging and Memory Study (SAMS) cohorts. We evaluated the discriminative accuracy of plasma p-tau181 for clinical AD diagnosis, association with amyloid beta peptides and p-tau181 concentrations in CSF, association with amyloid positron emission tomography (PET), and ability to predict longitudinal cognitive and functional change.RESULTS: The assay showed robust performance in differentiating AD from control participants (AUC 0.959, CI: 0.912 to 0.990), and was strongly associated with CSF p-tau181, CSF Abeta42/Abeta40 ratio, and amyloid-PET global SUVRs. Associations between plasma p-tau181 with CSF biomarkers were significant when examined separately in Abeta+ and Abeta- groups. Plasma p-tau181 significantly increased over time in CU and AD diagnostic groups. After controlling for clinical diagnosis, age, sex, and education, baseline plasma p-tau181 predicted change in MoCA overall and change in CDR Sum of Boxes in the AD group over follow-up of up to 5 years.CONCLUSIONS: This fully-automated and available blood-based biomarker assay therefore may be useful for early detection, diagnosis, prognosis, and treatment monitoring of AD.

View details for DOI 10.1186/s13195-022-01116-2

View details for PubMedID 36371232

Abstract

Neurodegenerative disorders are characterized by phenotypic changes and hallmark proteopathies. Quantifying these in archival human brain tissues remains indispensable for validating animal models and understanding disease mechanisms. We present a framework for nanometer-scale, spatial proteomics with multiplex ion beam imaging (MIBI) for capturing neuropathological features. MIBI facilitated simultaneous, quantitative imaging of 36 proteins on archival human hippocampus from individuals spanning cognitively normal to dementia. Customized analysis strategies identified cell types and proteopathies in the hippocampus across stages of Alzheimer's disease (AD) neuropathologic change. We show microglia-pathologic tau interactions in hippocampal CA1 subfield in AD dementia. Data driven, sample independent creation of spatial proteomic regions identified persistent neurons in pathologic tau neighborhoods expressing mitochondrial protein MFN2, regardless of cognitive status, suggesting a survival advantage. Our study revealed unique insights from multiplexed imaging and data-driven approaches for neuropathologic analysis and serves broadly as a methodology for spatial proteomic analysis of archival human neuropathology. TEASER: Multiplex Ion beam Imaging enables deep spatial phenotyping of human neuropathology-associated cellular and disease features.

View details for DOI 10.1186/s40478-022-01465-x

View details for PubMedID 36333818

Abstract

BACKGROUND AND OBJECTIVES: Limbic predominant age related TDP-43 encephalopathy neuropathologic change (LATE-NC) is a prevalent degenerative pathology in the oldest old who are the fastest growing segment of our population with the highest rates of dementia. We aimed to determine the relationship between LATE-NC and cognitive impairment and to identify its potential risk factors by studying its relationship with common past medical histories in an oldest old cohort.METHODS: Participants from The 90+ Study with longitudinal evaluations and autopsy data were included. Dementia status and impairment in 5 main cognitive domains were determined at postmortem conferences leveraging all clinical and neuropsychological data blind to neuropathological diagnosis. Medical history information was obtained from patients and their informants. LATE-NC and Alzheimer's disease neuropathologic change (ADNC) were considered present in those with TDP-43 pathology in hippocampus and/or neocortex and those with high likelihood of ADNC according to NIA-AA guidelines respectively. We examined the association of degenerative pathologies with cognitive outcomes and multiple comparisons adjusted relationship of medical history variables with LATE-NC and ADNC using logistic regressions adjusted for age at death, sex, and education.RESULTS: 328 participants were included in this study. LATE-NC was present in 32% of the participants. It had a significant association with the presence of dementia (OR: 2.8, 95% CI: 1.7-4.6) and impairment in memory (OR: 3.0, 95% CI: 1.8-5.1), language (OR: 2.6, 95% CI: 1.6-4.3), and orientation (OR: 3.5, 95% CI: 2.1-5.9). The association with impaired orientation was unique to LATE-NC and the strength and significance of the other associations were comparable to ADNC. Furthermore, we found history of osteoarthritis (OR: 0.37, adjusted 95% CI: 0.21-0.66) and hypertension (OR: 0.52, adjusted 95% CI: 0.28-0.98) were associated with a reduced likelihood of LATE-NC, but not ADNC.DISCUSSION: Our results suggest that LATE-NC is a prevalent degenerative pathology in the oldest old and has significant associations with dementia and impairment in cognitive domains with magnitudes that are comparable to ADNC. We also found that past medical histories of hypertension and osteoarthritis were associated with a lower likelihood of LATE-NC. This might help identify upstream mechanisms leading to this important pathology.

View details for DOI 10.1212/WNL.0000000000201345

View details for PubMedID 36302666

View details for DOI 10.3389/fneur.2022.1016040

View details for Web of Science ID 000882461500001

View details for PubMedID 36388213

View details for PubMedCentralID PMC9643380

Abstract

Therapeutic plasma exchange (TPE) has traditionally been used to selectively remove pathologic contents including autoantibodies, abnormal proteins, immune complexes, or toxins from a patient's plasma. In addition to the removal of molecular contributors to disease, fluid replacement and infusion of beneficial plasma constituents including albumin can be tapered based on the pathophysiologic mechanisms of the offending disease. This treatment modality has shown efficacy in symptomatic relief and slowing of disease progression for various neurologic, immunologic, and hematologic diseases. This review outlines the rationale for TPE in the treatment of Alzheimer's Disease (AD) through a potential mechanism leveraging the concentration gradient of amyloid peptides and the infusion of albumin, and critically reviews the clinical evidence for treatment of AD using TPE and albumin replacement. This review also highlights potential sources of bias that must be considered in conjunction with the evidence of efficacy for the use of TPE in AD.

View details for DOI 10.1016/j.tmrv.2022.09.005

View details for PubMedID 36357257

Abstract

To study pareidolias, or perceived meaningful objects in a meaningless stimulus, in patients across the Lewy body (LB) disease spectrum, where most do not report hallucinations or delusions.We studied illusory responses on the Noise Pareidolia Task in 300 participants [38 cognitively-impaired LB, 65 cognitively-unimpaired LB, 51 Alzheimer's disease-spectrum (AD-s), 146 Controls]. Pairwise between-group comparisons examined how diagnosis impacts the number of illusory responses. Ordinal regression analysis compared the number of illusory responses across diagnosis groups, adjusting for age, sex, and education. Analyses were repeated after removing participants with reported hallucinations or delusions.Cognitively-impaired LB participants were 12.3, 4.9, and 4.6 times more likely than Control, cognitively-unimpaired LB, and AD-s participants, respectively, to endorse illusory responses. After adjusting for age, sex and education, the probability of endorsing one or more illusory response was 61% in the cognitively-impaired LB group, compared to 26% in AD-s, 25% in cognitively-unimpaired LB, and 12% in Control participants. All results were similar after repeated analysis only in participants without hallucinations or delusions. In LB without hallucinations or delusions, 52% with mild cognitive impairment and 66.7% with dementia endorsed at least one illusory response.We found illusory responses are common in cognitively impaired LB patients, including those without any reported psychosis. Our data suggest that, prior to the onset of hallucinations and delusions, the Noise Pareidolia Task can easily be used to screen for unobtrusive pareidolias in all LB patients. This article is protected by copyright. All rights reserved.

View details for Web of Science ID 000859942301355

View details for PubMedID 36511519

Abstract

Mutations in the Leucine Rich Repeat Protein Kinase 2 gene (LRRK2) are genetic predispositions for Parkinson's Disease, of which the G2019S (GS) missense mutation is the most common. GS-LRRK2 has a hyperactive kinase, and although numerous drug discovery programs have targeted the LRRK2 kinase, few have reached clinical trials. We recently reported on the discovery of a novel LRRK2 kinase inhibitor chemotype, 1H-pyrazole biaryl sulfonamides. Although both potent and selective GS-LRRK2 inhibitors, 1H-pyrazole biaryl sulfonamides are incapable of crossing the blood-brain barrier. Retaining the core 1H-pyrazole and focusing our efforts on a phenylsulfonamide bioisosteric replacement, we report the discovery and preliminary development of azaspirocyclic 1H-3,4,5-trisubstituted pyrazoles as potent and selective (>2000-fold) GS-LRRK2 kinase inhibitors capable of entering rodent brain. The compounds disclosed here present an excellent starting point for the development of more brain penetrant compounds.

View details for DOI 10.1016/j.ejmech.2022.114693

View details for PubMedID 36049274

Abstract

Age-associated neurodegenerative changes, including amyloid beta(Abeta) plaques, neurofibrillary tangles (NFTs), and amyloid angiopathy comparable to those seen in the brains of human patients with Alzheimer's disease (AD), have been reported in the brains of aged bears. However, the significance of these findings in bears is unclear due to the difficulty in assessing cognitive impairment and the lack of standardized approaches for the semiquantitative evaluation of Abeta plaques and NFTs. In this study, we evaluate the neuropathologic changes in archival brain tissue of 2 aged polar bears (Ursus maritimus, ages 28 and 37) using the National Institute of Aging-Alzheimer Association (NIA-AA) consensus guidelines for the neuropathologic assessment of Alzheimer's Disease (AD). Both bears had an Abeta (A) score of 3 of 3, Braak stage (B score) of 2 of 3, and neuritic plaque (C) score of 3 of 3. These findings are consistent with the neurodegenerative changes observed in brains of patients with AD. The application of NIA-AA consensus guidelines, as applied to the neuropathologic assessment of the aged bears in this report, demonstrates the use of standardized semiquantitative assessment systems for comparative, translational studies of aging in a vulnerable wildlife species.

View details for DOI 10.30802/AALAS-CM-22-000036

View details for PubMedID 35882509

Abstract

Brains of 42 COVID-19 decedents and 107 non-COVID-19 controls were studied. RT-PCR screening of 16 regions from 20 COVID-19 autopsies found SARS-CoV-2 E gene viral sequences in 7 regions (2.5% of 320 samples), concentrated in 4/20 subjects (20%). Additional screening of olfactory bulb (OB), amygdala (AMY) and entorhinal area for E, N1, N2, RNA-dependent RNA polymerase, and S gene sequences detected one or more of these in OB in 8/21 subjects (38%). It is uncertain whether these RNA sequences represent viable virus. Significant histopathology was limited to 2/42 cases (4.8%), one with a large acute cerebral infarct and one with hemorrhagic encephalitis. Case-control RNAseq in OB and AMY found more than 5000 and 700 differentially expressed genes, respectively, unrelated to RT-PCR results; these involved immune response, neuronal constituents, and olfactory/taste receptor genes. Olfactory marker protein-1 reduction indicated COVID-19-related loss of OB olfactory mucosa afferents. Iba-1-immunoreactive microglia had reduced area fractions in cerebellar cortex and AMY, and cytokine arrays showed generalized downregulation in AMY and upregulation in blood serum in COVID-19 cases. Although OB is a major brain portal for SARS-CoV-2, COVID-19 brain changes are more likely due to blood-borne immune mediators and trans-synaptic gene expression changes arising from OB deafferentation.

View details for DOI 10.1093/jnen/nlac056

View details for PubMedID 35818336

Abstract

Stanford Pathology began stepwise subspecialty implementation of whole slide imaging (WSI) in 2018 soon after the first US Food and Drug Administration approval. In 2020, during the COVID-19 pandemic, the Centers for Medicare & Medicaid Services waived the requirement for pathologists to perform diagnostic tests in Clinical Laboratory Improvement Amendments (CLIA)-licensed facilities. This encouraged rapid implementation of WSI across all surgical pathology subspecialties.To present our experience with validation and implementation of WSI at a large academic medical center encompassing a caseload of more than 50000 cases per year.Validation was performed independently for 3 subspecialty services with a diagnostic concordance threshold above 95%. Analysis of user experience, staffing, infrastructure, and information technology was performed after department-wide expansion.Diagnostic concordance was achieved in 96% of neuropathology cases, 100% of gynecologic pathology cases, and 98% of immunohistochemistry cases. After full implementation, 8 high-capacity scanners were operational, with whole slide images generated on greater than 2000 slides per weekday, accounting for approximately 80% of histologic slides at Stanford Medicine. Multiple modifications in workflow and information technology were needed to improve performance. Within months of full implementation, most attending pathologists and trainees had adopted WSI for primary diagnosis.WSI across all surgical subspecialities is achievable at scale at an academic medical center; however, adoption required flexibility to adjust workflows and develop tailored solutions. WSI at scale supported the health and safety of medical staff while facilitating high-quality patient care and education during COVID-19 restrictions.

View details for DOI 10.5858/arpa.2021-0438-OA

View details for PubMedID 35802938

Abstract

Information about the equality of psychometric properties of the medical outcomes study (MOS) Short Form-36 (SF-36), a health status measure, across gender and across the lifespan for American Indian adults is lacking. We tested measurement invariance (configural, metric, scalar invariance) of the physical and mental components between gender and over time in a sample of 2,709 (1,054 men, 1,654 women) American Indian older adults at three time points, and across a 6-year time frame. Measurement invariance of a 2-factor higher-order model was demonstrated between gender at each time point. Tests of longitudinal invariance indicated longitudinal measurement invariance over time. Multiple-group latent means analysis indicated men had significantly higher physical and mental component latent means compared to women at each time point, and longitudinal latent means analysis found physical and mental component latent means decreased over time. The 2-factor higher-order model SF-36 is valid for American Indian older adults over a 6-year time frame. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

View details for DOI 10.1037/pas0001153

View details for Web of Science ID 000819646100001

View details for PubMedID 35787064

Abstract

We report on the initial 17 (11 male:6 female) brain autopsies from across Europe and the United States in the Parkinson's Progression Markers Initiative (PPMI). Clinical diagnoses were Parkinson's disease (n=15), multiple system atrophy (n=1), and Dementia with Lewy bodies (n=1); average age of death=728yr. Cognitive assessment at last evaluation was 5 with normal cognition, 7 with mild cognitive impairment, and 5 with dementia. Genetic assessment showed 4 participants were heterozygous or homozygous for GBA N370S and 3 were heterozygous carriers for LRRK2 R1441G or G2019S; 1 was an APOE 2 carrier and 5 were APOE 4 carriers. Longitudinal DAT neuroimaging as well as CSF and plasma biomarker data are summarized. Neuropathologic examination confirmed all clinical diagnoses and showed the expected frequencies of common comorbidities; no evidence of chronic traumatic encephalopathy was observed. Thus, brain autopsy data can provide confirmation, clarification, and new insights into the PD progression observed during life. As it grows, the PPMI brain autopsy program will provide a deeply-annotated research resource to the community of investigators focused on developing biomarkers for PD progression.

View details for DOI 10.1016/j.parkreldis.2022.06.017

View details for PubMedID 35803091

View details for DOI 10.4155/fmc-2022-0102

View details for PubMedID 35730403

Abstract

The extent to which the heterogeneity of gait and balance problems in PD may be explained by genetic variation is unknown. Variants in the glucocerebrosidase (GBA) gene are the strongest known genetic risk factor for PD and are associated with greater motor and cognitive severity. However, the impact of GBA variants on comprehensive measures of gait and balance and their relationship to cognition remains unknown. We aimed to determine differences in gait and balance impairments in those with and without GBA variants (mutation carriers and E326K polymorphism) and explore direct and indirect effects of GBA status on gait, balance, and cognition. 332 participants, 43 of whom had GBA variants, were recruited. Participants completed a comprehensive, objective assessment of gait and standing balance using body-worn inertial sensors. Group differences in gait and balance between PD with and without GBA variants were assessed with linear regression, adjusting for age, gender, clinical testing site, disease duration, and apolipoprotein E (APOE) 4 status. Structural equation modeling (SEM) explored direct relationships between GBA status and gait and balance and indirect relationships between GBA status and gait and balance via cognition. The GBA variant group had more impaired gait (pace and variability) and balance (sway area/jerk and sway velocity), than the non-GBA variant group. SEM demonstrated cognition as a mediator of GBA status on gait and balance. The close relationships among GBA, gait/balance, and cognition suggest potential for novel therapeutics to target the GBA pathway and/or cognition to improve mobility in PD GBA variants.

View details for DOI 10.1038/s41531-022-00344-5

View details for PubMedID 35725575

Abstract

BACKGROUND AND OBJECTIVES: Age is the largest risk factor for dementia. However, dementia is not universal, even among the oldest-old age groups. Following contemporary neuropathologic guidelines, our objectives were to describe the key neuropathologic lesions and their associations with antemortem cognition in oldest-old individuals.METHODS: Participants were those enrolled in The 90+ Study, a longitudinal, population-based study of aging/dementia in the oldest-old, who agreed to postmortem brain examination. All autopsied brains as of December 2020 were evaluated for prevalence of Alzheimer's disease neuropathologic change (ADNC) and non-ADNC neuropathologic comorbidities. Associations between neuropathologic lesions or total neuropathologic burden score (sum of the individual scores) and cognition were assessed using multinomial logistic regression and multiple linear regression. Separate regression analyses evaluated relationships between limbic-predominant age-related TDP-43 encephalopathy (LATE-NC) and hippocampal sclerosis (HS) or ADNC/primary age-related tauopathy (PART). Resistance, or failure to develop ADNC/PART, and resilience, inferred from higher than expected cognitive functioning, were evaluated in the presence or absence of non-ADNC neuropathologic features.RESULTS: The most common neuropathologic features in the sample (n=367) were ADNC/PART-related. Increased dementia odds were associated with elevated total neuropathologic burden (OR=1.5 [95% CI 1.3-1.7] p<0.0001), beta amyloid (OR=1.6 [95% CI 1.2-2.0] p<0.0001), neurofibrillary tangles (OR=2.6 [95% CI 1.7-4.1] p<0.0001), and LATE-NC (OR=2.3 [95% CI 1.7-3.1] p<0.0001), correcting for multiple comparisons. LATE-NC was associated with dementia with (OR=6.1 [95% CI 2.0-18.7] p=0.002) and without (OR=5.0 [95% CI 2.6-9.7] p<0.0001) co-occurring HS, and increased the odds of dementia among participants with ADNC (OR=5.0 [95% CI 2.7-9.2] p<0.0001). Resistance to moderate/severe ADNC/PART was rare (3%), but resilience to ADNC/PART was not (55%). Resilience was rarer in the presence of non-ADNC comorbid lesions, particularly LATE-NC. Among those with moderate/severe ADNC/PART, dementia odds increased with each non-ADNC comorbid lesion (e.g., 1 lesion: OR=2.4 [95% CI 1.3-4.5] p<0.005; 2 lesions: OR=5.9 [95% CI 2.8-12.3] p<0.0001).CONCLUSION: These results highlight the importance of non-ADNC neuropathologic comorbidity, predominantly LATE-NC, to cognition in the oldest-old. Given the cumulative effects of non-ADNC comorbid neuropathologic abnormalities, reducing their prevalence, especially LATE-NC, will be vital to the ultimate goal of reducing dementia burden in the oldest-old individuals.

View details for DOI 10.1212/WNL.0000000000200832

View details for PubMedID 35705500

Abstract

Limbic-predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC) and Alzheimer's disease neuropathologic change (ADNC) are each associated with substantial cognitive impairment in aging populations. However, the prevalence of LATE-NC across the full range of ADNC remains uncertain. To address this knowledge gap, neuropathologic, genetic, and clinical data were compiled from 13 high-quality community- and population-based longitudinal studies. Participants were recruited from United States (8 cohorts, including one focusing on Japanese-American men), United Kingdom (2 cohorts), Brazil, Austria, and Finland. The total number of participants included was 6196, and the average age of death was 88.1years. Not all data were available on each individual and there were differences between the cohorts in study designs and the amount of missing data. Among those with known cognitive status before death (n=5665), 43.0% were cognitively normal, 14.9% had MCI, and 42.4% had dementia-broadly consistent with epidemiologic data in this age group. Approximately 99% of participants (n=6125) had available CERAD neuritic amyloid plaque score data. In this subsample, 39.4% had autopsy-confirmed LATE-NC of any stage. Among brains with "frequent" neuritic amyloid plaques, 54.9% had comorbid LATE-NC, whereas in brains with no detected neuritic amyloid plaques, 27.0% had LATE-NC. Data on LATE-NC stages were available for 3803 participants, of which 25% had LATE-NC stage>1 (associated with cognitive impairment). In the subset of individuals with Thal Abeta phase=0 (lacking detectable Abeta plaques), the brains with LATE-NC had relatively more severe primary age-related tauopathy (PART). A total of 3267 participants had available clinical data relevant to frontotemporal dementia (FTD), and none were given the clinical diagnosis of definite FTD nor the pathological diagnosis of frontotemporal lobar degeneration with TDP-43 inclusions (FTLD-TDP). In the 10 cohorts with detailed neurocognitive assessments proximal to death, cognition tended to be worse with LATE-NC across the full spectrum of ADNC severity. This study provided a credible estimate of the current prevalence of LATE-NC in advanced age. LATE-NC was seen in almost 40% of participants and often, but not always, coexisted with Alzheimer's disease neuropathology.

View details for DOI 10.1007/s00401-022-02444-1

View details for PubMedID 35697880

Abstract

G2019S (GS) is the most prevalent mutation in the leucine rich repeat protein kinase 2 gene (LRRK2), a genetic predisposition that is common for Parkinson's disease, as well as for some forms of cancer, and is a shared risk allele for Crohn's disease. GS-LRRK2 has a hyperactive kinase, and although numerous drug discovery programs have targeted LRRK2 kinase, few have reached clinical development. We report the discovery and preliminary development of an entirely novel structural class of potent and selective GS-LRRK2 kinase inhibitors: biaryl-1H-pyrazoles.

View details for DOI 10.1021/acsmedchemlett.2c00116

View details for PubMedID 35707141

Abstract

BACKGROUND: Coding variation in the Leucine rich repeat kinase 2 gene linked to Parkinson's disease (PD) promotes enhanced activity of the encoded LRRK2 kinase, particularly with respect to autophosphorylation at S1292 and/or phosphorylation of the heterologous substrate RAB10.OBJECTIVE: To determine the inter-laboratory reliability of measurements of cellular LRRK2 kinase activity in the context of wildtype or mutant LRRK2 expression using published protocols.METHODS: Benchmark western blot assessments of phospho-LRRK2 and phospho-RAB10 were performed in parallel with in situ immunological approaches in HEK293T, mouse embryonic fibroblasts, and lymphoblastoid cell lines. Rat brain tissue, with or without adenovirus-mediated LRRK2 expression, and human brain tissues from subjects with or without PD, were also evaluated for LRRK2 kinase activity markers.RESULTS: Western blots were able to detect extracted LRRK2 activity in cells and tissue with pS1292-LRRK2 or pT73-RAB10 antibodies. However, while LRRK2 kinase signal could be detected at the cellular level with over-expressed mutant LRRK2 in cell lines, we were unable to demonstrate specific detection of endogenous cellular LRRK2 activity in cell culture models or tissues that we evaluated.CONCLUSION: Further development of reliable methods that can be deployed in multiple laboratories to measure endogenous LRRK2 activities are likely required, especially at cellular resolution.

View details for DOI 10.3233/JPD-213128

View details for PubMedID 35599495

View details for Web of Science ID 000798368400135

View details for Web of Science ID 000798368400137

View details for Web of Science ID 000894020500415

Abstract

We develop a deep learning approach, in silico immunohistochemistry (IHC), which takes routinely collected histochemical-stained samples as input and computationally generates virtual IHC slide images. We apply in silico IHC to Alzheimer's disease samples, where several hallmark changes are conventionally identified using IHC staining across many regions of the brain. In silico IHC computationally identifies neurofibrillary tangles, beta-amyloid plaques, and neuritic plaques at a high spatial resolution directly from the histochemical images, with areas under the receiver operating characteristic curve of between 0.88 and 0.92. In silico IHC learns to identify subtle cellular morphologies associated with these lesions and can generate in silico IHC slides that capture key features of the actual IHC.

View details for DOI 10.1016/j.crmeth.2022.100191

View details for PubMedID 35497493

Abstract

In recent years, metabolomics has been used as a powerful tool to better understand the physiology of neurodegenerative diseases and identify potential biomarkers for progression. We used targeted and untargeted aqueous, and lipidomic profiles of the metabolome from human cerebrospinal fluid to build multivariate predictive models distinguishing patients with Alzheimer's disease (AD), Parkinson's disease (PD), and healthy age-matched controls. We emphasize several statistical challenges associated with metabolomic studies where the number of measured metabolites far exceeds sample size. We found strong separation in the metabolome between PD and controls, as well as between PD and AD, with weaker separation between AD and controls. Consistent with existing literature, we found alanine, kynurenine, tryptophan, and serine to be associated with PD classification against controls, while alanine, creatine, and long chain ceramides were associated with AD classification against controls. We conducted a univariate pathway analysis of untargeted and targeted metabolite profiles and find that vitamin E and urea cycle metabolism pathways are associated with PD, while the aspartate/asparagine and c21-steroid hormone biosynthesis pathways are associated with AD. We also found that the amount of metabolite missingness varied by phenotype, highlighting the importance of examining missing data in future metabolomic studies.

View details for DOI 10.3390/metabo12040277

View details for PubMedID 35448464

Abstract

Cognitive resilience provides insights into maintaining good cognition despite dementia-related neuropathologic changes. It is of special interest in the oldest-old (age 90+) because age is the strongest risk factor for dementia. We describe the only participant of The 90+ Study, among 367 autopsies, who maintained normal cognition despite intermediate-high levels of 3 dementia-related neuropathologic changes, advanced age, and comorbidities associated with cognitive impairment. This man remained cognitively normal throughout 13 semi-annual study visits, last one being 4 months before his death at 96. His cognitive test scores remained around the 90th percentile for non-timed tests and declined from 90th to 50th percentile (significant for semantic fluency) for timed tests. He remained physically and cognitively active until death, despite extrapyramidal signs in the last year of life. Neuropathological examination revealed intermediate level of Alzheimer's disease neuropathologic change (Thal phase 5, Braak NFT stage IV, CERAD score 3), Lewy bodies and neurites in the olfactory bulb, brainstem and limbic areas (Braak PD stage 4), TDP-43 inclusions in the amygdala and hippocampus (LATE stage 2), and a microvascular lesion in putamen. This case demonstrates that cognitive impairment is not inevitable even in the oldest-old with mutltiple dementia-related neuropathologic changes.

View details for DOI 10.1016/j.neurobiolaging.2022.03.009

View details for PubMedID 35526514

Abstract

Bottom-up proteomics provides peptide measurements and has been invaluable for moving proteomics into large-scale analyses. Commonly, a single quantitative value is reported for each protein-coding gene by aggregating peptide quantities into protein groups following protein inference or parsimony. However, given the complexity of both RNA splicing and post-translational protein modification, it is overly simplistic to assume that all peptides that map to a singular protein-coding gene will demonstrate the same quantitative response. By assuming that all peptides from a protein-coding sequence are representative of the same protein, we may miss the discovery of important biological differences. To capture the contributions of existing proteoforms, we need to reconsider the practice of aggregating protein values to a single quantity per protein-coding gene.

View details for DOI 10.1021/acs.jproteome.1c00894

View details for PubMedID 35220718

Abstract

The spread of neurofibrillary tau pathology in Alzheimer disease (AD) mostly follows a stereotypical pattern of topographical progression but atypical patterns associated with interhemispheric asymmetry have been described. Because histopathological studies that used bilateral sampling are limited, this study aimed to assess interhemispheric tau pathology differences and the presence of topographically atypical cortical spreading patterns. Immunohistochemical staining for detection of tau pathology was performed in 23 regions of interest in 57 autopsy cases comparing bilateral cortical regions and hemispheres. Frequent mild (82% of cases) and occasional moderate (32%) interhemispheric density discrepancies were observed, whereas marked discrepancies were uncommon (7%) and restricted to occipital regions. Left and right hemispheric tau pathology dominance was observed with similar frequencies, except in Braak Stage VI that favored a left dominance. Interhemispheric Braak stage differences were observed in 16% of cases and were more frequent in advanced (IV-VI) versus early (I-III) stages. One atypical lobar topographical pattern in which occipital tau pathology density exceeded frontal lobe scores was identified in 4 cases favoring a left dominant asymmetry. We speculate that asymmetry and atypical topographical progression patterns may be associated with atypical AD clinical presentations and progression characteristics, which should be tested by comprehensive clinicopathological correlations.

View details for DOI 10.1093/jnen/nlac008

View details for PubMedID 35191506

Abstract

Parkinson's disease (PD) is associated with aberrant innate immune responses, including microglial activation and infiltration of peripheral myeloid cells into the central nervous system (CNS). Methods to investigate innate immune activation in PD are limited and have not yet elucidated key interactions between neuroinflammation and peripheral inflammation. Translocator protein 18 kDa (TSPO)-positron emission tomography (PET) is a widely evaluated imaging approach for studying activated microglia and peripheral myeloid lineage cells in vivo, however it is yet to be fully explored in PD. Herein we investigate the utility of TSPO-PET, in addition to PET imaging of triggering receptor expressed on myeloid cells 1 (TREM1) - a novel biomarker of proinflammatory myeloid cells - for detecting innate immune responses in the 6-hydroxydopamine (6-OHDA) mouse model of dopaminergic neuron degeneration. Methods: C57/BL6J and TREM1-knockout mice were stereotaxically injected with 6-OHDA in the left striatum; control mice were saline-injected. At day 7 or 14 post-surgery, mice were administered 18F-GE-180, 64Cu-TREM1-mAb or 64Cu-Isotype control-mAb and imaged by PET/CT. Ex vivo autoradiography (ARG) was performed to obtain high resolution images of tracer binding within the brain. Immunohistochemistry was conducted to verify myeloid cell activation and dopaminergic cell death and quantitative PCR and flow cytometry were completed to assess levels of target in the brain. Results: PET/CT images of both tracers showed elevated signal within the striatum of 6-OHDA-injected mice compared to those injected with saline. ARG afforded higher resolution brain images and revealed significant TSPO and TREM1 tracer binding within the ipsilateral striatum of 6-OHDA- compared to saline-injected mice at both 7- and 14-days post-toxin. Interestingly, 18F-GE-180 enabled detection of inflammation in the brain and peripheral tissues (blood and spleen) of 6-OHDA mice, whereas 64Cu-TREM1-mAb appeared to be more sensitive and specific for detecting neuroinflammation, in particular infiltrating myeloid cells, in these mice, as demonstrated by flow cytometry findings and higher tracer binding signal-to-background ratios in brain. Conclusion: TSPO- and TREM1-PET tracers are promising tools for investigating different cell types involved in innate immune activation in the context of dopaminergic neurodegeneration, thus warranting further investigation in other PD rodent models and human postmortem tissue to assess their clinical potential.

View details for DOI 10.2967/jnumed.121.263039

View details for PubMedID 35177426

Abstract

INTRODUCTION: Alzheimer disease (AD) and related dementias are characterized by damage caused by neuropathological lesions in the brain. These include AD lesions (plaques and tangles) and non-AD lesions such as vascular injury or Lewy bodies. We report here an assessment of lesion association to dementia in a large clinic-based population.METHODS: We identified 5272 individuals with neuropathological data from the National Alzheimer's Coordinating Center. Individual lesions, as well as a neuropathological composite score (NPCS) were tested for association with dementia, and both functional and neurocognitive impairment using regression models.RESULTS: Most individuals exhibited mixed pathologies, especially AD lesions in combination with non-AD lesions. All lesion types were associated with one or more clinical outcomes; most even while controlling for AD pathology. The NPCS was also associated with clinical outcomes.DISCUSSION: These data suggest mixed-type pathologies are extremely common in a clinic-based population and may contribute to dementia and cognitive impairment.

View details for DOI 10.1002/alz.12516

View details for PubMedID 35142102

Abstract

Multiple sclerosis (MS) is characterized by a targeted attack on oligodendroglia (OLG) and myelin by immune cells, which are thought to be the main drivers of MS susceptibility. We found that immune genes exhibit a primed chromatin state in single mouse and human OLG in a non-disease context, compatible with transitions to immune-competent states in MS. We identified BACH1 and STAT1 as transcription factors involved in immune gene regulation in oligodendrocyte precursor cells (OPCs). A subset of immune genes presents bivalency of H3K4me3/H3K27me3 in OPCs, with Polycomb inhibition leading to their increased activation upon interferon gamma (IFN-gamma) treatment. Some MS susceptibility single-nucleotide polymorphisms (SNPs) overlap with these regulatory regions in mouse and human OLG. Treatment of mouse OPCs with IFN-gamma leads to chromatin architecture remodeling at these loci and altered expression of interacting genes. Thus, the susceptibility for MS may involve OLG, which therefore constitutes novel targets for immunological-based therapies for MS.

View details for DOI 10.1016/j.neuron.2021.12.034

View details for PubMedID 35093191

Abstract

We describe the clinical and neuropathologic features of patients with Lewy body spectrum disorder (LBSD) carrying a nonsense variant, c.604C>T; p.R202X, in the glucocerebrosidase 1 (GBA) gene. While this GBA variant is causative for Gaucher's disease, the pathogenic role of this mutation in LBSD is unclear. Detailed neuropathologic evaluation was performed for one index case and a structured literature review of other GBA p.R202X carriers was conducted. Through the systematic literature search, we identified three additional reported subjects carrying the same GBA mutation, including one Parkinson's disease (PD) patient with early disease onset, one case with neuropathologically-verified LBSD, and one unaffected relative of a Gaucher's disease patient. Among the affected subjects carrying the GBA p.R202X, all males were diagnosed with Lewy body dementia, while the two females presented as PD. The clinical penetrance of GBA p.R202X in LBSD patients and families argues strongly for a pathogenic role for this variant, although presenting with a striking phenotypic heterogeneity of clinical and pathological features.

View details for DOI 10.3390/biomedicines10010160

View details for PubMedID 35052839

Abstract

Leucine-rich repeat kinase 2 (LRRK2) has taken center stage in Parkinson's disease (PD) research as mutations cause familial PD and more common variants increase lifetime risk for disease. One unique feature in LRRK2 is the coexistence of GTPase/Roc (Ras of complex) and kinase catalytic functions, bridged by a COR (C-terminal Of Roc) platform for dimerization. Multiple PD mutations are located within the Roc/GTPase domain and concomitantly lead to defective GTPase activity and augmented kinase activity in cells, supporting a crosstalk between GTPase and kinase domains. In addition, biochemical and structural data highlight the importance of Roc as a molecular switch modulating LRRK2 monomer-to-dimer equilibrium and building the interface for interaction with binding partners. Here we review the effects of PD Roc mutations on LRRK2 function and discuss the importance of Roc as a hub for multiple molecular interactions relevant for the regulation of cytoskeletal dynamics and intracellular trafficking pathways. Among the well-characterized Roc interactors, we focused on the cytoskeletal-related kinase p21-activated kinase 6 (PAK6). We report the affinity between LRRK2-Roc and PAK6 measured by microscale thermophoresis (MST). We further show that PAK6 can modulate LRRK2-mediated phosphorylation of RAB substrates in the presence of LRRK2 wild-type (WT) or the PD G2019S kinase mutant but not when the PD Roc mutation R1441G is expressed. These findings support a mechanism whereby mutations in Roc might affect LRRK2 activity through impaired protein-protein interaction in the cell.

View details for DOI 10.1016/j.brainres.2022.147781

View details for PubMedID 35016853

Abstract

Synaptic degeneration is one of the earliest and phenotypically most significant features associated with numerous neurodegenerative conditions, including Alzheimer's and Parkinson's diseases. Synaptic changes are also known to be important in neurocognitive disorders such as schizophrenia and autism spectrum disorders. Several labs, including ours, have demonstrated that conventional (fluorescence-based) flow cytometry of individual synaptosomes is a robust and reproducible method. However, the repertoire of probes needed to assess comprehensively the type of synapse, pathologic proteins (including protein products of risk genes discovered in GWAS), and markers of stress and injury far exceeds what is achievable with conventional flow cytometry. We recently developed a method that applies CyTOF (Cytometry by Time-Of-Flight mass spectrometry) to high-dimensional analysis of individual human synaptosomes, overcoming many of the multiplexing limitations of conventional flow cytometry. We call this new method Mass Synaptometry. Here we describe the preparation of synaptosomes from human and mouse brain, the generation and quality control of the "SynTOF" (Synapse by Time-Of-Flight mass spectrometry) antibody panel, the staining protocol, and CyTOF parameter setup for acquisition, post-acquisition processing, and analysis.

View details for DOI 10.1007/978-1-0716-1916-2_6

View details for PubMedID 35099792

Abstract

Mutations in the Leucine Rich Repeat Protein Kinase 2 gene (LRRK2) are the most common genetic causes of Parkinson's Disease (PD). The G2019S mutation is the most common inherited LRRK2 mutation, occurs in the kinase domain, and results in increased kinase activity. We report the discovery and development of compound 38, an indazole-based, G2019S-selective (>2000-fold vs. WT) LRRK2 inhibitor capable of entering rodent brain (Kp=0.5) and selectively inhibiting G2019S-LRRK2. The compounds disclosed herein present a starting point for further development of brain penetrant G2019S selective inhibitors that hopefully reduce lung phenotype side-effects and pave the way to providing a precision medicine for people with PD who carry the G2019S mutation.

View details for DOI 10.1016/j.ejmech.2021.114080

View details for PubMedID 34992038

Abstract

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View details for DOI 10.1126/sciadv.abk0473

View details for PubMedID 34910503

Abstract

BACKGROUND: Alzheimer disease (AD) is the most common cause of dementia. Upon autopsy, most dementia patients display the core AD brain lesions: neurofibrillary tangles (NFTs), neuritic plaques (NPs), and diffuse plaques (DPs). Often, patients display other non-AD lesions: Lewy bodies (LBs), cerebral amyloid angiopathy (CAA), arteriolosclerosis, hippocampal sclerosis (HS), and vascular brain injury (VBI). Previous population-based studies suggest that dementia of mixed pathologies is present common and associated with more severe cognitive impairment. Here, we report on the generalizability of these findings in a more heterogeneous clinic-based group and describe the contribution of individual lesions and lesion comorbidity to severity and progression of dementia.METHOD: We used the National Alzheimer's Coordinating Center (NACC) database, identifying 5,272 individuals with a neuropathology assessment. Both AD and non-AD lesions were scored as absent/mild, moderate, or severe. Individual lesion scores summed to construct a neuropathology composite score (NPCS). Individual lesions and NPCS were tested for association with neurocognitive and functional impairment using the Mini-Mental State Examination (MMSE) and the Clinical Dementia Rating sum of boxes (CDR-SOB), respectively, as endpoints in linear regression models. We also evaluated progression in 3,934 individuals with multiple visits using the NPCS and clinical outcomes in a longitudinal multilevel mixed model.RESULT: Individuals with mixed pathologies (AD plus non-AD) were more functionally and neurocognitively impaired than those with AD or non-AD lesions alone. Full models showed most lesions were significantly associated with cognitive function (p<0.05). NFTs, HS, and NPs showed the highest effect sizes while DPs and VBI showed the lowest. When modeling with NPCS, associations with MMSE and CDR-SOB were highly significant (p<2E-16). Finally, when controlling for sex and number of visits, NPCS was significantly associated with progression of cognitive decline (p < 0.0001).CONCLUSION: These data suggest that severity of lesions and lesion comorbidity are highly associated with dementia severity in the more heterogeneous clinic-based NACC dataset. These results (1) confirm the utility of neuropathological collections, (2) expand the generalizability of past findings to a clinic-based group, and (3) suggest that mixed-type pathologies are a major contributor to dementia.

View details for DOI 10.1002/alz.056249

View details for PubMedID 35109341

View details for DOI 10.1182/blood-2021-151064

View details for Web of Science ID 000736398800006

Abstract

BACKGROUND: Exploration of cerebrospinal fluid (CSF) amino acids and the impact of dietary intake on central levels may provide a comprehensive understanding of the metabolic component of Alzheimer's disease.OBJECTIVE: The objective of this exploratory study was to investigate the effects of two diets with varied nutrient compositions on change in CSF amino acids levels in adults with mild cognitive impairment (MCI) and normal cognition (NC). Secondary objectives were to assess the correlations between the change in CSF amino acids and change in Alzheimer's disease biomarkers.METHODS: In a randomized, parallel, controlled feeding trial, adults (NC, n=20; MCI, n=29) consumed a high saturated fat (SFA)/glycemic index (GI) diet [HIGH] or a low SFA/GI diet [LOW] for 4 weeks. Lumbar punctures were performed at baseline and 4 weeks.RESULTS: CSF valine increased and arginine decreased after the HIGH compared to the LOW diet in MCI (ps=0.03 and 0.04). This pattern was more prominent in MCI versus NC (diet by diagnosis interaction ps=0.05 and 0.09), as was an increase in isoleucine after the HIGH diet (p=0.05). Changes in CSF amino acids were correlated with changes in Alzheimer's disease CSF biomarkers Abeta42, total tau, and p-Tau 181, with distinct patterns in the relationships by diet intervention and cognitive status.CONCLUSION: Dietary intake affects CSF amino acid levels and the response to diet is differentially affected by cognitive status.

View details for DOI 10.3233/JAD-210471

View details for PubMedID 34602470

Abstract

The enzymes glycine amidinotransferase, mitochondrial (GATM also known as AGAT) and guanidinoacetate N-methyltransferase (GAMT) function together to synthesize creatine from arginine, glycine, and S-Adenosyl methionine. Deficiency in either enzyme or the creatine transporter, CT1, results in a devastating neurological disorder, Cerebral Creatine Deficiency Syndrome (CCDS). To better understand the pathophysiology of CCDS, we mapped the distribution of GATM and GAMT at single cell resolution, leveraging RNA sequencing analysis combined with in vivo immunofluorescence (IF). Using the mouse as a model system, we find that GATM and GAMT are coexpressed in several tissues with distinct and overlapping cellular sources, implicating local synthesis as an important mechanism of creatine metabolism in numerous organs. Extending previous findings at the RNA level, our analysis demonstrates that oligodendrocytes express the highest level of Gatm and Gamt of any cell type in the body. We confirm this finding in the mouse brain by IF, where GATM localizes to the mitochondria of oligodendrocytes, whereas both oligodendrocytes and cerebral cortical neurons express GAMT. Interestingly, the latter is devoid of GATM. Single nucleus assay for transposase-accessible chromatin sequencing (snATAC-seq) analysis of 4 brain regions highlights a similar primacy of oligodendrocytes in the expression of GATM and GAMT in the human central nervous system. Importantly, an active putative regulatory element within intron 2 of human GATM is detected in oligodendrocytes but not neurons.

View details for DOI 10.1016/j.brainres.2021.147627

View details for PubMedID 34418357

Abstract

Quantifying the physiology of aging is essential for improving our understanding of age-related disease and the heterogeneity of healthy aging. Recent studies have shown that in regression models using "-omic" platforms to predict chronological age, residual variation in predicted age is correlated with health outcomes, and suggest that these "omic clocks" provide measures of biological age. This paper presents predictive models for age using metabolomic profiles of cerebrospinal fluid from healthy human subjects, and finds that metabolite and lipid data are generally able to predict chronological age within 10 years. We use these models to predict the age of a cohort of subjects with Alzheimer's and Parkinson's disease and find an increase in prediction error, potentially indicating that the relationship between the metabolome and chronological age differs with these diseases. However, evidence is not found to support the hypothesis that our models will consistently over-predict the age of these subjects. In our analysis of control subjects, we find the carnitine shuttle, sucrose, biopterin, vitamin E metabolism, tryptophan, and tyrosine to be the most associated with age. We showcase the potential usefulness of age prediction models in a small dataset (n = 85), and discuss techniques for drift correction, missing data imputation, and regularized regression, which can be used to help mitigate the statistical challenges that commonly arise in this setting. To our knowledge, this work presents the first multivariate predictive metabolomic and lipidomic models for age using mass spectrometry analysis of cerebrospinal fluid.

View details for DOI 10.1093/gerona/glab212

View details for PubMedID 34382643

Abstract

Introduction: Parkinson's disease (PD) is associated with a range of cognitive deficits. Few studies have carefully examined the subtle impacts of PD on cognition among patients who do not meet formal criteria for MCI or dementia. The aim of the current study was thus to describe the impact of PD on cognition in those without cognitive impairment in a well-characterized cohort.Methods: Non-cognitively impaired participants (122 with PD, 122 age- and sex-matched healthy volunteers) underwent extensive cognitive testing. Linear regression analyses compared diagnostic group performance across cognitive measures. For cognitive tasks that were significantly different between groups, additional analyses examined group differences restricting the group inclusion to PD participants with mild motor symptoms or disease duration less than 10years.Results: Processing speed and semantic verbal fluency were significantly lower in the PD group (B =-3.77, 95% CIs [-5.76 to -1.77], p <.001, and B =-2.02, 95% CIs [-3.12, -0.92], p <.001, respectively), even after excluding those with moderate to severe motor symptoms (B =-2.73, 95% CIs [-4.94 to -0.53], p =.015 and B =-2.11, 95% CIs [-3.32 to -0.91], p <.001, respectively) or longer disease duration (B =-3.89, 95% CIs [-6.14 to -1.63], p <.001 and B =-1.58, 95% CIs [-2.78 to -0.37], p =.010, respectively). Semantic verbal fluency remained significantly negatively associated with PD diagnosis after controlling for processing speed (B =-1.66, 95% CIs [-2.79 to -0.53], p =.004).Conclusions: Subtle decline in specific cognitive domains may be present among people diagnosed with PD but without evidence to support a formal cognitive diagnosis. These results suggest the importance of early awareness of the potential for diminishing aspects of cognition in PD even among those without mild cognitive impairment or dementia.

View details for DOI 10.1080/13803395.2021.1927995

View details for PubMedID 34355669

View details for Web of Science ID 000671021700115

Abstract

The validation of the assessment of depression across ethnic groups is critical yet deficient for American Indian (AI) adults. Therefore, we assessed the psychometric properties of the Center for Epidemiological Studies-Depression (CES-D) in AI elders and tested differences in depression constructs between gender. Participants were 817 AI adults (68% women), mean age 73.2 years (SD = 6.1, range: 64-95) for women and 72.6 years (SD = 5.3, range: 65-90) for men., in the Cerebrovascular Disease and Its Consequences in AIs Study. We evaluated the factor structure of the 20-item and 12-item CES-D and tested measurement invariance between gender. Results demonstrated a poor fit for the 20-item CES-D and partial gender measurement invariance of the 12-item CES-D. AI female elders had significantly higher depression levels than AI male elders on the Depressed Affect subscale, the Somatic Symptoms subscale, and the Well-Being (reverse-coded) subscale. Further replication is needed, and we recommend future psychometric work with the 12-item CES-D with AI elders. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

View details for DOI 10.1037/pas0001024

View details for Web of Science ID 000654326700011

View details for PubMedID 34014718

View details for Web of Science ID 000671021700114

Abstract

OBJECTIVE: To develop a reliable and fast assay to quantify the alpha-synuclein (alpha-syn)-containing extracellular vesicles (EVs) in CSF and to assess their diagnostic potential for Parkinson disease (PD).METHODS: A cross-sectional, multicenter study was designed, including 170 patients with PD and 131 healthy controls (HCs) with a similar distribution of age and sex recruited from existing center studies at the University of Washington and Oregon Health and Science University. CSF EVs carrying alpha-syn or aggregated alpha-syn were quantified using antibodies against total or aggregated alpha-syn, respectively, and highly specific, sensitive, and rapid assays based on the novel Apogee nanoscale flow cytometry technology.RESULTS: No significant differences in the number and size distribution of total EVs between patients with PD and HCs in CSF were observed. When examining the total alpha-syn-positive and aggregated alpha-syn-positive EV subpopulations, the proportions of both among all detected CSF EVs were significantly lower in patients with PD compared to HCs (p < 0.0001). While each EV subpopulation showed better diagnostic sensitivity and specificity than total CSF alpha-syn measured directly with an immunoassay, a combination of the 2 EV subpopulations demonstrated a diagnostic accuracy that attained clinical relevance (area under curve 0.819, sensitivity 80%, specificity 71%).CONCLUSION: Using newly established, sensitive nanoscale flow cytometry assays, we have demonstrated that total alpha-syn-positive and aggregated alpha-syn-positive EVs in CSF may serve as a helpful tool in PD diagnosis.CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that total and aggregated alpha-syn-positive EVs in CSF identify patients with PD.

View details for DOI 10.1212/WNL.0000000000011853

View details for PubMedID 34032594

Abstract

Imbalance of excitatory and inhibitory neurotransmission is implicated in a wide range of psychiatric and neurologic disorders. Here we tested the hypothesis that insertion of a methyl group on the stereogenic alpha carbon of L-Glu or L-Gln would impact the gamma-aminobutyric acid (GABA) shunt and the glutamate-glutamine cycle. (S)-2-methylglutamate, or (S)-2MeGlu, was efficiently transported into brain and synaptosomes where it was released by membrane depolarization in a manner equivalent to endogenous L-Glu. (R)-2MeGlu was transported less efficiently into brain and synaptosomes but was not released by membrane depolarization. Each enantiomer of 2MeGlu had limited activity across a panel of over 30 glutamate and GABA receptors. While neither enantiomer of 2MeGlu was metabolized along the GABA shunt, (S)-2MeGlu was selectively converted to (S)-2-methylglutamine, or (S)-2MeGln, which was subsequently slowly hydrolyzed back to (S)-2MeGlu in brain. rac-2MeGln was also transported into brain, with similar efficiency as (S)-2MeGlu. A battery of behavioral tests in young adult wild type mice showed safety with up to single 900mg/kg dose of (R)-2MeGlu, (S)-2MeGlu, or rac-2MeGln, suppressed locomotor activity with single100mg/kg dose of (R)-2MeGlu or (S)-2MeGlu. No effect on anxiety or hippocampus-dependent learning was evident. Enantiomers of 2MeGlu and 2MeGln show promise as potential pharmacologic agents and imaging probes for cells that produce or transport L-Gln.

View details for DOI 10.1038/s41598-021-87569-1

View details for PubMedID 33854131

Abstract

Mass-tag cell barcoding has increased the throughput, multiplexing, and robustness of multiple cytometry approaches. Previously, we adapted mass cytometry for cells to analyze synaptosome preparations (mass synaptometry or SynTOF), extending mass cytometry to these smaller, anuclear particles. To improve throughput and individual event resolution, we report here the application of palladium-based barcoding in human synaptosomes. Up to 20 individual samples, each with a unique combinatorial barcode, were pooled for labeling with an antibody cocktail. Our synaptosome protocol used six palladium-based barcoding reagents, and in combination with sequential gating increased the identification of presynaptic events approximately fourfold. These same parameters also efficiently resolved two other anuclear particles: human red blood cells and platelets. The addition of palladium-based mass-tag barcoding to our approach improves mass cytometry of synaptic particles.

View details for DOI 10.1002/cyto.a.24340

View details for PubMedID 33818911

Abstract

Age-related neurodegeneration characteristic of late-onset Alzheimer's disease (LOAD) begins in middle age, well before symptoms. Translational models to identify modifiable risk factors are needed to understand etiology and identify therapeutic targets. Here, we outline the evidence supporting the vervet monkey (Chlorocebus aethiops sabaeus) as a model of aging-related AD-like neuropathology and associated phenotypes including cognitive function, physical function, glucose handling, intestinal physiology, and CSF, blood, and neuroimaging biomarkers. This review provides the most comprehensive multisystem description of aging in vervets to date. This review synthesizes a large body of evidence that suggests that aging vervets exhibit a coordinated suite of traits consistent with early AD and provide a powerful, naturally occurring model for LOAD. Notably, relationships are identified between AD-like neuropathology and modifiable risk factors. Gaps in knowledge and key limitations are provided to shape future studies to illuminate mechanisms underlying divergent neurocognitive aging trajectories and to develop interventions that increase resilience to aging-associated chronic disease, particularly, LOAD.

View details for DOI 10.1002/ajp.23260

View details for PubMedID 33818801

Abstract

The field of data science has great potential to address critical questions relevant for academic medical centers. Data science initiatives are consequently being established within academic medicine. At the cornerstone of such initiatives are scientists who practice data science. These scientists include biostatisticians, clinical informaticians, database and software developers, computational scientists, and computational biologists. Too often, however, those involved in the practice of data science are viewed by academic leadership as providing a noncomplex service to facilitate research and further the careers of other academic faculty. The authors contend that the success of data science initiatives relies heavily on the understanding that the practice of data science is a critical intellectual contribution to the overall science conducted at an academic medical center. Further, careful thought by academic leadership is needed for allocation of resources devoted to the practice of data science. At the Stanford University School of Medicine, the authors have developed an innovative model for a data science collaboratory based on 4 fundamental elements: an emphasis on collaboration over consultation; a subscription-based funding mechanism that reflects commitment by key partners; an investment in the career development of faculty who practice data science; and a strong educational component for data science members in team science and for clinical and translational investigators in data science. As data science becomes increasingly essential to learning health systems, centers that specialize in the practice of data science are a critical component of the research infrastructure and intellectual environment of academic medical centers.

View details for DOI 10.1097/ACM.0000000000004079

View details for PubMedID 33769342

Abstract

Efforts to characterize the late effects of traumatic brain injury (TBI) have been in progress for some time. In recent years much of this activity has been directed towards reporting of chronic traumatic encephalopathy (CTE) in former contact sports athletes and others exposed to repetitive head impacts. However, the association between TBI and dementia risk has long been acknowledged outside of contact sports. Further, growing experience suggests a complex of neurodegenerative pathologies in those surviving TBI, which extends beyond CTE. Nevertheless, despite extensive research, we have scant knowledge of the mechanisms underlying TBI-related neurodegeneration (TReND) and its link to dementia. In part, this is due to the limited number of human brain samples linked to robust demographic and clinical information available for research. Here we detail a National Institutes for Neurological Disease and Stroke Center Without Walls project, the COllaborative Neuropathology NEtwork Characterizing ouTcomes of TBI (CONNECT-TBI), designed to address current limitations in tissue and research access and to advance understanding of the neuropathologies of TReND. As an international, multidisciplinary collaboration CONNECT-TBI brings together multiple experts across 13 institutions. In so doing, CONNECT-TBI unites the existing, comprehensive clinical and neuropathological datasets of multiple established research brain archives in TBI, with survivals ranging minutes to many decades and spanning diverse injury exposures. These existing tissue specimens will be supplemented by prospective brain banking and contribute to a centralized route of access to human tissue for research for investigators. Importantly, each new case will be subject to consensus neuropathology review by the CONNECT-TBI Expert Pathology Group. Herein we set out the CONNECT-TBI program structure and aims and, by way of an illustrative case, the approach to consensus evaluation of new case donations.

View details for DOI 10.1186/s40478-021-01122-9

View details for PubMedID 33648593

Abstract

BACKGROUND: Alzheimer's disease neuropathologic change (ADNC) may contribute to dementia in patients with Lewy body disease (LBD) pathology.OBJECTIVE: To examine how co-occurring ADNC impacts domain specific cognitive impairments at each pathologic stage (brainstem, limbic, cerebral cortical) of LBD.METHODS: 2,433 participants with antemortem longitudinal neuropsychological assessment and postmortem neuropathological assessment from the National Alzheimer's Coordinating Center's Uniform Data Set were characterized based on the evaluation of ADNC and LBD. Longitudinal mixed-models were used to derive measures of cumulative cognitive deficit for each cognitive domain at each pathologic stage of LBD (brainstem, limbic, and cerebral cortical).RESULTS: 111 participants with a pathologic diagnosis of LBD, 741 participants with combined LBD and ADNC, 1,357 participants with ADNC only, and 224 with no pathology (healthy controls) were included in the analyses. In the executive/visuospatial domain, combined LBD and ADNC showed worse deficits than LBD only when Lewy bodies were confined to the brainstem, but no difference when Lewy bodies extended to the limbic or cerebral cortical regions. The cerebral cortical LBD only group exhibited greater executive/visuospatial deficits than the ADNC only group. By contrast, the ADNC only group and the combined pathology group both demonstrated significantly greater cumulative memory deficits relative to Lewy body disease only, regardless of stage.CONCLUSION: The impact of co-occurring ADNC on antemortem cumulative cognitive deficits varies not only by domain but also on the pathological stage of Lewy bodies. Our findings stress the cognitive impact of different patterns of neuropathological progression in Lewy body diseases.

View details for DOI 10.3233/JAD-201187

View details for PubMedID 33646154

Abstract

Alzheimer's disease (AD) is a pervasive, relentlessly progressive neurodegenerative disorder that includes both hereditary and sporadic forms linked by common underlying neuropathologic changes and neuropsychological manifestations. While a clinical diagnosis is often made on the basis of initial memory dysfunction that progresses to involve multiple cognitive domains, definitive diagnosis requires autopsy examination of the brain to identify amyloid plaques and neurofibrillary degeneration. Over the past 100 years, there has been remarkable progress in our understanding of the underlying pathophysiologic processes, pathologic changes, and clinical phenotypes of AD, largely because genetic pathways that include but expand beyond amyloid processing have been uncovered. This review discusses the current state of understanding of the genetics of AD with a focus on how these advances are both shaping our understanding of the disease and informing novel avenues and approaches for development of potential therapeutic targets.

View details for DOI 10.1146/annurev-pathmechdis-012419-032551

View details for PubMedID 33497263

Abstract

The severe impact on brain function and lack of effective therapy for patients with creatine (Cr) transporter deficiency motivated the generation of three ubiquitous Slc6a8 deficient mice (-/y). While each mouse knock-out line has similar behavioral effects at 2 to 3 months of age, other features critical to the efficient use of these mice in drug discovery are unclear or lacking: the concentration of Cr in brain and heart differ widely between mouse lines, there are limited data on histopathologic changes, and no data on Cr uptake. Here, we determined survival, measured endogenous Cr and uptake of its deuterium-labeled analogue Cr-d3 using a liquid chromatography coupled with tandem mass spectrometry assay, and performed comprehensive histopathologic examination on the Slc6a8-/y mouse developed by Skelton et. al. Our results show that Slc6a8-/y mice have widely varying organ-specific uptake of Cr-d3, significantly diminished growth with the exception of brain, progressive vacuolar myopathy, and markedly shortened lifespan. This article is protected by copyright. All rights reserved.

View details for DOI 10.1002/jimd.12358

View details for PubMedID 33389772

Abstract

One of the potential benefits of using data-independent acquisition (DIA) proteomics protocols is that information not originally targeted by the study may be present and discovered by subsequent analysis. Herein, we reanalyzed DIA data originally recorded for global proteomic analysis to look for isomerized peptides, which occur as a result of spontaneous chemical modifications to long-lived proteins. Examination of a large set of human brain samples revealed a striking relationship between Alzheimer's disease (AD) status and isomerization of aspartic acid in a peptide from tau. Relative to controls, a surprising increase in isomer abundance was found in both autosomal dominant and sporadic AD samples. To explore potential mechanisms that might account for these observations, quantitative analysis of proteins related to isomerization repair and autophagy was performed. Differences consistent with reduced autophagic flux in AD-related samples relative to controls were found for numerous proteins, including most notably p62, a recognized indicator of autophagic inhibition. These results suggest, but do not conclusively demonstrate, that lower autophagic flux may be strongly associated with loss of function in AD brains. This study illustrates that DIA data may contain unforeseen results of interest and may be particularly useful for pilot studies investigating new research directions. In this case, a promising target for future investigations into the therapy and prevention of AD has been identified.

View details for DOI 10.1021/acs.jproteome.1c00558

View details for PubMedID 34818016

Abstract

AMP-activated protein kinase (AMPK) is a molecular sensor that is critical for the maintenance of cellular energy homeostasis, disruption of which has been indicated in multiple neurodegenerative diseases including Alzheimer's disease (AD). Mammalian AMPK is a heterotrimeric complex and its enzymatic subunit exists in two isoforms: AMPK1 and AMPK2. Here we took advantage of a recently characterized non-human primate (NHP) model with sporadic AD-like neuropathology to explore potential relationships between AMPK signaling and AD-like neuropathology. Subjects were nine female vervet monkeys aged 19.5 to 23.4years old. Subjects were classified into three groups, control lacking AD pathology (n=3), moderate AD pathology (n=3), and more severe AD Pathology (n=3). We found increased activity (assessed by phosphorylation) of AMPK2 in hippocampi of NHP with AD-like neuropathology, compared to the subjects without AD pathology, with no alterations of AMPK1 activity. Across all subjects, CSF Abeta42 was inversely associated with cerebral amyloid plaque density. Further, A plaque burden is correlated with levels of either soluble or insoluble brain A measurement. Unbiased mass spectrometry based proteomics studies combined with bioinformatics analysis revealed that many of the dysregulated proteins characteristic of AD neuropathology are associated with AMPK signaling. Our findings on the AMPK molecular signaling cascades provide further support for use of the NHP model to investigate new therapeutic strategies and development of novel biomarkers for Alzheimer's disease.

View details for DOI 10.1016/j.nbd.2021.105463

View details for PubMedID 34363967

Abstract

Primary age-related tauopathy (PART) is a neurodegenerative pathology with features distinct from but also overlapping with Alzheimer disease (AD). While both exhibit Alzheimer-type temporal lobe neurofibrillary degeneration alongside amnestic cognitive impairment, PART develops independently of amyloid- (A) plaques. The pathogenesis of PART is not known, but evidencesuggests anassociation with genes that promote tau pathology and others that protect from A toxicity. Here, we performed a genetic association study in an autopsy cohort of individuals with PART (n=647) using Braak neurofibrillary tangle stage as a quantitative trait. We found some significant associations with candidate loci associated with AD (SLC24A4, MS4A6A, HS3ST1) and progressive supranuclear palsy (MAPT and EIF2AK3). Genome-wide association analysis revealed a novel significant association with a single nucleotide polymorphism on chromosome 4 (rs56405341) in a locus containing three genes, including JADE1 which was significantly upregulated in tangle-bearing neurons by single-soma RNA-seq. Immunohistochemical studies using antisera targeting JADE1 protein revealed localization within tau aggregates in autopsy brains with four microtubule-binding domain repeats (4R) isoforms and mixed 3R/4R, but not with 3R exclusively. Co-immunoprecipitation in post-mortem human PART brain tissue revealed a specific binding of JADE1 protein to four repeat tau lacking N-terminal inserts (0N4R). Finally, knockdown of the Drosophila JADE1 homolog rhinoceros (rno) enhanced tau-induced toxicity and apoptosis in vivo in a humanized 0N4R mutant tau knock-in model, as quantified by rough eye phenotype and terminal deoxynucleotidyl transferase dUTP nick end-labeling (TUNEL) in the fly brain. Together, these findings indicate that PART has a genetic architecture that partially overlaps with AD and other tauopathies and suggests a novel role for JADE1 as a modifier of neurofibrillary degeneration.

View details for DOI 10.1007/s00401-021-02379-z

View details for PubMedID 34719765

Abstract

Imbalance in the metabolic pathway linking excitatory and inhibitory neurotransmission has been implicated in multiple psychiatric and neurologic disorders. Recently, we described enantiomer-specific effects of 2-methylglutamate, which is not decarboxylated to the corresponding methyl analogue of gamma-aminobutyric acid (GABA): 4-aminopentanoic acid (4APA). Here we tested the hypothesis that 4APA also has enantiomer-specific actions in brain. Mouse cerebral synaptosome uptake (nmol/mg protein over 30 min) of (R)-4APA or (S)-4APA was time- and temperature dependent; however, the R enantiomer had greater uptake, reduction of endogenous GABA concentration, and release following membrane depolarization than did the S enantiomer. (S)-4APA exhibited some weak agonist (GABAA 43, GABAA 522, and GABAB B1/B2) and antagonist (GABAA 622) activity while (R)-4APA showed weak agonist activity only with GABAA 522. Both 4APA enantiomers (100 mg/kg IP) were detected in mouse brain 10 min after injection, and by one hour had reached concentrations that were stable over six hours; both enantiomers were cleared rapidly from mouse serum over six hours. Two-month old mice had no mortality following 100 to 900 mg/kg IP of each 4APA enantiomer but ded have similar dose-dependent reduction in distance moved in a novel cage. Neither enantiomer at 30 or 100 mg/kg impacted outcomes in twenty-three measures of well-being, activity chamber, or withdrawal from hotplate. Our results suggest that enantiomers of 4APA are active in mouse brain, and that (R)-4APA may act as a novel false neurotransmitter of GABA. Future work will focus on disease models and on possible applications as neuroimaging agents.

View details for DOI 10.1111/jnc.15474

View details for PubMedID 34273193

Abstract

Mortality due to Covid-19 is highly associated with advanced age, owing in large part to severe lower respiratory tract infection. SARS-CoV-2 utilizes the host ACE2 receptor for infection. Whether ACE2 abundance in the lung contributes to age-associated vulnerability is currently unknown. We set out to characterize the RNA and protein expression profiles of ACE2 in aging human lung in the context of phenotypic parameters likely to affect lung physiology. Examining publicly available RNA sequencing data, we discovered that mechanical ventilation is a critical variable affecting lung ACE2 levels. Therefore, we investigated ACE2 protein abundance in patients either requiring mechanical ventilation or spontaneously breathing. ACE2 distribution and expression were determined in archival lung samples by immunohistochemistry (IHC). Tissues were selected from the specimen inventory at a large teaching hospital collected between 2010-2020. Twelve samples were chosen from patients receiving mechanical ventilation for acute hypoxic respiratory failure (AHRF). Twenty samples were selected from patients not requiring ventilation. We compared samples across age, ranging from 40-83 years old in the ventilated cohort and 14-80 years old in the non-ventilated cohort. Within the alveolated parenchyma, ACE2 expression is predominantly observed in type II pneumocytes (or alveolar type II / AT2 cells) and alveolar macrophages. All 12 samples from our ventilated cohort showed histologic features of diffuse alveolar damage including reactive, proliferating AT2 cells. In these cases, ACE2 was strongly upregulated with age when normalized to lung area (p = 0.004) or cellularity (p = 0.003), associated with prominent expression in AT2 cells. In non-ventilated individuals, AT2 cell reactive changes were not observed and ACE2 expression did not change with age when normalized to lung area (p = 0.231) or cellularity (p = 0.349). In summary, ACE2 expression increases with age in the setting of alveolar damage observed in patients on mechanical ventilation, providing a potential mechanism for higher Covid-19 mortality in the elderly.

View details for DOI 10.1371/journal.pone.0247060

View details for PubMedID 33592054

Abstract

Cognitive impairment and its severe form dementia are increasingly prevalent in older adults and loom as a public health disaster unless effective interventions are developed. Cognitive impairment is a convergent trait caused by damage from an idiosyncratic mix of four prevalent diseases (Alzheimer disease; vascular brain injury; Lewy body diseases, such as Parkinson disease and dementia with Lewy bodies; and limbic-predominant age-related transactive response DNA-binding protein 43 encephalopathy) that is counterbalanced by individually varying resilience, which is comprised of reserve and compensation. Brain regional damage from each of these four prevalent diseases is generated by the net effect of injury and (mal)adaptive response and is accompanied by characteristic lesions. Existing therapeutics enhance resilience, whereas most agents under development target mechanisms of damage with only suppression of vascular brain injury yet to show therapeutic promise. We hope to anticipate future tailored interventions that target mechanisms of damage and thereby avert the oncoming surge of cognitive impairment and dementia in older adults. SIGNIFICANCE STATEMENT: Brain regional damage is generated by the net effect of injury and (mal)adaptive response. The extent to which signs and symptoms of such damage occur is influenced by an underlying resilience comprising reserve and compensation. Finding tailored interventions that target specific mechanisms of damage likely yields the most effective therapies.

View details for DOI 10.1124/pharmrev.120.000031

View details for PubMedID 33298513

Abstract

The late neuropathological effects of traumatic brain injury have yet to be fully elucidated, particularly with respect to community-based cohorts. To contribute to this critical gap in knowledge, we designed a multimodal neuropathological study, integrating traditional and quantitative approaches to detect pathologic changes in 532 consecutive brain autopsies from participants in the Adult Changes in Thought (ACT) study. Diagnostic evaluation including assessment for chronic traumatic encephalopathy (CTE) and quantitative immunoassay-based methods were deployed to examine levels of pathological (hyperphosphorylated) tau (pTau) and amyloid (A) beta in brains from ACT participants with (n = 107) and without (n = 425) history of remote TBI with loss of consciousness (w/LOC). Further neuropathological assessments included immunohistochemistry for alpha-synuclein and phospho-TDP-43 pathology and astro- (GFAP) and micro- (Iba1) gliosis, mass spectrometry analysis of free radical injury, and gene expression evaluation (RNA sequencing) in a smaller sub-cohort of matched samples (49 cases with TBI and 49 non-exposed matched controls). Out of 532 cases, only 3 (0.6%-none with TBI w/LOC history) showed evidence of the neuropathologic signature of chronic traumatic encephalopathy (CTE). Across the entire cohort, the levels of pTau and Abeta showed expected differences for brain region (higher levels in temporal cortex), neuropathological diagnosis (higher in participants with Alzheimer's disease), and APOE genotype (higher in participants with one or more APOE epsilon4 allele). However, no differences in PHF-tau or Abeta1-42 were identified by Histelide with respect to the history of TBI w/LOC. In a subset of TBI cases with more carefully matched control samples and more extensive analysis, those with TBI w/LOC history had higher levels of hippocampal pTau but no significant differences in Abeta, alpha-synuclein, pTDP-43, GFAP, Iba1, or free radical injury. RNA-sequencing also did not reveal significant gene expression associated with any measure of TBI exposure. Combined, these findings suggest long term neuropathological changes associated with TBI w/LOC may be subtle, involve non-traditional pathways of neurotoxicity and neurodegeneration, and/or differ from those in autopsy cohorts specifically selected for neurotrauma exposure.

View details for DOI 10.3389/fneur.2021.624696

View details for PubMedID 33796061

Abstract

BACKGROUND: Reduced cortical sensorimotor inhibition is associated with mobility and cognitive impairments in people with Parkinson's disease (PD) and older adults (OAs). However, there is a lack of clarity regarding the relationships among sensorimotor, cognitive, and mobility impairments. The purpose of this study was to determine how cortical sensorimotor inhibition relates to impairments in mobility and cognition in people with PD and OAs.METHODS: Cortical sensorimotor inhibition was characterized with short-latency afferent inhibition (SAI) in 81 people with PD and 69 OAs. Six inertial sensors recorded single- and dual-task gait and postural sway characteristics during a two-minute walk and a one-minute quiet stance. Cognition was assessed across the memory, visuospatial, executive function, attention, and language domains.RESULTS: SAI was significantly impaired in the PD compared to the OA group. The PD group preformed significantly worse across all gait and postural sway tasks. In PD, SAI significantly correlated with single-task foot strike angle and stride length variability, sway area, and jerkiness of sway in the coronal and sagittal planes. In OAs, SAI significantly related to single-task gait speed and stride length, dual-task stride length, and immediate recall (memory domain). No relationship among mobility, cognition, and SAI was observed.CONCLUSIONS: Impaired SAI related to slower gait in OA and to increased gait variability and postural sway in people with PD, all of which have been shown to be related to increased fall risk.

View details for DOI 10.1093/gerona/glaa300

View details for PubMedID 33252618

Abstract

Peripheral blood mononuclear cells (PBMCs) may provide insight into the pathogenesis of Alzheimer's disease (AD) or Parkinson's disease (PD). We investigated PBMC samples from 132 well-characterized research participants using seven canonical immune stimulants, mass cytometric identification of 35 PBMC subsets, and single-cell quantification of 15 intracellular signaling markers, followed by machine learning model development to increase predictive power. From these, three main intracellular signaling pathways were identified specifically in PBMC subsets from people with AD versus controls: reduced activation of PLCgamma2 across many cell types and stimulations and selectively variable activation of STAT1 and STAT5, depending on stimulant and cell type. Our findings functionally buttress the now multiply-validated observation that a rare coding variant in PLCG2 is associated with a decreased risk of AD. Together, these data suggest enhanced PLCgamma2 activity as a potential new therapeutic target for AD with a readily accessible pharmacodynamic biomarker.

View details for DOI 10.1126/sciadv.abd5575

View details for PubMedID 33239300

Abstract

Genome-wide association studies of neurological diseases have identified thousands of variants associated with disease phenotypes. However, most of these variants do not alter coding sequences, making it difficult to assign their function. Here, we present a multi-omic epigenetic atlas of the adult human brain through profiling of single-cell chromatin accessibility landscapes and three-dimensional chromatin interactions of diverse adult brain regions across a cohort of cognitively healthy individuals. We developed a machine-learning classifier to integrate this multi-omic framework and predict dozens of functional SNPs for Alzheimer's and Parkinson's diseases, nominating target genes and cell types for previously orphaned loci from genome-wide association studies. Moreover, we dissected the complex inverted haplotype of the MAPT (encoding tau) Parkinson's disease risk locus, identifying putative ectopic regulatory interactions in neurons that may mediate this disease association. This work expands understanding of inherited variation and provides a roadmap for the epigenomic dissection of causal regulatory variation in disease.

View details for DOI 10.1038/s41588-020-00721-x

View details for PubMedID 33106633

Abstract

Importance: Compared with non-Hispanic White individuals, African American individuals from the same community are approximately twice as likely to develop Alzheimer disease. Despite this disparity, the largest Alzheimer disease genome-wide association studies to date have been conducted in non-Hispanic White individuals. In the largest association analyses of Alzheimer disease in African American individuals, ABCA7, TREM2, and an intergenic locus at 5q35 were previously implicated.Objective: To identify additional risk loci in African American individuals by increasing the sample size and using the African Genome Resource panel.Design, Setting, and Participants: This genome-wide association meta-analysis used case-control and family-based data sets from the Alzheimer Disease Genetics Consortium. There were multiple recruitment sites throughout the United States that included individuals with Alzheimer disease and controls of African American ancestry. Analysis began October 2018 and ended September 2019.Main Outcomes and Measures: Diagnosis of Alzheimer disease.Results: A total of 2784 individuals with Alzheimer disease (1944 female [69.8%]) and 5222 controls (3743 female [71.7%]) were analyzed (mean [SD] age at last evaluation, 74.2 [13.6] years). Associations with 4 novel common loci centered near the intracellular glycoprotein trafficking gene EDEM1 (3p26; P=8.9*10-7), near the immune response gene ALCAM (3q13; P=9.3*10-7), within GPC6 (13q31; P=4.1*10-7), a gene critical for recruitment of glutamatergic receptors to the neuronal membrane, and within VRK3 (19q13.33; P=3.5*10-7), a gene involved in glutamate neurotoxicity, were identified. In addition, several loci associated with rare variants, including a genome-wide significant intergenic locus near IGF1R at 15q26 (P=1.7*10-9) and 6 additional loci with suggestive significance (P5*10-7) such as API5 at 11p12 (P=8.8*10-8) and RBFOX1 at 16p13 (P=5.4*10-7) were identified. Gene expression data from brain tissue demonstrate association of ALCAM, ARAP1, GPC6, and RBFOX1 with brain beta-amyloid load. Of 25 known loci associated with Alzheimer disease in non-Hispanic White individuals, only APOE, ABCA7, TREM2, BIN1, CD2AP, FERMT2, and WWOX were implicated at a nominal significance level or stronger in African American individuals. Pathway analyses strongly support the notion that immunity, lipid processing, and intracellular trafficking pathways underlying Alzheimer disease in African American individuals overlap with those observed in non-Hispanic White individuals. A new pathway emerging from these analyses is the kidney system, suggesting a novel mechanism for Alzheimer disease that needs further exploration.Conclusions and Relevance: While the major pathways involved in Alzheimer disease etiology in African American individuals are similar to those in non-Hispanic White individuals, the disease-associated loci within these pathways differ.

View details for DOI 10.1001/jamaneurol.2020.3536

View details for PubMedID 33074286

Abstract

CD19-directed immunotherapies are clinically effective for treating B cell malignancies but also cause a high incidence of neurotoxicity. A subset of patients treated with chimeric antigen receptor (CAR) Tcells or bispecific Tcell engager (BiTE) antibodies display severe neurotoxicity, including fatal cerebral edema associated with Tcell infiltration into the brain. Here, we report that mural cells, which surround the endothelium and are critical for blood-brain-barrier integrity, express CD19. We identify CD19 expression in brain mural cells using single-cell RNA sequencing data and confirm perivascular staining at the protein level. CD19 expression in the brain begins early in development alongside the emergence of mural cell lineages and persists throughout adulthood across brain regions. Mouse mural cells demonstrate lower levels of Cd19 expression, suggesting limitations in preclinical animal models of neurotoxicity. These data suggest an on-target mechanism for neurotoxicity in CD19-directed therapies and highlight the utility of human single-cell atlases for designing immunotherapies.

View details for DOI 10.1016/j.cell.2020.08.022

View details for PubMedID 32961131

Abstract

Neuropsychiatric symptoms are common in Parkinson's disease (PD). We investigated the relationship between neuropsychiatric symptoms and current and future diagnosis of PD dementia (PDD). Individuals with PD who had a study partner were enrolled (n=696). Study partners were administered the Neuropsychiatric Inventory or Neuropsychiatric Inventory Questionnaire at baseline. Participants were assigned a cognitive diagnosis at baseline and follow up visits. Hallucinations were significantly associated with a diagnosis of PDD cross-sectionally (p<0.001) and with shortened time to dementia longitudinally among initially nondemented participants (n=444; p=0.005). Screening for hallucinations may be useful for assessing risk of dementia in participants with PD.

View details for DOI 10.3233/JPD-202116

View details for PubMedID 32741842

Abstract

BACKGROUND: The objective of this study was to make a quantitative comparison of flortaucipir PET retention with pathological tau and beta-amyloid across a range of brain regions at autopsy.METHODS: Patients with dementia (two with clinical diagnosis of AD, one undetermined), nearing the end of life, underwent 20-min PET, beginning 80min after an injection of ~370 mBq flortaucipir [18F]. Neocortical, basal ganglia, and limbic tissue samples were obtained bilaterally from 19 regions at autopsy and subject-specific PET regions of interest corresponding to the 19 sampled target tissue regions in each hemisphere were hand drawn on the PET images. SUVr values were calculated for each region using a cerebellar reference region. Abnormally phosphorylated tau (Ptau) and amyloid-beta (Abeta) tissue concentrations were measured for each tissue region with an antibody capture assay (Histelide) using AT8 and H31L21 antibodies respectively.RESULTS: The imaging-to-autopsy interval ranged from 4-29days. All three subjects had intermediate to high levels of AD neuropathologic change at autopsy. Mean cortical SUVr averaged across all three subjects correlated significantly with the Ptau immunoassay (Pearson r = 0.81; p < 0.0001). When Ptau and Abeta1-42 were both included in the model, the Ptau correlation with flortaucipir SUVr was preserved but there was no correlation of Abeta1-42 with flortaucipir. There was also a modest correlation between limbic (hippocampal/entorhinal and amygdala) flortaucipir SUVr and Ptau (Pearson r = 0.52; p < 0.080). There was no significant correlation between SUVr and Ptau in basal ganglia.CONCLUSIONS: The results of this pilot study support a quantitative relationship between cortical flortaucipir SUVr values and quantitative measures of Ptau at autopsy. Additional research including more cases is needed to confirm the generalizability of these results. Trial registration, NIH Clinicaltrials.gov NCT # 02516046. Registered August 27, 2015. https://clinicaltrials.gov/ct2/show/NCT02516046?term=02516046&draw=2&rank=1.

View details for DOI 10.1186/s13550-020-00653-x

View details for PubMedID 32542468

View details for Web of Science ID 000568290500016

Abstract

Importance: Positron emission tomography (PET) may increase the diagnostic accuracy and confirm the underlying neuropathologic changes of Alzheimer disease (AD).Objective: To determine the accuracy of antemortem [18F]flortaucipir PET images for predicting the presence of AD-type tau pathology at autopsy.Design, Setting, and Participants: This diagnostic study (A16 primary cohort) was conducted from October 2015 to June 2018 at 28 study sites (27 in US sites and 1 in Australia). Individuals with a terminal illness who were older than 50 years and had a projected life expectancy of less than 6 months were enrolled. All participants underwent [18F]flortaucipir PET imaging, and scans were interpreted by 5 independent nuclear medicine physicians or radiologists. Supplemental autopsy [18F]flortaucipir images and pathological samples were also collected from 16 historically collected cases. A second study (FR01 validation study) was conducted from March 26 to April 26, 2019, in which 5 new readers assessed the original PET images for comparison to autopsy.Main Outcomes and Measures: [18F]flortaucipir PET images were visually assessed and compared with immunohistochemical tau pathology. An AD tau pattern of flortaucipir retention was assessed for correspondence with a postmortem B3-level (Braak stage V or VI) pathological pattern of tau accumulation and to the presence of amyloid-beta plaques sufficient to meet the criteria for high levels of AD neuropathological change. Success was defined as having at least 3 of the 5 readers above the lower bounds of the 95% CI for both sensitivity and specificity of 50% or greater.Results: A total of 156 patients were enrolled in the A16 study and underwent [18F]flortaucipir PET imaging. Of these, 73 died during the study, and valid autopsies were performed for 67 of these patients. Three autopsies were evaluated as test cases and removed from the primary cohort (n=64). Of the 64 primary cohort patients, 34 (53%) were women and 62 (97%) were white; mean (SD) age was 82.5 (9.6) years; and 49 (77%) had dementia, 1 (2%) had mild cognitive impairment, and 14 (22%) had normal cognition. Prespecified success criteria were met for the A16 primary cohort. The flortaucipir PET scans predicted a B3 level of tau pathology, with sensitivity ranging from 92.3% (95% CI, 79.7%-97.3%) to 100.0% (95% CI, 91.0%-100.0%) and specificity ranging from 52.0% (95% CI, 33.5%-70.0%) to 92.0% (95% CI, 75.0%-97.8%). A high level of AD neuropathological change was predicted with sensitivity of 94.7% (95% CI, 82.7%-98.5%) to 100.0% (95% CI, 90.8%-100.0%) and specificity of 50.0% (95% CI, 32.1%-67.9%) to 92.3% (95% CI, 75.9%-97.9%). The FR01 validation study also met prespecified success criteria. Addition of the supplemental autopsy data set and 3 test cases, which comprised a total of 82 patients and autopsies for both the A16 and FR01 studies, resulted in improved specificity and comparable overall accuracy. Among the 156 enrolled participants, 14 (9%) experienced at least 1 treatment-emergent adverse event.Conclusions and Relevance: This study's findings suggest that PET imaging with [18F]flortaucipir could be used to identify the density and distribution of AD-type tau pathology and the presence of high levels of AD neuropathological change, supporting a neuropathological diagnosis of AD.

View details for DOI 10.1001/jamaneurol.2020.0528

View details for PubMedID 32338734

View details for Web of Science ID 000536058001085

Abstract

Our understanding of Alzheimer's disease (AD) pathophysiology remains incomplete. Here we used quantitative mass spectrometry and coexpression network analysis to conduct the largest proteomic study thus far on AD. A protein network module linked to sugar metabolism emerged as one of the modules most significantly associated with AD pathology and cognitive impairment. This module was enriched in AD genetic risk factors and in microglia and astrocyte protein markers associated with an anti-inflammatory state, suggesting that the biological functions it represents serve a protective role in AD. Proteins from this module were elevated in cerebrospinal fluid in early stages of the disease. In this study of >2,000 brains and nearly 400 cerebrospinal fluid samples by quantitative proteomics, we identify proteins and biological processes in AD brains that may serve as therapeutic targets and fluid biomarkers for the disease.

View details for DOI 10.1038/s41591-020-0815-6

View details for PubMedID 32284590

Abstract

Cognitive dysfunction is common in Parkinson's disease (PD) and associated with reduced functional abilities and increased dependence. To date, however, little is known about the relationship between performance of instrumental activities of daily living (IADLs) and cognitive stages in PD, and there are conflicting reports as to whether declines in specific cognitive domains predict IADL impairment.Participants with PD were drawn from the Pacific Udall Center and included in the study if both participant and study partner IADL ratings and cognitive tests were completed (n = 192). Logistic regression analyses were performed to determine whether participant and/or study partner rating predicted mild cognitive impairment or dementia. Correlations are reported for the relationship between participant/study partner IADL reports as well as for specific cognitive tests.Although both participant and study partner ratings of IADL performance were associated with a diagnosis of PD with dementia, only participant self-rating of functional ability was significantly associated with a diagnosis of PD with mild cognitive impairment. Functional ability correlated most strongly with measures of processing speed, auditory working memory, and immediate verbal recall for both the participant and study partner ratings.For participants with PD in the early stages of cognitive decline, self-rating may be more sensitive to the impact of cognitive changes on IADL function than ratings made by a knowledgeable study partner. Changes in executive function, processing speed, and learning may indicate a higher likelihood of IADL impairment. Careful assessment of cognition and IADL performance is recommended to permit individualized interventions prior to significant disability.

View details for DOI 10.1002/mdc3.12870

View details for Web of Science ID 000507324100010

View details for PubMedID 31970213

View details for PubMedCentralID PMC6962683

Abstract

Recent studies in animal models demonstrate that certain misfolded proteins associated with neurodegenerative diseases can support templated misfolding of cognate native proteins, to propagate across neural systems, and to therefore have some of the properties of classical prion diseases like Creutzfeldt-Jakob disease. The National Institute of Aging convened a meeting to discuss the implications of these observations for research priorities. A summary of the discussion is presented here, with a focus on limitations of current knowledge, highlighting areas that appear to require further investigation in order to guide scientific practice while minimizing potential exposure or risk in the laboratory setting. The committee concluded that, based on all currently available data, although neurodegenerative disease-associated aggregates of several different non-prion proteins can be propagated from humans to experimental animals, there is currently insufficient evidence to suggest more than a negligible risk, if any, of a direct infectious etiology for the human neurodegenerative disorders defined in part by these proteins. Given the importance of this question, the potential for noninvasive human transmission of proteopathic disorders is deserving of further investigation.

View details for DOI 10.1093/jnen/nlaa109

View details for PubMedID 33000167

Abstract

Each additional copy of the apolipoprotein E4 (APOE4) allele is associated with a higher risk of Alzheimer's dementia, while the APOE2 allele is associated with a lower risk of Alzheimer's dementia, it is not yet known whether APOE2 homozygotes have a particularly low risk. We generated Alzheimer's dementia odds ratios and other findings in more than 5,000 clinically characterized and neuropathologically characterized Alzheimer's dementia cases and controls. APOE2/2 was associated with a low Alzheimer's dementia odds ratios compared to APOE2/3 and 3/3, and an exceptionally low odds ratio compared to APOE4/4, and the impact of APOE2 and APOE4 gene dose was significantly greater in the neuropathologically confirmed group than in more than 24,000 neuropathologically unconfirmed cases and controls. Finding and targeting the factors by which APOE and its variants influence Alzheimer's disease could have a major impact on the understanding, treatment and prevention of the disease.

View details for DOI 10.1038/s41467-019-14279-8

View details for PubMedID 32015339

Abstract

Cognitive impairment in Parkinson's disease (PD) is pervasive with potentially devastating effects. Identification of those at risk for cognitive decline is vital to identify and implement appropriate interventions. Robust multivariate approaches, including fixed-effect, mixed-effect, and multitask learning models, were used to study associations between biological, clinical, and cognitive factors and for predicting cognitive status longitudinally in a well-characterized prevalent PD cohort (n=827). Age, disease duration, sex, and GBA status were the primary biological factors associated with cognitive status and progression to dementia. Specific cognitive tests were better predictors of subsequent cognitive status for cognitively unimpaired and dementia groups. However, these models could not accurately predict future mild cognitive impairment (PD-MCI). Data collected from a large PD cohort thus revealed the primary biological and cognitive factors associated with dementia, and provide clinicians with data to aid in the identification of risk for dementia. Sex differences and their potential relationship to genetic status are also discussed.

View details for DOI 10.1038/s41531-020-00121-2

View details for PubMedID 34429432

Abstract

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

View details for DOI 10.1038/s41467-020-18044-0

View details for PubMedID 32820153

Abstract

Parkinson's disease is the second most common neurodegenerative disease after Alzheimer's disease and affects 1% of the population above 60 years old. Although Parkinson's disease commonly manifests with motor symptoms, a majority of patients with Parkinson's disease subsequently develop cognitive impairment, which often progresses to dementia, a major cause of morbidity and disability. Parkinson's disease is characterized by -synuclein accumulation that frequently associates with amyloid- and tau fibrils, the hallmarks of Alzheimer's disease neuropathological changes; this co-occurrence suggests that onset of cognitive decline in Parkinson's disease may be associated with appearance of pathological amyloid- and/or tau. Recent studies have highlighted the appearance of the soluble form of the triggering receptor expressed on myeloid cells 2 (sTREM2) receptor in CSF during development of Alzheimer's disease. Given the known association of microglial activation with advancing Parkinson's disease, we investigated whether CSF and/or plasma sTREM2 differed between CSF biomarker-defined Parkinson's disease participant subgroups. In this cross-sectional study, we examined 165 participants consisting of 17 cognitively normal elderly subjects, 45 patients with Parkinson's disease with no cognitive impairment, 86 with mild cognitive impairment, and 17 with dementia. Stratification of subjects by CSF amyloid- and tau levels revealed that CSF sTREM2 concentrations were elevated in Parkinson's disease subgroups with a positive tau CSF biomarker signature, but not in Parkinson's disease subgroups with a positive CSF amyloid- biomarker signature. These findings indicate that CSF sTREM2 could serve as a surrogate immune biomarker of neuronal injury in Parkinson's disease.

View details for DOI 10.1093/brain/awaa021

View details for PubMedID 32065223

Abstract

Artificial intelligence (AI) algorithms continue to rival human performance on a variety of clinical tasks, while their actual impact on human diagnosticians, when incorporated into clinical workflows, remains relatively unexplored. In this study, we developed a deep learning-based assistant to help pathologists differentiate between two subtypes of primary liver cancer, hepatocellular carcinoma and cholangiocarcinoma, on hematoxylin and eosin-stained whole-slide images (WSI), and evaluated its effect on the diagnostic performance of 11 pathologists with varying levels of expertise. Our model achieved accuracies of 0.885 on a validation set of 26 WSI, and 0.842 on an independent test set of 80 WSI. Although use of the assistant did not change the mean accuracy of the 11 pathologists (p=0.184, OR=1.281), it significantly improved the accuracy (p=0.045, OR=1.499) of a subset of nine pathologists who fell within well-defined experience levels (GI subspecialists, non-GI subspecialists, and trainees). In the assisted state, model accuracy significantly impacted the diagnostic decisions of all 11 pathologists. As expected, when the model's prediction was correct, assistance significantly improved accuracy (p=0.000, OR=4.289), whereas when the model's prediction was incorrect, assistance significantly decreased accuracy (p=0.000, OR=0.253), with both effects holding across all pathologist experience levels and case difficulty levels. Our results highlight the challenges of translating AI models into the clinical setting, and emphasize the importance of taking into account potential unintended negative consequences of model assistance when designing and testing medical AI-assistance tools.

View details for DOI 10.1038/s41746-020-0232-8

View details for PubMedID 32140566

View details for PubMedCentralID PMC7044422

Abstract

Purpose: Recently, the cerebellum's role in Parkinson's disease (PD) has been highlighted. Therefore, this study sought to test the hypothesis that functional connectivity (FC) between cerebellar and cortical nodes of the resting-state networks differentiates PD patients from controls by scanning participants at rest using functional magnetic resonance imaging (fMRI) and investigating connectivity of the cerebellar nodes of the resting-state networks. Materials and Methods: Sixty-two PD participants off medication for at least 12 h and 33 normal controls (NCs) were scanned at rest using blood oxygenation level-dependent fMRI scans. Motor and cognitive functions were assessed with the Movement Disorder Society's Revision of the Unified Parkinson's Disease Rating Scale III and Montreal Cognitive Assessment, respectively. Connectivity was investigated with cerebellar seeds defined by Buckner's 7-network atlas. Results: PD participants had significant differences in FC when compared to NC participants. Most notably, PD patients had higher FC between cerebellar nodes of the somatomotor network (SMN) and the corresponding cortical nodes. Cognitive functioning was differentially associated with connectivity of the cerebellar SMN and dorsal attention network. Further, cerebellar connectivity of frontoparietal and default mode networks correlated with the severity of motor function. Conclusion: Our study demonstrates altered cerebello-cortical FC in PD, as well as an association of this FC with PD-related motor and cognitive disruptions, thus providing additional evidence for the cerebellum's role in PD.

View details for DOI 10.3389/fneur.2020.594213

View details for PubMedID 33584497

Abstract

Artificial intelligence (AI) algorithms continue to rival human performance on a variety of clinical tasks, while their actual impact on human diagnosticians, when incorporated into clinical workflows, remains relatively unexplored. In this study, we developed a deep learning-based assistant to help pathologists differentiate between two subtypes of primary liver cancer, hepatocellular carcinoma and cholangiocarcinoma, on hematoxylin and eosin-stained whole-slide images (WSI), and evaluated its effect on the diagnostic performance of 11 pathologists with varying levels of expertise. Our model achieved accuracies of 0.885 on a validation set of 26 WSI, and 0.842 on an independent test set of 80 WSI. Although use of the assistant did not change the mean accuracy of the 11 pathologists (p=0.184, OR=1.281), it significantly improved the accuracy (p=0.045, OR=1.499) of a subset of nine pathologists who fell within well-defined experience levels (GI subspecialists, non-GI subspecialists, and trainees). In the assisted state, model accuracy significantly impacted the diagnostic decisions of all 11 pathologists. As expected, when the model's prediction was correct, assistance significantly improved accuracy (p=0.000, OR=4.289), whereas when the model's prediction was incorrect, assistance significantly decreased accuracy (p=0.000, OR=0.253), with both effects holding across all pathologist experience levels and case difficulty levels. Our results highlight the challenges of translating AI models into the clinical setting, and emphasize the importance of taking into account potential unintended negative consequences of model assistance when designing and testing medical AI-assistance tools.

View details for DOI 10.1038/s41746-020-0232-8

View details for PubMedID 33594170

Abstract

Cognitive impairment in Parkinson's disease (PD) is pervasive with potentially devastating effects. Identification of those at risk for cognitive decline is vital to identify and implement appropriate interventions. Robust multivariate approaches, including fixed-effect, mixed-effect, and multitask learning models, were used to study associations between biological, clinical, and cognitive factors and for predicting cognitive status longitudinally in a well-characterized prevalent PD cohort (n=827). Age, disease duration, sex, and GBA status were the primary biological factors associated with cognitive status and progression to dementia. Specific cognitive tests were better predictors of subsequent cognitive status for cognitively unimpaired and dementia groups. However, these models could not accurately predict future mild cognitive impairment (PD-MCI). Data collected from a large PD cohort thus revealed the primary biological and cognitive factors associated with dementia, and provide clinicians with data to aid in the identification of risk for dementia. Sex differences and their potential relationship to genetic status are also discussed.

View details for DOI 10.1038/s41531-020-00121-2

View details for PubMedID 32885039

View details for PubMedCentralID PMC7447766

Abstract

Imaging neurovascular disturbances in Parkinson's disease (PD) is an excellent measure of disease severity. Indeed, a disease-specific regional pattern of abnormal metabolism has been identified using positron emission tomography. Only a handful of studies, however, have applied perfusion MRI to detect this disease pattern. Our goal was to replicate the evaluation of a PD-related perfusion pattern using scaled subprofile modeling/principal component analysis (SSM-PCA).We applied arterial spin labeling (ASL) MRI for this purpose. Uniquely, we assessed this pattern separately in PD individuals ON and OFF dopamine medications. We further compared the existence of these patterns and their strength in each individual with their Movement Disorder Society-Unified Parkinson's Disease Rating Scale motor (MDS-UPDRS) scores, cholinergic tone as indexed by short-term afferent inhibition (SAI), and other neuropsychiatric tests.We observed a PD-related perfusion pattern that was similar to previous studies. The patterns were observed in both ON and OFF states but only the pattern in the OFF condition could significantly (AUC=0.72) differentiate between PD and healthy subjects. In the ON condition, PD subjects were similar to controls from a CBF standpoint (AUC=0.45). The OFF pattern prominently included the posterior cingulate, precentral region, precuneus, and the subcallosal cortex. Individual principal components from the ON and OFF states were strongly associated with MDS-UPDRS scores, SAI amplitude and latency.Using ASL, our study identified patterns of abnormal perfusion in PD and were associated with disease symptoms.

View details for DOI 10.1016/j.parkreldis.2020.05.014

View details for PubMedID 32559629

View details for DOI 10.1038/s41467-020-17148-x

Abstract

Background: Mobility and sensorimotor inhibition impairments are heterogeneous in Parkinson's disease (PD). Genetics may contribute to this heterogeneity since the apolipoprotein (APOE) 4 allele and glucocerebrosidase (GBA) gene variants have been related to mobility impairments in otherwise healthy older adult (OA) and PD cohorts. The purpose of this study is to determine if APOE or GBA genetic status affects sensorimotor inhibition and whether the relationship between sensorimotor inhibition and mobility differs in genetic sub-groups of PD. Methods: Ninety-three participants with idiopathic PD (53 non-carriers; 23 4 carriers; 17 GBA variants) and 72 OA (45 non-carriers; 27 4 carriers) had sensorimotor inhibition characterized by short-latency afferent inhibition. Mobility was assessed in four gait domains (pace/turning, rhythm, trunk, variability) and two postural sway domains (area/jerkiness and velocity) using inertial sensors. Results: Sensorimotor inhibition was worse in the PD than OA group, with no effect of genetic status. Gait pace/turning was slower and variability was higher (p < 0.01) in PD compared to OA. Postural sway area/jerkiness (p < 0.01) and velocity (p < 0.01) were also worse in the PD than OA group. Genetic status was not significantly related to any gait or postural sway domain. Sensorimotor inhibition was significantly correlated with gait variability (r = 0.27; p = 0.02) and trunk movement (r = 0.23; p = 0.045) in the PD group. In PD non-carriers, sensorimotor inhibition related to variability (r = 0.35; p = 0.010) and trunk movement (r = 0.31; p = 0.025). In the PD 4 group, sensorimotor inhibition only related to rhythm (r = 0.47; p = 0.024), while sensorimotor inhibition related to pace/turning (r = -0.49; p = 0.046) and rhythm (r = 0.59; p = 0.013) in the PD GBA group. Sensorimotor inhibition was significantly correlated with gait pace/turning (r = -0.27; p = 0.04) in the OA group. There was no relationship between sensorimotor inhibition and postural sway. Conclusion: 4 and GBA genetic status did not affect sensorimotor inhibition or mobility impairments in this PD cohort. However, worse sensorimotor inhibition was associated with gait variability in PD non-carriers, but with gait rhythm in PD 4 carriers and with gait rhythm and pace in PD with GBA variants. Impaired sensorimotor inhibition had a larger effect on mobility in people with PD than OA and affected different domains of mobility depending on genetic status.

View details for DOI 10.3389/fneur.2020.00893

View details for PubMedID 33013627

View details for PubMedCentralID PMC7498564

Abstract

OBJECTIVE: American Indians experience substantial health disparities relative to the US population, including vascular brain aging. Poorer cognitive test performance has been associated with cranial magnetic resonance imaging findings in aging community populations, but no study has investigated these associations in elderly American Indians.METHODS: We examined 786 American Indians aged 64 years and older from the Cerebrovascular Disease and its Consequences in American Indians study (2010-2013). Cranial magnetic resonance images were scored for cortical and subcortical infarcts, hemorrhages, severity of white matter disease, sulcal widening, ventricle enlargement, and volumetric estimates for white matter hyperintensities (WMHs), hippocampus, and brain. Participants completed demographic, medical history, and neuropsychological assessments including testing for general cognitive functioning, verbal learning and memory, processing speed, phonemic fluency, and executive function.RESULTS: Processing speed was independently associated with the presence of any infarcts, white matter disease, and hippocampal and brain volumes, independent of socioeconomic, language, education, and clinical factors. Other significant associations included general cognitive functioning with hippocampal volume. Nonsignificant, marginal associations included general cognition with WMH and brain volume; verbal memory with hippocampal volume; verbal fluency and executive function with brain volume; and processing speed with ventricle enlargement.CONCLUSIONS: Brain-cognition associations found in this study of elderly American Indians are similar to those found in other racial/ethnic populations, with processing speed comprising an especially strong correlate of cerebrovascular disease. These findings may assist future efforts to define opportunities for disease prevention, to conduct research on diagnostic and normative standards, and to guide clinical evaluation of this underserved and overburdened population.

View details for DOI 10.1017/S1355617719001073

View details for PubMedID 31791442

Abstract

Valid neuropsychological assessment is critical to the accurate diagnosis and effective treatment of diverse populations. American Indians and Alaska Natives experience substantial health disparities relative to the general U.S.Given the dearth of studies on neuropsychological health in this population, we aimed to characterize neuropsychological performance among older American Indians with respect to age, sex, education, income, and language use.From 2010 to 2014, we recruited 818 American Indians aged 60 and older from the Cerebrovascular Disease and Its Consequences in American Indians Study, who comprised all of the surviving members of a cardiovascular study (Strong Heart Study). This cohort from 11 tribes resided on or near their home reservations in three geographic regions (Northern Plains, Southern Plains, and Southwest). Using a cross-sectional design investigating potential vascular brain injury, we administered a brief, targeted neuropsychological and motor function assessments.Higher scores on neuropsychological tests were associated with younger age, female sex, more education, higher income, and less Native American language use. Similar associations were found for the motor tests, although men had higher scores on both motor function tests. After accounting for other sociocultural and health factors, age, sex, education, income, and Native American language use all had significant associations to the test scores.Our findings may be used to guide research and inform clinical practice. The development of future normative studies for older American Indians will be more culturally appropriate when sociocultural factors are included. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

View details for DOI 10.1037/neu0000574

View details for Web of Science ID 000494295100005

View details for PubMedID 31343235

Abstract

BACKGROUND: The Parkinson's Progression Markers Initiative (PPMI) is an ongoing observational, longitudinal cohort study of participants with Parkinson's disease, healthy controls, and carriers of the most common Parkinson's disease-related genetic mutations, which aims to define biomarkers of Parkinson's disease diagnosis and progression. All participants are assessed annually with a battery of motor and non-motor scales, 123-I Ioflupane dopamine transporter (DAT) imaging, and biological variables. We aimed to examine whether non-manifesting carriers of LRRK2 and GBA mutations have prodromal features of Parkinson's disease that correlate with reduced DAT binding.METHODS: This cross-sectional analysis is based on assessments done at enrolment in the subset of non-manifesting carriers of LRRK2 and GBA mutations enrolled into the PPMI study from 33 participating sites worldwide. The primary objective was to examine baseline clinical and DAT imaging characteristics in non-manifesting carriers with GBA and LRRK2 mutations compared with healthy controls. DAT deficit was defined as less than 65% of putamen striatal binding ratio expected for the individual's age. We used t tests, chi2 tests, and Fisher's exact tests to compare baseline demographics across groups. An inverse probability weighting method was applied to control for potential confounders such as age and sex. To account for multiple comparisons, we applied a family-wise error rate to each set of analyses. This study is registered with ClinicalTrials.gov, number NCT01141023.FINDINGS: Between Jan 1, 2014, and Jan 1, 2019, the study enrolled 208 LRRK2 (93% G2019S) and 184 GBA (96% N370S) non-manifesting carriers. Both groups were similar with respect to mean age, and about 60% were female. Of the 286 (73%) non-manifesting carriers that had DAT imaging results, 18 (11%) LRRK2 and four (3%) GBA non-manifesting carriers had a DAT deficit. Compared with healthy controls, both LRRK2 and GBA non-manifesting carriers had significantly increased mean scores on the Movement Disorders Society Unified Parkinson's Disease Rating Scale (total score 46 [SD 44] healthy controls vs 84 [73] LRRK2 vs 95 [92] GBA, p<00001 for both comparisons) and the Scale for Outcomes for PD - autonomic function (58 [37] vs 81 [59] and 84 [60], p<00001 for both comparisons). There was no difference in daytime sleepiness, anxiety, depression, impulsive-compulsive disorders, blood pressure, urate, and rapid eye movement (REM) behaviour disorder scores. Hyposmia was significantly more common only in LRRK2 non-manifesting carriers (69 [36%] of 194 healthy controls vs 114 [55%] of 208 LRRK2 non-manifesting carriers; p=00003). Finally, GBA but not LRRK2 non-manifesting carriers showed increased DAT striatal binding ratios compared with healthy controls in the caudate (healthy controls 298 [SD 063] vs GBA 326 [063]; p<00001), putamen (215 [056] vs 248 [052]; p<00001), and striatum (256 [057] vs 287 [055]; p<00001).INTERPRETATION: Our data show evidence of subtle motor and non-motor signs of Parkinson's disease in non-manifesting carriers compared with healthy controls that can precede DAT deficit. Longitudinal data will be essential to confirm these findings and define the trajectory and predictors for development of Parkinson's disease.FUNDING: Michael J Fox Foundation for Parkinson's Research.

View details for DOI 10.1016/S1474-4422(19)30319-9

View details for PubMedID 31678032

Abstract

Understanding tissue structure and function requires tools that quantify the expression of multiple proteins while preserving spatial information. Here, we describe MIBI-TOF (multiplexed ion beam imaging by time of flight), an instrument that uses bright ion sources and orthogonal time-of-flight mass spectrometry to image metal-tagged antibodies at subcellular resolution in clinical tissue sections. We demonstrate quantitative, full periodic table coverage across a five-log dynamic range, imaging 36 labeled antibodies simultaneously with histochemical stains and endogenous elements. We image fields of view up to 800 mum * 800 mum at resolutions down to 260 nm with sensitivities approaching single-molecule detection. We leverage these properties to interrogate intrapatient heterogeneity in tumor organization in triple-negative breast cancer, revealing regional variability in tumor cell phenotypes in contrast to a structured immune response. Given its versatility and sample back-compatibility, MIBI-TOF is positioned to leverage existing annotated, archival tissue cohorts to explore emerging questions in cancer, immunology, and neurobiology.

View details for DOI 10.1126/sciadv.aax5851

View details for PubMedID 31633026

Abstract

Autopsy measures of Alzheimer's disease neuropathology have been leveraged as endophenotypes in previous genome-wide association studies (GWAS). However, despite evidence of sex differences in Alzheimer's disease risk, sex-stratified models have not been incorporated into previous GWAS analyses. We looked for sex-specific genetic associations with Alzheimer's disease endophenotypes from six brain bank data repositories. The pooled dataset included 2701 males and 3275 females, the majority of whom were diagnosed with Alzheimer's disease at autopsy (70%). Sex-stratified GWAS were performed within each dataset and then meta-analysed. Loci that reached genome-wide significance (P < 5 * 10-8) in stratified models were further assessed for sex interactions. Additional analyses were performed in independent datasets leveraging cognitive, neuroimaging and CSF endophenotypes, along with age-at-onset data. Outside of the APOE region, one locus on chromosome 7 (rs34331204) showed a sex-specific association with neurofibrillary tangles among males (P = 2.5 * 10-8) but not females (P = 0.85, sex-interaction P = 2.9 * 10-4). In follow-up analyses, rs34331204 was also associated with hippocampal volume, executive function, and age-at-onset only among males. These results implicate a novel locus that confers male-specific protection from tau pathology and highlight the value of assessing genetic associations in a sex-specific manner.

View details for DOI 10.1093/brain/awz206

View details for PubMedID 31497858

Abstract

Previous systems-based proteomic approaches have characterized alterations in protein co-expression networks of unfractionated asymptomatic (AsymAD) and symptomatic Alzheimer's disease (AD) brains. However, it remains unclear how sample fractionation and sub-proteomic analysis influences the organization of these protein networks and their relationship to clinicopathological traits of disease. In this proof-of-concept study, we performed a systems-based sub-proteomic analysis of membrane-enriched post-mortem brain samples from pathology-free control, AsymAD, and AD brains (n = 6 per group). Label-free mass spectrometry based on peptide ion intensity was used to quantify the 18 membrane-enriched fractions. Differential expression and weighted protein co-expression network analysis (WPCNA) were then used to identify and characterize modules of co-expressed proteins most significantly altered between the groups. We identified a total of 27 modules of co-expressed membrane-associated proteins. In contrast to the unfractionated proteome, these networks did not map strongly to cell-type specific markers. Instead, these modules were principally organized by their associations with a wide variety of membrane-bound compartments and organelles. Of these, the mitochondrion was associated with the greatest number of modules, followed by modules linked to the cell surface compartment. In addition, we resolved networks with strong associations to the endoplasmic reticulum, Golgi apparatus, and other membrane-bound organelles. A total of 14 of the 27 modules demonstrated significant correlations with clinical and pathological AD phenotypes. These results revealed that the proteins within individual compartments feature a heterogeneous array of AD-associated expression patterns, particularly during the preclinical stages of disease. In conclusion, this systems-based analysis of the membrane-associated AsymAD brain proteome yielded a unique network organization highly linked to cellular compartmentalization. Further study of this membrane-associated proteome may reveal novel insight into the complex pathways governing the earliest stages of disease.

View details for DOI 10.3390/proteomes7030030

View details for PubMedID 31461916

Abstract

OBJECTIVES: Many survivors of sepsis suffer long-term cognitive impairment, but the mechanisms of this association remain unknown. The objective of this study was to determine whether sepsis is associated with cerebral microinfarcts on brain autopsy.DESIGN: Retrospective cohort study.SETTING AND SUBJECTS: Five-hundred twenty-nine participants of the Adult Changes in Thought, a population-based prospective cohort study of older adults carried out in Kaiser Permanente Washington greater than or equal to 65 years old without dementia at study entry and who underwent brain autopsy.MEASUREMENTS AND MAIN RESULTS: Late-life sepsis hospitalization was identified using administrative data. We identified 89 individuals with greater than or equal to 1 sepsis hospitalization during study participation, 80 of whom survived hospitalization and died a median of 169 days after discharge. Thirty percent of participants with one or more sepsis hospitalization had greater than two microinfarcts, compared with 19% participants without (chi p = 0.02); 20% of those with sepsis hospitalization had greater than two microinfarcts in the cerebral cortex, compared with 10% of those without (chi p = 0.01). The adjusted relative risk of greater than two microinfarcts was 1.61 (95% CI, 1.01-2.57; p = 0.04); the relative risk for having greater than two microinfarcts in the cerebral cortex was 2.12 (95% CI, 1.12-4.02; p = 0.02). There was no difference in Braak stage for neurofibrillary tangles or consortium to establish a registry for Alzheimer's disease score for neuritic plaques between, but Lewy bodies were less significantly common in those with sepsis.CONCLUSIONS: Sepsis was specifically associated with moderate to severe vascular brain injury as assessed by microvascular infarcts. This association was stronger for microinfarcts within the cerebral cortex, with those who experienced severe sepsis hospitalization being more than twice as likely to have evidence of moderate to severe cerebral cortical injury in adjusted analyses. Further study to identify mechanisms for the association of sepsis and microinfarcts is needed.

View details for DOI 10.1097/CCM.0000000000003924

View details for PubMedID 31389836

Abstract

Objective: Given the known strong relationship of DNA methylation with environmental exposure, we investigated whether brain regions affected in Parkinson disease (PD) were differentially methylated between PD cases and controls.Methods: DNA chip arrays were used to perform a genome-wide screen of DNA methylation on the dorsal motor nucleus of the vagus (DMV), substantia nigra (SN), and cingulate gyrus (CG) of pathologically confirmed PD cases and controls selected using the criteria of Beecham et al. Analysis examined differentially methylated regions (DMRs) between cases and controls for each brain area. RNA sequencing and pathway analysis were also performed for each brain area.Results: Thirty-eight PD cases and 41 controls were included in the analysis. Methylation studies revealed 234 significant DMR in the DMV, 44 in the SN, and 141 in the CG between cases and controls (Sidak p < 0.05). Pathway analysis of these genes showed significant enrichment for the Wnt signaling pathway (FDR < 0.01).Conclusions: Our data suggest that significant DNA methylation changes exist between cases and controls in PD, especially in the DMV, one of the areas affected earliest in PD. The etiology of these methylation changes is not yet known, but the predominance of methylation changes occurring in the DMV supports the hypothesis that vagus nerve function, perhaps involving the gastrointestinal system, is important in PD pathogenesis. These data also give independent support that genes involved in Wnt signaling are a likely factor in the neurodegenerative processes of PD.

View details for DOI 10.1212/NXG.0000000000000342

View details for PubMedID 31403079

View details for DOI 10.1093/brain/awz226

View details for PubMedID 31359039

View details for DOI 10.1002/gps.5108

View details for Web of Science ID 000471829900017

View details for Web of Science ID 000472806000230

View details for DOI 10.1093/brain/awz099

View details for Web of Science ID 000481419700013

Abstract

Both functional connectivity (FC) and blood oxygen level-dependent (BOLD) signal variability (SDBOLD) are methods to examine the physiological state of the brain. Although they are derived from signal changes and are related, few studies have explored their relationship. Here, we examined the relationship between SDBOLD and FC within the default mode network (DMN) in participants with Parkinson's disease ON and OFF dopaminergic medications. Dopaminergic medications had profound effects on both DMN FC and SDBOLD measured separately. Analyzing DMN FC and SDBOLD in a joint independent component analysis, we identified joint components of DMN FC and SDBOLD that were separately associated with measurements of motor and cognitive impairment. Dopaminergic medications had a differential effect on these components depending on these measures of disease severity, "normalizing" the relationships. Importantly, we show that dopaminergic medication status matters in imaging PD; and can affect both connectivity and SDBOLD. Imaging PD ON may lead to inflated estimates of SDBOLD and diminish the ability to measure changes associated with declining motor and cognitive capacities.

View details for DOI 10.1089/brain.2019.0677

View details for PubMedID 31131605

Abstract

OBJECTIVES: Insulin resistance is a substantial health issue for American Indians, with type 2 diabetes overrepresented in this population as compared to non-Hispanic whites. Insulin resistance and its related conditions in turn increase risk for dementia and cognitive impairment. The aim of the current study was to determine whether type 2 diabetes and insulin resistance at midlife was associated with later life cognitive testing in a large sample of older American Indians, aged 65 and over.METHODS: American Indian participants who underwent both fasting blood draw as part of the Strong Heart Study and had subsequent cognitive testing as part of the later adjunct Cerebrovascular Disease and its Consequences in American Indians study were included (n=790). Regression models examined type 2 diabetes and impaired fasting glucose and subsequent cognitive test performance as part of a longitudinal study design. The relationship between a continuous measure of insulin resistance and later cognitive test performance was assessed using generalized estimating equations.RESULTS: Controlling for demographic and clinical factors, verbal fluency and processing speed/working memory were significantly negatively associated with having type 2 diabetes and with insulin resistance, but not with impaired fasting glucose.CONCLUSION: In this sample of American Indians, type 2 diabetes at midlife was associated with subsequent lower performance on measures of executive function. These results may have important implications for future implementation of diagnostic and intervention services in this population.

View details for PubMedID 30924200

Abstract

The study of cognition in Parkinson's disease (PD) traditionally requires exhaustive recruitment strategies. The current study examines data collected by the Brain Health Registry (BHR) to determine whether ongoing efforts to improve the recruitment base for therapeutic trials in Alzheimer's disease may be similarly effective for PD research, and whether online cognitive measurements can discriminate between participants who do and do not report a PD diagnosis. Participants enrolled in the BHR (age 50) with self-reported PD data and online cognitive testing available were included (n=11,813). Associations between baseline cognitive variables and diagnostic group were analyzed using logistic regression. Linear mixed effects models were used to analyze longitudinal data. A total of 634 participants reported PD diagnosis at baseline with no self-reported cognitive impairment and completed cognitive testing. Measures of visual learning and memory, processing speed, attention, and working memory discriminated between self-reported PD and non-PD participants after correcting for multiple comparisons (p values< 0.006). Scores on all cognitive tests improved over time in PD and controls with the exception of processing speed, which remained stable in participants with PD while improving in those without. We demonstrate that a novel online approach to recruitment and longitudinal follow-up of study participants is effective for those with self-reported PD, and that significant differences exist between those with and without a reported diagnosis of PD on computerized cognitive measures. These results have important implications for recruitment of participants with PD into targeted therapeutic trials or large-scale genetic and cognitive studies.

View details for PubMedID 30909225

Abstract

A primary goal of research in cognitive impairment and dementia is to understand how some individuals retain sufficient cognitive function for a fulfilling life while many others are robbed of their independence, sometimes their essence, in the last years and decades of life. In this commentary, we propose operational definitions of the types of factors that may help individuals retain cognitive function with aging. We propose operational definitions of resistance, resilience, reserve, with an eye toward how these may be measured and interpreted, and how they may enable research aimed at prevention. With operational definitions and quantification of resistance, resilience, and reserve, a focused analytic search for their determinants and correlates can be undertaken. This approach, essentially a search to identify protective risk factors and their mechanisms, represents a relatively unexplored pathway toward the identification of candidate preventive interventions.

View details for PubMedID 30857563

View details for DOI 10.1186/s13195-019-0479-y

View details for Web of Science ID 000460874900001

View details for PubMedID 30784550

View details for DOI 10.1016/S1474-4422(19)30020-1

View details for Web of Science ID 000458509100014

Abstract

BACKGROUND: Clinicians and researchers commonly use global cognitive assessments to screen for impairment. Currently there are no published studies directly comparing the sensitivity and specificity of the Montreal Cognitive Assessment and Mattis Dementia Rating Scale-2 in PD. The objective of this study was to identify the relative sensitivity and specificity of the Montreal Cognitive Assessment and Mattis Dementia Rating Scale-2 in PD.METHODS: The Montreal Cognitive Assessment and Mattis Dementia Rating Scale-2 were administered to training and validation cohorts. Cutoff scores were determined within the training cohort (n = 85) to optimize sensitivity and specificity for cognitive impairment and were applied to an independent validation cohort (n = 521).RESULTS: The Montreal Cognitive Assessment was consistently sensitive across training and validation cohorts (90.0% and 80.3%, respectively), whereas the Mattis Dementia Rating Scale-2 was not (87.5% and 60.3%, respectively). In individual domains, the Montreal Cognitive Assessment remained sensitive to memory and visuospatial impairments (91.9% and 87.8%, respectively), whereas the Mattis Dementia Rating Scale-2 was sensitive to executive impairments (86.2%).CONCLUSION: The Montreal Cognitive Assessment and Mattis Dementia Rating Scale-2 demonstrated individual strengths. Future work should focus on developing domain-specific cognitive screening tools for PD. 2018 International Parkinson and Movement Disorder Society.

View details for PubMedID 30776152

View details for DOI 10.1002/mds.27575

View details for Web of Science ID 000458973000016

Abstract

To explore genetic and lifestyle risk factors of MRI-defined brain infarcts (BI) in large population-based cohorts.We performed meta-analyses of genome-wide association studies (GWAS) and examined associations of vascular risk factors and their genetic risk scores (GRS) with MRI-defined BI and a subset of BI, namely, small subcortical BI (SSBI), in 18 population-based cohorts (n = 20,949) from 5 ethnicities (3,726 with BI, 2,021 with SSBI). Top loci were followed up in 7 population-based cohorts (n = 6,862; 1,483 with BI, 630 with SBBI), and we tested associations with related phenotypes including ischemic stroke and pathologically defined BI.The mean prevalence was 17.7% for BI and 10.5% for SSBI, steeply rising after age 65. Two loci showed genome-wide significant association with BI: FBN2, p = 1.77 10-8; and LINC00539/ZDHHC20, p = 5.82 10-9. Both have been associated with blood pressure (BP)-related phenotypes, but did not replicate in the smaller follow-up sample or show associations with related phenotypes. Age- and sex-adjusted associations with BI and SSBI were observed for BP traits (p value for BI, p[BI] = 9.38 10-25; p[SSBI] = 5.23 10-14 for hypertension), smoking (p[BI] = 4.4 10-10; p[SSBI] = 1.2 10-4), diabetes (p[BI] = 1.7 10-8; p[SSBI] = 2.8 10-3), previous cardiovascular disease (p[BI] = 1.0 10-18; p[SSBI] = 2.3 10-7), stroke (p[BI] = 3.9 10-69; p[SSBI] = 3.2 10-24), and MRI-defined white matter hyperintensity burden (p[BI] = 1.43 10-157; p[SSBI] = 3.16 10-106), but not with body mass index or cholesterol. GRS of BP traits were associated with BI and SSBI (p 0.0022), without indication of directional pleiotropy.In this multiethnic GWAS meta-analysis, including over 20,000 population-based participants, we identified genetic risk loci for BI requiring validation once additional large datasets become available. High BP, including genetically determined, was the most significant modifiable, causal risk factor for BI.

View details for DOI 10.1212/WNL.0000000000006851

View details for Web of Science ID 000462547500009

View details for PubMedID 30651383

View details for PubMedCentralID PMC6369905

View details for DOI 10.1016/j.jneumeth.2018.11.008

View details for Web of Science ID 000456220900009

View details for DOI 10.3233/JAD-181009

View details for Web of Science ID 000464031500013

View details for DOI 10.1016/j.jalz.2018.06.3057

View details for Web of Science ID 000455493000010

View details for DOI 10.1016/j.jalz.2018.11.002

View details for Web of Science ID 000455493000012

Abstract

Here, we present unprocessed and preprocessed Attention Network Test data from 25 adults with Parkinson's disease and 21 healthy adults, along with the associated defaced structural scans. The preprocessed data has been processed with a provided Analysis of Functional NeuroImages afni_proc.py script and includes structural scans that were skull-stripped before defacing. All acquired demographic and neuropsychological data are included.

View details for DOI 10.12688/f1000research.19288.1

View details for PubMedID 32477494

Abstract

Alzheimer's disease (AD) differentially and specifically affects brain regions and neuronal cell types in a predictable pattern. Damage to the brain appears to spread and worsens with time, taking over more regions and activating multiple stressors that can converge to promote vulnerability of certain cell types. At the same time, other cell types and brain regions remain intact in the face of this onslaught of neuropathology. Although neuropathologic descriptions of AD have been extensively expanded and mapped over the last several decades, our understanding of the mechanisms underlying how certain regions and cell populations are specifically vulnerable or resistant has lagged behind. In this review, we detail what is known about the selectivity of local initiation of AD pathology in the hippocampus, its proposed spread via synaptic connections, and the diversity of clinical phenotypes and brain atrophy patterns that may arise from different fibrillar strains of pathologic proteins orgenetic predispositions. We summarize accumulated and emerging knowledge of the cellular and molecular basis for neuroanatomic selectivity, consider potential disease-relevant differences between vulnerable and resistant neuronal cell types and isolatemolecular markers to identify them.

View details for DOI 10.1007/s00401-019-02054-4

View details for PubMedID 31392412

View details for PubMedID 30642435

Abstract

We describe a recently recognized disease entity, limbic-predominant age-related TDP-43 encephalopathy (LATE). LATE neuropathological change (LATE-NC) is defined by a stereotypical TDP-43 proteinopathy in older adults, with or without coexisting hippocampal sclerosis pathology. LATE-NC is a common TDP-43 proteinopathy, associated with an amnestic dementia syndrome that mimicked Alzheimer's-type dementia in retrospective autopsy studies. LATE is distinguished from frontotemporal lobar degeneration with TDP-43 pathology based on its epidemiology (LATE generally affects older subjects), and relatively restricted neuroanatomical distribution of TDP-43 proteinopathy. In community-based autopsy cohorts, 25% of brains had sufficient burden of LATE-NC to be associated with discernible cognitive impairment. Many subjects with LATE-NC have comorbid brain pathologies, often including amyloid- plaques and tauopathy. Given that the 'oldest-old' are at greatest risk for LATE-NC, and subjects of advanced age constitute a rapidly growing demographic group in many countries, LATE has an expanding but under-recognized impact on public health. For these reasons, a working group was convened to develop diagnostic criteria for LATE, aiming both to stimulate research and to promote awareness of this pathway to dementia. We report consensus-based recommendations including guidelines for diagnosis and staging of LATE-NC. For routine autopsy workup of LATE-NC, an anatomically-based preliminary staging scheme is proposed with TDP-43 immunohistochemistry on tissue from three brain areas, reflecting a hierarchical pattern of brain involvement: amygdala, hippocampus, and middle frontal gyrus. LATE-NC appears to affect the medial temporal lobe structures preferentially, but other areas also are impacted. Neuroimaging studies demonstrated that subjects with LATE-NC also had atrophy in the medial temporal lobes, frontal cortex, and other brain regions. Genetic studies have thus far indicated five genes with risk alleles for LATE-NC: GRN, TMEM106B, ABCC9, KCNMB2, and APOE. The discovery of these genetic risk variants indicate that LATE shares pathogenetic mechanisms with both frontotemporal lobar degeneration and Alzheimer's disease, but also suggests disease-specific underlying mechanisms. Large gaps remain in our understanding of LATE. For advances in prevention, diagnosis, and treatment, there is an urgent need for research focused on LATE, including in vitro and animal models. An obstacle to clinical progress is lack of diagnostic tools, such as biofluid or neuroimaging biomarkers, for ante-mortem detection of LATE. Development of a disease biomarker would augment observational studies seeking to further define the risk factors, natural history, and clinical features of LATE, as well as eventual subject recruitment for targeted therapies in clinical trials.

View details for PubMedID 31039256

Abstract

Improved prediction of Parkinson's disease (PD) progression is needed to support clinical decision-making and to accelerate research trials.To examine whether baseline measures and their 1-year change predict longer-term progression in early PD.Parkinson's Progression Markers Initiative study data were used. Participants had disease duration 2 years, abnormal dopamine transporter (DAT) imaging, and were untreated with PD medications. Baseline and 1-year change in clinical, cerebrospinal fluid (CSF), and imaging measures were evaluated as candidate predictors of longer-term (up to 5 years) change in Movement Disorders Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) score and DAT specific binding ratios (SBR) using linear mixed-effects models.Among 413 PD participants, median follow-up was 5 years. Change in MDS-UPDRS from year-2 to last follow-up was associated with disease duration (=0.351; 95% CI=0.146, 0.555), male gender (=3.090; 95% CI=0.310, 5.869), and baseline (=-0.199; 95% CI=-0.315, -0.082) and 1-year change (=0.540; 95% CI=0.423, 0.658) in MDS-UPDRS; predictors in the model accounted for 17.6% of the variance in outcome. Predictors of percent change in mean SBR from year-2 to last follow-up included baseline rapid eye movement sleep behavior disorder score (=-0.6229; 95% CI=-1.2910, 0.0452), baseline (=7.232; 95% CI=2.268, 12.195) and 1-year change (=45.918; 95% CI=35.994,55.843) in mean striatum SBR, and 1-year change in autonomic symptom score (=-0.325;95% CI=-0.695, 0.045); predictors in the model accounted for 44.1% of the variance.Baseline clinical, CSF, and imaging measures in early PD predicted change in MDS-UPDRS and dopamine-transporter binding, but the predictive value of the models was low. Adding the short-term change of possible predictors improved the predictive value, especially for modeling change in dopamine-transporter binding.

View details for DOI 10.3233/JPD-181518

View details for Web of Science ID 000489899800003

View details for PubMedID 31450510

Abstract

Introduction: Cognitive impairment is a common complication of Parkinson's disease (PD) and identifying risk factors for progression to Parkinson's disease dementia (PDD) is important. However, little research has been done comparing the utility of commonly used cognitive screening tests in predicting cognitive progression in PD.Methods: We retrospectively reviewed data from patients with PD enrolled in the Pacific Udall Center who had baseline and longitudinal neuropsychological and global cognitive screening tests. The diagnostic accuracies of 3 common screening tests were compared: Montreal Cognitive Assessment (MoCA), Mattis Dementia Rating Scale (DRS-2), and Mini Mental Status Examination (MMSE). Cognitive diagnoses of PD with mild cognitive impairment (PD-MCI) and PDD were based on full neuropsychological testing and established Movement Disorder Society criteria. Logistic regression and Cox proportional hazards regression models were used to examine predictors of cognitive decline.Results: Four hundred seventy patients for whom scores on all 3 screening tests were available from the same assessment were included in a cross-sectional analysis. The MoCA demonstrated the best overall diagnostic accuracy for PD-MCI (AUC= 0.79, sensitivity= 76.4%) and for PDD (AUC= 0.89, sensitivity= 81.0%) compared to the DRS-2 and MMSE. A longitudinal analysis was performed on the subset of patients (316/470; 67.2%) who were nondemented at baseline and had undergone two or more assessments. After controlling for covariates, the MoCA was the only test associated with progression to PDD (OR= 1.27 95% CI 1.1 - 1.5, p=0.001) and faster time to dementia (HR = 1.3, 95% CI 1.1 - 1.4, p<0.0001).Conclusions: This study provides additional support for the use of the MoCA as a primary screening tool for cognitive impairment in PD and is the first to show that the MoCA is a predictor of conversion to PDD.

View details for DOI 10.1016/j.prdoa.2019.08.006

View details for PubMedID 32368733

Abstract

Gait and balance impairments are cardinal features of Parkinson's disease (PD) that require cognitive input. However, the extent to which specific gait and balance characteristics relate to cognition in PD is unclear. In addition, independent models of gait and balance have not been developed from the same cohort. We aimed to i) develop models of gait and balance in a large PD cohort and ii) determine which gait and balance characteristics best related to cognition.One hundred and ninety-eight people with PD were recruited to the Pacific Udall Center. Using six inertial sensors (APDM, Inc.), comprehensive gait measurements were collected over a 2-min continuous walk and comprehensive static balance measures were collected during a 60-second standing task. Six domains of cognition were assessed: global cognition, attention, executive function, language, memory, and visuospatial function. Correlations and hierarchical linear regression determined independent associations.Principal components analysis identified a gait model containing four domains accounting for 80.1% of total variance: pace/turning, rhythm, variability, and trunk. The balance model contained four independent domains accounting for 84.5% of total variance: sway area/jerkiness, sway velocity, sway frequency anteroposterior, and sway frequency mediolateral. Gait domains of pace/turning and variability were strongly associated with attention and executive function. Sway area and jerkiness of balance associated with attention and visuospatial function.Gait and balance characteristics were associated with specific types of cognition. The specific relationships between gait or balance with cognitive functions suggests shared cerebral cortical circuitry for mobility and cognitive functions.

View details for DOI 10.1016/j.parkreldis.2019.06.014

View details for PubMedID 31731260

Abstract

Introduction: Cognitive impairment is a common symptom of Parkinson's disease (PD) associated with reduced quality of life and a more severe disease state. Previous research has shown an association between visuospatial dysfunction and worse disease course; however, it is not clear whether this is separable from executive dysfunction and/or dementia. This study sought to determine whether distinct cognitive factors could be measured in a large PD cohort, and if those factors were differentially associated with other PD-related features, specifically to provide insight into visuospatial dysfunction. Methods: Non-demented participants with PD from the Pacific Udall Center were enrolled (n=197). Co-participants (n=104) completed questionnaires when available. Principal components factor analysis (PCFA) was utilized to group the neuropsychological test scores into independent factors by considering those with big factor loading (.40). Linear and logistic regression analyses were performed to examine the relationship between the cognitive factors identified in the PCFA and other clinical features of PD. Results: Six factors were extracted from the PCFA: 1) executive/processing speed, 2) visual learning & memory/visuospatial, 3) auditory working memory, 4) contextual verbal memory, 5) semantic learning & memory, and 6) visuospatial. Motor severity (p=0.001), mood (p<0.001), and performance on activities of daily living scores (informant: p <0.001, patient: p =0.009) were primarily associated with frontal and executive factors. General sleep disturbance (p<0.006) and hallucinations (p=0.002) were primarily associated with visuospatial functioning and visual learning/memory. Conclusions: Motor symptoms, mood, and performance on activities of daily living were primarily associated with frontal/executive factors. Sleep disturbance and hallucinations were associated with visuospatial functioning and visual learning/memory only, over and above executive functioning and regardless of cognitive disease severity. These findings support that visuospatial function in PD may indicate a more severe disease course, and that symptom management should be guided accordingly.

View details for DOI 10.1080/13803395.2019.1623180

View details for PubMedID 31177941

Abstract

Cerebrospinal fluid (CSF) levels of amyloid- 42 (A42) and tau have been evaluated as endophenotypes in Alzheimer's disease (AD) genetic studies. Although there are sex differences in AD risk, sex differences have not been evaluated in genetic studies of AD endophenotypes. We performed sex-stratified and sex interaction genetic analyses of CSF biomarkers to identify sex-specific associations. Data came from a previous genome-wide association study (GWAS) of CSF A42 and tau (1527 males, 1509 females). We evaluated sex interactions at previous loci, performed sex-stratified GWAS to identify sex-specific associations, and evaluated sex interactions at sex-specific GWAS loci. We then evaluated sex-specific associations between prefrontal cortex (PFC) gene expression at relevant loci and autopsy measures of plaques and tangles using data from the Religious Orders Study and Rush Memory and Aging Project. In A42, we observed sex interactions at one previous and one novel locus: rs316341 within SERPINB1 (p=0.04) and rs13115400 near LINC00290 (p=0.002). These loci showed stronger associations among females (=-0.03, p=4.2510-8; =0.03, p=3.9710-8) than males (=-0.02, p=0.009; =0.01, p=0.20). Higher levels of expression of SERPINB1, SERPINB6, and SERPINB9 in PFC was associated with higher levels of amyloidosis among females (corrected p values<0.02) but not males (p>0.38). In total tau, we observed a sex interaction at a previous locus, rs1393060 proximal to GMNC (p=0.004), driven by a stronger association among females (=0.05, p=4.5710-10) compared to males (=0.02, p=0.03). There was also a sex-specific association between rs1393060 and tangle density at autopsy (pfemale=0.047; pmale=0.96), and higher levels of expression of two genes within this locus were associated with lower tangle density among females (OSTN p=0.006; CLDN16 p=0.002) but not males (p0.32). Results suggest a female-specific role for SERPINB1 in amyloidosis and for OSTN and CLDN16 in tau pathology. Sex-specific genetic analyses may improve understanding of AD's genetic architecture.

View details for PubMedID 29967939

View details for PubMedCentralID PMC6280657

Abstract

INTRODUCTION: Nonhuman primates may serve as excellent models of sporadic age-associated brain beta-amyloid deposition and Alzheimer's disease pathologic changes. We examined whether a vervet nonhuman primate model recapitulated pathologic, physiologic, and behavioral features of early Alzheimer's disease.METHODS: Nine middle-aged (mean=11.2 years) and nine aged (mean=21.7 years) female vervet/African green monkeys underwent cerebrospinal fluid collection, gait speed measurement, and neuroimaging before neuropathologic assessment.RESULTS: beta-amyloid plaques were identified in all aged vervets and paired helical filament tau immunoreactivity was observed in all animals. Cerebrospinal fluid beta-amyloid42 and gait speed correlated negatively with age and plaque density. Greater plaque and paired helical filament tau burden predicted reduced volumes and CMRg in several brain regions.DISCUSSION: We observed a coordinated set of relationships among neuropathologic, cerebrospinal fluid, imaging, and behavioral modalities consistent with early Alzheimer's disease. Our results support future use of the vervet model to explore disease mechanisms, biomarkers, and novel therapeutic strategies.

View details for PubMedID 30467082

Abstract

BACKGROUND: Synaptic alterations, especially presynaptic changes, are cardinal features of neurodegenerative diseases and strongly correlate with cognitive decline.NEW METHOD: We report "Mass Synaptometry" for the high-dimensional analysis of individual human synaptosomes, enriched nerve terminals from brain. This method was adapted from cytometry by time-of-flight mass spectrometry (CyTOF), which is commonly used for single-cell analysis of immune and blood cells.RESULT: Here we overcome challenges for single synapse analysis by optimizing synaptosome preparations, generating a 'SynTOF panel,' recalibrating acquisition settings, and applying computational analyses. Through the analysis of 390,000 individual synaptosomes, we also provide proof-of principle validation by characterizing changes in synaptic diversity in Lewy Body Disease (LBD), Alzheimer's disease and normal brain.COMPARISON WITH EXISTING METHOD(S): Current imaging methods to study synapses in humans are capable of analyzing a limited number of synapses, and conventional flow cytometric techniques are typically restricted to fewer than 6 parameters. Our method allows for the simultaneous detection of 34 parameters from tens of thousands of individual synapses.CONCLUSION: We applied Mass Synaptometry to analyze 34 parameters simultaneously on more than 390,000 synaptosomes from 13 human brain samples. This new approach revealed regional and disease-specific changes in synaptic phenotypes, including validation of this method with the expected changes in the molecular composition of striatal dopaminergic synapses in Lewy body disease and Alzheimer's disease. Mass synaptometry enables highly parallel molecular profiling of individual synaptic terminals.

View details for PubMedID 30465796

Abstract

Neurodegenerative diseases, the most common among them Alzheimer's disease (AD) and Lewy body disease (LBD), are a group of progressive incurable illnesses. In both AD and LBD, abundant evidence points to the synapse as the critical and early focus of pathological changes. Here we present a method for the isolation and flow cytometric analysis of synaptosomes prepared from postmortem human brain tissue, which we also applied to animal models, including mice and nonhuman primates. The use of flow cytometry for analysis allows for relatively fast and efficient examination of thousands of synaptosome particles in a matter of minutes, and also makes it possible to use crude, rather than purified, synaptosomal preparation, thus conserving tissue resources. We have applied this method to study synaptic alteration in several brain regions in human research participants and animal models.

View details for DOI 10.1007/978-1-4939-8739-9_17

View details for PubMedID 32139977

View details for PubMedCentralID PMC7058378

View details for DOI 10.1016/j.parkreldis.2018.02.007

View details for Web of Science ID 000433273100006

View details for DOI 10.1007/978-1-4939-8739-9_17

View details for Web of Science ID 000463584900019

View details for DOI 10.3233/JAD-180162

View details for Web of Science ID 000457776400021

Abstract

The Alzheimer's Disease Sequencing Project (ADSP) used different criteria for assigning case and control status from the discovery and replication phases of the project. We considered data from a community-based prospective cohort study with autopsy follow-up where participants could be categorized as case, control, or neither by both definitions and compared the two sets of criteria.We used data from the Adult Changes in Thought (ACT) study including Diagnostic and Statistical Manual-IV criteria for dementia status, McKhann etal. criteria for clinical Alzheimer's disease, and Braak and Consortium to Establish a Registry for AD findings on neurofibrillary tangles and neuritic plaques to categorize the 621 ACT participants of European ancestry who died and came to autopsy. We applied ADSP discovery and replication definitions to identify controls, cases, and people who were neither controls nor cases.There was some agreement between the discovery and replication definitions. Major areas of discrepancy included the finding that only 40% of the discovery sample controls had sufficiently low levels of neurofibrillary tangles and neuritic plaques to be considered controls by the replication criteria and the finding that 16% of the replication phase cases were diagnosed with non-AD dementia during life and thus were excluded as cases for the discovery phase.These findings should inform interpretation of genetic association findings from the ADSP. Differences in genetic association findings between the two phases of the study may reflect these different phenotype definitions from the discovery and replication phase of the ADSP.

View details for DOI 10.1016/j.jalz.2017.09.010

View details for PubMedID 29055816

View details for PubMedCentralID PMC5723534

Abstract

The Dementia with Lewy Bodies (DLB) Consortium has refined its recommendations about the clinical and pathologic diagnosis of DLB, updating the previous report, which has been in widespread use for the last decade. The revised DLB consensus criteria now distinguish clearly between clinical features and diagnostic biomarkers, and give guidance about optimal methods to establish and interpret these. Substantial new information has been incorporated about previously reported aspects of DLB, with increased diagnostic weighting given to REM sleep behavior disorder and 123iodine-metaiodobenzylguanidine (MIBG) myocardial scintigraphy. The diagnostic role of other neuroimaging, electrophysiologic, and laboratory investigations is also described. Minor modifications to pathologic methods and criteria are recommended to take account of Alzheimer disease neuropathologic change, to add previously omitted Lewy-related pathology categories, and to include assessments for substantia nigra neuronal loss. Recommendations about clinical management are largely based upon expert opinion since randomized controlled trials in DLB are few. Substantial progress has been made since the previous report in the detection and recognition of DLB as a common and important clinical disorder. During that period it has been incorporated into DSM-5, as major neurocognitive disorder with Lewy bodies. There remains a pressing need to understand the underlying neurobiology and pathophysiology of DLB, to develop and deliver clinical trials with both symptomatic and disease-modifying agents, and to help patients and carers worldwide to inform themselves about the disease, its prognosis, best available treatments, ongoing research, and how to get adequate support.

View details for DOI 10.1212/WNL.0000000000004058

View details for Web of Science ID 000404516800017

View details for PubMedID 28592453

View details for PubMedCentralID PMC5496518

Abstract

This study sought to evaluate gender and APOE genotype-related differences in the concentrations of cerebrospinal fluid (CSF) biomarkers for Alzheimer's disease (AD) and cerebrovascular injury across the life span of cognitively normal adults.CSF amyloid beta1-42 (A42), phospho-tau-181 (p-tau181), and total tau were measured in 331 participants who were between the ages of 21 and 100. CSF E-selectin and vascular cell adhesion protein 1 (VCAM1) were measured in 249 participants who were between the ages of 50 and 100.CSF total tau and p-tau181 increased with age over the adult life span (p<0.01) with no gender differences in those increases. CSF A42 concentration varied according to age, gender, and APOE genotype (interaction of agegender4, p=0.047). CSF VCAM1, but not E-selectin, increased with age (p<0.01), but both were elevated in men compared to women (p<0.01).Female APOE-4 carriers appear at higher risk for AD after age 50. In contrast, men may experience a relatively higher rate of cerebrovascular injury in middle and early old age.

View details for DOI 10.1186/s13195-017-0271-9

View details for PubMedID 28673336

View details for PubMedCentralID PMC5496132

View details for Web of Science ID 000404906900168

View details for Web of Science ID 000404906900061

Abstract

Two population-based studies key to advancing knowledge of brain aging are the Honolulu-Asia Aging Study (HAAS) and the Nun Study. Harmonization of their neuropathologic data allows cross comparison, with findings common to both studies likely generalizable, while distinct observations may point to aging brain changes that are dependent on sex, ethnicity, environment, or lifestyle factors. Here, we expanded the neuropathologic evaluation of these 2 studies using revised NIA-Alzheimer's Association guidelines and compared directly the neuropathologic features of resistance and apparent cognitive resilience. There were significant differences in prevalence of Alzheimer disease neuropathologic change, small vessel vascular brain injury, and Lewy body disease between these 2 studies, suggesting that sex, ethnicity, and lifestyle factors may significantly influence resistance to developing brain injury with age. In contrast, hippocampal sclerosis prevalence was very similar, but skewed to poorer cognitive performance, suggesting that hippocampal sclerosis could act sequentially with other diseases to impair cognitive function. Strikingly, despite these observed differences, the proportion of individuals resistant to all 4 diseases of brain or displaying apparent cognitive resilience was virtually identical between HAAS and Nun Study participants. Future in vivo validation of these results awaits comprehensive biomarkers of these 4 brain diseases.

View details for DOI 10.1093/jnen/nlx030

View details for PubMedID 28499012

View details for Web of Science ID 000404949903030

Abstract

Estimates of hippocampal volume by magnetic resonance imaging have clinical and cognitive correlations and can assist in early Alzheimer disease diagnosis. However, little is known about the relationship between global or regional brain volumes and cognitive test performance in American Indians.American Indian participants (N=698; median age, 72 y) recruited for the Cerebrovascular Disease and its Consequences in American Indians study, an ancillary study of the Strong Heart Study cohort, were enrolled. Linear regression models assessed the relationship between magnetic resonance imaging brain volumes (total brain and hippocampi) and cognitive measures of verbal learning and recall, processing speed, verbal fluency, and global cognition.After controlling for demographic and clinical factors, all volumetric measurements were positively associated with processing speed. Total brain volume was also positively associated with verbal learning, but not with verbal recall. Conversely, left hippocampal volume was associated with both verbal learning and recall. The relationship between hippocampal volume and recall performance was more pronounced among those with lower scores on a global cognitive measure. Controlling for APOE 4 did not substantively affect the associations.These results support further investigation into the relationship between structural Alzheimer disease biomarkers, cognition, genetics, and vascular risk factors in aging American Indians.

View details for DOI 10.1097/WAD.0000000000000203

View details for Web of Science ID 000401899300002

View details for PubMedID 28538087

Abstract

Neurofibrillary tangles (NFTs), composed of hyperphosphorylated tau, are a key pathologic feature of Alzheimer's disease (AD). Tau phosphorylation is under the control of multiple kinases and phosphatases, including Fyn. Previously, our group found an association between 2 regulatory single nucleotide polymorphisms in the FYN gene with increased tau levels in the cerebrospinal fluid. In this study, we hypothesized that Fyn expression in the brain is influenced by AD status and genetic content. We found that Fyn protein, but not messenger RNA, levels were increased in AD patients compared to cognitively normal controls and are associated with regulatory region single nucleotide polymorphisms. In addition, the expression of the FYN 3'UTR can decrease expression in multiple cell lines, suggesting this regulatory region plays an important role in FYN expression. Taken together, these data suggest that FYN expression is regulated according to AD status and regulatory region haplotype, and genetic variants may be instrumental in the development of neurofibrillary tangles in AD and other tauopathies.

View details for DOI 10.1016/j.neurobiolaging.2016.11.001

View details for PubMedID 28033507

View details for PubMedCentralID PMC5358011

Abstract

Cognitive impairment in older individuals is a complex trait that in population-based studies most commonly derives from an individually varying mixture of Alzheimer disease, Lewy body disease, and vascular brain injury. We investigated the molecular composition of synaptic particles from three sources: consecutive rapid autopsy brains from the Adult Changes in Thought Study, a population-based cohort; four aged nonhuman primate brains optimally processed for molecular investigation; and targeted replacement transgenic mice homozygous for APOE 4. Our major goal was to characterize the molecular composition of human synaptic particles in regions of striatum and prefrontal cortex. We performed flow cytometry to measure six markers of synaptic subtypes, as well as amyloid 42 and paired helical filament tau. Our results showed selective degeneration of dopaminergic terminals throughout the striatum in individuals with Lewy body disease, and serotonergic degeneration in human ventromedial caudate nucleus from individuals with an APOE 4 allele. Similar results were seen in mouse caudate nucleus homozygous for APOE 4 via targeted replacement. Together, extension of these clinical, pathologic, and genetic associations from tissue to the synaptic compartment of cerebral cortex and striatum strongly supports our approach for accurately observing the molecular composition of human synapses by flow cytometry.

View details for DOI 10.1016/j.ajpath.2016.12.010

View details for PubMedID 28212814

View details for PubMedCentralID PMC5397713

Abstract

Genetic loci for Alzheimer's disease (AD) have been identified in whites of European ancestry, but the genetic architecture of AD among other populations is less understood.We conducted a transethnic genome-wide association study (GWAS) for late-onset AD in Stage 1 sample including whites of European Ancestry, African-Americans, Japanese, and Israeli-Arabs assembled by the Alzheimer's Disease Genetics Consortium. Suggestive results from Stage 1 from novel loci were followed up using summarized results in the International Genomics Alzheimer's Project GWAS dataset.Genome-wide significant (GWS) associations in single-nucleotide polymorphism (SNP)-based tests (P<5 10(-8)) were identified for SNPs in PFDN1/HBEGF, USP6NL/ECHDC3, and BZRAP1-AS1 and for the interaction of the (apolipoprotein E) APOE 4 allele with NFIC SNP. We also obtained GWS evidence (P<2.7 10(-6)) for gene-based association in the total sample with a novel locus, TPBG (P=1.8 10(-6)).Our findings highlight the value of transethnic studies for identifying novel AD susceptibility loci.

View details for DOI 10.1016/j.jalz.2016.12.012

View details for PubMedID 28183528

Abstract

Concerns regarding resource expenditures have been expressed about the 2012 NIA-AA Sponsored Guidelines for neuropathologic assessment of Alzheimer disease (AD) and related dementias. Here, we investigated a cost-reducing Condensed Protocol and its effectiveness in maintaining the diagnostic performance of Guidelines in assessing AD, Lewy body disease (LBD), microvascular brain injury, hippocampal sclerosis (HS), and congophilic amyloid angiopathy (CAA). The Condensed Protocol consolidates the same 20 regions into 5 tissue cassettes at 75% lower cost. A 28 autopsy brain-retrospective cohort was selected for varying levels of neuropathologic features in the Guidelines (Original Protocol), as well as an 18 consecutive autopsy brain prospective cohort. Three neuropathologists at 2 sites performed blinded evaluations of these cases. Lesion specificity was similar between Original and Condensed Protocols. Sensitivities for AD neuropathologic change, LBD, HS, and CAA were not substantially impacted by the Condensed Protocol, whereas sensitivity for microvascular lesions (MVLs) was decreased. Specificity for CAA was decreased using the Condensed Protocol when compared with the Original Protocol. Our results show that the Condensed Protocol is a viable alternative to the NIA-AA guidelines for AD neuropathologic change, LBD, and HS, but not MVLs or CAA, and may be a practical alternative in some practice settings.

View details for DOI 10.1093/jnen/nlw104

View details for PubMedID 28062571

Abstract

Great heterogeneity exists in survival and the interval between onset of motor symptoms and dementia symptoms across synucleinopathies. We aimed to identify genetic and pathological markers that have the strongest association with these features of clinical heterogeneity in synucleinopathies.In this retrospective study, we examined symptom onset, and genetic and neuropathological data from a cohort of patients with Lewy body disorders with autopsy-confirmed synucleinopathy (as of Oct 1, 2015) who were previously included in other studies from five academic institutions in five cities in the USA. We used histopathology techniques and markers to assess the burden of tau neurofibrillary tangles, neuritic plaques, -synuclein inclusions, and other pathological changes in cortical regions. These samples were graded on an ordinal scale and genotyped for variants associated with synucleinopathies. We assessed the interval from onset of motor symptoms to onset of dementia, and overall survival in groups with varying levels of comorbid Alzheimer's disease pathology according to US National Institute on Aging-Alzheimer's Association neuropathological criteria, and used multivariate regression to control for age at death and sex.On the basis of data from 213 patients who had been followed up to autopsy and met inclusion criteria of Lewy body disorder with autopsy-confirmed synucleinopathy, we identified 49 (23%) patients with no Alzheimer's disease neuropathology, 56 (26%) with low-level Alzheimer's disease neuropathology, 45 (21%) with intermediate-level Alzheimer's disease neuropathology, and 63 (30%) with high-level Alzheimer's disease neuropathology. As levels of Alzheimer's disease neuropathology increased, cerebral -synuclein scores were higher, and the interval between onset of motor and dementia symptoms and disease duration was shorter (p<00001 for all comparisons). Multivariate regression showed independent negative associations of cerebral tau neurofibrillary tangles score with the interval between onset of motor and dementia symptoms ( -40, 95% CI -55 to -26; p<00001; R(2) 022, p<00001) and with survival (-20, -32 to -08; 0003; 015, <00001) in models that included age at death, sex, cerebral neuritic plaque scores, cerebral -synuclein scores, presence of cerebrovascular disease, MAPT haplotype, and APOE genotype as covariates.Alzheimer's disease neuropathology is common in synucleinopathies and confers a worse prognosis for each increasing level of neuropathological change. Cerebral neurofibrillary tangles burden, in addition to -synuclein pathology and amyloid plaque pathology, are the strongest pathological predictors of a shorter interval between onset of motor and dementia symptoms and survival. Diagnostic criteria based on reliable biomarkers for Alzheimer's disease neuropathology in synucleinopathies should help to identify the most appropriate patients for clinical trials of emerging therapies targeting tau, amyloid- or synuclein, and to stratify them by level of Alzheimer's disease neuropathology.US National Institutes of Health (National Institute on Aging and National Institute of Neurological Disorders and Stroke).

View details for PubMedID 27979356

View details for DOI 10.1016/B978-0-12-804239-7.00055-X

View details for Web of Science ID 000463378100055

Abstract

Idiopathic normal pressure hydrocephalus (INPH) is a neurologic disease that affects <1% of those aged >65 years, but is difficult to distinguish from other diseases that present in this age group, such as Alzheimer's disease. Large volume lumbar puncture and an external lumbar drain trial (ELD) are used to make a clinical diagnosis of INPH, but the accuracy of ELD is suspected.To investigate proteomic cerebrospinal fluid (CSF) biomarker patterns in patients with INPH undergoing ELD to develop a quantitative diagnostic.Twenty patients with suspected INPH underwent an ELD trial and the CSF biomarkers AB1-42, total tau, and tau phosphorylated at amino acid 181 (p-tau) were quantified with immunoassays in specimens taken prior to ELD placement, after the ELD trial, and from ventricular samples collected at the time of permanent ventriculoperitoneal shunt placement.CSF total tau was elevated, on average, in pre- and post-ELD samples from patients who failed to improve clinically during the ELD trial, but the findings were marginally significant after correction for multiple comparisons. AB1-42 and p-tau concentrations were not significantly different in patients who either did or did not clinically improve after the ELD.CSF total tau is a potential novel biomarker for suspected INPH patients who will clinically improve, or have clinically improved, after an ELD trial. The small sample size of this study, which was due to the relative rarity of this condition, indicates that larger studies are needed to confirm the utility of this approach.

View details for PubMedID 28652949

View details for PubMedCentralID PMC5481176

Abstract

We characterized the relationship between late life cholesterol exposure and neuropathological outcomes in a community-based, older adult cohort. Adult Changes in Thought (ACT) is a cohort study that enrolls consenting, randomly selected, non-demented people aged 65 from a healthcare delivery system. We used late life HDL and total cholesterol lab values from Group Health computerized records, and calculated HDL and non-HDL levels. We evaluated neuropathological outcomes of Alzheimer's disease, cerebral amyloid angiopathy, vascular brain injury, and Lewy body disease. Using linear mixed models with age and antilipemic medication as predictors, we obtained predicted cholesterol values at age 70 and 10 years prior to death for individuals with available cholesterol data in 10-year exposure windows. We used logistic regression to determine whether predicted late life cholesterol levels were associated with neuropathological outcomes controlling for age at death, APOE genotype, sex, and their interactions with cholesterol levels. 525 decedents came to autopsy by 08/2014. Of these, plasma cholesterol concentration was available for 318 (age 70, model 1) and 396 (10 years prior to death, model 2) participants. We did not find associations between late life cholesterol and Alzheimer's disease neuropathological changes, and there were no associations between cholesterol levels and amyloid angiopathy or vascular brain injury. We observed an association between predicted non-HDL cholesterol at age 70 and Lewy body disease. Our study suggests an association between late life non-HDL cholesterol exposure and Lewy body disease. We did not observe associations between late life cholesterol levels and Braak stage or CERAD score.

View details for PubMedID 28731431

View details for PubMedCentralID PMC5604311

Abstract

Opioids may influence the development of Alzheimer's disease (AD). Some studies have observed AD pathology in the brains of opioid abusers. No study has examined the association between prescription opioid use and dementia-related neuropathologic changes.To examine the relationship between prescription opioid or NSAID use and dementia-related neuropathologic changes.Within a community-based autopsy cohort (N=420), we ascertained opioid and nonsteroidal anti-inflammatory drug (NSAID) use over a 10-year period from automated pharmacy data and calculated total standardized daily doses (TSDDs). A neuropathologist assessed outcomes including neuritic plaques, neurofibrillary tangles, and macroscopic infarcts. Outcome measures were dichotomized using established cutpoints. We used modified Poisson regression to calculate adjusted relative risks (RR) and 95% confidence intervals (CI), accounting for participant characteristics and using weighting to account for possible selection bias related to selection into the autopsy sample.Heavier opioid exposure was not associated with greater neuropathologic changes. For neuritic plaques, the adjusted RR [95% CI] was 0.99 [0.64-1.47] for 91+ TSDDs of opioids versus little to no use, and for neurofibrillary tangles, 0.97 [0.49-1.78]. People with heavy NSAID use had higher risk of neuritic plaques (RR 1.39 [1.01-1.89]) than those with little to no use, as we have previously reported. Neither opioid nor NSAID use was associated with higher risk of macroscopic infarcts or with Lewy body disease.Prescription opioid use is not associated with dementia-related neuropathologic changes, but heavy NSAID use may be. More research is needed examining chronic pain, its pharmacologic treatments, and neuropathologic changes.

View details for DOI 10.3233/JAD-160374

View details for PubMedID 28453469

Abstract

We present Omni-ATAC, an improved ATAC-seq protocol for chromatin accessibility profiling that works across multiple applications with substantial improvement of signal-to-background ratio and information content. The Omni-ATAC protocol generates chromatin accessibility profiles from archival frozen tissue samples and 50-m sections, revealing the activities of disease-associated DNA elements in distinct human brain structures. The Omni-ATAC protocol enables the interrogation of personal regulomes in tissue context and translational studies.

View details for PubMedID 28846090

Abstract

Long acting insulin detemir administered intranasally for three weeks enhanced memory for adults with Alzheimer's disease dementia (AD) or amnestic mild cognitive impairment (MCI). The investigation of longer-term administration is necessary to determine whether benefits persist, whether they are similar to benefits provided by regular insulin, and whether either form of insulin therapy affects AD biomarkers.The present study aimed to determine whether four months of treatment with intranasal insulin detemir or regular insulin improves cognition, daily functioning, and AD biomarkers for adults with MCI or AD.This randomized, double-blind, placebo-controlled trial included an intent-to-treat sample consisting of 36 adults diagnosed with MCI or mild to moderate AD. Participants received placebo (n=12), 40 IU of insulin detemir (n=12), or 40 IU of regular insulin (n=12) daily for four months, administered with a nasal delivery device. A cognitive battery was administered at baseline and after two and four months of treatment. MRI was administered for all participants and lumbar puncture for a subset (n=20) at baseline and four months. The primary outcome was change from baseline to four months on a memory composite (sum of Z scores for delayed list and story recall). Secondary outcomes included: global cognition (Alzheimer's Disease Assessment Scale-Cognition), daily functioning (Dementia Severity Rating Scale), MRI volume changes in AD-related regions of interest, and cerebrospinal fluid AD markers.The regular insulin treated group had better memory after two and four months compared with placebo (p<0.03). No significant effects were observed for the detemir-assigned group compared with the placebo group, or for daily functioning for either group. Regular insulin treatment was associated with preserved volume on MRI. Regular insulin treatment was also associated with reduction in the tau-P181/A42 ratio.Future research is warranted to examine the mechanistic basis of treatment differences, and to further assess the efficacy and safety of intranasal insulin.

View details for DOI 10.3233/JAD-161256

View details for Web of Science ID 000399933800028

View details for PubMedID 28372335

Abstract

IN BRIEF There has been a concurrent dramatic rise in type 2 diabetes and dementia in the United States, and type 2 diabetes shares common genetic and environmental risk factors and underlying pathology with both vascular and Alzheimer's dementias. Given the ability to identify this at-risk population and a variety of potential targeted treatments, type 2 diabetes represents a promising focus for a precision health approach to reduce the impact of cognitive decline and dementia in older adults.

View details for PubMedID 27899872

Abstract

Improving survival and extending the longevity of life for all populations requires timely, robust evidence on local mortality levels and trends. The Global Burden of Disease 2015 Study (GBD 2015) provides a comprehensive assessment of all-cause and cause-specific mortality for 249 causes in 195 countries and territories from 1980 to 2015. These results informed an in-depth investigation of observed and expected mortality patterns based on sociodemographic measures.We estimated all-cause mortality by age, sex, geography, and year using an improved analytical approach originally developed for GBD 2013 and GBD 2010. Improvements included refinements to the estimation of child and adult mortality and corresponding uncertainty, parameter selection for under-5 mortality synthesis by spatiotemporal Gaussian process regression, and sibling history data processing. We also expanded the database of vital registration, survey, and census data to 14294 geography-year datapoints. For GBD 2015, eight causes, including Ebola virus disease, were added to the previous GBD cause list for mortality. We used six modelling approaches to assess cause-specific mortality, with the Cause of Death Ensemble Model (CODEm) generating estimates for most causes. We used a series of novel analyses to systematically quantify the drivers of trends in mortality across geographies. First, we assessed observed and expected levels and trends of cause-specific mortality as they relate to the Socio-demographic Index (SDI), a summary indicator derived from measures of income per capita, educational attainment, and fertility. Second, we examined factors affecting total mortality patterns through a series of counterfactual scenarios, testing the magnitude by which population growth, population age structures, and epidemiological changes contributed to shifts in mortality. Finally, we attributed changes in life expectancy to changes in cause of death. We documented each step of the GBD 2015 estimation processes, as well as data sources, in accordance with Guidelines for Accurate and Transparent Health Estimates Reporting (GATHER).Globally, life expectancy from birth increased from 617 years (95% uncertainty interval 614-619) in 1980 to 718 years (715-722) in 2015. Several countries in sub-Saharan Africa had very large gains in life expectancy from 2005 to 2015, rebounding from an era of exceedingly high loss of life due to HIV/AIDS. At the same time, many geographies saw life expectancy stagnate or decline, particularly for men and in countries with rising mortality from war or interpersonal violence. From 2005 to 2015, male life expectancy in Syria dropped by 113 years (37-174), to 626 years (565-702). Total deaths increased by 41% (26-56) from 2005 to 2015, rising to 558 million (549 million to 566 million) in 2015, but age-standardised death rates fell by 170% (158-181) during this time, underscoring changes in population growth and shifts in global age structures. The result was similar for non-communicable diseases (NCDs), with total deaths from these causes increasing by 141% (126-160) to 398 million (392 million to 405 million) in 2015, whereas age-standardised rates decreased by 131% (119-143). Globally, this mortality pattern emerged for several NCDs, including several types of cancer, ischaemic heart disease, cirrhosis, and Alzheimer's disease and other dementias. By contrast, both total deaths and age-standardised death rates due to communicable, maternal, neonatal, and nutritional conditions significantly declined from 2005 to 2015, gains largely attributable to decreases in mortality rates due to HIV/AIDS (421%, 391-446), malaria (431%, 347-518), neonatal preterm birth complications (298%, 248-349), and maternal disorders (291%, 193-371). Progress was slower for several causes, such as lower respiratory infections and nutritional deficiencies, whereas deaths increased for others, including dengue and drug use disorders. Age-standardised death rates due to injuries significantly declined from 2005 to 2015, yet interpersonal violence and war claimed increasingly more lives in some regions, particularly in the Middle East. In 2015, rotaviral enteritis (rotavirus) was the leading cause of under-5 deaths due to diarrhoea (146000 deaths, 118000-183000) and pneumococcal pneumonia was the leading cause of under-5 deaths due to lower respiratory infections (393000 deaths, 228000-532000), although pathogen-specific mortality varied by region. Globally, the effects of population growth, ageing, and changes in age-standardised death rates substantially differed by cause. Our analyses on the expected associations between cause-specific mortality and SDI show the regular shifts in cause of death composition and population age structure with rising SDI. Country patterns of premature mortality (measured as years of life lost [YLLs]) and how they differ from the level expected on the basis of SDI alone revealed distinct but highly heterogeneous patterns by region and country or territory. Ischaemic heart disease, stroke, and diabetes were among the leading causes of YLLs in most regions, but in many cases, intraregional results sharply diverged for ratios of observed and expected YLLs based on SDI. Communicable, maternal, neonatal, and nutritional diseases caused the most YLLs throughout sub-Saharan Africa, with observed YLLs far exceeding expected YLLs for countries in which malaria or HIV/AIDS remained the leading causes of early death.At the global scale, age-specific mortality has steadily improved over the past 35 years; this pattern of general progress continued in the past decade. Progress has been faster in most countries than expected on the basis of development measured by the SDI. Against this background of progress, some countries have seen falls in life expectancy, and age-standardised death rates for some causes are increasing. Despite progress in reducing age-standardised death rates, population growth and ageing mean that the number of deaths from most non-communicable causes are increasing in most countries, putting increased demands on health systems.Bill & Melinda Gates Foundation.

View details for Web of Science ID 000385285000007

View details for PubMedCentralID PMC5388903

Abstract

Detergent insoluble inclusions of TDP-43 protein are hallmarks of the neuropathology in over 90% of amyotrophic lateral sclerosis (ALS) cases and approximately half of frontotemporal dementia (FTLD-TDP) cases. In TDP-43 proteinopathy disorders, lesions containing aggregated TDP-43 protein are extensively post-translationally modified, with phosphorylated TDP-43 (pTDP) being the most consistent and robust marker of pathological TDP-43 deposition. Abnormally phosphorylated TDP-43 has been hypothesized to mediate TDP-43 toxicity in many neurodegenerative disease models. To date, several different kinases have been implicated in the genesis of pTDP, but no phosphatases have been shown to reverse pathological TDP-43 phosphorylation. We have identified the phosphatase calcineurin as an enzyme binding to and catalyzing the removal of pathological C-terminal phosphorylation of TDP-43 in vitro. In C. elegans models of TDP-43 proteinopathy, genetic elimination of calcineurin results in accumulation of excess pTDP, exacerbated motor dysfunction, and accelerated neurodegenerative changes. In cultured human cells, treatment with FK506 (tacrolimus), a calcineurin inhibitor, results in accumulation of pTDP species. Lastly, calcineurin co-localizes with pTDP in degenerating areas of the central nervous system in subjects with FTLD-TDP and ALS. Taken together, these findings suggest calcineurin acts on pTDP as a phosphatase in neurons. Furthermore, patient treatment with calcineurin inhibitors may have unappreciated adverse neuropathological consequences.

View details for DOI 10.1007/s00401-016-1600-y

View details for PubMedID 27473149

View details for PubMedCentralID PMC5026939

Abstract

The late effects of traumatic brain injury (TBI) are of great interest, but studies characterizing these effects are limited.To determine whether TBI with loss of consciousness (LOC) is associated with an increased risk for clinical and neuropathologic findings of Alzheimer disease (AD), Parkinson disease (PD), and other dementias.This study analyzed data from the Religious Orders Study (ROS), Memory and Aging Project (MAP), and Adult Changes in Thought study (ACT). All ROS and MAP participants and a subset of ACT participants consent to autopsy. Studies performed annual (ROS and MAP) or biennial (ACT) cognitive and clinical testing to identify incident cases of dementia and AD. The 7130 participants included members of a Seattle-area health care delivery system (ACT), priests and nuns living in orders across the United States (ROS), and Chicago-area adults in retirement communities (MAP). Of these, 1589 underwent autopsy. Primary hypothesis was that TBI with LOC would be associated with increased risk for AD and neurofibrillary tangles. Data were accrued from 1994 to April 1, 2014.Self-reported TBI when the participant was free of dementia, categorized as no more than 1 vs more than 1 hour of LOC.Clinical outcomes included incident all-cause dementia, AD, and PD in all studies and incident mild cognitive impairment and progression of parkinsonian signs in ROS and MAP. Neuropathologic outcomes included neurofibrillary tangles, neuritic plaques, microinfarcts, cystic infarcts, Lewy bodies, and hippocampal sclerosis in all studies.Of 7130 participants (2879 [40.4%] men; overall mean [SD] age, 79.9 [6.9] years), 865 reported a history of TBI with LOC. In 45190 person-years of follow-up, 1537 incident cases of dementia and 117 of PD were identified. No association was found between TBI with LOC and incident dementia (ACT: HR for TBI with LOC 1 hour, 1.03; 95% CI, 0.83-1.27; HR for TBI with LOC >1 hour, 1.18; 95% CI, 0.77-1.78; ROS and MAP: HR for TBI with LOC 1 hour, 0.87; 95% CI, 0.58-1.29; HR for TBI with LOC >1 hour, 0.84; 95% CI, 0.44-1.57) or AD (findings similar to those for dementia). Associations were found for TBI with LOC and incident PD in ACT (HR for TBI with LOC >1 hour, 3.56; 95% CI, 1.52-8.28) and progression of parkinsonian signs in ROS and MAP (odds ratio [OR] for TBI with LOC 1 hour, 1.65; 95% CI, 1.23-2.21; OR for TBI with LOC >1 hour, 2.23; 95% CI, 1.16-4.29). Traumatic brain injury with LOC was associated with Lewy bodies (any Lewy body in ACT: RR for TBI with LOC >1 hour, 2.64; 95% CI, 1.40-4.99; Lewy bodies in substantia nigra and/or locus ceruleus in ACT: RR for TBI with LOC >1 hour, 3.30; 95% CI, 1.71-6.38; Lewy bodies in frontal or temporal cortex in ACT: RR for TBI with LOC >1 hour, 5.73; 95% CI, 2.18-15.0; ROS and MAP: RR for TBI with LOC 1 hour, 1.64; 95% CI, 1.00-2.70; pooled RR for TBI with LOC 1 hour, 1.59; 95% CI, 1.06-2.39) and microinfarcts (any cortical microinfarct in ROS and MAP: RR for TBI with LOC >1 hour, 2.12; 95% CI, 1.12-4.01; pooled RR for TBI with LOC >1 hour, 1.58; 95% CI, 1.06-2.35).Pooled clinical and neuropathologic data from 3 prospective cohort studies indicate that TBI with LOC is associated with risk for Lewy body accumulation, progression of parkinsonism, and PD, but not dementia, AD, neuritic plaques, or neurofibrillary tangles.

View details for DOI 10.1001/jamaneurol.2016.1948

View details for PubMedID 27400367

Abstract

Alzheimer's disease (AD) is the leading cause of dementia and mitigating amyloid- (A) levels may serve as a rational therapeutic avenue to slow AD progression. Pharmacologic inhibition of the Rho-associated protein kinases (ROCK1 and ROCK2) is proposed to curb A levels, and mechanisms that underlie ROCK2's effects on A production are defined. How ROCK1 affects A generation remains a critical barrier. Here, we report that ROCK1 protein levels were elevated in mild cognitive impairment due to AD (MCI) and AD brains compared to controls. A42 oligomers marginally increased ROCK1 and ROCK2 protein levels in neurons but strongly induced phosphorylation of Lim kinase 1 (LIMK1), suggesting that A42 activates ROCKs. RNAi depletion of ROCK1 or ROCK2 suppressed endogenous A40 production in neurons, and A40 levels were reduced in brains of ROCK1 heterozygous knock-out mice compared to wild-type littermate controls. ROCK1 knockdown decreased amyloid precursor protein (APP), and treatment with bafilomycin accumulated APP levels in neurons depleted of ROCK1. These observations suggest that reduction of ROCK1 diminishes A levels by enhancing APP protein degradation. Collectively, these findings support the hypothesis that both ROCK1 and ROCK2 are therapeutic targets to combat A production in AD. Mitigating amyloid- (A) levels is a rational strategy for Alzheimer's disease (AD) treatment, however, therapeutic targets with clinically available drugs are lacking. We hypothesize that A accumulation in mild cognitive impairment because of AD (MCI) and AD activates the RhoA/ROCK pathway which in turn fuels production of A. Escalation of this cycle over the course of many years may contribute to the buildup of amyloid pathology in MCI and/or AD.

View details for DOI 10.1111/jnc.13688

View details for PubMedID 27246255

View details for PubMedCentralID PMC4980252

Abstract

Mitochondrial dysfunction and oxidative damage are commonly associated with early stage Alzheimer disease (AD). The accumulation of somatic mutations in mitochondrial DNA (mtDNA) has been hypothesized to be a driver of these phenotypes, but the detection of increased mutation loads has been difficult due to a lack of sensitive methods. We used an ultrasensitive next generation sequencing technique to measure the mutation load of the entire mitochondrial genome. Here, we report a significant increase in the mtDNA mutation frequency in the hippocampus of early stage AD, with the cause of these mutations being consistent with replication errors and not oxidative damage. Ann Neurol 2016;80:301-306.

View details for DOI 10.1002/ana.24709

View details for PubMedID 27315116

View details for PubMedCentralID PMC4982791

Abstract

Improving survival and extending the longevity of life for all populations requires timely, robust evidence on local mortality levels and trends. The Global Burden of Disease 2015 Study (GBD 2015) provides a comprehensive assessment of all-cause and cause-specific mortality for 249 causes in 195 countries and territories from 1980 to 2015. These results informed an in-depth investigation of observed and expected mortality patterns based on sociodemographic measures.We estimated all-cause mortality by age, sex, geography, and year using an improved analytical approach originally developed for GBD 2013 and GBD 2010. Improvements included refinements to the estimation of child and adult mortality and corresponding uncertainty, parameter selection for under-5 mortality synthesis by spatiotemporal Gaussian process regression, and sibling history data processing. We also expanded the database of vital registration, survey, and census data to 14294 geography-year datapoints. For GBD 2015, eight causes, including Ebola virus disease, were added to the previous GBD cause list for mortality. We used six modelling approaches to assess cause-specific mortality, with the Cause of Death Ensemble Model (CODEm) generating estimates for most causes. We used a series of novel analyses to systematically quantify the drivers of trends in mortality across geographies. First, we assessed observed and expected levels and trends of cause-specific mortality as they relate to the Socio-demographic Index (SDI), a summary indicator derived from measures of income per capita, educational attainment, and fertility. Second, we examined factors affecting total mortality patterns through a series of counterfactual scenarios, testing the magnitude by which population growth, population age structures, and epidemiological changes contributed to shifts in mortality. Finally, we attributed changes in life expectancy to changes in cause of death. We documented each step of the GBD 2015 estimation processes, as well as data sources, in accordance with Guidelines for Accurate and Transparent Health Estimates Reporting (GATHER).Globally, life expectancy from birth increased from 617 years (95% uncertainty interval 614-619) in 1980 to 718 years (715-722) in 2015. Several countries in sub-Saharan Africa had very large gains in life expectancy from 2005 to 2015, rebounding from an era of exceedingly high loss of life due to HIV/AIDS. At the same time, many geographies saw life expectancy stagnate or decline, particularly for men and in countries with rising mortality from war or interpersonal violence. From 2005 to 2015, male life expectancy in Syria dropped by 113 years (37-174), to 626 years (565-702). Total deaths increased by 41% (26-56) from 2005 to 2015, rising to 558 million (549 million to 566 million) in 2015, but age-standardised death rates fell by 170% (158-181) during this time, underscoring changes in population growth and shifts in global age structures. The result was similar for non-communicable diseases (NCDs), with total deaths from these causes increasing by 141% (126-160) to 398 million (392 million to 405 million) in 2015, whereas age-standardised rates decreased by 131% (119-143). Globally, this mortality pattern emerged for several NCDs, including several types of cancer, ischaemic heart disease, cirrhosis, and Alzheimer's disease and other dementias. By contrast, both total deaths and age-standardised death rates due to communicable, maternal, neonatal, and nutritional conditions significantly declined from 2005 to 2015, gains largely attributable to decreases in mortality rates due to HIV/AIDS (421%, 391-446), malaria (431%, 347-518), neonatal preterm birth complications (298%, 248-349), and maternal disorders (291%, 193-371). Progress was slower for several causes, such as lower respiratory infections and nutritional deficiencies, whereas deaths increased for others, including dengue and drug use disorders. Age-standardised death rates due to injuries significantly declined from 2005 to 2015, yet interpersonal violence and war claimed increasingly more lives in some regions, particularly in the Middle East. In 2015, rotaviral enteritis (rotavirus) was the leading cause of under-5 deaths due to diarrhoea (146000 deaths, 118000-183000) and pneumococcal pneumonia was the leading cause of under-5 deaths due to lower respiratory infections (393000 deaths, 228000-532000), although pathogen-specific mortality varied by region. Globally, the effects of population growth, ageing, and changes in age-standardised death rates substantially differed by cause. Our analyses on the expected associations between cause-specific mortality and SDI show the regular shifts in cause of death composition and population age structure with rising SDI. Country patterns of premature mortality (measured as years of life lost [YLLs]) and how they differ from the level expected on the basis of SDI alone revealed distinct but highly heterogeneous patterns by region and country or territory. Ischaemic heart disease, stroke, and diabetes were among the leading causes of YLLs in most regions, but in many cases, intraregional results sharply diverged for ratios of observed and expected YLLs based on SDI. Communicable, maternal, neonatal, and nutritional diseases caused the most YLLs throughout sub-Saharan Africa, with observed YLLs far exceeding expected YLLs for countries in which malaria or HIV/AIDS remained the leading causes of early death.At the global scale, age-specific mortality has steadily improved over the past 35 years; this pattern of general progress continued in the past decade. Progress has been faster in most countries than expected on the basis of development measured by the SDI. Against this background of progress, some countries have seen falls in life expectancy, and age-standardised death rates for some causes are increasing. Despite progress in reducing age-standardised death rates, population growth and ageing mean that the number of deaths from most non-communicable causes are increasing in most countries, putting increased demands on health systems.Bill & Melinda Gates Foundation.

View details for DOI 10.1016/S0140-6736(15)61340-X

View details for Web of Science ID 000365992600030

View details for PubMedCentralID PMC5388903

Abstract

Up-to-date evidence about levels and trends in disease and injury incidence, prevalence, and years lived with disability (YLDs) is an essential input into global, regional, and national health policies. In the Global Burden of Disease Study 2013 (GBD 2013), we estimated these quantities for acute and chronic diseases and injuries for 188 countries between 1990 and 2013.Estimates were calculated for disease and injury incidence, prevalence, and YLDs using GBD 2010 methods with some important refinements. Results for incidence of acute disorders and prevalence of chronic disorders are new additions to the analysis. Key improvements include expansion to the cause and sequelae list, updated systematic reviews, use of detailed injury codes, improvements to the Bayesian meta-regression method (DisMod-MR), and use of severity splits for various causes. An index of data representativeness, showing data availability, was calculated for each cause and impairment during three periods globally and at the country level for 2013. In total, 35620 distinct sources of data were used and documented to calculated estimates for 301 diseases and injuries and 2337 sequelae. The comorbidity simulation provides estimates for the number of sequelae, concurrently, by individuals by country, year, age, and sex. Disability weights were updated with the addition of new population-based survey data from four countries.Disease and injury were highly prevalent; only a small fraction of individuals had no sequelae. Comorbidity rose substantially with age and in absolute terms from 1990 to 2013. Incidence of acute sequelae were predominantly infectious diseases and short-term injuries, with over 2 billion cases of upper respiratory infections and diarrhoeal disease episodes in 2013, with the notable exception of tooth pain due to permanent caries with more than 200 million incident cases in 2013. Conversely, leading chronic sequelae were largely attributable to non-communicable diseases, with prevalence estimates for asymptomatic permanent caries and tension-type headache of 24 billion and 16 billion, respectively. The distribution of the number of sequelae in populations varied widely across regions, with an expected relation between age and disease prevalence. YLDs for both sexes increased from 5376 million in 1990 to 7648 million in 2013 due to population growth and ageing, whereas the age-standardised rate decreased little from 11487 per 1000 people to 11031 per 1000 people between 1990 and 2013. Leading causes of YLDs included low back pain and major depressive disorder among the top ten causes of YLDs in every country. YLD rates per person, by major cause groups, indicated the main drivers of increases were due to musculoskeletal, mental, and substance use disorders, neurological disorders, and chronic respiratory diseases; however HIV/AIDS was a notable driver of increasing YLDs in sub-Saharan Africa. Also, the proportion of disability-adjusted life years due to YLDs increased globally from 211% in 1990 to 312% in 2013.Ageing of the world's population is leading to a substantial increase in the numbers of individuals with sequelae of diseases and injuries. Rates of YLDs are declining much more slowly than mortality rates. The non-fatal dimensions of disease and injury will require more and more attention from health systems. The transition to non-fatal outcomes as the dominant source of burden of disease is occurring rapidly outside of sub-Saharan Africa. Our results can guide future health initiatives through examination of epidemiological trends and a better understanding of variation across countries.Bill & Melinda Gates Foundation.

View details for DOI 10.1016/S0140-6736(15)60692-4

View details for Web of Science ID 000360287900025

View details for PubMedCentralID PMC4561509

Abstract

Up-to-date evidence on levels and trends for age-sex-specific all-cause and cause-specific mortality is essential for the formation of global, regional, and national health policies. In the Global Burden of Disease Study 2013 (GBD 2013) we estimated yearly deaths for 188 countries between 1990, and 2013. We used the results to assess whether there is epidemiological convergence across countries.We estimated age-sex-specific all-cause mortality using the GBD 2010 methods with some refinements to improve accuracy applied to an updated database of vital registration, survey, and census data. We generally estimated cause of death as in the GBD 2010. Key improvements included the addition of more recent vital registration data for 72 countries, an updated verbal autopsy literature review, two new and detailed data systems for China, and more detail for Mexico, UK, Turkey, and Russia. We improved statistical models for garbage code redistribution. We used six different modelling strategies across the 240 causes; cause of death ensemble modelling (CODEm) was the dominant strategy for causes with sufficient information. Trends for Alzheimer's disease and other dementias were informed by meta-regression of prevalence studies. For pathogen-specific causes of diarrhoea and lower respiratory infections we used a counterfactual approach. We computed two measures of convergence (inequality) across countries: the average relative difference across all pairs of countries (Gini coefficient) and the average absolute difference across countries. To summarise broad findings, we used multiple decrement life-tables to decompose probabilities of death from birth to exact age 15 years, from exact age 15 years to exact age 50 years, and from exact age 50 years to exact age 75 years, and life expectancy at birth into major causes. For all quantities reported, we computed 95% uncertainty intervals (UIs). We constrained cause-specific fractions within each age-sex-country-year group to sum to all-cause mortality based on draws from the uncertainty distributions.Global life expectancy for both sexes increased from 65.3 years (UI 65.0-65.6) in 1990, to 71.5 years (UI 71.0-71.9) in 2013, while the number of deaths increased from 47.5 million (UI 46.8-48.2) to 54.9 million (UI 53.6-56.3) over the same interval. Global progress masked variation by age and sex: for children, average absolute differences between countries decreased but relative differences increased. For women aged 25-39 years and older than 75 years and for men aged 20-49 years and 65 years and older, both absolute and relative differences increased. Decomposition of global and regional life expectancy showed the prominent role of reductions in age-standardised death rates for cardiovascular diseases and cancers in high-income regions, and reductions in child deaths from diarrhoea, lower respiratory infections, and neonatal causes in low-income regions. HIV/AIDS reduced life expectancy in southern sub-Saharan Africa. For most communicable causes of death both numbers of deaths and age-standardised death rates fell whereas for most non-communicable causes, demographic shifts have increased numbers of deaths but decreased age-standardised death rates. Global deaths from injury increased by 10.7%, from 4.3 million deaths in 1990 to 4.8 million in 2013; but age-standardised rates declined over the same period by 21%. For some causes of more than 100,000 deaths per year in 2013, age-standardised death rates increased between 1990 and 2013, including HIV/AIDS, pancreatic cancer, atrial fibrillation and flutter, drug use disorders, diabetes, chronic kidney disease, and sickle-cell anaemias. Diarrhoeal diseases, lower respiratory infections, neonatal causes, and malaria are still in the top five causes of death in children younger than 5 years. The most important pathogens are rotavirus for diarrhoea and pneumococcus for lower respiratory infections. Country-specific probabilities of death over three phases of life were substantially varied between and within regions.For most countries, the general pattern of reductions in age-sex specific mortality has been associated with a progressive shift towards a larger share of the remaining deaths caused by non-communicable disease and injuries. Assessing epidemiological convergence across countries depends on whether an absolute or relative measure of inequality is used. Nevertheless, age-standardised death rates for seven substantial causes are increasing, suggesting the potential for reversals in some countries. Important gaps exist in the empirical data for cause of death estimates for some countries; for example, no national data for India are available for the past decade.Bill & Melinda Gates Foundation.

View details for DOI 10.1016/S0140-6736(14)61682-2

View details for Web of Science ID 000347715900024

View details for PubMedCentralID PMC4340604

Abstract

Analysis of data derived from the Alzheimer's Disease Neuroimaging Initiative (ADNI) program showed plasma leptin levels in individuals with Mild Cognitive Impairment (MCI) or Alzheimer's disease (AD) to be lower than those of subjects with normal cognition (NC). Approximately 70% of both men and women with MCI have plasma leptin levels lower than the median values of NC. Additionally, half of these subjects carry at least one apolipoprotein-E4 (APOE-4) allele. A subgroup of participants also had cerebrospinal fluid (CSF) leptin measured. Plasma leptin typically reflected the levels of leptin in CSF in all groups (Control/MCI/AD) in both genders. The data suggest that plasma leptin deficiency provides an indication of potential CNS leptin deficiency, further supporting the exploration of plasma leptin as a diagnostic marker for MCI or AD. The important question is whether leptin deficiency plays a role in the causation of AD and/or its progression. If this is the case, individuals with early AD or MCI with low plasma leptin may benefit from leptin replacement therapy. Thus, these data indicate that trials of leptin in low leptin MCI/early-stage AD patients should be conducted to test the hypothesis.

View details for DOI 10.2174/1567205010666131212114156

View details for Web of Science ID 000333195900008

View details for PubMedID 24359504

View details for PubMedCentralID PMC4040126

Abstract

Treatment of Alzheimer's disease (AD) is significantly hampered by the lack of easily accessible biomarkers that can detect disease presence and predict disease risk reliably. Fluid biomarkers of AD currently provide indications of disease stage; however, they are not robust predictors of disease progression or treatment response, and most are measured in cerebrospinal fluid, which limits their applicability. With these aspects in mind, the aim of this article is to underscore the concerted efforts of the Blood-Based Biomarker Interest Group, an international working group of experts in the field. The points addressed include: (1) the major challenges in the development of blood-based biomarkers of AD, including patient heterogeneity, inclusion of the "right" control population, and the blood-brain barrier; (2) the need for a clear definition of the purpose of the individual markers (e.g., prognostic, diagnostic, or monitoring therapeutic efficacy); (3) a critical evaluation of the ongoing biomarker approaches; and (4) highlighting the need for standardization of preanalytical variables and analytical methodologies used by the field.

View details for DOI 10.1016/j.jalz.2013.01.013

View details for Web of Science ID 000329559300015

View details for PubMedID 23850333

Abstract

There is significant evidence for a central role of inflammation in the development of Alzheimer disease (AD). Epidemiological studies indicate that chronic use of nonsteroidal anti-inflammatory drugs (NSAIDs) reduces the risk of developing AD in healthy aging populations. As NSAIDs inhibit the enzymatic activity of the inflammatory cyclooxygenases COX-1 and COX-2, these findings suggest that downstream prostaglandin signaling pathways function in the preclinical development of AD. Here, we investigate the function of prostaglandin E(2) (PGE(2) ) signaling through its EP3 receptor in the neuroinflammatory response to A peptide.The function of PGE(2) signaling through its EP3 receptor was examined in vivo in a model of subacute neuroinflammation induced by administration of A(42) peptides. Our findings were then confirmed in young adult APPSwe-PS1E9 transgenic mice.Deletion of the PGE(2) EP3 receptor in a model of A(42) peptide-induced neuroinflammation reduced proinflammatory gene expression, cytokine production, and oxidative stress. In the APPSwe-PS1E9 model of familial AD, deletion of the EP3 receptor blocked induction of proinflammatory gene and protein expression and lipid peroxidation. In addition, levels of A peptides were significantly decreased, as were -secretase and C-terminal fragment levels, suggesting that generation of A peptides may be increased as a result of proinflammatory EP3 signaling. Finally, deletion of EP3 receptor significantly reversed the decline in presynaptic proteins seen in APPSwe-PS1E9 mice.Our findings identify the PGE(2) EP3 receptor as a novel proinflammatory, proamyloidogenic, and synaptotoxic signaling pathway, and suggest a role for COX-PGE(2) -EP3 signaling in the development of AD.

View details for DOI 10.1002/ana.23677

View details for Web of Science ID 000312940300017

View details for PubMedID 22915243

View details for PubMedCentralID PMC3509238

Abstract

Epilepsy is heritable, yet few causative gene mutations have been identified, and thus far no human epilepsy gene mutations have been found to produce seizures in invertebrates. Here we show that mutations in prickle genes are associated with seizures in humans, mice, and flies. We identified human epilepsy patients with heterozygous mutations in either PRICKLE1 or PRICKLE2. In overexpression assays in zebrafish, prickle mutations resulted in aberrant prickle function. A seizure phenotype was present in the Prickle1-null mutant mouse, two Prickle1 point mutant (missense and nonsense) mice, and a Prickle2-null mutant mouse. Drosophila with prickle mutations displayed seizures that were responsive to anti-epileptic medication, and homozygous mutant embryos showed neuronal defects. These results suggest that prickle mutations have caused seizures throughout evolution.

View details for DOI 10.1016/j.ajhg.2010.12.012

View details for Web of Science ID 000287684100002

View details for PubMedID 21276947

View details for PubMedCentralID PMC3035715

Abstract

Peripheral inflammation leads to immune responses in brain characterized by microglial activation, elaboration of proinflammatory cytokines and reactive oxygen species, and secondary neuronal injury. The inducible cyclooxygenase (COX), COX-2, mediates a significant component of this response in brain via downstream proinflammatory PG signaling. In this study, we investigated the function of the PGE2 E-prostanoid (EP) 4 receptor in the CNS innate immune response to the bacterial endotoxin LPS. We report that PGE2 EP4 signaling mediates an anti-inflammatory effect in brain by blocking LPS-induced proinflammatory gene expression in mice. This was associated in cultured murine microglial cells with decreased Akt and I-kappaB kinase phosphorylation and decreased nuclear translocation of p65 and p50 NF-kappaB subunits. In vivo, conditional deletion of EP4 in macrophages and microglia increased lipid peroxidation and proinflammatory gene expression in brain and in isolated adult microglia following peripheral LPS administration. Conversely, EP4 selective agonist decreased LPS-induced proinflammatory gene expression in hippocampus and in isolated adult microglia. In plasma, EP4 agonist significantly reduced levels of proinflammatory cytokines and chemokines, indicating that peripheral EP4 activation protects the brain from systemic inflammation. The innate immune response is an important component of disease progression in a number of neurodegenerative disorders, such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. In addition, recent studies demonstrated adverse vascular effects with chronic administration of COX-2 inhibitors, indicating that specific PG signaling pathways may be protective in vascular function. This study supports an analogous and beneficial effect of PGE2 EP4 receptor signaling in suppressing brain inflammation.

View details for DOI 10.4049/jimmunol.0903487

View details for Web of Science ID 000278516700071

View details for PubMedID 20483760

View details for PubMedCentralID PMC3103215

Abstract

Cyclooxygenase-2 (COX-2) is a neuronal immediate early gene that is regulated by N-methyl d aspartate (NMDA) receptor activity. COX-2 enzymatic activity catalyzes the first committed step in prostaglandin synthesis. Recent studies demonstrate an emerging role for the downstream PGE(2) EP2 receptor in diverse models of activity-dependent synaptic plasticity and a significant function in models of neurological disease including cerebral ischemia, Familial Alzheimer's disease, and Familial amyotrophic lateral sclerosis. Little is known, however, about the normal function of the EP2 receptor in behavior and cognition. Here we report that deletion of the EP2 receptor leads to significant cognitive deficits in standard tests of fear and social memory. EP2-/- mice also demonstrated impaired prepulse inhibition (PPI) and heightened anxiety, but normal startle reactivity, exploratory behavior, and spatial reference memory. This complex behavioral phenotype of EP2-/- mice was associated with a deficit in long-term depression (LTD) in hippocampus. Our findings suggest that PGE(2) signaling via the EP2 receptors plays an important role in cognitive and emotional behaviors that recapitulate some aspects of human psychopathology related to schizophrenia.

View details for DOI 10.1016/j.expneurol.2009.01.016

View details for Web of Science ID 000265859000009

View details for PubMedID 19416671

View details for PubMedCentralID PMC2720138

Abstract

Inflammation has emerged as an important factor in disease progression in human and transgenic models of amyotrophic lateral sclerosis (ALS). Recent studies demonstrate that the prostaglandin E(2) EP2 receptor is a major regulator of inflammatory oxidative injury in innate immunity. We tested whether EP2 signaling participated in disease pathogenesis in the G93A superoxide dismutase (SOD) model of familial ALS.We examined the phenotype of G93A SOD mice lacking the EP2 receptor and performed immunocytochemistry, quantitative reverse transcriptase polymerase chain reaction, and Western analyses to determine the mechanism of EP2 toxicity in this model.EP2 receptor is significantly induced in G93A SOD mice in astrocytes and microglia in parallel with increases in expression of proinflammatory enzymes and lipid peroxidation. In human ALS, EP2 receptor immunoreactivity was upregulated in astrocytes in ventral spinal cord. In aging G93A SOD mice, genetic deletion of the prostaglandin E(2)EP2 receptor improved motor strength and extended survival. Deletion of the EP2 receptor in G93A SOD mice resulted in significant reductions in levels of proinflammatory effectors, including cyclooxygenase-1, cyclooxygenase-2, inducible nitric oxide synthase, and components of the NADPH oxidase complex. In alternate models of inflammation, including the lipopolysaccharide model of innate immunity and the APPSwe-PS1DeltaE9 model of amyloidosis, deletion of EP2 also reduced expression of proinflammatory genes.These data suggest that prostaglandin E(2) signaling via the EP2 receptor functions in the mutant SOD model and more broadly in inflammatory neurodegeneration to regulate expression of a cassette of proinflammatory genes. Inhibition of EP2 signaling may represent a novel strategy to downregulate the inflammatory response in neurodegenerative disease.

View details for DOI 10.1002/ana.21437

View details for Web of Science ID 000259681700013

View details for PubMedID 18825663

View details for PubMedCentralID PMC2766522