Publications by authors named "Julie Schneider"

400 Publications

Proteomic identification of select protein variants of the SNARE interactome associated with cognitive reserve in a large community sample.

Acta Neuropathol 2021 Mar 1. Epub 2021 Mar 1.

Department of Psychiatry, University of British Columbia, Vancouver, BC, Canada.

Age-related neuropathologies progressively impair cognitive abilities by damaging synaptic function. We aimed to identify key components within the presynaptic SNARE (soluble N-ethylmaleimide-sensitive factor attachment protein receptor) machinery associated with cognitive performance and estimate their potential contribution to brain reserve in old age. We used targeted SRM proteomics to quantify amounts of 60 peptides, encoded in 30 different genes, in postmortem specimens of the prefrontal cortex from 1209 participants of two aging studies, with available antemortem cognitive evaluations and postmortem neuropathologic assessments. We found that select (but not all) proteoforms are strongly associated with cognitive function and the burden of Alzheimer's disease (AD) pathology. Specifically, greater abundance of STX1A (but not other syntaxins), SYT12, full-length SNAP25, and the GABAergic STXBP1 variant were robustly associated with better cognitive performance. By contrast, greater abundance of other presynaptic proteins (e.g., STXBP5 or tomosyn, STX7, or SYN2) showed a negative influence on cognition. Regression models adjusting for demographic and pathologic variables showed that altered levels of these protein species explained 7.7% additional between-subject variance in cognition (more than any individual age-related neuropathology in the model), suggesting that these molecules constitute key elements of brain reserve. Network analyses indicated that those peptides associated with brain reserve, and closest to the SNARE fusogenic activity, showed greater centrality measures and were better connected in the network. Validation assays confirmed the selective loss of the STX1A (but not STX1B) isoform in cognitively impaired cases. In rodent and human brains, STX1A was selectively located at glutamatergic terminals. However, in AD brains, STX1A was redistributed adjacent to neuritic pathology, and markedly expressed in astrocytes. Our study provides strong evidence, indicating that select presynaptic proteins are key in maintaining brain reserve. Compromised ability to sustain expression levels of these proteins may trigger synaptic dysfunction and concomitant cognitive impairment.
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http://dx.doi.org/10.1007/s00401-021-02282-7DOI Listing
March 2021

Limbic-predominant age-related TDP-43 encephalopathy neuropathologic change and microvascular pathologies in community-dwelling older persons.

Brain Pathol 2021 Feb 23:e12939. Epub 2021 Feb 23.

Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, IL, USA.

Limbic-predominant age-related transactive response DNA-binding protein 43 (TDP-43) encephalopathy neuropathologic change (LATE-NC) and microvascular pathologies, including microinfarcts, cerebral amyloid angiopathy (CAA), and arteriolosclerosis are common in old age. A relationship between LATE-NC and arteriolosclerosis has been reported in some but not all studies. The objectives of this study were to investigate the frequency of co-occurring LATE-NC and microvascular pathologies and test the hypothesis that arteriolosclerosis, specifically, is related to LATE-NC in brains from community-dwelling older persons. Analyses included 749 deceased participants with completed data on LATE-NC and microvascular pathology from 3 longitudinal clinical pathologic studies of aging. Given the specific interest in arteriolosclerosis, we expanded the examination of arteriolosclerosis to include not only the basal ganglia but also two additional white matter regions from anterior and posterior watershed territories. Ordinal logistic regression models examined the association of microvascular pathology with LATE-NC. LATE-NC was present in 409 (54.6%) decedents, of which 354 (86.5%) had one or multiple microvascular pathologies including 132 (32.3%) with moderate-severe arteriolosclerosis in basal ganglia, 195 (47.6%) in anterior watershed, and 144 (35.2%) in posterior watershed; 170 (41.5%) with moderate-severe CAA, and 150 (36.6%) with microinfarcts. In logistic regression models, only posterior watershed arteriolosclerosis, but not other regions of arteriolosclerosis was associated with a higher odds of more advanced LATE-NC stages (Odds Ratio = 1.12; 95% Confidence Interval = 1.01-1.25) after controlling for demographics, AD, and other age-related pathologies. Capillary CAA, but not the severity of CAA was associated with an increased odds of LATE-NC burden (Odds Ratio = 1.71; 95% Confidence Interval = 1.13-2.58). Findings were unchanged in analyses controlling for APOE ε4, vascular risk factors, or vascular diseases. These findings suggest that LATE-NC with microvascular pathology is a very common mixed pathology and small vessel disease pathology may contribute to LATE-NC in the aging brain.
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http://dx.doi.org/10.1111/bpa.12939DOI Listing
February 2021

What is 'Alzheimer's disease'? The neuropathological heterogeneity of clinically defined Alzheimer's dementia.

Curr Opin Neurol 2021 Feb 11. Epub 2021 Feb 11.

Rush Alzheimer's Disease Center, Chicago, Illinois, USA University of Rochester Center for Translational Neuromedicine, Rochester, NY, USA.

Purpose Of Review: Beta-amyloid with paired helical filaments (PHF)-tau neurofibrillary tangles define hallmark Alzheimer's disease neuropathologic changes (AD-NC). Yet persons with Alzheimer's dementia, defined broadly as an amnestic multidomain progressive dementia, often exhibit postmortem evidence of other neuropathologies including other neurodegenerative (Lewy body disease and transactive response DNA-binding protein disease) and vascular (vessel disease and tissue injuries) brain lesions. Clinicopathologic and epidemiologic analyses demonstrate the significance of these substrates, as coinciding neuropathologies mitigate the threshold for diagnosis of Alzheimer's dementia. In addition, other biologic processes may also independently underlie a progressive amnestic dementia. Advances in research on the relationship between age-related cognitive decline and the underlying neuropathologic substrates indicate that consensus neuropathologic criteria or disease nomenclature may need new considerations or refinement. This review appraises seminal literature as well as mixed pathologies and biological factors that may be determinants of clinical and pathologic disease.

Recent Findings: Cognition in aging (spanning from normal cognition to dementia) represents a clinical continuum. Traditional neuropathologic substrates of dementia however do not explain the variability of cognitive decline. Conversely, not all patients with AD-NC exhibit symptomatology of Alzheimer's dementia. In addition to diagnostic plaques and tangles, other neurodegenerative, cerebrovascular, and perivascular substrates manifest through discrete tissue lesions. Factors related to energetics, neurogenetics, neuroimmunology, resilience, proteinopathies, and waste clearance are increasingly suggested to be general drivers of disease. Recognition of novel neuroimmune pathways and brain-body connections further suggest there may be broader extracranial determinants of person-specific disease.

Summary: Alzheimer's dementia is a pathologically heterogeneous and biologically multilayered disease. Recent studies and exercises in nomenclature reveal shortcomings in existing terminologies. Recognizing and overcoming these limitations is required for experts to effectively communicate about and ultimately prevent and treat Alzheimer's dementia.
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http://dx.doi.org/10.1097/WCO.0000000000000912DOI Listing
February 2021

Regional brain iron associated with deterioration in Alzheimer's disease: A large cohort study and theoretical significance.

Alzheimers Dement 2021 Jan 25. Epub 2021 Jan 25.

Melbourne Dementia Research Centre, Florey Institute of Neuroscience and Mental Health, and The University of Melbourne, Parkville, Australia.

Objective: This paper is a proposal for an update of the iron hypothesis of Alzheimer's disease (AD), based on large-scale emerging evidence.

Background: Iron featured historically early in AD research efforts for its involvement in the amyloid and tau proteinopathies, APP processing, genetics, and one clinical trial, yet iron neurochemistry remains peripheral in mainstream AD research. Much of the effort investigating iron in AD has focused on the potential for iron to provoke the onset of disease, by promoting proteinopathy though increased protein expression, phosphorylation, and aggregation.

New/updated Hypothesis: We provide new evidence from a large post mortem cohort that brain iron levels within the normal range were associated with accelerated ante mortem disease progression in cases with underlying proteinopathic neuropathology. These results corroborate recent findings that argue for an additional downstream role for iron as an effector of neurodegeneration, acting independently of tau or amyloid pathologies. We hypothesize that the level of tissue iron is a trait that dictates the probability of neurodegeneration in AD by ferroptosis, a regulated cell death pathway that is initiated by signals such as glutathione depletion and lipid peroxidation.

Major Challenges For The Hypothesis: While clinical biomarkers of ferroptosis are still in discovery, the demonstration of additional ferroptotic correlates (genetic or biomarker derived) of disease progression is required to test this hypothesis. The genes implicated in familial AD are not known to influence ferroptosis, although recent reports on APP mutations and apolipoprotein E allele (APOE) have shown impact on cellular iron retention. Familial AD mutations will need to be tested for their impact on ferroptotic vulnerability. Ultimately, this hypothesis will be substantiated, or otherwise, by a clinical trial of an anti-ferroptotic/iron compound in AD patients.

Linkage To Other Major Theories: Iron has historically been linked to the amyloid and tau proteinopathies of AD. Tau, APP, and apoE have been implicated in physiological iron homeostasis in the brain. Iron is biochemically the origin of most chemical radicals generated in biochemistry and thus closely associated with the oxidative stress theory of AD. Iron accumulation is also a well-established consequence of aging and inflammation, which are major theories of disease pathogenesis.
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http://dx.doi.org/10.1002/alz.12282DOI Listing
January 2021

MarkVCID cerebral small vessel consortium: I. Enrollment, clinical, fluid protocols.

Alzheimers Dement 2021 Jan 21. Epub 2021 Jan 21.

Department of Neurology, Massachusetts General Hospital, Boston, Massachusetts, USA.

The concept of vascular contributions to cognitive impairment and dementia (VCID) derives from more than two decades of research indicating that (1) most older individuals with cognitive impairment have post mortem evidence of multiple contributing pathologies and (2) along with the preeminent role of Alzheimer's disease (AD) pathology, cerebrovascular disease accounts for a substantial proportion of this contribution. Contributing cerebrovascular processes include both overt strokes caused by etiologies such as large vessel occlusion, cardioembolism, and embolic infarcts of unknown source, and frequently asymptomatic brain injuries caused by diseases of the small cerebral vessels. Cerebral small vessel diseases such as arteriolosclerosis and cerebral amyloid angiopathy, when present at moderate or greater pathologic severity, are independently associated with worse cognitive performance and greater likelihood of dementia, particularly in combination with AD and other neurodegenerative pathologies. Based on this evidence, the US National Alzheimer's Project Act explicitly authorized accelerated research in vascular and mixed dementia along with frontotemporal and Lewy body dementia and AD itself. Biomarker development has been consistently identified as a key step toward translating scientific advances in VCID into effective prevention and treatment strategies. Validated biomarkers can serve a range of purposes in trials of candidate interventions, including (1) identifying individuals at increased VCID risk, (2) diagnosing the presence of cerebral small vessel disease or specific small vessel pathologies, (3) stratifying study participants according to their prognosis for VCID progression or treatment response, (4) demonstrating an intervention's target engagement or pharmacodynamic mechanism of action, and (5) monitoring disease progression during treatment. Effective biomarkers allow academic and industry investigators to advance promising interventions at early stages of development and discard interventions with low success likelihood. The MarkVCID consortium was formed in 2016 with the goal of developing and validating fluid- and imaging-based biomarkers for the cerebral small vessel diseases associated with VCID. MarkVCID consists of seven project sites and a central coordinating center, working with the National Institute of Neurologic Diseases and Stroke and National Institute on Aging under cooperative agreements. Through an internal selection process, MarkVCID has identified a panel of 11 candidate biomarker "kits" (consisting of the biomarker measure and the clinical and cognitive data used to validate it) and established a range of harmonized procedures and protocols for participant enrollment, clinical and cognitive evaluation, collection and handling of fluid samples, acquisition of neuroimaging studies, and biomarker validation. The overarching goal of these protocols is to generate rigorous validating data that could be used by investigators throughout the research community in selecting and applying biomarkers to multi-site VCID trials. Key features of MarkVCID participant enrollment, clinical/cognitive testing, and fluid biomarker procedures are summarized here, with full details in the following text, tables, and supplemental material, and a description of the MarkVCID imaging biomarker procedures in a companion paper, "MarkVCID Cerebral small vessel consortium: II. Neuroimaging protocols." The procedures described here address a range of challenges in MarkVCID's design, notably: (1) acquiring all data under informed consent and enrollment procedures that allow unlimited sharing and open-ended analyses without compromising participant privacy rights; (2) acquiring the data in a sufficiently wide range of study participants to allow assessment of candidate biomarkers across the various patient groups who might ultimately be targeted in VCID clinical trials; (3) defining a common dataset of clinical and cognitive elements that contains all the key outcome markers and covariates for VCID studies and is realistically obtainable during a practical study visit; (4) instituting best fluid-handling practices for minimizing avoidable sources of variability; and (5) establishing rigorous procedures for testing the reliability of candidate fluid-based biomarkers across replicates, assay runs, sites, and time intervals (collectively defined as the biomarker's instrumental validity). Participant Enrollment Project sites enroll diverse study cohorts using site-specific inclusion and exclusion criteria so as to provide generalizable validation data across a range of cognitive statuses, risk factor profiles, small vessel disease severities, and racial/ethnic characteristics representative of the diverse patient groups that might be enrolled in a future VCID trial. MarkVCID project sites include both prospectively enrolling centers and centers providing extant data and samples from preexisting community- and population-based studies. With approval of local institutional review boards, all sites incorporate MarkVCID consensus language into their study documents and informed consent agreements. The consensus language asks prospectively enrolled participants to consent to unrestricted access to their data and samples for research analysis within and outside MarkVCID. The data are transferred and stored as a de-identified dataset as defined by the Health Insurance Portability and Accountability Act Privacy Rule. Similar human subject protection and informed consent language serve as the basis for MarkVCID Research Agreements that act as contracts and data/biospecimen sharing agreements across the consortium. Clinical and Cognitive Data Clinical and cognitive data are collected across prospectively enrolling project sites using common MarkVCID instruments. The clinical data elements are modified from study protocols already in use such as the Alzheimer's Disease Center program Uniform Data Set Version 3 (UDS3), with additional focus on VCID-related items such as prior stroke and cardiovascular disease, vascular risk factors, focal neurologic findings, and blood testing for vascular risk markers and kidney function including hemoglobin A1c, cholesterol subtypes, triglycerides, and creatinine. Cognitive assessments and rating instruments include the Clinical Dementia Rating Scale, Geriatric Depression Scale, and most of the UDS3 neuropsychological battery. The cognitive testing requires ≈60 to 90 minutes. Study staff at the prospectively recruiting sites undergo formalized training in all measures and review of their first three UDS3 administrations by the coordinating center. Collection and Handling of Fluid Samples Fluid sample types collected for MarkVCID biomarker kits are serum, ethylenediaminetetraacetic acid-plasma, platelet-poor plasma, and cerebrospinal fluid (CSF) with additional collection of packed cells to allow future DNA extraction and analyses. MarkVCID fluid guidelines to minimize variability include fasting morning fluid collections, rapid processing, standardized handling and storage, and avoidance of CSF contact with polystyrene. Instrumental Validation for Fluid-Based Biomarkers Instrumental validation of MarkVCID fluid-based biomarkers is operationally defined as determination of intra-plate and inter-plate repeatability, inter-site reproducibility, and test-retest repeatability. MarkVCID study participants both with and without advanced small vessel disease are selected for these determinations to assess instrumental validity across the full biomarker assay range. Intra- and inter-plate repeatability is determined by repeat assays of single split fluid samples performed at individual sites. Inter-site reproducibility is determined by assays of split samples distributed to multiple sites. Test-retest repeatability is determined by assay of three samples acquired from the same individual, collected at least 5 days apart over a 30-day period and assayed on a single plate. The MarkVCID protocols are designed to allow direct translation of the biomarker validation results to multicenter trials. They also provide a template for outside groups to perform analyses using identical methods and therefore allow direct comparison of results across studies and centers. All MarkVCID protocols are available to the biomedical community and intended to be shared. In addition to the instrumental validation procedures described here, each of the MarkVCID kits will undergo biological validation to determine whether the candidate biomarker measures important aspects of VCID such as cognitive function. Analytic methods and results of these validation studies for the 11 MarkVCID biomarker kits will be published separately. The results of this rigorous validation process will ultimately determine each kit's potential usefulness for multicenter interventional trials aimed at preventing or treating small vessel disease related VCID.
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http://dx.doi.org/10.1002/alz.12215DOI Listing
January 2021

A cortical immune network map identifies distinct microglial transcriptional programs associated with β-amyloid and Tau pathologies.

Transl Psychiatry 2021 01 14;11(1):50. Epub 2021 Jan 14.

Center for Translational & Computational Neuroimmunology, Department of Neurology, Columbia University Medical Center, New York, NY, USA.

Microglial dysfunction has been proposed as one of the many cellular mechanisms that can contribute to the development of Alzheimer's disease (AD). Here, using a transcriptional network map of the human frontal cortex, we identify five modules of co-expressed genes related to microglia and assess their role in the neuropathologic features of AD in 540 subjects from two cohort studies of brain aging. Two of these transcriptional programs-modules 113 and 114-relate to the accumulation of β-amyloid, while module 5 relates to tau pathology. We replicate these associations in brain epigenomic data and in two independent datasets. In terms of tau, we propose that module 5, a marker of activated microglia, may lead to tau accumulation and subsequent cognitive decline. We validate our model further by showing that three representative module 5 genes (ACADVL, TRABD, and VASP) encode proteins that are upregulated in activated microglia in AD.
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http://dx.doi.org/10.1038/s41398-020-01175-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7809035PMC
January 2021

Early Selective Vulnerability of the CA2 Hippocampal Subfield in Primary Age-Related Tauopathy.

J Neuropathol Exp Neurol 2021 Jan;80(2):102-111

Department of Pathology and Nash Family Neuroscience, Icahn School of Medicine at Mount Sinai, New York, New York, USA.

Primary age-related tauopathy (PART) is a neurodegenerative entity defined as Alzheimer-type neurofibrillary degeneration primarily affecting the medial temporal lobe with minimal to absent amyloid-β (Aβ) plaque deposition. The extent to which PART can be differentiated pathoanatomically from Alzheimer disease (AD) is unclear. Here, we examined the regional distribution of tau pathology in a large cohort of postmortem brains (n = 914). We found an early vulnerability of the CA2 subregion of the hippocampus to neurofibrillary degeneration in PART, and semiquantitative assessment of neurofibrillary degeneration in CA2 was significantly greater than in CA1 in PART. In contrast, subjects harboring intermediate-to-high AD neuropathologic change (ADNC) displayed relative sparing of CA2 until later stages of their disease course. In addition, the CA2/CA1 ratio of neurofibrillary degeneration in PART was significantly higher than in subjects with intermediate-to-high ADNC burden. Furthermore, the distribution of tau pathology in PART diverges from the Braak NFT staging system and Braak stage does not correlate with cognitive function in PART as it does in individuals with intermediate-to-high ADNC. These findings highlight the need for a better understanding of the contribution of PART to cognitive impairment and how neurofibrillary degeneration interacts with Aβ pathology in AD and PART.
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http://dx.doi.org/10.1093/jnen/nlaa153DOI Listing
January 2021

Single cell RNA sequencing of human microglia uncovers a subset associated with Alzheimer's disease.

Nat Commun 2020 11 30;11(1):6129. Epub 2020 Nov 30.

Center for Translational and Computational Neuroimmunology, Columbia University Medical Center, New York, NY, USA.

The extent of microglial heterogeneity in humans remains a central yet poorly explored question in light of the development of therapies targeting this cell type. Here, we investigate the population structure of live microglia purified from human cerebral cortex samples obtained at autopsy and during neurosurgical procedures. Using single cell RNA sequencing, we find that some subsets are enriched for disease-related genes and RNA signatures. We confirm the presence of four of these microglial subpopulations histologically and illustrate the utility of our data by characterizing further microglial cluster 7, enriched for genes depleted in the cortex of individuals with Alzheimer's disease (AD). Histologically, these cluster 7 microglia are reduced in frequency in AD tissue, and we validate this observation in an independent set of single nucleus data. Thus, our live human microglia identify a range of subtypes, and we prioritize one of these as being altered in AD.
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http://dx.doi.org/10.1038/s41467-020-19737-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7704703PMC
November 2020

Vitamin D and Vitamin K Concentrations in Human Brain Tissue Are Influenced by Freezer Storage Time: The Memory and Aging Project.

J Nutr 2021 Jan;151(1):104-108

Jean Mayer US Department of Agriculture Human Nutrition Research Center on Aging at Tufts University, Boston, MA, USA.

Background: Vitamins D and K, which are present in human brain, may have a role in neurodegenerative disease.

Objectives: Given the interest in measuring nutrient concentrations in archived brain samples, it is important to evaluate whether freezer storage time affects these concentrations. Therefore, we evaluated differences in vitamin D and vitamin K concentrations in human brain samples stored for various lengths of time.

Methods: Postmortem brain samples were obtained from 499 participants in the Rush Memory and Aging Project (mean age 92 y, 72% female). Concentrations of vitamins D and K and their metabolites were measured in 4 regions (midtemporal cortex, midfrontal cortex, cerebellum, anterior watershed white matter) using LC-MS/MS and HPLC, respectively. The predominant forms were 25-hydroxycholecalciferol [25(OH)D3] and menaquinone-4 (MK4). ANOVA was used to determine if concentrations differed according to storage time.

Results: The geometric mean of the mean 25(OH)D3 concentration (across 4 regions) in brains stored for 1.1 to 6.0 y did not differ from that in brains stored ≤1.0 y (all P ≥ 0.37), whereas 25(OH)D3 in brains stored >6.0 y was 31-40% lower (P ≤ 0.003). MK4 had similar results, with the geometric mean MK4 concentration in the brains stored ≥9.0 y being 48-52% lower than those in brains stored ≤1.0 y (P ≤ 0.012). The 25(OH)D3 and MK4 concentrations were positively correlated across all 4 regions (all Spearman ρ ≥ 0.79, P < 0.001).

Conclusions: 25(OH)D3 and MK4 appear to be stable in brain tissue from older adults stored at -80°C for up to 6 and 9 y, respectively, but not longer. Freezer storage time should be considered in the design and interpretation of studies using archived brain tissue.
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http://dx.doi.org/10.1093/jn/nxaa336DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7779216PMC
January 2021

Association of Low Systolic Blood Pressure with Postmortem Amyloid-β and Tau.

J Alzheimers Dis 2020 ;78(4):1755-1764

Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, IL, USA.

Background: Vascular mechanisms may contribute to the accumulation of AD pathology.

Objective: We examined whether the burden of vascular risk factors proximate to death is associated with amyloid-β and tau levels or modified their known association.

Methods: We examined the brains of 1, 585 participants from two longitudinal community-based studies of older adults. Amyloid-β and tau were quantified by postmortem examination. The burden of vascular risk factors was summarized by calculating the Framingham general cardiovascular risk score (FRS) proximate to death. Using linear regressions, we examined the association of the FRS with the amyloid-β and tau levels and examined if the FRS modified the association of the amyloid-β with tau.

Results: On average, participants were nearly 90 years old and two-thirds were women. The FRS was not associated with amyloid-β (Spearman r  = -0.00, p  = 0.918) or tau (r = 0.01, p = 0.701). However, the FRS as a whole (estimate = -0.022, SE = 0.008, p = 0.009), and specifically the systolic blood pressure (SBP) component (estimate = -0.033, SE = 0.012, p = 0.009), modified the association of the amyloid-β with tau. Further analysis showed that the association between amyloid-β and tau was stronger at lower levels of SBP.

Conclusion: Late-life vascular risk scores were not related to postmortem levels of amyloid-β or tau. However, lower levels of vascular risk scores and SBP were associated with a stronger association between amyloid-β and tau. These data suggest that vascular risk factors may modify the relation of AD pathology markers to one another.
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http://dx.doi.org/10.3233/JAD-200412DOI Listing
January 2020

Dietary carotenoids related to risk of incident Alzheimer dementia (AD) and brain AD neuropathology: a community-based cohort of older adults.

Am J Clin Nutr 2020 Nov 12. Epub 2020 Nov 12.

Rush Institute for Healthy Aging, Rush University Medical Center, Chicago, IL, USA.

Background: Studies have reported a protective relation to cognitive decline with long-term intake of total and individual dietary carotenoids. However, the underlying mechanisms have not yet been clearly established in humans.

Objectives: To evaluate the prospective association between intakes of total and individual carotenoids and risk of incident Alzheimer dementia (AD) and explore the underlying neuropathological basis.

Methods: Among 927 participants from the Rush Memory and Aging Project who were free from AD at baseline and were followed up for a mean of 7 y, we estimated HRs for AD using Cox proportional hazards models by intakes of energy-adjusted carotenoids. Brain AD neuropathology was assessed in postmortem brain autopsies among 508 deceased participants. We used linear regression to assess the association of carotenoid intake with AD-related neuropathology.

Results: Higher intake of total carotenoids was associated with substantially lower hazard of AD after controlling for age, sex, education, ApoE-ε4, participation in cognitively stimulating activities, and physical activity level. Comparing the top and bottom quintiles (median intake: 24.8 compared with 6.7 mg/d) of total carotenoids, the multivariate HR (95% CI) was 0.52 (0.33, 0.81), P-trend < 0.01. A similar association was observed for lutein-zeaxanthin, a weaker linear inverse association was observed for β-carotene, and a marginally significant linear inverse association was found for β-cryptoxanthin. Among the deceased participants, consumers of higher total carotenoids (top compared with bottom tertile, 18.2 compared with 8.2 mg/d) had less global AD pathology (b: -0.10; SE = 0.04; P-trend = 0.01). For individual carotenoids, lutein-zeaxanthin and lycopene were inversely associated with brain global pathology, whereas lutein-zeaxanthin showed additional inverse associations with AD diagnostic score, neuritic plaque severity, and neurofibrillary tangle density and severity.

Conclusions: Our findings support a beneficial role of total carotenoid consumption, in particular lutein/zeaxanthin, on AD incidence that may be related to the inhibition of brain β-amyloid deposition and fibril formation.
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http://dx.doi.org/10.1093/ajcn/nqaa303DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7779228PMC
November 2020

Association of serial position scores on memory tests and hippocampal-related neuropathologic outcomes.

Neurology 2020 12 3;95(24):e3303-e3312. Epub 2020 Nov 3.

From the Department of Psychology (K.M.G.), York University, Toronto; Department of Psychiatry (W.G.H.), University of British Columbia, Vancouver Canada; and Departments of Neurological Sciences (R.S.W., S.E.L., D.A.B.), Psychiatry and Behavioral Sciences (R.S.W., P.A.B.), and Pathology (J.A.S.), Rush University Medical Center, Chicago, IL.

Objective: To determine whether serial position scores in verbal memory differentiate hippocampal-related neuropathologic outcomes, we examined these associations in a sample of older adults without dementia who underwent autopsy.

Methods: We used data from the Rush Memory and Aging Project, a longitudinal clinical-pathologic cohort study of community-dwelling adults. A total of 701 participants (mean age 82.7, 71.2% female) completed baseline cognitive evaluations and underwent brain autopsy to identify pathologic Alzheimer disease (AD), TDP-43 inclusions (defining limbic-predominant age-related TDP-43 encephalopathy [LATE]), and hippocampal sclerosis. The Consortium to Establish a Registry for Alzheimer's Disease word list memory test immediate recall trials provided serial position scores, which index the proportion of words recalled from the beginning (primacy scores) and end (recency scores) of a word list. Binary and ordinal logistic regressions examined associations between serial position scores and neuropathologic outcomes. Secondary outcomes included Alzheimer dementia and mild cognitive impairment proximate to death.

Results: Primacy and recency scores were uncorrelated ( = 0.07). Each SD of better primacy score was associated with lower likelihood of neuropathologic changes (24% lower LATE, 31% lower pathologic AD, 37% lower hippocampal sclerosis). For pathologic AD, better baseline primacy scores were associated with a 36% lower likelihood of comorbidity with LATE or hippocampal sclerosis. Primacy scores better discriminated between clinical diagnoses proximate to death, including those with mild cognitive impairment compared to no impairment. Recency scores showed weaker or no associations.

Conclusions: Primacy scores may be particularly sensitive markers of AD and related hippocampal neuropathologies. The differential predictive value of serial position scores suggests they offer complementary information about disease outcomes in addition to the routinely used total recall scores.
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http://dx.doi.org/10.1212/WNL.0000000000010952DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7836661PMC
December 2020

Brain arteriolosclerosis.

Acta Neuropathol 2021 01 24;141(1):1-24. Epub 2020 Oct 24.

Sanders-Brown Center on Aging, Department of Pathology, University of Kentucky, Lexington, KY, 40536, USA.

Brain arteriolosclerosis (B-ASC), characterized by pathologic arteriolar wall thickening, is a common finding at autopsy in aged persons and is associated with cognitive impairment. Hypertension and diabetes are widely recognized as risk factors for B-ASC. Recent research indicates other and more complex risk factors and pathogenetic mechanisms. Here, we describe aspects of the unique architecture of brain arterioles, histomorphologic features of B-ASC, relevant neuroimaging findings, epidemiology and association with aging, established genetic risk factors, and the co-occurrence of B-ASC with other neuropathologic conditions such as Alzheimer's disease and limbic-predominant age-related TDP-43 encephalopathy (LATE). There may also be complex physiologic interactions between metabolic syndrome (e.g., hypertension and inflammation) and brain arteriolar pathology. Although there is no universally applied diagnostic methodology, several classification schemes and neuroimaging techniques are used to diagnose and categorize cerebral small vessel disease pathologies that include B-ASC, microinfarcts, microbleeds, lacunar infarcts, and cerebral amyloid angiopathy (CAA). In clinical-pathologic studies that factored in comorbid diseases, B-ASC was independently associated with impairments of global cognition, episodic memory, working memory, and perceptual speed, and has been linked to autonomic dysfunction and motor symptoms including parkinsonism. We conclude by discussing critical knowledge gaps related to B-ASC and suggest that there are probably subcategories of B-ASC that differ in pathogenesis. Observed in over 80% of autopsied individuals beyond 80 years of age, B-ASC is a complex and under-studied contributor to neurologic disability.
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http://dx.doi.org/10.1007/s00401-020-02235-6DOI Listing
January 2021

An evaluation of manual tidal volume and respiratory rate delivery during simulated resuscitation.

Am J Emerg Med 2020 Oct 9. Epub 2020 Oct 9.

Rush University, Department of Cardiopulmonary Sciences, Division of Respiratory Care, Armour Academic Center, 600 S. Paulina St., Chicago, IL 60612, USA. Electronic address:

Introduction: Excessive minute ventilation during cardiac arrest may cause lung injury and decrease the effectiveness of cardiopulmonary resuscitation (CPR). However, little is known about how clinicians deliver tidal volumes and respiratory rates during CPR.

Methods: In this cross-sectional study, licensed practitioners attending an American Heart Association (AHA) Advanced Cardiac Life Support (ACLS) course performed CPR and manual ventilation on a high-fidelity simulator during the megacode portion of the course. Delivered tidal volumes and respiratory rates were measured on a monitor. During the first scenario, results were not displayed to participants, but were displayed during the second scenario.

Results: Fifty-two clinicians participated in this study. Average height was 169 (157,178) cm. Pre-monitor display tidal volumes delivered were larger in male participants compared to female participants (684.6 ± 134.4 vs 586.7 ± 167.6 ml, P = 0.05). Those using medium-sized gloves delivered smaller tidal volumes than those using small or large gloves. Twenty-two (42.3%) delivered tidal volume in the range of 5-8 ml/kg of predicted body weight for the simulation manikin, and 35 (67.3%) delivered tidal volumes with >20% variability among breaths. All participants met the target respiratory rate around 10 breaths/min.

Conclusion: Tidal volume delivery varied greatly during manual ventilation and fewer than half participants delivered tidal volume at 5-8 ml/kg to the manikin. Sex and glove size appeared to impact tidal volume delivery when the participants were unaware of what they were delivering. Participants were able to meet the target respiratory rate around 10 without audio or visual feedback.
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http://dx.doi.org/10.1016/j.ajem.2020.09.091DOI Listing
October 2020

Vascular contributions to cognitive impairment and dementia (VCID): A report from the 2018 National Heart, Lung, and Blood Institute and National Institute of Neurological Disorders and Stroke Workshop.

Alzheimers Dement 2020 12 8;16(12):1714-1733. Epub 2020 Oct 8.

National Heart, Lung, and Blood Institute, Bethesda, Maryland, USA.

Vascular contributions to cognitive impairment and dementia (VCID) are characterized by the aging neurovascular unit being confronted with and failing to cope with biological insults due to systemic and cerebral vascular disease, proteinopathy including Alzheimer's biology, metabolic disease, or immune response, resulting in cognitive decline. This report summarizes the discussion and recommendations from a working group convened by the National Heart, Lung, and Blood Institute and the National Institute of Neurological Disorders and Stroke to evaluate the state of the field in VCID research, identify research priorities, and foster collaborations. As discussed in this report, advances in understanding the biological mechanisms of VCID across the wide spectrum of pathologies, chronic systemic comorbidities, and other risk factors may lead to potential prevention and new treatment strategies to decrease the burden of dementia. Better understanding of the social determinants of health that affect risks for both vascular disease and VCID could provide insight into strategies to reduce racial and ethnic disparities in VCID.
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http://dx.doi.org/10.1002/alz.12157DOI Listing
December 2020

Common Brain Structural Alterations Associated with Cardiovascular Disease Risk Factors and Alzheimer's Dementia: Future Directions and Implications.

Neuropsychol Rev 2020 12 3;30(4):546-557. Epub 2020 Oct 3.

Rush Alzheimer's Disease Center, Rush University Medical Center, 1750 W Harrison Street, Suite 1000, Chicago, IL, 60612, USA.

Recent reports suggest declines in the age-specific risk of Alzheimer's dementia in higher income Western countries. At the same time, investigators believe that worldwide trends of increasing mid-life modifiable risk factors [e.g., cardiovascular disease (CVD) risk factors] coupled with the growth of the world's oldest age groups may nonetheless lead to an increase in Alzheimer's dementia. Thus, understanding the overlap in neuroanatomical profiles associated with CVD risk factors and AD may offer more relevant targets for investigating ways to reduce the growing dementia epidemic than current targets specific to isolated AD-related neuropathology. We hypothesized that a core group of common brain structural alterations exist between CVD risk factors and Alzheimer's dementia. Two co-authors conducted independent literature reviews in PubMed using search terms for CVD risk factor burden (separate searches for 'cardiovascular disease risk factors', 'hypertension', and 'Type 2 diabetes') and 'aging' or 'Alzheimer's dementia' with either 'grey matter volumes' or 'white matter'. Of studies that reported regionally localized results, we found support for our hypothesis, determining 23 regions commonly associated with both CVD risk factors and Alzheimer's dementia. Within this context, we outline future directions for research as well as larger cerebrovascular implications for these commonalities. Overall, this review supports previous as well as more recent calls for the consideration that both vascular and neurodegenerative factors contribute to the pathogenesis of dementia.
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http://dx.doi.org/10.1007/s11065-020-09460-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7718308PMC
December 2020

Risk of Transmissibility From Neurodegenerative Disease-Associated Proteins: Experimental Knowns and Unknowns.

J Neuropathol Exp Neurol 2020 11;79(11):1141-1146

Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.

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.
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http://dx.doi.org/10.1093/jnen/nlaa109DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7577514PMC
November 2020

Cross-Species Analyses Identify Dlgap2 as a Regulator of Age-Related Cognitive Decline and Alzheimer's Dementia.

Cell Rep 2020 09;32(9):108091

The Jackson Laboratory, Bar Harbor, ME 04609, USA; Graduate School of Biomedical Science and Engineering, The University of Maine, Orono, ME 04469, USA. Electronic address:

Genetic mechanisms underlying age-related cognitive decline and dementia remain poorly understood. Here, we take advantage of the Diversity Outbred mouse population to utilize quantitative trait loci mapping and identify Dlgap2 as a positional candidate responsible for modifying working memory decline. To evaluate the translational relevance of this finding, we utilize longitudinal cognitive measures from human patients, RNA expression from post-mortem brain tissue, data from a genome-wide association study (GWAS) of Alzheimer's dementia (AD), and GWAS results in African Americans. We find an association between Dlgap2 and AD phenotypes at the variant, gene and protein expression, and methylation levels. Lower cortical DLGAP2 expression is observed in AD and is associated with more plaques and tangles at autopsy and faster cognitive decline. Results will inform future studies aimed at investigating the cross-species role of Dlgap2 in regulating cognitive decline and highlight the benefit of using genetically diverse mice to prioritize novel candidates.
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http://dx.doi.org/10.1016/j.celrep.2020.108091DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7502175PMC
September 2020

Brain tocopherol levels are associated with lower activated microglia density in elderly human cortex.

Alzheimers Dement (N Y) 2020 24;6(1):e12021. Epub 2020 Aug 24.

Rush Institute for Healthy Aging Rush University Medical Center Chicago Illinois.

Introduction: Higher brain tocopherol levels have been associated with lower levels of Alzheimer's disease (AD) neuropathology; however, the underlying mechanisms are unclear.

Methods: We studied the relations of α- and γ-tocopherol brain levels to microglia density in 113 deceased participants from the Memory and Aging Project. We used linear regression analyses to examine associations between tocopherol levels and microglia densities in a basic model adjusted for age, sex, education, apolipoprotein E ()ε4 genotype (any ε4 allele vs. none) , and post-mortem time interval, and a second model additionally adjusted for total amyloid load and neurofibrillary tangle severity.

Results: Higher α- and γ-tocopherol levels were associated with lower total and activated microglia density in cortical but not in subcortical brain regions. The association between cortical α-tocopherol and total microglia density remained statistically significant after adjusting for AD neuropathology.

Discussion: These results suggest that the relation between tocopherols and AD might be partly explained by the alleviating effects of tocopherols on microglia activation.
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http://dx.doi.org/10.1002/trc2.12021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7444784PMC
August 2020

Genetic variants and functional pathways associated with resilience to Alzheimer's disease.

Brain 2020 08;143(8):2561-2575

Vanderbilt Memory and Alzheimer's Center, Vanderbilt University Medical Center, Nashville, TN, USA.

Approximately 30% of older adults exhibit the neuropathological features of Alzheimer's disease without signs of cognitive impairment. Yet, little is known about the genetic factors that allow these potentially resilient individuals to remain cognitively unimpaired in the face of substantial neuropathology. We performed a large, genome-wide association study (GWAS) of two previously validated metrics of cognitive resilience quantified using a latent variable modelling approach and representing better-than-predicted cognitive performance for a given level of neuropathology. Data were harmonized across 5108 participants from a clinical trial of Alzheimer's disease and three longitudinal cohort studies of cognitive ageing. All analyses were run across all participants and repeated restricting the sample to individuals with unimpaired cognition to identify variants at the earliest stages of disease. As expected, all resilience metrics were genetically correlated with cognitive performance and education attainment traits (P-values < 2.5 × 10-20), and we observed novel correlations with neuropsychiatric conditions (P-values < 7.9 × 10-4). Notably, neither resilience metric was genetically correlated with clinical Alzheimer's disease (P-values > 0.42) nor associated with APOE (P-values > 0.13). In single variant analyses, we observed a genome-wide significant locus among participants with unimpaired cognition on chromosome 18 upstream of ATP8B1 (index single nucleotide polymorphism rs2571244, minor allele frequency = 0.08, P = 2.3 × 10-8). The top variant at this locus (rs2571244) was significantly associated with methylation in prefrontal cortex tissue at multiple CpG sites, including one just upstream of ATPB81 (cg19596477; P = 2 × 10-13). Overall, this comprehensive genetic analysis of resilience implicates a putative role of vascular risk, metabolism, and mental health in protection from the cognitive consequences of neuropathology, while also providing evidence for a novel resilience gene along the bile acid metabolism pathway. Furthermore, the genetic architecture of resilience appears to be distinct from that of clinical Alzheimer's disease, suggesting that a shift in focus to molecular contributors to resilience may identify novel pathways for therapeutic targets.
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http://dx.doi.org/10.1093/brain/awaa209DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7447518PMC
August 2020

Deconvolving the contributions of cell-type heterogeneity on cortical gene expression.

PLoS Comput Biol 2020 08 17;16(8):e1008120. Epub 2020 Aug 17.

Departments of Statistics and Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada.

Complexity of cell-type composition has created much skepticism surrounding the interpretation of bulk tissue transcriptomic studies. Recent studies have shown that deconvolution algorithms can be applied to computationally estimate cell-type proportions from gene expression data of bulk blood samples, but their performance when applied to brain tissue is unclear. Here, we have generated an immunohistochemistry (IHC) dataset for five major cell-types from brain tissue of 70 individuals, who also have bulk cortical gene expression data. With the IHC data as the benchmark, this resource enables quantitative assessment of deconvolution algorithms for brain tissue. We apply existing deconvolution algorithms to brain tissue by using marker sets derived from human brain single cell and cell-sorted RNA-seq data. We show that these algorithms can indeed produce informative estimates of constituent cell-type proportions. In fact, neuronal subpopulations can also be estimated from bulk brain tissue samples. Further, we show that including the cell-type proportion estimates as confounding factors is important for reducing false associations between Alzheimer's disease phenotypes and gene expression. Lastly, we demonstrate that using more accurate marker sets can substantially improve statistical power in detecting cell-type specific expression quantitative trait loci (eQTLs).
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http://dx.doi.org/10.1371/journal.pcbi.1008120DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7451979PMC
August 2020

Brain pathologies are associated with both the rate and variability of declining motor function in older adults.

Acta Neuropathol 2020 10 14;140(4):587-589. Epub 2020 Aug 14.

Rush Alzheimer's Disease Center, Rush University Medical Center, 1750 West Harrison Street, Jelke Building, Suite 100, Chicago, IL, 60612, USA.

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http://dx.doi.org/10.1007/s00401-020-02212-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7501086PMC
October 2020

A novel SNCA E83Q mutation in a case of dementia with Lewy bodies and atypical frontotemporal lobar degeneration.

Neuropathology 2020 Dec 12;40(6):620-626. Epub 2020 Aug 12.

Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, Illinois, USA.

In this case report, we discuss a patient presenting with parkinsonism followed by a non-amnestic dementia with aphasic clinical features, as well as frontal dysexecutive syndrome. There was a family history of dementia with an autopsy diagnosis of "Pick's disease" in the proband's father. Neuroimaging of the patient revealed focal and severe temporal lobe and lesser frontoparietal lobe atrophy. At autopsy, there was severe frontotemporal lobar degeneration. Histologic evaluation revealed an absence of tau or transactivation response DNA-binding protein of 43 kDa (TDP) pathology but rather severe Lewy body deposition in the affected cortices. Genetic phenotyping revealed a novel missense mutation (p.E83Q) in exon 4 of the gene encoding α-synuclein (SNCA). This case study presents a patient with a novel SNCA E83Q mutation associated with widespread Lewy body pathology with prominent severe atrophy of the frontotemporal lobes and corresponding cognitive impairment.
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http://dx.doi.org/10.1111/neup.12687DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7787029PMC
December 2020

Limbic-predominant age-related TDP-43 encephalopathy in Black and White decedents.

Neurology 2020 10 5;95(15):e2056-e2064. Epub 2020 Aug 5.

From the Rush Alzheimer Disease Center (S.N., L.L.B., L.Y., R.S.W., D.A.B., J.A.S.) and Departments of Pathology (Neuropathology) (S.N., J.A.S.), Neurological Sciences (L.L.B., L.Y., R.S.W., D.A.B., J.A.S.), and Psychiatry and Behavioral Sciences (L.L.B., R.S.W.), Rush University Medical Center, Chicago, IL.

Objective: The association of limbic-predominant age-related transactive response DNA-binding protein 43 encephalopathy neuropathologic change (LATE-NC) with cognition and dementia was assessed in community-dwelling Black elders, and racial differences in these associations were tested.

Methods: Black (n = 76) and White (n = 152) decedents from 4 longitudinal clinical pathologic studies of aging were matched 2 to 1 by age at death, sex, years of education, dementia status, and follow-up time. LATE-NC detected by immunohistochemistry was dichotomized into none/mild and moderate/severe groups. Distribution and clinical and pathologic characteristics of LATE-NC and its association with cognitive profiles and odds of dementia were determined in Black decedents, and racial differences in these associations were assessed.

Results: The overall frequency of LATE-NC in Black and White decedents was similar (40.8% vs 45.4%). Black decedents with moderate/severe LATE-NC were older, had significantly lower global cognition scores, particularly in memory domains, and had higher frequency of Alzheimer disease, hippocampal sclerosis, and cerebral amyloid angiopathy than the LATE-NC none/mild group. LATE-NC in Black decents was independently associated with impaired global cognition, episodic and semantic memory, and visuospatial abilities. There were no racial differences in clinical features or pathologic distribution of LATE-NC except for a significant increase in the mean cytoplasmic inclusions in the entorhinal and mid temporal cortices in White compared to Black decedents. In addition, no racial differences in the cognitive profiles or the odds of dementia were observed in Black vs White decedents.

Conclusions: Consistent with findings in White decedents, LATE-NC in Black decedents is associated with impaired cognition, including memory domains.
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http://dx.doi.org/10.1212/WNL.0000000000010602DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7713750PMC
October 2020

Neuropathologic and Cognitive Correlates of Enlarged Perivascular Spaces in a Community-Based Cohort of Older Adults.

Stroke 2020 09 6;51(9):2825-2833. Epub 2020 Aug 6.

Department of Biomedical Engineering, Illinois Institute of Technology, Chicago (C.J.P., N.M., K.A.).

Background And Purpose: Enlarged perivascular spaces (EPVS) have been associated with aging, increased stroke risk, decreased cognitive function, and vascular dementia. However, the relationship of EPVS with age-related neuropathologies is not well understood. Therefore, the purpose of this study was to assess the neuropathologic correlates of EPVS in a large community-based cohort of older adults. The cognitive correlates of EPVS over and beyond those of other pathologies were also assessed.

Methods: This study included 654 older deceased and autopsied participants of 3 longitudinal community-based studies of aging that had available data on cognition, ex vivo brain magnetic resonance imaging, and detailed neuropathologic examination. EPVS seen on ex vivo magnetic resonance imaging were histologically validated. Experienced observers rated EPVS burden in ex vivo magnetic resonance imaging using a semiquantitative 4-level scale. Elastic-net regularized ordinal logistic regression was used to investigate associations of EPVS burden with age-related neuropathologies. Mixed-effects models of cognition controlling for neuropathologies, demographics, and clinical factors, were used to determine whether EPVS burden has additional contributions to cognitive decline.

Results: EPVS burden in the whole group was associated with gross infarcts (odds ratio=1.67, =0.0017) and diabetes mellitus (odds ratio=1.73, =0.004). When considering only nondemented participants (with mild or no cognitive impairment), EPVS burden was associated with gross infarcts (odds ratio=1.74, =0.016) and microscopic infarcts (odds ratio=1.79, =0.013). EPVS burden was associated with faster decline in visuospatial abilities (estimate=-0.009, =0.028), in the whole group, as well as lower levels of semantic memory (estimate=-0.13, =0.048) and visuospatial abilities (estimate=-0.11, =0.016) at the time of death.

Conclusions: EPVS and infarcts may share similar neurobiological pathways regardless of dementia status. EPVS burden is linked to diabetes mellitus independently of neuropathologies, extending recent findings in animal studies implicating diabetes mellitus in impairment of the glymphatic system. Finally, EPVS burden may reflect additional brain tissue injury that may contribute to cognitive decline, not captured with traditional neuropathologic measures.
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http://dx.doi.org/10.1161/STROKEAHA.120.029388DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7484322PMC
September 2020

Limbic-predominant age-related TDP-43 encephalopathy, ADNC pathology, and cognitive decline in aging.

Neurology 2020 10 4;95(14):e1951-e1962. Epub 2020 Aug 4.

From the Rush Alzheimer's Disease Center (A.K., L.Y., P.A.B., L.L.B., D.A.B., J.A.S.), Department of Pathology (A.K., J.A.S.), Department of Neurological Sciences (L.Y., L.L.B., D.A.B., J.A.S.), and Department of Behavioral Sciences (P.A.B., L.L.B.), Rush University Medical Center, Chicago, IL.

Objective: To examine the impact of 3 pathologic groups, pure limbic-predominant age-related transactive response DNA-binding protein 43 encephalopathy (LATE) neuropathologic changes (NC), pure Alzheimer disease neuropathologic change (ADNC), and mixed ADNC with LATE-NC, on late-life cognitive decline.

Methods: Data came from 1,356 community-based older persons who completed detailed annual cognitive testing and systematic neuropathologic examination at autopsy to identify LATE-NC, ADNC, and other age-related pathologies. Persons were categorized into (0) a group without a pathologic diagnosis of LATE or ADNC (n = 378), (1) LATE-NC without ADNC (n = 91), (2) ADNC without LATE-NC (n = 535), and (3) mixed ADNC with LATE-NC (n = 352). We used mixed-effect models to examine the group associations with rate of decline in global cognition and 5 cognitive domains and then examined whether age modified associations.

Results: Compared to those without LATE-NC or ADNC, those with pure LATE-NC had a faster decline in global cognition ( = 0.025) and episodic memory ( = 0.002); however, compared to persons with pure ADNC, those with pure LATE-NC showed a slower decline. Those with mixed ADNC with LATE-NC showed the fastest decline compared to those with either pathology alone. Persons ≥90 years of age with mixed ADNC with LATE-NC had slower cognitive decline compared to those ≤89 years of age.

Conclusion: Persons with pure LATE-NC follow a slower trajectory compared to those with pure ADNC. Those with mixed LATE/ADNC have a steeper decline than individuals with either pathology alone. In addition, age may modify the effect of pathology on cognitive decline. These findings have important implications for the development of biomarkers and prognosis for late-life cognitive decline.

Classification Of Evidence: This study provides Class I evidence that LATE-NC and Alzheimer disease pathologic changes are associated with different trajectories of late-life cognitive decline.
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http://dx.doi.org/10.1212/WNL.0000000000010454DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7682843PMC
October 2020

Brain γ-Tocopherol Levels Are Associated with Presynaptic Protein Levels in Elderly Human Midfrontal Cortex.

J Alzheimers Dis 2020 ;77(2):619-627

Rush Institute for Healthy Aging, Rush University Medical Center, Chicago, Illinois, USA.

Background: Higher vitamin E intake has been widely related to lower risks of cognitive decline and dementia. Animal models suggest that this relationship might be (partially) explained by the protection of vitamin E against presynaptic protein oxidation.

Objective: In this cross-sectional study, we aimed to examine the associations between brain tocopherols and presynaptic protein levels in elderly humans.

Methods: We examined associations of α- and γ-tocopherol brain levels with presynaptic protein levels in 113 deceased participants (age 88.5±6.0 years, 45 (40%) female) from the prospective Memory and Aging project. Three distinct presynaptic proteins, a SNARE protein composite, a synaptotagmin synaptophysin composite and the protein-protein interaction between synaptosomal-associated protein 25 (SNAP-25), and syntaxin were measured in two cortical brain regions. Linear regression models assessed associations of brain tocopherols with presynaptic protein levels.

Results: Higher brain γ-tocopherol levels were associated with higher levels of the SNARE protein composite, complexin-I, complexin-II, the synaptotagmin synaptophysin composite, and septin-5 in the midfrontal cortex (B(SE) = 0.272 to 0.412 (0.084 to 0.091), p < 0.001 to 0.003). When additionally adjusted for global Alzheimer's disease pathology, cerebral infarcts, and Lewy body disease pathology, these associations remained largely similar. No associations were found between α-tocopherol and presynaptic protein levels.

Conclusion: In this cross-sectional study, we found higher brain γ-tocopherol levels were associated with presynaptic protein levels in the midfrontal cortex. These results are consistent with a proposed role of vitamin E to maintain presynaptic protein levels.
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http://dx.doi.org/10.3233/JAD-200166DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7592653PMC
January 2020

BIN1 protein isoforms are differentially expressed in astrocytes, neurons, and microglia: neuronal and astrocyte BIN1 are implicated in tau pathology.

Mol Neurodegener 2020 07 29;15(1):44. Epub 2020 Jul 29.

Center for Translational & Computational Neuroimmunology, Department of Neurology and the Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University Irving Medical Center, 630 West 168th st, PH19-311, New York, NY, 10032, USA.

Background: Identified as an Alzheimer's disease (AD) susceptibility gene by genome wide-association studies, BIN1 has 10 isoforms that are expressed in the Central Nervous System (CNS). The distribution of these isoforms in different cell types, as well as their role in AD pathology still remains unclear.

Methods: Utilizing antibodies targeting specific BIN1 epitopes in human post-mortem tissue and analyzing mRNA expression data from purified microglia, we identified three isoforms expressed in neurons and astrocytes (isoforms 1, 2 and 3) and four isoforms expressed in microglia (isoforms 6, 9, 10 and 12). The abundance of selected peptides, which correspond to groups of BIN1 protein isoforms, was measured in dorsolateral prefrontal cortex, and their relation to neuropathological features of AD was assessed.

Results: Peptides contained in exon 7 of BIN1's N-BAR domain were found to be significantly associated with AD-related traits and, particularly, tau tangles. Decreased expression of BIN1 isoforms containing exon 7 is associated with greater accumulation of tangles and subsequent cognitive decline, with astrocytic rather than neuronal BIN1 being the more likely culprit. These effects are independent of the BIN1 AD risk variant.

Conclusions: Exploring the molecular mechanisms of specific BIN1 isoforms expressed by astrocytes may open new avenues for modulating the accumulation of Tau pathology in AD.
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http://dx.doi.org/10.1186/s13024-020-00387-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7389646PMC
July 2020

Person-specific contributions of brain pathologies to progressive parkinsonism in older adults.

J Gerontol A Biol Sci Med Sci 2020 Jul 28. Epub 2020 Jul 28.

Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, IL, USA.

Objective: Mixed-brain pathologies are the most common cause of progressive parkinsonism in older adults. We tested the hypothesis that the impact of individual pathologies associated with progressive parkinsonism, differ among older adults.

Methods: Data was from 1089 decedents who had undergone annual clinical testing and autopsy. Parkinsonism was based on a modified United Parkinson's Disease Rating Scale. Linear mixed-effects models were employed, to investigate the combinations of nine pathologies related to progressive parkinsonism. Then we estimated the person-specific contributions of each pathology for progressive parkinsonism.

Results: The average participant showed three pathologies. Parkinson's disease (PD) and four cerebrovascular pathologies [macroinfarcts, atherosclerosis, arteriolosclerosis and cerebral amyloid angiopathy (CAA)] but not AD, TDP-43, hippocampal sclerosis and microinfarcts, were independently associated with progressive parkinsonism. These pathologies accounted for 13% of additional variance of progressive parkinsonism. Thirty-one different combinations of these five pathologies were observed to be associated with progressive parkinsonism observed. On average, PD and CAA accounted respectively for 66% and 65% of person-specific progression of parkinsonism, while macroinfarcts, atherosclerosis and arteriolosclerosis accounted for 41%-48%.

Conclusion: There is much greater heterogeneity in the comorbidity and relative impact of individual brain pathologies affecting progressive parkinsonism than previously recognized and this may account in part for its phenotypic heterogeneity in older adults.
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http://dx.doi.org/10.1093/gerona/glaa176DOI Listing
July 2020

Measuring Statistical Learning Across Modalities and Domains in School-Aged Children Via an Online Platform and Neuroimaging Techniques.

J Vis Exp 2020 06 30(160). Epub 2020 Jun 30.

Department of Linguistics and Cognitive Science, University of Delaware;

Statistical learning, a fundamental skill to extract regularities in the environment, is often considered a core supporting mechanism of the first language development. While many studies of statistical learning are conducted within a single domain or modality, recent evidence suggests that this skill may differ based on the context in which the stimuli are presented. In addition, few studies investigate learning as it unfolds in real-time, rather focusing on the outcome of learning. In this protocol, we describe an approach for identifying the cognitive and neural basis of statistical learning, within an individual, across domains (linguistic vs. non-linguistic) and sensory modalities (visual and auditory). The tasks are designed to cast as little cognitive demand as possible on participants, making it ideal for young school-aged children and special populations. The web-based nature of the behavioral tasks offers a unique opportunity for us to reach more representative populations nationwide, to estimate effect sizes with greater precision, and to contribute to open and reproducible research. The neural measures provided by the functional magnetic resonance imaging (fMRI) task can inform researchers about the neural mechanisms engaged during statistical learning, and how these may differ across individuals on the basis of domain or modality. Finally, both tasks allow for the measurement of real-time learning, as changes in reaction time to a target stimulus is tracked across the exposure period. The main limitation of using this protocol relates to the hour-long duration of the experiment. Children might need to complete all four statistical learning tasks in multiple sittings. Therefore, the web-based platform is designed with this limitation in mind so that tasks may be disseminated individually. This methodology will allow users to investigate how the process of statistical learning unfolds across and within domains and modalities in children from different developmental backgrounds.
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http://dx.doi.org/10.3791/61474DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7425813PMC
June 2020