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1.
Neurology ; 2021 May 04.
Artigo em Inglês | MEDLINE | ID: mdl-33947778

RESUMO

OBJECTIVE: To test the hypothesis that fundamental relationships along the amyloid, tau, and neurodegeneration (A/T/N) cascade depend on synaptic integrity in older adults in-vivo and postmortem. METHODS: Two independent observational, cross-sectional cohorts: 1) in-vivo community-dwelling, clinically normal adults from the UCSF Memory and Aging Center completed lumbar puncture and MRI (exclusion criteria, CDR>0), and 2) postmortem decedents from the Rush Memory and Aging Project (exclusion criteria, inability to sign informed consent). In-vivo measures included cerebrospinal fluid (CSF) synaptic proteins (synaptotagmin-1, SNAP-25, neurogranin, and GAP-43), Aß42/40, ptau181, and MRI gray matter volume (GMV). Postmortem measures captured brain tissue levels of presynaptic proteins (complexin-I, complexin-II, VAMP, and SNARE complex), and neuritic plaque and neurofibrillary tangle (NFT) counts. Regression models tested statistical moderation of synaptic protein levels along the A/T/N cascade (synaptic proteins*amyloid on tau, and synaptic proteins*tau on GMV). RESULTS: 68 in-vivo older adults (age=71y, 43%F) and 633 decedents (age=90y, 68%F, 34% clinically normal) were included. Each in-vivo CSF synaptic protein moderated the relationship between Aß42/40 and ptau181 (-0.23<𝛽s<-0.12, ps<0.05) and the relationship between ptau and GMV (-0.49<𝛽s<-0.32, ps<0.05). Individuals with more abnormal CSF synaptic protein demonstrated expected relationships between Aß-ptau and ptau-brain volume, effects that were absent or reversed in those with more normal CSF synaptic protein. Postmortem analyses recapitulated CSF models. More normal brain tissue levels of complexin-I, VAMP, and SNARE moderated the adverse relationship between neuritic plaque and NFT counts (-0.10<𝛽s<-0.08, ps<0.05). CONCLUSIONS: Pathogenic relationships of Aß and tau may depend on synaptic state. Synaptic markers may help identify risk and/or resilience to AD proteinopathy.

2.
PLoS Genet ; 17(4): e1009406, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33830999

RESUMO

Phospholipase D3 (PLD3) is a protein of unclear function that structurally resembles other members of the phospholipase D superfamily. A coding variant in this gene confers increased risk for the development of Alzheimer's disease (AD), although the magnitude of this effect has been controversial. Because of the potential significance of this obscure protein, we undertook a study to observe its distribution in normal human brain and AD-affected brain, determine whether PLD3 is relevant to memory and cognition in sporadic AD, and to evaluate its molecular function. In human neuropathological samples, PLD3 was primarily found within neurons and colocalized with lysosome markers (LAMP2, progranulin, and cathepsins D and B). This colocalization was also present in AD brain with prominent enrichment on lysosomal accumulations within dystrophic neurites surrounding ß-amyloid plaques. This pattern of protein distribution was conserved in mouse brain in wild type and the 5xFAD mouse model of cerebral ß-amyloidosis. We discovered PLD3 has phospholipase D activity in lysosomes. A coding variant in PLD3 reported to confer AD risk significantly reduced enzymatic activity compared to wild-type PLD3. PLD3 mRNA levels in the human pre-frontal cortex inversely correlated with ß-amyloid pathology severity and rate of cognitive decline in 531 participants enrolled in the Religious Orders Study and Rush Memory and Aging Project. PLD3 levels across genetically diverse BXD mouse strains and strains crossed with 5xFAD mice correlated strongly with learning and memory performance in a fear conditioning task. In summary, this study identified a new functional mammalian phospholipase D isoform which is lysosomal and closely associated with both ß-amyloid pathology and cognition.

3.
Acta Neuropathol Commun ; 9(1): 71, 2021 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-33858515

RESUMO

Insulin is an important hormone for brain function, and alterations in insulin metabolism may be associated with neuropathology. We examined associations of molecular markers of brain insulin signaling with cerebrovascular disease. Participants were enrolled in the Religious Orders Study (ROS), an ongoing epidemiologic community-based, clinical-pathologic study of aging from across the United States. Using cross-sectional analyses, we studied a subset of ROS: 150 persons with or without diabetes, matched 1:1 by sex on age-at-death and education. We used ELISA, immunohistochemistry, and ex vivo stimulation with insulin, to document insulin signaling in postmortem midfrontal gyrus cortex tissue. Postmortem neuropathologic data identified cerebrovascular disease including brain infarcts, classified by number (as none for the reference; one; and more than one), size (gross and microscopic infarcts), and brain region/location (cortical and subcortical). Cerebral vessel pathologies were assessed, including severity of atherosclerosis, arteriolosclerosis, and amyloid angiopathy. In separate regression analyses, greater AKT1 phosphorylation at T308 following ex vivo stimulation with insulin (OR = 1.916; estimate = 0.650; p = 0.007) and greater pS616IRS1 immunolabeling in neuronal cytoplasm (OR = 1.610; estimate = 0.476; p = 0.013), were each associated with a higher number of brain infarcts. Secondary analyses showed consistent results for gross infarcts and microinfarcts separately, but no other association including by infarct location (cortical or subcortical). AKT S473 phosphorylation following insulin stimulation was associated with less amyloid angiopathy severity, but not with other vessel pathology including atherosclerosis and arteriolosclerosis. In summary, insulin resistance in the human brain, even among persons without diabetes, is associated with cerebrovascular disease and especially infarcts. The underlying pathophysiologic mechanisms need further elucidation. Because brain infarcts are known to be associated with lower cognitive function and dementia, these data are relevant to better understanding the link between brain metabolism and brain function.

4.
Neurology ; 2021 Apr 14.
Artigo em Inglês | MEDLINE | ID: mdl-33853892

RESUMO

OBJECTIVE: We tested the hypothesis that an inverse association exists between diabetes mellitus (DM) and hemoglobin A1C (A1C) with Transactive response DNA binding protein 43 (TDP-43) levels in older adults. METHODS: We leveraged antemortem and postmortem data of decedents from three community-based clinical-pathological studies. DM status, A1C levels, and medications for DM were documented annually. TDP-43 cytoplasmic inclusions, evaluated in 6 brain regions using immunohistochemistry, were used to obtain a semiquantitative TDP-43 score (0-5) in each region, and scores were averaged across regions to obtain a TDP-43 severity score. We used linear regressions to test the association of DM and A1C with the TDP-43 severity score. RESULTS: On average, participants (n=817) were 90 years old at the time of death, three fourth were women, and one fourth had DM. The mean A1C was 6.0% (SD=0.6). TDP-43 was observed in 54% of participants, and the mean TDP-43 score was 0.7 (range 0-4.5). A higher level of A1C was associated with a lower TDP-43 score (estimate=-0.156, S.E.=0.060, p=0.009) while DM had a borderline inverse association with the TDP-43 score (estimate=-0.163, S.E.=0.087, p=0.060). The association of higher levels of A1C with lower TDP-43 scores persisted after further adjustment by Apolipoprotein ε4, vascular risk factors, stroke, and hypoglycemic medications. Exclusion of the oldest old participants did not change the results. CONCLUSION: Overall, the results suggest that a high level of A1C is associated with less TDP-43 proteinopathy in older persons while the relationship of DM with TDP-43 needs further study.

5.
Stroke ; : STROKEAHA120030226, 2021 Apr 12.
Artigo em Inglês | MEDLINE | ID: mdl-33840227

RESUMO

BACKGROUND AND PURPOSE: The general cardiovascular Framingham risk score (FRS) identifies adults at increased risk for stroke. We tested the hypothesis that baseline FRS is associated with the presence of postmortem cerebrovascular disease (CVD) pathologies. METHODS: We studied the brains of 1672 older decedents with baseline FRS and measured CVD pathologies including macroinfarcts, microinfarcts, atherosclerosis, arteriolosclerosis, and cerebral amyloid angiopathy. We employed a series of logistic regressions to examine the association of baseline FRS with each of the 5 CVD pathologies. RESULTS: Average age at baseline was 80.5±7.0 years and average age at death was 89.2±6.7 years. A higher baseline FRS was associated with higher odds of macroinfarcts (odds ratio, 1.10 [95% CI, 1.07-1.13], P<0.001), microinfarcts (odds ratio, 1.04 [95% CI, 1.01-1.07], P=0.009), atherosclerosis (odds ratio, 1.07 [95% CI, 1.04-1.11], P<0.001), and arteriolosclerosis (odds ratio, 1.04 [95% CI, 1.01-1.07], P=0.005). C statistics for these models ranged from 0.537 to 0.595 indicating low accuracy for predicting CVD pathologies. FRS was not associated with the presence of cerebral amyloid angiopathy. CONCLUSIONS: A higher FRS score in older adults is associated with higher odds of some, but not all, CVD pathologies, with low discrimination at the individual level. Further work is needed to develop a more robust risk score to identify adults at risk for accumulating CVD pathologies.

6.
Stroke ; : STROKEAHA120030870, 2021 Apr 27.
Artigo em Inglês | MEDLINE | ID: mdl-33902300

RESUMO

BACKGROUND AND PURPOSE: The pathogenesis of cerebral small vessel disease remains incompletely understood. The relationship between circadian rhythm disturbances and histopathologic measures of cerebral small vessel disease has not been studied. We hypothesized that disrupted circadian rest-activity rhythms would be associated with a higher burden of cerebral small vessel disease pathology. METHODS: We studied 561 community-dwelling older adults (mean age at death, 91.2, 27.4% male) from the Rush Memory and Aging Project. We used actigraphy to quantify several measures of 24-hour rest-activity rhythmicity, including interdaily stability, intradaily variability, and amplitude, and used ordinal logistic regression models to relate these measures to the severity of cerebral arteriolosclerosis, atherosclerosis, macroinfarcts, and microinfarcts, assessed at autopsy. RESULTS: Lower interdaily stability was associated with a higher burden of arteriolosclerosis, higher intradaily variability was associated with a higher burden of atherosclerosis and subcortical infarcts, and lower amplitude was associated with a higher burden of arteriosclerosis, atherosclerosis and subcortical macroinfarcts. Moreover, the associations between interdaily stability and arteriolosclerosis and intradaily variability and subcortical infarcts were independent of cardiovascular risk factors, sleep fragmentation, and medical comorbidities. CONCLUSIONS: Disrupted rest-activity rhythms are associated with a greater burden of cerebral small vessel disease in older adults.

7.
Clin Cancer Res ; 2021 Apr 28.
Artigo em Inglês | MEDLINE | ID: mdl-33910935

RESUMO

The FDA Oncology Center of Excellence (OCE) is a leader within the agency in scientific outreach activities and regulatory science research. Based on analysis of scientific workshops, internal meetings and publications, the OCE identified nine scientific priority areas and one cross-cutting area of high interest for collaboration with external researchers. This paper describes the process for identifying these scientific interest areas and highlights funded and unfunded opportunities for external researchers to work with FDA staff on critical regulatory science challenges.

8.
Brain ; 2021 Mar 20.
Artigo em Inglês | MEDLINE | ID: mdl-33742668

RESUMO

The aging brain is vulnerable to a wide array of neuropathologies. Prior work estimated that the three most studied of these, Alzheimer's disease (AD), infarcts, and Lewy bodies, account for about 40% of the variation in late life cognitive decline. However, that estimate did not incorporate many other diseases that are now recognized as potent drivers of cognitive decline (e.g. limbic predominant age-related TDP-43 encephalopathy [LATE-NC], hippocampal sclerosis, other cerebrovascular conditions). We examined the degree to which person-specific cognitive decline in old age is driven by a wide array of neuropathologies. 1,164 deceased participants from two longitudinal clinical-pathologic studies, the Rush Memory and Aging Project and Religious Orders Study, completed up to 24 annual evaluations including 17 cognitive performance tests and underwent brain autopsy. Neuropathologic examinations provided 11 pathologic indices, including markers of AD, non-AD neurodegenerative diseases (i.e. LATE-NC, hippocampal sclerosis, Lewy bodies), and cerebrovascular conditions (i.e. macroscopic infarcts, microinfarcts, cerebral amyloid angiopathy, atherosclerosis, and arteriolosclerosis). Mixed effects models examined the linear relation of pathologic indices with global cognitive decline, and random change point models examined the relation of the pathologic indices with the onset of terminal decline and rates of preterminal and terminal decline. Cognition declined an average of about 0.10 unit per year (estimate = -0.101, SE = 0.003, p < 0.001) with considerable heterogeneity in rates of decline (variance estimate for the person-specific slope of decline was 0.0094, p < 0.001). When considered separately, 10 of the 11 pathologic indices were associated with faster decline and accounted for between 2 and 34% of the variation in decline, respectively. When considered simultaneously, the 11 pathologic indices together accounted for a total of 43% of the variation in decline; AD-related indices accounted for 30-36% of the variation, non-AD neurodegenerative indices 4-10%, and cerebrovascular indices 3-8%. Finally, the 11 pathologic indices combined accounted for less than a third of the variation in the onset of terminal decline (28%) and rates of preterminal (32%) and terminal decline (19%). Although age-related neuropathologies account for a large proportion of the variation in late life cognitive decline, considerable variation remains unexplained even after considering a wide array of neuropathologies. These findings highlight the complexity of cognitive aging and have important implications for the ongoing effort to develop effective therapeutics and identify novel treatment targets.

9.
Acta Neuropathol ; 141(5): 755-770, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33646358

RESUMO

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.

10.
Brain Pathol ; : e12939, 2021 Feb 23.
Artigo em Inglês | MEDLINE | ID: mdl-33624322

RESUMO

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.

11.
Curr Opin Neurol ; 34(2): 237-245, 2021 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-33591030

RESUMO

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-related 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.

12.
Alzheimers Dement ; 2021 Jan 25.
Artigo em Inglês | MEDLINE | ID: mdl-33491917

RESUMO

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.

13.
Transl Psychiatry ; 11(1): 50, 2021 01 14.
Artigo em Inglês | MEDLINE | ID: mdl-33446646

RESUMO

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 ß-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.

14.
J Neuropathol Exp Neurol ; 80(2): 102-111, 2021 Jan 20.
Artigo em Inglês | MEDLINE | ID: mdl-33367843

RESUMO

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-ß (Aß) 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 Aß pathology in AD and PART.

15.
Nat Commun ; 11(1): 6129, 2020 11 30.
Artigo em Inglês | MEDLINE | ID: mdl-33257666

RESUMO

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.

16.
J Nutr ; 2020 Nov 26.
Artigo em Inglês | MEDLINE | ID: mdl-33245132

RESUMO

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.

17.
Am J Clin Nutr ; 2020 Nov 12.
Artigo em Inglês | MEDLINE | ID: mdl-33184623

RESUMO

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 ß-carotene, and a marginally significant linear inverse association was found for ß-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 ß-amyloid deposition and fibril formation.

18.
Neurology ; 2020 Nov 03.
Artigo em Inglês | MEDLINE | ID: mdl-33144516

RESUMO

OBJECTIVE: To determine whether serial position scores in verbal memory differentiate hippocampal-related neuropathologic outcomes, we examined these associations in a sample of nondemented older adults who underwent autopsy. METHODS: We used data from the Rush Memory and Aging Project; a longitudinal clinical-pathologic cohort study of community-dwelling adults. Seven hundred one participants (mean age = 82.7, 71.2% female) completed baseline cognitive evaluations and underwent brain autopsy to identify pathologic AD, TDP-43 inclusions (defining limbic-predominant age-related TDP-43 encephalopathy [LATE]), and hippocampal sclerosis. The CERAD 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's dementia and mild cognitive impairment proximate to death. RESULTS: Primacy and recency scores were uncorrelated (r = 0.07). Each standard deviation 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.

19.
J Alzheimers Dis ; 2020 Nov 06.
Artigo em Inglês | MEDLINE | ID: mdl-33185594

RESUMO

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-ß 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-ß 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-ß and tau levels and examined if the FRS modified the association of the amyloid-ß with tau. RESULTS: On average, participants were nearly 90 years old and two-thirds were women. The FRS was not associated with amyloid-ß (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-ß with tau. Further analysis showed that the association between amyloid-ß and tau was stronger at lower levels of SBP. CONCLUSION: Late-life vascular risk scores were not related to postmortem levels of amyloid-ß or tau. However, lower levels of vascular risk scores and SBP were associated with a stronger association between amyloid-ß and tau. These data suggest that vascular risk factors may modify the relation of AD pathology markers to one another.

20.
J Neuropathol Exp Neurol ; 79(11): 1141-1146, 2020 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-33000167

RESUMO

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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