Brain arteriolosclerosis, a prominent small vessel pathology in the aging brain, is associated with cognitive impairment. Understanding the link between arteriolosclerosis and neurodegeneration may be crucial towards unravelling pathways by which arteriosclerosis contributes to cognitive impairment. Using a novel magnetic resonance imaging (MRI) in-vivo classifier for ARTerioloSclerosis termed ARTS, we examined cross-sectional associations between ARTS, cortical thickness, and cognition. Data came from 1054 older participants who were enrolled in one of five ongoing Rush Alzheimer's Disease Center cohort studies, underwent an in-vivo 3 T MRI scan, met the data requirements for ARTS and FreeSurfer processing, and completed cognitive evaluation within a year of MRI. Focusing on the last, most recent MRI scan, we assessed cross-sectional associations of ARTS score with cortical thickness (whole brain and regional measures) and cognitive outcomes (global and domain-specific), using separate linear regression models. Further, we examined whether cortical thickness mediates the relationship between ARTS and global cognition. Models were all adjusted for demographics, vascular risk factors, and scanners. At last analytic MRI scan, participants were on average 80 years old (SD=7) and 80 % were women. Higher ARTS score was associated with lower whole brain cortical thickness (estimate per 1-SD increase=-0.029, 95 % CI: -0.036, -0.022), and across each of the lobes (all P < .01), particularly in temporal lobe regions. Higher ARTS scores were associated with worse global cognition (estimate per 1-SD increase=-0.079, 95 % CI: -0.122, -0.035); also, more specifically higher ARTS score was related to poorer performance in the domains of semantic memory, perceptual speed, and visuospatial ability. In mediation analyses, cortical thickness accounted for 32 % of the association between ARTS score and global cognition. More cerebral arteriolosclerosis-related changes, measured by in-vivo ARTS, is associated with lower cortical thickness and cognitive functions. The association between ARTS and cognition is partially mediated by cortical thickness. Findings suggest that cerebral small vessel disease may contribute to cortical thickness, a marker of neurodegeneration, and contribute both directly and indirectly, to cognitive impairment.

Alzheimer's disease (AD) is defined by β-amyloid plaques and tau-containing neurofibrillary tangles, but the ensuing cellular derangements that culminate in neurodegeneration remain elusive. Here, a mechanistic link between two AD pathophysiological hallmarks: energy insufficiency and oxidative stress is revealed. It is demonstrated that mitochondrial function and glutathione (GSH) flux are coupled, impacting neuronal ferroptosis susceptibility. Analysis of proteomic data from the inferior temporal cortex of 625 subjects along a continuum of clinical and pathological changes in AD, reveals a prominent depletion of mitochondrial proteins. Biogenetic insufficiency in AD is reflected by a concurrent loss of GSH, which requires 2 ATP for its synthesis, and genetic and pharmacologic ATP depletion models confirm that ATP is rate-limiting for GSH. Accordingly, an unbiased association analysis uncovers mitochondrial proteins in positive correlation with total GSH (t-GSH) in AD subjects. But mitochondria also consume GSH via the SLC25A39 transporter. It is found that mitochondrial inhibition either increases or decreases ferroptosis susceptibility in cellular models, depending on contextual factors that dictate whether mitochondria act as a net GSH producer or consumer, respectively. Mitochondria therefore control GSH flux, and loss of energy output is consequently demonstrated as a liability for ferroptosis in AD.

Aberrant activation of tau kinases (tauK) has been proposed as a major step in tau hyperphosphorylation and misfolding, and subsequent formation of neurofibrillary tangles (NFT) in Alzheimer's disease (AD). However, evidence of tauK hyperactivation in actual AD brains is scarce and inconsistent, and their role in age-related cognitive decline remains undocumented. We evaluated activated/inhibited species of CDK5/p35/p25, GSK3α/β, and ERK1/2 as well as ten tau/phospho-tau (ptau) peptides (mapping Ser202, Thr217, Ser262, Ser305, and Ser404 phospho-residues) by Western blot or selected reaction monitoring proteomics, respectively, in postmortem dorsolateral prefrontal cortex (DLPFC) and hippocampal samples of 150 participants from the Rush Memory and Aging Project (MAP). Regression models and mediation analyses assessed the contributions of these variables to tau phosphorylation, NFT deposition and antemortem cognitive status of MAP participants. Surprisingly, greater p25 and p35 (indices for CDK5 activation) and lower pSer21/9-GSK3α/β (inhibited species) immunodensities were associated with lower ptau peptide amounts. Individuals with higher p25 cortical densities displayed better cognitive outcomes, particularly working memory. Statistical mediation analyses indicated that the beneficial effect of CDK5/p25 on cognition was mediated by lower densities of phospho-Thr217-tau and NFT deposition in DLPFC, and also identified Thr217 and Ser262 as the ptau sites with greatest influence in both NFT accumulation and cognitive impairment. The present data suggest that tau hyperphosphorylation, tangle deposition, and the subsequent cognitive impairment do not rely on aberrant activation of major tauKs. Additionally, novel evidence was provided for the beneficial contribution of cortical CDK5/p25 to the maintenance of working memory.

INTRODUCTION:ARTS, an in vivo marker of cerebral arteriolosclerosis, may identify older individuals at risk of mild cognitive impairment (MCI), dementia, and stroke due to cerebral small vessel disease, but deeper characterization in a large, diverse sample is needed. METHODS:Associations between ARTS and incident MCI, dementia, and stroke, and with several common vascular risk factors, were examined in 1226 older adults without dementia and within White (n = 707), Black (n = 400), and Latino (n = 110) subgroups. RESULTS:Higher ARTS score was associated (all ps < 0.01) with incident MCI (hazard ratio [HR] = 1.29), dementia (HR = 1.33), and stroke (HR = 1.52) and with diastolic/systolic blood pressure, self-reported hypertension, claudication, congestive heart failure, smoking, and glomerular filtration rate in the combined sample. Results varied across racial and ethnic groups. DISCUSSION:ARTS has utility as an in vivo marker of cerebral arteriolosclerosis and risk of MCI, dementia, and stroke. HIGHLIGHTS:ARTS score, an in vivo marker of cerebral arteriolosclerosis, was associated with incident mild cognitive impairment (MCI), dementia, and stroke in a diverse sample. ARTS score was associated with incident dementia in the non-Latino (NL) White and NL Black subgroups separately. ARTS score was associated with incident MCI in the NL Black subgroup. Common vascular risk factors were associated with ARTS score, consistent with ex vivo studies. ARTS has utility as a marker for the risk of MCI, dementia, and stroke.

White matter hyperintensities (WMH) and cerebral arteriosclerosis involving thickening of the vessel wall and stenosis of brain arterioles are common in older adults and associated with poor cognition. The Mediterranean-DASH Intervention for Neurodegenerative Disease (MIND) diet is associated with better cognition. Little is known about the association of the MIND diet with cerebrovascular outcomes and if this association mediates the link between diet and cognition. This study investigates the association of the MIND diet with WMH volume and arteriolosclerosis, and whether WMH and arteriosclerosis mediate the association between diet and cognition among community-dwelling older adults. The study includes 561 participants from an ongoing longitudinal cohort study, the Rush Memory and Aging Project with dietary and neuroimaging data available no more than a year apart. MIND diet scores were obtained using a valid >142-item food frequency questionnaire. In-vivo magnetic resonance imaging (MRI) data were collected using a 3T MRI scanner. WMH were segmented using a deep learning model. Arteriolosclerosis was assessed employing a fully automated in-vivo MRI-based marker named ARTS (ARTerioloSclerois). An ARTS score was generated for each participant (higher scores indicate a higher likelihood of arteriolosclerosis). Global cognition was assessed using 19-battery tests. Linear regression models controlled for age, sex, MRI scanner, and education. Mediation analysis was done using structural equation modeling. In our analytical sample (mean age (81 ± 7.5), 77% female, 16 ± 2.9 years of education a higher MIND diet score was associated with less WMH (β = -0.023, SE = 0.009, p = 0.015) and lower ARTS score (β = -0.013, SE = 0.004, p = 0.001). The effect estimates were stable when further controlled for BMI and physical activity. The MIND diet was associated with better global cognition (β = 0.0426, SE = 0.012, p = 0.0004), with an indirect association of 10.5% through ARTS score (β = 0.0045, SE = 0.0002, p = 0.038). Among community-dwelling older adults a higher MIND diet score is associated with less WMH and a lower likelihood of small vessel arteriosclerosis. The association of the MIND diet with cognition is partially mediated by arteriosclerosis. Lifestyle approaches such as adherence to a specific diet may improve cognition by maintaining the cerebrovascular health of older adults. Fundings sources : R01AG054476; R01AG17917; R01AG076143

BACKGROUND AND OBJECTIVES:A spectrum of neurologic complications associated with COVID-19 are well documented. While neuroinflammation in the brain of COVID-19 patients likely contributes to these complications, the mechanisms of neuroinflammation and correlates of neurologic complications remain elusive, especially since the etiologic pathogen of COVID-19, SARS-CoV-2, minimally invades the CNS. This study aimed to evaluate markers of neuroinflammation, IgG glycosylation patterns indicative of pro- or anti-inflammatory state, and prevalence of brain auto-reactive antibodies in the CSF of COVID-19 patients and their relationship to brain neuropathology. METHODS:We evaluated the CSF of 11 deceased unvaccinated COVID-19 donors and 13 matched non-COVID-19 controls. Markers of neuroinflammation, IgG glycosylation patterns, and brain auto-reactive antibodies were assessed, along with their correlation to brain neuropathology. Statistical analyses were performed to compare groups and assess relationships between variables, using non-parametric tests and bootstrap analysis. RESULTS:COVID-19 CSF showed higher levels of neopterin and ANNA-1, markers of neuroinflammation and autoimmunity, respectively, and lower IFN response compared to non-COVID-19 donors. In brain regions of high microglial activation, IL4 and RANTES were significantly increased. SARS-CoV-2 was undetectable in the CSF and brain of COVID-19 donors, yet anti-SARS-CoV-2 CSF antibodies were detected. Fucosylated IgG were associated with Spike IgG, CSF protein, and soluble CD14, whereas afucosylated bisecting IgG were inversely correlated with Spike IgG. Sialic acid containing IgG were positively correlated with IL1β and TNFα. These associations were not found in non-COVID-19 donors. Inflammatory agalactosylated fucosylated IgG (G0F) were associated with infiltrating CD4 + T cells in the brains of COVID-19 donors. COVID-19 donor CSF displayed higher levels of auto-reactive antibodies to human brain antigens compared to non-COVID-19 donors and donors with positive autoantibodies showed higher levels of neopterin. DISCUSSION:These data describe increased neuroinflammation and autoreactive antibody markers in the CSF of COVID-19 donors and suggest that IgG glycosylation and autoimmunity may contribute to COVID-19 pathology, highlighting potential mechanisms underlying the neurologic complications associated with COVID-19.

Evidence is accumulating that cerebral small vessel disease may contribute to neurodegeneration. Brain arteriolosclerosis, a prominent type of small vessel disease in the aging brain, is associated with cognition. Using a previously developed published automated in-vivo MRI classifier for arteriolosclerosis (ARTS), we examined cross-sectionally the associations between ARTS, cortical thinning, and cognition. Data came from 1,023 older participants from 5 ongoing Rush Alzheimer’s Disease Center cohort studies. Participants underwent detailed annual cognitive evaluations and completed at least one in-vivo 3T MRI scan and one cognitive evaluation during follow-up. In addition to global cognitive measures and MRI-derived measures for ARTS score, data including global and lobar cortical thinning composites calculated using FreeSurfer. Using the latest completed MRI scan and a close assessment of cognition, linear regression models were employed to examine the association of ARTS with cortical thinning (global and regional) and global cognition. Further, mediation analyses were used to examine whether cortical thinning mediates the relationship between ARTS and global cognition. Models were all adjusted for age, sex, education, vascular risk factors, and scanner site. Participants had an average age at 80 years (SD = 7) at last MRI scan, and 79% were women. Higher ARTS score was associated with global cortical thinning (estimate = -0.14; SE = 0.02, p<0.001), as well as regional cortical thinning in all four lobes (all p’s >0.017). Higher ARTS score was associated with lower global cognition (estimate = -0.49; SE = 0.10, p<0.001). In mediation analyses, cortical thinning accounted for 35% of the association between ARTS and global cognition. In vivo MRI-derived measures for cerebral arteriolosclerosis are associated with global and lobar cortical thinning. The association between ARTS and cognition is partially mediated by cortical thinning. Findings suggest that cerebral small vessel disease may contribute to neurodegeneration and, both directly and indirectly, to subsequent cognitive impairment.

OBJECTIVE:Cerebral amyloid angiopathy (CAA) involves β-amyloid deposition in the walls of cortical and leptomeningeal small vessels. Transverse relaxation rate (R2) is a major source of contrast in MRI. This study tested the hypothesis that CAA is associated with R2, extracted the spatial pattern of CAA-related R2 abnormalities, and evaluated R2 at different CAA severity levels in a large number of community-based older adults. METHODS:Cerebral hemispheres from 804 older adults who came to autopsy were included. All hemispheres underwent ex vivo MRI and detailed neuropathologic examination. R2 maps were generated from ex vivo MRI data. Voxel-wise and region-based regression analyses were conducted to investigate the association of R2 with CAA, controlling for other neuropathologies and demographics. R2 values at different CAA severity levels were also investigated. RESULTS:CAA severity was associated with a higher transverse relaxation rate R2 in cortical and juxtacortical frontal and medial temporal lobe regions, and in deep brain structures, independently of other neuropathologies and demographics. R2 abnormalities were significant in severe CAA, but were limited in terms of spatial extent and magnitude in moderate CAA, and were not detectable in mild CAA. INTERPRETATION:This is to our knowledge the first investigation of the link between CAA and R2, one of the major contrast mechanisms in MRI. R2 is sensitive to CAA-related brain abnormalities, primarily in moderate and severe stages of the disease. In vivo detection of CAA is an important challenge, and the present work contributes new knowledge that may aid toward this goal.

BACKGROUND:The pathological basis underlying motor impairment in older adults is partially accounted for by Alzheimer disease and related dementias pathologies. We tested the hypothesis that arteriolosclerosis, a pathological correlate of small vessel disease, outside the cerebrum is related to motor impairment in older adults above and beyond Alzheimer disease and related dementias pathologies. METHODS:The data were from decedents of a community-based clinical-autopsy study. Arteriolosclerosis was assessed in the cerebrum (as 1 of 10 Alzheimer disease and related dementias pathologies), midbrain, cerebellum, pons, and 4 levels of the spinal cord. Parkinsonism was assessed using the Unified Parkinson Disease Rating Scale. Other motor performances included timed-peg placement and finger tapping, grip and pinch strength, walking 8 ft and turning 360° twice, and sensor-derived metrics assessing tandem walk. Multivariate linear regression models were used to examine the association of arteriolosclerosis across varied motor performances. RESULTS:The participants (n=403) were on average 91.4 (6.1) years old at death, and 73.2% (n=295) were women. The frequency of moderate/severe arteriolosclerosis varied outside the cerebrum, ranging from 15.5% (40/258) in the pons to 49.6% (200/403) in the spinal cord. The correlation of the severity of arteriolosclerosis between these regions ranged from unrelated to modestly related. Spinal arteriolosclerosis was associated with impaired motor function (P=0.006), in particular more severe parkinsonism (estimate, 0.170; SE, 0.071; P=0.018) and less hand dexterity (estimate, -0.022; SE, 0.009; P=0.014). Arteriolosclerosis of the cerebellum was associated with impaired tandem walk (P=0.012), in particular more variability in the acceleration signal in the mediolateral direction (estimate, 0.023; SE, 0.011; P=0.040). Arteriolosclerosis in the pons or midbrain was not associated with motor performances. CONCLUSIONS:Arteriolosclerosis severity varies in the central nervous system tissues outside of the cerebrum and is differentially associated with varied motor performances, suggesting that the adverse motor consequences of small vessel disease in older adults may be underestimated by studies focusing only on the brain.

Hippocampal neuronal loss (HNL), LATE neuropathologic changes (LATE-NC), and Alzheimer’s disease (AD) are common neuropathological findings in older persons. However, the inter-relationship between AD, LATE-NC, HNL, and cognition is not well understood. Participants without known dementia (n = 420; mean age-at-death = 92 years, women = 72%) enrolled, in the Rush community-based cohorts and underwent annual cognitive testing and autopsy. At autopsy, the severity of HNL in the CA1-subiculum sector was semi-quantitatively graded from 0 (none) to 5 (severe) on H&E stain without regard to AD or LATE-NC pathology. Hippocampal sclerosis (HS) was defined as severe hippocampal neuronal loss (grade 5). Tau-tangle density, β-amyloid burden, LATE-NC, and other age-related pathologies were also recorded. Logistic regression and mixed-effect models adjusted for demographics and neuropathologies were used to examine the association of HNL with AD (tangles/ β-amyloid) and LATE-NC, and separately with cognitive decline. Path analyses examined the extent to which the associations of LATE-NC and tau tangles with cognitive decline was attributable to HNL. HNL was common: mild in 61%, moderate in 16%, and severe in 20% of participants. Advanced LATE-NC stage 2/3 and tau-tangles, but not β-amyloid pathology, were associated with worse hippocampal neuronal loss. More HNL was associated with faster decline in global cognition and four cognitive domains: episodic, semantic, and working memory and perceptual speed. These associations remained robust even after excluding participants with HS. LATE-NC and tangles were also associated with cognitive decline but the association between LATE-NC and cognitive decline was lost while the association of tangles with cognitive decline was partially attenuated after adding HNL in the model. The result from path anlayses suggested that two-thirds of the association between LATE-NC and cognitive decline was attributable to HNL whereas only 5% of the association of tau tangles was through HNL. Our results support that HNL and tangles are the major contributors of cognitive dysfunction. LATE-NC is also associated with cognitive decline but may causes most dysfunction via HNL.

The ARTS biomarker is a fully automated software container that predicts the presence of arteriolosclerosis based on in-vivo MRI data and demographic features. The present study describes findings from the instrumental and clinical validation of ARTS conducted by the MarkVCID consortium. Instrumental validation of ARTS involved assessment of inter-rater reliability, test-retest repeatability, and inter-scanner reproducibility. Inter-rater reliability was assessed by means of the intraclass correlation (ICC) between ARTS scores generated from all MarkVCID sites using data on 20 older adults. Test-retest repeatability was assessed by means of the ICC between test and retest ARTS scores from 41 older adults imaged twice. Inter-scanner reproducibility was assessed by means of the ICC between ARTS scores on 20 older adults imaged on 4 different scanners. Clinical validation of ARTS included two groups of non-demented older adults: N=156 participating in community cohort studies at Rush Alzheimer’s Disease Center; and N=906 participating in the Atherosclerosis Risk in Communities (ARIC) study. The primary prespecified hypothesis was that change in Trails B score (or perceptual speed score for Rush data) two years after baseline MRI is associated with baseline ARTS score, controlling for years of education. The secondary prespecified hypothesis was that baseline Trails B (or perceptual speed) is associated with baseline ARTS score, controlling for years of education. ARTS exhibited excellent inter-rater reliability (ICC=0.9999, p<10 -200 , CI:[0.99987, 0.99997]), test-retest repeatability (ICC=0.996, p<10 -42 , CI:[0.993, 0.998]), and inter-scanner reproducibility (ICC=0.955, p=0.00018, CI:[0.622,0.989]). In Rush data, a higher baseline ARTS score was associated with a faster two-year decline in perceptual speed (beta=-0.32, p=0.04, CI:[-0.63, -0.01]) (Figure 1A) and a lower baseline level of perceptual speed (beta=-1.04, p<10 -4 , CI:[-1.48, -0.60]) (Figure 1B). In ARIC data, a higher baseline ARTS score was associated with a faster annual increase in Trails B (beta=3.7, SE=1.7, p=0.03) (Figure 2A), and a higher baseline Trails B (beta=45.5, SE=5.8, p<10 -4 ) (Figure 2B). ARTS exhibited outstanding technical performance and baseline ARTS score was associated with subsequent decline in cognitive abilities known to be affected by small vessel disease. The above evidence supports ARTS as a marker of the risk of vascular contributions to cognitive impairment and dementia (VCID).

INTRODUCTION:This study investigates the inter-related roles of hippocampal neuronal loss (HNL), limbic-predominant age-related TAR-DNA binding protein of 43 kDa (TDP-43) encephalopathy neuropathologic changes (LATE-NC), and Alzheimer's disease neuropathologic changes (ADNC) on cognitive decline. METHODS:Participants underwent annual cognitive testing and autopsy. HNL, ADNC, LATE-NC, and other age-related pathologies were evaluated. Regression and mixed-effects models examined the association of HNL with ADNC and LATE-NC, and separately with cognitive decline. Path analyses examined the extent to which associations of LATE-NC and ADNC with cognitive decline were attributable to HNL. RESULTS:LATE-NC was associated with more severe HNL, but ADNC was associated only after excluding subjects with hippocampal sclerosis (HS). HNL was associated with faster decline in global cognition and episodic, semantic, and working memory. In path analyses, about 61% of the association of LATE-NC with cognitive decline was attributable to HNL, whereas for ADNC it was mostly independent of HNL. DISCUSSION:HNL has an independent contribution to cognitive decline and acts as a major step in LATE-NC-related cognitive decline. HIGHLIGHTS:Hippocampal neuronal loss (HNL) is associated with cognitive decline. HNL is a prominent feature of limbic-predominant age-related TDP-43 encephalopathy neuropathologic changes (LATE-NC) and less so with Alzheimer's disease neuropathologic changes (ADNC). HNL acts as a major pathway in cognitive decline for LATE-NC. Differential mechanisms in hippocampal degeneration are associated with LATE-NC versus ADNC.

BACKGROUND:Few neuropathologic studies focus on the associations of cerebrovascular pathologies with cognition in older Black adults. METHODS:We conducted a nested substudy of participants who were enrolled in 1 of 4 harmonized longitudinal cohort studies-the Minority Aging Research Study, African American Clinical Core, Rush Memory and Aging Project, and Religious Order Study before coming to autopsy. Neuropathologic evaluation included assessment of cerebrovascular and neurodegenerative pathologies. We first documented single and mixed cerebrovascular profiles and neurodegenerative pathologies in 112 Black decedents and examined the pathological burden with cognitive function proximate to death. In secondary analyses, we matched 2:1 the 112 Black decedents to 214 White decedents from the same cohorts using Mahalanobis distance matching and conducted linear regression models to examine racial differences in the burden of each vascular pathology and their associations with cognition. RESULTS:In older Black decedents, macroscopic infarcts were present in 37%, microinfarcts in 30%, basal ganglia arteriolosclerosis in 20%, cerebral amyloid angiopathy in 32%, and atherosclerosis in 14%. Single cerebrovascular profiles were present in 29% and mixed cerebrovascular profiles in 40%. Microinfarcts (estimate=-0.51, SE=0.23, P=0.03) and arteriolosclerosis in the basal ganglia (estimate =-0.29, SE=0.13, P=0.03) were associated with lower global cognition independent of neurodegenerative pathologies. Further, microinfarcts were associated with lower episodic and semantic memory, and perceptual speed, whereas arteriolosclerosis was associated with only semantic memory. Mixed vascular profiles were also associated with lower episodic memory and perceptual speed. In secondary analyses, the burden of cerebrovascular pathologies and cognitive associations were similar across races. CONCLUSIONS:Cerebrovascular pathologies are common in older Black decedents, most often as a mixed cerebrovascular pathology profile. Arteriosclerosis and microinfarcts were associated with lower cognition above and beyond the presence of neurodegenerative pathologies. Burden and cognitive associations with cerebrovascular pathologies were similar across races.

Despite transverse relaxation rate (R 2 ) being one of the fundamental contrasts in MRI, most investigations of brain R 2 and cognition have been cross-sectional and conducted in predominantly non-Latino White adults. We investigated the profile of R 2 as related to cognition in 212 older African Americans (~75 years of age) with longitudinal 3T MRI scans and cognitive test data to determine how changes in R 2 are associated with changes in cognition. For each participant, the slopes of global cognitive and five cognitive domain scores were each separately combined with voxel-specific slopes of R 2 in whole brain voxelwise analyses. Participants with less negative rates of R 2 change within left basal ganglia and centrum semiovale, bilateral hippocampal complex and temporal gyri, parietooccipital white matter, as well as posterior cingulate displayed less negative slopes in global cognition. Similar associations were seen for regional R 2 change and episodic memory (most robustly within bilateral hippocampi) as well as semantic memory (left greater than right hemisphere involvement). Results suggest a relatively wide distribution of regional associations between rates of changes in R 2 and changes in global cognition for older African Americans; a profile that became more regionally specific when considering individual cognitive domains. Relative preservation of tissue integrity across grey and white matter, and in key regions associated with specific cognitive domains, is associated with slower cognitive decline for older African Americans. These results may lay the foundation for more directed work to support healthy brain aging in older African Americans.

Peripheral nerve comprises a crucial component of the distributed motor/sensory system. However, there is a paucity of data on peripheral nerve morphology derived from large numbers of older adults. This study aimed to quantify the morphometric characteristics of myelinated nerve fibres of the tibial nerve obtained from deceased community-dwelling older adults and examine their association with age. The tibial nerves were obtained from consecutive autopsies of older adults without a history of diabetes who were participants of the Rush Memory and Aging Project, an ongoing longitudinal clinical-autopsy study. A nerve fascicle, obtained from a fixed popliteal segment of the tibial nerve, was separated from the blood vessels and adipose tissue for postmortem examination under an optical microscope. Morphometric characteristics of the myelinated nerve fibres were automatically segmented and quantified using our open-source software AxonDeepSeg. The participants (N = 140) had a mean age of 92.0 years (SD = 5.4) at death, and 72.1% (N = 101) were women. We examined 754 247 myelinated nerve fibres, with an average 5387 (SD = 3436) nerve fibres per participant. The average diameter of myelinated nerve fibres was 4.9 µm (SD = 3.1), axon diameter was 2.0 µm (SD = 1.4), myelin thickness was 1.4 µm (SD = 0.96) and the g-ratio (ratio of axon diameter to myelinated nerve fibre diameter) was 0.45 (SD = 0.17). The relationship between axon diameter and myelin thickness was nonlinear. Myelin was thicker in larger axons up to a diameter of 8 µm, beyond which myelin thickness plateaued. Older age at death was associated with smaller myelinated nerve fibres, smaller axons and thinner myelin. However, age at death was not correlated with myelinated nerve fibre density and was not associated with the average of g-ratio. The association between older age and smaller myelinated nerve fibres was largely attributable to a lower percentage of myelinated nerve fibres >8 µm. We conclude that the smaller tibial myelinated nerve fibres observed in older adults may reflect axonal atrophy rather than degeneration and regeneration of the myelinated nerve fibres. Further research is needed to investigate the pathologies and molecular mechanisms underlying these age-related morphometric changes and their clinical implications in older adults.

BACKGROUND AND OBJECTIVES:Intracranial atherosclerosis disease (ICAD) accounts for 30% of ischemic strokes, has the highest stroke recurrence rate, and is associated with accelerated cognitive decline. This study investigates associations between diet patterns and the risk of ICAD. METHOD:Participants in a longitudinal clinical neuropathologic cohort study, with complete dietary, medical history, and neuropathology data, were included. Diet scores were computed (median interval to death = 5.9 [3.0-8.7] years). History of hypertension (HTN) and myocardial infarction (MI) were self-reported. Large vessel ICAD was evaluated at the circle of Willis, and severity of ICAD was assessed based on number of atherosclerotic plaques, extent of vessel involvement, and degree of vessel occlusion to create a 4-level grading system (0-3). All regression models were adjusted for age, sex, education, caloric intake, and APOE4. RESULTS:Of the 676 participants (mean age at death = 91.1 years, SD = 6.1, 71% women), 361 (53%) had mild, 142 (21%) had moderate, and 28 (4%) had severe ICAD. There was no direct relationship between diet and ICAD. The association between ICAD and MI (OR 1.38, 95% CI 0.95-2.00) was not significant. HTN (OR 1.598, 95% CI 1.15-2.18) was positively associated with ICAD. The association of diet with ICAD differed by history of MI (Mediterranean-DASH intervention for neurodegenerative delay [MIND] [p = 0.007], MedDiet [p = 0.006]). The association between ICAD and the MIND diet also differed by whether HTN was reported (β = -0.212, SE = 0.111, p = 0.055) as did the relationship between ICAD and the MedDiet (β = -0.077, SE = 0.035, p = 0.029). In stratified analysis, among individuals with preexisting MI (N = 130), those with a better diet had lower odds of ICAD (MedDiet: OR 0.88, 95% CI 0.81-0.96; MIND: OR 0.69, 95% CI 0.53-0.90). DISCUSSION:A direct relationship between diet and ICAD was not seen. Stratified analysis suggested that healthy diet may be of value for individuals with HTN or MI: In these high-risk individuals, a healthy dietary pattern is associated with lower odds of severe large vessel ICAD. In vivo studies of dietary habits and brain health, specifically in those at high vascular risk, are needed.

Importance:Hippocampal sclerosis (HS), defined as severe neuronal loss and astrogliosis in coronal sections of the midhippocampus cornu ammonis 1 or subiculum, is an important pathology associated with limbic-predominant age-related transactive response DNA-binding protein 43 encephalopathy neuropathological change (LATE-NC), Alzheimer disease, and dementia. The association of diet with HS or HS with LATE-NC in humans remains underexplored. Objective:To investigate the association of the Mediterranean-Dietary Approaches to Stop Hypertension Intervention for Neurodegenerative Delay (MIND) diet with HS and HS with LATE-NC. Design, Setting, and Participants:This cohort study included autopsied participants from the ongoing Rush Memory and Aging Project cohort study. Participants with dietary and neuropathological data from 2004 to 2024 were included. Data were analyzed from April 3, 2024, to May, 13, 2025. Exposures:Mean MIND diet scores (range, 0-15; higher score indicates better diet), computed from all validated food frequency questionnaires administered annually for up to 18 years before death. Main Outcomes and Measures:The outcomes of interest were presence of HS, assessed using hematoxylin and eosin staining, and presence of LATE-NC, detected by TDP-43 immunohistochemistry in 8 brain regions. For a subset of 300 participants, hippocampal neuronal loss severity was scored using a semiquantitative scale from 0, indicating none, to 5, severe, and categorized as none to mild, moderate, and severe neuronal loss. Results:Among 809 participants (mean [SD] age at death, 91.3 [6.1] years; 538 [72%] female; mean [SD] follow-up, 7.2 [4.4] years), HS was present in 82 (10.1%) participants; 71 participants (9%) had both HS and LATE-NC, and in the scored subset, 43 participants (14%) had moderate and 35 participants (12%) had severe hippocampal neuronal loss. Higher MIND diet scores were associated with lower odds of HS (odds ratio [OR], 0.78; 95% CI, 0.65 to 0.95) and HS with LATE-NC (OR, 0.79; 95% CI, 0.64 to 0.97) after controlling for age at death, sex, education, total calories, APOE-ε4 status, AD, and vascular pathologies. In mediation analyses, the MIND diet was associated with less dementia at the time of death (β = -0.26; 95% CI, -0.36 to -0.15; P < .001), with an indirect association of 21% through HS (β = -0.05; 95% CI, -0.10 to -0.01; P = .02). A higher MIND diet score was associated with less hippocampal neuronal loss (P for trend = .01). Conclusions and Relevance:This cohort study of autopsied participants found that MIND diet adherence during follow-up was associated with a lower likelihood of HS, HS with LATE-NC, and hippocampal neuronal loss. The association of diet with dementia was partially mediated by its association with HS. These findings suggest that the MIND diet may reduce adverse brain health outcomes.

Age-related neurodegenerative and cerebrovascular neuropathologies often coexist in the brain of older adults and contribute to brain abnormalities, cognitive decline and dementia. While deep gray matter structures are implicated early and/or strongly in these processes, the independent effects of various age-related neuropathologies on these structures remain poorly understood. The goal of this study was to investigate the independent association of various age-related neuropathologies with the volume and shape of deep gray matter structures in a large number of community-based older adults that came to autopsy. Cerebral hemispheres from 842 participants of four community studies at the Rush Alzheimer's Disease Center were imaged with MRI ex vivo and underwent detailed neuropathologic examination. Linear regression was used to study the association of various neuropathologies with the volume and shape of six deep gray matter structures (hippocampus, amygdala, caudate, thalamus, nucleus accumbens, putamen) controlling for age at death, sex, years of education, scanner, and postmortem intervals. Both the volumetric and shape analyses showed independent associations of tangles with structural abnormalities in all deep brain structures, of limbic-predominant age-related TDP-43 encephalopathy neuropathological change (LATE-NC) with hippocampus and amygdala, of atherosclerosis with hippocampus, and of gross infarcts with caudate (all p  < 0.05 corrected for multiple comparisons). Shape analysis revealed the corresponding independent spatial patterns of inward deformation and also showed additional associations of neuropathologies with deep brain structures ( p  < 0.05 corrected for multiple comparisons). When analyses were repeated in left and right hemispheres separately, the results were mostly similar in both hemispheres. Mixed pathologies are very common in the older adult brain and the present comprehensive study disentangles their independent effects on multiple deep gray matter structures. These neuropathologic signatures may potentially be used in combination with other features toward in vivo prediction of neuropathologies which could have important implications in future clinical trials and the development of prevention and treatment strategies.

INTRODUCTION:Older Black adults are at risk of cerebral small vessel disease (CSVD), which contributes to dementia risk. Two subtypes of CSVD, arteriolosclerosis and ischemic lacunar infarcts, have been independently linked to lower cognition and higher dementia risk, but their combined effects on cognition in older Black adults are unclear. METHODS:Mixed models were used to examine the associations of in vivo measures of arteriolosclerosis (ARTS) and ischemic lacunar infarcts to cognitive level and change in 370 older Black adults without dementia.  RESULTS: Modeled together, higher ARTS load accounted for lower levels of global cognition, episodic memory, semantic memory, and perceptual speed, whereas higher infarct load accounted for lower levels of working memory. There were no associations with rate of cognitive change. DISCUSSION:Both arteriolosclerosis and ischemic infarcts impact the cognitive health of older Black adults, but arteriolosclerosis affects cognition more broadly and offers promise as an in vivo biomarker of dementia risk. HIGHLIGHTS:Older Black adults are at risk of cerebral small vessel disease (CSVD) and dementia. Examined magnetic resonance imaging-derived measure of arteriolosclerosis (ARTS), infarcts, and cognition. ARTS load was widely associated with lower cognition after adjusting for infarct load. Infarct load was specifically associated with lower complex attention. More within-Black in vivo studies of CSVD subtypes and cognition are needed.