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Veterinary Pathology Sep 2019During a screen for vascular phenotypes in aged laboratory mice, a unique discrete phenotype of hyaline arteriolosclerosis of the intertubular arteries and arterioles of...
During a screen for vascular phenotypes in aged laboratory mice, a unique discrete phenotype of hyaline arteriolosclerosis of the intertubular arteries and arterioles of the testes was identified in several inbred strains. Lesions were limited to the testes and did not occur as part of any renal, systemic, or pulmonary arteriopathy or vasculitis phenotype. There was no evidence of systemic or pulmonary hypertension, and lesions did not occur in ovaries of females. Frequency was highest in males of the SM/J (27/30, 90%) and WSB/EiJ (19/26, 73%) strains, aged 383 to 847 days. Lesions were sporadically present in males from several other inbred strains at a much lower (<20%) frequency. The risk of testicular hyaline arteriolosclerosis is at least partially underpinned by a genetic predisposition that is not associated with other vascular lesions (including vasculitis), separating out the etiology of this form and site of arteriolosclerosis from other related conditions that often co-occur in other strains of mice and in humans. Because of their genetic uniformity and controlled dietary and environmental conditions, mice are an excellent model to dissect the pathogenesis of human disease conditions. In this study, a discrete genetically driven phenotype of testicular hyaline arteriolosclerosis in aging mice was identified. These observations open the possibility of identifying the underlying genetic variant(s) associated with the predisposition and therefore allowing future interrogation of the pathogenesis of this condition.
Topics: Aging; Animals; Arteriosclerosis; Female; Genetic Predisposition to Disease; Hyalin; Male; Mice; Mice, Inbred Strains; Rodent Diseases; Testicular Diseases; Testis
PubMed: 31060453
DOI: 10.1177/0300985819844822 -
JAMA Neurology Nov 2019Chronic traumatic encephalopathy (CTE) is a neurodegenerative disease associated with repetitive head impacts, including those from US football, that presents with...
IMPORTANCE
Chronic traumatic encephalopathy (CTE) is a neurodegenerative disease associated with repetitive head impacts, including those from US football, that presents with cognitive and neuropsychiatric disturbances that can progress to dementia. Pathways to dementia in CTE are unclear and likely involve tau and nontau pathologic conditions.
OBJECTIVE
To investigate the association of white matter rarefaction and cerebrovascular disease with dementia in deceased men older than 40 years who played football and had CTE.
DESIGN, SETTING, AND PARTICIPANTS
This cross-sectional study involves analyses of data from the ongoing Understanding Neurologic Injury and Traumatic Encephalopathy (UNITE) Study, which is conducted via and included brain donors from the Veterans Affairs-Boston University-Concussion Legacy Foundation brain bank between 2008 and 2017. An original sample of 224 men who had played football and were neuropathologically diagnosed with CTE was reduced after exclusion of those younger than 40 years and those missing data.
EXPOSURES
The number of years of football play as a proxy for repetitive head impacts.
MAIN OUTCOMES AND MEASURES
Neuropathological assessment of white matter rarefaction and arteriolosclerosis severity (on a scale of 0-3, where 3 is severe); number of infarcts, microinfarcts, and microbleeds; and phosphorylated tau accumulation determined by CTE stage and semiquantitative rating of dorsolateral frontal cortex (DLFC) neurofibrillary tangles (NFTs) (none or mild vs moderate or severe). Informant-based retrospective clinical interviews determined dementia diagnoses via diagnostic consensus conferences.
RESULTS
A total of 180 men were included. The mean (SD) age of the sample at death was 67.9 (12.7) years. Of 180, 120 [66.7%]) were found to have had dementia prior to death. Moderate to severe white matter rarefaction (84 of 180 [46.6%]) and arteriolosclerosis (85 of 180 [47.2%]) were common; infarcts, microinfarcts, and microbleeds were not. A simultaneous equations regression model controlling for age and race showed that more years of play was associated with more severe white matter rarefaction (β, 0.16 [95% CI, 0.02-0.29]; P = .03) and greater phosphorylated tau accumulation (DLFC NFTs: β, 0.15 [95% CI, 0.004-0.30]; P = .04; CTE stage: β, 0.27 [95% CI, 0.14-0.41]; P < .001). White matter rarefaction (β, 0.16 [95% CI, 0.02-0.29]; P = .03) and DLFC NFTs (β, 0.16 [95% CI, 0.03-0.28]; P = .01) were associated with dementia. Arteriolosclerosis and years of play were not associated, but arteriolosclerosis was independently associated with dementia (β, 0.21 [95% CI, 0.07-0.35]; P = .003).
CONCLUSIONS AND RELEVANCE
Among older men who had played football and had CTE, more years of football play were associated with more severe white matter rarefaction and greater DLFC NFT burden. White matter rarefaction, arteriolosclerosis, and DLFC NFTs were independently associated with dementia. Dementia in CTE is likely a result of neuropathologic changes, including white matter rarefaction and phosphorylated tau, associated with repetitive head impact and pathologic changes not associated with head trauma, such as arteriolosclerosis.
PubMed: 31380975
DOI: 10.1001/jamaneurol.2019.2244 -
Journal of Neuropathology and... Apr 2023The relationship between past medical histories (PMH) and dementia-related neuropathologies is not well understood. Using the National Alzheimer's Coordinating Center...
The relationship between past medical histories (PMH) and dementia-related neuropathologies is not well understood. Using the National Alzheimer's Coordinating Center (NACC) database, we explored the relationship between patient-reported PMH and various vascular and degenerative neuropathologies. We examined the following PMH: transient ischemic attack (TIA), stroke, traumatic brain injury, seizures, hypertension, cardiovascular events, hypercholesterolemia, B12 deficiency, diabetes mellitus, and thyroid disease. We dichotomized the following neuropathologies: atherosclerosis, arteriolosclerosis, cerebral amyloid angiopathy (CAA), Alzheimer disease neuropathology (ADNP), Lewy bodies (LB), hippocampal sclerosis, frontotemporal lobar degeneration (FTLD), and TAR DNA-binding protein-43 (TDP-43). Separate logistic regression models assessed the relationship between the outcome of individual neuropathologies and all PMHs. Additional logistic regressions were stratified by sex to further examine these associations. Hypertension history was associated with an increased likelihood of atherosclerosis (OR = 1.7) and arteriolosclerosis (OR = 1.3), but decreased odds of ADNP (OR = 0.81), CAA (OR = 0.79), and LB (OR = 0.78). History of TIA was associated with an increased likelihood of atherosclerosis (OR = 1.3) and arteriolosclerosis (OR = 1.4) and lower odds of ADNP (OR = 0.72). Seizure history was associated with an increased likelihood of ADNP (OR = 1.9) and lower odds of FTLD (OR = 0.49). Hypertension history was associated with a greater likelihood of vascular pathologies yet a lower likelihood of ADNP and other neurodegenerative pathologies.
Topics: Humans; Alzheimer Disease; Brain; Arteriolosclerosis; Ischemic Attack, Transient; Frontotemporal Dementia; Hypertension; Atherosclerosis
PubMed: 36947583
DOI: 10.1093/jnen/nlad020 -
Annals of Neurology Nov 2023A definite diagnosis of cerebral amyloid angiopathy (CAA), characterized by the accumulation of amyloid β in walls of cerebral small vessels, can only be obtained...
OBJECTIVE
A definite diagnosis of cerebral amyloid angiopathy (CAA), characterized by the accumulation of amyloid β in walls of cerebral small vessels, can only be obtained through pathological examination. A diagnosis of probable CAA during life relies on the presence of hemorrhagic markers, including lobar cerebral microbleeds (CMBs). The aim of this project was to study the histopathological correlates of lobar CMBs in false-positive CAA cases.
METHODS
In 3 patients who met criteria for probable CAA during life, but showed no CAA upon neuropathological examination, lobar CMBs were counted on ex vivo 3T magnetic resonance imaging (MRI) and on ex vivo 7T MRI. Areas with lobar CMBs were next sampled and cut into serial sections, on which the CMBs were then identified.
RESULTS
Collectively, there were 25 lobar CMBs on in vivo MRI and 22 on ex vivo 3T MRI of the analyzed hemispheres. On ex vivo MRI, we targeted 12 CMBs for sampling, and definite histopathological correlates were retrieved for 9 of them, of which 7 were true CMBs. No CAA was found on any of the serial sections. The "culprit vessels" associated with the true CMBs instead showed moderate to severe arteriolosclerosis. Furthermore, CMBs in false-positive CAA cases tended to be located more often in the juxtacortical or subcortical white matter than in the cortical ribbon.
INTERPRETATION
These findings suggest that arteriolosclerosis can generate lobar CMBs and that more detailed investigations into the exact localization of CMBs with respect to the cortical ribbon could potentially aid the diagnosis of CAA during life. ANN NEUROL 2023;94:856-870.
Topics: Humans; Cerebral Hemorrhage; Amyloid beta-Peptides; Arteriolosclerosis; Cerebral Amyloid Angiopathy; White Matter; Magnetic Resonance Imaging
PubMed: 37548609
DOI: 10.1002/ana.26761 -
Alzheimer's & Dementia : the Journal of... Nov 2023We investigated the link between locus coeruleus (LC) pathology and cerebral microangiopathy in two large neuropathology datasets.
INTRODUCTION
We investigated the link between locus coeruleus (LC) pathology and cerebral microangiopathy in two large neuropathology datasets.
METHODS
We included data from the National Alzheimer's Coordinating Center (NACC) database (n = 2197) and Religious Orders Study and Rush Memory and Aging Project (ROSMAP; n = 1637). Generalized estimating equations and logistic regression were used to examine associations between LC hypopigmentation and presence of cerebral amyloid angiopathy (CAA) or arteriolosclerosis, correcting for age at death, sex, cortical Alzheimer's disease (AD) pathology, ante mortem cognitive status, and presence of vascular and genetic risk factors.
RESULTS
LC hypopigmentation was associated with higher odds of overall CAA in the NACC dataset, leptomeningeal CAA in the ROSMAP dataset, and arteriolosclerosis in both datasets.
DISCUSSION
LC pathology is associated with cerebral microangiopathy, independent of cortical AD pathology. LC degeneration could potentially contribute to the pathways relating vascular pathology to AD. Future studies of the LC-norepinephrine system on cerebrovascular health are warranted.
HIGHLIGHTS
We associated locus coeruleus (LC) pathology and cerebral microangiopathy in two large autopsy datasets. LC hypopigmentation was consistently related to arteriolosclerosis in both datasets. LC hypopigmentation was related to cerebral amyloid angiopathy (CAA) presence in the National Alzheimer's Coordinating Center dataset. LC hypopigmentation was related to leptomeningeal CAA in the Religious Orders Study and Rush Memory and Aging Project dataset. LC degeneration may play a role in the pathways relating vascular pathology to Alzheimer's disease.
Topics: Humans; Alzheimer Disease; Locus Coeruleus; Arteriolosclerosis; Cerebral Amyloid Angiopathy; Cerebral Small Vessel Diseases; Autopsy; Hypopigmentation
PubMed: 37095709
DOI: 10.1002/alz.13096 -
Stroke Jun 2021The general cardiovascular Framingham risk score (FRS) identifies adults at increased risk for stroke. We tested the hypothesis that baseline FRS is associated with the... (Clinical Trial)
Clinical Trial
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], <0.001), microinfarcts (odds ratio, 1.04 [95% CI, 1.01-1.07], =0.009), atherosclerosis (odds ratio, 1.07 [95% CI, 1.04-1.11], <0.001), and arteriolosclerosis (odds ratio, 1.04 [95% CI, 1.01-1.07], =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.
Topics: Age Factors; Aged; Aged, 80 and over; Autopsy; Brain; Cerebral Amyloid Angiopathy; Female; Humans; Intracranial Arteriosclerosis; Male; Risk Factors
PubMed: 33840227
DOI: 10.1161/STROKEAHA.120.030226 -
The Lancet. Healthy Longevity Mar 2023Population-based autopsy studies provide valuable insights into the causes of dementia but are limited by sample size and restriction to specific populations....
BACKGROUND
Population-based autopsy studies provide valuable insights into the causes of dementia but are limited by sample size and restriction to specific populations. Harmonisation across studies increases statistical power and allows meaningful comparisons between studies. We aimed to harmonise neuropathology measures across studies and assess the prevalence, correlation, and co-occurrence of neuropathologies in the ageing population.
METHODS
We combined data from six community-based autopsy cohorts in the US and the UK in a coordinated cross-sectional analysis. Among all decedents aged 80 years or older, we assessed 12 neuropathologies known to be associated with dementia: arteriolosclerosis, atherosclerosis, macroinfarcts, microinfarcts, lacunes, cerebral amyloid angiopathy, Braak neurofibrillary tangle stage, Consortium to Establish a Registry for Alzheimer's disease (CERAD) diffuse plaque score, CERAD neuritic plaque score, hippocampal sclerosis, limbic-predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC), and Lewy body pathology. We divided measures into three groups describing level of confidence (low, moderate, and high) in harmonisation. We described the prevalence, correlations, and co-occurrence of neuropathologies.
FINDINGS
The cohorts included 4354 decedents aged 80 years or older with autopsy data. All cohorts included more women than men, with the exception of one study that only included men, and all cohorts included decedents at older ages (range of mean age at death across cohorts 88·0-91·6 years). Measures of Alzheimer's disease neuropathological change, Braak stage and CERAD scores, were in the high confidence category, whereas measures of vascular neuropathologies were in the low (arterioloscerosis, atherosclerosis, cerebral amyloid angiopathy, and lacunes) or moderate (macroinfarcts and microinfarcts) categories. Neuropathology prevalence and co-occurrence was high (2443 [91%] of 2695 participants had more than one of six key neuropathologies and 1106 [41%] of 2695 had three or more). Co-occurrence was strongly but not deterministically associated with dementia status. Vascular and Alzheimer's disease features clustered separately in correlation analyses, and LATE-NC had moderate associations with Alzheimer's disease measures (eg, Braak stage ρ=0·31 [95% CI 0·20-0·42]).
INTERPRETATION
Higher variability and more inconsistency in the measurement of vascular neuropathologies compared with the measurement of Alzheimer's disease neuropathological change suggests the development of new frameworks for the measurement of vascular neuropathologies might be helpful. Results highlight the complexity and multi-morbidity of the brain pathologies that underlie dementia in older adults and suggest that prevention efforts and treatments should be multifaceted.
FUNDING
Gates Ventures.
Topics: Male; Female; Humans; Aged; Aged, 80 and over; Prevalence; Alzheimer Disease; Autopsy; Cross-Sectional Studies; Cerebral Amyloid Angiopathy; Atherosclerosis; Limbic Encephalitis
PubMed: 36870337
DOI: 10.1016/S2666-7568(23)00019-3 -
JAMA Neurology Jan 2023Scam susceptibility is associated with adverse financial and health outcomes, including an increased risk of cognitive decline and dementia. Very little is known about...
IMPORTANCE
Scam susceptibility is associated with adverse financial and health outcomes, including an increased risk of cognitive decline and dementia. Very little is known about the role of cerebrovascular pathologies with scam susceptibility.
OBJECTIVE
To examine the association of diverse cerebrovascular pathologies (globally and regionally) with scam susceptibility.
DESIGN, SETTING, AND PARTICIPANTS
This clinical-pathological cohort study included participants from 2 ongoing studies of aging that began enrollment in 1994 and 1997. In 2010, participants were enrolled in the decision-making and behavioral economics substudy and were followed up for a mean (SD) of 3.4 (2.6) years prior to death. From 1365 older persons with clinical evaluations, 69 were excluded for having dementia at baseline. From 538 older persons who died, 408 had annual assessments for scam susceptibility, cardiovascular risk burden, and cognitive function and consented to brain donation for detailed neuropathologic examination. Data were analyzed from June 2021 through September 2022.
EXPOSURES
Neuropathologic examination identified the presence of macroscopic and microscopic infarcts, atherosclerosis, arteriolosclerosis, cerebral amyloid angiopathy, and common neurodegenerative pathologies (Alzheimer disease, limbic-predominant age-related transactive response DNA-binding protein 43 encephalopathy, and Lewy bodies).
RESULTS
There was a total of 408 participants. The mean (SD) age at death was 91 (6.1) years, the mean (SD) amount of education was 15.6 (3.1) years, and 297 (73%) were women. Participants included 4 Latino individuals (1%), 7 non-Latino Black individuals (2%), and 397 non-Latino White individuals (97%). The frequency of participants with macroscopic infarcts was 38% (n = 154), microinfarcts was 40% (n = 163), and moderate to severe vessel disease; specifically, atherosclerosis was 20% (n = 83), arteriolosclerosis was 25% (n = 100), and cerebral amyloid angiopathy was 35% (n = 143). In linear regression models adjusted for demographics and neurodegenerative pathologies, macroscopic infarcts were associated with greater scam susceptibility (estimate [SE], 0.18 [0.07]; P = .009). This association persisted after adjusting for cardiovascular risk burden and global cognition. Regionally, infarcts localized to the frontal, temporal, and occipital lobes and thalamus were associated with greater scam susceptibility. Neither arteriosclerosis, atherosclerosis, cerebral amyloid angiopathy, nor microinfarcts were associated with scam susceptibility.
CONCLUSIONS AND RELEVANCE
Cerebrovascular pathologies, specifically cerebral infarcts, is linked with greater scam susceptibility in older adults, independent of common neurodegenerative diseases such as Alzheimer disease. Future studies examining in vivo magnetic resonance imaging markers of cerebrovascular pathologies with scam susceptibility and related decision-making outcomes will be important.
Topics: Humans; Female; Aged; Aged, 80 and over; Male; Alzheimer Disease; Cohort Studies; Arteriolosclerosis; Brain; Cerebral Amyloid Angiopathy; Stroke; Infarction; Atherosclerosis
PubMed: 36315115
DOI: 10.1001/jamaneurol.2022.3711 -
Translational Stroke Research Jun 2024In intracerebral hemorrhage (ICH) with pathology-proven etiology, we performed a systematic review and meta-analysis to elucidate the association between cerebral... (Meta-Analysis)
Meta-Analysis
In intracerebral hemorrhage (ICH) with pathology-proven etiology, we performed a systematic review and meta-analysis to elucidate the association between cerebral amyloid angiopathy (CAA) and arteriolosclerosis, and directly compared MRI and pathological changes of markers of cerebral small vessel disease (CSVD). Studies enrolling primary ICH who had received an etiological diagnosis through biopsy or autopsy were searched using Ovid MEDLINE, PubMed, and Web of Science from inception to June 8, 2022. We extracted pathological changes of CSVD for each patient whenever available. Patients were grouped into CAA + arteriolosclerosis, strict CAA, and strict arteriolosclerosis subgroups. Of 4155 studies identified, 28 studies with 456 ICH patients were included. The frequency of lobar ICH (p<0.001) and total microbleed number (p=0.015) differed among patients with CAA + arteriolosclerosis, strict CAA, and strict arteriolosclerosis. Concerning pathology, severe CAA was associated with arteriolosclerosis (OR 6.067, 95% CI 1.107-33.238, p=0.038), although this association was not statistically significant after adjusting for age and sex. Additionally, the total microbleed number (median 15 vs. 0, p=0.006) was higher in ICH patients with CAA evidence than those without CAA. The pathology of CSVD imaging markers was mostly investigated in CAA-ICH. There was inconsistency concerning CAA severity surrounding microbleeds. Small diffusion-weighted imaging lesions could be matched to acute microinfarct histopathologically. Studies that directly correlated MRI and pathology of lacunes, enlarged perivascular spaces, and atrophy were scarce. Arteriolosclerosis might be associated with severe CAA. The pathological changes of CSVD markers by ICH etiology are needed to be investigated further.
Topics: Humans; Cerebral Hemorrhage; Cerebral Small Vessel Diseases; Cerebral Amyloid Angiopathy; Arteriolosclerosis
PubMed: 37280502
DOI: 10.1007/s12975-023-01154-4 -
Acta Neuropathologica Sep 2023Hippocampal sclerosis of aging (HS-A) is a common age-related neuropathological lesion characterized by neuronal loss and astrogliosis in subiculum and CA1 subfield of...
Hippocampal sclerosis of aging (HS-A) is a common age-related neuropathological lesion characterized by neuronal loss and astrogliosis in subiculum and CA1 subfield of hippocampus. HS-A is associated with cognitive decline that mimics Alzheimer's disease. Pathological diagnosis of HS-A is traditionally binary based on presence/absence of the lesion. We compared this traditional measure against our novel quantitative measure for studying the relationship between HS-A and other neuropathologies and cognitive impairment. We included 409 participants from The 90+ study with neuropathological examination and longitudinal neuropsychological assessments. In those with HS-A, we examined digitized H&E and LFB stained hippocampal slides. The length of HS-A in each subfield of hippocampus and subiculum, each further divided into three subregions, was measured using Aperio eSlide Manager. For each subregion, the proportion affected by HS-A was calculated. Using regression models, both traditional/binary and quantitative measures were used to study the relationship between HS-A and other neuropathological changes and cognitive outcomes. HS-A was present in 48 (12%) of participants and was always focal, primarily affecting CA1 (73%), followed by subiculum (9%); overlapping pathology (subiculum and CA1) affected 18% of individuals. HS-A was more common in the left (82%) than the right (25%) hemisphere and was bilateral in 7% of participants. HS-A traditional/binary assessment was associated with limbic-predominant age-related TDP-43 encephalopathy (LATE-NC; OR = 3.45, p < 0.001) and aging-related tau astrogliopathy (ARTAG; OR = 2.72, p = 0.008). In contrast, our quantitative approach showed associations between the proportion of HS-A (CA1/subiculum/combined) and LATE-NC (p = 0.001) and arteriolosclerosis (p = 0.005). While traditional binary assessment of HS-A was associated with impaired memory (OR = 2.60, p = 0.007), calculations (OR = 2.16, p = 0.027), and orientation (OR = 3.56, p < 0.001), our quantitative approach revealed additional associations with impairments in language (OR = 1.33, p = 0.018) and visuospatial domains (OR = 1.37, p = 0.006). Our novel quantitative method revealed associations between HS-A and vascular pathologies and impairment in cognitive domains that were not detected using traditional/binary measures.
Topics: Aged, 80 and over; Female; Humans; Male; Aging; Cognition; Cognitive Dysfunction; Cohort Studies; Hippocampal Sclerosis; Hippocampus; Logistic Models; Neuropathology
PubMed: 37382680
DOI: 10.1007/s00401-023-02606-9