Amyloid pathology and vascular risk are associated with distinct patterns of cerebral white matter hyperintensities: A multicenter study in 3132 memory clinic patients.

INTRODUCTION: White matter hyperintensities (WMH) are associated with key dementia etiologies, in particular arteriolosclerosis and amyloid pathology. We aimed to identify WMH locations associated with vascular risk or cerebral amyloid-ß1-42 (Aß42)-positive status. METHODS: Individual patient data (n = 3,132; mean age 71.5 ± 9 years; 49.3% female) from 11 memory clinic cohorts were harmonized. WMH volumes in 28 regions were related to a vascular risk compound score (VRCS) and Aß42 status (based on cerebrospinal fluid or amyloid positron emission tomography), correcting for age, sex, study site, and total WMH volume. RESULTS: VRCS was associated with WMH in anterior/superior corona radiata (B = 0.034/0.038, p < 0.001), external capsule (B = 0.052, p < 0.001), and middle cerebellar peduncle (B = 0.067, p < 0.001), and Aß42-positive status with WMH in posterior thalamic radiation (B = 0.097, p < 0.001) and splenium (B = 0.103, p < 0.001). DISCUSSION: Vascular risk factors and Aß42 pathology have distinct signature WMH patterns. This regional vulnerability may incite future studies into how arteriolosclerosis and Aß42 pathology affect the brain's white matter. HIGHLIGHTS: Key dementia etiologies may be associated with specific patterns of white matter hyperintensities (WMH). We related WMH locations to vascular risk and cerebral Aß42 status in 11 memory clinic cohorts. Aß42 positive status was associated with posterior WMH in splenium and posterior thalamic radiation. Vascular risk was associated with anterior and infratentorial WMH. Amyloid pathology and vascular risk have distinct signature WMH patterns.

Serum levels of sonic hedgehog in patients with IgA nephropathy are closely associated with intrarenal arteriolar lesions.

BACKGROUND: Intrarenal arteriolar disease is a major risk factor for poor prognosis in immunoglobulin A nephropathy (IgAN). The morphologic factor sonic hedgehog (SHH) plays an important role in a variety of vascular diseases, so it may be directly or indirectly involved in the process of renal arteriolar disease. The purpose of this study was to investigate the correlation between serum SHH levels and renal arteriole disease in patients with IgAN. METHODS: Subjects with primary IgAN diagnosed by renal biopsy performed between October 2018 and August 2019 at the First Medical Center of the Chinese PLA General Hospital were recruited. Blood specimens were collected from the patients within 1 week before renal biopsy after they signed an informed consent form, and healthy controls were recruited for blood specimen collection during the same period. The concentration of serum SHH was measured by enzyme-linked immunosorbent assay in this population. RESULTS: Serum SHH levels were significantly lower in the IgAN group than in the control group. 41 of the 94 subjects diagnosed with IgAN had severe renal arteriolosclerosis and, compared to their less severely affected counterparts, were older, more hypertensive, and characterized by lower levels of SHH, higher levels of tubular atrophy/interstitial fibrosis and a higher Lee's classification. Serum SHH concentration was found to be an independent predictor of severe intrarenal arteriolosclerosis in IgAN subjects after correction using multivariate analysis. CONCLUSION: In this study, serum SHH levels were found to be significantly lower in patients with IgAN than in healthy subjects. Serum SHH may serve as a noninvasive biomarker of intrarenal arteriolosclerosis in patients with IgAN.

Changes in an in-vivo classifier of ARTerioloSclerosis (ARTS) with simultaneous change in cognition for older African Americans.

At autopsy, African American decedents often have mixed Alzheimer's and cerebrovascular brain pathologies including arteriolosclerosis. We applied a novel in-vivo classifier of ARTerioloSclerosis (ARTS) in 167 older African Americans (∼75y of age) with > 2 biennial 3 T MRI scans and > 3 years of associated cognitive follow-up to determine if ARTS scores (higher score=higher likelihood of arteriolosclerosis) changed over time and if this change associated with changes in cognition in the same individuals. Mixed effects regression models tested whether ARTS scores increased over time, while simultaneous mixed effects regression models estimated the simultaneous rates of change in both ARTS and cognition and the correlation of these changes. ARTS scores increased over time (estimate=0.030, SE=0.002, p < 0.0001). Faster increases in ARTS were associated with faster rates of global cognitive decline (r = -0.447, p = 0.006) and domain-specific cognitive functions. Applying an in-vivo marker of arteriolosclerosis in an African American cohort revealed that the likelihood of arteriolosclerosis increases over time, and participants whose ARTS scores increased more rapidly tended to have faster than average rates of cognitive decline.

Clinicopathological characteristics, risk factors and prognostic value of intrarenal vascular lesions in IgA nephropathy.

BACKGROUND: The aim was to study clinicopathological characteristics, risk factors and renal outcome in IgA nephropathy (IgAN) patients with vascular lesions. METHODS: We enrolled a Chinese cohort with 458 biopsy-confirmed primary IgAN patients for a retrospective analysis. They were divided into three groups according to vascular lesions: no vascular lesions (n = 239), arterio-/arteriolosclerosis (n = 181) and microangiopathic lesions (n = 38). The clinicopathological features and renal outcome were recorded. In univariate and multivariate models, association between vascular lesions and renal outcome and vascular lesions associated clinical factors were analyzed. RESULTS: Patients with vascular lesions presented worse clinical characteristics with regard to blood pressure and kidney function, and segmental glomerulosclerosis (S1), tubular atrophy/interstitial fibrosis (T1/2) and lymphocytes and monocytes infiltration were more common. Furthermore, older age, hyperuricemia, proteinuria, global glomerulosclerosis and endocapillary hypercellularity (E1) were more severe in patients with simple arterio-/arteriolosclerosis. By multivariate logistic regression, age, MAP and eGFR were significantly associated with vascular lesions. Vascular lesions, especially arterio-/arteriolosclerosis, were significantly associated with poorer renal survival in IgAN patients, and renal survival was similar whether patients with arterio-/arteriolosclerosis received immunosuppressive therapy. In addition to eGFR, arterio-/arteriolosclerosis, along with arterial intimal fibrosis, was an independent predictor for renal survival in multivariate Cox analyses. CONCLUSION: IgAN patients with vascular lesions, especially with arterio-/arteriolosclerosis, presented more severe clinicopathological features. Renal function, blood pressure and age contributed to distinguishing patients with vascular lesions. Arterio-/arteriolosclerosis lesions were associated with poorer renal survival.

Locus coeruleus pathology is associated with cerebral microangiopathy at autopsy.

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.

Association of vascular and degenerative brain pathologies and past medical history from the National Alzheimer's Coordinating Center Database.

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.

Arteriolosclerosis differs from venular collagenosis in relation to cerebrovascular parenchymal damages: an autopsy-based study.

BACKGROUND AND PURPOSE: Cerebrovascular parenchymal damage is prevalent in ageing brains; however, its vascular aetiology has not been fully elucidated. In addition to the underlying role of sclerotic arterioles, the correlation between collagenised venules has not been clarified. Here, we aimed to investigate the associations between microvascular injuries, including arteriolosclerosis and venular collagenosis, and related parenchymal damages in ageing brains, to investigate the underlying correlations. METHODS: We evaluated arteriolosclerosis and venular collagenosis in 7 regions from 27 autopsy cases with no history of stroke or brain tumour. The correlations between the ratio of arteriolosclerosis, venular collagenosis and the severity of cerebrovascular parenchymal damage, including lacunes, microinfarcts, myelin loss, and parenchymal and perivascular haemosiderin deposits, were assessed. RESULTS: Arteriolosclerosis and venular collagenosis became more evident with age. Arteriolosclerosis was associated with lacunes (p=0.004) and brain parenchymal haemosiderin deposits in the superior frontal cortex (p=0.024) but not with leukoaraiosis severity. Venular collagenosis was not associated with the number of lacunes or haemosiderin, while white matter generally became paler with severe venular collagenosis in the periventricular (ß=-0.430, p=0.028) and deep white matter (ß=-0.437, p=0.025). CONCLUSION: Our findings imply an important role for venular lesions in relation to microvessel-related parenchymal damage which is different from that for arteriolosclerosis. Different underlying mechanisms of both cerebral arterioles and venules require further investigation.

Association of Stroke and Cerebrovascular Pathologies With Scam Susceptibility in Older Adults.

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.

Pontine Arteriolosclerosis and Locus Coeruleus Oxidative Stress Differentiate Resilience from Mild Cognitive Impairment in a Clinical Pathologic Cohort.

Locus coeruleus (LC) neurodegeneration is associated with cognitive deterioration during the transition from normal cognition to mild cognitive impairment (MCI) and Alzheimer disease (AD). However, the extent to which LC degenerative processes differentiate cognitively normal, "resilient" subjects bearing a high AD pathological burden from those with MCI or AD remains unclear. We approached this problem by quantifying the number of LC neurons and the percentage of LC neurons bearing AT8 tau pathology, TDP-43 pathology, or a marker for DNA/RNA oxidative damage, in well-characterized subjects diagnosed as normal cognition-low AD pathology (NC-LP), NC-high AD pathology (NC-HP), MCI, or mild/moderate AD. In addition, the severity of pontine arteriolosclerosis in each subject was compared across the groups. There was a trend for a step-wise ∼20% loss of LC neuron number between the NC-LP, NC-HP and MCI subjects despite a successive, significant ∼80%-100% increase in tau pathology between these groups. In contrast, increasing pontine arteriolosclerosis severity scores and LC oxidative stress burden significantly separated the NC-LP/HP and MCI/AD groups via comparative, correlation, and regression analysis. Pontine perfusion, as well as LC neuronal metabolic and redox function, may impact noradrenergic LC modulation of cognition during the preclinical and prodromal stages of AD.

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

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.

Neuropathologic Findings in Chronic Kidney Disease (CKD).

Studying the neuropathologic autopsy findings in subjects with chronic kidney disease (CKD) or chronic renal failure (CRF) is difficult for several reasons: etiology of the CKD may be heterogeneous, affected patients may have one or more major co-morbidities that themselves can cause significant neurologic disease, and agonal events may result in significant findings that were of minimal significance earlier in a patient's life. We studied the constellation of neuropathologic abnormalities in 40 autopsy brains originating from subjects of ages 34-95 years (no children in the study). The most common pathologic change was that of ischemic infarcts (cystic, lacunar and/or microinfarcts), which were seen in over half of subjects. These were associated with both large artery atherosclerosis and arteriolosclerosis (A/S), the latter finding being present in 29/40 subjects. Charcot-Bouchard microaneurysms were present in the brains of three subjects, in one case associated with severe amyloid angiopathy. Microvascular calcinosis (medial sclerosis in the case of arterioles) was seen in the basal ganglia (n=8) and/or endplate region of the hippocampus (n=7) and occasional ischemic infarcts in one brain showed severe calcification. Sequelae of cerebrovascular disease (especially A/S or microvascular disease) are a common neuropathologic substrate for neurologic disability and brain lesions in this complex group of patients. Regulation of calcium metabolism within brain microvessel walls may be worthy of further research in both human brain specimens and animal models.

Peripheral arterial stiffness is correlated with intrarenal arteriolosclerosis according to biopsies from patients with kidney disease.

AIM: To investigate the possible associations between intrarenal arteriolosclerosis as determine by renal biopsy and endothelial function as well as arterial stiffness measured by peripheral arterial tonometry (EndoPAT). METHODS: This was a cross-sectional study. Patients who underwent both renal biopsy and EndoPAT were recruited, and intrarenal arteriolosclerosis was graded according to the pathological slice. Endothelial function and arterial stiffness were both measured by EndoPAT and were expressed by the reactive hyperemia index (RHI) and augmentation index (AIx), respectively. AIx@75, representing the AIx standardized to a heart rate of 75 bpm was also determined. RESULTS: In total, 113 patients were assessed, the mean age was 51 ± 13, and 68.1% were men. The natural logarithm RHI (LnRHI), AIx and AIx@75 were significantly different among different grades of intrarenal arteriolosclerosis (P = .030, P < .001, P < .001, respectively). In the multivariable adjusted model, for every SD increase in the AIx and AIx@75, the odds of having more severe arteriolosclerosis were 2.506 times (95% confidence interval [CI] 1.464-4.288, P = .001] and 3.191 times (95% CI 1.780-5.719, P < .001) higher, respectively, and the association between the LnRHI and intrarenal arteriolosclerosis was nullified (P = .059). The positive values of the AIx and AIx@75 for the diagnosis of severe intrarenal arteriolosclerosis were 0.80 (95% CI 0.73-0.88, P < .001) and 0.78 (95% CI 0.70-0.87, P < .001), respectively. CONCLUSION: Subjects with more severe intrarenal arteriolosclerosis have greater peripheral vascular stiffness; AIx and AIx@75 reflected peripheral vascular stiffness could be used to identify patients with severe intrarenal arteriolosclerosis.

Klotho Deficiency Induces Arteriolar Hyalinosis in a Trade-Off with Vascular Calcification.

Hyalinosis is a vascular lesion affecting the renal vasculature and contributing to aging-related renal function decline. We assessed whether arteriolar hyalinosis is caused by Klotho deficiency, a state known to induce both renal and vascular phenotypes associated with aging. Histochemistry was used to assess hyalinosis in Klotho-/- kidneys, compared with Klotho+/- and wild-type littermates. Immunohistochemistry was used to investigate vascular lesion composition and the different layers of the vascular wall. Finally, spironolactone was used to inhibit calcification in kl/kl mice, and vascular lesions were characterized in the kidney. Arteriolar hyalinosis was detected in Klotho-/- mice, which was present up to the afferent arterioles. Hyalinosis was accompanied by loss of α-smooth muscle actin expression, whereas the endothelial lining was mostly intact. Hyalinous lesions were positive for IgM and iC3b/c/d, indicating subendothelial leakage of plasma proteins. The presence of extracellular matrix proteins suggested increased production by smooth muscle cells (SMCs). Finally, in Klotho-/- mice with marked vascular calcification, treatment with spironolactone allowed for replacement of calcification by hyalinosis. Klotho deficiency potentiates both endothelial hyperpermeability and SMC dedifferentiation. In the absence of a calcification-inducing stimulus, SMCs assume a synthetic phenotype in response to subendothelial leakage of plasma proteins. In the kidney, this results in arteriolar hyalinosis, which contributes to the decline in renal function. Klotho may play a role in preventing aging-related arteriolar hyalinosis.

Extravascular fibrinogen in the white matter of Alzheimer's disease and normal aged brains: implications for fibrinogen as a biomarker for Alzheimer's disease.

The blood-brain barrier (BBB) regulates cerebrovascular permeability and leakage of blood-derived fibrinogen. Dysfunction of the BBB has been associated with cerebral arteriolosclerosis small vessel disease (SVD) and white matter lesions (WML). Furthermore, BBB dysfunction is associated with the pathogenesis of Alzheimer's disease (AD) with the presence of CSF plasma proteins suggested to be a potential biomarker of AD. We aimed to determine if extravascular fibrinogen in the white matter was associated with the development of AD hallmark pathologies, i.e., hyperphosphorylated tau (HPτ) and amyloid-ß (Aß), as well as SVD, cerebral amyloid angiopathy (CAA) and measures of white matter damage. Using human post-mortem brains, parietal tissue from 20 AD and 22 non-demented controls was quantitatively assessed for HPτ, Aß, white matter damage severity, axonal density, demyelination and the burden of extravascular fibrinogen in both WML and normal appearing white matter (NAWM). SVD severity was determined by calculating sclerotic indices. WML- and NAWM fibrinogen burden was not significantly different between AD and controls nor was it associated with the burden of HPτ or Aß pathology, or any measures of white matter damage. Increasing severity of SVD was associated with and a predictor of both higher WML- and NAWM fibrinogen burden (all P < 0.05) in controls only. In cases with minimal SVD NAWM fibrinogen burden was significantly higher in the AD cases (P < 0.05). BBB dysfunction was present in both non-demented and AD brains and was not associated with the burden of AD-associated cortical pathologies. BBB dysfunction was strongly associated with SVD but only in the non-demented controls. In cases with minimal SVD, BBB dysfunction was significantly worse in AD cases possibly indicating the influence of CAA. In conclusion, extravascular fibrinogen is not associated with AD hallmark pathologies but indicates SVD, suggesting that the presence of fibrinogen in the CSF is not a surrogate marker for AD pathology.

Sex differences in Alzheimer's disease and common neuropathologies of aging.

Alzheimer's dementia is significantly more common in women than in men. However, few pathological studies have addressed sex difference in Alzheimer's disease (AD) and other brain pathologies. We leveraged postmortem data from 1453 persons who participated in one of two longitudinal community-based studies of older adults, the Religious Orders Study and the Rush Memory and Aging Project. Postmortem examination identified AD pathologies, neocortical Lewy bodies, DNA-binding protein 43 (TDP-43), hippocampal sclerosis, gross and micro infarcts, atherosclerosis, arteriolosclerosis, and cerebral amyloid angiopathy. Linear and logistic regressions examined the association of sex with each of the pathologic measures. Two-thirds of subjects were women (n = 971; 67%), with a mean age at death of 89.8 (SD = 6.6) years in women and 87.3 (SD = 6.6) in men. Adjusted for age and education, women had higher levels on a global measure of AD pathology (estimate = 0.102, SE = 0.022, p < 0.001), and tau tangle density in particular (estimate = 0.334, SE = 0.074, p < 0.001), and there was a borderline difference between women and men in amyloid-ß load (estimate = 0.124, SE = 0.065, p = 0.056). In addition, compared to men, women were more likely to have more severe arteriolosclerosis (OR = 1.28, 95% CI:1.04-1.58, p = 0.018), and less likely to have gross infarcts (OR = 0.78, 95% CI:0.61-0.98, p = 0.037), although the association with gross infarct was attenuated after controlling for vascular risk factors. These data help elucidate the neuropathologic footprint of sex difference in AD and other common brain pathologies of aging.

Cutaneous Arteriolosclerosis Is Not Specific to Ischemic Hypertensive Leg Ulcers.

BACKGROUND: The histological characteristic of hypertensive leg ulcers (HLU) is the presence of "arteriolosclerosis." The pertinence of performing a skin biopsy to diagnose HLU is questionable, as cutaneous arteriolosclerosis may be related to patient comorbidities. The objective here was to evaluate the frequency of arteriolosclerosis in skin leg biopsies performed in patients without ulcer and in control patients with HLU. METHODS: We performed a retrospective study between January 2013 and July 2014. Patients were included if they had undergone a deep skin biopsy on the lower limbs, in the absence of any leg ulcer. Controls were patients with typical HLU. RESULTS: Fifty-eight patients and 6 controls were included. Hypertension was present in 25 patients (43%). Arteriolosclerosis, defined as fibrous endarteritis, was present in 35 out of 58 patients (60%) and in all of the controls. No hyalinosis or hyperplastic proliferative arteriolosclerosis was observed in the patients or controls. Only age was an independent factor associated with the presence of cutaneous arteriolosclerosis (p &x#3c; 0.0001). CONCLUSION: Cutaneous arteriolosclerosis is significantly and independently associated with age. Thus, skin biopsy seems not to be necessary for the diagnosis of HLU but only for a differential diagnosis.

Cerebral Small Vessel Disease.

Cerebral small vessel disease (CSVD) is composed of several diseases affecting the small arteries, arterioles, venules, and capillaries of the brain, and refers to several pathological processes and etiologies. Neuroimaging features of CSVD include recent small subcortical infarcts, lacunes, white matter hyperintensities, perivascular spaces, microbleeds, and brain atrophy. The main clinical manifestations of CSVD include stroke, cognitive decline, dementia, psychiatric disorders, abnormal gait, and urinary incontinence. Currently, there are no specific preventive or therapeutic measures to improve this condition. In this review, we will discuss the pathophysiology, clinical aspects, neuroimaging, progress of research to treat and prevent CSVD and current treatment of this disease.

Cerebrovascular pathology in Down syndrome and Alzheimer disease.

People with Down syndrome (DS) are at high risk for developing Alzheimer disease (AD) with age. Typically, by age 40 years, most people with DS have sufficient neuropathology for an AD diagnosis. Interestingly, atherosclerosis and hypertension are atypical in DS with age, suggesting the lack of these vascular risk factors may be associated with reduced cerebrovascular pathology. However, because the extra copy of APP leads to increased beta-amyloid peptide (Aß) accumulation in DS, we hypothesized that there would be more extensive and widespread cerebral amyloid angiopathy (CAA) with age in DS relative to sporadic AD. To test this hypothesis CAA, atherosclerosis and arteriolosclerosis were used as measures of cerebrovascular pathology and compared in post mortem tissue from individuals with DS (n = 32), sporadic AD (n = 80) and controls (n = 37). CAA was observed with significantly higher frequencies in brains of individuals with DS compared to sporadic AD and controls. Atherosclerosis and arteriolosclerosis were rare in the cases with DS. CAA in DS may be a target for future interventional clinical trials.

Spinal Arteriolosclerosis Is Common in Older Adults and Associated With Parkinsonism.

BACKGROUND AND PURPOSE: There are few studies of spinal microvascular pathologies in older adults. We characterized spinal cord microvascular pathologies and examined their associations with other spinal and brain postmortem indices and parkinsonism in older adults. METHODS: We documented 3 features of microvascular pathologies in spinal cord and brain specimens from 165 deceased older participants. We also measured spinal white matter pallor. Parkinsonian signs were assessed with a modified version of the motor section of the Unified Parkinson's Disease Rating Scale. We examined the associations of spinal arteriolosclerosis with other spinal and brain postmortem indices and parkinsonism proximate to death using regression models which controlled for age and sex. RESULTS: Microinfarcts and cerebral amyloid angiopathy were not observed within the spinal cord parenchyma. Spinal arteriolosclerosis was observed at all spinal levels (C7, T7, L4, S4) examined and was more severe posteriorly than anteriorly (posterior: 4.3, SD=0.72 versus anterior: 3.9, SD=0.74; t=14.58; P<0.001). Arteriolosclerosis was more severe in the spinal cord than in the brain (cord: 4.10, SD=0.70; brain: 3.5, SD=0.98; t=10.39; P<0.001). The severity of spinal arteriolosclerosis was associated with spinal white matter pallor (r=0.47; P<0.001). Spinal arteriolosclerosis accounted for ≈3% of the variation in parkinsonism in models controlling for age, sex, brain arteriolosclerosis, and cerebrovascular disease pathologies. Further models showed that the association of spinal arteriolosclerosis and parkinsonism was not mediated via spinal white matter pallor. CONCLUSIONS: Although the regional distribution of microvascular pathologies varies within the central nervous system, spinal arteriolosclerosis is common and may contribute to the severity of spinal white matter pallor and parkinsonism in older adults.