Small vessel cerebrovascular disease is associated with cognition in prospective Alzheimer's clinical trial participants.

BACKGROUND: Secondary prevention clinical trials for Alzheimer's disease (AD) target amyloid accumulation in asymptomatic, amyloid-positive individuals, but it is unclear to what extent other pathophysiological processes, such as small vessel cerebrovascular disease, account for participant performance on the primary cognitive outcomes in those trials. White matter hyperintensities are areas of increased signal on T2-weighted magnetic resonance imaging (MRI) that reflect small vessel cerebrovascular disease. They are associated with cognitive functioning in older adults and with clinical presentation and course of AD, particularly when distributed in posterior brain regions. The purpose of this study was to examine to what degree regional WMH volume is associated with performance on the primary cognitive outcome measure in the Anti-Amyloid Treatment in Asymptomatic Alzheimer's Disease (A4) study, a secondary prevention trial. METHODS: Data from 1791 participants (59.5% women, mean age (SD) 71.6 (4.74)) in the A4 study and the Longitudinal Evaluation of Amyloid Risk and Neurodegeneration (LEARN) companion study at the screening visit were used to quantify WMH volumes on T2-weighted fluid-attenuated inversion recovery (FLAIR) MR images. Cognition was assessed with the preclinical Alzheimer cognitive composite (PACC). We tested the association of total and regional WMH volumes with PACC performance, adjusting for age, education, and amyloid positivity status, with general linear models. We also considered interactions between WMH and amyloid positivity status. RESULTS: Increased frontal and parietal lobe WMH volume was associated with poorer performance on the PACC. While amyloid positivity was also associated with lower cognitive test scores, WMH volumes did not interact with amyloid positivity status. CONCLUSION: These results highlight the potential of small vessel cerebrovascular disease to drive AD-related cognitive profiles. Measures of small vessel cerebrovascular disease should be considered when evaluating outcome in trials, both as potential effect modifiers and as a possible target for intervention or prevention.

Inhibiting CSF1R alleviates cerebrovascular white matter disease and cognitive impairment.

White matter abnormalities, related to poor cerebral perfusion, are a core feature of small vessel cerebrovascular disease, and critical determinants of vascular cognitive impairment and dementia. Despite this importance there is a lack of treatment options. Proliferation of microglia producing an expanded, reactive population and associated neuroinflammatory alterations have been implicated in the onset and progression of cerebrovascular white matter disease, in patients and in animal models, suggesting that targeting microglial proliferation may exert protection. Colony-stimulating factor-1 receptor (CSF1R) is a key regulator of microglial proliferation. We found that the expression of CSF1R/Csf1r and other markers indicative of increased microglial abundance are significantly elevated in damaged white matter in human cerebrovascular disease and in a clinically relevant mouse model of chronic cerebral hypoperfusion and vascular cognitive impairment. Using the mouse model, we investigated long-term pharmacological CSF1R inhibition, via GW2580, and demonstrated that the expansion of microglial numbers in chronic hypoperfused white matter is prevented. Transcriptomic analysis of hypoperfused white matter tissue showed enrichment of microglial and inflammatory gene sets, including phagocytic genes that were the predominant expression modules modified by CSF1R inhibition. Further, CSF1R inhibition attenuated hypoperfusion-induced white matter pathology and rescued spatial learning impairments and to a lesser extent cognitive flexibility. Overall, this work suggests that inhibition of CSF1R and microglial proliferation mediates protection against chronic cerebrovascular white matter pathology and cognitive deficits. Our study nominates CSF1R as a target for the treatment of vascular cognitive disorders with broader implications for treatment of other chronic white matter diseases.

Frank's Sign: A Link Between Dermatovenerology, Cardiac Pathology, and Neurology.

Dear Editor, Although some of my colleagues may find this surprising, as a neurologist, I have noticed many connections between dermatology and neurology. Neurological and dermatological signs and symptoms are common in many clinical entities, especially in the so-called phakomatoses or neurocutaneous syndromes (Von Recklinghausen's disease type 1 and 2, Bourneville-Pringle syndrome, Sturge-Weber syndrome, Von Hippel-Lindau syndrome, Louis-Bar syndrome) (1). The terms "neurodermatitis" and "neurodermatology" also confirm the above. Inspection is the basis of every clinical examination and an integral part of both dermatological and neurological propaedeutics. Therefore, I would like to remind your readers of Frank's sign, another link between dermatology and neurology. Frank's sign is a diagonal earlobe crease (DELC) that extends backwards from the tragus at a 45-degree angle across the lobule to the auricular edge of the ear (Figure 1). It has been described as a dermatological marker for atherosclerosis. Frank's sign is named after Dr. Sanders T. Frank, who observed this crease in 20 patients with coronary artery disease and published his findings in The New England Journal of Medicine in 1973 (2). Although this sign has been known for more than 50 years, it is still not routinely employed in clinical practice. Histopathological examination of DELC-positive earlobes revealed myoelastofibrosis in the arterial vessel at the base of the earlobe, indicating that DELC is not a coincidental finding but is directly related to atherosclerosis (3). Following the finding of DELC in patients with coronary artery disease, numerous studies have confirmed the presence of DELC in peripheral vascular disease as well as cerebrovascular disease. I encountered the description of this sign as a student in the textbook of Internal Medicine in 1991 (4). This sign was also the subject of research by Croatian authors. In 1998, Miric et al. found that a positive Frank's sign carried a higher risk of heart attack (5,6). In 2008, Glavic et al. found a statistically significant association between Frank's sign and an increase in intima media thickness (IMT) of the common carotid artery as a surrogate marker of atherosclerosis, thus confirming the hypothesis that Frank's sign is an uncontrollable risk factor for cerebrovascular disease (such as gender or age) (7). In clinical practice, earlobe inspection should be considered an integral part of the physical examination. In the case of a positive Frank's sign, a color Doppler ultrasound examination of the neck arteries and a cardiologist's examination are recommended. The determination of Frank's sign can be used as a method of primary prevention for cardiovascular and cerebrovascular diseases.

Histopathological characterization of cerebral small vessel disease in epilepsy patients with temporal lobe epilepsy submitted to surgery: A case-control study.

BACKGROUND: Cerebrovascular disease (CVD) is a major contributor to epilepsy; however, patients with epilepsy also have a significantly increased risk of stroke. The way in which epilepsy contributes to the increased risk of stroke is still uncertain and is ill-characterized in neuropathological studies. A neuropathological characterization of cerebral small vessel disease (cSVD) in patients with chronic epilepsy was performed. METHODS: Thirty-three patients with refractory epilepsy and hippocampal sclerosis (HS) submitted to epilepsy surgery from a reference center were selected between 2010 and 2020 and compared with 19 autopsy controls. Five randomly selected arterioles from each patient were analyzed using a previously validated scale for cSVD. The presence of CVD disease imaging markers in pre-surgical brain magnetic resonance imaging (MRI) was studied. RESULTS: There were no differences in age (43.8 vs. 41.6 years; p = 0.547) or gender distribution (female gender 60.6% vs. male gender 52.6%; p = 0.575) between groups. Most CVD findings in brain MRI were mild. Patients had a mean time between the epilepsy onset and surgery of 26 ± 14.7 years and were medicated with a median number of three antiseizure medication (ASMs) [IQR 2-3]. Patients had higher median scores in arteriolosclerosis (3 vs. 1; p < 0.0001), microhemorrhages (4 vs. 1; p < 0.0001) and total score value (12 vs. 8.9; p = 0.031) in comparison with controls. No correlation was found between age, number of years until surgery, number of ASMs or cumulative defined daily dosage of ASM. CONCLUSION: The present study provides evidence supporting the increased burden of cSVD in the neuropathological samples of patients with chronic epilepsy.

Effects of Cerebrovascular and Lewy Body Pathology on Parkinsonian Signs in Community-Dwelling Older Adults.

BACKGROUND AND OBJECTIVES: The roles of Lewy body (LB) and separately of cerebrovascular disease (CVD) pathologies in the severity of parkinsonian signs are well recognized in old age. We investigated whether the 2 pathologies act synergistically to further potentiate the severity of parkinsonism beyond their separate effects. METHODS: We used postmortem data of decedents from 3 longitudinal community-based studies of aging who underwent annual clinical evaluation to assess parkinsonian signs using 26 items of the motor portion of a modified Unified Parkinson Disease Rating Scale. A summary score was developed from each item score to construct a global parkinsonian score, with a higher score indicating more severe parkinsonism. A detailed neuropathologic evaluation was performed to identify LB, Alzheimer disease pathology, nigral neuronal loss, atherosclerosis, macroscopic infarcts, and other CVD pathologies (arteriolosclerosis, cerebral amyloid angiopathy, and microscopic infarcts). A series of regression models with terms for LB, CVD pathology, and the interaction of LB with CVD pathologies was fit for global parkinsonism proximate to death and for individual parkinsonian signs scores including, parkinsonian gait, rigidity, tremor, and bradykinesia. RESULTS: In 1,753 participants (mean age at death = 89 years; 68% women), LB was observed in 26% of participants, and CVD pathologies were present in more than two-thirds of participants. LB and 3 CVD pathologies (atherosclerosis, arteriolosclerosis, and macroscopic infarcts) were each independently associated with the severity of global parkinsonism proximate to death (LB: ß = 0.318, SE = 0.08, p < 0.001; atherosclerosis: ß = 0.373, SE = 0.079, p < 0.001; arteriolosclerosis: ß = 0.253, SE = 0.078, p = 0.001; macroscopic infarcts: ß = 0.333, SE = 0.077, p < 0.001). A linear regression model adjusted for demographics, CVD, and neurodegenerative pathologies showed interaction between LB and macroscopic infarcts (ß = 0.463, SE = 0.168, p = 0.006), with LBs being associated with worse global parkinsonism when macroinfarcts are present. Similar interactions were found for atherosclerosis and LBs (ß = 0.371, SE = 0.173, p = 0.032) and for parkinsonian gait as the outcome (macroscopic infarcts: ß = 0.662, SE = 0.239, p = 0.005; atherosclerosis: ß = 0.509, SE = 0.246, p = 0.038). Findings were not affected when the 66 participants with a clinical diagnosis of Parkinson disease were excluded. By contrast, there were no interactions between LB and other CVD pathologies or between atherosclerosis and macroscopic infarcts for global parkinsonism proximate to death. DISCUSSION: These findings suggest that atherosclerosis and macroscopic infarcts interact with LB pathology to increase the severity of parkinsonism beyond their additive effects in older persons.

Disrupted Brain Functional Status in Patients with Reversible Cerebral Vasoconstriction Syndrome.

OBJECTIVES: The aim of this study was to investigate the functional networks in subjects with reversible cerebral vasoconstriction syndrome (RCVS) using resting-state functional magnetic resonance imaging (rs-fMRI). METHODS: We prospectively recruited patients with RCVS and healthy controls (HCs) between February 2017 and April 2021. The rs-fMRI data were analyzed using graph theory methods. We compared node-based global and regional topological metrics (Bundle 1) and network-based intranetwork and internetwork connectivity (Bundle 2) between RCVS patients and HCs. We also explored the associations of clinical and vascular (ie, the Lindegaard index, LI) parameters with significant rs-fMRI metrics. RESULTS: A total of 104 RCVS patients and 93 HCs were included in the final analysis. We identified significantly decreased local efficiency of the left dorsal anterior insula (dAI; p = 0.0005) in RCVS patients within 30 days after disease onset as compared to HCs, which improved 1 month later. RCVS patients also had increased global efficiency (p = 0.009) and decreased average degree centrality (p = 0.045), clustering coefficient (p = 0.033), and assortativity values (p = 0.003) in node-based analysis. In addition, patients with RCVS had increased internetwork connectivity of the default mode network (DMN) with the salience (p = 0.027) and dorsal attention (p = 0.016) networks. Significant correlations between LI and regional local efficiency in left dAI (rs = -0.418, p = 0.042) was demonstrated. INTERPRETATION: The significantly lower local efficiency of the left dAI, suggestive of impaired central autonomic modulation, was negatively correlated with vasoconstriction severity, which is highly plausible for the pathogenesis of RCVS. ANN NEUROL 2023;94:772-784.

Cerebral white matter rarefaction has both neurodegenerative and vascular causes and may primarily be a distal axonopathy.

Cerebral white matter rarefaction (CWMR) was considered by Binswanger and Alzheimer to be due to cerebral arteriolosclerosis. Renewed attention came with CT and MR brain imaging, and neuropathological studies finding a high rate of CWMR in Alzheimer disease (AD). The relative contributions of cerebrovascular disease and AD to CWMR are still uncertain. In 1181 autopsies by the Arizona Study of Aging and Neurodegenerative Disorders (AZSAND), large-format brain sections were used to grade CWMR and determine its vascular and neurodegenerative correlates. Almost all neurodegenerative diseases had more severe CWMR than the normal control group. Multivariable logistic regression models indicated that Braak neurofibrillary stage was the strongest predictor of CWMR, with additional independently significant predictors including age, cortical and diencephalic lacunar and microinfarcts, body mass index, and female sex. It appears that while AD and cerebrovascular pathology may be additive in causing CWMR, both may be solely capable of this. The typical periventricular pattern suggests that CWMR is primarily a distal axonopathy caused by dysfunction of the cell bodies of long-association corticocortical projection neurons. A consequence of these findings is that CWMR should not be viewed simply as "small vessel disease" or as a pathognomonic indicator of vascular cognitive impairment or vascular dementia.

Changes in Cardiovascular Health Across Midlife and Late-Life and Magnetic Resonance Imaging Markers of Cerebral Vascular Disease in Late-Life.

BACKGROUND: Cardiovascular health may be used for prevention of cerebral vascular disease; however, data on the association of cardiovascular health across midlife and late-life with late-life cerebral vascular disease are lacking. Our aim was to examine whether midlife or late-life cardiovascular health as well as changes of cardiovascular health within midlife and between midlife and late-life were associated with prevalence of magnetic resonance imaging markers of cerebral vascular disease at late-life. METHODS: Prospective cohort study including 1638 participants from the Atherosclerosis Risk in Communities Study who took part in 2 visits at midlife (mean ages, 53 and 59 years), and a late-life visit (mean age, 76 years). A cardiovascular health Life's Simple 7 score (range, 0-12/0-14, depending on diet availability) including 6 out of 7 items was calculated at each visit, with weight assigned to each item as poor (0), intermediate (1), or ideal (2). Participants underwent 3T brain magnetic resonance imaging scans in late-life visit. Outcomes were white matter hyperintensity volume, microbleeds, and lacunar, subcortical, and cortical infarcts at late-life. Linear and logistic regression models were used to assess the associations of cardiovascular health in midlife and late-life, and improvement of cardiovascular health within midlife, and from midlife to late-life with magnetic resonance imaging markers of cerebral vascular disease, adjusting for potential confounders. RESULTS: A higher cardiovascular health in midlife, improvement of cardiovascular health within midlife, higher cardiovascular health at late-life, and improvement of cardiovascular health from midlife to late-life were associated with a lower prevalence of cerebral vascular disease markers. For example, improvement in cardiovascular health (per point) from midlife to late-life was associated with smaller white matter hyperintensity volume (ß, -0.07 [95% CI, -0.10 to -0.04]) and lower odds of microbleeds (odds ratio, 0.93 [0.90-0.97]), lacunar (odds ratio, 0.93 [0.89-0.97]), subcortical (odds ratio, 0.93 [0.89-0.97]), and cortical infarcts (odds ratio, 0.92 [0.87-0.97]). CONCLUSIONS: Improving cardiovascular health within midlife and from midlife to late-life may prevent development of cerebral vascular disease.

Predicting cerebral white matter lesions based on the platelet-to-white blood cell ratio in hypertensive patients.

Hypertension is a common chronic disease affecting many people. White matter lesions (WMLs) are one of the imaging features of cerebrovascular disease. Predicting the possibility of developing syncretic WMLs in patients with hypertension may contribute to the early identification of serious clinical conditions. This study aims to build a model to identify patients who suffered from moderate-to-severe WMLs by using recognized WMLs risk factors including age and history of diabetes and a new factor named platelet-to-white blood cell ratio (PWR). A total of 237 patients were included in this study. The Affiliated ZhongDa Hospital of Southeast University Research Ethics Committee approved this study (Ethics No. 2019ZDSYLL189-P01). We developed a nomogram to predict the risk of syncretic WMLs in patients with hypertension using the above factors. Higher total scores on the nomogram indicated a higher risk of syncretic WMLs. This means older age, smaller PWR, and patients suffering from diabetes contributed to a greater chance for the patient to suffer from syncretic WMLs. We used a decision analysis curve(DCA) to determine the net benefit of the prediction model. The DCA we constructed showed that using our model to decide whether patients suffered from syncretic WMLs or not was better than assuming they all suffered from syncretic WMLs or all WMLs-free. As a result, the area under the curve of our model was 0.787. By integrating PWR, history of diabetes, and age, we could estimate integrated WMLs in hypertensive patients. This study provides a potential tool to identify cerebrovascular disease in patients with hypertension.

Pathophysiology, cellular and molecular mechanisms of large and small vessel diseases.

Cerebrovascular disease (CVD) is the second most common cause of cognitive impairment and dementia in aged population. CVD presents in a myriad number of clinical ways based on the functional location of pathology. While primary clinical emphasis has been placed on motor, speech and visual deficits, vascular cognitive decline is a vastly under recognized and devastating condition afflicting millions of Americans. CVD, a disease of the blood vessels that supply blood to brain involves an integration between small and large vessels. Cerebral large vessel diseases (LVD) are associated with atherosclerosis, artery-to-artery embolism, intracardiac embolism and a large vessel stroke leading to substantial functional disability. Cerebral small vessel disease (SVD) is critically involved in stroke, brain hemorrhages, cognitive decline and functional loss in elderly patients. An evolving understanding of cellular and molecular mechanisms emphasizes that inflammatory vascular changes contribute to systemic pathologic conditions of the central nervous systems (CNS), with specific clinical presentations including, cognitive decline. Advances in an understanding of pathophysiology of disease processes and therapeutic interventions may help improve outcomes. This review will focus on large and small vessels diseases and their relationship to vascular cognitive decline, atherosclerosis, stroke, and inflammatory neurodegeneration. We will also emphasize the molecular and cellular mechanisms, as well as genetic and epigenetic factors associated with LVD and SVD.

Reversible Cerebral Vasoconstriction Syndrome Patients with a History of Migraine: A Retrospective Case-control Study.

Objective We investigated the clinical characteristics of patients with reversible cerebral vasoconstrictor syndrome who had a history of migraine before the onset and considered the relationship between these two pathologies. Methods We investigated 98 patients who underwent magnetic resonance angiography within 14 days of the onset of reversible cerebral vasoconstriction syndrome at our hospital. Of these, 11 cases involved recurrences, so data from 87 patients were analyzed. Materials All consecutive patients diagnosed with reversible cerebral vasoconstrictor syndrome at our institution between October 2010 and July 2021. Results Fifty of the 87 patients (57%) had a history of migraine. A multivariate analysis revealed that the following clinical factors were significantly more frequent in patients with a history of migraine than in those without such a history: female sex; emotional situations as a trigger of the onset; presence of deep and subcortical white matter hyperintensity, absence of vasoconstriction in the M1 portion of the middle cerebral artery, and absence of other cerebral lesions on initial magnetic resonance imaging; absence of vasoconstriction of the basilar artery on follow-up magnetic resonance imaging; and progression of deep and subcortical white matter hyperintensity in the chronic stage. Conclusion Reversible cerebral vasoconstrictor syndrome patients with a history of migraine showed clinical features of migraine, including one aspect of cerebral small-vessel disease due to endothelial dysfunction, as a common causative condition.

Detection of Cerebrovascular Diseases using Novel Discrete Component Wavelet Cosine Transform.

AIMS: Detecting and classifying a brain tumor amid a sole image can be problematic for doctors, although improvements can be made with medical image fusions. BACKGROUND: A brain tumor develops in the tissues surrounding the brain or the skull and has a major impact on human life. Primary tumors begin within the brain, whereas secondary tumors, identified as brain metastasis tumors, are generated outside the brain. OBJECTIVE: This paper proposes hybrid fusion techniques to fuse multi-modal images. The evaluations are based on performance metrics, and the results are compared with conventional ones. METHODS: In this paper, pre-processing is done considering enhancement methods like Binarization, Contrast Stretching, Median Filter, & Contrast Limited Adaptive Histogram Equalization (CLAHE). Authors have proposed three techniques, PCA-DWT, DCT-PCA, and Discrete ComponentWaveletCosine Transform (DCWCT), which were used to fuse CT-MR images of brain tumors. RESULTS: The different features were evaluated from the fused images, which were classified using various machine learning approaches. Maximum accuracy of 97.9% and 93.5% is obtained using DCWCT for Support Vector Machine (SVM) and k Nearest Neighbor (kNN), respectively, considering the combination of both feature's shape & Grey Level Difference Statistics. The model is validated using another online dataset. CONCLUSION: It has been observed that the classification accuracy for detecting cerebrovascular disease is better after employing the proposed image fusion technique.

Brain Enlarged Perivascular Spaces as Imaging Biomarkers of Cerebrovascular Disease: A Clinical Narrative Review.

Perivascular spaces or Virchow-Robin spaces form pathways along the subarachnoid spaces that facilitate the effective clearance of brain metabolic by-products through intracellular exchange and drainage of cerebrospinal fluid. Best seen on magnetic resonance imaging of the brain, enlarged perivascular spaces (EPVSs) are increasingly recognized as potential imaging biomarkers of neurological conditions. EPVSs are an established subtype of cerebral small-vessel disease; however, their associations with other cerebrovascular disorders are yet to be fully understood. In particular, there has been great interest in the association between the various parameters of EPVSs, such as number, size, and topography, and vascular neurological conditions. Studies have identified cross-sectional and longitudinal relationships between EPVS parameters and vascular events, such as ischemic stroke (both clinical and silent), intracerebral hemorrhage, vascular risk factors, such as age and hypertension, and neurodegenerative processes, such as vascular dementia and Alzheimer disease. However, these studies are limited by heterogeneity of data and the lack of consistent results across studied populations. Existing meta-analyses also fail to provide uniformity of results. We performed a qualitative narrative review with an aim to provide an overview of the associations between EPVSs and cerebrovascular diseases, which may help recognize gaps in our knowledge, inform the design of future studies, and advance the role of EPVSs as imaging biomarkers.

Use of proton pump inhibitor may be associated with progression of cerebral small vessel disease.

Proton pump inhibitors (PPIs) are widely used for the treatment of gastrointestinal diseases. However, recent studies have shown that chronic PPI use is associated with the progression of endothelial senescence and cerebrovascular diseases. We hypothesized that PPI users might be vulnerable to fast progression of cerebral small vessel disease (SVD) with cumulative effects. Four hundred and eleven patients, who underwent brain magnetic resonance imaging, more than twice between January 2010 and December 2016 were screened. Patients aged < 50 years, and those who had concomitant diseases that might affect the progression of cerebral SVD were excluded. Baseline characteristics were collected. We evaluated the severity of SVD using the Fazekas score, the number of cerebral microbleeds (CMBs), and assessed the progression of SVD or CMBs based on the cumulative dose of PPIs. Among the included patients (N = 137), 39 were PPI ever-users. Univariate Cox regression analysis showed that PPI use was independently associated with the progression of Fazekas score only in the deep white matter hyperintensities (WMH) (hazard ratio [HR] 2.891, 95% confidence interval [CI] 1.210-6.906, P = 0.017). In multivariate Cox regression analysis, long-term PPI use was associated with a progression of Fazekas score in the deep WMH (HR 3.453, 95% CI 1.027-9.475, P = 0.045). However, PPI use was not associated with the progression of CMB. The present study results suggest that long-term use of PPIs is associated with the progression of deep cerebral WMH. Further research is needed using a large number of patients to validate this relationship.

Postmortem 7T MRI for guided histopathology and evaluation of cerebrovascular disease.

Postmortem (PM) magnetic resonance imaging (MRI) can serve as a bridge between in vivo imaging and histology by connecting MRI observed macrostructural findings to histological staining and microstructural changes. Data were acquired from 20 formalin-fixed brains including T2, T1, PD, and T2*-weighted images of left hemispheres and 6-mm-thick coronal slices. Tissue slices were bisected, aligned to MR images and used to guide histological sampling. Markers of myelin and oligodendroglia alterations were semiquantitatively rated and compared within white matter hyperintensities (WMHs) and normal-appearing white matter. Tissue priors were created from 3T in vivo data and used to guide segmentation of WMH. PM WMH and hemisphere volumes were compared to volumes derived from in vivo data. PM T2 WMH and T1 hemisphere volumes were correlated with in vivo 3T FLAIR WMH and T1 hemisphere volumes. WMH showed significant myelin loss, decreased GFAP expression and increased vimentin expression. MR-visible perivascular spaces and cortical microvascular lesions were successfully captured on histopathological sections. PM MRI can quantify cerebrovascular disease burden and guide tissue sampling, allowing for more comprehensive characterization of cerebrovascular disease that may be used to study etiologies of age-related cognitive change.

Frequency and Underlying Pathology of Pure Vascular Cognitive Impairment.

Importance: It is not clear how common pure vascular cognitive impairment (VCI) is in the absence of Alzheimer disease (AD) and/or other neurodegenerative pathologies. Objective: To identify participants without AD and other neurodegenerative pathologies and determine the extent to which cerebrovascular disease pathologies were associated with cognitive impairment. Design, Setting, and Participants: This clinical pathological study included participants from 2 ongoing community-based cohorts that began enrollment in 1994 and 1997. Prior to death, participants were observed for a mean (SD) of 8.4 (5.3) years with annual assessments. From 2096 participants who died, 1799 (85.8%) underwent autopsy and 1767 had complete postmortem pathological examination data at the time of data analyses. To identify participants without neurodegenerative pathologies, we categorized them in 3 subgroups. A vascular subgroup was composed of participants without significant levels of neurodegenerative brain pathologies. A neurodegenerative subgroup was composed of participants without significant levels of cerebrovascular disease pathologies. A mixed subgroup was composed of the rest of the participants. Data were analyzed from May 2021 to July 2022. Exposures: Brain pathology indices obtained by postmortem pathological assessments. Main Outcomes and Measures: The primary outcome was cognitive impairment defined by presence of mild cognitive impairment or dementia. The secondary outcome was cognition assessed by 19 neuropsychological tests. Results: Of 1767 included participants, 1189 (67.3%) were women, and the mean (SD) age at death was 89.4 (6.6) years. In the vascular subgroup (n = 369), cognitive impairment was present in 156 participants (42.3%) and was associated with cerebrovascular disease pathologies (macroinfarcts: odds ratio [OR], 2.05; 95% CI, 1.49-2.82; P < .001; arteriolosclerosis in basal ganglia: OR, 1.35; 95% CI, 1.04-1.76; P = .03) but not AD or other neurodegenerative pathologies, an indication of pure VCI. In mixed-effects models including all the pathologies, only macroinfarcts were associated with a faster cognitive decline rate (estimate, -0.019; SE, 0.005; P < .001) in the vascular subgroup. Further analyses identified macroinfarcts in the frontal white matter to be associated with faster cognitive decline rate when macroinfarcts of cortical and subcortical brain regions were examined in a single model. Conclusions and Relevance: In this study, pure VCI was not rare. Macroinfarcts, specifically in frontal white matter, were the main cerebrovascular disease pathologies associated with cognitive decline in pure VCI.

Cancer and Vascular Comorbidity Effects on Dementia Risk and Neuropathology in the Oldest-Old.

BACKGROUND: Dementia, vascular disease, and cancer increase with age, enabling complex comorbid interactions. Understanding vascular and cancer contributions to dementia risk and neuropathology in oldest-old may improve risk modification and outcomes. OBJECTIVE: Investigate the contributions of vascular factors and cancer to dementia and neuropathology. METHODS: Longitudinal clinicopathologic study of prospectively followed Mayo Clinic participants dying≥95 years-old who underwent autopsy. Participants were stratified by dementia status and compared according to demographics, vascular risk factors, cancer, and neuropathology. RESULTS: Participants (n = 161; 83% female; 99% non-Hispanic whites)≥95 years (95-106 years-old) with/without dementia did not differ based on demographics. APOE ɛ2 frequency was higher in no dementia (20/72 [28%]) versus dementia (11/88 [12%]; p = 0.03), but APOE ɛ4 frequency did not differ. Coronary artery disease was more frequent in no dementia (31/72 [43%]) versus dementia (23/89 [26%]; p = 0.03) associated with 56% lower dementia odds (odds ratio [OR] = 0.44 [confidence interval (CI) = 0.19-0.98]; p = 0.04) and fewer neuritic/diffuse plaques. Diabetes had an 8-fold increase in dementia odds (OR = 8.42 [CI = 1.39-163]; p = 0.02). Diabetes associated with higher cerebrovascular disease (Dickson score; p = 0.05). Cancer associated with 63% lower dementia odds (OR = 0.37 [CI = 0.17-0.78]; p < 0.01) and lower Braak stage (p = 0.01). CONCLUSION: Cancer exposure in the oldest-old was associated with lower odds of dementia and tangle pathology, whereas history of coronary artery disease was associated with lower odds of dementia and amyloid-ß plaque pathology. History of diabetes mellitus was associated with increased odds of dementia and cerebrovascular disease pathology. Cancer-related mechanisms and vascular risk factor reduction strategies may alter dementia risk and neuropathology in oldest-old.

Willis Lecture: Biomarkers for Inflammatory White Matter Injury in Binswanger Disease Provide Pathways to Precision Medicine.

Binswanger disease is the small vessel form of vascular cognitive impairment and dementia. Deposition of Alzheimer disease proteins can begin in midlife and progress slowly, whereas aging of the vasculature also can begin in midlife, continuing to progress into old age, making mixed dementia the most common type of dementia. Biomarkers facilitate the early diagnosis of dementias. It is possible to diagnose mixed dementia before autopsy with biomarkers for vascular disease derived from diffusor tensor images on magnetic resonance imaging and Alzheimer disease proteins, Aß (amyloid ß), and phosphorylated tau, in cerebrospinal fluid or in brain with positron emission tomography. The presence of vascular disease accelerates cognitive decline. Both misfolded proteins and vascular disease promote inflammation, which can be detected in cerebrospinal fluid by the presence of MMPs (matrix metalloproteinases), angiogenic growth factors, and cytokines. MMPs disrupt the blood-brain barrier and break down myelin, producing Binswanger disease's 2 main pathological features. Advances in detecting biomarkers in plasma will provide early detection of dementia and aided by machine learning and artificial intelligence, will enhance diagnosis and form the basis for early treatments.

Correlation between 24-Hour Ambulatory Blood Pressure Variability and White Matter Lesions in Patients with Cerebral Small Vascular Disease: A Cross-Sectional Study.

Objective: The goals of this study are to assess the correlation between 24-hour ambulatory blood pressure (BP) variability and white matter lesions (WML) in patients with cerebral small vascular disease (CSVD) and to provide guidance for the prevention of WML. Methods: A total of 136 patients diagnosed with CSVD and essential hypertension were recruited and divided into two groups. The Fazekas scale was used to quantify the severity of WML. The basic information, BP levels, BP variability, and circadian rhythm changes across these groups were recorded and compared. Results: The control group consisted of 40 subjects without WML (Fazekas score = 0), and the WML group was composed of 96 patients with WML (Fazekas score ≥ 1). Patients in the WML group were then divided into three subgroups: mild WML (n = 43, Fazekas score = 1), moderate WML (n = 24, Fazekas score = 2), and severe WML (n = 29, Fazekas score = 3-4). Age, history of diabetes, and serum uric acid levels were significantly increased between the WML and control groups (P < 0.05). The levels of 24-hour mean diastolic BP (F = 3.158, P = 0.026) and daytime mean systolic BP (F = 3.526, P = 0.017) were significantly increased between the control and WML groups. There was no significant difference in the rhythmic classification of BP among all groups (P > 0.05). An ordered multinomial logistic regression analysis revealed that age, triglyceride levels, and nondipper BP were independent risk factors in WML. Conclusion: Age, history of diabetes, serum uric acid levels, 24-hour mean systolic level, and daily mean systolic BP level were significantly increased between the WML and control groups. Age, triglyceride levels, and nondipper BP were independent risk factors in WML in patients with CSVD, while the 24-hour dynamic blood pressure standard deviation and 24-hour dynamic blood pressure coefficient of variation were not associated with the occurrence of WML.

Vascular Lesions and Brain Atrophy in Alzheimer's, Vascular and Mixed Dementia: An Optimized 3T MRI Protocol Reveals Distinctive Radiological Profiles.

BACKGROUND: Vascular lesions may be a common finding also in Alzheimer's dementia, but their role on cognitive status is uncertain. OBJECTIVE: The study aims to investigate their distribution in patients with Alzheimer's, vascular or mixed dementia and detect any distinctive neuroradiological profiles. METHODS: Seventy-six subjects received a diagnosis of Alzheimer's (AD=32), vascular (VD=26) and mixed (MD=18) dementia. Three independent raters assessed the brain images acquired with an optimized 3T MRI protocol (including (3D FLAIR, T1, SWI, and 2D coronal T2 sequences) using semiquantitative scales for vascular lesions (periventricular lesions (PVL), deep white matter lesions (DWML), deep grey matter lesions (DGML), enlarged perivascular spaces (PVS), and microbleeds (MB)) and brain atrophy (medial temporal atrophy (MTA), posterior atrophy (PA), global cortical atrophy- frontal (GCA-F) and Evans' index). RESULTS: Raters reached a good-to-excellent agreement for all scales (ICC ranging from 0.78-0.96). A greater number of PVL (p<0.001), DWML (p<0.001), DGML (p=0.010), and PVS (p=0.001) was observed in VD compared to AD, while MD showed a significant greater number of PVL (p=0.001), DWML (p=0.002), DGML (p=0.018), and deep and juxtacortical MB (p=0.006 and p<0.001, respectively). Comparing VD and MD, VD showed a higher number of PVS in basal ganglia and centrum semiovale (p=0.040), while MD showed more deep and juxtacortical MB (p=0.042 and p=0.022, respectively). No significant difference was observed in scores of cortical atrophy scales and Evans' index among the three groups. CONCLUSION: The proposed MRI protocol represents a useful advancement in the diagnostic assessment of patients with cognitive impairment by more accurately detecting vascular lesions, mainly microbleeds, without a significant increase in time and resource expenditure. Our findings confirm that white and grey matter lesions predominate in vascular and mixed dementia, whereas deep and juxtacortical microbleeds predominate in mixed dementia, suggesting that cerebral amyloid angiopathy could be the main underlying pathology.