Linking peripheral atherosclerosis to blood-brain barrier disruption: elucidating its role as a manifestation of cerebral small vessel disease in vascular cognitive impairment.

Aging plays a pivotal role in the pathogenesis of cerebral small vessel disease (CSVD), contributing to the onset and progression of vascular cognitive impairment and dementia (VCID). In older adults, CSVD often leads to significant pathological outcomes, including blood-brain barrier (BBB) disruption, which in turn triggers neuroinflammation and white matter damage. This damage is frequently observed as white matter hyperintensities (WMHs) in neuroimaging studies. There is mounting evidence that older adults with atherosclerotic vascular diseases, such as peripheral artery disease, ischemic heart disease, and carotid artery stenosis, face a heightened risk of developing CSVD and VCID. This review explores the complex relationship between peripheral atherosclerosis, the pathogenesis of CSVD, and BBB disruption. It explores the continuum of vascular aging, emphasizing the shared pathomechanisms that underlie atherosclerosis in large arteries and BBB disruption in the cerebral microcirculation, exacerbating both CSVD and VCID. By reviewing current evidence, this paper discusses the impact of endothelial dysfunction, cellular senescence, inflammation, and oxidative stress on vascular and neurovascular health. This review aims to enhance understanding of these complex interactions and advocate for integrated approaches to manage vascular health, thereby mitigating the risk and progression of CSVD and VCID.

Atherosclerotic burden and cerebral small vessel disease: exploring the link through microvascular aging and cerebral microhemorrhages.

Cerebral microhemorrhages (CMHs, also known as cerebral microbleeds) are a critical but frequently underestimated aspect of cerebral small vessel disease (CSVD), bearing substantial clinical consequences. Detectable through sensitive neuroimaging techniques, CMHs reveal an extensive pathological landscape. They are prevalent in the aging population, with multiple CMHs often being observed in a given individual. CMHs are closely associated with accelerated cognitive decline and are increasingly recognized as key contributors to the pathogenesis of vascular cognitive impairment and dementia (VCID) and Alzheimer's disease (AD). This review paper delves into the hypothesis that atherosclerosis, a prevalent age-related large vessel disease, extends its pathological influence into the cerebral microcirculation, thereby contributing to the development and progression of CSVD, with a specific focus on CMHs. We explore the concept of vascular aging as a continuum, bridging macrovascular pathologies like atherosclerosis with microvascular abnormalities characteristic of CSVD. We posit that the same risk factors precipitating accelerated aging in large vessels (i.e., atherogenesis), primarily through oxidative stress and inflammatory pathways, similarly instigate accelerated microvascular aging. Accelerated microvascular aging leads to increased microvascular fragility, which in turn predisposes to the formation of CMHs. The presence of hypertension and amyloid pathology further intensifies this process. We comprehensively overview the current body of evidence supporting this interconnected vascular hypothesis. Our review includes an examination of epidemiological data, which provides insights into the prevalence and impact of CMHs in the context of atherosclerosis and CSVD. Furthermore, we explore the shared mechanisms between large vessel aging, atherogenesis, microvascular aging, and CSVD, particularly focusing on how these intertwined processes contribute to the genesis of CMHs. By highlighting the role of vascular aging in the pathophysiology of CMHs, this review seeks to enhance the understanding of CSVD and its links to systemic vascular disorders. Our aim is to provide insights that could inform future therapeutic approaches and research directions in the realm of neurovascular health.

What is brain health?

The call to optimize brain health is now a local, regional and global priority. Organizations such as the World Health Organization, Centers for Disease Control and Prevention and Alzheimer's Association, American Academy of Neurology, World Federation of Neurology, and others have developed recommendations for the maintenance of brain health. Brain health definitions range from broad to narrow in scope and may focus on cognition or encompass broader core components such as cerebral, mental and social domains. In this manuscript we will explore various definitions of brain health and its core components, the importance of cognitive and functional domains, and briefly introduce the concept of cognitive medicine in the context of brain health.

Age-related loss of Notch3 underlies brain vascular contractility deficiencies, glymphatic dysfunction, and neurodegeneration in mice.

Vascular aging affects multiple organ systems, including the brain, where it can lead to vascular dementia. However, a concrete understanding of how aging specifically affects the brain vasculature, along with molecular readouts, remains vastly incomplete. Here, we demonstrate that aging is associated with a marked decline in Notch3 signaling in both murine and human brain vessels. To clarify the consequences of Notch3 loss in the brain vasculature, we used single-cell transcriptomics and found that Notch3 inactivation alters regulation of calcium and contractile function and promotes a notable increase in extracellular matrix. These alterations adversely impact vascular reactivity, manifesting as dilation, tortuosity, microaneurysms, and decreased cerebral blood flow, as observed by MRI. Combined, these vascular impairments hinder glymphatic flow and result in buildup of glycosaminoglycans within the brain parenchyma. Remarkably, this phenomenon mirrors a key pathological feature found in brains of patients with CADASIL, a hereditary vascular dementia associated with NOTCH3 missense mutations. Additionally, single-cell RNA sequencing of the neuronal compartment in aging Notch3-null mice unveiled patterns reminiscent of those observed in neurodegenerative diseases. These findings offer direct evidence that age-related NOTCH3 deficiencies trigger a progressive decline in vascular function, subsequently affecting glymphatic flow and culminating in neurodegeneration.

Impaired Neurovascular Coupling and Increased Functional Connectivity in the Frontal Cortex Predict Age-Related Cognitive Dysfunction.

Impaired cerebrovascular function contributes to the genesis of age-related cognitive decline. In this study, the hypothesis is tested that impairments in neurovascular coupling (NVC) responses and brain network function predict cognitive dysfunction in older adults. Cerebromicrovascular and working memory function of healthy young (n = 21, 33.2±7.0 years) and aged (n = 30, 75.9±6.9 years) participants are assessed. To determine NVC responses and functional connectivity (FC) during a working memory (n-back) paradigm, oxy- and deoxyhemoglobin concentration changes from the frontal cortex using functional near-infrared spectroscopy are recorded. NVC responses are significantly impaired during the 2-back task in aged participants, while the frontal networks are characterized by higher local and global connection strength, and dynamic FC (p < 0.05). Both impaired NVC and increased FC correlate with age-related decline in accuracy during the 2-back task. These findings suggest that task-related brain states in older adults require stronger functional connections to compensate for the attenuated NVC responses associated with working memory load.

Post-Stroke Brain Health Monitoring and Optimization: A Narrative Review.

Significant advancements have been made in recent years in the acute treatment and secondary prevention of stroke. However, a large proportion of stroke survivors will go on to have enduring physical, cognitive, and psychological disabilities from suboptimal post-stroke brain health. Impaired brain health following stroke thus warrants increased attention from clinicians and researchers alike. In this narrative review based on an open timeframe search of the PubMed, Scopus, and Web of Science databases, we define post-stroke brain health and appraise the body of research focused on modifiable vascular, lifestyle, and psychosocial factors for optimizing post-stroke brain health. In addition, we make clinical recommendations for the monitoring and management of post-stroke brain health at major post-stroke transition points centered on four key intertwined domains: cognition, psychosocial health, physical functioning, and global vascular health. Finally, we discuss potential future work in the field of post-stroke brain health, including the use of remote monitoring and interventions, neuromodulation, multi-morbidity interventions, enriched environments, and the need to address inequities in post-stroke brain health. As post-stroke brain health is a relatively new, rapidly evolving, and broad clinical and research field, this narrative review aims to identify and summarize the evidence base to help clinicians and researchers tailor their own approach to integrating post-stroke brain health into their practices.

Diffusion Restriction in the Splenium: A Comparative Study of Cytotoxic Lesions of the Corpus Callosum (CLOCCs) versus Lesions of Vascular Etiology.

Cytotoxic lesions of the corpus callosum (CLOCCs) have broad differential diagnoses. Differentiating these lesions from lesions of vascular etiology is of high clinical significance. We compared the clinical and radiological characteristics and outcomes between vascular splenial lesions and CLOCCs in a retrospective cohort study. We examined the clinical and radiologic characteristics and outcomes in 155 patients with diffusion restriction in the splenium of the corpus callosum. Patients with lesions attributed to a vascular etiology (N = 124) were older (64.1 vs. 34.6 years old, p < 0.001) and had >1 vascular risk factor (91.1% vs. 45.2%, p < 0.001), higher LDL and A1c levels, and echocardiographic abnormalities (all p ≤ 0.05). CLOCCs (N = 31) more commonly had midline splenial involvement (p < 0.001) with only splenial diffusion restriction (p < 0.001), whereas vascular etiology lesions were more likely to have multifocal areas of diffusion restriction (p = 0.002). The rate of in-hospital mortality was significantly higher in patients with vascular etiology lesions (p = 0.04). Across vascular etiology lesions, cardio-embolism was the most frequent stroke mechanism (29.8%). Our study shows that corpus callosum diffusion restricted lesions of vascular etiology and CLOCCs are associated with different baseline, clinical, and radiological characteristics and outcomes. Accurately differentiating these lesions is important for appropriate treatment and secondary prevention.

Study protocol for a longitudinal observational study of disparities in sleep and cognition in older adults: the DISCO study.

INTRODUCTION: Cognitive dysfunction, a leading cause of mortality and morbidity in the USA and globally, has been shown to disproportionately affect the socioeconomically disadvantaged and those who identify as black or Hispanic/Latinx. Poor sleep is strongly associated with the development of vascular and metabolic diseases, which correlate with cognitive dysfunction. Therefore, sleep may contribute to observed disparities in cognitive disorders. The Epidemiologic Study of Disparities in Sleep and Cognition in Older Adults (DISCO) is a longitudinal, observational cohort study that focuses on gathering data to better understand racial/ethnic sleep disparities and illuminate the relationship among sleep, race and ethnicity and changes in cognitive function. This investigation may help inform targeted interventions to minimise disparities in cognitive health among ageing adults. METHODS AND ANALYSIS: The DISCO study will examine up to 495 individuals aged 55 and older at two time points over 24 months. An equal number of black, white and Hispanic/Latinx individuals will be recruited using methods aimed for adults traditionally under-represented in research. Study procedures at each time point will include cognitive tests, gait speed measurement, wrist actigraphy, a type 2 home polysomnography and a clinical examination. Participants will also complete self-identified assessments and questionnaires on cognitive ability, sleep, medication use, quality of life, sociodemographic characteristics, diet, substance use, and psychological and social health. ETHICS AND DISSEMINATION: This study was approved by the Northwestern University Feinberg School of Medicine Institutional Review Board. Deidentified datasets will be shared via the BioLINCC repository following the completion of the project. Biospecimen samples from the study that are not being analysed can be made available to qualified investigators on review and approval by study investigators. Requests that do not lead to participant burden or that conflict with the primary aims of the study will be reviewed by the study investigators.

Diffusion-Restricted Lesions of the Splenium: Clinical Presentation, Radiographic Patterns, and Patient Outcomes.

Background and Objectives: Diffusion-restricted (DR) lesions of the splenium are encountered in a wide variety of pathologies, and their significance is often unclear. We sought to report the spectrum of clinical presentations, neuroimaging patterns, and the predictors of radiographic and clinical outcomes from DR splenial lesions. Methods: This was a single-center, retrospective cohort study from January 1, 2009, to August 1, 2020. A consecutive sample of 3,490 individuals who underwent brain MRI with reported corpus callosum lesions during the study period were evaluated for DR lesions in the corpus callosum. DR lesions were defined as increased signal intensity on diffusion-weighted imaging sequences with decreased signal intensity on apparent diffusion coefficient. Patients with prior neurosurgical procedures, hemorrhage-associated DR, anoxic brain injury, and chronic or previously known or characterized disease processes in the corpus callosum were excluded. Clinical and radiologic outcomes were ascertained, including readmissions within 1 year, in-hospital mortality rates, and resolution of DR at first follow-up imaging. Outcomes were defined a priori. Results: Two hundred patients met criteria for inclusion. The average age was 57 years (standard deviation 19 years). Near half of the patients were women (47%). Encephalopathy (55%), focal weakness (46.5%), and cortical signs (44%) were the most common presenting clinical features. Thirty-five cases (17.5%) had features consistent with cytotoxic lesions of the corpus callosum (CLOCCs). Vascular causes were most frequent (61%), followed by malignancy-related (15%) and trauma (8%). In-hospital mortality occurred in 8.5% of cases, 46.5% were readmitted to the hospital within 1 year, and 49.1% of patients had resolution of the splenial DR at the next scan. Backward stepwise regression models showed that mass effect was negatively associated with splenial DR resolution (odds ratio [OR]: 0.12, confidence interval [CI] 0.03-0.46, p = 0.002). Encephalopathy was significantly associated with in-hospital mortality (OR: 4.50, CI 1.48-17.95, p = 0.007). Patients with a CLOCC had less frequent readmissions at 1-year compared with patients without a CLOCC, p = 0.015. Discussion: Vascular DR lesions of the splenium were more common than CLOCCs and other etiologies in this cohort. While splenial DR lesions can present a clinical challenge, their associated clinical and radiographic characteristics may predict outcome and guide prognosis.

The role of population-level preventive care for brain health in ageing.

Over the past several decades, a worldwide demographic transition has led to an increasing number of older adults with chronic neurological conditions. These conditions, which have a profound effect on the cognitive function and physical ability of older adults, also have a long preclinical phase. This feature provides a unique opportunity to implement preventive measures for high-risk groups and the population as a whole, and therefore to reduce the burden of neurological diseases. The concept of brain health has emerged as the overarching theme to define overall brain function independently of underlying pathophysiological processes. We review the concept of brain health from the ageing and preventive care perspectives, discuss the mechanisms underpinning ageing and brain ageing, highlight the interplay of various forces resulting in deviation from brain health towards brain disease, and provide an overview of strategies to promote brain health with a life-course approach.

The Neurovasculome: Key Roles in Brain Health and Cognitive Impairment: A Scientific Statement From the American Heart Association/American Stroke Association.

BACKGROUND: Preservation of brain health has emerged as a leading public health priority for the aging world population. Advances in neurovascular biology have revealed an intricate relationship among brain cells, meninges, and the hematic and lymphatic vasculature (the neurovasculome) that is highly relevant to the maintenance of cognitive function. In this scientific statement, a multidisciplinary team of experts examines these advances, assesses their relevance to brain health and disease, identifies knowledge gaps, and provides future directions. METHODS: Authors with relevant expertise were selected in accordance with the American Heart Association conflict-of-interest management policy. They were assigned topics pertaining to their areas of expertise, reviewed the literature, and summarized the available data. RESULTS: The neurovasculome, composed of extracranial, intracranial, and meningeal vessels, as well as lymphatics and associated cells, subserves critical homeostatic functions vital for brain health. These include delivering O2 and nutrients through blood flow and regulating immune trafficking, as well as clearing pathogenic proteins through perivascular spaces and dural lymphatics. Single-cell omics technologies have unveiled an unprecedented molecular heterogeneity in the cellular components of the neurovasculome and have identified novel reciprocal interactions with brain cells. The evidence suggests a previously unappreciated diversity of the pathogenic mechanisms by which disruption of the neurovasculome contributes to cognitive dysfunction in neurovascular and neurodegenerative diseases, providing new opportunities for the prevention, recognition, and treatment of these conditions. CONCLUSIONS: These advances shed new light on the symbiotic relationship between the brain and its vessels and promise to provide new diagnostic and therapeutic approaches for brain disorders associated with cognitive dysfunction.

Blood pressure variability, dementia, and role of antihypertensive medications in older adults.

INTRODUCTION: We assessed the association between visit-to-visit blood pressure variability (BPV) up to 12 years and subsequent dementia risk, and tested the modifying effect of antihypertensive medications. METHODS: We studied 2234 participants from two community-based cohorts of older adults with normal cognition or mild cognitive impairment. Participants were followed through annual assessments for up to 27 years. Visit-to-visit BPV was quantified over 3, 6, 9, and 12 years, respectively. RESULTS: Higher systolic BPV (SBPV) during 3, 6, 9, and 12 years was associated with a subsequent increased risk of dementia, with hazard ratios ranging from 1.02 (95% confidence interval [CI]: 1.01-1.04) to 1.10 (95% CI: 1.05-1.16). The association between SBPV and dementia risk was stronger among participants not taking calcium channel blockers (p-for interaction < 0.05). DISCUSSION: Among older adults, long-term exposure to higher visit-to-visit SBPV is associated with an increased risk of dementia later in life, and calcium channel blockers may modify this association. HIGHLIGHTS: Among adults aged >65, higher systolic blood pressure variability spanning 3-12 years is associated with an increased risk of dementia later in life. Single blood pressure measurement or mean blood pressure levels does not seem to associate with dementia risk among older adults. The association between systolic blood pressure variability and dementia risk is stronger among those not taking calcium channel blocker medications.

The Role of Vascular Risk Factors in Cognitive Impairment and Dementia and Prospects for Prevention.

One of the most challenging clinical expressions of population aging is cognitive impairment and dementia. Among risk factors for the development of dementia, modifiable vascular risk factors have emerged as contributors to both vascular and nonvascular types of dementia. Epidemiologic studies have been particularly informative in understanding the link between vascular risks and dementia across the life course. We discuss vascular risks for dementia and cognitive impairment and practical management recommendations.

Brain Reserve, Resilience, and Cognitive Stimulation Across the Lifespan: How Do These Factors Influence Risk of Cognitive Impairment and the Dementias?

In the absence of effective treatments for dementia, maintaining cognitive health in old age is one of the major challenges facing aging societies. Interventions for cognitive health that are tailored to the person are more likely to bring the best benefits with a minimum burden. We review the existing literature on this topic and discuss the role of the primary care physician.

Carotid disease, cognition, and aging: time to redefine asymptomatic disease?

There is an increasing appreciation of the vascular contributions in the development of age-related cognitive impairment and dementia1,2. Identifying risk and maintaining cognitive health for successful aging is ever relevant in our aging population. Carotid disease, a well-established risk factor for stroke and often a harbinger of other vascular disease states, is also emerging as another vascular risk factor for age-related cognitive decline. When combined with vascular risk factors, the incidence of age-related carotid disease can be as high as 70%3,4. Historically, carotid disease has been dichotomized into two large groups in trial design, outcome measurements, and treatment decisions: symptomatic and asymptomatic carotid artery stenosis. The dichotomous distinction between asymptomatic and symptomatic carotid stenosis based on existing definitions may be limiting the care we are able to provide for patients classified as "asymptomatic" from their carotid disease. Medically, we now know that these patients should be treated with the same intensive medical therapy as those with "symptomatic" carotid disease. Emerging data also shows that hypoperfusion from asymptomatic disease may lead to significant cognitive impairment in the aging population, and it is plausible that most "age-related" cognitive changes may be reflective of vascular impairment and neurovascular dysfunction. While over the past 30 years medical, surgical, and radiological advances have pushed the field of neurovascular disease to significantly reduce the number of ischemic strokes, we are far from any meaningful interventions to prevent vascular cognitive impairment. In addition to including cognitive outcome measures, future studies of carotid disease will also benefit from including advanced neuroimaging modalities not currently utilized in standard clinical imaging protocols, such as perfusion imaging and/or functional connectivity mapping, which may provide novel data to better assess for hypoxic-ischemic changes and neurovascular dysfunction across diffuse cognitive networks. While current recommendations advise against widespread population screening for asymptomatic carotid stenosis, emerging evidence linking carotid stenosis to cognitive impairment prompts us to re-consider our approach for older patients with vascular risk factors who are at risk for cognitive decline.

Association of change in cardiovascular risk factors with incident dementia.

INTRODUCTION: We evaluated whether better cardiovascular health at midlife and improvement of cardiovascular health within midlife were associated with dementia risk. METHODS: Two longitudinal population-based studies were used: Atherosclerosis Risk in Communities (ARIC) (n = 11,460/visits at ages 54 and 60), and Age, Gene/Environment Susceptibility (AGES)-Reykjavik (n = 3907/visit at age 51). A cardiovascular health score (range 0-12/0-14, depending on diet availability) including six/seven items was calculated at each visit, with weight assigned to each item as poor (0), intermediate (1), or ideal (2). Cardiovascular health was defined as low (score 0-4/0-5), intermediate (5-7/6-9), or high (8-12/10-14). Incident dementia was ascertained through linkage to health records and with neuropsychological examinations. RESULTS: Midlife high compared to low cardiovascular health (hazard ratios [HRs]: for ARIC: 0.60 [95% confidence interval: 0.52, 0.69]); for AGES-Reykjavik: 0.83 [0.66, 0.99] and improvement of cardiovascular health score within midlife (HR per one-point increase: ARIC: 0.94 [0.92, 0.96]) were associated with lower dementia risk. DISCUSSION: Better cardiovascular health at midlife and improvement of cardiovascular health within midlife are associated with lower dementia risk. HIGHLIGHTS: Cardiovascular health and dementia were studied in two large cohort studies. Better cardiovascular health at midlife relates to lower dementia risk. Improvement of cardiovascular health within midlife relates to lower dementia risk. Promotion of cardiovascular health at midlife can help to reduce dementia risk.

Epigenetic and integrative cross-omics analyses of cerebral white matter hyperintensities on MRI.

Cerebral white matter hyperintensities on MRI are markers of cerebral small vessel disease, a major risk factor for dementia and stroke. Despite the successful identification of multiple genetic variants associated with this highly heritable condition, its genetic architecture remains incompletely understood. More specifically, the role of DNA methylation has received little attention. We investigated the association between white matter hyperintensity burden and DNA methylation in blood at ∼450 000 cytosine-phosphate-guanine (CpG) sites in 9732 middle-aged to older adults from 14 community-based studies. Single CpG and region-based association analyses were carried out. Functional annotation and integrative cross-omics analyses were performed to identify novel genes underlying the relationship between DNA methylation and white matter hyperintensities. We identified 12 single CpG and 46 region-based DNA methylation associations with white matter hyperintensity burden. Our top discovery single CpG, cg24202936 (P = 7.6 × 10-8), was associated with F2 expression in blood (P = 6.4 × 10-5) and co-localized with FOLH1 expression in brain (posterior probability = 0.75). Our top differentially methylated regions were in PRMT1 and in CCDC144NL-AS1, which were also represented in single CpG associations (cg17417856 and cg06809326, respectively). Through Mendelian randomization analyses cg06809326 was putatively associated with white matter hyperintensity burden (P = 0.03) and expression of CCDC144NL-AS1 possibly mediated this association. Differentially methylated region analysis, joint epigenetic association analysis and multi-omics co-localization analysis consistently identified a role of DNA methylation near SH3PXD2A, a locus previously identified in genome-wide association studies of white matter hyperintensities. Gene set enrichment analyses revealed functions of the identified DNA methylation loci in the blood-brain barrier and in the immune response. Integrative cross-omics analysis identified 19 key regulatory genes in two networks related to extracellular matrix organization, and lipid and lipoprotein metabolism. A drug-repositioning analysis indicated antihyperlipidaemic agents, more specifically peroxisome proliferator-activated receptor-alpha, as possible target drugs for white matter hyperintensities. Our epigenome-wide association study and integrative cross-omics analyses implicate novel genes influencing white matter hyperintensity burden, which converged on pathways related to the immune response and to a compromised blood-brain barrier possibly due to disrupted cell-cell and cell-extracellular matrix interactions. The results also suggest that antihyperlipidaemic therapy may contribute to lowering risk for white matter hyperintensities possibly through protection against blood-brain barrier disruption.