Neurovascular coupling, functional connectivity, and cerebrovascular endothelial extracellular vesicles as biomarkers of mild cognitive impairment.

INTRODUCTION: Mild cognitive impairment (MCI) is a prodromal stage of dementia. Understanding the mechanistic changes from healthy aging to MCI is critical for comprehending disease progression and enabling preventative intervention. METHODS: Patients with MCI and age-matched controls (CN) were administered cognitive tasks during functional near-infrared spectroscopy (fNIRS) recording, and changes in plasma levels of extracellular vesicles (EVs) were assessed using small-particle flow cytometry. RESULTS: Neurovascular coupling (NVC) and functional connectivity (FC) were decreased in MCI compared to CN, prominently in the left-dorsolateral prefrontal cortex (LDLPFC). We observed an increased ratio of cerebrovascular endothelial EVs (CEEVs) to total endothelial EVs in patients with MCI compared to CN, correlating with structural MRI small vessel ischemic damage in MCI. LDLPFC NVC, CEEV ratio, and LDLPFC FC had the highest feature importance in the random Forest group classification. DISCUSSION: NVC, CEEVs, and FC predict MCI diagnosis, indicating their potential as markers for MCI cerebrovascular pathology. HIGHLIGHTS: Neurovascular coupling (NVC) is impaired in mild cognitive impairment (MCI). Functional connectivity (FC) compensation mechanism is lost in MCI. Cerebrovascular endothelial extracellular vesicles (CEEVs) are increased in MCI. CEEV load strongly associates with cerebral small vessel ischemic lesions in MCI. NVC, CEEVs, and FC predict MCI diagnosis over demographic and comorbidity factors.

Clopidogrel use and smoking cessation result in lower coated-platelet levels after stroke.

Coated-platelets are a subset of highly procoagulant platelets elevated in patients with non-lacunar ischemic stroke and associated with stroke recurrence. Cross-sectional studies in controls have shown that smoking is associated with higher coated-platelet levels while chronic use of serotonin reuptake inhibitors (SSRIs), statins or aspirin is associated with lower coated-platelet levels. We now investigate if initiation of treatment with SSRIs, statins, clopidogrel, aspirin or oral anticoagulants and smoking cessation impacts coated-platelet levels at 90 days after ischemic stroke. Coated-platelet levels, reported as percent of cells converted to coated-platelets, were measured in 87 consecutive patients with stroke at baseline and repeated at 90 days. Repeated-measure ANOVA was used to determine if initiation of treatment with individual medications or smoking cessation impacted coated-platelet levels. Decreased coated-platelets levels at 90 days as compared to baseline were observed after initiation of treatment with clopidogrel (p = .0001, partial η2 = 0.17) and smoking cessation (p = .014, partial η2 = 0.10). Initiation of treatment with SSRIs, statins, aspirin or oral anticoagulants did not result in significant changes in coated-platelet potential. These novel longitudinal data suggest that clopidogrel therapy and smoking cessation attenuate coated-platelet potential at 90 days after ischemic stroke.

Role of age-related alterations of the cerebral venous circulation in the pathogenesis of vascular cognitive impairment.

There has been an increasing appreciation of the role of vascular contributions to cognitive impairment and dementia (VCID) associated with old age. Strong preclinical and translational evidence links age-related dysfunction and structural alterations of the cerebral arteries, arterioles, and capillaries to the pathogenesis of many types of dementia in the elderly, including Alzheimer's disease. The low-pressure, low-velocity, and large-volume venous circulation of the brain also plays critical roles in the maintenance of homeostasis in the central nervous system. Despite its physiological importance, the role of age-related alterations of the brain venous circulation in the pathogenesis of vascular cognitive impairment and dementia is much less understood. This overview discusses the role of cerebral veins in the pathogenesis of VCID. Pathophysiological consequences of age-related dysregulation of the cerebral venous circulation are explored, including blood-brain barrier disruption, neuroinflammation, exacerbation of neurodegeneration, development of cerebral microhemorrhages of venous origin, altered production of cerebrospinal fluid, impaired function of the glymphatics system, dysregulation of cerebral blood flow, and ischemic neuronal dysfunction and damage. Understanding the age-related functional and phenotypic alterations of the cerebral venous circulation is critical for developing new preventive, diagnostic, and therapeutic approaches to preserve brain health in older individuals.

Higher Coated-Platelet Levels in Acute Stroke are Associated with Lower Cognitive Scores at Three Months Post Infarction.

BACKGROUND: Coated-platelets are a subset of highly procoagulant platelets observed after dual agonist stimulation with collagen and thrombin. Coated-platelet levels are increased in acute stroke compared to controls, and higher levels are associated with stroke recurrence. We examined whether coated-platelet levels measured at the time of the stroke correlate with cognitive scores at 3 months following the brain infarction. METHODS: Coated-platelets were assayed in consecutive patients with nonlacunar stroke. Cognitive screening was performed using the Mini-Mental State Examination (MMSE) at 3 months after discharge. Linear regression, with adjustment for individual covariates, was used to model the association between coated-platelet levels and MMSE scores. RESULTS: One hundred and twenty-eight patients with a mean MMSE score of 26 points (range 14-30, standard deviation [SD] 3.1) and mean coated-platelet levels of 40.9% (range 5.2-76.2, SD 13.3), completed cognitive screening. An inverse linear association was found between coated-platelet levels and MMSE score, with higher levels seen in patients with lower MMSE scores (r = -.34, R2 = .12, P < .0001). This association remained despite adjustment for potential confounding factors. In the final model, higher coated-platelet levels (coefficient -.078, 95% confidence interval [CI]: -.12 to -.041, P < .0001), presence of hypertension (coefficient -2.42, 95% CI: -3.90 to -.95, P = .0015), and anticoagulant use at discharge (coefficient -1.48, 95% CI: -2.56 to -.39, P = .0079) were predictive of lower MMSE. CONCLUSIONS: These findings support a link between increased platelet procoagulant potential at the time of the stroke and development of cognitive impairment following cerebral infarction.

Cerebral microhemorrhages: mechanisms, consequences, and prevention.

The increasing prevalence of multifocal cerebral microhemorrhages (CMHs, also known as "cerebral microbleeds") is a significant, newly recognized problem in the aging population of the Western world. CMHs are associated with rupture of small intracerebral vessels and are thought to progressively impair neuronal function, potentially contributing to cognitive decline, geriatric psychiatric syndromes, and gait disorders. Clinical studies show that aging and hypertension significantly increase prevalence of CMHs. CMHs are also now recognized by the National Institutes of Health as a major factor in Alzheimer's disease pathology. Moreover, the presence of CMHs is an independent risk factor for subsequent larger intracerebral hemorrhages. In this article, we review the epidemiology, detection, risk factors, clinical significance, and pathogenesis of CMHs. The potential age-related cellular mechanisms underlying the development of CMHs are discussed, with a focus on the structural determinants of microvascular fragility, age-related alterations in cerebrovascular adaptation to hypertension, the role of oxidative stress and matrix metalloproteinase activation, and the deleterious effects of arterial stiffening, increased pulse pressure, and impaired myogenic autoregulatory protection on the brain microvasculature. Finally, we examine potential treatments for the prevention of CMHs based on the proposed model of aging- and hypertension-dependent activation of the reactive oxygen species-matrix metalloproteinases axis, and we discuss critical questions to be addressed by future studies.

Lower Coated-Platelet Levels Are Associated With Increased Mortality After Spontaneous Intracerebral Hemorrhage.

BACKGROUND AND PURPOSE: Coated-platelets are highly procoagulant platelets observed on dual-agonist stimulation with collagen and thrombin. Coated-platelet levels are decreased in patients with spontaneous intracerebral hemorrhage when compared with controls and inversely correlated with bleed volume. We sought to investigate whether coated-platelets are associated with increased mortality at 30 days after spontaneous intracerebral hemorrhage. METHODS: Coated-platelet levels were assayed in 95 consecutive patients with spontaneous intracerebral hemorrhage. The main outcome was mortality at 30 days according to coated-platelet levels at enrollment. Subjects were grouped into tertiles of the observed coated-platelet level distribution. Groups defined by tertile of coated-platelet level were compared using either ANOVA or a Kruskal-Wallis test for small group size for continuous measures and an exact Cochrane-Armitage trend test for categorical measures. Logistic regression was used to estimate the adjusted odds of death within 30 days associated with coated-platelet levels. RESULTS: Cumulative mortality at 30 days was 23% (22 subjects). Mortality at 30 days differed among the coated-platelet tertiles: 44% for the first tertile (lowest coated-platelet levels), 19% for the second tertile, and 6% for the third tertile (trend test; P=0.0004). Logistic regression examining the association between mortality and coated-platelet levels showed that the odds of death at 30 days in those with levels <27% (n=47) were 6.83× the odds for patients with levels ≥27% (95% confidence interval, 2.10-22.23). CONCLUSIONS: These results support a link between impaired coated-platelet potential and outcome in intracerebral hemorrhage.

Instrumental activities of daily living performance and role satisfaction in people with and without mild cognitive impairment: a pilot project.

OBJECTIVE: We investigated differences in observed performance of instrumental activities of daily living (IADLs) and self-reported satisfaction with social role performance between people with amnestic mild cognitive impairment (a-MCI) and age- and gender-matched control participants. METHOD: We measured observed performance of 14 IADLs using the Independence, Safety, and Adequacy domains of the Performance Assessment of Self-Care Skills (PASS) and the Patient-Reported Outcomes Measurement Information Systems (PROMIS) to examine satisfaction with social role performance. RESULTS: Total PASS scores were significantly lower in participants with a-MCI (median=40.6) than in control participants (median=44.2; p=.006). Adequacy scores were also significantly lower. No significant differences were found between groups on the PROMIS measures. CONCLUSION: IADL differences between groups were related more to errors in adequacy than to safety and independence. Occupational therapy practitioners can play a key role in the diagnosis and treatment of subtle IADL deficits in people with MCI.

Coated-platelets improve prediction of stroke and transient ischemic attack in asymptomatic internal carotid artery stenosis.

BACKGROUND AND PURPOSE: Coated-platelets, a subset of procoagulant platelets observed on dual agonist stimulation with collagen and thrombin, support a robust prothrombinase activity and provide a unique measure of platelet thrombotic potential. Coated-platelet levels are increased in large artery stroke, and higher levels are associated with early stroke recurrence, suggesting a potential role for risk stratification in asymptomatic patients with carotid artery stenosis. METHODS: Three-hundred twenty-nine consecutive patients with technically adequate carotid Doppler evaluation without stroke or transient ischemic attack (TIA) in the previous 6 months were enrolled as part of a prospective cohort study conducted during a 40-month period. The main outcome was occurrence of stroke or TIA according to coated-platelet levels and internal carotid stenosis severity at enrollment. The optimal cutoff value of coated-platelet levels was determined by recursive partitioning analysis. Event-free survival was estimated using Kaplan-Meier and Cox proportional hazards regression analyses. RESULTS: A cutoff of ≥45% for coated-platelet levels in combination with stenosis≥50% yielded a sensitivity of 0.78 (95% confidence interval, 0.51-1.0), specificity of 0.92 (0.89-0.95), positive predictive value of 0.21 (0.07-0.34), and a negative predictive value of 0.99 (0.98-1.0) for ipsilateral stroke or TIA. The incidence rate of ipsilateral stroke or TIA for patients with ≥50% stenosis and ≥45% coated-platelets was 21.5 per 100 person-years versus 1.27 per 100 person-years for patients with ≥50% stenosis and <45% coated-platelets (P<0.0001). CONCLUSIONS: Coated-platelet levels identify asymptomatic carotid stenosis patients at high risk for stroke or TIA, which suggests a role for coated-platelets in risk stratification before revascularization.

Elevated coated-platelets in symptomatic large-artery stenosis patients are associated with early stroke recurrence.

Coated-platelets are a subset of platelets with increased procoagulant potential observed upon dual agonist stimulation with collagen and thrombin. These prothrombotic platelets are elevated in patients with non-lacunar ischemic stroke and decreased in patients with spontaneous intracerebral hemorrhage compared to controls. We now investigated coated-platelet synthesis in patients with symptomatic large-artery stenosis and explored the association between coated-platelet levels and stroke recurrence at 3 months in this population. Coated-platelet levels were determined in 60 patients with either acute stroke or transient ischemic attack due to large-artery stenosis and 60 controls. Recurrent stroke incidence at 3 months was stratified by tertiles of coated-platelet levels and compared among groups using a log-rank test. Large-artery stenosis patients had significantly higher coated-platelet levels than controls (mean ± SD, 42.0 ± 15.5% vs. 29.4 ± 13.5%, p < 0.0001). The 3-month cumulative incidence of recurrent stroke was 41% for the highest, 6% for the middle, and 5% for the lowest tertile of coated-platelet levels (p = 0.0045). These results show that elevated coated-platelet levels in patients with symptomatic large-artery stenosis are associated with early stroke recurrence.

Coated-platelet levels are persistently elevated in patients with mild traumatic brain injury.

OBJECTIVE: Coated-platelets are procoagulant platelets that are elevated in patients with large-vessel ischemic stroke and are associated with stroke recurrence. Because of recent reports showing an increased risk for stroke following traumatic brain injury (TBI), we undertook a pilot study to investigate coated-platelet synthesis in veterans with TBI. DESIGN: Cross-sectional study. PARTICIPANTS: Forty patients with a diagnosis of mild TBI (mTBI) and 40 controls without a history of TBI and matched for age, gender, and ethnicity/race were enrolled in the study. MAIN MEASURE: Coated-platelet levels were determined in patients with mTBI and controls. The time period since most recent injury ranged from 6 months to 9 years. RESULTS: Coated-platelet levels were significantly higher for mTBI patients than for controls (mean ± SD = 52.0% ± 14.0% vs 35.4% ± 13.0%; P < .0001). No relationship between these levels and the length of time since the last injury was found (P = .5). CONCLUSIONS: Coated-platelet levels are markedly and persistently elevated in individuals with mTBI. These data suggest a link to previous findings of increased stroke risk and chronic inflammation among individuals who sustained a TBI.

Cerebral microbleeds in nonlacunar brain infarction are associated with lower coated-platelet levels.

BACKGROUND: Coated-platelets are a subset of platelets with high procoagulant potential observed on dual-agonist stimulation with collagen and thrombin. Coated-platelet levels are elevated in patients with nonlacunar ischemic stroke compared with controls, although the presence of early hemorrhagic transformation is associated with lower coated-platelet levels. In contrast to infarction, patients with spontaneous intracerebral hemorrhage have lower coated-platelet levels, and these levels inversely correlate with bleed size. Cerebral microbleeds (CMBs) represent previous small hemorrhagic occurrences. We undertook a pilot study to investigate coated-platelet production and the presence of CMBs in patients with nonlacunar ischemic stroke. METHODS: Coated-platelet levels were determined in 110 consecutive patients with a diagnosis of nonlacunar stroke. Microbleeds were identified using the published criteria by an experienced stroke neurologist. Coated-platelet levels were compared statistically between patients with and without CMBs using the nonparametric Wilcoxon rank sum test. RESULTS: Coated-platelet levels (median [interquartile range]) for all patients were 44.1% [34%-51.2%]. CMBs were detected in 22 patients (20%); these patients had significantly lower coated-platelet levels compared with those without CMBs (35.6% [22.6%-47.2%] versus 45.1% [36.1%-51.5%]; P = .025), whereas other demographic and clinical factors did not differ significantly. CONCLUSIONS: The presence of CMBs in patients with nonlacunar ischemic stroke is associated with lower levels of coated-platelets. Larger prospective studies are needed to better establish the potential connection between altered coated-platelet synthesis, microbleeds, cerebral infarction, and possible hemorrhage-prone vascular changes.

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.

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.

Neurovascular coupling impairment as a mechanism for cognitive deficits in COVID-19.

Components that comprise our brain parenchymal and cerebrovascular structures provide a homeostatic environment for proper neuronal function to ensure normal cognition. Cerebral insults (e.g. ischaemia, microbleeds and infection) alter cellular structures and physiologic processes within the neurovascular unit and contribute to cognitive dysfunction. COVID-19 has posed significant complications during acute and convalescent stages in multiple organ systems, including the brain. Cognitive impairment is a prevalent complication in COVID-19 patients, irrespective of severity of acute SARS-CoV-2 infection. Moreover, overwhelming evidence from in vitro, preclinical and clinical studies has reported SARS-CoV-2-induced pathologies in components of the neurovascular unit that are associated with cognitive impairment. Neurovascular unit disruption alters the neurovascular coupling response, a critical mechanism that regulates cerebromicrovascular blood flow to meet the energetic demands of locally active neurons. Normal cognitive processing is achieved through the neurovascular coupling response and involves the coordinated action of brain parenchymal cells (i.e. neurons and glia) and cerebrovascular cell types (i.e. endothelia, smooth muscle cells and pericytes). However, current work on COVID-19-induced cognitive impairment has yet to investigate disruption of neurovascular coupling as a causal factor. Hence, in this review, we aim to describe SARS-CoV-2's effects on the neurovascular unit and how they can impact neurovascular coupling and contribute to cognitive decline in acute and convalescent stages of the disease. Additionally, we explore potential therapeutic interventions to mitigate COVID-19-induced cognitive impairment. Given the great impact of cognitive impairment associated with COVID-19 on both individuals and public health, the necessity for a coordinated effort from fundamental scientific research to clinical application becomes imperative. This integrated endeavour is crucial for mitigating the cognitive deficits induced by COVID-19 and its subsequent burden in this especially vulnerable population.

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.

Decoding facial blends of emotion: visual field, attentional and hemispheric biases.

Most clinical research assumes that modulation of facial expressions is lateralized predominantly across the right-left hemiface. However, social psychological research suggests that facial expressions are organized predominantly across the upper-lower face. Because humans learn to cognitively control facial expression for social purposes, the lower face may display a false emotion, typically a smile, to enable approach behavior. In contrast, the upper face may leak a person's true feeling state by producing a brief facial blend of emotion, i.e. a different emotion on the upper versus lower face. Previous studies from our laboratory have shown that upper facial emotions are processed preferentially by the right hemisphere under conditions of directed attention if facial blends of emotion are presented tachistoscopically to the mid left and right visual fields. This paper explores how facial blends are processed within the four visual quadrants. The results, combined with our previous research, demonstrate that lower more so than upper facial emotions are perceived best when presented to the viewer's left and right visual fields just above the horizontal axis. Upper facial emotions are perceived best when presented to the viewer's left visual field just above the horizontal axis under conditions of directed attention. Thus, by gazing at a person's left ear, which also avoids the social stigma of eye-to-eye contact, one's ability to decode facial expressions should be enhanced.

Higher coated-platelet levels are associated with chronic hypertension in patients with transient ischemic attack.

Coated-platelets are procoagulant platelets observed upon dual stimulation with collagen and thrombin. We previously reported that coated-platelet levels are elevated in patients with transient ischemic attack (TIA) compared to controls and that these levels correlate with ABCD2 scores, a validated tool for identifying the short-term risk for stroke occurrence in TIA patients. We now investigate the effect of individual elements of the ABCD2 score on coated-platelet levels in TIA. Coated-platelet levels were measured in 124 TIA patients. A nine-way ANOVA evaluated the impact of components of the ABCD2 score (age, blood pressure (BP), clinical features, symptom duration, and diabetes), smoking, pertinent medications, race, and gender on coated-platelet levels. In the initial model, the only significant main effect was for BP; patients with BP ≥ 140/90 had higher coated-platelet levels than those without (mean ± SEM; 44.0 ± 2.1% vs. 35.4 ± 2.3%, p = 0.0007). Because the diagnosis of hypertension (HTN) requires multiple readings of elevated BP, we re-analyzed the data by replacing BP with HTN. In the second model, there were two significant main effects: HTN - with higher coated-platelet levels in patients with vs. those without HTN (46.3 ± 2.1% vs. 33.6 ± 2.1%, p < 0.0001), and symptom duration - with higher coated-platelet levels in patients with duration ≥60 minutes vs. those with duration <60 minutes (42.5 ± 2.0% vs. 37.4 ± 2.1%, p = 0.031). These data suggest a link between chronic HTN and platelet thrombotic potential.

Vascular mechanisms leading to progression of mild cognitive impairment to dementia after COVID-19: Protocol and methodology of a prospective longitudinal observational study.

INTRODUCTION: Mild cognitive impairment (MCI) is a prodromal stage to dementia, affecting up to 20% of the aging population worldwide. Patients with MCI have an annual conversion rate to dementia of 15-20%. Thus, conditions that increase the conversion from MCI to dementia are of the utmost public health concern. The COVID-19 pandemic poses a significant impact on our aging population with cognitive decline as one of the leading complications following recovery from acute infection. Recent findings suggest that COVID-19 increases the conversion rate from MCI to dementia in older adults. Hence, we aim to uncover a mechanism for COVID-19 induced cognitive impairment and progression to dementia to pave the way for future therapeutic targets that may mitigate COVID-19 induced cognitive decline. METHODOLOGY: A prospective longitudinal study is conducted at the University of Oklahoma Health Sciences Center. Patients are screened in the Department of Neurology and must have a formal diagnosis of MCI, and MRI imaging prior to study enrollment. Patients who meet the inclusion criteria are enrolled and followed-up at 18-months after their first visit. Visit one and 18-month follow-up will include an integrated and cohesive battery of vascular and cognitive measurements, including peripheral endothelial function (flow-mediated dilation, laser speckle contrast imaging), retinal and cerebrovascular hemodynamics (dynamic vessel retinal analysis, functional near-infrared spectroscopy), and fluid and crystalized intelligence (NIH-Toolbox, n-back). Multiple logistic regression will be used for primary longitudinal data analysis to determine whether COVID-19 related impairment in neurovascular coupling and increases in white matter hyperintensity burden contribute to progression to dementia.