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.

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.

Mild cognitive impairment (MCI) affects nearly 20% of older adults worldwide, with no targetable interventions for prevention. COVID-19 adversely affects cognition, with >70% of older adults with Long COVID presenting with cognitive complaints. Neurovascular coupling (NVC), an essential mechanism of cognitive function, declines with aging and is further attenuated in neurocognitive disorders. The effect of COVID-19 on NVC responses has yet to be addressed in older adults who are vulnerable to dementia progression. Participants with MCI and a history of COVID-19 (COV+, N = 31) and MCI participants with no history of infection (COV- N = 11) participated in this cross-sectional study to determine if COVID-19 affects cerebrocortical NVC responses and vascular function. Functional near-infrared spectroscopy was used to measure cerebrocortical NVC responses, and endothelial function was assessed via insonation of the brachial artery during a flow-mediated dilation protocol. NVC responses were elicited by the working memory n-back paradigm. NVC in the left dorsolateral prefrontal cortex and endothelial function was decreased in the COV+ group compared to the COV- group. These data provide mechanistic insight into how COVID-19 may exacerbate long-term cognitive sequela seen in older adults, highlighting the urgent need for further research and clinical trials to explore novel therapeutic interventions aimed at preserving/restoring NVC.

To examine the relationship between coated-platelet levels and the occurrence of major hemorrhagic complications following discharge in non-lacunar ischemic stroke.

To examine whether ADAMTS13 activity levels measured at the time of acute SARS-CoV-2 infection predict cognitive impairment after recovery.

IntroductionMild 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.MethodologyA 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.

Objective: To evaluate the impact of SARS-CoV-2 infection on the rate of progression to dementia in patients diagnosed with MCI prior to the COVID-19 pandemic. Background: Older age and vascular risk factors are associated with increased risk for developing more severe forms of COVID-19 and with increased rates of progression to dementia from MCI. We sought to determine if SARS-CoV-2 infection affects the rate of progression to dementia in a cohort of MCI patients diagnosed prior to the COVID-19 pandemic. Design/Methods: Consecutive MCI patients between June 30, 2019 and February 28, 2020 were identified by chart review in a large academic memory loss clinic. Patients were followed at regular intervals using telehealth and in-person visits. Progression to dementia was confirmed through neuropsychological testing and repeat imaging studies were completed. The impact of COVID-19, demographics and vascular risk factors on the rate progression to dementia was determined using logistic regression and Receiver Operator Characteristic (ROC) analyses. Significance was set at p < 0.05. Results: There were 118 patients diagnosed with MCI (mean age 75 years, average of 2.8 vascular risk factors). Thirty-three (28%) progressed to dementia over an average follow-up of 18 months. SARS-CoV-2 infection was confirmed by PCR in 18 patients (15.3%), with mild or moderate symptoms in most cases. Progression to dementia was noted in 10/18 (55.6%) patients with versus 23/100 (23%) patients without COVID-19 (p = 0.011). Age and SARS-CoV-2 infection were significantly associated with cognitive decline (AUC 0.724, 95% CI 0.623–0.825, p = 0.0002). On multiple logistic regression, COVID-19 was associated with a 4.39 (95% CI 1.48–13.04) increased odds of progression to dementia after adjusting for age (p = 0.008). Conclusions: These results indicate that Sars-CoV-2 infection in MCI patients with multiple vascular risk factors increases the risk for progression to dementia at 18 months. Disclosure: Angelia Kirkpatrick has nothing to disclose. Dr. Delpirou Nouh has nothing to disclose. Dr. Husain has nothing to disclose. Chao Xu has nothing to disclose. Andrea Vincent has received personal compensation for serving as an employee of Vista LifeSciences, Inc.. Andriy Yabluchanskiy has nothing to disclose. Anna Csiszar has nothing to disclose. Zoltan Ungvari has received personal compensation in the range of $5,000-$9,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Springer. Jim Scott has nothing to disclose. The institution of Dr. Prodan has received research support from US Department of Veterans Affairs (Merit award CX000340).

Cerebral small vessel disease (CSVD) is the leading cause of vascular cognitive impairment and is associated with COVID-19. However, contributing factors that often accompany CSVD pathology in COVID-19 patients may influence the incidence of cerebrovascular complications. Thus, a mechanism linking COVID-19 and CSVD has yet to be uncovered and differentiated from age-related comorbidities (i.e., hypertension), and medical interventions during acute infection. We aimed to evaluate CSVD in acute and recovered COVID-19 patients and to differentiate COVID-19-related cerebrovascular pathology from the above-mentioned contributing factors by assessing the localization of microbleeds and ischemic lesions/infarctions in the cerebrum, cerebellum, and brainstem. A systematic search was performed in December 2022 on PubMed, Web of Science, and Embase using a pre-established search criterion related to history of, or active COVID-19 with CSVD pathology in adults. From a pool of 161 studies, 59 met eligibility criteria and were included. Microbleeds and ischemic lesions had a strong predilection for the corpus callosum and subcortical/deep white matter in COVID-19 patients, suggesting a distinct CSVD pathology. These findings have important implications for clinical practice and biomedical research as COVID-19 may independently, and through exacerbation of age-related mechanisms, contribute to increased incidence of CSVD.

Introduction: Coated-platelets are a subset of highly procoagulant platelets observed upon dual-agonist stimulation with collagen and thrombin. Coated-platelet levels are elevated in patients with ischemic stroke and associated with stroke recurrence. Lower levels of coated-platelets are present in ischemic stroke patients with early hemorrhagic transformation or in those with microbleeds. We now investigate if the number and location of microbleeds are associated with coated-platelet levels following non-lacunar stroke. Methods: Coated-platelet levels, reported as percent of cells converted to coated-platelets, were assayed in consecutive stroke patients. The number and location of microbleeds (deep vs lobar/mixed) on 1.5 T MRI was recorded by two independent reviewers. Correlations between number of microbleeds and demographics, vascular risk factors, stroke subtype, medications and laboratory values (platelet count, MPV, Hgb, WBC, CRP) were calculated using the Spearman correlation coefficient. Logistic regression was used to identify factors independently associated with location. Results: There were 249 stroke patients analyzed, with a mean age of 65.7 years (range 42 to 91). Microbleeds were present in 72/249 patients (29%), ranged from 1 to 14 lesions and were classified as deep (47) or lobar/mixed (25) distribution. Inter-rater agreement was excellent (91%). The number of microbleeds correlated negatively with coated-platelet levels (adjusted r = -0.41, p < 0.001) after adjusting for age (r = 0.11, p = 0.09). Variables independently associated with lobar/mixed as opposed to deep location of microbleeds included coated-platelet levels (47.0±35.0% vs 26.7±10.2%, p = 0.005) and prior stroke (10/25 vs 9/47, p = 0.028). Conclusions: Lower levels of coated-platelets are associated with increased number of microbleeds. In addition, coated-platelet levels are higher in patients with lobar/mixed as compared to those with deep distribution of microbleeds, a finding possibly linked to amyloid metabolism abnormalities described in this subset of procoagulant platelets. These data support a role for differential involvement of platelet procoagulant potential in mechanisms leading to development of cerebral microbleeds.

Background: Dementia is the sixth leading cause of death in United States and causes significant disability in the aging population. Therefore, conversion of mild cognitive impairment (MCI) to dementia, and conditions affecting conversion (e.g., hypertension), is of the utmost public health concerns. COVID-19 has had a profound effect on the aging population with increased risk of cognitive dysfunction and cerebrovascular complications following recovery of infection. We have strong preliminary data that suggest COVID-19 increases progression rate from MCI to dementia compared to MCI patients with no COVID-19 history (56% vs 23%, respectively, p=0.011). However, mechanisms contributing to these findings have yet to be elucidated. Normal brain function is reliant on endothelium dependent cerebromicrovascular dilation to provide sufficient oxygen and nutrients to active neurons (neurovascular coupling [NVC]). Thus, due to COVID-19’s deleterious effects on the cerebrovasculature and association with cognitive impairment, it is necessary to investigate vascular mechanisms that may contribute to COVID-19 induced cognitive dysfunction. Our central hypothesis is that COVID-19 induces systemic endothelial dysfunction, impairing NVC responses and contributing to increased progression of MCI to dementia. Methods: We are addressing the central hypothesis through prospective follow-up design, assessing systemic and cerebrovascular function at baseline and 18-month follow-up in MCI patients with and without history of COVID-19 infection. We will collect 200 participants over the course of 3 years and progression to dementia data will be measured by semiannual evaluation in the Department of Neurology at the University of Oklahoma Health Sciences Center. Assessment of endothelial function was measured by laser speckle contrast imaging and flow mediated dilation studies. NVC responses were measured with functional near-infrared spectroscopy during cognitive stimulation with n-back test.Preliminary results: Our preliminary results were collected at baseline from 3 MCI patients with no history of cerebrovascular complications (1 COVID+ patient [77 years old, male]; 2 COVID- patients [55 and 65 years old, female]). COVID+ patient showed significant attenuation of NVC responses and peripheral macro- and microvascular endothelial function compared to COVID- patients. Conclusion: Preliminary data suggest that NVC and peripheral macro- and microvascular endothelium may be impaired in MCI patients with history of COVID-19 diagnosis. Further investigation into the role that COVID-19 has on cerebrovascular function and conversion to dementia will enhance the understanding of predisposing factors that influence progression to dementia. These findings may uncover a mechanism for how COVID-19 affects cognitive function, paving the way for future therapeutic interventions targeting neurovascular uncoupling as a prominent feature in the conversion to dementia. American Heart Association (AHA834339), the National Institute on Aging of National Institutes of Health (R01AG075834), and the NIA-supported Geroscience Training Program in Oklahoma (T32AG052363) This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

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.

Objective: To examine whether coated-platelet levels measured at the time of acute SARS-CoV-2 infection predict cognitive impairment after recovery from COVID-19. Background: Coated-platelets are a subset of highly procoagulant platelets observed upon dual agonist stimulation with collagen and thrombin. Coated-platelet levels are increased in ischemic stroke compared to controls, and higher levels are associated with stroke recurrence. Previously, we have shown that higher coated-platelet levels at baseline are predictive of death at 90 days in COVID-19. Cognitive symptoms are frequently reported after recovery from SARS-CoV-2 infection. Design/Methods: After consent, patients with acute SARS-CoV-2 infection were enrolled. Coated-platelet levels were assayed at the time of admission and then weekly during the hospitalization. Symptoms of post-COVID-19 syndrome were evaluated using the CDC questionnaire. Cognitive screening was completed by telephone using the MoCA test for the blind, version 8.1. Regression analysis was used to evaluate the effect of clinical variables, demographics and coated-platelet levels on MoCA score. Results: We recruited 38 patients admitted with COVID-19. The 32 surviving patients were interviewed by telephone for long COVID symptoms at 14.8±2.4 months after infection. Twenty subjects (67%) reported having ≥1 long-COVID symptoms, most often brain fog and fatigue (39.4%). Among the 29 subjects (average age 65.5 years, range 33–88) who agreed to complete MoCA testing, mean MoCA score was 16.6 (range 10–21), with 17 (58.6%) screening positive for cognitive impairment. Coated-platelet levels drawn at enrollment during hospitalization for COVID-19 were inversely associated with MoCA scores after adjusting for age and time from symptom onset (adjusted R2=0.2, p=0.037). A 10% absolute increase in baseline coated-platelet levels corresponded to a 1.3-point decrease in MoCA score (p=0.009). Conclusions: These findings suggest that platelet procoagulant potential is linked to long-term lower cognitive performance after SARS-CoV-2 infection. Future work is needed to investigate coated-platelets and post-COVID cognitive decline. Disclosure: Dr. Delpirou Nouh has nothing to disclose. The institution of Dr. Prodan has received research support from US Department of Veterans Affairs (Merit award CX000340). Chao Xu has nothing to disclose. Andrea Vincent has received personal compensation for serving as an employee of Vista LifeSciences, Inc.. Eleanor Mathews has nothing to disclose. Leslie Guthery has nothing to disclose. Mr. Sharps has nothing to disclose. Jim Scott has nothing to disclose. George Dale has nothing to disclose. Angelia Kirkpatrick has nothing to disclose.