Risk Of Vascular Cognitive Impairment Research Articles

Associations of self‐reported psychological stress with memory and cerebrospinal fluid biomarkers of Alzheimer’s disease in middle‐aged adults

AbstractBackgroundSelf‐reported psychological stress is associated with an increased risk of cognitive decline and dementia. However, it remains unclear whether stress is related to key biomarkers of Alzheimer’s disease (AD). This cross‐sectional study examined the relationship of psychological stress with memory and cerebrospinal fluid (CSF) biomarkers of AD in middle‐aged adults without dementia.MethodThe Healthy Brain Project (HBP) is a prospective web‐based study of adults aged between 40 and 70 years. A total of 2208 participants (76% female) completed the Depression, Anxiety, and Stress Scale (DASS) and Paired Associates Learning subtest of the CANTAB unsupervised on the HBP web platform. Additionally, a sub‐group of participants (n = 67; 41% APOE e4 carriers) attended an in‐person assessment where CSF samples were obtained to measure levels of amyloid‐beta (Aβ42), total tau (t‐tau), phosphorylated tau 181 (p‐tau), and neurofilament light chain (NFL). Separate linear regression analyses investigated associations of the DASS‐Stress score with memory performance and AD biomarkers. All analyses were adjusted for age, sex, education, and race.ResultIn the web‐based cohort, higher levels of self‐reported psychological stress were significantly associated with poorer memory (unstandardised β = ‐0.014, standard error [SE] = 0.004, p <.001). However, there were no significant associations between psychological stress and CSF levels of Aβ42, t‐tau, p‐tau, and NFL (all p > .05), with small effect sizes (Cohen’s f2 ≤ 0.05).ConclusionHigher levels of self‐reported psychological stress were associated with poorer memory in a large middle‐aged cohort but were not associated with AD biomarkers in a subset of participants with available CSF. One potential explanation is that non‐AD pathologies may underlie the relationship between stress and poorer memory; for example, poor coping strategies (e.g., smoking, overeating, and physical activity) might increase the risk of vascular cognitive impairment. However, it is also likely that the small sample size of the in‐clinic cohort was insufficient to detect any subtle relationships between stress and AD pathologies. Further research is needed to determine the associations between stress and the development of the clinical and biological manifestations of AD.

Vascular, Imaging and Cognition Association of China (VICA) Study: Rationale and Design

AbstractBackgroundChina has the highest number of patients with dementia in the world, and about 15‐30% of these cases are caused by vascular disease. Currently, the pathophysiological mechanism that cause vascular cognitive impairment (VCI) remain insufficiently understood. Therefore, early diagnosis and prognostic indicators of VCI are critically important for managing its onset and development To this end, several Chinese institutions have joined forces to establish “Vascular, Imaging and Cognition Association of China” (VICA) (Figure 1). The objective of VICA is to identify new targets for intervention and prompting intelligent graded and stratified treatment.MethodVICA is the first large‐scale multi‐center VCI consortium in China. It consists of seven advanced centers and over two hundred primary hospitals across the country. Included VICA are three different populations at risk for VCI: (a) high vascular risk factors for dementia, (b) cerebral small vessel disease, and (c) acute ischemic stroke or transient ischemic attacks (TIA).ResultAll individuals will be enrolled and monitored for at least 1 year using serial neuropsychological assessment, neuroimaging and collection of multi‐omics data from biospecimens (e.g., blood, urine, feces). In addition, a small sample of patients will undergo PET scans to determine whether neurodegenerative pathology (such as amyloid or tau accumulation) contributes to the course of vascular dementia. The enrollment procedure of patients with stroke or TIA is shown in Figure 2.ConclusionThe overall scientific aim of VICA is to guide early clinical diagnosis and early intervention of VCI based on the integration of multiple vascular risk factors, neuroimaging features and biomarkers. VICA represents a unique scientific resource that will help better understand the dynamics of cognitive change in different populations and identify new potential therapeutic targets for this condition.

Angiotensin II-mediated hippocampal hypoperfusion and vascular dysfunction contribute to vascular cognitive impairment in aged hypertensive rats.

Chronic hypertension increases the risk of vascular cognitive impairment (VCI) by ∼60%; however, how hypertension affects the vasculature of the hippocampus remains unclear but could contribute to VCI. Memory, hippocampal perfusion, and hippocampal arteriole (HA) function were investigated in male Wistar rats or spontaneously hypertensive rats (SHR) in early (4 to 5months old), mid (8 to 9months old), or late adulthood (14 to 15months old). SHR in late adulthood were chronically treated with captopril (angiotensin converting enzyme inhibitor) or apocynin (antioxidant) to investigate the mechanisms by which hypertension contributes to VCI. Impaired memory in SHR in late adulthood was associated with HA endothelial dysfunction, hyperconstriction, and ∼50% reduction in hippocampal blood flow. Captopril, but not apocynin, improved HA function, restored perfusion, and rescued memory function in aged SHR. Hippocampal vascular dysfunction contributes to hypertension-induced memory decline through angiotensin II signaling, highlighting the therapeutic potential of HAs in protecting neurocognitive health later in life. Vascular dysfunction in the hippocampus contributes to vascular cognitive impairment. Memory declines with age during chronic hypertension. Angiotensin II causes endothelial dysfunction in the hippocampus in hypertension. Angiotensin II-mediated hippocampal arteriole dysfunction reduces blood flow. Vascular dysfunction in the hippocampus impairs perfusion and memory function.

Clinical experience with the use of citicoline in mild cognitive impairment of vascular origin

Cardiovascular factors significantly increase the risk of vascular cognitive impairment (VCI). Currently, there are no specific treatments for VCI. A promising therapeutic strategy is the administration of citicoline, which has a neuroprotective effect.Objective: to evaluate the effect of treatment with citicoline (Noocil®) on cognitive function and quality of life (QoL)in patients with mild cognitive impairment (MCI) developed in a background of arterial hypertension and cerebral arteriosclerosis.Material and methods. An open-label prospective observational study enrolled 32 patients with neuroimaging-confirmed vascular cognitive impairment who received baseline therapy (antihypertensive, lipid-lowering, and antiplatelet therapy) and achieved target blood pressure and low-density lipoprotein cholesterol levels. All patients were assessed with a neuropsychological status assessment (MoCA-test). The efficacy of therapy was assessed by the Short Form-36 Quality of Life Questionnaire (SF-36).Results. The most common complaints of the patients were poor concentration, fatigue, forgetfulness, mood lability, sleep disturbances, more often in the form of early waking, and headaches. After 3 months of taking the drug Noocil®, all patients noted an increase in the ability to work, an improvement in concentration, memory and reproduction of the information received, both physical and mental indicators of QoL improved. The positive dynamics in terms of cognitive status (especially the functions of attention, short-term memory, several aspects of executive functions), QoL of patients, which was associated with the effect of Noocil® therapy, was accompanied by the absence of adverse events. A distinctive feature of domestic citicoline (Noocil®) is the presence of an original dosage form – a 240 ml bottle for oral administration, which improves adherence to long-term therapy.Conclusion. The efficacy, safety and good tolerability of Noocil® therapy in patients with predemental VCI was demonstrated.

Exploring what progress is being made in the development of health promotion material for vascular dementia: A systematic review of the evidence.

A systematic review conducted by Price and Keady (Journal of Nursing and Healthcare of Chronic Illness, 2, 88 and 2010) demonstrated that there was a dearth of health-promoting literature available for people diagnosed with vascular dementia. The correlation between health behavior and the onset of cardiovascular change that can lead to vascular dementia had demonstrated a need for health education and health-promoting information to be made accessible to vulnerable populations to ameliorate the risk of cognitive decline because of cardiovascular disease. Dementia is a progressive and life-limiting condition and with limited treatment options and a lack of progress in identifying a way to delay onset or even cure the condition. Focus must be targeted towards risk reduction strategies that serve to reduce onset and decline and limit the global burden on not only the individual with the condition and their carers but also to the health and social care economy. To identify the progress that has been made in developing health-promoting literature and patient education guidance since 2010 a systematic literature review was undertaken. Using thematic analysis, CINAHL, MEDLINE, and psych INFO databases were accessed and following PRISMA guidelines an inclusion and exclusion criteria was developed in order to locate peer-reviewed articles. Titles and abstracts were reviewed to identify a match with key terms, and from 133 screened abstracts eight studies met the inclusion requirements. From the eight studies, thematic analysis was implemented to identify shared understanding of experiences relating to health promotion in vascular dementia. The methodology for the study was replicated from the authors' previous systematic review in 2010. Five key themes were identified in the literature (Healthy heart healthy brain; Risk factors; Risk reduction/modification; Interventions; Absence of targeted health promotion). From what little evidence was available to review the thematic analysis has demonstrated developments in knowledge into the link between the onset of cognitive impairment and vascular dementia because of compromised cardiovascular health. Modifying health behavior has become essential in ameliorating the risk of vascular cognitive decline. With these developments the synthesis of the literature demonstrates that even with these insights there continues to be a lack of targeted material that individuals can access to understand the link between cardiovascular health and cognitive decline. It is recognized that maximizing cardiovascular health has the potential to lessen the risk of vascular cognitive impairment and vascular dementia developing and progressing yet targeted health promoting material remains lacking. With the developments in understanding the causal links between poor cardiovascular health, vascular cognitive impairment, and vascular dementia progress now needs to be made in developing targeted health promotion material for individuals to access to share this knowledge to reduce the potential onset and subsequent burden of dementia.

Impact of Bilingualism on the Cognitive Outcomes in Stroke Survivors: A Systematic Review (P4-12.005)

<h3>Objective:</h3> To examine existing evidence on the effect of bilingualism on cognitive outcomes in the stroke population. <h3>Background:</h3> Stroke is associated with an increased risk of vascular cognitive impairment. Bilingualism promotes cognitive reserve and resilience through the effect of language switching on the cognitive control systems and is suggested to delay cognitive impairment and dementia in non-stroke populations. However, the impact of bilingualism on cognitive outcomes in stroke patients has not been thoroughly examined. <h3>Design/Methods:</h3> We systematically reviewed published literature in medical databases that compared the cognitive assessment scores between mono-and bilingual stroke patients using cognitive assessment tool(s). We planned (1) a meta-analysis of outcome data using the subdomains of cognitive assessment tool(s); (2) a qualitative comparison if a meta-analysis was impossible. We assessed the study quality using the Joanna Briggs Institute tool. <h3>Results:</h3> Our literature search yielded 348 articles, and six were eligible for our systematic review (N=528 bilinguals; 737 monolinguals). One study was of good quality (Hope, 2015), and five were of moderate quality. We could not perform a meta-analysis because of disparate cohort characteristics and study methods, choice of cognitive tests, outcome measures, and lack of common data elements. Studies used one cognition and three language assessment batteries as cognitive assessment tools. In two studies, bilinguals performed better than monolinguals on cognitive tests (Paplikar, 2019; Alladi, 2016). On language assessment batteries, bilinguals performed better than monolinguals in four studies (Paplikar, 2019; Lahiri, 2020; Ardila, 2021; deLetter, 2021) and poorly in one study (Hope et al., 2015). ACE-R was significantly greater in bilinguals than monolinguals (Paplikar, 2019; Alladi, 2016). <h3>Conclusions:</h3> The current literature on the relationship between bilingualism and cognitive outcomes in stroke patients is sparse and insufficient. Harmonization of study methods (e.g., cognitive assessment tools) and common-data elements are critically needed to advance bilingualism research. <b>Disclosure:</b> Ms. Eldem has nothing to disclose. Mr. Misra has nothing to disclose. Dr. Quinn has nothing to disclose. Dr. Driskell has nothing to disclose. Dr. Perez has nothing to disclose. Dr. Carrión has nothing to disclose. Todd Constable has nothing to disclose. Dr. Schindler has received personal compensation for serving as an employee of Aeromics. Dr. Schindler has received personal compensation in the range of $50,000-$99,999 for serving as an officer or member of the Board of Directors for Aeromics. Dr. Schindler has received stock or an ownership interest from Aeromics. Dr. Schindler has received publishing royalties from a publication relating to health care. Dr. Zhao has nothing to disclose. Dr. Sico has nothing to disclose. Dr. Hinman has received personal compensation in the range of $5,000-$9,999 for serving as an Expert Witness for Bertoldo, Baker, Carter &amp; Smith. Dr. Hinman has received personal compensation in the range of $500-$4,999 for serving as an Expert Witness for Koskoff, Koskoff &amp; Bieder. Dr. Hinman has received personal compensation in the range of $5,000-$9,999 for serving as an Expert Witness for Matthew Millea, PC. Dr. Hinman has received personal compensation in the range of $500-$4,999 for serving as an Expert Witness for Popham Law Firm PC. Dr. Hinman has received stock or an ownership interest from Sage Cerebrovascular Diagnostics, Inc.. Dr. Hinman has received research support from NIH. Dr. Hinman has received research support from American Heart Association. Dr. Hinman has received research support from Reneuron. Dr. Hinman has received intellectual property interests from a discovery or technology relating to health care. Prof. Allore has received personal compensation in the range of $500-$4,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for American College of Rheumatology. The institution of Prof. Allore has received research support from NIH. Prof. Allore has received personal compensation in the range of $500-$4,999 for serving as a DSMB member with NIH. An immediate family member of Prof. Kiran has received personal compensation for serving as an employee of Constant Therapy. Prof. Kiran has received personal compensation in the range of $0-$499 for serving as an officer or member of the Board of Directors for Academy of Aphasia. Prof. Kiran has received personal compensation in the range of $500-$4,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Elsevier. Prof. Kiran has stock in Constant Therapy Health. The institution of Prof. Kiran has received research support from NIH. Jubin Abutalebi has nothing to disclose. Dr. Annoni has received personal compensation for serving as an employee of OMPharma, Switzerland . The institution of Dr. Annoni has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for CERC European Cardiovascular Research Centre . Dr. Mishra has nothing to disclose.

Abstract TMP33: Obesity And Hyperinsulinemia Impair Insulin Receptor Transport In The Brain Microvascular Endothelium

Introduction: Obesity afflicts over 650 million individuals worldwide and is a strong risk factor for both stroke and dementia. Hyperinsulinemia-induced insulin resistance, a finding commonly seen in obesity, is linked to brain insulin deficiency. As insulin is neuroprotective, impaired transport from the peripheral circulation into the brain may underlie the enhanced risk of vascular cognitive impairment in obese individuals. Thus, the focus of this study is to understand the role of aberrant insulin receptor endocytosis in impaired brain insulin transport associated with diet-induced obesity. Methods: C57Bl/6J mice were placed on a control or high fat diet beginning at 6 weeks of age for 24 weeks (n=3-5) and hippocampi collected to image microvascular receptor transport. To isolate the effects of insulin resistance, primary murine brain microvascular endothelial cells (MBEC) were exposed to hyperinsulinemia (HI; 20nM insulin for 12 hours). Naïve and HI cells were stimulated for 15 minutes with 20nM insulin and processed for immunoblotting, microscopy, and flow cytometry (n=3-12). Results: High fat diet fed mice exhibited reduced internalization of insulin receptor-positive vesicles in the vascular endothelium as compared to controls (0.27+/-0.04 v. 0.37+/-0.02). Correspondingly, HI MBECs displayed reduced insulin receptor internalization, disrupted actin architecture, and a decreased abundance of early endosomes as compared to naïve cells (0.90+/-0.12 v. 2.07+/-0.29). HI cells further demonstrated a shift towards increased endocytic vesicle formation and swelling relative to naïve cells (1.90+/-0.21 v. 1.04+/-0.08), the result of which may be due to an observed increase in endoplasmic reticulum stress and impaired nitric oxide synthase capacity. Conclusion: Diet-induced obesity impairs insulin receptor endocytosis into the brain vascular endothelium. These data suggest that hyperinsulinemia induces a compensatory shift in endocytic machinery, with receptors potentially becoming trapped within endocytic buds as opposed to trafficking into the cell. By uncovering the mechanisms linking obesity to cognitive decline, this study will help identify novel therapeutic targets for vascular cognitive impairment and dementia.

Circulating neurodegeneration biomarkers neurofilament light protein and p‐tau181 are increased in individuals with heart failure at risk for vascular cognitive impairment

AbstractBackgroundSystemic inflammation, which is present in heart failure (HF), is known to increase risk for dementia and development of vascular cognitive impairment and dementia (VCID). Both neurofilament light protein (NfL) and tau phosphorylated at threonine‐181 (p‐tau181) are well known biomarkers of neurodegeneration in both Alzheimer’s disease and non‐Alzheimer’s disease neurodegenerative diseases. The purpose of the present study was to determine if blood levels of NfL and p‐tau181 are increased in HF patients at risk for VCID.MethodWe performed a retrospective study of 58 participants from the previously completed TOPCAT trial (Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist). TOPCAT participants had symptomatic HF categorized using New York Heart Association (NYHA) criteria, were &gt; 50 years of age, and had ejection fraction (LVEF) ≥45%, assessed within 6 months from study start (n=58, 52% female). Control serum samples were obtained from age‐matched adults between 50‐85 with no known health issues (n=24, 50% female). NfL was measured using Simoa Quanterix and p‐Tau181 measured with SimoaHuman pTau‐181 V2 kit. Statistical analysis was performed using GraphPad and significance tested using Welch’s ANOVA, Dunnett’s post.ResultBaseline NfL levels were significantly higher in NYHA class I/II (n=56) and III/IV (n=54, p&lt;.0001) than measured in age‐matched controls (see table for values). Over 12‐months follow‐up, participants in NYHA class I/II had an increase in NfL of 9.6±5% relative to baseline and those in class III/IV had a 31.7±17% increase from baseline. P‐tau181 levels were also significantly higher in both NYHA class I/II (n=56) and III/IV (n=54, p=.0002) as compared to age‐matched controls (see table for values) with levels were significantly higher in class III/IV than in class I/II participants (ANOVA, Dunnett’s post, p&lt;.001). Levels of p‐tau181 did not show significant changes over the 12‐month time in any group.ConclusionThese results demonstrate that 2 well‐studied biomarkers of neurodegeneration, NfL and p‐tau181, are elevated in subjects with HF. Studies are underway to determine if biomarker levels correlate with measures of cognitive function and MRI measures of brain structure and function in HF patients. (Supported by NIA U01AG066623).

Magnetic resonance imaging reveals microemboli-mediated pathological changes in brain microstructure in diabetic rats: relevance to vascular cognitive impairment/dementia.

Diabetes doubles the risk of vascular cognitive impairment, but the underlying reasons remain unclear. In the present study, we determined the temporal and spatial changes in the brain structure after microemboli (ME) injection using diffusion MRI (dMRI). Control and diabetic rats received cholesterol crystal ME (40-70 µm) injections. Cognitive tests were followed up to 16 weeks, while dMRI scans were performed at baseline and 12 weeks post-ME. The novel object recognition test had a lower d2 recognition index along with a decrease in spontaneous alternations in the Y maze test in diabetic rats with ME. dMRI showed that ME injection caused infarction in two diabetic animals (n=5) but none in controls (n=6). In diabetes, radial diffusivity (DR) was increased while fractional anisotropy (FA) was decreased in the cortex, indicating loss of tissue integrity and edema. In the dorsal hippocampus, mean diffusivity (MD), axial diffusivity (DA), and DR were significantly increased, indicating loss of axons and myelin damage. Histological analyses confirmed more tissue damage and microglial activation in diabetic rats with ME. These results suggest that ME injury and associated cerebrovascular dysfunction are greater in diabetes, which may cause cognitive deficits. Strategies to improve vascular function can be a preventive and therapeutic approach for vascular cognitive impairment.

Lipid Peroxidation as a Marker of Apathy and Executive Dysfunction in Patients at Risk for Vascular Cognitive Impairment.

The co-occurrence of apathy and executive dysfunction, a correlate of vascular cognitive impairment (VCI), is highly prevalent, yet facilitating factors are largely unknown. This study investigates the relationship between lipid peroxidation, apathy, and executive dysfunction in patients at risk for VCI. In participants with coronary artery disease, who are at a high risk of VCI, apathy (Apathy Evaluation Scale), and executive function (composite z-score based on age and education population norms from trails making test B, animal naming, and phonemic fluency tests) were assessed. Serum concentrations of an early (lipid hydroperoxide (LPH)) and late (8-isoprostane (8-ISO)) lipid peroxidation marker, were measured and the 8-ISO/LPH ratio was calculated. Participants (n = 206, age±SD = 63.0±7.5, 80% men, total years of education = 15.9±3.4, AES score = 28.3±8.8, executive function = 0±1) demonstrated significantly different 8-ISO/LPH ratios between groups (F(3, 202) = 10.915, p &lt; 0.001) with increasing levels in the following order: no apathy or executive dysfunction, only executive dysfunction (executive function composite score≤-1), only apathy (AES≥28), and both apathy and executive dysfunction. A model adjusting for demographics showed that lipid peroxidation was associated with both apathy (B(SE) = 4.63 (0.954), t = 4.852, p &lt; 0.001) and executive function (B(SE) = -0.19 (0.079), t = -2.377, p = 0.018). However, when controlling for both demographics and vascular risk factors, lipid peroxidation was associated with only apathy (B(SE) = 3.11 (0.987), t = 3.149, p = 0.002). The results highlight a potentially important involvement of lipid peroxidation in the co-occurrence of apathy and executive dysfunction in those at risk for VCI.

Risk Assessment of Cnm-Positive Streptococcus mutans in Stroke Survivors (RAMESSES): Protocol for a Multicenter Prospective Cohort Study.

IntroductionThe role of commensal microbiota in systemic diseases, including brain diseases, has attracted increasing attention. Oral infectious diseases, such as dental caries and periodontitis, are also involved in cerebrovascular diseases and cognitive impairment. Cerebral microbleeds (CMBs) and intracerebral hemorrhage due to small vessel disease (SVD), are presumably associated with a high risk of vascular cognitive impairment and stroke. We previously reported that Streptococcus mutans (S. mutans, the main pathogen of dental caries), harboring the cnm gene that encodes the collagen-binding protein Cnm, is associated with the development of hypertensive intracerebral hemorrhage and aggravation of CMBs. We also proposed a mechanism by which the circulating Cnm-expressing S. mutans causes intracerebral hemorrhage or CMBs; it binds to denuded basement membranes mainly composed of collagen IV through damaged tight junctions or it directly invades endothelial cells, resulting in blood-brain barrier injury. In November 2018, we initiated a multicenter, prospective cohort study (RAMESSES: Risk Assessment of Cnm-positive S. mutans in Stroke Survivors; UMIN Clinical Trials Registry: UMIN000045559) to explore the longitudinal association between Cnm-positive S. mutans and CMBs with comprehensive dental findings, which should determine the effect of Cnm-positive S. mutans in the oral cavity on the risk of CMB development and cognitive decline.MethodsFifteen domestic institutes will be enlisted to enroll 230 patients who have at least one CMB in the deep brain area and develop a stroke within the past year. The prevalence of Cnm-positive S. mutans based on oral specimens and dental hygiene will be examined. The primary outcome is the number of newly developed deep CMBs. The secondary outcomes include the new development of lobar, subtentorial, or any type of CMBs; symptomatic intracerebral hemorrhage or ischemic stroke; changes in cognitive function or frailty; major bleeding; all-cause mortality; and antibody titers against periodontal pathogens. The observation period will be 2 years.DiscussionThe 2-year longitudinal prospective cohort study is expected to establish the role of Cnm-positive S. mutans in SVD including CMBs and intracerebral hemorrhage from the perspective of the “brain-oral axis” and provide guidance for novel prophylactic strategies against Cnm-positive S. mutans-induced SVD.

Treatment with the BCL-2/BCL-xL inhibitor senolytic drug ABT263/Navitoclax improves functional hyperemia in aged mice.

Moment-to-moment adjustment of regional cerebral blood flow to neuronal activity via neurovascular coupling (NVC or "functional hyperemia") has a critical role in maintenance of healthy cognitive function. Aging-induced impairment of NVC responses importantly contributes to age-related cognitive decline. Advanced aging is associated with increased prevalence of senescent cells in the cerebral microcirculation, but their role in impaired NVC responses remains unexplored. The present study was designed to test the hypothesis that a validated senolytic treatment can improve NVC responses and cognitive performance in aged mice. To achieve this goal, aged (24-month-old) C57BL/6 mice were treated with ABT263/Navitoclax, a potent senolytic agent known to eliminate senescent cells in the aged mouse brain. Mice were behaviorally evaluated (radial arms water maze) and NVC was assessed by measuring CBF responses (laser speckle contrast imaging) in the somatosensory whisker barrel cortex evoked by contralateral whisker stimulation. We found that NVC responses were significantly impaired in aged mice. ABT263/Navitoclax treatment improved NVC response, which was associated with significantly improved hippocampal-encoded functions of learning and memory. ABT263/Navitoclax treatment did not significantly affect endothelium-dependent acetylcholine-induced relaxation of aorta rings. Thus, increased presence of senescent cells in the aged brain likely contributes to age-related neurovascular uncoupling, exacerbating cognitive decline. The neurovascular protective effects of ABT263/Navitoclax treatment highlight the preventive and therapeutic potential of senolytic treatments (as monotherapy or as part of combination treatment regimens) as effective interventions in patients at risk for vascular cognitive impairment (VCI).

Policy recommendations to address gaps in research for women with heart disease, stroke and vascular cognitive impairment

Heart and brain conditions are inextricably linked; patients with heart disease and/or stroke increase their risk for vascular cognitive impairment (VCI) and vice versa. In Canada, 9 out of 10 individuals have at least one risk factor for heart conditions, stroke or VCI. Many of these risks are experienced disproportionally by women, resulting in worse health outcomes. Oftentimes, primary care duties also fall on women who must balance between managing their health and caregiving.

NMN Rescues Endothelial Function and Neurovascular Coupling, Improving Cognitive Function in Aged Mice

Adjustment of cerebral blood flow (CBF) to neuronal activity via neurovascular coupling (NVC) has an essential role in maintenance of healthy cognitive function. In aging increased oxidative stress and cerebromicrovascular endothelial dysfunction impair NVC, contributing to cognitive decline. There is increasing evidence showing that a decrease in NAD+ availability with age plays a critical role in a range of age-related cellular impairments but its role in impaired NVC responses remains unexplored. The present study was designed to test the hypothesis that restoring NAD+ concentration may exert beneficial effects on NVC responses in aging. To test this hypothesis 24-month-old C57BL/6 mice were treated with nicotinamide mononucleotide (NMN), a key NAD+ intermediate, for 2 weeks. NVC was assessed by measuring CBF responses (laser Doppler flowmetry) evoked by contralateral whisker stimulation. We found that NVC responses were significantly impaired in aged mice. NMN supplementation rescued NVC responses by increasing endothelial NO-mediated vasodilation, which was associated with significantly improved spatial working memory and gait coordination. These findings are paralleled by the sirtuin-dependent protective effects of NMN on mitochondrial production of reactive oxygen species and mitochondrial bioenergetics in cultured cerebromicrovascular endothelial cells derived from aged animals. Thus, a decrease in NAD+ availability contributes to age-related cerebromicrovascular dysfunction, exacerbating cognitive decline. The cerebromicrovascular protective effects of NMN highlight the preventive and therapeutic potential of NAD+ intermediates as effective interventions in patients at risk for vascular cognitive impairment (VCI).

Endostatin as a Mediator Between Endothelial Function and Cognitive Performance in Those at Risk for Vascular Cognitive Impairment

Background:Patients with coronary artery disease have an increased risk for developing vascular cognitive impairment. Endothelial function is often diminished and has been associated with lower cognitive performance in these patients. The link between endothelial function and cognition in coronary artery disease is not fully understood. Angiogenesis may play a role in mediating the association between endothelial function and cognition since angiogenic processes rely heavily on the endothelium.Objective:The aim of this study was to determine if markers of angiogenesis mediate the relationship between endothelial function and cognition in coronary artery disease patients.Methods:In 50 participants with coronary artery disease, endothelial function was assessed using peripheral arterial tonometry. Vascular endothelial growth factor (pro-angiogenic) and endostatin (anti-angiogenic) were measured in peripheral serum samples. Cognition was assessed using the Montreal Cognitive Assessment. A mediation analysis, using a bias corrected inferential bootstrapping method with 10,000 permutations, was used to determine if vascular endothelial growth factor or endostatin mediated an association between peripheral arterial tonometry measures and cognitive performance on the Montreal Cognitive Assessment.Results:Endostatin, but not vascular endothelial growth factor, mediated a relationship between endothelial function and cognitive performance when controlling for total years of education, body mass index, coronary artery bypass graft, stent, diabetes, and diuretic use. This analysis was also significant when delayed recall was substituted for the overall score on the Montreal Cognitive Assessment.Conclusion:These results suggest that endostatin mediates an association between endothelial function and cognitive performance in coronary artery disease.

Female Mice Are Resistant to Inward Remodeling of Parenchymal Arterioles Observed in Male Mice During Angiotensin II‐Induced Hypertension

Hypertension increases risk of vascular cognitive impairment and dementia (VCID) by impairing the structure and function of cerebral arteries. These arterial changes result in chronic hypoperfusion of the brain parenchyma and, eventually, cognitive impairment. Epidemiological studies suggest a sex difference in development of VCID, with women being protected from its development until late in age. We have previously shown that angiotensin II (AngII)‐hypertension led to inward hypotrophic remodeling and decreased wall stress in the parenchymal arterioles (PAs) of male mice. This PA remodeling in AngII‐hypertension was associated with reduced cerebral perfusion, increased myogenic tone, and cognitive dysfunction. Female mice, however, were protected from memory impairments despite a similar increase in blood pressure and decrease in cerebral perfusion measured by scanning laser Doppler. We hypothesized that AngII‐hypertension in female mice will cause a decrease in cerebral perfusion measured by laser speckle contrast, as well as a decrease in outer diameter, lumen diameter, and wall thickness in the PAs. Sixteen to eighteen‐week‐old female C56BL/6 mice were treated with AngII (1200 ng/kg/min via osmotic mini‐pump) for four weeks. This dose was selected to produce a similar increase in blood pressure to the previously studied male mice. Sham mice served as control. Blood pressure was measured by tail‐cuff plethysmography and pial blood flow was measured. After euthanasia, brains were collected and PAs were isolated and mounted on a pressure myograph for assessment of spontaneous myogenic tone generation and structure. PA structure was assessed by increasing intralumenal pressure from 3mmHg to 120mmHg in 20mmHg increments. Results are presented as means ± SEM and PA data are reported at an intralumenal pressure of 40mmHg (n=5–12). Systolic blood pressure was increased (Sham: 141 ± 7, AngII: 179 ± 7mmHg; p&lt;0.05) and cerebral perfusion was reduced in AngII‐hypertension (Sham: 328 ± 6, AngII: 288 ± 11 perfusion units; p&lt;0.05). AngII infusion slightly decreased lumen (Sham: 49 ± 3, AngII: 42 ± 4μm; p=0.17) and outer (Sham: 57 ± 4, AngII: 48 ± 4μm; p=0.11) diameters, although not significantly. AngII‐hypertension reduced wall thickness (Sham: 4 ± 0.3, AngII: 3 ± 0.2μm; p&lt;0.05) and wall area (Sham: 691 ± 83, AngII: 441 ± 52μm2; p&lt;0.05). PAs from female mice did not show reductions in wall stress (Sham: 241.8 ± 19, AngII: 268 ± 20dynes/cm2; p&gt;0.05) or generate more myogenic tone in response to hypertension (Sham: 27 ± 4, AngII: 22 ± 2%; p&gt;0.05). While AngII‐hypertension resulted in reductions in lumen diameter, outer diameter, wall thickness, and wall stress in the PAs of male mice, PAs of female mice had only reduced wall thickness with modest reductions in lumen and outer diameters. Preliminary data suggest that females may be resistant to inward PA remodeling during AngII‐hypertension, despite similar reductions in cerebral blood flow as male mice. This potential protection of the cerebrovascular structure and myogenic tone generation could explain the absence of cognitive dysfunction in response to hypertension in female mice.Support or Funding Information5T32GM092715‐14

Treatment with the poly(ADP‐ribose) polymerase inhibitor PJ‐34 improves cerebromicrovascular endothelial function, neurovascular coupling responses and cognitive performance in aged mice, supporting the NAD+ depletion hypothesis of neurovascular aging.

Adjustment of cerebral blood flow (CBF) to neuronal activity via neurovascular coupling (NVC) plays an important role in the maintenance of healthy cognitive function. Strong evidence demonstrates that age‐related cerebromicrovascular endothelial dysfunction and consequential impairment of NVC responses contribute importantly to cognitive decline. Recent studies demonstrate that NAD+ availability decreases with age in the vasculature and that supplemental NAD+ precursors can ameliorate cerebrovascular dysfunction, rescuing NVC responses and improving cognitive performance in aged mice. The mechanisms underlying the age‐related decline in [NAD+] in cells of the neurovascular unit are likely multifaceted and may include increased utilization of NAD+ by activated poly (ADP‐ribose) polymerase (PARP‐1). The present study was designed to test the hypothesis that inhibition of PARP‐1 activity may confer protective effects on neurovascular function in aging, similar to the recently demonstrated protective effects of treatment with the NAD+ precursor nicotinamide mononucleotide (NMN). To test this hypothesis, 24‐month‐old C57BL/6 mice were treated with PJ‐34, a potent PARP inhibitor, for 2 weeks. NVC was assessed by measuring CBF responses (laser speckle contrast imaging) in the somatosensory whisker barrel cortex evoked by contralateral whisker stimulation. We found that NVC responses were significantly impaired in aged mice. Treatment with PJ‐34 improved NVC responses by increasing endothelial NO‐mediated vasodilation, which was associated with significantly improved spatial working memory. PJ‐34 treatment also improved endothelium‐dependent acetylcholine‐induced relaxation of aorta rings. Thus, PARP‐1 activation, likely by decreasing NAD+ availability, contributes to age‐related endothelial dysfunction and neurovascular uncoupling, exacerbating cognitive decline. The cerebromicrovascular protective effects of pharmacological inhibition of PARP‐1 highlight the preventive and therapeutic potential of treatments that restore NAD+ homeostasis as effective interventions in patients at risk for vascular cognitive impairment (VCI).Support or Funding InformationThis work was supported by grants the Oklahoma Center for the Advancement of Science and Technology, the Oklahoma Shared Clinical and Translational Resources (OSCTR) program funded by the National Institute of General Medical Sciences (GM104938), the NIA‐supported Geroscience Training Program in Oklahoma (T32AG052363), the Oklahoma Nathan Shock Center (P30AG050911), the Cellular and Molecular GeroScience CoBRE (1P20GM125528, sub#5337), and the NIGMS supported Center of Biomedical Research Excellence (CoBRE).

Nicotinamide mononucleotide (NMN) supplementation rescues cerebromicrovascular endothelial function and neurovascular coupling responses and improves cognitive function in aged mice.

Adjustment of cerebral blood flow (CBF) to neuronal activity via neurovascular coupling (NVC) has an essential role in maintenance of healthy cognitive function. In aging increased oxidative stress and cerebromicrovascular endothelial dysfunction impair NVC, contributing to cognitive decline. There is increasing evidence showing that a decrease in NAD+ availability with age plays a critical role in a range of age‐related cellular impairments but its role in impaired NVC responses remains unexplored. The present study was designed to test the hypothesis that restoring NAD+ concentration may exert beneficial effects on NVC responses in aging. To test this hypothesis 24‐month‐old C57BL/6 mice were treated with nicotinamide mononucleotide (NMN), a key NAD+ intermediate, for 2 weeks. NVC was assessed by measuring CBF responses (laser Doppler flowmetry) evoked by contralateral whisker stimulation. We found that NVC responses were significantly impaired in aged mice. NMN supplementation rescued NVC responses by increasing endothelial NO‐mediated vasodilation, which was associated with significantly improved spatial working memory and gait coordination. These findings are paralleled by the sirtuin‐dependent protective effects of NMN on mitochondrial production of reactive oxygen species and mitochondrial bioenergetics in cultured cerebromicrovascular endothelial cells derived from aged animals. Thus, a decrease in NAD+ availability contributes to age‐related cerebromicrovascular dysfunction, exacerbating cognitive decline. The cerebromicrovascular protective effects of NMN highlight the preventive and therapeutic potential of NAD+ intermediates as effective interventions in patients at risk for vascular cognitive impairment (VCI).Support or Funding InformationThis work was supported by grants the Oklahoma Center for the Advancement of Science and Technology, the Oklahoma Shared Clinical and Translational Resources (OSCTR) program funded by the National Institute of General Medical Sciences (GM104938), the NIA‐supported Geroscience Training Program in Oklahoma (T32AG052363), the Oklahoma Nathan Shock Center (P30AG050911), the Cellular and Molecular GeroScience CoBRE (1P20GM125528, sub#5337), and the NIGMS supported Center of Biomedical Research Excellence (CoBRE).

Abstract TP413: Compliance to Consistent Home Blood Pressure Monitoring Reduces the Risk of Vascular Cognitive Impairment in Stroke Patients

Background: Hypertension (HTN) is a well-recognized risk factor for vascular cognitive decline. Poorly controlled HTN is common in the outpatient setting, with multi-factorial components including a lack of consistent, continuous and accurate reporting of blood pressure (BP) to help clinicians to tailor therapy. In the current prospective study, we explore the association of stroke patients’ at-home BP self-monitoring compliance with clinical and imaging risk markers of developing cognitive impairment. Method: 146 consecutive stroke outpatients with diagnosed HTN were recruited per IRB protocol. All patients received BP education at their first clinical visit and were encouraged to monitor BP at home on a daily basis for two weeks three times during the course of the 5-year study. Compliance with BP monitoring was evaluated by completed BP log and questionnaire in follow-up visits at fixed intervals. At the end of the study, white matter disease (WMD) severity was estimated by Fazekas and Sheltens scores. Cognitive impairment was assessed using Montreal Cognitive Assessment (MoCA) scales. Result: Only 16.4% (n=24) patients had “good compliance,” monitoring their home BP regularly and consistently as instructed. The compliant group had better controlled systolic and diastolic BP (Figure A, p&lt;0.05). As measured by Fazekas and Sheltens scales, patients compliant with BP monitoring had lower WMD burden (Figure B, p&lt;0.05), and higher MoCA scores (Figure C, p=0.012) compared to noncompliant patients. Conclusion: Compliance with at-home BP monitoring is essential for better BP control in vascular cognitive impairment (VCI) patients post stroke. Consistent home BP monitoring resulted in decreased imaging-apparent small vessel disease and better long-term cognitive performance. Expanded study with a larger patient cohort is ongoing to account for other behavioral and psycho-social factors and to create improved home monitoring technology and treatment strategies.

Spatial distribution and cognitive impact of cerebrovascular risk-related white matter hyperintensities

White matter hyperintensities (WMHs) are considered macroscale markers of cerebrovascular burden and are associated with increased risk of vascular cognitive impairment and dementia. However, the spatial location of WMHs has typically been considered in broad categories of periventricular versus deep white matter. The spatial distribution of WHMs associated with individual cerebrovascular risk factors (CVR), controlling for frequently comorbid risk factors, has not been systematically investigated at the population level in a healthy ageing cohort. Furthermore, there is an inconsistent relationship between total white matter hyperintensity load and cognition, which may be due to the confounding of several simultaneous risk factors in models based on smaller cohorts. We examined trends in individual CVR factors on total WMH burden in 13,680 individuals (aged 45-80) using data from the UK Biobank. We estimated the spatial distribution of white matter hyperintensities associated with each risk factor and their contribution to explaining total WMH load using voxel-wise probit regression and univariate linear regression. Finally, we explored the impact of CVR-related WMHs on speed of processing using regression and mediation analysis. Contrary to the assumed dominance of hypertension as the biggest predictor of WMH burden, we show associations with a number of risk factors including diabetes, heavy smoking, APOE ε4/ε4 status and high waist-to-hip ratio of similar, or greater magnitude to hypertension. The spatial distribution of WMHs varied considerably with individual cerebrovascular risk factors. There were independent effects of visceral adiposity, as measured by waist-to-hip ratio, and carriage of the APOE ε4 allele in terms of the unique spatial distribution of CVR-related WMHs. Importantly, the relationship between total WMH load and speed of processing was mediated by waist-to-hip ratio suggesting cognitive consequences to WMHs associated with excessive visceral fat deposition. Waist-to-hip ratio, diabetes, heavy smoking, hypercholesterolemia and homozygous APOE ε4 status are important risk factors, beyond hypertension, associated with WMH total burden and warrant careful control across ageing. The spatial distribution associated with different risk factors may provide important clues as to the pathogenesis and cognitive consequences of WMHs. High waist-to-hip ratio is a key risk factor associated with slowing in speed of processing. With global obesity levels rising, focused management of visceral adiposity may present a useful strategy for the mitigation of cognitive decline in ageing.