Cerebral Vascular Function Research Articles

Cerebral Vasomotor Reactivity to Carbon Dioxide Using the Rebreathe Technique: Assessment of Within-day and Between-day Repeatability.

The cerebral vasodilator response to increased arterial carbon dioxide (CO2) concentration, termed cerebral vasomotor reactivity (CVMR), is used to assess cerebral vascular function. We sought to assess the within-day and between-day repeatability of CVMR to rebreathing-induced hypercapnia. Twelve healthy adults performed a within-day short interval protocol (17±2 minutes between trials), ten performed a within-day long interval protocol (145±16 minutes between trials), and seventeen performed a between-day protocol (5±2 days between visits). Repeatability of the slope of the percent change in middle cerebral artery mean blood velocity (%MCAvmean) and cerebral vascular conductance index (%CVCi), to the change in partial pressure of end-tidal CO2 (PETCO2) between the two trials/days was assessed. Within-day short interval %MCAvmean slope demonstrated fair to excellent repeatability (intraclass correlation, ICC=0.92 [95% confidence interval 0.72-0.98]; p<0.001) while %CVCi slope showed more variability (ICC=0.84 [0.47-0.95]; p=0.002]). Within-day long interval, %MCAvmean (ICC=0.95 [0.80-0.99]) and %CVCi (ICC=0.94 [0.71-0.99]) slopes showed good to excellent and fair to excellent repeatability respectively (p<0.001 for both). For between-day trials, better repeatability was observed for %CVCi (ICC=0.85 [0.57-0.95]; p<0.001) compared to %MCAvmean (ICC=0.76 [0.33-0.91]; p=0.004) slope. These findings indicate repeatable within- and between-day CVMR responses to rebreathe induced hypercapnia. However, a longer interval may be better for within-day repeat trials, particularly for CVCi measures.

Inhibition of Soluble Epoxide Hydrolase Ameliorates Cerebral Blood Flow Autoregulation and Cognition in Alzheimer's Disease and Diabetes-Related Dementia Rat Models.

Alzheimer's Disease and Alzheimer's Disease-related dementias (AD/ADRD) pose major global healthcare challenges, with diabetes mellitus (DM) being a key risk factor. Both AD and DM-related ADRD are characterized by reduced cerebral blood flow, although the exact mechanisms remain unclear. We previously identified compromised cerebral hemodynamics as early signs in TgF344-AD and type 2 DM-ADRD (T2DN) rat models. Genome-wide studies have linked AD/ADRD to SNPs in soluble epoxide hydrolase (sEH). This study explored the effects of sEH inhibition with TPPU on cerebral vascular function and cognition in AD and DM-ADRD models. Chronic TPPU treatment improved cognition in both AD and DM-ADRD rats without affecting body weight. In DM-ADRD rats, TPPU reduced plasma glucose and HbA1C levels. Transcriptomic analysis of primary cerebral vascular smooth muscle cells from AD rats treated with TPPU revealed enhanced pathways related to cell contraction, alongside decreased oxidative stress and inflammation. Both AD and DM-ADRD rats exhibited impaired myogenic responses and autoregulation in the cerebral circulation, which were normalized with chronic sEH inhibition. Additionally, TPPU improved acetylcholine-induced vasodilation in the middle cerebral arteries (MCA) of DM-ADRD rats. Acute TPPU administration unexpectedly caused vasoconstriction in the MCA of DM-ADRD rats at lower doses. In contrast, higher doses or longer durations were required to induce effective vasodilation at physiological perfusion pressure in both control and ADRD rats. Additionally, TPPU decreased reactive oxygen species production in cerebral vessels of AD and DM-ADRD rats. These findings provide novel evidence that chronic sEH inhibition can reverse cerebrovascular dysfunction and cognitive impairments in AD/ADRD, offering a promising avenue for therapeutic development.

Clinical and physiological risk factors contributing to the restricted mobility in older adults: a longitudinal analysis

BackgroundMobility limitations (e.g., using wheelchair) have been closely linked to diminished functional independence and quality of life in older adults. The regulation of mobility is pertaining to multiple neurophysiologic and sociodemographic factors. We here aimed to characterize the relationships of these factors to the risk of restricted mobility in older adults.MethodsIn this longitudinal study, 668 older adults with intact mobility at baseline completed the baseline assessments of clinical characteristics, cognitive function, sleep quality, activities of daily living (ADL), walking performance, beat-to-beat blood pressure, and structural MRI of the brain. Then 506 of them (mean age = 70.7 ± 7.5 years) responded to the follow-up interview on the mobility limitation (as defined by if using wheelchair, cane, or walkers, or being disabled and lying on the bed) after 18 ± 3.5 months. Logistic regression analyses were performed to examine the relationships between the baseline characteristics and the follow-up mobility restriction.ResultsAt baseline, compared to intact-mobility group (n = 475), restricted-mobility group (n = 31) were older, with lower score of ADL and the Montreal Cognitive Assessment (MoCA), greater score of Pittsburgh Sleep Quality Index (PSQI), poorer cardio- and cerebral vascular function, and slower walking speeds (ps < 0.05). The logistic regression analysis demonstrated that participants who were with history of falls, uncontrolled-hypertension, and/or greater Fazekas scale (odds ratios (ORs):1.3 ~ 13.9, 95% confidence intervals (CIs) = 1.1 ~ 328.2), walked slower, and/or with lower ADL score (ORs: 0.0026 ~ 0.9; 95%CI: 0.0001 ~ 0.99) at baseline, would have significantly greater risk of restricted mobility (p < 0.05; VIFs = 1.2 ~ 1.9).ConclusionsThese findings provide novel profile of potential risk factors, including vascular characteristics, psycho-cognitive and motor performance, for the development of restricted mobility in near future in older adults, ultimately helping the design of appropriate clinical and rehabilitative programs for mobility in this population.

Cognitive function and bladder health among midlife adult women in the Coronary Artery Risk Development in Young Adults (CARDIA) study.

The aim of this study was to examine whether different aspects of women's cognitive function are associated with lower urinary tract symptoms (LUTS) and their impact. In 2010-2011, women aged 42 to 57 years in the Coronary Artery Risk Development in Young Adults study completed different tests of cognitive function, including the Digit Symbol Substitution Test, Rey Auditory Verbal Learning Test, and Stroop test. Two years later, data on LUTS and their impact were collected. LUTS/impact, a four-level composite variable ranging from bladder health to mild, moderate, and severe LUTS/impact, was regressed on each cognitive test separately, as well as a cognitive function composite variable. The analytic sample was composed of 1,021 women with complete data. When adjusting for sociodemographic variables (age, race, education) and gynecologic/obstetric variables (parity, menopausal status, hysterectomy, hormonal use), better performance on the cognitive function composite and Digit Symbol Substitution Test were both associated with lower odds of membership to a more severe LUTS/impact category (odds ratio, 0.90 [95% confidence interval, 0.83-0.98] and 0.89 [95% confidence interval, 0.82-0.97], respectively). These associations became nonsignificant when additionally adjusting for mechanisms that might explain an association between cognitive function and LUTS/impact, including health behaviors and health conditions that may covary with cerebral and peripheral vascular health and cognitive function. In this sample of midlife adult women, a modest association was found between better cognitive function and lower likelihood of LUTS/impact. Longitudinal studies are needed to further investigate the association between cognitive function and LUTS/impact, as well as potential explanatory mechanisms, particularly as women age and cognitive function varies to a greater degree.

Peripheral vascular dysfunction and the aging brain.

Aging is the greatest non-modifiable risk factor for most diseases, including cardiovascular diseases (CVD), which remain the leading cause of mortality worldwide. Robust evidence indicates that CVD are a strong determinant for reduced brain health and all-cause dementia with advancing age. CVD are also closely linked with peripheral and cerebral vascular dysfunction, common contributors to the development and progression of all types of dementia, that are largely driven by excessive levels of oxidative stress (e.g., reactive oxygen species [ROS]). Emerging evidence suggests that several fundamental aging mechanisms (e.g., "hallmarks" of aging), including chronic low-grade inflammation, mitochondrial dysfunction, cellular senescence and deregulated nutrient sensing contribute to excessive ROS production and are common to both peripheral and cerebral vascular dysfunction. Therefore, targeting these mechanisms to reduce ROS-related oxidative stress and improve peripheral and/or cerebral vascular function may be a promising strategy to reduce dementia risk with aging. Investigating how certain lifestyle strategies (e.g., aerobic exercise and diet modulation) and/or select pharmacological agents (natural and synthetic) intersect with aging "hallmarks" to promote peripheral and/or cerebral vascular health represent a viable option for reducing dementia risk with aging. Therefore, the primary purpose of this review is to explore mechanistic links among peripheral vascular dysfunction, cerebral vascular dysfunction, and reduced brain health with aging. Such insight and assessments of non-invasive measures of peripheral and cerebral vascular health with aging might provide a new approach for assessing dementia risk in older adults.

Treating ischemic stroke by improving vascular structure and promoting angiogenesis using Taohong Siwu Decoction: An integrative pharmacology strategy

Ethnopharmacological relevanceNeovessels represent a crucial therapeutic target and strategy for repairing ischemic tissue. Taohong Siwu Decoction (THSWD) exhibits potential in promoting angiogenesis to address ischemic stroke (IS). However, its impact on neovessel structure and function, alongside the underlying molecular mechanisms, remains elusive. Aim of the studyOur aim is to investigate the protective effects of THSWD on neovessel structure and function, as well as the associated molecular mechanisms, utilizing an integrative pharmacological approach. Materials and methodsWe initially employed behavioral tests, 2,3,5-triphenyltetrazolium chloride (TTC) staining, Haematoxylin-eosin (HE) staining, enzyme-linked immunosorbent assay (ELISA), Laser Doppler flowmetry (LDF), Evans blue staining, and immunofluorescence to evaluate the protective effects of THSWD on neovascular structure and function in middle cerebral artery occlusion/reperfusion (MCAO/R) rats. Subsequently, we utilized network pharmacology, metabolomics, and experimental validation to elucidate the underlying molecular mechanisms of THSWD in enhancing neovascular structure and function. ResultIn addition to significantly reducing neurological deficits and cerebral infarct volume, THSWD mitigated pathological damage, blood-brain barrier (BBB) leakage, and cerebral blood flow disruption. Moreover, it preserved neovascular structure and stimulated angiogenesis. THSWD demonstrated potential in ameliorating cerebral microvascular metabolic disturbances including lipoic acid metabolism, fructose and mannose metabolism, purine metabolism, and ether lipid metabolism. Consequently, it exhibited multifaceted therapeutic effects, encompassing anti-inflammatory, antioxidant, energy metabolism modulation, and antiplatelet aggregation properties. ConclusionTHSWD exhibited protective effects on cerebral vascular structure and function and facilitated angiogenesis by rectifying cerebral microvascular metabolic disturbances in MCAO/R rats. Furthermore, integrated pharmacology offers a promising approach for studying the intricate traditional Chinese medicine (TCM) system in IS treatment.

Dietary Effect on Peripheral and Cerebral Vascular Function in Adults with Non-Alcoholic Fatty Liver Disease

Objective: Non-alcoholic fatty liver disease (NAFLD) is a recognized independent risk factor for cardiovascular and cerebrovascular dysfunction. The present study evaluated the effect of dietary interventions on peripheral and cerebral vascular function in individuals with NAFLD. Methods: We studied 30 middle-aged adults (55±9 years) with NAFLD or with elevated NAFLD risk (with prediabetes symptoms). Liver fat content was assessed via 1H magnetic resonance spectroscopy. NAFLD was defined as liver fat proton density fat fraction (PDFF) exceeding 5%. Participants were randomly assigned to a low-carbohydrate diet (carbohydrate intake &lt;30 g/d) or a low-calorie diet (30% calorie intake reduction). Arterial stiffness (via brachial-ankle pulse wave velocity-baPWV), carotid artery intima-media thickness (IMT), endothelium-dependent vasodilation (via flow-mediated dilation-FMD), cerebrovascular reactivity (CVR) in the middle cerebral artery (MCA), and blood concentrations of cardiovascular risk factors were measured before and after a two-week dietary intervention. Results: Participants with NAFLD represented 70% of the current cohort. Following the dietary interventions, participants had significant reductions in body weight (95%CI [-3.22, -1.41 kg]) and fat mass (95%CI [-1.64, -0.56 kg]), accompanied by decreased liver fat content (95%CI [-2.62, -0.79%]). These changes were only evident in the NAFLD group with no significant differences between the two dietary interventions. Systolic and diastolic blood pressure as well as pulse pressure significantly decreased in both NAFLD and non-NAFLD groups. Total cholesterol (95%CI [-22.2, -1.5 mg/dL]) and triglyceride (95%CI [-30.4, -0.9 mg/dL]) concentrations decreased in those with NAFLD assigned to the low-carbohydrate diet. baPWV decreased (95%CI [-78.6, -12.4 cm/s]) only in individuals with NAFLD assigned to the low-calorie diet. FMD significantly increased (95%CI [0.5, 5.1%]) only in individuals with NAFLD assigned to the low-carbohydrate diet. Lower baseline liver fat content was associated with greater improvement in FMD (r=-0.60, p=0.008) in the NAFLD group. Carotid IMT and cerebrovascular parameters (e.g., pulsatility index, CVR, MCA blood flow velocity) remained unchanged in any groups. Changes in vascular function were not associated with the corresponding changes in liver fat content. Conclusion: The two-week dietary intervention involving either a low-carbohydrate or low-calorie diet elicited significant reductions in liver fat content and improvements in peripheral arterial stiffness and endothelium-dependent vasodilation in adults with NAFLD. UT Aging Initiatives. This is the full abstract presented at the American Physiology Summit 2024 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.

The impact of increased daily peanut consumption on indices of peripheral and cerebral vascular function in non-Hispanic Black individuals

Cardiovascular disease, neurocognitive conditions, and cerebral vascular diseases including cognitive impairment, stroke, and Alzheimer’s disease and related dementias disproportionately impact the Non-Hispanic Black (BL) population. The mechanisms are multifactorial but is related to reduced vascular function/health. Our lab, and others, have demonstrated that reduced nitric oxide (NO) bioavailability secondary to oxidative stress, systemic inflammation, and reduced L-arginine bioavailability contributes to reduced vascular function/health in this population. Increased dietary peanut consumption improves various physiological outcomes including blood pressure, cholesterol, type II diabetes, cognitive health, NO bioavailability, and vascular function/health. This improvement is related to increased bioavailability of L-arginine, reduced systemic inflammation, and antioxidant capacity. This study hypothesized that increased daily peanut consumption would improve indices of peripheral and cerebral vascular function/health in a cohort of BL individuals. Methods: Seventeen people participated (11 non-Hispanic White (WH) and 6 BL (age: WH 25±8, BL 21±2; BMI: WH 23±3, BL 22 ± 4; p&gt;0.05 for both). Measures were made before (pre) and after (post) 56 days of daily lightly salted peanut consumption (2 oz/day for females and 3 oz/day for males). Peripheral macro and microvascular function/health was assessed as brachial artery vasodilation (flow mediated dilation, %FMD) and forearm reactive hyperemia (peak mean forearm blood velocity (FBVmean) respectively following 5-min of suprasystolic cuff inflation. Cerebral vascular function/health was assessed as the cerebral vasodilator response during a hypercapnic challenge, i.e., the slope of % cerebral vascular conductance index (CVCi) relative to the change in end-tidal carbon dioxide concentration (ΔPETCO2). Results: There was no effect of race on peripheral macrovascular function assessed as %FMD (WH: 5.3 ±0.89, BL: 6.3 ±1.9 %, p=0.31) or peripheral microvascular function assessed as FBVmean (WH: 82.90 ± 4.5, BL: 72 ± 6.7 cm·s−1, p=0.13). Likewise, there no effect of treatment on %FMD (Pre: 5.4 ± 0.7, Post: 6.2 ± 2.1 %, p=0.46) or FBVmean (Pre: 81.4 ± 6.7, Post: 73.4 ± 8.8 cm·s−1, p=0.27). Lastly, there were no effect of race (WH: 4.0 ± 0.36, BL: 3.9 ± 0.6 %, p=0.85) or treatment (Pre: 3.9 ± 0.56, Post: 4.0 ± 0.39 %, p=0.79) on cerebral vascular function assessed as %CVCi during hypercapnia. Conclusion: The preliminary data suggest that 56 days of increased daily peanut consumption does not induce measurable improvements in indices of vascular function in a cohort of relatively young BL individuals. Future work will continue to assess this effect in a larger cohort of individuals as well as in individuals with existing conditions or diseases (i.e., hypertension, type II diabetes, etc.). Funding: Peanut Institute (982307). This is the full abstract presented at the American Physiology Summit 2024 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.

Indices of cerebral vascular function &amp; health in young healthy adults: impact of sex and race

Background: Cerebral vascular diseases and neurocognitive conditions including stroke, cognitive impairment, &amp; Alzheimer’s disease and related dementias are the fastest growing causes of morbidity and mortality. Studies have demonstrated sex differences in indices of physiological function associated with cardiovascular and metabolic disease risk/prevalence. Further, the incidence of these conditions is elevated in Black (BL) individuals; however, BL females have a reduced age adjusted stroke mortality compared to BL males. Reduced cerebral vascular function/health contributes to the risk for these conditions. Limited studies have examined the influence of sex and race on indices of cerebral vascular function/health. This study examined the potential interaction between race and sex in cerebral pulsatility index (PI: index of cerebral vascular stiffness) and cerebral vasomotor reactivity (CVMR) to a hypercapnic challenge (index of cerebral vasodilatory responsiveness). Hypothesis: We hypothesized: 1) females would have reduced PI and elevated CVMR relative to males. 2) BL individuals would exhibit augmented PI and reduced CVMR. 3) BL females would have reduced PI relative to BL males. 4) Lastly, we posit that CVMR will be negatively correlated with PI. Methods: Data is presented from 136 young healthy individuals. 40 BL males (age: 22±3 yr, BMI: 25±4 kg/m²), 37 BL females (age: 21±3 yr, BMI: 24±4 kg/m²), 39 White (WH) males (age: 24±3 yr, BMI: 25±3 kg/m²), and 20 WH females (age: 25±6 yr, BMI: 23±3 kg/m²). Heart rate, beat-to-beat blood pressure, end-tidal carbon dioxide concentration (PETCO2), and middle cerebral artery blood velocity (MCAv) were continuously recorded (minimum of 6 min). Cerebral vascular function/health was indexed as (a) PI ((MCAVv systolic − MCAv diastolic)/MCAv mean). (b) CVMR assessed as % increase in cerebral vascular conductance (CVCi) slope during a hypercapnic challenge (%CVCi/ΔPETCO2). Results: PI was elevated in males (male: 0.86±0.18, female: 0.77±0.11, P=0.03). There was no difference between races (WH: 0.83±0.19, BL: 0.79±0.13, P=0.27) nor was there a sex x race interaction ( P=0.54). CVMR assessed as %CVCi slope was not different between sexes (male: 2.4±1.7 %/mmHg, female: 2.7±1.2 %/mmHg, P=0.16) or BL &amp; WH (WH: 2.7±1.3 %/mmHg, BL: 2.4±1.1 %/mmHg, P=0.16). CVMR was lower in the BL males relative to the BL females (BL male: 2.0±0.9 %/mmHg, BL female: 2.8±1.2 %/mmHg, P=0.002). There was no difference between WH males and females ( P=0.88). Lastly, there was not a significant correlation between PI and CVMR to hypercapnia ( P=0.16). Conclusion: These preliminary data suggest that relatively young and otherwise health White and Black females have augmented indices of cerebral vascular function/health relative to males. Furthermore, BL males have reduced cerebral vasodilatory responsiveness to a hypercapnic stimuli. The University of Texas at Arlington College of Nursing and Health Innovation and Institutional Start up Funds to Dr. Brothers. This is the full abstract presented at the American Physiology Summit 2024 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.

Compounding Effects of Aging and Sex on Cerebrovascular Endothelial Mitochondria

Despite the increasing burden of age-related neurological diseases such as vascular cognitive impairment and dementia or Alzheimer’s disease, the underlying mechanisms of these pathologies are not clear. Nonetheless, structural and functional changes in the microvasculature represent probable pathological aspects of these age-associated diseases. The silent and cumulative changes in endothelial mitochondria with subsequently compromised cerebral vascular function are thought to play a central role in neurological disease development. We tested the hypothesis that mitochondrial morphological changes in endothelial cells facilitate the distinct aging- and sex-related differences in the cerebral microvascular proteome and energetics. Mito-dendra2 (mt-D2) labeled endothelial mitochondria were imaged in vivo via a cranial window using two-photon microscopy at 875 nm in young and old, male and female, mito-Dendra2 mice (YM, YF, OM, and OF, respectively). Mt-D2 associated signal was analyzed in 3D stacks using the Huygens Pro CE 23.04.0p3 object analyzer (160 images, originated from 4-5 mt-D2 mice/groups). We also measured mRNA copy numbers of mitochondrial fission and fusion genes in isolated, cortical microvessels (&lt;70 μm) from YM, YF, OM, and OF C57Bl/6J mice (n=7-11/age/sex) using ddPCR. Kruskal-Wallis test with Dwass-Steel-Critchlow-Fligner post-hoc comparisons were used to compare mt-D2 signal among YM, YF, OM, and OF, whereas Mann-Whitney U test determined changes across age and sex strata. p&lt;0.05 was considered statistically significant. mRNA copy numbers were normalized to housekeeping genes (GAPDH, β-actin, and HPRT-1) and compared with one-way ANOVA based on data distribution. Analysis of four object parameters revealed that object surface was smaller in old vs. young that was significant in YM vs. OM. We found significantly greater corrected lateral width in OM vs. YM, OF vs. YF, and in YF vs. YM. The lateral aspect ratio was significantly greater in YM vs. OM, in YF vs. OF, as well as in YM vs. YF. Accordingly, the axial sphericity of the principal box was significantly greater in OM vs. YM, in OF vs. YF, and in YF vs. YM. Normalized mRNA copy numbers of mitochondrial fission and fusion genes were not statistically different in our samples for DRP-1, Fis-1 or Mfn-1/2, Opa-1, respectively. These results suggest that aging driven morphological differences, such as the shortening of endothelial mt-D2 signal are, at least in part, facilitated by altered fission/fusion protein abundances and/or activity rather than transcriptional changes in our samples. Although we are still analyzing other morphological parameters, by assessing the effect sizes and their physiological relevance, we postulate that these morphological differences contribute to the vulnerability of the aged cerebral microvasculature to injury. AG083567, 3P30GM145498-01, U54GM104940, HL148836. This is the full abstract presented at the American Physiology Summit 2024 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.

In vivo phenotypic vascular dysfunction extends beyond the aorta in a mouse model for fibrillin-1 (Fbn1) mutation

In individuals with Marfan Syndrome (MFS), fibrillin-1 gene (FBN1) mutations can lead to vascular wall weakening and dysfunction. The experimental mouse model of MFS (Fbn1C1041G/+) has been advantageous in investigating MFS-associated life-threatening aortic aneurysms. It is well established that the MFS mouse model exhibits an accelerated-aging phenotype in elastic organs like the aorta, lung, and skin. However, the impact of Fbn1 mutations on the in vivo function and structure of various artery types with the consideration of sex and age, has not been adequately explored in real-time and a clinically relevant context. In this study, we investigate if Fbn1 mutation contributes to sex-dependent alterations in central and cerebral vascular function similar to phenotypic changes associated with normal aging in healthy control mice. In vivo ultrasound imaging of central and cerebral vasculature was performed in 6-month-old male and female MFS and C57BL/6 mice and sex-matched 12-month-old (middle-aged) healthy control mice. Our findings confirm aortic enlargement (aneurysm) and wall stiffness in MFS mice, but with exacerbation in male diameters. Coronary artery blood flow velocity (BFV) in diastole was not different but left pulmonary artery BFV was decreased in MFS and 12-month-old control mice regardless of sex. At 6 months of age, MFS male mice show decreased posterior cerebral artery BFV as compared to age-matched control males, with no difference observed between female cohorts. Reduced mitral valve early-filling velocities were indicated in MFS mice regardless of sex. Male MFS mice also demonstrated left ventricular hypertrophy. Overall, these results underscore the significance of biological sex in vascular function and structure in MFS mice, while highlighting a trend of pre-mature vascular aging phenotype in MFS mice that is comparable to phenotypes observed in older healthy controls. Furthermore, this research is a vital step in understanding MFS's broader implications and sets the stage for more in-depth future analyses, while providing data-driven preclinical justification for re-evaluating diagnostic approaches and therapeutic efficacy.

Heart-brain mapping: Cardiac atrial function is associated with distinct cerebral regions with high free water in older adults

Left atrial (LA) dysfunction has been linked to cognitive impairment and cerebrovascular dysfunction. Higher brain free-water (FW) derived from diffusion-MRI was associated with early and subtle cerebrovascular dysfunction and more severe cognitive impairment. We hypothesized that LA dysfunction would correlate with higher brain free-water (FW) among healthy older adults. 56 community older adults (73.13 ± 3.56 years; 24 female) with normal cognition and without known cardiovascular disease who had undergone cardiac-MRI, brain-MRI, and neuropsychological assessments were included. Whole-brain voxel-level general linear models were constructed to correlate brain FW measures with LA indices. We found lower scores in LA function measures were related to higher grey matter (GM) FW in regions including orbital frontal and right temporal regions (p < 0.01, family-wise error corrected). In parallel, LA dysfunction was associated with higher FW in white matter (WM) fibres including superior longitudinal fasciculus, internal capsule, and superior corona radiata. However, LA dysfunction was not related to WM tissue reduction and GM cortical thinning. Moreover, these cardiac-related higher brain FW were associated with lower executive function and higher serum B-type natriuretic peptide (p < 0.05, Holm–Bonferroni corrected). These findings may have implications for anti-ageing preventive strategies targeting cardiac and cerebral vascular functions to improve heart and brain outcomes.

Effects of butylphthalide on cerebral vascular circulation, coagulation function, and neurological function in patients with acute severe ischemic stroke following intravenous thrombolysis: a preliminary study

Objective To analyze the effects of Butylphthalide on cerebral vascular circulation, coagulation function, and neurological function in patients with acute severe ischemic stroke following intravenous thrombolysis. Methods Clinical efficacy, cerebral vascular circulation indicators [anterior cerebral artery (ACA), middle cerebral artery (MCA), vertebral artery (VA) blood flow velocity], coagulation function indicators [prothrombin time (PT), activated partial thromboplastin time (APTT), thrombin time (TT), fibrinogen (FIB)], neurological function indicators [Activities of Daily Living (ADL) score. Results The total effective rate of treatment in the control group was 76.47%, while in the observation group, it was 96.08%, with the observation group showing a significantly higher total effective rate than the control group (p < 0.05). Before treatment, there was no significant difference in ACA, MCA, and VA blood flow velocity between the two groups (p > 0.05). However, after treatment, the ACA, MCA, and VA blood flow velocity in the observation group were significantly higher than those in the control group (p < 0.05). Before treatment, there was no significant difference in PT, APTT, TT, and FIB levels between the two groups (p > 0.05). Conclusion In patients with acute severe ischemic stroke undergoing intravenous thrombolysis, the addition of Butylphthalide to the treatment regimen yields favorable clinical outcomes. Compared to Alteplase alone, the addition of Butylphthalide further improves cerebral vascular circulation and coagulation function, promoting the recovery and reconstruction of neurological function in patients. Importantly, the addition of Butylphthalide does not increase the risk of adverse reactions, making it a safe and ideal option for clinical application.

Abstract 17121: Elevated Aortic Stiffness and Impairments in Cerebrovascular Regulation in Cancer Survivorship

Background: Approximately 46% of cancer survivors report cognitive impairments across many types of cancer, which has been associated with anti-cancer therapy and often results in reduced quality of life. Pre-clinical studies suggest that predictors of cognitive decline may involve vascular dysfunction. We aimed to characterize local (cerebrovascular reactivity and cerebral autoregulation) and global (aortic arch stiffness) vascular regulation in cancer survivorship. Methods: Cerebral autoregulation was determined using Mx, a moving 10s-windowed correlation between finger plethysmography-derived blood pressure and cerebral blood velocity of the middle cerebral artery. Higher Mx values represent pressure-passive cerebral blood flow, indicating poor cerebral autoregulation. In addition, cerebral blood velocity, blood pressure, and end-tidal CO 2 were collected during a rebreathing task. MAP was used to calculate an index of cerebrovascular conductance (CVCi). Cerebrovascular reactivity was calculated as the change in cerebral blood velocity or CVCi over the change in end-tidal CO 2 . Aortic arch stiffness, as pulse wave velocity (aaPWV), was calculated from ultrasound scans of the aortic valve and the descending aorta. Differences between groups were assessed with Mann-Whitney tests. Results: Eleven women were recruited (5 controls and 6 cancer survivors who had received treatment). Cancer types included melanoma, lymphoma, and breast cancer. Age and resting MAP were similar between groups. Mx values were higher in cancer survivors (-0.13 ± 0.14 vs. 0.14 ± 0.11, p &lt; 0.05). Cerebrovascular reactivity, both absolute (2.8 ± 1.1 vs. 1.6 ± 0.8, p = 0.05) and as CVCi (16.8 ± 2.4 vs. 2.3 ± 9.4, p &lt; 0.05), were lower in cancer survivors. aaPWV was higher in cancer survivors (2.7 ± 0.8 vs. 3.8 ± 0.6, p &lt; 0.05). Across the entire study sample, aaPWV trended towards an association only with absolute cerebrovascular reactivity (Spearman r = -0.6, p = 0.054). Conclusion: Aortic stiffness was elevated and both cerebrovascular regulatory functions were impaired in cancer survivors compared to healthy controls. Present findings highlight the importance of monitoring cerebral and global vascular function in cancer survivors at high-risk for cognitive decline.

Patients with type 1 diabetes and albuminuria have a reduced brain glycolytic capability that is correlated with brain atrophy.

Patients with type 1 diabetes (T1D) demonstrate brain alterations, including white matter lesions and cerebral atrophy. In this case-control study, we investigated if a reason for this atrophy could be because of diabetes-related complications affecting cerebrovascular or cerebral glycolytic functions. Cerebral physiological dysfunction can lead to energy deficiencies and, consequently, neurodegeneration. We examined 33 patients with T1D [18 females, mean age: 50.8 years (range: 26-72)] and 19 matched healthy controls [7 females, mean age: 45.0 years (range: 24-64)]. Eleven (33%) of the patients had albuminuria. Total brain volume, brain parenchymal fraction, gray matter volume and white matter volume were measured by anatomical MRI. Cerebral vascular and glycolytic functions were investigated by measuring global cerebral blood flow (CBF), cerebral metabolic rate of oxygen (CMRO2) and cerebral lactate concentration in response to the inhalation of hypoxic air (12-14% fractional oxygen) using phase-contrast MRI and magnetic resonance spectroscopy (MRS) techniques. The inspiration of hypoxic air challenges both cerebrovascular and cerebral glycolytic physiology, and an impaired response will reveal a physiologic dysfunction. Patients with T1D and albuminuria had lower total brain volume, brain parenchymal fraction, and gray matter volume than healthy controls and patients without albuminuria. The inhalation of hypoxic air increased CBF and lactate in all groups. Patients with albuminuria had a significantly (p = 0.032) lower lactate response compared to healthy controls. The CBF response was lower in patients with albuminuria compared to healthy controls, however not significantly (p = 0.24) different. CMRO2 was unaffected by the hypoxic challenge in all groups (p > 0.16). A low lactate response was associated with brain atrophy, characterized by reduced total brain volume (p = 0.003) and reduced gray matter volume (p = 0.013). We observed a reduced response of the lactate concentration as an indication of impaired glycolytic activity, which correlated with brain atrophy. Inadequacies in upregulating cerebral glycolytic activity, perhaps from reduced glucose transporters in the brain or hypoxia-inducible factor 1 pathway dysfunction, could be a complication in diabetes contributing to the development of neurodegeneration and declining brain health.

The acute effect of whole-body heat therapy on peripheral and cerebral vascular reactivity in Black and White females.

Among females in the U.S., Black females suffer the most from cardiovascular disease and stroke. While the reasons for this disparity are multifactorial, vascular dysfunction likely contributes. Chronic whole-body heat therapy (WBHT) improves vascular function, but few studies have examined its acute effect on peripheral or cerebral vascular function, which may help elucidate chronic adaptative mechanisms. Furthermore, no studies have investigated this effect in Black females. We hypothesized that Black females would have lower peripheral and cerebral vascular function relative to White females and that one session of WBHT would mitigate these differences. Eighteen young, healthy Black (n=9; 21±3yr; BMI: 24.7±4.5kg/m2) and White (n=9; 27±3yr; BMI: 24.8±4.1kg/m2) females underwent one 60min session of WBHT (49°C water via a tube-lined suit). Pre- and 45min post-testing measures included post-occlusive forearm reactive hyperemia (peripheral microvascular function, RH), brachial artery flow-mediated dilation (peripheral macrovascular function, FMD), and cerebrovascular reactivity (CVR) to hypercapnia. Prior to WBHT, there were no differences in RH, FMD, or CVR (p>0.05 for all). WBHT improved peak RH in both groups (main effect of WBHT: 79.6±20.1cm/s to 95.9±30.0cm/s; p=0.004, g=0.787) but not Δ blood velocity (p>0.05 for both groups). WBHT improved FMD in both groups (6.2±3.4% to 8.8±3.7%; p=0.016, g=0.618) but had no effect on CVR in either group (p=0.077). These data indicate that one session of WBHT acutely improves peripheral micro- and macrovascular but not cerebral vascular function in Black and White females.

Cerebral venous congestion alters brain metabolite profiles, impairing cognitive function

Vascular cognitive impairment (VCI) represents the second most common cause of dementia after Alzheimer's disease, and pathological changes in cerebral vascular structure and function are pivotal causes of VCI. Cognitive impairment caused by arterial ischemia has been extensively studied the whole time; the influence of cerebral venous congestion on cognitive impairment draws doctors’ attention in recent clinical practice, but the underlying neuropathophysiological alterations are not completely understood. This study elucidated the specific pathogenetic role of cerebral venous congestion in cognitive-behavioral deterioration and possible electrophysiological mechanisms. Using cerebral venous congestion rat models, we found these rats exhibited decreased long-term potentiation (LTP) in the hippocampal dentate gyrus and impaired spatial learning and memory. Based on untargeted metabolomics, N-acetyl-L-cysteine (NAC) deficiency was detected in cerebral venous congestion rats; supplementation with NAC appeared to ameliorate synaptic deficits, rescue impaired LTP, and mitigate cognitive impairment. In a cohort of cerebral venous congestion patients, NAC levels were decreased; NAC concentration was negatively correlated with subjective cognitive decline (SCD) score but positively correlated with mini-mental state examination (MMSE) score. These findings provide a new perspective on cognitive impairment and support further exploration of NAC as a therapeutic target for the prevention and treatment of VCI.

Pod-based e-cigarettes versus combustible cigarettes: The impact on peripheral and cerebral vascular function and subjective experiences.

The vaping epidemic in the US has been largely attributed to the emergence of pod-based e-cigarette devices. While these devices continue to be promoted as alternatives to cigarettes, their impact on cardiovascular and behavioral outcomes remains incompletely understood. This study assessed the impact of pod-based e-cigarettes on peripheral and cerebral vascular function, along with subjective experiences among adult cigarette smokers. In a crossover laboratory design study, a total of 19 (e-cigarette naïve) cigarette smokers (aged 21-43 years) attended two lab sessions. In one session, participants smoked a cigarette and in the other, vaped a pod-based e-cigarette. Participants completed questions assessing subjective experiences. Peripheral macrovascular and microvascular function was assessed via brachial artery FMD and reactive hyperemia, while cerebral vascular function was assessed as the blood velocity response of the middle cerebral artery during hypercapnia. Measurements were taken before and after exposure. Compared with baseline, there was a reduction in peripheral macrovascular function (indexed by FMD), following e-cigarette (pre=9.3±4.3%; post=6.4±4.1%) and cigarette use (pre=10.2±3.7%; post=6.8±3.8%; main effect of time p<0.0001). Cerebral vascular function (indexed by cerebral vasodilatory response during hypercapnia) was also reduced following e-cigarette (pre=53±19%; post=44±15%) and cigarette use (pre=54±21%; post=44±17%; main effect of time p<0.01). The magnitude of reduction in peripheral and cerebral vascular function was similar between conditions (condition × time, p>0.05). Compared with vaping an e-cigarette, participants scored higher for measures of satisfaction, taste, puff liking, and suppression of craving following smoking (p>0.05). Similar to smoking, vaping a pod-based e-cigarette leads to an impairment in peripheral and cerebral vascular function while providing a reduced subjective experience compared with a cigarette among adult smokers. While these data challenge the notion that e-cigarette use is a safe and satisfactory alternative to cigarette use, large longitudinal studies are needed to assess the long-term impact of pod-based e-cigarette devices on cardiovascular and behavioral outcomes.

Age-dependent dysfunction of the cerebrovascular system in the zebrafish telencephalon

The brain is an essential organ that controls various biological activities via the nervous system. The cerebral blood vessels supply oxygen and nutrients to neuronal cells and carry away waste products, which is essential in maintaining brain functions. Aging affects cerebral vascular function and decreases brain function. However, the physiological process of age-dependent cerebral vascular dysfunction is not fully understood. In this study, we examined aging effects on cerebral vascular patterning, vascular function, and learning ability in adult zebrafish. We found that the tortuosity of the blood vessels was increased, and the blood flow rate was reduced with aging in the zebrafish dorsal telencephalon. Moreover, we found cerebral blood flow positively correlated with learning ability in middle-old-aged zebrafish, as in aged humans. In addition, we also found that the elastin fiber decreased in the middle-old-aged fish brain vessel, suggesting a possible molecular mechanism underlying vessel dysfunction. Therefore, adult zebrafish may serve as a useful model for studying the aging-dependent decline in vascular function and human diseases such as vascular dementia.

Cerebral vascular function in young, healthy non-Hispanic Black and White females

Non-Hispanic Black (BL) individuals are ~2-times more likely to suffer from conditions including cognitive dysfunction and Alzheimer’s disease and related dementias (ADRD) – conditions which are among the fastest growing causes of morbidity and mortality in the US. The prevalence of ADRD is expected to double by 2060 with a more rapid increase in the BL (and Hispanic) population. Importantly, reduced vascular function, particularly in the cerebral circulation, contributes to elevated risk for and prevalence of ADRD. While previous research has provided valuable insight into mechanisms of cerebral vascular dysfunction, this work has been primarily conducted in males and has largely not included socioeconomic/racial discrimination measurements, which are critical to understanding race/ethnicity-related disparities in cerebral vascular health. To our knowledge no studies have specifically examined cerebral vascular function in young, healthy BL females relative to WH females. Therefore, we tested the hypothesis that cerebral vascular function would be blunted in BL relative to WH females. METHODS: Eleven healthy WH (age: 26±7 yr; BMI: 26±3 kg/m2) and 17 healthy (age: 21±2 yr; BMI: 26±4 kg/m2) BL females participated. Beat-to-beat blood pressure, end-tidal carbon dioxide tension, and middle cerebral artery mean blood velocity (MCAVmean) were continuously collected. Transfer function analysis (i.e. gain, phase, and coherence) of blood pressure and MCAVmean were calculated in the very-low, low, and high-frequency ranges to assess cerebral autoregulation. Cerebral vascular function was also assessed as the % increase in MCA vascular conductance (CVCi = MCAVmean/mean arterial pressure) during administration of a hypercapnic gas (6% CO2 gas). Socioeconomic background and psychosocial stress exposures were assessed as: 1) parental education level; 2) adverse childhood experiences (ACEs); and 3) perceived ethnic discrimination (PEDQ). RESULTS: Transfer function analysis of gain, phase, and coherence was similar across all frequency ranges ( P&gt;0.05 for all) and the % increase in CVCi ( P=0.71) during hypercapnia was similar between BL and WH females. Although perceived ethnic discrimination was greater in BL relative to WH females ( P&lt;0.001), there were no group differences in parental education level nor ACEs ( P&gt;0.05 for both). CONCLUSION: These preliminary data suggest that cerebral vascular function is not different between young, healthy BL and WH females of similar socioeconomic background. Future studies should continue to examine these relationships but expand inclusion to a wider age group with a greater diversity in socioeconomic background. Funding: NIH R15 (HL156128, RMB) &amp; AHA Predoctoral Fellowship (915133, ZTM) 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.