Cerebrovascular Function Research Articles

Muscone and (+)-Borneol Cooperatively Strengthen CREB Induction of Claudin 5 in IL-1β-Induced Endothelium Injury.

Claudin 5 is one of the major proteins of tight junctions and is responsible for cerebrovascular integrity and BBB function. Muscone and (+)-borneol is the major ingredient of moschus and borneolum, respectively, with antioxidative and anti-inflammatory activities. This study investigated whether muscone and (+)-borneol combination protected claudin 5 by targeting ROS-mediated IL-1β accumulation. Muscone and (+)-borneol reduced cerebral infarct volume and cerebrovascular leakage with claudin 5 protection in mice after stroke, largely due to inhibiting ROS accumulation and inflammatory infiltrate of microglia. Muscone reduced ROS and then blocked the CaN/Erk1/2 pathway to decrease IL-1β release, while (+)-borneol removed mitochondrial ROS and attenuated the SDH/Hif-1α pathway to inhibit IL-1β transcription, thereby jointly reducing IL-1β production. Accumulated IL-1β disrupted cAMP/CREB activation and attenuated transcriptional regulation of claudin 5. Muscone and (+)-borneol combination cooperatively protected BBB function by blocking IL-1β-mediated cAMP/CREB/claudin 5 cascades. Mutation of Ser133 site of CREB or knockdown of claudin 5 weakened the effects of muscone and (+)-borneol on upregulation of TEER value and downregulation of FITC-dextran permeability, suggesting that targeting CREB/claudin 5 was an important strategy to protect vascular integrity. This study provided ideas for the studies of synergistic protection against ischemic brain injury about the active ingredients of traditional Chinese medicines (TCMs).

Functional near-infrared spectroscopy of prefrontal cortex during memory encoding and recall in elderly with type 2 diabetes mellitus.

Low-frequency Fahræus-Lindqvist-driven oscillations in the small vessels are crucial because oscillations in small vessels support nutrient supply. Understanding of this is critical in type 2 diabetes mellitus (T2DM) to develop therapeutic measures in order to prevent Alzheimer's Disease Related Dementias. Indeed, vascular factors are known to contribute to cerebrovascular disease as well as mild cognitive impairment and dementia, which are predicted to affect 152 million people by 2050 (Alzheimer's Disease International London, UK, 2019). In this clinical study, we performed functional near-infrared spectroscopy (fNIRS) of the forehead to investigate the effect of the Mini-Cog with three-item recall test on the prefrontal cortex (PFC) activation and the relative oscillatory power in the 0.01-0.02-Hz (FahræΣus-Lindqvist effect) and 0.021-0.052 Hz (smooth muscle autonomic innervation) frequency bands in elderly (60 years and older) T2DM and age-matched controls. We found a significant (p<0.01) difference in the PFC activation between elderly subjects with T2DM and age-matched elderly controls. Moreover, power spectral density (PSD) analysis revealed a significantly lower relative power in 0.021-0.052 Hz (smooth muscle autonomic innervation) frequency band in elderly subjects with T2DM during the Mini-Cog three-item recall test. Furthermore, a drop in the oscillatory power in the 0.01-0.02 Hz frequency band during Mini-Cog three-item recall test was found more pronounced in the elderly subjects with T2DM. Therefore, our study highlighted portable brain imaging to capture cerebrovascular reactivity to cognitive load that may provide a biomarker of cerebrovascular dysfunction in T2DM. Clinical Relevance-Our study establishes forehead portable brain imaging under cognitive load for monitoring cerebrovascular function in T2DM.

Cognitive Performance is Associated with Altered Cerebral Hemodynamics Assessed by Transcranial Ultrasound in Parkinson's Disease.

PurposeCognitive impairment (CI) is a common but debilitating non-motor symptom in Parkinson’s disease (PD). Although cerebrovascular functions are related to cognitive performance in healthy individuals, such a relation in PD remains elusive. This study aims to assess the association between cerebrovascular function and cognitive performance in PD individuals.Patients and MethodsTwo-hundred-and-one PD individuals were retrospectively included. They were subsequently divided into two groups: PD with normal cognition (PD-NC) and PD with CI (PD-CI). Cerebral hemodynamic characteristics of the middle cerebral arteries were assessed by transcranial ultrasound. The association between scores in each cognitive domain and cerebral hemodynamic parameters was further analyzed using regression analyses. Additionally, a binary logistic regression model with backward stepwise procedure was applied to build the model for discriminating CI in PD individuals. An independent dataset of additional 46 PD individuals was used further.ResultsThe PD-CI group showed a relatively lower end-diastolic blood flow velocity (EDV, p < 0.05) and a higher resistive index (RI, p < 0.05) compared to the PD-NC group. RI showed significant associations with the memory item score of Montreal Cognitive Assessment (p < 0.05). A model combining clinical and hemodynamic variables was established with optimal efficiency (area under the curve, AUC = 0.651). Further replication of the model in an independent dataset yielded a great consistency (AUC = 0.704).ConclusionIn our study, cerebrovascular functions were significantly associated with the cognitive performance in PD individuals, especially with the memory task. The established model was effective in identifying CI in PD individuals, which might be a potentially useful tool to screen the cognitive decline in PD individuals at an early stage of the disease. Further studies with larger sample sizes in different populations are warranted.

Is there a role of proinflammatory cytokines on degenerin-mediated cerebrovascular function in preeclampsia?

Preeclampsia (PE) is associated with adverse cerebrovascular effects during and following parturition including stroke, small vessel disease, and vascular dementia. A potential contributing factor to the cerebrovascular dysfunction is the loss of cerebral blood flow (CBF) autoregulation. Autoregulation is the maintenance of CBF to meet local demands with changes in perfusion pressure. When perfusion pressure rises, vasoconstriction of cerebral arteries and arterioles maintains flow and prevents the transfer of higher systemic pressure to downstream microvasculature. In the face of concurrent hypertension, loss of autoregulatory control exposes small delicate microvessels to injury from elevated systemic blood pressure. While placental ischemia is considered the initiating event in the preeclamptic cascade, the factor(s) mediating cerebrovascular dysfunction are poorly understood. Elevated plasma proinflammatory cytokines, such as tumor necrosis factor α (TNF‐α) and interleukin‐17 (IL‐17), are potential mediators of autoregulatory loss. Impaired CBF responses to increases in systemic pressure are attributed to the impaired pressure‐induced (myogenic) constriction of small cerebral arteries and arterioles in PE. Myogenic vasoconstriction is initiated by pressure‐induced vascular smooth muscle cell (VSMC) stretch. Recent studies from our laboratory group indicate that proinflammatory cytokines impair the myogenic mechanism of CBF autoregulation via inhibition of vascular degenerin proteins, putative mediators of myogenic constriction in VSMCs. This brief review links studies showing the effect of proinflammatory cytokines on degenerin expression and CBF autoregulation to the pathological cerebral consequences of preeclampsia.

Partial Endothelial Nitric Oxide Synthase Deficiency Exacerbates Cognitive Deficit and Amyloid Pathology in the APPswe/PS1ΔE9 Mouse Model of Alzheimer's Disease.

Increasing evidence implicates endothelial dysfunction in the pathogenesis of Alzheimer’s disease (AD). Nitric oxide (NO) derived from endothelial NO synthase (eNOS) is essential in maintaining cerebrovascular function and can modulate the production and clearance of amyloid beta (Aβ). APPswe/PSdE1 (APP/PS1) mice display age-related Aβ accumulation and memory deficits. In order to make the model more clinically relevant with an element of endothelial dysfunction, we generated APP/PS1/eNOS+/− mice by crossing complete eNOS deficient (eNOS−/−) mice and APP/PS1 mice. APP/PS1/eNOS+/− mice at 8 months of age displayed a more severe spatial working memory deficit relative to age-matched APP/PS1 mice. Moreover, immunohistochemistry and immunoblotting revealed significantly increased Aβ plaque load in the brains of APP/PS1/eNOS+/− mice, concomitant with upregulated BACE-1 (hence increased Aβ production), downregulated insulin-degrading enzyme (hence reduced Aβ clearance) and increased immunoreactivity and expression of microglia. The present study, for the first time, demonstrated that partial eNOS deficiency exacerbated behavioral dysfunction, Aβ brain deposition, and microglial pathology in APP/PS1 mice, further implicating endothelial dysfunction in the pathogenesis of AD. The present findings also provide the scientific basis for developing preventive and/or therapeutic strategies by targeting endothelial dysfunction.

Short-term effects of electronic cigarettes on cerebrovascular function: A time course study.

What is the central question of this study? Acute exposure to electronic cigarettes (Ecigs) triggers abnormal vascular responses in systemic arteries; however, effects on cerebral vessels are poorly understood and time for recovery is not known. We hypothesized that exposure to cigarettes or Ecigs would trigger rapid (<4h) impairment of the middle cerebral artery (MCA) but that this would resolve by 24h. What is the main finding and its importance? Cigarettes and Ecigs caused similar degree and duration of MCA impairment. We find it takes ~72hours after exposure for MCA function to return to normal. This suggests that Ecig use is likely to produce similar adverse vascular health outcomes to those seen with cigarette smoke. Temporal influences of electronic cigarettes (Ecigs) on blood vessels are poorly understood. In this study, we evaluated a single episode of cigarette versus Ecig exposure on middle cerebral artery (MCA) reactivity and determined how long after the exposure MCA responses took to return to normal. We hypothesized that cigarette and Ecig exposure would induce rapid (<4h) reduction in MCA endothelial function and would resolve within 24h. Sprague-Dawley rats (4months old) were exposed to either air (n=5), traditional cigarettes (20 puffs, n=16) or Ecigs (20-puff group, n=16; or 60-puff group, n=12). Thereafter, the cigarette and Ecig groups were randomly assigned for postexposure vessel myography testing on day0 (D0, 1-4h postexposure), day1 (D1, 24-28h postexposure), day2 (D2, 48-52h postexposure) and day3 (72-76h postexposure). The greatest effect on endothelium-dependent dilatation was observed within 24h of exposure (∼50% decline between D0 and D1) for both cigarette and Ecig groups, and impairment persisted with all groups for up to 3days. Changes in endothelium-independent dilatation responses were less severe (∼27%) and shorter lived (recovering by D2) compared with endothelium-dependent dilatation responses. Vasoconstriction in response to serotonin (5-HT) was similar to endothelium-independent dilatation, with greatest impairment (∼45% for all exposure groups) at D0-D1, returning to normal by D2. These data show that exposure to cigarettes and Ecigs triggers a similar level/duration of cerebrovascular dysfunction after a single exposure. The finding that Ecig (without nicotine) and cigarette (with nicotine) exposure produce the same effects suggesting that nicotine is not likely to be triggering MCA dysfunction, and that vaping (with/without nicotine) has potential to produce the same vascular harm and/or disease as smoking.

Time-course recovery of cerebral blood velocity metrics post aerobic exercise: a systematic review.

Currently, the standard approach for restricting exercise prior to cerebrovascular data collection varies widely between 6 and 24 h. This universally employed practice is a conservative approach to safeguard physiological alterations that could potentially confound one's study design. Therefore, the purpose of this systematic review was to amalgamate the existing literature examining the extent and duration of postexercise alterations in cerebrovascular function, measured via transcranial Doppler ultrasound. Furthermore, an exploratory aim was to scrutinize and discuss common biases/limitations in the previous studies to help guide future investigations. Search strategies were developed and imported into PubMed, SPORTDiscus, and Medline databases. A total of 595 records were screened and 35 articles met the inclusion criteria in this review, which included assessments of basic cerebrovascular metrics (n = 35), dynamic cerebral autoregulation (dCA; n = 9), neurovascular coupling (NVC; n = 2); and/or cerebrovascular reactivity (CVR-CO2; n = 1) following acute bouts of aerobic exercise. Across all studies, it was found that NVC was impacted for 1 h, basic cerebrovascular parameters and CVR-CO2 parameters for 2 h, and dCA metrics for 6 h postexercise. Therefore, future studies can provide participants with these evidence-based time restrictions, regarding the minimum time to abstain from exercise prior to data collection. However, it should be noted that other physiological mechanisms could still be altered (e.g., metabolic, hormonal, and/or autonomic influences), despite cerebrovascular function returning to baseline levels. Thus, future investigations should seek to control as many physiological influences when using cerebrovascular assessments, immediately following these time restraints. The main limitations/biases were lack of female participants, cardiorespiratory fitness, and consideration for vessel diameter.

Lag-Optimized Blood Oxygenation Level Dependent Cerebrovascular Reactivity Estimates Derived From Breathing Task Data Have a Stronger Relationship With Baseline Cerebral Blood Flow.

Cerebrovascular reactivity (CVR), an important indicator of cerebrovascular health, is commonly studied with the Blood Oxygenation Level Dependent functional MRI (BOLD-fMRI) response to a vasoactive stimulus. Theoretical and empirical evidence suggests that baseline cerebral blood flow (CBF) modulates BOLD signal amplitude and may influence BOLD-CVR estimates. We address how acquisition and modeling choices affect the relationship between baseline cerebral blood flow (bCBF) and BOLD-CVR: whether BOLD-CVR is modeled with the inclusion of a breathing task, and whether BOLD-CVR amplitudes are optimized for hemodynamic lag effects. We assessed between-subject correlations of average GM values and within-subject spatial correlations across cortical regions. Our results suggest that a breathing task addition to a resting-state acquisition, alongside lag-optimization within BOLD-CVR modeling, can improve BOLD-CVR correlations with bCBF, both between- and within-subjects, likely because these CVR estimates are more physiologically accurate. We report positive correlations between bCBF and BOLD-CVR, both between- and within-subjects. The physiological explanation of this positive correlation is unclear; research with larger samples and tightly controlled vasoactive stimuli is needed. Insights into what drives variability in BOLD-CVR measurements and related measurements of cerebrovascular function are particularly relevant when interpreting results in populations with altered vascular and/or metabolic baselines or impaired cerebrovascular reserve.

Lifestyle modification and cognitive function among individuals with resistant hypertension: cognitive outcomes from the TRIUMPH trial.

Resistant hypertension is associated with increased risk of cognitive decline, stroke, and dementia. Lifestyle modification has been suggested to improve cognitive function through its salutary effects on vascular function. Participants included 140 patients with resistant hypertension participating in the TRIUMPH trial. Participants were randomized to a cardiac rehabilitation-based lifestyle program (C-LIFE) or a standardized education and physician advice condition (SEPA). Participants completed a 45-min cognitive test battery consisting of tests of Executive Functioning and Learning, Memory, and Processing Speed. Biomarkers of vascular [flow mediated dilation of the brachial artery (FMD)], microvascular, and cerebrovascular function were also collected, in addition to weight, fitness, and ambulatory blood pressure. Participants averaged 63 years of age, 48% women, 59% black, and obese [mean BMI = 36 kg/m 2 (SD = 4)]. Cognitive performance improved across the entire cohort during the 4-month trial [ t -scores pretreatment = 48.9 (48, 50) vs. posttreatment = 50.0 (49, 51), P < 0.001]. Postintervention Executive Function/Learning composite performance was higher for participants in C-LIFE compared to SEPA ( d = 0.37, P = 0.039). C-LIFE intervention effects on Memory and Processing Speed were moderated by sex and baseline stroke risk, respectively ( P = 0.026 and P = 0.043 for interactions), such that males and participants with greater stroke risk showed the greatest cognitive changes. FMD [C-LIFE: +0.3% (-0.3, 1.0) vs. SEPA: -1.4% (-2.5, -0.3), P = 0.022], and microvascular function [C-LIFE: 97 (65, 130) vs. SEPA: 025 (-75, 23), P < 0.001] were improved in C-LIFE compared with SEPA, whereas cerebrovascular reactivity was not [C-LIFE: -0.2 (-0.4, 0) vs. SEPA: 0.1 (-0.2, 0.4), P = 0.197). Mediation analyses suggested that increased executive function/learning was associated with reduced ambulatory SBP levels secondary to weight loss [indirect effect: B = 0.25 (0.03, 0.71)]. Lifestyle modification individuals with resistant hypertension improves cognition, which appeared to be associated with reduced ambulatory SBP changes through weight loss. Cognitive improvements were accompanied by parallel improvements in endothelial and microvascular function.

Subclinical cognitive deficits are associated with reduced cerebrovascular response to visual stimulation in mid-sixties men

Reduced cerebrovascular response to neuronal activation is observed in patients with neurodegenerative disease. In the present study, we examined the correlation between reduced cerebrovascular response to visual activation (ΔCBFVis.Act) and subclinical cognitive deficits in a human population of mid-sixties individuals without neurodegenerative disease. Such a correlation would suggest that impaired cerebrovascular function occurs before overt neurodegenerative disease. A total of 187 subjects (age 64–67 years) of the Metropolit Danish Male Birth Cohort participated in the study. ΔCBFVis.Act was measured using arterial spin labelling (ASL) MRI. ΔCBFVis.Act correlated positively with cognitive performance in: Global cognition (p = 0.046), paired associative memory (p = 0.025), spatial recognition (p = 0.026), planning (p = 0.016), simple processing speed (p < 0.01), and with highly significant correlations with current intelligence (p < 10−5), and more complex processing speed (p < 10−3), the latter two explaining approximately 11–13% of the variance. Reduced ΔCBFVis.Act was independent of brain atrophy. Our findings suggest that inhibited cerebrovascular response to neuronal activation is an early deficit in the ageing brain and associated with subclinical cognitive deficits. Cerebrovascular dysfunction could be an early sign of a trajectory pointing towards the development of neurodegenerative disease. Future efforts should elucidate if maintenance of a healthy cerebrovascular function can protect against the development of dementia.

Chronic Cognitive and Cerebrovascular Function after Mild Traumatic Brain Injury in Rats.

Severe traumatic brain injury (TBI) results in cognitive dysfunction in part due to vascular perturbations. In contrast, the long-term vasculo-cognitive pathophysiology of mild TBI (mTBI) remains unknown. We evaluated mTBI effects on chronic cognitive and cerebrovascular function and assessed their interrelationships. Sprague-Dawley rats received midline fluid percussion injury (n = 20) or sham (n = 21). Cognitive function was assessed (3- and 6-month novel object recognition [NOR], novel object location [NOL], and temporal order object recognition [TOR]). Six-month cerebral blood flow (CBF) and cerebral blood volume (CBV) using contrast magnetic resonance imaging (MRI) and ex vivo circle of Willis artery endothelial and smooth muscle-dependent function were measured. mTBI rats showed significantly impaired NOR, with similar trends (non-significant) in NOL/TOR. Regional CBF and CBV were similar in sham and mTBI. NOR correlated with CBF in lateral hippocampus, medial hippocampus, and primary somatosensory barrel cortex, whereas it inversely correlated with arterial smooth muscle-dependent dilation. Six-month baseline endothelial and smooth muscle-dependent arterial function were similar among mTBI and sham, but post-angiotensin 2 stimulation, mTBI showed no change in smooth muscle-dependent dilation from baseline response, unlike the reduction in sham. mTBI led to chronic cognitive dysfunction and altered angiotensin 2-stimulated smooth muscle-dependent vasoreactivity. The findings of persistent pathophysiological consequences of mTBI in this animal model add to the broader understanding of chronic pathophysiological sequelae in human mild TBI.

The Effects of Aerobic Exercise Training on Cerebrovascular and Cognitive Function in Sedentary, Obese, Older Adults

Cerebrovascular function and cognition decline with age and are further exacerbated by obesity and physical inactivity. This decline may be offset by aerobic exercise training (AT). We investigated the effects of 16 weeks AT on cerebrovascular and cognitive function in sedentary, obese, older adults. Twenty-eight participants were randomly allocated to AT or a control group. Before and after the intervention, transcranial Doppler ultrasonography was used to measure the cerebrovascular responsiveness (CVR) to physiological (hypercapnia, 5% carbon dioxide) and cognitive stimuli. AT increased the CVR to hypercapnia (98.5 ± 38.4% vs. 58.0 ± 42.0%, P = 0.021), CVR to cognitive stimuli (25.9 ± 6.1% vs. 16.4 ± 5.4%, P < 0.001) and total composite cognitive score (111 ± 14 vs. 104 ± 14, P = 0.004) compared with the control group. A very strong relationship was observed between the number of exercise sessions completed and CVR to cognitive stimuli (r = 0.878, P < 0.001), but not for CVR to hypercapnia (r = 0.246, P = 0.397) or total composite cognitive score (r = 0.213, P = 0.465). Cerebrovascular function and cognition improved following 16 weeks of AT and a dose-response relationship exists between the amount of exercise sessions performed and CVR to cognitive stimuli.

Studies of Twin Responses to Understand Exercise THerapy (STRUETH): cerebrovascular function.

We studied monozygotic (MZ) and dizygotic (DZ) twin pairs following resistance (RES) and endurance (END) training to assess genetic and environmental contributions to cerebrovascular function. Cerebrovascular function (rest, autoregulation, hypercapnia, exercise) was assessed in 86 healthy same-sex MZ (30 pairs) and DZ (13 pairs) twins, who underwent 3months of END and RES. Carbon dioxide ( ), mean arterial pressure (MAP) and middle cerebral artery velocity (MCAv) were measured and MCAv resistance (MCACVRi ) was calculated. Resting MCAv reduced by -2.8cm/s following RES (P=0.024), with no change following END (-0.3cm/s, P=0.758). Change in MCACVRi following RES was +0.11mmHg/cm/s (P<0.001), which was significantly greater than END (+0.02mmHg/cm/s, P=0.030). MAP also increased following RES (+4mmHg, P=0.010), but not END (+1mmHg, P=0.518). No changes were apparent in . At rest, positive response rates following RES ranged from 27 to 71% and from 40 to 64% following END. Intraclass correlations between twins were moderate for most variables at baseline. In response to training, only MZ pairs were significantly correlated for a change in MCAv (P=0.005) and low frequency phase (P=0.047) following RES.This study is the first to compare cerebrovascular function following RES and END in MZ and DZ twins. Most individuals who did not respond to one modality were able to respond by switching modality, and baseline heritability estimates were higher than training response. Exercise professionals should therefore consider modality and environmental factors when optimising interventions. KEY POINTS: Characterising individual responses to resistance and endurance exercise training can inform optimal strategies for exercise prescription. This study utilised monozygotic and dizygotic twins in a randomised cross-over study to determine individual responsiveness to different modalities of exercise training. The influence of environment vs. genetics on cerebrovascular responses to training was determined. It is apparent that individuals respond differently to distinct exercise stimuli and that switching modality may be a beneficial way to obtain positive responses in cerebrovascular function. This study has implications for improving individualised exercise prescription to maintain or improve cerebrovascular structure and function.

Silent Infarcts, White Matter Integrity, and Oxygen Metabolic Stress in Young Adults With and Without Sickle Cell Trait.

Individuals with sickle cell anemia have heightened risk of stroke and cognitive dysfunction. Given its high prevalence globally, whether sickle cell trait (SCT) is a risk factor for neurological injury has been of interest; however, data have been limited. We hypothesized that young, healthy adults with SCT would show normal cerebrovascular structure and hemodynamic function. As a case-control study, young adults with (N=25, cases) and without SCT (N=24, controls) underwent brain magnetic resonance imaging to quantify brain volume, microstructural integrity (fractional anisotropy), silent cerebral infarcts (SCI), intracranial stenosis, and aneurysms. Pseudocontinuous arterial spin labeling and asymmetric spin echo sequences measured cerebral blood flow and oxygen extraction fraction, respectively, from which cerebral metabolic oxygen demand was calculated. Imaging metrics were compared between SCT cases and controls. SCI volume was correlated with baseline characteristics. Compared with controls, adults with SCT demonstrated similar normalized brain volumes (SCT 0.80 versus control 0.81, P=0.41), white matter fractional anisotropy (SCT 0.41 versus control 0.43, P=0.37), cerebral blood flow (SCT 62.04 versus control, 61.16 mL/min/100 g, P=0.67), oxygen extraction fraction (SCT 0.27 versus control 0.27, P=0.31), and cerebral metabolic oxygen demand (SCT 2.71 versus control 2.70 mL/min/100 g, P=0.96). One per cohort had an intracranial aneurysm. None had intracranial stenosis. The SCT cases and controls showed similar prevalence and volume of SCIs; however, in the subset of participants with SCIs, the SCT cases had greater SCI volume versus controls (0.29 versus 0.07 mL, P=0.008). Of baseline characteristics, creatinine was mildly elevated in the SCT cohort (0.9 versus 0.8 mg/dL, P=0.053) and correlated with SCI volume (ρ=0.49, P=0.032). In the SCT cohort, SCI distribution was similar to that of young adults with sickle cell anemia. Adults with SCT showed normal cerebrovascular structure and hemodynamic function. These findings suggest that healthy individuals with SCT are unlikely to be at increased risk for early or accelerated ischemic brain injury.

Cerebrovascular function and its association with systemic artery function and stiffness in older adults with and without mild cognitive impairment

PurposeOur aim was to compare cerebrovascular and systemic vascular function between older adults with and without mild cognitive impairment (MCI), and to determine which measures of vascular function best predict the presence of MCI.MethodsIn 41 adults with MCI and 33 adults without MCI (control) we compared middle cerebral artery velocity (MCAv) and cerebrovascular pulsatility index (PI) at rest, cerebrovascular reactivity to CO2, and responsiveness to changes in blood pressure (%∆MCAv/%∆MAP). Systemic vascular function was assessed by flow-mediated dilation (FMD) and stiffness by pulse wave velocity (PWV).ResultsCerebrovascular PI was higher in MCI compared with control (mean ± SD: 1.17 ± 0.27 vs. 1.04 ± 0.21), and MCI exhibited a lower %∆MCAv/%∆MAP (1.26 ± 0.44 vs. 1.50 ± 0.55%). Absolute (p = 0.76) and relative cerebrovascular reactivity to CO2 (p = 0.34) was similar between MCI and control. When age was included as a covariate the significant difference in cerebral PI between groups was lost. PWV was higher (13.2 ± 2.2 vs. 11.3 ± 2.5 m s−1) and FMD% (4.41 ± 1.70 vs. 5.43 ± 2.15%) was lower in MCI compared with control. FMD% was positively associated with PI across the cohort. Logistic regression analysis indicated that FMD and PWV significantly discriminated between MCI and controls, independent of age, whereas the inclusion of cerebrovascular measures did not improve the predictive accuracy of the model.ConclusionThese findings raise the possibility that early changes in systemic vascular stiffness and endothelial function may contribute to altered cerebrovascular haemodynamics and impaired cognitive function, and present potential targets for prevention and treatment strategies in people with MCI.

Cerebrovascular Function, Vascular Risk, and Lifestyle Patterns in Resistant Hypertension.

Impaired cerebrovascular reactivity (CVR) and blunted cerebral hemodynamic recruitment are thought to be important mechanisms linking hypertension to cerebrovascular and cognitive outcomes. Few studies have examined cardiovascular or dietary correlates of CVR among hypertensives. To delineate associations between cardiometabolic risk, diet, and cerebrovascular functioning among individuals with resistant hypertension from the TRIUMPH trial (n = 140). CVR was assessed by examining changes in tissue oxygenation (tissue oxygenation index [TOI] and oxygenated hemoglobin [HBO2]) using functional near-infrared spectroscopy (fNIRS) during a breath holding test, a standardized CVR assessment to elicit a hypercapnic response. Participants also underwent fNIRS during three cognitive challenge tasks. Vascular function was assessed by measurement of brachial artery flow-mediated dilation and hyperemic flow response. Cardiometabolic fitness was assessed from peak VO2 on an exercise treadmill test and body mass index. Dietary patterns were quantified using the DASH eating score. Cognitive function was assessed using a 45-minute test battery assessing Executive Function, Processing Speed, and Memory. Greater levels fitness (B = 0.30, p = 0.011), DASH compliance (B = 0.19, p = 0.045), and lower obesity (B = -0.30, p = 0.004), associated with greater changes in TOI, whereas greater flow-mediated dilation (B = 0.19, p = 0.031) and lower stroke risk (B = -0.19, p = 0.049) associated with greater HBO2. Similar associations were found for cerebral hemodynamic recruitment, and associations between CVR and cognition were moderated by duration of hypertension. Impaired CVR elevated cardiometabolic risk, obesity, vascular function, and fitness among hypertensives.

Influence of Cognitive Challenges During Exercise on Post‐Exercise Cerebrovascular Function

Peripheral vascular function is acutely improved following a single session of aerobic exercise. This improvement is likely due to increased blood flow during aerobic exercise. Cognitive activity and aerobic exercise both acutely increase cerebral blood flow, and while previous studies have examined the influence of acute exercise on post‐exercise cerebrovascular function, the effects of increased cognitive activity during exercise on post‐exercise cerebrovascular function remains unclear. Therefore, the purpose of this study was to examine the influence of increased cognitive activity during aerobic exercise on post‐exercise cerebrovascular function. We hypothesized that performing cognitive challenges during exercise would result in greater post‐exercise cerebrovascular function. METHODS: Ten participants (age: 27 ± 5 y; VO2max = 53 ± 10 mL/kg/min; men = 5, women = 5) completed 2 study days, in a randomized order, in which they either walked at 30% VO2max for 30 min (WALK) or walked at 30% VO2max for 30 min while completing N‐back cognitive tasks (WALK+COG). Cerebrovascular reactivity to hypercapnia (CVR) was measured pre‐ and 90 min post‐exercise as a measure of cerebrovascular function. Middle cerebral artery velocity (MCAv), mean arterial pressure (MAP), and end‐tidal CO2 (ETCO2) were continuously monitored during the hypercapnia protocol. Cerebrovascular conductance index (CVCi) was calculated as MCAv/MAP. CVR was calculated as the slope between the changes in MCAv or CVCi and ETCO2. RESULTS: During WALK and WALK+COG, there was no difference in MCAv from pre‐ to post‐exercise (p ≥ 0.05 for both), despite a significant post‐exercise reduction in ETCO2 (WALK: pre = 43 ± 2 mmHg, post = 41 ± 3 mmHg; WALK+COG: pre = 41 ± 4 mmHg, post = 40 ± 3 mmHg; p &lt; 0.05 for both). While WALK had no significant change in MAP from pre‐ to post‐exercise (p = 0.10), WALK+COG had a significant increase in MAP (pre = 88 ± 18 mmHg, post = 98 ± 14 mmHg; p = 0.01). Both WALK and WALK+COG had a decrease in CVCi from pre‐ to post‐exercise (WALK: pre = 0.70 ± 0.15 cm/s/mmHg, post = 0.65 ± 0.17 cm/s/mmHg; WALK+COG: pre = 0.75 ± 0.15 cm/s/mmHg, post = 0.66 ± 0.14 cm/s/mmHg; p &lt; 0.05 for both). There was no significant change in CVR from pre‐ to post‐exercise during either study days (assessed as MCAv or CVCi; p ≥ 0.05 for both). Finally, there was no significant difference in the magnitude of change in CVR from pre‐ to post‐exercise between the study days (assessed as MCAv or CVCi; p ≥ 0.05 for both). CONCLUSION: Cognitive challenges during exercise did not influence post‐exercise cerebrovascular function. Despite this finding, cognitive challenges during walking may influence resting systemic hemodynamics, as it resulted in an increased post‐exercise MAP compared with walking alone.

Latent Mixture Modeling to Identify Homogeneous Subgroups Predictive of Cerebrovascular Reactivity

IntroductionPrecision medicine is a growing topic of research within the medical community. However, the complex factors that influence disease progression and treatment efficacy often make the identification of small subgroups within large clinical populations challenging. Without strategies to identify subgroups that differentially respond to intervention, researchers and clinicians could overlook treatments that may benefit specific aspects within sizable clinical populations. Cerebrovascular disease results from the interaction of multiple risk factors, leading to varying pathologies including stroke and dementia. Identifying subgroups within the scope of cerebrovascular dysfunction risk will allow researchers to better identify individuals at risk for cerebrovascular disease and ultimately inform optimal treatment strategies. Latent mixture modeling (LMM) presents a novel, unbiased method to identify small homogeneous subgroups that have similar traits within the context of large heterogeneous cohorts. Using LMM, it is possible to detect the presence of latent categorical variables which correspond to unobserved subgroups. To assess the feasibility of LMM as a technique for forming subgroups that predict cerebrovascular health, we retrospectively analyzed data from 78 individuals including 12 measures of physical, metabolic, and cognitive health. Our hypothesis was that latent mixture modeling would identify subgroups formed around similar characteristics of physical, metabolic, cognitive, and psychological health. Further, we hypothesized that these subgroups would display differences in cerebrovascular reactivity (CVR).MethodsData from previous experiments conducted in our laboratory between 2018‐2020 were organized and prepared for analysis. Health measures included: body mass index, systolic blood pressure, heart rate, non‐HDL cholesterol, white blood cell count, albumin/globulin ratio, blood glucose, serum creatinine, total recall memory score, and patient‐reported perception of fear and anxiety. CVR was measured by transcranial Doppler ultrasound and calculated as the percent change (from baseline) in middle cerebral artery blood velocity (MCAv) per mmHg following a forced +9mmHg increase in end‐tidal CO2. LMM was used to identify latent classes based on the selected health measures, and then to assess whether CVR differed among the identified classes. The number of classes was picked based after examining a number of criteria including: Akaike, Bayesian, Sample Size Adjusted Bayesian Information Criteria, Entropy, and the VLMR and adjusted VLMR likelihood ratio tests. The BCH procedure was used for post‐hoc comparisons among classes.ResultsWe identified 4 homogeneous subgroup classes within our data. CVR was found to be significantly different when comparing class 1 and class 2 (p= 0.012) and there was a trend towards significance when comparing class 2 and class 4 (p= 0.063). These data suggest that the interaction of healthspan indicators influence differences in cerebrovascular endothelial function.

Differential Expression Profile of Sphingosine‐1‐Phosphate Receptors in Human Brain Vascular Smooth Muscle and Endothelial Cells Following Hypoxia Plus Glucose Deprivation

Sphingosine‐1‐phosphate receptors (S1PRs) and their signaling pathways play an important role in mediating vascular health and function. Upon ligand activation, S1PRs 1‐5 couple with diverse heterotrimeric G‐protein subunits (Gαi, Gαq/11, Gα12/13) initiating multimodal downstream signaling pathways which result in various physiological outcomes in the vasculature, including cell proliferation and migration, barrier integrity preservation or loss, contraction, and inflammation. Specifically, S1PR2 activation has been linked to endothelial activation, barrier integrity loss, and inflammation, whereas S1PR1 activation contributes to barrier integrity preservation, vasodilation, and anti‐inflammatory properties. Although the role of S1PRs during pathophysiological conditions such as acute ischemic stroke is under current investigation, S1PR expression in the brain vasculature following ischemic injury has not yet been investigated. Therefore, the present study characterized the expression profile of S1PRs 1‐5 in human brain microvascular endothelial cells (ECs) and brain vascular smooth muscle cells (VSMCs) following hypoxia plus glucose deprivation (HGD). Male ECs and VSMCs were exposed to either HGD (1% O2) or normoxia (21% O2) for 3h. Semi‐quantitative RT‐PCR was used to examine gene expression and concomitantly, protein levels were assessed with standard western blot and/or FIJI‐mediated ICC analysis. We hypothesized that ECs and VSMCs differentially express S1PRs 1‐5 both basally and during ischemia‐like conditions. At the mRNA level, S1PRs 1‐5 gene expression was observed in VSMCs with S1PR4 and 5 being just above the level of detection. S1PRs 1‐4 expression was detected in ECs with S1PR4 having the lowest expression. During normoxic conditions, we observed that S1PRs 1 and 3 mRNA levels were most prominently expressed in both the ECs and VSMCs. In ECs, HGD exposure did not alter the gene expression of S1PRs 1‐3. At the protein level, we observed that HGD increased S1PR1 levels, however S1PR2 and 3 protein levels were unaltered. In VSMCs, HGD increased both mRNA and protein levels of S1PR2 but did not alter S1PRs 1 and 3 mRNA expression and protein levels. In conclusion, acute exposure to HGD appears to differentially regulate S1PRs in VSMCs and ECs at the transcriptional and translational level, respectively. In VSMCs, HGD increased S1PR2 gene expression and protein levels, whereas in ECs, HGD increased S1PR1 protein levels. The differential expression in S1PRs both basally and following HGD exposure may suggest differential signaling mechanisms within the two brain vascular cell types. Furthermore, differential expression of S1PR1 and 2 highlight the potential beneficial and/or detrimental involvement of S1PRs in the pathophysiology of ischemic injury within the cerebrovasculature. Further investigation will be necessary to determine the signaling role of S1PRs and their impact on cerebrovascular cell function following acute ischemic injury in the brain.

Global Toll‐like Receptor 4 Knockout Prevents Cerebrovascular Dysfunction Associated with Chronic Stress

Chronic stress is a risk factor for many cerebrovascular diseases including stroke and vascular dementia and our lab has previously shown that chronic stress impairs cerebrovascular function and induces a pro‐inflammatory environment. It is possible that this pro‐inflammatory environment is driven by the activation of toll‐like receptor 4 (TLR4), a potent mediator of inflammation. However, the potential role of TLR4 in chronic stress induced cerebrovascular dysfunction has yet to be examined.Here, we utilized a global TLR4 knock out (TLR4‐/‐) combined with our unpredicted chronic mild stress paradigm (UCMS) to assess middle cerebral artery (MCA) function. At 18 weeks‐of‐age, mice underwent the UCMS paradigm (5 days/weeks for 7hrs/day) to elicit a chronic stress phenotype. On week 26, mice were euthanized and the MCAs were removed and positioned in a pressurized myobath. To test for vessel health, the MCA was exposed to increasing concentrations of acetylcholine (ACh; 10‐9M to 10‐4M), phenylephrine (PE; 10‐9M to 10‐4M), and sodium nitroprusside (SNP; 10‐9M to 10‐4M).TLR4‐/‐ mice displayed a similar MCA response to ACh compared to controls (18.4±0.7mm to 19.4±0.5mm, respectively). Mice exposed to UCMS displayed impaired MCA response to ACh while TLR4‐/‐ mice exposed to UCMS did not display MCA impairment in response to ACh (8.1±0.4mm vs 18.1±0.4mm, respectively; p&lt;0.05). No differences in response to SNP were noted between groups however both TLR4‐/‐and TLR4‐/‐ UCMS mice displayed an impaired response to PE compared to controls (‐16.6±2.3mm and ‐17.6±1.6mm and ‐24.2±2mm, respectively; p&lt;0.05).These data suggest that TLR4 may play a role in the cerebrovascular dysfunction associated with chronic stress.