An association between spontaneous hyperventilation, delayed cerebral ischemia, and poor clinical outcomes has been reported in subarachnoid hemorrhage. We evaluated the relationship between early ...pCO2 changes, ischemic lesions and outcomes in patients with intracerebral hemorrhage (ICH).
Consecutive patients with spontaneous ICH were enrolled in an observational cohort study conducted between 2006 and 2019. Patient characteristics and discharge outcome were prospectively recorded. Arterial blood gas (ABG) measurements and mechanical ventilation settings in the first 72 h of admission were retrospectively collected. MRI images were adjudicated for diffusion-restricted lesions consistent with ischemia and distant from the hematoma. We examined the associations between pCO2 changes, ischemic lesions, and discharge outcomes by univariate and adjusted analyses.
ABG data were available for 220 patients. Hyperventilation occurred in 52 (28%) cases and was not associated with clinical severity. Lower initial pCO2 was associated with greater risk of in-hospital death (OR 0.94 per mmHg, 95%CI 0.89, 0.996, p = 0.042) after adjustment for ICH Score, pneumonia and mechanical ventilation requirements. MRI data were available for 33 patients. Lower pCO2 was associated with a higher risk of ischemic lesions, except in patients with low initial systolic blood pressure (p < 0.05 for main and blood pressure interaction effects), after adjustment for other predictors.
In ICH patients with spontaneous ventilation, lower pCO2 was independently associated with greater risk of in-hospital death. In patients with elevated initial blood pressure, who undergo blood pressure reduction per guideline recommendations, lower pCO2 was associated with increased risk to develop ischemic lesions.
•Early hyperventilation occurs in 28% of patients with intracerebral hemorrhage and is not associated with severity.•Lower pCO2 is associated with greater risk of in-hospital death after adjusting for severity and respiratory comorbidities.•Lower pCO2 is associated with risk for ischemic lesions, particularly among patients with higher initial blood pressure.•Vasoconstrictive effects of hypocapnia may compound with other factors that reduce cerebral blood flow to cause ischemia.
Vascular aging affects multiple organ systems, including the brain, where it can lead to vascular dementia. However, a concrete understanding of how aging specifically affects the brain vasculature, ...along with molecular readouts, remains vastly incomplete. Here, we demonstrate that aging is associated with a marked decline in Notch3 signaling in both murine and human brain vessels. To clarify the consequences of Notch3 loss in the brain vasculature, we used single-cell transcriptomics and found that Notch3 inactivation alters regulation of calcium and contractile function and promotes a notable increase in extracellular matrix. These alterations adversely impact vascular reactivity, manifesting as dilation, tortuosity, microaneurysms, and decreased cerebral blood flow, as observed by MRI. Combined, these vascular impairments hinder glymphatic flow and result in buildup of glycosaminoglycans within the brain parenchyma. Remarkably, this phenomenon mirrors a key pathological feature found in brains of patients with CADASIL, a hereditary vascular dementia associated with NOTCH3 missense mutations. Additionally, single-cell RNA sequencing of the neuronal compartment in aging Notch3-null mice unveiled patterns reminiscent of those observed in neurodegenerative diseases. These findings offer direct evidence that age-related NOTCH3 deficiencies trigger a progressive decline in vascular function, subsequently affecting glymphatic flow and culminating in neurodegeneration.
Walking, especially while dual-tasking, requires functional activation of cognitive brain regions and their connected neural networks. This study examined the relationship between neurovascular ...coupling (NVC), as measured by the change in cerebral blood flow in response to performing a cognitive executive task, and dual-task walking performance.
Seventy community-dwelling older adults aged 84 ± 5 years within the Maintenance of Balance, Independent Living, Intellect and Zest in the Elderly (MOBILIZE) Boston Study were divided into LOW (n = 35) and HIGH (n = 35) NVC. NVC was quantified by transcranial Doppler ultrasound and stratified by the median change in cerebral blood flow velocity of the middle cerebral artery induced by the performance of the n-back task of executive function. Walking metrics included walking speed, step width, stride length, stride time, stride time variability, and double-support time from single- and dual-task walking conditions, as well as the "cost" of dual-tasking.
During both single- and dual-task walking, older adults with LOW NVC displayed narrower step width (p = .02 and p = .02), shorter stride length (p = .01 and p = .02), and longer double-support time (p = .03 and p = .002) when compared with the HIGH group. During single-task walking only, LOW NVC was also linked to slower walking speed (p = .02). These associations were independent of age, height, hypertension, atrial fibrillation, and assistive device. The LOW and HIGH NVC groups did not differ in dual-task costs to walking performance.
In older adults, diminished capacity to regulate cerebral blood flow in response to an executive function task is linked to worse walking performance under both single- and dual-task conditions, but not necessarily dual-task costs.
Chronic kidney disease increases stroke incidence and severity but the mechanisms behind this cerebro-renal interaction are mostly unexplored. Since both vascular beds share similar features, ...microvascular dysfunction could be the possible missing link. Therefore, we examined the relationship between renal function and cerebral autoregulation in the early hours post ischemia and its impact on outcome.
We enrolled 46 ischemic strokes (middle cerebral artery). Dynamic cerebral autoregulation was assessed by transfer function (coherence, phase and gain) of spontaneous blood pressure oscillations to blood flow velocity within 6 h from symptom-onset. Estimated glomerular filtration rate (eGFR) was calculated. Hemorrhagic transformation (HT) and white matter lesions (WML) were collected from computed tomography performed at presentation and 24 h. Outcome was evaluated with modified Rankin Scale at 3 months.
High gain (less effective autoregulation) was correlated with lower eGFR irrespective of infarct side (p < 0.05). Both lower eGFR and higher gain correlated with WML grade (p < 0.05). Lower eGFR and increased gain, alone and in combination, progressively reduced the odds of a good functional outcome ipsilateral OR = 4.39 (CI95% 3.15-25.6), p = 0.019; contralateral OR = 8.15 (CI95% 4.15-15.6), p = 0.002 and increased risk of HT ipsilateral OR = 3.48 (CI95% 0.60-24.0), p = 0.132; contralateral OR = 6.43 (CI95% 1.40-32.1), p = 0.034.
Lower renal function correlates with less effective dynamic cerebral autoregulation in acute ischemic stroke, both predicting a bad outcome. The evaluation of serum biomarkers of renal dysfunction could have interest in the future for assessing cerebral microvascular risk and relationship with stroke complications.
There is an increasing appreciation of the vascular contributions in the development of age-related cognitive impairment and dementia
1,2
. Identifying risk and maintaining cognitive health for ...successful aging is ever relevant in our aging population. Carotid disease, a well-established risk factor for stroke and often a harbinger of other vascular disease states, is also emerging as another vascular risk factor for age-related cognitive decline. When combined with vascular risk factors, the incidence of age-related carotid disease can be as high as 70%
3,4
. Historically, carotid disease has been dichotomized into two large groups in trial design, outcome measurements, and treatment decisions: symptomatic and asymptomatic carotid artery stenosis. The dichotomous distinction between asymptomatic and symptomatic carotid stenosis based on existing definitions may be limiting the care we are able to provide for patients classified as “asymptomatic” from their carotid disease. Medically, we now know that these patients should be treated with the same intensive medical therapy as those with “symptomatic” carotid disease. Emerging data also shows that hypoperfusion from asymptomatic disease may lead to significant cognitive impairment in the aging population, and it is plausible that most “age-related” cognitive changes may be reflective of vascular impairment and neurovascular dysfunction. While over the past 30 years medical, surgical, and radiological advances have pushed the field of neurovascular disease to significantly reduce the number of ischemic strokes, we are far from any meaningful interventions to prevent vascular cognitive impairment. In addition to including cognitive outcome measures, future studies of carotid disease will also benefit from including advanced neuroimaging modalities not currently utilized in standard clinical imaging protocols, such as perfusion imaging and/or functional connectivity mapping, which may provide novel data to better assess for hypoxic-ischemic changes and neurovascular dysfunction across diffuse cognitive networks. While current recommendations advise against widespread population screening for asymptomatic carotid stenosis, emerging evidence linking carotid stenosis to cognitive impairment prompts us to re-consider our approach for older patients with vascular risk factors who are at risk for cognitive decline.
Orthostatic intolerance and falls differ between sexes and change with age. However, it remains unclear what role cerebral autoregulation may play in this response. This study was designed to ...determine whether cerebral autoregulation, assessed using transcranial Doppler ultrasound, is more effective in elderly females than in males.
We used transcranial Doppler ultrasound to evaluate cerebral autoregulation in 544 (236 male) subjects older than age 70 years recruited as part of the MOBILIZE Boston study. The MOBILIZE Boston study is a prospective cohort study of a unique set of risk factors for falls in seniors in the Boston area. We assessed CO2 reactivity and transfer function gain, phase, and coherence during 5 minutes of quiet sitting and autoregulatory index during sit-to-stand tests.
Male subjects had significantly lower CO2 reactivity (males, 1.10 ± 0.03; females, 1.32 ± 0.43 (cm/s)/%CO2; P<0.001) and autoregulatory indices (males, 4.41 ± 2.44; female, 5.32 ± 2.47; P<0.001), higher transfer function gain (males, 1.34 ± 0.49; females, 1.19 ± 0.43; P=0.002), and lower phase (males, 42.7 ± 23.6; females, 49.4 ± 24.9; P=0.002) in the autoregulatory band, implying less effective cerebral autoregulation. However, reduced autoregulation in males was not below the normal range, indicating autoregulation was intact but less effective.
Female subjects were better able to maintain cerebral flow velocities during postural changes and demonstrated better cerebral autoregulation. The mechanisms of sex-based differences in autoregulation remain unclear but may partially explain the higher rates of orthostatic hypotension-related hospitalizations in elderly men.
Cardiometabolic and cerebrovascular disease are strong independent contributors to cognitive impairment in people living with HIV. Data suggest that cardiovascular risk may play a greater role in ...cognitive health in women than in men with HIV.
We performed a cross-sectional study of 104 participants with virologically suppressed HIV from 2 clinics in urban China. Participants underwent neuropsychological testing from which we calculated T scores globally and in 5 cognitive domains. We assessed cerebral vasoreactivity of the middle cerebral arteries in response to breath holding. We constructed linear regression models to determine associations between cerebrovascular and cognitive function overall and stratified by sex.
Women were younger than men (48 versus 51 years, P = 0.053), had fewer years of education (9 years versus 12 years, P = 0.004), and fewer cardiometabolic risk factors (0 versus 1 factor, P = 0.008). In a model with all participants, cerebrovascular function was significantly associated with global cognition (2.74 higher T score per 1-point higher cerebral vasoreactivity SE 1.30, P = 0.037). Cerebrovascular function remained significantly associated with global cognition among women (4.15 higher T score SE 1.78, P = 0.028) but not men (1.70 higher T score SE 1.74, P = 0.33). The relationships between cerebrovascular function and specific cognitive domains followed a similar pattern, with significant associations present among women but not men.
Women with well-controlled HIV may be more vulnerable to the effect of cerebrovascular injury on cognitive health than men. Studies evaluating strategies to protect against cognitive impairment in people living with HIV should include adequate representation of women and stratification of analyses by sex.
Soluble vascular cell adhesion molecule-1 (sVCAM-1) is associated with hypertension, vascular inflammation, and systemic endothelial dysfunction. We evaluated whether elevated plasma sVCAM-1 is ...associated with impaired cerebrovascular function and mobility impairments in elderly people. We studied the cross-sectional relationships between plasma sVCAM-1 level, gait speed, and cerebrovascular hemodynamics, and its longitudinal relationship with falls in 680 community-dwelling participants aged ≥65 years in the Maintenance of Balance, Independent Living, Intellect, and Zest in the Elderly (MOBILIZE) Boston Study. Falls were recorded prospectively for 1 year on daily calendars. sVCAM-1 was measured by ELISA assay and beat-to-beat blood flow velocity in the middle cerebral artery during rest and in response to changes in end-tidal CO2 was measured by transcranial Doppler ultrasound. sVCAM-1 concentration was 1094±340 ng/mL in normotensives, 1195±438 ng/mL in controlled hypertensives, and 1250±445 ng/mL in uncontrolled hypertensives (P=0.008). The mean resting blood flow velocity and cerebral vasomotor range were, respectively, 41.0±10.3 cm/s and 1.3±0.4 cm/s per millimeter of mercury. Elevated sVCAM-1 levels indicative of endothelial dysfunction were associated with reduced resting blood flow velocity (P=0.017) and cerebral vasomotor range (P=0.0048). Elevated sVCAM-1 levels were associated with slower gait speed (<0.8 m/s; odds ratio, 3.01; 95% confidence interval, 1.56-5.83; P=0.0011) and an increased odds of injurious falls (odds ratio, 2.4; 95% confidence interval, 1.4-4.2; P=0.0028). An elevated sVCAM-1 level may be a marker of cerebral blood flow dysregulation because of endothelial damage from hypertension. It may also signal the presence of cerebral microvascular disease and its clinical consequences, including slow gait speed and falls.
Short-term elevations in fine particulate matter air pollution (PM2.5) are associated with increased risk of acute cerebrovascular events. Evidence from the peripheral circulation suggests that ...vascular dysfunction may be a central mechanism. However, the effects of PM2.5 on cerebrovascular function and hemodynamics are unknown.
We used transcranial Doppler ultrasound to measure beat-to-beat blood flow velocity in the middle cerebral artery at rest and in response to changes in end-tidal CO2 (cerebral vasoreactivity) and arterial blood pressure (cerebral autoregulation) in 482 participants from the Maintenance of Balance, Independent Living, Intellect, and Zest in the Elderly (MOBILIZE) of Boston study. We used linear mixed effects models with random subject intercepts to evaluate the association between cerebrovascular hemodynamic parameters and mean PM2.5 levels 1 to 28 days earlier adjusting for age, race, medical history, meteorologic covariates, day of week, temporal trends, and season.
An interquartile range increase (3.0 µg/m(3)) in mean PM2.5 levels during the previous 28 days was associated with an 8.6% (95% confidence interval, 3.7%-13.8%; P<0.001) higher cerebral vascular resistance and a 7.5% (95% confidence interval, 4.2%-10.6%; P<0.001) lower blood flow velocity at rest. Measures of cerebral vasoreactivity and autoregulation were not associated with PM2.5 levels.
In this cohort of community-dwelling seniors, exposure to PM2.5 was associated with higher resting cerebrovascular resistance and lower cerebral blood flow velocity. If replicated, these findings suggest that alterations in cerebrovascular hemodynamics may underlie the increased risk of particle-related acute cerebrovascular events.
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