Cerebrovascular Reactivity Response Research Articles

Association of Medial Temporal Lobe Cerebrovascular Reactivity and Memory Function in Older Adults With and Without Cognitive Impairment.

Cerebrovascular reactivity (CVR) represents the ability of cerebral blood vessels to regulate blood flow in response to vasoactive stimuli and is related to cognition in cerebrovascular and neurodegenerative conditions. However, few studies have examined CVR in the medial temporal lobe, known to be affected early in Alzheimer disease and to influence memory function. We aimed to examine whether medial temporal CVR is associated with memory function in older adults with and without mild cognitive impairment (MCI). In this observational study, independently living older adults free of dementia or stroke were recruited from the community and underwent brain MRI, neuropsychological assessment, and blood draw in an academic research setting. pCASL MRI quantified medial temporal lobe cerebral perfusion during CVR response to hypercapnia. Hypercapnia was induced by visually guided breathing exercises (15 seconds breath holds) during capnographic monitoring. MCI diagnosis and memory performance were assessed through comprehensive neuropsychological assessment. Aβ42/40 and pTau181 levels were quantified in blood plasma. Logistic and hierarchical linear regression examined medial temporal CVR in relation to MCI diagnosis and memory function. In a sample of 144 older adults (mean age = 69.6 years; SD = 7.4%; 34.7% male; mean education = 16.6 years, SD = 2.3), CVR to hypercapnia in the medial temporal lobe was attenuated in individuals with MCI after adjusting for age, sex, education, apolipoprotein ε4 carrier status, Aβ42/40 and pTau181 levels, and vascular risk factors (OR = 0.87, 95% CI [0.77-0.97], p = 0.013). Cerebrovascular reactivity to hypercapnia was associated with verbal memory performance for stories (B = 0.33, 95% CI [0.09-0.57], p = 0.009), a word list (B = 0.10, 95% CI [0.001-0.20], p = 0.048), and visual memory (B = 0.33, 95% CI [0.09-0.57], p = 0.008). Deficits in medial temporal CVR are observed in older adults with MCI and are related to worse memory function. Findings suggest that medial temporal cerebrovascular dysfunction is related to cognition and memory before the onset of dementia, independent of changes in Alzheimer pathophysiologic markers. Limitations of the study include the cross-sectional design. Future longitudinal studies are warranted to examine whether early cerebrovascular changes can predict progressive memory decline.

Cerebrovascular reactivity and response times describe recent ischaemic symptomatology in patients with moyamoya.

Moyamoya is a non-atherosclerotic intracranial steno-occlusive condition that places patients at high risk for ischaemic stroke. Randomized trials of surgical revascularization demonstrating efficacy in ischaemic moyamoya have not been performed, and as such, biomarkers of parenchymal haemodynamic impairment are needed to assist with triage and evaluate post-surgical response. In this prospective study, we test the hypothesis that parenchymal cerebrovascular reactivity (CVR) metrics in response to a fixed-inspired 5% carbon dioxide challenge correlate with recent focal ischaemic symptoms. Hypercapnic reactivity blood oxygenation level-dependent MRI (echo time = 35 ms; spatial resolution = 3.5 × 3.5 × 3.5 mm) and catheter angiography assessments of cortical reserve capacity and vascular patency, respectively, in moyamoya disease and syndromic participants (n = 73) were performed in sequence. Cerebrovascular reactivity uncorrected for response time (CVRRAW) was quantified, and time regression analyses were applied to quantify maximum cerebrovascular reactivity (CVRMAX) and cerebrovascular reactivity response time (CVRDELAY). Symptomatology was categorized by a stroke neurologist by hemisphere: symptomatic (lateralizing ischaemic symptoms < 6 months) or asymptomatic (no ischaemic symptom history). Values are presented as median [interquartile range]; logistic regression assessed the association of cerebrovascular reactivity metrics with symptoms, controlling for age and sex. A total of 109 hemispheres, including 39 symptomatic and 70 asymptomatic hemispheres, met inclusion criteria. Symptomatic hemispheres displayed reduced CVRRAW (P < 0.01) (symptomatic = 0.45 [0.28-0.70] z-statistic/ΔEtCO2 versus asymptomatic = 0.67 [0.44-0.98] z-statistic/ΔEtCO2), lengthened CVRDELAY (P < 0.001) (symptomatic = 47.6 [37.7-57.0] seconds versus asymptomatic = 37.7 [30.4-46.4] seconds), and reduced CVRMAX (P = 0.037) (symptomatic = 1.31 [0.99-1.94] z-statistic/ΔEtCO2 versus asymptomatic = 1.64 [1.29-2.12] z-statistic/ΔEtCO2). CVRDELAY (P < 0.001) was found to be significantly related to age in asymptomatic hemispheres (0.33-unit increase/year). Of assessed measures, the receiver operating characteristic curves suggest that CVRDELAY is associated most closely with recent ischaemic symptoms (P < 0.001). Findings support that cerebrovascular reactivity metrics are uniquely altered in hemispheres with recent ischaemic symptoms, further motivating their utilization as biomarkers of ischaemic symptomatology and potential treatment efficacy in moyamoya disease and syndrome.

Cerebrovascular Reactivity Has Negligible Contribution to Hemodynamic Lag After Stroke: Implications for Functional Magnetic Resonance Imaging Studies.

Functional magnetic resonance imaging (fMRI) is ubiquitously used to study poststroke recovery. However, the fMRI-derived hemodynamic responses are vulnerable to vascular insult which can result in reduced magnitude and temporal delays (lag) in the hemodynamic response function (HRF). The cause of HRF lag remains controversial, and a better understanding of it is required to ensure accurate interpretation of poststroke fMRI studies. In this longitudinal study, we investigate the relationship between hemodynamic lag and cerebrovascular reactivity (CVR) following stroke. Voxel-wise lag maps were calculated relative to a mean gray matter reference signal for 27 healthy controls and 59 patients with stroke across 2 time points (≈2 weeks and ≈4 months poststroke) and 2 conditions: resting-state and breath-holding. The breath-holding condition was additionally used to calculate CVR in response to hypercapnia. HRF lag was computed for both conditions across tissue compartments: lesion, perilesional tissue, unaffected tissue of the lesioned hemisphere, and their homolog regions in the unaffected hemisphere. CVR and lag maps were correlated. Group, condition, and time effects were assessed using ANOVA analyses. Compared with the average gray matter signal, a relative hemodynamic lead was observed in the primary sensorimotor cortices in resting-state and bilateral inferior parietal cortices in the breath-holding condition. Whole-brain hemodynamic lag was significantly correlated across conditions irrespective of group, with regional differences across conditions suggestive of a neural network pattern. Patients showed relative lag in the lesioned hemisphere which significantly reduced over time. Breath-hold derived lag and CVR had no significant voxel-wise correlation in controls, or patients within the lesioned hemisphere or the homologous regions of the lesion and perilesional tissue in the right hemisphere (mean r<0.1). The contribution of altered CVR to HRF lag was negligible. We suggest that HRF lag is largely independent of CVR, and could partly reflect intrinsic neural network dynamics among other factors.

Near-infrared spectroscopy monitoring of neonatal cerebrovascular reactivity: where are we now?

Cerebrovascular reactivity defines the ability of the cerebral vasculature to regulate its resistance in response to both local and systemic factors to ensure an adequate cerebral blood flow to meet the metabolic demands of the brain. The increasing adoption of near-infrared spectroscopy (NIRS) for non-invasive monitoring of cerebral oxygenation and perfusion allowed investigation of the mechanisms underlying cerebrovascular reactivity in the neonatal population, confirming important associations with pathological conditions including the development of brain injury and adverse neurodevelopmental outcomes. However, the current literature on neonatal cerebrovascular reactivity is mainly still based on small, observational studies and is characterised by methodological heterogeneity; this has hindered the routine application of NIRS-based monitoring of cerebrovascular reactivity to identify infants most at risk of brain injury. This review aims (1) to provide an updated review on neonatal cerebrovascular reactivity, assessed using NIRS; (2) to identify critical points that need to be addressed with targeted research; and (3) to propose feasibility trials in order to fill the current knowledge gaps and to possibly develop a preventive or curative approach for preterm brain injury. IMPACT: NIRS monitoring has been largely applied in neonatal research to assess cerebrovascular reactivity in response to blood pressure, PaCO2 and other biochemical or metabolic factors, providing novel insights into the pathophysiological mechanisms underlying cerebral blood flow regulation. Despite these insights, the current literature shows important pitfalls that would benefit to be addressed in a series of targeted trials, proposed in the present review, in order to translate the assessment of cerebrovascular reactivity into routine monitoring in neonatal clinical practice.

Effects of candesartan on cerebral microvascular function in mild cognitive impairment: Results of two clinical trials.

Cerebral microvascular dysfunction is commonly seen in Alzheimer's disease (AD) and vascular cognitive impairment (VCI). Cerebrovascular reactivity (CVR) to CO2 reflects cerebral microvascular health and may be modulated by the renin-angiotensin system (RAS). This study aimed to investigate the effects of RAS modulation on CVR in individuals with mild cognitive impairment (MCI) due to underlying vascular or AD etiologies. This study presents findings of candesartan's effects on the secondary outcomes of two double-blind randomized clinical trials of 12-month therapy of candesartan versus lisinopril in VCI (CALIBREX (Candesartan vs Lisinopril Effects on the Brain and Endothelial Function in Executive MCI)) and candesartan versus placebo in prodromal AD (Candesartan's Effects on Alzheimer's Disease and Related Biomarkers (CEDAR)). Primary outcome results of these trials have been reported in previous publications. Participants underwent identical brain blood oxygenation level dependent (BOLD)-CVR in response to a 2-min CO2 challenge at baseline and 12 months. Regions of interest and voxel-wise CVR maps were derived from BOLD signal changes during CO2 challenge. CVR effects were compared between candesartan and lisinopril (CALIBREX) and candesartan and placebo (CEDAR) using mixed-model repeated measures. Data from 102 participants in the CALIBREX study (mean age = 65 years, 45% female, 63% African American) and 59 in the CEDAR study (mean age = 67 years, 32% female, 20% African American) were analyzed. Candesartan was associated with improved whole brain CVR compared to placebo in the CEDAR study (adjusted within-group mean difference for candesartan = 0.27 (95% confidence interval (CI) = 0.006, 0.53) vs placebo = -0.17 (95% CI = 0.42, 0.08), p-value = 0.018), and compared to lisinopril in the CALIBREX study (adjusted within-group mean difference for candesartan = 0.28 (95% CI = 0.10, 0.46) vs lisinopril = -0.08 (95% CI = -0.31, 0.14), p-value = 0.012), independent of blood pressure. In an exploratory meta-analysis of the two trials, improved CVR in the hippocampus was linked to improved attention and working memory (p = 0.044) and a trend for improved executive function (p = 0.087) with candesartan therapy. This study suggests that candesartan is associated with improved microvascular function in MCI, and these findings are independent of its blood pressure effect in these VCI and prodromal AD populations.

A Pilot Study to Investigate the Effect of Hypercapnia Training on Cerebrovascular Reactivity in Healthy Adults

ObjectiveHypercapnia, an elevated concentration of carbon dioxide (CO2) in the blood, is known to promote acute increases in cerebral blood flow (CBF). This pilot study aimed to investigate whether a novel training method involving repeated bouts of hypercapnia, would influence cerebrovascular reactivity response in healthy adults.HypothesisRepeated bouts of hypercapnia (as interval training) may promote beneficial adaptation to increase cerebrovascular reactivity.MethodsAdults over 40yrs old without known disease or cardiovascular risk factors, were recruited for a non‐randomized cross‐over design pilot study. Subjects completed a 2‐week control period followed by a 2‐week intervention. The intervention involved a progressive hypercapnia training program of six sessions, whereby subjects completed 4‐6 intervals of rebreathing oxygen until a target end‐tidal CO2 (up to 25mmHg above resting) was reached, separated by recovery intervals breathing room air. Cerebrovascular reactivity was measured during study testing visits at baseline, 2‐weeks (between control and intervention) and 4‐weeks (after intervention). During study visits subjects underwent a stepped CO2 protocol, involving 5‐min stages of inspired room air, 2% CO2, 4% CO2, and 6% CO2, while measuring middle cerebral artery velocity (CBFv) using transcranial doppler ultrasound, mean arterial pressure (MAP) by finger plethysmography, ventilation, and end‐tidal CO2. Cerebrovascular conductance (CVCi) was calculated as CBFv/MAP. The reactivity of CBFv (in cm/s/mmHg), CVCi (in cm/s/mmHg2), and MAP (in mmHg/mmHg) were calculated as the linear regression slope against end‐tidal CO2 during the stepped CO2 protocol. Chemosensitivity (in L/min/mmHg) is the linear regression slope of VE vs end‐tidal CO2.ResultsSix healthy adults (age: 56 ± 10; 2 females) completed the study. Study visit data are displayed in Table 1. Individual training data are presented in Table 2. Following the control period there was a large reduction from baseline in CBFv reactivity [2.81 ± 1.50 to 2.03 ± 1.03; effect size 0.9], CVCi reactivity [0.020 ± 0.015 to 0.015 ± 0.010; effect size 0.7], and MAP reactivity [0.95 ± 0.63 to 0.62 ± 0.42; effect size 0.6] with no change in chemosensitivity [0.99 ± 0.68 to 0.98 ± 0.51; effect size 0.0]. Following the intervention there was no change from the 2‐week study visit in CBFv reactivity [2.03 ± 1.03 to 2.01 ± 1.09; effect size 0.0], CVCi reactivity [0.015 ± 0.010 to 0.014 ± 0.010; effect size 0.1], and MAP reactivity [0.62 ± 0.42 to 0.72 ± 0.44; effect size 0.1] with a small increase in chemosensitivity [0.98 ± 0.51 to 1.04 ± 0.53; effect size 0.3].ConclusionPreliminary findings suggest a very brief progressive hypercapnia training program does not increase or desensitize cerebrovascular reactivity in healthy adults. These data also suggest an exaggerated cerebrovascular reactivity response may occur to an initial exposure of a stepped CO2 protocol (without familiarization), which appears to be driven by blood pressure response not chemosensitivity. Further research, particularly in populations with impaired cerebrovascular reactivity, is of interest for CBF regulation.

Early Cerebral Blood Flow Changes, Cerebrovascular Reactivity and Cortical Spreading Depolarizations in Experimental Mild Traumatic Brain Injury Model.

To investigate the spatiotemporal dynamics of early cerebral blood flow (CBF) changes, cerebrovascular reactivity (CVR), and vascular responses to cortical spreading depolarization (CSD) in an experimental mild traumatic brain injury (mTBI) model with laser speckle contrast imaging (LSCI) technique. The weight-drop model was used to induce blunt head trauma. The mice were divided into two groups as mild TBI (n=12), and sham (n=6). The animals underwent continuous LSCI before and for 1 hour after trauma to evaluate the regional CBF changes, CVR in response to CO2, and CSD-associated vascular responses induced by pinprick. Our minor blunt head trauma protocol induced CSD in only 2 (16.7%) animals, which were excluded from further analyses. Of the remaining animals, 30% showed slight hyperemia following trauma, with mild ipsilateral hemisphere oligemia (15%?20% decrease in CBF) on average compared to baseline (p=0.027) and contralateral hemisphere (p=0.029). Maximal CBF decrease was measured in the peri-impact area (24.1% ± 5.1%). No significant difference was found between the sham and mTBI groups and two hemispheres of the mTBI group or pre/post-CSD periods of CO2 reactivity, as well as the characteristics of vascular CSD responses (net ischemia: 52.3% ± 2.6% vs. 56.3% ± 1.9% and prolonged oligemia duration 44.8 ± 1.8 min vs. 49.8 ± 2.3 min). The ipsilateral hemisphere, particularly in the peri-impact area, had mild hypoperfusion, within the first hour of minor blunt head trauma in mice. Nonetheless, mTBI does not alter CVR and vascular responses to an induced CSD, thus the overall CVR is largely preserved in mTBI without significant structural damage despite a mildly decreased CBF in the hyperacute phase.

Cerebrovascular reactivity changes in acute concussion: a controlled cohort study.

Evidence suggests that cerebrovascular reactivity (CVR) increases within the first week after the incidence of concussion, indicating a disruption of normal autoregulation. We sought to extend these findings by investigating the effects of acute concussion on the speed of CVR response and by visualizing global and regional impairments in individual patients with acute concussion. Twelve patients aged 18-40 years who experienced concussion less than a week before this prospective study were included. Twelve age and sex-matched healthy subjects constituted the control group. In all subjects, CVR was assessed using blood oxygenation level-dependent (BOLD) echo-planar imaging with a 3.0T MRI scanner, in combination with changes in end-tidal partial pressure of CO2 (PETCO2). In each subject, we calculated the CVR amplitude and CVR response time in the gray and white matter using a step and ramp PETCO2 challenge. In addition, a separate group of 39 healthy controls who underwent the same evaluation was used to create atlases with voxel-wise mean and standard deviation of CVR amplitude and CVR response time. This allowed us to convert each metric of the 12 patients with concussion and the 12 healthy controls into z-score maps. These maps were then used to generate and compare z-scores for each of the two groups. Group differences were calculated using an unpaired t-test. All studies were well tolerated without any serious adverse events. Anatomical MRI was normal in all study subjects. No differences in CO2 stimulus and O2 targeting were observed between the two participant groups during BOLD MRI. With regard to the gray matter, the CVR magnitude step (P=0.117) and ramp + 10 (P=0.085) were not significantly different between patients with concussion and healthy controls. However, the tau value was significantly lower in patients with concussion than in the healthy controls (P=0.04). With regard to the white matter, the CVR magnitude step (P=0.003) and ramp + 10 (P=0.031) were significantly higher and the tau value (P=0.024) was significantly shorter in patients with concussion than in healthy controls. After z-score transformation, the z tau value was significantly lower in patients with concussion than in healthy controls (Grey matter P=0.021, White matter P=0.003). Comparison of the three parameters, z ramp + 10, z step, and z tau, between the two groups showed that z step (Grey matter P=0.035, White matter P=0.005) was the most sensitive parameter and that z ramp + 10 (Grey matter P=0.073, White matter P=0.126) was the least sensitive parameter. Concussion is associated with patient-specific abnormalities in BOLD cerebrovascular responsiveness that occur in the setting of normal global CVR. This study demonstrates that the measurement of CVR using BOLD MRI and precise CO2 control is a safe, reliable, reproducible, and clinically useful method for evaluating the state of patients with concussion. It has the potential to be an important tool for assessing the severity and duration of symptoms after concussion.

Regional differences in cerebrovascular reactivity in response to acute isocapnic hypoxia in healthy humans: Methodological considerations

The cerebrovasculature responds to blood gas challenges. Regional differences (anterior vs. posterior) in cerebrovascular responses to increases in CO2 have been extensively studied. However, regional cerebrovascular reactivity (CVR) responses to low O2 (hypoxia) are equivocal, likely due to differences in analysis. We assessed the effects of acute isocapnic hypoxia on regional CVR comparing absolute and relative (%-change) responses in the middle cerebral artery (MCA) and posterior cerebral artery (PCA). We instrumented 14 healthy participants with a transcranial Doppler ultrasound (cerebral blood velocity), finometer (beat-by-beat blood pressure), dual gas analyzer (end-tidal CO2 and O2), and utilized a dynamic end-tidal forcing system to elicit a single 5-min bout of isocapnic hypoxia (∼45 Torr PETO2, ∼80 % SpO2). During exposure to acute hypoxia, absolute responses were larger in the anterior compared to posterior cerebral circulation (P < 0.001), but were not different when comparing relative responses (P = 0.45). Consistent reporting of CVR to hypoxia will aid understanding normative responses, particularly in assessing populations with impaired cerebrovascular function.

A practical modification to a resting state fMRI protocol for improved characterization of cerebrovascular function

Cerebrovascular reactivity (CVR), defined here as the Blood Oxygenation Level Dependent (BOLD) response to a CO2 pressure change, is a useful metric of cerebrovascular function. Both the amplitude and the timing (hemodynamic lag) of the CVR response can bring insight into the nature of a cerebrovascular pathology and aid in understanding noise confounds when using functional Magnetic Resonance Imaging (fMRI) to study neural activity. This research assessed a practical modification to a typical resting-state fMRI protocol, to improve the characterization of cerebrovascular function. In 9 healthy subjects, we modelled CVR and lag in three resting-state data segments, and in data segments which added a 2–3 minute breathing task to the start of a resting-state segment. Two different breathing tasks were used to induce fluctuations in arterial CO2 pressure: a breath-hold task to induce hypercapnia (CO2 increase) and a cued deep breathing task to induce hypocapnia (CO2 decrease). Our analysis produced voxel-wise estimates of the amplitude (CVR) and timing (lag) of the BOLD-fMRI response to CO2 by systematically shifting the CO2 regressor in time to optimize the model fit. This optimization inherently increases gray matter CVR values and fit statistics. The inclusion of a simple breathing task, compared to a resting-state scan only, increases the number of voxels in the brain that have a significant relationship between CO2 and BOLD-fMRI signals, and improves our confidence in the plausibility of voxel-wise CVR and hemodynamic lag estimates. We demonstrate the clinical utility and feasibility of this protocol in an incidental finding of Moyamoya disease, and explore the possibilities and challenges of using this protocol in younger populations. This hybrid protocol has direct applications for CVR mapping in both research and clinical settings and wider applications for fMRI denoising and interpretation.

Contrasting Measures of Cerebrovascular Reactivity Between MRI and Doppler: A Cross-Sectional Study of Younger and Older Healthy Individuals.

Cerebrovascular reactivity (CVR) is used as an outcome measure of brain health. Traditionally, lower CVR is associated with ageing, poor fitness and brain-related conditions (e.g. stroke, dementia). Indeed, CVR is suggested as a biomarker for disease risk. However, recent findings report conflicting associations between ageing or fitness and CVR measures. Inconsistent findings may relate to different neuroimaging modalities used, which include transcranial Doppler (TCD) and blood-oxygen-level-dependant (BOLD) contrast magnetic resonance imaging (MRI). We assessed the relationship between CVR metrics derived from two common imaging modalities, TCD and BOLD MRI, within the same individuals and with expected significant differences (i.e., younger vs. older) to maximise the expected spread in measures. We conducted two serial studies using TCD- and MRI-derived measures of CVR (via inspired 5% CO2 in air). Study 1 compared 20 younger (24 ± 7 years) with 15 older (66 ± 7 years) participants, Study 2 compared 10 younger (22 ± 2 years) with 10 older (72 ± 4 years) participants. Combining the main measures across studies, no significant correlation (r = 0.15, p = 0.36) was observed between individual participant TCD- and BOLD-CVR measures. Further, these measures showed differential effects between age groups; with TCD-CVR higher in the older compared to younger group (4 ± 1 vs. 3 ± 1 %MCAv/mmHg PETCO2; p < 0.05, Hedges’ g = 0.75), whereas BOLD-CVR showed no difference (p = 0.104, Hedges’ g = 0.38). In Study 2 additional measures were obtained to understand the origin of the discrepancy: phase contrast angiography (PCA) MRI of the middle cerebral artery, showed a significantly lower blood flow (but not velocity) CVR response in older compared with younger participants (p > 0.05, Hedges’ g = 1.08). The PCA CVR metrics did not significantly correlate with the BOLD- or TCD-CVR measures. The differing CVR observations between imaging modalities were despite expected, correlated (r = 0.62–0.82), age-related differences in resting CBF measures across modalities. Taken together, findings across both studies show no clear relationship between TCD- and BOLD-CVR measures. We hypothesize that CVR differences between imaging modalities are in part due to the aspects of the vascular tree that are assessed (TCD:arteries; BOLD:venules/veins). Further work is needed to understand the between-modality CVR response differences, but caution is needed when comparing CVR metrics derived from different imaging modalities.

Study Protocol: The Heart and Brain Study.

BackgroundIt is well-established that what is good for the heart is good for the brain. Vascular factors such as hypertension, diabetes, and high cholesterol, and genetic factors such as the apolipoprotein E4 allele increase the risk of developing both cardiovascular disease and dementia. However, the mechanisms underlying the heart–brain association remain unclear. Recent evidence suggests that impairments in vascular phenotypes and cerebrovascular reactivity (CVR) may play an important role in cognitive decline. The Heart and Brain Study combines state-of-the-art vascular ultrasound, cerebrovascular magnetic resonance imaging (MRI) and cognitive testing in participants of the long-running Whitehall II Imaging cohort to examine these processes together. This paper describes the study protocol, data pre-processing and overarching objectives.Methods and DesignThe 775 participants of the Whitehall II Imaging cohort, aged 65 years or older in 2019, have received clinical and vascular risk assessments at 5-year-intervals since 1985, as well as a 3T brain MRI scan and neuropsychological tests between 2012 and 2016 (Whitehall II Wave MRI-1). Approximately 25% of this cohort are selected for the Heart and Brain Study, which involves a single testing session at the University of Oxford (Wave MRI-2). Between 2019 and 2023, participants will undergo ultrasound scans of the ascending aorta and common carotid arteries, measures of central and peripheral blood pressure, and 3T MRI scans to measure CVR in response to 5% carbon dioxide in air, vessel-selective cerebral blood flow (CBF), and cerebrovascular lesions. The structural and diffusion MRI scans and neuropsychological battery conducted at Wave MRI-1 will also be repeated. Using this extensive life-course data, the Heart and Brain Study will examine how 30-year trajectories of vascular risk throughout midlife (40–70 years) affect vascular phenotypes, cerebrovascular health, longitudinal brain atrophy and cognitive decline at older ages.DiscussionThe study will generate one of the most comprehensive datasets to examine the longitudinal determinants of the heart–brain association. It will evaluate novel physiological processes in order to describe the optimal window for managing vascular risk in order to delay cognitive decline. Ultimately, the Heart and Brain Study will inform strategies to identify at-risk individuals for targeted interventions to prevent or delay dementia.

Cerebrovascular reactivity measured in awake mice using diffuse correlation spectroscopy.

.Significance: Cerebrovascular reactivity (CVR), defined as the ability of the cerebral vasculature to dilate or constrict in response to a vasoactive stimulus, is an important indicator of the brain’s vascular health. However, mechanisms of cerebrovascular dysregulation are poorly understood, and no effective treatment strategies for impaired CVR exist. Preclinical murine models provide an excellent platform for interrogating mechanisms underlying CVR dysregulation and determining novel therapeutics that restore impaired CVR. However, quantification of CVR in mice is challenging.Aim: We present means of assessing CVR in awake mice using intraperitoneal injection of acetazolamide (ACZ) combined with continuous monitoring of cerebral blood flow.Approach: Measurements of cerebral blood flow were made with a minimally invasive diffuse correlation spectroscopy sensor that was secured to an optical window glued to the intact skull. Two source–detector separations (3 and 4.5 mm) per hemisphere were used to probe different depths. CVR was quantified as the relative increase in blood flow due to ACZ. CVR was assessed once daily for 5 days in 5 mice.Results: We found that CVR and the response half-time were remarkably similar across hemispheres and across 3- versus 4.5-mm separations, suggesting a homogenous, whole brain response to ACZ. Mean(std) intra- and intermouse coefficients of variations were 15(9)% and 19(10)%, respectively, for global CVR and 24(15)% and 27(11)%, respectively, for global response half-time.Conclusion: In sum, we report a repeatable method of measuring CVR in free-behaving mice which can be used to screen for impairments with disease and to track changes in CVR with therapeutic interventions.

Insights Into Cerebral Tissue-Specific Response to Respiratory Challenges at 7T: Evidence for Combined Blood Flow and CO2-Mediated Effects

Cerebrovascular reactivity (CVR) mapping is finding increasing clinical applications as a non-invasive probe for vascular health. Further analysis extracting temporal delay information from the CVR response provide additional insight that reflect arterial transit time, blood redistribution, and vascular response speed. Untangling these factors can help better understand the (patho)physiology and improve diagnosis/prognosis associated with vascular impairments. Here, we use hypercapnic (HC) and hyperoxic (HO) challenges to gather insight about factors driving temporal delays between gray-matter (GM) and white-matter (WM). Blood Oxygen Level Dependent (BOLD) datasets were acquired at 7T in nine healthy subjects throughout BLOCK- and RAMP-HC paradigms. In a subset of seven participants, a combined HC+HO block, referred as the “BOOST” protocol, was also acquired. Tissue-based differences in Rapid Interpolation at Progressive Time Delays (RIPTiDe) were compared across stimulus to explore dynamic (BLOCK-HC) versus progressive (RAMP-HC) changes in CO2, as well as the effect of bolus arrival time on CVR delays (BLOCK-HC versus BOOST). While GM delays were similar between the BLOCK- (21.80 ± 10.17 s) and RAMP-HC (24.29 ± 14.64 s), longer WM lag times were observed during the RAMP-HC (42.66 ± 17.79 s), compared to the BLOCK-HC (34.15 ± 10.72 s), suggesting that the progressive stimulus may predispose WM vasculature to longer delays due to the smaller arterial content of CO2 delivered to WM tissues, which in turn, decreases intravascular CO2 gradients modulating CO2 diffusion into WM tissues. This was supported by a maintained ∼10 s offset in GM (11.66 ± 9.54 s) versus WM (21.40 ± 11.17 s) BOOST-delays with respect to the BLOCK-HC, suggesting that the vasoactive effect of CO2 remains constant and that shortening of BOOST delays was be driven by blood arrival reflected through the non-vasodilatory HO contrast. These findings support that differences in temporal and magnitude aspects of CVR between vascular networks reflect a component of CO2 sensitivity, in addition to redistribution and steal blood flow effects. Moreover, these results emphasize that the addition of a BOOST paradigm may provide clinical insights into whether vascular diseases causing changes in CVR do so by way of severe blood flow redistribution effects, alterations in vascular properties associated with CO2 diffusion, or changes in blood arrival time.

MRI study of cerebral blood flow, vascular reactivity, and vascular coupling in systemic hypertension

Chronic hypertension alters cerebrovascular function, which can lead to neurovascular pathologies and increased susceptibility to neurological disorders. The purpose of this study was to utilize in vivo MRI methods with corroborating immunohistology to evaluate neurovascular dysfunction due to progressive chronic hypertension. The spontaneously hypertensive rat (SHR) model at different stages of hypertension was studied to evaluate: i) basal cerebral blood flow (CBF), ii) cerebrovascular reactivity (CVR) assessed by CBF and blood-oxygenation level dependent (BOLD) signal changes to hypercapnia, iii) neurovascular coupling from CBF and BOLD changes to forepaw stimulation, and iv) damage of neurovascular unit (NVU) components (microvascular, astrocyte and neuron densities). Comparisons were made with age-matched normotensive Wistar Kyoto (WKY) rats. In 10-week SHR (mild hypertension), basal CBF was higher (p < 0.05), CVR trended higher, and neurovascular coupling response was higher (p < 0.05), compared to normotensive rats. In 40-week SHR (severe hypertension), basal CBF, CVR, and neurovascular coupling response were reversed to similar or below normotensive rats, and were significantly different from 10-week SHR (p < 0.05). Immunohistological analysis found significantly reduced microvascular density, increased astrocytes, and reduced neuronal density in SHR at 40 weeks (p < 0.05) but not at 10 weeks (p > 0.05) in comparison to age-matched controls. In conclusion, we observed a bi-phasic basal CBF, CVR and neurovascular coupling response from early to late hypertension using in vivo MRI, with significant changes prior to changes in the NVU components from histology. MRI provides clinically relevant data that might be useful to characterize neurovascular pathogenesis on the brain in hypertension.

Impairment of cerebrovascular reactivity in response to hypercapnic challenge in a mouse model of repetitive mild traumatic brain injury

Incidences of repetitive mild TBI (r-mTBI), like those sustained by contact sports athletes and military personnel, are thought to be a risk factor for development of neurodegenerative disorders. Those suffering from chronic TBI-related illness demonstrate deficits in cerebrovascular reactivity (CVR), the ability of the cerebral vasculature to respond to a vasoactive stimulus. CVR is thus an important measure of traumatic cerebral vascular injury (TCVI), and a possible in vivo endophenotype of TBI-related neuropathogenesis. We combined laser speckle imaging of CVR in response to hypercapnic challenge with neurobehavioral assessment of learning and memory, to investigate if decreased cerebrovascular responsiveness underlies impaired cognitive function in our mouse model of chronic r-mTBI. We demonstrate a profile of blunted hypercapnia-evoked CVR in the cortices of r-mTBI mice like that of human TBI, alongside sustained memory and learning impairment, without biochemical or immunohistopathological signs of cerebral vessel laminar or endothelium constituent loss. Transient decreased expression of alpha smooth muscle actin and platelet-derived growth factor receptor β, indicative of TCVI, is obvious only at the time of the most pronounced CVR deficit. These findings implicate CVR as a valid preclinical measure of TCVI, perhaps useful for developing therapies targeting TCVI after recurrent mild head trauma.

The impact of hypertonic saline on cerebrovascular reactivity and compensatory reserve in traumatic brain injury: an exploratory analysis.

BackgroundIntravenous hypertonic saline is utilized commonly in critical care for treatment of acute or refractory elevations of intracranial pressure (ICP) in traumatic brain injury (TBI) patients. Though there is a clear understanding of the general physiological effects of a hypertonic saline solution over long periods of time, smaller epoch effects of hypertonic saline (HTS) have not been thoroughly analyzed. The aim of this study was to perform a direct evaluation of the high-frequency response of HTS on the cerebrovascular physiological responses in TBI.MethodsWe retrospectively reviewed our prospectively maintained adult TBI database for those with archived high-frequency cerebral physiology and available HTS treatment information. We evaluated different epochs of physiology around HTS bolus dosing, comparing pre- with post-HTS. We assessed for changes in slow fluctuations in ICP, pulse amplitude of ICP (AMP), cerebral perfusion pressure (CPP), mean arterial pressure (MAP), cerebrovascular reactivity (as measured through pressure reactivity index (PRx)), and cerebral compensatory reserve (correlation (R) between AMP (A) and ICP (P)). Comparisons of mean measures and percentage time above clinically relevant thresholds for the physiological parameters were compared pre- and post-HTS using descriptive statistics and Mann-Whitney U testing. We assessed for subgroups of physiological responses using latent profile analysis (LPA).ResultsFifteen patients underwent 69 distinct bolus infusions of hypertonic saline. Apart from the well-documented decrease in ICP, there was also a reduction in AMP. The analysis of cerebrovascular reactivity response to HTS solution had two main effects. For patients with grossly impaired cerebrovascular reactivity pre-HTS (PRx > + 0.30), HTS bolus led to improved reactivity. However, for those with intact cerebrovascular reactivity pre-HTS (PRx < 0), HTS bolus demonstrated a trend towards more impaired reactivity. This indicates that HTS has different impacts, dependent on pre-bolus cerebrovascular status. There was no significant change in metrics of cerebral compensatory reserve. LPA failed to demonstrate any subgroups of physiological responses to HTS administration.ConclusionsThe direct decrease in ICP and AMP confirms that a bolus dose of a HTS solution is an effective therapeutic agent for intracranial hypertension. However, in patients with intact autoregulation, hypertonic saline may impair cerebral hemodynamics. These findings regarding cerebrovascular reactivity remain preliminary and require further investigation.Electronic supplementary materialThe online version of this article (10.1007/s00701-020-04579-0) contains supplementary material, which is available to authorized users.

Cerebrovascular Reactivity After Sport Concussion: From Acute Injury to 1 Year After Medical Clearance.

Neuroimaging has identified significant disturbances in cerebrovascular reactivity (CVR) in the early symptomatic phase of sport-related concussion. However, less is known about how whole-brain alterations in CVR evolve after concussion and whether they remain present beyond medical clearance to return to play (RTP). In the present study, CVR was evaluated using blood-oxygenation-level-dependent functional magnetic resonance imaging (BOLD fMRI) during a respiratory challenge. Imaging data were collected for 110 university-level athletes, including 39 concussed athletes and 71 athletic controls. The concussed athletes were imaged at the acute phase of injury (1–7 days post-injury), the subacute phase (8-14 days post-injury), medical clearance to RTP, 1 month post-RTP, and 1 year post-RTP. Enhanced negative BOLD response to controlled breathing was seen at acute injury, with attenuation of the effect mainly occurring by 1 year post-RTP. Secondary analyses showed that greater symptom severity and prolonged recovery were associated with enhanced BOLD response in the acute phase of injury, but a more attenuated BOLD response in the subacute phase. This study provides novel information characterizing the CVR response after concussion and shows CVR to be a sensitive technique for evaluating long-term brain recovery.

Cerebrovascular reactivity in cerebral amyloid angiopathy, Alzheimer disease, and mild cognitive impairment.

To assess cerebrovascular reactivity in response to a visual task in participants with cerebral amyloid angiopathy (CAA), Alzheimer disease (AD), and mild cognitive impairment (MCI) using fMRI. This prospective cohort study included 40 patients with CAA, 22 with AD, 27 with MCI, and 25 healthy controls. Each participant underwent a visual fMRI task using a contrast-reversing checkerboard stimulus. Visual evoked potentials (VEPs) were used to compare visual cortex neuronal activity in 83 participants. General linear models using least-squares means, adjusted for multiple comparisons with the Tukey test, were used to estimate mean blood oxygen level-dependent (BOLD) signal change during the task and VEP differences between groups. After adjustment for age and hypertension, estimated mean BOLD response amplitude was as follows: CAA 1.88% (95% confidence interval [CI] 1.60%-2.15%), AD 2.26% (1.91%-2.61%), MCI 2.15% (1.84%-2.46%), and control 2.65% (2.29%-3.00%). Only patients with CAA differed from controls (p = 0.01). In the subset with VEPs, group was not associated with prolonged latencies or lower amplitudes. Lower BOLD amplitude response was associated with higher white matter hyperintensity (WMH) volumes in CAA (for each 0.1% lower BOLD response amplitude, the WMH volume was 9.2% higher, 95% CI 6.0%-12.4%) but not other groups (p = 0.002 for interaction) when controlling for age and hypertension. Mean visual BOLD response amplitude was lowest in participants with CAA compared to controls, without differences in VEP latencies and amplitudes. This suggests that the impaired visual BOLD response is due to reduced vascular reactivity in CAA. In contrast to participants with CAA, the visual BOLD response amplitude did not differ between those with AD or MCI and controls.

Age Of First Exposure Influences Cerebrovascular Reactivity In High School Football Athletes

Late-life physiological and clinical impairments are associated with age of first exposure (AFE) to tackle football. There is a dearth of literature describing how AFE may influence physiological outcomes in current high school football athletes. Cerebrovascular reactivity (CVR) measures the cerebral blood flow response to variations in carbon dioxide partial pressures. Understanding how AFE affects cerebrovascular function in high school athletes may offer insight into potential long-term deficits following cumulative head impact exposure. PURPOSE: To investigate how the age at which high school football athletes began playing tackle football influences baseline CVR. METHODS: High school football athletes [n=29; age=15.8 ± 1.1 yrs; height=175.8 ± 8.1cm; mass=75.1 ± 12.6kg] self-reported AFE (median AFE=13 years old, range=5-15). Transcranial Doppler (TCD) ultrasound was used to assess middle cerebral artery velocity (MCAv) prior to beginning the competitive season. Baseline MCAv was collected for 2 minutes. Changes in MCAv were measured in response to 5 breath-holding trials (20s breath-hold/40s rest) and 5 hyperventilation trials (20s hyperventilation/40s rest). We employed separate mixed effects models with quadratic mean structures to assess group differences in MCAv response to breath-holding and hyperventilation tasks. RESULTS: The AFE significantly predicted CVR during breath-holding (F1,1709=5.27, p=0.02) and hyperventilation (F1,1709=4.08, p=0.04). One-year increases in AFE were associated with a 0.69% reduction in average CVR response during breath-holding and a 0.58% increase in average CVR during hyperventilation. CONCLUSIONS: Though AFE is associated with CVR in high school football players, the underlying mechanisms driving the observed results are unclear. The effect of cumulative head impact exposure at the high school level is understudied despite long-term neurophysiological deficits reported in retired professional football players. Studying neurophysiological responses in young football players may provide important insights into addressing cerebrovascular function and other late-life physiological health in athletes.