Impaired Cerebrovascular Reactivity Research Articles

The voxel-wise analysis of false negative fMRI activation in regions of provoked impaired cerebrovascular reactivity.

Task-evoked Blood-oxygenation-level-dependent (BOLD-fMRI) signal activation is widely used to interrogate eloquence of brain areas. However, data interpretation can be improved, especially in regions with absent BOLD-fMRI signal activation. Absent BOLD-fMRI signal activation may actually represent false-negative activation due to impaired cerebrovascular reactivity (BOLD-CVR) of the vascular bed. The relationship between impaired BOLD-CVR and BOLD-fMRI signal activation may be better studied in healthy subjects where neurovascular coupling is known to be intact. Using a model-based prospective end-tidal carbon dioxide (CO2) targeting algorithm, we performed two controlled 3 tesla BOLD-CVR studies on 17 healthy subjects: 1: at the subjects’ individual resting end-tidal CO2 baseline. 2: Around +6.0 mmHg CO2 above the subjects’ individual resting baseline. Two BOLD-fMRI finger-tapping experiments were performed at similar normo- and hypercapnic levels. Relative BOLD fMRI signal activation and t-values were calculated for BOLD-CVR and BOLD-fMRI data. For each component of the cerebral motor-network (precentral gyrus, postcentral gyrus, supplementary motor area, cerebellum und fronto-operculum), the correlation between BOLD-CVR and BOLD-fMRI signal changes and t-values was investigated. Finally, a voxel-wise quantitative analysis of the impact of BOLD-CVR on BOLD-fMRI was performed. For the motor-network, the linear correlation coefficient between BOLD-CVR and BOLD-fMRI t-values were significant (p<0.01) and in the range 0.33–0.55, similar to the correlations between the CVR and fMRI Δ%signal (p<0.05; range 0.34–0.60). The linear relationship between CVR and fMRI is challenged by our voxel-wise analysis of Δ%signal and t-value change between normo- and hypercapnia. Our main finding is that BOLD fMRI signal activation maps are markedly dampened in the presence of impaired BOLD-CVR and highlights the importance of a complementary BOLD-CVR assessment in addition to a task-evoked BOLD fMRI to identify brain areas at risk for false-negative BOLD-fMRI signal activation.

Functional Neurosonology Reveals Impaired Cerebrovascular Reactivity in Multiple Sclerosis.

Vascular aspects like global cerebral hypoperfusion are frequently reported in patients with multiple sclerosis (MS). Although mechanistic question remains unanswered, this hemodynamic impairment may be caused by a widespread endothelial dysfunction. Furthermore, impaired cerebrovascular reactivity (CVR) has been described in patients with MS by means of hypercapnic perfusion magnetic resonance imaging (MRI). We sought to further evaluate potential hemodynamic restriction in patients with MS using functional sonographic methods. We evaluated consecutive patients with MS and healthy controls with adequate bilateral transtemporal window. CVR was assessed by bilateral transcranial Doppler monitoring of proximal middle cerebral arteries. Mean flow velocities were recorded before and after 30 seconds of breath holding. Vasomotor response was quantified by breath holding index (BHI). A total of 42 patients with MS (mean age 39 ± 12 years; 69% women) were compared to 31 healthy controls (mean age 35 ± 11 years; 71% women). BHI was lower in patients with MS compared to healthy controls (.70 ± .43 vs. .93 ± .55; P = .006), documenting a lower cerebrovascular response to hypercapnia. There was no correlation between patient age (r = .1254; P = .277), expanded disability status scale (r = .1838; P = .109), and disease duration (r = .1882; P = .101) with BHI in patients with MS. These preliminary sonographic findings appear to independently corroborate the previously reported observation of impaired CVR on brain MRI in patients with MS. However, the underlying pathophysiological mechanisms as well as the clinical impact of this observation remain elusive.

Normotensive African American Males Exhibit Augmented CD4 to CD8 T Cell Ratios Compared to Caucasian American Males

Hypertension is more prevalent in African Americans (AA) (45%) than the general U.S. population (33%). Notably, young AA males without overt signs of hypertension exhibit impaired brachial artery vasodilation, cerebrovascular reactivity, and microvascular function, but the cause of these vascular impairments remains incompletely understood. Although T cells are critical in rodent models of hypertension, less is known regarding the role of T cells in human hypertension, particularly as it relates to the greater prevalence of hypertension and vascular dysfunction in AA. Recent work in humans demonstrates that lower circulating CD4 to CD8 T cell ratios and elevated populations of CD28−CD57+ T cells are associated with advanced age, vascular dysfunction, and hypertension. Whether there is an alteration in the T cell phenotype that precedes hypertension in AA is unknown. Thus, we assessed T cell CD4, CD8, CD28, and CD57 cell surface markers in AA and Caucasian Americans (CA) and tested the hypothesis that AA would have elevated CD28−CD57+ cell fractions and reduced CD4 to CD8 ratios compared to CA.METHODSTwelve ml of blood from 11 young, apparently healthy males (6 AA, age 21 ± 1 years, BMI: 24.8 ± 1.8 kg/m2; 5 CA, age 25 ± 4 years, BMI: 23.1 ± 2.3 kg/m2) were obtained for analysis during a fasted venous blood draw. Peripheral blood mononuclear cells were isolated by density centrifugation. Cells were then stained with antibodies against CD3 (pan T cells), CD4 (T helper cells), and CD8 (cytotoxic T cells). Cells were also stained for antibodies against CD28 and CD57, which are cell surface markers associated with T cell aging. Cells were then analyzed via flow cytometry.RESULTSThe percentage of total T cells was similar in AA and CA (60.1 ± 4.3% vs. 60.7 ± 2.6%; p = 0.89). The percentage of total T cells that were CD4 cells in AA was higher relative to CA (61.5 ± 3.7% vs. 49.7 ± 1.4%; p = 0.03). Alternatively, the percentage of total T cells that were CD8 cells in AA was lower relative to CA (26.3 ± 2.8% vs. 39.6 ± 0.9%; p &lt; 0.01). The CD4 to CD8 ratio was higher in AA than CA (2.53 ± 0.39 vs. 1.26 ± 0.04; p = 0.02). Among CD4 cells, the fraction of CD28−CD57+ cells in AA was similar to that found in CA (0.63 ± 0.24% vs. 0.52 ± 0.31%; p = 0.78). Similarly, among CD8 cells, the fraction of CD28−CD57+ cells in AA was comparable to that found in CA (9.8 ± 4.6% vs. 13.5 ± 4.0%; p = 0.56).CONCLUSIONRacial differences in CD28−CD57+ cell fractions among both CD4 and CD8 T cells were not detected. However, contrary to our hypothesis, the CD4 to CD8 ratio was elevated in AA compared to CA. This was driven by higher CD4 and lower CD8 percentages in AA. Collectively, these results suggest that previously observed impairments in vascular function in young healthy AA males may not be attributable to a reduced CD4 to CD8 ratio nor an accumulation of CD28−CD57+ cells.Support or Funding InformationUTA Start‐up funds to R. Matthew BrothersThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Identifying asymptomatic patients at high-risk for stroke.

Carotid endarterectomy and carotid artery stenting, in addition to good medical therapy, halve long-term stroke risk in asymptomatic patients with carotid artery stenosis. Since the absolute benefits following successful intervention are moderate, identification of asymptomatic patients at high-risk of future stroke could maximize the effectiveness of carotid interventions. The aim of this paper is to summarize the evidence for high-risk features associated with increased long-term stroke risk in asymptomatic patients. There is a paucity of reliable data describing the effect of clinical features, imaging findings and plaque characteristics on increased long-term stroke risk. Clinical and imaging features such as contralateral symptoms, silent brain infarcts/embolic signals, progression of stenosis and impaired cerebrovascular reactivity may be associated with increased future risk of stroke. Plaque characteristics such as echolucency, large plaque size (≥80 mm), intra-plaque hemorrhage, lipid-rich necrotic core and thinned/ruptured fibrous cap may also increase future risk of stroke. Whilst these form the basis for European guidelines targeting carotid intervention in asymptomatic patients with tight stenosis, conclusive evidence of their utility is lacking. Results from ongoing large, multicenter randomized clinical trials comparing carotid endarterectomy and carotid artery stenting with good medical therapy may be consistent with earlier trials, showing a halving of the long-term risk of stroke following successful carotid revascularization. However, they may well lack sufficient statistical power to identify higher-risk subgroups in whom the absolute gains of treatment are significantly higher. Large contemporary cohort studies are needed to provide further clarity regarding high-risk features associated with increased long-term stroke risk in asymptomatic patients with carotid artery stenosis.

Progressive Cerebral Ischemia and Intracerebral Hemorrhage after Indirect Revascularization for a Patient with Cerebral Proliferative Angiopathy

We previously reported a patient with cerebral proliferative angiopathy (CPA) who showed cerebral ischemia in resting and acetazolamide-stressed N-isopropyl-p-[123I] iodoamphetamine single-photon emission computed tomography (123I-IMP-SPECT). At onset, the patient was treated conservatively. However, during the 2 years following initial onset, his hemiparesis and aphasia had gradually aggravated and his IQ scores were markedly decreased. MRI revealed progressive vascular proliferation and brain atrophy. 123I-IMP-SPECT showed more severely impaired cerebral blood flow (CBF) and cerebrovascular reactivity over the affected hemisphere. We performed an indirect revascularization to augment CBF; however, his neurological deficits were not improved and new arteriovenous shunts via extracranial-intracranial bypass were developed, followed by an asymptomatic small intracerebral hemorrhage.There are no reports on CPA patients who have shown cerebral hemorrhage after indirect revascularization. Treatments for CPA are still challenging and controversial. Cases with severe stenosis of the proximal arteries may benefit from indirect revascularization. But indirect bypass should not be indicated for such patients without main arterial stenosis, even if they have persistent ischemia.

High cholesterol triggers white matter alterations and cognitive deficits in a mouse model of cerebrovascular disease: benefits of simvastatin

Transgenic mice overexpressing transforming growth factor-β1 (TGF mice) display impaired cerebrovascular reactivity, cerebral hypoperfusion and neurovascular uncoupling, but no overt cognitive deficits until old age. Cardiovascular diseases are a major risk factor for vascular cognitive impairment and dementia (VCID). We investigated the impact of a high cholesterol diet (HCD) on cerebrovascular and cognitive function in adult (6 months) and aged (12 months) TGF mice, together with the potential benefit of simvastatin (SV), an anti-cholesterol drug with pleiotropic effects, in adult mice. HCD increased blood, but not brain, cholesterol levels in treated mice, which SV did not reduce. In WT mice, HCD induced small, albeit significant, impairment in endothelium-dependent dilatory function. In TGF mice, HCD worsened the established brain vessel dilatory dysfunction in an age-dependent manner and increased the number of string vessels in the white matter (WM), alterations respectively normalized and significantly countered by SV. HCD triggered cognitive decline only in TGF mice at both ages, a deficit prevented by SV. Concurrently, HCD upregulated galectin−3 immunoreactivity in WM microglial cells, a response significantly reduced in SV-treated TGF mice. Grey matter astrogliosis and microgliosis were not affected by HCD or SV. In the subventricular zone of adult HCD-treated TGF mice, SV promoted oligogenesis and migration of oligodendrocyte progenitor cells. The results demonstrate that an underlying cerebrovascular pathology increases vulnerability to cognitive failure when combined to another risk factor for dementia, and that WM alterations are associated with this loss of function. The results further indicate that myelin repair mechanisms, as triggered by SV, may bear promise in preventing or delaying cognitive decline related to VCID.

Comprehensive Characterization of Cerebrovascular Dysfunction in Blast Traumatic Brain Injury Using Photoacoustic Microscopy.

Blast traumatic brain injury (bTBI) is a leading contributor to combat-related injuries and death. Although substantial emphasis has been placed on blast-induced neuronal and axonal injuries, co-existing dysfunctions in the cerebral vasculature, particularly the microvasculature, remain poorly understood. Here, we studied blast-induced cerebrovascular dysfunctions in a rat model of bTBI (blast overpressure: 187.8 ± 18.3 kPa). Using photoacoustic microscopy (PAM), we quantified changes in cerebral hemodynamics and metabolism-including blood perfusion, oxygenation, flow, oxygen extraction fraction, and the metabolic rate of oxygen-4 h post-injury. Moreover, we assessed the effect of blast exposure on cerebrovascular reactivity (CVR) to vasodilatory stimulation. With vessel segmentation, we extracted these changes at the single-vessel level, revealing their dependence on vessel type (i.e., artery vs. vein) and diameter. We found that bTBI at this pressure level did not induce pronounced baseline changes in cerebrovascular diameter, blood perfusion, oxygenation, flow, oxygen extraction, and metabolism, except for a slight sO2 increase in small veins (<45 μm) and blood flow increase in large veins (≥45 μm). In contrast, this blast exposure almost abolished CVR, including arterial dilation, flow upregulation, and venous sO2 increase. This study is the most comprehensive assessment of cerebrovascular structure and physiology in response to blast exposure to date. The observed impairment in CVR can potentially cause cognitive decline due to the mismatch between cognitive metabolic demands and vessel's ability to dynamically respond to meet the demands. Also, the impaired CVR can lead to increased vulnerability of the brain to metabolic insults, including hypoxia and ischemia.

Resting CMRO2 fluctuations show persistent network hyper-connectivity following exposure to sub-concussive collisions.

Exposure to head impacts may alter brain connectivity within cortical hubs such as the default-mode network (DMN). However, studies have yet to consider the confounding effects of altered resting cerebral blood flow (CBF0) and cerebrovascular reactivity (CVR) on changes in connectivity following sub-concussive impacts. Here, 23 Canadian collegiate football players were followed during a season using calibrated resting-state MRI and helmet accelerometers to examine the interplay between the neural and vascular factors that determine functional connectivity (FC). Connectivity-based analyses using blood oxygen level dependent (BOLD) and cerebral metabolic rate of oxygen consumption (CMRO2) mapping were used to study the DMN longitudinally. Network-specific decreases in CBF0 were observed one month following the season, while impaired CVR was documented at both mid-season and one month following the season, compared to pre-season baseline. Alterations in CBF0 and BOLD-based CVR throughout the season suggest that neurophysiological markers may show different susceptibility timelines following head impacts. DMN connectivity was increased throughout the season, independent of changes in cerebrovascular physiology, suggesting that alterations in FC following sub-concussive impacts are robust and independent of changes in brain hemodynamics. No significant correlations between impact kinematics and DMN connectivity changes were documented in this study. Altogether, these findings create a strong paradigm for future studies to examine the underlying neural and vascular mechanisms associated with increases in network connectivity following repeated exposure to sub-concussive collisions, in an effort to improve management of head impacts in contact sports.

Improved White Matter Cerebrovascular Reactivity after Revascularization in Patients with Steno-Occlusive Disease.

One feature that patients with steno-occlusive cerebrovascular disease have in common is the presence of white matter (WM) lesions on MRI. The purpose of this study was to evaluate the effect of direct surgical revascularization on impaired WM cerebrovascular reactivity in patients with steno-occlusive disease. We recruited 35 patients with steno-occlusive disease, Moyamoya disease (n = 24), Moyamoya syndrome (n = 3), atherosclerosis (n = 6), vasculitis (n = 1), and idiopathic stenosis (n = 1), who underwent unilateral brain revascularization using a direct superficial temporal artery-to-MCA bypass (19 women; mean age, 45.8 ± 16.5 years). WM cerebrovascular reactivity was measured preoperatively and postoperatively using blood oxygen level-dependent (BOLD) MR imaging during iso-oxic hypercapnic changes in end-tidal carbon dioxide and was expressed as %Δ BOLD MR signal intensity per millimeter end-tidal partial pressure of CO2. WM cerebrovascular reactivity significantly improved after direct unilateral superficial temporal artery-to-middle cerebral artery (STA-MCA) bypass in the revascularized hemisphere in the MCA territory (mean ± SD, -0.0005 ± 0.053 to 0.053 ± 0.046 %BOLD/mm Hg; P < .0001) and in the anterior cerebral artery territory (mean, 0.0015 ± 0.059 to 0.021 ± 0.052 %BOLD/mm Hg; P = .005). There was no difference in WM cerebrovascular reactivity in the ipsilateral posterior cerebral artery territory nor in the vascular territories of the nonrevascularized hemisphere (P < .05). Cerebral revascularization surgery is an effective treatment for reversing preoperative cerebrovascular reactivity deficits in WM. In addition, direct-STA-MCA bypass may prevent recurrence of preoperative symptoms.

Hemodynamic Impairment Measured by Positron-Emission Tomography Is Regionally Associated with Decreased Cortical Thickness in Moyamoya Phenomenon.

Impaired cerebrovascular reactivity has been associated with decreased cortical thickness in patients with arterial occlusive diseases. This study tests the hypothesis that severe hemodynamic impairment, indicated by increased oxygen extraction fraction ratios on positron-emission tomography with 15O tracers, is associated with decreased cortical thickness in patients with Moyamoya phenomenon. Patients with unilateral or bilateral idiopathic Moyamoya phenomenon were recruited. Oxygen extraction fraction ratio maps were generated from cerebral images of O[15O] counts divided by H2[15O] counts with normalization by corresponding cerebellar counts. The normal range of the oxygen extraction fraction ratio was estimated from historically available healthy control subjects. Cortical thickness was estimated from T1-weighted MR imaging and FreeSurfer. Regional samples of oxygen extraction fraction ratios and cortical thicknesses were drawn using FreeSurfer parcellations, retaining only parcellations from the vascular territory of the middle cerebral artery. Complete MR imaging and PET datasets were available in 35 subjects, including 23 women; the mean age at scanning was 44 years. Patients with Moyamoya phenomenon had a significantly increased regional oxygen extraction fraction ratio compared with 15 healthy control subjects (P < .001). Regional oxygen extraction fraction ratio and age were significant predictors of cortical thickness (P < .001 for each) in a generalized linear mixed-effects model. Using hemisphere averages and patient averages, we found that only age was a significant predictor of cortical thickness (P < .001). Chronic hemodynamic impairment, as indicated by a higher regional oxygen extraction fraction ratio, was significantly predictive of reduced cortical thickness in mixed-effects analysis of FreeSurfer regions. This phenomenon may be related to reversible metabolic down-regulation.

Invited commentary

Invited commentary

Assessment of the Cerebral Hemodynamic Benefits of Carotid Artery Stenting for Patients with Preoperative Hemodynamic Impairment Using Cerebral Single Photon Emission Computed Tomography (SPECT) and Carbon Dioxide Inhalation.

BackgroundThe aim of this study was to evaluate the effects of carotid artery angioplasty and carotid artery stenting (CAS) on cerebral blood flow (CBF) and cerebrovascular reactivity (CVR) in patients with preoperative cerebrovascular hemodynamic impairment.Material/MethodsSeventeen patients with unilateral severe internal carotid artery (ICA) stenosis and ipsilateral CVR impairment underwent CAS. CBF and CVR were measured by single photon emission computed tomography (SPECT) with inhalation of carbon dioxide (CO2) one week before and three months after CAS. Sixty-eight ROIs in the middle cerebral artery (MCA) territory were analyzed in 17 patients.ResultsBefore CAS, CVR was impaired in all ROIs. CBF was impaired in 16 ROIs (23.5%). The percentage of ROIs with impaired CBF was significantly increased in patients with ≥90% carotid artery stenosis (p=0.047) without collateral flow through the circle of Willis (p=0.005). CAS significantly increased CVR in ROIs with a normal preoperative CBF and impaired CVR, indicating mild hemodynamic impairment (0.9±6.7% vs. 4.9±8.6%) (p=0.014). CAS significantly increased CBF in ROIs with preoperative impaired CBF and impaired CVR, indicating severe hemodynamic impairment (79.1±7.5% vs. 86.7±10.0%) (p<0.001). Following CAS, ROIs with normal CBF and impaired CVR had a significantly increased percentage of improved CVR (p=0.047); ROIs with impaired CBF and impaired CVR had a significantly increased percentage of improved CBF (p=0.027).ConclusionsThe severity of preoperative hemodynamic impairment, which is related to the degree of carotid artery stenosis and cerebral collateral flow, may influence hemodynamic benefits by CAS.

Long-term changes in cerebrovascular reactivity following EC-IC bypass for intracranial steno-occlusive disease

The purpose of this retrospective observational study is to investigate the long-term changes in cerebrovascular reactivity (CVR) as a measure of cerebral hemodynamics in patients with intracranial steno-occlusive disease (IC-SOD) after they have undergone an Extracranial–intracranial (EC-IC) bypass. Twenty-six patients suffering from IC-SOD were selected from our CVR database. Nineteen patients underwent unilateral and 7 underwent bilateral revascularization. CVR measurements were done using BOLD-MRI and precisely controlled CO2 and expressed as ΔBOLD (%)/Δ PETCO2 (mmHg). Trends in CVR over time were compared in both vascularized and non-vascularized hemispheres. Repeated measures analysis of variance with Greenhouse-Geisser correction was used to determine CVR changes within the grey matter MCA for longitudinal assessments. Overall, re-vascularized hemisphere showed a significant increase in CVR at the first follow-up, followed by a slight decrease at the second follow-up that significantly increased compared to the pre-bypass. However, the changes in the postoperative CVR were quite variable across the patients. Similar variability was seen in subsequent follow-ups, with a slight overall decline in the long term CVR as compared with first post-operative CVR. Our study demonstrates that EC-IC bypass has a beneficial long-term effect on cerebral hemodynamics and this effect varies between patients probably due to the variability in the underlying vascular pattern receiving the bypass. Hence, in the postoperative follow-up of patients routine functional imaging to monitor cerebral hemodynamics may be useful as the risk of stroke and cognitive decline remain present with impaired CVR.

Understanding the role of the perivascular space in cerebral small vessel disease.

Small vessel diseases (SVDs) are a group of disorders that result from pathological alteration of the small blood vessels in the brain, including the small arteries, capillaries and veins. Of the 35-36 million people that are estimated to suffer from dementia worldwide, up to 65% have an SVD component. Furthermore, SVD causes 20-25% of strokes, worsens outcome after stroke and is a leading cause of disability, cognitive impairment and poor mobility. Yet the underlying cause(s) of SVD are not fully understood. Magnetic resonance imaging has confirmed enlarged perivascular spaces (PVS) as a hallmark feature of SVD. In healthy tissue, these spaces are proposed to form part of a complex brain fluid drainage system which supports interstitial fluid exchange and may also facilitate clearance of waste products from the brain. The pathophysiological signature of PVS and what this infers about their function and interaction with cerebral microcirculation, plus subsequent downstream effects on lesion development in the brain has not been established. Here we discuss the potential of enlarged PVS to be a unique biomarker for SVD and related brain disorders with a vascular component. We propose that widening of PVS suggests presence of peri-vascular cell debris and other waste products that form part of a vicious cycle involving impaired cerebrovascular reactivity, blood-brain barrier dysfunction, perivascular inflammation and ultimately impaired clearance of waste proteins from the interstitial fluid space, leading to accumulation of toxins, hypoxia, and tissue damage. Here, we outline current knowledge, questions and hypotheses regarding understanding the brain fluid dynamics underpinning dementia and stroke through the common denominator of SVD.

Idiopathic basal ganglia calcification associated with cerebral micro-infarcts: a case report

BackgroundIdiopathic basal ganglia calcification (IBGC) is a rare neurodegenerative disorder characterized by symmetric intracranial calcium deposition. We report a patient with IBGC associated with cerebral infarction due to impairment of cerebrovascular reactivity based on single-photon emission computed tomography (SPECT) with acetazolamide challenge.Case presentationA 66-year-old male presented with right conjugate deviation, right hemiparesis and total aphasia due to a convulsive seizure. Brain computed tomography showed symmetric calcifications in the bilateral basal ganglia, thalamus, cerebellar dentate nuclei, which were consistent with IBGC. Diffusion-weighted brain magnetic resonance imaging showed multiple small infarctions in the bilateral cerebral subcortical area. In the search for the cause of cerebral infarction, SPECT with acetazolamide challenge revealed heterogeneous impairment of cerebrovascular reactivity in the whole brain, despite the absence of evidence for steno-occlusive changes in proximal arteries.ConclusionCerebrovascular insufficiency due to the lack of elasticity caused by microvascular calcification might have been one of the pathophysiological features of IBGC in this case. Thus, vascular calcification may cause cerebrovascular disturbance and could lead to ischemic stroke in patients with IBGC.

Performing under pressure: hypertension and the regulation of cerebral oxygen delivery.

Performing under pressure: hypertension and the regulation of cerebral oxygen delivery.

Transforming growth factor-β1 induces cerebrovascular dysfunction and astrogliosis through angiotensin II type 1 receptor-mediated signaling pathways.

Transgenic mice constitutively overexpressing the cytokine transforming growth factor-β1 (TGF-β1) (TGF mice) display cerebrovascular alterations as seen in Alzheimer's disease (AD) and vascular cognitive impairment and dementia (VCID), but no or only subtle cognitive deficits. TGF-β1 may exert part of its deleterious effects through interactions with angiotensin II (AngII) type 1 receptor (AT1R) signaling pathways. We test such interactions in the brain and cerebral vessels of TGF mice by measuring cerebrovascular reactivity, levels of protein markers of vascular fibrosis, nitric oxide synthase activity, astrogliosis, and mnemonic performance in mice treated (6 months) with the AT1R blocker losartan (10 mg/kg per day) or the angiotensin converting enzyme inhibitor enalapril (3 mg/kg per day). Both treatments restored the severely impaired cerebrovascular reactivity to acetylcholine, calcitonin gene-related peptide, endothelin-1, and the baseline availability of nitric oxide in aged TGF mice. Losartan, but not enalapril, significantly reduced astrogliosis and cerebrovascular levels of profibrotic protein connective tissue growth factor while raising levels of antifibrotic enzyme matrix metallopeptidase-9. Memory was unaffected by aging and treatments. The results suggest a pivotal role for AngII in TGF-β1-induced cerebrovascular dysfunction and neuroinflammation through AT1R-mediated mechanisms. Further, they suggest that AngII blockers could be appropriate against vasculopathies and astrogliosis associated with AD and VCID.

Impact of baseline CO2 on Blood-Oxygenation-Level-Dependent MRI measurements of cerebrovascular reactivity and task-evoked signal activation

Neurovascular coupling describes the cascade between neuronal activity and subsequent Blood-Oxygenation-Level-Dependent (BOLD) signal increase.Based on this premise, the correlation of this BOLD signal increase with a particular task, such as finger-tapping, is used to map neuronal activation. This signal increase may be dampened in brain areas exhibiting impaired cerebrovascular reactivity (BOLD-CVR), leading to false negative activation. Blood-oxygenation-level-dependent (BOLD) cerebrovascular reactivity (CVR) has also been used to optimize task evoked BOLD signal changes. To measure BOLD-CVR, controlled BOLD-CVR studies have commonly been performed using a preset isocapnic carbon dioxide (CO2; ~40 mmHg) baseline, independent of subjects' resting CO2. This arbitrary baseline, however, may influence BOLD-CVR measurements. We therefore performed BOLD-CVR, as well as BOLD fMRI during a controlled bilateral finger-tapping task in two groups of ten subjects: group A at subject's resting CO2 and group B at a preset isocapnic CO2 baseline (40 mmHg). Whole brain BOLD-CVR was significantly decreased for group B (group A 0.26 (SD 0.05) vs group B 0.16 (SD 0.05), p < 0.001). For the predefined hand area in the precentral cortex, BOLD-CVR and BOLD fMRI signal changes were significantly lower for group B (group A 0.20 (SD 0.04) vs group B 0.13 (SD 0.05), p < 0.01; 1.19 (SD 0.31) vs 0.62 (SD 0.37), p < 0.01).CO2 levels significantly influence both BOLD-CVR and BOLD fMRI measurements. Hence, for an accurate interpretation, baseline CO2 levels and BOLD CVR should be considered complementary to task evoked BOLD fMRI.

Intracranial and Extracranial Injury Burden as Drivers of Impaired Cerebrovascular Reactivity in Traumatic Brain Injury.

Impaired cerebrovascular reactivity has been associated with outcome following traumatic brain injury (TBI), but it is unknown how it is affected by trauma severity. Thus, we aimed to explore the relationship between intracranial (IC) and extracranial (EC) injury burden and cerebrovascular reactivity in TBI patients. We retrospectively included critically ill TBI patients. IC injury burden included detailed lesion and computerized tomography (CT) scoring (i.e., Marshall, Rotterdam, Helsinki, and Stockholm Scores) on admission. EC injury burden was characterized using the injury severity score (ISS) and the Acute Physiology and Chronic Health Evaluation II (APACHE II) score. Pressure reactivity index (PRx), pulse amplitude index (PAx), and RAC were used to assess autoregulation/cerebrovascular reactivity. We used univariate and multi-variate logistic regression techniques to explore relationships between IC and EC injury burden and autoregulation indices. A total of 358 patients were assessed. ISS and all IC CT scoring systems were poor predictors of impaired cerebrovascular reactivity. Only subdural hematomas and thickness of subarachnoid hemorrhage (SAH; p < 0.05, respectively) were consistently associated with dysfunctional cerebrovascular reactivity. High age (p < 0.01 for all) and admission APACHE II scores (p < 0.05 for all) were the two variables most strongly associated with abnormal cerebrovascular reactivity. In summary, diffuse IC injury markers (thickness of SAH and the presence of a subdural hematoma) and APACHE II were most associated with dysfunction in cerebrovascular reactivity after TBI. Standard CT scoring systems and evidence of macroscopic parenchymal damage are poor predictors, implicating potentially both microscopic injury patterns and host response as drivers of dysfunctional cerebrovascular reactivity. Age remains a major variable associated with cerebrovascular reactivity.

Impaired Cerebral Hemodynamics and Frailty in Patients with Cardiovascular Disease.

Recent studies suggest that impaired cerebrovascular reactivity (CVR), a marker of cerebral microvascular damage, is associated with a higher risk of stroke, cognitive decline, and mortality. We tested whether abnormal cerebrovascular status is associated with late-life frailty among men with pre-existing cardiovascular disease. A subset of 327 men (mean age at baseline 56.7 ± 6.5 years) who previously participated in the Bezafibrate Infarction Prevention (BIP) trial (1990-1997) and then in the BIP Neurocognitive Study underwent a neurovascular evaluation 14.6 ± 1.9 years after baseline (T1) and were evaluated for frailty 19.9 ± 1.0 years after baseline (T2). CVR was measured at T1 using the breath-holding index and carotid large-vessel disease using ultrasound. Frailty status was measured at T2 according to the physical phenotype developed by Fried. Patients were categorized into CVR tertiles with cutoff points at ≤0.57, 0.58-0.94, and ≥0.95 and also as normal or impaired (<0.69) CVR. We assessed the change in the odds of being in the advanced rank of frailty status (normal, prefrail, and frail) using ordered logistic regression. After adjustment, the estimated OR (95% confidence intervals) for increasing frailty in the lower tertile was 1.94 (1.09-3.46) and in the middle tertile 1.24 (0.70-2.19), compared with the higher CVR tertile. The estimated OR for increasing frailty for patients with impaired vs. normal CVR was 1.76 (1.11-2.80). These findings provide support that cerebral microvascular dysfunction among patients with pre-existing cardiovascular disease is related to prefrailty and frailty and suggest an added value of assessing the cerebral vascular functional status for identifying patients at-risk of developing frailty.