Neurovascular Coupling in Hypertension Is Impaired by IL-17A through Oxidative Stress.

Hypertension, a multifactorial chronic inflammatory condition, is an important risk factor for neurovascular and neurodegenerative diseases, including stroke and Alzheimer's disease. These diseases have been associated with higher concentrations of circulating interleukin (IL)-17A. However, the possible role that IL-17A plays in linking hypertension with neurodegenerative diseases remains to be established. Cerebral blood flow regulation may be the crossroads of these conditions because regulating mechanisms may be altered in hypertension, including neurovascular coupling (NVC), known to participate in the pathogenesis of stroke and Alzheimer's disease. In the present study, the role of IL-17A on NVC impairment induced by angiotensin (Ang) II in the context of hypertension was examined. Neutralization of IL-17A or specific inhibition of its receptor prevents the NVC impairment (p < 0.05) and cerebral superoxide anion production (p < 0.05) induced by Ang II. Chronic administration of IL-17A impairs NVC (p < 0.05) and increases superoxide anion production. Both effects were prevented with Tempol and NADPH oxidase 2 gene deletion. These findings suggest that IL-17A, through superoxide anion production, is an important mediator of cerebrovascular dysregulation induced by Ang II. This pathway is thus a putative therapeutic target to restore cerebrovascular regulation in hypertension.

Targeting the blood-brain barrier disruption in hypertension by ALK5/TGF-Β type I receptor inhibitor SB-431542 and dynamin inhibitor dynasore.

INTRODUCTION: In this study, we aimed to target two molecules, transforming growth factor-beta (TGF-ß) and dynamin to explore their roles in blood-brain barrier (BBB) disruption in hypertension. METHODS: For this purpose, angiotensin (ANG) II-induced hypertensive mice were treated with SB-431542, an inhibitor of the ALK5/TGF-ß type I receptor, and dynasore, an inhibitor of dynamin. Albumin-Alexa fluor 594 was used to assess BBB permeability. The alterations in the expression of claudin-5, caveolin (Cav)-1, glucose transporter (Glut)-1, and SMAD4 in the cerebral cortex and the hippocampus were evaluated by quantification of immunofluorescence staining intensity. RESULTS: ANG II infusion increased BBB permeability to albumin-Alexa fluor 594 which was reduced by SB-431542 (P < 0.01), but not by dynasore. In hypertensive animals treated with dynasore, claudin-5 immunofluorescence intensity increased in the cerebral cortex and hippocampus while it decreased in the cerebral cortex of SB-431542 treated hypertensive mice (P < 0.01). Both dynasore and SB-431542 prevented the increased Cav-1 immunofluorescence intensity in the cerebral cortex and hippocampus of hypertensive animals (P < 0.01). SB-431542 and dynasore decreased Glut-1 immunofluorescence intensity in the cerebral cortex and hippocampus of mice receiving ANG II (P < 0.01). SB-431542 increased SMAD4 immunofluorescence intensity in the cerebral cortex of hypertensive animals, while in the hippocampus a significant decrease was noted by both SB-431542 and dynasore (P < 0.01). CONCLUSION: Our data suggest that inhibition of the TGFß type I receptor prevents BBB disruption under hypertensive conditions. These results emphasize the therapeutic potential of targeting TGFß signaling as a novel treatment modality to protect the brain of hypertensive patients.

Relationship Between Arterial Stiffness Index, Pulse Pressure, and Magnetic Resonance Imaging Markers of White Matter Integrity: A UK Biobank Study.

Background: Alzheimer's disease and dementia in general constitute one of the major public health problems of the 21st century. Research in arterial stiffness and pulse pressure (PP) play an important role in the quest to reduce the risk of developing dementia through controlling modifiable risk factors. Objective: The aim of the study is to investigate the association between peripheral PP, arterial stiffness index (ASI) and brain integrity, and to discover if ASI is a better predictor of white matter integrity than peripheral PP. Materials and Methods: 17,984 participants 63.09 ± 7.31 from the UK Biobank were used for this study. ASI was estimated using infrared light (photoplethysmography) and peripheral PP was calculated by subtracting the diastolic from the systolic brachial blood pressure value. Measure of fractional anisotropy (FA) was obtained from diffusion imaging to estimate white matter microstructural integrity. White matter hyperintensities were segmented from the combined T1 and T2-weighted FLAIR images as a measure of irreversible white matter damage. Results: An important finding is that peripheral PP better predicts white matter integrity when compared to ASI. This finding is consistent until 75 years old. Interestingly, no significant relationship is found between either peripheral PP or ASI and white matter integrity after 75 years old. Conclusion: These results suggest that ASI from plethysmography should not be used to estimate cerebrovascular integrity in older adults and further question the relationship between arterial stiffness, blood pressure, and white matter damage after the age of 75 years old.

Arterial stiffness and age moderate the association between physical activity and global cognition in older adults.

BACKGROUND: Evidence supports that time spent on physical activity has beneficial effects on cognition in older adults. Nevertheless, whether these beneficial effects are still present at the intersection of different levels of arterial stiffness and age is uncertain. METHODS: One hundred and ten healthy older adults aged 60-75 years were examined for arterial stiffness [carotid-femoral pulse wave velocity (cf-PWV)], global cognition (composite score of Montreal Cognitive Assessment, and Mini-Mental State Examination), and self-reported physical activity (PACED diary). Using PROCESS macro for SPSS, we evaluated if cf-PWV (moderator 1), and age (moderator 2) moderate the relationship between physical activity (X) and global cognition (Y). The threshold for high stiffness was set at 8.5 m/s based on previous studies that reported this cut-off as more appropriate for classifying cerebrovascular risk groups. RESULTS: Physical activity had a positive effect on cognition in young-elderly adults (<68.5 years) with a cf-PWV of at least 8.5 m/s (ß = 0.48, SE = 0.193, P = 0.014, 95% CI = 0.100--0.868) and in elderly adults (≥68.5 years) with a cf-PWV of less than 8.5 m/s (ß = 0.56, SE = 0.230, P = 0.017, 95% CI = 0.104-1.018). This was not the case in elderly adults with a cf-PWV of at least 8.5 m/s (ß = 0.00, SE = 0.193, P = 0.998, 95% CI = -0.362 to 361), or in young-elderly adults with a cf-PWV of less than 8.5 m/s (ß = 0.16, SE = 0.247, P = 0.501, 95% CI = -0.326 to 656). CONCLUSION: The interaction between arterial stiffness and age moderated the effect of physical activity on global cognition. Time spent on physical activity alone might not be sufficient to achieve cognitive benefit over a specific threshold of arterial stiffness and age.

Impaired Hippocampal Neurovascular Coupling in a Mouse Model of Alzheimer's Disease.

Alzheimer's disease (AD), the most common form of dementia, is characterized by neuronal degeneration and cerebrovascular dysfunction. Increasing evidence indicates that cerebrovascular dysfunction may be a key or an aggravating pathogenic factor in AD. This emphasizes the importance to investigate the tight coupling between neuronal activity and cerebral blood flow (CBF) termed neurovascular coupling (NVC). NVC depends on all cell types of the neurovascular unit within which astrocytes are important players in the progression of AD. Hence, the objective of this study was to characterize the hippocampal NVC in a mouse model of AD. Hippocampal NVC was studied in 6-month-old amyloid-beta precursor protein (APP) transgenic mice and their corresponding wild-type littermates using in vivo laser Doppler flowmetry to measure CBF in area CA1 of the hippocampus in response to Schaffer collaterals stimulation. Ex vivo two-photon microscopy experiments were performed to determine astrocytic Ca2+ and vascular responses to electrical field stimulation (EFS) or caged Ca2+ photolysis in hippocampal slices. Neuronal synaptic transmission, astrocytic endfeet Ca2+ in correlation with reactive oxygen species (ROS), and vascular reactivity in the presence or absence of Tempol, a mimetic of superoxide dismutase, were further investigated using electrophysiological, caged Ca2+ photolysis or pharmacological approaches. Whisker stimulation evoked-CBF increases and ex vivo vascular responses to EFS were impaired in APP mice compared with their age-matched controls. APP mice were also characterized by decreased basal synaptic transmission, a shorter astrocytic Ca2+ increase, and altered vascular response to elevated perivascular K+. However, long-term potentiation, astrocytic Ca2+ amplitude in response to EFS, together with vascular responses to nitric oxide remained unchanged. Importantly, we found a significantly increased Ca2+ uncaging-induced ROS production in APP mice. Tempol prevented the vascular response impairment while normalizing astrocytic Ca2+ in APP mice. These findings suggest that NVC is altered at many levels in APP mice, at least in part through oxidative stress. This points out that therapies against AD should include an antioxidative component to protect the neurovascular unit.

Angiotensin II Disrupts Neurovascular Coupling by Potentiating Calcium Increases in Astrocytic Endfeet.

Background Angiotensin II (Ang II), a critical mediator of hypertension, impairs neurovascular coupling. Since astrocytes are key regulators of neurovascular coupling, we sought to investigate whether Ang II impairs neurovascular coupling through modulation of astrocytic Ca2+ signaling. Methods and Results Using laser Doppler flowmetry, we found that Ang II attenuates cerebral blood flow elevations induced by whisker stimulation or the metabotropic glutamate receptors agonist, 1S, 3R-1-aminocyclopentane-trans-1,3-dicarboxylic acid (P<0.01). In acute brain slices, Ang II shifted the vascular response induced by 1S, 3R-1-aminocyclopentane-trans-1,3-dicarboxylic acid towards vasoconstriction (P<0.05). The resting and 1S, 3R-1-aminocyclopentane-trans-1,3-dicarboxylic acid-induced Ca2+ levels in the astrocytic endfeet were more elevated in the presence of Ang II (P<0.01). Both effects were reversed by the AT1 receptor antagonist, candesartan (P<0.01 for diameter and P<0.05 for calcium levels). Using photolysis of caged Ca2+ in astrocytic endfeet or pre-incubation of 1,2-Bis(2-aminophenoxy)ethane-N,N,N',N'-tetra-acetic acid tetrakis (acetoxymethyl ester), we demonstrated the link between potentiated Ca2+ elevation and impaired vascular response in the presence of Ang II (P<0.001 and P<0.05, respectively). Both intracellular Ca2+ mobilization and Ca2+ influx through transient receptor potential vanilloid 4 mediated Ang II-induced astrocytic Ca2+ elevation, since blockade of these pathways significantly prevented the intracellular Ca2+ in response to 1S, 3R-1-aminocyclopentane-trans-1,3-dicarboxylic acid (P<0.05). Conclusions These results suggest that Ang II through its AT1 receptor potentiates the astrocytic Ca2+ responses to a level that promotes vasoconstriction over vasodilation, thus altering cerebral blood flow increases in response to neuronal activity.

Inflammation: A Mediator Between Hypertension and Neurodegenerative Diseases.

Hypertension is the most prevalent and modifiable risk factor for stroke, vascular cognitive impairment, and Alzheimer's disease. However, the mechanistic link between hypertension and neurodegenerative diseases remains to be understood. Recent evidence indicates that inflammation is a common pathophysiological trait for both hypertension and neurodegenerative diseases. Low-grade chronic inflammation at the systemic and central nervous system levels is now recognized to contribute to the physiopathology of hypertension. This review speculates that inflammation represents a mediator between hypertension and neurodegenerative diseases, either by a decrease in cerebral blood flow or a disruption of the blood-brain barrier which will, in turn, let inflammatory cells and neurotoxic molecules enter the brain parenchyma. This may impact brain functions including cognition and contribute to neurodegenerative diseases. This review will thus discuss the relationship between hypertension, systemic inflammation, cerebrovascular functions, neuroinflammation, and brain dysfunctions. The potential clinical future of immunotherapies against hypertension and associated cerebrovascular risks will also be presented.

Associations Between Relative Morning Blood Pressure, Cerebral Blood Flow, and Memory in Older Adults Treated and Controlled for Hypertension.

[Figure: see text].

Cerebrospinal Fluid Biomarkers, Brain Structural and Cognitive Performances Between Normotensive and Hypertensive Controlled, Uncontrolled and Untreated 70-Year-Old Adults.

Background: Hypertension is an important risk factor for Alzheimer's disease (AD). The pathophysiological mechanisms underlying the relationship between AD and hypertension are not fully understood, but they most likely involve microvascular dysfunction and cerebrovascular pathology. Although previous studies have assessed the impact of hypertension on different markers of brain integrity, no study has yet provided a comprehensive comparison of cerebrospinal fluid (CSF) biomarkers and structural brain differences between normotensive and hypertensive groups in a single and large cohort of older adults in relationship to cognitive performances. Objective: The aim of the present work was to investigate the differences in cognitive performances, CSF biomarkers and magnetic resonance imaging (MRI) of brain structure between normotensive, controlled hypertensive, uncontrolled hypertensive, and untreated hypertensive older adults from the Gothenburg H70 Birth Cohort Studies. Methods: As an indicator of vascular brain pathology, we measured white matter hyperintensities (WMHs), lacunes, cerebral microbleeds, enlarged perivascular space (epvs), and fractional anisotropy (FA). To assess markers of AD pathology/neurodegeneration, we measured hippocampal volume, temporal cortical thickness on MRI, and amyloid-ß42, phosphorylated tau, and neurofilament light protein (NfL) in cerebrospinal fluid. Various neuropsychological tests were used to assess performances in memory, attention/processing speed, executive function, verbal fluency, and visuospatial abilities. Results: We found more white matter pathology in hypertensive compared to normotensive participants, with the highest vascular burden in uncontrolled participants (e.g., lower FA, more WMHs, and epvs). No significant difference was found in any MRI or CSF markers of AD pathology/neurodegeneration when comparing normotensive and hypertensive participants, nor among hypertensive groups. No significant difference was found in most cognitive functions between groups. Conclusion: Our results suggest that good blood pressure control may help prevent cerebrovascular pathology. In addition, hypertension may contribute to cognitive decline through its effect on cerebrovascular pathology rather than AD-related pathology. These findings suggest that hypertension is associated with MRI markers of vascular pathology in the absence of a significant decline in cognitive functions.

Bisphosphoglycerate Mutase Deficiency Protects against Cerebral Malaria and Severe Malaria-Induced Anemia.

The replication cycle and pathogenesis of the Plasmodium malarial parasite involves rapid expansion in red blood cells (RBCs), and variants of certain RBC-specific proteins protect against malaria in humans. In RBCs, bisphosphoglycerate mutase (BPGM) acts as a key allosteric regulator of hemoglobin/oxyhemoglobin. We demonstrate here that a loss-of-function mutation in the murine Bpgm (BpgmL166P) gene confers protection against both Plasmodium-induced cerebral malaria and blood-stage malaria. The malaria protection seen in BpgmL166P mutant mice is associated with reduced blood parasitemia levels, milder clinical symptoms, and increased survival. The protective effect of BpgmL166P involves a dual mechanism that enhances the host's stress erythroid response to Plasmodium-driven RBC loss and simultaneously alters the intracellular milieu of the RBCs, including increased oxyhemoglobin and reduced energy metabolism, reducing Plasmodium maturation, and replication. Overall, our study highlights the importance of BPGM as a regulator of hemoglobin/oxyhemoglobin in malaria pathogenesis and suggests a new potential malaria therapeutic target.

A Cross-Sectional Study on the Impact of Arterial Stiffness on the Corpus Callosum, a Key White Matter Tract Implicated in Alzheimer's Disease.

BACKGROUND: Vascular risk factors such as arterial stiffness play an important role in the etiology of Alzheimer's disease (AD), presumably due to the emergence of white matter lesions. However, the impact of arterial stiffness to white matter structure involved in the etiology of AD, including the corpus callosum remains poorly understood. OBJECTIVE: The aims of the study are to better understand the relationship between arterial stiffness, white matter microstructure, and perfusion of the corpus callosum in older adults. METHODS: Arterial stiffness was estimated using the gold standard measure of carotid-femoral pulse wave velocity (cfPWV). Cognitive performance was evaluated with the Trail Making Test part B-A. Neurite orientation dispersion and density imaging was used to obtain microstructural information such as neurite density and extracellular water diffusion. The cerebral blood flow was estimated using arterial spin labelling. RESULTS: cfPWV better predicts the microstructural integrity of the corpus callosum when compared with other index of vascular aging (the augmentation index, the systolic blood pressure, and the pulse pressure). In particular, significant associations were found between the cfPWV, an alteration of the extracellular water diffusion, and a neuronal density increase in the body of the corpus callosum which was also correlated with the performance in cognitive flexibility. CONCLUSION: Our results suggest that arterial stiffness is associated with an alteration of brain integrity which impacts cognitive function in older adults.

Sex-moderated association between body composition and cognition in older adults.

BACKGROUND: Some studies have reported an association between body composition and cognition in older adults, but underlying mechanisms and physiological factors remain poorly understood. Moreover, sex-related differences in metabolic health and age-related cognitive decline have gained major interest lately. The present study investigated the potential moderating effect of sex on the relationship between body composition and cognition in older adults. METHODS: Global cognition, assessed by the Montreal Cognitive Assessment (MoCA), and body composition, measured using dual-energy x-ray absorptiometry (DXA), were analyzed in 155 women and 65 men aged 60 years old or more. Moderation analyses were computed to determine if sex moderates the effect of the different body composition parameters on the MoCA while controlling for the body mass index and the level of education of the participants. RESULTS: Sex moderated the association between total lean mass, trunk lean mass, arms lean mass, and the MoCA score. These body composition parameters were positively associated with cognition only in men. Fat mass was not associated with cognition in any sex. CONCLUSION: Overall, higher lean mass and in particular trunk and arms lean mass was associated with higher cognitive abilities in older men. Longitudinal studies or intervention studies are needed to further identify physiological mechanisms that sustain the relationship between lean mass and cognition.

Arterial stiffness cut-off value and white matter integrity in the elderly.

OBJECTIVE: Central artery stiffness is a confirmed predictor of cardiovascular health status that has been consistently associated with cognitive dysfunction and dementia. The European Society of Hypertension has established a threshold of arterial stiffness above which a cardiovascular event is likely to occur. However, the threshold at which arterial stiffness alters brain integrity has never been established. METHODS: The aim of this study is to determine the arterial stiffness cut-off value at which there is an impact on the white matter microstructure. This study has been conducted with 53 cognitively elderly without dementia. The integrity of the white matter was assessed using diffusion tensor metrics. Central artery stiffness was evaluated by measuring the carotid-femoral pulse wave velocity (cfPWV). The statistical analyses included 4 regions previously denoted vulnerable to increased central arterial stiffness (the corpus callosum, the internal capsule, the corona radiata and the superior longitudinal fasciculus). RESULTS: The results of this study call into question the threshold value of 10 m/s cfPWV established by the European Society of Hypertension to classify patients in neuro-cardiovascular risk groups. Our results suggest that the cfPWV threshold value would be approximately 8.5 m/s when the microstructure of the white matter is taken as a basis for comparison. CONCLUSIONS: Adjustment of the cfPWV value may be necessary for a more accurate distinction between lower and higher risk group of patients for white matter microstructural injury related to arterial stiffness. Targeting the highest risk group for prevention methods may, in turn, help preserve brain health and cognitive functions.

Diurnal blood pressure loads are associated with lower cognitive performances in controlled-hypertensive elderly individuals.

INTRODUCTION: Hypertension in midlife adults is associated with cognitive decline later in life. In individuals treated for hypertension, blood pressure (BP) loads have been associated with end organ damages. This study examines whether BP load inversely correlates with performance in cognitive tasks in normotensive or controlled hypertensive (CHT) individuals. METHODS: Participants between 60 and 75 years old were divided into normotensive participants who did not receive antihypertensive treatment (n = 49) and CHT patients (n = 28). They were evaluated for BP using ambulatory blood pressure monitoring and cognitive functions with tests assessing cognitive flexibility, working and episodic memory, and processing speed. RESULTS: Analysis of covariance between normotensive and CHT participants revealed lower cognitive performances on immediate and delayed recall and total number of words of the Rey Auditory Verbal Learning Test (P < 0.001). Spearman's correlations between BP loads and cognitive performances revealed inversed associations between diurnal systolic (SBP) loads and performances on the Trail Making Test Part B (TMTB) (P = 0.009), the TMTB-TMT Part A (P = 0.013), the Switching Cost of the color-word interference test (P = 0.020) and the Digit-Symbol Substitution Score tests (P = 0.018) in CHT. Diurnal diastolic (DBP) loads were inversely correlated to the TMTB (P = 0.014) and TMTB-TMT Part A (P = 0.006). In normotensive subjects, diurnal SBP loads were associated with the delayed recall of the Rey Auditory Verbal Learning Test (P = 0.031) and to the three components of the digit span (P < 0.05). CONCLUSION: Diurnal BP loads are associated with lower cognitive performances in CHT individuals. These results suggest a lowering of target levels of diurnal BPs and/or its variability.

Arterial stiffness and brain integrity: A review of MRI findings.

BACKGROUND: Given the increasing incidence of vascular diseases and dementia, a better understanding of the cerebrovascular changes induced by arterial stiffness is important for early identification of white and gray matter abnormalities that might antedate the appearance of clinical cognitive symptoms. Here, we review the evidence from neuroimaging demonstrating the impact of arterial stiffness on the aging brain. METHOD: This review presents findings from recent studies examining the association between arterial stiffness, cognitive function, cerebral hypoperfusion, and markers of neuronal fiber integrity using a variety of MRI techniques. RESULTS: Overall, changes associated with arterial stiffness indicates that the corpus callosum, the internal capsule and the corona radiata may be the most vulnerable regions to microvascular damage. In addition, the microstructural integrity of these regions appears to be associated with cognitive performance. Changes in gray matter structure have also been found to be associated with arterial stiffness and are present as early as the 5th decade. Moreover, low cerebral perfusion has been associated with arterial stiffness as well as lower cognitive performance in age-sensitive tasks such as executive function. CONCLUSION: Considering the established relationship between arterial stiffness, brain and cognition, this review highlights the need for future studies of brain structure and function in aging to implement measurements of arterial stiffness in parallel with quantitative imaging.

Arterial Stiffness Due to Carotid Calcification Disrupts Cerebral Blood Flow Regulation and Leads to Cognitive Deficits.

Background Arterial stiffness is associated with cognitive decline and dementia; however, the precise mechanisms by which it affects the brain remain unclear. Methods and Results Using a mouse model based on carotid calcification this study characterized mechanisms that could contribute to brain degeneration due to arterial stiffness. At 2 weeks postcalcification, carotid stiffness attenuated resting cerebral blood flow in several brain regions including the perirhinal/entorhinal cortex, hippocampus, and thalamus, determined by autoradiography ( P<0.05). Carotid calcification impaired cerebral autoregulation and diminished cerebral blood flow responses to neuronal activity and to acetylcholine, examined by laser Doppler flowmetry ( P<0.05, P<0.01). Carotid stiffness significantly affected spatial memory at 3 weeks ( P<0.05), but not at 2 weeks, suggesting that cerebrovascular impairments precede cognitive dysfunction. In line with the endothelial deficits, carotid stiffness led to increased blood-brain barrier permeability in the hippocampus ( P<0.01). This region also exhibited reductions in vessel number containing collagen IV ( P<0.01), as did the somatosensory cortex ( P<0.05). No evidence of cerebral microhemorrhages was present. Carotid stiffness did not affect the production of mouse amyloid-ß (Aß) or tau phosphorylation, although it led to a modest increase in the Aß40/Aß42 ratio in frontal cortex ( P<0.01). Conclusions These findings suggest that carotid stiffness alters brain microcirculation and increases blood-brain barrier permeability associated with cognitive impairments. Therefore, arterial stiffness should be considered a relevant target to protect the brain and prevent cognitive dysfunctions.

Astrocytic endfoot Ca2+ correlates with parenchymal vessel responses during 4-AP induced epilepsy: An in vivo two-photon lifetime microscopy study.

Neurovascular coupling (NVC) underlying the local increase in blood flow during neural activity forms the basis of functional brain imaging and is altered in epilepsy. Because astrocytic calcium (Ca2+) signaling is involved in NVC, this study investigates the role of this pathway in epilepsy. Here, we exploit 4-AP induced epileptic events to show that absolute Ca2+ concentration in cortical astrocyte endfeet in vivo correlates with the diameter of precapillary arterioles during neural activity. We simultaneously monitored free Ca2+ concentration in astrocytic endfeet with the Ca2+-sensitive indicator OGB-1 and diameter of adjacent arterioles in the somatosensory cortex of adult mice by two-photon fluorescence lifetime measurements following 4-AP injection. Our results reveal that, regardless of the mechanism by which astrocytic endfoot Ca2+ was elevated during epileptic events, increases in Ca2+ associated with vasodilation for each individual ictal event in the focus. In the remote area, increases in Ca2+ correlated with vasoconstriction at the onset of seizure and vasodilation during the later part of the seizure. Furthermore, a slow increase in absolute Ca2+ with time following multiple seizures was observed, which in turn, correlated with a trend of arteriolar constriction both at the epileptic focus and remote areas.

Arterial stiffness and white matter integrity in the elderly: A diffusion tensor and magnetization transfer imaging study.

BACKGROUND AND PURPOSE: The stiffness of large arteries and increased pulsatility can have an impact on the brain white matter (WM) microstructure, however those mechanisms are still poorly understood. The aim of this study was to investigate the association between central artery stiffness, axonal and myelin integrity in 54 cognitively unimpaired elderly subjects (65-75 years old). METHODS: The neuronal fiber integrity of brain WM was assessed using diffusion tensor metrics and magnetization transfer imaging as measures of axonal organization (Fractional anisotropy, Radial diffusivity) and state of myelination (Myelin volume fraction). Central artery stiffness was measured by carotid-femoral pulse wave velocity (cfPWV). Statistical analyses included 4 regions (the corpus callosum, the internal capsule, the corona radiata and the superior longitudinal fasciculus) which have been previously denoted as vulnerable to increased central artery stiffness. RESULTS: cfPWV was significantly associated with fractional anisotropy and radial diffusivity (p < 0.05, corrected for multiple comparisons) but not with myelin volume fraction. Findings from this study also show that improved executive function performance correlates with Fractional anisotropy positively (p < 0.05 corrected) as well as with myelin volume fraction and radial diffusivity negatively (p < 0.05 corrected). CONCLUSIONS: These findings suggest that arterial stiffness is associated with axon degeneration rather than demyelination. Controlling arterial stiffness may play a role in maintaining the health of WM axons in the aging brain.

CD4+ Regulatory T Lymphocytes Prevent Impaired Cerebral Blood Flow in Angiotensin II-Induced Hypertension.

Background Immune cells are key regulators of the vascular inflammatory response characteristic of hypertension. In hypertensive rodents, regulatory T lymphocytes (Treg, CD 4+ CD 25+) prevented vascular injury, cardiac damage, and endothelial dysfunction of mesenteric arteries. Whether Treg modulate the cerebrovascular damage induced by hypertension is unknown. Methods and Results C57 BL /6 mice were perfused with angiotensin II (Ang II ; 1000 ng/kg per minute) for 14 days and adoptive transfer of 3×105 CD 4+ CD 25+ T cells was performed via 2 intravenous injections. Control mice received a sham surgery and PBS . Treg prevented Ang II -induced neurovascular uncoupling ( P<0.05) and endothelial impairment ( P<0.05), evaluated by laser Doppler flowmetry in the somatosensory cortex. The neuroprotective effect of Treg was abolished when they were isolated from mice deficient in interleukin-10. Administration of interleukin-10 (60 ng/d) to hypertensive mice prevented Ang II -induced neurovascular uncoupling ( P<0.05). Treg adoptive transfer also diminished systemic inflammation induced by Ang II ( P<0.05), examined with a peripheral blood cytokine array. Mice receiving Ang II + Treg exhibited reduced numbers of Iba-1+ cells in the brain cortex ( P<0.05) and hippocampus ( P<0.001) compared with mice infused only with Ang II. Treg prevented the increase in cerebral superoxide radicals. Overall, these effects did not appear to be directly modulated by Treg accumulating in the brain parenchyma, because only a nonsignificant number of Treg were detected in brain. Instead, Treg penetrated peripheral tissues such as the kidney, inguinal lymph nodes, and the spleen. Conclusions Treg prevent impaired cerebrovascular responses in Ang II -induced hypertension. The neuroprotective effects of Treg involve the modulation of inflammation in the brain and periphery.