Cerebrovascular Alterations Research Articles

Role of hydrogen sulfide in cerebrovascular alteration during aging.

Hydrogen sulfide (H2S), a gasotransmitter molecule, has attracted attention as an endogenous signaling molecule because of its various pathological and physiological effects, including pathologies related to aging. In this review, we aimed to discuss the morphological changes in each vessel following aging, and to evaluate the possible role of H2S in the cerebrovascular alteration, such as arterial stiffness, microvessel loss, and blood-brain barrier disruption, with advancing age. Additionally, the review outlines the therapeutic efficacy of the H2S-releasing compounds on the cerebrovasculature. In the central nervous system, cerebrovascular aging can lead to the loss of blood-brain integrity, which causes cognitive impairment. The findings discussed in this review strongly support the notion that H2S has a potential therapeutic role in cerebrovascular alteration in aging.

Inflaming the Brain

Exactly how cerebrovascular alterations contribute to Alzheimer's disease (AD) is still unknown. Merlini etal. (2019) show that blood-derived fibrinogen leads to dendritic spine elimination and cognitive deficit via microglial CD11b/CD18. Fibrinogen may be a significant contributor to AD pathogenesis.

Fibrinogen Induces Microglia-Mediated Spine Elimination and Cognitive Impairment in an Alzheimer’s Disease Model

Cerebrovascular alterations are a key feature of Alzheimer's disease (AD) pathogenesis. However, whether vascular damage contributes to synaptic dysfunction and how it synergizes with amyloid pathology to cause neuroinflammation and cognitive decline remain poorly understood. Here, we show that the blood protein fibrinogen induces spine elimination and promotes cognitive deficits mediated by CD11b-CD18 microglia activation. 3D molecular labeling in cleared mouse and human AD brains combined with repetitive invivo two-photon imaging showed focal fibrinogen deposits associated with loss of dendritic spines independent of amyloid plaques. Fibrinogen-induced spine elimination was prevented by inhibiting reactive oxygen species (ROS) generation or genetic ablation of CD11b. Genetic elimination of the fibrinogen binding motif to CD11b reduced neuroinflammation, synaptic deficits, and cognitive decline in the 5XFAD mouse model of AD. Thus, fibrinogen-induced spine elimination and cognitive decline via CD11b link cerebrovascular damage with immune-mediated neurodegeneration and may have important implications in AD and related conditions.

Photoacoustic microscopy of obesity-induced cerebrovascular alterations

Cerebral small vessel disease has been linked to cognitive, psychiatric and physical disabilities, especially in the elderly. However, the underlying pathophysiology remains incompletely understood, largely due to the limited accessibility of these small vessels in the live brain. Here, we report an intravital imaging and analysis platform for high-resolution, quantitative and comprehensive characterization of pathological alterations in the mouse cerebral microvasculature. By exploiting multi-parametric photoacoustic microscopy (PAM), microvascular structure, blood perfusion, oxygenation and flow were imaged in the awake brain. With the aid of vessel segmentation, these structural and functional parameters were extracted at the single-microvessel level, from which vascular density, tortuosity, wall shear stress, resistance and associated cerebral oxygen extraction fraction and metabolism were also quantified. With the use of vasodilatory stimulus, multifaceted cerebrovascular reactivity (CVR) was characterized in vivo. By extending the classic Evans blue assay to in vivo, permeability of the blood-brain barrier (BBB) was dynamically evaluated. The utility of this enabling technique was examined by studying cerebrovascular alterations in an established mouse model of high-fat diet-induced obesity. Our results revealed increased vascular density, reduced arterial flow, enhanced oxygen extraction, impaired BBB integrity, and increased multifaceted CVR in the obese brain. Interestingly, the ‘counterintuitive’ increase of CVR was supported by the elevated active endothelial nitric oxide synthase in the obese mouse. Providing comprehensive and quantitative insights into cerebral microvessels and their responses under pathological conditions, this technique opens a new door to mechanistic studies of the cerebral small vessel disease and its implications in neurodegeneration and stroke.

Central nervous system involvement in late-onset Pompe disease: clues from neuroimaging and neuropsychological analysis.

Late-onset Pompe disease (LOPD) is a rare, multisystem disorder that is well established to mainly impair skeletal muscle function. Systematic studies exploring brain functions in LOPD are lacking. The aim of this study was to detect morphological and functional brain alterations as well as neuropsychological impairment in LOPD. We studied 21 patients (10 male, mean age 49±18.4years) with defined diagnosis of LOPD, divided into two groups: one with pre-symptomatic hyperCKemia with no muscle weakness and the second with limb-girdle muscle weakness. All patients underwent 3T magnetic resonance imaging (MRI) to obtain morphological/angiographic evaluation as well as normalized cortical brain volume and resting-state functional MRI. Fazekas score was applied to quantify white matter lesions, whereas Smoker's criteria were used to examine dolichoectasia. A complete neuropsychological assessment was performed. The MRI data showed that 12/21 patients (57%) demonstrated signs of cerebral vasculopathy, with a Fazekas score >2 in 67%. According to Smoker's criteria, 11/21 patients (52%) had a dolichoectasia of the vertebrobasilar system; an intracranial aneurysm was detected in 3/21 patients (14%). Resting-state functional MRI demonstrated significantly decreased brain connectivity in the salience network with a more relevant reduction in the bilateral middle and superior frontal gyrus. Gray matter atrophy correlated with age and disease duration. A mild impairment in executive functions was also identified. In this LOPD cohort the results showed morphological and functional brain alterations with mild neuropsychological dysfunction, mainly in the limb-girdle muscle weakness group. Cerebrovascular alterations seemed to be not related to common risk factors, suggesting a major role of enzymatic deficiency in the pathogenesis of brain abnormalities.

Apo\u03b54 disrupts neurovascular regulation and undermines white matter integrity and cognitive function

The ApoE4 allele is associated with increased risk of small vessel disease, which is a cause of vascular cognitive impairment. Here, we report that mice with targeted replacement (TR) of the ApoE gene with human ApoE4 have reduced neocortical cerebral blood flow compared to ApoE3-TR mice, an effect due to reduced vascular density rather than slowing of microvascular red blood cell flow. Furthermore, homeostatic mechanisms matching local delivery of blood flow to brain activity are impaired in ApoE4-TR mice. In a model of cerebral hypoperfusion, these cerebrovascular alterations exacerbate damage to the white matter of the corpus callosum and worsen cognitive dysfunction. Using 3-photon microscopy we found that the increased white matter damage is linked to an enhanced reduction of microvascular flow resulting in local hypoxia. Such alterations may be responsible for the increased susceptibility to hypoxic-ischemic lesions in the subcortical white matter of individuals carrying the ApoE4 allele.

Oxidative Stress: A Major Player in Cerebrovascular Alterations Associated to Neurodegenerative Events.

The brain is one of the most exquisite organs in the body with high metabolic demands, and requires a tight regulation of the surrounding environment. This tight control is exerted by the neurovascular unit (NVU) comprising different cell types, where endothelial cells play the commander-in-chief role. Thus, it is assumable that even slight perturbations in NVU might affect, in some cases irreversibly, brain homeostasis and health. In this line, recent findings support the two-hit vascular hypothesis for neurodegenerative conditions, where vascular dysfunction underlies the development of neurodegenerative diseases, such as Alzheimer’s disease (AD). Knowing that endothelial cells are rich in mitochondria and nicotinamide adenine dinucleotide phosphate (NADPH) oxidases, two major reactive oxygen species (ROS) sources, this review aims to gather information on how oxidative stress is in the front line of vascular alterations observed in brain aging and neurodegenerative conditions, particularly AD. Also, a brief discussion about the therapeutic strategies aimed to protect against cerebrovascular diseases is included.

Systematization, Description and Territory of The Middle and Rostral Cerebral Arteries in Broad-Snouted Caimans (Caiman latirostris)

Background: Information on the arterial vascularization of the broad-snouted caimans’ brain (Caiman latirostris), a specie from the Brazilian fauna, is inexistent and the literature consulted yielded only one description about the development of embryonic circulation and post-birth cerebrovascular alterations in the brain of three caymans. The objective of this study was to describe and systematize the cerebral arterial vascularization of this reptile, by providing a standard irrigation model with its major variations, in addition to determining its territorial vascular areas. Materials, Methods & Results: Thirty heads of male broad-snouted caimans (Caiman latirostris), with the neck segment, were used in the study. Additionally, two whole female and male specimens, with approximately 3 years of age and weighing between 8 to 10 Kg were also used. The animals were sacrificed according to routine slaughterhouse norms. The heads were sectioned at the third cervical vertebra level and the azygos carotid artery was cannulated. The arterial system was washed with 0.9% saline solution and filled with red-colored latex. The pieces were fixed in formaldehyde and the encephalon removed through a window made in the cranial vault, which was followed by removal of the dura mater and dissection of the arteries. The internal carotid arteries displayed an intercarotic anastomosis in the samples examined, continuing rostrally in 100% of the cases, exiting from the skull as the internal ophthalmic artery. The internal carotid arteries divided into a rostral branch and a short caudal branch at the hypophysis level, which continued naturally as the caudal cerebral artery. The rostral branch from both right and left antimeres was shown as a single branch in 86.7% and as double branch in 13.3% of the samples, and it formed the middle cerebral artery network. The rostral cerebral artery represented the terminal branch of the internal carotid artery’s rostral branch, and an osculum anastomosis between its terminal end and its contralateral homologous artery occurred, forming the rostral communicating artery and thus closing the cerebral artery circle rostrally. Discussion: To support the results of the discussion, we used information available on the encephalic vascularization of turtles, lizards, iguanas and crocodiles, due to the absence of important publications about Caiman latirostris. One single source of blood supply, solely originated from the left aortic arch, was observed in the two whole specimens. This source was called the azygos carotid artery. Such denomination was given because these species did not show a typical common carotid artery, as the ventral part of the neck, up to the mandible, was vascularized by branches from the subclavian arteries. Therefore, we named this single and unique source as the azygos carotid artery. The cerebral arterial circle was rostrally closed by an anastomosis between the terminal ends of the rostral cerebral artery. Consequently, the blood supply to the brain was made exclusively by the carotid system. The main differences of the cerebral vascularization observed in caymans were: a network formation of the middle cerebral artery.

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.

Association of cerebrovascular dysfunction with the development of Alzheimer\u2019s disease-like pathology in OXYS rats

BackgroundCerebrovascular dysfunction plays a critical role in the pathogenesis of Alzheimer’s disease (AD): the most common cause of dementia in the elderly. The involvement of neurovasculature disorders in the progression of AD is now increasingly appreciated, but whether they represent initial factors or late-stage pathological changes during the disease is unclear. Using senescence-accelerated OXYS rats, which simulate key characteristics of sporadic AD, we evaluated contributions of cerebrovascular alterations to the disease development. At preclinical, early, and advanced stages of AD-like pathology, in the hippocampus of OXYS and Wistar (control) rats, we evaluated (i) the blood vessel state by histological and electron-microscopic analyses; (ii) differences in gene expression according to RNA sequencing (RNA-Seq) to identify the metabolic processes and pathways associated with blood vessel function; (iii) the amount of vascular endothelial growth factor (VEGF) by western blot and immunohistochemical analysis.ResultsWe observed a loss of hippocampal blood vessel density and ultrastructural changes of those blood vessels in OXYS rats at the early stage of AD-like pathology. There were significant alterations in the vessels and downregulation of VEGF with an increased amount of amyloid β1–42 there at the advanced stage of the disease. According to RNA-Seq data analysis, major alterations in cerebrovascular processes of OXYS rats were associated with blood vessel development, circulatory system processes, the VEGF signaling pathway, and vascular smooth muscle contraction. At preclinical and early stages of the AD-like pathology, these processes were upregulated and then downregulated with age. At the advanced stage in OXYS rats, differentially expressed genes (DEGs) were associated with downregulation of cerebrovascular function as compared to Wistar rats. Among the 46 DEGs at the preclinical stage of the disease, 28 DEGs at the early stage, and among 85 DEGs at the advanced stage, using functional analysis and gene network construction, we identified genes (Nos1, P2rx4, Pla2g6, and Bdkrb2) probably playing a significant role in the development of cerebrovascular dysfunction in OXYS rats.ConclusionsChanges in expression of the genes functionally associated with cerebrovascular processes already in the early period of life may contribute to the development of AD-like pathology in OXYS rats.

Longitudinal, transcranial measurement of functional activation in the rat brain by diffuse correlation spectroscopy.

.Neural activity is an important biomarker for the presence of neurodegenerative diseases, cerebrovascular alterations, and brain trauma; furthermore, it is a surrogate marker for treatment effects. These pathologies may occur and evolve in a long time-period, thus, noninvasive, transcutaneous techniques are necessary to allow a longitudinal follow-up. In the present work, we have customized noninvasive, transcutaneous, diffuse correlation spectroscopy (DCS) to localize changes in cerebral blood flow (CBF) induced by neural activity. We were able to detect changes in CBF in the somatosensory cortex by using a model of electrical forepaw stimulation in rats. The suitability of DCS measurements for longitudinal monitoring was demonstrated by performing multiple sessions with the same animals at different ages (from 6 to 18 months). In addition, functional DCS has been cross-validated by comparison with functional magnetic resonance imaging (fMRI) in the same animals in a subset of the time-points. The overall results obtained with transcutaneous DCS demonstrates that it can be utilized in longitudinal studies safely and reproducibly to locate changes in CBF induced by neural activity in the small animal brain.

Assessment of hypertensive cerebrovascular alterations with multiband Look-Locker arterial spin labeling.

To quantitatively assess the hypertension-induced cerebrovascular alterations by measuring the dynamics of arterial spin labeling (ASL) signals. The multiband Look-Locker ASL (MB LL-ASL) technique was evaluated in comparison to a single-band LL-ASL for three healthy subjects. Also, seven healthy subjects were scanned to determine the strength of the vascular crushing gradients applied to separate arterial from tissue ASL signal. With the optimized MB LL-ASL technique, multiple parameters, cerebral blood flow (CBF), transit times to artery (tA ), and capillary (tC ), delivery duration of labeled blood (τ), and arterial blood volume (CBVa ), were simultaneously quantified for age-matched eight control and eight hypertensive subjects with 259 msec of temporal resolution and 20 slices covering the whole-brain region at 3T. While CBF of hypertensives were comparable with those of normotensives (CBF of normotensives vs. hypertensives = 62.2 ± 6.87 vs. 61.9 ± 8.94 ml/100g/min, P = 0.960 for the whole gray matter), tC and τ were prolonged in hypertensives in most brain regions (tC = 1.30 ± 0.09 vs. 1.76 ± 0.16 sec, P = 0.034; τ = 1.46 ± 0.10 vs. 2.30 ± 0.22 sec, P = 0.006 for the whole gray matter). Two regions showed the increased CBVa in hypertensives compared to normotensives (hippocampus and thalamus with P = 0.009 and 0.035, respectively). Hypertension slows the perfusion dynamics, while the remaining CBF is unchanged. A detailed characterization of regional cerebrovascular impairments by MB-LL-ASL technique provides better understanding of hypertension-induced cerebrovascular modifications. 1 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2018;47:663-672.

Structural and functional brain alterations in a murine model of Angiotensin II-induced hypertension.

Hypertension is a main risk factor for the development of cerebral small vessel disease (cSVD) - a major contributor to stroke and the most common cause of vascular dementia. Despite the increasing socioeconomic importance arising from cSVD, currently only a few specific treatment strategies with proven efficacy are known. Fundamental to the lack of specific treatments is poor understanding of the disease pathogenesis and a lack of appropriate animal models resembling all symptoms of the human disease. However, chronic hypertensive rat models have been shown to bear similarities to most key features of cSVD. Despite a significantly larger toolbox available for genotypic and phenotypic modifications compared to rats, mouse models of hypertension are unusual when modeling cSVD and associated cognitive impairment experimentally. In the present study, we therefore characterized hypertension-mediated cerebrovascular alterations and accompanying structural and functional consequences by simultaneously treating adult wild-type mice (C57BL/6N) with Angiotensin II (AngII) and the nitric oxide synthases inhibitor L-NAME for 4weeks. Hypertension associated to cerebral alterations reminiscent of early-onset cSVD and vascular cognitive impairment when combined with additional AngII bolus injections. Most importantly, preventing the elevation of blood pressure (BP) protected from the development of cSVD symptoms and associated cognitive decline. Our data strongly support the suitability of this particular mouse model of AngII-induced hypertension as an appropriate animal model for early-onset cSVD and hence, vascular cognitive impairment, pathologies commonly preceding vascular dementia.

P.1.a.033 - Transcriptional mechanisms mediated by cortisol treatment

White matter abnormalities due to age-related cerebrovascular alterations is a common pathological hallmark associated with functional impairment in the elderly which has been modeled in chronically hypoperfused mice. 5-Methylcytosine (5mC) and its oxidized derivative 5-hydroxymethylcytosine (5hmC) are DNA modifications that have been recently linked with age-related neurodegeneration and cerebrovascular pathology. Here we conducted a pilot investigation of whether chronic cerebral hypoperfusion might affect genomic distribution of these modifications and/ or a Ten-Eleven Translocation protein 2 (TET2) which catalyses hydroxymethylation in white and grey matter regions of this animal model. Immunohistochemical evaluation of sham and chronically hypoperfused mice a month after surgery revealed significant (p<0.05) increases in the proportion of 5hmC positive cells, Iba1 positive inflammatory microglia, and NG2 positive oligodendroglial progenitors in the hypoperfused corpus callosum. In the same white matter tract there was an absence of hypoperfusion-induced alterations in the proportion of 5mC, TET2 positive cells and CC1 positive mature oligodrendrocytes. Correlation analysis across animals within both treatment groups demonstrated a significant association of the elevated 5hmC levels with increases in the proportion of inflammatory microglia only (p=0.01) in the corpus callosum. In vitro studies revealed that 5hmC is lost during oligodendroglial maturation but not microglial activation. Additionally, TET1, TET2, and TET3 protein levels showed dynamic alterations during oligodendroglial development and following oxidative stress in vitro. Our study suggests that 5hmC exhibits white matter tract and cell type specific dynamics following chronic cerebral hypoperfusion in mice.

New strategies for neuroprotection in glaucoma, a disease that affects the central nervous system

Glaucoma is a disease where retinal ganglion cells (RGC) are specifically affected though a number of evidences endorse the hypothesis that glaucoma is a neuro-degenerative disorder of the central nervous system and suggest a possible connection between glaucomatous damage and cerebrovascular alterations. The mechanisms underlying RGC loss are not yet fully known but alterations of the autophagy machinery have been recently proposed as a potential contributing factor as for Alzheimer's disease. Here we review the current literature on new strategies for neuroprotection in glaucoma, focusing on pharmacologic strategies to minimize RGC damage.

Effects of AT1 receptor antagonism on kainate-induced seizures and concomitant changes in hippocampal extracellular noradrenaline, serotonin, and dopamine levels in Wistar-Kyoto and spontaneously hypertensive rats

In the management of epilepsy, AT1 receptor antagonists have been suggested as an additional treatment strategy. A hyperactive brain angiotensin (Ang) II system and upregulated AT1 receptors are implicated in the cerebrovascular alterations in a genetic form of hypertension. Uncontrolled hypertension could also, in turn, be a risk factor for a seizure threshold decrease and development of epileptogenesis. The present study aimed to assess the effects of the selective AT1 receptor antagonist ZD7155 on kainic acid (KA)-induced status epilepticus (SE) development and accompanying changes in the hippocampal extracellular (EC) neurotransmitter levels of noradrenaline (NAD), serotonin (5-HT), and dopamine (DA) in spontaneously hypertensive rats (SHRs) and their parent strain Wistar-Kyoto (WKY) rats, since monoamines are well-known neurotransmitters involved in mechanisms of both epilepsy and hypertension. Status epilepticus was evoked in freely moving rats by a repetitive intraperitoneal (i.p.) administration of KA in subconvulsant doses. In the treatment group, ZD7155 (5mg/kg i.p.) was coadministered with the first KA injection. Spontaneously hypertensive rats exhibited higher susceptibility to SE than WKY rats, but the AT1 receptor antagonist did not alter the development of SE in SHRs or in WKY rats. In vivo microdialysis demonstrated significant KA-induced increases of the hippocampal NAD and DA levels in SHRs and of NAD, 5-HT, and DA in WKY rats. Although SHRs developed more severe seizures while receiving a lower dose of KA compared to WKY rats, AT1 receptor antagonism completely prevented all KA-induced increases of hippocampal monoamine levels in both rat strains without affecting seizure development per se. These results suggest a lack of direct relationship between KA-induced seizure susceptibility and adaptive changes of hippocampal NAD, 5-HT, and DA levels in the effects of ZD7155 in WKY rats and SHRs.

Issues in the Diagnosis and Treatment of Primary Aldosteronism.

Primary aldosteronism (PA) is associated with a high rate of cardio- and cerebrovascular complications and metabolic alterations. PA is also recognized as the most frequent, although often unrecognized, secondary form of hypertension. Guidelines have been released to assist clinicians in the diagnostic work-up and subtype differentiation of PA. In this review we discuss and compare the available guidelines in the context of our professional experience and evaluate diagnostic and therapeutic aspects that are still a matter of debate.

Diagnosis of cerebral vasospasm and risk of delayed cerebral ischemia related to aneurysmal subarachnoid haemorrhage: an overview of available tools.

In the first weeks following aneurysmal subarachnoid haemorrhage, cerebrovascular alterations may impact the outcome significantly. Diagnosis of cerebral vasospasm and detection of alterations at risk of delayed cerebral ischemia are key targets to be monitored in the post-acute phase. Available tools include clinical monitoring, as well as studies that can detect possible arterial narrowing, alterations of perfusion, metabolism and neurophysiology. Each technique is able to investigate possible vascular impairment and has different advantages and limits. All available techniques have been described. Among these, the most practical have been selected and compared for their peculiar characteristics. Based on this analysis, a flowchart to monitor these patients is finally proposed.

Abstract 119: Apoe-ɛ4 Is Associated With Cerebrovascular Insufficiency, Increased Susceptibility to White Matter Injury and Cognitive Dysfunction

ApoE-ɛ4 (apoE4) is a risk factor for white matter ischemic lesions (Neurology 81:292, 2013) and Alzheimer’s disease (Neuron 63:287, 2009). However, the underlying mechanisms remain to be defined. We tested the hypothesis that the apoE4 allele is associated with alterations in the regulation of the cerebral circulation and increased white matter susceptibility to ischemic injury. To this end, we used human ApoE targeted replacement mice (Sullivan et al., JBC, 272:17972, 1997) in which cerebral blood flow (CBF) was measured by laser-Doppler flowmetry in the somatosensory cortex under anesthesia (n=5/group; age 4 mo.). In apoE4 mice, the increase in CBF produced by whisker stimulation (WS) or by topical application of the endothelium-dependent vasodilator acetylcholine (ACh) was attenuated (WS, -48%; ACh, -39%; p&lt;0.05; mean±SE). Next, we asked if this neurovascular dysfunction increases the propensity of apoE4 mice to develop white matter ischemic lesions. White matter hypoperfusion was induced in the corpus callosum by bilateral carotid artery stenosis (BCAS) with microcoils for 4 weeks. BCAS led to more severe white matter injury in apoE4 than in apoE3 mice. Thus, BCAS reduced myelin density more in apoE4 (10±1 relative fluorescence units) than in apoE3 mice (15±1), a reduction of 33% (p&lt;0.05). Furthermore, the axonal nodal structure, assessed by the NaV1.6/caspr index, was disrupted in apoE4 mice (normal index 0.5; BCAS apoE3: 0.58±0.13; BCAS apoE4: 1.05±0.13; p&lt;0.05 from apoE3). BCAS induced impairments in spatial memory in the Y-maze test (arm alternation rate), an effect worse in apoE4 (43±3%) than apoE3 mice (52±3) (p&lt;0.05). These findings suggest that the apoE4 allele is associated with cerebrovascular dysfunction, which leads to more severe white matter damage and cognitive deficits following exposure to chronic cerebral hypoperfusion. Cerebrovascular alterations in apoE4 carriers may play a role in the cognitive impairment associated with vascular risk factors and in the ischemic pathology associated with Alzheimer's disease.

The presence of white matter lesions is not associated with non-alcoholic fatty liver disease but with its histological severity

Background: Nonalcoholic fatty liver disease (NAFLD) has been associated with increased cardiovascular risk, including coronary artery disease and cerebrovascular events. No studies however assessed the potential relationship between NAFLD and subclinical cerebrovascular alterations. We tested the correlation between NAFLD and its histological severity with vascular white matter lesions (WML) in patients with biopsy-proven NAFLD and in non steatosic controls.