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Genetic cerebral vessel disease

T Michael De Silva, Mary L Modrick, Fabrice Dabertrand, Frank M Faraci
Vascular aging fundamentally contributes to large and small vessel disease. Despite the importance of such changes for brain function, mechanisms that mediate such changes are poorly defined. We explored mechanisms that underlie changes with age, testing the hypothesis that ROCK (Rho kinase) plays an important role. In C57BL/6 mice, baseline diameters of isolated pressurized parenchymal arterioles were similar in adult (4-5 month) and old mice (22±1 month; ≈15±1 µm). Endothelium-dependent dilation was impaired in old mice compared with adults in a pathway-specific manner...
March 12, 2018: Hypertension
Matilde Balbi, Matthieu P Vanni, Max J Vega, Gergely Silasi, Yuki Sekino, Jamie D Boyd, Jeffrey M LeDue, Timothy H Murphy
Small vessel disease is characterized by sporadic obstruction of small vessels leading to neuronal cell death. These microinfarcts often escape detection by conventional magnetic resonance imaging and are identified only upon postmortem examination. Our work explores a brain-wide microinfarct model in awake head-fixed mice, where occlusions of small penetrating arterioles are reproduced by endovascular injection of fluorescent microspheres. Mesoscopic functional connectivity was mapped longitudinally in awake GCaMP6 mice using genetically encoded calcium indicators for transcranial wide-field calcium imaging...
January 1, 2018: Journal of Cerebral Blood Flow and Metabolism
R Espert, M Gadea, M Alino, J Oltra-Cucarella, C Perpina
INTRODUCTION: Moyamoya disease (MMD) is an occlusive cerebrovascular disease characterized by progressive stenosis or occlusion in the terminal portion of the bilateral internal carotid arteries, affecting both children and adults. AIM: To conduct a review and update on MMD from a clinical, neuroradiological, neuropsychological and genetic perspective. DEVELOPMENT: In this pathology, which occurs with ischemia or cerebral hemorrhage, an unusual compensatory vascular network (moyamoya vessels) develops at the base of the brain in the form of collateral channels...
March 1, 2018: Revista de Neurologia
Michael M Wang
Cerebral small-vessel disease is a prevalent condition that is strongly associated with ischemic stroke and dementia. The most prevalent inherited cause of cerebral small-vessel disease is CADASIL, cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy, a disorder linked to mutations in NOTCH3. The most common symptoms of CADASIL are small ischemic strokes and/or transient ischemic attacks and cognitive impairment, appearing in middle age, that may progress to frank vascular dementia...
2018: Handbook of Clinical Neurology
Huan T Nguyen, Satoru Noguchi, Kazuma Sugie, Yoshiyuki Matsuo, Chuyen T H Nguyen, Hitoshi Koito, Ichiro Shiojima, Ichizo Nishino, Hiroyasu Tsukaguchi
Lysosomal associated membrane protein 2 (LAMP2) is physiologically implicated in autophagy. A genetic LAMP2 defect causes Danon disease, which consists of two major phenotypes of myopathy and cardiomyopathy. In addition, arteriopathy may manifest on rare occasions but the pathological basis remains unknown. We encountered two Danon families that developed small-vessel vasculopathy in the coronary or cerebral arteries. To investigate the underlying mechanisms, we characterized the biological features of LAMP-2-deficient mice and cultured cells...
February 20, 2018: Scientific Reports
Wen-Lei Shi, Yong-Biao Zhang, Wei Wei, Hong-Yan Gao, Yong-Hua Huang
BACKGROUND: Leukoaraiosis, a subtype of cerebral small vessel disease, is a common condition found on CT or MRI in elderly people. Leukoaraiosis is strongly associated with cognitive impairment, mental abnormality, gait disorders and urinary dysfunction. However, the genetic risk of leukoaraiosis is largely unknown. OBJECTIVE: The goal of this study is to identify the loss-of-function mutations for leukoaraiosis in Chinese. METHODS: We performed whole-genome sequencing on 11 leukoaraiosis patients and further validated the candidate mutations and tags of the candidate genes in 304 individuals including 160 patients and 144 healthy controls using Sequenom MassARRAY platform...
February 8, 2018: Biochemical and Biophysical Research Communications
Marco Duering, Sofia Finsterwalder, Ebru Baykara, Anil Man Tuladhar, Benno Gesierich, Marek J Konieczny, Rainer Malik, Nicolai Franzmeier, Michael Ewers, Eric Jouvent, Geert Jan Biessels, Reinhold Schmidt, Frank-Erik de Leeuw, Ofer Pasternak, Martin Dichgans
INTRODUCTION: Diffusion tensor imaging detects early tissue alterations in Alzheimer's disease and cerebral small vessel disease (SVD). However, the origin of diffusion alterations in SVD is largely unknown. METHODS: To gain further insight, we applied free water (FW) imaging to patients with genetically defined SVD (Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy [CADASIL], n = 57), sporadic SVD (n = 444), and healthy controls (n = 28)...
February 16, 2018: Alzheimer's & Dementia: the Journal of the Alzheimer's Association
Mohaddeseh Salehi, Mona Amin-Beidokhti, Behnam Safarpour Lima, Milad Gholami, Gholam-Reza Javadi, Reza Mirfakhraie
Introduction: Migraine is a painful complex neurovascular disease characterized by recurrent moderate-to-severe headaches. Increased level of homocysteine is related to dilation of cerebral vessels and endothelial injury that could trigger migraine attacks. Functional polymorphisms in the MTHFR gene affect homocysteine metabolism and, therefore, play an important role in the etiology of the disease. Objectives: We aimed to investigate the possible association between MTHFR gene rs4846049, C677T, and A1298C polymorphisms and the risk of migraine in Iranian population...
2018: Journal of Pain Research
Mark A Rodrigues, Neshika Samarasekera, Christine Lerpiniere, Catherine Humphreys, Mark O McCarron, Philip M White, James A R Nicoll, Cathie L M Sudlow, Charlotte Cordonnier, Joanna M Wardlaw, Colin Smith, Rustam Al-Shahi Salman
BACKGROUND: Identification of lobar spontaneous intracerebral haemorrhage associated with cerebral amyloid angiopathy (CAA) is important because it is associated with a higher risk of recurrent intracerebral haemorrhage than arteriolosclerosis-associated intracerebral haemorrhage. We aimed to develop a prediction model for the identification of CAA-associated lobar intracerebral haemorrhage using CT features and genotype. METHODS: We identified adults with first-ever intracerebral haemorrhage diagnosed by CT, who died and underwent research autopsy as part of the Lothian IntraCerebral Haemorrhage, Pathology, Imaging and Neurological Outcome (LINCHPIN) study, a prospective, population-based, inception cohort...
January 10, 2018: Lancet Neurology
Marie-Gabrielle Duperron, Christophe Tzourio, Muralidharan Sargurupremraj, Bernard Mazoyer, Aïcha Soumaré, Sabrina Schilling, Philippe Amouyel, Ganesh Chauhan, Yi-Cheng Zhu, Stéphanie Debette
BACKGROUND AND PURPOSE: The genetic contribution to dilated perivascular space (dPVS) burden-an emerging MRI marker of cerebral small vessel disease-is unknown. We measured the heritability of dPVS burden and its shared heritability with other MRI markers of cerebral small vessel disease. METHODS: The study sample comprised 1597 participants from the population-based Three City (3C) Dijon Study, with brain MRI and genome-wide genotyping (mean age, 72.8±4.1 years; 61% women)...
February 2018: Stroke; a Journal of Cerebral Circulation
Lian Duan, Ling Wei, Yanghua Tian, Zhengshan Zhang, Panpan Hu, Qiang Wei, Sugang Liu, Jun Zhang, Yuyang Wang, Desheng Li, Weizhong Yang, Rui Zong, Peng Xian, Cong Han, Xiangyang Bao, Feng Zhao, Jie Feng, Wei Liu, Wuchun Cao, Guoping Zhou, Chunyan Zhu, Fengqiong Yu, Weimin Yang, Yu Meng, Jingye Wang, Xianwen Chen, Yu Wang, Bing Shen, Bing Zhao, Jinghai Wan, Fengyu Zhang, Gang Zhao, Aimin Xu, Xuejun Zhang, Jianjun Liu, Xianbo Zuo, Kai Wang
BACKGROUND AND PURPOSE: Moyamoya disease (MMD) is a rare cerebral vasculopathy characterized by bilateral internal carotid artery stenosis and often leads to stroke in children or young adults. Although familial inheritance is well recognized, the genetic basis of MMD remains poorly understood. METHODS: A 2-stage genome-wide association study was conducted involving 1492 cases and 5084 controls. In the discovery stage, logistic regression was used to test associations, and imputation was conducted based on genotyped single-nucleotide polymorphisms (SNPs)...
January 2018: Stroke; a Journal of Cerebral Circulation
Masayo Koide, Arash Moshkforoush, Nikolaos M Tsoukias, David C Hill-Eubanks, George C Wellman, Mark T Nelson, Fabrice Dabertrand
Cerebral small vessel diseases (SVDs) encompass a group of genetic and sporadic pathological processes leading to brain lesions, cognitive decline, and stroke. There is no specific treatment for SVDs, which progress silently for years before becoming clinically symptomatic. Here, we examine parallels in the functional defects of parenchymal arterioles in CADASIL, a monogenic form of SVD, and in response to subarachnoid hemorrhage, a common type of hemorrhagic stroke that also targets the brain microvasculature...
December 15, 2017: Microcirculation: the Official Journal of the Microcirculatory Society, Inc
James D Stefaniak, Li Su, Elijah Mak, Nasim Sheikh-Bahaei, Katie Wells, Karen Ritchie, Adam Waldman, Craig W Ritchie, John T O'Brien
INTRODUCTION: Cerebral small vessel disease (CSVD) is associated with late-onset Alzheimer's disease (LOAD) and might contribute to the relationship between apolipoprotein E ε4 (APOE ε4) and LOAD, in older people. However, it is unclear whether CSVD begins in middle age in individuals genetically predisposed to LOAD. METHODS: We assessed the relationship between radiological markers of CSVD, white matter hyperintensities and microbleeds, and genetic predisposition to LOAD in a cross-sectional analysis of cognitively normal subjects aged 40-59 years recruited from the PREVENT Dementia study...
February 2018: Alzheimer's & Dementia: the Journal of the Alzheimer's Association
Franc Llorens, Katrin Thüne, Waqas Tahir, Eirini Kanata, Daniela Diaz-Lucena, Konstantinos Xanthopoulos, Eleni Kovatsi, Catharina Pleschka, Paula Garcia-Esparcia, Matthias Schmitz, Duru Ozbay, Susana Correia, Ângela Correia, Ira Milosevic, Olivier Andréoletti, Natalia Fernández-Borges, Ina M Vorberg, Markus Glatzel, Theodoros Sklaviadis, Juan Maria Torres, Susanne Krasemann, Raquel Sánchez-Valle, Isidro Ferrer, Inga Zerr
BACKGROUND: YKL-40 (also known as Chitinase 3-like 1) is a glycoprotein produced by inflammatory, cancer and stem cells. Its physiological role is not completely understood but YKL-40 is elevated in the brain and cerebrospinal fluid (CSF) in several neurological and neurodegenerative diseases associated with inflammatory processes. Yet the precise characterization of YKL-40 in dementia cases is missing. METHODS: In the present study, we comparatively analysed YKL-40 levels in the brain and CSF samples from neurodegenerative dementias of different aetiologies characterized by the presence of cortical pathology and disease-specific neuroinflammatory signatures...
November 10, 2017: Molecular Neurodegeneration
Gang Zheng, Qianlei Zheng, Qianwei Xu
Cerebral small vessel disease (CSVD) primarily affects the perforating cerebral arterioles and capillaries, and results in injury to subcortical grey and white matter. Despite advances in determining the genetic basis of CSVD, the molecular mechanisms underlying the development and progression of CSVD remain unclear. The present study aimed to identify significant signaling pathways associated with CSVD based on differential pathway network analysis. Combining CSVD microarray data with human protein-protein interaction data and data from the Reactome pathway database, pathway interactions were constructed using the Spearman's correlation coefficient strategy...
November 2017: Experimental and Therapeutic Medicine
Naveed Akhtar, Abdul Salam, Saadat Kamran, Atlantic D'Souza, Yahia Imam, Ahmed Own, Ahmed ElSotouhy, Surjith Vattoth, Paula Bourke, Zain Bhutta, Sujatha Joseph, Mark Santos, Rabia Ali Khan, Ashfaq Shuaib
Asymptomatic small vessel disease (SVD), including white matter hyperintensities (WMHIs), periventricular hyperintensities (PVHIs), silent stroke (SS), and cerebral microbleeds (CMBs), increases the risk of stroke. There are limited studies of SVD in subjects from the Middle East and Southeast Asia (SA). All patients admitted to stroke service between 2014 and 2015 were reviewed for presence of "pre-existing" SVD. Stroke mimics with no previous history of stroke were used as controls. There were 1727 patients admitted with stroke...
November 3, 2017: Translational Stroke Research
Ming Yao, Daping Lv, Jiajia Huo, Zhongwu Sun
BACKGROUND: Cerebral small vessel disease (SVD) can cause cognitive impairment, disability, and dementia. While it's still unclear about the pathogenesis of SVD, several risk factors of SVD have been identified, and studies suggested that hypertension may play a critical role in SVD. Furthermore, studies have demonstrated that CYP2J2 isoform, 50 G>T variant, is associated with increase the risk of ischemic stroke. Thus, we hypothesized that CYP2J2 50 G>T variant is associated with increased risk of cerebral SVD...
October 17, 2017: Current Neurovascular Research
Nobuto Kakuda, Tomohiro Miyasaka, Noriyuki Iwasaki, Takashi Nirasawa, Satoko Wada-Kakuda, Junko Takahashi-Fujigasaki, Shigeo Murayama, Yasuo Ihara, Masaya Ikegawa
Amyloid β (Aβ) deposition in the brain is an early and invariable feature of Alzheimer's disease (AD). The Aβ peptides are composed of about 40 amino acids and are generated from amyloid precursor proteins (APP), by β- and γ-secretases. The distribution of individual Aβ peptides in the brains of aged people, and those suffering from AD and cerebral amyloid angiopathy (CAA), is not fully characterized. We employed the matrix-assisted laser desorption/ionization-imaging mass spectrometry (MALDI-IMS) to illustrate the spatial distribution of a broad range of Aβ species in human autopsied brains...
October 16, 2017: Acta Neuropathologica Communications
Santiago Martinez Sosa, Kenneth J Smith
The deep and periventricular white matter is preferentially affected in several neurological disorders, including cerebral small vessel disease (SVD) and multiple sclerosis (MS), suggesting that common pathogenic mechanisms may be involved in this injury. Here we consider the potential pathogenic role of tissue hypoxia in lesion development, arising partly from the vascular anatomy of the affected white matter. Specifically, these regions are supplied by a sparse vasculature fed by long, narrow end arteries/arterioles that are vulnerable to oxygen desaturation if perfusion is reduced (as in SVD, MS and diabetes) or if the surrounding tissue is hypoxic (as in MS, at least)...
October 15, 2017: Clinical Science (1979-)
Ikuko Mizuta, Akiko Watanabe-Hosomi, Takashi Koizumi, Mao Mukai, Ai Hamano, Yasuhiro Tomii, Masaki Kondo, Masanori Nakagawa, Hidekazu Tomimoto, Teruyuki Hirano, Makoto Uchino, Osamu Onodera, Toshiki Mizuno
PURPOSE: Definite diagnosis of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukocencephalopathy (CADASIL) is mostly done by identification of NOTCH3 mutations. We aimed to develop criteria for selecting patients suspected for CADASIL to undergo genetic testing. SUBJECTS AND METHODS: All subjects were Japanese. We recruited CADASIL patients genetically diagnosed up until 2011 (n=37, Group 1) or after 2011 (n=65, Group 2), 67 young stroke patients (≤55 years old), and 53 NOTCH3-negative CADASIL-like patients...
October 15, 2017: Journal of the Neurological Sciences
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