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Genetic Contribution to Brain Arterial Dilatation and its Role in Cognition and dementia

遗传对脑动脉扩张的影响及其在认知和痴呆中的作用

基本信息

批准号：
10394254
负责人：
Jose Gutierrez
金额：
$ 78.12万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-08-15 至 2024-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10394254
关键词：
Address Affect Aging Alzheimer&apos s Disease Alzheimer&apos s disease pathology Alzheimer&apos s disease risk American Arteries Atherosclerosis Atherosclerosis Risk in Communities Biological Assay Blood Flow Velocity Blood Vessels Blood capillaries Brain Brain Infarction Caliber Carbon Dioxide Categories Cerebral Atheroscleroses Cerebrovascular Circulation Cerebrovascular Disorders Cerebrum Clinical Cognition Communities Connective Tissue Connective Tissue Diseases Data Dementia Dilatation - action Disease Distal Event Functional disorder Future General Population Genes Genetic Genetic Determinism Health Homeostasis Impaired cognition Individual Inherited Ipsilateral Link Magnetic Resonance Angiography Measurement Measures Mechanics Mediating Meta-Analysis Modification Outcome Participant Pathologic Patients Persons Phenotype Physiological Population Population Study Predisposing Factor Predisposition Reporting Research Priority Risk Risk Factors Role Single Nucleotide Polymorphism Statistical Models Stenosis Syndrome Testing Uncertainty Vascular Dementia Vascular Diseases Washington base brain health cerebral hemodynamics cerebrovascular health cognitive function cognitive performance cognitive testing dementia risk epidemiology study follow-up genetic approach genetic risk factor genome wide association study genomic locus hemodynamics imaging biomarker middle cerebral artery neuroimaging new therapeutic target novel novel therapeutics prospective time use trait vascular contributions

项目摘要

PROJECT SUMMARY/ABSTRACT: Alzheimer disease is expected to affect over 13 million Americans by 2050. There is ample evidence that relates vascular disease to Alzheimer disease, and the vascular contributions to cognitive decline and dementia are a national research priority. Data from our group and others have demonstrated that brain large artery disease is an important determinant of cerebrovascular health and, consequently, of cognitive function. For example, narrowing of the brain arteries due to atherosclerosis has been associated with an increased risk of Alzheimer disease and vascular dementia. The field has long focused on atherosclerosis and stenosis as the sole contributors to cerebrovascular health, however. We believe that brain arterial dilatation may also be deleterious to brain health. Consequently, we propose a change in the paradigm of brain large artery disease that goes beyond atherosclerosis and/or stenosis, and incorporates brain arterial dilatation as a distinct pathological phenotype. We postulated that, as with many anthropomorphic measurements, the diameters of brain arteries are normally distributed and that the extremes of this distribution are pathological. We have confirmed this hypothesis. We reported that among individuals with the largest or the smallest brain arterial diameters, the risk of vascular event is higher. The increased risk of vascular events among these individuals with extreme cerebral phenotypes is partially explained by the co-existence of systemic but not necessarily cerebral atherosclerosis. We have also demonstrated that non-atherosclerotic brain arterial aging relates to Alzheimer pathology independent of atherosclerosis and brain infarcts. We have gathered preliminary data showing that brain arterial diameters are associated non-linearly with cognition, so that individuals with narrowed or dilated brain arteries have poorer cognitive performance compared with those with average arterial diameters. Because brain arterial dilatation is understudied, it will be the focus of our proposal. Brain arterial dilatation may occur among patients with genetic syndromes predisposing to weaker connective tissue, but it is unclear whether genetic predisposing factors exist in the general population. It is plausible that the mechanical effects of brain arterial dilatation over the distal arteriolar and capillary flow may disrupt cerebral autoregulation, and explain the relationship with parenchymal functions such as cognition. It remains unclear whether these genetic factors are effect modifiers or direct contributors to cognition. This proposal aims to address these uncertainties. In Aim 1, we will define genetic loci that relate to brain arterial dilatation in >5,000 participants of four well-characterized, population-based studies with longitudinal follow-up who also have neuroimaging and cognitive assessments. In Aim 2, we will establish the hemodynamic consequences of brain arterial dilatation by relating it to cerebral blood flow velocities and autoregulation. In Aim 3, we will first confirm the relationship between brain arterial dilatation with cognitive performance and risk of dementia. We will then perform a modification analysis using genetic loci related to brain arterial dilatation and measures of autoregulation as presumed effect modifiers. At the conclusion of these studies, we will definitively establish a role for brain arterial dilatation in cognition and dementia. We will identify genetic and physiological traits that will help us identify mechanisms to pursue further with sequencing approaches and functional assays, which in turn may enable discovery of novel therapeutic targets.

项目总结/文摘:

项目成果

期刊论文数量（14）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Cerebrovascular Contributions to Neurocognitive Disorders in People Living With HIV.

DOI：
10.1097/qai.0000000000002729
发表时间：
2021-09-01
期刊：
Journal of acquired immune deficiency syndromes (1999)
影响因子：
0
作者：
Gutierrez J;Porras TN;Yoo-Jeong M;Khasiyev F;Igwe KC;Laing KK;Brickman AM;Pavol M;Schnall R
通讯作者：
Schnall R

Brain artery diameters and risk of dementia and stroke.

脑动脉直径与痴呆和中风的风险。

DOI：
10.1002/alz.13712
发表时间：
2024
期刊：
Alzheimer's & dementia : the journal of the Alzheimer's Association
影响因子：
0
作者：
Melgarejo,JesusD;Gurel,Kursat;Compton,CassidyRose;Liu,Minghua;Guzman,Vanessa;Assuras,Stephanie;Levin,BonnieE;Elkind,MitchellSV;Ikram,MKamran;Kavousi,Maryam;Ikram,MArfan;Wright,Clinton;Crivello,Fabrice;Laurent,Alexandre;T
通讯作者：
T

The Longitudinal Effects of Blood Pressure and Hypertension on Neurocognitive Performance in People Living With HIV.

血压和高血压对HIV患者神经认知性能的纵向影响。

DOI：
10.1097/qai.0000000000002740
发表时间：
2021-10-01
期刊：
Journal of acquired immune deficiency syndromes (1999)
影响因子：
0
作者：
Guzman VA;Cham H;Gutierrez J;Byrd D;Morris EP;Tureson K;Morgello S;Mindt MR;Manhattan HIV Brain Bank
通讯作者：
Manhattan HIV Brain Bank

Letter by Gutierrez Regarding Article, "Dual Antiplatelet Therapy Improves Functional Outcome in Patients With Progressive Lacunar Strokes".

Gutierrez 关于文章“双重抗血小板治疗改善进行性腔隙性中风患者的功能结果”的信函。