Small vessel disease and beta-amyloid deposition in mildly impaired cognition

描述（由申请人提供）：我们建议在轻度损伤人群中研究脑小血管疾病的MRI标志物与认知下降之间的相关性，包括符合MCI研究标准的个体和不符合这些标准但有一些认知下降证据的个体。由于证据表明，与阿尔茨海默病（包括神经元缠结和老年斑）相关的病理性脑变化改变了小血管疾病和认知之间的关系，因此迫切需要将阿尔茨海默病病理学的体内标志物纳入脑小血管疾病影响的纵向研究中。因此，目前的建议代表了一个重要的进步，通过测量阿尔茨海默病的病理学的标志性特征，纤维状β-淀粉样蛋白沉积的证据匹兹堡化合物B（PI B）保留在PET上，除了小血管疾病的MRI标志物。这项拟议的研究将补充目前正在进行的大型神经影像学研究，具体解决小血管疾病和灌注的高级MRI标志物，纤维状β淀粉样蛋白沉积的PET标志物和认知能力下降之间的关系。将检验以下假设：1）小血管疾病所致的白色损害与认知功能下降相关，与脑β-淀粉样蛋白沉积量无关，2）小血管疾病所致的白色损害通过损害特定脑区引起认知功能障碍，3）小血管疾病所致的白色损害进展是由相对低灌注区域的缺血引起的。将从社区招募轻度受损的非痴呆受试者，并每年随访认知功能下降。这是一个研究的人群，因为它是一个理想的治疗目标，旨在减少由血管疾病引起的认知能力下降的负担。研究程序将包括基线时的PET和MRI，以及随访期间的第二次MRI。这项纵向研究将1）提供与小血管疾病MRI标志物相关的下降率估计值，可用于轻度受损受试者的未来临床试验设计，2）确定小血管疾病损伤的神经解剖学表型，其将比当前的全球疾病指标更准确地预测认知下降，和3）鉴定脑灌注作为治疗的潜在靶点以防止白色物质损伤的进展。 脑血管病相关的小血管疾病很常见，可引起无症状性中风和白色物质损伤，MRI上可见，导致认知能力下降。目前尚不清楚这些MRI异常与阿尔茨海默病（另一种常见的衰老病理学）共存的频率，以及这些MRI异常与认知能力下降之间的关系是否受到阿尔茨海默病类型病理学存在或不存在的影响。我们计划研究轻度损伤受试者中小血管疾病的MRI标记物、阿尔茨海默型病理学的PET标记物、脑灌注和认知之间的关系。我们的研究结果将有助于临床试验的设计，以通过定义小血管疾病和阿尔茨海默病型病理学的成像标志物及其对认知能力下降的影响来预防痴呆症。

DESCRIPTION (provided by applicant): We propose to study the association between MRI markers of cerebral small vessel disease and cognitive decline in a population with mild impairment, both in individuals who meet research criteria for MCI and in individuals who fall short of these criteria but have some evidence of cognitive decline. Because evidence shows that pathological brain changes associated with Alzheimer's disease (including neurofibrillary tangles and senile plaques) modify the relationship between small vessel disease and cognition, there is a critical need to incorporate in vivo markers of Alzheimer's pathology into longitudinal studies of the effect of cerebral small vessel disease. The current proposal therefore represents an important advance by measuring a hallmark feature of Alzheimer's pathology, fibrillar beta-amyloid deposition by evidence of Pittsburgh Compound B (PIB) retention on PET, in addition to MRI markers of small vessel disease. The proposed study will complement current ongoing large neuroimaging studies by specifically addressing the relationship between advanced MRI markers of small vessel disease and perfusion, a PET marker of fibrillar beta-amyloid deposition, and cognitive decline. The following hypotheses will be tested: 1) white matter damage from small vessel disease is associated with cognitive decline, independent of the amount of cerebral beta-amyloid deposition, 2) white matter damage from small vessel disease causes cognitive impairment by damaging specific brain regions, and 3) progression of white matter damage from small-vessel disease is caused by ischemia in areas of relative hypoperfusion. Mildly impaired non-demented subjects will be recruited from the community and followed annually for cognitive decline. This is an population for study because it is an ideal target for therapies designed to reduce the burden of cognitive decline caused by vascular disease. Study procedures will include PET and MRI at baseline, with a second MRI during follow-up. This longitudinal study will 1) provide estimates of the rate of decline associated with MRI markers of small vessel disease that may be used in the design of future clinical trials in mildly impaired subjects, 2) identify a neuroanatomic phenotype of damage from small vessel disease that will more accurately predict cognitive decline than current global disease measures, and 3) identify cerebral perfusion as a potential target for therapies to prevent progression of white matter damage. Age-related small-vessel disease of the brain is common and causes silent stroke and damage to the white matter, visible on MRI, resulting in cognitive decline. It is not known how often these MRI abnormalities coexist with Alzheimer's disease, another common pathology of aging, and whether the relationship between these MRI abnormalities and cognitive decline is influenced by the presence or absence of Alzheimer-type pathology. We plan to study the relationship between MRI markers of small vessel disease, a PET marker of Alzheimer-type pathology, brain perfusion and cognition in subjects with mild impairments. Our results will aid the design of clinical trials to prevent dementia by defining imaging markers of small vessel disease and Alzheimer-type pathology and their effects on cognitive decline.