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大脑小血管疾病的MRI标记物与认知能力下降之间的关系，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能力下降证据的个体。由于有证据表明，与阿尔茨海默病相关的病理性脑改变（包括神经原纤维缠结和老年斑）改变了小血管疾病与认知之间的关系，因此迫切需要将阿尔茨海默病病理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病理学的标志性特征，纤维状β -淀粉样蛋白沉积，通过PET上匹兹堡化合物B （PIB）保留的证据，以及小血管疾病的MRI标记。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标记物，纤维β -淀粉样蛋白沉积的PET标记物与认知能力下降之间的关系。以下假设将被验证：1)小血管疾病引起的白质损伤与认知能力下降有关，与大脑β -淀粉样蛋白沉积的数量无关；2)小血管疾病引起的白质损伤通过损害特定脑区域导致认知功能障碍；3)小血管疾病引起的白质损伤的进展是由相对灌注不足区域的缺血引起的。将从社区招募轻度受损的非痴呆受试者，每年随访一次认知能力下降情况。这是一个值得研究的人群，因为它是一个理想的治疗目标，旨在减轻由血管疾病引起的认知能力下降的负担。研究程序包括基线时的PET和MRI，随访时进行第二次MRI检查。这项纵向研究将1)提供与小血管疾病MRI标记物相关的衰退率的估计，这可能用于未来轻度受损受试者的临床试验设计；2)确定小血管疾病损伤的神经解剖表型，这将比目前的全球疾病测量更准确地预测认知衰退；3)确定脑灌注作为预防白质损伤进展的治疗的潜在靶点。

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.