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标记物与认知功能下降之间的联系，这既包括符合MCI研究标准的个人，也包括未达到这些标准但有一些认知能力下降证据的个人。由于有证据表明与阿尔茨海默病相关的病理性大脑变化(包括神经原纤维缠结和老年斑)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的活体标志物纳入对脑小血管疾病影响的纵向研究中。因此，目前的建议代表着一项重要的进步，通过测量阿尔茨海默病病理的一个标志性特征，即通过匹兹堡化合物B(PIB)在PET上滞留的证据，以及小血管疾病的MRI标记物，来测量纤维β淀粉样蛋白沉积。这项拟议的研究将补充目前正在进行的大型神经成像研究，具体解决小血管疾病的高级MRI标记物和灌注、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。将检验以下假设：1)小血管疾病造成的白质损害与认知能力下降有关，与大脑β-淀粉样蛋白沉积量无关；2)小血管疾病引起的白质损害通过损害特定的大脑区域而导致认知损害；以及3)小血管疾病引起的白质损害的进展是由相对低灌注区的缺血引起的。轻度受损的非痴呆受试者将从社区招募，并每年追踪认知能力下降的情况。这是一个值得研究的群体，因为他们是旨在减轻血管疾病导致的认知能力下降负担的治疗的理想目标。研究程序将包括基线时的正电子发射计算机断层扫描(PET)和核磁共振成像(MRI)，在随访期间进行第二次核磁共振成像。这项纵向研究将1)提供与小血管疾病MRI标记物相关的下降率估计，可用于设计未来的轻度受损受试者的临床试验；2)确定小血管疾病损害的神经解剖学表型，它将比目前的全球疾病指标更准确地预测认知能力下降；3)确定脑灌注作为预防白质损害进展的治疗的潜在靶点。 与年龄相关的脑部小血管疾病很常见，会导致静止性中风和脑白质损伤(在MRI上可以看到)，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(阿尔茨海默病)共存的频率，阿尔茨海默病是另一种常见的衰老病理，也不知道这些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的影响。我们计划研究小血管疾病的MRI标记物，阿尔茨海默型病理的PET标记物，脑灌注和轻度损伤受试者的认知之间的关系。我们的结果将通过定义小血管疾病和阿尔茨海默型病理的成像标记物及其对认知能力下降的影响来帮助设计预防痴呆症的临床试验。

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.