Characterizing TDP-43 related hippocampal degeneration and memory loss in aging

项目摘要/摘要 TDP已成为与阿尔茨海默病临床相关的一种重要和常见的年龄相关病理 综合症。TDP病理在大量的老年人大脑中被发现，并且与 间歇性记忆障碍。TDP病理表现为“正常衰老”，伴随和不伴随。 阿尔茨海默病(AD)的病理，并作为主要组成部分的海马硬化(HS)。临床部 与TDP病理相关的综合征模拟并恶化了阿尔茨海默氏症的临床综合征。TDP(带 而没有HS)的病理通常发生在AD的混合病理中，并降低了 痴呆症(降低韧性)。在没有AD病理诊断的情况下，也会发生TDP，其中 分别与记忆力丧失和模拟AD的痴呆症相关。新出现的数据表明，TDP 病理学对公共卫生有很大的影响。然而，我们对TDP和TDP的了解仍然存在许多空白 相关的神经退行性变和认知障碍。要推进这一领域，需要更好地定义TDP 衰老综合征的病理学与目前可用的工具。海马体在大多数与年龄相关的疾病中都是脆弱的 痴呆，但对TDP病理在海马区变性和痴呆中的具体作用知之甚少。 随着年龄的增长，记忆力丧失。这项建议的目标是阐明形态和神经行为。 TDP病理表型。假设TDP具有独特的海马区退行性变特征。 以及相关的认知和行为缺陷，这些缺陷可以与AD和血管病理分开。我们 充分利用老年人的丰富资源，充分利用老年人的特点和纵向跟踪 没有痴呆症的社区居住受试者的随访率和尸检率都很高。第一个目标是 我们对大脑进行研究，以研究TDP病理与神经元、星形胶质细胞和小胶质细胞的关系。 在海马区的多个区域的密度；并执行更广泛的搜索HS是片状的和低于- 被认可了。在第二个目标中，我们使用体外MRI成像来将海马的大小和形状与TDP联系起来 控制阿尔茨海默病和血管病变。在第三个目标中，我们创建了一个海马体形状/大小成像 对TDP进行评分，并将该评分从体外转换为体内，并从病理上验证这些患者的标志物 通过体内扫描死亡并进行尸检。在第四个目标中，我们研究了早期神经行为和 TDP病理的认知特点。最后，在目标5a中，我们研究了TDP被 使用关于神经元、神经胶质细胞和HS的新数据，与记忆力下降有关。在5b中，我们调查了 体内TDP成像评分与记忆力下降和阿尔茨海默氏型痴呆的发生有关。这些 TDP在衰老中的病理研究将推动该领域的发展，并具有很大的潜力加强和我们的 阿尔茨海默型临床综合征谱系中TDP的认识与诊断

PROJECT SUMMARY/ABSTRACT TDP has emerged as an important and common age-related pathology related to the Alzheimer’s clinical syndrome. TDP pathology is found in large number of older brains and is strongly and independently related to episodic memory impairment. TDP pathology occurs in “normal aging,” with and without concomitant Alzheimer’s disease (AD) pathology, and as a primary component hippocampal sclerosis (HS). The clinical syndrome associated with TDP pathology mimics and worsens the Alzheimer’s clinical syndrome. TDP (with and without HS) pathology commonly occurs with AD as mixed pathology and lowers the threshold for dementia (lowers resilience). TDP also occurs in the absence of a pathologic diagnosis of AD and therein is separately associated with memory loss and a dementia that mimics AD. Emerging data suggest that TDP pathology has a large public health impact. Yet, there remain many gaps in our knowledge regarding TDP and related neurodegeneration and cognitive impairment. To advance the field requires better defining the TDP pathology of aging syndrome with currently available tools. The hippocampus is vulnerable in most age-related dementias, but little is known about the specific role for TDP pathology in hippocampal degeneration and memory loss in aging. The goal of this proposal is to elucidate the morphologic and neurobehavioral phenotype of TDP pathology. The hypothesis is that TDP has a unique profile of hippocampal degeneration and associated cognitive and behavioral deficits that can be separated from AD and vascular pathologies. We capitalize on a rich large resource of older persons from well characterized and longitudinally followed older community dwelling subjects enrolled without dementia with high follow-up and autopsy rates. In the first aim we investigate brains to study the association of TDP pathology with neurons, astrocyte and microglial densities in multiple regions of hippocampus; and perform a broader search for HS which is patchy and under- recognized. In the second aim we use ex-vivo MRI imaging to link hippocampal size and shape to TDP after controlling for AD and vascular pathologies. In the third aim we create a hippocampal shape/size imaging score for TDP and translate this score from ex-vivo to in-vivo and pathologically validate the marker in those with in-vivo scans that die and come to autopsy. In the fourth aim we investigate the early neurobehavioral and cognitive characteristics of TDP pathology. Finally, in aim 5a we investigate the mechanism by which TDP is associated with memory decline using the new data on neurons, glia, and HS. In 5b we investigate whether the in-vivo TDP imaging score is associated with memory decline and incident Alzheimer’s type dementia. These studies on TDP pathology in aging will advance the field and have a strong potential to enhance and our understanding and the diagnosis of TDP in the spectrum of Alzheimer’s type clinical syndrome.