NEUROPATHOLOGY AND MECHANISMS IN PRECLINICAL AD

阿尔茨海默病(AD)从临床前阶段到轻度认知障碍(MCI)再到痴呆症，经过多年的发展。临床前AD的概念来自于几项纵向研究中进行的严格的临床和病理相关性，包括我们在巴尔的摩老龄化纵向研究(BLSA)上的研究。在神经病理学上，临床前AD通常可以由认知正常的受试者出现实质性的神经炎性斑块和神经原纤维/tau改变来定义。在这个项目中，我们建议进行研究，以实现从结构和生化参数方面对临床前AD进行更严格的定义。具体地说，我们将测量来自BLSA的个体在海马体和内嗅觉皮质(ERG)特定区域的神经元数量和突触标记的变化。 临床队列，包括对照组、临床前AD和MCI。我们还将研究在临床前AD中，Abeta和神经原纤维/tau的变化如何相互作用，并促进海马区和内嗅皮层的神经元和突触变性。具体地说，我们将集中在CA1锥体神经元的树突场，以及第二层ERC神经元通过穿支通路投射到颗粒细胞的分子层。彻底了解AD的临床前阶段和神经退行性变的早期机制是至关重要的，因为这一阶段是AD预防和治疗新策略使用的理想时间窗口。

Alzheimer's disease (AD) progresses over many years from a preclinical stage to mild cognitive impairment (MCI) to dementia. The notion of preclinical AD has emerged from rigorous clinical and pathological correlations conducted in several longitudinal studies, including ours on the Baltimore Longitudinal Study of Aging (BLSA). Neuropathologically, preclinical AD can be generally defined by the presence of substantial neuritic plaques and neurofibrillary/tau changes in subjects with documented normal cognition. In this project, we propose studies to achieve a more rigorous definition of preclinical AD in terms of structural and biochemical parameters. Specifically, we will measure changes in the number of neurons and synaptic markers in specific regions of the hippocampus and entorhinal cortex (ERG) of individuals from the BLSA and Clinic cohorts, including controls, preclinical AD, and MCI. We will also examine how Abeta and neurofibrillary/tau changes interact and contribute to neuronal and synaptic degeneration in the hippocampus and entorhinal cortex in preclinical AD. Specifically, we will focus on the dendritic field of CA1 pyramidal neurons and on the projections of layer II ERC neurons via the perforant pathway onto the molecular layer of granule cells. A thorough understanding of the preclinical stage of AD and the early mechanism of neurodegeneration is critical since this stage represents and ideal temporal window for the use of emerging preventive and therapeutic strategies in AD.