NEUROPATHOLOGY AND MECHANISMS IN PRECLINICAL AD

阿尔茨海默病（AD）从临床前阶段发展到轻度认知障碍（MCI）再到痴呆，需要多年的时间。临床前阿尔茨海默病的概念是在几项纵向研究中进行的严格的临床和病理相关性中出现的，包括我们在巴尔的摩衰老纵向研究（BLSA）上的研究。神经病理学上，临床前阿尔茨海默病通常可以通过在记录正常认知的受试者中存在大量神经斑块和神经原纤维/tau蛋白改变来定义。在本项目中，我们提出了从结构和生化参数方面对临床前AD进行更严格定义的研究。具体来说，我们将测量来自BLSA个体的海马和内嗅皮层（ERG）特定区域的神经元数量和突触标记物的变化

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.