Selective age-related vulnerability in human perirhinal and lateral entorhinal cortices

描述(申请人提供)：间歇性记忆丧失是衰老的标志之一，也是痴呆症的重要危险因素。鉴于老龄化人口的迅速增加和阿尔茨海默病(AD)发病率的增加，了解与年龄相关的记忆衰退的神经基础是至关重要的。众所周知，记忆的形成在很大程度上依赖于内侧颞叶(MTL)内的大脑区域。先前的衰老研究集中在海马区与年龄相关的变化，但海马区外MTL皮质的变化引起的关注较少。这些皮质似乎在功能上是分开的，因此，周围皮质(PRC)主要由对物品或物体的记忆参与，而海马旁皮质(PHC)则由对空间配置或背景的记忆参与。动物研究进一步证明，这种分工延伸到内嗅觉皮质(EC)，外侧部分(LEC)支持物体记忆，内侧部分(MEC)支持空间记忆。我们设计了一项耗费物体和空间记忆的辨别任务，并使用高分辨率功能磁共振不仅复制了PRC和PHC之间的分离，而且关键地展示了人类LEC和MEC之间类似的对象/空间分离的关键证据。与这些进展相关的是，最近的神经认知老化的啮齿动物模型已经发现了PRC/LEC通路中与认知衰退相关的病理的选择性脆弱性。LEC/PRC(经鼻)区也是第一个在AD小鼠模型中沉积纠缠病理的区域，从AD患者的死后组织(即Braak I期)也可以明显看出这一点。基于我们在功能上分离人类PRC/LEC和PHC/MEC网络的高度创新的方法，我们提出了一系列新颖的实验来表征老年人PRC和LEC中最早的行为缺陷和功能异常。此外，我们打算探讨海马齿状回(DG)/CA3和上游PRC/LEC之间结构连接的特定破坏，这些结构连接通过外侧穿支路径投射到DG/CA3。我们以前曾报道过使用尖端超高分辨率扩散成像的老年人穿透路径退化。在这里，我们将使用新的技术将穿通径分为内侧部分和外侧部分，并将检验这种退化在外侧部分更严重的假设。拟议的项目建立在我们实验室过去五年的工作基础上，该实验室成功地将数十年的动物和计算模型转化为人类衰老条件。我们使用多模式高分辨率MRI技术识别了与年龄相关的记忆丧失相关的DG/CA3的异常情况。我们的建议在方法和假设方面都朝着创新的方向扩展了这项工作。该项目有望显著提高我们对衰老过程中记忆缺陷的神经生物学基础的理解，并可能为治疗和干预提供高度选择性的神经靶点。

DESCRIPTION (provided by applicant): Episodic memory loss is one of the hallmarks of aging and is an important risk factor for dementia. Given the rapid rise in the aging population and the increased prevalence of Alzheimer's disease (AD), understanding the neural basis of age-related memory decline is of the utmost importance. The formation of memories is known to depend critically on brain regions within the medial temporal lobes (MTL). Prior aging research has focused on age-related changes in the hippocampus, but changes in extrahippocampal MTL cortices have garnered less attention. These cortices appear to be functionally segregated such that the perirhinal cortex (PRC) is primarily engaged by memory for items or objects, whereas the parahippocampal cortex (PHC) is engaged by memory for spatial configurations or contexts. Animal studies have further demonstrated that that this division of labor extends into the entorhinal cortex (EC), with the lateral portion (LEC) supporting object memory and the medial portion (MEC) supporting spatial memory. We designed a discrimination task taxing both object and spatial memory and used high-resolution functional MRI to not only replicate the dissociation between PRC and PHC, but also critically demonstrated key evidence of a similar object/spatial dissociation between LEC and MEC in humans. Related to these advancements, recent rodent models of neurocognitive aging have identified a selective vulnerability in the PRC/LEC pathway to pathology associated with cognitive decline. The LEC/PRC (transentorhinal) region is also the first to deposit tangle pathology in AD mouse models, which is also clear from postmortem tissue from AD patients (i.e. Braak Stage I). Building on our highly innovative approach to functionally segregate the human PRC/LEC and PHC/MEC networks, we propose a novel series of experiments to characterize the earliest behavioral deficits and functional aberrations in the PRC and LEC in older adults. Furthermore, we intend to probe for specific disruptions in structural connectivity between the hippocampal dentate (DG)/CA3 and upstream PRC/LEC, which project to the DG/CA3 via the lateral perforant path. We have previously reported perforant path degradation in older adults using cutting-edge ultrahigh- resolution diffusion imaging. Here, we will use novel techniques to segment the perforant path into medial and lateral portions and will test the hypothesis that this degradation is more severe in the lateral portion. The proposed project builds on the last five years of work from our lab, which successfully translates decades of animal and computational models to the human aging condition. We have identified aberrant conditions in the DG/CA3 associated with age-related memory loss using multimodal high-resolution MRI techniques. Our proposal here extends this work in an innovative direction both in terms of approach and hypothesis. This project is expected to significantly improve our understanding of the neurobiological bases of memory deficits in aging, and may yield highly selective neural targets for treatments and interventions.