Tackling Memory Deficits in Neurodegenerative Dementias using 7T-fMRI Investigations of Hippocampal Subfield Connectivity

神经退行性痴呆（NDs），包括阿尔茨海默氏痴呆（AD）和额颞叶痴呆（FTD）是一种进行性致命疾病，在欧洲影响着1000多万人。记忆障碍是NDs的早期标志，是一个重大负担。自传体记忆（AM）的缺陷对个人和他们的家庭来说尤其具有毁灭性，因为患者失去了回忆过去时刻的能力。尽管它对日常生活有巨大的影响，但记忆诊所并没有对AM缺陷进行标准评估，而且在理解相关的神经机制方面存在空白。辅助AM的神经网络以海马体为中心，与包括腹内侧前额叶皮层（vmPFC）和后皮层在内的全脑网络一起。所有这些地区在非传染性疾病中受到不同程度的影响。特别是，阿尔茨海默病的海马受到影响，FTD的行为变异（bvFTD）的vmPFC受到影响，后皮质萎缩（PCA）的后皮质受到影响。尽管在所有这些NDs中都描述了一般的记忆缺陷，但还没有系统的研究表明AM缺陷与特定疾病的神经病理学模式有关。我们知道海马体是AM的核心参与者，是一个异质性的大脑结构，包括几个解剖学上不同的子区，它们对AM的贡献不同。此外，海马亚区在早期AD中受到不同的影响，并且可能在bvFTD和PCA中受到影响。然而，没有数据表明AM期间海马子区激活或连通性在nd中是如何受到不同影响的。功能磁共振成像（fMRI）允许全脑网络的调查。然而，标准全脑3特斯拉fMRI的分辨率被限制在大约。3毫米。这种相对较低的空间分辨率严重限制了神经网络分析。相比之下，最新的7T-fMRI技术可以对整个大脑进行亚毫米级分辨率的扫描。这种高分辨率允许研究新皮层和小亚结构（如海马亚区）之间的网络相互作用。因此，本文提出的具体研究目标是：1。利用7特斯拉功能磁共振成像（Tesla fMRI）研究几种神经解剖学上不同的NDs中AM损伤的神经网络功能障碍；将网络功能障碍的神经解剖学模式与这些疾病中所见的特定神经认知缺陷联系起来。提出的研究有助于深入剖析关键记忆结构的功能角色。在这样做的过程中，这项工作允许AM网络机制的可测试的新理论模型，有可能改变我们对人类记忆的神经元基础的理解。此外，这项工作将有助于表征几种NDs的AM缺陷和网络功能障碍，从而在早期鉴别诊断和疾病进展评估中实现有希望的临床相关结果。

Neurodegenerative Dementias (NDs), including Alzheimer’s Dementia (AD) and Frontotemporal Dementia (FTD) are progressive, lethal diseases affecting more than 10 million people in Europe. Memory impairment, an early hallmark of NDs, represents a major burden. Especially devastating to individuals and their families are deficits in autobiographical memory (AM), by which patients lose the ability to recall moments from the past. Despite its huge impact on daily life, AM deficits are not being standardly assessed in memory clinics, and there is a gap in understanding the neural mechanisms involved. The neural network subserving AM is centered on the hippocampus, alongside a brain-wide network including the ventromedial prefrontal cortex (vmPFC) and the posterior neocortex. All of these regions are differentially affected in NDs. In particular, the hippocampus is affected in AD, the vmPFC in the behavioural variant of FTD (bvFTD), and the posterior neocortex in posterior cortical atrophy (PCA). Whereas general mnemonic deficits have been described in all of these NDs, there has been no systematic investigation of AM deficits in relation to disease-specific patterns of neuropathology. We know that the hippocampus, a central player in AM, is a heterogeneous brain structure comprising several anatomically distinct subfields which contribute differently to AM. Furthermore, hippocampal subfields are differentially affected in early AD, and likely in bvFTD and PCA. Nonetheless, there are no data on how hippocampal subfield activation or connectivity during AM are differently affected in NDs.Functional magnetic resonance imaging (fMRI) allows the investigation of whole-brain networks. However, the resolution of standard whole-brain 3 Tesla fMRI is limited to approx. 3 mm. This relatively low spatial resolution places severe limitations on neural network analysis. By comparison, recent advances in 7T-fMRI allow submillimeter resolution across the whole brain. This high resolution allows investigation of network interactions between neocortex and small substructures such as hippocampal subfields. Thus, the specific goals of the proposed research are: 1. To exploit 7 Tesla fMRI to investigate neuronal network dysfunction underlying AM impairment in several neuroanatomically distinct NDs;2. To relate the neuroanatomical patterns of network dysfunction to the specific neurocognitive deficits seen in these disorders.The proposed research facilitates an in-depth dissection of the functional roles of crucial memory structures. In doing so, this work permits testable new theoretical models of AM network mechanisms, potentially transforming our understanding of the neuronal underpinnings of human memory. In addition, this work will aid in the characterization of AM deficits and network dysfunction in several NDs enabling promising clinically-relevant outcomes valuable in early differential diagnosis, and assessment of disease progression.