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

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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.