Assessing Diffusion MRI Metrics for Detecting Changes of Synaptic Density in Alzheimer's Disease

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Project Abstract Synaptic structure and function are the keys to several neurodegenerative disorders, including Alzheimer’s disease (AD). Specifically, dysfunctional synapses and dysregulated synaptic plasticity in the hippocampus are responsible for early memory and cognitive decline in AD. Invasive tools, such as electrophysiological or immunohistochemical techniques, have been for decades to study synaptic morphology and density in animal models or human postmortem brain samples. Nevertheless, it has been challenging to study synaptic structure in living humans. The goals of the proposed research are: (1) to characterize the ability of in vivo diffusion MRI techniques to detect alterations of axodendritic synapse density in a mouse model of Alzheimer’s disease and (2) to assess the translational utility of such diffusion metrics for future in vivo human brain studies. A recent milestone in radiopharmaceutical development enables the possibility of studying synaptic vesicle glycoprotein 2A (SV2A) in vivo via PET imaging. PET imaging with the 11C-UCB-J tracer has shown a reduction of SV2A binding in mild cognitive impairment and AD patients. Despite its molecular accuracy, PET imaging suffers from disadvantages including high cost, low spatial resolution, and ionizing radiation exposure. On the other hand, MRI is a safe, non-invasive, and non-irradiating imaging technique that provides at least a 5-fold better spatial resolution. The modern advancement in diffusion MRI provides metrics that reflect neurite density (i.e., axons and dendrites) via compartment modeling of intracellular volume fraction. Using in vivo diffusion compartment-modeling imaging on the human brain, our laboratory demonstrated a significant decrease in intra-neurite volume fraction in white-matter areas consequent to mild traumatic brain injury, normal aging, and mild cognitive decline. We have also demonstrated decreased intra-neurite volume fraction in the human hippocampal subfields associated with poor performance in cognitive and verbal learning assessments across the clinical AD continuum. Cumulatively, our and others’ results in human studies suggest these advanced diffusion metrics are sensitive to brain degenerations and associated with cognitive and memory declines, which are thought to be caused by dysfunctional and dysregulated synapses. Nevertheless, there has not been direct evidence nor detailed characterization connecting these advanced diffusion metrics and synaptic density. The proposed research aims to address this knowledge gap.