Selective vulnerability in Alzheimer’s disease and frontotemporal degeneration: integration of postmortem MRI, mass-spectrometry and histopathology

Understanding selective vulnerability is one of the most fundamental challenges in the field of neurodegenerative disease. While structural MRI is widely used in clinical diagnostic settings, it lacks more fine-grained information on the nature of the observed atrophy. The current proposal aims for a multidisciplinary integration of postmortem MRI with in-depth protein and cellular analyses using histopathology and mass-spectrometry. The unique combination of these modalities allows a bidirectional approach. First, we will link cellular and molecular protein signatures to atrophy patterns informing on selectively vulnerable (i) brain regions as well as (ii) brain networks. Second, postmortem MRI will be of substantial value to put the observed histopathological and mass-spectrometric regional findings in a broader, whole-brain network context. Third, recent methods for MRI-based disease staging allows us to situate an individual’s brain and the different brain regions on a disease continuum that will enable us to define the type of neuropathological and mass-spectrometric changes occurring in a given disease stage. The three modalities (postmortem MRI, histopathology and mass-spectrometry) will be applied in two neurodegenerative diseases: Alzheimer’s disease (preclinical and symptomatic), and patients with frontotemporal lobar degeneration (FTLD, behavioral variant and primary progressive aphasia), and will be compared to cognitively intact controls.