High-plex Digital Spatial Profiling Identifies Subregion-Dependent Directed Proteome Changes Across Multiple Variants of Dementia

Frontotemporal lobar degeneration (FTLD) is the leading cause of dementia in patients under the age of 65. Even in a single anatomical region, there is variance within pathological protein deposition as a result of FTLD. This spectrum of pathology leads to difficulty in identification of the disease during its progression and consequential varied post mortem clinicopathological diagnoses. NanoString GeoMx Digital Spatial Profiling (DSP) is a novel method that leverages the ability to spatially multiplex protein biomarkers of interest. We utilized NanoString DSP to investigate the proteome geography at two levels of the cortex and the subcortical white matter in patients with various types of dementia (Alzheimers disease, FTLD-c9ALS, FTLD-17, FTLD-TDP, FTLD-GRN; n=6 per syndrome) and neurologically healthy controls (NHC). Analysis of 75 different protein biomarkers of interest revealed both a disease and cortical subregion specific biomarker profile. Layers II-V of the cortex from diseased individuals displayed the greatest protein dysregulation as compared to NHC. Additionally, out of all disease groups within cortical layer 1, II-V and white matter, the FTLD-17 group had the most significant protein dysregulation as compared to NHC--specifically associated with immune cell pathways. Traditional biomarkers of dementia, such as various phosphorylated tau proteins and amyloid-{beta} 42 displayed dysregulation, however our data suggest spatial enrichment in distinct to cortical sublayers. In conclusion, we observed that depending on the variant of disease, specific protein deposits either span multiple levels of cortical geography or only a single layer. Thus, the specific localization of these deposits could potentially be used to elucidate region-specific pathologic biomarkers unique to individual variants of dementia.