Spatial covariance of mGluR5 density and structural degeneration in behavioral variant frontotemporal degeneration

Post-mortem human brain tissue and in vivo imaging studies of behavioral variant frontotemporal degeneration (bvFTD) suggest that metabotropic glutamate receptors (mGluR) may be vulnerable to the disease process. However, these studies lack evidence demonstrating how loss of mGluR relates to clinical features of bvFTD, hindering efforts to identify appropriate therapeutic strategies. Thus, we leveraged existing normative receptor density maps, and a large cohort of individuals with bvFTD to elucidate relationships among structural degeneration, glutamatergic receptor density, and clinical features. We obtained receptor density maps from the neuromaps repository, which contains positron emission tomography-derived receptor maps across many neurotransmitter systems, including mGluR5 and N-methyl-D-aspartate (NMDA). We quantified the spatial covariance of structural degeneration and glutamate receptor density maps in 106 individuals with bvFTD and 165 cognitively unimpaired (CU) individuals. Covariance of each participant's regional cortical volumes and normative receptor density in each region of the Schaefer 100 (7 network) parcellation was computed. Negative covariance indicates a high spatial correspondence such that regions with greater structural degeneration also have high receptor density. Within bvFTD, we tested whether greater spatial covariance of structural degeneration and receptor density maps were associated with disease stage and severity, executive function, and neuropsychiatric symptoms. Comparing bvFTD with CU, we observed significant spatial covariance of structural degeneration and mGluR5, but not NMDA. In bvFTD, greater covariance of structural degeneration and mGluR5 maps was associated with more advanced disease stage (p = .003) and severity (p < .001), and worse category (p < .001) and letter-guided (p < .001) fluency and digit span backward (p = .0257) but not neuropsychiatric symptom severity. Neurodegeneration in bvFTD appears to preferentially affect cortical regions with higher normative mGluR5 density, as reflected by spatial covariance between structural degeneration and mGluR5 maps in a clinically well-characterized cross-sectional cohort. Furthermore, greater covariance of mGluR5 density and structural degeneration with both disease severity and executive dysfunction elucidates potential neural mechanisms of core clinical features of bvFTD. Future work examining in vivo glutamate could provide further insight into the natural history of glutamate dysfunction in bvFTD, facilitating testing of glutamatergic therapies.