Spatial covariance of glutamatergic receptors and cortical atrophy in frontotemporal degeneration
Poster No:
118
Submission Type:
Abstract Submission
Authors:
Melanie Matyi1, Maggie Pecsok1, Christopher Olm1, Hamsanandini Radhakrishnan1, Jeffrey Phillips1, Philip Cook1, James Gee1, David Irwin1, Corey McMillan1, David Roalf1, Lauren Massimo1
Institutions:
1University of Pennsylvania, Philadelphia, PA
First Author:
Co-Author(s):
Introduction:
The glutamatergic (Glu) system is often dysfunctional in neurodegenerative diseases, including in behavioral variant frontotemporal dementia (bvFTD) (Huber et al., 2022). The proposed mechanism of Glu in neurodegeneration is progressive; an initial increase in Glu results in excitotoxicity and, in turn, cell death and decreased Glu levels (Mark et al., 2001). Indeed, an NMDA receptor antagonist achieves clinical benefit in Alzheimer's Disease but is ineffective for bvFTD (Boxer et al., 2013). However, the timing in which Glu is targeted may be critical for therapeutic benefit (e.g., block receptors early in disease to reduce excitotoxicity vs. stimulate Glu late in disease to restore excitatory neurotransmission). Despite evidence of Glu deficits in bvFTD (Murley & Rowe, 2018), these have not been mapped to disease stage. A greater understanding of Glu dysfunction in the natural history of bvFTD is needed to identify appropriate treatment targets and timing to attenuate symptoms. Therefore, we examined spatial covariance of Glu receptors with brain volume in a large sample of bvFTD patients across disease stages. We hypothesized that bvFTD would exhibit greater correspondence of Glu receptor density and brain volume compared to cognitively normal (CN) participants and greater correspondence between atrophied regions and receptor density with increasing disease severity.
Methods:
Participants were 124 bvFTD and 178 CN with T1w MRI and Clinical Dementia Rating (CDR), reflecting disease stage. T1w data were processed with ANTs (Tustison et al., 2014) and volumes were w-scored with age and MRI protocol using CN data. Negative w-scored volumes reflect atrophied regions. T1w data and the two Glu receptor density maps available in neuromaps (Hansen et al., 2022; Markello et al., 2022) were parcellated with the Schaefer 100x7 atlas (Schaefer et al., 2018). Spatial covariance of brain volume with receptor maps was calculated (Fig. 1a), where negative covariance reflected atrophy-receptor density match. The absolute value of spatial covariance reflected magnitude of covariance (Fig. 1b). ANCOVAs assessed differences in spatial covariance by group and CDR. Analyses covaried for age, sex, MRI protocol and mean brain volume.
Results:
Spatial covariance of brain volume and mGluR5, but not NMDA, receptor density significantly differed by group. bvFTD patients showed more negative (F(1, 296) = 79.45, p < .001; Fig. 2a) and greater magnitude (F(1, 296) = 24.09, p < .001; Fig. 2b) of covariance, indicating that regions with greater atrophy also had a greater density of mGluR5. Within bvFTD patients, more negative (F(3, 116) = 8.38, p < .001; Fig. 2c) and greater magnitude (F(3, 116) = 8.24, p < .001; Fig. 2d) of covariance were related to increasing CDR. That is, as the strength of association between brain volume and mGluR5 density increased, and as the covariance of regions with greater atrophy and mGluR5 density increased, disease severity also increased.
Conclusions:
Results establish the association of a component of the Glu system, mGluR5 density, with bvFTD disease in a novel manner. Interestingly, we identified no effect of NMDA, consistent with the lack of therapeutic benefit in bvFTD of NMDA therapy. We demonstrate preferential atrophy in bvFTD in regions of higher mGluR5 density and illustrate significantly higher patterns of covariance in moderate (CDR=2) compared to mild (CDR=1) dementia, consistent with the hypothesis that the Glu system is vulnerable to neurodegeneration in bvFTD. Thus, results indicate that the timing of Glu-targeted intervention is likely critical, as covariance becomes stronger with disease stage. The study's cross-sectional design limits conclusions on the role of co-localized mGluR5 density and atrophy in contributing to disease progression. Future longitudinal analysis and expansion of the current study to measure mGluR5 or Glu levels in vivo could provide additional insights into the natural history of Glu dysfunction in bvFTD.
Disorders of the Nervous System:
Neurodegenerative/ Late Life (eg. Parkinson’s, Alzheimer’s) 1
Neuroanatomy, Physiology, Metabolism and Neurotransmission:
Cortical Anatomy and Brain Mapping
Transmitter Receptors 2
Transmitter Systems
Novel Imaging Acquisition Methods:
Anatomical MRI
Keywords:
Aging
CHEMOARCHITECTURE
Degenerative Disease
Glutamate
Neurotransmitter
Positron Emission Tomography (PET)
STRUCTURAL MRI
1|2Indicates the priority used for review
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Provide references using APA citation style.
Hansen, J. Y., et al. (2022). Mapping neurotransmitter systems to the structural and functional organization of the human neocortex. Nature Neuroscience, 25(11), 1569–1581.
Huber, N., et al. (2022). Deficient neurotransmitter systems and synaptic function in frontotemporal lobar degeneration—Insights into disease mechanisms and current therapeutic approaches. Molecular Psychiatry, 27(3), 1300–1309.
Mark, L. P., et al. (2001). Pictorial Review of Glutamate Excitotoxicity: Fundamental Concepts for Neuroimaging. AJNR: American Journal of Neuroradiology, 22(10), 1813–1824.
Markello, R. D., et al. (2022). neuromaps: Structural and functional interpretation of brain maps. Nature Methods, 19(11), 1472–1479.
Schaefer, A., et al. (2018). Local-Global Parcellation of the Human Cerebral Cortex from Intrinsic Functional Connectivity MRI. Cerebral Cortex, 28(9), 3095–3114.
Tustison, N. J., et al. (2014). Large-scale evaluation of ANTs and FreeSurfer cortical thickness measurements. NeuroImage, 99, 166–179.