In vivo characterization of metabotropic glutamate receptor type five vulnerability in behavioral variant FTD and Alzheimer's disease: An [11C]ABP688 PET/ VBM /DBM study

Abstract

Introduction: Behavioral variant frontotemporal dementia (bvFTD) and Alzheimer’s disease (AD) are progressive neurodegenerative syndromes characterized by atrophy in frontal, limbic, and temporal brain regions.While glutamatergic projection neurons are highly affected in both diseases, such abnormalities have yet to be systemically characterized, principally due the lack of suitable molecular probes. Using [C]ABP688, a novel Positron Emission Tomography (PET) radiopharmaceutical for in-vivo quantification of mGluR5, and voxel based/deformation based morphometry (VBM/ DBM), we sought to determine the extent of receptor decrements and the overlap between the topography of such declines and atrophy within frontal, limbic, and temporal brain regions. Methods: We analyzed a sample of 5 bvFTD and 8 AD subjects who had [C]ABP688/MRI data collected within a two-week period. Diagnosis of bvFTD and AD were issued on the basis of the FTDC criteria, and the NIA-AA criteria, respectively. PET binding potential maps (BPND) were calculated using the cerebellar cortex as a reference region. PET images were subsequently registered to ICBM152 space nonlinearly. For VBM, T1 MRIs were registered to ICBM152 space nonlinearly, and segmented into gray matter (GM), white matter (GM), and cerebrospinal fluid (CSF). GM maps were then blurred with a 10mm Gaussian kernel. For DBM, the magnitude of each vector of the Jacobian deformation field was computed. Voxel-based group differences were obtained by comparing bvFTD and AD using RMINC.Results:No significant between group differences were found in terms of age, gender, handedness, educational attainment and MMSE (p < 0.05). Relative to AD, bvFTD was associated with greater decrements in mGluR5, with maxima in orbitofrontal cortex, insula, superior temporal gyrus, frontal opercula, and anterior temporal lobe. Structural changes were likewise greater in bvFTD, with maxima in the insula, basal ganglia, and amygdala. Conclusion: Together, these results support the vulnerability of the glutamatergic system in both bvFTD and AD. Minimal topographical overlap between structural and receptor declines suggest mGluR5 decrements are more extensive than brain atrophy. Furthermore, regional differences between bvFTD and AD indicate disease-specific patterns of glutamatergic neurodegeneration.