title: Cerebral hypometabolism and grey matter density in MAPT intron 10 +3 mutation carriers.
abstract: Multiple systems tauopathy with presenile dementia (MSTD), a form of frontotemporal dementia with parkinsonism-17 with tau inclusions (FTDP-17T), is a neurodegenerative disorder caused by an (a) to (g) transition at position +3 of intron 10 of the microtubule associated protein tau (MAPT) gene. The mutation causes overexpression of 4 repeat (4R) tau isoforms with increased 4R/3R ratio leading to neurodegeneration. Clinically, these patients primarily present with behavioral variant FTD (bvFTD) and show disinhibition, disordered social comportment, and impaired executive function, memory, and speech. While altered glucose metabolism has been reported in subjects with sporadic bvFTD, it has yet to be investigated in an FTDP-17 sample of this size. In this study, eleven mutation carriers (5 males; mean age = 48.0 ± 6.9 years) and eight non-carriers (2 males; mean age = 43.7 ± 12.0 years) from a MSTD family were imaged using [(18)F]fluorodeoxyglucose (FDG) positron emission tomography (PET). Eight of the MAPT intron 10 +3 mutation carriers met diagnostic criteria for bvFTD at the time of the PET scan, while three MAPT intron 10 +3 carriers were not cognitively impaired at the time of scan. Non-carriers had no clinically-relevant cognitive impairment at the time of the PET scan. Additionally, ten mutation carriers (5 males; mean age = 48.04 ± 2.1 years) and seven non-carriers (2 males; mean age 46.1 ± 4.1 years) underwent magnetic resonance imaging (MRI) which is an expanded sample size from a previous study. Seven MAPT mutation carriers met diagnostic criteria for bvFTD at the time of the MRI scan. Images were assessed on a voxel-wise basis for the effect of mutation carrier status. SPM8 was used for preprocessing and statistical analyses. Compared to non-carriers, MAPT mutation carriers showed lower [(18)F]FDG uptake bilaterally in the medial temporal lobe, and the parietal and frontal cortices. Anatomical changes were predominantly seen bilaterally in the medial temporal lobe areas which substantially overlapped with the hypometabolism findings. These anatomical and metabolic changes overlap previously described patterns of neurodegeneration in MSTD patients and are consistent with the characteristics of their cognitive dysfunction. These results suggest that neuroimaging can describe the neuropathology associated with this MAPT mutation.
authors: Center for Neuroimaging, Department of Radiology and Imaging Sciences, Indiana University School of Medicine Indianapolis, IN, USA ; Indiana Alzheimer Disease Center, Indiana University School of Medicine Indianapolis, IN, USA ; Program in Medical Neuroscience, Paul and Carole Stark Neurosciences Research Institute, Indiana University School of Medicine Indianapolis, IN, USA.
authors: Kacie D
authors: KD
authors: Deters
authors: Center for Neuroimaging, Department of Radiology and Imaging Sciences, Indiana University School of Medicine Indianapolis, IN, USA ; Indiana Alzheimer Disease Center, Indiana University School of Medicine Indianapolis, IN, USA.
authors: Shannon L
authors: SL
authors: Risacher
authors: Indiana Alzheimer Disease Center, Indiana University School of Medicine Indianapolis, IN, USA ; Department of Neurology, Indiana University School of Medicine Indianapolis, IN, USA.
authors: Martin R
authors: MR
authors: Farlow
authors: Indiana Alzheimer Disease Center, Indiana University School of Medicine Indianapolis, IN, USA ; Department of Psychiatry, Indiana University School of Medicine Indianapolis, IN, USA.
authors: Frederick W
authors: FW
authors: Unverzagt
authors: Center for Neuroimaging, Department of Radiology and Imaging Sciences, Indiana University School of Medicine Indianapolis, IN, USA ; Indiana Alzheimer Disease Center, Indiana University School of Medicine Indianapolis, IN, USA ; Program in Medical Neuroscience, Paul and Carole Stark Neurosciences Research Institute, Indiana University School of Medicine Indianapolis, IN, USA ; Department of Neurology, Indiana University School of Medicine Indianapolis, IN, USA.
authors: David A
authors: DA
authors: Kareken
authors: Center for Neuroimaging, Department of Radiology and Imaging Sciences, Indiana University School of Medicine Indianapolis, IN, USA ; Indiana Alzheimer Disease Center, Indiana University School of Medicine Indianapolis, IN, USA.
authors: Gary D
authors: GD
authors: Hutchins
authors: Center for Neuroimaging, Department of Radiology and Imaging Sciences, Indiana University School of Medicine Indianapolis, IN, USA ; Indiana Alzheimer Disease Center, Indiana University School of Medicine Indianapolis, IN, USA.
authors: Karmen K
authors: KK
authors: Yoder
authors: Indiana Alzheimer Disease Center, Indiana University School of Medicine Indianapolis, IN, USA ; Department of Pathology and Laboratory Medicine, Indiana University School of Medicine Indianapolis, IN, USA.
authors: Jill R
authors: JR
authors: Murrell
authors: Indiana Alzheimer Disease Center, Indiana University School of Medicine Indianapolis, IN, USA ; Department of Pathology and Laboratory Medicine, Indiana University School of Medicine Indianapolis, IN, USA.
authors: Salvatore
authors: S
authors: Spina
authors: Indiana Alzheimer Disease Center, Indiana University School of Medicine Indianapolis, IN, USA ; Department of Pathology and Laboratory Medicine, Indiana University School of Medicine Indianapolis, IN, USA.
authors: Francine
authors: F
authors: Epperson
authors: Indiana Alzheimer Disease Center, Indiana University School of Medicine Indianapolis, IN, USA ; Department of Biostatistics, Indiana University School of Medicine Indianapolis, IN, USA.
authors: Sujuan
authors: S
authors: Gao
authors: Center for Neuroimaging, Department of Radiology and Imaging Sciences, Indiana University School of Medicine Indianapolis, IN, USA ; Indiana Alzheimer Disease Center, Indiana University School of Medicine Indianapolis, IN, USA ; Department of Neurology, Indiana University School of Medicine Indianapolis, IN, USA ; Department of Psychiatry, Indiana University School of Medicine Indianapolis, IN, USA.
authors: Andrew J
authors: AJ
authors: Saykin
authors: Indiana Alzheimer Disease Center, Indiana University School of Medicine Indianapolis, IN, USA ; Department of Pathology and Laboratory Medicine, Indiana University School of Medicine Indianapolis, IN, USA.
authors: Bernardino
authors: B
authors: Ghetti
keywords: Multiple system tauopathy with presenile dementia (MSTD); [18F]fluorodeoxyglucose positron emission tomography ([18F]FDG PET); behavioral variant frontotemporal dementia; frontotemporal dementia with parkinsonism-17 with tau inclusions (FTDP-17T); magentic resonance imaging (MRI); microtubule associated protein tau (MAPT); neuroimaging
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