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Abstract
Objective: We sought to determine whether the Val158Met polymorphism in the catechol-O-methyltransferase (COMT) gene influences neurodegeneration within dopamine-innervated brain regions.
Methods: A total of 252 subjects, including healthy controls and patients with Alzheimer disease, behavioral variant frontotemporal dementia, and semantic dementia, underwent COMT genotyping and structural MRI.
Results: Whole-brain voxel-wise regression analyses revealed that COMT Val158Met Val allele dosage, known to produce a dose-dependent decrease in synaptic dopamine (DA) availability, correlated with decreased gray matter in the region of the ventral tegmental area (VTA), ventromedial prefrontal cortex, bilateral dorsal midinsula, left dorsolateral prefrontal cortex, and right ventral striatum. Unexpectedly, patients carrying a Met allele showed greater VTA volumes than age-matched controls. Gray matter intensities within COMT-related brain regions correlated with cognitive and behavioral deficits.
Conclusions: The results are consistent with the hypothesis that increased synaptic DA catabolism promotes neurodegeneration within DA-innervated brain regions.
GLOSSARY
- ABI=
- Applied Biosystems Inc.;
- AD=
- Alzheimer disease;
- bvFTD=
- behavioral variant frontotemporal dementia;
- CDR=
- Clinical Dementia Rating;
- COMT=
- catechol-O-methyltransferase;
- DA=
- dopamine;
- dlPFC=
- dorsolateral prefrontal cortex;
- dMI/FO=
- dorsal midinsula/frontal operculum;
- MAC=
- Memory and Aging Center;
- MPRAGE=
- magnetization-prepared rapid gradient echo;
- SemD=
- semantic dementia;
- TIV=
- total intracranial volume;
- UCSF=
- University of California, San Francisco;
- VBM=
- voxel-based morphometry;
- vmPFC=
- ventromedial prefrontal cortex;
- VStr=
- ventral striatum;
- VTA=
- ventral tegmental area
Footnotes
Study funding: Supported by grants from the National Institute of Aging (AG19724 and AG1657303 to B.L.M.), the Larry L. Hillblom Foundation (grant 2005/2T to W.W.S.), National Institute of Mental Health (NIMH grant K08 MH065938 to S.J.B.), and the Stephen D. Bechtel Foundation to S.J.B.
Supplemental data at www.neurology.org
- Received October 16, 2011.
- Accepted January 23, 2012.
- Copyright © 2012 by AAN Enterprises, Inc.
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