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Association between dopamine D4 receptor polymorphism and age related changes in brain glucose metabolism.

ABSTRACT: Aging is associated with reductions in brain glucose metabolism in some cortical and subcortical regions, but the rate of decrease varies significantly between individuals, likely reflecting genetic and environmental factors and their interactions. Here we test the hypothesis that the variant of the dopamine receptor D4 (DRD4) gene (VNTR in exon 3), which has been associated with novelty seeking and sensitivity to environmental stimuli (negative and positive) including the beneficial effects of physical activity on longevity, influence the effects of aging on the human brain. We used positron emission tomography (PET) and [(18)F]fluoro-D-glucose ((18)FDG) to measure brain glucose metabolism (marker of brain function) under baseline conditions (no stimulation) in 82 healthy individuals (age range 22-55 years). We determined their DRD4 genotype and found an interaction with age: individuals who did not carry the 7-repeat allele (7R-, n?=?53) had a significant (p<0.0001) negative association between age and relative glucose metabolism (normalized to whole brain glucose metabolism) in frontal (r?=?-0.52), temporal (r?=?-0.51) and striatal regions (r?=?-0.47, p<0.001); such that older individuals had lower metabolism than younger ones. In contrast, for carriers of the 7R allele (7R+ n?=?29), these correlations with age were not significant and they only showed a positive association with cerebellar glucose metabolism (r?=?+0.55; p?=?0.002). Regression slopes of regional brain glucose metabolism with age differed significantly between the 7R+ and 7R- groups in cerebellum, inferior temporal cortex and striatum. These results provide evidence that the DRD4 genotype might modulate the associations between regional brain glucose metabolism and age and that the carriers of the 7R allele appear to be less sensitive to the effects of age on brain glucose metabolism.

SUBMITTER: Volkow ND

PROVIDER: S-EPMC3661541 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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Association between dopamine D4 receptor polymorphism and age related changes in brain glucose metabolism.

Volkow Nora D ND Tomasi Dardo D Wang Gene-Jack GJ Telang Frank F Fowler Joanna S JS Goldstein Rita Z RZ Klein Nelly N Wong Christopher C Swanson James M JM Shumay Elena E

PloS one 20130522 5

Aging is associated with reductions in brain glucose metabolism in some cortical and subcortical regions, but the rate of decrease varies significantly between individuals, likely reflecting genetic and environmental factors and their interactions. Here we test the hypothesis that the variant of the dopamine receptor D4 (DRD4) gene (VNTR in exon 3), which has been associated with novelty seeking and sensitivity to environmental stimuli (negative and positive) including the beneficial effects of ...[more]

PMID: 23717434

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Project description:α-Synuclein aggregation has been linked to Gaucher's disease (GD) and Krabbe's disease (KD), lysosomal conditions affecting glycosphingolipid metabolism. α-Synuclein pathology has been directly attributed to the dysregulation of glycosphingolipids in both conditions, specifically to increased galactosylsphingosine (psychosine) content in the context of KD. Furthermore, the gene (GALC) coding for the psychosine degrading enzyme galactosylceramidase (GALC), has recently been identified as a risk loci for Parkinson's disease. However, it is unknown if changes in psychosine metabolism and GALC activity in the context of the aging human brain correlate with Parkinson's disease. We investigated psychosine accumulation and GALC activity in the aging brain using fresh frozen post-mortem tissue from Parkinson's (PD, n = 10), Alzheimer's (AD, n = 10), and healthy control patients (n = 9), along with tissue from neuropsychiatric patients (schizophrenia, bipolar disorder and depression, n = 15 each). An expanded mutational analysis of PD (n = 20), AD (n = 10), and healthy controls (n = 30) examined if PD was correlated with carriers for severe GALC mutations. Psychosine content within the cerebral cortex of PD patients was elevated above control patients. Within all patients, psychosine displayed a significant (p<0.05) and robust regional distribution in the brain with higher levels in the white matter and substantia nigra. A mutational analysis revealed an increase in the incidence of severe GALC mutations within the PD patient population compared to the cohorts of Alzheimer's patients and healthy controls tested. In addition to α-synuclein pathology identified in the KD brain, control patients identified as GALC mutational carriers or possessing a GALC pathogenic variant had evidence of α-synuclein pathology, indicating a possible correlation between α-synuclein pathology and dysregulation of psychosine metabolism in the adult brain. Carrier status for GALC mutations and prolonged exposure to increased psychosine could contribute to α-synuclein pathology, supporting psychosine metabolism by galactosylceramidase as a risk factor for Parkinson's disease.

Dataset Information

Association between dopamine D4 receptor polymorphism and age related changes in brain glucose metabolism.

Publications

Association between dopamine D4 receptor polymorphism and age related changes in brain glucose metabolism.

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