Catechol-O-methyltransferase valine(158)methionine polymorphism modulates brain networks underlying working memory across adulthood.
BACKGROUND
Cognitive abilities decline with age with large individual variability. Genetic variations have been suggested to be an important source for some of this heterogeneity. Among these variations, those related to the dopaminergic system, particularly the valine(158)methionine polymorphism in catechol-O-methyltransferase (COMTval(158)met), have been implicated in modulating age-related changes in executive function.


METHODS
We studied 75 subjects (age 21-90 years) using functional neuroimaging while they performed a low-level working memory (WM) task to explore the effects of aging, of the COMTval(158)met polymorphism, and their interactions on the physiological patterns of interconnected cortical activity engaged by WM.


RESULTS
Our results show that val homozygotes and older subjects showed increased activity in dorsolateral prefrontal cortex (DLPFC) and decreased activity in ventrolateral prefrontal cortex (VLPFC) relative to met homozygotes and younger subjects, respectively. Interestingly, there were also independent effects of the COMTval(158)met polymorphism and age on the strength of connectivity between brain regions within the left prefrontal-parietal network; val homozygotes and older subjects showed greater connectivity between the DLPFC and other brain regions within the network and met homozygotes showed greater connectivity between the VLPFC and other brain regions within the network. Furthermore, the greater functional connectivity strength of DLPFC in val homozygotes relative to met homozygotes was much more pronounced in older adults


CONCLUSIONS
Our findings suggest that the COMTval(158)met polymorphism modulates both the activity and functional connectivity of brain regions within WM networks and most importantly that this effect is exaggerated with increasing age, contributing to the variability in age-related decline in executive cognition.
Sambataro
Fabio
F
Genes, Cognition, and Psychosis Program, Clinical Brain Disorders Branch, National Institute of Mental Health Intramural Research Program, National Institutes of Health, Bethesda, Maryland 20892, USA.
Reed
Jeff D
JD
Murty
Vishnu P
VP
Das
Saumitra
S
Tan
Hao Yang
HY
Callicott
Joseph H
JH
Weinberger
Daniel R
DR
Mattay
Venkata S
VS
D000328:Adult; D000367:Age Factors; D000368:Aged; D000369:Aged, 80 and over; D001921:Brain / Q000033:anatomy & histology / Q000098:blood supply / Q000502:physiology*; D001931:Brain Mapping; D002394:Catechol O-Methyltransferase / Q000235:genetics*; D005260:Female; D006801:Humans; D007091:Image Processing, Computer-Assisted / Q000379:methods; D016014:Linear Models; D008279:Magnetic Resonance Imaging; D008297:Male; D008570:Memory, Short-Term / Q000502:physiology*; D008715:Methionine / Q000235:genetics*; D008875:Middle Aged; D009434:Neural Pathways / Q000033:anatomy & histology / Q000098:blood supply / Q000502:physiology; D009483:Neuropsychological Tests; D010100:Oxygen / Q000097:blood; D011110:Polymorphism, Genetic / Q000235:genetics*; D025341:Principal Component Analysis; D011930:Reaction Time / Q000235:genetics; D013997:Time Factors; D014633:Valine / Q000235:genetics*; D055815:Young Adult
D008715:Methionine; D002394:Catechol O-Methyltransferase; D014633:Valine; D010100:Oxygen