TY - JOUR
T1 - Catechol-O-Methyltransferase Valine158Methionine Polymorphism Modulates Brain Networks Underlying Working Memory Across Adulthood
AU - Sambataro, Fabio
AU - Reed, Jeff D.
AU - Murty, Vishnu P.
AU - Das, Saumitra
AU - Tan, Hao Yang
AU - Callicott, Joseph H.
AU - Weinberger, Daniel R.
AU - Mattay, Venkata S.
N1 - Funding Information:
This work was supported by the National Institute of Mental Health Intramural Research Program. The study protocol was approved by the Intramural Review Board of the National Institute of Mental Health and appropriate procedures were used concerning the human subjects involved.
PY - 2009/9/15
Y1 - 2009/9/15
N2 - 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 valine158methionine polymorphism in catechol-O-methyltransferase (COMTval158met), 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 COMTval158met 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 COMTval158met 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 COMTval158met 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.
AB - 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 valine158methionine polymorphism in catechol-O-methyltransferase (COMTval158met), 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 COMTval158met 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 COMTval158met 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 COMTval158met 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.
KW - Aging
KW - COMT
KW - functional magnetic resonance imaging
KW - independent component analysis
KW - working memory
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U2 - 10.1016/j.biopsych.2009.04.014
DO - 10.1016/j.biopsych.2009.04.014
M3 - Article
C2 - 19539269
AN - SCOPUS:68949175708
SN - 0006-3223
VL - 66
SP - 540
EP - 548
JO - Biological psychiatry
JF - Biological psychiatry
IS - 6
ER -