Catechol-O-methyltransferase valine(158)methionine polymorphism modulates brain networks underlying working memory across adulthood

Abstract

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.

Figures

Figure 1

Effect of COMTval158met polymorphism on brain activation during a 1-back working memory task. Individuals homozygous for val allele (val/val, n = 24) show greater signal change relative to heterozygote subjects (val/met, n = 31), who in turn show greater signal change relative to subjects homozygous for met allele (met/met, n = 20). (A) Thresholded statistical t-map (val/val > val/met > met/met) of DLPFC activation (1-back–0-back) surface-rendered on the MNI brain template (p < .005); (B) Percent signal change during working memory (1-back–0-back) in the left DLPFC (MNI coordinates of peak cluster: BA 9; x = −38, y = 41, z = 42 mm) as a function of COMTval158met genotype. Bar graphs represent mean percent signal change of the BOLD response for each genotype group. Error bars indicate one standard error of the mean. BA, Brodmann area; BOLD, blood oxygenation level-dependent; COMT, catechol-O-methyltransferase; DLPFC, dorsolateral prefrontal cortex; met, methionine; MNI, Montreal Neurological Institute; val, valine.

Figure 2

Effect of age on brain activations during a 1-back working memory task. Older adults show increased activation in left DLPFC (MNI coordinates of peak cluster: x = −45, y = 15, z = 34 mm) and bilateral posterior parietal cortices. Thresholded statistical t-map of left DLPFC activation (1-back–0-back) surface-rendered on the MNI brain template (p < .005). DLPFC, dorsolateral prefrontal cortex; MNI, Montreal Neurological Institute.

Figure 3

Working memory task-related functional networks. Three COIs were identified: (A) left frontoparietal (r = .60); (B) medial frontal (r = .50); and (C) posterior parietal (r = .50). Surface-rendered maps display the spatial pattern of the independent components identified. Time courses represent the temporal profile of each component (blue) overlaid on the paradigm “box-car” design (red). R values indicate the Pearson’s correlation between the time course of the component and the task design. All images are thresholded at p < .05 FDR-corrected for the whole brain. COI, component of interest; FDR, false discovery rate.

Figure 4

Effect of COMTval158met polymorphism on the left prefrontal-parietal COI. (A) and (B) Val homozygotes show greater connectivity in left DLPFC (MNI coordinates of peak cluster: BA 9; x = −34, y = 41, z = 34 mm) relative to heterozygotes and met homozygotes, whereas (C) and (D) met homozygotes show higher connectivity in left VLPFC (MNI coordinates of peak cluster: BA 44; x = −45, y = 15, z = 8 mm). Thresholded statistical t-maps of connectivity (val/val > val/met > met/met) (A,C) are surface-rendered on the MNI brain template (p < .005). Bar graphs (B,D) represent parameter estimates of the BOLD response for each genotype group measured in arbitrary units. Error bars indicate one standard error of the mean. BA, Brodmann area; BOLD, blood oxygenation level-dependent; COI, component of interest; COMT, catechol-O-methyltransferase; DLPFC, dorsolateral prefrontal cortex; met, methionine; MNI, Montreal Neurological Institute; val, valine; VLPFC, ventrolateral prefrontal cortex.

Figure 5

Interaction COMTval158met polymorphism by age on the left prefrontal-parietal COI. (A) Older adults show greater COMTval158met-related inefficiency in left-DLPFC (MNI coordinates of peak cluster: BA9; x = −34, y = 41, z = 34 mm) relative to younger subjects. (B) COMTval158met effect, which is indicated by the slope of the lines, was greater in older subjects compared with younger subjects. Thresholded statistical t-map of activation (A) is surface-rendered on the MNI brain template (p < .005). Graph represents parameter estimates of the BOLD response for each genotype and age group measured in arbitrary units. BA, Brodmann area; BOLD, blood oxygenation level-dependent; COMT, catechol-O-methyltransferase; DLPFC, dorsolateral prefrontal cortex; met, methionine; MNI, Montreal Neurological Institute; val, valine.

Figure 6

Effect of COMTval158met polymorphism on the medial frontal COI. (A) and (B) Met homozygotes show greater activity in medial BA 10/ACC (MNI coordinates of peak cluster: BA 9; x = −15, y = 49, z = −8 mm) relative to heterozygotes and val homozygotes. (C) Met homozygotes did not show an age-related effect on the correlation between the time course of the COI and the task design (Pearson’s r = −.05, p = .85), whereas (D) val homozygotes show a decline with age of this correlation (Pearson’s r = −.43, p = .03). Thresholded statistical t-map of activation (A) is surface-rendered on the MNI brain template (p < .005). Bar graphs (B) represent parameter estimates of the BOLD response for each genotype group measured in arbitrary units. Error bars indicate one standard error of the mean. Scatterplots report the age (measured in years) and time course-task design correlation (measured by the betas of this correlation). Lines indicate the best fit for the age by time course-task design relationship. ACC, anterior cingulated cortex; BA, Brodmann area; BOLD, blood oxygenation level-dependent; COI, component of interest; COMT, catechol-O-methyltransferase; met, methionine; MNI, Montreal Neurological Institute; val, valine.

Figure 7

Theoretical inverted-U model describing the effects of COMTval158met genotype and aging on PFC DA signaling and function across adulthood. Val homozygotes show lower prefrontal function relative to met homozygotes (↔). Age-related decline () in dopaminergic system results in a leftward shift on the x axis of the inverted-U curve resulting in a decline in PFC function. This leftward shift with aging puts older val homozygotes on the steeper portion of the inverted-U curve leading to an exaggerated effect of the COMTval158met polymorphism on PFC function in older adults when compared with younger adults in response to similar COMTval158met effects on DA levels (ΔDA). COMT, catechol-O-methyltransferase; DA, dopamine; met, methionine; PFC, prefrontal cortex; val, valine. The above figure is modified after Figure 1 in Nagel et al. (14).