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. 2022 Apr 27:16:838228.
doi: 10.3389/fnhum.2022.838228. eCollection 2022.

Contributions of the Catechol-O-Methyltransferase Val158Met Polymorphism to Changes in Brain Iron Across Adulthood and Their Relationships to Working Memory

Jonatan Gustavsson  1 , Goran Papenberg  1 , Farshad Falahati  1 , Erika J Laukka  1   2 , Grégoria Kalpouzos  1
Affiliations

Contributions of the Catechol-O-Methyltransferase Val158Met Polymorphism to Changes in Brain Iron Across Adulthood and Their Relationships to Working Memory

Jonatan Gustavsson et al. Front Hum Neurosci. .

Abstract

Ageing is associated with excessive free brain iron, which may induce oxidative stress and neuroinflammation, likely causing cognitive deficits. Lack of dopamine may be a factor behind the increase of iron with advancing age, as it has an important role in cellular iron homoeostasis. We investigated the effect of COMT Val 158 Met (rs4680), a polymorphism crucial for dopamine degradation and proxy for endogenous dopamine, on iron accumulation and working memory in a longitudinal lifespan sample (n = 208, age 20-79 at baseline, mean follow-up time = 2.75 years) using structural equation modelling. Approximation of iron content was assessed using quantitative susceptibility mapping in striatum and dorsolateral prefrontal cortex (DLPFC). Iron accumulated in both striatum and DLPFC during the follow-up period. Greater iron accumulation in DLPFC was associated with more deleterious change in working memory. Older (age 50-79) Val homozygotes (with presumably lower endogenous dopamine) accumulated more iron than older Met carriers in both striatum and DLPFC, no such differences were observed among younger adults (age 20-49). In conclusion, individual differences in genetic predisposition related to low dopamine levels increase iron accumulation, which in turn may trigger deleterious change in working memory. Future studies are needed to better understand how dopamine may modulate iron accumulation across the human lifespan.

Keywords: COMT; QSM; SEM; ageing; brain iron; dopamine; longitudinal; working memory.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

FIGURE 1
FIGURE 1
(A) Example of a QSM (quantitative susceptibility mapping) image. Higher signal intensity denotes higher iron load. Striatum is represented by caudate (red outline) and putamen (blue outline). (B) Image illustrating dorsolateral prefrontal cortex with rostral middle-frontal cortex in blue colour and caudal middle-frontal cortex in red colour.
FIGURE 2
FIGURE 2
Graphical representation of the change regression model for iron accumulation and working memory change in (A) striatum and (B) DLPFC. Observed variables are indicated by boxes and latent factors are indicated by circles. Regressions are indicated with one-headed arrows and covariances with two-headed arrows. Figures present standardised parameter estimates. All models were adjusted for age, sex, and education, as well as change in grey-matter volume in case of iron accumulation. T1, baseline; T2, follow-up; e, error term; WM, working memory; BD, binding task; 2B, 2-back task; 3B, 3-back task. (*p < 0.05, **p < 0.01, ***p < 0.001).
FIGURE 3
FIGURE 3
Accumulation of iron [susceptibility increase in parts per million (ppm)] in (A,B) striatum and (C,D) DLPFC. Error bars ± 1 SE. * indicates significant difference in iron accumulation based on structural equation modeling (*p < 0.05, **p < 0.01, ***p < 0.001).
FIGURE 4
FIGURE 4
Association between changes in working memory and iron accumulation [susceptibility increase in parts per million (ppm)]. Top row: Younger (A) Met/Met, (B) Met/Val, and (C) Val/Val carriers. Bottom row: Older (D) Met/Met, (E) Met/Val, and (F) Val/Val carriers. Plots are based on imputed factor scores. * indicates marginal multivariate outlier whose exclusion led to a marginally significant association (see text).
See this image and copyright information in PMC

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