Prospective neurochemical characterization of child offspring of parents with bipolar disorder

Abstract

We wished to determine whether decreases in N-acetyl aspartate (NAA) and increases in myoinositol (mI) concentrations as a ratio of creatine (Cr) occurred in the dorsolateral prefrontal cortex (DLPFC) of pediatric offspring of parents with bipolar disorder (BD) and a healthy comparison group (HC) over a 5 year period using proton magnetic resonance spectroscopy (1H-MRS). Sixty-four youth (9–18 years old) of parents with BD (36 with established BD, and 28 offspring with symptoms subsyndromal to mania) and 28 HCs were examined for group differences in NAA/Cr and mI/Cr in the DLPFC at baseline and follow-up at either 8, 10, 12, 52, 104, 156, 208, or 260 weeks. No significant group differences were found in metabolite concentrations at baseline or over time. At baseline, BD offspring had trends for higher mI/Cr concentrations in the right DLPFC than the HC group. mI/Cr concentrations increased with age, but no statistically significant group differences were found between groups on follow up. It may be the case that with intervention, youth at risk for BD are normalizing otherwise potentially aberrant neurochemical trajectories in the dorsolateral prefrontal cortex. A longer period of follow up may be required before observing any group differences.

Longitudinal proton spectroscopy study of the prefrontal cortex in youth at risk for bipolar disorder before and after their first mood episode

“…The value of these post hoc analyses rely on the ability to further investigate brain neurochemistry as a function of “pure” familial risk for bipolar disorder, as no differences were found between at‐risk youth without psychopathology and HC. Indeed, regarding the ACC, these negative results are consistent with smaller prior studies in at‐risk youth, further suggesting that, at‐risk status, per se, is not associated with abnormal 1 H‐MRS neurochemistry profile in the bilateral VLPFC and ACC.…”

“…To date, very few 1 H‐MRS studies have examined baseline abnormalities and longitudinal changes in prefrontal cortex neurochemistry in youth at increased risk for bipolar I disorder. Prior to our study, only one 1 H‐MRS study have examined brain neurochemistry in the bilateral dorsolateral prefrontal cortex of at‐risk youth in a prospective fashion, which also yielded negative results . Different from our study, they included at‐risk youth with established bipolar disorder (therefore, after their first mood episode), or with subthreshold mania (therefore, medicated sample or with more severe psychopathology).…”

“…Our study advances those negative findings by using a different methodology. In our study, at baseline, at‐risk subjects were unaffected by major depressive disorder or bipolar disorder, and were mostly (79%) medication naïve, allowing us to characterize the baseline 1 H‐MRS metabolite profile in the VLPFC and ACC without burden of illness or medication effects, frequent confounders in prior 1 H‐MRS imaging studies of at‐risk youth . Moreover, by examining at‐risk without mood disorders at baseline and following them up until the development of a first mood episode, we were able to examine baseline neurochemistry and longitudinal changes as a function of risk and development of mood disorders.…”

“…In at‐risk youth, increased myo‐inositol levels in the prefrontal cortex and cerebellar vermis, reduced glutamate in the ACC, and decreased choline‐containing compounds in the cerebellar vermis have been described . Other 1 H‐MRS studies of the ACC, dorsolateral prefrontal cortex, and dorsomedial and ventromedial prefrontal cortex in at‐risk youth have been negative . In common, these previous findings are limited by small sample sizes and mostly cross‐sectional design.…”

Variants in Ion Channel Genes Link Phenotypic Features of Bipolar Illness to Specific Neurobiological Process Domains

“…An MRS study of BD subjects showed significantly lower adenosine diphosphate concentrations in the ventrolateral prefrontal cortex of euthymic subjects [140]. A prospective MRS study of offspring of parents with BD found a trend towards increased myo-inositol/Cr concentrations in the dorsolateral prefrontal cortex compared to controls [141]. Another study has shown reduced expression of Na-K-ATPase in response to ethacrynic acid ionic stress challenges in lymphoblastoid cell lines of Old Order Amish BD subjects compared to control subjects within the same Amish pedigree [142].…”