Decreased Brain Levels of Vitamin B12 in Aging, Autism and Schizophrenia

Abstract

Many studies indicate a crucial role for the vitamin B12 and folate-dependent enzyme methionine synthase (MS) in brain development and function, but vitamin B12 status in the brain across the lifespan has not been previously investigated. Vitamin B12 (cobalamin, Cbl) exists in multiple forms, including methylcobalamin (MeCbl) and adenosylcobalamin (AdoCbl), serving as cofactors for MS and methylmalonylCoA mutase, respectively. We measured levels of five Cbl species in postmortem human frontal cortex of 43 control subjects, from 19 weeks of fetal development through 80 years of age, and 12 autistic and 9 schizophrenic subjects. Total Cbl was significantly lower in older control subjects (> 60 yrs of age), primarily reflecting a >10-fold age-dependent decline in the level of MeCbl. Levels of inactive cyanocobalamin (CNCbl) were remarkably higher in fetal brain samples. In both autistic and schizophrenic subjects MeCbl and AdoCbl levels were more than 3-fold lower than age-matched controls. In autistic subjects lower MeCbl was associated with decreased MS activity and elevated levels of its substrate homocysteine (HCY). Low levels of the antioxidant glutathione (GSH) have been linked to both autism and schizophrenia, and both total Cbl and MeCbl levels were decreased in glutamate-cysteine ligase modulatory subunit knockout (GCLM-KO) mice, which exhibit low GSH levels. Thus our findings reveal a previously unrecognized decrease in brain vitamin B12 status across the lifespan that may reflect an adaptation to increasing antioxidant demand, while accelerated deficits due to GSH deficiency may contribute to neurodevelopmental and neuropsychiatric disorders.

Short-term sleep deprivation leads to decreased systemic redox metabolites and altered epigenetic status

“…We have previously shown that decreased GSH levels and elevated oxidative stress can subsequently result in altered epigenetic changes, specifically DNA methylation levels via the vitamin-B12-dependent enzyme methionine synthase [29]. In agreement, we observed that sleep deprivation increased the global DNA methylation levels.…”

Genetics and epigenetics of autism: A Review

“…Subcutaneous methyl‐B12 in children with autism has shown improvement with the clinician‐rated score on the Clinical Global Impressions Scale, and was positively correlated with increases in plasma methionine, and decreases in S‐adenosyl‐1‐HCy and improvement in the S‐adenosylmethionine‐to‐S‐adenosyl‐1‐HCy ratio . This is consistent with the observation that the levels of B12 were threefold lower in the brains of autistic subjects compared with age‐matched controls ( n = 12) …”

Happily (n)ever after: Aging in the context of oxidative stress, proteostasis loss and cellular senescence

“…Subsequently vitamin B 12 deficiency leads to elevated homocysteine, and impaired folate metabolism [306]. Decreased vitamin B 12 concentrations have been demonstrated in postmortem human frontal cortex from patients with autism and schizophrenia, as well as to decline with age (range from 19 weeks pregnancy to 80 years) [307].…”