title: 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.
authors.affiliation: Department of Pharmaceutical Sciences, Northeastern University, Boston, MA, 02115, United States of America.
authors.forename: Yiting
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Pharmaceutical Sciences, Northeastern University, Boston, MA, 02115, United States of America.|Department of Surgery, Laboratory of Nutrition and Metabolism at BIDMC, Harvard Medical School, Boston, MA, 02215, United States of America.
authors.forename: Nathaniel W
authors.initials: NW
authors.lastname: Hodgson
authors.affiliation: Department of Pharmaceutical Sciences, Northeastern University, Boston, MA, 02115, United States of America.|Department of Pharmaceutical Sciences, Nova Southeastern University College of Pharmacy, Fort Lauderdale, FL, 33328, United States of America.
authors.forename: Malav S
authors.initials: MS
authors.lastname: Trivedi
authors.affiliation: Department of Medicine (Biomedical Genetics Section), Genetics & Genomics, Boston University School of Medicine, Boston, MA, 02118, United States of America.
authors.forename: Hamid M
authors.initials: HM
authors.lastname: Abdolmaleky
authors.affiliation: Center for Psychiatric Neuroscience, Department of Psychiatry, Lausanne University Hospital, Lausanne, Switzerland.
authors.forename: Margot
authors.initials: M
authors.lastname: Fournier
authors.affiliation: Center for Psychiatric Neuroscience, Department of Psychiatry, Lausanne University Hospital, Lausanne, Switzerland.
authors.forename: Michel
authors.initials: M
authors.lastname: Cuenod
authors.affiliation: Center for Psychiatric Neuroscience, Department of Psychiatry, Lausanne University Hospital, Lausanne, Switzerland.
authors.forename: Kim Quang
authors.initials: KQ
authors.lastname: Do
authors.affiliation: Department of Pharmaceutical Sciences, Northeastern University, Boston, MA, 02115, United States of America.|Department of Pharmaceutical Sciences, Nova Southeastern University College of Pharmacy, Fort Lauderdale, FL, 33328, United States of America.
authors.forename: Richard C
authors.initials: RC
authors.lastname: Deth
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000375:Aging / Q000378:metabolism*; D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D001321:Autistic Disorder / Q000235:genetics / Q000378:metabolism*; D002648:Child; D002675:Child, Preschool; D019175:DNA Methylation / Q000235:genetics*; D005625:Frontal Lobe / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000235:genetics*; D005721:Glutamate-Cysteine Ligase / Q000235:genetics; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008875:Middle Aged; D012559:Schizophrenia / Q000235:genetics / Q000378:metabolism*; D014805:Vitamin B 12 / Q000031:analogs & derivatives* / Q000235:genetics / Q000378:metabolism*; D055815:Young Adult
chemical_list: D000975:Antioxidants; C019476:mecobalamin; C560749:GCLM protein, mouse; D005721:Glutamate-Cysteine Ligase; D005978:Glutathione; D014805:Vitamin B 12