Decreased Brain Levels of Vitamin B12 in Aging, Autism and Schizophrenia
Publication Date
January 22, 2016
Journal
PLOS ONE
Authors
Yiting Zhang, Nathaniel W. Hodgson, Malav S. Trivedi, Hamid M. Abdolmaleky, et al
Volume
11
Issue
1
Pages
e0146797
DOI
https://dx.plos.org/10.1371/journal.pone.0146797
Publisher URL
http://journals.plos.org/plosone/article?id=10.1371%2Fjournal.pone.0146797
PubMed
http://www.ncbi.nlm.nih.gov/pubmed/26799654
PubMed Central
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4723262
Europe PMC
http://europepmc.org/abstract/MED/26799654
Web of Science
000368655300037
Scopus
84958205925
Mendeley
http://www.mendeley.com/research/decreased-brain-levels-vitamin-b12-aging-autism-schizophrenia-3
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{"title"=>"Decreased brain levels of vitamin B12 in aging, autism and schizophrenia", "type"=>"journal", "authors"=>[{"first_name"=>"Yiting", "last_name"=>"Zhang", "scopus_author_id"=>"57096136900"}, {"first_name"=>"Nathaniel W.", "last_name"=>"Hodgson", "scopus_author_id"=>"55538730500"}, {"first_name"=>"Malav S.", "last_name"=>"Trivedi", "scopus_author_id"=>"55194537800"}, {"first_name"=>"Hamid M.", "last_name"=>"Abdolmaleky", "scopus_author_id"=>"8744606800"}, {"first_name"=>"Margot", "last_name"=>"Fournier", "scopus_author_id"=>"14019553600"}, {"first_name"=>"Michel", "last_name"=>"Cuenod", "scopus_author_id"=>"57198283549"}, {"first_name"=>"Kim Quang", "last_name"=>"Do", "scopus_author_id"=>"23148952700"}, {"first_name"=>"Richard C.", "last_name"=>"Deth", "scopus_author_id"=>"7005767425"}], "year"=>2016, "source"=>"PLoS ONE", "identifiers"=>{"issn"=>"19326203", "doi"=>"10.1371/journal.pone.0146797", "sgr"=>"84958205925", "scopus"=>"2-s2.0-84958205925", "pmid"=>"26799654", "pui"=>"608240801"}, "id"=>"487824a8-8ff2-3a1a-b268-dcff1e764333", "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.", "link"=>"http://www.mendeley.com/research/decreased-brain-levels-vitamin-b12-aging-autism-schizophrenia-3", "reader_count"=>72, "reader_count_by_academic_status"=>{"Unspecified"=>1, "Professor > Associate Professor"=>2, "Researcher"=>9, "Student > Doctoral Student"=>4, "Student > Ph. D. Student"=>20, "Student > Postgraduate"=>4, "Other"=>9, "Student > Master"=>8, "Student > Bachelor"=>13, "Lecturer"=>1, "Professor"=>1}, "reader_count_by_user_role"=>{"Unspecified"=>1, "Professor > Associate Professor"=>2, "Researcher"=>9, "Student > Doctoral Student"=>4, "Student > Ph. D. Student"=>20, "Student > Postgraduate"=>4, "Other"=>9, "Student > Master"=>8, "Student > Bachelor"=>13, "Lecturer"=>1, "Professor"=>1}, "reader_count_by_subject_area"=>{"Unspecified"=>2, "Biochemistry, Genetics and Molecular Biology"=>12, "Nursing and Health Professions"=>2, "Agricultural and Biological Sciences"=>13, "Medicine and Dentistry"=>28, "Design"=>1, "Neuroscience"=>5, "Chemistry"=>3, "Psychology"=>3, "Computer Science"=>1, "Immunology and Microbiology"=>1, "Engineering"=>1}, "reader_count_by_subdiscipline"=>{"Design"=>{"Design"=>1}, "Engineering"=>{"Engineering"=>1}, "Medicine and Dentistry"=>{"Medicine and Dentistry"=>28}, "Neuroscience"=>{"Neuroscience"=>5}, "Chemistry"=>{"Chemistry"=>3}, "Psychology"=>{"Psychology"=>3}, "Immunology and Microbiology"=>{"Immunology and Microbiology"=>1}, "Agricultural and Biological Sciences"=>{"Agricultural and Biological Sciences"=>13}, "Computer Science"=>{"Computer Science"=>1}, "Nursing and Health Professions"=>{"Nursing and Health Professions"=>2}, "Biochemistry, Genetics and Molecular Biology"=>{"Biochemistry, Genetics and Molecular Biology"=>12}, "Unspecified"=>{"Unspecified"=>2}}, "reader_count_by_country"=>{"Canada"=>1, "United States"=>2, "Finland"=>1, "United Kingdom"=>1}, "group_count"=>3}

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Figshare

  • {"files"=>["https://ndownloader.figshare.com/files/2632449", "https://ndownloader.figshare.com/files/2632450"], "description"=>"<div><p>Many studies indicate a crucial role for the vitamin B<sub><b>12</b></sub> and folate-dependent enzyme methionine synthase (MS) in brain development and function, but vitamin B<sub>12</sub> status in the brain across the lifespan has not been previously investigated. Vitamin B<sub>12</sub> (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 B<sub>12</sub> 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.</p></div>", "links"=>[], "tags"=>["Low levels", "brain vitamin B 12 status", "19 weeks", "substrate homocysteine", "Brain development", "Cbl species", "AdoCbl levels", "methylmalonylCoA mutase", "antioxidant glutathione", "43 control subjects", "hcy", "Total Cbl", "vitamin B 12", "antioxidant demand", "GSH deficiency", "vitamin B 12 status", "80 years", "Decreased Brain Levels", "MS activity", "subjects MeCbl", "brain samples", "GSH levels", "60 yrs", "MeCbl levels"], "article_id"=>1641008, "categories"=>["Biological Sciences", "Science Policy"], "users"=>["Yiting Zhang", "Nathaniel W. Hodgson", "Malav S. Trivedi", "Hamid M. Abdolmaleky", "Margot Fournier", "Michel Cuénod", "Kim Quang Do", "Richard C. Deth"], "doi"=>["https://dx.doi.org/10.1371/journal.pone.0146797.s001", "https://dx.doi.org/10.1371/journal.pone.0146797.s002"], "stats"=>{"downloads"=>4, "page_views"=>1, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Decreased_Brain_Levels_of_Vitamin_B12_in_Aging_Autism_and_Schizophrenia_/1641008", "title"=>"Decreased Brain Levels of Vitamin B12 in Aging, Autism and Schizophrenia", "pos_in_sequence"=>0, "defined_type"=>4, "published_date"=>"2016-01-28 12:40:16"}
  • {"files"=>["https://ndownloader.figshare.com/files/2632443"], "description"=>"<p>Endocytosis brings TC-bound Cbl species to lysosomes where axial ligands are removed by MMACHC and MeCbl or AdoCbl are subsequently formed by SAM and ATP-dependent pathways, respectively. MeCbl is a required cofactor for methionine synthase, whose activity supports a large number of methylation reactions, including DNA methylation, as well as dopamine-stimulated phospholipid methylation, carried out by the D4 dopamine receptor (D4R). AdoCbl supports MMACoA mutase in mitochondria. Cysteine, which is rate-limiting for GSH synthesis, can be provided either by cellular uptake via the cysteine/glutamate transporter EAAT3 (excitatory amino acid transporter 3) or by transsulfuration of HCY via cystathionine. The latter pathway is restricted in human brain, increasing the importance of growth factor-dependent cysteine uptake by EAAT3.</p>", "links"=>[], "tags"=>["Low levels", "brain vitamin B 12 status", "19 weeks", "substrate homocysteine", "Brain development", "Cbl species", "AdoCbl levels", "methylmalonylCoA mutase", "antioxidant glutathione", "43 control subjects", "hcy", "Total Cbl", "vitamin B 12", "antioxidant demand", "GSH deficiency", "vitamin B 12 status", "80 years", "Decreased Brain Levels", "MS activity", "subjects MeCbl", "brain samples", "GSH levels", "60 yrs", "MeCbl levels"], "article_id"=>1641002, "categories"=>["Biological Sciences", "Science Policy"], "users"=>["Yiting Zhang", "Nathaniel W. Hodgson", "Malav S. Trivedi", "Hamid M. Abdolmaleky", "Margot Fournier", "Michel Cuénod", "Kim Quang Do", "Richard C. Deth"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0146797.g001", "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Cobalamin_related_redox_metabolic_pathways_in_neuronal_cells_/1641002", "title"=>"Cobalamin-related redox metabolic pathways in neuronal cells.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2016-01-28 12:40:13"}
  • {"files"=>["https://ndownloader.figshare.com/files/2632444"], "description"=>"<p>(a) The general structure of Cbl species in which “X” represents various ligands linked to the cobalt atom, giving rise to the five different Cbl species measured in postmortem frontal cortex. (b) Total Cbl levels in frontal cortex of control subjects divided into four age groups: 0–20 yrs (n = 12), 21–40 yrs (n = 5), 41–60 yrs (n = 10) and 61–80 yrs (n = 12). (c) Levels of five individual Cbl species of control subjects in four age groups. (d) Age-dependent decrease of MeCbl in human frontal cortex (n = 43). Inset: Age trends of serum Cbl, frontal cortex total Cbl and MeCbl. Serum Cbl data is from Ref. 30. (e) Total Cbl levels in placenta (n = 6), frontal cortex of fetal (n = 4) and control (0–20 yrs) subjects (n = 12). (f) Levels of five individual Cbl species in placenta (n = 6), frontal cortex of fetal (n = 4) and control (0–20 yrs) subjects (n = 12). * Indicates a significant difference from 0–20 yrs group (* p < 0.05, ** p < 0.01, *** p < 0.001).</p>", "links"=>[], "tags"=>["Low levels", "brain vitamin B 12 status", "19 weeks", "substrate homocysteine", "Brain development", "Cbl species", "AdoCbl levels", "methylmalonylCoA mutase", "antioxidant glutathione", "43 control subjects", "hcy", "Total Cbl", "vitamin B 12", "antioxidant demand", "GSH deficiency", "vitamin B 12 status", "80 years", "Decreased Brain Levels", "MS activity", "subjects MeCbl", "brain samples", "GSH levels", "60 yrs", "MeCbl levels"], "article_id"=>1641003, "categories"=>["Biological Sciences", "Science Policy"], "users"=>["Yiting Zhang", "Nathaniel W. Hodgson", "Malav S. Trivedi", "Hamid M. Abdolmaleky", "Margot Fournier", "Michel Cuénod", "Kim Quang Do", "Richard C. Deth"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0146797.g002", "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Cobalamin_status_in_human_frontal_cortex_/1641003", "title"=>"Cobalamin status in human frontal cortex.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2016-01-28 12:40:14"}
  • {"files"=>["https://ndownloader.figshare.com/files/2632445"], "description"=>"<p>(a) Total Cbl levels in frontal cortex of autistic subjects (n = 12) and aged-matched controls (n = 9). (b) Levels of five individual Cbl species in frontal cortex of autistic subjects (n = 12) and aged-matched controls (n = 9). (c) Total Cbl levels in frontal cortex of schizophrenic subjects (n = 9) and aged-matched controls (n = 9). (d) Levels of five individual Cbl species in frontal cortex of schizophrenic subjects (n = 9) and aged-matched controls (n = 9). * Indicates a significant difference from control group (* p < 0.05, ** p < 0.01, *** p < 0.001).</p>", "links"=>[], "tags"=>["Low levels", "brain vitamin B 12 status", "19 weeks", "substrate homocysteine", "Brain development", "Cbl species", "AdoCbl levels", "methylmalonylCoA mutase", "antioxidant glutathione", "43 control subjects", "hcy", "Total Cbl", "vitamin B 12", "antioxidant demand", "GSH deficiency", "vitamin B 12 status", "80 years", "Decreased Brain Levels", "MS activity", "subjects MeCbl", "brain samples", "GSH levels", "60 yrs", "MeCbl levels"], "article_id"=>1641004, "categories"=>["Biological Sciences", "Science Policy"], "users"=>["Yiting Zhang", "Nathaniel W. Hodgson", "Malav S. Trivedi", "Hamid M. Abdolmaleky", "Margot Fournier", "Michel Cuénod", "Kim Quang Do", "Richard C. Deth"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0146797.g003", "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Cobalamin_status_in_autism_and_schizophrenia_/1641004", "title"=>"Cobalamin status in autism and schizophrenia.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2016-01-28 12:40:14"}
  • {"files"=>["https://ndownloader.figshare.com/files/2632446"], "description"=>"<p>(a) Redox and methylation pathway metabolites in control subjects of 0–20 yrs (n = 12) compared to subjects of 61–80 yrs (n = 10). (b) GSH/GSSG ratio (left) and SAM/SAH ratio (right) in aging. (c) Redox and methylation pathway metabolites in frontal cortex of autistic subjects (n = 9) compared to age-matched controls (n = 9). (d) GSH/GSSG ratio (left) and SAM/SAH ratio (right) in autism. * Indicates a significant difference from 0–20 yrs group (panels a and b) or control group (panels c and d) (* p < 0.05, ** p < 0.01, *** p < 0.001).</p>", "links"=>[], "tags"=>["Low levels", "brain vitamin B 12 status", "19 weeks", "substrate homocysteine", "Brain development", "Cbl species", "AdoCbl levels", "methylmalonylCoA mutase", "antioxidant glutathione", "43 control subjects", "hcy", "Total Cbl", "vitamin B 12", "antioxidant demand", "GSH deficiency", "vitamin B 12 status", "80 years", "Decreased Brain Levels", "MS activity", "subjects MeCbl", "brain samples", "GSH levels", "60 yrs", "MeCbl levels"], "article_id"=>1641005, "categories"=>["Biological Sciences", "Science Policy"], "users"=>["Yiting Zhang", "Nathaniel W. Hodgson", "Malav S. Trivedi", "Hamid M. Abdolmaleky", "Margot Fournier", "Michel Cuénod", "Kim Quang Do", "Richard C. Deth"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0146797.g004", "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Redox_and_methylation_metabolites_in_aging_and_autism_/1641005", "title"=>"Redox and methylation metabolites in aging and autism.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2016-01-28 12:40:13"}
  • {"files"=>["https://ndownloader.figshare.com/files/2632447"], "description"=>"<p>Methionine synthase activity in frontal cortex of autistic and age-matched control subjects measured either with only endogenous Cbl or with the addition of OHCbl. * Indicates a significant difference from control group (* p < 0.05, ** p < 0.01, *** p < 0.001).</p>", "links"=>[], "tags"=>["Low levels", "brain vitamin B 12 status", "19 weeks", "substrate homocysteine", "Brain development", "Cbl species", "AdoCbl levels", "methylmalonylCoA mutase", "antioxidant glutathione", "43 control subjects", "hcy", "Total Cbl", "vitamin B 12", "antioxidant demand", "GSH deficiency", "vitamin B 12 status", "80 years", "Decreased Brain Levels", "MS activity", "subjects MeCbl", "brain samples", "GSH levels", "60 yrs", "MeCbl levels"], "article_id"=>1641006, "categories"=>["Biological Sciences", "Science Policy"], "users"=>["Yiting Zhang", "Nathaniel W. Hodgson", "Malav S. Trivedi", "Hamid M. Abdolmaleky", "Margot Fournier", "Michel Cuénod", "Kim Quang Do", "Richard C. Deth"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0146797.g005", "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Methionine_synthase_activity_in_autism_/1641006", "title"=>"Methionine synthase activity in autism.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2016-01-28 12:40:14"}
  • {"files"=>["https://ndownloader.figshare.com/files/2632448"], "description"=>"<p>(a) Redox and methylation metabolite levels in frontal cortex of GCLM KO mice at P40 and P90 (n = 7). Results are expressed as a percentage of the WT level of each metabolite. (b) Levels of five individual Cbl species in frontal cortex of GLCM KO and WT mice at P40 and P90. Inset indicates total Cbl levels. * Indicates a significant difference from control group (* p < 0.05, ** p < 0.01, *** p < 0.001).</p>", "links"=>[], "tags"=>["Low levels", "brain vitamin B 12 status", "19 weeks", "substrate homocysteine", "Brain development", "Cbl species", "AdoCbl levels", "methylmalonylCoA mutase", "antioxidant glutathione", "43 control subjects", "hcy", "Total Cbl", "vitamin B 12", "antioxidant demand", "GSH deficiency", "vitamin B 12 status", "80 years", "Decreased Brain Levels", "MS activity", "subjects MeCbl", "brain samples", "GSH levels", "60 yrs", "MeCbl levels"], "article_id"=>1641007, "categories"=>["Biological Sciences", "Science Policy"], "users"=>["Yiting Zhang", "Nathaniel W. Hodgson", "Malav S. Trivedi", "Hamid M. Abdolmaleky", "Margot Fournier", "Michel Cuénod", "Kim Quang Do", "Richard C. Deth"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0146797.g006", "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Redox_and_methylation_metabolite_and_cobalamin_status_in_GCLM_KO_mice_/1641007", "title"=>"Redox and methylation metabolite and cobalamin status in GCLM KO mice.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2016-01-28 12:40:15"}

PMC Usage Stats | Further Information

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  • {"unique-ip"=>"135", "full-text"=>"141", "pdf"=>"17", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"10", "supp-data"=>"1", "cited-by"=>"0", "year"=>"2019", "month"=>"4"}
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  • {"unique-ip"=>"274", "full-text"=>"349", "pdf"=>"20", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"8", "supp-data"=>"1", "cited-by"=>"1", "year"=>"2019", "month"=>"9"}
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Relative Metric

{"start_date"=>"2016-01-01T00:00:00Z", "end_date"=>"2016-12-31T00:00:00Z", "subject_areas"=>[]}
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