Vitamin B12, folic acid, and the nervous system

doi:10.1016/S1474-4422(06)70598-1

The Lancet Neurology

Volume 5, Issue 11, November 2006, Pages 949-960

https://doi.org/10.1016/S1474-4422(06)70598-1 Get rights and content

Summary

There are many reasons for reviewing the neurology of vitamin-B12 and folic-acid deficiencies together, including the intimate relation between the metabolism of the two vitamins, their morphologically indistinguishable megaloblastic anaemias, and their overlapping neuropsychiatric syndromes and neuropathology, including their related inborn errors of metabolism. Folates and vitamin B12 have fundamental roles in CNS function at all ages, especially the methionine-synthase mediated conversion of homocysteine to methionine, which is essential for nucleotide synthesis and genomic and non-genomic methylation. Folic acid and vitamin B12 may have roles in the prevention of disorders of CNS development, mood disorders, and dementias, including Alzheimer's disease and vascular dementia in elderly people.

Section snippets

Historical background

In the late 19th century, Leichtenstern¹ and Lichtheim² wrote the earliest accounts of the neurological associations of megaloblastic anaemia; they described typical lesions in the posterior and lateral columns of the spinal cord of which Russell and colleagues³ soon coined the term “subacute combined degeneration of the cord” (SCD). In the first third of the 20th century, before the availability of liver therapy, the neuropsychiatry and neuropathology of megaloblastic anaemia was thoroughly

Vitamin B12 and folate metabolism

Reviews of the structure, binding, absorption, transport, metabolism, function, and interaction of vitamin B12 and folates, and the polymorphisms of folate-related enzymes can be found elsewhere.12, 13, 17, 21, 24, 25, 26, 27 A key interaction is that between vitamin B12 and folate in the synthesis of methionine from homocysteine by methionine synthase, in which both 5-methyl-tetrahydrofolate and methyl-vitamin-B12 are cofactors (figure 1), a reaction that can be inhibited by nitrous oxide. The

Neurology of vitamin-B12 deficiency

Kinnier Wilson wrote the best review of the older detailed description of the overlapping syndromes of peripheral neuropathy, SCD, autonomic dysfunction, optic atrophy, mood and behaviour changes, psychosis, memory impairment, and cognitive decline.⁶ Recent studies have concentrated on early diagnosis and treatment based on the modern techniques for the separation of the megaloblastic anaemias.

Patients may present to haematologists and physicians with megaloblastic anaemia or to neurologists

Neurology of folic-acid deficiency

The first reports of megaloblastic anaemia due to folate deficiency associated with spinal-cord, peripheral-nerve, and mental disorders appeared in the mid-1960s.51, 52 These were soon followed by accounts of folate-responsive neuropsychiatric disorders in patients deficient in folate with or without anaemia or macrocytosis.53, 54, 55, 56

The reported neuropsychiatric effects of folate deficiency are remarkably similar to those described for vitamin-B12 deficiency. Shorvon and colleagues²⁹

Vitamin-B12 deficiency

Two-thirds of patients with vitamin-B12 deficiency and neurological complications are still functionally independent at the time of diagnosis, and only about 10% are severely disabled.31, 32 The severity of the neurological disorder correlates with the duration of symptoms but also inversely with the haemoglobin concentration.³¹

The treatment of neuropsychiatric disorders is empirical, based mainly on haematological experience rather than neurological study.7, 32 Although remission of

Neural-tube defects

Inadequate maternal folate intake and status is one of several well-established factors that can increase the risk of neural-tube defects, especially spina bifida and anencephaly.14, 114, 117, 118 Impaired vitamin-B12 status and high plasma homocysteine are also suspected to be additional or related risk factors.119, 120 Periconceptional preventive treatment with 400 μg folic acid significantly reduces the risk of such defects but at least a third of neural-tube defects are not preventable with

Dissociation

An issue that has puzzled many for a century is the lack of association between the haematological and neuropsychiatric manifestations of vitamin-B12 or folate deficiencies.6, 7, 8, 10, 29, 30, 31 This dissociation has led to repeated suggestions that the nervous-system disorders must have a different mechanism to the megaloblastic anaemia.7, 10, 30, 31 To some extent, the dissociation is illusory, reinforced by the relatively early modern diagnosis of these disorders. In the first third of the

Conclusions

Vitamin-B12 and folic-acid deficiency and related inborn errors of metabolism may result in similar megaloblastic anaemias and overlapping neuropsychiatric complications. In the early stages there is often dissociation between the neuropsychiatric and haematological manifestations, as occurs in other general metabolic disorders that affect the CNS. The occurrence of CNS complications is influenced by the duration as well as the severity of either deficiency, by predisposing genetic factors,

Search strategy and selection criteria

References for this review were identified through searches of PubMed most recently done on June 1, 2006, and of the authors' files from 1966. The search terms were “vitamin B12”, “folic acid”, “folate”, “nervous system”, “neuropathy”, “dementia”, “epilepsy”, “multiple sclerosis”, “nitrous oxide”. Relevant textbooks were also used. The final reference list was generated on the basis of originality and relevance to each of the subtopics reviewed.

References (150)

O Leichtenstern
Progressive perniciöse anämie bei tabeskranken
Dtsch Med Wochenschr
(1884)
L Lichtheim
Zur kenntniss der perniciösen anämie
Munch Med Wochenschr
(1887)
JSR Russell et al.
Subacute combined degeneration of the spinal cord
Brain
(1900)
HW Woltmann
The nervous symptoms in pernicious anaemia: an analysis of 150 cases
Am J Med Sci
(1919)
RS Ahrens
Neurologic aspects of primary anaemia
Arch Neurol Psychiatry
(1932)
SA Kinnier Wilson
I Chanarin
The megaloblastic anaemias
(1969)
SO Schwartz et al.
The long-term evaluation of folic acid in the treatment of pernicious anaemia
J Lab Clin Med
(1950)
BE Hall et al.
Experience with pteroylglutamic (synthetic folic) acid in the treatment of pernicious anaemia
J Lab Clin Med
(1947)
EH Reynolds
Folic acid, vitamin B12 and the nervous system: historical aspects

EH Reynolds

Folic acid, ageing, depression, and dementia

BMJ

(2002)

MS Morris

Homocysteine and Alzheimer's disease

Lancet Neurol

(2003)

M Lucock

Is folic acid the ultimate functional food component for disease prevention?

BMJ

(2004)

BJ Iskandar et al.

Folic acid supplementation enhances repair in the adult central nervous system

Ann Neurol

(2004)

G Ravaglia et al.

Homocystine and folate as risk factors for dementia and Alzheimer disease

Am J Clin Nutr

(2005)

T Bottiglieri

Homocysteine and folate metabolism in depression

Prog Neuro-Psychopharmacol Biol Psychiatry

(2005)

J Durga et al.

Folate and the methylenetetrahydrofolate reductase 677C-T mutation correlate with cognitive performance

Neurobiol Aging

(2006)

CJ Dickinson

Does folic acid harm people with vitamin B12 deficiency?

Q J Med

(1995)

EH Reynolds

Benefits and risks of folic acid to the nervous system

J Neurol Neurosurg Psychiatry

(2002)

R Surtees

Cobalamin and folate responsive disorders

M Lucock

Folic acid: nutritional biochemistry, molecular biology, and role in disease processes

Mol Genet Metab

(2000)

R Carmel et al.

Update on cobalamin, folate, and homocysteine

Hematology Am Soc Hematol Educ Program

(2003)

MJ Koury et al.

New insights into erythropoiesis: the roles of folate, vitamin B12, and iron

Annu Rev Nutr

(2004)

EH Reynolds

Neurological aspects of folate and vitamin B12 metabolism

SD Shorvon et al.

The neuropsychiatry of megaloblastic anaemia

BMJ

(1980)

J Lindenbaum et al.

Neuropsychiatric disorders caused by cobalamin deficiency in the absence of anaemia or macrocytosis

N Engl J Med

(1988)

EB Healton et al.

Neurologic aspects of cobalamin deficiency

Medicine

(1991)

DG Savage et al.

Neurological complications of acquired cobalamin deficiency: clinical aspects

Bailliere's Clin Haematol

(1996)

SH Sigal et al.

Plasma R binder deficiency and neurologic disease

N Engl J Med

(1987)

EH Reynolds et al.

Subacute combined degeneration with high serum vitamin B12 level and abnormal vitamin B12 binding protein: new cause of an old syndrome

Arch Neurol

(1993)

EJ Fine et al.

The neurophysiological profile of vitamin B12 deficiency

Muscle Nerve

(1990)

DK Zucker et al.

B12 deficiency and psychiatric disorders: case report and literature review

Biol Psychiatry

(1981)

AH Waters et al.

Studies on the folic acid activity of human serum

J Clin Pathol

(1961)

EH Reynolds

Interrelationships between the neurology of folate and vitamin B12, deficiency

RB Layzer

Myeloneurophathy after prolonged exposure to nitrous oxide

Lancet

(1978)

H Admir et al.

Severe neurologic deficit after nitrous oxide anaesthesia

Anaesthesiology

(1995)

B Riedel et al.

Co-ordinate variations in methylmalonyl-CoA mutase and methionine synthase, and the cobalamin cofactors in human glioma cells during nitrous oxide exposure and the subsequent recovery phase

Biochem J

(1999)

JAL Amess et al.

Megaloblastic haemopoiesis in patients receiving nitrous oxide

Lancet

(1978)

JF Nunn

Clinical aspects of the interaction between nitrous oxide and vitamin B12

Br J Anaesth

(1987)

EH Reynolds et al.

Multiple sclerosis associated with vitamin B12 deficiency

Arch Neurol

(1991)

RF Crellin et al.

Multiple sclerosis and macrocytosis

Acta Neurol Scand

(1990)

EH Reynolds et al.

Vitamin B12 metabolism in multiple sclerosis

Arch Neurol

(1992)

R Sandyk et al.

Vitamin B12 and its relationship to age of onset of multiple sclerosis

Int J Neurosci

(1993)

HT Besler et al.

Lipoprotein oxidation, plasma total antioxidant capacity and homocysteine level in patients with multiple sclerosis

Nutr Neurosci

(2003)

M Vrethem et al.

Increased plasma homocysteine levels without signs of vitamin B12 deficiency in patients with multiple sclerosis assessed by blood and cerebrospinal fluid homocysteine and methylmalonic acid

Mult Scler

(2003)

EH Reynolds

Multiple sclerosis and vitamin B12 metabolism

J Neuroimmunol

(1992)

Cited by (603)

Serum binding folate receptor autoantibodies lower in autistic boys and positively-correlated with folate
2024, Biomedicine and Pharmacotherapy
Folate receptor autoantibody (FRAA) has caught increasing attention since its discovery in biological fluids of patients with autism spectrum disorder (ASD), but quantification and understanding of its function are still in their infancy. In this study, we aimed to quantify serum binding-FRAA and explore its relation with serum folate, vitamin B₁₂ (VB₁₂) and ferritin. We quantitated serum binding-FRAA in 132 ASD children and 132 typically-developing (TD) children, as well as serum levels of folate, VB₁₂ and ferritin. The results showed that serum binding-FRAA in the ASD group was significantly lower than that in the TD group (p < 0.0001). Further analysis showed that the difference between these two groups was attributed to boys in each group, not girls. There was no statistically significant difference in folate levels between the ASD and TD groups (p > 0.05). However, there was significant difference in boys between these two groups, not girls. Additionally, the combination of nitrite and binding-FRAA showed potential diagnostic value in patients with ASD (AUC > 0.7). Moreover, in the ASD group, the level of folate was consistent with that of binding-FRAA, whereas in the TD group, the binding-FRAA level was high when the folate level was low. Altogether, these differences revealed that the low serum FRAA in autistic children was mediated by multiple factors, which deserves more comprehensive investigation with larger population and mechanistic studies.
Tributyltin causes generational neurodevelopmental toxicity and the protective effect of folic acid in zebrafish
2024, Journal of Environmental Sciences (China)
Tributyltin (TBT), a common organotin environmental pollutant, may pose a threat to human development during critical early-life periods. We aimed to assess the neurodevelopmental intergenerational toxicity of early-life exposure to TBT and the protective effect of DNA methyl donor folic acid (FA). Specifically, after early-life exposure (1–21 days post-fertilization, dpf) to TBT (0, 1, 10 and 100 ng/L), zebrafish (Danio rerio) were cultured in clean medium until sexual maturity. The exposed females were mated with unexposed males to produce embryos (F1). The F1 generation were cultured (4–120 hours post-fertilization, hpf) with and without 1 mmol/L FA. The neurotoxic effects of early-life TBT exposure for zebrafish and their offspring (F1) were significantly enhanced anxiety and reduced aggression, decreased gene expression of DNA methyltransferase in the brain and increased serotonin levels in the body. Moreover, the intergenerational neurodevelopmental toxicity, as manifested in the F1 generation, was attenuated by FA supplementation. In summary, early-life TBT exposure led to intergenerational neurodevelopmental deficits in zebrafish, and DNA methyl donors had a protective effect on F1 neurodevelopment, which can inform the prevention and treatment of intergenerational neurotoxicity due to organotin pollutants.
Folate receptor alpha autoantibodies in the serum of patients with relapsing–remitting multiple sclerosis (RRMS)
2024, Clinical Neurology and Neurosurgery
Multiple sclerosis (MS) is a potentially progressive, autoimmune neurologic disorder of the central nervous system (CNS), resulting from an autoimmune attack on central nervous system white matter. Folate deficiencies are linked to DNA instability and breakdown of phospholipid membranes and thus might affect myelin integrity. Folic acid exerts its effects through its receptors (FRs). Folate receptor alpha autoantibodies (FRAA) can block folate transport to the brain. Due to important role of folate in the pathogenesis of MS, in this project we aimed to study FRAA serum levels in patients with relapsing remitting multiple sclerosis (RRMS).
Fifty-four patients with RRMS and 58 healthy individuals were enrolled in this study. Serum samples were collected from all participants and folate receptor alpha autoantibody (FRAA) serum concentration was measured by Enzyme-linked immunosorbent assay (ELISA).
The results showed that FRAA serum levels in patients with RRMS is 67.20 ± 19.79 ng/ml as compared to controls which was 37.32 ± 13.26 ng/ml. Significant increase in folate receptor autoantibody serum concentration was seen in patients with RRMS when compared to control group (P = 0.007). The results showed that a high concentration of folate receptor autoantibody is associated with RRMS. We have also found that 85.18% (46/54) of patients with RRMS were positive for serum FRAA, whereas the prevalence in controls was only 46.55% (27/58).
It is concluded that serum FRAA are more prevalent in RRMS patients than controls. The findings also suggest that FRAA might be involved in the pathophysiology of RRMS.
Vitamin B<inf>12</inf>-folic acid supplementation improves memory by altering mitochondrial dynamics, dendritic arborization, and neurodegeneration in old and amnesic male mice
2024, Journal of Nutritional Biochemistry
Memory impairment during aging and amnesia is attributed to compromised mitochondrial dynamics and mitophagy and other mitochondrial quality control mechanisms. Mitochondrial dynamics involves the continuous process of fission and fusion of mitochondria within a cell and is a fundamental mechanism for regulating mitochondrial quality and function. An extensive range of potential nutritional supplements has been shown to improve mitochondrial health, synaptic plasticity, and cognitive functions. Previous findings revealed that supplementation of vitamin B₁₂-folic acid reduces locomotor deficits and mitochondrial abnormalities but enhances mitochondrial and neuronal health. The present study aims to explore the impact of combined vitamin B₁₂-folic acid supplementation on mitochondrial dynamics, neuronal health, and memory decline in old age and scopolamine-induced amnesia, which remains elusive. The results demonstrated that supplementation led to a noteworthy increase in recognition and spatial memory and expression of memory-related protein BDNF in old and amnesic mice. Moreover, the decrease in the fragmented mitochondrial number was validated by the downregulation of mitochondrial fission p-Drp1 (S616) protein and the increase in elongated mitochondria by the upregulation of mitochondrial fusion Mfn2 protein. The increased spine density and dendritic arborization in old and amnesic mice upon supplementation were confirmed by the enhanced expression level of PSD95 and synaptophysin. Furthermore, supplementation reduced ROS production, inhibited Caspase-3 activation, mitigated neurodegeneration, and enhanced mitochondrial membrane potential, ATP production, Vdac1 expression, myelination, in old and amnesic mice. Collectively, our findings imply that combined supplementation of vitamin B₁₂-folic acid improves mitochondrial dynamics and neuronal health, and leads to recovery of memory during old age and amnesia.
Pediatric Nutrition: Implications for the Developing Microbiota–Gut–Brain Axis
2024, The Gut-Brain Axis, Second Edition
The first 1000 days of life represent a critical window of opportunity to optimize neurodevelopment, the failure of which can have long-term implications for both mental health and quality of life. There is increasing evidence of a bidirectional cross-talk between the microbiota, the gut, and the brain, known as the microbiome–gut–brain axis (MGBA). Nutrition in early life contributes to neurodevelopment directly and indirectly through the MGBA. Human milk contains nutrients and bioactive components that support brain development and establishment of a bifidobacteria-predominant microbiota and some studies report greater neurocognitive outcomes among breastfed compared to formula-fed infants. Most studies of the MGBA used rodents, however, the young pig has characteristics that make it a superior model for the human. Herein, we summarize the associations between the MGBA and neurocognitive development in human infants and describe the evidence for modulation of neurocognitive development by nutrients and milk bioactives in the young pig model.
A review on important aspects of gelatin in the research and development of hydrogels for Vit−B<inf>12</inf> delivery applications
2023, Journal of Drug Delivery Science and Technology
The search for biomaterials that can used in the production of high-throughput systems to suit the loading and release needs of water–soluble bioactive agents has been a long-standing question. The maintenance of the integrity of these agents for a relatively long period is a great challenge to therapies of diseases associated with B12 vitamin (Vit−B₁₂) deficiencies, which require long–term use of medicines and high therapeutic doses. The effects of the Vit−B₁₂ deficiency are of great concern among the elderly, pregnant women, and vegetarians. In addition, SARS-CoV-2 infection markedly reduces the level of Vit−B₁₂ in patients with or without comorbidity. Millions of people worldwide suffer from some illness related to Vit−B₁₂ deficiency. Gelatin is particularly attractive in biomedical use due to its excellent biocompatibility and low allergenic potential. The use of gelatin in combination with chemical modification strategies of polymers to create a safe system for drug delivery, for which deficiency associated-disease prevention or long-term treatments are required, could address the increasing demand for Vit−B₁₂. This review describes important aspects of gelatin hydrogels and Vit−B₁₂ and their potential use in biotechnology. The recent advances in the research and the mechanisms by which hydrogels could enhance Vit−B₁₂ treatment were also reviewed.

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ReviewVitamin B12, folic acid, and the nervous system

Summary

Section snippets

Historical background

Vitamin B12 and folate metabolism

Neurology of vitamin-B12 deficiency

Neurology of folic-acid deficiency

Vitamin-B12 deficiency

Neural-tube defects

Dissociation

Conclusions

Search strategy and selection criteria

Progressive perniciöse anämie bei tabeskranken

Dtsch Med Wochenschr

Zur kenntniss der perniciösen anämie

Munch Med Wochenschr

Subacute combined degeneration of the spinal cord

Brain

The nervous symptoms in pernicious anaemia: an analysis of 150 cases

Am J Med Sci

Neurologic aspects of primary anaemia

Arch Neurol Psychiatry

The megaloblastic anaemias

The long-term evaluation of folic acid in the treatment of pernicious anaemia

J Lab Clin Med

Experience with pteroylglutamic (synthetic folic) acid in the treatment of pernicious anaemia

J Lab Clin Med

Folic acid, vitamin B12 and the nervous system: historical aspects

Folic acid, ageing, depression, and dementia

BMJ

Homocysteine and Alzheimer's disease

Lancet Neurol

Is folic acid the ultimate functional food component for disease prevention?

BMJ

Folic acid supplementation enhances repair in the adult central nervous system

Ann Neurol

Homocystine and folate as risk factors for dementia and Alzheimer disease

Am J Clin Nutr

Homocysteine and folate metabolism in depression

Prog Neuro-Psychopharmacol Biol Psychiatry

Folate and the methylenetetrahydrofolate reductase 677C-T mutation correlate with cognitive performance

Neurobiol Aging

Does folic acid harm people with vitamin B12 deficiency?

Q J Med

Benefits and risks of folic acid to the nervous system

J Neurol Neurosurg Psychiatry

Cobalamin and folate responsive disorders

Folic acid: nutritional biochemistry, molecular biology, and role in disease processes

Mol Genet Metab

Update on cobalamin, folate, and homocysteine

Hematology Am Soc Hematol Educ Program

New insights into erythropoiesis: the roles of folate, vitamin B12, and iron

Annu Rev Nutr

Neurological aspects of folate and vitamin B12 metabolism

The neuropsychiatry of megaloblastic anaemia

BMJ

Neuropsychiatric disorders caused by cobalamin deficiency in the absence of anaemia or macrocytosis

N Engl J Med

Neurologic aspects of cobalamin deficiency

Medicine

Neurological complications of acquired cobalamin deficiency: clinical aspects

Bailliere's Clin Haematol

Plasma R binder deficiency and neurologic disease

N Engl J Med

Subacute combined degeneration with high serum vitamin B12 level and abnormal vitamin B12 binding protein: new cause of an old syndrome

Arch Neurol

The neurophysiological profile of vitamin B12 deficiency

Muscle Nerve

B12 deficiency and psychiatric disorders: case report and literature review

Biol Psychiatry

Studies on the folic acid activity of human serum

J Clin Pathol

Interrelationships between the neurology of folate and vitamin B12, deficiency

Myeloneurophathy after prolonged exposure to nitrous oxide

Lancet

Severe neurologic deficit after nitrous oxide anaesthesia

Anaesthesiology

Co-ordinate variations in methylmalonyl-CoA mutase and methionine synthase, and the cobalamin cofactors in human glioma cells during nitrous oxide exposure and the subsequent recovery phase

Biochem J

Megaloblastic haemopoiesis in patients receiving nitrous oxide

Review
Vitamin B12, folic acid, and the nervous system