Cobalamin deficiency, hyperhomocysteinemia, and dementia

Abstract

Introduction: Although consensus guidelines recommend checking serum B12 in patients with dementia, clinicians are often faced with various questions: (1) Which patients should be tested? (2) What test should be ordered? (3) How are inferences made from such testing? (4) In addition to serum B12, should other tests be ordered? (5) Is B12 deficiency compatible with dementia of the Alzheimer's type? (6) What is to be expected from treatment? (7) How is B12 deficiency treated?

Methods: On January 31st, 2009, a Medline search was performed revealing 1,627 citations related to cobalamin deficiency, hyperhomocysteinemia, and dementia. After limiting the search terms, all abstracts and/or articles and other references were categorized into six major groups (general, biochemistry, manifestations, associations and risks, evaluation, and treatment) and then reviewed in answering the above questions.

Results: The six major groups above are described in detail. Seventy-five key studies, series, and clinical trials were identified. Evidence-based suggestions for patient management were developed.

Discussion: Evidence is convincing that hyperhomocysteinemia, with or without hypovitaminosis B12, is a risk factor for dementia. In the absence of hyperhomocysteinemia, evidence is less convincing that hypovitaminosis B12 is a risk factor for dementia. B12 deficiency manifestations are variable and include abnormal psychiatric, neurological, gastrointestinal, and hematological findings. Radiological images of individuals with hyperhomocysteinemia frequently demonstrate leukoaraiosis. Assessing serum B12 and treatment of B12 deficiency is crucial for those cases in which pernicious anemia is suspected and may be useful for mild cognitive impairment and mild to moderate dementia. The serum B12 level is the standard initial test: 200 picograms per milliliter or less is low, and 201 to 350 picograms per milliliter is borderline low. Other tests may be indicated, including plasma homocysteine, serum methylmalonic acid, antiparietal cell and anti-intrinsic factor antibodies, and serum gastrin level. In B12 deficiency dementia with versus without pernicious anemia, there appear to be different manifestations, need for further workup, and responses to treatment. Dementia of the Alzheimer's type is a compatible diagnosis when B12 deficiency is found, unless it is caused by pernicious anemia. Patients with pernicious anemia generally respond favorably to supplemental B12 treatment, especially if pernicious anemia is diagnosed early in the course of the disease. Some patients without pernicious anemia, but with B12 deficiency and either mild cognitive impairment or mild to moderate dementia, might show some degree of cognitive improvement with supplemental B12 treatment. Evidence that supplemental B12 treatment is beneficial for patients without pernicious anemia, but with B12 deficiency and moderately-severe to severe dementia is scarce. Oral cyanocobalamin is generally favored over intramuscular cyanocobalamin.

Keywords: Alzheimer; B12; cobalamin; cognitive dysfunction; cognitive impairment; cyanocobalamin; dementia; homocysteine; homocystinuria; hyperhomocysteinemia.

Figure 1

Folate cycle, methionine cycle, and transsulfuration pathway. Copyright © 2005. Adapted with permission from Davis SR, Quinlivan EP, Shelnutt KP, et al. Homocysteine synthesis is elevated but total remethylation is unchanged by the methylenetetrahydrofolate reductase 677C->T polymorphism and by dietary folate restriction in young women. J Nutr. 2005;135(5):1045–1050. Notes: This schematic is of the folate cycle (left), methionine cycle (right), and transsulfuration pathway (bottom), with homocysteine being the common substance to all three. Folic acid (synthetic) is converted by DHFR to dihydrofolic acid (dietary), which is converted by DHFR to THF, which enters the folate cycle: THF →N⁵,N¹⁰-methylene THF → N⁵-methyl THF → THF. In this last step, vitamin B12 is required as a cofactor for MS. With low or absent vitamin B12, this last step is hindered leading to the methylfolate trap with elevated CH₃-THF. Homocysteine metabolism: homocysteine is produced in the methionine cycle by the deadenosylation/hydration of AdoHcy, and is either remethylated to methionine, by the methionine cycle or catabolized to cysteine, by the transsulfuration pathway. Note the AdoHcy deadenosylation/hydration to Hcy is a reversible reaction favoring homocysteine adenosylation/hydration to AdoHcy. Methyl groups produced by AdoMet demethylation to AdoHcy are used for nucleic acid, protein, lipid, and neurotransmitter biosynthesis. Cysteine is a nonessential amino acid used in the biosynthesis of proteins, glutathione, coenzyme A, taurine, and inorganic sulfur. Glutathione is an antioxidant that protects cells from ROS. Abbreviations: AdoHcy, S-adenosylhomocysteine; AdoMet, S-adenosylmethionine; BHMT, betaine-homocysteine methyltransferase; CBS, cystathionine β-synthase; CGL, cystathionine gamma-lyase; CH₂THF, methylenetetrahydrofolate; -CH₃, methyl group; CH₃THF methyl tetrahydrofolate; DHFR, dihydrofolate reductase; MAT, methionine adenosyltransferases; MS, methionine synthase; MTHFR, methylenetetrahydrofolate reductase; PLP, pyridoxal phosphate (the active form of vitamin B6, pyridoxine); ROS, reactive oxygen species; SAHH, S-adenosylhomocysteine hydrolase; SHMT, serine hydroxymethyltransferase; THF, tetrahydrofolate.

Figure 2

Illustration of a biologically plausible deleterious cycle of reactive oxygen species (ROS), homocysteine (Hcy), and immune activation that possibly may be involved in the pathogenesis of Alzheimer’s disease.

Figure 3

Guidelines for the workup of dementia. Note: Excellent guidelines for the diagnosis of dementia also are available at http://www.cmaj.ca/cgi/content/full/178/7/825. Abbreviations: AD, Alzheimer’s disease; APOE, apolipoprotein E; CAT, computerized axial tomography; CJD, Creutzfeldt-Jakob Disease; CNS, central nervous system; DAT, Dementia of the Alzheimer Type; DLB, Dementia with Lewy Bodies; DSM-IIR, Diagnostic and Statistical Manual of Mental Disorders-III-Revised; DSM-IV, Diagnostic and Statistical Manual of Mental Disorders-IV; EEG, electroencephalogram; FTD, frontotemporal dementia; MRI, magnetic resonance imaging; NINCDS-ADRDA, National Institute of Neurologic, Communicative Disorders and Stroke–Alzheimer’s Disease and Related Disorders Association; PET, positron emission tomography; SPECT, single photon emission computerized tomography; V aD, vascular dementia.

Figure 4

Suggestions for vitamin B12 workup and treatment in patients with suspected neuropathology. Notes: *Studies have reliably shown that PO cyanocobalamin therapy is another option. Abbreviations: μmol/L, micromoles per liter; CBC, complete blood count; Hcy, homocysteine; Hgb, hemoglobin; IM, intramuscular; MCV, mean corpuscular volume; PA, pernicious anemia; pg/mL, picograms per milliliter; PO, oral; SC, subcutaneous.