Cobalamin deficiency, hyperhomocysteinemia, and dementia

Figures & data

Table

Abyad, 2002	Fox, 1975	McMahon, 2006
Aisen, 2008	Healton, 1991	Nilsson, 2001
Bolaman, 2003	Hvas 2004	Osimani, 2005
Bryan, 2002	Ikeda, 1992	Remington, 2009
Carmel, 1995	Kalita, 2008	Seal, 2002
Clarke, 2003	Kwok, 1998	Stott, 2005
Crystal, 1994	Kwok, 2008	Sun, 2007
Cunha, 1990	La Rue, 1997	Teunisse, 1996
Cunha, 1995	Lehmann, 2003	van Asselt, 2001
Eastley, 2000	Levine 2006	van Dyck, 2008
El Otmani, 2008	Lin, 2008	van Uffelen, 2008
Eussen, 2006	Lindenbaum, 1988	Wolters, 2005
Fourniere, 1997	Martin, 1992

Table 1 Causes of hyperhomocysteinemia and B12 deficiency

Causes of hyperhomocysteinemia
Genetic deficiencies and polymorphisms^Citation52,Citation58 methylenetetrahydrofolate reductase methionine synthetase cystathionine beta-synthetase Drugs levodopa (L-dopa) – due to its metabolism^Citation46,Citation51,Citation54 nitrous oxide – due to methionine synthetase inhibition^Citation48,Citation49,Citation53 others Nutritional deficiencies vitamin B6 folate vitamin B12 (caused by pernicious anemia, celiac disease, and others) Other factors^Citation7,Citation18,Citation19,Citation39,Citation52,Citation57,Citation59^–^Citation61 advanced age male gender renal insufficiency
Causes of B12 deficiency^Citation45,Citation47,Citation50,Citation55,Citation56,Citation62 Genetic deficiencies of intrinsic factor – due to inability to absorb B12 at the distal ileum Genetic deficiencies or polymorphisms of transcobalamin II – due to inability or impediment of B12 cellular uptake Diseases affecting salivary glands – due to R-protein hyposecretion Gastric disease, resection, or bypass surgery – due to lack of hydrochloric acid and pepsin, which are required to separate animal protein from dietary B12, causing food-cobalamin malabsorption (eg, Helicobacter pylori infection) Diseases affecting gastric parietal cells – due to hyposecretion and inhibition of intrinsic factor (eg, pernicious anemia) Diseases affecting the pancreas and upper small intestine – due to lack of pancreatic enzymes and insufficient elevation of pH, which are required to separate R protein from B12 (eg, pancreatic insufficiency and ileal resection) Ileal disease or resection – due to specific inability to absorb the intrinsic factor-B12 complex (eg, celiac disease) V arious malabsorption syndromes Medications histamine type 2 receptor blockers protein pump inhibitors Dietary deficiencies (eg, vegetarian diet) Advancing age

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.

Table 2 Examples of multiple binary variables in studies examining efficacy of B12 treatment on cognition

No	Time course	Type of study	Absence/presence of cognitive dysfunction	B12 status*	Study results; author, year
1	Retrospective and cross-sectional	Not case control	Absent	Unknown	Positive; La Rue, 1997
2		Not case control	Absent	Low	Positive; Healton, 19911
3		Not case control	Present	Low	Positive; Lindenbaum, 1988 El Otmani, 20082 Fox, 19753 Healton, 19911
4		Case control	Absent	Normal	Negative; Lin, 20084
5		Case control	Present	Low	Negative; Eastley, 20005
6		Case control	Present	Low	Positive; Eastley, 20005 Osimani, 20056
7		Not randomized controlled trial	Absent	Low	Positive; van Asselt, 2001
8	Prospective	Not randomized controlled trial	Present	Unknown	Positive; Ikeda, 19927
9		Not randomized controlled trial	Present	Normal	Positive; Lehmann, 20038
10		Not randomized controlled trial	Present	Low	Negative; Carmel,1995 Crystal, 19949 Cunha, 199010 Kwok, 200811 Teunisse, 199612 van Dyck, 200813
11		Not randomized controlled trial	Present	Low	Positive; Abyad, 200214 Cunha, 199515 Kalita, 2008 Kwok, 200811 Martin, 199216 Nilsson, 200117
12		Randomized controlled trial	Absent	Unknown	Negative; Stott, 200518 Wolters, 2005
13		Randomized controlled trial	Absent	Unknown	Positive; Bryan, 2002
14		Randomized controlled trial	Absent	Normal	Positive; Levine, 200619
15		Randomized controlled trial	Absent	Low	Negative; Eussen, 2006 Kwok, 1998 McMahon, 2006
16		Randomized controlled trial	Present	Unknown	Negative; van Uffelen, 2008
17		Randomized controlled trial	Present	Unknown	Positive; Remington, 200920
18		Randomized controlled trial	Present	Normal	Negative; Aisen, 2008 Clarke, 200321 Sun, 2007
19		Randomized controlled trial	Present	Low	Negative; Clarke, 200321 Fourniere, 1997 Hvas, 2004 Seal, 2002
20		Randomized controlled trial	Present	Low	Positive; Bolaman, 200322

Notes:

1 Subjects had nervous system involvement;

2 N = 1;

3 N = 1;

4 sample consisted of asymptomatic nursing home males;

5 results were negative for subjects with dementia, and positive for those with mild cognitive impairment;

6 baseline neuropsychiatric tests determined those who did not improve from those who improved;

7 B12 status was not a major factor mentioned in the methods or results sections, treatment consisted of intravenous mecobalamin;

8 subjects had normal vitamin B12, hyperhomocysteinemia, and mild cognitive impairment at baseline, and there were no subjects who progressed to dementia;

9 N = 3;

10 N = 13;

11 delirium improved, but dementia did not improve;

12 N = 26;

13 N = 28;

14 shorter duration of cognitive dysfunction was associated with greater response to B12 treatment;

15 outcome was obtained in 19/46 patients, 16/19 worsened, and 3/16 improved with B12 therapy, those who improved had mild dementia of less than two years duration;

16 individuals who were symptomatic less than 12 months improved with B12 therapy;

17 those with mild-moderate dementia and those with hyperhomocysteinemia improved with supplemental B12 therapy;

18 subjects were elders with ischemic vascular disease;

19 subjects had schizophrenia;

20 the dietary supplement also contained N-acetylcysteine, S-adenosylmethionine, and multiple other ingredients;

21 the sample presumably included those with normal and low serum B12;

22 all subjects had pernicious anemia, oral was compared with intramuscular cyanocobalamin.

* Binary variables include B12 status: known versus unknown, and known-normal versus known-low.

Table 3a Studies showing vitamin B12 treatment is not associated with improved cognitive function or prevention of dementia

No	Principal author, Year	Study design	Type of sample	N	Duration	Major measures	Exposures/treatments	Major results/outcomes
1	Aisen, 2008	A multicenter, randomized, doubleblind, controlled clinical trial	Patients with mild to moderate AD and normal folic acid, vitamin b12, and Hcy levels	409	18 months	ADAS-cog	High-dose folic acid, vitamin B6, and vitamin B12 treatment	Vitamin treatment was not beneficial on the rate of change in the ADAS-cog score
2	Carmel, 1995	Prospective investigation	Demented and nondemented patients with low serum B12	16	NA	Neurological examination, EEG, visual evoked potentials, somatosensory potentials, dUST, plasma Hcy, serum MMA	Vitamin B12 treatment	50% of patients had abnormal dUST, 44% had increased plasma Hcy and/or MMA, 73% had mild neurological abnormalities (primarily neuropathies), 75% had EE G abnormalities, 77% had abnormal visual evoked potentials, 33% had abnormal somatosensory potentials Although B12 treatment improved most abnormalities, it did not improve cognitive function in the 13 demented patients
3	Clarke, 2003	Randomized, double-blind, placebo-controlled trial	Individuals with MCI or dementia, irrespective of baseline serum B12 and plasma Hcy levels	149	3 months	Cognitive function assessment, plasma Hcy, serum folate, serum B12, urine 11-dehydrothromboxane B2 (a marker of platelet activation) and 8-epiprostaglandin F2alpha (a marker of reactive oxygen species)	Low-dose aspirin treatment, folic acid and B12 treatment, vitamin E and vitamin C treatment, placebo	Treatment did not affect cognitive function
4	Crystal, 1994	Cohort	Ambulatory, nondemented, healthy elderly	79 of 388 individuals developed dementia	60 months	Specific neuropsychological tests, serum B12	Vitamin B12 treatment	22 of 388 patients had low serum B12 levels; 3 of these became demented. 57 of 388 individuals had higher B12 levels. AD incidence among the low B12 group was 4.5% compared with 7.5% in the higher B12 group. Mean B12 level at time of diagnosis in subjects who developed AD was 551 pg/mL. There was no evidence of hematologic abnormalities among the 22 subjects with low B12. Of the 3 low B12 patients who became demented, none responded to IM B12
5	Cunha, 1990	Prospective investigation	Demented elderly outpatients	13 of 110 patients had low serum B12	NA	Mental status examination	Vitamin B12 treatment	Mental status examination did not improve, and most cases demonstrated persistent cognitive deterioration
6	Eastley, 2000*	Case-control	Mildly cognitive impaired or demented outpatients with low serum B12	88	NA	Specific neuropsychological tests, Hgb, MCV, serum B12	Vitamin B12 treatment	There were no cases of arrestable or reversible dementia. Demented patients with low serum B12 did no better with B12 treatment than demented controls without low serum B12
7	Eussen, 2006	Randomized, double-blind, placebo-controlled trial	Elders with mild vitamin B12 deficiency	195	6 months	Specific neuropsychological tests	Vitamin B12 treatment, folic acid and vitamin B12 treatment, or placebo	Neither treatment group demonstrated cognitive improvement. The placebo group demonstrated greater memory improvement than the vitamin B12-alone group
8	Fourniere, 1997	Randomized, placebo-controlled trial	Demented individuals with low serum B12	NA	NA	NA	Vitamin B12 treatment	No improvement in cognitive function
9	Hvas, 2004	Randomized, placebo-controlled	Individuals with elevated plasma MMA, not previously treated with vitamin B12, many of whom had cognitive impairment at baseline	140	3 months	Cognitive function assessed by the CAMCOG, MMSE, and a 12-words learning test, depressive symptoms evaluated by the MDI	Vitamin B12	Treatment group did no better than placebo group on any of the measured outcomes of cognitive function or depressive symptoms
10	Kwok, 1998	Randomized clinical trial	Apparently healthy elders with low serum B12	50	4 months	MMSE, specific neuropsychological tests, serum B12, serum MMA	Vitamin B12 treatment or no intervention	Individuals treated with IM B12 performed more poorly on motor function scores compared with the control group Individuals treated with intramuscular B12 demonstrated improvement in performance IQ, but the improvement was not statistically significant compared with the control group Overall, individuals treated with intramuscular B12 showed no improvement in cognitive function compared with the control group
11	Kwok, 2008*	Clinical trial	Mild to moderately demented patients with low serum B12	30	9 months	MMSE, specific neuropsychological tests, serum B12	Vitamin B12 treatment	There were no significant changes in cognitive function or behavioral symptoms
12	Lin, 2008	Case-control	Asymptomatic nursing home elderly males, excluding those with renal insufficiency or low serum B12	419		Vitamin B12 supplementation status, MMSE, GDS, serum B12	Vitamin B12 supplementation	Cognitive impairment and depression prevalences were similar in those taking and not taking B12 supplements. MMSE and GDS were similar between those taking and not taking B12 supplements
13	McMahon, 2006	Randomized, double-blind, placebo-controlled trial	Healthy elders with plasma Hcy at least 13 μmol per liter	276	24 months	Plasma Hcy	Folate, vitamin B6, and vitamin B12 treatment	Hcy lowering therapy did not improve cognitive function in elders with Hcy
14	Seal, 2002	Randomized, placebo-controlled trial	Demented individuals with low serum b12	NA	NA	NA	Vitamin B12 treatment	No improvement in cognitive function
15	Stott, 2005	Randomized, double-blind, placebo-controlled trial	Elders with ischemic vascular disease	185	12 months	Specific neuropsychological tests, plasma Hcy	Folic acid and vitamin B12 treatment, riboflavin treatment, or vitamin B6 treatment	Folic acid and vitamin B12 did not improve cognitive function in elders with ischemic vascular disease
16	Sun, 2007	Randomized, double-blind, placebo-controlled trial	Elders with mild to moderate AD and normal serum folate and B12	89	6 months	ADAS-cog, ADL evaluation, serum folate, serum B12, plasma Hcy	AChE I and mecobalamin plus multivitamin containing vitamin B6, folic acid, other vitamins, and iron or AChE I and placebo	Supplemental mecobalamin plus multivitamin was no different than placebo in ADAS-cog scores and ADL evaluations
17	Teunisse, 1996	Prospective investigation	Outpatients with dementia	26 of 170 had low serum B12	6 months	Cognitive function, dementia severity, ADL’s, behavioral disturbances, caregiver burden, serum B12	Vitamin B12 treatment	B12 treatment did not improve functioning in demented patients with low serum B12. The rate of dementia deterioration in patients with low serum B12 was the same as those with AD
18	van Dyck, 2008	Clinical trial with blinded raters and a comparison group	Elderly, demented, nursing home residents with low serum B12	28 in the low serum B12 group, 28 in the comparison group with normal serum B12	2 months	DRS, BPRS, GDS, serum B12	Vitamin B12 treatment	B12 treatment did not produce significant effects on cognitive or psychiatric variables B12 treatment produced significant improvement in hematologic and metabolic parameters
19	van Uffelen, 2008	Randomized, placebo-controlled trial	Community-dwelling elders with MCI	152	12 months	Specific neuropsychological tests, quality of life measurements	Moderate intensity walking program versus a low intensity placebo activity; combined vitamin B6, folic acid, and vitamin B12 treatment versus placebo	Those in the moderate intensity walking group showed small improvements or trends in a few of the subscales of neuropsychological tests. Those in the vitamin treatment group were no different than placebo across cognitive function measurements
20	Wolters, 2005	Randomized, double-blind, placebo-controlled trial	Healthy, free-living, well-nourished, elderly women without dementia	220	6 months	Specific neuropsychological tests, RBC folate, RBC functional B6 activity, serum folate, serum B12, plasma Hcy, serum MMA	Multivitamin supplementation	Multivitamin supplementation did not improve cognitive function

Table 3b Studies showing vitamin B12 treatment is associated with improved cognitive function or prevention of dementia

No	Principal Author, Year	Study design	Type of sample	N	Duration	Major measures	Exposures/treatments	Major results/outcomes
1	Abyad, 2002	Single-blind clinical trial	Cognitively impaired nursing home residents and geriatric outpatients with low serum B12	62	12 months	MMSE, clock drawing test, caregiver interviews	Vitamin B12 treatment	40 of 56 patients completing the study showed cognitive improvement. The shorter the duration of cognitive dysfunction, the greater the response to parenteral B12 therapy
2	Bolaman, 2003	Randomized clinical trial	Patients 16 years of age or older with megaloblastic anemia due to B12 deficiency	60	3 months	WBC count, reticulocyte count, Hgb, MCV, platelet count, serum B12, neurological evaluation, including MMSE and assessment of vibration, light touch, and pain Baseline neurological findings included recall and/or concentration deficit in 7 patients, loss of the sense of light touch and pain in 9 patients, and loss of the sense of vibration in 5 patients	PO versus IM vitamin B12	In both groups, serum B12 increased. In both groups, Hgb, WBC count, and platelet count increased, MCV decreased, and reticulocytosis was observed. Neurologic improvement was detected in 7 of 9 patients in the PO B12 group and 9 of 12 patients in the IM B12 group
3	Bryan, 2002	Randomized clinical trial	Nondemented, healthy adult women	211	1 month	Food frequency questionnaire, specific neuropsychological tests, subjective mood assessment	Usual dietary intake of B-complex vitamins, combined vitamin 6, folate, and vitamin B12 treatment, or placebo	Dietary intake status was associated with speed of processing, recall, recognition, and verbal ability. Supplemental B12 slightly improved memory, but had no effect on mood
4	Cunha, 1995	Clinical trial	Elderly demented outpatients	46 of 181 individuals had low serum B12	3 to 24 months	MMSE, serum B12	Vitamin B12 treatment	Outcome was obtained in 19 of the 46 patients with low serum B12. 16 of the 19 cognitively declined; 3 of the 19 cognitively improved. The 3 that improved had mild dementia of less than 2 years duration
5	Eastley, 2000*	Case-control	Mildly cognitive impaired or demented outpatients with low serum B12	88	NA	Specific neuropsychological tests, Hgb, MCV, serum B12	Vitamin B12 treatment	Patients with low serum B12 and MCI, treated with B12, improved in verbal fluency compared to controls
6	El Otmani, 2008	Case series	Patients with B12 deficiency involving the nervous system	27	NA	Neurological examination, serum B12	Vitamin B12 treatment	Of 27 cases, 1 had dementia, which improved with B12 treatment Of the remaining cases, 12 improved neurologically with B12 treatment
7	Fox, 1975	Case series	Patients with dementia	40	NA	Various laboratory and radiological tests, including computerized axial tomography	Vitamin B12 treatment	A patient with dementia with PA demonstrated marked improvement with B12 treatment
8	Healton, 1991	Case series	Patients with B12 deficiency involving the nervous system	143	204 months	Neurologic impairment quantitative severity score, Hct, MCV, neutrophil count, platelet count, serum B12	Vitamin B12 treatment	Of 121 episodes of low serum B12, 64 had a partial response and 57 had a complete response
9	Ikeda, 1992	Prospective investigation	Individuals with AD	10	NA	Intellectual function rating scales, serum B12, serum B12 unsaturated binding capacities, CSF B12	Vitamin B12 treatment	IV mecobalamin improved memory, emotional function, and interpersonal communication. Improvement of interpersonal communication and memory occurred after a serum B12 threshold was maintained for sufficient time and at relatively higher CSF B12 levels
10	Kalita, 2008	Clinical trial of patients, compared with a representative control group	Patients with low serum B12 and/or megaloblastic bone marrow	36	3 months	Neurological examination, MMSE, craniospinal MRI, cognitive evoked potentials, WBC count, RBC count, RBC indices, Hgb, serum chemistry, HIV titer, thyroid profile, antiparietal cell antibodies	Vitamin B12 treatment	The presenting syndrome was myelopathy in 8, cognitive in 1, myeloneuropathy in 10, myelocognitive in 8, and myeloneurocognitive in 9 patients. MMSE was abnormal in 17 patients. Cranial MRI demonstrated cortical atrophy in 1 and multiple white matter hyperintensities in 3 patients. P3 latency was either prolonged or unrecordable in 15 patients compared to controls. Both MMSE and P3 latency improved
11	Kwok, 2008*	Clinical trial	Mild to moderately demented patients with low serum B12	30	9 months	MMSE, specific neuropsychological test, serum B12	Vitamin B12 treatment	DRS significantly decreased between baseline and 9 months
12	La Rue, 1997	Retrospective analysis	Community-dwelling elders without MCI or dementia	137	72 months	Specific neuropsychological tests, current and past intake of dietary proteins, dietary vitamins, and supplements	Dietary and supplemental vitamin B12 intake	Higher past B12 intake was related to better performance on recall, visuospatial, or abstraction testing
13	Lehmann, 2003	Clinical trial	Mildly cognitive impaired patients with HHcy, normal serum B12 and normal serum folate	30	9 months	Plasma albumin, plasma Hcy, serum B12, serum folate, CSF albumin, CSF tau protein, Baseline CSF-to-plasma albumin ratio was higher in patients compared to a control group.	Combined vitamin B6, folic acid, and vitamin B12 treatment	Reduction of the CSF-to-plasma albumin ratio CSF tau protein levels did not significantly change, although there was a numeric decline. None of the patients progressed to dementia during the treatment period
14	Levine, 2006	Randomized, double-blind, placebo controlled	Individuals with HHcy and schizophrenia	42	3 months	Neuropsychological testing, including the WCST, PANSS	Vitamin B12 treatment	Neuropsychological testing, in general, and the WCST, in particular, improved in the treatment group. PANSS declined in the treatment group
15	Lindenbaum, 1988	Case series	Patients with B12 deficiency involving the nervous system	141	NA	Neurologic impairment quantitative severity score, Hct, MCV, neutrophil count, platelet count, serum B12, plasma Hcy, serum MMA	Vitamin B12 treatment	Of 121 episodes of low serum B12, all patients responded to B12 treatment, except one patient who died All patients with neuropsychiatric findings associated with low serum B12 with HHcy or HMMA responded to B12 treatment
16	Martin, 1992	Clinical trial	Cognitively impaired elderly with low serum B12	18	6 months	MDRS	Vitamin B12 treatment	11 patients improved cognitively with IM cyanocobalamin. Patients symptomatic for less than 12 months gained an average of 20 points on the MDRS; patients symptomatic greater than 12 months lost an average of three points
17	Nilsson, 2001	Prospective investigation	Demented elderly	33	NA	MMSE, cognitive testing for memory and attention, serum B12, blood folate, plasma Hcy, serum MMA	Folic acid and vitamin B12 treatment	Patients with mild-moderate dementia and elevated plasma Hcy clinically improved, with increased test scores, while severely demented patients and those with normal plasma Hcy levels did not clinically improve
18	Osimani, 2005	Case-control	Demented patients with low serum B12	19	12 months	Specific neuropsychological tests serum B12	Vitamin B12 treatment	Twelve patients improved with treatment; seven patients did not improve with treatment. Baseline neuropsychological tests distinguished those who improved from those who did not improve
19	Remington, 2009	Randomized, placebo-controlled	Individuals institutionalized with moderate to severe AD	12	9 months	Cognitive and functional rating scales, including DRS, CDT, NPI, and ADCS-ADL	A dietary supplement containing folic acid, vitamin B12, alpha-tocopherol, SAM, N-acetyl cysteine, and acetyl-L-carnitine	Treatment group demonstrated a delay in decline in the DRS and CDT, 30% improvement in the NPI, and maintenance of performance in the ADCS-ADL
20	van Asselt, 2001	Single-blind, placebo-controlled clinical trial	Healthy, cognitively intact, communitydwelling elders with low serum B12	16	6 months	Serum B12, plasma Hcy, serum MMA, quantitative EEG, specific neuropsychological tests	1 month placebo treatment, followed by 5 months vitamin B12 treatment	After B12 treatment, serum B12 increased and plasma Hcy and serum MMA decreased. Quantitative EEG showed more fast activity and less slow activity, which was associated with improved performance on the Verbal Word Learning Test, Verbal Fluency, and Similarities. Psychometric test performance improved on the Verbal Word Learning Test, Verbal Fluency, and Similarities. Lower plasma Hcy concentrations were related to increased fast activity on quantitative EEG and improved performance on the Verbal Word Learning Test and Similarities.

Abbreviations: Abeta40, amyloid beta-protein ending in Val-40; Abeta42, amyloid beta-protein ending in Ala-42; AChE I, acetylcholinesterase inhibitor; AD, Alzheimer’s disease; ADAS-cog, Alzheimer Disease Assessment Scale – cognitive subscale; ADCS-ADL, Alzheimer Disease Cooperative Study-Activities of Daily Living; ADL, activity of daily living; BPRS, Brief Psychiatric Rating Scale; CAMCOG, Cambridge Cognitive Examination; CDT, Clock Drawing Test; CSF, cerebrospinal fluid; DRS, Dementia Rating Scale; DUST, deoxyuridine suppression test; EEG, electroencephalogram; GDS, Geriatric Depression Scale; Hct, hematocrit; Hcy, homocysteine; Hgb, hemoglobin; HHcy, hyperhomocysteinemia; HIV, Human Immunodeficiency Virus; HMMA, hypermethylmalonic acidemia; IM, intramuscular; IV, intravenous; MCI, mild cognitive impairment; MCV, mean corpuscular volume; MDI, Major Depression Inventory; MDRS, Mattis Dementia Rating Scale; MMA, methylmalonic acid; MMSE, Mini-Mental State Examination; MRI, magnetic resonance image; NA, not applicable or available; NPI, Neuropsychiatric Inventory; PA, pernicious anemia; PANSS, Positive and Negative Syndrome Scale; PO, oral; RBC, red blood cell; WCST, Wisconsin Card Sorting Test;

*Study appears in two areas of table based on outcomes.

Table 4 Factors associated with cognitive improvement in B12 supplementation of B12-deficient dementia

Etiology Treatment of B12 deficiency caused by pernicious anemia generally is associated with cognitive improvement. Treatment of B12 deficiency caused by etiologies other than pernicious anemia generally is not associated with cognitive improvement.

Homocysteine state Presence of hyperhomocysteinemia at treatment onset is associated with improvement, whereas absence is not.^Citation37,Citation358

Disease duration Duration of disease two years or less is associated with improvement, whereas duration of disease more than two years is not.^Citation24,Citation180,Citation346,Citation356

Disease intensity Mild cognitive impairment and mild to moderate dementia are associated with improvement, whereas moderately severe to severe dementia is not.^Citation24,Citation180,Citation350,Citation358,Citation359 Four^Citation306,Citation351,Citation353,Citation357 of five^Citation306,Citation351,Citation353,Citation357,Citation473 prospective studies, in individuals without cognitive dysfunction, showed supplemental B12 does not improve cognitive function, including in those with hypovitaminosis B12^Citation351,Citation353 and hyperhomocysteinemia.^Citation357

Treatment type Compounds Glutathionylcobalamin used by neurons under oxidative stress conditions^Citation146 not commercially available^Citation146,Citation290 Cyanocobalamin not used by neurons under oxidative stress conditions^Citation146,Citation290 commercially available Hydroxocobalamin not used by neurons under oxidative stress conditions^Citation146,Citation290 commercially available Mecobalamin not used by neurons under oxidative stress conditions^Citation146,Citation290 commercially available Routes of administration Cyanocobalamin can be administered orally, sublingually, intranasally, intramuscularly, subcutaneously, or intravenously The intravenous route is not advised unless the patient is in renal failure, since more than 98% of an intravenous dose may be lost in the urine. Methylcobalamin Oral doses do not increase serum or cerebral spinal fluid B12 levels^Citation490 do not improve cognitive function or activities of daily living in patients with Alzheimer’s disease^Citation361 Intramuscular or intravenous doses are required Intravenous doses have been shown to improve cognition, communication, emotions, and memory in patients with Alzheimer's disease.^Citation475 Whether or not methyl donors or antioxidants are administered N-acetylcysteine, a cell-permeate glutathione precursor,^Citation483 when combined with B12, improves cognition in patients with HHcy.^Citation474,Citation488 S-adenosylmethionine may be a useful adjunct for treatment of depression,^Citation477^–^Citation479,Citation485,Citation487 associated with Parkinson’s disease,^Citation481 human immunodeficiency virus infection,^Citation494 and fibromyalgia.^Citation495 Betaine lowers systemic Hcy^Citation476,Citation482,Citation491,Citation492 and may delay illness progression in Alzheimer’s disease.^Citation486 Homocysteine methylation to methionine occurs by one of two means methionine synthetase converting methyltetrahydrofolate to tetrahydrofolate, with methyltetrahydrofolate as the methyl group donor – occurs in all cells betaine homocysteine methyltransferase converting betaine to dimethylglycine, with betaine as the methyl group donor^Citation17,Citation58,Citation484 – confined to the liver and kidneys^Citation480,Citation489,Citation493 This may not matter in the treatment of dementia, as a leaky blood brain barrier may allow influx of systemic homocysteine.

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