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Vitamin B12 deficiency and neurological complications

Low concentrations of folate and B12 are common in dementia patients. Vitamin B12 and folate are important for the synthesis of DNA and different methylation reactions that take place in the brain (methylation of DNA, RNA, myelin, phospholipids, receptors, and neurotransmitters). Serum B12 levels < 250 pmol/L were associated with a 2fold increased risk for incident Alzheimer disease (AD) within three years in Swedish elderly aging ≥ 75 years (1). B12 levels were also significantly lower in AD patients compared with healthy controls (69 – 88 years) living in Turkey (2) and in > 55 years old Italians (3) and subjects from England (4). Furthermore, patients with neuropsychiatric disorders had reduced levels of SAM in cerebrospinal fluid (5). Additionally, in patients with AD, the SAM levels post-mortem were very low in the brain and cerebrospinal fluid (6). Disorders of methylation capacity might enhance formation of β-amyloid and tau proteins in brains of AD patients (7).

In subjects > 70 years, the incidence of AD increased by 2fold when B12 was < 150 pmol/L compared with subjects with higher vitamin concentrations (1). Dementia has also been linked to low serum concentrations of holoTC, the metabolically active form of B12. Additionally, serum concentrations of B-vitamins were negatively related to deficits in neurocognitive tests (8). The association between B12 deficiency and depression has also been documented in elderly women (9).

The association of neurodegenerative disease with sub-clinical low-normal B12 levels is not confined to AD. Mean serum B12 levels were low but within the reference range in vascular dementia patients (169 pmol/L) vs. healthy controls (390 pmol/L; p < 0.001) (2) and in patients with Parkinson’s disease (PD) (216 pmol/L) vs. controls (284 pmol/L; p < 0.05) (10). Low-normal serum B12 levels (< 308 pmol/L) were associated with a faster rate of brain volume loss in one study of 107 community-dwelling elderly (11). A large study of 1,102 elderly subjects (> 60 years) also revealed an association between B12 deficiency (< 148 pmol/L) and white matter lesions (p = 0.001) (12).

Vitamin B12 deficiency and cognitive impairment (CI)

Furthermore, B12 deficiency is also related to cognitive impairment (CI) (13). In one study, low serum B12 concentrations (< 148 pmol/L) were associated with lower mini-mental state examination (MMSE) scores in AD patients (14.7 vs. 16.9; p <0.01; n = 643) (14). Stuerenburg et al. (15) described an association between CI in patients with AD and low serum B12 concentrations. In their study, the MMSE scores of AD patients in the bottom 10th percentile of B12 concentrations (< 136 pmol/L; MMSE 15.7) were significantly lower than MMSE scores for AD patients in the upper 10th percentile of B12 concentrations (> 441 pmol/L; MMSE 20.0). Neither B12 concentration nor MMSE score were associated with age in this study. In a large longitudinal study 1,648 subjects were followed over ten years to investigate whether B12 deficiency precedes neurodegenerative diseases (16). The data confirmed that B12 deficiency (<150 pmol/L) preceded a decline in cognition as measured by MMSE score in those aged ≥65 years. This study, however, has not proven that B12 deficiency caused cognitive decline but possibly those having B12 deficiency had a faster rate of cognitive decline compared to those having normal B12 status. Siuda et al. (17) compared 55 cases having mild cognitive impairment (MCI) with 44 age-, gender-, and education-matched healthy controls; they found that MCI patients had a lower mean serum B12 concentrations (338 vs. 397 pmol/L; p = 0.012).

The relation between CI and low serum B12 concentrations has also been found in other neurological diseases. Lower B12 concentrations were found in cognitively impaired (MMSE < 26) PD patients compared with non-impaired PD patients (203 vs. 227 pmol/L) (10). Additionally, 830 community-dwelling participants (≥ 75 years) were studied for cognitive impairment (MMSE < 22) and serum B12 concentrations. Serum B12 in the lower quartile (< 157 pmol/L) was associated with a 2fold-increased risk of CI when compared with B12 in the upper quartile (> 275 pmol/L) (18). Contrary, in a longitudinal study of 499 elderly subjects (> 70 years) B12 concentrations were neither associated with CI at baseline (measured by standardized cognitive performance tests) nor with increased risk of developing dementia over a seven year period (19).

In a clinical study (20), peripheral neuropathy occurred in 40% of B12 deficient subjects. Vitamin B12 deficiency can cause lesions in spinal cord, peripheral nerves, and cerebrum; improvements have been reported after initiation of vitamin treatment (21). The neurological symptoms in older people, whose high tHcy and/or low B12 concentrations were normalized through substitution with B-vitamins, tended to improve after long-term follow-up treatment (22). The most common symptoms are sensory disturbances in the extremities, memory loss, dementia, and psychosis. Polyneuropathy is also a common complication of long term uncontrolled diabetes mellitus affecting approximately 30 – 40% of the patients (23). The presence of polyneuropathy symptoms is strongly associated with B12 status and is a significant predictor of mortality in patients with diabetes.

The neurologic manifestations start with a demyelination of the nerve, followed by axonal degeneration and eventual irreversible damage due to axonal death. The spinal cord, brain, optic nerves, and peripheral nerves may all be affected by B12 deficiency. In a study evaluating the neuro-physiological and magnetic resonance imaging (MRI) changes in patients having B12 deficiency and neurological syndromes, the evoked potentials and MRI changes were found to be consistent with focal demyelination of white matter in the spinal cord and optic nerve (24).

The diagnosis of B12 deficiency is typically based on measurement of serum B12 level. However, about 50% of patients with subclinical deficiency have normal serum B12 concentrations. HoloTC, MMA in serum, and plasma tHcy can show pathological changes at early stages of B12 depletion. B12 deficiency causes HHCY that is associated with the risk of stroke and cardiovascular diseases (CVDs).

Vitamin B12 deficiency and stroke

The incidence of silent brain infarction increases with age. Clinical trials show that elderly subjects with this lesion have significantly higher plasma tHcy concentrations compared with those without brain infarction (25). Using brain computed tomography (CT), silent brain infarctions were linked to HHCY and low B-vitamin status (26). Studies with magnetic resonance angiography (MRA) confirm that lowering of tHcy by folic acid (FA) and vitamin B6 slightly improves cerebrovascular and cerebral indices (27). In a recent, placebo-controlled vitamin supplementation study (FA 0.8 mg, B12 0.5 mg, vitamin B6 20 mg/d) performed over 24 months in elderly people with MCI, Smith et al. (28) reported a lower rate of accelerated brain atrophy as shown by MRI in the vitamin arm compared with the placebo arm.

In the Rotterdam study, it was estimated that each 1 mmol/L increase in plasma tHcy concentrations were associated with a 6 – 7% increase in the risk of stroke (29). In the Physicians Health Study, a slight increase in the risk of stroke (1.4fold) was observed in subjects with plasma tHcy > 12.7 µmol/L compared with subjects having tHcy concentrations less than this value (30). A report from the HOPE-2 study documented that daily supplements of FA, vitamin B6, and B12 for 5 years reduced the risk of stroke by 25% (30). The beneficial effect of vitamins was larger in subjects with a certain risk profile or medications, and no marked effect was observed during the first 3 years of supplementation. Patients receiving anti-platelet agents or cholesterol lowering drugs or those from countries with folate fortification were less likely to benefit, suggesting a complex pattern of interaction between treatments, risk factors, and benefit (31).

In a meta-analysis of eight randomized vitamin treatment trials performed over a median duration of 5 years and involving 37,485 individuals (31), treatment studies with B-vitamins (FA, vitamin B6 and/or B12) were analyzed with respect to the risk of stroke, cancer, and vascular diseases. Despite a clear tendency [OR (95% CI) = 0.96 (0.87 – 1.06)] for decreasing the risk of stroke by B-vitamins, the effect was not statistically significant. However, many studies did not control for other medications or risk factors. In addition, all studies included in this meta-analysis were secondary prevention studies. In an earlier report, a decrease in the risk of stroke was obtained following treatment lasting over 3 years (32). The reduction in the risk of stroke was 23% when plasma tHcy was decreased by more than 20%. Patients who had no history of stroke, or those not on FA fortifications showed a reduction in risk of 25%.

Lee et al. (33) published a meta-analysis on the efficacy of tHcy-lowering therapy with FA in stroke prevention. This study included 13 randomized controlled trials that had enrolled > 39,000 participants undergoing therapy with FA and B-vitamins to decrease plasma tHcy and where stroke was reported as an outcome measure. Across all trials, FA supplementation was associated with a trend showing a slight benefit, but which did not achieve statistical significance [relative risk (RR) 0.93; 95% CI, 0.85 – 1.03; p = 0.16)]. However, the RR for non-secondary prevention trials was statistically significant 0.89 (95% CI, 0.79 – 0.99; p = 0.03). In stratified analyses, a greater beneficial effect was seen in the trials testing combination therapy of FA plus vitamin B6 and B12 (RR 0.83; 95% CI, 0.71 – 0.97; p = 0.02). The authors concluded that FA supplementation did not demonstrate any major effect in averting stroke. 

Plasma concentrations of tHcy correlated with those of amyloid-β (40 and 42) in 150 survivors of recent mild-to-moderate stroke events (34). However, B-vitamin treatment (FA 2.5 mg, B12 0.4 mg, and vitamin B6 25 mg) for 2 years did not significantly lower plasma amyloid-β. Depression affects approximately 30% of stroke survivors (35). B-vitamins supplementation (FA 2 mg, B12 0.5 mg, and vitamin B6 25 mg) for a mean of 7.1 years among survivors of stroke or transient ischemic attack resulted in a lower risk of major depression compared with the placebo group (18.4 vs. 23.3%) (36).

References

1.     Wang HX, Wahlin A, Basun H, Fastbom J, Winblad B, Fratiglioni L. Vitamin B(12) and folate in relation to the development of Alzheimer's disease. Neurology 2001;56:1188-94.
2.     Koseoglu E, Karaman Y. Relations between homocysteine, folate and vitamin B12 in vascular dementia and in Alzheimer disease. Clin Biochem 2007;40:859-63.
3.     Malaguarnera M, Ferri R, Bella R, Alagona G, Carnemolla A, Pennisi G. Homocysteine, vitamin B12 and folate in vascular dementia and in Alzheimer disease. Clin Chem Lab Med 2004;42:1032-5.
4.     Clarke R, Smith AD, Jobst KA, Refsum H, Sutton L, Ueland PM. Folate, vitamin B12, and serum total homocysteine levels in confirmed Alzheimer disease. Arch Neurol 1998;55:1449-55.
5.     Weir DG, Scott JM. Brain function in the elderly: role of vitamin B12 and folate. Br Med Bull 1999;55:669-82.
6.     Morrison LD, Smith DD, Kish SJ. Brain S-adenosylmethionine levels are severely decreased in Alzheimer's disease. J Neurochem 1996;67:1328-31.
7.     Scarpa S, Fuso A, D'Anselmi F, Cavallaro RA. Presenilin 1 gene silencing by S-adenosylmethionine: a treatment for Alzheimer disease? FEBS Lett 2003;541:145-8.
8.     Graham IM, Daly LE, Refsum HM, Robinson K, Brattstrom LE, Ueland PM et al. Plasma homocysteine as a risk factor for vascular disease. The European Concerted Action Project. JAMA 1997;277:1775-81.
9.     Penninx BW, Guralnik JM, Ferrucci L, Fried LP, Allen RH, Stabler SP. Vitamin B(12) deficiency and depression in physically disabled older women: epidemiologic evidence from the Women's Health and Aging Study. Am J Psychiatry 2000;157:715-21.
10.     Triantafyllou NI, Nikolaou C, Boufidou F, Angelopoulos E, Rentzos M, Kararizou E et al. Folate and vitamin B12 levels in levodopa-treated Parkinson's disease patients: their relationship to clinical manifestations, mood and cognition. Parkinsonism Relat Disord 2008;14:321-5.
11.     Vogiatzoglou A, Refsum H, Johnston C, Smith SM, Bradley KM, de JC et al. Vitamin B12 status and rate of brain volume loss in community-dwelling elderly. Neurology 2008;71:826-32.
12.     de Lau LM, Smith AD, Refsum H, Johnston C, Breteler MM. Plasma vitamin B12 status and cerebral white-matter lesions. J Neurol Neurosurg Psychiatry 2009;80:149-57.
13.     Moore E, Mander A, Ames D, Carne R, Sanders K, Watters D. Cognitive impairment and vitamin B12: a review. Int Psychogeriatr 2012;1-16.
14.     Whyte EM, Mulsant BH, Butters MA, Qayyum M, Towers A, Sweet RA et al. Cognitive and behavioral correlates of low vitamin B12 levels in elderly patients with progressive dementia. Am J Geriatr Psychiatry 2002;10:321-7.
15.     Stuerenburg HJ, Mueller-Thomsen T, Methner A. Vitamin B 12 plasma concentrations in Alzheimer disease. Neuro Endocrinol Lett 2004;25:176-7.
16.     Clarke R, Sherliker P, Hin H, Nexo E, Hvas AM, Schneede J et al. Detection of vitamin B12 deficiency in older people by measuring vitamin B12 or the active fraction of vitamin B12, holotranscobalamin. Clin Chem 2007;53:963-70.
17.     Siuda J, Gorzkowska A, Patalong-Ogiewa M, Krzystanek E, Czech E, Wiechula B et al. From mild cognitive impairment to Alzheimer's disease - influence of homocysteine, vitamin B12 and folate on cognition over time: results from one-year follow-up. Neurol Neurochir Pol 2009;43:321-9.
18.     Hin H, Clarke R, Sherliker P, Atoyebi W, Emmens K, Birks J et al. Clinical relevance of low serum vitamin B12 concentrations in older people: the Banbury B12 study. Age Ageing 2006;35:416-22.
19.     Kado DM, Karlamangla AS, Huang MH, Troen A, Rowe JW, Selhub J, Seeman TE. Homocysteine versus the vitamins folate, B6, and B12 as predictors of cognitive function and decline in older high-functioning adults: MacArthur Studies of Successful Aging. Am J Med 2005;118:161-7.
20.     Shorvon SD, Carney MW, Chanarin I, Reynolds EH. The neuropsychiatry of megaloblastic anaemia. Br Med J 1980;281:1036-8.
21.     Lorenzl S, Vogeser M, Muller-Schunk S, Pfister HW. Clinically and MRI documented funicular myelosis in a patient with metabolical vitamin B12 deficiency but normal vitamin B12 serum level. J Neurol 2003;250:1010-1.
22.     McCaddon A. Homocysteine and cognitive impairment; a case series in a General Practice setting. Nutr J 2006;5:6.
23.     Ziegler D, Zentai CP, Perz S, Rathmann W, Haastert B, Doring A, Meisinger C. Prediction of mortality using measures of cardiac autonomic dysfunction in the diabetic and nondiabetic population: the MONICA/KORA Augsburg Cohort Study. Diabetes Care 2008;31:556-61.
24.     Misra UK, Kalita J, Das A. Vitamin B12 deficiency neurological syndromes: a clinical, MRI and electrodiagnostic study. Electromyogr Clin Neurophysiol 2003;43:57-64.
25.     Matsui T, Arai H, Yuzuriha T, Yao H, Miura M, Hashimoto S et al. Elevated plasma homocysteine levels and risk of silent brain infarction in elderly people. Stroke 2001;32:1116-9.
26.     Polyak Z, Stern F, Berner YN, Sela BA, Gomori JM, Isayev M et al. Hyperhomocysteinemia and vitamin score: correlations with silent brain ischemic lesions and brain atrophy. Dement Geriatr Cogn Disord 2003;16:39-45.
27.     Vermeulen EG, Stehouwer CD, Valk J, van der Knaap M, van den Berg M, Twisk JW et al. Effect of homocysteine-lowering treatment with folic acid plus vitamin B on cerebrovascular atherosclerosis and white matter abnormalities as determined by MRA and MRI: a placebo-controlled, randomized trial. Eur J Clin Invest 2004;34:256-61.
28.     Smith AD, Smith SM, de Jager CA, Whitbread P, Johnston C, Agacinski G et al. Homocysteine-lowering by B vitamins slows the rate of accelerated brain atrophy in mild cognitive impairment: a randomized controlled trial. PLoS ONE 2010;5:e12244.
29.     Verhoef P, Hennekens CH, Malinow MR, Kok FJ, Willett WC, Stampfer MJ. A prospective study of plasma homocyst(e)ine and risk of ischemic stroke. Stroke 1994;25:1924-30.
30.     Saposnik G, Ray JG, Sheridan P, McQueen M, Lonn E. Homocysteine-lowering therapy and stroke risk, severity, and disability: additional findings from the HOPE 2 trial. Stroke 2009;40:1365-72.
31.     Clarke R, Halsey J, Lewington S, Lonn E, Armitage J, Manson JE et al. Effects of lowering homocysteine levels with B vitamins on cardiovascular disease, cancer, and cause-specific mortality: Meta-analysis of 8 randomized trials involving 37 485 individuals. Arch Intern Med 2010;170:1622-31.
32.     Wang X, Qin X, Demirtas H, Li J, Mao G, Huo Y et al. Efficacy of folic acid supplementation in stroke prevention: a meta-analysis. Lancet 2007;369:1876-82.
33.     Lee M, Hong KS, Chang SC, Saver JL. Efficacy of homocysteine-lowering therapy with folic Acid in stroke prevention: a meta-analysis. Stroke 2010;41:1205-12.
34.     Viswanathan A, Raj S, Greenberg SM, Stampfer M, Campbell S, Hyman BT, Irizarry MC. Plasma Abeta, homocysteine, and cognition: the Vitamin Intervention for Stroke Prevention (VISP) trial. Neurology 2009;72:268-72.
35.     Almeida OP, McCaul K, Hankey GJ, Norman P, Jamrozik K, Flicker L. Homocysteine and depression in later life. Arch Gen Psychiatry 2008;65:1286-94.
36.     Almeida OP, Marsh K, Alfonso H, Flicker L, Davis TM, Hankey GJ. B-vitamins reduce the long-term risk of depression after stroke: The VITATOPS-DEP trial. Ann Neurol 2010;68:503-10.