Saturday, September 19, 2009
From International Journal of Clinical Practice
Homocysteine, Vitamin B12, Folate and Cognitive Functions: A Systematic and Critical Review of the Literature
CM
Summary and Introduction
Summary
Elevated serum homocysteine, decreased folate and low vitamin B12 serum levels are associated with poor cognitive function, cognitive decline and dementia. Despite evidence of an epidemiological association, randomised controlled trials did not provide any clear evidence so far that supplementation with vitamin B12 and/or folate improves dementia or slows cognitive decline, even though it might normalise homocysteine levels. In this report, we review the current knowledge on the relationship between homocysteine, folate and vitamin B12 levels and the way their disruption influences cognitive function in adults.
Introduction
The prevalence of cognitive impairment increases with advancing age, making it a major public health concern in ageing populations. Dementia represents the main cause of cognitive problems among the elderly people and is characterised by a progressive deterioration of cognitive skills, leading ultimately to difficulties performing daily activities. The number of people suffering from dementia might triple over the next 50 years, for reasons of an increase in the proportion of the oldest-old segment of the population[1]. Alzheimer disease (AD) accounts for about two-thirds of dementia. The prevalence of AD rises exponentially with age, affecting 50% of adults aged 95 years. Other causes of dementia are Lewy body dementia, vascular dementia, Parkinson's disease-associated dementia, fronto-temporal dementia and reversible dementias. Measures for prevention of cognitive impairment are crucial for many reasons, most notably the lack of efficient therapies, the high prevalence of dementia and the devastating consequences of dementia for patients' caregivers and healthcare system.
The most relevant risk factors for AD are advancing age, female gender and low level of education. Other non-genetic risk factors for AD include cardiovascular disease, stroke, hypertension, diabetes and traumatic head injury. Biomarkers associated with the risk of late-life cognitive impairment or dementia are not well-described and poorly understood. Despite this, it is interesting from a physiopathological perspective to take into account the nutritional component and diet.
An association between neuropsychiatric or neurological disorders (e.g. 'subacute combined degeneration of the cord') and vitamin B12 (cobalamin) deficiency has been recognised since pernicious anaemia was first described in 1849[2]. Inappropriate levels of vitamin B are a common cause of the reversible type of dementia. The association between vitamin B abnormalities and impaired cognitive function or dementia remains questionable as studies and interventional trials have reported conflicting results.
Several human studies have demonstrated a link between vitamin B deficiency (or hyperhomocysteinemia) and cognition. However, these studies were very heterogeneous in terms of the populations studied, cut-offs used to define vitamin B deficiency, definitions of vitamin B deficiency (serum levels, dietary intakes), assessments of cognitive impairment, definitions of cognitive impairment [incident dementia, prevalent dementia, type of dementia, mild cognitive impairment (MCI)] and study designs. Thus, comparing studies is difficult and caution is necessary when analysing and interpreting the results.
In this article, we distinguished three types of studies: cross-sectional studies, longitudinal studies, featuring a generally more adequate nutrient exposure and intervention studies with vitamin B supplementation.
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References
- Ziegler-Graham K, Brookmeyer R, Johnson E, Arrighi HM. Worldwide variation in the doubling time of Alzheimer's disease incidence rates. Alzheimers Dement 2008; 4: 316-23.
- Addison T. Anemia: disease of the suprarenal capsules. Lond Med Gaz 1849; 43: 517.
- Andrès E, Loukili NH, Noel E et al. Vitamin B12 (cobalamin) deficiency in elderly patients. CMAJ 2004; 171: 251-9.
- Clarke R. B-vitamins and prevention of dementia. Proc Nutr Soc 2008; 67: 75-81.
- 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.
- Köseoglu E, Karaman Y. Relations between homocysteine, folate and vitamin B12 in vascular dementia and in Alzheimer disease. Clin Biochem 2007; 40: 859-63.
- Quadri P, Fragiacomo C, Pezzati R et al. Homocysteine, folate, and vitamin B-12 in mild cognitive impairment, Alzheimer disease, and vascular dementia. Am J Clin Nutr 2004; 80: 114-22.
- Feng L, Ng TP, Chuah L, Niti M, Kua EH. Homocysteine, folate, and vitamin B-12 and cognitive performance in older Chinese adults: findings from the Singapore Longitudinal Ageing Study. Am J Clin Nutr 2006; 84: 1506-12.
- Miller JW, Green R, Ramos MI et al. Homocysteine and cognitive function in the Sacramento Area Latino Study on Aging. Am J Clin Nutr 2003; 78: 441-7.
- Arioğul S, Cankurtaran M, Dağli N, Khalil M, Yavuz B. Vitamin B12, folate, homocysteine and dementia: are they really related? Arch Gerontol Geriatr 2005; 40: 139-46.
- Ravaglia G, Forti P, Maioli F et al. Elevated plasma homocysteine levels in centenarians are not associated with cognitive impairment. Mech Ageing Dev 2000; 121: 251-61.
- Seshadri S, Beiser A, Selhub J et al. Plasma homocysteine as a risk factor for dementia and Alzheimer's disease. N Engl J Med 2002; 346: 476-83.
- Luchsinger JA, Tang MX, Shea S, Miller J, Green R, Mayeux R. Plasma homocysteine levels and risk of Alzheimer disease. Neurology 2004; 62: 1972-6.
- Mooijaart SP, Gussekloo J, Frölich M et al. Homocysteine, vitamin B-12, and folic acid and the risk of cognitive decline in old age: the Leiden 85-Plus study. Am J Clin Nutr 2005; 82: 866-71.
- Tucker KL, Qiao N, Scott T, Rosenberg I, Spiro A 3rd. High homocysteine and low B vitamins predict cognitive decline in aging men: the Veterans Affairs Normative Aging Study. Am J Clin Nutr 2005; 82: 627-35.
- Fioravanti M, Ferrario E, Massaia M et al. Low folate levels in the cognitive decline of elderly patients and the efficacy of folate as a treatment for improving memory deficits. Arch Gerontol Geriatr 1998; 26: 1-13.
- Bryan J, Calvaresi E, Hughes D. Short-term folate, vitamin B-12 or vitamin B-6 supplementation slightly affects memory performance but not mood in women of various ages. J Nutr 2002; 132: 1345-56.
- Sommer BR, Hoff AL, Costa M. Folic acid supplementation in dementia: a preliminary report. J Geriatr Psychiatry Neurol 2003; 16: 156-9.
- Durga J, van Boxtel MP, Schouten EG et al. Effect of 3-year folic acid supplementation on cognitive function in older adults in the FACIT trial: a randomised, double blind, controlled trial. Lancet 2007; 369: 208-16.
- Rapin JR, LePoncin M, Grebyl J. Blood folates deficiencies and cognitive functions in aging. Trends Biomed Gerontol 1988; 1: 315-23.
- Eussen SJ, de Groot LC, Joosten LW et al. Effect of oral vitamin B-12 with or without folic acid on cognitive function in older people with mild vitamin B-12 deficiency: a randomized, placebo-controlled trial. Am J Clin Nutr 2006; 84: 361-70.
- Hvas AM, Juul S, Lauritzen L, Nexø E, Ellegaard J. No effect of vitamin B-12 treatment on cognitive function and depression: a randomized placebo controlled study. J Affect Disord 2004; 81: 269-73.
- McMahon JA, Green TJ, Skeaff CM, Knight RG, Mann JI, Williams SM. A controlled trial of homocysteine lowering and cognitive performance. N Engl J Med 2006; 354: 2764-72.
- Aisen PS, Schneider LS, Sano M et al. High dose B vitamin supplementation and cognitive decline in Alzheimer disease. A randomized Controlled trial. JAMA 2008; 300: 1774-83.
- Lewerin C, Matousek M, Steen G, Johansson B, Steen B, Nilsson-Ehle H. Significant correlations of plasma homocysteine and serum methylmalonic acid with movement and cognitive performance in elderly subjects but no improvement from short-term vitamin therapy: a placebo-controlled randomized study. Am J Clin Nutr 2005; 81: 1155-62.
- Dali-Youcef N, Andrès E. An update on cobalamin deficiency in adults. QJM 2009; 102: 17-28.
- Malouf R, Grimley Evans J. Folic acid with or without vitamin B12 for the prevention and treatment of healthy elderly and demented people. Cochrane Database Syst Rev 2008; 8: CD004514.
Authors and Disclosures
As an organization accredited by the ACCME, MedscapeCME requires everyone who is in a position to control the content of an education activity to disclose all relevant financial relationships with any commercial interest. The ACCME defines "relevant financial relationships" as financial relationships in any amount, occurring within the past 12 months, including financial relationships of a spouse or life partner, that could create a conflict of interest.
MedscapeCME encourages Authors to identify investigational products or off-label uses of products regulated by the US Food and Drug Administration, at first mention and where appropriate in the content.
Author(s)
Thomas Vogel, MD
Pôle de Gériatrie, Hôpitaux Universitaires de Strasbourg, Hôpital de la Robertsau, Pavillon Schutzenberger, Strasbourg Cedex, France
Disclosure: Thomas Vogel, MD, has disclosed no relevant financial relationships.
Nassim Dali-Youcef, PhD
Pôle de Biologie, Nouvel Hôpital Civil, Hôpitaux Universitaires de Strasbourg, Strasbourg Cedex, France
Disclosure: Nassim Dali-Youcef, PhD, has disclosed no relevant financial relationships.
Georges Kaltenbach, MD
Pôle de Gériatrie, Hôpitaux Universitaires de Strasbourg, Hôpital de la Robertsau, Pavillon Schutzenberger, Strasbourg Cedex, France
Disclosure: Georges Kaltenbach, MD, has disclosed no relevant financial relationships.
Emmanuel Andrès, MD
Service de Médecine Interne, Clinique Médicale B, Hôpital Civil, Hôpitaux Universitaires de Strasbourg, Strasbourg Cedex, France
Disclosure: Emmanuel Andrès, MD, has disclosed no relevant financial relationships.
CME Author(s)
Désirée Lie, MD, MSEd
Clinical Professor, Family Medicine, University of California, Orange; Director, Division of Faculty Development, UCI Medical Center, Orange, California
Disclosure: Désirée Lie, MD, MSEd, has disclosed no relevant financial relationships.
Editor(s)
Graham Jackson, MD, FESC, FRCP, FACC
Honorary Consultant Cardiologist, Cardiothoracic Centre, Guy's and St. Thomas' Hospital, London, United Kingdom
Disclosure: Graham Jackson, MD, FESC, FRCP, FACC, has disclosed that he has served as an academic advisor for Pfizer Inc.; Eli Lilly & Co., Inc.; Plethora Solutions Limited; Shire; and SERVIER, and has served as chairman of the Sexual Dysfunction Association. Dr. Jackson regularly gives sponsored lectures that are rigorously noncommercial.
Leslie Citrome, MD, MPH
Director, Clinical Research and Evaluation Facility, Nathan S. Kline Institute for Psychiatric Research, Orangeburg, New York; Professor of Psychiatry, New York University School of Medicine, New York, NY
Disclosure: Leslie Citrome, MD, MPH, has disclosed that he is a consultant for, has received honoraria from, or has conducted clinical research supported by Abbott Laboratories; AstraZeneca Pharmaceuticals LP; Avanir Pharmaceuticals; Azur Pharma Ltd.; Barr Pharmaceuticals, Inc.; Bristol-Myers Squibb Company; Eli Lilly & Co., Inc.; Forest Research Institute; GlaxoSmithKline; Janssen; Jazz Pharmaceuticals, Inc.; Pfizer Inc.; and Vanda Pharmaceuticals Inc.
Karen Costenbader, MD, MPH
Rheumatology and Immunology, Brigham and Women's Hospital, Boston, Massachusetts
Disclosure: Karen Costenbader, MD, MPH, has disclosed no relevant financial relationships.
Serge Jabbour, MD
Associate Professor of Clinical Medicine, Division of Endocrinology, Diabetes, and Metabolic Diseases, Department of Medicine, Jefferson Medical College/Thomas Jefferson University, Philadelphia, Pennsylvania
Disclosure: Serge Jabbour, MD, has disclosed that he has served on the speaker's bureau for Amylin Pharmaceuticals, Inc. and Eli Lilly & Co., Inc.
Rubin Minhas
General Practitioner; Honorary Senior Lecturer, Faculty of Science, Technology, and Medical Studies, University of Kent, Kent, United Kingdom
Disclosure: Rubin Minhas, has disclosed no relevant financial relationships.
Matt Rosenberg, MD, BA
Medical Director, Mid-Michigan Health Centers, Jackson, Michigan
Disclosure: Matt Rosenberg, MD, BA, has disclosed that he has served as a consultant for Abbott Laboratories; Allergan, Inc.; Astellas Pharma, Inc.; GlaxoSmithKline; Novartis Pharmaceuticals Corporation; Ortho-McNeil-Janssen Pharmaceuticals, Inc.; Pfizer Inc.; Roche Laboratories Inc.; sanofi-aventis; and Verathon Inc. Dr. Rosenberg has also disclosed that he has received fees for non-CME services from Abbott Laboratories; Allergan, Inc.; Astellas Pharma, Inc.; GlaxoSmithKline; Esprit Pharma; Ortho-McNeil-Janssen Pharmaceuticals, Inc.; and Roche Laboratories Inc., and conducted research funded by sanofi-aventis.
Jagdish Sharma, FRCP, FESO
Sherwood Forest NHS Trust, Nottinghamshire, United Kingdom
Disclosure: Jagdish Sharma, FRCP, FESO, has disclosed no relevant financial relationships.
Anthony Wierzbicki, FACA, FACB
Senior Lecturer in Chemical Pathology, St. Thomas' Hospital, London, United Kingdom
Disclosure: Anthony Wierzbicki, FACA, FACB, has disclosed that he has received support for travel from Abbott Laboratories; AstraZeneca Pharmaceuticals LP; Merck KGaA; and Merck Sharp & Dohme, and received lecture honoraria from Abbott Laboratories; AstraZeneca Pharmaceuticals LP; Bristol-Myers Squibb Company; Genzyme Corporation; Gilead Sciences, Inc.; Merck KGaA; Merck Sharp & Dohme; Pfizer Inc.; Roche Laboratories Inc.; Schering-Plough Corporation; and Solvay/Fournier. Dr. Wierzbicki is an advisory board member for Abbott Laboratories; AstraZeneca Pharmaceuticals LP; Bristol-Myers Squibb Company; Genzyme Corporation; Gilead Sciences, Inc.; Kowa Company Ltd.; LifeCycle Pharma; Merck KGaA; Merck Sharp & Dohme; Pfizer Inc.; Roche Laboratories Inc.; Schering-Plough Corporation; Solvay/Fournier; Surface Logix, Inc.; and Takeda Pharmaceuticals North America, Inc.
Mark Harries, MA, PhD, FRCP
Consultant in Medical Oncology, Guy's and St. Thomas' Hospital, London, United Kingdom
Disclosure: Mark Harries, MA, PhD, FRCP, has disclosed no relevant financial relationships.
Gabrielle Cremer, MD
Cremer Consulting, Strasbourg, France
Disclosure: Gabrielle Cremer, MD, has disclosed no relevant financial relationships.
Carol Peckham
Site Editorial Director, MedscapeCME
Disclosure: Carol Peckham has disclosed no relevant financial relationships.
CME Information
CME Released: 08/31/2009; Valid for credit through 08/31/2010
Target Audience
This activity is intended for primary care clinicians, geriatricians, neurologists, psychiatrists, and other specialists who care for older adults.
Goal
The goal of this activity is to review the association between vitamin B12 and folic acid deficiency, homocysteinemia, and cognitive decline in adults.
Learning Objectives
Upon completion of this activity, participants will be able to:
- Describe tests and their limitations for the diagnosis of vitamin B deficiencies
- Describe types of studies linking vitamin B with cognitive function
- Advise patients on use of folic acid and vitamin B12 for preventing cognitive decline
Credits Available
Physicians - maximum of 0.50 AMA PRA Category 1 Credit(s)™
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E Released: 08/31/2009; Valid for credit through 08/31/2010
