UNIVERSIDAD POLITÉCNICA DE MADRID FACULTAD DE CIENCIAS DE LA ACTIVIDAD FÍSICA Y DEL DEPORTE - INEF Evolution and treatment of vitamin B12 deficiency as a risk factor for (cognitive and functional) neurodegenerative diseases in institutionalized elderly Evolución y tratamiento de la deficiencia de vitamina B12 como factor de riesgo de enfermedades neurodegenerativas (cognitivas y funcionales) en las personas mayores institucionalizadas TESIS DOCTORAL ULRIKE ALBERS Licenciada en Ciencia y Tecnología de los Alimentos 2012 DEPARTAMENTO DE SALUD Y RENDIMIENTO HUMANO FACULTAD DE CIENCIAS DE LA ACTIVIDAD FÍSICA Y DEL DEPORTE - INEF Evolution and treatment of vitamin B12 deficiency as a risk factor for (cognitive and functional) neurodegenerative diseases in institutionalized elderly Evolución y tratamiento de la deficiencia de vitamina B12 como factor de riesgo de enfermedades neurodegenerativas (cognitivas y funcionales) en las personas mayores institucionalizadas Ulrike Albers Licenciada en Ciencia y Tecnología de los Alimentos Directores: María Marcela González Gross, Doctora en Farmacia, Profesora Titular de la Universidad Politécnica de Madrid Agustín Meléndez Ortega, Doctor en Ciencias de la Actividad Física y del Deporte, Profesor “Ad honorem” de la Universidad Politécnica de Madrid Madrid, 2012 Photo: Foto Krummen, Lingen Ulrike Albers, 2012 Edita: Universidad Politécnica, Av. Ramiro Maeztu 7, 28040 Madrid Imprime: MuzArt, Impresión Digital; c/ Gaztambide, 56; 28015 Madrid ISBN-10: 84-96398-59-5 ISBN-13: 978-84-96398-59-7 Tribunal nombrado por el Magfco. y Excmo. Sr. Rector de la Universidad Politécnica de Madrid, el día 20 de junio de 2012. PRESIDENTE: D. Luis A. Moreno Aznar, PhD VOCAL: Dña Mary Ward, PhD VOCAL: Dña Ángeles Carbajal Azcona, PhD VOCAL: Dña Christina Breidenassel, PhD SECRETARIA: Dña Ma del Carmen González Chamorro, PhD Realizado el acto de defensa y lectura de la Tesis el día 20 de junio de 2012 en Madrid. Calificación: EL PRESIDENTE LOS VOCALES LA SECRETARIA On ne reçoit pas la sagesse, il faut la découvrir soi-même après un trajet que personne ne peut faire pour nous, ne peut nous épargner, car elle est un point de vue sur les choses. A la recherche du temps perdu, Marcel Proust A Pilar Carazo Salmerón This PhD Thesis has been possible thanks to the following grants and funding: Project I Project title Vitamin B12 deficiency as a risk factor for neurodegenerative diseases. Longitudi- nal study for the evaluation of changes in the vitamin B12 status in Spanish elderly. (P061100509); funded by Axis-Shield Diagnostics Ltd. and Abbott Diagnostics. S.A. Project II Project title Vitamin B12 deficiency as a risk factor for neurodegenerative diseases. Effect of a cobalamin supplement during one month. (P051100649); supported by Whitehall Much GmbH and Abbott Diagnostics. S.A. Ulrike Albers has been financially supported by the University Politécnica de Madrid with a predoctoral scholarship (2008-2011). Grants from the Universidad Politécnica de Madrid to do internships in the following institutions. • Instituto de Medicina Molecular, Lisbon, Portugal. 20th of September-20th De- cember 2009. • Centre d’Investigations Cliniques CHU-Inserm, CIC 9301. Lille, France. 2nd October-31st of December 2010. • School of Biomedical Sciences, University of Ulster, Coleraine, UK. 18th June- 18th September 2011. PUBLICATONS AND PRESENTATIONS FROM THE THESIS Refereed Conference Proceedings and Abstracts Albers U, Pedrero R, Moran P, Cañada D, Meléndez A, González-Gross M. One year follow-up of biochemical and cobalamin status among Spanish institutionalized el- derly. 11th European Nutrition Conference (FENS). Madrid, Spain. 26-29.10.2011. Ann Nutr Metab 2011, 58(suppl 3): 48. González-Gross M, Pedrero-Chamizo R, Albers U. Interrelación entre la condición física, el estado nutricional vitamínico y el estado cognitivo y su influencia sobre la cal- idad de vida en mayores. 4° Congreso internacional de Actividad Física Deportiva para Mayores. Málaga, Spain. 4-6.03.2011. Proceedings ISBN 978-84-777858980. pp. 71-86. Albers U, Palacios G, Pedrero-Chamizo R, Meléndez A, Pietrzik K, González-Gross M. Plurimedication among Spanish institutionalized elderly, a fact that should be con- sidered when examining their nutritional status. II World Congress of Public Health Nutrition and I Latin American Congress of Community Nutrition. Porto, Portu- gal. 23-25.09.2010. Public Health Nutr 2010, 13(9A): 248. Pedrero-Chamizo R, Albers U, Valtueña J, Casajús JA, Castillo MJ, González -Gross M. Strength training is essential in elderly women. 5th World Conference on Women and Sport. Sydney, Australia. 20-23.05.2010. Abstract Book ISBN 978-0-9806738- 0-7, 2010. Pedrero-Chamizo R, Albers U, Valtueña J, Moreno S, Pietrzik K, Castillo MJ González- Gross M. Relation Between Physical Strength and Cognitive Function in Spanish In- stitutionalized Elderly. 3rd International Congress on Physical Activity and Public Health (ICPAPH). Toronto, Canada. 5-8.05.2010. Pedrero Chamizo R, Albers U, Morencos E, Pastor JC, Meléndez A, Castillo MJ, González–Gross M. Valoración del estado nutricional en mayores institucionalizados a través de diferentes marcadores. II Congreso de la FESNAD. Barcelona. Spain. 3-5.03.2010. Albers U, Pedrero-Chamizo R, Meléndez A, Castillo MJ, Pietrzik K, González-Gross M. How effective can a 500 µg oral supplement of vitamin B12 for just 28 days be for institutionalized elderly? XIXth IAGG World Congress of Gerontology and Geriatrics. Paris, France. 5-9.07.2009 Pedrero-Chamizo R, Albers U, Valtueña J, Cañada D, Jathe R, Meléndez A, Castillo MJ, González-Gross M: Evolución de los niveles de fuerza en población mayor insti- tucionalizada de la Comunidad de Madrid. III Jornadas Nacionales de Medicina del Deporte. Zaragoza, Spain. 29-30.05.2009. Pedrero-Chamizo R, Albers U, Valtueña J, Jiménez-Pavón D, Meléndez A, González- Gross M. Valores de referencia en fuerza de prensión manual en población mayor institucionalizada y de vida independiente. III Congreso Internacional de Actividad Físico Deportiva para Mayores. Málaga, Spain. 12-14.03.2009 Pedrero-Chamizo R, Albers U, Piera M, Jiménez-Pavón D, Meléndez A, Castillo MJ, González-Gross M. Gender, age and cognitive score effects on strength in Spanish institutionalized elderly. 13th Annual Congress of the European College of Sport Sciences. Estoril, Portugal. 9-12.07.2008 Pedrero-Chamizo R, Albers U, Valtueña J, Pietrzik K, Meléndez A, Castillo MJ, González-Gross M. Vitamin B12 deficiency. Effects on physical strength and cog- nitive health in Spanish institutionalized elderly. 6th international Conference on Nutrition and Fitness. Athens, Greece. 15-17.05.2008 Albers, U, Pedrero R, Díaz V, Tobaruela JL, Pietrzik K, Castillo MJ, Meléndez A, González-Gross M. Gender differences in vitamin B12 status and functional fitness parameters in Spanish institutionalized elderly. The 6th World Congress on The Aging Male. Tampa, Florida, United States, 21-24.02.2008. Pedrero R, Albers U, Jiménez-Pavón D, Cupeiro R, Meléndez A, Castillo MJ, Gutiér- rez A, González-Gross M. Valoración funcional en personas mayores institucional- izadas. XII Congreso Nacional de la Federación Española de Medicina del De- porte. Sevilla, Spain. 24-27.10.2007. Albers U, Meléndez A, Pietrzik K, Tobaruela JL, Castillo MJ, González-Gross M. Effectiveness of oral Vitamin B12 supplementation in Spanish institutionalized elderly. 7th International Conference VITAMINS - Nutrition and Diagnostics. Prague, Czech Republic. 19-21.09.2007. Albers U, Díaz V, Peinado A, Alvarez M, Sola R, Pietrzik K, Caballero J, Meléndez A, Castillo MJ, González-Gross M. Physical strength and Vitamin B12 in relation to cognitive score in Spanish institutionalized elderly. 10th European Nutrition Con- ference Paris, France. 10-13.07.2007. Ann Nutr Metab 2007; 51 (suppl 1): 119-120. Refereed Journal Publications Albers U, Palacios G, Pedrero-Chamizo R, Meléndez A, Pietrzik K, González-Gross M. La polimedicación en mayores institucionalizados. Su efecto sobre los niveles de vitamina B12, folato y homocisteína. Nutr Hosp. 2012;27(1): 296-300. Albers U, Pedrero R, Meléndez A, Pietrzik K, Castillo MJ, González-Gross M. Ef- fectiveness of a 28 days oral cyanocobalamin supplementation on vitamin B status in Spanish institutionalized elderly. (accepted in Int J Vitam Nutr Res) Contents Contents I List of Tables V List of Figures VII Nomenclature IX Glossary XI Abstract of the Thesis XIII Resumen de la Tesis XVII 1 INTRODUCTION 1 1.1 Introduction to the Thesis . 1 1.2 Significance of the Thesis . 5 2 REVIEW OF RELATED LITERATURE 9 2.1 Definition of Vitamin B12 and Food Sources . 9 2.2 Dietary Sources and Availability . 10 2.3 Requirements for the Daily Intake of Cobalamin in the Elderly . 11 2.4 Absorption, Storage and Excretion of Vitamin B12 ......... 12 2.4.1 Absorption and Storage . 12 2.4.2 Enterohepatic Circulation and Excretion of Vitamin B12 . 14 2.5 Functions of Vitamin B12 ....................... 15 2.6 Prevalence of Vitamin B12 Deficiency in the Elderly . 16 2.6.1 Factors Contributing to Poor Vitamin B12 Status with Ageing 16 I 2.6.2 Other Causes and Effects of Vitamin B12 Deficiency in the Elderly . 18 2.7 Clinical and Subclinical Manifestations of Vitamin B12 Deficiency in the Elderly . 19 2.7.1 Neurologic Effects of Vitamin B12 Deficiency . 19 2.7.2 Vitamin B12 and Cognitive Impairment . 20 2.7.3 Haematologic Effects of Deficiency . 21 2.7.4 Cardiovascular Effects of Deficiency . 22 2.7.5 Cognitive Impairment and the Function of the Neuromus- cular System . 23 2.8 Laboratory Diagnosis of Vitamin B Deficiency . 25 2.8.1 Indicators of Haematologic Status . 28 2.8.2 Serum or Plasma Cobalamin Levels . 28 2.8.3 Holotranscobalamin (HoloTC, Active B12)......... 28 2.8.4 Serum Methylmalonic Acid . 29 2.8.5 Serum Homocysteine Concentration . 29 2.9 Oral Supplements as Alternatives to Conventional Vitamin B12 Treatment............................... 29 3 HYPOTHESES AND OBJECTIVES 33 3.1 Hypotheses of Study I . 33 3.2 Objectives of Study I . 33 3.3 Hypotheses of Study II . 33 3.4 Objectives of Study II .