What is the Impact of Education on Huntington’s Disease? Jose Luis Lo ´ pez-Sendo ´ n, MD, 1,2 Ana Royuela, PhD, 3,4 Patricia Trigo, PhD, 1,2 Michael Orth, MD, 5 Herwig Lange, MD, PhD, 6 Ralf Reilmann, MD, PhD, 7 Jennifer Keylock, 8 Hugh Rickards, MD, PhD, 8 Silvia Piacentini, Prof., 9 Ferdinando Squitieri, MD, PhD, 10 Bernhard Landwehrmeyer, MD, 5 Marie-Noelle Witjes-Ane, 11 Caroline. K. Jurgens, 11 Raymund. A.C. Roos, PhD, 11 Victor Abraira, PhD, 3,4 Justo. G. de Ye ´ benes, MD, PhD 1,2 *, and the European HD Network 1 Department of Neurology, Hospital Ramon y Cajal, Madrid, Spain 2 CIBERNED, ISCIII, Madrid, Spain 3 CIBERESP, Madrid, Spain 4 Clinical Biostatistics Unit, Hospital Ramo ´ n y Cajal, Madrid, Spain 5 Department of Neurology, University of Ulm, Ulm, Germany 6 Reha Zentrum Dinslaken, Dinslaken, Germany 7 Department of Neurology, University of Muenster, Muenster, Germany 8 Department of Neurology, University of Birmingham, Birmingham, United Kingdom 9 Department of Neurology, University of Florence, Florence, Italy 10 Neurogenetics and Rare Disease Centre, IRCCS Neuromed, Pozzili, Italy 11 Department of Neurology, Leiden University Medical Centre, Leiden, The Netherlands ABSTRACT: Huntington’s disease (HD) is a neuro- degenerative disease caused by a cytosine adenosine guanine (CAG) expansion in the huntingtin gene. The length of the triplet repeat is the most important factor in determining age of onset and the severity of the dis- ease, but substantial variability of these parameters is attributed to other factors. To investigate the relation- ship between the years of education and the age at onset and the severity of the phenotype in patients with HD, we applied multiple linear regression analysis to examine the impact of education on the age at onset and the severity of the clinical scores assessed by the Unified Huntington’s Disease Rating Scale (UHDRS) of 891 patients with HD from the multinational observatio- nal study ‘‘Registry’’ conducted by the European Hun- tintgton’s Disease Network. The model was adjusted for CAG repeat length and age at the time of assessment. Patients with lengthier education exhibited earlier esti- mated age at onset but less severe clinical scores (motor 523.6, P 5 0.006; cognitive 5 27.0, P < 0.001; behavioral 523.0, P < 0.001; and functional capacity 5 1.1 points, P < 0.001) than those with shorter educa- tion, after controlling for age and number of CAG repeats. These differences persisted throughout all quartiles of disease severity. An earlier recognition of symptoms and manifestations among the more edu- cated patients could explain the earlier estimated age at onset in this group. The link between better clinical UHDRS scores and higher education might reflect a beneficial effect of education or its covariates on the course of HD. V C 2011 Movement Disorder Society Key Words: Huntington’s disease; education; neuro- protection; age at onset; UHDRS scores Huntington’s disease (HD) is an autosomal domi- nant hereditary progressive disorder characterized by motor abnormalities, cognitive decline, and behavioral disturbances. 1–5 The clinical phenotype is extremely variable in terms of age at onset, type of manifesta- tions, and speed of progression. HD is caused by a variable expansion of the number of CAG repeats of the huntingtin gene, 6 which codes for an expanded chain of polyglutamines in the N-terminal portion of the huntingtin protein. 7–10 The length of the CAG repeat is inversely correlated with the age at onset of ------------------------------------------------------------ Additional Supporting Information may be found in the online version of this article. *Correspondence to: Justo. G. de Ye ´ benes, Department of Neurology, Hospital Ramon y Cajal, Carr. de Colmenar km 9,1. Madrid 28034, Spain; jgyebenes@yahoo.com Relevant conflicts of interest/financial disclosures: This work is supported in part by grants from the Spanish Ministry of Health, FIS 2007/PI07025, CAM 0202/2006, and CIBER 2006/05/0059. ‘‘Registry’’ and other activities of the Euro HD Network are supported by the CHDI Foundation. Full financial disclosures and author roles can be found in the online version of this article. Received: 22 February 2010; Revised: 18 May 2010; Accepted: 9 July 2010 Published online 22 March 2011 in Wiley Online Library (wileyonlinelibrary.com). DOI: 10.1002/23385 RESEARCH ARTICLE Movement Disorders, Vol. 26, No. 8, 2011 1489