longitudinal study of cognition in primary progressive multiple sclerosis

doi:10.1093/brain/awh602 Brain (2005), 128, 2891–2898 A longitudinal study of cognition in primary progressive multiple sclerosis S. J. Camp,1 V. L. Stevenson,1 A. J. Thompson,1 G. T. Ingle,1 D. H. Miller,1 C. Borras,2 B. Brochet,3 V. Dousset,3 M. Falautano,4 M. Filippi,4 N. F. Kalkers,5 X. Montalban,2 C. H. Polman5 and D. W. Langdon1,6 1 Department of Clinical Neurology, Institute of Neurology, London, UK, 2Unitat de Neuroimmunologia Clinica, Hospitals Vall d’Hebron, Barcelona, Spain, 3Fédération des Neurosciences Cliniques de CHU de Bordeaux, Hôpital Pellegrin, Bordeaux, France, 4Department of Neuroscience, Scientific Institute Ospedale San Raffaele, Milan, Italy, 5University Hospital, Free University, Amsterdam, The Netherlands and 6Department of Psychology, Royal Holloway, University of London, Egham, UK Correspondence to: A. J. Thompson, Institute of Neurology, Queen Square, London WC1N 3BG, UK E-mail: There are few longitudinal studies of cognition in patients with multiple sclerosis, and the results of these studies remain inconclusive. No serial neuropsychological data of an exclusively primary progressive series are available. Cross-sectional analyses have revealed significant correlations between cognition and magnetic resonance imaging (MRI) parameters in primary progressive multiple sclerosis (PPMS). This study investigated cognitive and MRI change in 99 PPMS patients from five European centres for 2 years. They were assessed at 12 month intervals using the Brief Repeatable Battery, a reasoning test, and a measure of depression. The MRI parameters of T1 hypointensity load, T2 lesion load, and partial brain volume were also calculated at each time point. There were no significant differences between the mean cognitive scores of the patients at year 0 and year 2. However, one-third of the patients demonstrated absolute cognitive decline on individual test scores. Results indicated that initial cognitive status on entry into the study was a good predictor of cognitive ability at 2 years. There was only a small number of significant correlations between changes in cognition and changes on MRI, notably T1 hypointensity load with the two attentional tasks (r = 0.266, P = 0.017; r = 0.303, P = 0.012). It is probable that multiple factors underlie this weak relation between the cognitive and MRI measures. Keywords: cognitive function; longitudinal study; MRI; multiple sclerosis; primary progressive Abbreviations: BRB = Brief Repeatable Battery; EDSS = Expanded Disability Status Scale; MADRS = Montgomery and Asberg Depression Rating Scale; MRI = magnetic resonance imaging; PPMS = primary progressive multiple sclerosis; SPMS = secondary progressive multiple sclerosis; RRMS = relapsing remitting multiple sclerosis; VESPAR = Verbal and Spatial Reasoning Test; SDMT = Symbol Digits Modalities Test; PASAT = Paced Auditory Serial Addition Task; WLG = Word List Generation Test Received January 31, 2005. Revised May 17, 2005. Accepted June 27, 2005. Advance Access publication July 27, 2005 Introduction Primary progressive multiple sclerosis (PPMS) occurs in 10–15% of patients with multiple sclerosis. By definition, these patients experience a progressive disease course from onset without any relapses or remission. Because of their comparative rarity, PPMS patients are less often studied (Thompson et al., 2000). The frequency of cognitive impairment in PPMS has been variously quoted as 7% (Comi et al., 1995) and 29% (Camp et al., 1999). The cognitive skills reported to be impaired in PPMS include attention and working memory (Camp et al., 1999; Foong et al., 2000; De Sonneville et al., 2002; Huijbregts et al., 2004), verbal memory (Camp et al., 1999; Gaudino et al., 2001; Blum et al., 2002; Huijbregts et al., 2004), spatial memory (Huijbregts et al., 2004; but not consistently, see Camp et al., 1999; Gaudino et al., 2001), spatial reasoning (Camp et al., 1999) and verbal fluency (Camp et al., 1999; Huijbregts et al., 2004). Spatial perception and word definition have been reported intact (Gaudino et al., 2001), as has verbal reasoning (Camp et al., 1999). # The Author (2005). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: 2892 Brain (2005), 128, 2891–2898 Reports comparing cognitive function in PPMS with other multiple sclerosis subtypes are equivocal, although emerging differences in the pathological characteristics maintain interest in the comparison (Bruck et al., 2002). PPMS patients were found to perform better than secondary progressive multiple sclerosis (SPMS) patients on a spatial working memory task involving planning (Foong et al., 2000) and a spatial memory task (Gaudino et al., 2001); but PPMS patients have also demonstrated poorer spatial recall and verbal fluency than SPMS patients (Huijbregts et al., 2004), a specific deficit in word fragment completion, that was not present in relapsing remitting multiple sclerosis (RRMS) or SPMS (Blum et al., 2002) and impaired complex attention skills, verbal memory and verbal fluency, compared with RRMS patients (Gaudino et al., 2001; Huijbregts et al., 2004). Cognitive dysfunction in PPMS correlates modestly with magnetic resonance imaging (MRI) parameters (Camp et al., 1999). Controlled, cross-sectional, neuropsychological studies of multiple sclerosis patients have demonstrated that cognitive deficits may occur early in the disease process, and worsen as the disease progresses (Heaton et al., 1985; Beatty et al., 1989; Ron et al., 1991). Patients with optic neuritis, and brainstem or spinal cord lesions, which are frequently the harbinger of multiple sclerosis (Francis et al., 1987; Miller et al., 1989), have been reported as demonstrating mild cognitive deficits (Lyon-Caen et al., 1986; Callanan et al., 1989; Feinstein et al., 1992a), while RR patients show mild to moderate forms of impairment (Heaton et al., 1985; Beatty et al., 1989), and SP patients exhibit more severe deficiencies (Heaton et al., 1985; Beatty et al., 1988; Feinstein et al., 1992b). Less is known about progressive deterioration of neuropsychological skills in multiple sclerosis. Correlations between cognitive impairment and indicators of disease progression, such as disability and disease duration, are inconsistent, with some reports showing a significant correlation between cognitive impairment and physical disability (Beatty et al., 1990; McIntosh-Michaelis et al., 1991; Rao et al., 1991; Kessler et al., 1992; Basso et al., 1996; Troyer et al., 1996), while others have recorded no significant relationship (Jennekens-Schinkel et al., 1990; Minden et al., 1990; Mariani et al., 1991; Ron et al., 1991; Maurelli et al., 1992; Patti et al., 1995). The data regarding the relationship between cognitive function and disease duration are equally mixed, with most researchers reporting no correlation (Beatty et al., 1990; Jennekens-Schinkel et al., 1990; Minden (...truncated)