The unique impact of changes in normal appearing brain tissue on cognitive dysfunction in secondary progressive multiple sclerosis patients Darcy Cox a , Daniel Pelletier a , Claude Genain a , Sharmila Majumdar b , Ying Lu b , Sarah Nelson b and David C Mohr* ,a,c,d a Department of Neurology, University of California, San Francisco, CA, USA; b Department of Radiology, University of California, San Francisco, CA, USA; c Department of Psychiatry, University of California, San Francisco, CA, USA; d San Francisco Veterans Affairs Medical Center, San Francisco, CA, USA Objective: The purpose of this study was to examine the relationships between cognitive functioning, whole brain magnetic transfer ratio (MTR) imaging, supratentorial 1 H-magnetic resonance spectroscopy imaging ( 1 HMRSI), and conventional T 1 and T 2 imaging in a homogenous sample of SPMS patients. Methods: Nineteen patients underwent a single 90-min imaging session that obtained T 1 -and T 2 - weighted images and MTR. 1 HMRSI was obtained on 14 of these patients. Patients underwent a neuropsychological battery, which was used to create an integrated measure of cognitive impairment. Cognitive impairment was the dependent variable in two hierarchical multiple regression analyses in which T 2 lesion load, T 1 lesion load, and MTR or NAA/Cr were entered sequentially. Results: MTR was significantly related to cognitive functioning (DR 2  /0.22, P  /0.02) after accounting for T 2 lesion load (DR 2  /0.33, P  /0.01) and T 1 lesion load (DR 2  /0.00, P  /0.98). NAA/Cr was not significantly related to cognitive functioning. Conclusions: Cognitive dysfunction may act as a clinical marker of normal appearing brain tissue pathology in multiple sclerosis. Multiple Sclerosis (2004) 10, 626  /629 Key words: multiple sclerosis; MRI; cognitive impairment; neuropsychological assessment; spectroscopy; magnetic transfer ratio imaging Multiple sclerosis (MS) is a chronic, often disabling disease in which the immune system attacks the myelin sheath around the axons of the central nervous system, resulting in a heterogeneous set of symptoms. 1 Cognitive impairments are a very common set of symptoms, affect- ing between 40% and 65% of patients. 2  4 The manifesta- tion of cognitive dysfunction is also heterogeneous, and can include deficits in speed of processing, memory disturbance, and impaired executive functioning. 5  11 A number of studies have examined the relationship between cognitive functioning and conventional neuroi- maging, including T 2 - and T 1 -weighted magnetic reso- nance imaging (MRI) and have generally found moderate relationships. 7,10,12  16 However, it is increasingly clear that pathological abnormalities exist in normal appearing brain tissue (NABT) outside MS lesions identified by conventional neuroimaging. Magnetic transfer ratio (MTR) imaging and magnetic resonance spectroscopy (MRS) imaging have shown significant differences in NABT between the brains of MS patients and healthy controls, and the abnormalities in MS patients are correlated with clinical disability. 17  20 The relationship between MRS and cognitive functioning remains relatively ambiguous, 21 although right hemisphere MRS measures correlate more with cognitive functioning than left hemisphere. 22 Several studies have found that the relationship between MTR and cognitive dysfunction may be greater than the rela- tionship between conventional MRI and cognitive dys- function. 7,17,23,24 However, previous MTR studies have either not directly examined the relative improvement of MTR over conventional MRI to explain cognitive deficits, or they have used a heterogeneous sample of patients (SRMS and relapsing /remitting MS). Additionally, as lesion type, lesion burden, atrophy and prevalence of cognitive dysfunction can vary depending on disease course, previous findings may lack clarity due to lack of sample differentiation. The purpose of this study was to examine the effects of MTR on cognitive functioning relative to conventional MRI in a homogenous sample of SPMS patients. Methods There were 19 patients with confirmed secondary pro- gressive MS (SPMS) 25,26 from the University of California, San Francisco MS Center. Participants were free of glucocorticoid treatments for at least one month prior to the assessment; disease-modifying medications (inter- feron-B, glatiramer acetate, mitoxantrone) were permitted. Neurological and neuroimaging data were collected on the same day. Neuropsychological assessment was conducted on the same day for most patients, but not more than one month following the date of the neuroimaging. *Correspondence: David C Mohr, VAMC, 4150 Clement St. (116-A), San Francisco, CA 94131, USA. E-mail: dmohr@itsa.ucsf.edu Received 1 December 2003; revised 22 April 2004; accepted 7 June 2004 Multiple Sclerosis 2004; 10: 626  /629 www.multiplesclerosisjournal.com # Arnold 2004 10.1191/1352458504ms1095oa