Structural and cognitive correlates of fatigue in progressive multiple sclerosis

ABSTRACT

Background: Fatigue in multiple sclerosis (MS) is a debilitating symptom and experienced by most patients. In recent studies investigating this phenomenon, the majority of patients had a relapsing-remitting disease course.

Methods: Patients with progressive MS participating in one of three treatment trials during a period from 2010 to 2014 were included. Fatigue was assessed with the Fatigue Scale for Motor and Cognitive Functions (FSMC) and patients were further examined with a cognitive test battery, including Symbol Digit Modalities Test (SDMT), and 3 T MRI with subsequent quantitative analyses of 13 cortical regions of interest, deep grey matter and lesion volume.

Results: Twenty-two patients were enrolled. The thickness of the pre-central gyrus correlated significantly with motor fatigue. We found only a non-significant trend towards a correlation between cognitive fatigue and the thickness of the pre-central gyrus, the parietal inferior supra-marginal gyrus and the opercular part of the inferior frontal gyrus. 36% of participants had impaired processing speed and 9% had normal function on all tests. The scores on the FSMC-cognitive scale were related to performance on SDMT.

Conclusion: In this exploratory study of patients with progressive MS, fatigue was related to processing speed. Motor fatigue was also related to the cortical thickness of the primary motor cortex and there was a trend towards a relationship between cognitive fatigue and the thickness of cortical areas involved in attentional processes. Additional studies are needed to further elucidate the relationship between regional cortical atrophy, cognitive functioning and the perception of fatigue.

Abbreviations: FSMC: Motor and Cognitive Functions; MS: Multiple Sclerosis; SDMT: Symbol Digit Modalities Test; MRI: Magnetic Resonance Imaging; RRMS: Relapsing-Remitting Disease Course; EDSS: Kurtzke Expanded Disability Status Scale; FLAIR: Fluid Attenuated Inversion Recovery; NAWM: Normal-Appearing White Matter; CGM: Cortical Grey Matter; CTh: Cortical Thickness; ROIs: Regions of Interest; Raven: Raven Progressive Matrices; TM A: Trail Making A; TM B: Trail Making B; Rey: Rey Complex Figure; Similarities: WAIS III Similarities; Stroop: Stroop Colour Naming Test; BDI: Becks Depression Inventory II.

KEYWORDS:

• Primary progressive multiple sclerosis
• secondary progressive
• multiple sclerosis
• fatigue
• cognition
• magnetic resonance imaging

Highlights

1. In progressive MS fatigue is related to processing speed.

2. In progressive MS motor fatigue is related to cortical thickness of the primary motor cortex.

3. In progressive MS cognitive fatigue is related to cortical thickness within areas related to attentional processes.

Acknowledgments

We are grateful to Annette Larsen (DMSC) for contacts to participants and related logistics, Hanne Schmidt (DRCMR) and Sascha Gude (DRCMR) involved through reader centre analysis pipeline. We thank Christian Thode Larsen for advice on Freesurfer.

Disclosure statement

No potential conflict of interest was reported by the authors.

Additional information

Funding

This research did not receive any specific grants from funding agencies in the public, commercial, or not-for-profit sectors, but the department has received research support from Biogen Idec, Bayer Schering, Merck Serono, TEVA, Baxter, Sanofi-Aventis, BioMS, Novartis, Bayer, RoFAR, Roche and Genzyme, and from the Danish Multiple Sclerosis Society, the Danish Medical Research Council and the European Union Sixth Framework Programme: Life Sciences, Genomics and Biotechnology for Health.

Notes on contributors

Anne Katrine Andreasen

Anne Katrine Andreasen is a board certified neurologist who holds a PhD within the area of Fatigue in multiple sclerosis and the relationship to processing speed, central motor activation and regional brain atrophy.

Pernille Iversen

Pernille Iversen holds a Ph.D in bioinformatics and has been data managing specialist and Manager of the Reader Centre at the Danish Research Centre for Magnetic Resonance (DRCMR).

Lisbet Marstrand

Lisbeth Marstrand holds a PhD and is Neuropsychologist at Copenhagen University Hospital, Rigshospitalet, Danish Multiple Sclerosis Center.

Volkert Siersma

Volkert Siersma is Statistician and lecturer at Research Unit for General Practice. He holds a PhD regarding the interactions between disease development and interventions.

Hartwig Roman Siebner

Hartwig Roman Siebner is head of research at the Center for Functional and Diagnostic Imaging and Research, Danish Research Center for Magnetic Resonance (DRCMR), Copenhagen University Hospital Hvidovre. He is Clinical Professor with special focus on Precision Medicine, Faculty of Health and Medical Sciences, Institute of Clinical Medicine, University of Copenhagen and Head of Research, Movement Disorders Research Group Department of Neurology, Copenhagen University Hospital Bispebjerg. Prof. Siebner's main research interests are Brain-circuit informed precision medicine, Brain connectivity and plasticity, Brain imaging of neurological and psychiatric diseases, Non-invasive brain stimulation, Multimodal brain mapping and, Human sensory-motor control and decision making.

Finn Sellebjerg

Finn Sellebjerg is professor of Neurology at the University of Copenhagen and head of the Danish Multiple Sclerosis Center, Department of Neurology, Rigshospitalet, University of Copenhagen. During the past 20 years Finn Sellebjerg has been involved in studies addressing the role of antibodies, the role of chemokines and matrix metalloproteases in leukocyte recruitment in multiple sclerosis, in several clinical trials and in studies addressing immune activation and immunogenetics in multiple sclerosis. His current research is focused on understanding the effect of MS therapies and the development of biomarkers for treatment monitoring, immunogenetics and clinical treatment trials. Furthermore, he is engaged in several ongoing single-center and multi-center treatment trials in progressive MS.