Outcome measures for central nervous system evaluation in myotonic dystrophy type 1 may be confounded by deficits in motor function or insight

Hamilton, M. J., McLean, J., Cumming, S., Ballantyne, B., McGhie, J., Jampana, R., Longman, C., Evans, J. J. , Monckton, D. G. and Farrugia, M. E. (2018) Outcome measures for central nervous system evaluation in myotonic dystrophy type 1 may be confounded by deficits in motor function or insight. Frontiers in Neurology, 9, 780. (doi: 10.3389/fneur.2018.00780) (PMID:30333784) (PMCID:PMC6176265)

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Abstract

Background: Central nervous system involvement in myotonic dystrophy type 1 (DM1) is associated with cognitive deficits, impaired social performance and excessive somnolence, which greatly impact quality of life. With the advent of clinical trials in DM1, there is a pressing need to identify outcome measures for quantification of central symptoms that are feasible and valid. In this context, we sought to evaluate neuropsychological and self-reported measures currently recommended by expert consensus, with particular reference to their specificity for central nervous system involvement in a moderate-sized DM1 cohort. Methods: Forty-five adults with DM1 and 20 controls completed neuropsychology assessments and symptom questionnaires. Those without contraindication also underwent MRI brain, from which global gray matter volume and white matter lesion volume were quantified. CTG repeat was measured by small pool PCR, and was screened for the presence of variant repeat sequences. Results: The neuropsychology test battery was well tolerated and detected impairment across various domains in the DM1 group vs. controls. Large effect sizes in the Stroop and Trail Making Tests were however attenuated by correction for basic speed, which could be influenced by dysarthria and upper limb weakness, respectively. Low mood was strongly associated with increased self-reporting of central symptoms, including cognitive impairment. Conversely, self-reported cognitive impairment did not generally predict poorer performance in neuropsychology assessments, and there was a trend toward greater self-reporting of low mood and cognitive problems in those with milder white matter change on MRI. Global gray matter volume correlated with performance in several neuropsychology assessments in a multivariate model with age and sex, while white matter lesion volume was associated with executive dysfunction reported by a proxy. Screening for variant repeats was positive in three individuals, who reported mild muscle symptoms. Conclusions: Identification of outcome measures with good specificity for brain involvement in DM1 is challenging, since complex cognitive assessments may be compromised by peripheral muscle weakness and self-reported questionnaires may be influenced by mood and insight. This highlights the need for further large, longitudinal studies to identify and validate objective measures, which may include imaging biomarkers and cognitive measures not influenced by motor speed.

Item Type:Articles
Additional Information:This study was funded by grants from Muscular Dystrophy UK (Ref: MC3/1073) and Chief Scientist Office Scotland (Ref: CAF/MD/15/01). The Monckton group (University of Glasgow) also thank the Myotonic Dystrophy Support Group (UK) for their continued support.
Keywords:Myotonic dystrophy, outcome measures, voxel based morphometry, neuropsychology assessment, small pool PCR.
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Longman, Dr Cheryl and Jampana, Dr Ravi and Evans, Professor Jonathan and Hamilton, Dr Mark and Monckton, Professor Darren and McGhie, Mrs Josephine and Cumming, Dr Sarah
Authors: Hamilton, M. J., McLean, J., Cumming, S., Ballantyne, B., McGhie, J., Jampana, R., Longman, C., Evans, J. J., Monckton, D. G., and Farrugia, M. E.
College/School:College of Medical Veterinary and Life Sciences > Institute of Health and Wellbeing > Mental Health and Wellbeing
College of Medical Veterinary and Life Sciences > Institute of Molecular Cell and Systems Biology
College of Medical Veterinary and Life Sciences > Institute of Neuroscience and Psychology
College of Medical Veterinary and Life Sciences > School of Medicine, Dentistry & Nursing
Journal Name:Frontiers in Neurology
Publisher:Frontiers Media
ISSN:1664-2295
ISSN (Online):1664-2295
Copyright Holders:Copyright © 2018 Hamilton, McLean, Cumming, Ballantyne, McGhie, Jampana, Longman, Evans, Monckton and Farrugia
First Published:First published in Frontiers in Neurology 9:780
Publisher Policy:Reproduced under a Creative Commons License

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
171804Structural CNS changes, neuropsychological impairment and sleep disturbance in type 1 Myotonic dystrophy - a genotype-phenotype studyDarren MoncktonMuscular Dystrophy UK (MUSCDYST)MC3/1073/3MCSB - Molecular Genetics