Features of GBA-associated Parkinson’s disease at presentation in the UK Tracking Parkinson’s study

Malek, N. et al. (2018) Features of GBA-associated Parkinson’s disease at presentation in the UK Tracking Parkinson’s study. Journal of Neurology, Neurosurgery and Psychiatry, 89(7), pp. 702-709. (doi: 10.1136/jnnp-2017-317348) (PMID:29378790) (PMCID:PMC6031283)

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Abstract

Objectives: To examine the influence of the glucocerebrosidase (GBA) mutation carrier state on age at onset of Parkinson’s disease (PD), the motor phenotype and cognitive function at baseline assessment in a large cohort of UK patients. We also analysed the prevalence of mood and behavioural problems that may confound the assessment of cognitive function. Methods: We prospectively recruited patients with PD in the Tracking Parkinson’s study. We fully sequenced the GBA gene in all recently diagnosed patients (≤3.5 years). We examined cognitive (Montreal Cognitive Assessment) and motor (Movement Disorder Society Unified Parkinson’s Disease Rating Scale part 3) function at a baseline assessment, at an average of 1.3 years after diagnosis. We used logistic regression to determine predictors of PD with mild cognitive impairment and PD with dementia. Results: We studied 1893 patients with PD: 48 (2.5%) were heterozygous carriers for known Gaucher’s disease (GD) causing pathogenic mutations; 117 (6.2%) had non-synonymous variants, previously associated with PD, and 28 (1.5%) patients carried variants of unknown significance in the GBA gene. L444P was the most common pathogenic GBA mutation. Patients with pathogenic GBA mutations were on average 5 years younger at disease onset compared with non-carriers (P=0.02). PD patients with GD-causing mutations did not have an increased family risk of PD. Patients with GBA mutations were more likely to present with the postural instability gait difficulty phenotype compared with non-carriers (P=0.02). Patients carrying pathogenic mutations in GBA had more advanced Hoehn and Yahr stage after adjustment for age and disease duration compared with non-carriers (P=0.005). There were no differences in cognitive function between GBA mutation carriers and non-carriers at this early disease stage. Conclusions: Our study confirms the influence of GBA mutations on the age of onset, disease severity and motor phenotype in patients with PD. Cognition did not differ between GBA mutation carriers and non-carriers at baseline, implying that cognitive impairment/dementia, reported in other studies at a later disease stage, is not present in recently diagnosed cases. This offers an important window of opportunity for potential disease-modifying therapy that may protect against the development of dementia in GBA-PD.

Item Type:Articles
Additional Information:The research was funded by Parkinson’s UK and supported by the National Institute for Health Research (NIHR) DeNDRoN network, the NIHR Newcastle Biomedical Research Centre based at Newcastle upon Tyne Hospitals NHS Foundation Trust and Newcastle University, and the NIHR funded Biomedical Research Centre in Cambridge.
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Grosset, Dr Donald and Grosset, Dr Katherine
Authors: Malek, N., Weil, R. S., Bresner, C., Lawton, M. A., Grosset, K. A., Tan, M., Bajaj, N., Barker, R. A., Burn, D. J., Foltynie, T., Hardy, J., Wood, N. W., Ben-Shlomo, Y., Williams, N. W., Grosset, D. G., and Morris, H. R.
College/School: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:Journal of Neurology, Neurosurgery and Psychiatry
Publisher:BMJ Publishing Group
ISSN:0022-3050
ISSN (Online):1468-330X
Published Online:29 January 2018
Copyright Holders:Copyright © 2018 The Authors
First Published:First published in Journal of Neurology, Neurosurgery, and Psychiatry 89:702-709
Publisher Policy:Reproduced under a Creative Commons License

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
525044PROBAND: Parkinson's repository of biosamples and networked datasetsDonald GrossetParkinson's UK (PARKINSO)J-1101RI NEUROSCIENCE & PSYCHOLOGY