Tags

Type your tag names separated by a space and hit enter

Features of GBA-associated Parkinson's disease at presentation in the UK Tracking Parkinson's study.
J Neurol Neurosurg Psychiatry 2018; 89(7):702-709JN

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.

CLINICAL TRIAL REGISTRATION

NCT02881099; Results.

Authors+Show Affiliations

Department of Neurology, Ipswich Hospital NHS Trust, Ipswich, UK.Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK.Institute of Psychological Medicine and Clinical Neurosciences, MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University, Cardiff, UK.School of Social and Community Medicine, University of Bristol, Bristol, UK.Department of Neurology, Institute of Neurological Sciences, Queen Elizabeth University Hospital, Glasgow, Scotland.Department of Clinical Neuroscience, UCL Institute of Neurology, London, UK.Department of Neurology, Queen's Medical Centre, Nottingham, UK.Department of Clinical Neurosciences, John van Geest Centre for Brain Repair, Cambridge, UK.Faculty of Medical Sciences, University of Newcastle, Newcastle upon Tyne, UK.Sobell Department of Motor Neuroscience, UCL Institute of Neurology, London, UK.Department of Molecular Neuroscience, Reta Lila Weston Laboratories, UCL Institute of Neurology, London, UK.Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK.School of Social and Community Medicine, University of Bristol, Bristol, UK.Institute of Psychological Medicine and Clinical Neurosciences, MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University, Cardiff, UK.Department of Neurology, Institute of Neurological Sciences, Queen Elizabeth University Hospital, Glasgow, Scotland.Department of Clinical Neuroscience, UCL Institute of Neurology, London, UK.No affiliation info available

Pub Type(s)

Journal Article
Multicenter Study
Observational Study
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

29378790

Citation

Malek, Naveed, et al. "Features of GBA-associated Parkinson's Disease at Presentation in the UK Tracking Parkinson's Study." Journal of Neurology, Neurosurgery, and Psychiatry, vol. 89, no. 7, 2018, pp. 702-709.
Malek N, Weil RS, Bresner C, et al. Features of GBA-associated Parkinson's disease at presentation in the UK Tracking Parkinson's study. J Neurol Neurosurg Psychiatry. 2018;89(7):702-709.
Malek, N., Weil, R. S., Bresner, C., Lawton, M. A., Grosset, K. A., Tan, M., ... Morris, H. R. (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.
Malek N, et al. Features of GBA-associated Parkinson's Disease at Presentation in the UK Tracking Parkinson's Study. J Neurol Neurosurg Psychiatry. 2018;89(7):702-709. PubMed PMID: 29378790.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Features of GBA-associated Parkinson's disease at presentation in the UK Tracking Parkinson's study. AU - Malek,Naveed, AU - Weil,Rimona S, AU - Bresner,Catherine, AU - Lawton,Michael A, AU - Grosset,Katherine A, AU - Tan,Manuela, AU - Bajaj,Nin, AU - Barker,Roger A, AU - Burn,David J, AU - Foltynie,Thomas, AU - Hardy,John, AU - Wood,Nicholas W, AU - Ben-Shlomo,Yoav, AU - Williams,Nigel W, AU - Grosset,Donald G, AU - Morris,Huw R, AU - ,, Y1 - 2018/01/29/ PY - 2017/09/29/received PY - 2017/11/30/revised PY - 2018/01/03/accepted PY - 2018/1/31/pubmed PY - 2019/10/8/medline PY - 2018/1/31/entrez SP - 702 EP - 709 JF - Journal of neurology, neurosurgery, and psychiatry JO - J. Neurol. Neurosurg. Psychiatry VL - 89 IS - 7 N2 - 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. CLINICAL TRIAL REGISTRATION: NCT02881099; Results. SN - 1468-330X UR - https://www.unboundmedicine.com/medline/citation/29378790/Features_of_GBA_associated_Parkinson's_disease_at_presentation_in_the_UK_Tracking_Parkinson's_study_ L2 - http://jnnp.bmj.com/cgi/pmidlookup?view=long&pmid=29378790 DB - PRIME DP - Unbound Medicine ER -