Parkinson's disease; Neurodegeneration; Dementia; age at onset; polygenic risk score; severity; aging; motor symptoms; non-motor symptoms
Abstract :
[en] Several phenotypic differences observed in Parkinson's disease (PD) patients have been linked to age at onset (AAO). We endeavoured to find out whether these differences are due to the ageing process itself by using a combined dataset of idiopathic PD (n = 430) and healthy controls (HC; n = 556) excluding carriers of known PD-linked genetic mutations in both groups. We found several significant effects of AAO on motor and non-motor symptoms in PD, but when comparing the effects of age on these symptoms with HC (using age at assessment, AAA), only positive associations of AAA with burden of motor symptoms and cognitive impairment were significantly different between PD vs HC. Furthermore, we explored a potential effect of polygenic risk score (PRS) on clinical phenotype and identified a significant inverse correlation of AAO and PRS in PD. No significant association between PRS and severity of clinical symptoms was found. We conclude that the observed non-motor phenotypic differences in PD based on AAO are largely driven by the ageing process itself and not by a specific profile of neurodegeneration linked to AAO in the idiopathic PD patients.
Research center :
- Luxembourg Centre for Systems Biomedicine (LCSB): Clinical & Experimental Neuroscience (Krüger Group) - Luxembourg Centre for Systems Biomedicine (LCSB): Bioinformatics Core (R. Schneider Group) - Luxembourg Centre for Systems Biomedicine (LCSB): Biomedical Data Science (Glaab Group)
Disciplines :
Biotechnology Life sciences: Multidisciplinary, general & others Neurology Human health sciences: Multidisciplinary, general & others
Author, co-author :
Pavelka, Lukas
Rauschenberger, Armin ; University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > Biomedical Data Science
Landoulsi, Zied ; University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > Bioinformatics Core
Pachchek, Sinthuja ; University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > Translational Neuroscience
May, Patrick ; University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > Bioinformatics Core
Glaab, Enrico ; University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > Biomedical Data Science
NCER-PD, Consortium
Other collaborator :
Krüger, Rejko ; University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > Translational Neuroscience
External co-authors :
yes
Language :
English
Title :
Age at onset as stratifier in idiopathic Parkinson's disease - effect of ageing and polygenic risk score on clinical phenotypes
Publication date :
2022
Journal title :
NPJ Parkinson's Disease
ISSN :
2373-8057
Publisher :
Nature Publishing Group, New-York, United States - New York
Elizabeth, Qian & Yue, Huang Subtyping of Parkinson’s disease - where are we up to? Aging Dis. 10, 1130–1139 (2019). DOI: 10.14336/AD.2019.0112
Rodríguez-Violante, M., Cervantes-Arriaga, A., Fahn, S. & Tolosa, E. Two-hundred years later: Is Parkinson’s disease a single defined entity? Rev. Invest Clin. 69, 308–313 (2017).
Krüger, R. et al. Classification of advanced stages of Parkinson’s disease: translation into stratified treatments. J. Neural Transm. 124, 1015–1027 (2017). DOI: 10.1007/s00702-017-1707-x
Pagano, G., Ferrara, N., Brooks, D. J. & Pavese, N. Age at onset and Parkinson disease phenotype. Neurology 86, 1400–1407 (2016). DOI: 10.1212/WNL.0000000000002461
Jellinger, K. A. Parkinson disease with old-age onset. Arch. Neurol. 60, 1814–1815 (2003). DOI: 10.1001/archneur.60.12.1814
Zhou, M. Z. et al. The association between non-motor symptoms in Parkinson’s disease and age at onset. Clin. Neurol. Neurosurg. 115, 2103–2107 (2013). DOI: 10.1016/j.clineuro.2013.07.027
Ferguson, L. W., Rajput, A. H. & Rajput, A. Early-onset vs. Late-onset Parkinson’s disease: a clinical-pathological study. Can. J. Neurol. Sci. 43, 113–119 (2016). DOI: 10.1017/cjn.2015.244
Jellinger, K. A. Very old onset parkinsonism: a clinical-pathological study. Parkinsonism Relat. Disord. 57, 39–43 (2018). DOI: 10.1016/j.parkreldis.2018.07.015
Ohnmacht, J., May, P., Sinkkonen, L. & Krüger, R. Missing heritability in Parkinson’s disease: the emerging role of non-coding genetic variation. J. Neural Transm. 127, 729–748 (2020). DOI: 10.1007/s00702-020-02184-0
Escott-Price, V., International Parkinson’s Disease Genomics Consortium & Nalls, M. A. et al. Polygenic risk of Parkinson disease is correlated with disease age at onset. Ann. Neurol. 77, 582–591 (2015). DOI: 10.1002/ana.24335
Gan-Or, Z. et al. The Quebec Parkinson network: a researcher-patient matching platform and multimodal biorepository. J. Parkinsons Dis. 10, 301–313 (2020). DOI: 10.3233/JPD-191775
Santos García, D. et al. COPPADIS-2015 (COhort of Patients with PArkinson’s DIsease in Spain, 2015): an ongoing global Parkinson’s disease project about disease progression with more than 1000 subjects included. Results from the baseline evaluation. Eur. J. Neurol. 26, 1399–1407 (2019). DOI: 10.1111/ene.14008
Marek, K. et al. The Parkinson’s progression markers initiative (PPMI) - establishing a PD biomarker cohort. Ann. Clin. Transl. Neurol. 5, 1460–1477 (2018). DOI: 10.1002/acn3.644
Diederich, N. J., Moore, C. G., Leurgans, S. E., Chmura, T. A. & Goetz, C. G. Parkinson disease with old-age onset: a comparative study with subjects with middle-age onset. Arch. Neurol. 60, 529–533 (2003). DOI: 10.1001/archneur.60.4.529
Wickremaratchi, M. M. et al. The motor phenotype of Parkinson’s disease in relation to age at onset. Mov. Disord. 26, 457–463 (2011). DOI: 10.1002/mds.23469
Mehanna, R., Moore, S., Hou, J. G., Sarwar, A. I. & Lai, E. C. Comparing clinical features of young onset, middle onset and late onset Parkinson’s disease. Parkinsonism Relat. Disord. 20, 530–534 (2014). DOI: 10.1016/j.parkreldis.2014.02.013
Chase, B. A. & Markopoulou, K. Olfactory dysfunction in familial and sporadic Parkinson’s Disease. Front Neurol. 11, 447 (2020). DOI: 10.3389/fneur.2020.00447
Kim, R., Shin, J. H., Park, S., Kim, H. J. & Jeon, B. Longitudinal evolution of non-motor symptoms according to age at onset in early Parkinson’s disease. J. Neurol. Sci. 418, 117157 (2020). DOI: 10.1016/j.jns.2020.117157
Pettigrew, C. & Soldan, A. Defining cognitive reserve and implications for cognitive aging. Curr. Neurol. Neurosci. Rep. 19, 1 (2019). DOI: 10.1007/s11910-019-0917-z
Johnson, S. B. & Meltzer, L. J. Disentangling the effects of current age, onset age, and disease duration: parent and child attitudes toward diabetes as an exemplar. J. Pediatr. Psychol. 27, 77–86 (2002). DOI: 10.1093/jpepsy/27.1.77
Blauwendraat, C. et al. Genetic modifiers of risk and age at onset in GBA associated Parkinson’s disease and Lewy body dementia [published correction appears in Brain. Brain 143, 234–248 (2020). DOI: 10.1093/brain/awz350
Yahalom, G. et al. Age at onset of Parkinson’s disease among Ashkenazi Jewish patients: contribution of environmental factors, LRRK2 p.G2019S and GBA p.N370S mutations. J. Parkinsons Dis. 10, 1123–1132 (2020). DOI: 10.3233/JPD-191829
Hernandez, D. G., Reed, X. & Singleton, A. B. Genetics in Parkinson disease: Mendelian versus non-Mendelian inheritance. J. Neurochem. 139, 59–74 (2016). DOI: 10.1111/jnc.13593
Manolio, T. A. et al. Finding the missing heritability of complex diseases. Nature 461, 747–753 (2009). DOI: 10.1038/nature08494
Liu, G. et al. Genome-wide survival study identifies a novel synaptic locus and polygenic score for cognitive progression in Parkinson’s disease. Nat. Genet 53, 787–793 (2021). DOI: 10.1038/s41588-021-00847-6
Ihle, J. et al. DIGPD study group; Parkinson’s disease polygenic risk score is not associated with impulse control disorders: a longitudinal study. Parkinsonism Relat. Disord. 75, 30–33 (2020). DOI: 10.1016/j.parkreldis.2020.03.017
Paul, K. C., Schulz, J., Bronstein, J. M., Lill, C. M. & Ritz, B. R. Association of polygenic risk score with cognitive decline and motor progression in Parkinson disease. JAMA Neurol. 75, 360–366 (2018). DOI: 10.1001/jamaneurol.2017.4206
Alves, G. et al. Incidence of Parkinson’s disease in Norway: the Norwegian ParkWest study. J. Neurol. Neurosurg. Psychiatry 80, 851–857 (2009). DOI: 10.1136/jnnp.2008.168211
Granieri, E. et al. Parkinson’s disease in Ferrara, Italy, 1967 through 1987. Arch. Neurol. 48, 854–857 (1991). DOI: 10.1001/archneur.1991.00530200096026
Winter, Y. et al. Incidence of Parkinson’s disease and atypical parkinsonism: Russian population-based study. Mov. Disord. 25, 349–356 (2010). DOI: 10.1002/mds.22966
Savica, R., Grossardt, B. R., Rocca, W. A. & Bower, J. H. Parkinson disease with and without Dementia: a prevalence study and future projections. Mov. Disord. 33, 537–543 (2018). DOI: 10.1002/mds.27277
Litvan, I. et al. SIC Task Force appraisal of clinical diagnostic criteria for parkinsonian disorders. Mov. Disord. 18, 467–486 (2003). DOI: 10.1002/mds.10459
Hipp, G. et al. The Luxembourg Parkinson’s study: a comprehensive approach for stratification and early diagnosis. Front Aging Neurosci. 10, 326 (2018). DOI: 10.3389/fnagi.2018.00326
Blauwendraat, C. et al. NeuroChip, an updated version of the NeuroX genotyping platform to rapidly screen for variants associated with neurological diseases. Neurobiol. Aging 57, 247.e9–247.e13 (2017). DOI: 10.1016/j.neurobiolaging.2017.05.009
Das, S. et al. Next-generation genotype imputation service and methods. Nat. Genet 48, 1284–1287 (2016). DOI: 10.1038/ng.3656
Korlach, Jonas et al. Real-time DNA sequencing from single polymerase molecules. Methods Enzymol. 472, 431–455 (2010). DOI: 10.1016/S0076-6879(10)72001-2
Poplin, R. et al. A universal SNP and small-indel variant caller using deep neural networks. Nat. Biotechnol. 36, 983–987 (2018). DOI: 10.1038/nbt.4235
Nalls, M. A. et al. Identification of novel risk loci, causal insights, and heritable risk for Parkinson’s disease: a meta-analysis of genome-wide association studies. Lancet Neurol. 18, 1091–1102 (2019). DOI: 10.1016/S1474-4422(19)30320-5
