Prediction of cognition in Parkinson's disease with a clinical-genetic score: a longitudinal analysis of nine cohorts

Cognitive decline is a debilitating manifestation of disease progression in Parkinson's disease. We aimed to develop a clinical-genetic score to predict global cognitive impairment in patients with the disease.In this longitudinal analysis, we built a prediction algorithm for global cognitive impairment (defined as Mini Mental State Examination [MMSE] ≤25) using data from nine cohorts of patients with Parkinson's disease from North America and Europe assessed between 1986 and 2016. Candidate predictors of cognitive decline were selected through a backward eliminated Cox's proportional hazards analysis using the Akaike's information criterion. These were used to compute the multivariable predictor on the basis of data from six cohorts included in a discovery population. Independent replication was attained in patients from a further three independent longitudinal cohorts. The predictive score was rebuilt and retested in 10 000 training and test sets randomly generated from the entire study population.3200 patients with Parkinson's disease who were longitudinally assessed with 27 022 study visits between 1986 and 2016 in nine cohorts from North America and Europe were assessed for eligibility. 235 patients with MMSE ≤25 at baseline and 135 whose first study visit occurred more than 12 years from disease onset were excluded. The discovery population comprised 1350 patients (after further exclusion of 334 with missing covariates) from six longitudinal cohorts with 5165 longitudinal visits over 12·8 years (median 2·8, IQR 1·6-4·6). Age at onset, baseline MMSE, years of education, motor exam score, sex, depression, and β-glucocerebrosidase (GBA) mutation status were included in the prediction model. The replication population comprised 1132 patients (further excluding 14 patients with missing covariates) from three longitudinal cohorts with 19 127 follow-up visits over 8·6 years (median 6·5, IQR 4·1-7·2). The cognitive risk score predicted cognitive impairment within 10 years of disease onset with an area under the curve (AUC) of more than 0·85 in both the discovery (95% CI 0·82-0·90) and replication (95% CI 0·78-0·91) populations. Patients scoring in the highest quartile for cognitive risk score had an increased hazard for global cognitive impairment compared with those in the lowest quartile (hazard ratio 18·4 [95% CI 9·4-36·1]). Dementia or disabling cognitive impairment was predicted with an AUC of 0·88 (95% CI 0·79-0·94) and a negative predictive value of 0·92 (95% 0·88-0·95) at the predefined cutoff of 0·196. Performance was stable in 10 000 randomly resampled subsets.Our predictive algorithm provides a potential test for future cognitive health or impairment in patients with Parkinson's disease. This model could improve trials of cognitive interventions and inform on prognosis.National Institutes of Health, US Department of Defense.We thank all study participants, their families, and friends for their support and participation, and our study coordinators. The co-investigators and contributors from Parkinson's Disease Biomarkers Program, Harvard Biomarkers Study, Drug Interaction with Genes in Parkinson's Disease (DIGPD), Parkinson Research Examination of CEP-1347 Trial (PreCEPT) and a longitudinal follow-up of the PRECEPT study cohort (PostCEPT), Parkinsonism Incidence, Cognition and Non-motor heterogeneity in Cambridgeshire (PICNICS), Cambridgeshire Parkinson's Incidence from GP to Neurologist (CamPaIGN), PROfiling PARKinson's disease study (PROPARK), as well as acknowledgments for Parkinson's Progression Marker Initiative and Deprenyl and Tocopherol Antioxidative Therapy of Parkinsonism (DATATOP) are listed in the appendix. This work was supported in part by National Institutes of Health grants U01 NS082157, U01NS095736 (to CRS), US Department of Defense grants W81XWH-1–0007 (BR) and W81XWH-15–10007 (to CRS); MEMO Hoffman Foundation (to CRS); Brigham and Women's Hospital Departmental Funds (to BB). The Harvard Biomarkers Study is supported by the Harvard NeuroDiscovery Center, the Parkinson's Disease Biomarkers Program U01 NS082157, U01NS100603 of the National Institute of Neurological Disorders and Stroke (NINDS), and the Massachusetts Alzheimer's Disease Research Center P50 AG005134 grant of the National Institute on Aging, Harvard Aging Brain Study grant P01 AG036694. The PreCEPT and PostCEPT cohort was funded by Cephalon Inc and Lundbeck for the parent PRECEPT clinical trial and follow-up PostCEPT cohort, and the Department of Defense Neurotoxin Exposure Treatment Parkinson's Research Program (W23RRYX7022N606), NINDS Data and Organizing Center's (NS050095), the Parkinson's Disease Foundation (New York, NY, USA). Additional funding information for the PreCEPT and PostCEPT cohort and corresponding investigators is listed in Ravina et al. The CamPaIGN and PICNICS studies received funding support from the Wellcome Trust, MRC, Parkinson's UK, Cure-PD, the Patrick Berthoud Trust, the Van Geest Foundation, and National Institute for Health Research funding of a Biomedical Research Centre at the University of Cambridge and Addenbrooke's Hospital. DIGPD cohort was promoted by the Assistance Publique Hôpitaux de Paris, and funded by the French clinical research hospital programme (code AOR08010). The research leading to these results has received funding from the programme Investissements d'Avenir ANR-10-IAIHU-06. DATATOP was supported by NIH grant NS24778. The PROPARK study was funded by the Prinses Beatrix Fonds (project number WAR05–0120), the van Alkemade-Keuls Foundation (Stichting Alkemade-Keuls), and the International Parkinson Foundation (Stichting ParkinsonFonds)

Epididymal specific, selenium-independent GPX5 protects cells from oxidative stress-induced lipid peroxidation and DNA mutation

Can selenium (Se) independent, epididymal-specific glutathione peroxidase 5 (GPX5) protect CHO-K1 cells from oxidative damage and, more specifically, from lipid peroxidation and DNA mutation?CHO-K1 cells expressing GPX5 have increased resistance to oxidative challenge and, more specifically, decreased levels of lipid peroxidation and decreased levels of the downstream DNA lesion 8-oxo-7,8-dihydroguanine (8-oxodG) compared with control cells.GPX5 associates with sperm during transit of the epididymis, and has been postulated to protect sperm from peroxide-mediated attack. However, its function as an active glutathione peroxidase has been questioned due to substitution of the classical selenocysteine residue at its active site. Indirect evidence for a functional role for GPX5 has been provided by in vivo studies, in particular from the GPX5 knockout mouse whereby offspring sired by GPX5(/) males have a higher rate of spontaneous abortion and developmental defects, attributed to increased oxidative injury (8-oxodG) to sperm DNA, but only when the GPX5(/) males are over 1 year of age. Interestingly, we have previously shown severely reduced levels of GPX5 in humans.To look more directly at its role in protection against oxidative damage, we have used an in vitro system, generating a CHO-K1 mammalian cell line expressing recombinant rat GPX5.We have used the recombinant CHO-K1 cells to determine whether GPX5 is able to protect these cells from an administered oxidative challenge, using a range of approaches. We compared the viability of GPX5-expressing cells with control cells by both MTT and trypan blue exclusion assays. We next investigated whether GPX5 protects the cells specifically from lipid peroxidation, by using the fluorescent reporter molecule C11-BODIPY(581/591), and thus from downstream DNA mutation, by comparing levels of the DNA lesion 8-oxodG. We also investigated whether GPX5 can be transferred to rat sperm via epididymosomes.GPX5-expressing CHO-K1 cells had increased viability compared with control cells following oxidative challenge (P 0.005). We also found that GPX5-expressing CHO-K1 cells had significantly lower levels of C11-BODIPY(581/591) oxidation, and hence lipid peroxidation, compared with control cells. Levels of 8-oxodG DNA damage were also markedly lower in the nuclei of GPX5-expressing cells than in control cells. Finally, we showed that GPX5 can be transferred to rat sperm via epididymosomes.GPX5 is not active in glutathione peroxidase assays using H2O2 as the substrate. However, the related non-mammalian Se-independent GPXs show preference for electron donors other than glutathione, with a number utilizing thioredoxin as a reducing equivalent. Hence, the in vitro activity of GPX5 needs to be assessed using a range of alternative substrates and electron donors. GPX5 is secreted by the epididymis and associates with the sperm plasma membrane. We showed that this transfer can occur via epididymosomes; however, the mechanism for transfer and the identity of a potential binding partner in the sperm membrane needs to be determined. Finally, our study utilized an in vitro system that needs to be translated to human sperm.Our study supports an important role for GPX5 as an antioxidant, possibly acting as a phospholipid hydroperoxidase and participating in the maintenance of cell and DNA integrity.This project was funded in part by the BBSRC. The authors declare no conflict of interest.</p