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Creation of a gene expression classifier for predicting Parkinson’s disease rate of progression

Abstract

Parkinson’s disease (PD) etiology is heterogeneous, genetic, and multi-factorial, resulting in a varied disease from a mild slow progression to a more severe rapid progression. Prognostic information on the nature of the patient’s disease at diagnosis aids the physician in counseling patients on treatment options and life planning. In a cohort of PD patients from the PPMI study, the relative gene expression levels of SKP1A, UBE2K, ALDH1A1, PSMC4, HSPA8 and LAMB2 were measured in baseline blood samples by real-time quantitative PCR. At baseline PD patients were up to 2 years from diagnosis, H&Y scale ≤ 2 and PD treatment naïve. PD-Prediction algorithm comprised of ALDH1A1, LAMB2, UBE2K, SKP1A and age was created by logistic regression for predicting progression to ≤ 70% Modified Schwab and England Activities of Daily Living (S&E-ADL). In relation to patients negative for PD-Prediction (n = 180), patients positive (n = 30) for Cutoff-1 (at 82% specificity, 80.0% sensitivity) had positive hazard ratio (HR+) of 10.6 (95% CI, 2.2–50.1), and positive (n = 23) for Cutoff-2 (at 93% specificity, 47% sensitivity) had HR+ of 17.1 (95% CI, 3.2–89.9) to progress to ≤ 70% S&E-ADL within 3 years (P value < 0.0001). Likewise, patients positive for PD-Prediction Cutoff-1 (n = 49) had HR+ 4.3 (95% CI, 1.6–11.6) for faster time to H&Y 3 in relation to patients negative (n = 170) for PD-Prediction (P value = 0.0002). Our findings show an algorithm that seems to predict fast PD progression and may potentially be used as a tool to assist the physician in choosing an optimal treatment plan, improving the patient’s quality of life and overall health outcome.

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Acknowledgements

The Michael J Fox Foundation supported this work (Gift ID: 10866). The clinical data and blood samples were from the Parkinson’s Progression Marker Initiative (PPMI) study, which is supported by the Michael J Fox Foundation for Parkinson’s Research and is co-funded by the Michael J Fox Foundation for Parkinson’s Research, Abbvie, Avid Radiopharmaceuticals, Biogen Idec, Bristol-Myers Squibb, Covance, Eli Lilly and Co, F Hoffman-La Roche, GE Healthcare, Genentech, GlaxoSmithKline, Lundbeck, Merck, MesoScale, Piramal, Pfizer, and UCB. Data used in the preparation of this article were obtained from the Parkinson’s Progression Markers Initiative (PPMI) database (https://www.ppmi-info.org/data). For up-to-date information on the study, https://www.ppmi-info.org.

Funding

PPMI is sponsored by the Michael J. Fox Foundation for Parkinson’s Research (MJFF) and is co-funded by MJFF, Abbvie, Avid Radiopharmaceuticals, Biogen Idec, Bristol-Myers Squibb, Covance, Eli Lilly & Co., F. Hoffman-La Roche, Ltd., GE Healthcare, Genentech, GlaxoSmithKline, Lundbeck, Merck, MesoScale, Piramal, Pfizer and UCB.

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JMR is a senior adviser and shareholder of BioShai Ltd. JSY was employed by Bioshai and had received share options of BioShai Ltd. ND was employed by Bioshai and had received share options of BioShai Ltd. DM was an employee of Bioshai and had received share options of BioShai Ltd. MBHY and PR are advisors and shareholders of BioShai Ltd. The patent—USA provisional 62/583,132, related to this work was assigned to BioShai Ltd.

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Correspondence to Jose Martin Rabey.

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Rabey, J.M., Yarden, J., Dotan, N. et al. Creation of a gene expression classifier for predicting Parkinson’s disease rate of progression. J Neural Transm 127, 755–762 (2020). https://doi.org/10.1007/s00702-020-02194-y

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  • DOI: https://doi.org/10.1007/s00702-020-02194-y

Keywords

  • Parkinson’s disease
  • Modified Schwab and England Activities of Daily Living
  • Hoehn and Yahr
  • Biomarker
  • Prognosis
  • Gene expression classifier