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Selected autonomic signs and symptoms as risk markers for phenoconversion and functional dependence in prodromal Parkinson’s disease

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Abstract

Purpose

To determine whether dysautonomia can stratify individuals with other prodromal markers of Parkinson’s disease (PD) for risk of phenoconversion and functional decline, which may help identify subpopulations appropriate for experimental studies.

Methods

Data were obtained from Parkinson’s Progression Markers Initiative. Cohorts without PD but with at-risk features were included (hyposmia and/or rapid-eye-movement-sleep behavior disorder, LRRK2 gene mutation, GBA gene mutation). Dysautonomia measures included Scales-for-Outcomes-in-Parkinson’s-Disease Autonomic (SCOPA-AUT), seven SCOPA-AUT subscales, and cardiovascular dysfunction (supine hypertension, low pulse pressure, neurogenic orthostatic hypotension). Outcome measures were phenoconversion and Schwab-and-England Activities-of-Daily-Living (SE-ADL) ≤ 70, which indicates functional dependence. Cox proportional-hazards regression was used to evaluate survival to phenoconversion/SE-ADL ≤ 70 for each dysautonomia measure. If a significant association was identified, a likelihood-ratio test was employed to evaluate whether a significant interaction existed between the measure and cohort. If so, regression analysis was repeated stratified by cohort.

Results

Median follow-up was 30 months. On multivariable analysis, gastrointestinal and female sexual dysfunction subscales were associated with increased risk of phenoconversion, while the cardiovascular subscale and neurogenic orthostatic hypotension were associated with increased risk of SE-ADL ≤ 70; respective hazard ratios (95% confidence intervals) were 1.13 (1.01–1.27), 3.26 (1.39–7.61), 1.87 (1.16–2.99), 5.45 (1.40–21.25). Only the association between the cardiovascular subscale and SE-ADL ≤ 70 was modified by cohort.

Conclusions

Symptoms of gastrointestinal and female sexual dysfunction predict phenoconversion in individuals with other risk markers for PD, while signs and symptoms of cardiovascular dysfunction may be associated with functional decline.

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Acknowledgements

Data used in the preparation of this article were obtained from the Parkinson’s Progression Markers Initiative (PPMI) database (www.ppmi-info.org/data). PPMI—a public–private partnership—is funded by the Michael J. Fox Foundation and funding partners 4D Pharma, AbbVie, AcureX Therapeutics, Allergan, Amathus Therapeutics, ASAP, Avid Radiopharmaceuticals, BIAL Biotech, Biogen, BioLegend, Bristol-Myers Squibb, Calico, Celgene, DaCapo Brain Science, Denali, The Edmond J. Safra Foundation, GE Healthcare, Genentech, GlaxoSmithKline, Golub Capital, Handl Therapeutics, Insitro, Janssen Neuroscience, Lilly, Lundbeck, Merck, Meso Scale Discovery, Neurocrine Biosciences, Pfizer, Piramal, Prevail, Roche, Sanofi Genzyme, Servier, Takeda, Teva, UCB, Verily, and Voyager Therapeutics. For up-to-date information on the study, visit www.ppmi-info.org.

Funding

This work was supported by the National Institutes of Health Pharmacoepidemiology T32 Grant GM075766, provided by the Perelman School of Medicine at the University of Pennsylvania.

Author information

Authors and Affiliations

  1. Department of Neurology, Perelman School of Medicine at the University of Pennsylvania, 3900 Woodland Ave., Philadelphia, PA, 19104, USA

    Cameron Miller-Patterson

  2. Department of Biostatistics, Epidemiology, and Informatics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA

    Jesse Y. Hsu

  3. Department of Neurology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA

    Lana M. Chahine

  4. Department of Neurology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA

    James F. Morley

  5. Department of Epidemiology and Neurology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA

    Allison W. Willis

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  1. Cameron Miller-Patterson
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Contributions

CMP developed the hypothesis, designed and performed the analysis, and prepared the manuscript. JYH provided guidance on statistical analysis and revisions for the manuscript. LMC, JFM, and AWW provided guidance on the analysis plan and revisions for the manuscript.

Corresponding author

Correspondence to Cameron Miller-Patterson.

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Conflict of interest

Dr. Miller-Patterson has nothing to disclose. Dr. Hsu has received personal compensation in the range of $10,000–$49,999 for serving as Editor, Associate Editor, or Editorial Advisory Board Member for National Kidney Foundation and Public Library of Science. Dr. Chahine has received personal compensation in the range of $500–$4,999 for serving as a consultant for Gray Matters Technology. Dr. Chahine has received research support from University of Pittsburgh Medical Center, Michael J. Fox Foundation, and Biogen/Parkinson Study Group. Dr. Chahine has received publishing royalties from a publication relating to health care. Dr. Morley has nothing to disclose. Dr. Willis has received personal compensation in the range of $0–$499 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Pharmacoepidemiology and Drug Safety. Dr. Willis has received research support from National Institutes of Health, National Institute on Aging, Biogen, Parkinson Foundation, and Arcadia.

Ethical approval

Each Parkinson’s Progression Markers Initiative site received approval from an ethics committee on human experimentation in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki and its later amendments before study initiation and obtained written informed consent from each study participant.

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Miller-Patterson, C., Hsu, J.Y., Chahine, L.M. et al. Selected autonomic signs and symptoms as risk markers for phenoconversion and functional dependence in prodromal Parkinson’s disease. Clin Auton Res 32, 463–476 (2022). https://doi.org/10.1007/s10286-022-00889-8

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  • DOI: https://doi.org/10.1007/s10286-022-00889-8

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