Using prodromal non-motor symptoms to predict Parkinson's disease onset and motor phenotype

Joshua Pearson; James B Badenoch; Daniel Van Wamelen

doi:10.1136/jnnp-2024-335429

Using prodromal non-motor symptoms to predict Parkinson's disease onset and motor phenotype

Joshua Pearson, James B Badenoch, Daniel Van Wamelen

Research output: Contribution to journal › Article › peer-review

Abstract

BACKGROUND: Non-motor symptoms are highly prevalent in prodromal Parkinson's disease (PD); however, their impact on PD trajectory remains largely unexplored. We aimed to assess whether prevalent prodromal non-motor symptoms could predict future motor phenotype and time-to-PD diagnosis.

METHODS: We studied the prodromal cohort of the ongoing Parkinson's Progression Markers Initiative (n=958), which prospectively assesses individuals with prodromal PD features (genetic: n=361, hyposmia: n=298, rapid eye movement behaviour disorder: n=136, combination: n=163) with up to 10 years of follow-up. The presence of prevalent prodromal symptoms was defined by evidence-based cut-off scores. In unmedicated or OFF-state PD converters (total n=52), binary logistic regression models established whether these predicted non-tremor-dominant (n=35) and tremor-dominant (n=17) motor phenotypes at diagnosis. Cox proportional hazards models determined whether identified prodromal symptoms predicted a shorter time-to-phenoconversion across all PD converters (n=59) and non-converters (n=343). Both models adjusted for age and sex.

RESULTS: Prodromal anxiety and hyposmia were each associated with an increased risk of subsequent non-tremor-dominant PD, compared with other motor phenotypes (adjusted OR=4.45, 95% CI 1.34 to 15.27 and adjusted OR=3.90, 95% CI 1.01 to 15.16, respectively). Concurrent prodromal anxiety and hyposmia predicted an increased risk of PD phenoconversion over time (HR=4.93, 95% CI 2.71 to 8.98).

CONCLUSION: In this exploratory analysis, individuals with prodromal hyposmia and anxiety phenoconverted to PD sooner and more often had a non-tremor-dominant phenotype, potentially reflecting more widespread pathology or specific pathophysiology underlying these symptoms. This may improve phenotyping prodromal PD and stratifying poorer prognostic trajectories for earlier and more personalised management.

Original language	English
Journal	Journal of neurology, neurosurgery, and psychiatry
DOIs	https://doi.org/10.1136/jnnp-2024-335429
Publication status	E-pub ahead of print - 19 Jun 2025

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10.1136/jnnp-2024-335429

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@article{cacb77d6a87548e5b91dd2bfd2dec520,

title = "Using prodromal non-motor symptoms to predict Parkinson's disease onset and motor phenotype",

abstract = "BACKGROUND: Non-motor symptoms are highly prevalent in prodromal Parkinson's disease (PD); however, their impact on PD trajectory remains largely unexplored. We aimed to assess whether prevalent prodromal non-motor symptoms could predict future motor phenotype and time-to-PD diagnosis.METHODS: We studied the prodromal cohort of the ongoing Parkinson's Progression Markers Initiative (n=958), which prospectively assesses individuals with prodromal PD features (genetic: n=361, hyposmia: n=298, rapid eye movement behaviour disorder: n=136, combination: n=163) with up to 10 years of follow-up. The presence of prevalent prodromal symptoms was defined by evidence-based cut-off scores. In unmedicated or OFF-state PD converters (total n=52), binary logistic regression models established whether these predicted non-tremor-dominant (n=35) and tremor-dominant (n=17) motor phenotypes at diagnosis. Cox proportional hazards models determined whether identified prodromal symptoms predicted a shorter time-to-phenoconversion across all PD converters (n=59) and non-converters (n=343). Both models adjusted for age and sex.RESULTS: Prodromal anxiety and hyposmia were each associated with an increased risk of subsequent non-tremor-dominant PD, compared with other motor phenotypes (adjusted OR=4.45, 95% CI 1.34 to 15.27 and adjusted OR=3.90, 95% CI 1.01 to 15.16, respectively). Concurrent prodromal anxiety and hyposmia predicted an increased risk of PD phenoconversion over time (HR=4.93, 95% CI 2.71 to 8.98).CONCLUSION: In this exploratory analysis, individuals with prodromal hyposmia and anxiety phenoconverted to PD sooner and more often had a non-tremor-dominant phenotype, potentially reflecting more widespread pathology or specific pathophysiology underlying these symptoms. This may improve phenotyping prodromal PD and stratifying poorer prognostic trajectories for earlier and more personalised management.",

author = "Joshua Pearson and Badenoch, {James B} and {Van Wamelen}, Daniel",

note = "{\textcopyright} Author(s) (or their employer(s)) 2025. No commercial re-use. See rights and permissions. Published by BMJ Group.",

year = "2025",

month = jun,

day = "19",

doi = "10.1136/jnnp-2024-335429",

language = "English",

journal = "Journal of neurology, neurosurgery, and psychiatry",

issn = "0022-3050",

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TY - JOUR

T1 - Using prodromal non-motor symptoms to predict Parkinson's disease onset and motor phenotype

AU - Pearson, Joshua

AU - Badenoch, James B

AU - Van Wamelen, Daniel

PY - 2025/6/19

Y1 - 2025/6/19

N2 - BACKGROUND: Non-motor symptoms are highly prevalent in prodromal Parkinson's disease (PD); however, their impact on PD trajectory remains largely unexplored. We aimed to assess whether prevalent prodromal non-motor symptoms could predict future motor phenotype and time-to-PD diagnosis.METHODS: We studied the prodromal cohort of the ongoing Parkinson's Progression Markers Initiative (n=958), which prospectively assesses individuals with prodromal PD features (genetic: n=361, hyposmia: n=298, rapid eye movement behaviour disorder: n=136, combination: n=163) with up to 10 years of follow-up. The presence of prevalent prodromal symptoms was defined by evidence-based cut-off scores. In unmedicated or OFF-state PD converters (total n=52), binary logistic regression models established whether these predicted non-tremor-dominant (n=35) and tremor-dominant (n=17) motor phenotypes at diagnosis. Cox proportional hazards models determined whether identified prodromal symptoms predicted a shorter time-to-phenoconversion across all PD converters (n=59) and non-converters (n=343). Both models adjusted for age and sex.RESULTS: Prodromal anxiety and hyposmia were each associated with an increased risk of subsequent non-tremor-dominant PD, compared with other motor phenotypes (adjusted OR=4.45, 95% CI 1.34 to 15.27 and adjusted OR=3.90, 95% CI 1.01 to 15.16, respectively). Concurrent prodromal anxiety and hyposmia predicted an increased risk of PD phenoconversion over time (HR=4.93, 95% CI 2.71 to 8.98).CONCLUSION: In this exploratory analysis, individuals with prodromal hyposmia and anxiety phenoconverted to PD sooner and more often had a non-tremor-dominant phenotype, potentially reflecting more widespread pathology or specific pathophysiology underlying these symptoms. This may improve phenotyping prodromal PD and stratifying poorer prognostic trajectories for earlier and more personalised management.

AB - BACKGROUND: Non-motor symptoms are highly prevalent in prodromal Parkinson's disease (PD); however, their impact on PD trajectory remains largely unexplored. We aimed to assess whether prevalent prodromal non-motor symptoms could predict future motor phenotype and time-to-PD diagnosis.METHODS: We studied the prodromal cohort of the ongoing Parkinson's Progression Markers Initiative (n=958), which prospectively assesses individuals with prodromal PD features (genetic: n=361, hyposmia: n=298, rapid eye movement behaviour disorder: n=136, combination: n=163) with up to 10 years of follow-up. The presence of prevalent prodromal symptoms was defined by evidence-based cut-off scores. In unmedicated or OFF-state PD converters (total n=52), binary logistic regression models established whether these predicted non-tremor-dominant (n=35) and tremor-dominant (n=17) motor phenotypes at diagnosis. Cox proportional hazards models determined whether identified prodromal symptoms predicted a shorter time-to-phenoconversion across all PD converters (n=59) and non-converters (n=343). Both models adjusted for age and sex.RESULTS: Prodromal anxiety and hyposmia were each associated with an increased risk of subsequent non-tremor-dominant PD, compared with other motor phenotypes (adjusted OR=4.45, 95% CI 1.34 to 15.27 and adjusted OR=3.90, 95% CI 1.01 to 15.16, respectively). Concurrent prodromal anxiety and hyposmia predicted an increased risk of PD phenoconversion over time (HR=4.93, 95% CI 2.71 to 8.98).CONCLUSION: In this exploratory analysis, individuals with prodromal hyposmia and anxiety phenoconverted to PD sooner and more often had a non-tremor-dominant phenotype, potentially reflecting more widespread pathology or specific pathophysiology underlying these symptoms. This may improve phenotyping prodromal PD and stratifying poorer prognostic trajectories for earlier and more personalised management.

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U2 - 10.1136/jnnp-2024-335429

DO - 10.1136/jnnp-2024-335429

M3 - Article

C2 - 40537250

SN - 0022-3050

JO - Journal of neurology, neurosurgery, and psychiatry

JF - Journal of neurology, neurosurgery, and psychiatry

ER -

Using prodromal non-motor symptoms to predict Parkinson's disease onset and motor phenotype

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