Hypoxic conditioning in Parkinson’s disease: randomized controlled multiple N-of-1 trials

Jules M. Janssen Daalen, Marjan J. Meinders, Federica Giardina, Soania Mathur, Philip N. Ainslie, Dick H. J. Thijssen and Bastiaan R. Bloem ()
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Jules M. Janssen Daalen: Cognition and Behavior; Department of Neurology; Center of Expertise for Parkinson & Movement Disorders
Marjan J. Meinders: Cognition and Behavior; Department of Neurology; Center of Expertise for Parkinson & Movement Disorders
Federica Giardina: Biostatistics Group
Soania Mathur: UnshakeableMD
Philip N. Ainslie: School of Health and Exercise Sciences
Dick H. J. Thijssen: Department of Physiology
Bastiaan R. Bloem: Cognition and Behavior; Department of Neurology; Center of Expertise for Parkinson & Movement Disorders

Nature Communications, 2025, vol. 16, issue 1, 1-12

Abstract: Abstract Preclinical evidence suggests positive symptomatic and neuroprotective effects of hypoxic conditioning in Parkinson’s disease (PD). This study (NCT05214287) investigated the safety, feasibility, short-term symptomatic and downstream effects of hypoxic conditioning in individuals with PD. 20 individuals with PD (mean age 62, 10 women, Hoehn-Yahr 1.5-3) completed randomized controlled double-blinded multiple N-of-1 trials. Each participant underwent five different 45-minute hypoxia interventions in duplicate: continuous hypoxia at FiO2 0.163 and 0.127, intermittent (five-minute intervals interspersed with normoxia) at FiO2 0.163 and 0.127, and placebo. Primary outcomes were safety and feasibility as measured by adverse events, vital parameter disturbances, participant-rated discomfort and feasibility questionnaires. Secondary outcomes were short-term participant-rated and assessor-rated symptom scores. Exploratory indicators of target engagement were serum erythropoietin, brain-derived neurotrophic factor (BDNF), glial fibrillary acidic protein (GFAP), neurofilament light-chain (NfL), platelet-derived growth factor-receptor-β (PDGFRβ) and cortisol. Secondary outcomes were evaluated using frequentist and Bayesian analysis. 20 participants completed the protocol. The trial met its primary endpoints for safety and feasibility. 95 adverse events occurred, including one moderate and three serious events. Adverse events were not dose-dependent and occurred at comparable incidence following hypoxia and placebo. Hypoxic conditioning was well-tolerated. Low-FIO2 protocols caused significant oxygen desaturations in two participants. Participants considered longer-term application feasible. Intermittent hypoxia at FIO2 0.163 modestly improved most participant-rated symptoms for several hours compared to placebo, but not assessor-rated scales. One hour after intervention, serum markers did not differ between interventions. Hypoxic conditioning is safe and feasible in individuals with PD, and specific protocols may be associated with short-term symptom improvement. These findings inform and support follow-up studies of longer-term safety and efficacy of hypoxic conditioning.

Date: 2025
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DOI: 10.1038/s41467-025-63324-2

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