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

Janssen Daalen, JM ORCID: 0000-0001-6290-5882, Meinders, MJ ORCID: 0000-0001-6491-7035, Giardina, F ORCID: 0000-0002-3710-0940, Mathur, S ORCID: 0000-0002-6224-7573, Ainslie, PN, Thijssen, DHJ ORCID: 0000-0002-7707-5567 and Bloem, BR ORCID: 0000-0002-6371-3337 (2025) Hypoxic conditioning in Parkinson’s disease: randomized controlled multiple N-of-1 trials. Nature Communications, 16 (1). p. 8469. ISSN 2041-1723

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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 FiO20.163 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 FIO20.163 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.

Item Type:	Article
Uncontrolled Keywords:	Aged; Female; Humans; Male; Middle Aged; Brain-Derived Neurotrophic Factor; Double-Blind Method; Erythropoietin; Hypoxia; Parkinson Disease; Treatment Outcome; 32 Biomedical and Clinical Sciences; 3202 Clinical Sciences; Brain Disorders; Clinical Research; Patient Safety; Neurodegenerative; Aging; Complementary and Integrative Health; Neurosciences; Parkinson's Disease; Clinical Trials and Supportive Activities; 6.1 Pharmaceuticals; Neurological; Aged; Female; Humans; Male; Middle Aged; Brain-Derived Neurotrophic Factor; Double-Blind Method; Erythropoietin; Hypoxia; Parkinson Disease; Treatment Outcome
Subjects:	B Philosophy. Psychology. Religion > BF Psychology R Medicine > RA Public aspects of medicine > RA0421 Public health. Hygiene. Preventive Medicine
Divisions:	Sport and Exercise Sciences
Publisher:	Springer
Date of acceptance:	14 August 2025
Date of first compliant Open Access:	17 October 2025
Date Deposited:	17 Oct 2025 12:50
Last Modified:	17 Oct 2025 13:00
DOI or ID number:	10.1038/s41467-025-63324-2
URI:	https://researchonline.ljmu.ac.uk/id/eprint/27365

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