Reply to: Hypoxia treatment of Parkinson’s disease may disrupt the circadian system

Background Introduction In recent years, increasing attention has been given to hypoxia-based treatment for persons with neurodegenerative and mitochondrial disease, as reflected by the significant rise in publications from basic [1], preclinical [2] and clinical [3, 4] research groups. Hypoxia treatment is based on the idea of hypoxic conditioning and adaptations induced by hypoxia. Recently, we published a protocol paper to assess the safety, feasibility, and acute symptomatic effects of single sessions of continuous and intermittent hypoxia (for 45 min, at FiO2 0.133 and 0.163) in persons with Parkinson’s disease (PD) [3]. In Coste & Touitou’s recent correspondence [5] to our protocol [6], they highlighted the potential for circadian rhythm disturbances induced by hypoxia in PD. This interesting insight is based on their two different studies, in which a phase shift in circadian rhythm (as measured by cortisol and melatonin) was observed after eight-hours-long ‘chronic’ exposure to hypoxia [7, 8]. Coste & Touitou [6] carefully considered that hypoxia-based interventions could therefore induce changes in circadian rhythm, and this may in turn affect the outcome of these interventions. Here, we discuss important differences between chronic hypoxia, which resembles hypoxia as a disease model for sleep apnea, and hypoxic conditioning

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

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

Randomized controlled trial of intermittent hypoxia in Parkinson’s disease: study rationale and protocol

Background Parkinson’s disease (PD) is a neurodegenerative disease for which no disease-modifying therapies exist. Preclinical and clinical evidence suggest that repeated exposure to intermittent hypoxia might have short- and long-term benefits in PD. In a previous exploratory phase I trial, we demonstrated that in-clinic intermittent hypoxia exposure is safe and feasible with short-term symptomatic effects on PD symptoms. The current study aims to explore the safety, tolerability, feasibility, and net symptomatic effects of a four-week intermittent hypoxia protocol, administered at home, in individuals with PD. Methods/Design: This is a two-armed double-blinded randomized controlled trial involving 40 individuals with mild to moderate PD. Participants will receive 45 min of normobaric intermittent hypoxia (fraction of inspired oxygen 0.16 for 5 min interspersed with 5 min normoxia), 3 times a week for 4 weeks. Co-primary endpoints include nature and total number of adverse events, and a feasibility-tolerability questionnaire. Secondary endpoints include Movement Disorders Society-Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) part II and III scores, gait tests and biomarkers indicative of hypoxic dose and neuroprotective pathway induction. Discussion This trial builds on the previous phase I trial and aims to investigate the safety, tolerability, feasibility, and net symptomatic effects of intermittent hypoxia in individuals with PD. Additionally, the study aims to explore induction of relevant neuroprotective pathways as measured in plasma. The results of this trial could provide further insight into the potential of hypoxia-based therapy as a novel treatment approach for PD

Wall shear stress as measured in vivo: consequences for the design of the arterial system

Based upon theory, wall shear stress (WSS), an important determinant of endothelial function and gene expression, has been assumed to be constant along the arterial tree and the same in a particular artery across species. In vivo measurements of WSS, however, have shown that these assumptions are far from valid. In this survey we will discuss the assessment of WSS in the arterial system in vivo and present the results obtained in large arteries and arterioles. In vivo WSS can be estimated from wall shear rate, as derived from non-invasively recorded velocity profiles, and whole blood viscosity in large arteries and plasma viscosity in arterioles, avoiding theoretical assumptions. In large arteries velocity profiles can be recorded by means of a specially designed ultrasound system and in arterioles via optical techniques using fluorescent flow velocity tracers. It is shown that in humans mean WSS is substantially higher in the carotid artery (1.1–1.3 Pa) than in the brachial (0.4–0.5 Pa) and femoral (0.3–0.5 Pa) arteries. Also in animals mean WSS varies substantially along the arterial tree. Mean WSS in arterioles varies between about 1.0 and 5.0 Pa in the various studies and is dependent on the site of measurement in these vessels. Across species mean WSS in a particular artery decreases linearly with body mass, e.g., in the infra-renal aorta from 8.8 Pa in mice to 0.5 Pa in humans. The observation that mean WSS is far from constant along the arterial tree implies that Murray’s cube law on flow-diameter relations cannot be applied to the whole arterial system. Because blood flow velocity is not constant along the arterial tree either, a square law also does not hold. The exponent in the power law likely varies along the arterial system, probably from 2 in large arteries near the heart to 3 in arterioles. The in vivo findings also imply that in in vitro studies no average shear stress value can be taken to study effects on endothelial cells derived from different vascular areas or from the same artery in different species. The cells have to be studied under the shear stress conditions they are exposed to in real life

Respiratory Dysfunction and Abnormal Hypoxic Ventilatory Response in Mild to Moderate Parkinson's Disease

Background: Respiratory dysfunction is an important contributor to morbidity and mortality in advanced Parkinson's disease (PD), but it is unclear what parameters are sensitive to diagnose and monitor respiratory dysfunction across disease phases. Objectives: We aimed to characterize respiratory dysfunction in mild to moderate PD. Methods: In 20 individuals without cardiopulmonary comorbidity, pulmonary and inspiratory muscle function testing were performed ON-medication. Subsequently, the acute ventilatory response to hypoxia (HVR) was assessed by gradually decreasing FIO2 from 0.209 (room air) to 0.127, which was compared to eight age- and sex-matched healthy controls under arterial blood gas monitoring. Lastly, on different days, the same 20 individuals with PD underwent six blinded exposures to 45-min normobaric hypoxia at FiO2 0.163 and 0.127 or placebo OFF-medication to assess breathing responses. Results: At rest, individuals with greatest PD severity had a lower tidal volume (pairwise comparisons: 0.59 vs. 0.74, P = 0.038–0.050) and tended to have a higher breathing frequency (17.7 vs. 14.4, P = 0.076), despite normal pulmonary function. A 45-min exposure to hypoxia induced a significantly lower acute HVR in individuals with PD compared to controls (−0.0489 vs. 0.133 L.min/%, P = 0.0038). Acute HVR was reduced regardless of disease severity. Subacute HVR in individuals with milder disease tended to be higher compared to those with more advanced disease (P = 0.079). Conclusions: Respiratory dysfunction is present in individuals with PD, including those with relatively mild disease severity, and is characterized by altered breathing patterns at rest, as well as a lower HVR, despite normal pulmonary and inspiratory muscle function testing

Tissue Doppler imaging of carotid plaque wall motion: a pilot study

BACKGROUND: Studies suggest the physical and mechanical properties of vessel walls and plaque may be of clinical value in the diagnosis and treatment of cardiovascular atherosclerotic disease. The purpose of this pilot study was to investigate the potential clinical application of ultrasound Tissue Doppler Imaging (TDI) of Arterial Wall Motion (AWM) and to quantify simple wall motion indices in normal and diseased carotid arteries. METHODS: 224 normal and diseased carotid arteries (0–100% stenoses) were imaged in 126 patients (age 25–88 years, mean 68 ± 11). Longitudinal sections of the carotid bifurcation were imaged using a Philips HDI5000 scanner and L12-5 probe under optimized TDI settings. Temporal and spatial AWMs were analyzed to evaluate the vessel wall displacements and spatial gradients at peak systole averaged over 5 cardiac cycles. RESULTS: AWM data were successfully extracted in 91% of cases. Within the carotid bifurcation/plaque region, the maximum wall dilation at peak systole ranged from -100 to 750 microns, mean 335 ± 138 microns. Maximum wall dilation spatial gradients ranged 0–0.49, mean 0.14 ± 0.08. The AWM parameters showed a wide variation and had poor correlation with stenoses severity. Case studies illustrated a variety of pertinent qualitative and quantitative wall motion features related to the biophysics of arterial disease. CONCLUSION: Our clinical experience, using a challenging but realistic imaging protocol, suggests the use of simple quantitative AWM measures may have limitations due to high variability. Despite this, pertinent features of AWM in normal and diseased arteries demonstrate the potential clinical benefit of the biomechanical information provided by TDI