This study investigates whether intermittent hypoxia (IH) and physical activity (PA), either alone or in combination (simultaneously or sequentially), can improve cognitive function and brain health in middle-aged adults (50-65 years old). The hypothesis is that (1) each intervention alone (IHT or PA) provides cognitive benefits and (2) combining IHT with PA may yield additive or synergistic effects, particularly when administered simultaneously rather than sequentially. By comparing these distinct interventions, the study aims to determine which approach best preserves or enhances cognitive performance in middle-aged adults. Findings from this research may inform non-pharmacological strategies to promote healthy aging and reduce the risk of age-related cognitive decline.
Rapid demographic aging worldwide is driving a surge in age-related conditions, including neurodegenerative diseases and cognitive disorders. Projections estimate that the number of people living with dementia could reach 78 million by 2030 and 139 million by 2050, underscoring the urgent need for effective, non-pharmacological strategies to preserve brain health. Intermittent hypoxia (IH) and physical activity (PA) are two promising interventions that may help prevent or mitigate cognitive decline. IH-an approach involving repeated cycles of reduced oxygen (11-16% FiO₂) followed by normoxic recovery-has shown benefits across diverse health domains (cardiovascular, metabolic, respiratory, and neurological), potentially through mechanisms such as the activation of Hypoxia-Inducible Factor (HIF), enhanced vascular endothelial growth factor (VEGF) production, and anti-apoptotic pathways. PA is widely recognized for its positive impact on overall health, including cognitive function and neuroplasticity. The primary objective of this study is to evaluate the effects of IH and PA-administered individually, sequentially, or simultaneously-on cognitive performance and brain health in adults aged 50 to 65. The study will determine whether combining these interventions produces additive or synergistic benefits beyond those observed with each intervention alone. A total of approximately 176 participants will be enrolled and randomly assigned to one of five groups: (1) PA only, (2) IH only, (3) PA + IH sequentially, (4) PA + IH simultaneously, or (5) a control group receiving "placebo" hypoxia. Each participant will complete 18 sessions over a 6-week period (3 sessions per week), with sessions conducted in a hypoxic chamber at CIC 1402 and at the exercise testing facility of the University of Poitiers. Outcome measures include comprehensive cognitive testing (global cognition, reaction time, executive function, and divided attention), assessments of autonomy (e.g., activities of daily living), and physiological parameters (e.g., SpO₂, cerebral oxygenation, heart rate, and blood pressure). Biomarker analysis will include brain-derived neurotrophic factor (BDNF), VEGF, irisin, and markers of HIF activation to elucidate the mechanisms underlying any observed improvements. Vascular function will be assessed using Doppler ultrasound and near-infrared spectroscopy (NIRS), and daily activity levels will be monitored with accelerometers. Inclusion criteria require participants to be 50-65 years old, with a Montreal Cognitive Assessment (MoCA) score ≥24, no participation in other exercise interventions in the past 6 months, and no altitude exposure above 1,500 m in the preceding 3 months. Additional eligibility requirements include the absence of chronic kidney, cardiovascular, metabolic, neurological, or orthopedic disease, as well as no significant respiratory history. Exclusion criteria include active smoking, major cardiovascular complications within the last 3 months, severe hypertension, chronic respiratory insufficiency, diabetes, or any other condition that could compromise safety or study compliance. A qualified medical doctor will confirm eligibility during the inclusion process. By evaluating different delivery methods of IH and PA, this research aims to identify the most effective, non-pharmacological approach to preserving-or potentially enhancing-cognitive function in middle-aged adults. Findings may contribute to targeted preventive strategies and novel therapeutic interventions, addressing the growing public health burden of age-related cognitive decline.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
PREVENTION
Masking
SINGLE
Enrollment
176
Moderate-Intensity Aerobic Exercise (\~60-70% of maximum heart rate) and Intermittent Hypoxia (maintained between 80-90% during hypoxic phases)
Moderate-Intensity Aerobic Exercise (\~60-70% of maximum heart rate)
Exposure to normoxic air (FiO₂ \~20.9%) instead of actual hypoxia.
Cognitive Function: Montreal Cognitive Assessment (MoCA)
1-Montreal Cognitive Assessment (MoCA) * Score Range: 0 to 30 * Interpretation: Higher scores indicate better cognitive function.
Time frame: Baseline (Week 0),Week 1 (after 3 sessions), Week 6 (post-intervention, after session 18)
Cerebral Oxygenation - Tissue Saturation Index (TSI)
* Method: Near-Infrared Spectroscopy (NIRS) * Measure: Tissue Saturation Index (TSI), expressed as a percentage (%) * Interpretation: Higher TSI values indicate better cerebral oxygenation, reflecting efficient oxygen delivery and utilization in brain tissue.
Time frame: Baseline (Week 0), Week 1 (after 3 sessions), Week 6 (post-intervention, after session 18)
Biomarker Analysis- Brain-Derived Neurotrophic Factor (BDNF) Levels
* Method: Enzyme-Linked Immunosorbent Assay (ELISA) * Unit of Measure: pg/mL * Interpretation: Higher BDNF levels indicate greater neuroplasticity, neuronal survival, and cognitive function support.
Time frame: Baseline (Week 0), Week 1 (after 3 sessions), Week 6 (post-intervention, after session 18)
Cerebral blood flow
Method: Transcranial Doppler (TCD) Measures: Mean, systolic, and diastolic blood flow velocities in cerebral arteries. Interpretation: Higher flow velocities indicate increased cerebral perfusion, while reduced velocities may reflect impaired blood flow regulation or vascular resistance.
Time frame: Baseline (Week 0), Week 1 (after 3 sessions), Week 6 (post-intervention, after session 18)
Cognitive Function: Stroop Test
The Stroop Test is a widely used cognitive assessment tool designed to measure executive function, specifically selective attention, cognitive flexibility, and inhibitory control. It evaluates the ability to suppress automatic responses and manage conflicting information. -Score Range: Reaction Time (measured in milliseconds, ms): Represents the time taken to respond in each condition. Accuracy Percentage (%): Indicates the proportion of correct responses relative to total trials. -Interpretation: Lower reaction times indicate faster cognitive processing and improved efficiency in managing conflicting information. Higher accuracy percentages reflect better cognitive control, attentional capacity, and inhibitory function. Performance in the incongruent condition is of particular interest, as it requires greater cognitive effort and executive control.
Time frame: Baseline (Week 0), Week 1 (after 3 sessions), Week 6 (post-intervention, after session 18)
Cognitive Function: N-Back
The N-Back Test is a cognitive task designed to assess working memory, attention, and cognitive flexibility. It requires participants to continuously monitor a sequence of stimuli (e.g., letters, numbers, or shapes) and determine whether the current stimulus matches one presented N steps earlier in the sequence. The task increases in difficulty as N increases, demanding greater mental effort to update and maintain information in working memory. -Score Range: Accuracy Percentage (%): Proportion of correct responses over total trials. Reaction Time (ms): Time taken to respond to correct matches. -Interpretation: Higher accuracy reflects better working memory capacity and attentional control. Faster reaction times indicate efficient cognitive processing. Performance decline in higher N levels suggests increased cognitive load and reduced working memory capacity. Deficits in accuracy or reaction time may indicate difficulties in executive function and attentional flexibility.
Time frame: Baseline (Week 0),Week 1 (after 3 sessions), Week 6 (post-intervention, after session 18)
Cognitive Function:Operation Span Test Task
The Operation Span (O-Span) Test is a cognitive task designed to assess working memory capacity and attentional control. It requires participants to simultaneously process and store information, challenging their ability to maintain and manipulate information while handling a secondary task. The test includes: Two training trials for familiarization. Six experimental trials, with letter sequences ranging from four to six letters. -Score Range: Absolute Span Score: 0 to 12 (number of correctly recalled letter sequences). Interpretation: Higher scores indicate greater working memory capacity and better attentional control. Lower scores may suggest difficulties in managing cognitive load and maintaining task-relevant information under distraction. Performance reflects the ability to simultaneously process and store information, which is critical for complex cognitive tasks such as reasoning, problem-solving, and multitasking.
Time frame: Baseline (Week 0),Week 1 (after 3 sessions), Week 6 (post-intervention, after session 18)
Cognitive Function: The Trail Making Test
The Trail Making Test (TMT) is a widely used neuropsychological assessment designed to evaluate processing speed, cognitive flexibility, attention, and executive functioning. It consists of two parts: * TMT-A: Measures visual scanning, processing speed, and motor function. Participants connect numbers in ascending order (e.g., 1 → 2 → 3) as quickly as possible. * TMT-B: Assesses cognitive flexibility and task-switching ability. Participants alternate between numbers and letters in sequential order (e.g., 1 → A → 2 → B → 3 → C). * Score Range: Outcome Measure: Time (in seconds) taken to complete each part. Higher scores (longer times) indicate slower processing speed and reduced cognitive flexibility. -Interpretation: Lower scores (faster completion time) indicate better processing speed, visual attention, and cognitive flexibility. Higher scores (longer completion time) may reflect impairments in executive function, attention, or visuomotor speed.
Time frame: Baseline (Week 0), Week 1 (after 3 sessions), Week 6 (post-intervention, after session 18)
Cerebral Oxygenation - Oxyhemoglobin (O₂Hb)
* Method: Near-Infrared Spectroscopy (NIRS) * Measure: Oxyhemoglobin (O₂Hb), expressed in micromolar concentration (µM) * Interpretation: Higher O₂Hb levels indicate greater oxygen availability and delivery to brain tissues.
Time frame: Baseline (Week 0), Week 1 (after 3 sessions), Week 6 (post-intervention, after session 18)
Cerebral Oxygenation - Deoxyhemoglobin (HHb)
* Method: Near-Infrared Spectroscopy (NIRS) * Measure: Deoxyhemoglobin (HHb), expressed in micromolar concentration (µM) * Interpretation: Elevated HHb levels may suggest reduced oxygen extraction or utilization, potentially indicating impaired cerebral oxygenation.
Time frame: Baseline (Week 0), Week 1 (after 3 sessions), Week 6 (post-intervention, after session 18)
Cerebral Oxygenation - Total Hemoglobin (tHb)
* Method: Near-Infrared Spectroscopy (NIRS) * Measure: Total Hemoglobin (tHb), expressed in micromolar concentration (µM) * Interpretation: Higher tHb values reflect greater blood volume in cerebral tissue, which may indicate increased cerebral perfusion.
Time frame: Baseline (Week 0), Week 1 (after 3 sessions), Week 6 (post-intervention, after session 18)
Biomarker Analysis-Vascular Endothelial Growth Factor (VEGF) Levels
* Method: Enzyme-Linked Immunosorbent Assay (ELISA) * Unit of Measure: pg/mL * Interpretation: Increased VEGF levels suggest enhanced angiogenesis, vascular function, and cerebral blood flow.
Time frame: Baseline (Week 0), Week 1 (after 3 sessions), Week 6 (post-intervention, after session 18)
Biomarker Analysis -Irisin Levels
* Method: Enzyme-Linked Immunosorbent Assay (ELISA) * Unit of Measure: ng/mL * Interpretation: Higher irisin levels indicate improved metabolic regulation, muscle-derived neuroprotection, and brain function.
Time frame: Baseline (Week 0), Week 1 (after 3 sessions), Week 6 (post-intervention, after session 18)
Biomarker Analysis-Hypoxia-Inducible Factor-1 Alpha (HIF-1α) Pathway Activation
* Method: Quantitative Polymerase Chain Reaction (qPCR) / Western Blot * Unit of Measure: Relative expression level (fold change compared to baseline) * Interpretation: Increased HIF-1α activation suggests enhanced cellular adaptation to hypoxia, improved metabolic regulation, and potential neuroprotection.
Time frame: Baseline (Week 0), Week 1 (after 3 sessions), Week 6 (post-intervention, after session 18)
Autonomy and Daily Functioning (Activities of Daily Living Scale)
* Full Name: Activities of Daily Living (ADL) Scale * Description: This scale assesses an individual's ability to perform essential daily activities independently. It evaluates functions such as dressing, bathing, eating, mobility, toileting, and grooming. * Score Range: 0 to 6 * Interpretation: A higher score indicates greater independence, while a lower score reflects higher dependency in daily functioning.
Time frame: Baseline, and post-intervention (week 6, session 18)
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