High-intensity exercise (HIT) combined with creatine monohydrate supplementation (CM) confers greater neurocognitive benefits than either alone.

Hypothesis

High-intensity exercise (HIT) combined with creatine monohydrate supplementation (CM) confers greater neurocognitive benefits than either alone.

Rationale

Combining HIT with CM may enhance creatine’s transport to the brain, leading to greater cognitive, antioxidant, and neuroprotective effects. This is due to creatine’s ability to cross the blood-brain barrier (BBB), potentially increased by exercise-induced blood flow, vasodilation within the brain, and hormonal responses that further stimulate brain creatine uptake. Querido

This mechanistic basis may provide a theoretical framework for enhancing the benefits of other nutraceuticals.

Exercise Brain Benefits

Exercise boosts cerebral blood flow through vasodilation, increased circulatory volume, and enhanced neurovascular coupling, directing blood flow to the brain regions actively engaged in the exercise. High-intensity exercise improves cognitive function and brain health by increasing cerebral blood flow, BDNF, IGF-1, and osteocalcin. S.E. Browne

Creatine Brain Benefits

Creatine supplementation has been shown to improve cognitive function and provide neuroprotection in persons with neurocognitive impairment. J.F. Sandkühler

Creatine supplementation increases brain creatine levels. During stress or trauma, such as intense exercise, creatine supplementation improves oxidative DNA injury and normalizes brain and body creatine levels. S. Forbes

A 2023 review study published in Sports Medicine found long-term high-dosage creatine supplementation increases brain creatine stores, improves cognition and memory, especially in older adults or during times of metabolic stress (e.g. sleep deprivation), improves aspects of recovery from traumatic brain injury in children, and has the potential to reduce symptoms of depression and anxiety. D. Candow

Creatine has shown neuroprotection in PD patients with cognitive decline via creatine transporter uptake. In a rodent model, high-dosage creatine was shown to exert anti-inflammatory, antioxidative, and anti-aggregant effects on α-synucleinopathy. Y. Leem H. Chang

A long-term, multicenter, double-blind, parallel-group, placebo-controlled, 1:1 randomized efficacy trial for 10g of creatine in PD patients showed benefit to the Unified Parkinson’s Disease Rating Scale (UPDRS) both at 1 year and at 18 months, but eventually terminated early with no determined harm or benefit. K. Kieburtz

To address the nutritional requirements for the demands of the HIT group, each participant will also consume a post-workout protein shake.

Exercise and Cerebral Blood Flow

Aerobic exercise can increase cerebral blood flow and potentially enhance BBB permeability, at least temporarily. For the given volumetric load and intensity of the HIT exercise protocol, cardiovascular output will be high, around 75% HRmax (possibly higher for untrained PD patients, depending on individual motor efficiency). The cardiovascular intensity alone should be sufficient to significantly increase cerebral blood flow and promote physiological adaptations.

High-intensity strength training (HIT) increases IGF-1 levels more significantly compared to cardiovascular training. IGF-1 enhances creatine uptake in muscles, and creatine supplementation further increases IGF-1 mRNA expression in human skeletal muscle, providing a synergistic benefit that supports improved muscle performance and recovery, indirectly benefiting cognitive function through reduced fatigue and better overall physical health.

Due to its high energy requirements, brain cells are susceptible to Reactive Oxygen and Nitrogen Species (RONS), mitochondrial damage, and energy depletion. Strength training produces less RONS due to its reliance on the TCA cycle, resulting in lower ratio of oxidative stress than the amount of cardio required to achieve same cerebral blood flow and hormonal benefits.

Creatine Supplementation Studies

Research indicates that creatine supplementation can improve cognitive function and has neuroprotective effects. However, the dosage and duration required for optimal cognitive benefits are still under investigation.

Combined Effects

Many studies have examined the combined effects of exercise and creatine on muscle performance and recovery, but research on cognitive outcomes is less extensive. The hypothesis that HIT could enhance cerebral creatine uptake is supported by the rationale of increased blood flow and transporter activity.

Enhanced Recovery

Intense exercise and cognitive activity depletes brain phosphocreatine (Pcr) levels. Creatine supplementation can mitigate this depletion and improve recovery from high-intensity exercise, as well as cognitive function. C. Rae, A.C. Passaquin

Decreased Oxidative Stress

CM supplementation decreases oxidative stress by reducing the immediate demand on oxidative phosphorylation (OXPHOS) and its production of RONS, and by directly scavenging free radicals. H. Arazi

Double Crossover Design Overview

Participants: Individuals with early Parkinson’s disease (PD) and mild MDS-UPDRS impairment, randomly selected into groups:

Sequence 1
  1. HIT + CM
  2. HIT + Placebo
  3. CM Only
  4. Placebo
Sequence 2
  1. HIT + Placebo
  2. CM Only
  3. Placebo only
  4. HIT + CM
Sequence 3
  1. CM Only
  2. Placebo
  3. HIT + CM
  4. HIT + Placebo
Sequence 4
  1. Placebo
  2. HIT + CM
  3. HIT + Placebo
  4. CM Only

Each participant gets all interventions to control for individual differences, reduce the number of participants needed, and ensure every participant receives an active intervention. Each intervention phase is followed by a 4 week washout period and testing, to monitor possible carryover effects.

Duration: 16 weeks is adequate for observing potential cognitive and neuroprotective effects. Exercise Protocol: High-Intensity Training (HIT): Exercises: Olympic lifts and plyometrics. Frequency & Duration: 70 minutes (including warm-up and cool down), six times per week, supervised to ensure safety, form, and protocol adherence.

For transparency, participants must be fully informed about the potential benefits and risks associated with both the active treatment and the possibility of receiving placebo.

CM Supplementation

Dosage: 10 g of CM daily, split into two 5 g doses (pre- and post-workout), during warm-up and cool-down for HIT group.

Approach for Intensity

Initial Assessment

Assess participants’ current fitness levels, physical condition, and any potential limitations. Develop individualized exercise plans based on the baseline fitness evaluation. Strength Assessment: Calculate 10 RM for deadlift, squat, overhead press, bench press, barbell row, and box jump (height in cm).

For box jump assessment tests, calculate vertical jump, then move to a lower height and gradually increase within a safety threshold to the trainee’s comfort level.

For some bodyweight exercises, it is not possible to directly calculate the 10 RM as for weighted exercises. Instead, use the following formula:

max_reps * intensity * target_reps/10

For example, if the client can do 8 pushups and the desired intensity is 80% of 10 RM for 6 reps, do 8 × 0.8 × 6/10 ≈ 4 pushups. Adjust the number of reps as appropriate to roughly match the desired intensity level.

Progressive Intensity

Begin with 50-60% of maximal 10 repetition effort (10 rm), and increase the intensity 5% every 2-4 weeks, with rest between sets below 60s. Target Intensity Range: Aim to reach and maintain an intensity level of 70-85% of maximal effort for most of the intervention period. This range is typically sufficient to increase blood flow and confer cognitive benefits without excessive risk.

Sessions

  • Day 1: HIT + Zone 2 Cardio
  • Day 2: Zone 3 Cardio (40 min ergometer)
  • Day 3: HIT + Active Recovery
  • Day 4: Zone 3 Cardio
  • Day 5: HIT + Zone 2 Cardio
  • Day 6: Zone 3 Cardio
  • Day 7: HIT + Active Recovery

Zone 3 is 30 min of ergometer at 70% HRMax, at the trainee’s convenience.

Zone 2 is 40 min of walking, monitored with a fitness tracker, at the trainee’s convenience.

Active recovery is 10 minutes of walking, monitored with a fitness tracker, followed by a gentle 30 minute group session consisting of a series of instructor-led mobility movements.

Moderate Intensity Exercise (Zone 3) improves increasing cerebral blood flow and cardiovascular health at a reduced injury risk.

Low Intensity Cardio (Zone 2) improves aerobic endurance and promote recovery, ensuring sustained exercise adherence and minimizing injury risk.

Active Recovery promotes recovery, reduces soreness, and promotes relaxation, contributing to program sustainability.

Incorporating moderate or low intensity exercise and active recovery into a high-intensity training (HIT) routine for individuals, especially those with early Parkinson’s disease (PD), can help mitigate the risk of burnout, overtraining, and CNS overstimulation while still promoting various physiological and cognitive benefits. Here’s a proposed routine that balances HIT with cardio and recovery:

Each 70 minute HIT session begins with a 20 minute warm up, followed by 30 minutes of work, and ends with a 20 minute cool down. Warm Up: 15 minutes of working exercises performed at 40–50% of 10 RM for 10 sets of 3-5 and 10 minutes of mobility and light stretching to avoid injury and improve recovery (hang stretch, scapular pushup, cat/cow, walking, box squat, half kneel hip flexor stretch, etc.). Cool down: 10 minutes of low intensity cardiovascular exercise (fast walking) and 10 minutes of stretching.

HIT Progressive Intensity Exercise Protocol

4 times per week, 30 minutes of working sets, 60 – 75s rest between sets for a total of 15 sets.

Weeks 1-4:
Moderate intensity (50-60% of 10 RM) Volume: 15 sets of 10 repetitions
Weeks 5-8
Increase to moderate-high intensity (65-75% of 10 RM) Volume: 15 sets of 8-10 repetitions
Weeks 9-12
Further increase to high intensity (80-90% of 10 RM) Volume: 15 sets of 6-8 repetitions
Weeks 13-16
High-intensity (95-105% of 10 RM) Volume: 15 sets of 3-5 repetitions
Safety and Monitoring

All sessions are supervised by trained professionals to monitor form, intensity, and safety. Feedback and Adjustments: Regularly check in with participants to assess their comfort, fatigue levels, and any adverse effects. Adjust the intensity as needed based on individual responses.

Assessment

Cognitive Performance Tests
Backward digit span for working memory and MDS-UPDRS
MRI
To measure creatine levels in the brain and assess neuroprotective effects.
Blood Biomarkers
IGF-1, BDNF, osteocalcin, and oxidative stress markers.

References

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