Exploring the Effects of Exercise on Memory and Cognition in Parkinson´s Disease (EMCo)

The study aims to assess the effects of cardiovascular (aerobic) training on memory formation and cognitive function in people with Parkinson's disease. Participants will be randomly allocated to one of two groups either performing cardiovascular training (experimental group) or stretching (control group) for twelve weeks, three times a week. The primary aim is to examine whether moderate-intense cardiovascular training (MICT) improves procedural memory formation (primary outcome) compared to stretching. Secondary outcomes include episodic memory formation, cognitive function, cardiorespiratory fitness, sleep quality, and brain-derived neurotrophic factor (BDNF) blood concentration levels.

Study Overview

• Status: Recruiting
• Conditions: Parkinson Disease
• Intervention / Treatment: Behavioral: cardiovascular training; Behavioral: stretching

Detailed Description

Besides the disabling cardinal motor symptoms, non-motor symptoms are a common clinical feature of Parkinson's disease (PD). These non-motor symptoms include, amongst others, cognitive decline and memory deficits. A growing body of evidence suggests that cardiovascular training has the potential to induce functional and structural brain changes that can translate into improved cognitive function, including memory. While data is mainly derived from studying rodents and healthy populations, cardiovascular exercise might also counteract cognitive decline and memory deficits in people with Parkinson's disease (pwPD). Therefore, the primary aim of the study is to investigate the effects of a twelve-week cardiovascular training on memory formation in pwPD.

In a randomized controlled trial, 60 persons with mild to moderate PD (i.e., Hoehn & Yahr ≤3) will either perform moderate-intensity cardiovascular training (experimental group) or stretching (control group) for twelve weeks (three times per week, totaling 36 training sessions; duration per training session 30 to 55 min). Participants will perform a procedural memory task before and after the intervention to analyze the effects on non-declarative memory formation (primary outcome). In addition, secondary and exploratory analyses will include the assessment of episodic memory formation, cognitive function, cardiorespiratory fitness, sleep quality, and BDNF blood concentration levels. The findings of the present study contribute to the current discussion on the neuroplastic effects of cardiovascular training and may have important implications for neurorehabilitation in pwPD.

• Study Type: Interventional
• Enrollment (Estimated): 60
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Simon Steib, Prof. Dr.; Phone Number: +49 6221/544643; Email: simon.steib@issw.uni-heidelberg.de
• Study Contact Backup: Name: Philipp Wanner, Dr.; Phone Number: +49 6221/544633; Email: philipp.wanner@issw.uni-heidelberg.de

Study Locations

• Germany
  • Baden-Wuerttemberg
    • Heidelberg, Baden-Wuerttemberg, Germany, 69120
      • Recruiting
      • Heidelberg University
      • Contact: Simon Steib, Prof. Dr.; Phone Number: +49 6221/544643; Email: simon.steib@issw.uni-heidelberg.de
      • Contact: Philipp Wanner, Dr.; Phone Number: +49 6221/544633; Email: philipp.wanner@issw.uni-heidelberg.de

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Diagnosed Parkinson's disease
• Disease stage ≤3 on the Hoehn & Yahr scale
• Age ranging from 50 - 80 years
• Naive to the memory tasks (primary outcomes)
• Ability to stand and walk at least 10 meters independently

Exclusion Criteria:

• Atypical Parkinsonism
• Significant level of cognitive impairment (i.e., Montreal Cognitive Assessment <21)
• Deep brain stimulation or brain pacemaker
• Diagnosed psychiatric illness
• Known clinically relevant neurological, internal or orthopedic conditions besides Parkinsonism that would interfere with the exercise paradigm
• Exceeding the recommended level of cardiovascular exercise for older adults (i.e., cardiovascular exercise done ≥150 min per week of moderate-intensity or ≥75 min per week of vigorous-intensity)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: cardiovascular training; The experimental group will perform a cardiovascular training three times a week over 12 weeks.	Behavioral: cardiovascular training; Cardiovascular training will be performed in supervised sessions and in small groups of 2-5 persons at the study site. The training is performed on a cycle ergometer at 60% of peak power output (Wmax) for 30 min (i.e., 5 min warm-up, 20 min at 60% Wmax, 5 min cool-down) three times a week for twelve weeks. The exercise program will be increased by 5 min (max. 55 min) and 5% of intensity (in Watt) every two weeks. If participants report a too low (i.e., Borg scale ≤ 11) or too high (i.e., Borg scale ≥ 16) subjective rate of perceived exertion (RPE; Borg scale 6-20) intensity will be increased or decreased until the target levels are met (i.e., Borg scale 12-15). During training, heart rate, intensity (in Watt) and RPE will be monitored. Participants missing training sessions will be offered an additional week to perform up to three training sessions.
Active Comparator: stretching; The active control group will perform a stretching training three times a week over 12 weeks.	Behavioral: stretching; The stretching training will be performed in supervised sessions and in small groups of 2-5 persons at the study site. Stretching training consists of lying, seated, and standing flexibility exercises (according to the recommendations of the American Parkinson´s Disease Foundation and the Parkinson Society Canada) for 30 min (i.e., 5 min warm-up, 20 min main part, 5 min cool-down) three times a week for twelve weeks. The exercise program will be increased by 5 min (i.e., adding additional repetitions and exercises; max. 55 min) every two weeks. Intensity of stretching exercises will be assessed by subjective rate of perceived muscle tension on a visual analog scale (VAS) from 0 to 10 and will be moderate defined as 5 to 7 on the VAS. During training VAS, heart rate, and RPE will be monitored. Participants missing training sessions will be offered an additional week to perform up to three training sessions.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Non-declarative, procedural memory (motor sequence learning) global learning score - Visuomotor Serial Targeting Task (VSTT)	To evaluate non-declarative (procedural) memory formation, a Visuomotor Serial Targeting Task (VSTT) will be used, which is widely applied to study motor sequence learning. A global motor learning score (i.e., [relative] change from start of encoding to 24h recall test) will be calculated for explicit (i.e., correct anticipatory movements defined as movements with onset times lower than in random trials and directed to the correct target [directional error at peak velocity <22°]) and implicit (i.e., spatial error to target defined as shortest distance of the movement end point from the center of the target) components of motor sequence learning and the change (delta) in the global motor learning scores from pre- to post-assessment will be analyzed. Hence, two outcome measures from the VSTT are considered to answer the primary research question: (i) change in explicit global motor learning score, and (ii) change in implicit global motor learning score from pre- to post-assessment.	Week 1-2: pre-assessment (baseline within two weeks before intervention), Week 15-16: post-assessment (within two weeks after intervention)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Non-declarative, procedural memory (motor sequence learning) encoding and consolidation - Visuomotor Serial Targeting Task (VSTT)	To evaluate the effects on the different processes of non-declarative (procedural) memory formation, the encoding (i.e., relative change in performance from beginning to end of practice) and consolidation (i.e., relative change in performance from end of practice to a 24h recall test) of the motor sequence will be investigated for the implicit and explicit components, respectively. This results in four secondary outcome variables for the VSTT: (i) change in encoding of the explicit component from pre- to post assessment; (ii) change in encoding of the implicit component from pre- to post assessment; (iii) change in consolidation of the explicit component from pre- to post assessment; (iv) change in consolidation of the implicit component from pre- to post-assessment.	Week 1-2: pre-assessment (baseline within two weeks before intervention), Week 15-16: post-assessment (within two weeks after intervention)
Declarative, episodic memory (verbal learning) - Rey Auditory Verbal Learning Test	To evaluate the effects on declarative (episodic) memory, the German version of the Rey Auditory Verbal Learning Test will be used. Similar to non-declarative (procedural) memory (i) the change in global episodic learning score (i.e., correctly recalled words at 24 h recall test) from pre- to post-intervention will be analyzed in a first step followed by a separate analysis of (ii) the change in encoding (i.e., correctly recalled words after listening five times to the wordlist) from pre- to post-intervention and (iii) the change in consolidation (i.e., change in correctly recalled words from end of encoding to recall test) from pre- to post-intervention.	Week 1-2: pre-assessment (baseline within two weeks before intervention), Week 15-16: post-assessment (within two weeks after intervention)
Cognitive function	To evaluate the effects on cognitive function, the domains: (i) short-term memory (Digit and Spatial Span Task forward: length of correctly reproduced sequence of digits/locations), (ii) working memory (Digit and Spatial Span Task backward: length of correctly reproduced sequence of digits/locations), (iii) inhibition (Stroop Test interference score: number of correctly named colors in the color-word condition compared to the predicted color-word score), and (vi) cognitive flexibility (Trail Making Test A & B trail flexibility score: time to complete test B compared to test A) will be assessed. A composite score including all domains to analyze change in global cognitive function from pre- to post-assessment will be calculated followed by a separate analysis of the change in the individual test scores from pre- to post-assessment.	Week 1-2: pre-assessment (baseline within two weeks before intervention), Week 15-16: post-assessment (within two weeks after intervention)
Cardiovascular fitness	To evacuate the effects on cardiorespiratory fitness, a graded exercise test (GXT) on a cycle ergometer with spiroergometry will be performed and the change in peak oxygen consumption (VO2peak) from pre- to post intervention will be analyzed.	Week 1-2: pre-assessment (baseline within two weeks before intervention), Week 15-16: post-assessment (within two weeks after intervention)
Objective sleep efficiency	To evaluate the effects on objective sleep quality, the change in sleep efficiency from pre- to post-assessment using wrist-worn actigraphy (ActiGraph GT9X; ActiGraph; Pensacola; USA) will be assessed.	Week 1-2: pre-assessment (baseline within two weeks before intervention), Week 15-16: post-assessment (within two weeks after intervention)
Subjective sleep disturbance	To evaluate the effects on subjective sleep quality, the change in subjective disease-related sleep disturbance from pre- to post-assessment using the Parkinson's Disease Sleep Scale 2 (PDDS-2) total score will be assessed.	Week 1-2: pre-assessment (baseline within two weeks before intervention), Week 15-16: post-assessment (within two weeks after intervention)
Brain-derived neurotrophic factor (BDNF) blood concentration level	To evaluate the effects on brain-derived neurotrophic factor (BDNF), serum blood samples at rest will be collected and the change from pre- to post-assessment will be analyzed.	Week 1-2: pre-assessment (baseline within two weeks before intervention), Week 15-16: post-assessment (within two weeks after intervention)

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Non-declarative, procedural memory (motor sequence learning) further variables - Visuomotor Serial Targeting Task (VSTT)	In addition to the (a) number of correct anticipatory movements and (b) spatial error to target (i.e., primary outcomes), (i) onset time (i.e., time between target display and out movement start), (ii) movement time (i.e., time from out movement start to end), (iii) peak velocity, (iv) directional error at peak velocity (i.e., angular deviation between real and ideal movement trajectory at peak velocity), (v) spatial error to ideal movement (i.e., root mean squared error between real and ideal movement trajectory), and (vi) normalized hand-path area (i.e., area enclosed by the out and in movement divided by the squared path length) will be inspected to analyze practice-related changes in temporal and kinematic movement characteristics.	Week 1-2: pre-assessment (baseline within two weeks before intervention), Week 15-16: post-assessment (within two weeks after intervention)
Sociodemographic & physical characteristics	Age, biological sex; Years of education; Height, weight, body mass index; Handedness (Edinburgh Handedness Inventory)	Week 1-2: pre-assessment (baseline within two weeks before intervention), Week 15-16: post-assessment (within two weeks after intervention)
Non-motor symptoms (nonmotor experiences of daily living) - Movement Disorder Society Unified Parkinson's Disease Rating Scale Part I	Movement Disorder Society Unified Parkinson's Disease Rating Scale (UPDRS) Part I total score (0-52)	Week 1-2: pre-assessment (baseline within two weeks before intervention), Week 15-16: post-assessment (within two weeks after intervention)
Motor symptoms (motor examination) - Movement Disorder Society Unified Parkinson's Disease Rating Scale Part III	Movement Disorder Society Unified Parkinson's Disease Rating Scale (UPDRS) Part III total score (0-132)	Week 1-2: pre-assessment (baseline within two weeks before intervention), Week 15-16: post-assessment (within two weeks after intervention)
Total daily medication - Levodopa equivalent daily dose	Total levodopa equivalent daily dose (LEDD) in mg	Week 1-2: pre-assessment (baseline within two weeks before intervention), Week 15-16: post-assessment (within two weeks after intervention)
Cognitive status - Montreal Cognitive Assessment	Montreal Cognitive Assessment (MoCA) total score (0-30 points)	Week 1-2: pre-assessment (baseline within two weeks before intervention), Week 15-16: post-assessment (within two weeks after intervention)
Quality of life - Parkinson´s Disease Questionnaire-39	Parkinson´s Disease Questionnaire-39 (PDQ-39) dimension scores (0-100) and total score (0-100)	Week 1-2: pre-assessment (baseline within two weeks before intervention), Week 15-16: post-assessment (within two weeks after intervention)
Objective sleep quality	Actigraphy (wrist-worn accelerometer for seven days and nights): sleep onset latency, total sleep time, wake after sleep onset, number of awakenings	Week 1-2: pre-assessment (baseline within two weeks before intervention), Week 15-16: post-assessment (within two weeks after intervention)
Subjective sleep quality	Pittsburgh Sleep Quality Index (PSQI) total score (0-21 points)	Week 1-2: pre-assessment (baseline within two weeks before intervention), Week 15-16: post-assessment (within two weeks after intervention)
Daytime sleepiness	Epworth Sleepiness Scale (ESS) total score (0-10 points)	Week 1-2: pre-assessment (baseline within two weeks before intervention), Week 15-16: post-assessment (within two weeks after intervention)
Severity of depression - Beck Depression Inventory	Beck Depression Inventory (BDI) total score (0-63)	Week 1-2: pre-assessment (baseline within two weeks before intervention), Week 15-16: post-assessment (within two weeks after intervention)
Severity of anxiety - Beck Anxiety Index	Beck Anxiety Index (BAI) total score (0-63)	Week 1-2: pre-assessment (baseline within two weeks before intervention), Week 15-16: post-assessment (within two weeks after intervention)
Objective physical activity	Actigraphy (wrist-worn accelerometer for seven days): total volume of physical activity, steps per day, minutes spent at different intensity levels, total daily vector magnitude counts	Week 1-2: pre-assessment (baseline within two weeks before intervention), Week 15-16: post-assessment (within two weeks after intervention)
Subjective physical activity last week	International Physical Activity Questionnaire (IPAQ) - short form: MET hours per week	Week 1-2: pre-assessment (baseline within two weeks before intervention), Week 15-16: post-assessment (within two weeks after intervention)
Subjective physical activity last four weeks	German Physical Activity Questionnaire 50+ (German PAQ 50+): MET hours per week	Week 1-2: pre-assessment (baseline within two weeks before intervention), Week 15-16: post-assessment (within two weeks after intervention)

Collaborators and Investigators

• Sponsor: Heidelberg University
• Collaborators: University Hospital Heidelberg; Universitätsmedizin Mannheim; German Foundation for Neurology; SRH Kurpfalzkrankenhaus Heidelberg
• Investigators: Principal Investigator: Simon Steib, Prof. Dr., Heidelberg University; Principal Investigator: Philipp Wanner, Dr., Heidelberg University

Publications and helpful links

Helpful Links

• Project website

Study record dates

Study Major Dates

• Study Start (Actual): February 27, 2024
• Primary Completion (Estimated): December 1, 2026
• Study Completion (Estimated): July 1, 2027

Study Registration Dates

• First Submitted: May 3, 2024
• First Submitted That Met QC Criteria: August 28, 2024
• First Posted (Actual): August 30, 2024

Study Record Updates

• Last Update Posted (Actual): August 30, 2024
• Last Update Submitted That Met QC Criteria: August 28, 2024
• Last Verified: August 1, 2024

More Information

Terms related to this study

• Keywords: memory; sleep; rehabilitation; cognition; Parkinson's Disease; aerobic exercise; neuroplasticity; motor learning; retention; consolidation; brain-derived neurotrophic factor; acquisition; cardiovascular training; encoding
• Additional Relevant MeSH Terms: Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Parkinsonian Disorders; Basal Ganglia Diseases; Movement Disorders; Synucleinopathies; Neurodegenerative Diseases; Parkinson Disease
• Other Study ID Numbers: EMCo

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: The anonymized data will be shared after completion of the study and publication of the primary results (presumably via OpenScienceFramework - OSF; https://osf.io/).
• IPD Sharing Time Frame: After completion of the study and publication of the primary outcome for at least ten years
• IPD Sharing Access Criteria: open data (presumably CC-BY Attribution 4.0 International licence)
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No