Muscle-tendon Pathology and Metabolic Dysregulation in CP

Muscle-tendon Pathology, Metabolic Dysregulation and Chronic Inflammation in Adolescents and Young Adults With Moderate to Severe Spastic Cerebral Palsy

The main aim of this project is to gain knowledge about the muscle-tendon pathology of moderately to severely affected young people with cerebral palsy and their risk for cardiometabolic diseases and chronic inflammation. Furthermore, it will be investigated whether there are associations between the existing pathophysiology as well as inactivity and muscle function, cardiometabolic risk factors and inflammation. Moreover, the potential of the target group for adaptation of its muscular, cardiorespiratory, and endocrine system will be investigated.

The study parameters will be determined in adolescents and young adults aged 14 to 25 years with moderate to severe spastic cerebral palsy and compared with those of their less severely affected and healthy peers (cross-sectional study). In addition, the more affected individuals will participate in a 12-week training intervention (longitudinal study) performed with special tricycles (i.e., Frame Runners).

To measure the study parameters, ultrasound, strength tests, near-infrared spectroscopy, blood analyses, and spiroergometry will be used. The fitness training will be performed two times a week for 12 weeks with the Frame Runners.

Study Overview

• Status: Recruiting
• Conditions: Cerebral Palsy, Spastic
• Intervention / Treatment: Other: Cardiorespiratory fitness training

Detailed Description

Background: Spastic cerebral palsy (CP) is a neuro-developmental disorder in children. Although the initial brain injury is not progressive, muscle pathology, a leading sign in affected individuals, is an on-going process. Individuals with CP are less physically active compared to their typically developing (TD) peers and severely affected individuals are most sedentary. Therefore, increased muscle wasting, decreased muscle function and cardiorespiratory fitness, metabolic dysregulation, and chronic low-grade inflammation might exist in the latter group. However, information is scarce and the role of muscle-tendon pathology and physical inactivity remains to be elucidated. Finally, it is unknown whether their tissues and organs may still adapt to health-inducing stimuli.

Objectives: The main project aims are 1) to enhance our understanding of spastic muscle-tendon pathology, risk of cardiometabolic disease, and chronic inflammation likely present in young people with more severe spastic CP, and 2) to uncover the relationship of muscle-tendon alterations and physical inactivity on muscle function and metabolism as well as cardiometabolic risk factors and systemic inflammation. Moreover, the potential for adaptation of their muscular, cardiorespiratory, and endocrine system will be investigated.

Methods: A cross-sectional study will be performed to compare severely impaired adolescents and young adults with spastic CP, their mildly affected CP and TD peers. The former group will further participate in a 12-week cardiorespiratory fitness training with Frame Runners. Muscle-tendon properties will be examined using ultrasound and shear wave elastography, and muscle function and metabolism with dynamometry and near infrared spectroscopy. Blood samples will be analyzed assessing metabolic parameters, and pro-inflammatory cytokines. Cardiorespiratory fitness will be investigated using the 6-Minute Frame Running Test and gas exchange analysis. Physical activity will be evaluated with accelerometers and activity diaries. Mental well-being and quality of life will be assessed by use of the CPCHILD™ questionnaire.

• Study Type: Observational
• Enrollment (Estimated): 50

Contacts and Locations

• Study Contact: Name: Annika Kruse, Dr.; Phone Number: 00433163802329; Email: annika.kruse@uni-graz.at
• Study Contact Backup: Name: Martin Svehlik, Dr. med.; Phone Number: 004331638514129; Email: martin.svehlik@medunigraz.at

Study Locations

• Austria
  • Graz, Austria, 8010
    • Recruiting
    • Institute of Human Movement Science, Sport and Health, University of Graz
    • Contact: Sebastian Ruin, Univ.-Prof.; Phone Number: 00433163802336; Email: sebastian.ruin@uni-graz.at

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult
• Accepts Healthy Volunteers: Yes

• Sampling Method: Non-Probability Sample

Study Population

The patient selection is based on the inclusion and exclusion criteria from the patient pool of the local clinic for Orthopaedics and Traumatology. In addition, other interested persons/families will be informed about the study via other clinics, (pediatric orthopedic) elective medical practices, rehabilitation centers and physiotherapy facilities within the city and the surrounding area.

Description

Inclusion Criteria:

• spastic cerebral palsy
• mildly, moderately or severly affected (Gross Motor Function Classification System level I-IV)
• age range 14 - 25 years
• ability to accept and follow verbal instructions
• strong communication skills
• sufficient vision (visual function that enables safe movement with reference to people and obstacles)
• less than 15 hours of experience with the Frame Runners; healthy peers in the same age range

Exclusion Criteria:

• other forms of cerebral palsy
• orthopaedic surgery in the last 12 months
• Botulinum toxin application in the last 6 months

Study Plan

How is the study designed?

Number of groups / cohorts

3

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Group 1: healthy individuals (cross-sectional study); Typically developed adolescents and young adults will be recruited and measured once within the cross-sectional study.
Group 2: mildly affected individuals with cerebral palsy (cross-sectional study); Mildly affected adolescents and young adults will be recruited and measured once within the cross-sectional study.
Group 3: moderately and severely affected individuals with cerebral palsy (cross-sectional study); The results of the baseline assessment (T0) of the adolescents and young adults with moderate to severe cerebral palsy will be compared with group 1 and group 2. After the baseline assessment (T0) also used for the group comparison (see description above), group 3 enters a 12-week control period following daily routines. After the 12 weeks, the individuals will be assessed (T1) and will then start with the 12-week cardiorespiratory fitness training. The final assessment (T2) will terminate study participation of group 3.	Other: Cardiorespiratory fitness training; Cardiorespiratory fitness training will be performed two times a week for one hour in small groups (4-5 people). The training will be conducted outdoors at track and field facilities with at least two coaches.; Other Names: Frame Running

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Muscle fascicle length and muscle thickness	cm	Group 1 & 2: baseline (T0); Group 3: baseline (T0), pre-measurement (T1, 13 weeks), post-measurement (T2, 27 weeks)
Muscle fascicle pennation angle	degrees	Group 1 & 2: baseline (T0); Group 3: baseline (T0), pre-measurement (T1, 13 weeks), post-measurement (T2, 27 weeks)
Passive muscle stiffness	kilopascal (kPa)	Group 1 & 2: baseline (T0); Group 3: baseline (T0), pre-measurement (T1, 13 weeks), post-measurement (T2, 27 weeks)
Isometric muscle strength	kg	Group 1 & 2: baseline (T0); Group 3: baseline (T0), pre-measurement (T1, 13 weeks), post-measurement (T2, 27 weeks)
Muscle tissue oxygenation	Tissue saturation index (TSI)	Group 1 & 2: baseline (T0); Group 3: baseline (T0), pre-measurement (T1, 13 weeks), post-measurement (T2, 27 weeks)
Exosome size	nanometers (nm)	Group 1 & 2: baseline (T0); Group 3: baseline (T0), pre-measurement (T1, 13 weeks), post-measurement (T2, 27 weeks)
Exosome content	number/ml	Group 1 & 2: baseline (T0); Group 3: baseline (T0), pre-measurement (T1, 13 weeks), post-measurement (T2, 27 weeks)
Micro ribonucleic acid (RNA) cargo	expression level	Group 1 & 2: baseline (T0); Group 3: baseline (T0), pre-measurement (T1, 13 weeks), post-measurement (T2, 27 weeks)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Metabolic parameters	Glucose, C-peptide, free fatty acids, cholesterol, triglycerides, high-density lipoprotein, low-density lipoprotein in mmol/l	Group 1 & 2: baseline (T0); Group 3: baseline (T0), pre-measurement (T1, 13 weeks), post-measurement (T2, 27 weeks)
Pro-inflammatory cytokines	e.g., Interleukin 6, tumor necrosis factor alpha in pg/ml	Group 1 & 2: baseline (T0); Group 3: baseline (T0), pre-measurement (T1, 13 weeks), post-measurement (T2, 27 weeks)
Resting, mean, and peak heart rate	beats/min	Group 1 & 2: baseline (T0); Group 3: baseline (T0), pre-measurement (T1, 13 weeks), measurement after 6 weeks of training (T1_6weeks, 20 weeks), post-measurement (T2, 27 weeks)
Resting blood pressure	mmHg	Group 1 & 2: baseline (T0); Group 3: baseline (T0), pre-measurement (T1, 13 weeks), post-measurement (T2, 27 weeks)
Distance covered	m	Group 1 & 2: baseline (T0); Group 3: baseline (T0), pre-measurement (T1, 13 weeks), measurement after 6 weeks of training (T1_6weeks, 20 weeks), post-measurement (T2, 27 weeks)
Peak oxygen uptake (VO2peak), Peak ventilation (VEpeak)	l/min	Group 1 & 2: baseline (T0); Group 3: baseline (T0), pre-measurement (T1, 13 weeks), measurement after 6 weeks of training (T1_6weeks, 20 weeks), post-measurement (T2, 27 weeks)
Peak respiratory frequency	breaths/min	Group 1 & 2: baseline (T0); Group 3: baseline (T0), pre-measurement (T1, 13 weeks), measurement after 6 weeks of training (T1_6weeks, 20 weeks), post-measurement (T2, 27 weeks)
Respiratory exchange ratio	peak carbon dioxide production (VCO2peak)/VO2peak	Group 1 & 2: baseline (T0); Group 3: baseline (T0), pre-measurement (T1, 13 weeks), measurement after 6 weeks of training (T1_6weeks, 20 weeks), post-measurement (T2, 27 weeks)
VEpeak/VO2peak	ratio	Group 1 & 2: baseline (T0); Group 3: baseline (T0), pre-measurement (T1, 13 weeks), measurement after 6 weeks of training (T1_6weeks, 20 weeks), post-measurement (T2, 27 weeks)
VEpeak/VCO2peak	ratio	Group 1 & 2: baseline (T0); Group 3: baseline (T0), pre-measurement (T1, 13 weeks), measurement after 6 weeks of training (T1_6weeks, 20 weeks), post-measurement (T2, 27 weeks)
Perceived exertion	6-20 Borg Scale	Group 1 & 2: baseline (T0); Group 3: baseline (T0), pre-measurement (T1, 13 weeks), measurement after 6 weeks of training (T1_6weeks, 20 weeks), post-measurement (T2, 27 weeks)
Well-being and quality of life	Caregiver Priorities and Child Health Index of Life with Disabilities (CPCHILD™) questionnaire	Group 1 & 2: baseline (T0); Group 3: baseline (T0), pre-measurement (T1, 13 weeks), post-measurement (T2, 27 weeks)
Total physical activity, time spent in different intensities	min	Group 1 & 2: within 1 week between familiarisation and baseline (T0); Group 3: within 1 week after baseline (T0), within 1 week after post-measurement (T2, 28 weeks)
Passive range of motion (sagittal plane) of hip, knees, ankles	degrees	Group 1 & 2: baseline (T0); Group 3: baseline (T0), pre-measurement (T1, 13 weeks), post-measurement (T2, 27 weeks)
Step count	number	Group 1 & 2: within 1 week between familiarisation and baseline (T0); Group 3: within 1 week after baseline (T0), within 1 week after post-measurement (T2, 28 weeks)

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Body height	cm	Group 1 & 2: baseline (T0); Group 3: baseline (T0), pre-measurement (T1, 13 weeks), post-measurement (T2, 27 weeks)
Body weight	kg	Group 1 & 2: baseline (T0); Group 3: baseline (T0), pre-measurement (T1, 13 weeks), post-measurement (T2, 27 weeks)
Body mass index (BMI)	Body height and weight will be combined to calculate the BMI in kg/m^2	Group 1 & 2: baseline (T0); Group 3: baseline (T0), pre-measurement (T1, 13 weeks), post-measurement (T2, 27 weeks)
Modified Ashworth Scale Score of the Plantar flexors	number	Group 2: baseline (T0); Group 3: baseline (T0), pre-measurement (T1, 13 weeks), post-measurement (T2, 27 weeks)

Collaborators and Investigators

• Sponsor: University of Graz
• Collaborators: Karolinska Institutet; Medical University of Graz
• Investigators: Principal Investigator: Annika Kruse, Dr., Institute of Human Movement Science, Sport and Health, University of Graz

Publications and helpful links

General Publications

• Graham HK, Rosenbaum P, Paneth N, Dan B, Lin JP, Damiano DL, Becher JG, Gaebler-Spira D, Colver A, Reddihough DS, Crompton KE, Lieber RL. Cerebral palsy. Nat Rev Dis Primers. 2016 Jan 7;2:15082. doi: 10.1038/nrdp.2015.82.
• Narayanan UG, Fehlings D, Weir S, Knights S, Kiran S, Campbell K. Initial development and validation of the Caregiver Priorities and Child Health Index of Life with Disabilities (CPCHILD). Dev Med Child Neurol. 2006 Oct;48(10):804-12. doi: 10.1017/S0012162206001745.
• Bell KJ, Ounpuu S, DeLuca PA, Romness MJ. Natural progression of gait in children with cerebral palsy. J Pediatr Orthop. 2002 Sep-Oct;22(5):677-82.
• Nooijen CF, Slaman J, Stam HJ, Roebroeck ME, Berg-Emons RJ; Learn2Move Research Group. Inactive and sedentary lifestyles amongst ambulatory adolescents and young adults with cerebral palsy. J Neuroeng Rehabil. 2014 Apr 3;11:49. doi: 10.1186/1743-0003-11-49.
• Verschuren O, Peterson MD, Balemans AC, Hurvitz EA. Exercise and physical activity recommendations for people with cerebral palsy. Dev Med Child Neurol. 2016 Aug;58(8):798-808. doi: 10.1111/dmcn.13053. Epub 2016 Feb 7.
• Howard JJ, Herzog W. Skeletal Muscle in Cerebral Palsy: From Belly to Myofibril. Front Neurol. 2021 Feb 18;12:620852. doi: 10.3389/fneur.2021.620852. eCollection 2021.

Study record dates

Study Major Dates

• Study Start (Actual): March 8, 2024
• Primary Completion (Estimated): December 31, 2025
• Study Completion (Estimated): December 31, 2025

Study Registration Dates

• First Submitted: March 11, 2024
• First Submitted That Met QC Criteria: March 19, 2024
• First Posted (Actual): March 26, 2024

Study Record Updates

• Last Update Posted (Actual): March 26, 2024
• Last Update Submitted That Met QC Criteria: March 19, 2024
• Last Verified: March 1, 2024

More Information

Terms related to this study

• Keywords: Cerebral Palsy; Spasticity; Muscle; Cardiorespiratory Fitness; Frame Running
• Additional Relevant MeSH Terms: Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Neurologic Manifestations; Brain Damage, Chronic; Musculoskeletal Diseases; Muscular Diseases; Neuromuscular Manifestations; Muscle Hypertonia; Cerebral Palsy; Muscle Spasticity
• Other Study ID Numbers: 10.55776/V992

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Open access to research data on which the research publications are based will be provided following the Criteria for Open Research Data presented by the Austrian Science fund (FWF). If data can be shared (i.e., anonymisation can be ensured), it will be deposited under the Creative Commons (CC BY) licence.
• IPD Sharing Time Frame: Research data on which future papers are based will be made available shortly after publication.
• IPD Sharing Access Criteria: Individual participant data (IPD) will be provided under the CC BY licence.

Drug and device information, study documents

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