Comparison of Frailty, Physical Fitness Parameters, and Irisin Levels Between Patients With Multiple Sclerosis and Healthy Volunteers

Multiple Sclerosis (MS) is a chronic immune-mediated and neurodegenerative disease of the central nervous system that often affects young adults and is more common in women. In addition to neurological disability, individuals with MS frequently experience frailty, a condition characterized by reduced physiological reserve, weakness, fatigue, decreased physical activity, and increased vulnerability to stressors. Frailty in MS is associated with poorer mobility, higher fall risk, reduced quality of life, and increased healthcare utilization. Irisin, a hormone released from skeletal muscles during exercise, is linked to energy metabolism and muscle function, and lower levels have been associated with reduced physical performance and sarcopenia. However, the relationship between frailty, physical fitness, and irisin levels in individuals with MS has not been sufficiently explored.

This study aims to compare frailty status, physical fitness parameters, and circulating irisin levels between patients with MS and healthy volunteers aged 18-65 years. Participants will undergo assessments including the Functional Independence Measure, Frailty Index, Berg Balance Scale, 6-Minute Walk Test, and handgrip strength measurement. Blood samples will also be collected to determine irisin levels using the ELISA method. Statistical analyses will evaluate differences between groups and correlations among frailty, functional performance, and irisin levels. The findings are expected to improve understanding of frailty mechanisms in MS and contribute to developing targeted rehabilitation and management strategies.

Study Overview

• Status: Not yet recruiting
• Conditions: MULTIPL SCLEROSİS

Detailed Description

Multiple Sclerosis (MS) is a chronic, immune-mediated, and neurodegenerative disorder of the central nervous system, characterized by inflammation, demyelination, and progressive axonal damage. It predominantly affects young adults and has a higher prevalence among women. The disease course is highly variable, often leading to a wide range of physical, cognitive, and psychosocial impairments that can significantly impact daily functioning and long-term quality of life.

In addition to neurological disability, individuals with MS frequently experience frailty, a multidimensional clinical syndrome marked by diminished physiological reserve and reduced resilience to internal and external stressors. Frailty is typically characterized by symptoms such as generalized weakness, persistent fatigue, decreased physical activity, slowed motor performance, and increased vulnerability to adverse health outcomes. In the context of MS, frailty represents an important but underrecognized condition that may exacerbate disease burden and accelerate functional decline.

The presence of frailty in individuals with MS has been associated with poorer mobility, impaired balance, increased risk of falls, reduced independence in activities of daily living, and a decline in overall quality of life. Furthermore, frailty contributes to higher rates of hospitalization, increased healthcare utilization, and greater economic burden. Despite its clinical significance, the underlying biological and functional mechanisms contributing to frailty in MS remain insufficiently understood.

Recent attention has been directed toward irisin, a myokine released from skeletal muscle in response to physical activity and exercise. Irisin is known to play a role in energy homeostasis, glucose metabolism, and the browning of white adipose tissue, thereby contributing to improved metabolic efficiency. Additionally, irisin has been linked to muscle strength, physical performance, and the prevention of sarcopenia. Lower circulating levels of irisin have been associated with decreased muscle function, reduced exercise capacity, and increased frailty in various populations. However, the relationship between irisin levels, frailty status, and physical fitness in individuals with MS has not yet been adequately investigated.

Therefore, the primary aim of this study is to compare frailty status, physical fitness parameters, and circulating irisin levels between patients diagnosed with MS and age- and sex-matched healthy individuals between the ages of 18 and 65 years. A secondary objective is to explore the potential associations between these variables within the MS population.

Participants will undergo a comprehensive evaluation protocol before rehabilitation protocol starts and without any intervention to the patients., including validated clinical and functional assessments. Functional independence will be measured using the Functional Independence Measure (FIM), while frailty status will be assessed through the Frailty Index. Balance performance will be evaluated using the Berg Balance Scale, and aerobic capacity and endurance will be measured with the 6-Minute Walk Test. In addition, upper extremity muscle strength will be assessed via handgrip dynamometry. To complement these functional assessments, venous blood samples will be collected from all participants, and circulating irisin levels will be quantified using the enzyme-linked immunosorbent assay (ELISA) method.

Statistical analyses will be conducted to determine differences between the MS and healthy control groups in terms of frailty, physical fitness parameters, and irisin levels. Furthermore, correlation analyses will be performed to investigate potential relationships among frailty status, functional performance measures, and circulating irisin concentrations.

It is anticipated that the findings of this study will provide valuable insights into the interplay between frailty, physical fitness, and biochemical markers in individuals with MS. A better understanding of these relationships may help clarify the mechanisms underlying frailty in this population and support the development of more targeted, multidisciplinary rehabilitation and disease management strategies aimed at improving functional outcomes and overall quality of life.

• Study Type: Observational
• Enrollment (Estimated): 782

Contacts and Locations

• Study Contact: Name: Hüseyin Tas, physiotherapist; Phone Number: +905340789769 +905340789769; Email: hsyntas07@gmail.com
• Study Contact Backup: Name: Ozlem Kuculmez, Asist. prof. dr.; Phone Number: +90555620521 +90555620521; Email: akanozlem07@gmail.com

Study Locations

• Turkey (Türkiye)
  • Alanya
    • Antalya, Alanya, Turkey (Türkiye), 07400
      • Baskent University Alanya Hospital
      • Contact: Ozlem Kuculmez, Asist Prof Dr; Phone Number: +905555620521 +905555620521; Email: akanozlem07@gmail.com
      • Contact: Sevgi Ikbali Afsar, Prof. dr.; Phone Number: +905388868596 +905388868596; Email: ikbaliafsar@hotmail.com
      • Principal Investigator: Hüseyin Taş, Physiotherapist
      • Sub-Investigator: Seher Ulker, Asist. Prof. Dr.
      • Sub-Investigator: Ozlem Kuculmez, Asist. Prof. Dr.

Participation Criteria

Eligibility Criteria

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

• Sampling Method: Probability Sample

Study Population

Patients aged 18-65 diagnosed with MS who applied to the Başkent University Alanya Hospital Center Physical Medicine and Rehabilitation outpatient clinic between April 1, 2026, and May 30 2026, and healthy volunteers aged 18-65 years with similar demographic characteristics (age, gender, etc.) will be included.

Description

Inclusion Criteria:

• Patients aged 18-65 evaluated by neurology and diagnosed with definitive MS via objective methods (MRI, lumbar puncture, etc.).
• Healthy volunteers aged 18-65.
• Being literate in Turkish.
• Participants who provide a consent form to participate in the study.

Exclusion Criteria:

• Being younger than 18 or older than 65.
• Presence of any concomitant neurological disease other than MS.
• Presence of an uncontrolled systemic disease at a level that would affect the evaluation.
• Presence of cognitive impairment or psychiatric illness at a level that would affect the evaluation.
• Having had an MS attack or received steroid treatment in the last month.
• Presence of an orthopedic disability that prevents evaluations.

Study Plan

How is the study designed?

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort
multple sclerosis; Patients aged 18-65 diagnosed with Multiple Sclerosis (diagnosed with MRI, lumbar puncture, etc) who applied to the Başkent University Alanya Hospital Center Physical Medicine and Rehabilitation outpatient clinic between April 1, 2026, and May 30 2026
control group; healthy volunteers aged 18-65 years with similar demographic characteristics (age, gender, etc.) like multiple sclerosis group

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
fraility index	The Frailty Index (FI) is a quantitative measure of frailty based on the concept of "accumulated deficits," first developed by researchers including Kenneth Rockwood and Arnold Mitnitski. It reflects the proportion of health deficits an individual has out of a defined total number assessed. Deficits can include symptoms, diseases, disabilities, cognitive impairments, abnormal laboratory values, or functional limitations, typically numbering 30-70 variables. Each deficit is scored as 0 (absent) or 1 (present), though intermediate values (e.g., 0.5) may be used for partial impairment. The Frailty Index is calculated by dividing the number of deficits present by the total number measured (e.g., 10 deficits out of 40 variables = FI of 0.25). Scores range from 0 to 1, with higher values indicating greater frailty; commonly, <0.10 suggests robustness, 0.10-0.24 mild frailty, 0.25-0.39 moderate frailty, and ≥0.40 severe frailty.	3 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
irisin level	Irisin is a 112-amino acid polypeptide hormone first identified in 2012. It is released from skeletal muscle during exercise and plays a role in energy metabolism by promoting the browning of white adipose tissue, thereby increasing energy expenditure. Exercise-induced muscle contraction elevates intracellular calcium (Ca²⁺) levels, which stimulates AMP-activated protein kinase (AMPK) phosphorylation. This activation triggers irisin production through the AMPK-PGC-1α-FNDC5 signaling pathway. Circulating irisin levels have therefore been proposed as a biomarker of muscle mass and physical performance. Reduced irisin concentrations have been observed in individuals with sarcopenia and pre-sarcopenia compared to non-sarcopenic controls.	3 months
Functional Independence Measure (FIM)	The Functional Independence Measure (FIM) is a standardized assessment tool developed in the 1980s by the Uniform Data System for Medical Rehabilitation to evaluate a patient's level of disability and functional independence, particularly in rehabilitation settings. It assesses 18 items across six domains: self-care (eating, grooming, bathing, dressing, toileting), sphincter control (bladder and bowel management), transfers (bed, chair, toilet, tub/shower), locomotion (walking or wheelchair use and stairs), communication (comprehension and expression), and social cognition (social interaction, problem-solving, memory). Each item is scored on a 7-point scale, where 7 indicates complete independence, 6 modified independence (use of device or extra time), 5 supervision or setup, 4 minimal assistance (patient performs 75% or more of the task), 3 moderate assistance (50-74%), 2 maximal assistance (25-49%), and 1 total assistance (less than 25% effort or requires two helpers). The total FIM	3 months
6-Minute Walk Test:	Measures functional walking capacity and endurance. It is a simple, practical, and widely used functional exercise test that measures the distance an individual can walk on a flat, hard surface in six minutes. It is designed to assess submaximal aerobic capacity and endurance, reflecting daily activity performance rather than maximal exercise capacity. The test is commonly used in patients with cardiovascular, pulmonary, or musculoskeletal conditions, as well as in older adults and those undergoing rehabilitation. Standardized protocols recommend a 30-meter corridor, with patients instructed to walk as far as possible in six minutes at a self-paced speed, allowing rests if needed. The primary outcome is the total distance walked (6-minute walk distance, 6MWD), often compared to reference values based on age, sex, height, and weight.	3 months
• BERG Balance Scale:	The Berg Balance Scale (BBS) is a widely used clinical tool designed to assess balance and risk of falls in adults, especially older adults and individuals with neurological or musculoskeletal impairments. Developed by Katherine Berg in 1989, the BBS evaluates a person's ability to maintain balance during static and dynamic tasks through 14 functional activities, including sitting to standing, standing unsupported, reaching forward, turning, retrieving objects from the floor, and standing on one foot. Each task is scored on a 5-point scale (0-4), where 0 indicates the lowest level of function and 4 reflects independent and safe performance. The maximum total score is 56, with higher scores indicating better balance. Commonly used cutoffs suggest that a score below 45 may indicate increased fall risk, while lower scores correlate with greater functional impairment.	3 months

Collaborators and Investigators

• Sponsor: Baskent University

Publications and helpful links

General Publications

• Molaei F, Zanotto A, Tabatabaei A, Lynch SG, Troen BR, Sosnoff JJ, et al. Frailty in multiple sclerosis: A scoping review. Multiple Sclerosis and Related Disorders. 2024:106157.
• Zanotto T, Galperin I, Mirelman A, Chen L, Regev K, Karni A, et al. Association between frailty and free-living walking performance in people with multiple sclerosis. Physical therapy. 2023;103(5):pzad032.
• Liu S, Cui F, Ning K, Wang Z, Fu P, Wang D, Xu H. Role of irisin in physiology and pathology. Front Endocrinol (Lausanne). 2022 Sep 26;13:962968. doi: 10.3389/fendo.2022.962968.
• A Validation of the Functional Independence Measure (FIM) and Its Performance Among Rehabilitation Patients. Archives of Physical Medicine and Rehabilitation 1993; 74 : 531-536
• Idiman, Egemen, et al. "Cross-cultural adaptation and validation of multiple sclerosis quality of life questionnaire (MSQOL-54) in a Turkish multiple sclerosis sample." Journal of the neurological sciences 240.1-2 (2006): 77-80.
• Savci, Sema, et al. "Six-minute walk distance as a measure of functional exercise capacity in multiple sclerosis." Disability and rehabilitation 27.22 (2005): 1365-1371.
• Sahin, Fusun, et al. "Reliability and validity of the Turkish version of the Berg Balance Scale." Journal of geriatric physical therapy 31.1 (2008): 32-37.
• Zanotto, T., Rice, L. A., & Sosnoff, J. J. (2022). Frailty among people with multiple sclerosis who are wheelchair users. PloSone, 17(7), e0271688.
• Searle SD, Mitnitski A, Gahbauer EA, Gill TM, Rockwood K. A standard procedure for creating a frailty index. BMC Geriatr. 2008 Sep 30;8:24. doi: 10.1186/1471-2318-8-24. PMID: 18826625; PMCID: PMC2573877.

Study record dates

Study Major Dates

• Study Start (Estimated): April 1, 2026
• Primary Completion (Estimated): May 30, 2026
• Study Completion (Estimated): June 30, 2026

Study Registration Dates

• First Submitted: March 12, 2026
• First Submitted That Met QC Criteria: April 3, 2026
• First Posted (Actual): April 13, 2026

Study Record Updates

• Last Update Posted (Actual): April 13, 2026
• Last Update Submitted That Met QC Criteria: April 3, 2026
• Last Verified: April 1, 2026

More Information

Terms related to this study

• Keywords: muscle weakness; biomarker; functional performance; multiple sclerosis; physical fitness
• Additional Relevant MeSH Terms: Neurologic Manifestations; Musculoskeletal Diseases; Nervous System Diseases; Muscular Diseases; Neuromuscular Manifestations; Pathologic Processes; Autoimmune Diseases; Immune System Diseases; Demyelinating Autoimmune Diseases, CNS; Autoimmune Diseases of the Nervous System; Demyelinating Diseases; Pathological Conditions, Signs and Symptoms; Signs and Symptoms; Multiple Sclerosis; Muscle Weakness
• Other Study ID Numbers: KA25/237

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

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