Comparison of Frailty, Physical Fitness Parameters, and Irisin Levels Between Patients With Multiple Sclerosis and Healthy Volunteers
Conditions: MULTIPL SCLEROSİS
Sponsor: Baskent University

 
  
                        BASKENT UNIVERSİTY STUDY PROTOCOL 
 
PROJECT NO: KA25/237 
 
ETHİCAL APPROVAL DATE AND NUMBER: E-94603339-604.01-485865 / 24.07.2025 
 
PROJECT TITLE: Comparison of Frailty, Physical Fitness Parameters, and Irisin Levels Between 
Patients with Multiple Sclerosis and Healthy Volunteers  
 
INTRODUCTION AND GENERAL INFORMATION  
Multiple Sclerosis (MS) is a chronic, immune-mediated, inflammatory, and neurodegenerative 
disorder of the central nervous system (CNS), characterized by demyelination and axonal 
degeneration. The pathological process leads to focal plaques and lesions resulting from 
inflammation and axonal loss. MS predominantly affects the white matter of the brain, spinal cord, 
and optic nerves, although gray matter structures, including the cerebral cortex, may also be 
involved. Disease onset typically occurs between 20 and 40 years of age, and women are affected 
approximately two to three times more frequently than men. Globally, both the incidence and 
prevalence of MS have increased in recent decades. This rise is largely attributed to advances in 
neuroimaging and diagnostic criteria, improved treatment strategies that prolong survival, and more 
accurate case ascertainment.  
Frailty is a significant and increasingly recognized clinical concern in individuals with MS. It is 
defined as a state of reduced physiological reserve and increased vulnerability to stressors, resulting 
in impaired ability to maintain homeostasis. Frailty is characterized by weakness, reduced stress 
tolerance, impaired adaptive capacity, and heightened sensitivity to adverse events. It is a 
multidimensional construct encompassing physical, cognitive, psychological, social, and 
environmental domains. Physical frailty is commonly identified by clinical features such as fatigue 
or exhaustion, unintentional weight loss, decreased physical activity, slowed gait speed, and 
reduced muscle strength.  
Frailty is more prevalent among individuals with MS who have higher levels of disability; however, 
it is also observed in patients with low scores on the Expanded Disability Status Scale (EDSS), 
indicating that factors beyond neurological disability contribute to its development. Comparative 
studies have demonstrated that frailty levels are significantly higher in individuals with MS 
compared to healthy controls. Furthermore, the Frailty Index has been shown to correlate 
significantly with EDSS scores, comorbid conditions, educational level, disease duration, and 
quality of life. Importantly, frailty has also been independently associated with fall history, 
regardless of age, sex, or disease severity.  
A recent systematic analysis published in 2024 examined studies evaluating the prevalence and 
clinical implications of frailty in MS. Reported prevalence rates ranged from 17% to 66% among 
outpatient populations. Evidence suggests that frailty develops earlier in individuals with MS 
compared to the general population. Higher disability levels, longer disease duration, and 
progressive MS phenotypes are consistently associated with increased frailty risk. Additionally, 
frailty has been strongly linked to reduced walking performance, poor sleep quality, fatigue, 
diminished quality of life, increased fall risk, greater healthcare utilization, and mortality. Notably, 
frailty and disability demonstrate distinct associations with gait parameters, highlighting the need 
for targeted rehabilitation strategies. Overall, frailty represents a common  

yet under-investigated clinical issue in MS, and a better understanding of its mechanisms is essential 
for early identification and intervention.  
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.  
The aim of the present study is to investigate the relationship between frailty, physical fitness 
parameters, and circulating irisin levels in patients with multiple sclerosis.  
 
MATERIAL AND METHOD  
Research Type: Designed as a randomized controlled study.  
Research Sample: 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.  
(Note: Please check the dates in the original text, as 08.2025 to 02.2025 suggests a chronological 
discrepancy).  
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.  
 Patients and healthy volunteers who do not agree to sign the informed consent form.  
 

Evaluation of Participants:  
Demographic data (age, gender, height, weight, occupation, education level, BMI, marital status, 
disease duration, MS type) will be collected. All participants will be evaluated by an experienced 
physiatrist using the Functional Independence Measure (FIM), Frailty Index, Berg Balance 
Scale, 6-Minute Walk Test, and Jamar hand dynamometer for handgrip strength.  
Additionally, blood samples will be taken from all participants at 10:00 AM during the evaluation 
to measure irisin levels using the ELISA method.  
Assessment Tools:  
 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 score ranges from 18 (complete dependence) to 126 (full 
independence), with higher scores reflecting greater functional ability. It is widely used in inpatient 
rehabilitation to track patient progress, guide treatment planning, and estimate the level of care 
required after discharge.  
 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. The FI is widely used in geriatric medicine 
and research to predict adverse outcomes such as falls, hospitalization, disability, and mortality. In 
this study 30 variables were included for FI calculation according to Searle et al.‘s study. ( )  
 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.  
 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.  
 
STATISTICAL EVALUATION  
"Student’s t-Test" will be used to compare two independent groups if parametric assumptions are 
met; otherwise, the "Mann Whitney U Test" will be used. Relationships between qualitative 
variables will be examined with "Chi-Square" or "Fisher's Exact Test." Relationships between 
quantitative variables will be investigated with Pearson or Spearman Correlation tests. The Type I 
error probability will be taken as $\alpha=0.05$.  
Sample size: Calculated using G*Power 3.1.9.4. To provide 95% power at a 95% confidence level 
with an effect size of $d=0.84$, a total of 76 individuals (39 per group) must be included (18).  
 
RESEARCH HYPOTHESES  
 Although MS patients consist of a young population, frailty is detected more frequently in this 
group compared to healthy volunteers.  
 Irisin levels are significantly lower in participants where frailty is detected.  
 
KEY WORDS: biomarker, functional performance, physical fitness, multiple sclerosis, muscle 
weakness,