With our study, the investigators aim to assess the impact of the fatigue experienced during daily life activities (tiredness) and whether there is a relationship with muscle fatigue during an exercise task.

The results of this study may be used to improve the assessment of fatigue in older adults and enhance clinical management.

1. General information An increase in fatigue is considered one of the main causes of reduced quality of life in older adults and in people suffering from chronic diseases. However, the investigators still know little about the mechanisms underlying fatigue in older adults, mainly because most of the available tools were developed to assess this symptom in younger populations with specific diseases, without proper adjustments for physical activity or age.

   In 2015, the Pittsburgh Fatigability Scale (PFS) was developed as a self-administered questionnaire to assess both physical and mental fatigue in older adults. The PFS consists of 10 questions describing activities of varying duration and intensity. The other scale the investigators will ask participants to complete is called the Fatigue Severity Scale (FSS): a 9-item questionnaire that evaluates fatigue intensity in various situations over the past week.

   Participants' fatigue will also be assessed during two motor tasks simulating daily activities: a handgrip test and a seated leg exercise mimicking walking.

   If participants decide to take part in our research project, participants will complete the PFS and FSS questionnaires once (5-10 minutes) and perform two brief motor exercises to determine the onset and progression of muscle fatigue. The exercises will last about 20 minutes, with an additional 10 minutes for preparation. Each contraction will last a maximum of 2 minutes.

   The project will last 12 months (Swiss section) and will be conducted at [(1) the nursing homes of the Multistruttura di Bellinzona, the Fondazione Parco San Rocco facilities in Morbio Inferiore and Coldrerio, and the Opera Charitas nursing home in Sonvico] (period: December 2024 - May 2025); and (2) at the [San Raffaele University Research Institute] in Milan, Italy, where 40 older adults with Parkinson's disease will participate (September 2026 - March 2027).

   This research project is conducted in accordance with Swiss legislation and current international ethical guidelines. It has been reviewed and approved by the Ethics Committee of the Canton of Ticino.

2. Study procedure

The testing session will last a maximum of 30 minutes and will include the following steps:

Discussion of the study procedures.

Verification of appropriate leg clothing. The exercise can be performed either by wearing shorts or by rolling up long trousers to expose the upper half of the thigh.

Review of the completed Pittsburgh Fatigability Scale (PFS) questionnaire and completion of the Fatigue Severity Scale (FSS), both available in Italian.

Performance of two motor exercises (a surrogate walking test and a handgrip test).

1. First, participants will be instructed on how to perform the surrogate walking test, which evaluates leg muscle fatigue.

   During the exercise, participants will push with their legs and foot on a movable platform that slides along rails within the device. The sliding motion is resisted by elastic bands that stretch and shorten as participants push. The exercise will be repeated for several cycles until participants are told to stop. To measure muscle fatigue, surface electrodes (non-invasive) will be placed on the skin over two thigh muscles.

2. After a 5-minute rest, participants will be asked to perform the handgrip test with participants' right hand (see Figure 3). The maximal handgrip test will be performed while seated, with participants' forearm resting on a table. The test will be repeated several times until participants are instructed to stop.

The principal investigator and the investigators at the local sites have approved the protocol version 1.2 dated 3/1/2024 and confirm to conduct the project according to the protocol, the Swiss legal requirements, the current version of the World Medical Association Declaration of Helsinki and the principles and procedures for integrity in scientific research involving human beings.

The multidimensional evaluation of fatigability will be conducted with (Site 1) older residents at the Charitas Foundation (TI, Switzerland), (Site 2) Multistruttura Sezione Anziani of the City of Bellinzona (TI, Switzerland), (Site 3) Parco San Rocco Foundation (TI, Switzerland); and (Site 4) active older people recruited at gym courses held by Pro Senectute Ticino and Moesano (TI, Switzerland). These participants will serve as controls for the matched participants with Parkinson's Disease (PD) that will be recruited at the (Site 5) University hospital San Raffaele, Milan (Italy).

The planned measures comprise supervised motor tasks and self-assessment questionnaires. Participants will be instructed and supervised during the exercises. Therefore, no risks of the procedure have been identified. The selected measures entail only minimal risks and burdens for the participants.

1. Study design: Cross-sectional observational study in older people (active community-dwelling and residential in a nursing home, and outpatients with Parkinson's disease (PD)). Treatments are not affected by this study. The project setup is multicenter and international, with four sites in Switzerland, and one site in Italy. A cross-sectional study is appropriate to measure at one given point the variables of interest in different populations. The control group will give comparative scores about fatigability in older adults with PD.

   Participants at Sites 1-4 were recruited through study presentation meetings, which took place at nursing homes and gyms where physical exercise sessions for older adults were organized. Participants at Site 5 will be recruited at the San Raffaele Hospital.

2. Procedures: A single measurement session, in a dedicated space, on the arranged date/hour, will be held.

After the candidate has signed the informed consent, the data listed below will be collected, by interview (I), and from clinical records (CR), prior to the enrolment in the study:

• Sociodemographic information (age, gender, height, weight) (CR);
• Information about any disabilities (CR);
• Concurrent illnesses (CR);
• Concurrent symptoms, directly reported by the patient (I);
• Main drug treatments that may interfere with the fatigue level (CR).

After the enrolling of the subject in the study, the following procedures will be performed:

i) Assessment of physical and mental perceived fatigability: before performance measurements, the participants will be asked to complete the PFS-Italian version and the Fatigue Severity Scale (FSS). The proposed questionnaires are validated Italian versions. All the procedures are highly standardized; thus, the expected bias should be negligible.

ii) Physical performance measurements: the repetitive hand-grip test will be performed in a sitting position, with the arm at 90° of flexion and wrist positioned in a supine position and neutral wrist posture. The hand-grip task will be performed using the force fiber Optic Response Pad used in fMRI, grip force transducer (fORP 932 Package, Current Designs, Philadelphia, USA).

The fatiguing protocol of upper and lower limbs will be characterized by the following contractions:

• Two maximal isometric contractions (MVC) of 3-4 s.
• An isometric contraction at 20% MVC lasting 20 s.
• A dynamic series of contractions lasting 120 s.
• An isometric contraction at 20% MVC lasting 20 s.
• A maximal isometric contraction (MVC) of 3-4 s Participants will perform active knee extension and flexions, cadenced using a metronome with a foot drive device called Minivector® (Easytech, Borgo San Lorenzo, Italy) placed on the floor and fixed with straps to the chair. Participants will be instructed to move the foot platform between a fixed range. The Minivector is a class I CE certified medical device (UE Regulation 2017/745).

Performance fatigability will be assessed by means of surface electromyography (sEMG) electrodes placed on the vastus medialis (VM) and vastus lateralis (VL) muscles. Surface EMG signals will be recorded with electrodes applied on the skin overlying the muscles as previously described.

Inclusion Criteria:

• Age greater than 65 years.

Exclusion Criteria:

• No understanding of the project language (Italian);
• Moderate to severe dementia, with a Short Portable Mental Status Questionnaire (SPMSQ) score ≥1 [Pfeiffer, 1975] or Cognitive Performance Scale (CPS) ≥3 [Morris et al., 1994];
• Psychiatric disorders and moderate neurodegenerative diseases;
• Delirium;
• Persistent infections;
• Inability to follow the study procedures (due to psychological disorders or dementia);
• Severe hearing problem;
• Unable or refuse to perform the physical tests (maximal handgrip strength, leg extension);
• Severe cardiovascular and lung diseases (acute infection, heart, or lung failure, unstable angina and myocardial infarction during the previous month);
• Renal failure, hepatic dysfunction;
• Recent major surgery;
• Severe cardiovascular exacerbations (RR > 240/120, HR above the age predicted maximum of 220-Age);
• Participation in another study with investigational drug within the 30 days preceding and during the present study;
• Drug treatments that may interfere with the fatigue level;
• Lifestyle factors and / or persistent addictions (drug or alcohol abuse).

Three cohorts:

1. Nursing homes OA 40 residents in a nursing home of southern Switzerland will be recruited. The study will not affect any treatment. The key inclusion criteria for the participants' eligibility will be age greater than 80 years, modified Barthel Index score ≥85 points [Tofani et al., 2019] and ADL index score ≤12 points [Katz et al., 1963].
2. Community-dwelling OA 40 active community-dwelling older people will be recruited. The key inclusion criterion for the participants' eligibility is an age comprised between 65 and 75 years.
3. 40 older outpatients with early phases of PD will be recruited.

People with PD fulfilling the key inclusion and the following criterium are eligible for this study (see above):

• Primary parkinsonism stages I-III of clinical disability, according to Hoehn and Yahr [1967].