基于健康习惯的教育计划，以改善神经退行性疾病女性的生活质量和社会心理状况：咨询协议研究（第2阶段） (ADVICE Phase 2)

Participants will complete 36 strength sessions (3 times a week) at a moderate intensity, 6 educational nutritional intervention sessions, and 8 sessions on energy and fatigue management.

This arm of the study consists of a supervised strength training program, conducted over 12 weeks with three weekly sessions. The sessions follow a wave-like periodization, with intensities ranging from 70% to 85% of 1-RM. Exercises focus on enhancing neuromuscular strength in the lower limbs, such as leg presses and hip extensions, under the supervision of a multidisciplinary team.

Participants will also receive nutritional guidance based on the Mediterranean diet, as well as cognitive-behavioral therapy strategies aimed at optimizing fatigue management and boosting energy levels.

Participants will be involved in an unsupervised, self-directed program focusing on physical exercise (three times per week), nutrition and cognitive-behavioral habits.

This arm of the study consists of a self-guided and unsupervised program based on physical exercise (3 times per week), nutrition, and cognitive-behavioral habits. Participants will access online modules that provide guidelines for performing resistance exercises with bands, dietary recommendations following the principles of the Mediterranean diet, and cognitive-behavioral techniques for fatigue management.

Satisfaction with Physical Activity will be measured using an eight-item, 5-point Likert scale

Satisfaction with Physical Activity will be measured using an eight-item, 5-point Likert scale

The Visual Analogue Scale for Fatigue (VAS-F) assesses subjective levels of fatigue and energy

The Visual Analogue Scale for Fatigue (VAS-F) assesses subjective levels of fatigue and energy

Fatigue perception will be measured using the MFIS. This scale is a 21-item multidimensional questionnaire that evaluates the physical, cognitive, and psychosocial effects of fatigue on a five-point ordinal scale (with a maximum total score of 84).

Fatigue perception will be measured using the MFIS. This scale is a 21-item multidimensional questionnaire that evaluates the physical, cognitive, and psychosocial effects of fatigue on a five-point ordinal scale (with a maximum total score of 84)

The inflammatory profile evaluates key cytokines, including IFN-γ, IL-6, TNF-α, IL-10, and TGF-β1, to assess systemic inflammation and immune response dynamics

The inflammatory profile evaluates key cytokines, including IFN-γ, IL-6, TNF-α, IL-10, and TGF-β1, to assess systemic inflammation and immune response dynamics

The hormonal profile includes the assessment of TSH, progesterone (PG), luteinizing hormone (LH), follicle-stimulating hormone (FSH), estradiol, and testosterone to evaluate endocrine function, menstrual cycle phases, and hormonal balance.

Brain-Derived Neurotrophic Factor (BDNF) is a protein involved in neuroplasticity, cognitive function, and neuronal survival, serving as a blood biomarker for brain health and adaptability.

Brain-Derived Neurotrophic Factor (BDNF) is a protein involved in neuroplasticity, cognitive function, and neuronal survival, serving as a blood biomarker for brain health and adaptability

Neurofilament light chain (NFL) is one of the most relevant biomarkers in multiple sclerosis (MS). The Simoa detection technique (ultrasensitive single-molecule array) allows its analysis in serum, providing both the total value and the Z-Score, enabling precise assessment of axonal damage and disease progression.

Neurofilament light chain (NFL) is one of the most relevant biomarkers in multiple sclerosis (MS). The Simoa detection technique (ultrasensitive single-molecule array) allows its analysis in serum, providing both the total value and the Z-Score, enabling precise assessment of axonal damage and disease progression.

Physical self-perception will be evaluated using six subscales-sports competence, physical condition, body attractiveness, physical strength, general physical self-perception, and overall self-perception-on a 5-point Likert scale

Physical self-perception will be evaluated using six subscales-sports competence, physical condition, body attractiveness, physical strength, general physical self-perception, and overall self-perception-on a 5-point Likert scale

Participants will undergo the 2-minute walk test, during which they will walk at their preferred, self-selected speed to assess walking endurance. The test course will be rectangular, with corners marked by cones. Participants will be allowed to rest during the test, if necessary, but the clock will not stop during these rest periods. The total distance covered will be recorded

Participants will undergo the 2-minute walk test, during which they will walk at their preferred, self-selected speed to assess walking endurance. The test course will be rectangular, with corners marked by cones. Participants will be allowed to rest during the test, if necessary, but the clock will not stop during these rest periods. The total distance covered will be recorded

The Pain Catastrophizing Scale will measure catastrophic thoughts related to pain, focusing on rumination and helplessness, with responses on a similar scale

The Pain Catastrophizing Scale will measure catastrophic thoughts related to pain, focusing on rumination and helplessness, with responses on a similar scale

The Multiple Sclerosis Quality of Life-54 will gauge quality of life across 14 subscales, yielding physical and mental health composite scores

The Multiple Sclerosis Quality of Life-54 will gauge quality of life across 14 subscales, yielding physical and mental health composite scores

Description: The State-Trait Anxiety Inventory will measure both situational and general anxiety on a 4-point scale

The State-Trait Anxiety Inventory will measure both situational and general anxiety on a 4-point scaleTime Frame: Before the first training session

Participants will sit in a chair with both legs flexed at a 90-degree angle, and the tested ankle securely attached to a customized device with a load cell (MuscleLab Force Sensor, Ergotest AS, Langesund, Norway). They will perform three maximum contractions, each lasting 2 seconds, with 3 minutes of rest in between. The RFD will be analyzed. Testing will begin with the right leg, and the repetition with the highest recorded value for each leg will be used in the analysis

Participants will sit in a chair with both legs flexed at a 90-degree angle, and the tested ankle securely attached to a customized device with a load cell (MuscleLab Force Sensor, Ergotest AS, Langesund, Norway). They will perform three maximum contractions, each lasting 2 seconds, with 3 minutes of rest in between. The RFD will be analyzed. Testing will begin with the right leg, and the repetition with the highest recorded value for each leg will be used in the analysis

Participants will sit in a chair with both legs flexed at a 90-degree angle, and the tested ankle securely attached to a customized device with a load cell (MuscleLab Force Sensor, Ergotest AS, Langesund, Norway).Participants will perform three 5-second MVIC, with 3 minutes of rest in between. Testing will always begin with the right leg, and the contraction with the highest recorded MVIC value will be used in the analysis Time Frame: Before the first training session

Participants will sit in a chair with both legs flexed at a 90-degree angle, and the tested ankle securely attached to a customized device with a load cell (MuscleLab Force Sensor, Ergotest AS, Langesund, Norway).Participants will perform three 5-second MVIC, with 3 minutes of rest in between. Testing will always begin with the right leg, and the contraction with the highest recorded MVIC value will be used in the analysis Time Frame: Before the first training session

To measure neural drive, the electromyographic activity (sEMG) of the right leg's vastus lateralis will be recorded during the MVIC (Delsys Trigno, Delsys Inc., Boston, MA) with skin prepared and electrode positioning following SENIAM guidelines. EMG peak will be analyzed. The EMG peak during MVIC will represent the maximum neural drive

To measure neural drive, the electromyographic activity (sEMG) of the right leg's vastus lateralis will be recorded during the MVIC (Delsys Trigno, Delsys Inc., Boston, MA) with skin prepared and electrode positioning following SENIAM guidelines. EMG peak will be analyzed. The EMG peak during MVIC will represent the maximum neural drive

Two bipolar electrodes (10×15 cm) will be placed on the right quadriceps, with electrical stimulation controlled by Signal 6.0 software (CED, Cambridge, England) at 100 Hz frequency, 50 pulses, 0.009 s pulse duration, and 0.01 s interval, set to 40-50% of MVIC. Central activation ratio (CAR) will be assessed through a sequence of one supramaximal twitch, a 100 Hz tetanic train, an MVIC with superimposed tetanic train, followed by a potentiated tetanic train and a potentiated supramaximal twitch. This sequence will be repeated twice with 2-minute rests, and twitch-to-tetanus ratio, MVIC peak, and maximum force values will be calculated for CAR. The CAR will be calculated using the following formula: "CAR= " "Force during MVIC" /"Force during MVIC + supramaximal stimulation"

Two bipolar electrodes (10×15 cm) will be placed on the right quadriceps, with electrical stimulation controlled by Signal 6.0 software (CED, Cambridge, England) at 100 Hz frequency, 50 pulses, 0.009 s pulse duration, and 0.01 s interval, set to 40-50% of MVIC. Central activation ratio (CAR) will be assessed through a sequence of one supramaximal twitch, a 100 Hz tetanic train, an MVIC with superimposed tetanic train, followed by a potentiated tetanic train and a potentiated supramaximal twitch. This sequence will be repeated twice with 2-minute rests, and twitch-to-tetanus ratio, MVIC peak, and maximum force values will be calculated for CAR. The CAR will be calculated using the following formula: "CAR= " "Force during MVIC" /"Force during MVIC + supramaximal stimulation"

Isometric grip strength will be measured with an electronic dynamometer (K-Force Grip, Kinvent, Montpellier, France) as participants stand with elbows extended. Each hand will perform 3 trials, with 30 seconds rest between attempts

Isometric grip strength will be measured with an electronic dynamometer (K-Force Grip, Kinvent, Montpellier, France) as participants stand with elbows extended. Each hand will perform 3 trials, with 30 seconds rest between attempts

The Pendulum Test is used to assess the level of spasticity by evaluating the resistance to passive movement in the affected limb. The test involves moving the limb in a pendulum-like motion and observing the fluidity of the movement, with increased resistance indicating higher spasticity levels

The Pendulum Test is used to assess the level of spasticity by evaluating the resistance to passive movement in the affected limb. The test involves moving the limb in a pendulum-like motion and observing the fluidity of the movement, with increased resistance indicating higher spasticity levels

Muscle characteristics (frequency, stiffness, degradation) assessed with MyotonPRO (MyotonPRO, Myoton AS, Estonia)

Muscle characteristics (frequency, stiffness, degradation) assessed with MyotonPRO (MyotonPRO, Myoton AS, Estonia)

Gait speed will be determined with the 10-meter walk test using two photocells (Ergotest Technology AS, Langesund, Norway) at 5 and 10 meters; participants will complete two maximum-speed trials, with the slower time recorded

Gait speed will be determined with the 10-meter walk test using two photocells (Ergotest Technology AS, Langesund, Norway) at 5 and 10 meters; participants will complete two maximum-speed trials, with the slower time recorded

Balance is measured with static trials on a force platform (Ergotest Technology AS, Langesund, Norway), where participants stand barefoot with arms at their sides for two 30-second trials each

Balance is measured with static trials on a force platform (Ergotest Technology AS, Langesund, Norway), where participants stand barefoot with arms at their sides for two 30-second trials each

Balance is measured with static trials on a force platform (Ergotest Technology AS, Langesund, Norway), where participants stand barefoot with arms at their sides for two 30-second trials each

Balance is measured with static trials on a force platform (Ergotest Technology AS, Langesund, Norway), where participants stand barefoot with arms at their sides for two 30-second trials each

The sit-to-stand test requires participants to rise as quickly as possible from a seated position with 90º knee flexion and arms crossed

The sit-to-stand test requires participants to rise as quickly as possible from a seated position with 90º knee flexion and arms crossed

In the Timed Up-and-Go test, participants move from sitting to standing, walk 3 meters, turn, return, and sit

In the Timed Up-and-Go test, participants move from sitting to standing, walk 3 meters, turn, return, and sit

To measure delayed onset muscle soreness (DOMS), a 10-point visual analogue scale shall be used, where 1 = no pain and 10 = intolerable pain

Participants will be instructed and familiarized with the use of the RPE scale during the familiarization phase. RPE will be assessed before, during (after each exercise within the session), and after the training session using the Borg 6-20 RPE scale

The VAS-F will be used to measure fatigue. This scale, is subdivided into two subscales: fatigue and energy. The VAS-F features a 100 mm long horizontal line, with the term "none" at one end and "very severe" at the opposite end. Participants are required to mark the point on the line corresponding to their perception of the severity of fatigue between these two endpoints.

Anthropometric measurements will be taken to assess body morphology, fat distribution, and potential alterations due to multiple sclerosis (MS), such as muscle atrophy or changes in body fat percentage. These measurements provide valuable information regarding comorbidities, including abdominal obesity and cardiovascular risk, which are particularly relevant in MS due to factors like reduced mobility or medication use

Anthropometric measurements will be taken to assess body morphology, fat distribution, and potential alterations due to multiple sclerosis (MS), such as muscle atrophy or changes in body fat percentage. These measurements provide valuable information regarding comorbidities, including abdominal obesity and cardiovascular risk, which are particularly relevant in MS due to factors like reduced mobility or medication use

Bioimpedance will be used to assess body composition, including body fat percentage, lean mass, and total body water. These measurements are important for understanding changes in body composition due to multiple sclerosis (MS), as the disease can impact muscle mass, fluid balance, and fat distribution. Bioimpedance provides valuable insight into the health status and nutritional needs of individuals with MS

Bioimpedance will be used to assess body composition, including body fat percentage, lean mass, and total body water. These measurements are important for understanding changes in body composition due to multiple sclerosis (MS), as the disease can impact muscle mass, fluid balance, and fat distribution. Bioimpedance provides valuable insight into the health status and nutritional needs of individuals with MS

To assess physical activity in patients with multiple sclerosis (MS), both the International Physical Activity Questionnaire (IPAQ) and triaxial accelerometers can be adapted to account for the mobility limitations often experienced by these individuals. The IPAQ can be tailored by including questions that specifically address low-impact or moderate-intensity activities, considering factors such as fatigue and muscle weakness. Triaxial accelerometers, which measure movement in three planes (vertical, lateral, and anterior-posterior), provide a more detailed and precise measurement of physical activity, capturing even small movements or low-intensity activities such as walking short distances. Together, these tools allow for a comprehensive assessment of physical activity levels in MS patients, while considering their unique needs and capabilities. Additionally, the MET (Metabolic Equivalent of Task) methodology should be adjusted to reflect the lower intensity of activities commonly p

To assess physical activity in patients with multiple sclerosis (MS), both the International Physical Activity Questionnaire (IPAQ) and triaxial accelerometers can be adapted to account for the mobility limitations often experienced by these individuals. The IPAQ can be tailored by including questions that specifically address low-impact or moderate-intensity activities, considering factors such as fatigue and muscle weakness. Triaxial accelerometers, which measure movement in three planes (vertical, lateral, and anterior-posterior), provide a more detailed and precise measurement of physical activity, capturing even small movements or low-intensity activities such as walking short distances. Together, these tools allow for a comprehensive assessment of physical activity levels in MS patients, while considering their unique needs and capabilities. Additionally, the MET (Metabolic Equivalent of Task) methodology should be adjusted to reflect the lower intensity of activities commonly p

Mediterranean Diet adherence questionnaires and food diaries could be effective tools for evaluating nutrition, particularly if MS patients have poor consumption of essential nutrients for their overall health

Mediterranean Diet adherence questionnaires and food diaries could be effective tools for evaluating nutrition, particularly if MS patients have poor consumption of essential nutrients for their overall health

The Kurtzke Disability Scale (EDSS) is divided into 8 functional systems (FS); four primary: pyramidal function, cerebellar function, sensory function, and brainstem function; and four secondary: sphincters, vision, mental, and others. For each FS, a severity score is provided, ranging from 0 to 6 or 7. The overall score of the scale is measured on a 20-item scale (from 0 to 10 points, increasing in half-point increments). Up to 3.5, the score obtained in each FS and the number of affected FS automatically determine the EDSS score. From 4 to 7, the definition of each level is also given by the ability to walk (ability to walk without stopping, need for assistance)

The Kurtzke Disability Scale (EDSS) is divided into 8 functional systems (FS); four primary: pyramidal function, cerebellar function, sensory function, and brainstem function; and four secondary: sphincters, vision, mental, and others. For each FS, a severity score is provided, ranging from 0 to 6 or 7. The overall score of the scale is measured on a 20-item scale (from 0 to 10 points, increasing in half-point increments). Up to 3.5, the score obtained in each FS and the number of affected FS automatically determine the EDSS score. From 4 to 7, the definition of each level is also given by the ability to walk (ability to walk without stopping, need for assistance).

Subjective sleep quality will be measured using the Karolinska Sleep Diary questionnaire [73]. The questionnaire includes the following items: a) sleep quality (very poor [1] - very good [5]), b) sleep tranquility (very restless [1] - very calm [5]), c) ease of falling asleep (very difficult [1] - very easy [5]), d) awakenings (woke up too early [1] - did not wake up early [3]), e) ease of waking up (very difficult [1] - very easy [5]), f) feeling of rest (did not rest at all [1] - fully rested [3]), and g) sufficient sleep (no, definitely too little [1] - yes, definitely enough [5]).

Subjective sleep quality will be measured using the Karolinska Sleep Diary questionnaire [73]. The questionnaire includes the following items: a) sleep quality (very poor [1] - very good [5]), b) sleep tranquility (very restless [1] - very calm [5]), c) ease of falling asleep (very difficult [1] - very easy [5]), d) awakenings (woke up too early [1] - did not wake up early [3]), e) ease of waking up (very difficult [1] - very easy [5]), f) feeling of rest (did not rest at all [1] - fully rested [3]), and g) sufficient sleep (no, definitely too little [1] - yes, definitely enough [5]).

Sleep quality based on actigraphy will be evaluated using the Actiwatch wGT3X-BT activity monitoring system (Cambridge Neurotechnology, Cambridge, UK) [74]. This device uses a piezoelectric accelerometer to measure activity. Participants will wear the Actiwatch on their non-dominant wrist. The lower sensitivity threshold for actigraphy will be set at 80 counts/epoch. Data analysis will begin at the start of the nighttime rest period (bedtime) and conclude at the start of daytime activity (wake-up time).

Sleep quality based on actigraphy will be evaluated using the Actiwatch wGT3X-BT activity monitoring system (Cambridge Neurotechnology, Cambridge, UK) [74]. This device uses a piezoelectric accelerometer to measure activity. Participants will wear the Actiwatch on their non-dominant wrist. The lower sensitivity threshold for actigraphy will be set at 80 counts/epoch. Data analysis will begin at the start of the nighttime rest period (bedtime) and conclude at the start of daytime activity (wake-up time)

To measure delayed onset muscle soreness (DOMS), a 10-point visual analogue scale shall be used, where 1 = no pain and 10 = intolerable pain

Participants will be instructed and familiarized with the use of the RPE scale during the familiarization phase. RPE will be assessed before, during (after each exercise within the session), and after the training session using the Borg 6-20 RPE scale

The VAS-F will be used to measure fatigue. This scale, is subdivided into two subscales: fatigue and energy. The VAS-F features a 100 mm long horizontal line, with the term "none" at one end and "very severe" at the opposite end. Participants are required to mark the point on the line corresponding to their perception of the severity of fatigue between these two endpoints.