Exercise in Alzheimer's Disease: Functional Biomarkers (AD-GUT-EX)
Physical Exercise in Alzheimer's Disease: Impact on Functional Biomarkers and the Muscle-Gut-Brain Axis
Alzheimer's disease (AD) is the leading cause of dementia worldwide and involves systemic alterations beyond the brain, such as loss of muscle strength, chronic low-grade inflammation, and gut microbiome dysbiosis. Physical exercise is a promising non-pharmacological therapy, and velocity-based resistance training has proven safe and effective in older adults. However, the effects of performing resistance exercises at high versus moderate velocity in people with AD remain unknown, and human evidence on how exercise modulates the gut microbiome in AD is very limited. This study aims to assess and compare the effects of two velocity-based resistance training modalities (high load at moderate velocity and moderate load at high velocity) versus usual care on the gut microbiome, systemic inflammation, plasma biomarkers, biological age, and intrinsic capacity in older adults with mild-to-moderate AD, using cognitively healthy older adults as a reference group.
Descripción general del estudio
Estado
Intervención / Tratamiento
Descripción detallada
Alzheimer's disease (AD) is the leading cause of dementia worldwide, affecting more than 50 million people, a figure projected to exceed 150 million by 2050, with a high economic and social burden that increases with disease severity. Beyond the accumulation of amyloid-β and hyperphosphorylated tau in the brain, AD involves systemic alterations even in early stages, including the progressive loss of muscle mass and strength (sarcopenia), chronic low-grade inflammation and disruption of the gut-brain axis. In this context, physical exercise has emerged as a high-impact adjuvant therapy capable of inducing relevant neurobiological and systemic adaptations. Among the available training modalities, velocity-based resistance training (i.e., controlling the execution velocity of each repetition to individualize the training load) has been shown to be safe and effective in older adults. However, the effects of executing resistance exercises at high velocity with moderate loads (e.g., 40-60% of one-repetition maximum [1RM]) versus moderate velocity with high loads (e.g., 60-80% 1RM) remain unexplored in people with AD. These exercise-induced adaptations can be monitored through circulating biomarkers that capture different biological responses: brain-derived neurotrophic factor (BDNF), a key mediator of neuronal survival and synaptic plasticity; the testosterone/cortisol ratio, an indicator of anabolic-catabolic balance; phosphorylated tau 217 (p-tau217), one of the most specific plasma markers of AD pathology; and Klotho, a protein linked to healthy aging with neuroprotective and anti-inflammatory functions. In parallel, the gut microbiome has gained prominence as a key modulator of the muscle-gut-brain axis. People with AD show reduced microbial diversity, an expansion of pro-inflammatory species and a reduction of short-chain fatty acid-producing bacteria, which compromise intestinal and blood-brain barrier integrity and amplify systemic inflammation. Although animal models consistently show that exercise promotes beneficial taxa and is associated with cognitive improvements, human studies have focused mainly on healthy older adults, and evidence in people diagnosed with AD is very limited. Moreover, molecular changes should translate into clinically relevant benefits. The World Health Organization's intrinsic capacity framework (cognition, locomotion, vitality, psychological and sensory domains) offers an integrative approach linking biological mechanisms with functional outcomes, together with sarcopenia, frailty, functional independence and caregiver burden. Therefore, this randomized controlled trial will compare two velocity-based resistance training modalities with usual care in older adults with mild-to-moderate AD, including a cognitively healthy reference group, to determine which modality has the greatest impact on the muscle-gut-brain axis, biological aging and intrinsic capacity, and whether these effects persist after detraining.
Tipo de estudio
Inscripción (Estimado)
Fase
- No aplica
Contactos y Ubicaciones
Estudio Contacto
- Nombre: Alejandro Santos-Lozano, PhD
- Número de teléfono: 22292 +34983001000
- Correo electrónico: asantos@uemc.es
Copia de seguridad de contactos de estudio
- Nombre: Fabrzio Evangelista, Nurse
Ubicaciones de estudio
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Valladolid
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Valladolid, Valladolid, España, 47012
- Miguel de Cervantes European University
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Sub-Investigador:
- María Merino País, MSc, PhD student
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Sub-Investigador:
- Susana López Ortiz, PhD
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Sub-Investigador:
- Celia García Chico, PhD
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Contacto:
- Francisco Javier Gutiérrez Pecharrómán
- Número de teléfono: 22293 +34 983 001 000
- Correo electrónico: dit@uemc.es
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Investigador principal:
- Alejandro Santos Lozano, PhD
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Investigador principal:
- Fabrizio Evangelista, MSc
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Sub-Investigador:
- Alba Canteli Diez, MSc, PhD student
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Sub-Investigador:
- Virginia Carbajosa Rodríguez, PhD
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Sub-Investigador:
- Sara del Amo Ramos, MD
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Sub-Investigador:
- Daniel Arévalo Sillero, MSc
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Sub-Investigador:
- Mónica Álvarez Muñoz, MD
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Sub-Investigador:
- Javier Guitiérrez Redondo
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Sub-Investigador:
- Francisco Javier Iruzubieta Barragan, PhD
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Criterios de participación
Criterio de elegibilidad
Edades elegibles para estudiar
Acepta Voluntarios Saludables
Géneros elegibles para el estudio
Descripción
Inclusion Criteria - participants with Alzheimer's Disease
- Age ≥ 60 years
- Medical diagnosis of mild or moderate Alzheimer's disease based on clinical criteria and plasma biomarkers.
- Able to perform physical activity according to medical assessment
- Written informed consent from the participant or, when capacity is insufficient, from the legal representative
Inclusion Criteria - cognitively healthy reference group
- Age ≥ 60 years
- No medical diagnosis of Alzheimer's disease or cognitive impairment according to clinical criteria
- Preserved functional autonomy
- Able to perform physical activity according to medical assessment
- Written informed consent
Exclusion Criteria:
- Major surgery in the previous 3 months
- Total functional dependence
- Uncontrolled neuromuscular disease or severe heart disease
- Antibiotic, probiotic or corticosteroid treatment in the 4 weeks before biological sample collection
Plan de estudios
¿Cómo está diseñado el estudio?
Detalles de diseño
- Propósito principal: Investigación de servicios de salud
- Asignación: Aleatorizado
- Modelo Intervencionista: Asignación paralela
- Enmascaramiento: Único
Armas e Intervenciones
Grupo de participantes/brazo |
Intervención / Tratamiento |
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Experimental: Alzheimer's disease - High load
Participants with mild-to-moderate AD perform 12 weeks of supervised based resistance training at 60-80% 1RM, 3 sessions/week, plus usual care. Followed by 12 weeks of detraining. |
Supervised resistance training programme lasting 12 weeks, with 3 sessions per week of 60 minutes each. Each session consists of a 15-minute mobility warm-up, in which one set of 10 repetitions with a load of 10% of body weight is performed for each exercise; a 35-minute main part with five exercises performed on guided resistance machines (leg press, leg extension, leg curl, chest press and seated row) in circuit format at 60-80% of one-repetition maximum (1RM); and a 10-minute cool-down with mobility and flexibility exercises. Training volume will be progressively increased throughout the programme by increasing the number of repetitions and sets per exercise. |
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Experimental: Alzheimer's disease - Moderate load
Participants with mild-to-moderate AD perform 12 weeks of supervised based resistance training at 40-60% 1RM, 3 sessions/week, plus usual care. Followed by 12 weeks of detraining. |
Supervised resistance training programme lasting 12 weeks, with 3 sessions per week of 60 minutes each. Each session consists of a 15-minute mobility warm-up, in which one set of 10 repetitions with a load of 10% of body weight is performed for each exercise; a 35-minute main part with five exercises performed on guided resistance machines (leg press, leg extension, leg curl, chest press and seated row) in circuit format at 40-60% of one-repetition maximum (1RM); and a 10-minute cool-down with mobility and flexibility exercises. Training volume will be progressively increased throughout the programme by increasing the number of repetitions and sets per exercise. |
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Sin intervención: Alzheimer's disease - Usual care
Participants with mild-to-moderate AD continue their usual care only (cognitive therapy, music therapy or other routine therapies). |
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Otro: Healthy reference group
Cognitively healthy adults aged ≥ 60 years, not randomized for the longitudinal phase and not undergoing structured exercise. At week 1 they will be randomized to a single high-load session, a single moderate-load session or no exercise for the acute sub-study. |
One acute session of 60 minutes each. The session consists of a 15-minute mobility warm-up, in which one set of 10 repetitions with a load of 10% of body weight is performed for each exercise; a 35-minute main part with five exercises performed on guided resistance machines (leg press, leg extension, leg curl, chest press and seated row) in circuit format at 60% of one-repetition maximum (1RM); and a 10-minute cool-down with mobility and flexibility exercises. One acute session of 60 minutes each. The session consists of a 15-minute mobility warm-up, in which one set of 10 repetitions with a load of 10% of body weight is performed for each exercise; a 35-minute main part with five exercises performed on guided resistance machines (leg press, leg extension, leg curl, chest press and seated row) in circuit format at 40% of one-repetition maximum (1RM); and a 10-minute cool-down with mobility and flexibility exercises. |
¿Qué mide el estudio?
Medidas de resultado primarias
Medida de resultado |
Medida Descripción |
Periodo de tiempo |
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Gut microbiome
Periodo de tiempo: Baseline, week 12 of intervention
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Participants will collect a stool sample at home using a commercial collection kit (REAL Stool Sample Collection Microbiome kit, Durviz S.L., Valencia, Spain). Samples will be divided into three aliquots and stored at -80ºC within 2 hours of collection. Microbial DNA will be extracted and the gut microbiome will be analysed by next-generation sequencing of the 16S rRNA gene. |
Baseline, week 12 of intervention
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Inflammation indices - Systemic Inflammation Response Index
Periodo de tiempo: Baseline, week 1 of intervention, week 12 of intervention and week 12 of detraining
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Fasting venous blood samples will be collected by a qualified nurse from the antecubital vein and complete blood count will be assessed by flow cytometry to assess the Systemic Inflammation Response Index (SIRI) . SIRI = (neutrophils × monocytes) / lymphocytes All cell counts will be expressed as ×10⁹ cells/L or equivalent. |
Baseline, week 1 of intervention, week 12 of intervention and week 12 of detraining
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Plasma biomarkers - Brain-derived neurotrophic factor
Periodo de tiempo: Baseline, week 1 of intervention, week 12 of intervention and week 12 of detraining
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Plasma concentrations of Brain-derived neutrophic factor (BDNF) will be measured by Enzyme-Linked ImmunoSorbent Assay (ELISA). Fasting venous blood samples will be collected by a qualified nurse from the antecubital vein into EDTA-treated vacutainers and centrifuged at 1500g for 10 minutes. Plasma will then undergo a second centrifugation at 2500g for 15 minutes and be stored in cryogenic vials at -80ºC. Results will be expressed in pg/mL or ng/mL. |
Baseline, week 1 of intervention, week 12 of intervention and week 12 of detraining
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Inflammation indices - Aggregate Index of Systemic Inflammation
Periodo de tiempo: Baseline, week 1 of intervention, week 12 of intervention and week 12 of detraining
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Fasting venous blood samples will be collected by a qualified nurse from the antecubital vein and complete blood count will be assessed by flow cytometry to assess the Aggregate Index of Systemic Inflammation (AISI). AISI = (neutrophils × monocytes × platelets) / lymphocytes All cell counts will be expressed as ×10⁹ cells/L or equivalent. |
Baseline, week 1 of intervention, week 12 of intervention and week 12 of detraining
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Plasma biomarkers - p-tau217
Periodo de tiempo: Baseline, week 1 of intervention, week 12 of intervention and week 12 of detraining
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Plasma concentrations of p-tau217 will be measured by ELISA. Fasting venous blood samples will be collected by a qualified nurse from the antecubital vein into EDTA-treated vacutainers and centrifuged at 1500g for 10 minutes. Plasma will then undergo a second centrifugation at 2500g for 15 minutes and be stored in cryogenic vials at -80ºC. Results will be expressed in pg/mL or ng/mL. |
Baseline, week 1 of intervention, week 12 of intervention and week 12 of detraining
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Plasma biomarkers - Klotho
Periodo de tiempo: Baseline, week 1 of intervention, week 12 of intervention and week 12 of detraining
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Plasma concentrations of klotho will be measured by ELISA. Fasting venous blood samples will be collected by a qualified nurse from the antecubital vein into EDTA-treated vacutainers and centrifuged at 1500g for 10 minutes. Plasma will then undergo a second centrifugation at 2500g for 15 minutes and be stored in cryogenic vials at -80ºC. Results will be expressed in pg/mL or ng/mL. |
Baseline, week 1 of intervention, week 12 of intervention and week 12 of detraining
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Plasma biomarkers - Testosterone/cortisol ratio
Periodo de tiempo: Baseline, week 1 of intervention, week 12 of intervention and week 12 of detraining
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Plasma ratio of testosterone/cortisol will be assessed by ELISA. Fasting venous blood samples will be collected by a qualified nurse from the antecubital vein into EDTA-treated vacutainers and centrifuged at 1500g for 10 minutes. Plasma will then undergo a second centrifugation at 2500g for 15 minutes and be stored in cryogenic vials at -80ºC. Results will be expressed in pg/mL or ng/mL. |
Baseline, week 1 of intervention, week 12 of intervention and week 12 of detraining
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Biological age
Periodo de tiempo: Baseline, week 1 of intervention, week 12 of intervention and week 12 of detraining
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Fasting venous blood samples will be collected by a qualified nurse from the antecubital vein and analysed at the Hospital Universitario Río Hortega laboratory. PhenoAge clock based on crhonological age and nine blood biomarkers: albumin, creatinine, glucose, C-reactive protein, lymphocyte %, mean corpuscular volume, red blood cell distribution width, alkaline phosphatase and white blood count). PhenoAge acceleration (years) will be computed as the residual from regression PhenoAge on chronological age. |
Baseline, week 1 of intervention, week 12 of intervention and week 12 of detraining
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Medidas de resultado secundarias
Medida de resultado |
Medida Descripción |
Periodo de tiempo |
|---|---|---|
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Intrinsic capacity - Cognition
Periodo de tiempo: Baseline, week 1 of intervention (only verbal fluency), week 12 of intervention and week 12 of detraining
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Cognition will be measured by Mini-Mental State Examination (0-35 points). |
Baseline, week 1 of intervention (only verbal fluency), week 12 of intervention and week 12 of detraining
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Intrinsic capacity - Cognition
Periodo de tiempo: Baseline, week 1 of intervention (only verbal fluency), week 12 of intervention and week 12 of detraining
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Cognition will also be measured by Clock Drawing Test (0-10 points) |
Baseline, week 1 of intervention (only verbal fluency), week 12 of intervention and week 12 of detraining
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Intrinsic capacity - Cognition
Periodo de tiempo: Baseline, week 1 of intervention (only verbal fluency), week 12 of intervention and week 12 of detraining
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Cognition will also be measured verbal fluency (words/min). |
Baseline, week 1 of intervention (only verbal fluency), week 12 of intervention and week 12 of detraining
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Intrinsic capacity - Locomotion
Periodo de tiempo: Baseline, week 12 of intervention and week 12 of detraining
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Locomotion will be assessed using the Short Physical Performance Battery (0-12 points). |
Baseline, week 12 of intervention and week 12 of detraining
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Intrinsic capacity - Locomotion
Periodo de tiempo: Baseline, week 12 of intervention and week 12 of detraining
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Locomotion will be also assessed using the sit-to-stand muscle power (W) measured by PowerFrail app. |
Baseline, week 12 of intervention and week 12 of detraining
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Intrinsic capacity - Vitality
Periodo de tiempo: Baseline, week 12 of intervention and week 12 of detraining
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Vitality will be measured by Mini-Nutritional Assessment (0-30 points). |
Baseline, week 12 of intervention and week 12 of detraining
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Intrinsic capacity - Vitality
Periodo de tiempo: Baseline, week 12 of intervention and week 12 of detraining
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Vitality will also be measured by peak expiratory peak flow (L/min). |
Baseline, week 12 of intervention and week 12 of detraining
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Intrinsic capacity - Vitality
Periodo de tiempo: Baseline, week 12 of intervention and week 12 of detraining
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Vitality will also be measured by handgrip strength (kg). |
Baseline, week 12 of intervention and week 12 of detraining
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Intrinsic capacity - Psychological
Periodo de tiempo: Baseline, week 12 of intervention and week 12 of detraining
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Psychological domain will be assessed using the Cornell Scale for Depression in Dementia (0-38 points). |
Baseline, week 12 of intervention and week 12 of detraining
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Intrinsic capacity - Psychological
Periodo de tiempo: Baseline, week 12 of intervention and week 12 of detraining
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Psychological domain will also be assessed using the Geriatric Depression Scale-10 (0-10 points). |
Baseline, week 12 of intervention and week 12 of detraining
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Intrinsic capacity - Psychological
Periodo de tiempo: Baseline, week 12 of intervention and week 12 of detraining
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Psychological domain will also be assessed using the Neuropsychiatric inventory. |
Baseline, week 12 of intervention and week 12 of detraining
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Intrinsic capacity - Sensory capacity
Periodo de tiempo: Baseline, week 12 of intervention and week 12 of detraining
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Sensory domain will be assessed by self-, clinician- or caregiver-reported vision and hearing problems |
Baseline, week 12 of intervention and week 12 of detraining
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Quadriceps muscle thickness
Periodo de tiempo: Baseline, week 12 of intervention and week 12 of detraining
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Rectus femoris and vastus lateralis thickness (cm) will be measured with a real-time B-mode ultrasound (MyLab Gamma, Esaote, Genoa, Italy) and a linear transducer (SL 1543, 3-13 MHz; Esaote) |
Baseline, week 12 of intervention and week 12 of detraining
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Functional outcomes - Functional capacity
Periodo de tiempo: Baseline, week 12 of intervention and week 12 of detraining
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Functional capacity will be assessed using the 6-Minute walking test (6MWT). Participants will walk along a 30-metre corridor marked every 10 metres to cover the maximum distance possible in six minutes. Total distance will be recorded (in meters). r. |
Baseline, week 12 of intervention and week 12 of detraining
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Functional outcomes - Functional independence in basic activities of daily living
Periodo de tiempo: Baseline, week 12 of intervention and week 12 of detraining
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The Barthel Index assesses ten basic activities of daily living. The score ranges from 0 to 100 points, with higher scores indicating greater independence: total dependence (0-20), severe (21-60), moderate (61-90), mild dependence (91-99) and independence (100). |
Baseline, week 12 of intervention and week 12 of detraining
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Functional outcomes - Heart rate recovery
Periodo de tiempo: Baseline, week 12 of intervention and week 12 of detraining
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Additionally to the distance, heart rate recovery (bpm) will be calculated as the difference between heart rate at the end of the test (6MWT) and one minute after |
Baseline, week 12 of intervention and week 12 of detraining
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Functional outcomes - Functional independence in instrumental activities of daily living
Periodo de tiempo: Baseline, week 12 of intervention and week 12 of detraining
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The Lawton and Brody Scale evaluates eight instrumental activities of daily living. The score ranges from 0 to 8 points, with lower scores indicating greater dependence. |
Baseline, week 12 of intervention and week 12 of detraining
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Clinical outcomes - Bioimpedance
Periodo de tiempo: Baseline, week 12 of intervention and week 12 of detraining
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The NUTRILAB bioimpedance device (AKERN Srl, Florence, Italy) will be used. This non-invasive method measures the body's resistance and reactance of the body to the passage of a low-intensity electric current and enables the determination of various body parameters. Bioimpedance provides accurate data on body fat percentage, muscle mass, total body water and other relevant indicators such as phase angle and Z-score. Users will be instructed to remove all metal-containing objects and remain in a supine position on a couch during the measurements, with the legs in 45° abduction, the shoulders in 30° abduction relative to the center of the body and the hands in pronation. After cleaning the skin with alcohol, two adhesive electrodes (Biatrodes Akern Srl, Florence, Italy) will be placed on the surface of the right hand and two on the right foot. The measurement results will be given in different unit measures depending on the specific variable assessed |
Baseline, week 12 of intervention and week 12 of detraining
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Clinical outcomes - Risk of sarcopenia
Periodo de tiempo: Baseline, week 12 of intervention and week 12 of detraining
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Sarcopenia will be assessed following the European Working Group on Sarcopenia in Older People (EWGSOP2) algorithm. |
Baseline, week 12 of intervention and week 12 of detraining
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Clinical outcomes - Comorbidities
Periodo de tiempo: Baseline, week 12 of intervention and week 12 of detraining
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Comorbidities will be recorded through the Charlson Comorbidity Index. Score is given in points, ith higher scores indicating greater comorbidity burden. |
Baseline, week 12 of intervention and week 12 of detraining
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Pyschosocial outcomes - Caregiver burden
Periodo de tiempo: Baseline, week 12 of intervention and week 12 of detraining
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Caregiver burden will be assessed by the Zarit Burden Interview. It consists of 22 items on the caregiver's psychosocial, economic and emotional well-being. The score ranges from 0 to 88 points, with higher scores indicating greater caregiver burden. |
Baseline, week 12 of intervention and week 12 of detraining
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Pyschosocial outcomes - Socio-familial situation
Periodo de tiempo: Baseline, week 12 of intervention and week 12 of detraining
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The Gijón Socio-Familial Assessment will be used. It evaluates five dimensions: personal situation, economic situation, housing, social relationships and support from the social network. The score ranges from 5 to 25 points, with higher scores indicating greater social risk (15 or more indicates a social problem). |
Baseline, week 12 of intervention and week 12 of detraining
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Términos relacionados con este estudio
Palabras clave
Términos MeSH relevantes adicionales
Otros números de identificación del estudio
- PI-DOC013-ADD-GUT-EXERCISE
Información sobre medicamentos y dispositivos, documentos del estudio
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