The Impact of 6-months of Resistance Training on Brain and Muscle Health in Older Adults With MCI

The goal of this clinical trial is to learn about the effect of long resistance training intervention on brain and muscle health in older adults with mild cognitive impairment (MCI). The main question it aims to answer is whether progressive resistance training can prevent/delay neurodegenerative/pro-inflammatory processes that are detrimental to cognition, mobility, vitality, and mental health of older adults with MCI. Participants will undergo 6 months of supervise resistance training. Subjects in the intervention group will undergo sessions of structural and functional magnetic resonance imaging, proton magnetic resonance spectroscopy at baseline and end of intervention. Blood analyses and functional and cognitive tests will be performed at baseline after 3 months from the start of intervention and at the end of the intervention. Observations obtained from the intervention group will compare to data collected from age-matched active control group who will undergo flexibility training of lower limb muscles.

Physical exercise appears to be effective in preventing transitions from normal cognitive aging to mild cognitive impairments (MCI) and from MCI to dementia-related disorders such as Alzheimer's disease (AD). The investigators will examine the longitudinal effects of progressive resistance training on biomarkers of (neuro)inflammation and neuroplasticity in a cohort of community-dwelling older individuals at high risk of developing MCI. The investigators will focus specifically on the effects of 24 weeks of resistance training on structural and neurochemical properties of the hippocampus and associations between exercise-induced changes in those properties and improvement in functional ability as quantified by pre-to-post changes in the mobility, cognition, psychological and vitality composites of intrinsic capacity (IC). Similarly, the investigators will examine the association between exercise-induced changes in global internal capacity index and exercise-induced changes in the expressions of inflammatory biomarkers (specifically, IL-1β, IL-6, IL-10, IL-18, kynurenine, and TNFa), myokines (specifically, BDNF, IGF-1, irisin), and circulating biomarkers of neurodegeneration (specifically, neurofilament light chain - NfL), tauopathy (specifically, total and phosphorylated tau181) and amyloid pathology (specifically, Aβ42/Aβ40 ratio). Blood samples will be collected between 8 a.m. and 11 a.m. after fasting. Behavioral outcome measures from gait/balance tests, handgrip strength test, cognitive tests, psychological tests, etc. and serum/plasma levels of the circulating biomarkers will be assessed at baseline, mid-intervention time (12 weeks), immediately post-intervention time (24 weeks), and at six-month follow-up (48 weeks). Structural MRI (sMRI) images, diffusion MRI (dMRI) images, resting state functional MRI (rs-fMRI) data and proton magnetic resonance spectroscopy (1H-MRS) data from the brain and T1-wighted images and 1H-MRS spectra from the lower-limb musculature will be collected at baseline and immediately post-treatment time (24 weeks) using a Siemens 3T Skyra scanner. Findings from this study will be used to provide evidence-based frameworks for implementation of longitudinal exercise interventions in prevention of dementia-related neurodegenerative disease among older with MCI. Further, the investigators will assess the effects of exercise on longitudinal changes in muscle mass, muscle strength, and neuromuscular functioning and examine the associations between these changes and exercise induced changes in locomotion capacity and postural stability as well as the prevention of sarcopenia and frailty. Secondary (exploratory) outcome measures will be (1) effects of the longitudinal strength training program on brain structural and neurochemical properties and (2) demographic factors, physiological properties and/or biomarkers that predict response to the intervention.

Eligibility Criteria:
Inclusion Criteria:

* Male and female 65+ years old,
* Community-dwelling,
* Sedentary (not engaged in any structured activity for exercise) or non-sedentary individuals who engaged in mild recreational activities for less than 150 min/week.
* A score of 18 to 25 on the Montreal Cognitive Assessment (MoCA) with or without a diagnosis of MCI. The diagnosis of MCI will be confirmed by a qualified mental health care specialist at the screening evaluation according to the International Classification of Diseases (ICD-10) and the Petersen criteria (Petersen et al, 2014).
* Fluent in Lithuanian.

Exclusion Criteria:

* Age \< 65 years.
* MoCA ≥ 26 or MoCA \< 18,
* Symptomatic heart or cardiopulmonary disorders, diabetes, diagnosis of renal/hepatic disease, oncology, brain injury, diagnosis of neurologic, psychiatric, or musculoskeletal diseases.
* Physical or orthopedic conditions (rheumatic symptoms, chronic pain, fractures, acute muscle injuries) that limit the subject's ability to participate in the training program.
* Moderate to severe intake of alcohol (intake of 3 drinks or more/day for men and 2 drink or more/day for women).
* Current smoker
* Intake of drugs or psychiatric medications.
* Contraindications to perform MRI (e.g., claustrophobia, cardiac pacemaker, internal pacing wires, metal implants, etc.).
* Body mass index (BMI) \> 35 kg/m2 or body weight \> 130 kg.
* Participation in routine exercise or physical activities (IPAQ).