Investigating Loss of Neuromuscular Junction Transmission Fidelity in Older Adults

Study Overview
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Brief Summary
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Sarcopenia is a condition characterised by age-related loss of muscle mass and function. Factors affecting the strength of muscle contraction independent of mass, such as neuromuscular junction (NMJ) transmission, are increasingly suspected as important contributors to the development of age-related physical disability. The group of investigators leading the current study, have recently demonstrated NMJ transmission deficits in aged mice, but whether this translates in older human individuals is not known The primary aim is to assess whether clinically meaningfull muscle weakness is associated with NMJ transmission deficits in older human individuals with clinically meaningfull muscle weakness. The secondary aim is to assess whether NMJ transmission deficits correlate with different measures of functional capacity to inform future trials of the most appropriate choice of tests.

Detailed Description
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The study is a cross-sectional pilot study and will be led by investigators: Professor Brian Clark, PhD, Ohio University Professor William David Arnold, MD, Ohio State University Up to 16 older (>70 yrs.) individuals and 8 healthy younger (18-50 yrs.) individuals will be included in this cross-sectional pilot study. To assess whether clinically meaningfull muscle weakness is associated with NMJ transmission failure, results from single fiber EMG analyses and repetitive nerve stimulation in older individuals with clinically meaningfull muscle weakness will be compared to those obtained in older adults without muscle weakness and with healthy young individuals. To assess whether NMJ transmission deficits correlates with different measures of functional capacity, a series of different functional tests will be performed.

Official Title
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Investigating Loss of Neuromuscular Junction Transmission Fidelity in Older Adults

Conditions
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Sarcopenia

Participation Criteria
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Eligibility Criteria
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Inclusion Criteria Men and women 70+ years of age OR men and women 18-50 years old Body mass index between 19 and 40 kg/m2. Willingness to undergo all testing procedures, maintain current diet during the study period, and adhere to the study protocol. Exclusion Criteria: Neuromuscular Disease (ie. movement disorder, or overt neurological disease, such as Sensory Neuropathy with Sensory Ataxia, Apraxia, Post-Polio Syndrome, Mitochondrial Myopathy, Myelopathy, myasthenia gravis) Neurological Disease (ie. Dementia (Alzheimers, multi-infarct, fronto-temporal); multiple sclerosis, amyotrophic lateral sclerosis, Parkinsons Disease, cerebellar ataxia, or significant cognitive impairment (a score of 22 or less on the Montreal Cognitive Assessment (MOCA)) Musculoskeletal disorders (ie. rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, acute gout or osteoarthritis limiting mobility) Terminal illness(i.e., Cancer, myeloma, acute leukaemia) Uncontrolled Psychiatric disorder (ie. bipolar, schizophrenia, major depression) Cardiovascular Diseases (ie. NYHA Class III or IV congestive heart failure, clinically significant aortic stenosis, recent history of cardiac arrest, uncontrolled atrial fibrillation, use of a cardiac defibrillator, or uncontrolled angina or hypertension) Other significant conditions (ie, that would impact safety and/or compliance to the protocol (e.g. chronic renal failure requiring peritoneal or hemodialysis, chronic liver disease, blood dyscrasia, carcinoma within last 3 years, severe inflammatory bowel disease, severe respiratory disease (uncontrolled asthma, COPD), etc) Drug or alcohol abuse Not meeting MRI eligibility (e.g. metal implants, reported pregnancy or positive pregnancy test at the time of imaging for women aged 55 years or younger); Not meeting the DEXA eligibility (e.g. reported pregnancy or positive pregnancy test at the time of imaging for women aged 55 years or younger); Failure to provide informed consent; Subjects who do not answer male or female to the question of biological sex Currently or recently (within the last 1 year) taking gender affirming hormones.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Older Individuals<br> | |
| Healthy young to middle aged Individuals<br> | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Single Fiber Electromyography (sfEMG) | sfEMG of the vastus lateralis will be performed to ascertain NMJ transmission at a minimum of 30 synapses per participant. | Baseline | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Repetitive Nerve Stimulation | As additional measures of NMJ transmission, Repetitive Nerve Stimulation (3Hz) of the spinal accessory nerve (recorded from the trapezius) and fibular nerve (recorded from tibialis anterior) will be performed | Baseline | 
| Magnetic Resonance Imaging | Assessment of thigh muscle cross-sectional area | Baseline | 
| Dual Energy X-ray Absorption (DEXA) Scanning | Assessment of appendicular lean mass | Baseline | 
| Dual Energy X-ray Absorption (DEXA) Scanning | Assessment of total lean mass | Baseline | 
| Dual Energy X-ray Absorption (DEXA) Scanning | Assessment of total mass | Baseline | 
| Dual Energy X-ray Absorption (DEXA) Scanning | ND Upper Thigh Lean Mass | Baseline | 
| Dual Energy X-ray Absorption (DEXA) Scanning | Assessment of bone mineral density | Baseline | 
| Dual Energy X-ray Absorption (DEXA) Scanning | Assessment of percent body fat | Baseline | 
| Short Physical Performance Battery (SPPB) | Total Short Physical Performance Battery test score ranging from 0 (worst performance) to 12 (best performance) | Baseline | 
| Short Physical Performance Battery (SPPB) - Chair Stand Test | Chair Stand Test score ranging from 0 (worst performance) to 4 (best performance) | Baseline | 
| Short Physical Performance Battery (SPPB) - Standing Balance Test | Standing Balance Test score ranging from 0 (worst performance) to 4 (best performance) | Baseline | 
| Short Physical Performance Battery (SPPB) - 4 Meter Walk Test | 4 Meter Walk Test score ranging from 0 (worst performance) to 4 (best performance) | Baseline | 
| Stair Climb Power Test | Assessment of lower leg power | Baseline | 
| Hand Grip Dynamometry | Assessment of Hand Grip Strength | Baseline | 
| Four Square Test | Assessment of coordination | Baseline | 
| Isometric and Isokinetic Leg Extension Strength | Assessment of isometric and isokinetic leg extonsor strength. Isokinetic leg extensor strength is also used for weakness classification in older adults | Baseline | 
| 60-Sec MVC Fatigue Test | Assessment of lower extremity fatigue | Baseline | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Neuromuscular Junction Transmission, Neuromuscular Disease, Repetitive Nerve Stimulation, Single Fiber EMG