Studies Of Hereditary Neurological Disease: Clinical Trials

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The purpose of this research program is to develop safe and effective treatments for hereditary neurological disorders. Specific research accomplishments in the past year include the following: : (1) We analyzed quantitative maps of T1 and T2 relaxation times and muscle fat fraction measurements in magnetic resonance imaging of the upper arm skeletal muscles and heart in ambulatory boys with Duchenne muscular dystrophy (DMD) and age-range-matched healthy volunteer boys. The cardiac-optimized sequences detected fatty infiltration and edema in the upper arm skeletal muscles but not the myocardium in these Duchenne muscular dystrophy boys who had normal ejection fraction. Imaging the heart and skeletal muscle using the same magnetic resonance imaging methods during a single scan may be useful in assessing relative disease status and therapeutic response in clinical trials of Duchenne muscular dystrophy. (2) We also examined exercise effects on muscle water T2 in patients with DMD. In 12 DMD subjects and 19 controls, lower leg muscle fat (%) was measured by Dixon and muscle water T2 and R2 (1/T2) by the tri-exponential model. Muscle water R2 was measured again at 3 hours after an ankle dorsiflexion exercise. The muscle fat fraction was higher in DMD participants than in controls (p<.001) except in the tibialis posterior muscle. Muscle water T2 was measured independent of the degree of fatty degeneration in DMD muscle. At baseline, muscle water T2 was higher in all but the extensor digitorum longus muscles of DMD participants than controls (p<.001). DMD participants had a lower muscle torque (p<.001) and exerted less power (p<.01) during exercise than controls. Nevertheless, muscle water R2 decreased (T2 increased) after exercise from baseline in DMD subjects and controls with greater changes in the target muscles of the exercise than in ankle plantar-flexor muscles. Skeletal muscle water T2 is a sensitive biomarker of the disease status in DMD and of the exercise response in DMD patients and controls. (3) The effects of spinal bulbar muscular atrophy (SBMA) on quality of life (QoL) are not well understood. We studied symptoms from the patient's perspective, and the impact these symptoms have on QoL. We conducted open-ended interviews with 21 adult males with genetically confirmed SBMA. Using a qualitative framework technique, interviews were coded and analyzed to identify symptoms and resulting themes. From these interviews, 729 quotations were extracted. We identified 200 SBMA-specific symptoms and 20 symptomatic themes. Weakness was mentioned by all interviewees. Symptoms within the domain of mental health and the specific themes of emotional issues and psychological impact were also frequently mentioned. Numerous symptoms affect QoL for SBMA subjects. We identified previously unrecognized symptoms that are important to address in enhancing clinical care for patients with SBMA, and in developing tools to evaluate efficacy in future clinical trials.