Studies Of Hereditary Neurological Disease: Clinical Trials

National Institute Of Neurological Disorders And Stroke

Investigators

Linked publications, trials & patents

Abstract

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) Spinal and bulbar muscular atrophy (SBMA) is caused by polyglutamine expansion in the androgen receptor. As an X-linked disease dependent on androgens, symptoms and findings are only fully manifest in males. We described a 40-year-old male-to-female transgender SBMA patient who developed full disease manifestations despite undetectable levels of androgens. We used cell culture and animal models to show that spironolactone, the anti-androgen she had taken for 15 years, promotes nuclear localization and toxicity of the mutant protein, which may explain the disease manifestations in this patient. (2) We explored the use of IDEAL-CPMG MRI technique to simultaneously measure skeletal muscle apparent fat fraction (AFF) and water (T2,w) in patients with Duchenne muscular dystrophy (DMD). In twenty healthy volunteer (HV) boys and thirteen subjects with DMD, thigh muscle AFF was measured by Dixon and IDEAL-CPMG, with the IDEAL-CPMG also providing T2,w as a measure of muscle inflammatory activity. A subset of subjects with DMD was followed up during a 48-week clinical study. AFF in the thigh muscles of subjects with DMD was significantly increased compared to HV boys (p < 0.001). Dixon and IDEAL-CPMG AFF strongly correlated and were in good agreement. Muscle T2,w measured by IDEAL-CPMG was independent of changes in AFF. Muscle T2,w was higher in the biceps femoris and vastus lateralis muscles of subjects with DMD (p < 0.05). There was a strong correlation (p < 0.004) between AFF in all thigh muscles and six-minute walk distance in subjects with DMD. IDEAL-CPMG allowed independent and simultaneous quantification of skeletal muscle fatty degeneration and disease activity in DMD. IDEAL-CPMG AFF and T2,w may be useful as biomarkers in clinical trials of DMD as the technique disentangles two competing biological processes.