Studies Of Hereditary Neurological Disease: Clinical Trials

该研究项目的目的是为遗传性神经系统疾病开发安全有效的治疗方法。过去一年的具体研究成果包括： (1)我们分析了T1和T2弛豫时间和肌肉脂肪分数测量的上臂骨骼肌和心脏的磁共振成像的定量地图与杜氏肌营养不良症（DMD）和年龄范围匹配的健康志愿者男孩。心脏优化序列检测到上臂骨骼肌的脂肪浸润和水肿，但在这些射血分数正常的杜氏肌营养不良症男孩中没有检测到心肌。在单次扫描期间使用相同的磁共振成像方法对心脏和骨骼肌进行成像可能有助于评估Duchenne肌营养不良症临床试验中的相对疾病状态和治疗反应。 (2)我们还研究了运动对DMD患者肌肉水T2的影响。在12例DMD患者和19例对照者中，用狄克逊法测量小腿肌肉脂肪（%），用三指数模型测量肌水T2和R2（1/T2）。在踝关节背屈运动后3小时再次测量肌肉水R2。除了胫骨后肌外，DMD患者的肌肉脂肪分数高于对照组（p<0.001）。肌水T2的测量不依赖于DMD肌肉中脂肪变性的程度。在基线时，DMD参与者除趾长伸肌外的所有肌水T2均高于对照组（p<0.001）。DMD参与者的肌肉扭矩较低（p<0.001），运动时的力量也比对照组小（p<0.01）。然而，DMD受试者和对照组运动后肌肉水R2从基线下降（T2增加），运动目标肌肉的变化大于踝跖屈肌。骨骼肌水T2是DMD疾病状态以及DMD患者和对照组运动反应的敏感生物标志物。 (3)脊髓性延髓肌萎缩症（SBMA）对生活质量（QoL）的影响还不清楚。我们从患者的角度研究了症状，以及这些症状对生活质量的影响。我们进行了开放式采访与21名成年男性基因证实SBMA。使用定性框架技术，访谈编码和分析，以确定症状和由此产生的主题。从这些访谈中，提取了729条引文。我们确定了200个SBMA特异性症状和20个症状主题。所有受访者都提到了弱点。心理健康领域内的症状以及情感问题和心理影响的具体主题也经常被提及。许多症状影响SBMA受试者的生活质量。我们确定了以前未被认识到的症状，这些症状在加强SBMA患者的临床护理和开发工具以评估未来临床试验的疗效方面非常重要。

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.