Studies Of Hereditary Neurological Disease: Clinical Trials

这项研究计划的目的是开发安全有效的遗传性神经疾病治疗方法。过去一年的具体研究成果包括： (1)我们分析了Duchenne肌营养不良症(DMD)和年龄匹配的健康志愿者男孩的T1和T2弛豫时间定量图和磁共振成像上臂骨骼肌和心脏的肌肉脂肪分数测量结果。心脏优化序列在这些射血分数正常的Duchenne肌营养不良症男孩中检测到上臂骨骼肌中的脂肪渗透和水肿，但没有检测到心肌。在一次扫描中使用相同的磁共振成像方法对心脏和骨骼肌进行成像，可能有助于在Duchenne肌营养不良症的临床试验中评估相对疾病状态和治疗反应。 (2)观察运动对DMD患者肌肉水分T2的影响。对12例DMD患者和19例对照组，用Dixon法测量小腿肌脂(%)，用三指数模型测量肌水T2和R2(1/T2)。在踝关节背屈运动后3h再次测量肌肉水分R2。除胫骨后肌外，DMD参与者的肌肉脂肪分数高于对照组(p&lt；.001)。肌肉水分T2的测量与DMD肌肉的脂肪变性程度无关。在基线时，DMD参与者除指长伸肌外的所有肌肉水分T2均高于对照组(P&lt；.001)。与对照组相比，DMD参与者的肌肉扭矩更小(P&lt；.001)，运动时力量也更小(P&lt；.01)。然而，在运动后，DMD受试者和对照组的肌肉水分R2减少(T2增加)，运动的目标肌肉的变化比脚踝足底屈肌的变化更大。骨骼肌水T2是反映DMD疾病状态和DMD患者和对照组运动反应的敏感生物标志物。 (3)脊髓延髓性肌萎缩症(SBMA)对生活质量(QOL)的影响尚不清楚。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。我们对21名成年男性进行了开放式访谈，这些患者都患有基因确诊的SBMA。使用定性框架技术，对访谈进行编码和分析，以确定症状和结果主题。从这些采访中，我们提取了729条语录。我们确定了200个SBMA特定症状和20个症状主题。所有受访者都提到了弱点。精神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，这些症状对于加强对SBMA患者的临床护理以及在未来的临床试验中开发评估疗效的工具都是重要的。

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.