Diffusion MRI Biomarkers of Peripheral Nerve Trauma

周围神经创伤的弥散 MRI 生物标志物

• 批准号: 10588922
• 负责人: Richard Dortch
• 金额: $ 82.47万
• 依托单位: ST. JOSEPH'S HOSPITAL AND MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-05-01 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10588922
• 关键词: Acute; Address; Age; Anisotropy; Axon; Biological Assay; Biological Markers; Brain; Characteristics; Clinical; Collaborations; Data; Development; Diffusion; Diffusion Magnetic Resonance Imaging; Early identification; Edema; Evaluation; Failure; Forearm; Goals; Histology; Human; Inflammation; Injury; Magnetic Resonance Imaging; Methods; Modeling; Monitor; Motor; Muscle denervation procedure; Muscular Atrophy; Natural regeneration; Nature; Nerve; Nerve Regeneration; Neuroma; Noise; Operative Surgical Procedures; Outcome; Pain; Pathologic; Pathology; Patient-Focused Outcomes; Patients; Performance; Peripheral Nerves; Peripheral nerve injury; Phase II/III Trial; Physicians; Pre-Clinical Model; Process; Prognosis; Quality Control; Rattus; Readiness; Recommendation; Recording of previous events; Recovery; Repeat Surgery; Reporting; Resolution; Scanning; Scientist; Sensitivity and Specificity; Sensorimotor functions; Sensory; Severities; Signal Transduction; Site; Specificity; Surgeon; Techniques; Testing; Time; Translating; Trauma; Traumatic Nerve Injury; Validation; Vendor; axonal sprouting; behavioral outcome; biomarker development; biomarker discovery; clinical application; clinical care; clinical decision-making; clinical trial readiness; cohort; computer framework; density; imaging biomarker; improved; improved outcome; indexing; innovation; magnetic resonance imaging biomarker; nerve injury; nerve repair; nerve transection; novel; peripheral nerve damage; predict clinical outcome; programs; regenerative therapy; reinnervation; repaired; research clinical testing; response biomarker; sex; surgery outcome

PROJECT SUMMARY Peripheral nerve damage following trauma results in catastrophic loss of sensorimotor function if not treated in a timely manner. In severe cases, surgical repair is required to regain function, but outcomes remain subopti- mal (with a failure rate reaching 40%). While electrodiagnostics are valuable indicators of nerve function and muscle denervation, they are often challenging to interpret early post-injury, limiting our ability to determine if surgical intervention is warranted. After surgery, it can also take many months for electrodiagnostics to indicate whether axons are sprouting across the repair site and regenerating toward their motor or sensory target. In both cases, this often results in a “wait and watch” approach that relies on the clinical manifestations of rein- nervation (e.g., the return of sensorimotor function), which ultimately delays clinical decision-making and in- creases the likelihood of permanent muscle atrophy, sensory loss, and the formation of painful neuromas. Giv- en these limitations, a biomarker that monitors nerve regeneration throughout the recovery process would im- prove sensorimotor outcomes by allowing for the earlier identification of i) nerves that require surgery and ii) failed repairs after surgery, even guiding re-operation (when necessary) in the latter case. Diffusion tensor im- aging (DTI) is an MRI method that yields indices (e.g., fractional anisotropy, FA) sensitive to nerve pathologies. We previously demonstrated that i) FA values from ex vivo rat nerves relate to axon density and behavioral outcomes following trauma and surgical repair and ii) FA values from human nerves report on failed surgeries, successful reoperations, and injury severity. While promising, larger-scale studies are required for clinical vali- dation given the heterogeneous nature of traumatic nerve injuries. Furthermore, we know that DTI lacks speci- ficity in the presence of concurrent edema and de/regeneration early after trauma. In line with these challeng- es, our overarching goal is to move nerve diffusion biomarkers toward clinical trial readiness by i) developing advanced diffusion methods with increased pathological specificity to regeneration; ii) demonstrating con- sistency across MRI vendors/sites; iii) and providing clinical validation by expanding to a larger-scale, multi-site study to evaluate whether pre- and post-surgical diffusion MRI predicts clinical outcomes. This multi-PI project represents a unique collaboration between scientists with expertise in advanced peripheral nerve MRI and world-class peripheral nerve surgeons. We will use the complementary technical and clinical expertise of the team to identify novel diffusion-based biomarkers based on the spherical mean technique (SMT) and opti- mize/evaluate performance. We hypothesize that SMT parameters predict surgical outcomes with higher levels of sensitivity and specificity than both DTI and standard clinical methods. If successful, these SMT-based bi- omarkers will allow physicians to recommend surgical interventions and detect failed repairs earlier than is cur- rently possible. Once established, these methods will also likely be of clinical utility in proximal injuries, where the prognosis for recovery is currently poor due to the prolonged time required to detect failed regeneration.

项目摘要 创伤后的周围神经损伤会导致感觉运动功能的灾难性丧失 及时的方式。在严重的情况下，需要手术维修才能保持功能，但结果仍然是次序 MAL（失败率达到40％）。虽然电诊断是神经功能和 肌肉的神经保护，他们经常受到挑战，要解释早期伤害后，限制了我们确定是否的能力 有必要进行手术干预。手术后，电诊断者也可能需要数月的时间才能表明 轴突是否在维修部位发芽并朝向其电动机或感觉目标。在 两种情况下，这通常都会导致一种“等待和观察”方法，依赖于重新的临床表现 神经（例如，感觉运动函数的返回），最终延迟了临床决策和内在 给予 在这些局限 通过允许对需要手术和II的神经的较早鉴定来证明感觉运动结果 手术后的维修失败，甚至在后一种情况下引导重新操作（必要时）。扩散张量 衰老（DTI）是一种MRI方法，它产生对神经病理敏感的指标（例如，分数各向异性，FA）。 我们先前证明了i）与轴突密度和行为相关的离体大鼠神经的FA值 创伤和手术修复后的结果以及II）人类神经的FA值报告了手术失败， 成功的重新手术和伤害严重程度。虽然有希望的临床瓣膜需要进行大规模研究 鉴于创伤性神经损伤的异质性质。此外，我们知道DTI缺乏指定 根据这些挑战 - es，我们的总体目标是将神经扩散生物标志物转移到临床试验中，i）开发 高级扩散方法具有增加对再生的病理特异性； ii）证明 MRI供应商/站点的统一性； iii）并通过扩展到大型多站点来提供临床验证 研究术前和手术后扩散MRI是否预测临床结果。这个多PI项目 代表具有高级外周神经MRI和 世界一流的外周神经外科医生。我们将使用完整的技术和临床专业知识 团队基于球形平均技术（SMT）和光学识别基于扩散的生物标志物 小型/评估性能。我们假设SMT参数可以预测具有较高水平的手术结果 比DTI和标准临床方法的灵敏度和特异性。如果成功，这些基于SMT的双 Omarkers将允许医生推荐手术干预措施并检测到的维修失败，而不是cur- 在出租上可能。一旦建立，这些方法也可能是近端损伤中的临床实用性 由于检测到再生所需的时间延长，恢复的预后目前很差。