Prospective Neuroimaging in Huntington's Disease

描述(申请人提供)：亨廷顿病(HD)是一种破坏性的常染色体显性遗传性进行性神经退行性疾病。正在开发新的治疗方法来减缓疾病的进展或推迟其发病。在临床上测试这些化合物是一项重大挑战，因为潜在的受试者数量有限，要么是遗传上有患HD的风险，要么是已经有症状。目前，HD的治疗试验依赖于诊断和进展的临床措施，这些措施变化很大，变化也相对较慢，因此需要大量受试者和长时间的随访。迫切需要开发替代标记物，例如神经解剖学测量，它比可变的临床测量更准确地与进展相关，或者可能预测发病。神经成像技术提供了一种在活体内前瞻性检查HD大脑的方法。 我们开发了新的神经成像技术，使我们能够对发生在整个大脑中的进行性区域萎缩进行高精度、可靠和快速的形态测量。我们有初步证据表明，在基因阳性的症状前个体中会发生区域性脑萎缩，这使得在临床诊断HD之前就可以检测到它并进行纵向评估。确诊时，萎缩在许多皮质和皮质下区域明显，并以特定的模式发生，这可能与疾病的特定临床特征相对应。我们的数据挑战了HD患者对基底节变性的传统关注，为更早和更广泛地参与许多额外的脑区提供了证据，并极大地丰富了脑成像的潜力，以帮助阐明症状的结构基础，同时为神经保护治疗的反应提供相关的生物标记物，可以在有症状和症状前的患者中进行测试。 我们建议对有症状前和有症状的HD患者进行前瞻性的纵向神经影像研究，以充分描述整个疾病中发生的区域性和渐进性变化。我们将与标准临床测量方法相比，确定我们的形态测量方法作为疾病开始和疾病进展的替代标志的敏感性和可靠性，以确定它们作为替代标志的潜力。

DESCRIPTION (provided by applicant): Huntington's disease (HD) is a devastating autosomal dominant progressive neurodegenerative disorder. New therapies are being developed to slow disease progression or to delay its onset. Testing these compounds clinically is a major challenge because there are limited numbers of potential subjects either genetically at-risk for HD or already symptomatic. Currently, therapeutic trials in HD rely on clinical measures of diagnosis and progression, which are quite variable and also change relatively slowly and thus require large numbers of subjects and long periods of follow-up. There is a critical need to develop surrogate markers, such as neuroanatomic measures, which more precisely correlate with progression than variable clinical measures or which may be predictive of onset. Neuroimaging technology provides a way to prospectively examine the HD brain in vivo. We have developed novel neuro-imaging technologies that enable us to obtain highly accurate, reliable, and rapid morphometric measurements of progressive regional atrophy occurring in the entire brain. We have preliminary evidence that regional brain atrophy occurs in gene-positive presymptomatic individuals, permitting its detection and longitudinal assessment even before HD can be diagnosed clinically. By the time of diagnosis, atrophy is apparent in many cortical and subcortical regions and appears to occur in particular patterns, which likely correspond to the appearance of specific clinical features of the disease. Our data challenges the traditional focus on basal ganglia degeneration in HD, provides evidence for earlier and more extensive involvement of many additional brain regions, and greatly enriches the potential for brain imaging to help elucidate the structural basis of symptoms while providing relevant biological markers for response to neuroprotective therapies that can be tested in both symptomatic and presymptomatic patients. We propose to perform a prospective, longitudinal neuro-imaging study of presymptomatic and symptomatic individuals with HD to fully characterize the regional and progressive changes that occur throughout the disease. We will determine the sensitivity and reliability of our morphometric measures as surrogate markers of disease onset and disease progression in comparison to standard clinical measures to determine their potential as surrogate markers.