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Spasticity and Upper Motor Neuron Disorders

痉挛和上运动神经元疾病

基本信息

批准号：
10001304
负责人：
Mary Kay Floeter
金额：
$ 16.12万
依托单位：
NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

项目摘要

Primary lateral sclerosis (PLS) is a rare, sporadic upper motor neuron disorder thought to be a variant of the amyotrophic lateral sclerosis (ALS) family of motor neuron disorders. In PLS, motor neurons of the spinal cord and brainstem are clinically spared, in contrast to ALS patients. PLS patients typically have a normal lifespan, surviving more than a decade after symptoms begin. In this natural history study that began in FY2000, we previously showed that the rate of progression was most rapid in the first years after symptoms begin, often reaching a plateau after seven to eight years. This clinical course suggests that there may be a limited time window during which corticospinal neurons degenerate, and when potential interventions should be targeted. Unfortunately, making the diagnosis of PLS relies on clinical criteria that require symptoms to be present for 3-5 years without development of lower motor neuron signs. In the first several years of symptoms, clinical signs alone do not allow distinction between PLS and amyotrophic lateral sclerosis (ALS). A biomarker to help identify patients with PLS in the first years of symptoms is needed. The clinic was closed to new patients in 2016 with follow-up visits on enrolled patients held through spring 2019. In FY 19 we reported the results of a neuroimaging study to look for findings that emerge early, within the first years after the onset of symptoms. We collected clinical data and MRI scans on a cohort of patients with pre-PLS symptoms for 5 years or less, who were subsequently followed beyond 5 years of symptoms and met clinical criteria for the diagnosis PLS. We found reduced functional connectivity between the motor cortex and other regions of the brain in pre-PLS patients. This contrasts with reported findings in ALS patients. White matter changes also occurred in pre-PLS patients, but atrophy of the motor cortex was not seen. A larger prospective study comparing ALS and pre-PLS patients is needed to establish whether functional connectivity can be used to distinguish PLS from ALS in the first years of symptoms. In the second study in this project, whole genome sequencing in PLS and family members, analysis by collaborators continues with no clear associations to date.

原发性侧索硬化症 (PLS) 是一种罕见的散发性上运动神经元疾病，被认为是肌萎缩性侧索硬化症 (ALS) 运动神经元疾病家族的变体。与 ALS 患者相比，PLS 患者的脊髓和脑干运动神经元在临床上并未受到影响。 PLS 患者通常有正常的寿命，在症状出现后可以存活十多年。在这项于 2000 财年开始的自然历史研究中，我们之前表明，症状出现后的头几年进展速度最快，通常在七到八年后达到稳定水平。这一临床过程表明，皮质脊髓神经元退化可能存在一个有限的时间窗口，此时应针对潜在的干预措施。不幸的是，PLS 的诊断依赖于临床标准，即症状持续 3-5 年且未出现下运动神经元体征。在症状出现的最初几年，仅凭临床体征无法区分 PLS 和肌萎缩侧索硬化症 (ALS)。需要一种生物标志物来帮助识别 PLS 患者在出现症状的最初几年。该诊所于 2016 年对新患者关闭，并对入组患者进行随访直至 2019 年春季。2019 财年，我们报告了一项神经影像学研究的结果，以寻找症状出现后最初几年内早期出现的发现。我们收集了一组 PLS 前症状持续 5 年或更短时间的患者的临床数据和 MRI 扫描，随后对这些患者进行了超过 5 年症状的随访，并符合诊断 PLS 的临床标准。我们发现 PLS 前患者的运动皮层和大脑其他区域之间的功能连接减少。这与 ALS 患者的报告结果形成鲜明对比。 PLS前患者的白质也发生变化，但没有看到运动皮层萎缩。需要进行一项更大规模的前瞻性研究来比较 ALS 和 PLS 前患者，以确定功能连接是否可用于在症状最初几年区分 PLS 和 ALS。在该项目的第二项研究中，对 PLS 和家庭成员进行全基因组测序，合作者继续进行分析，迄今为止尚未发现明确的关联。