Spasticity and Upper Motor Neuron Disorders

原发性侧索硬化（PLS）是一种罕见的散发性上运动神经元疾病，被认为是肌萎缩侧索硬化（ALS）家族运动神经元疾病的一种变体。在PLS中，脊髓和脑干的运动神经元在临床上被保留，与ALS患者相反。PLS患者通常有正常的寿命，在症状开始后存活超过十年。在这项始于2000财年的自然史研究中，我们先前表明，在症状开始后的头几年，进展速度最快，通常在7至8年后达到平稳期。这一临床过程表明，皮质脊髓神经元退行性变可能有一个有限的时间窗口，在此期间应该针对潜在的干预措施。不幸的是，对PLS的诊断依赖于临床标准，要求症状存在3-5年而未出现下运动神经元体征。在最初几年的症状，临床体征单独不允许区分PLS和肌萎缩侧索硬化症（ALS）。需要一种生物标志物来帮助在症状出现的头几年识别PLS患者。

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.