Primary lateral sclerosis (PLS) is a rare, sporadic upper motor neuron disorder thought to be related to amyotrophic lateral sclerosis (ALS). PLS patients have a long survival, and motor neurons of the spinal cord and brainstem are clinically spared, in contrast to ALS. The etiology of PLS is unknown. PLS patients have a mean survival of more than a decade after symptom onset, but previous work from our group showed that the rate of progression is 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, the diagnosis of PLS is based 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 marker to help identify patients with PLS in the first years of symptoms is needed. Previous work from our group found particular neuroimaging changes in patients with long-standing, established PLS. Using diffusion tensor imaging (DTI), we showed loss of the integrity of the corticospinal tract and mid-portion of the corpus callosum that was relatively stable over two years of follow-up. Focal atrophy and thinning of the motor cortex continued at a slow rate, even in patients with symptoms for more than a decade. Changes in cerebrocerebellar connectivity also occurred. The timing of when such imaging findings emerge in the course of PLS is unknown. To elucidate early neuroimaging findings in PLS, as of FY17, we completed a 4-year project to collect clinical and imaging data on a cohort of patients with pre-PLS patients symptoms for 5 years or less who were followed longitudinally until meeting clinical criteria for a diagnosis of clinical PLS. We are in the process of analyzing the imaging battery, which consists of structural and functional data. The same imaging battery was acquired over the same time frame on patients with longstanding, established PLS and a cohort of healthy controls. A second study in this project is exploring genetic causes or contributions to PLS. In FY17, whole genome sequencing was completed for 50 genomes: seven trios (PLS patients and both parents) and twenty-nine individuals). A collaborator, Dr. Bryan Traynor, is overseeing the bioinformatics in his laboratory in the National Institute of Aging.
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