Primary lateral sclerosis (PLS) is a rare, sporadic upper motor neuron disorder thought to be related to amyotrophic lateral sclerosis (ALS). PLS differs from ALS in that neurodegeneration fails to spread to any significant extent beyond the motor cortex. Unlike ALS, PLS patients have a long survival, and motor neurons of the spinal cord and brainstem are clinically spared. There is considerable interest in the causes of PLS and whether PLS patients may provide clues to potential mechanisms that limit progression of neurodegeneration. Previous work from our group showed different alterations of white matter tracts in patients with ALS and patients with long-standing, established PLS using diffusion tensor imaging. During FY16, we continued longitudinal clinical assessments and imaging of a cohort of patients with clinically definite PLS and new PLS patients enrolled within 5 years of symptom onset to look for early neuroimaging changes. The imaging battery included diffusion tensor imaging, high resolution T1 images, and resting state fMRI. The acquisition of neuroimaging data was completed, and analysis will begin in FY17. The cohort of PLS patients will continue to be followed clinically, although enrollment of additional patients has ended. Two projects are underway to explore potential causes of PLS. In collaboration with Dr. David Wang, iPS neurons have been generated from PLS patient lymphocytes to study candidate disease mechanisms. Additionally, we have collected blood for whole genome sequencing of PLS patients with living parents (trios), and from individual PLS patients (singletons). In collaboration with the laboratory of Dr. Bryan Traynor, National Institute of Aging, fifty genomes have been collected and the DNA is ready for sequencing as a batch, beginning at end FY16. Analysis of genomic data is planned for FY17.
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