Although primary lateral sclerosis (PLS) is generally considered to be a motor neuron disorder, its relationship to amyotrophic lateral sclerosis (ALS) and other motor neuron disorders is uncertain. Patients with PLS have a median survival of more than a decade, in contrast to the 3-5 year median survival of patients after diagnosis of ALS. In PLS, degeneration is restricted to the corticospinal, or upper motor neurons, in the brain, without significant degeneration of motor neurons in the spinal cord and brainstem. There is considerable interest in whether PLS and ALS are the same disorder and, if so, factors that limit disease progression in PLS. We have been studying imaging biomarkers that may distinguish PLS and ALS or correspond to clinical measures of progression. In FY12 we completed analysis of the longitudinal arm of a study of structural MRI changes in brains of PLS and ALS patients with quantitative imaging techniques. In the cross-sectional arm of this study, we found that the pattern of white matter disruption in the corticospinal tract differed between ALS and PLS patients and from healthy age-matched controls. A consistent finding was that fractional anisotropy in the motor fibers of the corpus callosum was reduced in both PLS and ALS patients. Approximately half of the patients were able to complete follow-up testing a mean of 1 year (ALS) or 2 years (PLS) later. Based on the longitudinal data, we hypothesize that there is an evolution of imaging changes as upper motor neurons degenerate, with early disruption of affected white matter tracts. Postmortem study of two ALS patients showed accumulation of iron within microglia in the motor cortex, corresponding to a particular signal seen on MRI studies, most evident with 7Tesla imaging. The next step in this project is to identify imaging markers that change earlier in the course of the disease. Toward that end, in FY12 we began a new study in healthy volunteers to assess the reproducibility of imaging markers and physiological measures that are candidates for earlier detection of upper motor neuron dysfunction. In FY12, we completed our sites accrual target for the multicenter collaborative study with investigators at Columbia University to examine the role of oxidative stress in progression of motor neuron diseases. We completed the annual visits on previously enrolled patients, and are on target for completing the last visit in this study in 3 years.
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