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. PLS differs from ALS in its duration, with a median survival of more than a decade, in contrast to the median survival of 3-5 years in ALS. The long survival is closely linked to the restriction of disease to the corticospinal, or upper motor neurons, of the brain. Understanding progression in motor neuron diseases is important because most patients will only be identified after disease begins, and treatments will likely focus on arresting disease progression. It is not really known whether clinical symptoms continue to progress throughout the lifetime of a patient with PLS and whether progression occurs at a steady pace. In FY09, we compiled and analyzed prospectively obtained clinical measures of motor speed and function in 50 patients with PLS who were enrolled in a longitudinal natural history protocol between 2000 and 2008. This study found steady spread of symptoms from one limb to another primarily in one subtype of patients, whose symptoms began in their legs and ascended. However, within newly affected limbs of all subtypes of PLS patients, clinical measures of movement worsened at a more rapid pace in the first years, and subsequently stabilized without continued progression. This finding has implications for using clinical measures of motor speed as an outcome measure in future clinical trials. One hypothesis is that the different motor neuron disorder phenotypes progressive muscular atrophy, ALS, frontotemporal dementia (FTD) and PLS are variants of the same neurodegenerative process with regional differences in the distribution of pathology. To test this hypothesis we have been carrying out a 3-year protocol that includes neuropsychological tests, psychiatric assessment, and quantitative MRI imaging. The goals of this study is determine the extent of non-motor, frontal cortical dysfunction in PLS patients, and to compare these to patients with ALS and age-matched healthy control subjects. The imaging studies will elucidate regional differences in anatomical involvement of cortical grey and white matter. The enrollment and baseline testing for this protocol was completed in FY09, and data analysis is underway. In preparation for analyzing patient images, a methodological study to examine the intra- and inter-rater reliability and test-retest reliability of the quantitative imaging methods was carried out in FY09.
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