Parkinson's Disease, Cortical Dysfunction, and Alpha-Synuclein

The ability to understand how Parkinson's disease neurodegeneration leads to cortical dysfunction will be critical for developing therapeutic advances in Parkinson's disease dementia. The overall purpose of this project was to study the small-amplitude cortical myoclonus in Parkinson's disease as an in vivo model of focal cortical dysfunction secondary to Parkinson's disease neurodegeneration. The objectives were to test the hypothesis that cortical myoclonus in Parkinson's disease is linked to abnormal levels of alpha-synuclein in the primary motor cortex and to define its relationship to various biochemical, clinical, and pathological measures. The primary motor cortex was evaluated for 11 Parkinson's disease subjects with and 8 without electrophysiologically confirmed cortical myoclonus (the Parkinson's disease + myoclonus group and the Parkinson's disease group, respectively) who had premortem movement and cognitive testing. Similarly assessed 9 controls were used for comparison. Measurements for alpha-synuclein, A beta-42 peptide, and other biochemical measures were made in the primary motor cortex. A 36% increase in alpha-synuclein was found in the motor cortex of Parkinson's disease + myoclonus cases when compared with Parkinson's disease without myoclonus. This occurred without significant differences in insoluble alpha-synuclein, phosphorylated to total alpha-synuclein ratio, or A beta-42 peptide levels. Higher total motor cortex alpha-synuclein levels significantly correlated with the presence of cortical myoclonus but did not correlate with multiple clinical or pathological findings. These results suggest an association between elevated alpha-synuclein and the dysfunctional physiology arising from the motor cortex in Parkinson's disease + myoclonus cases. Alzheimer's disease pathology was not associated with cortical myoclonus in Parkinson's disease. Cortical myoclonus arising from the motor cortex is a model to study cortical dysfunction in Parkinson's disease. (C) 2011 Movement Disorder Society