Pathogenesis Of Essential Tremor: Cerebellar Metabolism

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DESCRIPTION (provided by applicant): Essential tremor (ET) is the most common tremor disorder, twenty times more prevalent than Parkinson's disease. Up to 6% of the general population has ET. Uncontrollable trembling eventually forces 10 - 25% of patients to retire prematurely. There is no cure, and few medications lessen the tremor, although deep brain stimulation has provided promising results. Clinical evidence and neuro-imaging studies suggest that the cerebellum is centrally involved in ET, and evidence from clinical and animal studies suggests that there may be a disturbance in the gamma amino butyric acid (GABA) neurotransmitter system. While ET is clinically progressive, little is known about its underlying pathology. There have been few published postmortem examinations. The fundamental question in ET research is whether an underlying pathology can be identified in terms of morphological or morphometric changes of specific cell types in specific brain regions? Second, is there a neurotransmitter abnormality in ET, either resulting as a consequence of cell loss or in the absence of cell loss? The proposed study will be a collaborative effort involving four centers in the United States and Canada where archival postmortem tissue on 24 ET patients is available. In addition, with the help of the International Essential Tremor Foundation, we will establish at Columbia University a centralized repository for new prospectively-collected ET brains, collecting 36 additional ET brains during the five-year period. The 60 ET brains will be compared with 40 control brains. Primary Aim 1 is to study the pathology of ET to determine whether there are changes in specific brain regions. Using conventional morphological methods and quantitative morphometric assessments (stereology), tissue will be examined for changes, including cell loss, in the main region of interest (cerebellar hemispheres) and in secondary regions of interest (red nuclei, thalami, inferior olivary nuclei). We hypothesize that changes and cell loss in the cerebellum will be present to a greater extent in ET than in control brains. Primary Aim 2 is to study the GABA neurotransmitter system. We hypothesize that there will be differences in cerebellar GABA-ergic immuno-labeling in ET compared to control brains. Current therapies for ET have come to us by serendipity and are ineffective in up to 50% of patients. Knowledge of the pathological changes and neurochemical abnormality in ET is critical for the design of new therapies for ET.