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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS042859-03
Application #
6924552
Study Section
Brain Disorders and Clinical Neuroscience 5 (BDCN)
Program Officer
Oliver, Eugene J
Project Start
2003-08-01
Project End
2008-07-31
Budget Start
2005-08-01
Budget End
2006-07-31
Support Year
3
Fiscal Year
2005
Total Cost
$462,197
Indirect Cost
Name
Columbia University (N.Y.)
Department
Neurology
Type
Schools of Medicine
DUNS #
621889815
City
New York
State
NY
Country
United States
Zip Code
10032
Louis, Elan D (2018) Essential tremor then and now: How views of the most common tremor diathesis have changed over time. Parkinsonism Relat Disord 46 Suppl 1:S70-S74
Louis, Elan D (2018) The evolving definition of essential tremor: What are we dealing with? Parkinsonism Relat Disord 46 Suppl 1:S87-S91
Benito-León, Julián; Mato-Abad, Virginia; Louis, Elan D et al. (2017) White matter microstructural changes are related to cognitive dysfunction in essential tremor. Sci Rep 7:2978
Serrano, J Ignacio; Romero, Juan P; Castillo, Ma Dolores Del et al. (2017) A data mining approach using cortical thickness for diagnosis and characterization of essential tremor. Sci Rep 7:2190
Sánchez-Ferro, Á; Benito-León, J; Louis, E D et al. (2017) Cognition in non-demented Parkinson's disease vs essential tremor: A population-based study. Acta Neurol Scand 136:393-400
Kuo, Sheng-Han; Wang, Jie; Tate, William J et al. (2017) Cerebellar Pathology in Early Onset and Late Onset Essential Tremor. Cerebellum 16:473-482
Louis, Elan D; Patel, Amar; Gerrard, Jason L (2017) What is the pathway forward for the surgical management of essential tremor? Ann Neurol 81:351-353
Kuo, Sheng-Han; Lin, Chi-Ying; Wang, Jie et al. (2017) Climbing fiber-Purkinje cell synaptic pathology in tremor and cerebellar degenerative diseases. Acta Neuropathol 133:121-138
Louis, Elan D; Rabinowitz, Daniel; Choe, Matthew et al. (2016) Mapping Purkinje Cell Placement Along the Purkinje Cell Layer: an Analysis of Postmortem Tissue from Essential Tremor Patients vs. Controls. Cerebellum 15:726-731
Benito-León, Julián; Louis, Elan D; Puertas-Martín, Verónica et al. (2016) Cognitive and neuropsychiatric features of orthostatic tremor: A case-control comparison. J Neurol Sci 361:137-43

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