Essential tremor (ET) is one of the most common neurological diseases yet it is also among the least studied. Few medications treat the disorder, which is usually progressive. Although it is as much as twenty times more prevalent than Parkinson's disease, at the time of our original application (2002), we noted that there were only 15 postmortems, most of which were from the pre-modern era. Hence, there was almost no knowledge of the underlying pathology of ET. Although often reiterated that 'there is no pathology'in ET, this was not based on rigorous study. Since 2003, our goal has been to establish the Essential Tremor Centralized Brain Repository to address a fundamental question in ET research: can an underlying pathology be identified in terms of morphological changes in specific brain regions? After intensively collecting and then studying 51 ET brains and 34 control brains, we have discovered that, indeed, there are identifiable pathological changes in the ET brain: 82.3% of ET brains have cerebellar degenerative changes in the form of increased numbers of torpedoes and mild reduction in Purkinje cell (PC) number ("cerebellar ET") whereas 17.7% have brainstem Lewy bodies. Hence, at this point, we have described several basic changes in the ET brain. Clinical differences between the two pathologically-identified subtypes of ET have not been well studied. We now wish to move beyond our initial work.
SPECIFIC AIM 1 is to advance our knowledge of the postmortem changes in patients with cerebellar ET (Aim 1A) and Lewy body ET (Aim 1B) through detailed studies of PC neuronal morphology.
In Aim 1 A, we will also begin to study neurofilament proteins. Because our previous analyses were confined to a single region of one cerebellar hemisphere, we will broaden our scope to include each of the other functional-anatomic regions of the cerebellum (Aim 1C).
In Aim 1 D, we will extend our analyses to the thalamus.
SPECIFIC AIM 2 is to establish basic links between clinical features and postmortem brain changes (clinical-pathological correlation). The clinical evaluation in our 2002 application was, by design, brief and indirect (telephone and videotape). Now our aim is to conduct a comprehensive in- person clinical evaluation of 175 elderly ET cases, 44 of whom we expect to die during this five year proposal. In doing so, we can begin to identify the specific clinical features that characterize patients with each of the two pathological subtypes of ET. Our goal is to advance this field by: (1) increasing our understanding of the pathological anatomy of ET, and (2) forging the needed links between what physicians observe in living patients and what we uncover in detailed postmortem studies.

Public Health Relevance

Essential tremor (ET) is among the most common neurological diseases, yet until recently there had been very few postmortem studies. After intensively collecting and studying 51 ET brains and 34 control brains over the past 5 years, we have discovered that, indeed, there are identifiable pathological changes in the ET brain.
Our aims i n this competitive renewal application are to advance our knowledge of the postmortem changes in ET with more detailed quantitative morphological studies of Purkinje cells (Aim 1) and to establish basic links between clinical features and postmortem brain changes (Aim 2). Our tissue-based research will place us in unique a position to begin to address basic mechanistic questions about ET and may allow treating physicians to predict during life which subtype of ET a patient is likely to have.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS042859-09
Application #
8312599
Study Section
Special Emphasis Panel (ZRG1-BDCN-N (02))
Program Officer
Gwinn, Katrina
Project Start
2001-12-01
Project End
2014-07-31
Budget Start
2012-08-01
Budget End
2014-07-31
Support Year
9
Fiscal Year
2012
Total Cost
$649,065
Indirect Cost
$245,919
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 (2014) Essential tremor: from bedside to bench and back to bedside. Curr Opin Neurol 27:461-7
Louis, Elan D (2014) Re-thinking the biology of essential tremor: from models to morphology. Parkinsonism Relat Disord 20 Suppl 1:S88-93
Louis, Ravi J; Lee, Michelle; Kuo, Sheng-Han et al. (2014) Cellular density in the cerebellar molecular layer in essential tremor, spinocerebellar ataxia, and controls. Parkinsonism Relat Disord 20:1270-3
Louis, Elan D; Michalec, Monika (2014) Validity of a screening question for head tremor: an analysis of four essential tremor case samples. Neuroepidemiology 43:65-70
Lin, Chi-Ying; Louis, Elan D; Faust, Phyllis L et al. (2014) Abnormal climbing fibre-Purkinje cell synaptic connections in the essential tremor cerebellum. Brain 137:3149-59
Louis, Elan D; Lee, Michelle; Cortés, Etty et al. (2014) Matching asymmetry of tremor with asymmetry of postmortem cerebellar hemispheric changes in essential tremor. Cerebellum 13:462-70
Benito-León, Julián; Romero, Juan Pablo; Louis, Elan D et al. (2014) Faster cognitive decline in elders without dementia and decreased risk of cancer mortality: NEDICES Study. Neurology 82:1441-8
Rao, Ashwini K; Chou, Aileen; Bursley, Brett et al. (2014) Systematic review of the effects of exercise on activities of daily living in people with Alzheimer's disease. Am J Occup Ther 68:50-6
Louis, Elan D (2014) Understanding essential tremor: progress on the biological front. Curr Neurol Neurosci Rep 14:450
Pan, Jie J; Lee, Michelle; Honig, Lawrence S et al. (2014) Alzheimer's-related changes in non-demented essential tremor patients vs. controls: links between tau and tremor? Parkinsonism Relat Disord 20:655-8

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