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 #
5R01NS042859-08
Application #
8109864
Study Section
Special Emphasis Panel (ZRG1-BDCN-N (02))
Program Officer
Sieber, Beth-Anne
Project Start
2001-12-01
Project End
2013-07-31
Budget Start
2011-08-01
Budget End
2012-07-31
Support Year
8
Fiscal Year
2011
Total Cost
$650,617
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; Patel, Amar; Gerrard, Jason L (2017) What is the pathway forward for the surgical management of essential tremor? Ann Neurol 81:351-353
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
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
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
Wang, Jie; Kelly, Geoffrey C; Tate, William J et al. (2016) Excitatory Amino acid transporter expression in the essential tremor dentate nucleus and cerebellar cortex: A postmortem study. Parkinsonism Relat Disord 32:87-93
Louis, Elan D; Clark, Lorraine; Ottman, Ruth (2016) Familial Aggregation and Co-Aggregation of Essential Tremor and Parkinson's Disease. Neuroepidemiology 46:31-6
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
Louis, Elan D; Factor-Litvak, Pam (2016) Screening for and Estimating the Prevalence of Essential Tremor: A Random-Digit Dialing-Based Study in the New York Metropolitan Area. Neuroepidemiology 46:51-6
Kuo, Sheng-Han; Lin, Chi-Ying; Wang, Jie et al. (2016) Deep brain stimulation and climbing fiber synaptic pathology in essential tremor. Ann Neurol 80:461-5
Louis, Elan D; Collins, Kathleen; Rohl, Brittany et al. (2016) Self-reported physical activity in essential tremor: Relationship with tremor, balance, and cognitive function. J Neurol Sci 366:240-245

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