Despite its high prevalence, essential tremor (ET) it is among the least-studied and most poorly- understood neurological diseases. On the most basic biological level, little is known about its underlying pathologic-anatomy and pathophysiology. Recent postmortem studies report a 30 - 40% loss of Purkinje cells (PCs) in ET, suggesting that on a mechanistic level, this common neurological disease could be neurodegenerative. But postmortem results have been mixed. At the moment, the central debate in the ET field revolves around the question, """"""""is PC loss a feature of ET""""""""? Unfortunately, the approach to this question has thus far been limited to postmortem studies and a fresh approach is needed. PCs, in the cerebellar cortex, are the major storehouse of brain gamma-aminobutyric acid (GABA), releasing their GABA into the synaptic cleft at the level of the cerebellar dentate nucleus. Thus, cerebellar dentate GABA level is a convenient in vivo marker of PC number. Furthermore, N-acetylaspartate (NAA), an amino acid found in the cytosol of neurons, is a convenient in vivo marker of neuronal integrity in the cerebellar cortex. The long-term goal of the proposed research is to elucidate the basic nature of the underlying pathophysiology of ET. The objective of this research project, which is the next step toward attainment of this long-term goal, is to perform in-vivo magnetic resonance spectroscopy (MRS) to quantify levels of GABA in the cerebellar dentate and NAA in the cerebellar cortex in 50 ET cases vs. 50 controls, both cross-sectionally and longitudinally. The central hypothesis for the proposed research is that there is a progressive destruction of PCs in ET. We plan to accomplish the overall objective of this application by pursuing the following three aims.
Aim 1 : In this cross-sectional neuroimaging aim, we will use MRS at baseline (Years 1 - 2) to assess in vivo cerebellar dentate GABA levels and cerebellar cortex NAA levels (NAA/total creatine, tCR) in ET cases and controls.
Aim 2 : In this longitudinal neuroimaging aim, we will perform a second MRS study (Years 4 - 5) to assess in vivo cerebellar cortex NAA/tCR levels and, in an exploratory manner, dentate GABA levels, to determine whether there is a longitudinal decline in these levels in 50 ET cases in excess of any longitudinal decline in these levels in 50 controls.
Aim 3 : We will cross validate the in vivo MRS findings with postmortem histological and biochemical findings in the brains of 10 - 15 of 50 ET cases whom we expect to die during the 5 year study. We expect that the proposed research will elucidate the underlying disease pathophysiology and provide useful diagnostic biomarkers as well as markers of disease progression for future neuroprotective trials.

Public Health Relevance

Recent postmortem studies report a 30 - 40% loss of Purkinje cells in essential tremor (ET), suggesting that on a mechanistic level, this extraordinarily common neurological disease could very well be neurodegenerative. At the moment, the central debate in the ET field revolves around the question, is Purkinje cell loss a feature of ET?;the goal of the proposed research, which uses in-vivo magnetic resonance spectroscopy to measure gamma-aminobutyric acid and N-acetylaspartate levels in the cerebellum, is to address this question. We expect that the proposed research will elucidate the underlying disease pathophysiology and provide useful diagnostic biomarkers as well as markers of disease progression for future neuroprotective trials.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS085136-02
Application #
8734499
Study Section
Clinical Neuroscience and Neurodegeneration Study Section (CNN)
Program Officer
Gwinn, Katrina
Project Start
2013-09-15
Project End
2018-07-31
Budget Start
2014-09-01
Budget End
2015-07-31
Support Year
2
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Columbia University (N.Y.)
Department
Neurology
Type
Schools of Medicine
DUNS #
City
New York
State
NY
Country
United States
Zip Code
10032
Louis, Elan D; Lenka, Abhishek (2017) The Olivary Hypothesis of Essential Tremor: Time to Lay this Model to Rest? Tremor Other Hyperkinet Mov (N Y) 7:473
Louis, Elan D; Kuo, Sheng-Han; Tate, William J et al. (2017) Cerebellar pathology in childhood-onset vs. adult-onset essential tremor. Neurosci Lett 659:69-74
Louis, Elan D; Hernandez, Nora; Dyke, Jonathan P et al. (2017) In Vivo Dentate Nucleus Gamma-aminobutyric Acid Concentration in Essential Tremor vs. Controls. Cerebellum :
Lenka, Abhishek; Pal, Pramod Kumar; Bhatti, Danish Ejaz et al. (2017) Pathogenesis of Primary Orthostatic Tremor: Current Concepts and Controversies. Tremor Other Hyperkinet Mov (N Y) 7:513
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
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Lenka, Abhishek; Benito-León, Julian; Louis, Elan D (2017) Is there a Premotor Phase of Essential Tremor? Tremor Other Hyperkinet Mov (N Y) 7:498
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
Dyke, Jonathan P; Cameron, Eric; Hernandez, Nora et al. (2017) Gray matter density loss in essential tremor: a lobule by lobule analysis of the cerebellum. Cerebellum Ataxias 4:10
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

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