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 #
7R01NS085136-03
Application #
9103663
Study Section
Clinical Neuroscience and Neurodegeneration Study Section (CNN)
Program Officer
Gwinn, Katrina
Project Start
2015-08-01
Project End
2018-07-31
Budget Start
2015-08-01
Budget End
2016-07-31
Support Year
3
Fiscal Year
2015
Total Cost
$628,630
Indirect Cost
$140,665
Name
Yale University
Department
Neurology
Type
Schools of Medicine
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06510
Louis, Elan D; Meyers, James H; Cristal, Ashley D et al. (2018) Transient, Isolated Head Tremor in ""Unaffected"" Individuals: Is Essential Tremor an Even More Prevalent Disease Than We Suppose? Front Neurol 9:570
Cameron, Eric; Dyke, Jonathan P; Hernandez, Nora et al. (2018) Cerebral gray matter volume losses in essential tremor: A case-control study using high resolution tissue probability maps. Parkinsonism Relat Disord 51:85-90
Lee, Danielle; Gan, Shi-Rui; Faust, Phyllis L et al. (2018) Climbing fiber-Purkinje cell synaptic pathology across essential tremor subtypes. Parkinsonism Relat Disord 51:24-29
Louis, Elan D; Meyers, James H; Cristal, Ashley D et al. (2018) Unaffected first-degree relatives of essential tremor cases have more imbalance than age-matched control subjects. Parkinsonism Relat Disord 52:24-29
Cristal, Ashley D; Chen, Karen P; Hernandez, Nora Cristina et al. (2018) Knowledge about Essential Tremor: A Study of Essential Tremor Families. Front Neurol 9:27
Louis, Elan D; Hernandez, Nora; Dyke, Jonathan P et al. (2018) In Vivo Dentate Nucleus Gamma-aminobutyric Acid Concentration in Essential Tremor vs. Controls. Cerebellum 17:165-172
Louis, Elan D; Kuo, Sheng-Han; Tate, William J et al. (2018) Heterotopic Purkinje Cells: a Comparative Postmortem Study of Essential Tremor and Spinocerebellar Ataxias 1, 2, 3, and 6. Cerebellum 17:104-110
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
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

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