Essential tremor (ET) is the most common cause of tremor in humans yet its etiology remains unclear. Environmental toxicants are likely to contribute to its etiology. Such factors are thought to play an important role in other neuro-degenerative diseases,but their role in ET has received less attention. During the last eight years (2000 - 2008), we have studied several putative toxicants. Harmane (1-methyl-9H-pyrido[3,4-b]indole) is the most promising early candidate in the search for environmental risk factors for ET. During the past three years (2005 - 2008), we studied several potential mechanisms that could underlie elevated blood harmane concentrations in our clinic-based sample of ET cases in New York. These studies suggest that dietary factors might play a role. In tandem with these studies, we have continued to collect blood harmane samples in New York. Moving forward, our goal is to now definitely establish the links between this neurotoxin and ET. This is a five-year competitive renewal in which we propose to address four inter-related questions. First, although elevated harmane concentrations have been observed in ET cases in blood, brain concentrations of this neurotoxin have not been investigated. ET is a brain disease and the brain is the presumed target organ of this neurotoxin. Are harmane concentrations elevated in the ET brain (Specific Aim 1)? Second, our finding was derived from a single study of ET cases primarily from one tertiary referral center in New York. If one were to sample a group of ET cases ascertained in a completely different manner (i.e., community-based) half-way around the world, would one find an elevated blood harmane concentration (Specific Aim 2)? Third, our finding of an elevated harmane concentration was a cross-sectional observation, sampling blood at a single time point. It is not clear whether these same ET cases would persist in demonstrating elevated blood harmane concentrations if re-assessed at a second time point several years later (Specific Aim 3)? Finally, one study found elevated blood harmane concentrations in Parkinson's disease, raising the question as to whether elevated blood harmane is specifically linked with ET or is merely a more general, global marker of neurological illness (Specific Aim 4)? Approximately 50% of ET cases are non-familial. Given its population prevalence of 4.0% in persons age >40 years, then 2.0% of the population aged >40 years has a non-familial form of ET, yet the environmental underpinnings for this tremor are just beginning to be explored. Identification and understanding of these toxicants is the first step in preventing a progressive neurological disease with few treatment options.

Public Health Relevance

We estimate that 2.0% of the population aged >40 years has sporadic (i.e., non-familial) essential tremor (ET), yet the environmental underpinnings for this tremor are just beginning to be explored. Harmane (1-methyl-9H- pyrido[3,4-b]indole) is the most promising early candidate in the search for environmental risk factors for ET. This is a five-year competitive renewal in which we propose to firmly establish the links between this neurotoxin and ET.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS039422-13
Application #
8462692
Study Section
Neurological, Aging and Musculoskeletal Epidemiology (NAME)
Program Officer
Gwinn, Katrina
Project Start
1999-12-01
Project End
2014-04-30
Budget Start
2013-05-01
Budget End
2014-04-30
Support Year
13
Fiscal Year
2013
Total Cost
$532,481
Indirect Cost
$179,059
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 (2015) Medication non-adherence in essential tremor. Parkinsonism Relat Disord 21:138-41
Louis, E D; Michalec, M (2015) Reduced body mass index in essential tremor: a study of 382 cases and 392 matched controls. Eur J Neurol 22:384-8
Louis, Elan D; Factor-Litvak, Pam; Michalec, Monika et al. (2014) Blood harmane (1-methyl-9H-pyrido[3,4-b]indole) concentration in dystonia cases vs. controls. Neurotoxicology 44:110-3
Louis, Elan D; Faust, Phyllis L (2014) Purkinje cell loss in essential tremor. Mov Disord 29:1329-30
Romero, Juan Pablo; Benito-Leon, Julian; Mitchell, Alex J et al. (2014) Under reporting of dementia deaths on death certificates using data from a population-based study (NEDICES). J Alzheimers Dis 39:741-8
Romero, Juan Pablo; Benito-León, Julián; Louis, Elan D et al. (2014) Alzheimer's disease is associated with decreased risk of cancer-specific mortality: a prospective study (NEDICES). J Alzheimers Dis 40:465-73
Benito-León, Julián; Louis, Elan D; Villarejo-Galende, Alberto et al. (2014) Long sleep duration in elders without dementia increases risk of dementia mortality (NEDICES). Neurology 83:1530-7
Louis, Elan D; Michalec, Monika (2014) Semi-quantitative data on ethanol consumption in 354 ET cases and 370 controls. J Neurol Sci 347:174-8
Louis, Elan D (2014) 'Essential tremor' or 'the essential tremors': is this one disease or a family of diseases? Neuroepidemiology 42:81-9
Contador, I; Bermejo-Pareja, F; Mitchell, A J et al. (2014) Cause of death in mild cognitive impairment: a prospective study (NEDICES). Eur J Neurol 21:253-e9

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