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.
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.
|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|
|Alcalay, R N; Wolf, P; Levy, O A et al. (2018) Alpha galactosidase A activity in Parkinson's disease. Neurobiol Dis 112:85-90|
|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|
|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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|Benito-León, Julián; Laurence, Martin (2017) The Role of Fungi in the Etiology of Multiple Sclerosis. Front Neurol 8:535|
|Benito-León, Julián; Mato-Abad, Virginia; Louis, Elan D et al. (2017) White matter microstructural changes are related to cognitive dysfunction in essential tremor. Sci Rep 7:2978|
|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|
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