Environmental Epidemiology of Essential Tremor

Parkinson Disease Clinical Trial

— RULET  

Official title:

Environmental Epidemiology of Essential Tremor

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT04576676
• Other study ID #: STU-2020-0563
• Secondary ID: R01NS094607
• Status: Completed
• Start date: July 2, 2020
• Est. completion date: July 19, 2023

Study information

• Verified date: September 2023
• Source: University of Texas Southwestern Medical Center
• Contact: n/a
• Is FDA regulated: No
• Study type: Observational

Clinical Trial Summary

This study's research is devoted to studying the causes of tremor, and especially essential tremor (ET), which is the most common type of tremor. Previous studies have revealed a link between harmane [HA], a dietary neurotoxin, and ET; these studies now also suggest a link between this toxin and Parkinson's disease (PD), a related tremor disorder. Yet these links are tentative rather than conclusively established; therefore, in this new patient-based proposal, which incorporates investigations spanning two continents (North America and Europe), utilizes several complementary study designs (prospective cohort, case control), and draws on several types of tissue (blood, brain), the investigator's goal is to nail down the links between HA and ET and to further solidify the emerging links between HA and PD.

Description:

This research is devoted to studying the causes of tremor, and especially essential tremor (ET), which is the most common type of tremor. Since 2000, this lab has been investigating whether several environmental neurotoxins are associated with ET. A link between harmane (HA) (1-methyl-9H-pyrido[3,4-b]indole) and ET has been emerging from these studies, which show that blood and brain HA concentration ([HA]) is elevated in ET cases (esp. familial ET) vs. control subjects. HA is a neurotoxin present in the diet (esp. in meat). Administration of HA to laboratory animals produces severe action tremor resembling ET. Yet the link between HA and ET has not been convincingly established. All epidemiological studies have been case-control studies; thus, it is not clear whether high blood [HA] precedes the onset of ET. Aim 1 of this proposal will address this issue. The HA story has also become more complex and multi-dimensional. Thus, the investigators were recently intrigued to find that blood [HA] was higher in Parkinson's disease (PD) cases than controls in New York. HA is structurally similar to MPTP, a neurotoxin closely linked with PD. ET and PD are both tremor disorders; some patients develop both disorders (ET+PD; i.e., they are comorbid for the two conditions). Whether the HA - PD link is reproducible, whether it tracks with the subtype of PD in which tremor rather than bradykinesia/rigidity is the predominant feature, and whether biomarker findings from blood also occur in the target organ of interest (i.e., the brain) in PD is not known. Aim 2 of this proposal will address this myriad of issues. Finally, whether individuals who are comorbid for both ET and PD have the highest blood [HA] is not known. Aim 3 of this proposal will address this issue. To close these gaps in knowledge, in this application, the investigators propose a 5-year study with 3 inter-related aims that draw on several types of human tissue (blood, brain): AIM 1: To nail down the links between HA and ET by studying the association between baseline blood [HA] and the development of incident ET in a cohort study. AIM 2: To further solidify the emerging links between HA and PD by extending our observations to another country (Spain). AIM 3: To assess blood levels of HA in patients who have both ET and PD (ET+PD). This would be the only study heading in this direction - exploring the etiological role of environmental factors, and more specifically toxins, in ET. It would thus complement the many ongoing studies searching for ET genes. The study could lead to the clear identification of the first modifiable risk factor for ET (i.e., dietary HA).This would also be the only study assessing the possible etiological role and tissue concentrations of this toxin, HA, which is structurally similar to MPTP, in patients with PD.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 1497
• Est. completion date: July 19, 2023
• Est. primary completion date: December 20, 2022
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 50 Years and older

Eligibility

Inclusion Criteria:

• Essential Tremor

• Subjects must be 50 years of age or older.

• Subjects must have been diagnosed with Essential Tremor

• Subjects must live within 3 hours of UTSW

• Parkinson's Disease

• Subjects must be 50 years of age or older.

• Subjects must have been diagnosed with Parkinson's Disease

• Subjects must live within 3 hours of UTSW

• Healthy Individuals

• Healthy individuals living within 3 hours of UTSW

• Subjects must be 50 years of age or older

• You are healthy and have not being diagnosed with any neurological disease

• Essential Tremor and Parkinson's Disease

• Subjects must be 50 years of age or older.

• Subjects must have been diagnosed with Essential Tremor

• Subjects must have been diagnosed with Parkinson's Disease preceded by at least 3 years of enrollment in study

• Subjects must live within 3 hours of UTSW

Exclusion Criteria:

• Healthy Individuals

• Subjects with medical history of neurological conditions

• Subjects with family history of neurological condition

• Subjects with spouse diagnosed with Essential Tremor or Parkinson's Disease

• Essential Tremor

• Subjects with medical history of another movement disorder such as Parkinson's Disease or dystonia

• Subjects with head tremor that preceded hand tremor

• Parkinson's Disease

--Subjects with medical history of Essential Tremor

• Essential Tremor and Parkinson's Disease

• Criteria that does not meet inclusion

Related Conditions & MeSH terms

• Essential Tremor
• Parkinson Disease
• Tremor

Locations

Country	Name	City	State
United States	University of Texas Southwestern	Dallas	Texas

Sponsors (4)

Lead Sponsor	Collaborator
University of Texas Southwestern Medical Center	National Institute of Neurological Disorders and Stroke (NINDS), Purdue University, Yale University

Country where clinical trial is conducted

United States, 

References & Publications (16)

Bain PG, Findley LJ, Thompson PD, Gresty MA, Rothwell JC, Harding AE, Marsden CD. A study of hereditary essential tremor. Brain. 1994 Aug;117 ( Pt 4):805-24. doi: 10.1093/brain/117.4.805. — View Citation

Benito-Leon J, Louis ED, Bermejo-Pareja F; Neurological Disorders in Central Spain (NEDICES) Study Group. Population-based case-control study of cognitive function in essential tremor. Neurology. 2006 Jan 10;66(1):69-74. doi: 10.1212/01.wnl.0000192393.05850.ec. — View Citation

Benito-Leon J, Louis ED, Bermejo-Pareja F; Neurological Disorders in Central Spain Study Group. Risk of incident Parkinson's disease and parkinsonism in essential tremor: a population based study. J Neurol Neurosurg Psychiatry. 2009 Apr;80(4):423-5. doi: 10.1136/jnnp.2008.147223. — View Citation

Bhalsing KS, Saini J, Pal PK. Understanding the pathophysiology of essential tremor through advanced neuroimaging: a review. J Neurol Sci. 2013 Dec 15;335(1-2):9-13. doi: 10.1016/j.jns.2013.09.003. Epub 2013 Sep 10. — View Citation

Fekete R, Jankovic J. Revisiting the relationship between essential tremor and Parkinson's disease. Mov Disord. 2011 Feb 15;26(3):391-8. doi: 10.1002/mds.23512. — View Citation

Gironell A, Kulisevsky J, Barbanoj M, Lopez-Villegas D, Hernandez G, Pascual-Sedano B. A randomized placebo-controlled comparative trial of gabapentin and propranolol in essential tremor. Arch Neurol. 1999 Apr;56(4):475-80. doi: 10.1001/archneur.56.4.475. — View Citation

Louis ED, Applegate LM, Factor-Litvak P, Parides MK, Andrews L. Essential tremor: occupational exposures to manganese and organic solvents. Neurology. 2004 Dec 14;63(11):2162-4. doi: 10.1212/01.wnl.0000145600.91491.f2. — View Citation

Louis ED, Benito-Leon J, Moreno-Garcia S, Vega S, Romero JP, Bermejo-Pareja F, Gerbin M, Viner AS, Factor-Litvak P, Jiang W, Zheng W. Blood harmane (1-methyl-9H-pyrido[3,4-b]indole) concentration in essential tremor cases in Spain. Neurotoxicology. 2013 Jan;34:264-8. doi: 10.1016/j.neuro.2012.09.004. Epub 2012 Sep 12. — View Citation

Louis ED, Benito-Leon J, Ottman R, Bermejo-Pareja F; Neurological Disorders in Central Spain (NEDICES) Study Group. A population-based study of mortality in essential tremor. Neurology. 2007 Nov 20;69(21):1982-9. doi: 10.1212/01.wnl.0000279339.87987.d7. — View Citation

Louis ED, Ferreira JJ. How common is the most common adult movement disorder? Update on the worldwide prevalence of essential tremor. Mov Disord. 2010 Apr 15;25(5):534-41. doi: 10.1002/mds.22838. — View Citation

Louis ED, Vonsattel JP, Honig LS, Lawton A, Moskowitz C, Ford B, Frucht S. Essential tremor associated with pathologic changes in the cerebellum. Arch Neurol. 2006 Aug;63(8):1189-93. doi: 10.1001/archneur.63.8.1189. — View Citation

Louis ED, Zheng W, Applegate L, Shi L, Factor-Litvak P. Blood harmane concentrations and dietary protein consumption in essential tremor. Neurology. 2005 Aug 9;65(3):391-6. doi: 10.1212/01.wnl.0000172352.88359.2d. — View Citation

Louis ED. Clinical practice. Essential tremor. N Engl J Med. 2001 Sep 20;345(12):887-91. doi: 10.1056/NEJMcp010928. No abstract available. — View Citation

MARSHALL J. Observations on essential tremor. J Neurol Neurosurg Psychiatry. 1962 May;25(2):122-5. doi: 10.1136/jnnp.25.2.122. No abstract available. — View Citation

Moncrieff J. Determination of pharmacological levels of harmane, harmine and harmaline in mammalian brain tissue, cerebrospinal fluid and plasma by high-performance liquid chromatography with fluorimetric detection. J Chromatogr. 1989 Nov 24;496(2):269-78. doi: 10.1016/s0378-4347(00)82576-1. — View Citation

Skog K, Solyakov A, Arvidsson P, Jagerstad M. Analysis of nonpolar heterocyclic amines in cooked foods and meat extracts using gas chromatography-mass spectrometry. J Chromatogr A. 1998 Apr 17;803(1-2):227-33. doi: 10.1016/s0021-9673(97)01266-1. — View Citation

* Note: There are 16 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Level of Harmane in Blood	Two vials of veinous blood will be collected from each participant and analyzed for the level of harmane. Specimen collection done at the Aston Care Center and sent to Purdue University for analysis.	Day 1
Primary	Archimedes Spirals	Each participant will draw two spirals with each hand, used to assess the frequency and severity of one's tremor and to confirm their diagnosis.	Day 1
Primary	Video Interview	After a participant has met the eligibility criteria, they participate in a two hour video interview, where a series of questionnaires is administered, as well as a videotaped neurological/movement assessment. Video is reviewed by study's PI and participant's tremor is rated on a fixed, numerical scale from 0.0 to 4.0, where 4.0 indicates a more severe tremor.	Day 1
Secondary	Cumulative Illness Rating Scale (CIRS)	CIRS quantifies the burden of disease in elderly patients (comorbidity scale; ranges from 0-42 where 42 indicates highest number and severity of illnesses measured).	Day 1
Secondary	Montreal Cognitive Assessment (MoCA)	The MoCA is a cognitive screening test designed to assist Health Professionals in the detection of mild cognitive impairment and Alzheimer's disease. Scores range from 0-30.	Day 1
Secondary	Food Frequency Questionnaire	Developed at Harvard University, the Food Frequency Questionnaire (FFQ) is a limited checklist of foods and beverages with a frequency response section for subjects to report how often each item was consumed over a specified period of time.	Day 1
Secondary	Meat Questionnaire	Asks participants to indicate how often they eat chicken, beef and pork products, and how well done the meats were cooked.	Day 1
Secondary	MDS-Unified Parkinson's Disease Rating Scale	The UPDRS scale refers to Unified Parkinson Disease Rating Scale, and it is a rating tool used to gauge the course of Parkinson's disease in patients. Each of the ratings ranges from 0 to 4. The original UPDRS included only integers, but some use 0.5 increments; however, use of these 0.5 increments has not undergone clinimetric testing or validation. The total score for subscale 3 ranges from 0 to 108, the sum of scores from 27 observations.	Day 1
Secondary	Apathy Evaluation Scale (AES)	The Apathy Evaluation Scale (AES) is a method for measuring apathy resulting from brain-related pathology.	Day 1
Secondary	Beck's Depression Inventory	The Beck Depression Inventory (BDI, BDI-1A, BDI-II) is a 21-question multiple-choice self-report inventory, one of the most widely used psychometric tests for measuring the severity of depression.; Like the BDI, the BDI-II also contains 21 questions, each answer being scored on a scale value of 0 to 3. Higher total scores indicate more severe depressive symptoms. The standardized cutoffs used differ from the original: 0-13: minimal depression 14-19: mild depression 20-28: moderate depression 29-63: severe depression.	Day 1
Secondary	Epworth Sleepiness Scale	The ESS is a self-administered questionnaire with 8 questions. Respondents are asked to rate, on a 4-point scale (0-3), their usual chances of dozing off or falling asleep while engaged in eight different activities. Most people engage in those activities at least occasionally, although not necessarily every day. The ESS score (the sum of 8 item scores, 0-3) can range from 0 to 24. The higher the ESS score, the higher that person's average sleep propensity in daily life (ASP), or their 'daytime sleepiness'.	Day 1
Secondary	Hamilton Anxiety Rating Scale (HAM-A)	The HAM-A was one of the first rating scales developed to measure the severity of anxiety symptoms. Each item is scored on a scale of 0 (not present) to 4 (severe), with a total score range of 0-56, where <17 indicates mild severity, 18-24 mild to moderate severity and 25-30 moderate to severe.	Day 1
Secondary	Patient Health Questionnaire-9	The Patient Health Questionnaire (PHQ)-9 is the major depressive disorder (MDD) module of the full PHQ. Used to provisionally diagnose depression and grade severity of symptoms in general medical and mental health settings.	Day 1
Secondary	Pittsburgh Sleep Quality Index	PSQI was designed to evaluate overall sleep quality. A total score of "5" or greater is indicative of poor sleep quality.	Day 1
Secondary	The Snaith-Hamilton Pleasure Scale (SHAPS)	The SHAPS is a 14-item scale that measures anhedonia, the inability to experience pleasure. The items cover the domains of: social interaction, food and drink, sensory experience, and interest/pastimes. A score of 2 or less constitutes a "normal" score, while an "abnormal" score is defined as 3 or more.	Day 1
Secondary	Tremor Disability Questionnaire	Assesses a valid index of tremor-induced disability	Day 1
Secondary	Tremor Embarrassment Assessment (TEA)	TEA is a tool to quantitatively assess the level of embarrassment experienced due to one's tremor.	Day 1