Environmental Epidemiology of Essential Tremor (RULET)

September 18, 2023 updated by: Elan Louis, University of Texas Southwestern Medical Center
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.

Study Overview

Status

Completed

Conditions

Detailed 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.

Study Type

Observational

Enrollment (Actual)

1497

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact Backup

Study Locations

  • United States
    • Texas
      • Dallas, Texas, United States, 75235
        • University of Texas Southwestern

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

50 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

Yes

Sampling Method

Non-Probability Sample

Study Population

Individuals above the age of 50, living within a 3 hour driving radius of UT Southwestern.

Description

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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Observational Models: Case-Control
  • Time Perspectives: Prospective

Cohorts and Interventions

Group / Cohort
Essential Tremor
  1. Subjects must be 50 years of age or older.
  2. Subjects must have been diagnosed with Essential Tremor
  3. Subjects must live within 3 hours of UTSW

Subjects will be screened for eligibility over the phone, and if eligible, will partake in a virtual video conference with a research assistant. Subjects will also travel to the Aston Building at UTSW for a blood draw.
Parkinson's Disease
  1. Subjects must be 50 years of age or older.
  2. Subjects must have been diagnosed with Parkinson's Disease
  3. Subjects must live within 3 hours of UTSW

Subjects will be screened for eligibility over the phone, and if eligible, will partake in a virtual video conference with a research assistant. Subjects will also travel to the Aston Building at UTSW for a blood draw.
Healthy Individuals
  1. Healthy individuals living within 3 hours of UTSW
  2. Subjects must be 50 years of age or older
  3. You are healthy and have not being diagnosed with any neurological disease

Subjects will be screened for eligibility over the phone, and if eligible, will partake in a virtual video conference with a research assistant. Subjects will also travel to the Aston Building at UTSW for a blood draw.
Essential Tremor and Parkinson's Disease
  1. Subjects must be 50 years of age or older.
  2. Subjects must have been diagnosed with Essential Tremor
  3. Subjects must have been diagnosed with Parkinson's Disease preceded by at least 3 years of enrollment in study
  4. Subjects must live within 3 hours of UTSW

Subjects will be screened for eligibility over the phone, and if eligible, will partake in a virtual video conference with a research assistant. Subjects will also travel to the Aston Building at UTSW for a blood draw.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Level of Harmane in Blood
Time Frame: Day 1
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
Archimedes Spirals
Time Frame: Day 1
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
Video Interview
Time Frame: Day 1
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 Outcome Measures

Outcome Measure
Measure Description
Time Frame
Cumulative Illness Rating Scale (CIRS)
Time Frame: Day 1
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
Montreal Cognitive Assessment (MoCA)
Time Frame: Day 1
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
Food Frequency Questionnaire
Time Frame: Day 1
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
Meat Questionnaire
Time Frame: Day 1
Asks participants to indicate how often they eat chicken, beef and pork products, and how well done the meats were cooked.
Day 1
MDS-Unified Parkinson's Disease Rating Scale
Time Frame: Day 1
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
Apathy Evaluation Scale (AES)
Time Frame: Day 1
The Apathy Evaluation Scale (AES) is a method for measuring apathy resulting from brain-related pathology.
Day 1
Beck's Depression Inventory
Time Frame: Day 1

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
Epworth Sleepiness Scale
Time Frame: Day 1
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
Hamilton Anxiety Rating Scale (HAM-A)
Time Frame: Day 1
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
Patient Health Questionnaire-9
Time Frame: Day 1
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
Pittsburgh Sleep Quality Index
Time Frame: Day 1
PSQI was designed to evaluate overall sleep quality. A total score of "5" or greater is indicative of poor sleep quality.
Day 1
The Snaith-Hamilton Pleasure Scale (SHAPS)
Time Frame: Day 1
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
Tremor Disability Questionnaire
Time Frame: Day 1
Assesses a valid index of tremor-induced disability
Day 1
Tremor Embarrassment Assessment (TEA)
Time Frame: Day 1
TEA is a tool to quantitatively assess the level of embarrassment experienced due to one's tremor.
Day 1

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

University of Texas Southwestern Medical Center

Collaborators

Yale University
National Institute of Neurological Disorders and Stroke (NINDS)
Purdue University

Investigators

  • Study Director: Nora C Hernandez, M.D., UTSW Medical Center
  • Study Director: Allison Powell, BA, UTSW Medical Center

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

July 2, 2020

Primary Completion (Actual)

December 20, 2022

Study Completion (Actual)

July 19, 2023

Study Registration Dates

First Submitted

September 29, 2020

First Submitted That Met QC Criteria

September 29, 2020

First Posted (Actual)

October 6, 2020

Study Record Updates

Last Update Posted (Actual)

September 21, 2023

Last Update Submitted That Met QC Criteria

September 18, 2023

Last Verified

September 1, 2023

More Information

Terms related to this study

Additional Relevant MeSH Terms

Other Study ID Numbers

  • STU-2020-0563
  • R01NS094607 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

YES

IPD Plan Description

We are committed to making the resources of this study widely available not only to scientists studying ET but to those studying other neurological and neurodegenerative diseases as well, and especially to those who are studying PD. Thus, sharing data generated by this project is an important part of our proposed activities and will be carried out in a number of different ways. Our Data Sharing plan will adhere to the general principles outlined in the NIH Data Sharing Policy and Implementation Guidance.

The aims of the present proposal not only include clinical data but also data from measurement of harmane in blood and brain tissue samples. Data/tissue will be shared for all study participants that have consented to data sharing. Participants who did not give consent for data sharing will be excluded.

IPD Sharing Time Frame

Data will become available after the recruitment is complete and the biological samples have been analyzed.

IPD Sharing Access Criteria

The results and conclusions of our analysis will be shared at global scientific meetings and in the scientific literature (during publication in peer-reviewed journals). An additional mechanism of sharing data will be in the form of supplements to the additional data, which, for most journals, is on-line.

The data will be entered into SPSS data files. Original data files for individual runs will be shared with colleagues who possess the means and knowledge to utilize them, under collaborative agreement. To strengthen data confidentiality and safeguard the privacy of study participants, we will make data available to approved researchers under a data-sharing agreement that provides for (1) a commitment to using the data only for research purposes and not to identify any individual participant; (2) a commitment to securing the data using appropriate computer technology and (3) a commitment to destroying or returning the data after analyses are completed.

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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