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Contributions of mTBI to Neurodegeneration Due to CTE and Alzheimer's Disease

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ClinicalTrials.gov Identifier: NCT04124029
Recruitment Status : Not yet recruiting
First Posted : October 11, 2019
Last Update Posted : October 11, 2019
Sponsor:
Information provided by (Responsible Party):
Katherine Turk, VA Boston Healthcare System

Brief Summary:
This is a research study that aims to examine whether veterans with mild Traumatic Brain Injuries are at risk for dementia by studying their memory, brain wave activity, brain structure and proteins that can be elevated after brain injury and in dementia.

Condition or disease Intervention/treatment
Mild Traumatic Brain Injury Moderate Traumatic Brain Injury Mild Cognitive Impairment Device: No Intervention is used for this study but all subjects will be asked to complete EEG testing and an MRI scan. Procedure: No intervention is used for this study but all subjects will be asked to complete a venous blood draw procedure and a lumbar puncture procedure.

Detailed Description:

The specific aim of this project is to examine whether veterans with mild Traumatic Brain Injuries are at risk for dementia by studying their memory, brain wave activity, brain structure and proteins that can be elevated after brain injury and in dementia.

This study will recruit patients with a history of mild-moderate traumatic brain injury, mild cognitive impairment, as well as healthy controls in order to better understand how single or repetitive mild Traumatic brain injuries may contribute to the development of dementia. It will be prospective in nature. Participants will be asked to complete a series of 3 study sessions. During the first study session, each subject will be asked to complete a neuropsychological assessment. If the subject's testing scores fall under the study criteria, they will also be asked to complete a computer task. In the second study session, we will measure the subjects brain waves using an EEG while they complete a computer task. During the computer task the subjects will be asked to study a list of words and we will test the subjects on their memory for those words. During the final study session, we will ask subjects to complete: (1) an MRI, (2) a standard blood draw procedure, and (3) a lumbar puncture procedure.

Clinical Implications: These studies will provide a better understanding of which individuals with Traumatic Brain Injury will develop dementia, and how many years in the future dementia may occur.


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Study Type : Observational
Estimated Enrollment : 800 participants
Observational Model: Case-Control
Time Perspective: Prospective
Official Title: Contributions of Mild Traumatic Brain Injury to Neurodegeneration Due to Chronic Traumatic Encephalopathy and Alzheimer's Disease
Estimated Study Start Date : March 31, 2020
Estimated Primary Completion Date : March 31, 2025
Estimated Study Completion Date : March 31, 2025


Group/Cohort Intervention/treatment
Younger mild Traumatic Brain Injury
mTBI subjects aged 30-59 yo will be recruited who have a physician diagnosis of 1 or more mTBI episodes without concomitant moderate or severe TBI diagnosis (loss of consciousness greater than 30 minutes, posttraumatic amnesia greater than 24 hours, or altered mental status greater than 24 hours). mTBI subjects must pass effort measures on the TOMM and have intact color vision and visual acuity of 20/30 or better in order to be included in the study.
Device: No Intervention is used for this study but all subjects will be asked to complete EEG testing and an MRI scan.
No intervention will be used.

Procedure: No intervention is used for this study but all subjects will be asked to complete a venous blood draw procedure and a lumbar puncture procedure.
No intervention will be used.

Older mild Traumatic Brain Injury
mTBI subjects aged 60- 90 yo will be recruited who have a physician diagnosis of 1 or more mTBI episodes without concomitant moderate or severe TBI diagnosis (loss of consciousness greater than 30 minutes, posttraumatic amnesia greater than 24 hours, or altered mental status greater than 24 hours). mTBI subjects must pass effort measures on the TOMM and have intact color vision and visual acuity of 20/30 or better in order to be included in the study.
Device: No Intervention is used for this study but all subjects will be asked to complete EEG testing and an MRI scan.
No intervention will be used.

Procedure: No intervention is used for this study but all subjects will be asked to complete a venous blood draw procedure and a lumbar puncture procedure.
No intervention will be used.

moderate Traumatic Brain Injury
TBI control subjects, age-, education- and sex-matched with mTBI subjects (aged 30-90) will be recruited who have a physician diagnosis of 1 or more moderate TBI episodes (loss of consciousness greater than 30 minutes, posttraumatic amnesia greater than 24 hours, or altered mental status greater than 24 hours). Moderate TBI subjects must pass effort measures on the TOMM and have intact color vision and visual acuity of 20/30 or better in order to be included in the study.
Device: No Intervention is used for this study but all subjects will be asked to complete EEG testing and an MRI scan.
No intervention will be used.

Procedure: No intervention is used for this study but all subjects will be asked to complete a venous blood draw procedure and a lumbar puncture procedure.
No intervention will be used.

Mild Cognitive Impairment
MCI control subjects, age-, education- and sex-matched with older mTBI subjects (aged 60-90) will be recruited if they meet diagnostic criteria for MCI (without a history of TBI) based on the judgement of a behavioral neurologist following the 2011 MCI criteria. Specifically, subjects will test in the impaired range on one or more cognitive domains on neuropsychological testing and will not have impairments in function (i.e. will not meet diagnostic criteria for dementia). MCI subjects will be matched for their MoCA score with older mTBI subjects. Of note, subjects with MCI may or may not meet diagnostic criteria for MCI due to AD. The intent of this control group is to recruit a broad range of MCI subjects without TBI as controls for subjects with cognitive impairment who have a history of mTBI.
Device: No Intervention is used for this study but all subjects will be asked to complete EEG testing and an MRI scan.
No intervention will be used.

Procedure: No intervention is used for this study but all subjects will be asked to complete a venous blood draw procedure and a lumbar puncture procedure.
No intervention will be used.

Younger Healthy Controls
Cognitively normal control subjects, age-, education- and sex-matched with younger mTBI subjects, but lacking and mTBI history. All subjects must be within 1 standard deviation of normal on all neuropsychologic testing in order to be enrolled.
Device: No Intervention is used for this study but all subjects will be asked to complete EEG testing and an MRI scan.
No intervention will be used.

Procedure: No intervention is used for this study but all subjects will be asked to complete a venous blood draw procedure and a lumbar puncture procedure.
No intervention will be used.

Older Healthy Controls
Cognitively normal control subjects, age-, education- and sex-matched with older mTBI subjects, but lacking and mTBI history. All subjects must be within 1 standard deviation of normal on all neuropsychologic testing in order to be enrolled.
Device: No Intervention is used for this study but all subjects will be asked to complete EEG testing and an MRI scan.
No intervention will be used.

Procedure: No intervention is used for this study but all subjects will be asked to complete a venous blood draw procedure and a lumbar puncture procedure.
No intervention will be used.




Primary Outcome Measures :
  1. To better understand the contribution of mild Traumatic Brain Injury (mTBI) to neurodegeneration with the intent of detecting early behavioral, physiologic, anatomic, and protein evidence of neurodegeneration due to AD and CTE [ Time Frame: 5 years ]
    The work proposed will allow exploration of the relationships between behavioral, ERP, MRI, and CSF measures at a variety of points along the disease continuum and will allow for future longitudinal studies in this cohort


Secondary Outcome Measures :
  1. Recognition Memory [ Time Frame: 5 Years ]
    Recognition memory will be examined using behavioral estimation techniques to see if recognition memory will be worse in patients with an increased number of mild TBI and with increased time since mild TBI.

  2. EEG peak amplitude and latency [ Time Frame: 5 years ]
    We are trying to see if electrophysiological correlates of recollection will be decreased in patients with a greater number of mTBI episodes and those with increased time since mTBI episodes; and if the electrophysiological correlates of familiarity will be decreased in patients with dementia who have imaging and CSF biomarkers consistent with neurodegeneration.

  3. Cortical, quantitative MRI volume measurements [ Time Frame: 5 years ]
    We are trying to see if global cortical atrophy, hippocampal and extrahippocampal MTL atrophy will be increased in patients with a greater number of mTBI episodes and those with increased time since mTBI episodes.

  4. CSF Proteinopathy [ Time Frame: 5 years ]
    We are trying to see if a CSF proteinopathy will be present in patients with a greater number of mTBI episodes and those with increased time since mTBI episodes.


Biospecimen Retention:   Samples With DNA
We will be obtaining whole blood samples and cerebrospinal fluid samples from subjects. Whole blood samples will be used to test for the e4 variant of the APOE gene. Cerebrospinal fluid will be extracted to examine the proteinopathy associated with each groups.


Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   30 Years to 90 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Sampling Method:   Non-Probability Sample
Study Population
Patients from the memory disorders clinic will be recruited if they have a (1) history of mild TBI, (2) history of moderate TBI, or (3) mild cognitive impairment or. In addition, we will be recruiting healthy controls that meet satisfy the inclusion and exclusion criteria of the study.
Criteria

Inclusion Criteria:

  • Age 30-90, right handed, intact color vision, visual acuity of 20/30 or better, and will pass effort measures on the TOMM. Patients must have intact decision making capacity. Patients must have no contraindications to lumbar puncture including being on a blood thinner, aspirin or Plavix, have no space occupying lesion on magnetic resonance imaging (MRI), an International Normalized Ratio (INR) value < 1.4 and platelet count >50,000, and no epidural infection or overlying cellulitis over the lumbar spine. PTSD will be accounted for as a potential confounder and its presence will be included as a covariate in all analyses. We will recruit all subjects without regard to gender, race, ethnicity, socioeconomic and other factors to allow results of this research to yield the greatest generalizability.

mild TBI Subjects: Subjects will be recruited who have a physician diagnosis of 1 or more mTBI episodes without concomitant moderate or severe TBI diagnosis (loss of consciousness greater than 30 minutes, posttraumatic amnesia greater than 24 hours, or altered mental status greater than 24 hours).

Moderate TBI Subjects: Subjects will be recruited who have a physician diagnosis of 1 or more moderate TBI episodes (loss of consciousness greater than 30 minutes, posttraumatic amnesia greater than 24 hours, or altered mental status greater than 24 hours).

MCI Subjects: Subjects will be recruited that meet diagnostic criteria for MCI (without a history of TBI) based on the judgement of a behavioral neurologist following the 2011 MCI criteria. Specifically, subjects will test in the impaired range on one or more cognitive domains on neuropsychological testing and will not have impairments in function (i.e. will not meet diagnostic criteria for dementia). MCI subjects will be matched for their MoCA score with OTBI subjects. Of note, subjects with MCI may or may not meet diagnostic criteria for MCI due to AD (117). The intent of this control group is to recruit a broad range of MCI subjects without TBI as controls for subjects with cognitive impairment who have a history of mTBI.

Healthy Controls: Cognitively normal control subjects, age-, education- and sex-matched with mild TBI subjects, but lacking and TBI history. All subjects must be within 1 standard deviation of normal on all neuropsychologic testing in order to be enrolled.

Exclusion Criteria:

  • If their primary language is not English, are unable to understand the informed consent process, or have a clinically significant problem with any of the following conditions:

    1. a history of mild TBI within 1 year of study, (2) suicidal or homicidal ideation requiring intervention, (3) schizophrenia, (4) bipolar disorder, (5) active alcohol or drug abuse, (6) clinically significant neurological disease other than those stated in the inclusion criteria, (7) impaired decision making ability. Patients will be excluded if there are contraindications to MRI including implants, shrapnel, aneurysm clips, pacemaker, or pregnancy. In addition, non-TBI subjects must not have had an TBI. No contraindication to lumbar puncture or blood draw including being on a blood thinner, aspirin or Plavix, and has no space occupying lesion on MRI that makes lumbar puncture contraindicated.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04124029


Contacts
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Contact: Katherine Turk, MD 857-364-2139 kturk@bu.edu
Contact: Kylie Schiloski, BA 857-364-2142 kaschilo@bu.edu

Locations
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United States, Massachusetts
VA Boston Healthcare System Not yet recruiting
Jamaica Plain, Massachusetts, United States, 02130
Contact: Katherine Turk, MD    857-364-2139    kturk@bu.edu   
Contact: Kylie Schiloski, BA    857-364-2142    kaschilo@bu.edu   
Sponsors and Collaborators
VA Boston Healthcare System
Investigators
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Principal Investigator: Katherin Turk, MD VA BU

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Responsible Party: Katherine Turk, Neurologist, VA Boston Healthcare System
ClinicalTrials.gov Identifier: NCT04124029     History of Changes
Other Study ID Numbers: I01-CX-19-008-CDA
First Posted: October 11, 2019    Key Record Dates
Last Update Posted: October 11, 2019
Last Verified: October 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: De-identified data will be shared with other investigators upon written request.

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Katherine Turk, VA Boston Healthcare System:
Mild Traumatic Brain Injury
Moderate Traumatic Brain Injury
Alzheimer's Disease
Chronic Traumatic Encephalopathy
Neurodegeneration
Additional relevant MeSH terms:
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Brain Injuries
Brain Injuries, Traumatic
Brain Concussion
Chronic Traumatic Encephalopathy
Wounds and Injuries
Brain Diseases
Craniocerebral Trauma
Trauma, Nervous System
Head Injuries, Closed
Wounds, Nonpenetrating
Brain Injury, Chronic
Alzheimer Disease
Nerve Degeneration
Cognitive Dysfunction
Dementia
Central Nervous System Diseases
Nervous System Diseases
Tauopathies
Neurodegenerative Diseases
Neurocognitive Disorders
Mental Disorders
Cognition Disorders
Pathologic Processes