Contributions of mTBI to Neurodegeneration Due to Chronic Traumatic Encephalopathy (CTE) and Alzheimer's Disease (AD)

Sponsor

VA Office of Research and Development (U.S. Fed)

Overall Status

Recruiting

CT.gov ID

NCT04124029

Collaborator

VA Boston Healthcare System (U.S. Fed)

800

Enrollment

Location

Anticipated Duration (Months)

13.3

Patients Per Site Per Month

Study Details

Study Description

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	Phase
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, the investigators will measure the subjects brain waves using an EEG while they complete a computer task. During the computer task, subjects will be asked to study a list of words and the investigators will test the subjects on their memory for those words. During the final study session, the investigators will ask subjects to complete (1) an MRI scan, (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.

Study Design

Study Type:

Observational

Anticipated 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 Alzheimers Disease

Actual Study Start Date :

Jul 1, 2021

Anticipated Primary Completion Date :

Jun 30, 2026

Anticipated Study Completion Date :

Jun 30, 2026

Arms and Interventions

Arm	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 Test of Memory Malingering (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) 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 Montreal Cognitive Assessment (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.

Outcome Measures

Primary Outcome Measures

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 [5 years]
The work proposed will allow exploration of the relationships between behavioral, event-related potential (ERP), MRI, and cerebrospinal fluid (CSF) measures at a variety of points along the disease continuum and will allow for future longitudinal studies in this cohort

Secondary Outcome Measures

Recognition Memory [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.
EEG peak amplitude and latency [5 years]
The investigators 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.
Cortical, quantitative MRI volume measurements [5 years]
The investigators are trying to see if global cortical atrophy, hippocampal and extrahippocampal medial temporal lobe (MTL) atrophy will be increased in patients with a greater number of mTBI episodes and those with increased time since mTBI episodes.
CSF Proteinopathy [5 years]
The investigators 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.

Eligibility Criteria

Criteria

Ages Eligible for Study:

30 Years to 90 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Yes

Inclusion Criteria:

All Subjects:

Intact color vision
Visual acuity of 20/30 (or better)
Patients must 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
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

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
Mild TBI: Loss of consciousness greater than 30 minutes, posttraumatic amnesia greater than 24 hours, and/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
Moderate TBI: loss of consciousness greater than 30 minutes, posttraumatic amnesia greater than 24 hours, and 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
Subjects with MCI may or may not meet diagnostic criteria for MCI due to AD
MCI subjects will be matched for their MoCA score with older TBI subjects

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

The investigators will recruit all subjects without regard to gender, race, ethnicity, socioeconomic status, or other factors to allow results of this research to yield the greatest generalizability

Exclusion Criteria:

All Subjects:

If the primary language is not English
Are unable to understand the informed consent process
Have a clinically significant problem with any of the following conditions:
A history of TBI within 1 year of study
Suicidal or homicidal ideation requiring intervention
Schizophrenia
Bipolar disorder
Active alcohol or drug abuse
Clinically significant neurological disease other than those stated in the inclusion criteria
Impaired decision-making ability
Patients will be excluded if there are contraindications to MRI including:
Implants
Shrapnel
Aneurysm clips
Pacemaker
Pregnancy
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
No space occupying lesion on MRI that makes lumbar puncture contraindicated