Long-Term Effects of Repetitive, Low-Level Blast Exposure on Special Operations Forces Service Members (ReBlast)

Pilot Study of Long-Term Effects of Repetitive, Low-Level Blast Exposure (RLLBE) on Special Operations Forces (SOF) Service Members

This is a pilot study to identify biomarkers that individually, and in combination, demonstrate the greatest sensitivity to repetitive, low-level blast exposure (RLLBE) neurotrauma in Special Operations Forces (SOF) personnel. The proposed cross-sectional, multimodal study will elucidate the potential effects of long-term RLLBE by comparing biomarkers across subjects.

Study Overview

• Status: Completed
• Conditions: Traumatic Brain Injury; Blast Injuries
• Intervention / Treatment: Diagnostic test: 3T Connectome MRI; Diagnostic test: 7 Tesla MRI; Diagnostic test: TSPO PET; Diagnostic test: Tau PET; Diagnostic test: Cognitive and Behavioral Assessments; Diagnostic test: Blood Biomarkers

Detailed Description

The proposal includes a comprehensive battery of assessments characterized by high-field neuroimaging, proteomics, and experimental cognitive and neurobehavioral evaluations, which will be implemented alongside standardized clinical diagnostic tools. The results will inform the design of a larger trial to validate the diagnostic utility of these biomarkers as well as their ability to predict RLLBE-related clinical outcomes. A secondary aim will be to define the underlying mechanisms, risk and resilience factors, and clinical phenotypes associated with RLLBE.

Biomarkers assessed over the course of a two-day evaluation will include:

1. 3 Tesla Connectome MRI to detect structural disruption of brain networks
2. 7 Tesla MRI to detect functional disruption of brain networks
3. Translocator protein (TSPO) PET - ligand [11C]-PBR28 to detect neuroinflammation
4. Tau PET - ligand [18F]-MK6240 to detect tau deposition
5. Neurocognitive assessments to detect signs of cognitive/behavioral dysfunction
6. Self-report indicators of cognitive/behavioral dysfunction
7. Blood biomarkers to detect evidence of blast injury using proteomics and metabolomics

We hypothesize that a multimodal assessment using Connectome MRI, 7 Tesla MRI, TSPO PET, Tau PET, cognitive/behavioral tests, proteomics and metabolomics will identify biomarkers of RLLBE-related brain injury.

• Study Type: Observational
• Enrollment (Actual): 30

Contacts and Locations

Study Locations

• United States
  • Massachusetts
    • Boston, Massachusetts, United States, 02114
      • Massachusetts General Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 25 years to 45 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Male

• Sampling Method: Non-Probability Sample

Study Population

U.S. Special Operations Forces personnel

Description

Inclusion Criteria:

1. Adults aged 25-45 years of age
2. Males, regardless of race or ethnicity
3. Active duty Special Operation Forces
4. History of combat deployment confirmed by Veterans Affairs (VA) or Department of Defense (DOD) records (defined as: while serving in the U.S. military, individual was deployed to a region of conflict)
5. History of combat exposure during any deployment as measured by endorsement of any item on the Combat Exposure Scale (CES)

Exclusion Criteria:

1. History of moderate or severe traumatic brain injury (TBI) (using the VA/DOD definition: initial Glasgow Coma Scale score < 13, coma duration > ½ hr, post-traumatic amnesia duration > 24 hr, or abnormal structural brain imaging)
2. History of major neurologic disorder such as stroke or spinal cord injury resulting in a significant decrement in functional status or loss of independent living capacity
3. Untreated or unstable severe psychiatric condition (e.g., schizophrenia or bipolar disorder) that is likely to impact study participation or ability to complete study procedures
4. Current severe medical condition (excluding currently diagnosed mild TBI or concussion) that requires long-term treatments (e.g., cancer, diabetes mellitus, human immunodeficiency virus, autoimmune disorders)
5. Any cardiac, respiratory, or other medical condition that may affect cerebral metabolism
6. Benzodiazepines other than lorazepam, desmethyldiazepam and oxazepam within past month

7. MRI contraindications

   1. Metal in the body that would make an MRI scan unsafe, such as pacemakers, medication pumps, aneurysm clips, metallic prostheses (including metal pins and rods, heart valves or cochlear implants), shrapnel fragments, permanent eye liner or small metal fragments in the eye
   2. Pre-existing medical conditions including a likelihood of developing seizures or claustrophobic reactions, and any greater than normal potential for cardiac arrest
   3. Inability to lie supine for up to 2 hours in the MRI scanner, as assessed by physical examination and medical history (e.g., back pain, arthritis)
   4. > 300 lbs (weight limit of the MRI table)
8. Prior radiation exposure of ≥ 50 mSv over the past 12 months, in the context of research, as determined by review of DOD medical records (e.g., prior imaging studies) and self-report
9. Any condition which, in the opinion of the Principal Investigator, may cause undue risk to the subject
10. Other: Any condition or characteristic that in the judgment of the Principal Investigator would create a logistical or safety contraindication to enrollment (e.g., shoulder width greater than the bore of the MRI or PET/MRI machines)

Study Plan

How is the study designed?

Number of groups / cohorts

1

Cohorts and Interventions

Group / Cohort

Intervention / Treatment

Special Operations Forces (SOF) Personnel; n=30 SOF Personnel

Diagnostic test: 3T Connectome MRI; MRI scan of structural connectivity; Diagnostic test: 7 Tesla MRI; MRI scan of functional connectivity; Diagnostic test: TSPO PET; PET scan of neuroinflammation; Diagnostic test: Tau PET; PET scan of tau deposition; Diagnostic test: Cognitive and Behavioral Assessments; Assessments of memory, attention, complex reasoning, mood and other cognitive/behavioral domains; Diagnostic test: Blood Biomarkers; Blood-based assessments of proteomic and metabolic biomarkers of brain injury

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Diffusion MRI structural connectivity	measured by white matter tractography	Day 1
fMRI resting state functional connectivity	measured by default mode network connectivity	Day 2
PET Neuroinflammation	measured by standardized uptake value ratio of TSPO ligand [11C]PBR28	Day 1
PET Tau deposition	measured by standardized uptake value ratio of [18F]MK6240	Day 2
Neurofilament Light Chain	measured by serum concentration of neurofilament light chain	Day 1, after 6-8 hour fasting
Cognitive Function	measured by the Trail Making Test	Day 1
Behavioral symptoms	measured by the Neurobehavioral Symptom Inventory	Day 2
Physical symptoms	measured by the Neurobehavioral Symptom Inventory	Day 2

Collaborators and Investigators

• Sponsor: Massachusetts General Hospital

Study record dates

Study Major Dates

• Study Start (Actual): July 1, 2021
• Primary Completion (Actual): February 28, 2023
• Study Completion (Actual): February 28, 2023

Study Registration Dates

• First Submitted: December 9, 2021
• First Submitted That Met QC Criteria: December 20, 2021
• First Posted (Actual): January 10, 2022

Study Record Updates

• Last Update Posted (Actual): April 4, 2023
• Last Update Submitted That Met QC Criteria: April 3, 2023
• Last Verified: April 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Craniocerebral Trauma; Trauma, Nervous System; Barotrauma; Brain Injuries; Wounds and Injuries; Brain Injuries, Traumatic; Blast Injuries
• Other Study ID Numbers: 2020P002695

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No