Regional Brain Glucose Hypometabolism in OIF Veterans with mTBI

Elaine R. Peskind, MD

Co-Director, VISN 20 Mental Illness Research, Education, and Clinical Center (MIRECC)

Friends of Alzheimer’s Research Professor,Department of Psychiatry & Behavioral Sciences

University of Washington School of Medicine

The Controversy

• Controversy about etiology, course, and treatment of persistent somatic, cognitive, and behavioral symptoms in OIF/OEF veterans following mTBI.

• Do these chronic symptoms reflect persistent structural or functional brain damage?

The Controversy (continued)

• An epidemiological study in military personnel found that symptoms of chronic mTBI (except for headache) more correlated with PTSD and depression.

• However, many skilled clinicians are convinced that war combatants’ chronic symptoms of mTBI reflect real albeit subtle persistent brain damage.

Subjects

• 12 male OIF veterans with blast-induced mTBI

» Mean age 32.0 ± 8.5 years (range 24-49)

• 12 cognitively normal community volunteers

» Mean age 53.0 ± 4.6 years (range 49-56; 7M, 5F)

Neurocognitive Assessments

• Alzheimer’s Disease Research Center Uniform Dataset

• University of Pennsylvania Computerized Neurocognitive Battery

• Ruff 2 & 7 Selective Attention Test

• Controlled Word Association Test

• Sentence Repetition

• Wechsler Test of Adult Reading

• Test of Memory Malingering

Neurologic Assessments

• Neurologic exam

• Unified Parkinson’s Disease Rating Scale

• Brief Smell Identification Test

Behavioral Assessments

• Clinician Administered PTSD Scale (CAPS)

• PTSD Checklist – Military (PCL-M)

• Patient Health Questionnaire (PHQ)-9

• Alcohol Use Disorders Identification Test – Consumption (AUDIT-C)

• Pittsburgh Sleep Quality Index (PSQI)

• Neurobehavioral Symptom Inventory (NSI)

Quantification of Cumulative Blast Exposure (QCuBE)

• Numbers of exposures to blast

• Number of episodes of blast-concussion induced loss of consciousness (LOC)

• Date of first, last blast exposure

• History of non-blast head trauma (e.g., sports-related, motor vehicle accident)

Quantification of Cumulative Blast Exposure (QCuBE) - continued

• Intensive characterization of worst 5 exposures» Type of explosive device

» “Tamping” forces

» Distance from blast center

» Tactical details, e.g.:Open air vs. in building or vehicle, head/body position

relative to blastProtective equipmentSecondary, tertiary TBI

» Immediate symptoms

Recruitment/Retention Progress to Date

• 19 OIF veterans with mTBI consented

• 27 more recruited (in past month)

• 14 completed all study measures

• 2 undergoing study procedures

• 1 refused LP

• 1 failed neuropsych effort measures

mTBI Study: Subject Demographics (N = 12)

Mean ± SD Range

Age 32.0 ± 8.5 24-49

Education (yrs.) 13.8 ± 1.9 11-16

Combat Experiences Scale 12.9 ± 1.83 9-15

CAPS 56.67 ± 30.83 0-100

PCL-M 32.33 ± 18.04 5-59

PHQ-9 9.75 ± 8.53 0-25

AUDIT-C 5.58 ± 2.5 1-9

PSQI 9.09 ± 3.14 5-15

TBI Symptom Questionnaire

Ringing in ears 10 Sensitivity to light 4

Forgetfulness 9 Fatigue 4

Feeling anxious or tense 9 Poor coordination 4

Difficulty falling or staying asleep 8 Numbness on parts of body 4

Irritability 8 Loss of balance 3

Sensitivity to noise 8 Vision problems 3

Hearing difficulty 6 Getting into fights 3

Poor frustration tolerance 6 Apathy 3

Mood swings 6 Disinhibition 2

Headaches 6 Feeling dizzy 2

Feeling depressed or sad 6 Change in taste/smell 1

Slowed thinking 6 Slowness in speech 1

Poor concentration 6 Nausea 1

Difficulty making decisions 5 Loss/increased appetite 1

# endorsing moderate-severe symptoms (N = 12)

QCuBE Data (N=12)

Mean ± SD Range

Years since most recent blast 3.5 ± 1.2 2-5

# of blast-related LOCs while deployed 1.0 ± 1.35 0-4

All blasts while deployed to Iraq 13.0 ± 14.0 3-51

Received medical attention in field 2.4 ± 3.7 0-10

Total number of blasts without LOC 28.9 ± 35.4 4-100

# of blast-related LOCs while in military 1.0 ± 1.35 0-4

All military blasts 29.9 ± 35.9 5-102

All LOCs while in military (any cause) 1.5 ± 1.88 0-5

Other non-blast head trauma (# of incidents) 1.7 ± 2.0 0-5

# of times “knocked out” in entire life 1.75 ± 1.76 0-5

Range of Blast Forces

Performance on Standard Neuropsychological Assessments in

mTBI subjects (N=12)

04/19/23 Prazosin/MR 15

Penn Computerized Neurocognitive Battery Accuracy Scores (N=12)

04/19/23 Prazosin/MR 16

Penn Computerized Neurocognitive Battery Speed Scores (N=12)

04/19/23 Prazosin/MR 17

FDG PET and MRI

• Standard brain FDG PET imaging» 10 mCi [F-18]FDG» 3D Image acquisition (GE Advance scanner)

• T1-Weighted and Diffusion Tensor Imaging» 3T MR scanner (Achieva, Philips Medical Systems)» 8 channel sense head coil» 3D MPRAGE T1-weighted scans» Axial DTI of the whole brain, 32 gradient directions» Resting-state fMRI – for functional connectivity» Cross-relaxation imaging of demyelination» T2 FLAIR

Minoshima, et al. J Nucl Med 1995

Composite Z-Score Map of Brain Glucose Hypometabolism in mTBI Subjects (N=12)

Compared to Community Volunteers (N=12)

04/19/23 Prazosin/MR 21

04/19/23 Prazosin/MR 22

Conclusions

• Blast-exposed OIF veterans with chronic mTBI have persistent glucose hypometabolism in cerebellum, pons, thalamus, and medial temporal lobes years after blast exposure

• Cognitive and behavioral/emotional symptoms resemble the “cerebellar cognitive-affective syndrome”

Conclusions

• FDG-PET findings appear to be independent of the presence or absence of PTSD.

• These findings support the hypothesis that regional brain hypometabolism may provide a substrate for chronic mTBI symptoms in blast-exposed combat veterans.

Future Plans

• MRI analysis pending» Diffusion tensor imaging

» Cross-relaxation imaging

» Default state BOLD fMRI

• CSF biomarker measurements pending» Normative sample of >150 controls (age 21-50) already

collected

• Dept. of Defense grant submission

• Iraq deployed control groups: mTBI without PTSD, PTSD without mTBI, neither mTBI nor PTSD

• Longitudinal follow-up

CSF Biomarkers

• Total tau, phospho-tau181

• A42

• neurofilament low molecular mass protein (NFL)

• Brain-derived neurotrophic factor (BDNF)

• F2-isoprostanes

• Interleukin-8

• Beta2-microglobulin

• ? Acute markers: spectrin degradation products, S100, neprolysin

04/19/23 Prazosin/MR 28

Fiber Tracking

Image processing and olfactory tract localization

Winner: Society of Nuclear Medicine Correlative Imaging Council (Walter Wolf) Award