Regional Brain Glucose Hypometabolism in OIF Veterans with mTBI

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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 Alzheimers Research Professor,
• Department of Psychiatry Behavioral Sciences
• University of Washington School of Medicine

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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?

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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.

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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)

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Neurocognitive Assessments

• Alzheimers 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

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Neurologic Assessments

• Neurologic exam
• Unified Parkinsons Disease Rating Scale
• Brief Smell Identification Test

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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)

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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)

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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 blast
• Protective equipment
• Secondary, tertiary TBI
• Immediate symptoms

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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

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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
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TBI Symptom Questionnaire
endorsing moderate-severe symptoms (N 12)
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
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QCuBE Data (N12)
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
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Range of Blast Forces
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Performance on Standard Neuropsychological
Assessments in mTBI subjects (N12)
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Penn Computerized Neurocognitive Battery Accuracy
Scores (N12)
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Penn Computerized Neurocognitive Battery Speed
Scores (N12)
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FDG PET and MRI

• Standard brain FDG PET imaging
• 10 mCi F-18FDG
• 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

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Minoshima, et al. J Nucl Med 1995
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Composite Z-Score Map of Brain Glucose
Hypometabolism in mTBI Subjects (N12) Compared
to Community Volunteers (N12)
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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

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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.

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Future Plans

• MRI analysis pending
• Diffusion tensor imaging
• Cross-relaxation imaging
• Default state BOLD fMRI
• CSF biomarker measurements pending
• Normative sample of gt150 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

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CSF Biomarkers

• Total tau, phospho-tau181
• A?42
• neurofilament low molecular mass protein (NFL)
• Brain-derived neurotrophic factor (BDNF)
• F2-isoprostanes
• Interleukin-8
• Beta2-microglobulin
• ? Acute markers spectrin degradation products,
  S100?, neprolysin

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Image processing and olfactory tract localization
Fiber Tracking
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Winner Society of Nuclear Medicine Correlative
Imaging Council (Walter Wolf) Award