1. Bennet I. Omalu, M.D., M.P.H. Forensic Pathologist/ Neuropathologist
THE FORENSIC NEUROPATHOLOGY OF BLUNT FORCE TRAUMA OF THE BRAIN Part 5: Diffuse Traumatic Brain Injury
Bennet I. Omalu, M.D., M.P.H.
Forensic Pathologist/ Neuropathologist

2. DIFFUSE TRAUMATIC BRAIN INJURY
The sine qua non of Diffuse Traumatic Brain Injury is Diffuse Traumatic Axonal Injury
Typically associated with diffuse inertial biomechanical loading and acceleration-deceleration shearing forces
Axonal injury is not localized to a single region of the brain, it is diffusely spread
Para-sagittal structures of the brain are most vulnerable especially the splenium of the corpus callosum
Diffuse Traumatic Axonal Injury is associated with gliding contusions
Note that axonal injury may be associated with non-traumatic causes like viral encephalitis, hypoxic injury and toxic encephalopathies, traumatic axonal injury is solely caused by trauma

3. DIFFUSE TRAUMATIC BRAIN INJURY
There are three neuropathologic grades of diffuse traumatic axonal injury:
Adams Grade 1 DAI
Diffuse cytotoxic edema, + APP immunohistochemistry
Adams Grade 2 DAI
Diffuse cytotoxic edema, petechial/ecchymotic hemorrhages in corpus callosum, + APP
Adams Grade 3 DAI
Diffuse cytotoxic edema, petechial/ ecchymotic hemorrhages in corpus callosum and dorso-lateral brainstem, + APP. Typically associated with loss of consciousness at the scene

4. PATHOLOGIC DIAGNOSIS OF DIFFUSE AXONAL INJURY
Following gross grading of DAI, tissue immuno-histochemistry must be performed using antibodies for Amyloid Precursor Protein [APP]
Amyloid Precursor Protein [APP]
A single-membrane spanning protein found in cell membranes and membranous organelles of every cell
Involved in diverse metabolic and regulatory cell pathways including cell adhesion and inter-cellular signaling
Encoded by APP gene on Chromosome 21
Parent compound of Beta-Amyloid peptide of Alzheimer’s Disease
Synthesized in the perikaryon
Fast antero-grade and retro-grade axonal transport by microtubules [ mm/day]
Without axonal injury APP is not detected by tissue immunohistochemistery

5. PATHOLOGIC DIAGNOSIS OF DIFFUSE AXONAL INJURY
Amyloid Precursor Protein [APP], cont’d
Following axonal injury and disruption of the micro-tubule cytoskeleton, APP accumulates both proximally and distally to point of axonal injury
It takes APP 2 – 3 hours post injury to accumulate sufficiently to be detected
This can shorten to 1 hour with antigen retrieval methods
APP has been observed up to 99 days post injury [3 months]
APP associated with diffuse hypoxic-ischemic injury shows a geographic pattern of immunopositivity
Trauma-induced DAI exhibits a diffuse focal pattern of APP+
Using silver impregnation and H&E stains, axonal injury can be identified after 15 hours of injury, axonal spheroids of Cajal, axonal viscosities and swellings may be seen
APP immuno-histochemistry is an important tool in medico-legal cases

6. DAI AND APP *
Adams Grade 2 DAI with corpus callosal hemorrhages and a small gliding contusion [*]

7. Axonal Spheroids and Varicosities
DAI AND APP
APP IMMUNOSTAIN
H&E
Axonal Spheroids and Varicosities

8. OTHER TYPES OF DIFFUSE BRAIN INJURY
DIFFUSE VASCULAR INJURY
Presents immediately after trauma, usually fatal
Brain exhibits only peri-vascular petechial and micro-hemorrhages in lobar cortical white matter
DIFFUSE CEREBRAL FAT EMBOLISM
Associated with fractures of long bones with surgical fixation/manipulation
Associated with extensive soft tissue and crush injuries
Presents 2 to 3 days after trauma
Manifests as diffuse cortical white matter petechial perivascular hemorrhages
Fat stains show intra-luminal fat globules in penetrating parenchymal vessels
Peri-vascular rarefaction and demyelination may follow