Alzforum thanks Sam Gandy, Soong Ho Kim, and Effie Mitsis at Mount Sinai School of Medicine for preparing this meeting summary, edited by Tom Fagan.
There is now convincing evidence that traumatic brain injury can lead to pathologies, including deposition of amyloid-β, that are akin to those seen in certain neurodegenerative disorders. But what are the underlying molecular and cellular events that precipitate such pathology? This was one of the topics discussed at Clinical and Molecular Biology of Acute and Chronic Traumatic Encephalopathies, a Keystone symposium held 26 February-2 March 2012.
Stephen Ahlers, Naval Medical Research Center, Silver Spring, Maryland, discussed blast-induced brain neurotrauma (BINT) in military personnel and in an animal model of acute or repeated exposure to trauma, which simulates the multiple exposures of military personnel deployed to war zones (i.e., Iraq and Afghanistan). Ahlers (see slides) noted overlap between PTSD and neurotrauma, and the relationship of BINT to chronic traumatic encephalopathy (CTE) and Alzheimer’s disease. He focused on mild TBI, considered to be the most pervasive form of brain injury in the military, indicating that the greatest challenges currently in TBI research are in identifying whether mild BINT is similar to classic types of concussion, where the borderline between BINT and PTSD lies, and whether BINT is a new problem entirely, since previously the symptoms associated with artillery battles were considered to be PTSD rather than organic. Ahlers discussed the findings of the Breacher Study, which was conducted in instructors who are exposed to blast on multiple occasions, and students, who are not exposed to blast as frequently as are instructors. Breachers are military or civilian personnel who are trained to use explosives to blast through buildings or walls, and are thus exposed to multiple blast and are at risk for BINT. The study found no effects in students, but instructors exhibited signs of cognitive impairment and showed changes on neuroimaging. The take-home message is that the number of blast exposures over time is important, and that future experiments need to be developed to characterize the impairment from blast. Regarding animal studies, the goal is to elucidate the natural history of repeated exposure to blast overpressure (BOP) on brain function and physiology. Ahlers characterized the BOP threshold for disruption, identified the importance of orientation of the animal to the BOP wave, and reported on pathologic outcomes, including Aβ changes in brain, and the effect of BOP on learning and memory. In a paper in Frontiers in Neurology (see Ahlers et al., 2012), Ahlers and colleagues classify two types of consequences of blast brain injury and associated parameters (blast frequency, intensity, physical forces, clinical manifestations, onset, radiology/pathology, and biomarkers).
Nicholas Tustison, also at UVA, emphasized that TBI is a complex disease process involving mechanical disruption of brain tissue and activation of secondary injury cascades, which culminate in widespread axonal disconnection, neuronal cell death, and loss of function. Diffusion tensor imaging affords quantification of microstructural white matter injury, while high-resolution T1-weighted sequences allow for computation of cortical thickness and density maps that could help characterize TBI, said Tustison (see slides). Although advances in equipment and sequence design have yielded dramatic improvements in image quality in recent years, image analysis is critical to accurately detecting subtle alterations that may reflect clinically significant disease. Beginning with a description of white matter changes in TBI, followed by a discussion of specific metrics used in DTI analysis (fractional anisotropy and mean diffusivity), and the types of DTI analytic possibilities (i.e., manual and automated regions of interest, tractography and tract-based spatial statistics [TBSS], and voxel-based morphometry), Tustison asked, What is the best method for identifying effects of blast TBI in the military? In sum, he reviewed current approaches for the computational analysis of DTI and cortical maps in TBI, and by presenting work conducted in their lab at UVA, discussed how to optimize their use.
Meeting co-organizer Samuel Gandy, Mount Sinai Medical Center, New York, discussed the Alzheimer’s "nexus," focusing on three main questions:
1. Can our understanding of late-onset AD pathology inform our understanding of post-trauma AD?
2. Can post-traumatic AD be distinguished from AD without a history of TBI?
3. How can our understanding of AD be applied to experimental therapeutics for post-traumatic AD?
Gandy reviewed recent findings from transgenic mouse studies and clinical trials that indicate pre- and post-amyloid vaccination in mice and passive immunotherapy in humans did not lead to cognitive improvement, despite a lowering of amyloid burden (see slides). These findings raise the question of the "right target" in AD, and whether treating a single target will ever be sufficient, said Gandy. He then turned to the role of TBI in neurodegeneration, and potential pathways that may be involved. He emphasized the role of signal transduction in Aβ regulation, and noted the value of mGluR antagonists as a potential treatment for neurodegenerative dementia. He reported that mGluR signaling may be involved in regulating Aβ42 metabolism at the synapse. He showed that mGluR2/3 antagonists lower levels of various Aβ conformers in the hippocampus and cortex, and that they correct Aβ-induced contextual memory deficits, improve novel object recognition, and decrease anxiety in APP transgenic mice. Gandy revealed that BCI-632, a neurogenic compound, improves outcomes following experimental TBI. He suggested that mGluR2/3 antagonists and pro-neurogenic/pro-autophagic compounds may be useful in preventing or treating late neurodegenerative sequelae of TBI. Gandy then questioned the role of ApoE4, noting that an important issue for clarification is whether ApoE4 exacerbates tau pathology independently of effects on Aβ42. Gandy wondered, for example, if bapineuzumab infusion should be tested during acute post-TBI phase, and if ApoE4 alters the structure and/or conformation of both plaques and tangles visualized using luminescent conjugated oligothiophenes.
Christopher Giza, University of California, Los Angeles, described two potential ways to treat developmental TBI—a ketone diet and D-cycloserine. The ketogenic diet reduced lesion volume in immature rats after controlled cortical impact (CCI), a model of TBI that causes cellular energy crisis due to disrupted mitochondrial function. CCI induces upregulation of monocarboxylate transporter 2, a transporter of ketone bodies, which helped the animals to utilize more ketones in the diet. D-cycloserine, a partial agonist for NMDA receptors, restored hippocampal NMDA NR2A subunits in P19 rat pups that were diminished by fluid percussion injury (FPI). FPI reduced NMDAR postsynaptic currents, which led to impaired memory tasks in these animals. This decreased network activation was also observed in children who suffered TBI during a spatial working memory task. D-cycloserine also activated CaMKII levels, and improved spatial and object recognition memory in the P19 pups. Lastly, using a repeat closed head injury model in juvenile P35 rats, Giza showed that a second injury occurring 24 hours after the first (during the period of post-TBI hypometabolism) actually worsened the metabolic crisis, while a second injury sustained five days after the first (at a time of recovery from hypometabolism) did not show additive/worsened metabolic consequences (see slides).
- Keystone: Traumatic Brain Injury—Epidemiology and Characteristics
- Keystone: Sports-Related Injury and Chronic Traumatic Encephalopathy
- Keystone: TBI—Learning From Markers, Models, and Diseases
- Keystone: Diagnosis and Model Treatments for Traumatic Brain Injury
- Ahlers ST, Vasserman-Stokes E, Shaughness MC, Hall AA, Shear DA, Chavko M, McCarron RM, Stone JR. Assessment of the effects of acute and repeated exposure to blast overpressure in rodents: toward a greater understanding of blast and the potential ramifications for injury in humans exposed to blast. Front Neurol. 2012;3:32. PubMed.
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