Keystone: TBI—Learning From Markers, Models, and Diseases

Series - Keystone: Researchers Report on Traumatic Encephalopathy Meeting:

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.

Injury to the brain, even what might be considered mild, can have devastating consequences on brain physiology. But how can scientists probe how the brain responds to injury? At Clinical and Molecular Biology of Acute and Chronic Traumatic Encephalopathies, a Keystone symposium held 26 February-2 March 2012, researchers showed how they can use animal models, and both imaging and fluid markers, to get a better handle on the pathological changes evoked by brain injury.

Andrew Mayer, Mind Research Network, Albuquerque, New Mexico, asked if biomarkers might help map recovery from traumatic brain injury. He showed that the term “mild” to describe some types of TBI may be inadequate (see slides). He noted that there are many diffuse injury mechanisms, but the pathophysiology underlying mild TBI and how these injuries change as a function of time remain unclear. While DTI holds promise for in-vivo characterization of white matter pathology, said Mayer, the direction and magnitude of anisotropic diffusion abnormalities continue to be debated. Findings in the field are varied, with increased, decreased, or no difference in fractional anisotropy reported. Mayer presented an independent replication (using 28 subjects) of previous findings of increased FA during the semi-acute phase of injury in a cohort of 22 individuals. He has also carried out a prospective study on the putative recovery of diffusion abnormalities among 26 volunteers. He applied novel analytic strategies to capture spatially heterogeneous white matter injuries. Results indicated that a general pattern of high anisotropic diffusion/low radial diffusivity in various white matter tracts in both the replication or original cohorts, but this was only consistently observed in the genu, or anterior end, of the corpus callosum across both samples. Mayer identified a greater number of localized clusters (i.e., lesions) having increased anisotropic diffusion across both cohorts, confirming heterogeneity in white matter injury. Finally, evidence that lesions recover in patients re-examined across a four-month interval correlated with a reduction in self-reported post-concussive symptoms. Mayer concluded that diffusion abnormalities are associated with cytotoxic edema secondary to mechanical damage, resulting in changes in ionic homeostasis, and alterations in the ratio of intracellular and extracellular water.

Kathryn Saatman, University of Kentucky, Lexington, reported acute activation of calpain in the cortex and hippocampus in rodent models of contusion TBI, while axonal calpain activation was seen in diffuse or mild repetitive TBI (see slides). Rats exposed to TBI, then treated with the calpain inhibitor AK295, more quickly recovered motor function and had improved memory, though the inhibitor was not neuroprotective when given prophylactically. Mice overexpressing the human endogenous calpain inhibitor, calpastatin, exhibited reduced proteolysis of cortical α-spectrin and sodium channels after contusion TBI. Motor and cognitive deficits were less severe in the transgenic mice after injury. Similar approaches, using calpain inhibitor treatment or genetic overexpression of calpastatin, have been successful in reducing cognitive impairment, tau phosphorylation, and amyloid-β plaque formation in transgenic mouse models (APP/PS1) of Alzheimer’s disease.

David Brody, Washington University School of Medicine, St. Louis, Missouri, showed that interstitial fluid (ISF) amyloid-β (Aβ) levels are dynamic in humans and can change up to eightfold during hours and days after brain injury (see slides). Increased ISF Aβ levels over time after injury correlate with improved global neurological status (as reflected in better Glasgow Coma Score). In contrast, mean ISF tau levels in the initial 12 hours after injury inversely correlate with clinical outcomes at six months. In PDAPP, Tg2576, and wild-type mice, controlled cortical impact TBI decreased PBS-soluble Aβ and acutely reduced ISF Aβ, the latter being correlated with reduced neuronal activity. In comparison, Brody detected increased insoluble Aβ in injured axons of 3xTg-AD and APP/PS1 mice.

Keeping with the Aβ theme, Douglas Smith, University of Pennsylvania, Philadelphia, reviewed current knowledge of diffuse axonal injury (DAI) and changes in Aβ metabolism. DAI is caused by stretch injury, which breaks microtubules and partially interrupts axonal transport, leading to axonal swelling and APP accumulation. Repetitive mild stretch of axons (repetitive mTBI) induced Ca2+ influx and upregulation of Na+ channels, noted Smith. He observed long-term axonal pathology in human tissue up to six months postmortem, where Aβ, APP, tau, and neurofilaments co-localized with PS1 and BACE1. More thioflavin S-positive Aβ plaques were detected in TBI patients postmortem, compared to diffuse plaques in controls. He detected acute Aβ plaque formation in 30 percent of TBI patients, which he attributed to a polymorphism of neprilysin, an Aβ-degrading enzyme.

To map amyloid deposition in TBI patients in vivo, David Menon, University of Cambridge, U.K., used PET-PIB imaging to create non-displaceable-binding potential (BPND) maps using a simplified reference tissue model. Compared to controls, diffuse high PIB BPND signals increased in both gray and white matter in TBI brains during eight weeks post-injury. To avoid nonspecific binding and provide detailed assessment of temporal patterns, PIB BPND was measured only in cerebral cortex regions of interest, and results from each patient plotted against time post-TBI. PIB binding in the region rose above the normal range in the second week and normalized after four weeks. Using autoradiography, he also measured titrated PIB in postmortem brains from patients who died between three hours and eight weeks post-TBI. PIB robustly and specifically bound to the cortical tissue. Rachel Bennett, also from WashU, created three lines of AD-ApoE mice by crossing 3xTg-AD animals with those carrying knocked-in human ApoE2, ApoE3, or ApoE4 alleles. Bennett gave a single controlled cortical impact (CCI) to six- to eight-month-old AD-ApoE mice and then measured APP, Aβ40, and tau levels. APP and Aβ40 levels increased after the injury. AD-ApoE4 mice exhibited more APP than AD-ApoE2 and AD-ApoE3. In contrast, Aβ40 increased equally in all AD-ApoE mice. No pre-/post-TBI difference in tau level emerged, but AD-ApoE4 mice accumulated more tau than AD-ApoE2 and AD-ApoE3 mice.

Andrei Irimia, University of California, Los Angeles, discussed patient-tailored quantification of brain atrophy in TBI and CTE using multimodal neuroimaging. Multimodal imaging (MMl) can aid in the formulation of therapies to accelerate recovery from brain injury and improve quality of life. Longitudinal quantification of brain atrophy due to CTE and TBI provides significant neurobiological and clinical insight into the progression of these conditions. Irimia and colleagues hypothesized that their MMI framework allows for the detection and characterization of significant gray matter (GM) and white matter (WM) atrophy occurring between acute and chronic stages of TBI/CTE (see slides). The group acquired structural imaging at 1.5 Tesla, both acutely (three days post-injury) and chronically (180 days post-injury), using T1, fast spin echo, gradient echo, long tau inversion recovery, DTI, diffusion-weighted imaging, and susceptibility-weighted imaging techniques. Gray/white matter pathology metrics and segmentations of acute lesions, hemorrhage, and edema were obtained. Cortical parcellation yielded brain morphometrics and volumetrics, and DTI-based white matter fiber tracking was conducted to render structural connectivity matrices. The group identified individual fiber tracts exhibiting statistically significant atrophy, and they correlated volumetric atrophy measures against computed bi-frontal, bi-caudate, ventricular, Evan's, and Huckman's indices. The presence of gray/white matter atrophy was identified in all subjects, and detailed descriptive metrics computed for each cortical region and fiber tract involved. The atrophy quantification framework was more comprehensive compared to using only traditional atrophy indices because, in addition to relevant metrics, it offered the ability to map atrophy and identify significantly affected white matter fibers. These strategies may help clinicians and healthcare providers design improved methods for patient monitoring and rehabilitation.

Linda Van Eldik, at the University of Kentucky, Lexington, showed that a novel, orally active blood-brain barrier-penetrant compound, MW151, suppressed production of proinflammatory cytokines (IL-1β, TNF-α, S100B) in Aβ-induced brain injury, which helped to maintain synaptic integrity and recover hippocampus-dependent cognitive performance. MW151 treatment also helped in two animal TBI models of diffuse axonal injury (cortical impact and midline fluid percussion) when administered a few hours post-injury to mimic the time gap of injury to trauma center (see slides). Post-TBI, MW151 also prevented the typical increase in seizure susceptibility, glial activation, and cognitive deterioration after seizure induction with a second “hit” by electroconvulsive shock.

This is Part 4 of a five-part series. See also Part 1, Part 2, Part 3, Part 5. Read a PDF of the entire series.

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References

News Citations

  1. Keystone: Traumatic Brain Injury—Epidemiology and Characteristics
  2. Keystone: Sports-Related Injury and Chronic Traumatic Encephalopathy
  3. Keystone: Metabolic and Axonal Dysfunction in Traumatic Brain Injury
  4. Keystone: Diagnosis and Model Treatments for Traumatic Brain Injury

Other Citations

  1. slides

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