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.

Over the last decade, scientists have realized that brain injury, including single traumatic events and multiple mild concussions, can precipitate similar pathologies to those found in people with neurodegenerative conditions such as Alzheimer’s, frontotemporal dementia, and amyotrophic lateral sclerosis. This has led to intense study into the nexus between brain injury and neurodegeneration. At Clinical and Molecular Biology of Acute and Chronic Traumatic Encephalopathies, a Keystone symposium held 26 February-2 March 2012, scientists gathered to discuss the latest research advances in this field. Alzforum thanks meeting co-organizer Samuel Gandy, Mount Sinai Medical Center, New York, and colleagues Soong Ho Kim and Effie Mitsis for preparing brief summaries of the meeting. We also thank the many speakers for their input and for providing their slides for our readers to peruse.

The meeting started with Steven DeKosky, University of Virginia, Charlottesville. DeKosky reviewed the current understanding of the causes, and the short- and long-term consequences, of traumatic brain injury (TBI). Long-term outcomes in TBI differ depending on age at TBI and whether there was a single or multiple trauma. Pathologies of long-term TBI include chronic neurological and cognitive disorder, chronic traumatic encephalopathy (CTE), and Alzheimer’s disease (AD). CTE is characterized by neurofibrillary tangles and TDP-43 inclusions, noted DeKosky. Acute, single-incident, severe injuries (e.g., a car accident) increase risk for AD, whilst less severe repetitive injuries (e.g., boxing) lead to neurofibrillary tangle-based CTE. Long-term effects of TBI are often manifested later in life, and ApoE4 carriers have a 10-fold increased risk for dementia after TBI, said DeKosky.

Introducing a broad definition of TBI that encompasses all causes, Andrew Maas, Antwerp University Hospital, Belgium, suggested it would help reporting, comparing, and interpreting worldwide TBI studies. He suggested that epidemiology of TBI is changing in Europe; the overall incidence fell due to fewer traffic accidents, but more falls and contusions occur in older age groups. The consequences of this shift in demographics include different pathologies and comorbidities, and concern over the use of anticoagulants, which aggravate TBI. However, no change in clinical outcome was observed, despite the change in the epidemiology. Standardized epidemiologic monitoring should be considered essential to achieve targeted prevention goals and efficient trauma management, suggested Maas (see slides).

Kevin Guskiewicz, University of North Carolina, Chapel Hill, highlighted the diversity of sports-related concussions, which requires individual treatment strategies. Athletes with prior concussions have increased susceptibility to further concussions, which are associated with chronic symptoms. After a concussion, it is critical to carry out a serial assessment of acute symptoms (somatic, neurobehavioral, and cognitive) before they resolve, usually within about seven days, said Guskiewicz. Longitudinal population-based studies are needed to understand long-term effects of repetitive mild TBI (mTBI) and sub-concussive events, he said. One such study demonstrated that retired football players exhibit atrophy of white and grey matter, and suffer from memory problems, mild cognitive impairment (MCI), and clinical depression.

In that vein, Victoria Johnson found that chronic inflammation persists in the corpus callosum (CC) for years following a single TBI in humans. Johnson, from the University of Pennsylvania, Philadelphia, noted that on postmortem, CR3/43- and CD68-positive amoeboid microglia were found in the CC of more than one-third of cases with moderate (two weeks to one year) and long-term (one to 47 years) survival, but none in healthy controls or the acute TBI group. The thickness of the CC was dramatically reduced in those surviving TBI over one year.

Jenna Ziebell, from the Spinal Cord & Brain Injury Research Center, Lexington, Kentucky, reported that rod-like microglia were observed in the somatosensory barrel cortex of rats after midline fluid percussion injury (FPI). Iba1-positive rod microglia were elongated, and they aligned themselves with neuronal dendrites and axons. These changes were evident from day 1 to 28 post-injury; however, they were most prominent at day 7. Rod microglia were labeled with Iba1 as well as CD68 and OX6, but not CD11b or CD11C.

Ramesh Nayak outlined the possibility of using CNS antigens in re-circulating phagocytes as a source of biomarkers for TBI at different disease stages. Nayak, from the diagnostics company MSDx in Tucson, Arizona, compared two biomarkers, tau and hippocalcin 1, between relapsing remitting multiple sclerosis (RRMS) patients and healthy controls. After using appropriate cutoff values, he detected both tau and hippocalcin 1 in one of 12 control lysates and seven of 18 RRMS lysates. Comparing the two groups for either biomarker did not yield a statistically significant difference, but a comparison between controls and RRMS patients who were positive for either tau or hippocalcin 1 (one out of 12, nine out of 18, respectively) provided a statistically significant difference (see slides).

On the therapeutic front, Sarah Hellewell, Monash University, Melbourne, Australia, tested if erythropoietin (EPO) aids in a diffuse traumatic axonal injury (TAI) and hypoxia rat model. EPO administration one hour and 24 hours post-injury decreased the number of axonal bulbs in the CC, rescued MAP2 loss in the cortex and caudate nucleus, and reduced the number of CD68-positive macrophages/microglia in the brain. In addition, hypoxia rapidly upregulated EPO receptor expression.

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


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News Citations

  1. Keystone: Sports-Related Injury and Chronic Traumatic Encephalopathy
  2. Keystone: Metabolic and Axonal Dysfunction in Traumatic Brain Injury
  3. Keystone: TBI—Learning From Markers, Models, and Diseases
  4. Keystone: Diagnosis and Model Treatments for Traumatic Brain Injury

Other Citations

  1. slides

Further Reading