Blood-based biomarkers

Over the last 12 months significant interest and research in mild TBI and concussion, including expanding the horizon for blood-based biomarkers, has increased. Because TBI, especially mTBI and concussion, present significant challenges to accurately, reproducibly and rapidly establish diagnosis and provide serial monitoring the need for objective, non-invasive biomarkers exposing underlying fundamentals of host defense responses to the trauma has mushroomed. Researchers from Baylor College of Medicine, Houston, TX and the University of Pennsylvania, Philadelphia reported that plasma levels of calpain-cleaved aII-spectrin N-terminal fragment (SNTF) was elevated in 7 of 17 mTBI cases but in no uninjured controls (Front. Neurol., 18 November 2013 | doi: 10.3389/fneur.2013.00190). However, specificity for mTBI was questioned because SNTF levels were increased in some individuals with orthopedic injuries.


Swedish and UK scientists, using techniques developed at Quanterix Corp, Lexington, Massachusetts, reported in a paper published in JAMA Neurology (JAMA Neurol. doi:10.1001/jamaneurol.2014.367) that total tau (T-tau) correlated well with concussion in plasma of professional hockey players in Sweden, and influenced decision of players for return to play. In addition to T-tau they evaluated several other protein-based biomarkers, which did not correlate well. This paper is important since techniques developed at Quanterix used SIMOA (Single Molecule Array) technology an ultrasensitive, multiplexed technique for detection of proteins and nucleic acids. They concluded that since sports-related concussion in professional ice hockey players is associated with acute axonal and astroglial injury, T-tau may prove useful in larger studies.

Prion-like Neurodegeneration

Increasing evidence for a “prion-like” spread for tau protein inclusions following Traumatic Brain Injury (TBI) is being increasingly reported in the literature. This is critical since the effects from even a mild TBI can last for a long time impacting quality of life. Consequences such as Alzheimer’s disease (AD) or even more commonly, Chronic Traumatic Encephalopathy (CTE), develop after repeated mild TBI or concussion. Understanding what may be occurring at the cellular level may allow for paradigm shifts in drug target identity.  Using controlled cortical impact (CCI), several research groups found neuronal inclusions and widespread cognitive deficits in injured animals.

pHLOGISTIX scientists have used the CCI model to assess the benefits of treating mild TBI in mice with fragments of recombinant thrombomodulin (rTM) to improve neurobehavioral deficits and reduce abnormal protein aggregation into neuronal inclusions.  Over the last two years prion-like, abnormal protein aggregation has been documented not only for tau but for also for α-synuclein (α-syn), dominant protein in Lewy bodies (LBs) in Parkinson’s disease (PD), as well as TDP-43 in amyotrophic lateral sclerosis (ALS; Lou Gehrig’s disease) inclusions.  Several groups have utilized rodents, either rats or mice, with mutations in various genes or even native animals and showed evidence for the prion-like spread.  Such reports underscore the company’s efforts to define new drug targets while emphasizing that rTM, especially the C-type lectin D1 domain of, has significant benefit in reducing neuroinflammation and decreasing protein aggregation.

Dr. Stanley Prusiner, Nobel Prize winner for Physiology or Medicine in 1997 from the University of California San Francisco (UCSF) for the initial discovery and understanding of prion proteins in scrapie, mad cow disease and Jakob-Creutzfeldt diseases in the 1980s, is developing an approach to formation of “tau prions” in transgenic mice following TBI. This model is critical since for new drug discovery efforts since conversion of native tau to prion tau with progression to CTE is more uniform than in other tau diseases (“tauopathies”) and occurs much more rapidly. Furthermore, in a study funded by the Dana Foundation , UCSF scientists are using genetically-engineered bioluminescent molecular imaging of tau to monitor serial changes in TBI-injured single animals over time in order to facilitate understanding of disease processes correlated with neurobehavior.  Furthermore, Drs. Virginia Lee, John Trojanowski and their colleagues at the University of Pennsylvania Center for Neurodegenerative Disease Research have shown that preformed fibrils (PFFs) of α-syn can form tau protein inclusions in neurons in mice injected with these PFFs and that different “strains” of PFFs will or will not induce tau “prions.”.

Although in most cases the classic prion diseases are infectious, whereas at present prion-like proteins in AD, PD, ALS or CTE appear only to seed aggregates, nonetheless in all cases the aggregated proteins gain a toxic function (“gain of function”) and/or lose normal function (“loss of function”). So, the prion paradigm, as a unifying pathogenic principle, may allow for new therapeutic directions in this large class of untreatable diseases.

Regardless whether infectious or seed-capable, these seminal observations inform pHLOGISTIX drug development, as well as our diagnostic endeavors and will guide future strategies.

pHLOGISTIX to Partner with Innovative Technology Development Foundation

Innovative Technology Development Foundation (ITDF), a not for profit 501(c)3 public charity, was organized to work alongside pHLOGISTIX LLC for TBI and neurodegenerative disorders.

DOD and DVA to Intensively Study PTSD and mTBI

In recent years there has been a lack of clear criteria within the military for diagnosis and treatment of PTSD and this resulted in the reversal of close to 40 percent of PTSD diagnoses.  There is some evidence that 15-20% of all returning combatants from OEF/OIF and Afghanistan have PTSD, and this has led to a concerted effort by the Department of Defense (DOD) and the Department of Veterans Affairs (DVA) to improve the situation.

It was recently announced that traumatic brain injury (TBI) and post-traumatic stress disorder (PTSD) will begin using new criteria for diagnosis and treatment in the military, DOD, and by DVA at VA hospitals. Both the DOD and DVA announced last month an investment of more than $100 million for research into improving diagnosis and treatment of mild TBI (mTBI) and PTSD. Two groups, the Consortium to Alleviate PTSD (CAP) and the Chronic Effects of Neurotrauma Consortium (CENC) will be jointly managed by VA, and by the Congressionally Directed Medical Research Programs (CDMRP), on behalf of the DOD. According to Assistant Secretary of Defense for Health Affairs Jonathan Woodson, “these consortia will bring together leading scientists and researchers devoted to the health and welfare of our nation’s service members and veterans.” He added, “a primary goal of CENC is to

As reported in Time online:
– For PTSD, CAP “will study potential indicators of the trauma, as well as prevention strategies, possible interventions, and improved treatments. Biomarker-based research will be a key factor in CAP’s studies,” the CDMRP says. PTSD afflicts some troops after combat tours, and causes anxiety, depression and other mental ills.

– For mTBI, CENC will try “to establish an understanding of the after-effects of a mTBI. Potential comorbidities also will be studied; that is, conditions associated with and worsen because of a neurotrauma,” the CDMRP says. TBI is a physical wound – a concussion – usually suffered by troops near the shock waves of an improvised explosive device. It can bruise the brain and cause mood changes, fatigue and sleeping more – or less – than usual.

Football’s Link to Mild Traumatic Brain Injury

Is football too dangerous? This was the title of an article in Junior Scholastic, a publication aimed at high schoolers and their parents. The article went on to discuss the sequelae (conditions the consequence of a previous disease or injury) and quoted Robert Cantu, MD, a Clinical Professor of Neurosurgery at Boston University School of Medicine (BUSM), who said that he’s seen far too many players, even young ones, “who’ve had their lives altered” by concussions. Cantu is also Co-Director of the Center for the Study of Traumatic Encephalopathy (CSTE) at BUSM.

It is important to realize that football players might suffer thousands of small blows to the head over a lifetime of playing, especially if they go on to play at the professional level. Such repetitive blows can lead to repeated bouts of mild TBI (mTBI) or concussions that eventually can lead to a brain disorder known as chronic traumatic encephalopathy (CTE). CTE, known previously as punch-drunk syndrome, was first observed in boxers (dementia pugilistica) and in clinical terms can cause memory loss, depression, and even dementia. As recently as the 1990s repetitive blows to the head were not considered a cause of later problems for either American or Australian football players but, beginning in late 2010, CTE has received greater attention with publications from BUSM and others.

CTE differs from Alzheimer’s disease (AD) neuropathologically in that it consists primarily of neuroinflammation and abnormal deposits within and outside nerve cells (neurons) called neurofibrillary tangles (NFTS). AD also has NFTs but is also primarily characterized by amyloid plaques outside of neurons. The NFTs are composed chiefly of abnormal amounts and types of a microtubule-associated protein called tau, and CTE and other conditions, including AD, are referred to as tauopathies.