October 19-21, 2016

Dr. Festoff, PHLOGISTIX founder, presented a paper and poster entitled “Clinical biomarkers of blood-brain barrier (BBB) dysfunction and progression to neurodegeneration in Alzheimer’s disease” at The Lancet Neurology Conference Preclinical neurodegenerative disease: towards prevention and early diagnosis

August 2016

PHLOGISTIX Founder, Dr. Festoff, published a paper in the August 2016 issue of the Journal of Neuroinflammation with colleagues Drs. Luca Cucullo and Ravi Sajji of the Texas Tech University Heath Sciences Center (TTUHSC) School of Pharmacy at Amarillo, TX. The article was the result of work by PHLOGISTIX and the Blood Brain Research Center of TTUHSC, in association with KUMC,showing clear evidence that damage-associated molecules (DAMPs), amyloid beta peptide (A) and high mobility group box protein 1 (HMGB1), are elevated in the mild cognitive impairment (MCI) to Alzheimer’s disease (AD) continuum. This suggest their potential use as biomarkers in preclinical AD diagnosis in at-risk populations. These would include genetics-at–risk, age-at- risk and head injury-at-risk cohorts.

Since publication, the web-based Altmetrics, a metrics and qualitative database complementary to traditional, citation-based metrics has scored this article https://www.altmetric.com/details/10815432#score Compared to these this article has done particularly well and is in the 91st percentile: it’s in the top 10% of all research outputs ever tracked by Altmetric.

Article published

The Founder, Dr. Festoff, published a paper in the August 2016 issue of the Journal of Neuroinflammation with colleagues Drs. Luca Cucullo and Ravi Sajji of the Texas Tech University Heath Sciences Center (TTUHSC) School of Pharmacy at Amarillo, TX, and Patrick van Dreden of Diagnostica Stago, Gennevilliers, France. The article was the result of work by PHLOGISTIX and the Blood Brain Research Center of TTUHSC, in association with the University of Kansas Medical Center (KUMC), that showed clear evidence that damage-associated molecules (DAMPs), amyloid beta peptide (Ab) and high mobility group box protein 1 (HMGB1), are elevated in the mild cognitive impairment (MCI) to Alzheimer’s disease (AD) continuum suggesting their potential use as biomarkers in pre-clinical AD diagnosis in at-risk populations (J. Neuroinflammation, 2016 Aug 24;13(1):194. doi: 10.1186/s12974-016-0670-z). These would include genetics-at–risk, age-at-risk and head injury-at-risk cohorts. [Read more…]

PHLOGISTIX FOUNDER SPEAKS AT RESEARCH SYMPOSIUM

PHLOGISTIX FOUNDER, Dr. Barry Festoff, was Distinguished Speaker at the Texas Tech University Health Sciences Center (TTUHSC) at Amarillo Annual Research Days Symposium June 11, 2015. Dr. Festoff gave a lecture entitled “Translational Approaches to Diagnosis and Monitoring of Concussion Leading to Neurodegenerative Diseases”

CTE Found in former NFL players brains

Scientists Dissected the Brains of 79 NFL Players. What They Found Is Disturbing

Neuropathology experts at the Boston University (BU) CTE Center in Boston analyzed the brains of 79 former NFL players who had come to autopsy after death. Strikingly, 76 of these showed the hallmarks of CTE. They have now examined 128 brains in all and 101 of these showed this evidence–from high school players to professionals. Of interest, one local Kansas City area high school player who had died on the field after a repetitive brain injury at the homecoming game of his senior year–it isn’t known exactly how many concussions he had experienced before his death at age 17–was amongst those the BU CTE Center examined and found tell-tale CTE findings. His tragic case was the subject of several reports including that of neurosurgeon Dr. Sanjay Gupta on a CNN Special  (http://www.cnn.com/2012/01/27/health/big-hits-broken-dreams-brain-bank/).

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.

A Long Way from Being Over

Furthermore, the concussions problems for football are a long way from being over.  It may just be the beginning with a sustained wave of future lawsuits, additional stories, and demands for fundamental changes in how football is played, at the earliest times and levels: Pop Warner leagues, middle and high school, college all the way to the NFL.  Although the three-quarters of a billion dollar settlement suppresses discovery into the aspects of the suit, other pressures will clearly pave the way for further research into the long-term effects of brain damage from repeated blows to the head.

 

NFL Players File Separate Lawsuit

Although the NFL would prefer it, the matter is not settled since several days later,  four other former NFL players filed a separate lawsuit against the NFL.

Subsequent information indicated that older players might not actually participate in the settlement, especially older players and those who died before 2006, even if their brains demonstrated changes of either Alzheimer’s disease (AD) or Chronic Traumatic Encephalopathy (CTE). Furthermore, newer information was that possibly legal fees WOULD come out of the settlement.

NFL Concussion Settlement

On August 29, 2013, Federal District Judge Anita Brody approved a settlement between the NFL and more than 2000 former NFL payers amounting to $765 million:

According to the agreement, the NFL will pay $675 million to players and their families according to an agreed-upon schedule. Forbes Magazine broke the remainder down as follows:

In addition to the monetary relief provided to the players and their families, the NFL and NFL Properties will make the following payments:

  • No more than $75 million for baseline medical exams;
  • $10 million for a research and education fund;
  • No more than $4 million to pay for the costs of notice to the members of the class of plaintiffs;
  • $2 million representing one-half of the compensation of the Settlement Administrator; and
  • Legal fees and litigation expenses to the plaintiffs’ counsel (to be determined by the court).