Chronic Traumatic Encephalopathy (CTE) and Traumatic Brain Injury (TBI)

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TimGDixon
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Chronic Traumatic Encephalopathy (CTE) and Traumatic Brain Injury (TBI)

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Chronic Traumatic Encephalopathy (CTE) and Traumatic Brain Injury (TBI)

Traumatic brain injury (TBI) is an alteration of brain function results from a blow or jolt to the head or penetrating head injury. TBI is heterogeneous in its cause and can be seen as a two-step event: 1) a primary injury, which can be focal or diffuse, caused by mechanical impact, that results in primary pathological events such as hemorrhage and ischemia, tearing of tissue and axonal injuries; 2) a secondary injury such as diffuse inflammation, cell death and gliosis, which is a consequence of the primary one. This secondary injury starts immediately after injury and can continue for weeks and is thought to involve an active inhibition of neural stem cell activity.

Collectively, these events lead to neurodegeneration. It is known that a large fraction of TBI is mild, and thus may go undiagnosed immediately after injury. Undiagnosed and untreated TBI presents a risk because some signs and symptoms may be delayed from days to months after injury, and may have significant impact on the patient's physical, emotional, behavioral, social, or family status if untreated, and may result in a functional impairment. Because secondary damage from the injury continues after the initial impact, early treatment (and thus rapid diagnosis), particularly point-of-care treatment, is desirable.

An ideal therapy for TBI would reduce the injury infarct size as well as limiting the secondary inflammatory responses. In the U.S., about 1.5 million people per year suffer a traumatic brain injury (TBI), reflecting physical damage to the brain that compromises brain function either temporarily or permanently. Of the total number so injured, some 50,000 die while another 80,000 have some degree of disability. The leading causes of TBI are accidents (auto, bicycle, pedestrian), assault, and sport-related injury.

Head injuries are described as being open or closed. Open head injuries involve penetration of the scalp and skull by bullets, sharp objects, or skull fractures resulting in laceration of brain tissue.

Closed injuries occur when rapid brain acceleration or deceleration results from shaking, crash, falls or other sudden insult. This rapid acceleration or deceleration can damage the brain at the point of contact (coup) or opposite that point (countercoup). The temporal and frontal lobes are most susceptible to damage, which can involve axon and/or blood vessel tearing. Torn blood vessels can leak and lead to hematomas, contusions, or intracerebral and subarachnoid hemorrhages.

Concussion is described as an immediate, but transient, loss of consciousness accompanied by a short period of amnesia. However, the TBI victim may appear to be dazed, disoriented or confused. A concussion may be accompanied by convulsions, hypotension, fainting and facial pallor. These signs and symptoms are usually short-lived in cases of single, uncomplicated concussion.

Traumatic brain injury can be both acute, occurring recently, as well as of the chronic form resulting from the long-term consequences of such acute brain injuries including the effects of inflammation and scarring on the brain tissue.

Football and soccer players appear to suffer a significantly higher frequency of concussion than athletes in other sports. Professional football players in the National Football League (NFL) have recently brought to the public's attention the long-term consequences of multiple concussions incurred during their playing days. Included as frequently reported signs are loss of cognition, decreased communicative skills, compromised emotional stability, poor coordination, memory loss and dementia.

CTE is a neurodegenerative disease associated with repetitive head impacts (RHI), typically sustained through exposure to contact sports (1-3). Clinically, CTE is characterized by abnormalities in behavior (e.g. explosivity, impulsivity, physical and verbal violence, disinhibition), mood (e.g. hopelessness, suicidality, anxiety, and apathy), cognition (e.g. impairment in memory, executive function, attention and concentration, dementia), and motor function (e.g. ataxia, parkinsonism) (4). Distinguishing CTE clinically can be difficult because of its symptomatic overlap with other neurological diseases, including Alzheimer disease (AD) dementia and Parkinson disease (PD). In addition, co-morbid pathologies are common in CTE (5). Therefore, determining the pathologies that underlie the clinical heterogeneity in CTE is important for understanding pathogenesis and to aid clinical diagnosis and eventually target treatment.

Chronic traumatic encephalopathy is diagnosed neuropathologically by the accumulation of hyperphosphorylated and aggregated tau in neurons, astrocytes, and cell processes around small vessels and in the depths of the cerebral sulci (6). In American football players, the number of years of contact sports play significantly predicts the severity of tau pathology in the dorsolateral frontal cortex and the CTE stage (7). In addition, RHI may accelerate and alter the deposition and pathological progression of other neurodegenerative proteins. For example, individuals with a history of RHI and neuropathological diagnosis of CTE accumulate β-amyloid (Aβ) at a younger age and at an accelerated rate compared to a general autopsy cohort.

Studies have shown that CTE is observed from multiple concussions over a protracted period of time. A series of postmortem brains from U.S. military veterans exposed to blast and/or concussive injury were shown to possess taupathy similar to the CTE neuropathology that was observed in young amateur American football players and a professional wrestler with histories of concussive injuries.

The relationship between taupathy and CTE is further confirmed in a blast neurotrauma mouse model that recapitulated CTE-linked neuropathology in wild-type C57BL/6 mice. Neuropathology was evident 2 weeks after exposure to a single blast. Blast-exposed mice demonstrated phosphorylated tauopathy, myelinated axonopathy, microvasculopathy, chronic neuroinflammation, and neurodegeneration in the absence of macroscopic tissue damage or hemorrhage.

Blast exposure induced persistent hippocampal-dependent learning and memory deficits that persisted for at least 1 month and correlated with impaired axonal conduction and defective activity-dependent long-term potentiation of synaptic transmission. Intracerebral pressure recordings demonstrated that shock waves traversed the mouse brain with minimal change and without thoracic contributions. Kinematic analysis revealed blast-induced head oscillation at accelerations sufficient to cause brain injury. Head immobilization during blast exposure prevented blast-induced learning and memory deficits.

The contribution of blast wind to injurious head acceleration may be a primary injury mechanism leading to blast-related TBI and CTE. These data identify common pathogenic determinants leading to CTE in blast-exposed military veterans and head-injured athletes and additionally provide mechanistic evidence linking blast exposure to persistent impairments in neurophysiological function, learning, and memory. Accordingly, the invention provides means of inhibit and/or reversing phosphorylated tauopathy, myelinated axonopathy, microvasculopathy, chronic neuroinflammation, and neurodegeneration.

Pterostilbene for Prevention and Treatment of Chronic Traumatic Encephalopathy

NeuroStilbene™ is an intranasal delivered version of NanoStilbene™ made from Pterostilbene that has been shown to successfully prevent the development of brain injury in an animal model of Chronic Traumatic Encephalopathy

Pterostilbene, (trans-3,5-dimethoxy-4-hydroxystilbene) is a stilbene compound that is structurally similar to other popular stilbenes such as resveratrol or piceatannol; it is named after its first discovered source (the pterocarpus genus) but is also a component of blueberries and grape products. It is a phytoalexin (a compound produced by plants as a defense against parasites and insects) similar to resveratrol albeit more potent.

The current data provided in the licensed patent strongly supports the possibility that receiving NeuroStilbene before sports-related brain injuries will prevent the development of Chronic Traumatic Encephalopathy. And although this data demonstrates a reduction in tau and suppression of brain cell damage with NeuroStilbene™, clinical trials are needed before specific medical claims can be made.

That being said, there are numerous peer reviewed scientific publications showing pterostilbene protects against brain damage in a variety of settings. For example, some studies show pterostilbene suppresses inflammation associated memory decline, other studies show pterostilbene suppresses hemorrhagic brain injury and neuronal cell death and yet other ones show protection of the brain against damage associated with lack of oxygen and aging.

Given all this supporting data, it is a logical extension to believe that NanoStilbene™, which is a more potent formulation of pterostilbene, would possess activity against Chronic Traumatic Encephalopathy.

Previous clinical studies by TSOI have demonstrated that NanoStilbene™, of which is also marketed as NeuroStilbene™, possesses superior distribution and half-life of pterostilbene when administered to healthy volunteers.

Examples:
The following Example is directed to treatment of traumatic brain injury in a mouse model. Control and test animals were subjected to head trauma daily (for 4 or 7 days) according to the method described in Mannix et al. Annals of Neurology, Vol., 74, No.1 1 pp. 65-75 (2013). Experimental group received doses of pterostilbene 10-50 mg/kg of body weight once a day.

One aspect of the model focuses on the ability of the test animals to find a submerged (hidden) platform that offers a safe haven upon which they can stand after being injured and placed in a pool of water. This test measured learning process and memory of the tested mice. Non-injured mice (the sham controls) took about 30 seconds to locate the pad on test day one. This time dropped during successive test days.

Two other groups of mice then received controlled blows to the head and were then treated by administration of pterostilbene or a placebo. Placebo treated animals generally performed worse than the sham mice while the pterostilbene treated animals generally performed in superior manner to the control injured mice.

In this same example a histopathologic evaluation was conducted on the brains of mice subjected to traumatic brain injury. Proteins were extracted from tissue and proteins separated by gel electrophoresis and blotted. Proteins specific to astrocytes (GFAP) and microglia (IBA1) were identified by western blotting and scanned (normalized to beta actin). The GFAP (astrocyte marker) and IBA1 (microglial marker) experiments showed reduced expression of in GFAP or dIBA1 expression in the cortex of pterostilbene treated mice as compared to controls.

Additionally, histopathologic evaluation of the brains of the animals from the several groups showed that the administration of pterostilbene inhibited microglia migration in the hippocampus, which is the portion of the brain associated with memory, compared with administration of placebo.

In a second example, the animal model described above is utilized and section of the brain are performed in order to visualize brain damage. As seen below, treatment with pterostilbene was associated with reduction in brain damage.

mousebrains.png
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References:

1. Stein, T. D., Alvarez, V. E., and McKee, A. C. (2015) Concussion in Chronic Traumatic Encephalopathy. Curr Pain Headache Rep 19, 47
2. McKee, A. C., Stern, R. A., Nowinski, C. J., Stein, T. D., Alvarez, V. E., Daneshvar, D. H., Lee, H. S., Wojtowicz, S. M., Hall, G., Baugh, C. M., Riley, D. O., Kubilus, C. A., Cormier, K. A., Jacobs, M. A., Martin, B. R., Abraham, C. R., Ikezu, T., Reichard, R. R., Wolozin, B. L., Budson, A. E., Goldstein, L. E., Kowall, N. W., and Cantu, R. C. (2013) The spectrum of disease in chronic traumatic encephalopathy. Brain 136, 43-64
3. Stein, T. D., Montenigro, P. H., Alvarez, V. E., Xia, W., Crary, J. F., Tripodis, Y., Daneshvar, D. H., Mez, J., Solomon, T., Meng, G., Kubilus, C. A., Cormier, K. A., Meng, S., Babcock, K., Kiernan, P., Murphy, L., Nowinski, C. J., Martin, B., Dixon, D., Stern, R. A., Cantu, R. C., Kowall, N. W., and McKee, A. C. (2015) Beta-amyloid deposition in chronic traumatic encephalopathy. Acta Neuropathol 130, 21-34
4. Montenigro, P. H., Baugh, C. M., Daneshvar, D. H., Mez, J., Budson, A. E., Au, R., Katz, D. I., Cantu, R. C., and Stern, R. A. (2014) Clinical subtypes of chronic traumatic encephalopathy: literature review and proposed research diagnostic criteria for traumatic encephalopathy syndrome. Alzheimers Res Ther 6, 68
5. Mez, J., Daneshvar, D. H., Kiernan, P. T., Abdolmohammadi, B., Alvarez, V. E., Huber, B. R., Alosco, M. L., Solomon, T. M., Nowinski, C. J., McHale, L., Cormier, K. A., Kubilus, C. A., Martin, B. M., Murphy, L., Baugh, C. M., Montenigro, P. H., Chaisson, C. E., Tripodis, Y., Kowall, N. W., Weuve, J., McClean, M. D., Cantu, R. C., Goldstein, L. E., Katz, D. I., Stern, R. A., Stein, T. D., and McKee, A. C. (2017) Clinicopathological Evaluation of Chronic Traumatic Encephalopathy in Players of American Football. JAMA 318, 360-370
6. McKee, A. C., Cairns, N. J., Dickson, D. W., Folkerth, R. D., Keene, C. D., Litvan, I., Perl, D. P., Stein, T. D., Vonsattel, J. P., Stewart, W., Tripodis, Y., Crary, J. F., Bieniek, K. F., Dams-O'Connor, K., Alvarez, V. E., Gordon, W. A., and group, T. C. (2016) The first NINDS/NIBIB consensus meeting to define neuropathological criteria for the diagnosis of chronic traumatic encephalopathy. Acta Neuropathol 131, 75-86
7. Poole, V. N., Abbas, K., Shenk, T. E., Breedlove, E. L., Breedlove, K. M., Robinson, M. E., Leverenz, L. J., Nauman, E. A., Talavage, T. M., and Dydak, U. (2014) MR spectroscopic evidence of brain injury in the non-diagnosed collision sport athlete. Dev Neuropsychol 39, 459-473
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curncman
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Re: Chronic Traumatic Encephalopathy (CTE) and Traumatic Brain Injury (TBI)

Post by curncman »

I hope our IND gets first-of-it’s-kind phase 2 FDA approval so that lots of prying eyes are out there looking for partnerships soon!
I am well wisher of everyone! GOD will pardon all your sins but not your Central Nervous System! Think Positive!
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