Introduction: Chronic traumatic encephalopathy (CTE) is a progressive neurodegenerative disorder that is defined, neuropathologically, by the presence of aggregated hyperphosphorylated tau in the neurons and astrocytes of the perivascular area that is located deep in the cerebral sulci. The lesion is associated with repetitive brain trauma, from the spectrum of asymptomatic subconcussive head injury to grossly identifiable features of concussion. Although the diagnostic neuropathology of CTE is well-characterized, the precise mechanism that causes this to occur in CTE is not yet clearly elucidated. The features of hyperphosphorylated tau in CTE is quite similar with Alzheimer’s Disease (AD), as is the reduced expression of certain genes that are required to dephosphorylate tau, which is the putative culprit in the generation of amyloid aggregates and hyperphosphorylated tau.1 In comparison, Parkinson’s Disease (PD) is a neurodegenerative disease that is caused by accumulation of misfolded alpha-synuclein (α-syn) that causes the formation of intraneuronal Lewy Body aggregates. The pattern of accumulation for α-syn involves the olfactory bulb and the gut with progressive involvement of the posterior part of the brain.2 Despite establishing the presence of two different intraneuronal inclusions for CTE and PD, contact sports associated with the clinical spectrum of CTE has been shown to present with Parkinsonian features along with dementia. Mood disorders has been reported to occur in patients with these neurologic conditions. Several studies have documented that patients had a previous experience of traumatic brain injury prior to the diagnosis of Bipolar Disorder (BD). A review of electronic literature suggested that having an earlier diagnosis of BD increased the likelihood of having a diagnosis of PD in the future. Objectives: This research aimed to compare the over- and underexpressed genes in cases with Parkinson's Disease (PD), cases with Bipolar Disorder (BD), and cases with Chronic Traumatic Encephalopathy (CTE) versus normal controls. This was done to determine if parallel overexpression in certain genes may indicate the possible association at the level of gene expression. Identifying similar RNA sequence establishing gene expression may provide an insight to the relationship of the diseases in terms of pathobiological behavior. Determining the similar over- or underexpression pattern may provide an insight on the common pathobiologic mechanisms that may be the reason for the three disorders being associated by way of pre-morbid or co-morbid condition. Methodology: Transcripts from the public domain archive of the NCBI SRA were identified for the RNA sequence (RNAseq) of interest using the search string “Chronic Traumatic Encephalopathy”, “Bipolar Disorder”, and “Parkinson”. Only public domain transcriptome files of post-mortem brain samples labeled as RNAseq data extracted thru the Illumina platform that have a paired normal control were selected. A total of ten (10) cases for each disorder and thirty (30) normal subjects for control in the NCBI SRA RNAseq database with a whole exome sequence file that was available for public domain use was utilized for differential gene expression analysis. Results and Discussion: Among 21,122 identified genes from the RNAseq, the analysis was able to identify 26 genes exhibiting increased expression of up to >15 log2 fold change among cases with CTE, PD, and BD compared with normal controls. In contradistinction, only 6 well-described genes exhibited a decreased expression among cases with CTE and BD compared to normal controls. However, there were no identified genes that exhibited underexpression in cases with PD compared with normal controls. The identification of parallel gene overexpression among the CTE, BD, and PD groups with respect to structural integrity, cellular metabolism, homeo-stasis, and apoptosis may indicate a common pathway that have been initiated as part of the response to maintain tissue function or as a consequence of the underlying pathobiologic mechanism that caused the primary lesion. In comparison, the underexpressed genes detected in the CTE and BD cases compared to the normal controls and the PD cases may indicate the lack of genes that have a role in repressing the mRNA for protein coding. Conclusion The overexpression of genes responsible for homeostasis, regulation of inflammation, balance of apoptosis and anti-apoptosis, and maintenance of structural integrity among the CTE, BD, and PD groups indicate that there is an interrelated mechanism that serves converging pathways as part of the response to lesional- forming structures in the brain. The goal of studies such as this is to have a better understanding on the common pathways that explain the interrelatedness of brain disorders and the putative mechanism for being co-morbid and pre-morbid conditions of each other.
Chronic Traumatic Encephalopathy

This experimental study was aimed to evaluate the injurious effects of chronic traumatic brain injury on cortex mitochondrial function in rats. The head of rat was impacted by a metal sphere in a weight-drop device twice per day for 30 days, cortex mitochondria were isolated. Then the mitochondria membrane fluidity, swelling, respiratory function, the activities of mitochondria respiratory enzymes and superoxide dismutase (SOD), the levels of phospholipid, malondial dehyde (MDA) and Ca2+ were determined to analyze the function of mitochondria. The data indicated that chronic closed traumatic brain injury caused severe neuronal mitochondrial injuries. The swelling of mitochondria was aggravated, the decomposability of mitochondrial membrane phospholipid was increased, the membrane fluidity of mitochondria was decreased; the chronic closed traumatic brain injury also significantly depressed the activities of respiratory enzymes and SOD of mitochondria, increased the level of MDA and Ca2+. The chronic closed traumatic brain injury induced damage to rat cortex mitochondria. The mechanisms may be derived from the secondary increase of free radicals induced by mitochondrial membrane injury and the obstacle of rat brain energy metabolism.
Animals ; Brain Injury, Chronic ; pathology ; physiopathology ; Cerebral Cortex ; pathology ; physiopathology ; Male ; Mitochondria ; pathology ; physiology ; Random Allocation ; Rats ; Rats, Sprague-Dawley

Chronic traumatic encephalopathy (CTE) is a progressive neurodegenerative disorder that is associated with repetitive head injury and has distinctive neuropathological features that differentiate this disease from other neurodegenerative diseases. Intraneuronal tau aggregates, although they occur in different patterns, are diagnostic neuropathological features of CTE, but the precise mechanism of tauopathy is not known in CTE. We performed whole RNA sequencing analysis of post-mortem brain tissue from patients with CTE and compared the results to normal controls to determine the transcriptome signature changes associated with CTE. The results showed that the genes related to the MAP kinase and calcium-signaling pathways were significantly downregulated in CTE. The altered expression of protein phosphatases (PPs) in these networks further suggested that the tauopathy observed in CTE involves common pathological mechanisms similar to Alzheimer's disease (AD). Using cell lines and animal models, we also showed that reduced PPP3CA/PP2B phosphatase activity is directly associated with increases in phosphorylated (p)-tau proteins. These findings provide important insights into PP-dependent neurodegeneration and may lead to novel therapeutic approaches to reduce the tauopathy associated with CTE.
Alzheimer Disease ; Brain ; Brain Injury, Chronic* ; Cell Line ; Craniocerebral Trauma ; Gene Expression Profiling* ; Humans ; Models, Animal ; Neurodegenerative Diseases ; Phosphoprotein Phosphatases ; Phosphotransferases ; Sequence Analysis, RNA ; Tauopathies* ; Transcriptome*

OBJECTIVE: : To investigate the effects of cysteinyl leukotrienes receptor (CysLTR) antagonists on global cerebral ischemia/reperfusion (CI/R) injury in gerbils, and to explore its mechanism. METHODS: : Totally 40 gerbils weighting 45-65 g were randomized into sham, saline, Pranlukast and HAMI 3379 groups with 10 animals in each. The CI/R model was established in gerbils by bilateral common carotid occlusion for 10 min followed by reperfusion. After ischemia, the CysLTR antagonists Pranlukast (0.1 mg/kg) and HAMI 3379 (0.1 mg/kg) were injected intraperitoneally for 5 consecutive days in the last two groups,while the former two groups were injected with saline only (10 mL/kg). After 24 h or 14 d reperfusion, neurological deficit score was evaluated and the behavioral dysfunction was assessed, respectively. And 14 d after reperfusion, the neuron morphology of cerebral cortex was observed in brain sections stained with Cresyl violet. In addition, the Iba-1 (microgila) and GFAP (astrocyte) positive cells in cerebral cortex were observed by using immunohistochemitry method. RESULTS: : CI/R models were successfully established in 21 out of 30 gerbils with 7 in saline group, 6 in Pranlukast group, and 8 in HAMI 3379 group. Compared with saline group, Pranlukast and HAMI 3379 significantly attenuated neurological deficits, improved the behavioral function 24 h after reperfusion(all <0.01); Pranlukast and HAMI 3379 also significantly improved the behavioral function 14 days after reperfusion(<0.05 or <0.01). Compared with saline group, the neurological symptom scores in Pranlukast and HAMI 3379 groups presented a trend of amelioration 14 d after reperfusion, but it was not significant(>0.05). In addition, Pranlukast and HAMI 3379 also inhibited the neuron loss and injury, suppressed microgila and astrocyte activation 14 d after reperfusion(all <0.01). CONCLUSIONS : CysLTR antagonists Pranlukast and HAMI 3379 have long-term neuroprotective effect on chronic brain injury induced by global cerebral ischemia/reperfusion in gerbils.
Animals ; Behavior, Animal ; drug effects ; Brain Injury, Chronic ; drug therapy ; Brain Ischemia ; Gerbillinae ; Leukotriene Antagonists ; pharmacology ; therapeutic use ; Neuroprotective Agents ; pharmacology ; therapeutic use ; Random Allocation ; Receptors, Leukotriene ; metabolism ; Reperfusion Injury ; drug therapy

Here we present an autopsy case of chronic traumatic encephalopathy (CTE) in a 36-year-old man. He had a history of febrile seizures at the age of four and was severely demented at age 10 when he was admitted to a mental hospital. He had suffered repetitive self-harm, such as frequent banging of the head on the wall in his hospital record, but he had no clear history between the ages of four and ten. Autopsy revealed global cerebral atrophy, including the basal ganglia, thalamus, hippocampus, amygdala, mammilary bodies and lateral geniculate bodies. This case showed typical pathological features of CTE. Phosphorylated tau (p-tau)-positive neurofibrillary tangles (NFTs) and neuropil threads (NT) we are widely distributed in the brain, especially in the depth of the cerebral sulci. NFT and NT were also found in the basal ganglia, thalamus, amygdala and brainstem. Scanty β-amyloid deposits were found in the motor and sensory cortices, but α-synuclein was completely negative in the brain. This example showed that CTE can occur in young ages and that even children can experience CTE dementia.
Adult ; Amygdala ; Atrophy ; Autopsy* ; Basal Ganglia ; Brain ; Brain Injuries ; Brain Injury, Chronic* ; Brain Stem ; Child* ; Dementia ; Geniculate Bodies ; Head ; Hippocampus ; Hospital Records ; Hospitals, Psychiatric ; Humans ; Neurofibrillary Tangles ; Neuropil Threads ; Pathology ; Seizures, Febrile ; Thalamus

Dementia pugilistica (DP) or chronic traumatic encephalopathy (CTE) is a neurodegenerative disease or dementia that may affect amateur or professional boxers as well as athletes in other sports who suffer concussions. The condition is thought to affect around 15% to 20% of professional boxers and caused by repeated concussive or subconcussive blows. CTE was in the past referred to as dementia pugilistica, which reflected the prevailing notion that this condition was restricted to boxers. Recent research, however, has demonstrated neuropathological evidence of CTE in retired American football players, a professional wrestler, a professional hockey player and a soccer player, as well as in nonathletes. It is probable that many individuals are susceptible to CTE, including those who experience falls, motor vehicle accidents, assaults, epileptic seizures, or military combat, and that repeated mild closed head trauma of diverse origin is capable of instigating the neurodegenerative cascade leading to CTE. We report a 62-year old man suspicious of dementia pugilistica with clinical features of frontotemporal dementia and parkinsonism.
Athletes ; Brain Injury, Chronic ; Dementia ; Epilepsy ; Football ; Frontotemporal Dementia ; Head Injuries, Closed ; Hockey ; Humans ; Military Personnel ; Motor Vehicles ; Neurodegenerative Diseases ; Parkinsonian Disorders ; Soccer ; Sports

PURPOSE: A number of studies have examined the B-type natriuretic peptide level in dialysis patients and in patients with lesser degrees of renal insufficiency. However, relationships between BNP and renal function are unknown. We sought to assess the diagnostic utility of BNP in differentiating congestive heart failure (CHF) from non-congestive heart failure (non-CHF) in patients with renal insufficiency. METHODS: BNP levels were obtained in 395 patients presenting to our emergency department with dyspnea. Of those 395 patients, 48 patients showed renal insufficiency. Patients transferred to other hospitals and those in a donot- resuscitate state were excluded. RESULTS: In patients with acute renal failure, patients with CHF (n=8) had BNP levels of 360+/-254 pg/ml whereas patients with non-CHF (n=3) had BNP levels of 114+/-103 pg/ml; however, this difference was not statistically significant. In patients with chronic renal failure, patients with CHF (n=22) had BNP levels of 1147+/-635 pg/ml, which was significantly higher than the BNP levels of 459+/-508 pg/ml for patients with non-CHF (n=7) (p=0.01). The area under the receiver operating curve, which plots sensitivity versus specificity for BNP levels in separating congestive heart failure from non-congestive heart failure in patients with chronic renal failure, was 0.805 (p=0.01). The diagnostic accuracy of BNP at a cutoff of 600 pg/ml was 76 %. CONCLUSION: The BNP cut-off value for diagnosis of CHF in patients with chronic renal failure is 600 pg/ml.
Acute Kidney Injury ; Diagnosis* ; Dialysis ; Dyspnea ; Emergency Service, Hospital ; Estrogens, Conjugated (USP)* ; Heart Failure* ; Humans ; Kidney Failure, Chronic ; Natriuretic Peptide, Brain* ; Renal Insufficiency ; Sensitivity and Specificity

Magnetic resonance imaging(MRI) and computed tomography(CT) in 30 patients with severe head trauma were compared. MRI was superior to CT in detection of intracerebral and extracerebral traumatic lesions. The results obtained were as follows : 1) 27 intracerebral(18 cerebral contusions, 5 diffuse axonal injuries & 4 intracerebral hematomas) and 13 extracerebral traumatic lesions(4 acute epidural hematomas, 4 subdural hygromas, 2 subarachnoid hemorrhages, 1 acute subdural hematoma, 1 chronic subdural hematoma & 1 pneumocephalus) in 30 patients were seen on CT and/or MRI. 2) Group I lesions which seen on MRI and not seen on CT were 5 diffuse axonal injuries(100%), & 8 cerebral contusions(44%), and group II lesions which seen on CT and MRI with better visualization on MRI were 6 cerebral contusions(33%), 2 intracerebral hematomas(50%), & 3 subdural hygromas(75%). 3) Group III lesions which seen on CT and MRI equally well were 4 cerebral contusions(22%), 2 intracerebral hematomas(50%), 2 acute epidural hematomas(50%), 2 subarachnoid hemorrhages(100%), 1 chronic subdural hematoma(100%), 1 subdural hygroma(25%) & 1 pneumocephalus(100%). 4) Group IV lesions which seen on CT and MRI with better visualization on CT were 2 acute epidural hematomas(50%), & 1 acute subdural hematoma(100%), and lesion which seen on CT and not seen on MRI was not. 5) 21 intracerebral lesions of group I and II were located on temporal(11), parietal(3), frontal(2) and occipital lobes(2), basal ganglia(1), brain stem(1) and cerebellum(1). 6) We recommended MRI in the acute stage of severe head trauma for accurate diagnosis and evaluation of intracerebral traumatic lesions, especially diffuse axonal injuries and cerebral contusions, which were not visualized clearly on CT.
Axons ; Brain ; Contusions ; Craniocerebral Trauma* ; Diagnosis ; Diffuse Axonal Injury ; Head* ; Hematoma ; Hematoma, Subdural, Acute ; Hematoma, Subdural, Chronic ; Humans ; Magnetic Resonance Imaging* ; Subarachnoid Hemorrhage ; Subdural Effusion

The pathological features of Alzheimer's disease are senile plaques which are aggregates of β-amyloid peptides and neurofibrillary tangles in the brain. Neurofibrillary tangles are aggregates of hyperphosphorylated tau proteins, and these induce various other neurodegenerative diseases, such as progressive supranuclear palsy, corticobasal degeneration, frontotemporal lobar degeneration, frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17), and chronic traumatic encephalopathy. In the case of Alzheimer's disease, the measurement of neurofibrillary tangles associated with cognitive decline is suitable for differential diagnosis, disease progression assessment, and to monitor the effects of therapeutic treatment. This review discusses considerations for the development of tau ligands for imaging and summarizes the results of the first-in-human and preclinical studies of the tau tracers that have been developed thus far. The development of tau ligands for imaging studies will be helpful for differential diagnosis and for the development of therapeutic treatments for tauopathies including Alzheimer's disease.
Alzheimer Disease ; Brain ; Brain Injury, Chronic ; Chromosomes, Human, Pair 17 ; Diagnosis, Differential ; Disease Progression ; Frontotemporal Dementia ; Frontotemporal Lobar Degeneration ; Ligands ; Neurodegenerative Diseases ; Neurofibrillary Tangles ; Parkinsonian Disorders ; Peptides ; Plaque, Amyloid ; Supranuclear Palsy, Progressive ; tau Proteins ; Tauopathies

Chronic traumatic encephalopathy (CTE) is a distinct neurodegenerative disease that associated with repetitive head trauma. CTE is neuropathologically defined by the perivascular accumulation of abnormally phosphorylated tau protein in the depths of the sulci in the cerebral cortices. In advanced CTE, hyperphosphorylated tau protein deposits are found in widespread regions of brain, however the mechanisms of the progressive neurodegeneration in CTE are not fully understood. In order to identify which proteomic signatures are associated with CTE, we prepared RIPA-soluble fractions and performed quantitative proteomic analysis of postmortem brain tissue from individuals neuropathologically diagnosed with CTE. We found that axonal guidance signaling pathwayrelated proteins were most significantly decreased in CTE. Immunohistochemistry and Western blot analysis showed that axonal signaling pathway-related proteins were down regulated in neurons and oligodendrocytes and neuron-specific cytoskeletal proteins such as TUBB3 and CFL1 were reduced in the neuropils and cell body in CTE. Moreover, oligodendrocyte-specific proteins such as MAG and TUBB4 were decreased in the neuropils in both gray matter and white matter in CTE, which correlated with the degree of axonal injury and degeneration. Our findings indicate that deregulation of axonal guidance proteins in neurons and oligodendrocytes is associated with the neuropathology in CTE. Together, altered axonal guidance proteins may be potential pathological markers for CTE.
Axons ; Blotting, Western ; Brain Injury, Chronic ; Brain ; Cell Body ; Cerebral Cortex ; Craniocerebral Trauma ; Cytoskeletal Proteins ; Gray Matter ; Humans ; Immunohistochemistry ; Neurodegenerative Diseases ; Neurons ; Neuropathology ; Neuropil ; Oligodendroglia ; tau Proteins ; White Matter