The Experts below are selected from a list of 177 Experts worldwide ranked by ideXlab platform
John Q Trojanowski - One of the best experts on this subject based on the ideXlab platform.
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enhanced neurofibrillary tangle formation cerebral atrophy and cognitive deficits induced by repetitive mild brain injury in a transgenic tauopathy mouse model
Journal of Neurotrauma, 2005Co-Authors: Yasumasa Yoshiyama, Kunihiro Uryu, Makoto Higuchi, Luca Longhi, Rachel C Hoover, Scott Fujimoto, Tracy K Mcintosh, Virginia M Y Lee, John Q TrojanowskiAbstract:Traumatic brain injury (TBI) is a risk factors for Alzheimer's disease (AD), and repetitive TBI (rTBI) may culminate in Dementia Pugilistica (DP), a syndrome characterized by progressive Dementia, ...
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Enhanced neurofibrillary tangle formation, cerebral atrophy, and cognitive deficits induced by repetitive mild brain injury in a transgenic tauopathy mouse model
'Mary Ann Liebert Inc', 2005Co-Authors: Yasumasa Yoshiyama, Kunihiro Uryu, Makoto Higuchi, Luca Longhi, Scott Fujimoto, Virginia M Y Lee, R. Hoover, T. Mcintosh, John Q TrojanowskiAbstract:Traumatic brain injury (TBI) is a risk factors for Alzheimer's disease (AD), and repetitive TBI (rTBI) may culminate in Dementia Pugilistica (DP), a syndrome characterized by progressive Dementia, parkinsonism, and the hallmark brain lesions of AD, including neurofibrillary tangles (NFTs), formed by abnormal tau filaments and senile plaques (SPs) composed of Abeta fibrils. Previous study showed that mild rTBI (mrTBI) accelerated the deposition of Abeta in the brains of transgenic (Tg) mice (Tg2576) that over-express human Abeta precursor proteins with the familial AD Swedish mutations (APP695swe) and model of AD-like amyloidosis. Here, we report studies of the effects of mrTBI on AD-like tau pathologies in Tg mice expressing the shortest human tau isoform (T44) subjected to mrTBI, causing brain concussion without structural brain damage to simulate injuries linked to DP. Twelve-month-old Tg T44 (n = 18) and wild-type (WT; n = 24) mice were subjected to mrTBI (four times a day, 1 day per week, for 4 weeks; n = 24) or sham treatment (n = 18). Histopathological analysis of mice at 9 months after mrTBI revealed that one of the Tg T44 mice showed extensive telencephalic NFT and cerebral atrophy. Although statistical analysis of neurobehavioral tests at 6 months after mrTBI did not show any significant difference in any of groups of mice, the Tg T44 mouse with extensive NFT had an exceptionally low neurobehavioral score. The reasons for the augmentation of tau pathologies in only one T44 tau Tg mouse subjected to mrTBI remain to be elucidated
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tau isoform profile and phosphorylation state in Dementia Pugilistica recapitulate alzheimer s disease
Acta Neuropathologica, 2001Co-Authors: M L Schmidt, Virginia M Y Lee, Victoria Zhukareva, Kathy Newell, John Q TrojanowskiAbstract:Insights into mechanisms of familial Alzheimer's disease (AD) caused by genetic mutations have emerged rapidly compared to sporadic AD. Indeed, despite identification of several sporadic AD risk factors, it remains enigmatic how or why they predispose to neurodegenerative disease. For example, traumatic brain injury (TBI) predisposes to AD, and recurrent TBI in career boxers may cause a progressive memory disorder associated with AD-like brain pathology known as Dementia Pugilistica (DP). Although the reasons for this are unknown, repeated TBI may cause DP by mechanisms similar to those involved in AD. To investigate this possibility, we compared the molecular profile of tau pathologies in DP with those in AD and showed that the same tau epitopes map to filamentous tau inclusions in AD and DP brains, while the abnormal tau proteins isolated from DP brains are indistinguishable from the six abnormally phosphorylated brain tau isoforms in AD brains. Thus, these data suggest that recurrent TBI may cause DP by activating pathological mechanisms similar to those that cause brain degeneration due to accumulations of filamentous tau lesions in AD, and similar, albeit attenuated, activation of these processes by a single TBI may increase susceptibility to sporadic AD decades after the event.
Michel Goedert - One of the best experts on this subject based on the ideXlab platform.
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Novel tau filament fold in chronic traumatic encephalopathy encloses hydrophobic molecules
Nature, 2019Co-Authors: Benjamin Falcon, Jasenko Zivanov, Wenjuan Zhang, Alexey G. Murzin, Holly J. Garringer, Ruben Vidal, R. Anthony Crowther, Kathy L. Newell, Bernardino Ghetti, Michel GoedertAbstract:Cryo-electron microscopy structures of tau filaments from the brains of three individuals with chronic traumatic encephalopathy reveal distinct assembled tau conformers, with a novel protofilament fold enclosing hydrophobic molecules. Chronic traumatic encephalopathy (CTE) is a neurodegenerative tauopathy that is associated with repetitive head impacts or exposure to blast waves. First described as punch-drunk syndrome and Dementia Pugilistica in retired boxers^ 1 – 3 , CTE has since been identified in former participants of other contact sports, ex-military personnel and after physical abuse^ 4 – 7 . No disease-modifying therapies currently exist, and diagnosis requires an autopsy. CTE is defined by an abundance of hyperphosphorylated tau protein in neurons, astrocytes and cell processes around blood vessels^ 8 , 9 . This, together with the accumulation of tau inclusions in cortical layers II and III, distinguishes CTE from Alzheimer’s disease and other tauopathies^ 10 , 11 . However, the morphologies of tau filaments in CTE and the mechanisms by which brain trauma can lead to their formation are unknown. Here we determine the structures of tau filaments from the brains of three individuals with CTE at resolutions down to 2.3 Å, using cryo-electron microscopy. We show that filament structures are identical in the three cases but are distinct from those of Alzheimer’s and Pick’s diseases, and from those formed in vitro^ 12 – 15 . Similar to Alzheimer’s disease^ 12 , 14 , 16 – 18 , all six brain tau isoforms assemble into filaments in CTE, and residues K274–R379 of three-repeat tau and S305–R379 of four-repeat tau form the ordered core of two identical C-shaped protofilaments. However, a different conformation of the β-helix region creates a hydrophobic cavity that is absent in tau filaments from the brains of patients with Alzheimer’s disease. This cavity encloses an additional density that is not connected to tau, which suggests that the incorporation of cofactors may have a role in tau aggregation in CTE. Moreover, filaments in CTE have distinct protofilament interfaces to those of Alzheimer’s disease. Our structures provide a unifying neuropathological criterion for CTE, and support the hypothesis that the formation and propagation of distinct conformers of assembled tau underlie different neurodegenerative diseases.
Virginia M Y Lee - One of the best experts on this subject based on the ideXlab platform.
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enhanced neurofibrillary tangle formation cerebral atrophy and cognitive deficits induced by repetitive mild brain injury in a transgenic tauopathy mouse model
Journal of Neurotrauma, 2005Co-Authors: Yasumasa Yoshiyama, Kunihiro Uryu, Makoto Higuchi, Luca Longhi, Rachel C Hoover, Scott Fujimoto, Tracy K Mcintosh, Virginia M Y Lee, John Q TrojanowskiAbstract:Traumatic brain injury (TBI) is a risk factors for Alzheimer's disease (AD), and repetitive TBI (rTBI) may culminate in Dementia Pugilistica (DP), a syndrome characterized by progressive Dementia, ...
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Enhanced neurofibrillary tangle formation, cerebral atrophy, and cognitive deficits induced by repetitive mild brain injury in a transgenic tauopathy mouse model
'Mary Ann Liebert Inc', 2005Co-Authors: Yasumasa Yoshiyama, Kunihiro Uryu, Makoto Higuchi, Luca Longhi, Scott Fujimoto, Virginia M Y Lee, R. Hoover, T. Mcintosh, John Q TrojanowskiAbstract:Traumatic brain injury (TBI) is a risk factors for Alzheimer's disease (AD), and repetitive TBI (rTBI) may culminate in Dementia Pugilistica (DP), a syndrome characterized by progressive Dementia, parkinsonism, and the hallmark brain lesions of AD, including neurofibrillary tangles (NFTs), formed by abnormal tau filaments and senile plaques (SPs) composed of Abeta fibrils. Previous study showed that mild rTBI (mrTBI) accelerated the deposition of Abeta in the brains of transgenic (Tg) mice (Tg2576) that over-express human Abeta precursor proteins with the familial AD Swedish mutations (APP695swe) and model of AD-like amyloidosis. Here, we report studies of the effects of mrTBI on AD-like tau pathologies in Tg mice expressing the shortest human tau isoform (T44) subjected to mrTBI, causing brain concussion without structural brain damage to simulate injuries linked to DP. Twelve-month-old Tg T44 (n = 18) and wild-type (WT; n = 24) mice were subjected to mrTBI (four times a day, 1 day per week, for 4 weeks; n = 24) or sham treatment (n = 18). Histopathological analysis of mice at 9 months after mrTBI revealed that one of the Tg T44 mice showed extensive telencephalic NFT and cerebral atrophy. Although statistical analysis of neurobehavioral tests at 6 months after mrTBI did not show any significant difference in any of groups of mice, the Tg T44 mouse with extensive NFT had an exceptionally low neurobehavioral score. The reasons for the augmentation of tau pathologies in only one T44 tau Tg mouse subjected to mrTBI remain to be elucidated
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tau isoform profile and phosphorylation state in Dementia Pugilistica recapitulate alzheimer s disease
Acta Neuropathologica, 2001Co-Authors: M L Schmidt, Virginia M Y Lee, Victoria Zhukareva, Kathy Newell, John Q TrojanowskiAbstract:Insights into mechanisms of familial Alzheimer's disease (AD) caused by genetic mutations have emerged rapidly compared to sporadic AD. Indeed, despite identification of several sporadic AD risk factors, it remains enigmatic how or why they predispose to neurodegenerative disease. For example, traumatic brain injury (TBI) predisposes to AD, and recurrent TBI in career boxers may cause a progressive memory disorder associated with AD-like brain pathology known as Dementia Pugilistica (DP). Although the reasons for this are unknown, repeated TBI may cause DP by mechanisms similar to those involved in AD. To investigate this possibility, we compared the molecular profile of tau pathologies in DP with those in AD and showed that the same tau epitopes map to filamentous tau inclusions in AD and DP brains, while the abnormal tau proteins isolated from DP brains are indistinguishable from the six abnormally phosphorylated brain tau isoforms in AD brains. Thus, these data suggest that recurrent TBI may cause DP by activating pathological mechanisms similar to those that cause brain degeneration due to accumulations of filamentous tau lesions in AD, and similar, albeit attenuated, activation of these processes by a single TBI may increase susceptibility to sporadic AD decades after the event.
Ann C Mckee - One of the best experts on this subject based on the ideXlab platform.
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Chronic Traumatic Encephalopathy: Where Are We and Where Are We Going? Current Neurology and Neuroscience Reports 2013
2020Co-Authors: Jesse Mez, Robert A Stern, Ann C MckeeAbstract:Abstract Chronic traumatic encephalopathy (CTE, previously called punch drunk and Dementia Pugilistica) has a rich history in the medical literature in association with boxing, but has only recently been recognized with other contact sports, such as football and ice hockey, as well as with military blast injuries. CTE is thought to be a neurodegenerative disease associated with repeated concussive and subconcussive blows to the head. There is characteristic gross and microscopic pathology found in the brain, including frontal and temporal atrophy, axonal degeneration, and hyperphosphorylated tau and TAR DNA-binding protein 43 pathology. Clinically, there are characteristic progressive deficits in cognition (memory, executive dysfunction), behavior (explosivity, aggression), mood (depression, suicidality), and motor function (parkinsonism), which correlate with the anatomic distribution of brain pathology. While CTE shares clinical and neuropathological traits with other neurodegenerative diseases, the clinical syndrome and the neuropathology as a whole are distinct from other neurodegenerative diseases. Here we review the CTE literature to date. We also draw on the literature from mild traumatic brain injury and other neurodegenerative Dementias, particularly when these studies provide guidance for future CTE research. We conclude by suggesting seven essential areas for future CTE research
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biochemical consequences of traumatic brain injury in Dementia Pugilistica
Alzheimers & Dementia, 2012Co-Authors: Tyler A Kokjohn, Chera L Maarouf, Ian D Daugs, Marwan N Sabbagh, Ann C Mckee, Thomas G Beach, Alex E RoherAbstract:ASSOCIATED VARIANTS IN A BRAIN EXPRESSION GENOME-WIDE ASSOCIATION STUDY (EGWAS) Nilufer Ertekin-Taner, Fanggeng Zou, High Seng Chai, Curtis Younkin, Julia Crook, Vernon Pankratz, Mariet Allen, Minerva Carrasquillo, Christopher Rowley, Asha Nair, Sumit Middha, Sooraj Maharjan, Thuy Nguyen, Li Ma, Kimberly Malphrus, Ryan Palusak, Sarah Lincoln, Gina Bisceglio, Constantin Georgescu, Naomi Kouri, Christopher Kolbert, Jin Jen, Ronald Petersen, Neill Graff-Radford, Dennis Dickson, Steven Younkin, Mayo Clinic, Jacksonville, Florida, United States; Mayo Clinic, Rochester, Minnesota, United States.
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chronic traumatic encephalopathy a potential late effect of sport related concussive and subconcussive head trauma
Clinics in Sports Medicine, 2011Co-Authors: Brandon E Gavett, Robert A Stern, Ann C MckeeAbstract:It has been understood for decades that participation in certain sporting activities may increase an athlete’s risk of developing a neurodegenerative disease later in life. Not surprisingly, this association was originally noted in boxers, athletes who receive numerous blows to the head during training and competition. In 1928, Harrison Martland, a New Jersey pathologist and medical examiner, first described the clinical spectrum of abnormalities found in "nearly one half of the fighters who have stayed in the game long enough" [1.] Boxers exhibiting cognitive, behavioral, or motor abnormalities were well known to lay persons, sportswriters, and others within the boxing community and were referred to by a variety of terms, such as “punch drunk,” “goofy,” and “slug-nutty” [2, 3;] later, the more formal term Dementia Pugilistica was introduced in order to lend medical validity to the condition [4.] By the 1970s, a sufficient number of boxers with Dementia Pugilistica had been studied pathologically to support the conclusion that this form of neurodegeneration was similar to, but distinguishable from, other causes of neurodegenerative disease [5.] As evidence pertaining to the clinical and neuropathological consequences of repeated mild head trauma grew, it became clear that this pattern of neurodegeneration was not restricted to boxers, and the term chronic traumatic encephalopathy (CTE), originally coined by Miller [6,] became most widely used. Over the last several decades, clinical and neuropathological evidence of CTE has emerged in association with a variety of sports, including American football, professional wrestling, professional hockey, soccer, as well as other activities associated with repetitive mild head trauma, such as physical abuse, epileptic seizures, and head banging [7, 8, 9, 10, 11, 12, 13.] Although the incidence and prevalence of CTE is currently unclear, it likely varies by sport, position, duration of exposure, and age at the time of initial or subsequent head trauma, as well as with additional variables such as genetic predisposition. To date, there have been no randomized neuropathological studies of CTE in deceased athletes, and as such, there is a selection bias in the cases that have come to autopsy. If one considers the prevalence in deceased professional American football players who died between February 2008 and June 2010, there were 321 known player deaths [14] and the brains of 12 of the 321 underwent postmortem neuropathological examination at Boston University Center for the Study of Traumatic Encephalopathy (BU CSTE). All 12 examined neuropathologically showed evidence of CTE, suggesting an estimated lifetime prevalence rate of at least 3.7%. If one assumes that all deceased players who did not come to autopsy did not have CTE, and that the amount of head trauma in professional football has remained fairly constant over the past 5 decades, a prevalence rate of 3.7% would result. Although this represents a conservative estimate, it suggests a significant public health risk for persons who suffer repetitive mild traumatic brain injury.
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chronic traumatic encephalopathy in athletes progressive tauopathy after repetitive head injury
Journal of Neuropathology and Experimental Neurology, 2009Co-Authors: Ann C Mckee, Robert C Cantu, Christopher J Nowinski, Tessa E Hedleywhyte, Brandon E Gavett, Andrew E Budson, Veronica Santini, H J Lee, Caroline A Kubilus, Robert A SternAbstract:Since the 1920s, it has been known that the repetitive brain trauma associated with boxing may produce a progressive neurological deterioration, originally termed Dementia Pugilistica, and more recently, chronic traumatic encephalopathy (CTE). We review 48 cases of neuropathologically verified CTE recorded in the literature and document the detailed findings of CTE in 3 profession althletes, 1 football player and 2 boxers. Clinically, CTE is associated with memory disturbances, behavioral and personality changes, parkinsonism, and speech and gait abnormalities. Neuropathologically, CTE is characterized by atrophy of the cerebral hemispheres, medial temporal lobe, thalamus, mammillary bodies, and brainstem, with ventricular dilatation and a fenestrated cavum septum pellucidum. Microscopically, there are extensive tau-immunoreactive neurofibrillary tangles, astrocytic tangles, and spindle-shaped and threadlike neurites throughout the brain. The neurofibrillary degeneration of CTE is distinguished from other tauopathies by preferential involvement of the superficial cortical layers, irregular patchy distribution in the frontal and temporal cortices, propensity for sulcal depths, prominent perivascular, periventricular, and subpial distribution, and marked accumulation of tau-immunoreactive astrocytes. Deposition of beta-amyloid, most commonly as diffuse plaques, occurs in fewer than half the cases. Chronic traumatic encephalopathy is a neuropathologically distinct slowly progressive tauopathy with a clear environmental etiology.
Benjamin Falcon - One of the best experts on this subject based on the ideXlab platform.
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Novel tau filament fold in chronic traumatic encephalopathy encloses hydrophobic molecules
Nature, 2019Co-Authors: Benjamin Falcon, Jasenko Zivanov, Wenjuan Zhang, Alexey G. Murzin, Holly J. Garringer, Ruben Vidal, R. Anthony Crowther, Kathy L. Newell, Bernardino Ghetti, Michel GoedertAbstract:Cryo-electron microscopy structures of tau filaments from the brains of three individuals with chronic traumatic encephalopathy reveal distinct assembled tau conformers, with a novel protofilament fold enclosing hydrophobic molecules. Chronic traumatic encephalopathy (CTE) is a neurodegenerative tauopathy that is associated with repetitive head impacts or exposure to blast waves. First described as punch-drunk syndrome and Dementia Pugilistica in retired boxers^ 1 – 3 , CTE has since been identified in former participants of other contact sports, ex-military personnel and after physical abuse^ 4 – 7 . No disease-modifying therapies currently exist, and diagnosis requires an autopsy. CTE is defined by an abundance of hyperphosphorylated tau protein in neurons, astrocytes and cell processes around blood vessels^ 8 , 9 . This, together with the accumulation of tau inclusions in cortical layers II and III, distinguishes CTE from Alzheimer’s disease and other tauopathies^ 10 , 11 . However, the morphologies of tau filaments in CTE and the mechanisms by which brain trauma can lead to their formation are unknown. Here we determine the structures of tau filaments from the brains of three individuals with CTE at resolutions down to 2.3 Å, using cryo-electron microscopy. We show that filament structures are identical in the three cases but are distinct from those of Alzheimer’s and Pick’s diseases, and from those formed in vitro^ 12 – 15 . Similar to Alzheimer’s disease^ 12 , 14 , 16 – 18 , all six brain tau isoforms assemble into filaments in CTE, and residues K274–R379 of three-repeat tau and S305–R379 of four-repeat tau form the ordered core of two identical C-shaped protofilaments. However, a different conformation of the β-helix region creates a hydrophobic cavity that is absent in tau filaments from the brains of patients with Alzheimer’s disease. This cavity encloses an additional density that is not connected to tau, which suggests that the incorporation of cofactors may have a role in tau aggregation in CTE. Moreover, filaments in CTE have distinct protofilament interfaces to those of Alzheimer’s disease. Our structures provide a unifying neuropathological criterion for CTE, and support the hypothesis that the formation and propagation of distinct conformers of assembled tau underlie different neurodegenerative diseases.