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      Tauopathy PET and amyloid PET in the diagnosis of chronic traumatic encephalopathies: studies of a retired NFL player and of a man with FTD and a severe head injury

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          Abstract

          Single, severe traumatic brain injury (TBI) which elevates CNS amyloid, increases the risk of Alzheimer's disease (AD); while repetitive concussive and subconcussive events as observed in athletes and military personnel, may increase the risk of chronic traumatic encephalopathy (CTE). We describe two clinical cases, one with a history of multiple concussions during a career in the National Football League (NFL) and the second with frontotemporal dementia and a single, severe TBI. Both patients presented with cognitive decline and underwent [ 18F]-Florbetapir positron emission tomography (PET) imaging for amyloid plaques; the retired NFL player also underwent [ 18F]-T807 PET imaging, a new ligand binding to tau, the main constituent of neurofibrillary tangles (NFT). Case 1, the former NFL player, was 71 years old when he presented with memory impairment and a clinical profile highly similar to AD. [ 18F]-Florbetapir PET imaging was negative, essentially excluding AD as a diagnosis. CTE was suspected clinically, and [ 18F]-T807 PET imaging revealed striatal and nigral [ 18F]-T807 retention consistent with the presence of tauopathy. Case 2 was a 56-year-old man with personality changes and cognitive decline who had sustained a fall complicated by a subdural hematoma. At 1 year post injury, [ 18F]-Florbetapir PET imaging was negative for an AD pattern of amyloid accumulation in this subject. Focal [ 18F]-Florbetapir retention was noted at the site of impact. In case 1, amyloid imaging provided improved diagnostic accuracy where standard clinical and laboratory criteria were inadequate. In that same case, tau imaging with [ 18F]-T807 revealed a subcortical tauopathy that we interpret as a novel form of CTE with a distribution of tauopathy that mimics, to some extent, that of progressive supranuclear palsy (PSP), despite a clinical presentation of amnesia without any movement disorder complaints or signs. A key distinguishing feature is that our patient presented with hippocampal involvement, which is more frequently seen in CTE than in PSP. In case 2, focal [ 18F]-Florbetapir retention at the site of injury in an otherwise negative scan suggests focal amyloid aggregation. In each of these complex cases, a combination of [ 18F]-fluorodeoxyglucose, [ 18F]-Florbetapir and/or [ 18F]-T807 PET molecular imaging improved the accuracy of diagnosis and prevented inappropriate interventions.

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          Chronic traumatic encephalopathy in athletes: progressive tauopathy after repetitive head injury.

          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.
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            Chronic neuropathologies of single and repetitive TBI: substrates of dementia?

            Traumatic brain injury (TBI) has long been recognized to be a risk factor for dementia. This association has, however, only recently gained widespread attention through the increased awareness of 'chronic traumatic encephalopathy' (CTE) in athletes exposed to repetitive head injury. Originally termed 'dementia pugilistica' and linked to a career in boxing, descriptions of the neuropathological features of CTE include brain atrophy, cavum septum pellucidum, and amyloid-β, tau and TDP-43 pathologies, many of which might contribute to clinical syndromes of cognitive impairment. Similar chronic pathologies are also commonly found years after just a single moderate to severe TBI. However, little consensus currently exists on specific features of these post-TBI syndromes that might permit their confident clinical and/or pathological diagnosis. Moreover, the mechanisms contributing to neurodegeneration following TBI largely remain unknown. Here, we review the current literature and controversies in the study of chronic neuropathological changes after TBI.
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              Chronic traumatic encephalopathy in a National Football League player.

              We present the results of the autopsy of a retired professional football player that revealed neuropathological changes consistent with long-term repetitive concussive brain injury. This case draws attention to the need for further studies in the cohort of retired National Football League players to elucidate the neuropathological sequelae of repeated mild traumatic brain injury in professional football. The patient's premortem medical history included symptoms of cognitive impairment, a mood disorder, and parkinsonian symptoms. There was no family history of Alzheimer's disease or any other head trauma outside football. A complete autopsy with a comprehensive neuropathological examination was performed on the retired National Football League player approximately 12 years after retirement. He died suddenly as a result of coronary atherosclerotic disease. Studies included determination of apolipoprotein E genotype. Autopsy confirmed the presence of coronary atherosclerotic disease with dilated cardiomyopathy. The brain demonstrated no cortical atrophy, cortical contusion, hemorrhage, or infarcts. The substantia nigra revealed mild pallor with mild dropout of pigmented neurons. There was mild neuronal dropout in the frontal, parietal, and temporal neocortex. Chronic traumatic encephalopathy was evident with many diffuse amyloid plaques as well as sparse neurofibrillary tangles and tau-positive neuritic threads in neocortical areas. There were no neurofibrillary tangles or neuropil threads in the hippocampus or entorhinal cortex. Lewy bodies were absent. The apolipoprotein E genotype was E3/E3. This case highlights potential long-term neurodegenerative outcomes in retired professional National Football League players subjected to repeated mild traumatic brain injury. The prevalence and pathoetiological mechanisms of these possible adverse long-term outcomes and their relation to duration of years of playing football have not been sufficiently studied. We recommend comprehensive clinical and forensic approaches to understand and further elucidate this emergent professional sport hazard.
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                Author and article information

                Journal
                Transl Psychiatry
                Transl Psychiatry
                Translational Psychiatry
                Nature Publishing Group
                2158-3188
                September 2014
                16 September 2014
                1 September 2014
                : 4
                : 9
                : e441
                Affiliations
                [1 ]Department of Psychiatry, Icahn School of Medicine at Mount Sinai , New York, NY, USA
                [2 ]Mount Sinai's Alzheimer's Disease Research Center, Icahn School of Medicine at Mount Sinai , New York, NY, USA
                [3 ]James J. Peters VA Medical Center , Bronx, NY, USA
                [4 ]Department of Neurology, Icahn School of Medicine at Mount Sinai , New York, NY, USA
                [5 ]The NFL Neurological Program, Icahn School of Medicine at Mount Sinai , New York, NY, USA
                [6 ]Department of Nuclear Medicine, Icahn School of Medicine at Mount Sinai , New York, NY, USA
                [7 ]Fishberg Department of Neuroscience, Icahn School of Medicine at Mount Sinai , New York, NY, USA
                [8 ]Department of Radiology, Icahn School of Medicine at Mount Sinai , New York, NY, USA
                [9 ]Institute for Neurodegenerative Disorders, Yale University , New Haven, CT, USA
                [10 ]Department of Rehabilitation Medicine, Icahn School of Medicine at Mount Sinai , New York, NY, USA
                [11 ]Department of Neurology, University of Virginia , Charlottesville, VA, USA
                Author notes
                [* ]Mount Sinai's Alzheimer's Disease Research Center, James J. Peters VA Medical Center and Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, Box 1187 , New York, NY 10029, USA. E-mail: samuel.gandy@ 123456mssm.edu
                [✠]

                Deceased.

                Article
                tp201491
                10.1038/tp.2014.91
                4203018
                25226550
                9a905dff-8ae2-4c8d-8746-a4b3aae2158d
                Copyright © 2014 Macmillan Publishers Limited

                This work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 3.0 Unported License. The images or other third party material in this article are included in the article's Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-sa/3.0/

                History
                : 09 March 2014
                : 12 August 2014
                : 13 August 2014
                Categories
                Case Report

                Clinical Psychology & Psychiatry
                Clinical Psychology & Psychiatry

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