The neuropathology of sport

May combine two claims.

Focal accumulations of paired helical filament (PHF)-tau as neurofibrillary tangles and dot and spindle-shaped neurites around small blood vessels were found at the depth of the sulci in four cases; in two cases the PHF-tau immunoreactivity was consistent with Stage I CTE and in one case with Stage II CTE.

“Focal accumulations of paired helical filament (PHF)-tau as neurofibrillary tangles (NFTs) and dot and spindle-shaped neurites around small blood vessels were found at the depth of the sulci in four cases; in two cases the PHF-tau immunoreactivity was consistent with Stage I CTE and in one case with Stage II CTE.”

• AssumptionRests on an assumption: The 117 athletes in the mTBI brain bank are representative of athletes who sustain concussions, so neuropathological findings in them can be generalized to concussion pathology in athletes.

May combine two claims.

Of the 117 athletes, there were 115 males and 2 females, ranging in age at death from 14 to 98 years, mean 54.1 ± 22.3 years, including 6 athletes who died within 6 months of a reported concussion (6 males, 0 females, 14-28 years old at death, mean 18.6 ± 3.75 years).

“Of these 117 athletes, there were 115M:2F, ranging in age at death from 14 to 98 years, mean 54.1 – 22.3 years, including 6 athletes who died within 6 months of a reported concussion (6 M:0F, 14–28 years old at death, mean 18.6 – 3.75 years) (Table 1).”

• AssumptionRests on an assumption: The 117 athletes in the mTBI brain bank are representative of athletes who sustain concussions, so neuropathological findings in them can be generalized to concussion pathology in athletes.

May combine two claims.

Three of the six cases showed TDP-43 immunopositive neurites in the white matter and one case displayed mild beta amyloid deposition in leptomeningeal vessels.

“In addition, three of the six cases showed TDP-43 immunopositive neurites in the white matter and one case displayed mild beta amyloid (Ab) deposition in leptomeningeal vessels.”

• AssumptionRests on an assumption: The 117 athletes in the mTBI brain bank are representative of athletes who sustain concussions, so neuropathological findings in them can be generalized to concussion pathology in athletes.

May combine two claims.

Stage III CTE is characterized by reduced brain weight, mild frontal and temporal atrophy, enlargement of lateral and third ventricles, septal abnormalities in 50%, pallor of locus coeruleus and substantia nigra, atrophy of mammillary bodies, thalamus and hypothalamus, thinning of corpus callosum, and widespread NFTs including in hippocampus, entorhinal cortex, amygdala, nucleus basalis of Meynert

“In Stage III CTE, most brains show reduced brain weight, mild frontal and temporal atrophy, and enlargement of the lateral and third ventricles. Septal abnormalities are common (50 %), including cavum septum pellucidum or septal fenestrations. There is often pallor of the locus coeruleus and substantia nigra, atrophy of the mammillary bodies, thalamus and hypothalamus, and thinning of the corpus”

• cites [128] McKee AC, Stein TD, Nowinski CJ, Stern RA, Daneshvar DH, Alvarez VE, Lee HS, Hall G, Wojtowicz SM, Baugh CM, Riley DO, Kubilus CA, Cormier KA, Jacobs MA, Martin BR, Abraham CR, Ikezu T, Reichard RR, Wolozin BL, Budson AE, Goldstein LE, Kowall NW, Cantu RC (2013) The spectrum of disease in chronic traumatic encephalopathy. Brain 136(Pt 1):43–64. doi: 10.1093/brain/aws307 sourceNot checked yet

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• AssumptionRests on an assumption: The provisional pathological diagnostic criteria and four-stage staging system for CTE are valid for classifying the cases described.

May combine two claims.

In our autopsy series, suicide claimed the life of 33% of NFL players with Stage II CTE, and suicide combined with drug or alcohol abuse accounted for 55% of deaths.

“In our autopsy series, suicide claimed the life of 33 % NFL players with Stage II CTE and suicide combined with drug or alcohol abuse accounted for 55 % of deaths (Table 2).”

• AssumptionRests on an assumption: The autopsy series of neuropathologically confirmed CTE cases is representative enough to estimate co-occurrence, clinical features, and mortality patterns.

May combine two claims. The quote only partly states this claim.

Stage IV CTE is characterized by significant reduction of brain weight, pronounced atrophy of frontal and temporal lobes, medial temporal lobe, and anterior thalamus, marked enlargement of lateral and third ventricles, severe spongiosus of layer 2, widespread neuronal loss, severe PHF-tau deposition, and severe widespread TDP-43 deposition.

“Brains with Stage IV CTE usually show significant reduction of brain weight (Fig. 4), with pronounced atrophy of the frontal and temporal lobes, medial temporal lobe, and anterior thalamus. The hypothalamic floor is thinned, the mammillary bodies are darkly discolored and atrophied, and there is marked enlargement of the lateral and third ventricles.”

• cites [128] McKee AC, Stein TD, Nowinski CJ, Stern RA, Daneshvar DH, Alvarez VE, Lee HS, Hall G, Wojtowicz SM, Baugh CM, Riley DO, Kubilus CA, Cormier KA, Jacobs MA, Martin BR, Abraham CR, Ikezu T, Reichard RR, Wolozin BL, Budson AE, Goldstein LE, Kowall NW, Cantu RC (2013) The spectrum of disease in chronic traumatic encephalopathy. Brain 136(Pt 1):43–64. doi: 10.1093/brain/aws307 sourceNot checked yet

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• AssumptionRests on an assumption: The provisional pathological diagnostic criteria and four-stage staging system for CTE are valid for classifying the cases described.

May combine two claims.

Stage II CTE is characterized by multiple foci of PHF-tau pathology at the depths of sulci, commonly in frontal, temporal, parietal, insular, and septal cortices; NFTs in superficial layers of adjacent cerebral cortex, locus coeruleus, and substantia innominata, with medial temporal lobe structures spared; mild neurofibrillary degeneration in deep structures; and rare TDP-43 neuropil threads and

“Microscopically, multiple foci of PHF-tau pathology are found at the depths of the sulci, commonly in the frontal, temporal, parietal, insular, and septal cortices (Figs. 2, 3, 6). NFTs are also found in superficial layers of the adjacent cerebral cortex, locus coeruleus and substantia innominata, but the medial temporal lobe structures are spared. Deep structures such as the substantia nigra, dor”

• cites [128] McKee AC, Stein TD, Nowinski CJ, Stern RA, Daneshvar DH, Alvarez VE, Lee HS, Hall G, Wojtowicz SM, Baugh CM, Riley DO, Kubilus CA, Cormier KA, Jacobs MA, Martin BR, Abraham CR, Ikezu T, Reichard RR, Wolozin BL, Budson AE, Goldstein LE, Kowall NW, Cantu RC (2013) The spectrum of disease in chronic traumatic encephalopathy. Brain 136(Pt 1):43–64. doi: 10.1093/brain/aws307 sourceNot checked yet

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• AssumptionRests on an assumption: The provisional pathological diagnostic criteria and four-stage staging system for CTE are valid for classifying the cases described.

May combine two claims.

Symptoms in Stage III CTE include memory loss, executive dysfunction, explosivity, difficulty with attention and concentration, and aggression; 75% of subjects in our series were considered cognitively impaired.

“Symptoms in Stage III CTE include memory loss, executive dysfunction, explosivity, difficulty with attention and concentration, and aggression. 75 % of subjects in our series were considered cognitively impaired.”

• AssumptionRests on an assumption: The clinical symptoms reported in subjects with each CTE stage are attributable to the CTE pathology rather than to other causes.

May combine two claims.

Stage I CTE is characterized by one or two isolated perivascular foci of PHF-tau NFTs and dot-like neuropil threads, most commonly at the depths of cerebral sulci of the frontal cortex, usually with subpial PHF-tau positive astrocytes; NFTs are also commonly found in the locus coeruleus; about half of Stage I cases have abnormal TDP-43 inclusions within subcortical frontal white matter and fornix;

“Microscopically, there are one or two isolated perivascular foci of PHF-tau NFTs and dot-like neuropil threads, most commonly found at the depths of cerebral sulci of the frontal cortex (Fig. 2) and usually in association with subpial PHF-tau positive astrocytes. NFTs are also commonly found in the locus coeruleus. About half of Stage I cases will also have abnormal TDP-43 inclusions within the s”

• cites [128] McKee AC, Stein TD, Nowinski CJ, Stern RA, Daneshvar DH, Alvarez VE, Lee HS, Hall G, Wojtowicz SM, Baugh CM, Riley DO, Kubilus CA, Cormier KA, Jacobs MA, Martin BR, Abraham CR, Ikezu T, Reichard RR, Wolozin BL, Budson AE, Goldstein LE, Kowall NW, Cantu RC (2013) The spectrum of disease in chronic traumatic encephalopathy. Brain 136(Pt 1):43–64. doi: 10.1093/brain/aws307 sourceNot checked yet

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• AssumptionRests on an assumption: The provisional pathological diagnostic criteria and four-stage staging system for CTE are valid for classifying the cases described.

May combine two claims.

Symptoms in Stage IV CTE include severe executive dysfunction and memory loss with dementia; most subjects also show profound loss of attention and concentration, language difficulties, explosivity, aggressive tendencies, paranoia, depression, and gait and visuospatial difficulties.

“Symptoms in Stage IV CTE include severe executive dysfunction and memory loss with dementia. Most subjects also show profound loss of attention and concentration, language difficulties, explosivity, aggressive tendencies, paranoia, depression, and gait and visuospatial difficulties.”

• AssumptionRests on an assumption: The clinical symptoms reported in subjects with each CTE stage are attributable to the CTE pathology rather than to other causes.

May combine two claims.

In our series, Stage II CTE Ab plaques were found only in an 87-year-old former NFL player, and vascular Ab was found only in a 28-year-old former NHL player.

“In Stage II CTE in our series, Ab plaques were found only in an 87-year-old former NFL player, and vascular Ab was found only in a 28-year-old former NHL player.”

• AssumptionRests on an assumption: The autopsy series of neuropathologically confirmed CTE cases is representative enough to estimate co-occurrence, clinical features, and mortality patterns.

May combine two claims.

As in Stage II, 33% of former NFL players with Stage III CTE committed suicide, and suicide combined with drug or alcohol abuse led to 55% of deaths in Stage III CTE in our series.

“As in Stage II, 33 % of former NFL players with Stage III CTE committed suicide, and suicide combined with drug or alcohol abuse led to 55 % of deaths in Stage III CTE in our series (Table 2).”

• AssumptionRests on an assumption: The autopsy series of neuropathologically confirmed CTE cases is representative enough to estimate co-occurrence, clinical features, and mortality patterns.

May combine two claims.

Symptoms in Stage II CTE are variable, but in some instances there are prominent behavioral and personality changes, paranoia, irritability, depression, headaches, and short-term memory loss.

“Symptoms in Stage II CTE are variable, but in some instances there are prominent behavioral and personality changes, paranoia, irritability, depression, headaches, and short-term memory loss.”

• AssumptionRests on an assumption: The clinical symptoms reported in subjects with each CTE stage are attributable to the CTE pathology rather than to other causes.

May combine two claims.

Among American football players, the stage of CTE at death significantly correlates with age at death, number of years playing football, and number of years after retirement from football.

“Among American football players, the stage of CTE at death significantly correlates with age at death, number of years playing football, and number of years after retirement from football [128].”

• cites [128] McKee AC, Stein TD, Nowinski CJ, Stern RA, Daneshvar DH, Alvarez VE, Lee HS, Hall G, Wojtowicz SM, Baugh CM, Riley DO, Kubilus CA, Cormier KA, Jacobs MA, Martin BR, Abraham CR, Ikezu T, Reichard RR, Wolozin BL, Budson AE, Goldstein LE, Kowall NW, Cantu RC (2013) The spectrum of disease in chronic traumatic encephalopathy. Brain 136(Pt 1):43–64. doi: 10.1093/brain/aws307 sourceNot checked yet

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• AssumptionRests on an assumption: The provisional pathological diagnostic criteria and four-stage staging system for CTE are valid for classifying the cases described.

May combine two claims.

Most subjects with CTE-MND (63%) presented with motor weakness, atrophy, and fasciculations indistinguishable from sporadic ALS and developed mild cognitive and behavioral symptoms several years after the onset of motor symptoms.

“Most subjects (63 %) presented with motor weakness, atrophy, and fasciculations indistinguishable from sporadic ALS and developed mild cognitive and behavioral symptoms several years after the onset of motor symptoms.”

• AssumptionRests on an assumption: The autopsy series of neuropathologically confirmed CTE cases is representative enough to estimate co-occurrence, clinical features, and mortality patterns.

May combine two claims.

In our current experience of 103 neuropathologically confirmed cases of CTE, co-existent LBD was found in 12 (12%) cases, MND in 13 (13%), AD in 15 (15%), and FTLD in 6 (6%).

“In our current experience of 103 neuropathologically confirmed cases of CTE, co-existent LBD was found in 12 (12 %) cases, MND in 13 (13 %), AD in 15 (15 %), and FTLD in 6 (6 %), suggesting that either repetitive trauma or the accumulation of tau pathology in CTE provokes the deposition of other abnormal proteins involved in neurodegeneration [127, 128].”

• cites [127] McKee AC, Gavett BE, Stern RA, Nowinski CJ, Cantu RC, Kowall NW, Perl DP, Hedley-Whyte ET, Price B, Sullivan C, Morin P, Lee HS, Kubilus CA, Daneshvar DH, Wulff M, Budson AE (2010) TDP-43 proteinopathy and motor neuron disease in chronic traumatic encephalopathy. J Neuropathol Exp Neurol. doi: 10.1097/NEN.0b013e3181ee7d85 sourceNot checked yet

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• cites [128] McKee AC, Stein TD, Nowinski CJ, Stern RA, Daneshvar DH, Alvarez VE, Lee HS, Hall G, Wojtowicz SM, Baugh CM, Riley DO, Kubilus CA, Cormier KA, Jacobs MA, Martin BR, Abraham CR, Ikezu T, Reichard RR, Wolozin BL, Budson AE, Goldstein LE, Kowall NW, Cantu RC (2013) The spectrum of disease in chronic traumatic encephalopathy. Brain 136(Pt 1):43–64. doi: 10.1093/brain/aws307 sourceNot checked yet

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• AssumptionRests on an assumption: The autopsy series of neuropathologically confirmed CTE cases is representative enough to estimate co-occurrence, clinical features, and mortality patterns.

May combine two claims.

In our series, CTE was found in the brains of five hockey players, including four former NHL players.

“In our series, CTE was found in the brains of five hockey players, including four former NHL players.”

• AssumptionRests on an assumption: The autopsy series of neuropathologically confirmed CTE cases is representative enough to estimate co-occurrence, clinical features, and mortality patterns.

May combine two claims.

Stage II and III disease correlate with the onset of overt symptoms and mental distress, including depression and death due to suicide, alcohol, or drug overdose.

“Stage II and III disease correlate with the onset of overt symptoms and mental distress, including depression and death due to suicide, alcohol, or drug overdose.”

• AssumptionRests on an assumption: The clinical symptoms reported in subjects with each CTE stage are attributable to the CTE pathology rather than to other causes.

May combine two claims.

Physical exercise improves cognitive function, learning and memory, and significantly moderates age-related cognitive decline.

“improves cognitive function, learning and memory, and significantly moderates age-related cognitive decline [2, 97, 104, 110, 187, 188, 200], reviewed in [10].”

• cites [2] Ang ET, Dawe GS, Wong PT, Moochhala S, Ng YK (2006) Alterations in spatial learning and memory after forced exercise. Brain Res 1113(1):186–193. doi: 10.1016/j.brainres.2006.07.023 sourceNot checked yet

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• cites [97] Huang AM, Jen CJ, Chen HF, Yu L, Kuo YM, Chen HI (2006) Compulsive exercise acutely upregulates rat hippocampal brain-derived neurotrophic factor. J Neural Transm 113(7):803–811. doi: 10.1007/s00702-005-0359-4 sourceNot checked yet

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• cites [104] Lakka TA, Laaksonen DE (2007) Physical activity in prevention and treatment of the metabolic syndrome. Applied physiology, nutrition, and metabolism. Physiologie appliquee, nutrition et metabolisme 32(1):76–88. doi: 10.1139/h06-113 sourceNot checked yet

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• cites [110] Leung FP, Yung LM, Laher I, Yao X, Chen ZY, Huang Y (2008) Exercise, vascular wall and cardiovascular diseases: an update (Part 1). Sports Med 38(12):1009–1024. doi: 10.2165/00007256-200838120-00005 sourceNot checked yet

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• cites [187] van Praag H, Shubert T, Zhao C, Gage FH (2005) Exercise enhances learning and hippocampal neurogenesis in aged mice. J Neurosci 25(38):8680–8685. doi: 10.1523/JNEUROSCI.1731-05.2005 sourceNot checked yet

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• cites [188] Vaynman S, Gomez-Pinilla F (2006) Revenge of the “sit”: how lifestyle impacts neuronal and cognitive health through molecular systems that interface energy metabolism with neuronal plasticity. J Neurosci Res 84(4):699–715. doi: 10.1002/jnr.20979 sourceNot checked yet

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• cites [200] Yung LM, Laher I, Yao X, Chen ZY, Huang Y, Leung FP (2009) Exercise, vascular wall and cardiovascular diseases: an update (part 2). Sports Med 39(1):45–63. doi: 10.2165/00007256-200939010-00004 sourceNot checked yet

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• cites [10] Bherer L, Erickson KI, Liu-Ambrose T (2013) A review of the effects of physical activity and exercise on cognitive and brain functions in older adults. J Aging Res 2013:657508. doi: 10.1155/2013/657508Not checked yet

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Increased baseline physical activity reduces the risk of developing dementia by 28% and of developing Alzheimer's disease by 45%.

“Prospective epidemiological studies show that increased baseline physical activity reduces the risk of developing dementia by 28 % and of developing AD by 45 % [58, 83].”

• cites [58] Erickson KI, Weinstein AM, Lopez OL (2012) Physical activity, brain plasticity, and Alzheimer’s disease. Arch Med Res 43(8):615–621. doi: 10.1016/j.arcmed.2012.09.008 sourceNot checked yet

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• cites [83] Hamer M, Chida Y (2009) Physical activity and risk of neurodegenerative disease: a systematic review of prospective evidence. Psychol Med 39(1):3–11. doi: 10.1017/S0033291708003681 sourceNot checked yet

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In the hippocampus, BDNF promotes the production and survival of new neurons from stem cells and the integration of new neurons into existing neuronal circuits.

“In the hippocampus, BDNF promotes the production and survival of new neurons from stem cells and the integration of new neurons into existing neuronal circuits [141], reviewed in [160].”

• cites [141] Murer MG, Yan Q, Raisman-Vozari R (2001) Brain-derived neurotrophic factor in the control human brain, and in Alzheimer’s disease and Parkinson’s disease. Prog Neurobiol 63(1):71–124 sourceNot checked yet

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• cites [160] Rothman SM, Griffioen KJ, Wan R, Mattson MP (2012) Brain-derived neurotrophic factor as a regulator of systemic and brain energy metabolism and cardiovascular health. Ann N Y Acad Sci 1264(1):49–63. doi: 10.1111/j.1749-6632.2012.06525.x sourceNot checked yet

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May combine two claims.

Exercise training is associated with improved endothelial function, decreased arterial stiffness, and greater vascular reactivity in coronary artery disease, heart failure, and peripheral vascular disease.

“Exercise training is also associated with improved endothelial function, decreased arterial stiffness, and greater vascular reactivity associated with coronary artery disease, heart failure, and peripheral vascular disease [110].”

• cites [110] Leung FP, Yung LM, Laher I, Yao X, Chen ZY, Huang Y (2008) Exercise, vascular wall and cardiovascular diseases: an update (Part 1). Sports Med 38(12):1009–1024. doi: 10.2165/00007256-200838120-00005 sourceNot checked yet

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May combine two claims.

Exercise is neuroprotective, delays the onset and progression, and reduces the risk for many neurodegenerative diseases, including Alzheimer's disease and Parkinson's disease.

“Exercise has also been shown to be neuroprotective, to delay the onset and progression, and reduce the risk for many neurodegenerative diseases, including Alzheimer’s disease (AD) and Parkinson’s disease (PD) [17, 39, 58, 89, 108, 163, 193, 199].”

• cites [17] Buchman AS, Boyle PA, Yu L, Shah RC, Wilson RS, Bennett DA (2012) Total daily physical activity and the risk of AD and cognitive decline in older adults. Neurology 78(17):1323–1329. doi: 10.1212/WNL.0b013e3182535d35 sourceNot checked yet

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• cites [39] Cotman CW, Berchtold NC, Christie LA (2007) Exercise builds brain health: key roles of growth factor cascades and inflammation. Trends Neurosci 30(9):464–472. doi: 10.1016/j.tins.2007.06.011 sourceNot checked yet

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• cites [58] Erickson KI, Weinstein AM, Lopez OL (2012) Physical activity, brain plasticity, and Alzheimer’s disease. Arch Med Res 43(8):615–621. doi: 10.1016/j.arcmed.2012.09.008 sourceNot checked yet

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• cites [89] Heyn P, Abreu BC, Ottenbacher KJ (2004) The effects of exercise training on elderly persons with cognitive impairment and dementia: a meta-analysis. Arch Phys Med Rehabil 85(10):1694–1704 sourceNot checked yet

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• cites [108] Lautenschlager NT, Cox KL, Flicker L, Foster JK, van Bockxmeer FM, Xiao J, Greenop KR, Almeida OP (2008) Effect of physical activity on cognitive function in older adults at risk for Alzheimer disease: a randomized trial. JAMA 300(9):1027–1037. doi: 10.1001/jama.300.9.1027 sourceNot checked yet

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• cites [163] Sattler C, Erickson KI, Toro P, Schroder J (2011) Physical fitness as a protective factor for cognitive impairment in a prospective population-based study in Germany. J Alzheimers Dis 26(4):709–718. doi: 10.3233/JAD-2011-110548 sourceNot checked yet

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• cites [193] Weuve J, Kang JH, Manson JE, Breteler MM, Ware JH, Grodstein F (2004) Physical activity, including walking, and cognitive function in older women. JAMA 292(12):1454–1461. doi: 10.1001/jama.292.12.1454 sourceNot checked yet

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• cites [199] Yaffe K, Barnes D, Nevitt M, Lui LY, Covinsky K (2001) A prospective study of physical activity and cognitive decline in elderly women: women who walk. Arch Intern Med 161(14):1703–1708 sourceNot checked yet

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Higher levels of physical activity, exercise training, and overall cardiorespiratory fitness reduce the risk for hypertension, obesity, type 2 diabetes mellitus, stroke, and metabolic syndrome, and lower cardiovascular mortality.

“Higher levels of physical activity, exercise training, and overall cardiorespiratory fitness reduce the risk for hypertension, obesity, type 2 diabetes mellitus, stroke, and metabolic syndrome, as well as lower cardiovascular mortality [104, 110, 178, 200].”

• cites [104] Lakka TA, Laaksonen DE (2007) Physical activity in prevention and treatment of the metabolic syndrome. Applied physiology, nutrition, and metabolism. Physiologie appliquee, nutrition et metabolisme 32(1):76–88. doi: 10.1139/h06-113 sourceNot checked yet

  Not checked in the free run.

• cites [110] Leung FP, Yung LM, Laher I, Yao X, Chen ZY, Huang Y (2008) Exercise, vascular wall and cardiovascular diseases: an update (Part 1). Sports Med 38(12):1009–1024. doi: 10.2165/00007256-200838120-00005 sourceNot checked yet

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• cites [178] Swift DL, Lavie CJ, Johannsen NM, Arena R, Earnest CP, O’Keefe JH, Milani RV, Blair SN, Church TS (2013) Physical activity, cardiorespiratory fitness, and exercise training in primary and secondary coronary prevention. Circ J Off J Jpn Circ Soc 77(2):281–292Not checked yet

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• cites [200] Yung LM, Laher I, Yao X, Chen ZY, Huang Y, Leung FP (2009) Exercise, vascular wall and cardiovascular diseases: an update (part 2). Sports Med 39(1):45–63. doi: 10.2165/00007256-200939010-00004 sourceNot checked yet

  Not checked in the free run.

May combine two claims.

BDNF acts on neurons to promote growth, increase synaptic plasticity, and enhance resistance to injury and neurodegeneration.

“BDNF acts on neurons to promote growth, increase synaptic plasticity, and enhance resistance to injury and neurodegeneration.”

May combine two claims.

Physical activity increases antioxidant enzymes, including superoxide dismutase and heat shock proteins, and reduces reactive oxygen species.

“Physical activity increases antioxidant enzymes, including superoxide dismutase and heat shock proteins, and reduces reactive oxygen species [178].”

• cites [178] Swift DL, Lavie CJ, Johannsen NM, Arena R, Earnest CP, O’Keefe JH, Milani RV, Blair SN, Church TS (2013) Physical activity, cardiorespiratory fitness, and exercise training in primary and secondary coronary prevention. Circ J Off J Jpn Circ Soc 77(2):281–292Not checked yet

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Physical exercise directly promotes neurogenesis, cell survival, synaptogenesis, synaptic plasticity, and angiogenesis.

“physical exercise also directly promotes neurogenesis, cell survival [187], synaptogenesis, synaptic plasticity [54, 96] and angiogenesis [99]”

• cites [187] van Praag H, Shubert T, Zhao C, Gage FH (2005) Exercise enhances learning and hippocampal neurogenesis in aged mice. J Neurosci 25(38):8680–8685. doi: 10.1523/JNEUROSCI.1731-05.2005 sourceNot checked yet

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• cites [54] Eadie BD, Redila VA, Christie BR (2005) Voluntary exercise alters the cytoarchitecture of the adult dentate gyrus by increasing cellular proliferation, dendritic complexity, and spine density. J Comp Neurol 486(1):39–47. doi: 10.1002/cne.20493 sourceNot checked yet

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• cites [96] Hu S, Ying Z, Gomez-Pinilla F, Frautschy SA (2009) Exercise can increase small heat shock proteins (sHSP) and pre- and post-synaptic proteins in the hippocampus. Brain Res 1249:191–201. doi: 10.1016/j.brainres.2008.10.054 sourceNot checked yet

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• cites [99] Isaacs KR, Anderson BJ, Alcantara AA, Black JE, Greenough WT (1992) Exercise and the brain: angiogenesis in the adult rat cerebellum after vigorous physical activity and motor skill learning. J Cereb Blood Flow Metab 12(1):110–119. doi: 10.1038/jcbfm.1992.14 sourceNot checked yet

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Improved physical fitness is associated with more efficient cognitive functions, and longitudinal studies show less cognitive decline in working memory, processing speed, attention, and executive function in older adults without dementia.

“Cross-sectional studies show that improved physical fitness is associated with more efficient cognitive functions and longitudinal studies show less cognitive decline in working memory, processing speed, attention, and executive function in older adults without dementia [170].”

• cites [170] Smith PJ, Blumenthal JA, Hoffman BM, Cooper H, Strauman TA, Welsh-Bohmer K, Browndyke JN, Sherwood A (2010) Aerobic exercise and neurocognitive performance: a meta-analytic review of randomized controlled trials. Psychosom Med 72(3):239–252. doi: 10.1097/PSY.0b013e3181d14633 sourceNot checked yet

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Aerobic exercise increases hippocampal and cortical volume and significantly improves spatial memory after 1 year.

“Aerobic exercise increases hip-pocampal and cortical volume and significantly improves spatial memory after 1 year [57].”

• cites [57] Erickson KI, Voss MW, Prakash RS, Basak C, Szabo A, Chaddock L, Kim JS, Heo S, Alves H, White SM, Wojcicki TR, Mailey E, Vieira VJ, Martin SA, Pence BD, Woods JA, McAuley E, Kramer AF (2011) Exercise training increases size of hippocampus and improves memory. Proc Natl Acad Sci USA 108(7):3017–3022. doi: 10.1073/pnas.1015950108 sourceNot checked yet

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Regular exercise produces beneficial effects on high-density lipoprotein-cholesterol levels, glucose control, weight control, resting heart rate, and blood pressure.

“Regular exercise produces beneficial effects in high-density lipoprotein-cholesterol levels, glucose control, weight control, and resting heart rate and blood pressure [178].”

• cites [178] Swift DL, Lavie CJ, Johannsen NM, Arena R, Earnest CP, O’Keefe JH, Milani RV, Blair SN, Church TS (2013) Physical activity, cardiorespiratory fitness, and exercise training in primary and secondary coronary prevention. Circ J Off J Jpn Circ Soc 77(2):281–292Not checked yet

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May combine two claims.

Exercise training suppresses chronic low-grade inflammation and reduces levels of C-reactive protein and TNF-alpha.

“Exercise training also suppresses chronic low-grade inflammation and reduces levels of C-reactive protein and TNF-alpha [152].”

• cites [152] Petersen AM, Pedersen BK (2005) The anti-inflammatory effect of exercise. J Appl Physiol (1985) 98(4):1154–1162. doi: 10.1152/japplphysiol.00164.2004 sourceNot checked yet

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Early post-injury exercise reverses memory deficits and inhibits the progression of neurodegeneration following TBI.

“early post-injury exercise has been shown to reverse memory deficits and inhibit the progression of neurodegeneration following TBI [27].”

• cites [27] Chen MF, Huang TY, Kuo YM, Yu L, Chen HI, Jen CJ (2013) Early postinjury exercise reverses memory deficits and retards the progression of closed-head injury in mice. J Physiol 591(Pt 4):985–1000. doi: 10.1113/jphysiol.2012.241125 sourceNot checked yet

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71% of affected second-impact syndrome athletes have been American football players, usually at the high school level, but younger players and collegiate athletes have occasionally been reported.

“71 % of the affected athletes have been American football players, usually at the high school level, but younger players and collegiate athletes have occasionally been reported.”

May combine two claims.

Treadmill exercise improves hippocampus-dependent spatial learning and memory as well as aversive memory.

“Treadmill exercise also improves hippocampus-dependent spatial learning and memory as well as aversive memory [2, 3, 25, 97, 112, 174, 186, 187].”

• cites [2] Ang ET, Dawe GS, Wong PT, Moochhala S, Ng YK (2006) Alterations in spatial learning and memory after forced exercise. Brain Res 1113(1):186–193. doi: 10.1016/j.brainres.2006.07.023 sourceNot checked yet

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• cites [3] Ang ET, Gomez-Pinilla F (2007) Potential therapeutic effects of exercise to the brain. Curr Med Chem 14(24):2564–2571 sourceNot checked yet

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• cites [25] Chen HI, Lin LC, Yu L, Liu YF, Kuo YM, Huang AM, Chuang JI, Wu FS, Liao PC, Jen CJ (2008) Treadmill exercise enhances passive avoidance learning in rats: the role of down-regulated serotonin system in the limbic system. Neurobiol Learn Mem 89(4):489–496. doi: 10.1016/j.nlm.2007.08.004 sourceNot checked yet

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• cites [97] Huang AM, Jen CJ, Chen HF, Yu L, Kuo YM, Chen HI (2006) Compulsive exercise acutely upregulates rat hippocampal brain-derived neurotrophic factor. J Neural Transm 113(7):803–811. doi: 10.1007/s00702-005-0359-4 sourceNot checked yet

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• cites [112] Liu YF, Chen HI, Yu L, Kuo YM, Wu FS, Chuang JI, Liao PC, Jen CJ (2008) Upregulation of hippocampal TrkB and synaptotagmin is involved in treadmill exercise-enhanced aversive memory in mice. Neurobiol Learn Mem 90(1):81–89. doi: 10.1016/j.nlm.2008.02.005 sourceNot checked yet

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• cites [174] Soya H, Nakamura T, Deocaris CC, Kimpara A, Iimura M, Fujikawa T, Chang H, McEwen BS, Nishijima T (2007) BDNF induction with mild exercise in the rat hippocampus. Biochem Biophys Res Commun 358(4):961–967. doi: 10.1016/j.bbrc.2007.04.173 sourceNot checked yet

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• cites [186] van Praag H, Christie BR, Sejnowski TJ, Gage FH (1999) Running enhances neurogenesis, learning, and long-term potentiation in mice. Proc Natl Acad Sci USA 96(23):13427–13431 sourceNot checked yet

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• cites [187] van Praag H, Shubert T, Zhao C, Gage FH (2005) Exercise enhances learning and hippocampal neurogenesis in aged mice. J Neurosci 25(38):8680–8685. doi: 10.1523/JNEUROSCI.1731-05.2005 sourceNot checked yet

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The largest number of deaths in the US National Registry of Sudden Death in Young Athletes was reported in American football (148 [57%]), including 17 high school athletes who sustained concussions shortly before a fatal head trauma (second-impact syndrome).

“with the largest number of deaths reported in American football (148 [57 %]), including 17 high school athletes who sustained concussions shortly before a fatal head trauma (“second-impact syndrome”) [181].”

• cites [181] Thomas M, Haas TS, Doerer JJ, Hodges JS, Aicher BO, Garberich RF, Mueller FO, Cantu RC, Maron BJ (2011) Epidemiology of sudden death in young, competitive athletes due to blunt trauma. Pediatrics 128(1):e1–e8. doi: 10.1542/peds.2010-2743 sourceNot checked yet

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Exercise improves motor performance in individuals with Parkinson's disease, lowers disability in multiple sclerosis, improves functionality in individuals with motor neuron disease, and improves cognitive, mood and motor recovery from TBI.

“exercise also improves motor performance in individuals with Parkinson’s disease [153], lowers disability in multiple sclerosis [161], improves functionality in individuals with motor neuron disease [46], and improves cognitive, mood and motor recovery from TBI, although the precise timing and intensity of the beneficial exercise after TBI remain to be determined [62, 197].”

• cites [153] Petzinger GM, Fisher BE, McEwen S, Beeler JA, Walsh JP, Jakowec MW (2013) Exercise-enhanced neuroplasticity targeting motor and cognitive circuitry in Parkinson’s disease. Lancet Neurol 12(7):716–726. doi: 10.1016/S1474-4422(13)70123-6 sourceNot checked yet

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• cites [161] Sa MJ (2013) Exercise therapy and multiple sclerosis: a systematic review. J Neurol. doi: 10.1007/s00415-013-7183-9Not checked yet

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• cites [46] Dal Bello-Haas V, Florence JM (2013) Therapeutic exercise for people with amyotrophic lateral sclerosis or motor neuron disease. The Cochrane Database Syst Rev 5:CD005229. doi: 10.1002/14651858.CD005229.pub3 sourceNot checked yet

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Second-impact syndrome occurs when an athlete sustains an initial mild head injury or concussion, then suffers a second head injury before the symptoms associated with the first impact have cleared, with resultant diffuse cerebral swelling and grave deterioration.

“Second-impact syndrome (SIS) occurs when an athlete sustains an initial mild head injury or concussion, then suffers a second head injury before the symptoms associated with the first impact have cleared, with resultant diffuse cerebral swelling and grave deterioration [19, 20, 113, 133, 137, 164].”

• cites [19] Cantu R, Gean A (2010) Second impact syndrome in a small SDH: an uncommon catastrophic result of repetitive head injury with a characteristic imaging appearance. J Neurotrauma. doi: 10.1089/neu.2010.1334 sourceNot checked yet

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• cites [20] Cantu RC (1998) Second-impact syndrome. Clin Sports Med 17(1):37–44 sourceNot checked yet

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• cites [113] Logan SM, Bell GW, Leonard JC (2001) Acute subdural hematoma in a high school football player after 2 unreported episodes of head trauma: a case report. J Athl Train 36(4):433–436Not checked yet

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• cites [133] Miele VJ, Carson L, Carr A, Bailes JE (2004) Acute on chronic subdural hematoma in a female boxer: a case report. Med Sci Sports Exerc 36(11):1852–1855 sourceNot checked yet

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• cites [137] Mori T, Katayama Y, Kawamata T (2006) Acute hemispheric swelling associated with thin subdural hematomas: pathophysiology of repetitive head injury in sports. Acta Neurochirurgica Supplement 96:40–43 sourceNot checked yet

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• cites [164] Saunders RL, Harbaugh RE (1984) The second impact in catastrophic contact-sports head trauma. JAMA 252(4):538–539 sourceNot checked yet

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Analysis of the 30-year US National Registry of Sudden Death in Young Athletes from 1980 to 2009 found 1,827 deaths in athletes aged 21 years or younger, including 261 (14%) due to trauma, most often to the head and neck.

“Analysis of the 30-year US National Registry of Sudden Death in Young Athletes from 1980 to 2009 found 1,827 deaths in athletes aged 21 years or younger (mean 16 – 2 years; 90 % male) including 261 (14 %) due to trauma, most often to the head and neck.”

• cites [181] Thomas M, Haas TS, Doerer JJ, Hodges JS, Aicher BO, Garberich RF, Mueller FO, Cantu RC, Maron BJ (2011) Epidemiology of sudden death in young, competitive athletes due to blunt trauma. Pediatrics 128(1):e1–e8. doi: 10.1542/peds.2010-2743 sourceNot checked yet

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Rodents that run voluntarily on running wheels exhibit increased numbers of dendritic spines and synapses in hippocampal neurons, increased neurogenesis, and improved performance in some behavioral tests of cognitive function.

“Rodents that run voluntarily on running wheels exhibit increased numbers of dendritic spines and synapses in hippocampal neurons, increased neurogenesis, and improved performance in some behavioral tests of cognitive function [59, 185].”

• cites [59] Farmer J, Zhao X, van Praag H, Wodtke K, Gage FH, Christie BR (2004) Effects of voluntary exercise on synaptic plasticity and gene expression in the dentate gyrus of adult male Sprague–Dawley rats in vivo. Neuroscience 124(1):71–79. doi: 10.1016/j.neuroscience.2003.09.029 sourceNot checked yet

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• cites [185] Valois RF, Zullig KJ, Huebner ES, Drane JW (2004) Physical activity behaviors and perceived life satisfaction among public high school adolescents. J Sch Health 74(2):59–65 sourceNot checked yet

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All reported cases of second-impact syndrome have involved young athletes, predominantly males (90%) ranging in age from 10 to 24 years, mean age 17.9 years.

“All reported cases of SIS have involved young athletes, predominantly males (90 %) ranging in age from 10 to 24 years, mean age 17.9 years [137].”

• cites [137] Mori T, Katayama Y, Kawamata T (2006) Acute hemispheric swelling associated with thin subdural hematomas: pathophysiology of repetitive head injury in sports. Acta Neurochirurgica Supplement 96:40–43 sourceNot checked yet

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The mortality rate in the US National Registry of Sudden Death in Young Athletes was 0.11 in 100,000 participants (95% confidence interval 0.08-0.15).

“The mortality rate was 0.11 in 100,000 participants (95 % confidence interval 0.08–0.15)”

• cites [181] Thomas M, Haas TS, Doerer JJ, Hodges JS, Aicher BO, Garberich RF, Mueller FO, Cantu RC, Maron BJ (2011) Epidemiology of sudden death in young, competitive athletes due to blunt trauma. Pediatrics 128(1):e1–e8. doi: 10.1542/peds.2010-2743 sourceNot checked yet

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In a cohort of 3,207 male nonprofessional rugby players followed for one or more seasons, the incidence of mTBI was 7.97 per 1,000 player game hours, with 313 players (9.8%) sustaining one or more mTBIs during the study.

“In a cohort of 3,207 male nonprofessional rugby players followed for one or more seasons, the incidence of mTBI was 7.97 per 1,000 player game hours, with 313 players (9.8 %) sustaining 1 or more mTBIs during the study.”

• cites [94] Hong YT, Veenith T, Dewar D, Outtrim JG, Mani V, Williams C, Pimlott S, Hutchinson PJ, Tavares A, Canales R, Mathis CA, Klunk WE, Aigbirhio FI, Coles JP, Baron JC, Pickard JD, Fryer TD, Stewart W, Menon DK (2013) Amyloid Imaging With Carbon 11-Labeled Pittsburgh Compound B for Traumatic Brain Injury. JAMA Neurol. doi: 10.1001/jamaneurol.2013.4847 sourceNot checked yet

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High school football was associated with a concussion rate of 0.21 per 1,000 athlete exposures in practice and 1.55 concussions per 1,000 athlete exposures in competitions, compared to 0.39 per 1,000 athlete exposures in practice and 3.02 per 1,000 athlete exposures in competitions in collegiate football players.

“high school football was associated with concussion rate of 0.21 per 1,000 athlete exposures (A–E) in practice and 1.55 concussions per 1,000 A–E in competitions, compared to 0.39 per 1,000 A-E in practice and a rate of 3.02 concussions per 1,000 A-E in competitions in collegiate football players [68].”

• cites [68] Gessel LM, Fields SK, Collins CL, Dick RW, Comstock RD (2007) Concussions among United States high school and collegiate athletes. J Athl Train 42(4):495–503Not checked yet

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Symptoms from concussion and other forms of mTBI are usually self-limited and resolve spontaneously over a period of several weeks, although 10-30% of individuals develop prolonged symptoms.

“Symptoms from concussion and other forms of mTBI are usually self-limited and resolve spontaneously over a period of several weeks, although 10–30 % of individuals develop prolonged symptoms.”

• cites [51] Dean PJ, Sterr A (2013) Long-term effects of mild traumatic brain injury on cognitive performance. Frontiers Hum Neurosci 7:30. doi: 10.3389/fnhum.2013.00030Not checked yet

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Traumatic axonal injury does not uniformly affect all axonal populations; smaller, unmyelinated axons may be more susceptible to damage from concussive forces than larger myelinated axons.

“Traumatic axonal injury (TAI) does not uniformly affect all axonal populations; smaller, unmyelinated axons may be more susceptible to damage from concussive forces than larger myelinated axons [158].”

• cites [158] Reeves TM, Phillips LL, Povlishock JT (2005) Myelinated and unmyelinated axons of the corpus callosum differ in vulnerability and functional recovery following traumatic brain injury. Exp Neurol 196(1):126–137. doi: 10.1016/j.expneurol.2005.07.014 sourceNot checked yet

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Estimates of the concussion rate in high school soccer range from 1.38 concussions per 1,000 game time athlete exposures for boys to 1.80 for girls.

“Estimates of the concussion rate in high school soccer range from 1.38 concussions per 1,000 game time A-E for boys to 1.80 for girls [68].”

• cites [68] Gessel LM, Fields SK, Collins CL, Dick RW, Comstock RD (2007) Concussions among United States high school and collegiate athletes. J Athl Train 42(4):495–503Not checked yet

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Studies using accelerometers found linear accelerations as high as 54.7g in high school players heading a soccer ball kicked from a distance of 30 yards, more than the average peak accelerations of 29.2 or 35g that occur in football or ice hockey.

“Studies using accelerometers to measure the peak accelerations of the head during soccer heading found linear accelerations as high as 54.7g in high school players heading a soccer ball kicked from a distance of 30 yards, more than the average peak accelerations of 29.2 or 35g that occur in football or ice hockey [142].”

• cites [142] Naunheim RS, Standeven J, Richter C, Lewis LM (2000) Comparison of impact data in hockey, football, and soccer. J Trauma 48(5):938–941 sourceNot checked yet

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Pathological studies of acute concussion and post-concussive syndrome are rare and often include subjects with more severe traumatic injuries, but multifocal traumatic axonal injury, microhemorrhage, and microglial activation have been reported.

“Pathological studies of acute concussion and PCS are rare and often include subjects with more severe traumatic injuries, but multifocal traumatic axonal injury TAI, microhemorrhage, and microglial activation have been reported [12, 150].”

• cites [12] Blumbergs PC, Scott G, Manavis J, Wainwright H, Simpson DA, McLean AJ (1994) Staining of amyloid precursor protein to study axonal damage in mild head injury. Lancet 344(8929):1055–1056 sourceNot checked yet

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• cites [150] Oppenheimer DR (1968) Microscopic lesions in the brain following head injury. J Neurol Neurosurg Psychiatry 31(4):299–306 sourceNot checked yet

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The Centers for Disease Control estimates that 1.6 to 3.8 million concussions occur in sports and recreational activities annually in the US.

“The Centers for Disease Control estimates that 1.6 to 3.8 million concussions occur in sports and recreational activities annually in the US [47].”

• cites [47] Daneshvar DH, Nowinski CJ, McKee AC, Cantu RC (2011) The epidemiology of sport-related concussion. Clin Sports Med 30(1):1–17, vii. doi: 10.1016/j.csm.2010.08.006 sourceNot checked yet

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Clinical and functional impairments in cognition have been correlated with the frequency of impacts to the head in high school and collegiate football players wearing helmet-mounted accelerometers, although not all helmet sensor studies have supported this relationship.

“Clinical and functional impairments in cognition have also been correlated with the frequency of impacts to the head in high school and collegiate football players wearing helmet-mounted accelerometers [16, 121, 180], although not all helmet sensor studies have supported this relationship [81].”

• cites [16] Breedlove EL, Robinson M, Talavage TM, Morigaki KE, Yoruk U, O’Keefe K, King J, Leverenz LJ, Gilger JW, Nauman EA (2012) Biomechanical correlates of symptomatic and asymptomatic neurophysiological impairment in high school football. J Biomech 45(7):1265–1272. doi: 10.1016/j.jbiomech.2012.01.034 sourceNot checked yet

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• cites [121] McAllister TW, Flashman LA, Maerlender A, Greenwald RM, Beckwith JG, Tosteson TD, Crisco JJ, Brolinson PG, Duma SM, Duhaime AC, Grove MR, Turco JH (2012) Cognitive effects of one season of head impacts in a cohort of collegiate contact sport athletes. Neurology 78(22):1777–1784. doi: 10.1212/WNL.0b013e3182582fe7 sourceNot checked yet

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• cites [180] Talavage TM, Nauman EA, Breedlove EL, Yoruk U, Dye AE, Morigaki KE, Feuer H, Leverenz LJ (2013) Functionally-detected cognitive impairment in high school football players without clinically-diagnosed concussion. J Neurotrauma. doi: 10.1089/neu.2010.1512Not checked yet

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• cites [81] Gysland SM, Mihalik JP, Register-Mihalik JK, Trulock SC, Shields EW, Guskiewicz KM (2012) The relationship between subconcussive impacts and concussion history on clinical measures of neurologic function in collegiate football players. Ann Biomed Eng 40(1):14–22. doi: 10.1007/s10439-011-0421-3 sourceNot checked yet

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Diffusion tensor imaging provides information about the white matter microstructure and fiber tract integrity and is emerging as a valuable tool in refining the diagnosis, prognosis, and management of mTBI.

“Diffusion tensor imaging (DTI), however, provides information about the white matter microstructure and fiber tract integrity and is emerging as a valuable tool in refining the diagnosis, prognosis, and management of mTBI [5, 149, 196].”

• cites [5] Aoki Y, Inokuchi R, Gunshin M, Yahagi N, Suwa H (2012) Diffusion tensor imaging studies of mild traumatic brain injury: a meta-analysis. J Neurol Neurosurg Psychiatry 83(9):870–876. doi: 10.1136/jnnp-2012-302742 sourceNot checked yet

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• cites [149] Oni MB, Wilde EA, Bigler ED, McCauley SR, Wu TC, Yallampalli R, Chu Z, Li X, Hunter JV, Vasquez AC, Levin HS (2010) Diffusion tensor imaging analysis of frontal lobes in pediatric traumatic brain injury. J Child Neurol 25(8):976–984. doi: 10.1177/0883073809356034 sourceNot checked yet

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• cites [196] Wilde EA, McCauley SR, Hunter JV, Bigler ED, Chu Z, Wang ZJ, Hanten GR, Troyanskaya M, Yallampalli R, Li X, Chia J, Levin HS (2008) Diffusion tensor imaging of acute mild traumatic brain injury in adolescents. Neurology 70(12):948–955. doi: 10.1212/01.wnl.0000305961.68029.54 sourceNot checked yet

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Depression in former professional football players is also associated with increased fractional anisotropy on DTI, as well as white matter abnormalities on structural imaging.

“Depression in these athletes is also associated with increased fractional anisotropy on DTI, as well as white matter abnormalities on structural imaging [87, 176].”

• cites [87] Hart J Jr, Kraut MA, Womack KB, Strain J, Didehbani N, Bartz E, Conover H, Mansinghani S, Lu H, Cullum CM (2013) Neuroimaging of cognitive dysfunction and depression in aging retired National Football League players: a cross-sectional study. JAMA Neurol 70(3):326–335. doi: 10.1001/2013.jamaneurol.340 sourceNot checked yet

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• cites [176] Strain J, Didehbani N, Cullum CM, Mansinghani S, Conover H, Kraut MA, Hart J Jr, Womack KB (2013) Depressive symptoms and white matter dysfunction in retired NFL players with concussion history. Neurology 81(1):25–32. doi: 10.1212/WNL.0b013e318299ccf8 sourceNot checked yet

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The severity of symptoms after mTBI correlates with reduction of white matter integrity on DTI, suggesting that persistent microstructural brain injury underlies the symptoms of post-concussive syndrome.

“the severity of symptoms after mTBI correlates with reduction of white matter integrity on DTI, suggesting that persistent microstructural brain injury underlies the symptoms of PCS [45].”

• cites [45] Cubon VA, Putukian M, Boyer C, Dettwiler A (2011) A diffusion tensor imaging study on the white matter skeleton in individuals with sports-related concussion. J Neurotrauma 28(2):189–201. doi: 10.1089/neu2010.1430 sourceNot checked yet

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NFTs in CTE differ from AD in topography, and individual NFTs in CTE are generally larger with more dot-like and spindle-shaped neurites.

“In addition to a different topography of NFTs in CTE compared to AD, the size of individual NFTs in CTE is generally larger and the neurites are more dot like and spindle shaped [128].”

• cites [128] McKee AC, Stein TD, Nowinski CJ, Stern RA, Daneshvar DH, Alvarez VE, Lee HS, Hall G, Wojtowicz SM, Baugh CM, Riley DO, Kubilus CA, Cormier KA, Jacobs MA, Martin BR, Abraham CR, Ikezu T, Reichard RR, Wolozin BL, Budson AE, Goldstein LE, Kowall NW, Cantu RC (2013) The spectrum of disease in chronic traumatic encephalopathy. Brain 136(Pt 1):43–64. doi: 10.1093/brain/aws307 sourceNot checked yet

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Astrocytic PHF-tau pathology in CTE is predominantly 4R tau immunopositive and more widely distributed than that reported in the medial temporal lobe in aging and AD.

“Astrocytic PHF-tau pathology in CTE is predominantly 4R tau immunopositive, but more widely distributed than that reported in the medial temporal lobe in aging and AD [103, 114].”

• cites [103] Lace G, Ince PG, Brayne C, Savva GM, Matthews FE, de Silva R, Simpson JE, Wharton SB (2012) Mesial temporal astrocyte tau pathology in the MRC-CFAS ageing brain cohort. Dement Geriatr Cogn Disord 34(1):15–24. doi: 10.1159/000341581 sourceNot checked yet

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• cites [114] Lopez-Gonzalez I, Carmona M, Blanco R, Luna-Munoz J, Martinez-Mandonado A, Mena R, Ferrer I (2013) Characterization of thorn-shaped astrocytes in white matter of temporal lobe in Alzheimer’s disease brains. Brain Pathol 23(2):144–153. doi: 10.1111/j.1750-3639.2012.00627.x sourceNot checked yet

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The clinical symptoms associated with CTE were examined in case summaries throughout the twentieth century; however, the disease presentation described in these reports was inconsistent.

“The clinical symptoms associated with this disease were examined in case summaries throughout the twentieth century; however, the disease presentation described in these reports was inconsistent [38, 65, 92, 100, 126].”

• cites [38] Corsellis JA, Bruton CJ, Freeman-Browne D (1973) The aftermath of boxing. Psychol Med 3(3):270–303 sourceNot checked yet

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• cites [65] Geddes JF, Vowles GH, Nicoll JA, Revesz T (1999) Neuronal cytoskeletal changes are an early consequence of repetitive head injury. Acta Neuropathol (Berl) 98(2):171–178 sourceNot checked yet

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• cites [92] Hof PR, Knabe R, Bovier P, Bouras C (1991) Neuropathological observations in a case of autism presenting with self-injury behavior. Acta Neuropathol (Berl) 82(4):321–326 sourceNot checked yet

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• cites [100] Jordan BD, Kanik AB, Horwich MS, Sweeney D, Relkin NR, Petito CK, Gandy S (1995) Apolipoprotein E epsilon 4 and fatal cerebral amyloid angiopathy associated with dementia pugilistica. Ann Neurol 38(4):698–699. doi: 10.1002/ana.410380429 sourceNot checked yet

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• cites [126] McKee AC, Cantu RC, Nowinski CJ, Hedley-Whyte ET, Gavett BE, Budson AE, Santini VE, Lee HS, Kubilus CA, Stern RA (2009) Chronic traumatic encephalopathy in athletes: progressive tauopathy after repetitive head injury. J Neuropathol Exp Neurol 68(7):709–735. doi: 10.1097/NEN.0b013e3181a9d503 sourceNot checked yet

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Geddes described argyrophilic, PHF-tau positive neocortical NFTs and neurites arranged in groups around small intracortical blood vessels in the absence of Ab, a feature that distinguishes early CTE from other tauopathies.

“Geddes described argyrophilic, PHF-tau positive neocortical NFTs and neurites, strikingly arranged in groups around small intracortical blood vessels, in the absence of Ab [65], a feature that has recently been found to distinguish even early stages of CTE from other tauopathies.”

• cites [65] Geddes JF, Vowles GH, Nicoll JA, Revesz T (1999) Neuronal cytoskeletal changes are an early consequence of repetitive head injury. Acta Neuropathol (Berl) 98(2):171–178 sourceNot checked yet

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In CTE, neuronal loss occurs in the cerebellar tonsils and substantia nigra, and neurofibrillary degeneration occurs in the substantia nigra and cerebral cortex.

“Neuronal loss was noted in the cerebellar tonsils and substantia nigra with Cresyl violet stain, and there was neurofibrillary degeneration of the substantia nigra and cerebral cortex using Von Braunmühl’s silver stain.”

• cites [38] Corsellis JA, Bruton CJ, Freeman-Browne D (1973) The aftermath of boxing. Psychol Med 3(3):270–303 sourceNot checked yet

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Young control subjects in studies interpreting locus coeruleus phosphorylated tau abnormalities as early AD pathology were not screened for a history of exposure to mTBI, despite mTBI being common among young individuals and 17% of control subjects dying from acute trauma or accidental death.

“Although some studies have interpreted phosphorylated tau abnormalities in the locus coeruleus to be an early stage of AD pathology [15], young control subjects were not screened for a history of exposure to mTBI despite the fact that mTBI is common among young individuals and that 17 % of the control subjects died from acute trauma or accidental death.”

• cites [15] Braak H, Del Tredici K (2011) The pathological process underlying Alzheimer’s disease in individuals under thirty. Acta Neuropathol (Berl) 121(2):171–181. doi: 10.1007/s00401-010-0789-4 sourceNot checked yet

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Stress and resultant axonal injury are greatest at the interface of two tissues with differing viscoelastic properties, and the depths of cortical sulci are areas of stress concentration.

“Stress and resultant axonal injury are greatest at the interface of two tissues with differing viscoelastic properties (such as between blood vessels and brain, or between gray and white matter) and the depths of the cortical sulci are areas of stress concentration [11, 28, 33].”

• cites [11] Blennow K, Hardy J, Zetterberg H (2012) The neuropathology and neurobiology of traumatic brain injury. Neuron 76(5):886–899. doi: 10.1016/j.neuron.2012.11.021 sourceNot checked yet

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• cites [28] Chen XH, Siman R, Iwata A, Meaney DF, Trojanowski JQ, Smith DH (2004) Long-term accumulation of amyloid-beta, beta-secretase, presenilin-1, and caspase-3 in damaged axons following brain trauma. Am J Pathol 165(2):357–371 sourceNot checked yet

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• cites [33] Cloots RJ, Gervaise HM, van Dommelen JA, Geers MG (2008) Biomechanics of traumatic brain injury: influences of the morphologic heterogeneities of the cerebral cortex. Ann Biomed Eng 36(7):1203–1215. doi: 10.1007/s10439-008-9510-3 sourceNot checked yet

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CTE is similar to AD in its tau isoform profile and phosphorylation state, and neuronal tau pathology is immunoreactive to both 3R and 4R tau.

“CTE is similar to AD in its tau isoform profile and phosphorylation state [165], and neuronal tau pathology is immunoreactive to both 3R and 4R tau [128].”

• cites [165] Schmidt ML, Zhukareva V, Newell KL, Lee VM, Trojanowski JQ (2001) Tau isoform profile and phosphorylation state in dementia pugilistica recapitulate Alzheimer’s disease. Acta Neuropathol (Berl) 101(5):518–524 sourceNot checked yet

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• cites [128] McKee AC, Stein TD, Nowinski CJ, Stern RA, Daneshvar DH, Alvarez VE, Lee HS, Hall G, Wojtowicz SM, Baugh CM, Riley DO, Kubilus CA, Cormier KA, Jacobs MA, Martin BR, Abraham CR, Ikezu T, Reichard RR, Wolozin BL, Budson AE, Goldstein LE, Kowall NW, Cantu RC (2013) The spectrum of disease in chronic traumatic encephalopathy. Brain 136(Pt 1):43–64. doi: 10.1093/brain/aws307 sourceNot checked yet

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Two presentations of CTE were found: one consisting of behavioral and mood symptoms usually appearing in the third decade of life (mean age at onset of 35 years) and another consisting of cognitive impairment and memory loss developing in the fifth decade (mean age at onset of 59 years).

“Specifically, two presentations of CTE were found, one that consisted of behavioral and mood symptoms usually appearing in the third decade of life (mean age at onset of 35 years) and another consisting of cognitive impairment and memory loss developing in the fifth decade (mean age at onset of 59 years).”

• cites [175] Stern RA, Daneshvar DH, Baugh CM, Seichepine DR, Montenigro PH, Riley DO, Fritts NG, Stamm JM, Robbins CA, McHale L, I. S, Stein TD, V. A, Goldstein LE, Budson AE, Kowall NW, Nowinski CJ, Cantu RC, McKee AC (2013) Clinical presentation of neuropathologically-confirmed chronic traumatic encephalopathy in athletes. Neurology (in Press) sourceNot checked yet

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Medial temporal lobe PHF-tau pathology is not found in early stages of CTE, while it is considered the hallmark of emerging or preclinical AD pathology.

“Additionally, medial temporal lobe PHF-tau pathology is not found in early stages of CTE, while it is considered the hallmark of emerging or preclinical AD pathology.”

May combine two claims.

The locus coeruleus shows neurofibrillary PHF-tau pathology in early stages of CTE, which can be substantial even in individuals under the age of 30.

“Characteristically, the locus coeruleus shows neurofibrillary PHF-tau pathology in early stages of CTE, which can be substantial even in individuals under the age of 30.”

May combine two claims.

Stage I CTE is most likely preclinical, although some subjects with Stage I pathology report vague and non-specific symptoms such as headache, loss of attention and concentration, short-term memory difficulties, and depression.

“This stage is most likely preclinical, although some subjects with Stage I pathology report vague and non-specific symptoms such as headache, loss of attention and concentration, short-term memory difficulties, and depression.”

• AssumptionRests on an assumption: The provisional pathological diagnostic criteria and four-stage staging system for CTE are valid for classifying the cases described.

May combine two claims.

Factors that might contribute to increased vulnerability to trauma in the developing brain include age-specific differences in myelination rates, synaptic pruning, neurotrophic factor levels, brain water content, cerebral blood flow, and glucocorticoid receptor expression.

“Factors that might contribute to increased vulnerability to trauma in the developing brain include age-specific differences in myelination rates, synaptic pruning, neurotrophic factor levels, brain water content, cerebral blood flow, and glucocorticoid receptor expression [69, 76, 183].”

• cites [69] Giedd JN, Blumenthal J, Jeffries NO, Castellanos FX, Liu H, Zijdenbos A, Paus T, Evans AC, Rapoport JL (1999) Brain development during childhood and adolescence: a longitudinal MRI study. Nat Neurosci 2(10):861–863. doi: 10.1038/13158 sourceNot checked yet

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• cites [76] Grieve SM, Korgaonkar MS, Clark CR, Williams LM (2011) Regional heterogeneity in limbic maturational changes: evidence from integrating cortical thickness, volumetric and diffusion tensor imaging measures. Neuroimage 55(3):868–879. doi: 10.1016/j.neuroimage.2010.12.087 sourceNot checked yet

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• cites [183] Uematsu A, Matsui M, Tanaka C, Takahashi T, Noguchi K, Suzuki M, Nishijo H (2012) Developmental trajectories of amygdala and hippocampus from infancy to early adulthood in healthy individuals. PLoS ONE 7(10):e46970. doi: 10.1371/journal.pone.0046970PONE-D-12-12929 sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Axonal pathology is present at all stages of CTE and becomes more severe as CTE stage advances.

“In addition to PHF-tau pathology, axonal pathology is present at all stages of CTE and becomes more severe as CTE stage advances [72, 128].”

• cites [72] Goldstein LE, Fisher AM, Tagge CA, Zhang XL, Velisek L, Sullivan JA, Upreti C, Kracht JM, Ericsson M, Wojnarowicz MW, Goletiani CJ, Maglakelidze GM, Casey N, Moncaster JA, Minaeva O, Moir RD, Nowinski CJ, Stern RA, Cantu RC, Geiling J, Blusztajn JK, Wolozin BL, Ikezu T, Stein TD, Budson AE, Kowall NW, Chargin D, Sharon A, Saman S, Hall GF, Moss WC, Cleveland RO, Tanzi RE, Stanton PK, McKee AC (2012) Chronic traumatic encephalopathy in blast-exposed military veterans and a blast neurotrauma mouse model. Sci Transl Med 4(134):134ra60. doi: 10.1126/scitranslmed.3003716 sourceNot checked yet

  Not checked in the free run.

• cites [128] McKee AC, Stein TD, Nowinski CJ, Stern RA, Daneshvar DH, Alvarez VE, Lee HS, Hall G, Wojtowicz SM, Baugh CM, Riley DO, Kubilus CA, Cormier KA, Jacobs MA, Martin BR, Abraham CR, Ikezu T, Reichard RR, Wolozin BL, Budson AE, Goldstein LE, Kowall NW, Cantu RC (2013) The spectrum of disease in chronic traumatic encephalopathy. Brain 136(Pt 1):43–64. doi: 10.1093/brain/aws307 sourceNot checked yet

  Not checked in the free run.

May combine two claims.

The developing brain may be more susceptible to poor outcomes following TBI; studies suggest children and adolescents experience prolonged recovery rates after TBI compared to adults and poorer outcome.

“In addition, the developing brain may be more susceptible to poor outcomes following TBI. Studies have suggested that children and adolescents experience prolonged recovery rates after TBI compared to adults [61] and poorer outcome [70].”

• cites [61] Field M, Collins MW, Lovell MR, Maroon J (2003) Does age play a role in recovery from sports-related concussion? A comparison of high school and collegiate athletes. J Pediatr 142(5):546–553. doi: 10.1067/mpd.2003.190 sourceNot checked yet

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• cites [70] Giza CC, Griesbach GS, Hovda DA (2005) Experience-dependent behavioral plasticity is disturbed following traumatic injury to the immature brain. Behav Brain Res 157(1):11–22. doi: 10.1016/j.bbr.2004.06.003 sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Despite evidence for Ab deposition in moderate to severe TBI, Ab plaques have not been found in early or mild stages of CTE in young individuals, but occur in older subjects with CTE in association with increased age at death.

“However, despite evidence for Ab deposition in moderate to severe TBI [94], Ab plaques have not been found in early or mild stages of CTE in young individuals [65, 66, 72, 91, 126] but occur in older subjects with CTE in association with increased age at death [128].”

• cites [94] Hong YT, Veenith T, Dewar D, Outtrim JG, Mani V, Williams C, Pimlott S, Hutchinson PJ, Tavares A, Canales R, Mathis CA, Klunk WE, Aigbirhio FI, Coles JP, Baron JC, Pickard JD, Fryer TD, Stewart W, Menon DK (2013) Amyloid Imaging With Carbon 11-Labeled Pittsburgh Compound B for Traumatic Brain Injury. JAMA Neurol. doi: 10.1001/jamaneurol.2013.4847 sourceNot checked yet

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• cites [65] Geddes JF, Vowles GH, Nicoll JA, Revesz T (1999) Neuronal cytoskeletal changes are an early consequence of repetitive head injury. Acta Neuropathol (Berl) 98(2):171–178 sourceNot checked yet

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• cites [66] Geddes JF, Vowles GH, Robinson SF, Sutcliffe JC (1996) Neurofibrillary tangles, but not Alzheimer-type pathology, in a young boxer. Neuropathol Appl Neurobiol 22(1):12–16 sourceNot checked yet

  Not checked in the free run.

• cites [72] Goldstein LE, Fisher AM, Tagge CA, Zhang XL, Velisek L, Sullivan JA, Upreti C, Kracht JM, Ericsson M, Wojnarowicz MW, Goletiani CJ, Maglakelidze GM, Casey N, Moncaster JA, Minaeva O, Moir RD, Nowinski CJ, Stern RA, Cantu RC, Geiling J, Blusztajn JK, Wolozin BL, Ikezu T, Stein TD, Budson AE, Kowall NW, Chargin D, Sharon A, Saman S, Hall GF, Moss WC, Cleveland RO, Tanzi RE, Stanton PK, McKee AC (2012) Chronic traumatic encephalopathy in blast-exposed military veterans and a blast neurotrauma mouse model. Sci Transl Med 4(134):134ra60. doi: 10.1126/scitranslmed.3003716 sourceNot checked yet

  Not checked in the free run.

• cites [91] Hof PR, Bouras C, Buee L, Delacourte A, Perl DP, Morrison JH (1992) Differential distribution of neurofibrillary tangles in the cerebral cortex of dementia pugilistica and Alzheimer’s disease cases. Acta Neuropathol (Berl) 85(1):23–30 sourceNot checked yet

  Not checked in the free run.

• cites [126] McKee AC, Cantu RC, Nowinski CJ, Hedley-Whyte ET, Gavett BE, Budson AE, Santini VE, Lee HS, Kubilus CA, Stern RA (2009) Chronic traumatic encephalopathy in athletes: progressive tauopathy after repetitive head injury. J Neuropathol Exp Neurol 68(7):709–735. doi: 10.1097/NEN.0b013e3181a9d503 sourceNot checked yet

  Not checked in the free run.

• cites [128] McKee AC, Stein TD, Nowinski CJ, Stern RA, Daneshvar DH, Alvarez VE, Lee HS, Hall G, Wojtowicz SM, Baugh CM, Riley DO, Kubilus CA, Cormier KA, Jacobs MA, Martin BR, Abraham CR, Ikezu T, Reichard RR, Wolozin BL, Budson AE, Goldstein LE, Kowall NW, Cantu RC (2013) The spectrum of disease in chronic traumatic encephalopathy. Brain 136(Pt 1):43–64. doi: 10.1093/brain/aws307 sourceNot checked yet

  Not checked in the free run.

May combine two claims.

The early and predominant involvement of PHF-tau pathology in the superior and dorsolateral frontal lobes in football players parallels the high frequency of impacts to the top of the head compared to the front, back, and side of the head in football, as well as fMRI data showing activation impairment in dorsolateral prefrontal cortex associated with higher numbers of head collisions to the top--

“The early and predominant involvement of PHF-tau pathology in the superior and dorsolateral frontal lobes in football players parallels the high frequency of impacts to the top of the head compared to those to the front, back, and side of the head in football [79], as well as fMRI data showing activation impairment in dorsolateral prefrontal cortex that is associated with significantly higher num”

• cites [79] Guskiewicz KM, Mihalik JP, Shankar V, Marshall SW, Crowell DH, Oliaro SM, Ciocca MF, Hooker DN (2007) Measurement of head impacts in collegiate football players: relationship between head impact biomechanics and acute clinical outcome after concussion. Neurosurgery 61(6):1244–1252; discussion 1252–1243. doi: 10.1227/01.neu.0000306103.68635.1a sourceNot checked yet

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• cites [180] Talavage TM, Nauman EA, Breedlove EL, Yoruk U, Dye AE, Morigaki KE, Feuer H, Leverenz LJ (2013) Functionally-detected cognitive impairment in high school football players without clinically-diagnosed concussion. J Neurotrauma. doi: 10.1089/neu.2010.1512Not checked yet

  Not checked in the free run.

May combine two claims.

Rodent studies have shown that glucocorticoids and stress increase tau phosphorylation and cognitive deficits, and PHF-tau immunoreactivity in opiate user brains is significantly higher than in age-matched controls.

“Rodent studies have shown that glucocorticoids and stress increase tau phosphorylation and cognitive deficits [75, 144, 173], and PHF-tau immunoreactivity in opiate user brains is significantly higher than in age-matched controls [4].”

• cites [75] Green KN, Billings LM, Roozendaal B, McGaugh JL, LaFerla FM (2006) Glucocorticoids increase amyloid-beta and tau pathology in a mouse model of Alzheimer’s disease. J Neurosci 26(35):9047–9056. doi: 10.1523/JNEUROSCI.2797-06.2006 sourceNot checked yet

  Not checked in the free run.

• cites [144] Okawa Y, Ishiguro K, Fujita SC (2003) Stress-induced hyperphosphorylation of tau in the mouse brain. FEBS Lett 535(1–3):183–189 sourceNot checked yet

  Not checked in the free run.

• cites [173] Sotiropoulos I, Catania C, Riedemann T, Fry JP, Breen KC, Michaelidis TM, Almeida OF (2008) Glucocorticoids trigger Alzheimer disease-like pathobiochemistry in rat neuronal cells expressing human tau. J Neurochem 107(2):385–397. doi: 10.1111/j.1471-4159.2008.05613.x sourceNot checked yet

  Not checked in the free run.

• cites [4] Anthony IC, Norrby KE, Dingwall T, Carnie FW, Millar T, Arango JC, Robertson R, Bell JE (2010) Predisposition to accelerated Alzheimer-related changes in the brains of human immunodeficiency virus negative opiate abusers. Brain 133(Pt 12):3685–3698. doi: 10.1093/brain/awq263 sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Abnormal TDP-43 pathology is found in all stages of CTE; in early stages the inclusions consist of neuritic threads and dot-like inclusions in subpial, perivascular, and periventricular regions; cytoplasmic neuronal inclusions are first seen in Stage II disease and are characteristic of late stages where they partially co-localize with PHF-tau inclusions.

“Abnormal TDP-43 pathology is found in all stages of CTE. In early stages the inclusions consist of neuritic threads and dot-like inclusions in subpial, perivascular, and periventricular regions; cytoplasmic neuronal inclusions are first seen in Stage II disease and are characteristic of late stages where they partially co-localize with PHF-tau inclusions [128].”

• cites [128] McKee AC, Stein TD, Nowinski CJ, Stern RA, Daneshvar DH, Alvarez VE, Lee HS, Hall G, Wojtowicz SM, Baugh CM, Riley DO, Kubilus CA, Cormier KA, Jacobs MA, Martin BR, Abraham CR, Ikezu T, Reichard RR, Wolozin BL, Budson AE, Goldstein LE, Kowall NW, Cantu RC (2013) The spectrum of disease in chronic traumatic encephalopathy. Brain 136(Pt 1):43–64. doi: 10.1093/brain/aws307 sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Either repetitive trauma or the accumulation of tau pathology in CTE provokes the deposition of other abnormal proteins involved in neurodegeneration.

“In our current experience of 103 neuropathologically confirmed cases of CTE, co-existent LBD was found in 12 (12 %) cases, MND in 13 (13 %), AD in 15 (15 %), and FTLD in 6 (6 %), suggesting that either repetitive trauma or the accumulation of tau pathology in CTE provokes the deposition of other abnormal proteins involved in neurodegeneration [127, 128].”

• cites [127] McKee AC, Gavett BE, Stern RA, Nowinski CJ, Cantu RC, Kowall NW, Perl DP, Hedley-Whyte ET, Price B, Sullivan C, Morin P, Lee HS, Kubilus CA, Daneshvar DH, Wulff M, Budson AE (2010) TDP-43 proteinopathy and motor neuron disease in chronic traumatic encephalopathy. J Neuropathol Exp Neurol. doi: 10.1097/NEN.0b013e3181ee7d85 sourceNot checked yet

  Not checked in the free run.

• cites [128] McKee AC, Stein TD, Nowinski CJ, Stern RA, Daneshvar DH, Alvarez VE, Lee HS, Hall G, Wojtowicz SM, Baugh CM, Riley DO, Kubilus CA, Cormier KA, Jacobs MA, Martin BR, Abraham CR, Ikezu T, Reichard RR, Wolozin BL, Budson AE, Goldstein LE, Kowall NW, Cantu RC (2013) The spectrum of disease in chronic traumatic encephalopathy. Brain 136(Pt 1):43–64. doi: 10.1093/brain/aws307 sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Some data suggests that trauma and athletic exposure are risk factors for developing ALS, although there are conflicting reports regarding single versus repetitive head injury.

“Some data suggests that trauma and athletic exposure are risk factors for developing ALS [30, 31, 166], although there are conflicting reports regarding single versus repetitive head injury [24].”

• cites [30] Chio A, Benzi G, Dossena M, Mutani R, Mora G (2005) Severely increased risk of amyotrophic lateral sclerosis among Italian professional football players. Brain 128(Pt 3):472–476. doi: 10.1093/brain/awh373 sourceNot checked yet

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• cites [31] Chio A, Calvo A, Dossena M, Ghiglione P, Mutani R, Mora G (2009) ALS in Italian professional soccer players: the risk is still present and could be soccer-specific. Amyotroph Lateral Scler 10(4):205–209. doi: 10.1080/17482960902721634 sourceNot checked yet

  Not checked in the free run.

• cites [166] Schmidt S, Kwee LC, Allen KD, Oddone EZ (2010) Association of ALS with head injury, cigarette smoking and APOE genotypes. J Neurol Sci 291(1–2):22–29. doi: 10.1016/j.jns.2010.01.011 sourceNot checked yet

  Not checked in the free run.

• cites [24] Chen H, Richard M, Sandler DP, Umbach DM, Kamel F (2007) Head injury and amyotrophic lateral sclerosis. Am J Epidemiol 166(7):810–816. doi: 10.1093/aje/kwm153 sourceNot checked yet

  Not checked in the free run.

May combine two claims.

TDP-43 binds to many cellular transcripts including tau and alpha synuclein, and its dysregulation may underlie some of the pathologies seen with these proteins; TDP-43 may influence tau isoform expression.

“TDP-43 binds to many cellular transcripts including tau and alpha synuclein, and its dysregulation may underlie some of the pathologies seen with these proteins [162]. In particular, TDP-43 may influence tau iso-form expression [136].”

• cites [162] Sato T, Takeuchi S, Saito A, Ding W, Bamba H, Matsuura H, Hisa Y, Tooyama I, Urushitani M (2009) Axonal ligation induces transient redistribution of TDP-43 in brainstem motor neurons. Neuroscience 164(4):1565–1578. doi: 10.1016/j.neuroscience.2009.09.050 sourceNot checked yet

  Not checked in the free run.

• cites [136] Morales R, Green KM, Soto C (2009) Cross currents in protein misfolding disorders: interactions and therapy. CNS Neurol Disord: Drug Targets 8(5):363–371 sourceNot checked yet

  Not checked in the free run.

May combine two claims.

TDP-43 is an RNA-binding protein that regulates RNA metabolism, including mRNA splicing, stability, and transport; after acute traumatic injury in animal models, TDP-43 expression is upregulated and TDP-43 relocates from the neuronal nucleus to accumulate in the neuronal cytoplasm.

“TDP-43 is an RNA-binding protein that regulates RNA metabolism, including mRNA splicing, stability, and transport [167]. After acute traumatic injury in animal models, TDP-43 expression is upregulated and TDP-43 relocates from the neuronal nucleus to accumulate in the neuronal cytoplasm [134, 135]”

• cites [167] Sephton CF, Cenik B, Cenik BK, Herz J, Yu G (2012) TDP-43 in central nervous system development and function: clues to TDP-43-associated neurodegeneration. Biol Chem 393(7):589–594. doi: 10.1515/hsz-2012-0115 sourceNot checked yet

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• cites [134] Moisse K, Mepham J, Volkening K, Welch I, Hill T, Strong MJ (2009) Cytosolic TDP-43 expression following axotomy is associated with caspase 3 activation in NFL−/− mice: support for a role for TDP-43 in the physiological response to neuronal injury. Brain Res 1296:176–186. doi: 10.1016/j.brainres.2009.07.023 sourceNot checked yet

  Not checked in the free run.

• cites [135] Moisse K, Volkening K, Leystra-Lantz C, Welch I, Hill T, Strong MJ (2009) Divergent patterns of cytosolic TDP-43 and neuronal progranulin expression following axotomy: implications for TDP-43 in the physiological response to neuronal injury. Brain Res 1249:202–211. doi: 10.1016/j.brainres.2008.10.021 sourceNot checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S3 (load-bearing).

In different autopsy series, the percentage of former professional American football players who have died and donated their brains to research varies from 50%, 80%, to 97%.

“In different autopsy series, the percentage of former professional American football players who have died and donated their brains to research varies from 50 % [88], 80 % [146], to 97 %) [128].”

• cites [88] Hazrati LN, Tartaglia MC, Diamandis P, Davis KD, Green RE, Wennberg R, Wong JC, Ezerins L, Tator CH (2013) Absence of chronic traumatic encephalopathy in retired football players with multiple concussions and neurological symptomatology. Frontiers Hum Neurosci 7:222. doi: 10.3389/fnhum.2013.00222 sourceNot checked yet

  Not checked in the free run.

• cites [146] Omalu B, Bailes J, Hamilton RL, Kamboh MI, Hammers J, Case M, Fitzsimmons R (2011) Emerging histomorphologic phenotypes of chronic traumatic encephalopathy in American athletes. Neurosurgery 69(1):173–183; discussion 183. doi: 10.1227/NEU.0b013e318212bc7b sourceNot checked yet

  Not checked in the free run.

• cites [128] McKee AC, Stein TD, Nowinski CJ, Stern RA, Daneshvar DH, Alvarez VE, Lee HS, Hall G, Wojtowicz SM, Baugh CM, Riley DO, Kubilus CA, Cormier KA, Jacobs MA, Martin BR, Abraham CR, Ikezu T, Reichard RR, Wolozin BL, Budson AE, Goldstein LE, Kowall NW, Cantu RC (2013) The spectrum of disease in chronic traumatic encephalopathy. Brain 136(Pt 1):43–64. doi: 10.1093/brain/aws307 sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Individuals who present with motor symptoms of MND have milder CTE at death (Stages II-III), a reflection of their shortened life span, whereas those who present with cognitive symptoms die with advanced CTE (Stage III and IV).

“Individuals who present with motor symptoms of MND have milder CTE at death (Stages II–III), a reflection of their shortened life span, whereas those who present with cognitive symptoms die with advanced CTE (Stage III and IV).”

• AssumptionRests on an assumption: The provisional pathological diagnostic criteria and four-stage staging system for CTE are valid for classifying the cases described.

May combine two claims.

American football is the most common sport associated with CTE, accounting for more than half of reported cases; 75% of reported football players with CTE played at the professional level.

“American football is the most common sport associated with CTE, accounting for more than half of reported cases; 75 % of reported football players with CTE played at the professional level.”

Classified as probably not a substantial claim. May combine two claims.

An initial trauma may induce a focal change in PHF-tau and continued exposure to repetitive trauma may induce multifocal, more widespread PHF-tau changes.

“The sequence of neuropathological changes in CTE—first as a single focus and later as multiple perivascular foci of PHF-tau at the depths of the cerebral sulci—and their association with acute axonal injury and microbleeds suggest that an initial trauma may induce a focal change in PHF-tau and that continued exposure to repetitive trauma may induce multifocal, more widespread PHF-tau changes (Now”

• cites (Nowinski, personal communication)Not checked yet

  Not checked in the free run.

Classified as probably not a substantial claim. May combine two claims.

The incidence and prevalence of CTE are not currently known and their precise determination will require longitudinal clinical studies and the capability to accurately diagnose CTE during life.

“The incidence and prevalence of CTE are not currently known and their precise determination will require longitudinal clinical studies and the capability to accurately diagnose CTE during life.”

May combine two claims.

CTE has been reported most frequently in American football players and boxers, but players of other sports are also vulnerable, including those participating in ice hockey, professional wrestling, soccer, rugby, and baseball.

“CTE has been reported most frequently in American football players and boxers, but players of other sports are also vulnerable, including those participating in ice hockey, professional wrestling, soccer, rugby, and baseball.”

Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

Whether an isolated PHF-tau lesion advances to involve adjacent brain parenchyma may depend on additional factors, including age, gender, exposure to other toxins, and genetic susceptibilities.

“Whether an isolated PHF-tau lesion advances to involve adjacent brain parenchyma may depend on additional factors, including age, gender, exposure to other toxins, and genetic susceptibilities.”

Probably not a substantial claim: may not pass S2 (checkable), S3 (load-bearing), S4 (based). May combine two claims.

Accepting trauma as the primary cause for CTE would have enormous financial repercussions, necessitate major changes in the play or management of many popular sports, and constitute a paradigm shift in the science of neurodegeneration.

“Resistance is perhaps understandable, as accepting trauma as the primary cause for CTE would have enormous financial repercussions, as well as necessitate major changes in the play or management of many popular sports and constitute a paradigm shift in the science of neurode-generation.”

Probably not a substantial claim: may not pass S3 (load-bearing).

The progression of CTE from a multifocal state (Stage II) to widespread disease (Stage III) might represent a period of exponential increase in PHF-tau accumulation, hypothetically from such mechanisms as protein templating or other modes of interneuronal spreading.

“The progression of CTE from a multifocal state (Stage II) to widespread disease (Stage III) might represent a period of exponential increase in PHF-tau accumulation, hypothetically from such mechanisms as protein templating or other modes of interneuronal spreading [128].”

• cites [128] McKee AC, Stein TD, Nowinski CJ, Stern RA, Daneshvar DH, Alvarez VE, Lee HS, Hall G, Wojtowicz SM, Baugh CM, Riley DO, Kubilus CA, Cormier KA, Jacobs MA, Martin BR, Abraham CR, Ikezu T, Reichard RR, Wolozin BL, Budson AE, Goldstein LE, Kowall NW, Cantu RC (2013) The spectrum of disease in chronic traumatic encephalopathy. Brain 136(Pt 1):43–64. doi: 10.1093/brain/aws307 sourceNot checked yet

  Not checked in the free run.

May combine two claims.

The play of sports is associated with risks including TBI, catastrophic traumatic injury and death.

“Nonetheless, the play of sports is also associated with some risks, including risks for TBI, catastrophic traumatic injury and death.”

May combine two claims.

Three of the hockey players were enforcers, which likely contributed to their overall exposure to repetitive brain trauma.

“Three of the hockey players were enforcers, which likely contributed to their overall exposure to repetitive brain trauma.”

May combine two claims.

There is growing awareness that repetitive minor TBIs may lead to persistent cognitive, behavioral, and psychiatric problems and, rarely, to the development of CTE.

“There is also growing awareness that repetitive minor TBIs may lead to persistent cognitive, behavioral, and psychiatric problems and, rarely, to the development of CTE.”

Probably not a substantial claim: may not pass S3 (load-bearing).

It is possible, even likely, that some individuals develop a single isolated focus of PHF-tau that never progresses.

“It is possible, even likely, that some individuals develop a single isolated focus of PHF-tau that never progresses.”