DNA repair deficiency and senescence in concussed professional athletes involved in contact sports

May combine two claims.

DNA damage was seen in peri-neuronal glial cells, ependymal and subependymal cells, oligodendrocytes in the white matter, and sub-pial astrocytes.

“DNA damage was seen in peri-neuronal glial cells (Fig. 1a), ependymal and subependymal cells (Fig. 1b), oligodendrocytes in the white matter (Fig. 1c), and sub-pial astrocytes (Fig. 1d).”

May combine two claims.

DNA damage was not seen in neurons, and endothelial cells were spared.

“DNA damage was not seen in neurons, and spared endothelial cells.”

May combine two claims.

Among mTBI cases, 14 (50%) were stage one, 5 (17.9%) stage two, and 9 (32.1%) stage three.

“Fourteen (50%) cases were considered stage one, which presented with DNA damage throughout the ependymal lining only (Fig. 2).”

• Also stated in: § DNA damage assessment and distribution · plain

  “Five (17.9%) cases were considered stage two, which presented with DNA damage throughout the ependymal lining, and additionally in astrocytes in sub-ventricular (Fig. 2) and sub-pial areas, and peri-neuronal glial cells.”

• Also stated in: § DNA damage assessment and distribution · plain

  “Nine (32.1%) cases were considered stage three, which presented with DNA damage in the ependymal lining, astrocytes in grey matter (peri-neuronal satellite cells), sub-pial region, and surrounding cortical tissue, and additionally in oligodendrocytes of the white matter.”

May combine two claims.

Stage one cases had mean positive cell density of 46% for ependymal cells, and no positive astrocytes or oligodendrocytes; stage two had 74% ependymal, 12% astrocytes, no oligodendrocytes; stage three had 96% ependymal, 51% astrocytes, 34% oligodendrocytes.

“Stage one cases had a mean positive cell density of 46% for ependymal cells, and no positive astrocytes or oligodendrocytes. Stage two cases had a mean positive cell density of 74% for ependymal cells, 12% for astrocytes, and no positive oligodendrocytes. Stage three cases had a mean positive cell density of 96% for ependymal cells, 51% for astrocytes, and 34% for oligodendrocytes.”

May combine two claims.

Sub-pial GFAP-positive processes were normal in control cases with no evidence of DNA damage.

“In contrast, sub-pial GFAP-positive processes were normal in control cases with no evidence of DNA damage (Fig. 11e and f).”

May combine two claims.

Lamin B1 was normally expressed in control brains but reduced in expression in mTBI cases.

“The second protein lost in mTBI brains compared to controls was lamin B1. Indeed, lamin B1 was normally expressed in control brains (Fig. 9a) but reduced in expression in our cases (Fig. 9b).”

May combine two claims.

Cases showed decreased expression of DDB1, DDB2, ATRIP, and ATR, although not all statistically significant.

“cases showed decreased expression of genes involved in the DDR specifically to single-stranded DNA breaks, although not all of these were statistically significant. These included DDB1 (p = 0.05), DDB2 (p = 0.24), ATRIP (p = 0.01), and ATR (p = 0.02).”

May combine two claims.

In the neurodegenerative pathology group (n=20), DNA damage was found in 80% of cases, with 35% stage one, 17% stage two, and 47% stage three.

“in the neurodegenerative pathology group (n = 20), DNA damage was found in 80% of cases, with 35% being stage one, 17% stage two, and 47% stage three.”

May combine two claims.

DNA repair genes displayed a general trend towards decreased expression with 36 genes significantly down-regulated and 9 genes significantly up-regulated in mTBI brains compared to controls.

“DNA repair genes displayed a general trend towards decreased expression with 36 genes significantly down-regulated (Fig. 5a) and 9 genes significantly up-regulated (Fig. 5b) in mTBI brains compared to a control (p ≤ 0.05).”

May combine two claims.

In the no pathology group (n=8), 50% of cases presented with DNA damage; within this group, 75% were stage one and 25% were stage two.

“In the no pathology group (n = 8), 50% of cases presented with DNA damage. Within this group, 75% were stage one and 25% were stage two.”

May combine two claims.

In 70% of CTE cases (n=10) DNA damage was evident; within this, 66.6% were stage one, 16.6% stage two, and 16.6% stage three.

“In 70% of CTE cases (n = 10) DNA damage was evident, and within this 66.6% were stage one, 16.6% were stage two, and 16.6% were stage three.”

May combine two claims.

In both mild and severe tauopathies, DNA damage ranged from stage 0 to stage 3, with some cases accumulating extensive tau but presenting with no DNA damage.

“Indeed, in both mild and severe tauopathies, the DNA damage ranged from stage 0 to stage three, with some cases accumulating extensive tau but presenting with no DNA damage (Fig. 14b).”

May combine two claims.

Numerous mTBI cases with no tau deposits showed DNA damage, generally within lower stages and primarily confined to the ependymal lining.

“Furthermore, numerous cases with no tau deposits did show DNA damage, but generally remained within the lower stages of distribution, primarily confined to the ependymal lining”

May combine two claims.

TERT and IFNG were significantly up-regulated in mTBI brains.

“Two genes associated with senescence were significantly up-regulated in mTBI brains (Fig. 6b). TERT, which is up-regulated in response to shortened telomeres [96], was significantly over-expressed (p = 0.04) in mTBI brains. Furthermore IFNG, a soluble cytokine which induces senescence through p53 signaling [75], was significantly over-expressed (p = 0.04) in mTBI brains.”

May combine two claims.

Brains from individuals with history of mTBI present with both DNA damage and gene expression changes supportive of the acquisition of cellular senescence.

“In this study, we showed that brains from individuals with history of mTBI present with both DNA damage and gene expression changes supportive of the acquisition of cellular senescence.”

May combine two claims.

There were different degrees of DNA damage in glial cells, and genes which drive and protect against senescence were up-regulated and down-regulated, respectively.

“There were different degrees of DNA damage in glial cells, and genes which drive and protect against senescence were up-regulated and down-regulated, respectively.”

May combine two claims.

In some cases, damage was limited to the ependymal lining of the ventricles; in others, it was more extensive and involved more brain areas and additional cell types including astrocytes and oligodendrocytes.

“In some cases, damage was limited to the ependymal lining of the ventricles and in others, it was more extensive and involved more brain areas and additional cell types including astrocytes and oligodendrocytes.”

May combine two claims.

mTBI brains revealed loss of lamin B1 and H3K27Me3 expression in glial cells, consistent with reports on senescence.

“Additionally, mTBI brains revealed loss of lamin B1 and H3K27Me3 expression in glial cells consistent with reports on senescence.”

May combine two claims.

As shown by immunohistochemistry for γH2AX, senescent cells were widespread and accumulated in a specific and consistent pattern of distribution.

“As shown by immunohistochemistry for γH2AX, senescent cells were widespread, and accumulated in a specific and consistent pattern of distribution.”

May combine two claims.

In mTBI brains compared to controls, 36 DNA repair genes were significantly down-regulated and only 9 genes were significantly up-regulated.

“we saw a general trend of decreased expression in mTBI brains compared to controls with 36 genes being significantly down-regulated and only 9 genes significantly up-regulated.”

May combine two claims.

In this study, we revealed several changes in neurons suggesting changes in genome integrity, nuclear membrane structure, and axonal signalling.

“In this study, we have revealed several changes in neurons suggesting changes in genome integrity, nuclear membrane structure, and axonal signalling.”

May combine two claims.

Nearly every case presented was symptomatic, but several cases did not show any abnormal neuropathological changes.

“Nearly every case presented was symptomatic, but several cases did not show any abnormal neuropathological changes.”

May combine two claims.

DNA damage and evidence of cellular senescence was widespread.

“In contrast, DNA damage and evidence of cellular senescence was widespread”

May combine two claims.

mTBI cases with mild and severe tauopathy tended to have higher levels of DNA damage than mTBI cases with no tauopathy, and controls with no mTBI history and no tauopathy did not have any DNA damage.

“When we further stratified our cases by the level of tau burden, we found that mTBI cases with mild and severe tauopathy tended to have higher levels of DNA damage than mTBI cases with no tauopathy, and that controls with no mTBI history and no tauopathy did not have any DNA damage.”

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

Approximately 20% of individuals with mTBI experience symptoms for longer than 3 months and are diagnosed with post-concussive syndrome.

“approximately 20% go on to experience these symptoms for longer than 3 months, at which point they are diagnosed with post-concussive syndrome (PCS) [59].”

• cites [59] Hiploylee C, Duford P, Davis HS et al (2017) Longitudinal study of postconcussion syndrome: not everyone recovers. J Neurotrauma 34(18):1511–1523 sourceNot checked yet

  Not checked in the free run.

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

Accumulation of DNA damage has been shown to predict progression from mild cognitive impairment to AD prior to the emergence of any neuropathology.

“accumulation of DNA damage has been shown to predict progression from mild cognitive impairment (MCI) to AD prior to the emergence of any neuropathology [91].”

• cites [91] Lovell MA, Markesbery WR (2007) Oxidative DNA damage in mild cognitive impairment and late-stage Alzheimer’s disease. Nucleic Acids Res 35(22):7497–7404 sourceNot checked yet

  Not checked in the free run.

Classified as probably not a substantial claim.

Markers of senescence were elevated in a mouse model of mTBI.

“More recently, markers of senescence were shown to be elevated in a mouse model of mTBI [153]”

• cites [153] Tominaga T, Ryo S, Okada Y, Kawamata T, Kibayashi K (2019) Senescence-associated-β-galactosidase staining following traumatic brain injury in the mouse cerebrum. PLoS One 14(3):e0213673 sourceNot checked yet

  Not checked in the free run.

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

mTBI, especially when experienced repetitively, is linked to several broad symptoms involving mood, behavior, and cognitive changes.

“mTBI, especially when experienced repetitively [52], is linked to several symptoms which are broad in nature, involving mood, behavior, and cognitive changes [126, 140].”

• cites [126] Polinder S, Cnossen MC, Real RGL et al (2018) A multidimensional approach to post-concussion symptoms in mild traumatic brain injury. Front Neurol 9:1113 sourceNot checked yet

  Not checked in the free run.

• cites [140] Silverberg ND, Lange RT, Millis SR et al (2013) Post-concussion symptom reporting after multiple mild traumatic brain injuries. J Neurotrauma 30:1398–1404 sourceNot checked yet

  Not checked in the free run.

Classified as probably not a substantial claim.

Failure of the DDR to properly repair DNA results in accumulation of DNA damage and subsequently cellular senescence.

“Failure of the DDR to properly repair DNA results in the accumulation of DNA damage and subsequently cellular senescence, and as such it plays a crucial role in maintaining the genomic integrity and cellular function [92, 121, 168].”

• cites [92] Lukas J, Lukas C, Bartek J (2011) More than just a focus: the chromatin response to DNA damage and its role in genome integrity maintenance. Nat Cell Biol 13(10):1161–1169 sourceNot checked yet

  Not checked in the free run.

• cites [121] Ou HL, Schumacher B (2018) DNA damage responses and p53 in the aging process. Blood 131(5):488–495 sourceNot checked yet

  Not checked in the free run.

• cites [168] Whitaker SJ (1992) DNA damage by drugs and radiation: what is important and how is it measured? Eur J Cancer 28(1):273–276 sourceNot checked yet

  Not checked in the free run.

Classified as probably not a substantial claim.

In previous work, widespread accumulation of DNA damage and up-regulation of DDR signaling gene expression was presented in men with history of mTBI.

“In our previous work, we presented widespread accumulation of DNA damage and up-regulation of DDR signaling gene expression in men with history of mTBI [135].”

• cites [135] Schwab N, Tator C, Hazrati LN (2019) DNA damage as a marker of brain damage in individuals with history of concussions. Lab Investig 99(7):1008–1018 sourceNot checked yet

  Not checked in the free run.

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

Deficiencies in DNA repair underlie several neurological conditions in both humans and animal models.

“Deficiencies in DNA repair are known to underlie several neurological conditions in both humans and animal models [103, 147].”

• cites [103] McKinnon PJ (2009) DNA repair deficiency and neurological disease. Nat Rev Neurosci 10(2):100–112 sourceNot checked yet

  Not checked in the free run.

• cites [147] Subba Rao K (2007) Mechanisms of disease: DNA repair defects and neurological disease. Nat Clin Pract Neurol 3(3):162–172 sourceNot checked yet

  Not checked in the free run.

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

AD brains have decreased base-excision repair (BER) pathway activity.

“AD brains have been reported as having decreased base-excision repair (BER) pathway activity [87].”

• cites [87] Lillenes MS, Rabano A, Stoen M et al (2016) Altered DNA base excision repair profile in brain tissue and blood in Alzheimer’s disease. Mol Brain 9:61 sourceNot checked yet

  Not checked in the free run.

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

In AD, a two-fold increase in DNA damage has been found in the cortex compared to healthy controls.

“In AD, a two-fold increase in DNA damage has been found in the cortex compared to healthy controls [113].”

• cites [113] Mullaart E, Boerrigter ME, Ravid R, Swaab DF, Vijg J (1990) Increased levels of DNA breaks in cerebral cortex of Alzheimer’s disease patients. Neurobiol Aging 11(3):169–173 sourceNot checked yet

  Not checked in the free run.

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

CTE is described clinically by a set of non-specific but severe symptoms including depression, anxiety, motor dysfunction, aggression, irritability, memory loss, and suicidality.

“However, CTE is described clinically by a set of non-specific but yet severe symptoms including depression, anxiety, motor dysfunction, aggression, irritability, memory loss, and suicidality [4, 68, 94].”

• cites [4] Antonius D, Mathew N, Picano J et al (2014) Behavioral health symptoms associated with chronic traumatic encephalopathy: a critical review of the literature and recommendations for treatment and research. J Neuropsychiatr Clin Neurosci 26(4):313–322 sourceNot checked yet

  Not checked in the free run.

• cites [68] Iverson GL, Keene CD, Perry G, Castellani RJ (2018) The need to separate chronic traumatic encephalopathy from clinical features. J Alzheimers Dis 61(1):17–28 sourceNot checked yet

  Not checked in the free run.

• cites [94] Mahar I, Alosco ML, McKee AC (2017) Psychiatric phenotypes in chronic traumatic encephalopathy. Neurosci Biobehav Rev 83:622–630 sourceNot checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

Emerin is a structural integral protein that stabilizes chromatin and regulates gene expression.

“Emerin is a structural integral protein which acts to stabilize chromatin and regulate gene expression [108].”

• cites [108] Mickiewicz E, Tilgner K, Barker N et al (2006) The inner membrane protein emerin regulates B-catenin activity by restricting its accumulation in the nucleus. EMBO J 25(14):3275–3285 sourceNot checked yet

  Not checked in the free run.

May combine two claims.

This deficient DNA repair and DNA damage-induced cellular senescence may affect neurons and be the driver of brain dysfunction in mTBI, predisposing progression to neurodegenerative diseases.

“and propose that this may affect neurons and be the driver of brain dysfunction in mTBI, predisposing the progression to neurodegenerative diseases.”

May combine two claims.

Decreased expression of DNA repair genes suggests inefficient DNA repair pathways in this cohort, conferring susceptibility to cellular senescence and subsequent brain dysfunction after mTBI.

“Decreased expression of DNA repair genes suggests inefficient DNA repair pathways in this cohort, conferring susceptibly to cellular senescence and subsequent brain dysfunction after mTBI.”

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

Loss of myelin basic protein has been associated with ageing and neurodegenerative conditions.

“and for which loss has been associated with ageing and neurodegenerative conditions [164].”

• cites [164] Weil MT, Mobius W, Winkler A, et al. (2016). Loss of myelin basic protein function triggers myelin breakdown in models of demyelinating diseaseNot checked yet

  Not checked in the free run.

May combine two claims.

Involvement in contact sports and a history of multiple concussions causes long-term effects on brain health.

“Involvement in contact sports and a history of multiple concussions has been shown to cause long-term effects on brain health [27, 88, 95]”

• cites [27] Davis GA, Castellani RJ, McCrory P (2015) Neurodegeneration and sport. Neurosurgery 76(6):643–655 sourceNot checked yet

  Not checked in the free run.

• cites [88] Ling H, Hardy J, Zetterberg H (2015) Neurological consequences of traumatic brain injuries in sports. Mol Cell Neurosci 66(Pt B):114–122 sourceNot checked yet

  Not checked in the free run.

• cites [95] Maroon JC, Winkelman R, Bost J, Amos A, Mathyssek C, Miele V (2015) Chronic traumatic encephalopathy in contact sports: a review of all reported pathological cases. PLoS One 10(2):e0117338 sourceNot checked yet

  Not checked in the free run.

May combine two claims.

A major gap in understanding mTBI-associated brain dysfunction is the discordance between pathology load and severity of symptoms, often in younger individuals: cases with head trauma often have microscopic foci of proteinopathy yet present with severe and diverse symptoms.

“However, a major gap in knowledge in our understanding of mTBI-associated brain dysfunction is the discordance between the pathology load and severity of symptoms, often in younger individuals: cases with a history of head trauma often have microscopic foci of proteinopathy, yet present with severe and diverse symptoms [134].”

• cites [134] Schwab N, Hazrati LN (2018) Assessing the limitations and biases in the current understanding of chronic traumatic encephalopathy. J Alzheimers Dis 64(4):1067–1076 sourceNot checked yet

  Not checked in the free run.

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

CTE is pathologically defined by the presence of focal perivascular p-tau in neurons and astrocytes, in the depths of cortical sulci.

“CTE is pathologically defined by the presence of focal perivascular p-tau in neurons and astrocytes, in the depths of cortical sulci [100].”

• cites [100] McKee AC, Cairns NJ, Dickson DW et al (2016) The first NINDS/NIBIB consensus meeting to define neuropathological criteria for the diagnosis of chronic traumatic encephalopathy. Acta Neuropathol 131:75–86 sourceNot checked yet

  Not checked in the free run.

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

The diagnostic criteria for CTE has no lower bound, meaning that one focus of p-tau is sufficient for a diagnosis.

“The diagnostic criteria for CTE has no lower bound, meaning that one focus of p-tau is sufficient for a diagnosis [100].”

• cites [100] McKee AC, Cairns NJ, Dickson DW et al (2016) The first NINDS/NIBIB consensus meeting to define neuropathological criteria for the diagnosis of chronic traumatic encephalopathy. Acta Neuropathol 131:75–86 sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Cases with severe tauopathy and no detectable γH2AX showed markers of DDR and senescence by NanoString, which may indicate loss of γH2AX expression rather than absence of DNA damage.

“These cases when analyzed individually did show markers of DDR and senescence as detected by NanoString, which may indicate the loss of γH2AX expression and not necessarily absence of DNA damage.”

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

Each case was diagnosed by a staff neuropathologist and a resident in neuropathology, and select cases were reviewed blindly by different neuropathologists in other institutions.

“Each case was diagnosed by a staff neuropathologist and a resident in neuropathology and select cases were reviewed blindly by different neuropathologist in other institutions.”

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

In each slide, three regions of interest were chosen blindly from specified areas.

“In each slide, three regions of interest were chosen blindly from the following areas: the ependymal lining, subependymal areas, cortical grey matter, subpial areas, and white matter.”

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

Myelin basic protein is a key structural protein for myelin, comprising approximately 30% of all myelin protein in the central nervous system.

“Myelin basic protein is a key structural protein for myelin, comprising approximately 30% of all myelin protein in the central nervous system [110]”

• cites [110] Morrel P, Quarles RH (1999) Basic neurochemistry: molecular, cellular, and medical aspects: characteristic composition of myelin. Lippincott-Raven, PhiladelphiaNot checked yet

  Not checked in the free run.

May combine two claims.

Brains of contact-sports athletes are characterized by deficient DNA repair and DNA damage-induced cellular senescence.

“We therefore suggest that brains of contact-sports athletes are characterized by deficient DNA repair and DNA damage-induced cellular senescence”

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

Enhanced levels of SASP factors have been associated with late-life depression.

“Enhanced levels of SASP factors have been associated with late-life depression [32]”

• cites [32] Diniz BS, Reynolds CF III, Sibile E et al (2017) Enhanced molecular aging in late-life depression: the senescent associated secretory phenotype. Am J Geriatr Psychiatry 25(1):64–72 sourceNot checked yet

  Not checked in the free run.

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

Senescence has the potential to spread damage to surrounding tissue via paracrine signaling with SASP factors, while simultaneously using autocrine reinforcement to maintain their senescent phenotype.

“Senescence has the potential to spread damage to surrounding tissue via paracrine signaling with SASP factors, while simultaneously using autocrine reinforcement to maintain their senescent phenotype [48].”

• cites [48] Gonzalez-Meljem JM, Apps JR, Fraser HC, Martinez-Barbera JP (2018) Paracrine roles of cellular senescence in promoting tumourigenesis. Br J Cancer 118(10):1283–1288 sourceNot checked yet

  Not checked in the free run.

Classified as probably not a substantial claim.

In these individuals, H2AX has been degraded over time due to chronic levels of oxidative stress caused by cellular senescence.

“We suspect that in these individuals H2AX has been degraded over time, due to chronic levels of oxidative stress caused by cellular senescence.”

May combine two claims.

Cellular senescence may be one of the main mechanisms by which mTBI leads to diverse, widespread, and debilitating symptoms, and represents a more plausible mechanistic explanation for mTBI-induced brain dysfunction.

“Cellular senescence may therefore be one of the main mechanism by which mTBI leads to the presentation of diverse, widespread, and debilitating symptoms in individuals who experience mTBI, and represents a more plausible mechanistic explanation to mTBI-induced brain dysfunction”

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

Both pharmacological and pharmacogenetic clearance of these senescent cells alleviated anxiety behavior and enhanced adult neurogenesis.

“Furthermore, both pharmacological and pharmacogenetic clearance of these senescent cells alleviated anxiety behavior and enhanced adult neurogenesis [74].”

• cites [74] Kern S, Skoog I, Borjesson-Hanson A et al (2014) Higher CSF interleukin-6 and CSF interleukin-8 in current depression in older women. Results from a population-based sample. Brain Behav Immun 41:55–58 sourceNot checked yet

  Not checked in the free run.

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

High levels of SASP factors in the CSF have been suggested to play a role in increasing susceptibility to neurodegenerative disorders.

“In addition, high levels of SASP factors in the CSF has been suggested to play a role in increasing susceptibility to neurodegenerative disorders [47].”

• cites [47] Gomes de Andrade G, Reck Cechinel L, Bertoldi K et al (2018) The aging process alters IL-1β and CD63 levels differently in extracellular vesicles obtained from the plasma and cerebrospinal fluid. Neuroimmunomodulation 25(1):18–22 sourceNot checked yet

  Not checked in the free run.

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

In a recent paper on obesity-induced senescence, Ogrodnik et al. reported accumulation of senescent glial cells in the periventricular region of the lateral ventricle, and associated this with anxiety and impaired neurogenesis.

“In a recent paper on obesity-induced senescence, Ogrodnik et al. reported accumulation of senescent glial cells in the periventricular region of the lateral ventricle, and associated this with anxiety and impaired neurogenesis [120].”

• cites [120] Ogrodnik M, Zhu Y, Langhi LGP et al (2019) Obesity-induced cellular senescence drives anxiety and impairs neurogenesis. Cell Metab 29(5):1061–1077 sourceNot checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

The authors of that study concluded that the clinical significance of CTE-pathology remains uncertain and that it is likely a co-morbidity rather than the cause of dementia in former athletes.

“Furthermore, the authors concluded that the clinical significance of CTE-pathology remains uncertain, and that it is likely a co-morbidity rather than the cause of dementia in former athletes [83].”

• cites [83] Lee EB, Kinch K, Johnson VE, Trojanowski JQ, Smith DH, Stewart W (2019) Chronic traumatic encephalopathy is a common co-morbidity, but less frequent primary dementia in former soccer and rugby players. Acta Neuropathol. https://doi.org/10.1007/s00401-019-02030-y sourceNot checked yet

  Not checked in the free run.

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

Accumulation of senescent cells is thought to contribute to anxiety.

“accumulation of senescent cells are thought to contribute to anxiety [60]”

• cites [60] Hoare M, Narita M (2013) Transmitting senescence to the cell neighbourhood. Nat Cell Biol 15(8):887–889 sourceNot checked yet

  Not checked in the free run.

May combine two claims.

H2AX deficiency has been linked to chronic neurobehavioral symptoms and an impaired ability to respond to ROS.

“H2AX deficiency has also been linked to chronic neurobehavioral symptoms and an impaired ability to respond to ROS [167]”

• cites [167] Weyemi U, Paul BD, Snowman AD et al (2018) Histone H2AX deficiency causes neurobehavioral deficits and impaired redox homeostasis. Nat Commun 9(1):1526 sourceNot checked yet

  Not checked in the free run.

May combine two claims.

CTE-consistent pathology has been reported in cases with no history of head trauma, indicating that it may be a common pathology within the general population and not specific to the aftermath of mTBI.

“It is also important to note that CTE-consistent pathology has been reported in cases with no history of head trauma, further indicating that it may be a common pathology within the general population and not specific to the aftermath of mTBI [55, 69, 89, 119].”

• cites [55] Hazrati LN, Tartaglia MC, Diamandis P et al (2013) Absence of chronic traumatic encephalopathy in retired football players with multiple concussions and neurological symptomatology. Front Hum Neurosci 7:222 sourceNot checked yet

  Not checked in the free run.

• cites [69] Iverson GL, Luoto TM, Karhunen PJ, Castellani RJ (2019) Mild chronic traumatic encephalopathy neuropathology in people with no known participation in contact sports or history of repetitive neurotrauma. J Neuropathol Exp Neurol. https://doi.org/10.1093/jnen/nlz045 sourceNot checked yet

  Not checked in the free run.

• cites [89] Ling H, Holton JL, Shaw K, Davey K, Lashley T, Revesz T (2015) Histological evidence of chronic traumatic encephalopathy in a large series of neurodegenerative diseases. Acta Neuropathol 130:891–893 sourceNot checked yet

  Not checked in the free run.

• cites [119] Noy S, Krawitz S, Del Bigio MR (2016) Chronic traumatic encephalopathy-like abnormalities in a routine neuropathology service. J Neuropathol Exp Neurol 75(12):1145–1154 sourceNot checked yet

  Not checked in the free run.

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

In a recent study of former athletes, CTE-consistent pathology was found in 73% of cases, and all of these presented with multiple mixed neurodegenerative pathologies, most notably AD-consistent pathology.

“Although CTE-consistent pathology was found in 73% of cases, all of these presented with multiple mixed neurodegenerative pathologies, most notably AD-consistent pathology.”

• cites [83] Lee EB, Kinch K, Johnson VE, Trojanowski JQ, Smith DH, Stewart W (2019) Chronic traumatic encephalopathy is a common co-morbidity, but less frequent primary dementia in former soccer and rugby players. Acta Neuropathol. https://doi.org/10.1007/s00401-019-02030-y sourceNot checked yet

  Not checked in the free run.

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

High levels of interleukin-6 and 8, two key mediators of the SASP, are significantly elevated in the CSF of aged women with clinical depression compared to those without depression.

“For instance, high levels of interleukin-6 and 8, two key mediators of the SASP, are found to be significantly elevated in the CSF of aged women with clinical depression [74] compared to those without depression”

• cites [74] Kern S, Skoog I, Borjesson-Hanson A et al (2014) Higher CSF interleukin-6 and CSF interleukin-8 in current depression in older women. Results from a population-based sample. Brain Behav Immun 41:55–58 sourceNot checked yet

  Not checked in the free run.

May combine two claims.

There are other molecular processes driving symptoms and perhaps driving pathology seen after mTBI.

“We therefore suggest that there are other molecular processes driving symptoms and perhaps driving pathology seen after mTBI.”

May combine two claims.

These individuals acquired cellular senescence during their playing career from multiple mTBIs, and this chronic low-level inflammation was sustained into late-life, leading to H2AX degradation and a lack of γH2AX reactivity.

“Indeed, we suggest that these individuals acquired cellular senescence during their playing career from multiple mTBIs, and that this chronic low-level inflammation was sustained into late-life, in turn leading to H2AX degradation and a lack of γH2AX reactivity in these cases.”

May combine two claims.

p-tau in the CSF has been shown to not correlate to any neuropsychological changes and is not associated with AD progression in APOE3-carrying AD patients.

“Furthermore, p-tau in the CSF has been shown to not correlate to any neuropsychological changes [53], and are not associated with AD progression in APOE3-carrying AD patients [77].”

• cites [53] Haldenwanger A, Eling P, Kastrup A, Hildebrandt H (2010) Correlation between cognitive impairment and CSF biomarkers in amnesic MCI, non-amnesic MCI, and Alzheimer’s disease. J Alzheimers Dis 22(3):971–980 sourceNot checked yet

  Not checked in the free run.

• cites [77] Koch G, Di Lorenzo F, Loizzo S et al (2017) CSF tau is associated with impaired cortical plasticity, cognitive decline, and astrocyte survival only in APOE4-positive Alzhaimer’s disease. Sci Rep 7(1):13728 sourceNot checked yet

  Not checked in the free run.

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

Neuroinflammation markers in the CSF are strongly associated with cerebral tau pathology in older adults.

“Indeed, neuroinflammation markers in the CSF are strongly associated with cerebral tau pathology in older adults [127].”

• cites [127] Popp J, Oikonomidi A, Tautvydaite D et al (2017) Markers of neuroinflammation associated with Alzheimer’s disease pathology in older adults. Brain Behav Immun 62:203–211 sourceNot checked yet

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May combine two claims.

In senescent cells, lamin B1 expression is reduced, resulting in rearrangement of heterochromatic regions into senescence-associated heterochromatic foci (SAHF) and large-scale changes in gene expression.

“However, in senescent cells lamin B1 expression is reduced [40], resulting in rearrangement of heterochromatic regions into senescence-associated heterochromatic foci (SAHF) and large-scale changes in gene expression [138].”

• cites [40] Freund A, Laberge R-M, Demaria M, Campisi J (2012) Lamin B1 loss is a senescence associated biomarker. Mol Biol Cell 23:2066–2075 sourceNot checked yet

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• cites [138] Shah PP, Donahue G, Otte GL, Capell BC, Nelson DM, Cao K (2013) Lamin B1 depletion in senescent cells triggers large-scale changes in gene expression and the chromatin landscape. Genes Dev 27(16):1787–1799 sourceNot checked yet

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Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

In a study on hyperglycemia, exposure to high levels of glucose resulted in increased levels of ROS in hepatocytes; initially this led to increased expression of DNA repair genes, but long-term exposure eventually led to reduced expression of DNA repair genes and subsequent accumulation of DNA damage.

“In a study on hyperglycemia, for example, it was found that exposure to high levels of glucose resulted in increased levels of ROS in hepatocytes [122]. Initially, this led to increased expression of DNA repair genes, however long-term exposure eventually led to the reduced expression of DNA repair genes and subsequent accumulation of DNA damage [122].”

• cites [122] Pang J, Xi C, Dai Y, Gong H, Zhang TM (2012) Altered expression of base excision repair genes in response to high glucose-induced oxidative stress in HepG2 hepatocytes. Med Sci Monit 18(7):BR281–BR285 sourceNot checked yet

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Lamin B1 normally functions to tether heterochromatin to the inner nuclear membrane, preventing its transcription.

“Lamin B1 normally functions to tether heterochromatin to the inner nuclear membrane, preventing its transcription [15].”

• cites [15] Camps J, Erdos MR, Ried T (2015) The role of Lamin B1 for the maintenance of nuclear structure and function. Nucleus 6(1):8–14 sourceNot checked yet

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

Loss of the trimethylation status of H3K27Me3 has been reported to induce senescence through the up-regulation of SASP and p16 pathways, and its loss/decrease is considered a marker of senescent cells.

“Loss of the trimethylation status of H3K27Me3 has been reported to induce senescence through the up-regulation of SASP and p16 pathways, and its loss/decrease is therefore considered a marker of senescent cells [64, 66, 170].”

• cites [64] Iida A, Iwagawa T, Baba Y et al (2015) Roles of histone H3K27 trimethylase Ezh2 in retinal proliferation and differentiation. Dev Neurobiol 75(9):947–960 sourceNot checked yet

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• cites [66] Ito T, Teo YV, Evans SA, Neretti N, Sedivy JM (2018) Regulation of cellular senescence by polycomb chromatin modifiers through distinct DNA damage- and histone methylation-dependent pathways. Cell Rep 22(13):3480–3492 sourceNot checked yet

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• cites [170] Zhang Y, Chang JF, Sun J, et al (2018) Histone H3K27 methylation is required for NHEJ and genome stability by modulating the dynamics of FANCD2 on chromatin. J Cell Sci 131(12). sourceNot checked yet

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

Reduced expression of DNA repair genes due to increased levels of oxidative stress has been implicated in several other human diseases, including diabetes, obesity, and glaucoma.

“In fact, reduced expression of DNA repair genes due to increased levels of oxidative stress has been implicated with several other human diseases, including diabetes [84], obesity [137], and glaucoma [109].”

• cites [84] Lee SC, Chan JCN (2015) Evidence for DNA damage as a biological link between diabetes and cancer. Chin Med J 128(11):1543–1548 sourceNot checked yet

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• cites [137] Setayesh T, Nersesyan A, Misik M et al (2018) Impact of obesity and overweight on DNA stability: few facts and many hypotheses. Mutat Res 777:64–91 sourceNot checked yet

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• cites [109] Mohanty K, Dada R, Dada T (2017) Oxidative DNA damage and reduced expression of DNA repair genes: role in primary open angle glaucoma (POAG). Ophthalmic Genet 38(5):446–450 sourceNot checked yet

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

The mechanism by which DNA repair genes are down-regulated in association with cellular senescence may be due to chronically increased levels of oxidative stress associated with a pro-inflammatory toxic environment.

“The mechanism by which DNA repair genes are down-regulated in association with cellular senescence, is not entirely clear, but may be due to chronically increased levels of oxidative stress associated with a pro-inflammatory toxic environment [49].”

• cites [49] Graziano S, Johnston R, Deng O, Zhang J, Gonzalo S (2016) Vitamin D/vitamin D receptor axis regulates DNA repair during oncogene-induced senescence. Oncogene 35:5362–5376 sourceNot checked yet

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When astrocytes become senescent they no longer provide trophic support to the neuron, disturbing normal neuronal function.

“For instance, when astrocytes become senescent they no longer provide trophic support to the neuron, disturbing normal neuronal function [43].”

• cites [43] Garwood CJ, Ratcliffe LE, Simpson JE, Heath PR, Ince PG, Wharton SB (2017) Review: Astrocytes in Alzheimer's disease and other age-associated dementias: a supporting player with a central role. Neuropathol Appl Neurobiol 43(4):281–298 sourceNot checked yet

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Women face additional sources of DNA damage compared to men, and an inefficient DNA repair response may exacerbate this discrepancy.

“Thus, women face additional sources of DNA damage compared to men, and an inefficient DNA repair response may exacerbate this discrepancy.”

May combine two claims.

Following mTBI, women tend to experience more symptoms and take significantly longer to recover compared to men.

“Following mTBI, women tend to experience more symptoms and take significantly longer to recover compared to men for reasons currently unknown [28, 51, 67, 114].”

• cites [28] Davis-Hayes C, Gossett JD, Levine WN et al (2017) Sex-specific outcomes and predictors of concussion recovery. J Am Acad Orthop Surg 25(12):818–828 sourceNot checked yet

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• cites [51] Gupte R, Brooke WM, Vukas RR, Pierce JD, Harris JL (2019) Sex differences in traumatic brain injury: what we know and what we should know. J Neurotrauma. https://doi.org/10.1089/neu.2018.6171 sourceNot checked yet

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• cites [67] Iverson GL, Gardner AJ, Terry DP et al (2017) Predictors of clinical recovery from concussion: a systematic review. Br J Sports Med 51(12):941–948 sourceNot checked yet

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• cites [114] Munivenkatappa A, Agrawal A, Shukla DP, Kumaraswamy D, Devi BI (2016) Traumatic brain injury: does gender influence outcomes? Int J Crit Illn Inj Sci 6(2):70–73 sourceNot checked yet

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The swollen astrocytic cell bodies and beaded processes are a hallmark of senescence in astrocytes, suggesting that these cells have taken on a secretive function.

“This is a hallmark of senescence in astrocytes, suggesting that these cells have taken on a secretive function [25].”

• cites [25] Crowe EP, Tuzer F, Gregory BD, Donahue G, Gosai SJ, Cohen J (2016) Changes in the transcriptome of human astrocytes accompanying oxidative stress-induced senescence. Front Aging Neurosci 8:208 sourceNot checked yet

  Not checked in the free run.

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Genetic polymorphisms in genes encoding DNA repair proteins may lead to more or less efficient DNA repair and therefore confer, respectively, a decreased or an increased risk of suffering long-term symptoms and neurodegenerative disease after mTBI.

“Indeed, genetic polymorphisms in genes encoding DNA repair proteins may lead to more or less efficient DNA repair and therefore confer, respectively, a decreased or an increased risk of suffering long-term symptoms and neurodegenerative disease after mTBI.”

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

Inefficient DNA repair pathways may underlie sex differences in the experience of concussion.

“In particular, it is possible that inefficient DNA repair pathways underlie sex differences in the experience of concussion.”

May combine two claims.

Ovariectomy in female rats has been shown to protect against hippocampal DNA damage and improve memory function.

“Furthermore, ovariectomy in female rats has been shown to protect against hippocampal DNA damage and improve memory function [85].”

• cites [85] Leffa DD, Damiani AP, Damazio DD et al (2014) Long-term effects of ageing and ovariectomy on aversive and recognition memory and DNA damage in the hippocampus of female rats. Acta Neuropsychiatr 26(3):161–169 sourceNot checked yet

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Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

Astrocytes comprise the majority of all brain cells and are immediate responders to brain trauma, infections, and neurodegeneration.

“Astrocytes comprise the majority of all brain cells, and are immediate responders to brain trauma, infections, and neurodegeneration [142].”

• cites [142] Sofroniew MV, Vinters HV (2010) Astrocytes: biology and pathology. Acta Neuropathol 119(1):7–35 sourceNot checked yet

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Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

Senescent endothelial cells may disrupt the integrity of the blood-brain barrier, an effect associated with age-related cognitive decline.

“Lastly, senescent endothelial cells may disrupt the integrity of the blood-brain barrier [1], an effect which has been associated with age-related cognitive decline [150].”

• cites [1] Abazov VM, Abbott B, Abolins M et al (2016) Measurement of the semileptonic branching ratio of B_{s};{0} to an orbitally excited D_{s};{**} state: Br(B_{s};{0}-->D_{s1};{−}(2536) mu;{+}nuX) physical review letters. 2009;102:051801.Yamazaki Y, Baker DJ, Tachibana M, Liu CC, van Deursen JM, Brott TG, et al. vascular cell senescence contributes to blood-brain barrier breakdown. Stroke 47(4):1068–1077 sourceNot checked yet

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• cites [150] Swenson BL, Meyer CF, Bussian TJ, Baker DJ (2018) Senescence in aging and disorders of the central nervous system. Trans Med Aging 3:17–25 sourceNot checked yet

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

In response to various stressors such as hydrogen peroxide and ionizing radiation, astrocytes become senescent.

“Indeed, in response to various stressors such as hydrogen peroxide [9] and ionizing radiation [173], astrocytes become senescent.”

• cites [9] Bitto A, Sell C, Crowe E et al (2010) Stress-induced senescence in human and rodent astrocytes. Exp Cell Res 316:2961–2968 sourceNot checked yet

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• cites [173] Zou Y, Zhang N, Ellerby LM et al (2012) Responses of human embryonic stem cells and their differentiated progeny to ionizing radiation. Biochem Biophys Res Commun 426(1):100–105 sourceNot checked yet

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Microglia from aged human brains are generally swollen and show fragmentation of processes thought to contribute to neuronal death.

“Indeed, microglia from aged human brains are generally swollen and show fragmentation of processes thought to contribute to neuronal death [38].”

• cites [38] Flaary B (2005) The role of microglial cellular senescence in the aging and Alzheimer diseased brain. Rejuvenation Res 8(2):82–85 sourceNot checked yet

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Microglia can become senescent, which affects their ability to mediate immune responses in the CNS in response to injury or infection.

“Microglia also can become senescent, which affects their ability to mediate immune responses in the CNS in response to injury or infection [23].”

• cites [23] Conde JR, Streit WJ (2006) Effect of aging on the microglial response to peripheral nerve injury. Neurobiol Aging 27:1451–1461 sourceNot checked yet

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Astrogliosis in these individuals was thought to be the basis of post-traumatic stress disorder (PTSD) in soldiers who had suffered blast exposure-related mTBI.

“Furthermore, astrogliosis in these individuals was thought to be the basis of post-traumatic stress disorder (PTSD) in soldiers who had suffered blast exposure-related mTBI [139].”

• cites [139] Shively SB, Edgerton SL, Iacono D et al (2017) Localized cortical chronic traumatic encephalopathy pathology after single, severe axonal injury in human brain. Acta Neuropathol 133(3):353–366 sourceNot checked yet

  Not checked in the free run.

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

Astrocytic senescence has been reported in brains of aged animals, indicating a correlation between brain ageing and astrocytic senescence.

“Furthermore, astrocytic senescence has been reported in brains of aged animals [118, 124], indicating that there is a correlation between brain ageing and astrocytic senescence.”

• cites [118] Nichols NR, Day JR, Laping NJ, Johnson SA, Finch CE (1993) GFAP mRNA increases with age in rat and human brain. Neurobiol Aging 14(5):421–429 sourceNot checked yet

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• cites [124] Pertusa M, Garcia-Matas S, Rodriguez-Farre E, Sanfeliu C, Cristofol R (2007) Astrocytes aged in vitro show a decreased neuroprotective capacity. J Neurochem 101(3):794–805 sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Cellular senescence in glial cells has vast repercussions on the integrity of neuronal function and global brain health, resulting in widespread tissue dysfunction and the emergence of neurological symptoms.

“Cellular senescence in glial cells therefore has vast repercussions on the integrity of neuronal function and global brain health, resulting in widespread tissue dysfunction and, inevitably, the emergence of neurological symptoms.”

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

The role of senescent cells in cognitive decline and p-tau pathology has been demonstrated in a transgenic mouse model of AD, in which eliminating senescent cells through senolytic intervention resulted in reduced tau phosphorylation, improved cognitive outcomes, and prevention of upregulation of senescence genes.

“The role of senescent cells in cognitive decline and p-tau pathology has been demonstrated in a transgenic mouse model of AD, in which eliminating senescent cells through senolytic intervention resulted in reduced tau phosphorylation, improved cognitive outcomes, and the prevention of the upregulation of senescence genes [14].”

• cites [14] Bussian TJ, Aziz A, Meyer CF, Swenson BL, van Deursen JM, Baker DJ (2018) Clearance of senescent glial cells prevents tau-dependent pathology and cognitive decline. Nature 562(7728):578–582 sourceNot checked yet

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In the context of traumatic brain injury, post-mortem human brains after blast exposure show astrogliosis in sub-pial regions, specifically surrounding the grey-white matter junctions, in the subpial area and lining of ventricles.

“In the context of traumatic brain injury, post-mortem human brains after blast exposure show astrogliosis in sub-pial regions, specifically surrounding the grey-white matter junctions, in the subpial area and lining of ventricles [139].”

• cites [139] Shively SB, Edgerton SL, Iacono D et al (2017) Localized cortical chronic traumatic encephalopathy pathology after single, severe axonal injury in human brain. Acta Neuropathol 133(3):353–366 sourceNot checked yet

  Not checked in the free run.

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

Tau protein has been found to be normally expressed within the nucleus of neurons.

“Tau protein, most well-known as a structural molecule of the cytoskeleton in the axons and for its involvement in AD pathogenesis in its hyperphosphorylated form, has been found to be normally expressed within the nucleus of neurons [12].”

• cites [12] Bukar Maina M, Al-Hilaly YK, Serpell LC (2016) Nuclear tau and its potential role in Alzheimer’s disease. Biomolecules 6:9 sourceNot checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

In studies on ALS, loss of crucial BRG1 subunits was found to cause dendritic attrition, which was delayed by overexpressing BRG1.

“In studies on ALS for example, loss of crucial BRG1 subunits was found to cause dendritic attrition, which was delayed by overexpressing BRG1 [152].”

• cites [152] Tibshirani M, Zhao B, Gentil B et al (2017) Dysregulation of chromatin remodelling complexes in amyotrophic lateral sclerosis. Hum Mol Genet 26(21):4142–4152 sourceNot checked yet

  Not checked in the free run.

Classified as probably not a substantial claim.

BRG1 is a transcription factor critical for healthy neuronal gene expression and functioning, including neuronal differentiation and the function of synapses.

“BRG1 is a transcription factor critical for healthy neuronal gene expression and functioning, including neuronal differentiation and the function of synapses [97].”

• cites [97] Matsumoto S, Banine F, Struve J, Xing R, Adams C, Liu Y, Metzger D, Chambon P, Rao MS, Sherman LS (2006) Brg1 is required for murine neural stem cell maintenance and gliogenesis. Dev Biol 289:373–383 sourceNot checked yet

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Cellular senescence is a powerful mechanism affecting mainly glial cells and capable of inducing overall brain dysfunction, in many instances without visible structural damage on histological examination, and leading to important neurocognitive deficits.

“Cellular senescence is therefore a powerful mechanism affecting mainly glial cells and capable of inducing overall brain dysfunction, in many instance without visible structural damage on histological examination, and leading to important neurocognitive deficits.”

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

Glial cells are critical support cells for neurons, and their loss can induce neuronal dysfunction.

“It is well known that glial cells are critical support cells for neurons [159], and that their loss can induce neuronal dysfunction [72].”

• cites [159] Von Bernhardi R, Eugenin-von Bernhardi J, Flores B et al (2016) Glial cells and integrity of the nervous system. Adv Exp Med Biol 949:1–24 sourceNot checked yet

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• cites [72] Kaminsky N, Bihari O, Kanner S et al (2016) Connecting malfunctioning glial cells and brain degenerative disorders. Genomics Proteomics Bioinformatics 14(3):155–165 sourceNot checked yet

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Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

Intranuclear tau has been shown to interact with nucleic acid proteins and other nuclear proteins, and various studies have suggested that it is essential for genome integrity.

“Intranuclear tau has been shown to interact with nucleic acid proteins and other nuclear proteins, and various studies ranging from cell culture to human brain have suggested that it is essential for genome integrity [12].”

• cites [12] Bukar Maina M, Al-Hilaly YK, Serpell LC (2016) Nuclear tau and its potential role in Alzheimer’s disease. Biomolecules 6:9 sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Loss of BRG1 expression is an important marker of neuronal function and may have implications for clinical manifestation.

“Together, the literature indicates that loss of BRG1 expression is an important marker of neuronal function, and may have implications for clinical manifestation.”

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

Mutations in BRG1 led to reduced dendritic spine density, impaired synapse activity, and neurological deficits in a study on autism spectrum disorder.

“Furthermore, mutations in BRG1 led to reduced dendritic spine density, impaired synapse activity, and neurological deficits in a study on autism spectrum disorder [171].”

• cites [171] Zhang Z, Cao M, Chan CW et al (2016) Autism-associated chromatin regulator Brg1/SmarcA4 is required for synapse development and myocyte enhancer factor 2-mediated synapse remodeling. Mol Cell Biol 36:70–83 sourceNot checked yet

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These results suggest that neuronal axonal structure is maintained, but their myelination may be disrupted.

“These results suggest that neuronal axonal structure is maintained, but their myelination may be disrupted.”

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

Intranuclear tau is thought to bind to chromatin and stabilize it in response to cellular stressors such as heat.

“In particular, intranuclear tau is thought to bind to chromatin and stabilize it in response to cellular stressors such heat [149].”

• cites [149] Sultan A, Nesslany F, Violet M et al (2011) Nuclear tau, a key player in neuronal DNA protection. J Biol Chem 268(6):4566–4575 sourceNot checked yet

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Individuals with damage in oligodendrocytes may have a decreased ability to myelinate neuronal axons, potentially leading to disruption in neuronal communication.

“We suggest that individuals with damage in oligodendrocytes may have a decreased ability to myelinate neuronal axons, potentially leading to disruption in neuronal communication.”

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

Senescent glial cells may impact neuronal functioning such that their basic properties, namely genome integrity, nuclear membrane structure, and communication between cells and networks, may be disrupted.

“Although these results are fairly preliminary, we believe that senescent glial cells may impact neuronal functioning such that their basic properties, namely genome integrity, nuclear membrane structure, and communication between cells and networks, may be disrupted.”

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

A recent study on post-mortem AD brains revealed translocation of intranuclear tau to the soma in diseased brains compared to controls, indicating that intranuclear tau may also play a role in its pathogenesis.

“A recent study on post-mortem AD brains revealed translocation of intranuclear tau to the soma in diseased brains compared to controls [57], indicating that intranuclear tau may also play a role in its pathogenesis.”

• cites [57] Hernandez-Ortega K, Garcia-Esparcia P, Gil L, Lucas JJ, Ferrer I (2016) Altered machinery of protein synthesis in Alzheimer's: from the nucleolus to the ribosome. Brain Pathol 26(5):593–605 sourceNot checked yet

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Abnormal protein deposits in the brain may not be the only explanation of symptoms, and other unknown molecular mechanisms may be driving brain dysfunction, leaving protein deposits as an end-point process.

“This points to the idea that abnormal protein deposits in the brain may not be the only explanation of symptoms, and that perhaps other unknown molecular mechanisms are driving brain dysfunction, leaving protein deposits as an end-point process.”

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

Cellular senescence has been suggested as a contributing factor causing neurodegenerative pathology and has been hypothesized to be involved in AD pathogenesis.

“Indeed, cellular senescence has been suggested as a contributing factor causing neurodegenerative pathology [143], and has been hypothesized to be involved in AD pathogenesis [46].”

• cites [143] Stein D, Toiber D (2017) DNA damage and neurodegeneration: the unusual subject. Neural Regen Res 12(9):1441–1442 sourceNot checked yet

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• cites [46] Golde TE, Miller VM (2009) Proteinopathy-induced neuronal senescence: a hypothesis for brain failure in Alzheimer’s and other neurodegenerative diseases. Alzheimers Res Ther 1(2):5 sourceNot checked yet

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Loss of emerin can lead to disruption of signaling pathways critical for maintaining normal transcription and implies disruption of healthy structural integrity of the nuclear membrane.

“Loss of emerin can lead to disruption of signaling pathways critical for maintaining normal transcription [78] and implies disruption of healthy structural integrity of the nuclear membrane.”

• cites [78] Kock AJ, Holaska JM (2014) Emerin in health and disease. Semin Cell Dev Biol 29:95–106 sourceNot checked yet

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Probably not a substantial claim: may not pass S4 (based). May combine two claims.

A significant decrease in myelination, even in small regions, may be sufficient to disrupt communications through large networks and therefore possibly lead to neurological dysfunction.

“A significant decrease in myelination, even in small regions, may be sufficient to disrupt communications through large networks and therefore possibly lead to neurological dysfunction.”

Classified as probably not a substantial claim.

The assumption that pathological protein burden reflects clinical presentation in neurodegenerative diseases has been called to question.

“Recently, the assumption that pathological protein burden reflects clinical presentation in neurodegenerative diseases has been called to question [35].”

• cites [35] Espay AJ, Vizcarra JA, Marsili L et al (2019) Revisiting protein aggregation as pathogenic in sporadic Parkinson and Alzheimer diseases. Neuroloy 92(7):329–337 sourceNot checked yet

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May combine two claims.

Cellular senescence represents a plausible pathophysiological mechanism which can contribute to symptoms and possibly drive neurodegenerative disease in the context of mTBI.

“In light of these discrepancies, we therefore suggest that cellular senescence represents a plausible pathophysiological mechanism which can contribute to symptoms and possibly drive neurodegenerative disease in the context of mTBI.”

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

Another important target of CHEK2 phosphorylation is p53, a critical transcriptional regulator of cellular senescence.

“Another important target of CHEK2 phosphorylation is p53 [169], a critical transcriptional regulator of cellular senescence [130].”

• cites [169] Zannini L, Delia D, Buscemi G (2014) CHK2 kinase in the DNA damage response and beyond. J Mol Cell Biol 6(6):442–457 sourceNot checked yet

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• cites [130] Rufini A, Tucci P, Celardo I, Melino G (2013) Senescence and aging: the critical roles of p53. Oncogene 32(43):5129–5143 sourceNot checked yet

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

Age-related tau astrogliopathy (ARTAG) is a phenomenon in which p-tau accumulates in astrocytes of various brain regions.

“Another exemplary phenomenon is age-related tau astrogliopathy (ARTAG), in which p-tau accumulates in astrocytes of various brain regions [79].”

• cites [79] Kovacs GG, Ferrer I, Grinberg LT et al (2016) Aging-related tau astrogliopathy (ARTAG): harmonized evaluation strategy. Acta Neuropathol 131(1):87–102 sourceNot checked yet

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Probably not a substantial claim: may not pass S2 (checkable), S3 (load-bearing).

It is possible that the acquisition of cellular senescence after mTBI renders brains more susceptible to neurodegenerative disease through a mechanism yet to be unraveled.

“Although this study did not directly assess the role of cellular senescence in the emergence of neuropathology, it is possible that the acquisition of cellular senescence after mTBI renders brains more susceptible to neurodegenerative disease through a mechanism yet to be unraveled.”

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

Low stages of γH2AX confined to the ependymal lining may have significantly larger effects due to involvement of paracrine signalling in the CSF.

“Although, as discussed above, low stages of γH2AX confined to the ependymal lining, may have significantly larger effects due to involvement of paracrine signalling in the CSF.”

May combine two claims.

DDR proteins CHEK1 and CHEK2 have been shown to phosphorylate tau protein and contribute to its accumulation.

“In particular, DDR proteins CHEK1 and CHEK2 have been shown to phosphorylate tau protein, and contribute to its accumulation [65].”

• cites [65] Iijima-Ando K, Zhai L, Gatt A, Shenton C, Iijima K (2010) A DNA damage-activated checkpoint kinase phosphorylates tau and enhances tau-induced neurodegeneration. Hum Mol Gen 19(10):1930–1938 sourceNot checked yet

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Probably not a substantial claim: may not pass S2 (checkable), S3 (load-bearing).

The interaction of these multiple factors may contribute to the heterogeneity in pathological outcomes associated with mTBI.

“The interaction of these multiple factors may even contribute to the heterogeneity in pathological outcomes associated with mTBI.”

May combine two claims.

Upregulation of CHEK1 and CHEK2 may cause both increased p-tau burden and accumulation of senescent cells.

“Upregulation of CHEK1 and CHEK2 may therefore cause both increased p-tau burden and accumulation of senescent cells.”

Classified as probably not a substantial claim.

Loss of lamin B1 has been associated with cognitive decline and neurodegenerative pathology.

“Loss of lamin B1 has been associated with cognitive decline and neurodegenerative pathology [20, 56].”

• cites [20] Coffinier C, Jung HJ, Nobumori C et al (2011) Deficiencies in Lamin B1 and Lamin B2 cause neurodevelopmental defects and distinct nuclear shape abnormalities in neurons. Mol Biol Cell 22:4683–4693 sourceNot checked yet

  Not checked in the free run.

• cites [56] Heng MY, Lin ST, Verret L, Huang Y, Kamiya S, Padiath QS (2013) Lamin B1 mediates cell-autonomous neuropathology in a leukodystrophy mouse model. J Clin Invest 123(6):2719–2729 sourceNot checked yet

  Not checked in the free run.

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

The neuropathology of mTBI is complex and reflects several different diseases including AD, PD, FTD, ALS, and CTE.

“As we have described, the neuropathology of mTBI is quite complex and reflects several different diseases including AD, PD, FTD, ALS, and CTE.”

May combine two claims.

Inefficient DNA repair and subsequent DNA damage-induced cellular senescence precedes neuropathological changes and renders mTBI brains susceptible to neurodegenerative pathology.

“Indeed, we propose that inefficient DNA repair and subsequent DNA damage-induced cellular senescence precedes neuropathological changes, and renders mTBI brains susceptible to neurodegenerative pathology.”

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

Because some mTBI cases with severe proteinopathy presented with no DNA damage, this reinforces the notion that γH2AX is degraded in some individuals with chronic history of head trauma, and that this depletion may contribute to the emergence of neurological symptoms.

“Indeed, because some mTBI cases with severe proteinopathy presented with no DNA damage this reinforces the previously discussed notion that perhaps γH2AX is degraded in some individuals with chronic history of head trauma, and that this depletion may contribute to the emergence of neurological symptoms.”

May combine two claims.

Even in cases with no evidence of DNA damage, symptoms and pathology associated with mTBI may emerge due to upregulation of the DDR, the degradation of H2AX, and/or the loss of lamin B1 attributed to senescence.

“In summary, even in cases with no evidence of DNA damage, symptoms and pathology associated with mTBI may emerge due to upregulation of the DDR, the degradation of H2AX, and/or the loss of lamin B1 attributed to senescence.”

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

AD has been explicitly referred to as an acquired neurodegenerative laminopathy, and lamin dysfunction has been shown to drive tau-mediated neurodegeneration.

“Indeed, AD has been explicitly referred to as an acquired neurodegenerative laminopathy [41], and lamin dysfunction has been shown to drive tau-mediated neurodegeneration [42].”

• cites [41] Frost B (2016) Alzheimer’s disease: an acquired neurodegenerative laminopathy. Nucleus 7(3):275–283 sourceNot checked yet

  Not checked in the free run.

• cites [42] Frost B, Bardai FH, Feany MB (2016) Lamin dysfunction mediates neurodegeneration in tauopathies. Curr Biol 26(1):129–136 sourceNot checked yet

  Not checked in the free run.