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Cited by 45Traumatic Brain Injury ResearchAmyotrophic Lateral Sclerosis ResearchAlzheimer's disease research and treatments

Chronic Traumatic Encephalopathy Within an Amyotrophic Lateral Sclerosis Brain Bank Cohort

Open access
Walt, Gabriel S, Burris, Hannah M, Brady, Christopher B, Spencer, Keith R, Alvarez, Victor E, Huber, Bertrand R, Guilderson, Latease, Abdul Rauf, Nazifa +9 more·2018·Journal of Neuropathology & Experimental Neurology
DOI 10.1093/jnen/nly092PMC PMC6927868
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Abstract

Chronic traumatic encephalopathy (CTE) is a progressive neurodegenerative disorder linked to repetitive head impacts and has been associated with amyotrophic lateral sclerosis (ALS), a fatal, degenerative neuromuscular disorder. The Department of Veterans Affairs Biorepository Brain Bank (VABBB) is a tissue repository that collects antemortem disease progression data and postmortem central nervous system tissue from veterans with ALS. We set out to determine the frequency of co-morbid ALS and CTE in the VABBB cohort and to characterize the clinical, genetic, and pathological distinctions between participants with ALS only and those with both ALS and CTE (ALS+CTE). Of 155 participants, 9 (5.8%) had neuropathologically confirmed ALS+CTE. Participants with ALS+CTE were more likely to have a history of traumatic brain injury (p < 0.001), served during the first Persian Gulf War (p < 0.05), and to have more severe tau pathology within the frontal cortex and spinal cord (p < 0.05). The most common exposures to head impacts included contact sports (n = 5) and military service (n = 2). Clinically, participants with ALS+CTE were more likely to have bulbar onset ALS (p = 0.006), behavioral changes (p = 0.002), and/or mood changes (p < 0.001). Overall, compared with ALS in isolation, comorbid ALS+CTE is associated with a history of TBI and has a distinct clinical and pathological presentation.

AI snapshot

Written from the paper’s full text.

TL;DR

In a VA brain bank cohort of 155 deceased veterans with neuropathologically confirmed ALS or related motor neuron disease, 9 (5.8%) had comorbid CTE. ALS+CTE was associated with TBI history, bulbar onset, mood/behavioral changes, and greater tau pathology in frontal cortex and spinal cord.

Key findings

  • 9/155 participants (5.8%) had neuropathologically confirmed ALS+CTE; all 9 were male and all had some head-impact history (8 with TBI, 6 with RHI). Of 16 participants with a TBI history, 8 (50%) received a comorbid CTE diagnosis at autopsy.
  • Compared with ALS alone, ALS+CTE had significantly more TBI history (8/9 [89%] vs 8/146 [5%], p < 0.001), bulbar onset (56% vs 14%, p = 0.006), mood disorders (78% vs 23%, p = 0.001), and behavioral disorders (44% vs 5%, p = 0.002).
  • Tau pathology was increased in ALS+CTE: middle frontal cortex frequency (p = 0.002) and severity (p < 0.001), and spinal cord severity in cervical (p = 0.024), thoracic (p = 0.014), and lumbar (p = 0.007) regions. ALSFRS-R at death (12.9 vs 12.8, p = 0.989) and DFS progression rate (−0.5 vs −0.6, p = 0.689) did not differ significantly.
  • Service era differed: ALS+CTE participants were less likely to have served in Vietnam (p < 0.05) and more likely to have served in the first Persian Gulf War (p < 0.05). No known ALS mutations were found in the 5 tested ALS+CTE participants; 9 ALS-only participants had known mutations, including 3 with C9orf72, but differences were not significant.

Methods

  • Design: analysis of the Department of Veterans Affairs Biorepository Brain Bank (VABBB), a longitudinal ALS tissue repository. Since 2006, 287 veterans with ALS enrolled; 156 were deceased with complete neuropathological evaluation and cortical/spinal cord tau immunostaining; 1 was excluded for not meeting ALS neuropathological criteria, leaving 155.
  • Data: antemortem clinical/functional data collected by telephone interview, mail questionnaires, and medical record review; TBI and RHI defined from history; ALSFRS-R used for motor function. Postmortem neuropathological examination was blinded to clinical features; CTE diagnosed by consensus criteria; tau pathology in dorsolateral frontal cortex and spinal cord scored semiquantitatively 0–3; genetic testing used NeuroChip and OmniExpress.
  • Analysis: IBM SPSS Statistics v20; Mann-Whitney U tests, Fisher exact tests, and Pearson chi-squared tests with Bonferroni corrections; alpha = 0.05.

Limitations

  • Stated: enrollment via the Durham VA ALS Registry and passive methods may introduce bias; TBI/RHI exposure was determined by retrospective review, which may bias results; the veteran population limits generalizability; and the small number of ALS+CTE participants limits power for many analyses.
  • Evident from the text: the cohort was 99% male and 89% White and veteran-only, so findings may not generalize to women, non-veterans, or more diverse populations.
  • Evident from the text: missing data affect some comparisons (e.g., RHI data were not available for the majority of ALS-only cases; ALSFRS-R was unavailable for postmortem enrollees; genetic testing was performed in 98 participants), and tau pathology was assessed semiquantitatively at death, when advanced disease may preclude detection of earlier changes.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1093/jnen/nly092

Cites

58 of 58 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

29 of 40 cited sources checked · 15 supported · 0 flagged · accuracy not yet measured

  • Premisecitation

    In a veteran cohort, those with head injury, especially head injuries within 15 years prior to diagnosis, were significantly more likely to have developed ALS.

    “Moreover, in a veteran cohort, those with head injury, especially head injuries within 15 years prior to diagnosis, were found to be significantly more likely to have developed ALS (16).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [16] Schmidt, 2010, Association of ALS with head injury, cigarette smoking and APOE genotypes, J Neurol Sci source

      The Results (Association of ALS with Head Injury; page not supplied) report significantly higher ALS odds for veterans whose last head injury occurred within 15 years before the reference date (OR 2.33, 95% CI 1.18–4.61). They also state that the absolute number of head injuries was not associated with ALS, so the claim is too broad if it says head injury generally was significantly associated. The paper uses the reference date, rather than diagnosis, for the 15-year interval. (LLM, conf=0.84)

      Experimental — accuracy not yet measured
  • Premisecitation

    TBI may be an environmental risk factor for ALS.

    “One such environmental risk factor may be traumatic brain injury (TBI).Chen et al found that individuals were 11 times more likely to develop ALS if they reported multiple head injuries within the last 10 years prior to diagnosis (14)”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [14] Chen, 2007, Head injury and amyotrophic lateral sclerosis, Am J Epidemiol source
  • Findingcitation

    There was a significantly increased TDP-43 stage using the criteria of Brettschneider et al in participants with ALS+CTE.

    “However, there was a significantly increased TDP-43 stage using the criteria of Brettschneider et al in participants with ALSþCTE (27).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [27] Brettschneider, 2013, Stages of pTDP‐43 pathology in amyotrophic lateral sclerosis, Ann Neurol source
  • Premisecitation

    A recent study demonstrated phosphorylation of tau at Thr 175 and Thr 231 in individuals with CTE and ALS+CTE, but not in participants with sporadic ALS without CTE.

    “A recent study demonstrated phosphorylation of tau at Thr 175 and Thr 231 in individuals with CTE and ALSþCTE, but not in participants with sporadic ALS without CTE (45).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [45] Moszczynski, 2018, Pathologic Thr(175) tau phosphorylation in CTE and CTE with ALS, Neurology source

      The Abstract Results and Discussion report phosphorylation of tau at Thr175 and Thr231 in CTE and CTE-ALS. The Methods list CTE, CTE-ALS, and neurologically healthy control cases—not participants with sporadic ALS. Although the Discussion mentions an absence of spinal-cord tau deposition in sporadic ALS, this study did not demonstrate the claimed absence of phosphorylation at both sites in such participants. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
  • Premisecitation

    Individuals with ALS are at higher risks for falls compared to the general population.

    “In addition, individuals with ALS are at higher risks for falls compared to the general population and therefore may have an increased risk for developing CTE (42).”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [42] Kehyayan, 2014, Profile of patients with amyotrophic lateral sclerosis across continuum of care, Can J Neurol Sci source

      The Health and Social-Economic Profile reports higher fall rates for people with ALS than for the comparison group in home care. But the Case Ascertainment and Sample Size sections define that group as patients in care settings without specified neurological conditions, not the general population. The cited paper therefore supports a narrower comparison than the claim makes. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
  • Classified as probably not a substantial claim. 41
  • May combine two claims. 42

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

    Premisecitation

    CTE stage (I to IV) is based on extent and severity of ptau pathology.

    “The stage of CTE (I to IV) is based on the extent and severity of ptau pathology (8).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [8] McKee, 2013, The spectrum of disease in chronic traumatic encephalopathy, Brain source

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

    Premisecitation

    ALS onset is most often sporadic, with approximately 10% of cases considered familial; there is a known genetic component for approximately 5%-10% of sporadic cases and 60% of familial cases.

    “ALS onset is most often sporadic, with approximately 10% of cases considered familial.There is a known genetic component for approximately 5%-10% of sporadic cases and 60% of familial cases (12,13).”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites [12] Logroscino, 2010, Incidence of amyotrophic lateral sclerosis in Europe, J Neurol Neurosurg Psychiatry source

      The citation follows the sentence claiming known genetic components in 5%–10% of sporadic cases and 60% of familial cases. The Results section discusses regional differences in familial ALS cases, but neither it nor the passages retrieved for genetic components and those percentages addresses the claimed figures. (LLM, conf=0.75)

      Experimental — accuracy not yet measured
    • cites [13] Tiryaki, 2014, ALS and other motor neuron diseases, Continuum (Minneap Minn) source

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

    Premisecitation

    Pathologically, CTE is characterized by accumulation of hyperphosphorylated tau aggregated in neurons, astrocytes, and cell processes around small vessels and in depths of cerebral sulci.

    “Pathologically, CTE is characterized by accumulation of hyperphosphorylated tau (ptau) that is aggregated in neurons, astrocytes, and cell processes around small vessels and in the depths of the cerebral sulci (7).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [7] McKee, 2016, The first NINDS/NIBIB consensus meeting to define neuropathological criteria for the diagnosis of chronic traumatic encephalopathy, Acta Neuropathol source

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

    Premisecitation

    Incidence estimates for ALS range from about 2 to 3 per 100,000 people per year; ALS is more common in males and military veterans.

    “Incidence estimates for ALS range from about 2 to 3 per 100 000 people per year; ALS is more common in males and military veterans (11,12).”
    Quote in the paperNot a substantial claim2 of 2 sources checked
    • cites [11] Bieniek, 2015, Chronic traumatic encephalopathy pathology in a neurodegenerative disorders brain bank, Acta Neuropathol source

      Split into 2 atoms — 0 confirmed, 0 partially supported, 0 disputed, 0 misattributed, 2 unverifiable. Expand the claim to see per-atom verdicts.

      Experimental — accuracy not yet measured
    • cites [12] Logroscino, 2010, Incidence of amyotrophic lateral sclerosis in Europe, J Neurol Neurosurg Psychiatry source

      Split into 2 atoms — 1 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

      Experimental — accuracy not yet measured

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

    Premisecitation

    Cognition is affected in a majority of ALS cases at some point in disease course.

    “Cognition is also affected in a majority of cases at some point in the disease course (10).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [10] Strong, 2017, Amyotrophic lateral sclerosis—Frontotemporal spectrum disorder (ALS-FTSD): Revised diagnostic criteria, Amyotroph Lateral Scler Frontotemporal Degener source

      The Discussion reports that more than 50% of ALS patients prospectively assessed had some form of frontotemporal disruption or dementia. That category includes behavioural dysfunction, so it does not establish that cognition specifically is affected in a majority, nor does the passage establish the claim’s ‘at some point in the disease course’ timing. (LLM, conf=0.86)

      Experimental — accuracy not yet measured

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

    Premisecitation

    The clinical syndrome of CTE includes behavioral, mood, and cognitive dysfunction as well as occasional extrapyramidal motor symptoms.

    “The clinical syndrome of CTE continues to be refined but includes behavioral, mood, and cognitive dysfunction as well as occasional motor symptoms that are typically extrapyramidal (1,2).”
    Quote in the paperNot a substantial claim2 of 2 sources checked
    • cites [1] McKee, 2009, Chronic traumatic encephalopathy in athletes: Progressive tauopathy after repetitive head injury, J Neuropathol Exp Neurol source
    • cites [2] Gavett, 2011, Chronic traumatic encephalopathy: A potential late effect of sport-related concussive and subconcussive head trauma, Clin Sports Med source

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

    Premisecitation

    Other studies have not found a modifying effect of head injury on ALS.

    “although other studies have not found a modifying effect of head injury on ALS (15).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [15] Fournier, 2015, Head injury does not alter disease progression or neuropathologic outcomes in ALS, Neurology source

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

    Premisecitation

    DFS score has been used to indicate functional progression and disease duration in other ALS cohorts.

    “This score, the DFS score, has been used to indicate functional progression and disease duration in other ALS cohorts (25).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [25] Labra, 2016, Rate of disease progression: A prognostic biomarker in ALS, J Neurol Neurosurg Psychiatry source

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

    Premisecitation

    Chen et al found individuals were 11 times more likely to develop ALS if they reported multiple head injuries within last 10 years prior to diagnosis.

    “Chen et al found that individuals were 11 times more likely to develop ALS if they reported multiple head injuries within the last 10 years prior to diagnosis (14), although other studies have not found a modifying effect of head injury on ALS (15).”
    Quote in the paperNot a substantial claim2 of 2 sources checked
    • cites [14] Chen, 2007, Head injury and amyotrophic lateral sclerosis, Am J Epidemiol source

      The results (p. 811) report more than an 11-fold higher ALS risk among people with repeated head injuries whose latest injury occurred within 10 years before diagnosis. The claim implies that the multiple injuries all occurred within that period and omits that the estimate came from a post-hoc exploratory analysis based on small numbers. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
    • cites [15] Fournier, 2015, Head injury does not alter disease progression or neuropathologic outcomes in ALS, Neurology source

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

    Premisecitation

    Environmental factors are believed to play an important role in development of ALS.

    “As a result, environmental factors are believed to play an important role in the development of ALS (12).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [12] Logroscino, 2010, Incidence of amyotrophic lateral sclerosis in Europe, J Neurol Neurosurg Psychiatry source

      The Introduction (page unavailable) says environmental risk factors may be relevant to ALS pathogenesis, and the Discussion speculates that an environmental risk factor may contribute to differences in disease onset between men and women. The paper does not establish or assert that environmental factors play an important role in ALS development generally; it describes the cause of ALS as unknown. (LLM, conf=0.82)

      Experimental — accuracy not yet measured

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

    Premisecitation

    Participants with ALS have been shown to have an elevated frequency of minor to major depressive symptoms of approximately 27%.

    “Participants with ALS have been shown to have an elevated frequency of minor to major depressive symptoms of approximately 27% (42), which is similar to the frequency of mood disorders amongst the VABBB ALS participants (26%).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [42] Kehyayan, 2014, Profile of patients with amyotrophic lateral sclerosis across continuum of care, Can J Neurol Sci source

      The Health and Social-Economic Profile table reports potential minor-to-major depressive episodes in 27.2% of ALS patients receiving home care, versus 14.5% of the home-care comparison group. The approximately 27% figure is supported for that setting, but not for ALS participants across all settings: the corresponding figures are 38.4% in nursing homes and 38.8% in complex continuing care. No page number is available in our copy. (LLM, conf=0.86)

      Experimental — accuracy not yet measured

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

    Premisecitation

    Bulbar onset ALS has been associated with faster disease progression.

    “Although bulbar onset ALS has been associated with faster disease progression (44), DFS rates were not significantly different between participants with ALSþCTE and ALS only although this analysis is likely underpowered due to the small number of participants with CTE.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [44] Chio, 2009, Prognostic factors in ALS: A critical review, Amyotroph Lateral Scler source

      The Site of onset section says bulbar-onset ALS is associated with a worse prognosis than spinal-onset ALS. The review discusses progression rates separately, but does not establish that bulbar onset itself is associated with faster disease progression. (LLM, conf=0.85)

      Experimental — accuracy not yet measured

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

    Premisecitation

    Individuals with a history of repetitive head impacts and CTE may be at risk for multiple neurodegenerations including beta-amyloid deposition and Lewy body disease.

    “Moreover, individuals with a history of repetitive head impacts and CTE may be at risk for multiple neurodegenerations including bamyloid deposition (49) and Lewy body disease (50).”
    Quote in the paperNot a substantial claim2 of 2 sources checked
    • cites [49] Stein, 2015, Beta-amyloid deposition in chronic traumatic encephalopathy, Acta Neuropathol source
    • cites [50] Adams, 2018, Lewy body pathology and chronic traumatic encephalopathy associated with contact sports, J Neuropathol Exp Neurol source

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

    Premisecitation

    Most of the RHI exposures in this cohort have been previously related to the development of CTE, including bull riding.

    “Most of these exposures have been previously related to the development of CTE, including bull riding, which was recently reported in association with CTE (41).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [41] Keene, 2018, First confirmed case of chronic traumatic encephalopathy in a professional bull rider, Acta Neuropathol source

  • May combine two claims.

    Premisecitation

    The presence of comorbid ALS+CTE in an ALS cohort parallels similar findings of CTE in neurodegenerative cohorts, e.g. 6% in an MSA cohort, 6% in an American football CTE group, and 11.9%-32% in a group of various diseases.

    “The presence of comorbid ALSþCTE in an ALS cohort parallel similar findings of CTE in neurodegenerative cohorts, e.g.6% in an multiple system atrophy (MSA) cohort as reported by Koga et al (46), 6% in an American football CTE group (47) and 11.9%-32% in a group of various diseases reported by Ling et al (48).”
    Quote in the paperNot a substantial claim2 of 3 sources checked
    • cites [46] Koga, 2016, Chronic traumatic encephalopathy pathology in multiple system atrophy, J Neuropathol Exp Neurol source
    • cites [47] Mez, 2017, Clinicopathological evaluation of chronic traumatic encephalopathy in players of American football, JAMA source

      The Discussion (page not available in our copy) reports comorbid motor neuron disease among football players with severe CTE pathology, supporting the comparison with ALS+CTE. It does not give a 6% figure for that comorbidity, so the specific percentage attributed to this paper is not verified. The MSA and other-disease figures are attributed to separate citations, not this source. (LLM, conf=0.83)

      Experimental — accuracy not yet measured
    • cites [48] Ling, 2015, Histological evidence of chronic traumatic encephalopathy in a large series of neurodegenerative diseases, Acta Neuropathol source

  • May combine two claims.

    Findingreasoning

    One participant did not meet criteria for neuropathological diagnosis of ALS and was excluded, resulting in 155 deceased participants selected for study.

    “One participant did not meet criteria for neuropathological diagnosis of ALS and was excluded, resulting in a total of 155 deceased participants selected for the study.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    In entire cohort, 153 (99%) had neuropathologically confirmed ALS and 2 (1%) had motor neuron disease with prominent lower motor degeneration consistent with primary muscular atrophy.

    “In the entire cohort, 153 (99%) had neuropathologically confirmed ALS and 2 (1%) had motor neuron disease with prominent lower motor degeneration consistent with primary muscular atrophy.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Mean age at onset was younger in ALS+CTE by about 7 years, although not significant (52.9 vs 59.9, p=0.096).

    “Mean age at onset was younger in participants with co-morbid CTE by about 7 years, although this did not reach significance (52.9 years vs 59.9 years, p ¼ 0.096).”
    Quote in the paperNot a substantial claim

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

    Findingown data

    Of 155 participants, 152 had available clinical medical records.

    “Of the 155 participants, 152 had available clinical medical records.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: Missing clinical medical records (3 ALS only) do not bias the comparisons.

  • May combine two claims.

    Findingown data

    Stage distribution: one stage I, 4 stage II, 3 stage III, one stage IV.

    “One participant was stage I, 4 participants were stage II, 3 participants were stage III, and one participant was stage IV.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Between groups, differences in number of mutations were not significant for C9orf72 (0% vs 3%, p=0.36) or all tested mutations (0% vs 10%, p=1.00), although comparison likely underpowered.

    “Between the 2 groups, differences in the number of mutations were not significant for C9orf72 mutations (0% vs 3%, p ¼ 0.36), or for all tested mutations (0% vs 10%, p ¼ 1.00), although this comparison is likely underpowered.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Nine participants in ALS only group tested positive for known genetic mutation, and 3 had C9orf72 mutation.

    “Nine participants in the ALS only group tested positive for a known genetic mutation, and 3 of these participants had a C9orf72 mutation.”
    Quote in the paperNot a substantial claim

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

    Findingown data

    Ethnicity: 139 not Hispanic (89%), 2 Hispanic (1%), 14 missing (10%).

    “With regards to ethnicity, 139 (89%) of participants were not Hispanic or Latino, 2 (1%) were Hispanic or Latino, and 14 (10%) did not provide information.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Of 21 participants with history of either TBI or RHI, 9 (43%) had pathological diagnosis of CTE and 12 (57%) did not.

    “Overall, there were a total of 21 participants with a history of either TBI or RHI: 9 (43%) had a pathological diagnosis of CTE (CTE-1-9) and 12 (57%) did not (ALS-1-12, Table 1).”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Clinical history data (TBI, RHI, mood, behavioral, cognitive) obtained from participant/proxy questionnaires and medical records accurately reflect participants' actual exposures and symptoms.

  • May combine two claims.

    Findingown data

    No apparent differences between groups in progression of ALS symptoms: ALSFRS-R score at death (12.9 vs 12.8, p=0.989) and DFS (-0.5 vs -0.6, p=0.689) not significantly different.

    “There were also no apparent differences between groups in the progression of ALS symptoms: the ALSFRS-R score at death (12.9 vs 12.8, p ¼ 0.989) and the DFS (À0.5 vs À0.6, p ¼ 0.689) were not significantly different between the groups.”
    Quote in the paperNot a substantial claim

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

    Findingown data

    Cohort was predominantly male (99%).

    “The cohort was predominantly male (99%).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Service era distribution was significantly different between groups (χ2=17.7, p=0.013) such that ALS+CTE were less likely to serve in Vietnam (p<0.05) and more likely to have served in first Persian Gulf War (p<0.05).

    “However, the service era distribution was significantly different between groups (v 2 ¼ 17.7, p ¼ 0.013) such that participants with ALSþCTE were less likely to serve in Vietnam (p < 0.05) and more likely to have served in the first Persian Gulf War (p < 0.05, Table 3).”
    Quote in the paperNot a substantial claim

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

    Findingown data

    Since inception in 2006, VABBB enrolled 287 veterans with ALS.

    “Since its inception in 2006, the VABBB has enrolled a total of 287 veterans with ALS.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    For 152 participants with clinical records, 40 (26%) had mood changes or mood disorder, 12 (8%) behavioral changes, 12 (8%) cognitive impairment.

    “For the 152 participants with clinical records, 40 (26%) had noted mood changes or a mood disorder diagnosis, 12 (8%) had behavioral changes, and 12 (8%) had cognitive impairment.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: Clinical history data (TBI, RHI, mood, behavioral, cognitive) obtained from participant/proxy questionnaires and medical records accurately reflect participants' actual exposures and symptoms.
    • Rests on an assumption: Missing clinical medical records (3 ALS only) do not bias the comparisons.

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

    Findingown data

    In 2 participants, head impact exposure was associated with military service.

    “In 2 participants, head impact exposure was associated with military service.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: Clinical history data (TBI, RHI, mood, behavioral, cognitive) obtained from participant/proxy questionnaires and medical records accurately reflect participants' actual exposures and symptoms.

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

    Findingown data

    ALS disease duration ranged from 6 to 504 months with mean 126 and median 96.

    “ALS disease duration ranged from 6 to 504 months with a mean duration of 126 months and median of 96 months.”
    Quote in the paperNot a substantial claim

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

    Findingown data

    Twenty-six (17%) had family history of neurological disease, and 13 (8%) had family history specific for ALS.

    “Twenty-six (17%) had a family history of neurological disease, and of this group 13 (8%) had a family history specific for ALS.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Sixteen (11%) had record of at least 1 TBI, 12 (8%) had record of exposure to RHI, and 7 (5%) had history of both TBI and RHI.

    “Sixteen (11%) had a record of at least 1 TBI, 12 (8%) had a record of exposure to a form of RHI (e.g.participation in contact sports), and 7 (5%) had a history of both TBI and RHI.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: Clinical history data (TBI, RHI, mood, behavioral, cognitive) obtained from participant/proxy questionnaires and medical records accurately reflect participants' actual exposures and symptoms.

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

    Findingown data

    Race distribution: 138 White (89%), 4 Black (3%), 1 Asian (<1%), 10 missing (8%).

    “One hundred thirtyeight participants were White (89%), 4 were Black or African American (3%), 1 was Asian (<1%), and 10 did not provide information (8%).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    All 9 participants with ALS+CTE were male, and all had history of some form of head impact: 8 had history of at least 1 moderate to severe TBI, and 6 had confirmed history of RHI from contact or alternative sports or military-related activities.

    “All 9 participants with ALSþCTE were male, and all had a history of some form of head impact: 8 had a history of at least 1 moderate to severe TBI, and 6 had confirmed history of RHI from contact or alternative sports or military-related activities.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: Clinical history data (TBI, RHI, mood, behavioral, cognitive) obtained from participant/proxy questionnaires and medical records accurately reflect participants' actual exposures and symptoms.

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

    Findingown data

    Military branch distribution: Army 71 (46%), Navy 38 (24%), Air Force 31 (19%), Marines 8 (6%), Coast Guard 2 (1%), Army and Air Force 1 (<1%), unavailable 4 (3%).

    “Veterans previously served in the following branches of the US Armed Forces: Army 71 (46%), Navy 38 (24%), Air Force 31 (19%), Marines 8 (6%), Coast Guard 2 (1%), Army and Air Force 1 (<1%), and information was unavailable for 4 (3%).”
    Quote in the paperNot a substantial claim

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

    Findingown data

    Ninety-eight participants were tested postmortem for genetic mutations known to be associated with neurological disease.

    “Ninety-eight participants were tested postmortem for genetic mutations known to be associated with neurological disease.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    One of 9 ALS+CTE (CTE-4) had family history of ALS, but genetic testing did not reveal known ALS mutations.

    “One of the 9 participants with ALSþCTE (CTE-4) had a family history of ALS, but genetic testing on this subject did not reveal any known ALS mutations.”
    Quote in the paperNot a substantial claim

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

    Findingown data

    Mean age at death was 70.3 years, median 71.8.

    “The mean age at death was 70.3 years, and the median was 71.8 years.”
    Quote in the paperNot a substantial claim

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

    Findingown data

    Age at onset known for 140, mean 59.6 years.

    “Age at onset of ALS symptoms was known for 140 participants, and the mean age at onset was 59.6 years.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    No significant differences in total years of service or military branch between ALS and ALS+CTE.

    “There were no significant differences in total number of years of service or in military branch between participants with ALS and ALSþCTE.”
    Quote in the paperNot a substantial claim

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

    Findingown data

    Eight donors were White, and one was Asian.

    “Eight donors were White, and one was Asian.”
    Quote in the paperNot a substantial claim

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

    Findingown data

    Mean time in active military service, based on available info for 149 participants, was 6.1 years.

    “Mean time in active military service, based on available information for 149 participants, was 6.1 years.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    All participants with ALS+CTE had tau-positive NFTs and 4/9 had tau-positive glial tangles.

    “All participants with ALSþCTE had tau-positive NFTs and 4/9 had tau-positive glial tangles.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: Semiquantitative tau pathology scores (0-3) reliably reflect severity of tau pathology.

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

    Findingown data

    Onset site: 65 (42%) lower extremity, 41 (27%) upper extremity, 21 (14%) bulbar, 1 (<1%) respiratory, unknown 25 (16%).

    “Of the 153 participants with a neuropathologically confirmed ALS diagnosis, 65 (42%) of participants had lower extremity onset, 41 (27%) participants had upper extremity onset, 21 (14%) of participants had bulbar onset, and one (<1%) participant had respiratory onset.Onset site was unknown for the remaining 25 (16%) of participants.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    TDP-43 inclusions were present in 7 participants and involved frontal cortex in 3 (CTE-1,7,5).

    “TDP-43 inclusions were present in 7 participants and involved the frontal cortex in 3 participants (CTE-1, CTE-7, and CTE-5).”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: Semiquantitative tau pathology scores (0-3) reliably reflect severity of tau pathology.

  • May combine two claims.

    Findingcitation

    The frequency of mood disorders amongst the VABBB ALS participants was 26%, similar to the 27% reported in ALS.

    “Participants with ALS have been shown to have an elevated frequency of minor to major depressive symptoms of approximately 27% (42), which is similar to the frequency of mood disorders amongst the VABBB ALS participants (26%).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Age of onset was lower in participants with CTE, though this difference did not reach statistical significance.

    “Age of onset was lower in participants with CTE, though this difference did not reach statistical significance.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Within participants with ALS+CTE, RHI exposure was due to contact sports exposure in 4 (44%), military service in one (11%), and both in one (11%).

    “Within participants with ALSþCTE, RHI exposure was due to contact sports exposure (e.g.tackle football) in 4 (44%), military service (frequent aircraft carrier landings) in one (11%), and both (bull riding and grenade blast exposure) in one (11%).”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    CTE can only be definitely diagnosed postmortem, and prevalence and incidence remain unknown.

    “Thus far, CTE can only be definitely diagnosed postmortem, and the prevalence and incidence of the disorder remain unknown (2,(5)(6)(7)(8)(9).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites (2,(5)(6)(7)(8)(9)

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

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

    Premisecitation

    Repetitive head impacts, including concussion and subconcussion, may result from contact sports, military-related activities, and motor vehicle accidents.

    “Repetitive head impacts, including concussion and subconcussion, may result from a number of sources including participation in contact sports, military-related activities, and motor vehicle accidents (1)(2)(3)(4).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites (1)(2)(3)(4)

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

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

    Premisecitation

    The clinical presentation of CTE is typically insidious and often occurs years after the traumatic exposure.

    “The clinical presentation of CTE is typically insidious and often occurs years after the traumatic exposure (1,2,(4)(5)(6).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites (1,2,(4)(5)(6)

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

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

    Study design and conductnone given

    Procedures were in accordance with ethical standards required by VA Boston Healthcare System IRB and VA Office of Research and Development.

    “Procedures were in accordance with ethical standards required by the VA Boston Healthcare System Institutional Review Board and VA Office of Research and Development.”
    Quote in the paperNot a substantial claim

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

    Study design and conductnone given

    Neuropathologists were blinded to clinical features of participants.

    “Neuropathologists were blinded to clinical features of the participants.”
    Quote in the paperNot a substantial claim

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

    Study design and conductown data

    Septal abnormalities could not be optimally assessed due to midline cut necessary to process half cerebrum for freezing and half for fixation.

    “Septal abnormalities could not be optimally assessed due to the midline cut necessary to process half the cerebrum for freezing and half for fixation.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    US military veterans have increased frequency of ALS, and veteran population has higher head injury prevalence than comparable civilian population.

    “US military veterans have an increased frequency of ALS, and the veteran population has higher head injury prevalence than the comparable civilian population (16)(17)(18).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites (16)(17)(18)

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

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

    Study design and conductcitation

    ALSFRS-R is a widely used and validated measure to evaluate functional status in ALS.

    “The ALSFRS-R is a widely used and validated measure to evaluate functional status in ALS (20).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [20] Kollewe, 2008, ALSFRS-R score and its ratio: A useful predictor for ALS-progression, J Neurol Sci source

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

    Study design and conductcitation

    Administration of ALSFRS-R by trained non-clinicians has been demonstrated to have exemplary inter-rater, intra-rater, and telephone-administered reliability.

    “The administration of the ALSFRS-R by trained non-clinicians has been demonstrated to have exemplary inter-rater, intra-rater, and telephone-administered reliability (21).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [21] Kaufmann, 2007, and telephone‐administered reliability of the ALSFRS‐R in a multicenter clinical trial, Amyotroph Lateral Scler source

  • May combine two claims.

    Interpretationown data

    Overall, compared with ALS in isolation, comorbid ALS+CTE is associated with a history of TBI and has a distinct clinical and pathological presentation.

    “Overall, compared with ALS in isolation, comorbid ALSþCTE is associated with a history of TBI and has a distinct clinical and pathological presentation.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Clinical history data (TBI, RHI, mood, behavioral, cognitive) obtained from participant/proxy questionnaires and medical records accurately reflect participants' actual exposures and symptoms.
    • Rests on an assumption: Semiquantitative tau pathology scores (0-3) reliably reflect severity of tau pathology.
    • Rests on an assumption: The VABBB cohort of deceased veterans with ALS is not systematically biased in ways that affect comparisons between ALS+CTE and ALS only.

  • May combine two claims.

    Premisecitation

    The VABBB follows veterans with ALS or related motor neuron disorders during life and collects CNS tissue after death.

    “The VABBB follows veterans with ALS or related motor neuron disorders during life and then collects, processes, and stores CNS tissue after death (19).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [19] Greenfield, 2008

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

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

    Premisecitation

    The VABBB is a longitudinal research project and tissue repository that collects functional, disease progression, and neuropathological data from enrolled veterans across the United States.

    “The Department of Veterans Affairs Biorepository Brain Bank (VABBB) is a longitudinal research project and tissue repository that collects extensive functional, disease progression, and neuropathological data from enrolled veterans across the United States (18).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [18] Brady, 2013, The Department of Veterans Affairs Biorepository Brain Bank: A national resource for amyotrophic lateral sclerosis research, Amyotroph Lateral Scler Frontotemporal Degener source

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

    Study design and conductnone given

    Veterans were initially enrolled via outreach to the Durham VA ALS Registry and subsequently through passive methods such as online articles, use of a website, and unsolicited referrals from clinics aware of the project, all of which may introduce bias.

    “Veterans were initially enrolled via outreach to the Durham VA ALS Registry and subsequently through passive methods such as online articles, use of a website, and unsolicited referrals from clinics aware of the project, all of which may introduce bias.”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    CTE is often associated with mood and behavioral dysfunction.

    “CTE is often associated with mood and behavioral dysfunction (6).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [6] Daneshvar, 2015, Post-traumatic neurodegeneration and chronic traumatic encephalopathy, Mol Cell Neurosci source

  • May combine two claims.

    Interpretationreasoning

    Veterans' exposure to combat, combat training, and contact sports may predispose them to head injuries to a greater degree than the general population, limiting the generalizability of the study.

    “Veterans are at increased risk for ALS development (51) and their exposure to combat, combat training, and contact sports may predispose them to head injuries to a greater degree than the general population, limiting the generalizability of the study.”
    Quote in the paperNot a substantial claim

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

    Interpretationnone given

    Both ALS and MSA populations are at a high risk of falls after the onset of neurological disease.

    “The prevalence of CTE found in an MSA cohort is similar to the prevalence found in this study (5.8%), and both populations are at a high risk of falls after the onset of neurological disease.”
    Quote in the paperNot a substantial claim
65 of 65

  • The paper relies on this without support.

    Clinical history data (TBI, RHI, mood, behavioral, cognitive) obtained from participant/proxy questionnaires and medical records accurately reflect participants' actual exposures and symptoms.

    “Longitudinal clinical data was collected via telephone interview of the participant (or proxy in cases where the participant was unable to speak), questionnaires completed via the mail, and medical record review by study staff using the VA's Compensation and Pension Record Interchange medical record system (18).”

  • The paper relies on this without support.

    Semiquantitative tau pathology scores (0-3) reliably reflect severity of tau pathology.

    “Tau pathology in the dorsolateral frontal cortex and spinal cord was scored on a semiquantitative scale from 0 to 3.”

  • The paper relies on this without support.

    The VABBB cohort of deceased veterans with ALS is not systematically biased in ways that affect comparisons between ALS+CTE and ALS only.

    “Of the 287 total participants enrolled, 156 were deceased with a complete neuropathological evaluation with cortical and spinal cord tau immunostaining for the current analyses.”

  • The paper relies on this without support.

    Missing clinical medical records (3 ALS only) do not bias the comparisons.

    “All 3 of the cases missing clinical medical records were participants with ALS only.”

  • The paper relies on this without support.

    Veterans are at risk for CTE from exposure to multiple sources of trauma, including combat-related activities, blast exposures, training exercises, recreational activities, as well as motor vehicle accidents, falls, and contact sports participation.

    “In addition, veterans are at risk for CTE from exposure to multiple sources of trauma, including combat-related activities, blast exposures, training exercises, recreational activities, as well as motor vehicle accidents, falls, and contact sports participation.”
5 of 5

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • Army and Air Force branch counts conflict across sections

    Major

    The cohort summary reports 71 Army and 31 Air Force veterans, while Table 3 reports 28 plus 3 Army veterans and 68 plus 3 Air Force veterans. The totals appear reversed.

  • Percentage with missing race information is incorrect

    Minor

    Ten participants out of 155 is 6.5%, not the reported 8%.

    Reported 8 · recomputed 6.451613

  • Overall male percentage conflicts with group counts

    Minor

    Table 2 reports 143 male participants with ALS only and 9 with ALS and CTE. Together, 152 of 155 participants were male, or approximately 98%, rather than 99%.

  • DFS formulas have opposite signs

    Minor

    The Methods subtract the baseline score from 48, whereas the Table 2 footnote subtracts 48 from the baseline score. These definitions yield progression rates with opposite signs.

  • Six cases are listed for a count of five

    Minor

    The statement reports corpus callosum thinning in five participants but names six cases.

  • Marine participant with CTE is absent from Table 3

    Minor

    The case descriptions identify CTE-9 as a Marine veteran, but Table 3 reports no Marines in the ALS-plus-CTE group.

6 of 6

Cites

Flagged first, then by citations

Research works printed but not linked: 1

  1. Cedarbaum, 1997, J Neurol Sci, S1

Cited by

Sorted by citations

Related

Authors
Walt, G. S., Burris, H. M., Brady, C. B., Spencer, K. R., Alvarez, V. E., Huber, B. R., Guilderson, L., Abdul Rauf, N., Collins, D., Singh, T., Mathias, R., Averill, J. G., Walker, S. E., Robey, I., McKee, A. C., Kowall, N. W., & Stein, T. D.
Affiliations
  • VA Boston Healthcare System (US)
  • Boston University (US)
  • VA Boston Healthcare System, Boston, Massachusetts
  • Southern Arizona VA Health Care System (US)
Corresponding author
Stein, Thor D
ORCID
Venue
Journal of Neuropathology & Experimental Neurology
Publisher
Oxford University Press (OUP)
Published
2018-10-09
Volume
77
Issue
12
Pages
1091-1100
ISSN
  • 0022-3069 (ISSN-L)
  • 1554-6578
DOI
10.1093/jnen/nly092
PMC
PMC6927868
OpenAlex
W2897778842
Semantic Scholar
19bbbdaccdbff42f29ca8fd1022477309fd13d44
Cited by
45
References
54
Citations by year
2026: 3 · 2025: 6 · 2024: 2 · 2023: 6 · 2022: 8 · 2021: 8 · 2020: 4 · 2019: 6 · 2018: 2
FWCI
3.40
Type
journal article
Language
en
Open access
Licence
public-domain
Locations
  • Journal of Neuropathology & Experimental Neurology (publishedVersion, public-domain)
  • PubMed (publishedVersion)
  • PubMed Central (submittedVersion)
Funders
NIH
Topics
  • Health Sciences › Medicine › Epidemiology › Traumatic Brain Injury Research
  • Health Sciences › Medicine › Neurology › Amyotrophic Lateral Sclerosis Research
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
Keywords
chronic traumatic encephalopathy, amyotrophic lateral sclerosis, comorbidities, traumatic brain injury, tau pathology, veterans, Gulf War, bulbar onset, behavior change, mood changes, repetitive head impacts, contact sports, military service
MeSH terms
Chronic Traumatic Encephalopathy, Adult, Aged, Aged, 80 and over, Amyotrophic Lateral Sclerosis, Brain, Female, Humans, Longitudinal Studies, Male, Middle Aged, Tissue Banks, United States, United States Department of Veterans Affairs, Cohort Studies, Comorbidity

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-18.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-18.

Cited sources are checked by gpt-6-sol.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

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