Multi-Modal Biomarkers of Repetitive Head Impacts and Traumatic Encephalopathy Syndrome: A Clinicopathological Case Series

Asken, Breton M; Tanner, Jeremy A.; VandeVrede, Lawren; Casaletto, Kaitlin B.; Staffaroni, Adam M.; Mundada, Nidhi S.; Fonseca, Corrina; Iaccarino, Leonardo; Joie, Renaud La; Tsuei, Torie; Mladinov, Miho; Grant, Harli; Shankar, Ranjani; Wang, Kevin; Xu, Haiyan; Cobigo, Yann; Rosen, Howie; Gardner, Raquel C.; Perry, David C.; Miller, Bruce L.; Spina, Salvatore; Seeley, William W.; Kramer, Joel H.; Grinberg, Lea T.; Rabinovici, Gil D.

doi:10.1089/neu.2022.0060

Cited by 25 publications

(29 citation statements)

References 67 publications

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“…The evidence is however not yet conclusive at population level (James et al, 2021) or targeted at top professional football players (Cornali et al, 2022). A word of caution also comes from post‐mortem data which highlight the likelihood of multiple neuropathologies as source for increased body fluid Nf levels (Asken et al, 2022).…”

Section: Diseasesmentioning

confidence: 99%

The 2022 Lady Estelle Wolfson lectureship on neurofilaments

Petzold

2022

Journal of Neurochemistry

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Neurofilament proteins (Nf) have been validated and established as a reliable body fluid biomarker for neurodegenerative pathology. This review covers seven Nf isoforms, Nf light (NfL), two splicing variants of Nf medium (NfM), two splicing variants of Nf heavy (NfH), -internexin (INA) and peripherin (PRPH). The genetic and epigenetic aspects of Nf are discussed as relevant for neurodegenerative diseases and oncology. The comprehensive list of mutations for all Nf isoforms covers Amyotrophic Lateral Sclerosis, Charcot-Marie Tooth disease, Spinal muscular atrophy, Parkinson Disease and Lewy Body Dementia. Next, emphasis is given to the expanding field of post-translational modifications (PTM) of the Nf amino acid residues. Protein structural aspects are reviewed alongside PTMs causing neurodegenerative pathology and human autoimmunity. Molecular visualisations of NF PTMs, assembly and stoichiometry make use of Alphafold2 modelling. The implications for Nf function on the cellular level and axonal transport are discussed. Neurofilament aggregate formation and proteolytic breakdown are reviewed as relevant for biomarker tests and disease.Likewise, Nf stoichiometry is reviewed with regard to in vitro experiments and as a compensatory mechanism in neurodegeneration. The review of Nf across a spectrum of 87 diseases from all parts of medicine is followed by a critical appraisal of 33

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Section: Diseasesmentioning

confidence: 99%

The 2022 Lady Estelle Wolfson lectureship on neurofilaments

Petzold

2022

Journal of Neurochemistry

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“…15 Other studies in small numbers of soccer, rugby, and American football players have also shown frequent comorbid pathologies including AD, CTE, and TDP-43. 21,22 All of these pathologies can contribute to dementia. Therefore, the contributions of CTE and other pathologies to cognitive impairment in participants with a history of RHI warrant further investigation.…”

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confidence: 99%

Relative Contributions of Mixed Pathologies to Cognitive and Functional Symptoms in Brain Donors Exposed to Repetitive Head Impacts

Saltiel,

Tripodis,

Menzin

et al. 2023

Annals of Neurology

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ObjectiveExposure to repetitive head impacts (RHI) is associated with later‐life cognitive symptoms and neuropathologies including chronic traumatic encephalopathy (CTE). Cognitive decline in community cohorts is often due to multiple pathologies; however, the frequency and contributions of these pathologies to cognitive impairment in people exposed to RHI is unknown. Here, we examined the relative contributions of 13 neuropathologies to cognitive symptoms and dementia in RHI‐exposed brain donors.MethodsNeuropathologists examined brain tissue from 571 RHI‐exposed donors and assessed for the presence of 13 neuropathologies, including CTE, Alzheimer disease (AD), Lewy body disease (LBD), and TDP‐43 inclusions. Cognitive status was assessed by presence of dementia, Functional Activities Questionnaire (FAQ), and Cognitive Difficulties Scale (CDS). Spearman's rho was calculated to assess intercorrelation of pathologies. Additionally, frequencies of pathological co‐occurrence were compared to a simulated distribution assuming no intercorrelation. Logistic and linear regressions tested associations between neuropathologies and dementia status and cognitive scale scores.ResultsThe sample age range was 18–97 (median: 65.0 [IQR 46.0–76.0]). 77.2% of donors had at least one moderate–severe neurodegenerative or cerebrovascular pathology. Stage III‐IV CTE was the most common neurodegenerative disease (43.1%), followed by TDP‐43 pathology, AD, and hippocampal sclerosis. Neuropathologies were intercorrelated and there were fewer unique combinations than expected if pathologies were independent (p < 0.001). The greatest contributors to dementia were AD, neocortical LBD, hippocampal sclerosis, CAA, and CTE.InterpretationIn this sample of RHI‐exposed brain donors with wide‐ranging ages, multiple neuropathologies were common and correlated. Mixed neuropathologies, including CTE, underlie cognitive impairment in contact sport athletes.This article is protected by copyright. All rights reserved.

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“…A major goal for using imaging modalities to potentially help diagnose CTE would be to identify pathology consistent with the disease prior to autopsy. Magnetic resonance imaging (MRI) can detect cerebral atrophy, axonal injury, dilated perivascular spaces, ventricular enlargement, and cavum septum pellucidum [6,[48][49][50][51][52]. MRI with FLAIR can be used to assess white matter hyperintensities and can represent a variety of neuropathology [53].…”

Section: Diagnosticsmentioning

confidence: 99%