LATE-NC staging in routine neuropathologic diagnosis: an update

Nelson, Peter T.; Lee, Edward B.; Cykowski, Matthew D.; Alafuzoff, Irina; Arfanakis, Konstantinos; Attems, Johannes; Brayne, Carol; Corrada, María M.; Dugger, Brittany N.; Flanagan, Margaret E.; Ghetti, Bernardino; Grinberg, Lea T.; Grossman, Murray; Grothe, Michel J.; Halliday, Glenda M.; Hasegawa, Masato; Hokkanen, Suvi R. K.; Hunter, Sally; Jellinger, K. A.; Kawas, Claudia H.; Keene, C. Dirk; Kouri, Naomi; Kovács, Gábor G.; Leverenz, James B.; Latimer, Caitlin S.; Mackenzie, Ian R.; Mao, Qinwen; McAleese, Kirsty E.; Merrick, Richard; Montine, Thomas J.; Murray, Melissa E.; Myllykangas, Liisa; Nag, Sukriti; Neltner, Janna H.; Newell, Kathy L.; Rissman, Robert A.; Saito, Yuko; Sajjadi, S. Ahmad; Schwetye, Katherine E.; Teich, Andrew F.; Thal, Dietmar Rudolf; Tomé, Sandra O.; Troncoso, Juan C.; Wang, Shih‐Hsiu J.; White, Charles L.; Wısnıewskı, Thomas; Yang, Hyun‐Sik; Schneider, Julie A.; Dickson, Dennis W.; Neumann, Manuela

doi:10.1007/s00401-022-02524-2

Cited by 64 publications

(67 citation statements)

References 163 publications

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“…CTE with HS was associated with greater RHI exposure (reported as contact sport playing years) compared to those with CTE without HS. Although TDP-43 pathology in CTE bears some similarities to limbic-predominant age-related TDP-43 encephalopathy neuropathologic changes (LATE-NC), it was recently recommended that the diagnosis of LATE-NC be avoided in CTE cases until future studies determine whether TDP-43 pathology in CTE is unique to CTE or a manifestation of early-onset LATE-NC [86].…”

Section: Relationship Between Rhi Cte Tdp-43 and Alsmentioning

confidence: 99%

Chronic traumatic encephalopathy (CTE): criteria for neuropathological diagnosis and relationship to repetitive head impacts

et al. 2023

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Over the last 17 years, there has been a remarkable increase in scientific research concerning chronic traumatic encephalopathy (CTE). Since the publication of NINDS–NIBIB criteria for the neuropathological diagnosis of CTE in 2016, and diagnostic refinements in 2021, hundreds of contact sport athletes and others have been diagnosed at postmortem examination with CTE. CTE has been reported in amateur and professional athletes, including a bull rider, boxers, wrestlers, and American, Canadian, and Australian rules football, rugby union, rugby league, soccer, and ice hockey players. The pathology of CTE is unique, characterized by a pathognomonic lesion consisting of a perivascular accumulation of neuronal phosphorylated tau (p-tau) variably alongside astrocytic aggregates at the depths of the cortical sulci, and a distinctive molecular structural configuration of p-tau fibrils that is unlike the changes observed with aging, Alzheimer’s disease, or any other tauopathy. Computational 3-D and finite element models predict the perivascular and sulcal location of p-tau pathology as these brain regions undergo the greatest mechanical deformation during head impact injury. Presently, CTE can be definitively diagnosed only by postmortem neuropathological examination; the corresponding clinical condition is known as traumatic encephalopathy syndrome (TES). Over 97% of CTE cases published have been reported in individuals with known exposure to repetitive head impacts (RHI), including concussions and nonconcussive impacts, most often experienced through participation in contact sports. While some suggest there is uncertainty whether a causal relationship exists between RHI and CTE, the preponderance of the evidence suggests a high likelihood of a causal relationship, a conclusion that is strengthened by the absence of any evidence for plausible alternative hypotheses. There is a robust dose–response relationship between CTE and years of American football play, a relationship that remains consistent even when rigorously accounting for selection bias. Furthermore, a recent study suggests that selection bias underestimates the observed risk. Here, we present the advances in the neuropathological diagnosis of CTE culminating with the development of the NINDS–NIBIB criteria, the multiple international studies that have used these criteria to report CTE in hundreds of contact sports players and others, and the evidence for a robust dose–response relationship between RHI and CTE.

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Section: Relationship Between Rhi Cte Tdp-43 and Alsmentioning

confidence: 99%

Chronic traumatic encephalopathy (CTE): criteria for neuropathological diagnosis and relationship to repetitive head impacts

et al. 2023

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“…The pattern of hippocampal and frontal TDP-43 positivity in combination with hippocampal sclerosis resembles limbic-predominant age-related TDP-43 encephalopathy (LATE), but the extensive frontal depositions and the young age makes this diagnosis unlikely. [ 57 , 58 ]…”

Section: Discussionmentioning

confidence: 99%

Severe CTE and TDP-43 pathology in a former professional soccer player with dementia: a clinicopathological case report and review of the literature

van Amerongen,

Kamps,

Kaijser

et al. 2023

acta neuropathol commun

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In the last decades, numerous post-mortem case series have documented chronic traumatic encephalopathy (CTE) in former contact-sport athletes, though reports of CTE pathology in former soccer players are scarce. This study presents a clinicopathological case of a former professional soccer player with young-onset dementia. The patient experienced early onset progressive cognitive decline and developed dementia in his mid-50 s, after playing soccer for 12 years at a professional level. While the clinical picture mimicked Alzheimer’s disease, amyloid PET imaging did not provide evidence of elevated beta-amyloid plaque density. After he died in his mid-60 s, brain autopsy showed severe phosphorylated tau (p-tau) abnormalities fulfilling the neuropathological criteria for high-stage CTE, as well as astrocytic and oligodendroglial tau pathology in terms of tufted astrocytes, thorn-shaped astrocytes, and coiled bodies. Additionally, there were TAR DNA-binding protein 43 (TDP-43) positive cytoplasmic inclusions in the frontal lobe and hippocampus, and Amyloid Precursor Protein (APP) positivity in the axons of the white matter. A systematic review of the literature revealed only 13 other soccer players with postmortem diagnosis of CTE. Our report illustrates the complex clinicopathological correlation of CTE and the need for disease-specific biomarkers.

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“…In addition to hematoxylin and eosin plus luxol fast blue histochemical staining for assessment of vascular brain injury (VBI) and hippocampal sclerosis (HS), immunohistochemistry for Aβ plaques (anti-b-Amyloid, 6E10, Biolegend, cat#803002, dilution 1:1000), and neurofibrillary degeneration (PHF-Tau, AT8, ThermoScientific, cat#MN1020, dilution 1:1000) was performed in specified regions 47 . Antibodies to phospho-TDP-43 (anti-pTPD-43, S409/410, Millipore, cat#MABN14, dilution 1:300) and phospho-alpha-synuclein (Anti-Alpha-synuclein, ps129, Abcam, cat#ab51253, dilution 1:1000) also were used in specified regions 47 , 49 . All cases were originally evaluated by one of the co-authors who is a board-certified neuropathologist (C.L., C.D.K., or T.J.M.)…”

Section: Methodsmentioning

confidence: 99%

Brain proteomic analysis implicates actin filament processes and injury response in resilience to Alzheimer’s disease

et al. 2023

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Resilience to Alzheimer’s disease is an uncommon combination of high disease burden without dementia that offers valuable insights into limiting clinical impact. Here we assessed 43 research participants meeting stringent criteria, 11 healthy controls, 12 resilience to Alzheimer’s disease and 20 Alzheimer’s disease with dementia and analyzed matched isocortical regions, hippocampus, and caudate nucleus by mass spectrometry-based proteomics. Of 7115 differentially expressed soluble proteins, lower isocortical and hippocampal soluble Aβ levels is a significant feature of resilience when compared to healthy control and Alzheimer’s disease dementia groups. Protein co-expression analysis reveals 181 densely-interacting proteins significantly associated with resilience that were enriched for actin filament-based processes, cellular detoxification, and wound healing in isocortex and hippocampus, further supported by four validation cohorts. Our results suggest that lowering soluble Aβ concentration may suppress severe cognitive impairment along the Alzheimer’s disease continuum. The molecular basis of resilience likely holds important therapeutic insights.

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LATE-NC staging in routine neuropathologic diagnosis: an update

Cited by 64 publications

References 163 publications

Chronic traumatic encephalopathy (CTE): criteria for neuropathological diagnosis and relationship to repetitive head impacts

Chronic traumatic encephalopathy (CTE): criteria for neuropathological diagnosis and relationship to repetitive head impacts

Severe CTE and TDP-43 pathology in a former professional soccer player with dementia: a clinicopathological case report and review of the literature

Brain proteomic analysis implicates actin filament processes and injury response in resilience to Alzheimer’s disease

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