Increased phosphorylated tau pTau-181 is associated with neurological [PASC] in essential workers: a prospective cohort study…, 2026, Yang+

[SNT Gatchaman]

Increased phosphorylated tau pTau-181 is associated with neurological post-acute sequelae of coronavirus disease in essential workers: a prospective cohort study before and after COVID-19 onset

Spoiler: Authors

Yang; Fontana; Clouston; Luft

BACKGROUND
The COVID-19 pandemic led to a spectrum of post-acute sequelae including several neurological complications including cognitive dysfunction labelled Neurological PASC (N-PASC). We hypothesised that N-PASC was associated with changes in neurological biomarkers after COVID-19.

METHODS
N-PASC was established when individuals reported accepted neurological symptoms persisting for ≥3 months arising alongside validated COVID-19. Plasma samples were retrieved from before and after COVID-19 onset among all (n = 227) essential workers who developed COVID-19 with N-PASC and demographically matched with data from 227 controls who either developed COVID-19 without N-PASC (n = 124) or did not develop COVID-19 before follow-up (n = 103). We used single molecular analysis measured pTau-181, GFAP, NfL, Aβ40/42, and total Aβ burden (IAB). Risk factors for N-PASC were examined prior to COVID-19 infection. Multivariable adjusted generalised linear longitudinal modelling with random intercepts was used to examine changes in biomarkers after COVID-19 onset.

FINDINGS
N-PASC was only associated with higher IAB before COVID-19 onset (area under the receiver-operating curve = 0.77). Longitudinal analyses revealed plasma pTau-181 levels increased by 59.3% (95% C.I. = [45.2, 73.4] P = 0.006) following COVID-19 onset in participants who developed N-PASC that were worst among participants reporting central nervous symptoms persisting ≥1.5 years. Post-COVID-19 decreased GFAP and NfL were associated with peripheral symptoms of N-PASC, but not with increased pTau-181. Having ≥20% increases in pTau-181 were associated with increased Aβ40/42 levels at follow-up, and with central neurological symptoms including lingering brain fog and loss of taste/smell.

INTERPRETATION
N-PASC with symptoms consistent with central damage were associated with increased pTau-181 levels. Increases in pTau-181 were associated with increased risk of changes to amyloid biomarkers consistent with Alzheimers disease in participants with N-PASC and could therefore inform N-PASC prognostication.

FUNDING
This study was supported in part by funding from the Centers for Disease Control and Prevention (CDC/NIOSH CDC-75D30122c15522) and the National Institutes of Health (NIH/NIA AG049953).

Web | DOI | eBioMedicine | Open Access

 

[Eleanor]

Post-COVID-19 decreased GFAP and NfL were associated with peripheral symptoms of N-PASC, but not with increased pTau-181.

whereas this study found increased GFAP

Thread 'Blood–brain barrier disruption and sustained systemic inflammation in individuals with long COVID-associated cognitive impairment, 2024, Greene et al'

Jan 30, 2023

Preprint
Blood-brain barrier disruption in Long COVID-associated cognitive impairment
Chris Greene, Ruairi Connolly, Declan Brennan, Aoife Laffan, Eoin O'Keeffe, Lilia Zaporojan, Emma Connolly, Cliona Ni Cheallaigh, Niall Conlon, Colin Doherty, Matthew Campbell

Vascular disruption has been heavily implicated in COVID-19 pathogenesis and may predispose the neurological sequelae associated with the condition now known as long COVID. To date, no studies have objectively assessed blood-brain barrier (BBB) function in individuals with neurological complications stemming from...

• SNT Gatchaman
• blood brain barrier brain imaging coagulation csf dce-mri endothelial gfap icam-1 inflammation long covid long covid clinic mri p-selectin pf4 platelets s100 scam-1 spike protein t cells tgf-beta tnf
• Replies: 44
• Forum: Long Covid research

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Individuals with brain fog had signicantly increased GFAP (*p = 0.022), TGFβ (**p = 0.004) and IL8 (*p = 0.0427) compared to unaffected, recovered, and long COVID without brain fog.

 

[SNT Gatchaman]

One potentially paradoxical finding was that higher pre-COVID-19 NfL was weakly associated with higher risk of N-PASC but that individuals with N-PASC then saw decreased NfL and GFAP following COVID-19 onset appears paradoxical. We did not find that this was associated with evidence of increased pTau-181 but, instead, found that the decrease in NfL was coupled with reduced GFAP.

They offer a some possible explanations —

One possibility is that reductions in GFAP and NfL indicate that the neuroimmune system is repairing itself and utilising these proteins to aid in neurogenesis, but if so the presence of persistent symptoms seems unlikely and we would expect to see glial activation in autopsy studies, a result that has not been identified. An alternative explanation may be that in some individuals, COVID-19-related neuroinflammation restricted glymphatic clearance causing increased aggregation of larger proteins (like NfL or GFAP: width ∼10 nm) but potentially allowing smaller proteins like pTau-181 (5 nm) to pass through unimpeded.

while results for GFAP and NfL appear to go in an incorrect direction, it is worth noting that GFAP and NfL may be expressed by other tissues including in the reproductive organs (GFAP, NfL) and eyes (NfL) and so decrements in the blood may not directly reflect changes in the brain. Future research is needed that specifically examines whether changes in the blood are correlated with similar changes evident in the brains of individuals with N-PASC.