Abstract

BackgroundBlood neurofilament light (Nfl) and total-tau (t-tau) have been described to be increased in several neurological conditions, including prion diseases and other neurodegenerative dementias. Here, we aim to determine the accuracy of plasma Nfl and t-tau in the differential diagnosis of neurodegenerative dementias and their potential value as prognostic markers of disease severity.MethodsPlasma Nfl and t-tau were measured in healthy controls (HC, n = 70), non-neurodegenerative neurological disease with (NND-Dem, n = 17) and without dementia syndrome (NND, n = 26), Alzheimer’s disease (AD, n = 44), Creutzfeldt-Jakob disease (CJD, n = 83), dementia with Lewy bodies/Parkinson’s disease with dementia (DLB/PDD, n = 35), frontotemporal dementia (FTD, n = 12), and vascular dementia (VaD, n = 22). Biomarker diagnostic accuracies and cutoff points for the diagnosis of CJD were calculated, and associations between Nfl and t-tau concentrations with other fluid biomarkers, demographic, genetic, and clinical data in CJD cases were assessed. Additionally, the value of Nfl and t-tau predicting disease survival in CJD was evaluated.ResultsAmong diagnostic groups, highest plasma Nfl and t-tau concentrations were detected in CJD (fold changes of 38 and 18, respectively, compared to HC). Elevated t-tau was able to differentiate CJD from all other groups, whereas elevated Nfl concentrations were also detected in NND-Dem, AD, DLB/PDD, FTD, and VaD compared to HC. Both biomarkers discriminated CJD from non-CJD dementias with an AUC of 0.93. In CJD, plasma t-tau, but not Nfl, was associated with PRNP codon 129 genotype and CJD subtype. Positive correlations were observed between plasma Nfl and t-tau concentrations, as well as between plasma and CSF concentrations of both biomarkers (p < 0.001). Nfl was increased in rapidly progressive AD (rpAD) compared to slow progressive AD (spAD) and associated to Mini-Mental State Examination results. However, Nfl displayed higher accuracy than t-tau discriminating CJD from rpAD and spAD. Finally, plasma t-tau, but not plasma Nfl, was significantly associated with disease duration, offering a moderate survival prediction capacity.ConclusionsPlasma Nfl and t-tau are useful complementary biomarkers for the differential diagnosis of CJD. Additionally, plasma t-tau emerges as a potential prognostic marker of disease duration.

Highlights

  • Blood neurofilament light (Nfl) and total-tau (t-tau) have been described to be increased in several neurological conditions, including prion diseases and other neurodegenerative dementias

  • The highest Nfl concentrations were detected in Creutzfeldt-Jakob disease (CJD) followed by neurological conditions either without (NND)-Dem, vascular dementia (VaD), dementia with Lewy bodies (DLB)/Parkinson’s disease dementia (PDD), Alzheimer’s disease (AD), Fronto-temporal dementia (FTD), NND, and healthy controls (HC) (Table 1 and Fig. 1a)

  • In a multicomparative analysis corrected for covariates, Nfl concentrations were increased in CJD compared to HC, NND, AD, DLB/PDD, FTD, and VaD (p < 0.001), in AD compared to HC (p < 0.001) and NND (p = 0.002), in DLB/PDD compared to HC and NND (p < 0.001), in FTD compared to HC (p = 0.020), and in VaD compared to HC and NND (p < 0.001)

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Summary

Introduction

Blood neurofilament light (Nfl) and total-tau (t-tau) have been described to be increased in several neurological conditions, including prion diseases and other neurodegenerative dementias. We aim to determine the accuracy of plasma Nfl and t-tau in the differential diagnosis of neurodegenerative dementias and their potential value as prognostic markers of disease severity. Neurodegenerative dementias are a group of clinically heterogeneous diseases characterized by gradual progression of cognitive dysfunction, psychiatric and behavioral symptoms, and movement deficits. They can be associated either with the aggregation and accumulation of misfolded proteins (i.e., Alzheimer’s disease (AD), fronto-temporal dementia (FTD), dementia with Lewy bodies (DLB), Parkinson’s disease dementia (PDD), and CreutzfeldtJakob disease (CJD)) or with brain damage due to impaired blood flow, leading to vascular dementia (VaD). The observation that Nfl is associated to survival and disease severity in many neurodegenerative conditions suggests a potential role as dynamic and prognostic marker [7,8,9]

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