Abstract
Rapidly progressive dementia (RPD) is an umbrella term referring to several conditions causing a rapid neurological deterioration associated with cognitive decline and short disease duration. They comprise Creutzfeldt–Jakob disease (CJD), the archetypal RPD, rapidly progressive variants of the most common neurodegenerative dementias (NDs), and potentially treatable conditions such as infectious or autoimmune encephalitis and cerebrovascular disease. Given the significant clinical and, sometimes, neuroradiological overlap between these different disorders, biofluid markers also contribute significantly to the differential diagnosis. Among them, the neurofilament light chain protein (NfL) has attracted growing attention in recent years as a biofluid marker of neurodegeneration due to its sensitivity to axonal damage and the reliability of its measurement in both cerebrospinal fluid (CSF) and blood. Here, we summarize current knowledge regarding biological and clinical implications of NfL evaluation in biofluids across RPDs, emphasizing CJD, and other prion diseases. In the latter, NfL demonstrated a good diagnostic and prognostic accuracy and a potential value as a marker of proximity to clinical onset in pre-symptomatic PRNP mutation carriers. Similarly, in Alzheimer’s disease and other NDs, higher NfL concentrations seem to predict a faster disease progression. While increasing evidence indicates a potential clinical value of NfL in monitoring cerebrovascular disease, the association between NfL and prediction of outcome and/or disease activity in autoimmune encephalitis and infectious diseases has only been investigated in few cohorts and deserves confirmatory studies. In the era of precision medicine and evolving therapeutic options, CSF and blood NfL might aid the diagnostic and prognostic assessment of RPDs and the stratification and management of patients according to disease progression in clinical trials.
Highlights
Progressive dementia (RPD) is an umbrella term that comprehends several heterogenous diseases characterized by a rapidly progressive cognitive decline and a short disease duration, typically 1–2 years between onset and occurrence of dementia and/or of 2–3 years from onset to death (Cohen et al, 2015; Grau-Rivera et al, 2015; Geschwind and Murray, 2018; Rudge et al, 2018; Zerr and Hermann, 2018)
Multivariate analyses adjusted for age and codon 129 genotype showed that cerebrospinal fluid (CSF) and blood neurofilament light chain protein (NfL), CSF tau, and CSF 14-3-3 were still predictive of survival (Staffaroni et al, 2019; Abu-Rumeileh et al, 2020a; Llorens et al, 2020a)
We have provided an overview of currently available CSF and blood NfL data on Rapidly progressive dementia (RPD)
Summary
Progressive dementia (RPD) is an umbrella term that comprehends several heterogenous diseases characterized by a rapidly progressive cognitive decline and a short disease duration, typically 1–2 years between onset and occurrence of dementia and/or of 2–3 years from onset to death (Cohen et al, 2015; Grau-Rivera et al, 2015; Geschwind and Murray, 2018; Rudge et al, 2018; Zerr and Hermann, 2018). A significant proportion of non-prion RPDs may show positivity in one or more of these tests, whereas, on the other hand, atypical disease subtypes with slower progression may escape recognition (Hamlin et al, 2012; Lattanzio et al, 2017; Rudge et al, 2018). In this regard, the prion real-time quacking-induced conversion (RT-QuIC) assay with its virtually full specificity for prion disease significantly contributed to the improvement of the diagnostic assessment of RPDs (Candelise et al, 2020).
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