Cerebrospinal fluid neurofilament light in suspected sporadic Creutzfeldt-Jakob disease

Abstract

Sporadic Creutzfeldt-Jakob disease (sCJD) is the most common form of human prion disease. It is invariably fatal and displays a short clinical disease stage. The key event in sCJD is the propagation of a betasheet rich conformer of the physiological PrP C protein, known as PrP Sc. Neuropathological disease characteristics include gliosis, neuronal loss and spongiform degeneration; disease clinical manifestations refer to mental and visual disabilities, cognitive impairment, gait or limb ataxia, myoclonus and mutism. Definite sCJD diagnosis requires post-mortem brain material histopathological examination. However, highly certain pre-mortem differential diagnosis is desired to exclude other treatable disorders and to reduce disease transmission risks. Detection and/or quantification of cerebrospinal fluid (CSF) biomarkers reflecting neuronal damage and PrP C misfolding in the diseased brain significantly enhance pre-mortem diagnosis. Previously established and newly identified biomarkers are used towards this direction. Increased CSF Neurofilament light chain (NFL) concentrations have been reported in several neurological disorders, including prion diseases. In the present study, we analyzed CSF NFL levels in two independent patient cohorts, consisting of highly suspected sCJD cases that were further classified as sCJD or non-CJD according to established diagnostic criteria. CSF NFL concentrations were increased in sCJD compared to non-CJD cases in both cohorts (area under the curve (with 95% confidence interval) equal to 0.89 (0.82 to 0.97) and 0.86 (0.77 to 0.96), respectively. CSF NFL was associated neither to age nor to sex but correlated with total-tau concentrations in both cohorts. Overall, our data provide independent validation of CSF NFL utility in sCJD differential diagnosis.

Diagnostic Accuracy of Prion Disease Biomarkers in Iatrogenic Creutzfeldt-Jakob Disease

“…While it is possible that RT-QuIC signal does not really reflect the degree of cerebral PrP pathogenesis, it may also be speculated that PrP seeding capacity for pathological conversion is not linked in a straightforward manner to neuronal damage and neuro-inflammation. By contrast, positive correlations were observed between several neuronal damage and neuro-inflammation markers, in line with those previously detected in sCJD [27,28,30,56,57]. Positive correlation between Nfl and t-tau with YKL-40 suggests a pathogenic association between astroglial activation and axonal injury in iCJD.…”

Cerebrospinal Fluid and Blood Neurofilament Light Chain Protein in Prion Disease and Other Rapidly Progressive Dementias: Current State of the Art

“…Several studies (Table 1) evaluated CSF NfL in the prion disease spectrum. They showed significantly increased mean levels in most disease subtypes compared to non-neurodegenerative controls and other NDs (Steinacker et al, 2016;Kovacs et al, 2017;Abu-Rumeileh et al, 2018b, 2019aKanata et al, 2019;Vallabh et al, 2020). Interestingly, CSF NfL concentration varied significantly among sCJD subtypes and only partially correlated with t-tau levels (Abu-Rumeileh et al, 2018b;, suggesting that the two markers reflect distinct pathophysiological mechanisms.…”

“…Interestingly, CSF NfL, either alone or in combination with other biomarkers, yielded a performance similar to t-tau in the distinction of prion disease from other NDs (AUC 0.926 vs. 0.939) and showed even a higher diagnostic value than t-tau in the specific comparisons between atypical prion disease and other rpNDs (AUC 0.839 vs. 0.722) (Abu-Rumeileh et al, 2018b). However, the biomarker accuracy for an early clinical diagnosis should be ideally assessed in a clinically or neuropathological based cohort of patients with heterogeneous RPD etiologies raising the clinical suspicion of prion disease, but only a few studies considered this approach (Kovacs et al, 2017;Abu-Rumeileh et al, 2019aKanata et al, 2019). In this type of studies, CSF NfL diagnostic accuracy (AUC 0.451-0.890) was significantly lower than that of CSF t-tau (AUC 0.849-0.918) and/or protein 14-3-3 (AUC 0.711-0.908) (Kovacs et al, 2017;Abu-Rumeileh et al, 2018bKanata et al, 2019).…”

“…However, the biomarker accuracy for an early clinical diagnosis should be ideally assessed in a clinically or neuropathological based cohort of patients with heterogeneous RPD etiologies raising the clinical suspicion of prion disease, but only a few studies considered this approach (Kovacs et al, 2017;Abu-Rumeileh et al, 2019aKanata et al, 2019). In this type of studies, CSF NfL diagnostic accuracy (AUC 0.451-0.890) was significantly lower than that of CSF t-tau (AUC 0.849-0.918) and/or protein 14-3-3 (AUC 0.711-0.908) (Kovacs et al, 2017;Abu-Rumeileh et al, 2018bKanata et al, 2019). Indeed, increased levels of NfL are detected in most vascular, and neuroinflammatory diseases, and even in neurodegenerative disorders commonly associated with a slower progressive course than RPDs.…”

Review: Fluid biomarkers in the human prion diseases

“…Although this is likely to limit its value as a diagnostic test applied in isolation, it may still have useful roles to play. CSF NfL concentrations are also raised in several types of inherited prion disease where other established CSF biomarkers have tended to have lower sensitivity, and it may have greater value in distinguishing atypical slower cases of sCJD from particular alternative diagnoses such as rapidly progressing AD (64,65). It might also have potential as a highly sensitive, inclusive initial step in a diagnostic algorithm aiming to increase ascertainment of atypical cases, but would need to be combined with other more specific tests, and this would need to be evaluated directly in the relevant patient populations.…”