Comparison between plasma and cerebrospinal fluid biomarkers for the early diagnosis and association with survival in prion disease

Abstract

ObjectiveTo compare the diagnostic accuracy and the prognostic value of blood and cerebrospinal fluid (CSF) tests across prion disease subtypes.MethodsWe used a single-molecule immunoassay to measure tau and neurofilament light chain (NfL) protein levels in the plasma and assessed CSF total(t)-tau, NfL and protein 14-3-3 levels in patients with prion disease (n=336), non-prion rapidly progressive dementias (n=106) and non-neurodegenerative controls (n=37). We then evaluated each plasma and CSF marker for diagnosis and their association with survival, taking into account the disease subtype, which is a strong independent prognostic factor in prion disease.ResultsPlasma tau and NfL concentrations were higher in patients with prion disease than in non-neurodegenerative controls and non-prion rapidly progressive dementias. Plasma tau showed higher diagnostic value than plasma NfL, but a lower accuracy than the CSF proteins t-tau and 14-3-3. In the whole prion cohort, both plasma (tau and NfL) and CSF (t-tau, 14-3-3 and NfL) markers were significantly associated with survival and showed similar prognostic values. However, the intrasubtype analysis revealed that only CSF t-tau in sporadic Creutzfeldt-Jakob disease (sCJD) MM(V)1, plasma tau and CSF t-tau in sCJD VV2, and plasma NfL in slowly progressive prion diseases were significantly associated with survival after accounting for covariates.ConclusionsPlasma markers have lower diagnostic accuracy than CSF biomarkers. Plasma tau and NfL and CSF t-tau are significantly associated with survival in prion disease in a subtype-specific manner and can be used to improve clinical trial stratification and clinical care.

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

“…However, in contrast to the CSF analyte, blood NfL levels did not significantly differ among the most prevalent sCJD subtypes (Kovacs et al, 2017;Thompson et al, 2018;Abu-Rumeileh et al, 2020a). Interestingly, sCJD VV2, typically characterized by the highest CSF NfL and t-tau values among sCJD subtypes (Lattanzio et al, 2017;Abu-Rumeileh et al, 2018b, showed similar blood NfL and reduced blood tau levels compared with the MM(V)1 type (Kovacs et al, 2017;Abu-Rumeileh et al, 2020a). These data suggest that the different regional lesion profiles between the two CJD subtypes (Parchi et al, 1999;Baiardi et al, 2017), particularly the early cortical neuronal damage featuring MM(V)1 but not VV2, might be responsible for a higher spill over of these molecules in the blood compared to other brain regions (Abu-Rumeileh et al, 2020a).…”

“…More recently, blood NfL levels were also found significantly higher in patients with prion disease belonging to all CJD forms and subtypes than both controls and other NDs ( Table 1; Steinacker et al, 2016;Kovacs et al, 2017;Thompson et al, 2018Thompson et al, , 2020Abu-Rumeileh et al, 2020a). However, in contrast to the CSF analyte, blood NfL levels did not significantly differ among the most prevalent sCJD subtypes (Kovacs et al, 2017;Thompson et al, 2018;Abu-Rumeileh et al, 2020a).…”

“…More recently, blood NfL levels were also found significantly higher in patients with prion disease belonging to all CJD forms and subtypes than both controls and other NDs ( Table 1; Steinacker et al, 2016;Kovacs et al, 2017;Thompson et al, 2018Thompson et al, , 2020Abu-Rumeileh et al, 2020a). However, in contrast to the CSF analyte, blood NfL levels did not significantly differ among the most prevalent sCJD subtypes (Kovacs et al, 2017;Thompson et al, 2018;Abu-Rumeileh et al, 2020a). Interestingly, sCJD VV2, typically characterized by the highest CSF NfL and t-tau values among sCJD subtypes (Lattanzio et al, 2017;Abu-Rumeileh et al, 2018b, showed similar blood NfL and reduced blood tau levels compared with the MM(V)1 type (Kovacs et al, 2017;Abu-Rumeileh et al, 2020a).…”

“…Interestingly, sCJD VV2, typically characterized by the highest CSF NfL and t-tau values among sCJD subtypes (Lattanzio et al, 2017;Abu-Rumeileh et al, 2018b, showed similar blood NfL and reduced blood tau levels compared with the MM(V)1 type (Kovacs et al, 2017;Abu-Rumeileh et al, 2020a). These data suggest that the different regional lesion profiles between the two CJD subtypes (Parchi et al, 1999;Baiardi et al, 2017), particularly the early cortical neuronal damage featuring MM(V)1 but not VV2, might be responsible for a higher spill over of these molecules in the blood compared to other brain regions (Abu-Rumeileh et al, 2020a). An overview of the distribution of CSF and blood NfL and a comparison with other classic and new biofluid markers across distinct prion disease forms and subtypes are provided in Table 2.…”

“…Regarding the diagnostic value of blood NfL, only three studies to date evaluated the marker in clinically and/or neuropathological heterogeneous cohorts of RPDs (Kovacs et al, 2017;Abu-Rumeileh et al, 2020a;Thompson et al, 2020). They obtained similar results, namely, the lower value of blood NfL compared to blood tau in the discrimination between prion (or sCJD) and non-prion RPDs (NfL: AUC 0.497-0.724 vs. tau: AUC 0.722-0.837) (Kovacs et al, 2017;Abu-Rumeileh et al, 2020a;Thompson et al, 2020). Notably, the performance of classic CSF markers such as CSF t-tau and 14-3-3 appeared significantly superior to both plasma tau and NfL, raising the question of the real utility of blood surrogate markers in the diagnostic assessment of RPDs (Abu-Rumeileh et al, 2020a).…”