Longitudinal plasma biomarker profiling in fatal familial insomnia

Fatal familial insomnia (FFI) is a genetic prion disease linked to the D178N-129M PRNP mutation. This disease manifests unpredictably during adulthood, leading to death within two years from onset. The absence of prodromal biomarkers hinders early diagnosis and therapeutic intervention. This study aimed to identify plasma biomarkers for early detection and disease monitoring.

Longitudinal plasma samples were collected from 48 individuals: 22 non-carrier controls and 26 FFI mutation carriers, including 10 who converted from asymptomatic to symptomatic stages. We measured NfL, previously shown to increase presymptomatically in some slow-progressing genetic prion diseases, and five additional proteins: MMP-9 (blood-brain barrier disruption), PPIA (neuroinflammation), α-synuclein (synaptic function), YKL-40 (glial activation), and BD-tau (neurodegeneration). A subset of samples was also analyzed with the NULISAseq CNS Panel 120, a multiplex assay for CNS proteins.

NfL levels rose sharply at symptom onset in converters and continued to increase in the symptomatic phase. Although asymptomatic carriers showed higher NfL levels than controls, variability limited its predictive value. Other markers (MMP-9, α-syn, PPIA, YKL-40, BD-tau) showed inconsistent or no changes. NULISA analysis confirmed NfL elevation and identified 14 differentially expressed proteins in carriers vs. controls, such as GFAP, tau, and neurogranin, which were elevated only during the symptomatic phase.

In conclusion, while NfL is a promising marker for monitoring disease progression, no plasma biomarker reliably identified the prodromal phase, highlighting the need for more sensitive tools for early FFI diagnosis.

This work was supported by JPND 2021-650-130 (PROFFILE).