# Cerebrospinal Fluid Biomarkers in Creutzfeldt–Jakob Disease: Diagnostic Value, Limitations, and Future Multi-Omics Strategies

## TL;DR

This paper reviews cerebrospinal fluid biomarkers for diagnosing and monitoring Creutzfeldt–Jakob disease, highlighting their strengths, limitations, and future multi-omics strategies.

## Contribution

The paper proposes a novel three-tier biomarker framework integrating RT-QuIC, injury-severity indicators, and multi-omics signatures for improved diagnosis and prognosis.

## Key findings

- CSF biomarkers like 14-3-3 and RT-QuIC have variable sensitivity and specificity for diagnosing CJD.
- Assay variability and inter-laboratory inconsistencies limit current biomarker reliability.
- A three-tier framework combining RT-QuIC, tau/NfL/pNFH, and multi-omics signatures is proposed for early detection and prognosis.

## Abstract

Creutzfeldt–Jakob disease (CJD) is a rare but devastating neurodegenerative disorder characterized by the pathological misfolding of the cellular prion protein (PrPC) into the pathogenic isoform-scrapie prion protein (PrPSc), ultimately leading to fatal outcomes. Cerebrospinal fluid (CSF) biomarkers play a pivotal role in early diagnosis, longitudinal monitoring, and prognostic assessment, thereby enhancing the clinical management of this challenging disease. This review summarizes the established CSF biomarkers, 14-3-3 protein, tau protein (total tau), phosphorylated tau isoforms, α-synuclein, neurofilament light chain (Nfl), S100B, neuron-specific enolase (NSE), and phosphorylated neurofilament heavy chain (pNFH), highlighting typical sensitivity ranges (14-3-3 ~70–85%; RT-QuIC > 90%) and subtype-dependent performance variation. We further dissect limitations related to assay variability, inter-laboratory cut-off inconsistencies, and reduced specificity in non-prion dementias. Looking ahead, we discuss emerging multi-omics discovery, integration of CSF with blood-based biomarkers and imaging signatures, and AI-enabled diagnostic modeling. We propose a three-tier biomarker framework combining Real-Time Quaking-Induced Conversion (RT-QuIC) as a confirmatory assay, tau/NfL/pNFH as injury-severity indicators, and multi-omics-derived signatures for early detection and prognosis stratification.