Challenges and Revisions in Diagnostic Criteria: Advancing Early Detection of Prion Diseases
Abstract
1. Introduction
2. CSF Biomarkers
2.1. The 14-3-3 Proteins
2.2. Total Tau (t-tau) Protein
2.3. Real-Time Quaking-Induced Conversion (RT-QuIC) Assay
2.4. Neurofilament Light Chain (NfL)
2.5. Magnetic Resonance Imaging (MRI) Biomarkers
2.6. The Combination of Biomarkers
3. Diagnostic Accuracy
4. The Critical Role of Early Diagnosis in Prion Diseases: Current Perspectives and Evolving Diagnostic Approaches
4.1. Fundamental Importance of Early Diagnosis
4.2. Therapeutic Implications and Research Perspectives
4.3. Magnetic Resonance Imaging in Prion Disease Diagnosis
- 1.
- The simplified criteria maintained diagnostic accuracy (92.3% sensitivity, 85.7% specificity) while being easier to apply, potentially enabling faster diagnosis.
- 2.
- Early-stage imaging characteristics:
- DWI shows hyperintense signals first;
- Fluid-Attenuated Inversion Recovery (FLAIR) may initially appear normal;
- ADC maps show iso- to hypointense signals in affected areas.
- 3.
- Multimodal imaging importance:
- DWI is most sensitive for early detection;
- FLAIR complements DWI and helps rule out other conditions;
- Combined DWI-FLAIR-ADC approach provides most reliable early diagnosis.
- 4.
- Expert application of the criteria significantly outperformed routine diagnostic reports, suggesting the importance of neuroradiologist experience in early detection.
4.4. RT-QuIC Analysis: A Revolutionary Diagnostic Tool
4.5. Clinical Applications and Limitations
4.6. Unusual Clinical Presentations of Sporadic CJD
4.6.1. Visual Disorders (Heidenhain Variant of CJD)
4.6.2. Seizures Pattern
4.6.3. Psychiatric Disorders
4.6.4. Movement Disorders
4.6.5. Aphasia
4.6.6. Stroke-like Onset Pattern
4.7. Differentiation Between CJD and Mimics
4.8. Diagnostic Indicators for Early Detection
4.9. Diagnostic Criteria at Early Stages of sCJD
- 1.
- In our clinical experience, early-stage CJD typically presents with minimal symptomatology, manifesting zero to one of the established clinical criteria (rapidly progressive cognitive impairment, myoclonus, visual impairment or cerebellar disturbance, pyramidal or extrapyramidal disorders).
- 2.
- CSF analysis reveals characteristic patterns:
- Minimal to absent pleocytosis;
- Protein levels within physiological parameters;
- Modest elevation of total tau protein;
- Approximately 50% RT-QuIC positivity.
- 3.
- Characteristic neuroimaging findings include
- Restricted diffusion in caudate or caudate/putamen or caudate/putamen/thalamus, or at least two cortical regions (temporal, parietal, occipital) on MRI brain scan, no subcortical white matter involvement, no isolated restricted diffusion in the thalamus. Characteristic hyperintensities may be seen on FLAIR images, but DWI sequences are required to confirm CJD-typical restricted diffusion and corresponding Apparent diffusion coefficient (ADC) hypo–iso intensities;
- FLAIR isointensities in cortical regions;
- Basal ganglia demonstrating hyperintensities on both FLAIR and DWI;
- Notable absence of hyperperfusion on Arterial Spin Labeling (ASL) imaging; presence of significant hyperperfusion suggests alternative diagnoses.
4.10. Future Directions and Emerging Technologies
4.11. Implications for Clinical Practice and Research
5. Conclusions and Future Perspectives
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Biomarker | Sample Type | Features | Sensitivity (%) | Specificity (%) |
---|---|---|---|---|
14-3-3 Protein | CSF | Marker of acute neurodegeneration. Elevated in Creutzfeldt–Jakob disease (CJD). Less sensitive and specific than RT-QuIC but useful as a supplementary diagnostic tool. | 80–90 | 70–92 |
RT-QuIC | CSF | Gold standard for prion disease diagnosis. Highly sensitive and specific. | 90–100 | 95–100 |
Neuron-Specific Enolase (NSE) | CSF, Blood | Increases as CJD progresses. Also elevated in other neurodegenerative diseases, reducing specificity. | 65–85 | 50–75 |
Tau Protein | CSF | Indicator of neuronal damage. Also elevated in Alzheimer’s disease, reducing specificity. | 85–95 | 50–80 |
α-Synuclein | CSF | Useful for differentiating CJD from Lewy body dementia (DLB) and Parkinson’s disease (PD). | 65–85 | 50–75 |
Neurofilament Light Chain (NfL) | CSF, Serum | Elevated in various neurodegenerative diseases. Also high in ALS, FTD, and other conditions. Can be measured in blood. | 85–95 | 60–85 |
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Shimamura, M.I.; Satoh, K. Challenges and Revisions in Diagnostic Criteria: Advancing Early Detection of Prion Diseases. Int. J. Mol. Sci. 2025, 26, 2037. https://doi.org/10.3390/ijms26052037
Shimamura MI, Satoh K. Challenges and Revisions in Diagnostic Criteria: Advancing Early Detection of Prion Diseases. International Journal of Molecular Sciences. 2025; 26(5):2037. https://doi.org/10.3390/ijms26052037
Chicago/Turabian StyleShimamura, Mika Inada, and Katsuya Satoh. 2025. "Challenges and Revisions in Diagnostic Criteria: Advancing Early Detection of Prion Diseases" International Journal of Molecular Sciences 26, no. 5: 2037. https://doi.org/10.3390/ijms26052037
APA StyleShimamura, M. I., & Satoh, K. (2025). Challenges and Revisions in Diagnostic Criteria: Advancing Early Detection of Prion Diseases. International Journal of Molecular Sciences, 26(5), 2037. https://doi.org/10.3390/ijms26052037