Prion diseases: current understanding of pathogenesis, diagnosis, and treatment (narrative review)

Prion diseases (PD) represent a group of rare yet fatal neurodegenerative disorders caused by the conformational transformation of the cellular prion protein into its pathological isoform. Despite their low incidence, these diseases remain a significant medical and social challenge due to the lack of effective treatments and the risk of iatrogenic transmission.

Purpose of the review was to identify key unresolved issues in PD research, including molecular mechanisms of pathogenesis, opportunities for early diagnosis, and promising therapeutic approaches, as well as to outline the most critical directions for future studies.

A systematic literature search was conducted in PubMed, Google Scholar, eLibrary, and CyberLeninka databases for the period 2016–2025. Fifty-one relevant publications were selected, comprising original studies, reviews, and clinical cases. The analysis was performed in accordance with CINAR guidelines and SANRA criteria.

Modern diagnostic techniques (RT-QuIC, DWI-MRI) have significantly improved the detection of PD, though their widespread implementation is hindered by high costs and the need for specialized expertise. The most promising therapeutic strategies include monoclonal antibodies (PRN100), antisense oligonucleotides, and CRISPR/Cas9 technology. Epidemiological data confirm a decline in variant Creutzfeldt – Jakob disease (vCJD) cases due to enhanced biosafety measures, though risks associated with prolonged incubation periods persist.

To enhance the diagnosis and treatment of PD, it is essential to establish a national registry, expand laboratory networks, train specialists, and strengthen biosafety protocols. Future research should focus on combined therapeutic strategies and in-depth exploration of the molecular mechanisms underlying these disorders.

1. Uttley L, Carroll C, Wong R, Hilton DA, Stevenson M. Creutzfeldt-Jakob disease: a systematic review of global incidence, prevalence, infectivity, and incubation. Lancet Infect Dis. 2020; 20(1): e2-e10. doi: 10.1016/S1473-3099(19)30615-2

2. Zavadenko NN, Khondkaryan GSh, Bembeeva RTs, Kholin AA, Saverskaya EN. Human prion diseases: current issues. S.S. Korsakov Journal of Neurology and Psychiatry. 2018; 118(6): 88-95. (In Russ.). doi: 10.17116/jnevro20181186188

3. Zhu C, Aguzzi A. Prion protein and prion disease at a glance. J Cell Sci. 2021; 134(1): jcs245605. doi: 10.1242/jcs.245605

4. Knight R. Clinical diagnosis of human prion disease. Prog Mol Biol Transl Sci. 2020; 175: 1-18. doi: 10.1016/bs.pmbts.2020.07.006

5. Tokumaru AM, Saito Y, Murayama S. Diffusion-Weighted Imaging is Key to Diagnosing Specific Diseases. Magn Reson Imaging Clin N Am. 2021; 29: 163-83. doi: 10.1016/j.mric.2021.02.001

6. Park HY, Kim M, Suh CH, Kim SY, Shim WH, Kim SJ. Diagnostic value of diffusion-weighted brain magnetic resonance imaging in patients with sporadic Creutzfeldt–Jakob disease: a systematic review and meta-analysis. Eur Radiol. 2021; 31(9): 6883-94. doi: 10.1007/s00330-021-08031-4

7. KongY, Chen Z,WangX,WangW, ZhangJ. Diagnostic Utility of Cerebrospinal Fluid α-Synuclein in Creutzfeldt-Jakob Disease: A Systematic Review and Meta-Analysis. J Alzheimers Dis. 2022; 89(2): 493-503. doi: 10.3233/JAD-220425

8. Altuna M, Ruiz I, Zelaya MV, Mendioroz M. Role of Biomarkers for the Diagnosis of Prion Diseases: A Narrative Review. Medicina (Kaunas). 2022; 58(4): 473. doi: 10.3390/medicina58040473

9. Mead S, Khalili-Shirazi A, Potter C, Mok T, Nihat A, Hyare H, et al. Prion protein monoclonal antibody (PRN100) therapy for Creutzfeldt-Jakob disease: evaluation of a first-in-human treatment programme. Lancet Neurol. 2022; 21(4): 343-54. doi: 10.1016/S1474-4422(22)00082-5

10. Benavente R, Morales R. Therapeutic perspectives for prion diseases in humans and animals. PLoS Pathog. 2024; 20(12): e1012676. doi: 10.1371/journal.ppat.1012676

11. Vallabh SM, Minikel EV, Schreiber SL, Lander ES. Towards a treatment for genetic prion disease: trials and biomarkers. Lancet Neurol. 2020; 19(4): 361-8. doi: 10.1016/S1474-4422(20)30029-9

12. Hernaiz A, Toivonen JM, Bolea R, Martin-Burriel I. Epigenetic Changes in Prion and Prion-like Neurodegenerative Diseases: Recent Advances, Potential as Biomarkers, and Future Perspectives. Int J Mol Sci. 2022; 23(20): 12609. doi: 10.3390/ijms232012609

13. Pogue AI, Lukiw WJ. microRNA-146a-5p, Neurotropic Viral Infection and Prion Disease (PrD). Int J Mol Sci. 2021; 22(17): 9198. doi: 10.3390/ijms22179198

14. Anderson KN, Overcast WB, Brosch JR, Graner BD, Veronesi MC. Prionopathies and Prionlike Protein Aberrations in Neurodegenerative Diseases. Neurographics. 2021; 11(2): 127-48. doi: 10.3174/ng.2102001

15. Miroshnikov AB, Khadartsev AA, Pavlov EA, Shevtsov AV, Rybakova PD, Meshtel AV, et al. Development and justification of a guide for narrative literature reviews: the CINAR checklist. Journal of New Medical Technologies. 2024; 6(4-2). (In Russ.). doi: 10.24412/2075-4094-2024-6-4-2

16. Baethge C, et al. SANRA-a scale for the quality assessment of narrative review articles. Res Integr Peer Rev. 2019; 4: 5. doi: 10.1186/s41073-019-0064-8

17. Nafe R, Arendt CT, Hattingen E. Human prion diseases and the prion protein – what is the current state of knowledge? Transl Neurosci. 2023; 14: 20220315. doi: 10.1515/tnsci-2022-0315

18. Baiardi S, Mammana A, Capellari S, Parchi P. Human prion disease: molecular pathogenesis, and possible therapeutic targets and strategies. Expert Opin Ther Targets. 2023; 27(12): 1271-84. doi: 10.1080/14728222.2023.2199923

19. Jurcau MC, Jurcau A, Diaconu RG, Hogea VO, Nunkoo VS. A Systematic Review of Sporadic Creutzfeldt-Jakob Disease: Pathogenesis, Diagnosis, and Therapeutic Attempts. Neurol Int. 2024; 16(5): 1039-65. doi: 10.3390/neurolint16050079

20. Li B, Chen M, Zhu C. Neuroinflammation in Prion Disease. Int J Mol Sci. 2021; 22(4): 2196. doi: 10.3390/ijms22042196

21. Contiliani DF, Ribeiro YdA, de Moraes VN, Pereira TC. MicroRNAs in Prion Diseases-From Molecular Mechanisms to Insights in Translational Medicine. Cells. 2021; 10(7): 1620. doi: 10.3390/cells10071620

22. Goldman JS, Vallabh SM. Genetic counseling for prion disease: Updates and best practices. Genet Med. 2022; 24(9): 1993-2003. doi: 10.1016/j.gim.2022.06.003

23. Appleby BS, Shetty S, Elkasaby M. Genetic aspects of human prion diseases. Front Neurol. 2022; 13: 1003056. doi: 10.3389/fneur.2022.1003056

24. Jankovska N, Rusina R, Bruzova M, Parobkova E, Olejar T, Matej R. Human Prion Disorders: Review of the Current Literature and a Twenty-Year Experience of the National Surveillance Center in the Czech Republic. Diagnostics (Basel). 2021; 11(10): 1821. doi: 10.3390/diagnostics11101821

25. McDermott EA, Watson N, Tam J, Centola J, Kurucu King H, Mackenzie J, et al. Sporadic Creutzfeldt–Jakob disease in adults over 80 years: a 10-year review of United Kingdom surveillance. Age Ageing. 2024; 53: aiae086. doi: 10.1093/ageing/aiae086

26. Tam J, Centola J, Kurudzhu H, Mok T, Nihat A, Hyare H, et al. Sporadic Creutzfeldt–Jakob Disease in the young (50 and below): 10-year review of United Kingdom surveillance. J Neurol. 2023; 270: 1036-46. doi: 10.1007/s00415-022-11467-3

27. European Centre for Disease Prevention and Control. Variant Creutzfeldt-Jakob disease: annual epidemiological report for 2022 [Internet]. Stockholm: ECDC; 2024. URL: https://www.ecdc.europa.eu/sites/default/files/documents/VCJD_AER_2022_Report.pdf [date of access: Jun 15, 2024].

28. Shi Q, Chen C, Xiao K, Zhou W, Gao C, Gao L, et al. Characteristics of Different Types of Prion Diseases – China’s Surveillance. China CDC Wkly. 2022; 4(33): 723-8. doi: 10.46234/ccdcw2022.151

29. Rasheed U, Khan S, Khalid M, Noor A, Zafar S. A systemic analysis of Creutzfeldt-Jakob disease cases in Asia. Prion. 2024; 18(1): 11-27. doi: 10.1080/19336896.2024.2311950

30. Kim DY, Shim KH, Bagyinszky E, An SSA. Prion Mutations in Republic of Korea, China, and Japan. Int J Mol Sci. 2022; 24(1): 625. doi: 10.3390/ijms24010625

31. Popova TE, Tappakhov AA, Davydova TK, et al. Creutzfeldt–Jakob disease in the Republic of Sakha (Yakutia)]. Neurology, Neuropsychiatry, Psychosomatics. 2020; 12(2): 86-91 (In Russ.). doi: 10.14412/2074-2711-2020-2-86-91

32. Ershova AA, Kotov AS. Creutzfeldt–Jakob disease: description of three clinical cases. L.O. Badalyan NeurologicalJournal. 2022; 3(1): 42-48. (In Russ.). doi: 10.46563/2686-8997-2022-3-1-42-48

33. Ritchie DL, Barria MA. Prion Diseases: A Unique Transmissible Agent or a Model for Neurodegenerative Diseases? Biomolecules. 2021; 11(2): 207. doi: 10.3390/biom11002007

34. Jellinger KA, Wenning GK, Stefanova N. Is multiple system atrophy a prion-like disorder? Int J Mol Sci. 2021; 22(18): 10093. doi: 10.3390/ijms221810093

35. Chrobak AA, Panczyszyn-Trzewik P, Król P, Pawelec-Bąk M, Dudek D, Siwek M. New Light on Prions: Putative Role of PrP^C in Pathophysiology of Mood Disorders. Int J Mol Sci. 2024; 25(5): 2967. doi: 10.3390/ijms25052967

36. Ghazanfar A, Pittford A, Fernando K. Sporadic Creutzfeldt–Jakob Disease: Finding the Needle in the Haystack. Cureus. 2024; 16(7): e64548. doi: 10.7759/cureus.64548

37. Ritchie DL, Smith C. Pathological spectrum of sporadic Creutzfeldt–Jakob disease. Pathology. 2025; 57(1): 196-206. doi: 10.1016/j.pathol.2024.09.005

38. Mbizvo GK, Ziso B, Larner AJ. Epilepsy and prion diseases: A narrative review. Epilepsy Behav. 2021; 115: 107630. doi: 10.1016/j.yebeh.2020.107630

39. Yukang T, Jiaquan L, Xiaoling L, Yiliang L, Guohong X, Caixia X, et al. A fatal familial insomnia patient newly diagnosed as having depression: A case report. Medicine (Baltimore). 2021; 100(41): e27544. doi: 10.1097/MD.0000000000027544

40. Takada LT, Kim MO, Metcalf S, Illán Gala I, Geschwind MD. Prion disease. In: Geschwind DH, Paulson HL, Klein C, editors. Handbook of Clinical Neurology. Elsevier. 2018; 148: 441-64. doi: 10.1016/B978-0-444-64076-5.00029-6

41. Watson N, Brandel JP, Green A, Hermann P, Ladogana A, LindsayT, et al. The importance of ongoing international surveillance for Creutzfeldt–Jakob disease. Nat Rev Neurol. 2021; 17: 362-79. doi: 10.1038/s41582-021-00488-7

42. Shim KH, Sharma N, An SSA. Prion therapeutics: Lessons from the past. Prion. 2022; 16(1): 265-94. doi: 10.1080/19336896.2022.2153551

43. Kalnov SL, Verkhovsky OA, Tsibezov VV, Alekseev KP, Chudakova DA, Filatov IE, et al. Intravital diagnosis of prion diseases. Problems of Virology. 2020; 65(6): 326-34. (In Russ.). doi: 10.36233/0507-4088-2020-65-6-3

44. Bawa AP, Zhang Y. Creutzfeldt–Jakob Disease: A Focused Literature Review and Retrospective Case Series of Five Patients from a Community Hospital. J Neurol Exp Neurosci. 2022; 8(1): 13-7. doi: 10.17756/jnen.2022-082

45. Huang B, Shaffian N, Masi PJ, Gordon ML, Franceschi AM, Giliberto L. Creutzfeldt–Jakob disease presenting as psychiatric disorder: case presentation and systematic review. Front Neurol. 2024; 15: 1428021. doi: 10.3389/fneur.2024.1428021

46. Srichawla BS. Sporadic Creutzfeldt–Jakob Disease with Status Epilepticus: Molecular Mechanisms and a Scoping Review of the Literature. Cureus. 2022; 14(8): e28649. doi: 10.7759/cureus.28649

47. Krawczuk D, Kulczyńska-Przybik A, Mroczko B. Clinical Application of Blood Biomarkers in Neurodegenerative Diseases-Present and Future Perspectives. Int J Mol Sci. 2024; 25: 8132. doi: 10.3390/ijms25158132

48. Franko E, Wehner T, Joly O, Lowe J, Porter MC, Kenny J, et al. Quantitative EEG parameters correlate with the progression of human prion diseases. J Neurol Neurosurg Psychiatry. 2016; 87(10): 1061-7. doi: 10.1136/jnnp-2016-313501

49. Poleggi A, Baiardi S, Ladogana A, Parchi P. The Use of Real-Time Quaking-Induced Conversion for the Diagnosis of Human Prion Diseases. Front Aging Neurosci. 2022; 14: 874734. doi: 10.3389/fnagi.2022.874734

50. Katsikaki G, Dagklis IE, Angelopoulos P, Ntantos D, Prevezianou A, Bostantjopoulou S. Atypical and early symptoms of sporadic Creutzfeldt–Jakob disease: Case series and review of the literature. Int J Neurosci. 2020; 130(12): 1294-302. doi: 10.1080/00207454.2020.1759594

51. Vascellari S, Orrù CD, Caughey B. Real-Time Quaking-Induced Conversion Assays for Prion Diseases, Synucleinopathies, and Tauopathies. Front Aging Neurosci. 2022; 14: 853050. doi: 10.3389/fnagi.2022.853050

52. Wu J, Chen D, Shi Q, Dong X. Protein amplification technology: New advances in human prion disease diagnosis. Biosaf Health. 2021; 3(6): 325-32. doi: 10.1016/j.bsheal.2021.09.003

53. Frontzek K, Aguzzi A. Recent developments in antibody therapeutics against prion disease. Emerg Top Life Sci. 2020; 4(2): 169-73. doi: 10.1042/ETLS20200002