Sporadic Creutzfeldt-Jakob Disease (sCJD) 

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Overview

Sporadic Creutzfeldt-Jakob disease (sCJD) is the most common form of this fatal neurodegenerative disease.1 The disease is rare, with only 2 cases per million worldwide, and typically affects individuals over the age of 60.1 It is classified as a human prion disease and is caused by the abnormal folding of the human prion protein (PrP).2 These misfolded proteins aggregate in the brain, causing rapidly progressive dementia and motor deficits, such as loss of coordination and visual disturbances. However, age, symptoms, and progression rate can vary significantly.1 This article will discuss the causes, symptoms, diagnosis, treatment, and prognosis, and address some frequently asked questions. It is not designed to replace medical advice; if you are concerned about any symptoms, it is important to consult your doctor.

Pathophysiology

The role of prion proteins

Proteins are biomolecules, made from long chains of amino acids, which specialise to perform specific roles throughout the body. Each protein is encoded by a gene, which is a section of DNA, folded into chromosomes and contained within the nucleus (contains all the genetic material of a cell) of nearly every cell in the body.3 During protein production, DNA is replicated inside the nucleus, producing a copy called RNA, which is then translated into a chain of amino acids at the ribosome, inside the cell.3 Normally, proteins undergo folding and quality control in the endoplasmic reticulum of the cell to prevent abnormal protein accumulation.4 

Prions (PrP’s) are one type of cellular protein, which are encoded by the gene PRNP, and are highly concentrated in the nervous system, where they have multiple roles.5 The central nervous system (CNS) consists of the brain and spinal cord, where electrical signals are generated and transmitted across networks of neurons (nerve cells).1,6 In sCJD, these glycoproteins become abnormally folded into the infectious prion PrPSc. The misfolded proteins aggregate, meaning they clump together, forming deposits across the brain.1,7 This disturbs the normal functioning of the CNS, leading to fatal neurodegeneration.7 

What causes prion misfolding?

Research in this area is ongoing, however, a number of factors have been found to trigger prion misfolding, including: 

How prion misfolding affects the brain

This accumulation of misfolded prion proteins leads to several changes in the brain:2

Signs and symptoms of sCJD

Although symptoms and rate of progression can vary significantly,15 the most common can be categorised into:

 Motor symptoms

Cognitive symptoms

  • Memory impairment: delayed verbal recall, naming and learning16
  • Mood changes: severe depression, anxiety and withdrawal7
  • Executive functioning difficulties: ability to plan, focus, multi-task, emotional and behavioural regulation16, 17
  • Loss of intellect7
  • Personality changes such as agitation or confusion18
  • Hallucinations7

Advanced symptoms

  • Dysphagia: swallowing difficulties
  • Loss of speech
  • Loss of voluntary movement
  • Urinary and bowel incontinence
  • Loss of appetite
  • Loss of insight and awareness 
  • Pneumonia or respiratory failure7

Diagnosis of sCJD

There are a range of diagnostic tests that individuals may require to receive the correct diagnosis:

Magnetic resonance imaging (MRI)

An MRI scan of the brain is one of the main diagnostic tests. It is a painless scan lasting 15-90 minutes, and images are produced using a strong magnet and radio waves.19 Specifically, diffusion-weighted imaging (DW-MRI) is superior in detecting changes in the brain, such as hypersensitivity in at least two cortical areas or cerebral atrophy.11,20 Abnormalities are correctly detected in 96% of individuals with sCJD.21

Electroencephalogram (EEG)

An EEG is a painless procedure lasting 20-40 minutes. Approximately 20 small electrodes are attached to the scalp and connected to a machine to record electrical activity in the brain. This can detect abnormalities shown in sCJD, such as periodic sharp wave complexes.21 However, EEG is less sensitive than an MRI, with only 69% sensitivity, and may show normal results in the early stages of the disease, so it should be used in conjunction with other tests.21

Lumbar puncture

A lumbar puncture is a more invasive procedure, involving the insertion of a needle into the space between the lumbar (lower spinal) vertebrae. The procedure takes 45 minutes and can be uncomfortable, but is very safe.22 It is used to obtain a sample of cerebrospinal fluid (CSF). CSF is a clear fluid that surrounds the central nervous system and can be tested for biomarkers of sCJD. 

One of the main biomarkers is the 14-3-3 protein. A positive test can help to confirm the diagnosis of sCJD. However, sensitivity is lower in the early stages of the disease, meaning the test may produce a false negative.20 Alternatively, the test may provide a false positive in individuals experiencing acute stroke, dementia, subarachnoid haemorrhage, or glioblastoma, so further tests may be necessary.23 In addition, the RT- QuIC test is positive in 95% of individuals with sCJD.24 Tau proteins are also significantly elevated in sCJD but are not currently part of the clinical criteria for diagnosis.20 

Brain biopsy

A biopsy involves obtaining a sample of tissue from the brain for analysis, either using tissue obtained during surgery or via stereotactic biopsy. It is, however, a very invasive procedure, so is avoided where possible, as it is unlikely to change the course of treatment.25

Treatment and management

There is currently no cure for sCJD, so treatment is focused on providing symptom relief, specialist and supportive care. 

Symptomatic treatment

  • Myoclonus can be treated using sodium valproate and clonazepam7
  • Dysphagia can be treated using a modified, soft diet, speech and language therapist support and/or inserting a feeding tube7,24 
  • Depression and anxiety can be treated using antidepressants such as SSRIs7
  • Pain may be treated with opiate-based medication7
  • Motor symptoms may be treated with the support of a physiotherapist or occupational therapist24 

Specialist care

In the UK, individuals with suspected CJD are referred to the National Care Team for CJD in Edinburgh or the National Prion Clinic in London. Specialist doctors will liaise with the local care team, assisting with diagnosis and management.7

Supportive and palliative care 

Rapid disease progression means that care preferences should be discussed soon after diagnosis. Individuals often need significant care and support, which may include: 

  • An advanced directive is a statement of treatment preferences written with the individual in advance of disease progression7
  • Social services can provide financial advice and community care planning24 
  • Palliative hospice care
  • Carer breaks and respite care7

This can be a distressing and emotional time for individuals and their families/carers. If you are concerned about yourself or a loved one, you can reach out for emotional and practical support here

Research and advances

New research is focused on recruiting autoimmune cells to develop gene therapy, targeted immunomodulator therapy, stem cell technology and protein degradation therapy.26 For example, the development of monoclonal antibody (PRN100) therapy, which inhibits the misfolded prion protein proliferation, has proven safe and effective in individuals with CJD, although findings are still in the early stages.27 

Research is also continually developing into identifying proteins as diagnostic biomarkers. For example; α-Synuclein, a synaptic protein, and plasma glial fibrillary acidic protein (pl-GFAP), a filament protein, have been found to be higher in the CSF of individuals with sCJD compared to dementia.28,29 This could lead to the development of additional biomarkers. However, large-scale randomised control trials are difficult to achieve in research due to the low incidence of CJD and the rapid progression of symptoms.26 

FAQs

What is the prognosis/life expectancy of sCJD?

Sadly, 90% of individuals with sCJD will die within a year of symptom onset, although this can range from a few months to a few years.24 

What is the difference between familial CJD and sporadic CJD?

Familial CJD is inherited, meaning it is due to a germline mutation, whereas sporadic CJD occurs spontaneously, due to a somatic mutation. Although symptoms present similarly, they develop more rapidly in sporadic CJD (around 6 months), versus around 2 years in familial CJD.1,7

Which are the differential diagnoses to consider?

Alzheimer’s disease, dementia with Lewy bodies, Huntington’s disease, progressive supranuclear palsy, frontotemporal dementia, multiple sclerosis, and Pick disease may need to be ruled out by healthcare professionals.23 MRI can also rule out other conditions such as ischaemia.20 

Is sCJD infectious?

sCJD can only be transmitted through the consumption or injection of infected tissue; it cannot be transmitted through physical contact or bodily fluids.7

Summary

Sporadic CJD is a rare, fatal neurodegenerative disease. It is caused by the spontaneous misfolding of the prion protein and affects the central nervous system. Symptoms such as dementia, myoclonus, ataxia and visual disturbances develop and progress rapidly. Individuals typically die within a year of symptom onset and require significant care and support. Treatment currently focuses on providing symptom relief, but there is no cure. 

References

  1.  Zerr I, Parchi P. Sporadic creutzfeldt–jakob disease. In: Handbook of Clinical Neurology [Internet]. Elsevier; 2018 [cited 2024 Jun 16]. p. 155–74. Available from: https://linkinghub.elsevier.com/retrieve/pii/B978044463945500009
  2. Creutzfeldt-Jakob Disease. National Institute of Neurological Disorders and Stroke [Internet]. [cited 2024 Jun 16]. Available from: https://www.ninds.nih.gov/health-information/disorders/creutzfeldt-jakob-disease
  3.  LaPelusa A, Kaushik R. Physiology, proteins. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024 [cited 2024 Jun 17]. Available from: http://www.ncbi.nlm.nih.gov/books/NBK555990/
  4. Zhang K, Kaufman RJ. Protein folding in the endoplasmic reticulum and the unfolded protein response. In: Starke K, Gaestel M, editors. Molecular Chaperones in Health and Disease [Internet]. Berlin/Heidelberg: Springer-Verlag; 2006 [cited 2024 Jun 17]. p. 69–91. Available from: http://link.springer.com/10.1007/3-540-29717-0_3
  5. Nafe R, Arendt CT, Hattingen E. Human prion diseases and the prion protein – what is the current state of knowledge? Translational Neuroscience [Internet]. 2023 [cited 2024 Jun 18];14(1):20220315. Available from: https://www.degruyter.com/document/doi/10.1515/tnsci-2022-0315/html
  6. Kim MO, Takada LT, Wong K, Forner SA, Geschwind MD. Genetic prp prion diseases. Cold Spring Harb Perspect Biol [Internet]. 2018 [cited 2024 Jun 17];10(5):a033134. Available from: http://cshperspectives.cshlp.org/lookup/doi/10.1101/cshperspect.a033134
  7. NHS. Creutzfeldt-Jakob disease. In: NHS [Internet]. 2017 [cited 2024 Jun 17]. Creutzfeldt-Jakob disease. Available from: https://www.nhs.uk/conditions/creutzfeldt-jakob-disease-cjd/
  8.  Bernardini A, Gigli GL, Janes F, Pellitteri G, Ciardi C, Fabris M, et al. Creutzfeldt-Jakob disease after COVID-19: infection-induced prion protein misfolding? A case report. Prion [Internet]. 2022 [cited 2024 Jun 18];16(1):78–83. Available from: https://www.tandfonline.com/doi/full/10.1080/19336896.2022.2095185
  9. Liberski PP. Spongiform change--an electron microscopic view. Folia Neuropathologica [Internet]. 2004 [cited 2024 Jun 18]; 42 Suppl B:59–70. Available from: https://pubmed.ncbi.nlm.nih.gov/16903142/.
  10. Spocter MA, Hopkins WD, Barks SK, Bianchi S, Hehmeyer AE, Anderson SM, et al. Neuropil distribution in the cerebral cortex differs between humans and chimpanzees. J of Comparative Neurology [Internet]. 2012 [cited 2024 Jun 17];520(13):2917–29. Available from: https://onlinelibrary.wiley.com/doi/10.1002/cne.23074
  11. Brain magnetic resonance imaging (Mri) | pathology | school of medicine | case western reserve university [Internet]. 2022 [cited 2024 Jun 18]. Available from: https://case.edu/medicine/pathology/divisions/national-prion-disease-pathology-surveillance-center/human-prion-diseases/brain-magnetic-resonance-imaging-mri
  12. Thameem Dheen S, Kaur C, Ling E-A. Microglial Activation and its Implications in the Brain Diseases. Current Medicinal Chemistry [Internet]. 2007 [cited 2024 Jun 18]; 14(11):1189–97. Available from: https://pubmed.ncbi.nlm.nih.gov/17504139/.
  13. Budak M, Zochowski M. Synaptic failure differentially affects pattern formation in heterogenous networks. Front Neural Circuits [Internet]. 2019 [cited 2024 Jun 17];13:31. Available from: https://www.frontiersin.org/article/10.3389/fncir.2019.00031/full
  14.  Navid J, Day GS, Strain J, Perrin RJ, Bucelli RC, Dincer A, et al. Structural signature of sporadic Creutzfeldt–Jakob disease. Euro J of Neurology [Internet]. 2019 [cited 2024 Jun 18];26(8):1037–43. Available from: https://onlinelibrary.wiley.com/doi/10.1111/ene.13930
  15. Bosque PJ, Tyler KL. Prions and prion diseases of the central nervous system(Transmissible neurodegenerative diseases). In: Mandell, Douglas, and Bennett’s Principles and Practice of Infectious Diseases [Internet]. Elsevier; 2015 [cited 2024 Jun 18]. p. 2142-2153.e4. Available from: https://linkinghub.elsevier.com/retrieve/pii/B9781455748013001818
  16. Sundaram SE, Staffaroni AM, Walker NC, Casaletto KB, Casey M, Golubjatnikov A, et al. Baseline neuropsychological profiles in prion disease predict survival time. Ann Clin Transl Neurol [Internet]. 2020 [cited 2024 Jun 18];7(9):1535–45. Available from: https://onlinelibrary.wiley.com/doi/10.1002/acn3.51115
  17. Diamond A. Executive functions. Annu Rev Psychol [Internet]. 2013 [cited 2024 Jun 18];64(1):135–68. Available from: https://www.annualreviews.org/doi/10.1146/annurev-psych-113011-143750
  18. Tan B, Morales Mangual C, Mahmud I, Tongo ND, Mararenko L, Kay A. A case report of probable sporadic creutzfeldt-jakob disease: how to approach early diagnosis? Cureus [Internet]. 2017 [cited 2024 Jun 18]; Available from: http://www.cureus.com/articles/7117-a-case-report-of-probable-sporadic-creutzfeldt-jakob-disease-how-to-approach-early-diagnosis
  19. NHS. Overview - MRI Scan. In: NHS [Internet]. 2017 [cited 2024 Jun 18]. MRI scan. Available from: https://www.nhs.uk/conditions/mri-scan/
  20. Hermann P, Appleby B, Brandel JP, Caughey B, Collins S, Geschwind MD, et al. Biomarkers and diagnostic guidelines for sporadic Creutzfeldt-Jakob disease. The Lancet Neurology [Internet]. 2021[cited 2024 Jun 18];20(3):235–46. Available from: https://linkinghub.elsevier.com/retrieve/pii/S1474442220304774
  21. Mundlamurri R, Shah R, Adiga Ms, Chatterjee A, Gautham B, Raghavendra K, et al. EEG observations in probable sporadic CJD. Ann Indian Acad Neurol [Internet]. 2020 [cited 2024 Jun 18];23(6):760. Available from: https://journals.lww.com/10.4103/aian.AIAN_672_20
  22. Chelsea and Westminster Hospital NHS Foundation Trust [Internet]. [cited 2024 Jun 18]. Lumbar puncture. Available from: https://www.chelwest.nhs.uk/your-visit/patient-leaflets/paediatrics/lumbar-puncture
  23. Mastrianni JA. The genetics of prion diseases. Genetics in Medicine [Internet]. 2010 [cited 2024 Jun 18];12(4):187–95. Available from: https://linkinghub.elsevier.com/retrieve/pii/S1098360021021079
  24. Fact sheets — CJD support network. CJD support network [Internet]. 2022 [cited 2024 Jun 19]. Available from: https://cjdsupport.co.uk/fact-sheets/
  25. Manix M, Kalakoti P, Henry M, Thakur J, Menger R, Guthikonda B, et al. Creutzfeldt-Jakob disease: updated diagnostic criteria, treatment algorithm, and the utility of brain biopsy. FOC [Internet]. 2015 [cited 2024 Jun 19];39(5):E2. Available from: https://thejns.org/view/journals/neurosurg-focus/39/5/article-pE2.xml
  26. Liu F, Lü W, Liu L. New implications for prion diseases therapy and prophylaxis. Front Mol Neurosci [Internet]. 2024 [cited 2024 Jun 19];17:1324702. Available from: https://www.frontiersin.org/articles/10.3389/fnmol.2024.1324702/full
  27. 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. The Lancet Neurology [Internet]. 2022 [cited 2024 Jun 19];21(4):342–54. Available from: https://linkinghub.elsevier.com/retrieve/pii/S1474442222000825
  28. Kruse N, Heslegrave A, Gupta V, Foiani M, Villar‐Piqué A, Schmitz M, et al. Interlaboratory validation of cerebrospinal fluid α‐synuclein quantification in the diagnosis of sporadic Creutzfeldt‐Jakob disease. Alz & Dem Diag Ass & Dis Mo [Internet]. 2018 [cited 2024 Jun 18];10(1):461–70. Available from: https://alz-journals.onlinelibrary.wiley.com/doi/10.1016/j.dadm.2018.06.005
  29. Bentivenga GM, Baiardi S, Mastrangelo A, Zenesini C, Mammana A, Rossi M, et al. Diagnostic and prognostic value of plasma gfap in sporadic creutzfeldt–jakob disease in the clinical setting of rapidly progressive dementia. IJMS [Internet]. 2024 [cited 2024 Jun 18];25(10):5106. Available from: https://www.mdpi.com/1422-0067/25/10/5106

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Kate Baird

BSc Biology, The Open University

Kate has several years of experience working in neurological and psychological services. She is a research collaborator at the University of Edinburgh specialising in eating disorders and autism.

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