Prion Diseases
Prion diseases, also known as transmissible spongiform encephalopathies (TSEs), are a unique class of fatal neurodegenerative disorders caused by the misfolding and aggregation of the prion protein. Unlike all other infectious diseases, prions contain no nucleic acid — the infectious agent is a misfolded conformer of a normal host protein. Sporadic Creutzfeldt-Jakob disease (sCJD) is by far the most common human prion disease and is one of the most rapidly progressive dementias encountered in neurologic practice. The development of the RT-QuIC assay has revolutionized antemortem diagnosis, often obviating the need for brain biopsy. However, the inability to treat or halt disease progression makes prion diseases among the most devastating diagnoses in neurology. Critically, the practicing neurologist must also recognize that several treatable conditions — most notably autoimmune encephalitis — can closely mimic prion disease and must be excluded.
Bottom Line
- Pathogenic mechanism: Misfolded prion protein (PrPSc) acts as a template, converting normal cellular prion protein (PrPC) into the pathogenic conformation through a self-propagating process; no nucleic acid, no immune response
- Sporadic CJD: Accounts for 85–90% of cases; presents with rapidly progressive dementia, myoclonus, and multifocal neurologic signs; median survival 5–12 months
- Most sensitive early diagnostic test: MRI showing cortical ribboning and/or caudate/putamen hyperintensity on DWI — sensitivity >90% when performed with appropriate sequences
- RT-QuIC: CSF real-time quaking-induced conversion assay has sensitivity >90% and specificity ~99%; has largely replaced brain biopsy for antemortem diagnosis
- EEG periodic sharp waves: Classic but present in only ~60% of sCJD cases and typically later in the disease course; more characteristic of the MM1 subtype
- Genetic forms: 10–15% of cases; PRNP gene mutations; includes fatal familial insomnia (D178N-129M) and Gerstmann-Sträussler-Scheinker syndrome (P102L)
- Variant CJD: Linked to bovine spongiform encephalopathy (BSE); younger patients, psychiatric onset, "pulvinar sign" on MRI, longer disease course
- Critical clinical imperative: Always exclude treatable mimics (autoimmune encephalitis, Hashimoto encephalopathy, CNS lymphoma, rapidly progressive Alzheimer disease) before accepting a prion diagnosis
- No treatment: Supportive and palliative care; median survival 5 months for sCJD; prion-specific therapies remain investigational
Prion Biology and Pathogenesis
The prion hypothesis, advanced by Stanley Prusiner in 1982 (Nobel Prize, 1997), proposes that the infectious agent in TSEs is composed solely of protein. The normal cellular prion protein (PrPC) is a glycosylphosphatidylinositol (GPI)-anchored cell surface glycoprotein encoded by the PRNP gene on chromosome 20. PrPC is expressed widely in the nervous system but its precise physiologic function remains incompletely understood, though roles in copper homeostasis, cell signaling, and synaptic function have been proposed.
Mechanism of Prion Propagation
The Protein-Only Hypothesis
- Conformational change: PrPSc (the pathogenic conformer) has a predominantly beta-sheet structure, compared to the alpha-helix-rich PrPC; this conformational change renders PrPSc insoluble, protease-resistant, and prone to aggregation
- Templated conversion: PrPSc physically interacts with PrPC and acts as a template, inducing the normal protein to refold into the pathogenic conformation; this creates an exponential amplification cascade
- No immune response: Because PrPSc is a self-protein (albeit misfolded), the immune system does not recognize it as foreign; there is no inflammatory infiltrate, no antibody response, and no fever
- Spongiform change: Accumulation of PrPSc in the neuropil produces vacuolation (spongiform change), neuronal loss, astrogliosis, and amyloid plaque formation in some subtypes
- Strain diversity: Different conformations of PrPSc produce distinct "strains" with characteristic clinical phenotypes, brain region targeting, incubation periods, and glycosylation patterns — explaining the diversity of prion diseases from a single protein
Codon 129 Polymorphism
The PRNP codon 129 encodes either methionine (M) or valine (V). The genotype at this locus (MM, MV, or VV) profoundly influences susceptibility to prion disease and disease phenotype. In the general population, approximately 37–40% are MM, 50% are MV, and 10–13% are VV. Homozygosity at codon 129 (MM or VV) increases susceptibility to sporadic CJD. Almost all cases of variant CJD have occurred in MM individuals.
Classification of Human Prion Diseases
| Category | Disease | Frequency | Mechanism | Key Features |
|---|---|---|---|---|
| Sporadic | Sporadic CJD (sCJD) | 85–90% of all prion disease | Spontaneous misfolding or somatic PRNP mutation | Rapidly progressive dementia, myoclonus; 6 molecular subtypes |
| Sporadic fatal insomnia (sFI) | Very rare | Spontaneous | Thalamic degeneration; intractable insomnia; autonomic dysfunction | |
| Genetic (10–15%) | Familial CJD (fCJD) | Most common genetic form | PRNP mutations (E200K most common worldwide) | Similar to sCJD; autosomal dominant; variable penetrance |
| Fatal familial insomnia (FFI) | Rare | D178N mutation with M at codon 129 (cis) | Progressive insomnia, autonomic dysfunction, motor signs; thalamic-predominant pathology | |
| Gerstmann-Sträussler-Scheinker (GSS) | Rare | P102L mutation most classic | Slowly progressive cerebellar ataxia, late dementia; multicentric amyloid plaques; survival 3–10 years | |
| Acquired | Variant CJD (vCJD) | <1% overall; ~230 cases total worldwide | Dietary exposure to BSE prions | Young patients, psychiatric onset, painful dysesthesias, pulvinar sign, longer course (median 14 months) |
| Iatrogenic CJD (iCJD) | Rare; declining | Contaminated dura mater grafts, corneal transplants, cadaveric growth hormone, neurosurgical instruments | Incubation period years to decades; clinical phenotype depends on route of inoculation |
Sporadic CJD — Clinical Features
Sporadic CJD occurs worldwide with an incidence of approximately 1–2 cases per million per year. Mean age of onset is 60–65 years, though cases have been reported from the third to ninth decade. There is no sex predominance. The cause of the initial PrPC misfolding event in sCJD remains unknown.
Presenting Symptoms and Disease Course
Clinical Features of sCJD by Phase
- Early phase (weeks 1–8): Cognitive decline (most common), often with prominent executive and visuospatial deficits; personality and behavioral changes; fatigue, malaise; may mimic depression or anxiety initially
- Progressive phase (weeks to months): Rapidly worsening dementia; myoclonus (especially stimulus-sensitive/startle myoclonus — present in ~80% at some point); cerebellar ataxia; visual disturbances (cortical visual loss, visual hallucinations); pyramidal signs (hyperreflexia, extensor plantar responses); extrapyramidal signs (rigidity, bradykinesia)
- Late phase: Akinetic mutism — patient is mute, immobile, unresponsive but may have preserved eye tracking; global myoclonus; progressive to death
- Median survival: ~5 months (MM1 subtype) to ~12 months (other subtypes); 90% die within 1 year of symptom onset
Molecular Subtypes of sCJD
sCJD is classified into 6 molecular subtypes based on the combination of codon 129 genotype (MM, MV, or VV) and PrPSc type (type 1 or type 2, distinguished by protease-resistant fragment size). Each subtype has a characteristic clinical phenotype and pattern of brain involvement.
| Subtype | Frequency | Clinical Phenotype | MRI Pattern | EEG PSWCs | Median Survival |
|---|---|---|---|---|---|
| MM1/MV1 | ~65–70% | Classic: rapid dementia, myoclonus, visual symptoms (Heidenhain variant if occipital-predominant) | Cortical ribboning + striatal; widespread DWI changes | Present (~75%) | ~4–5 months |
| VV2 | ~15% | Cerebellar ataxia predominant; dementia later; longer prodrome | Thalamic > cortical; cerebellar atrophy | Less common | ~6–7 months |
| MV2K | ~8% | Ataxia, dementia, extrapyramidal signs; resembles kuru-like CJD | Variable cortical/subcortical | Uncommon | ~18 months |
| MM2C (cortical) | ~2% | Progressive dementia without myoclonus; slower course | Cortical ribboning | Absent | ~16 months |
| MM2T (thalamic) | ~2% | Sporadic fatal insomnia: intractable insomnia, autonomic dysfunction, motor signs | Thalamic; FDG-PET shows thalamic hypometabolism | Absent | ~16 months |
| VV1 | ~1% | Young onset; progressive dementia; slow progression | Cortical; may lack striatal involvement | Absent | ~20+ months |
Diagnostic Approach
The diagnosis of sCJD has been transformed by advances in neuroimaging and CSF biomarkers. The 2018 CDC diagnostic criteria incorporate MRI and RT-QuIC, enabling confident antemortem diagnosis in most cases.
MRI — The Most Sensitive Early Test
MRI Findings in sCJD
- DWI sequence: The single most sensitive MRI sequence for CJD; should always be included in the workup of rapidly progressive dementia
- Cortical ribboning: High signal in the cortical ribbon on DWI (and to a lesser extent FLAIR), often asymmetric and involving ≥3 cortical regions; represents cortical spongiform change and gliosis
- Caudate and putamen hyperintensity: High signal in the caudate head and/or putamen on DWI; the caudate is especially characteristic; may be unilateral or bilateral
- Combined cortical + striatal: The most common pattern in MM1 sCJD; provides the highest diagnostic specificity
- Sensitivity: >90% for DWI across all sCJD subtypes; sensitivity for FLAIR alone is lower (~75–80%)
- Specificity: ~95% when strict criteria applied (high cortical signal on DWI that does not follow a vascular territory)
- Pitfall: DWI signal in CJD does NOT correspond to acute ischemia; ADC maps may show reduced, normal, or elevated diffusion depending on disease stage
- Thalamic signal: Pulvinar sign (bilateral pulvinar hyperintensity) is characteristic of variant CJD but NOT typical of sCJD; hockey stick sign (pulvinar + dorsomedial thalamus) is even more specific for vCJD
CSF Biomarkers
| Biomarker | Sensitivity | Specificity | Clinical Utility |
|---|---|---|---|
| RT-QuIC | >90% (92–96%) | ~99–100% | The most important CSF test; detects PrPSc seeding activity; has largely replaced brain biopsy for antemortem diagnosis; may be negative in certain subtypes (VV2, MM2) |
| 14-3-3 protein | ~85–95% | ~60–80% | Nonspecific marker of rapid neuronal destruction; elevated in stroke, encephalitis, seizures; low specificity limits utility; included in older diagnostic criteria |
| Total tau protein | ~80–90% | ~85% | Levels >1,150 pg/mL are suggestive of CJD; correlates with rate of neurodegeneration; more specific than 14-3-3 |
| Neuron-specific enolase (NSE) | ~70–80% | ~80% | Elevated in CJD but nonspecific; rarely used in isolation; supplements other markers |
| Neurofilament light (NfL) | High | Low for CJD specifically | Markedly elevated in CJD but also in many other neurodegenerative diseases; useful for monitoring rapid neurodegeneration |
EEG
EEG Findings in CJD
- Periodic sharp wave complexes (PSWCs): Bi- or triphasic sharp waves at 0.5–2 Hz frequency, generalized or lateralized; present in ~60% of sCJD overall; most common in the MM1 subtype (~75%)
- Temporal evolution: Early disease may show only nonspecific slowing; PSWCs typically emerge in the middle to late stages; very late disease may show suppressed or flat background
- Specificity: PSWCs are not pathognomonic — they can occur in metabolic encephalopathies (hepatic, renal), Hashimoto encephalopathy, lithium toxicity, and other conditions
- Absent in: Variant CJD (where the EEG typically shows nonspecific slowing without PSWCs), GSS, FFI, and some sCJD subtypes (VV2, MM2)
- Clinical correlation: PSWCs often correlate with the emergence of myoclonus; their appearance in the clinical context of rapidly progressive dementia is highly suggestive
CDC Diagnostic Criteria for sCJD (2018)
| Classification | Criteria |
|---|---|
| Definite | Neuropathologically confirmed (brain biopsy or autopsy) with PrPSc detection by immunohistochemistry, Western blot, or other validated methods |
| Probable | Progressive neuropsychiatric disorder + positive RT-QuIC (in CSF or other tissue); OR progressive dementia with at least 2 of: myoclonus, visual/cerebellar, pyramidal/extrapyramidal, akinetic mutism — PLUS at least one of: (a) PSWCs on EEG, (b) positive 14-3-3 with duration <2 years, (c) characteristic MRI (caudate/putamen or ≥2 cortical regions on DWI/FLAIR) |
| Possible | Progressive dementia <2 years duration with at least 2 of: myoclonus, visual/cerebellar, pyramidal/extrapyramidal, akinetic mutism — but without supportive diagnostic tests |
Genetic Prion Diseases
Genetic prion diseases account for 10–15% of all human prion disease and result from pathogenic mutations in the PRNP gene. They are inherited in an autosomal dominant pattern, though penetrance varies by mutation. Over 60 pathogenic PRNP mutations have been identified. Genetic testing should be considered in any prion disease patient with a family history of dementia, ataxia, or psychiatric illness, and in patients with atypical presentations.
Fatal Familial Insomnia (FFI)
FFI — Clinical Features
- Mutation: D178N substitution in PRNP gene, with methionine at codon 129 on the mutant allele (cis configuration); the same D178N mutation with valine at codon 129 produces familial CJD instead — a remarkable genotype-phenotype relationship
- Onset: Typically in the 50s (range 20s–70s)
- Cardinal feature: Progressive, intractable insomnia — initially difficulty maintaining sleep, evolving to near-complete inability to sleep; polysomnography shows absent or severely disrupted sleep architecture
- Autonomic dysfunction: Hyperhidrosis, tachycardia, hypertension, hyperthermia, sphincter disturbances; reflects selective thalamic (especially mediodorsal and anterior nuclei) degeneration
- Motor signs: Myoclonus, ataxia, dysarthria, dysphagia; pyramidal signs late
- Cognitive features: Attention and executive deficits; oneiric stupor (dream-like confusional state); frank dementia late
- Imaging: MRI may be normal early; FDG-PET shows characteristic thalamic hypometabolism; late MRI may show thalamic and cortical atrophy
- Survival: Median 18 months (range 8–72 months)
Gerstmann-Sträussler-Scheinker Syndrome (GSS)
GSS — Clinical Features
- Mutations: P102L is the most common ("classic GSS"); other mutations include A117V, F198S, D202N
- Onset: Typically 40s–60s, though younger onset reported
- Hallmark: Slowly progressive cerebellar ataxia over years — distinguishes GSS from the rapid course of CJD
- Dementia: Occurs later in the disease course, often after years of cerebellar symptoms
- Other features: Dysarthria, nystagmus, spastic paraparesis (some mutations), peripheral neuropathy (some mutations), pyramidal signs
- Neuropathology: Multicentric PrP amyloid plaques in the cerebellum and cerebral cortex — distinctive pathologic feature
- Survival: 3–10 years — significantly longer than CJD
- EEG: PSWCs are absent; nonspecific slowing only
Variant CJD (vCJD)
Variant CJD was first identified in the United Kingdom in 1996 and is linked to dietary exposure to bovine spongiform encephalopathy (BSE, "mad cow disease") prions. Approximately 230 cases have been reported worldwide, with the vast majority in the UK. The incidence has markedly declined since the implementation of BSE control measures in the food supply.
| Feature | Sporadic CJD | Variant CJD |
|---|---|---|
| Age at onset | Mean ~65 years | Mean ~28 years (range 12–74) |
| Presenting features | Rapidly progressive dementia, myoclonus | Psychiatric symptoms (depression, anxiety, withdrawal), painful dysesthesias, then dementia and ataxia |
| Disease duration | Median 5 months | Median 14 months |
| MRI hallmark | Cortical ribboning, caudate/putamen (DWI) | Pulvinar sign (bilateral posterior thalamic hyperintensity on FLAIR/T2); hockey stick sign |
| EEG | PSWCs in ~60% | Non-specific slowing; PSWCs absent |
| CSF 14-3-3 | Usually positive | Often negative |
| Tonsil biopsy | Not useful (PrPSc not in lymphoid tissue) | Positive for PrPSc (lymphoreticular tropism); used diagnostically |
| Codon 129 | All genotypes (MM most common) | Almost exclusively MM (one possible VV case reported) |
| Neuropathology | Spongiform change, gliosis | Florid plaques (PrP amyloid plaques surrounded by spongiform vacuoles — "daisy" appearance) |
Iatrogenic CJD
Routes of Iatrogenic Transmission
- Dura mater grafts: Cadaveric dura grafts (particularly Lyodura brand) used in neurosurgery; most common source of iCJD historically; incubation period averages ~12 years (range 1.5–30 years); presents similarly to sCJD
- Cadaveric pituitary hormones: Growth hormone and gonadotropin derived from pooled cadaveric pituitaries; incubation period ~12–30 years; often presents with progressive cerebellar ataxia before dementia
- Corneal transplants: Extremely rare; fewer than 5 documented cases
- Contaminated neurosurgical instruments: PrPSc is remarkably resistant to standard sterilization; cases documented from shared EEG depth electrodes and neurosurgical equipment
- Current relevance: Cadaveric dura grafts and pituitary hormones are no longer used; however, long incubation periods mean new cases can still present decades after exposure; surgical instrument contamination remains a theoretical ongoing risk
Differential Diagnosis — Treatable Mimics
Perhaps the most important clinical responsibility when evaluating a suspected prion disease is the rigorous exclusion of treatable conditions that can produce a rapidly progressive dementia with features overlapping CJD. A comprehensive workup for reversible causes should be completed before concluding a prion diagnosis.
Treatable Mimics of CJD — Must Exclude
- Autoimmune encephalitis: The most important treatable mimic; anti-NMDAR, anti-LGI1, anti-CASPR2, anti-AMPAR encephalitis can all produce rapidly progressive cognitive decline, seizures, and movement disorders; some autoimmune encephalitides produce DWI signal changes mimicking CJD; ALWAYS check serum and CSF autoimmune encephalitis panels
- Hashimoto encephalopathy (SREAT): Steroid-responsive encephalopathy with high anti-TPO/anti-thyroglobulin antibodies; can present with myoclonus, cognitive decline, seizures, and EEG changes; dramatic response to corticosteroids
- CNS lymphoma: Primary CNS lymphoma can cause rapidly progressive cognitive decline; MRI may show DWI restriction; CSF cytology, flow cytometry, and sometimes biopsy needed
- Rapidly progressive Alzheimer disease: Unusual AD variants can progress over months; CSF AD biomarkers (Aβ42/40 ratio, p-tau) help distinguish; amyloid PET may be useful
- CNS vasculitis: Can produce multifocal cortical DWI changes mimicking CJD; angiography and/or brain/meningeal biopsy may be needed
- Toxic-metabolic: Bismuth toxicity, lithium toxicity, hepatic encephalopathy, uremia — can produce myoclonus and cognitive decline with triphasic waves on EEG
- Paraneoplastic syndromes: Anti-Hu, anti-CV2/CRMP5, anti-amphiphysin — can cause rapidly progressive cerebellar or cognitive syndromes
- Intravascular lymphoma: Rare but can mimic CJD with multifocal DWI lesions and rapid progression
Recommended Workup for Rapidly Progressive Dementia
- MRI brain with DWI: Essential; look for cortical ribboning, caudate/putamen signal; also evaluate for alternative diagnoses
- CSF: RT-QuIC, 14-3-3, total tau, routine studies (cell count, protein, glucose, cytology), autoimmune encephalitis panel, oligoclonal bands
- Serum: Autoimmune encephalitis panel, anti-TPO/anti-thyroglobulin, comprehensive metabolic panel, TSH, vitamin B12, RPR/FTA-ABS, HIV, heavy metals
- EEG: Look for PSWCs; also evaluate for subclinical seizures (non-convulsive status epilepticus can mimic RPD)
- CT body (if paraneoplastic suspected): Occult malignancy screen
- PRNP genetic testing: Consider in all suspected prion cases; essential if family history or atypical features
- Brain biopsy: Rarely needed with positive RT-QuIC; reserved for atypical cases where treatable diagnoses remain in the differential and non-invasive workup is inconclusive
Management and Prognosis
There is no disease-modifying or curative treatment for any human prion disease. Management is supportive and palliative, with the goal of maintaining dignity and comfort through the disease course.
Supportive Care
Principles of Prion Disease Management
- Myoclonus treatment: Clonazepam (0.5–2 mg BID-TID) is the most effective agent for startle myoclonus; valproic acid and levetiracetam are alternatives
- Seizure management: Standard AEDs; seizures occur in ~15–20% of CJD patients
- Behavioral symptoms: Agitation and psychosis may respond to low-dose antipsychotics (quetiapine, haloperidol); however, extrapyramidal side effects are a concern given the existing extrapyramidal features of CJD
- Nutritional support: Dysphagia develops early to mid-disease; PEG tube placement may be considered depending on goals of care discussion
- Palliative care: Early palliative care referral is essential; goals of care discussions should occur promptly given the uniformly fatal prognosis; many families choose hospice enrollment
- Advanced directives: Should be addressed as soon as possible after diagnosis, while the patient retains capacity
- Caregiver support: The rapid cognitive and physical decline is devastating for families; social work, counseling, and support group referrals should be provided
Investigational Therapies
Multiple therapeutic approaches are under investigation, though none has demonstrated clinical efficacy to date. Antisense oligonucleotides (ASOs) targeting PRNP mRNA are in clinical trials and represent the most promising approach, aiming to reduce PrPC substrate availability and thereby slow disease progression. Other approaches include anti-PrP antibodies, small molecule PrPSc stabilizers, and immunotherapeutic strategies.
Infection Control and Biosafety
Prion Decontamination and Biosafety
- Resistance to standard sterilization: PrPSc is extraordinarily resistant to conventional decontamination methods — it is NOT inactivated by standard autoclaving (121°C for 15 minutes), formalin fixation, UV radiation, ionizing radiation, or alcohol
- Effective decontamination: Instruments that contact high-infectivity tissues (brain, spinal cord, dura, posterior eye) require: (1) immersion in 1N NaOH or sodium hypochlorite (≥20,000 ppm) for 1 hour, followed by (2) autoclaving at 134°C for 1 hour; OR (3) formic acid (96%) for 1 hour
- Single-use instruments: For known or suspected prion disease cases, disposable instruments should be used whenever possible and incinerated afterward
- Tissue handling: Brain biopsy specimens from suspected CJD should be handled with prion-specific precautions; formalin fixation alone does NOT eliminate infectivity; pathology laboratory should be notified in advance
- Standard patient care: Routine clinical care (blood draws, physical examination) does NOT pose a significant transmission risk; standard universal precautions are sufficient for non-surgical patient contact
- Body fluids: Blood, urine, CSF, and saliva are considered low-infectivity in sCJD (though blood-borne transmission has occurred with vCJD); standard precautions apply
- Autopsy: Autopsy is strongly encouraged for definitive diagnosis and surveillance; must be performed under enhanced biosafety conditions
RT-QuIC: Transforming Prion Diagnosis
The real-time quaking-induced conversion (RT-QuIC) assay represents the single most important diagnostic advance in prion disease in the past two decades. The assay exploits the templated conversion mechanism of prion disease: recombinant PrPC substrate is incubated with a patient's CSF sample, and if PrPSc seeds are present, they induce conversion and amyloid fibril formation that is detected by thioflavin T fluorescence in real time.
RT-QuIC Key Points
- Sensitivity: 92–96% for sCJD across studies; highest for MM1 subtype (~97%); lower for VV2 (~85%) and MM2 subtypes (~80%)
- Specificity: ~99–100% in most studies; essentially no false positives in validated assays
- Impact on clinical practice: Has largely eliminated the need for brain biopsy to diagnose CJD; a positive RT-QuIC in the appropriate clinical and MRI context is sufficient for a "probable CJD" diagnosis
- Alternative substrates: Second-generation assays using bank vole PrP as substrate ("BV RT-QuIC") show improved sensitivity for some subtypes
- Nasal brushings: RT-QuIC performed on olfactory mucosa nasal brushings shows promising sensitivity (~97%) and may offer a less invasive sampling method than lumbar puncture
- Limitations: Not universally available; requires specialized laboratory; turnaround time 3–7 days; false negatives possible in non-MM1 subtypes and early disease; not validated for monitoring disease progression
- Skin RT-QuIC: Emerging evidence suggests PrPSc can be detected in skin biopsy specimens using RT-QuIC, potentially offering another diagnostic avenue
Prion Disease Surveillance
Prion disease surveillance programs operate in many countries and serve critical roles in monitoring disease incidence, detecting emerging strains (such as vCJD), identifying iatrogenic clusters, and supporting research. In the United States, the National Prion Disease Pathology Surveillance Center at Case Western Reserve University performs free diagnostic testing (including RT-QuIC, PRNP sequencing, and neuropathologic examination) for clinicians who submit specimens. Autopsy rates for suspected CJD cases should be maximized to ensure accurate surveillance data.
References
- Prusiner SB. Prions. Proc Natl Acad Sci U S A. 1998;95(23):13363-13383.
- Geschwind MD. Prion diseases. Continuum (Minneap Minn). 2015;21(6 Neuroinfectious Disease):1612-1638.
- Zerr I, Kallenberg K, Summers DM, et al. Updated clinical diagnostic criteria for sporadic Creutzfeldt-Jakob disease. Brain. 2009;132(Pt 10):2659-2668.
- McGuire LI, Peden AH, Orru CD, et al. Real time quaking-induced conversion analysis of cerebrospinal fluid in sporadic Creutzfeldt-Jakob disease. Ann Neurol. 2012;72(2):278-285.
- Orru CD, Groveman BR, Hughson AG, et al. Rapid and sensitive RT-QuIC detection of human Creutzfeldt-Jakob disease using cerebrospinal fluid. mBio. 2015;6(1):e02451-14.
- Parchi P, Giese A, Capellari S, et al. Classification of sporadic Creutzfeldt-Jakob disease based on molecular and phenotypic analysis of 300 subjects. Ann Neurol. 1999;46(2):224-233.
- Gambetti P, Kong Q, Zou W, et al. Sporadic and familial CJD: classification and characterisation. Br Med Bull. 2003;66:213-239.
- Will RG, Ironside JW, Zeidler M, et al. A new variant of Creutzfeldt-Jakob disease in the UK. Lancet. 1996;347(9006):921-925.
- Montagna P, Gambetti P, Cortelli P, et al. Familial and sporadic fatal insomnia. Lancet Neurol. 2003;2(3):167-176.
- Hermann P, Appleby B, Brandel JP, et al. Biomarkers and diagnostic guidelines for sporadic Creutzfeldt-Jakob disease. Lancet Neurol. 2021;20(3):235-246.
- Vallabh SM, Minikel EV, Schreiber SL, et al. Towards a treatment for genetic prion disease: trials and biomarkers. Lancet Neurol. 2020;19(4):361-368.
- Staffaroni AM, Kramer JH, Casey M, et al. Association of blood and cerebrospinal fluid tau level and other biomarkers with survival time in sporadic Creutzfeldt-Jakob disease. JAMA Neurol. 2019;76(8):969-977.
- Zanusso G, Monaco S, Bhatt J, et al. Olfactory mucosa as an antemortem diagnostic site for prion disease. N Engl J Med. 2003;348(8):711-719.
- Brown P, Brandel JP, Sato T, et al. Iatrogenic Creutzfeldt-Jakob disease, final assessment. Emerg Infect Dis. 2012;18(6):901-907.
- WHO. WHO infection control guidelines for transmissible spongiform encephalopathies. Geneva: World Health Organization; 2000.