Creutzfeldt-Jakob disease

Creutzfeldt-Jakob disease (CJD) is a neurodegenerative condition that is caused by misfolded protein particles (prions). Prion diseases are very rare overall. CJD is the most common prion disease in humans. In most cases, no direct cause of CJD can be established. However, there are also familial forms due to gene mutation or acquired forms as prion particles can be transmitted between individuals, making CJD an infectious disease. Accumulation of prion particles in the brain eventually leads to neuronal degeneration and clinical onset of the disease. The cardinal symptoms of CJD are rapidly progressive dementia and myoclonus. Most patients die within 12 months following disease manifestation. Imaging, EEG, and cerebrospinal fluid (CSF) tests provide diagnostic evidence, although a definite diagnosis can only be made via biopsy or autopsy. To date, no curative treatment is available.

• CJD is the most common prion disease in humans. ^[1][2]
• In the US, there are approximately 1–1.5 cases of sporadic CJD per million population annually.
• Mean age of onset of sporadic CJD: ∼ 60 years ^[3]

Epidemiological data refers to the US, unless otherwise specified.

CJD is caused by misfolded proteins (prions, PrP^Sc) that are either produced by affected individual themselves, or taken up from an exogenous source. ^[4][5][6]

• Sporadic (∼ 85%): no identifiable source
• Familial (∼ 10–15%): associated with various mutations (e.g., deletions, insertions, nonsense or missense variants) affecting the prion protein gene (PRNP gene) ^[7]
• Acquired (< 1%)
  • Iatrogenic CJD: transmission during medical procedures, such as:
    • Brain surgery (surgical equipment)
    • Organ transplantation (e.g., corneal transplant)
    • Blood transfusion
  • Variant CJD (vCJD)
    • Occurs due to ingestion of beef infected with bovine spongiform encephalopathy (BSE)
    • BSE is a transmissible prion disease occurring in cattle also known as “mad cow disease”

• Conversion of normal cellular prion proteins with alpha-helical structure (PrP^c) to prions that demonstrate an increase in beta-pleated sheet structure (PrP^Sc) → conformational change of physiological PrP^c; → PrP^Sc accumulation and plaque formation → neuronal cell death → progression to spongiform encephalopathy ^[8][9][10]
• Since misfolded prions are insoluble, they deposit as plaques resistant to proteases and standard autoclaving, thus contributing to the formation of more PrP^Sc.

The latency period until symptom onset varies greatly with the type of exposition (e.g., between 5 and 30 years in some cases of iatrogenic CJD). ^[11]

• Prodromal symptoms
  • Sleep disorders
  • Headaches
  • Fatigue
• Neurological symptoms
  • Cerebellar disturbances (e.g., gait instability) and extrapyramidal deficits
  • Myoclonus
    • Often triggered by startling (e.g., loud noises)
    • Also associated with metabolic abnormalities found in liver and renal failure
  • Ataxia
  • Seizures
• Neuropsychiatric symptoms
  • Rapidly progressing dementia (weeks to months)
  • Personality changes
  • Akinetic mutism ^[12]
  • Visual hallucinations
  • Depression
• Autonomic nervous system dysregulation (e.g., sweating)

Rapidly progressive dementia and myoclonic jerks are the hallmarks of Creutzfeldt-Jakob disease.

Instrumental diagnostics ^[3]

• CSF analysis ^[13]
  • ↑ Neuron specific enolase
  • ↑ S100 protein
  • ↑ Tau protein
  • ↑ 14-3-3 protein
• RT-QuIC: a diagnostic tool for sporadic Creutzfeldt-Jakob disease ^[14]
  • Involves mixing of CSF taken from an individual with suspected CJD with recombinant prion protein (rPrP) and thioflavin T.
  • If CSF contains PrP^Sc, PrP^Sc will induce conformation changes in rPrP.
  • Aggregated rPrP fibrils bind to thioflavin T, which will start to fluoresce.
  • Fluorescence can be measured and shows a characteristic sigmoidal curve.
  • The whole process can take up to 90 hours.
• Imaging: : MRI frequently shows hyperintensity in the basal ganglia, insular cortices, and the frontal cortices
• EEG: : triphasic periodic sharp wave complexes with a frequency of 1–2 Hz
• Brain biopsy
  • Diagnosis can only be confirmed by biopsy/autopsy and subsequent neuropathological examination.
  • Microscopic findings include spongiform degeneration (e.g., intracytoplasmic vacuoles within the neurons of cerebral and cerebellar cortex that can be seen on H&E), gliosis and, in rare cases, amyloid plaques.

Other diseases commonly associated with the development of dementia:

• Other prion diseases
  • Gerstmann-Sträussler-Scheinker syndrome
  • Kuru: found initially in tribes that practice cannibalism
  • Fatal familial insomnia
• Huntington disease
• Encephalopathy due to mitochondrial myopathy (e.g., MELAS)
• Encephalitis
• Wilson disease
• See “Differential diagnosis of subtypes of dementia.”

The differential diagnoses listed here are not exhaustive.

• No curative therapy available: Sporadic CJD typically leads to death within one year of symptom onset. ^[1][2]
• Symptomatic treatment and eventually palliative care

Following disease manifestation, most individuals with sporadic CJD die within 12 months, usually from complications such as pneumonia.