Creutzfeldt–Jakob disease

• 1. Introduction

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  Creutzfeldt-Jakob disease, usually shortened to CJD, leaves a strange mark on the human brain. Under a microscope, a sample of affected tissue is riddled with tiny holes where nerve cells have died, and whole regions can resemble a sponge. The disease is incurable and always fatal. It belongs to a family called the prion diseases, which are caused by infectious proteins that have folded into an abnormal shape. This documentary follows three questions. How can a single misfolded protein spread itself through a brain? How did a rare illness come to be passed between patients by medical tools and treatments? And how do doctors recognise a disease whose early symptoms look like so many others?

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• 2. Folding Gone Wrong

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  The healthy version of the prion protein is called PrPC, and it carries out a wide range of jobs in the central nervous system. Its diseased form is called PrPSc. The CJD prion pushes normal protein molecules to refold into the diseased shape, so the number of misfolded molecules grows exponentially. Insoluble protein piles up inside affected cells, disrupts how the neurons work, and eventually kills them.

  At the molecular level, mutations in the gene for the prion protein can turn regions that are mostly alpha helix into beta pleated sheets. That change leaves the protein unable to be digested. Once a defective protein reaches the brain, it induces other prion protein molecules to misfold. The result is a self-sustaining feedback loop.

  Current research suggests that small, highly toxic clumps called oligomeric aggregates do the real damage. They interact with cell surfaces and disrupt neurons. Their binding to normal prion protein may trigger toxic signals similar to those produced by oligomeric beta-amyloid, which harms synapses in Alzheimer's disease. Different shapes of PrPSc, often called strains, are thought to explain why the subtypes of prion disease differ in symptoms and speed.

  A common variation at codon 129 of the PRNP gene, where the protein carries either methionine or valine, also matters. People with two matching copies are over-represented among sporadic cases and tend to have shorter incubation periods. For the sporadic cases, one hypothesis is that the ageing of cellular machinery eventually causes the first misfolding, which may explain why the disease usually appears late in life.

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• 3. Naming the Disease

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  In 1920, the German neurologist Hans Gerhard Creutzfeldt published the first description of the illness. Alfons Maria Jakob, another German neurologist, described it shortly afterward. The combined name was introduced in 1922 by Walther Spielmeyer. Even so, some clinical findings in those first papers do not match today's criteria, and it has been speculated that at least two of the people in the early studies had a different illness.

  Friedrich Meggendorfer, a German psychiatrist and neurologist who lived from 1880 to 1953, gave an early description of the inherited form. Decades later, Stanley B. Prusiner of the University of California, San Francisco, received the Nobel Prize in Physiology or Medicine in 1997. The prize recognised his work on prions, which the citation called "a new biological principle of infection".

  Not everyone accepts the protein explanation. In January 2007, the Yale University neuropathologist Laura Manuelidis and her colleagues reported virus-like particles in naturally and experimentally infected animals. They wrote that "the high infectivity of comparable, isolated virus-like particles that show no intrinsic PrP by antibody labeling, combined with their loss of infectivity when nucleic acid-protein complexes are disrupted, make it likely that these 25-nm particles are the causal TSE virions".

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• 4. The Course of Illness

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  Rapidly progressive dementia is usually the first sign, bringing memory loss, personality changes, and hallucinations. Jerky muscle movements called myoclonus appear in about 90% of cases, though they can be absent at the start. Anxiety, depression, paranoia, obsessive-compulsive symptoms, and psychosis are all common. Physical trouble follows, including impaired speech, poor balance and coordination, changes in the way a person walks, and a rigid posture. In rare cases, people experience the alien limb phenomenon. Later stages bring blindness, deafness, weakness, and coma.

  The timeline can be brutally short. Sporadic CJD can be fatal within months or even weeks, and most affected people die about six months after the first symptoms, often of pneumonia caused by a weakened cough reflex. About 15% of patients survive two years or longer. About 70% of sufferers die within a year of diagnosis.

  Michael Homer, a former Vice President of Netscape, was diagnosed in 2007 after persistent memory problems. The British journalist Graham Usher died of CJD in New York in August 2013. Rebecca D. Lockhart, a former speaker of the Utah House of Representatives, died in January 2015, within a few weeks of her diagnosis. John Carroll, a former editor of The Baltimore Sun and the Los Angeles Times, died in Kentucky in June 2015, five months after he was diagnosed. The actress Barbara Tarbuck died on the 26th of December 2016. José Baselga, a clinical oncologist who had headed the oncology division at AstraZeneca, died in Cerdanya on the 21st of March 2021.

  As of 1981, nobody was known to have lived longer than two and a half years after symptoms began. Jonathan Simms, a Northern Irish man with the variant form, broke that pattern. He lived for 10 years after his diagnosis, received experimental treatment with a drug called pentosan polysulfate, and died in 2011.

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• 5. Three Origins

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  An EU study found that "87% of cases were sporadic, 8% genetic, 5% iatrogenic and less than 1% variant." Sporadic CJD arises when a person's own prion protein misfolds spontaneously, with no outside source. Familial CJD comes from an inherited mutation in the PRNP gene, which runs in a family. Iatrogenic CJD is caused by contact with infected tissue during a medical procedure. All types are transmissible, however they began in the first person.

  Variant CJD is a type of acquired disease that people are thought to contract by eating food from animals infected with bovine spongiform encephalopathy, known as mad cow disease. The two forms differ sharply. Classic CJD has a median age at death of 68 years and a median illness of 4-5 months. Variant CJD has a median age at death of 28 years and a median illness of 13-14 months, with prominent psychiatric and behavioral symptoms.

  Among the Fore people of Papua New Guinea, a related prion illness called kuru once spread through funerary cannibalism. The men ate the muscle tissue of the dead, while women and children ate other parts, including the brain. Women and children were therefore more likely than men to contract kuru.

  Surveillance studies from 2005 onward put the global rate at 1-2 cases per million people each year. The disease is found most often in people aged 55-65, and deaths under the age of 30 are extremely rare. A 2020 study noted that sporadic CJD rose in the United Kingdom from 1990 to 2018. Possible reasons include an ageing population, greater clinician awareness, and more accurate diagnosis, along with heavier surveillance prompted by mad cow disease. CJD may also be mistaken for stroke, general dementia, or other conditions.

  In April 2024, a report described two hunters from the same lodge who were found in 2022 to have sporadic CJD after eating deer meat infected with chronic wasting disease. The authors suggested a potential link between the two diseases.

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• 6. Contaminated Instruments

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  The first report of suspected iatrogenic CJD appeared in 1974. Animal experiments showed that the corneas of infected animals could transmit the disease, and that the agent travels along the visual pathways. A second case linked to a corneal transplant was reported without details.

  In 1977, silver electrodes previously used in the brain of a person with CJD were reported to have transmitted the disease. Transmission happened even though the electrodes had been treated with ethanol and formaldehyde. Retrospective studies found four other likely cases. The chance of infection from one contaminated instrument is unknown, but it is not 100%. In some cases, the exposure came weeks after the instrument was used on a CJD patient.

  A review published in 1979 had already counted 25 cases linked to dura mater grafts across nine countries. In the 1980s, a dura mater product called Lyodura was shown to pass CJD from donor to recipient. Canada banned it, yet Japan kept using it until 1993. By 1985, case reports in the United States showed that pituitary growth hormone extracted from cadavers could transmit CJD when injected. Recombinant growth hormone, which carries no such risk, has since replaced it. In 1992, injected human gonadotropin was recognised as another route.

  Australia has documented 10 healthcare-acquired cases. Five patients, treated for infertility or short stature, received contaminated pituitary extract hormone, and no new cases appeared after 1991. The other five received dura mater grafts during brain surgery. New Zealand reported a 1989 case in a 25-year-old man who also received a dura mater transplant.

  In 1988, a man from Manchester, New Hampshire, died of CJD. Massachusetts General Hospital believed he acquired it from a surgical instrument at a podiatrist's office. In September 2013, another Manchester resident was found to have died of the disease three months after brain surgery at Catholic Medical Center. A surgical probe from that operation had been reused. Officials identified thirteen people at three hospitals who might have been exposed, but called the risk "extremely low".

  Routine sterilization may not inactivate prions. The World Health Organization and the US Centers for Disease Control and Prevention recommend destroying instruments used in such cases immediately. If that is not possible, they advise combining heat with chemical decontamination. Detergents and enzymes similar to those in biological washing powders have proved a more practical method of breaking prions down.

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• 7. Proving the Diagnosis

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  Testing for CJD has long been difficult, because early symptoms are vague and brain tissue is hard to obtain safely. Doctors suspect the disease when rapidly worsening dementia appears alongside muscle jerks, trouble with balance and walking, and visual disturbances. An electroencephalogram can show periodic sharp wave complexes, which develop in half of people with sporadic CJD, mostly in later stages.

  Spinal fluid offers more clues. Damaged nerve cells release 14-3-3 and tau proteins into it, and raised levels appear in 90% of prion diseases. Specificity is 95% when symptoms strongly suggest CJD, but only 70% in less typical cases. Strokes, brain inflammation, and seizures can also raise these markers. The real-time quaking-induced conversion assay, known as RT-QuIC, amplifies misfolded PrPSc. Second-generation versions on spinal fluid reach sensitivity of 90-97% and near 100% specificity in sporadic CJD.

  In 2014, a human study showed that a nasal brushing could detect prion protein in olfactory epithelial cells. RT-QuIC can now also be run on nasal swabs and skin biopsies, with reported sensitivities of roughly 90-100%. In 2010, a New York team detected PrPSc in sheep's blood even when it was present at only one part in one hundred billion.

  Magnetic resonance imaging shows a feature called cortical ribboning, in which bright ribbon-like bands appear in the cortex. In patients with rapidly progressive dementia, MRI has 91% sensitivity and 97% specificity. The most common pattern, seen in 60% of cases, involves the cortex and striatum together. In variant CJD, the pulvinar sign, a bilateral bright signal in the thalamus, appears in more than 75% of cases.

  Tissue remains the most definitive evidence, though even a biopsy is not always conclusive. The classic finding is spongiform change, with round vacuoles from one to 50 micrometers across in all six layers of the cerebral cortex. Alzheimer's disease, ischemia, and frontotemporal dementia can also cause vacuolization, but those vacuoles look clear and punched out. Because a biopsy may miss the affected area, a negative result does not rule out CJD. Screening tests to find infected people before symptoms, such as blood donors, are not yet available.

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• 8. The Search for Treatment

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  As of 2025, no cure or effective treatment exists, and care is palliative. Sedatives and antidepressants can ease anxiety and depression. Clonazepam or sodium valproate can calm the myoclonic jerks, and opiates can help with pain. Seizures are very uncommon, but antiepileptic drugs can treat them.

  Pentosan polysulfate may slow progression, and it may have contributed to longer than expected survival in seven people who were studied. The CJD Therapy Advisory Group to the UK Health Departments said the data were not sufficient to support claims of effectiveness. A 2007 review of 26 people treated with it found no proof of efficacy. In 2012, researchers argued that the drug had often been given too late in the illness.

  Quinacrine, a medicine originally created for malaria, was tested in a rigorous UK trial reported in Lancet Neurology. It had no measurable effect on the course of CJD. Amphotericin B and doxorubicin have also been investigated without strong evidence of benefit. Astemizole, a medication approved for human use, showed anti-prion activity. In mice with scrapie, a prion disease, researchers studied RNA interference, which blocks production of the protein that the disease turns into prions.

  Between 2018 and 2022, scientists at University College London gave a monoclonal antibody against prion protein, code-named PRN100, to six people with CJD. The antibody appeared safe and reached the brain. Treated patients still declined, and none lived longer than expected, yet the team called the early results encouraging. They proposed a larger study, ideally starting treatment at the earliest possible point.

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