Creutzfelt-Jacob Disease (CJD)

1
Creutzfelt-Jacob Disease(CJD)

• A transmissible spongiform encephalopathy or
  prion disease

2
CJD and TSEs

• Creutzfelt-Jacob disease (CJD) is one of a small
  group of disease classified as transmissible
  spongiform encephalopathies (TSEs)

• The leading hypothesis is that TSEs are not
  transmitted by microbes or viruses, but are
  spread by specific misshaped proteins, given the
  name prion proteins

3
CJD and TSEs

• At present, only 6 human man diseases are thought
  to be caused by prion proteins Creutzfelt-Jacob
  disease, new variant CJD (vCJD),
  Gertmann-Straussler-Scheinker syndrome, fatal
  familial insomnia, kuru, and possibly Alpers'
  disease.

4
CJD and TSEs

• There are up to 25 prion diseases that have been
  identified in animals, including scrapie (sheep),
  bovine spongiform encephalopathy (cattle), and
  chronic wasting disease (deer elk).

5
History of CJD and prion diseases

• 5th Century BC
• Hippocrates described disease with symptoms
  similar to TSE that was occurring in sheep and
  cattle
• 4th and 5th Century AD
• Similar disease was recorded by the Roman Renatus
• 1755
• Great Britains House of Commons discussed the
  epidemic of scrapie in sheep
• 1759
• There were unsupported claims scrapie might be
  contagious

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History of CJD and prion diseases

• Early 20th Century
• Despite earlier failures in attempting to show
  transmission of scrapie, it was finally proven
  through the intraocular injection of infected
  nervous tissue from diseased sheep, to healthy
  sheep, which then developed the disease.
• First instance showing transmissibility of TSEs.
• 1921
• The first described case of disease that became
  known at Creutzfeldt-Jakob disease
• 1950s and 60s
• The disease kuru was described and was shown to
  be transmitted via cannibalism.
• Scrapie-Iike lesions were found the brains of
  kuru victims.
• Kuru and CJD shown to be transmissable to
  chimpanzees.

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History of CJD and prion diseases

• 1980s Stanley Prusiner put forth the hypothesis
  that that a protein was responsible for the
  transfer of the disease
• 1988 Neuropathology, bovine spongiform
  encephalopathy (BSE), AKA mad cow disease was
  described in cows
• Late 1980s the prevalence of BSE in British
  cattle caused concerns that BSE might be
  transferable to humans. BSE believed to result
  from scrapie jumping species to cows
• 1990s a new disease similar to CJD and kuru
  called new variant CJD was found in humans who
  had been exposed to BSE infected cattle or their
  products.

8
Case Study

• Patient had a surgical procedure in 1971, at age
  38.
• Determined to be the most likely source of the
  infection, after CJD diagnosis
• Occurred before prion hypothesis or before it was
  believed the infectious agent was resistant to
  sterilization techniques
• Long incubation period
• The malformed prion protein induces refolding of
  normal proteins like itself
• Slow process at first (exponential growth)
• Much longer replication times than microbes
• It takes time to build up the levels of
  mis-folded prion protein in neural tissue
• CJD first suspected 1.5 months after first
  consulting physicians (11 weeks after first
  symptoms)
• CJD diagnosis at 2 months
• Diagnostic Tests
• Electroencephalograph
• Cerebrospinal fluid analysis for 14-3-3 protein
• MRI of the brain

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Case Study

• Final stages of disease progression (months 5 6)
• Profound dementia
• Loss of speech, nearly complete inability to move
• Treatment focused on comfort measures, symptom
  management, sedation, and prevention of
  opportunistic infections in hospital
• Death, age 68, occurred 25 weeks after first
  seeking medical help for symptoms (31 weeks after
  first signs and symptoms)
• Cause of death was pneumonia due to inability to
  clear lungs
• Infection of others?
• Because of knowledge of CJT being passed by
  prions, appropriate precautions were taken
  clinically and post mortem, so it is unlikely
  that others were infected after the acute stage
  of the disease. Transmissibility is believed to
  be low during incubation period. The patient was
  not a blood or tissue donor before or after onset
  of symptoms, which would have been been a risk
  for transmission.

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Etiologic Agent Pathophysiology

• The infectious agent in Creutzfeldt-Jacob disease
  (CJD) is a mis-folded protein. This malformed
  protein has fewer alpha-helices and more
  beta-sheets than the normal protein.

Exposure to the malformed prion protein, can
induce correctly folded proteins of the same
type, to re-fold into the mutant form of the
protein.
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Etiologic Agent Pathophysiology
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Etiologic Agent Pathophysiology

• The disease state results from build-up of the
  malformed protein in neural tissues which kills
  neural cells.
• Incubation period can range from months to
  decades.
• The death of the nerve cells and glial cells is
  the cause of all signs and symptoms of CJD and
  other TSE diseases.
• Most instances of CJD are sporadic, occur in
  people with no known risk factors or gene
  mutations unknown source
• Some cases of CJD are transmitted by exposure to
  prion-contaminated instruments, tissues, serum,
  hormones, etc, from individuals with CJD -
  known or suspected source

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The Leading Hypothesis

• Protein-only hypothesis
• The protein is believed to be the sole infectious
  agent.
• It induces its own replication by causing
  conformational (folding) changes in normal
  proteins

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The 2 Competing Hypotheses

• Multi-component hypotheses
• Proposes prion protein is the infectious agent
  for the disease
• Also proposes that more than just the mutated
  prion protein is required cofactors also
• Cofactors may include lipids and nucleic acids
  (but no genomic information contributes to the
  disease)
• Cofactors may form part of the prion or serve as
  catalysts for the refolding of normal proteins
• Viral hypothesis
• Postulates that an infectious virus causes the
  disease
• Support for this hypothesis is waning
• Mostly a holdover of the long-held belief that a
  virus must be responsible for this type of disease

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Related Human Prion Diseases

• There are 2 inherited human prion diseases, fatal
  familial insomnia and Gertmann-Straussler-Scheinke
  r syndrome. These diseases are caused by the
  inheritance of mutations in the PRNP gene from a
  parent. The mutation results in a prion protein
  being made which folds incorrectly without
  exposure to malformed proteins.
• There are believed to be cases of the hereditary
  TSEs that resulted from random point mutations in
  the PRNP gene, rather than being present in the
  genes of a parent.
• The human disease new variant CJD (vCJD) is
  caused by exposure to cows (or their products)
  that were infected with the prion disease bovine
  spongiform encephalopathy (BSE) commonly known as
  mad cow disease.

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Pathology

• Human prion disease share 4 characteristics
• 1 spongiform changes in brain tissues lesions
  leave holes in tissue making it appear spongy
• Neuronal loss death of neuron cells
• Astrocytosis death of glial cells
• Amyloid plaque formation some features are
  found in animal prion diseases

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Clinical Signs and Symptoms of CJD

• Personality changes
• Psychiatric problems (depression)
• Lack of coordination and control
• Ataxia
• Involuntary jerky movements
• Unusual sensations
• Insomnia
• Confusion
• Memory problems
• Final stages of the disease
• Dementia
• Loss of ability to speak
• Loss of ability to move
• Eventual death

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Virulence Factors

• While not true virulence factors as we see in
  microbial diseases, there are several
  characteristics of all prion diseases which
  facilitate their transmission.
• Long incubation periods (months to decades)
• No signs or symptoms during incubation
• So far, no way of detecting the mutated prion
  protein in living individuals
• Examinations of brain tissue after death is only
  sure way to confirm CJD and other TSEs
• Research is working on promising technology which
  may solve this

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Virulence Factors

• Documented Zoonotic infection of animal TSE
  diseases to humans
• Scrapie may be the origin of BSE
• BSE is the causative prion for new variant CJD
• Chronic wasting disease (deer elk) is being
  watched closely to see if it jumps to humans.
  Hunter are given advise to reduce any risk from
  game animals they harvest
• Prion proteins are highly stable very resistant
  to usual sterilization procedures
• Boiling, autoclave, cooking and other heat
  sterilization methods dont denature the prion
  protein
• Irradiation dose not denature the prion protein
• Special proteases, bleach, acid baths followed by
  autoclaving seem effective
• We dont know how long mutated prion proteins
  persist on surfaces or in contaminated tissues.
• Some TSE may be transmissible thru aerosols (tiny
  droplets)

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Modes of Transmission

• CJD is mostly a sporadic disease. No mode of
  transmission is proven to account for common form
  of the disease.
• New variant CJD (nvCJD)is believed to occur in
  humans as a result of exposure to bovine
  spongiform encephalopathy
• A hereditary form of CJD (fCJD) occurs as a
  result of an inherited defective gene that
  promotes the misfolding of the prion protein with
  no exposure to malformed proteins
• Exposure or consumption of tissues from animals
  with any TSE is considered a risk factor
• Nervous tissue (brain and spinal cord) have
  highest concentration of prion proteins

21
Diagnostic Procedures

• Electroencephalograph
• Cerebrospinal fluid analysis for 14-3-3 protein
• MRI of the brain
• Brain Biopsy
• Autopsy, post mortem

22
Prevention Measures

• Feeding of rendered mammal proteins to mammals in
  human food chain (sheep, goats, cows, farmed
  deer, elk, etc) has been banned in most developed
  countries
• Brain and spinal cord are separated from carcass
  early in butchering process
• Hunters in CWD affected areas are advised to bone
  out meat and avoid contact of meat with any
  nervous tissue.
• Elimination of cannibalistic funerary practices
  in New Guinea contributed to the end of kuru
  epidemic

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Treatment of CJD

• No known cure, therapy or vaccine for TSE
  diseases
• Treatment of the disease is primarily limited to
  treatment of symptoms and palliative care
• Study of kuru suggests there may have been
  resistance factors in some individuals in the
  population
• Active research in all avenues of treatment is
  ongoing

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Prevalence of CJD

• 102 cases in Oregon (1991-2009) an avg. of 5.7
  per year)
• About 1 case per million people, per year, in the
  US of the common (sporadic) form of CJD
• About 1 case per million people, per year, world
  wide

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Why is this an important disease to study?

• CJD and all other known prion diseases are fatal
• Evidence suggests that prion diseases can jump
  species
• Humans have contact with most of these species
• BSE is still occasionally discovered we eat
  lots of beef
• Because of long incubation period, epidemics
  could become wide spread, before signs of disease
  start appearing
• The Prion hypothesis was one of the most
  significant and controversial biological
  proposals in the modern era of biology

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References

• Articles, books
• Belay, E. (1999). Transmissible spongiform
  encephelopathies in humans. Annual Review of
  Microbiology, 53, 238-314. Retrieved from
  http//www.cdc.gov/ncidod/dvrd/prions/resources/Be
  layE_Annu_Rev_Microbio.pdf
• Cowan, M., Bunn, J. (2013). Microbiology
  fundamentals A clinical approach. (pp. 477-478).
  New York McGraw-Hill.
• Webpages
• CJD (creutzfeldt-jakob disease, classic). (n.d.).
  Retrieved from http//www.cdc.gov/ncidod/dvrd/cjd/
  index.htm
• Creutzfeldtjakob disease. (n.d.). Retrieved from
  http//en.wikipedia.org/wiki/Creutzfeldt-Jakob_dis
  ease
• Oregon Health Authorty. (2009, Sept 28). Oregon
  reprted deaths fromm creutzfeldt-jacob disease,
  1991- present. Retrieved from http//public.health
  .oregon.gov/DiseasesConditions/DiseasesAZ/bse/Docu
  ments/cjdeath.pdf
• Prion. (n.d.). Retrieved from http//en.wikipedia.
  org/wiki/Prion
• Prion diseases. (n.d.). Retrieved from
  http//www.cdc.gov/ncidod/dvrd/prions/
• Transmissible spongiform encephalopathy. (n.d.).
  Retrieved from http//en.wikipedia.org/wiki/Transm
  issible_spongiform_encephalopathy
• vCJD (variant creutzfeldt-jakob disease). (n.d.).
  Retrieved from http//www.cdc.gov/ncidod/dvrd/vcjd
  /index.htm

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Photos, Illustrations

• Deyo, S., Deyo, H. (Producer). (2001). CJD USA
  map. Print Photo. Retrieved from
  http//www.millennium-ark.net/News_Files/Newslette
  rs/News010113/News010113C.html
• (n.d.). Major regions of the human brain affected
  by tse. Web Graphic. Retrieved from
  http//whyfiles.org/193prion/3.html
• (n.d.). Normal to abnormal protein. Web
  Graphic. Retrieved from http//memory.ucsf.edu/cj
  d/overview/biology/proteins/multiple/cause
• (n.d.). Plaques from creutzfeldtjakob disease in
  the brain.. Web Photo. Retrieved from
  http//thedallasgeek.com/2010/07/31/creutzfeldtja
  kob-disease-cjd/
• (n.d.). Prion theory. Web Photo. Retrieved from
  http//lawrencekok.blogspot.com/2011/04/ib-biology
  -microbes-proteins-and-prions.html
• (n.d.). Prion graphic, mayo foundation. Web
  Graphic. Retrieved from http//thedallasgeek.file
  s.wordpress.com/2010/07/r7_prion.jpg
• (n.d.). Prions, image 1 and image 2. Web
  Graphic. Retrieved from http//www.stanford.edu/g
  roup/virus/prion/2004anderson/index.html
• (n.d.). Deer with chronic wasting disease (cwd).
  Web Photo. Retrieved from http//www.prwatch.org
  /news/2012/05/11500/media-coverage-mad-cow-usda-ca
  lls-misleading-columbia-journalism-review-calls-sa
  n
• (n.d.). sheep. Web Photo. Retrieved from
  http//upload.wikimedia.org/wikipedia/commons/3/3d
  /Take_ours!.jpg
• (n.d.). madcow2. Web Photo. Retrieved from
  http//www.topsecretwriters.com/2011/11/mad-cow-di
  sease-bse/madcow2/

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