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Prion Diseases. CMED 526/EPI 526 - May 6 th , 2009 Robert Harrington, DVM, PhD USDA – Agricultural Research Service UW – Dept. of Comparative Medicine Transmissible Spongiform Encephalopathies~Prion Disease. NORMAL. ABNORMAL. PrP c. PrP d. -helix rich.

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Prion Diseases

CMED 526/EPI 526 - May 6th, 2009

Robert Harrington, DVM, PhD

USDA – Agricultural Research Service

UW – Dept. of Comparative Medicine

transmissible spongiform encephalopathies prion disease
Transmissible Spongiform Encephalopathies~Prion Disease





-helix rich

-sheet rich

Prusiner, et al.

prp conversion
PrP Conversion




tse pathogenesis
TSE Pathogenesis
  • Transmission occurs by oral route
  • PrPd localizes to regional lymphoid tissue
    • Transient in some species
  • Migration to central nervous system
    • Retrograde along nerves
    • Blood-borne transport
  • Accumulation in brain with subsequent neurodegeneration
  • Postmortem
    • Microscopic pathology
    • Immunohistochemistry
    • ELISA, Immunoblotting
    • Bioassay
  • Antemortem
    • Same techniques as above applied to:
    • Brain biopsy
    • Tonsil, lymph node, third eyelid biopsy, or rectal
    • ? Blood test ?

Figure 3: Photomicrographs illustrating increased diameter and density of vacuoles in TME positive IC recipient (top row, a, b, c), as compared to CWD positive IC recipient, (middle row, d, e, f) and absence of lesions in CWD negative IC recipient (bottom, row, g, h, i). Left column = cerebral cortex, middle column = hippocampus, right column = thalamus. All sections stained with hematoxylin and eosin. Bar=100 µm.

animal prion disease
Animal Prion Disease
  • Scrapie - sheep, goats
  • Chronic Wasting Disease (CWD) - deer, elk, moose
  • Bovine Spongiform Encephalopathy (BSE) - cattle
  • Transmissible mink encephalopathy (TME) - mink
  • Feline spongiform encephalopathy - large & domestic cats
  • Spongiform encephalopathy of captive ungulates - exotic hoof-stock in zoological parks
human prion disease
Human Prion Disease
  • Sporadic
    • Creutzfeldt-Jakob disease (CJD)
  • Familial (genetic)
    • Familial CJD
    • Gerstman-Straussler-Scheinker Syndrome (GSS)
    • Fatal Familial Insomnia (FFI)
  • Acquired by transmission
    • Kuru
    • Iatrogenic CJD (neurosurgical instruments, dura mater grafts)
    • Variant CJD (vCJD)

Human PrP Mutations

Jackson, G S et al. Mol Pathol 2001;54:393-399

transmission within species
Transmission Within Species

vertical and horizontal

in utero, fetal fluids, fetal membranes



Oral (urine, feces, or blood?)


Direct only through bite wounds


Foodborne (MBM)

No direct transmission

from cow to cow

Foodborne, blood,

tissue transplant, HGH, instruments

species barrier concept
Species Barrier Concept
  • Transmission within a species may occur readily
  • Barrier between species limits transmission
    • Inefficient transmission
    • Extended incubation times
    • Low or non-existent rate of disease
  • Serial passage
    • Required to overcome species barrier
    • Progressive reduction in incubation time
    • Increased rate of disease
transmission between species
Transmission Between Species


recognition of bse
Recognition of BSE
  • Late 1985: Unusual neurologic disease in UK cattle
  • Insidious onset
    • Irritabilty, agression
    • Motor system impairment (ataxia)
    • Difficulty in rising (e.g. “downer cow”)
    • Decreased milk production
    • Wasting
    • Death
  • Predominantly dairy cattle
    • Feeding practices
    • Relative herd age
  • Neuropathology similar to Scrapie
    • Vacuolation, PrPd, astrocytosis, Scrapie associated fibrils
cause of bse
Cause of BSE
  • Ruminant tissue in food chain
    • Meat and bone meal (MBM)
    • Scrapie
    • Sporadic BSE in cattle
  • Alternative theories
    • Human tissue?
    • Toxin?
    • Environmental?
    • Other?
bse epidemic
BSE Epidemic
  • ~180,000 cumulative cases in UK
  • Peaked at 37,000 cases per annum in 1992
  • Recycling of ruminant tissue in food chain implicated
  • Progressive decline with introduction of feed bans


Transmissible Spongiform Encephalopathy as a Zoonotic Disease, Brown, P., et. al. ILSI, March 2003

spread of bse epidemic
Spread of BSE Epidemic
  • 1990: Domestic BSE detected in Switzerland, imported cases in Portugal
  • 1999: 7 other EU countries with domestic BSE
  • Jan 2000 to Oct 2002: 11 additional EU countries
  • 2001: BSE detected in Japan
  • 2002: BSE detected in Israel
  • 2003: BSE in Canadian cow
bse in the united states
BSE in the United States
  • 30-40 million cattle slaughtered/year
  • 1997: ban on feeding US cattle meat-and-bone meal
  • 3 cases to date - RARE!
    • 2003: 6.5yo dairy cow imported from Canada
    • 2004: 12yo beef cow born and raised in Texas
    • 2006: 10yo beef cow in Alabama uncertain origin
    • Were there previously unrecognized cases?
bse in the united states23
BSE in the United States
  • 2003: Additional measures post WA BSE case
    • “downer” cattle excluded from human consumption
    • Ban on SRM from animals >30 months of age from human consumption
    • Ban on mechanically-separated meat
new variant cjd
New variant CJD
  • Unusual form of neurologic disease in teenagers and young adults
  • Spongiform encephalopathy
  • Neuropathology not consistent with sporadic forms of CJD
  • Stimulus for US National Prion Disease Center
percent distribution of non iatrogenic uk vcjd and us cjd deaths by age group 1995 2005
Percent distribution of non-iatrogenic# UK vCJD and US CJD deaths, by age group, 1995-2005


# Excludes blood transfusion-associated vCJD and pituitary hormone- or dural graft-associated CJD

* UK vCJD deaths, including UK-related nonresident cases, 1995-2003 (Will, RG; personal communication, 2004)

** US CJD deaths, 1995- 2001.


Western Blots

Jackson, G S et al. Mol Pathol 2001;54:393-399

bse vcjd link
  • New variant disease that differs from classical CJD
    • Similarities to BSE
    • Geographically related to areas of BSE
    • Hypothesis: consumption of contaminated beef products
  • Epidemiologic curve
  • Animal challenge studies
  • Molecular biology
bse and vcjd
BSE and vCJD

Hilton, 2006. J of Pathology, 208:134

animal challenge studies
Animal Challenge Studies
  • BSE → primates ≈ vCJD → primates
    • Similar lesions and biochemistry
  • Transgenic mice
    • BSE → humanized mice
    • vCJD → bovinized mice
    • Lesions, biochemistry of BSE ≈ vCJD regardless of mouse type
    • Both differ from sCJD

Western Blots

Jackson, G S et al. Mol Pathol 2001;54:393-399

continuing us cattle surveillance
Continuing US Cattle Surveillance
  • USDA National Veterinary Services Laboratory
    • AAVLD certified labs, refer positives to NVSL
  • If 1 case per 1 million slaughter then 95% CI requires:
    • All slaughters = 2,995,731
    • Suspect cattle = 40,000 (neuro signs, fallen, “downers”)
    • 45,803 samples in 2007
    • Meets OIE “controlled risk” classification
  • National animal ID system
continuing us human surveillance
Continuing US Human Surveillance
  • National Prion Disease Center
    • Established 1996
  • Monitoring for unusual trends in mortality data
  • ↑ # of autopsies in US, ↑ # of referrals
  • CJD monitoring in CWD endemic areas
cwd to humans
CWD to Humans?
  • CJD flatline in endemic areas
  • Challenge studies indicate natural transmission is unlikely
    • Cattle
    • Mink
    • Humanized Tg mice
cwd risk reduction
CWD risk reduction?
  • Hunting
    • Avoid endemic areas
    • Test animals in effected areas
  • Consumption
    • Don’t eat brain, nerves, spleen, lymph nodes, or eyes
    • Avoid composite foods (sausage, head cheese)
  • Prion diseases vary by species, distinct differences
  • TSE transmission usually limited to within a species
  • Only Scrapie and CWD are readily transmissible
  • Species barrier limits transmission between species
Do you think this study supportsthe association of beef consumption as a primary risk factor for development of vCJD?

Did the study authors take adequate measures to address the limitations to the study design?What other measures could they have considered?