Creutzfeldt-Jakob Disease (CJD)

CJD is a fatal brain disease first classified in the

1920’s; CJD was named after H.G. Creutzfeldt and A.
Jakob who first described the disorder.

CJD is thought to be a prion-related disease that

affects the gray matter of the central nervous
system.

CJD is one of five prion diseases known to affect

humans (CJD, Gerstmann-Straussler-Scheinker
Disease, Kuru, nvCJD and fatal insomnia). These
were first known as “transmissible spongiform
encephalopathies.” They may be transmitted
between humans and animals and often leave the
brain riddled with holes giving it a spongy
appearance.

A prion is similar to a virus, only it has a smaller level

of nucleic acid. It is not a microorganism as is a
bacterium, but rather a particle.

As many as 13% of Alzheimer patients were found

upon autopsy to have had CJD instead.
The formation of vacuoles within brain tissues gives rise to
spongiform degeneration. (A) During the early stages of
CJD, brain tissues begin to form vacuoles that range from
5mm to 20mm. (B) The brain tissue in the later stages of
CJD have vacuoles that range from 50mm to 70mm.
http://www.arches.uga.edu/~steph116/figure2.htm
Microscopy of the normal brain (top left) shows dark-
staining neurons in the cerebral cortex with no spongy
change in surrounding tissue. In classical CJD (top
right), brain cortex contains numerous small vacuoles
that give a spongelike appearance. In new-variant CJD
(bottom left), the cortex shows less severe sponginess
but contains "florid" plaques--aggregates of amloid
material surrounded by spongy change. Florid plaques
in new-variant CJD (bottom right) stain intensely for
prion protein (brown).
Courtesy of James W. Ironside, National CJD Surveillance Unit

http://pubs.acs.org/hotartcl/cenear/980209/micro.html
Immunohistochemistry of cerebral cortex and hippocampal
regions of transgenic mouse brain showing abnormal PrP
immunoreactivity, including PrP-positive florid plaques
(enlarged in insets).

(A) vCJD-inoculated 129MM Tg35 mouse.

(B) BSE-inoculated 129MM Tg35 mouse.

(C) vCJD-inoculated 129MM Tg45 mouse.

(D) BSE-inoculated 129MM Tg45 mouse.
http://embojournal.npgjournals.com/cgi/content/full/21/23/6358/CDF653F1
Small, intense foci of disease-associated PrP positivity within
the intracranial vessels in sporadic Creutzfeldt-Jakob
disease visualized by the PET blot technique (a). These
intense clustered deposits appear to follow a linear pattern of
labeling (b). The control section for these in which the
antibody was omitted is shown in (c). Magnification, x60.
http://ajp.amjpathol.org/cgi/content/full/161/6/1979/F2

Comparison of Classic Viruses and Prions

Virus Prion
Filterable, infectious Yes Yes
agents
Presence of Nucleic Yes Yes but very
Acid small
Defined Morphology Yes No
by electron
microscopy
Presence of protein Yes Yes
Disinfection by: Yes No

Formaldehyde Some No

Proteases Most No

Heat (80°C) Yes No

Cytopathological Yes No
effect
Incubation period Depends on Long
virus
Immune response Yes No
Interferon production Yes No
Inflammatory Yes No
response

http://www.fortunecity.co.uk/roswell/psychic/24/prionpage/Project.htm
Disease-associated prion protein (PrP) deposits in vessel walls. a:
PrP immunoreactivity (IR) (indicated by an arrow) in the media of
basilar artery in sporadic Creutzfeldt-Jakob disease (sCJD) (3F4;
magnification, x100; enlarged in right upper corner, magnification,
x750). b: Perivascular PrP IR (left side of picture; 12F10;
magnification, x750) correlates with CD68 IR (right side of picture;
magnification, x750) in variant CJD (vCJD). c: Extensive PrP IR
throughout an intracerebral (basal ganglia) vessel wall in vCJD (3F4;
magnification, x500). d: PrP IR in the outer part of the media in
extracranial carotid artery in vCJD (6H4; magnification x200; enlarged
in right upper corner, magnification, x750). e: PrP IR (left side of
picture; 3F4; magnification, x200) in a deep perforating artery in sCJD
correlates with CD68 IR (right side of picture; magnification, x200). f:
PrP IR (left side of picture; 3F4; magnification, x200) in a deep
perforating artery in sCJD correlates with HLA-DR IR (right side of
picture; magnification, x200).
http://ajp.amjpathol.org/cgi/content/full/161/6/1979/F1
 Prions are infectious proteins noted by a change in
the 3-dimensional shape of the normal prion protein
in the brain. The prion then converts normal protein
in the brain to pathogenic prions by binding to them.

The propagation of infectious prion protein occurs via conversion of

normal prion protein (PrPc, left) to a disease-causing form (PrPSc, right).
In the refolding process, some of the -helical regions (purple coils) in
PrPc unfold, forming an extended ß-sheet region (flat blue arrows).
Courtesy of Fred Cohen, UCSF
http://pubs.acs.org/hotartcl/cenear/980209/prop.html
 Differences Between Classic Creutzfeldt-Jakob
Disease (CJD) & Variant Creutzfeldt-Jakob
Disease (vCJD)
CJD:
Classic CJD was first discovered in 1920.
Occurs most commonly in individuals between the
ages of 55 and 75.
Found in 1 of 1 million persons per year
(approximately 200 cases per year in the U.S.).

vCJD:
There have been about 153 confirmed cases of vCJD.

In 1996, a variant of the Classic CJD, vCJD, was

reported 9 years after the discovery of BSE (Bovine
Spongiform Encephalopathy, aka Mad Cow Disease).
The strain of prion disease that causes vCJD in
humans is identical to the strain that causes BSE
typically seen in cattle. This suggests that vCJD
results from exposure to the agent that causes BSE.
Exposure is likely via consumption of meat from
cattle infected with BSE.
Worldwide, there have been >200,000 known cases
of cattle diagnosed with BSE.

Clinical Signs of BSE in Cattle:

 Changes in temperament (nervousness or

aggression)
 Abnormal posture
  Incoordination and difficulty rising
 Decreased milk production
 Loss of body condition, despite continued
appetite

Incubation Period:

 2 – 8 years; once symptoms present, death

occurs usually within 2 weeks to 6 months.

Diagnosis:

 Post mortem microscopic examination of brain

tissue
 Post mortem tests to detect the partially-
proteinase resistant form of prion protein

Transmission:

 Feed that contains infected animal byproducts

Clinical signs of CJD in people:

 Disorientation/General confusion
 Personality changes
 Insomnia
 Depression
 Difficulty walking
 Rapid progressive dementia
 Visual impairment
Advanced stages –
 Monoclonus (involuntary contraction of limb as with
knee jerk)
 Loss of recognition of familiar objects or people
  Difficulty with speech and language

Incubation period:
 As long as 20 years (depending on type of CJD)
Diagnosis:
 EEG (electrical activity of brain is abnormal and shows
periodic sharp wave discharges)
 MRI (high signal changes in deep brain structures such
as basal ganglia & thalamus)
 Lumbar puncture to test for presence of 14-3-3 protein

The tests above can only lead to speculative diagnosis;

100% confirmation of diagnosis may be reached by:

 Post mortem brain tissue biopsy

Transmission:
 Mutation in gene coding (Sporadic & Familial CJD)
 Contaminated neurosurgical instruments (Iatrogenic
CJD)
 Contaminated human organs or hormones
 Contaminated meat
 Blood (though a very low risk)
GENETIC (or FAMILIAL) CJD
Account for about 10 – 15% of CJD cases.

In this form, CJD is caused by an inherited abnormal gene.

The illness is therefore not "caught" in any way and there is no causal
relationship between this form and BSE.

In most cases, the illness is known within the family because of the
family history. Occasionally, genetic cases are seen in which no
previous family history is identified.

IATROGENIC CJD
There are only a few deaths per year due to iatrogenic CJD.
This is CJD which has been accidentally transmitted during the
course of medical or surgical procedures.

The most important example of this in the United Kingdom relates to

CJD transmitted via Human Growth Hormone treatment in childhood.

SPORADIC CJD
Sporadic CJD is numerically the most common form of CJD
(approximately 80 – 85% of CJD cases).

It affects about one person per million of the population. There are
therefore some fifty to sixty deaths per year due to sporadic CJD in
the United Kingdom. Similar figures are seen in other countries such
as Australia, Canada and the USA.

The cause of sporadic CJD remains uncertain. The most favored

theory suggests that the normal prion protein in the brain undergoes
a spontaneous change to the abnormal form, resulting in disease. If
this theory is correct (and it has not been proven) then the disease
arises simply as a chance event inside the brain. On this basis, it
would not be "caught" in any way.

It tends to affect middle-aged and elderly people.

VARIANT CJD (vCJD)
vCJD accounts for approximately 5% of confirmed CJD cases.

Variant CJD was first reported in 1996.

The current view on variant CJD is that it has resulted from

transmission of infection from BSE in cattle to humans via infectivity
in food.

Average age of onset is 27 years of age.

Symptoms of vCJD tends to last longer than those of sporadic CJD.