Prion Disease Flashcards
In which disease was associated with prion?
Spongiform encephalopathy in man.
First reported Prion disease
1920’s: Creutzfeldt and Jakob reported spongiform encephalopathy in man.
Definition of Prion
A prion is a protein that is infectious, causing transmissible spongiform encephalopathy and perhaps other neurologic diseases.
T/F Prion is mainly associated with the nucleic acids
There is no nucleic acid associated with prions.
What do prions resistant to?
Prions are resistant to agents that digest, denature, or modify other proteins.
Infection control to prevent Prion
Inactivation of prion contaminated surgical instruments requires treatment with 1N NaOH or sodium hypochlorite followed by prolonged autoclaving.
Surfaces in contact with infected tissues need to be decontaminated by flooding with 2N NaOH or undiluted sodium hypochlorite for 1 hour, then rinsed with water.
PrP
The abbreviation for prion protein, with its gene PRNP on chromosome 20.
PrPc - exam
The normal cellular prion protein which exists on the surfaces of neuronal cells, non-neuronal brain cells, lymphocytes, red blood cells, platelets, and other cells. It has mostly α-helices in its conformation. (C=cellular).
PrPc- exam
reversibly binds to copper which is involved in endocytosis and neurotransmission.
PrPc
Normal protein c
PrPSc - exam
A misfolded version of PrPc, with many β-helices in its conformation, with the PrPSc able to stack into amyloid fibrils which kill neurons. (Sc=scrapie, a prion disease of sheep)
T/F
PrPSc is able to induce the normal PrPc to convert to PrPSc.
True
PrPSc and Lymphoid Tissue - Exam
Follicular germinal dendritic cells in lymphoid tissue are reservoirs of exogenously acquired PrPSc.
PrPSc transport to the nervous system can occur via axonal transport, e.g., autonomic nerves
PrPc
Normal
a- helices: 43%
b-sheet 0.3%
PrPSc
Misfolded
a-helices: 30%
b-sheet: 43% –> makes it protease resistant
How does PrPSc formed? - exam
PrPc comes into contact with PrPSc (the disease causing protein) which converts the normal protein into a misfolded one
How PrpSc increased in numbers? Exam
The misfolded proteins form fibrils, some of which break apart and induce more PrPc to be converted to PrPSc.
Neuropathology of Prion Disease
The definitive diagnosis of prion disease is based on pathologic examination of brain tissue at autopsy or biopsy, the latter not usually done due to risk of the procedure and the potential exposure risk.
How do get a definite diagnosis of prion disease with neuropathy
pathologic examination of brain tissue at autopsy or biopsy
Microscopic features observed with spongiform invasion
H+E stain showing spongiform changes (vacuoles)
Microscopic features with prion protein
Tissue stained with antibody to PrPSc, demonstrating prion protein
Prion disease in animals called?
Scrapie
Scrapie, definition
Seen in sheep and goats (animals affected scraped against fences)
Bovine spongiform encephalopathy (BSE)
Mad cow disease was seen in cows in 1980’s in the U.K.
Chronic wasting disease (CWD)
Seen in deer, elk, moose, caribou in the U.S.
Chronic wasting disease (CWD) also associated with:
- Camel prion disease
- Transmissible mink encephalopathy
- Feline spongiform encephalopathy
- Ungulate spongiform encephalopathy
Etiologies of Prion Disease in Man
Acquired 1% (Transmitted)
Genetic 14%
(Mutation of prion protein gene PRNP)
Sporadic Creutzfeldt Jakob Disease 85%
(Normal protein spontaneously misfolds)
Sporadic Creutzfeldt Jakob Disease - exam
85%
(Normal protein spontaneously misfolds)
Genetic Prion disease
(% and types )
14%
Mutation of prion protein gene PRNP)
1)Genetic CJD
2) Fatal familial insomnia
3)Gerstmann-Straussler-
Scheinker
Acquired Prion disease
(% and types)
1%
Transmitted
1) Kuru
2) Iatrogenic CJD
3) Variant CJD
Age of Onset of Prion Disease
Lots of variation, but in general
sCJD is seen in later life
gCJD in seen in mid-life
vCJD is seen in early life
Prevalence of Prion Disease
There are 1-2 cases per million individuals per year.
1 of every 7000 deaths in the U.S. is due to prion disease.
In 2019 there were 561 deaths due to CJD reported by the CDC.
Clinical Presentations of sCJD
Cognitive decline 31%
Visual abnormalities 17% (Heidenhain variant)
Affective (mood) issues 15%
Classic CJD (memory and gait
issues with myoclonus) 13%
Ataxia 9% (Oppenheimer - Brownell variant)
Undetermined 15%
Probable sCJD associated at least two of:
1) myoclonus;
2) cerebellar or visual symptoms
3) pyramidal symptoms (weakness) or extrapyramidal symptoms (tremors, Parkinson’s gait);
4) akinetic mutism (lack of voluntary speech and movement)
Probable sCJD associated at least one of: Exam
1) EEG with periodic sharp wave complexes;
2) 14-3-3 in CSF with disease duration under 2 years;
3) MRI with abnormalities of basal ganglia or two cortical regions
Cf. At least two of
● myoclonus;
● cerebellar or visual symptoms;
● pyramidal symptoms (weakness) or extrapyramidal symptoms (tremors, Parkinson’s gait);
● akinetic mutism (lack of voluntary speech and movement)
Survival Time in Sporadic Creutzfeldt-Jakob Disease
Only 20% of patients with sCJD live over 1 year; most die within 4-6 months
MRI Brain in sCJD
Brain MRI is abnormal in 95-98% of patients, but findings can be easily missed or attributed to another diagnosis.
Testing of CSF for Prion Disease
- Markers of brain cell damage
14-3-3: of limited value
Tau: normal around 200
Alzheimer’s :300-500
Prion disease in thousands
Disease specific test - RT-QuIC: detects abnormal prion protein
What are the three testing CSF tools for Prion Disease?
14-3-3- test
Tau test
RT-QulC test
Sensitivity and Specificity of CSF Prion Tests
Sensitivity:
14-3-3: 81%
Tau: 96%
RT-QulC: 95%
Specify:
14-3-3: 43%
Tau: 71%
RT-QulC: 100%
Real-Time Quaking-Induced Conversion (RT-QuIC)
*ThT is thioflavin T which fluoresces when bound to the amyloid fibrils
Currently performed only at the National Prion Disease Pathology Surveillance Center (NPDPSC)
Genetic Prion Disease
A mutation in the gene coding for prion protein PrPc causes an abnormal protein PrPm to be produced which is at risk to misfold into PrPSc.
There are different mutations, each of which has a different penetrance (likelihood) of causing disease, ranging from 0.2% to 88%.
Clinical Manifestations of Genetic Prion Disease - Genetic CJD
Multiple different mutations have been found
Resembles classic sporadic CJD
T/F
Genetic CJD resembles classic sporadic CJD
True
Clinical Manifestations of Genetic Prion Disease- Fatal Familial Insomnia
D178N-129 mutation
Insomnia with neuropsychiatric symptoms and dementia late in the illness
Fatal familial insomnia (FFI)
a rare genetic degenerative brain disorder. It is characterized by an inability to sleep (insomnia) that may be initially mild, but progressively worsens, leading to significant physical and mental deterioration.
Clinical Manifestations of Genetic Prion Disease (Gerstmann-Straussler-Scheinker Syndrome)
Cerebellar signs and symptoms with Parkinsonian features early, dementia later
Long duration (5 or more years)
Diagnostic tests may be negative***
T/F
Kuru disease associated with ataxia and and dementia
True
Acquired Prion Disease-Kuru
Kuru was the first prion disease discovered in human beings in women and children in Papua New Guinea.
Features included dementia and ataxia.
It was caused by the consumption of the brains of deceased persons during death rituals in which women and children would partake in the mortuary feasts of the loved ones who died
The first prion disease discovered in human beings in women and children in Papua New Guinea.
Kuru
Acquired Prion Disease-Iatrogenic CJD
Either brain tissue or CSF must be
placed in the central nervous system (e.g. cadaveric dura mater graft , contaminated EEG probes or neurosurgery instruments);
placed in the body (e.g., corneal transplant or human growth hormone injections);
ingested; or,
transfused (only vCJD).*******
Diagnosis of Acquired Prion Disease-Iatrogenic CJD
We now use synthetic dura mater grafts, laboratory manufactured human growth hormone, and there is vigorous screening of donors of corneas for grafting.
Characteristics of vCJD (Acquired Prion Disease-Variant CJD)
First reported in 1996 in the U.K.
Caused by
1) ingestion of meat contaminated by mad cow disease prion, (BSE), with a few secondary cases related 2) to receipt of blood donated by a patient with vCJD.
The BSE prion is not in muscle but in brain, spinal cord, and lymphoid tissue of the affected cow.
3) Young age of onset (mean 29), perhaps related to greater amount of gut related lymphoreticular tissue in young people
4) Psychiatric and sensory symptoms at onset; then ataxia, movement disorders, and dementia later
5) Longer duration of illness (mean of 14 months for vCJD vs 4-5 months for sCJD)
Characteristics of vCJD (Acquired Prion Disease-Variant CJD) - part 2
1) Low sensitivity of 14-3-3 and Tau and even RT-QuIC (25%), unrevealing EEG
2) MRI with hockey stick sign involving pulvinar nucleus of thalamus
3) Tonsillar biopsy may be useful, as there is a tropism for lymphoid organs (including the tonsils and appendix).
4) Involves protease digestion, then Western blot analysis for PrPSc.
5) All 232 patients to date had contaminated beef from the U.K. or were secondary cases from transfusion of blood of non-leukocyte depleted RBC between 1996 and 1999
T/F
Tonsillar biopsy may be useful, as there is a tropism for lymphoid organs to diagnosis the vCDJ
True
Which prion variant has
low sensitivity of 14-3-3 and Tau and even RT-QuIC (25%), unrevealing EEG
vCJD (Acquired Prion Disease-Variant CJD)
Which prion variant associated with MRI with hockey stick sign involving pulvinar nucleus of thalamus
vCJD (Acquired Prion Disease-Variant CJD)
T/F
Temporal association between the BSE epidemic was lead to outbreak of vCJD.
True
Bovine Spongiform Encephalopathy and vCJD
BSE was first reported in 1986 in the U.K., with the origination not known (possibly from sheep scrapie, or human CJD).
BSE was perpetuated by feeding cattle meat and bone meal, with cases markedly reduced after regulation of feed (dietary protective measures).
T/F
vCJD represents bovine-to-human transmission of BSE.
True
T/F
Transmission of scrapie prions to a non-human primate after an extended silent incubation period was reported:
True
Visual abnormalities % and associated variant?
17% (Heidenhain variant)
Classic CJD (memory and gait issues with myoclonus)
13%
Morbidity of prion disease
Only 20% of patients with sCJD live over 1 year; most die within 4-6 months
What are the three variants of prion disease associated with ataxia
Kuru
Oppenheimer Barownell variant(sCDJ)
Acquired Prion Disease-Variant CJD(vCJD)
T/F
Acquired Prion Disease-Variant CJD (vCJD) caused by Bovine (BSE)
True
T/F
The BSE prion mostly found in muscle neurons which causes ataxia
False
The BSE prion is not in muscle but in brain, spinal cord, and lymphoid tissue of the affected cow
Where do BSE prions infect?
The BSE prion is not in muscle but in brain, spinal cord, and lymphoid tissue of the affected cow
T/F
Scrapie is not transmissible to primates with incubation periods compatible with their life expectancy, although fourfold longer than BSE.
False
T/F
Dementia is one of the early symptoms associated with vCDJ
False
Psychiatric and sensory symptoms at onset; then ataxia, movement disorders, and dementia later
T/F vCJD has shorter duration of illness than sCJDas it seen in early life
False
Longer duration of illness
14 months for vCJD (but early life)
4-5 months for sCJD(but later life)
