Prion Disease

Question 1

In which disease was associated with prion?

Answer 1

Spongiform encephalopathy in man.

Question 2

First reported Prion disease

Answer 2

1920’s: Creutzfeldt and Jakob reported spongiform encephalopathy in man.

Question 3

Definition of Prion

Answer 3

A prion is a protein that is infectious, causing transmissible spongiform encephalopathy and perhaps other neurologic diseases.

Question 4

T/F Prion is mainly associated with the nucleic acids

Answer 4

There is no nucleic acid associated with prions.

Question 5

What do prions resistant to?

Answer 5

Prions are resistant to agents that digest, denature, or modify other proteins.

Question 6

Infection control to prevent Prion

Answer 6

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.

Question 7

PrP

Answer 7

The abbreviation for prion protein, with its gene PRNP on chromosome 20.

Question 8

PrPc - exam

Answer 8

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).

Question 9

PrPc- exam

Answer 9

reversibly binds to copper which is involved in endocytosis and neurotransmission.

Question 10

PrPc

Answer 10

Normal protein c

Question 11

PrPSc - exam

Answer 11

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)

Question 12

T/F
PrPSc is able to induce the normal PrPc to convert to PrPSc.

Answer 12

True

Question 13

PrPSc and Lymphoid Tissue - Exam

Answer 13

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

Question 14

PrPc

Answer 14

Normal
a- helices: 43%
b-sheet 0.3%

Question 15

PrPSc

Answer 15

Misfolded
a-helices: 30%
b-sheet: 43% –> makes it protease resistant

Question 16

How does PrPSc formed? - exam

Answer 16

PrPc comes into contact with PrPSc (the disease causing protein) which converts the normal protein into a misfolded one

Question 17

How PrpSc increased in numbers? Exam

Answer 17

The misfolded proteins form fibrils, some of which break apart and induce more PrPc to be converted to PrPSc.

Question 18

Neuropathology of Prion Disease

Answer 18

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.

Question 19

How do get a definite diagnosis of prion disease with neuropathy

Answer 19

pathologic examination of brain tissue at autopsy or biopsy

Question 20

Microscopic features observed with spongiform invasion

Answer 20

H+E stain showing spongiform changes (vacuoles)

Question 21

Microscopic features with prion protein

Answer 21

Tissue stained with antibody to PrPSc, demonstrating prion protein

Question 22

Prion disease in animals called?

Answer 22

Scrapie

Question 23

Scrapie, definition

Answer 23

Seen in sheep and goats (animals affected scraped against fences)

Question 24

Bovine spongiform encephalopathy (BSE)

Answer 24

Mad cow disease was seen in cows in 1980’s in the U.K.

Question 25

Chronic wasting disease (CWD)

Answer 25

Seen in deer, elk, moose, caribou in the U.S.

Question 26

Chronic wasting disease (CWD) also associated with:

Answer 26

1. Camel prion disease 2. Transmissible mink encephalopathy 3. Feline spongiform encephalopathy 4. Ungulate spongiform encephalopathy

Question 27

Etiologies of Prion Disease in Man

Answer 27

Acquired 1% (Transmitted) Genetic 14% (Mutation of prion protein gene PRNP) Sporadic Creutzfeldt Jakob Disease 85% (Normal protein spontaneously misfolds)

Question 28

Sporadic Creutzfeldt Jakob Disease - exam

Answer 28

85% (Normal protein spontaneously misfolds)

Question 29

Genetic Prion disease (% and types )

Answer 29

14% Mutation of prion protein gene PRNP) 1)Genetic CJD 2) Fatal familial insomnia 3)Gerstmann-Straussler- Scheinker

Question 30

Acquired Prion disease (% and types)

Answer 30

1% Transmitted 1) Kuru 2) Iatrogenic CJD 3) Variant CJD

Question 31

Age of Onset of Prion Disease

Answer 31

Lots of variation, but in general sCJD is seen in later life gCJD in seen in mid-life vCJD is seen in early life

Question 32

Prevalence of Prion Disease

Answer 32

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.

Question 33

Clinical Presentations of sCJD

Answer 33

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%

Question 34

Probable sCJD associated at least two of:

Answer 34

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)

Question 35

Probable sCJD associated at least one of: Exam

Answer 35

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)

Question 36

Survival Time in Sporadic Creutzfeldt-Jakob Disease

Answer 36

Only 20% of patients with sCJD live over 1 year; most die within 4-6 months

Question 37

MRI Brain in sCJD

Answer 37

Brain MRI is abnormal in 95-98% of patients, but findings can be easily missed or attributed to another diagnosis.

Question 38

Testing of CSF for Prion Disease

Answer 38

1. 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 2. RT-QuIC: detects abnormal prion protein

Question 39

What are the three testing CSF tools for Prion Disease?

Answer 39

14-3-3- test Tau test RT-QulC test

Question 40

Sensitivity and Specificity of CSF Prion Tests

Answer 40

Sensitivity: 14-3-3: 81% Tau: 96% RT-QulC: 95% Specify: 14-3-3: 43% Tau: 71% RT-QulC: 100%

Question 41

Real-Time Quaking-Induced Conversion (RT-QuIC)

Answer 41

*ThT is thioflavin T which fluoresces when bound to the amyloid fibrils Currently performed only at the National Prion Disease Pathology Surveillance Center (NPDPSC)

Question 42

Genetic Prion Disease

Answer 42

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%.

Question 43

Clinical Manifestations of Genetic Prion Disease - Genetic CJD

Answer 43

Multiple different mutations have been found Resembles classic sporadic CJD

Question 44

T/F Genetic CJD resembles classic sporadic CJD

Answer 44

True

Question 45

Clinical Manifestations of Genetic Prion Disease- Fatal Familial Insomnia

Answer 45

D178N-129 mutation Insomnia with neuropsychiatric symptoms and dementia late in the illness

Question 46

Fatal familial insomnia (FFI)

Answer 46

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.

Question 47

Clinical Manifestations of Genetic Prion Disease (Gerstmann-Straussler-Scheinker Syndrome)

Answer 47

Cerebellar signs and symptoms with Parkinsonian features early, dementia later Long duration (5 or more years) Diagnostic tests may be negative*******

Question 48

T/F Kuru disease associated with ataxia and and dementia

Answer 48

True

Question 49

Acquired Prion Disease-Kuru

Answer 49

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

Question 50

The first prion disease discovered in human beings in women and children in Papua New Guinea.

Answer 50

Kuru

Question 51

Acquired Prion Disease-Iatrogenic CJD

Answer 51

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).*********

Question 52

Diagnosis of Acquired Prion Disease-Iatrogenic CJD

Answer 52

We now use synthetic dura mater grafts, laboratory manufactured human growth hormone, and there is vigorous screening of donors of corneas for grafting.

Question 53

Characteristics of vCJD (Acquired Prion Disease-Variant CJD)

Answer 53

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)

Question 54

Characteristics of vCJD (Acquired Prion Disease-Variant CJD) - part 2

Answer 54

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

Question 55

T/F Tonsillar biopsy may be useful, as there is a tropism for lymphoid organs to diagnosis the vCDJ

Answer 55

True

Question 56

Which prion variant has low sensitivity of 14-3-3 and Tau and even RT-QuIC (25%), unrevealing EEG

Answer 56

vCJD (Acquired Prion Disease-Variant CJD)

Question 57

Which prion variant associated with MRI with hockey stick sign involving pulvinar nucleus of thalamus

Answer 57

vCJD (Acquired Prion Disease-Variant CJD)

Question 58

T/F Temporal association between the BSE epidemic was lead to outbreak of vCJD.

Answer 58

True

Question 59

Bovine Spongiform Encephalopathy and vCJD

Answer 59

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).

Question 60

T/F vCJD represents bovine-to-human transmission of BSE.

Answer 60

True

Question 61

T/F Transmission of scrapie prions to a non-human primate after an extended silent incubation period was reported:

Answer 61

True

Question 62

Visual abnormalities % and associated variant?

Answer 62

17% (Heidenhain variant)

Question 63

Classic CJD (memory and gait issues with myoclonus)

Answer 63

13%

Question 64

Morbidity of prion disease

Answer 64

Only 20% of patients with sCJD live over 1 year; most die within 4-6 months

Question 65

What are the three variants of prion disease associated with ataxia

Answer 65

Kuru Oppenheimer Barownell variant(sCDJ) Acquired Prion Disease-Variant CJD(vCJD)

Question 66

T/F Acquired Prion Disease-Variant CJD (vCJD) caused by Bovine (BSE)

Answer 66

True

Question 67

T/F The BSE prion mostly found in muscle neurons which causes ataxia

Answer 67

False The BSE prion is not in muscle but in brain, spinal cord, and lymphoid tissue of the affected cow

Question 68

Where do BSE prions infect?

Answer 68

The BSE prion is not in muscle but in brain, spinal cord, and lymphoid tissue of the affected cow

Question 69

T/F Scrapie is not transmissible to primates with incubation periods compatible with their life expectancy, although fourfold longer than BSE.

Answer 69

False

Question 70

T/F Dementia is one of the early symptoms associated with vCDJ

Answer 70

False Psychiatric and sensory symptoms at onset; then ataxia, movement disorders, and dementia later

Question 71

T/F vCJD has shorter duration of illness than sCJDas it seen in early life

Answer 71

False Longer duration of illness 14 months for vCJD (but early life) 4-5 months for sCJD(but later life)