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C3 CLINICAL > Clinical Presentations of CJD & Neuroimaging of Human Prion Disease > Flashcards

Clinical Presentations of CJD & Neuroimaging of Human Prion Disease Flashcards

1
Q

What are examples of Transmissible spongiform encephalopathies?

A
  1. Scrapie
    - Sheeps and goats
  2. Transmissible mink encephalopathy
    - Mink
  3. Chronic wasting diseases
    - Mule, deer and elk
  4. Bovine spongiform encephalopathy
    - Domestic cats
  5. Others
    - Zoo animals
  6. Kuru, CJD, Gerstmann-Straussler-Scheinker disease
    - Humans
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2
Q

What are the features of Kuru?

A

• Epidemic disorder of the Eastern island of prominence of Papua New Guinea
• Practiced cannibalism as a ritual – to respect dead
• Known in 1950’s
• Can take Kuru brain and inject into a Chimpanzee and it would die of kuru-like illness
• Pathological material of kuru looks just like sheep-scrapie
• BSE entered the human food chain
- Industrial practice of farming in the 80’s
- Cow died – All the useful tissues been taken off for various human products

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3
Q

What is Prion neuropathology?

A
  1. Spongiosis
    - Holes
    - Vacuoles in dead neurons
  2. Astrocytosis
  3. Neuronal loss
  4. Specific feature: proteinaceous deposits
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4
Q

Normal human prion protein and the prion mechanism:

A
  • Misfolded protein
  • Ability to transmit their misfolded shape onto normal variants of the same protein
  • 253 amino acids
  • 22 axons, open reading frame
  • Entirely within the second axons
  • GPI anchored
  • Largely alpha helical structure (3 helices, 1 disulphide bonds)
  • Sugar moieties - Different protein states, monoglycoslated, un-glycosylated, di-glycosylated
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5
Q

What does fragmentation process create?

A

more substrate for further reaction

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6
Q

What are there different pathological clinical phenotypes for?

A

CJD

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7
Q

Experimentally, how can they be transmitted from generation to generation?

A

By injecting another animal and the animal dies - inject again - form of inheritably of information encoded in the pathogen

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8
Q

What is the abnormal protein?

A

Flexible

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9
Q

What are examples of Human prion disease?

A
  1. Inherited (15%)
  2. Sporadic (85%)
  3. Acquired (rare)
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10
Q

What is Cortico-basal syndrome dominated by?

A

Extrapyramidal symptoms and signs, dyspraxia, asymmetry

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11
Q

What are the features of classical CJD?

A
  1. Global cognitive decline
  2. Cerebellar ataxia
  3. Myoclonus
  4. Motor signs
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12
Q

What are examples of pure cognitive presentation?

A
  1. Executive dysfunction
  2. Expressive dysphasia
  3. Parietal lobe signs, apraxia
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13
Q

Ataxic variant

A

No significant cognitive involvement or myoclonus

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14
Q

What are examples of psychiatric/behavioural presentation?

A
  1. Depression
  2. Withdrawn or aggressive
  3. Delusions and hallucinations
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15
Q

Visual variant

A
  1. Cortical blindness
  2. Hallucinations
  3. Very distressing and rapid clinical course
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16
Q

Sleep/thalamic disordered sleep

A
  1. Disordered sleep

2. peripheral pain and/or sensory disturbances

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17
Q

Stroke-like

A
  1. Highly asymmetrical rapid-onset motor presentation
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18
Q

What are treatable causes that may mimic sCJD?

A
  1. '’Steroid responsive’’ or autoimmune chronic encephalitis NMDA, VGKC
  2. Primary or secondary vasculitis (white matter change)
  3. Viral encephalitis (HIV, HSV, PML)
  4. Hepatic encephalopathy
  5. Neoplastic/paraneoplastic syndromes
  6. Vitamin deficiencies
  7. Drug toxicities
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19
Q

What are other neurodegenerative disorders?

A
  1. AD
  2. Lewy-body dementia
  3. FTD-MND
  4. Others
20
Q

What are the incidence of sporadic and variant CJD?

A
  • 150 cases of human prion diseases a year
  • National specialist services
  • It steadily rises
  • In Europe: rising steadily and increases
  • Variability of better diagnostic tests
  • E.g. UK, Germany, France
21
Q

What has been developped to track the trajectory of CJD very accurately and statistically favourable properties?

A

Developed instruments and questionnaires

  • Record multiple times how severe someone is affected using a tool
22
Q

What is a linear trajectory?

A

Regress rates of progression

23
Q

What do prion protein gene have?

A

a common amino acid polymorphism in it at position 1-29 between amino acid methionine and valine and that is predicted to be in the centre of the abnormal structure

24
Q

If you have methionine only in body

A

homozygous MM- reduce protein that like to adopt a methionine shape – a fold or twist in abnormal form that likes methionine at that residue

25
Q

What are the sporadic CJD: investigations?

A
  1. CSF: raised 14-3-3 protein - 85% sensitive
    - Rt-QUIC - 90% sensitive
  2. EEG: pseudoperiodic sharp wave activity in around 40-50% (serial EEG to demonstrate)
  3. MRI: becoming most valuable test - 90% sensitive (DWI, FLAIR, sequence test)
26
Q

What does diffusivity changes in the cortex relate to?

A

Holes in CJD

27
Q

What are the clinical features of sporadic CJD?

A
  1. Very fast, but doesn’t spread
  2. little peripheral prion infection
  3. Caudate, putamen, cortex, thalamus
  4. Monoglycosylated on Western blot
  5. Transmission to laboratory animals
28
Q

What are the clinical features of variant CJD?

A
  1. Modestly fast, no evidence of ‘‘spread’’
  2. Marked peripheral infection
  3. Stratium, Pulvinar nucleus
  4. Not modified by oral or IV exposure
  5. Diglycosylated on Western
  6. Transmission to laboratory animals
29
Q

What is brighter than thalamus in sporadic CJD?

A

Stratium

30
Q

What is brighter than stratium in variant CJD?

A

Thalamus

31
Q

What does Stratium, thalamus and cortex have in sporadic CJD?

A

95% sensitive

32
Q

Where is white matter disease often observed in?

A

scan and swelling in the T1 scan – in stratium – encephalitis

33
Q

MRI findings are commonly missed at initial report:

A
  • Chances of CJD being reported to local radiologist
  • Differential diagnosis of CJD is only 50%
  • Development of computational tools to prompt a physician assessor of a scan with a rare disease
34
Q

What is the process of RT-QUIC test?

A
  • It is a biofluid biomarker diagnostic
  • There is a prion seed in the biofluid
  • Put it in a reaction mixture that contains recombinant PRP – bacterially produced PRP without any glycosylation at high concentration in various salts and buffers
  • Incubate at 40 degrees and shake
  • Shaking has a structural impact on the aggregates where you form bubbles at the water surface
35
Q

Sonication

A
  • Produce aggressive shearing forces on proteinaceous aggregates
  • By incubation you replicate the prion process
  • With the addition of energy from shaking/sonication – convert all of the recombinant protein into the abnormal form
  • Monitor with dyes
  • Lag time – burst of exponential growth and levels off as substrate is depleted/exhausted
  • This test has a sensitivity of above 90%
36
Q

What is an example of Acquired disease?

A

• BSE-vCJD:

  • The peak of the epidemic related to recycling of cattle back in feed
  • Entire herd were incarnated and buried – probably all infected
37
Q

What are vCJD presenting features?

A
  1. Psychiatric abnormalities

2. Dysaesthesiae

38
Q

What are examples of psychiatric abnormalities?

A
  • Depression, anxiety, social withdrawal, other behavioural change
  • Delusions (complex, unsustained)
  • Hallucinations (auditory or visual)
39
Q

What is dysaesthesiae and pain?

A
  • Usually lower limbs: persistent and unrelated to anxiety level; no sensory signs
40
Q

What are vCJD: later clinical features?

A 
•	Dementia
-	Usually 5-6 months after onset
•	Ataxia
-	6-7 months after onset
•	Myoclonus, chorea, athetosis
-	9 months after onset
•	Akinetic mutism
-	12-14 months after onset
41
Q

What is the biochemical profiles in human prion diseases?

A
  • In each lane, there are 3 bands
  • Western blot is stained with a prion protein antibody
  • The bands are PRP immunoreactive
  • 3 bands = different glycosylation states
  • Different migration rates of 3 bands in different types of sporadic CJD
  • Variant CJD has diglycosylation band
  • Variant CJD shape, strain can accomodate sugars much more effectively than sporadic CJD sugars
42
Q

What does variant CJD have?

A

Different molecular patterns and also deposits in peripheral tissues as well as in the brain

43
Q

Where does variant CJD deposit in?

A

Lymphoreticular tissues

Appendix tissue

44
Q

What is the main concern of variant CJD transmission through?

A
  1. Blood
  2. Blood products
  3. Surgery
  4. Dentistry
  5. Organ donation
45
Q

Inherited Prion Disease

A
  1. Gerstmann-Straussler-Scheinker disease (GSS) typically 102L
    - progressive chronic axtaxia with pyramidal features with a late onset dementia
  2. Fatal Familial Insomnia (FFI) 129m-178N
    - Progressive insomnia, dysautonomia and dementia
  3. Familial CJD typically 200K
    - A spectrum of dementia, myoclonus, ataxia, chorea seizures, amytrophic features
46
Q

When should people have PRNP genotype screening?

A

Due to the phenotypic variability and the occassional atypical histology

Anyone with unexplained ataxia or dementia

C3 CLINICAL (27 decks)

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