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C3 CLINICAL > Pathology of Dementias > Flashcards

Pathology of Dementias Flashcards

1
Q

What is the procedure of Brain donation at Queen Square Brain Bank?

A
  1. Hemi-dissect the brain
  2. Half is placed in Formalin for 3 weeks
  3. The other slice is coronally sliced
  4. Placed on brass plates that have been frozen and stored at -80 degrees
  5. Place the tissue on them, they rapidly freeze
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2
Q

What is the implication of freezing?

A

Maintain morphology of tissue

Use them for either histology or extract DNA/RNA

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3
Q

What is every brain?

A

standardised

Take the same block from different brains - help with diagnosis

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4
Q

What is used to cut the brain into thin sections?

A

Microtome

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5
Q

What are the slides that are placed onto glass slides stained with?

A

Immunohistochemistry

Allows for the abnormalities to turn into colour

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6
Q

What is the process of immunohistochemistry?

A
  1. Process the brain onto wax
  2. Remove all the wax from the sections - with Zyelin
  3. Tag with antibodies that recognise the abnormalities
  4. Use other antibodies that amplify the original abnormalities and tag with chromogen or a dye that is observed under the microscope
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7
Q

What are examples of Neurodegenerative disorders?

A
  1. Alzheimer’s disease
  2. Frontotemporal dementia
  3. Familial British Dementia
  4. Familial Danish Dementia
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8
Q

What are examples of Frontotemporal dementia?

A
  1. Progressive supranuclear palsy (PSP)
  2. Corticobasal degeneration (CBD)
  3. FTLD-TDP
  4. FTLD-FUS
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9
Q

What do we look for down the microscope?

A
  1. Abnormalities - What isn’t normal
  2. Cell types involved (Neurons or glial cells)
  3. Regions of the brain affected
  4. How affected the regions are
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10
Q

What are the two 3 major types that Glial cells are broken down into?

A
  1. Microglia
  2. Astrocytes
  3. Oligodendrocytes
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11
Q

What is microglia used for?

A

Synaptic pruning

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12
Q

What is Astrocytes?

A

Attachs to neurons and the blood vessels

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13
Q

What do oligodendrocytes do?

A

Myelinate the axons

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14
Q

What are neurons?

A

Electrically excitable cells that receives, processes and transmits information through electrical and chemical signals

Messages are transmitted through synapses

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15
Q

What are examples of specialised neurons?

A
  1. Sensory neuron
  2. Motor neuron
  3. Interneurons
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16
Q

What is the structure of the neurons?

A
  1. Cell body
  2. Dendrites
  3. Axon
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17
Q

What are features of astrocytes?

A
  1. Blood-brain barrier
  2. Provide nutrients to nervous tissue
  3. Envelop synapses made by neurons
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18
Q

What are features of Microglia?

A
  1. Resident macrophages
  2. Maintenance of CNS
  3. Inflammation
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19
Q

What do oligodendrocytes do?

A
  1. Support and insulation to axons
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20
Q

What is the most common form of dementia?

A

Alzheimer’s disease

- Clear-cut clinical history of worsening cognition

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21
Q

What is the neuropathology of Alzheimer’s disease?

A
  1. Brain atrophy
  2. Amyloid plaques composed of AB [form clumps around the cell types]
  3. Neurofibrillary tangles composed of Tau [proteins that is built up within the neurons]
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22
Q

What is the percentage of inherited forms of Alzheimer’s disease?

A

<5%

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23
Q

What are the 3 genes involved in Alzheimer’s disease?

A
  1. ABPP (chromosome 21)
  2. Presenilin-1 (14)
  3. Presenilin-2 (1)
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24
Q

What are the genetic risk factors for Alzheimer’s disease?

A
  1. Apolipoprotein E4 allele

2. TREM2 variants

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25
Q

What are the macroscopic features of Alzheimer’s disease?

A
  1. Lateral ventricles are enlarged
  2. Thickness of the cortex is smaller than the normal control [Atrophy or brain shrinkage]
  • Amount of brain tissue that is lost in the frontal cortex compared to the normal control
  • Size of hippocampus enlarged
  • Memory and cognition
26
Q

What is cerebral amyloid angiopathy?

A

Condition in which proteins called amyloid build up on the walls of the arteries in the brain

27
Q

How does CAA increase the risk for stroke?

A

Bleeding and dementia

28
Q

What are the features of AB?

A
  • Produced from cleavage of the amyloid precursor protein (ABPP)
  • Mutations in the ABPP gene cause Alzheimer’s disease (AD), implicating APP metabolism in the pathogenesis of AD
  • Depending on where the mutations in ABPP are located influences the pathological and biochemical hallmarks found
  • There is more deposition of AB in the blood vessels compared to the other mutations where we see more plaques
29
Q

What is Tau?

A
  • A microtubule associated binding protein
  • Six tau isoforms expressed in adult human brain
  • Equal amounts of 3R and 4R tau are found in healthy adults
  • Expression of tau twice as high in grey matter compared to white matter
  • Pathologically tau is hyperphosphorylated
  • Forms abnormal structures visible using electron microscopy
  • Visualised pathologically using tau antibodies
30
Q

What are the neuropathological features of Alzheimers disease?

A
  1. AB extracellular plaques [build up around the blood vessels] - either diffuse or cord plaque
  2. Cerebral amyloid angiopathy (CAA) - AB proteins are deposited within blood vessels
  3. Neurofibrillary tangles - Tau proteins are deposited within the neurons
31
Q

What are the Thal phases?

A 
•	Cut different brain regions
•	Cut different cortical areas 
•	Phase 1
-	Look for amyloid plaques in the frontal temporal parietal and occipital cortex regions
•	Phase 2 
-	Where there is AB deposition in the hippocampus
•	Phase 3
-	AB deposition in the basal ganglia
•	Phase 4
-	AB deposition in the substantia nigra
•	Phase 5
-	AB deposition in the cerebellum
32
Q

What does the progression of neurofibrillary tangles (NFT) pathology of Alzheimer’s disease follow?

A

A pattern that is described by Braak and Braak

33
Q

What is Braak & Braak stages?

A
  1. Stage I-II: NFTs in the mediotemporal lobe structures (entorhinal cortex, transentorhinal cortex, hippocampus)
  2. Stage III-IV: NFTs are prominent in limbic structures
  3. Stage V-VI: NFTs become numerous in isocortex
34
Q

What is the CERAD diagnosis of AD?

A
  • Frequency of the cord plaques, not the diffuse plaques
  • Grade it from sparse, moderate and frequent depending on the number of cord plaques we see in the frontal, temporal and parietal cortices
35
Q

What are clinical features of AD?

A
  1. Group of early onset dementias
  2. Second most-common dementia under the age of 65
  3. Prevalence 15-22/100,000
  4. Equal gender distribution
36
Q

What do AD present with?

A

Three major clinical syndromes:

  1. Behavioural FTD
  2. Semantic dementia (SD)
  3. Progressive non-fluent aphasia (PNFA)
37
Q

What can Frontotemporal dementia overlap with?

A
  1. motor neuron disease/Amyotrophic lateral sclerosis (MND/ALS)
  2. Corticobasal syndrome (CBS)
  3. Progressive supranuclear palsy (PSP)
38
Q

Frontotemporal dementia?

A

Highly heritable

• 30-50% reporting with a positive family history

39
Q

What are the mutations in the three genes for Frontotemporal dementia?

A
  • Progranulin (GRN)
  • Microtubule-associated protein (MAPT)
  • Chromosome 9 open reading frame 72 (C9orf72)
40
Q

3R Tau

A

Exon 10 is spliced out

41
Q

4R Tau

A

Exon 10 is spliced in

The longer form

42
Q

What does 4R Tauopathies encompass?

A

A number of diseases:- Corticobasal Degeneration (CBD)

  • Progressive supranuclear Palsy (PSP)
  • Argyriphilic Grain disease /(AGD)
43
Q

What can cause 4R pathology?

A

Different mutations of Tau gene

44
Q

What is the major pathological features that distinguishes CBD?

A

Astrocytic plaques

45
Q

Progressive Suparanuclear Palsy:

A

• Subthalamic nucleus is quite grey in the normal control
• Superior cerebellar peduncle is atrophied
• Dentate nucleus becomes blurred and discoloured
• Can predict what the underlying pathology is going to be
• Under microscope
- Can see neurofibrillary tangles
- Pathology in the astrocytes
- The cell bodies of astrocyte are affected – Tufted astrocytes
- Top 2 bands as positive

46
Q

What can mutation in the mAPT gene cause?

A

3R or 4R Tau pathology

47
Q

What is TDP-43?

A
  1. Member of heterogenous nuclear ribonucleoproteins (hnRNP) protein family
  2. Contains a nuclear import and export signal
  3. Multifunctional RNA binding protein
  4. RNA transport between intracellular compartments
  5. Human TARDBP gene is located on chromosome 1p36 and encodes a 414-residue protein of 43KDa
48
Q

What are features of FTLD?

A
  1. Many neuronal cytoplasmic inclusions (NCI)
  2. Many short dystrophic neurites
  3. Predominantly layer 2
  4. Ocassional neuronal intranuclear inclusions (NII)
49
Q

What are features of FTLD-TDP type B?

A
  1. Moderate neuronal cytoplasmic inclusions
  2. Few dystrophic neurites
  3. Present in all cortical layers
50
Q

What are features of FTLD-TDP type C?

A
  1. Few neuronal cytoplasmic inclusions
  2. Many long dystrophic neurites
  3. Predominantly layer 2
51
Q

What are features of FTLD-TDP type D?

A
  1. Many neuronal intranuclear inclusion
  2. Few neuronal cytoplasmic inclusion
  3. Many short dystrophic neurites
  4. Present in all cortical layers
52
Q

C9orf72:

A
  • Unique own pathology
  • Sections from hippocampus and cerebellum
  • TDP-43 inclusions are seen however when spanned with p62 which stains any protein that’s tagged to be disposed of – the number far out weighted the number of TDP-43 inclusions
  • They should be mirror images of each other
  • Raised antibodies to the protein that’s formed from the expansion repeat – these inclusions were positive for this protein
  • The p62 were staining all the small inclusions in the cerebellum
  • Cerebellum is full of these inclusions as well
  • C9orf72 didn’t fit into one pathological category
  • It had the type B pathologies which were the more granular type of inclusions that spanned the 6 cortical layers
53
Q

FUS

A
  • Protein found within the nucleus
  • It is involved with shuttling RNA/DNA with nucleus to cytoplasm
  • Mutations are associated only with motor neuron disease or ALS
  • There are 2 cases that are related at the brain bank
  • FUS clumped together in the nucleus and cytoplasm
54
Q

What do FBD and FDD dementia share common features with Alzheimer’s disease?

A
  1. Parenchymal amyloid and preamyloid deposits
  2. Neurofibrillary tangles composed of tau
  3. Widespread inflammatory response
  4. Cerebral amyloid angiopathy
55
Q

FBD and FDD

A
  1. Early onset with mutations in the bRI2 gene
  2. FBD; Stop-to-Arginine mutation producing ABri amyloid
  3. FDD; duplication insertion producing ADan amyloid
56
Q

What are the three pedigrees clinical described for FBD?

A
  1. Worster-Drought pedigreee
  2. Second pedigree in 1996 (1840’s)
  3. Third pedigree with BRI2 mutation
57
Q

What are the onset of symptoms, age at death and features of FBD?

A
  1. Onset of symptoms: 48 years (40-60 years)
  2. Age at Death 56 years (48-70 years)
  3. Dementia, spastic paralysis, mutism and quadraplegia
58
Q

What are the macroscopic observation of FBD?

A
  1. Slightly reduced brain weight
  2. Thickening of the leptomeningeal blood vessels
  3. Mild to moderate diffuse atrophy of cerebral and cerebellar hemispheres
  4. Brainstem and spinal cord appeared normal
59
Q

What are the macroscopic description of FDD?

A
  1. Brain weights were within normal limits
  2. The lateral ventricles were dilated
  3. Thinning of the cortical ribbon and reduction in bulk of the white matter bulk
  4. The hippocampi were reduced in bulk. The brainstem and cerebellum were atrophic
  5. The spinal cord were narrowed in the antero-posterior dimension and on slicing showed yellow discolorination
60
Q

What are the various protein aggregates that dementia is associated with?

A
  1. AB
  2. Tau
  3. TDP-43
  4. FUS
  5. ABri
  6. ADan
61
Q

How is the pathological diagnosis of dementia made by?

A

Identifying specific morphological changes and also the biochemical/genetic abnormalities

62
Q

What is the importance of clinico-pathological studies?

A

To refine the pathological diagnosis earlier in life for when disease modifying therapies are available

C3 CLINICAL (27 decks)

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