Neurodegenerative Pathology facts

Question 1

What are the genes that when you see them you must think Alzheimers?

Answer 1

Mutations in three key genes, presenilin-1, presenilin-2, and APP, predispose to early-onset Alzheimer’s disease. The possession of an apolipoprotein ε4 allele is a risk factor for late-onset Alzheimer’s disease.

Question 2

What is the macroscopic/gross appearance of alzheimers brain?

Answer 2

Macroscopic appearance of brain in AD. (picture of brain with shriveled temporal lobe and really big sulci)
The pattern of atrophy typically seen in AD is characteristic, but not specific for the disease. In this case the leptomeninges have been stripped from one half of a brain to show the regional atrophy clearly.
(a) Lateral view showing severe atrophy of the temporal lobe with less severe atrophy of the parietal and frontal lobes. The occipital lobe is spared.

Question 3

On histology, you see lots of white, big dots. They are obviously vacuoles. What do you think?

Answer 3

Alzheimers, or some type of diffuse neuronal death degen disease.
Severe neuronal loss from the cortex in AD, with associated astrocytic gliosis, results in irregular coarse vacuolation termed status spongiosus.

Question 4

You see a histology slide characterized by status spongiosus and you think?

Answer 4

Alzheimers, or some type of diffuse neuronal death degen disease.
Severe neuronal loss from the cortex in AD, with associated astrocytic gliosis, results in irregular coarse vacuolation termed status spongiosus.

Question 5

What is the silver impregnation stain used for?

Answer 5

Palmgren silver impregnation in AD.
*good for neurofibrillary tangles, but not specific for amyolid plaque build-up
Silver impregnation of cerebral cortex reveals a plaque and NFTs. This type of stain is not sensitive to amyloid, seen in the center of the plaque as a yellow background, but is good for detecting NFTs and plaque-related neurites.

Question 6

Phosphorylated Tau immunostaining is good for what?

Answer 6

NFT tau immunostaining.
Immunostaining with antisera to phosphorylated tau protein is increasingly used as a routine method for detecting NFTs.
Staining will detect established NFTs, as well as pretangles – dispersed small aggregates of tau that are probably precursors of NFTs.
Many extracellular (‘ghost’) NFTs are, however, not immunoreactive for tau.

Question 7

What exactly are neurofibrillary tangles?

Answer 7

Bundles of paired helical filaments in the cytoplasm of neurons that displace or encircle the nucleus
Filaments are primarily composed of hyperphosphorylated forms of the protein tau (normally involved in microtubule assembly)

Question 8

On an HandE stained slide, what does an amyloid plaque look like?

Answer 8

Plaques in AD.
(d) Mature plaque. In sections stained with hematoxylin and eosin, neuritic plaques are seen as an ill-defined area of condensation in the neuropil with an eosinophilic plaque core.
Nuclei of microglial or astrocytic cells may be seen radiating around the plaque periphery.

Question 9

On immunostaining for neuritic plaques, what is the common finding?

Answer 9

(c) Classic (mature) or neuritic plaques. These are extracellular, roughly spherical, focal aggregates of amyloid material, 60–120μm in diameter, that are often separated into dense core and peripheral halo regions.
* Neuronal cell processes traversing the plaque are prominent on silver staining and appear enlarged and distorted.
* Immunostaining (see (g)) shows processes containing tau protein, some of which are unequivocally neuronal, but others may be astroglial. There may be associated reactive astrocytes as well as activated microglial cells.

Question 10

What are you looking for on histology of cerebral amyloid angiopathy?

Answer 10

31.4 AD cerebral amyloid (congophilic) angiopathy. (a) In hematoxylin and eosin stained sections, as here, the vessels affected by amyloid are thick-walled and have a homogeneous pink appearance.

Question 11

What special technique confirms presence of cerebral amyloid angiopathy?

Answer 11

31.4 AD cerebral amyloid (congophilic) angiopathy. (c) The amyloid nature can be confirmed by polarizing light microscopy, which reveals apple-green birefringence and dichroism. (Congo red, polarized light)

Question 12

In what order is a-beta laid down in plaques in the brain?

Answer 12

1 – neocortex
2 – medial temporal lobe
3 – basal ganglia and diencephalon
4 – brainstem
5 – cerebellum

Question 13

What are the “ABCs” of a neuropathologists grading of alzheimers?

Answer 13

An “ABC” score to describe AD neuropathologic changes:
A - Thal phase of the extent ofAmyloid deposition
B - Braak and Braak neurofibrillary stage
C - Neuritic plaque density score of CERAD

Examples:
A1 B1 C1 = Thal phase 1 or 2, Braak NFT stage 1 or 2, CERAD “sparse”
A2 B2 C2 = Thal phase 3, Braak NFT stage 3 or 4, CERAD “moderate”
A3 B3 C3 = Thal phase 4 or 5, Braak NFT stage 5 or 6, CERAD “frequent”

Question 14

Aphasia is an important clinical classifcation of what degen disease?

Answer 14

FTLD - frontotemporal lobar dementia

Question 15

What protein is often implicated in cases of FTLD?

Answer 15

TAR-DNA binding protein 43
TDP-43 is a major constituent of ubiquitin positive inclusions in both FTLD and ALS
TDP-43 inclusions are usually associated with mutations in progranulin, a growth factor secreted in response to injury and/or inflammation

Question 16

what are the macroscopic/gross features of pick’s disease?

Answer 16

(a) Lateral view of brain. There is sharp demarcation (arrow) between the atrophic frontal lobe and the posterior part of the cerebrum. Temporal atrophy is moderate in this case.

Question 17

You can see Pick bodies on HandE stain. What do they look like?

Answer 17

Pick bodies: well demarcated round, slightly basophilic inclusions in neuronal cytoplasm
They are shown here in the amygdala.

Question 18

What is another helpful stain to see pick bodies?

Answer 18

Silver impregnation of Pick bodies in neurons of the hippocampal dentate gyrus will show bright black spots in the neurons’ cytoplasm

Question 19

Immunostaining for phosphorylated Tau will have what appearance in Picks disease (FTD)?

Answer 19

The tau is not uniformly long and through the whole neuron. They form the Pick bodies, which are really small and discrete balls of phosphorylated tau

Question 20

What are the macroscopic/gross features of ALS in the spinal cord?

Answer 20

The upper motor (anterior) roots appear
normal while the lower cervical anterior
roots are severely atrophic.
*in the brain you see Shrinkage of part of the precentral gyrus in severe amyotrophic lateral sclerosis

Question 21

A histology slide of the spinal cord will show what changes in severe ALS?

Answer 21

loss of neuronal density in the anterior horn of the spinal cord. reflects loss of alpha motor neurons

Question 22

There is a neuronal body found in ALS. what is it?

Answer 22

27.4 Neuronal inclusion bodies in ALS seen on hematoxylin and eosin staining. (a) Bunina bodies (arrow) are small eosinophilic inclusions, 2–5µm in diameter. They are often arranged in small beaded chains and are sparse in most ALS cases.

Question 23

what immunostaining technique is ALS specific?

Answer 23

27.5 Ubiquitin-immunoreactive neuronal inclusions in ALS. (a) These skeins of thread-like structures are the commonest ubiquitin-immunoreactive neuronal inclusions in ALS.

Question 24

What are the really classic pathology findings of parkinsons disease?

Answer 24

Depigmentation of the substantia nigra and locus ceruleus
‘Pigment incontinence’ and pigmentophagy
Neurons in these regions contain eosinophilic intracytoplasmic round inclusions: Lewy bodies

Question 25

What proteins in particular might you immunostain for in parkinsons disease?

Answer 25

(genetics of parkinsons)
PARK1 – alpha-synuclein (4q21-q22): AD
PARK2 – Parkin (6q25.2-q27) AR juvenile
PARK 3 through 11 – some AD, some AR, with differing ages of onset

Question 26

If you are shown a histology slide and you see obvious lewy bodies, what clinical history do you need to differentiate the other possible disease besides parkinsons?

Answer 26

*dementia with lewy body disease - DLB
*different progression with :
Progressive cognitive decline
Fluctuating cognition with pronounced variations in attention and alertness
Recurrent visual hallucinations that are usually well-formed and detailed
Spontaneous features of parkinsonism

• histology shows: Lewy bodies in substantia nigra in DLB. Lewy bodies and pale bodies are seen in residual neurons of the substantia nigra. The appearances are identical to those in Parkinson’s disease.

Question 27

What are you looking for on gross evaluation of a brain to dx Huntingtons?

Answer 27

Progressive degeneration of the striatum (caudate and putamen) and frontal cortex with neuronal loss and gliosis

Question 28

The gross atrophy of the basal ganglia in huntingtons looks like what on histology?

Answer 28

30.3 (a) Rarefaction and gliosis of the putamen in HD of moderate severity. The smaller neurons are mostly lost, but some of the large neurons (arrow) are spared, as is usual until quite late in the disease. The smaller neurons normally outnumber the large neurons by 150–250-fold.