LM 2.8: Cellular Neuropathology

Question 1

which neurological cells are most susceptible to injury?

Answer 1

neurons

they are the most metabolically active and require the most oxygen so when there’s a cardiac problem, neurons are usually the first to go

Question 2

in which diseases are oligodendrocytes selectively injured in?

Answer 2

1. multiple sclerosis
2. leucodystrophies
3. autoimmune attacks like acute disseminated encephalomyelitis (ADEM)
4. infections like progressive multifocal leucoencephalopathy (PML) which is often caused by JC virus

Question 3

which neurological cells are most resistant to injury?

Answer 3

astrocytes

they’re the last things to go like if you have a stroke, what’s left is usually astrocytes that show reactive changes to survive the stroke that killed everything else

Question 4

which region of the brain is selectively vulnerable in global ischemia?

Answer 4

excitotoxic injury to the hipopocampal neurons –> this is because all the other neurons that are dying send signals to the hippocampus and kill them from overstimulation = excitotoxic

there’s also selective injury to cerebellar Purkinje cells

Question 5

which region of the brain is selectively vulnerable in Huntington?

Answer 5

caudate nucleus and putamen

Question 6

which region of the brain is selectively vulnerable in Parkinsons?

Answer 6

substantia nigra of the basal ganglia

Question 7

which region of the brain is selectively vulnerable in amyotrophic lateral sclerosis?

Answer 7

motor neurons

Question 8

what is Nissl substance?

Answer 8

stacks of rough ER in the body of the neuron

they look like dark blue clumps in the body of the neuron (blue because they’re acidic)

Question 9

how can you tell an astrocyte on an H&E stain?

Answer 9

doesn’t have a small nucleus like the oligodendrocyte

Question 10

how do you know if a neuron is dead in an H&E stain?

Answer 10

if it’s red and you can’t see the nucleolus it’s dead!

also the nucleus will be small

Question 11

what is central chromatolysis?

Answer 11

this is what happens to a neuron when you damage or cut off it’s axon; it’s unique to the brain

a neuron exists to send signals down the axon so without the axon it’ll try to repair the damage and you’ll see some histologic changes in the neuron:

1. margination of nissl substance with central clearing of the cytoplasm = all the nissle substance is on the edges of the cell body and the middle off the cell is all clear cytoplasm = central chromatolysis

so the cytoplasm is being filled with smooth ER which is going to rebuild the axon and it’s shoving aside the rough ER which is usually there to make proteins and ship them down the axon for signaling

2. peripheral displacement of the nucleus because the smooth ER is pushing it out of the way too!

Question 12

what are axonal swellings?

Answer 12

if you damage or break an axon, there will still be stuff going down the axon and once it gets to the breaking point of the axon you’ll get a pile up that looks like a balloon

so this occurs at axonal breakage points but it doesn’t last for too long

it’s usually following closed-head trauma due to a stretching and snapping of long fibers (like with shaken baby syndrome)

there are also some diseases that can cause axonal swelling that’s not due to trauma; instead it’s because the transport doesn’t happen correctly and the stuff that’s supposed to be transported just piles up –> usually due to cerebellar degenerations

it can also be caused by vitamin E deficiency (rare)

Question 13

what can cause axonal swellings?

Answer 13

1. trauma
2. neuronal degeneration; usually cerebellar
3. vitamin E deficiency

Question 14

what do you see in an H&E stain of an axonal swelling?

Answer 14

a little pink ball that’s a swollen damaged axon

Question 15

what are neuronal inclusions?

Answer 15

something inside the neuron that shouldn’t be there!

Question 16

what 3 conditions can cause neuronal inclusions?

Answer 16

1. viral
   ex. herpes, rabies, CMV, measles can form a virus wad in the axon = viral inclusion

remember the Guarnari bodies from pox virus?? this is them! they’re extranuclear inclusions!

2. neurodegenerative diseases cause filaments to pile up in the neuron and cause filamentous inclusions
   ex. neurofibrillary tangle, Lewy body, Pick body
3. neuronal storage diseases –> there’s an enzyme that’s supposed to be degrading something but it’s abnormal so the substance doesn’t get broken down and it piles up

Question 17

which viruses specifically attack the meninges?

Answer 17

1. coxacki
2. echo
3. mumps

Question 18

which viruses specifically attack the temporal lobes?

Answer 18

herpes simplex

Question 19

which viruses specifically attack the dorsal ganglia?

Answer 19

herpes zoster

lies dormant in the dorsal ganglia and reemerge to give you shingles

Question 20

which viruses specifically attack the motor neurons?

Answer 20

1. poliovirus

2. west nile

Question 21

which virus specifically attacks the cholinergic neurons?

Answer 21

rabies

rabies starts out in a muscle peripherally and then it travels retrograde up the neuron to get to the brain and it does this by having this tropism for cholinergic neurons which are what are going down and innervating the muscles

Question 22

which viruses specifically attack the oligodendrocytes?

Answer 22

JC virus –> leads to PML

Question 23

which diseases can cause filamentous inclusions? what is the specific name for each filamentous inclusion associated with the specific disease?

Answer 23

1. Alzheimers = neurofibrillary tangle (large, flame-shaped)
2. Pick disease = Pick body (large)
3. Frontotemporal dementia = TDP-43 inclusion (small)
4. dementia with Lewy bodies = cortical Lewy body (small)
5. Parkinson’s = classic brainstem Lewy body (large)

Question 24

which diseases are neuronal metabolic storage diseases?

Answer 24

1. glycogenoses (Pompe)
2. sphingolipidoses (Tay-Sachs)
3. sulfatidoses (Gauchers, Niemann-Pick)
4. mucopolysaccharidoses (Herler)

Question 25

what is the trans-synaptic degeneration of neurons?

Answer 25

it’s secondary degeneration of a neuron connected to a dying neuron that is totally unique to the CNS

so if there’s a neuron that doesn’t have other neurons to talk to, it’ll just give up and die – this can happen in an antegrate or retrograde fashion

this is pretty hard to do though unless you’re in a dedicated tract like the optic tract that synapses at exactly one neuron so they’re not connected to millions of cells and you could kill them easily like when you lose an eye

it’s potentially reversible if you can reconnect the neuron

Question 26

what are the types of oligodendroglial inclusions?

Answer 26

1. viral

2. filaments

Question 27

which virus can cause a viral oligodendroglial inclusions?

Answer 27

PML caused by JC virus or papova virus

on an H&E stain, chromatin is pushed to the rim and the cytoplasm looks smudgy purple because it’s all virus!!

Question 28

what can cause filamentus oligodendroglial inclusions?

Answer 28

glial cell inclusions can occur in some non-Alzheimer neurodegenerative diseases like corticobasal degeneration or multiple system atrophy, etc.

Question 29

what do oligodendrocyte inclusions look like?

Answer 29

oligodendrocytes looks like there are whispy brown extensions attached to them

Question 30

what can astrocytes do when everything else has been damaged?

Answer 30

1. gliosis
2. rosenthal fibers
3. glial cytoplasmic inclusions
4. make cytokines

Question 31

what is gliosis?

Answer 31

hypertrophy and hyperplasia with synthesis of glial filaments

this is the brain equivalent of a scar

Question 32

what are rosenthal fibers?

Answer 32

swellings of processes with heat-shock proteins

they look like cork screws in H&E stains and are bright pink – kind of hard to tell they have anything to do with astrocytes but they are swellings of astrocytes!

Question 33

how can astrocytes make cytokines in response to injury?

Answer 33

so they interact with the immune system to some extent

they react to injury and have some paraimmune function

Question 34

what are gemistiocytic astrocytes?

Answer 34

they’re enlarged astrocytes as a response to injury

they also have processes extending from them that look like stars; hence astrocytes

these are activated astrocytes after they’re responded to injury! eventually they can form a gliosis which is a brain scar

Question 35

what do astrocytes do in Alzheimers?

Answer 35

they surround the alzheimers plaque to try and bock it off by forming filaments and engulfing it!

Question 36

what is the function of microglia?

Answer 36

they are the innate immune system of the brain

they come from bone marrow in embryologic life so they’re immigrants to the brain after development and they stay there forever

they’re the CNS equivalent of macrophages and they form the brains first line of immune response

they respond to challenge with:
1. hypertrophy and hyperplasia

2. production of cytokines = IL-1, TNF-alpha
3. phagocytosis

they can also be seen inside Alzheimer’s plaques!

Question 37

what do microglia do when they’re not responding as macrophages?

Answer 37

synaptic remodeling

Question 38

what do microglia look like on an H&E stain?

Answer 38

irregular looking dark pink circles that you can only see in a specific immunohistochemistry stain that is specific for IL-1 that’s being released by the microglia

Question 39

what are the 3 main metabolic brain disorders?

Answer 39

1. hypoglycemia
2. hyperglycemia
3. hepatic encephalopathy

Question 40

what is the effect of hypoglycemia on the brain?

Answer 40

low blood sugar that is honestly similar to the same effects hypoxia causes because neurons require both glucose and oxygen

so if you have an insulin overdose you can get neuron damage

Question 41

what is hyperglycemia effect on the brain?

Answer 41

dehydration affects brain function because high sugar draws water out of the brain and dehydrates it

overly rapid rehydration can actually cause cerebral edema! brain swelling causes terrible problems because there’s nowhere for the swelling to go inside the skull

Question 42

what is hepatic encephalopathy?

Answer 42

if you have liver failure, ammonia starts to break down in the blood = hyperammonemia

this leads to confusion and can progress to coma

Question 43

what are the 2 main toxic disorders associated with the brain?

Answer 43

1. ethanol
2. methanol
3. carbon monoxide
4. radiation
5. combined methotrexate and radiation injury

Question 44

what is the toxic effect of ethanol on the brain?

Answer 44

massive, acute ethanol intoxication can cause cerebral swelling and death

unclear if ethanol alone has any chronic effects on the CNS

however fetal exposure to ethanol has severe neurologic deficits

associated nutritional deficiencies likely cause cerebellar dermal atrophy and WK syndrome

Question 45

what is the toxic effect of methanol on the brain?

Answer 45

retinal degeneration that can lead to blindness

bilateral necrosis of the putamen (basal ganglia)

Question 46

what is the toxic effect of carbon monoxide on the brain?

Answer 46

similar to hypoxic injury because CO2 kicks oxygen off of the RBCs since it has a higher affinity

bilateral necrosis of the globus pallidus can occur (basal ganglia)

delayed demyelination can also occur if you survive CO poisoning but this is rare

Question 47

what is the toxic effect of radiation on the brain?

Answer 47

this can happen following radiotherapy for a malignant brain tumor

radionecrosis of the brain is due to endothelial injury with fibrinoid degeneration of vessel and thrombosis

radiation mainly effects the cells that are dividing so why does it effect the brain? it injures blood vessels because they’re mitotically active

the blood vessels on H&E look hot pink = fibrinoid necrosis

Question 48

what is the toxic effect of combined methotrexate and radiation injury?

Answer 48

it’s white matter necrosis that can occur months after exposure to methotrexate/radiation

so methotrexate exacerbates the effects of normal radiation