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Flashcards in LEC-3 Neuropathology Deck (72):

The principal functional unit of the CNS is...?



Describe acute neuronal injury.

  • "Red neurons"
  • Acute CNS hypoxia/ischemia cause cell death by either necrosis or apoptosis. "Red neurons" are evident with H&E 12-24 hrs after irreversible hypoxic insult.
  • The morphologic features consist of cell body shrinkage, pyknosis of nucleus, disappearance of nucleolus, loss of Nissl, intense eosinophilia of cytoplasm.


Describe subacute and chronic neuronal injury.

  • "Degeneration" - Neuronal death occurs due to a progressive disease process (e.g. ALS).
  • Characteristic histologic feature: cell loss (often of functionally related groups of neurons) and reactive gliosis.
  • Early on, cell loss is not evident, but associated reactive glial changes are the best indicator of pathology.
  • Cell loss mainly due to apoptosis.


In the context of subacute and chronic neuronal injury what is neuronal trans-synaptic degeneration?

Seen when there is a destructive process that interrupts the majority of the afferent input to a group of neurons.


What is the axonal reaction?

The reaction within the cell body that attends regeneration of the axon; best seen in anterior horn cells of the spinal cord when motor axons are cut or seriously damaged.


What are the features of the axonal reaction?

Increased protein synthesis associated with axonal sprouting; enlargement and rounding up of cell body, peripheral displacement of nucleus, enlargement of nucleolus, dispersion of Nissl from center to periphery of cell (central chromatolysis).


Neuronal inclusions may occur as a manifestation of aging, when there are intracytoplasmic accumulations of complex lipids (___________).



Abnormal cytoplasmic deposition of complex lipids and other substances also occurs in ___________________________ in which substrates or intermediates accumulate.

genetically determined disorders of metabolism


Viral infection can lead to abnormal intranuclear inclusions, as seen in __________.

Herpetic infection


Viral infection can lead to abnormal cytoplasmic inclusions, as seen in _______.

Rabies. (Negri body)


Viral infection can lead to abnormal nuclear AND cytoplasmic inclusions, as seen in _______.

Cytomegalovirus (CMV) infection


Some degenerative diseases of the CNS are associated with neuronal intracytoplasmic inclusions, such as neurofibrillary tangles of _______ and Lewy bodies of _______.

  • Alzheimer disease
  • Parkinson disease


Other degenerative diseases of the CNS are associated with abnormal vacuolization of the perikaryon and neuronal cell processes in the neuropil (seen in _______).

Creutzfeldt-Jakob disease


Why are these disorders referred to as proteinopathies?

  • Because the aggregates are highly resistant to degradation, contain proteins with altered conformation, and may result from mutations that affect protein folding, ubiquitination, and intracellular trafficking.
  • In many of these diseases, the visibile aggregates are not the basis of cellular injuries; rather, small multimers of the proteins (oligomers) are the critical mediatiors of the damage.


What cell type derives its name from its star-shaped appearance?



Astrocytes have multipolar, branching cytoplasmic processes that emanate from the cell body and contain ___, a cell type-specific intermediate filament.

Glial fibrillary acidic protein (GFAP)


What is the function of astrocytes?

Astrocytes act as metabolic buffers and detoxifiers within the brain.


Besides the metabolic buffer and detoxifier function of astrocytes, what other function do astrocytes serve (through their foot processes)?

The foot processes surround capillaries or extend into the subpial and sub ependymal zones, where they contribute to BARRIER functions controlling the flow of macromolecules between blood, CSF, and brain.


What is the most important indicator of CNS injury?

Gliosis (or astrogliosis) is the most important histopathologic indicator of CNS injury, regardless of etiology, and is characterized by both hypertrophy and hyperplasia.


Describe what happens to astrocytes in the astrogliosis reaction.

  • The nuclei of astrocytes, which are typically round to oval (10 um wide) with evenly dispersed, pale chromatin become enlarged, vesicular, and develop prominent nuclei.
  • The previously scant cytoplasm expands to a bright pink, irregular swath around an eccentric nucleus, from which emerge numerous stout, ramifying processes.


Astrocytes that have undergone the astrogliosis reaction are called...?

Gemistocytic astrocytes


When directly injured, astrocytes can react with...?

Cytoplasmic swelling


What direct astrocyte injuries can lead to cytoplasmic swelling?

Acute insults that cause the cell's ATP-dependent ion channels to fail, as in hypoxia, hypoglycemia, and toxic injuries.


Describe the Alzheimer type II astrocyte.

A gray-matter cell with a large (two to three times normal) nucleus, pale-staining central chromatin, an intranuclear glycogen droplet, and a prominent nuclear membrane and nucleolus.


Why is the name Alzheimer type II astrocyte a misnomer?

It is mainly not seen in Alzheimer disease but in individuals with long-standing hyperammonemia due to chronic liver disease, Wilson disease, or hereditary metabolic disorders of the urea cycle.


Astrocytes are not spared from processes that cause the formation of cytoplasmic inclusion bodies. What are Rosenthal fibers?

Thick, elongated, brightly eosinophilic, somewhat irregular structures that occur within astrocyte processes, and contain two heat-shock proteins (alphabeta-crystallin and hsp27) as well as ubiquitin.


In what conditions are Rosenthal fibers observed?

Rosenthal fibers are typically found in regions of long-standing gliosis; they are also characteristic of one type of glial tumor, pilocytic astrocytoma.


In Alexander disease, a leukodystrophy associated with a mutation in the gene encoding GFAP, abundant Rosenthal fibers are found in periventricular, perivascular, and subpial locations. More commonly seen are...?

Corpora amylacea (or polyglucosan bodies)


What are corpora amylacea?

Round, faintly basophilic, periodic acid-Schiff (PAS) positive, concentrically lamellated structures of 5-50 um diameter that are located wherever there are astrocytic end processes, especially in subpial and perivascular zones.


What do corpora amylacea consist of, primarily?

Glycosaminoglycan polymers, and heat-shock proteins and ubiquitin.


In contrast to astrocytes, which other glial cells do not participate in the active response to CNS injury and show a more limited repertoire of reactions?

Oligodendrocytes and ependyma


What is the function of oligodendroglia cytoplasmic processes?

They wrap around axons and form myelin.


Each oligodendrocyte myelinates (one/many) internodes on (one/many) axons.

Many, many


Injury or apoptosis of oligodendroglial cells is a features of what disease states?

Acquired demyelinating disorders and leukodystrophies


Oligodendroglial nuclei may harbor viral inclusions in...?

Progressive multifocal leukoencephalopathy.


Glial cytoplasmic inclusions, primarily composed of α-synuclein, are found in oligodendrocytes in what disease?

Multiple system atrophy (MSA)


_________, the ciliated columnar epithelial cells lining the ventricles, do not have specific patterns of reaction.

Ependymal cells


What happens to ependymal cells when there is inflammation or marked dilation of the ventricular system?

Disruption of the ependymal lining is paired with proliferation of subependymal astrocytes to produce small irregularities on the ventricular surfaces (ependymal granulations).


Certain infectious agents, particularly _______, may produce extensive ependymal injury, with viral inclusions in ependymal cells.



______ are mesoderm-derived cells whose primary function is to serve as a fixed macrophage system in the CNS.



Microglia share many surface markers with what cells?

Peripheral monocytes, tissue macrophages (Such as CR3 and CD68)


What are the microglial responses to injury?

  1. Proliferating
  2. Developing elongated nuclei (rod cells), as in neurosyphilis
  3. Forming aggregates about small aggregates (microglial nodules)
  4. Congregating around cell bodies of dying neurons (neuronophagia)


In addition to resident microglia, ______ are the principal phagocytic cells present in inflammatory foci.

Blood-derived macrophages


________ is an acute flu-like illness which may (or may not) result in permanent loss of muscle strength due to destruction of innervating motor neurons.



How does the polio virus enter the body?

Through the GI tract


After entering the body through the GI tract, how does the polio virus take effect?

Reaches the cell bodies of the motor neurons in the spinal cord (possibly by travelling up the neuronal axon), where synthesis of neuronal proteins is interrupted in favor of synthesis of viral proteins, with consequent damage to or destruction of the neuron.


______ is a disease of unknown etiology (it is usually not genetic) which occurs in middle age and causes progressive paralysis and eventual death.

Amyotrophic lateral sclerosis (ALS)

  • a natural disease of the spinal cord


What is the "mechanism" of ALS?

Dissociation of cytoskeletal elements in the proximal axon on neurons. Slow anterograde axonal transport, which depends on this cytoskeleton, is interrupted and neurofilaments, which are normally transported down the axon by this slow anterograde axonal transport, accumulate in the proximal axon causing swelling.


What is the "end result" of the cytoskeletal disruption of ALS?

Swelling and accumulation of neurofilaments in the proximal axon


What toxin causes injury to the action potential conductance mechanism?

Tetrodotoxin, produced by puffer fish


What is the "mechanism" of tetrodotoxin injury to the action potential conductance?

Blocks the sodium channel in the neuronal cell membrane, causing failure of action potential propagation and paralysis.


Nerve ending innervating skeletal muscle release what neurotransmitter?



How does alpha-latrotoxin (produced by black widow spiders) affect the neuromuscular junction?

Stimulates excessive release of acetylcholine. Thus, a black widow spider bite is followed by severe local cramps and then (after all of the neuronal Ach is depleted), paralysis.


What is the most powerful biological poison known?

Botulinum toxin. It is produced by an anaerobic bacterium that can grow in incompletely sterilized can foods and is fatal in nanogram quantities.


How does botulinum toxin take effect?

By blocking the release of acetylcholine, with consequent paralysis.


What is Lambert-Eaton syndrome?

In some patients with cancer, an "autoimmune" antibody is made which cross reacts with a voltage-gated calcium channel at motor nerve endings and interferes with release of Ach causing muscle weakness.


Tetanus toxin also acts on presynaptic nerve endings, but it acts on different neurons. Describe the action of this toxin produced by anaerobic bacteria in infected puncture wounds.

The toxin is carried to the spinal cord by retrograde transport up neuronal axons. There, it finds the nerve endings of inhibitory (glycine-secreting) neurons and binds to these, preventing release of the inhibitory neurotransmitter glycine. Thus, unopposed excitatory input to motor neurons and uncontrolled muscle contraction (tetanus) occur.


_________ is a disease in which "autoimmune" antibodies against acetylcholine receptors block these receptors, causing muscle weakness.

Myasthenia gravis


What do myasthenia gravis and Eaton-Lambert syndrome have in common?

They both cause muscle weakness due to the action of an autoantibody.

  • Eaton-Lambert: autoantibody interferes with presynaptic voltage-gated calcium channels and Ach is not released sufficiently.
  • Myasthenia gravis: autoantibody interferes with postsynaptic acetylcholine receptors


In the peripheral nervous system myelin is formed by...?

Schwann cells


How does lead interfere with the function of Schwann cells?

Lead damages capillaries, thus gaining entrance to the usually protected nerve, and then poisons Schwann cells, probably by damaging their mitochondria.


What other toxin, besides lead poisoning, poisons Schwann cells and causes demyelination of nerve fibers and loss of nerve function?

Diptheria toxin


Lead probably damages Schwann cell mitochondria, but how does Diptheria toxin damage Schwann cells?

By inhibiting Scwhann cell protein synthesis.


In the central nervous system myelin is produced by...?



What pathology interferes with oligodendrocyte myelination function?

Some papova viruses preferentially attack oligodendrocytes, causing a rapidly progressive, fatal dementing illness ("progressive multifocal leukoencephalopathy" or PML).


There are two diseases that cause immune system-mediated damage to myelin. What are they?

  • Multiple sclerosis (CNS)
  • Guillan-Barre polyneuritis (PNS)


What happens to the detached distal axonal fragment following the severing of an axon?

The distal axonal fragment is no longer supported by the neuronal cell body and is not viable, and thus degenerates.

  • First, irregular swellings (varicosities) develop and then it fragments. Then the myelin sheath degenerates (a process called secondary demyelination, i.e. secondary to axonal degeneration, rather than primary myelin or myelin-forming cell damage). The myelin first swells, then breaks up into fragments which are digested by Schwann cell or oligodendrocyte.
  • After about three months of this, specialized white blood cells (macrophages) arrive to ingest and remove the degraded myelin and axonal remnants.


The complex sequence of events in the previous card (axonal degeneration and secondary myelin degeneration following axonal severance) is known as...?

Wallerian degeneration


While the distal axon is undergoing Wallerian degeneration, what happens to the neuronal cell body and proximal axonal stump?

  • The Nissl substance breaks up, the cell body swells, and the nucleus is pushed to the periphery. This series of events is called CENTRAL CHROMATOLYSIS. The cell is altering its metabolism to support regeneration of the severed axon.
  • New axonal sprouts appear at the severed stump of the axon and seek out the endoneurial "tube" of the distal axon composed of basement membrane and containing Schwann cells.
  • If this is still intact the axonal sprouts will grow along it to reach the target organ and re-establish innervation. This reinnervation only occurs in the PNS.


HIV in the brain selectively infects...?



How do HIV-infected microglia appear?

Enlarged cells around blood vessels or as small clusters of microglia (microglial nodules) in the parenchyma.


The neurotoxic and neurodegenerative effects of HIV are thought to result from...?

Excess production of cytokines by infected microglia.