A. Cells of the Central Nervous System (CNS)

1. Neurons
   1. Largest somatic cells
   2. Very high metabolism (oxygen utilization)
2. Neurosecretory Cells
3. Astrocytes
4. Oligodendrocytes
   1. Very large cells which produce myelin sheaths
   2. Very high metabolism to maintain sheaths
5. Ependymal Cells
6. Choroid Plexus Cells
7. Pituicytes
8. Pinealocytes
9. Microglia (resident macrophages)
10. Meninges
11. Blood vessels and inflammatory cells

B. Cells of the Peripheral Nervous System (PNS)

1. Neurons
   1. Ganglionic
   2. Neurosecretory
2. Schwann Cells: myelin production, nerve regeneration
3. Fibroblasts
4. Peripheral Nerve sheath cells
   1. Endoneurium
   2. Epineurium
   3. Perineurium

C. Neuronal Injury

1. Focal Axonal Destruction
2. Axonal Swelling
3. Distal Axonopathy ("Dying-Back" Neuropathy)
4. Demyelination
5. Transynaptic Degeneration
6. Sprouting

D. Focal Axonal Destruction

1. Etiology
   1. Infarction
   2. Toxin mediated destruction
   3. Metabolic disorders
   4. Inflammation
   5. Tumor
   6. Trauma
2. Axon distal to injury usually degenerates, called Wallerian Degeneration
3. Axons of PNS can usually regenerate
   1. Depends on type of insult and many other factors
   2. In general, CNS axons and neurons cannot regeneration
4. Fate of Cell bodies of transected neurons:
   1. Central chromatolysis (axonal reaction): may allow repair
   2. Simple Atrophy, followed by cell death and disintegration
5. Central Chromatolysis
   1. Primarily a regenerative reaction where lysis of Nissl bodies occurs centrally
   2. Nissl bodies = cytoplasmic rough (ribosomal) endoplasmic reticulum (ER)
   3. Structural (secreted and membrane) proteins produced in rough ER
   4. Process reaches maximum in 15-20 days
   5. Cell body becomes swollen and rounded, with nucleus moving to periphery
   6. Granular endoplasmic reticulum replaced by marked increase in polysomes to central chromatolytic area, moving protein synthesis into the center
   7. Thus, protein synthesis shifts away from neurotransmitters, into structural proteins
   8. Either recovery, or degeneration, will eventually occur
   9. Recovery may take up to 100 days - axons grow ~1mm per day
6. Wallerian Degeneration in the PNS
   1. Disintegration of axon distal to point of axonal transection
   2. Fragmentation of axon is extensive over first 1.5-4 days
   3. Myelin retracts at nodes of transection, and disintegration occurs
   4. Schwann cells proliferate within a tube of their residual basement membrane
   5. Longitudinal columns of myelin provide a pathway for regeneration of axons
7. Wallerian Degeneration in the CNS
   1. CNS axonal degeneration takes place over days to weeks
   2. Myelin changes also occur, with delayed manifestation over several weeks
   3. Once a CNS axon degenerates, some axon sprouting can occur
   4. Experimenal approaches to induce CNS regeneration are under way

E. Axonal Swelling

1. Focal Enlargement
   1. Distal end of proximal stump of transected axon
   2. Near origin of axon when transport disturbances occur.
2. Histology
   1. Appear as eosinophilic, irregular, roughly spherical bodies on hematoxylin / eosin stain
   2. May be little more than normal axonal diameter, as as large as cell body.
3. Ultrastructure
   1. Crowds of organelles
   2. Filled predominantly with neurofilaments or transmitter-filled vesicles
4. Organelle Rich Swelling
   1. Both sides of acute axonal transection
   2. Ends of axons making abnormal or abortive attempts at regeneration
   3. Neuroaxonal Dystrophy: degeneration at axon terminals
   4. Impaired fast transport
5. Neurofilament-Rich Swelling
   1. Proximal axon of anterior horn cells in ALS
   2. Impaired slow transport

F. Distal Axonopathy ("Dying-Back" Neuropathy)

1. Terminal axon undergoes degeneration
2. Proximal axon and perikaryon remain morphologically normal
3. Degeneration appears at progressively more proximal points with time progression.
4. Mechanism:
   1. Failure of perikaryon to shift into protein synthesis for regeneration
   2. Failure of axonal transport to deliver proteins for repair.
5. Characteristic of Amyotrophic Lateral Sclerosis (Lou-Gerig's Disease, ALS)
   1. Corticospinal tract degeneration seen in caudal cord.
   2. More difficult to demonstrate proximal degeneration.
6. Characteristic also of polyneuropathies
   1. Toxic damage
   2. Vitamin Deficiencies
   3. Alcoholism
   4. Multiple myeloma
   5. Diabetes
   6. Uremia

G. Demyelination

1. Loss of myelin between a few Nodes of Ronvier leads to loss or slowing of conduction
2. May be caused by immune attack, ischemia, or infection

H. Transsynaptic Degeneration

1. Degeneration due to loss of synaptic inpuut.
2. Regions Commonly Affected
   1. Retina, Optic Nerves and Tract - degeneration in lateral geniculate body
   2. Other neurons with single major innervation susceptible
3. Motor neurons of spinal anterior horns do not degenerate after corticospinal tract interruption, probably due to multiple additional inputs
4. Size of cell body decreases first, with slow degeration in adults
5. Occurs in prenatal or postnatal life, with little residua due to greater adaptibility

I. Sprouting

1. Wallerian degeneration of synapses stimulates sproating of preterminal axons
2. These boutons synapse on neuron in areas left by degenerated axons
3. Process also takes place in PNS
   1. Affects muscles partially denervated by peripheral neuropathies or motor neuron disease
   2. Leads to enlargement of remaining motor units

J. Causes of Neuronal Death

1. Axonal transection: Wallerian Degeneration or Atrophy
2. Loss of Synaptic Input: Distal Axonopathy
3. Ischemic Necrosis
4. Trauma
5. Toxic, Nutritional, Genetic
6. Apoptosis (variety of causes, many idiopathic)
7. Examples:
   1. Alzheimer's Disease: cerebral cortex
   2. Huntington's Disease: neostriatum
   3. ALS: Brain and Spinal Cord
   4. Status Epilepticus (Transient Ischemia or Anoxia): Hippocampus
   5. Parkinson's Disease: Substantia Nigra
   6. Herpes Encephalitis: temporal lobe
   7. Tay-Sachs Disease: throughout the brain
   8. Toxins
   9. Vascular occlusion

1. Light staining nucleus
2. Larger than oligodendrocytes
3. More amample cytoplasm
4. Cytoplasmic proteins included GFAP (glial fibrillary acidic protein) and S100

B. Reactive Astrocytes and Gliosis

1. Cytoplasmic changes allow visualization (with hematoxylin/eosin) following injury
2. Altered reactive astrocytes are called Gemistocytes or Gemistocytic Astrocytes
   1. Homogenously potent pink cytoplasm with cell body hypertrophy
   2. Rounded cells within irregular thread-like processes eminating from cell bodies
   3. Increase in GFAP accompanies these reactive changes
   4. Also called astrocytosis
3. The thread-like emanating processes continue to expand over time
   1. They eventually form tough scar-like walls
   2. This is referred to referred to as Fibrillary Gliosis
4. Variations may be seen
   1. No cytoplasmic changes but nuclear enlargement with fibrillary gliosis
   2. Seen in chronic degenerative diseases including multiple sclerosis and ischemia

C. Alzheimer Astrocytes

1. Alzheimer Type II Cells
   1. Pale, enlarged astrocytic nuclei without visible cytoplasm
   2. Represent poisoned cells, do not express GFAP
   3. Occur in brain associated with hepatic (encephalopathy) disease or uremia
2. Alzheimer Type I Cells
   1. Extremely large cells, larger than Type II
   2. Large amounts of eosinophilic cytoplasm and exceedingly bizarre nuclei
   3. Wilson's Disease (Copper overload with hepatocellular degeneration)

D. Rosenthal Fibers

1. Occur in diseases of longstading astrocytic hypertrophy
2. Irregular, elongated or globular, densely eosinophilic bodies (5-8µm)
3. Usually found amidst bundles of glial filaments; may be degenerated astrocytes
4. Diseases observed in:
   1. Astrocytomas
   2. Gliotic edge of old brain injury
   3. Old multiple sclerosis plaque
   4. Alexander's Disease: rare neurological disorder of infancy (mental + motor degeneration)

E. Corpora Amylacea

1. Spherical, PAS+ (Carbohydrate) bodies, very common. Average diameter ~15µm
2. Common, especially in brains of older persons.
3. Common in areas of gliosis, but of no pathological significance

1. Small appearing cells actually very large with myelin sheath exensions
2. Responsible for CNS myelin production and maintenance
3. High metabolic activity makes them very susceptible to ischemia and anoxia

B. Damage

1. Loss of myelin
2. Multifocal Leukoencephalopathy
   1. Viral infection of oligodendrocytes
   2. Confluent patches of demyelination
   3. Nuclei of residual oligodendrocytes show intranuclear inclusions
3. Multiple Sclerosis (MS)
   1. Destruction of oligodendrocytes, presumably immune mediated
   2. Plaques in this disease lack oligodendrocytes
   3. CNS neurons are eventually destroyed by inflammatory process as well
   4. Wallerian degeneration ensues
4. CNS Ischemia
   1. Oligodendrocytes are more susceptible to anoxic injury than astrocytes
   2. Thus, in ischemia may see patches of demyelination.

1. Lining of the ventricles
2. Is not a barrier to passage of fluid or protein between parenchyma and ventricles
3. Neural Stem Cells [1]
   1. Neural stem cells capable of regeneration found in subependymal zone
   2. These stem cells ("brain marrow") also found in hippocampus

B. Pathologic Processes

1. Resistant to most pathological processes
2. Infection of ventricles (for example, with syphilis) may lead to cell loss
3. May involve glial proliferation with ependymal granulations in ventricle wall
4. Hydrocephalus may lead to disruption of lining

References

1. Steindler DA and Pincus DW. 2002. Lancet. 346(9311):1047