Chapter 1 : The Cells of the CNS

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Clinical Neuroscience: Pathological changes in Neurones and Glial Cells

Peripheral Nerve Pathology

Axons in peripheral nerves are susceptible to damage by trauma in the form of nerve compression or transection. When motoneurones are injured, the muscles they innervate become weak or paralysed. These conditions are referred to as a lower motoneurone lesions. If the nerve is subjected to external pressure, Wallerian degeneration may occur beyond the site of the compression. In Wallerian degeneration, the axon degenerates distal to a focal lesion that interrupts axonal transport in both directions; at the same time the cell body shows chromatolysis.

Peripheral axons are capable of regeneration, and this can occur when nerve compression is relieved, or the cut ends of a peripheral nerve are delicately sewn together.

Axons also show two other forms of pathological change:

  • Myelinated axons may show segmental demyelination, and
  • Unmyelinated axons may show regions where they are dilated and filled with vesicles, disorganised neurotubules and neurofilaments and accumulations of other subcellular organelles (probably due to stagnation of axoplasmic flow). Sometimes this is called the 'dying back' phenomenon, and eventually the distal axon becomes atrophic and breaks down.

Axon terminals may also retract as a result of disorders such as polio or motoneurone disease, and metabolic diseases such as diabetes or alcoholism/vitamin defieciencies, and poisoning with heavy metals, such as lead or mercury, or a wide variety of industrial chemicals and some drugs.

Clinical Neurophysiological Investigations are used to diagnose peripheral nerve disorders, and to follow the process of regeneration. These involve studying the results of Nerve Conduction Tests and Electromyography, which provide infomation about the conduction velocity of axons involved, and of the degree of reinnervation of skeletal muscles. Other tests, such as the Visual Evoked Potential, investigate the speed of conduction in the visual pathway and this has proved useful in the diagnosis of some demyelinating disorders, such as Multiple Sclerosis.


Neurodegenerative Diseases

Neurodegenerative Diseases are diseases that result in the progressive death of neurones, particularly within the central nervous system. These include Alzheimer's Disease, Parkinson's Disease and Huntington's Disease, which involve cellular pathology, such as inclusion bodies within neurones of the cerebral cortex, the substantial nigra and other structures. The symptoms of Alzheimer's Disease include dementia, (including memory loss, difficulties with thinking, problem-solving or language), and motor changes that depend on which neuronal pathways are affected by these changes. In Parkinson's Disease there are changes in muscle control and tone, as well as mood (depression). Other degenerative conditions affect neuronal networks in the cerebellum or autonomic nervous system (Multiple Systems Atrophy and its variants).

These neurodegenerative conditions are often associated with aging. However Friedreich's Ataxia is an inherited neurodegenerative disease which affects young people, and the viral infection poliomyelitis attacks motoneurones and can cause paralysis (often in young people).


Pathological Changes in Neurones in Neurodegeneration

Neurones within the brains of patients with neurodegenerative disorders often show intracellular inclusions, many of which seem to consist of abnormal molecules derived from normal components of the neurone, including misfolded proteins. These include the neurofibrillary tangles in Alzheimer's Disease and Lewy Bodies in Parkinson's Disease, and nuclear inclusions in neurones of patients with Huntington's Disease.

In addition there is an accumulation of extracellular insoluble beta-amyloid in Alzheimer's Disease. Amyloid Protein Precursor (APP) is a normal protein in many neurones, but in Alzheimer's Disease, an insoluble polymer called beta-amyloid accumulates OUTSIDE the neurone, and contributes of neuronal degeneration.

Normally, the initial cleavage of APP is by an enzyme, alpha-secretase, and the product is sufficiently souble to be removed. Some authors believe that beta-amyloid is produced by the enzyme beta-secretase (BACE1), and the product is able to polymerise and become an insoluble form of amyloid protein (beta-Amyloid).

It is interesting that not all types of neurones are equally affected by Alzheimer's disease, which begs the question of how neurones are involved in the development of plaques of insoluble beta-amyloid.

In all of these pathological changes there is evidence of misfolding of proteins.

Neurofibrillary tangles appear to be an aggregation of a misfolded form of tau protein, a normal component of neurotubules. Alpha-synuclein is another protein, present in normal neurones, that can accumulate in degenerating nerve cells, particularly in association with Lewy Bodies in Parkinson's Disease. Some authors believe that these inclusions disrupt axonal transport, which results in a lack of chemical communication between the cell body and the axonal terminal and a consequent inability to sustain the terminal and synaptic transmission.


Pathological Changes involving Glial Cells

Pathology of Glial Cells

Multiple sclerosis (MS) affects nerve cells in the brain and spinal cord by damaging the myelin sheath provided by the oligodendrocytes, and causing a failure of axonal conduction. This results in patients having problems with muscle movement, balance and vision. The myelin of peripheral nerves produced by Schwann cells is not affected by this disease.

While the cause is not clear, the underlying mechanism is thought to be either destruction of CNS myelin by the inmmune system (autoimmunity), or a failure of production of myelin.  

One hypothesis is that the blood brain barrier is breached because of infection, such as a viral infection. The entry of T-lymphocytes, activated by the virus, into the CNS may cause an autoimmune attack on oligodendrocytes, resulting in a loss of myelin.

Pathological Changes in Schwann Cells in Peripheral Nerves.

In some peripheral neuropathies, such as those associated with diabetes or lead poisoning, isolated Schwann cells may degenerate: this is known as Segmental Demyelination because one segment of myelin is lost, and this results in a reduction of the speed of conduction in the affected axons. These changes are quite separate form the changes in central myelination seen in multiple sclerosis.


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HumanPhysiology.Academy 2014-2015