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A correlation between demyelination and axonal degeneration observed at autopsy is supported by imaging studies, including those that compare the concentrations of N-acetyl aspartate.119 For example, one study measured the levels of NAA, an amino acid found only in neurons that serves as a biological marker for integrity of the axon and neuronal cell body. The brains of MS patients showed significantly greater side-to-side differences in levels of NAA, indicating decreased neuronal integrity on the side of the brain with lower NAA levels. There was a correlation between this asymmetry in motor function and the asymmetry of NAA concentrations in the internal capsule.119 Insights into processes that lead to demyelination and axon damage can be obtained by analyzing T1-weighted image hypointensities, proton spectroscopy, MTI, and DTI and by correlating these measures with clinical and pathological findings.

Gliosis. Gliosis is a prominent feature of the MS lesion, but it is best regarded as a secondary phenomenon.146 Whenever the CNS is damaged, it undergoes an injury response, usually called reactive gliosis or glial scarring. The response is broadly the same whatever the source of injury, although the details vary somewhat with different types of pathology.67 The glial reaction to injury includes recruitment of oligodendrocyte precursor cells, stem cells, microglia, and astrocytes. Formation of the glial scar after CNS injury generally occurs over a period of weeks. Microglia are typically the first cell types to enter the lesion. In the normal brain, they are quiescent with short, branched processes. Following injury, they exhibit various changes, including activation, cell division, and migration to the injury site.67 During activation, microglia display conspicuous functional plasticity, which involves changes in cell morphology, cell surface receptor expression, and production of growth factors and cytokines, and they become, in general, more macrophage like.208 Microglia can be either neurotoxic or neurotrophic.

The final glial scar is made up mainly of a meshwork of tightly interwoven astrocyte processes, attached to one another by tight junctions and gap junctions and surrounded by extracellular matrix (reviewed in 1999 by Fawcett and Asher67). (Astrocytes are irregularly star-shaped, background structural cells of the nervous system.) Gliosis is usually restricted to the area of demyelination, but it sometimes extends beyond that area. There is no specific way to identify the presence and extent of gliosis in MS lesions through MRI, although the T1 signal might be more sensitive to gliosis than the T2 signal.24

The role of astrocytes in gliosis is not completely known.146 Since there is evidence that glial scars can inhibit both axon growth and myelination, it is clearly important to know what causes them to form, what cells are involved, why they are inhibitory, and how to manipulate them. Finally, although gliosis is generally considered harmful, there is also evidence that the gliotic ensheathment of demyelinated axons might favor the restoration of nerve conduction.221



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