Neuropathology and Disease Progression in Multiple Sclerosis

Abstract

The histopathology of multiple sclerosis (MS) is characterized by focal inflammation, demyelination, loss of oligodendrocytes, reactive astrogliosis, and axonal pathology. Of these hallmarks, myelin loss has attracted most interest, and MS research has historically focused on mechanisms associated with inflammatory demyelination and remyelination. Although the neuropathology of MS is primarily demyelinating, a number of reports describe axonal injury in the disease [1-9]. In fact, axonal pathology in MS lesions was described more than a century ago [10]. Charcot (1868), for example, discussed MS lesions in terms of demyelination and astrogliosis, but he also mentioned axonal loss [11]. Current data on axonal pathology in MS have been provided through a variety of approaches, including magnetic resonance imaging (MRI) [7, 12-14], magnetic resonance spectroscopy (MRS) [2, 3, 5, 15] and morphological analysis of brain sections [4, 9]. Immunohistochemical studies have recently emphasized the correlation between inflammation and axonal damage during the early stages of MS [4, 9]. In addition, long-term axonal pathology has been described in a number of myelin protein gene knockout and trans-genic mice models [6, 8, 16], as well as in chronic MS patients [17, 18], indicating that lack of myelin-related molecules can result in axonal pathology. Together, these data suggest that cumulative axonal degeneration constitutes a significant pathogenic component of MS, and indicate that loss of axons may be a main determinant of the progressive neurological disability seen in these patients [1, 3, 5, 6, 8, 17].