Neurodegenerative Disorders

Amyotrophic lateral sclerosis (ALS) and hereditary spastic paraplegia (HSP), unlike MS, are classic neurodegenerative diseases, each with distinct clinical and pathological features. A unifying element of these disorders, however, is the presence of significant nerve fiber loss in various tracts (Fig. 2).

ALS is a form of motor neuron disease characterized by progressive weakness and paralysis of skeletal muscle resulting from the selective degeneration of motor neurons in the brain and spinal cord. With a typical age of onset in the sixth and seventh decade of life, the clinical course is relentlessly progressive, with death usually resulting within 1 to 5 years (Nguyen et al., 2000). Approximately 90% of ALS cases are sporadic, and 10% are familial, with up to 20% of the familial cases having a missense mutation in the gene for Cu/Zn superoxide dismutase 1 (SOD1).

The motor system is the cardinal target of the pathological insult with both upper and lower motor neurons being affected; however, cases of ALS usually demonstrate either predominantly upper or lower motor neuron involvement. The degeneration of motor neurons appears to be size selective, with motor neurons of large axonal diameter (a-motor neurons) primarily affected with relative preservation of the motor neurons of small axonal caliber (Nguyen et al., 2000). Acute neuronal injury, as visualized by APP immunohisto-chemistry, has been shown to occur in the perikarya of anterior horn neurons and proximal axonal swellings in cases with mild lesions and shorter disease duration and not in areas of more severe pathology or of longer duration (Sasaki and Iwata, 1999). APP expression has also been described in the corticospinal tracts, anterior columns, and anterior roots (Murakami et al., 1995). The temporally acute nature of APP expression suggests that neuronal injury is an early event in ALS that may precede the progressive neurodegenerative processes characteristic of the disease.

It has been shown that neuronal and axonal loss occurs in ALS. Severe neuronal loss associated with fibrillary gliosis is known to affect the anterior horn cells at all levels of the spinal cord and in Clarke's column at the thoracic segments. Axonal loss has been described in the corpus callosum, posterior limb of the internal capsule, middle third of the crus cerebri, centrum semiovale, and the lateral column of all spinal cord segments (Takahashi et al., 1997). The abundant presence of ubiquinated dystrophic neurites at the end of the corticospinal tracts compared to the motor cortex indicate a "dying-back" process may be operative in the corticospinal axonal degeneration observed in the disease (Schiffer et al., 1994). Unfortunately, clinicopathological studies relating the distribution and extent of such axonal loss to functional disability in ALS are notably sparse and warrant attention in future studies (Fig. 3).

HSP encompasses a heterogeneous group of rare, genetic neurodegenerative disorders unified by the presence of progressive weakness and spasticity predominantly affecting the lower limbs. Conventionally, the disease is categorized into pure and complicated forms, the latter defined by the presence of additional neurological and non-neurological manifestations such as optic atrophy, retinopathy, cognitive decline, epilepsy, cerebellar ataxia, extrapyramidal disease, amyotrophy, and muscle atrophy (Crosby and Proukakis, 2002; Okuda et al., 2002). The mode of inheritance in HSP is varied, with autosomal dominant, autosomal recessive, and X-linked forms having been described in both pure and complicated subtypes (reviewed in Reid et al., 2003).

Pathological studies have classified the pattern of damage seen in HSP as that of a "dying back" process in which the long ascending (sensory) and long descending (corti-cospinal) tracts in the spinal cord degenerate progressively from their distal ends. Diffuse axonal swellings are not a prominent feature (Schwarz and Liu, 1956; Behan and Maia, 1974). A study investigating the distribution and extent of

Figure 3 Marchi-stained transverse sections of the medulla (upper panel) and spinal cord (lower panel) taken from mild (right) and severe (left) cases of amyotrophic lateral sclerosis. Note the degree of Marchi-positivity in the corticospinal tracts of severe cases of amyotrophic lateral sclerosis. Positive Marchi-staining represents axonal degeneration. Magnified images (x 100) are taken from the corticospinal tracts in the medullary pyramids and lateral columns of the spinal cord.

Figure 3 Marchi-stained transverse sections of the medulla (upper panel) and spinal cord (lower panel) taken from mild (right) and severe (left) cases of amyotrophic lateral sclerosis. Note the degree of Marchi-positivity in the corticospinal tracts of severe cases of amyotrophic lateral sclerosis. Positive Marchi-staining represents axonal degeneration. Magnified images (x 100) are taken from the corticospinal tracts in the medullary pyramids and lateral columns of the spinal cord.

axonal loss of the long tracts found that axonal loss in HSP was widespread and tract-specific. In the corticospinal tracts, axonal loss occurred throughout the spinal cord, with an average axonal loss of 62%. In contrast, axonal loss in the sensory tracts was restricted to the cervical and upper thoracic regions of the spinal cord, with an average axonal loss of 29%. Unlike in MS, the axonal loss observed in HSP appears to affect both the small- (<3 mm2) and large- (>3 mm2) diameter nerve fiber populations. The lack of correlations between axonal loss and disease duration in HSP suggest that axonal loss occurs at an early, subclinical stage with symptoms visible only once a threshold of axonal loss has been surpassed (DeLuca et al., 2004b).

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