As described in the previous chapters, the established view of ALS is that of a corticomotoneuronal system disease with involvement of bulbar and spinal motoneurons as well as corticospinal tracts and other descending pathways. The specific pattern of involvement makes the disease relatively unique. This particular selective vulnerability holds true for the majority of patients, but there are some who exhibit features of motoneuron destruction and loss of descending tracts with additional features indicative of involvement of structures outside the ‘motor system’. For instance, some ALS patients have dementia, extrapyramidal features, sensory findings or autonomic involvement. How many such patients there are is difficult to determine. These cases are often identified in large ALS clinics where more vigorous case ascertainment is achieved. For example, overt clinical dementia occurs in fewer than 5 per cent of ALS patients (Strong et al., 1996). But, using formal psychometric testing, as many as 35 per cent of ALS patients show some evidence of cognitive impairment. PET has revealed abnormalities in dopamine metabolism in a number of ALS patients who do not have clinical evidence of PD. Also, functional MRI has demonstrated widespread abnormalities outside the primary motor cortex in many ALS patients with or without dementia or unusual clinical features. These variations of the typical presentation of ALS raise two important issues regarding the definition of the disease. First, to what extent are nervous system regions outside the ‘motor system’ involved in ALS?