Regional cerebral metabolic rates for glucose (rCMRGlc) were analyzed in 19 studies of 12 patients with amyotrophic lateral sclerosis (ALS) by positron emission tomography (PET) with [18F]2-fluoro-2-deoxy-D-glucose. In the 8 ALS patients with upper motor neuron signs, the mean cortical rCMRGlc was significantly lower than in 11 age-matched control subjects (p less than 0.01). The degree of hypometabolism correlated with the duration of the clinical signs and extended throughout the cortex and basal ganglia, but not to the cerebellum. Of the 4 such patients who had repeat PET scans, 3 demonstrated significant subsequent reduction in the rCMRGlc, corresponding to the worsening of the clinical picture. In contrast, 4 ALS patients with disease confined to lower motor neurons and 3 patients with lower motor neuron disease from old paralytic poliomyelitis had normal or near-normal rCMRGlc throughout the brain. Because histological evidence shows no generalized neuronal cell loss in the cortex of ALS patients, including in some cases the primary motor regions, the demonstration of severe generalized hypometabolism in structurally normal cortex indicates that some cortical neurons exist in a state of neuronal nonfunction, rather than cell death, and that anatomoclinical correlations may be more complex. The data also indicate that ALS with upper motor neuron involvement extends beyond the corticospinal tracts and differs in cortical function from the ALS confined to lower motor neurons or the other lower motor neuron disorders.