PET measurements of regional cerebral blood flow (rCBF) were used to explore frontal lobe dysfunction in amyotrophic lateral sclerosis (ALS). An activation paradigm of executive frontal lobe function (verbal fluency), which contrasted rCBF during word generation and word repetition, was used. Two groups of ALS patients, defined by the presence or absence of cognitive impairment (ALSi) (impaired, n = 6: ALSu unimpaired, n = 6) were compared with healthy age-matched controls (n = 6). Patient selection was based on prior performance on a written test of verbal fluency. Additional neuropsychological assessment of the patients revealed evidence of executive and memory dysfunction in the ALSi group only, with marked deficits in tests of intrinsic generation. The ALSi patients displayed significantly (P < 0.001) impaired activation in cortical and subcortical regions including the dorsolateral prefrontal cortex (DLPFC; areas 46 and 9), lateral premotor cortex (areas 8 and 6), medial prefrontal and premotor cortices (areas 8 and 9), insular cortex bilaterally and the anterior thalamic nuclear complex. Although the three groups showed matched word generation performance on the scanning paradigm, the ALSu group displayed a relatively unimpaired pattern of activation. These results support the presence of extra-motor neuronal involvement, particularly along a thalamo-frontal association pathway, in some non-demented ALS patients. In addition, this study suggests dysfunction of DLPFC in some ALS patients with associated cognitive impairments.

Neuropsychological assessment of 16 clinically non-demented patients with amyotrophic lateral sclerosis (ALS) and 16 age-matched controls revealed significantly (P < 0.05) impaired verbal fluency and picture recall in the ALS patients. On the basis of their verbal fluency scores, two subgroups of the ALS patients (five high, five low scores) and a different group of five age-matched controls then underwent positron emission tomographic (PET) measurement of regional cerebral blood flow (rCBF). Scans were performed in the resting state and while subjects performed stereotyped or freely selected movements of a joystick with their right hand. The pattern of cerebral activation associated with self-generated activity was determined by comparing the profile of rCBF during freely selected and stereotyped joystick movements. Statistical parametric mapping was used to determine significant differences in rCBF between the groups at rest and during activation. Regional cerebral blood flow at rest was significantly (P < 0.01) reduced in the anterior cingulate cortex of both ALS subgroups in comparison with controls. The profile of cortical and subcortical activation during performance of freely selected joystick movements relative to stereotyped movements was abnormal in ALS patients: (i) ALS patients with a normal fluency score showed significantly (P < 0.01) attenuated rCBF responses in comparison with controls in the left medial prefrontal cortex (Brodmann area 10) and the right and left parahippocampal gyri; (ii) ALS patients with impaired verbal fluency showed significantly (P < 0.01) attenuated rCBF responses in comparison with controls in the right and left medial prefrontal cortex (areas 9 and 10), the rostral aspects of the right anterior cingulate cortex (areas 24 and 32), the right parahippocampal gyrus and the anterior thalamic nuclear complex; (iii) ALS patients with impaired verbal fluency showed significantly (P < 0.01) attenuated rCBF responses in comparison with patients with normal verbal fluency in the right parahippocampal gyrus, the anterior thalamic nuclear complex and the rostral anterior cingulate cortex (area 24). Regional cerebral blood flow at rest in the right parahippocampal gyrus of ALS patients was significantly correlated with verbal fluency score (P = 0.01) and picture recall score (P = 0.01). Activation of the anterior thalamic nuclear complex in ALS patients was also significantly correlated with verbal fluency score (P = 0.001) and picture recall score (P = 0.01). The results show that abnormalities of function are present in regions along a limbo-thalamo-cortical pathway in some ALS patients during performance of a self-generated motor task.(ABSTRACT TRUNCATED AT 400 WORDS)