Brain (1996), 119, 2105-2120 Frontal lobe dysfunction in amyotrophic lateral sclerosis A PET study S. Abrahams,1 L. H. Goldstein,1 J. J. M. Kew,3 D. J. Brooks,3 C. M. Lloyd,2 C. D. Frith34 and P. N. Leigh2 Downloaded from https://academic.oup.com/brain/article/119/6/2105/466663 by guest on 27 September 2021 1 Department of Psychology, Institute of Psychiatry, the Correspondence to: Dr Sharon Abrahams, Department of 2Department of Clinical Neurosciences, Institute of Psychology, Institute of Psychiatry, De Crespigny Park, Psychiatry and King's College Hospital Medical School, London SE5 8AF, UK the 3MRC Cyclotron Unit, Hammersmith Hospital and the ^Wellcome Department of Cognitive Neurology, Institute of Neurology, London, UK Summary PET measurements of regional cerebral blood flow (rCBF) (P < 0.001) impaired activation in cortical and subcortical were used to explore frontal lobe dysfunction in amyotrophic regions including the dorsolateral prefrontal cortex (DLPFC; lateral sclerosis (ALS). An activation paradigm of executive areas 46 and 9), lateral premotor cortex (areas 8 and 6), frontal lobe function (verbal fluency), which contrasted rCBF medial prefrontal and premotor cortices (areas 8 and 9), during word generation and word repetition, was used. Two insular cortex bilaterally and the anterior thalamic nuclear groups of ALS patients, defined by the presence or complex. Although the three groups showed matched word absence of cognitive impairment (ALSi) (impaired, n = 6; generation performance on the scanning paradigm, the ALSu ALSu, unimpaired, n = 6) were compared with healthy group displayed a relatively unimpaired pattern of activation. age-matched controls (n = 6). Patient selection was based These results support the presence of extra-motor neuronal on prior performance on a written test of verbal fluency. involvement, particularly along a thalamo-frontal association Additional neuropsychological assessment of the patients pathway, in some non-demented ALS patients. In addition, revealed evidence of executive and memory dysfunction this study suggests dysfunction of DLPFC in some ALS in the ALSi group only, with marked deficits in tests of patients with associated cognitive impairments. intrinsic generation. The ALSi patients displayed significantly Keywords: frontal lobes; cognitive impairment; ALS; PET; verbal fluency Abbreviations: ALS = amyotrophic lateral sclerosis; ALSi = cognitively impaired ALS patients; ALSu, = cognitively unimpaired ALS patients; DLPFC = dorsolateral prefrontal cortex; rCBF = regional cerebral blood flow; RMJT = random movement joystick task; SPM = statistical parametric mapping; VFI = Verbal Fluency Index; WCST = Wisconsin Card Sorting Test Introduction Amyotrophic lateral sclerosis is a progressive disorder Dementia occurs in -3% of patients with sporadic ALS characterized by degeneration of the corticospinal tract and (Kew and Leigh, 1992, 1994), and such patients display lower motor neurons of the brainstem and spinal cord. Hence cognitive and behavioural changes characteristic of frontal most research on the mechanisms of neurodegeneration in lobe dysfunction (Neary et al., 1990; Peavy et al., 1992). The ALS has focused on the motor system. There is, however, underlying pathology in these cases consists of spongiform increasing evidence that ALS should be regarded as a neuronal degeneration in layers 2 and 3 of the prefrontal and multisystem disorder and that cortical involvement extends temporal cortex (Hudson, 1981; Wikstrom etal., 1982; Morita beyond the confines of the primary motor areas (Smith, 1960; et al., 1987; Neary et al., 1990; Wightman et al, 1992) with Kew et al., 1993a, b; Leigh et al., 1994; Talbot et al., 1995). additional involvement of regions within the limbic system © Oxford University Press 1996 2106 S. Abrahams et al. (the hippocampal formation, subiculum and amygdala) ALS patients with cognitive impairment, and also (Okamoto et al., 1991; Wightman et al., 1992; Kato et al., demonstrated that verbal fluency appears to be a sensitive 1994). indicator of such cortical dysfunction. In non-demented patients with sporadic ALS cognitive In the present investigation, we used PET to further explore changes have been reported in a number of neuropsycho- frontal lobe functions in ALS using a verbal fluency activation logical investigations (Gallassi et al., 1985, 1989; David and paradigm. The task was based closely on a study by Frith Gillham, 1986; Ludolph et al., 1992; Kew et al., 1993b). et al. (1991a) and contrasts rCBF increases during two These studies have revealed a pattern of frontal lobe (execut- conditions, orthographically based word generation and word ive) and memory deficits, clearly suggestive of cortical repetition. Word generation is known to produce relative involvement extending beyond the motor system. Executive activation of the DLPFC (Frith et al., 1991a). The purpose dysfunction has been demonstrated using tests of verbal of this study was to identify the neural basis of the marked Downloaded from https://academic.oup.com/brain/article/119/6/2105/466663 by guest on 27 September 2021 reasoning, visual attention, picture sequencing and category abnormalities of verbal fluency detected in some ALS subjects formation on the Wisconsin Card Sorting Test (WCST) and to test the hypothesis that such subjects show impaired (Gallassi et al., 1985, 1989; David and Gillham, 1986; Talbot activation of prefrontal and subcortical areas, previously et al., 1995). However, the most striking and consistent shown to be implicated in ALS (Kew et al., 1993a). impairment is found using tests of verbal fluency, which require rapid word generation, typically involving ortho- graphic or category-based procedures (Gallassi et al., 1985, 1989; Ludolph et al., 1992; Kew et al., 1993*). Memory and Material and methods learning impairments have also been reported using tests of Amyotrophic lateral sclerosis patients prose recall, word list and verbal paired associate learning, Twelve patients with sporadic ALS, recruited from the and picture recall (Gallassi et al., 1985, 1989; David and Maudsley/King's College Hospital, London MND Care and Gillham, 1986; Iwasaki et al., 1990; Kew et al., \993b). Research Centre, were studied. All patients had clinical and Further insight into the neural basis of the cognitive electrophysiological evidence of combined upper and lower changes in ALS has been provided by a PET study (Kew motor neuron involvement and were classified as 'definite' et al., 1993a, b). This was conducted using a motor paradigm or 'probable' ALS according to the El Escorial criteria which compared paced joystick movements in a freely chosen (Swash and Leigh, 1992; World Federation of Neurology (random) direction to movements only in a forward direction Research Group, 1994). The clinical characteristics of the (stereotyped). The study showed impaired activation of patients are presented in Table 1. No patient had a history medial prefrontal cortex (Brodmann areas 10 and 32), anterior of cerebrovascular disease, hypertension or diabetes, and cingulate gyrus, parahippocampal gyrus and anterior thalamic none was taking psychoactive drugs or any medication that nuclear complex, in ALS subjects selected on the basis of might influence CBF. All patients were right handed. Patients abnormal verbal fluency scores (Kew et al., 1993£>). Such were excluded if severity of speech, swallowing or respiratory dysfunction was less marked in patients with unimpaired symptoms would have hindered their task performance verbal fluency. This study therefore revealed clear evidence (speaking whilst lying supine in the PET scanner). Prior to of medial prefrontal cortex dysfunction, in non-demented the investigation, the patients underwent a pilot of the test Table 1 Clinical characteristics of 12 ALS patients Patient Pseudo- Bulbar Wasting Wasting Fasciculations Spasticity Spasticity Hyper- Babinski (group) bulbar involvement UL LL (UL and LL) UL LL reflexia sign Palsy (LMN) (UMN) 1 (ALSu) — + + + + — — + — 2 (ALSu) - + + + + + - + + 3 (ALSu) + + + - + + + + + 4 (ALSu) - - + - + + - + + 5 (ALSu) - - + - + - + + + 6 (ALSu) - - + + + - - + - 7 (ALSi) - - + + + - + + + 8 (ALSi) - - + + + - - + - 9 (ALSi) - + - + + - - + + 10 (ALSi) + + + - + + + + + 11 (ALSi) + + - - + - + + + 12 (ALSi) + + + + + + + + - Pseudobulbar palsy evidence: brisk jaw jerk, spasticity of factila and or tongue muscles, spastic dysarthria. Bulbar involvement evidence nasal speech, fasciculations, wasting of tongue and weak cough. UMN = upper motor neuron; LMN = lower motor neuron. UL = upper limb; LL = Lower Limb. + = present/positive; - = absent/negative; ALSu = ALS unimpaired; ALSi = ALS impaired. Frontal lobe activation in ALS 2107 Table 2 Subject characteristics but were not examined in detail neurologically. None had any neurological symptoms or a history of any neurological ALSu ALSi Controls disease. Details (age and gender) are presented in Table 2. (n = 6) (» = 6) (« = 6) Written informed consent was given by all subjects. The Age (years) 57.3 (10.3) 57.3 (13.2) 57.7 (9.7) study was approved by the Hammersmith Hospital and Gender 6M, OF 5M, IF 4M, 2F Maudsley Hospital ethics committees, and permission to VFI 4.2 (10) 14.1 (10.8) 4.8 (2.0) administer radioactive H I5O was obtained from ARSAC Duration (months) 25.7 (17.0) 22.7 (15.0) NA 2 Bulbar function 19.8 (0.4) 17.5 (3.3) NA (UK). Spinal function 15.2 (1.7) 14.7 (2.9) NA Total disability 35.0 (1.9) 32.2 (2.7) NA HAD anxiety 6.2 (3.0) 6.8 (2.8) 5.5 (4.1)