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Cognitive deficits in non-demented amyotrophic lateral sclerosis patients: a neuropsychological investigation
JOURNAL OF THE
NEUROLOGICAL SCIENCES ELSEVIER
Journal of the Neurological Sciences 129 (Suppl.) (1995) 54-55
Cognitive deficits in non-demented amyotrophic lateral sclerosis patients: a neuropsychological investigation S. A b r a h a m s
a, L . H . G o l d s t e i n a,*, C . M . L l o y d
b D.J.
B r o o k s e, P . N . L e i g h b
a Department of Psychology, Institute of Psychiatry, De Crespigny Park, London SE5 8AF, UK b Department of Neurology, Institute of Psychiatry, and King's College School of Medicine and Dentistry, Denmark Hill, London SE5 8AF, UK c MRC Cyclotron Unit, Hammersmith Hospital, Du Cane Road, London WI2 OILS, UK Accepted 21 February 1995
Keywords: ALS; P s e u d o b u l b a r palsy; Cognition
Amyotrophic lateral sclerosis (ALS) is not typically thought to be associated with cognitive impairment. Over the last ten years, however, subtle cognitive deficits have been noted in non-demented patients with ALS (Gallassi et al., 1985,1989; David and Gillham, 1986; Ludolph et al., 1992; Kew et al., 1993). These deficits include abnormal design and verbal fluency, visual attention and performance on the Wisconsin Card Sorting Test, and impaired verbal and visual learning and recall. Recently we found that the degree of impaired verbal fluency was related to the extent of dysfunction of a fronto-thalamo-limbic brain system (Kew et al., 1993). In addition different subtypes of MND may be accompanied by differing degrees of cognitive impairment (Gallassi et al., 1985,1989; David and Gillham, 1986). In particular neuropsychological deficits may be more prominent in patients with more advanced disease and with bulbar symptoms (David and Gillham, 1986) but all these studies have used small number of patients. In this study we wished to test the hypothesis that ALS patients with pseudobulbar palsy would have greater cognitive impairment than ALS patients without these symptoms. A total of 52 ALS patients were subdivided into two groups. The first comprised 28 patients with classical ALS but without pseudobulbar involvement (ALS-non pb) and the second comprised 24 patients with classical ALS, who also had pseudobulbar palsy (ALS-pb). A control group of 34 age-
* Corresponding author. Tel.: (+44-171) 919-3381; Fax: (+44-171) 703-9989. 0022-510X/95/$09.50 @ 1995 Elsevier Science B.V. All rights reserved SSDI 0022-51 0 X ( 9 5 ) 0 0 0 6 3 - 1
matched normal adults was also studied. All were assessed with a range of neuropsychological tests, including the National Adult Reading Test-Revised (NART-R) to estimate premorbid IQ, a short form of the WAIS-R to provide an estimate of current Verbal IQ, the Recognition Memory Test (Warrington, 1984), verbal Paired Associate learning from the Wechsler Memory Scale-Revised, the Kendrick Object Learning Test (Kendrick, 1985), the full version of the Wisconsin Card Sorting Test, and four versions of a self-ordered pointing test (Petrides and Milner, 1982), which is a test of working memory, requiring strategy formation for good performance. In addition a written verbal fluency task (Milner, 1964) was administered. In the latter subjects were required to write down as many words as they could think of beginning with the letter S in 5 rain, and as many four-lettered words beginning with the letter C as they could in 4 min. Our use of this test also incorporated a copying condition which controlled for speed of writing whereby the time to copy the preciously generated words was subtracted from the total task time. This permitted the calculation of a Verbal Fluency Index (VFI), a measure of the average time taken to think of each word. All subjects were also asked to complete the Hospital Anxiety and Depression Scale (Zigmond and Snaith, 1983). There was no between groups difference on the measure of anxiety, with all group means also falling below the scores indicative of clinical anxiety. The ALS-pb and ALS-non pb groups scored higher than controls on the depression measure, but again the means were well below the scores for clinical depression on this scale. Data analysis revealed that the predicted premorbid level of IQ, estimated from the NART-R, correlated with some test scores (Paired
S. Abrahams et al. / Journal of the Neurological Sciences 129 (Suppl.) (1995) 54-55
Associate Learning, Word Recognition (Warrington, 1984), V F I , the S e l f - O r d e r e d Pointing tasks a n d V e r b a l IQ) so in the s u b s e q u e n t b e t w e e n g r o u p c o m p a r i s o n s N A R T - R I Q e s t i m a t e s were i n c l u d e d in analysis of covariance. O r t h o g o n a l c o n t r a s t s w e r e used for the b e t w e e n g r o u p c o m p a r i s o n s so that the scores of all A L S p a t i e n t s ( A L S - p b and A L S - n o n pb) w e r e t o g e t h e r c o m p a r e d to the controls, a n d the two p a t i e n t g r o u p s ' scores w e r e c o m p a r e d to each other. A s with o u r p r e v i o u s study (Kew et al., 1993) the analysis r e v e a l e d that the p a t i e n t s were overall imp a i r e d on the V e r b a l F l u e n c y task, this time p r o d u c i n g higher indices t h a n the c o n t r o l s (p = 0.027). T h e A L S p a t i e n t s t h e r e f o r e w e r e taking l o n g e r t h a n the c o n t r o l s to g e n e r a t e the r e q u i r e d words, irrespective of any writing difficulties they m a y have b e e n experiencing. In a d d i t i o n the A L S - p b g r o u p was significantly m o r e imp a i r e d on this m e a s u r e t h a n the A L S - n o n p b g r o u p ( p = 0.041). A l t h o u g h not significant, t h e r e was also a t e n d e n c y for t h e A L S p a t i e n t s to achieve fewer categories a n d m a k e m o r e e r r o r s t h a n c o n t r o l s on the W i s c o n s i n C a r d Sorting T e s t ( p = 0.06 a n d p --- 0.067, respectively), a n o t h e r test of frontal lobe function. O n tests o f m e m o r y we only f o u n d a non-significant tend e n c y for the A L S p a t i e n t s as a w h o l e g r o u p to perform w o r s e t h a n controls on the K e n d r i c k O b j e c t L e a r n i n g T e s t ( p = 0.085) b u t on b o t h the raw a n d age scaled scores, the A L S p a t i e n t s were p o o r e r t h a n controis on the W o r d R e c o g n i t i o n test ( p = 0.037 a n d p = 0.029, respectively). In a d d i t i o n the A L S - n o n pb g r o u p p e r f o r m e d significantly w o r s e t h a n the A L S - p b g r o u p on o n e of the versions of the S e l f - O r d e r e d Pointing test, involving drawings o f everyday objects ( p = 0.029). O n c e again, t h e r e f o r e , it has b e e n shown t h a t as a group, A L S p a t i e n t s p e r f o r m p o o r l y on verbal fluency. This i m p a i r m e n t is p a r t i c u l a r l y p r o m i n e n t in p a t i e n t s with p s e u d o b u l b a r palsy. If we c o m p a r e the p e r c e n t a g e of p e o p l e within e a c h of the p r e s e n t A L S s u b g r o u p s , whose V F I scores fell m o r e t h a n 2 SD b e l o w the m e a n V F I of t h e controls, we find that 8.7% of the A L S - n o n p b a n d 45% of the A L S - p b g r o u p h a d scores m o r e t h a n 2 S D b e l o w this m e a n . T a k i n g a less stringent a p p r o a c h , 34.8% of the A L S - n o n p b and 55% of the A L S - p b g r o u p s h a d scores falling m o r e t h a n 1 SD b e l o w the m e a n V F I score of the c o n t r o l group. A l t h o u g h the V F I was b a s e d on a w r i t t e n task, the scores for t h e A L S p a t i e n t s c o r r e l a t e d significantly with m e a s u r e s of B u l b a r S p e e c h F u n c t i o n ( p = 0.007) a n d of Swallowing ( p = 0.047) on the A L S Severity Scale (Hillel et al., 1989) but not with a m e a s u r e of u p p e r limb i m p a i r m e n t . M o r e studies a r e n e e d e d to d e c i d e w h e t h e r difficulties in subvocalisation c o u l d acc o u n t for t h e s e c o r r e l a t i o n s , and for the g r e a t e r im-
55
p a i r m e n t of the A L S - p b g r o u p on a task which m a y e n c o u r a g e s o u n d - b a s e d g e n e r a t i o n a n d spelling of words. In s u m m a r y , we have f o u n d t h a t i m p a i r m e n t of V e r b a l F l u e n c y is c o m m o n in A L S , a n d is especially linked with p s e u d o b u l b a r palsy. O u r studies have rev e a l e d s o m e i m p a i r m e n t s of m e m o r y , a n d less consistent i m p a i r m e n t s on o t h e r tests of f r o n t a l l o b e function. A l t h o u g h m o r e striking in p a t i e n t s with p s e u d o b u l b a r symptoms, cognitive i m p a i r m e n t is not r e s t r i c t e d to this group; r a t h e r , cognitive i m p a i r m e n t s on f o r m a l n e u r o p s y c h o l o g i c a l testing a p p e a r to be an integral p a r t of A L S , in k e e p i n g with the evidence from o u r P E T studies which show e x t r a - m o t o r involvement (Kew et al., 1993).
Acknowledgements This w o r k was s u p p o r t e d by the M e d i c a l R e s e a r c h Council, U K .
References David, A. and Gillham, R. (1986) Neuropsychological study of motor neurone disease. Psychosomatics, 27: 441-445. Gallassi, R., Montagna, P., Ciardulli, C., Lorusso, S., Mussuto, V. and Stracciari, A. (1985) Cognitive impairment in motor neurone disease. Acta Neurol. Scand., 71: 480-484. Gallassi, R., Montagna, P., Morreale, A., Lorusso, S., Tinuper, P., Daidone, R. and Lugaresi, E. (1989) Neuropsychological, electroencephalogram and brain computed tomography findings in motor neurone disease. Eur. Neurol., 29: 115-120. Hillel, A.D., Miller, R.M., Yorkston, K., McDonald, E., Norris, F.H. and Konikao, N. (1989) Amyotrophic lateral sclerosis severity scale. Neuroepidemiology, 8: 142-150. Kendrick, D. (1985) Cognitive Tests for the Elderly, NFER-Nelson, Windsor. Kew, J.J.M., Goldstein, L.H., Leigh, P.N., Abrahams, S., Cosgrave, N., Passingham, R.E., Frackowiak, R.S.J. and Brooks, D.J. (1993) The relationship between abnormalities of cognitive function and cerebral activation in amyotrophic lateral sclerosis. A neuropsychological and positron emission tomography study. Brain, 116: 1399-1423. Ludolph, A.C., Langen, K.J., Regard, M., Herzog, H., Kempo, B. and Kurwert, T. (1992) Frontal lobe function in amyotrophic lateral sclerosis: a neuropsychologic and positron emission tomography study. Acta Neurol. Scand., 85: 81-89. Milner, B. (1964). Some effects of frontal lobectomy in man. In: J.M. Warren and K. Akert (Eds.), The Frontal Granular Cortex and Behavior, McGraw Hill, New York, NY, pp. 313-334. Petrides, M. and Milner, B. (1982). Deficits on subject-ordered tasks after frontal- and temporal-lobe lesions in man. Neuropsychologia, 20: 249-262. Warrington, E.K. (1984) Recognition Memory Test, NFER-Nelson, Windsor. Zigmond, A.S. and Snaith, R.P. (1983) The hospital anxiety and depression scale. Acta Psychiat. Scand., 67: 361-370.
NEUROLOGICAL SCIENCES ELSEVIER
Journal of the Neurological Sciences 129 (Suppl.) (1995) 54-55
Cognitive deficits in non-demented amyotrophic lateral sclerosis patients: a neuropsychological investigation S. A b r a h a m s
a, L . H . G o l d s t e i n a,*, C . M . L l o y d
b D.J.
B r o o k s e, P . N . L e i g h b
a Department of Psychology, Institute of Psychiatry, De Crespigny Park, London SE5 8AF, UK b Department of Neurology, Institute of Psychiatry, and King's College School of Medicine and Dentistry, Denmark Hill, London SE5 8AF, UK c MRC Cyclotron Unit, Hammersmith Hospital, Du Cane Road, London WI2 OILS, UK Accepted 21 February 1995
Keywords: ALS; P s e u d o b u l b a r palsy; Cognition
Amyotrophic lateral sclerosis (ALS) is not typically thought to be associated with cognitive impairment. Over the last ten years, however, subtle cognitive deficits have been noted in non-demented patients with ALS (Gallassi et al., 1985,1989; David and Gillham, 1986; Ludolph et al., 1992; Kew et al., 1993). These deficits include abnormal design and verbal fluency, visual attention and performance on the Wisconsin Card Sorting Test, and impaired verbal and visual learning and recall. Recently we found that the degree of impaired verbal fluency was related to the extent of dysfunction of a fronto-thalamo-limbic brain system (Kew et al., 1993). In addition different subtypes of MND may be accompanied by differing degrees of cognitive impairment (Gallassi et al., 1985,1989; David and Gillham, 1986). In particular neuropsychological deficits may be more prominent in patients with more advanced disease and with bulbar symptoms (David and Gillham, 1986) but all these studies have used small number of patients. In this study we wished to test the hypothesis that ALS patients with pseudobulbar palsy would have greater cognitive impairment than ALS patients without these symptoms. A total of 52 ALS patients were subdivided into two groups. The first comprised 28 patients with classical ALS but without pseudobulbar involvement (ALS-non pb) and the second comprised 24 patients with classical ALS, who also had pseudobulbar palsy (ALS-pb). A control group of 34 age-
* Corresponding author. Tel.: (+44-171) 919-3381; Fax: (+44-171) 703-9989. 0022-510X/95/$09.50 @ 1995 Elsevier Science B.V. All rights reserved SSDI 0022-51 0 X ( 9 5 ) 0 0 0 6 3 - 1
matched normal adults was also studied. All were assessed with a range of neuropsychological tests, including the National Adult Reading Test-Revised (NART-R) to estimate premorbid IQ, a short form of the WAIS-R to provide an estimate of current Verbal IQ, the Recognition Memory Test (Warrington, 1984), verbal Paired Associate learning from the Wechsler Memory Scale-Revised, the Kendrick Object Learning Test (Kendrick, 1985), the full version of the Wisconsin Card Sorting Test, and four versions of a self-ordered pointing test (Petrides and Milner, 1982), which is a test of working memory, requiring strategy formation for good performance. In addition a written verbal fluency task (Milner, 1964) was administered. In the latter subjects were required to write down as many words as they could think of beginning with the letter S in 5 rain, and as many four-lettered words beginning with the letter C as they could in 4 min. Our use of this test also incorporated a copying condition which controlled for speed of writing whereby the time to copy the preciously generated words was subtracted from the total task time. This permitted the calculation of a Verbal Fluency Index (VFI), a measure of the average time taken to think of each word. All subjects were also asked to complete the Hospital Anxiety and Depression Scale (Zigmond and Snaith, 1983). There was no between groups difference on the measure of anxiety, with all group means also falling below the scores indicative of clinical anxiety. The ALS-pb and ALS-non pb groups scored higher than controls on the depression measure, but again the means were well below the scores for clinical depression on this scale. Data analysis revealed that the predicted premorbid level of IQ, estimated from the NART-R, correlated with some test scores (Paired
S. Abrahams et al. / Journal of the Neurological Sciences 129 (Suppl.) (1995) 54-55
Associate Learning, Word Recognition (Warrington, 1984), V F I , the S e l f - O r d e r e d Pointing tasks a n d V e r b a l IQ) so in the s u b s e q u e n t b e t w e e n g r o u p c o m p a r i s o n s N A R T - R I Q e s t i m a t e s were i n c l u d e d in analysis of covariance. O r t h o g o n a l c o n t r a s t s w e r e used for the b e t w e e n g r o u p c o m p a r i s o n s so that the scores of all A L S p a t i e n t s ( A L S - p b and A L S - n o n pb) w e r e t o g e t h e r c o m p a r e d to the controls, a n d the two p a t i e n t g r o u p s ' scores w e r e c o m p a r e d to each other. A s with o u r p r e v i o u s study (Kew et al., 1993) the analysis r e v e a l e d that the p a t i e n t s were overall imp a i r e d on the V e r b a l F l u e n c y task, this time p r o d u c i n g higher indices t h a n the c o n t r o l s (p = 0.027). T h e A L S p a t i e n t s t h e r e f o r e w e r e taking l o n g e r t h a n the c o n t r o l s to g e n e r a t e the r e q u i r e d words, irrespective of any writing difficulties they m a y have b e e n experiencing. In a d d i t i o n the A L S - p b g r o u p was significantly m o r e imp a i r e d on this m e a s u r e t h a n the A L S - n o n p b g r o u p ( p = 0.041). A l t h o u g h not significant, t h e r e was also a t e n d e n c y for t h e A L S p a t i e n t s to achieve fewer categories a n d m a k e m o r e e r r o r s t h a n c o n t r o l s on the W i s c o n s i n C a r d Sorting T e s t ( p = 0.06 a n d p --- 0.067, respectively), a n o t h e r test of frontal lobe function. O n tests o f m e m o r y we only f o u n d a non-significant tend e n c y for the A L S p a t i e n t s as a w h o l e g r o u p to perform w o r s e t h a n controls on the K e n d r i c k O b j e c t L e a r n i n g T e s t ( p = 0.085) b u t on b o t h the raw a n d age scaled scores, the A L S p a t i e n t s were p o o r e r t h a n controis on the W o r d R e c o g n i t i o n test ( p = 0.037 a n d p = 0.029, respectively). In a d d i t i o n the A L S - n o n pb g r o u p p e r f o r m e d significantly w o r s e t h a n the A L S - p b g r o u p on o n e of the versions of the S e l f - O r d e r e d Pointing test, involving drawings o f everyday objects ( p = 0.029). O n c e again, t h e r e f o r e , it has b e e n shown t h a t as a group, A L S p a t i e n t s p e r f o r m p o o r l y on verbal fluency. This i m p a i r m e n t is p a r t i c u l a r l y p r o m i n e n t in p a t i e n t s with p s e u d o b u l b a r palsy. If we c o m p a r e the p e r c e n t a g e of p e o p l e within e a c h of the p r e s e n t A L S s u b g r o u p s , whose V F I scores fell m o r e t h a n 2 SD b e l o w the m e a n V F I of t h e controls, we find that 8.7% of the A L S - n o n p b a n d 45% of the A L S - p b g r o u p h a d scores m o r e t h a n 2 S D b e l o w this m e a n . T a k i n g a less stringent a p p r o a c h , 34.8% of the A L S - n o n p b and 55% of the A L S - p b g r o u p s h a d scores falling m o r e t h a n 1 SD b e l o w the m e a n V F I score of the c o n t r o l group. A l t h o u g h the V F I was b a s e d on a w r i t t e n task, the scores for t h e A L S p a t i e n t s c o r r e l a t e d significantly with m e a s u r e s of B u l b a r S p e e c h F u n c t i o n ( p = 0.007) a n d of Swallowing ( p = 0.047) on the A L S Severity Scale (Hillel et al., 1989) but not with a m e a s u r e of u p p e r limb i m p a i r m e n t . M o r e studies a r e n e e d e d to d e c i d e w h e t h e r difficulties in subvocalisation c o u l d acc o u n t for t h e s e c o r r e l a t i o n s , and for the g r e a t e r im-
55
p a i r m e n t of the A L S - p b g r o u p on a task which m a y e n c o u r a g e s o u n d - b a s e d g e n e r a t i o n a n d spelling of words. In s u m m a r y , we have f o u n d t h a t i m p a i r m e n t of V e r b a l F l u e n c y is c o m m o n in A L S , a n d is especially linked with p s e u d o b u l b a r palsy. O u r studies have rev e a l e d s o m e i m p a i r m e n t s of m e m o r y , a n d less consistent i m p a i r m e n t s on o t h e r tests of f r o n t a l l o b e function. A l t h o u g h m o r e striking in p a t i e n t s with p s e u d o b u l b a r symptoms, cognitive i m p a i r m e n t is not r e s t r i c t e d to this group; r a t h e r , cognitive i m p a i r m e n t s on f o r m a l n e u r o p s y c h o l o g i c a l testing a p p e a r to be an integral p a r t of A L S , in k e e p i n g with the evidence from o u r P E T studies which show e x t r a - m o t o r involvement (Kew et al., 1993).
Acknowledgements This w o r k was s u p p o r t e d by the M e d i c a l R e s e a r c h Council, U K .
References David, A. and Gillham, R. (1986) Neuropsychological study of motor neurone disease. Psychosomatics, 27: 441-445. Gallassi, R., Montagna, P., Ciardulli, C., Lorusso, S., Mussuto, V. and Stracciari, A. (1985) Cognitive impairment in motor neurone disease. Acta Neurol. Scand., 71: 480-484. Gallassi, R., Montagna, P., Morreale, A., Lorusso, S., Tinuper, P., Daidone, R. and Lugaresi, E. (1989) Neuropsychological, electroencephalogram and brain computed tomography findings in motor neurone disease. Eur. Neurol., 29: 115-120. Hillel, A.D., Miller, R.M., Yorkston, K., McDonald, E., Norris, F.H. and Konikao, N. (1989) Amyotrophic lateral sclerosis severity scale. Neuroepidemiology, 8: 142-150. Kendrick, D. (1985) Cognitive Tests for the Elderly, NFER-Nelson, Windsor. Kew, J.J.M., Goldstein, L.H., Leigh, P.N., Abrahams, S., Cosgrave, N., Passingham, R.E., Frackowiak, R.S.J. and Brooks, D.J. (1993) The relationship between abnormalities of cognitive function and cerebral activation in amyotrophic lateral sclerosis. A neuropsychological and positron emission tomography study. Brain, 116: 1399-1423. Ludolph, A.C., Langen, K.J., Regard, M., Herzog, H., Kempo, B. and Kurwert, T. (1992) Frontal lobe function in amyotrophic lateral sclerosis: a neuropsychologic and positron emission tomography study. Acta Neurol. Scand., 85: 81-89. Milner, B. (1964). Some effects of frontal lobectomy in man. In: J.M. Warren and K. Akert (Eds.), The Frontal Granular Cortex and Behavior, McGraw Hill, New York, NY, pp. 313-334. Petrides, M. and Milner, B. (1982). Deficits on subject-ordered tasks after frontal- and temporal-lobe lesions in man. Neuropsychologia, 20: 249-262. Warrington, E.K. (1984) Recognition Memory Test, NFER-Nelson, Windsor. Zigmond, A.S. and Snaith, R.P. (1983) The hospital anxiety and depression scale. Acta Psychiat. Scand., 67: 361-370.