Abstract
The pattern of cortical and subcortical neuropathologic lesions in corticobasal degeneration (CBD) should predict a specific cognitive profile in this disease.To characterize this profile and to determine its specificity by comparison with progressive supranuclear palsy (PSP) and senile dementia of the Alzheimer's type (SDAT), we used an extensive neuropsychological battery assessing global efficiency, executive functions, various tests of encoding and retrieval, dynamic motor organization, and upper limb praxis. We compared the performance of patients with CBD (n equals 15) with that of controls (n equals 19) matched for age and education, and with that of patients with PSP and SDAT (15 in each group), matched for severity of dementia and depression. Patients with CBD showed: (1) a moderate global deterioration; (2) a dysexecutive syndrome similar to that of patients with PSP and more severe than in SDAT; (3) explicit learning deficits, without retention difficulties and easily compensated by using the same semantic cues at encoding and retrieval as in PSP; this was in contrast with SDAT where cued recall and recognition were also impaired; (4) disorders of dynamic motor execution (temporal organization, bimanual coordination, control, and inhibition) similar to those of patients with PSP and not in SDAT; (5) asymmetric praxis disorders (posture imitation, symbolic gesture execution, and object utilization) that were not observed in PSP or SDAT. Patients with CBD show a specific neuropsychological pattern associating a dysexecutive syndrome, likely due to degeneration of the basal ganglia and prefrontal cortex, and asymmetric praxis disorders, which might be related to premotor and parietal lobe lesions. This neuropsychological profile may help to distinguish this condition clinically from other neurodegenerative diseases.
NEUROLOGY 1995;45: 1477-1483
Corticobasal degeneration (CBD) is a slowly progressive disorder with asymmetric onset, characterized by an akineto-rigid syndrome (unresponsive to levodopa), apraxia, dystonia, and postural abnormalities, [1-6] associated with an asymmetric hypometabolism contralateral to the more affected limb in PET studies. [4-6] Corticodentatonigral degeneration with neuronal achromasia is the pathologic hallmark. [1-4] Cortical lesions predominate in the frontoparietal cortex, without significant hippocampal damage. Subcortical lesions are mainly in the thalamus, the striatum, and the substantia nigra.
Given the definite pattern of neuronal lesions, we should expect a specific cognitive profile, involving at least executive functions and retrieval processes in relation to degenerative lesions of the frontal cortex and the striatum, and gestural abilities due to the involvement of the parietal cortex. Because there has been only one neuropsychological study in these patients, published as an abstract, [7] the aims of our study were to analyze the cognitive pattern of CBD using an extensive neuropsychological battery, including dynamic motor and gestural disorder exploration, and to compare this pattern with that of progressive supranuclear palsy (PSP), characterized mainly by diffuse subcortical lesions, [8] and senile dementia of the Alzheimer's type (SDAT), characterized mainly by histologic changes in the hippocampus and associative cortex. [9]
Methods.
Subjects.
Fifteen patients, all right-handed, with diagnosis of probable CBD were studied (mean age plus minus SD: 67.8 plus minus 8.0 years; mean level of education: 9.2 plus minus 2.1 years). All fulfilled the following criteria [10]: (1) progressive course of the disease; (2) no evidence of detectable focal lesion on CT or MRI; (3) disease duration less than 10 years; (4) clearly asymmetric onset of the disease, (5) parkinsonism (bradykinesia and rigidity); (6) praxic disorders; (7) absence of dysautonomia and supranuclear palsy; (8) no significant improvement with levodopa. To support the diagnosis, all patients were studied with PET and showed the asymmetric subcortico-cortical hypometabolism contralateral to the more affected limb that is characteristic of the disease. [4-6] Other clinical characteristics included: dysarthria (n equals 8), postural instability (n equals 8), dystonia (n equals 7), myoclonus (n equals 4), cortical sensory loss (n equals 2), and alien limb (n equals 2). The more affected limb was the right one in 11 patients, the left one in four. Mean disease duration was 3.4 plus minus 2.2 years.
Patients with PSP (n equals 15; mean age: 70.3 plus minus 4.5 years; mean level of education: 8.6 plus minus 0.6 years) met the following criteria [11]: (1) progressive course of the disease; (2) no evidence of a focal lesion on a sensorimotor examination or CT scan; (3) disease duration less than 10 years; (4) severe postural instability and falls without specific etiology; (5) parkinsonism (bradykinesia and axial rigidity); (6) supranuclear vertical ophthalmoplegia; (7) either pseudobulbar palsy or dystonic dysarthria; (8) no significant improvement with levodopa treatment (less than 25%). Duration of disease was 4.9 plus minus 3.5 years. The mean Hoehn and Yahr [12] stage was 3.9 plus minus 0.8. The mean baseline disability score, assessed with the Unified Parkinson's Disease Rating Scale, [13] was 37.3 plus minus 13.9.
Probable SDAT was diagnosed according to the National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer's Disease and Related Disorders Association Work Group criteria. [14] Neurologic examination and serum analyses were normal in all patients (n equals 15; mean age: 72.1 plus minus 6.0 years; mean education level: 9.6 plus minus 2.3 years). Ischemic scores were not higher than 4 in any patient. [15] CT scan was normal in 11 patients and showed some degree of cortical atrophy in four others. Duration of disease was 2.5 plus minus 1.2 years. The mean score on the Mini-Mental State Examination [16] was 21.5 plus minus 1.2. Social autonomy [17] was affected in 10 patients.
The three groups of patients were matched for the severity of dementia, which was moderate on the Mattis Dementia Rating Scale [18] (110.7 plus minus 16.0 in CBD, 110.8 plus minus 10.3 in PSP, 112.9 plus minus 13.1 in SDAT), and depression, which was mild on the Montgomery and Asberg Depression Rating Scale [19] (9.3 plus minus 5.4 in CBD, 12.6 plus minus 4.2 in PSP, 8.1 plus minus 5.2 in SDAT). Informed consent was obtained from every subject after the nature of the procedures had been fully explained.
Nineteen subjects without neurologic or psychiatric disease served as controls. They did not differ significantly from patients for age (73.4 plus minus 6.4 years) or level of education (8.1 plus minus 2.1 years). Their mean scores were 28.4 plus minus 0.9 on the Mini-Mental State Examination [16] and 6.4 plus minus 3.8 on the Montgomery and Asberg Depression Rating Scale. [19]
General neuropsychological assessment.
Global efficiency, executive functions, explicit memory, and spatial functions were assessed.
Global evaluation.
Global intellectual and memory performance were evaluated with the Mattis Dementia Rating Scale, the Raven 47 Colored Progressive Matrices (PM 47), and the Wechsler Memory Scale, to compare the cognitive pattern of the three groups of patients at the same level of global deterioration.
Executive functions.
The simplified version of the Wisconsin Card Sorting Test, [20] verbal fluency tests (category fluency: animal names in 1 minute; phonemic fluency: words beginning with ``M'' in 1 minute), [21] and a graphic series [22] were used to evaluate executive functions. Behavioral abnormalities (prehension, imitation, and utilization behaviors; inertia; and indifference) observed in patients with frontal lobe lesions [23] were also assessed, using a scale with precise steps ranging from 4 (normal behavior) to 0 (very severe abnormality). For instance, the score of imitation behavior was: (4) if the patient was perplexed by the examiner's arbitrary gestures; (3) if the patient asked if he had to imitate; (2) if the patient imitated, but stopped when asked by the examiner not to imitate; (1) if the patient imitated again after a short distracting period; (0) if the patient continued to imitate, while the examiner was saying not to do so. Previous studies have shown the reliability of these various tests, [20-23] particularly when they are included in an extensive battery. [24,25] From the performance of these tasks, a frontal score was defined, [11] which has been shown to be related to frontal hypometabolism in PSP. [26] Is the dysexecutive syndrome of CBD as severe as that of PSP?
Explicit memory tests.
Specific aspects of explicit memory were studied with two complementary tests that permit differentiation of the true amnesic syndrome of SDAT, compatible with lesions of hippocampus and temporal cortex, and the inefficient planning of memory processes observed in PSP and other predominantly subcortical neurodegenerative diseases. The California Verbal Learning Test [27] includes the following steps: (1) learning, across five trials, of a 16-item shopping list (the Monday list or list A) belonging to four embedded semantic categories (tools, spices and herbs, fruits, clothing); (2) one recall trial of an interference list of 16 shopping items (the Tuesday list or list B) belonging to four embedded semantic categories (fishes, spices and herbs, fruits, utensils), two of which are common with list A; (3) short-delay free recall of list A; (4) short-delay cued recall of list A, providing the subject with each of the four category names to facilitate recall; (5) long-delay free recall of list A (after a delay of 20 minutes); (6) long-delay cued recall of list A; and (7) recognition of the list A items from a variety of foils, including items of list B from semantically similar and different categories.
In a different session, the subjects were given the Grober and Buschke Test [28] with controlled encoding and selective reminding. In this task, encoding is controlled by asking the examinee to point to and read aloud each of the 16 to-be-remembered items, presented four at a time, in response to its semantic category. Our adaptation of the procedure used written printed words on cards, rather than labeled pictures. All 16 items had to be retrieved at immediate cued recall before starting memory assessment, which consisted of three consecutive series of free recall and cued recall with selective reminding. These series were separated by 20-second, counting-backward periods, in order to obtain recall from secondary memory. Whenever a subject was unable to retrieve an item at cued recall, the correct answer was provided by the examiner. The numbers of correct answers retrieved by the subject at either free or cued recall for a given series were added to obtain a total recall score. Maximum total score for the three series was 48. Free recall, cued recall, and yes-no recognition performance were also measured after a delay of 20 minutes.
Spatial functions.
Visuospatial and visuoconstructive abilities, sensitive to parietal lesions, were assessed with the Corsi Block Span in direct and inverse orders, two drawings, and items 0, 3, and 5 of the Wechsler Adult Intelligence Scale Block Design Subtest. Body schema was evaluated with designation of 10 body parts and with Head's test. [22]
Dynamic motor and gestural organization.
Different aspects of motor and gestural control, such as temporal organization, bimanual coordination, interference inhibition, and buccofacial and upper limb gestures, were assessed because they are sensitive to frontal and parietal dysfunction. Unimanual and bimanual dexterity were measured with the Purdue Pegboard Test. [29] Tapping reproduction, rhythm reproduction, unimanual (fist-edge-palm) and bimanual (left hand fist-right hand fingers extended--switch hand positions simultaneously) motor series, graphic series (alternating squares and diamonds), go-no go (one tap--hand up; two taps--hand down), and one tap-two taps (subject taps once when the examiner taps twice and vice versa) were adapted from Luria. [22] Untouched hand up evaluated the ability to respond to conflicting commands including the two hands. [30] Oral apraxia was investigated with the execution of 10 gestures on command and on imitation. [31] Upper limb praxis was assessed with (1) reproduction of 10 different positions for each part of the upper limbs (arm, hand, fingers), adapted from Jason, [32] and of 10 bimanual positions, such as intricated finger rings; (2) execution on command and on imitation, and recognition of 10 symbolic gestures [31]; (3) execution with and without object (pantomime by the examinee) and recognition without object (pantomime by the examiner) of 10 actions requiring object utilization. [33] For oral and upper limb gestures, one point was scored for a correct performance, 0.5 point when the trial had to be repeated, 0 point in case of failure on the second trial. The reliability of praxis tests is reasonably well established. [31-34] Experimental data are beginning to be obtained for tests of dynamic motor organization. [24,29,30,35]
Statistical analyses.
The four groups of subjects were compared all together by nonparametric analyses, given variance heterogeneity. Multiple testing was dealt with by a step-down procedure based on the Tukey-Welsch specification of nominal levels and on Kruskal-Wallis statistics (Hochberg and Tamhane, [36] pages 69, 110 to 111, and 246 to 249). This procedure allows, at a global familywise error rate of 0.05, inferences on any subset homogeneity hypothesis between groups of subjects (the four groups in this study) for a given group of variables. Control of the error rates was considered separately for each group of neuropsychological variables: global evaluation (four variables), executive functions (eight variables), explicit memory tests (23 variables), spatial functions (five variables), dynamic motor control (nine variables), and praxis (12 variables).
Results.
General neuropsychological assessment.
Global efficiency and executive functions of patients with CBD were significantly impaired when compared with controls. The relative scores of both groups were: 110.7 plus minus 16.0 for patients versus 141.1 plus minus 3.0 for controls for the Mattis scale, 89.9 plus minus 20.0 versus 110.9 plus minus 13.8 for the Raven PM 47, 88.7 plus minus 15.6 versus 111.8 plus minus 9.1 for the Wechsler Memory Scale, 2.2 plus minus 1.7 versus 5.6 plus minus 1.1 for the Wisconsin Card Sorting Test number of criteria, 10.7 plus minus 5.0 versus 16.8 plus minus 4.7 for category fluency, 4.7 plus minus 3.8 versus 9.8 plus minus 4.0 for phonemic fluency, 0.0 plus minus 0.0 versus 9.8 plus minus 0.4 for graphic series, 2.3 plus minus 1.3 versus 4.0 plus minus 0.0 for prehension behavior, 2.1 plus minus 0.9 versus 4.0 plus minus 0.0 for imitation behavior, and 25.7 plus minus 12.1 versus 58.5 plus minus 2.6 for the global frontal score. There was no significant between-groups difference for utilization behavior. The performance of patients with CBD was similar to that of patients with PSP for all tests, except the graphic series was more impaired in CBD (0.0 plus minus 0.0 versus 3.3 plus minus 4.1). Utilization behavior, however, was only observed in five CBD patients, as opposed to 11 patients with PSP. The frontal score was more impaired in patients with CBD (25.7 plus minus 12.1) than in patients with SDAT (37.9 plus minus 13.9), although the difference was significant only for graphic series (0.0 plus minus 0.0 versus 5.5 plus minus 3.2), prehension (2.3 plus minus 1.3 versus 3.8 plus minus 0.6), and imitation (2.1 plus minus 0.9 versus 3.3 plus minus 1.0) behaviors.
A complete evaluation of explicit memory was available for 10 patients with CBD. These 10 patients had the same clinical and neuropsychological characteristics as their whole group. On the California Verbal Learning Test (free encoding situation), their performance was lower in all subtests when compared with controls Figure 1, but the difference was not significant, given the variability of the results of patients with CBD and the correction for multiple comparisons. The performance of CBD patients was similar to that of PSP patients, but better than that of SDAT patients for short- and long-delay free recall Figure 1 and false positives at recognition (m equals 3.7 plus minus 2.6 in CBD versus 10.5 plus minus 3.1 in SDAT, p less than 0.05).
Figure 1. California Verbal Learning Test. Performance in controls and patients with corticobasal degeneration (CBD), progressive supranuclear palsy (PSP), and senile dementia of the Alzheimer's type (SDAT). A1 equals list A trial 1; A5 equals list A trial 5; B equals interfering list B; SDFR equals short-delay free recall; SDCR equals short-delay cued recall; LDFR equals long-delay free recall; LDCR equals long-delay cued recall. Results are expressed as mean plus minus SEM.
On the Grober and Buschke test (controlled encoding situation), the performance of patients with CBD, although lower, did not significantly differ from that of controls Figure 2. Global free recall (18.9 plus minus 7.0 in CBD versus 25.9 plus minus 7.0 in controls) and global total recall (42.5 plus minus 7.9 in CBD versus 46.2 plus minus 1.7 in controls) showed no significant difference between the two groups. The performance of patients with CBD did not significantly differ from that of patients with PSP, but was significantly better than that of patients with SDAT for immediate free recall (18.9 plus minus 7.0 in CBD versus 7.7 plus minus 7.4 in SDAT, p less than 0.05) and total recall (42.5 plus minus 7.9 in CBD versus 24.4 plus minus 9.7 in SDAT, p less than 0.05), and for delayed free recall and total recall Figure 2.
Figure 2. Grober and Buschke Test. Performance in controls and patients with corticobasal degeneration (CBD), progressive supranuclear palsy (PSP), and senile dementia of the Alzheimer's type (SDAT) at the three trials and the delayed trial (from left to right) and in the free recall and total recall (from top to bottom). Results are expressed as mean plus minus SEM. x equals p less than 0.05 when compared with CBD, after correction for multiple comparisons.
On tests of visuospatial functions and body schema the performance of patients with CBD differed from that of controls only for Corsi Block Span direct (2.9 plus minus 2.0 versus 5.0 plus minus 0.0) and inverse (2.0 plus minus 1.5 versus 4.0 plus minus 0.5), but not for construction (2.4 plus minus 2.3 versus 4.9 plus minus 0.4), body part designation (14.6 plus minus 6.8 versus 20.0 plus minus 0.0), or Head's test (5.9 plus minus 4.7 versus 10.0 plus minus 0.0).
Dynamic motor and gestural organization.
All patients with CBD and SDAT, seven patients with PSP, and eight controls completed the whole battery. All characteristics of these subgroups of PSP patients and controls were similar to those of their whole groups. The performance of patients with CBD Table 1.* was significantly lower than that of controls for all tests, except for rhythm reproduction, go-no go, and untouched hand up tests, where the variance was very high in CBD patients, and the recognition tests of symbolic and object use gestures, where scores were almost normal. It was also significantly lower than that of SDAT patients for the majority of tests and than that of PSP patients in tests of upper limb praxis. In contrast, the performance of CBD patients was similar to that of patients with PSP on nearly all tests of dynamic motor control and execution, except that unimanual and bimanual dexterity were more impaired in CBD.
Table 1. Dynamic motor and gestural tests
Asymmetry of the motor and gestural disorders.
Performance was similar for the two upper limbs in controls and patients with PSP and SDAT. In patients with CBD, in contrast, it was lower for the more affected limb on all unimanual tests, although the performance of the less affected limb was inferior to that of controls, showing that the deficits affected both sides.
Influence of the laterality of the more affected upper limb.
The more affected limb was the right one in 11 patients and the left one in four patients. In the latter subgroup, visuospatial tests (PM 47, Corsi Block Span, constructive tests) were more impaired.
Discussion.
Patients with CBD were moderately demented, confirming previous studies that showed a moderate cognitive deterioration in association with the motor disorders. [1-7] Their neuropsychological pattern differed, however, from that of PSP and SDAT patients matched for severity of dementia. These results must be interpreted cautiously, since our inclusion criteria, although in agreement with those of other clinical studies, [3-7,37] have likely increased the homogeneity of our group of patients. For instance, the introduction of praxic disorders as an inclusion criterion reinforces the clinical diagnosis, [1-7] but may constitute a bias, since about 20% of patients with CBD did not have apraxia [37] and were excluded from the study. Furthermore, as in all clinical studies, a neuropathologic investigation would not confirm the clinical diagnosis in all patients. We believe our results probably characterize a majority of patients with CBD, but not all patients, and should be confirmed by neuropathologic verification.
General neuropsychological assessment.
The cognitive deterioration resembles the subcorticofrontal dysfunction in patients with neurodegenerative damage of the basal ganglia: a dysexecutive syndrome as severe as that of patients with PSP, and a learning deficit that can be alleviated by semantic cueing. [38,39] Along with those similarities, however, we observed some subtle differences between CBD and PSP patients: utilization behavior, related to a release of the activities of the parietal lobes, was less frequent in CBD, probably because there is parietal lobe dysfunction in this disease [23]; the self activation of retrieval processes was partly preserved in CBD, since semantic control of encoding (Grober and Buschke Test) improved the free recall performance of these patients, whereas PSP patients need, in addition, semantic cueing at recall to normalize their performance. [39] CBD may be more associated with an encoding than with a retrieval deficit.
The cognitive pattern of CBD patients, however, differed more strikingly from that of SDAT patients, whose performance showed a less severe dysexecutive syndrome, but more severe learning deficits in the controlled encoding situation and impaired delayed recall and recognition.
Dynamic motor and gestural organization.
Performance on motor and gestural organization showed dramatic differences between CBD patients and SDAT patients on nearly all tests, and between CBD patients and PSP patients on tests of upper limb praxis. All the tests used for the assessment of manual dexterity, motor programming, and execution of gestures showed impairment in CBD, except those that rely on recognition. This preservation of normal identification of gestures suggests that mental representations or conceptual aspects of gestures are not involved in the disease. Instead, movement activation and execution were impaired at all levels of organization: (1) disorder of motor control and specific activation of simple movements, as shown by difficulties exhibited in unimanual and bimanual dexterity, significantly more severe than those of patients with PSP or SDAT; (2) disturbances of motor programming, as shown by impaired performance in temporal organization, bimanual coordination, control and inhibition of interfering motor activities, also present in PSP; (3) disorders of posture reproduction, symbolic gesture evocation and imitation, object use gestures without (pantomime) and with objects, not observed in patients with SDAT or PSP.
The abnormalities do not conform to a strict definition of apraxia, [34] because of the severe impairment of manual dexterity. The disruption of voluntary movements, however, goes ``beyond that which might be explained by concomitant motor or sensory signs'' [5] and raises the question of an underlying apraxic disorder in relation to the cortical parietal involvement reported in the disease both in postmortem [1,2] and in metabolic [6] studies. Furthermore, the less-affected limb also showed gesture disorders in this study and another. [37] This latter study also found that these disorders were more frequent in patients who had initial symptoms in the right limb (left hemisphere dysfunction), in agreement with the predominant storage of ``movement formulae'' in the left hemisphere. [34] We did not observe conceptual apraxia, [40,41] related to severe cognitive impairment and probably diffuse lesions in CBD. [37] The gesture disorders would therefore correspond to ideomotor apraxia, [34] the more frequent type of apraxia in CBD. [37] Three of our patients, however, with early disease, had unilateral right apraxia that might correspond to ``limb kinetic apraxia'' described in patients with lesions in premotor cortex. [42] Constructive praxis was relatively preserved in patients in our study given the predominance of left hemisphere degeneration, but was impaired in the four patients with predominant right hemisphere lesions. Buccofacial apraxia was also specific to patients with CBD, but was milder than limb apraxia.
Acknowledgments
We thank Florence Calicis, Chantal Wyns, and Martial Van der Linden, who kindly permitted use of their French adaptation of the Grober and Buschke Test; Anne Marie Bonnet and Agnes Michon, who permitted us to examine their patients; Pr. Alain Mallet and Sylvie Escolano (Departement de Biomathemathiques et Informatique Medicale, Universite Pierre et Marie Curie, Faculte de Medecine Pitie-Salpetriere), members of the Groupe d'Epidemiologie et Recherche Clinique (GERC), for their kind advice and help in statistical analyses.
- Copyright 1995 by Advanstar Communications Inc.
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