J Neural Transm (2010) 117:369–375 DOI 10.1007/s00702-009-0365-z
MOVEMENT DISORDERS - ORIGINAL ARTICLES
Cognition in multiple system atrophy: neuropsychological profile and interaction with mood Meirav Balas • Yacov Balash • Nir Giladi Tanya Gurevich
•
Received: 11 October 2009 / Accepted: 23 December 2009 / Published online: 21 January 2010 Ó Springer-Verlag 2010
Abstract We evaluated cognitive functions and mood in two groups of patients with multiple system atrophy (MSA) in order to determine the influence of mood on cognitive performance. Our aim was to differentiate between parkinsonism-predominant (MSA-P) and cerebellar-predominant (MSA-C) MSA based on those parameters. Fifteen MSA-P and 10 MSA-C patients underwent neuropsychological tests that examined executive functions (working memory, response inhibition, and verbal reproduction), verbal learning and memory, verbal and visual reasoning, and processing speed. Anxiety and depression were also assessed. The findings on their cognitive performance and mood were compared to those of healthy controls and also discussed in relation to a group of Parkinson’s disease (PD) patients. The results showed that cognitive and mood characteristics could distinguish MSA-P from MSA-C and that anxiety and depression are related to cognitive decline. Compared with healthy controls, MSA-P patients showed reduced verbal retrieval (immediate, P \ 0.019; long-term, P \ 0.018) while MSA-C patients had difficulties in learning new verbal information (P \ 0.022) and in controlling attention (P \ 0.023). These data indicate that MSA-P and MSA-C appear to have, at least in part,
M. Balas (&) Y. Balash N. Giladi T. Gurevich Movement Disorder Unit, Department of Neurology, Tel-Aviv Sourasky Medical Center, Tel-Aviv, Israel e-mail:
[email protected] M. Balas Y. Balash N. Giladi T. Gurevich Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel M. Balas The Brain Behavior Research Center, University of Haifa, Haifa, Israel
different cognitive and mood profiles. The neuropsychological assessments of MSA patients should test for and then take into account their level of anxiety and depression, insofar as it might have an adverse effect on their cognitive performance. Keywords Multiple system atrophy Parkinsonian type Cerebellar type Executive functions Mood
Introduction Multiple system atrophy (MSA) is a sporadic progressive neurodegenerative disease that includes varying combinations of Parkinsonism, cerebellar and pyramidal signs, and autonomic failure (Gilman et al. 2000). The brain pathology of MSA has been observed in cortical and sub-cortical regions, the substantia nigra, olives (Wenning et al. 1995; Schrag et al. 2000), basal ganglia, supplementary and primary motor cortices, the reticular formation, and the pontocerebellar system (Papp and Lantos 1994). In addition to these motor symptoms, cognitive deficits have also been reported in MSA (Robbins et al. 1994; Meco et al. 1996; Monza et al. 1998; Lange et al. 2003; Kawai et al. 2008; Chang et al. 2009), although dementia is thought to be an exclusion criterion for the diagnosis of MSA (Gilman et al. 1999). Two types of MSA are distinguished clinically (Gilman et al. 1999), Parkinsonism predominant (MSA-P) that occurs in 80% of the patients, and cerebellar predominant (MSA-C) that is found in 20% of the patients (Quinn 1989; Gilman et al. 1998). The main sites of pathology in MSA-P are the striatonigral system (Kume et al. 1993; Wenning et al. 1996) and the basal ganglia with its cortical targets of striatal projections, such as the primary
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sensorimotor, lateral premotor, and prefrontal cortices (Brenneis et al. 2003; Lee et al. 2004). In MSA-C, neurodegeneration is mainly found in the olivopontocerebellar system (Kume et al. 1993; Wenning et al. 1996; Lee et al. 2004). Kawai et al. (2008) recently used neuropsychological tests and single photon emission computed tomography (SPECT) to evaluate cognitive functions and brain blood flow in MSA-P and MSA-C patients. Patients with MSA-P showed reduced performance in visuospatial, constructional, and executive functions, and their poor cognitive performance was associated with prefrontal and temporal brain activation. Patients with MSA-C were also impaired in visuospatial and the constructional tests, which were related to activation of the frontal lobe and the cerebellum. The conventional classification of MSA patients into MSA-P or MSA-C in the clinical setting is determined solely by motor syndrome. Our first aim of the current investigation was to test whether each MSA type has its own profile of cognitive functions and mood. In Kawai et al.’s (2008) study, both types of MSA patients reported significant high levels of depression. In another study, MSA-C patients reported that they had high levels of anxiety (Chang et al. 2009). Neither of these two studies, however, controlled for the effect of mood in the analysis of their results. Therefore, in order to test the cognitive deficits of the patients without the adverse effect of mood, we statistically accounted for anxiety and depression. Our second aim was to distinguish cognitive features of MSA from those of Parkinson’s disease (PD) based on previous findings on executive dysfunction (e.g., Soliveri et al. 2000; Stocchi and Brusa 2000; Santangelo et al. 2007) and depression (e.g., Starkstein et al. 1990; Stocchi and Brusa 2000) (reviewed in Cummings 1992; Dubois and Pillon 1997; Marsh 2000; Caballol et al. 2007; Reijnders et al. 2008) in both MSA groups and in PD.
Methods Subjects The study was composed of two groups of MSA patients (MSA-P and MSA-C), one group of PD patients, and one control group. The MSA patients were diagnosed and divided into Parkinsonian or cerebellar type by at least two movement disorders specialists and were found to fulfil diagnostic criteria for MSA (Gilman et al. 1999). Fifteen patients were diagnosed as having MSA-P (9 males and 6 females, mean age 61.8 ± 9.6 years), and 10 patients as having MSA-C (6 males and 4 females, mean age 59.8 ± 11.8 years). In the MSA-C group, five patients did not use any medication, one patient used dopamine agonist, one used medications for orthostatic hypotension (midodrine and fludrocortisone), three used amantadine, and two used levodopa. In the MSA-P group, 10 patients used amantadine, 10 used levodopa, 4 used dopamine agonists and selegiline, and 3 patients used midodrine and fludrocortisone, in different combinations. PD was diagnosed according to the UK Brain Bank criteria (Hughes et al. 1992) and accepted criteria (Douglas et al. 1999). The PD group was composed of 12 patients (8 males and 4 females, mean age 60.6 ± 9.6 years). All the PD patients used levodopa, eight used dopamine agonists and selegiline, and three used amantadine, in different combinations. No PD patient used pramipexol that may improve mood. The severity of the disease in MSA patients was assessed according to Unified Multiple System Atrophy Rating Scale (UMSARS) (Wenning et al. 2004). Table 1 summarizes the background characteristics of the groups. Patients with dementia according to DSM IV or with additional diseases that could affect cognitive performance were excluded. Patients with ineligible speech and/or severe blurred vision were excluded from the study
Table 1 Background characteristics of the patients (MSA-P, MSA-C, PD) and the controls Controls (N = 10)
MSA-P (N = 15)
MSA-C (N = 10)
PD (N = 12)
P value*
Gender (male/female)
6/4
9/6
6/4
8/4
Age (years)
57.4 ± 3.3
61.8 ± 9.6
59.8 ± 11.8
60.6 ± 9.6
0.786
Education (years) Disease duration (years)
13.7 ± 4.1 –
11.9 ± 4.3 5.3 ± 4.1
14.0 ± 2.9 3.2 ± 1.3
15.5 ± 1.4 6.9 ± 6.4
0.076 0.169
UMSARS, part 1
–
16.0 ± 6.3
14.7 ± 9.1
–
0.683
UMSARS, part 2
–
18.2 ± 6.2
18.1 ± 9.8
–
0.972
UMSARS, part 4
–
2.1 ± 0.8
2.4 ± 0.7
–
0.319
MSA-P MSA of parkinsonian type, MSA-C MSA of cerebellar type, PD Parkinson’s disease, UMSARS Unified Multiple System Atrophy Rating Scale, UMSARS part 1 Historical review, UMSARS part 2 Motor Examination Scale, UMSARS part 4 Global Disability Scale * ANOVA comparing each characteristic in the four groups in age, education, and disease duration; Independent t tests between MSA-P and MSA-C in the three parts of the UMSARS
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as well. The healthy controls were 10 subjects (6 males and 4 females mean age 55.9 ± 11.7 years) with no history of head injury, or neurological, psychiatric, or physical illness. Procedure We compared the results of cognitive and mood evaluations of MSA-P, MSA-C, PD, and healthy controls. The study was retrospective; the data were collected from the medical files of the patients observed in the Movement Disorders Unit of Tel-Aviv Sourasky Medical Center who underwent neuropsychological assessment during their follow-up. The study was approved by the Ethics Committee of Tel-Aviv Medical Center (#08-438). All subjects signed a consent form to undergo a neuropsychological evaluation. The control subjects underwent similar neuropsychological assessments after signing a consent form. Neuropsychological tests A set of cognitive tests as well as self-report inventories for evaluating state and trait anxiety (Spielberger 1983) and depression (Beck et al. 1961) were used. The selected tests required verbal and not motor responses in order to reduce the influence of any existing motor slowness on cognitive performance. The tests included the Rey auditory verbal learning test (RAVLT) (Rey 1964), which is a verbal learning test that evaluates episodic memory, delayed recall, recognition, and interference. This test consists of 9 parts: immediate memory of a 15-word list (list A), 4 learning repetitions of list A, immediate memory of another 15-word list (list B), recall of list A, delayed recall of list A and recognition of the words of list A. Executive functions were evaluated by digit span, a subtest from WAIS-III, that measures the span of immediate verbal recall and mental tracking, and the color-word Stroop test (Stroop 1935) that measures visual selective attention and the ability to inhibit a pre-potent response. Reasoning skills were evaluated by two tests, the similarities subtest from
WAIS-III for abstract verbal reasoning, and the picture completion subtest from WAIS-III for visual reasoning. The former test measures the ability to form verbal concepts and to reason by analogy, and the latter test measures attention to visual details and the ability to separate essential from non-essential elements in pictures. In addition, we used the phonemic and semantic verbal fluency tests that measure executive functions and evaluate the ability of verbal reproduction. Data analysis The background parameters (age, education, disease duration) of the 4 groups (MSA-P, MSA-C, PD, Controls) were compared by one-way analysis of variance (ANOVA) with Group as the independent variable and the background parameters as the dependent variables (Table 1). We sought to determine which cognitive tests the patient groups performed significantly different from the controls. Two phases of statistical analysis were applied. In the first phase, we compared the scores of the mood inventories (state anxiety, trait anxiety, and depression) between each patient group and the control group using independent t tests (Table 2). We also compared each cognitive test between each patient group and the control group (Table 3, non-corrected P values). In the second phase, we applied a multiple general linear model with mood scores as covariates to account for reduced cognitive performance that might be related to high levels of anxiety or depression. The dependent variables were the cognitive tests that yielded significant difference (P \ 0.05) in the first phase, the fixed factor was Group (Controls vs. MSA, MSA-P, MSA-C, or PD) and the covariates were the mood inventories (Table 3, corrected P values). The covariates for each comparison were determined according to the inventories that were significantly different between each patient group and the control group in the first phase (Table 2), i.e., depression and state anxiety in MSA, depression, state and trait anxiety in MSA-P and PD, and state anxiety in MSA-C.
Table 2 Independent t tests of mood characteristics of the patients and the controls Controls (N = 10)
MSA-P (N = 15)
Score
Score
MSA-C (N = 10) P
Score
PD (N = 12) P
Score
P
State anxiety
27.2 ± 6.6
38.4 ± 11.7
0.022*
39.5 ± 10.0
0.009*
42.6 ± 6.2
0.027*
Trait anxiety
35.0 ± 4.4
45.4 ± 12.3
0.032*
41.4 ± 12.7
0.187
45.2 ± 5.28
0.000**
5.3 ± 5.2
13.2 ± 7.6
0.013*
13.1 ± 10.7
0.063
10.2 ± 3.9
0.000**
Depression
MSA-P MSA of parkinsonian type, MSA-C MSA of cerebellar type, PD Parkinson’s disease The P value column in each group of patients refers to the independent t test results between the group and the controls * P \ 0.05 ** P \ 0.001
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Table 3 The comparisons between the patient and control groups in the cognitive tests Controls MSA-P (N = 15) (N = 10) Mean score Mean score P(nc)
MSA-C (N = 10) P(c)
Mean score
P(nc)
PD (N = 12) P(c)
Mean score
P(nc)
Digit span
15.4 ± 6.9
12.9 ± 3.5
0.250
15.3 ± 2.7
0.967
14.6 ± 3.9
0.758
Similarities
24.4 ± 3.4
18.1 ± 7.3
0.019* 0.538
19.8 ± 7.2
0.086
22.0 ± 5.8
0.264
Stroop Verbal phonological fluency
79.5 ± 32.9 126.6 ± 116.0 0.226 43.2 ± 10.9 28.5 ± 18.1 0.031* 0.549
Verbal semantic fluency
21.9 ± 5.9
15.0 ± 7.1
0.019* 0.462
P(c)
133.8 ± 68.4 0.041* 0.023* 266.4 ± 556.8 0.304 31.1 ± 8.9 0.014* 0.165 34.3 ± 8.5 0.045* 0.747 17.0 ± 3.7
0.040* 0.129
18.6 ± 5.5
0.188
RAVLT Immediate memory
6.4 ± 1.5
4.14 ± 1.9
0.006* 0.008*
4.6 ± 1.2
0.010* 0.005*
5.1 ± 1.5
0.078
First repetition
8.7 ± 2.1
6.2 ± 1.8
0.007* 0.019*
6.4 ± 1.8
0.018* 0.022*
7.4 ± 1.8
0.137
Second repetition
9.7 ± 2.1
7.7 ± 2.4
0.048* 0.084
8.1 ± 1.5
0.068
8.5 ± 1.7
0.158
Third repetition
11.1 ± 2.2
8.7 ± 2.6
0.028* 0.044*
9.5 ± 1.1
0.056
8.8 ± 1.6
Fourth repetition
12.0 ± 1.6
9.2 ± 3.1
0.018* 0.029*
10.6 ± 2.2
0.131
10.2 ± 2.4
Immediate memory—list B
0.013* 0.080 0.057
4.5 ± 3.1
6.9 ± 3.8
0.098
7.5 ± 1.8
0.075
6.8 ± 2.8
0.715
Fifth repetition
10.8 ± 2.1
6.9 ± 3.9
0.010* 0.032*
7.5 ± 1.8
0.002* 0.001*
6.8 ± 2.8
0.002* 0.002*
Delayed recall
9.9 ± 2.8
6.7 ± 4.1
0.049* 0.061
7.0 ± 2.8
0.036* 0.013*
6.1 ± 2.7
0.004* 0.004*
11.3 ± 2.4
12.6 ± 2.3
Recognition
13.7 ± 1.8
11.2 ± 3.2
0.037* 0.134
0.022* 0.055
0.226
The P values refer to the two phases of analysis (see the ‘statistical analysis’ section) P non-corrected [P(nc)] the value in the first phase without accounting for mood P corrected [P(c)] the value in the second phase that accounted for mood
Borderline significant P value
* Significant P value according to P \ 0.05
Finally, we computed Pearson correlations to test the associations between disease duration and age with cognitive decline in those tests that were significantly different between each patient group and the control group after accounting for mood. For each patient group, we also tested the correlations between disease duration and age with the mood scores that were found to be significantly different from the control group.
Results The background characteristics of the patients and the controls were well-matched (age and education between the four groups and disease duration between the patient groups) (Table 1). The comparison of depression and anxiety levels between the patients and the controls showed that the MSA-P and PD patients reported significantly greater state anxiety, trait anxiety, and depression than controls (Table 2). MSA-C patients reported a significantly increased state anxiety (the level of anxiety experienced during the time of the examination) compared to controls. Table 3 presents the results of the two-phase analysis of the cognitive performance of all three patient groups in the various neuropsychological tests compared with the
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healthy controls. Without accounting for mood, compared with controls the MSA-P patients showed a significantly reduced performance in the similarities subtest, in both verbal fluency tests, and in all parts of the RAVLT, except for the immediate memory of list B. After accounting for state anxiety, trait anxiety and depression, their performance was still reduced compared to controls in all parts of the RAVLT, except for the second repetition and the delayed recall of list A. The similarities and the fluencies tests were not significantly different from the controls after accounting for mood. The MSA-C group did not show a significantly reduced performance in the similarities subtest compared to controls, even before accounting for state anxiety. However, the MSA-C patients showed a significantly reduced performance in the Stroop test compared to controls, both before and after accounting for anxiety. After accounting for anxiety, the performance of the MSAC patients in most learning phases of the RAVLT was not significantly deficient as opposed to that of the MSA-P patients. The MSA-C group showed a significant reduced performance in immediate memory, in the first repetition, in the fifth repetition, and in the delayed recall of list A. They also showed a tendency to perform the recognition phase more poorly than the controls. Finally, the PD patients had reduced verbal phonological fluency and
Cognition in multiple system atrophy
reduced third repetition of the RAVLT test compared to controls, before accounting for state anxiety, trait anxiety, and depression. After accounting for mood, their performance in the fifth repetition and the delayed recall of list A remained significantly reduced compared to controls. The correlation analysis showed that while there was no significant correlation between disease duration and cognitive decline in the MSA-C and PD groups, the MSA-P patients showed significant correlations with the first (r = -0.586, P = 0.028), the third (r = -0.603, P = 0.022), the fourth (r = -0.678, P = 0.007) and the fifth (r = -0.647, P = 0.012) repetitions of list A in the RAVLT. The correlations between age and cognitive decline were also significant only for the MSA-P patients: immediate memory (r = -0.487, P = 0.077), the first (r = -0.752, P = 0.002), the third (r = -0.713, P = 0.004), the fourth (r = -0.846, P = 0.000) and the fifth (r = -0.679, P = 0.008) repetitions of list A in the RAVLT. Furthermore, the correlation between disease duration and state anxiety in the MSA-C group was significant (r = 0.687, P = 0.028), but there was no significant relation between disease duration and mood in the MSA-P and PD patients. Finally, no significant correlations were found between age and mood in any group.
Discussion In the current study, we tested a set of cognitive tests and mood inventories in MSA-P, MSA-C, and PD patients to characterize the distinctive cognitive and emotional profile for each patient group. We also tested the relation between mood and cognitive performance. Our results showed that cognitive and mood characteristics can distinguish between these three groups of patients, and that the parameters of anxiety and depression are related to cognitive decline. Previous studies demonstrated that anxiety and depression are related to cognitive performance (reviewed in: Beaudreau and O’Hara 2008) and might also be used as predictors to cognitive decline (Sinoff and Werner 2003). High levels of anxiety were shown to be associated with reduced episodic memory (Airaksinen et al. 2005), delayed verbal memory, information processing speed (Booth et al. 2006) and executive functions (Airaksinen et al. 2005; Booth et al. 2006). Depressed individuals showed impaired cognition expressed as executive dysfunction (Castaneda et al. 2008) and reduced episodic memory (Airaksinen et al. 2006). In the current study, MSA-P, and PD patients reported abnormally increased levels of depression and anxiety while MSA-C patients reported higher anxiety levels than healthy adults. In line with previous findings, we demonstrated that anxiety and depression were related to reduced executive regulation, abstract reasoning, and
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episodic learning. In addition to a mood–cognition relation, we examined the association between mood to disease duration and age; the decline in mood was not correlated with disease duration or with age in MSA-P or PD, but MSA-C patients had increased levels of anxiety as the disease progressed (but not with age). We suggest that while the affective disturbance in MSA-P and PD is partially the result of primary neurodegeneration, it is worsened in MSA-C because of disease progression. In light of the recognized mood–cognitive relation (e.g., Airaksinen et al. 2005; Booth et al. 2006; Castaneda et al. 2008) we controlled for mood when we tested the patients’ cognitive profiles. The MSA-P patients showed impaired retrieval of a new list of words without any decrease in the ability to learn it (i.e., their recognition ability was normal). In contrast, the MSA-C patients were less impaired in retrieving the list from memory but they showed difficulty in learning and long-term memory. They also had reduced capability to control attention. The PD group was generally less impaired, but showed deficiency in long-term recall of the learned words. All the groups showed retroactive interference, i.e., a difficulty to correctly recall the original list of words following the administration of a new list. These results suggest that the MSA-P patients had poorer cognitive performance compared with the MSA-C patients. It was recently shown that neuropsychological performances are correlated with brain atrophy in MSA (Chang et al. 2009). As such, it might be that the difference in cognitive performance between the two MSA types originates from different patterns of neurodegeneration atrophy. Previous findings showed that the basal ganglia are involved in working memory and immediate verbal recall from memory. Accordingly, PD patients have reduced ability to retrieve new learnt information (e.g., Rinne et al. 2000) and here we found that MSA-P patients had similar impairment. MSA-C patients, however, had reduced longterm recall and recognition. The relation of the cerebellum to cognitive functioning is still not clear but it was suggested that the cerebellum is related to encoding and maintenance of verbal information (Chen and Desmond 2005). Considering that disease progression and age can have a major impact on cognitive decline, we tested the relation between these factors and cognitive performance. Our results did not show such an influence in MSA-C patients, but disease duration and age were related to cognitive decline in MSA-P patients, possibly suggesting that the cognitive deficit is worsened with the degenerative process and with the progress of age in MSA-P but it is independent of disease progression and age in MSA-C. Surprisingly, the patients in the PD group showed only few cognitive deficits that were not correlated with either disease duration or age. It should be noted, however, that
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disease progression in PD is slower than in MSA and that the disease duration was not long nor was the age advanced among our PD patients. To summarize, the results of this study showed that emotional factors are strongly related to cognitive performance in MSA and in PD. Neuropsychological assessment that aims to test the cognitive performance of patients with these conditions should take their emotional state into account when assessing their status. Furthermore, MSA-P and MSA-C patients can be differentiated based on their cognitive deficits: patients with MSA-P demonstrate reduced verbal retrieval ability while MSA-C have difficulties in learning new verbal information and in controlling attention. Acknowledgment
Esther Eshkol is thanked for editorial assistance.
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