J Neurol DOI 10.1007/s00415-014-7389-5
ORIGINAL COMMUNICATION
Measuring disease progression in corticobasal syndrome Nancy Huang • Michael Hornberger John R. Hodges • James R. Burrell
•
Received: 24 March 2014 / Revised: 23 May 2014 / Accepted: 24 May 2014 Ó Springer-Verlag Berlin Heidelberg 2014
Abstract Corticobasal syndrome (CBS) is a complex neurodegenerative disorder with marked clinical, neuropsychological, and pathological heterogeneity. Measurement of disease progression in CBS is complex and little understood. This study aimed to establish clinical and neuropsychological indicators of prognosis in CBS. Patients with CBS were retrospectively recruited from a frontotemporal dementia specific research clinic. All patients underwent detailed clinical and neuropsychological testing including the frontotemporal dementia rating scale (FRS). Using the differences in FRS logit scores over a period of 12 months, CBS patients were divided into rapid and slow progressor groups. Demographic, clinical and neuropsychological features were compared between the two groups. Sixteen participants who met defined criteria were included (9 males, 7 females; mean age 65.8 ± 22 years; median symptom duration 51.8 ± 22 years; mean duration of follow-up 11.4 ± 2.8 months). There were no significant differences between the rapid and slow progressors in age, gender, symptom duration, motor/cognitive presentation, and ACE-R scores at baseline. Clinically, slow progressors were significantly more likely to have a motor speech disorder, with a trend for more frequent dysgraphia, whereas rapid progressors were more likely to exhibit surface dyslexia. Rapid and slow Electronic supplementary material The online version of this article (doi:10.1007/s00415-014-7389-5) contains supplementary material, which is available to authorized users. N. Huang M. Hornberger J. R. Hodges J. R. Burrell (&) Neuroscience Research Australia, Barker Street, Randwick, Sydney NSW 2031, Australia e-mail: [email protected] N. Huang J. R. Hodges J. R. Burrell University of New South Wales, Sydney, Australia
progressor groups did not differ on neuropsychological performance. The presence of motor speech disorder, dysgraphia, and surface dyslexia may be useful in differentiating patients with rapid progression of CBS from those with a more indolent disease course. Keywords Corticobasal syndrome Disease progression Clinicopathological correlation Functional rating scale Addenbrooke’s cognitive examination-revised
Introduction Corticobasal syndrome (CBS) is characterised by marked clinical, neuropsychological, and pathological heterogeneity [1–9]. Some patients with CBS may develop a relatively pure motor syndrome, whereas others develop a combination of motor and cognitive deficits. Heterogeneity in the clinical presentation of CBS presents challenges for diagnosis and management of CBS. In particular, determining the prognosis of an individual patient with CBS, using existing clinical tools, is difficult. One factor that may influence patient outcome in CBS is the underlying pathology. Originally, CBS was associated with corticobasal degeneration [2, 10], but several other pathologies, such as progressive supranuclear palsy [11], Alzheimer’s disease [12, 13], and tau-negative frontotemporal lobar degeneration [12, 14–16], have been described more recently. Some studies have suggested a better prognosis in CBS due to underlying tau-positive, compared to tau-negative, pathologies [17, 18], but other studies have reported the converse [19]. The pattern of clinical features in CBS may reflect the underlying pathology to a certain extent. For example, patients with CBS due to underlying Alzheimer’s
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pathology may present earlier in life [4, 12], have a higher rate of myoclonus [4], and be more impaired at presentation [12] compared to cases due to corticobasal degeneration. Separately, patients with CBS due to underlying progressive supranuclear palsy may have increased falls [12, 20]. Finally, CBS may present with language dysfunction, but the pattern of deficits may differ depending on the underlying pathology. For example, CBS due to Alzheimer’s pathology may present with impaired sentence repetition [9], whereas apraxia of speech similar to that seen in the progressive non-fluent aphasia phenotype of frontotemporal dementia, may indicate underlying tauopathy [21, 22]. The neuropsychological features of CBS as well as their relationship to the underlying pathology vary significantly [23, 24]. Visuospatial dysfunction may predict underlying Alzheimer’s pathology [9, 12], but the significance of other cognitive deficits [25] is still virtually unknown. Similarly, the significance of behavioural disturbances in CBS has not been investigated. Currently, no clinical or neuropsychological instruments have been developed to measure outcome or decline in CBS. Indeed, tracking progression is particularly difficult given the degree of clinical heterogeneity encountered in individual CBS patients. One approach to measuring decline in CBS may be to use the functional rating scale (FRS). The FRS was developed to track functional decline in frontotemporal dementia [26], which shares many characteristics with CBS. Importantly, the FRS assesses performance on a wide range of tasks requiring both motor and cognitive abilities, which should make it useful in assessing patient outcome in CBS. The present study aimed to determine the degree of functional impairment in a cohort of CBS patients using the FRS, and to contrast this with performance on cognitive screening tests. In addition, baseline clinical and neuropsychological predictors of patient outcome in CBS were investigated, using changes on the FRS over time to define rapidly and slowly progressive patient groups. Given that language dysfunction is often a presenting symptom of CBS [27], and may be related to the underlying pathology [28], we hypothesized that the pattern of language impairment would vary between the two groups.
after detailed clinical and neuropsychological assessments, and magnetic resonance imaging of the brain. Specifically, an experienced behavioural neurologist systematically assessed each patient using a predetermined clinical assessment tool. Informant interviews were performed to probe for behavioural changes. Patients who had completed the FRS and Addenbrooke’s Cognitive ExaminationRevised (ACE-R) [30], at baseline and at 12 months, were included in the study. The study received institutional ethics approval and all patients provided informed written consent prior to participation. Patients with an alternate neurological diagnosis were excluded from the study. Specifically, patients with a history of stroke, hydrocephalus, cerebral malignancy, brain injury, substance abuse, psychiatric disease, or other neurodegenerative syndromes (e.g. Parkinson’s disease, LewyBody disease, progressive supranuclear palsy, frontotemporal dementia, and typical Alzheimer’s disease) were excluded. In addition, routine blood tests were conducted to exclude any treatable causes of dementia. Frontotemporal dementia rating scale The FRS was used to grade behavioural disturbance and functional impairment [26]. The FRS is an informant-based assessment tool that investigates patient performance on activities of daily living across seven domains: behaviour, outings and shopping, household chores and telephone use, finances, medications, meal preparation and eating, self care and mobility. Symptoms were graded on a 3-point scale: ‘all the time’ (0 point), ‘sometimes’ (0 point), or ‘never’ (1 point). If any activity was not part of the patient’s pre-morbid repertoire, performance was categorised as ‘not applicable’ on that particular item. Raw scores on the FRS were converted to percentages, which were then converted to a logit score, to avoid cultural or gender bias [26]. A lower logit score indicated greater behavioural and functional disturbance. Behavioural and functional disturbance was categorised according to the logit score as ‘very mild’ ([4.12), ‘mild’ (4.11–1.92), ‘moderate’ (1.91 to -0.40), ‘severe’ (0.39 to -2.58), ‘very severe’ (-2.57 to -4.99), and ‘profound’ (\-4.99) [26], thus indicating disease severity. FRS group assignment
Methods Patients Patients with CBS were recruited from a frontotemporal dementia specific research clinic based at Neuroscience Research Australia. The diagnosis of CBS was made according to the Modified Bak and Hodges criteria [29],
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The outcome of CBS patients was classified according to changes in the FRS over the period of follow-up (12 months). Specifically, the change in FRS logit score was determined for each individual patient by mediansplitting the CBS patient sample. Rapid progressors were defined by a faster decline in logit score than the median change, while slow progressors were defined by slower decline in logit score than the median change.
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Clinical examination
Statistical analysis
A structured clinical assessment was systematically performed in all CBS patients. Particular emphasis was placed on the assessment of clinical signs that may prove useful in sub-classification of CBS patients. In particular, language, praxis, and motor function were investigated in detail. Both spoken language and written language were examined. The presence of dysarthria and word-finding difficulty in spontaneous speech were noted, as were motor speech, phonological, and syntactic errors. Arrays of toy animals and household tools were used to assess for anomia and word comprehension. Single word and sentence repetition were assessed, and errors on reading irregular words (i.e. surface dyslexia) or handwriting were noted. Orobuccal praxis was examined using imitation of actions (e.g. ‘‘puff out your cheeks’’, ‘‘lick crumbs from your lips’’). Limb praxis was assessed using imitation of meaningless and meaningful hand gestures (e.g. ‘‘thumbs up’’, ‘‘A-Okay’’). Gait disturbance, postural instability, dystonia, alien limb phenomenon, myoclonus, and parkinsonian features such as tremor, rigidity, and bradykinesia were noted in both upper limbs.
Data were analysed by NH and JRB using SPSS version 21.0. Continuous variables were analysed using the independent t test when normally distributed and the Mann– Whitney test when non-normally distributed. Pair-wise comparisons within groups were performed using the Wilcoxon signed-rank test, when non-normally distributed, to compare baseline and follow-up FRS logit scores. Categorical differences were analysed with the Chi squared test. Significance threshold was set at P \ 0.05. Spearman’s bivariate correlation was used to explore the relationship between FRS logit score and performance on the ACE-R. Bonferroni correction was used to control for multiple comparisons. Continuous variables are presented as mean ± standard deviation.
Addenbrooke’s cognitive examination-revised Cognitive screening was performed using the ACE-R [30]. The ACE-R is scored out of a total of 100 points and assesses five cognitive domains; attention/orientation (18 points), memory (26 points), fluency (14 points), language (26 points) and visuospatial function (16 points). The ACER takes between 12 and 20 min to administer and a score of \88/100 detects dementia with a sensitivity of 0.94 and a specificity of 0.89 [30].
Amyloid imaging Amyloid imaging was performed in 14 (87.5 %) patients using Pittsburgh Compound type B positron emission tomography (PiB-PET), according to the procedure described elsewhere [9]. Briefly, each patient received *370 MBq 11C-PiB intravenously over 1 min. Scans were then acquired over 30 min, starting 40 min after PiB infusion, on a Phillips AllegroTM PET camera. Standardised uptake value ratios (SUVR) were calculated for multiple brain regions in each individual patient. CBS patients with ‘high’ PiB binding (i.e. mean SUVR [ 1.5) [31, 32] were classified as PiB-positive and those with ‘low’ PiB binding (i.e. mean SUVR \ 1.5) were classified as PiBnegative.
Results Demographics The demographic data of the total CBS population are summarized in Table 1. In total, 16 CBS patients, of whom 9 (56.3 %) were male, were included in the study. The mean age of patients was 65.8 ± 7.4 years, mean symptom duration was 51.8 ± 22 months, and the mean duration of follow-up was 11.4 ± 2.8 months. Pure motor presentation Table 1 Demographic features of CBS patients at baseline CBS patients N
16
Age (years)
65.8 ± 7.4
Male gender (%) Symptom duration (months)
9 (56.3) 51.8 ± 22
Follow-up duration (months)
11.4 ± 2.8
Motor symptoms on presentation (%)
10 (62.5)
Cognitive symptoms on presentation (%)
8 (50)
PiB imaging (%)
14 (87.5)
PiB positive (%)
4 (28.6)
ACE-R Attention
15.8 ± 3.3
Memory
20.8 ± 5.1
Fluency
6.8 ± 4.6
Language
20.9 ± 5.2
Visuospatial
11.5 ± 3.3
Total
75.7 ± 16.9
FRS stage Mild
12.5 %
Moderate Severe
56.3 % 31.3 %
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was seen in 8 (50 %) of CBS patients, whereas a pure cognitive presentation occurred in 6 (37.5 %). Two patients had a combination of motor and cognitive deficits (12.5 %) at presentation. Of the 16 CBS patients, 14 underwent amyloid imaging with PiB-PET, and 4 patients (28.6 %) were PiB-positive, consistent with underlying Alzheimer’s disease pathology [33–35]. There was no significant difference in the proportion of PiB-positive patients in the rapid and slow progressor groups.
Table 2 Demographic features of rapidly and slowly progressive CBS patients at baseline
Follow-up duration (months)
12.5 ± 1.5
10.4 ± 3.4
NS
Motor symptoms on presentation (%)
5 (62.5)
5 (62.5)
NS
Clinical features: CBS cohort
Cognitive symptoms on presentation (%)
3 (37.5)
5 (62.5)
NS
A high proportion of CBS patients demonstrated language impairment and all patients demonstrated evidence of apraxia (Supplementary Table 1). Dysgraphia was the most common language abnormality, present in seven (58.3 %) of patients, but errors in single word and sentence repetition, as well as motor speech, were also noted. All CBS patients had evidence of limb apraxia on testing, manifest as impaired imitation of meaningless and meaningful hand gestures. Orobuccal apraxia was found in one-third of CBS patients. Parkinsonism was almost universal in CBS patients, typically manifest as rigidity and bradykinesia, rather than tremor (Supplementary Table 2). Gait disturbance (53.3 %) and postural instability (40 %) were common, but other motor features such as dystonia, myoclonus, and alien limb phenomenon were each present in less than 20 % of patients.
PiB imaging (%)
7 (87.5)
7 (87.5)
NS
PiB positive (%)
1 (14.3)
3 (42.9)
NS
Frontotemporal dementia rating scale The mean FRS logit score for CBS patients was 0.53 ± 1.3 at baseline and 0.10 ± 1.21 at follow-up. Over the period of follow-up, an improvement in the rating of behavioural and functional impairment was detected in five CBS patients, reflected in a significantly (P \ 0.05) improved FRS logit score. In the remaining CBS patients, the mean change in FRS logit score from baseline to follow-up was -1.0 ± 0.6. The median change in FRS logit score for the whole CBS cohort (-0.4) was used to define ‘‘rapid progressors’’ (decline in FRS logit score more than 0.4) and ‘‘slow progressors’’ (decline in FRS logit less than 0.4). There were no significant differences in the mean age, gender, symptom duration, or follow-up duration between the rapid progressor and slow progressor groups at baseline (Table 2). In addition, there was no significant difference in the percentage of CBS patients with ‘‘mild’’, ‘‘moderate’’, and ‘‘severe’’ behavioural and functional disturbance
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Rapid progressors
Slow progressors
P value
N
8
8
Age (years)
63.9 ± 5.5
67.8 ± 8.8
NS
Male gender (%) Symptom duration (months)
6 (75) 45 ± 26.5
3 (37.5) 58.5 ± 15.3
NS NS
ACE-R Attention
16.4 ± 1.7
15.1 ± 4.4
NS
Memory
21.5 ± 3.7
20 ± 6.3
NS
Fluency
6.6 ± 4.8
6.9 ± 4.7
NS
Language
22.8 ± 2.5
19.1 ± 6.7
NS
Visuospatial
11.8 ± 3
11.3 ± 3.8
NS
Total
79 ± 9.1
72.4 ± 22.4
NS
Mild
1 (12.5 %)
1 (12.5 %)
NS
Moderate
6 (75 %)
3 (37.5 %)
NS
Severe
1 (12.5 %)
4 (50 %)
NS
FRS stage
There were no statistically significant differences in the demographic features, ACE-R scores and FRS staging between the rapid and slow progressors
at baseline as classified by the FRS, nor in the mean logit score at baseline between the two groups. Clinical features: rapid compared to slow progressors Both rapid and slow progressor groups demonstrated a high rate of language impairment, but the pattern of deficits was slightly different (Fig. 1; Table 3). Specifically, five (62.5 %) of the slow progressor patients demonstrated motor speech disturbance, which was not detected in any of the rapid progressor patients (P \ 0.05). Of these five patients, four had undergone PiB-PET imaging and only one had a positive result indicating underlying Alzheimer’s pathology (P = 0.270). Separately, there was a trend (P = 0.08) for an increased rate of dysgraphia in the slow progressors. In contrast, there was a trend (P = 0.09) for surface dyslexia in the rapid progressor group (42.9 %). There were no significant differences between the two groups on other aspects of language impairment, frequency or characteristics of orobuccal or limb apraxia, or in the frequency and characteristics of motor dysfunction and parkinsonism (Table 4).
J Neurol Table 3 Language and praxis impairments in rapid and slowly progressing CBS patients Rapid progressors (%)
Slow progressors (%)
P Value
Language
6 (85.7)
6 (75)
NS
Dysarthria
2 (28.6)
2 (25)
NS
Motor speech disorder
0 (0)
5 (62.5)
\0.05
Phonological errors
3 (42.9)
2 (25)
NS
Syntactic errors
0 (0)
2 (25)
NS
Word-finding difficulties
2 (28.6)
2 (25)
NS
Anomia
0 (0)
2 (25)
NS
Word repetition errors
3 (42.9)
5 (62.5)
NS
Sentence repetition errors
2 (28.6)
2 (25)
NS
Impaired word comprehension
1 (14.3)
1 (12.5)
NS
Surface dyslexia
3 (42.9)
0 (0)
0.09
Dysgraphia
2 (33.3)
5 (83.3)
0.08
Apraxia
7 (100)
8 (100)
NS
Orobuccal
3 (42.9)
2 (25)
NS
Impaired meaningless gestures—right
7 (100)
7 (87.5)
NS
Impaired meaningless gestures—left
6 (85.7)
7 (87.5)
NS
Addenbrooke’s cognitive examination-revised
Impaired meaningful gestures—right
7 (100)
7 (87.5)
NS
Patients with CBS demonstrated a range of cognitive deficits, reflected in impaired performance on the ACE-R (Table 1). The mean ACE-R total for the CBS cohort was 75.7 ± 16.9, and patients demonstrated particular impairment on the verbal fluency (6.8 ± 4.6) and visuospatial subtasks (11.5 ± 3.3) [30]. No significant differences between the ACE-R total, or ACE-R subscores, was detected between the rapid and slow progressor CBS groups. Correlations were performed between the FRS logit score and the ACE-R total, and ACE-R subscores. Bonferroni correction was used for multiple comparison correction, which resulted in a significance threshold of P \ 0.008 (i.e. 0.05/6). Using this approach, a significant correlation was demonstrated with the FRS logit score and the ACE-R memory subscore (r = 0.72, P = 0.002). There were also trends for correlation between the FRS logit score and the ACE-R total (r = 0.565, P = 0.023) and ACE-R visuospatial subscore (r = 0.527, P = 0.036), but these correlations remained not significant after application of the Bonferroni correction. There was no correlation between the FRS logit score and other ACE-R subtasks.
Impaired meaningless gestures—left
6 (85.7)
7 (87.5)
NS
Fig. 1 Language dysfunction in rapid and slow progressing CBS patients. A significantly increased proportion of slow progressors had motor speech disorder compared to rapid progressors, and there was a trend for increased dysgraphia compared to rapid progressors. On the other hand, only rapid progressors demonstrated surface dyslexia. (*P \ 0.09, **P \ 0.05)
The pattern of language dysfunction differed between rapid and slow progressors. Slow progressors demonstrated motor speech disorder more frequently than the rapid progressors (P \ 0.05). In addition, there was a trend for slow progressors to have more dysgraphia (P = 0.08), whereas there was a trend (P = 0.09) for rapid progressors to have more surface dyslexia
Discussion The present study investigated behavioural and functional impairment differences in CBS as a function of disease progression for the first time. As in previous studies, CBS patients demonstrated marked range of clinical, neuropsychological and motor symptoms such as language, praxis, and motor disturbances. Once the patients were split into rapid and slow progressor groups a different picture emerged, with slow progressor patients having more motor speech disturbances. By contrast, no other cognitive, behavioural, or motor impairments reliably distinguished the two groups. Thus motor speech disturbance encountered in CBS patients may offer some insight into patient prognosis.
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J Neurol Table 4 Motor features in rapid and slow progressing CBS patients
Gait disorder
Rapid progressors (%)
Slow progressors (%)
P value
3 (42.9)
5 (62.5)
NS
Postural instability
2 (28.6)
4 (50)
NS
Eye movement abnormalities Dystonia
2 (28.6)
1 (12.5)
NS
0 (0)
1 (12.5)
NS
Myoclonus
1 (14.3)
0 (0)
NS
Alien limb phenomenon
0 (0)
1 (12.5)
NS
Parkinsonism
6 (85.7)
8 (100)
NS
Left-sided tremor
1 (14.3)
1 (12.5)
NS
Left-sided rigidity
5 (71.4)
4 (50)
NS
Left-sided bradykinesia Right-sided tremor
5 (71.4)
6 (75)
NS
0 (0)
0 (0)
NS
Right-sided rigidity
5 (71.4)
5 (62.5)
NS
Right-sided bradykinesia
5 (71.4)
7 (87.5)
NS
The pattern of motor disturbances did not differ significantly between the rapid and slow progressor groups
One of the greatest challenges in the assessment and management of CBS patients is the accurate measurement of the varied deficits, both motor and cognitive, encountered in the syndrome. Very few attempts at staging CBS have been made, presumably reflecting the heterogeneous clinical features and patterns of progression in the syndrome. One clinically based staging system, based on the spread limb apraxia, was proposed, but performance on neuropsychological tests or everyday motor tasks was not considered [36]. We tried to address this issue in the present study by employing a novel disease progression scale (FRS) in addition to more traditional cognitive screening tools, to document behavioural and functional impairment. Although the FRS was originally developed for use in frontotemporal dementia (FTD), many of the cognitive and behavioural changes in CBS overlap with FTD. Separately, the types of functional impairment documented by the FRS are not specific to FTD, suggesting that it may be useful in other neurodegenerative diseases, such as motor neuron disease [37]. The present study demonstrated a significant correlation between functional and behavioural disturbance and memory, but no significant correlation with performance in other cognitive domains, or with cognitive performance overall. Correlation between cognitive performance and functional impairment in everyday life may be expected, but these results suggest that the FRS could detect additional disability not measured by traditional cognitive tests, and may therefore allow detection of novel deficits in CBS.
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The pattern of language disturbance at baseline in CBS patients differed according to their eventual outcome. For example, slow progressors had a significantly increased rate of motor speech disorder, and a trend for an increased dysgraphia, when compared to rapid progressors. Motor speech disorder is a distinctive feature of progressive nonfluent aphasia and is considered a reliable marker of tau pathologies, such as corticobasal degeneration or pathological progressive supranuclear palsy [38]. The clinical overlap between progressive non-fluent aphasia and CBS is well known with several case reports documenting cases of progressive non-fluent aphasia that later develop clinical signs of CBS [3, 39–41]. One possibility is that the slow progressor group in the current study had a higher rate of cases due to underlying tau pathology, although further studies with pathological confirmation are required to test this hypothesis. Additionally, the present study found a trend for an increased rate of dysgraphia in the slow progressors. Dysgraphia is another recognised presenting feature of CBS [42], but whether the presence of dysgraphia predicts a specific underlying pathology, or outcome, remains uncertain. Interestingly, this study demonstrated no difference in the pattern of motor deficits between the rapid and slow progressors. Specifically, neurological assessments for tremor, limb weakness, swallowing difficulties, gait disturbances, frequencies of falls, myoclonus and respiratory symptoms were similar between the two prognostic groups. These findings suggest that motor impairment per se might not be a good indicator for disease progression in CBS. Instead, future assessment of patients with CBS should focus on cognitive domains, particularly language disturbances. Indeed, our study corroborates previous similar cognitive [43, 44] and language studies [21, 45] that were conducted cross-sectionally. Our study extends these findings by demonstrating that the pattern of cognitive, in particular language, symptoms is associated with disease progression in CBS over a 12 months’ period. Despite these promising findings, our study had several limitations. Firstly, the relatively small size of the study population reduces the power of the study and, consistent with other CBS studies [46, 47], is a reflection of the rarity of the disorder. Secondly, the underlying pathological diagnosis was not available in CBS cases, although the use of PiB-PET was important, if only in the detection of cases due to underlying Alzheimer’s pathology. Finally, it is possible that the 12-month follow-up period was not long enough for patient outcome to become clear. Longer periods of follow-up may have allowed clinical and neuropsychological differences to declare themselves. Finally, the CBS patients in the present study were recruited from a cognitive disorders clinic, potentially introducing bias towards more cognitively affected patients, and away from
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CBS patients with pure motor involvement. Nonetheless, the results of the present study suggest that the use of functional measures, such as the FRS, add a further dimension to the monitoring of disease progression in CBS. Furthermore, detailed clinical assessment of language may prove useful in predicting outcome in CBS cases. Conflicts of interest On behalf of all authors, the corresponding author states that there is no conflict of interest.
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ORIGINAL COMMUNICATION
Measuring disease progression in corticobasal syndrome Nancy Huang • Michael Hornberger John R. Hodges • James R. Burrell
•
Received: 24 March 2014 / Revised: 23 May 2014 / Accepted: 24 May 2014 Ó Springer-Verlag Berlin Heidelberg 2014
Abstract Corticobasal syndrome (CBS) is a complex neurodegenerative disorder with marked clinical, neuropsychological, and pathological heterogeneity. Measurement of disease progression in CBS is complex and little understood. This study aimed to establish clinical and neuropsychological indicators of prognosis in CBS. Patients with CBS were retrospectively recruited from a frontotemporal dementia specific research clinic. All patients underwent detailed clinical and neuropsychological testing including the frontotemporal dementia rating scale (FRS). Using the differences in FRS logit scores over a period of 12 months, CBS patients were divided into rapid and slow progressor groups. Demographic, clinical and neuropsychological features were compared between the two groups. Sixteen participants who met defined criteria were included (9 males, 7 females; mean age 65.8 ± 22 years; median symptom duration 51.8 ± 22 years; mean duration of follow-up 11.4 ± 2.8 months). There were no significant differences between the rapid and slow progressors in age, gender, symptom duration, motor/cognitive presentation, and ACE-R scores at baseline. Clinically, slow progressors were significantly more likely to have a motor speech disorder, with a trend for more frequent dysgraphia, whereas rapid progressors were more likely to exhibit surface dyslexia. Rapid and slow Electronic supplementary material The online version of this article (doi:10.1007/s00415-014-7389-5) contains supplementary material, which is available to authorized users. N. Huang M. Hornberger J. R. Hodges J. R. Burrell (&) Neuroscience Research Australia, Barker Street, Randwick, Sydney NSW 2031, Australia e-mail: [email protected] N. Huang J. R. Hodges J. R. Burrell University of New South Wales, Sydney, Australia
progressor groups did not differ on neuropsychological performance. The presence of motor speech disorder, dysgraphia, and surface dyslexia may be useful in differentiating patients with rapid progression of CBS from those with a more indolent disease course. Keywords Corticobasal syndrome Disease progression Clinicopathological correlation Functional rating scale Addenbrooke’s cognitive examination-revised
Introduction Corticobasal syndrome (CBS) is characterised by marked clinical, neuropsychological, and pathological heterogeneity [1–9]. Some patients with CBS may develop a relatively pure motor syndrome, whereas others develop a combination of motor and cognitive deficits. Heterogeneity in the clinical presentation of CBS presents challenges for diagnosis and management of CBS. In particular, determining the prognosis of an individual patient with CBS, using existing clinical tools, is difficult. One factor that may influence patient outcome in CBS is the underlying pathology. Originally, CBS was associated with corticobasal degeneration [2, 10], but several other pathologies, such as progressive supranuclear palsy [11], Alzheimer’s disease [12, 13], and tau-negative frontotemporal lobar degeneration [12, 14–16], have been described more recently. Some studies have suggested a better prognosis in CBS due to underlying tau-positive, compared to tau-negative, pathologies [17, 18], but other studies have reported the converse [19]. The pattern of clinical features in CBS may reflect the underlying pathology to a certain extent. For example, patients with CBS due to underlying Alzheimer’s
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pathology may present earlier in life [4, 12], have a higher rate of myoclonus [4], and be more impaired at presentation [12] compared to cases due to corticobasal degeneration. Separately, patients with CBS due to underlying progressive supranuclear palsy may have increased falls [12, 20]. Finally, CBS may present with language dysfunction, but the pattern of deficits may differ depending on the underlying pathology. For example, CBS due to Alzheimer’s pathology may present with impaired sentence repetition [9], whereas apraxia of speech similar to that seen in the progressive non-fluent aphasia phenotype of frontotemporal dementia, may indicate underlying tauopathy [21, 22]. The neuropsychological features of CBS as well as their relationship to the underlying pathology vary significantly [23, 24]. Visuospatial dysfunction may predict underlying Alzheimer’s pathology [9, 12], but the significance of other cognitive deficits [25] is still virtually unknown. Similarly, the significance of behavioural disturbances in CBS has not been investigated. Currently, no clinical or neuropsychological instruments have been developed to measure outcome or decline in CBS. Indeed, tracking progression is particularly difficult given the degree of clinical heterogeneity encountered in individual CBS patients. One approach to measuring decline in CBS may be to use the functional rating scale (FRS). The FRS was developed to track functional decline in frontotemporal dementia [26], which shares many characteristics with CBS. Importantly, the FRS assesses performance on a wide range of tasks requiring both motor and cognitive abilities, which should make it useful in assessing patient outcome in CBS. The present study aimed to determine the degree of functional impairment in a cohort of CBS patients using the FRS, and to contrast this with performance on cognitive screening tests. In addition, baseline clinical and neuropsychological predictors of patient outcome in CBS were investigated, using changes on the FRS over time to define rapidly and slowly progressive patient groups. Given that language dysfunction is often a presenting symptom of CBS [27], and may be related to the underlying pathology [28], we hypothesized that the pattern of language impairment would vary between the two groups.
after detailed clinical and neuropsychological assessments, and magnetic resonance imaging of the brain. Specifically, an experienced behavioural neurologist systematically assessed each patient using a predetermined clinical assessment tool. Informant interviews were performed to probe for behavioural changes. Patients who had completed the FRS and Addenbrooke’s Cognitive ExaminationRevised (ACE-R) [30], at baseline and at 12 months, were included in the study. The study received institutional ethics approval and all patients provided informed written consent prior to participation. Patients with an alternate neurological diagnosis were excluded from the study. Specifically, patients with a history of stroke, hydrocephalus, cerebral malignancy, brain injury, substance abuse, psychiatric disease, or other neurodegenerative syndromes (e.g. Parkinson’s disease, LewyBody disease, progressive supranuclear palsy, frontotemporal dementia, and typical Alzheimer’s disease) were excluded. In addition, routine blood tests were conducted to exclude any treatable causes of dementia. Frontotemporal dementia rating scale The FRS was used to grade behavioural disturbance and functional impairment [26]. The FRS is an informant-based assessment tool that investigates patient performance on activities of daily living across seven domains: behaviour, outings and shopping, household chores and telephone use, finances, medications, meal preparation and eating, self care and mobility. Symptoms were graded on a 3-point scale: ‘all the time’ (0 point), ‘sometimes’ (0 point), or ‘never’ (1 point). If any activity was not part of the patient’s pre-morbid repertoire, performance was categorised as ‘not applicable’ on that particular item. Raw scores on the FRS were converted to percentages, which were then converted to a logit score, to avoid cultural or gender bias [26]. A lower logit score indicated greater behavioural and functional disturbance. Behavioural and functional disturbance was categorised according to the logit score as ‘very mild’ ([4.12), ‘mild’ (4.11–1.92), ‘moderate’ (1.91 to -0.40), ‘severe’ (0.39 to -2.58), ‘very severe’ (-2.57 to -4.99), and ‘profound’ (\-4.99) [26], thus indicating disease severity. FRS group assignment
Methods Patients Patients with CBS were recruited from a frontotemporal dementia specific research clinic based at Neuroscience Research Australia. The diagnosis of CBS was made according to the Modified Bak and Hodges criteria [29],
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The outcome of CBS patients was classified according to changes in the FRS over the period of follow-up (12 months). Specifically, the change in FRS logit score was determined for each individual patient by mediansplitting the CBS patient sample. Rapid progressors were defined by a faster decline in logit score than the median change, while slow progressors were defined by slower decline in logit score than the median change.
J Neurol
Clinical examination
Statistical analysis
A structured clinical assessment was systematically performed in all CBS patients. Particular emphasis was placed on the assessment of clinical signs that may prove useful in sub-classification of CBS patients. In particular, language, praxis, and motor function were investigated in detail. Both spoken language and written language were examined. The presence of dysarthria and word-finding difficulty in spontaneous speech were noted, as were motor speech, phonological, and syntactic errors. Arrays of toy animals and household tools were used to assess for anomia and word comprehension. Single word and sentence repetition were assessed, and errors on reading irregular words (i.e. surface dyslexia) or handwriting were noted. Orobuccal praxis was examined using imitation of actions (e.g. ‘‘puff out your cheeks’’, ‘‘lick crumbs from your lips’’). Limb praxis was assessed using imitation of meaningless and meaningful hand gestures (e.g. ‘‘thumbs up’’, ‘‘A-Okay’’). Gait disturbance, postural instability, dystonia, alien limb phenomenon, myoclonus, and parkinsonian features such as tremor, rigidity, and bradykinesia were noted in both upper limbs.
Data were analysed by NH and JRB using SPSS version 21.0. Continuous variables were analysed using the independent t test when normally distributed and the Mann– Whitney test when non-normally distributed. Pair-wise comparisons within groups were performed using the Wilcoxon signed-rank test, when non-normally distributed, to compare baseline and follow-up FRS logit scores. Categorical differences were analysed with the Chi squared test. Significance threshold was set at P \ 0.05. Spearman’s bivariate correlation was used to explore the relationship between FRS logit score and performance on the ACE-R. Bonferroni correction was used to control for multiple comparisons. Continuous variables are presented as mean ± standard deviation.
Addenbrooke’s cognitive examination-revised Cognitive screening was performed using the ACE-R [30]. The ACE-R is scored out of a total of 100 points and assesses five cognitive domains; attention/orientation (18 points), memory (26 points), fluency (14 points), language (26 points) and visuospatial function (16 points). The ACER takes between 12 and 20 min to administer and a score of \88/100 detects dementia with a sensitivity of 0.94 and a specificity of 0.89 [30].
Amyloid imaging Amyloid imaging was performed in 14 (87.5 %) patients using Pittsburgh Compound type B positron emission tomography (PiB-PET), according to the procedure described elsewhere [9]. Briefly, each patient received *370 MBq 11C-PiB intravenously over 1 min. Scans were then acquired over 30 min, starting 40 min after PiB infusion, on a Phillips AllegroTM PET camera. Standardised uptake value ratios (SUVR) were calculated for multiple brain regions in each individual patient. CBS patients with ‘high’ PiB binding (i.e. mean SUVR [ 1.5) [31, 32] were classified as PiB-positive and those with ‘low’ PiB binding (i.e. mean SUVR \ 1.5) were classified as PiBnegative.
Results Demographics The demographic data of the total CBS population are summarized in Table 1. In total, 16 CBS patients, of whom 9 (56.3 %) were male, were included in the study. The mean age of patients was 65.8 ± 7.4 years, mean symptom duration was 51.8 ± 22 months, and the mean duration of follow-up was 11.4 ± 2.8 months. Pure motor presentation Table 1 Demographic features of CBS patients at baseline CBS patients N
16
Age (years)
65.8 ± 7.4
Male gender (%) Symptom duration (months)
9 (56.3) 51.8 ± 22
Follow-up duration (months)
11.4 ± 2.8
Motor symptoms on presentation (%)
10 (62.5)
Cognitive symptoms on presentation (%)
8 (50)
PiB imaging (%)
14 (87.5)
PiB positive (%)
4 (28.6)
ACE-R Attention
15.8 ± 3.3
Memory
20.8 ± 5.1
Fluency
6.8 ± 4.6
Language
20.9 ± 5.2
Visuospatial
11.5 ± 3.3
Total
75.7 ± 16.9
FRS stage Mild
12.5 %
Moderate Severe
56.3 % 31.3 %
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was seen in 8 (50 %) of CBS patients, whereas a pure cognitive presentation occurred in 6 (37.5 %). Two patients had a combination of motor and cognitive deficits (12.5 %) at presentation. Of the 16 CBS patients, 14 underwent amyloid imaging with PiB-PET, and 4 patients (28.6 %) were PiB-positive, consistent with underlying Alzheimer’s disease pathology [33–35]. There was no significant difference in the proportion of PiB-positive patients in the rapid and slow progressor groups.
Table 2 Demographic features of rapidly and slowly progressive CBS patients at baseline
Follow-up duration (months)
12.5 ± 1.5
10.4 ± 3.4
NS
Motor symptoms on presentation (%)
5 (62.5)
5 (62.5)
NS
Clinical features: CBS cohort
Cognitive symptoms on presentation (%)
3 (37.5)
5 (62.5)
NS
A high proportion of CBS patients demonstrated language impairment and all patients demonstrated evidence of apraxia (Supplementary Table 1). Dysgraphia was the most common language abnormality, present in seven (58.3 %) of patients, but errors in single word and sentence repetition, as well as motor speech, were also noted. All CBS patients had evidence of limb apraxia on testing, manifest as impaired imitation of meaningless and meaningful hand gestures. Orobuccal apraxia was found in one-third of CBS patients. Parkinsonism was almost universal in CBS patients, typically manifest as rigidity and bradykinesia, rather than tremor (Supplementary Table 2). Gait disturbance (53.3 %) and postural instability (40 %) were common, but other motor features such as dystonia, myoclonus, and alien limb phenomenon were each present in less than 20 % of patients.
PiB imaging (%)
7 (87.5)
7 (87.5)
NS
PiB positive (%)
1 (14.3)
3 (42.9)
NS
Frontotemporal dementia rating scale The mean FRS logit score for CBS patients was 0.53 ± 1.3 at baseline and 0.10 ± 1.21 at follow-up. Over the period of follow-up, an improvement in the rating of behavioural and functional impairment was detected in five CBS patients, reflected in a significantly (P \ 0.05) improved FRS logit score. In the remaining CBS patients, the mean change in FRS logit score from baseline to follow-up was -1.0 ± 0.6. The median change in FRS logit score for the whole CBS cohort (-0.4) was used to define ‘‘rapid progressors’’ (decline in FRS logit score more than 0.4) and ‘‘slow progressors’’ (decline in FRS logit less than 0.4). There were no significant differences in the mean age, gender, symptom duration, or follow-up duration between the rapid progressor and slow progressor groups at baseline (Table 2). In addition, there was no significant difference in the percentage of CBS patients with ‘‘mild’’, ‘‘moderate’’, and ‘‘severe’’ behavioural and functional disturbance
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Rapid progressors
Slow progressors
P value
N
8
8
Age (years)
63.9 ± 5.5
67.8 ± 8.8
NS
Male gender (%) Symptom duration (months)
6 (75) 45 ± 26.5
3 (37.5) 58.5 ± 15.3
NS NS
ACE-R Attention
16.4 ± 1.7
15.1 ± 4.4
NS
Memory
21.5 ± 3.7
20 ± 6.3
NS
Fluency
6.6 ± 4.8
6.9 ± 4.7
NS
Language
22.8 ± 2.5
19.1 ± 6.7
NS
Visuospatial
11.8 ± 3
11.3 ± 3.8
NS
Total
79 ± 9.1
72.4 ± 22.4
NS
Mild
1 (12.5 %)
1 (12.5 %)
NS
Moderate
6 (75 %)
3 (37.5 %)
NS
Severe
1 (12.5 %)
4 (50 %)
NS
FRS stage
There were no statistically significant differences in the demographic features, ACE-R scores and FRS staging between the rapid and slow progressors
at baseline as classified by the FRS, nor in the mean logit score at baseline between the two groups. Clinical features: rapid compared to slow progressors Both rapid and slow progressor groups demonstrated a high rate of language impairment, but the pattern of deficits was slightly different (Fig. 1; Table 3). Specifically, five (62.5 %) of the slow progressor patients demonstrated motor speech disturbance, which was not detected in any of the rapid progressor patients (P \ 0.05). Of these five patients, four had undergone PiB-PET imaging and only one had a positive result indicating underlying Alzheimer’s pathology (P = 0.270). Separately, there was a trend (P = 0.08) for an increased rate of dysgraphia in the slow progressors. In contrast, there was a trend (P = 0.09) for surface dyslexia in the rapid progressor group (42.9 %). There were no significant differences between the two groups on other aspects of language impairment, frequency or characteristics of orobuccal or limb apraxia, or in the frequency and characteristics of motor dysfunction and parkinsonism (Table 4).
J Neurol Table 3 Language and praxis impairments in rapid and slowly progressing CBS patients Rapid progressors (%)
Slow progressors (%)
P Value
Language
6 (85.7)
6 (75)
NS
Dysarthria
2 (28.6)
2 (25)
NS
Motor speech disorder
0 (0)
5 (62.5)
\0.05
Phonological errors
3 (42.9)
2 (25)
NS
Syntactic errors
0 (0)
2 (25)
NS
Word-finding difficulties
2 (28.6)
2 (25)
NS
Anomia
0 (0)
2 (25)
NS
Word repetition errors
3 (42.9)
5 (62.5)
NS
Sentence repetition errors
2 (28.6)
2 (25)
NS
Impaired word comprehension
1 (14.3)
1 (12.5)
NS
Surface dyslexia
3 (42.9)
0 (0)
0.09
Dysgraphia
2 (33.3)
5 (83.3)
0.08
Apraxia
7 (100)
8 (100)
NS
Orobuccal
3 (42.9)
2 (25)
NS
Impaired meaningless gestures—right
7 (100)
7 (87.5)
NS
Impaired meaningless gestures—left
6 (85.7)
7 (87.5)
NS
Addenbrooke’s cognitive examination-revised
Impaired meaningful gestures—right
7 (100)
7 (87.5)
NS
Patients with CBS demonstrated a range of cognitive deficits, reflected in impaired performance on the ACE-R (Table 1). The mean ACE-R total for the CBS cohort was 75.7 ± 16.9, and patients demonstrated particular impairment on the verbal fluency (6.8 ± 4.6) and visuospatial subtasks (11.5 ± 3.3) [30]. No significant differences between the ACE-R total, or ACE-R subscores, was detected between the rapid and slow progressor CBS groups. Correlations were performed between the FRS logit score and the ACE-R total, and ACE-R subscores. Bonferroni correction was used for multiple comparison correction, which resulted in a significance threshold of P \ 0.008 (i.e. 0.05/6). Using this approach, a significant correlation was demonstrated with the FRS logit score and the ACE-R memory subscore (r = 0.72, P = 0.002). There were also trends for correlation between the FRS logit score and the ACE-R total (r = 0.565, P = 0.023) and ACE-R visuospatial subscore (r = 0.527, P = 0.036), but these correlations remained not significant after application of the Bonferroni correction. There was no correlation between the FRS logit score and other ACE-R subtasks.
Impaired meaningless gestures—left
6 (85.7)
7 (87.5)
NS
Fig. 1 Language dysfunction in rapid and slow progressing CBS patients. A significantly increased proportion of slow progressors had motor speech disorder compared to rapid progressors, and there was a trend for increased dysgraphia compared to rapid progressors. On the other hand, only rapid progressors demonstrated surface dyslexia. (*P \ 0.09, **P \ 0.05)
The pattern of language dysfunction differed between rapid and slow progressors. Slow progressors demonstrated motor speech disorder more frequently than the rapid progressors (P \ 0.05). In addition, there was a trend for slow progressors to have more dysgraphia (P = 0.08), whereas there was a trend (P = 0.09) for rapid progressors to have more surface dyslexia
Discussion The present study investigated behavioural and functional impairment differences in CBS as a function of disease progression for the first time. As in previous studies, CBS patients demonstrated marked range of clinical, neuropsychological and motor symptoms such as language, praxis, and motor disturbances. Once the patients were split into rapid and slow progressor groups a different picture emerged, with slow progressor patients having more motor speech disturbances. By contrast, no other cognitive, behavioural, or motor impairments reliably distinguished the two groups. Thus motor speech disturbance encountered in CBS patients may offer some insight into patient prognosis.
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J Neurol Table 4 Motor features in rapid and slow progressing CBS patients
Gait disorder
Rapid progressors (%)
Slow progressors (%)
P value
3 (42.9)
5 (62.5)
NS
Postural instability
2 (28.6)
4 (50)
NS
Eye movement abnormalities Dystonia
2 (28.6)
1 (12.5)
NS
0 (0)
1 (12.5)
NS
Myoclonus
1 (14.3)
0 (0)
NS
Alien limb phenomenon
0 (0)
1 (12.5)
NS
Parkinsonism
6 (85.7)
8 (100)
NS
Left-sided tremor
1 (14.3)
1 (12.5)
NS
Left-sided rigidity
5 (71.4)
4 (50)
NS
Left-sided bradykinesia Right-sided tremor
5 (71.4)
6 (75)
NS
0 (0)
0 (0)
NS
Right-sided rigidity
5 (71.4)
5 (62.5)
NS
Right-sided bradykinesia
5 (71.4)
7 (87.5)
NS
The pattern of motor disturbances did not differ significantly between the rapid and slow progressor groups
One of the greatest challenges in the assessment and management of CBS patients is the accurate measurement of the varied deficits, both motor and cognitive, encountered in the syndrome. Very few attempts at staging CBS have been made, presumably reflecting the heterogeneous clinical features and patterns of progression in the syndrome. One clinically based staging system, based on the spread limb apraxia, was proposed, but performance on neuropsychological tests or everyday motor tasks was not considered [36]. We tried to address this issue in the present study by employing a novel disease progression scale (FRS) in addition to more traditional cognitive screening tools, to document behavioural and functional impairment. Although the FRS was originally developed for use in frontotemporal dementia (FTD), many of the cognitive and behavioural changes in CBS overlap with FTD. Separately, the types of functional impairment documented by the FRS are not specific to FTD, suggesting that it may be useful in other neurodegenerative diseases, such as motor neuron disease [37]. The present study demonstrated a significant correlation between functional and behavioural disturbance and memory, but no significant correlation with performance in other cognitive domains, or with cognitive performance overall. Correlation between cognitive performance and functional impairment in everyday life may be expected, but these results suggest that the FRS could detect additional disability not measured by traditional cognitive tests, and may therefore allow detection of novel deficits in CBS.
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The pattern of language disturbance at baseline in CBS patients differed according to their eventual outcome. For example, slow progressors had a significantly increased rate of motor speech disorder, and a trend for an increased dysgraphia, when compared to rapid progressors. Motor speech disorder is a distinctive feature of progressive nonfluent aphasia and is considered a reliable marker of tau pathologies, such as corticobasal degeneration or pathological progressive supranuclear palsy [38]. The clinical overlap between progressive non-fluent aphasia and CBS is well known with several case reports documenting cases of progressive non-fluent aphasia that later develop clinical signs of CBS [3, 39–41]. One possibility is that the slow progressor group in the current study had a higher rate of cases due to underlying tau pathology, although further studies with pathological confirmation are required to test this hypothesis. Additionally, the present study found a trend for an increased rate of dysgraphia in the slow progressors. Dysgraphia is another recognised presenting feature of CBS [42], but whether the presence of dysgraphia predicts a specific underlying pathology, or outcome, remains uncertain. Interestingly, this study demonstrated no difference in the pattern of motor deficits between the rapid and slow progressors. Specifically, neurological assessments for tremor, limb weakness, swallowing difficulties, gait disturbances, frequencies of falls, myoclonus and respiratory symptoms were similar between the two prognostic groups. These findings suggest that motor impairment per se might not be a good indicator for disease progression in CBS. Instead, future assessment of patients with CBS should focus on cognitive domains, particularly language disturbances. Indeed, our study corroborates previous similar cognitive [43, 44] and language studies [21, 45] that were conducted cross-sectionally. Our study extends these findings by demonstrating that the pattern of cognitive, in particular language, symptoms is associated with disease progression in CBS over a 12 months’ period. Despite these promising findings, our study had several limitations. Firstly, the relatively small size of the study population reduces the power of the study and, consistent with other CBS studies [46, 47], is a reflection of the rarity of the disorder. Secondly, the underlying pathological diagnosis was not available in CBS cases, although the use of PiB-PET was important, if only in the detection of cases due to underlying Alzheimer’s pathology. Finally, it is possible that the 12-month follow-up period was not long enough for patient outcome to become clear. Longer periods of follow-up may have allowed clinical and neuropsychological differences to declare themselves. Finally, the CBS patients in the present study were recruited from a cognitive disorders clinic, potentially introducing bias towards more cognitively affected patients, and away from
J Neurol
CBS patients with pure motor involvement. Nonetheless, the results of the present study suggest that the use of functional measures, such as the FRS, add a further dimension to the monitoring of disease progression in CBS. Furthermore, detailed clinical assessment of language may prove useful in predicting outcome in CBS cases. Conflicts of interest On behalf of all authors, the corresponding author states that there is no conflict of interest.
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