Abstracts
Cognitive dysfunction may occur in 17-40% of patients with multiple system atrophy (MSA). It has been suggested a milder cognitive impairment in cerebellar (MSA-C) than in parkinsonian variant (MSA-P). However, differences in cognitive profiles remain under discussion.
Objective
To evaluate cognitive features in a series of patients with “probable MSA” from Argentina.
Method
After informed consent was obtained, an extensive cognitive tests battery was administered. Nine patients (6 MSA-P and 3 MSA-C) composed the sample.
Results
Depression was detected in 43% of patients. Seven patients showed at least one cognitive domain impairment. Temporospatial orientation, visuospatial abilities, executive and attentional functions, episodic memory and language were compromised in MSA-P, while MSA-C dysfunction was restricted to attentional and executive domains.
Conclusion
Despite the small sample size, our findings could suggest a more widespread cognitive impairment in MSA-P than MSA-C.
parkinsonism; multiple system atrophy; cognition
Disfunção cognitiva pode ocorrer em 17-40 % dos pacientes com atrofia de múltiplos sistemas (AMS). Alguns estudos têm sugerido a presença de disfunção cognitiva mais leve nos pacientes com AMS do tipo cerebelar (AMS-C) do que na variante parkinsoniana (AMS-P).
Objetivo
Avaliar os perfis cognitivos de uma série de pacientes argentinos com “Provável AMS”.
Método
Foram selecionados 6 AMS-P e 3 AMS–C aos quais foi aplicada uma extensa bateria de testes cognitivos.
Resultados
Depressão foi detectada em 43% dos pacientes. Sete pacientes apresentaram comprometimento de pelo menos um domínio cognitivo. As funções de orientação temporo-espacial, habilidades visuo-espaciais, função executiva e de atenção, memória episódica e linguagem foram comprometidas em pacientes com AMS-P. Nos pacientes com AMS-C as dificuldades cognitivas ficaram restritas às funções executivas e de atenção.
Conclusão
Apesar do pequeno tamanho da amostra, nossos achados sugerem que pacientes com AMS-P apresentam um comprometimento cognitivo mais amplo do que pacientes com AMS-C.
parkinsonismo; atrofia de múltiplos sistemas; cognição
Multiple system atrophy (MSA) is a rare, adult-onset, progressive neurodegenerative
disease characterized by parkinsonism, cerebellar ataxia, corticospinal tract
dysfunction and non-motor symptoms including autonomic failure, sleep disorders and
respiratory manifestations. In 1998 Gilman et al. proposed the first consensus criteria
diagnosis of MSA11 . Gilman S, Low P, Quinn N, Albanese A, Ben-Shlomo Y, Fowler C et
al. Consensus statement on the diagnosis of multiple system atrophy. J Neurol
Sci. 1999;163(1):94-8.
http://dx.doi.org/10.1016/S0022-510X(98)00304-9
https://doi.org/10.1016/S0022-510X(98)00...
, and a revised
consensus was published in 200822 . Gilman S, Wenning GK, Low PA, Brooks DJ, Mathias CJ, Trojanowski
JQ et al. Second consensus statement on the diagnosis of multiple system
atrophy. Neurology. 2008;71(9):670-6.
http://dx.doi.org/10.1212/01.wnl.0000324625.00404.15
https://doi.org/10.1212/01.wnl.000032462...
. Two
clinical MSA categories can be distinguished: MSA-P with predominant parkinsonism and
striatonigral involvement, and MSA-C dominated by cerebellar ataxia reflecting
olivopontocerebellar involvement33 . Wenning GK, Stefanova N. Recent developments in multiple system
atrophy. J Neurol. 2009;246(11):1791-808.
http://dx.doi.org/10.1007/s00415-009-5173-8
https://doi.org/10.1007/s00415-009-5173-...
.
A frontal-type cognitive impairment profile has been described in MSA patients44 . Robbins TW, James M, Lange KW, Owen AM, Quinn NP, Marsden CD.
Cognitive performance in multiple system atrophy. Brain. 1992;115(1):271-91.
http://dx.doi.org/10.1093/brain/115.1.271
https://doi.org/10.1093/brain/115.1.271...
,55 . Berent S, Giordani B, Gilman S, Trask CL, Little RJ, Johanns JR et
al. Patterns of neuropsychological performance in multiple system atrophy
compared to sporadic and hereditary olivopontocerebellar atrophy. Brain Cogn.
2002;50(2):194-206.
http://dx.doi.org/10.1016/s0278-2626(02)00503-1
https://doi.org/10.1016/s0278-2626(02)00...
and although dementia appears as a non-supportive
feature of MSA, recent evidence suggests that cognitive dysfunction may be more frequent
than previously reported, with a prevalence between 17-40%66 . Kawai Y, Suenaga M, Takeda A, Ito M, Watanabe H, Tanaka H et al.
Cognitive impairments in multiple system atrophy: MSA-C vs MSA-P. Neurology.
2008;70(16 Pt 2):1390-6.
http://dx.doi.org/10.1212/01.wnl.0000310413.04462.6a
https://doi.org/10.1212/01.wnl.000031041...
7 . Brown RG, Lacomblez L, Landwehrmeyer BG, Bak T, Uttner I, Dubois B
et al. Cognitive impairment in patients with multiple system atrophy and
progressive supranuclear palsy. Brain. 2010;133(8):2382-93.
http://dx.doi.org/10.1093/brain/awq158
https://doi.org/10.1093/brain/awq158...
-88 . Siri C, Duerr S, Canesi M, Delazer M, Esselink R, Bloem BR et al.
A cross-sectional multicenter study of cognitive and behavioural features in
multiple system atrophy patients of the parkinsonian and cerebellar type. J
Neural Transm. 2013;120(4):613-8.
http://dx.doi.org/10.1007/s00702-013-0997-x
https://doi.org/10.1007/s00702-013-0997-...
.
In some studies, patients with MSA-P have shown involvement of verbal retrieval and
visuospatial and executive abilities, and patients with MSA-C have shown compromise in
visuospatial functions, learning new verbal information, verbal fluency and attention
tests66 . Kawai Y, Suenaga M, Takeda A, Ito M, Watanabe H, Tanaka H et al.
Cognitive impairments in multiple system atrophy: MSA-C vs MSA-P. Neurology.
2008;70(16 Pt 2):1390-6.
http://dx.doi.org/10.1212/01.wnl.0000310413.04462.6a
https://doi.org/10.1212/01.wnl.000031041...
,99 . Balas M, Balash Y, Giladi N, Gurevich T. Cognition in multiple
system atrophy: neuropsychological profile and interaction with mood. J Neural
Transm. 2010;117(3):369-75.
http://dx.doi.org/10.1007/s00702-009-0365-z
https://doi.org/10.1007/s00702-009-0365-...
,1010 . Bürk K, Daum I, Rüb U. Cognitive function in multiple
system atrophy of the cerebellar type. Mov Disord. 2006;21(6):772-6.
http://dx.doi.org/10.1002/mds.20802
https://doi.org/10.1002/mds.20802...
. It has been suggested that MSA-C patients may have a
milder degree of cognitive involvement compared with patients with MSA-P66 . Kawai Y, Suenaga M, Takeda A, Ito M, Watanabe H, Tanaka H et al.
Cognitive impairments in multiple system atrophy: MSA-C vs MSA-P. Neurology.
2008;70(16 Pt 2):1390-6.
http://dx.doi.org/10.1212/01.wnl.0000310413.04462.6a
https://doi.org/10.1212/01.wnl.000031041...
. On the other hand, some studies did
not find any differences in the cognitive performance between the 2 subtypes of MSA,
with 41% of MSA patients showing frontal lobe-related function involvement88 . Siri C, Duerr S, Canesi M, Delazer M, Esselink R, Bloem BR et al.
A cross-sectional multicenter study of cognitive and behavioural features in
multiple system atrophy patients of the parkinsonian and cerebellar type. J
Neural Transm. 2013;120(4):613-8.
http://dx.doi.org/10.1007/s00702-013-0997-x
https://doi.org/10.1007/s00702-013-0997-...
.
To the best of our knowledge, no data about MSA cognitive impairment are available from Latin America. The present study was conducted to assess cognitive and mood impairment in a series of MSA patients from Argentina.
Method
The study was approved by our institutional review board, and all participants signed a written informed consent in accordance with Good Clinical Practice guidelines and the Declaration of Helsinki. Patients fulfilling consensus criteria of clinical diagnosis of “probable MSA” composed the sample. Clinical evaluation of MSA patients included the Hoehn and Yahr (HY) scale.
An extensive neuropsychological test battery was administered that included: the Mini Mental State Examination (MMSE) as a global measure; the California Verbal Learning Test (CVLT) and the Wechsler Memory Scale to evaluate episodic memory; the Clock drawing Test and Block Design to evaluate visuospatial abilities; Direct and Inverse Span and Trail Making Test A (TMT A) to evaluate attentional functions; semantic fluency, phonological fluency and Boston Naming Test to evaluate language; and Trail Making Test B (TMT B) to evaluate executive functions. The results in each test were compared with normative data for age and education, and a Z score of less than 1.5 was considered abnormal. The Beck Inventory was selected to assess depressive symptoms, with a cut-off score of 9 for depression, and the Hospitality Anxiety and Depression scale – Anxiety (HAD-A) to assess anxiety symptoms, with a cut-off score of 8 for anxiety. Descriptive statistics were used to analyze the data. Statistical analysis was performed using the software program SPSS (Windows Release 11.0; SPSS Inc, Chicago, Illinois), non-parametric tests (Mann-Whitney U test) were used when appropriate (p≤0.05).
Results
The study population included 5 men and 4 women with probable MSA (6 MSA-P, 3 MSA-C) according to the revised consensus diagnostic criteria2. Socio-demographic data, MMSE, Beck Inventory and HAD-A results are shown in Table 1. When we compared MSA-C vs. MSA-P, we found no significant difference in disease duration and HY stage. The results on each cognitive test for the whole group and for each MSA subtype are shown in Table 2.
When considering the whole group, MSA patients demonstrated difficulties in the encoding of the CVLT and in TMT B (Table 2). At least one cognitive domain was impaired in 7/9 of MSA patients (78%), and 5 of them were of the MSA-P subtype. Impaired attention, executive dysfunction, and episodic memory dysfunction were present in 5/9 (55%) patients each while visuospatial dysfunction (3/9, 33%), language alterations (3/9, 33%) and temporospatial dysfunction (1/9, 11%) were less prominent. In general, despite similar disease severity cognitive impairments were more widespread in MSA-P patients compared to MSA-C patients. Depression was identified in 3/7 patients (43%), while anxiety was observed in 1/7 patients (14%).
Discussion
This is the first study to investigate cognitive function in patients with probable
MSA from Argentina. As reported in the literature, cognitive dysfunction was
frequent in this MSA sample. Episodic memory and attentional and executive deficits
were the most prevalent cognitive alterations observed. Some of these cognitive
abilities depend on prefrontal cortical areas and on their connections with frontal
subcortical structures, which are usually involved in MSA1111 . Chang CC, Chang YY, Chang WN, Lee YC, Wang YL, Lui CC et al.
Cognitive deficits in multiple system atrophy correlate with frontal atrophy and
disease duration. Eur J Neurol. 2009;16(10):1144-50.
http://dx.doi.org/10.1111/j.1468-1331.2009.02661.x
https://doi.org/10.1111/j.1468-1331.2009...
. Temporospatial disorientation, episodic memory
and visuospatial and language dysfunctions were exclusively identified in patients
with the MSA-P variant. Interestingly, some of these cognitive alterations may not
be identified with global cognitive screening tests such as the MMSE: in this sample
the median of the MMSE score was 29, ranging from 25 to 30.
In agreement with previous reports, mild to moderate deficits in executive functions
and impairment in attention and phonological fluency were observed in this
population1212 . Soliveri P, Monza D, Paridi D, et al. Neuropsychological follow up
in patients with Parkinson's disease, striatonigral degeneration-type
multisystem atrophy, and progressive supranuclear palsy. J Neurol Neurosurg
Psychiatry. 2000;69(3):313-8.
http://dx.doi.org/10.1136/jnnp.69.3.313
https://doi.org/10.1136/jnnp.69.3.313...
,1313 . Spaccavento S, Del Prete M, Loverre A, Craca A, Nardulli R.
Multiple system atrophy with early cognitive deficits: a case report. Neurocase.
2013;19(6):613-22.
http://dx.doi.org/10.1080/13554794.2012.713494
https://doi.org/10.1080/13554794.2012.71...
.
Although the occurrence of different cognitive patterns between both subtypes of MSA
remains under discussion66 . Kawai Y, Suenaga M, Takeda A, Ito M, Watanabe H, Tanaka H et al.
Cognitive impairments in multiple system atrophy: MSA-C vs MSA-P. Neurology.
2008;70(16 Pt 2):1390-6.
http://dx.doi.org/10.1212/01.wnl.0000310413.04462.6a
https://doi.org/10.1212/01.wnl.000031041...
,88 . Siri C, Duerr S, Canesi M, Delazer M, Esselink R, Bloem BR et al.
A cross-sectional multicenter study of cognitive and behavioural features in
multiple system atrophy patients of the parkinsonian and cerebellar type. J
Neural Transm. 2013;120(4):613-8.
http://dx.doi.org/10.1007/s00702-013-0997-x
https://doi.org/10.1007/s00702-013-0997-...
, in this sample we identified a more widespread cognitive
dysfunction in MSA-P with respect to MSA-C. In fact, cognitive performance in MSA-P
was compromised in multiple cognitive domains (temporospatial orientation,
visuospatial abilities, executive and attentional functions, episodic memory and
language), while in MSA-C, the cognitive dysfunction was restricted to attentional
and executive deficits (frontal-executive disorder). However, these results must be
analyzed cautiously, considering the sample size. Nevertheless, cognitive impairment
observed in MSA-P could contribute to support the hypothesis of an earlier basal
ganglia neuronal dysfunction in this clinical variant. Moreover the lack of
differences in disease severity as determined by HY stage would support more
widespread P type related cognitive deficits, despite the caution of very few cases
only.
On the other hand, it has been reported that MSA patients may have more depression
than patients with PD88 . Siri C, Duerr S, Canesi M, Delazer M, Esselink R, Bloem BR et al.
A cross-sectional multicenter study of cognitive and behavioural features in
multiple system atrophy patients of the parkinsonian and cerebellar type. J
Neural Transm. 2013;120(4):613-8.
http://dx.doi.org/10.1007/s00702-013-0997-x
https://doi.org/10.1007/s00702-013-0997-...
,1212 . Soliveri P, Monza D, Paridi D, et al. Neuropsychological follow up
in patients with Parkinson's disease, striatonigral degeneration-type
multisystem atrophy, and progressive supranuclear palsy. J Neurol Neurosurg
Psychiatry. 2000;69(3):313-8.
http://dx.doi.org/10.1136/jnnp.69.3.313
https://doi.org/10.1136/jnnp.69.3.313...
. In this sample, Beck inventory showed significant
depressive symptoms in more than 40% of the patients that were evaluated, while
anxiety symptoms were only significant in one patient. Depression tended to be more
severely in patients with MSA-C, probably reflecting a cerebellocortical circuits
involvement.
The limitations of the present study included, the absence of epidemiological or demographic data of MSA from Latin America and more specifically from Argentina, the lack of neuropathological confirmation and the small number of patients. However, the presence of cognitive dysfunction in at least one cognitive domain appears to be in accordance with other international series and contribute to support the cognitive impairment in MSA.
In conclusion, patients with MSA showed cognitive impairment in different sub-domains, with a more widespread impairment in MSA-P than MSA-C. Extensive studies are required to identify the anatomical correlation or risk factor specific to each subtype. A larger scale population study is ongoing.
Acknowledgments
Authors would like to thank all patients, their families, and the Neuropsychologists of Instituto de Neurociencias Buenos Aires (INEBA) who evaluated our patients.
References
-
1Gilman S, Low P, Quinn N, Albanese A, Ben-Shlomo Y, Fowler C et al. Consensus statement on the diagnosis of multiple system atrophy. J Neurol Sci. 1999;163(1):94-8. http://dx.doi.org/10.1016/S0022-510X(98)00304-9
» https://doi.org/10.1016/S0022-510X(98)00304-9 -
2Gilman S, Wenning GK, Low PA, Brooks DJ, Mathias CJ, Trojanowski JQ et al. Second consensus statement on the diagnosis of multiple system atrophy. Neurology. 2008;71(9):670-6. http://dx.doi.org/10.1212/01.wnl.0000324625.00404.15
» https://doi.org/10.1212/01.wnl.0000324625.00404.15 -
3Wenning GK, Stefanova N. Recent developments in multiple system atrophy. J Neurol. 2009;246(11):1791-808. http://dx.doi.org/10.1007/s00415-009-5173-8
» https://doi.org/10.1007/s00415-009-5173-8 -
4Robbins TW, James M, Lange KW, Owen AM, Quinn NP, Marsden CD. Cognitive performance in multiple system atrophy. Brain. 1992;115(1):271-91. http://dx.doi.org/10.1093/brain/115.1.271
» https://doi.org/10.1093/brain/115.1.271 -
5Berent S, Giordani B, Gilman S, Trask CL, Little RJ, Johanns JR et al. Patterns of neuropsychological performance in multiple system atrophy compared to sporadic and hereditary olivopontocerebellar atrophy. Brain Cogn. 2002;50(2):194-206. http://dx.doi.org/10.1016/s0278-2626(02)00503-1
» https://doi.org/10.1016/s0278-2626(02)00503-1 -
6Kawai Y, Suenaga M, Takeda A, Ito M, Watanabe H, Tanaka H et al. Cognitive impairments in multiple system atrophy: MSA-C vs MSA-P. Neurology. 2008;70(16 Pt 2):1390-6. http://dx.doi.org/10.1212/01.wnl.0000310413.04462.6a
» https://doi.org/10.1212/01.wnl.0000310413.04462.6a -
7Brown RG, Lacomblez L, Landwehrmeyer BG, Bak T, Uttner I, Dubois B et al. Cognitive impairment in patients with multiple system atrophy and progressive supranuclear palsy. Brain. 2010;133(8):2382-93. http://dx.doi.org/10.1093/brain/awq158
» https://doi.org/10.1093/brain/awq158 -
8Siri C, Duerr S, Canesi M, Delazer M, Esselink R, Bloem BR et al. A cross-sectional multicenter study of cognitive and behavioural features in multiple system atrophy patients of the parkinsonian and cerebellar type. J Neural Transm. 2013;120(4):613-8. http://dx.doi.org/10.1007/s00702-013-0997-x
» https://doi.org/10.1007/s00702-013-0997-x -
9Balas M, Balash Y, Giladi N, Gurevich T. Cognition in multiple system atrophy: neuropsychological profile and interaction with mood. J Neural Transm. 2010;117(3):369-75. http://dx.doi.org/10.1007/s00702-009-0365-z
» https://doi.org/10.1007/s00702-009-0365-z -
10Bürk K, Daum I, Rüb U. Cognitive function in multiple system atrophy of the cerebellar type. Mov Disord. 2006;21(6):772-6. http://dx.doi.org/10.1002/mds.20802
» https://doi.org/10.1002/mds.20802 -
11Chang CC, Chang YY, Chang WN, Lee YC, Wang YL, Lui CC et al. Cognitive deficits in multiple system atrophy correlate with frontal atrophy and disease duration. Eur J Neurol. 2009;16(10):1144-50. http://dx.doi.org/10.1111/j.1468-1331.2009.02661.x
» https://doi.org/10.1111/j.1468-1331.2009.02661.x -
12Soliveri P, Monza D, Paridi D, et al. Neuropsychological follow up in patients with Parkinson's disease, striatonigral degeneration-type multisystem atrophy, and progressive supranuclear palsy. J Neurol Neurosurg Psychiatry. 2000;69(3):313-8. http://dx.doi.org/10.1136/jnnp.69.3.313
» https://doi.org/10.1136/jnnp.69.3.313 -
13Spaccavento S, Del Prete M, Loverre A, Craca A, Nardulli R. Multiple system atrophy with early cognitive deficits: a case report. Neurocase. 2013;19(6):613-22. http://dx.doi.org/10.1080/13554794.2012.713494
» https://doi.org/10.1080/13554794.2012.713494
Publication Dates
-
Publication in this collection
Oct 2014
History
-
Received
13 May 2014 -
Reviewed
01 July 2014 -
Accepted
21 July 2014