14/12/21 10:06 MDS SIC Blog: Cognitive Impairment in Multiple System Atrophy

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Cognitive Impairment in Multiple System

Atrophy

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About the Authors

Dr. Shunsuke Koga, MD, PhD

Research Fellow

Department of Neuroscience

Mayo Clinic Jacksonville

USA

Professor Takayoshi Shimohata, MD, PhD

Chair, Department of Neurology, Gifu University Graduate School of Medicine,

Japan

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Professor Gregor Wenning, MD, PhD, MSc

Chair Division of Clinical Neurobiology 

Department of Neurology 

Medical University of Innsbruck

Austria

About the Contributor

 

Blog Prepared by SIC member:

Dr. Han-Lin Chiang, MD

Attending Physician

Department of Neurology

Taipei Veterans General Hospital

Taiwan

Date: April 2020

Prepared by SIC Member: Han-Lin Chiang, MD

Authors: Shunsuke Koga, MD, PhD; Takayoshi Shimohata, MD, PhD; Gregor Wenning, MD,
PhD, MSc

Blog Editor: Un Jung Kang, MD

Introduction

Multiple system atrophy (MSA) is a devastating adult-onset neurodegenerative disease with

the combined features of autonomic failure, parkinsonism, cerebellar dysfunction, and
pyramidal signs of various degrees. Consensus diagnostic criteria for MSA consider dementia
as a non-supporting feature1. However, recent studies suggested that cognitive impairment

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can be part of the presenting features in MSA and may occur even before motor symptom
onset. To raise the awareness of this frequently overlooked clinical feature in MSA, we have
asked three experts, Dr. Koga, Prof. Shimohata, and Prof. Wenning, to discuss the clinical
characteristics, diagnosis, and pathophysiology of cognitive impairment in MSA. (Authors are
listed in alphabetical order)  

How common is mild cognitive impairment or dementia in patients with MSA? Can it be seen
as an early feature of the disease? 

Dr. Koga

Based on the current clinical diagnostic criteria for multiple system atrophy (MSA), dementia
is one of the non-supporting features for MSA diagnosis; however, a subset of patients with
MSA can present with mild cognitive impairment.1, 2 The frequency of cognitive impairment
in MSA varies among studies. In autopsy-confirmed cases, it ranges from 20% to 37%.3-7 b)
We previously reported that 33 out of 102 MSA patients (32%) had cognitive impairment;
however, only one patient showed cognitive impairment as an initial symptom.6 A recent
retrospective study revealed that 32 out of 160 patients (20%) had cognitive impairment,
which appeared on average, 4.1 years after the onset of the disease.7 

It should be noted that comorbid pathologies, such as Alzheimer’s disease, Lewy body
disease, hippocampal sclerosis, and cerebrovascular disease, can potentially cause dementia.
In such cases, cognitive impairment can be presented as an early feature. Although rare,
frontotemporal lobar degeneration associated with α-synuclein (FTLD-synuclein) can
develop dementia as an early feature of the disease. FTLD-synuclein is an extreme variant of
MSA, characterized by severe frontotemporal lobe atrophy and numerous neuronal
cytoplasmic inclusions in the limbic system.8 Aside from this rare variant, cognitive
impairment is not considered an early feature of MSA. 

Prof. Shimohata

Based on a comprehensive evidence-based review, the Neuropsychology Task Force of the

MDS Multiple System Atrophy (MODIMSA) Study Group suggests that cognitive impairment
is present in patients with multiple system atrophy (MSA) more frequently than previously
considered2. Previous studies reported that cognitive impairment in patients with MSA
correlates with their disease duration9, severe motor disability10, and cardiovascular
dysautonomia10, 11, . We also demonstrated that impairment of global cognitive function
(MMSE score) was related to long disease duration, global disability due to disease (high
UMSARS part 1 and part 4 scores), and autonomic dysfunction (high residual urine volume
and short CVRR)12. 

Interestingly, MSA patients with early cognitive impairment have been described13, and in
some patients, the cognitive impairment has preceded motor impairment11.

Prof. Wenning

Mild cognitive impairment has been reported in up to 40 % of MSA patients6, 14 and can also
occur in early stage of disease. Nonetheless, severe cognitive decline that significantly
disrupts daily living is uncommon in MSA.

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a) Which cognitive domain is most likely to be affected in patients with MSA? b) What do you
think is the most suitable neuropsychiatric test to detect cognitive impairment in MSA
patients? c) Are there different patterns of cognitive impairment between MSA-P and MSA-C
patients? 

Dr. Koga

a) Multiple cognitive domains can be affected, but the frontal-executive function is most
likely declined in MSA, which is similar to progressive supranuclear palsy.2, 6, 10, 15 

b) Montreal Cognitive Assessment (MoCA) and Mini-Mental State Examination (MMSE) are
commonly used to screen global cognitive impairment in dementia as well as other
neurodegenerative diseases. For Parkinson’s disease, MoCA was more sensitive to detect
mild decline, especially executive dysfunction, than MMSE.16, 17 These tests have also been
applied to MSA patients. Although an MSA-specific screening cut-off score <27 on MMSE can
be useful,18 MoCA seems to be more sensitive to detect the mild cognitive decline.19 Mattis
Dementia Rating Scale is also useful to assess overall cognitive function in MSA, but it takes
much longer than MoCA or MMSE, so MoCA is the most suitable test to screen the cognition
in MSA patients.

c) This is a difficult question because the underlying pathology of cognitive impairment in

MSA remains elusive. It is possible to assume that MSA-P can more likely develop subcortical
type cognitive impairment, whereas MSA-C may more likely show cerebellar-type cognitive
deficits. Several studies reported no significant difference in the frequency and profile of
cognitive impairment between MSA-P and MSA-C,6, 20 while others demonstrated different
patterns.21, 22 Further studies are necessary to clarify the correlation between MSA
subtypes and the profile of cognitive impairment.

Prof. Shimohata

We previously demonstrated that cognitive impairment and frontal-lobe impairment were

frequently observed in 17 patients with probable MSA (31.3 and 26.7%, respectively)23. This
finding supports the previous observation that the impairment in cognitive function or
frontal-lobe function is a distinct clinical presentation of MSA9, 22. Therefore, the suitable
neuropsychiatric test is a test to detect frontal dysfunction, such as processing speed and
attention/executive functions. It has been reported that patients with MSA-P show more
severe and more widespread cognitive dysfunctions than patients with MSA-C22.

Prof. Wenning

Slight to moderate deficits frequently involve executive functions and verbal memory. Several
neuropsychiatric tests exist to evaluate cognition in MSA. Some tests (MMSE, Frontal
Assessment Battery, MoCA) are useful as screening tests. In contrast, the CERAD-plus test
battery is a comprehensive test assessing global cognition, object naming, verbal memory,
constructive abilities, figural memory, semantic and phonological word fluency, psychomotor
speed and cognitive flexibility. Although, comparative studies that have been conducted on
cognitive impairment in both motor subtypes reported heterogeneous results20, 22, 24 ,
overall the cognitive profiles in MSA-P and MSA-C are similar.

What is known about the pathophysiology (and possible treatment) for cognitive impairment
in MSA? 

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Dr. Koga

The responsible brain regions for cognitive impairment may vary depending on the affected
cognitive domains. Based on imaging studies, prefrontal lobe, cerebral white matter,
subcortical structures, and cerebellum have been proposed to be involved.12, 22, 25, 26 For
example, Frontal Assessment Battery scores negatively correlated with periventricular and
deep white matter lesions, suggesting frontal dysfunction in MSA can be explained by the
degeneration of cerebral white matter.12 The volume reduction in the posterior cerebellum
was correlated with MoCA scores, suggesting the posterior cerebellum and the cerebellum-
to-cortex circuit also play a role in cognitive impairment in MSA.26  

There are no convincing neuropathologic studies that can explain the responsible brain
regions for cognitive impairment in MSA. Lewy body-like neuronal cytoplasmic inclusions in
the neocortex and neuronal inclusions in the limbic system have been proposed, but the
correlation between the pathologic burden and cognitive impairment has not been
clarified.4-6

Prof. Shimohata

A previous study demonstrated that MSA patients with cognitive impairment had a greater
burden of neuronal cytoplasmic inclusions in the dentate gyrus than patients without
cognitive impairment6. Although several clinical trials have been performed, it is unfortunate
that the therapeutic effect for cognitive impairment in MSA has not investigated sufficiently.
Future studies need to determine whether therapies that target a-synuclein improve
cognitive impairment in MSA.

Prof. Wenning

The pathophysiologic mechanisms are still unclear.  It is suggested that underlying
degeneration of basal ganglia and secondarily disrupted striato-pallido-thalamocortical
circuits play an important role in the development of cognitive deficits2, 27.  Up to now, no
therapy is available that can improve cognitive functions.

Summary

Mild cognitive dysfunction is not uncommon in patients with MSA and is more likely to
develop in patients with longer disease duration but can rarely present as an initial symptom.
Similar to other parkinsonian disorders, the frontal-executive function is most frequently
involved, but severe cognitive decline compromising daily livings is uncommon. Further
researches are needed to determine the pathophysiology and treatment for cognitive
dysfunction in MSA.

References

1.    Gilman S, Wenning GK, Low PA, et al. Second consensus statement on the diagnosis of
multiple system atrophy. Neurology 2008;71:670-676.

2.    Stankovic I, Krismer F, Jesic A, et al. Cognitive impairment in multiple system atrophy: a
position statement by the Neuropsychology Task Force of the MDS Multiple System Atrophy
(MODIMSA) study group. Mov Disord 2014;29:857-867.

3.    Wenning GK, Tison F, Ben Shlomo Y, Daniel SE, Quinn NP. Multiple system atrophy: a
review of 203 pathologically proven cases. Mov Disord 1997;12:133-147.

4.    Cykowski MD, Coon EA, Powell SZ, et al. Expanding the spectrum of neuronal pathology
in multiple system atrophy. Brain 2015;138:2293-2309.

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5.    Homma T, Mochizuki Y, Komori T, Isozaki E. Frequent globular neuronal cytoplasmic

inclusions in the medial temporal region as a possible characteristic feature in multiple
system atrophy with dementia. Neuropathology 2016;36:421-431.

6.    Koga S, Parks A, Uitti RJ, et al. Profile of cognitive impairment and underlying pathology in
multiple system atrophy. Mov Disord 2017;32:405-413.

7.    Miki Y, Foti SC, Asi YT, et al. Improving diagnostic accuracy of multiple system atrophy: a
clinicopathological study. Brain 2019.

8.    Aoki N, Boyer PJ, Lund C, et al. Atypical multiple system atrophy is a new subtype of
frontotemporal lobar degeneration: frontotemporal lobar degeneration associated with
alpha-synuclein. Acta Neuropathol 2015;130:93-105.

9.    Chang CC, Chang YY, Chang WN, et al. Cognitive deficits in multiple system atrophy
correlate with frontal atrophy and disease duration. Eur J Neurol 2009;16:1144-1150.

10.    Brown RG, Lacomblez L, Landwehrmeyer BG, et al. Cognitive impairment in patients
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11.    Kitayama M, Wada-Isoe K, Irizawa Y, Nakashima K. Assessment of dementia in patients

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12.    Hatakeyama M, Sato T, Takahashi T, et al. Predictors of cognitive impairment in multiple

system atrophy. J Neurol Sci 2018;388:128-132.

13.    Konagaya M, Sakai M, Matsuoka Y, Konagaya Y, Hashizume Y. Multiple system atrophy

with remarkable frontal lobe atrophy. Acta Neuropathol 1999;97:423-428.

14.    Koga S, Aoki N, Uitti RJ, et al. When DLB, PD, and PSP masquerade as MSA: an autopsy
study of 134 patients. Neurology 2015;85:404-412.

15.    Fiorenzato E, Antonini A, Wenning G, Biundo R. Cognitive impairment in multiple

system atrophy. Mov Disord 2017;32:1338-1339.

16.    Hoops S, Nazem S, Siderowf AD, et al. Validity of the MoCA and MMSE in the detection
of MCI and dementia in Parkinson disease. Neurology 2009;73:1738-1745.

17.    Dalrymple-Alford JC, MacAskill MR, Nakas CT, et al. The MoCA: well-suited screen for
cognitive impairment in Parkinson disease. Neurology 2010;75:1717-1725.

18.    Auzou N, Dujardin K, Biundo R, et al. Diagnosing dementia in multiple system atrophy by
applying Movement Disorder Society diagnostic criteria for Parkinson's disease dementia.
Parkinsonism Relat Disord 2015;21:1273-1277.

19.    Fiorenzato E, Weis L, Falup-Pecurariu C, et al. Montreal Cognitive Assessment (MoCA)

and Mini-Mental State Examination (MMSE) performance in progressive supranuclear palsy
and multiple system atrophy. J Neural Transm (Vienna) 2016;123:1435-1442.

20.    Siri C, Duerr S, Canesi M, et al. A cross-sectional multicenter study of cognitive and
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type. J Neural Transm (Vienna) 2013;120:613-618.

21.    Kawahara Y, Ikeda Y, Deguchi K, et al. Simultaneous assessment of cognitive and

affective functions in multiple system atrophy and cortical cerebellar atrophy in relation to
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22.    Kawai Y, Suenaga M, Takeda A, et al. Cognitive impairments in multiple system atrophy:
MSA-C vs MSA-P. Neurology 2008;70:1390-1396.

23.    Kawamura K, Shimohata T, Nakayama H, Tomita M, Ozawa T, Nishizawa M. Factors

influencing the cognitive function in patients with multiple system atrophy. Mov Disord
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24.    Stanzani-Maserati M, Gallassi R, Calandra-Buonaura G, et al. Cognitive and sleep

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25.    Fiorenzato E, Weis L, Seppi K, et al. Brain structural profile of multiple system atrophy
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26.    Yang H, Wang N, Luo X, et al. Cerebellar atrophy and its contribution to motor and
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27.    Brown RG, Marsden CD. 'Subcortical dementia': the neuropsychological evidence.
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