Cognitive Impairment in Multiple System Atrophy

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
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 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 dysautonomia^{10, 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 patients^{6, 14} and can also occur in early stage of disease. Nonetheless, severe cognitive decline that significantly disrupts daily living is uncommon in MSA.

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 MSA^{9, 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 results^{20, 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? 

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 deficits^{2, 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.

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