Cognitive Impairment in Multi-System Atrophy: Is It Time to Update Diagnostic Criteria?

Cognitive impairment (CI) is well-recognized in Parkinson disease, but less so in other parkinsonian disorders like multiple system atrophy (MSA), so much so that features of dementia are considered nonsupportive of a diagnosis of MSA despite consistent evidence that it contributes to the clinical picture.^1-3

Cognitive impairment is far more common in MSA than generally recognized, ranging from 22% to 37% of patients on autopsy, and expressed broadly across multiple domains. The majority of investigations compare MSA with progressive supranuclear palsy (PSP), as they share a number of similar clinical characteristics. Recent studies have demonstrated nearly identical profiles of the specific CI patterns observed in MSA and PSP. The primary dysfunction in both disorders is usually observed in executive function, with additional impairments of memory and visuospatial function.¹ Problems with verbal fluency may be predictive of CI in MSA, while motor impairment is the most significant predictor of severity.¹

The MSA-CI Profile

A 2010 study by Brown, et al² that retrospectively evaluated 372 patients with MSA and 311 patients with PSP from the Neuroprotection and Natural History in Parkinson Plus Syndromes cohort reported frontotemporal impairment in 31.2% of patients with MSA and 62% of patients with PSP. Of more importance, they found that “the impaired patients in the two groups were largely indistinguishable, qualitatively and quantitatively.”

The patients with CI tended to be older and had more severe clinical disease, regardless of whether they were diagnosed with MSA or PSP.² There was a weak association with longer duration of disease in impaired patients, which did not necessarily correspond to disease stage. Although CI has previously been presumed to be a late-stage event, it was observed in early stages in 22% and 50% of patients with MSA and PSP, respectively.² “Significant cognitive impairment appears consistent with a diagnosis of multiple system atrophy, even early in the disease, with important implications for diagnosis, research and management,” the investigators wrote.

In the majority (64.4%) of cases of MSA, the original diagnosis remained unchanged by the identification of CI, while the remainder were reclassified as having PSP, Lewy body disease, or amyotrophic lateral sclerosis.²

A 2016 retrospective study by Koga, et al³ identified similar patterns in a cohort of 102 patients with MSA from the Mayo Clinic brain bank. The findings suggested a strong correlation between higher burden of neuronal cytoplasmic inclusions in the limbic regions of the brain and greater risk for CI in one-third of the cohort.³

CI Patterns in MSA Variants

Two major variations of MSA exist, classified by distinct motor phenotypes: a parkinsonian subtype (MSA-P) characterized by prominent akinetic rigidity, and a cerebellar subtype (MSA-C), of which the most prominent feature is ataxia. Both types are associated with CI, which appears at a mean 7 years after initial diagnosis,³ although evidence early in the disease course is also possible.

In MSA-P, the primary domain affected by CI is executive function, which is reported in up to 49% of cases.¹ Executive function covers a broad range of abilities, and CI results in reductions in speed of thought processing and a lessened ability to solve problems; problems shifting attention, mental flexibility, and abstract reasoning; and a tendency toward perseveration. Attention and working memory are impaired to varying degrees, while conceptual thinking and inhibitory reflexes are less often affected.

Evaluation of MSA-C patients has been less frequently conducted. The domain most affected is memory, manifesting as difficultly in learning, while impairments of memory recall and recognition have also been reported.^1,5 Studies assessing impairment of attention and visuospatial performance in patients with MSA-C have produced less conclusive results.¹ Kawai and colleagues, in a comparative study of MSA-P and MSA-C, found that CI in the latter was confined largely to impairment of visuospatial capacities, while MSA-P involved multiple domains, which they attributed to variations in subcortical degeneration patterns in the two MSA subtypes.⁴

A 2014 position paper published in Movement Disorders by the MODIMSA Study Group¹ observed that the shorter survival associated with MSA may mask a potentially higher rate of cognitive decline, as the incidence of CI in patients who live longer than 8 years is nearly 50%. “If the disease did not have such a rapid course, the cumulative prevalence of dementia in MSA would be similar to that of Parkinson disease,” they wrote. They concluded that the quantitative differences between CI in MSA and synucleinopathies, including PSP, may be important to clinical discrimination of these diseases.

Although the evidence for CI in MSA is admittedly more limited than in PD, it is now substantial enough to address modification of diagnostic criteria to include the potential for CI at any stage of the disease. According to Brown and colleagues,² “cognitive impairment should not be an exclusion criterion for the diagnosis of multiple system atrophy in research and clinical trials.”

The MODIMSA group has set short-term goals that include the further quantification of CI in MSA, and detailing the underlying mechanisms for the purpose of revising current consensus criteria for the diagnosis of MSA.¹

References

1. 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.
2. Brown RG, Lacomblez L, Landwehrmeyer BG, et al. Cognitive impairment in patients with multiple system atrophy and progressive supranuclear palsy. Brain. 2010:133;2382–2393.
3. 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.
4. Kawai Y, Suenaga M, Takeda A, et al. Cognitive impairments in multiple system atrophy. Neurology. 2015;70:1390-1396.
5. Lee MJ, Shin JH, Seoung JK, et al. Cognitive impairments associated with morphological changes in cortical and subcortical structures in multiple system atrophy of the cerebellar type. Eur J Neurol. 2016;23:92-100.