Cognitive Impairment in Multiple System Atrophy

Multiple system atrophy (MSA) is a rare, rapidly progressive neurodegenerative disorder characterised by parkinsonism, cerebellar ataxia and autonomic failure. Historically, cognitive impairment was considered uncommon and served as an exclusion criterion for diagnosis. However, mounting evidence now recognises a spectrum of cognitive deficits in MSA, ranging from mild executive dysfunction and attentional lapses to multidomain impairment and, in some cases, frank dementia. Executive dysfunction, characterised by difficulties in planning, set-shifting and inhibitory control, appears to be the earliest and most consistent feature. Memory and visuospatial skills are variably affected, while language and semantic knowledge are relatively preserved until later stages. Neuroimaging studies reveal atrophy and hypometabolism in frontal cortical regions and subcortical structures, reflecting disruption of cortico-subcortical loops. Pathologically, MSA is an α-synucleinopathy marked by glial cytoplasmic inclusions predominantly in oligodendrocytes, but neuronal loss and synaptic dysfunction within prefrontal, parietal and limbic networks contribute to cognitive decline. Behavioural disturbances, such as apathy, anxiety and rapid eye movement sleep behaviour disorder, often accompany cognitive changes and may herald disease progression. Although the mechanisms underlying cognitive impairment remain incompletely defined, altered neurotransmitter systems, including noradrenergic and dopaminergic pathways, are implicated. Recognition of cognitive features in MSA has practical implications for patient management and the development of biomarkers to track disease onset and progression.

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Cognitive Impairment in Multiple System Atrophy publication trend

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Technical terms

α-Synucleinopathy: A disorder characterised by abnormal accumulation of the protein α-synuclein, especially in oligodendrocytes and neurons.

Glial cytoplasmic inclusions: Abnormal deposits of α-synuclein within oligodendrocytes, defining the pathological hallmark of MSA.

FDG-PET: A molecular imaging technique that measures regional cerebral glucose metabolism using the tracer 18F-fluorodeoxyglucose.

Neuromelanin-sensitive MRI: Magnetic resonance imaging sequence that detects neuromelanin pigment in catecholaminergic nuclei, such as the locus coeruleus.

Executive functions: Higher-order cognitive processes including planning, task-switching and inhibitory control.

References

1. The Pathobiology of Behavioral Changes in Multiple System Atrophy: An Update †. International Journal of Molecular Sciences (2024).
2. Characteristics of cerebral glucose metabolism in patients with cognitive impairment in multiple system atrophy. Frontiers in Aging Neuroscience (2025).
3. Locus coeruleus neuromelanin, cognitive dysfunction, and brain metabolism in multiple system atrophy. Journal of Neurology (2025).