Neural Correlates of Apathy in Multiple System Atrophy: A Clinical and Perfusion Imaging Study

Apathy is a frequent nonmotor symptom of multiple system atrophy (MSA) that worsens quality of life. Although frontostriatal dysfunction has been implicated in apathy, its neural basis in MSA remains insufficiently characterized.

To identify the neural substrates of apathy associated with MSA-specific neurodegenerative processes.

This retrospective cross-sectional study included 76 patients with cognitively preserved clinically established/probable MSA who underwent clinical and neuropsychological assessments, including the Apathy Scale and a separate depression measure, magnetic resonance imaging, and cerebral blood flow single-photon emission computed tomography. Clinical variables, gray matter volume, and voxel-wise perfusion were compared between apathy and non-apathy groups. Multivariate logistic regression was used to analyze the independent association of the significant perfusion cluster with apathy, and seed-based covariance analysis was used to explore network alterations.

Apathy was present in 55.3% of patients and did not differ between motor subtypes. Compared with the non-apathy group, the apathy group showed lower visuospatial scores and frequency of neurogenic orthostatic hypotension, similar depression scores and gray matter volume, and reduced perfusion in the medial prefrontal cortex on voxel-wise perfusion analysis. These findings remained independently associated with apathy after adjustment for clinical variables. Seed-based covariance analysis suggested reduced positive covariance between the medial prefrontal cortex and cerebellar regions, predominantly in the posterior lobe.

Apathy was common in MSA even with relatively preserved global cognition and distinct from depression. In addition to medial frontostriatal dysfunction, exploratory findings suggested that mechanisms related to cerebellar cognitive affective syndrome may contribute to its pathophysiology.