Subregional analysis of the amygdala, thalamus, and hypothalamus at the pre-decline stage in Parkinson’s disease with later cognitive impairment

Cognitive decline in Parkinson's disease (PD) significantly impacts patients' quality of life, yet early detection remains challenging. While structural brain abnormalities in cortical regions have been widely documented using magnetic resonance imaging (MRI), subcortical regions have received less analytical attention despite their potential role as early biomarkers. This study investigated changes in specific subregions of the amygdala, thalamus, and hypothalamus in patients with PD before cognitive decline development. We analyzed MRI data from 163 participants (97 healthy controls [HC] and 66 patients with PD) from the Parkinson's Progression Markers Initiative database. The patients with PD were classified based on cognitive status during a four-year follow-up: 21 who developed cognitive impairment (PDCI) and 45 who maintained normal cognition (PDNC). Cognitive function was assessed using the Montreal Cognitive Assessment and domain-specific tests. The PDCI group showed significantly lower corrected brain volumes in specific subregions of the amygdala (left basal nucleus), thalamus (bilateral lateral geniculate nuclei, right medial dorsal nucleus, and right anterior pulvinar nucleus), and hypothalamus (bilateral anterior-superior and left superior tubular parts) compared to that of HC. A significant difference between the PDCI and PDNC groups was observed only in the left lateral geniculate nucleus. In contrast, widespread structural changes were observed in cortical regions in the PDCI group, which showed stronger correlations with memory, attention, executive function, and visuospatial abilities. Hazard ratio analysis confirmed that structural changes in multiple cortical regions were significant predictors of cognitive decline. Although structural alterations were observed in subcortical regions, cortical changes demonstrated stronger associations with cognitive decline. These findings suggest that structural abnormalities may appear in the cerebral cortex before the stage proposed by conventional α-synuclein propagation models, potentially involving multiple mechanisms beyond α-synuclein, including global neural circuit dysfunction, disruption of neurotransmitter systems, breakdown of compensatory mechanisms, and coexisting pathologies (beta-amyloid and tau proteins). This study provides insights into early brain changes in PD and emphasizes the need for a comprehensive approach considering multiple mechanisms in early diagnosis and intervention strategies for PD-related cognitive impairment.