Beyond normal aging: differential effects of white matter hyperintensities on cognition in Parkinson’s disease

Background and purpose: Cognitive impairment is a prominent non-motor symptom of Parkinson’s disease (PD). Current evidence supports that white matter hyperintensity (WMH) is associated with cognitive impairment in PD. However, it remains uncertain whether WMH exerts a differential impact on cognition in PD compared to normal aging, and whether specific lesion patterns underlie domain-specific cognitive deficits. The aim of the present thesis work is to investigate whether the association of WMH burden with cognitive performance differs between PD and normal aging. Further, this study examines whether the severity and localization of WMH contribute to domain-specific cognitive dysfunction across the entire PD cognitive spectrum. Methods: A total of 64 patients with PD and 84 controls underwent a standardized neuropsychological evaluation covering six cognitive domains: attention and working memory, executive functions, language, memory, visuospatial abilities and social cognition. This assessment enabled the classification of PD patients across the full range of cognitive functioning along the entire cognitive spectrum—PD with normal cognition (PD-NC), mild cognitive impairment (PD-MCI) and dementia (PDD)—and similarly to identify cognitively unimpaired and MCI individuals in the control group. WMH burden was assessed using the Fazekas scale and an automatic voxel-wise lesion segmentation tool (LST-AI; Wiltgen et al., 2024); lesion segmentation maps were normalized to a study template (ANTs; Avants et al., 2014) and parcellated into six cerebral lobes (i.e., frontal, cingulate, occipital, temporal, parietal and insular), one deep/periventricular white-matter (deep/pv WM) region and one cerebellar WM region (FreeSurfer), to derive group-level frequency maps and regional WMH volumes. Results: Quantitatively, total WMH volume was higher in the overall PD group and compared with CU, and similarly in the cognitively impaired PD subgroup (PD-MCI + PDD group) than CU. Of note, PD-NC did not differ from CU. Regionally, PD showed greater occipital WMH relative to CU, whereas PD-CI showed greater occipital, cingulate and deep/pv WMH. No significant differences emerged in the direct comparison PD-CI vs. PD-NC. Across the PD group, greater lesion volume in frontal, cingulate, parietal, and deep/pv WM was associated with poorer performance in most cognitive domains (all pFDR < 0.05). Conclusion: WMHs were strongly associated with multidomain cognitive dysfunctions in PD. In particular, quantitative and regional mapping analyses showed that increasing WMH burden was associated with cognitive worsening across PD cognitive statuses. These findings support a vascular co-pathology within the heterogeneous cognitive presentation of PD and underscore the need for standardized WMH assessment, vascular risk management, and longitudinal multifactorial studies to clarify how mixed pathologies jointly shape cognition in PD.