White matter hyperintensities mediate the impact of amyloid ß on future freezing of gait in Parkinson's disease.

Abstract Background Freezing of gait (FOG) is a common symptom in Parkinson’s Disease (PD) patients. Previous studies have reported relationships between FOG, substantia nigra (SN) degeneration, dopamine transporter (DAT) concentration, as well as amyloid β deposition. However, there is a paucity of research on the concurrent impact of white matter damage. Objectives To assess the inter-relationships between these different co-morbidities, their impact on future FOG and whether they act independently of each other. Methods We used baseline MRI and longitudinal gait data from 423 de novo PD patients from the Parkinson’s Progression Markers Initiative (PPMI). We used deformation based morphometry (DBM) from T1-weighted MRI to measure SN atrophy, and segmentation of white matter hyperintensities (WMH) as a measure of WM pathological load. Putamen and caudate DAT levels from SPECT as well as cerebrospinal fluid (CSF) amyloid β were obtained directly from the PPMI. Following correlation analyses, we investigated whether WMH burden mediates the impact of amyloid β on future FOG. Results SN DBM, WMH load, putamen and caudate DAT activity and CSF amyloid β levels were significantly different between PD patients with and without future FOG (p Conclusions Amyloid β might impact future FOG in PD patients through an increase in WMH burden, in a pathway independent of Lewy body pathology.