Microstructural changes in white matter associated with freezing of gait in Parkinson's disease

In Parkinson's disease (PD), freezing of gait (FOG) is associated with widespread functional and structural gray matter changes throughout the brain. Previous study of freezing-related white matter changes was restricted to brainstem and cerebellar locomotor tracts. This study was undertaken to determine the spatial distribution of white matter damage associated with FOG by combining whole brain and striatofrontal seed-based diffusion tensor imaging. Diffusion-weighted images were collected in 26 PD patients and 16 age-matched controls. Parkinson's disease groups with (n = 11) and without freezing of gait (n = 15) were matched for age and disease severity. We applied tract-based spatial statistics to compare fractional anisotropy and mean diffusivity of white matter structure across the whole brain between groups. Probabilistic tractography was used to evaluate fractional anisotropy and mean diffusivity of key subcortico-cortical tracts. Tract-based spatial statistics revealed decreased fractional anisotropy in PD with FOG in bilateral cerebellar and superior longitudinal fascicle clusters. Increased mean diffusivity values were apparent in the right internal capsule, superior frontal cortex, anterior corona radiata, the left anterior thalamic radiation, and cerebellum. Tractography showed consistent white matter alterations in striatofrontal tracts through the putamen, caudate, pallidum, subthalamic nucleus, and in connections of the cerebellar peduncle with subthalamic nucleus and pedunculopontine nucleus bilaterally. We conclude that FOG is associated with diffuse white matter damage involving major cortico-cortical, corticofugal motor, and several striatofrontal tracts in addition to previously described cerebello-pontine connectivity changes. These distributed white matter abnormalities may contribute to the motor and non-motor correlates of FOG.