Objective: Niemann-Pick type C (NPC) disease is a progressive neurovisceral disorder with disrupted intracellular cholesterol metabolism, that results in significant alterations to neuronal and axonal structure. Adult patients present with ataxia, gaze palsy, impaired cognition and neuropsychiatric illness, but the neural substrate has not been well-characterized in vivo. Our aim was to investigate a well-characterized sample of adults with confirmed NPC for grey and white matter abnormalities.
Methods: We utilized a combination of optimized voxel-based morphometry (VBM) of T1-weighted images and tract-based spatial statistics (TBSS) of diffusion-tensor images (DTI) to examine grey matter volume and white matter structural differences in six adult NPC patients and eighteen gender- and age-matched controls.
Results: NPC patients demonstrated bilateral grey matter reductions in large clusters in bilateral hippocampus, thalamus, superior cerebellum and insula, in addition to smaller regions of inferoposterior cortex. Patients demonstrated widespread reductions in fractional anisotropy in major white matter tracts. Subsequent analysis of measures of axial and radial diffusivity suggest that these changes are contributed to by both impaired myelination and altered axonal structure.
Conclusions: Findings in grey matter areas are broadly consistent with human and animal studies of selective vulnerability of neuronal populations to the neuropathology of NPC, whereas more widespread white matter changes are consistent with the hypothesis that disrupted myelination and axonal structure predate changes to the neuronal cell body. These findings suggest that volumetric analysis of grey matter and diffusion tensor imaging may be useful modalities for indexing illness stage, and monitoring response to emerging treatment.