  The loss of melanized neurons in the substantia nigra pars compacta is a
primary feature in Parkinson's disease (PD). Iron deposition occurs in
conjunction with this loss. Loss of nigral neurons should remove barriers for
diffusion and increase diffusivity of water molecules in regions undergoing
this loss. In metrics from single-compartment diffusion tensor imaging models,
these changes should manifest as increases in mean diffusivity and the free
water compartment as well as and reductions in fractional anisotropy. However,
studies examining nigral diffusivity changes from PD with single-compartment
models have yielded inconclusive results and emerging evidence in control
subjects indicates that iron corrupts diffusivity metrics derived from
single-compartment models.
  Iron-sensitive data and diffusion data were analyzed in two cohorts. The
effect of iron on diffusion measures from single- and bi-compartment models was
assessed in both cohorts.
  Measures sensitive to the free water compartment and iron content were found
to increase in substantia nigra of the PD group in both cohorts. However,
diffusion markers derived from the single-compartment model were not replicated
across cohorts. Correlations were seen between single-compartment diffusion
measures and iron markers in the discovery cohort and validation cohort but no
correlation was observed between a measure from the bi-compartment model
related to the free water compartment and iron markers in either cohort.
  The variability of single-compartment nigral diffusion metrics in PD may be
attributed to competing influences of increased iron content, which drives
diffusivity down, and increases in the free water compartment, which drives
diffusivity up. In contrast to diffusion metrics derived from the
single-compartment model, no relationship was seen between iron and the free
water compartment in substantia nigra.
