Free-water imaging in Parkinson’s disease and atypical parkinsonism

Abstract

Conventional single tensor diffusion analysis models have provided mixed findings in the substantia nigra of Parkinson's disease, but recent work using a bi-tensor analysis model has shown more promising results. Using a bi-tensor model, free-water values were found to be increased in the posterior substantia nigra of Parkinson's disease compared with controls at a single site and in a multi-site cohort. Further, free-water increased longitudinally over 1 year in the posterior substantia nigra of Parkinson's disease. Here, we test the hypothesis that other parkinsonian disorders such as multiple system atrophy and progressive supranuclear palsy have elevated free-water in the substantia nigra. Equally important, however, is whether the bi-tensor diffusion model is able to detect alterations in other brain regions beyond the substantia nigra in Parkinson's disease, multiple system atrophy, and progressive supranuclear palsy and to accurately distinguish between these diseases. Free-water and free-water-corrected fractional anisotropy maps were compared across 72 individuals in the basal ganglia, midbrain, thalamus, dentate nucleus, cerebellar peduncles, cerebellar vermis and lobules V and VI, and corpus callosum. Compared with controls, free-water was increased in the anterior and posterior substantia nigra of Parkinson's disease, multiple system atrophy, and progressive supranuclear palsy. Despite no other changes in Parkinson's disease, we observed elevated free-water in all regions except the dentate nucleus, subthalamic nucleus, and corpus callosum of multiple system atrophy, and in all regions examined for progressive supranuclear palsy. Compared with controls, free-water-corrected fractional anisotropy values were increased for multiple system atrophy in the putamen and caudate, and increased for progressive supranuclear palsy in the putamen, caudate, thalamus, and vermis, and decreased in the superior cerebellar peduncle and corpus callosum. For all disease group comparisons, the support vector machine 10-fold cross-validation area under the curve was between 0.93-1.00 and there was high sensitivity and specificity. The regions and diffusion measures selected by the model varied across comparisons and are consistent with pathological studies. In conclusion, the current study used a novel bi-tensor diffusion analysis model to indicate that all forms of parkinsonism had elevated free-water in the substantia nigra. Beyond the substantia nigra, both multiple system atrophy and progressive supranuclear palsy, but not Parkinson's disease, showed a broad network of elevated free-water and altered free-water corrected fractional anisotropy that included the basal ganglia, thalamus, and cerebellum. These findings may be helpful in the differential diagnosis of parkinsonian disorders, and thereby facilitate the development and assessment of targeted therapies.

Free water improves detection of changes in the substantia nigra in parkinsonism: A multisite study

“…Each ROI was 8 voxels in size. The substantia nigra was identified in accordance with previous work where inter-rater reliability has been high 5,10 . To assess inter-rater reliability in this study, novice raters who were blind to group diagnoses drew ROIs of 10 subjects from each group across each site.…”

“…Previous reports have shown that putaminal MD U can be useful to distinguish the parkinsonian variant of MSA from PD but not from PSP 23 . Diffusivity changes of the middle cerebellar peduncle, however, may provide additional information 10,22 . Our findings of changes in the posterior nigra are in line with pathological studies that report degeneration in the ventro-lateral tier of the substantia nigra in patients with degenerative parkinsonism 1 .…”

“…fractional volume of the free-water compartment) in the substantia nigra is increased in PD compared with control subjects in both a single site cohort and the multi-site cohort from the Parkinson’s Progressive Marker Initiative (PPMI) 5 . Also, it was found that free-water in the substantia nigra increases over time in PD 9 , and is elevated in MSA and PSP 10 . While there is much promise in using a bi-tensor model, these sample sizes have been small, and there has not been a study directly comparing the utility of a bi-tensor model with the single-tensor model in the substantia nigra for PD, MSA, and PSP patients across several sites.…”

Diagnosis of multiple system atrophy

“…Interestingly, a prospective study showed progressive abnormalities of the diffusivity of the putamen over time, thus allowing the possibility of using DWI imaging as a marker of disease progression and an outcome measure in clinical trials for MSA (Pellecchia et al, 2011). Diffusion tensor imaging (DTI), a similar technique to DWI which analyzes the three-dimensional shape of the diffusion and produces 3-D neural tract images (Huisman, 2010), is being increasingly used to distinguish MSA from PD and PSP (Du et al, 2017; Ofori et al, 2017; Planetta et al, 2016; Prodoehl et al, 2013; Worker et al, 2014). …”

Novel Diffusion-Kurtosis-Informed Template Reduces Distortions due to Partial Volume Effects and Improves Statistical between-Group Comparisons

“…The FWE method, in contrast, allows one to map the relative free water fraction within a voxel as an additional contrast. A useful application of free water fraction mapping was demonstrated, for example, in studies of Parkinson's disease [70][71][72]. Nevertheless, as a pure correction method, the D-KIT revealed itself as simple and robust in efficiently reducing PVE along the tissue borders without paying the penalty of potential errors introduced by (non-trivial) fitting and regularisation procedures.…”