We have adopted a simple and practical approach to drawing the ROI, which could easily be implemented in any clinical radiological setting, with good reproducibility (inter‐rater and intra‐rater consensus for both FA and ADC measurements were high). The reproducibility of the previous pilot study using more complex methodology was not available.18
Our study demonstrated a lower FA value in the substantia nigra in patients with PD compared with controls. However, no statistically significant differences were seen in the other regions.
Our results support post‐mortem findings that the substantia nigra is the most severely affected primary site of pathology in this condition.1,2
In the late stages of PD, secondary degeneration may be present in the basal ganglia and extrastriatal regions. The absence of DTI differences in the basal ganglia structures between our study groups could be partly due to the exclusion of the most severe PD cases from the study (those who were severely immobile or demented). Interestingly, the FA values in the substantia nigra were higher than those of the thalamus, which was also the finding of Yoshikawa and colleagues,18
wherein detailed tracing and drawing of multiple ROIs along a postulated nigrostriatal pathway was employed.
Our ADC values were similar in patients with PD and controls, although there was a trend towards a higher value in the substantia nigra in PD. Some DTI studies have suggested that FA is more sensitive to alterations in microstructural integrity than ADC. In addition, we only used 2 b
values in the measurement of ADC. Schocke and colleagues20
found increased putamen diffusivity in 11 patients with multiple system atrophy (parkinsonian variant) compared with 17 patients with PD and 10 controls. Their study also revealed no difference in ADC values in the basal ganglia and substantia nigra between PD and controls.
While the biophysical basis of a deceased FA value in relation to neurodegenerative disorders (decrease in number or density of axons, reduced axonal myelination or orientational coherence of the fibre tract) has not been fully clarified, it is likely that change in FA value corresponds to neuronal loss. Supporting this is our finding in the linear multivariate analysis which showed an inverse correlation between clinical severity (H&Y staging) and the FA value in patients with PD. Our findings suggest that FA measurements of the substantia nigra could serve as a marker for disease progression and therapeutic response.
To assess the potential utility of the FA values we acquired from our study cohort in clinical practice, we evaluated the sensitivity, specificity, and positive and negative predictive values using receiver operating characteristic curve analysis. While the median FA value was lower in PD, there was considerable overlap of FA values between patients and controls (fig 2, supplementary file; the supplementary file can be viewed on the J Neurol Neurosurg Psychiatry
website at http://www.jnnp.com/supplemental
). The area under the curve was modest (fig 3, supplementary file; the supplementary file can be viewed on the J Neurol Neurosurg Psychiatry
website at http://www.jnnp.com/supplemental
), suggesting that the discriminative property of the FA value as a sole diagnostic tool in PD may not be robust enough. These data suggest that no single FA value in the substantia nigra could be used with absolute certainty for both screening and diagnosis of PD.
There are some inherent limitations in our study. The cross sectional design did not allow us to measure FA values serially for individual subjects in a longitudinal manner. Ideally, a prospective study to measure FA values at fixed time points over a period of a few years would generate a set of data for the rate of decline of the FA value in PD and healthy controls. This information could be a useful quantitative and objective reference when monitoring patients' responses to neuroprotective or therapeutic clinical trials. We did not include other neurodegenerative diseases with parkinsonism in our study and hence our findings could not be generalised beyond our two study groups. Thus we cannot comment on whether a low FA value could help differentiate between PD and other causes of parkinsonism.
In conclusion, we have demonstrated in a large, prospective, case control study that the FA value in the substantia nigra on DTI was lower in PD compared with healthy controls, and correlated inversely with the clinical severity of PD. Because of the overlap of FA values between PD and controls, no single FA value had both a high positive and negative predictive power. Further longitudinal studies would be helpful to assess the clinical utility of serial FA measurement of the substantia nigra as an objective quantitative measure of disease progression and therapeutic response.