There were three novel findings in this study. First, we demonstrated that the FA values were reduced in the SN of early stage, unmedicated patients with PD. Second, the difference between de novo patients with PD and healthy control subjects was greatest in the caudal ROI of the SN compared with the middle and rostral SN ROI. Third, all de novo patients with PD were distinguished from all healthy individuals with 100% sensitivity and specificity. These findings were consistent across two independent, blinded raters. Our DTI assessment therefore detected not only group differences, but also accurate individual assignment.
In humans, two previous studies using DTI showed that FA in the substantia nigra is reduced in patients with PD compared to healthy individuals.4,6
In those studies, patients were more severely impaired than the patients in the current study, and the patients in these two previous studies were examined while on dopaminergic medication. The current study extends the previous literature to show that early stage, de novo patients with PD have reduced FA in the SN. In addition, although group-level differences for FA in the SN were significant in both previous studies between patients with PD and control subjects,4,6
on an individual basis, FA measures could not identify PD patients consistently. For instance, a case-controlled study4
reported an area under the curve that was considered modest (0.653), suggesting that DTI may not be a promising method for identifying PD in individual subjects.
Many factors may influence the ability of DTI to discriminate patients with PD from healthy individuals. These factors include the field strength of the magnet, spatial resolution, signal-to-noise ratio, contrast-to-noise ratio, image artifacts, and zones within the SN where the ROI are drawn. Previous DTI studies have used MRI at 1.5 Tesla.4,6
In contrast, the current study was carried out using a high-resolution DTI sequence at 3 Tesla with state-of-the-art parallel imaging techniques. This technique allows a high spatial resolution to be achieved with adequate signal-to-noise ratio. Three 30.6 mm3
ROI were drawn in targeted segments of the SN. Previous DTI studies have typically drawn one ROI in the SN. One study4
reported using a single ROI volume of 40 mm3
. Our choice of using three smaller ROI based on the known degeneration pattern in PD may have strengthened our ability to target specific regions of degeneration in the SN and detect regional changes. The finding that the caudal ROI was more impaired than the middle and rostral ROI is in line with pathologic patterns of nigral degeneration and suggests that DTI-based FA is a measure that anatomically focuses on the main target of PD-related pathology.
There are two likely explanations for the between-group difference in FA in the rostral and caudal ROI, and these are not mutually exclusive. The first explanation is that the rostral region of the hypointense area of a T2-weighted image may include more than just the SN. T2-weighted images with proton density-weighted spin-echo and fast short inversion time inversion-recovery imaging show that the rostral part of the hypointense region on an axial slice of a T2-weighted image contains both the SN and cerebral peduncle. Our rostral ROI may have included the SN and cerebral peduncle, and this may have decreased our ability to separate PD from healthy individuals in the rostral SN. This limitation does not apply to the caudal ROI, where the most robust effects were observed. It is important to note that the control ROI that was placed lateral to the SN in the cerebral peduncle ( and appendix e-1) did not differ for any measure between groups. Also, the FA value in the cerebral peduncle was considerably higher than the FA value for the rostral ROI of the SN (e-data). The second explanation is that degeneration in the SN of patients with PD occurs more in the ventral and caudal portion compared with the rostral portion of the SN. Indeed, postmortem studies in humans have shown dopaminergic cell loss mostly occurs in the ventrolateral and caudal segment of the SN pars compacta, whereas normal aging affects cells in the dorsomedial SN pars compacta.3
The greatest difference was found in the caudal ROI and this is consistent with the region of the SN where dopaminergic cell loss primarily occurs in PD.1,3
Also, the current finding that the caudal portion of the SN is more impaired than the rostral segment is consistent with recent proton density imaging techniques reflecting higher iron content caudally.5
Other neuroimaging tests such as PET or SPECT distinguish patients with PD from healthy individuals. PET scans assessing [18
]F-dopa uptake distinguished 100% of clinically moderate patients with PD from healthy controls,20
with 85% correctly distinguished early in the disease.21
When the tracer [11-C]FE-CIT was used, PET scans correctly distinguished 100% of the individuals with mild PD from healthy controls.22
An overall sensitivity and specificity of 96% was observed in distinguishing individuals with mild to severe PD from healthy controls when using SPECT with the tracer [123
Our data suggest that high resolution DTI performs as well as PET and SPECT. The current findings are important because PET units are more limited in availability than 3 Tesla MRI units, and the cost of PET is higher than MRI.24
Most importantly, DTI is noninvasive and does not require the use of radioactive tracers, suggesting its potential safe application for longitudinal follow-up and repeated assessments.25
Future studies may investigate whether DTI can detect preclinical degeneration in the SN and serve as a predictive test of PD. In addition, although previous studies show promise in using DTI to differentiate PD from atypical parkinsonism,26–28
large scale studies that use DTI in comparison with the gold standard of diagnosis by a movement disorders neurologist in different patient cohorts are needed. The effects of disease progression and medication intervention on DTI-based measures also need to be delineated.