To our knowledge, this is the first systematic study to demonstrate the usefulness of simultaneous assessment of ADC and FA values on multiple regions, including the pons, cerebellum and putamen in MSA, PD and controls. We showed that low FA and high ADC values in these regions were significant even in MSA cases without HCB or DPH signs, suggesting that FA and ADC assessment can be a potent procedure to detect early involvement in MSA without diagnostic MRI findings. In particular, 90.0% of probable MSA‐P cases showed a combination of low FA and high ADC values in one or more of the three areas, but no PD patients showed both low FA and high ADC values in any of the three areas. In addition, 57.1% of PD cases showed a combination of normal FA and ADC values in all three areas. These results suggest that combined evaluation of FA and ADC values in early disease stages provides an accurate method for differentiating MSA‐P from PD.
ADC values measure the average water diffusion. High putaminal ADC values were reported to be helpful in differentiating MSA‐P from PD.12
Subsequently, brainstem ADC values in MSA‐C were demonstrated to be increased.13
As increases in ADC values have been shown in certain other diseases19,20,21
and in normal aging,22
high ADC values are thought to reflect destruction of tissue architecture. In contrast, FA values are new parameters specifically measuring the degree of anisotropy of the diffusing water along different axes of the image, enabling useful quantitative estimation of decreased tissue anisotropy reflecting degeneration. Reduced FA values have been reported in certain other diseases23,24,25
and in normal aging.26
More recently, decreased FA values in cerebellopetal fibres and pyramidal tracts have been reported in MSA‐C,14
and low FA values are also thought to reflect destruction of tissue architecture. In this study, we demonstrated that by using small voxels and optimised parameters,16
as well as a generalised autocalibrating partially parallel acquisitions (GRAPPA)17
algorithm for suppressing artefact and noise to obtain reliable ADC and FA values, as evidenced by clear tractography results, increased ADC and decreased FA values could reflect destruction of brainstem, cerebellar or putaminal tissue architecture resulting from neuronal loss and/or gliosis, enhancing random mobility of free water molecules within the tissue. Our results support previous observations and extend the significance of FA and ADC values in the diagnosis of MSA‐P, even in cases without DPH or HCB signs.
Some of our MSA‐P or PD cases showed a combination of normal FA but high ADC or low FA but normal ADC values in various regions. As above, high ADC and low FA values could reflect similar destruction of tissue architecture and have been demonstrated in various pathological changes, including brain atrophy, atherosclerotic change and normal aging.22,26
However, these parameters are based on different pathological conditions. This may be one of the reasons why some cases showed normal FA but high ADC or low FA but normal ADC values. Furthermore, only cases of MSA‐P had both low FA and high ADC values in each of the three areas. FA and ADC values may mutually provide additional information about the evolution of the disease that is not available from one method. These findings suggest that the combined evaluation of FA and ADC values could be more useful for early detection of pathological involvement in MSA‐P than evaluation of either of these separately.
With respect to location, pontine FA and ADC values were especially useful markers in diagnosing MSA‐P compared with those in the cerebellum and putamen. Although degeneration of olivopontocerebellar systems is evident from clinical features and MRI findings in MSA‐C, these changes are not apparent in the early phase of MSA‐P. The present study clearly demonstrated that even though reductions in FA values and increases in ADC values in the pons and cerebellum were more remarkable in MSA‐C than in MSA‐P, these changes were still highly evident in MSA‐P. The question arises as to why significantly abnormal ADC and FA values can be seen in the pons even in early phase MSA. Patients with early stage MSA in Caucasian populations have been reported to show selective neuronal cell loss in the substantia nigra and locus coeruleus, with relative sparing of both the striatum and the olivopontocerebellar system.27
One possible explanation may be that ADC and FA values have the potential to detect minimal and subclinical, but accumulated, neurodegeneration in the pons, because the pons contains the neurons and fibre tracts (eg, the pontine nuclei, transverse pontine fibres and corticospinal tracts) that are preferentially effected in MSA and thus could accumulate and reflect the MSA specific neurodegenerative process at an early phase of illness. Alternatively, it could be due to differences in the pathological features of MSA among Japanese and Caucasian populations. We previously reported that MSA‐C was more frequent, and MSA‐P less frequent, in Japanese populations11
compared with Western populations,3
and also that proton magnetic resonance spectroscopy (1
H‐MRS) showed significantly lower N‐acethylaspartate/creatine ratios in the basis pontis suggesting more neuroaxonal loss or dysfunction in MSA‐P than in PD.28
The olivopontocerebellar system shows more profound degeneration in Japanese MSA‐P. While further study is needed to address this issue, we suggest that the pons is a beneficial region to detect early pathological change in MSA.
In previous reports,12
ADC values in the dorsolateral putaminal ROIs were reported to be more useful in distinguishing MSA from PD compared with those in the anteroventral ROIs. It is interesting that this result corresponded well to the spatial distribution of pathological lesions in the putamen in MSA. In contrast, we used relatively large sized ROIs than previous reports to obtain reliable data under our MRI conditions, such as higher magnetic field strength, special software and parameters to analyse FA and ADC values. In addition, as some MSA and PD patients showed obscure putaminal edges on MRI, we set the ROIs in the relatively midst putamen, including dorsolateral parts. These specific MRI conditions may have caused the differences in the sensitivity and specificity in the putamen between our study and previous ones. These discrepancies may also be explained by ethnic differences. The olivopontocerebellar system could be more severely affected in Japanese than in Western populations. A multicentre survey will be needed to clarify the optimised size of ROIs, magnetic field strengths and parameters to standardise the FA and ADC values as diagnostic criteria.
In summary, combined evaluation of FA and ADC values in the putamen, cerebellum and putamen would provide useful information for highly and accurate differentiation of MSA‐P from PD. Such early FA reduction and ADC increase are likely to be associated with subtle early degenerative processes in MSA, even without diagnostic magnetic resonance signal abnormalities. In addition, to justify our conclusion, it will be necessary to apply this algorithm, in a prospective manner, to patients with possible MSA without diagnostic MRI findings, and to determine whether these patients will develop full blown MSA symptoms in several years.