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February 26, 2002; 58 (4) Articles

Diffusion-weighted MRI differentiates the Parkinson variant of multiple system atrophy from PD

M.F.H. Schocke, K. Seppi, R. Esterhammer, C. Kremser, W. Jaschke, W. Poewe, G. K. Wenning
First published February 26, 2002, DOI: https://doi.org/10.1212/WNL.58.4.575
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Abstract

Objective and Background: Routine MRI as well as MR volumetry and MRS have been shown to contribute to the differential diagnosis of the Parkinson variant of multiple system atrophy (MSA-P) and PD. However, it is currently unknown whether diffusion-weighted imaging (DWI) discriminates these disorders.

Methods: Ten patients with MSA-P (mean age, 64 years) were studied, 11 with PD (mean age, 64 years), and seven healthy volunteers (mean age, 59 years) matched for age and disease duration. Regional apparent diffusion coefficients (rADC) were determined in different brain regions including basal ganglia, gray matter, white matter, substantia nigra, and pons.

Results: Patients with MSA-P had higher putaminal rADC (median 0.791 × 103/mm2/s) than both patients with PD (median 0.698 × 103/mm2/s, p < 0.001) and healthy volunteers (median 0.727 × 103/mm2/s, p < 0.001). There were no significant differences in putaminal rADC between patients with PD and healthy volunteers. Moreover, none of the putaminal rADC values in the PD and control group surpassed the lowest value in the MSA-P group. There were no significant group differences in the rADC values in other brain regions such as pons, substantia nigra, globus pallidus, caudate nucleus, thalamus, or gray and white matter. Putaminal rADC values correlated significantly with Unified PD Rating Scale OFF scores in patients with MSA as measured by the Spearman rank test.

Conclusion: DWI, even if measured in the slice direction only, is able to discriminate MSA-P and both patients with PD and healthy volunteers on the basis of putaminal rADC values. The increased putaminal rADC values in Parkinson variant of multiple system atrophy are likely to reflect ongoing striatal degeneration, whereas most neuropathologic studies reveal intact striatum in PD. Diffusion-weighted imaging may represent a useful diagnostic tool that can provide additional support for a diagnosis of Parkinson variant of multiple system atrophy.

Multiple system atrophy (MSA) is a sporadic, progressive, adult-onset disorder associated with varying degrees of parkinsonism, autonomic dysfunction, and cerebellar ataxia. Neuropathologically, the Parkinson variant of MSA (striatonigral degeneration type, MSA-P) is characterized by selective neuronal loss and gliosis predominantly affecting the basal ganglia, substantia nigra, olivopontocerebellar pathways, and the intermediolateral cell column of the spinal cord.1 Diagnosis in life is often difficult, especially in early stages of the disease, and differentiation from PD carries a high rate of misdiagnosis.1 An early differentiation between MSA-P and PD is important for several reasons. First, morbidity and mortality are higher in patients with MSA-P, who often respond poorly to levodopa and whose motor disability progresses more rapidly than in patients with PD.2-4⇓⇓ Second, specific therapeutic needs of patients with MSA-P, such as early autonomic and urogenital disturbances, must be recognized because they can be treated effectively. Third, inclusion of patients with misdiagnosed MSA-P in pharmacologic and neurosurgical treatment trials for PD may be avoided.5-8⇓⇓⇓

The diagnostic role of routine MRI, MRS, and volumetric MRI in MSA-P vs PD has been investigated by a number of groups.9-13⇓⇓⇓⇓ Routine MRI failed to differentiate MSA-P and PD in as many as 44% of cases.9 MRS studies have shown reduced but overlapping N-acetylaspartate (NAA)-to-creatine and NAA-to-choline ratios in the lentiform nucleus of patients with MSA-P vs patients with PD and normal controls.10,11⇓ A previous volumetric analysis has shown a complete discrimination of patients with MSA-P and PD by application of stepwise discriminant analysis.12 However, MRS and volumetric studies are time-consuming and require specialized hardware and software, thus limiting their general use.

In contrast to MRS and volumetric analysis, diffusion-weighted MRI (DWI) is a rapid and more economical tool that is available on most of the clinical 1.5-T MR scanners. DWI is commonly used to determine the random movement of water molecules that is aligned with fiber tracts in CNS. Quantification of diffusion is possible by applying field gradients of different degrees of diffusion sensitization, allowing the calculation of the apparent diffusion coefficient (ADC) in tissue. Because the CNS is organized in bundles of fiber tracts, the water molecules move mainly along these structures, whereas diffusion perpendicular to the fiber tracts is restricted.14 Thus pathologic processes such as neuronal loss and secondary astrogliosis remove some of the “restricting” barriers, increasing the mobility of water molecules within the tissue architecture. Thus pathologic processes that modify tissue integrity can result in an increased ADC.15

We have investigated for the first time whether DWI can detect tissue architecture disruption due to neuronal loss and gliosis in MSA-P. We have asked in particular whether subregional ADC on DWI scans are increased in early MSA-P compared with early PD. Furthermore, we evaluated the diagnostic validity (sensitivity, specificity, positive predictive value, interrater reliability) of DWI abnormalities by comparing patients with MSA-P with patients with PD and healthy controls. For comparison, we have also analyzed MSA-P–related structural changes on conventional MRI including putaminal atrophy and hyperintensity.9

Patients and methods.

Patients.

Ten consecutive patients with probable MSA-P16 and 11 consecutive patients with PD17 matched for age, disease duration, and Hoehn and Yahr OFF stage were recruited at a Parkinson outpatient clinic. Clinical diagnosis of probable MSA-P and PD was made according to established criteria16,17⇓ by a movement disorder specialist experienced in parkinsonian disorders. A detailed clinical history and a careful neurologic examination were performed to exclude the presence of parkinsonian disorders (e.g., progressive supranuclear palsy, corticobasal degeneration, lower body parkinsonism).

In addition, seven age-matched, healthy volunteers were examined. Informed consent was obtained from all participants. Demographic and clinical data on patients and controls are listed in table 1.

View this table:
Table 1.

Clinical data in PD, in the Parkinson variant of multiple system atrophy, and controls

MRI protocol.

Conventional dual-echo fast spin-echo and DWI sequences were performed in all patients and healthy volunteers using a 1.5-T whole-body MR scanner (Magnetom Vision, Siemens, Erlangen, Germany) and a circular polarized head coil. The dual-echo spin-echo sequence had a repetition time of 3,500 ms, echo times of 22 and 90 ms, a slice thickness of 2 mm, a matrix of 256 × 256 pixels, and a field of view of 200 ms. This sequence was performed twice providing 2 × 15 slices that were interleaved without any gap. DWI scans were acquired using a spin-echo type of echoplanar imaging (EPI) sequence with diffusion-sensitizing gradients switched in slice direction and three different b-values (30, 300, and 1,100 s/mm2). Sequential sampling of k-space was used with an effective echo time of 123 ms, a bandwidth of 1250 Hz/pixel, and an acquisition matrix of 128 × 128, which was interpolated to 256 × 256 during image calculation. The DWI sequence provided 20 consecutive slices with a slice thickness of 3 mm and a field of view of 230 mm. The acquisition time of each DWI sequence was 5 seconds.

Image analysis.

Two blinded independent raters evaluated the conventional dual-echo fast spin-echo scans for the presence or absence of putaminal atrophy and hyperintensity, those findings occurring significantly more often in patients with MSA than in controls and patients with PD.9,18⇓

ADC maps were calculated by fitting the logarithm of the signal intensity as a function of the gradient factor “b” over three different b-values for each pixel.19 After calculation of ADC maps, regional ADC (rADC) values were determined by segmentation of selected brain regions including basal ganglia, substantia nigra, pons, and white and gray matter (parietal cortex) using the EPI images with the lowest b-value. These images provide a good contrast between gray and white matter and permit a sufficient differentiation of different brain structures. The segmented regions of interest (ROI) were copied on the ADC maps in order to obtain the mean rADC values. To assess the inter- and intrarater reliability of the segmentation procedure, rADC of the ROI of 10 consecutive subjects (PD: 5; MSA-P: 3; controls: 2) were segmented by two blinded raters with profound skills in neuroanatomy in two measurements.

Statistical analysis.

Data were tabulated and analyzed using SPSS 10.0 for windows (SPSS Inc., Chicago, IL). Interrater reliability for the evaluation of the abnormal findings on the conventional dual-echo MRI scans was calculated with Cohen’s κ. If the ratings differed between the two observers, the findings were reevaluated by both observers and committed to a consensus. To calculate the inter- and intrarater reliability for the segmentation procedure, rADC values of the segmented ROI were compared by the Pearson correlation test. Statistical comparison of the concordant abnormal findings on routine MRI was performed with the Fisher’s exact test.

One-way analysis of variance followed by post hoc Bonferroni correction was used for comparison of the age at examination between groups (PD, MSA, healthy volunteers). Group comparison of disease duration was performed by an unpaired t-test. Unified PD Rating Scale (UPDRS) OFF scores and the Hoehn and Yahr OFF stages in patients with MSA-P and PD were compared by the Mann–Whitney U test.

Because the mean rADC values of most brain regions were not normally distributed, as revealed by the Shapiro–Wilks test, the Kruskal–Wallis test was applied for further statistical comparisons of the mean rADC values. When detecting significant effects in the Kruskal–Wallis test, multiple-group comparisons were performed by using post hoc Mann–Whitney U tests. Regional ADC values and disease severity as measured by the UPDRS OFF scores were correlated for each patient group by the Spearman rank test.

The significance level was set at p < 0.05; significance levels from 0.0 to -0.10 were defined as trend. Because of the multiple-group comparisons, the significance level of the Mann–Whitney U tests was set at a lower threshold (p < 0.05/3 = 0.017). Pearson and Spearman rank correlation coefficients of 0.35 to 0.49 were interpreted empirically as low, those of 0.5 to 0.79 as moderate, and those of ≥0.8 as high. Results are reported as means (± SD) or medians (range) depending on the test used for statistical evaluation.

Results.

Patients.

Patient age was not significantly different between groups at the time of MRI examination. Mean age at examination was 64 (SD 8.9) years in patients with PD, 64 (SD 6.8) years in patients with MSA-P, and 59 (SD 6.8) years in the healthy volunteers. There were no differences in disease duration of patients with PD (2.8 years, SD 0.9) and patients with MSA-P (2.9 years, SD 1.1). Patients with MSA-P (median, 38; range, 33 to 53) had significantly higher UPDRS OFF scores than patients with PD (median, 26; range, 13 to 36; p = 0.001). The Hoehn and Yahr OFF stages of both patient groups, however, were similar (MSA-P range, II to III; PD range, I to III, p > 0.1). A summary of the clinical findings is given in table 1.

DWI.

The interrater reliability of the segmentation procedure was 0.88 for the first measurement and 0.91 for the second measurement (Pearson correlation coefficient). The intrarater reliability was 0.94 for Rater 1 and 0.90 for Rater 2 (Pearson correlation coefficient).

Comparing all three groups, the Kruskal–Wallis test revealed a significant difference of rADC in the putamen (p < 0.001), whereas rADC group differences regarding thalamus (p = 0.056), caudate nucleus (p = 0.052), and white matter (p = 0.099) failed to reach significance. Regional ADC group differences of other segmented brain regions showed no trends toward significance using the Kruskal–Wallis test. Further testing with the Mann–Whitney U test revealed a significant increase in putaminal rADC values in patients with MSA-P (median, 0.791 × 103/mm2/s; range, 0.760 to 1.032 × 103/mm2/s) compared with patients with PD (median, 0.698 × 103/mm2/s; range, 0.585 to 0.759 × 103/mm2/s; p < 0.001) and healthy volunteers (median, 0.727 × 103/mm2/s; range, 0.635 to 0.754 × 103/mm2/s; p < 0.001). Moreover, none of the putaminal rADC values in the MSA-P group surpassed the highest value in the PD and control group (figure 1). The putaminal rADC values did not differ significantly between patients with PD and healthy volunteers. When using putaminal rADC values of ≥0.760 × 103/mm2/s to distinguish MSA-P from PD or controls, optimal diagnostic accuracy for MSA-P could be obtained (table 2). Figure 2 shows the ADC maps calculated by fitting over three b-values in the patient and control groups demonstrating the marked difference in putaminal ADC between patients with MSA-P and PD as well as controls. The Spearman rank test revealed a moderate correlation between putaminal rADC values and UPDRS OFF scores in patients with MSA (r = 0.71; p = 0.022), whereas putaminal rADC did not show a significant correlation with UPDRS OFF scores in patients with PD. The rADC of the remaining ROI did not correlate with UPDRS OFF scores in either patient group.

Figure

Figure 1. Scatter graph putaminal regional apparent diffusion coefficients (rADC) values (103/mm2/s) from patients with PD (1), patients with the parkinson variant of multiple system atrophy (MSA-P, 2), and controls.3 Note that none of the putaminal rADCave values in the MSA-P group surpasses the highest value in the PD or control group.

View this table:
Table 2.

Diffusion-weighted imaging and MRI (1.5 T) differentiates the Parkinson variant of multiple system atrophy from PD and controls

Figure

Figure 2. Apparent diffusion coefficient (ADC) maps (diffusion gradient switched in slice direction) calculated by fitting over 3 b-values in PD (A), the Parkinson variant of multiple system atrophy (MSA-P) (B), and controls (C). Blue, green, red, and black represent descending regional ADC values. Note the marked difference in putaminal ADC maps between MSA-P (B) and PD (A) as well as controls (C).

Routine MRI.

Interrater reliability was excellent for both putaminal atrophy (κ = 0.81) and putaminal hyperintense rim (κ = 0.83). Putaminal atrophy was seen exclusively in patients with MSA-P (60% of the patients with MSA-P; table 3). Eighty percent of the patients with MSA-P exhibited a putaminal hyperintense rim, which was seen in only one patient with a clinical diagnosis of PD (see table 3). Follow-up examination 1.5 years after MRI examination revealed no atypical features or loss of levodopa response. Table 2 shows sensitivity (relative number of patients with MSA-P identified by the abnormal finding), positive predictive value (probability of having MSA-P given the abnormal finding), and specificity (probability of not having MSA-P given the absence of the abnormal finding) of the abnormal putaminal findings on routine MRI.

View this table:
Table 3.

Diffusion-weighted imaging and MRI (1.5-T) data in PD, in the Parkinson variant of multiple system atrophy, and controls

Discussion.

A range of neuroimaging methods have been previously employed to differentiate MSA from other parkinsonian disorders, in particular PD. In studies using T2- and T1-weighted MRI, the most prominently involved brain region in patients with MSA was the putamen followed by the caudate nucleus and the substantia nigra.20-22⇓⇓ Moreover, some patients with MSA showed infratentorial atrophy.20 Hyperintense alterations of the putamen on T2-weighted images occur predominantly in patients with MSA-P.23 A systematic analysis of routine MRI in patients with MSA reported alterations such as hyperintensive putaminal rim, putaminal atrophy, and hyperintensive putamen.9 However, a substantial minority of patients fulfilling diagnostic criteria for clinically probable MSA-P had entirely normal MRI findings (44% at 0.5 T and 18% at 1.5 T). Therefore, routine MRI failed to discriminate MSA-P from PD reliably.9

In our study, we evaluated 2-mm-thick, T2-, and proton-density–weighted slices of the basal ganglia using the criteria as previously described.9,18⇓ Patients with MSA-P and PD were matched for age and disease duration. Therefore, at the time of scanning, parkinsonian motor disability in OFF as assessed by the UPDRS was more advanced in MSA-P compared with PD, reflecting differences in the natural history of these disorders. However, overall motor disability according to the Hoehn and Yahr OFF stage was similar in both patient groups. The MR features, occurring most frequently in our patients with MSA-P, included a hyperintense putaminal rim and putaminal atrophy. We detected a higher specificity and sensitivity for these MR signs than previously reported.9 This may be related to the thinner slice thickness of our images, providing better spatial resolution with less partial volume effects. One patient with clinically probable PD, however, showed a hyperintense putaminal rim. Furthermore, two patients with MSA-P did not show any abnormalities on conventional MRI. Consequently, the assessment of conventional MRI did not provide a complete differentiation between patients with PD and MSA-P, as already reported previously.9,18⇓

Another approach to the differentiation of parkinsonian syndromes involves volumetric MRI and MRS studies. A previous study showed significant reductions in mean striatal and brainstem volumes in patients with MSA-P compared with patients with PD and controls. By application of stepwise discriminant analysis, no patient with PD was classified as having MSA-P and vice versa.12 Previous spectroscopic studies showed reduced but overlapping NAA-to-creatine and NAA-to-choline ratios in the lentiform nucleus of patients with MSA-P compared with patients with PD or controls, presumably reflecting neuronal loss.10,11⇓ Both volumetric and MRS studies indicate a neuronal loss in the striatum of patients with MSA and are helpful for distinguishing patients with PD and MSA,10-12⇓⇓ but both methods are costly, time-consuming, and only available in specialized research centers.

In contrast to MR volumetry and MRS, DWI is available on nearly all clinical 1.5-T MR scanners. The advantages of the DWI sequence used in our study are the very short acquisition time, the relatively high spatial resolution, and the absolute quantitation by calculating ADC maps. DWI is a relatively new MR technique that has been widely employed in stroke studies in order to identify ischemic brain lesions early and accurately and to discriminate dead from salvageable tissue.24 In recent studies, neurodegenerative diseases such as AD, different dementia forms, and neurodegeneration after stroke were investigated with the help of DWI detecting a loss of integrity of the white matter fiber tracts in different brain regions.25-27⇓⇓ Because DWI in the CNS reflects the random water movement along the fiber tracts, DWI can detect loss of tissue integrity by showing regions with an increased ADC due to increased water movement.14 In the literature, only one study employed DWI in patients with different parkinsonian syndromes. In this study, DWI was used only for the accurate delineation of the substantia nigra.27

In our study, patients with MSA-P showed significantly increased rADC values in the putamen. The increased putaminal rADC values in MSA-P are likely to reflect ongoing neuronal degeneration and astrogliosis, whereas most neuropathologic studies reveal intact striatum in PD.28-30⇓⇓ Neuronal loss and gliosis may result in destruction of tissue architecture and in consequent increase in ADC. The prominent involvement of the putamen detected by DWI in our study is consistent with the underlying neuropathology of striatonigral degeneration 31-33⇓⇓ as well as MR features including putaminal atrophy and hyperintensities on routine MRI,20-23,34⇓⇓⇓⇓ striatal volume loss on MR volumetry,12 and a reduced NAA-to-creatine ratio in the nucleus lentiformis on MRS.10,11⇓

In contrast to the analysis of our conventional MRI, patients with MSA-P could be completely distinguished from patients with PD and healthy volunteers based on the DWI scans. Only a previous volumetric MR study obtained similar excellent diagnostic accuracy in the discrimination of patients with MSA-P and PD by using a linear discriminant analysis.12 Moreover, our study shows that putaminal rADC correlate with disease severity as measured by UPDRS OFF scores in patients with MSA-P. In keeping with this observation, previous structural or functional imaging studies were also able to correlate putaminal signal change35 or dopamine D2 receptor loss36 with clinical measures of parkinsonian disability in MSA.

The segmentation of the different ROI was done manually, similar to previous planimetric studies.37,38⇓ Planimetry is known as a fast and easy technique and gives a good estimation of the volume,39 which is error-prone when assessing small differences in volumes. In our study, however, segmentation was applied for the evaluation of rADC but not of volumes. Furthermore, we segmented on diffusion-weighted EPI images with a low b-factor, providing a good T2 contrast. Therefore basal ganglia structures were relatively easy to delineate. This may explain our good inter- and intrarater reliability, comparable to previous volumetric MR studies.12,39⇓

For DWI we used a sequence with diffusion-sensitizing gradients only in slice direction, which may result in underestimation of diffusion-related, pathologic alterations in the brain.40 This might explain the nonsignificant rADC change in the caudate nucleus and substantia nigra. Possibly, the fiber tracts in these brain regions might be adversely oriented, resulting in widely scattered rADC values, as indicated by our results. Future studies should 1) perform diffusion tensor or trace imaging in order to investigate possible changes in other basal ganglia, including caudate nucleus and substantia nigra, and 2) compare MSA-P with a broader range of parkinsonian disorders including PD, progressive supranuclear palsy, corticobasal degeneration, and lower body parkinsonism.

Acknowledgments

Supported by the Austrian Federal Ministry of Science and Transport (GZ 70038/2 PR 4/98).

Footnotes

  • Presented as a poster at the 53rd Annual Meeting of the American Academy of Neurology; Philadelphia, PA; May 5–12, 2001. The poster was highlighted in the “Neuroimaging” Topic Highlight Session.

  • Received July 2, 2001.
  • Accepted October 31, 2001.

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  • Submissions should not have more than 5 authors. (Exception: original author replies can include all original authors of the article)
  • Submit only on articles published within 6 months of issue date.
  • Do not be redundant. Read any comments already posted on the article prior to submission.
  • Submitted comments are subject to editing and editor review prior to posting.

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