Introduction
Materials and methods
Subjects
Derivation cohort | Validation cohort | |||||||
---|---|---|---|---|---|---|---|---|
CTR (n = 30) | PSP (n = 8) |
P
| CTR (n = 21) | PD (n = 10) | PSP (n = 27) | MSA-P (n = 11) |
P
| |
Gender female:male | 16:14 | 4:4 | 0.59a
| 9:12 | 4:6 | 13:14 | 7:4 | 0.68a
|
Age, years | 69 (67–72) | 70 (68–75) | 0.38c
| 69 (65–76) | 68 (59–70) | 68 (65–71) | 64 (56–76) | 0.21b
|
Disease duration, years | n.d. | 5 (4–7) | n.d. | 4 (2–7) | 3 (2–4) | 3 (3–5) | 0.54b
| |
Hoehn and Yahr | 0 | 4 (3–5) | 0 | 2 (1–3) | 3 (3–4) | 3 (3–4) | ≤0.00bdf
| |
Schwab and England, IQL | 100 | 55 (22–87) | ≤0.00c
| 100 | 90 (90–100) | 70 (60–80) | 70 (70–80) | ≤0.00bcdefh
|
Pons area, mm2
| 525 (490–546) | 434 (402–527) | 0.01c
| 531 (505–556) | 519 (477–536) | 474 (418–515) | 485 (429–522) | ≤0.00bce
|
Midbrain area, mm2
| 108 (97–126) | 71 (46–80) | 0.00c
| 117 (103–126) | 116 (108–161) | 63 (55–71) | 113 (103–132) | ≤0.00bcdg
|
Midbrain/pons ratio | 0.21 (0.19–0.25) | 0.16 (0.11–0.18) | <0.001c
| 0.21 (0.20–0.24) | 0.24 (0.21–0.31) | 0.14 (0.12–0.15) | 0.22 (0.21–0.25) | ≤0.00bcdg
|
Thalamus, cm3
| 9.3 ± 0.7 | 7.9 ± 0.5 | <0.001c
| 8.7 ± 0.7 | 10.1 ± 1.0 | 8.3 ± 1.3 | 8.9 ± 1.1 | <0.01dh
|
Caudate nucleus, cm3
| 4.4 ± 0.4 | 3.7 ± 0.4 | 0.001c
| 4.4 ± 4.5 | 4.7 ± 6.6 | 4.2 ± 0.8 | 4.0 ± 0.6 | 0.23b
|
Putamen, cm3
| 5.7 ± 0.5 | 4.7 ± 0.5 | 0.001c
| 5.5 ± 0.6 | 6.1 ± 0.7 | 4.7 ± 1.2 | 4.6 ± 0.7 | <0.01def
|
Globus pallidus, cm3
| 2.2 ± 0.2 | 1.7 ± 0.4 | 0.001c
| 2.2 ± 0.5 | 2.2 ± 0.2 | 1.8 ± 0.6 | 1.8 ± 0.6 | <0.01cdf
|
UPDRS motor score, IQL | 0 (0–2) | 43 (32–57) | <0.001c
| n.d. | n.d. | n.d. | n.d. | |
Tandem gait test, IQL | 0 | 3 (2–3) | <0.001c
| n.d. | n.d. | n.d. | n.d. | |
MMSE score, IQL | 29 (28–30) | 26 (20–27) | <0.001c
| n.d. | n.d. | n.d. | n.d. | |
AQT color-form, sec | 62 (57–68) | 218 (90–296) | <0.001c
| n.d. | n.d. | n.d. | n.d. |
Data acquisition and processing
Analysis of diffusion parameters
-
For ROI-based estimation of diffusion parameters, ROIs were outlined manually on parameter maps by one trained investigator (YS). All ROIs were outlined twice with an interval of 3 months (average intra-rater variability >0.9 for all ROIs). FA- and directionally color-encoded FA maps were used to outline all ROIs, except for the RN and deep cerebellar nuclei (DCN), where the non-diffusion-weighted map was used (Fig. 1). The ROI size was adjusted in each subject to maximize coverage of each structure, while minimizing partial volume effects from neighboring areas. Contamination from cerebrospinal fluid (CSF), which has isotropic diffusion with a high MD, was avoided by excluding voxels adjacent to the third and lateral ventricles.×
-
The head of the caudate nucleus was delineated in a single slice at the level where it was most conspicuous. The thalamus and putamen were delineated in 5–8 consecutive slices at the level of the internal capsule, the thalamus adjacent to the interthalamic adhesion, and the putamen to the extreme capsule. The VA and VL nuclei of the thalamus (VAVL) were identified on FA color maps as green voxels (Fig. 1) [31, 32], in the anterior part of the lateral thalamus close to the genu of the internal capsule, while excluding the three most medial voxels that were regarded to comprise the medial dorsal nuclei. The lateral posterior nucleus (LP) and ventral posterior (VP) nuclear complex of the thalamus (LPVP) were identified on FA color maps as violet voxels (Fig. 1) [31, 32] adjacent to the posterior limb of the internal capsule and anterior to the pulvinar in red. The RN was identified as a circular area of signal hypointensity in the midbrain on non-diffusion-weighted maps and delineated in at least two consecutive axial slices. The SCP was delineated on two consecutive sagittal slices. The midbrain and the pons were delineated on five consecutive sagittal slices, with ROIs including the whole structure. The manual approach proposed by Oba et al. [33] was used to identify the boundaries of the pons and the midbrain. For each structure, the average FA and MD value from the right and left hemisphere was calculated.
-
TBSS (v 1.03), part of the FRMIB Software Library (FSL), was employed as a complementary analysis tool for diffusion parameters in the thalamus. Comparisons were performed in PSP vs controls in the derivation cohort and in PSP vs controls, PD and MSA-P in the validation cohort (Fig. 2) [34]. FA and MD maps were registered onto the 1 mm3 FMRIB58 FA template in MNI152 standard space, using the linear and nonlinear registration tools FLIRT and FNIRT [35, 36]. Before registration, the diffusion maps were masked with the FSL Brain Extraction Tool (BET) [37]. The normalized maps were skeletonized by projection onto the FMRIB58 template skeleton. Finally, the skeletonized maps were masked to include only voxels from the thalamus. The masking was done using the left and right thalamus regions in the MNI152 space Harvard-Oxford subcortical atlas, together with the requirement that the MD of the normalized maps must be less than unity in the control subjects of the derivation cohort [38].×
-
For probabilistic tractography of the DRTT, its inferior and superior part were constructed each using a seed ROI placed in the DCN and VAVL of the contralateral thalamus, respectively, and an include ROI in the SCP (Fig. 1). The left and right DRTT were then constructed by combining the inferior and superior DRTT into one tract, selecting fibers passing through include ROIs in these three locations, DCN, SCP, and VAVL. All tracts were visually inspected. The tractography procedure did not generate tracts in two controls from the derivation cohort (unilaterally) as well as in four PSP patients (one patient bilaterally and three unilateral) and one control (unilateral) in the validation cohort.
Volumetric analysis
Statistical analysis
Results
Demographics
Diffusion parameters
-
In the derivation cohort, we found that patients with PSP have increased MD in the whole thalamus, the thalamic nuclei (VAVL and LPVP), and the midbrain (Table 2). Significant changes of MD (increase with 9–12 %) were found in the caudate head, thalamus, VAVL, LPVP, and midbrain. Values of FA were reduced with 12–19 % for the SCP and midbrain in PSP patients.Table 2Regional fractional anisotropy and mean diffusivity values in two cohortsRegionParameterDerivation cohortValidation cohortFACTRPSPCTRPDPSPMSA-PCaudate head0.16 (0.14–0.18)0.18 (0.15–0.20)0.16 (0.14–0.20)0.17 (0.14–0.19)0.18 (0.15–0.20)0.16 (0.15–0.21)Putamen0.15 (0.14–0.17)0.16 (0.13–0.19)0.19 (0.17–0.20)0.20 (0.18–0.22)0.18 (0.17–0.20)c0.22 (0.20–0.24)Thalamus0.29 (0.28–0.31)0.28 (0.25–0.30)0.32 (0.30–0.33)0.31 (0.30–0.33)0.30 (0.29–0.33)0.31 (0.29–0.33)VAVL0.28 (0.26–0.30)0.27 (0.24–0.30)0.31 (0.30–0.33)0.32 (0.29–0.34)0.29 (0.26–0.32)a0.31 (0.29–0.33)LPVP0.27 (0.25–0.29)0.26 (0.24–0.28)0.29 (0.26–0.32)0.31 (0.29–0.33)0.31 (0.29–0.33)0.31 (0.29–0.35)Red nucleus0.45 (0.40–0.52)0.45 (0.40–0.51)0.54 (0.49–0.58)0.53 (0.47–0.54)0.50 (0.45–0.56)0.51 (0.43–0.56)SCP0.66 (0.62–0.68)0.54 (0.42–0.70)a0.78 (0.75–0.82)0.79 (0.71–0.84)0.66 (0.60–0.71)bc0.75 (0.73–0.76)Pons0.35 (0.34–0.38)0.33 (0.32–0.36)0.41 (0.39–0.46)0.40 (0.37–0.44)0.39 (0.36–0.42)0.39 (0.34–0.39)Midbrain0.40 (0.36–0.42)0.35 (0.30–0.38)a0.45 (0.43–0.48)0.47 (0.45–0.48)0.40 (0.38–0.43)abc0.45 (0.43–0.49)DRTT left0.38 (0.33–0.39)0.33 (0.25–0.38)0.38 (0.35–0.40)0.39 (0.36–0.41)0.30 (0.27–0.34)abc0.37 (0.31–0.38)DRTT right0.37 (0.33–0.40)0.30 (0.26–0.35)a0.36 (0.33–0.37)0.38 (0.36–0.44)0.26 (0.24–0.29)abc0.32 (0.31–0.36)cMDCaudate head0.68 (0.66–0.73)0.74 (0.63–0.79)a0.79 (0.76–0.87)0.81 (0.77–0.91)0.82 (0.75–0.96)0.76 (0.68–0.85)Putamen0.68 (0.64–0.71)0.70 (0.66–0.76)0.81 (0.75–0.86)0.78 (0.76–0.86)0.86 (0.80–0.96)a0.88 (0.84–1.04)edThalamus0.71 (0.69–0.73)0.79 (0.71–0.89)a0.79 (0.75–0.82)0.77 (0.76–0.81)0.84 (0.79–0.88)abc0.78 (0.77–0.80)VAVL0.72 (0.70–0.74)0.81 (0.71–0.89)a0.79 (0.76–0.81)0.79 (0.77–0.83)0.86 (0.82–0.93)abc0.80 (0.76–0.83)LPVP0.70 (0.68–0.72)0.77 (0.71–0.93)a0.76 (0.72–0.81)0.71 (0.70–0.75)0.81 (0.76–0.89)bc0.74 (0.74–0.75)Red nucleus0.48 (0.43–0.53)0.55 (0.42–0.59)0.53 (0.45–0.60)0.53 0.48–0.58)0.61 (0.55–0.68)a0.61 (0.52–0.62)SCP0.82 (0.76–0.86)0.85 (0.79–1.11)0.83 (0.76–0.88)0.82 (0.76–0.89)0.94 (0.90–1.10)ab0.92 (0.87–0.97)dPons0.63 (0.60–0.66)0.65 (0.62–0.70)0.72 (0.70–0.75)0.72 (0.70–0.75)0.76 (0.72–0.79)a0.75 (0.75–0.78)deMidbrain0.68 (0.66–0.72)0.74 (0.71–0.81)a0.74 (0.73–0.76)0.73 (0.71–0.76)0.83 (0.80–0.85)abc0.75 (0.70–0.78)DRTT left0.89 (0.84–0.93)1.02 (0.86–1.18)1.1 (1.02–1.15)1.03 (0.97–1.11)1.37 (1.27–1.52)abc1.21 (1.02–1.23)cDRTT right0.87 (0.80–0.93)0.99 (0.82–1.07)a1.16 (1.05–1.20)1.06 (0.99–1.10)1.50 (1.34–1.55)abc1.22 (1.16–1.30)c
-
In the validation cohort, patients with PSP showed higher MD values in the whole thalamus, the VAVL nuclei of the thalamus and the midbrain compared to controls, patients with PD, and patients with MSA-P (Table 2). Patients with MSA-P displayed higher MD values in the pons than controls and patients with PD but not compared to patients with PSP (Table 2). The values of MD in PSP were increased with 6–9 % in the putamen, thalamus, VAVL, LPVP, and pons and with 12–15 % for midbrain, SCP, and red nucleus. Values of FA in PSP were reduced with 5–6 % in the putamen and VAVL, with 11–15 % in midbrain and SCP.
-
In the patients with PSP, MD changes in the thalamus did not correlate with volumetric measurements in any of the cohorts.
-
In the derivation cohort, PSP patients showed significantly higher MD than controls in 75 % of the skeletonized voxels in the thalamus (Fig. 2). In the validation cohort, patients with PSP were found to have a higher MD in the thalamus than controls (75 % significant voxels). In the derivation cohort, a higher MD was also found in the PSP group compared to both PD (67 % significant voxels) and MSA-P (53 % significant voxels). Furthermore, a reduced FA was observed in PSP vs controls in both cohorts and in PSP vs IPD in the derivation cohort (30–50 % significant voxels).
-
As many of the changes in diffusion parameters in patients with PSP observed above were localized in structures associated with the DRTT (i.e., SCP, midbrain, and ventral thalamus); probabilistic tractography of this tract was performed. In the derivation cohort, elevation in MD and reduction of FA was seen in patients with PSP, even though it only reached significance on the right side (P < 0.05) (Table 2 and Fig. 3c, d). Value of FA was reduced with 19 %, and value of MD was increased with 14 % for right DRTT in PSP patients. Similar to the derivation cohort, tractography of the DRTT in patients with PSP in the validation cohort exhibited reduced FA and increased MD in the DRTT on both sides when compared to both controls and patients with PD or MSA-P (Table 2 and Fig. 3a, b). The values of FA were reduced with 21–28 %, and values of MD in PSP were increased with 24–29 % in the left and right DRTT.×
Volumetric measurements
Correlation between clinical scales and diffusion parameters of thalamus and dentatorubrothalamic tract in progressive supranuclear palsy
PSPRS items | PSPRS items scores | FA | MD | ||
---|---|---|---|---|---|
Thalamus | VAVL | Thalamus | VAVL | ||
History | 7.25 ± 4.62 | −0.383 | −0.575 | 0.611 | 0.659 |
Mentation | 4.25 ± 3.88 | −0.849‡ | −0.506 | 0.892‡ | 0.892‡ |
Bulbar | 2 ± 1.6 | −0.835† | −0.933‡ | 0.651 | 0.749† |
Ocular motor | 8.88 ± 2.85 | −0.759† | −0.313 | 0.699 | 0.723† |
Limb motor | 5.75 ± 1.67 | −0.776† | −0.325 | 0.801† | 0.776† |
Gate and midline | 11 ± 7.19 | −0.735† | −0.578 | 0.783† | 0.807† |
Total | 39.13 ± 18.11 | −0.833† | −0.738† | 0.905‡ | 0.929‡ |
Diagnostic accuracy of diffusion parameters of the midbrain, dentatorubrothalamic tract, and thalamus in progressive supranuclear palsy
ROC (95 % CI) | Cutoff MD [μm2/ms] | Sensitivity % | Specificity % | |
---|---|---|---|---|
PSP vs controls | ||||
Thalamus | 0.77 (0.64–0.91) | 0.80 | 74 | 67 |
DRTT R | 0.95 (0.88–1.00) | 1.23 | 96 | 81 |
Midbrain | 0.86 (0.74–0.98) | 0.77 | 85 | 81 |
PSP vs PD and MSA-P | ||||
Thalamus | 0.81 (0.68–0.93) | 0.79 | 81 | 77 |
DRTT R | 0.94 (0.87–1.0) | 1.25 | 92 | 81 |
Midbrain | 0.90 (0.88–0.99) | 0.78 | 81 | 81 |
PSP vs PD, MSA-P, and controls | ||||
Thalamus | 0.79 (0.68–0.9) | 0.8 | 74 | 71 |
DRTT R | 0.94 (0.89–0.99) | 1.24 | 96 | 79 |
Midbrain | 0.88 (0.79–0.97) | 0.77 | 85 | 79 |