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Fibre-specific white matter reduction in patients with multiple system atrophy: comparison of parkinsonian and cerebellar subtypes1Chang Gung University, Taoyuan, Taiwan, 2Chang Gung Memorial Hospital, Taoyuan, Taoyuan, Taiwan, 3Chang Gung Memorial Hospital, Linkou, Taoyuan, Taiwan
Synopsis
Precise differentiation between MSA subtype is critical in medical intervention and prognosis. The results of previous studies using DTI to differentiate subtypes of MSA is controversial. We use fixel based analysis to examine the tract-specific differences in white matter between individuals with MSA and healthy controls. The results demonstrate the white matter degeneration in specific fibre bundle, including middle cerebellar peduncle, pontine crossing tract and cerebellar white matter tracts in the early MSA-C patients; in contrast, this pattern was not observed in MSA-P patients. This suggests that FBA may be a sensitive marker for early differential diagnosis of MSA subtype.
Introduction
Multiple system atrophy (MSA) is a rare, fatal neurodegenerative disorder with autonomic impairment plus predominantly levodopa-refractory parkinsonism (in the parkinsonian subtype, MSA-P) or cerebellar syndrome (in the cerebellar subtype, MSA-C).1,2 Precise differentiation among two subtypes is challenging because of the overlap both in clinical and histopathological.3,4 Medication strategies and prognosis vary with the subtype of the disease.5,6 Thus, an objective diagnostic biomarker is crucial for disease-modifying therapy. However, previous studies using diffusion tensor imaging for the differentiation of subtype of MSA is debated.7-9Fixel Based analysis (FBA) is a novel framework that provides fibre-specific comparison in the white matter (WM). FBA can be used to analyze distinct fiber populations within a voxel (termed “fixels”).10 FBA is capable of evaluating multiple fibre bundles within a voxel and enables the assessment of both micro-structural (intra-axonal fibre volume, Fibre Density) and macro-structural (fibre bundle width, Fibre Cross-section) changes in the white matter.10
The different pattern of WM degeneration could be observed between subtypes in the earlier stage in patients with MSA.7 Thus, the study aimed to determine the white matter differences by FBA in patients with MSA, especially between MSA-P and MSA-C. Patients with MSA were further divided into the group with long (> 3 years) and short (≦ 3 years) disease duration to examine whether the different pattern of WM degeneration was detected in an earlier stage.
Methods
Image AcquisitionImage were acquired from 40 probable MSA patients and 40 age and gender-matched healthy control subjects using a 3T MR scanner (Magnetom Trio, Erlangen, Siemens, Germany). Diffusion-weighted images were acquired with spin-echo echo-planar imaging (SE-EPI) sequence and three different imaging protocols. Forty slices were acquired to cover the brain. Two diffusion weighting values (b-values) – 0 and 1000 sec/mm2- were used in the analysis. A T1-weighted images were acquired with magnetization prepared rapid acquisition gradient echo (T1-MPRAGE) sequence (160 axial slices; voxel size 1 mm x 1 mm x1 mm; TR/TE= 2000 ms/2.63 ms; flip angle= 9°; field of view= 224 mm x 256 mm) was also obtained from each subject. The demographic data and imaging parameters were listed in Table 1.
Fixel Based Analysis
FBA was performed using the MRtrix3 according to recommended procedures.10 Diffusion data underwent preprocessing, including denoising, Gibbs ringing removal, motion and distortion correction, bias field correction.10 A study-specific template was generated, to which all subjects and subsequent image data were registered to. Single-tissue constraint spherical deconvolution (CSD) was used for computing fibre density (FD) and fibre cross-section (FC) with fibre orientation distributions (FODs).11A combined index fibre density and cross-section (FDC) was calculated by multiplying FD and FC.10
Statistical analysis
Family-wise error (FWE)-corrected p-values were assigned to each fixel with nonparametric permutation testing and connectivity-based fixel enhancement (CFE).12 Significance was denoted by FWE-corrected p-value < 0.05. To visualize the findings, significant fixels were then displayed using mrview tool in MRtrix3.
Results
Figure 1 showed significant changes in FD (upper row), FC (middle row) and FDC (lower row) from patients with MSA compared with healthy controls. The main reduction of fixels were identified in the middle cerebellar peduncle, pontine crossing tract, bilateral cerebral peduncle, superior cerebellar peduncle, internal capsule and corticospinal tract. Significant FC increase was identified in the fornix.The difference of white matter degeneration between subtype in patients with disease duration≦3 years and > 3 years was shown in figure 2. In the patients with disease duration≦3 years, FC and FDC of middle cerebellar peduncle, pontine crossing tract and cerebellar white matter tracts were significantly decreased in MSA-C. Furthermore, FD of MSA-P demonstrated extensive FD loss compared to MSA-C in patients with disease duration > 3 years.
The Difference of white matter between subtype in FC was represented in figure 3. No difference was observed in all three groups of MSA patients with disease duration ≦3 years; however, fixels of fornix were significantly increased in the group of MSA(All) and MSA-P with disease duration > 3 years.
Discussion
Our results demonstrate distinct pattern of white matter degeneration between MSA subtypes. The regions of fixels with significant change were congruent with the locations of white matter lesion reported by DTI literature.13-15 In early MSA, MSA-C was detected to have more WM involvement in comparison to MSA-P. This result endorse previous DTI findings.7To our surprise, the FC of fornix was significantly increased compared to healthy controls. This phenomenon accompany with disease progression and exist only in MSA-P subtype. Previous literature16 indicates other cell death mechanisms besides apoptosis might responsible for neuronal death in MSA. Previous study report necroptosis, which is a regulated necrosis and characterized by cell swelling, play an important role in pathogenesis of Parkinson’s disease17. Since both MSA and Parkinson’s Disease are classified as “α-Synucleinopathies”.18 The increase of fibre bundle width of fornix might owing to the necroptosis-induced cell swelling. Widespread FD loss together with significant FC increase in fornix, which exclusive exist in late MSA-P suggest the possibility of worse survival in MSA-P as reported by previous literature.2,5
Conclusion
Our findings indicate FBA may serve as a biomarker for early differential diagnosis of MSA. It can potentially aid in treatment efficacy, and consequently increased quality of life of patients.Acknowledgements
No acknowledgement found.References
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