Analyzing the co-localization of substantia nigra hyper-echogenicities and iron accumulation in Parkinson's disease: A multi-modal atlas study with transcranial ultrasound and MRI

Abstract

Background: Transcranial B-mode sonography (TCS) can detect hyperechogenic speckles in the area of the substantia nigra (SN) in Parkinson's disease (PD). These speckles correlate with iron accumulation in the SN tissue, but an exact volumetric localization in and around the SN is still unknown. Areas of increased iron content in brain tissue can be detected in vivo with magnetic resonance imaging, using quantitative susceptibility mapping (QSM).

Methods: In this work, we i) acquire, co-register and transform TCS and QSM imaging from a cohort of 23 PD patients and 27 healthy control subjects into a normalized atlas template space and ii) analyze and compare the 3D spatial distributions of iron accumulation in the midbrain, as detected by a signal increase (TCS+ and QSM+) in both modalities.

Results: We achieved sufficiently accurate intra-modal target registration errors (TRE<1 mm) for all MRI volumes and multi-modal TCS-MRI co-localization (TRE<4 mm) for 66.7% of TCS scans. In the caudal part of the midbrain, enlarged TCS+ and QSM+ areas were located within the SN pars compacta in PD patients in comparison to healthy controls. More cranially, overlapping TCS+ and QSM+ areas in PD subjects were found in the area of the ventral tegmental area (VTA).

Conclusion: Our findings are concordant with several QSM-based studies on iron-related alterations in the area SN pars compacta. They substantiate that TCS+ is an indicator of iron accumulation in Parkinson's disease within and in the vicinity of the SN. Furthermore, they are in favor of an involvement of the VTA and thereby the mesolimbic system in Parkinson's disease.

Keywords: Multi-modal registration; Parkinson's disease; Quantitative susceptibility mapping; Substantia nigra; Transcranial sonography.

Fig. 1

Graphical abstract for multi-modal TCS-MRI atlas creation: 2D TCS images are acquired and 3D TCS volumes of the midbrain region are reconstructed. TCS+ voxels ipsilateral to the transducer are manually segmented. Each 3D TCS volume is registered to the same participant's cranial MRI scan via initial head surface alignment and subsequent fine-tuning using a multi-modal ultrasound-MRI intensity-based registration algorithm. An average brain template is created from MRI using a multi-variate optimal template building approach. The resulting transformations are used to deform TCS images and TCS+ segmentations into template space. Here, group analysis is performed on QSM-MR image volumes using voxel-wise statistical testing to localize QSM+ voxels with statistically significant difference between HC and PD (yellow contours). Group-wise TCS+ is localized separately for HC (green contours) and PD (red contours) by voxel-wise thresholding at 50% of the group size (i.e. majority voting). Co-localization of QSM+ and TCS+ is analyzed qualitatively and quantitatively, in particular with respect to the SN area (dark green contour: SN pars reticulate, dark brown contour: SN pars compacta).

Fig. 2

Localization of QSM+ and TCS+. Smaller image panels show axial slices through the T2*w(30 ms) template MRI from −12 mm (top-left) to −6.5 mm (bottom-right), caudal of the AC-PC line, and in 0.5 mm slice distances. Expert-segmented atlas structures are delineated with faint colors (blue: MB, green: SNr, brown: SNc, cyan: VTA, yellow: PBP, red: RN). Upper panel: Bright yellow outlines indicate QSM+ regions, i.e. voxels with significantly higher iron accumulation in PD patients compared to a group of normal controls (yellow outlines). Middle panel: TCS+ HC delineated with bright green color, and TCS+ PD with bright red. Bottom panel: Co-localization of QSM+ and TCS+ in template space. Again, yellow indicates significant QSM+ regions, green and red represent TCS+ regions of HC and PD groups, respectively.

Fig. 3

Localization of QSM+ and TCS+ in 3D. As in Fig. 2, regions QSM+ (yellow), TCS+ HC (green, top figure), and TCS+ PD (red, bottom figure) are visualized in template space, along with a caudal slice of the midbrain region from the T2*w(30 ms) template. A surface model of the midbrain region (extracted from the TCS atlas template) is shown for reference. The 3D coordinate vectors indicate the right (R), anterior (A) and superior (S) direction.