Introduction

Differentiating atypical parkinsonism (AP) from idiopathic Parkinson’s disease (PD) remains a challenge in clinical practice. It is estimated that a quarter of atypical parkinsonisms are misdiagnosed as Parkinson’s disease¹.

A recent review² found three MRI techniques to have sensitivies and specificites of 80% and above to differentiate diagnosed PD and AP patients, using specific midbrain structures, namely:

• Quantitative susceptibility mapping (QSM) to quantify iron accumulation in midbrain structures such as the substantia nigra (SN) substructures, pars compacta (SNpc) and pars reticulata (SNpr), as well as the red and subthalamic nucleus^3,4.
• Quantifying brainstem atrophy^5,6 as well as cerebellar peduncle and third ventricle atrophy⁷ on high-resolution T1-weighted MPRAGE images.
• Fractional anisotropy (FA) to quantify demyelination of white matter tracts^8,9 in the brainstem structures such as the superior and middle cerebral peduncle (SCP and MCP).

In addition, Neuromelanine (NM) MRI in the SN and LC is a clinically suitable technique, since it requires no post-processing and is readily available from a heavily MT-weighted sequence on clinical scanners. Clinical studies however report high specificity yet low sensitivity for differentiating PD vs AP^10,11.

Having all four techniques could give the necessary information required to make a differential diagnosis of suspected patients. Previous studies^10,12,13 use volumetric or area-derived metrics from small structures (substantia nigra, locus coeruleus, cerebral peduncles) as biomarkers, but structure delineation and understanding confounding factors can be challenging when using only one contrast. Previous studies have combined neuromelanine with iron imaging for similar purposes^10,14,15.

The disappereance of the LC is an relevant biomarker¹¹, however imaging and locating the LC is challenging. Brainstem DTI could offer an additional landmark.
In this work, we demonstrate initial in-vivo results from a healthy volunteer using a dedicated atypical parkinsonism protocol, to explore how acquiring all four contrasts could aid interpretation and diagnosis when used in patients.

Methods

The dedicated Parkinsonism protocol was developed on a 3T GE Signa Premier MRI scanner equipped with a 48 channel head-coil.
For one volunteer (female, 18yo) we acquired a sagittal T₁-SPGR (Flip angle 12^o, matrix size 240x240x176, voxel size 1mm isotropic, acq time 4:41), an axial MT-weighted (flip angle 40^o, 2D-GRE, flip angle 40^o, matrix size 512x320x20, voxel size 0.4x0.7x1.5mm, vendor MT pulse with offset 1200Hz, TE 8.1ms, TR 240ms, NEX 3, acq time 12 minutes), a 3D multi-echo gradient echo (TE₁=13ms, ...,TE₈=37.6ms,echo-spacing 3.5ms, matrix 320x226x82, voxel size 0.86x0.x86x1mm) and a DTI scan (singleshot EPI, matrix 128x128x50, voxel size 1.75x1.75x2mm, TE 77.0ms, TR 2869ms, SMS2, phase acceleration 2, 10 interleaved volumes with b=0 and 64 directions with b=1000).

QSM images were produced using the MEDI toolbox^16,17. DTI-derived FA maps were produced using FSL dtifit¹⁸, after susceptibility¹⁹ and eddy current correction²⁰. All images were co-registered to the T1-weighted image using MITK²⁵.

Results

Figure 1 shows the 4 imaging techniques used in this work.

Figure 2 zooms in around the substantia nigra. MT-weighted imaging shows the neuromelanine-rich substantia nigra pars compacta (SNpc) as a hyperintense area (Fig. 2AB) and the MT+QSM overlay shows the iron-rich neighbouring substructures of the substantia nigra, the pars reticulata (SNpr) (Fig. 2CD). The overlap in QSM and NM signal could be due both iron and NM being present in both substructures, and signal changes in the overlap was found as a useful PD biomarker¹³. Adjacent to these are white matter tracts from the cerebral peduncle (Fig. 2EF), which are highly anisotropic as shown clearly as an area with high FA in an FA map. Parkinson patients are expected to lose neuromelanine and accumulate iron in the substantia nigra, and having multiple contrasts could improve area delineation.

Figure 3 shows the three contrasts around the locus coeruleus, two thin rod-shaped structures in the pons rich in neuromelanine (Fig. 3AB) which due to their small size are difficult to image. Figures 3CD shows the LC posterior to two longitudinal WM tracts, that are visible using FA, which probably represent the medial or dorsal longitudinal fasciculus (MLF or DLF), or a combination of both. This relationship between the LC and MLF could be useful when locating the LC in parkinsonism patients for whom, due to neuromelanine loss, the LC becomes less visible with disease progression¹¹. Reduced FA in the Superior Cerebral Peduncle (SCP, annotated in purple) is a potential biomarker for AP^8,9. Figures 3EF shows elevated susceptibility spots at the same location, which could be due to iron content from the LC²¹.

Discussion and conclusion

We imaged structures related to atypical parkinsonism by integrating the combined information obtained from 4 pertinent MRI techniques. Visualising diffusion metrics, iron and neuromelanine concentration relies on different forms of neurodegeneration, however interpreting confounding effects (e.g. iron and DTI^22,23) is a subject of future research.
Many recent studies on differentiating parkinsonism use combined QSM-and-neuromelanine^10,14,15 images for ROI-based image analysis. DTI-metrics have been used in the same way²⁴. We show that having all three could aid localisation and interpretation.
Our pilot result was based on one healthy volunteer, future work will investigate its merit in patient populations and other known brainstem structures identified as biomarkers².

In conclusion, a dedicated parkinsonism imaging protocol could improve the delineation of anatomical structures, improving ROI-based methods for the differential diagnosis of atypical parkinsonisms.

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