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Evaluating iron overload in Nigrosome 1 via Quantitative Susceptibility Mapping at 7T in prodromal stages of Parkinson’s disease
Marta Lancione1,2, Graziella Donatelli2,3, Eleonora Del Prete4, Nicole Campese4, Daniela Frosini4, Matteo Cencini1,2, Mauro Costagli1,5, Giacomo Lucchi6, Michela Tosetti1,2, Massimiliano Godani7, Dario Arnaldi5,8, Michele Terzaghi9,10, Claudio Pacchetti11, Pietro Cortelli12,13, Enrica Bonanni4, Roberto Ceravolo4, and Mirco Cosottini6
1IRCCS Stella Maris, Pisa, Italy, 2Imago7 Research Foundation, Pisa, Italy, 3Neuroradiology Unit, Azienda Ospedaliero-Universitaria Pisana, Pisa, Italy, 4Neurology Unit, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy, 5Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Sciences (DINOGMI), University of Genoa, Genoa, Italy, 6Neuroradiology Unit, Department of Translational Research on New Technologies in Medicine and Surgery, University of Pisa, Pisa, Italy, 7Neurology Unit, Sant'Andrea Hospital, La Spezia, Italy, 8IRCCS Ospedale Policlinico San Martino, Genoa, Italy, 9Unit of Sleep Medicine and Epilepsy, IRCCS Mondino Foundation, Pavia, Italy, 10Department of Brain and Behavioral Sciences, University of Pavia, Pavia, Italy, 11Parkinson's Disease and Movement Disorders Unit, IRCCS Mondino Foundation, Pavia, Italy, 12Clinica Neurologica Rete Metropolitana, IRCCS Istituto Scienze Neurologiche Bologna, Bologna, Italy, 13Department of Biomedical and Neuromotor Sciences (DIBINEM), University of Bologna, Bologna, Italy

Synopsis

iRBD is a prodromal stage of α-synucleinopathies, like PD. Iron deposition is increased in the substantia nigra of PD patients, mainly in Nigrosome-1 (N1). Here, we estimated N1 iron content in PD, iRBD patients and healthy controls using QSM at 7T to investigate group differences and correlation with disease duration. PD patients showed increased N1 susceptibility compared to controls and iRBD patients but no correlation with disease duration. N1 susceptibility in iRBD patients was not different from controls but correlated with disease duration. Hence, in prodromal stages of α-synucleinopathies, QSM can reveal progressive N1 iron accumulation as the disease evolves.

Introduction

Idiopathic rapid eye movement (REM) behavioral disorder (iRBD) is a prodromal stage of α-synucleinopathies, such as Parkinson’s disease (PD), which are characterized by the loss of dopaminergic neurons in substantia nigra (SN), especially in the Nigrosome 1 (N1), associated with abnormal iron load. Iron deposition in SN has been suggested to contribute to the degeneration of dopaminergic neurons and its assessment in iRBD patients may provide further insight into the relationship between iron accumulation and disease development. Iron-related signal changes in SN have been reported in most PD patients1,2 and Quantitative Susceptibility Mapping (QSM) revealed altered susceptibility (πœ’) in PD patients in the whole SN3–7, in its pars compacta (SNc)8–10 and reticulata (SNr)8,9. In iRBD patients, instead, QSM studies on the whole SN7,11,12 or in its functional subregions13 showed conflicting results. In this work, we directly targeted N1 and estimated iron content in PD, iRBD patients and healthy controls (HC) using QSM performed at 7T in order to investigate differences between groups and the correlation with disease duration.

Methods

We included 43 PD patients in early stages (ePD; disease duration<4 years), 30 iRBD patients and 14 HCs. A 3D Gradient-Recalled Multi-Echo sequence was acquired on a 7T MRI scanner (GE-MR950) with the following parameters: TR=54.1ms; TE1:ΔTE:TE7=5.6:6.0:41.8ms; voxel size=0.6×0.6×0.6mm3. Susceptibility maps were computed from the phase signal of each echo using a Laplacian-based phase unwrapping algorithm14, V-SHARP background field removal15 and iLSQR algorithm for dipole deconvolution16 (available in STI Suite), and then averaged across TEs. A study-specific template was created via ANTs using the magnitude image averaged across TEs of HCs. As N1 may not be clearly visible in patients, N1 ROIs were manually drawn on the magnitude images of HCs, warped onto the template and averaged together to obtain probabilistic N1 ROIs, then thresholded to a probability of 0.4 (Figure 1). Susceptibility maps of patients and HCs were then warped to the template space. For each subject, we considered the N1 (left or right) showing the highest mean πœ’ for statistical analysis, according to radiological criteria2. Magnitude images were examined by a radiologist to assess the appearance of the trilaminar organization of SN2 and the presence of an oval-shaped hyperintensity located dorsolaterally in the SN between two hypointense layers, corresponding to N1. Sex distribution of the populations (ePD, iRBD and HC) were compared using chi-square test. Age and QSM data were analyzed via Kruskal-Wallis omnibus tests, post-hoc Dunn’s test and Dunn-Sidak correction. Diagnostic accuracy was assessed via the area under the curve (AUC) of the receiver operating characteristic (ROC). The correlation between πœ’ and disease duration since the onset of symptoms was evaluated with the Spearman rank correlation test.

Results

We found no significant differences in sex distribution between groups. Age differences were significant (p<0.05) but no significant correlation was found between age and N1 susceptibility. The appearance of N1 was labeled as pathological in 86% and 45% of ePD and iRBD patients, respectively (Figure 2). The omnibus test revealed significant differences in N1 πœ’ between ePD, iRBD and HC (p<0.0001): ePD patients showed increased πœ’ with respect to both HC (p<0.01) and iRBD patients (p<0.0001) (Figure 3A). The AUC obtained in discriminating ePD from iRBD patients was 0.77 (specificity=0.80, sensitivity=0.73). Moreover, PD and HC could be discriminated with an AUC of 0.83, (specificity=0.93, sensitivity=0.71) (Figure 3B). Though not significantly, iRBD patients with abnormal N1 appearance (iRBD+) had slightly higher QSM values than others (iRBD-), leading to a smaller difference with the ePD group (p<0.05) (Figure 4). Positive correlation (r=0.475; p<0.01) emerged between susceptibility in N1 and disease duration in iRBD patients, but no significant correlation was found for ePD patients (Figure 5).

Discussion

Iron concentration in N1 was higher for ePD patients than for HC, in agreement with previous studies investigating susceptibility in SNc3,8–10,17. The accumulation of iron in N1 in the iRBD group is comparable to that in HC, in accordance with previous studies that considered average QSM values in the whole SN7,11,12 or in its functional subregions13. However, another study reported higher SN πœ’ in iRBD patients compared to HC, but lower than ePD7. These slightly inconsistent results could be accounted for by the different degree of nigral pathology in iRBD patients enrolled in each study and the different portion of SN considered. The correlation between N1 πœ’ and duration of iRBD indicates that iron accumulation increases along with disease evolution. No correlation was found between ePD duration and N1 susceptibility, so it can be assumed that further iron accumulation is not significant once motor symptoms appear, at least in the first stages of the disease.

Conclusion

Our work suggests the potential of N1 iron load detection via QSM as a biomarker for the assessment of PD and of ongoing neurodegeneration in its prodromal stages, such as iRBD.

Acknowledgements

This study was supported by Ricerca Finalizzata RF-2013-02354829 “Seven Tesla MR imaging as a preclinical biomarker in populations at risk for Parkinson’s disease” funded by the Italian Ministry of Health and the Tuscany Region. This work has been partially supported also by grants “RC 2018-2020” and “5 per mille” to IRCCS Fondazione Stella Maris, funded by the Italian Ministry of Health.

References

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Figures

Figure 1: Pipeline for ROIs creation. N1 ROIs were manually drawn on the T2*-weighted images of healthy controls, that were bias-corrected, skull-stripped and used to create a study-specific template (A). Probabilistic N1 ROIs were obtained by averaging the ROIs of each control subject warped to the template. They were then thresholded to 0.4 and binarized (B). A transformation warp was computed to transform the T2*-weighted image of each subject to the template space and applied to πœ’ maps (C).

Figure 2: T2*-weighted images of N1 in four representative subjects. In healthy controls (A), N1 appears as an oval-shaped hyperintensity (white arrows) surrounded by two hypointense layers and located dorsolaterally in the SN. This structure is also visible in some patients with iRBD (B), while this is not the case for other iRBD patients (45%) (C) and for the great majority (86%) of PD patients (D).

Figure 3: Panel A: Box plot displaying group differences in N1 πœ’ between ePD patients, iRBD patients and HC (Kruskal-Wallis test p-value is reported in the top left corner). Post-hoc Dunn’s tests reaching significance after Dunn-Sidak correction are indicated by the asterisks (* p<0.05, ** p<0.01, *** p<0.001, **** p<0.0001). Panel B: ROC curves computed when discriminating PD from iRBD (solid line) and PD from HC (dashed line). The dots represent the optimal cut-off values of each curve.

Figure 4: Panel A: Group differences in N1 πœ’ between iRBD patients with normal and pathological SN appearance (iRBD- and iRBD+, respectively) Although the difference does not reach significance, iRBD+ patients reported slightly higher πœ’ than iRBD-. Panel B: difference in N1 πœ’ with ePD patients is reduced when considering iRBD+ patients only instead of the whole iRBD population.

Figure 5: Correlation of N1 πœ’ and disease duration. A significant positive correlation was found for iRBD (p<0.01; panel A) but not for the ePD group (panel B).

Proc. Intl. Soc. Mag. Reson. Med. 30 (2022)
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DOI: https://doi.org/10.58530/2022/2270