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Background: The utility of imaging methods to detect iron content in the substantia nigra pars compacta (SNc) and free water imaging in the posterior substantia nigra (pSN) has the potential to be imaging markers for the detection of Parkinson’s disease (PD). Objective: This study aimed to compare the discriminative power of above methods, and whether the combination can improve the diagnostic potential of PD. Methods: Quantitative susceptibility mapping (QSM) and diffusion-weighted data were obtained from 41 healthy controls (HC), 37 patients with idiopathic REM sleep behavior disorder (RBD), and 65 patients with PD. Mean QSM values of bilateral SNc and mean isotropic volume fraction (Viso) values of bilateral pSN (mean QSM|Viso values of bilateral SNc|pSN) were separately calculated and compared among the groups. Results: Mean QSM|Viso values of bilateral SNc|pSN were significantly higher for RBD and PD patients compared to HC and were significantly higher in PD patients than in RBD patients. The power of the mean QSM|Viso values of bilateral SNc|pSN and combined mean QSM and Viso values was 0.873, 0.870, and 0.961 in discriminating PD and HC, 0.779, 0.719, and 0.864 in discriminating RBD from HC, 0.634, 0.636, and 0.689 in discriminating PD and RBD patients. Conclusion: QSM and free water imaging have similar discriminative power in the detection of prodromal and clinical PD, while combination of these two methods increases discriminative power. Our findings suggest that the combination of QSM and free water imaging has the potential to become an imaging marker for the diagnosis of PD.

Background Pathogenic variants in the glucocerebrosidase gene (GBA) have been identified as the most common genetic risk factor for Parkinson's disease (PD). However, the features of substantia nigra damage in GBA pathogenic variant carriers remain unclear. Objective We aimed to evaluate the microstructural changes in the substantia nigra in non‐manifesting GBA pathogenic variant carriers (GBA‐NMC) and PD patients with GBA pathogenic variant (GBA‐PD) with free‐water imaging. Methods First, we compared free water values in the posterior substantia nigra between non‐manifesting non‐carriers (NMNC, n = 29), GBA‐NMC (n = 26), and GBA‐PD (n = 16). Then, free water values in the posterior substantia nigra were compared between GBA‐PD and early‐ (n = 19) and late‐onset (n = 40) idiopathic PD (iPD) patients. Furthermore, we examined whether the baseline free water values could predict the progressions of clinical symptoms. Results The free water values in the posterior substantia nigra were significantly higher in the GBA‐NMC and GBA‐PD groups compared to NMNC, and were significantly increased in the GBA‐PD group than both early‐ and late‐onset iPD. Free water values in the posterior substantia nigra could predict the progression of anxiety and cognitive decline in GBA‐NMC and GBA‐PD groups. Conclusions We demonstrate that free water values are elevated in the substantia nigra and predict the development of non‐motor symptoms in GBA‐NMC and GBA‐PD. Our findings demonstrate that a significant nigral impairment already exists in GBA‐NMC, and nigral injury may be more severe in GBA‐PD than in iPD. These results support that free‐water imaging can as a potential early marker of substantia nigra damage. © 2023 International Parkinson and Movement Disorder Society.

IntroductionThe ventral tegmental area (VTA) is less affected compared to substantia nigra pars compacta (SNc) in Parkinson's disease (PD). This study aimed to quantitatively evaluate iron content in the VTA across different stages of PD in order to help explain the selective loss of dopamine neurons in PD.MethodsQuantitative susceptibility mapping (QSM) data were obtained from 101 PD patients, 35 idiopathic rapid eye movement sleep behavior disorder (RBD) patients, and 62 healthy controls (HCs). The mean QSM values in the VTA and SNc were calculated and compared among the groups.ResultsBoth RBD and PD patients had increased iron values in the bilateral SNc compared with HCs. RBD and PD patients in the Hoehn–Yahr (H & Y) stage 1 did not show elevated iron values in the VTA, while PD patients with more than 1.5 H & Y staging had increased iron values in bilateral VTA compared to HCs.DiscussionThis study shows that there is no increased iron accumulation in the VTA during the prodromal and early clinical stages of PD, but iron deposition increases significantly as the disease becomes more severe.

Noninvasive diffusion magnetic resonance imaging (dMRI) has been widely employed in both clinical and research settings to investigate brain tissue microstructure. Despite the evidence that dMRI‐derived fractional anisotropy (FA) correlates with white matter properties, the metric is not specific. Recent studies have reported that FA is dependent on the b ‐value, and its origin has primarily been attributed to either the influence of microstructure or the noise‐floor effect. A systematic investigation into the inter‐relationship of these two effects is however still lacking. This study aims to quantify contributions of the reported differences in intra‐ and extra‐neurite diffusivity to the observed changes in FA, in addition to the noise in measurements. We used in‐vivo and post‐mortem human brain imaging, as well as numerical simulations and histological validation, for this purpose. Our investigations reveal that the percentage difference of FA between b ‐values (pdFA) has significant positive associations with neurite density index (NDI), which is derived from in‐vivo neurite orientation dispersion and density imaging (NODDI), or Bielschowsky's silver impregnation (BIEL) staining sections of fixed post‐mortem human brain samples. Furthermore, such an association is found to be varied with Signal‐to‐Noise Ratio (SNR) level, indicating a nonlinear interaction effect between tissue microstructure and noise. Finally, a multicompartment model simulation revealed that these findings can be driven by differing diffusivities of intra‐ and extra‐neurite compartments in tissue, with the noise‐floor further amplifying the effect. In conclusion, both the differences in intra‐ and extra‐neurite diffusivity and noise‐floor effects significantly contribute to the FA difference associated with the b ‐value.