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Parkinson's disease (PD) is commonly characterized by asymmetrical motor impairment. This study aimed to clarify the iron distributions in PD patients with significant motor asymmetry and their longitudinal alterations. This study included 123 PD patients and 121 normal controls. Thirty-eight PD patients were revisited. PD patients with significant motor asymmetry were identified by using an objective criterion. Inter-group, inter-hemisphere and inter-visit differences of regional tissue susceptibility were analyzed. Iron accumulation in dominantly and non-dominantly affected substantia nigra (SN) were observed in PD patients with motor asymmetry compared with normal controls (p < 0.005, Bonferroni corrected). Iron accumulation in the dominantly affected SN was significantly higher than that in the non-dominantly affected SN (p < 0.01, Bonferroni corrected). After follow-up, time effect on the iron content in SN was observed, directing to decrease in PD patients with motor asymmetry without hemispherical difference (p < 0.05). In conclusion, asymmetrical iron accumulation in SN was associated with the motor asymmetry in PD at baseline, while along the disease evolution iron content in SN became longitudinally decreased. All these findings provide new evidence for PD pathogenesis that the abnormal iron metabolism in SN is complicated and not always unidirectional.

Background: Dysfunction of iron metabolism, especially in substantia nigra (SN), is widely acknowledged in Parkinson's disease (PD), but the genetic influence on iron deposition remains largely unknown. Thus, in this study, we aimed to investigate potential genetic impacts on iron deposition in PD. Methods: Seventy‐four subjects, including 38 patients with PD and 36 age‐matched normal controls, participated in this study. Imaging genetic association analysis was used to identify the specific influence of single nucleotide polymorphism (SNP) on iron‐related quantitative traits (QT). Genetic effects on iron deposition at the disease level, SNP level, and their interactive effect were highlighted. Results: Four strong SNP–QT associations were detected: rs602201‐susceptibility of bilateral SN, rs198440‐susceptibility of left SN, and rs7895403‐susceptibility of left caudate head. Detailed analyses showed that: (1) significant iron deposition was exclusively found in bilateral SN in PD; (2) altered polymorphisms of the A allele/A− genotype of rs602201 and G allele/G− genotype of rs198440 and rs7895403 were more frequently observed in PD; (3) for rs602201, among all subjects, A− genotype carriers showed significantly increased iron content than TT genotype in bilateral SN; for rs198440 and rs7895403, G− carriers showed increased iron content than AA genotype in left SN and left caudate head, respectively; and (4) rs602201 exhibited significant SNP‐by‐disease interaction in bilateral SN. Conclusions: This study shows that rs602201 and rs198440 have a stimulative impact on nigral iron deposition in PD, which provides improved understanding of iron‐related pathogenesis in PD, and specifically, that vulnerability to iron deposition in SN is genetic‐based. [ABSTRACT FROM AUTHOR]

Background: In Parkinson's disease (PD), excessive iron deposition in the substantia nigra may exacerbate α-synuclein aggregation, facilitating the degeneration of dopaminergic neurons and their neural projection. Objective: To investigate the interaction effect between nigral iron deposition and PD status on brain networks. Methods: Eighty-five PD patients and 140 normal controls (NC) were included. Network function and nigral iron were measured using multi-modality magnetic resonance imaging. According to the median of nigral magnetic susceptibility of NC (0.095 ppm), PD and NC were respectively divided into high and low nigral iron group. The main and interaction effects were investigated by mixed effect analysis. Results: The main effect of disease was observed in basal ganglia network (BGN) and visual network (VN). The interaction effect between nigral iron and PD status was observed in left inferior frontal gyrus and left insular lobe in BGN, as well as right middle occipital gyrus, right superior temporal gyrus, and bilateral cuneus in VN. Furthermore, multiple mediation analysis revealed that the functional connectivity of interaction effect clusters in BGN and medial VN partially mediated the relationship between nigral iron and Unified Parkinson's Disease Rating Scale II score. Conclusion: Our study demonstrates an interaction of nigral iron deposition and PD status on brain networks, that is, nigral iron deposition is associated with the change of brain network configuration exclusively when in PD. We identified a potential causal mediation pathway for iron to affect disease severity that was mediated by both BGN dysfunction and VN hyperfunction in PD. [ABSTRACT FROM AUTHOR]

Background: Excessive iron accumulation is one of the main pathogeneses of Parkinson's disease (PD). Ceruloplasmin plays an important role in keeping the iron homoeostasis.Purpose: To explore the association between serum ceruloplasmin depletion and subcortical iron distribution in PD.Study Type: Prospective.Population: One hundred and twenty-one normal controls, 34 PD patients with low serum ceruloplasmin (PD-LC), and 28 patients with normal serum ceruloplasmin (PD-NC).Sequence: Enhanced susceptibility-weighted angiography (ESWAN) on a 3 T scanner.Assessment: Quantitative susceptibility mapping was employed to quantify the regional iron content by using a semi-automatic method. Serum ceruloplasmin concentration was measured from peripheral blood sample. Clinical assessments were conducted by a neurologist.Statistical Tests: General linear model was used to compare the intergroup difference of region iron distribution among groups, and the statistics was adjusted by Bonferroni method (P < 0.01). Partial correlation analysis was used to detect the association between regional iron distribution and serum ceruloplasmin concentration (P < 0.05).Results: Compared with normal controls, significant iron accumulation in substantia nigra, putamen, and red nucleus was observed in PD-LC, while the only region showing significant iron accumulation was SN in PD-NC. Between PD-NC and PD-LC, the iron accumulation in putamen remained significantly different, which had a negative correlation with serum ceruloplasmin in whole PD patients (r = -0.338, P = 0.008).Data Conclusion: Nigral iron accumulation characterizes PD patients without significant association with serum ceruloplasmin. Differentially, when PD patients appear with reduced serum ceruloplasmin, more widespread iron accumulation would be expected with additionally involving putamen and red nucleus. All these findings provide insightful evidence for the abnormal iron metabolism behind the ceruloplasmin depletion in PD. EVIDENCE LEVEL: 2 TECHNICAL EFFICACY: 2. [ABSTRACT FROM AUTHOR]

• Iron deposition significantly increases with aging in many subcortical nuclei, with uneven distribution within nuclei. • In PD, iron is progressively deposited in the substantia nigra and red nucleus. • In AD, iron is strongly deposited in caudate and putamen. • Regional iron deposition can delineate brain degeneration and predict the severity of neurodegenerative diseases. Brain iron deposition is a promising marker for human brain health, providing insightful information for understanding aging as well as neurodegenerations, e.g., Parkinson's disease (PD) and Alzheimer's disease (AD). To comprehensively evaluate brain iron deposition along with aging, PD-related neurodegeneration, from prodromal PD (pPD) to clinical PD (cPD), and AD-related neurodegeneration, from mild cognitive impairment (MCI) to AD, a total of 726 participants from July 2013 to December 2020, including 100 young adults, 189 old adults, 184 pPD, 171 cPD, 31 MCI and 51 AD patients, were included. Quantitative susceptibility mapping data were acquired and used to quantify regional magnetic susceptibility, and the resulting spatial standard deviations were recorded. A general linear model was applied to perform the inter-group comparison. As a result, relative to young adults, old adults showed significantly higher iron deposition with higher spatial variation in all of the subcortical nuclei (p < 0.01). pPD showed a high spatial variation of iron distribution in the subcortical nuclei except for substantia nigra (SN); and iron deposition in SN and red nucleus (RN) were progressively increased from pPD to cPD (p < 0.01). AD showed significantly higher iron deposition in caudate and putamen with higher spatial variation compared with old adults, pPD and cPD (p < 0.01), and significant iron deposition in SN compared with old adults (p < 0.01). Also, linear regression models had significances in predicting motor score in pPD and cPD (R mean = 0.443, P permutation = 0.001) and cognition score in MCI and AD (R mean = 0.243, P permutation = 0.037). In conclusion, progressive iron deposition in the SN and RN may characterize PD-related neurodegeneration, namely aging to cPD through pPD. On the other hand, extreme iron deposition in the caudate and putamen may characterize AD-related neurodegeneration. [ABSTRACT FROM AUTHOR]