Relationship Between Brain Iron Deposition and Mitochondrial Dysfunction in Idiopathic Parkinson’s Disease

BackgroundThe underlying pathophysiology of Parkinson's disease is complex, involving different molecular pathways, including brain iron deposition and mitochondrial dysfunction. At a molecular level, these disease mechanisms are likely interconnected. Therefore, they offer potential strategies for disease-modifying treatments. We aimed to investigate subcortical brain iron deposition as a potential predictor of the bioenergetic status in patients with idiopathic Parkinson’s disease. MethodsThirty patients with idiopathic Parkinson's disease underwent multimodal MR imaging (T1, susceptibility-weighted imaging, SWI) and 31Phosphorus Magnetic Resonance Spectroscopy Imaging. Contrast-to-noise ratios based on the SWI images of the putamen, caudate, globus pallidus, and thalamus for each hemisphere were used in a multiple linear regression model to predict in vivo metabolites. ResultsSubcortical brain iron deposition, particularly in the putamen and globus pallidus, was highly predictive of the region-specific amount of high-energy-containing phosphorus metabolites in our subjects. ConclusionsOur study suggests that brain iron deposition but not the variability of individual volumetric measurements are highly predictive of mitochondrial impairment in vivo. These findings offer the opportunity, e.g., by using chelating therapies, to improve mitochondrial bioenergetics in patients with idiopathic Parkinson's disease.

Characterization of Brain Iron Deposition Pattern and Its Association With Genetic Risk Factor in Alzheimer’s Disease Using Susceptibility-Weighted Imaging

The presence of iron is an important factor for normal brain functions, whereas excessive deposition of iron may impair normal cognitive function in the brain and lead to Alzheimer’s disease (AD). MRI has been widely applied to characterize brain structural and functional changes caused by AD. However, the effectiveness of using susceptibility-weighted imaging (SWI) for the analysis of brain iron deposition is still unclear, especially within the context of early AD diagnosis. Thus, in this study, we aim to explore the relationship between brain iron deposition measured by SWI with the progression of AD using various feature selection and classification methods. The proposed model was evaluated on a 69-subject SWI imaging dataset consisting of 24 AD patients, 21 mild cognitive impairment patients, and 24 normal controls. The identified AD progression-related regions were then compared with the regions reported from previous genetic association studies, and we observed considerable overlap between these two. Further, we have identified a new potential AD-related gene (MEF2C) closely related to the interaction between iron deposition and AD progression in the brain.

Brain Iron Imaging Markers in the Presence of White Matter Hyperintensities

PurposeTo investigate the relationship between pathological brain iron deposition and white matter hyperintensities (WMHs) in cerebral small vessel disease (CSVD), via Monte Carlo simulations of magnetic susceptibility imaging and a novel imaging marker called the Expected Iron Coefficient (EIC).MethodsA synthetic pathological model of a different number of impenetrable spheres at random locations was employed to represent pathological iron deposition. The diffusion process was simulated with a Monte Carlo method with adjustable parameters to manipulate sphere size, distribution, and extracellular properties. Quantitative susceptibility mapping (QSM) was performed in a clinical dataset to study CSVD to derive and evaluate QSM, R2*, the iron microenvironment coefficient (IMC), and EIC in the presence of WMHs.ResultsThe simulations show that QSM signals increase in the presence of increased tissue iron, confirming that the EIC increases with pathology. Clinical results demonstrate that while QSM, R2*, and the IMC do not show differences in brain iron, the EIC does in the context of CSVD.ConclusionThe EIC is more sensitive to subtle changes in brain iron deposition caused by pathology, even when QSM, R2*, and the IMC do not.

Elevated Heme Oxygenase-1 Correlates With Increased Brain Iron Deposition Measured by Quantitative Susceptibility Mapping and Decreased Hemoglobin in Patients With Parkinson’s Disease

Background: Brain iron deposition, low hemoglobin (HGB), and increased heme oxygenase-1 (HO-1) have been implicated in Parkinson’s disease (PD). However, the association among them in PD is poorly studied.Objective: To explore the association of the level of HO-1 with brain iron deposition and low level of HGB in PD.Methods: A total of 32 patients with PD and 26 controls were recruited for this study. C57BL/6 male mice were used in generating 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced chronic PD model. The Levels of serum HO-1 and HGB of human subjects and mice were assayed by ELISA, blood routine test, respectively. Quantitative susceptibility mapping (QSM) was used to quantitatively analyze brain iron deposition in human subjects and mice. HO-1 inhibitor (Sn-protoporphyrin, SnPP) was used to suppress the function and expression of HO-1 in PD mice. Correlations between the concentration of serum HO-1 and iron deposition of the region of interests (ROIs), levels of HGB, between the three factors mentioned above, and scores of clinical scales were explored in PD patients.Results: This study revealed significant elevation of the serum HO-1 concentration, iron deposition within bilateral substantial nigra (SN), red nucleus (RN), and putamen (PUT) and decrease of HGB level in PD patients. There was a significantly positive correlation between the serum HO-1 concentration and iron deposition within SN, an inverse correlation between the serum HO-1 concentration and HGB level in PD patients. A significant increase in HO-1 expression of serum and iron deposition in SN was also observed in the PD mouse model, and the SnPP could significantly reduce iron deposition in the SN.Conclusions: The high level of HO-1 may be the common mechanism of iron deposition and low HGB in PD. Therefore, the findings presented in this study indicate that HO-1 correlates with brain iron deposition and anemia in PD.

Increased Brain Iron Deposition in the Putamen in Patients with Type 2 Diabetes Mellitus Detected by Quantitative Susceptibility Mapping

Background. The underlying brain structural changes in type 2 diabetes mellitus (T2DM) patients have attracted increasing attention. The insulin-resistant state causes iron overload in neurons and leads to lesions in the central nervous system. Quantitative susceptibility mapping (QSM) can provide a noninvasive quantitative analysis of brain iron deposition. We aimed to compare the difference of brain iron deposition in the gray matter nucleus between T2DM patients and healthy elderly individuals using QSM. Methods. Thirty-two T2DM patients and thirty-two age- and gender-matched healthy controls (HCs) were enrolled in this research. Twenty-three patients and twenty-six HCs underwent cognitive assessments. Brain QSM maps were computed from multiecho GRE data using morphology-enabled dipole inversion with automatic uniform cerebrospinal fluid zero reference algorithm (MEDI+0). ITK-SNAP was used to measure the susceptibility values reflecting the content of iron in the regions of interest (ROIs). Results. The study included thirty-two T2DM patients (20 males and 12 females; mean age of 61.09±9.99 years) and 32 HCs (14 males and 18 females; mean age of 59.09±9.77 years). These participants had no significant difference in age or gender (P>0.05). Twenty-three patients with T2DM (11 males and 12 females; mean age, 64.65±8.44 years) and twenty-six HCs (14 males and 12 females; mean age, 62.30±6.13 years) received an assessment of cognitive function. T2DM patients exhibited an obviously (t=3.237, P=0.003) lower Montreal Cognitive Assessment (MoCA) score (26.78±2.35; HCs, 28.42±0.64; normal standard ≥26) and a higher Stroop color-word test (SCWT)-C score [87(65,110); HC, 63(60,76.75), Z=−2.232, P=0.003] than HCs. The mean susceptibility values in the putamen appeared obviously higher in T2DM patients than in HCs (t=−3.994, P<0.001). The susceptibility values and cognitive assessment scores showed no obvious association (P>0.05). However, an obvious correlation was observed between the changes in the susceptibility values in the putamen and the thalamus/dentate nucleus (r=0.404, P<0.001; r=0.423, P<0.001). Conclusion. T2DM patients showed increased susceptibility values in the putamen and had declines in executive functions, but the linear association between them was not statistically significant. Changes in susceptibility values in the putamen indicated increased iron deposition and might be used as a quantitative imaging marker of central nervous system injury in T2DM patients. QSM might be able to help probe micro neuronal damage in gray matter and provide information on diabetic encephalopathy.