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Chen Y, Luo X, Yin Y, Thomas ER, Liu K, Wang W, Li X. The interplay of iron, oxidative stress, and α-synuclein in Parkinson's disease progression. Mol Med 2025; 31:154. [PMID: 40287631 PMCID: PMC12034127 DOI: 10.1186/s10020-025-01208-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2024] [Accepted: 04/10/2025] [Indexed: 04/29/2025] Open
Abstract
The irreversible degeneration of dopamine neurons induced by α-synuclein (α-syn) aggregation in the substantia nigra is the central pathological feature of Parkinson's disease (PD). Neuroimaging and pathological autopsy studies consistently confirm significant iron accumulation in the brain of PD patients, suggesting a critical role for iron in disease progression. Current research has established that iron overload induces ferroptosis in dopaminergic neurons, evidence indicates that the impact of iron on PD pathology extends beyond ferroptosis. Iron also plays a regulatory role in modulating α-syn, affecting its aggregation, spatial conformation, post-translational modifications, and mRNA stability. Iron-induced α-syn aggregation can contribute to dopaminergic neurodegeneration through additional mechanisms, potentially creating a feedback loop in which α-syn further enhances iron accumulation, thus perpetuating a vicious cycle of neurotoxicity. Given α-syn's intrinsically disordered structure, targeting iron metabolism presents a promising therapeutic strategy for PD. Therefore, the development of iron chelators, alone or in combination with other therapeutic drugs, may offer a beneficial approach to alleviating PD symptoms and slowing disease progression.
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Affiliation(s)
- Yan Chen
- Department of Psychiatry, The Affiliated Zigong Hospital, Zigong Mental Health Center, Zigong Institute of Brain Science, Southwest Medical University, Luzhou, 646000, China
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Southwest Medical University, Luzhou, 646000, China
- Department of Dermatology, The Affiliated Hospital, Southwest Medical University, Luzhou, 646000, China
| | - Xixi Luo
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Southwest Medical University, Luzhou, 646000, China
| | - Yukun Yin
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Southwest Medical University, Luzhou, 646000, China
| | | | - Kezhi Liu
- Department of Psychiatry, The Affiliated Zigong Hospital, Zigong Mental Health Center, Zigong Institute of Brain Science, Southwest Medical University, Luzhou, 646000, China
| | - Wenjun Wang
- Department of Psychiatry, The Affiliated Zigong Hospital, Zigong Mental Health Center, Zigong Institute of Brain Science, Southwest Medical University, Luzhou, 646000, China.
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Southwest Medical University, Luzhou, 646000, China.
| | - Xiang Li
- Department of Psychiatry, The Affiliated Zigong Hospital, Zigong Mental Health Center, Zigong Institute of Brain Science, Southwest Medical University, Luzhou, 646000, China.
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Southwest Medical University, Luzhou, 646000, China.
- Health Science Center, Xi'an Jiaotong University, Xi'an, 710061, China.
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Hewlett M, Oran O, Liu J, Drangova M. Prospective motion correction for R 2 * and susceptibility mapping using spherical navigators. Magn Reson Med 2025; 93:1642-1656. [PMID: 39627965 PMCID: PMC11782710 DOI: 10.1002/mrm.30385] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2024] [Revised: 10/30/2024] [Accepted: 11/08/2024] [Indexed: 02/01/2025]
Abstract
PURPOSE To perform prospective motion correction (PMC) for improvedR 2 * $$ {R}_2^{\ast } $$ and susceptibility mapping using a purely navigator-based approach. METHODS Spherical navigators (SNAVs) were combined with an additional FID readout for simultaneous measurement of motion and zeroth-order field shifts. The resulting FIDSNAVs were interleaved for PMC of a multi-echo gradient echo sequence with retrospectiveB 0 $$ {B}_0 $$ correction. Experiments were performed on a 3T scanner with a 32-channel head coil. Performance was assessed in five volunteers with motion prompts derived from real unintentional motion trajectories. RESULTS At short TEs, PMC alone was sufficient to achieve good image quality; at longer TEs, retrospectiveB 0 $$ {B}_0 $$ correction was often just as important for artifact reduction as motion correction. Both PMC and retrospectiveB 0 $$ {B}_0 $$ correction reduced error inR 2 * $$ {R}_2^{\ast } $$ and susceptibility maps for all participants. Residual artifacts were observed in the most severe motion case. CONCLUSION Combining SNAVs with an additional FID readout enables simultaneous motion and field correction with no additional hardware requirements, improving the fidelity of quantitative mapping in the presence of motion.
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Affiliation(s)
- Miriam Hewlett
- Robarts Research InstituteThe University of Western Ontario
LondonOntarioCanada
- Department of Medical BiophysicsThe University of Western OntarioLondonOntarioCanada
| | - Omer Oran
- Siemens Healthcare LimitedOakvilleOntarioCanada
| | - Junmin Liu
- Robarts Research InstituteThe University of Western Ontario
LondonOntarioCanada
| | - Maria Drangova
- Robarts Research InstituteThe University of Western Ontario
LondonOntarioCanada
- Department of Medical BiophysicsThe University of Western OntarioLondonOntarioCanada
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Wen J, Guo T, Duanmu X, Wu C, Wu H, Zhou C, Zheng Q, Yuan W, Qin J, Zhu Z, Wu J, Chen J, Xu J, Yan Y, Tian J, Zhang B, He H, Zhang M, Guan X, Xu X. Gradients of Nigrostriatal Iron Deposition in Healthy Aging and Synucleinopathies. CNS Neurosci Ther 2025; 31:e70359. [PMID: 40130468 PMCID: PMC11933852 DOI: 10.1111/cns.70359] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2024] [Revised: 03/07/2025] [Accepted: 03/17/2025] [Indexed: 03/26/2025] Open
Abstract
AIMS To investigate the gradients of nigrostriatal iron deposition in aging, Parkinson's disease (PD), and multiple system atrophy (MSA). METHODS This study included 100 young healthy controls, 171 old healthy controls (OHC), 231 PD, and 24 MSA patients. The brain iron content was quantified by quantitative susceptibility mapping. A spatial function method was employed to map the iron gradient along the principal axis of the subcortical structure. General linear models were used to compare differences in iron gradients between groups. Partial correlation was used to analyze the relationship between iron content and symptoms of synucleinopathies. RESULTS Nigrostriatal iron deposition in all gradient directions was observed during aging (p < 0.05). Compared to OHC, iron deposition was significant in nearly all substantia nigra (SN) segments in both PD and MSA (p < 0.05). MSA showed significant iron deposition in the posterolateral putamen compared to PD (p < 0.05). Iron deposition in the SN in PD and putamen in MSA correlated with disease severity. CONCLUSION Iron deposition in all gradient directions occurred in the nigrostriatal system during healthy aging, and this was more evident in the SN in both PD and MSA, with MSA displaying additional iron deposition in the posterolateral putamen.
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Affiliation(s)
- Jiaqi Wen
- Department of Radiology, the Second Affiliated HospitalZhejiang University School of MedicineHangzhouChina
- Joint Laboratory of Clinical Radiology, the Second Affiliated HospitalZhejiang University School of MedicineHangzhouChina
| | - Tao Guo
- Department of Radiology, the Second Affiliated HospitalZhejiang University School of MedicineHangzhouChina
- Joint Laboratory of Clinical Radiology, the Second Affiliated HospitalZhejiang University School of MedicineHangzhouChina
| | - Xiaojie Duanmu
- Department of Radiology, the Second Affiliated HospitalZhejiang University School of MedicineHangzhouChina
- Joint Laboratory of Clinical Radiology, the Second Affiliated HospitalZhejiang University School of MedicineHangzhouChina
| | - Chenqing Wu
- Department of Radiology, the Second Affiliated HospitalZhejiang University School of MedicineHangzhouChina
- Joint Laboratory of Clinical Radiology, the Second Affiliated HospitalZhejiang University School of MedicineHangzhouChina
| | - Haoting Wu
- Department of Radiology, the Second Affiliated HospitalZhejiang University School of MedicineHangzhouChina
- Joint Laboratory of Clinical Radiology, the Second Affiliated HospitalZhejiang University School of MedicineHangzhouChina
| | - Cheng Zhou
- Department of Radiology, the Second Affiliated HospitalZhejiang University School of MedicineHangzhouChina
- Joint Laboratory of Clinical Radiology, the Second Affiliated HospitalZhejiang University School of MedicineHangzhouChina
| | - Qianshi Zheng
- Department of Radiology, the Second Affiliated HospitalZhejiang University School of MedicineHangzhouChina
- Joint Laboratory of Clinical Radiology, the Second Affiliated HospitalZhejiang University School of MedicineHangzhouChina
| | - Weijin Yuan
- Department of Radiology, the Second Affiliated HospitalZhejiang University School of MedicineHangzhouChina
- Joint Laboratory of Clinical Radiology, the Second Affiliated HospitalZhejiang University School of MedicineHangzhouChina
| | - Jianmei Qin
- Department of Radiology, the Second Affiliated HospitalZhejiang University School of MedicineHangzhouChina
- Joint Laboratory of Clinical Radiology, the Second Affiliated HospitalZhejiang University School of MedicineHangzhouChina
| | - Zihao Zhu
- Department of Radiology, the Second Affiliated HospitalZhejiang University School of MedicineHangzhouChina
- Joint Laboratory of Clinical Radiology, the Second Affiliated HospitalZhejiang University School of MedicineHangzhouChina
| | - Jingjing Wu
- Department of Radiology, the Second Affiliated HospitalZhejiang University School of MedicineHangzhouChina
- Joint Laboratory of Clinical Radiology, the Second Affiliated HospitalZhejiang University School of MedicineHangzhouChina
| | - Jingwen Chen
- Department of Radiology, the Second Affiliated HospitalZhejiang University School of MedicineHangzhouChina
- Joint Laboratory of Clinical Radiology, the Second Affiliated HospitalZhejiang University School of MedicineHangzhouChina
| | - Jingjing Xu
- Department of Radiology, the Second Affiliated HospitalZhejiang University School of MedicineHangzhouChina
- Joint Laboratory of Clinical Radiology, the Second Affiliated HospitalZhejiang University School of MedicineHangzhouChina
| | - Yaping Yan
- Department of Neurology, the Second Affiliated HospitalZhejiang University School of MedicineHangzhouChina
| | - Jun Tian
- Department of Neurology, the Second Affiliated HospitalZhejiang University School of MedicineHangzhouChina
| | - Baorong Zhang
- Department of Neurology, the Second Affiliated HospitalZhejiang University School of MedicineHangzhouChina
| | - Hongjian He
- Center for Brain Imaging Science and Technology, College of Biomedical Engineering and Instrument ScienceZhejiang UniversityHangzhouChina
| | - Minming Zhang
- Department of Radiology, the Second Affiliated HospitalZhejiang University School of MedicineHangzhouChina
- Joint Laboratory of Clinical Radiology, the Second Affiliated HospitalZhejiang University School of MedicineHangzhouChina
| | - Xiaojun Guan
- Department of Radiology, the Second Affiliated HospitalZhejiang University School of MedicineHangzhouChina
- Joint Laboratory of Clinical Radiology, the Second Affiliated HospitalZhejiang University School of MedicineHangzhouChina
| | - Xiaojun Xu
- Department of Radiology, the Second Affiliated HospitalZhejiang University School of MedicineHangzhouChina
- Joint Laboratory of Clinical Radiology, the Second Affiliated HospitalZhejiang University School of MedicineHangzhouChina
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Bhagaloo KA, Yu L, West EA, Chandler DJ, Shcherbik N. Alterations in iron levels in the locus coeruleus of a transgenic Alzheimer's disease rat model. Neurosci Lett 2025; 850:138151. [PMID: 39922529 DOI: 10.1016/j.neulet.2025.138151] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2024] [Revised: 02/04/2025] [Accepted: 02/05/2025] [Indexed: 02/10/2025]
Abstract
Iron is essential for brain function, acting as a cofactor for enzymes involved in neurotransmitter synthesis and metabolism. However, dysregulated iron homeostasis is increasingly linked to neurodegenerative diseases, including Alzheimer's disease (AD). The locus coeruleus (LC), a norepinephrine-producing brainstem nucleus, is among the earliest regions affected in AD, yet its iron dynamics remain poorly understood. This study presents the first comprehensive analysis of iron content in the LC by combining a transgenic AD rat model, precise anatomical isolation, and Inductively Coupled Plasma Mass Spectrometry for high-sensitivity metal quantification. This approach enabled the profiling of iron and zinc concentrations in the LC, uncovering novel insights into iron dysregulation in AD. We observed a significant genotype-specific increase in LC iron levels in TgF344-AD rats compared to wild-type controls. Notably, our findings reveal distinct iron alterations in TgF344-AD rats, suggesting a previously unrecognized role for iron homeostasis in LC dysfunction. These results provide new perspectives on iron dysregulation in AD pathology and its potential as a therapeutic target.
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Affiliation(s)
| | - Lei Yu
- Department of Chemistry and Biochemistry, Rowan University, Glassboro, NJ, 08028, United States
| | - Elizabeth A West
- Department of Cell Biology and Neuroscience, Rowan-Virtua SOM, Stratford, NJ, 08084, United States
| | - Daniel J Chandler
- Department of Cell Biology and Neuroscience, Rowan-Virtua SOM, Stratford, NJ, 08084, United States
| | - Natalia Shcherbik
- Department of Cell Biology and Neuroscience, Rowan-Virtua SOM, Stratford, NJ, 08084, United States; Department of Molecular Biology, Rowan-Virtua SOM, Stratford, NJ, 08084, United States.
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Duță C, Muscurel C, Dogaru CB, Stoian I. Ferroptosis-A Shared Mechanism for Parkinson's Disease and Type 2 Diabetes. Int J Mol Sci 2024; 25:8838. [PMID: 39201524 PMCID: PMC11354749 DOI: 10.3390/ijms25168838] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2024] [Revised: 07/31/2024] [Accepted: 08/06/2024] [Indexed: 09/02/2024] Open
Abstract
Type 2 diabetes (T2D) and Parkinson's disease (PD) are the two most frequent age-related chronic diseases. There are many similarities between the two diseases: both are chronic diseases; both are the result of a decrease in a specific substance-insulin in T2D and dopamine in PD; and both are caused by the destruction of specific cells-beta pancreatic cells in T2D and dopaminergic neurons in PD. Recent epidemiological and experimental studies have found that there are common underlying mechanisms in the pathophysiology of T2D and PD: chronic inflammation, mitochondrial dysfunction, impaired protein handling and ferroptosis. Epidemiological research has indicated that there is a higher risk of PD in individuals with T2D. Moreover, clinical studies have observed that the symptoms of Parkinson's disease worsen significantly after the onset of T2D. This article provides an up-to-date review on the intricate interplay between oxidative stress, reactive oxygen species (ROS) and ferroptosis in PD and T2D. By understanding the shared molecular pathways and how they can be modulated, we can develop more effective therapies, or we can repurpose existing drugs to improve patient outcomes in both disorders.
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6
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Zhu S, Shi Y, Chen Z, Long Z, Wan L, Chen D, Yuan X, Fu Y, Deng F, Long X, Du K, Qiu R, Tang B, Wang C, Jiang H. The characteristic and biomarker value of transcranial sonography in cerebellar ataxia. Ann Clin Transl Neurol 2024; 11:2100-2111. [PMID: 38924300 PMCID: PMC11330234 DOI: 10.1002/acn3.52131] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2023] [Revised: 05/18/2024] [Accepted: 05/24/2024] [Indexed: 06/28/2024] Open
Abstract
OBJECTIVE Transcranial sonography (TCS) is a noninvasive neuroimaging technique, visualizing deep brain structures and the ventricular system. Although widely employed in diagnosing various movement disorders, such as Parkinson's disease and dystonia, by detecting disease-specific abnormalities, the specific characteristics of the TCS in cerebellar ataxia remain inconclusive. We aimed to assess the potential value of TCS in patients with cerebellar ataxias for disease diagnosis and severity assessment. METHODS TCS on patients with genetic and acquired cerebellar ataxia, including 94 with spinocerebellar ataxias (SCAs) containing 10 asymptomatic carriers, 95 with cerebellar subtype of multiple system atrophy (MSA-C), and 100 healthy controls (HC), was conducted. Assessments included third ventricle width, substantia nigra (SN) and lentiform nucleus (LN) echogenicity, along with comprehensive clinical evaluations and genetic testing. RESULTS The study revealed significant TCS abnormalities in patients with cerebellar ataxia, such as enlarged third ventricle widths and elevated rates of hyperechogenic SN and LN. TCS showed high accuracy in distinguishing patients with SCA or MSA-C from HC, with an AUC of 0.870 and 0.931, respectively. TCS abnormalities aided in identifying asymptomatic SCA carriers, effectively differentiating them from HC, with an AUC of 0.725. Furthermore, third ventricle width was significantly correlated with SARA and ICARS scores in patients with SCA3 and SCOPA-AUT scores in patients with MSA-C. The SN area and SARA or ICARS scores in patients with SCA3 were also positively correlated. INTERPRETATION Our findings illustrate remarkable TCS abnormalities in patients with cerebellar ataxia, serving as potential biomarkers for clinical diagnosis and progression assessment.
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Affiliation(s)
- Sudan Zhu
- Department of Neurology, Xiangya HospitalCentral South UniversityChangshaChina
| | - Yuting Shi
- Department of Neurology, Xiangya HospitalCentral South UniversityChangshaChina
- Key Laboratory of Hunan Province in Neurodegenerative DisordersCentral South UniversityChangshaChina
| | - Zhao Chen
- Department of Neurology, Xiangya HospitalCentral South UniversityChangshaChina
- Key Laboratory of Hunan Province in Neurodegenerative DisordersCentral South UniversityChangshaChina
- National Clinical Research Center for Geriatric Disorders, Xiangya HospitalCentral South UniversityChangshaChina
- Hunan International Scientific and Technological Cooperation Base of Neurodegenerative and Neurogenetic DiseasesChangshaChina
| | - Zhe Long
- Department of Neurology, The Second Xiangya HospitalCentral South UniversityChangshaChina
- Clinical Medical Research Center for Stroke Prevention and Treatment of Hunan Province, Department of Neurology, The Second Xiangya HospitalCentral South UniversityChangshaChina
| | - Linlin Wan
- Department of Neurology, Xiangya HospitalCentral South UniversityChangshaChina
- Key Laboratory of Hunan Province in Neurodegenerative DisordersCentral South UniversityChangshaChina
- National Clinical Research Center for Geriatric Disorders, Xiangya HospitalCentral South UniversityChangshaChina
- Department of Radiology, Xiangya HospitalCentral South UniversityChangshaChina
- National International Collaborative Research Center for Medical MetabolomicsCentral South UniversityChangshaChina
| | - Daji Chen
- Department of Neurology, Xiangya HospitalCentral South UniversityChangshaChina
| | - Xinrong Yuan
- Department of Neurology, Xiangya HospitalCentral South UniversityChangshaChina
| | - You Fu
- Department of Neurology, Xiangya HospitalCentral South UniversityChangshaChina
| | - Feiyan Deng
- Department of Neurology, Xiangya HospitalCentral South UniversityChangshaChina
| | - Xiafei Long
- Department of Neurology, Xiangya HospitalCentral South UniversityChangshaChina
| | - Kefang Du
- Department of Neurology, Xiangya HospitalCentral South UniversityChangshaChina
| | - Rong Qiu
- School of Computer Science and EngineeringCentral South UniversityChangshaChina
| | - Beisha Tang
- Department of Neurology, Xiangya HospitalCentral South UniversityChangshaChina
- Key Laboratory of Hunan Province in Neurodegenerative DisordersCentral South UniversityChangshaChina
- National Clinical Research Center for Geriatric Disorders, Xiangya HospitalCentral South UniversityChangshaChina
- Hunan International Scientific and Technological Cooperation Base of Neurodegenerative and Neurogenetic DiseasesChangshaChina
| | - Chunrong Wang
- Key Laboratory of Hunan Province in Neurodegenerative DisordersCentral South UniversityChangshaChina
- Department of Pathology, Xiangya HospitalCentral South UniversityChangshaChina
| | - Hong Jiang
- Department of Neurology, Xiangya HospitalCentral South UniversityChangshaChina
- Key Laboratory of Hunan Province in Neurodegenerative DisordersCentral South UniversityChangshaChina
- National Clinical Research Center for Geriatric Disorders, Xiangya HospitalCentral South UniversityChangshaChina
- Hunan International Scientific and Technological Cooperation Base of Neurodegenerative and Neurogenetic DiseasesChangshaChina
- National International Collaborative Research Center for Medical MetabolomicsCentral South UniversityChangshaChina
- Department of Neurology, The Third Xiangya HospitalCentral South UniversityChangshaChina
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Currim F, Tanwar R, Brown-Leung JM, Paranjape N, Liu J, Sanders LH, Doorn JA, Cannon JR. Selective dopaminergic neurotoxicity modulated by inherent cell-type specific neurobiology. Neurotoxicology 2024; 103:266-287. [PMID: 38964509 PMCID: PMC11288778 DOI: 10.1016/j.neuro.2024.06.016] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2024] [Revised: 06/27/2024] [Accepted: 06/28/2024] [Indexed: 07/06/2024]
Abstract
Parkinson's disease (PD) is a debilitating neurodegenerative disease affecting millions of individuals worldwide. Hallmark features of PD pathology are the formation of Lewy bodies in neuromelanin-containing dopaminergic (DAergic) neurons of the substantia nigra pars compacta (SNpc), and the subsequent irreversible death of these neurons. Although genetic risk factors have been identified, around 90 % of PD cases are sporadic and likely caused by environmental exposures and gene-environment interaction. Mechanistic studies have identified a variety of chemical PD risk factors. PD neuropathology occurs throughout the brain and peripheral nervous system, but it is the loss of DAergic neurons in the SNpc that produce many of the cardinal motor symptoms. Toxicology studies have found specifically the DAergic neuron population of the SNpc exhibit heightened sensitivity to highly variable chemical insults (both in terms of chemical structure and mechanism of neurotoxic action). Thus, it has become clear that the inherent neurobiology of nigral DAergic neurons likely underlies much of this neurotoxic response to broad insults. This review focuses on inherent neurobiology of nigral DAergic neurons and how such neurobiology impacts the primary mechanism of neurotoxicity. While interactions with a variety of other cell types are important in disease pathogenesis, understanding how inherent DAergic biology contributes to selective sensitivity and primary mechanisms of neurotoxicity is critical to advancing the field. Specifically, key biological features of DAergic neurons that increase neurotoxicant susceptibility.
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Affiliation(s)
- Fatema Currim
- School of Health Sciences, Purdue University, West Lafayette, IN 47901, USA; Purdue Institute for Integrative Neuroscience, Purdue University, West Lafayette, IN 47901, USA
| | - Reeya Tanwar
- School of Health Sciences, Purdue University, West Lafayette, IN 47901, USA; Purdue Institute for Integrative Neuroscience, Purdue University, West Lafayette, IN 47901, USA
| | - Josephine M Brown-Leung
- School of Health Sciences, Purdue University, West Lafayette, IN 47901, USA; Purdue Institute for Integrative Neuroscience, Purdue University, West Lafayette, IN 47901, USA
| | - Neha Paranjape
- Pharmaceutical Sciences and Experimental Therapeutics, College of Pharmacy, University of Iowa, Iowa City, IA 52242, USA
| | - Jennifer Liu
- Departments of Neurology and Pathology, Duke University School of Medicine, Durham, NC 27710, USA; Duke Center for Neurodegeneration and Neurotherapeutics, Duke University School of Medicine, Durham, NC 27710, USA
| | - Laurie H Sanders
- Departments of Neurology and Pathology, Duke University School of Medicine, Durham, NC 27710, USA; Duke Center for Neurodegeneration and Neurotherapeutics, Duke University School of Medicine, Durham, NC 27710, USA
| | - Jonathan A Doorn
- Pharmaceutical Sciences and Experimental Therapeutics, College of Pharmacy, University of Iowa, Iowa City, IA 52242, USA
| | - Jason R Cannon
- School of Health Sciences, Purdue University, West Lafayette, IN 47901, USA; Purdue Institute for Integrative Neuroscience, Purdue University, West Lafayette, IN 47901, USA.
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Meyyappan M, Babu B, Anitha M, Ganesan G, S A, Natarajan P. Role of Diffusion Tensor Imaging in Early Diagnosis and Characterization of Movement Disorders. Cureus 2024; 16:e53580. [PMID: 38449950 PMCID: PMC10914641 DOI: 10.7759/cureus.53580] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/04/2024] [Indexed: 03/08/2024] Open
Abstract
BACKGROUND Symptoms of movement disorders in early stages are similar, which makes definite diagnosis difficult. Hence this study was conducted to explore the role of diffusion tensor imaging (DTI) in enhancing the early diagnosis and characterization of movement disorders. METHODOLOGY A cross-sectional study was conducted including 60 subjects. All of them were reviewed using conventional magnetic resonance imaging (MRI) and movement disorder DTI protocol. Commercially available software was used to produce fractional anisotropy (FA) maps. Post-processing 3D reconstruction was done to obtain tractograms. Both single and multiple regions of interest (ROIs) were selected for tractography in the pons, midbrain, substantia nigra (SN) and cerebellum. MRI and DTI images were interpreted and correlated with confirmatory diagnosis. RESULTS According to DTI diagnosis, out of the 30 cases, 28 had movement disorders. Among cases, 36.67% had Parkinson's disease (PD), 23.33% had progressive supranuclear palsy (PSP), 16.67% had essential tremor, 13.33% had multi-system atrophy (MSA) C, and 3.33% had MSA P. DTI correctly classified all cases with PD and PSP. All cases with long disease duration and 88.24% of cases with short disease duration were also correctly classified. A statistically significant difference was observed in the proportion of diagnosis between DTI and conventional MRI. CONCLUSION DTI has high sensitivity and specificity for the diagnosis of movement disorders. It is capable of early diagnosis of movement disorders and also differentiating and subcategorizing them.
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Affiliation(s)
- M Meyyappan
- Radiology, Panimalar Medical College Hospital and Research Institute, Chennai, IND
| | - Biji Babu
- Radiology, Panimalar Medical College Hospital and Research Institute, Chennai, IND
| | - M Anitha
- Radiology, Panimalar Medical College Hospital and Research Institute, Chennai, IND
| | - Gopinath Ganesan
- Radiology, Panimalar Medical College Hospital and Research Institute, Chennai, IND
| | - Anita S
- Radiology, Panimalar Medical College Hospital and Research Institute, Chennai, IND
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Duanmu X, Wen J, Tan S, Guo T, Zhou C, Wu H, Wu J, Cao Z, Liu X, Chen J, Wu C, Qin J, Gu L, Yan Y, Zhang B, Zhang M, Guan X, Xu X. Aberrant dentato-rubro-thalamic pathway in action tremor but not rest tremor: A multi-modality magnetic resonance imaging study. CNS Neurosci Ther 2023; 29:4160-4171. [PMID: 37408389 PMCID: PMC10651946 DOI: 10.1111/cns.14339] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2023] [Revised: 05/14/2023] [Accepted: 06/24/2023] [Indexed: 07/07/2023] Open
Abstract
AIMS The purpose of this study was to clarify the dentato-rubro-thalamic (DRT) pathway in action tremor in comparison to normal controls (NC) and disease controls (i.e., rest tremor) by using multi-modality magnetic resonance imaging (MRI). METHODS This study included 40 essential tremor (ET) patients, 57 Parkinson's disease (PD) patients (29 with rest tremor, 28 without rest tremor), and 41 NC. We used multi-modality MRI to comprehensively assess major nuclei and fiber tracts of the DRT pathway, which included decussating DRT tract (d-DRTT) and non-decussating DRT tract (nd-DRTT), and compared the differences in DRT pathway components between action and rest tremor. RESULTS Bilateral dentate nucleus (DN) in the ET group had excessive iron deposition compared with the NC group. Compared with the NC group, significantly decreased mean diffusivity and radial diffusivity were observed in the left nd-DRTT in the ET group, which were negatively correlated with tremor severity. No significant difference in each component of the DRT pathway was observed between the PD subgroup or the PD and NC. CONCLUSION Aberrant changes in the DRT pathway may be specific to action tremor and were indicating that action tremor may be related to pathological overactivation of the DRT pathway.
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Affiliation(s)
- Xiaojie Duanmu
- Department of Radiology, The Second Affiliated HospitalZhejiang University School of MedicineHangzhouChina
| | - Jiaqi Wen
- Department of Radiology, The Second Affiliated HospitalZhejiang University School of MedicineHangzhouChina
| | - Sijia Tan
- Department of Radiology, The Second Affiliated HospitalZhejiang University School of MedicineHangzhouChina
| | - Tao Guo
- Department of Radiology, The Second Affiliated HospitalZhejiang University School of MedicineHangzhouChina
| | - Cheng Zhou
- Department of Radiology, The Second Affiliated HospitalZhejiang University School of MedicineHangzhouChina
| | - Haoting Wu
- Department of Radiology, The Second Affiliated HospitalZhejiang University School of MedicineHangzhouChina
| | - Jingjing Wu
- Department of Radiology, The Second Affiliated HospitalZhejiang University School of MedicineHangzhouChina
| | - Zhengye Cao
- Department of Radiology, The Second Affiliated HospitalZhejiang University School of MedicineHangzhouChina
| | - Xiaocao Liu
- Department of Radiology, The Second Affiliated HospitalZhejiang University School of MedicineHangzhouChina
| | - Jingwen Chen
- Department of Radiology, The Second Affiliated HospitalZhejiang University School of MedicineHangzhouChina
| | - Chenqing Wu
- Department of Radiology, The Second Affiliated HospitalZhejiang University School of MedicineHangzhouChina
| | - Jianmei Qin
- Department of Radiology, The Second Affiliated HospitalZhejiang University School of MedicineHangzhouChina
| | - Luyan Gu
- Department of Neurology, The Second Affiliated HospitalZhejiang University School of MedicineHangzhouChina
| | - Yaping Yan
- Department of Neurology, The Second Affiliated HospitalZhejiang University School of MedicineHangzhouChina
| | - Baorong Zhang
- Department of Neurology, The Second Affiliated HospitalZhejiang University School of MedicineHangzhouChina
| | - Minming Zhang
- Department of Radiology, The Second Affiliated HospitalZhejiang University School of MedicineHangzhouChina
| | - Xiaojun Guan
- Department of Radiology, The Second Affiliated HospitalZhejiang University School of MedicineHangzhouChina
| | - Xiaojun Xu
- Department of Radiology, The Second Affiliated HospitalZhejiang University School of MedicineHangzhouChina
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Chen ZT, Pan CZ, Ruan XL, Lei LP, Lin SM, Wang YZ, Zhao ZH. Evaluation of ferritin and TfR level in plasma neural-derived exosomes as potential markers of Parkinson's disease. Front Aging Neurosci 2023; 15:1216905. [PMID: 37794977 PMCID: PMC10546046 DOI: 10.3389/fnagi.2023.1216905] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2023] [Accepted: 09/04/2023] [Indexed: 10/06/2023] Open
Abstract
Introduction Early diagnosis of Parkinson's disease (PD) remains challenging. It has been suggested that abnormal brain iron metabolism leads to excessive iron accumulation in PD, although the mechanism of iron deposition is not yet fully understood. Ferritin and transferrin receptor (TfR) are involved in iron metabolism, and the exosome pathway is one mechanism by which ferritin is transported and regulated. While the blood of healthy animals contains a plentiful supply of TfR-positive exosomes, no studies have examined ferritin and TfR in plasma neural-derived exosomes. Methods Plasma exosomes were obtained from 43 patients with PD and 34 healthy controls. Neural-derived exosomes were isolated with anti-human L1CAM antibody immunoabsorption. Transmission electron microscopy and western blotting were used to identify the exosomes. ELISAs were used to quantify ferritin and TfR levels in plasma neural-derived exosomes of patients with PD and controls. Receivers operating characteristic (ROC) curves were applied to map the diagnostic accuracy of ferritin and TfR. Independent predictors of the disease were identified using logistic regression models. Results Neural-derived exosomes exhibited the typical exosomal morphology and expressed the specific exosome marker CD63. Ferritin and TfR levels in plasma neural-derived exosomes were significantly higher in patients with PD than controls (406.46 ± 241.86 vs. 245.62 ± 165.47 ng/μg, P = 0.001 and 1728.94 ± 766.71 vs. 1153.92 ± 539.30 ng/μg, P < 0.001, respectively). There were significant positive correlations between ferritin and TfR levels in plasma neural-derived exosomes in control group, PD group and all the individuals (rs = 0.744, 0.700, and 0.752, respectively). The level of TfR was independently associated with the disease (adjusted odds ratio 1.002; 95% CI 1.000-1.003). ROC performances of ferritin, TfR, and their combination were moderate (0.730, 0.812, and 0.808, respectively). However, no relationship was found between the biomarkers and disease progression. Conclusion It is hypothesized that ferritin and TfR in plasma neural-derived exosomes may be potential biomarkers for PD, and that they may participate in the mechanism of excessive iron deposition in PD.
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Affiliation(s)
- Zhi-ting Chen
- Department of Neurology, Fujian Medical University Union Hospital, Fuzhou, Fujian, China
| | - Chu-zhui Pan
- Shengli Clinical Medical College of Fujian Medical University, Fuzhou, Fujian, China
- Department of Neurology, Fujian Provincial Hospital, Fuzhou, Fujian, China
| | - Xing-lin Ruan
- Department of Neurology, Fujian Medical University Union Hospital, Fuzhou, Fujian, China
| | - Li-ping Lei
- Shengli Clinical Medical College of Fujian Medical University, Fuzhou, Fujian, China
- Department of Neurology, Fujian Provincial Hospital, Fuzhou, Fujian, China
| | - Sheng-mei Lin
- Shengli Clinical Medical College of Fujian Medical University, Fuzhou, Fujian, China
- Department of Neurology, Fujian Provincial Hospital, Fuzhou, Fujian, China
| | - Yin-zhou Wang
- Shengli Clinical Medical College of Fujian Medical University, Fuzhou, Fujian, China
- Department of Neurology, Fujian Provincial Hospital, Fuzhou, Fujian, China
| | - Zhen-Hua Zhao
- Shengli Clinical Medical College of Fujian Medical University, Fuzhou, Fujian, China
- Department of Neurology, Fujian Provincial Hospital, Fuzhou, Fujian, China
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Wang Y, Wu S, Li Q, Sun H, Wang H. Pharmacological Inhibition of Ferroptosis as a Therapeutic Target for Neurodegenerative Diseases and Strokes. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2023; 10:e2300325. [PMID: 37341302 PMCID: PMC10460905 DOI: 10.1002/advs.202300325] [Citation(s) in RCA: 58] [Impact Index Per Article: 29.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/14/2023] [Revised: 05/23/2023] [Indexed: 06/22/2023]
Abstract
Emerging evidence suggests that ferroptosis, a unique regulated cell death modality that is morphologically and mechanistically different from other forms of cell death, plays a vital role in the pathophysiological process of neurodegenerative diseases, and strokes. Accumulating evidence supports ferroptosis as a critical factor of neurodegenerative diseases and strokes, and pharmacological inhibition of ferroptosis as a therapeutic target for these diseases. In this review article, the core mechanisms of ferroptosis are overviewed and the roles of ferroptosis in neurodegenerative diseases and strokes are described. Finally, the emerging findings in treating neurodegenerative diseases and strokes through pharmacological inhibition of ferroptosis are described. This review demonstrates that pharmacological inhibition of ferroptosis by bioactive small-molecule compounds (ferroptosis inhibitors) could be effective for treatments of these diseases, and highlights a potential promising therapeutic avenue that could be used to prevent neurodegenerative diseases and strokes. This review article will shed light on developing novel therapeutic regimens by pharmacological inhibition of ferroptosis to slow down the progression of these diseases in the future.
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Affiliation(s)
- Yumin Wang
- Department of Respiratory and Critical Care MedicineAerospace Center HospitalPeking University Aerospace School of Clinical MedicineBeijing100049P. R. China
| | - Shuang Wu
- Department of NeurologyZhongnan Hospital of Wuhan UniversityWuhan430000P. R. China
| | - Qiang Li
- Department of NeurologyThe Affiliated Hospital of Chifeng UniversityChifeng024005P. R. China
| | - Huiyan Sun
- Chifeng University Health Science CenterChifeng024000P. R. China
| | - Hongquan Wang
- Tianjin Medical University Cancer Institute and HospitalNational Clinical Research Center for CancerTianjin's Clinical Research Center for CancerKey Laboratory of Cancer Prevention and TherapyTianjin300060P. R. China
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Viktorinova A. Future Perspectives of Oxytosis/Ferroptosis Research in Neurodegeneration Diseases. Cell Mol Neurobiol 2023; 43:2761-2768. [PMID: 37093436 PMCID: PMC11410136 DOI: 10.1007/s10571-023-01353-5] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2022] [Accepted: 04/14/2023] [Indexed: 04/25/2023]
Abstract
The current report briefly summarizes the existing hypotheses and relevant evidence of oxytosis/ferroptosis-mediated cell death and outlines future perspectives of neurodegeneration research. Furthermore, it highlights the potential application of specific markers (e.g., activators, inhibitors, redox modulators, antioxidants, iron chelators) in the study of regulatory mechanisms of oxytosis/ferroptosis. It appears that these markers may be a suitable option for experimental investigations targeting key pathways of oxytosis/ferroptosis, such as the inhibition of the cystine/glutamate antiporter/glutathione/glutathione peroxidase 4 axis, glutamate oxidative toxicity, glutathione depletion, iron dyshomeostasis, iron-mediated lipid peroxidation, and others. From a clinical perspective, an innovative research approach to investigate the oxytosis/ferroptosis pathways in cells of the central nervous system and their relationship to neurodegenerative diseases is desirable. It is necessary to expand the existing knowledge about the molecular mechanisms of neurodegenerative diseases and to provide innovative diagnostic procedures to prevent their progression, as well as to develop effective neuroprotective treatment. The importance of preclinical studies focused predominantly on oxytosis/ferroptosis inhibitors (iron chelators or lipoxygenase inhibitors and lipophilic antioxidants) that could chelate iron or inhibit lipid peroxidation is also discussed. Specifically, this targeted inhibition of neuronal death could represent a potential therapeutic strategy for some neurodegenerative diseases.
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Affiliation(s)
- Alena Viktorinova
- Faculty of Medicine, Institute of Medical Chemistry, Biochemistry and Clinical Biochemistry, Comenius University in Bratislava, Sasinkova 2, 811 08, Bratislava, Slovakia.
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13
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Nepozitek J, Varga Z, Dostalova S, Perinova P, Keller J, Robinson S, Ibarburu V, Prihodova I, Bezdicek O, Ruzicka E, Sonka K, Dusek P. Magnetic susceptibility changes in the brainstem reflect REM sleep without atonia severity in isolated REM sleep behavior disorder. NPJ Parkinsons Dis 2023; 9:112. [PMID: 37452075 PMCID: PMC10349141 DOI: 10.1038/s41531-023-00557-2] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2023] [Accepted: 07/05/2023] [Indexed: 07/18/2023] Open
Abstract
REM sleep without atonia (RWA) is the hallmark of isolated REM sleep behavior disorder (iRBD) and is caused by neurodegeneration of brainstem structures. Previously, quantitative susceptibility mapping (QSM) was shown to detect microstructural tissue changes in neurodegenerative diseases. The goal of the study was to compare brainstem magnetic susceptibility (MS) in iRBD and controls using the voxel-based QSM approach and to examine the association between brainstem MS and severity of RWA in iRBD. Sixty iRBD patients and 41 healthy controls were included in the study. Phasic, tonic, mixed RWA and SINBAR score was quantified. QSM maps were reconstructed with QSMbox software from a multi-gradient-echo sequence acquired at 3T MRI system and normalized using a custom T1 template. Voxel-based analysis with age and gender as covariates was performed using a two-sample t-test model for between-group comparison and using a linear regression model for association with the RWA parameters. Statistical maps were generated using threshold free cluster enhancement with p-value p < 0.05, corrected for family wise error. Compared to controls, the iRBD group had higher MS in bilateral substantia nigra (SN), red nucleus and the ventral tegmental area. MS positively correlated with iRBD duration in the right pedunculotegmental nucleus and white matter of caudal mesencephalic and pontine tegmentum and with phasic RWA in bilateral SN. QSM was able to detect MS abnormalities in several brainstem structures in iRBD. Association of MS levels in the brainstem with the intensity of RWA suggests that increased iron content in SN is related to RWA severity.
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Affiliation(s)
- Jiri Nepozitek
- Department of Neurology and Center of Clinical Neuroscience, First Faculty of Medicine, Charles University and General University Hospital in Prague, Prague, Czech Republic.
| | - Zsoka Varga
- Department of Neurology and Center of Clinical Neuroscience, First Faculty of Medicine, Charles University and General University Hospital in Prague, Prague, Czech Republic
| | - Simona Dostalova
- Department of Neurology and Center of Clinical Neuroscience, First Faculty of Medicine, Charles University and General University Hospital in Prague, Prague, Czech Republic
| | - Pavla Perinova
- Department of Neurology and Center of Clinical Neuroscience, First Faculty of Medicine, Charles University and General University Hospital in Prague, Prague, Czech Republic
| | - Jiri Keller
- Radiodiagnostic Department, Na Homolce Hospital, Prague, Czech Republic
| | - Simon Robinson
- Department of Biomedical Imaging and Image-guided Therapy, Medical University of Vienna, Vienna, Austria
- Centre of Advanced Imaging, University of Queensland, Brisbane, Queensland, Australia
| | - Veronika Ibarburu
- Department of Neurology and Center of Clinical Neuroscience, First Faculty of Medicine, Charles University and General University Hospital in Prague, Prague, Czech Republic
| | - Iva Prihodova
- Department of Neurology and Center of Clinical Neuroscience, First Faculty of Medicine, Charles University and General University Hospital in Prague, Prague, Czech Republic
| | - Ondrej Bezdicek
- Department of Neurology and Center of Clinical Neuroscience, First Faculty of Medicine, Charles University and General University Hospital in Prague, Prague, Czech Republic
| | - Evzen Ruzicka
- Department of Neurology and Center of Clinical Neuroscience, First Faculty of Medicine, Charles University and General University Hospital in Prague, Prague, Czech Republic
| | - Karel Sonka
- Department of Neurology and Center of Clinical Neuroscience, First Faculty of Medicine, Charles University and General University Hospital in Prague, Prague, Czech Republic
| | - Petr Dusek
- Department of Neurology and Center of Clinical Neuroscience, First Faculty of Medicine, Charles University and General University Hospital in Prague, Prague, Czech Republic
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14
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Outeiro TF, Alcalay RN, Antonini A, Attems J, Bonifati V, Cardoso F, Chesselet MF, Hardy J, Madeo G, McKeith I, Mollenhauer B, Moore DJ, Rascol O, Schlossmacher MG, Soreq H, Stefanis L, Ferreira JJ. Defining the Riddle in Order to Solve It: There Is More Than One "Parkinson's Disease". Mov Disord 2023. [PMID: 37156737 DOI: 10.1002/mds.29419] [Citation(s) in RCA: 18] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2023] [Revised: 03/30/2023] [Accepted: 04/05/2023] [Indexed: 05/10/2023] Open
Abstract
BACKGROUND More than 200 years after James Parkinsondescribed a clinical syndrome based on his astute observations, Parkinson's disease (PD) has evolved into a complex entity, akin to the heterogeneity of other complex human syndromes of the central nervous system such as dementia, motor neuron disease, multiple sclerosis, and epilepsy. Clinicians, pathologists, and basic science researchers evolved arrange of concepts andcriteria for the clinical, genetic, mechanistic, and neuropathological characterization of what, in their best judgment, constitutes PD. However, these specialists have generated and used criteria that are not necessarily aligned between their different operational definitions, which may hinder progress in solving the riddle of the distinct forms of PD and ultimately how to treat them. OBJECTIVE This task force has identified current in consistencies between the definitions of PD and its diverse variants in different domains: clinical criteria, neuropathological classification, genetic subtyping, biomarker signatures, and mechanisms of disease. This initial effort for "defining the riddle" will lay the foundation for future attempts to better define the range of PD and its variants, as has been done and implemented for other heterogeneous neurological syndromes, such as stroke and peripheral neuropathy. We strongly advocate for a more systematic and evidence-based integration of our diverse disciplines by looking at well-defined variants of the syndrome of PD. CONCLUSION Accuracy in defining endophenotypes of "typical PD" across these different but interrelated disciplines will enable better definition of variants and their stratification in therapeutic trials, a prerequisite for breakthroughs in the era of precision medicine. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
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Affiliation(s)
- Tiago F Outeiro
- Department of Experimental Neurodegeneration, Center for Biostructural Imaging of Neurodegeneration, University Medical Center Goettingen, Goettingen, Germany
- Max Planck Institute for Multidisciplinary Sciences, Goettingen, Germany
- Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle, United Kingdom
| | - Roy N Alcalay
- Neurological Institute, Tel-Aviv Sourasky Medical Center, Tel Aviv, Israel
- Department of Neurology, Columbia University Irving Medical Center, New York, New York, USA
| | - Angelo Antonini
- Department of Neurosciences (DNS), Padova University, Padova, Italy
| | - Johannes Attems
- Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle, United Kingdom
| | - Vincenzo Bonifati
- Department of Clinical Genetics, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands
| | - Francisco Cardoso
- Movement Disorders Unit, Neurology Service, Internal Medicine Department, The Federal University of Minas Gerais, Belo Horizonte, Brazil
| | | | - John Hardy
- Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, London, United Kingdom
- UK Dementia Research Institute at UCL and Department of Neurodegenerative Disease, UCL Institute of Neurology, University College London, London, United Kingdom
- Reta Lila Weston Institute, UCL Queen Square Institute of Neurology, London, United Kingdom
- UCL Movement Disorders Centre, University College London, London, United Kingdom
- Institute for Advanced Study, The Hong Kong University of Science and Technology, Hong Kong, China
| | | | - Ian McKeith
- Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle, United Kingdom
| | - Brit Mollenhauer
- Department of Neurology, University Medical Center, Göttingen, Germany
- Paracelsus-Elena-Klinik, Kassel, Germany
| | - Darren J Moore
- Department of Neurodegenerative Science, Van Andel Institute, Grand Rapids, Michigan, USA
| | - Olivier Rascol
- Department of Neurosciences, Clinical Investigation Center CIC 1436, Parkinson Toulouse Expert Centre, NS-Park/FCRIN Network and Neuro Toul COEN Centre, Toulouse University Hospital, INSERM, University of Toulouse 3, Toulouse, France
| | - Michael G Schlossmacher
- Program in Neuroscience and Division of Neurology, The Ottawa Hospital, Ottawa, Ontario, Canada
- University of Ottawa Brain and Mind Research Institute, Ottawa, Ontario, Canada
| | - Hermona Soreq
- The Institute of Life Sciences and The Edmond and Lily Safra Center of Brain Science, The Hebrew University of Jerusalem, Jerusalem, Israel
| | - Leonidas Stefanis
- First Department of Neurology, National and Kapodistrian University of Athens Medical School, Athens, Greece
- Biomedical Research Foundation of the Academy of Athens, Athens, Greece
- Laboratory of Clinical Pharmacology and Therapeutics, Faculdade de Medicina, Universidade de Lisboa, Lisbon, Portugal
| | - Joaquim J Ferreira
- Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Lisbon, Portugal
- CNS-Campus Neurológico, Torres Vedras, Portugal
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15
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Wang S, Wu T, Cai Y, Yu Y, Chen X, Wang L. Neuromelanin magnetic resonance imaging of substantia nigra and locus coeruleus in Parkinson's disease with freezing of gait. Front Aging Neurosci 2023; 15:1060935. [PMID: 36819729 PMCID: PMC9932285 DOI: 10.3389/fnagi.2023.1060935] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2022] [Accepted: 01/16/2023] [Indexed: 02/05/2023] Open
Abstract
Background The downregulation of monoamines, especially dopamine in substantia nigra (SN) and norepinephrine in locus coeruleus (LC), may be responsible for freezing of gait (FOG) pathological basis in Parkinson's disease (PD). Methods Thirty-two Parkinson's disease patients with freezing of gait (PD-FOG), 32 Parkinson's disease patients without freezing of gait (PD-NFOG) and 32 healthy controls (HC) underwent neuromelanin magnetic resonance imaging (NM-MRI). The volume, surface area and contrast to noise ratio (CNR) of SN and LC were measured and compared. The correlation analyses were conducted between the measurements of SN and LC with clinical symptoms. We plotted the receiver operating characteristic (ROC) curve and determined the sensitivity and specificity of the CNR of SN and LC for discriminating the PD-FOG from the PD-NFOG. Results Both PD-FOG and PD-NFOG showed decreased volume, surface area and CNR of SN compared with HC. The PD-FOG exhibited decreased volume and surface area of LC compared with both PD-NFOG and HC groups, and decreased CNR of LC compared with HC group. The volume, surface area and CNR of SN were negatively correlated with the Unified Parkinson's Disease Rating Scale part III scores. The illness durations in PD patients were negatively correlated with the volume, surface area of SN, while not the CNR. And the volume and surface area of LC were negatively correlated with new freezing of gait questionnaire scores. ROC analyses indicated that the area under the curve (AUC) was 0.865 and 0.713 in the CNR of SN and LC, respectively, in PD versus HC, whereas it was 0.494 and 0.637 respectively, in PD-FOG versus PD-NFOG. Among these, for discriminating the PD from the HC, the sensitivity and specificity in the CNR of the SN was 90.6 and 71.9%, respectively, when the cut-off value was set at 2.101; the sensitivity and specificity in the CNR of the LC was 90.6 and 50.0%, respectively, when the cut-off value for CNR was set at 1.411. Conclusion The dopaminergic changes in the SN were found across both PD-FOG and PD-NFOG, whilst LC noradrenergic neuron reduction was more evident in PD-FOG.
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Affiliation(s)
- Shangpei Wang
- Department of Radiology, The Second Hospital of Anhui Medical University, Hefei, Anhui, China
| | - Tong Wu
- Department of Neurology, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
| | - Yajie Cai
- Department of Radiology, The Second Hospital of Anhui Medical University, Hefei, Anhui, China
| | - Yongqiang Yu
- Department of Radiology, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China,*Correspondence: Yongqiang Yu, ✉
| | - Xianwen Chen
- Department of Neurology, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China,Xianwen Chen, ✉
| | - Longsheng Wang
- Department of Radiology, The Second Hospital of Anhui Medical University, Hefei, Anhui, China,Longsheng Wang, ✉
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Hu R, Gao B, Tian S, Liu Y, Jiang Y, Li W, Li Y, Song Q, Wang W, Miao Y. Regional high iron deposition on quantitative susceptibility mapping correlates with cognitive decline in type 2 diabetes mellitus. Front Neurosci 2023; 17:1061156. [PMID: 36793541 PMCID: PMC9922715 DOI: 10.3389/fnins.2023.1061156] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2022] [Accepted: 01/10/2023] [Indexed: 01/31/2023] Open
Abstract
Objective To quantitatively evaluate the iron deposition and volume changes in deep gray nuclei according to threshold-method of quantitative susceptibility mapping (QSM) acquired by strategically acquired gradient echo (STAGE) sequence, and to analyze the correlation between the magnetic susceptibility values (MSV) and cognitive scores in type 2 diabetes mellitus (T2DM) patients. Methods Twenty-nine patients with T2DM and 24 healthy controls (HC) matched by age and gender were recruited in this prospective study. QSM images were used to evaluate whole-structural volumes (Vwh), regional magnetic susceptibility values (MSVRII), and volumes (VRII) in high-iron regions in nine gray nuclei. All QSM data were compared between groups. Receiver operating characteristic (ROC) analysis was used to assess the discriminating ability between groups. The predictive model from single and combined QSM parameters was also established using logistic regression analysis. The correlation between MSVRII and cognitive scores was further analyzed. Multiple comparisons of all statistical values were corrected by false discovery rate (FDR). A statistically significant P-value was set at 0.05. Results Compared with HC group, the MSVRII of all gray matter nuclei in T2DM were increased by 5.1-14.8%, with significant differences found in bilateral head of caudate nucleus (HCN), right putamen (PUT), right globus pallidus (GP), and left dentate nucleus (DN) (P < 0.05). The Vwh of most gray nucleus in T2DM group were decreased by 1.5-16.9% except bilateral subthalamic nucleus (STN). Significant differences were found in bilateral HCN, bilateral red nucleus (RN), and bilateral substantia nigra (SN) (P < 0.05). VRII was increased in bilateral GP, bilateral PUT (P < 0.05). VRII/Vwh was also increased in bilateral GP, bilateral PUT, bilateral SN, left HCN and right STN (P < 0.05). Compared with the single QSM parameter, the combined parameter showed the largest area under curve (AUC) of 0.86, with a sensitivity of 87.5% and specificity of 75.9%. The MSVRII in the right GP was strongly associated with List A Long-delay free recall (List A LDFR) scores (r = -0.590, P = 0.009). Conclusion In T2DM patients, excessive and heterogeneous iron deposition as well as volume loss occurs in deep gray nuclei. The MSV in high iron regions can better evaluate the distribution of iron, which is related to the decline of cognitive function.
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17
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Langley J, Hwang KS, Hu XP, Huddleston DE. Nigral volumetric and microstructural measures in individuals with scans without evidence of dopaminergic deficit. Front Neurosci 2022; 16:1048945. [PMID: 36507343 PMCID: PMC9731284 DOI: 10.3389/fnins.2022.1048945] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2022] [Accepted: 10/28/2022] [Indexed: 11/25/2022] Open
Abstract
Introduction Striatal dopamine transporter (DAT) imaging using 123I-ioflupane single photon positron emitted computed tomography (SPECT) (DaTScan, GE) identifies 5-20% of newly diagnosed Parkinson's disease (PD) subjects enrolling in clinical studies to have scans without evidence of dopaminergic deficit (SWEDD). These individuals meet diagnostic criteria for PD, but do not clinically progress as expected, and they are not believed to have neurodegenerative Parkinsonism. Inclusion of SWEDD participants in PD biomarker studies or therapeutic trials may therefore cause them to fail. DaTScan can identify SWEDD individuals, but it is expensive and not widely available; an alternative imaging approach is needed. Here, we evaluate the use of neuromelanin-sensitive, iron-sensitive, and diffusion contrasts in substantia nigra pars compacta (SNpc) to differentiate SWEDD from PD individuals. Methods Neuromelanin-sensitive, iron-sensitive, and diffusion imaging data for SWEDD, PD, and control subjects were downloaded from the Parkinson's progression markers initiative (PPMI) database. SNpc volume, SNpc iron (R 2), and SNpc free water (FW) were measured for each participant. Results Significantly smaller SNpc volume was seen in PD as compared to SWEDD (P < 10-3) and control (P < 10-3) subjects. SNpc FW was elevated in the PD group relative to controls (P = 0.017). No group difference was observed in SNpc R 2. Conclusion In conclusion, nigral volume and FW in the SWEDD group were similar to that of controls, while a reduction in nigral volume and increased FW were observed in the PD group relative to SWEDD and control participants. These results suggest that these MRI measures should be explored as a cost-effective alternative to DaTScan for evaluation of the nigrostriatal system.
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Affiliation(s)
- Jason Langley
- Center for Advanced Neuroimaging, University of California, Riverside, Riverside, CA, United States
| | - Kristy S. Hwang
- Department of Neurosciences, University of California, San Diego, San Diego, CA, United States
| | - Xiaoping P. Hu
- Center for Advanced Neuroimaging, University of California, Riverside, Riverside, CA, United States
- Department of Bioengineering, University of California, Riverside, Riverside, CA, United States
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18
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Naji N, Lauzon ML, Seres P, Stolz E, Frayne R, Lebel C, Beaulieu C, Wilman AH. Multisite reproducibility of quantitative susceptibility mapping and effective transverse relaxation rate in deep gray matter at 3 T using locally optimized sequences in 24 traveling heads. NMR IN BIOMEDICINE 2022; 35:e4788. [PMID: 35704837 DOI: 10.1002/nbm.4788] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/01/2022] [Revised: 05/28/2022] [Accepted: 06/05/2022] [Indexed: 06/15/2023]
Abstract
Iron concentration in the human brain plays a crucial role in several neurodegenerative diseases and can be monitored noninvasively using quantitative susceptibility mapping (QSM) and effective transverse relaxation rate (R2 *) mapping from multiecho T2 *-weighted images. Large population studies enable better understanding of pathologies and can benefit from pooling multisite data. However, reproducibility may be compromised between sites and studies using different hardware and sequence protocols. This work investigates QSM and R2 * reproducibility at 3 T using locally optimized sequences from three centers and two vendors, and investigates possible reduction of cross-site variability through postprocessing approaches. Twenty-four healthy subjects traveled between three sites and were scanned twice at each site. Scan-rescan measurements from seven deep gray matter regions were used for assessing within-site and cross-site reproducibility using intraclass correlation coefficient (ICC) and within-subject standard deviation (SDw) measures. In addition, multiple QSM and R2 * postprocessing options were investigated with the aim to minimize cross-site sequence-related variations, including: mask generation approach, echo-timing selection, harmonizing spatial resolution, field map estimation, susceptibility inversion method, and linear field correction for magnitude images. The same-subject cross-site region of interest measurements for QSM and R2 * were highly correlated (R2 ≥ 0.94) and reproducible (mean ICC of 0.89 and 0.82 for QSM and R2 *, respectively). The mean cross-site SDw was 4.16 parts per billion (ppb) for QSM and 1.27 s-1 for R2 *. For within-site measurements of QSM and R2 *, the mean ICC was 0.97 and 0.87 and mean SDw was 2.36 ppb and 0.97 s-1 , respectively. The precision level is regionally dependent and is reduced in the frontal lobe, near brain edges, and in white matter regions. Cross-site QSM variability (mean SDw) was reduced up to 46% through postprocessing approaches, such as masking out less reliable regions, matching available echo timings and spatial resolution, avoiding the use of the nonconsistent magnitude contrast between scans in field estimation, and minimizing streaking artifacts.
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Affiliation(s)
- Nashwan Naji
- Department of Biomedical Engineering, University of Alberta, Edmonton, Alberta, Canada
| | - M Louis Lauzon
- Departments of Radiology and Clinical Neurosciences, Hotchkiss Brain Institute, University of Calgary, Calgary, Alberta, Canada
- Seaman Family MR Research Centre, Foothills Medical Centre, Calgary, Alberta, Canada
| | - Peter Seres
- Department of Biomedical Engineering, University of Alberta, Edmonton, Alberta, Canada
| | - Emily Stolz
- Department of Biomedical Engineering, University of Alberta, Edmonton, Alberta, Canada
| | - Richard Frayne
- Departments of Radiology and Clinical Neurosciences, Hotchkiss Brain Institute, University of Calgary, Calgary, Alberta, Canada
- Seaman Family MR Research Centre, Foothills Medical Centre, Calgary, Alberta, Canada
| | - Catherine Lebel
- Department of Radiology, Alberta Children's Hospital Research Institute and Hotchkiss Brain Institute, University of Calgary, Calgary, Alberta, Canada
| | - Christian Beaulieu
- Department of Biomedical Engineering, University of Alberta, Edmonton, Alberta, Canada
| | - Alan H Wilman
- Department of Biomedical Engineering, University of Alberta, Edmonton, Alberta, Canada
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19
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Khedher L, Bonny JM, Marques A, Durand E, Pereira B, Chupin M, Vidal T, Chassain C, Defebvre L, Carriere N, Fraix V, Moro E, Thobois S, Metereau E, Mangone G, Vidailhet M, Corvol JC, Lehéricy S, Menjot de Champfleur N, Geny C, Spampinato U, Meissner W, Frismand S, Schmitt E, Doé de Maindreville A, Portefaix C, Remy P, Fénelon G, Luc Houeto J, Colin O, Rascol O, Peran P, Durif F, R study group. Intrasubject subcortical quantitative referencing to boost MRI sensitivity to Parkinson's disease. Neuroimage Clin 2022; 36:103231. [PMID: 36279753 PMCID: PMC9668635 DOI: 10.1016/j.nicl.2022.103231] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2022] [Revised: 10/10/2022] [Accepted: 10/10/2022] [Indexed: 11/06/2022]
Abstract
Several postmortem studies have shown iron accumulation in the substantia nigra of Parkinson's disease patients. Iron concentration can be estimated via MRI-R2∗ mapping. To assess the changes in R2∗ occurring in Parkinson's disease patients compared to controls, a multicentre transversal study was carried out on a large cohort of Parkinson's disease patients (n = 163) with matched controls (n = 82). In this study, 44 patients and 11 controls were removed due to motion artefacts, 21 patient and 6 controls to preserve matching. Thus, 98 patients and 65 age and sex-matched healthy subjects were selected with enough image quality. The study was conducted on patients with early to late stage Parkinson's disease. The images were acquired at 3Tesla in 12 clinical centres. R2∗ values were measured in subcortical regions of interest (substantia nigra, red nucleus, striatum, globus pallidus externus and globus pallidus internus) contralateral (dominant side) and ipsilateral (non dominant side) to the most clinically affected hemibody. As the observed inter-subject R2∗ variability was significantly higher than the disease effect, an original strategy (intrasubject subcortical quantitative referencing, ISQR) was developed using the measurement of R2∗ in the red nucleus as an intra-subject reference. R2∗ values significantly increased in Parkinson's disease patients when compared with controls; in the substantia nigra (SN) in the dominant side (D) and in the non dominant side (ND), respectively (PSN_D and PSN_ND < 0.0001). After stratification into four subgroups according to the disease duration, no significant R2∗ difference was found in all regions of interest when comparing Parkinson's disease subgroups. By applying our ISQR strategy, R2(ISQR)∗ values significantly increased in the substantia nigra (PSN_D and PSN_ND < 0.0001) when comparing all Parkinson's disease patients to controls. R2(ISQR)∗ values in the substantia nigra significantly increased with the disease duration (PSN_D = 0.01; PSN_ND = 0.03) as well as the severity of the disease (Hoehn & Yahr scale <2 and ≥ 2, PSN_D = 0.02). Additionally, correlations between R2(ISQR)∗ and clinical features, mainly related to the severity of the disease, were found. Our results support the use of ISQR to reduce variations not directly related to Parkinson's disease, supporting the concept that ISQR strategy is useful for the evaluation of Parkinson's disease.
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Affiliation(s)
- Laila Khedher
- University Clermont Auvergne, CNRS, Clermont Auvergne INP, Institut Pascal, Clermont-Ferrand, France,AgroResonance, INRAE, 2018. Nuclear Magnetic Resonance Facility for Agronomy, Food and Health, doi: 10.15454/1.5572398324758228E12, France,Corresponding author at: AgroResonance, INRAE, UR370 QuaPA, Saint-Genès-Champanelle F-63122, France.
| | - Jean-Marie Bonny
- AgroResonance, INRAE, 2018. Nuclear Magnetic Resonance Facility for Agronomy, Food and Health, doi: 10.15454/1.5572398324758228E12, France,AgroResonance UR370 QuaPA - INRAE, Saint-Genès-Champanelle 63122, France
| | - Ana Marques
- University Clermont Auvergne, CNRS, Clermont Auvergne INP, Institut Pascal, Clermont-Ferrand, France,Clermont-Ferrand University Hospital, Neurology Department and NS-PARK/FCRIN Network, Clermont-Ferrand, France
| | - Elodie Durand
- University Clermont Auvergne, CNRS, Clermont Auvergne INP, Institut Pascal, Clermont-Ferrand, France,Clermont-Ferrand University Hospital, Neurology Department and NS-PARK/FCRIN Network, Clermont-Ferrand, France
| | - Bruno Pereira
- Clermont-Ferrand University Hospital, Biostatistics Unit (DRCI), Clermont-Ferrand, France
| | - Marie Chupin
- Sorbonne Université, Institut du Cerveau - ICM, CATI, Assistance Publique Hôpitaux de Paris, Inserm, CNRS, Département de Neurologie and NS-PARK/FCRIN Network, CIC Neurosciences, Hôpital Pitié-Salpêtrière, Paris, France
| | - Tiphaine Vidal
- University Clermont Auvergne, CNRS, Clermont Auvergne INP, Institut Pascal, Clermont-Ferrand, France,Clermont-Ferrand University Hospital, Neurology Department and NS-PARK/FCRIN Network, Clermont-Ferrand, France
| | - Carine Chassain
- University Clermont Auvergne, CNRS, Clermont Auvergne INP, Institut Pascal, Clermont-Ferrand, France,Clermont-Ferrand University Hospital, Neurology Department and NS-PARK/FCRIN Network, Clermont-Ferrand, France
| | - Luc Defebvre
- Department of Movement Disorder and NS-PARK/FCRIN Network, Inserm 1172 University of Lille, Lille, France
| | - Nicolas Carriere
- Department of Movement Disorder and NS-PARK/FCRIN Network, Inserm 1172 University of Lille, Lille, France
| | - Valerie Fraix
- Service de Neurologie, CHU de Grenoble and NS-PARK/FCRIN Network, Université Grenoble Alpes, Grenoble Institute of Neuroscience, Grenoble, France
| | - Elena Moro
- Service de Neurologie, CHU de Grenoble and NS-PARK/FCRIN Network, Université Grenoble Alpes, Grenoble Institute of Neuroscience, Grenoble, France
| | - Stéphane Thobois
- CNRS, Institut des Sciences Cognitives Marc Jeannerod, UMR 5229 CNRS, Lyon, France,Université Claude Bernard, Lyon I, Lyon, France,Hospices Civils de Lyon, Hôpital Neurologique Pierre Wertheimer, Service de Neurologie C and NS-PARK/FCRIN Network, Lyon, France
| | - Elise Metereau
- CNRS, Institut des Sciences Cognitives Marc Jeannerod, UMR 5229 CNRS, Lyon, France,Université Claude Bernard, Lyon I, Lyon, France,Hospices Civils de Lyon, Hôpital Neurologique Pierre Wertheimer, Service de Neurologie C and NS-PARK/FCRIN Network, Lyon, France
| | - Graziella Mangone
- Sorbonne Université, Institut du Cerveau - ICM, Assistance Publique Hôpitaux de Paris, Inserm, CNRS, Département de Neurologie and NS-PARK/FCRIN Network, CIC Neurosciences, Hôpital Pitié-Salpêtrière, Paris, France
| | - Marie Vidailhet
- Sorbonne Université, Institut du Cerveau - ICM, Assistance Publique Hôpitaux de Paris, Inserm, CNRS, Département de Neurologie and NS-PARK/FCRIN Network, CIC Neurosciences, Hôpital Pitié-Salpêtrière, Paris, France
| | - Jean-Christophe Corvol
- Sorbonne Université, Institut du Cerveau - ICM, Assistance Publique Hôpitaux de Paris, Inserm, CNRS, Département de Neurologie and NS-PARK/FCRIN Network, CIC Neurosciences, Hôpital Pitié-Salpêtrière, Paris, France
| | - Stéphane Lehéricy
- Sorbonne Université, Institut du Cerveau - ICM, Assistance Publique Hôpitaux de Paris, Inserm, CNRS, Département de Neurologie and NS-PARK/FCRIN Network, CIC Neurosciences, Hôpital Pitié-Salpêtrière, Paris, France
| | - Nicolas Menjot de Champfleur
- Department of Neuroradiology, Montpellier University Hospital Center, Gui de Chauliac Hospital, Montpellier, France,I2FH, Institut d'Imagerie Fonctionnelle Humaine, Hôpital Gui de Chauliac, CHRU de Montpellier, Montpellier, France
| | - Christian Geny
- Department of Geriatrics and NS-PARK/FCRIN Network, Montpellier University Hospital, Montpellier University, Montpellier, France,EuroMov Laboratory, University of Montpellier, 700 Avenue du Pic Saint Loup, Montpellier, Montpellier 34090, France
| | - Umberto Spampinato
- Service de Neurologie - Maladies Neurodégénératives and NS-PARK/FCRIN Network, CHU Bordeaux, Bordeaux F-33000, France
| | - Wassilios Meissner
- Service de Neurologie - Maladies Neurodégénératives and NS-PARK/FCRIN Network, CHU Bordeaux, Bordeaux F-33000, France,Univ. Bordeaux, CNRS, IMN, UMR 5293, Bordeaux, Bordeaux F-33000, France,Dept. Medicine, University of Otago, Christchurch, and New Zealand Brain Research Institute, Christchurch, New Zealand
| | - Solène Frismand
- Service de Neurologie and NS-PARK/FCRIN Network, CHRU-Nancy, Nancy, France
| | - Emmanuelle Schmitt
- Service de Neurologie and NS-PARK/FCRIN Network, CHRU-Nancy, Nancy, France
| | | | - Christophe Portefaix
- Department of Radiology, Hôpital Maison blanche, Reims, France,CReSTIC Laboratory (EA 3804), University of Reims Champagne-Ardenne, Reims, France
| | - Philippe Remy
- Centre Expert Parkinson and NS-PARK/FCRIN Network, CHU Henri Mondor, AP-HP et Equipe Neuropsychologie Interventionnelle, INSERM-IMRB, Faculté de Santé, Université Paris-Est Créteil et Ecole Normale Supérieure Paris Sorbonne Université, Créteil, France
| | - Gilles Fénelon
- Centre Expert Parkinson and NS-PARK/FCRIN Network, CHU Henri Mondor, AP-HP et Equipe Neuropsychologie Interventionnelle, INSERM-IMRB, Faculté de Santé, Université Paris-Est Créteil et Ecole Normale Supérieure Paris Sorbonne Université, Créteil, France
| | - Jean Luc Houeto
- INSERM, CHU de Poitiers, Université de Poitiers, Centre d’Investigation Clinique CIC1402, Service de Neurologie and NS-PARK/FCRIN Network, Poitiers, France – CHU - Centre Expert Parkinson de Limoges, Limoges, France
| | - Olivier Colin
- INSERM, CHU de Poitiers, Université de Poitiers, Centre d’Investigation Clinique CIC1402, Service de Neurologie and NS-PARK/FCRIN Network, Poitiers, France– CH Brive la Gaillarde, France
| | - Olivier Rascol
- Centre d'Investigation Clinique CIC 1436, UMR 1214 TONIC and NS-PARK/FCRIN Network, INSERM, CHU de Toulouse et Université de Toulouse3, Toulouse, France
| | - Patrice Peran
- Centre d'Investigation Clinique CIC 1436, UMR 1214 TONIC and NS-PARK/FCRIN Network, INSERM, CHU de Toulouse et Université de Toulouse3, Toulouse, France
| | - Franck Durif
- University Clermont Auvergne, CNRS, Clermont Auvergne INP, Institut Pascal, Clermont-Ferrand, France,Clermont-Ferrand University Hospital, Neurology Department and NS-PARK/FCRIN Network, Clermont-Ferrand, France
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20
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Rong Y, Xu Z, Zhu Y, Zhang X, Lai L, Sun S, Gao M, Guo P, Zhang G, Geng Y, Ma X, Wu S, Yang L, Shen Z, Guan J. Combination of Quantitative Susceptibility Mapping and Diffusion Kurtosis Imaging Provides Potential Biomarkers for Early-Stage Parkinson's Disease. ACS Chem Neurosci 2022; 13:2699-2708. [PMID: 36047877 DOI: 10.1021/acschemneuro.2c00321] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023] Open
Abstract
Purpose: This study aimed to detect changes in iron deposition and neural microstructure in the substantia nigra (SN), red nucleus (RN), and basal ganglia of Parkinson's disease (PD) patients at different stages using quantitative susceptibility mapping and diffusion kurtosis imaging to identify potential indicators of early-stage PD. Methods: We enrolled 20 early-stage and 15 late-stage PD patients, as well as 20 age- and sex-matched controls. All participants underwent quantitative susceptibility mapping and diffusion kurtosis imaging to determine magnetic susceptibility (MS), fractional anisotropy (FA), mean diffusivity (MD), and mean kurtosis (MK) in several brain regions. Results: Compared with the control group, MS and MK values in the SN were significantly increased in the early- and late-stage PD group, whereas MS values in the red nucleus (RN), globus pallidus (GP), and caudate nucleus (CN), FA value in the CN and GP, and MK value in the CN and putamen (PU) were significantly increased in the late-stage PD group. There were positive correlations between MS and MK values in the CN and MS and FA values in the GP. Furthermore, the combination of MS and MK values in the SN provided high accuracy for distinguishing early-stage PD patients from controls. Conclusions: This study identified MS and MK in the SN as potential indicators of early-stage PD.
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Affiliation(s)
- Yunjie Rong
- Department of Ultrasound, Foshan Women and Children's Hospital Affiliated to Southern Medical University, Foshan 528000, China
| | - Zhifeng Xu
- Department of Radiology, The First People's Hospital of Foshan, Foshan 528041, China
| | - Ye Zhu
- Department of Radiology, The First People's Hospital of Foshan, Foshan 528041, China
| | - Xianhai Zhang
- Department of Radiology, The First People's Hospital of Foshan, Foshan 528041, China
| | - Lingfeng Lai
- Department of Radiology, The Second Affiliated Hospital of Shantou University Medical College, Shantou 515041, China
| | - Shuyi Sun
- Department of Radiology, The Second Affiliated Hospital of Shantou University Medical College, Shantou 515041, China
| | - Mingyong Gao
- Department of Radiology, The First People's Hospital of Foshan, Foshan 528041, China
| | - Pi Guo
- Laboratory of Statistics, Shantou University Medical College, Shantou 515041, China
| | - Guohua Zhang
- Department of Neurology, The First People's Hospital of Foshan, Foshan 528041, China
| | - Yiqun Geng
- Laboratory of Molecular Pathology, Shantou University Medical College, Shantou 515041, China
- Provincial Key Laboratory of Infectious Diseases and Molecular Immunopathology, Shantou 515041, Guangdong, China
| | - Xilun Ma
- Department of Radiology, The First Affiliated Hospital of Shantou University Medical College, Shantou 515000, China
| | - Shuohua Wu
- Department of Radiology, The Second Affiliated Hospital of Shantou University Medical College, Shantou 515041, China
| | - Lin Yang
- Department of Radiology, The Second Affiliated Hospital of Shantou University Medical College, Shantou 515041, China
| | | | - Jitian Guan
- Department of Radiology, The Second Affiliated Hospital of Shantou University Medical College, Shantou 515041, China
- Provincial Key Laboratory of Infectious Diseases and Molecular Immunopathology, Shantou 515041, Guangdong, China
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21
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Arribarat G, Cartiaux B, Boucher S, Montel C, Gros-Dagnac H, Fave Y, Péran P, Mogicato G, Deviers A. Ex vivo susceptibility-weighted imaging anatomy of canine brain–comparison of imaging and histological sections. Front Neuroanat 2022; 16:948159. [PMID: 36124091 PMCID: PMC9481421 DOI: 10.3389/fnana.2022.948159] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2022] [Accepted: 08/17/2022] [Indexed: 11/13/2022] Open
Abstract
Now that access of large domestic mammals to high-field MRI becomes more common, techniques initially implemented for human patients can be used for the structural and functional study of the brain of these animals. Among them, susceptibility-weighted imaging (SWI) is a recent technique obtained from gradient echo (GE) imaging that allow for an excellent anatomical tissue contrast and a non-invasive assessment of brain iron content. The goal of this study was to design an optimal GE SWI imaging protocol to be used in dogs undergoing an MRI examination of the brain in a 3-Tesla scanner. This imaging protocol was applied to ex vivo brains from four dogs. The imaging protocol was validated by visual inspection of the SWI images that provided a high anatomical detail, as demonstrated by their comparison with corresponding microscopic sections. As resolvable brain structures were labeled, this study is the first to provide an anatomic description of SWI images of the canine brain. Once validated in living animals, this GE SWI imaging protocol could be easily included in routine neuroimaging protocols to improve the diagnosis of various intracranial diseases of dogs, or be used in future comparative studies aiming at evaluating brain iron content in animals.
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Affiliation(s)
- Germain Arribarat
- ToNIC, Toulouse NeuroImaging Center, Université de Toulouse, INSERM, UPS, Toulouse, France
| | - Benjamin Cartiaux
- ToNIC, Toulouse NeuroImaging Center, Université de Toulouse, INSERM, UPS, ENVT, Toulouse, France
| | - Samuel Boucher
- ToNIC, Toulouse NeuroImaging Center, Université de Toulouse, INSERM, UPS, Toulouse, France
| | - Charles Montel
- ToNIC, Toulouse NeuroImaging Center, Université de Toulouse, INSERM, UPS, ENVT, Toulouse, France
| | - Hélène Gros-Dagnac
- ToNIC, Toulouse NeuroImaging Center, Université de Toulouse, INSERM, UPS, Toulouse, France
| | - Yoann Fave
- ToNIC, Toulouse NeuroImaging Center, Université de Toulouse, INSERM, UPS, Toulouse, France
| | - Patrice Péran
- ToNIC, Toulouse NeuroImaging Center, Université de Toulouse, INSERM, UPS, Toulouse, France
| | - Giovanni Mogicato
- ToNIC, Toulouse NeuroImaging Center, Université de Toulouse, INSERM, UPS, ENVT, Toulouse, France
- *Correspondence: Giovanni Mogicato
| | - Alexandra Deviers
- ToNIC, Toulouse NeuroImaging Center, Université de Toulouse, INSERM, UPS, ENVT, Toulouse, France
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22
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Du G, Wang E, Sica C, Chen H, De Jesus S, Lewis MM, Kong L, Connor J, Mailman RB, Huang X. Dynamics of Nigral Iron Accumulation in Parkinson's Disease: From Diagnosis to Late Stage. Mov Disord 2022; 37:1654-1662. [PMID: 35614551 PMCID: PMC9810258 DOI: 10.1002/mds.29062] [Citation(s) in RCA: 28] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2022] [Revised: 04/08/2022] [Accepted: 05/02/2022] [Indexed: 01/05/2023] Open
Abstract
BACKGROUND Higher nigral iron has been reported in Parkinson's disease (PD). OBJECTIVE The aim is to understand the dynamics of nigral iron accumulation in PD and its association with drug treatment. METHODS Susceptibility magnetic resonance imaging data were obtained from 79 controls and 18 drug-naive (PDDN ) and 87 drug-treated (PDDT ) PD patients. Regional brain iron in basal ganglia and cerebellar structures was estimated using quantitative susceptibility mapping. Nigral iron was compared between PDDN and PDDT subgroups defined by disease duration (early [PDE, <2 years], middle [PDM, 2-6 years], and later [PDL, >6 years]). Associations with both disease duration and types of antiparkinson drugs were explored using regression analysis. RESULTS Compared to controls, PDDN had lower iron in the substantia nigra (P = 0.018), caudate nucleus (P = 0.038), and globus pallidus (P = 0.01) but not in the putamen or red nucleus. In contrast, PDDT had higher iron in the nigra (P < 0.001) but not in other regions, compared to either controls or PDDN . Iron in the nigra increased with disease duration (PDE > PDDN [P = 0.001], PDM > PDE [P = 0.045]) except for PDM versus PDL (P = 0.226). Levodopa usage was associated with higher (P = 0.013) nigral iron, whereas lower nigral iron was correlated with selegiline usage (P = 0.030). CONCLUSION Nigral iron is lower before the start of dopaminergic medication and then increases throughout the disease until it plateaus at late stages, suggesting increased iron may not be an etiological factor. Interestingly, PD medications may have differential associations with iron accumulation that need further investigation. © 2022 International Parkinson and Movement Disorder Society.
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Affiliation(s)
- Guangwei Du
- Department of Neurology, Penn State Milton S. Hershey Medical Center, Hershey PA 17033
- Department of Radiology, Penn State Milton S. Hershey Medical Center, Hershey PA 17033
| | - Ernest Wang
- Department of Neurology, Penn State Milton S. Hershey Medical Center, Hershey PA 17033
| | - Christopher Sica
- Department of Radiology, Penn State Milton S. Hershey Medical Center, Hershey PA 17033
| | - Hairong Chen
- Department of Neurology, Penn State Milton S. Hershey Medical Center, Hershey PA 17033
| | - Sol De Jesus
- Department of Neurology, Penn State Milton S. Hershey Medical Center, Hershey PA 17033
| | - Mechelle M. Lewis
- Department of Neurology, Penn State Milton S. Hershey Medical Center, Hershey PA 17033
- Department of Pharmacology, Pennsylvania State College of Medicine, Hershey, PA 17033
| | - Lan Kong
- School of Public Health Sciences, Pennsylvania State College of Medicine, Hershey, PA 17033
| | - James Connor
- Department of Neurosurgery, Penn State Milton S. Hershey Medical Center, Hershey PA 17033
| | - Richard B. Mailman
- Department of Neurology, Penn State Milton S. Hershey Medical Center, Hershey PA 17033
- Department of Pharmacology, Pennsylvania State College of Medicine, Hershey, PA 17033
| | - Xuemei Huang
- Department of Neurology, Penn State Milton S. Hershey Medical Center, Hershey PA 17033
- Department of Pharmacology, Pennsylvania State College of Medicine, Hershey, PA 17033
- Department of Kinesiology, Pennsylvania State University, University Park PA 16802
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23
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David S, Jhelum P, Ryan F, Jeong SY, Kroner A. Dysregulation of Iron Homeostasis in the Central Nervous System and the Role of Ferroptosis in Neurodegenerative Disorders. Antioxid Redox Signal 2022; 37:150-170. [PMID: 34569265 DOI: 10.1089/ars.2021.0218] [Citation(s) in RCA: 78] [Impact Index Per Article: 26.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Significance: Iron accumulation occurs in the central nervous system (CNS) in a variety of neurological conditions as diverse as spinal cord injury, stroke, multiple sclerosis, Parkinson's disease, and others. Iron is a redox-active metal that gives rise to damaging free radicals if its intracellular levels are not controlled or if it is not properly sequestered within cells. The accumulation of iron occurs due to dysregulation of mechanisms that control cellular iron homeostasis. Recent Advances: The molecular mechanisms that regulate cellular iron homeostasis have been revealed in much detail in the past three decades, and new advances continue to be made. Understanding which aspects of iron homeostasis are dysregulated in different conditions will provide insights into the causes of iron accumulation and iron-mediated tissue damage. Recent advances in iron-dependent lipid peroxidation leading to cell death, called ferroptosis, has provided useful insights that are highly relevant for the lipid-rich environment of the CNS. Critical Issues: This review examines the mechanisms that control normal cellular iron homeostasis, the dysregulation of these mechanisms in neurological disorders, and more recent work on how iron can induce tissue damage via ferroptosis. Future Directions: Quick and reliable tests are needed to determine if and when ferroptosis contributes to the pathogenesis of neurological disorders. In addition, there is need to develop better druggable agents to scavenge lipid radicals and reduce CNS damage for neurological conditions for which there are currently few effective treatments. Antioxid. Redox Signal. 37, 150-170.
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Affiliation(s)
- Samuel David
- Centre for Research in Neuroscience, The Research Institute of the McGill University Health Centre, Montreal, Canada
| | - Priya Jhelum
- Centre for Research in Neuroscience, The Research Institute of the McGill University Health Centre, Montreal, Canada
| | - Fari Ryan
- Centre for Research in Neuroscience, The Research Institute of the McGill University Health Centre, Montreal, Canada
| | - Suh Young Jeong
- Department of Molecular & Medical Genetics, Oregon Health & Science University, Portland, Oregon, USA
| | - Antje Kroner
- Department of Neurosurgery, Medical College of Wisconsin, Milwaukee, Wisconsin, USA
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24
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Wenger E, Polk SE, Kleemeyer MM, Weiskopf N, Bodammer NC, Lindenberger U, Brandmaier AM. Reliability of quantitative multiparameter maps is high for magnetization transfer and proton density but attenuated for R 1 and R 2 * in healthy young adults. Hum Brain Mapp 2022; 43:3585-3603. [PMID: 35397153 PMCID: PMC9248308 DOI: 10.1002/hbm.25870] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2021] [Revised: 03/07/2022] [Accepted: 03/23/2022] [Indexed: 11/24/2022] Open
Abstract
We investigate the reliability of individual differences of four quantities measured by magnetic resonance imaging‐based multiparameter mapping (MPM): magnetization transfer saturation (MT), proton density (PD), longitudinal relaxation rate (R1), and effective transverse relaxation rate (R2*). Four MPM datasets, two on each of two consecutive days, were acquired in healthy young adults. On Day 1, no repositioning occurred and on Day 2, participants were repositioned between MPM datasets. Using intraclass correlation effect decomposition (ICED), we assessed the contributions of session‐specific, day‐specific, and residual sources of measurement error. For whole‐brain gray and white matter, all four MPM parameters showed high reproducibility and high reliability, as indexed by the coefficient of variation (CoV) and the intraclass correlation (ICC). However, MT, PD, R1, and R2* differed markedly in the extent to which reliability varied across brain regions. MT and PD showed high reliability in almost all regions. In contrast, R1 and R2* showed low reliability in some regions outside the basal ganglia, such that the sum of the measurement error estimates in our structural equation model was higher than estimates of between‐person differences. In addition, in this sample of healthy young adults, the four MPM parameters showed very little variability over four measurements but differed in how well they could assess between‐person differences. We conclude that R1 and R2* might carry only limited person‐specific information in some regions of the brain in healthy young adults, and, by implication, might be of restricted utility for studying associations to between‐person differences in behavior in those regions.
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Affiliation(s)
- Elisabeth Wenger
- Center for Lifespan Psychology, Max Planck Institute for Human Development, Berlin, Germany
| | - Sarah E Polk
- Center for Lifespan Psychology, Max Planck Institute for Human Development, Berlin, Germany
| | - Maike M Kleemeyer
- Center for Lifespan Psychology, Max Planck Institute for Human Development, Berlin, Germany
| | - Nikolaus Weiskopf
- Wellcome Centre for Human Neuroimaging, UCL Queen Square Institute of Neurology, University College London, London, UK.,Department of Neurophysics, Max Planck Institute for Human Cognitive and Brain Sciences, Leipzig, Germany.,Felix Bloch Institute for Solid State Physics, Faculty of Physics and Earth Sciences, Leipzig University, Leipzig, Germany
| | - Nils C Bodammer
- Center for Lifespan Psychology, Max Planck Institute for Human Development, Berlin, Germany
| | - Ulman Lindenberger
- Center for Lifespan Psychology, Max Planck Institute for Human Development, Berlin, Germany.,Max Planck UCL Centre for Computational Psychiatry and Ageing Research, Berlin, Germany
| | - Andreas M Brandmaier
- Center for Lifespan Psychology, Max Planck Institute for Human Development, Berlin, Germany.,Max Planck UCL Centre for Computational Psychiatry and Ageing Research, Berlin, Germany.,Department of Psychology, MSB Medical School Berlin, Berlin, Germany
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Lewis MM, Albertson RM, Du G, Kong L, Foy A, Huang X. Parkinson’s Disease Progression and Statins: Hydrophobicity Matters. JOURNAL OF PARKINSON'S DISEASE 2022; 12:821-830. [PMID: 34958045 PMCID: PMC10141621 DOI: 10.3233/jpd-212819] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
Background: Recent randomized clinical trials using hydrophobic statins reported no influence on Parkinson’s disease (PD) clinical progression. Hydrophobicity is a key determinant for blood-brain barrier penetrance. Objective: Investigate a potential effect of statins on PD progression. Methods: Statin use was determined at baseline and subtyped according to hydrophobicity in 125 PD patients participating in the PD Biomarker Program (PDBP, 2012–2015) at our site. Clinical (N = 125) and susceptibility MRI (N = 86) data were obtained at baseline and 18-months. Movement Disorders Society-Unified PD Rating Scales were used to track progression of non-motor (MDS-UPDRS-I) and motor (MDS-UPDRS-II) symptoms, and rater-based scores (MDS-UPDRS-III) of patients in the “on” drug state. R2* values were used to capture pathological progression in the substantia nigra. Associations between statin use, its subtypes, and PD progression were evaluated with linear mixed effect regressions. Results: Compared to statin non-users, overall statin or lipophilic statin use did not significantly influence PD clinical or imaging progression. Hydrophilic statin users, however, demonstrated faster clinical progression of non-motor symptoms [MDS-UPDRS-I (β= 4.8, p = 0.010)] and nigral R2* (β= 3.7, p = 0.043). A similar trend was found for MDS-UPDRS-II (β= 3.9, p = 0.10), but an opposite trend was observed for rater-based MDS-UPDRS-III (β= –7.3, p = 0.10). Compared to lipophilic statin users, hydrophilic statin users also showed significantly faster clinical progression of non-motor symptoms [MDS-UPDRS-I (β= 5.0, p = 0.020)], but R2* did not reach statistical significance (β= 2.5, p = 0.24). Conclusion: This study suggests that hydrophilic, but not lipophilic, statins may be associated with faster PD progression. Future studies may have clinical and scientific implications.
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Affiliation(s)
- Mechelle M. Lewis
- Department of Neurology, Pennsylvania State University Milton S. Hershey Medical Center, Hershey, PA, USA
- Department of Pharmacology, Pennsylvania State University Milton S. Hershey Medical Center, Hershey, PA, USA
| | - Richard M. Albertson
- Department of Neurology, Pennsylvania State University Milton S. Hershey Medical Center, Hershey, PA, USA
| | - Guangwei Du
- Department of Neurology, Pennsylvania State University Milton S. Hershey Medical Center, Hershey, PA, USA
| | - Lan Kong
- Department of Public Health Sciences, Pennsylvania State University Milton S. Hershey Medical Center, Hershey, PA, USA
| | - Andrew Foy
- Department of Public Health Sciences, Pennsylvania State University Milton S. Hershey Medical Center, Hershey, PA, USA
- Department of Medicine, Pennsylvania State University Milton S. Hershey Medical Center, Hershey, PA, USA
| | - Xuemei Huang
- Department of Neurology, Pennsylvania State University Milton S. Hershey Medical Center, Hershey, PA, USA
- Department of Pharmacology, Pennsylvania State University Milton S. Hershey Medical Center, Hershey, PA, USA
- Department of Radiology, Pennsylvania State University Milton S. Hershey Medical Center, Hershey, PA, USA
- Department of Neurosurgery, Pennsylvania State University Milton S. Hershey Medical Center, Hershey, PA, USA
- Department of Kinesiology, Pennsylvania State University Milton S. Hershey Medical Center, Hershey, PA, USA
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Jia F, Li H, Jiao Q, Li C, Fu L, Cui C, Jiang H, Zhang L. Deubiquitylase OTUD3 prevents Parkinson’s disease through stabilizing iron regulatory protein 2. Cell Death Dis 2022; 13:418. [PMID: 35490179 PMCID: PMC9056525 DOI: 10.1038/s41419-022-04704-0] [Citation(s) in RCA: 24] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2021] [Revised: 02/13/2022] [Accepted: 03/02/2022] [Indexed: 11/16/2022]
Abstract
Iron deposits are neuropathological hallmark of Parkinson’s disease (PD). Iron regulatory protein 2 (IRP2) is a key factor in regulating brain iron homeostasis. Although two ubiquitin ligases that promote IRP2 degradation have been identified, the deubiquitylase for stabilization of IRP2 in PD remains undefined. Here, we report OTUD3 (OTU domain-containing protein 3) functions as a deubiquitylase for IRP2, interacts with IRP2 in the cytoplasm, de-polyubiquitylates, and stabilizes IRP2 protein in an iron-independent manner. Depletion of OTUD3 results in a disorder of iron metabolism. OTUD3 knockout mice display nigral iron accumulation, motor deficits, and nigrostriatal dopaminergic neurodegeneration, which resembles the pathology of PD. Consistently, decreased levels of OTUD3 are detected in transgenic PD mice expressing A53T mutant of human α-synuclein. Five single nucleotide polymorphism mutations of OTUD3 are present in cases of sporadic PD or controls, although no significant associations of OTUD3 SNPs with sporadic PD are detected. Taken together, these findings demonstrate that OTUD3 is a bona fide deubiquitylase for IRP2 and plays a critical role in the nigral iron deposits in PD.
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Yang L, Cheng Y, Sun Y, Xuan Y, Niu J, Guan J, Rong Y, Jia Y, Zhuang Z, Yan G, Wu R. Combined Application of Quantitative Susceptibility Mapping and Diffusion Kurtosis Imaging Techniques to Investigate the Effect of Iron Deposition on Microstructural Changes in the Brain in Parkinson's Disease. Front Aging Neurosci 2022; 14:792778. [PMID: 35370619 PMCID: PMC8965454 DOI: 10.3389/fnagi.2022.792778] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2021] [Accepted: 02/23/2022] [Indexed: 02/05/2023] Open
Abstract
OBJECTIVES Brain iron deposition and microstructural changes in brain tissue are associated with Parkinson's disease (PD). However, the correlation between these factors in Parkinson's disease has been little studied. This study aimed to use quantitative susceptibility mapping combined with diffusion kurtosis imaging to investigate the effects of iron deposition on microstructural tissue alterations in the brain. METHODS Quantitative susceptibility mapping and diffusion kurtosis imaging were performed on 24 patients with early PD, 13 patients with advanced PD, and 25 healthy controls. The mean values of magnetic susceptibility and diffusion kurtosis were calculated for the bilateral substantia nigra, red nucleus, putamen, globus pallidus, and caudate nucleus, and compared between the groups. Correlation analyses between the diffusion kurtosis of each nucleus and its magnetic susceptibility parameters in PD patients and healthy controls were performed. RESULTS The study found a significant increase in iron deposition in the substantia nigra, red nucleus, putamen and globus pallidus, bilaterally, in patients with PD. Mean kurtosis values were increased in the substantia nigra but decreased in the globus pallidus; axial kurtosis values were decreased in both the substantia nigra and red nucleus; radial kurtosis values were increased in the substantia nigra but showed an opposite trend in the globus pallidus and caudate nucleus. In the substantia nigra of patients with PD, magnetic susceptibility was positively correlated with mean and radial kurtosis values, and negatively correlated with axial kurtosis. None of these correlations were significantly different in the control group. In the putamen, magnetic susceptibility was positively correlated with mean, axial, and radial kurtosis only in patients with advanced-stage PD. CONCLUSION Our study provides new evidence for brain iron content and microstructural alterations in patients with PD. Iron deposition may be a common mechanism for microstructural alterations in the substantia nigra and putamen of patients with PD. Tracking the dynamic changes in iron content and microstructure throughout the course of PD will help us to better understand the dynamics of iron metabolism and microstructural alterations in the pathogenesis of PD and to develop new approaches to monitor and treat PD.
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Affiliation(s)
- Lin Yang
- Department of Radiology, The Second Affiliated Hospital of Xiamen Medical College, Xiamen, China
- Department of Radiology, The Second Affiliated Hospital, Medical College of Shantou University, Shantou, China
| | - Yan Cheng
- Department of Radiology, The Second Affiliated Hospital, Medical College of Shantou University, Shantou, China
| | - Yongyan Sun
- Department of Pharmacy, Guangdong Second Provincial General Hospital, Zhuhai Hospital, Zhuhai, China
| | - Yinghua Xuan
- Department of Basic Medicine, Xiamen Medical College, Xiamen, China
| | - Jianping Niu
- Department of Neurology, The Second Affiliated Hospital of Xiamen Medical College, Xiamen, China
| | - Jitian Guan
- Department of Radiology, The Second Affiliated Hospital, Medical College of Shantou University, Shantou, China
| | - Yunjie Rong
- Department of Ultrasound, Foshan Women and Children’s Hospital Affiliated to Southern Medical University, Foshan, China
| | - Yanlong Jia
- Department of Radiology, The Second Affiliated Hospital, Medical College of Shantou University, Shantou, China
| | - Zerui Zhuang
- Department of Neurosurgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
| | - Gen Yan
- Department of Radiology, The Second Affiliated Hospital of Xiamen Medical College, Xiamen, China
| | - Renhua Wu
- Department of Radiology, The Second Affiliated Hospital, Medical College of Shantou University, Shantou, China
- Guangdong Provincial Key Laboratory for Breast Cancer Diagnosis and Treatment, Cancer Hospital of Shantou University Medical College, Shantou, China
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Miletić S, Bazin PL, Isherwood SJS, Keuken MC, Alkemade A, Forstmann BU. Charting human subcortical maturation across the adult lifespan with in vivo 7 T MRI. Neuroimage 2022; 249:118872. [PMID: 34999202 DOI: 10.1016/j.neuroimage.2022.118872] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2021] [Revised: 12/20/2021] [Accepted: 01/03/2022] [Indexed: 12/26/2022] Open
Abstract
The human subcortex comprises hundreds of unique structures. Subcortical functioning is crucial for behavior, and disrupted function is observed in common neurodegenerative diseases. Despite their importance, human subcortical structures continue to be difficult to study in vivo. Here we provide a detailed account of 17 prominent subcortical structures and ventricles, describing their approximate iron and myelin contents, morphometry, and their age-related changes across the normal adult lifespan. The results provide compelling insights into the heterogeneity and intricate age-related alterations of these structures. They also show that the locations of many structures shift across the lifespan, which is of direct relevance for the use of standard magnetic resonance imaging atlases. The results further our understanding of subcortical morphometry and neuroimaging properties, and of normal aging processes which ultimately can improve our understanding of neurodegeneration.
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Affiliation(s)
- Steven Miletić
- University of Amsterdam, Department of Psychology, Integrative Model-based Cognitive Neuroscience research unit (IMCN), Nieuwe Achtergracht 129B, Amsterdam 1001 NK, the Netherlands.
| | - Pierre-Louis Bazin
- University of Amsterdam, Department of Psychology, Integrative Model-based Cognitive Neuroscience research unit (IMCN), Nieuwe Achtergracht 129B, Amsterdam 1001 NK, the Netherlands; Max Planck Institute for Human Cognitive and Brain Sciences, Departments of Neurophysics and Neurology, Stephanstraße 1A, Leipzig, Germany
| | - Scott J S Isherwood
- University of Amsterdam, Department of Psychology, Integrative Model-based Cognitive Neuroscience research unit (IMCN), Nieuwe Achtergracht 129B, Amsterdam 1001 NK, the Netherlands
| | - Max C Keuken
- University of Amsterdam, Department of Psychology, Integrative Model-based Cognitive Neuroscience research unit (IMCN), Nieuwe Achtergracht 129B, Amsterdam 1001 NK, the Netherlands
| | - Anneke Alkemade
- University of Amsterdam, Department of Psychology, Integrative Model-based Cognitive Neuroscience research unit (IMCN), Nieuwe Achtergracht 129B, Amsterdam 1001 NK, the Netherlands
| | - Birte U Forstmann
- University of Amsterdam, Department of Psychology, Integrative Model-based Cognitive Neuroscience research unit (IMCN), Nieuwe Achtergracht 129B, Amsterdam 1001 NK, the Netherlands.
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Boas SM, Joyce KL, Cowell RM. The NRF2-Dependent Transcriptional Regulation of Antioxidant Defense Pathways: Relevance for Cell Type-Specific Vulnerability to Neurodegeneration and Therapeutic Intervention. Antioxidants (Basel) 2021; 11:antiox11010008. [PMID: 35052512 PMCID: PMC8772787 DOI: 10.3390/antiox11010008] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2021] [Revised: 12/09/2021] [Accepted: 12/14/2021] [Indexed: 12/11/2022] Open
Abstract
Oxidative stress has been implicated in the etiology and pathobiology of various neurodegenerative diseases. At baseline, the cells of the nervous system have the capability to regulate the genes for antioxidant defenses by engaging nuclear factor erythroid 2 (NFE2/NRF)-dependent transcriptional mechanisms, and a number of strategies have been proposed to activate these pathways to promote neuroprotection. Here, we briefly review the biology of the transcription factors of the NFE2/NRF family in the brain and provide evidence for the differential cellular localization of NFE2/NRF family members in the cells of the nervous system. We then discuss these findings in the context of the oxidative stress observed in two neurodegenerative diseases, Parkinson's disease (PD) and amyotrophic lateral sclerosis (ALS), and present current strategies for activating NFE2/NRF-dependent transcription. Based on the expression of the NFE2/NRF family members in restricted populations of neurons and glia, we propose that, when designing strategies to engage these pathways for neuroprotection, the relative contributions of neuronal and non-neuronal cell types to the overall oxidative state of tissue should be considered, as well as the cell types which have the greatest intrinsic capacity for producing antioxidant enzymes.
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Affiliation(s)
- Stephanie M. Boas
- Department of Neuroscience, Southern Research, 2000 9th Avenue South, Birmingham, AL 35205, USA; (S.M.B.); (K.L.J.)
- Department of Cell, Developmental, and Integrative Biology, University of Alabama at Birmingham, 1720 2nd Avenue South, Birmingham, AL 35294, USA
| | - Kathlene L. Joyce
- Department of Neuroscience, Southern Research, 2000 9th Avenue South, Birmingham, AL 35205, USA; (S.M.B.); (K.L.J.)
- Department of Cell, Developmental, and Integrative Biology, University of Alabama at Birmingham, 1720 2nd Avenue South, Birmingham, AL 35294, USA
| | - Rita M. Cowell
- Department of Neuroscience, Southern Research, 2000 9th Avenue South, Birmingham, AL 35205, USA; (S.M.B.); (K.L.J.)
- Department of Cell, Developmental, and Integrative Biology, University of Alabama at Birmingham, 1720 2nd Avenue South, Birmingham, AL 35294, USA
- Correspondence:
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Al-Okbi SY, Mabrok HB, Al-Siedy ESK, Mohamed RS, Ramadan AA. Iron status, immune system, and expression of brain divalent metal transporter 1 and dopamine receptors D1 interrelationship in Parkinson’s disease and the role of grape seed and green coffee bean extracts and quercetin in mitigating the disease in rats. JOURNAL OF HERBMED PHARMACOLOGY 2021. [DOI: 10.34172/jhp.2022.07] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022] Open
Abstract
Introduction: Parkinson’s disease (PD) is a neurodegenerative disease with a prevalence of 1% in the elderly worldwide. The aim of the research is to study the interrelationship of iron status, the immune system including inflammatory cytokines, brain divalent metal transporter 1 (DMT1), and dopamine receptors D1 (DRD1) in a PD rat model. The potential protective effects of grape seed and green coffee bean ethanol extracts and quercetin were also studied. Methods: Phenolic and flavonoid contents of grape seed and green coffee bean and in vitro free radicals scavenging activities of the extracts and quercetin were determined. Male rats were divided into five groups. Group 1 served as normal control (NC), group 2 represented Parkinsonian control (PC). Groups 3, 4, and 5 were the test groups treated by daily oral green coffee bean, grape seed extracts, and quercetin, respectively. PD was induced by rotenone in groups 2 to 5. Brain oxidative stress, DMT1, and DRD1 expressions, and histopathology were assessed. Parameters of the immune system, represented by plasma interferon-gamma (IFNγ) and CD4, and brain tumor necrosis factor-alpha (TNF-α) along with iron status were also determined. Results: Phenolic and flavonoid contents of green coffee bean were high compared to grape seed (P < 0.05). Quercetin experienced the highest in-vitro free radicals scavenging activities. Iron deficiency anemia, together with elevated IFNγ, TNF-α, DMT1 expressions, and brain malondialdehyde (MDA) were demonstrated in PC compared to NC (P < 0.05). Also, reduction in CD4 and brain reduced-glutathione (GSH) (P < 0.05) were noticed in PC with brain histopathological alterations. Different treatments showed variable improvements in the majority of parameters (P < 0.05) and brain histopathology. Conclusion: Iron deficiency anemia might result from cytokine elevation in PD. Reduced DRD1 and altered immune system including cytokines together with increased brain DMT1 might induce neurodegeneration in PD. Different treatments showed variable neuroprotective effects through modulation of inflammation, oxidative stress, immune system, iron status, DMT1, and DRD1.
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Affiliation(s)
| | - Hoda Bakr Mabrok
- Nutrition and Food Sciences Department, National Research Centre, Cairo, Egypt
| | | | - Rasha Salah Mohamed
- Nutrition and Food Sciences Department, National Research Centre, Cairo, Egypt
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Langley J, Huddleston DE, Hu X. Nigral diffusivity, but not free water, correlates with iron content in Parkinson's disease. Brain Commun 2021; 3:fcab251. [PMID: 34805996 PMCID: PMC8599079 DOI: 10.1093/braincomms/fcab251] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2021] [Revised: 08/18/2021] [Accepted: 09/20/2021] [Indexed: 11/13/2022] Open
Abstract
The loss of melanized neurons in the substantia nigra pars compacta is a primary feature in Parkinson's disease. Iron deposition occurs in conjunction with this loss. Loss of nigral neurons should remove barriers for diffusion and increase diffusivity of water molecules in regions undergoing this loss. In metrics from single-compartment diffusion tensor imaging models, these changes should manifest as increases in mean diffusivity and reductions in fractional anisotropy as well as increases in the free water compartment in metrics derived from bi-compartment models. However, studies examining nigral diffusivity changes from Parkinson's disease with single-compartment models have yielded inconclusive results and emerging evidence in control subjects indicates that iron corrupts diffusivity metrics derived from single-compartment models. We aimed to examine Parkinson's disease-related changes in nigral iron and diffusion measures from single- and bi-compartment models as well as assess the effect of iron on these diffusion measures in two separate Parkinson's cohorts. Iron-sensitive data and diffusion data were analysed in two cohorts: First, a discovery cohort consisting of 71 participants (32 control participants and 39 Parkinson's disease participants) was examined. Second, an external validation cohort, obtained from the Parkinson's Progression Marker's Initiative, consisting of 110 participants (58 control participants and 52 Parkinson's disease participants) was examined. The effect of iron on diffusion measures from single- and bi-compartment models was assessed in both cohorts. Measures sensitive to the free water compartment (discovery cohort: P = 0.006; external cohort: P = 0.01) and iron content (discovery cohort: P < 0.001; validation cohort: P = 0.02) were found to increase in substantia nigra of the Parkinson's disease group in both cohorts. However, diffusion markers derived from the single-compartment model (i.e. mean diffusivity and fractional anisotropy) were not replicated across cohorts. Correlations were seen between single-compartment diffusion measures and iron markers in the discovery cohort (iron-mean diffusivity: r = -0.400, P = 0.006) and validation cohort (iron-mean diffusivity: r = -0.387, P = 0.003) but no correlation was observed between a measure from the bi-compartment model related to the free water compartment and iron markers in either cohort. In conclusion, the variability of nigral diffusion metrics derived from the single-compartment model in Parkinson's disease may be attributed to competing influences of increased iron content, which tends to drive diffusivity down, and increases in the free water compartment, which tends to drive diffusivity up. In contrast to diffusion metrics derived from the single-compartment model, no relationship was seen between iron and the free water compartment in substantia nigra.
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Affiliation(s)
- Jason Langley
- Center for Advanced Neuroimaging, University of California Riverside, Riverside, CA 92521, USA
| | | | - Xiaoping Hu
- Center for Advanced Neuroimaging, University of California Riverside, Riverside, CA 92521, USA.,Department of Bioengineering, University of California Riverside, Riverside, CA 92521, USA
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Riederer P, Monoranu C, Strobel S, Iordache T, Sian-Hülsmann J. Iron as the concert master in the pathogenic orchestra playing in sporadic Parkinson's disease. J Neural Transm (Vienna) 2021; 128:1577-1598. [PMID: 34636961 PMCID: PMC8507512 DOI: 10.1007/s00702-021-02414-z] [Citation(s) in RCA: 45] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2021] [Accepted: 08/29/2021] [Indexed: 02/07/2023]
Abstract
About 60 years ago, the discovery of a deficiency of dopamine in the nigro-striatal system led to a variety of symptomatic therapeutic strategies to supplement dopamine and to substantially improve the quality of life of patients with Parkinson's disease (PD). Since these seminal developments, neuropathological, neurochemical, molecular biological and genetic discoveries contributed to elucidate the pathology of PD. Oxidative stress, the consequences of reactive oxidative species, reduced antioxidative capacity including loss of glutathione, excitotoxicity, mitochondrial dysfunction, proteasomal dysfunction, apoptosis, lysosomal dysfunction, autophagy, suggested to be causal for ɑ-synuclein fibril formation and aggregation and contributing to neuroinflammation and neural cell death underlying this devastating disorder. However, there are no final conclusions about the triggered pathological mechanism(s) and the follow-up of pathological dysfunctions. Nevertheless, it is a fact, that iron, a major component of oxidative reactions, as well as neuromelanin, the major intraneuronal chelator of iron, undergo an age-dependent increase. And ageing is a major risk factor for PD. Iron is significantly increased in the substantia nigra pars compacta (SNpc) of PD. Reasons for this finding include disturbances in iron-related import and export mechanisms across the blood-brain barrier (BBB), localized opening of the BBB at the nigro-striatal tract including brain vessel pathology. Whether this pathology is of primary or secondary importance is not known. We assume that there is a better fit to the top-down hypotheses and pathogens entering the brain via the olfactory system, then to the bottom-up (gut-brain) hypothesis of PD pathology. Triggers for the bottom-up, the dual-hit and the top-down pathologies include chemicals, viruses and bacteria. If so, hepcidin, a regulator of iron absorption and its distribution into tissues, is suggested to play a major role in the pathogenesis of iron dyshomeostasis and risk for initiating and progressing ɑ-synuclein pathology. The role of glial components to the pathology of PD is still unknown. However, the dramatic loss of glutathione (GSH), which is mainly synthesized in glia, suggests dysfunction of this process, or GSH uptake into neurons. Loss of GSH and increase in SNpc iron concentration have been suggested to be early, may be even pre-symptomatic processes in the pathology of PD, despite the fact that they are progression factors. The role of glial ferritin isoforms has not been studied so far in detail in human post-mortem brain tissue and a close insight into their role in PD is called upon. In conclusion, "iron" is a major player in the pathology of PD. Selective chelation of excess iron at the site of the substantia nigra, where a dysfunction of the BBB is suggested, with peripherally acting iron chelators is suggested to contribute to the portfolio and therapeutic armamentarium of anti-Parkinson medications.
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Affiliation(s)
- P Riederer
- Clinic and Policlinic for Psychiatry, Psychosomatics and Psychotherapy, University Hospital Wuerzburg, University of Wuerzburg, Wuerzburg, Germany. .,Department of Psychiatry, University of Southern Denmark, Odense, Denmark.
| | - C Monoranu
- Institute of Pathology, Department of Neuropathology, University of Wuerzburg, Wuerzburg, Germany
| | - S Strobel
- Institute of Pathology, Department of Neuropathology, University of Wuerzburg, Wuerzburg, Germany
| | - T Iordache
- George Emil Palade University of Medicine, Pharmacy, Science and Technology of Targu Mures, Târgu Mureș, Romania
| | - J Sian-Hülsmann
- Department of Medical Physiology, University of Nairobi, P.O. Box 30197, Nairobi, 00100, Kenya
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Lee H, Cho H, Lee MJ, Kim TH, Roh J, Lee JH. Differential Effect of Iron and Myelin on Susceptibility MRI in the Substantia Nigra. Radiology 2021; 301:682-691. [PMID: 34609198 DOI: 10.1148/radiol.2021210116] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
Abstract
Background The heterogeneous composition of substantia nigra (SN), including iron, nigrosome-1 substructure, and myelinated white matter, complicates the interpretation of MRI signals. Purpose To investigate R2* and quantitative susceptibility mapping (QSM) in the SN subdivisions of participants with Parkinson disease and healthy control subjects. Materials and Methods In this prospective study conducted from November 2018 to November 2019, participants with Parkinson disease and sex-matched healthy control subjects underwent 3-T MRI. R2* and QSM values were measured and compared in the anterior SN and posterior SN at the rostral (superior) and caudal (inferior) levels. Postmortem MRI and histology correlation of midbrain tissues was evaluated to investigate the effect of myelin and iron in the SN on R2* and QSM values. Results Forty individuals were evaluated: 20 healthy control subjects (mean age, 61 years ± 3 [standard deviation]; 10 men) and 20 participants with Parkinson disease (mean age, 61 years ± 4; 10 men). The R2* values of participants with Parkinson disease were higher in all subdivisions of the SN compared with R2* values in healthy control subjects (all P < .05). For QSM, no evidence of a difference was found in the rostral posterior SN (healthy control subjects, 54.1 ppb ± 21.0; Parkinson disease, 62.2 ppb ± 19.8; P = .49). The combination of rostral R2* and caudal QSM values resulted in an area under the receiver operating characteristic curve of 0.84. R2* values showed higher correlation with QSM values at the caudal level than at the rostral level within each group (all P < .001). Postmortem investigation demonstrated that R2* and QSM values showed weak correlation in the myelin-rich areas (r = 0.22 and r = 0.36, P < .001) and strong correlation in myelin-scanty areas (r ranged from approximately 0.52 to approximately 0.78, P < .001) in the SN. Conclusion Considering the iron and myelin distribution in the substantia nigra subdivisions, the subdivisional analysis of substantia nigra using R2* and quantitative susceptibility mapping might aid in specifically differentiating individuals with Parkinson disease from healthy control subjects. © RSNA, 2021 Online supplemental material is available for this article.
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Affiliation(s)
- Hansol Lee
- From the Department of Biomedical Engineering, Ulsan National Institute of Science and Technology, Ulsan, South Korea (H.L., H.J.C.); Department of Neurology, Pusan National University Hospital, Pusan National University School of Medicine and Biomedical Research Institute, Busan, South Korea (M.J.L); and Research Institute for Convergence of Biomedical Science and Technology (T.H.K.) and Departments of Radiology (J.R.) and Neurology (J.H.L.), Research Institute for Convergence of Biomedical Science and Technology, Pusan National University Yangsan Hospital, 20 Geumo-ro, Mulgeum-eup, Yangsan-si, Gyeongsangnam-do, South Korea
| | - HyungJoon Cho
- From the Department of Biomedical Engineering, Ulsan National Institute of Science and Technology, Ulsan, South Korea (H.L., H.J.C.); Department of Neurology, Pusan National University Hospital, Pusan National University School of Medicine and Biomedical Research Institute, Busan, South Korea (M.J.L); and Research Institute for Convergence of Biomedical Science and Technology (T.H.K.) and Departments of Radiology (J.R.) and Neurology (J.H.L.), Research Institute for Convergence of Biomedical Science and Technology, Pusan National University Yangsan Hospital, 20 Geumo-ro, Mulgeum-eup, Yangsan-si, Gyeongsangnam-do, South Korea
| | - Myung Jun Lee
- From the Department of Biomedical Engineering, Ulsan National Institute of Science and Technology, Ulsan, South Korea (H.L., H.J.C.); Department of Neurology, Pusan National University Hospital, Pusan National University School of Medicine and Biomedical Research Institute, Busan, South Korea (M.J.L); and Research Institute for Convergence of Biomedical Science and Technology (T.H.K.) and Departments of Radiology (J.R.) and Neurology (J.H.L.), Research Institute for Convergence of Biomedical Science and Technology, Pusan National University Yangsan Hospital, 20 Geumo-ro, Mulgeum-eup, Yangsan-si, Gyeongsangnam-do, South Korea
| | - Tae-Hyung Kim
- From the Department of Biomedical Engineering, Ulsan National Institute of Science and Technology, Ulsan, South Korea (H.L., H.J.C.); Department of Neurology, Pusan National University Hospital, Pusan National University School of Medicine and Biomedical Research Institute, Busan, South Korea (M.J.L); and Research Institute for Convergence of Biomedical Science and Technology (T.H.K.) and Departments of Radiology (J.R.) and Neurology (J.H.L.), Research Institute for Convergence of Biomedical Science and Technology, Pusan National University Yangsan Hospital, 20 Geumo-ro, Mulgeum-eup, Yangsan-si, Gyeongsangnam-do, South Korea
| | - Jieun Roh
- From the Department of Biomedical Engineering, Ulsan National Institute of Science and Technology, Ulsan, South Korea (H.L., H.J.C.); Department of Neurology, Pusan National University Hospital, Pusan National University School of Medicine and Biomedical Research Institute, Busan, South Korea (M.J.L); and Research Institute for Convergence of Biomedical Science and Technology (T.H.K.) and Departments of Radiology (J.R.) and Neurology (J.H.L.), Research Institute for Convergence of Biomedical Science and Technology, Pusan National University Yangsan Hospital, 20 Geumo-ro, Mulgeum-eup, Yangsan-si, Gyeongsangnam-do, South Korea
| | - Jae-Hyeok Lee
- From the Department of Biomedical Engineering, Ulsan National Institute of Science and Technology, Ulsan, South Korea (H.L., H.J.C.); Department of Neurology, Pusan National University Hospital, Pusan National University School of Medicine and Biomedical Research Institute, Busan, South Korea (M.J.L); and Research Institute for Convergence of Biomedical Science and Technology (T.H.K.) and Departments of Radiology (J.R.) and Neurology (J.H.L.), Research Institute for Convergence of Biomedical Science and Technology, Pusan National University Yangsan Hospital, 20 Geumo-ro, Mulgeum-eup, Yangsan-si, Gyeongsangnam-do, South Korea
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Genetic differences in ethanol consumption: effects on iron, copper, and zinc regulation in mouse hippocampus. Biometals 2021; 34:1059-1066. [PMID: 34176056 PMCID: PMC9833394 DOI: 10.1007/s10534-021-00327-8] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2021] [Accepted: 06/21/2021] [Indexed: 01/13/2023]
Abstract
One common characteristic of neurodegenerative diseases is dysregulation of iron, usually with observed increases in its concentration in various regions. Heavy alcohol consumption is believed to contribute to such iron dysregulation in the brain with accompanying dementia. To examine this effect and related genetic-based individual differences in an animal model, we subjected female mice from 12 BXD recombinant inbred strains to 16 weeks of alcohol consumption using the drinking in the dark (DID) method. Daily consumption was recorded and at the end of 16 weeks hippocampus tissues harvested. Concentrations of iron, copper and zinc were measured using X-ray fluorescence technology. The results showed that, DID increased iron overall across all strains, ranging from 3 to 68%. Copper and Zinc both decreased, ranging from 0.4-42 and 5-35% respectively. Analysis of variance revealed significant strain by treatment interactions for all three metals. Additionally, in the DID group, we observed strain differences in reduction of hippocampus mass. These findings are particularly interesting to us because high alcohol consumption in humans has been associated with neurodegeneration and dementia related to disruption of iron regulation. The findings of alcohol consumption associated decreases in copper and zinc are novel. The role of copper regulation and neurological function related to alcohol consumption is as yet largely unexplored. The role of zinc is better known as a neuromodulator in the hippocampus and appears to be protective against neurological damage. It would seem then, that the alcohol-related decrease in zinc in the hippocampus would be of concern and warrants further study.
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Sun J, Chen R, Tong Q, Ma J, Gao L, Fang J, Zhang D, Chan P, He H, Wu T. Convolutional neural network optimizes the application of diffusion kurtosis imaging in Parkinson's disease. Brain Inform 2021; 8:18. [PMID: 34585306 PMCID: PMC8479023 DOI: 10.1186/s40708-021-00139-z] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2021] [Accepted: 08/11/2021] [Indexed: 11/25/2022] Open
Abstract
Objectives The literature regarding the use of diffusion-tensor imaging-derived metrics in the evaluation of Parkinson’s disease (PD) is controversial. This study attempted to assess the feasibility of a deep-learning-based method for detecting alterations in diffusion kurtosis measurements associated with PD. Methods A total of 68 patients with PD and 77 healthy controls were scanned using scanner-A (3 T Skyra) (DATASET-1). Meanwhile, an additional five healthy volunteers were scanned with both scanner-A and an additional scanner-B (3 T Prisma) (DATASET-2). Diffusion kurtosis imaging (DKI) of DATASET-2 had an extra b shell compared to DATASET-1. In addition, a 3D-convolutional neural network (CNN) was trained from DATASET-2 to harmonize the quality of scalar measures of scanner-A to a similar level as scanner-B. Whole-brain unpaired t test and Tract-Based Spatial Statistics (TBSS) were performed to validate the differences between the PD and control groups using the model-fitting method and CNN-based method, respectively. We further clarified the correlation between clinical assessments and DKI results. Results An increase in mean diffusivity (MD) was found in the left substantia nigra (SN) in the PD group. In the right SN, fractional anisotropy (FA) and mean kurtosis (MK) values were negatively correlated with Hoehn and Yahr (H&Y) scales. In the putamen (Put), FA values were positively correlated with the H&Y scales. It is worth noting that these findings were only observed with the deep learning method. There was neither a group difference nor a correlation with clinical assessments in the SN or striatum exceeding the significance level using the conventional model-fitting method. Conclusions The CNN-based method improves the robustness of DKI and can help to explore PD-associated imaging features. Supplementary Information The online version contains supplementary material available at 10.1186/s40708-021-00139-z.
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Affiliation(s)
- Junyan Sun
- Department of Neurobiology, Neurology and Geriatrics, Xuanwu Hospital of Capital Medical University, National Clinical Research Center for Geriatric Disease, Beijing, 100053, China
| | - Ruike Chen
- Center for Brain Imaging Science and Technology, College of Biomedical Engineering and Instrumental Science, Zhejiang University, Hangzhou, 310027, Zhejiang, China
| | - Qiqi Tong
- Center for Brain Imaging Science and Technology, College of Biomedical Engineering and Instrumental Science, Zhejiang University, Hangzhou, 310027, Zhejiang, China.,Research Center for Healthcare Data Science, Zhejiang Lab, Hangzhou, Zhejiang, China
| | - Jinghong Ma
- Department of Neurology, Xuanwu Hospital of Capital Medical University, Beijing, China
| | - Linlin Gao
- Department of Neurobiology, Neurology and Geriatrics, Xuanwu Hospital of Capital Medical University, National Clinical Research Center for Geriatric Disease, Beijing, 100053, China
| | - Jiliang Fang
- Department of Radiology, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Dongling Zhang
- Department of Neurobiology, Neurology and Geriatrics, Xuanwu Hospital of Capital Medical University, National Clinical Research Center for Geriatric Disease, Beijing, 100053, China
| | - Piu Chan
- Department of Neurobiology, Neurology and Geriatrics, Xuanwu Hospital of Capital Medical University, National Clinical Research Center for Geriatric Disease, Beijing, 100053, China.,Clinical Center for Parkinson's Disease, Capital Medical University, Beijing, China.,Key Laboratory for Neurodegenerative Disease of the Ministry of Education, Beijing Key Laboratory for Parkinson's Disease, Parkinson Disease Center of Beijing Institute for Brain Disorders, Beijing, China.,National Clinical Research Center for Geriatric Disorders, Beijing, China
| | - Hongjian He
- Center for Brain Imaging Science and Technology, College of Biomedical Engineering and Instrumental Science, Zhejiang University, Hangzhou, 310027, Zhejiang, China. .,Key Laboratory for Biomedical Engineering of Ministry of Education, Zhejiang University, Hangzhou, 310027, Zhejiang, China.
| | - Tao Wu
- Department of Neurobiology, Neurology and Geriatrics, Xuanwu Hospital of Capital Medical University, National Clinical Research Center for Geriatric Disease, Beijing, 100053, China. .,Clinical Center for Parkinson's Disease, Capital Medical University, Beijing, China. .,Key Laboratory for Neurodegenerative Disease of the Ministry of Education, Beijing Key Laboratory for Parkinson's Disease, Parkinson Disease Center of Beijing Institute for Brain Disorders, Beijing, China. .,National Clinical Research Center for Geriatric Disorders, Beijing, China.
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Liu Y, Xiao B, Zhang C, Li J, Lai Y, Shi F, Shen D, Wang L, Sun B, Li Y, Jin Z, Wei H, Haacke EM, Zhou H, Wang Q, Li D, He N, Yan F. Predicting Motor Outcome of Subthalamic Nucleus Deep Brain Stimulation for Parkinson's Disease Using Quantitative Susceptibility Mapping and Radiomics: A Pilot Study. Front Neurosci 2021; 15:731109. [PMID: 34557069 PMCID: PMC8452872 DOI: 10.3389/fnins.2021.731109] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2021] [Accepted: 08/17/2021] [Indexed: 12/02/2022] Open
Abstract
Background Emerging evidence indicates that iron distribution is heterogeneous within the substantia nigra (SN) and it may reflect patient-specific trait of Parkinson’s Disease (PD). We assume it could account for variability in motor outcome of subthalamic nucleus deep brain stimulation (STN-DBS) in PD. Objective To investigate whether SN susceptibility features derived from radiomics with machine learning (RA-ML) can predict motor outcome of STN-DBS in PD. Methods Thirty-three PD patients underwent bilateral STN-DBS were recruited. The bilateral SN were segmented based on preoperative quantitative susceptibility mapping to extract susceptibility features using RA-ML. MDS-UPDRS III scores were recorded 1–3 days before and 6 months after STN-DBS surgery. Finally, we constructed three predictive models using logistic regression analyses: (1) the RA-ML model based on radiomics features, (2) the RA-ML+LCT (levodopa challenge test) response model which combined radiomics features with preoperative LCT response, (3) the LCT response model alone. Results For the predictive performances of global motor outcome, the RA-ML model had 82% accuracy (AUC = 0.85), while the RA-ML+LCT response model had 74% accuracy (AUC = 0.83), and the LCT response model alone had 58% accuracy (AUC = 0.55). For the predictive performance of rigidity outcome, the accuracy of the RA-ML model was 80% (AUC = 0.85), superior to those of the RA-ML+LCT response model (76% accuracy, AUC = 0.82), and the LCT response model alone (58% accuracy, AUC = 0.42). Conclusion Our findings demonstrated that SN susceptibility features from radiomics could predict global motor and rigidity outcomes of STN-DBS in PD. This RA-ML predictive model might provide a novel approach to counsel candidates for STN-DBS.
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Affiliation(s)
- Yu Liu
- Department of Radiology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Bin Xiao
- School of Biomedical Engineering, Institute for Medical Imaging Technology, Shanghai Jiao Tong University, Shanghai, China
| | - Chencheng Zhang
- Department of Neurosurgery, Center for Functional Neurosurgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Junchen Li
- Department of Radiology, Changshu Hospital Affiliated to Nanjing University of Chinese Medicine, Changshu, China
| | - Yijie Lai
- Department of Neurosurgery, Center for Functional Neurosurgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Feng Shi
- Shanghai United Imaging Intelligence Co., Ltd., Shanghai, China
| | - Dinggang Shen
- Shanghai United Imaging Intelligence Co., Ltd., Shanghai, China.,School of Biomedical Engineering, ShanghaiTech University, Shanghai, China.,Department of Artificial Intelligence, Korea University, Seoul, South Korea
| | - Linbin Wang
- Department of Neurosurgery, Center for Functional Neurosurgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Bomin Sun
- Department of Neurosurgery, Center for Functional Neurosurgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yan Li
- Department of Radiology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Zhijia Jin
- Department of Radiology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Hongjiang Wei
- School of Biomedical Engineering, Med-X Research Institute, Shanghai Jiao Tong University, Shanghai, China
| | - Ewart Mark Haacke
- Department of Radiology, Wayne State University, Detroit, MI, United States
| | - Haiyan Zhou
- Department of Neurology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Qian Wang
- School of Biomedical Engineering, Institute for Medical Imaging Technology, Shanghai Jiao Tong University, Shanghai, China
| | - Dianyou Li
- Department of Neurosurgery, Center for Functional Neurosurgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Naying He
- Department of Radiology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Fuhua Yan
- Department of Radiology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
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Yu B, Li L, Guan X, Xu X, Liu X, Yang Q, Wei H, Zuo C, Zhang Y. HybraPD atlas: Towards precise subcortical nuclei segmentation using multimodality medical images in patients with Parkinson disease. Hum Brain Mapp 2021; 42:4399-4421. [PMID: 34101297 PMCID: PMC8357000 DOI: 10.1002/hbm.25556] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2020] [Revised: 05/27/2021] [Accepted: 05/30/2021] [Indexed: 12/29/2022] Open
Abstract
Human brain atlases are essential for research and surgical treatment of Parkinson's disease (PD). For example, deep brain stimulation for PD often requires human brain atlases for brain structure identification. However, few atlases can provide disease-specific subcortical structures for PD, and most of them are based on T1w and T2w images. In this work, we construct a HybraPD atlas using fused quantitative susceptibility mapping (QSM) and T1w images from 87 patients with PD. The constructed HybraPD atlas provides a series of templates, that is, T1w, GRE magnitude, QSM, R2*, and brain tissue probabilistic maps. Then, we manually delineate a parcellation map with 12 bilateral subcortical nuclei, which are highly related to PD pathology, such as sub-regions in globus pallidus and substantia nigra. Furthermore, we build a whole-brain parcellation map by combining existing cortical parcellation and white-matter segmentation with the proposed subcortical nuclei map. Considering the multimodality of the HybraPD atlas, the segmentation accuracy of each nucleus is evaluated using T1w and QSM templates, respectively. The results show that the HybraPD atlas provides more accurate segmentation than existing atlases. Moreover, we analyze the metabolic difference in subcortical nuclei between PD patients and healthy control subjects by applying the HybraPD atlas to calculate uptake values of contrast agents on positron emission tomography (PET) images. The atlas-based analysis generates accurate disease-related brain nuclei segmentation on PET images. The newly developed HybraPD atlas could serve as an efficient template to study brain pathological alterations in subcortical regions for PD research.
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Affiliation(s)
- Boliang Yu
- School of Information Science and TechnologyShanghaiTech UniversityShanghaiChina
| | - Ling Li
- PET Center, Huashan HospitalFudan UniversityShanghaiChina
| | - Xiaojun Guan
- Department of Radiology, The Second Affiliated HospitalZhejiang University School of MedicineHangzhouChina
| | - Xiaojun Xu
- Department of Radiology, The Second Affiliated HospitalZhejiang University School of MedicineHangzhouChina
| | - Xueling Liu
- Department of Radiology, Huashan HospitalFudan UniversityShanghaiChina
| | - Qing Yang
- Institute of Brain‐Intelligence Technology, Zhangjiang LaboratoryShanghaiChina
| | - Hongjiang Wei
- Institute for Medicine Imaging Technology, School of Biomedical EngineeringShanghai Jiao Tong UniversityShanghaiChina
| | - Chuantao Zuo
- PET Center, Huashan HospitalFudan UniversityShanghaiChina
| | - Yuyao Zhang
- School of Information Science and TechnologyShanghaiTech UniversityShanghaiChina
- Shanghai Engineering Research Center of Intelligent Vision and ImagingShanghaiTech UniversityShanghaiChina
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Düzel E, Costagli M, Donatelli G, Speck O, Cosottini M. Studying Alzheimer disease, Parkinson disease, and amyotrophic lateral sclerosis with 7-T magnetic resonance. Eur Radiol Exp 2021; 5:36. [PMID: 34435242 PMCID: PMC8387546 DOI: 10.1186/s41747-021-00221-5] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2020] [Accepted: 04/07/2021] [Indexed: 12/18/2022] Open
Abstract
Ultra-high-field (UHF) magnetic resonance (MR) scanners, that is, equipment operating at static magnetic field of 7 tesla (7 T) and above, enable the acquisition of data with greatly improved signal-to-noise ratio with respect to conventional MR systems (e.g., scanners operating at 1.5 T and 3 T). The change in tissue relaxation times at UHF offers the opportunity to improve tissue contrast and depict features that were previously inaccessible. These potential advantages come, however, at a cost: in the majority of UHF-MR clinical protocols, potential drawbacks may include signal inhomogeneity, geometrical distortions, artifacts introduced by patient respiration, cardiac cycle, and motion. This article reviews the 7 T MR literature reporting the recent studies on the most widespread neurodegenerative diseases: Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis.
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Affiliation(s)
- Emrah Düzel
- Otto-von-Guericke University Magdeburg, Magdeburg, Germany. .,German Center for Neurodegenerative Diseases (DZNE), Magdeburg, Germany. .,University College London, London, UK.
| | - Mauro Costagli
- IRCCS Stella Maris, Pisa, Italy.,University of Genoa, Genova, Italy
| | - Graziella Donatelli
- Fondazione Imago 7, Pisa, Italy.,Azienda Ospedaliero Universitaria Pisana, Pisa, Italy
| | - Oliver Speck
- Otto-von-Guericke University Magdeburg, Magdeburg, Germany.,German Center for Neurodegenerative Diseases (DZNE), Magdeburg, Germany
| | - Mirco Cosottini
- Azienda Ospedaliero Universitaria Pisana, Pisa, Italy.,University of Pisa, Pisa, Italy
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Fu X, Deng W, Cui X, Zhou X, Song W, Pan M, Chi X, Xu J, Jiang Y, Wang Q, Xu Y. Time-Specific Pattern of Iron Deposition in Different Regions in Parkinson's Disease Measured by Quantitative Susceptibility Mapping. Front Neurol 2021; 12:631210. [PMID: 34421781 PMCID: PMC8371047 DOI: 10.3389/fneur.2021.631210] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2020] [Accepted: 06/24/2021] [Indexed: 11/13/2022] Open
Abstract
Studies have shown the spatial specificity of cranial iron deposition in different regions in Parkinson's disease (PD). However, the time-specific patterns of iron deposition are not yet clear. The purpose of this study was to investigate the time pattern of iron variations and its clinical relevance in multiple gray matter nuclei in PD using quantitative susceptibility mapping (QSM). Thirty controls and 33 PD patients were enrolled, namely, 11 cases of early stage of PD (ESP) and 22 cases of advanced stage of PD (ASP) according to the Hoehn-Yahr stages. The iron content in the subcortical nuclei covering substantia nigra (SN), red nucleus (RN), head of the caudate nucleus (CN), globus pallidus (GP), and putamen (PT) was measured using QSM, and the clinical symptoms of PD were evaluated by various rating scales. The QSM values in SN, RN, GP, and PT significantly increased in PD patients compared with the controls. Further subgroup comparison with the controls indicated that the iron content in SN and GP (paleostriatum) gradually elevated in the whole disease duration and was related to clinical features. While the iron content in RN and PT (neostriatum) only elevated significantly in ESP patients, further iron deposition was not obvious in ASP patients. Our study confirmed that QSM could be used as a disease biomarker and could be suitable for longitudinal monitoring. However, considering the temporal characteristics of iron deposition in neostriatum, iron deposition in the neostriatum should be paid more attention in the early stage of the disease, even in the preclinical stage, in future research.
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Affiliation(s)
- Xiaodi Fu
- Department of Neurology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Wenbin Deng
- Department of Neurology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Xiangqin Cui
- Department of Neurology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Xiao Zhou
- Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, United States
| | - Weizheng Song
- Department of Neurosurgery, the Eighth People's Hospital of Chengdu, Chengdu, China
| | - Mengqiu Pan
- Department of Neurology, Guangdong 999 Brain Hospital, Guangzhou, China
| | - Xiao Chi
- Department of Neurology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Jinghui Xu
- The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Ying Jiang
- The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Qun Wang
- Department of Neurology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Yunqi Xu
- Department of Neurology, Nanfang Hospital, Southern Medical University, Guangzhou, China
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Toxic Feedback Loop Involving Iron, Reactive Oxygen Species, α-Synuclein and Neuromelanin in Parkinson's Disease and Intervention with Turmeric. Mol Neurobiol 2021; 58:5920-5936. [PMID: 34426907 DOI: 10.1007/s12035-021-02516-5] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2021] [Accepted: 08/03/2021] [Indexed: 12/20/2022]
Abstract
Parkinson's disease (PD) is a movement disorder associated with severe loss of mainly dopaminergic neurons in the substantia nigra. Pathological hallmarks include Lewy bodies, and loss of neuromelanin, due to degeneration of neuromelanin-containing dopaminergic neurons. Despite being described over 200 years ago, the etiology of PD remains unknown. Here, we highlight the roles of reactive oxygen species (ROS), iron, alpha synuclein (α-syn) and neuromelanin in a toxic feedback loop culminating in neuronal death and spread of the disease. Dopaminergic neurons are particularly vulnerable due to decreased antioxidant concentration with aging, constant exposure to ROS and presence of neurotoxic compounds (e.g. ortho-quinones). ROS and iron increase each other's levels, creating a state of oxidative stress. α-Syn aggregation is influenced by ROS and iron but also increases ROS and iron via its induced mitochondrial dysfunction and ferric-reductase activity. Neuromelanin's binding affinity is affected by increased ROS and iron. Furthermore, during neuronal death, neuromelanin is degraded in the extracellular space, releasing its bound toxins. This cycle of events continues to neighboring neurons in the form of a toxic loop, causing PD pathology. The increase in ROS and iron may be an important target for therapies to disrupt this toxic loop, and therefore diets rich in certain 'nutraceuticals' may be beneficial. Turmeric is an attractive candidate, as it is known to have anti-oxidant and iron chelating properties. More studies are needed to test this theory and if validated, this would be a step towards development of lifestyle-based therapeutic modalities to complement existing PD treatments.
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Parkinson's disease multimodal imaging: F-DOPA PET, neuromelanin-sensitive and quantitative iron-sensitive MRI. NPJ Parkinsons Dis 2021; 7:57. [PMID: 34238927 PMCID: PMC8266835 DOI: 10.1038/s41531-021-00199-2] [Citation(s) in RCA: 33] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2021] [Accepted: 06/16/2021] [Indexed: 11/08/2022] Open
Abstract
Parkinson's disease (PD) is a neurodegenerative synucleinopathy characterized by the degeneration of neuromelanin (NM)-containing dopaminergic neurons and deposition of iron in the substantia nigra (SN). How regional NM loss and iron accumulation within specific areas of SN relate to nigro-striatal dysfunction needs to be clarified. We measured dopaminergic function in pre- and postcommissural putamen by [18F]DOPA PET in 23 Parkinson's disease patients and 23 healthy control (HC) participants in whom NM content and iron load were assessed in medial and lateral SN, respectively, by NM-sensitive and quantitative R2* MRI. Data analysis consisted of voxelwise regressions testing the group effect and its interaction with NM or iron signals. In PD patients, R2* was selectively increased in left lateral SN as compared to healthy participants, suggesting a local accumulation of iron in Parkinson's disease. By contrast, NM signal differed between PD and HC, without specific regional specificity within SN. Dopaminergic function in posterior putamen decreased as R2* increased in lateral SN, indicating that dopaminergic function impairment progresses with iron accumulation in the SN. Dopaminergic function was also positively correlated with NM signal in lateral SN, indicating that dopaminergic function impairment progresses with depigmentation in the SN. A complex relationship was detected between R2* in the lateral SN and NM signal in the medial SN. In conclusion, multimodal imaging reveals regionally specific relationships between iron accumulation and depigmentation within the SN of Parkinson's disease and provides in vivo insights in its neuropathology.
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Wang YC, Huang APH, Yuan SP, Huang CY, Wu CC, Poly TN, Atique S, Kung WM. Association between Anemia and Risk of Parkinson Disease. Behav Neurol 2021; 2021:8360627. [PMID: 34306250 PMCID: PMC8279865 DOI: 10.1155/2021/8360627] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2021] [Accepted: 06/19/2021] [Indexed: 02/08/2023] Open
Abstract
METHODS We systematically searched articles on electronic databases such as PubMed, Embase, Scopus, and Google Scholar between January 1, 2000 and July 30, 2020. Articles were independently evaluated by two authors. We included observational studies (case-control and cohort) and calculated the risk ratios (RRs) for associated with anemia and PD. Heterogeneity among the studies was assessed using the Q and I 2 statistic. We utilized the random-effect model to calculate the overall RR with 95% CI. RESULTS A total of 342 articles were identified in the initial searches, and 7 full-text articles were evaluated for eligibility. Three articles were further excluded for prespecified reasons including insufficient data and duplications, and 4 articles were included in our systematic review and meta-analysis. A random effect model meta-analysis of all 4 studies showed no increased risk of PD in patients with anemia (N = 4, RRadjusted = 1.17 (95% CI: 0.94-1.45, p = 0.15). However, heterogeneity among the studies was significant (I 2 = 92.60, p = <0.0001). The pooled relative risk of PD in female patients with anemia was higher (N = 3, RRadjusted = 1.14 (95% CI: 0.83-1.57, p = 0.40) as compared to male patients with anemia (N = 3, RRadjusted = 1.09 (95% CI: 0.83-1.42, p = 0.51). CONCLUSION This is the first meta-analysis that shows that anemia is associated with higher risk of PD when compared with patients without anemia. However, more studies are warranted to evaluate the risk of PD among patients with anemia.
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Affiliation(s)
- Yao-Chin Wang
- Department of Emergency, Min-Sheng General Hospital, Taoyuan, Taiwan
- Graduate Institute of Injury Prevention and Control, College of Public Health, Taipei Medical University, Taipei, Taiwan
| | - Abel Po-Hao Huang
- Division of Neurosurgery, Department of Surgery, National Taiwan University Hospital, Taipei, Taiwan
| | - Sheng-Po Yuan
- Graduate Institute of Biomedical Informatics, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan
- Department of Otorhinolaryngology, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan
- Department of Otorhinolaryngology, Shuang-Ho Hospital, Taipei Medical University, New Taipei City, Taiwan
| | - Chu-Ya Huang
- Taiwan College of Healthcare Executives, Taipei, Taiwan
| | - Chieh-Chen Wu
- Department of Exercise and Health Promotion, College of Kinesiology and Health, Chinese Culture University, Taipei, Taiwan
| | - Tahmina Nasrin Poly
- Graduate Institute of Biomedical Informatics, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan
| | - Suleman Atique
- Department of Health Informatics, College of Public Health and Health Informatics, University of Ha'il, Ha'il, Saudi Arabia
| | - Woon-Man Kung
- Department of Exercise and Health Promotion, College of Kinesiology and Health, Chinese Culture University, Taipei, Taiwan
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Mursaleen L, Noble B, Somavarapu S, Zariwala MG. Micellar Nanocarriers of Hydroxytyrosol Are Protective against Parkinson's Related Oxidative Stress in an In Vitro hCMEC/D3-SH-SY5Y Co-Culture System. Antioxidants (Basel) 2021; 10:antiox10060887. [PMID: 34073115 PMCID: PMC8226543 DOI: 10.3390/antiox10060887] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2021] [Revised: 05/26/2021] [Accepted: 05/27/2021] [Indexed: 12/21/2022] Open
Abstract
Hydroxytyrosol (HT) is a natural phenolic antioxidant which has neuroprotective effects in models of Parkinson’s disease (PD). Due to issues such as rapid metabolism, HT is unlikely to reach the brain at therapeutic concentrations required for a clinical effect. We have previously developed micellar nanocarriers from Pluronic F68® (P68) and dequalinium (DQA) which have suitable characteristics for brain delivery of antioxidants and iron chelators. The aim of this study was to utilise the P68 + DQA nanocarriers for HT alone, or in combination with the iron chelator deferoxamine (DFO), and assess their physical characteristics and ability to pass the blood–brain barrier and protect against rotenone in a cellular hCMEC/D3-SH-SY5Y co-culture system. Both HT and HT + DFO formulations were less than 170 nm in size and demonstrated high encapsulation efficiencies (up to 97%). P68 + DQA nanoformulation enhanced the mean blood–brain barrier (BBB) passage of HT by 50% (p < 0.0001, n = 6). This resulted in increased protection against rotenone induced cytotoxicity and oxidative stress by up to 12% and 9%, respectively, compared to the corresponding free drug treatments (p < 0.01, n = 6). This study demonstrates for the first time the incorporation of HT and HT + DFO into P68 + DQA nanocarriers and successful delivery of these nanocarriers across a BBB model to protect against PD-related oxidative stress. These nanocarriers warrant further investigation to evaluate whether this enhanced neuroprotection is exhibited in in vivo PD models.
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Affiliation(s)
- Leah Mursaleen
- Centre for Nutraceuticals, School of Life Sciences, University of Westminster, 115 New Cavendish Street, London W1W 6UW, UK; (L.M.); (B.N.)
- Department of Pharmaceutics, UCL School of Pharmacy, 29–39 Brunswick Square, London WC1N 1AX, UK
- Cure Parkinson’s, 120 New Cavendish Street, Fitzrovia, London W1W 6XX, UK
| | - Brendon Noble
- Centre for Nutraceuticals, School of Life Sciences, University of Westminster, 115 New Cavendish Street, London W1W 6UW, UK; (L.M.); (B.N.)
| | - Satyanarayana Somavarapu
- Department of Pharmaceutics, UCL School of Pharmacy, 29–39 Brunswick Square, London WC1N 1AX, UK
- Correspondence: (S.S.); (M.G.Z.)
| | - Mohammed Gulrez Zariwala
- Centre for Nutraceuticals, School of Life Sciences, University of Westminster, 115 New Cavendish Street, London W1W 6UW, UK; (L.M.); (B.N.)
- Correspondence: (S.S.); (M.G.Z.)
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Zhang X, Chai C, Ghassaban K, Ye J, Huang Y, Zhang T, Wu W, Zhu J, Zhang X, Haacke EM, Wang Z, Xue R, Xia S. Assessing brain iron and volume of subcortical nuclei in idiopathic rapid eye movement sleep behavior disorder. Sleep 2021; 44:6279094. [PMID: 34015127 DOI: 10.1093/sleep/zsab131] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2020] [Revised: 04/30/2021] [Indexed: 12/20/2022] Open
Abstract
STUDY OBJECTIVES The relationship of iron with cognitive and motor impairment in idiopathic rapid eye movement sleep behavior disorder (iRBD) remains unknown. METHODS Twenty-nine (29) patients and 28 healthy controls (HCs) underwent susceptibility weighted imaging and susceptibility mapping. These images were used to evaluate the nigrosome-1 (N1) sign in the substantia nigra (SN), global and regional high-iron (RII) content and volume of subcortical nuclei. RESULTS The number of iRBD patients with N1 loss (12) was significantly higher than HCs (2) (P=0.005). Compared with HCs, the iRBD patients had reduced volume of the right caudate nucleus (RCN) (P<0.05, FDR correction) but no significant changes in global and RII iron of the subcortical nuclei (all P>0.05, FDR correction). Multiple regression analysis revealed that: for cognitive function, the RII iron of the RCN was significantly correlated with visuospatial function and the global iron of the right dentate nucleus (RDN) was correlated with memory function; for motor function, the RII iron of the left DN (LDN) and global iron of the left CN correlated with the Alternate-Tap test (left, average), the global iron of the LDN correlated with the Alternate-Tap test (right), and the global iron of the left GP correlated with the 3-meter Timed Up and Go test (all P<0.05, FDR correction). CONCLUSIONS Our exploratory analysis found that iRBD patients had a higher incidence of N1 loss and reduced RCN volume after FDR correction. Cognitive and motor impairment were associated with iron deposition in several cerebral nuclei after FDR correction.
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Affiliation(s)
- Xuan Zhang
- Department of Neurology, Tianjin Medical University General Hospital Airport Site, Tianjin, China
| | - Chao Chai
- Department of Radiology, Tianjin First Central Hospital, Tianjin Medical Imaging Institute, School of Medicine, Nankai University, Tianjin, China
| | - Kiarash Ghassaban
- Department of Radiology, Wayne State University, Detroit, Michigan, USA.,SpinTech MRI Inc., Bingham Farms, Michigan, USA
| | - Jingyi Ye
- Department of Neurology, Tianjin Medical University General Hospital, Tianjin, China
| | - Yaqin Huang
- Department of Neurology, Tianjin Medical University General Hospital, Tianjin, China
| | - Tong Zhang
- Department of Radiology, Tianjin First Central Hospital, Tianjin Medical Imaging Institute, School of Medicine, Nankai University, Tianjin, China
| | - Wei Wu
- Department of Neurology, Tianjin Medical University General Hospital, Tianjin, China
| | - Jinxia Zhu
- MR Collaboration, Siemens Healthcare Ltd., Beijing, China
| | | | - E Mark Haacke
- Department of Radiology, Wayne State University, Detroit, Michigan, USA.,SpinTech MRI Inc., Bingham Farms, Michigan, USA
| | - Zhiyun Wang
- Department of Neurology, Tianjin First Central Hospital, Tianjin, China
| | - Rong Xue
- Department of Neurology, Tianjin Medical University General Hospital Airport Site, Tianjin, China.,Department of Neurology, Tianjin Medical University General Hospital, Tianjin, China
| | - Shuang Xia
- Department of Radiology, Tianjin First Central Hospital, Tianjin Medical Imaging Institute, School of Medicine, Nankai University, Tianjin, China
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45
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El-Gamal M, Salama M, Collins-Praino LE, Baetu I, Fathalla AM, Soliman AM, Mohamed W, Moustafa AA. Neurotoxin-Induced Rodent Models of Parkinson's Disease: Benefits and Drawbacks. Neurotox Res 2021; 39:897-923. [PMID: 33765237 DOI: 10.1007/s12640-021-00356-8] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2018] [Revised: 03/13/2021] [Accepted: 03/18/2021] [Indexed: 12/21/2022]
Abstract
Parkinson's disease (PD), the second most common neurodegenerative disorder, is characterized by cardinal motor impairments, including akinesia and tremor, as well as by a host of non-motor symptoms, including both autonomic and cognitive dysfunction. PD is associated with a death of nigral dopaminergic neurons, as well as the pathological spread of Lewy bodies, consisting predominantly of the misfolded protein alpha-synuclein. To date, only symptomatic treatments, such as levodopa, are available, and trials aiming to cure the disease, or at least halt its progression, have not been successful. Wong et al. (2019) suggested that the lack of effective therapy against neurodegeneration in PD might be attributed to the fact that the molecular mechanisms standing behind the dopaminergic neuronal vulnerability are still a major scientific challenge. Understanding these molecular mechanisms is critical for developing effective therapy. Thirty-five years ago, Calne and William Langston (1983) raised the question of whether biological or environmental factors precipitate the development of PD. In spite of great advances in technology and medicine, this question still lacks a clear answer. Only 5-15% of PD cases are attributed to a genetic mutation, with the majority of cases classified as idiopathic, which could be linked to exposure to environmental contaminants. Rodent models play a crucial role in understanding the risk factors and pathogenesis of PD. Additionally, well-validated rodent models are critical for driving the preclinical development of clinically translatable treatment options. In this review, we discuss the mechanisms, similarities and differences, as well as advantages and limitations of different neurotoxin-induced rat models of PD. In the second part of this review, we will discuss the potential future of neurotoxin-induced models of PD. Finally, we will briefly demonstrate the crucial role of gene-environment interactions in PD and discuss fusion or dual PD models. We argue that these models have the potential to significantly further our understanding of PD.
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Affiliation(s)
- Mohamed El-Gamal
- Toxicology Department, Faculty of Medicine, Mansoura University, Mansoura, Egypt. .,Medical Experimental Research Center (MERC), Faculty of Medicine, Mansoura University, Mansoura, Egypt.
| | - Mohamed Salama
- Toxicology Department, Faculty of Medicine, Mansoura University, Mansoura, Egypt.,Medical Experimental Research Center (MERC), Faculty of Medicine, Mansoura University, Mansoura, Egypt.,Global Brain Health Institute (GBHI), Trinity College Dublin (TCD), Dublin, Ireland
| | | | | | - Ahmed M Fathalla
- Department of Pharmacology, Faculty of Medicine, Suez Canal University, Ismailia, Egypt
| | - Amira M Soliman
- Department of Pharmacology, Faculty of Medicine, Suez Canal University, Ismailia, Egypt
| | - Wael Mohamed
- Clinical Pharmacology Department, Faculty of Medicine, Menoufia University, Mansoura, Egypt.,Department of Basic Medical Science, Kulliyyah of Medicine, International Islamic University, Kuantan, Pahang, Malaysia
| | - Ahmed A Moustafa
- School of Social Sciences and Psychology and Marcs Institute for Brain and Behaviour, Western Sydney University, Sydney, NSW, Australia.,Department of Human Anatomy and Physiology, the Faculty of Health Sciences, University of Johannesburg, Johannesburg, South Africa
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46
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Is Chelation Therapy a Potential Treatment for Parkinson's Disease? Int J Mol Sci 2021; 22:ijms22073338. [PMID: 33805195 PMCID: PMC8036775 DOI: 10.3390/ijms22073338] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2021] [Revised: 02/25/2021] [Accepted: 03/06/2021] [Indexed: 12/14/2022] Open
Abstract
Iron loading in some brain regions occurs in Parkinson’s Disease (PD), and it has been considered that its removal by iron chelators could be an appropriate therapeutic approach. Since neuroinflammation with microgliosis is also a common feature of PD, it is possible that iron is sequestered within cells as a result of the “anaemia of chronic disease” and remains unavailable to the chelator. In this review, the extent of neuroinflammation in PD is discussed together with the role played by glia cells, specifically microglia and astrocytes, in controlling iron metabolism during inflammation, together with the results of MRI studies. The current use of chelators in clinical medicine is presented together with a discussion of two clinical trials of PD patients where an iron chelator was administered and showed encouraging results. It is proposed that the use of anti-inflammatory drugs combined with an iron chelator might be a better approach to increase chelator efficacy.
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47
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de Oliveira RV, Pereira JS. Utility of manual fractional anisotropy measurements in the management of patients with Parkinson disease: a feasibility study with a 1.5-T magnetic resonance imaging system. Acta Radiol Open 2021; 10:2058460121993477. [PMID: 33747550 PMCID: PMC7903830 DOI: 10.1177/2058460121993477] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2020] [Accepted: 01/20/2021] [Indexed: 11/29/2022] Open
Abstract
Background Diffusion tensor imaging has emerged as a promising tool for quantitative analysis of neuronal damage in Parkinson disease, with potential value for diagnostic and prognostic evaluation. Purpose The aim of this study was to examine Parkinson disease-associated alterations in specific brain regions revealed by diffusion tensor imaging and how such alterations correlate with clinical variables. Material and Methods Diffusion tensor imaging was performed on 42 Parkinson disease patients and 20 healthy controls with a 1.5-T scanner. Manual fractional anisotropy measurements were performed for the ventral, intermediate, and dorsal portions of the substantia nigra, as well as for the cerebral peduncles, putamen, thalamus, and supplementary motor area. The correlation analysis between these measurements and the clinical variables was performed using χ2 variance and multiple linear regression. Results Compared to healthy controls, Parkinson disease patients had significantly reduced fractional anisotropy values in the substantia nigra (P < .05). Some fractional anisotropy measurements in the substantia nigra correlated inversely with duration of Parkinson disease and Parkinson disease severity scores. Reduced fractional anisotropy values in the substantia nigra were also correlated inversely with age variable. fractional anisotropy values obtained for the right and left putamen varied significantly between males and females in both groups. Conclusion Manual fractional anisotropy measurements in the substantia nigra were confirmed to be feasible with a 1.5-T scanner. Diffusion tensor imaging data can be used as a reliable biomarker of Parkinson disease that can be used to support diagnosis, prognosis, and progression/treatment monitoring.
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Affiliation(s)
- Romulo V de Oliveira
- Diagnostic Imaging Section, Pedro Ernesto University Hospital, State University of Rio de Janeiro, Rio de Janeiro, Brazil.,Diagnosticos da America SA, Rio de Janeiro, Brazil.,Diagnostic Imaging Center, São Lucas Copacabana Hospital, Rio de Janeiro, Brazil.,Post Graduate Program Stricto Sensu in Medical Sciences at the Faculty of Medical Sciences, State University of Rio de Janeiro, Rio de Janeiro, Brazil
| | - João S Pereira
- Post Graduate Program Stricto Sensu in Medical Sciences at the Faculty of Medical Sciences, State University of Rio de Janeiro, Rio de Janeiro, Brazil.,Movement Disorders Section, Neurology Service, Pedro Ernesto University Hospital, State University of Rio de Janeiro, Rio de Janeiro, Brazil
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48
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Cell specific quantitative iron mapping on brain slices by immuno-µPIXE in healthy elderly and Parkinson's disease. Acta Neuropathol Commun 2021; 9:47. [PMID: 33752749 PMCID: PMC7986300 DOI: 10.1186/s40478-021-01145-2] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2020] [Accepted: 02/28/2021] [Indexed: 12/17/2022] Open
Abstract
Iron is essential for neurons and glial cells, playing key roles in neurotransmitter synthesis, energy production and myelination. In contrast, high concentrations of free iron can be detrimental and contribute to neurodegeneration, through promotion of oxidative stress. Particularly in Parkinson’s disease (PD) changes in iron concentrations in the substantia nigra (SN) was suggested to play a key role in degeneration of dopaminergic neurons in nigrosome 1. However, the cellular iron pathways and the mechanisms of the pathogenic role of iron in PD are not well understood, mainly due to the lack of quantitative analytical techniques for iron quantification with subcellular resolution. Here, we quantified cellular iron concentrations and subcellular iron distributions in dopaminergic neurons and different types of glial cells in the SN both in brains of PD patients and in non-neurodegenerative control brains (Co). To this end, we combined spatially resolved quantitative element mapping using micro particle induced X-ray emission (µPIXE) with nickel-enhanced immunocytochemical detection of cell type-specific antigens allowing to allocate element-related signals to specific cell types. Distinct patterns of iron accumulation were observed across different cell populations. In the control (Co) SNc, oligodendroglial and astroglial cells hold the highest cellular iron concentration whereas in PD, the iron concentration was increased in most cell types in the substantia nigra except for astroglial cells and ferritin-positive oligodendroglial cells. While iron levels in astroglial cells remain unchanged, ferritin in oligodendroglial cells seems to be depleted by almost half in PD. The highest cellular iron levels in neurons were located in the cytoplasm, which might increase the source of non-chelated Fe3+, implicating a critical increase in the labile iron pool. Indeed, neuromelanin is characterised by a significantly higher loading of iron including most probable the occupancy of low-affinity iron binding sites. Quantitative trace element analysis is essential to characterise iron in oxidative processes in PD. The quantification of iron provides deeper insights into changes of cellular iron levels in PD and may contribute to the research in iron-chelating disease-modifying drugs.
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Song T, Li J, Mei S, Jia X, Yang H, Ye Y, Yuan J, Zhang Y, Lu J. Nigral Iron Deposition Is Associated With Levodopa-Induced Dyskinesia in Parkinson's Disease. Front Neurosci 2021; 15:647168. [PMID: 33828454 PMCID: PMC8019898 DOI: 10.3389/fnins.2021.647168] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2020] [Accepted: 02/16/2021] [Indexed: 11/29/2022] Open
Abstract
Objective To investigate iron deposition in the substantia nigra (SN) of Parkinson’s disease (PD) patients associated with levodopa-induced dyskinesia (LID). Methods Seventeen PD patients with LID, 17 PD patients without LID, and 16 healthy controls were recruited for this study. The mean QSM values of the whole, left, and right SN were compared among the three groups. A multivariate logistic regression model was constructed to determine the factors associated with increased risk of LID. The receiver operating characteristic curve of the QSM value of SN in discriminating PD with and without LID was evaluated. Results The mean QSM values of the whole and right SN in the PD with LID were higher than those in the PD without LID (∗P = 0.03, ∗P = 0.03). Multivariate logistic regression analysis revealed that the QSM value of whole, left, or right SN was a predictor of the development of LID (∗P = 0.03, ∗P = 0.04, and ∗P = 0.04). The predictive accuracy of LID in adding the QSM value of the whole, left, and right SN to LID-related clinical risk factors was 70.6, 64.7, and 67.6%, respectively. The QSM cutoff values between PD with and without LID of the whole, left, and right SN were 148.3, 165.4, and 152.7 ppb, respectively. Conclusion This study provides the evidence of higher iron deposition in the SN of PD patients with LID than those without LID, suggesting that the QSM value of the SN may be a potential early diagnostic neuroimaging biomarker for LID.
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Affiliation(s)
- Tianbin Song
- Department of Radiology and Nuclear Medicine, Xuanwu Hospital, Capital Medical University, Beijing, China.,Beijing Key Laboratory of Magnetic Resonance Imaging and Brain Informatics, Beijing, China
| | - Jiping Li
- Beijing Institute of Functional Neurosurgery, Xuanwu Hospital, Capital Medical University, Beijing, China
| | - Shanshan Mei
- Department of Neurology, Xuanwu Hospital, Capital Medical University, Beijing, China
| | - Xiaofei Jia
- Beijing Institute of Functional Neurosurgery, Xuanwu Hospital, Capital Medical University, Beijing, China
| | - Hongwei Yang
- Department of Radiology and Nuclear Medicine, Xuanwu Hospital, Capital Medical University, Beijing, China.,Beijing Key Laboratory of Magnetic Resonance Imaging and Brain Informatics, Beijing, China
| | - Yongquan Ye
- UIH America, Inc., Houston, TX, United States
| | - Jianmin Yuan
- Central Research Institute, UIH Group, Shanghai, China
| | - Yuqing Zhang
- Beijing Institute of Functional Neurosurgery, Xuanwu Hospital, Capital Medical University, Beijing, China
| | - Jie Lu
- Department of Radiology and Nuclear Medicine, Xuanwu Hospital, Capital Medical University, Beijing, China.,Beijing Key Laboratory of Magnetic Resonance Imaging and Brain Informatics, Beijing, China
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50
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Saikiran P. Effectiveness of QSM over R2* in assessment of parkinson's disease - A systematic review. Neurol India 2021; 68:278-281. [PMID: 32415005 DOI: 10.4103/0028-3886.284377] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022]
Abstract
The incidence and prevalence of Parkinson's (PD) are increasing rapidly in developing countries. PD is difficult to diagnose based on clinical assessment. Presently, magnetic resonance imaging (MRI) methods such as R2* and Quantitative Susceptibility Mapping (QSM) were found to be useful in diagnosing the PD based on the iron deposition in different regions of the brain. The objective of this review was to evaluate the efficacy of QSM over R2* in assessment of PD. A comprehensive literature search was made on PubMed-Medline, CINAHL, Science Direct, Scopus, Web of Science, and the Cochrane library databases for original research articles published between 2000 and 2018. Original articles that reported the efficacy of QSM and R2* in assessment of PD were included. A total of 327 studies were identified in the literature search. However, only ten studies were eligible for analysis. Of the ten studies, five studies compared the accuracy of QSM over R2* in measuring the iron deposition in different regions of brain in PD. Our review found that QSM has better accuracy in identifying iron deposition in PD patients compared to R2*. However, there is discrepancy in the results between MRI Imaging methods and Postmortem studies. Additional longitudinal research studies are needed to provide a strong evidence base for the use of MRI imaging methods such as R2*and QSM in accurately measuring iron deposition in different regions of brain and serve as biomarkers in PD.
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Affiliation(s)
- Pendem Saikiran
- Department of Medical Imaging Technology, Manipal Academy of Higher Education, Manipal, Karnataka, India
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- Department of Medical Imaging Technology, Manipal Academy of Higher Education, Manipal, Karnataka, India
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