Impairment of Motor Function Correlates with Neurometabolite and Brain Iron Alterations in Parkinson’s Disease

Pesch, Beate; Casjens, Swaantje; Woitalla, Dirk; Dharmadhikari, Shalmali; Edmondson, David; Zella, Maria Angela Samis; Lehnert, Martin; Lotz, Anne; Herrmann, Lennard; Muhlack, Siegfried; Kraus, P. H.; Yeh, Chien-Lin; Glaubitz, Benjamin; Schmidt‐Wilcke, Tobias; Gold, Ralf; Thriel, Christoph van; Brüning, Thomas; Tönges, Lars; Dydak, Ulrike

doi:10.3390/cells8020096

Cited by 28 publications

(20 citation statements)

References 51 publications

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“…Further, in this work, the ability to separate the high and normal RII iron content patients using QSM data led to the finding that there are in fact group differences in UPDRS-III scores. Similarly, by using R2 ∗ , Pesch et al (2019) found a correlation between iron content and UPDRS-III scores in the SN of 35 PD patients. However, their R2 ∗ measurements were not corrected for age.…”

Section: Discussionmentioning

confidence: 89%

Regional High Iron in the Substantia Nigra Differentiates Parkinson’s Disease Patients From Healthy Controls

Ghassaban

Sethi

et al. 2019

Front. Aging Neurosci.

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Background: Iron is important in the pathophysiology of Parkinson’s disease (PD) specifically related to degeneration of the substantia nigra (SN). Magnetic resonance imaging (MRI) can be used to measure brain iron in the entire structure but this approach is insensitive to regional changes in iron content. Objective: The goal of this work was to use quantitative susceptibility mapping (QSM) and R2 ∗ to quantify both global and regional brain iron in PD patients and healthy controls (HC) to ascertain if regional changes correlate with clinical conditions and can be used to discriminate patients from controls. Methods: Susceptibility and R2 ∗ maps of 25 PD and 24 HC subjects were reconstructed from data collected on a 3T GE scanner. For the susceptibility maps, three-dimensional regions-of-interest (ROIs) were traced on eight deep gray matter (DGM) structures and an age-based threshold was applied to define regions of high iron content. The same multi-slice ROIs were duplicated on the R2 ∗ maps as well. Mean susceptibility values of both global and regional high iron (RII) content along with global R2 ∗ values were measured and compared not only between the two cohorts, but also to susceptibility and R2 ∗ baselines as a function of age. Finally, clinical features were compared for those PD patients lying above and below the upper 95% regional susceptibility-age prediction intervals. Results: The SN was the only structure showing significantly higher susceptibility in PD patients compared to controls globally ( p < 0.01) and regionally ( p < 0.001). The R2 ∗ values were also higher only in the SN of PD patients compared to the healthy cohort ( p < 0.05). Furthermore, those patients with abnormal susceptibility values lying above the upper 95% prediction intervals had significantly higher united Parkinson’s diagnostic rating scores. R2 ∗ values had larger errors and showed larger dispersion as a function of age than QSM data for global analysis while the dispersion was significantly less for QSM using the RII iron content. Conclusion: Abnormal iron deposition in the SN, especially in RII areas, could serve as a biomarker to distinguish PD patients from HC and to assess disease severity.

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Section: Discussionmentioning

confidence: 89%

Regional High Iron in the Substantia Nigra Differentiates Parkinson’s Disease Patients From Healthy Controls

Ghassaban

Sethi

et al. 2019

Front. Aging Neurosci.

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“…One article only provided the ranges of the values (22). Four articles did not report values as mean ± SD but as median (range) (10,16,23,24).…”

Section: Articles Reviewmentioning

confidence: 99%

“…In all studies, one or two reviewers blinded to the subject characteristics analyzed the MRI images and drew the contours of the SN (or its different subregions) by hand. As for studies using R2 * MRI, 16 studies drew the SN ROI on anatomical images [T2-weighted images (8,9,11,20,38,43), T2 * -weighted images (10,12,13,17,22,28,29,41), or T1weighted (16,24)], and nine used quantitative maps [six used QSM maps (14,30,31,39,42,44), one used an R2 * map (40), one used a T2 * map (23), one used a T1 map (32), two used magnetization transfer (MT) images, and one of them combined with an anatomical T1-weighted image (33,37)]. The majority of studies assumed that the SN corresponded to the hypointense region on T2-weighted images between the red nucleus and the cerebral peduncle (8,10,20,23,38).…”

Section: Regions Of Interest In the Snmentioning

confidence: 99%

“…Others have only reported increased iron contents in some SN subregions (12,13) or have not reported any increase in iron levels (14). Moreover, the role of iron for monitoring disease progression in PD and its correlation with clinical symptoms is still under debate (15)(16)(17). Finally, to estimate iron content, a wide variety of techniques have been employed, and no systematic comparison of the results from these studies has yet been carried out.…”

Section: Introductionmentioning

confidence: 99%

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Iron Imaging as a Diagnostic Tool for Parkinson's Disease: A Systematic Review and Meta-Analysis

et al. 2020

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Background: Parkinson's disease (PD) is a progressive neurodegenerative disease whose main neuropathological feature is the loss of dopaminergic neurons of the substantia nigra (SN). There is also an increase in iron content in the SN in postmortem and imaging studies using iron-sensitive MRI techniques. However, MRI results are variable across studies. Objectives: We performed a systematic meta-analysis of SN iron imaging studies in PD to better understand the role of iron-sensitive MRI quantification to distinguish patients from healthy controls. We also studied the factors that may influence iron quantification and analyzed the correlations between demographic and clinical data and iron load. Methods: We searched PubMed and ScienceDirect databases (from January 1994 to December 2019) for studies that analyzed iron load in the SN of PD patients using T2 * , R2 * , susceptibility weighting imaging (SWI), or quantitative susceptibility mapping (QSM) and compared the values with healthy controls. Details for each study regarding participants, imaging methods, and results were extracted. The effect size and confidence interval (CI) of 95% were calculated for each study as well as the pooled weighted effect size for each marker over studies. Hence, the correlations between technical and clinical metrics with iron load were analyzed. Results: Forty-six articles fulfilled the inclusion criteria including 27 for T2 * /R2 * measures, 10 for SWI, and 17 for QSM (3,135 patients and 1,675 controls). Eight of the articles analyzed both R2 * and QSM. A notable effect size was found in the SN in PD for R2 * increase (effect size: 0.84, 95% CI: 0.60 to 1.08), for SWI measurements (1.14, 95% CI: 0.54 to 1.73), and for QSM increase (1.13, 95% CI: 0.86 to 1.39). Correlations between imaging measures and Unified Parkinson's Disease Rating Scale (UPDRS) scores were mostly observed for QSM. Conclusions: The consistent increase in MRI measures of iron content in PD across the literature using R2 * , SWI, or QSM techniques confirmed that these measurements provided reliable markers of iron content in PD. Several of these measurements correlated with the severity of motor symptoms. Lastly, QSM appeared more robust and reproducible than R2 * and more suited to multicenter studies.

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“…In this context, it is of fundamental importance to consider the interplay between metals and peptides. It is well-established that amyloid β and α-synuclein deposits in human brain tissue are associated with metal accumulations, and these metals can affect the aggregation kinetics of amyloidogenic peptides and proteins through the induction of conformational change and/or metal-catalysed oxidation of the protein backbone [11,12,13,14,15,16,17,18,19,20,21,22,23]. It has been postulated that binding of metallic counter-ions neutralises charge repulsion, permitting the formation of more compact and structured conformations, such as those that comprise filamentous Lewy bodies [23].…”

Section: Introductionmentioning

confidence: 99%

Emerging Approaches to Investigate the Influence of Transition Metals in the Proteinopathies

Lermyte

Everett

Brooks

et al. 2019

Cells

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Transition metals have essential roles in brain structure and function, and are associated with pathological processes in neurodegenerative disorders classed as proteinopathies. Synchrotron X-ray techniques, coupled with ultrahigh-resolution mass spectrometry, have been applied to study iron and copper interactions with amyloid β (1–42) or α-synuclein. Ex vivo tissue and in vitro systems were investigated, showing the capability to identify metal oxidation states, probe local chemical environments, and localize metal-peptide binding sites. Synchrotron experiments showed that the chemical reduction of ferric (Fe3+) iron and cupric (Cu2+) copper can occur in vitro after incubating each metal in the presence of Aβ for one week, and to a lesser extent for ferric iron incubated with α-syn. Nanoscale chemical speciation mapping of Aβ-Fe complexes revealed a spatial heterogeneity in chemical reduction of iron within individual aggregates. Mass spectrometry allowed the determination of the highest-affinity binding region in all four metal-biomolecule complexes. Iron and copper were coordinated by the same N-terminal region of Aβ, likely through histidine residues. Fe3+ bound to a C-terminal region of α-syn, rich in aspartic and glutamic acid residues, and Cu2+ to the N-terminal region of α-syn. Elucidating the biochemistry of these metal-biomolecule complexes and identifying drivers of chemical reduction processes for which there is evidence ex-vivo, are critical to the advanced understanding of disease aetiology.

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Impairment of Motor Function Correlates with Neurometabolite and Brain Iron Alterations in Parkinson’s Disease

Cited by 28 publications

References 51 publications

Regional High Iron in the Substantia Nigra Differentiates Parkinson’s Disease Patients From Healthy Controls

Regional High Iron in the Substantia Nigra Differentiates Parkinson’s Disease Patients From Healthy Controls

Iron Imaging as a Diagnostic Tool for Parkinson's Disease: A Systematic Review and Meta-Analysis

Emerging Approaches to Investigate the Influence of Transition Metals in the Proteinopathies

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