The whole-brain pattern of magnetic susceptibility perturbations in Parkinson's disease

Although iron-mediated oxidative stress has been proposed as a potential pathomechanism in Parkinson's disease, the global distribution of iron accumulation in Parkinson's disease has not yet been elucidated. This study used a new magnetic resonance imaging contrast, quantitative susceptibility mapping, and state-of-the-art methods to map for the first time the whole-brain landscape of magnetostatic alterations as a surrogate for iron level changes in n = 25 patients with idiopathic Parkinson's disease versus n = 50 matched controls. In addition to whole-brain analysis, a regional study including sub-segmentation of the substantia nigra into dorsal and ventral regions and qualitative assessment of susceptibility maps in single subjects were also performed. The most remarkable basal ganglia effect was an apparent magnetic susceptibility increase-consistent with iron deposition-in the dorsal substantia nigra, though an effect was also observed in ventral regions. Increased bulk susceptibility, additionally, was detected in rostral pontine areas and in a cortical pattern tightly concordant with known Parkinson's disease distributions of α-synuclein pathology. In contrast, the normally iron-rich cerebellar dentate nucleus returned a susceptibility reduction suggesting decreased iron content. These results are in agreement with previous post-mortem studies in which iron content was evaluated in specific regions of interest; however, extensive neocortical and cerebellar changes constitute a far more complex pattern of iron dysregulation than was anticipated. Such findings also stand in stark contrast to the lack of statistically significant group change using conventional magnetic resonance imaging methods namely voxel-based morphometry, cortical thickness analysis, subcortical volumetry and tract-based diffusion tensor analysis; confirming the potential of whole-brain quantitative susceptibility mapping as an in vivo biomarker in Parkinson's disease

Multi-centre and multi-vendor reproducibility of a standardized protocol for quantitative susceptibility Mapping of the human brain at 3T

Quantitative Susceptibility Mapping (QSM) is an MRI-based technique allowing the non-invasive quantification of iron content and myelination in the brain. The RIN – Neuroimaging Network established an optimized and harmonized protocol for QSM across ten sites with 3T MRI systems from three different vendors to enable multicentric studies. The assessment of the reproducibility of this protocol is crucial to establish susceptibility as a quantitative biomarker. In this work, we evaluated cross-vendor reproducibility in a group of six traveling brains. Then, we recruited fifty-one volunteers and measured the variability of QSM values in a cohort of healthy subjects scanned at different sites, simulating a multicentric study. Both voxelwise and Region of Interest (ROI)-based analysis on cortical and subcortical gray matter were performed. The traveling brain study yielded high structural similarity (∼0.8) and excellent reproducibility comparing maps acquired on scanners from two different vendors. Depending on the ROI, we reported a quantification error ranging from 0.001 to 0.017 ppm for the traveling brains. In the cohort of fifty-one healthy subjects scanned at nine different sites, the ROI-dependent variability of susceptibility values, of the order of 0.005–0.025 ppm, was comparable to the result of the traveling brain experiment. The harmonized QSM protocol of the RIN – Neuroimaging Network provides a reliable quantification of susceptibility in both cortical and subcortical gray matter regions and it is ready for multicentric and longitudinal clinical studies in neurological and pychiatric diseases

Brain iron deposition is linked with cognitive severity in Parkinson’s disease

Background: Dementia is common in Parkinson’s disease (PD) but measures that track cognitive change in PD are lacking. Brain tissue iron accumulates with age and co-localises with pathological proteins linked to PD dementia such as amyloid. We used quantitative susceptibility mapping (QSM) to detect changes related to cognitive change in PD. Methods: We assessed 100 patients with early-stage to mid-stage PD, and 37 age-matched controls using the Montreal Cognitive Assessment (MoCA), a validated clinical algorithm for risk of cognitive decline in PD, measures of visuoperceptual function and the Movement Disorders Society Unified Parkinson’s Disease Rating Scale part 3 (UPDRS-III). We investigated the association between these measures and QSM, an MRI technique sensitive to brain tissue iron content. Results: We found QSM increases (consistent with higher brain tissue iron content) in PD compared with controls in prefrontal cortex and putamen (p<0.05 corrected for multiple comparisons). Whole brain regression analyses within the PD group identified QSM increases covarying: (1) with lower MoCA scores in the hippocampus and thalamus, (2) with poorer visual function and with higher dementia risk scores in parietal, frontal and medial occipital cortices, (3) with higher UPDRS-III scores in the putamen (all p<0.05 corrected for multiple comparisons). In contrast, atrophy, measured using voxel-based morphometry, showed no differences between groups, or in association with clinical measures. Conclusions: Brain tissue iron, measured using QSM, can track cognitive involvement in PD. This may be useful to detect signs of early cognitive change to stratify groups for clinical trials and monitor disease progression

Quantitative Susceptibility Mapping in Cognitive Decline: A Review of Technical Aspects and Applications

In the human brain, essential iron molecules for proper neurological functioning exist in transferrin (tf) and ferritin (Fe3) forms. However, its unusual increment manifests iron overload, which reacts with hydrogen peroxide. This reaction will generate hydroxyl radicals, and irons higher oxidation states. Further, this reaction causes tissue damage or cognitive decline in the brain and also leads to neurodegenerative diseases. The susceptibility difference due to iron overload within the volume of interest (VOI) responsible for field perturbation of MRI and can benefit in estimating the neural disorder. The quantitative susceptibility mapping (QSM) technique can estimate susceptibility alteration and assist in quantifying the local tissue susceptibility differences. It has attracted many researchers and clinicians to diagnose and detect neural disorders such as Parkinsons, Alzheimers, Multiple Sclerosis, and aging. The paper presents a systematic review illustrating QSM fundamentals and its processing steps, including phase unwrapping, background field removal, and susceptibility inversion. Using QSM, the present work delivers novel predictive biomarkers for various neural disorders. It can strengthen new researchers fundamental knowledge and provides insight into its applicability for cognitive decline disclosure. The paper discusses the future scope of QSM processing stages and their applications in identifying new biomarkers for neural disorders

Multi-centre and multi-vendor reproducibility of a standardized protocol for quantitative susceptibility Mapping of the human brain at 3T

: Quantitative Susceptibility Mapping (QSM) is an MRI-based technique allowing the non-invasive quantification of iron content and myelination in the brain. The RIN - Neuroimaging Network established an optimized and harmonized protocol for QSM across ten sites with 3T MRI systems from three different vendors to enable multicentric studies. The assessment of the reproducibility of this protocol is crucial to establish susceptibility as a quantitative biomarker. In this work, we evaluated cross-vendor reproducibility in a group of six traveling brains. Then, we recruited fifty-one volunteers and measured the variability of QSM values in a cohort of healthy subjects scanned at different sites, simulating a multicentric study. Both voxelwise and Region of Interest (ROI)-based analysis on cortical and subcortical gray matter were performed. The traveling brain study yielded high structural similarity (∼0.8) and excellent reproducibility comparing maps acquired on scanners from two different vendors. Depending on the ROI, we reported a quantification error ranging from 0.001 to 0.017&nbsp;ppm for the traveling brains. In the cohort of fifty-one healthy subjects scanned at nine different sites, the ROI-dependent variability of susceptibility values, of the order of 0.005-0.025&nbsp;ppm, was comparable to the result of the traveling brain experiment. The harmonized QSM protocol of the RIN - Neuroimaging Network provides a reliable quantification of susceptibility in both cortical and subcortical gray matter regions and it is ready for multicentric and longitudinal clinical studies in neurological and pychiatric diseases

Cortical Iron Disrupts Functional Connectivity Networks Supporting Working Memory Performance in Older Adults

Excessive brain iron negatively affects working memory and related processes but the impact of cortical iron on task-relevant, cortical brain networks is unknown. We hypothesized that high cortical iron concentration may disrupt functional circuitry within cortical networks supporting working memory performance. Fifty-five healthy older adults completed an N-Back working memory paradigm while functional magnetic resonance imaging (fMRI) was performed. Participants also underwent quantitative susceptibility mapping (QSM) imaging for assessment of non-heme brain iron concentration. Additionally, pseudo continuous arterial spin labeling scans were obtained to control for potential contributions of cerebral blood volume and structural brain images were used to control for contributions of brain volume. Task performance was positively correlated with strength of task-based functional connectivity (tFC) between brain regions of the frontoparietal working memory network. However, higher cortical iron concentration was associated with lower tFC within this frontoparietal network and with poorer working memory performance after controlling for both cerebral blood flow and brain volume. Our results suggest that high cortical iron concentration disrupts communication within frontoparietal networks supporting working memory and is associated with reduced working memory performance in older adults

Multi-centre, multi-vendor reproducibility of 7T QSM and R2* in the human brain: Results from the UK7T study

Introduction We present the reliability of ultra-high field T2* MRI at 7T, as part of the UK7T Network's “Travelling Heads” study. T2*-weighted MRI images can be processed to produce quantitative susceptibility maps (QSM) and R2* maps. These reflect iron and myelin concentrations, which are altered in many pathophysiological processes. The relaxation parameters of human brain tissue are such that R2* mapping and QSM show particularly strong gains in contrast-to-noise ratio at ultra-high field (7T) vs clinical field strengths (1.5–3T). We aimed to determine the inter-subject and inter-site reproducibility of QSM and R2* mapping at 7T, in readiness for future multi-site clinical studies. Methods Ten healthy volunteers were scanned with harmonised single- and multi-echo T2*-weighted gradient echo pulse sequences. Participants were scanned five times at each “home” site and once at each of four other sites. The five sites had 1× Philips, 2× Siemens Magnetom, and 2× Siemens Terra scanners. QSM and R2* maps were computed with the Multi-Scale Dipole Inversion (MSDI) algorithm (https://github.com/fil-physics/Publication-Code). Results were assessed in relevant subcortical and cortical regions of interest (ROIs) defined manually or by the MNI152 standard space. Results and Discussion Mean susceptibility (χ) and R2* values agreed broadly with literature values in all ROIs. The inter-site within-subject standard deviation was 0.001–0.005 ppm (χ) and 0.0005–0.001 ms−1 (R2*). For χ this is 2.1–4.8 fold better than 3T reports, and 1.1–3.4 fold better for R2*. The median ICC from within- and cross-site R2* data was 0.98 and 0.91, respectively. Multi-echo QSM had greater variability vs single-echo QSM especially in areas with large B0 inhomogeneity such as the inferior frontal cortex. Across sites, R2* values were more consistent than QSM in subcortical structures due to differences in B0-shimming. On a between-subject level, our measured χ and R2* cross-site variance is comparable to within-site variance in the literature, suggesting that it is reasonable to pool data across sites using our harmonised protocol. Conclusion The harmonized UK7T protocol and pipeline delivers on average a 3-fold improvement in the coefficient of reproducibility for QSM and R2* at 7T compared to previous reports of multi-site reproducibility at 3T. These protocols are ready for use in multi-site clinical studies at 7T

Charting human subcortical maturation across the adult lifespan with in vivo 7 T MRI

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