Application of Laplacian-based Methods to Multi-echo Phase Data for Accurate Susceptibility Mapping

In Susceptibility Mapping (SM) using multi-echo gradient-echo phase data, unwrapping and/or background-Òeld removal is often performed using Laplacian-based methods. However, SM pipelines in the literature have applied these methods at di×erent stages. Here, using simulated and acquired images, we compared the performance of three pipelines that apply Laplacian-based methods at di× erent stages. We showed that Laplacian-based methods alter the linearity of the phase over time. We demonstrated that only a processing pipeline that takes this into account, i.e. by Òtting the multi-echo data over time to correctly estimate a Òeld map before applying Laplacian-based methods, gives accurate susceptibility values

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

Mixed methodology in human brain research: integrating MRI and histology

Postmortem magnetic resonance imaging (MRI) can provide a bridge between histological observations and the in vivo anatomy of the human brain. Approaches aimed at the co-registration of data derived from the two techniques are gaining interest. Optimal integration of the two research fields requires detailed knowledge of the tissue property requirements for individual research techniques, as well as a detailed understanding of the consequences of tissue fixation steps on the imaging quality outcomes for both MRI and histology. Here, we provide an overview of existing studies that bridge between state-of-the-art imaging modalities, and discuss the background knowledge incorporated into the design, execution and interpretation of postmortem studies. A subset of the discussed challenges transfer to animal studies as well. This insight can contribute to furthering our understanding of the normal and diseased human brain, and to facilitate discussions between researchers from the individual disciplines

Brain Iron Accumulation in Atypical Parkinsonian Syndromes: in vivo MRI Evidences for Distinctive Patterns

Recent data suggest mechanistic links among perturbed iron homeostasis, oxidative stress, and misfolded protein aggregation in neurodegenerative diseases. Iron overload and toxicity toward dopaminergic neurons have been established as playing a role in the pathogenesis of Parkinson's disease (PD). Brain iron accumulation has also been documented in atypical parkinsonian syndromes (APS), mainly comprising multiple system atrophy (MSA), and progressive supranuclear palsy (PSP). Iron-sensitive magnetic resonance imaging (MRI) has been applied to identify iron-related signal changes for the diagnosis and differentiation of these disorders. Topographic patterns of widespread iron deposition in deep brain nuclei have been described as differing between patients with MSA and PSP and those with PD. A disease-specific increase of iron occurs in the brain regions mainly affected by underlying disease pathologies. However, whether iron changes are a primary pathogenic factor or an epiphenomenon of neuronal degeneration has not been fully elucidated. Moreover, the clinical implications of iron-related pathology in APS remain unclear. In this review study, we collected data from qualitative and quantitative MRI studies on brain iron accumulation in APS to identify disease-related patterns and the potential role of iron-sensitive MRI

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

Validation of quantitative susceptibility mapping with Perls' iron staining for subcortical gray matter

Quantitative susceptibility mapping (QSM) measures bulk susceptibilities in the brain, which can arise from many sources. In iron-rich subcortical gray matter (GM), non-heme iron is a dominant susceptibility source. We evaluated the use of QSM for iron mapping in subcortical GM by direct comparison to tissue iron staining. We performed in situ or in vivo QSM at 4.7 T combined with Perls' ferric iron staining on the corresponding extracted subcortical GM regions. This histochemical process enabled examination of ferric iron in complete slices that could be related to susceptibility measurements. Correlation analyses were performed on an individual-by individual basis and high linear correlations between susceptibility and Perls' iron stain were found for the three multiple sclerosis (MS) subjects studied (R-2 = 0.75, 0.62, 0.86). In addition, high linear correlations between susceptibility and transverse relaxation rate (R2*) were found (R-2 = 0.88, 0.88, 0.87) which matched in vivo healthy subjects (R-2 = 0.87). This work validates the accuracy of QSM for brain iron mapping and also confirms ferric iron as the dominant susceptibility source in subcortical GM, by demonstrating high linear correlation of QSM to Perls' ferric iron staining. (C) 2014 Elsevier Inc. All rights reserved

Quantitative Assessment Of Brain Iron Content As A Function Of Age Using Magnetic Resonance Imaging

As the most abundant transition metal in the brain, iron is known to play a key role in a variety of functional and cellular processes. Recent in vivo and post-mortem studies have shown that the levels of iron deposition in the brain, particularly in deep gray matter nuclei, vary as a function of age. On the other hand, elevated iron has also been associated with some neurodegenerative diseases such as Multiple Sclerosis (MS) and Parkinson’s disease (PD) among others. Magnetic Resonance Imaging (MRI) is a widely used non-invasive and non-ionizing imaging modality which is sensitive to magnetic properties of materials through their magnetic susceptibilities. This makes it particularly useful in imaging as iron (which is paramagnetic) and calcium (which is diamagnetic). Recent developments in magnetic susceptibility mapping have made it possible to track iron changes in the brain. In this thesis, Quantitative Susceptibility Mapping (QSM) is used to establish a baseline of iron content in the basal ganglia, midbrain, and cerebellar major nuclei as a function of age in healthy controls using both global (whole 3D structural region) and regional (high iron content region) analyses. In agreement with previous studies, we found that in the global analysis a positive linear susceptibility-age correlation was observed in the putamen, caudate nucleus, and red nucleus while the susceptibility distributions across the lifespan were quite scattered in the globus pallidus, substantia nigra, thalamus, pulvinar thalamus and dentate nucleus. All structures, with the exception of the thalamus, showed increasing susceptibility trend as a function of age in the whole-region analysis. However, in the high iron content region, strong and considerably less scattered correlations were shown between age and magnetic susceptibility in most of the structures, except for the thalamus. These sensitive and robust regional susceptibility-age correlations have the potential to be utilized as a new baseline to investigate abnormal iron content in neurological diseases

Magnetic resonance imaging techniques for diagnostics in Parkinson’s disease and atypical parkinsonism

Background: Parkinson’s disease (PD) is a neurodegenerative disease characterized by rigidity, hypokinesia, tremor and postural instability. PD is a clinical diagnosis based on neurological examination, patient history and treatment response. Similar symptoms can be caused by other movement disorders such as progressive supranuclear palsy (PSP) and multiple system atrophy (MSA), making it difficult to clinically separate them in early stages. However, these diseases differ in underlying pathology, treatment and prognosis. PSP and MSA have more rapid deterioration and develop additional symptoms such as impaired eye movements or autonomic dysfunction. Magnetic resonance imaging (MRI) is commonly performed as part of the clinical work-up in patients presenting with parkinsonism. There are no overt changes on structural MRI in PD. In atypical parkinsonian syndromes there are typically no visible changes until later disease stages. Purpose: The aim of this thesis is to evaluate novel MRI techniques for diagnostics and for investigation of disease processes in Parkinson’s disease, PSP and MSA. Paper I: A retrospective cohort from Karolinska University Hospital (102 participants; 62 PD, 15 PSP, 11 MSA, 14 controls) was assessed using susceptibility mapping processed from susceptibility weighted imaging. We show that there is elevated susceptibility in the red nucleus and the globus pallidus in PSP compared to PD, MSA and controls. Higher susceptibility levels were also seen in MSA compared to PD in the putamen, and in PD compared to controls in the substantia nigra. Using the red nucleus susceptibility as a diagnostic biomarker, PSP could be separated from PD with an accuracy of 97% (based on the area under the receiver operating characteristic curve, AUC), from MSA with AUC 75% and from controls with AUC 98%. We concluded that susceptibility changes, particularly in the red nucleus in PSP, could be potential biomarkers for differential diagnostics in parkinsonism. Paper II: A prospective cohort from Lund, the BioFINDER study (199 participants; 134 PD, 11 PSP, 10 MSA, 44 controls), was investigated using the susceptibility mapping pipeline developed for Paper I. The finding from Paper I with elevated susceptibility in the red nucleus was validated for PSP compared to PD, MSA and controls. The elevated putaminal susceptibility was also confirmed in MSA compared to PD. The potential role of red nucleus susceptibility as a biomarker for separating PSP from PD and MSA was also similar to the results in Paper I, with AUC 98% for separating PSP from PD and AUC 96% for separating PSP from MSA. We concluded that we could confirm our previous findings from Paper I, with the red nucleus susceptibility being a potential biomarker for separating PSP from PD and MSA. Paper III: A retrospective cohort from Karolinska University Hospital (196 participants; 140 PD, 29 PSP, 27 MSA) was evaluated to employ automated volumetric brainstem segmentation using FreeSurfer. The volumetric approach was compared to manual planimetric measurements: midbrain-pons ratio, magnetic resonance parkinsonism index 1.0 and 2.0. Intra- and inter-scanner as well as intra- and inter-rater reliability were calculated. We found good repeatability in both automated volumetric and manual planimetric measurements. Normalized midbrain volume performed better than the planimetric measurements for separating PSP from PD. We concluded that, if further developed and incorporated in a radiology workflow, automated brainstem volumetry could increase availability of brainstem metrics and possibly save time for radiologists conducting manual measurements. Paper IV: Two cohorts, a retrospective from Karolinska University Hospital (184 participants; 129 PD, 28 PSP, 27 MSA) and a prospective from Lund (185 participants; 125 PD, 11 PSP, 8 MSA, 41 controls), were studied to investigate a new method of creating T1-/T2-weighted ratio images and its diagnostic capabilities in differentiating parkinsonian disorders. In the explorative retrospective cohort, differences in white matter normalized T1-/T2- weighted ratios were seen in the caudate nucleus, putamen, thalamus, subthalamic nucleus and red nucleus in PSP compared to PD; in the caudate nucleus and putamen in MSA compared to PD and in the subthalamic nucleus and the red nucleus in PSP compared to MSA. These differences were validated externally in the prospective cohort, where the changes could be confirmed in the subthalamic nucleus and the red nucleus in PSP compared to PD and MSA. We concluded that there are different patterns of white matter normalized T1-/T2-weighted ratio between the disorders and that this reflects differences in underlying pathophysiology. The T1-/T2-weighted ratio should be further investigated for better understanding of pathological processes in parkinsonian disorders and could possibly be utilized for diagnostic purposes if further developed

Differentiating the Substantia Nigra and Ventral Tegmental Area in Early-stage Parkinson\u27s Disease Using Iron Imaging

Excessive midbrain iron accumulation in Parkinson’s Disease (PD) contributes to degeneration of the substantia nigra pars compacta (SNc) and ventral tegmental area (VTA). Despite this understanding, there are no validated PD biomarkers. Magnetic resonance imaging (MRI) can localize and quantify brain iron for diagnosis of PD. Seventeen early-stage PD patients and twenty-one controls were scanned at 3T and 7T MRI. Using quantitative susceptibility mapping (QSM) and R2* relaxometry, we analyzed the average iron content in the SNc, substantia nigra pars reticulata (SNr), and VTA. QSM detected significantly higher SNc iron content in PD patients compared to controls at both field strengths. R2* only detected differences at 7T and showed lower sensitivity and diagnostic accuracy in diagnostic biomarker analyses. As predicted, the SNr and VTA were spared from iron accumulation. SNc iron overload in early-stage PD, best detected using QSM, could be the first diagnostic biomarker of PD following validation