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The mechanisms responsible for the selective vulnerability of specific neuronal populations in Parkinson's disease are poorly understood. Oxidative stress secondary to brain iron accumulation is one postulated mechanism. We measured iron deposition in 180 cortical regions of 96 patients with Parkinson's disease and 35 control subjects using quantitative susceptibility mapping. We estimated the expression of 15 745 genes in the same regions using transcriptomic data from the Allen Human Brain Atlas. Using partial least squares regression, we then identified the profile of gene transcription in the healthy brain that underlies increased cortical iron in patients with Parkinson's disease relative to controls. Applying gene ontological tools, we investigated the biological processes and cell types associated with this transcriptomic profile and identified the sets of genes with spatial expression profiles in control brains that correlated significantly with the spatial pattern of cortical iron deposition in Parkinson's disease. Gene ontological analyses revealed that these genes were enriched for biological processes relating to heavy metal detoxification, synaptic function and nervous system development and were predominantly expressed in astrocytes and glutamatergic neurons. Furthermore, we demonstrated that the genes differentially expressed in Parkinson's disease are associated with the pattern of cortical expression identified in this study. Our findings provide mechanistic insights into regional selective vulnerabilities in Parkinson's disease, particularly the processes involving iron accumulation., (© The Author(s) (2021). Published by Oxford University Press on behalf of the Guarantors of Brain.)

Background Abnormal findings at brain MRI in patients with neurologic Wilson disease (WD) are characterized by signal intensity changes and cerebral atrophy. T2 signal hypointensities and atrophy are largely irreversible with treatment; their relationship with permanent disability has not been systematically investigated. Purpose To investigate associations of regional brain atrophy and iron accumulation at MRI with clinical severity in participants with neurologic WD who are undergoing long-term anti-copper treatment. Materials and Methods Participants with WD and controls were compared in a prospective study performed from 2015 to 2019. MRI at 3.0 T included three-dimensional T1-weighted and six-echo multigradient-echo pulse sequences for morphometry and quantitative susceptibility mapping, respectively. Neurologic severity was assessed with the Unified WD Rating Scale (UWDRS). Automated multi-atlas segmentation pipeline with dual contrast (susceptibility and T1) was used for the calculation of volumes and mean susceptibilities in deep gray matter nuclei. Additionally, whole-brain analysis using deformation and surface-based morphometry was performed. Least absolute shrinkage and selection operator regression was used to assess the association of regional volumes and susceptibilities with the UWDRS score. Results Twenty-nine participants with WD (mean age, 47 years ± 9 [standard deviation]; 15 women) and 26 controls (mean age, 45 years ± 12; 14 women) were evaluated. Whole-brain analysis demonstrated atrophy of the deep gray matter nuclei, brainstem, internal capsule, motor cortex and corticospinal pathway, and visual cortex and optic radiation in participants with WD ( P < .05 at voxel level, corrected for family-wise error). The UWDRS score was negatively correlated with volumes of putamen ( r = -0.63, P < .001), red nucleus ( r = -0.58, P = .001), globus pallidus ( r = -0.53, P = .003), and substantia nigra ( r = -0.50, P = .006) but not with susceptibilities. Only the putaminal volume was identified as a stable factor associated with the UWDRS score ( R 2 < .001) using least absolute shrinkage and selection operator regression. Conclusion Individuals with Wilson disease (WD) had widespread brain atrophy most pronounced in the central structures. The putaminal volume was associated with the Unified WD Rating Scale score and can be used as a surrogate imaging marker of clinical severity. © RSNA, 2021 P < .001) using least absolute shrinkage and selection operator regression. Conclusion Individuals with Wilson disease (WD) had widespread brain atrophy most pronounced in the central structures. The putaminal volume was associated with the Unified WD Rating Scale score and can be used as a surrogate imaging marker of clinical severity. © RSNA, 2021 Supplemental material is available for this article. See also the editorial by Du and Bydder in this issue.

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., Competing Interests: Competing interests: RSW has received personal fees from GE healthcare. A-ES has received personal fees from MedTronic. JA-C has equity and a full-time appointment at Tenoke Limited., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY. Published by BMJ.)

Background: Mitochondrial membrane protein-associated neurodegeneration is an autosomal-recessive disorder caused by C19orf12 mutations and characterized by iron deposits in the basal ganglia., Objectives: The aim of this study was to quantify iron concentrations in deep gray matter structures using quantitative susceptibility mapping MRI and to characterize metabolic abnormalities in the pyramidal pathway using 1 H MR spectroscopy in clinically manifesting membrane protein-associated neurodegeneration patients and asymptomatic C19orf12 gene mutation heterozygous carriers., Methods: We present data of 4 clinically affected membrane protein-associated neurodegeneration patients (mean age: 21.0 ± 2.9 years) and 9 heterozygous gene mutation carriers (mean age: 50.4 ± 9.8 years), compared to age-matched healthy controls. MRI assessments were performed on a 7.0 Tesla whole-body system, consisting of whole-brain gradient-echo scans and short echo time, single-volume MR spectroscopy in the white matter of the precentral/postcentral gyrus. Quantitative susceptibility mapping, a surrogate marker for iron concentration, was performed using a state-of-the-art multiscale dipole inversion approach with focus on the globus pallidus, thalamus, putamen, caudate nucleus, and SN., Results and Conclusion: In membrane protein-associated neurodegeneration patients, magnetic susceptibilities were 2 to 3 times higher in the globus pallidus (P = 0.02) and SN (P = 0.02) compared to controls. In addition, significantly higher magnetic susceptibility was observed in the caudate nucleus (P = 0.02). Non-manifesting heterozygous mutation carriers exhibited significantly increased magnetic susceptibility (relative to controls) in the putamen (P = 0.003) and caudate nucleus (P = 0.001), which may be an endophenotypic marker of genetic heterozygosity. MR spectroscopy revealed significantly increased levels of glutamate, taurine, and the combined concentration of glutamate and glutamine in membrane protein-associated neurodegeneration, which may be a correlate of corticospinal pathway dysfunction frequently observed in membrane protein-associated neurodegeneration patients. © 2019 International Parkinson and Movement Disorder Society., (© 2019 International Parkinson and Movement Disorder Society.)

Purpose: The quality and precision of post-mortem MRI microscopy may vary depending on the embedding medium used. To investigate this, our study evaluated the impact of 5 widely used media on: (1) image quality, (2) contrast of high spatial resolution gradient-echo (T 1 and T 2 * ), and (4) quantitative susceptibility measurements (QSM) of post-mortem brain specimens.2 * ), and (4) quantitative susceptibility measurements (QSM) of post-mortem brain specimens., Methods: Five formaldehyde-fixed brain slices were scanned using 7.0T MRI in: (1) formaldehyde solution (formalin), (2) phosphate-buffered saline (PBS), (3) deuterium oxide (D 2 O), (4) perfluoropolyether (Galden), and (5) agarose gel. SNR and contrast-to-noise ratii (SNR/CNR) were calculated for cortex/white matter (WM) and basal ganglia/WM regions. In addition, median R 2 * and QSM values were extracted from caudate nucleus, putamen, globus pallidus, WM, and cortical regions., Results: PBS, Galden, and agarose returned higher SNR/CNR compared to formalin and D 2 O. Formalin fixation, and its use as embedding medium for scanning, increased tissue R 2 * . Imaging with agarose, D 2 O, and Galden returned lower R 2 * values than PBS (and formalin). No major QSM offsets were observed, although spatial variance was increased (with respect to R 2 * behaviors) for formalin and agarose., Conclusions: Embedding media affect gradient-echo image quality, R 2 * , and QSM in differing ways. In this study, PBS embedding was identified as the most stable experimental setup, although by a small margin. Agarose and Galden were preferred to formalin or D 2 O embedding. Formalin significantly increased R 2 * causing noisier data and increased QSM variance., (© 2018 International Society for Magnetic Resonance in Medicine.)

Purpose: Recent literature has shown the potential of high-resolution quantitative susceptibility mapping (QSM) with ultra-high field MRI for imaging the anatomy, the vasculature, and investigating their magnetostatic properties. Higher spatial resolutions, however, translate to longer scans resulting, therefore, in higher vulnerability to, and likelihood of, subject movement. We propose a gradient-recalled echo sequence with prospective motion correction (PMC) to address such limitation., Methods: Data from 4 subjects were acquired at 7T. The effect of small and large motion on QSM with and without PMC was assessed qualitatively and quantitatively. Full brain QSM and QSM-based venograms with up to 0.33 mm isotropic voxel size were reconstructed., Results: With PMC, motion artifacts in QSM and QSM-based venograms were largely eliminated, enabling-in both large- and small-amplitude motion regimes-accurate depiction of the cortex, vasculature, and other small anatomical structures that are often blurred as a result of head movement or indiscernible at lower image resolutions. Quantitative analyses demonstrated that uncorrected motion could bias regional susceptibility distributions, a trend that was greatly reduced with PMC., Conclusion: Qualitatively, PMC prevented image degradation because of motion artifacts, providing highly detailed QSM images and venograms. Quantitatively, PMC increased the reproducibility of susceptibility measures., (© 2018 International Society for Magnetic Resonance in Medicine.)

Purpose: Background-field removal is a crucial preprocessing step for quantitative susceptibility mapping (QSM). Remnants from this step often contaminate the estimated local field, which in turn leads to erroneous tissue-susceptibility reconstructions. The present work aimed to mitigate this undesirable behavior with the development of a new approach that simultaneously decouples background contributions and local susceptibility sources on QSM inversion., Methods: Input phase data for QSM can be seen as a composite scalar field of local effects and residual background components. We developed a new weak-harmonic regularizer to constrain the latter and to separate the 2 components. The resulting optimization problem was solved with the alternating directions of multipliers method framework to achieve fast convergence. In addition, for convenience, a new alternating directions of multipliers method-based preconditioned nonlinear projection onto dipole fields solver was developed to enable initializations with wrapped-phase distributions. Weak-harmonic QSM, with and without nonlinear projection onto dipole fields preconditioning, was compared with the original (alternating directions of multipliers method-based) total variation QSM algorithm in phantom and in vivo experiments., Results: Weak-harmonic QSM returned improved reconstructions regardless of the method used for background-field removal, although the proposed nonlinear projection onto dipole fields method often obtained better results. Streaking and shadowing artifacts were substantially suppressed, and residual background components were effectively removed., Conclusion: Weak-harmonic QSM with field preconditioning is a robust dipole inversion technique and has the potential to be extended as a single-step formulation for initialization with uncombined multi-echo data., (© 2018 International Society for Magnetic Resonance in Medicine.)

Purpose: Parametric imaging methods (e.g., T 1 relaxation time mapping) have been shown to be more reproducible across time and vendors than weighted (e.g., T 1 -weighted) images. The purpose of this work was to more extensively evaluate the validity of this assertion., Methods: Seven volunteers underwent twice-repeated acquisitions of variable flip-angle T 1 mapping, including B 1 + calibration, on a 3T Philips Achieva and 3T Siemens Trio scanner. Intra-scanner and inter-vendor T 1 variability were calculated. To determine T 1 reproducibility levels in longitudinal settings, or after changing hardware or software, four additional data sets were acquired from two of the participants; one participant was scanned on a different 3T Siemens Trio scanner and another on the same 3T Philips Achieva scanner but after a software upgrade., Results: Intra-scanner variability of voxel-wise T 1 values was consistent between the two vendors, averaging 0.7/0.7/1.3/1.4% in white matter/cortical gray matter/subcortical gray matter/cerebellum, respectively. We observed, however, a systematic bias between the two vendors of https://doi.org/10.0/7.8/8.6/10.0%, respectively. The T 1 bias across two scanners of the same model was greater than intra-scanner variability, although still only at 1.4/1.0/1.9/2.3%, respectively. A greater bias was identified for data sets acquired before/after software upgrade in white matter/cortical gray matter (3.6/2.7%) whereas variability in subcortical gray matter/cerebellum was comparable (1.7/1.9%)., Conclusion: We established intra- and inter-vendor reproducibility levels for a widely used T 1 mapping protocol. We anticipate that these results will guide the design of multi-center studies, particularly those encompassing multiple vendors. Furthermore, this baseline level of reproducibility should be established or surpassed during the piloting phase of such studies., (© 2018 International Society for Magnetic Resonance in Medicine.)

Quantitative Susceptibility Mapping (QSM), best known as a surrogate for tissue iron content, is becoming a highly relevant MRI contrast for monitoring cellular and vascular status in aging, addiction, traumatic brain injury and, in general, a wide range of neurological disorders. In this study we present a new Bayesian QSM algorithm, named Multi-Scale Dipole Inversion (MSDI), which builds on the nonlinear Morphology-Enabled Dipole Inversion (nMEDI) framework, incorporating three additional features: (i) improved implementation of Laplace's equation to reduce the influence of background fields through variable harmonic filtering and subsequent deconvolution, (ii) improved error control through dynamic phase-reliability compensation across spatial scales, and (iii) scalewise use of the morphological prior. More generally, this new pre-conditioned QSM formalism aims to reduce the impact of dipole-incompatible fields and measurement errors such as flow effects, poor signal-to-noise ratio or other data inconsistencies that can lead to streaking and shadowing artefacts. In terms of performance, MSDI is the first algorithm to rank in the top-10 for all metrics evaluated in the 2016 QSM Reconstruction Challenge. It also demonstrated lower variance than nMEDI and more stable behaviour in scan-rescan reproducibility experiments for different MRI acquisitions at 3 and 7 Tesla. In the present work, we also explored new forms of susceptibility MRI contrast making explicit use of the differential information across spatial scales. Specifically, we show MSDI-derived examples of: (i) enhanced anatomical detail with susceptibility inversions from short-range dipole fields (hereby referred to as High-Pass Susceptibility Mapping or HPSM), (ii) high specificity to venous-blood susceptibilities for highly regularised HPSM (making a case for MSDI-based Venography or VenoMSDI), (iii) improved tissue specificity (and possibly statistical conditioning) for Macroscopic-Vessel Suppressed Susceptibility Mapping (MVSSM), and (iv) high spatial specificity and definition for HPSM-based Susceptibility-Weighted Imaging (HPSM-SWI) and related intensity projections., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)

Purpose To investigate the whole-brain landscape of iron-related abnormalities in amyotrophic lateral sclerosis (ALS) by using the in vivo MRI technique of quantitative susceptibility mapping (QSM). Materials and Methods For this prospective study, 28 patients with ALS (mean age, 61 years; age range, 43-77 years; 18 men [mean age, 61 years; range, 43-77 years] and 10 women [mean age, 61 years; range, 47-74 years]) recruited between January 17, 2014, and September 4, 2015, and 39 matched control subjects (mean age, 61 years; age range, 39-77 years; 24 men [mean age, 62 years; range, 39-77 years] and 15 women [mean age, 59 years; range, 39-73 years]) were examined by using structural and susceptibility 3.0-T MRI techniques. Group data were cross sectionally compared with family-wise error (FWE) corrections by using voxel-based morphometry (random-field theory), cortical thickness analysis (Monte Carlo simulated), subcortical volumetry (Bonferroni-corrected Wilcoxon rank-sum testing), and QSM analysis (cluster-enhanced whole-brain permutation testing and Bonferroni-corrected rank-sum testing in regions of interest). In patients with ALS, a potential relationship between diffusion and susceptibility measurements in the corticospinal tracts (CSTs) was also examined by using Spearman rank-correlation tests. Results Conventional structural measures failed to identify atrophy in the present cohort (FWE P > .05). However, QSM identified several whole-brain abnormalities (FWE P < .05) in ALS. Regionally, higher susceptibility (expressed as means in parts per million ± standard errors of the mean) was confirmed in the motor cortex (ALS = 0.0188 ± 0.0003, control = 0.0173 ± 0.0003; P < .001), the left substantia nigra (ALS = 0.127 ± 0.004, control = 0.113 ± 0.003; P = .008), the right substantia nigra (ALS = 0.141 ± 0.005, control = 0.120 ± 0.003; P < .001), the globus pallidus (ALS = 0.086 ± 0.003, control = 0.075 ± 0.002; P = .003), and the red nucleus (ALS = 0.115 ± 0.004, control = 0.098 ± 0.003; P < .001). Lower susceptibility was found in CST white matter (ALS = -0.047 ± 0.001, control = -0.043 ± 0.001; P = .01). Nigral and pallidal QSM values were cross correlated in ALS (ρ 2 = 0.42, P < .001), a phenomenon visually traceable in many individual patients. QSM in the CST in ALS also correlated with diffusion-tensor metrics in this tract (ρ 2 = 0.25, P = .007). Conclusion Whole-brain MRI quantitative susceptibility mapping analysis is sensitive to tissue alterations in amyotrophic lateral sclerosis that may be relevant to pathologic changes. © RSNA, 2018.

Individuals with Down syndrome (DS) are more likely to experience earlier onset of multiple facets of physiological aging. This includes brain atrophy, beta amyloid deposition, cognitive decline, and Alzheimer's disease-factors indicative of brain aging. Here, we employed a machine learning approach, using structural neuroimaging data to predict age (i.e., brain-predicted age) in people with DS (N = 46) and typically developing controls (N = 30). Chronological age was then subtracted from brain-predicted age to generate a brain-predicted age difference (brain-PAD) score. DS participants also underwent [ 11 C]-PiB positron emission tomography (PET) scans to index the levels of cerebral beta amyloid deposition, and cognitive assessment. Mean brain-PAD in DS participants' was +2.49 years, significantly greater than controls (p < 0.001). The variability in brain-PAD was associated with the presence and the magnitude of PiB-binding and levels of cognitive performance. Our study indicates that DS is associated with premature structural brain aging, and that age-related alterations in brain structure are associated with individual differences in the rate of beta amyloid deposition and cognitive impairment., (Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.)

Quantitative susceptibility mapping (QSM) has recently emerged as a novel magnetic resonance imaging (MRI) method to detect non-haem iron deposition, calcifications, demyelination and vascular lesions in the brain. It has been suggested that QSM is more sensitive than the more conventional quantifiable MRI measure, namely the transverse relaxation rate, R2*. Here, we conducted the first high-resolution, whole-brain, simultaneously acquired, comparative study of the two techniques using 7Tesla MRI. We asked which of the two techniques would be more sensitive to explore global differences in tissue composition in elderly adults relative to young subjects. Both QSM and R2* revealed strong age-related differences in subcortical regions, hippocampus and cortical grey matter, particularly in superior frontal regions, motor/premotor cortices, insula and cerebellar regions. Within the basal ganglia system-but also hippocampus and cerebellar dentate nucleus-, QSM was largely in agreement with R2* with the exception of the globus pallidus. QSM, however, provided superior anatomical contrast and revealed age-related differences in the thalamus and in white matter, which were otherwise largely undetected by R2* measurements. In contrast, in occipital cortex, age-related differences were much greater with R2* compared to QSM. The present study, therefore, demonstrated that in vivo QSM using ultra-high field MRI provides a novel means to characterise age-related differences in the human brain, but also combining QSM and R2* using multi-gradient recalled echo imaging can potentially provide a more complete picture of mineralisation, demyelination and/or vascular alterations in aging and disease., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Disruption of iron homeostasis as a consequence of aging is thought to cause iron levels to increase, potentially promoting oxidative cellular damage. Therefore, understanding how this process evolves through the lifespan could offer insights into both the aging process and the development of aging-related neurodegenerative brain diseases. This work aimed to map, in vivo for the first time with an unbiased whole-brain approach, age-related iron changes using quantitative susceptibility mapping (QSM)--a new postprocessed MRI contrast mechanism. To this end, a full QSM standardization routine was devised and a cohort of N = 116 healthy adults (20-79 years of age) was studied. The whole-brain and ROI analyses confirmed that the propensity of brain cells to accumulate excessive iron as a function of aging largely depends on their exact anatomical location. Whereas only patchy signs of iron scavenging were observed in white matter, strong, bilateral, and confluent QSM-age associations were identified in several deep-brain nuclei--chiefly the striatum and midbrain-and across motor, premotor, posterior insular, superior prefrontal, and cerebellar cortices. The validity of QSM as a suitable in vivo imaging technique with which to monitor iron dysregulation in the human brain was demonstrated by confirming age-related increases in several subcortical nuclei that are known to accumulate iron with age. The study indicated that, in addition to these structures, there is a predilection for iron accumulation in the frontal lobes, which when combined with the subcortical findings, suggests that iron accumulation with age predominantly affects brain regions concerned with motor/output functions., Significance Statement: This study used a whole--brain imaging approach known as quantitative susceptibility mapping (QSM) to provide a novel insight into iron accumulation in the brain across the adult lifespan. Validity of the method was demonstrated by showing concordance with ROI analysis and prior knowledge of iron accumulation in subcortical nuclei. We discovered that, beyond these regions, there is extensive involvement of the frontal lobes that has been missed by past ROI analyses. Broadly speaking, therefore, the motor system selectively accumulates iron with age. The results offer insights into the aging process, but also offer a new approach to studying the role of iron dysregulation in the evolution of age-related neurodegenerative diseases., (Copyright © 2016 Acosta-Cabronero et al.)

This study aimed to test the superiority proposed by Abbott et al. (2011) of their Voxel based iterative sensitivity (VBIS) method over Voxel Based Morphometry using T2-weighted images (T2-VBM), in detecting intensity changes in Alzheimer's disease (AD). A comparison was made first in simulated intensity lesions and then in AD patients. Intensity changes were evaluated in the whole-brain with VBIS and with a simple intensity-based approach and in specific tissue classes with the conventional VBM method of using tissue probability segments. Results showed that VBIS performed well in the simulated environment though it showed no superiority in detecting the lesion compared to the much simpler VBM approach. The VBIS method, however, failed to detect any meaningful signal intensity reduction in AD patient data. Moreover, its whole brain approach was contaminated by the excess cerebrospinal fluid signal (very bright on T2-weighted scans) in areas of maximal measurable atrophy (mesial temporal lobes); this gave rise to spurious signal intensity increases in these regions in AD. The same artefact was observed for both intensity-based methods but not with the conventional VBM approach of performing statistics on grey matter segments. In conclusion, no evidence was found to indicate that VBIS offers benefits over T2-VBM in AD, nor in simulation intensity lesions. The study highlights the necessity of empirically testing voxel-based analysis techniques rather than merely claiming superiority of one method over another on theoretical grounds., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Background: This study explores the magnetostatic properties of the Alzheimer's disease brain using a recently proposed, magnetic resonance imaging, postprocessed contrast mechanism. Quantitative susceptibility mapping (QSM) has the potential to monitor in vivo iron levels by reconstructing magnetic susceptibility sources from field perturbations. However, with phase data acquired at a single head orientation, the technique relies on several theoretical approximations and requires fast-evolving regularisation strategies., Methods: In this context, the present study describes a complete methodological framework for magnetic susceptibility measurements with a review of its theoretical foundations., Findings and Significance: The regional and whole-brain cross-sectional comparisons between Alzheimer's disease subjects and matched controls indicate that there may be significant magnetic susceptibility differences for deep brain nuclei--particularly the putamen--as well as for posterior grey and white matter regions. The methodology and findings described suggest that the QSM method is ready for larger-scale clinical studies.

Although magnetic resonance imaging is a standard investigation in neurodegenerative disease, sensitive and specific markers for the underlying histopathological diagnosis are largely lacking. This report presents evidence to indicate that corticobasal degeneration and progressive supranuclear palsy, in particular, might be identifiable at a single subject level with diffusion tensor imaging. Patients with clinical diagnoses of Alzheimer's disease, semantic dementia and non-fluent primary progressive aphasia (n = 9 each) were contrasted with control subjects (n = 26) with the diffusion tensor imaging measures: fractional anisotropy, axial and radial diffusivity. At 1 year follow-up, all participants with non-fluent primary progressive aphasia had evolved either corticobasal degeneration (n = 5) or progressive supranuclear palsy (n = 4). The corticobasal degeneration/progressive supranuclear palsy set showed white matter abnormalities involving the entire cerebrum. Individual maps were similar to the group level results, even in the most minimally impaired patients. Fractional anisotropy was consistently the most sensitive metric. In Alzheimer's disease and semantic dementia, by contrast, group level and individual analyses revealed limited areas of abnormality centred on the posterior cingulate and rostral temporal lobes, respectively. In both groups radial diffusivity was the most sensitive metric. Scrutiny of the standard scores for each group's most sensitive metric revealed that, although the values for every patient with corticobasal degeneration or progressive supranuclear palsy fell outside 95% of the normal mean, none of the other two groups' members had values outside this range. Further underscoring the hypothesis that this finding relates specifically to a diffuse pathological process in the white matter of the tauopathies, and is not merely a function of disease severity, a grey matter analysis consisting of group level voxel-based morphometry revealed only focal areas of atrophy in all three groups. Consistent with past reports for the respective clinical syndromes, these were centred on the left frontal operculum and caudate nucleus in non-fluent primary progressive aphasia (the corticobasal degeneration/progressive supranuclear palsy set), anterior temporal lobes in semantic dementia, and hippocampus and posterior cingulate gyrus in Alzheimer's disease. Detection of this extensive white matter lesion in corticobasal degeneration and progressive supranuclear palsy-a pathologically proven feature of these conditions--in single subjects with diffusion tensor imaging appears to have strong diagnostic marker potential for these diseases.

Diffusion tensor imaging (DTI) detects white matter damage in neuro-psychiatric disorders, but data on reliability of DTI measures across more than two scanners are still missing. In this study we assessed multicenter reproducibility of DTI acquisitions based on a physical phantom as well as brain scans across 16 scanners. In addition, we performed DTI scans in a group of 26 patients with clinically probable Alzheimer's disease (AD) and 12 healthy elderly controls at one single center. We determined the variability of fractional anisotropy (FA) measures using manually placed regions of interest as well as automated tract based spatial statistics and deformation based analysis. The coefficient of variation (CV) of FA was 6.9% for the physical phantom data. The mean CV across the multicenter brain scans was 14% for tract based statistics, and 29% for deformation based analysis. The degree of variation was higher in less organized fiber tracts. Our findings suggest that a clinical and physical phantom study involving more than two scanners is indispensable to detect potential sources of bias and to reliably estimate effect size in multicenter diagnostic trials using DTI., (2011 Elsevier Ireland Ltd. All rights reserved.)

Voxel-based morphometry (VBM) of T1-weighted magnetic resonance (MR) images has been widely used to identify regional atrophy in neurodegenerative conditions such as Alzheimer's disease (AD). In theory, however, T2-weighting should be more sensitive to tissue pathology, though until recently, volumetric T2-weighted images were unavailable. We tested the hypothesis that T2-VBM would be more sensitive to grey matter pathology in AD than T1-VBM using the recently-developed SPACE acquisition, which provides true-3D, high-resolution T2-weighted images. This was contrasted to conventional T1-weighted MPRAGE images acquired at the same session and resolution. All of the atrophic regions identified with T1-VBM were also identified with T2-VBM. Additional abnormalities were, however, identified with T2-VBM and the distribution of these bore a striking resemblance to the distribution of amyloid plaque deposition in AD, suggesting that T2-VBM detects signal changes due to histopathology over and above those attributable to atrophy. In keeping with this hypothesis, the relevant statistical tests demonstrated that the difference in sensitivity was caused by an apparent change in T2-weighted signal intensity that was not present in T1-weighted images. These results suggest that T2-VBM has the potential to advance VBM beyond atrophy detection to more expansive applications in tissue pathology mapping., (Copyright © 2011 Elsevier Inc. All rights reserved.)

This study evaluates the application of (i) skull-stripping methods (hybrid watershed algorithm (HWA), brain surface extractor (BSE) and brain-extraction tool (BET2)) and (ii) bias correction algorithms (nonparametric nonuniform intensity normalisation (N3), bias field corrector (BFC) and FMRIB's automated segmentation tool (FAST)) as pre-processing pipelines for the technique of voxel-based morphometry (VBM) using statistical parametric mapping v.5 (SPM5). The pipelines were evaluated using a BrainWeb phantom, and those that performed consistently were further assessed using artificial-lesion masks applied to 10 healthy controls compared to the original unlesioned scans, and finally, 20 Alzheimer's disease (AD) patients versus 23 controls. In each case, pipelines were compared to each other and to those from default SPM5 methodology. The BET2+N3 pipeline was found to produce the least miswarping to template induced by real abnormalities, and performed consistently better than the other methods for the above experiments. Occasionally, the clusters of significant differences located close to the boundary were dragged out of the glass-brain projections -- this could be corrected by adding background noise to low-probability voxels in the grey matter segments. This method was confirmed in a one-dimensional simulation and was preferable to threshold and explicit (simple) masking which excluded true abnormalities.

Background: In Wilson's disease (WD), demyelination, rarefaction, gliosis, and iron accumulation in the deep gray matter cause opposing effects on T2 -weighted MR signal. However, the degree and interplay of these changes in chronically treated WD patients has not been quantitatively studied.Purpose: To compare differences in brain multiparametric mapping between controls and chronically treated WD patients with neurological (neuro-WD) and hepatic (hep-WD) forms to infer the nature of residual WD neuropathology.Study Type: Cross-sectional.Population/subjects: Thirty-eight WD patients (28 neuro-WD, 10 hep-WD); 26 healthy controls.Field Strength/sequence: 3.0T: susceptibility, T2 *, T2 , T1 relaxometry; 1.5T: T2 , T1 relaxometry.Assessment: The following 3D regions of interest (ROIs) were manually segmented: globus pallidus, putamen, caudate nucleus, and thalamus. Mean bulk magnetic susceptibility, T2 *, T2 , and T1 relaxation times were calculated for each ROI.Statistical Tests: The effect of group (neuro-WD, hep-WD, controls) and age was assessed using a generalized least squares model with different variance for each ROI and quantitative parameter. A general linear hypothesis test with Tukey adjustment was used for post-hoc between-group analysis; P < 0.05 was considered significant.Results: Susceptibility values were higher in all ROIs in neuro-WD compared to controls and hep-WD (P < 0.001). In basal ganglia, lower T2 and T2 * were found in neuro-WD compared to controls (P < 0.01) and hep-WD (P < 0.05) at 3.0T. Much smaller intergroup differences for T2 in basal ganglia were observed at 1.5T compared to 3.0T. In the thalamus, increased susceptibility in neuro-WD was accompanied by increased T1 at both field strengths (P < 0.001 to both groups), and an increased T2 at 1.5T only (P < 0.001 to both groups).Data Conclusion: We observed significant residual brain MRI abnormalities in neuro-WD but not in hep-WD patients on chronic anticopper treatment. Patterns of changes were suggestive of iron accumulation in the basal ganglia and demyelination in the thalamus; 3.0T was more sensitive for detection of the former and 1.5T of the latter abnormality.Level Of Evidence: 2 Technical Efficacy Stage: 3 J. Magn. Reson. Imaging 2020;51:1829-1835. [ABSTRACT FROM AUTHOR]

Background: Sporadic degenerative ataxia patients fall into 2 major groups: multiple system atrophy with predominant cerebellar ataxia (MSA-C) and sporadic adult-onset ataxia (SAOA). Both groups have cerebellar volume loss, but little is known about the differential involvement of gray and white matter in MSA-C when compared with SAOA.Objectives: The objective of this study was to identify structural differences of brain gray and white matter between both patient groups.Methods: We used magnetic resonance imaging to acquire T1-weighted images and diffusion tensor images from 12 MSA-C patients, 31 SAOA patients, and 55 healthy controls. Magnetic resonance imaging data were analyzed with voxel-based-morphometry, tract-based spatial statistics, and tractography-based regional diffusion tensor images analysis.Results: Whole-brain and cerebellar-focused voxel-based-morphometry analysis showed gray matter volume loss in both patient groups when compared with healthy controls, specifically in the cerebellar areas subserving sensorimotor functions. When compared with controls, the SAOA and MSA-C patients showed white matter loss in the cerebellum, whereas brainstem white matter was reduced only in the MSA-C patients. The tract-based spatial statistics revealed reduced fractional anisotropy within the pons and cerebellum in the MSA-C patients both in comparison with the SAOA patients and healthy controls. In addition, tractography-based regional analysis showed reduced fractional anisotropy along the corticospinal tracts in MSA-C, but not SAOA.Conclusion: Although in our cohort extent and distribution of gray and white matter loss were similar between the MSA-C and SAOA patients, magnetic resonance imaging data showed prominent microstructural white matter involvement in the MSA-C patients that was not present in the SAOA patients. Our findings highlight the significance of microstructural white matter changes in the differentiation between both conditions. © 2020 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society. [ABSTRACT FROM AUTHOR]

Wilson's disease is an autosomal-recessive disorder of copper metabolism with neurological and hepatic presentations. Chelation therapy is used to 'de-copper' patients but neurological outcomes remain unpredictable. A range of neuroimaging abnormalities have been described and may provide insights into disease mechanisms, in addition to prognostic and monitoring biomarkers. Previous quantitative MRI analyses have focused on specific sequences or regions of interest, often stratifying chronically treated patients according to persisting symptoms as opposed to initial presentation. In this cross-sectional study, we performed a combination of unbiased, whole-brain analyses on T1-weighted, fluid-attenuated inversion recovery, diffusion-weighted and susceptibility-weighted imaging data from 40 prospectively recruited patients with Wilson's disease (age range 16-68). We compared patients with neurological (n = 23) and hepatic (n = 17) presentations to determine the neuroradiological sequelae of the initial brain injury. We also subcategorized patients according to recent neurological status, classifying those with neurological presentations or deterioration in the preceding 6 months as having 'active' disease. This allowed us to compare patients with active (n = 5) and stable (n = 35) disease and identify imaging correlates for persistent neurological deficits and copper indices in chronically treated, stable patients. Using a combination of voxel-based morphometry and region-of-interest volumetric analyses, we demonstrate that grey matter volumes are lower in the basal ganglia, thalamus, brainstem, cerebellum, anterior insula and orbitofrontal cortex when comparing patients with neurological and hepatic presentations. In chronically treated, stable patients, the severity of neurological deficits correlated with grey matter volumes in similar, predominantly subcortical regions. In contrast, the severity of neurological deficits did not correlate with the volume of white matter hyperintensities, calculated using an automated lesion segmentation algorithm. Using tract-based spatial statistics, increasing neurological severity in chronically treated patients was associated with decreasing axial diffusivity in white matter tracts whereas increasing serum non-caeruloplasmin-bound ('free') copper and active disease were associated with distinct patterns of increasing mean, axial and radial diffusivity. Whole-brain quantitative susceptibility mapping identified increased iron deposition in the putamen, cingulate and medial frontal cortices of patients with neurological presentations relative to those with hepatic presentations and neurological severity was associated with iron deposition in widespread cortical regions in chronically treated patients. Our data indicate that composite measures of subcortical atrophy provide useful prognostic biomarkers, whereas abnormal mean, axial and radial diffusivity are promising monitoring biomarkers. Finally, deposition of brain iron in response to copper accumulation may directly contribute to neurodegeneration in Wilson's disease. [ABSTRACT FROM AUTHOR]

The mechanisms responsible for the selective vulnerability of specific neuronal populations in Parkinson's disease are poorly understood. Oxidative stress secondary to brain iron accumulation is one postulated mechanism. We measured iron deposition in 180 cortical regions of 96 patients with Parkinson's disease and 35 control subjects using quantitative susceptibility mapping. We estimated the expression of 15 745 genes in the same regions using transcriptomic data from the Allen Human Brain Atlas. Using partial least squares regression, we then identified the profile of gene transcription in the healthy brain that underlies increased cortical iron in patients with Parkinson's disease relative to controls. Applying gene ontological tools, we investigated the biological processes and cell types associated with this transcriptomic profile and identified the sets of genes with spatial expression profiles in control brains that correlated significantly with the spatial pattern of cortical iron deposition in Parkinson's disease. Gene ontological analyses revealed that these genes were enriched for biological processes relating to heavy metal detoxification, synaptic function and nervous system development and were predominantly expressed in astrocytes and glutamatergic neurons. Furthermore, we demonstrated that the genes differentially expressed in Parkinson's disease are associated with the pattern of cortical expression identified in this study. Our findings provide mechanistic insights into regional selective vulnerabilities in Parkinson's disease, particularly the processes involving iron accumulation. [ABSTRACT FROM AUTHOR]