Objective: To visualize the encoding capability of magnetic resonance fingerprinting (MRF) dictionaries. Materials and methods: High-dimensional MRF dictionaries were simulated and embedded into a lower-dimensional space using t-distributed stochastic neighbor embedding (t-SNE). The embeddings were visualized via colors as a surrogate for location in low-dimensional space. First, we illustrate this technique on three different MRF sequences. We then compare the resulting embeddings and the color-coded dictionary maps to these obtained with a singular value decomposition (SVD) dimensionality reduction technique. We validate the t-SNE approach with measures based on existing quantitative measures of encoding capability using the Euclidean distance. Finally, we use t-SNE to visualize MRF sequences resulting from an MRF sequence optimization algorithm. Results: t-SNE was able to show clear differences between the color-coded dictionary maps of three MRF sequences. SVD showed smaller differences between different sequences. These findings were confirmed by quantitative measures of encoding. t-SNE was also able to visualize differences in encoding capability between subsequent iterations of an MRF sequence optimization algorithm. Discussion: This visualization approach enables comparison of the encoding capability of different MRF sequences. This technique can be used as a confirmation tool in MRF sequence optimization.

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Introduction: Cushing's disease (CD) is a rare and severe endocrine disease characterized by hypercortisolemia. Previous studies have found structural brain alterations in remitted CD patients compared to healthy controls, specifically in the anterior cingulate cortex (ACC). However, potential mechanisms through which these persistent alterations may have occurred are currently unknown. Methods: Structural 3T MRI's from 25 remitted CD patients were linked with gene expression data from neurotypical donors, derived from the Allen Human Brain Atlas. Differences in gene expression between the ACC and an unaffected control cortical region were examined, followed by a Gene Ontology (GO) enrichment analysis. A cell type enrichment analysis was conducted on the differentially expressed genes, and a disease association enrichment analysis was conducted to determine possible associations between differentially expressed genes and specific diseases. Subsequently, cortisol sensitivity of these genes in existing datasets was examined. Results: The gene expression analysis identified 300 differentially expressed genes in the ACC compared to the cortical control region. GO analyses found underexpressed genes to represent immune function. The cell type specificity analysis indicated that underexpressed genes were enriched for deactivated microglia and oligodendrocytes. Neither significant associations with diseases, nor evidence of cortisol sensitivity with the differentially expressed genes were found. Discussion: Underexpressed genes in the ACC, the area vulnerable to permanent changes in remitted CD patients, were often associated with immune functioning. The specific lack of deactivated microglia and oligodendrocytes implicates protective effects of these cell types against the long-term effects of cortisol overexposure.

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Structural covariance networks are able to identify functionally organized brain regions by gray matter volume covariance across a population. We examined the transcriptomic signature of such anatomical networks in the healthy brain using postmortem microarray data from the Allen Human Brain Atlas. A previous study revealed that a posterior cingulate network and anterior cingulate network showed decreased gray matter in brains of Parkinson's disease patients. Therefore, we examined these two anatomical networks to understand the underlying molecular processes that may be involved in Parkinson's disease. Whole brain transcriptomics from the healthy brain revealed upregulation of genes associated with serotonin, GPCR, GABA, glutamate, and RAS-signaling pathways. Our results also suggest involvement of the cholinergic circuit, in which genes NPPA, SOSTDC1, and TYRP1 may play a functional role. Finally, both networks were enriched for genes associated with neuropsychiatric disorders that overlap with Parkinson's disease symptoms. The identified genes and pathways contribute to healthy functions of the posterior and anterior cingulate networks and disruptions to these functions may in turn contribute to the pathological and clinical events observed in Parkinson's disease.

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The biological mechanisms underlying inter-individual differences in human stress reactivity remain poorly understood. We aimed to identify the molecular underpinning of aberrant neural stress sensitivity in individuals at risk for schizophrenia. Linking mRNA expression data from the Allen Human Brain Atlas to task-based fMRI revealed 201 differentially expressed genes in cortex-specific brain regions differentially activated by stress in individuals with low (healthy siblings of schizophrenia patients) or high (healthy controls) stress sensitivity. These genes are associated with stress-related psychiatric disorders (e.g. schizophrenia and anxiety) and include markers for specific neuronal populations (e.g. ADCYAP1, GABRB1, SSTR1, and TNFRSF12A), neurotransmitter receptors (e.g. GRIN3A, SSTR1, GABRB1, and HTR1E), and signaling factors that interact with the corticosteroid receptor and hypothalamic-pituitary-adrenal axis (e.g. ADCYAP1, IGSF11, and PKIA). Overall, the identified genes potentially underlie altered stress reactivity in individuals at risk for schizophrenia and other psychiatric disorders and play a role in mounting an adaptive stress response in at-risk individuals, making them potentially druggable targets for stress-related diseases.

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Cortical atrophy is a common manifestation in Parkinson’s disease (PD), particularly in advanced stages of the disease. To elucidate the molecular underpinnings of cortical thickness changes in PD, we performed an integrated analysis of brain-wide healthy transcriptomic data from the Allen Human Brain Atlas and patterns of cortical thickness based on T1-weighted anatomical MRI data of 149 PD patients and 369 controls. For this purpose, we used partial least squares regression to identify gene expression patterns correlated with cortical thickness changes. In addition, we identified gene expression patterns underlying the relationship between cortical thickness and clinical domains of PD. Our results show that genes whose expression in the healthy brain is associated with cortical thickness changes in PD are enriched in biological pathways related to sumoylation, regulation of mitotic cell cycle, mitochondrial translation, DNA damage responses, and ER-Golgi traffic. The associated pathways were highly related to each other and all belong to cellular maintenance mechanisms. The expression of genes within most pathways was negatively correlated with cortical thickness changes, showing higher expression in regions associated with decreased cortical thickness (atrophy). On the other hand, sumoylation pathways were positively correlated with cortical thickness changes, showing higher expression in regions with increased cortical thickness (hypertrophy). Our findings suggest that alterations in the balanced interplay of these mechanisms play a role in changes of cortical thickness in PD and possibly influence motor and cognitive functions.@en

Brain iron accumulation has been found to accelerate disease progression in amyloid-β(Aβ) positive Alzheimer patients, though the mechanism is still unknown. Microglia have been identified as key players in the disease pathogenesis, and are highly reactive cells responding to aberrations such as increased iron levels. Therefore, using histological methods, multispectral immunofluorescence and an automated in-house developed microglia segmentation and analysis pipeline, we studied the occurrence of iron-accumulating microglia and the effect on its activation state in human Alzheimer brains. We identified a subset of microglia with increased expression of the iron storage protein ferritin light chain (FTL), together with increased Iba1 expression, decreased TMEM119 and P2RY12 expression. This activated microglia subset represented iron-accumulating microglia and appeared morphologically dystrophic. Multispectral immunofluorescence allowed for spatial analysis of FTL⁺Iba1⁺-microglia, which were found to be the predominant Aβ-plaque infiltrating microglia. Finally, an increase of FTL⁺Iba1⁺-microglia was seen in patients with high Aβ load and Tau load. These findings suggest iron to be taken up by microglia and to influence the functional phenotype of these cells, especially in conjunction with Aβ.

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Quality assessment of different Magnetic Resonance Fingerprinting (MRF) sequences and their corresponding dictionaries remains an unsolved problem. In this work we present a method in which we approach analysis of MRF dictionaries by performing dimensionality reduction and representing them as low-dimensional point sets (embeddings). Dimensionality reduction was performed using a modification of the t-Distributed Stochastic Neighbor Embedding (t-SNE) algorithm. First, we demonstrated stability of calculated embeddings that allows neglecting the stochastic nature of t-SNE. Next, we proposed and analyzed two algorithms for comparing the embeddings. Finally, we performed two simulations in which we reduced the MRF sequence/dictionary in length or size and analyzed the influence of this reduction on the resulting embedding. We believe that this research can pave the way to development of a software tool for analysis, including better understanding, optimization and comparison, of different MRF sequences.

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Purpose: Intravascular optical coherence tomography (OCT) is widely used for analysis of the coronary artery disease. Its high spatial resolution allows for visualization of arterial tissue components in detail. There are different OCT systems on the market, each of which produces data characterized by its own intensity range and distribution. These differences should be taken into account for the development of image processing algorithms. In order to overcome this difference in the intensity range and distribution, we developed a framework for matching intensities based on the exact histogram matching technique. Methods: In our method, the key step for using the exact histogram matching is to determine the target histogram. For this, we proposed two schemes: a global scheme that uses a single histogram as the target histogram for all the pullbacks, and a local scheme that selects for each single image a target histogram from a predefined database. These two schemes are compared on a unique dataset containing pairs of pullbacks that were acquired shortly after each other with systems from two vendors, St. Jude and Terumo. Pullbacks were aligned according to anatomical landmarks, and a database of matched histogram pairs was created. A leave-one-out cross validation was used to compare performance of the two schemes. The matching accuracy was evaluated by comparing: (a) histograms using Euclidean (dx2) and Kolmogorov–Smirnov (dKS) distances, and (b) median intensity level within anatomical regions of interest. Results: Leave-one-out validation indicated that both matching schemes yield comparably high accuracies across the entire validation dataset. The local scheme outperforms the global scheme with marginally lower dissimilarities at both histogram level and intensity level. High visual similarity was observed when comparing the matched images to their aligned counterparts. Conclusion: Both local and global schemes are robust and produce accurate intensity matching. While local scheme performs marginally better than the global scheme, it requires a predefined histogram dataset and is more time consuming. Thus, for offline standardization of the images, the local scheme should be preferred for being more accurate. For online standardization or when another system is involved, the global scheme can be used as a simple and nearly-as-accurate alternative.@en

Purpose To develop and validate a method for performing inter-station intensity standardization in multispectral whole-body MR data. Methods Different approaches for mapping the intensity of each acquired image stack into the reference intensity space were developed and validated. The registration strategies included: “direct” registration to the reference station (Strategy 1), “progressive” registration to the neighboring stations without (Strategy 2), and with (Strategy 3) using information from the overlap regions of the neighboring stations. For Strategy 3, two regularized modifications were proposed and validated. All methods were tested on two multispectral whole-body MR data sets: a multiple myeloma patients data set (48 subjects) and a whole-body MR angiography data set (33 subjects). Results For both data sets, all strategies showed significant improvement of intensity homogeneity with respect to vast majority of the validation measures (P < 0.005). Strategy 1 exhibited the best performance, closely followed by Strategy 2. Strategy 3 and its modifications were performing worse, in majority of the cases significantly (P < 0.05). Conclusions We propose several strategies for performing inter-station intensity standardization in multispectral whole-body MR data. All the strategies were successfully applied to two types of whole-body MR data, and the “direct” registration strategy was concluded to perform the best. Magn Reson Med 77:422–433, 2017. © 2016 The Authors Magnetic Resonance in Medicine published by Wiley Periodicals, Inc. on behalf of International Society for Magnetic Resonance in Medicine @en

Magnetic resonance imaging (MRI) has become increasingly important in ischemic stroke experiments in mice, especially because it enables longitudinal studies. Still, quantitative analysis of MRI data remains challenging mainly because segmentation of mouse brain lesions in MRI data heavily relies on time-consuming manual tracing and thresholding techniques. Therefore, in the present study, a fully automated approach was developed to analyze longitudinal MRI data for quantification of ischemic lesion volume progression in the mouse brain. We present a level-set-based lesion segmentation algorithm that is built using a minimal set of assumptions and requires only one MRI sequence (T2) as input. To validate our algorithm we used a heterogeneous data set consisting of 121 mouse brain scans of various age groups and time points after infarct induction and obtained using different MRI hardware and acquisition parameters. We evaluated the volumetric accuracy and regional overlap of ischemic lesions segmented by our automated method against the ground truth obtained in a semi-automated fashion that includes a highly time-consuming manual correction step. Our method shows good agreement with human observations and is accurate on heterogeneous data, whilst requiring much shorter average execution time. The algorithm developed here was compiled into a toolbox and made publically available, as well as all the data sets.

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Cytosine-adenine-guanine (CAG) repeat expansions in the coding regions of nine polyglutamine (polyQ) genes (HTT, ATXN1, ATXN2, ATXN3, CACNA1A, ATXN7, ATN1, AR, and TBP) are the cause of several neurodegenerative diseases including Huntington’s disease (HD), six different spinocerebellar ataxias (SCAs), dentatorubral-pallidoluysian atrophy, and spinobulbar muscular atrophy. The expanded CAG repeat length in the causative gene is negatively related to the age-at-onset (AAO) of clinical symptoms. In addition to the expanded CAG repeat length in the causative gene, the normal CAG repeats in the other polyQ genes can affect the AAO, suggesting functional interactions between the polyQ genes. However, there is no detailed assessment of the relationships among polyQ genes in pathologically relevant brain regions. We used gene co-expression analysis to study the functional relationships among polyQ genes in different brain regions using the Allen Human Brain Atlas (AHBA), a spatial map of gene expression in the healthy brain. We constructed co-expression networks for seven anatomical brain structures, as well as a region showing a specific pattern of atrophy in HD patients detected by magnetic resonance imaging (MRI) of the brain. In this HD-associated region, we found that ATN1 and ATXN2 were co-expressed and shared co-expression partners which were enriched for DNA repair genes. We observed a similar co-expression pattern in the frontal lobe, parietal lobe, and striatum in which this relation was most pronounced. Given that the co-expression patterns for these anatomical structures were similar to those for the HD-associated region, our results suggest that their disruption is likely involved in HD pathology. Moreover, ATN1 and ATXN2 also shared many co-expressed genes with HTT, the causative gene of HD, across the brain. Although this triangular relationship among these three polyQ genes may also be dysregulated in other polyQ diseases, stronger co-expression patterns between ATN1 and ATXN2 observed in the HD-associated region, especially in the striatum, may be more specific to HD.@en

We present a combined report on the results of three editions of the Cell Tracking Challenge, an ongoing initiative aimed at promoting the development and objective evaluation of cell segmentation and tracking algorithms. With 21 participating algorithms and a data repository consisting of 13 data sets from various microscopy modalities, the challenge displays today's state-of-the-art methodology in the field. We analyzed the challenge results using performance measures for segmentation and tracking that rank all participating methods. We also analyzed the performance of all of the algorithms in terms of biological measures and practical usability. Although some methods scored high in all technical aspects, none obtained fully correct solutions. We found that methods that either take prior information into account using learning strategies or analyze cells in a global spatiotemporal video context performed better than other methods under the segmentation and tracking scenarios included in the challenge.

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In this data report we make available to the community a highly variable longitudinal MRI mouse brain data set of ischemic lesion after transient middle cerebral artery occlusion (tMCAo). Together with the provided semi-automated and automated segmentations, these data can be used to further improve the method proposed by Mulder et al. (2017) and also to serve as a benchmark for comparison between different approaches to segment ischemic lesions in MRI mouse brain data. It can also be used to develop and validate algorithms that further classify the stroke area into core and penumbra. • The data were collected from mice: (i) of different ages, (ii) of two different strains, (iii) at different time points after the ischemic infarct induction, (iv) from two laboratories, (v) using two different MRI systems, and (vi) using three different sets of acquisition parameters. • Segmentations of the ischemic lesions are provided as well. These were obtained by: (i) two observers using a semi-automated method and (ii) using the novel automated segmentation approach described by Mulder et al. (2017). • Type/format of data: raw files, MetaImage files, text/Excel files, analyzed data. • The following set of images associated with each of the 121 scans is included: raw Bruker MRI data (reference scan, T2 scan with all echoes, calculated T2-weighted map), automated segmentations of the ischemic lesions and semi-automated segmentations by two observers. • For 99 of these scans, an accompanying set of Bruker MR diffusion maps, containing the Diffusion-Weighted Image (DWI) and calculated Apparent Diffusion Coefficient (ADC) maps, is included. • Acquisition hardware: small-animal Bruker MRI systems (7 T and 11.7 T). • Experimental set-up: infarct was induced in male mice of different age and background, using the tMCAo model. After that, MRI scans at different time points after infarct induction were acquired. • Data sources: Leiden, Netherlands; Cologne, Germany. • Data accessibility: all related data sets (121 T2 scans + template + 99 diffusion scans) were deposited in the public Dryad Digital Repository (https://doi.org/10.5061/dryad.1m528).@en

Background: Evaluating inflammatory changes over time on MR images of the spine in patients with suspected axial Spondyloarthritis (axSpA) can be a labor-intensive task, requiring readers to manually search for and perceptually align a set of vertebrae between two scans. The purpose of this study was to assess the feasibility of computer-aided (CA) evaluation of such inflammatory changes in a framework where scans from two time points are fused into a single color-encoded image integrated into an interactive scoring tool. Methods: For 30 patients from the SPondyloArthritis Caught Early (SPACE) cohort (back pain ≥ 3 months, ≤ 2 years, onset < 45 years), baseline and follow-up MR scans acquired 9-12 months apart were fused into a single color-encoded image through locally-rigid image registration to evaluate inflammatory changes in 23 vertebral units (VUs). Scoring was performed by two expert readers on a (-2, 2) scale using an interactive scoring tool. For comparison of direction of change (increase/decrease) indicated by an existing reference, Berlin method scores ((-3, 3) scale) of the same MR scans from a different ongoing study were used. The distributions of VU-level differences between CA readers and between the CA and Berlin methods (sign of change scores) across patients were analyzed descriptively. Patient-level agreement between CA readers was assessed by intraclass correlation coefficient (ICC). Results: Five patients were excluded from evaluation due to failed vertebrae segmentation. Patient-level inter-reader agreement ICC was 0.56 (95% CI: 0.22 to 0.78). Mean VU-level inter-reader differences across 25 patients ranged (-0.04, 0.12) with SD range (0, 0.45). Across all VUs, inter-reader differences ranged (-1, 1) in 573/575 VUs (99.7%). Mean VU-level inter-method differences across patients ranged (-0.04, 0.08) with SD range (0, 0.61). Across all VUs, inter-method differences ranged (-1, 1) in 572/575 VUs (99.5%). Conclusions: Fusion of MR scans of the spine from two time points into a single color-encoded image allows for direct visualization and measurement of inflammatory changes over time in patients with suspected axSpA.

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With an increasing number of large-scale population-based cardiac magnetic resonance (CMR) imaging studies being conducted nowadays, there comes the mammoth task of image annotation and image analysis. Such population-based studies would greatly benefit from automated pipelines, with an efficient CMR image analysis workflow. The purpose of this work is to investigate the feasibility of using a fully-automatic pipeline to segment the left ventricular endocardium and epicardium simultaneously on two orthogonal (vertical and horizontal) long-axis cardiac cine MRI scans. The pipeline is based on a multi-atlas-based segmentation approach and a spatio-temporal registration approach. The performance of the method was assessed by: (i) comparing the automatic segmentations to those obtained manually at both the end-diastolic and end-systolic phase, (ii) comparing the automatically obtained clinical parameters, including end-diastolic volume, end-systolic volume, stroke volume and ejection fraction, with those defined manually and (iii) by the accuracy of classifying subjects to the appropriate risk category based on the estimated ejection fraction. Automatic segmentation of the left ventricular endocardium was achieved with a Dice similarity coefficient (DSC) of 0.93 on the end-diastolic phase for both the vertical and horizontal long-axis scan; on the end-systolic phase the DSC was 0.88 and 0.85, respectively. For the epicardium, a DSC of 0.94 and 0.95 was obtained on the end-diastolic vertical and horizontal long-axis scans; on the end-systolic phase the DSC was 0.90 and 0.88, respectively. With respect to the clinical volumetric parameters, Pearson correlation coefficient (R) of 0.97 was obtained for the end-diastolic volume, 0.95 for end-systolic volume, 0.87 for stroke volume and 0.84 for ejection fraction. Risk category classification based on ejection fraction showed that 80% of the subjects were assigned to the correct risk category and only one subject (< 1%) was more than one risk category off. We conclude that the proposed automatic pipeline presents a viable and cost-effective alternative for manual annotation.

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