Lower arterial cerebral blood flow is associated with worse neuroinflammation and immunomodulation composite proteomic scores.

BACKGROUND: Brain hypoperfusion is linked with worse physical, cognitive and MRI outcomes in multiple sclerosis (MS). Understanding the proteomic signatures related to hypoperfusion could provide insights into the pathophysiological mechanism. METHODS: 140 people with MS (pwMS; 86 clinically isolated syndrome (CIS)/relapsing-remitting (RRMS) and 54 progressive (PMS)) were included. Cerebral arterial blood flow (CABF) was determined using ultrasound Doppler measurement as the sum of blood flow in the bilateral common carotid arteries and vertebral arteries. Proteomic analysis was performed using the Multiple Sclerosis Disease Activity (MSDA) test assay panel performed on the Olink™ platform. The MSDA test measures the concentrations of 18 proteins that are age and sex-adjusted. It utilizes a stacked classifier logistic regression model to determine 4 disease pathway scores (immunomodulation, neuroinflammation, myelin biology, and neuroaxonal integrity) as well as an overall disease activity score (1 to 10). MRI measures of T2 lesion volume (LV) and whole brain volume (WBV) were derived. RESULTS: The pwMS were on average 54 years old and had an average CABF of 951 mL/min. There were no differences in CABF between CIS/RRMS vs. PMS groups. Lower CABF levels were correlated with the overall disease activity score (r = -0.26, p = 0.003) and with the neuroinflammation (r = -0.29, p = 0.001), immunomodulation (r = -0.26, p = 0.003) and neuroaxonal integrity (r = -0.23, p = 0.007) pathway scores. After age and body mass index (BMI)-adjustment, lower CABF remained associated with the neuroinflammatory (r = -0.23, p = 0.011) and immunomodulation (r = -0.20, p = 0.024) pathway scores. The relationship between CABF and the neuroinflammation pathway score remained significant after adjusting for T2-LV and WBV (p = 0.038). Individual analyses identified neurofilament light chain, CCL-20 and TNFSF13B as contributors. When compared to the highest quartile (>1133.5 mL/min), the pwMS in the lowest CABF quartile (<764 mL/min) had greater overall disease activity score (p = 0.003), neuroinflammation (p = 0.001), immunomodulation (p = 0.004) and neuroaxonal integrity pathway scores (p = 0.007). CONCLUSION: Lower cerebral arterial perfusion in MS is associated with changes in neuroinflammatory/immunomodulation pathways and their respective proteomic biomarkers. These findings may suggest a relationship between the hypoperfusion and pro-inflammatory MS changes rather than being merely an epiphenomenon subsequent to lower energy demands.

Proteomic signatures of physical, cognitive, and imaging outcomes in multiple sclerosis.

BACKGROUND: A quantitative measurement of serum proteome biomarkers that would associate with disease progression endpoints can provide risk stratification for persons with multiple sclerosis (PwMS) and supplement the clinical decision-making process. MATERIALS AND METHODS: In total, 202 PwMS were enrolled in a longitudinal study with measurements at two time points with an average follow-up time of 5.4 years. Clinical measures included the Expanded Disability Status Scale, Timed 25-foot Walk, 9-Hole Peg, and Symbol Digit Modalities Tests. Subjects underwent magnetic resonance imaging to determine the volumetric measures of the whole brain, gray matter, deep gray matter, and lateral ventricles. Serum samples were analyzed using a custom immunoassay panel on the Olink™ platform, and concentrations of 18 protein biomarkers were measured. Linear mixed-effects models and adjustment for multiple comparisons were performed. RESULTS: Subjects had a significant 55.6% increase in chemokine ligand 20 (9.7 pg/mL vs. 15.1 pg/mL, p < 0.001) and neurofilament light polypeptide (10.5 pg/mL vs. 11.5 pg/mL, p = 0.003) at the follow-up time point. Additional changes in CUB domain-containing protein 1, Contactin 2, Glial fibrillary acidic protein, Myelin oligodendrocyte glycoprotein, and Osteopontin were noted but did not survive multiple comparison correction. Worse clinical performance in the 9-HPT was associated with neurofilament light polypeptide (p = 0.001). Increases in several biomarker candidates were correlated with greater neurodegenerative changes as measured by different brain volumes. CONCLUSION: Multiple proteins, selected from a disease activity test that represent diverse biological pathways, are associated with physical, cognitive, and radiographic outcomes. Future studies should determine the utility of multiple protein assays in routine clinical care.

Clinical validation of a multi-protein, serum-based assay for disease activity assessments in multiple sclerosis.

An 18-protein multiple sclerosis (MS) disease activity (DA) test was validated based on associations between algorithm scores and clinical/radiographic assessments (N = 614 serum samples; Train [n = 426; algorithm development] and Test [n = 188; evaluation] subsets). The multi-protein model was trained based on presence/absence of gadolinium-positive (Gd+) lesions and was also strongly associated with new/enlarging T2 lesions, and active versus stable disease (composite of radiographic and clinical evidence of DA) with improved performance (p < 0.05) compared to the neurofilament light single protein model. The odds of having ≥1 Gd+ lesions with a moderate/high DA score were 4.49 times that of a low DA score, and the odds of having ≥2 Gd+ lesions with a high DA score were 20.99 times that of a low/moderate DA score. The MSDA Test was clinically validated with improved performance compared to the top-performing single-protein model and can serve as a quantitative tool to enhance the care of MS patients.

Proteomics and relationship with axonal pathology in multiple sclerosis: 5-year diffusion tensor imaging study.

Blood-based biomarkers can be economic and easily accessible tools for monitoring and predicting disease activity in multiple sclerosis. The objective of this study was to determine the predictive value of a multivariate proteomic assay for concurrent and future microstructural/axonal brain pathology in a longitudinal study of a heterogeneous group of people with multiple sclerosis. A proteomic analysis was obtained on serum samples from 202 people with multiple sclerosis (148 relapsing-remitting and 54 progressive) at baseline and 5-year follow-up. The concentration of 21 proteins related to multiple pathways of multiple sclerosis pathophysiology was derived using Proximity Extension Assay on the Olink platform. Patients were imaged on the same 3T MRI scanner at both timepoints. Тhe rate of whole brain, white matter and grey matter atrophy over the 5-year follow-up was determined using the multi-timepoint Structural Image Evaluation, using Normalisation, of Atrophy algorithms. Lesion burden measures were also assessed. The severity of microstructural axonal brain pathology was quantified using diffusion tensor imaging. Fractional anisotropy and mean diffusivity of normal-appearing brain tissue, normal-appearing white matter, grey matter, T2 and T1 lesions were calculated. Age, sex and body mass index-adjusted step-wise regression models were used. Glial fibrillary acidic protein was the most common and highest-ranked proteomic biomarker associated with greater concurrent microstructural central nervous system alterations (P < 0.001). The rate of whole brain atrophy was associated with baseline levels of glial fibrillary acidic protein, protogenin precursor, neurofilament light chain and myelin oligodendrocyte (P < 0.009), whereas grey matter atrophy was associated with higher baseline neurofilament light chain, higher osteopontin and lower protogenin precursor levels (P < 0.016). Higher baseline glial fibrillary acidic protein level was a significant predictor of future severity of the microstructural CNS alterations as measured by normal-appearing brain tissue fractional anisotropy and mean diffusivity (standardized ß = -0.397/0.327, P < 0.001), normal-appearing white matter fractional anisotropy (standardized ß = -0.466, P < 0.0012), grey matter mean diffusivity (standardized ß = 0.346, P < 0.011) and T2 lesion mean diffusivity (standardized ß = 0.416, P < 0.001) at the 5-year follow-up. Serum levels of myelin-oligodendrocyte glycoprotein, neurofilament light chain, contactin-2 and osteopontin proteins were additionally and independently associated with worse concomitant and future axonal pathology. Higher glial fibrillary acidic protein levels were associated with future disability progression (Exp(B) = 8.65, P = 0.004). Multiple proteomic biomarkers are independently associated with greater severity of axonal brain pathology as measured by diffusion tensor imaging in multiple sclerosis. Baseline serum glial fibrillary acidic protein levels can predict future disability progression.

Spinal Cord Atrophy Predicts Progressive Disease in Relapsing Multiple Sclerosis.

OBJECTIVE: A major challenge in multiple sclerosis (MS) research is the understanding of silent progression and Progressive MS. Using a novel method to accurately capture upper cervical cord area from legacy brain MRI scans we aimed to study the role of spinal cord and brain atrophy for silent progression and conversion to secondary progressive disease (SPMS). METHODS: From a single-center observational study, all RRMS (n = 360) and SPMS (n = 47) patients and 80 matched controls were evaluated. RRMS patient subsets who converted to SPMS (n = 54) or silently progressed (n = 159), respectively, during the 12-year observation period were compared to clinically matched RRMS patients remaining RRMS (n = 54) or stable (n = 147), respectively. From brain MRI, we assessed the value of brain and spinal cord measures to predict silent progression and SPMS conversion. RESULTS: Patients who developed SPMS showed faster cord atrophy rates (-2.19%/yr) at least 4 years before conversion compared to their RRMS matches (-0.88%/yr, p < 0.001). Spinal cord atrophy rates decelerated after conversion (-1.63%/yr, p = 0.010) towards those of SPMS patients from study entry (-1.04%). Each 1% faster spinal cord atrophy rate was associated with 69% (p < 0.0001) and 53% (p < 0.0001) shorter time to silent progression and SPMS conversion, respectively. INTERPRETATION: Silent progression and conversion to secondary progressive disease are predominantly related to cervical cord atrophy. This atrophy is often present from the earliest disease stages and predicts the speed of silent progression and conversion to Progressive MS. Diagnosis of SPMS is rather a late recognition of this neurodegenerative process than a distinct disease phase. ANN NEUROL 2022;91:268-281.

Remote Digital Psychiatry for Mobile Mental Health Assessment and Therapy: MindLogger Platform Development Study.

BACKGROUND: Universal access to assessment and treatment of mental health and learning disorders remains a significant and unmet need. There are many people without access to care because of economic, geographic, and cultural barriers, as well as the limited availability of clinical experts who could help advance our understanding and treatment of mental health. OBJECTIVE: This study aims to create an open, configurable software platform to build clinical measures, mobile assessments, tasks, and interventions without programming expertise. Specifically, our primary requirements include an administrator interface for creating and scheduling recurring and customized questionnaires where end users receive and respond to scheduled notifications via an iOS or Android app on a mobile device. Such a platform would help relieve overwhelmed health systems and empower remote and disadvantaged subgroups in need of accurate and effective information, assessment, and care. This platform has the potential to advance scientific research by supporting the collection of data with instruments tailored to specific scientific questions from large, distributed, and diverse populations. METHODS: We searched for products that satisfy these requirements. We designed and developed a new software platform called MindLogger, which exceeds the requirements. To demonstrate the platform's configurability, we built multiple applets (collections of activities) within the MindLogger mobile app and deployed several of them, including a comprehensive set of assessments underway in a large-scale, longitudinal mental health study. RESULTS: Of the hundreds of products we researched, we found 10 that met our primary requirements with 4 that support end-to-end encryption, 2 that enable restricted access to individual users' data, 1 that provides open-source software, and none that satisfy all three. We compared features related to information presentation and data capture capabilities; privacy and security; and access to the product, code, and data. We successfully built MindLogger mobile and web applications, as well as web browser-based tools for building and editing new applets and for administering them to end users. MindLogger has end-to-end encryption, enables restricted access, is open source, and supports a variety of data collection features. One applet is currently collecting data from children and adolescents in our mental health study, and other applets are in different stages of testing and deployment for use in clinical and research settings. CONCLUSIONS: We demonstrated the flexibility and applicability of the MindLogger platform through its deployment in a large-scale, longitudinal, mobile mental health study and by building a variety of other mental health-related applets. With this release, we encourage a broad range of users to apply the MindLogger platform to create and test applets to advance health care and scientific research. We hope that increasing the availability of applets designed to assess and administer interventions will facilitate access to health care in the general population.

QSIPrep: an integrative platform for preprocessing and reconstructing diffusion MRI data.

Diffusion-weighted magnetic resonance imaging (dMRI) is the primary method for noninvasively studying the organization of white matter in the human brain. Here we introduce QSIPrep, an integrative software platform for the processing of diffusion images that is compatible with nearly all dMRI sampling schemes. Drawing on a diverse set of software suites to capitalize on their complementary strengths, QSIPrep facilitates the implementation of best practices for processing of diffusion images.

A Precision Medicine Tool for Patients With Multiple Sclerosis (the Open MS BioScreen): Human-Centered Design and Development.

BACKGROUND: Patients with multiple sclerosis (MS) face several challenges in accessing clinical tools to help them monitor, understand, and make meaningful decisions about their disease course. The University of California San Francisco MS BioScreen is a web-based precision medicine tool initially designed to be clinician facing. We aimed to design a second, openly available tool, Open MS BioScreen, that would be accessible, understandable, and actionable by people with MS. OBJECTIVE: This study aimed to describe the human-centered design and development approach (inspiration, ideation, and implementation) for creating the Open MS BioScreen platform. METHODS: We planned an iterative and cyclical development process that included stakeholder engagement and iterative feedback from users. Stakeholders included patients with MS along with their caregivers and family members, MS experts, generalist clinicians, industry representatives, and advocacy experts. Users consisted of anyone who wants to track MS measurements over time and access openly available tools for people with MS. Phase I (inspiration) consisted of empathizing with users and defining the problem. We sought to understand the main challenges faced by patients and clinicians and what they would want to see in a web-based app. In phase II (ideation), our multidisciplinary team discussed approaches to capture, display, and make sense of user data. Then, we prototyped a series of mock-ups to solicit feedback from clinicians and people with MS. In phase III (implementation), we incorporated all concepts to test and iterate a minimally viable product. We then gathered feedback through an agile development process. The design and development were cyclical-many times throughout the process, we went back to the drawing board. RESULTS: This human-centered approach generated an openly available, web-based app through which patients with MS, their clinicians, and their caregivers can access the site and create an account. Users can enter information about their MS (basic level as well as more advanced concepts), visualize their data longitudinally, access a series of algorithms designed to empower them to make decisions about their treatments, and enter data from wearable devices to encourage realistic goal setting about their ambulatory activity. Agile development will allow us to continue to incorporate precision medicine tools, as these are validated in the clinical research arena. CONCLUSIONS: After engaging intended users into the iterative human-centered design of the Open MS BioScreen, we will now monitor the adaptation and dissemination of the tool as we expand its functionality and reach. The insights generated from this approach can be applied to the development of a number of self-tracking, self-management, and user engagement tools for patients with chronic conditions.

Longitudinal Disconnection Tractograms to Investigate the Functional Consequences of White Matter Damage: An Automated Pipeline.

BACKGROUND AND PURPOSE: Neurosurgical resection is one of the few opportunities researchers have to image the human brain pre- and postfocal damage. A major challenge associated with brains undergoing surgical resection is that they often do not fit brain templates most image-processing methodologies are based on. Manual intervention is required to reconcile the pathology, requiring time investment and introducing reproducibility concerns, and extreme cases must be excluded. METHODS: We propose an automatic longitudinal pipeline based on High Angular Resolution Diffusion Imaging acquisitions to facilitate a Pathway Lesion Symptom Mapping analysis relating focal white matter injury to functional deficits. This two-part approach includes (i) automatic segmentation of focal white matter injury from anisotropic power differences, and (ii) modeling disconnection using tractography on the single-subject level, which specifically identifies the disconnections associated with focal white matter damage. RESULTS: The advantages of this approach stem from (1) objective and automatic lesion segmentation and tractogram generation, (2) objective and precise segmentation of affected tissue likely to be associated with damage to long-range white matter pathways (defined by anisotropic power), (3) good performance even in the cases of anatomical distortions by use of nonlinear tensor-based registration, which aligns images using an approach sensitive to white matter microstructure. CONCLUSIONS: Mapping a system as variable and complex as the human brain requires sample sizes much larger than the current technology can support. This pipeline can be used to execute large-scale, sufficiently powered analyses by meeting the need for an automatic approach to objectively quantify white matter disconnection.

Combining Citizen Science and Deep Learning to Amplify Expertise in Neuroimaging.

Big Data promises to advance science through data-driven discovery. However, many standard lab protocols rely on manual examination, which is not feasible for large-scale datasets. Meanwhile, automated approaches lack the accuracy of expert examination. We propose to (1) start with expertly labeled data, (2) amplify labels through web applications that engage citizen scientists, and (3) train machine learning on amplified labels, to emulate the experts. Demonstrating this, we developed a system to quality control brain magnetic resonance images. Expert-labeled data were amplified by citizen scientists through a simple web interface. A deep learning algorithm was then trained to predict data quality, based on citizen scientist labels. Deep learning performed as well as specialized algorithms for quality control (AUC = 0.99). Combining citizen science and deep learning can generalize and scale expert decision making; this is particularly important in disciplines where specialized, automated tools do not yet exist.

From the Wet Lab to the Web Lab: A Paradigm Shift in Brain Imaging Research.

Web technology has transformed our lives, and has led to a paradigm shift in the computational sciences. As the neuroimaging informatics research community amasses large datasets to answer complex neuroscience questions, we find that the web is the best medium to facilitate novel insights by way of improved collaboration and communication. Here, we review the landscape of web technologies used in neuroimaging research, and discuss future applications, areas for improvement, and the limitations of using web technology in research. Fully incorporating web technology in our research lifecycle requires not only technical skill, but a widespread culture change; a shift from the small, focused "wet lab" to a multidisciplinary and largely collaborative "web lab."

A browser-based tool for visualization and analysis of diffusion MRI data.

Human neuroscience research faces several challenges with regards to reproducibility. While scientists are generally aware that data sharing is important, it is not always clear how to share data in a manner that allows other labs to understand and reproduce published findings. Here we report a new open source tool, AFQ-Browser, that builds an interactive website as a companion to a diffusion MRI study. Because AFQ-Browser is portable-it runs in any web-browser-it can facilitate transparency and data sharing. Moreover, by leveraging new web-visualization technologies to create linked views between different dimensions of the dataset (anatomy, diffusion metrics, subject metadata), AFQ-Browser facilitates exploratory data analysis, fueling new discoveries based on previously published datasets. In an era where Big Data is playing an increasingly prominent role in scientific discovery, so will browser-based tools for exploring high-dimensional datasets, communicating scientific discoveries, aggregating data across labs, and publishing data alongside manuscripts.

Cluster Confidence Index: A Streamline-Wise Pathway Reproducibility Metric for Diffusion-Weighted MRI Tractography.

BACKGROUND: Diffusion-weighted magnetic resonance imaging tractography can be used to create models of white matter fascicles. Anatomical and pathological variability between subjects can drastically alter the tractography output, so standardizing results across a cohort is nontrivial. Furthermore, tractography methods have inherently low reproducibility due to stochasticity (for probabilistic methods) and subjective decisions, since the final fascicle model often requires a manual intervention step performed by an expert human operator to control both outliers and systematic false-positive pathways, as defined by prior knowledge of anatomy. METHODS: We present an approach that computationally assigns a cluster confidence index (CCI) reflecting the reproducibility of that pathway in the context of a streamline dataset. This metric is a tractography algorithm-agnostic tool that can be applied to any dataset of streamlines. RESULTS: Applications of this metric include systematic elimination of outlier streamlines using a CCI threshold and interactive filtering by CCI to facilitate manual segmentation of fascicle models. CONCLUSIONS: This method is intended to replace the application of a streamline density threshold so that outliers are eliminated based on low pathway density instead of voxel-wise density.

Human aging reduces the neurobehavioral influence of motivation on episodic memory.

The neural circuitry mediating the influence of motivation on long-term declarative or episodic memory formation is delineated in young adults, but its status is unknown in healthy aging. We examined the effect of reward and punishment anticipation on intentional declarative memory formation for words using an event-related functional magnetic resonance imaging (fMRI) monetary incentive encoding task in twenty-one younger and nineteen older adults. At 24-hour memory retrieval testing, younger adults were significantly more likely to remember words associated with motivational cues than neutral cues. Motivational enhancement of memory in younger adults occurred only for recollection ("remember" responses) and not for familiarity ("familiar" responses). Older adults had overall diminished memory and did not show memory gains in association with motivational cues. Memory encoding associated with monetary rewards or punishments activated motivational (substantia nigra/ventral tegmental area) and memory-related (hippocampus) brain regions in younger, but not older, adults during the target word periods. In contrast, older and younger adults showed similar activation of these brain regions during the anticipatory motivational cue interval. In a separate monetary incentive delay task that did not require learning, we found evidence for relatively preserved striatal reward anticipation in older adults. This supports a potential dissociation between incidental and intentional motivational processes in healthy aging. The finding that motivation to obtain rewards and avoid punishments had reduced behavioral and neural influence on intentional episodic memory formation in older compared to younger adults is relevant to life-span theories of cognitive aging including the dopaminergic vulnerability hypothesis.

Mindcontrol: A web application for brain segmentation quality control.

Tissue classification plays a crucial role in the investigation of normal neural development, brain-behavior relationships, and the disease mechanisms of many psychiatric and neurological illnesses. Ensuring the accuracy of tissue classification is important for quality research and, in particular, the translation of imaging biomarkers to clinical practice. Assessment with the human eye is vital to correct various errors inherent to all currently available segmentation algorithms. Manual quality assurance becomes methodologically difficult at a large scale - a problem of increasing importance as the number of data sets is on the rise. To make this process more efficient, we have developed Mindcontrol, an open-source web application for the collaborative quality control of neuroimaging processing outputs. The Mindcontrol platform consists of a dashboard to organize data, descriptive visualizations to explore the data, an imaging viewer, and an in-browser annotation and editing toolbox for data curation and quality control. Mindcontrol is flexible and can be configured for the outputs of any software package in any data organization structure. Example configurations for three large, open-source datasets are presented: the 1000 Functional Connectomes Project (FCP), the Consortium for Reliability and Reproducibility (CoRR), and the Autism Brain Imaging Data Exchange (ABIDE) Collection. These demo applications link descriptive quality control metrics, regional brain volumes, and thickness scalars to a 3D imaging viewer and editing module, resulting in an easy-to-implement quality control protocol that can be scaled for any size and complexity of study.

BIDS apps: Improving ease of use, accessibility, and reproducibility of neuroimaging data analysis methods.

The rate of progress in human neurosciences is limited by the inability to easily apply a wide range of analysis methods to the plethora of different datasets acquired in labs around the world. In this work, we introduce a framework for creating, testing, versioning and archiving portable applications for analyzing neuroimaging data organized and described in compliance with the Brain Imaging Data Structure (BIDS). The portability of these applications (BIDS Apps) is achieved by using container technologies that encapsulate all binary and other dependencies in one convenient package. BIDS Apps run on all three major operating systems with no need for complex setup and configuration and thanks to the comprehensiveness of the BIDS standard they require little manual user input. Previous containerized data processing solutions were limited to single user environments and not compatible with most multi-tenant High Performance Computing systems. BIDS Apps overcome this limitation by taking advantage of the Singularity container technology. As a proof of concept, this work is accompanied by 22 ready to use BIDS Apps, packaging a diverse set of commonly used neuroimaging algorithms.

Mindboggling morphometry of human brains.

Mindboggle (http://mindboggle.info) is an open source brain morphometry platform that takes in preprocessed T1-weighted MRI data and outputs volume, surface, and tabular data containing label, feature, and shape information for further analysis. In this article, we document the software and demonstrate its use in studies of shape variation in healthy and diseased humans. The number of different shape measures and the size of the populations make this the largest and most detailed shape analysis of human brains ever conducted. Brain image morphometry shows great potential for providing much-needed biological markers for diagnosing, tracking, and predicting progression of mental health disorders. Very few software algorithms provide more than measures of volume and cortical thickness, while more subtle shape measures may provide more sensitive and specific biomarkers. Mindboggle computes a variety of (primarily surface-based) shapes: area, volume, thickness, curvature, depth, Laplace-Beltrami spectra, Zernike moments, etc. We evaluate Mindboggle's algorithms using the largest set of manually labeled, publicly available brain images in the world and compare them against state-of-the-art algorithms where they exist. All data, code, and results of these evaluations are publicly available.

Intra- and interscanner variability of magnetic resonance imaging based volumetry in multiple sclerosis.

Brain volumetric measurements in multiple sclerosis (MS) reflect not only disease-specific processes but also other sources of variability. The latter has to be considered especially in multicenter and longitudinal studies. Here, we compare data generated by three different 3-Tesla magnetic resonance scanners (Philips Achieva; Siemens Verio; GE Signa MR750). We scanned two patients diagnosed with relapsing remitting MS six times per scanner within three weeks (T1w and FLAIR, 3D). We assessed T2-hyperintense lesions by an automated lesion segmentation tool and determined volumes of grey matter (GM), white matter (WM) and whole brain (GM+WM) from the lesion-filled T1-weighted images using voxel-based morphometry (SPM8/VBM8) and SIENAX (FSL). We measured cortical thickness using FreeSurfer from both, lesion-filled and original T1-weighted images. We quantified brain volume changes with SIENA. In both patients, we found significant differences in total lesion volume, global brain tissue volumes and cortical thickness measures between the scanners. Morphometric measures varied remarkably between repeated scans at each scanner, independent of the brain imaging software tool used. We conclude that for cross-sectional multicenter studies, the effect of different scanners has to be taken into account. For longitudinal monocentric studies, the expected effect size should exceed the size of false positive findings observed in this study. Assuming a physiological loss of brain volume of about 0.3% per year in healthy adult subjects (Good et al., 2001), which may double in MS (De Stefano et al., 2010; De Stefano et al., 2015), with current tools reliable estimation of brain atrophy in individual patients is only possible over periods of several years.

Association of HLA Genetic Risk Burden With Disease Phenotypes in Multiple Sclerosis.

IMPORTANCE: Although multiple HLA alleles associated with multiple sclerosis (MS) risk have been identified, genotype-phenotype studies in the HLA region remain scarce and inconclusive. OBJECTIVES: To investigate whether MS risk-associated HLA alleles also affect disease phenotypes. DESIGN, SETTING, AND PARTICIPANTS: A cross-sectional, case-control study comprising 652 patients with MS who had comprehensive phenotypic information and 455 individuals of European origin serving as controls was conducted at a single academic research site. Patients evaluated at the Multiple Sclerosis Center at University of California, San Francisco between July 2004 and September 2005 were invited to participate. Spinal cord imaging in the data set was acquired between July 2013 and March 2014; analysis was performed between December 2014 and December 2015. MAIN OUTCOMES AND MEASURES: Cumulative HLA genetic burden (HLAGB) calculated using the most updated MS-associated HLA alleles vs clinical and magnetic resonance imaging outcomes, including age at onset, disease severity, conversion time from clinically isolated syndrome to clinically definite MS, fractions of cortical and subcortical gray matter and cerebral white matter, brain lesion volume, spinal cord gray and white matter areas, upper cervical cord area, and the ratio of gray matter to the upper cervical cord area. Multivariate modeling was applied separately for each sex data set. RESULTS: Of the 652 patients with MS, 586 had no missing genetic data and were included in the HLAGB analysis. In these 586 patients (404 women [68.9%]; mean [SD] age at disease onset, 33.6 [9.4] years), HLAGB was higher than in controls (median [IQR], 0.7 [0-1.4] and 0 [-0.3 to 0.5], respectively; P = 1.8 × 10-27). A total of 619 (95.8%) had relapsing-onset MS and 27 (4.2%) had progressive-onset MS. No significant difference was observed between relapsing-onset MS and primary progressive MS. A higher HLAGB was associated with younger age at onset and the atrophy of subcortical gray matter fraction in women with relapsing-onset MS (standard ß = -1.20 × 10-1; P = 1.7 × 10-2 and standard ß = -1.67 × 10-1; P = 2.3 × 10-4, respectively), which were driven mainly by the HLA-DRB1*15:01 haplotype. In addition, we observed the distinct role of the HLA-A*24:02-B*07:02-DRB1*15:01 haplotype among the other common DRB1*15:01 haplotypes and a nominally protective effect of HLA-B*44:02 to the subcortical gray atrophy (standard ß = -1.28 × 10-1; P = 5.1 × 10-3 and standard ß = 9.52 × 10-2; P = 3.6 × 10-2, respectively). CONCLUSIONS AND RELEVANCE: We confirm and extend previous observations linking HLA MS susceptibility alleles with disease progression and specific clinical and magnetic resonance imaging phenotypic traits.