Biology subjects

Henry, R. G.

Publications and source records attributed to Henry, R. G..

3 recordsLinked to original sources

bioRxiv2018

Longitudinally persistent cerebrospinal fluid B-cells resist treatment in multiple sclerosis

B-cells are key contributors to chronic autoimmune pathology in multiple sclerosis (MS). Clonally related B-cells exist in the cerebrospinal fluid (CSF), meninges, and central nervous system (CNS) parenchyma of MS patients. Longitudinally stable CSF oligoclonal band (OCB) antibody patterns suggest some local CNS B-cell persistence; however, the longitudinal B-cell dynamics within and between the CSF and blood remain unknown. We sought to address this by performing immunoglobulin heavy chain variable region repertoire sequencing on B-cells from longitudinally collected blood and CSF samples of MS patients (n=10). All patients were untreated at the time of the initial sampling; the majority (n=7) were treated with immune modulating therapies 1.2 (+/-0.3 SD) years later during the second sampling. We found clonal persistence of B-cells in the CSF of five patients; these B-cells were frequently immunoglobulin (Ig) class-switched and CD27+. We identified specific blood B-cell subsets that appear to provide input into CNS repertoires over time. We demonstrate complex patterns of clonal B-cell persistence in CSF and blood, even in patients on high-efficacy immune modulating therapy. Our findings support the concept that peripheral B-cell activation and CNS-compartmentalized immune mechanisms are in part therapy-resistant.

immunology↗

bioRxiv2017

An automated statistical technique for counting distinct multiple sclerosis lesions can recover aspects of lesion history and provide relevant disease information

BackgroundLesion load is a common biomarker in multiple sclerosis, yet it has historically shown modest associations with clinical outcomes. Lesion count, which encapsulates the natural history of lesion formation and is thought to provide complementary information, is difficult to assess in patients with confluent (i.e. spatially overlapping) lesions. We introduce a statistical technique for cross-sectionally counting pathologically distinct lesions.\n\nMethodsMRI is used to assess the probability of lesion at each location. The texture of this map is quantified using a novel technique, and clusters resembling the center of a lesion are counted.\n\nResultsValidity was demonstrated by comparing the proposed count to a gold-standard count in 60 subjects observed longitudinally. The counts were highly correlated (r = .97, p < .001) and not significantly different (t59 = -0.83, p > .40). Reliability was determined using 14 scans of a clinically stable subject acquired at 7 sites, and variability of lesion count was equivalent to that of lesion load. Accounting for lesion load and age, lesion count was negatively associated (t58 = -2.73, p < .01) with the Expanded Disability Status Scale (EDSS). Average lesion size had a higher association with EDSS (r =.35, p < .01) than lesion load (r = .10, p > .40) or lesion count (r = -.12, p > .30) alone.\n\nConclusionThese findings demonstrate that it is possible to recover important aspects of the natural history of lesion formation without longitudinal data, and suggest that lesion size provides complementary information about disease.\n\nGrant SupportThe project described was supported in part by the NIH grants R01 NS085211, R21 NS093349, and R01 NS094456 from the National Institute of Neurological Disorders and Stroke (NINDS). The study was also supported by the Intramural Research Program of NINDS and the Race to Erase MS Foundation. The content is solely the responsibility of the authors and does not necessarily represent the official views of the funding agencies.

neuroscience↗

bioRxiv2017

Investigating The Functional Consequence Of White Matter Damage: An Automatic Pipeline To Create Longitudinal Disconnection Tractograms

Neurosurgical resection is one of the few opportunities researchers have to image the human brain both prior to and following focal damage. One of the challenges associated with studying brains undergoing surgical resection is that they often do not fit the brain templates most image-processing methodologies are based on, so manual intervention is required to reconcile the pathology and the most extreme cases must be excluded. Manual intervention requires significant time investment and introduces reproducibility concerns. 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. 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 in the patient space, which aligns images using white matter contrast. 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.\n\nAbbreviations\n\nFundingThis work was supported by the National Institutes of Health [5R01NS066654-05]; KJ was supported by the Department of Defense (DoD) [National Defense Science & Engineering Graduate Fellowship (NDSEG) Program].

bioengineering↗