Advanced Magnetic Resonance Imaging Biomarkers of the Injured Spinal Cord: A Comparative Study of Imaging and Histology in Human Traumatic Spinal Cord Injury.

A significant problem in the diagnosis and management of traumatic spinal cord injury (tSCI) is the heterogeneity of secondary injury and the prediction of neurological outcome. Imaging biomarkers specific to myelin loss and inflammation after tSCI would enable detailed assessment of the pathophysiological processes underpinning secondary damage to the cord. Such biomarkers could be used to biologically stratify injury severity and better inform prognosis for neurological recovery. While much work has been done to establish magnetic resonance imaging (MRI) biomarkers for SCI in animal models, the relationship between imaging findings and the underlying pathology has been difficult to discern in human tSCI because of the paucity of human spinal cord tissue. We utilized post-mortem spinal cords from individuals who had a tSCI to examine this relationship by performing ex vivo MRI scans before histological analysis. We investigated the correlation between the histological distribution of myelin loss and inflammatory cells in the injured spinal cord and a number of myelin and inflammation-sensitive MRI measures: myelin water fraction (MWF), inhomogeneous magnetization transfer ratio (ihMTR), and diffusion tensor and diffusion kurtosis imaging-derived fractional anisotropy (FA) and axial, radial, and mean diffusivity (AD, RD, MD). The histological features were analyzed by staining with Luxol Fast Blue (LFB) for myelin lipids and Class II major histocompatibility complex (Class II MHC) and CD68 for microglia and macrophages. Both MWF and ihMTR were strongly correlated with LFB staining for myelin, supporting the use of both as biomarkers for myelin loss after SCI. A decrease in ihMTR was also correlated with the presence of Class II MHC positive immune cells. FA and RD correlated with both Class II MHC and CD68 and may therefore be useful biomarkers for inflammation after tSCI. Our work demonstrates the utility of advanced MRI techniques sensitive to biological tissue damage after tSCI, which is an important step toward using these MRI techniques in the clinic to aid in decision-making.

Regulation of stress granule formation in human oligodendrocytes.

Oligodendrocyte (OL) injury and subsequent loss is a pathologic hallmark of multiple sclerosis (MS). Stress granules (SGs) are membrane-less organelles containing mRNAs stalled in translation and considered as participants of the cellular response to stress. Here we show SGs in OLs in active and inactive areas of MS lesions as well as in normal-appearing white matter. In cultures of primary human adult brain derived OLs, metabolic stress conditions induce transient SG formation in these cells. Combining pro-inflammatory cytokines, which alone do not induce SG formation, with metabolic stress results in persistence of SGs. Unlike sodium arsenite, metabolic stress induced SG formation is not blocked by the integrated stress response inhibitor. Glycolytic inhibition also induces persistent SGs indicating the dependence of SG formation and disassembly on the energetic glycolytic properties of human OLs. We conclude that SG persistence in OLs in MS reflects their response to a combination of metabolic stress and pro-inflammatory conditions.

The CALIPR framework for highly accelerated myelin water imaging with improved precision and sensitivity.

Quantitative magnetic resonance imaging (MRI) techniques are powerful tools for the study of human tissue, but, in practice, their utility has been limited by lengthy acquisition times. Here, we introduce the Constrained, Adaptive, Low-dimensional, Intrinsically Precise Reconstruction (CALIPR) framework in the context of myelin water imaging (MWI); a quantitative MRI technique generally regarded as the most rigorous approach for noninvasive, in vivo measurement of myelin content. The CALIPR framework exploits data redundancy to recover high-quality images from a small fraction of an imaging dataset, which allowed MWI to be acquired with a previously unattainable sequence (fully sampled acquisition 2 hours:57 min:20 s) in 7 min:26 s (4.2% of the dataset, acceleration factor 23.9). CALIPR quantitative metrics had excellent precision (myelin water fraction mean coefficient of variation 3.2% for the brain and 3.0% for the spinal cord) and markedly increased sensitivity to demyelinating disease pathology compared to a current, widely used technique. The CALIPR framework facilitates drastically improved MWI and could be similarly transformative for other quantitative MRI applications.

Sirtuins and Metabolism Biomarkers in Relapsing-Remitting and Secondary Progressive Multiple Sclerosis: a Correlation Study with Clinical Outcomes and Cognitive Impairments.

Multiple sclerosis (MS) is a primary inflammatory demyelinating disease with different clinical courses and subtypes. The present study aimed to determine whether mitochondrial dysfunction and sirtuins 1 and 3, as metabolism and epigenetic modifying factors, might contribute to MS disease progression measured by physical disability and cognitive impairment.The volunteers (n = 20 controls, n = 59 MS) were recruited and assessed for cognitive function and disability scores; then, patients were clinically classified as relapsing-remitting (RR) in remission phase, RR in relapse phase, and secondary progressive MS. We measured sirtuin (SIRT) 1 and 3 levels, mitochondrial complex I, IV, aconitase, and α-ketoglutarate dehydrogenase (α-KGD) activity in the peripheral blood mononuclear cells (PBMCs). Furthermore, SIRT1, pyruvate, lactate, and cytochrome c (Cyt c) were determined in plasma. Finally, we performed postmortem tissue immunohistochemistry to assess the level of SIRT1 and SIRT3 in the brain lesions of patients with MS.Increased disability and cognitive impairment in patients were correlated. Plasma level of lactate showed a correlation with the disability in MS patients; moreover, a trend toward increased Cyt c plasma level was observed. Investigation of PBMCs exhibited decreased SIRT1 during the relapse phase along with a reduced complex IV activity in all MS subgroups. α-KGD activity was significantly increased in the RR-remission, and SIRT3 was elevated in RR-relapse group. This elevation correlated with disability and cognitive impairment. Finally, immunohistochemistry demonstrated increased levels of SIRT1 and 3 in the brain active lesion of patients with MS.Our data suggest that mitochondrial dysfunction and alteration in some epigenetics and metabolism modifying factors in the CNS and peripheral blood cells may contribute or correlate with MS progression.

International Spinal Cord Injury Biobank: A Biorepository and Resource for Translational Research.

Over the past few decades, tremendous advances have been made in our understanding of the biological changes underpinning the devastating impairment of traumatic spinal cord injury (SCI). Much of this scientific research has focused on animal models of SCI, and comparatively little has been done in human SCI, largely because biospecimens from human SCI patients are not readily available. This paucity of scientific enquiry in human SCI represents an important void in the spectrum of translational research, as biological differences between animal models and the human condition need to be considered in the pre-clinical development of therapeutic approaches. The International Spinal Cord Injury Biobank (ISCIB) is a multi-user biorepository with the mission of accelerating therapeutic development in traumatic SCI through improved biological understanding of human injury, and the vision of serving as a global research resource where human SCI biospecimens are shared with researchers around the world. Aligned with internationally recognized best practices, ISCIB's formal governance structure and standard operating procedures have earned it official biobank certification through the Canadian Tissue Repository Network. Herein, we describe the translational research gap that ISCIB is helping to fill; its structure, governance and certification; how data and samples are accrued, processed and stored; and finally, the process through which samples and data are shared with global researchers. The purpose of this paper describing ISCIB is to serve as an introductory guidance document for the wider community of SCI researchers. By helping researchers understand the contents of ISCIB and the process of accessing biospecimens, we seek to further ISCIB's vision as being a resource for human and translational research in SCI, with the ultimate goal of finding disease-modifying therapies for this disabling condition.

Serum neurofilament light chain correlates with myelin and axonal magnetic resonance imaging markers in multiple sclerosis.

BACKGROUND: Neurofilaments are cytoskeletal proteins that are detectable in the blood after neuroaxonal injury. Multiple sclerosis (MS) disease progression, greater lesion volume, and brain atrophy are associated with higher levels of serum neurofilament light chain (NfL), but few studies have examined the relationship between NfL and advanced magnetic resonance imaging (MRI) measures related to myelin and axons. We assessed the relationship between serum NfL and brain MRI measures in a diverse group of MS participants. METHODS AND MATERIALS: 103 participants (20 clinically isolated syndrome, 33 relapsing-remitting, 30 secondary progressive, 20 primary progressive) underwent 3T MRI to obtain myelin water fraction (MWF), geometric mean T2 (GMT2), water content, T1; high angular resolution diffusion imaging (HARDI)-derived axial diffusivity (AD), radial diffusivity (RD), fractional anisotropy (FA); diffusion basis spectrum imaging (DBSI)-derived AD, RD, FA; restricted, hindered, water and fiber fractions; and volume measurements of normalized brain, lesion, thalamic, deep gray matter (GM), and cortical thickness. Multiple linear regressions assessed the strength of association between serum NfL (dependent variable) and each MRI measure in whole brain (WB), normal appearing white matter (NAWM) and T2 lesions (independent variables), while controlling for age, expanded disability status scale, and disease duration. RESULTS: Serum NfL levels were significantly associated with metrics of axonal damage (FA: R2WB-HARDI = 0.29, R2NAWM-HARDI = 0.31, R2NAWM-DBSI = 0.30, R2Lesion-DBSI = 0.31; AD: R2WB-HARDI=0.31), myelin damage (MWF: R2WB = 0.29, R2NAWM = 0.30, RD: R2WB-HARDI = 0.32, R2NAWM-HARDI = 0.34, R2Lesion-DBSI = 0.30), edema and inflammation (T1: R2Lesion = 0.32; GMT2: R2WB = 0.31, R2Lesion = 0.31), and cellularity (restricted fraction R2WB = 0.30, R2NAWM = 0.32) across the entire MS cohort. Higher serum NfL levels were associated with significantly higher T2 lesion volume (R2 = 0.35), lower brain structure volumes (thalamus R2 = 0.31; deep GM R2 = 0.33; normalized brain R2 = 0.31), and smaller cortical thickness R2 = 0.31). CONCLUSION: The association between NfL and myelin MRI markers suggest that elevated serum NfL is a useful biomarker that reflects not only acute axonal damage, but also damage to myelin and inflammation, likely due to the known synergistic myelin-axon coupling relationship.

Diffusely abnormal white matter in multiple sclerosis.

MRI enables detailed in vivo depiction of multiple sclerosis (MS) pathology. Localized areas of MS damage, commonly referred to as lesions, or plaques, have been a focus of clinical and research MRI studies for over four decades. A nonplaque MRI abnormality which is present in at least 25% of MS patients but has received far less attention is diffusely abnormal white matter (DAWM). DAWM has poorly defined boundaries and a signal intensity that is between normal-appearing white matter and classic lesions on proton density and T2 -weighted images. All clinical phenotypes of MS demonstrate DAWM, including clinically isolated syndrome, where DAWM is associated with higher lesion volume, reduced brain volume, and earlier conversion to MS. Advanced MRI metric abnormalities in DAWM tend to be greater than those in NAWM, but not as severe as focal lesions, with myelin, axons, and water-related changes commonly reported. Histological studies demonstrate a primary lipid abnormality in DAWM, with some axonal damage and lesser involvement of myelin proteins. This review provides an overview of DAWM identification, summarizes in vivo and postmortem observations, and comments on potential pathophysiological mechanisms, which may underlie DAWM in MS. Given the prevalence and potential clinical impact of DAWM, the number of imaging studies focusing on DAWM is insufficient. Characterization of DAWM significance and microstructure would benefit from larger longitudinal and additional quantitative imaging efforts. Revisiting data from previous studies that included proton density and T2 imaging would enable retrospective DAWM identification and analysis.

Nonlesional diffusely abnormal appearing white matter in clinically isolated syndrome: Prevalence, association with clinical and MRI features, and risk for conversion to multiple sclerosis.

BACKGROUND AND PURPOSE: While diffusely abnormal white matter (DAWM) is a nonlesional MRI abnormality identified in ∼25% of patients with multiple sclerosis (MS), it has yet to be investigated in patients at an earlier disease stage, namely clinically isolated syndrome (CIS). The goals of this study were to (1) determine the prevalence of DAWM in patients with a CIS suggestive of MS, (2) evaluate the association between DAWM and demographic, clinical, and MRI features, and (3) evaluate the prognostic significance of DAWM on conversion from CIS to MS. METHODS: One hundred and forty-two CIS participants were categorized into DAWM and non-DAWM groups at baseline and followed for up to 24 months or until MS diagnosis. The primary outcome was conversion to MS (2005 McDonald criteria) within 6 months. RESULTS: DAWM was present in 27.5% of participants, and was positively associated with brainstem symptom onset, receiving corticosteroids, dissemination in space, and T2 lesion volume. DAWM was associated with an increased risk of conversion to MS over 6 months after adjustment for age and disability (hazard ratio [HR] = 2.24, p = 0.004). This association remained at a trend-level after adjustment for high-risk imaging features (HR = 1.68, p = 0.10). CONCLUSIONS: DAWM is present in a similar proportion of patients with CIS and clinically definite MS, and it is associated with increased risk of conversion to MS over 6 months.

Interleukin-1 receptor antagonist: An exploratory plasma biomarker that correlates with disability and provides pathophysiological insights in relapsing-remitting multiple sclerosis.

BACKGROUND: Multiple sclerosis (MS) is a chronic inflammatory demyelinating and neurodegenerative disorder. Interleukin-1 receptor antagonist (IL-1RA) is an endogenous soluble antagonist of the IL-1 receptor and blocks the pro-inflammatory effects of IL-1ß known to contribute to MS pathology. The objectives of this study were to determine whether IL-1RA is associated with disability in MS and how this correlates with neurofilament light (NfL) levels in cerebrospinal fluid (CSF). METHODS: Peripheral blood and CSF were collected from consenting MS patients. Patient demographic and clinical variables, including past relapse activity, were also collected. Circulating levels of IL-1RA, IL-18, and IL-1ß were measured in plasma; IL-1RA and NfL were measured in the CSF via Bio-plex multiplex immunoassay kits and ELISA, respectively. IL-1RA expression was investigated in vitro using primary human macrophages and microglia, and in situ using post-mortem MS tissue. RESULTS: Following a multiple regression analysis, IL-1RA levels in plasma correlated with expanded disability status scale score independent of all other variables. In a separate cohort, CSF IL-1RA significantly correlated with NfL. In vitro, induction of the NLRP3 inflammasome, a pathological hallmark within MS lesions, led to increased release of IL-1RA from primary human microglia and macrophages. In the CNS, IL-1RA+ macrophages/microglia were present at the rim of mixed active/inactive MS lesions. CONCLUSIONS: Results presented in this study demonstrate that IL-1RA is a novel exploratory biomarker in relapsing-remitting MS, which correlates with disability and provides mechanistic insights into the regulatory inflammatory responses within the demyelinated CNS.

Temperature dependence and histological correlation of inhomogeneous magnetization transfer and myelin water imaging in ex vivo brain.

PURPOSE: The promise of inhomogeneous magnetization transfer (ihMT) as a new myelin imaging method was studied in ex vivo human brain tissue and in relation to myelin water fraction (MWF). The temperature dependence of both methods was characterized, as well as their correspondence with a histological measure of myelin content. Unfiltered and filtered ihMT protocols were studied by adjusting the saturation scheme to preserve or attenuate signal from tissue with short dipolar relaxation time T1D. METHODS: ihMT ratio (ihMTR) and MWF maps were acquired at 7 T from formalin-fixed human brain samples at 22.5 °C, 30 °C and 37 °C. The impact of temperature on unfiltered ihMTR, filtered ihMTR and MWF was investigated and compared to myelin basic protein staining. RESULTS: Unfiltered ihMTR exhibited no temperature dependence, whereas filtered ihMTR increased with increasing temperature. MWF decreased at higher temperature, with an increasing prevalence of areas where the myelin water signal was unreliably determined, likely related to a reduction in T2 peak separability at higher temperatures ex vivo. MWF and ihMTR showed similar per-sample correlation with myelin staining at room temperature. At 37 °C, filtered ihMTR was more strongly correlated with myelin staining and had increased dynamic range compared to unfiltered ihMTR. CONCLUSIONS: Given the temperature dependence of filtered ihMT, increased dynamic range, and strong myelin specificity that persists at higher temperatures, we recommend carefully controlled temperatures close to 37 °C for filtered ihMT acquisitions. Unfiltered ihMT may also be useful, due to its independence from temperature, higher amplitude values, and sensitivity to short T1D components. Ex vivo myelin water imaging should be performed at room temperature, to avoid fitting issues found at higher temperatures.

Diffusely Abnormal White Matter, T2 Burden of Disease, and Brain Volume in Relapsing-Remitting Multiple Sclerosis.

BACKGROUND AND PURPOSE: Multiple sclerosis (MS) diffusely abnormal white matter (DAWM) is a mildly hyperintense magnetic resonance imaging abnormality distinct from typical lesions. Our goal was to investigate the prevalence and natural history of DAWM in a large cohort (n = 348) of relapsing-remitting MS (RRMS) patients. METHODS: The presence of DAWM and relationship to changes in T2 burden of disease (BOD), brain volume (brain fractional ratio, BFR), and disability (Expanded Disability Status Scale, EDSS) were investigated at baseline and year 7-8 (long-term follow-up, LTF). RESULTS: DAWM was present in 25.3% (88 of 348) of patients at baseline. At LTF, DAWM was unchanged in 69.3% (61 of 88), decreased in 28.4% (25 of 88), and increased in 2.3% (2 of 88) of patients. Baseline BOD and change in BOD did not significantly differ between patients with and without DAWM. DAWM was associated with greater reduction in BFR at LTF (P = .038). DAWM and DAWM change did not predict EDSS or EDSS progression. CONCLUSIONS: DAWM is present in a quarter of RRMS patients, and rarely increases or develops de novo. DAWM predicts brain atrophy but does not predict physical disability. Because of its posterior periventricular location, further investigation is warranted to evaluate its relationship to other measures of disability, including visual spatial processing and cognitive function.

Correlating new directional measures of myelin and axonal integrity in T2-weighted MRI with quantitative histology in multiple sclerosis.

BACKGROUND: Imaging measurement of structure alignment has shown increasing importance in determining tissue properties. It is not known if a similar ability for characterizing neuropathology exists. NEW METHODS: This study aimed to validate a new alignment-assessing method for measuring myelin and axonal properties using quantitative histological metrics. The new method involved analysis of the Fourier transform (FT) power spectrum in standard magnetic resonance imaging (MRI). T2-weighted MRI were collected from 10 post-mortem multiple sclerosis (MS) brain samples. Three tissue types were examined: lesions, diffusely abnormal white matter, and normal appearing white matter. MRI analysis included computing the FT power spectrum; extracting alignment histograms; and calculating dominant orientation and alignment complexity (angular entropy). Post MRI, the brain samples were processed for myelin and axonal staining, and the stained images were used to derive quantitative orientation measures using structure tensor analysis for MRI comparison. RESULTS: There were significant differences in orientation metrics between tissue types in both MRI and histology, and MRI measurements correlated strongly with histological indices. Moreover, the joint effect of myelin and axonal entropy explained over 95% of the variance of MRI angular entropy. COMPARISON WITH EXISTING METHOD: There is no established method for characterizing myelin and axonal pathology using standard MRI. Advanced MRI methods have the potential to do this but are still in research development and are not yet routinely acquired in clinical practice. CONCLUSIONS: Alignment measurement using clinical MRI scans may become a valuable new method for characterizing myelin and axonal properties in MS patients.

Coexistence of Multiple Sclerosis and Alzheimer's disease: A review.

BACKGROUND: People with multiple sclerosis (MS) are living longer than ever and will likely face the same age-related diseases as other seniors; however, there is strikingly little information on the coexistence of MS with many common diseases of aging. In particular, little appears to be known about the coexistence of MS with Alzheimer's disease (AD), the most common form of dementia. METHODS: In this review, we explore what is known about the coexistence of MS and AD, including a focused literature search to identify any reports of individuals with both MS and AD (PubMed, to May 2017). We also discuss the wider epidemiology, diagnosis, and pathophysiology of MS and AD. RESULTS: In total, we found 24 individuals with pathological features of both MS and AD described as case series or reports (published between 1976-2014), but no epidemiological or population-based studies, aside from one conference proceeding (2011). Comorbid MS and AD was reported in a broad range of MS disease courses including relapsing-remitting, primary progressive, secondary progressive and so-called 'benign.' Despite the clear diagnostic challenges involved, these individual case reports provide evidence that AD and MS can coexist in the same person. CONCLUSION: In summary, we highlight a major knowledge gap in our understanding of two potentially common neurological conditions. With the ageing population, and an estimated 2.3 million people living with MS and 46 million with AD or other dementias worldwide, it will become increasingly important to recognize and understand how to manage individuals with these complex comorbid conditions.

Myelin water imaging to detect demyelination and remyelination and its validation in pathology.

Damage to myelin is a key feature of multiple sclerosis (MS) pathology. Magnetic resonance imaging (MRI) has revolutionized our ability to detect and monitor MS pathology in vivo. Proton density, T1 and T2 can provide qualitative contrast weightings that yield superb in vivo visualization of central nervous system tissue and have proved invaluable as diagnostic and patient management tools in MS. However, standard clinical MR methods are not specific to the types of tissue damage they visualize, and they cannot detect subtle abnormalities in tissue that appears otherwise normal on conventional MRIs. Myelin water imaging is an MR method that provides in vivo measurement of myelin. Histological validation work in both human brain and spinal cord tissue demonstrates a strong correlation between myelin water and staining for myelin, validating myelin water as a marker for myelin. Myelin water varies throughout the brain and spinal cord in healthy controls, and shows good intra- and inter-site reproducibility. MS plaques show variably decreased myelin water fraction, with older lesions demonstrating the greatest myelin loss. Longitudinal study of myelin water can provide insights into the dynamics of demyelination and remyelination in plaques. Normal appearing brain and spinal cord tissues show reduced myelin water, an abnormality which becomes progressively more evident over a timescale of years. Diffusely abnormal white matter, which is evident in 20%-25% of MS patients, also shows reduced myelin water both in vivo and postmortem, and appears to originate from a primary lipid abnormality with relative preservation of myelin proteins. Active research is ongoing in the quest to refine our ability to image myelin and its perturbations in MS and other disorders of the myelin sheath.

Myelin regulatory factor drives remyelination in multiple sclerosis.

Remyelination is limited in the majority of multiple sclerosis (MS) lesions despite the presence of oligodendrocyte precursor cells (OPCs) in most lesions. This observation has led to the view that a failure of OPCs to fully differentiate underlies remyelination failure. OPC differentiation requires intricate transcriptional regulation, which may be disrupted in chronic MS lesions. The expression of few transcription factors has been differentially compared between remyelinating lesions and lesions refractory to remyelination. In particular, the oligodendrocyte transcription factor myelin regulatory factor (MYRF) is essential for myelination during development, but its role during remyelination and expression in MS lesions is unknown. To understand the role of MYRF during remyelination, we genetically fate mapped OPCs following lysolecithin-induced demyelination of the corpus callosum in mice and determined that MYRF is expressed in new oligodendrocytes. OPC-specific Myrf deletion did not alter recruitment or proliferation of these cells after demyelination, but decreased the density of new glutathione S-transferase π positive oligodendrocytes. Subsequent remyelination in both the spinal cord and corpus callosum is highly impaired following Myrf deletion from OPCs. Individual OPC-derived oligodendrocytes, produced in response to demyelination, showed little capacity to express myelin proteins following Myrf deletion. Collectively, these data demonstrate a crucial role of MYRF in the transition of oligodendrocytes from a premyelinating to a myelinating phenotype during remyelination. In the human brain, we find that MYRF is expressed in NogoA and CNP-positive oligodendrocytes. In MS, there was both a lower density and proportion of oligodendrocyte lineage cells and NogoA+ oligodendrocytes expressing MYRF in chronically demyelinated lesions compared to remyelinated shadow plaques. The relative scarcity of oligodendrocyte lineage cells expressing MYRF in demyelinated MS lesions demonstrates, for the first time, that chronic lesions lack oligodendrocytes that express this necessary transcription factor for remyelination and supports the notion that a failure to fully differentiate underlies remyelination failure.

An Unusual Case of Rabies Encephalitis.

Human rabies encephalitis is rare in Canada, with only five cases reported in the past 30 years. The first and only patient who contracted rabies encephalitis in British Columbia died in 2003. Here we provide the first detailed clinical and pathological description of that case, which had several unusual features, including preexisting immunosuppression, paralytic presentation, prolonged survival, focal lesions on neuroimaging and severe neuropathology with focal necrosis, intense inflammation, and abundant viral inclusion bodies.

Ionotropic glutamate receptor expression in human white matter.

Glutamate is the key excitatory neurotransmitter of the central nervous system (CNS). Its role in human grey matter transmission is well understood, but this is less clear in white matter (WM). Ionotropic glutamate receptors (iGluR) are found on both neuronal cell bodies and glia as well as on myelinated axons in rodents, and rodent WM tissue is capable of glutamate release. Thus, rodent WM expresses many of the components of the traditional grey matter neuron-to-neuron synapse, but to date this has not been shown for human WM. We demonstrate the presence of iGluRs in human WM by immunofluorescence employing high-resolution spectral confocal imaging. We found that the obligatory N-methyl-d-aspartic acid (NMDA) receptor subunit GluN1 and the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor subunit GluA4 co-localized with myelin, oligodendroglial cell bodies and processes. Additionally, GluA4 colocalized with axons, often in distinct clusters. These findings may explain why human WM is vulnerable to excitotoxic events following acute insults such as stroke and traumatic brain injury and in more chronic inflammatory conditions such as multiple sclerosis (MS). Further exploration of human WM glutamate signalling could pave the way for developing future therapies modulating the glutamate-mediated damage in these and other CNS disorders.

Complement and Humoral Adaptive Immunity in the Human Choroid Plexus: Roles for Stromal Concretions, Basement Membranes, and Epithelium.

The choroid plexus (CP) provides a barrier to entry of toxic molecules from the blood into the brain and transports vital molecules into the cerebrospinal fluid. While a great deal is known about CP physiology, relatively little is known about its immunology. Here, we show immunohistochemical data that help define the role of the CP in innate and adaptive humoral immunity. The results show that complement, in the form of C1q, C3d, C9, or C9neo, is preferentially deposited in stromal concretions. In contrast, immunoglobulin (Ig) G (IgG) and IgA are more often found in CP epithelial cells, and IgM is found in either locale. C4d, IgD, and IgE are rarely, if ever, seen in the CP. In multiple sclerosis CP, basement membrane C9 or stromal IgA patterns were common but were not specific for the disease. These findings indicate that the CP may orchestrate the clearance of complement, particularly by deposition in its concretions, IgA and IgG preferentially via its epithelium, and IgM by either mechanism.

Amyotrophic lateral sclerosis presentation of a human T-lymphotropic virus type-1 myelopathy--insight into pathogenesis.

A 41-year-old human T-lymphotropic virus type 1-positive woman developed a syndrome with upper and lower motor neuron signs sometime after bilateral vertebral artery dissections. Over 2 years, she developed a progressive myelopathy affecting predominantly the motor system. She had the picture of a 'person in a barrel' and died from complications. At autopsy, spinal cord revealed inflammatory infiltrates and extensive gliosis involving mainly the anterior horns. The vertebral arterial dissections may have permitted the entry of infected lymphocytes and macrophages, secreting cytokines and metalloproteinases, into the medulla progressing to the spinal cord. Few cases with pathological correlation have been reported.

Pathological correlates of magnetic resonance imaging texture heterogeneity in multiple sclerosis.

OBJECTIVE: To analyze the texture of T2-weighted magnetic resonance imaging (MRI) of postmortem multiple sclerosis (MS) brain, and to determine whether and how MRI texture correlates with tissue pathology. METHODS: Ten brain samples from 3 subjects with MS were examined. Areas of complete, partial, or no loss of Luxol fast blue (myelin) and Bielschowsky (axons) staining were marked on histological images, and matched on corresponding MRI as lesions, diffusely abnormal white matter (DAWM), and normal-appearing white matter (NAWM). The number of CD45(+) cells (inflammation) was also counted. MRI texture was computed using polar Stockwell transform and compared to histology. RESULTS: Thirty-four lesions, 17 DAWM regions, and 36 NAWM regions were identified. After mixed effects modeling, MRI texture heterogeneity was greater in lesions than in DAWM (p < 0.001) and NAWM (p < 0.001), and was greater in DAWM than in NAWM (p < 0.001); the number of CD45+ cells was greater in both lesions (p < 0.001) and DAWM (p = 0.005) than in NAWM. In MRI, a gradient of texture heterogeneity was detected in lesions, with gradual tapering toward perilesional NAWM. Moreover, besides univariate correlation with histological markers, texture heterogeneity correlated independently with normalized myelin density (p < 0.01) when random effects were considered. Within sample, MRI texture correlated with myelin and axonal density in 7 of 10 samples (p < 0.01). INTERPRETATION: Texture analysis performed on routine clinical magnetic resonance images may be a potential measure of tissue integrity. Tissues with more severe myelin and axonal pathology are associated with greater texture heterogeneity.