Richard L. Yates

Cognitive impairment in multiple sclerosis: clinical, radiologic and pathologic insights.

Cognitive impairment is a common and debilitating feature of multiple sclerosis (MS) that has only recent gained considerable attention. Clinical neuropsychological studies have made apparent the multifaceted nature of cognitive troubles often encountered in MS and continue to broaden our understanding of its complexity. Radiographic studies have started to decipher the neuroanatomic substrate of MS‐related cognitive impairment and have shed light onto its pathogenesis. Where radiographic studies have been limited by inadequate resolution or non‐specificity, pathological studies have come to the fore. This review aims to provide an overview of the nature of cognitive impairment typically seen in MS and to explore the literature on imaging and pathological studies relevant to its evolution. In particular, the relative contributions of gray (ie, cerebral cortex, hippocampus, thalamus and basal ganglia) and white matter to MS‐related cognitive impairment will be discussed and the importance of interconnectivity between structures highlighted. The pressing need for longitudinal studies combining standardized neuropsychometric, paraclinical and radiographic outcomes obtained during life with post‐mortem tissue analysis after death is presented.

Neurite dispersion: a new marker of multiple sclerosis spinal cord pathology?

Conventional magnetic resonance imaging (MRI) of the multiple sclerosis spinal cord is limited by low specificity regarding the underlying pathological processes, and new MRI metrics assessing microscopic damage are required. We aim to show for the first time that neurite orientation dispersion (i.e., variability in axon/dendrite orientations) is a new biomarker that uncovers previously undetected layers of complexity of multiple sclerosis spinal cord pathology. Also, we validate against histology a clinically viable MRI technique for dispersion measurement (neurite orientation dispersion and density imaging,NODDI), to demonstrate the strong potential of the new marker.

Olfactory Pathology in Central Nervous System Demyelinating Diseases.

Olfactory dysfunction is common in multiple sclerosis (MS). Olfactory bulb and tract pathology in MS and other demyelinating diseases remain unexplored. A human autopsy cohort of pathologically confirmed cases encompassing the spectrum of demyelinating disease (MS; n = 17), neuromyelitis optica [(NMO); n = 3] and acute disseminated encephalomyelitis [(ADEM); n = 7] was compared to neuroinflammatory [herpes simplex virus encephalitis (HSE); n = 3], neurodegenerative [Alzheimers disease (AD); n = 4] and non‐neurologic (n = 8) controls. For each case, olfactory bulbs and/or tracts were stained for myelin, axons and inflammation. Inferior frontal cortex and hippocampus were stained for myelin in a subset of MS and ADEM cases. Olfactory bulb/tract demyelination was frequent in all demyelinating diseases [MS 12/17 (70.6%); ADEM 3/7 (42.9%); NMO 2/3 (66.7%)] but was absent in HSE, AD and non‐neurologic controls. Inflammation was greater in the demyelinating diseases compared to non‐neurologic controls. Olfactory bulb/tract axonal loss was most severe in MS where it correlated significantly with the extent of demyelination (r = 0.610, P = 0.009) and parenchymal inflammation (r = 0.681, P = 0.003). The extent of olfactory bulb/tract demyelination correlated with that found in the adjacent inferior frontal cortex but not hippocampus. We provide unequivocal evidence that olfactory bulb/tract demyelination is frequent, can occur early and is highly inflammatory, and is specific to demyelinating disease.

Fibrin(ogen) and neurodegeneration in the progressive multiple sclerosis cortex.

Neuronal loss, a key substrate of irreversible disability in multiple sclerosis (MS), is a recognized feature of MS cortical pathology of which the cause remains unknown. Fibrin(ogen) deposition is neurotoxic in animal models of MS, but has not been evaluated in human progressive MS cortex. The aim of this study was to investigate the extent and distribution of fibrin(ogen) in progressive MS cortex and elucidate its relationship with neurodegeneration.

The influence of HLA-DRB1*15 on motor cortical pathology in multiple sclerosis

Multiple sclerosis (MS) is a common and heterogeneous CNS inflammatory demyelinating disease. The HLA‐DRB1 locus may influence clinical outcome. MS cortical pathology is frequent and correlates with measures of clinical disability, including motoric dysfunction that is a predominant feature of disease progression. The influence of HLA‐DRB1*15 on motor cortical pathology is unknown.

Loss of galectin-3 decreases the number of immune cells in the subventricular zone and restores proliferation in a viral model of multiple sclerosis.

Multiple sclerosis (MS) frequently starts near the lateral ventricles, which are lined by subventricular zone (SVZ) progenitor cells that can migrate to lesions and contribute to repair. Because MS‐induced inflammation may decrease SVZ proliferation and thus limit repair, we studied the role of galectin‐3 (Gal‐3), a proinflammatory protein. Gal‐3 expression was increased in periventricular regions of human MS in post‐mortem brain samples and was also upregulated in periventricular regions in a murine MS model, Theilers murine encephalomyelitis virus (TMEV) infection. Whereas TMEV increased SVZ chemokine (CCL2, CCL5, CCL, and CXCL10) expression in wild type (WT) mice, this was inhibited in Gal‐3−/− mice. Though numerous CD45+ immune cells entered the SVZ of WT mice after TMEV infection, their numbers were significantly diminished in Gal‐3−/− mice. TMEV also reduced neuroblast and proliferative SVZ cell numbers in WT mice but this was restored in Gal‐3−/− mice and was correlated with increased numbers of doublecortin+ neuroblasts in the corpus callosum. In summary, our data showed that loss of Gal‐3 blocked chemokine increases after TMEV, reduced immune cell migration into the SVZ, reestablished SVZ proliferation and increased the number of progenitors in the corpus callosum. These results suggest Gal‐3 plays a central role in modulating the SVZ neurogenic niches response to this model of MS. GLIA 2016;64:105–121

A framework for optimal whole-sample histological quantification of neurite orientation dispersion in the human spinal cord

BACKGROUND The complexity of fibre distributions in tissues is an important microstructural feature, now measurable in vivo by magnetic resonance imaging (MRI) through orientation dispersion (OD) indices. OD metrics have gained popularity for the characterisation of neurite morphology, but they still lack systematic validation. This paper demonstrates a framework for whole-sample histological quantification of OD in spinal cord specimens, potentially useful for validating MRI-derived OD estimates. NEW METHOD Our methodological framework is based on (i) sagittal sectioning; (ii) Palmgrens silver staining; (iii) structure tensor (ST) analysis; (iv) directional statistics. Novel elements are the data-driven optimisation of the spatial scale of ST analysis, and a new multivariate, weighted directional statistical approach for anisotropy-informed quantification of OD. RESULTS Palmgrens silver staining of sagittal spinal cord sections provides robust visualisation of neuronal elements, enabling OD quantification. The choice of spatial scale of ST analysis influences OD values, and weighted directional statistics provide OD maps with high contrast-to-noise. Segmentation of neurites prior to OD quantification is recommended. COMPARISON WITH EXISTING METHODS Our framework can potentially provide OD even in demyelinating diseases, where myelin-based histology is not suitable. As compared to conventional univariate approaches, our multivariate weighted directional statistics improve the contrast-to-noise of OD maps and more accurately describe the distribution of ST metrics. CONCLUSIONS Our framework enables practical whole-specimen characterisation of OD in the spinal cord. We recommend tuning the scale of ST analysis for optimal OD quantification, as well as neurite segmentation and weighted directional statistics, of which examples are provided herein.

Cortical lesions and HLA genotype: Still a grey area?

Substantial evidence suggests that cortical tissue injury plays a key role in the progression of permanent disability in multiple sclerosis (MS). Cortical demyelination occurs early, becomes more extensive with time and eventually exceeds the extent of white matter pathology in progressive disease. However our understanding of the mechanisms driving cortical demyelination remains poor. As a result, we lack the therapeutic targets that could enable cortical disease burden to be reduced and disease progression to be halted. A greater knowledge of the factors that drive pathology in the MS cortex is therefore desperately needed in order to develop novel medicines that can ameliorate disease burden in the progressive stage.

From Nose to Gut - The Role of the Microbiome in Neurological Disease

Inflammation and neurodegeneration are key features of many chronic neurological diseases, yet the causative mechanisms underlying these processes are poorly understood. There has been mounting interest in the role of the human microbiome in modulating the inflammatory milieu of the central nervous system (CNS) in health and disease. To date, most research has focussed on a gut‐brain axis, with other mucosal surfaces being relatively neglected. We herein take the novel approach of comprehensively reviewing the roles of the microbiome across several key mucosal interfaces – the nose, mouth, lung and gut – in health and in Parkinsons disease (PD), Alzheimers disease (AD) and multiple sclerosis (MS). This review systematically appraises the anatomical and microbiological landscape of each mucosal surface in health and disease before considering relevant mechanisms that may influence the initiation and progression of PD, AD and MS. The cumulative effects of dysbiosis from the nose to the gut may contribute significantly to neurological disease through a wide variety of mechanisms, including direct translocation of bacteria and their products, and modulation of systemic or CNS‐specific immunity. This remains an understudied and exciting area for future research and may lead to the development of therapeutic targets for chronic neurological disease.

The cortical blood–brain barrier in multiple sclerosis: a gateway to progression?

Despite the historical focus on white matter pathology, it is now increasingly recognised that cortical tissue injury is critical to disease outcome. Cortical pathology occurs from the earliest disease stages, predominates in progressive MS, and correlates with physical and cognitive disability [1]. However, our understanding of disease processes operative in the MS cortex remains poor and, in particular, the contribution of BBB dysfunction has been relatively overlooked. A recent radiological study and pathological findings from our group make steps to address these shortcomings and provide fresh insight into the role of BBB dysfunction in cortical pathology. Maranzano et al. undertook a retrospective analysis of serial MRI scans from an early MS cohort. Over a 2-year period, 36% of MS patients had cortical gadolinium (Gd)enhancing lesions, of which 95% were leukocortical [2]. While MRI studies are limited in their ability to detect cortical lesions, these findings importantly corroborate previous histological work showing that a subset of early cortical lesions are associated with BBB disruption [3]. These findings in early disease are substantiated by our work in progressive MS [4]. We have shown that fibrin(ogen), a surrogate marker of BBB disruption, is deposited across the motor cortex. Importantly, levels of fibrin(ogen) correlated with both defective cortical fibrinolysis and neuronal loss, which supports previous work on the proinflammatory and neurotoxic effects of fibrin(ogen) [5]. Given these findings, we propose that cortical BBB disruption might lead to persistent fibrin clots throughout the MS cortex, which may contribute to neurodegeneration and disability progression. Taken together these two studies raise a number of interesting points. Firstly, we found that extracellular fibrin(ogen) is predominantly deposited in deeper cortical layers. The proximity of these layers to the subjacent white matter may implicate the early leukocortical lesions observed by Maranzano et al. as a source of fibrin(ogen). The aberrant fibrinolysis we observed in the MS cortex could enable this early fibrin(ogen) to remain in the cortex for decades and lead to neurodegeneration, particularly in the functionally relevant cortical layer 5 neurons. While this link is appealing, leukocortical lesions were not detected in any appreciable quantity in our cohort, although this may be confounded by postmortem biases. Further, the significant remyelinating capacity of the cortex relative to underlying white matter [6] could lead to the persistence of fibrin(ogen) and neuronal loss long after a lesion has remyelinated. Alternatively, fibrin(ogen) may accumulate over decades through a chronically dysfunctional BBB. Here, traditional Gd-enhancement appears to have limited sensitivity [7] and more sensitive MRI [8, 9] and nuclear imaging techniques [10] may hold promise. Ultimately, development of nuclear imaging techniques with fibrin(ogen) labelling may provide the definitive answer. Secondly, fibrin(ogen) was almost exclusively found in grey matter, often with a sharp border with the clear underlying white matter. Whether there are specific disease mechanisms or vascular changes that facilitate fibrin(ogen) deposition in this distribution requires further investigation. It will also be important to appreciate differences in microenvironment between white and grey matter, and even between different cortical layers, that could alter the metabolism of extravasated fibrin(ogen) over microscopic distances. The role of chronic meningeal inflammation and/or its associated diffusible factors in fibrin(ogen) processing also remains unknown and warrants further study. In summary, these two studies challenge the fundamental concept that BBB disruption is not a feature of MS cortical * Gabriele C. DeLuca gabriele.deluca@ndcn.ox.ac.uk