The prevalence and topography of spinal cord demyelination in multiple sclerosis: a retrospective study.

Spinal cord pathology is a major determinant of irreversible disability in progressive multiple sclerosis. The demyelinated lesion is a cardinal feature. The well-characterised anatomy of the spinal cord and new analytic approaches allows the systematic study of lesion topography and its extent of inflammatory activity unveiling new insights into disease pathogenesis. We studied cervical, thoracic, and lumbar spinal cord tissue from 119 pathologically confirmed multiple sclerosis cases. Immunohistochemistry was used to detect demyelination (PLP) and classify lesional inflammatory activity (CD68). Prevalence and distribution of demyelination, staged by lesion activity, was determined and topographical maps were created to identify patterns of lesion prevalence and distribution using mixed models and permutation-based voxelwise analysis. 460 lesions were observed throughout the spinal cord with 76.5% of cases demonstrating at least 1 lesion. The cervical level was preferentially affected by lesions. 58.3% of lesions were inflammatory with 87.9% of cases harbouring at least 1 inflammatory lesion. Topographically, lesions consistently affected the dorsal and lateral columns with relative sparing of subpial areas in a distribution mirroring the vascular network. The presence of spinal cord lesions and the proportion of active lesions related strongly with clinical disease milestones, including time from onset to wheelchair and onset to death. We demonstrate that spinal cord demyelination is common, highly inflammatory, has a predilection for the cervical level, and relates to clinical disability. The topography of lesions in the dorsal and lateral columns and relative sparing of subpial areas points to a role of the vasculature in lesion pathogenesis, suggesting short-range cell infiltration from the blood and signaling molecules circulating in the perivascular space incite lesion development. These findings challenge the notion that end-stage progressive multiple sclerosis is 'burnt out' and an outside-in lesional gradient predominates in the spinal cord. Taken together, this study provides support for long-term targeting of inflammatory demyelination in the spinal cord and nominates vascular dysfunction as a potential target for new therapeutic approaches to limit irreversible disability.

Microglia directly associate with pericytes in the central nervous system.

Cerebral blood flow (CBF) is important for the maintenance of brain function and its dysregulation has been implicated in Alzheimer's disease (AD). Microglia associations with capillaries suggest they may play a role in the regulation of CBF or the blood-brain-barrier (BBB). We explored the relationship between microglia and pericytes, a vessel-resident cell type that has a major role in the control of CBF and maintenance of the BBB, discovering a spatially distinct subset of microglia that closely associate with pericytes. We termed these pericyte-associated microglia (PEM). PEM are present throughout the brain and spinal cord in NG2DsRed × CX3 CR1+/GFP mice, and in the human frontal cortex. Using in vivo two-photon microscopy, we found microglia residing adjacent to pericytes at all levels of the capillary tree and found they can maintain their position for at least 28 days. PEM can associate with pericytes lacking astroglial endfeet coverage and capillary vessel width is increased beneath pericytes with or without an associated PEM, but capillary width decreases if a pericyte loses a PEM. Deletion of the microglia fractalkine receptor (CX3 CR1) did not disrupt the association between pericytes and PEM. Finally, we found the proportion of microglia that are PEM declines in the superior frontal gyrus in AD. In summary, we identify microglia that specifically associate with pericytes and find these are reduced in number in AD, which may be a novel mechanism contributing to vascular dysfunction in neurodegenerative diseases.

Tuberous sclerosis complex-1 (TSC1) contributes to selective neuronal vulnerability in Alzheimer's disease.

AIMS: Selective neuronal vulnerability of hippocampal Cornu Ammonis (CA)-1 neurons is a pathological hallmark of Alzheimer's disease (AD) with an unknown underlying mechanism. We interrogated the expression of tuberous sclerosis complex-1 (TSC1; hamartin) and mTOR-related proteins in hippocampal CA1 and CA3 subfields. METHODS: A human post-mortem cohort of mild (n = 7) and severe (n = 10) AD and non-neurological controls (n = 9) was used for quantitative and semi-quantitative analyses. We also developed an in vitro TSC1 knockdown model in rat hippocampal neurons, and transcriptomic analyses of TSC1 knockdown neuronal cultures were performed. RESULTS: We found a selective increase of TSC1 cytoplasmic inclusions in human AD CA1 neurons with hyperactivation of one of TSC1's downstream targets, the mammalian target of rapamycin complex-1 (mTORC1), suggesting that TSC1 is no longer active in AD. TSC1 knockdown experiments showed accelerated cell death independent of amyloid-beta toxicity. Transcriptomic analyses of TSC1 knockdown neuronal cultures revealed signatures that were significantly enriched for AD-related pathways. CONCLUSIONS: Our combined data point to TSC1 dysregulation as a key driver of selective neuronal vulnerability in the AD hippocampus. Future work aimed at identifying targets amenable to therapeutic manipulation is urgently needed to halt selective neurodegeneration, and by extension, debilitating cognitive impairment characteristic of AD.

Neurovascular coupling mechanisms in health and neurovascular uncoupling in Alzheimer's disease.

To match the metabolic demands of the brain, mechanisms have evolved to couple neuronal activity to vasodilation, thus increasing local cerebral blood flow and delivery of oxygen and glucose to active neurons. Rather than relying on metabolic feedback signals such as the consumption of oxygen or glucose, the main signalling pathways rely on the release of vasoactive molecules by neurons and astrocytes, which act on contractile cells. Vascular smooth muscle cells and pericytes are the contractile cells associated with arterioles and capillaries, respectively, which relax and induce vasodilation. Much progress has been made in understanding the complex signalling pathways of neurovascular coupling, but issues such as the contributions of capillary pericytes and astrocyte calcium signal remain contentious. Study of neurovascular coupling mechanisms is especially important as cerebral blood flow dysregulation is a prominent feature of Alzheimer's disease. In this article we will discuss developments and controversies in the understanding of neurovascular coupling and finish by discussing current knowledge concerning neurovascular uncoupling in Alzheimer's disease.

Anterior optic pathway pathology in CNS demyelinating diseases.

The anterior optic pathway is one of the preferential sites of involvement in CNS inflammatory demyelinating diseases, such as multiple sclerosis and neuromyelitis optica, with optic neuritis being a common presenting symptom. What is more, optic nerve involvement in these diseases is often subclinical, with optical coherence tomography demonstrating progressive neuroretinal thinning in the absence of optic neuritis. The pathological substrate for these findings is poorly understood and requires investigation. We had access to post-mortem tissue samples of optic nerves, chiasms and tracts from 29 multiple sclerosis (mean age 59.5, range 25-84 years; 73 samples), six neuromyelitis optica spectrum disorders (mean age 56, range 18-84 years; 22 samples), six acute disseminated encephalomyelitis (mean age 25, range 10-39 years; 12 samples) cases and five non-neurological controls (mean age 55.2, range 44-64 years; 16 samples). Formalin-fixed paraffin-embedded samples were immunolabelled for myelin, inflammation (microglial/macrophage, T- and B-cells, complement), acute axonal injury and astrocytes. We assessed the extent and distribution of these markers along the anterior optic pathway for each case in all compartments (i.e. parenchymal, perivascular and meningeal), where relevant. Demyelinated plaques were classified as active based on established criteria. In multiple sclerosis, demyelination was present in 82.8% of cases, of which 75% showed activity. Microglia/macrophage and lymphocyte inflammation were frequently found both in the parenchymal and meningeal compartments in non-demyelinated regions. Acute axonal injury affected 41.4% of cases and correlated with extent of inflammatory activity in each compartment, even in cases that died at advanced age with over 20 years of disease duration. An antero-posterior gradient of anterior optic pathway involvement was observed with optic nerves being most severely affected by inflammation and acute axonal injury compared with the optic tract, where a higher proportion of remyelinated plaques were seen. In neuromyelitis optica spectrum disorder, cases with a history of optic neuritis had extensive demyelination and lost aquaporin-4 reactivity. In contrast, those without prior optic neuritis did not have demyelination but rather diffuse microglial/macrophage, T- and B-lymphocyte inflammation in both parenchymal and meningeal compartments, and acute axonal injury was present in 75% of cases. Acute demyelinating encephalomyelitis featured intense inflammation, and perivenular demyelination in 33% of cases. Our findings suggest that chronic inflammation is frequent and leads to neurodegeneration in multiple sclerosis and neuromyelitis optica, regardless of disease stage. The chronic inflammation and subsequent neurodegeneration occurring along the optic pathway broadens the plaque-centred view of these diseases and partly explains the progressive neuroretinal changes observed in optic coherence tomography studies.

Cognitive decline and diabetes: a systematic review of the neuropathological correlates accounting for cognition at death.

Given conflicting findings in epidemiologic studies, we determined the relative contributions of different neuropathologies to the excess risk of cognitive decline in diabetes mellitus (DM) through a systematic review of the literature. Included studies compared subjects with and without DM and reported neuropathological outcomes accounting for cognition at death. Data on Alzheimer's disease (AD) pathology, cerebrovascular disease and non-vascular, non-AD pathology were extracted from each study. Eleven studies (n=6 prospective cohorts, n=5 retrospective post-mortem series, total n=6330) met inclusion criteria. All 11 studies quantified AD changes and 10/11 measured cerebrovascular disease: macroscopic lesions (n=9), microinfarcts (n=8), cerebral amyloid angiopathy (CAA, n=7), lacunes (n=6), white matter disease (n=5), haemorrhages (n=4), microbleeds (n=1), hippocampal microvasculature (n=1). Other pathology was infrequently examined. No study reported increased AD pathology in DM, three studies showed a decrease (n=872) and four (n= 4018) showed no difference, after adjustment for cognition at death. No study reported reduced cerebrovascular pathology in DM. Three studies (n=2345) reported an increase in large infarcts, lacunes and microinfarcts. One study found lower cognitive scores in DM compared to non-DM subjects despite similar cerebrovascular and AD-pathology load suggesting contributions from other neuropathological processes. In conclusion, lack of an association between DM and AD-related neuropathology was consistent across studies, irrespective of methodology. In contrast to AD, DM was associated with increased large and small vessel disease. Data on other pathologies such as non-AD neurodegeneration, and blood-brain-barrier breakdown were lacking. Further studies evaluating relative contributions of different neuropathologies to the excess risk of DM are needed.

Genes and environment in multiple sclerosis: Impact of temporal changes in the sex ratio on recurrence risks.

OBJECTIVE: To evaluate the impact of temporal increase of female to male (F:M) sex ratio for persons with multiple sclerosis (MS) on the familial risk (empiric recurrence risks or RRs) for biological relatives of affected individuals. METHODS: Detailed family histories were systematically obtained from people with MS attending the University of British Columbia Hospital MS Clinic. The study cohort was born in 1970 or more recently. Data were collected from 1 September 2015 to 31 January 2019. The study was designed to allow only one proband per family. Age-corrected RRs for biological relatives of probands were calculated based on a modification of the maximum-likelihood approach. RESULTS: Data analyses were possible for 746 unique probands (531 females; 215 males) and 19,585 of their biological relatives. RRs were temporally impacted. CONCLUSION: Both genetic sharing and environmental factors are important in determining RRs. It appears that there is an increase in MS risk due to environmental factors in later life (i.e. not shared family environment). Environmental exposures in genetically predisposed individuals might be driving the MS risk. The increase in F:M ratio of RRs for sisters/brothers of female probands over time is likely due to environmental differences.

An In-vivo 1H-MRS short-echo time technique at 7T: Quantification of metabolites in chronic multiple sclerosis and neuromyelitis optica brain lesions and normal appearing brain tissue.

Magnetic Resonance Spectroscopy (MRS) allows for the non-invasive quantification of neurochemicals and has the potential to differentiate between the pathologically distinct diseases, multiple sclerosis (MS) and AQP4Ab-positive neuromyelitis optica spectrum disorder (AQP4Ab-NMOSD). In this study we characterised the metabolite profiles of brain lesions in 11 MS and 4 AQP4Ab-NMOSD patients using an optimised MRS methodology at ultra-high field strength (7T) incorporating correction for T2 water relaxation differences between lesioned and normal tissue. MS metabolite results were in keeping with the existing literature: total N-acetylaspartate (NAA) was lower in lesions compared to normal appearing brain white matter (NAWM) with reciprocal findings for myo-Inositol. An unexpected subtlety revealed by our technique was that total NAA differences were likely driven by NAA-glutamate (NAAG), a ubiquitous CNS molecule with functions quite distinct from NAA though commonly quantified together with NAA in MRS studies as total NAA. Surprisingly, AQP4Ab-NMOSD showed no significant differences for total NAA, NAA, NAAG or myo-Inositol between lesion and NAWM sites, nor were there any differences between MS and AQP4Ab-NMOSD for a priori hypotheses. Post-hoc testing revealed a significant correlation between NAWM Ins:NAA and disability (as measured by EDSS) for disease groups combined, driven by the AP4Ab-NMOSD group. Utilising an optimised MRS methodology, our study highlights some under-explored subtleties in MRS profiles, such as the absence of myo-Inositol concentration differences in AQP4Ab-NMOSD brain lesions versus NAWM and the potential influence of NAAG differences between lesions and normal appearing white matter in MS.

Vascular disease and multiple sclerosis: a post-mortem study exploring their relationships.

Vascular comorbidities have a deleterious impact on multiple sclerosis clinical outcomes but it is unclear whether this is mediated by an excess of extracranial vascular disease (i.e. atherosclerosis) and/or of cerebral small vessel disease or worse multiple sclerosis pathology. To address these questions, a study using a unique post-mortem cohort wherein whole body autopsy reports and brain tissue were available for interrogation was established. Whole body autopsy reports were used to develop a global score of systemic vascular disease that included aorta and coronary artery atheroma, cardiac hypertensive disease, myocardial infarction and ischaemic stroke. The score was applied to 85 multiple sclerosis cases (46 females, age range 39 to 84 years, median 62.0 years) and 68 control cases. Post-mortem brain material from a subset of the multiple sclerosis (n = 42; age range 39-84 years, median 61.5 years) and control (n = 39) cases was selected for detailed neuropathological study. For each case, formalin-fixed paraffin-embedded tissue from the frontal and occipital white matter, basal ganglia and pons was used to obtain a global cerebral small vessel disease score that captured the presence and/or severity of arteriolosclerosis, periarteriolar space dilatation, haemosiderin leakage, microinfarcts, and microbleeds. The extent of multiple sclerosis-related pathology (focal demyelination and inflammation) was characterized in the multiple sclerosis cases. Regression models were used to investigate the influence of disease status on systemic vascular disease and cerebral small vessel disease scores and, in the multiple sclerosis group, the relationship between multiple sclerosis-related pathology and both vascular scores. We show that: (i) systemic cardiovascular burden, and specifically atherosclerosis, is lower and cerebral small vessel disease is higher in multiple sclerosis cases that die at younger ages compared with control subjects; (ii) the association between systemic vascular disease and cerebral small vessel disease is stronger in patients with multiple sclerosis compared with control subjects; and (iii) periarteriolar changes, including periarteriolar space dilatation, haemosiderin deposition and inflammation, are key features of multiple sclerosis pathology outside the classic demyelinating lesion. Our data argue against a common primary trigger for atherosclerosis and multiple sclerosis but suggest that an excess burden of cerebral small vessel disease in multiple sclerosis may explain the link between vascular comorbidity and accelerated irreversibility disability.

Distinct influence of different vascular risk factors on white matter brain lesions in multiple sclerosis.

OBJECTIVE: To determine if vascular risk factor (VRF), that is, smoking, arterial hypertension (HT), dyslipidaemia and diabetes, have an effect on multiple sclerosis (MS) pathology as measured by MS typical brain lesions, we have compared brain MRIs from patients with MS with and without VRF age-matched and sex-matched. METHODS: Brain MRIs from five centres were scored for the presence of Dawson's fingers (DF) and juxtacortical lesions (JCL). A regression model was built to predict the effect of each individual VRF on DF and JCL, considering age and disease duration. RESULTS: 92 MS cases without VRF and 106 MS with one or more VRF (80 ever-smokers, 43 hypertensives, 25 dyslipidaemics and 10 diabetics) were included. Ever-smoking associated with a higher burden of DF (Exp(B)=1.29, 95% CI 1.10 to 1.51, p<0.01) and JCL (Exp(B)=1.38, 95% CI 1.21 to 1.57, p<0.01). No other VRF had an impact on DF. Dyslipidaemia associated with increased JCL (Exp(B)=1.30, 95% CI 1.10 to 1.56, p<0.01) but HT did not associate with any of the outcomes. CONCLUSIONS: Individual VRF appear to affect MS-specific lesions differently. An increase in MS lesions was mainly seen in smokers; however, this VRF is most likely to be present from onset of MS, and other VRF effects may be partly mitigated by treatment. Our findings support that treating VRF and cessation of smoking may be important in the management of MS.

CLIPPERS: A case report with radiology, three serial biopsies and a literature review.

Chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS) is a rare central nervous system inflammatory disorder primarily affecting the brainstem and cerebellum. We report a case of CLIPPERS in a 45-year-old man presenting with left facial numbness and dizziness. Imaging studies were conducted repeatedly over an 8-year follow-up period. Given diagnostic uncertainty in the early stages of the disease, three serial biopsies were obtained, which together with the clinical and radiological findings, led to the diagnosis. This case highlights the diagnostic challenges regarding the rare entity of CLIPPERS and discusses the main differential diagnoses that are necessary to consider. Additionally, some of the atypical features of this case, including the presenting finding of a large, solidly enhancing lesion on radiological imaging and prominent plasma cells on pathology, contribute to expanding the spectrum of appearances for CLIPPERS.

A randomised double-blind placebo-controlled feasibility trial of flavonoid-rich cocoa for fatigue in people with relapsing and remitting multiple sclerosis.

The impact of flavonoids on fatigue has not been investigated in relapsing and remitting multiple sclerosis (RRMS). OBJECTIVE: To determine the feasibility and estimate the potential effect of flavonoid-rich cocoa on fatigue and fatigability in RRMS. METHODS: A randomised double-blind placebo-controlled feasibility study in people recently diagnosed with RRMS and fatigue, throughout the Thames Valley, UK (ISRCTN69897291). During a 6-week intervention participants consumed a high or low flavonoid cocoa beverage daily. Fatigue and fatigability were measured at three visits (weeks 0, 3 and 6). Feasibility and fidelity were assessed through recruitment and retention, adherence and a process evaluation. RESULTS: 40 people with multiple sclerosis (10 men, 30 women, age 44±10 years) were randomised and allocated to high (n=19) or low (n=21) flavonoid groups and included in analysis. Missing data were <20% and adherence to intervention of allocated individuals was >75%. There was a small effect on fatigue (Neuro-QoL: effect size (ES) 0.04, 95% CI -0.40 to 0.48) and a moderate effect on fatigability (6 min walk test: ES 0.45, 95% CI -0.18 to 1.07). There were seven adverse events (four control, three intervention), only one of which was possibly related and it was resolved. CONCLUSION: A flavonoid beverage demonstrates the potential to improve fatigue and fatigability in RRMS.

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

OBJECTIVE: 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. METHODS: A postmortem cohort of pathologically confirmed MS (n = 47) and control (n = 10) cases was used. The extent and distribution of fibrin(ogen) was assessed and related to measures of demyelination, inflammation, and neuronal density. In a subset of cases (MS, n = 20; control, n = 10), expression of plasminogen activator inhibitor 1 (PAI-1), a key enzyme in the fibrinolytic cascade, was assessed and related to the extent of fibrin(ogen). RESULTS: Motor cortical fibrin(ogen) deposition was significantly over-represented in MS compared to control cases in all compartments studied (ie, extracellular [p = 0.001], cell body [p = 0.003], and neuritic/glial-processes [p = 0.004]). MS cases with high levels of extracellular fibrin(ogen) had significantly upregulated PAI-1 expression in all cortical layers assessed (p < 0.05) and reduced neuronal density (p = 0.017), including in the functionally-relevant layer 5 (p = 0.001). INTERPRETATION: For the first time, we provide unequivocal evidence that fibrin(ogen) is extensively deposited in progressive MS motor cortex, where regulation of fibrinolysis appears perturbed. Progressive MS cases with severe fibrin(ogen) deposition have significantly reduced neuronal density. Future studies are needed to elucidate the provenance and putative neurotoxicity of fibrin(ogen), and its potential impact on clinical disability. Ann Neurol 2017;82:259-270.

Vascular pathology in multiple sclerosis: reframing pathogenesis around the blood-brain barrier.

Blood-brain barrier (BBB) disruption has long been recognised as an important early feature of multiple sclerosis (MS) pathology. Traditionally, this has been seen as a by-product of the myelin-specific immune response. Here, we consider whether vascular changes instead play a central role in disease pathogenesis, rather than representing a secondary effect of neuroinflammation or neurodegeneration. Importantly, this is not necessarily mutually exclusive from current hypotheses. Vascular pathology in a genetically predisposed individual, influenced by environmental factors such as pathogens, hypovitaminosis D and smoking, may be a critical initiator of a series of events including hypoxia, protein deposition and immune cell egress that allows the development of a CNS-specific immune response and the classical pathological and clinical hallmarks of disease. We review the changes that occur in BBB function and cerebral perfusion in patients with MS and highlight genetic and environmental risk factors that, in addition to modulating immune function, may also converge to act on the vasculature. Further context is provided by contrasting these changes with other neurological diseases in which there is also BBB malfunction, and highlighting current disease-modifying therapies that may also have an effect on the BBB. Indeed, in reframing current evidence in this model, the vasculature could become an important therapeutic target in MS.

Brain lesion distribution criteria distinguish MS from AQP4-antibody NMOSD and MOG-antibody disease.

IMPORTANCE: Neuromyelitis optica spectrum disorders (NMOSD) can present with very similar clinical features to multiple sclerosis (MS), but the international diagnostic imaging criteria for MS are not necessarily helpful in distinguishing these two diseases. OBJECTIVE: This multicentre study tested previously reported criteria of '(1) at least 1 lesion adjacent to the body of the lateral ventricle and in the inferior temporal lobe; or (2) the presence of a subcortical U-fibre lesion or (3) a Dawson's finger-type lesion' in an independent cohort of relapsing-remitting multiple sclerosis (RRMS) and AQP4-ab NMOSD patients and also assessed their value in myelin oligodendrocyte glycoprotein (MOG)-ab positive and ab-negative NMOSD. DESIGN: Brain MRI scans were anonymised and scored on the criteria by 2 of 3 independent raters. In case of disagreement, the final opinion was made by the third rater. PARTICIPANTS: 112 patients with NMOSD (31 AQP4-ab-positive, 21 MOG-ab-positive, 16 ab-negative) or MS (44) were selected from 3 centres (Oxford, Strasbourg and Liverpool) for the presence of brain lesions. RESULTS: MRI brain lesion distribution criteria were able to distinguish RRMS with a sensitivity of 90.9% and with a specificity of 87.1% against AQP4-ab NMOSD, 95.2% against MOG-ab NMOSD and 87.5% in the heterogenous ab-negative NMOSD cohort. Over the whole NMOSD group, the specificity was 89.7%. CONCLUSIONS: This study suggests that the brain MRI criteria for differentiating RRMS from NMOSD are sensitive and specific for all phenotypes.

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, Theiler's 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 niche's response to this model of MS.

Back on the scent: the olfactory system in CNS demyelinating diseases.

Olfactory dysfunction is recognised across an ever broadening spectrum of neuropsychiatric conditions including central nervous system (CNS) demyelinating diseases such as multiple sclerosis (MS) and neuromyelitis optica (NMO). In this review, we unravel the striking evidence highlighting how olfactory loss is a common clinical feature in MS and NMO. We provide an overview of the supportive psychophysical, electrophysiological, radiological and pathological data that point to the anatomical substrate of olfactory deficits in these diseases. The pattern of underlying pathology affecting the olfactory system is shown to be complex, involving multiple structures that are affected in different ways throughout the course of the disease. This review is the first to synthesise the expanding body of literature on the topic, provides novel insight into the way in which the olfactory system is affected in CNS demyelinating diseases, and raises intriguing questions about the role of this system in the pathogenesis of these diseases.

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

AIM: 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. METHODS: A pathologically confirmed age- and sex-matched HLA-DRB1*15+ (n = 21) and HLA-DRB1*15- (n = 26) MS post-mortem cohort was used for detailed pathologic analyses. For each case, adjacent sections of motor cortex were stained for myelin and inflammation, to evaluate the extent and distribution of motor cortical pathology. A subset of MS cases (n = 42) had spinal cord (SC) pathologic outcome data available for comparison. RESULTS: Motor cortical demyelination was more pronounced in younger cases (r = -0.337, P < 0.05), with MS cases carrying the HLA-DRB1*15 allele driving this effect (r = -0.612, P < 0.01). HLA-DRB1*15+ MS cases had more severe motor cortical parenchymal (P < 0.05), perivascular (P < 0.05) and meningeal (P < 0.05) T-cell inflammation compared to HLA-DRB1*15- cases. HLA-DRB1*15 status significantly influenced the extent of motor cortical microglial burden in both NAGM (P < 0.0001) and lesions (P < 0.01) in MS cases. Relationships between the extent of motor cortical and SC pathology were limited, but when present were primarily driven by HLA-DRB1*15+ cases. CONCLUSION: HLA-DRB1*15 status has a significant association with the extent of inflammation in the MS motor cortex, the extent of demyelination in younger MS cases, and influences relationships between motor cortical and SC pathology.

Motor skill learning induces changes in white matter microstructure and myelination.

Learning a novel motor skill is associated with well characterized structural and functional plasticity in the rodent motor cortex. Furthermore, neuroimaging studies of visuomotor learning in humans have suggested that structural plasticity can occur in white matter (WM), but the biological basis for such changes is unclear. We assessed the influence of motor skill learning on WM structure within sensorimotor cortex using both diffusion MRI fractional anisotropy (FA) and quantitative immunohistochemistry. Seventy-two adult (male) rats were randomly assigned to one of three conditions (skilled reaching, unskilled reaching, and caged control). After 11 d of training, postmortem diffusion MRI revealed significantly higher FA in the skilled reaching group compared with the control groups, specifically in the WM subjacent to the sensorimotor cortex contralateral to the trained limb. In addition, within the skilled reaching group, FA across widespread regions of WM in the contralateral hemisphere correlated significantly with learning rate. Immunohistological analysis conducted on a subset of 24 animals (eight per group) revealed significantly increased myelin staining in the WM underlying motor cortex in the hemisphere contralateral (but not ipsilateral) to the trained limb for the skilled learning group versus the control groups. Within the trained hemisphere (but not the untrained hemisphere), myelin staining density correlated significantly with learning rate. Our results suggest that learning a novel motor skill induces structural change in task-relevant WM pathways and that these changes may in part reflect learning-related increases in myelination.

Casting light on multiple sclerosis heterogeneity: the role of HLA-DRB1 on spinal cord pathology.

Clinical heterogeneity in multiple sclerosis is the rule. Evidence suggests that HLA-DRB1*15 may play a role in clinical outcome. Spinal cord pathology is common and contributes significantly to disability in the disease. The influence of HLA-DRB1*15 on multiple sclerosis spinal cord pathology is unknown. A post-mortem cohort of pathologically confirmed cases with multiple sclerosis (n = 108, 34 males) with fresh frozen material available for genetic analyses and fixed material for pathology was used. HLA-DRB1 alleles were genotyped to select a subset of age- and sex-matched HLA-DRB1*15-positive (n = 21) and negative (n = 26) cases for detailed pathological analyses. For each case, transverse sections from three spinal cord levels (cervical, thoracic and lumbar) were stained for myelin, axons and inflammation. The influence of HLA-DRB1*15 on pathological outcome measures was evaluated. Carriage of HLA-DRB1*15 significantly increased the extent of demyelination (global measure 15+: 23.7% versus 15-: 12.16%, P = 0.004), parenchymal (cervical, P < 0.01; thoracic, P < 0.05; lumbar, P < 0.01) and lesional inflammation (border, P = 0.001; periplaque white matter, P < 0.05) in the multiple sclerosis spinal cord. HLA-DRB1*15 influenced demyelination through controlling the extent of parenchymal inflammation. Meningeal inflammation correlated significantly with small fibre axonal loss in the lumbar spinal cord (r = -0.832, P = 0.003) only in HLA-DRB1*15-positive cases. HLA-DRB1*15 significantly influences pathology in the multiple sclerosis spinal cord. This study casts light on the role of HLA-DRB1*15 in disease outcome and highlights the powerful approach of using microscopic pathology to clarify the way in which genes and clinical phenotypes of neurological diseases are linked.