Search

Clinical trials of neuroprotective interventions in multiple sclerosis require outcome measures that reflect the disease pathology. Measures of neuroaxonal integrity in the anterior visual pathways are of particular interest in this context, however imaging of the optic nerve is technically challenging. We therefore developed a 3T optic nerve diffusion tensor imaging protocol incorporating fat and cerebrospinal fluid suppression and without parallel imaging. The sequence used a scheme with six diffusion-weighted directions, b = 600 smm(-2) plus one b ≈ 0 (b(0)) and 40 repetitions, averaged offline, giving an overall scan time of 30 minutes. A coronal oblique orientation was used with voxel size 1.17 mm x 1.17 mm x 4 mm, We validated the sequence in 10 MS patients with a history of optic neuritis and 11 healthy controls: mean fractional anisotropy was reduced in the patients: 0.346(±0.159) versus 0.528(±0.123), p

Randomised, placebo-controlled trials are the gold standard for the assessment of safety and efficacy of new treatments. Although study design is challenging, success ultimately depends on recruitment and retention of subjects. MS-SMART [NCT01910259] is a multi-arm, phase 2b study in secondary progressive multiple sclerosis (SPMS), currently recruiting 440 patients in the UK. We describe here in detail our recruitment experience so far in the largest centre (planned 40% of total). Potentially eligible participants were identified through a number of routes: consultant referrals (22%); dedicated website [www.ms-smart.org] (76%); presentations at MS centres (0.4%), referrals from MS nurses (2%). Of c700 patients, 150 were uncontactable, and so 550 underwent a simple pre-screening telephone questionnaire. Two hundred were eligible of which 150 agreed to attend for formal screening and 130 were randomised. We conclude that direct consultant referral and a dedicated website are the most successful recruiting methods in this SPMS trial. This independent research is awarded by the Efficacy and Mechanism Evaluation. Programme (EME) and funded by the Medical Research Council (MRC) and the Multiple Sclerosis Society (MS Society) and managed by the National Institute for Health Research (NIHR) on behalf of the MRC-NIHR partnership.

MS-SMART is an ongoing multicentre, multi-arm, double blind, placebo-controlled phase IIb randomised controlled trial to establish whether putative neuroprotective drugs (fluoxetine,riluzole,amiloride or placebo) can slow down the progression of brain volume loss in secondary progressive multiple sclerosis (SPMS) over 96 weeks using MRI-derived Percentage Brain Volume Change (PBVC) as the primary outcome. 360 patients have been screened so far, 328 (92%) consented and 272 randomized (65% of the total UK cohort–440). Patients will have outcome-data collected after 0,24,48 and 96 weeks. The trial is using a range of conventional and novel imaging techniques to better understand neuroprotection in SPMS. Core data includes: new and enlarging T2 lesions count, persistent new T1 hypointense lesion, whole brain atrophy, grey matter volume, and advanced imaging in 2 centres [cervical cord area change,MR spectroscopy and Magnetic Transfer Ratio (MTR)]. Additional measures include: CSF neurofilament levels and optical coherence tomography (OCT) to measure Retinal Nerve Fibre Layer (RNFL) thickness. This abstract describes the ongoing status of the trial. This independent research is awarded by the Efficacy and Mechanism Evaluation Programme (EME) and funded by the Medical Research Council (MRC) and the Multiple Sclerosis Society (MS Society) and managed by the National Institute for Health Research (NIHR) on behalf of the MRC-NIHR partnership.

Background Cooling is the single most effective treatment for acute neuronal injury. Understanding the molecular mechanisms that mediate cooling-induced neuroprotection might yield novel therapeutic targets for neurodegenerative disease. Many of these disorders involve modulation of tau, a protein that is enriched in neurons and becomes hyperphosphorylated in hypothermic, injury-resistant rodent brains as well as in Alzheimer's disease. We sought to establish a new model for exploring human tau physiology and its role in neuroprotection in the context of therapeutic hypothermia. Methods Functional cortical neurons (hCNs) were differentiated from three independent human pluripotent stem-cell lines and validated for regional identity and tau status. Matched cultures were incubated at 37°C or clinically targeted temperatures for therapeutic hypothermia (32°C) and suspended animation (28°C). Effects of cooling on tau status and neuronal injury elicited by common neurotoxic stressors were established. Injury experiments were repeated while manipulating tau phosphorylation. Findings hCN differentiation featured transitions in tau status, recapitulating transcriptional and post-translational human in-vivo cortical tau development. Key aspects of this development were reversed by cooling. Notably, cooling induced tau hyperphosphorylation via rapid inhibition of the major tau phosphatase, protein phosphatase 2A (PP2A). Multiplexed injury analysis confirmed that hypothermia robustly protected hCNs from oxidative (100 μM hydrogen peroxide) and excitotoxic (30 μM glutamate) stress (at 28°C, injury was reduced by 78% and 56%, respectively; p Interpretation To our knowledge, this is the first study of human neuronal tau physiology under hypothermic conditions. Although definitive experiments are needed, our findings support previous work linking phospho-tau to neuroprotection. Furthermore, cold-induced tau hyperphosphorylation is a potential trigger for proteostatic priming, a recently discovered mechanism of hypothermic preconditioning in hCNs. Exploiting these cryobiological effects might lead to new treatments for acute and chronic neuronal injury. Funding Wellcome Trust, Anne Rowling Regenerative Neurology Clinic, Euan MacDonald Centre for Motor Neurone Disease Research.

Application of multidimensional assessment batteries is a well-established approach to detect cognitive impairment in multiple sclerosis (MS), the best known example being the Brief Repeatable Neuropsychological Battery. Although relatively easy to administer, these batteries require equipment, training and take 30–60 min.1 Current bedside screening techniques based on the Symbol Digit Modality Test, Paced Auditory Serial Additions Test (PASAT) and Faces Symbol Test are quick to administer (5–10 min), but they also require training and availability of relevant equipment.2 A rapid portable screening test that could be widely applied at the bedside or in the busy clinic is therefore highly desirable. Given that deficits in both phonemic (letter) and semantic (category) fluency are common in progressive MS and have been described among the earliest detectable cognitive features, both are of interest as candidate screening tests.3 Testing requires the subject to generate words beginning with a given letter (eg, p) or semantic category (eg, animals) over a defined time period (usually 1 min). Crucially, minimal test equipment is …

Background Progressive MS is associated with a high frequency of cognitive impairment. 1 However, it is not clear to what extent this reflects global dysfunction, or independent deficits in specific functions.Reduced speed of information processing, together with impairment in executive functions, recall–memory, and attention are the most frequently described deficits, particularly in the most extensively studied patient group with relapsing–remitting disease. 2 However, language and visuospatial functions have rarely been evaluated, despite evidence of involvement in large cohort studies, 3 as well as in studies specifically assessing these domains. 4 It therefore remains unclear whether cognitive dysfunction in MS reflects a universal deficit of all functions, or whether impairment of specific functions occurs independently. Objective To characterise patterns of cognitive impairment in progressive MS on a multi–dimensional cognitive assessment tool well established in neurodegenerative diseases. Methods Patients with secondary (SPMS; n=60) and primary progressive MS (PPMS; n=28) were assessed using the Addenbrooke9s Cognitive Examination–Revised (ACE–R) multi–dimensional cognitive assessment scale. Independent dimensions of impairment and their relative contribution to the overall burden of cognitive dysfunction were then determined by hierarchical factor analysis. Results Two independent dimensions of impairment were seen: frontal–executive (attention, verbal fluency, recall) on one hand, and language and visuospatial functions on the other. These accounted for 55% and 45% respectively of the variance not explained by a global influence (14.2% and 11.6% respectively of total variance). Isolated language and visuospatial dysfunction was seen in both groups, whereas isolated impairment in frontal–executive functions was underrepresented in SPMS (p=0.001) and not seen in PPMS patients (p=0.040). Conclusions In addition to a prominent global influence on cognitive performance, patients with progressive MS commonly exhibit independent language and visuospatial deficits. Evaluation of these abilities should therefore be included in clinical assessment of cognition in progressive MS. The underrepresentation of frontal–executive dysfunction also seen in our study raises the possibility that language and visuospatial deficits may be characteristic of cognitive impairment in progressive MS.

Background Multiple Sclerosis affects over 2.1 million people worldwide, 1 with over half of the prevalent population characterised by progressive forms of disease that result in the steady accumulation of fixed disability. 2 The absence of treatments for progressive MS therefore represents a major unmet clinical need. 3 Based on increasing experimental evidence that mesenchymal stem cells (MSCs) have biological properties of potential therapeutic relevance, 4 and beneficial effects across a range of disease models, 5 we assessed the safety and efficacy of autologous MSCs as a potential neuroprotective therapy for secondary progressive MS. 6 Methods Ten patients with secondary progressive MS involving the visual pathways (EDSS 5.5 to 6.5), received intravenous infusion of autologous bone marrow–derived MSCs derived using the European Group for Blood and Marrow Transplantation ex–vivo expansion procedures in a prospective open label phase IIA proof of concept study, registered at ClinicalTrials.gov NCT00395200. Adverse events were compared between pre–treatment and post–treatment periods of up to 20 and 10 months respectively. Using the anterior visual pathway as a model of wider disease, efficacy outcomes were also chosen to assess change at the point of treatment in functional, structural, and physiological measures. Blinded endpoint analyses were used for electrophysiological and selected imaging outcomes. Results MSCs were successfully isolated, expanded, characterised, and administered in all patients. The mean dose was 1·6×106 cells (min–max range 1·1–2·0) per kg bodyweight. One patient developed a transient rash not requiring treatment shortly after treatment; and two patients had self–limiting bacterial infections 3–4 weeks after treatment. No serious adverse events were observed. Improvement following treatment was seen in visual acuity and VER latency (difference in monthly rates of change: –0·02 LogMAR units [95% CI –0·03 to –0·01], p=0·003); and –1·33 ms [95% CI –2·44 to –0·21], p=0.020), with an increase in optic nerve area (difference in monthly rates of change 0·13 mm2 [95% CI 0·04 to 0·22], p=0·006). Exploratory analysis for non–linear effects showed cessation of treatment effects approximately six months after intravenous infusion. Conclusions Autologous MSCs can be safely administered in secondary progressive MS with evidence to suggest structural, functional and physiological improvement following treatment consistent with neuroprotection. The transient treatment response seen implied a likely requirement for repeat infusions to sustain benefit in the long–term.

Hypothermia is potently neuroprotective, but the molecular basis of this effect remains obscure. Changes in neuronal tau protein are of interest, since tau becomes hyperphosphorylated in injury-resistant, hypothermic brains. Noting inter-species differences in tau isoforms, we have used functional cortical neurons differentiated from human pluripotent stem cells (hCNs) to interrogate tau modulation during hypothermic preconditioning at clinically-relevant temperatures. Key tau developmental transitions (phosphorylation status and splicing shift) are recapitulated during hCN differentiation and subsequently reversed by mild (32 °C) to moderate (28 °C) cooling — conditions which reduce oxidative and excitotoxic stress-mediated injury in hCNs. Blocking a major tau kinase decreases hCN tau phosphorylation and abrogates hypothermic neuroprotection, whilst inhibition of protein phosphatase 2A mimics cooling-induced tau hyperphosphorylation and protects normothermic hCNs from oxidative stress. These findings indicate a possible role for phospho-tau in hypothermic preconditioning, and suggest that cooling drives human tau towards an earlier ontogenic phenotype whilst increasing neuronal resilience to common neurotoxic insults. This work provides a critical step forward in understanding how we might exploit the neuroprotective benefits of cooling without cooling patients., Highlights • Cooling reverses aspects of tau ontogenesis in human cortical neurons and preconditions them against two key neurotoxins. • Hyperphosphorylation of tau in cooled neurons is mediated by PP2A inhibition. • Pharmacological PP2A inhibition protects normothermic neurons from oxidative stress. Studies of hibernating mammals suggest that modification of neuronal tau protein may contribute to hypothermic neuroprotection. Tau is also modified during brain development, after brain trauma and in neurodegenerative disease. Rzechorzek et al. show that cooling human neurons protects them against injury caused by excitotoxic and oxidative stress – important mediators of neuronal death in acute and chronic brain disorders. This protection is partly due to inhibition of an enzyme, which increases tau phosphorylation and contributes to reversed tau development under cooled conditions. These findings highlight how we might exploit cooling without cooling patients — by mimicking its protective effects pharmacologically.