Publications by authors named "Yves Lapierre"

33 Publications

Participation in and outcomes from a 12-month tailored exercise programme for people with multiple sclerosis (MSTEP©): a randomized trial.

Clin Rehabil 2020 Jul 21;34(7):927-937. Epub 2020 May 21.

Department of Kinesiology and Physical Education, McGill University, Montreal, QC, Canada.

Objective: To estimate, among people with multiple sclerosis, the extent to which a personally tailored exercise programme (MSTEP©) resulted in greater improvements in exercise capacity and related outcomes over 12 months in comparison with general exercise guidelines.

Design: Two-group randomized trial.

Subjects: Ambulatory and sedentary.

Interventions: MSTEP©, a personally adapted exercise regimen done on most days including two days of high intensity exercise; guidelines recommending 30 minutes of moderate intensity aerobic and strength training two times per week.

Main Measures: Primary outcome was peak oxygen consumption (VO) at 12 months; secondary outcomes were composite measures of physical function, fatigue, and health-related quality of life.

Results: In total, 137 people were randomized, 66 were lost over 12 months leaving 71 with outcome data, 34 in MSTEP© group, and 37 in the Guideline group. Exercise enjoyment and confidence and exercise-induced fatigue predicted retention. There were no differences between groups on the proportion making a 10% increase in VO (27.1% MSTEP© vs 29.6% Guidelines; OR: 0.83; 95% CI: 0.23-3.08) by the 12 month assessment. The effect on fatigue was larger in the MSTEP© group than the Guideline groups (OR: 1.59; 95% CI: 0.93-2.74), the effect on physical function was more modest (OR: 1.35; 95% CI: 0.80-2.25), and null for health-related quality of life outcomes.

Conclusions: The disappointing exercise retention suggests that people with multiple sclerosis may not consider exercise important to their brain health. Either type of exercise resulted in stable exercise capacity over 1 year in those sticking with the programme.
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http://dx.doi.org/10.1177/0269215520923089DOI Listing
July 2020

Noninvasive tongue stimulation combined with intensive cognitive and physical rehabilitation induces neuroplastic changes in patients with multiple sclerosis: A multimodal neuroimaging study.

Mult Scler J Exp Transl Clin 2017 Jan-Mar;3(1):2055217317690561. Epub 2017 Feb 1.

Department of Neurology and Neurosurgery, Faculty of Medicine, McGill University, Canada; Cognitive Neuroscience, Montreal Neurological Institute, Canada.

Background: Multiple sclerosis (MS) patients have central nervous system (CNS) lesions that may impede cognitive and sensorimotor function. Few rehabilitative therapies are available.

Objectives: The objective of this paper is to study effects of noninvasive tongue stimulation using the Portable Neuromodulation Stimulator (PoNS™) combined with intensive cognitive and physical rehabilitation on working memory, gait, balance and concomitant changes in the brain.

Methods: Fourteen MS patients, seven each in an active and a sham stimulation group, participated. Participants received intensive physical therapy and working memory training for 14 weeks. Functional magnetic resonance imaging (fMRI) using motor imagery and working-memory tasks were completed prior to and following therapy, as were sensory organization tests (SOT), motor performance measures, and neuropsychological assessment.

Results: On the SOT, the active group showed significant improvement from baseline. fMRI revealed significant blood oxygen level-dependent signal changes in the left primary motor cortex for the Active Group, while the sham group had increased activity in bilateral premotor cortices. All individuals improved on working-memory tasks, but only the active group showed increased dorsolateral prefrontal cortex activity.

Conclusions: In this cohort of MS patients, the results suggest that PoNS stimulation can enhance motor performance and working memory while also driving neuroplasticity. Further studies are warranted to explore these findings.
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http://dx.doi.org/10.1177/2055217317690561DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5466147PMC
February 2017

Corrigendum to "Intracortical inhibition abnormality during the remission phase of multiple sclerosis is related to upper limb dexterity and lesions" [Clin. Neurophysiol. 127 (2016) 1503-1511].

Clin Neurophysiol 2017 02 7;128(2):393. Epub 2017 Jan 7.

Research Institute of the McGill University Health Centre, 2155 Guy Street, 5th Floor, Montreal, Que. H3H 2R9, Canada; Department of Neurology and Neurosurgery, McGill University, 845 Rue Sherbrooke Ouest, Montréal, Que., Canada.

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http://dx.doi.org/10.1016/j.clinph.2016.11.022DOI Listing
February 2017

Trajectory of MS disease course for men and women over three eras.

Mult Scler 2017 Apr 11;23(4):534-545. Epub 2016 Jul 11.

School of Physical and Occupational Therapy, Faculty of Medicine, McGill University, Montreal, QC, Canada/Division of Clinical Epidemiology, McGill University Health Center, Montreal, QC, Canada.

Background: Heterogeneity in disease course exists within multiple sclerosis (MS) subtypes.

Objective: The objective was to estimate disease course heterogeneity over three distinct onset periods (pre-1995, 1995-2004, and 2005-present) for men and women.

Methods: Group-based trajectory model (GBTM) was used to estimate clusters of patients following stable or unstable disease progression trajectories based on the Expanded Disability Status Scale (EDSS). Inception cohorts were generated from the Montreal Neurological Institute MS Clinic registry. Stable trajectories were defined as an EDSS ⩽3.0 and change ⩽1 point over the study period. Annualized relapse rate (ARR) based on the first 5 years of disease was an explanatory variable.

Results: Proportion of women classified as stable was 0% for pre-1995, 69.0% for 1995-2004, and 83.9% post-2005; for men, these proportions were 18.4%, 41.4%, and 53.8%, respectively. Men had lower percentage of stable disease than women in both post-1995 cohorts (chi-square p < 0.0001). ARR was associated with higher disability trajectories in both post-1995 cohort (odds ratios >1.0) but not in the pre-1995 cohort.

Conclusion: Large proportions of patients remain stable at their initial disability level for at least 15 years. Higher ARR increases the odds of patients being in a higher disability trajectory in the latter cohorts.
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http://dx.doi.org/10.1177/1352458516655478DOI Listing
April 2017

Immunoablation and autologous haemopoietic stem-cell transplantation for aggressive multiple sclerosis: a multicentre single-group phase 2 trial.

Lancet 2016 Aug 9;388(10044):576-85. Epub 2016 Jun 9.

Ottawa Hospital Research Institute, Ottawa, ON, Canada; Department of Medicine, University of Ottawa, Ottawa, ON, Canada; The Ottawa Hospital MS Clinic, Ottawa, ON, Canada.

Background: Strong immunosuppression, including chemotherapy and immune-depleting antibodies followed by autologous haemopoietic stem-cell transplantation (aHSCT), has been used to treat patients with multiple sclerosis, improving control of relapsing disease. We addressed whether near-complete immunoablation followed by immune cell depleted aHSCT would result in long-term control of multiple sclerosis.

Methods: We did this phase 2 single-arm trial at three hospitals in Canada. We enrolled patients with multiple sclerosis, aged 18-50 years with poor prognosis, ongoing disease activity, and an Expanded Disability Status Scale of 3.0-6.0. Autologous CD34 selected haemopoietic stem-cell grafts were collected after mobilisation with cyclophosphamide and filgrastim. Immunoablation with busulfan, cyclophosphamide, and rabbit anti-thymocyte globulin was followed by aHSCT. The primary outcome was multiple sclerosis activity-free survival (events were clinical relapse, appearance of a new or Gd-enhancing lesion on MRI, and sustained progression of Expanded Disability Status Scale score). This study was registered at ClinicalTrials.gov, NCT01099930.

Findings: Between diagnosis and aHSCT, 24 patients had 167 clinical relapses over 140 patient-years with 188 Gd-enhancing lesions on 48 pre-aHSCT MRI scans. Median follow-up was 6.7 years (range 3.9-12.7). The primary outcome, multiple sclerosis activity-free survival at 3 years after transplantation was 69.6% (95% CI 46.6-84.2). With up to 13 years of follow-up after aHSCT, no relapses occurred and no Gd enhancing lesions or new T2 lesions were seen on 314 MRI sequential scans. The rate of brain atrophy decreased to that expected for healthy controls. One of 24 patients died of transplantation-related complications. 35% of patients had a sustained improvement in their Expanded Disability Status Scale score.

Interpretation: We describe the first treatment to fully halt all detectable CNS inflammatory activity in patients with multiple sclerosis for a prolonged period in the absence of any ongoing disease-modifying drugs. Furthermore, many of the patients had substantial recovery of neurological function despite their disease's aggressive nature.

Funding: Multiple Sclerosis Scientific Research Foundation.
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http://dx.doi.org/10.1016/S0140-6736(16)30169-6DOI Listing
August 2016

Cortical Damage and Disability in Multiple Sclerosis: Relation to Intracortical Inhibition and Facilitation.

Brain Stimul 2016 Jul-Aug;9(4):566-73. Epub 2016 Jan 21.

Research Institute of the McGill University Health Centre, 2155 Guy Street, 5th Floor, Montreal, Quebec H3H 2R9, Canada; Department of Neurology and Neurosurgery, McGill University, 845 Rue Sherbrooke Ouest, Montreal, Quebec, Canada.

Background: Multimodal research combining biomarkers of intracortical activity and cortical damage could shed light on pathophysiological and adaptive neural processes related to the clinical severity of neurological conditions such as multiple sclerosis (MS).

Objective: Among people with relapsing-remitting and progressive forms of MS, we assessed the extent to which transcranial magnetic stimulation (TMS)-based biomarkers of excitatory and inhibitory cortical activity are related to cortical damage and clinical impairment.

Methods: Participants included 18 healthy individuals and 36 people with MS who had a relapsing-remitting or progressive clinical course. Using TMS, intracortical facilitation (ICF), short-interval intracortical inhibition (SICI), long-interval intracortical inhibition (LICI), and cortical silent period (CSP) were obtained. Cortical volume and cortical magnetization transfer ratio (MTR) were quantified. Disability was assessed with Multiple Sclerosis Functional Composite (MSFC).

Results: Lower mean MTR within the cerebral cortex correlated with shorter CSP among MS participants with a progressive, but not a relapsing-remitting, clinical course. Within the cortical hand knob region targeted with TMS, lower MTR was correlated with lower SICI only among individuals with relapsing-remitting MS. Longer CSP, higher ICF, lower cortical MTR, and sex were all independent significant predictors of poor upper extremity motor performance, while only cortical MTR was a significant independent predictor of total MSFC score among people with MS.

Conclusions: Cortical damage and cortical activity (both inhibitory and excitatory) may contribute to the severity of motor disability experienced by people with MS. When interpreting TMS-based outcomes, cortical integrity, clinical course, and symptom type should be considered.
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http://dx.doi.org/10.1016/j.brs.2016.01.003DOI Listing
October 2017

Canadian Experience with Fingolimod: Adherence to Treatment and Monitoring.

Can J Neurol Sci 2016 Mar 25;43(2):278-83. Epub 2016 Jan 25.

7Novartis Pharmaceuticals Canada Inc.,Dorval,Quebec.

Background: The Canadian GILENYA® Go ProgramTM provides education and support to people with relapsing-remitting multiple sclerosis during fingolimod treatment.

Methods: Data were collected and analyzed from the time of the first individual enrolled in March 2011 to March 31, 2014. Individuals were excluded if they withdrew from the program prior to receiving the first dose, or had not completed the first dose observation (FDO) at the time of data cut-off. Reports of adverse effects were validated with a database of adverse events reported to Novartis Pharmaceuticals Canada Inc.

Results: A total of 2,399 individuals had completed FDO at the end of the three-year observation period. Mean age was 41.2 years; 75.2% were female. The most recent prior therapies reported were interferon-β agents (50.2%), glatiramer acetate (31.1%), natalizumab (14.2%), no prior therapy (3.3%), and other agent (1.1%). Reasons for switching to fingolimod were lack of efficacy (34.9%), side effects (34.6%), and dissatisfaction with injections/infusion (30.4%). Continuation rates with fingolimod at 12, 24 and 30 months were 80.7%, 76.6% and 76.0%, respectively. The discontinuation rate due to reported lack of efficacy during the three-year period was 1.3%. There was 94.4% adherence to the scheduled ophthalmic examination.

Conclusions: The GILENYA® Go ProgramTM captures data for virtually all fingolimod-treated patients in Canada, enabling the evaluation of fingolimod use in routine practice. Ongoing patient support and reminders to take the medication, in conjunction with physicians' and/or patients' perception of the efficacy and tolerability of fingolimod, resulted in a high rate of continuation during longer-term therapy.
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http://dx.doi.org/10.1017/cjn.2015.325DOI Listing
March 2016

Intracortical inhibition abnormality during the remission phase of multiple sclerosis is related to upper limb dexterity and lesions.

Clin Neurophysiol 2016 Feb 31;127(2):1503-1511. Epub 2015 Aug 31.

Research Institute of the McGill University Health Centre, 2155 Guy Street, 5th Floor, Montreal, Que. H3H 2R9, Canada; Department of Neurology and Neurosurgery, McGill University, 845 Rue Sherbrooke Ouest, Montréal, Que., Canada. Electronic address:

Objective: The impact of inhibitory cortical activity on motor impairment of people with relapsing-remitting multiple sclerosis (RRMS) has not been fully elucidated despite its relevance to neurorehabilitation. The present study assessed the extent to which transcranial magnetic stimulation (TMS)-based metrics of intracortical inhibition are related to motor disability and brain damage.

Methods: Participants included forty-three persons with RRMS in the remitting phase and twenty-nine healthy controls. We stimulated the dominant hemisphere and recorded from the dominant hand to assess short-interval intracortical inhibition (SICI) and cortical silent period (CSP) duration. Disability was evaluated with the Multiple Sclerosis Functional Composite (MSFC). Regional cortical thickness and lesion volume were measured.

Results: RRMS participants with dominant upper limb dexterity impairments had prolonged CSP, but equivalent SICI, compared to participants with preserved function. CSP was not related to walking or cognitive performance. Higher normalized lesion volume correlated with longer CSP duration. When adjusting for normalized lesion volume, longer CSP significantly predicted worse dominant upper extremity impairment.

Conclusions: High intracortical inhibition possibly contributes to (or prevents remission from) motor impairment. Lesions may be associated with intracortical inhibition shifts.

Significance: CSP duration and lesion burden should be considered when developing interventions aiming to mitigate motor impairment.
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http://dx.doi.org/10.1016/j.clinph.2015.08.011DOI Listing
February 2016

Multiple sclerosis (MS) for the urologist: What should urologists know about MS?

Neurourol Urodyn 2016 Feb 24;35(2):174-9. Epub 2015 Jan 24.

Department of Urology, Jewish General Hospital, McGill University, Montreal, Quebec, Canada.

Unlabelled: Multiple sclerosis (MS) is a unique central nervous system (CNS) inflammatory disease with a broad spectrum of clinical presentations, which are time- and disease progression-related. It usually affects young adults, with a female predominance of 3:1. Men are more likely to develop symptoms at a slightly older age with a more progressive disease course. Diagnosis relies on a combination of clinical, radiological, and laboratory investigations, with a central role of magnetic resonance imaging (MRI). Although the exact etiology is still obscure, the leading hypothesis behind MS relapses is acute inflammatory attacks on CNS myelin and axons. This complex process involves B and T cells together with macrophages and microglia. Genetic and environmental factors are thought to be major contributors to the disease's evolution. MS therapies consist of long-term (immunomodulatory) management, focusing on disease modification, and short-term symptomatic control. Symptomatic treatment includes pharmacological and non-pharmacological methods to protect function and restore quality of life (QoL). The introduction and development of disease-modifying medications provide opportunities to change the face of this disease, enhancing QoL over the long-term. Interferon (INF) and Glatiramer acetate (GLAT) represent first line medications with limited effect and relatively fair safety profile. Newer medications with improved efficacy along with a more hazardous side effect profile are now considered second line therapy.

Conclusions: The present review summarizes current knowledge of this frequent disease. Urologists must acquire a deeper understanding for better integration of practice recommendations.
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http://dx.doi.org/10.1002/nau.22713DOI Listing
February 2016

Anti-JC Virus Antibody Prevalence in Canadian MS Patients.

Can J Neurol Sci 2014 Nov 4;41(6):748-52. Epub 2014 Nov 4.

7Biogen Idec Inc.,Cambridge,MA,USA.

Background: Anti-John Cunningham (JCV) antibodies have been detected in approximately 50% to 60% of multiple sclerosis (MS) patients. Age, sex, and geographic location have been associated with seroprevalence differences. We describe anti-JCV antibody prevalence in the Canadian cohort of patients enrolled in the JCV Epidemiology in MS study.

Methods: This cross-sectional multicenter study evaluated the effects of demographic and disease characteristics on anti-JCV antibody seroprevalence in MS patients irrespective of disease type and treatment. A single blood sample was collected for analysis of anti-JCV antibodies using a two-step enzyme-linked immunosorbent assay (ELISA). Chi-square and logistic regression tests were used to determine significance.

Results: A total of 4198 Canadian MS patients participated in the study; the overall anti-JCV antibody prevalence was 56.3% (95% confidence interval: 54.8% to 57.8%). Seroprevalence was significantly associated with age (increasing from 45% in young to 61% in those >60 years), sex, and region (p<0.0001 for age and sex; p=0.005 for region). No significant differences in anti-JCV antibody prevalence were associated with race, MS disease type and duration, or number and duration of treatments. Immunosuppressant use was associated with a higher seroprevalence rate (63.4%) compared with no immunosuppressant use (55.9%; p=0.040).

Conclusions: Canadian MS patients had an overall anti-JCV antibody seroprevalence that was consistent with previous studies using the two-step ELISA. Significant associations of anti-JCV antibody positivity were found with age, sex, region, and immunosuppressant therapy, whereas seroprevalence was not associated with race, MS type, MS duration, or number or duration of MS treatments.
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http://dx.doi.org/10.1017/cjn.2014.32DOI Listing
November 2014

Naive CD4 T-cell activation identifies MS patients having rapid transition to progressive MS.

Neurology 2014 Feb 22;82(8):681-90. Epub 2014 Jan 22.

From Neuroscience (E.Z., L.F.-G.), Department of Pathology (D.G.H.), and McGill Centre for Bioinformatics (M.H.), McGill University, Montreal; Neurology (J.A., A.B.-O., Y.L.), Montreal Neurological Hospital, Montreal, Canada; and Neurology (S.B.), UCSF, San Francisco, CA.

Objective: Our objective was to determine whether altered naive CD4 T-cell biology contributes to development of disease progression in secondary progressive multiple sclerosis (SPMS).

Methods: We compared the naive CD4 T-cell gene expression profiles of 19 patients with SPMS and 14 healthy controls (HCs) using a whole-genome microarray approach. We analyzed surface protein expression of critical genes by flow cytometry after T-cell receptor (TCR) stimulation of naive CD4 T cells isolated from HCs and patients with SPMS.

Results: Hierarchical clustering segregated patients with SPMS into 2 subgroups: SP-1, which had a short duration of relapsing-remitting multiple sclerosis (MS), and SP-2, which had a long duration of relapsing-remitting MS. SP-1 patients upregulated numerous immune genes, including genes within TCR and toll-like receptor (TLR) signaling pathways. SP-2 patients showed immune gene downregulation in comparison with HCs. We identified an SP-1-specific transcriptional signature of 3 genes (TLR4, TLR2, and chemokine receptor 1), and these genes had higher surface protein expression in SP-1 than in SP-2. After TCR stimulation for 48 hours, only SP-1 showed a progressive linear increase in TLR2 and TLR4 protein expression.

Conclusions: Differences in naive CD4 T-cell biology, notably of TCR and TLR signaling pathways, identified patients with MS with more rapid conversion to secondary progression, a critical determinant of long-term disability in MS.
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http://dx.doi.org/10.1212/WNL.0000000000000146DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3945666PMC
February 2014

The role of exercise in modifying outcomes for people with multiple sclerosis: a randomized trial.

BMC Neurol 2013 Jun 28;13:69. Epub 2013 Jun 28.

Division of Clinical Epidemiology, Royal Victoria Hospital, McGill University Health Centre, Montreal, QC H3A 1A1, Canada.

Background: Despite the commonly known benefits of exercise and physical activity evidence shows that persons Multiple Sclerosis (MS) are relatively inactive yet physical activity may be even more important in a population facing functional deterioration. No exercise is effective if it is not done and people with MS face unique barriers to exercise engagement which need to be overcome. We have developed and pilot tested a Multiple Sclerosis Tailored Exercise Program (MSTEP) and it is ready to be tested against general guidelines for superiority and ultimately for its impact on MS relevant outcomes. The primary research question is to what extent does an MS Tailored Exercise Program (MSTEP) result in greater improvements in exercise capacity and related outcomes over a one year period in comparison to a program based on general guidelines for exercise among people with MS who are sedentary and wish to engage in exercise as part of MS self-management.

Methods/design: The proposed study is an assessor-blind, parallel-group, randomized controlled trial (RCT). The duration of the intervention will be one year with follow-up to year two. The targeted outcomes are exercise capacity, functional ambulation, strength, and components of quality of life including frequency and intensity of fatigue symptoms, mood, global physical function, health perception, and objective measures of activity level. Logistic regression will be used to test the main hypothesis related to the superiority of the MSTEP program based on a greater proportion of people making a clinically relevant gain in exercise capacity at 1 year and at 2 years, using an intention-to-treat approach. Sample size will be 240 (120 per group).

Discussion: The MS community is clearly looking for interventions to help alleviate the disabling sequelae of MS and promote health. Exercise is a well-known intervention which has known benefits to all, yet few exercise regularly. For people with MS, the role of exercise in MS management needs to be rigorously assessed to inform people as to how best to use exercise to reduce disability and promote health.

Trial Registration: Clinical Trials.gov: NCT01611987.
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http://dx.doi.org/10.1186/1471-2377-13-69DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3706216PMC
June 2013

Treatment optimization in MS: Canadian MS Working Group updated recommendations.

Can J Neurol Sci 2013 May;40(3):307-23

Ottawa Hospital Research Institute, University of Ottawa, Ottawa.

The Canadian Multiple Sclerosis Working Group (CMSWG) developed practical recommendations in 2004 to assist clinicians in optimizing the use of disease-modifying therapies (DMT) in patients with relapsing multiple sclerosis. The CMSWG convened to review how disease activity is assessed, propose a more current approach for assessing suboptimal response, and to suggest a scheme for switching or escalating treatment. Practical criteria for relapses, Expanded Disability Status Scale (EDSS) progression and MRI were developed to classify the clinical level of concern as Low, Medium and High. The group concluded that a change in treatment may be considered in any RRMS patient if there is a high level of concern in any one domain (relapses, progression or MRI), a medium level of concern in any two domains, or a low level of concern in all three domains. These recommendations for assessing treatment response should assist clinicians in making more rational choices in their management of relapsing MS patients.
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http://dx.doi.org/10.1017/s0317167100014244DOI Listing
May 2013

Exercise barriers and preferences among women and men with multiple sclerosis.

Disabil Rehabil 2013 Mar;35(5):353-61

School of Physical and Occupational Therapy, Faculty of Medicine, McGill University, Montreal, Quebec, Canada.

Purpose: The primary objective of this study was to estimate the extent to which women and men with MS present different exercise barriers. The secondary objective was to estimate the extent to which women and men with MS present different perceived-health, depressive symptoms, and current exercise routines or preferences.

Methods: This was a cross sectional survey.

Results: 417 people with MS completed a survey of exercise barriers and current exercise routines, perceived-health and depressive symptoms. The top three exercise barriers were: too tired; impairment; and lack of time, regardless of their gender. Regardless of their gender, three times/week and 60 min/session was identified as the most common current exercise structure among physically active participants. The top three currently preferred exercise by men included walking, strengthening/weights and flexibility/stretch exercise. Women reported the same three exercises but flexibility/stretch exercise were slightly more popular than other exercise. Similarities in perceived health status and depressive symptoms were seen between women and men; expect more men were diagnosed with progressive MS (20% higher) than women, leading to a higher rate of men reporting problems with mobility.

Conclusion: Women and men with MS differed very little on exercise barriers and current exercise routines, perceived health and depressive symptoms. Even though MS is generally considered a woman's disease, this study did not find a strong need to develop gender specific exercise or physical activity interventions for this population.
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http://dx.doi.org/10.3109/09638288.2012.742574DOI Listing
March 2013

MS, MRI, and the 2010 McDonald criteria: a Canadian expert commentary.

Neurology 2012 Dec;79(23 Suppl 2):S1-15

Division of Neurology, St. Michael's Hospital, University of Toronto, Toronto, Canada.

Since the first development of diagnostic criteria for multiple sclerosis (MS), there have been regular revisions of disease definitions and diagnostic thresholds aimed at improving specificity while maintaining sensitivity. The central requirements for diagnosis of MS are dissemination in space (DIS) and dissemination in time (DIT) of lesions in the CNS, with the proviso that there should be no alternate diagnosis that better explains the clinical presentation. The most definitive diagnosis is the purely clinical one, with 2 separate attacks of symptoms (fulfilling DIT criteria) involving at least 2 different areas of the CNS (fulfilling DIS criteria). In patients who have had a first but not a second clinical attack, the McDonald criteria provide guidance on how paraclinical evidence can be used to support a diagnosis of MS. Recently, the McDonald criteria were revised and new definitions for DIS and DIT proposed. In response to that revision, a panel of Canadian MS neurologists and one neuroradiologist created this commentary regarding the clinical implications and applications of the 2010 McDonald criteria.
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http://dx.doi.org/10.1212/WNL.0b013e318277d144DOI Listing
December 2012

Polysomnographic measures of disturbed sleep are associated with reduced quality of life in multiple sclerosis.

J Neurol Sci 2012 May 16;316(1-2):158-63. Epub 2012 Jan 16.

Department of Neurology and Neurosurgery, Montreal Neurological Institute and Hospital, McGill University Health Centre, 3801 University St., Montreal, Quebec, Canada.

Background: The relationship of objective sleep parameters with health-related quality of life (HRQoL) in multiple sclerosis (MS) has not been studied.

Objective: To evaluate the relationship between polysomnographic (PSG) parameters and HRQoL in MS.

Methods: Ambulatory MS patients without a known sleep disorder completed the Short Form (36) Health Survey (SF-36), pain visual analog scale, and two consecutive overnight PSGs. HRQoL was assessed using SF-36 Physical and Mental Component Summary (PCS, MCS) scores. Standard objective PSG measures of sleep quality were determined. The relationship between objective sleep parameters and HRQoL was evaluated with multivariate linear regression, adjusting for age, sex, body mass index, disability, and pain.

Results: 62 MS patients were included. PSG measures of sleep disruption including stage changes, awakenings, time in N1 sleep, and apnea-hypopnea and total arousal indices were negatively associated (p<0.05) with MCS scores (lower scores indicating poorer HRQoL). PSG parameters reflective of better sleep quality including total sleep time, sleep efficiency, and time in REM sleep were positively associated with MCS scores. PSG parameters were not significantly associated with PCS scores.

Conclusions: PSG-documented sleep disruption negatively impacts, while better objective sleep quality positively impacts on the mental domain of HRQoL in MS.
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http://dx.doi.org/10.1016/j.jns.2011.12.013DOI Listing
May 2012

Large, nonplateauing relationship between clinical disability and cerebral white matter lesion load in patients with multiple sclerosis.

Arch Neurol 2012 Jan;69(1):89-95

Magnetic Resonance Spectroscopy Unit, McConnell Brain Imaging Centre, Montreal Neurological Institute, McGill University, 801 University St, Montreal, Quebec, Canada H3A 2B4.

Objective: To better characterize the relationship between cerebral white matter lesion load (CWM-LL) and clinical disability by (1) covering the entire range of the Kurtzke Expanded Disability Status Scale (EDSS), (2) minimizing nonbiological sources of variability, and (3) increasing pathologic specificity by studying CWM lesions that are hypointense on T1-weighted magnetic resonance imaging.

Design: Cross-sectional, retrospective study.

Setting: Hospital-based multiple sclerosis (MS) clinic. Patients  A total of 110 patients with untreated MS were recruited and studied from June 1, 1997, through June 30, 2003.

Main Outcome Measures: Cube-rooted CWM-LL and EDSS-measured clinical disability scores.

Results: We found a large, nonplateauing relationship between cube-rooted CWM-LL and concurrent EDSS scores, more so for T1-hypointense than T2-hyperintense lesions (r = 0.619 vs 0.548). Correlations between the EDSS scores and CWM-LL diminished when, as typically done in clinical trials, only those patients with EDSS scores of 0 to 6.0 were studied (n = 92; r = 0.523 for T1-hypointense lesions and r = 0.457 for T2-hyperintense lesions); more important, a series of boot-strapped correlations suggested that this decrease was not simply due to smaller sample size, and these relationships remained even after correcting for disease duration.

Conclusion: A large, nonplateauing relationship exists between CWM-LL and EDSS-measured clinical disability when patients with MS are studied to examine the entire range of disability, minimize nonbiological sources of variability, and increase pathologic specificity.
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http://dx.doi.org/10.1001/archneurol.2011.765DOI Listing
January 2012

Reduction of the peripheral blood CD56(bright) NK lymphocyte subset in FTY720-treated multiple sclerosis patients.

J Immunol 2011 Jul 27;187(1):570-9. Epub 2011 May 27.

Neuroimmunology Unit, Montreal Neurological Institute, McGill University, Montreal, Quebec H3A 2B4, Canada.

FTY720 (fingolimod) treatment of multiple sclerosis (MS) results in lymphopenia due to increased recruitment into and decreased egress from secondary lymphoid organs of CCR7(+) lymphocytes. Although absolute numbers of NK lymphocytes were reported as being unaltered in FTY720-treated MS patients (MS-FTY), such analyses did not detect a change in a minor subset. Because expression of CCR7 has been described on CD56(bright) NK cells, a minority population of NK cells, we investigated the effect of FTY720 treatment on the phenotype and function of human NK cells in the peripheral circulation of MS patients. MS-FTY patients displayed a decreased proportion of peripheral CD56(bright)CD62L(+)CCR7(+) NK cells compared with untreated MS and healthy donors. In vitro treatment with FTY720-P increased migration of untreated donor NK cells to CXCL12 while reducing the response to CX3CL1 with similar migration responses seen in NK cells from MS-FTY patients. FTY720-P inhibited sphingosine 1-phosphate-directed migration of CD56(bright) and CD56(dim) NK cells subsets from untreated healthy donors. IL-12- and IL-15-stimulated NK cells from MS-FTY patients displayed similar capacity to produce IFN-γ, TNF, IL-10, and MIP-1α cytokines/chemokines compared with NK cells from untreated healthy donors and displayed comparable levels of degranulation in response to K562 tumor cells compared with untreated donors. Subset alterations and function of NK cell populations will need to be considered as part of assessing overall immunosurveillance capacity of patients with MS who will receive sustained FTY720 therapy.
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http://dx.doi.org/10.4049/jimmunol.1003823DOI Listing
July 2011

Reduced thymic output and peripheral naïve CD4 T-cell alterations in primary progressive multiple sclerosis (PPMS).

J Neuroimmunol 2011 Apr 26;233(1-2):233-9. Epub 2011 Jan 26.

Department of Pathology, McGill University, 3775 rue University, Montreal, QC, Canada H3A 2B4.

We compared naïve CD4 and CD8 T-cell homeostasis in primary progressive multiple sclerosis (PPMS), relapsing-remitting MS (RRMS) and controls. Quantitation of signal joint T-cell receptor (TCR) excision circles (sjTRECs) and quantitative estimates of daily thymic export confirm our previous report of reduced thymic output in RRMS and demonstrate reduced thymic output in PPMS. In PPMS, the decreasing % CD31+ naïve CD4 T-cells but constant sjTRECs and constant naïve CD4 T-cell numbers with age, together with increased Bcl-2 expression suggest increased TCR signaling with increased naïve T-cell survival. We conclude PPMS patients have peripheral immune alterations related to reduced thymic output.
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http://dx.doi.org/10.1016/j.jneuroim.2010.12.007DOI Listing
April 2011

Distinct properties of circulating CD8+ T cells in FTY720-treated patients with multiple sclerosis.

Arch Neurol 2010 Dec;67(12):1449-55

Montreal Neurological Institute, QC, Canada.

Objective: To define the capacity of peripheral blood CD8(+) T cells from patients with multiple sclerosis (MS) receiving fingolimod (FTY720) to migrate in response to chemokines that contribute to trafficking into the central nervous system.

Design: Peripheral blood T cells of FTY720-treated patients with MS (MS-FTY) are mainly CD8(+) CCR7⁻ effector memory cells as CCR7(+) T cells are inhibited from exiting from secondary lymph nodes. Migration of CD8(+) T cells from MS-FTY patients and untreated donors to chemokines CXCL12 and CCL2 was assayed in vitro. Expression of CCL2 receptor (CCR2), CCR7, CD28, and CD27 on CD8(+) T cells was determined by flow cytometry.

Setting: Montreal Neurological Institute's clinical research unit. Patients The MS-FTY patients were part of the extension phase of FTY720 clinical trials for relapsing-remitting MS.

Results: In vitro addition of active (phosphorylated) FTY720 increased migration of CD8(+) T cells from untreated patients to CXCL12 and CCL2. The CD8(+) or CD8(+) CCR7⁻ T cells from MS-FTY patients migrated less to CXCL12 and CCL2 compared with those from untreated donors. The proportion of CD8(+) CCR7⁻ cells that express the CCL2 chemokine receptor, CCR2, was significantly reduced in the MS-FTY group. The CD8(+) CCR7⁻ cells from the MS-FTY patients were enriched with CD27⁻ CD28⁻ (late effector) memory cells, a population with reduced expression of CCR2 compared with early (CD27(+) CD28(+)) effector memory cells.

Conclusions: Therapy with FTY720 results in a subset of CD8(+) T cells with distinct functional migratory properties dominating the peripheral circulation. The expected forthcoming use of FTY720 as a sustained therapy for MS will clarify how this redistribution of lymphocyte populations affects the overall process of immune surveillance.
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http://dx.doi.org/10.1001/archneurol.2010.312DOI Listing
December 2010

Reconstitution of circulating lymphocyte counts in FTY720-treated MS patients.

Clin Immunol 2010 Oct;137(1):15-20

Neuroimmunology Unit, Montreal Neurological Institute, McGill University, Montreal, Quebec, Canada.

FTY720 (Fingolimod) reduces multiple sclerosis disease activity by inducing lymphopenia and inhibiting lymphocyte re-entry from lymph nodes. Peripheral lymphocyte reconstitution following drug discontinuation has been considered relatively rapid (2-4 weeks), based on short-term studies. We investigated the kinetics of lymphocyte reconstitution in MS patients in open label extension phases of FTY720 clinical trials who discontinued therapy after prolonged use (>1-5 years), and examined histological features of a mediastinal lymph node obtained from a lymphopenic FTY720 patient. Although three patients showed reconstitution of peripheral lymphocytes within the predicted timeline, two patients continued to be lymphopenic 9 and 34 months after therapy cessation. Lymph nodes from the latter patient showed preserved architecture. Notwithstanding preserved lymph node integrity, time for lymphocyte reconstitution after prolonged FTY720 therapy can be significantly greater than predicted by shorter-term studies. This is relevant for clinical decisions regarding management of patients using this therapy and for introducing alternate therapies.
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http://dx.doi.org/10.1016/j.clim.2010.06.005DOI Listing
October 2010

Thymic involution and proliferative T-cell responses in multiple sclerosis.

J Neuroimmunol 2010 Apr 12;221(1-2):73-80. Epub 2010 Mar 12.

Department of Pathology, McGill University, Montreal, Quebec, Canada.

We investigated naïve CD4 T-cell homeostasis in relapsing-remitting multiple sclerosis (RRMS). Quantification of signal joint T-cell receptor excision circles in FACS-isolated CD31hi cells, which correspond closely to CD4 recent thymic emigrants (RTEs), indicates that young patients have reduced generation of CD4 RTEs compared to age-matched controls. In RRMS, compared to controls, CXCR4 analyses indicate age-associated thymic output of progressively immature CD4 RTEs, and Ki-67 data demonstrate altered T-cell proliferative responses that fail to maintain naïve CD4 T-cell numbers with age. Thus, RRMS patients have early thymic involution with compensatory homeostatic peripheral T-cell proliferative responses that may predispose patients to autoreactivity.
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http://dx.doi.org/10.1016/j.jneuroim.2010.02.005DOI Listing
April 2010

(1)H-MRSI evidence for cortical gray matter pathology that is independent of cerebral white matter lesion load in patients with secondary progressive multiple sclerosis.

J Neurol Sci 2009 Jul 20;282(1-2):72-9. Epub 2009 Feb 20.

Magnetic Resonance Spectroscopy Unit, McConnell Brain Imaging Centre, Montreal Neurological Institute and Hospital, McGill University, Quebec, Canada.

We examined: (i) neuro-axonal disturbance (as indicated by (1)H-MRSI NA/Cr values) in the cortical grey matter (cGM) of 10 untreated patients with relapsing-remitting (RR) and 10 with secondary-progressive (SP) multiple sclerosis (MS), and (ii) the relationships between cGM-NA/Cr values and the degree of EDSS-measured clinical disability and cerebral white-matter (WM) lesion load (LL) in these patients. Whereas mean and median cGM-NA/Cr values in our RR group were similar to those in 18 age-matched normal controls (NC), large statistically-significant decreases (between 14.3% and 18.5%) were found in our SP group relative to both our RR and NC groups. When data from all patients was combined, we found: (i) a large negative correlation between EDSS scores and cGM-NA/Cr values (r=-0.55); and (ii) a larger negative correlation of cGM-NA/Cr values with cerebral T1-hypointese WM-LL (T1-LL, r=-0.73) than with cerebral T2-hyperintense-LL (T2-LL, r=-0.63). Importantly, (i) correlations of WM-LL with cGM-NA/Cr were larger in the RR group than in the SP group (T1-LL: r=-0.79 vs. -0.54; T2-LL: r=-0.63 vs. -0.51), and (ii) cerebral WM-LL values could not fully account for the extent of the decrease in mean cGM-NA/Cr that was seen in our SP group relative to our NC group. Our observations are consistent with the possibilities that: (i) in patients with RR-MS, (1)H-MRSI-measured cGM neuro-axonal disturbances are strongly related to the effects of axonal transection that are associated with cerebral WM lesions; and (ii) in patients with SP-MS, such cGM neuro-axonal disturbances are more severe and are associated with a more-widespread degenerative process (which probably includes a considerable degree of cortical demyelination).
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http://dx.doi.org/10.1016/j.jns.2009.01.015DOI Listing
July 2009

Elevated serum inflammatory markers in post-poliomyelitis syndrome.

J Neurol Sci 2008 Aug 12;271(1-2):80-6. Epub 2008 May 12.

Department of Neurology and Neurosurgery, Montreal Neurological Institute and Hospital, Montreal, Quebec, Canada.

Objectives: To determine (i) whether serum inflammatory markers TNFalpha, IL-1beta. IL-6, and leptin are increased in post-poliomyelitis syndrome (PPS) compared to healthy controls; and (ii) whether an association exists between elevated inflammatory markers and clinical parameters in PPS. The cause of PPS is unknown, but abnormal inflammatory responses have been implicated in several small studies.

Methods: Serum inflammatory markers were measured (by Luminex) in 51 PPS patients and 26 normal controls. Clinical parameters assessed included disease duration, muscle strength (Medical Research Council sumscore), fatigue (Fatigue Severity Scale and Multidimensional Fatigue Inventory), and pain (visual analog scale scores).

Results: In PPS, TNFalpha levels, as well as IL-6 and leptin were significantly increased compared to controls (Wilcoxon rank-sum test, p=0.03 for TNFalpha, p=0.03 for IL-6, p=0.01 for leptin). The elevated TNFalpha levels in PPS were associated with increased pain due to illness (Spearman correlation coefficient r=0.36, 95% C.I. 0.09 to 0.57) and specifically, with muscle pain (r=0.38, 95% C.I. 0.11 to 0.59). There were no correlations between inflammatory markers in PPS and joint pain, muscle strength, fatigue, or disease duration.

Conclusions: Serum TNFalpha, IL-6 and leptin levels are abnormally increased in PPS patients. Elevated TNFalpha levels appear to be specifically associated with increased muscle pain.
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http://dx.doi.org/10.1016/j.jns.2008.03.015DOI Listing
August 2008

Induction of antigen-specific tolerance in multiple sclerosis after immunization with DNA encoding myelin basic protein in a randomized, placebo-controlled phase 1/2 trial.

Arch Neurol 2007 Oct 13;64(10):1407-15. Epub 2007 Aug 13.

Montreal Neurological Institute, Montreal, Quebec, Canada.

Objective: To assess safety and immune modulation by BHT-3009, a tolerizing DNA vaccine encoding full-length human myelin basic protein, in patients with multiple sclerosis (MS).

Design: The study was a randomized, double-blind, placebo-controlled trial. Subjects receiving placebo were crossed over into an active arm after treatment unblinding.

Setting: The trial was conducted at 4 academic institutions within North America. Patients Thirty patients with relapsing-remitting or secondary progressive MS who were not taking any other disease-modifying drugs were enrolled in the trial. Further, the patients were required to have either 1 to 5 gadolinium-enhancing lesions on screening brain magnetic resonance imaging (MRI), a relapse in the previous 2 years, or disease worsening in the previous 2 years.

Interventions: BHT-3009 was administered as intramuscular injections at weeks 1, 3, 5, and 9 after randomization into the trial, with or without 80 mg of daily oral atorvastatin calcium in combination. Three dose levels of BHT-3009 were tested (0.5 mg, 1.5 mg, and 3 mg).

Main Outcome Measures: The primary outcome measures were safety and tolerability of BHT-3009. Secondary outcome measures included the number and volume of gadolinium-enhanced lesions on MRI, relapses, and analysis of antigen-specific immune responses.

Results: BHT-3009 was safe and well tolerated, provided favorable trends on brain MRI, and produced beneficial antigen-specific immune changes. These immune changes consisted of a marked decrease in proliferation of interferon-gamma-producing, myelin-reactive CD4+ T cells from peripheral blood and a reduction in titers of myelin-specific autoantibodies from cerebral spinal fluid as assessed by protein microarrays. We did not observe a substantial benefit of the atorvastatin combination compared with BHT-3009 alone.

Conclusion: In patients with MS, BHT-3009 is safe and induces antigen-specific immune tolerance with concordant reduction of inflammatory lesions on brain MRI.
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http://dx.doi.org/10.1001/archneur.64.10.nct70002DOI Listing
October 2007

Potential for interferon beta-induced serum antibodies in multiple sclerosis to inhibit endogenous interferon-regulated chemokine/cytokine responses within the central nervous system.

Arch Neurol 2006 Sep;63(9):1296-9

Neuroimmunology Unit and Multiple Sclerosis Clinic, Montreal Neurological Institute, 3801 University Street, Montreal, Quebec.

Background: A proportion of patients with multiple sclerosis (MS) receiving systemic interferon beta therapy will develop serum neutralizing antibodies (NAbs) that can reduce the activity of the drug. Interferon-beta (IFN-beta) is produced by glial cells within the central nervous system. Although systemic interferon beta does not access the central nervous system, titers of serum NAbs may be sufficient that some will access the central nervous system.

Objective: To address whether serum samples that contain high titers of NAbs could inhibit glial cell production of chemokines and cytokines that are regulated by endogenous IFN-beta.

Design: We used an in vitro assay involving toll-like receptor 3 ligand (polyinosinic-polycytidylic acid) signaling to assess the effect of serum samples containing high titers of NAbs (1800-20 000 U) on production of the chemokine CXCL10 and the cytokine interleukin 6 by human astrocytes.

Results: Serum samples positive for NAbs significantly inhibited polyinosinic-polycytidylic acid-induced CXCL10 and IL-6 production by astrocytes.

Conclusion: High-titer NAbs to interferon beta may block endogenous IFN-beta function and alter the chemokine/cytokine microenvironment within the central nervous system, thereby modulating the profile and course of the local inflammatory response.
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http://dx.doi.org/10.1001/archneur.63.9.1296DOI Listing
September 2006

Neuromyelitis optica with hypothalamic involvement.

Mult Scler 2005 Oct;11(5):617-21

McGill University Health Centre, The Montreal Neurological Institute and Hospital, 3801 University Street, Montreal, Quebec, Canada.

We describe two cases of neuromyelitis optica (NMO) with clinical and radiographically confirmed features of hypothalamic involvement, in the absence of other parenchymal brain lesions. Their course is otherwise typical of Devic's form of NMO. A review of the literature identifies additional cases of NMO in which clinical features attributable to under-recognized dysfunction of the hypothalamic-pituitary axis were present. We propose that the currently accepted criteria for the diagnosis of NMO could be revisited to recognize the possibility of lesions developing within hypothalamic structures.
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http://dx.doi.org/10.1191/1352458505ms1200crDOI Listing
October 2005

Axonal injury in the cerebral normal-appearing white matter of patients with multiple sclerosis is related to concurrent demyelination in lesions but not to concurrent demyelination in normal-appearing white matter.

Neuroimage 2006 Jan 29;29(2):637-42. Epub 2005 Aug 29.

Department of Neurology and Neurosurgery, Montreal Neurological Institute and Hospital, Montreal, Quebec, Canada H3A 2B4.

We assessed axonal injury and demyelination in the cerebral normal-appearing white matter (NAWM) of MS patients in a pilot study using proton magnetic resonance spectroscopic imaging and quantitative magnetization transfer (MT) imaging. Resonance intensities of N-acetylaspartate (NAA) relative to creatine (Cr) were measured in a large central brain volume. NAA/Cr in NAWM was estimated by regression of the NAA/Cr in each voxel against white matter fraction and extrapolation to a white matter fraction of 1. The fractional size of the semi-solid pool (F) was obtained from the binary spin bath model of MT by computing the model parameters from multiple MT-weighted and relaxometry acquisitions. F in NAWM was significantly smaller in the patients [0.109 (0.009)] relative to controls [0.123 (0.007), P = 0.011], but did not differ between RR [0.1085] and SP [0.1087] patients [P > 0.99]. NAA/Cr and F in the NAWM were not correlated (r = 0.16, P > 0.7), mainly due to a lack of variation in F among patients. This may indicate a floor to the extent of myelin pathology that can occur in NAWM before a lesion appears, or that axonal damage is not strictly related to demyelination. The correlation between NAWM NAA/Cr and T2w lesion volume was not significant (P > 0.1). However, dividing the lesion volumes by the mean F in T2w lesions resulted in a quantity that correlated well with NAWM NAA/Cr (r = -0.78, P = 0.038), possibly reflecting the association of Wallerian degeneration in the NAWM with axonal transection associated with demyelination within lesions.
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http://dx.doi.org/10.1016/j.neuroimage.2005.07.017DOI Listing
January 2006

Axonal damage in multiple sclerosis patients with high versus low expanded disability status scale score.

Can J Neurol Sci 2004 May;31(2):225-8

Montreal Neurological Hospital, Department of Neurology and Neurosurgery, Montreal, Quebec, Canada.

Background: The pathophysiological basis for differences in disability in patients with multiple sclerosis is unclear.

Methods: We used magnetic resonance imaging to examine whether differences in disability in cohorts of multiple sclerosis patients with similar T2-weighted lesion volume and disease duration were associated with a more destructive disease process in the more disabled patients.

Results: The benign and severely disabled groups had similar brain atrophy metrics and similar decreases of the neuronal marker, N-acetylaspartate, in the normal appearing white matter of the cerebrum on magnetic resonance spectroscopy examination in vivo. The severely disabled cohort had more spinal cord atrophy.

Conclusion: The dissociation of spinal cord atrophy and cerebral atrophy between these two groups suggests that the difference between the more benign and more disabled groups cannot be explained by a more aggressive pathological process that is affecting the entire neuroaxis in a homogeneous fashion.
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http://dx.doi.org/10.1017/s0317167100053877DOI Listing
May 2004

Type 2 monocyte and microglia differentiation mediated by glatiramer acetate therapy in patients with multiple sclerosis.

J Immunol 2004 Jun;172(11):7144-53

Neuroimmunology Unit, Montreal Neurological Institute, McGill University, Montreal, Quebec, Canada.

Glatiramer acetate (GA) therapy of patients with multiple sclerosis (MS) represents a unique setting in which in vivo Th2 deviation of T cells is consistently observed and associated with clinical benefit in a human autoimmune disease. We postulated that APCs are important targets of GA therapy and demonstrate that treatment of MS patients with GA reciprocally regulates the IL-10/IL-12 cytokine network of monocytes in vivo. We further show that Th1- or Th2-polarized GA-reactive T cells isolated from untreated or treated MS patients mediate type 1 and 2 APC differentiation of human monocytes, based on their ability to efficiently induce subsequent Th1 and Th2 deviation of naive T cells, respectively. These observations are extended to human microglia, providing the first demonstration of type 2 differentiation of CNS-derived APCs. Finally, we confirm that the fundamental capacity of polarized T cells to reciprocally modulate APC function is not restricted to GA-reactive T cells, thereby defining a novel and dynamic positive feedback loop between human T cell and APC responses. In the context of MS, we propose that GA therapy results in the generation of type 2 APCs, contributing to Th2 deviation both in the periphery and in the CNS of MS patients. In addition to extending insights into the therapeutic mode of action of GA, our findings revisit the concept of bystander suppression and underscore the potential of APCs as attractive targets for therapeutic immune modulation.
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http://dx.doi.org/10.4049/jimmunol.172.11.7144DOI Listing
June 2004