Montreal, Canada

The Montreal Neurological Institute and Hospital is an academic medical centre dedicated to neuroscience research, training and clinical care. The institute is part of McGill University and the hospital is one of the six teaching hospitals of the McGill University Health Centre. They occupy separate sections of the same buildings on McGill's downtown Montreal campus next to Molson Stadium. The institute and hospital are locally known as "The Neuro." Wikipedia.


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Sormani M.P.,University of Genoa | Arnold D.L.,Montreal Neurological Institute | De Stefano N.,University of Siena
Annals of Neurology | Year: 2014

Objective To evaluate the extent to which treatment effect on brain atrophy is able to mediate, at the trial level, the treatment effect on disability progression in relapsing-remitting multiple sclerosis (RRMS). Methods We collected all published randomized clinical trials in RRMS lasting at least 2 years and including as endpoints disability progression (defined as 6 or 3 months confirmed 1-point increase on the Expanded Disability Status Scale), active magnetic resonance imaging (MRI) lesions (defined as new/enlarging T2 lesions), and brain atrophy (defined as change in brain volume between month 24 and month 6-12). Treatment effects were expressed as relative reductions. A linear regression, weighted for trial size and duration, was used to assess the relationship between the treatment effects on MRI markers and on disability progression. Results Thirteen trials including >13,500 RRMS patients were included in the meta-analysis. Treatment effects on disability progression were correlated with treatment effects both on brain atrophy (R2 = 0.48, p = 0.001) and on active MRI lesions (R2 = 0.61, p < 0.001). When the effects on both MRI endpoints were included in a multivariate model, the correlation was higher (R2 = 0.75, p < 0.001), and both variables were retained as independently related to the treatment effect on disability progression. Interpretation In RRMS, the treatment effect on brain atrophy is correlated with the effect on disability progression over 2 years. This effect is independent of the effect of active MRI lesions on disability; the 2 MRI measures predict the treatment effect on disability more closely when used in combination. ANN NEUROL 2014;75:43-49 © 2014 American Neurological Association.


Trempe J.-F.,Montreal Neurological Institute
Current Opinion in Structural Biology | Year: 2011

Polyubiquitin chains are assembled through the formation of an isopeptide bond between a lysine side-chain or terminal amino group of a proximal ubiquitin moiety and the carboxy-terminal of a distal ubiquitin moiety. Protein substrates tagged by polyubiquitin chains of different linkages undergo different fates. Many polyubiquitin chain types have been characterized so far, notably Lys11, Lys48, Lys63 and linear chains. These different types of chains are synthesized, disassembled and recognized by selective enzymes and receptors. Here I survey the structural basis for the selective binding of polyubiquitin chains of specific linkages, with an emphasis on recent advances in our understanding of polyubiquitin chain structure and functions. Recent work suggests linkage-type discrimination by members of the NF-κb signalling and DNA repair pathways and a specific role for Lys48-linked polyubiquitin chain recognition by proteasome-associated proteins. © 2011 Elsevier Ltd.


Dagher A.,Montreal Neurological Institute
Trends in Endocrinology and Metabolism | Year: 2012

Obesity is a neurobehavioral disorder that results from a combination of overeating and insufficient physical activity. Finely tuned mechanisms exist to match food intake to caloric expenditure. However, faced with abundant inexpensive and calorie-dense foods, many humans (and perhaps most) have a tendency to consume beyond their caloric needs. The brain controls food intake by sensing internal energy-balance signals and external cues of food availability, and by controlling feeding behavior; it is therefore at the centre of the obesity problem. This article reviews the recent use of functional brain imaging in humans to study the neural control of appetite, and how the neural systems involved may cause vulnerability to overeating in the obesogenic environment. © 2012 Elsevier Ltd.


Perucca P.,Montreal Neurological Institute | Gilliam F.G.,Geisinger Health System
The Lancet Neurology | Year: 2012

More than 150 years after bromide was introduced as the first antiepileptic drug, adverse effects remain a leading cause of treatment failure and a major determinant of impaired health-related quality of life in people with epilepsy. Adverse effects can develop acutely or many years after starting treatment and can affect any organ or structure. In the past two decades, many efforts have been made to reduce the burden of antiepileptic drug toxicity. Several methods to screen and quantify adverse effects have been developed. Patient profiles associated with increased risk of specific adverse effects have been uncovered through advances in the areas of epidemiology and pharmacogenomics. Several new-generation antiepileptic drugs with improved tolerability profiles and reduced potential for drug interaction have been added to the therapeutic armamentarium. Overall, these advances have expanded the opportunities to tailor treatment with antiepileptic drugs, to enhance effectiveness and minimise the risk of toxic effects. © 2012 Elsevier Ltd.


Tsuchida A.,Montreal Neurological Institute | Fellows L.K.,Montreal Neurological Institute
Cortex | Year: 2013

Executive function encompasses a range of control processes supporting flexible, goal-directed behaviour. Attentional set-shifting, updating of information in working memory, and inhibitory control have been proposed as key components of executive function, but debate continues as to the validity of this conceptual framework, and the neural substrates of these putative components. Here we examined prefrontal structure-function relationships for each of these component processes in a large cohort of patients with focal prefrontal damage. Forty-five patients with focal damage to various sectors of prefrontal cortex (PFC), and 50 demographically matched healthy control subjects performed an attention shifting task, the Stroop colour naming task, and a spatial search task. Voxel-based lesion-symptom mapping revealed that damage to left ventrolateral PFC led to impaired performance on both the Stroop and attention shifting tasks. In contrast, performance of the spatial search task depended on several regions within PFC, but notably not left ventrolateral PFC. These observations were confirmed with direct comparison of performance between patients grouped according to lesion location. This dissociation partly supports the component process view of executive function, distinguishing the goal-directed regulation of attention (perhaps specifically in the verbal domain) from the requirements of the spatial search task, including the updating of information in spatial working memory. These findings are easier to reconcile with modular, material-specific accounts than with more unitary models of executive function. © 2012 Elsevier Ltd.


Antonicka H.,Montreal Neurological Institute | Shoubridge E.A.,Montreal Neurological Institute
Cell Reports | Year: 2015

Cytoplasmic RNA granules play a central role in mRNA metabolism, but the importance of mitochondrial RNA granules remains relatively unexplored. We characterized their proteome and found that they contain a large toolbox of proteins dedicated to RNA metabolism. Investigation of four uncharacterized putative RNA-binding proteins-two RNA helicases, DHX30 and DDX28, and two proteins of the Fas-activated serine-threonine kinase (FASTKD) family, FASTKD2 and FASTKD5-demonstrated that both helicases and FASTKD2 are required formitochondrial ribosome biogenesis. RNA-sequencing (RNA-seq) analysis showed that DDX28 and FASTKD2 bound the 16S rRNA. FASTKD5 is required for maturing precursor mRNAs that are not flanked by tRNAs and that therefore cannot be processed by the canonical mRNA maturation pathway. Silencing FASTKD5 rendered mature COX I mRNA almost undetectable, which severely reduced the synthesis of COX I, resulting in a complex IV assembly defect. These data demonstrate that mitochondrial RNA granules are centers for posttranscriptional RNA processing and the biogenesis of mitochondrial ribosomes. © 2015 The Authors.


Bar-Or A.,Montreal Neurological Institute
Experimental Neurology | Year: 2014

Teriflunomide (Aubagio®) is a once-daily oral immunomodulatory disease modifying therapy (DMT) presently approved in several regions, including Europe, North America, Latin America and Australia, for the treatment of relapsing forms of multiple sclerosis (RMS; RRMS). The therapeutic mode of action of teriflunomide in MS continues to be investigated. This review summarizes the main efficacy and safety results of the clinical trial program leading to teriflunomide's approval, highlights a number of practical clinical considerations, and overviews its presumed therapeutic mode of action (MOA) based on pharmacokinetic and pharmacodynamic observations and the growing body of teriflunomide-related in vitro, pre-clinical (animal model), and in vivo human studies. © 2014 Elsevier Inc.


Durcan T.M.,Montreal Neurological Institute | Fon E.A.,Montreal Neurological Institute
Genes and Development | Year: 2015

Two Parkinson’s disease (PD)-associated proteins, the mitochondrial kinase PINK1 and the E3-ubiquitin (Ub) ligase PARKIN, are central to mitochondrial quality control. In this pathway, PINK1 accumulates on defective mitochondria, eliciting the translocation of PARKIN from the cytosol to mediate the clearance of damaged mitochondria via autophagy (mitophagy). Throughout the different stages of mitophagy, post-translational modifications (PTMs) are critical for the regulation of PINK1 and PARKIN activity and function. Indeed, activation and recruitment of PARKIN onto damaged mitochondria involves PINK1mediated phosphorylation of both PARKIN and Ub. Through a stepwise cascade, PARKIN is converted from an autoinhibited enzyme into an active phospho-Ubdependent E3 ligase. Upon activation, PARKIN ubiquitinates itself in concert with many different mitochondrial substrates. The Ub conjugates attached to these substrates can in turn be phosphorylated by PINK1, which triggers further cycles of PARKIN recruitment and activation. This feed-forward amplification loop regulates both PARKIN activity and mitophagy. However, the precise steps and sequence of PTMs in this cascade are only now being uncovered. For instance, the Ub conjugates assembled by PARKIN consist predominantly of noncanonical K6-linked Ub chains. Moreover, these modifications are reversible and can be disassembled by deubiquitinating enzymes (DUBs), including Ub-specific protease 8 (USP8), USP15, and USP30. However, PINK1-mediated phosphorylation of Ub can impede the activity of these DUBs, adding a new layer of complexity to the regulation of PARKINmediated mitophagy by PTMs. It is therefore evident that further insight into how PTMs regulate the PINK1– PARKIN pathway will be critical for our understanding of mitochondrial quality control. © 2015 Durcan and Fon.


La Piana R.,Montreal Neurological Institute
Archives of neurology | Year: 2012

To report a novel mutation in the gene EIF2B3 responsible for a late-onset form of vanishing white matter disease. Case report. University teaching hospital. A 29-year-old pregnant woman with a history of premature ovarian failure and hemiplegic migraines presented with a 10-week history of progressive confusion and headaches. Magnetic resonance imaging of the brain revealed a diffuse leukoencephalopathy. Sequencing of the exons and intron boundaries of EIF2B3 uncovered 2 missense mutations: c.260C>T(p.Ala87Val) and c.272G>A(p.Arg91His). To our knowledge,the latter missense mutation has never been previously reported. This is the second report of adult-onset vanishing white matter disease due to mutations in EIF2B3 and the first report of the c.272G>A (p.Arg91His) missense mutation.


Twelve neurological disorders are caused by gene-specific CAG/CTG repeat expansions that are highly unstable upon transmission to offspring. This intergenerational repeat instability is clinically relevant since disease onset, progression and severity are associated with repeat size. Studies of model organisms revealed the involvement of some DNA replication and repair genes in the process of repeat instability, however, little is known about their role in patients. Here, we used an association study to search for genetic modifiers of (CAG)n instability in 137 parent-child transmissions in Machado-Joseph disease (MJD/SCA3). With the hypothesis that variants in genes involved in DNA replication, repair or recombination might alter the MJD CAG instability patterns, we screened 768 SNPs from 93 of these genes. We found a variant in ERCC6 (rs2228528) associated with an expansion bias of MJD alleles. When using a gene-gene interaction model, the allele combination G-A (rs4140804-rs2972388) of RPA3-CDK7 is also associated with MJD instability in a direction-dependent manner. Interestingly, the transcription-coupled repair factor ERCC6 (aka CSB), the single-strand binding protein RPA, and the CDK7 kinase part of the TFIIH transcription repair complex, have all been linked to transcription-coupled repair. This is the first study performed in patient samples to implicate specific modifiers of CAG instability in humans. In summary, we found variants in three transcription-coupled repair genes associated with the MJD mutation that points to distinct mechanisms of (CAG)n instability.

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