YEAR IN REVIEW
Neurodegenerative Brain Diseases Group, Department of Molecular Genetics, VIB and Laboratory of Neurogenetics, Institute BornBunge, University of Antwerp, Universiteitsplein 1, B‑2610 Antwerp, Belgium (J. van der Zee, C. Van Broeckhoven). Correspondence to: C. Van Broeckhoven [email protected] Acknowledgements The authors thank J.-J. Martin and A. Sieben for the immunohistochemistry images and expert support. The authors receive funding from the Belgian Science Policy Office Interuniversity Attraction Poles programme, the European Centers of Excellence in Neurodegeneration, the Methusalem Excellence programme, the Alzheimer Research Foundation, the Medical Foundation Queen Elisabeth, the Research Foundation Flanders, the Agency for Innovation by Science and Technology Flanders, the University of Antwerp Research Fund, and the MetLife Foundation Award for Medical Research.
72 | FEBRUARY 2014 | VOLUME 10
intermediate repeats. Hum. Mutat. 34, 363–373 (2013). 6. Dols-Icardo, O. et al. Characterization of the repeat expansion size in C9orf72 in amyotrophic lateral sclerosis and frontotemporal dementia. Hum. Mol. Genet. http://dx.doi.org/10.1093/hmg/ddt460. 7. Van Langenhove, T. et al. Distinct clinical characteristics of C9orf72 expansion carriers compared with GRN, MAPT, and nonmutation carriers in a Flanders-Belgian FTLD cohort. JAMA Neurol. 70, 365–373 (2013). 8. Mori, K. et al. The C9orf72 GGGGCC repeat is translated into aggregating dipeptide-repeat proteins in FTLD/ALS. Science 339, 1335–1338 (2013). 9. Mackenzie, I. R. et al. Dipeptide repeat protein pathology in C9ORF72 mutation cases: clinicopathological correlations. Acta Neuropathol. 126, 859–879 (2013). 10. Lagier-Tourenne, C. et al. Targeted degradation of sense and antisense C9orf72 RNA foci as therapy for ALS and frontotemporal degeneration. Proc. Natl Acad. Sci. USA 110, E4530–E4539 (2013).
Competing interests The authors declare no competing interests. 1.
2.
3.
4.
5.
DeJesus-Hernandez, M. et al. Expanded GGGGCC hexanucleotide repeat in noncoding region of C9ORF72 causes chromosome 9p-linked FTD and ALS. Neuron 72, 245–256 (2011). Renton, A. E. et al. A hexanucleotide repeat expansion in C9ORF72 is the cause of chromosome 9p21-linked ALS-FTD. Neuron 72, 257–268 (2011). Gijselinck, I. et al. A C9orf72 promoter repeat expansion in a Flanders-Belgian cohort with disorders of the frontotemporal lobar degeneration-amyotrophic lateral sclerosis spectrum: a gene identification study. Lancet 11, 54–65 (2012). Cruts, M., Gijselinck, I., Van Langenhove, T., van der Zee, J. & Van Broeckhoven, C. Current insights into the C9orf72 repeat expansion diseases of the FTLD/ALS spectrum. Trends Neurosci. 36, 450–499 (2013). van der Zee, J. et al. A pan-European study of the C9orf72 repeat associated with FTLD: geographic prevalence, genomic instability, and
MULTIPLE SCLEROSIS IN 2013
Novel triggers, treatment targets and brain atrophy measures Xavier Montalban and Mar Tintoré
2013 witnessed advances in many aspects of multiple sclerosis (MS) research. Two studies highlighted a potential role for salt as an MS trigger, and one immunomodulatory drug performed well in clinical trials. Moreover, treatment effects of MS drugs were shown to correlate inversely with brain atrophy and disease progression. Montalban, X. & Tintoré, M. Nat. Rev. Neurol. 10, 72–73 (2014); published online 7 January 2014; doi:10.1038/nrneurol.2013.274
The year 2013 came to a close with improved understanding of how well-known environ mental factors associated with multiple sclerosis (MS) contribute to the development of this disease. In addition, treatment advances have widened the scope to tackle brain atrophy and disease p rogression in patients with MS. The past 50 years have witnessed a marked increase in the incidence of autoimmune diseases, which has probably been driven by changes in environmental factors. Epidemiological risk factors for MS include vitamin D deficiency, exposure to Epstein–Barr virus in early childhood, and cigarette smoking. Recent studies have shown that components of the daily diet and gut microbiota can strongly affect the levels of effector T cells in the gut; one such dietary factor could well be salt. In 2013, two independent groups came to the conclusion
that increased sodium chloride concentrations can promote autoimmune diseases by stimulating induction of IL‑17-producing helper T (TH17) cells from CD4+ T cells. Wu et al. showed that increased salt concentrations in vitro or in mice (via a high-salt diet) induced expression of serum glucocorticoid kinase 1 (SGK1) in T cells and enhanced
Ross Everhard | Dreamstime.com
DPR pathology in a rare, TDP‑43-negative Belgian carrier of a C9orf72 repeat expansion5 and aggregates composed of a DPR core surrounded by TDP‑43 suggested that RAN translation and DPR aggregation are early pathological events that precede and potentially trigger TDP‑43 accumulation.8,9 As such, Mori and colleagues demonstrated that DPR inclusion pathology is a direct consequence of the C9orf72 repeat expansion and that DPR aggregation due to RAN translation is the key pathological feature of C9orf72-related FTLD and ALS. Subsequently, they proposed that the current pathological classification and nomenclature should be revised in these patients to FTLD-DPR. In addition to DPR accumulation and TDP‑43 pathology, previously proposed disease mechanisms probably also contribute, in part, to disease. These mechanisms include haploi nsufficiency through loss of gene expression3–5 and RNA toxicity caused by sequestration of RNAbinding proteins. 1,10 An important next step will be to be determine the individual contribution of these four mechanisms to disease, and to characterize the early and late pathological events and how they contribute to the phenotype. Over the years, it has become increasingly clear that FTLD represents one of the most heterogeneous neurodegenerative brain diseases, with three major genes, disease mechanisms and neuropathologies complicating patient diagnosis, care and treatment (Figure 1). This heterogeneity has direct implications for translational research and therapy development, and suggests the potential for personalized medicine on the basis of the molecular signature of the FTLD subtype.
www.nature.com/nrneurol © 2014 Macmillan Publishers Limited. All rights reserved
YEAR IN REVIEW Key advances ■■ Increased sodium chloride concentrations can promote autoimmune diseases1,2 ■■ Regular smoking is associated with more-severe disease and faster disability progression in multiple sclerosis (MS); smoking cessation is associated with slower disability progression4 ■■ Daclizumab—a monoclonal antibody— was well tolerated and reduced disease activity in relapsing MS6 ■■ Brain atrophy measures are feasible measures for treatment effects in drug trials for MS8
TH17 differentiation.1 Kleinewietfeld et al. found that modest increases in sodium chloride concentration could stimulate a nearly logarithmic induction of IL‑17 in naive CD4+ cells in vitro that was mediated through p38/MAPK, NFAT5 and SGK1.2 In agreement with these findings, addition of salt to the diet of mice with experimental autoimmune encephalomyelitis—the main animal model of MS—led to severe symptom worsening and increased numbers of TH17 cells.2 These two studies suggest that high salt intake could trigger tissue inflammation and autoimmune disease. Whether salt intake is causally related to development of autoimmune disease in humans, however, is yet to be proved. Smoking has long been linked with increased risk of developing MS, but studies on its potential influence on the clinical course of the disease have yielded conflicting results. A possible association between smoking and disease progression in MS is of particular interest given the reported negative correlation between smoking and the risk of some neurodegenerative conditions such as Parkinson disease.3 Manouchehrinia et al.4 analysed data from 895 patients with MS, about half of whom were regular smokers at the time of disease onset or diagnosis. The results suggested regular smoking is associated with more-severe disease and faster disability progression. In addition, smoking cessation—whether before or after MS onset—was associated with a slower progression of disability.3 Notwithstanding the retrospective nature of this study, measures to prevent and reduce smoking in MS are warranted. Targeted immunotherapy to provide treatment benefits while avoiding adverse immunom odulatory effects remains an elusive goal in the management of autoimmune diseases. Previous studies in patients with relapsing–remitting forms
of MS (RRMS) suggest that daclizumab— a monoclonal antibody that binds CD25, the α‑subunit of the T‑cell IL‑2 receptor (IL2RA)—used in combination with IFN‑β was well tolerated and reduced disease activity in patients who were refractory to IFN‑β alone.5 In 2013, Gold et al. conducted a randomized, double-blind, placebo-controlled, phase III trial of daclizumab high-yield process (HYP) in patients with RRMS.6 The HYP form of the drug has the same amino acid sequence as previous versions but differs in its glycosylation profile, resulting in decreased antibody-dependent cellular cytotoxicity. Patients were randomly assigned to receive subcutaneous injections of daclizumab HYP or placebo, every 4 weeks for 52 weeks. Daclizumab HYP treatment was associated with a significantly reduced annualized relapse rate and disability progression compared with placebo.6 A genomewide association scan for MS risk genes and candidate gene association studies previously highlighted the locus encompassing IL2RA, making this treatment especially relevant to MS.7 Interestingly, circulating levels of CD56bright natural killer cells increased in patients treated with daclizumab HYP versus placebo, suggesting that CD56bright natural killer cells might mediate the therapeutic effects of daclizumab HYP in MS, although this suggestion has yet to be confirmed. In most individuals with MS, the disease evolves from a relapsing to a progressive form and, in about 15% of cases, MS presents as purely progressive. A neurodegenerative process is thought to underlie progressive MS. Neurodegeneration begins early in MS and contributes to accumulation of irreversible disability. Measurements of percentage brain volume changes and brain paren chymal fraction over time are among the most well-studied methods for quantifying neurodegeneration in MS. Brain atrophy measures correlate with neurological and neuropsychological disability and are feasible outcome measures in large-scale multicentre studies. Recently, Sormani et al. performed a metaanalysis to assess the relationship between the size of a treatment effect on brain atrophy and disability progression.8 The investigators reviewed all randomized trials that evaluated the effects of disease-modifying drugs on both brain atrophy and disability progression in RRMS. Finally, 13 trials involving around 13,500 patients were included in the analysis. Treatment effects on disability progression correlated significantly with treatment effects on brain atrophy and active MRI lesions.
NATURE REVIEWS | NEUROLOGY
Inclusion of treatment effects on both MRI end points in a multivariate model strengthened the correlation, and both variables were independently related to treatment effect on disability progression. This study shows that treatment effects on brain atrophy and MRI measures can be used as a surrogate outcome for treatment effects on clinical outcome, and might form useful end points in future trials of disease-modifying t herapies for MS. In summary, research in 2013 improved our ability to understand, treat and prevent disease progression in MS. The outlook for MS—an area now in front-line research— continues to improve. Reducing disease progression and neuroprotection are becoming realistic goals to be expected for the next decade. Department of Neurology/Neuroimmunology, Centre d’Esclerosi Múltiple de Catalunya (Cemcat), Hospital Universitari Vall d’Hebron, Edifici Cemcat, Passeig de la Vall d’Hebron 119‑129, 08035 Barcelona, Spain (X. Montalban, M. Tintoré). Correspondence to: X. Montalban [email protected] Competing interests X. Montalban declares associations with the following companies: Almirall, Bayer, Biogen Idec, GeNeuro, Genzyme, Merck, Novartis, Roche, Sanofi, Teva. M. Tintoré declares associations with the following companies: Bayer, Biogen Idec, Genzyme, Merck, Novartis, Teva. See the article online for full details of the relationships. 1.
2.
3.
4.
5.
6.
7.
8.
Wu, C. et al. Induction of pathogenic TH17 cells by inducible salt-sensing kinase SGK1. Nature 496, 513–517 (2013). Kleinewietfeld, M. et al. Sodium chloride drives autoimmune disease by the induction of pathogenic TH17 cells. Nature 496, 518–522 (2013). Nicoletti, A. et al. Voluptuary habits and clinical subtypes of Parkinson’s disease: the FRAGAMP case control study. Mov. Disord. 25, 2387–2394 (2010). Manouchehrinia, A. et al. Tobacco smoking and disability progression in multiple sclerosis: United Kingdom cohort study. Brain 136, 2298–2304 (2013). Wynn, D. et al. Daclizumab in active relapsing multiple sclerosis (CHOICE study): a phase 2, randomised, double-blind, placebo-controlled, add-on trial with interferon beta. Lancet Neurol. 9, 381–390 (2010). Gold, R. et al. Daclizumab high-yield process in relapsing–remitting multiple sclerosis (SELECT): a randomised, double-blind, placebo-controlled trial. Lancet 381, 2167–2175 (2013). International Multiple Sclerosis Genetics Consortium & The Wellcome Trust Case Control Consortium 2. Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis. Nature 476, 214–219 (2011). Sormani, M. P., Arnold, D. L. & De Stefano, N. Treatment effect on brain atrophy correlates with treatment effect on disability in multiple sclerosis. Ann. Neurol. http://dx.doi.org/ 10.1002/ana.24018.
VOLUME 10 | FEBRUARY 2014 | 73 © 2014 Macmillan Publishers Limited. All rights reserved
Neurodegenerative Brain Diseases Group, Department of Molecular Genetics, VIB and Laboratory of Neurogenetics, Institute BornBunge, University of Antwerp, Universiteitsplein 1, B‑2610 Antwerp, Belgium (J. van der Zee, C. Van Broeckhoven). Correspondence to: C. Van Broeckhoven [email protected] Acknowledgements The authors thank J.-J. Martin and A. Sieben for the immunohistochemistry images and expert support. The authors receive funding from the Belgian Science Policy Office Interuniversity Attraction Poles programme, the European Centers of Excellence in Neurodegeneration, the Methusalem Excellence programme, the Alzheimer Research Foundation, the Medical Foundation Queen Elisabeth, the Research Foundation Flanders, the Agency for Innovation by Science and Technology Flanders, the University of Antwerp Research Fund, and the MetLife Foundation Award for Medical Research.
72 | FEBRUARY 2014 | VOLUME 10
intermediate repeats. Hum. Mutat. 34, 363–373 (2013). 6. Dols-Icardo, O. et al. Characterization of the repeat expansion size in C9orf72 in amyotrophic lateral sclerosis and frontotemporal dementia. Hum. Mol. Genet. http://dx.doi.org/10.1093/hmg/ddt460. 7. Van Langenhove, T. et al. Distinct clinical characteristics of C9orf72 expansion carriers compared with GRN, MAPT, and nonmutation carriers in a Flanders-Belgian FTLD cohort. JAMA Neurol. 70, 365–373 (2013). 8. Mori, K. et al. The C9orf72 GGGGCC repeat is translated into aggregating dipeptide-repeat proteins in FTLD/ALS. Science 339, 1335–1338 (2013). 9. Mackenzie, I. R. et al. Dipeptide repeat protein pathology in C9ORF72 mutation cases: clinicopathological correlations. Acta Neuropathol. 126, 859–879 (2013). 10. Lagier-Tourenne, C. et al. Targeted degradation of sense and antisense C9orf72 RNA foci as therapy for ALS and frontotemporal degeneration. Proc. Natl Acad. Sci. USA 110, E4530–E4539 (2013).
Competing interests The authors declare no competing interests. 1.
2.
3.
4.
5.
DeJesus-Hernandez, M. et al. Expanded GGGGCC hexanucleotide repeat in noncoding region of C9ORF72 causes chromosome 9p-linked FTD and ALS. Neuron 72, 245–256 (2011). Renton, A. E. et al. A hexanucleotide repeat expansion in C9ORF72 is the cause of chromosome 9p21-linked ALS-FTD. Neuron 72, 257–268 (2011). Gijselinck, I. et al. A C9orf72 promoter repeat expansion in a Flanders-Belgian cohort with disorders of the frontotemporal lobar degeneration-amyotrophic lateral sclerosis spectrum: a gene identification study. Lancet 11, 54–65 (2012). Cruts, M., Gijselinck, I., Van Langenhove, T., van der Zee, J. & Van Broeckhoven, C. Current insights into the C9orf72 repeat expansion diseases of the FTLD/ALS spectrum. Trends Neurosci. 36, 450–499 (2013). van der Zee, J. et al. A pan-European study of the C9orf72 repeat associated with FTLD: geographic prevalence, genomic instability, and
MULTIPLE SCLEROSIS IN 2013
Novel triggers, treatment targets and brain atrophy measures Xavier Montalban and Mar Tintoré
2013 witnessed advances in many aspects of multiple sclerosis (MS) research. Two studies highlighted a potential role for salt as an MS trigger, and one immunomodulatory drug performed well in clinical trials. Moreover, treatment effects of MS drugs were shown to correlate inversely with brain atrophy and disease progression. Montalban, X. & Tintoré, M. Nat. Rev. Neurol. 10, 72–73 (2014); published online 7 January 2014; doi:10.1038/nrneurol.2013.274
The year 2013 came to a close with improved understanding of how well-known environ mental factors associated with multiple sclerosis (MS) contribute to the development of this disease. In addition, treatment advances have widened the scope to tackle brain atrophy and disease p rogression in patients with MS. The past 50 years have witnessed a marked increase in the incidence of autoimmune diseases, which has probably been driven by changes in environmental factors. Epidemiological risk factors for MS include vitamin D deficiency, exposure to Epstein–Barr virus in early childhood, and cigarette smoking. Recent studies have shown that components of the daily diet and gut microbiota can strongly affect the levels of effector T cells in the gut; one such dietary factor could well be salt. In 2013, two independent groups came to the conclusion
that increased sodium chloride concentrations can promote autoimmune diseases by stimulating induction of IL‑17-producing helper T (TH17) cells from CD4+ T cells. Wu et al. showed that increased salt concentrations in vitro or in mice (via a high-salt diet) induced expression of serum glucocorticoid kinase 1 (SGK1) in T cells and enhanced
Ross Everhard | Dreamstime.com
DPR pathology in a rare, TDP‑43-negative Belgian carrier of a C9orf72 repeat expansion5 and aggregates composed of a DPR core surrounded by TDP‑43 suggested that RAN translation and DPR aggregation are early pathological events that precede and potentially trigger TDP‑43 accumulation.8,9 As such, Mori and colleagues demonstrated that DPR inclusion pathology is a direct consequence of the C9orf72 repeat expansion and that DPR aggregation due to RAN translation is the key pathological feature of C9orf72-related FTLD and ALS. Subsequently, they proposed that the current pathological classification and nomenclature should be revised in these patients to FTLD-DPR. In addition to DPR accumulation and TDP‑43 pathology, previously proposed disease mechanisms probably also contribute, in part, to disease. These mechanisms include haploi nsufficiency through loss of gene expression3–5 and RNA toxicity caused by sequestration of RNAbinding proteins. 1,10 An important next step will be to be determine the individual contribution of these four mechanisms to disease, and to characterize the early and late pathological events and how they contribute to the phenotype. Over the years, it has become increasingly clear that FTLD represents one of the most heterogeneous neurodegenerative brain diseases, with three major genes, disease mechanisms and neuropathologies complicating patient diagnosis, care and treatment (Figure 1). This heterogeneity has direct implications for translational research and therapy development, and suggests the potential for personalized medicine on the basis of the molecular signature of the FTLD subtype.
www.nature.com/nrneurol © 2014 Macmillan Publishers Limited. All rights reserved
YEAR IN REVIEW Key advances ■■ Increased sodium chloride concentrations can promote autoimmune diseases1,2 ■■ Regular smoking is associated with more-severe disease and faster disability progression in multiple sclerosis (MS); smoking cessation is associated with slower disability progression4 ■■ Daclizumab—a monoclonal antibody— was well tolerated and reduced disease activity in relapsing MS6 ■■ Brain atrophy measures are feasible measures for treatment effects in drug trials for MS8
TH17 differentiation.1 Kleinewietfeld et al. found that modest increases in sodium chloride concentration could stimulate a nearly logarithmic induction of IL‑17 in naive CD4+ cells in vitro that was mediated through p38/MAPK, NFAT5 and SGK1.2 In agreement with these findings, addition of salt to the diet of mice with experimental autoimmune encephalomyelitis—the main animal model of MS—led to severe symptom worsening and increased numbers of TH17 cells.2 These two studies suggest that high salt intake could trigger tissue inflammation and autoimmune disease. Whether salt intake is causally related to development of autoimmune disease in humans, however, is yet to be proved. Smoking has long been linked with increased risk of developing MS, but studies on its potential influence on the clinical course of the disease have yielded conflicting results. A possible association between smoking and disease progression in MS is of particular interest given the reported negative correlation between smoking and the risk of some neurodegenerative conditions such as Parkinson disease.3 Manouchehrinia et al.4 analysed data from 895 patients with MS, about half of whom were regular smokers at the time of disease onset or diagnosis. The results suggested regular smoking is associated with more-severe disease and faster disability progression. In addition, smoking cessation—whether before or after MS onset—was associated with a slower progression of disability.3 Notwithstanding the retrospective nature of this study, measures to prevent and reduce smoking in MS are warranted. Targeted immunotherapy to provide treatment benefits while avoiding adverse immunom odulatory effects remains an elusive goal in the management of autoimmune diseases. Previous studies in patients with relapsing–remitting forms
of MS (RRMS) suggest that daclizumab— a monoclonal antibody that binds CD25, the α‑subunit of the T‑cell IL‑2 receptor (IL2RA)—used in combination with IFN‑β was well tolerated and reduced disease activity in patients who were refractory to IFN‑β alone.5 In 2013, Gold et al. conducted a randomized, double-blind, placebo-controlled, phase III trial of daclizumab high-yield process (HYP) in patients with RRMS.6 The HYP form of the drug has the same amino acid sequence as previous versions but differs in its glycosylation profile, resulting in decreased antibody-dependent cellular cytotoxicity. Patients were randomly assigned to receive subcutaneous injections of daclizumab HYP or placebo, every 4 weeks for 52 weeks. Daclizumab HYP treatment was associated with a significantly reduced annualized relapse rate and disability progression compared with placebo.6 A genomewide association scan for MS risk genes and candidate gene association studies previously highlighted the locus encompassing IL2RA, making this treatment especially relevant to MS.7 Interestingly, circulating levels of CD56bright natural killer cells increased in patients treated with daclizumab HYP versus placebo, suggesting that CD56bright natural killer cells might mediate the therapeutic effects of daclizumab HYP in MS, although this suggestion has yet to be confirmed. In most individuals with MS, the disease evolves from a relapsing to a progressive form and, in about 15% of cases, MS presents as purely progressive. A neurodegenerative process is thought to underlie progressive MS. Neurodegeneration begins early in MS and contributes to accumulation of irreversible disability. Measurements of percentage brain volume changes and brain paren chymal fraction over time are among the most well-studied methods for quantifying neurodegeneration in MS. Brain atrophy measures correlate with neurological and neuropsychological disability and are feasible outcome measures in large-scale multicentre studies. Recently, Sormani et al. performed a metaanalysis to assess the relationship between the size of a treatment effect on brain atrophy and disability progression.8 The investigators reviewed all randomized trials that evaluated the effects of disease-modifying drugs on both brain atrophy and disability progression in RRMS. Finally, 13 trials involving around 13,500 patients were included in the analysis. Treatment effects on disability progression correlated significantly with treatment effects on brain atrophy and active MRI lesions.
NATURE REVIEWS | NEUROLOGY
Inclusion of treatment effects on both MRI end points in a multivariate model strengthened the correlation, and both variables were independently related to treatment effect on disability progression. This study shows that treatment effects on brain atrophy and MRI measures can be used as a surrogate outcome for treatment effects on clinical outcome, and might form useful end points in future trials of disease-modifying t herapies for MS. In summary, research in 2013 improved our ability to understand, treat and prevent disease progression in MS. The outlook for MS—an area now in front-line research— continues to improve. Reducing disease progression and neuroprotection are becoming realistic goals to be expected for the next decade. Department of Neurology/Neuroimmunology, Centre d’Esclerosi Múltiple de Catalunya (Cemcat), Hospital Universitari Vall d’Hebron, Edifici Cemcat, Passeig de la Vall d’Hebron 119‑129, 08035 Barcelona, Spain (X. Montalban, M. Tintoré). Correspondence to: X. Montalban [email protected] Competing interests X. Montalban declares associations with the following companies: Almirall, Bayer, Biogen Idec, GeNeuro, Genzyme, Merck, Novartis, Roche, Sanofi, Teva. M. Tintoré declares associations with the following companies: Bayer, Biogen Idec, Genzyme, Merck, Novartis, Teva. See the article online for full details of the relationships. 1.
2.
3.
4.
5.
6.
7.
8.
Wu, C. et al. Induction of pathogenic TH17 cells by inducible salt-sensing kinase SGK1. Nature 496, 513–517 (2013). Kleinewietfeld, M. et al. Sodium chloride drives autoimmune disease by the induction of pathogenic TH17 cells. Nature 496, 518–522 (2013). Nicoletti, A. et al. Voluptuary habits and clinical subtypes of Parkinson’s disease: the FRAGAMP case control study. Mov. Disord. 25, 2387–2394 (2010). Manouchehrinia, A. et al. Tobacco smoking and disability progression in multiple sclerosis: United Kingdom cohort study. Brain 136, 2298–2304 (2013). Wynn, D. et al. Daclizumab in active relapsing multiple sclerosis (CHOICE study): a phase 2, randomised, double-blind, placebo-controlled, add-on trial with interferon beta. Lancet Neurol. 9, 381–390 (2010). Gold, R. et al. Daclizumab high-yield process in relapsing–remitting multiple sclerosis (SELECT): a randomised, double-blind, placebo-controlled trial. Lancet 381, 2167–2175 (2013). International Multiple Sclerosis Genetics Consortium & The Wellcome Trust Case Control Consortium 2. Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis. Nature 476, 214–219 (2011). Sormani, M. P., Arnold, D. L. & De Stefano, N. Treatment effect on brain atrophy correlates with treatment effect on disability in multiple sclerosis. Ann. Neurol. http://dx.doi.org/ 10.1002/ana.24018.
VOLUME 10 | FEBRUARY 2014 | 73 © 2014 Macmillan Publishers Limited. All rights reserved
