Motor neuron disease includes a heterogeneous group of relentless progressive neurological disorders defined and characterized by the degeneration of motor neurons.Amyotrophic lateral sclerosis is the most common and ...Motor neuron disease includes a heterogeneous group of relentless progressive neurological disorders defined and characterized by the degeneration of motor neurons.Amyotrophic lateral sclerosis is the most common and aggressive form of motor neuron disease with no effective treatment so far.Unfortunately,diagnostic and prognostic biomarkers are lacking in clinical practice.Neurofilaments are fundamental structural components of the axons and neurofilament light chain and phosphorylated neurofilament heavy chain can be measured in both cerebrospinal fluid and serum.Neurofilament light chain and phosphorylated neurofilament heavy chain levels are elevated in amyotrophic lateral sclerosis,reflecting the extensive damage of motor neurons and axons.Hence,neurofilaments are now increasingly recognized as the most promising candidate biomarker in amyotrophic lateral sclerosis.The potential usefulness of neurofilaments regards various aspects,including diagnosis,prognosis,patient stratification in clinical trials and evaluation of treatment response.In this review paper,we review the body of literature about neurofilaments measurement in amyotrophic lateral sclerosis.We also discuss the open issues concerning the use of neurofilaments clinical practice,as no overall guideline exists to date;finally,we address the most recent evidence and future perspectives.展开更多
Whereas the effect of interferons (IFNs) on magnetic resonance imaging (MRI) outcome measures in patients with multiple sclerosis (MS) has been convincingly shown, little work has been done to define the between-patie...Whereas the effect of interferons (IFNs) on magnetic resonance imaging (MRI) outcome measures in patients with multiple sclerosis (MS) has been convincingly shown, little work has been done to define the between-patient heterogeneity of treatment response. Our aim was to assess the distribution of the effect of IFNβ - 1b in terms of reduction of active T2 lesions in patients with MS. Using a fixed and a random effects model, we investigated the distribution of active T2 lesions reduction over a three-year follow up in response to treatment with 250 mcg IFNβ -1b every other day in 695 patients with a complete MRI data-set of the 718 (97 % ) enrolled in the European, multicenter, randomised, double-blind, placebo-controlled trial of secondary progressive MS. The two statistical models consistently showed that the between-patient response to IFNβ -1b, in terms of reduction of active T2 lesions, is highly heterogeneous. Whereas treated patients have a high probability (more than 65 % ) of showing an active T2 lesion reduction equal to or greater than 60 % , there is also a 7 % probability for treated patients not to show any reduction of MRI-detected disease activity during the course of the trial or even to have an increase of T2 active lesions. This study might be regarded as a first step toward the definition of markers potentially useful to identify IFNβ treatment responders and non-responders with regard to T2 lesion activity.展开更多
Background In patients who present with clinically isolated syndromes suggesti ve of multiple sclerosis, interferon beta 1a is effective in delaying evolution to clinically definite disease and in reducing MRI measure...Background In patients who present with clinically isolated syndromes suggesti ve of multiple sclerosis, interferon beta 1a is effective in delaying evolution to clinically definite disease and in reducing MRI measured disease activity. We aimed to assess whether this drug can also reduce the rate of brain volume de crease in such patients enrolled in the ETOMS (early treatment of multiple scler osis) trial. Methods MRI data for brain volume measurements at baseline, month 1 2, and month 24 were available from 131, 111, and 112 patients assigned treatmen t (22 μg interferon beta 1a), and 132, 98, and 99 patients assigned placebo re spectively. Normalised brain parenchymal volume (NBV) at baseline and percentage brain volume changes (PBVC) were measured with a fully automated segmentation technique. The primary endpoint was conversion to clinically definite multiple s clerosis due to clinical relapse. Analysis was by intention to treat. Findings 4 1 (31%) of 131 patients on interferon beta 1a and 62 (47%) of 132 on placebo converted to clinically definite multiple sclerosis (odds ratio 0.52 [95%CI 0. 3 1-0.86], p=0.0115). Mean PBVC for patients on placebo was -0.83%during the f i rst year, -0.67%during the second year, and -1.68%during the entire study pe riod. Respective values for treated patients were -0.62%, -0.61%, and -1.18 %. The changes in brain volume were significant in both groups at all timepoint s. A significant treatment effect was detected for month 24 versus baseline valu es (p=0.0031). The number of new T2 lesions formed during the first year correla ted weakly with PBVC during the second year. Interpretation Early treatment with interferon beta 1a is effective in reducing conversion to clinically definite multiple sclerosis and in slowing progressive loss of brain tissue in patients w ith clinically isolated syndromes. The modest correlation between newlesion form ation and brain volume decrease suggests that inflammatory and neurodegenerative processes are, at least partly, dissociated from the earliest clinical stage of multiple sclerosis onwards.展开更多
Among multiple sclerosis(MS)susceptibility genes,the strongest non-human leukocyte antigen(HLA)signal in the Italian population maps to the TNFSF14 gene encoding LIGHT,a glycoprotein involved in dendritic cell(DC)matu...Among multiple sclerosis(MS)susceptibility genes,the strongest non-human leukocyte antigen(HLA)signal in the Italian population maps to the TNFSF14 gene encoding LIGHT,a glycoprotein involved in dendritic cell(DC)maturation.Through fine-mapping in a large Italian dataset(4,198 patients with MS and3,903 controls),we show that the TNFSF14 intronic SNP rs1077667 is the primarily MS-associated variant in the region.Expression quantitative trait locus(e QTL)analysis indicates that the MS risk allele is significantly associated with reduced TNFSF14 messenger RNA levels in blood cells,which is consistent with the allelic imbalance in RNA-Seq reads(P<0.0001).The MS risk allele is associated with reduced levels of TNFSF14 gene expression(P<0.01)in blood cells from 84 Italian patients with MS and 80 healthy controls(HCs).Interestingly,patients with MS are lower expressors of TNFSF14 compared to HC(P<0.007).Individuals homozygous for the MS risk allele display an increased percentage of LIGHT-positive peripheral blood myeloid DCs(CD11 c+,P=0.035)in 37 HCs,as well as in in vitro monocyte-derived DCs from 22 HCs(P=0.04).Our findings suggest that the intronic variant rs1077667 alters the expression of TNFSF14 in immune cells,which may play a role in MS pathogenesis.展开更多
Cervical cord magnetization transfer ratio (MTR) histograms were obtained from 45 patients at presentation with clinically isolated syndromes (CIS) suggestive ofmultiple sclerosis (MS). The mean values of MTR histogra...Cervical cord magnetization transfer ratio (MTR) histograms were obtained from 45 patients at presentation with clinically isolated syndromes (CIS) suggestive ofmultiple sclerosis (MS). The mean values of MTR histogram derived metrics were not different between CIS patients and healthy control subjects or between patients with and without evidence of disease dissemination in time. Only three patients showed significantly lower cord MTR values than control subjects. These findings suggest the absence of intrinsic structural damage of the cervical cord soon after the onset of CIS suggestive of MS, even in those patients with an early evolution to MS.展开更多
文摘Motor neuron disease includes a heterogeneous group of relentless progressive neurological disorders defined and characterized by the degeneration of motor neurons.Amyotrophic lateral sclerosis is the most common and aggressive form of motor neuron disease with no effective treatment so far.Unfortunately,diagnostic and prognostic biomarkers are lacking in clinical practice.Neurofilaments are fundamental structural components of the axons and neurofilament light chain and phosphorylated neurofilament heavy chain can be measured in both cerebrospinal fluid and serum.Neurofilament light chain and phosphorylated neurofilament heavy chain levels are elevated in amyotrophic lateral sclerosis,reflecting the extensive damage of motor neurons and axons.Hence,neurofilaments are now increasingly recognized as the most promising candidate biomarker in amyotrophic lateral sclerosis.The potential usefulness of neurofilaments regards various aspects,including diagnosis,prognosis,patient stratification in clinical trials and evaluation of treatment response.In this review paper,we review the body of literature about neurofilaments measurement in amyotrophic lateral sclerosis.We also discuss the open issues concerning the use of neurofilaments clinical practice,as no overall guideline exists to date;finally,we address the most recent evidence and future perspectives.
文摘Whereas the effect of interferons (IFNs) on magnetic resonance imaging (MRI) outcome measures in patients with multiple sclerosis (MS) has been convincingly shown, little work has been done to define the between-patient heterogeneity of treatment response. Our aim was to assess the distribution of the effect of IFNβ - 1b in terms of reduction of active T2 lesions in patients with MS. Using a fixed and a random effects model, we investigated the distribution of active T2 lesions reduction over a three-year follow up in response to treatment with 250 mcg IFNβ -1b every other day in 695 patients with a complete MRI data-set of the 718 (97 % ) enrolled in the European, multicenter, randomised, double-blind, placebo-controlled trial of secondary progressive MS. The two statistical models consistently showed that the between-patient response to IFNβ -1b, in terms of reduction of active T2 lesions, is highly heterogeneous. Whereas treated patients have a high probability (more than 65 % ) of showing an active T2 lesion reduction equal to or greater than 60 % , there is also a 7 % probability for treated patients not to show any reduction of MRI-detected disease activity during the course of the trial or even to have an increase of T2 active lesions. This study might be regarded as a first step toward the definition of markers potentially useful to identify IFNβ treatment responders and non-responders with regard to T2 lesion activity.
文摘Background In patients who present with clinically isolated syndromes suggesti ve of multiple sclerosis, interferon beta 1a is effective in delaying evolution to clinically definite disease and in reducing MRI measured disease activity. We aimed to assess whether this drug can also reduce the rate of brain volume de crease in such patients enrolled in the ETOMS (early treatment of multiple scler osis) trial. Methods MRI data for brain volume measurements at baseline, month 1 2, and month 24 were available from 131, 111, and 112 patients assigned treatmen t (22 μg interferon beta 1a), and 132, 98, and 99 patients assigned placebo re spectively. Normalised brain parenchymal volume (NBV) at baseline and percentage brain volume changes (PBVC) were measured with a fully automated segmentation technique. The primary endpoint was conversion to clinically definite multiple s clerosis due to clinical relapse. Analysis was by intention to treat. Findings 4 1 (31%) of 131 patients on interferon beta 1a and 62 (47%) of 132 on placebo converted to clinically definite multiple sclerosis (odds ratio 0.52 [95%CI 0. 3 1-0.86], p=0.0115). Mean PBVC for patients on placebo was -0.83%during the f i rst year, -0.67%during the second year, and -1.68%during the entire study pe riod. Respective values for treated patients were -0.62%, -0.61%, and -1.18 %. The changes in brain volume were significant in both groups at all timepoint s. A significant treatment effect was detected for month 24 versus baseline valu es (p=0.0031). The number of new T2 lesions formed during the first year correla ted weakly with PBVC during the second year. Interpretation Early treatment with interferon beta 1a is effective in reducing conversion to clinically definite multiple sclerosis and in slowing progressive loss of brain tissue in patients w ith clinically isolated syndromes. The modest correlation between newlesion form ation and brain volume decrease suggests that inflammatory and neurodegenerative processes are, at least partly, dissociated from the earliest clinical stage of multiple sclerosis onwards.
基金supported by the Italian Foundation of Multiple Sclerosis(FISM,2011/R/142015/R/10,2019/R-Multi/033)by the Italian Ministry of Health(RF-2016-02361294)the AGING Project for Department of Excellence at the Department of Translational Medicine(DIMET),Universitàdel Piemonte Orientale,Novara,Italy+1 种基金supported by Consorzio Interuniversitario di Biotecnologie(CIB)partially supported by Multiple MS project(Horizon 2020 European Grant 733161),Stockholm。
文摘Among multiple sclerosis(MS)susceptibility genes,the strongest non-human leukocyte antigen(HLA)signal in the Italian population maps to the TNFSF14 gene encoding LIGHT,a glycoprotein involved in dendritic cell(DC)maturation.Through fine-mapping in a large Italian dataset(4,198 patients with MS and3,903 controls),we show that the TNFSF14 intronic SNP rs1077667 is the primarily MS-associated variant in the region.Expression quantitative trait locus(e QTL)analysis indicates that the MS risk allele is significantly associated with reduced TNFSF14 messenger RNA levels in blood cells,which is consistent with the allelic imbalance in RNA-Seq reads(P<0.0001).The MS risk allele is associated with reduced levels of TNFSF14 gene expression(P<0.01)in blood cells from 84 Italian patients with MS and 80 healthy controls(HCs).Interestingly,patients with MS are lower expressors of TNFSF14 compared to HC(P<0.007).Individuals homozygous for the MS risk allele display an increased percentage of LIGHT-positive peripheral blood myeloid DCs(CD11 c+,P=0.035)in 37 HCs,as well as in in vitro monocyte-derived DCs from 22 HCs(P=0.04).Our findings suggest that the intronic variant rs1077667 alters the expression of TNFSF14 in immune cells,which may play a role in MS pathogenesis.
文摘Cervical cord magnetization transfer ratio (MTR) histograms were obtained from 45 patients at presentation with clinically isolated syndromes (CIS) suggestive ofmultiple sclerosis (MS). The mean values of MTR histogram derived metrics were not different between CIS patients and healthy control subjects or between patients with and without evidence of disease dissemination in time. Only three patients showed significantly lower cord MTR values than control subjects. These findings suggest the absence of intrinsic structural damage of the cervical cord soon after the onset of CIS suggestive of MS, even in those patients with an early evolution to MS.
