BACKGROUND: Because secondary progressive multiple sclerosis (SPMS) is associated with worse prognosis, early predictive tools are needed. We aimed to use systematic literature review and advanced methods to create and validate a clinical tool for estimating individual patient risk of transition to SPMS over five years. METHODS: Data from the Jacobs Multiple Sclerosis Center (JMSC) and the Multiple Sclerosis Center Amsterdam (MSCA) was collected between 1994 and 2022. Participants were relapsing-remitting adult patients at initial evaluation. We created the tool in four stages: (1) identification of candidate predictors from systematic literature review, (2) ordinal cutoff determination, (3) feature selection, (4) feature weighting. RESULTS: Patients in the development/internal-validation/external-validation datasets respectively (n = 787/n = 522/n = 877) had a median age of 44.1/42.4/36.6 and disease duration of 7.7/6.2/4.4 years. From these, 12.6 %/10.2 %/15.4 % converted to SPMS (median=4.9/5.2/5.0 years). The DAAE Score was named from included predictors: Disease duration, Age at disease onset, Age, EDSS. It ranges from 0 to 12 points, with risk groups of very-low=0-2, low=3-7, medium=8-9, and high≥10. Risk of transition to SPMS increased proportionally across these groups in development (2.7 %/7.4 %/18.8 %/40.2 %), internal-validation (2.9 %/6.8 %/26.8 %/36.5 %), and external-validation (7.5 %/9.6 %/22.4 %/37.5 %). CONCLUSION: The DAAE Score estimates individual patient risk of transition to SPMS consistently across datasets internationally using clinically-accessible data. With further validation, this tool could be used for clinical risk estimation.
- MeSH
- chronicko-progresivní roztroušená skleróza * diagnóza MeSH
- dospělí MeSH
- hodnocení rizik metody MeSH
- lidé středního věku MeSH
- lidé MeSH
- progrese nemoci * MeSH
- relabující-remitující roztroušená skleróza diagnóza MeSH
- reprodukovatelnost výsledků MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- validační studie MeSH
BACKGROUND: New/enlarging T2 lesion count and T2-lesion volume (LV) are used as conventional secondary endpoints in clinical trials of patients with multiple sclerosis (PwMS). However, those outcomes may have several limitations, such as inability to account for heterogeneity of lesion formation/enlargement frequency and their dynamic volumetric behavior. Measurement of volume rather than count of new/enlarging lesions may be more representative outcome of dynamic changes over time. OBJECTIVES: To investigate whether new/enlarging T2-LV is more predictive of confirmed disability progression (CDP), compared to total T2-LV or new/enlarging T2 lesion count over long-term follow-up. METHODS: We studied 176 early relapsing-remitting PwMS who were followed with annual MRI examinations over 10 years. T2-LV, new/enlarging T2-LV, and new/enlarging lesion count were determined. Cumulative count/volumes were obtained. 10-year CDP was confirmed after 48-weeks. ANCOVA analysis detected MRI outcome differences in stable (n = 76) and CDP (n = 100) groups at different time points, after correction for multiple comparisons. RESULTS: PwMS with CDP had greater cumulative new/enlarging T2-LV at 4 years (p = 0.049), and enlarging T2-LV at 4- (p = 0.039) and 6-year follow-up (p = 0.032), compared to stable patients. PwMS with CDP did not differ from stable ones in new/enlarging T2 lesion count or total T2-LV at any of the study timepoints. PwMS with Expanded Disability Status Scale change >2.0 had significantly greater enlarging T2 lesion count (p = 0.01) and enlarging T2-LV (p = 0.038) over the 10-year follow-up. CONCLUSION: Enlargement of T2 lesions is more strongly associated with long-term disability progression compared to other conventional T2 lesion-based outcomes.
- MeSH
- atrofie patologie MeSH
- lidé MeSH
- magnetická rezonanční tomografie MeSH
- mozek patologie MeSH
- progrese nemoci MeSH
- relabující-remitující roztroušená skleróza * diagnostické zobrazování patologie MeSH
- roztroušená skleróza * diagnostické zobrazování patologie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
BACKGROUND AND PURPOSE: White matter (WM) tract disruption impacts volume loss in connected deep gray matter (DGM) over 5 years in people with multiple sclerosis (PwMS). However, the timeline of this phenomenon remains poorly characterized. MATERIALS AND METHODS: Annual serial MRI for 181 PwMS was retrospectively analyzed from a 10-year clinical trial database. Annualized thalamic atrophy, DGM atrophy, and disruption of connected WM tracts were measured. For time series analysis, ~700 epochs were collated using a sliding 5-year window, and regression models predicting 1-year atrophy were applied to characterize the influence of new tract disruption from preceding years, while controlling for whole brain atrophy and other relevant factors. RESULTS: Disruptions of WM tracts connected to the thalamus were significantly associated with thalamic atrophy 1 year later (β: 0.048-0.103). This effect was not observed for thalamic tract disruption concurrent with the time of atrophy nor for thalamic tract disruption preceding the atrophy by 2-4 years. Similarly, disruptions of white matter tracts connected to the DGM were significantly associated with DGM atrophy 1 year later (β: 0.078-0.111), but not for tract disruption concurrent with, nor preceding the atrophy by 2-4 years. CONCLUSION: Increased rates of thalamic and DGM atrophy were restricted to 1 year following newly developed disruption in connected WM tracts. In research and clinical settings, additional gray matter atrophy may be expected 1 year following new lesion growth in connected white matter.
- MeSH
- atrofie patologie MeSH
- bílá hmota * diagnostické zobrazování patologie MeSH
- lidé MeSH
- magnetická rezonanční tomografie MeSH
- mozek diagnostické zobrazování patologie MeSH
- retrospektivní studie MeSH
- roztroušená skleróza * komplikace diagnostické zobrazování patologie MeSH
- šedá hmota diagnostické zobrazování patologie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
BACKGROUND AND PURPOSE: A high variability of brain MRI volume change measurement renders challenging its interpretation in multiple sclerosis (MS). Occurrence and clinical relevance of observed apparent brain volume increase (BVI) in MS patients have not been investigated yet. The objective was to quantify the prevalence and factors associated with BVI. METHODS: We examined 366 MS patients (2,317 scans) and 44 controls (132 scans). Volumetric analysis of brain volume changes was performed by SIENA and ScanView. BVI was defined as brain volume change >0%. We compared characteristics of patients with and without BVI. RESULTS: BVI was found in 26.3% (from 1,951) longitudinal scans (SIENA). If BVI occurred, a probability that BVI will be repeated consecutively more than or equal to two times was 15.9%. The repeated BVI was associated with clinical disease activity in 50% of cases. BVI was associated with shorter time and lower T2 lesion volume increase between two MRI scans, and higher normalized brain volume (all P < .0001). A proportion of scans with BVI was higher when analyzed by ScanView (35.3%) and in controls (36.4% by SIENA). CONCLUSIONS: BVI occurs in a great proportion of MR scans over short-term follow-up and is not associated with disease stabilization. Although BVI can be caused by several factors, the results indicate that measurement error may contribute to BVI in the majority of cases. Clinicians should be aware of the frequent occurrence of apparent BVI, interpret brain volume changes in MS patients with great caution, and use methods with precise quantification of brain volume changes.
- MeSH
- dospělí MeSH
- interpretace obrazu počítačem * MeSH
- lidé středního věku MeSH
- lidé MeSH
- magnetická rezonanční tomografie * MeSH
- mozek diagnostické zobrazování patologie MeSH
- roztroušená skleróza diagnostické zobrazování patologie MeSH
- velikost orgánu MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
BACKGROUND The added value of neurofilament light chain levels in serum sNfL to the concept of no evidence of disease activity 3 NEDA 3 has not yet been investigated in detail OBJECTIVE To assess whether combination of sNfL with NEDA 3 status improves identification of patients at higher risk of disease activity during the following year METHODS We analyzed 369 blood samples from 155 ear
BACKGROUND: Increased blood brain barrier (BBB) permeability, CNS inflammation and neuroaxonal damage are pathological hallmarks in early multiple sclerosis (MS). OBJECTIVE: To investigate the associations of neurofilament light chain (NfL) levels with measures of BBB integrity and central nervous system (CNS) inflammation in MS during the first demyelinating event. METHODS: Blood and cerebrospinal fluid (CSF) were obtained from 142 MS (McDonald 2017) treatment-naive patients from the SET study (63% female; age: 29.7 ± 7.9 years) following the disease onset. NfL, albumin, immunoglobulin G (IgG), and immunoglobulin M (IgM) levels were measured in CSF and blood samples. Albumin quotient was computed as a marker of BBB integrity. Immune cell subset counts in CSF were measured using flow cytometry. MS risk factors, such as Human leukocyte antigen DRB1 locus gene (HLA DRB1)*1501, anti-Epstein-Barr virus (EBV) antibodies, and 25-hydroxy vitamin D3, were also measured. RESULTS: Higher serum NfL (sNfL) levels were associated with higher albumin quotient (p < 0.001), CSF CD80+ (p = 0.012), and CD80+ CD19+ (p = 0.015) cell frequency. sNfL levels were also associated with contrast-enhancing and T2 lesions on brain magnetic resonance imaging (MRI; all p ⩽ 0.001). Albumin quotient was not associated with any of the MS risk factors assessed. sNfL levels were associated with anti-EBV viral capsid antigen (VCA) IgG levels (p = 0.0026). CONCLUSION: sNfL levels during the first demyelinating event of MS are associated with greater impairment of BBB integrity, immune cell extravasation, and brain lesion activity on MRI.
- MeSH
- biologické markery MeSH
- dospělí MeSH
- hematoencefalická bariéra * MeSH
- intermediární filamenta MeSH
- lidé MeSH
- lymfocyty MeSH
- mladý dospělý MeSH
- neurofilamentové proteiny MeSH
- rizikové faktory MeSH
- roztroušená skleróza * MeSH
- Check Tag
- dospělí MeSH
- lidé MeSH
- mladý dospělý MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
OBJECTIVE: To describe the dynamics of brain volume loss (BVL) at different stages of relapsing-remitting multiple sclerosis (RRMS), to describe the association between BVL and clinical measures, and to investigate an effect of treatment escalation on the rate of BVL. METHODS: Together, 1903 patients predominantly with RRMS from the Avonex-Steroids-Azathioprine cohort (N = 166), the study of early IFN-β1a treatment cohort (N = 180), and the quantitative MRI cohort (N = 1,557) with ≥2 MRI scans and ≥1-year of follow-up were included. Brain MRI scans (N = 7,203) were performed using a single 1.5-T machine. Relationships between age or disease duration and global and tissue-specific BVL rates were analyzed using mixed models. RESULTS: Age was not associated with the rate of BVL (β = -0.003; Cohen f2 = 0.0005; adjusted p = 0.39). Although disease duration was associated with the rate of BVL, its effect on the BVL rate was minimal (β = -0.012; Cohen f2 = 0.004; adjusted p = 4 × 10-5). Analysis of association between tissue-specific brain volume changes and age (β = -0.019 to -0.011; adjusted p = 0.028-1.00) or disease duration (β = -0.028 to -0.008; adjusted p = 0.16-0.96) confirmed these results. Although increase in the relapse rate (β = 0.10; adjusted p = 9 × 10-9), Expanded Disability Status Scale (EDSS; β = 0.17; adjusted p = 8 × 10-5), and EDSS change (β = 0.15; adjusted p = 2 × 10-5) were associated with accelerated rate of BVL, their effect on the rate of BVL was minimal (all Cohen f2 ≤ 0.007). In 94 patients who escalated therapy, the rate of BVL decreased following treatment escalation by 0.29% (β = -0.29; Cohen f2 = 0.133; p = 5.5 × 10-8). CONCLUSIONS: The rate of BVL is relatively stable throughout the course of RRMS. The accelerated BVL is weakly associated with concurrent higher disease activity, and timely escalation to high-efficacy immunotherapy helps decrease the rate of BVL.
- MeSH
- atrofie patologie MeSH
- dospělí MeSH
- kohortové studie MeSH
- lidé středního věku MeSH
- lidé MeSH
- longitudinální studie MeSH
- magnetická rezonanční tomografie MeSH
- mozek patologie MeSH
- progrese nemoci MeSH
- prospektivní studie MeSH
- roztroušená skleróza patologie MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- klinické zkoušky MeSH
- pozorovací studie MeSH
- práce podpořená grantem MeSH
- randomizované kontrolované studie MeSH
BACKGROUND: The role of cholesterol homeostasis in neuroaxonal injury in multiple sclerosis is not known. OBJECTIVE: The objective of the study is to investigate the associations of cerebrospinal fluid (CSF) and serum neurofilament light chain levels (CSF-NfL and sNfL, respectively), which are biomarkers of neuroaxonal injury, with cholesterol biomarkers at the clinical onset of multiple sclerosis. METHODS: sNfL, serum cholesterol profile (total cholesterol, high-density lipoprotein cholesterol, and low-density lipoprotein cholesterol), serum apolipoprotein (Apo) levels (ApoA-I, ApoA-II, ApoB, and ApoE), and albumin quotient were obtained for 133 patients (63% female, age: 29.9 ± 8.0 years) during the first demyelinating event. CSF-NfL was available for 103 (77%) patients. RESULTS: CSF-NfL and sNfL were negatively associated with serum ApoA-II (P = .005, P < .001) and positively associated with albumin quotient (P < .001, P < .0001). In addition, higher CSF-NfL was associated with lower serum ApoA-I (P = .009) levels and higher sNfL was associated with lower high-density lipoprotein cholesterol (P = .010). In stepwise regression, age (P = .045), serum ApoA-II (P = .022), and albumin quotient (P < .001) were associated with CSF-NfL; albumin quotient (P = .002) and ApoA-II (P = .001) were associated with sNfL. Path analysis identified parallel pathways from ApoA-II (P = .009) and albumin quotient (P < .001) to the sNfL outcome that were mediated by CSF-NfL (P < .001). The associations of CSF-NfL with ApoA-I (P = .014) and ApoA-II (P = .015) and sNfL with ApoA-II (P < .001) remained significant after adjusting for number of contrast-enhancing lesions and T2 lesion volume. CONCLUSION: Lower serum ApoA-II and ApoA-I levels are associated with greater neuroaxonal injury as measured by CSF-NfL.
- MeSH
- apolipoprotein A-I krev MeSH
- apolipoprotein A-II krev MeSH
- dospělí MeSH
- lidé MeSH
- longitudinální studie MeSH
- neurofilamentové proteiny mozkomíšní mok MeSH
- neuroprotektivní látky krev mozkomíšní mok MeSH
- prognóza MeSH
- prospektivní studie MeSH
- roztroušená skleróza krev mozkomíšní mok patologie MeSH
- Check Tag
- dospělí MeSH
- lidé MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
OBJECTIVE: To determine whether serum neurofilament light chain (sNfL) levels are associated with recent MRI activity in patients with relapsing-remitting MS (RRMS). METHODS: This observational study included 163 patients (405 samples) with early RRMS from the Study of Early interferon-beta1a (IFN-β1a) Treatment (SET) cohort and 179 patients (664 samples) with more advanced RRMS from the Genome-Wide Association Study of Multiple Sclerosis (GeneMSA) cohort. Based on annual brain MRI, we assessed the ability of sNfL cutoffs to reflect the presence of combined unique active lesions, defined as new/enlarging lesion compared with MRI in the preceding year or contrast-enhancing lesion. The probability of active MRI lesions among patients with different sNfL levels was estimated with generalized estimating equations models. RESULTS: From the sNfL samples ≥90th percentile, 81.6% of the SET (OR = 3.4, 95% CI = 1.8-6.4) and 48.9% of the GeneMSA cohort samples (OR = 2.6, 95% CI = 1.7-3.9) was associated with radiological disease activity on MRI. The sNfL level between the 10th and 30th percentile was reflective of negligible MRI activity: 1.4% (SET) and 6.5% (GeneMSA) of patients developed ≥3 active lesions, 5.8% (SET) and 6.5% (GeneMSA) developed ≥2 active lesions, and 34.8% (SET) and 11.8% (GeneMSA) showed ≥1 active lesion on brain MRI. The sNfL level <10th percentile was associated with even lower MRI activity. Similar results were found in a subgroup of clinically stable patients. CONCLUSIONS: Low sNfL levels (≤30th percentile) help identify patients with MS with very low probability of recent radiologic disease activity during the preceding year. This result suggests that in future, sNfL assessment may substitute the need for annual brain MRI monitoring in considerable number (23.1%-36.4%) of visits in clinically stable patients.
- MeSH
- dospělí MeSH
- kohortové studie MeSH
- lidé středního věku MeSH
- lidé MeSH
- magnetická rezonanční tomografie MeSH
- mladý dospělý MeSH
- neurofilamentové proteiny krev MeSH
- progrese nemoci * MeSH
- relabující-remitující roztroušená skleróza krev diagnóza patologie MeSH
- senzitivita a specificita MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mladý dospělý MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- pozorovací studie MeSH
- práce podpořená grantem MeSH
BACKGROUND: Volumetric MRI surrogate markers of disease progression are lacking. OBJECTIVE: To establish cut-off values of brain volume loss able to discriminate between healthy controls and MS patients. METHODS: In total, 386 patients after first demyelinating event suggestive of MS (CIS), 964 relapsing-remitting MS (RRMS) patients, 63 secondary-progressive MS (SPMS) patients and 58 healthy controls were included in this longitudinal study. A total of 11,438 MRI scans performed on the same MRI scanner with the same protocol were analysed. Annualised percentage changes of whole brain, grey matter, thalamus and corpus callosum volumes were estimated. We investigated cut-offs able to discriminate between healthy controls and MS patients. RESULTS: At a predefined specificity of 90%, the annualised percentage change cut-off of corpus callosum volume (-0.57%) was able to distinguish between healthy controls and patients with the highest sensitivity (51% in CIS, 48% in RRMS and 42% in SPMS patients). Lower sensitivities (22%-49%) were found for cut-offs of whole brain, grey matter and thalamic volume loss. Among CIS and RRMS patients, cut-offs were associated with greater accumulation of disability. CONCLUSION: We identified cut-offs of annualised global and regional brain volume loss rates able to discriminate between healthy controls and MS patients.
- MeSH
- atrofie patologie MeSH
- corpus callosum diagnostické zobrazování patologie MeSH
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- longitudinální studie MeSH
- magnetická rezonanční tomografie normy MeSH
- mladiství MeSH
- mladý dospělý MeSH
- mozek diagnostické zobrazování patologie MeSH
- progrese nemoci * MeSH
- roztroušená skleróza diagnóza diagnostické zobrazování patologie MeSH
- šedá hmota diagnostické zobrazování patologie MeSH
- senioři MeSH
- senzitivita a specificita MeSH
- thalamus diagnostické zobrazování patologie MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mladiství MeSH
- mladý dospělý MeSH
- mužské pohlaví MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- pozorovací studie MeSH
- práce podpořená grantem MeSH
