Longitudinal analysis of new multiple sclerosis lesions with magnetization transfer and diffusion tensor imaging.

OBJECTIVE: The potential of magnetization transfer imaging (MTI) and diffusion tensor imaging (DTI) for the detection and evolution of new multiple sclerosis (MS) lesions was analyzed. METHODS: Nineteen patients with MS obtained conventional MRI, MTI, and DTI examinations bimonthly for 12 months and again after 24 months at 1.5 T MRI. MTI was acquired with balanced steady-state free precession (bSSFP) in 10 min (1.3 mm3 isotropic resolution) yielding both magnetization transfer ratio (MTR) and quantitative magnetization transfer (qMT) parameters (pool size ratio (F), exchange rate (kf), and relaxation times (T1/T2)). DTI provided fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD), and radial diffusivity (RD). RESULTS: At the time of their appearance on MRI, the 21 newly detected MS lesions showed significantly reduced MTR/F/kf and prolonged T1/T2 parameters, as well as significantly reduced FA and increased AD/MD/RD. Significant differences were already observed for MTR 4 months and for qMT parameters 2 months prior to lesions' detection on MRI. DTI did not show any significant pre-lesional differences. Slightly reversed trends were observed for most lesions up to 8 months after their detection for qMT and less pronounced for MTR and three diffusion parameters, while appearing unchanged on MRI. CONCLUSIONS: MTI provides more information than DTI in MS lesions and detects tissue changes 2 to 4 months prior to their appearance on MRI. After lesions' detection, qMT parameter changes promise to be more sensitive than MTR for the lesions' evolutional assessment. Overall, bSSFP-based MTI adumbrates to be more sensitive than MRI and DTI for the early detection and follow-up assessment of MS lesions. CLINICAL RELEVANCE STATEMENT: When additionally acquired in routine MRI, fast bSSFP-based MTI can complement the MRI/DTI longitudinal lesion assessment by detecting MS lesions 2-4 months earlier than with MRI, which could implicate earlier clinical decisions and better follow-up/treatment assessment in MS patients. KEY POINTS: • Magnetization transfer imaging provides more information than DTI in multiple sclerosis lesions and can detect tissue changes 2 to 4 months prior to their appearance on MRI. • After lesions' detection, quantitative magnetization transfer changes are more pronounced than magnetization transfer ratio changes and therefore promise to be more sensitive for the lesions' evolutional assessment. • Balanced steady-state free precession-based magnetization transfer imaging is more sensitive than MRI and DTI for the early detection and follow-up assessment of multiple sclerosis lesions.

Diagnostic delay of multiple sclerosis: prevalence, determinants and consequences.

BACKGROUND: Early diagnosis and treatment of patients with multiple sclerosis (MS) are associated with better outcomes; however, diagnostic delays remain a major problem. OBJECTIVE: Describe the prevalence, determinants and consequences of delayed diagnoses. METHODS: This single-centre ambispective study analysed 146 adult relapsing-remitting MS patients (2016-2021) for frequency and determinants of diagnostic delays and their associations with clinical, cognitive, imaging and biochemical measures. RESULTS: Diagnostic delays were identified in 77 patients (52.7%), including 42 (28.7%) physician-dependent cases and 35 (24.0%) patient-dependent cases. Diagnosis was delayed in 22 (15.1%) patients because of misdiagnosis by a neurologist. A longer diagnostic delay was associated with trends towards greater Expanded Disability Status Scale (EDSS) scores (B = 0.03; p = 0.034) and greater z-score of the blood neurofilament light chain (B = 0.35; p = 0.031) at the time of diagnosis. Compared with patients diagnosed at their first clinical relapse, patients with a history of >1 relapse at diagnosis (n = 63; 43.2%) had a trend towards greater EDSS scores (B = 0.06; p = 0.006) and number of total (B = 0.13; p = 0.040) and periventricular (B = 0.06; p = 0.039) brain lesions. CONCLUSION: Diagnostic delays in MS are common, often determined by early misdiagnosis and associated with greater disease burden.

Validation of the Czech Version of the Dysphagia in Multiple Sclerosis Questionnaire (DYMUS).

Dysphagia is a common symptom of neurological disease, including multiple sclerosis (MS). The DYsphagia in MUltiple Sclerosis (DYMUS) questionnaire was developed as a screening tool for swallowing problems. The purpose of the present study was to validate the Czech version of the DYMUS questionnaire. We validated the questionnaire on a sample of 435 patients with MS and 135 healthy controls (HC) chosen by accidental sampling from larger, long-term studies conducted by the Prague MS Center. For the purposes of this study, we used both electronic (primary method of distribution) and paper-based (backup) versions of the questionnaire. The internal consistency of the whole scale was satisfactory (Cronbach's α =0.833). The DYMUS mean score in HC was 0.215 (standard deviation [SD] = 0.776). Normative data suggested a cut-off value for dysphagia between 1 and 2 points. Principal component analysis (PCA) showed a two-factor structure of the adapted scale. However, the structure did not completely correspond to the originally proposed dimensions of dysphagia for solids and liquids; our data supported dropout of item Q10. Criterion validity was proved by the difference in dysphagia between HC and patients MS (U = 25,546, p < 0.001) and by a positive correlation with the EDSS (Kendall's tau-b = 0.169, p < 0.001) and other patient-reported outcomes. The Czech version of the DYMUS questionnaire is a valid and reliable tool for evaluating swallowing impairment in Czech-speaking patients with MS. Moreover, the questionnaire can be administered electronically, with a paper-based backup.

Internal comorbidities and complications of multiple sclerosis therapy - don't be caught off guard!

Multiple sclerosis (MS) is a chronic autoimmune disease of the central nervous system, mainly affecting young adults. Factors positively influencing its course include early antiinflammatory treatment and the influencing of other comorbidities. The most common comorbidities occurring in MS patients with a higher frequency than in the general population are neurological, psychiatric, cardiovascular, metabolic and autoimmune. Just as comorbidity compensation affects the course of MS, in some cases, MS decompensation is associated with a worse course of associated diseases. Due to common risk factors and partially shared immunopathogenesis, treatment covering multiple conditions can be used, especially for some autoimmune diseases. On the other hand, some drugs may potentiate the development of other autoimmunity or disorder. A special topic is the side effects and complications of treatment (especially infections and malignancies) of disease-modifying therapies used in patients with MS. However, the potential treatment discontinuation carries significant risks and should always be discussed with the MS specialist. Therefore, close interdisciplinary collaboration is crucial.

Brainstem lesions are associated with diffuse spinal cord involvement in early multiple sclerosis.

BACKGROUND: Early infratentorial and focal spinal cord lesions on magnetic resonance imaging (MRI) are associated with a higher risk of long-term disability in patients with multiple sclerosis (MS). The role of diffuse spinal cord lesions remains less understood. The purpose of this study was to evaluate focal and especially diffuse spinal cord lesions in patients with early relapsing-remitting MS and their association with intracranial lesion topography, global and regional brain volume, and spinal cord volume. METHODS: We investigated 58 MS patients with short disease duration (< 5 years) from a large academic MS center and 58 healthy controls matched for age and sex. Brain, spinal cord, and intracranial lesion volumes were compared among patients with- and without diffuse spinal cord lesions and controls. Binary logistic regression models were used to analyse the association between the volume and topology of intracranial lesions and the presence of focal and diffuse spinal cord lesions. RESULTS: We found spinal cord involvement in 75% of the patients (43/58), including diffuse changes in 41.4% (24/58). Patients with diffuse spinal cord changes exhibited higher volumes of brainstem lesion volume (p = 0.008). The presence of at least one brainstem lesion was associated with a higher probability of the presence of diffuse spinal cord lesions (odds ratio 47.1; 95% confidence interval 6.9-321.6 p < 0.001) as opposed to focal spinal cord lesions (odds ratio 0.22; p = 0.320). Patients with diffuse spinal cord lesions had a lower thalamus volume compared to patients without diffuse spinal cord lesions (p = 0.007) or healthy controls (p = 0.002). CONCLUSIONS: Diffuse spinal cord lesions are associated with the presence of brainstem lesions and with a lower volume of the thalamus. This association was not found in patients with focal spinal cord lesions. If confirmed, thalamic atrophy in patients with diffuse lesions could increase our knowledge on the worse prognosis in patients with infratentorial and SC lesions.

Serum neurofilament light chain reflects inflammation-driven neurodegeneration and predicts delayed brain volume loss in early stage of multiple sclerosis.

BACKGROUND: Serum neurofilament light chain (sNfL) is a marker of neuroaxonal injury. There is a lack of studies investigating the dynamics of relationships between sNfL levels and radiological disease activity over long-term follow-up in multiple sclerosis (MS). OBJECTIVES: To investigate the relationship among repeated measures of sNfL, lesion burden accumulation, brain volume loss and clinical measures. METHODS: We investigated 172 patients in the early stages of MS (McDonald 2017 criteria). Clinical exams were performed every 3 months and brain magnetic resonance imaging (MRI) scans were collected annually over 48 months. sNfL levels were measured in serum by Simoa assay at the time of treatment initiation and then annually over 36 months. RESULTS: In repeated-measures analysis, considering all time points, we found a strong relationship between percentage changes of sNfL and lesion burden accumulation assessed by T1 lesion volume (p < 0.001) and T2 lesion number (p < 0.001). There was no relationship between percentage changes of sNfL and brain volume loss over 36 months (p > 0.1). Early sNfL levels were associated with delayed brain volume loss after 48 months (p < 0.001). Patients with No Evidence of Disease Activity (NEDA-3) status showed lower sNfL levels compared with active MS patients. CONCLUSIONS: sNfL is associated with ongoing neuroinflammation and predictive of future neurodegeneration in early MS.

Impact of 3 Tesla MRI on interobserver agreement in clinically isolated syndrome: A MAGNIMS multicentre study.

BACKGROUND: Compared to 1.5 T, 3 T magnetic resonance imaging (MRI) increases signal-to-noise ratio leading to improved image quality. However, its clinical relevance in clinically isolated syndrome suggestive of multiple sclerosis remains uncertain. OBJECTIVES: The purpose of this study was to investigate how 3 T MRI affects the agreement between raters on lesion detection and diagnosis. METHODS: We selected 30 patients and 10 healthy controls from our ongoing prospective multicentre cohort. All subjects received baseline 1.5 and 3 T brain and spinal cord MRI. Patients also received follow-up brain MRI at 3-6 months. Four experienced neuroradiologists and four less-experienced raters scored the number of lesions per anatomical region and determined dissemination in space and time (McDonald 2010). RESULTS: In controls, the mean number of lesions per rater was 0.16 at 1.5 T and 0.38 at 3 T ( p = 0.005). For patients, this was 4.18 and 4.40, respectively ( p = 0.657). Inter-rater agreement on involvement per anatomical region and dissemination in space and time was moderate to good for both field strengths. 3 T slightly improved agreement between experienced raters, but slightly decreased agreement between less-experienced raters. CONCLUSION: Overall, the interobserver agreement was moderate to good. 3 T appears to improve the reading for experienced readers, underlining the benefit of additional training.

Diagnosis of adult-onset MELAS syndrome in a 63-year-old patient with suspected recurrent strokes - a case report.

BACKGROUND: Mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (MELAS) is a mitochondrial cytopathy caused by mutations in mitochondrial DNA. Clinical manifestation is typically before the age of 40. CASE PRESENTATION: We present the case of a 63-year-old female in whom the symptoms of MELAS were initially misdiagnosed as episodes of recurrent ischemic strokes. Brain imaging including MRI, clinical and laboratory findings that lent cues to the diagnosis of MELAS are discussed. In addition, MRI findings in MELAS in comparison to imaging mimics of MELAS are presented. CONCLUSIONS: This case underscores the importance of considering MELAS as a potential cause of recurrent stroke-like events if imaging findings are untypical for cerebral infarction, even among middle-aged patients with vascular risk factors.

Neurostatus e-Scoring improves consistency of Expanded Disability Status Scale assessments: A proof of concept study.

BACKGROUND: To improve the consistency of standardized Expanded Disability Status Scale (EDSS) assessments, an electronic data capture tool and analysis tool was developed, Neurostatus e-Scoring (NESC). This tool allows real-time feedback by comparing entries with established scoring rules. OBJECTIVE: To test whether using NESC reduces inconsistencies as compared to the paper-and-pencil version of the Expanded Disability Status Scale (pEDSS). METHODS: In all, 100 multiple sclerosis (MS) patients were assessed in random order on the same day by pairs of neurologists, one using pEDSS and one NESC. We compared inter-rater reliability and frequency of inconsistencies in Neurostatus subscores, functional system (FS) scores, ambulation and EDSS steps. RESULTS: Inconsistencies of any type were more likely to occur when using pEDSS (mean odds ratio (95% confidence interval (CI)) = 2.93 (1.62; 5.29)). This was also the case for FS score inconsistencies (2.54 (1.40; 4.61)) and more likely for patients in the lower EDSS range (⩽3.5 vs >3.5) (5.32 (1.19; 23.77)). Overall, inter-rater agreement for the assessed Neurostatus subscores was high (median and inter-quartile range = 0.84 (0.73, 0.81)). CONCLUSION: Our data provide class II evidence that the use of NESC increases consistency of standardized EDSS assessments, and may thus have the potential to decrease noise and increase power of MS clinical trials.

The role of cerebellar abnormalities in neuromyelitis optica--a comparison with multiple sclerosis and healthy controls.

BACKGROUND: In relapsing-remitting multiple sclerosis (RRMS), the cerebellum is a known predilection site for atrophy. Neuromyelitis optica (NMO) is characterized by extensive lesions in the spinal cord and optic nerve; however, cerebellar involvement has been less studied. Secondary degeneration of the spinocerebellar tract could impact the cerebellum in NMO. OBJECTIVE: We aimed to investigate whether spinal cord and cerebellar volume measures differ between patients with NMO and RRMS. METHODS: Volumetric analyses of the cerebellum (TCV), the upper cervical cord (UCV) as well as the whole brain (NBV) of age- and gender-matched patients with NMO (n=30; 56% AQP4 +ve) and RRMS (n=25) were performed on 3T brain magnetic resonance imaging (MRI) and compared with 34 healthy controls (HC). RESULTS: UCV was significantly reduced in NMO patients (6.3 cm(3)) as compared with HC (6.7 cm(3)), while patients with MS had reduced brain volumes compared with HC (NBV=1482 cm(3); p<0.001; TCV=188 cm(3); p=0.042), but UCV close to normal values. Patients with RRMS and NMO differed in NBV (p=0.001; lower in RRMS) and by trend (towards reduction in RRMS) in cerebellar volume (p=0.06). CONCLUSIONS: While atrophy seems to be diffuse in MS patients, a rather focussed pattern with predominant involvement of the UCV was observed in NMO patients.

Label-fusion-segmentation and deformation-based shape analysis of deep gray matter in multiple sclerosis: the impact of thalamic subnuclei on disability.

Deep gray matter (DGM) atrophy has been reported in patients with multiple sclerosis (MS) already at early stages of the disease and progresses throughout the disease course. We studied DGM volume and shape and their relation to disability in a large cohort of clinically well-described MS patients using new subcortical segmentation methods and shape analysis. Structural 3D magnetic resonance images were acquired at 1.5 T in 118 patients with relapsing remitting MS. Subcortical structures were segmented using a multiatlas technique that relies on the generation of an automatically generated template library. To localize focal morphological changes, shape analysis was performed by estimating the vertex-wise displacements each subject must undergo to deform to a template. Multiple linear regression analysis showed that the volume of specific thalamic nuclei (the ventral nuclear complex) together with normalized gray matter volume explains a relatively large proportion of expanded disability status scale (EDSS) variability. The deformation-based displacement analysis confirmed the relation between thalamic shape and EDSS scores. Furthermore, white matter lesion volume was found to relate to the shape of all subcortical structures. This novel method for the analysis of subcortical volume and shape allows depicting specific contributions of DGM abnormalities to neurological deficits in MS patients. The results stress the importance of ventral thalamic nuclei in this respect.

Tract-wise microstructural analysis informs on current and future disability in early multiple sclerosis.

OBJECTIVES: Microstructural characterization of patients with multiple sclerosis (MS) has been shown to correlate better with disability compared to conventional radiological biomarkers. Quantitative MRI provides effective means to characterize microstructural brain tissue changes both in lesions and normal-appearing brain tissue. However, the impact of the location of microstructural alterations in terms of neuronal pathways has not been thoroughly explored so far. Here, we study the extent and the location of tissue changes probed using quantitative MRI along white matter (WM) tracts extracted from a connectivity atlas. METHODS: We quantified voxel-wise T1 tissue alterations compared to normative values in a cohort of 99 MS patients. For each WM tract, we extracted metrics reflecting tissue alterations both in lesions and normal-appearing WM and correlated these with cross-sectional disability and disability evolution after 2 years. RESULTS: In early MS patients, T1 alterations in normal-appearing WM correlated better with disability evolution compared to cross-sectional disability. Further, the presence of lesions in supratentorial tracts was more strongly associated with cross-sectional disability, while microstructural alterations in infratentorial pathways yielded higher correlations with disability evolution. In progressive patients, all major WM pathways contributed similarly to explaining disability, and correlations with disability evolution were generally poor. CONCLUSIONS: We showed that microstructural changes evaluated in specific WM pathways contribute to explaining future disability in early MS, hence highlighting the potential of tract-wise analyses in monitoring disease progression. Further, the proposed technique allows to estimate WM tract-specific microstructural characteristics in clinically compatible acquisition times, without the need for advanced diffusion imaging.

The typical duration of migraine aura: a systematic review.

BACKGROUND: According to ICHD-II, and as proposed for ICHD-III, non-hemiplegic migraine aura (NHMA) symptoms last between five and 60 minutes whereas hemiplegic migraine aura can be longer. In ICHD-III it is proposed to label aura longer than an hour and less than a week as probable migraine with aura. We tested whether this was appropriate based on the available literature. METHODS: We performed a systematic literature search identifying articles pertaining to a typical or prolonged duration of NHMA. We also performed a comprehensive literature search in order to identify all population-based studies or case series in which clinical features of NHMA, including but not restricted to aura duration, were reported, in order to gain a complete coverage of the available scientific data on aura duration. RESULTS: We did not find any article exclusively focusing on the prevalence of a prolonged aura or more generally on typical NHMA duration. We found 10 articles that investigated NHMA features, including the aura duration. Five articles recorded the proportion of patients in whom whole NHMA lasted for more than one hour, which was the case in 12%-37% of patients. Six articles reported some information on the duration of single NHMA symptoms: visual aura disturbances lasting for more than one hour occurred in 6%-10% of patients, sensory aura in 14%-27% of patients and aphasic aura in 17%-60% of patients. CONCLUSIONS: The data indicate the duration of NHMA may be longer than one hour in a significant proportion of migraineurs. This seems to be especially true for non-visual aura symptoms. The term probable seems inappropriate in ICHD-III so we propose reinstating the category of prolonged aura for patients with symptoms longer than an hour and less than one week.

Periventricular gradient of T1 tissue alterations in multiple sclerosis.

OBJECTIVE: Pathology in multiple sclerosis is not homogenously distributed. Recently, it has been shown that structures adjacent to CSF are more severely affected. A gradient of brain tissue involvement was shown with more severe pathology in periventricular areas and in proximity to brain surfaces such as the subarachnoid spaces and ependyma, and hence termed the "surface-in" gradient. Here, we study whether (i) the surface-in gradient of periventricular tissue alteration measured by T1 relaxometry is already present in early multiple sclerosis patients, (ii) how it differs between early and progressive multiple sclerosis patients, and (iii) whether the gradient-derived metrics in normal-appearing white matter and lesions correlate better with physical disability than conventional MRI-based metrics. METHODS: Forty-seven patients with early multiple sclerosis, 52 with progressive multiple sclerosis, and 92 healthy controls were included in the study. Isotropic 3D T1 relaxometry maps were obtained using the Magnetization-Prepared 2 Rapid Acquisition Gradient Echoes sequence at 3 T. After spatially normalizing the T1 maps into a study-specific common space, T1 inter-subject variability within the healthy cohort was modelled voxel-wise, yielding a normative T1 atlas. Individual comparisons of each multiple sclerosis patient against the atlas were performed by computing z-scores. Equidistant bands of voxels were defined around the ventricles in the supratentorial white matter; the z-scores in these bands were analysed and compared between the early and progressive multiple sclerosis cohorts. Correlations between both conventional and z-score-gradient-derived MRI metrics and the Expanded Disability Status Scale were assessed. RESULTS: Patients with early and progressive multiple sclerosis demonstrated a periventricular gradient of T1 relaxation time z-scores. In progressive multiple sclerosis, z-score-derived metrics reflecting the gradient of tissue abnormality in normal-appearing white matter were more strongly correlated with disability (maximal rho = 0.374) than the conventional lesion volume and count (maximal rho = 0.189 and 0.21 respectively). In early multiple sclerosis, the gradient of normal-appearing white matter volume with z-scores > 2 at baseline correlated with clinical disability assessed at two years follow-up. CONCLUSION: Our results suggest that the surface-in white matter gradient of tissue alteration is detectable with T1 relaxometry and is already present at clinical disease onset. The periventricular gradients correlate with clinical disability. The periventricular gradient in normal-appearing white matter may thus qualify as a promising biomarker for monitoring of disease activity from an early stage in all phenotypes of multiple sclerosis.

To be or not to be vaccinated: The risk of MS or NMOSD relapse after COVID-19 vaccination and infection.

BACKGROUND: COVID-19 vaccination and infection are speculated to increase the activity of immune-mediated diseases, including multiple sclerosis (MS) and neuromyelitis optica spectrum disorder (NMOSD). The aim of this study was to evaluate a short-term risk of relapse after COVID-19 vaccination and COVID-19 infection in patients with these demyelinating disorders of the central nervous system and to determine disease exacerbation risk factors. METHODS: Data in this retrospective, observational cohort study was collected via the Czech nationwide registry ReMuS from March 1, 2020, to October 30, 2021. We compared the proportion of patients with at least one clinical relapse in the 90 days following vaccination or infection to the 90-day intervals during the year before. For the evaluation of the risk factors of relapse, a comparison between groups with and without relapses after COVID-19 vaccination or infection was made. RESULTS: We identified 1661 vaccinated (90.11% BNT162b2) patients with MS without a history of COVID-19 and 495 unvaccinated patients with MS who experienced COVID-19. A mild increase in the proportion of patients with at least one clinical relapse (-360 to -270 days: 4.46%; -270 to -180: 4.27%; -180 to -90: 3.85%; -90 to 0: 3.79% vs. 0 to +90 days: 5.30%) after vaccination in patients with MS was observed, as well as a rise in the proportion of patients with at least one clinical relapse after COVID-19. Lower age was associated with MS relapse after vaccination or infection. Although there were only 17 vaccinated and eight post-COVID-19 patients with NMOSD, the results were broadly consistent with those of patients with MS. CONCLUSION: There is a mild increase in the relapse incidence after the COVID-19 vaccination. The risks, however, need to be balanced against the risks of COVID-19 itself, also leading to the rise in relapse rate and particularly to morbidity and mortality.

Interpretation of Brain Volume Increase in Multiple Sclerosis.

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.

Isolated Cognitive Decline in Neurologically Stable Patients with Multiple Sclerosis.

(1) Background: Cognitive deterioration is an important marker of disease activity in multiple sclerosis (MS). It is vital to detect cognitive decline as soon as possible. Cognitive deterioration can take the form of isolated cognitive decline (ICD) with no other clinical signs of disease progression present. (2) Methods: We investigated 1091 MS patients from the longitudinal GQ (Grant Quantitative) study, assessing their radiological, neurological, and neuropsychological data. Additionally, the confirmatory analysis was conducted. Clinical disease activity was defined as the presence of new relapse or disability worsening. MRI activity was defined as the presence of new or enlarged T2 lesions on brain MRI. (3) Results: Overall, 6.4% of patients experienced cognitive decline and 4.0% experienced ICD without corresponding clinical activity. The vast majority of cognitively worsening patients showed concomitant progression in other neurological and radiologic measures. There were no differences in disease severity between completely stable patients and cognitively worsening patients but with normal cognition at baseline. (4) Conclusions: Only a small proportion of MS patients experience ICD over short-term follow-up. Patients with severe MS are more prone to cognitive decline; however, patients with normal cognitive performance and mild MS might benefit from the early detection of cognitive decline the most.

Validating atlas-based lesion disconnectomics in multiple sclerosis: A retrospective multi-centric study.

The translational potential of MR-based connectivity modelling is limited by the need for advanced diffusion imaging, which is not part of clinical protocols for many diseases. In addition, where diffusion data is available, brain connectivity analyses rely on tractography algorithms which imply two major limitations. First, tracking algorithms are known to be sensitive to the presence of white matter lesions and therefore leading to interpretation pitfalls and poor inter-subject comparability in clinical applications such as multiple sclerosis. Second, tractography quality is highly dependent on the acquisition parameters of diffusion sequences, leading to a trade-off between acquisition time and tractography precision. Here, we propose an atlas-based approach to study the interplay between structural disconnectivity and lesions without requiring individual diffusion imaging. In a multi-centric setting involving three distinct multiple sclerosis datasets (containing both 1.5 T and 3 T data), we compare our atlas-based structural disconnectome computation pipeline to disconnectomes extracted from individual tractography and explore its clinical utility for reducing the gap between radiological findings and clinical symptoms in multiple sclerosis. Results using topological graph properties showed that overall, our atlas-based disconnectomes were suitable approximations of individual disconnectomes from diffusion imaging. Small-worldness was found to decrease for larger total lesion volumes thereby suggesting a loss of efficiency in brain connectivity of MS patients. Finally, the global efficiency of the created brain graph, combined with total lesion volume, allowed to stratify patients into subgroups with different clinical scores in all three cohorts.

The weak association between neurofilament levels at multiple sclerosis onset and cognitive performance after 9 years.

BACKGROUND: Neurofilament light chain level in serum (sNfL) and cerebrospinal fluid (CSF-NfL) is a promising biomarker of disease activity in multiple sclerosis (MS). However, predictive value of neurofilaments for development of cognitive decline over long-term follow-up has not been extensively studied. OBJECTIVE: To investigate the relationship between early neurofilament levels and cognitive performance after 9-years. METHODS: We included 58 MS patients from the SET study. sNfL levels were measured at screening, at 1 and 2 years. CSF-NfL were measured in 36 patients at screening. Cognitive performance was assessed by the Brief International Cognitive Assessment for Multiple Sclerosis and the Paced Auditory Serial Addition Test-3 s at baseline, at 1, 2 and 9 years. Association between neurofilament levels and cognition was analyzed using Spearman´s correlation, logistic regression and mixed models. RESULTS: We did not observe associations among early sNfL levels and cross-sectional or longitudinal cognitive measures, except of a trend for association between higher sNfL levels at screening and lower California Verbal Learning Test-II (CVLT-II) scores at year 1 (rho=-0.31, unadjusted p = 0.028). Higher sNfL level was not associated with increased risk of cognitive decline, except of a trend for greater risk of CVLT-II decrease in patients with higher sNfL levels at 1 year (OR=15.8; 95% CI=1.7-147.0; unadjusted p = 0.015). Similar trends were observed for CSF-NfL. CONCLUSION: We found only weak association between sNfL levels at disease onset and evolution of cognitive performance over long-term follow-up.

Additive Effect of Spinal Cord Volume, Diffuse and Focal Cord Pathology on Disability in Multiple Sclerosis.

Introduction: Spinal cord (SC) pathology is strongly associated with disability in multiple sclerosis (MS). We aimed to evaluate the association between focal and diffuse SC abnormalities and spinal cord volume and to assess their contribution to physical disability in MS patients. Methods: This large sample-size cross-sectional study investigated 1,249 patients with heterogeneous MS phenotypes. Upper cervical-cord cross-sectional area (MUCCA) was calculated on an axial 3D-T2w-FatSat sequence acquired at 3T using a novel semiautomatic edge-finding tool. SC images were scored for the presence of sharply demarcated hyperintense areas (focal lesions) and homogenously increased signal intensity (diffuse changes). Patients were dichotomized according EDSS in groups with mild (EDSS up to 3.0) and moderate (EDSS ≥ 3.5) physical disability. Analysis of covariance was used to identify factors associated with dichotomized MUCCA. In binary logistic regression, the SC imaging parameters were entered in blocks to assess their individual contribution to risk of moderate disability. In order to assess the risk of combined SC damage in terms of atrophy and lesional pathology on disability, secondary analysis was carried out where patients were divided into four categories (SC phenotypes) according to median dichotomized MUCCA and presence/absence of focal and/or diffuse changes. Results: MUCCA was strongly associated with total intracranial volume, followed by presence of diffuse SC pathology, and disease duration. Compared to the reference group (normally appearing SC, MUCCA>median), patients with the most severe SC changes (SC affected with focal and/or diffuse lesions, MUCCA