Longitudinal assessment of neurocognitive function in people with relapsing multiple sclerosis initiating alemtuzumab in routine clinical practice: LEM-COG study results.

BACKGROUND: Alemtuzumab is effective in reducing relapse rate and disability, but limited data exist on its effect on cognitive function in relapsing multiple sclerosis (RMS). The present study assessed neurocognitive function and safety associated with alemtuzumab treatment in RMS. METHODS: This longitudinal, single-arm, prospective study included people with RMS (aged 25-55 years) who were treated with alemtuzumab in clinical practice in the United States of America and Canada. The first participant was enrolled in December 2016. The primary endpoint was the change from baseline to post-baseline (month [M] 12/24) in MS-COGnitive (MS-COG) composite score. Secondary endpoints included Paced Auditory Serial Addition Test (PASAT), Symbol Digit Modalities Test (SDMT), Brief Visuospatial Memory Test-Revised (BVMT-R), Selective Reminding Test (SRT), Controlled Oral Word Association Test (COWAT), and Automated Neuropsychological Assessment Metrics (ANAM) scores. Depression and fatigue were assessed using Hamilton Rating Scale-Depression (HAM-D) and Fatigue Severity Scale (FSS)/Modified Fatigue Impact Scale (MFIS), respectively. Magnetic resonance imaging (MRI) parameters were assessed when available. Safety was assessed throughout the study. Descriptive statistics were used for the pre-specified statistical analyses. Since the study was terminated early (November 2019) because of operational and resource difficulties, post hoc analyses for statistical inference were performed among participants who had a baseline value and at least one complete post-baseline assessment for cognitive parameters, fatigue, or depression. RESULTS: Of the 112 participants enrolled, 39 were considered as the primary analysis population at M12. At M12, a mean change of 0.25 (95% confidence interval [CI]: 0.04, 0.45; p = 0.0049; effect size [ES]: 0.39) was observed in the MS-COG composite score. Improvements were observed in processing speed (based on PASAT and SDMT; p < 0.0001; ES: 0.62), as well as in individual PASAT, SDMT and COWAT scores. An improvement was also noted in HAM-D (p = 0.0054; ES: -0.44), but not in fatigue scores. Among MRI parameters, decreases in burden of disease volume (BDV; ES: -0.12), new gadolinium-enhancing lesions (ES: -0.41) and newly active lesions (ES: -0.07) were observed at M12. About 92% of participants showed stable or improved cognitive status at M12. There were no new safety signals reported in the study. The most common adverse events (≥10% of participants) were headache, fatigue, nausea, insomnia, urinary tract infection, pain in extremity, chest discomfort, anxiety, dizziness, arthralgia, flushing, and rash. Hypothyroidism (3.7%) was the most frequent adverse event of special interest. CONCLUSION: The findings from this study suggest that alemtuzumab has a positive impact on cognitive function with significant improvements in processing speed and depression in people with RMS over a period of 12 months. The safety profile of alemtuzumab was consistent with previous studies.

Eculizumab-related drug reaction in a patient with neuromyelitis optica.

Eculizumab is approved for treatment of antibody positive neuromyelitis optica, myasthenia gravis, and hematologic disorders like paroxysmal nocturnal hemoglobinuria. Drug rash has not yet been reported as a side effect of eculizumab. We report a case of a cutaneous drug reaction soon after introduction of eculizumab therapy in a patient with refractory neuromyelitis optica. Clinicians should be aware of a drug reaction as a possible adverse reaction to eculizumab.

Chronic Lymphocytic Inflammation with Pontine Perivascular Enhancement Responsive to Steroids May Extend above and below Pons and Is Associated with Other Autoimmune Diseases.

Many autoimmune diseases can affect the central nervous system, and their varying clinical presentations often confound a straightforward diagnosis. In this report, we describe a unique presentation of CLIPPERS syndrome. To our knowledge, this is the first case to demonstrate significant supratentorial involvement with symmetric and non-confluent lesions in the medial orbitofrontal cortex; additionally, this is the second case to describe an association between diagnoses of hypothyroidism and CLIPPERS.

Robustness of Brain Structural Networks Is Affected in Cognitively Impaired MS Patients.

The robustness of brain structural networks, estimated from diffusion MRI data, may be relevant to cognition. We investigate whether measures of network robustness, such as Ollivier-Ricci curvature, can explain cognitive impairment in multiple sclerosis (MS). We assessed whether local (i.e., cortical area) and/or global (i.e., whole brain) robustness, differs between cognitively impaired (MSCI) and non-impaired (MSNI) MS patients. Fifty patients, with Expanded Disability Status Scale mean (m): 3.2, disease duration m: 12 years, and age m: 40 years, were enrolled. Cognitive impairment scores were estimated from the Minimal Assessment of Cognitive Function in Multiple Sclerosis. Images were obtained in a 3T MRI using a diffusion protocol with a 2 min acquisition time. Brain structural networks were created using 333 cortical areas. Local and global robustness was estimated for each individual, and comparisons were performed between MSCI and MSNI patients. 31 MSCI and 10 MSNI patients were included in the analyses. Brain structural network robustness and centrality showed significant correlations with cognitive impairment. Measures of network robustness and centrality identified specific cortical areas relevant to MS-related cognitive impairment. These measures can be obtained on clinical scanners and are succinct yet accurate potential biomarkers of cognitive impairment.

Frontal aslant tracts as correlates of lexical retrieval in MS.

INTRODUCTION: Previous studies reveal that a newly described white matter pathway, the frontal aslant tract (FAT), connecting inferior and superior frontal gyri has a role in speech and language functions. We explored the role of this tract in a phonemic and semantic fluency tasks in a cohort of multiple sclerosis patients diagnosed with cognitive impairment. METHODS: Thirty-five MS patients with varying degrees of cognitive impairment underwent diffusion tensor imaging and the Controlled Associated Word Test. Fractional anisotropy (FA) of FAT and arcuate fasciculus (AF) were obtained through a supervised, atlas-based tissue segmentation and parcellation method. Phonemic and semantic fluency scores were obtained from COWAT. We ran a multivariate regression model, and partial correlation analyses adjusted for age, education, and lesion load, and corrected for multiple comparisons. False discovery rate (FDR) was used for the correction of multiple comparisons. RESULTS: Bilateral FAT FA showed significant association with phonemic verbal fluency task (Left; r = 0.46, p = 0.0058 and right; r = 0.46, p = 0.0059) but not semantic fluency task and this relation remained significant after FDR correction (p = 0.02 bilaterally). Although left AF showed some significant association with phonemic fluency task, this relation was insignificant after FDR correction. CONCLUSION: We show that bilateral FAT are correlates of phonemic verbal fluency task but not semantic in an MS cohort with cognitive impairment. This finding suggests that FAT is more specialized in lexical retrieval function as semantic fluency test encompasses all the functions except the lexical retrieval.

Tumefactive demyelination: Clinical outcomes, lesion evolution and treatments.

OBJECTIVE: Large demyelinating lesions with possible mass effect (tumefactive multiple sclerosis or tumefactive demyelination) can be mistaken for tumour-like space-occupying lesions suggesting a malignant outcome. METHODS: We reviewed our own experience of multiple sclerosis subjects (n = 28) with tumefactive demyelination to determine the relationship between clinical outcomes and lesion evolution, clinical outcomes and their relationship to different therapies. Patients with central nervous system demyelinating disease were identified from our database over the last 10 years. RESULTS: No patient increased in extended disability status scale (EDSS). Overall, lesion regression was associated with improved EDSS. Lesion regression was also associated with therapy versus no therapy. No specific therapy or corticosteroid infusions improved EDSS over the long term. The absence of enhancement on follow up on magnetic resonance imaging portended lesion regression. CONCLUSION: Tumefactive demyelination may predict a more benign overall course and is susceptible to traditional immunomodulatory treatments.

Imaging outcome measures of neuroprotection and repair in MS: A consensus statement from NAIMS.

OBJECTIVE: To summarize current and emerging imaging techniques that can be used to assess neuroprotection and repair in multiple sclerosis (MS), and to provide a consensus opinion on the potential utility of each technique in clinical trial settings. METHODS: Clinicians and scientists with expertise in the use of MRI in MS convened in Toronto, Canada, in November 2016 at a North American Imaging in Multiple Sclerosis (NAIMS) Cooperative workshop meeting. The discussion was compiled into a manuscript and circulated to all NAIMS members in attendance. Edits and feedback were incorporated until all authors were in agreement. RESULTS: A wide spectrum of imaging techniques and analysis methods in the context of specific study designs were discussed, with a focus on the utility and limitations of applying each technique to assess neuroprotection and repair. Techniques were discussed under specific themes, and included conventional imaging, magnetization transfer ratio, diffusion tensor imaging, susceptibility-weighted imaging, imaging cortical lesions, magnetic resonance spectroscopy, PET, advanced diffusion imaging, sodium imaging, multimodal techniques, imaging of special regions, statistical considerations, and study design. CONCLUSIONS: Imaging biomarkers of neuroprotection and repair are an unmet need in MS. There are a number of promising techniques with different strengths and limitations, and selection of a specific technique will depend on a number of factors, notably the question the trial seeks to answer. Ongoing collaborative efforts will enable further refinement and improved methods to image the effect of novel therapeutic agents that exert benefit in MS predominately through neuroprotective and reparative mechanisms.

Myelinating Proteins in MS Are Linked to Volumetric Brain MRI Changes.

BACKGROUND AND PURPOSE: There is evidence of a relationship between promyelinating proteins and clinical multiple sclerosis (MS) activity during clinical relapse or recovery from clinical relapses. We examined the linkage between promyelinating biomarkers and volumetric changes in MS subjects during serial magnetic resonance imaging (MRI). METHODS: We enrolled 13 MS subjects with active brain MRI scans not on disease modifying therapies. Subjects underwent baseline MRI, serum, and cerebrospinal fluid (CSF) sampling. Qualitative changes, new/resolving gadolinium, new/enlarging/diminishing T2 and T1 hypointense lesions, were compared to baseline in subsequent MRI scans, and volumetric analysis was calculated. Analysis of biomarkers on serial CSF samples was performed only in subjects with qualitative (and quantitative) changes on MRI. The study was performed at a MS Center of Excellence academic medical center. RESULTS: There was increased CSF neural cell adhesion molecule (N-CAM) during increased qualitative T1 activity. A positive correlation between CSF and serum N-CAM and T1 lesion volume was observed. A negative correlation between serum brain-derived neurotrophic factor (BDNF) and BPH (T1 vol/T2 vol + T1 vol) was observed. CONCLUSIONS: Increased N-CAM levels may be related to repair or remyelination following injury to the brain as shown by increased T1 volumes. Our data suggest an early kind of blood signaling that induces release of peripheral BDNF levels.

Effect of Nonmyeloablative Hematopoietic Stem Cell Transplantation vs Continued Disease-Modifying Therapy on Disease Progression in Patients With Relapsing-Remitting Multiple Sclerosis: A Randomized Clinical Trial.

Importance: Hematopoietic stem cell transplantation (HSCT) represents a potentially useful approach to slow or prevent progressive disability in relapsing-remitting multiple sclerosis (MS). Objective: To compare the effect of nonmyeloablative HSCT vs disease-modifying therapy (DMT) on disease progression. Design, Setting, and Participants: Between September 20, 2005, and July 7, 2016, a total of 110 patients with relapsing-remitting MS, at least 2 relapses while receiving DMT in the prior year, and an Expanded Disability Status Scale (EDSS; score range, 0-10 [10 = worst neurologic disability]) score of 2.0 to 6.0 were randomized at 4 US, European, and South American centers. Final follow-up occurred in January 2018 and database lock in February 2018. Interventions: Patients were randomized to receive HSCT along with cyclophosphamide (200 mg/kg) and antithymocyte globulin (6 mg/kg) (n = 55) or DMT of higher efficacy or a different class than DMT taken during the previous year (n = 55). Main Outcomes and Measures: The primary end point was disease progression, defined as an EDSS score increase after at least 1 year of 1.0 point or more (minimal clinically important difference, 0.5) on 2 evaluations 6 months apart, with differences in time to progression estimated as hazard ratios. Results: Among 110 randomized patients (73 [66%] women; mean age, 36 [SD, 8.6] years), 103 remained in the trial, with 98 evaluated at 1 year and 23 evaluated yearly for 5 years (median follow-up, 2 years; mean, 2.8 years). Disease progression occurred in 3 patients in the HSCT group and 34 patients in the DMT group. Median time to progression could not be calculated in the HSCT group because of too few events; it was 24 months (interquartile range, 18-48 months) in the DMT group (hazard ratio, 0.07; 95% CI, 0.02-0.24; P < .001). During the first year, mean EDSS scores decreased (improved) from 3.38 to 2.36 in the HSCT group and increased (worsened) from 3.31 to 3.98 in the DMT group (between-group mean difference, -1.7; 95% CI, -2.03 to -1.29; P < .001). There were no deaths and no patients who received HSCT developed nonhematopoietic grade 4 toxicities (such as myocardial infarction, sepsis, or other disabling or potential life-threatening events). Conclusions and Relevance: In this preliminary study of patients with relapsing-remitting MS, nonmyeloablative HSCT, compared with DMT, resulted in prolonged time to disease progression. Further research is needed to replicate these findings and to assess long-term outcomes and safety. Trial Registration: ClinicalTrials.gov Identifier: NCT00273364.

Standardizing Magnetic Resonance Imaging Protocols, Requisitions, and Reports in Multiple Sclerosis: An Update for Radiologist Based on 2017 Magnetic Resonance Imaging in Multiple Sclerosis and 2018 Consortium of Multiple Sclerosis Centers Consensus Guidelines.

The advent of magnetic resonance imaging has improved our understanding of the pathophysiology and natural course of multiple sclerosis (MS). The ability of magnetic resonance imaging to show the evolution of MS lesions on sequential scans has brought it to be one of the endpoints in clinical trials for disease-modifying therapies. Based on the most updated consensus guidelines from the American (Consortium of MS Centers) and European (Magnetic Resonance Imaging in MS) boards of experts in MS, this document shows the most relevant landmarks related to imaging findings, diagnostic criteria, indications to obtain a magnetic resonance, scan protocols and sequence options for patients with MS. Although incorporating the knowledge derived from the research arena into the daily clinical practice is always challenging, in this article, the authors provide useful recommendations to improve the information contained in the magnetic resonance report oriented to facilitate communication between radiologists and specialized medical teams involved in MS patients' multidisciplinary care.

Yakovlev's Basolateral Limbic Circuit in Multiple Sclerosis Related Cognitive Impairment.

BACKGROUND AND PURPOSE: In 1948, Paul Yakovlev described an additional limbic circuit located basolateral to James Papez's circuit (1937) and included orbitofrontal cortex, amygdala, and dorsomedial nucleus of thalamus. This circuit is shown to be an important component of subcortical cognitive abilities. We aimed to demonstrate this circuit in a multiple sclerosis (MS) cohort using diffusion tensor imaging (DTI) and evaluate its role in MS-related cognitive impairment (CI). METHODS: We enrolled cognitively intact (n = 10) and impaired (n = 36) MS patients who underwent a comprehensive cognitive assessment; the minimal assessment of cognitive function in MS (MACFIMS) and structural magnetic resonance imaging. Correlation analyses between volumetric and DTI-derived values of the orbitofrontothalamic (OFT), amygdalothalamic tracts (ATTs), and dorsomedial nucleus of thalamus and CI index derived from MACFIMS were computed after adjustment for age, education, and lesion load. RESULTS: We observed a consistent trend between CI index and bilateral dorsomedial nucleus' mean diffusivity (MD) (r = .316; P = .02), left OFT Fractional anisotropy (FA) (r = -.302; P = .02), MD (r = .380; .006), and radial diffusivities (RDs) (r = .432; P = .002), also with right ATT FA (r = -.475; P = .0006) and left ATT FA ( = -.487; P = .0005). After Bonferroni correction, correlations of left OFT RD and right and left ATT FA with CI were found to be significant. CONCLUSIONS: Our study provides in vivo DTI delineation of Yakovlev's historical basolateral limbic circuit and establishes a role in MS-related CI. These findings may potentially pave the way for future clinical studies using targeted invasive and noninvasive neurostimulation modalities for CI in MS.

Mapping the trajectory of the amygdalothalamic tract in the human brain.

Although the thalamus is not considered primarily as a limbic structure, abundant evidence indicates the essential role of the thalamus as a modulator of limbic functions indirectly through the amygdala. The amygdala is a central component of the limbic system and serves an essential role in modulating the core processes including the memory, decision-making, and emotional reactions. The amygdalothalamic pathway is the largest direct amygdalo-diencephalic connection in the primates including the human brain. Given the crucial role of the amygdalothalamic tract (ATT) in memory function and diencephalic amnesia in stroke patients, diffusion tensor imaging may be helpful in better visualizing the surgical anatomy of this pathway noninvasively. To date, few diffusion-weighted studies have focused on the amygdala, yet the fine neuronal connection of the amygdala and thalamus known as the ATT has yet to be elucidated. This study aimed to investigate the utility of high spatial resolution diffusion tensor tractography for mapping the trajectory of the ATT in the human brain. We studied 15 healthy right-handed human subjects (12 men and 3 women with age range of 24-37 years old). Using a high-resolution diffusion tensor tractography technique, for the first time, we were able to reconstruct and measure the trajectory of the ATT. We further revealed the close relationship of the ATT with the temporopontine tract and the fornix bilaterally in 15 healthy adult human brains.

Quantitative Limbic System Mapping of Main Cognitive Domains in Multiple Sclerosis.

BACKGROUND AND OBJECTIVE: Cognitive impairment (CI) is common in multiple sclerosis (MS), but underlying mechanisms and their imaging correlates are not completely understood. The gray and white matter structures of the limbic system (LS) play crucial roles in different aspects of cognition. To investigate their role in MS related CI, and since a detailed evaluations are lacking in the literature, we used a comprehensive neuroimaging approach to evaluate CI's correlations with the main components of the LS. METHODS: Ten non-cognitively impaired MS patients and 30 MS patients with diagnosed CI, who underwent a comprehensive neuropsychological evaluation were included in the analysis. Microstructural integrity, volumetry of main limbic gray and white matter structures and cortical thickness were assessed for associations with CI. RESULTS: Fornix and cingulum/cingulate cortices were found to be the strongest correlates of CI in MS. As expected, LS' gray and white matter structures were involved in various cognitive functions. Uncinate fasciculi showed significant correlation with verbal and visuospatial learning and memory, phonemic and semantic fluency; hippocampi with visuospatial skills, phonemic and semantic fluency, executive functions, and processing speed; thalami with verbal learning, visuospatial skills, semantic fluency; and amygdala with verbal recognition discrimination. CONCLUSION: This comprehensive neuroimaging approach elucidated the role of the main limbic structures in cognitive functions associated with MS-related CI.

Long-term follow-up of a randomized study of combination interferon and glatiramer acetate in multiple sclerosis: Efficacy and safety results up to 7 years.

BACKGROUND: To report the long-term results of the blinded extension phase of the randomized, controlled study of the combined use of interferon beta-1a (IFN) 30µg IM weekly and glatiramer acetate (GA) 20mg daily compared to each agent alone in relapsing-remitting multiple sclerosis (RRMS). METHODS: 1008 RRMS patients were followed on protocol until the last participant enrolled completed 3 years, allowing some subjects to be followed for up to 7 years. The primary endpoint was reduction in annualized relapse rate. Secondary outcomes included time to confirmed disability, Multiple Sclerosis Functional Composite (MSFC) score and MRI metrics. RESULTS: Similar to the core study, combination IFN + GA was not superior to the better of the single agents (GA) in risk of relapse. Both the combination therapy and GA were significantly better than IFN in reducing the risk of relapse. The combination was not better than either agent alone in lessening confirmed EDSS worsening or change in MSFC. Also similar to the core result, the combination was superior to either agent alone in reducing new lesion activity, but the 3 year MRI result did not presage a clinical benefit over the extended observation interval. CONCLUSION: Combining GA & IFN did not produce a significant clinical benefit over the entire study duration. The earlier effect on reducing MRI activity did not result in a later clinical advantage. The combination showed a sustained advantage in reducing disease activity free status.

Ethical Considerations of Patient-Funded Research for Multiple Sclerosis Therapeutics.

Patient-funded research has started to emerge in multiple sclerosis studies, such as low-dose naltrexone and stem-cell therapy. While these represent greater opportunities for the physician, scientist, and patient, ethical concerns concerning protocol review, conflict of interests, and protection of subjects are reviewed.

Novel fMRI working memory paradigm accurately detects cognitive impairment in multiple sclerosis.

BACKGROUND: Cognitive impairment (CI) cannot be diagnosed by magnetic resonance imaging (MRI). Functional magnetic resonance imaging (fMRI) paradigms, such as the immediate/delayed memory task (I/DMT), detect varying degrees of working memory (WM). Preliminary findings using I/DMT showed differences in blood oxygenation level dependent (BOLD) activation between impaired (MSCI, n = 12) and non-impaired (MSNI, n = 9) multiple sclerosis (MS) patients. OBJECTIVES: The aim of the study was to confirm CI detection based on I/DMT BOLD activation in a larger cohort of MS patients. The role of T2 lesion volume (LV) and Expanded Disability Status Scale (EDSS) in magnitude of BOLD signal was also sought. METHODS: A total of 50 patients (EDSS mean ( m) = 3.2, disease duration (DD) m = 12 years, and age m = 40 years) underwent the Minimal Assessment of Cognitive Function in Multiple Sclerosis (MACFIMS) and I/DMT. Working memory activation (WMa) represents BOLD signal during DMT minus signal during IMT. CI was based on MACFIMS. RESULTS: A total of 10 MSNI, 30 MSCI, and 4 borderline patients were included in the analyses. Analysis of variance (ANOVA) showed MSNI had significantly greater WMa than MSCI, in the left prefrontal cortex and left supplementary motor area ( p = 0.032). Regression analysis showed significant inverse correlations between WMa and T2 LV/EDSS in similar areas ( p = 0.005, 0.004, respectively). CONCLUSION: I/DMT-based BOLD activation detects CI in MS. Larger studies are needed to confirm these findings.

Limbic Pathway Correlates of Cognitive Impairment in Multiple Sclerosis.

BACKGROUND AND PURPOSE: Distinct injuries to various limbic white matter pathways have been reported to be associated with different aspects of cognitive dysfunction in multiple sclerosis (MS). Diffusion tensor imaging (DTI) offers a noninvasive method to map tissue microstructural organization. We utilized quantitative magnetic resonance imaging methods to analyze the main limbic system-white matter structures in MS patients with cognitive impairment (CI). METHODS: Ten cognitively nonimpaired MS (MSNI) patients and 36 patients with diagnosed CI (MSCI) underwent the minimal assessment of Cognitive Function in MS (MACFIMS) battery. DTI measures of fornix, cingulum, uncinate fasciculus (UF) included tract volume and corresponding fractional anisotropy (FA), mean (MD), axial (AD), and radial (AD) diffusivities. These were statistically analyzed for associations with CI after adjusting for the confounders. RESULTS: Fornix FA and RD, left cingulum FA, MD, and RD, right cingulum FA, MD, and RD, and left UF FA showed significant differences between MSNI and MSCI (P < .001). Fornix FA (r = -.6) and RD (r = .52), and right cingulum FA (r = -.54) and RD (r = .5) correlated significantly with CI in regression analyses. CONCLUSIONS: The extent of disruption of microstructural disorganization in the main limbic pathways using DTI impacts the extent of CI seen in subjects with MS.

Patient-specific 3D FLAIR for enhanced visualization of brain white matter lesions in multiple sclerosis.

PURPOSE: To improve the conspicuity of white matter lesions (WMLs) in multiple sclerosis (MS) using patient-specific optimization of single-slab 3D fluid-attenuated inversion recovery (FLAIR) magnetic resonance imaging (MRI). MATERIALS AND METHODS: Sixteen MS patients were enrolled in a prospective 3.0T MRI study. FLAIR inversion time and echo time were automatically optimized for each patient during the same scan session based on measurements of the relative proton density and relaxation times of the brain tissues. The optimization criterion was to maximize the contrast between gray matter (GM) and white matter (WM), while suppressing cerebrospinal fluid. This criterion also helps increase the contrast between WMLs and WM. The performance of the patient-specific 3D FLAIR protocol relative to the fixed-parameter protocol was assessed both qualitatively and quantitatively. RESULTS: Patient-specific optimization achieved a statistically significant 41% increase in the GM-WM contrast ratio (P < 0.05) and 32% increase in the WML-WM contrast ratio (P < 0.01) compared with fixed-parameter FLAIR. The increase in WML-WM contrast ratio correlated strongly with echo time (P < 10-11 ). Two experienced neuroradiologists indicated substantially higher lesion conspicuity on the patient-specific FLAIR images over conventional FLAIR in 3-4 cases (intrarater correlation coefficient ICC = 0.72). In no case was the image quality of patient-specific FLAIR considered inferior to conventional FLAIR by any of the raters (ICC = 0.32). CONCLUSION: Changes in proton density and relaxation times render fixed-parameter FLAIR suboptimal in terms of lesion contrast. Patient-specific optimization of 3D FLAIR increases lesion conspicuity without scan time penalty, and has potential to enhance the detection of subtle and small lesions in MS. LEVEL OF EVIDENCE: 1 Technical Efficacy: Stage 1 J. MAGN. RESON. IMAGING 2017;46:557-564.

Diffusion Tensor Imaging-Defined Sulcal Enlargement Is Related to Cognitive Impairment in Multiple Sclerosis.

BACKGROUND AND PURPOSE: Cerebrospinal fluid (CSF) in the brain can be compartmentalized into two main divisions: ventricular CSF and subarachnoid space (sulcal CSF). Changes in CSF volumetry are seen in many neurological conditions including multiple sclerosis (MS) and found to correlate with clinical outcomes. We aimed to test the relation between the volumetry of sulcal and ventricular CSF and cognitive impairment (CI) based on the minimal assessment of cognitive function in MS (MACFIMS) in patients with MS. MATERIAL AND METHODS: Forty-six patients with MS underwent the MACFIMS battery and classified as nonimpaired (MSNI) (n = 10) and cognitively impaired (MSCI) (n = 30) and borderline (MSBD) MS patients (n = 6). Volumes of sulcal and ventricular CSF along with global gray and white matter volumes and cortical thickness were obtained by diffusion tensor imaging (DTI) and T1-weighted (T1w)-based segmentation. These measures were statistically analyzed for associations with CI after adjusting for the age, education in years, lesion load, and disease duration. RESULTS: Sulcal CSF showed the strongest correlation with CI (r = .51, P = .001) in our cohort, whereas ventricular CSF (P = .28, P = .19) along with cortical thickness and gray matter volume failed to show a significant correlation. Group analyses unadjusted for multiple comparisons showed significant difference in volumes of sulcal CSF and ventricular CSF between MSNI and MSCI groups (P < .05). CONCLUSION: Sulcal CSF correlates with CI in patients with MS, possibly explained by cortical atrophy. DTI/T1w-based sulcal CSF segmentation method might be used as an indirect and simple neuroimaging marker to monitor CI in MS patients.