Lung Ultrasound to Diagnose Pulmonary Congestion Among Patients on Hemodialysis: Comparison of Full Versus Abbreviated Scanning Protocols.

RATIONALE & OBJECTIVE: Pulmonary congestion contributes to morbidity and mortality in patients with kidney failure on hemodialysis, but physical assessment is an insensitive approach to its detection. Lung ultrasound is useful for assessing the presence and severity of pulmonary congestion, but the most widely validated 28-zone study is cumbersome. We sought to compare abbreviated 4-, 6-, and 8-zone studies to 28-zone studies. STUDY DESIGN: Diagnostic test study. SETTING & PARTICIPANTS: Convenience sample of 98 patients with kidney failure on hemodialysis presenting to an emergency department in the United States. TESTS COMPARED: 4-, 6-, and 8-zone lung ultrasound studies versus a 28-zone lung ultrasound. OUTCOME: Prediction of pulmonary congestion and 30-day mortality. RESULTS: All patients completed a 28-zone lung ultrasound. Correlation coefficients (nonparametric Spearman) between each of the studies were high (all values > 0.84). Bland-Altman analysis showed good agreement. Each of the short-form studies discriminated well with area under the receiver-operator characteristic curve > 0.83 for no-to-mild versus moderate-to-severe pulmonary congestion. During a median follow-up period of 778 days, 46 (47%) died. Patients with moderate-to-severe pulmonary congestion on lung ultrasound had a 30-day mortality rate similar to that observed among patients with no-to-mild pulmonary congestion (OR, 0.95 [95% CI, 0.70-1.29]). LIMITATIONS: Single-center study conducted in an emergency care setting, convenience sample of patients, and lack of long-term follow-up data. CONCLUSIONS: Among hemodialysis patients presenting to an emergency department, 4-, 6-, or 8-zone lung ultrasounds were comparable to 28-zone studies for the assessment of pulmonary congestion. The mortality rates did not differ between those with no-to-mild and moderate-to-severe pulmonary congestion.

Decreasing brain iron in multiple sclerosis: The difference between concentration and content in iron MRI.

Increased brain iron concentration is often reported concurrently with disease development in multiple sclerosis (MS) and other neurodegenerative diseases. However, it is unclear whether the higher iron concentration in patients stems from an influx of iron into the tissue or a relative reduction in tissue compartments without much iron. By taking into account structural volume, we investigated tissue iron content in the deep gray matter (DGM) over 2 years, and compared findings to previously reported changes in iron concentration. 120 MS patients and 40 age- and sex-matched healthy controls were included. Clinical testing and MRI were performed both at baseline and after 2 years. Overall, iron content was calculated from structural MRI and quantitative susceptibility mapping in the thalamus, caudate, putamen, and globus pallidus. MS patients had significantly lower iron content than controls in the thalamus, with progressive MS patients demonstrating lower iron content than relapsing-remitting patients. Over 2 years, iron content decreased in the DGM of patients with MS, while it tended to increase or remain stable among controls. In the thalamus, decreasing iron content over 2 years was associated with disability progression. Our study showed that temporally increasing magnetic susceptibility in MS should not be considered as evidence for iron influx because it may be explained, at least partially, by disease-related atrophy. Declining DGM iron content suggests that, contrary to the current understanding, iron is being removed from the DGM in patients with MS.

Serum neurofilament light chain level associations with clinical and cognitive performance in multiple sclerosis: A longitudinal retrospective 5-year study.

BACKGROUND: A limited number of studies investigated associations between serum neurofilament light chain (sNfL) and cognition in persons with multiple sclerosis (PwMS). OBJECTIVE: To assess cross-sectional and longitudinal associations between sNfL levels, clinical, and cognitive performance in PwMS and age-matched healthy controls (HCs). MATERIALS: One hundred twenty-seven PwMS (85 relapsing-remitting MS/42 progressive MS), 20 clinically isolated syndrome patients, and 52 HCs were followed for 5 years. sNfL levels were measured using the single-molecule array (Simoa) assay and quantified in picograms per milliliter. Expanded Disability Status Scale (EDSS), walking, and manual dexterity tests were obtained. At follow-up, Brief International Cognitive Assessment for MS (BICAMS) was utilized. Cognitively impaired (CI) status was derived using HC-based z-scores. Age-, sex-, and education-adjusted analysis of covariance (ANCOVA) and regression models were used. Multiple comparison-adjusted values of q < 0.05 were considered significant. RESULTS: In PwMS, sNfL levels were cross-sectionally associated with walking speed (r = 0.235, q = 0.036), manual dexterity (r = 0.337, q = 0.002), and cognitive processing speed (CPS; r =-0.265, q = 0.012). Baseline sNfL levels predicted 5-year EDSS scores (r = 0.25, q = 0.012), dexterity (r = 0.224, q = 0.033), and CPS (r =-0.205, q = 0.049). CI patients had higher sNfL levels (27.2 vs. 20.6, p = 0.016) and greater absolute longitudinal sNfL increase when compared with non-CI patients (4.8 vs. 0.7, p = 0.04). CONCLUSION: Higher sNfL levels are associated with poorer current and future clinical and cognitive performance.

Oxysterols and apolipoproteins in multiple sclerosis: a 5 year follow-up study.

The purpose of this work was to investigate whether changes in oxysterol and apolipoprotein levels over 5 years are associated with disease course and disability progression in multiple sclerosis (MS). This study included 139 subjects [39 healthy controls (HCs), 61 relapsing-remitting MS (RR-MS) patients, and 39 progressive MS (P-MS) patients]. Oxysterols [24-hydroxycholesterol (24HC), 25-hydroxycholesterol (25HC), 27-hydroxycholesterol (27HC), 7α-hydroxycholesterol (7αHC), and 7-ketocholesterol (7KC)] were measured at baseline and 5 years using a novel mass spectrometric method, and apolipoproteins were measured using immunoturbidometric diagnostic kits. Levels of 24HC (P = 0.004), 25HC (P = 0.029), and 27HC (P = 0.026) increased in P-MS patients. 7KC (P = 0.047) and 7αHC (P = 0.001) levels decreased in RR-MS patients, and there were no changes in any oxysterols in HCs. In MS patients, ApoC-II (all P ≤ 0.01) and ApoE (all P ≤ 0.01) changes were positively associated with all oxysterol levels. Increases in 24HC (P = 0.038) and ApoB (P = 0.038) and decreases in 7KC (P = 0.020) were observed in RR-MS patients who converted to secondary P-MS (SP-MS) at follow-up and in SP-MS patients compared with RR-MS patients. Oxysterols and their associations with apolipoproteins differed between MS patients and HCs over 5 years. Oxysterol and apolipoprotein changes were associated with conversion to SP-MS.

Assessment of mesoscopic properties of deep gray matter iron through a model-based simultaneous analysis of magnetic susceptibility and R2* - A pilot study in patients with multiple sclerosis and normal controls.

Most studies of brain iron relied on the effect of the iron on magnetic resonance (MR) relaxation properties, such as R2∗, and bulk tissue magnetic susceptibility, as measured by quantitative susceptibility mapping (QSM). The present study exploited the dependence of R2∗ and magnetic susceptibility on physical interactions at different length-scales to retrieve information about the tissue microenvironment, rather than the iron concentration. We introduce a method for the simultaneous analysis of brain tissue magnetic susceptibility and R2∗ that aims to isolate those biophysical mechanisms of R2∗ -contrast that are associated with the micro- and mesoscopic distribution of iron, referred to as the Iron Microstructure Coefficient (IMC). The present study hypothesized that changes in the deep gray matter (DGM) magnetic microenvironment associated with aging and pathological mechanisms of multiple sclerosis (MS), such as changes of the distribution and chemical form of the iron, manifest in quantifiable contributions to the IMC. To validate this hypothesis, we analyzed the voxel-based association between R2∗ and magnetic susceptibility in different DGM regions of 26 patients with multiple sclerosis and 33 age- and sex-matched normal controls. Values of the IMC varied significantly between anatomical regions, were reduced in the dentate and increased in the caudate of patients compared to controls, and decreased with normal aging, most strongly in caudate, globus pallidus and putamen.

Atrophied Brain T2 Lesion Volume at MRI Is Associated with Disability Progression and Conversion to Secondary Progressive Multiple Sclerosis.

Background Atrophied T2 lesion volume at MRI is an imaging measure that reflects the replacement of T2 lesions by cerebrospinal fluid spaces in patients with multiple sclerosis (MS). Purpose To investigate the association of atrophied T2 lesion volume and development of disability progression (DP) and conversion to secondary progressive MS (SPMS). Materials and Methods This retrospective study included 1612 participants recruited from 2006 to 2016 and followed up for 5 years with clinical and MRI examinations. Accumulation of T2 lesion volume, atrophied T2 lesion volume, percentage brain volume change (PBVC), and percentage ventricular volume change (PVVC) were measured. Disability progression and secondary progressive conversion were defined by using standardized guidelines. Analysis of covariance (ANCOVA) adjusted for age and Cox regression adjusted for age and sex were used to compare study groups and explore associations between MRI and clinical outcomes. Results A total of 1314 patients with MS (1006 women; mean age, 46 years ± 11 [standard deviation]) and 124 patients with clinically isolated syndrome (100 women; mean age, 39 years ± 11) along with 147 healthy control subjects (97 women; mean age, 42 years ± 13) were evaluated. A total of 336 of 1314 (23%) patients developed DP, and in 67 of 1213 (5.5%) the disease converted from clinically isolated syndrome (CIS) or relapsing-remitting MS (RRMS) to SPMS. Patients with conversion to DP had higher atrophied T2 lesion volume (+34.4 mm3; 95% confidence interval [CI]: 17.2 mm3, 51.5 mm3; d = 0.27; P < .001) and PBVC (-0.21%; 95% CI: -0.36%, -0.05%; d = 0.19; P = .042) but not PVVC (0.36%; 95% CI: -0.93%, 1.65%; d = 0.04; P = .89) or T2 lesion volume change (-64.5 mm3; 95% CI: -315.2 mm3, 186.3 mm3; d = 0.03; P = .67) when compared with DP nonconverters. ANCOVA showed that atrophied T2 lesion volume was associated with conversion from CIS or RRMS to SPMS (+26.4 mm3; 95% CI: 4.2 mm3, 56.9 mm3; d = 0.23; P = .002) but not PBVC (-0.14%; 95% CI: -0.46%, 0.18%; d = 0.11; P = .66), PVVC (+0.18%; 95% CI: -2.49%, 2.72%; d = 0.01; P = .75), or T2 lesion volume change (-46.4 mm3; 95% CI: -460.8 mm3, 367.9 mm3; d = 0.03; P = .93). At Cox regression analysis, only atrophied T2 lesion volume was associated with the DP (hazard ratio, 1.23; P < .001) and conversion to SPMS (hazard ratio, 1.16; P = .008). Conclusion Atrophied brain T2 lesion volume is a robust MRI marker of MS disability progression and conversion into a secondary progressive disease course. © RSNA, 2019 Online supplemental material is available for this article. See also the editorial by Chiang in this issue.

Ventral posterior substantia nigra iron increases over 3 years in Parkinson's disease.

BACKGROUND: Parkinson's disease (PD) is characterized in part by the progressive accumulation of iron within the substantia nigra (SN); however, its spatial and temporal dynamics remain relatively poorly understood. OBJECTIVES: The objective of this study was to investigate spatial patterns and temporal evolution of SN iron accumulation in PD. METHODS: A total of 18 PD patients (mean disease duration = 6.2 years) receiving dopaminergic therapy and 16 healthy controls were scanned with 3T MRI at baseline and 3 years later using quantitative susceptibility mapping, an indirect marker of iron content. Iron was assessed separately in the posterior SN and anterior SN at the ventral and dorsal levels of the SN. The results were corrected for the false discovery rate. RESULTS: A significant group effect was found for the ventral posterior SN (P < .001) and anterior SN (P = .042) quantitative susceptibility mapping as well as significant group x time interaction effects (P = .02 and P = .043, respectively). In addition, a significant intragroup change during 3 years of follow-up was found only in the ventral posterior SN of PD (P = .012), but not healthy controls. No significant effects were detected for any dorsal SN measures. No associations were identified with clinical measures. CONCLUSIONS: We found both cross-sectional and longitudinal SN iron changes to be confined to its more ventral location in PD. Because pathology studies also show the ventral SN to degenerate early and to the greatest extent in PD, the assessment of iron levels by quantitative susceptibility mapping in this area may potentially represent a disease progression biomarker in PD. © 2019 International Parkinson and Movement Disorder Society.

Altered nuclei-specific thalamic functional connectivity patterns in multiple sclerosis and their associations with fatigue and cognition.

BACKGROUND: The thalamus, affected early in multiple sclerosis (MS), is a heterogeneous composition of functionally distinct nuclei and is associated with fatigue, cognition, and other outcomes. However, most previous functional imaging studies considered the thalamus only as a whole. OBJECTIVE: To investigate MS-related abnormalities in nuclei-specific thalamic functional connectivity (FC) and their associations with fatigue and cognitive outcomes. METHODS: Resting-state functional magnetic resonance imaging (fMRI) was analyzed in 64 MS patients and 26 healthy controls (HC). Whole-brain FC maps for four thalamic subregions seeds were computed for each subject. FC maps were compared between groups, and group by FC interaction effects were assessed for fatigue and cognitive measures. RESULTS: MS patients had decreased FC between the left medial thalamic nuclei and left angular gyrus and reduced FC between the left posterior thalamic nuclei and left supramarginal gyrus, as well as decreased right medial thalamic nuclei connectivity with bilateral caudate/thalamus and left cerebellar areas (p < 0.05 corrected). MS patients had increased FC between the left anterior thalamic nuclei and anterior cingulate cortex bilaterally. There were significant relationships between connectivity alterations and fatigue and cognitive measures between groups (p < 0.05 corrected). CONCLUSION: FC alteration is nuclei-specific and is differentially associated with fatigue and cognition.

No association between variations in extracranial venous anatomy and clinical outcomes in multiple sclerosis patients over 5 years.

BACKGROUND: No longitudinal, long-term, follow-up studies have explored the association between presence and severity of variations in extracranial venous anatomy, and clinical outcomes in patients with multiple sclerosis (MS). OBJECTIVE: This prospective 5-year follow-up study assessed the relationship of variations in extracranial venous anatomy, indicative of chronic cerebrospinal venous insufficiency (CCSVI) on Doppler sonography, according to the International Society for Neurovascular Disease (ISNVD) proposed consensus criteria, with clinical outcomes and disease progression in MS patients. METHODS: 90 MS patients (52 relapsing-remitting, RRMS and 38 secondary-progressive, SPMS) and 38 age- and sex-matched HIs were prospectively followed for 5.5 years. Extracranial and transcranial Doppler-based venous hemodynamic assessment was conducted at baseline and follow-up to determine the extent of variations in extracranial venous anatomy. Change in Expanded Disability Status Scale (∆EDSS), development of disability progression (DP) and annualized relapse rate (ARR) were assessed. RESULTS: No significant differences were observed in MS patients, based on their presence of variations in extracranial venous anatomy at baseline or at the follow-up, in ∆EDSS, development of DP or ARR. While more MS patients had ISNVD CCSVI criteria fulfilled at baseline compared to HIs (58% vs. 37%, p = 0.03), no differences were found at the 5-year follow-up (61% vs. 56%, p = 0.486). DISCUSSION: This is the longest follow-up study assessing the longitudinal relationship between the presence of variations in extracranial venous anatomy and clinical outcomes in MS patients. CONCLUSION: The presence of variations in extracranial venous anatomy does not influence clinical outcomes over the 5-year follow-up in MS patients.

Abnormal venous postural control: multiple sclerosis-specific change related to gray matter pathology or age-related neurodegenerative phenomena?

BACKGROUND: Autonomic nervous system dysfunction has been previously observed in multiple sclerosis (MS) patients. OBJECTIVE: To assess associations between magnetic resonance imaging-detected neuroinflammatory and neurodegenerative pathology and postural venous flow changes indicative of autonomic nervous system function. METHODS: We used a standardized 3T magnetic resonance imaging protocol to scan 138 patients with MS and 49 healthy controls. Lesion volume and brain volumes were assessed. The cerebral venous flow (CVF) was examined by color-Doppler sonography in supine and upright positions and the difference was calculated as ΔCVF. Based on ΔCVF, subjects were split into absolute or quartile groups. Student's t test, χ2-test, and analysis of covariance adjusted for age and sex were used accordingly. Benjamini-Hochberg procedure corrected the p-values for multiple comparisons. RESULTS: No differences were found between healthy controls and patients with MS in both supine and upright Doppler-derived CVF, nor in prevalence of abnormal postural venous control. Patients with absolute negative ΔCVF had higher disability scores (p = 0.013), lower gray matter (p = 0.039) and cortical (p = 0.044) volumes. The negative ΔCVF MS group also showed numerically worse bladder/bowel function when compared to the positive ΔCVF (2.3 vs. 1.5, p = 0.052). Similarly, the lowest quartile ΔCVF MS group had higher T1-lesion volumes (p = 0.033), T2-lesion volumes (p = 0.032), and lower deep gray matter (p = 0.043) and thalamus (p = 0.033) volumes when compared to those with higher ΔCVF quartiles. CONCLUSION: No difference in postural venous outflow between patients with MS and healthy controls was found. However, when the abnormal ΔCVF is present within the MS population, it may be associated with more inflammatory and neurodegenerative pathology. Further studies should explore whether the orthostatic venous changes are an aging or an MS-related phenomenon and if the etiology is due to impaired autonomic nervous system functioning.

Mapping of thalamic magnetic susceptibility in multiple sclerosis indicates decreasing iron with disease duration: A proposed mechanistic relationship between inflammation and oligodendrocyte vitality.

Recent advances in susceptibility MRI have dramatically improved the visualization of deep gray matter brain regions and the quantification of their magnetic properties in vivo, providing a novel tool to study the poorly understood iron homeostasis in the human brain. In this study, we used an advanced combination of the recent quantitative susceptibility mapping technique with dedicated analysis methods to study intra-thalamic tissue alterations in patients with clinically isolated syndrome (CIS) and multiple sclerosis (MS). Thalamic pathology is one of the earliest hallmarks of MS and has been shown to correlate with cognitive dysfunction and fatigue, but the mechanisms underlying the thalamic pathology are poorly understood. We enrolled a total of 120 patients, 40 with CIS, 40 with Relapsing Remitting MS (RRMS), and 40 with Secondary Progressive MS (SPMS). For each of the three patient groups, we recruited 40 controls, group matched for age- and sex (120 total). We acquired quantitative susceptibility maps using a single-echo gradient echo MRI pulse sequence at 3 T. Group differences were studied by voxel-based analysis as well as with a custom thalamus atlas. We used threshold-free cluster enhancement (TFCE) and multiple regression analyses, respectively. We found significantly reduced magnetic susceptibility compared to controls in focal thalamic subregions of patients with RRMS (whole thalamus excluding the pulvinar nucleus) and SPMS (primarily pulvinar nucleus), but not in patients with CIS. Susceptibility reduction was significantly associated with disease duration in the pulvinar, the left lateral nuclear region, and the global thalamus. Susceptibility reduction indicates a decrease in tissue iron concentration suggesting an involvement of chronic microglia activation in the depletion of iron from oligodendrocytes in this central and integrative brain region. Not necessarily specific to MS, inflammation-mediated iron release may lead to a vicious circle that reduces the protection of axons and neuronal repair.

Brain Iron at Quantitative MRI Is Associated with Disability in Multiple Sclerosis.

Purpose To study deep gray matter susceptibility in multiple sclerosis (MS) by using quantitative susceptibility mapping (QSM) and to assess the relationship between susceptibility and clinical disability. Materials and Methods For this prospective study between March 2009 and November 2013, 600 participants with MS (452 with relapsing-remitting MS and 148 with secondary progressive MS) and 250 age- and sex-matched healthy control participants were imaged with 3.0-T MRI to measure magnetic susceptibility. Deep gray matter susceptibility (in parts per billion) was analyzed by using region of interest and voxelwise methods. QSM and MRI volumetric differences between study groups and associations with clinical outcomes were assessed. Analysis of covariance, multivariable linear regression, and voxelwise analyses, controlling for age and sex, were used to compare study groups and to explore associations between MRI and clinical outcomes. Results Compared with control participants, participants with MS presented with lower thalamic susceptibility (-7.5 ppb vs -1.1 ppb; P < .001) and higher susceptibility of basal ganglia (62 ppb vs 54.8 ppb; P < .001). Lower thalamic susceptibility was associated with longer disease duration (ß = -0.42; P = .002), higher degree of disability (ß = -0.64; P = .03), and secondary-progressive course (ß = -4.3; P = .009). Higher susceptibility of the globus pallidus was associated with higher disability (ß = 2; P = .03). After correcting for each individual structural volume in voxelwise analysis, lower thalamic susceptibility and higher susceptibility of the globus pallidus remained associated with clinical disability (P < .05). Conclusion Quantitative susceptibility mapping (QSM) suggests that altered deep gray matter iron is associated with the evolution of multiple sclerosis (MS) and on disability accrual, independent of tissue atrophy. © RSNA, 2018 Online supplemental material is available for this article.

Multimodal Imaging of Retired Professional Contact Sport Athletes Does Not Provide Evidence of Structural and Functional Brain Damage.

BACKGROUND: Long-term consequences of playing professional football and hockey on brain function and structural neuronal integrity are unknown. OBJECTIVES: To investigate multimodal metabolic and structural brain magnetic resonance imaging (MRI) differences in retired professional contact sport athletes compared with noncontact sport athletes. METHODS: Twenty-one male contact sport athletes and 21 age-matched noncontact sport athletes were scanned on a 3 tesla (3T) MRI using a multimodal imaging approach. The MRI outcomes included presence, number, and volume of focal white matter signal abnormalities, volumes of global and regional tissue-specific brain structures, diffusion-tensor imaging tract-based spatial statistics measures of mean diffusivity and fractional anisotropy, quantitative susceptibility mapping of deep gray matter, presence, number, and volume of cerebral microbleeds, MR spectroscopy N-acetyl-aspartate, glutamate, and glutamine concentrations relative to creatine and phosphor creatine of the corpus callosum, and perfusion-weighted imaging mean transit time, cerebral blood flow, and cerebral blood volume outcomes. Subjects were also classified as having mild cognitive impairment. RESULTS: No significant differences were found for structural or functional MRI measures between contact sport athletes and noncontact sport athletes. CONCLUSIONS: This multimodal imaging study did not show any microstructural, metabolic brain tissue injury differences in retired contact versus non-contact sport athletes.

Methods for the computation of templates from quantitative magnetic susceptibility maps (QSM): Toward improved atlas- and voxel-based analyses (VBA).

PURPOSE: To develop and assess a method for the creation of templates for voxel-based analysis (VBA) and atlas-based approaches using quantitative magnetic susceptibility mapping (QSM). MATERIALS AND METHODS: We studied four strategies for the creation of magnetic susceptibility brain templates, derived as successive extensions of the conventional template generation (CONV) based on only T1 -weighted (T1 w) images. One method that used only T1 w images involved a minor improvement of CONV (U-CONV). One method used only magnetic susceptibility maps as input for template generation (DIRECT), and the other two used a linear combination of susceptibility and T1 w images (HYBRID) and an algorithm that directly used both image modalities (MULTI), respectively. The strategies were evaluated in a group of N = 10 healthy human subjects and semiquantitatively assessed by three experienced raters. Template quality was compared statistically via worth estimates (WEs) obtained with a log-linear Bradley-Terry model. RESULTS: The overall quality of the templates was better for strategies including both susceptibility and T1 w contrast (MULTI: WE = 0.62; HYBRID: WE = 0.21), but the best method depended on the anatomical region of interest. While methods using only one modality resulted in lower WEs, lowest overall WEs were obtained when only T1 w images were used (DIRECT: WE = 0.12; U-CONV: WE = 0.05). CONCLUSION: Template generation strategies that employ only magnetic susceptibility contrast or both magnetic susceptibility and T1 w contrast produce templates with the highest quality. The optimal approach depends on the anatomical structures of interest. The established approach of using only T1 w images (CONV) results in reduced image quality compared to all other approaches studied. LEVEL OF EVIDENCE: 2 Technical Efficacy: Stage 1 J. Magn. Reson. Imaging 2017;46:1474-1484.

Interdependence of oxysterols with cholesterol profiles in multiple sclerosis.

PURPOSE: To investigate levels of oxysterols in healthy control (HC) and multiple sclerosis (MS) patients and their interdependence with demographic, clinical characteristics, and cholesterol biomarkers. METHODS: This study included 550 subjects (203 HC, 221 relapsing-remitting MS (RR-MS), 126 progressive MS (P-MS)). A complete lipid profile including total cholesterol (TC); high-density lipoprotein-cholesterol (HDL-C); low-density lipoprotein-cholesterol (LDL-C); apolipoproteins (Apo) A1, A2, B, and E; C-reactive protein (CRP); 24-hydroxycholesterol (HC); 25-HC; 27-HC; 7α-HC; and 7-ketocholesterol (KC) was obtained. Lipoprotein particle sizing by proton nuclear magnetic resonance (H1 NMR) was available for 432 subjects. RESULTS: The levels of 24-HC, 27-HC, and 7α-HC (all p < 0.015) were lower in MS compared to HC, and 7-KC was higher in P-MS compared to RR-MS ( p < 0.001). TC, LDL-C, and ApoB were associated with higher levels of all oxysterols (all p < 0.05) in HC. In MS, LDL-C was associated with higher levels of 24-HC, 25-HC, 7-KC, and 7α-HC (all p < 0.05), while TC and ApoB were associated with increased levels of all oxysterols (all p < 0.005). CONCLUSION: The findings of lower 24-HC, 27-HC, and 7α-HC in MS compared to HC and higher 7-KC in P-MS compared to RR-MS indicate that the oxysterol network is disrupted in MS.

Leptomeningeal contrast enhancement is associated with progression of cortical atrophy in MS: A retrospective, pilot, observational longitudinal study.

BACKGROUND: Leptomeningeal contrast enhancement (LM CE) has been recently described in multiple sclerosis (MS) patients as a potential in vivo marker of cortical pathology. OBJECTIVES: To investigate the association of LM CE and development of cortical atrophy in 50 MS patients (27 relapsing-remitting (RR) and 23 secondary-progressive (SP)) followed for 5 years. METHODS: The presence and number of LM CE foci were assessed only at the 5-year follow-up using three-dimensional (3D) fluid-attenuated inversion recovery magnetic resonance imaging (MRI) sequence obtained 10 minutes after single dose of gadolinium injection on 3T scanner. The percentage change in whole brain, cortical and deep gray matter (GM) volumes, and lesion volume (LV) was measured between baseline and the 5-year follow-up. RESULTS: In total, 25 (50%) of MS patients had LM CE at the 5-year follow-up. Significantly more SPMS patients (12, 85.7%) had multiple LM CE foci, compared to those with RRMS (2, 18.2%) ( p = 0.001). MS patients with LM CE showed significantly greater percentage decrease in total GM (-3.6% vs -2%, d = 0.80, p = 0.006) and cortical (-3.4% vs -1.8%, d = 0.84, p = 0.007) volumes and greater percentage increase in ventricular cerebrospinal fluid (vCSF) volume (22.8% vs 9.9%, d = 0.90, p = 0.003) over the follow-up, compared to those without. CONCLUSION: In this retrospective, pilot, observational longitudinal study, the presence of LM CE was associated with progression of cortical atrophy over 5 years.

Cerebral Microbleeds in Multiple Sclerosis Evaluated on Susceptibility-weighted Images and Quantitative Susceptibility Maps: A Case-Control Study.

Purpose To assess cerebral microbleed (CMB) prevalence in patients with multiple sclerosis (MS) and clinically isolated syndrome (CIS) and associations with clinical outcomes. Materials and Methods CMBs are associated with aging and neurodegenerative disorders. The prevalence of CMBs has not previously been well established. In this study, 445 patients with MS (266 with relapsing-remitting MS, 138 with secondary progressive MS, and 41 with primary progressive MS), 45 patients with CIS, 51 patients with other neurological diseases, and 177 healthy control subjects (HCs) underwent 3-T magnetic resonance (MR) imaging and clinical examinations. A subset of 168 patients with MS and 50 HCs underwent neuropsychological testing. Number of CMBs was assessed on susceptibility-weighted minimum intensity projections by using the Microbleed Anatomic Rating Scale; volume was calculated by using quantitative susceptibility maps. Differences between groups were analyzed with the χ2 test, Fisher exact test, Student t test, and analysis of variance; associations of CMBs with clinical and other MR imaging outcomes were explored with correlation and regression analyses. Because CMB frequency increases with age, prevalence was investigated in participants at least 50 years of age and younger than 50 years. Results Significantly more patients with MS than HCs had CMBs (19.8% vs 7.4%, respectively; P = .01) in the group at least 50 years old. A trend toward greater presence of CMBs was found in patients with MS (P = .016) and patients with CIS who were younger than 50 years (P = .039) compared with HCs. In regression analysis adjusted for age, hypertension, and normalized brain volume, increased number of CMBs was significantly associated with increased physical disability in the MS population (R2 = 0.23, P < .0001). In correlation analysis, increased number of CMBs was significantly associated with deteriorated auditory and verbal learning and memory (P = .006) and visual information processing speed trends (P = .049) in patients with MS. Conclusion Monitoring CMBs may be relevant in patients with MS and CIS at higher risk for developing cognitive and physical disability. © RSNA, 2016 Online supplemental material is available for this article.

Randomised natalizumab discontinuation study: taper protocol may prevent disease reactivation.

OBJECTIVES: To compare two modes of natalizumab cessation interventions: immediate versus tapered down, as measured by serial MRI and the occurrence of relapses during a 12-month period. BACKGROUND: Weighing progressive multifocal encephalopathy risk associated with ≥24 months of natalizumab therapy against the benefits of disease control, we initiated a natalizumab discontinuation study. METHODS: A phase IV, 12-month, single-blinded randomised (MRI) study. Fifty relapsing patients with multiple sclerosis (MS) who had been on natalizumab therapy ≥24 months and were contemplating natalizumab discontinuation were enrolled. Participants were randomised to either the immediate discontinuation group (IDG) or the tapered group (TG). IDG discontinued natalizumab at once and initiated another disease modifying therapy (DMT) following the last natalizumab infusion, while the TG received two more natalizumab infusions, at 6 and 8 weeks (14 weeks from study entry) before initiating another DMT. Standardised MRI was performed at baseline, 6 and 12 months from the last natalizumab infusion. RESULTS: A higher rate of relapses in the IDG (n=28) compared to the TG (n=8) over 12 months from the last infusion (p=0.007) was observed, most relapses occurred within 3 months of discontinuation (20 vs 7 relapses, p=0.012). The IDG showed a higher number of new T2 lesions within 6-12 months of discontinuation (p=0.025), a higher mean absolute T2-LV change from 0 to 12 months (1.1 vs 0.1 mL, p=0.024) and a higher number of new T1-hypointense lesions over 0-12 months (p=0.005) as well as from baseline to 6 months (p=0.026) compared to the TG. CONCLUSIONS: Natalizumab discontinuation therapy was associated with development of new disease activity. Our tapered protocol showed benefits, as patients in the TG experienced less relapses and lower accumulation of MRI lesions compared to those in the IDG.

Cardiovascular risk factors are associated with increased lesion burden and brain atrophy in multiple sclerosis.

BACKGROUND: Cardiovascular (CV) risk factors have been associated with changes in clinical outcomes in patients with multiple sclerosis (MS). OBJECTIVES: To investigate the frequency of CV risks in patients with MS and their association with MRI outcomes. METHODS: In a prospective study, 326 patients with relapsing-remitting MS and 163 patients with progressive MS, 61 patients with clinically isolated syndrome (CIS) and 175 healthy controls (HCs) were screened for CV risks and scanned on a 3T MRI scanner. Examined CV risks included hypertension, heart disease, smoking, overweight/obesity and type 1 diabetes. MRI measures assessed lesion volumes (LVs) and brain atrophy. Association between individual or multiple CV risks and MRI outcomes was examined adjusting for age, sex, race, disease duration and treatment status. RESULTS: Patients with MS showed increased frequency of smoking (51.7% vs 36.5%, p = 0.001) and hypertension (33.9% vs 24.7%, p=0.035) compared with HCs. In total, 49.9% of patients with MS and 36% of HCs showed ≥ 2 CV risks (p = 0.003), while the frequency of ≥ 3 CV risks was 18.8% in the MS group and 8.6% in the HCs group (p = 0.002). In patients with MS, hypertension and heart disease were associated with decreased grey matter (GM) and cortical volumes (p < 0.05), while overweight/obesity was associated with increased T1-LV (p < 0.39) and smoking with decreased whole brain volume (p = 0.049). Increased lateral ventricle volume was associated with heart disease (p = 0.029) in CIS. CONCLUSIONS: Patients with MS with one or more CV risks showed increased lesion burden and more advanced brain atrophy.

A serial 10-year follow-up study of brain atrophy and disability progression in RRMS patients.

BACKGROUND: We explored the evolution of brain atrophy in relation to development of confirmed disability progression (CDP) on serial 1.5T magnetic resonance imaging (MRI) scans over a 10-year period in 181 patients with early relapsing-remitting multiple sclerosis (RRMS). METHODS: At 10-year follow-up, they were divided into those with (100) or without (76) CDP (confirmed after 48 weeks). Changes in whole brain (WB), cortical, gray matter (GM), white matter, and ventricular cerebrospinal fluid (vCSF) volumes were calculated on three-dimensional T1-weighted (3D-T1) scans between all available time points. RESULTS: In multiple sclerosis (MS) patients with CDP compared to those without, the greatest effect size percentage volume change from baseline to follow-up was detected for WB (d = 0.55, -7.5% vs -5.2%, p < 0.001), followed by vCSF (d = 0.51, +41.1% vs +25.7%, p < 0.001), cortical (d = 0.49, -7.7% vs -6.2%, p = 0.001), and GM (d = 0.40, -7.1% vs -5.8%, p = 0.006) volumes. Mixed-effects model analysis, adjusted for age, sex, and treatment change, showed significant interactions between CDP status and percentage changes for WB and vCSF (p < 0.001), cortical (p = 0.02), and GM (p = 0.04) volumes. CONCLUSIONS: WB and cortical atrophy, and enlargement of vCSF spaces are associated with development of CDP on serial yearly MRI assessments over a period of 10 years.