Sara Hussein

Retinal nerve fiber layer thickness is associated with brain MRI outcomes in multiple sclerosis

Multiple sclerosis is characterized by the dual pathological processes of inflammation and neurodegeneration. Conventional MRI techniques are considered the best tools for assessing and monitoring lesion burden and inflammation but are limited in their ability to assess axonal loss. Optical coherence tomography (OCT) is a simple high-resolution technique that uses near infrared light to quantify the thickness of the retinal nerve fiber layer (RNFL), which contains only non-myelinated axons. RNFL thickness (RNFLT) was measured using OCT on thirty consecutive MS patients (60 eyes). Eighteen patients underwent quantitative MRI analysis including T1- and T2-lesion volumes (LV), normalized brain volume (NBV), normalized cortical, white and gray matter volumes (NCV, NWMV, and NGMV), and mean whole brain diffusivity (MD). There was a strong association between NBV and average RNFL thickness (p<0.001, partial rp=0.77). The T2-LV and NWMV were significantly associated with average RNFL thickness (p=0.002, partial rp= -0.76 and p=0.005, partial rp=0.68, respectively) and there were trends toward association with T1-LV (p=0.041) and NGMV (p=0.067). There was negative correlation between average RNFL thickness (average of both eyes) and disability as assessed by EDSS (p=0.02). The results support potential usefulness of OCT for MS patient monitoring and research applications.

Extent of cerebellum, subcortical and cortical atrophy in patients with MS: A case-control study

Cortical and subcortical atrophy occurs in multiple sclerosis (MS) and relates to clinical outcomes. FreeSurfer, a voxel-based automated software for brain reconstruction was used to investigate the extent of subcortical and cortical atrophy in 71 MS and 17 clinically isolated syndrome (CIS) patients, and 38 normal controls (NC), and to relate group differences to disease type and severity. Segmentation was performed on 3D SPGR T1-weighted MRI 1.5T images. Region-specific subcortical tissue volumes were calculated in mm(3) and cortical thickness in mm. Logistic regression and general linear model analyses, adjusted for age and intracranial volume, examined differences between NC, MS and CIS patients and disease subtypes. The MS group was characterized by significantly lower volumes of thalamus (left and right p<0.0001), left inferior lateral ventricle, third ventricle (p<0.0001), ventral diencephalon, pallidum and putamen bilaterally, as well as of right accumbens and brainstem with corresponding bilateral increase in volumes of lateral ventricles (p<0.01). Focal cortical atrophy areas in the thalamus, inferior parietal lobule of left hemisphere and in right precuneus were also significant in the MS sample. Versus CIS patients, RR or progressive MS patients showed significantly lower volumes of subcortical regions and cortical thinning. Hippocampal atrophy appeared only in advanced disease stages. Cerebellum WM volumes were significantly lower in MS and CIS patients vs. NC. Subcortical and cortical atrophy correlated with higher disability as measured by EDSS. This study confirmed selective deep gray matter atrophy (mostly thalamic), revealed cerebellum WM atrophy from the earliest clinical stages, and showed that cortical thinning advances with disease progression.

Serum lipid profiles are associated with disability and MRI outcomes in multiple sclerosis

BackgroundThe breakdown of the blood-brain-barrier vascular endothelium is critical for entry of immune cells into the MS brain. Vascular co-morbidities are associated with increased risk of progression. Dyslipidemia, elevated LDL and reduced HDL may increase progression by activating inflammatory processes at the vascular endothelium.ObjectiveTo assess the associations of serum lipid profile variables (triglycerides, high and low density lipoproteins (HDL, LDL) and total cholesterol) with disability and MRI measures in multiple sclerosis (MS).MethodsThis study included 492 MS patients (age: 47.1 ± 10.8 years; disease duration: 12.8 ± 10.1 years) with baseline and follow-up Expanded Disability Status Score (EDSS) assessments after a mean period of 2.2 ± 1.0 years. The associations of baseline lipid profile variables with disability changes were assessed. Quantitative MRI findings at baseline were available for 210 patients.ResultsEDSS worsening was associated with higher baseline LDL (p = 0.006) and total cholesterol (p = 0.001, 0.008) levels, with trends for higher triglyceride (p = 0.025); HDL was not associated. A similar pattern was found for MSSS worsening. Higher HDL levels (p < 0.001) were associated with lower contrast-enhancing lesion volume. Higher total cholesterol was associated with a trend for lower brain parenchymal fraction (p = 0.033).ConclusionsSerum lipid profile has modest effects on disease progression in MS. Worsening disability is associated with higher levels of LDL, total cholesterol and triglycerides. Higher HDL is associated with lower levels of acute inflammatory activity.

Relationship of optic nerve and brain conventional and non-conventional MRI measures and retinal nerve fiber layer thickness, as assessed by OCT and GDx: A pilot study

BACKGROUND Measurement of retinal nerve fiber layer (RNFL) thickness in multiple sclerosis (MS) is gaining increasing attention. OBJECTIVES To explore the relationship between RNFL thickness as measured by optical coherence tomography (OCT) and scanning laser polarimetry with variable corneal compensation (GDx), and conventional and non-conventional optic nerve and brain MRI measures. METHODS Twelve relapsing-remitting (RR) MS patients (12 affected and 12 unaffected eyes) and 4 age- and sex-matched normal controls (NC) (8 unaffected eyes) were enrolled. Four MS patients had a history of bilateral optic neuritis (ON), four had a history of unilateral ON, and 4 had no history of ON. Optic nerve MRI measurements included the length of T2 lesions, measurement of optic nerve atrophy, magnetization transfer ratio (MTR) and diffusion tensor imaging (DTI) measures. Optic nerve atrophy was measured by a novel method with high reproducibility. Brain MRI measurements included T1 and T2 lesion volumes (LVs) and their relative MTRs, and tissue class specific atrophy, MTR and DTI measures. Measures of RNFL were evaluated with OCT and GDx. We also evaluated both high and low contrast letter acuities (LCLA) in order to determine the relationship between vision, MRI metrics, and retinal structural architecture. RESULTS LCLA, RNFL-OCT and optic nerve radius measures showed more robust differences between NC and MS patients, and between MS patients with affected and unaffected eyes. T2-LV and T1-LV, as well as gray matter atrophy, DTI and MTR measures were related to LCLA and RNFL thickness. Unique additive variance regression models showed that both brain and optic nerve MRI measures independently accounted for about 50% of the variance in LCLA and RNFL thickness. In reverse models, about 20% of the additional independent variance was explained by optic nerve or brain MRI metrics. CONCLUSIONS Measurement of RNFL thickness and radius of the optic nerve should be preferred to the other optic nerve MRI measures in clinical studies. Whole brain lesion and GM measures are predictive of impaired visual function with corresponding structural concomitants.

Vitamin D metabolites are associated with clinical and MRI outcomes in multiple sclerosis patients

Purpose The associations between vitamin D and MRI measures of brain tissue injury have not been previously investigated in multiple sclerosis (MS). This research evaluates the significance of vitamin D and its active metabolites in brain tissue injury and clinical disability in MS patients. Methods The study population consisted of 193 MS patients (152 women and 41 men; mean age 46.1 (SD 8.4) years; disease duration 13.8 (SD 8.4) years). Serum levels of 25-hydroxyvitamin D3 (25(OH)VD3), 25-hydroxyvitamin D2 (25(OH)VD2), 1α, 25-dihydroxyvitamin D3 (1, 25(OH)2VD3) and 24(R), 25-dihydroxyvitamin D3 (24, 25(OH)2VD3) were measured using a novel capillary liquid–chromatography–mass spectrometry method. Disability was assessed with the Expanded Disability Status Scale (EDSS) and the MS Severity Scale (MSSS). MRI measures included T2 lesion volume (LV), T1-LV and brain parenchymal fraction. The associations between deseasonalised levels of vitamin D metabolites and clinical and MRI measurements were assessed using regression analyses. Results Lower deseasonalised levels of total 25(OH)VD (p=0.029), 25(OH)VD3 (p=0.032) and 24, 25(OH)2VD3 (p=0.005) were associated with higher MSSS. Similarly, lower deseasonalised levels of 24, 25(OH)2VD3 (p=0.012) were associated with higher EDSS. Higher values of the 25(OH)VD3 to 24, 25(OH)2VD3 ratio were associated with higher MSSS (p=0.041) and lower brain parenchymal fraction (p=0.008). Conclusions Vitamin D metabolites have protective associations with disability and brain atrophy in MS. In particular, the results indicate strong associations for the 24, 25(OH)2VD3 metabolite, which has not been extensively investigated in MS patients.

Evolution of different MRI measures in patients with active relapsing-remitting multiple sclerosis over 2 and 5 years: a case–control study

Background: There is growing evidence for the concept of multiple sclerosis (MS) as an inflammatory neurodegenerative disease, with a different pattern of atrophy evolution in grey matter (GM) and white matter (WM) tissue compartments. Objective: We aimed to investigate the evolution of different MRI measures in early relapsing-remitting patients with MS and in normal controls (NCs) over 2 years. We also evaluated the progression of these MRI measures in a subset of patients who were followed for up to 5 years. Methods: Included in this study were 147 patients who participated in the combination ASA (Avonex Steroids Azathioprine) study and completed full treatment, clinical and MRI assessment at 0, 12 and 24 months. A subgroup of 66 patients was followed for 36 months, 51 patients for 48 months and 43 patients for 60 months. Mean age at baseline was 30.7 years, mean disease duration was 5.5 years, mean EDSS was 1.8 and mean annualised relapse rate before study entry was 1.7. MRI scans were performed on a 1.5T scanner every 2 months for the first 2 years and thereafter once yearly for up to 5 years. In addition to the MS group, 27 NCs were examined at months 0, 12 and 24 using the same MRI protocol. Percentage brain volume change (PBVC), GM volume (GMV), WM volume (WMV) and peripheral grey volume (PGV) were measured annually using SIENA/X software. T2-hyperintense lesion volume (LV), lateral ventricle volume (LVV) and third ventricle width (3VW) were also assessed annually. Results: Over the period of 0–24 months, patients with MS lost significantly more GMV (−2.6% vs −0.72%, p<0.001), PGV (−2.4% vs −1.03%, p<0.001) and PBVC (−1.2% vs −0.22%, p<0.001), and increased in LVV (+16.6% vs +0.55%, p<0.003) and 3VW (+9.3% vs 0%, p = 0.003), when compared with NCs. Within-person change in MRI measures for patients with MS over 5 years was −4.2% for PBVC, −6.2% for GMV, −5.8% for PGV, −0.5% for WMV (all p<0.001), +68.7 for LVV (p<0.001), +4% for 3VW (p<0.001) and +42% for T2-LV (p<0.001). Conclusions: Our study confirmed a different pattern of GM, WM and central atrophy progression over 2 years between patients with MS and NCs. The study showed a different evolution of tissue compartment atrophy measures in patients with MS, with faster decline in cortical and deep GM regions, as well as periventricular WM regions, over a 5-year period.

Lipid profiles are associated with lesion formation over 24 months in interferon-β treated patients following the first demyelinating event

Objectives To investigate the associations of serum lipid profile with disease progression in high-risk clinically isolated syndromes (CIS) after the first demyelinating event. Methods High density lipoprotein cholesterol (HDL-C), low density lipoprotein cholesterol (LDL-C) and total cholesterol (TC) were obtained in pretreatment serum from 135 high risk patients with CIS (≥2 brain MRI lesions and ≥2 oligoclonal bands) enrolled in the Observational Study of Early Interferon β-1a Treatment in High Risk Subjects after CIS study (SET study), which prospectively evaluated the effect of intramuscular interferon β-1a treatment following the first demyelinating event. Thyroid stimulating hormone, free thyroxine, 25-hydroxy vitamin D3, active smoking status and body mass index were also obtained. Clinical and MRI assessments were obtained within 4 months of the initial demyelinating event and at 6, 12 and 24 months. Results The time to first relapse and number of relapses were not associated with any of the lipid profile variables. Higher LDL-C (p=0.006) and TC (p=0.001) levels were associated with increased cumulative number of new T2 lesions over 2 years. Higher free thyroxine levels were associated with lower cumulative number of contrast-enhancing lesions (p=0.008). Higher TC was associated as a trend with lower baseline whole brain volume (p=0.020). Higher high density lipoprotein was associated with higher deseasonalised 1,25-dihydroxy vitamin D3 (p=0.003) levels and a trend was found for deseasonalised 25-hydroxy vitamin D3 (p=0.014). Conclusions In early multiple sclerosis, lipid profile variables particularly LDL-C and TC levels are associated with inflammatory MRI activity measures.

Environmental factors associated with disease progression after the first demyelinating event: results from the multi-center SET study.

Objectives To investigate the associations of environmental MS risk factors with clinical and MRI measures of progression in high-risk clinically isolated syndromes (CIS) after the first demyelinating event. Methods We analyzed 211 CIS patients (age: 28.9±7.8 years) enrolled in the SET study, a multi-center study of high-risk CIS patients. Pre-treatment samples were analyzed for IgG antibodies against cytomegalovirus (anti-CMV), Epstein Barr virus (EBV) early nuclear antigen-1 (EBNA-1), viral capsid antigen (VCA), early antigen-diffuse (EA-D), 25 hydroxy-vitamin D3 and cotinine levels and HLA DRB1*1501 status. The inclusion criteria required evaluation within 4 months of the initial demyelinating event, 2 or more brain MRI lesions and the presence of two or more oligoclonal bands in cerebrospinal fluid. All patients were treated with interferon-beta. Clinical and MRI assessments were obtained at baseline, 6, 12, and 24 months. Results The time to first relapse decreased and the number of relapses increased with anti-CMV IgG positivity. Smoking was associated with increased number and volume of contrast-enhancing lesions (CEL) during the 2-year period. The cumulative number of CEL and T2 lesions during the 2-year period was greater for individuals in the highest quartile of anti-EBV VCA IgG antibodies. The percent loss of brain volume was increased for those in the highest quartile of with anti-EBV VCA IgG antibodies. Conclusions Relapses in CIS patients were associated with CMV positivity whereas anti-EBV VCA positivity was associated with progression on MRI measures, including accumulation of CEL and T2 lesions and development of brain atrophy.

Increased tissue damage and lesion volumes in African Americans with multiple sclerosis

Background: African American (AA) patients with multiple sclerosis (MS) have more rapid disease progression and poorer responses to disease-modifying therapies than white American (WA) patients with MS. Objectives: To investigate brain MRI characteristics in AA compared to WA in a cohort of consecutive patients with MS. Methods: We studied 567 patients with MS (age: 45.1 ± SD 9.8 years, disease duration: 13.4 ± 8.6 years), comprised of 488 WA and 79 AA. All patients obtained clinical and quantitative MRI evaluation. The majority of patients, 96% of AA and 94% of WA, were on disease-modifying therapies. The MRI measures included T1-, T2-, and gadolinium contrast-enhancing (CE) lesion volumes (LV) and CE number, global and tissue-specific brain atrophy, and magnetization transfer ratio (MTR) in lesions and normal-appearing gray matter (NAGM) and white matter (NAWM). The associations between race and clinical and MRI measurements were assessed in regression analysis. Results: The MTR values in lesions and in NAGM and NAWM were significantly lower in AA compared to WA. The AA group had 31% greater T2-LV and 101% greater T1-LV compared to WA. The MS Severity Score for AA (mean ± SD = 4.3 ± 2.9) was greater than for WA (3.8 ± 2.5), despite a shorter disease duration in AA, indicating more aggressive clinical disease. Conclusions: African American patients showed increased tissue damage, as measured by magnetization transfer ratio, and presented higher lesion volumes compared to white Americans. The greater tissue damage and faster lesion volume accumulation may explain the rapid clinical progression in African American patients.

Signal abnormalities on 1.5 and 3 Tesla brain MRI in multiple sclerosis patients and healthy controls. A morphological and spatial quantitative comparison study

Previous studies in patients with multiple sclerosis (MS) revealed increased lesion count and volume on 3 T compared to 1.5 T. Morphological and spatial lesion characteristics between 1.5 T and 3 T have not been examined. The aim of this study was to investigate the effect of changing from a 1.5 T to a 3 T MRI scanner on the number, volume and spatial distribution of signal abnormalities (SA) on brain MRI in a sample of MS patients and normal controls (NC), using pair- and voxel-wise comparison procedures. Forty-one (41) MS patients (32 relapsing-remitting and 9 secondary-progressive) and 38 NC were examined on both 1.5 T and 3 T within one week in random order. T2-weighted hyperintensities (T2H) and T1-weighted hypointensities (T1H) were outlined semiautomatically by two operators in a blinded fashion on 1.5 T and 3 T images. Spatial lesion distribution was assessed using T2 and T1 voxel-wise SA probability maps (SAPM). Pair-wise analysis examined the proportion of SA not simultaneously outlined on 1.5 T and 3 T. A posteriori unblinded analysis was conducted to examine the non-overlapping identifications of SA between the 1.5 T and 3 T. For pair-wise T2- and T1-analyses, a higher number and individual volume of SA were detected on 3 T compared to 1.5 T (p<0.0001) in both MS and NC. Logistic regression analysis showed that the likelihood of missing SA on 1.5 T was significantly higher for smaller SA in both MS and NC groups. SA probability map (SAPM) analysis revealed significantly more regionally distinct spatial SA differences on 3 T compared to 1.5 T in both groups (p<0.05); these were most pronounced in the occipital, periventricular and cortical regions for T2H. This study provides important information regarding morphological and spatial differences between data acquired using 1.5 T and 3 T protocols at the two scanner field strengths.