Niels Bergsland

Abnormal subcortical deep-gray matter susceptibility-weighted imaging filtered phase measurements in patients with multiple sclerosis: a case-control study.

OBJECTIVE To investigate abnormal phase on susceptibility-weighted imaging (SWI)-filtered phase images indicative of iron content, in subcortical deep-gray matter (SDGM) of multiple sclerosis (MS) patients and healthy controls (HC), and to explore its relationship with MRI outcomes. METHODS 169 relapsing-remitting (RR) and 64 secondary-progressive (SP) MS patients, and 126 age- and sex-matched HC were imaged on a 3T scanner. Mean phase of the abnormal phase tissue (MP-APT), normal phase tissue volume (NPTV) and normalized volume were determined for total SDGM, caudate, putamen, globus pallidus, thalamus, pulvinar nucleus of thalamus (PVN), hippocampus, amygdala, nucleus accumbens, red nucleus and substantia nigra. 63 HC were used for establishment of normal reference phase values, while additional 63 HC were used for blinded comparisons with MS patients. RESULTS Increased MP-APT, decreased normalized volume and decreased NPTV were detected in total SDGM, caudate, putamen, globus pallidus, thalamus and PVN in MS patients compared to HC (p<.0004). MS patients also showed decreased volume in hippocampus (<.0001) and decreased NPTV in the hippocampus, amygdala and accumbens (<.0004). SPMS patients had increased MP-APT, decreased volume and decreased NPTV in total SDGM, caudate and amygdala compared to RRMS (p<.005), while individual measure differences were also detected in putamen, thalamus, hippocampus and accumbens (p<.006). RRMS patients showed a significant relationship between increased MP-APT and increased lesion burden and more advanced brain atrophy (p<.004). CONCLUSIONS Abnormal phase, indicative of higher iron content was significantly increased in MS patients compared to HC, and was related to more severe lesion burden and brain atrophy.

Subcortical and Cortical Gray Matter Atrophy in a Large Sample of Patients with Clinically Isolated Syndrome and Early Relapsing-Remitting Multiple Sclerosis

Brain atrophy is commonly seen in patients with chronic MS. Here, the authors assessed 212 patients with clinically isolated syndrome and early RRMS for atrophy of gray matter. In both groups the cortex displayed no significant atrophy but the deep gray matter nuclei (caudate, thalamus, globus pallidus, putamen, and hippocampus) showed significant atrophy during the first 4 years of the disease. Deep gray matter atrophy may play a relevant role in patient symptoms and seems to appear and progress from the earliest stages of the disease. BACKGROUND AND PURPOSE: Recent studies have shown that selective regional, but not global, GM atrophy occurs from clinical onset to conversion to clinically definite MS. Our aim was to investigate the difference in the extent of SDGM and cortical atrophy in a large sample of patients with CIS and early RRMS and to explore the relationship between SDGM and cortical atrophy and other MR imaging and clinical outcomes. MATERIALS AND METHODS: Two hundred twelve patients with CIS recruited at the first clinical event (mean age, 29.3 years; median EDSS, 1.5; median disease duration, 3 months) and 177 patients with early RRMS (mean age, 30.7 years; median EDSS, 2.0; median disease duration, 47 months) were imaged on a 1.5T scanner by using a high-resolution 3D T1 spoiled gradient-recalled sequence. Volumetric data for SDGM structures were obtained by using FSL FIRST, while whole-brain, GM, white matter, cortical, and lateral ventricle volumes were estimated by using SIENAX software. Comparisons between the groups were adjusted for age and sex. RESULTS: Patients with early RRMS showed significantly lower SDGM but not cortical volumes compared with patients with CIS. The most apparent SDGM differences were evident in the caudate and thalamus (P < .0001), total SDGM (P = .0001), and globus pallidus (P = .01). Patients with CIS with a median T2 lesion volume >4.49 mL showed lower total SDGM, caudate, thalamus (P < .001), globus pallidus (P = .007), hippocampus (P = .004), and putamen (P = .01) volumes and higher lateral ventricle volume (P = .001) than those with a median T2 lesion volume <4.49 mL. Decreased thalamic volume showed the most consistent relationship with MR imaging outcomes (P < .0001) in patients with CIS. CONCLUSIONS: Significant SDGM, but not cortical, atrophy develops during the first 4 years of the RRMS. GM atrophy is relevant for disease progression from the earliest clinical stages.

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.

Thalamic Atrophy Is Associated with Development of Clinically Definite Multiple Sclerosis

PURPOSE To investigate the association between the development of thalamic and cortical atrophy and the conversion to clinically definite multiple sclerosis (CDMS) in patients with clinically isolated syndrome (CIS). MATERIALS AND METHODS This prospective study was approved by the institutional review board. Informed consent was given by 216 CIS patients, and patients were treated with 30 µg of intramuscular interferon β1a once a week. They were assessed with a magnetic resonance (MR) imaging examination at baseline, 6 months, 1 year, and 2 years. Patients were evaluated within 4 months of an initial demyelinating event, had two or more brain lesions on MR images, and had two or more oligoclonal bands in cerebrospinal fluid. MR imaging measures of progression included cumulative number and volume of contrast agent-enhanced (CE) new and enlarged T2 lesions, and changes in whole-brain, tissue-specific global, and regional gray matter volumes. Regression and mixed-effect model analyses were used. RESULTS Over 2 years, 92 of 216 patients (42.6%) converted to CDMS; 122 (56.5%) CIS patients fulfilled McDonald 2005 criteria and 153 (70.8%) fulfilled McDonald 2010 criteria for MR imaging dissemination in time and space. The mean time to first relapse was 3.1 months, and mean annual relapse rate was 0.46. In mixed-effect model analysis, the lateral ventricle volume (P = .005), accumulation of CE (P = .007), new total T2 (P = .009) and new enlarging T2 lesions (P = .01) increase, and thalamic (P = .009) and whole-brain (P = .019) volume decrease were associated with development of CDMS. In multivariate regression analysis, decrease in thalamic volumes and increase in lateral ventricle volumes (P = .009) were MR imaging variables associated with the development of CDMS. CONCLUSION Measurement of thalamic atrophy and increase in ventricular size in CIS is associated with CDMS development and should be used in addition to the assessment of new T2 and CE lesions.

Brain atrophy and disability progression in multiple sclerosis patients: a 10-year follow-up study.

Objectives To identify MRI biomarkers associated with long-term disability progression in patients with multiple sclerosis (MS), and to define the rate of evolution of global, tissue-specific and regional atrophy in patients with MS over long-term. Methods MRI of the brain and clinical neurological assessment was performed in 81 patients at time of first visit and after 5 and 10 years of follow-up. MRI was acquired on 1.5 T scanners. T1-lesion and T2-lesion volumes (LVs) were calculated. Global and tissue-specific atrophy changes were longitudinally assessed, using a direct measurement approach, by calculating percentage volume changes between different time points. Regional tissue volumes for the subcortical deep grey matter (SDGM) structures were also obtained. Disability progression was defined as an increase in Expanded Disability Status Scale of ≥1.0 compared to baseline at 5-year and 10-year follow-up. Results Over 5 years, patients with disability progression showed significantly increased loss of whole brain (−3.8% vs −2.0%, p<0.001), cortical (−3.4% vs −1.8%, p=0.009) and putamen volume changes (−10.6% vs −3.8%, p=0.003) compared to patients with no disability progression. No significant change in white matter (WM) volume was observed when comparing progressing and non-progressing patients. Over 10 years, there was a trend for greater decrease in whole brain volume (−5.5% vs −3.7%, p=0.015) in the progressing patients. No significant changes in LV measures were detected between the patients with and without disability progression. Conclusion This long-term study shows that whole brain, cortical and putamen atrophy occurs throughout the 10-year follow-up of this MS cohort and is more pronounced in the group that showed disability progression at 5, but not at 10 years of follow-up. Overall, GM atrophy showed better association with disease progression than WM atrophy over 5-year and 10-year follow-up.

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.

Hypoperfusion of brain parenchyma is associated with the severity of chronic cerebrospinal venous insufficiency in patients with multiple sclerosis: a cross-sectional preliminary report

BackgroundSeveral studies have reported hypoperfusion of the brain parenchyma in multiple sclerosis (MS) patients. We hypothesized a possible relationship between abnormal perfusion in MS and hampered venous outflow at the extracranial level, a condition possibly associated with MS and known as chronic cerebrospinal venous insufficiency (CCSVI).MethodsWe investigated the relationship between CCSVI and cerebral perfusion in 16 CCSVI MS patients and 8 age- and sex-matched healthy controls. Subjects were scanned in a 3-T scanner using dynamic susceptibility, contrast-enhanced, perfusion-weighted imaging. Cerebral blood flow (CBF), cerebral blood volume (CBV) and mean transit time (MTT) were measured in the gray matter (GM), white matter (WM) and the subcortical GM (SGM). The severity of CCSVI was assessed according to the venous hemodynamic insufficiency severity score (VHISS) on the basis of the number of venous segments exhibiting flow abnormalities.ResultsThere was a significant association between increased VHISS and decreased CBF in the majority of examined regions of the brain parenchyma in MS patients. The most robust correlations were observed for GM and WM (r = -0.70 to -0.71, P < 0.002 and P corrected = 0.022), and for the putamen, thalamus, pulvinar nucleus of thalamus, globus pallidus and hippocampus (r = -0.59 to -0.71, P < 0.01 and P corrected < 0.05). No results for correlation between VHISS and CBV or MTT survived multiple comparison correction.ConclusionsThis pilot study is the first to report a significant relationship between the severity of CCSVI and hypoperfusion in the brain parenchyma. These preliminary findings should be confirmed in a larger cohort of MS patients to ensure that they generalize to the MS population as a whole. Reduced perfusion could contribute to the known mechanisms of virtual hypoxia in degenerated axons.

Randomized study of interferon beta-1a, low-dose azathioprine,and low-dose corticosteroids in multiple sclerosis

Background Studies evaluating interferon beta (IFNβ) for multiple sclerosis (MS) showed only partial efficacy. In many patients, IFNβ does not halt relapses or disability progression. One strategy to potentially enhance efficacy is to combine IFNβ with classical immunosuppressive agents, such as azathioprine (AZA) or corticosteroids, commonly used for other autoimmune disorders. Objective The Avonex–Steroids–Azathioprine study was placebo-controlled trial and evaluated efficacy of IFNβ-1a alone and combined with low-dose AZA alone or low-dose AZA and low-dose corticosteroids as initial therapy. Methods A total of 181 patients with relapsing–remitting MS (RRMS) were randomized to receive IFNβ-1a 30 μg intramuscularly (IM) once weekly, IFNβ-1a 30 μg IM once weekly plus AZA 50 mg orally once daily, or IFNβ-1a 30 μg IM once weekly plus AZA 50 mg orally once daily plus prednisone 10 mg orally every other day. The primary end point was annualized relapse rate (ARR) at 2 years. Patients were eligible for enrollment in a 3-year extension. Results At 2 years, adjusted ARR was 1.05 for IFNβ-1a, 0.91 for IFNβ-1a plus AZA, and 0.73 for combination. The cumulative probability of sustained disability progression was 16.8% for IFNβ-1a, 20.7% for IFNβ-1a plus AZA, and 17.5% for combination. There were no statistically significant differences among groups for either measure at 2 and 5 years. Percent T2 lesion volume change at 2 years was significantly lower for combination (+14.5%) versus IFNβ-1a alone (+30.3%, P < 0.05). Groups had similar safety profiles. Conclusion In IFNβ-naïve patients with early active RRMS, combination treatment did not show superiority over IFNβ-1a monotherapy.

Gray matter atrophy and disability progression in patients with early relapsing-remitting multiple sclerosis A 5-year longitudinal study

We assessed the relationship between gray matter (GM) and white matter (WM) atrophy and clinical status in early relapsing-remitting multiple sclerosis (MS) patients over 5 years. A group of 181 patients who participated in the ASA (Avonex-Steroid-Azathioprine) study and had complete clinical and MRI assessments over 2 and 5 years was investigated. One hundred seventy (170) patients completed the 12-month follow-up, 147 the 24-month, 98 the 36-month, 65 the 48-month and 47 the 60-month. Changes in GM (GMV), WM (WMV) and peripheral GM (PGV) volumes, whole brain volume (percentage brain volume change PBVC), lateral ventricle volume (LVV), third ventricle width (3VW) and T2-lesion volume (T2-LV) were measured. Patients were assigned according to their clinical status to one of two groups: the Stable group, and the Reached Confirmed Sustained Progression (RCSP) group (24-week interval). At 0-6 months PBVC and GMV, at 0-12 months PBVC, GMV and T2-LV, at 0-24 months PBVC and GMV, at 0-36 months PBVC, GMV and T2-LV, and at 0-48 PBVC predicted the differences between the RCSP and Stable groups. PBVC and LVV showed the strongest ability to differentiate patients who presented 0 or >or=3 relapses in the Stable group. Decline in PBVC and GMV were predictive markers of disability deterioration. Correlation of T2-LV with clinical status was weaker and decreased over time. Higher number of relapses was associated with faster decline in whole brain volume.