Jesper Hagemeier

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.

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.

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.

Iron deposition in multiple sclerosis lesions measured by susceptibility-weighted imaging filtered phase: A case control study

To investigate phase lesions identified on susceptibility‐weighted imaging (SWI)‐filtered phase images in patients with multiple sclerosis (MS), clinically isolated syndrome (CIS) and healthy controls (HC). To relate phase lesion characteristics to other clinical and MRI outcomes.

Iron deposition on SWI-filtered phase in the subcortical deep gray matter of patients with clinically isolated syndrome may precede structure-specific atrophy.

BACKGROUND AND PURPOSE: Increasing evidence suggests that iron deposition is present in the later stages of MS. In this study we examined abnormal phase values, indicative of increased iron content on SWI-filtered phase images of the SDGM in CIS patients and HC. We also examined the association of abnormal phase with conventional MR imaging outcomes at first clinical onset. MATERIALS AND METHODS: Forty-two patients with CIS (31 female, 11 male) and 65 age and sex-matched HC (41 female, 24 male) were scanned on a 3T scanner. Mean age was 40.1 (SD = 10.4) years in patients with CIS, and 42.8 (SD = 14) years in HC, while mean disease duration was 1.2 years (SD = 1.3) in patients with CIS. MP-APT, NPTV, and normalized volume measurements were derived for all SDGM structures. Parametric and nonparametric group-wise comparisons were performed, and associations were determined with other MR imaging metrics. RESULTS: Patients with CIS had significantly increased MP-APT (P = .029) and MP-APT volume (P = .045) in the pulvinar nucleus of the thalamus compared with HC. Furthermore, the putamen (P = .004), caudate (P = .035), and total SDGM (P = .048) displayed significant increases in MP-APT volume, while MP-APT was also significantly increased in the putamen (P = .029). No global or regional volumetric MR imaging differences were found between the study groups. Significant correlations were observed between increased MP-APT volumes of total SDGM, caudate, thalamus, hippocampus, and substantia nigra with white matter atrophy and increased T2 lesion volume (P < .05). CONCLUSION: Patients with CIS showed significantly increased content and volume of iron, as determined by abnormal SWI-phase measurement, in the various SDGM structures, suggesting that iron deposition may precede structure-specific atrophy.

Risk factors for chronic cerebrospinal venous insufficiency (CCSVI) in a large cohort of volunteers.

Background The role of intra- and extra-cranial venous system impairment in the pathogenesis of various vascular, inflammatory and neurodegenerative neurological disorders, as well as in aging, has not been studied in detail. Nor have risk factors been determined for increased susceptibility of venous pathology in the intra-cranial and extra-cranial veins. The aim of this study was to investigate the association between presence of a newly proposed vascular condition called chronic cerebrospinal venous insufficiency (CCSVI) and environmental factors in a large volunteer control group without known central nervous system pathology. Methods and Findings The data were collected in a prospective study from 252 subjects who were screened for medical history as part of the entry criteria and participated in the case-control study of CCSVI prevalence in multiple sclerosis (MS) patients, and then were analyzed post-hoc. All participants underwent physical and Doppler sonography examinations, and were assessed with a structured environmental questionnaire. Fullfilment of ≥2 positive venous hemodynamic (VH) criteria on Doppler sonography was considered indicative of CCSVI diagnosis. Risk and protective factors associated with CCSVI were analyzed using logistic regression analysis. Seventy (27.8%) subjects presented with CCSVI diagnosis and 153 (60.7%) presented with one or more VH criteria. The presence of heart disease (p = .001), especially heart murmurs (p = .007), a history of infectious mononucleosis (p = .002), and irritable bowel syndrome (p = .005) were associated with more frequent CCSVI diagnosis. Current or previous smoking (p = .029) showed a trend for association with more frequent CCSVI diagnosis, while use of dietary supplements (p = .018) showed a trend for association with less frequent CCSVI diagnosis. Conclusions Risk factors for CCSVI differ from established risk factors for peripheral venous diseases. Vascular, infectious and inflammatory factors were associated with higher CCSVI frequency.

Brain iron accumulation in aging and neurodegenerative disorders

Over the decades, various studies have established an association between accumulation of iron and both aging and neurodegenerative disorders such as Alzheimer’s disease and Parkinson’s disease. Excess levels of iron can lead to increased oxidative stress through Fenton chemistry, and depletion of iron can similarly have deleterious effects. In addition, metal ions are known to be involved in both Alzheimer’s disease and Parkinson’s disease protein aggregation. Metal ion chelators have been extensively investigated in preclinical models, and may prove to be appropriate for modulating brain iron levels in age-related neurodegenerative disorders. Investigating age-related iron deposition is vital, and can possibly aid in determining at-risk groups and diagnosing neurodegenerative diseases at an early stage. Novel imaging methods have enabled researchers to examine iron deposition in vivo, and offer a noninvasive method of monitoring the progression of accumulation, and possible therapeutic effects of chelating compounds.

Higher weight in adolescence and young adulthood is associated with an earlier age at multiple sclerosis onset

Background: Growing evidence suggests an association between adolescent obesity and increased risk of multiple sclerosis (MS). Objective: The objective of this paper is to investigate whether weight or body mass index (BMI) in adolescence and young adulthood was associated with age at MS symptom onset. Methods: Our cohort is comprised of a sub-group of 184 women enrolled in the New York State MS Consortium registry. Individuals were asked to recall their weight at the time of first menstruation and at age 25. BMI was calculated accordingly for age 25. Regression analyses were carried out to investigate the association between weight or BMI and age at onset. Results: Weight at menarche was significantly related to younger age at symptom onset (β = −0.073, p = 0.001). These results were also found at age 25 for weight (β = −0.080, p < 0.001) and BMI (β = −0.448, p = 0.001). Significantly earlier disease onset (26.9 years ±9.9) was observed in individuals who were overweight at 25 compared to those who were not overweight (32.1 years ±9.2, p = 0.006). Conclusions: Women who reported higher weight in adolescence and BMI in early adulthood were younger at MS onset. Future research should investigate whether there is a causal link between body weight and MS, as prevention lifestyle and dietary interventions could be implemented.

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.