Disability Improvement Is Associated with Less Brain Atrophy Development in Multiple Sclerosis.

BACKGROUND AND PURPOSE: It is unknown whether deceleration of brain atrophy is associated with disability improvement in patients with MS. Our aim was to investigate whether patients with MS with disability improvement develop less brain atrophy compared with those who progress in disability or remain stable. MATERIALS AND METHODS: We followed 980 patients with MS for a mean of 4.8 ± 2.4 years. Subjects were divided into 3 groups: progress in disability (n = 241, 24.6%), disability improvement (n = 101, 10.3%), and stable (n = 638, 65.1%) at follow-up. Disability improvement and progress in disability were defined on the basis of the Expanded Disability Status Scale score change using standardized guidelines. Stable was defined as nonoccurrence of progress in disability or disability improvement. Normalized whole-brain volume was calculated using SIENAX on 3D T1WI, whereas the lateral ventricle was measured using NeuroSTREAM on 2D-T2-FLAIR images. The percentage brain volume change and percentage lateral ventricle volume change were calculated using SIENA and NeuroSTREAM, respectively. Differences among groups were investigated using ANCOVA, adjusted for age at first MR imaging, race, T2 lesion volume, and corresponding baseline structural volume and the Expanded Disability Status Scale. RESULTS: At first MR imaging, there were no differences among progress in disability, disability improvement, and the stable groups in whole-brain volume (P = .71) or lateral ventricle volume (P = .74). During follow-up, patients with disability improvement had the lowest annualized percentage lateral ventricle volume change (1.6% ± 2.7%) followed by patients who were stable (2.1% ± 3.7%) and had progress in disability (4.1% ± 5.5%), respectively (P < .001). The annualized percentage brain volume change values were -0.7% ± 0.7% for disability improvement, -0.8% ± 0.7% for stable, and -1.1% ± 1.1% for progress in disability (P = .001). CONCLUSIONS: Patients with MS who improve in their clinical disability develop less brain atrophy across time compared with those who progress.

A Serial 10-Year Follow-Up Study of Atrophied Brain Lesion Volume and Disability Progression in Patients with Relapsing-Remitting MS.

BACKGROUND AND PURPOSE: Disappearance of T2 lesions into CSF spaces is frequently observed in patients with MS. Our aim was to investigate temporal changes of cumulative atrophied brain T2 lesion volume and 10-year confirmed disability progression. MATERIALS AND METHODS: We studied 176 patients with relapsing-remitting MS who underwent MR imaging at baseline, 6 months, and then yearly for 10 years. Occurrence of new/enlarging T2 lesions, changes in T2 lesion volume, and whole-brain, cortical and ventricle volumes were assessed yearly between baseline and 10 years. Atrophied T2 lesion volume was calculated by combining baseline lesion masks with follow-up CSF partial volume maps. Ten-year confirmed disability progression was confirmed after 48 weeks. ANCOVA detected MR imaging outcome differences in stable (n = 76) and confirmed disability progression (n = 100) groups at different time points; hierarchic regression determined the unique additive variance explained by atrophied T2 lesion volume regarding the association with confirmed disability progression, in addition to other MR imaging metrics. Cox regression investigated the association of early MR imaging outcome changes and time to development of confirmed disability progression. RESULTS: The separation of stable-versus-confirmed disability progression groups became significant even in the first 6 months for atrophied T2 lesion volume (140% difference, Cohen d = 0.54, P = .004) and remained significant across all time points (P ≤ .007). The hierarchic model, including all other MR imaging outcomes during 10 years predicting confirmed disability progression, improved significantly after adding atrophied T2 lesion volume (R 2 = 0.27, R 2 change 0.11, P = .009). In Cox regression, atrophied T2 lesion volume in 0-6 months (hazard ratio = 4.23, P = .04) and 0-12 months (hazard ratio = 2.41, P = .022) was the only significant MR imaging predictor of time to confirmed disability progression. CONCLUSIONS: Atrophied T2 lesion volume is a robust and early marker of disability progression in relapsing-remitting MS.

Brain Atrophy Is Associated with Disability Progression in Patients with MS followed in a Clinical Routine.

BACKGROUND AND PURPOSE: The assessment of brain atrophy in a clinical routine is not performed routinely in multiple sclerosis. Our aim was to determine the feasibility of brain atrophy measurement and its association with disability progression in patients with MS followed in a clinical routine for 5 years. MATERIALS AND METHODS: A total of 1815 subjects, 1514 with MS and 137 with clinically isolated syndrome and 164 healthy individuals, were collected retrospectively. Of 11,794 MR imaging brain scans included in the analysis, 8423 MRIs were performed on a 3T, and 3371 MRIs, on a 1.5T scanner. All patients underwent 3D T1WI and T2-FLAIR examinations at all time points of the study. Whole-brain volume changes were measured by percentage brain volume change/normalized brain volume change using SIENA/SIENAX on 3D T1WI and percentage lateral ventricle volume change using NeuroSTREAM on T2-FLAIR. RESULTS: Percentage brain volume change failed in 36.7% of the subjects; percentage normalized brain volume change, in 19.2%; and percentage lateral ventricle volume change, in 3.3% because of protocol changes, poor scan quality, artifacts, and anatomic variations. Annualized brain volume changes were significantly different between those with MS and healthy individuals for percentage brain volume change (P < .001), percentage normalized brain volume change (P = .002), and percentage lateral ventricle volume change (P = .01). In patients with MS, mixed-effects model analysis showed that disability progression was associated with a 21.9% annualized decrease in percentage brain volume change (P < .001) and normalized brain volume (P = .002) and a 33% increase in lateral ventricle volume (P = .004). CONCLUSIONS: All brain volume measures differentiated MS and healthy individuals and were associated with disability progression, but the lateral ventricle volume assessment was the most feasible.

Impact of Focal White Matter Damage on Localized Subcortical Gray Matter Atrophy in Multiple Sclerosis: A 5-Year Study.

BACKGROUND AND PURPOSE: It is unclear to what extent subcortical gray matter atrophy is a primary process as opposed to a result of focal white matter damage. Correlations between WM damage and atrophy of subcortical gray matter have been observed but may be partly attributable to indirect relationships between co-occurring processes arising from a common cause. Our aim was to cross-sectionally and longitudinally characterize the unique impact of focal WM damage on the atrophy of connected subcortical gray matter regions, beyond what is explainable by global disease progression. MATERIALS AND METHODS: One hundred seventy-six individuals with MS and 47 healthy controls underwent MR imaging at baseline and 5 years later. Atrophy and lesion-based disruption of connected WM tracts were evaluated for 14 subcortical gray matter regions. Hierarchic regressions were applied, predicting regional atrophy from focal WM disruption, controlling for age, sex, disease duration, whole-brain volume, and T2-lesion volume. RESULTS: When we controlled for whole-brain volume and T2-lesion volume, WM tract disruption explained little additional variance of subcortical gray matter atrophy and was a significant predictor for only 3 of 14 regions cross-sectionally (ΔR2 = 0.004) and 5 regions longitudinally (ΔR2 = 0.016). WM tract disruption was a significant predictor for even fewer regions when correcting for multiple comparisons. CONCLUSIONS: WM tract disruption accounts for a small percentage of atrophy in connected subcortical gray matter when controlling for overall disease burden and is not the primary driver in most cases.

Evaluation of Leptomeningeal Contrast Enhancement Using Pre-and Postcontrast Subtraction 3D-FLAIR Imaging in Multiple Sclerosis.

BACKGROUND AND PURPOSE: Leptomeningeal contrast enhancement is found in patients with multiple sclerosis, though reported rates have varied. The use of 3D-fluid-attenuated inversion recovery pre- and postcontrast subtraction imaging may more accurately determine the frequency of leptomeningeal contrast enhancement. The purpose of this study was to investigate the frequency of leptomeningeal contrast enhancement using the pre- and postcontrast subtraction approach and to evaluate 3 different methods of assessing the presence of leptomeningeal contrast enhancement. MATERIALS AND METHODS: We enrolled 258 consecutive patients with MS (212 with relapsing-remitting MS, 32 with secondary-progressive MS, and 14 with clinically isolated syndrome) who underwent both pre- and 10-minute postcontrast 3D-FLAIR sequences after a single dose of gadolinium injection on 3T MR imaging. The analysis included leptomeningeal contrast-enhancement evaluation on 3D-FLAIR postcontrast images in native space (method A), on pre- and postcontrast 3D-FLAIR images in native space (method B), and on pre-/postcontrast 3D-FLAIR coregistered and subtracted images (method C, used as the criterion standard). RESULTS: In total, 51 (19.7%) patients with MS showed the presence of leptomeningeal contrast enhancement using method A; 39 (15.1%), using method B; and 39 (15.1%), using method C (P = .002). Compared with method C as the criterion standard, method A showed 89.8% sensitivity and 92.7% specificity, while method B showed 84.6% sensitivity and 97.3% specificity (P < .001) at the patient level. Reproducibility was the highest using method C (κ agreement, r = 088, P < .001). The mean time to analyze the 3D-FLAIR images was significantly lower with method C compared with methods A and B (P < .001). CONCLUSIONS: 3D-FLAIR postcontrast imaging offers a sensitive method for detecting leptomeningeal contrast enhancement in patients with MS. However, the use of subtraction imaging helped avoid false-positive cases, decreased reading time, and increased the accuracy of leptomeningeal contrast-enhancement foci detection in a clinical routine.

Feasibility of Brain Atrophy Measurement in Clinical Routine without Prior Standardization of the MRI Protocol: Results from MS-MRIUS, a Longitudinal Observational, Multicenter Real-World Outcome Study in Patients with Relapsing-Remitting MS.

BACKGROUND AND PURPOSE: Feasibility of brain atrophy measurement in patients with MS in clinical routine, without prior standardization of the MRI protocol, is unknown. Our aim was to investigate the feasibility of brain atrophy measurement in patients with MS in clinical routine. MATERIALS AND METHODS: Multiple Sclerosis and Clinical Outcome and MR Imaging in the United States (MS-MRIUS) is a multicenter (33 sites), retrospective study that included patients with relapsing-remitting MS who began treatment with fingolimod. Brain MR imaging examinations previously acquired at the baseline and follow-up periods on 1.5T or 3T scanners with no prior standardization were used, to resemble a real-world situation. Brain atrophy outcomes included the percentage brain volume change measured by structural image evaluation with normalization of atrophy on 2D-T1-weighted imaging and 3D-T1WI and the percentage lateral ventricle volume change, measured by VIENA on 2D-T1WI and 3D-T1WI and NeuroSTREAM on T2-fluid-attenuated inversion recovery examinations. RESULTS: A total of 590 patients, followed for 16 months, were included. There were 585 (99.2%) T2-FLAIR, 425 (72%) 2D-T1WI, and 166 (28.2%) 3D-T1WI longitudinal pairs of examinations available. Excluding MR imaging examinations with scanner changes, the analyses were available on 388 (65.8%) patients on T2-FLAIR for the percentage lateral ventricle volume change, 259 and 257 (43.9% and 43.6%, respectively) on 2D-T1WI for the percentage brain volume change and the percentage lateral ventricle volume change, and 110 (18.6%) on 3D-T1WI for the percentage brain volume change and percentage lateral ventricle volume change. The median annualized percentage brain volume change was -0.31% on 2D-T1WI and -0.38% on 3D-T1WI. The median annualized percentage lateral ventricle volume change was 0.95% on 2D-T1WI, 1.47% on 3D-T1WI, and 0.90% on T2-FLAIR. CONCLUSIONS: Brain atrophy was more readily assessed by estimating the percentage lateral ventricle volume change on T2-FLAIR compared with the percentage brain volume change or percentage lateral ventricle volume change using 2D- or 3D-T1WI in this observational retrospective study. Although measurement of the percentage brain volume change on 3D-T1WI remains the criterion standard and should be encouraged in future prospective studies, T2-FLAIR-derived percentage lateral ventricle volume change may be a more feasible surrogate when historical or other practical constraints limit the availability of percentage brain volume change on 3D-T1WI.

Effect of natalizumab on brain atrophy and disability progression in multiple sclerosis patients over 5 years.

BACKGROUND AND PURPOSE: The long-term benefit of natalizumab on brain atrophy progression in multiple sclerosis (MS) patients is unknown. Our aim was to investigate its effect over 5 years. METHODS: This prospective study included 60 relapsing MS patients who started natalizumab treatment in years 2006-2007. RESULTS: At the 5-year follow-up, 20 patients discontinued natalizumab after an average of 29.5 cycles, 27 continued natalizumab treatment with some periods of honeymoon (average of 38.4 infusions) and 13 never stopped natalizumab (average of 60.6 infusions). In multiple linear regression analysis, adjusted for age, sex and baseline magnetic resonance imaging (MRI) status, the number of natalizumab infusions was associated with decrease of relapse rate (adjusted P = 0.037), but no association was found with the progression of disability, accumulation of lesion burden or brain volume loss. However, only one (8%) patient in the continuous monthly group experienced disability progression compared to 10 (37%) in the non-continuous and seven (35%) in the discontinuation natalizumab groups. At the follow-up, two patients had died [one from a fatal case of progressive multifocal leukoencephalopathy (PML) and one from a car accident] and 15 patients were lost to follow-up. There was another case of non-fatal PML over the follow-up. CONCLUSIONS: In line with previous reports, MS patients with longer and continuous use of natalizumab had fewer relapses and remained stable in their disability status. No difference in lesion burden accumulation or brain atrophy development was found in relation to the duration of natalizumab use. PML occurred in 2.5% of patients in this small sample cohort. Given the increased risk of PML and uncertain benefit of prolonged natalizumab use on clinical and MRI outcomes of disease progression found in this study, a careful risk-benefit therapeutic assessment is mandatory.

Autoimmune Comorbidities Are Associated with Brain Injury in Multiple Sclerosis.

BACKGROUND AND PURPOSE: The effect of comorbidities on disease severity in MS has not been extensively characterized. We determined the association of comorbidities with MR imaging disease severity outcomes in MS. MATERIALS AND METHODS: Demographic and clinical history of 9 autoimmune comorbidities confirmed by retrospective chart review and quantitative MR imaging data were obtained in 815 patients with MS. The patients were categorized on the basis of the presence/absence of total and specific comorbidities. We analyzed the MR imaging findings, adjusting for key covariates and correcting for multiple comparisons. RESULTS: Two hundred forty-one (29.6%) study subjects presented with comorbidities. Thyroid disease had the highest frequency (n = 97, 11.9%), followed by asthma (n = 41, 5%), type 2 diabetes mellitus (n = 40, 4.9%), psoriasis (n = 33, 4%), and rheumatoid arthritis (n = 22, 2.7%). Patients with MS with comorbidities showed decreased whole-brain and cortical volumes (P < .001), gray matter volume and magnetization transfer ratio of normal-appearing brain tissue (P < .01), and magnetization transfer ratio of gray matter (P < .05). Psoriasis, thyroid disease, and type 2 diabetes mellitus comorbidities were associated with decreased whole-brain, cortical, and gray matter volumes (P < .05). Psoriasis was associated with a decreased magnetization transfer ratio of normal-appearing brain tissue (P < .05), while type 2 diabetes mellitus was associated with increased mean diffusivity (P < .01). CONCLUSIONS: The presence of comorbidities in patients with MS is associated with brain injury on MR imaging. Psoriasis, thyroid disease, and type 2 diabetes mellitus comorbidities were associated with more severe nonconventional MR imaging outcomes.

Cognitive and White Matter Tract Differences in MS and Diffuse Neuropsychiatric Systemic Lupus Erythematosus.

BACKGROUND AND PURPOSE: Multiple sclerosis and neuropsychiatric systemic lupus erythematosus are autoimmune diseases with similar CNS inflammatory and neurodegenerative characteristics. Our aim was to investigate white matter tract changes and their association with cognitive function in patients with MS and those with neuropsychiatric systemic lupus erythematosus compared with healthy controls by using diffusion tensor imaging. MATERIALS AND METHODS: Thirty patients with relapsing-remitting MS and 23 patients with neuropsychiatric systemic lupus erythematosus matched for disease severity and duration and 43 healthy controls were scanned with 3T MR imaging. The DTI was postprocessed, corrected for lesions, and analyzed with tract-based spatial statistics. Cognitive assessment included examination of processing speed; visual, auditory/verbal, and visual-spatial memory; and sustained attention and executive function. Differences were considered significant at P < .05. RESULTS: Tract-based spatial statistics analysis revealed significantly decreased fractional anisotropy and increased mean diffusivity in patients with MS compared with healthy controls, decreased fractional anisotropy in patients with MS compared with those with neuropsychiatric systemic lupus erythematosus, and an increased mean diffusivity in patients with neuropsychiatric systemic lupus erythematosus compared with healthy controls. Patients with MS showed decreased fractional anisotropy throughout central WM pathways, including the corpus callosum and the inferior longitudinal and fronto-occipital fasciculi compared with those with neuropsychiatric systemic lupus erythematosus. Altered cognitive scores in patients with MS were significantly associated with decreased fractional anisotropy and increased mean diffusivity in all examined domains, while in patients with diffuse neuropsychiatric systemic lupus erythematosus, only decreased fractional anisotropy in the superior WM pathways showed significant association with executive function. CONCLUSIONS: Patients with MS and neuropsychiatric systemic lupus erythematosus showed widespread WM tract alterations outside overt lesions, though more severe changes were identified in patients with MS. The WM tract changes were associated with cognitive dysfunction in all explored domains only in patients with MS.

Longitudinal Mixed-Effect Model Analysis of the Association between Global and Tissue-Specific Brain Atrophy and Lesion Accumulation in Patients with Clinically Isolated Syndrome.

BACKGROUND AND PURPOSE: The relationship between lesion formation and brain atrophy development in the early phase of multiple sclerosis is unclear. We investigated the association between new lesion accumulation and brain atrophy progression in patients with clinically isolated syndrome over 48 months. MATERIALS AND METHODS: Patients with clinically isolated syndrome (n = 210) were evaluated with 1.5T MR imaging at baseline and at 6, 12, 24, 36, and 48 months as part of a multicenter observational study of early administration of intramuscular interferon ß-1a. Mixed-effect model analyses, adjusted for age, sex, and treatment status, investigated the association between accumulation of contrast-enhancing and T2 lesions and brain-volume percent changes in a 48-month period. RESULTS: In patients with clinically isolated syndrome, the average whole-brain volume decreased 2.5%, the mean lateral ventricle volume increased 16.9%, and a mean of 7.7 new/enlarging T2 lesions accumulated over the follow-up period. Patients with clinically isolated syndrome who showed greater percentages of change in whole-brain, white and gray matter, cortical, and lateral ventricle volumes over the follow-up period had more severe lesion outcomes at baseline (all P < .007). There were significant associations between decreased individual brain-volume measures at baseline and greater percentages of change during follow-up (P < .05). We found a significant association between the total cumulative number of new/enlarging T2 lesions and the evolution of whole-brain (P < .001), lateral ventricle (P = .007), gray matter and thalamic (P = .013), subcortical deep gray matter (P = .015), and cortical (P = .036) volumes over the follow-up period. CONCLUSIONS: Lesion accumulation and brain-volume changes occur simultaneously in the early phase of clinically isolated syndrome. More severe lesion and brain-volume outcomes at baseline were associated with greater development of brain atrophy over the follow-up period in patients with clinically isolated syndrome.

Iron and volume in the deep gray matter: association with cognitive impairment in multiple sclerosis.

BACKGROUND AND PURPOSE: There is a well-established correlation between deep gray matter atrophy and cognitive dysfunction in MS. However, the cause of these signs of neurodegeneration is poorly understood. Iron accumulation in the deep gray matter is higher in patients with MS compared with age- and sex-matched healthy controls, and could contribute to disease progression. Our objective was to evaluate the relationship between iron and cognition in several deep gray matter structures while accounting for the influence of volume loss. MATERIALS AND METHODS: Eighty-five patients with MS and 27 healthy volunteers underwent 3T MR imaging and neuropsychological examination. We used SWI filtered phase to analyze the mean phase of low-phase voxels, indicative of abnormal iron accumulation. RESULTS: Correlations between mean phase of low-phase voxels and cognitive tests were found in the caudate nucleus (r = 0.240 and 0.232), putamen (r = 0.368, 0.252, and 0.238), globus pallidus (r = 0.235), and pulvinar nucleus of thalamus (r = 0.244, 0.255, and 0.251) (P < .05). However, correlations between structure volume and cognition were more robust. Furthermore, the introduction of structure volume into hierarchical regression analyses after iron metrics significantly improved most models, and mean phase of low-phase voxels did not account for significant variance after volume. CONCLUSIONS: These findings suggest that iron accumulation plays a significant, if minor, role in MS cognitive decline.

Subcortical atrophy is associated with cognitive impairment in mild Parkinson disease: a combined investigation of volumetric changes, cortical thickness, and vertex-based shape analysis.

BACKGROUND AND PURPOSE: The involvement of subcortical deep gray matter and cortical thinning associated with mild Parkinson disease remains poorly understood. We assessed cortical thickness and subcortical volumes in patients with Parkinson disease without dementia and evaluated their associations with cognitive dysfunction. MATERIALS AND METHODS: The study included 90 patients with mild Parkinson disease without dementia. Neuropsychological assessments classified the sample into patients with mild cognitive impairment (n = 25) and patients without cognitive impairment (n = 65). Volumetric data for subcortical structures were obtained by using the FMRIB Integrated Registration and Segmentation Tool while whole-brain, gray and white matter volumes were estimated by using Structural Image Evaluation, with Normalization of Atrophy. Vertex-based shape analyses were performed to investigate shape differences in subcortical structures. Vertex-wise group differences in cortical thickness were also assessed. Volumetric comparisons between Parkinson disease with mild cognitive impairment and Parkinson disease with no cognitive impairment were performed by using ANCOVA. Associations of subcortical structures with both cognitive function and disease severity were assessed by using linear regression models. RESULTS: Compared with Parkinson disease with no cognitive impairment, Parkinson disease with mild cognitive impairment demonstrated reduced volumes of the thalamus (P = .03) and the nucleus accumbens (P = .04). Significant associations were found for the nucleus accumbens and putamen with performances on the attention/working memory domains (P < .05) and nucleus accumbens and language domains (P = .04). The 2 groups did not differ in measures of subcortical shape or in cortical thickness. CONCLUSIONS: Patients with Parkinson disease with mild cognitive impairment demonstrated reduced subcortical volumes, which were associated with cognitive deficits. The thalamus, nucleus accumbens, and putamen may serve as potential biomarkers for Parkinson disease-mild cognitive impairment.

Retinal nerve fiber layer thickness and thalamus pathology in multiple sclerosis patients.

BACKGROUND AND PURPOSE: Visual impairments are frequent in multiple sclerosis (MS). Optic neuritis can directly reduce retinal nerve fiber layer (RNFL) thickness. Our objectives were to evaluate associations of the RNFL thickness (RNFLT) of MS patients with magnetic resonance imaging (MRI) measures of regional brain atrophy and tissue injury in the post-chiasmatic deep gray matter (GM) section of the visual pathway. METHODS: Retinal nerve fiber layer thickness was measured using optical coherence tomography (OCT) in 96 relapsing-remitting MS (RR-MS) patients and 46 controls. MRI was obtained within ±3 months of OCT. RNFLT associations with MRI measures from diffusion tensor imaging and regional and tissue specific atrophy were assessed. RESULTS: In RR-MS, lower RNFLT was associated with lower white matter volume and lower whole brain volume. Lower RNFLT was associated with lower total deep gray matter volume and lower thalamus volume. Lower RNFLT was associated with greater mean diffusivity (MD) in normal appearing (NA) brain tissue and NA gray matter. Trends were found for lower RNFLT with greater MD in NA white matter and thalamus. RNFLT in controls was not associated with MD. CONCLUSIONS: Lower RNFLT is associated with microscopic tissue injury in NA regions of the brain and with neurodegeneration of the deep gray matter and thalamus in RR-MS.

Subcortical deep gray matter pathology in patients with multiple sclerosis is associated with white matter lesion burden and atrophy but not with cortical atrophy: a diffusion tensor MRI study.

BACKGROUND AND PURPOSE: The association between subcortical deep gray matter, white matter, and cortical pathology is not well understood in MS. The aim of this study was to use DTI to investigate the subcortical deep gray matter alterations and their relationship with lesion burden, white matter, and cortical atrophy in patients with MS and healthy control patients. MATERIALS AND METHODS: A total of 210 patients with relapsing-remitting MS, 75 patients with progressive MS, and 110 healthy control patients were included in the study. DTI metrics in whole brain, normal-appearing white matter, normal-appearing gray matter, and subcortical deep gray matter structures were compared. The association between DTI metrics of the subcortical deep gray matter structures with lesion burden, normalized white matter volume, and normalized cortical volume was investigated. RESULTS: DTI measures were significantly different in whole brain, normal-appearing white matter, and normal-appearing gray matter among the groups (P < .01). Significant differences in DTI diffusivity of total subcortical deep gray matter, caudate, thalamus, and hippocampus (P < .001) were found. DTI diffusivity of total subcortical deep gray matter was significantly associated with normalized white matter volume (P < .001) and normalized cortical volume (P = .033) in healthy control patients. In both relapsing and progressive MS groups, the DTI subcortical deep gray matter measures were associated with the lesion burden and with normalized white matter volume (P < .001), but not with normalized cortical volume. CONCLUSIONS: These findings suggest that subcortical deep gray matter abnormalities are associated with white matter lesion burden and atrophy, whereas cortical atrophy is not associated with microstructural alterations of subcortical deep gray matter structures in patients with MS.

Effect of age on MRI phase behavior in the subcortical deep gray matter of healthy individuals.

BACKGROUND AND PURPOSE: It has been demonstrated that increased levels of iron in the brain occur with aging. In this study we investigated the nature of the association between age and SWI-filtered phase values, indicative of iron content, in the subcortical deep gray matter of healthy individuals. MATERIALS AND METHODS: A total of 210 healthy individuals (men: n = 89, women: n = 121), mean age, 39.8 years (standard deviation = 15.5; range = 6-76 years), were imaged on a 3T scanner. Mean MRI phase, mean phase of low-phase voxels, and normalized volumes were determined for total subcortical deep gray matter, caudate, putamen, globus pallidus, thalamus, pulvinar nucleus, hippocampus, amygdala, nucleus accumbens, red nucleus, and substantia nigra. Linear and nonlinear regression models were used to explore the relationship between phase and volume measures, and aging. RESULTS: Mean phase values of subcortical deep gray matter structures showed a quadratic relationship, with individuals in late middle age (40-59 years) having the lowest mean phase values, followed by a reversal of this trend in the elderly. In contrast, mean phase of low-phase voxel measurements showed strong negative linear relationships with aging. Significantly lower phase values were detected in women compared with men (P < .001), whereas no sex differences were observed for mean phase of low-phase voxels. Normalized volume measurements were also linearly related to aging, and women showed smaller normalized volumes of subcortical deep gray matter structures than men (P < .001). Lower mean phase of low-phase voxels was related to decreased volume measures. CONCLUSIONS: A strong association between phase (quadratic effect; phase decreases are followed by increases), mean phase of low-phase voxels (linear effect), volume (linear effect), and age was observed. Low phase was related to brain atrophy.

Multimodal imaging in systemic lupus erythematosus patients with diffuse neuropsychiatric involvement.

OBJECTIVES: The objective of this paper is to investigate conventional and nonconventional brain magnetic resonance imaging (MRI) findings in systemic lupus erythematosus (SLE) patients with diffuse neuropsychiatric involvement (dNPSLE) compared to healthy controls (HCs). METHODS: Twenty-six (26) SLE patients with one or more diffuse NP syndromes related to the central nervous system (CNS) (dNPSLE) and 36 age- and sex-matched HCs were scanned on a 3T MRI using a multimodal imaging approach. Univariate and multivariate analyses were used to determine MRI-specific measure differences between dNPSLE and HCs for lesion burden, tissue-specific atrophy, magnetization transfer ratio (MTR) and diffusion-tensor imaging (DTI) outcomes. RESULTS: In univariate analyses, dNPSLE patients showed significantly increased T1 lesion number (p = .001) and T1-lesion volume (LV, p = .008) compared to HCs. dNPSLE patients showed decreased whole brain volume (p < .0001), gray matter volume (p < .0001), cortical volume (p < .0001) and increased lateral ventricle volume (p = .004) compared to HCs. dNPSLE patients had increased axial diffusivity (AD) of NAWM (p = .008) and NA brain tissue (p = .017) compared to HCs. In the multivariate regression analysis, decreased cortical volume was associated with SLE (R (2) = 0.59, p < .0001). CONCLUSIONS: This study shows that cortical and central atrophy are associated with SLE patients with diffuse CNS syndromes. Microscopic tissue injury in the NAWM on AD DTI measures in SLE patients indicates a predominant reduction of axonal density.

Evolution of cortical and thalamus atrophy and disability progression in early relapsing-remitting MS during 5 years.

BACKGROUND AND PURPOSE: Pathologic changes in GM have an important role in MS. We investigated the association between SDGM and cortical volume changes and disability progression in early RRMS. MATERIALS AND METHODS: One hundred eighty patients with RRMS had clinical assessment during 5 years and were divided into those with or without SDP at 5 years by the usual definition in treatment trials. The number of available MR imaging scans at various time points was the following: at baseline, 178; and at 6 months, 172; at 12 months, 175; at 24 months, 155; at 36 months, 160; at 48 months, 158; and at 60 months, 162, respectively. Longitudinal changes in cortical, GM, and WM volume were calculated by using the direct method. RESULTS: At 5 years, 90 patients with RRMS experienced SDP and 90 had stable disease. At baseline, patients with SDP had longer disease duration, greater T2-lesion volume, and smaller whole-brain, WM, cortical, and SDGM volume (P < .01). At 5 years, patients with SDP had significantly greater percentage decreases from baseline compared with those without SDP in the volume of the whole brain (P < .0001), cortex (P = .001), GM (P = .003), and thalamus (P = .01). In patients who developed SDP at 5 years and those who did not, mixed-effect models, adjusted for age, disease duration, and change of the treatment status, showed significant interactions between SDP status at 5 years and changes with time in whole-brain, cortical, lateral ventricle (all P < .001), thalamus (P = .006), and total SDGM (P = .0095) volume. CONCLUSIONS: SDP is associated with progression of cortical, central, and thalamic atrophy in early RRMS during 5 years.

No association between conventional brain MR imaging and chronic cerebrospinal venous insufficiency in multiple sclerosis.

BACKGROUND AND PURPOSE: CCSVI has been reported to occur at high frequency in MS. Its significance in relation to MR imaging parameters also needs to be determined, both in patients with MS and HCs. Therefore, this study determined the associations of CCSVI and conventional MR imaging outcomes in patients with MS and in HCs. MATERIALS AND METHODS: T2, T1, and gadolinium lesion number, LV, and brain atrophy were assessed on 3T MR imaging in 301 subjects, of whom 162 had RRMS, 66 had secondary-progressive MS subtype, and 73 were HCs. CCSVI was assessed using extracranial and transcranial Doppler evaluation. The MR imaging measure differences were explored with 27 borderline cases for CCSVI, added to both the negative and positive CCSVI groups to assess sensitivity of the results of these cases. RESULTS: No significant differences between subjects with and without CCSVI were found in any of the individual diagnostic subgroups or MS disease subtypes for lesion burden and atrophy measures, independently of the CCSVI classification criteria used, except for a trend for higher T2 lesion number (irrespective of how borderline cases were classified) and lower brain volume (when borderline cases were included in the positive group) in patients with RRMS with CCSVI. No CCSVI or MR imaging differences were found between 26 HCs with, or 47 without, a familial relationship. CONCLUSIONS: CCSVI is not associated with more severe lesion burden or brain atrophy in patients with MS or in HCs.

Subcortical and cortical gray matter atrophy in a large sample of patients with clinically isolated syndrome and early relapsing-remitting multiple sclerosis.

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.

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.