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Bianca Weinstock-Guttman

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15 papers

1 author row

YNICL Journal 2025 Journal Article

Thalamic iron in multiple sclerosis: Waning support for the early-rise late-decline hypothesis

Fahad Salman
Niels Bergsland
Michael G. Dwyer
Jack A Reeves
Abhisri Ramesh
Dejan Jakimovski
Bianca Weinstock-Guttman
Robert Zivadinov

BACKGROUND: Studies of thalamic iron levels in multiple sclerosis (MS) have yielded variable findings, potentially due to differences in study cohorts. For example, studies in relatively young cohorts (average ages below 40 years) have reported elevated susceptibility in people with MS (pwMS), whereas studies in older cohorts (above 40 years) found decreased susceptibility. OBJECTIVE: To test the "early-rise late-decline" hypothesis, which posits that age differences in study cohorts are responsible for conflicting findings regarding thalamic susceptibility in MS. METHODS: We chose to replicate one of the previous studies that showed evidence of elevated thalamic iron concentrations in younger pwMS (Rudko et al., 2014). We also replicated a study involving older pwMS (Pudlac et al., 2020) to serve as a control. We assessed thalamic susceptibility using the QSM processing and analysis methodology outlined by Rudko et al. RESULTS: Although cohort characteristics, QSM processing, and analytical methods were closely matched, we found significantly lower thalamic susceptibility in the younger pwMS compared to controls (-1.1 ± 7.8 vs. 5.4 ± 6.1 ppb; effect sizes: -0.35 to -0.91). Study outcomes were robust across a wide range of regularization parameters, with effect size differences influenced by background field removal regularization. A similar pattern was observed in the older cohort, where thalamic susceptibility was again lower in pwMS compared to controls (4.0 ± 9.5 vs. 9.6 ± 10.7 ppb; effect size: -0.55). CONCLUSIONS: Our findings contradict the "early rise" hypothesis of thalamic iron levels in pwMS. The consistency of our results across multiple analyses suggests that QSM processing artifacts are unlikely to explain previous reports of increased thalamic iron. Instead, these variations may stem from demographic or clinical differences, such as geographical factors and treatment regimens.

YNICL Journal 2024 Journal Article

Thalamic atrophy and dysconnectivity are associated with cognitive impairment in a multi-center, clinical routine, real-word study of people with relapsing-remitting multiple sclerosis

Robert Zivadinov
Niels Bergsland
Dejan Jakimovski
Bianca Weinstock-Guttman
Lorena Lorefice
Menno M. Schoonheim
Sarah A. Morrow
Mary Ann Picone

BACKGROUND: Prior research has established a link between thalamic pathology and cognitive impairment (CI) in people with multiple sclerosis (pwMS). However, the translation of these findings to pwMS in everyday clinical settings has been insufficient. OBJECTIVE: To assess which global and/or thalamic imaging biomarkers can be used to identify pwMS at risk for CI and cognitive worsening (CW) in a real-world setting. METHODS: This was an international, multi-center (11 centers), longitudinal, retrospective, real-word study of people with relapsing-remitting MS (pwRRMS). Brain MRI exams acquired at baseline and follow-up were collected. Cognitive status was evaluated using the Symbol Digit Modalities Test (SDMT). Thalamic volume (TV) measurement was performed on T2-FLAIR, as well as on T1-WI, when available. Thalamic dysconnectivity, T2-lesion volume (T2-LV), and volumes of gray matter (GM), whole brain (WB) and lateral ventricles (LVV) were also assessed. RESULTS: 332 pwMS were followed for an average of 2.8 years. At baseline, T2-LV, LVV, TV and thalamic dysconnectivity on T2-FLAIR (p < 0.016), and WB, GM and TV volumes on T1-WI (p < 0.039) were significantly worse in 90 (27.1 %) CI vs. 242 (62.9 %) non-CI pwRRMS. Greater SDMT decline over the follow-up was associated with lower baseline TV on T2-FLAIR (standardized β = 0.203, p = 0.002) and greater thalamic dysconnectivity (standardized β = -0.14, p = 0.028) in a linear regression model. CONCLUSIONS: PwRRMS with thalamic atrophy and worse thalamic dysconnectivity present more frequently with CI and experience greater CW over mid-term follow-up in a real-world setting.

YNIMG Journal 2022 Journal Article

Susceptibility networks reveal independent patterns of brain iron abnormalities in multiple sclerosis

Jack A. Reeves
Niels Bergsland
Michael G. Dwyer
Gregory E. Wilding
Dejan Jakimovski
Fahad Salman
Balint Sule
Nicklas Meineke

Brain iron homeostasis is necessary for healthy brain function. MRI and histological studies have shown altered brain iron levels in the brains of patients with multiple sclerosis (MS), particularly in the deep gray matter (DGM). Previous studies were able to only partially separate iron-modifying effects because of incomplete knowledge of iron-modifying processes and influencing factors. It is therefore unclear to what extent and at which stages of the disease different processes contribute to brain iron changes. We postulate that spatially covarying magnetic susceptibility networks determined with Independent Component Analysis (ICA) reflect, and allow for the study of, independent processes regulating iron levels. We applied ICA to quantitative susceptibility maps for 170 individuals aged 9-81 years without neurological disease ("Healthy Aging" (HA) cohort), and for a cohort of 120 patients with MS and 120 age- and sex-matched healthy controls (HC; together the "MS/HC" cohort). Two DGM-associated "susceptibility networks" identified in the HA cohort (the Dorsal Striatum and Globus Pallidus Interna Networks) were highly internally reproducible (i.e. "robust") across multiple ICA repetitions on cohort subsets. DGM areas overlapping both robust networks had higher susceptibility levels than DGM areas overlapping only a single robust network, suggesting that these networks were caused by independent processes of increasing iron concentration. Because MS is thought to accelerate brain aging, we hypothesized that associations between age and the two robust DGM-associated networks would be enhanced in patients with MS. However, only one of these networks was altered in patients with MS, and it had a null age association in patients with MS rather than a stronger association. Further analysis of the MS/HC cohort revealed three additional disease-related networks (the Pulvinar, Mesencephalon, and Caudate Networks) that were differentially altered between patients with MS and HCs and between MS subtypes. Exploratory regression analyses of the disease-related networks revealed differential associations with disease duration and T2 lesion volume. Finally, analysis of ROI-based disease effects in the MS/HC cohort revealed an effect of disease status only in the putamen ROI and exploratory regression analysis did not show associations between the caudate and pulvinar ROIs and disease duration or T2 lesion volume, showing the ICA-based approach was more sensitive to disease effects. These results suggest that the ICA network framework increases sensitivity for studying patterns of brain iron change, opening a new avenue for understanding brain iron physiology under normal and disease conditions.

YNICL Journal 2021 Journal Article

Brain atrophy and lesion burden are associated with disability progression in a multiple sclerosis real-world dataset using only T2-FLAIR: The NeuroSTREAM MSBase study

Michael Barnett
Niels Bergsland
Bianca Weinstock-Guttman
Helmut Butzkueven
Tomas Kalincik
Patricia Desmond
Frank Gaillard
Vincent Van Pesch

BACKGROUND: Methodological challenges limit the use of brain atrophy and lesion burden measures in the follow-up of multiple sclerosis (MS) patients on clinical routine datasets. OBJECTIVE: To determine the feasibility of T2-FLAIR-only measures of lateral ventricular volume (LVV) and salient central lesion volume (SCLV), as markers of disability progression (DP) in MS. METHODS: A total of 3,228 MS patients from 9 MSBase centers in 5 countries were enrolled. Of those, 2,875 (218 with clinically isolated syndrome, 2,231 with relapsing-remitting and 426 with progressive disease subtype) fulfilled inclusion and exclusion criteria. Patients were scanned on either 1.5 T or 3 T MRI scanners, and 5,750 brain scans were collected at index and on average after 42.3 months at post-index. Demographic and clinical data were collected from the MSBase registry. LVV and SCLV were measured on clinical routine T2-FLAIR images. RESULTS: Longitudinal LVV and SCLV analyses were successful in 96% of the scans. 57% of patients had scanner-related changes over the follow-up. After correcting for age, sex, disease duration, disability, disease-modifying therapy and LVV at index, and follow-up time, MS patients with DP (n = 671) had significantly greater absolute LVV change compared to stable (n = 1,501) or disability improved (DI, n = 248) MS patients (2.0 mL vs. 1.4 mL vs. 1.1 mL, respectively, ANCOVA p < 0.001, post-hoc pair-wise DP vs. Stable p = 0.003; and DP vs. DI, p = 0.002). Similar ANCOVA model was also significant for SCLV (p = 0.03). CONCLUSIONS: LVV-based atrophy and SCLV-based lesion outcomes are feasible on clinically acquired T2-FLAIR scans in a multicenter fashion and are associated with DP over mid-term.

YNICL Journal 2021 Journal Article

Clinical feasibility of longitudinal lateral ventricular volume measurements on T2-FLAIR across MRI scanner changes

Dejan Jakimovski
Robert Zivadinov
Niels Bergsland
Deepa P. Ramasamy
Jesper Hagemeier
Antonia Valentina Genovese
David Hojnacki
Bianca Weinstock-Guttman

BACKGROUND: Greater brain atrophy is associated with disability progression (DP) in patients with multiple sclerosis (PwMS). However, methodological challenges limit its routine clinical use. OBJECTIVE: To determine the feasibility of atrophy measures as markers of DP in PwMS scanned across different MRI field strengths. METHODS: A total of 980 PwMS were scanned on either 1.5 T or 3.0 T MRI scanners. Demographic and clinical data were retrospectively collected, and the presence of DP was determined according to standard clinical trial criteria. Lateral ventricular volume (LVV) change was measured with the NeuroSTREAM technique on clinical routine T2-FLAIR images. Percent brain volume change (PBVC) was measured using SIENA and ventricular cerebrospinal fluid (vCSF) % change was measured using VIENA and SIENAX algorithms on 3D T1-weighted images (WI). Stable vs. DP PwMS were compared using analysis of covariance (ANCOVA). Mixed modeling determined the effect of MRI scanner change on MRI-derived atrophy measures. RESULTS: Longitudinal LVV analysis was successful in all PwMS. SIENA-based PBVC and VIENA-based changes failed in 37.6% of cases, while SIENAX-based vCSF failed in 12.9% of cases. PwMS with DP (n = 241) had significantly greater absolute (20.9% vs. 8.7%, d = 0.66, p < 0.001) and annualized LVV % change (4.1% vs. 2.3%, d = 0.27, p < 0.001) when compared to stable PwMS (n = 739). In subjects with both analyses available, both 3D-T1 and T2-FLAIR-based analyses differentiated PwMS with DP (n = 149). However, only NeuroSTREAM and VIENA-based LVV/vCSF were able to show greater atrophy in PwMS that were scanned on different scanners. PBVC and SIENAX-based vCSF % changes were significantly affected by scanner change (Beta = -0.16, t-statistics = -2.133, p = 0.033 and Beta = -2.08, t-statistics = -4.084, p < 0.001), whereas no MRI scanner change effects on NeuroSTREAM-based PLVVC and VIENA-based vCSF % change were noted. CONCLUSIONS: LVV-based atrophy on T2-FLAIR is a clinically relevant measure in spite of MRI scanner changes and mild disability levels.

YNICL Journal 2021 Journal Article

Quantifying disease pathology and predicting disease progression in multiple sclerosis with only clinical routine T2-FLAIR MRI

Tom A. Fuchs
Michael G. Dwyer
Dejan Jakimovski
Niels Bergsland
Deepa P. Ramasamy
Bianca Weinstock-Guttman
Ralph HB Benedict
Robert Zivadinov

BACKGROUND: Although quantitative measures from research-quality MRI provide a means to study multiple sclerosis (MS) pathology in vivo, these metrics are often unavailable in legacy clinical datasets. OBJECTIVE: To determine how well an automatically-generated quantitative snapshot of brain pathology, measured only on clinical routine T2-FLAIR MRI, can substitute for more conventional measures on research MRI in terms of capturing multi-factorial disease pathology and providing similar clinical relevance. METHODS: MRI with both research-quality sequences and conventional clinical T2-FLAIR was acquired for 172 MS patients at baseline, and neurologic disability was assessed at baseline and five-years later. Five measures (thalamus volume, lateral ventricle volume, medulla oblongata volume, lesion volume, and network efficiency) for quantifying disparate aspects of neuropathology from low-resolution T2-FLAIR were applied to predict standard research-quality MRI measures. They were compared in regard to association with future neurologic disability and disease progression over five years. RESULTS: = 0.366, p < 0.001). They also similarly predicted disability progression over five years (%-correctly-classified = 69.8, p = 0.034), compared to standard research-quality MRI (%-correctly-classified = 72.4%, p = 0.022) in relapsing-remitting MS. CONCLUSION: A set of five T2-FLAIR-only measures can substitute for standard research-quality MRI, especially in relapsing-remitting MS. When only clinical T2-FLAIR is available, it can be used to obtain substantially more quantitative information about brain pathology and disability than is currently standard practice.

YNIMG Journal 2019 Journal Article

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

Yanis Taege
Jesper Hagemeier
Niels Bergsland
Michael G. Dwyer
Bianca Weinstock-Guttman
Robert Zivadinov
Ferdinand Schweser

Most studies of brain iron relied on the effect of the iron on magnetic resonance (MR) relaxation properties, such as R 2 ∗, and bulk tissue magnetic susceptibility, as measured by quantitative susceptibility mapping (QSM). The present study exploited the dependence of R 2 ∗ and magnetic susceptibility on physical interactions at different length-scales to retrieve information about the tissue microenvironment, rather than the iron concentration. We introduce a method for the simultaneous analysis of brain tissue magnetic susceptibility and R 2 ∗ that aims to isolate those biophysical mechanisms of R 2 ∗ -contrast that are associated with the micro- and mesoscopic distribution of iron, referred to as the Iron Microstructure Coefficient (IMC). The present study hypothesized that changes in the deep gray matter (DGM) magnetic microenvironment associated with aging and pathological mechanisms of multiple sclerosis (MS), such as changes of the distribution and chemical form of the iron, manifest in quantifiable contributions to the IMC. To validate this hypothesis, we analyzed the voxel-based association between R 2 ∗ and magnetic susceptibility in different DGM regions of 26 patients with multiple sclerosis and 33 age- and sex-matched normal controls. Values of the IMC varied significantly between anatomical regions, were reduced in the dentate and increased in the caudate of patients compared to controls, and decreased with normal aging, most strongly in caudate, globus pallidus and putamen.

YNICL Journal 2018 Journal Article

Changes of deep gray matter magnetic susceptibility over 2 years in multiple sclerosis and healthy control brain

Jesper Hagemeier
Robert Zivadinov
Michael G. Dwyer
Paul Polak
Niels Bergsland
Bianca Weinstock-Guttman
Joshua Zalis
Andreas Deistung

In multiple sclerosis, pathological changes of both tissue iron and myelin occur, yet these factors have not been characterized in a longitudinal fashion using the novel iron- and myelin-sensitive quantitative susceptibility mapping (QSM) MRI technique. We investigated disease-relevant tissue changes associated with myelin loss and iron accumulation in multiple sclerosis deep gray matter (DGM) over two years. One-hundred twenty (120) multiple sclerosis patients and 40 age- and sex-matched healthy controls were included in this prospective study. Written informed consent and local IRB approval were obtained from all participants. Clinical testing and QSM were performed both at baseline and at follow-up. Brain magnetic susceptibility was measured in major DGM structures. Temporal (baseline vs. follow-up) and cross-sectional (multiple sclerosis vs. controls) differences were studied using mixed factorial ANOVA analysis and appropriate t-tests. At either time-point, multiple sclerosis patients had significantly higher susceptibility in the caudate and globus pallidus and lower susceptibility in the thalamus. Over two years, susceptibility increased significantly in the caudate of both controls and multiple sclerosis patients. Inverse thalamic findings among MS patients suggest a multi-phase pathology explained by simultaneous myelin loss and/or iron accumulation followed by iron depletion and/or calcium deposition at later stages.

YNICL Journal 2018 Journal Article

Iron-related gene variants and brain iron in multiple sclerosis and healthy individuals

Jesper Hagemeier
Murali Ramanathan
Ferdinand Schweser
Michael G. Dwyer
Fuchun Lin
Niels Bergsland
Bianca Weinstock-Guttman
Robert Zivadinov

Brain iron homeostasis is known to be disturbed in multiple sclerosis (MS), yet little is known about the association of common gene variants linked to iron regulation and pathological tissue changes in the brain. In this study, we investigated the association of genetic determinants linked to iron regulation with deep gray matter (GM) magnetic susceptibility in both healthy controls (HC) and MS patients. Four hundred (400) patients with MS and 150 age- and sex-matched HCs were enrolled and obtained 3T MRI examination. Three (3) single nucleotide polymorphisms (SNPs) associated with iron regulation were genotyped: two SNPs in the human hereditary hemochromatosis protein gene HFE: rs1800562 (C282Y mutation) and rs1799945 (H63D mutation), as well as the rs1049296 SNP in the transferrin gene (C2 mutation). The effects of disease and genetic status were studied using quantitative susceptibility mapping (QSM) voxel-based analysis (VBA) and region-of-interest (ROI) analysis of the deep GM. The general linear model framework was used to compare groups. Analyses were corrected for age and sex, and adjusted for false discovery rate. We found moderate increases in susceptibility in the right putamen of participants with the C282Y (+6. 1ppb) and H63D (+6. 9ppb) gene variants vs. non-carriers, as well as a decrease in thalamic susceptibility of progressive MS patients with the C282Y mutation (left: −5. 3ppb, right: −6. 7ppb, p<0. 05). Female MS patients had lower susceptibility in the caudate (−6. 0ppb) and putamen (left: −3. 9ppb, right: −4. 6ppb) than men, but only when they had a wild-type allele (p<0. 05). Iron-gene linked increases in putamen susceptibility (in HC and relapsing remitting MS) and decreases in thalamus susceptibility (in progressive MS), coupled with apparent sex interactions, indicate that brain iron in healthy and disease states may be influenced by genetic factors.

YNIMG Journal 2018 Journal Article

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

Ferdinand Schweser
Ana Luiza Raffaini Duarte Martins
Jesper Hagemeier
Fuchun Lin
Jannis Hanspach
Bianca Weinstock-Guttman
Simon Hametner
Niels Bergsland

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

YNICL Journal 2015 Journal Article

Increased contrast enhancing lesion activity in relapsing–remitting multiple sclerosis migraine patients

Elliot Graziano
Jesper Hagemeier
Bianca Weinstock-Guttman
Deepa P. Ramasamy
Robert Zivadinov

BACKGROUND AND OBJECTIVES: While the literature supports the idea that multiple sclerosis (MS) and migraine are related, the exact mechanism(s) of this association is not well understood. Observations of increased contrast enhancing (CE) lesion activity in individual MS patients suffering from migraine prompted us to determine a relationship between migraine and MRI outcomes in a large cohort of MS patients. METHODS: We included 509 MS and 64 clinically isolated syndrome (CIS) patients and 251 age- and sex-matched healthy individuals (HIs) who obtained 3 T MRI and were assessed for history of migraine. Number and volume of T2, T1 and CE lesions and brain volume measures were determined. The MRI findings were analyzed adjusting for key covariates and correcting for multiple comparisons. RESULTS: More MS (22.2%) and CIS (17.2%) patients had migraine, compared to HIs (14.6%, p = 0.067). More MS patients with migraine presented with CE lesions compared to those without (35.4% vs. 23.7%, p = 0.013). MS migraine patients had significantly increased number (p = 0.019) and volume (p = 0.022) of CE lesions compared to those without. In the regression analysis, MS migraine patients had an increased number of CE lesions (B = 1.242, p = 0.001), specifically those with relapsing-remitting disease course (B = 1.377, p = 0.001). No significant association of other MRI measures and migraine was found in MS and CIS patients or in HIs. CONCLUSIONS: Our findings suggest an increased inflammatory pathobiology in MS patients with migraine headaches requiring possibly more frequent MRIs and also more efficient anti-inflammatory treatment.

YNIMG Journal 2012 Journal Article

Abnormal subcortical deep-gray matter susceptibility-weighted imaging filtered phase measurements in patients with multiple sclerosis

Robert Zivadinov
Mari Heininen- Brown
Claudiu V. Schirda
Guy U. Poloni
Niels Bergsland
Christopher R. Magnano
Jacqueline Durfee
Cheryl Kennedy

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.

YNIMG Journal 2007 Journal Article

Independent contributions of cortical gray matter atrophy and ventricle enlargement for predicting neuropsychological impairment in multiple sclerosis

Ayda Tekok-Kilic
Ralph H.B. Benedict
Bianca Weinstock-Guttman
Michael G. Dwyer
Dominic Carone
Bhooma Srinivasaraghavan
Viritha Yella
Nadir Abdelrahman

The primary goal of this study was to investigate associations between regional gray matter (GM) atrophy and neuropsychological function in multiple sclerosis (MS), while accounting for the influence of central brain atrophy (i. e. third ventricle enlargement). Using a cross-sectional design, we studied 59 MS patients with brain MRI and neuropsychological testing. Regional gray matter fractions (rGMFs) were calculated from MRI images for 11 homologous brain areas using the semiautomatic brain region extraction (SABRE) technique. Neuropsychological testing followed consensus panel guidelines and included tests emphasizing episodic memory, working memory and processing speed. The analytic approach was stepwise linear regression, with forward selection and p <0. 05 threshold for significance. Consistent with previous research, there were significant correlations between third ventricle width and neuropsychological tests. Stepwise linear regression analyses controlling for third ventricle width retained rGMFs obtained from specific regions within the prefrontal cortex. Left frontal atrophy was associated with tests emphasizing auditory/verbal memory. Right frontal atrophy was associated with impairment in visual episodic and working memory. For the first time, we show an independent relationship between cortical atrophy and cognitive impairment after accounting for the effects of central atrophy.

YNIMG Journal 2007 Journal Article

Quantitative diffusion weighted imaging measures in patients with multiple sclerosis

Eleonora Tavazzi
Michael G. Dwyer
Bianca Weinstock-Guttman
Jordan Lema
Stefano Bastianello
Roberto Bergamaschi
Vittorio Cosi
Ralph H.B. Benedict

Diffusion-weighted imaging (DWI) has been proposed as a sensitive measure of disease severity capable of detecting subtle changes in gray matter and white matter brain compartments in patients with multiple sclerosis (MS). However, DWI has been applied to the study of MS clinical subtypes in only a few studies. The objective of this study was to demonstrate the validity of a novel, fully automated method for the calculation of quantitative DWI measures. We also wanted to assess the correlation between whole brain (WB)-DWI variables and clinical and MRI measures of disease severity in a large cohort of MS patients. For this purpose we studied 432 consecutive MS patients (mean age 44. 4±10. 2 years), 16 patients with clinically isolated syndrome (CIS) and 38 normal controls (NC) using 1. 5 T brain MRI. Clinical disease subtypes were as follows: 294 relapsing–remitting (RR), 123 secondary-progressive (SP) and 15 primary-progressive (PP). Mean disease duration was 12±10 years. Mean Expanded Disability Status Scale (EDSS) was 3. 3±2. 1. Brain parenchymal fraction (BPF), gray matter fraction (GMF) and white matter fraction (WMF) were calculated using a fully automated method. Mean parenchymal diffusivity (MPD) maps were created. DWI indices of peak position (PP), peak height (PH), MPD and entropy (ENT) were obtained. T2- and T1-lesion volumes (LV), EDSS, ambulation index (AI) and nine-hole peg test (9-HPT) were also assessed. MS patients had significantly lower BPF (d =1. 26; p <0. 001) and GMF (d =0. 61; p =0. 003), and higher ENT (d =1. 2; p <0. 0001), MPD (d =1. 04; p <0. 0001) and PH (d =0. 47; p =0. 045) than NC subjects. A GLM analysis, adjusted for age and multiple comparisons, revealed significant differences between different clinical subtypes for BPF, GMF, ENT, PH, PP, T2-LV and T1-LV (p <0. 0001), WMF (p =0. 001) and MPD (p =0. 023). In RR and SP MS patients, ENT showed a more robust correlation with other MRI (r =0. 54 to 0. 67, p <0. 0001) and clinical (r =0. 31 to 0. 36, p <0. 0001) variables than MPD (r =0. 23 to 0. 41, p <0. 001 for MRI and r =0. 13 to 0. 18; p =0. 006 to p <0. 001 for clinical variables). The GMF and BPF showed a slightly stronger relationship with all clinical variables (r =0. 33 to 0. 48; p <0. 0001), when compared to both lesion and DWI measures. ENT (R 2 =0. 28; p <0. 0001) and GMF (R 2 =0. 26; p <0. 001) were best related with SP disease course. This study highlights the validity of DWI in discerning differences between NC and MS patients, as well as between different MS subtypes. ENT is a sensitive marker of overall brain damage that is strongly related to clinical impairment in patients with SP MS.

YNIMG Journal 2005 Journal Article

The relationship between whole brain volume and disability in multiple sclerosis: A comparison of normalized gray vs. white matter with misclassification correction

Michael P. Sanfilipo
Ralph H.B. Benedict
Jitendra Sharma
Bianca Weinstock-Guttman
Rohit Bakshi

We used SPM99 to obtain normalized whole brain volumes of gray matter, white matter, and total parenchyma in patients with multiple sclerosis (MS) (n = 41) and age-/sex-matched normal controls (n = 18). As SPM99's automated gray/white matter volumes were significantly influenced by tissue compartment misclassification due to the effect of MS-related brain lesions, we corrected these automated volumes for misclassification before performing our primary analyses. For MS patients (disease duration = 9. 5 ± 6. 3 years; EDSS score = 3. 2 ± 1. 8; 25FTW = 6. 6 ± 3. 1 s), we also measured lesion load (total T1 hypointense [T1LV] and FLAIR hyperintense lesion volume [FLLV]), central brain atrophy (third ventricular width [TVW] and bicaudate ratio [BCR]), and clinical status (Expanded Disability Status Scale [EDSS] and 25-ft timed walk [25FTW]). Patients with MS had lower gray matter (707 ± 33 cm3 [−3. 9%], P = 0. 003) and total parenchymal volume (1088 ± 48 cm3 [−3. 8%], P = 0. 003), but only a trend for lower white matter volume (381 ± 25 cm3 [−3. 7%], P = 0. 052) relative to normal controls (gray matter: 736 ± 33 cm3; total parenchyma: 1132 ± 49 cm3; white matter: 396 ± 26 cm3). Gray matter atrophy was related to clinical status (EDSS, 25FTW, and disease duration), lesion load (T1LV and FLLV), and central brain atrophy (TVW and BCR), whereas white matter atrophy was related to only central brain atrophy. These findings suggest that gray matter loss is related to other aspects of brain pathology and has more clinical relevance than white matter atrophy in MS.