Publications

2013
William B White, Ravi Marfatia, Julia Schmidt, Dorothy B Wakefield, Richard F Kaplan, Richard W Bohannon, Charles B Hall, Charles R Guttmann, Nicola Moscufo, Douglas Fellows, and Leslie Wolfson. 2013. “INtensive versus standard ambulatory blood pressure lowering to prevent functional DeclINe in the ElderlY (INFINITY).” Am Heart J, 165, 3, Pp. 258-265.e1.Abstract
Reductions in mobility and cognitive function linked to accrual of brain microvascular disease related white matter hyperintensities (WMHs) on magnetic resonance imaging can occur in older hypertensive patients in as little as 2 years. We have designed a trial evaluating 2 levels of ambulatory blood pressure (ABP) control in individuals with normal or mildly impaired mobility and cognition who have detectable cerebrovascular disease (>0.5% WMH fraction of intracranial volume) on functional outcomes. The study is a prospective randomized, open-label trial with blinded end points, in patients ages ≥75 years with elevated 24-hour systolic blood pressure (BP) (145 mm Hg in the untreated state) who do not have unstable cardiovascular disease, heart failure, or stroke. The primary and key secondary outcomes in the trial are change from baseline in mobility and cognitive function and damage to brain white matter as demonstrated by accrual of WMH volume and changes in diffusion tensor imaging. Approximately 300 patients will be enrolled, and 200 randomized to 1 of 2 levels of ABP control (intensive to achieve a goal 24-hour systolic BP of ≤130 mm Hg or standard to achieve a goal 24-hour systolic BP of ≤145 mm Hg) for a total of 36 months using similar antihypertensive regimens. The analytical approach provides 85% power to show a clinically meaningful effect in differences in mobility accompanied by quantitative differences in WMH between treatment groups. The INFINITY trial is the first to guide antihypertensive therapy using ABP monitoring rather than clinic BP to reduce cerebrovascular disease.
Claudio Gobbi, Dominik S Meier, François Cotton, Martina Sintzel, David Leppert, Charles RG Guttmann, and Chiara Zecca. 2013. “Interferon beta 1b following natalizumab discontinuation: one year, randomized, prospective, pilot trial.” BMC Neurol, 13, Pp. 101.Abstract
BACKGROUND: Natalizumab (NTZ) discontinuation leads to multiple sclerosis reactivation.The objective of this study is to compare disease activity in MS patients who continued on NTZ treatment to those who were switched to subcutaneous interferon 1b (IFNB) treatment. METHODS: 1-year randomized, rater-blinded, parallel-group, pilot study (ClinicalTrial.gov ID: NCT01144052). Relapsing remitting MS patients on NTZ for ≥12 months who had been free of disease activity on this therapy (no relapses and disability progression for ≥6 months, no gadolinium-enhancing lesions on baseline MRI) were randomized to NTZ or IFNB. Primary endpoint was time to first on-study relapse. Additional clinical, MRI and safety parameters were assessed. Analysis was based on intention to treat. RESULTS: 19 patients (NTZ n=10; IFNB n=9) with similar baseline characteristics were included. 78% of IFNB treated patients remained relapse free (NTZ group: 100%), and 25% remained free of new T2 lesions (NTZ group: 62.5%). While time to first on-study relapse was not significantly different between groups (p=0.125), many secondary clinical and radiological endpoints (number of relapses, proportion of relapse free patients, number of new T2 lesions) showed a trend, or were significant (new T2 lesions at month 6) in favoring NTZ. CONCLUSIONS: De-escalation therapy from NTZ to IFNB over 1 year was associated with some clinical and radiological disease recurrence. Overall no major safety concerns were observed.
Michele Cavallari, Nicola Moscufo, Pawel Skudlarski, Dominik Meier, Victoria P Panzer, Godfrey D Pearlson, William B White, Leslie Wolfson, and Charles RG Guttmann. 2013. “Mobility impairment is associated with reduced microstructural integrity of the inferior and superior cerebellar peduncles in elderly with no clinical signs of cerebellar dysfunction.” Neuroimage Clin, 2, Pp. 332-40.Abstract
While the cerebellum plays a critical role in motor coordination and control no studies have investigated its involvement in idiopathic mobility impairment in community-dwelling elderly. In this study we tested the hypothesis that structural changes in the cerebellar peduncles not detected by conventional magnetic resonance imaging are associated with reduced mobility performance. The analysis involved eighty-five subjects (age range: 75-90 years) who had no clinical signs of cerebellar dysfunction. Based on the short physical performance battery (SPPB) score, we defined mobility status of the subjects in the study as normal (score 11-12, n = 26), intermediate (score 9-10, n = 27) or impaired (score < 9, n = 32). We acquired diffusion tensor imaging data to obtain indices of white matter integrity: fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD) and radial diffusivity (RD). Using a parcellation atlas, regional indices within the superior, middle, and inferior cerebellar peduncles (ICP, MCP, SCP) were calculated and their associations with mobility performance were analyzed. Subjects with impaired mobility showed reduced FA and AD values in the ICP and SCP but not in the MCP. The ICP-FA, ICP-AD and SCP-FA indices showed a significant association with the SPPB score. We also observed significant correlation between ICP-FA and walk time (r = - 0.311, p = 0.004), as well as between SCP-AD and self-paced maximum walking velocity (r = 0.385, p = 0.003) and usual walking velocity (r = 0.400, p = 0.002). In logistic regression analysis ICP-FA and ICP-AD together explained 51% of the variability in the mobility status of a sample comprising the normal and impaired subgroups, and correctly classified more than three-quarters of those subjects. Our findings suggest that presence of microstructural damage, likely axonal, in afferent and efferent connections of the cerebellum contributes to the deterioration of motor performance in older people.
T Kalincik, CRG Guttmann, J Krasensky, M Vaneckova, P Lelkova, M Tyblova, Z Seidl, PL De Jager, E Havrdova, and D Horakova. 2013. “Multiple sclerosis susceptibility loci do not alter clinical and MRI outcomes in clinically isolated syndrome.” Genes Immun, 14, 4, Pp. 244-8.Abstract
It has not yet been established whether genetic predictors of multiple sclerosis (MS) susceptibility also influence disease severity and accumulation of disability. Our aim was to evaluate associations between 16 previously validated genetic susceptibility markers and MS phenotype. Patients with clinically isolated syndrome verified by positive magnetic resonance imaging (MRI) and cerebrospinal fluid findings (n=179) were treated with interferon-β. Disability and volumetric MRI parameters were evaluated regularly for 2 years. Sixteen single-nucleotide polymorphisms (SNPs) previously validated as predictors of MS susceptibility in our cohort and their combined weighted genetic risk score (wGRS) were tested for associations with clinical (conversion to MS, relapses and disability) and MRI disease outcomes (whole brain, grey matter and white matter volumes, corpus callosum cross-sectional area, brain parenchymal fraction, T2 and T1 lesion volumes) 2 years from disease onset using mixed-effect models. We have found no associations between the tested SNPs and the clinical or MRI outcomes. Neither the combined wGRS predicted MS activity and progression over 2-year follow-up period. Power analyses confirmed 90% power to identify clinically relevant changes in all outcome variables. We conclude that the most important MS susceptibility loci do not determine MS phenotype and disease outcomes.
Riley Bove, Alexander Musallam, Brian C Healy, Maria Houtchens, Bonnie I Glanz, Samia Khoury, Charles R Guttmann, Philip L De Jager, and Tanuja Chitnis. 2013. “No sex-specific difference in disease trajectory in multiple sclerosis patients before and after age 50.” BMC Neurol, 13, Pp. 73.Abstract
BACKGROUND: The disease course in multiple sclerosis (MS) is influenced by many factors, including age, sex, and sex hormones. Little is known about sex-specific changes in disease course around age 50, which may represent a key biological transition period for reproductive aging. METHODS: Male and female subjects with no prior chemotherapy exposure were selected from a prospective MS cohort to form groups representing the years before (38-46 years, N=351) and after (54-62 years, N=200)age 50. Primary analysis assessed for interaction between effects of sex and age on clinical (Expanded Disability Status Scale, EDSS; relapse rate) and radiologic (T2 lesion volume, T2LV; brain parenchymal fraction, BPF) outcomes. Secondarily, we explored patient-reported outcomes (PROs). RESULTS: As expected, there were age- and sex- related changes with male and older cohorts showing worse disease severity (EDSS), brain atrophy (BPF), and more progressive course.There was no interaction between age and sex on cross-sectional adjusted clinical (EDSS, relapse rate) or radiologic (BPF, T2LV) measures, or on 2-year trajectories of decline.There was a significant interaction between age and sex for a physical functioning PRO (SF-36): the older female cohort reported lower physical functioning than men (p=0.002). There were no differences in depression (Center for Epidemiological Study - Depression, CES-D) or fatigue (Modified Fatigue Impact Scale, MFIS) scores. CONCLUSIONS: There was no interaction between age and sex suggestive of an effect of reproductive aging on clinical or radiologic progression. Prospective analyses across the menopausal transition are needed.
Tanuja Chitnis, Charles R Guttmann, Alexander Zaitsev, Alexander Musallam, Bianca Weinstock-Guttman, Ann Yeh, Moses Rodriguez, Jayne Ness, Mark P Gorman, Brian C Healy, Nancy Kuntz, Dorothee Chabas, Jonathan B Strober, Emmanuelle Waubant, Lauren Krupp, Daniel Pelletier, Bradley Erickson, Niels Bergsland, and Robert Zivadinov. 2013. “Quantitative MRI analysis in children with multiple sclerosis: a multicenter feasibility pilot study.” BMC Neurol, 13, Pp. 173.Abstract
BACKGROUND: Pediatric multiple sclerosis (MS) is a rare disorder with significant consequences. Quantitative MRI measurements may provide significant insights, however multicenter collaborative studies are needed given the small numbers of subjects. The goal of this study is to demonstrate feasibility and evaluate lesion volume (LV) characteristics in a multicenter cohort of children with MS. METHODS: A common MRI-scanning guideline was implemented at six member sites of the U.S. Network of Pediatric MS Centers of Excellence. We included in this study the first ten scans performed at each site on patients meeting the following inclusion criteria: pediatric RRMS within 3 years of disease onset, examination within 1 month of MRI and no steroids 1 month prior to MRI. We quantified T2 number, T2-LV and individual lesion size in a total of 53 MRIs passing quality control procedures and assessed gadolinium-enhancing lesion number and LV in 55 scans. We studied MRI measures according to demographic features including age, race, ethnicity and disability scores, controlling for disease duration and treatment duration using negative binomial regression and linear regression. RESULTS: The mean number of T2 lesions was 24.30 ± 19.68 (range:1-113) and mean gadolinium-enhancing lesion count was 1.85 ± 5.84, (range:0-32). Individual lesion size ranged from 14.31 to 55750.60 mm3. Non-white subjects had higher T2-LV (unadjusted pT2-LV = 0.028; adjusted pT2-LV = 0.044), and maximal individual T2-LV (unadjusted pMax = 0.007; adjusted pMax = 0.011) than white patients. We also found a trend toward larger mean lesion size in males than females (p = 0.07). CONCLUSION: Assessment of MRI lesion LV characteristics is feasible in a multicenter cohort of children with MS.
Christian Clemm von Hohenberg, Michael F Schocke, Marlene C Wigand, Wolfgang Nachbauer, Charles RG Guttmann, Marek Kubicki, Martha E Shenton, Sylvia Boesch, and Karl Egger. 2013. “Radial diffusivity in the cerebellar peduncles correlates with clinical severity in Friedreich ataxia.” Neurol Sci, 34, 8, Pp. 1459-62.Abstract
Friedreich ataxia (FRDA) is a common inherited ataxia, caused by an expanded GAA repeat sequence in the Frataxin (FXN) gene. The proprioceptive system, which enters the cerebellum through the cerebellar peduncles, is a primary focus of pathology. In this study, we investigate the relationship of clinical and genetic data with diffusion-tensor imaging (DTI) indices reflecting white matter integrity of the cerebellar peduncles. Nine FRDA patients underwent DTI. After between-subject registration using tract-based spatial statistics, a white matter atlas was used for computing average values of DTI indices in the regions of interest. These were the inferior, middle and superior cerebellar peduncles (ICP, MCP, SCP). For Bonferroni correction, significance threshold was set to p < 0.0056. We found that radial diffusivity (D(⊥)) within the ICP significantly correlated with scores on the Friedreich Ataxia Rating Scale (FARS, Spearman's ρ = 0.883, p = 0.0016, all two-sided) and, at trend level, with number of trinucleotide repeats (ρ = 0.812, p = 0.008). D(⊥) in the SCP correlated with scores on the Scale for the Assessment and Rating of Ataxia (SARA, ρ = 0.867, p = 0.0025). These findings support the role of DTI, and especially D(⊥), as an informative biomarker in FRDA.
Leslie Wolfson, Dorothy B Wakefield, Nicola Moscufo, Richard F Kaplan, Charles B Hall, Julia A Schmidt, Charles RG Guttmann, and William B White. 2013. “Rapid buildup of brain white matter hyperintensities over 4 years linked to ambulatory blood pressure, mobility, cognition, and depression in old persons.” J Gerontol A Biol Sci Med Sci, 68, 11, Pp. 1387-94.Abstract
BACKGROUND: Brain white matter hyperintensities (WMH) are associated with functional decline in older people. We performed a 4-year cohort study examining progression of WMH, its effects on mobility, cognition, and depression with the role of clinic and 24-hour ambulatory systolic blood pressure as a predisposing factor. METHODS: Ninety-nine subjects, 75-89 years were stratified by age and mobility, with the 67 completing 4-years comprising the cohort. Mobility, cognition, depressive symptoms, and ambulatory blood pressure were assessed, and WMH volumes were determined by quantitative analysis of magnetic resonance images. RESULTS: WMH increased from 0.99±0.98% of intracranial cavity volume at baseline to 1.47±1.2% at 2 years and 1.74±1.30% after 4 years. Baseline WMH was associated with 4-year WMH (p < .0001), explaining 83% of variability. Small, but consistent mobility decrements and some evidence of cognitive decline were noted over 4 years. Regression analyses using baseline and 4-year WMHs were associated with three of five mobility measures, two of four cognitive measures and the depression scale, all performed at 4 years. Increases in ambulatory systolic blood pressure but not clinic systolic blood pressure during the initial 2 years were associated with greater WMH accrual during those years, while ambulatory systolic blood pressure was related to WMH at 4 years. CONCLUSION: Declines in mobility, cognition, and depressive symptoms were related to WMH accrual over 4 years, and WMH was related to out-of-office blood pressure. This suggests that prevention of microvascular disease, even in asymptomatic older persons, is fundamental for preserving function. There may be value in tighter 24-hour blood pressure control in older persons although this requires further investigation.
2012
Mark P Gorman, Jan-Mendelt Tillema, Annika M Ciliax, Charles RG Guttmann, and Tanuja Chitnis. 2012. “Daclizumab use in patients with pediatric multiple sclerosis.” Arch Neurol, 69, 1, Pp. 78-81.Abstract
BACKGROUND: Daclizumab, a humanized monoclonal antibody specific for the interleukin 2 receptor α chain, reduces clinical and magnetic resonance imaging disease activity in patients with adult-onset multiple sclerosis (MS) as monotherapy or add-on therapy with interferon. OBJECTIVE: To report the use of daclizumab in pediatric-onset MS. DESIGN: Case series. SETTING: Two comprehensive pediatric MS centers. PATIENTS: Seven patients with pediatric-onset MS with clinical and magnetic resonance imaging disease activity despite first-line disease-modifying therapy. INTERVENTION: Intravenous daclizumab, 1 mg/kg monthly. MAIN OUTCOME MEASURES: Annualized relapse rates, Expanded Disability Status Scale scores, contrast-enhancing lesions, and adverse effects. RESULTS: Treatment with daclizumab, primarily combined with interferon, was associated with reductions in annualized relapse rates and contrast-enhancing lesions and with reduction or stabilization of Expanded Disability Status Scale scores in each patient. However, 4 patients had relapses and new contrast-enhancing lesions during daclizumab treatment. No significant adverse effects occurred. CONCLUSION: Daclizumab may be a safe and at least partially effective treatment option for patients with pediatric-onset MS with disease activity despite first-line disease-modifying therapy.
S Hannoun, F Durand-Dubief, C Confavreux, D Ibarrola, N Streichenberger, F Cotton, CRG Guttmann, and D Sappey-Marinier. 2012. “Diffusion tensor-MRI evidence for extra-axonal neuronal degeneration in caudate and thalamic nuclei of patients with multiple sclerosis.” AJNR Am J Neuroradiol, 33, 7, Pp. 1363-8.Abstract
BACKGROUND AND PURPOSE: MS is an inflammatory demyelinating disease affecting both WM and GM. While WM lesions are easily visualized by conventional MR imaging, the detection of GM alterations remains challenging. This diffusion tensor MR imaging study aimed to detect and characterize diffuse microscopic alterations in 2 deep GM structures, the caudate nucleus and the thalamus, in patients with RR and SP MS. The relationship between diffusivity markers, and atrophy of the caudate and the thalamus, as well as brain lesion load and clinical status of the patients was also explored. MATERIALS AND METHODS: Twenty-three RR and 18 SP patients, along with 27 healthy controls, underwent MR imaging examination including anatomic and DTI acquisitions. Volumes, mean FA, and MD of the caudate and the thalamus, as well as WM lesion volumes, were assessed. RESULTS: FA was significantly (P < .001) increased in the caudate and the thalamus of patients with MS compared with controls, and was higher in SP compared with RR patients. Increased FA was associated with volume decreases of caudate (r = -0.712; P < .001) and thalamus (r = -0.407; P < .01) in patients with MS. WM T2 lesion load was significantly associated with caudate (r = 0.611; P < .001) and thalamic (r = 0.354; P < .05) FA. Caudate FA, and, to a lesser extent, thalamic FA, were associated with functional deficits, as measured by EDSS and MSFC. CONCLUSIONS: Increased FA in the caudate and the thalamus may constitute a sensitive marker of MS pathologic processes, such as loss of dendrites and/or swelling of neuronal cell bodies.
A Ceccarelli, JS Jackson, S Tauhid, A Arora, J Gorky, E Dell'Oglio, A Bakshi, T Chitnis, SJ Khoury, HL Weiner, CRG Guttmann, R Bakshi, and M Neema. 2012. “The impact of lesion in-painting and registration methods on voxel-based morphometry in detecting regional cerebral gray matter atrophy in multiple sclerosis.” AJNR Am J Neuroradiol, 33, 8, Pp. 1579-85.Abstract
BACKGROUND AND PURPOSE: VBM has been widely used to study GM atrophy in MS. MS lesions lead to segmentation and registration errors that may affect the reliability of VBM results. Improved segmentation and registration have been demonstrated by WM LI before segmentation. DARTEL appears to improve registration versus the USM. Our aim was to compare the performance of VBM-DARTEL versus VBM-USM and the effect of LI in the regional analysis of GM atrophy in MS. MATERIALS AND METHODS: 3T T1 MR imaging scans were acquired from 26 patients with RRMS and 28 age-matched NC. LI replaced WM lesions with normal-appearing WM intensities before image segmentation. VBM analysis was performed in SPM8 by using DARTEL and USM with and without LI, allowing the comparison of 4 VBM methods (DARTEL + LI, DARTEL - LI, USM + LI, and USM - LI). Accuracy of VBM was assessed by using NMI, CC, and a simulation analysis. RESULTS: Overall, DARTEL + LI yielded the most accurate GM maps among the 4 methods (highest NMI and CC, P < .001). DARTEL + LI showed significant GM loss in the bilateral thalami and caudate nuclei in patients with RRMS versus NC. The other 3 methods overestimated the number of regions of GM loss in RRMS versus NC. LI improved the accuracy of both VBM methods. Simulated data suggested the accuracy of the results provided from patient MR imaging analysis. CONCLUSIONS: We introduce a pipeline that shows promise in limiting segmentation and registration errors in VBM analysis in MS.
Jennifer Moodie, Brian C Healy, Guy J Buckle, Susan A Gauthier, Bonnie I Glanz, Ashish Arora, Antonia Ceccarelli, Shahamat Tauhid, Xue-Mei Han, Arun Venkataraman, Tanuja Chitnis, Samia J Khoury, Charles RG Guttmann, Howard L Weiner, Mohit Neema, and Rohit Bakshi. 2012. “Magnetic resonance disease severity scale (MRDSS) for patients with multiple sclerosis: a longitudinal study.” J Neurol Sci, 315, 1-2, Pp. 49-54.Abstract
BACKGROUND: We previously described a composite MRI scale combining T1-lesions, T2-lesions and whole brain atrophy in multiple sclerosis (MS): the magnetic resonance disease severity scale (MRDSS). OBJECTIVE: Test strength of the MRDSS vs. individual MRI measures for sensitivity to longitudinal change. METHODS: We studied 84 MS patients over a 3.2±0.3 year follow-up. Baseline and follow-up T2-lesion volume (T2LV), T1-hypointense lesion volume (T1LV), and brain parenchymal fraction (BPF) were measured. MRDSS was the combination of standardized T2LV, T1/T2 ratio and BPF. RESULTS: Patients had higher MRDSS at follow-up vs. baseline (p<0.001). BPF decreased (p<0.001), T1/T2 increased (p<0.001), and T2LV was unchanged (p>0.5). Change in MRDSS was larger than the change in MRI subcomponents. While MRDSS showed significant change in relapsing-remitting (RR) (p<0.001) and secondary progressive (SP) phenotypes (p<0.05), BPF and T1/T2 ratio changed only in RRMS (p<0.001). Longitudinal change in MRDSS was significantly different between RRMS and SPMS (p=0.0027); however, change in the individual MRI components did not differ. Evaluation with respect to predicting on-study clinical worsening as measured by EDSS revealed a significant association only for T2LV (p=0.038). CONCLUSION: Results suggest improved sensitivity of MRDSS to longitudinal change vs. individual MRI measures. MRDSS has particularly high sensitivity in RRMS.
Nicola Moscufo, Leslie Wolfson, Dominik Meier, Maria Liguori, Peter G Hildenbrand, Dorothy Wakefield, Julia A Schmidt, Godfrey D Pearlson, and Charles RG Guttmann. 2012. “Mobility decline in the elderly relates to lesion accrual in the splenium of the corpus callosum.” Age (Dordr), 34, 2, Pp. 405-14.Abstract
In a previous cross-sectional study on baseline data, we demonstrated that the volume of brain white matter hyperintensities (WMH) in the splenium of corpus callosum (SCC) predicted the current mobility function of older persons. The primary aim of this follow-up study was to determine the relation of WMH volume change in SCC (SCC-∆WMH) with change in mobility measures. A secondary aim was to characterize the global and regional progression of WMH. Mobility function and WMH burden were evaluated at baseline and at 2 years in 77 community-dwelling individuals (baseline age, 82 ± 4). Regional WMH in SCC, as well as genu and body of corpus callosum, subregions of corona radiata, and superior longitudinal fasciculus were determined using a white matter parcellation atlas. The total WMH volume increased 3.3 ± 3.5 ml/year, mainly through enlargement. Significant WMH increases were observed in all selected regions, particularly within the corona radiata. While at baseline and follow-up we observed correlations between WMH burden and several measures of mobility, longitudinal change correlated only with change in chair rise (CR). SCC-∆WMH showed the highest correlation (r = -0.413, p = 0.0002) and was the best regional predictor of CR decline (OR = 1.5, r(2) = 0.3). The SCC-∆WMH was more than five times larger in the CR-decline group compared to the no-decline group (p = 0.0003). The SCC-∆WMH (top quartile) showed a higher sensitivity/specificity for CR decline compared to change in total WMH, 63/88% versus 52/84%, respectively. The findings suggest that accrual of WMHs in posterior areas of the brain supporting inter-hemispheric integration and processing of visual-spatial information is a mechanism contributing to age-related mobility deterioration.
Christopher M Holland, Arnaud Charil, Istvan Csapo, Zsuzsanna Liptak, Masanori Ichise, Samia J Khoury, Rohit Bakshi, Howard L Weiner, and Charles RG Guttmann. 2012. “The relationship between normal cerebral perfusion patterns and white matter lesion distribution in 1,249 patients with multiple sclerosis.” J Neuroimaging, 22, 2, Pp. 129-36.Abstract
BACKGROUND AND PURPOSE: The pathological differences underlying the clinical disease phases in multiple sclerosis (MS) are poorly characterized. We sought to explore the relationship between the distribution of white matter (WM) lesions in relapsing-remitting (RR) and secondary progressive (SP) MS and the normal regional variability of cerebral perfusion. METHODS: WM lesions were identified and quantified on a single magnetic resonance imaging scan from 1,249 patients with MS. The spatial distribution of lesions was compared between early RR, late RR, and SP MS in the context of normal cerebral perfusion patterns provided by a single-photon emission-computed tomography atlas of healthy individuals. RESULTS: Patients with SP MS had more distinct and larger lesions than patients with RR MS. Across all subjects, lesions were present in regions of relatively lower normal perfusion than normal appearing WM. Further, lesions in SP MS were more common in areas of lower perfusion as compared to the lesion distribution in early and late RR MS. CONCLUSION: Chronic plaques were more prevalent in WM regions with lower relative perfusion. Lesions in more highly perfused regions were more commonly observed in early RR MS and therefore, may be more likely to successfully remyelinate and resolve.
Adam B Cohen, Mohit Neema, Ashish Arora, Elisa Dell'Oglio, Ralph HB Benedict, Shahamat Tauhid, Daniel Goldberg-Zimring, Christian Chavarro-Nieto, Antonella Ceccarelli, Joshua P Klein, James M Stankiewicz, Maria K Houtchens, Guy J Buckle, David C Alsop, Charles RG Guttmann, and Rohit Bakshi. 2012. “The relationships among MRI-defined spinal cord involvement, brain involvement, and disability in multiple sclerosis.” J Neuroimaging, 22, 2, Pp. 122-8.Abstract
OBJECTIVE: To determine the interrelationships between MRI-defined lesion and atrophy measures of spinal cord involvement and brain involvement and their relationships to disability in a small cohort of patients with multiple sclerosis (MS). BACKGROUND: Although it is known that cervical spinal cord atrophy correlates with disability in MS, it is unknown whether it is the most important determinant when compared to other regions of the central nervous system (CNS). Furthermore, it is not clear to what extent brain and cord lesions and atrophy are related. DESIGN AND METHODS: 3T MRI of the whole brain and whole spinal cord was obtained in 21 patients with MS, including 18 with relapsing-remitting, one with secondary progressive, one with primary progressive, and one with a clinically isolated syndrome. Brain global gray and white matter volumes were segmented with Statistical Parametric Mapping 8. Spinal cord contour volume was segmented in whole by a semi-automated method with bins assigned to either the cervical or thoracic regions. All CNS volumes were normalized by the intracranial volume. Brain and cord T2 hyperintense lesions were segmented using a semi-automated edge finding tool. RESULTS: Among all MRI measures, only upper cervical spinal cord volume significantly correlated with Expanded Disability Status Scale score (r =-.515, P = .020). The brain cord relationships between whole or regional spinal cord volume or lesions and gray matter, white matter, or whole brain volume or whole brain lesions were generally weak and all nonsignificant. CONCLUSIONS AND RELEVANCE: In this preliminary study of mildly disabled, treated MS patients, cervical spinal cord atrophy most strongly correlates with physical disability in MS when accounting for a wide range of other CNS measures of lesions and atrophy, including thoracic or whole spinal cord volume, and cerebral gray, white or whole brain volume. The weak relationship between spinal cord and brain lesions and atrophy may suggest that they progress rather independently in patients with MS.
2011
JP Klein, A Arora, M Neema, BC Healy, S Tauhid, D Goldberg-Zimring, C Chavarro-Nieto, JM Stankiewicz, AB Cohen, GJ Buckle, MK Houtchens, A Ceccarelli, E Dell'Oglio, CRG Guttmann, DC Alsop, DB Hackney, and R Bakshi. 2011. “A 3T MR imaging investigation of the topography of whole spinal cord atrophy in multiple sclerosis.” AJNR Am J Neuroradiol, 32, 6, Pp. 1138-42.Abstract
BACKGROUND AND PURPOSE: Spinal cord atrophy is a common feature of MS. However, it is unknown which cord levels are most susceptible to atrophy. We performed whole cord imaging to identify the levels most susceptible to atrophy in patients with MS versus controls and also tested for differences among MS clinical phenotypes. MATERIALS AND METHODS: Thirty-five patients with MS (2 with CIS, 27 with RRMS, 2 with SPMS, and 4 with PPMS phenotypes) and 27 healthy controls underwent whole cord 3T MR imaging. The spinal cord contour was segmented and assigned to bins representing each C1 to T12 vertebral level. Volumes were normalized, and group comparisons were age-adjusted. RESULTS: There was a trend toward decreased spinal cord volume at the upper cervical levels in PPMS/SPMS versus controls. A trend toward increased spinal cord volume throughout the cervical and thoracic cord in RRMS/CIS versus controls reached statistical significance at the T10 vertebral level. A statistically significant decrease was found in spinal cord volume at the upper cervical levels in PPMS/SPMS versus RRMS/CIS. CONCLUSIONS: Opposing pathologic factors impact spinal cord volume measures in MS. Patients with PPMS demonstrated a trend toward upper cervical cord atrophy. However patients with RRMS showed a trend toward increased volume at the cervical and thoracic levels, which most likely reflects inflammation or edema-related cord expansion. With the disease causing both expansion and contraction of the cord, the specificity of spinal cord volume measures for neuroprotective therapeutic effect may be limited.
Angela L Jefferson, Christopher M Holland, David F Tate, Istvan Csapo, Athena Poppas, Ronald A Cohen, and Charles RG Guttmann. 2011. “Atlas-derived perfusion correlates of white matter hyperintensities in patients with reduced cardiac output.” Neurobiol Aging, 32, 1, Pp. 133-9.Abstract
Reduced cardiac output is associated with increased white matter hyperintensities (WMH) and executive dysfunction in older adults, which may be secondary to relations between systemic and cerebral perfusion. This study preliminarily describes the regional distribution of cerebral WMH in the context of a normal cerebral perfusion atlas and aims to determine if these variables are associated with reduced cardiac output. Thirty-two participants (72 ± 8 years old, 38% female) with cardiovascular risk factors or disease underwent structural MRI acquisition at 1.5T using a standard imaging protocol that included FLAIR sequences. WMH distribution was examined in common anatomical space using voxel-based morphometry and as a function of normal cerebral perfusion patterns by overlaying a single photon emission computed tomography (SPECT) atlas. Doppler echocardiogram data was used to dichotomize the participants on the basis of low (n=9) and normal (n=23) cardiac output. Global WMH count and volume did not differ between the low and normal cardiac output groups; however, atlas-derived SPECT perfusion values in regions of hyperintensities were reduced in the low versus normal cardiac output group (p<0.001). Our preliminary data suggest that participants with low cardiac output have WMH in regions of relatively reduced perfusion, while normal cardiac output participants have WMH in regions with relatively higher regional perfusion. This spatial perfusion distribution difference for areas of WMH may occur in the context of reduced systemic perfusion, which subsequently impacts cerebral perfusion and contributes to subclinical or clinical microvascular damage.
William B White, Leslie Wolfson, Dorothy B Wakefield, Charles B Hall, Patrick Campbell, Nicola Moscufo, Julia Schmidt, Richard F Kaplan, Godfrey Pearlson, and Charles RG Guttmann. 2011. “Average daily blood pressure, not office blood pressure, is associated with progression of cerebrovascular disease and cognitive decline in older people.” Circulation, 124, 21, Pp. 2312-9.Abstract
BACKGROUND: High blood pressure (BP) is a risk factor for cerebrovascular disease, including stroke. Little is known about the importance of BP on the progression of microvascular disease of the brain, which has been associated with functional decline in mobility and cognition in older people. METHODS AND RESULTS: This was a prospective cohort of subjects 75 to 89 years of age to determine relations among vascular risk factors, white matter hyperintensity volume, and functional status. Ninety-nine subjects were enrolled through the use of a balanced 3×3 matrix stratified by age and mobility performance, and 72 subjects completed all sets of baseline and follow-up studies at 2 years. Subjects were excluded if there were medications or systemic or neurological diseases that could compromise mobility. Ambulatory and clinic BP monitoring, magnetic resonance imaging, gait studies, and neuropsychological testing were performed at baseline and after 24 months. Brain classification into normal white matter and T2-hyperintense white matter hyperintensity volume was performed with semiautomated segmentation. Quantitative measures of mobility and cognitive function were obtained longitudinally. Increased ambulatory systolic BP, but not clinic systolic BP, from baseline to 24 month follow-up was associated with increased white matter hyperintensity volume over that same period, as well as measures of executive function/processing speed. Similar associations were observed for 24-hour BP, awake BP, and sleep BP but not for the surge between the sleep and awake time at the 24-month time point. CONCLUSIONS: These data demonstrate for the first time the importance of 24-hour systolic BP in the progression of brain white matter hyperintensity volume burden associated with impairment of cognitive function in older people. The 24-hour systolic BP may be a potential target for intervention in the elderly to reduce vascular disease of the brain and impairment of function.
James M Stankiewicz, Bonnie I Glanz, Brian C Healy, Ashish Arora, Mohit Neema, Ralph HB Benedict, Zachary D Guss, Shahamat Tauhid, Guy J Buckle, Maria K Houtchens, Samia J Khoury, Howard L Weiner, Charles RG Guttmann, and Rohit Bakshi. 2011. “Brain MRI lesion load at 1.5T and 3T versus clinical status in multiple sclerosis.” J Neuroimaging, 21, 2, Pp. e50-6.Abstract
BACKGROUND/PURPOSE: To assess correlation between brain lesions and clinical status with 1.5T and 3T magnetic resonance imaging (MRI). METHODS: Brain MRI fluid-attenuated inversion-recovery (FLAIR) sequences were performed in 32 multiple sclerosis (MS) patients. Expanded Disability Status Scale (EDSS) score (mean±standard deviation) was 2±2.0 (range 0-8), disease duration 9.3±8.0 (range .8-29) years. RESULTS: FLAIR lesion volume (FLLV) at 3T was higher than at 1.5T (P=.01). Correlation between 1.5T FLLV and EDSS score was poor, while 3T FLLV correlated moderately and significantly (rs=.39, P=.03). When controlling for age and depression, correlations between FLLV and cognitive measures were significant at 1.5T for the Judgment of Line Orientation test (JLO) (rs=-.44, P=.05), the Symbol Digit Modalities Test (SDMT) (rs=-.49, P=.02), and the California Verbal Learning Test Delayed Free Recall (CVLT DR) (rs=-.44, P=.04). Correlations at 3T were also significant for these tests, but of greater magnitude: JLO (rs=-.70, P=.0005), SDMT (rs=-.73, P=.0001), CVLT DR (rs=-.061, P=.003). Additional significant correlations obtained only at 3T included the 2 second-paced auditory serial addition test (rs=-.55, P=.01), the Brief Visuospatial Memory Test-Delayed Free Recall (rs=-.56, P=.007), and the California Verbal Learning Test Total Recall (rs=-.42, P=.05). CONCLUSION: MRI at 3T may boost sensitivity and improve validity in MS brain lesion assessment.
Nicola Moscufo, Charles RG Guttmann, Dominik Meier, Istvan Csapo, Peter G Hildenbrand, Brian C Healy, Julia A Schmidt, and Leslie Wolfson. 2011. “Brain regional lesion burden and impaired mobility in the elderly.” Neurobiol Aging, 32, 4, Pp. 646-54.Abstract
This study investigated the relationship of brain white matter (WM) lesions affecting specific neural networks with decreased mobility in ninety-nine healthy community-dwelling subjects ≥75 years old prospectively enrolled by age and mobility status. We assessed lesion burden in the genu, body and splenium of corpus callosum; anterior, superior and posterior corona radiata; anterior and posterior limbs of internal capsule; corticospinal tract; and superior longitudinal fasciculus. Burden in the splenium of corpus callosum (SCC) demonstrated the highest correlation particularly with walking speed (r=0.4, p<10(-4)), and in logistic regression it was the best regional predictor of low mobility performance. We also found that independent of mobility, corona radiata has the largest lesion burden with anterior (ACR) and posterior (PCR) aspects being the most frequently affected. The results suggest that compromised inter-hemispheric integration of visuospatial information through the SCC plays an important role in mobility impairment in the elderly. The relatively high lesion susceptibility of ACR and PCR in all subjects may obscure the importance of these lesions in mobility impairment.

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