Federico Torelli, Nicola Moscufo, Girolamo Garreffa, Fabio Placidi, Andrea Romigi, Silvana Zannino, Marco Bozzali, Fabrizio Fasano, Giovanni Giulietti, Ina Djonlagic, Atul Malhotra, Maria Grazia Marciani, and Charles RG Guttmann. 2011. “Cognitive profile and brain morphological changes in obstructive sleep apnea.” Neuroimage, 54, 2, Pp. 787-93.Abstract
Obstructive sleep apnea (OSA) is accompanied by neurocognitive impairment, likely mediated by injury to various brain regions. We evaluated brain morphological changes in patients with OSA and their relationship to neuropsychological and oximetric data. Sixteen patients affected by moderate-severe OSA (age: 55.8±6.7 years, 13 males) and fourteen control subjects (age: 57.6±5.1 years, 9 males) underwent 3.0 Tesla brain magnetic resonance imaging (MRI) and neuropsychological testing evaluating short- and long-term memory, executive functions, language, attention, praxia and non-verbal learning. Volumetric segmentation of cortical and subcortical structures and voxel-based morphometry (VBM) were performed. Patients and controls differed significantly in Rey Auditory-Verbal Learning test (immediate and delayed recall), Stroop test and Digit span backward scores. Volumes of cortical gray matter (GM), right hippocampus, right and left caudate were smaller in patients compared to controls, with also brain parenchymal fraction (a normalized measure of cerebral atrophy) approaching statistical significance. Differences remained significant after controlling for comorbidities (hypertension, diabetes, smoking, hypercholesterolemia). VBM analysis showed regions of decreased GM volume in right and left hippocampus and within more lateral temporal areas in patients with OSA. Our findings indicate that the significant cognitive impairment seen in patients with moderate-severe OSA is associated with brain tissue damage in regions involved in several cognitive tasks. We conclude that OSA can increase brain susceptibility to the effects of aging and other clinical and pathological occurrences.
M Liguori, BC Healy, BI Glanz, SJ Khoury, N Moscufo, HL Weiner, PL De Jager, and CR Guttmann. 2011. “HLA (A-B-C and -DRB1) alleles and brain MRI changes in multiple sclerosis: a longitudinal study.” Genes Immun, 12, 3, Pp. 183-90.Abstract
Several major histocompatibility complex (MHC) alleles have been postulated to influence the susceptibility to multiple sclerosis (MS), as well as its clinical/radiological course. In this longitudinal observation, we further explored the impact of human leukocyte antigen (HLA) class I/II alleles on MS outcomes, and we tested the hypothesis that HLA DRB1*1501 might uncover different strata of MS subjects harboring distinct MHC allele associations with magnetic resonance imaging (MRI) measures. Five hundred eighteen MS patients with two-digit HLA typing and at least one brain MRI were recruited for the study. T2-weighted hyperintense lesion volume (T2LV) and brain parenchymal fraction (BPF) were acquired at each time point. The association between allele count and MRI values was determined using linear regression modeling controlling for age, disease duration and gender. Analyses were also stratified by the presence/absence of HLA DRB1*1501. HLA DRB1*04 was associated with higher T2LV (P=0.006); after stratification, its significance remained only in the presence of HLA DRB1*1501 (P=0.012). The negative effect of HLA DRB1*14 on T2LV was exerted in DRB1*1501-negative group (P=0.012). Longitudinal analysis showed that HLA DRB1*10 was significantly protective on T2LV accrual in the presence of HLA DRB1*1501 (P=0.002). Although the majority of our results did not withstand multiple comparison correction, the differential impact of several HLA alleles in the presence/absence of HLA DRB1*1501 suggests that they may interact in determining the different phenotypic expressions of MS.
A Mike, BI Glanz, P Hildenbrand, D Meier, K Bolden, M Liguori, E Dell'Oglio, BC Healy, R Bakshi, and CRG Guttmann. 2011. “Identification and clinical impact of multiple sclerosis cortical lesions as assessed by routine 3T MR imaging.” AJNR Am J Neuroradiol, 32, 3, Pp. 515-21.Abstract
BACKGROUND AND PURPOSE: Histopathologic studies have reported widespread cortical lesions in MS; however, in vivo detection by using routinely available pulse sequences is challenging. We investigated the relative frequency and subtypes of cortical lesions and their relationships to white matter lesions and cognitive and physical disability. MATERIALS AND METHODS: Cortical lesions were identified and classified on the basis of concurrent review of 3D FLAIR and 3D T1-weighted IR-SPGR 3T MR images in 26 patients with MS. Twenty-five patients completed the MACFIMS battery. White matter lesion volume, cortical lesion number, and cortical lesion volume were assessed. RESULTS: Overall, 249 cortical lesions were detected. Cortical lesions were present in 24/26 patients (92.3%) (range per patient, 0-30; mean, 9.6 ± 8.8). Most (94.4%, n = 235) cortical lesions were classified as mixed cortical-subcortical (type I); the remaining 5.6% (n = 14) were classified as purely intracortical (type II). Subpial cortical lesions (type III) were not detected. White matter lesion volume correlated with cortical lesion number and cortical lesion volume (r(S) = 0.652, r(S) = 0.705, respectively; both P < .001). After controlling for age, depression, and premorbid intelligence, we found that all MR imaging variables (cortical lesion number, cortical lesion volume, white matter lesion volume) correlated with the SDMT score (R(2) = 0.513, R(2) = 0.449, R(2) = 0.418, respectively; P < .014); cortical lesion number also correlated with the CVLT-II scores (R(2) = 0.542-0.461, P < .043). The EDSS scores correlated with cortical lesion number and cortical lesion volume (r(S) = 0.472, r(S) = 0.404, respectively; P < .05), but not with white matter lesion volume. CONCLUSIONS: Our routinely available imaging method detected many cortical lesions in patients with MS and was useful in their precise topographic characterization in the context of the gray matter-white matter junction. Routinely detectable cortical lesions were related to physical disability and cognitive impairment.
Farzaneh A Sorond, Dan K Kiely, Andrew Galica, Nicola Moscufo, Jorge M Serrador, Ike Iloputaife, Svetlana Egorova, Elisa Dell'Oglio, Dominik S Meier, Elizabeth Newton, William P Milberg, Charles RG Guttmann, and Lewis A Lipsitz. 2011. “Neurovascular coupling is impaired in slow walkers: the MOBILIZE Boston Study.” Ann Neurol, 70, 2, Pp. 213-20.Abstract
OBJECTIVE: Neurovascular coupling may be involved in compensatory mechanisms responsible for preservation of gait speed in elderly people with cerebrovascular disease. Our study examines the association between neurovascular coupling in the middle cerebral artery and gait speed in elderly individuals with impaired cerebral vasoreactivity. METHODS: Twenty-two fast and 20 slow walkers in the lowest quartile of cerebral vasoreactivity were recruited from the MOBILIZE Boston Study. Neurovascular coupling was assessed in bilateral middle cerebral arteries by measuring cerebral blood flow during the N-Back task. Cerebral white matter hyperintensities were measured for each group using magnetic resonance imaging. RESULTS: Neurovascular coupling was attenuated in slow compared to fast walkers (2.8%; 95% confidence interval [CI], -0.9 to 6.6 vs 8.2%; 95% CI, 4.7-11.8; p = 0.02). The odds ratio of being a slow walker was 6.4 (95% CI, 1.7-24.9; p = 0.007) if there was a high burden of white matter hyperintensity; however, this risk increased to 14.5 (95% CI, 2.3-91.1; p = 0.004) if neurovascular coupling was also attenuated. INTERPRETATION: Our results suggest that intact neurovascular coupling may help preserve mobility in elderly people with cerebral microvascular disease.
Maria Liguori, Dominik S Meier, Peter Hildenbrand, Brian C Healy, Tanuja Chitnis, Natalie F Baruch, Samia J Khoury, Howard L Weiner, Rohit Bakshi, Frederik Barkhof, and Charles RG Guttmann. 2011. “One year activity on subtraction MRI predicts subsequent 4 year activity and progression in multiple sclerosis.” J Neurol Neurosurg Psychiatry, 82, 10, Pp. 1125-31.Abstract
OBJECTIVE: To investigate the predictive value of 1 year subtraction MRI (sMRI) on activity and progression over the next 4 years in early phase multiple sclerosis (MS). To compare sensitivity of sMRI and contrast enhanced MRI towards disease activity. METHODS: The study was performed on 127 MS patients with brain MRI within 5 years of symptom onset (y0), after 1 year (y1) and after 5 years (y5). Measures of clinical (Expanded Disability Status Scale, relapse rate) and conventional MRI outcomes (brain parenchyma fraction (BPF); T2 lesion volume (T2LV); contrast enhancing lesions (CEL)) were available at all time points. sMRI was obtained from y1-y0, y5-y1 and y5-y0 image pairs and the number of new, enlarged, resolved and regressed lesions was counted. RESULTS: One year lesion change measured by sMRI predicted sMRI lesion change (p<0.0001), BPF and T2LV (p<0.05) changes, as well as clinical relapse rate (p<0.02) in the subsequent 4 years. sMRI measures were retained in stepwise predictive models that included other candidate MRI predictors. Active lesions on sMRI over a 1, 4 or 5 year interval provided a more sensitive assessment of disease activity than number of CEL at y0, y1 and/or y5: 83%, 93% and 90% of patients without CEL showed sMRI activity during the y1-y0, y5-y1, and y5-y0 intervals. CONCLUSIONS: sMRI is a feasible and sensitive tool for detecting MS activity and may provide an alternative to contrast enhanced MRI in clinical practice, particularly in cases where CEL are not available or inconclusive. Furthermore, sMRI metrics combined with conventional MRI outcomes (CEL, T2LV, BPF) can increase the prediction of longer term MRI activity and progression.
David F Tate, Mehul Sampat, Jaroslaw Harezlak, Mark Fiecas, Joseph Hogan, Jeffrey Dewey, Daniel McCaffrey, Daniel Branson, Troy Russell, Jared Conley, Michael Taylor, Giovanni Schifitto, Giavoni Schifitto, J Zhong, Eric S Daar, Jeffrey Alger, Mark Brown, Elyse Singer, T Campbell, D McMahon, Y Tso, Janetta Matesan, Scott Letendre, S Paulose, Michelle Gaugh, C Tripoli, Constantine Yiannoutsos, Erin D Bigler, Ronald A Cohen, Charles RG Guttmann, and Bradford Navia. 2011. “Regional areas and widths of the midsagittal corpus callosum among HIV-infected patients on stable antiretroviral therapies.” J Neurovirol, 17, 4, Pp. 368-79.Abstract
Recent reports suggest that a growing number of human immunodeficiency virus (HIV)-infected persons show signs of persistent cognitive impairment even in the context of combination antiretroviral therapies (cART). The basis for this finding remains poorly understood as there are only a limited number of studies examining the relationship between CNS injury, measures of disease severity, and cognitive function in the setting of stable disease. This study examined the effects of HIV infection on cerebral white matter using quantitative morphometry of the midsagittal corpus callosum (CC) in 216 chronically infected participants from the multisite HIV Neuroimaging Consortium study currently receiving cART and 139 controls. All participants underwent MRI assessment, and HIV-infected subjects also underwent measures of cognitive function and disease severity. The midsagittal slice of the CC was quantified using two semi-automated procedures. Group comparisons were accomplished using ANOVA, and the relationship between CC morphometry and clinical covariates (current CD4, nadir CD4, plasma and CSF HIV RNA, duration of HIV infection, age, and ADC stage) was assessed using linear regression models. HIV-infected patients showed significant reductions in both the area and linear widths for several regions of the CC. Significant relationships were found with ADC stage and nadir CD4 cell count, but no other clinical variables. Despite effective treatment, significant and possibly irreversible structural loss of the white matter persists in the setting of chronic HIV disease. A history of advanced immune suppression is a strong predictor of this complication and suggests that antiretroviral intervention at earlier stages of infection may be warranted.
Mehul P Sampat, Brian C Healy, Dominik S Meier, Elisa Dell'Oglio, Maria Liguori, and Charles RG Guttmann. 2010. “Disease modeling in multiple sclerosis: assessment and quantification of sources of variability in brain parenchymal fraction measurements.” Neuroimage, 52, 4, Pp. 1367-73.Abstract
The measurement of brain atrophy from magnetic resonance imaging (MRI) has become an established method of estimating disease severity and progression in multiple sclerosis (MS). Most commonly reported in the form of brain parenchymal fraction (BPF), it is more sensitive to the degenerative component of the disease and shows progression more reliably than lesion burden. Typically, the reliability of BPF and other morphometric measurements is assessed by evaluating scan-rescan experiments. While these experiments provide good estimates of real-life error related to imperfect patient repositioning in the MRI scanner, measurement variance due to physiological and reversible pathological fluctuations in brain volume are not taken into account. In this work, we propose a new model for estimating variability in serial morphometry, particularly the BPF measurement. Specifically, we attempt to detect and explicitly model the remaining sources of error to more accurately describe the overall variability in BPF measurements. Our results show that sources of variability beyond subject repositioning error are important and cannot be ignored. We demonstrate that scan-rescan experiments only provide a lower bound on the true error in repeated measurements of patients' BPF. We have estimated the variance due to patient repositioning during scan-rescan (sigma(sr)(2) = 3.0e-06), variance assigned to physiological fluctuations (sigma(p)(2) = 5.74e-06) and the variance associated with lesion activity (sigma(les)(2) = 1.09e-05). These variance components can be used to determine the relative impact of their sources on sample size estimates for studies investigating change over time in MS patients. Our results demonstrate that sample size calculations based exclusively on scan-rescan variability (sigma(sr)) are likely to underestimate the number of patients required. If the physiological variability (sigma(p)) is incorporated in sample size calculations, the required sample size would increase by a factor of 5.69 based on standard t-test sample size calculation.
BC Healy, M Liguori, D Tran, T Chitnis, B Glanz, C Wolfish, S Gauthier, G Buckle, M Houtchens, L Stazzone, S Khoury, R Hartzmann, M Fernandez-Vina, DA Hafler, HL Weiner, CRG Guttmann, and PL De Jager. 2010. “HLA B*44: protective effects in MS susceptibility and MRI outcome measures.” Neurology, 75, 7, Pp. 634-40.Abstract
OBJECTIVE: In addition to the main multiple sclerosis (MS) major histocompatibility complex (MHC) risk allele (HLA DRB1*1501), investigations of the MHC have implicated several class I MHC loci (HLA A, HLA B, and HLA C) as potential independent MS susceptibility loci. Here, we evaluate the role of 3 putative protective alleles in MS: HLA A*02, HLA B*44, and HLA C*05. METHODS: Subjects include a clinic-based patient sample with a diagnosis of either MS or a clinically isolated syndrome (n = 532), compared to subjects in a bone marrow donor registry (n = 776). All subjects have 2-digit HLA data. Logistic regression was used to determine the independence of each allele's effect. We used linear regression and an additive model to test for correlation between an allele and MRI and clinical measures of disease course. RESULTS: After accounting for the effect of HLA DRB1*1501, both HLA A*02 and HLA B*44 are validated as susceptibility alleles (p(A*02) 0.00039 and p(B*44) 0.00092) and remain significantly associated with MS susceptibility in the presence of the other allele. Although A*02 is not associated with MS outcome measures, HLA B*44 demonstrates association with a better radiologic outcome both in terms of brain parenchymal fraction and T2 hyperintense lesion volume (p = 0.03 for each outcome). CONCLUSION: The MHC class I alleles HLA A*02 and HLA B*44 independently reduce susceptibility to MS, but only HLA B*44 appears to influence disease course, preserving brain volume and reducing the burden of T2 hyperintense lesions in subjects with MS.
Bastiaan Moraal, Ivo J van den Elskamp, Dirk L Knol, Bernard MJ Uitdehaag, Jeroen JG Geurts, Hugo Vrenken, Petra JW Pouwels, Ronald A van Schijndel, Dominik S Meier, Charles RG Guttmann, and Frederik Barkhof. 2010. “Long-interval T2-weighted subtraction magnetic resonance imaging: a powerful new outcome measure in multiple sclerosis trials.” Ann Neurol, 67, 5, Pp. 667-75.Abstract
OBJECTIVE: To compare long-interval T2-weighted subtraction (T2w-Sub) imaging with monthly gadolinium-enhanced T1-weighted (Gd-T1w) imaging for (1) detection of active lesions, (2) assessment of treatment efficacy, and (3) statistical power, in a multiple sclerosis (MS), phase 2, clinical trial setting. METHODS: Magnetic resonance imaging (MRI) data over 9 months from 120 patients (61 treatment, 59 placebo) from the oral temsirolimus trial were used. T2w-Sub images were scored for active lesions, independent of the original reading of the monthly Gd-T1w images. Treatment efficacy was evaluated using the nonparametric Mann-Whitney U test, and parametric negative binomial (NB)-regression and power calculations were conducted. RESULTS: Datasets from 116 patients (58 treatment, 58 placebo) were evaluated. The mean number of T2w-Sub lesions in the treatment group was 3.0 (+/-4.6) versus 5.9 (+/-8.8) for placebo; the mean cumulative number of new Gd-T1w lesions in the treatment group was 5.5(+/-9.1) versus 9.1(+/-17.2) for placebo. T2w-Sub imaging showed increased power to assess treatment efficacy compared with Gd-T1w imaging, when evaluated by Mann-Whitney U test (p = 0.017 vs p = 0.177), or NB-regression without (p = 0.011 vs p = 0.092) or with baseline adjustment (p < 0.001 vs p = 0.002). Depending on the magnitude of the simulated treatment effect, sample size calculations showed reductions of 22 to 34% in the number of patients (translating into reductions of 81-83% in the number of MRI scans) needed to detect a significant treatment effect in favor of T2w-Sub imaging. INTERPRETATION: Compared with monthly Gd-T1w imaging, long-interval T2w-Sub MRI exhibited increased power to assess treatment efficacy, and could greatly increase the cost-effectiveness of phase 2 MS trials by limiting the number of patients, contrast injections, and MRI scans needed.
Zongqi Xia, Lori B Chibnik, Bonnie I Glanz, Maria Liguori, Joshua M Shulman, Dong Tran, Samia J Khoury, Tanuja Chitnis, Todd Holyoak, Howard L Weiner, Charles RG Guttmann, and Philip L De Jager. 2010. “A putative Alzheimer's disease risk allele in PCK1 influences brain atrophy in multiple sclerosis.” PLoS One, 5, 11, Pp. e14169.Abstract
BACKGROUND: Brain atrophy and cognitive dysfunction are neurodegenerative features of Multiple Sclerosis (MS). We used a candidate gene approach to address whether genetic variants implicated in susceptibility to late onset Alzheimer's Disease (AD) influence brain volume and cognition in MS patients. METHODS/PRINCIPAL FINDINGS: MS subjects were genotyped for five single nucleotide polymorphisms (snps) associated with susceptibility to AD: PICALM, CR1, CLU, PCK1, and ZNF224. We assessed brain volume using Brain Parenchymal Fraction (BPF) measurements obtained from Magnetic Resonance Imaging (MRI) data and cognitive function using the Symbol Digit Modalities Test (SDMT). Genotypes were correlated with cross-sectional BPF and SDMT scores using linear regression after adjusting for sex, age at symptom onset, and disease duration. 722 MS patients with a mean (±SD) age at enrollment of 41 (±10) years were followed for 44 (±28) months. The AD risk-associated allele of a non-synonymous SNP in the PCK1 locus (rs8192708G) is associated with a smaller average brain volume (P=0.0047) at the baseline MRI, but it does not impact our baseline estimate of cognition. PCK1 is additionally associated with higher baseline T2-hyperintense lesion volume (P=0.0088). Finally, we provide technical validation of our observation in a subset of 641 subjects that have more than one MRI study, demonstrating the same association between PCK1 and smaller average brain volume (P=0.0089) at the last MRI visit. CONCLUSION/SIGNIFICANCE: Our study provides suggestive evidence for greater brain atrophy in MS patients bearing the PCK1 allele associated with AD-susceptibility, yielding new insights into potentially shared neurodegenerative process between MS and late onset AD.
Samia J Khoury, Brian C Healy, Pia Kivisäkk, Vissia Viglietta, Svetlana Egorova, Charles RG Guttmann, Josiah F Wedgwood, David A Hafler, Howard L Weiner, Guy Buckle, Sandra Cook, and Susheel Reddy. 2010. “A randomized controlled double-masked trial of albuterol add-on therapy in patients with multiple sclerosis.” Arch Neurol, 67, 9, Pp. 1055-61.Abstract
BACKGROUND: Interleukin 12 (IL-12), a cytokine that promotes generation of helper T cells subtype 1, is increased in multiple sclerosis. Albuterol sulfate, a β2-adrenergic agonist, reduces IL-12 expression, so we tested the effect of albuterol as an add-on treatment to glatiramer acetate therapy. OBJECTIVES: To investigate the clinical and immunologic effects of albuterol treatment as an add-on therapy in patients starting glatiramer acetate treatment. DESIGN: Single-center double-masked clinical trial. SETTING: Academic research. Patients Subjects with relapsing-remitting multiple sclerosis. MAIN OUTCOME MEASURES: In this single-center double-masked clinical trial, subjects with relapsing-remitting multiple sclerosis were randomized to receive a subcutaneous injection of glatiramer acetate (20 mg) plus an oral dose of placebo daily for 2 years or a subcutaneous injection of glatiramer acetate (20 mg) plus an oral dose of albuterol daily for 2 years. The primary clinical efficacy measurement was the change in Multiple Sclerosis Functional Composite at 2 years, and the primary immunologic end point was the change in expression of IL-13 and interferon γ at each study time point. The classification level of evidence from this trial is C for each question, as this is the first class II clinical trial addressing the efficacy of glatiramer acetate plus albuterol. RESULTS: Forty-four subjects were randomized to receive glatiramer acetate plus albuterol or glatiramer acetate plus placebo, and 39 subjects contributed to the analysis. Improvement in the Multiple Sclerosis Functional Composite was observed in the glatiramer acetate plus albuterol group at the 6-month (P = .005) and 12-month (P = .04) time points but not at the 24-month time point. A delay in the time to first relapse was also observed in the glatiramer acetate plus albuterol group (P = .03). Immunologically, IL-13 and interferon-γ production decreased in both treatment groups, and a treatment effect on IL-13 production was observed at the 12-month time point (P < .05). Adverse events were generally mild, and only 3 moderate or severe events were considered related to the treatment. CONCLUSION: Treatment with glatiramer acetate plus albuterol is well tolerated and improves clinical outcomes in patients with multiple sclerosis. TRIAL REGISTRATION: Identifier: NCT00039988.
Jeffrey Dewey, George Hana, Troy Russell, Jared Price, Daniel McCaffrey, Jaroslaw Harezlak, Ekta Sem, Joy C Anyanwu, Charles R Guttmann, Bradford Navia, Ronald Cohen, and David F Tate. 2010. “Reliability and validity of MRI-based automated volumetry software relative to auto-assisted manual measurement of subcortical structures in HIV-infected patients from a multisite study.” Neuroimage, 51, 4, Pp. 1334-44.Abstract
The automated volumetric output of FreeSurfer and Individual Brain Atlases using Statistical Parametric Mapping (IBASPM), two widely used and well published software packages, was examined for accuracy and consistency relative to auto-assisted manual (AAM) tracings (i.e., manual correction of automated output) when measuring the caudate, putamen, amygdala, and hippocampus in the baseline scans of 120 HIV-infected patients (86.7% male, 47.3+/-6.3y.o., mean HIV duration 12.0+/-6.3years) from the NIH-funded HIV Neuroimaging Consortium (HIVNC) cohort. The data was examined for accuracy and consistency relative to auto-assisted manual tracing, and construct validity was assessed by correlating automated and AAM volumetric measures with relevant clinical measures of HIV progression. When results were averaged across all patients in the eight structures examined, FreeSurfer achieved lower absolute volume difference in five, higher sensitivity in seven, and higher spatial overlap in all eight structures. Additionally, FreeSurfer results exhibited less variability in all measures. Output from both methods identified discrepant correlations with clinical measures of HIV progression relative to AAM segmented data. Overall, FreeSurfer proved more effective in the context of subcortical volumetry in HIV-patients, particularly in a multisite cohort study such as this. These findings emphasize that regardless of the automated method used, visual inspection of segmentation output, along with manual correction if necessary, remains critical to ensuring the validity of reported results.
DS Meier, KE Balashov, B Healy, HL Weiner, and CRG Guttmann. 2010. “Seasonal prevalence of MS disease activity.” Neurology, 75, 9, Pp. 799-806.Abstract
OBJECTIVE: This observational cohort study investigated the seasonal prevalence of multiple sclerosis (MS) disease activity (likelihood and intensity), as reflected by new lesions from serial T2-weighted MRI, a sensitive marker of subclinical disease activity. METHODS: Disease activity was assessed from the appearance of new T2 lesions on 939 separate brain MRI examinations in 44 untreated patients with MS. Likelihood functions for MS disease activity were derived, accounting for the temporal uncertainty of new lesion occurrence, individual levels of disease activity, and uneven examination intervals. Both likelihood and intensity of disease activity were compared with the time of year (season) and regional climate data (temperature, solar radiation, precipitation) and among relapsing and progressive disease phenotypes. Contrast-enhancing lesions and attack counts were also compared for seasonal effects. RESULTS: Unlike contrast enhancement or attacks, new T2 activity revealed a likelihood 2-3 times higher in March-August than during the rest of the year, and correlated strongly with regional climate data, in particular solar radiation. In addition to the likelihood or prevalence, disease intensity was also elevated during the summer season. The elevated risk season appears to lessen for progressive MS and occur about 2 months earlier. CONCLUSION: This study documents evidence of a strong seasonal pattern in subclinical MS activity based on noncontrast brain MRI. The observed seasonality in MS disease activity has implications for trial design and therapy assessment. The observed activity pattern is suggestive of a modulating role of seasonally changing environmental factors or season-dependent metabolic activity.
Dorothy B Wakefield, Nicola Moscufo, Charles R Guttmann, George A Kuchel, Richard F Kaplan, Godfrey Pearlson, and Leslie Wolfson. 2010. “White matter hyperintensities predict functional decline in voiding, mobility, and cognition in older adults.” J Am Geriatr Soc, 58, 2, Pp. 275-81.Abstract
OBJECTIVES: To compare magnetic resonance imaging data with functional assessments of mobility, urinary control, and cognition to determine common or distinctive features in the distribution of brain white matter hyperintensities (WMHs) associated with functional decline and impairment. DESIGN: Baseline data from subjects aged 75 to 89 enrolled in a longitudinal study. Assessors and subjects were blinded to group assignment. SETTING: Healthy community-dwelling volunteers. PARTICIPANTS: Ninety-nine subjects were enrolled using a balanced 3 x 3 matrix stratified according to age and mobility performance. Exclusion criteria were medication, systemic conditions, and neurological diseases that can compromise mobility. MEASUREMENTS: WMHs were identified using a semi-automated segmentation method, and regional burdens were assessed using a white matter parcellation atlas. Quantitative measures of mobility, urinary incontinence (UI) severity, and executive function and processing speed were obtained. RESULTS: WMHs occur predictably in predominantly periventricular areas. There were powerful correlations between total (tWMH) and regional (rWMH) WMH, with correlation coefficients of 0.5 to 0.9 for eight of 10 structures analyzed. tWMH predicted functional measures of UI, mobility, executive function, and processing speed nearly as well as the best regional measures. The total volume of WMHs independently explains 5% to 11% of the variability for mobility, UI severity, executive function, and processing speed and is a sensitive (0.7-0.8) predictor of functional decline. The odds of decline in each of the three functional domains was 1.5 to 2.4 times greater with each 1% increase in tWMH. CONCLUSION: This work establishes the importance of brain WMH burden in three major geriatric syndromes. The findings support the inclusion of total WMH burden as a risk factor in the predictive and diagnostic criteria.
Mohit Neema, Daniel Goldberg-Zimring, Zachary D Guss, Brian C Healy, Charles RG Guttmann, Maria K Houtchens, Howard L Weiner, Mark A Horsfield, David B Hackney, David C Alsop, and Rohit Bakshi. 2009. “3 T MRI relaxometry detects T2 prolongation in the cerebral normal-appearing white matter in multiple sclerosis.” Neuroimage, 46, 3, Pp. 633-41.Abstract
MRI at 3 T has increased sensitivity in detecting overt multiple sclerosis (MS) brain lesions; a growing body of data suggests clinically relevant damage occurs in the normal-appearing white matter (NAWM). We tested a novel pulse sequence to determine whether 3 T MRI spin-spin relaxometry detected damage in NAWM of MS patients (n=13) vs. age-matched normal controls [(NL) (n=11)]. Baseline characteristics of the MS group were: age (mean+/-SD) 42.5+/-5.4 (range 33-51 years), disease duration 9.0+/-6.4 (range 1-22 years), Expanded Disability Status Scale score 2.5+/-1.7 (range 1-6.5). Brain MRI measures, obtained at 3 T, included global and regional NAWM transverse relaxation rate [R2 (=1/T2)], derived from 3D fast spin-echo T2 prepared images, and global white matter volume fraction derived from SPGR images. The regional NAWM areas investigated were the frontal lobe, parietal lobe, and the genu and splenium of the corpus callosum. Mean NAWM R2 was lower (indicating T2 prolongation) in MS than NL in the whole brain (p=0.00047), frontal NAWM (p=0.00015), parietal NAWM (p=0.0069) and callosal genu (p=0.0019). Similarly, R2 histogram peak position was lower in NAWM in MS than NL in the whole brain (p=0.019). However, the normalized WM volume fractions were similar in both MS and NL (p>0.1). This pilot study suggests that a novel 3D fast spin-echo pulse sequence at 3 T, used to derive R2 relaxation maps, can detect tissue damage in the global and regional cerebral NAWM of MS patients that is missed by conventional lesion and atrophy measures. Such findings may represent demyelination, inflammation, glial proliferation and axonal loss.
Mohit Neema, Ashish Arora, Brian C Healy, Zachary D Guss, Steven D Brass, Yang Duan, Guy J Buckle, Bonnie I Glanz, Lynn Stazzone, Samia J Khoury, Howard L Weiner, Charles RG Guttmann, and Rohit Bakshi. 2009. “Deep gray matter involvement on brain MRI scans is associated with clinical progression in multiple sclerosis.” J Neuroimaging, 19, 1, Pp. 3-8.Abstract
BACKGROUND: Conventional brain MRI lesion measures have unreliable associations with clinical progression in multiple sclerosis (MS). Gray matter imaging may improve clinical-MRI correlations. METHODS: We tested if gray matter MRI measures and conventional measures of lesions/atrophy predicted clinical progression in a 4-year longitudinal study of 97 patients with MS. Baseline and follow-up brain MRI were analyzed for basal ganglia and thalamic normalized T2 signal intensity, whole brain T2-hyperintense lesion volume, and whole brain atrophy. Logistic regression tested the ability of baseline or on-study change in MRI to predict disability progression, as reported by area under the receiver operator characteristics curve (AUC). RESULTS: Lower caudate T2-intensity at baseline (P= .04; AUC = .69) and on-study decreasing T2-intensity in the putamen (P= .03; AUC = .70) and thalamus (P= .01; AUC = .71) were the MRI variables associated with clinical progression when regression modeling was adjusted for length of follow-up interval, baseline EDSS, disease duration, age, and sex. CONCLUSIONS: Gray matter T2-hypointensity, suggestive of excessive iron deposition is associated with worsening disability in patients with MS. Gray matter MRI assessment may be able to capture neurodegenerative aspects of the disease, with more clinical relevance than derived from conventional MRI measures. J Neuroimaging 2009;19:3-8.
SA Gauthier, BI Glanz, M Mandel, Antonios Tsagkaropoulos, Mohit Neema, James Stankiewicz, Ashish Arora, Yang Duan, Zsuzsanna Liptak, Svetlana Egorova, Guy J Buckle, Rohit Bakshi, CRG Guttmann, SJ Khoury, and HL Weiner. 2009. “Incidence and factors associated with treatment failure in the CLIMB multiple sclerosis cohort study.” J Neurol Sci, 284, 1-2, Pp. 116-9.Abstract
OBJECTIVE: To determine the rate of treatment failure in patients outside of a controlled treatment trial and to ascertain the factors physicians used to make this decision. METHODS: One hundred and thirty four patients with the diagnosis of relapsing-remitting (RR) multiple sclerosis (MS) or clinically isolated symptom (CIS) enrolled in the CLIMB study (Comprehensive Longitudinal Investigation of Multiple Sclerosis at the Brigham and Women's Hospital) were treated with either interferon beta or glatiramer acetate as their initial treatment for MS. RESULTS: The probability of failing initial treatment within 3 years was 30%. Clinical activity, defined as relapses and/or progression in disability, determined treatment failure in 35.7% (n=10) of nonresponders. New T2 hyperintense or gadolinium-enhancing lesions on MRI was used to define treatment failure in 28.6% (n=8) and new MRI lesions were used in combination with clinical activity in 35.7% (n=10). Treatment failures had a higher T2 hyperintense lesion volume (p=0.015) and number of gadolinium-enhancing lesions (p=0.0001) on the enrollment MRI than responders. CONCLUSIONS: These observations demonstrate that treating physicians use both clinical and MRI parameters to define a response to treatment and initiation of a treatment change and that baseline MRI identified those with increased risk of treatment failure.
George A Kuchel, Nicola Moscufo, Charles R Guttmann, Neer Zeevi, Dorothy Wakefield, Julia Schmidt, Catherine E Dubeau, and Leslie Wolfson. 2009. “Localization of brain white matter hyperintensities and urinary incontinence in community-dwelling older adults.” J Gerontol A Biol Sci Med Sci, 64, 8, Pp. 902-9.Abstract
BACKGROUND: Because white matter hyperintensities (WMHs) on magnetic resonance imaging (MRI) may be linked to geriatric syndromes involving mobility, cognition, and affect, we postulated that involvement of areas critical to bladder control could influence urinary incontinence (UI). METHODS: One hundred community-dwelling individuals (75-89 years) were recruited into three groups stratified by age and gender reflecting normal and mildly and moderately impaired mobility. Baseline incontinence status and related symptoms were evaluated in 97 individuals using validated instruments (3IQ, Urinary Incontinence Severity Index, Urogenital Distress Inventory, Incontinence Impact Questionnaire). Regional WMH was measured using an MRI brain imaging segmentation pipeline and WM tract-based parcellation atlas. RESULTS: Sixty-two (64%) of the participants were incontinent, mostly with urgency (37; 60%) and moderate-severe symptoms (36; 58%). Incontinent individuals were more likely to be women with worse scores for depression and mobility. WMH located in right inferior frontal regions predicted UI severity, with no significant relationship with incontinence, incontinence type, bother, or functional impact. As regards WM tracts, WMH within regions normally occupied by the anterior corona radiata predicted severity and degree of bother, cingulate gyrus predicted incontinence and severity, whereas cingulate (hippocampal portion) and superior fronto-occipital fasciculus predicted severity. CONCLUSIONS: Presence of WMH in right inferior frontal regions and selected WM tracts predicts incontinence, incontinence severity, and degree of bother. Our observations support the findings of recent functional MRI studies indicating a critical role for the cingulum in bladder control, while also suggesting potential involvement of other nearby WM tracts such as anterior corona radiata and superior fronto-occipital fasciculus.
Susan A Gauthier, Annika M Berger, Zsuzsanna Liptak, Yang Duan, Svetlana Egorova, Guy J Buckle, Bonnie I Glanz, Samia J Khoury, Rohit Bakshi, Howard L Weiner, and Charles RG Guttmann. 2009. “Rate of brain atrophy in benign vs early multiple sclerosis.” Arch Neurol, 66, 2, Pp. 234-7.Abstract
BACKGROUND: Benign multiple sclerosis (MS) is defined by minimal or no disability after many years of observation, therefore a less degenerative disease process is suspected to be present in this subset of patients. OBJECTIVE: To compare brain atrophy rates in patients with long-standing benign MS vs typical early MS. DESIGN: A longitudinal prospective cohort study and a retrospective database review. SETTING: An academic MS center. PATIENTS: Thirty-nine patients with clinically defined benign MS and an age-matched group of 40 patients with early relapsing-remitting MS. MAIN OUTCOME MEASURES: Baseline demographic, treatment, brain magnetic resonance imaging measures, and annualized atrophy rates, derived from serial brain parenchymal fraction measurements across 2 years, were compared. RESULTS: In the baseline analysis, patients with benign MS were matched to the early MS group on age, sex, treatment with immunomodulatory therapy, T2 lesion volume, and brain parenchymal fraction. The mean (SD) annualized brain atrophy rate in patients with benign MS (-0.16% [0.51%]) was lower than that in patients with early MS (-0.46% [0.72%]) (P = .02). The difference remained significant after controlling for age, sex, and treatment (P = .04). CONCLUSIONS: Serial magnetic resonance imaging revealed a low 2-year rate of brain atrophy in patients with clinically benign MS, suggesting a less prominent degenerative component in its pathogenesis than in patients with typical early MS. Identification of patients with a low rate of brain atrophy may indicate a benign course.
MP Sampat, AM Berger, BC Healy, P Hildenbrand, J Vass, DS Meier, T Chitnis, HL Weiner, R Bakshi, and CRG Guttmann. 2009. “Regional white matter atrophy--based classification of multiple sclerosis in cross-sectional and longitudinal data.” AJNR Am J Neuroradiol, 30, 9, Pp. 1731-9.Abstract
BACKGROUND AND PURPOSE: The different clinical subtypes of multiple sclerosis (MS) may reflect underlying differences in affected neuroanatomic regions. Our aim was to analyze the effectiveness of jointly using the inferior subolivary medulla oblongata volume (MOV) and the cross-sectional area of the corpus callosum in distinguishing patients with relapsing-remitting multiple sclerosis (RRMS), secondary-progressive multiple sclerosis (SPMS), and primary-progressive multiple sclerosis (PPMS). MATERIALS AND METHODS: We analyzed a cross-sectional dataset of 64 patients (30 RRMS, 14 SPMS, 20 PPMS) and a separate longitudinal dataset of 25 patients (114 MR imaging examinations). Twelve patients in the longitudinal dataset had converted from RRMS to SPMS. For all images, the MOV and corpus callosum were delineated manually and the corpus callosum was parcellated into 5 segments. Patients from the cross-sectional dataset were classified as RRMS, SPMS, or PPMS by using a decision tree algorithm with the following input features: brain parenchymal fraction, age, disease duration, MOV, total corpus callosum area and areas of 5 segments of the corpus callosum. To test the robustness of the classification technique, we applied the results derived from the cross-sectional analysis to the longitudinal dataset. RESULTS: MOV and central corpus callosum segment area were the 2 features retained by the decision tree. Patients with MOV >0.94 cm(3) were classified as having RRMS. Patients with progressive MS were further subclassified as having SPMS if the central corpus callosum segment area was <55.12 mm(2), and as having PPMS otherwise. In the cross-sectional dataset, 51/64 (80%) patients were correctly classified. For the longitudinal dataset, 88/114 (77%) patient time points were correctly classified as RRMS or SPMS. CONCLUSIONS: Classification techniques revealed differences in affected neuroanatomic regions in subtypes of multiple sclerosis. The combination of central corpus callosum segment area and MOV provides good discrimination among patients with RRMS, SPMS, and PPMS.