Dominik S. Meier

Time-series analysis of MRI intensity patterns in multiple sclerosis

In progressive neurological disorders, such as multiple sclerosis (MS), magnetic resonance imaging (MRI) follow-up is used to monitor disease activity and progression and to understand the underlying pathogenic mechanisms. This article presents image postprocessing methods and validation for integrating multiple serial MRI scans into a spatiotemporal volume for direct quantitative evaluation of the temporal intensity profiles. This temporal intensity signal and its dynamics have thus far not been exploited in the study of MS pathogenesis and the search for MRI surrogates of disease activity and progression. The integration into a four-dimensional data set comprises stages of tissue classification, followed by spatial and intensity normalization and partial volume filtering. Spatial normalization corrects for variations in head positioning and distortion artifacts via fully automated intensity-based registration algorithms, both rigid and nonrigid. Intensity normalization includes separate stages of correcting intra- and interscan variations based on the prior tissue class segmentation. Different approaches to image registration, partial volume correction, and intensity normalization were validated and compared. Validation included a scan-rescan experiment as well as a natural-history study on MS patients, imaged in weekly to monthly intervals over a 1-year follow-up. Significant error reduction was observed by applying tissue-specific intensity normalization and partial volume filtering. Example temporal profiles within evolving multiple sclerosis lesions are presented. An overall residual signal variance of 1.4% +/- 0.5% was observed across multiple subjects and time points, indicating an overall sensitivity of 3% (for axial dual echo images with 3-mm slice thickness) for longitudinal study of signal dynamics from serial brain MRI.

Impaired cerebrovascular hemodynamics are associated with cerebral white matter damage

White matter hyperintensities (WMH) in elderly individuals with vascular diseases are presumed to be due to ischemic small vessel diseases; however, their etiology is unknown. We examined the cross-sectional relationship between cerebrovascular hemodynamics and white matter structural integrity in elderly individuals with vascular risk factors. White matter hyperintensity volumes, fractional anisotropy (FA), and mean diffusivity (MD) were obtained from MRI in 48 subjects (75±7years). Pulsatility index (PI) and dynamic cerebral autoregulation (dCA) was assessed using transcranial Doppler ultrasound of the middle cerebral artery. Dynamic cerebral autoregulation was calculated from transfer function analysis (phase and gain) of spontaneous blood pressure and flow velocity oscillations in the low (LF, 0.03 to 0.15 Hz) and high (HF, 0.16 to 0.5 Hz) frequency ranges. Higher PI was associated with greater WMH (P<0.005). Higher phase across all frequency ranges was associated with greater FA and lower MD (P<0.005). Lower gain was associated with higher FA in the LF range (P=0.001). These relationships between phase and FA were significant in the territories limited to the middle cerebral artery as well as across the entire brain. Our results show a strong relationship between impaired cerebrovascular hemodynamics (PI and dCA) and loss of cerebral white matter structural integrity (WMH and DTI metrics) in elderly individuals.

Brain regional lesion burden and impaired mobility in the elderly

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.

Identification and Clinical Impact of Multiple Sclerosis Cortical Lesions as Assessed by Routine 3T MR Imaging

It is possible that many if not most clinical symptoms of multiple sclerosis patients are due to plaques in the gray matter and not in the white matter as commonly believed (remember that myelinated fibers are found in cortical and deep gray matter). Could it be that because cortical plaques are not routinely seen at 1.5T we do not think about this issue? Here, the authors studied 26 patients with 3D FLAIR and inversion recovery spoiled gradient recalled sequences at 3T and found cortical plaques in 24 of them. The volume and load of these cortical plaques correlated with those seen in white matter. Cortical lesions also correlated with verbal learning test disability scale results better than white matter lesion load. Conclusion: routinely detectable cortical lesions were related to physical disability and cognitive impairment. 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 (rS = 0.652, rS = 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 (R2 = 0.513, R2 = 0.449, R2 = 0.418, respectively; P < .014); cortical lesion number also correlated with the CVLT-II scores (R2 = 0.542–0.461, P < .043). The EDSS scores correlated with cortical lesion number and cortical lesion volume (rS = 0.472, rS = 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.

Seasonal prevalence of MS disease activity

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.

Neurovascular Coupling is Impaired in Slow Walkers: The MOBILIZE Boston Study

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.

Subtraction MR images in a multiple sclerosis multicenter clinical trial setting.

PURPOSE To explore the applicability of subtraction magnetic resonance (MR) images to (a) detect active multiple sclerosis (MS) lesions, (b) directly quantify lesion load change, and (c) detect treatment effects (distinguish treatment arms) in a placebo-controlled multicenter clinical trial by comparing the subtraction scheme with a conventional pair-wise comparison of nonregistered MR images. MATERIALS AND METHODS Forty-six pairs of MR studies in 40 patients (31 women; mean age, 31.9 years) from a multicenter clinical trial were used. The clinical trial was approved by local ethics review boards, and all subjects gave written informed consent. Active MS lesions were scored by two independent raters, and lesion load measurements were conducted by using semiautomated software. Lesion counts were evaluated by using the Wilcoxon signed rank test, interrater agreement was evaluated by using the intraclass correlation coefficient (ICC), and treatment (interferon beta-1b) effect was evaluated by using the Mann-Whitney U test. RESULTS When subtraction images were used, there was a 1.7-fold increase in the detection of positive active lesions, as compared with native image pairs, and significantly greater interobserver agreement (ICC = 0.98 vs 0.91, P < .001). Subtraction images also allowed direct quantification of positive disease activity, a measure that provided sufficient power to distinguish treatment arms (P = .012) compared with the standard measurement of total lesion load change on native images (P = .455). CONCLUSION MR image subtraction enabled detection of higher numbers of active MS lesions with greater interobserver agreement and exhibited increased power to distinguish treatment arms, as compared with a conventional pair-wise comparison of nonregistered MR images.

Predicting Clinical Progression in Multiple Sclerosis With the Magnetic Resonance Disease Severity Scale

BACKGROUND Individual magnetic resonance imaging (MRI) disease severity measures, such as atrophy or lesions, show weak relationships to clinical status in patients with multiple sclerosis (MS). OBJECTIVE To combine MS-MRI measures of disease severity into a composite score. DESIGN Retrospective analysis of prospectively collected data. SETTING Community-based and referral subspecialty clinic in an academic hospital. PATIENTS A total of 103 patients with MS, with a mean (SD) Expanded Disability Status Scale (EDSS) score of 3.3 (2.2), of whom 62 (60.2%) had the relapsing-remitting, 33 (32.0%) the secondary progressive, and 8 (7.8%) the primary progressive form. MAIN OUTCOME MEASURES Brain MRI measures included baseline T2 hyperintense (T2LV) and T1 hypointense (T1LV) lesion volume and brain parenchymal fraction (BPF), a marker of global atrophy. The ratio of T1LV to T2LV (T1:T2) assessed lesion severity. A Magnetic Resonance Disease Severity Scale (MRDSS) score, on a continuous scale from 0 to 10, was derived for each patient using T2LV, BPF, and T1:T2. RESULTS The MRDSS score averaged 5.1 (SD, 2.6). Baseline MRI and EDSS correlations were moderate for BPF, T1:T2, and MRDSS and weak for T2LV. The MRDSS showed a larger effect size than the individual MRI components in distinguishing patients with the relapsing-remitting form from those with the secondary progressive form. Models containing either T2LV or MRDSS were significantly associated with disability progression during the mean (SD) 3.2 (0.3)-year observation period, when adjusting for baseline EDSS score. CONCLUSION Combining brain MRI lesion and atrophy measures can predict MS clinical progression and provides the basis for developing an MRI-based continuous scale as a marker of MS disease severity.

Development and evaluation of a dual-modality (MRI/SPECT) molecular imaging bioprobe.

Specific bioprobes for single photon emission computed tomography (SPECT) and magnetic resonance imaging (MRI) have enormous potential for use in cancer imaging in near-future clinical settings. The authors describe the development of dual modality molecular imaging bioprobes, in the form of magnetic nanoparticles (NPs) conjugated to antibodies, for SPECT and MRI of mesothelin-expressing cancers. The bioprobes were developed by conjugating (111)In labeled antimesothelin antibody mAbMB to superparamagnetic iron oxide NPs. Our experimental findings provide evidence that such bioprobes retain their magnetic properties as well as the ability to specifically localize in mesothelin-expressing tumors. It is anticipated that combining SPECT with MR will help obtain both functional and anatomical imaging information with high signal sensitivity and contrast, thereby providing a powerful diagnostic tool for early diagnosis and treatment planning of mesothelin-expressing cancers.

MR Imaging Intensity Modeling of Damage and Repair In Multiple Sclerosis: Relationship of Short-Term Lesion Recovery to Progression and Disability

BACKGROUND AND PURPOSE: Formation of lesions in multiple sclerosis (MS) shows pronounced short-term fluctuation of MR imaging hyperintensity and size, a qualitatively known but poorly characterized phenomenon. With the use of time-series modeling of MR imaging intensity, our study relates the short-term dynamics of new T2 lesion formation to those of contrast enhancement and markers of long-term progression of disease. MATERIALS AND METHODS: We analyzed 915 examinations from weekly to monthly MR imaging in 40 patients with MS using a time-series model, emulating 2 opposing processes of T2 prolongation and shortening, respectively. Patterns of activity, duration, and residual hyperintensity within new T2 lesions were measured and evaluated for relationships to disability, atrophy, and clinical phenotype in long-term follow-up. RESULTS: Significant T2 activity was observed for 8 to 10 weeks beyond contrast enhancement, which suggests that T2 MR imaging is sensitive to noninflammatory processes such as degeneration and repair. Larger lesions showed longer subacute phases but disproportionally more recovery. Patients with smaller average peak lesion size showed trends toward greater disability and proportional residual damage. Higher rates of disability or atrophy were associated with subjects whose lesions showed greater residual hyperintensity. CONCLUSION: Smaller lesions appeared disproportionally more damaging than larger lesions, with lesions in progressive MS smaller and of shorter activity than in relapsing-remitting MS. Associations of lesion dynamics with rates of atrophy and disability and clinical subtype suggest that changes in lesion dynamics may represent a shift from inflammatory toward degenerative disease activity and greater proximity to a progressive stage, possibly allowing staging of the progression of MS earlier, before atrophy or disability develops.