Disease correlates of rim lesions on quantitative susceptibility mapping in multiple sclerosis.

Quantitative susceptibility mapping (QSM), an imaging technique sensitive to brain iron, has been used to detect paramagnetic rims of iron-laden active microglia and macrophages in a subset of multiple sclerosis (MS) lesions, known as rim+ lesions, that are consistent with chronic active lesions. Because of the potential impact of rim+ lesions on disease progression and tissue damage, investigating their influence on disability and neurodegeneration is critical to establish the impact of these lesions on the disease course. This study aimed to explore the relationship between chronic active rim+ lesions, identified as having a hyperintense rim on QSM, and both clinical disability and imaging measures of neurodegeneration in patients with MS. The patient cohort was composed of 159 relapsing-remitting multiple sclerosis patients. The Expanded Disability Status Scale (EDSS) and Brief International Cognitive Assessment for Multiple Sclerosis, which includes both the Symbol Digit Modalities Test and California Verbal Learning Test-II, were used to assess clinical disability. Cortical thickness and thalamic volume were evaluated as imaging measures of neurodegeneration. A total of 4469 MS lesions were identified, of which 171 QSM rim+ (3.8%) lesions were identified among 57 patients (35.8%). In a multivariate regression model, as the overall total lesion burden increased, patients with at least one rim+ lesion on QSM performed worse on both physical disability and cognitive assessments, specifically the Symbol Digit Modalities Test (p = 0.010), California Verbal Learning Test-II (p = 0.030), and EDSS (p = 0.001). In a separate univariate regression model, controlling for age (p < 0.001) and having at least one rim+ lesion was related to more cortical thinning (p = 0.03) in younger patients (< 45 years). Lower thalamic volume was associated with older patients (p = 0.038) and larger total lesion burden (p < 0.001); however, the association did not remain significant with rim+ lesions (p = 0.10). Our findings demonstrate a novel observation that chronic active lesions, as identified on QSM, modify the impact of lesion burden on clinical disability in MS patients. These results support further exploration of rim+ lesions for therapeutic targeting in MS to reduce disability and subsequent neurodegeneration.

Dimethyl Fumarate Reduces Inflammation in Chronic Active Multiple Sclerosis Lesions.

BACKGROUND AND OBJECTIVES: To determine the effects of dimethyl fumarate (DMF) and glatiramer acetate on iron content in chronic active lesions in patients with multiple sclerosis (MS) and in human microglia in vitro. METHODS: This was a retrospective observational study of 34 patients with relapsing-remitting MS and clinically isolated syndrome treated with DMF or glatiramer acetate. Patients had lesions with hyperintense rims on quantitative susceptibility mapping, were treated with DMF or glatiramer acetate (GA), and had a minimum of 2 on-treatment scans. Changes in susceptibility in rim lesions were compared among treatment groups in a linear mixed effects model. In a separate in vitro study, induced pluripotent stem cell-derived human microglia were treated with DMF or GA, and treatment-induced changes in iron content and activation state of microglia were compared. RESULTS: Rim lesions in patients treated with DMF had on average a 2.77-unit reduction in susceptibility per year over rim lesions in patients treated with GA (bootstrapped 95% CI -5.87 to -0.01), holding all other variables constant. Moreover, DMF but not GA reduced inflammatory activation and concomitantly iron content in human microglia in vitro. DISCUSSION: Together, our data indicate that DMF-induced reduction of susceptibility in MS lesions is associated with a decreased activation state in microglial cells. We have demonstrated that a specific disease modifying therapy, DMF, decreases glial activity in chronic active lesions. Susceptibility changes in rim lesions provide an in vivo biomarker for the effect of DMF on microglial activity. CLASSIFICATION OF EVIDENCE: This study provided Class III evidence that DMF is superior to GA in the presence of iron as a marker of inflammation as measured by MRI quantitative susceptibility mapping.

Longitudinal change in magnetic susceptibility of new enhanced multiple sclerosis (MS) lesions measured on serial quantitative susceptibility mapping (QSM).

PURPOSE: To measure the longitudinal change in multiple sclerosis (MS) lesion susceptibility using quantitative susceptibility mapping (QSM). MATERIALS AND METHODS: The study was approved by our Institutional Review Board. Longitudinal changes in quantitative susceptibility values of new enhanced-with-Gd MS lesions were measured at baseline magnetic resonance imaging (MRI) and on a follow-up MRI in 29 patients within 2 years using a 3D multiple echo gradient echo sequence on a 3T scanner. Paired t-test and the generalized estimating equations (GEE) model was used to analyze the longitudinal change. RESULTS: Lesion susceptibility values relative to normal-appearing white matter (NAWM) changed from 3.61 ± 6.11 ppb when enhanced-with-Gd at the baseline MRI to 20.42 ± 10.23 ppb when not-enhanced-with-Gd at the follow-up MRI (P < 0.001). CONCLUSION: MS lesion susceptibility value increases significantly as the lesion evolves from enhanced-with-Gd to not-enhanced-with-Gd, serving as a disease biomarker. J. Magn. Reson. Imaging 2016;44:426-432.

Gadolinium-Enhancing Lesions Lead to Decreases in White Matter Tract Fractional Anisotropy in Multiple Sclerosis.

PURPOSE: Although MRI identification of new lesions forms the basis for monitoring disease progression in multiple sclerosis patients, how lesion activity relates to longitudinal white matter changes in the brain is unknown. We hypothesized that patients with gadolinium-enhancing lesions would show greater longitudinal decline in fractional anisotropy in major tracts compared to those with stable disease. METHODS: Thirty patients with relapsing-remitting multiple sclerosis were included in this study-13 had enhancing lesions at baseline and 17 did not. Each patient underwent at least two 3 Tesla contrast-enhanced MRI scans with a DTI sequence with a median interval of 2.1 years between scans. The forceps major and minor of the corpus callosum and the bilateral corticospinal tracts were selected as the major white matter tracts of interest. These tracts were reconstructed using region-of-interest placement on standard anatomical landmarks and a fiber assignment by continuous tracking algorithm using TrackVis (version 0.5.2.2) software. Mixed-effects regression models were used to determine the association between enhancing lesions and subsequent longitudinal change in fractional anisotropy. RESULTS: In patients with enhancing lesions, there was greater decline in fractional anisotropy compared to those with stable disease in the forceps major (P = .026), right corticospinal tract (P = .032), and marginally in the left corticospinal tract (P = .050), but not the forceps minor (P = .11). CONCLUSION: Fractional anisotropy of major white matter tracts declined more rapidly in patients with enhancing lesions, suggesting greater diffuse white matter injury with active inflammatory disease. DTI may provide a means of monitoring white matter injury following relapses.

Surveillance after resection of vestibular schwannoma: measurement techniques and predictors of growth.

OBJECTIVES: To compare different methods of measuring tumor growth after resection of vestibular schwannoma and to identify predictors of growth. STUDY DESIGN: Retrospective case review. SETTING: Tertiary referral center, inpatient surgery with ambulatory follow-up. PATIENTS: All patients who underwent vestibular schwannoma resection by the senior author from September 1991 to April 2012 and had two or more postoperative MRI scans. INTERVENTIONS: Vestibular schwannoma resection. Measurement of tumor size and enhancement pattern on postoperative magnetic resonance imaging scans. MAIN OUTCOME MEASURES: Tumor size as measured in one (linear), two (planar), and three (volumetric) dimensions using standard radiology workstation tools versus time elapsed since surgical resection. RESULTS: Eighty-eight patients were included with mean follow-up of 3.9 years. Linear measurement of tumor size was found to have modest correlation with planar and volumetric measurements. Excellent correlation was found between the planar and volumetric methods. Nodular enhancement increased risk for tumor growth (OR 6.25, p = 0.03 on planar analysis). If there was growth, tumors with nodular enhancement typically showed increase in size beginning 2 years postoperatively, whereas those with linear or no enhancement were typically stable in size through 5 years. Younger age and larger preoperative tumor size were also risk factors for growth (OR 0.9/p = 0.01 and OR 1.09/p = 0.02). CONCLUSION: Simple planar measurement is an efficient method that correlates well with the more time-consuming volumetric method. The major risk factor for tumor growth is nodular enhancement on a baseline scan, a finding that warrants annual MRI beginning 2 years postoperatively. Younger age and larger preoperative size minimally increased risk of growth.

Quantitative susceptibility mapping of multiple sclerosis lesions at various ages.

PURPOSE: To assess multiple sclerosis (MS) lesions at various ages by using quantitative susceptibility mapping (QSM) and conventional magnetic resonance (MR) imaging. MATERIALS AND METHODS: Retrospectively selected were 32 clinically confirmed MS patients (nine men and 23 women; 39.3 years ± 10.9) who underwent two MR examinations (interval, 0.43 years ± 0.16) with three-dimensional gradient-echo sequence from August 2011 to August 2012. To estimate the ages of MS lesions, MR examinations performed 0.3-10.6 years before study examinations were studied. Hyperintensity on T2-weighted images was used to define MS lesions. QSM images were reconstructed from gradient-echo data. Susceptibility of MS lesions and temporal rates of change were obtained from QSM images. Lesion susceptibilities were analyzed by t test with intracluster correlation adjustment and Bonferroni correction in multiple comparisons. RESULTS: MR imaging of 32 patients depicted 598 MS lesions, of which 162 lesions (27.1%) in 23 patients were age measurable and six (1.0%) were only visible at QSM. The susceptibilities relative to normal-appearing white matter (NAWM) were 0.53 ppb ± 3.34 for acute enhanced lesions, 38.43 ppb ± 13.0 (positive; P < .01) for early to intermediately aged nonenhanced lesions, and 4.67 ppb ± 3.18 for chronic nonenhanced lesions. Temporal rates of susceptibility changes relative to cerebrospinal fluid were 12.49 ppb/month ± 3.15 for acute enhanced lesions, 1.27 ppb/month ± 2.31 for early to intermediately aged nonenhanced lesions, and -0.004 ppb/month ± 0 for chronic nonenhanced lesions. CONCLUSION: Magnetic susceptibility of MS lesions increased rapidly as it changed from enhanced to nonenhanced, it attained a high susceptibility value relative to NAWM during its initial few years (approximately 4 years), and it gradually dissipated back to susceptibility similar to that of NAWM as it aged, which may provide new insight into pathophysiologic features of MS lesions. Online supplemental material is available for this article.

Neuroimaging of cerebrovascular disease in the aging brain.

Cerebrovascular disease remains a significant public health burden with its greatest impact on the elderly population. Advances in neuroimaging techniques allow detailed and sophisticated evaluation of many manifestations of cerebrovascular disease in the brain parenchyma as well as in the intracranial and extracranial vasculature. These tools continue to contribute to our understanding of the multifactorial processes that occur in the age-dependent development of cerebrovascular disease. Structural abnormalities related to vascular disease in the brain and vessels have been well characterized with CT and MRI based techniques. We review some of the pathophysiologic mechanisms in the aging brain and cerebral vasculature and the related structural abnormalities detectable on neuroimaging, including evaluation of age-related white matter changes, atherosclerosis of the cerebral vasculature, and cerebral infarction. In addition, newer neuroimaging techniques, such as diffusion tensor imaging, perfusion techniques, and assessment of cerebrovascular reserve, are also reviewed, as these techniques can detect physiologic alterations which complement the morphologic changes that cause cerebrovascular disease in the aging brain.Further investigation of these advanced imaging techniques has potential application to the understanding and diagnosis of cerebrovascular disease in the elderly.

Outcomes-based assessment of a new reference standard for delayed cerebral ischemia related to vasospasm in aneurysmal subarachnoid hemorrhage.

RATIONALE AND OBJECTIVES: The purpose is to perform outcomes-based assessment of a new reference standard for delayed cerebral ischemia (DCI) related to vasospasm. MATERIALS AND METHODS: Retrospective study was performed with consecutive aneurysmal subarachnoid hemorrhage (A-SAH) patients between January 2002 and May 2009. A new reference standard for DCI was applied to the study population incorporating clinical and imaging criteria. Diagnostic accuracy was determined by chart diagnosis. Outcome measures for assessment included: permanent neurologic deficits, infarction, functional disability, treatment, and discharge status. Medical record review was performed by two blinded observers. Chi-square test calculated statistical significance between DCI and no DCI groups. RESULTS: A total of 137 patients were included; 59% (81/137) classified as DCI and 41% (56/137) as no DCI by the reference standard. Overall accuracy is 96% (95% confidence interval 92-99) with 100% sensitivity, 92% specificity, 94% positive and 100% negative predictive values. Patients classified as DCI had 40% (32/81) permanent neurologic deficits and 57% (46/81) infarction compared to 0% (0/56) classified as no DCI. DCI patients had 33% (27/81) functional disability compared to 13% (7/56) classified as no DCI. Ninety-four percent (76/81) DCI patients received treatment compared to 0% (0/56) classified as no DCI. DCI group had 46% (37/81) discharged to rehabilitation facilities and 11% (9/81) mortality compared to 25% (14/56) and 2% (1/56), respectively, in no DCI group. There are statistically significant differences (P < .0001) between DCI and no DCI groups for all outcome measures. CONCLUSION: This new reference standard has high diagnostic accuracy for DCI related to vasospasm. The outcomes-based assessment further supports its accuracy in correctly classifying A-SAH patients.

Comparison of CT perfusion and digital subtraction angiography in the evaluation of delayed cerebral ischemia.

RATIONALE AND OBJECTIVES: Delayed cerebral ischemia (DCI) is a devastating condition that occurs secondary to aneurysmal subarachnoid hemorrhage (A-SAH). The purpose is to compare computed tomography perfusion (CTP) and digital subtraction angiography (DSA) for determining DCI in A-SAH. MATERIALS AND METHODS: A retrospective study of A-SAH patients admitted at our institution between December 2004 and December 2008 was performed. CTP and DSA were obtained at days 6-8 after aneurysm rupture. Both qualitative and quantitative analyses of CT perfusion deficits were performed. DSA was categorized as presence or absence of vasospasm. The reference standard for determining DCI was based on clinical deterioration or infarction on CT or MRI. The test characteristics of CTP and DSA were calculated and their graphs of conditional probabilities were constructed using Bayesian analysis. RESULTS: Fifty-seven patients were included; 79% (45/57) had DCI. Seventy percent (40/57) had CTP perfusion deficits; 80% (36/45) of the DCI and 33% (4/12) of no DCI patients. Sixty-three percent (36/57) had DSA demonstrating vasospasm; 73% (33/45) of the DCI and 25% (3/12) of no DCI patients. Quantitative analysis of the CTP data revealed a significant difference in cerebral blood flow values for the DCI (29.4 mL/100 g/minute) and no DCI groups (40.5 mL/100 g/minute, P = .0213). The sensitivity, specificity, and positive and negative predictive values for CTP were 0.80 (95% CI 0.68-0.92), 0.67 (95% CI 0.40-0.93), 0.90 (95% CI 0.82-0.96), 0.47 (95% CI 0.27-0.62), and for DSA were 0.73 (95% CI 0.60-0.86), 0.75 (95% CI 0.50-0.99), 0.92 (95% CI 0.82-0.98), and 0.43 (95% CI 0.26-0.53), respectively. CONCLUSION: CTP and DSA have similar test characteristics and Bayesian analysis for determining DCI in A-SAH patients.

Role of CT perfusion imaging in the diagnosis and treatment of vasospasm.

The current role of CT perfusion (CTP) imaging in the diagnosis and treatment of vasospasm in the setting of aneurysmal subarachnoid hemorrhage is discussed in this article, with specific attention directed towards defining the terminology of vasospasm and delayed cerebral ischemia. A commonly used CTP technique in clinical practice is described. A review of the literature regarding the usefulness of CTP for the diagnosis of vasospasm and its role in guiding treatment are discussed. Recent research advances in the utilization of CTP and associated ongoing challenges are also presented.

Developing a new reference standard: is validation necessary?

RATIONALE AND OBJECTIVES: A gold standard is often an imperfect diagnostic test, falling short of achieving 100% accuracy in clinical practice. Using an imperfect gold standard without fully comprehending its limitations and biases can lead to erroneous classification of patients with and without disease. This will ultimately affect treatment decisions and patient outcomes. Therefore, validation is essential before implementing a reference standard into practice. Performing a comprehensive validation process is discussed, along with its advantages and challenges. The different types of validation methods are reviewed. An example from our work in developing a new reference standard for vasospasm diagnosis in aneurysmal subarachnoid hemorrhage patients is provided. CONCLUSION: Employing a new reference standard may result in a definitional shift of the disease and classification scheme of patients; therefore, it is important to also assess the impact of a new reference standard on patient outcomes and its clinical effectiveness.

Validation of a new reference standard for the diagnosis of vasospasm.

RATIONALE AND OBJECTIVES: The purpose of our study is to perform an internal validation of a new reference standard for vasospasm diagnosis in aneurysmal subarachnoid hemorrhage (A-SAH) patients. MATERIALS AND METHODS: A retrospective study was performed on A-SAH patients between January 2002 and May 2009. All patients were applied to this new reference standard using a multistage hierarchical approach incorporating clinical and imaging criteria. An internal validation method was performed in two phases to compare the new reference standard with digital subtraction angiography (DSA) and to assess accuracy. In Phase I, the diagnostic outcomes from DSA at the primary level were compared with the secondary/tertiary levels in the reference standard. In Phase II, the new reference standard was compared with chart diagnosis. Accuracy test characteristics, agreement rates, kappa values, and bias indices were calculated. RESULTS: In Phase I (n = 85), there was 87% agreement rate, 0.674 kappa, and 0.12 bias index. However, there was 100% agreement in patients diagnosed with vasospasm by DSA. Sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were 100%, 61%, 83%, and 100% respectively. In Phase II (n = 137), there was 91% agreement rate, 0.824 kappa, and 0.04 bias index. Sensitivity, specificity, PPV, and NPV were 88%, 95%, 96%, and 87%, respectively. CONCLUSION: Performing validation methods for a new reference standard is an evolving and ongoing process because limitations and bias in the reference standard are identified. Based on the results of this internal validation, a modification in the new reference standard is made at the primary level, resulting in improvement in its accuracy and classification of A-SAH patients.