Paul S. Morgan

Characterization of Complicated Carotid Plaque With Magnetic Resonance Direct Thrombus Imaging in Patients With Cerebral Ischemia

Background Thromboembolic disease secondary to complicated carotid atherosclerotic plaque is a major cause of cerebral ischemia. Clinical management relies on the detection of significant (>70%) carotid stenosis. A large proportion of patients suffer irreversible cerebral ischemia as a result of lesser degrees of stenosis. Diagnostic techniques that can identify nonstenotic high‐risk plaque would therefore be beneficial. High‐risk plaque is defined histologically if it contains hemorrhage/thrombus. Magnetic resonance direct thrombus imaging (MRDTI) is capable of detecting methemoglobin within intraplaque hemorrhage. We assessed this as a marker of complicated plaque and compared its accuracy with histological examination of surgical endarterectomy specimens. Methods and Results Sixty‐three patients underwent successful MRDTI and endarterectomy with histological examination. Of these, 44 were histologically defined as complicated (type VI plaque). MRDTI demonstrated 3 false‐positive and 7 false‐negative results, giving a sensitivity and specificity of 84%, negative predictive value of 70%, and positive predictive value of 93%. The interobserver (κ=0.75)and intraobserver (κ=0.9) agreement for reading MRDTI scans was good. Conclusions MRDTI of the carotid vessels in patients with cerebral ischemia is an accurate means of identifying histologically confirmed complicated plaque. The high contrast generated by short T1 species within the plaque allows for ease of interpretation, making this technique highly applicable in the research and clinical setting for the investigation of carotid atherosclerotic disease. (Circulation. 2003;107:3047‐3052.)

Disconnection as a mechanism for cognitive dysfunction in multiple sclerosis

Disconnection of cognitively important processing regions by injury to the interconnecting white matter provides a potential mechanism for cognitive dysfunction in multiple sclerosis. The contribution of tract-specific white matter injury to dysfunction in different cognitive domains in patients with multiple sclerosis has not previously been studied. We apply tract-based spatial statistics (TBSS) to diffusion tensor imaging (DTI) in a cohort of multiple sclerosis patients to identify loci where reduced white matter tract fractional anisotropy (FA) predicts impaired performance in cognitive testing. Thirty-seven multiple sclerosis patients in remission (median age 43.5 years; Expanded Disability Status Scale range 1.5-6.5; 35 relapsing remitting, two secondary-progressive) underwent 3 T MRI including high-resolution DTI. Multiple sclerosis patients underwent formal testing of performance in multiple cognitive domains. Normalized cognitive scores were used for voxel-wise statistical analysis using TBSS, while treating age as a covariate of no interest. Permutation-based inference on cluster size (t > 2, P <0.05 corrected) was used to correct for multiple comparisons. Statistical mapping revealed differential patterns of FA reduction for tests of sustained attention, working memory and processing speed, visual working memory and verbal learning and recall. FA was not associated with frontal lobe function or visuospatial perception. Cognitively relevant tract localizations only partially overlapped with areas of high FLAIR lesion probability, confirming the contribution of normal-appearing white matter abnormality to cognitive dysfunction. Of note, tract localizations showing significant associations with cognitive impairment were found to interconnect cortical regions thought to be involved in processing in these cognitive domains, or involve possible compensatory processing pathways. This suggests that TBSS reveals functionally relevant tract injury underlying cognitive dysfunction in patients with multiple sclerosis.

Diagnosis of Lower-Limb Deep Venous Thrombosis: A Prospective Blinded Study of Magnetic Resonance Direct Thrombus Imaging

Despite considerable recent advances in diagnostic techniques for lower-limb deep venous thrombosis (DVT), current methods have disadvantages. Ultrasonography, the most accurate noninvasive test, is widely available and cheap. As such, it has largely replaced venography as the test of first choice for symptomatic DVT. In a recent meta-analysis, the sensitivity of ultrasonography was 89% overall for symptomatic DVT and 97% for above-knee thrombosis (1). Large outcome studies have shown that patients may be safely left untreated after a negative result on ultrasonography if they have a low clinical risk score, a low d-dimer level, or a negative result on repeated ultrasonography at 1 week (2-4). However, these strategies may be complex and still require 3% to 34% of outpatients and most inpatients to undergo repeated ultrasonography at 1 week (2-4). In practice, retesting after 1 week is inconvenient, and physicians often rely on a single test or request immediate venography (5). Other problems with ultrasonography include poor sensitivity for asymptomatic disease, difficulties in diagnosing DVT recurrence, and limited visualization in the pelvis (1, 6, 7). Impedance plethysmography is also commonly used; however, it has a lower diagnostic accuracy than ultrasonography and has similar weaknesses in the setting of recurrent thrombosis, asymptomatic DVT, and DVT below the knee or in the pelvis (1, 4, 6). Computed tomography and magnetic resonance imaging techniques can visualize DVT above the knee and in the pelvis but in general are unsuccessful below the knee (8-10). The ability of these techniques to diagnose DVT recurrence and asymptomatic disease has not been tested. Venography is the reference standard diagnostic test, but it has in large part been replaced by noninvasive tests. In clinical practice, it is the most reliable test for the diagnosis of asymptomatic thrombosis and thrombosis isolated within the calf or pelvis. However, imaging in the pelvis is inadequate in up to 24% of normal studies, and the proximal extent of thrombosis is frequently not delineated in patients with above-knee DVT (11). Underfilling of vessels and vessels overlying one another also create problems with venography below the knee. Studies have shown that interobserver variability for venography is high (10% to 16%), especially below the knee ( = 0.46 to 0.73 below the knee and 0.46 to 0.84 above the knee) (12, 13). In addition, a high proportion of studies are nondiagnostic for possible DVT recurrence (1, 6). A noninvasive test is needed that accurately diagnoses above-knee DVT and thrombus below the knee, in the pelvis, and in asymptomatic limbs. Unlike most imaging techniques, which identify thrombus as filling defects, magnetic resonance direct thrombus imaging (MRDTI) visualizes thrombus against a suppressed background (14). In an unblinded comparison with venography, we previously showed that MRDTI precisely visualizes acute deep venous thrombus (14, 15). In the current study, we sought to assess prospectively whether MRDTI is a reliable diagnostic test for suspected acute symptomatic DVT. Methods The ethics committee at our institution granted approval for the study, and all participants gave written informed consent. With the exceptions of pregnant women, patients with known contrast allergy, and those with renal failure, all patients with DVT suspected on the basis of lower limb symptoms are investigated by using venography at our institution. Participants were recruited after routine venography was done between May 1998 and September 1999. During this time, 338 consecutive patients underwent routine contrast venography. Consecutive patients with positive venograms were selected, along with one quarter of those with negative venograms, according to a predetermined random sequence. This protocol was chosen to equalize the numbers of positive and negative cases and was based on a 6-month audit of venograms in our institution that found that 22% of venograms were positive. Clinical diagnostic criteria were not used, and the decision to request investigation for suspected DVT had been made by the attending clinician; however, patients who did not have leg symptoms were not recruited. Other exclusion criteria were failed or inconclusive venography, failed or inconclusive MRDTI, contraindications to MRI, and claustrophobia (Figure 1). Individual venous segments that were nondiagnostic at venography were also excluded from analysis. Figure 1. Outline of the study. Magnetic resonance direct thrombus imaging was performed on all patients recruited within 48 hours of venography. The scans were interpreted by an experienced radiologist (reviewer A) and by a nonradiologist (reviewer B) trained to read MRDTI scans. For venograms and MRDTI scans, the reviewers noted the presence or absence of DVT; the diagnostic classification of DVT, divided into isolated calf DVT, femoropopliteal DVT, and ileofemoral DVT; and the presence of thrombus in the calf, femoropopliteal, and iliac venous segments. Venograms were obtained and initially reported by the radiologists on duty. This initial report was used to make recruitment decisions; if the results were discordant with those of MRDTI, ultrasonography was also performed. However, ultrasonography was not used in the calculations of the accuracy of MRDTI. After completion of the study, venograms were interpreted by an independent radiologist, and these results were used as the gold standard against which MRDTI was compared. Results of MRDTI and venography were reported without knowledge of the results of other tests and the other readings. The d-dimer level was measured in all patients at the time of the MRDTI scan by using the Nycocard (Nycomed Pharma AS, Asker, Norway) technique (normal level < 0.3 mg/L). Venography Venography was performed by cannulating a dorsal pedal vein with a 21-gauge needle and rapidly injecting 50 to 100 mL of iodinated contrast medium (I2, 300 mg/mL), with the patient supine and tilted 30 degrees with his or her feet downward. A tourniquet was applied above the ankle. Anteroposterior and two oblique views of the deep calf and popliteal veins were obtained. Views of the femoral and iliac veins were then obtained. The study result was considered positive if intraluminal filling defects were seen or persistent nonfilling of veins with a sharp cut-off was detected. Magnetic Resonance Imaging Magnetic resonance imaging was performed by using a 1.5-Tesla unit (Siemens Vision, Erlangen, Germany) with a T1-weighted magnetization-prepared three-dimensional gradient-echo sequence. The sequence included a water-only excitation radiofrequency pulse to abolish the fat signal, and the effective inversion time was chosen to nullify the blood signal. Imaging was performed from the ankle to the inferior vena cava in two imaging blocks with a total acquisition time of 12 minutes by using a 55-cm body coil. Both legs were imaged simultaneously. Scanning was performed by radiographers in all cases. Image assessment involved reading of coronal source data and standard image reconstruction techniques. Acute thrombus was diagnosed on the basis of its high signal against the suppressed background (Figure 2). Figure 2. Magnetic resonance direct thrombus imaging in three patients. A. arrows B. arrows C. single arrows double arrow Ultrasonography Color flow and compression ultrasonographic images of the symptomatic limb from the common femoral vein distally were obtained by using a 5-MHz linear array transducer. As much of the superficial femoral vein as possible was imaged, together with the popliteal vein and the calf veins. Augmentation of flow was used to verify patency. Examinations were performed by senior radiologists, and DVT was confirmed in all cases by noncompressibility on gray-scale images. The sonographer was unaware of the other test results, but in cases of possible isolated calf thrombosis, he or she was told to concentrate the examination below the knee to maximize accuracy in this region. Statistical Analysis Sensitivity and specificity were calculated for the overall diagnosis of DVT; diagnosis of isolated calf DVT, femoropopliteal DVT, and ileofemoral DVT; and presence of thrombus in the calf, femoropopliteal vein, and iliac vein. Exact CIs were calculated. Interobserver error was calculated for these observations by using the weighted statistic with equally spaced weights for positive, nondiagnostic, and negative studies. Confidence intervals for the statistic were calculated from asymptotic estimations of the standard error. Calculations were performed by using SPSS software (SPSS, Inc., Chicago, Illinois). Results One hundred four patients were recruited according to our protocol (Figure 1). The time between venography and MRDTI was less than 8 hours in 28 patients, 8 to 24 hours in 44 patients, and 24 to 48 hours in 32 patients. Age ranged from 20 to 95 years, and symptom onset varied from 1 to 35 days. Ninety-five patients were referred from medical specialties and 9 from surgical specialties; 47 were inpatients and 57 were outpatients. Both reviewers reported that 3 of 5 patients with ipsilateral total hip replacements had nondiagnostic MRDTI scans. Venography diagnosed femoropopliteal DVT in 1 of these patients and was negative in 2 patients. These 3 patients were excluded from further analysis, leaving 101 patients in the study. One patient could tolerate only the first scanning block from ankle to thigh level owing to claustrophobia; however, femoropopliteal DVT could still be diagnosed. All other patients tolerated MRI. Eighteen of 148 patients (12%) were excluded from the study. Fifteen patients could not undergo MRI because of contraindications (9 patients) or claustrophobia (6 patients), and 3 patients had inconclusive results on MRDTI. Venography failed (29 patients) or was inconclusive (11 patients) in 12% of patients (40 of 338). Venography was inconclusive

Detection of intraplaque hemorrhage by magnetic resonance imaging in symptomatic patients with mild to moderate carotid stenosis predicts recurrent neurological events.

BACKGROUND Carotid endarterectomy is beneficial in severe (>70%) symptomatic carotid stenosis. The risk of stroke in moderate carotid stenosis (50%-69%) is modest, and so the role of carotid endarterectomy in this group is unclear. Intraplaque hemorrhage is associated with advanced atherosclerosis and can be detected in the carotid arteries by magnetic resonance imaging. This study evaluates whether magnetic resonance imaging detected intraplaque hemorrhage (MR IPH) can identify patients with symptomatic mild to moderate carotid stenosis who are at higher risk of ipsilateral transient ischemic attack (TIA) and stroke. METHODS Prospective longitudinal cohort study of symptomatic patients with mild to moderate (30%-69%) carotid stenosis followed up for 2 years after imaging for IPH using magnetic resonance imaging. RESULTS Sixty four participants were followed up for a median of 28 months (interquartile range 26-30) after MRI of the carotid arteries. Thirty-nine (61%) ipsilateral arteries showed intraplaque hemorrhage. During follow-up, five ipsilateral strokes and a total of 14 ipsilateral ischemic events were observed. Thirteen of these ischemic events, of which five were strokes, occurred in those with ipsilateral carotid intraplaque hemorrhage (hazard ratio = 9.8, 95% confidence interval 1.3-75.1, P = .03). CONCLUSIONS MR IPH is a good predictor of ipsilateral stroke and TIA in patients with symptomatic mild to moderate (30%-69%) carotid stenosis. This technique could help in the selection of patients for carotid endarterectomy.

Pyramidal tract mapping by diffusion tensor magnetic resonance imaging in multiple sclerosis: improving correlations with disability

Background: Current magnetic resonance imaging (MRI) outcome measures such as T2 lesion load correlate poorly with disability in multiple sclerosis. Diffusion tensor imaging (DTI) of the brain can provide unique information regarding the orientation and integrity of white matter tracts in vivo. Objective: To use this information to map the pyramidal tracts of patients with multiple sclerosis, investigate the relation between burden of disease in the tracts and disability, and compare this with more global magnetic resonance estimates of disease burden. Methods: 25 patients with relapsing-remitting multiple sclerosis and 17 healthy volunteers were studied with DTI. An algorithm was used that automatically produced anatomically plausible maps of white matter tracts. The integrity of the pyramidal tracts was assessed using relative anisotropy and a novel measure (Lt) derived from the compounded relative anisotropy along the tracts. The methods were compared with both traditional and more recent techniques for measuring disease burden in multiple sclerosis (T2 lesion load and “whole brain” diffusion histograms). Results: Relative anisotropy and Lt were significantly lower in patients than controls (p < 0.05). Pyramidal tract Lt in the patients correlated significantly with both expanded disability status scale (r = −0.48, p < 0.05), and to a greater degree, the pyramidal Kurtzke functional system score (KFS-p) (r = −0.75, p < 0.0001). T2 lesion load and diffusion histogram parameters did not correlate with disability. Conclusions: Tract mapping using DTI is feasible and may increase the specificity of MRI in multiple sclerosis by matching appropriate tracts with specific clinical scoring systems. These techniques may be applicable to a wide range of neurological conditions.

Parietal updating of limb posture: an event-related fMRI study.

The posterior parietal cortex (PPC) is thought to integrate different kinds of sensory information (e.g., visual, auditory, somatosensory) to produce multiple representations of space that are each associated with different types or combinations of action; such as saccadic eye movements and reaching or grasping movements of the upper limb. Lesion studies in monkeys and in humans have shown that reaching movements to visually defined and to posturally defined targets can be dissociated from one another; indicating that different regions of the parietal cortex may code the same movement in either extrinsic (visual) or intrinsic (postural) coordinates. These studies also suggest that regions within the posterior parietal cortex play an important role in maintaining an accurate and up-to-date representation of the current postural state of the body (the body schema). We used event-related functional magnetic resonance imaging (fMRI) to investigate those brain areas involved in maintaining and updating postural (i.e., non-visual) representations of the upper limb that participate in the accurate control of reaching movements. We show that a change in the posture of the upper-limb is associated with a significant increase in BOLD activation in only one brain region--the superior parietal cortex, particularly the medial aspect (precuneus). We note that this finding is consistent with the suggestion, based upon human neurological investigations and monkey electrophysiology, that this region of the PPC may participate in the dynamic representation of the body schema, and is the most likely location for damage leading to errors in visually guided reaching to non-foveated target locations. We also note that this brain area corresponds to a region of PPC recently identified as the human homologue of the Parietal Reach Region (PRR) observed in the monkey brain that has been thought to represent reaching movements in eye-centred coordinates.

In-Vivo Mapping of the Human Locus Coeruleus

The locus coeruleus (LC) is a brainstem structure that has widespread cortical and sub-cortical projections to modulate states of attention. Our understanding of the LCs role in both normal attention and clinical populations affected by disrupted attention would be advanced by having in vivo functional and structural markers of the human LC. Evidence for LC activation can be difficult to interpret because of uncertainty about whether brainstem activity can be accurately localized to the LC. High resolution T1-turbo spin echo (T1-TSE) magnetic resonance imaging (MRI) (in-plane resolution of 0.4 mm x 0.4 mm) was used in this study to characterize the location and distribution probability of the LC across 44 adults ranging in age from 19 to 79 years. Utilizing a study-specific brainstem template, the individual brainstems were aligned into standard space, while preserving variations in LC signal intensity. Elevated T1-TSE signal was observed in the rostral pons that was strongly correlated with the position and concentration of LC cells previously reported in a study of post-mortem brains (r=0.90). The elevated T1-TSE signal was used to produce a probabilistic map of the LC in standard Montreal Neurological Institute (MNI) coordinate space. This map can be used to test hypotheses about the LC in human structural and functional imaging studies. Such efforts will contribute to our understanding of attention systems in normal and clinical populations.

DEMONSTRATING THE PERIVASCULAR DISTRIBUTION OF MS LESIONS IN VIVO WITH 7-TESLA MRI

While most white matter (WM) demyelinating lesions in multiple sclerosis (MS) have a perivascular distribution, heterogeneity in lesion pathology has been shown to include a variable relationship between lesions and parenchymal blood vessels.1 Reports that such lesion characteristics at brain biopsy predict treatment response suggest that identifying perivascular lesions in vivo could be clinically relevant.2 It is unclear, however, to what extent the age and topographic location of a lesion influence its vascular anatomy. This pilot study aimed to develop an imaging technique capable of defining the relationship between demyelination and small parenchymal blood vessels in MS. Comparison between T2-weighted MR images at 1.5 tesla with subsequent venography has previously been used to determine the relationship of lesions to blood vessels.3 While this technique can demonstrate an MS lesion and a blood vessel in close proximity, the inability to demonstrate both structures simultaneously means the exact spatial relationship cannot be defined or followed longitudinally. Ultra-high field human MRI offers an increased signal to noise ratio and enhanced spatial resolution compared to clinical MRI scanners, at the expense of increased radiofrequency and static field inhomogeneity which result in a (smooth) variation of intensity across the image and distortions at structural boundaries. T2* contrast observed at ultra high field strengths …

Correction of spatial distortion in EPI due to inhomogeneous static magnetic fields using the reversed gradient method

To derive and implement a method for correcting spatial distortion caused by in vivo inhomogeneous static magnetic fields in echo‐planar imaging (EPI).

Ultra-high-field imaging distinguishes MS lesions from asymptomatic white matter lesions

Objectives: To investigate whether multiple sclerosis (MS) and non-MS white matter brain lesions can be distinguished by their appearance on 7 T T2*-weighted MRI. Methods: This was an observational study of 28 patients with MS and 17 patients with cerebral white matter lesions who did not have MS. Subjects were imaged using 7 T T2*-weighted imaging. White matter lesions were identified and analyzed for volume, location, and perivenous appearance. Results: Out of 901 lesions identified in patients with MS, 80% were perivenous. In comparison, 19% of 428 lesions identified in patients without MS had a perivenous appearance. Seven-Tesla T2*-weighted MRI reliably distinguished all patients with clinically definite MS (>40% lesions appeared perivenous) from those without clinical MS (<40% lesions appeared perivenous). Perivenous lesion appearance was more predictive of MS (odds ratio [OR] 14, p < 0.001) than subcortical or periventricular lesion location (OR 4.5, p < 0.001, and OR 2.4, p = 0.009). Perivenous lesion appearance was observed with a similar frequency in patients with clinically isolated syndrome of demyelination and in early (gadolinium-enhancing) MS lesions. Conclusion: Perivenous lesion location on 7 T T2*-weighted imaging is predictive of the presence of demyelination. Optimization of this imaging technique at lower magnetic resonance field strengths would offer benefit for the diagnosis of MS.