John Huston

Effect of a Novel Free Radical Scavenger, Edaravone (MCI-186), on Acute Brain Infarction

Edaravone, a novel free radical scavenger, demonstrates neuroprotective effects by inhibiting vascular endothelial cell injury and ameliorating neuronal damage in ischemic brain models. The present study was undertaken to verify its therapeutic efficacy following acute ischemic stroke. We performed a multicenter, randomized, placebo-controlled, double-blind study on acute ischemic stroke patients commencing within 72 h of onset. Edaravone was infused at a dose of 30 mg, twice a day, for 14 days. At discharge within 3 months or at 3 months after onset, the functional outcome was evaluated using the modified Rankin Scale. Two hundred and fifty-two patients were initially enrolled. Of these, 125 were allocated to the edaravone group and 125 to the placebo group for analysis. Two patients were excluded because of subarachnoid hemorrhage and disseminated intravascular coagulation. A significant improvement in functional outcome was observed in the edaravone group as evaluated by the modified Rankin Scale (p = 0.0382). Edaravone represents a neuroprotective agent which is potentially useful for treating acute ischemic stroke, since it can exert significant effects on functional outcome as compared with placebo.

Primary central nervous system vasculitis: analysis of 101 patients

To analyze the clinical findings, response to therapy, outcome, and incidence of primary central nervous system vasculitis (PCNSV) in a large cohort from a single center

High-resolution intracranial and cervical MRA at 3.0T: technical considerations and initial experience.

Initial experience with intracranial and cervical MRA at 3.0T is reported. Phantom measurements (corrected for relaxation effects) show S/N (3.0T) = 2.14 ± 0.08 × S/N (1.5T) in identical‐geometry head coils. A 3.0T 3DTOF intracranial imaging protocol with higher‐order autoshimming was developed and compared to 1.5T 3DTOF in 12 patients with aneurysms. A comparison by two radiologists showed the 3.0T to be significantly better (P < 0.001) for visualization of the aneurysms. The feasibility of cervical and intracranial contrast enhanced MR angiography (CEMRA) at 3.0T is also examined. The relaxivity of the gadolinium contrast agent decreases by only about 4–7% when the field strength is increased from 1.5 to 3.0T. Cervical 3.0T CEMRA was obtained in eight patients, two of whom had 1.5T studies available for direct comparison. Image comparison suggests 3.0T to be a favorable field strength for cervical CEMRA. Voxel volumes of 0.62–0.73 mm3 (not including zero‐filling) were readily achieved at 3.0T with the use of a single‐channel transmit‐receive head or cervical coil, a 25 mL bolus of gadoteridol, and a 3D pulse sequence with a 66% sampling efficiency. This spatial resolution allowed visualization of intracranial aneurysms, carotid dissections, and atherosclerotic disease including ulcerations. Potential drawbacks of 3.0T MRA are increased SAR and T  *2 dephasing compared to 1.5T. Image comparison suggests signal loss due to T  *2 dephasing will not be substantially more problematic than at 1.5T. The dependence of RF power deposition on TR for CEMRA is calculated and discussed. Magn Reson Med 46:955–962, 2001.

Lessons learned from whole exome sequencing in multiplex families affected by a complex genetic disorder, intracranial aneurysm

Genetic risk factors for intracranial aneurysm (IA) are not yet fully understood. Genomewide association studies have been successful at identifying common variants; however, the role of rare variation in IA susceptibility has not been fully explored. In this study, we report the use of whole exome sequencing (WES) in seven densely-affected families (45 individuals) recruited as part of the Familial Intracranial Aneurysm study. WES variants were prioritized by functional prediction, frequency, predicted pathogenicity, and segregation within families. Using these criteria, 68 variants in 68 genes were prioritized across the seven families. Of the genes that were expressed in IA tissue, one gene (TMEM132B) was differentially expressed in aneurysmal samples (n=44) as compared to control samples (n=16) (false discovery rate adjusted p-value=0.023). We demonstrate that sequencing of densely affected families permits exploration of the role of rare variants in a relatively common disease such as IA, although there are important study design considerations for applying sequencing to complex disorders. In this study, we explore methods of WES variant prioritization, including the incorporation of unaffected individuals, multipoint linkage analysis, biological pathway information, and transcriptome profiling. Further studies are needed to validate and characterize the set of variants and genes identified in this study.

Imaging artifacts at 3.0T

Clinical MRI at a field strength of 3.0T is finding increasing use. However, along with the advantages of 3.0T, such as increased SNR, there can be drawbacks, including increased levels of imaging artifacts. Although every imaging artifact observed at 3.0T can also be present at 1.5T, the intensity level is often higher at 3.0T and thus the artifact is more objectionable. This review describes some of the imaging artifacts that are commonly observed with 3.0T imaging, and their root causes. When possible, countermeasures that reduce the artifact level are described. J. Magn. Reson. Imaging 2006.

Intracranial aneurysms in patients with coarctation of the aorta: a prospective magnetic resonance angiographic study of 100 patients.

OBJECTIVE To determine the frequency of intracranial aneurysms (IAs) detected in patients with coarctation of the aorta (CoA) with use of magnetic resonance angiography. PATIENTS AND METHODS From January 1, 1980, to September 30, 2002, 277 adult patients with CoA were seen at the Mayo Clinic in Rochester, Minn, and were invited to participate in a study to detect IAs. Of these 277 patients (mean +/- SD age, 41.6 +/- 16.5; 70 men), 100 underwent cranial magnetic resonance angiography. RESULTS Ten patients had an IA (95% confidence interval, 5%-18%), with a mean diameter of 3.5 mm (range, 2.0-8.0 mm). The frequency of IA was significantly higher than that predicted in the general population (10% vs 2%; P < .001). One patient had surgical intervention. No clinical or geographical differences were found between patients with CoA and IA and patients with CoA and no IA. CONCLUSIONS The frequency of IA among patients with CoA is approximately 5-fold that of the general population. Although no risk factors were identified in this cohort, additional prospective evaluation is warranted. These data suggest that noninvasive cerebral imaging to screen for IA should be considered in patients with CoA.

Measurement of cerebrospinal fluid flow at the cerebral aqueduct by use of phase-contrast magnetic resonance imaging: technique validation and utility in diagnosing idiopathic normal pressure hydrocephalus.

OBJECTIVE We analyzed the reliability of a protocol for measuring quantitative cerebrospinal fluid (CSF) flow at the cerebral aqueduct and established the range of CSF flows in normal elderly patients, patients with Alzheimer’s and other forms of dementia, and patients with idiopathic normal pressure hydrocephalus (NPH). METHODS A constant flow phantom was used to establish the accuracy of the CSF flow measurement. The clinical variability of the measurement was estimated by calculating the standard deviations and coefficients of variation of intra- and interobserver and intertrial data sets derived from three normal volunteers. A total of 236 patients were studied, including 47 normal elderly patients, 115 patients with cognitive impairment (9 with mild cognitive impairment, 46 with Alzheimer’s disease, and 60 with other cognitive impairment), 31 patients in whom NPH was suspected but ultimately excluded, and 43 patients with a final clinical diagnosis of NPH. RESULTS The intraobserver, interobserver, and intertrial measurement variations of 6.4, 5.4, and 8.8%, respectively, were substantially smaller than the wide variation observed among subjects. There was no statistically significant difference in flow between normal elderly patients and patients with cognitive impairment (P = 0.91). When these populations were pooled, the average flow was 8.47 ml/min (standard deviation, 4.23; range, 0.9–18.5 ml/min). The average flow rate in patients with a final clinical diagnosis of NPH was 27.4 ml/min (standard deviation, 15.3; range, 3.13–62.2 ml/min). This was significantly higher than the flow rate in each of the other three groups (all, P < 0.001). CONCLUSION CSF flow measurements of less than 18 ml/min with a sinusoidal flow pattern are normal. CSF flow of greater than 18 ml/min suggests idiopathic NPH.

Decreased brain stiffness in Alzheimer's disease determined by magnetic resonance elastography

To test patient acceptance and reproducibility of the 3D magnetic resonance elastography (MRE) brain exam using a soft vibration source, and to determine if MRE could noninvasively measure a change in the elastic properties of the brain parenchyma due to Alzheimers disease (AD).

Aspirin as a Promising Agent for Decreasing Incidence of Cerebral Aneurysm Rupture

Background and Purpose— Chronic inflammation is postulated as an important phenomenon in intracranial aneurysm wall pathophysiology. This study was conducted to determine if aspirin use impacts the occurrence of intracranial aneurysm rupture. Methods— Subjects enrolled in the International Study of Unruptured Intracranial Aneurysms (ISUIA) were selected from the prospective untreated cohort (n=1691) in a nested case–control study. Cases were subjects who subsequently had a proven aneurysmal subarachnoid hemorrhage during a 5-year follow-up period. Four control subjects were matched to each case by site and size of aneurysm (58 cases, 213 control subjects). Frequency of aspirin use was determined at baseline interview. Aspirin frequency groups were analyzed for risk of aneurysmal hemorrhage. Bivariable and multivariable analyses were performed using conditional logistic regression. Results— A trend of a protective effect for risk of unruptured intracranial aneurysm rupture was observed. Patients who used aspirin 3× weekly to daily had an OR for hemorrhage of 0.40 (95% CI, 0.18–0.87); reference group, no use of aspirin), patients in the “< once a month” group had an OR of 0.80 (95% CI, 0.31–2.05), and patients in the “> once a month to 2×/week” group had an OR of 0.87 (95% CI, 0.27–2.81; P=0.025). In multivariable risk factor analyses, patients who used aspirin 3 times weekly to daily had a significantly lower odds of hemorrhage (adjusted OR, 0.27; 95% CI, 0.11–0.67; P=0.03) compared with those who never take aspirin. Conclusions— Frequent aspirin use may confer a protective effect for risk of intracranial aneurysm rupture. Future investigation in animal models and clinical studies is needed.

Sample Size Calculation for Clinical Trials Using Magnetic Resonance Imaging for the Quantitative Assessment of Carotid Atherosclerosis

PURPOSE To provide sample size calculation for the quantitative assessment of carotid atherosclerotic plaque using non-invasive magnetic resonance imaging in multi-center clinical trials. METHODS. As part of a broader double-blind randomized trial of an experimental pharmaceutical agent, 20 asymptomatic placebo-control subjects were recruited from 5 clinical sites for a multi-center study. Subjects had 4 scans in 13 weeks on GE 1.5 T scanners, using TOF, T1-/PD-/T2- and contrast-enhanced Tl-weighted images. Measurement variability was assessed by comparing quantitative data from the index carotid artery over the four time points. The wall/outer wall (W/OW) ratio was calculated as wall volume divided by outer wall volume. The percent lipid-rich/necrotic core (%LR/NC) and calcification (%Ca) were measured as a proportion of the vessel wall. For %LR/NC and %Ca, only those subjects that exhibited LR/NC or Ca components were used in the analysis. RESULTS Measurement error was 5.8% for wall volume, 3.2% for W/OW ratio, 11.1% for %LR/NC volume and 18.6% for %Ca volume. Power analysis based on these values shows that a study with 14 participants in each group could detect a 5% change in W/OW ratio, 10% change in wall volume, and 20% change in %LR/NC volume (power = 80%, p < .05). The calculated measurement errors presume any true biological changes were negligible over the 3 months that subjects received placebo. CONCLUSION In vivo MRI is capable of quantifying plaque volume and plaque composition, such as %lipid-rich/necrotic core and %calcification, in the clinical setting of a multi-center trial with low inter-scan variability. This study provides the basis for sample size calculation of future MRI trials.