Glymphatics Visualization after Focused Ultrasound-Induced Blood-Brain Barrier Opening in Humans.

It is currently unclear whether the glymphatic system, a brain-wide interstitial fluid-cerebrospinal fluid exchange described in rodents, exists in humans. Focal blood-brain barrier disruption using magnetic resonance-guided focused ultrasound allows parenchymal penetration of gadobutrol contrast, creating an opportunity to study glymphatics in vivo noninvasively. We describe patterns of contrast distribution in the perivascular space, subarachnoid space, and space surrounding large veins draining toward the dural sinuses on fluid-attenuated inversion recovery in subjects with Alzheimer disease and amyotrophic lateral sclerosis. This is the first evidence suggesting glymphatic efflux persists in humans. It's relevance to proteinopathies and drug delivery is discussed. ANN NEUROL 2019;86:975-980.

Imaging for Neuroprognostication After Cardiac Arrest: Systematic Review and Meta-analysis.

BACKGROUND: Predicting neurological outcome in comatose survivors of cardiac arrest relies on clinical findings, radiological and neurophysiological test results. To evaluate the predictive accuracy of brain computed tomography (CT) and magnetic resonance imaging (MRI) for prognostication of neurological outcomes after cardiac arrest. METHODS: We searched MEDLINE (database inception to August 2018) and included all observational cohort studies or randomized controlled trials including adult (16 years or older) survivors of cardiac arrest which evaluated the diagnostic accuracy of CT or MRI for predicting neurologic outcome or mortality. Study quality was assessed using the Quality Assessment of Diagnostic Accuracy Studies 2 tool. All review stages were conducted independently by 2 reviewers, and where possible data were pooled using bivariate meta-analysis. The main outcome was to evaluate the of accuracy of CT and MRI in neuroprognostication of patients after cardiac arrest. RESULTS: We included 44 studies that examined brain CT (n = 24) or MRI (n = 21) in 4008 (n per study, 9-398) patients. Decreased grey to white matter ratio on CT (20 studies) was useful for predicting poor neurological outcome (sensitivity 0.44, 95% CI 0.29-0.60; specificity 0.97, 95% CI 0.93-0.99; positive likelihood ratio [LR+] 13.8, 95% CI 6.9-27.7). Similarly, diffusion-weighted imaging (DWI) on MRI (16 studies; sensitivity 0.77, 95% CI 0.65-0.85; specificity 0.92, 95% CI 0.85-0.96; LR+ 9.2, 95% CI 5.2-16.4) and DWI and fluid-attenuated inversion recovery (FLAIR) MRI (4 studies, sensitivity 0.70, 95% CI 0.43-0.88; specificity 0.95, 95% CI 0.79-0.99; LR+ 13.4, 95% CI 3.5-51.2) were useful for predicting poor neurological outcomes. We found marked heterogeneity in timing of radiological examinations and neurological assessments relative to the cardiac arrest. CONCLUSION: Decreased grey to white matter ratio on CT and DWI or DWI and FLAIR on MRI are useful adjuncts for predicting poor early neurological outcome after cardiac arrest.

Magnetic resonance thermometry of flowing blood.

Blood temperature is a key determinant of tissue temperature and can be altered under normal physiological states, such as exercise, in diseases such as stroke or iatrogenically in therapies which modulate tissue temperature, such as therapeutic hypothermia. Currently available methods for the measurement of arterial and venous temperatures are invasive and, for small animal models, are impractical. Here, we present a methodology for the measurement of intravascular and tissue temperature by magnetic resonance imaging (MRI) using the lanthanide agent TmDOTMA- (DOTMA, tetramethyl-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid; Tm, thulium). The approach makes use of phase-sensitive imaging measurements, combined with spectrally selective excitation, to monitor the temperature-dependent shift in the resonance of proton nuclei associated with water and with methyl groups of TmDOTMA- . Measurements were first made in a flow phantom modelling diastolic blood flow in the mouse aorta or inferior vena cava (IVC) and imaged using 7-T preclinical MRI with a custom-built surface coil. Flowing and static fluid temperatures agreed to within 0.12°C for these experiments. Proof-of-concept experiments were also performed on three healthy adult mice, demonstrating temperature measurements in the aorta, IVC and kidney following a bolus injection of contrast agent. A small (0.7-1°C), but statistically significant, higher kidney temperature compared with the aorta (p = 0.002-0.007) and IVC (p = 0.003-0.03) was shown in all animals. These findings demonstrate the feasibility of the technique for in vivo applications and illustrate how the technique could be used to explore the relationship between blood and tissue temperature for a wide range of applications.

Differentiating radiation necrosis from tumor progression in brain metastases treated with stereotactic radiotherapy: utility of intravoxel incoherent motion perfusion MRI and correlation with histopathology.

Radiation necrosis is a serious potential adverse event of stereotactic radiosurgery that cannot be reliably differentiated from recurrent tumor using conventional imaging techniques. Intravoxel incoherent motion (IVIM) is a magnetic resonance imaging (MRI) based method that uses a diffusion-weighted sequence to estimate quantitative perfusion and diffusion parameters. This study evaluated the IVIM-derived apparent diffusion coefficient (ADC) and perfusion fraction (f), and compared the results to the gold standard histopathological-defined outcomes of radiation necrosis or recurrent tumor. Nine patients with ten lesions were included in this study; all lesions exhibited radiographic progression after stereotactic radiosurgery for brain metastases that subsequently underwent surgical resection due to uncertainty regarding the presence of radiation necrosis versus recurrent tumor. Pre-surgical IVIM was performed to obtain f and ADC values and the results were compared to histopathology. Five lesions exhibited pathological radiation necrosis and five had predominantly recurrent tumor. The IVIM perfusion fraction reliably differentiated tumor recurrence from radiation necrosis (fmean = 10.1 ± 0.7 vs. 8.3 ± 1.2, p = 0.02; cutoff value of 9.0 yielding a sensitivity/specificity of 100%/80%) while the ADC did not distinguish between the two (ADCmean = 1.1 ± 0.2 vs. 1.2 ± 0.4, p = 0.6). IVIM shows promise in differentiating recurrent tumor from radiation necrosis for brain metastases treated with radiosurgery, but needs to be validated in a larger cohort.

Temporal evolution of perfusion parameters in brain metastases treated with stereotactic radiosurgery: comparison of intravoxel incoherent motion and dynamic contrast enhanced MRI.

Intravoxel incoherent motion (IVIM) is a magnetic resonance imaging (MRI) technique that is seeing increasing use in neuro-oncology and offers an alternative to contrast-enhanced perfusion techniques for evaluation of tumor blood volume after stereotactic radiosurgery (SRS). To date, IVIM has not been validated against contrast enhanced techniques for brain metastases after SRS. In the present study, we measure blood volume for 20 brain metastases (15 patients) at baseline, 1 week and 1 month after SRS using IVIM and dynamic contrast enhanced (DCE)-MRI. Correlation between blood volume measurements made with IVIM and DCE-MRI show poor correlation at baseline, 1 week, and 1 month post SRS (r = 0.33, 0.14 and 0.30 respectively). At 1 week after treatment, no significant change in tumor blood volume was found using IVIM or DCE-MRI (p = 0.81 and 0.41 respectively). At 1 month, DCE-MRI showed a significant decrease in blood volume (p = 0.0002). IVIM, on the other hand, demonstrated the opposite effect and showed a significant increase in blood volume at 1 month (p = 0.03). The results of this study indicate that blood volume measured with IVIM and DCE-MRI are not equivalent. While this may relate to differences in the type of perfusion information each technique is providing, it could also reflect a limitation of tumor blood volume measurements made with IVIM after SRS. IVIM measurements of tumor blood volume in the month after SRS should therefore be interpreted with caution.

Prevalence of white matter hyperintensities is not elevated in a large sample of adolescents and young adults with bipolar disorder.

OBJECTIVE: The increased prevalence rate of white matter hyperintensities is one of the most consistently reported brain abnormalities in adults with bipolar disorder. However, findings in children and adolescents with bipolar disorder are less consistent. Prior studies have been constrained by small sample sizes and/or poor age- and sex-matching of healthy controls. We examined this topic in the largest sample of adolescents with bipolar disorder to date. METHODS: T2-weighted 3-Tesla magnetic resonance imaging data were acquired for 83 adolescents with bipolar disorder diagnosed via the Kiddie Schedule for Affective Disorders and the Schizophrenia, Present and Lifetime version semi-structured interview and 64 age- and sex-matched healthy controls. All acquired scans were examined by neuroradiologists and the presence or absence of white matter hyperintensities was determined for each participant. RESULTS: The prevalence of white matter hyperintensities did not differ between adolescents with bipolar disorder (13.3%) and controls (21.9%; χ2 = 1.90; p = 0.168). CONCLUSION: In contrast to the study hypothesis, the prevalence of white matter hyperintensities was not higher in adolescents with bipolar disorder than controls. The large sample size and good matching for age and sex bolster the reliability of this negative finding. Future studies are warranted to evaluate the prevalence, incidence, and predictors of white matter hyperintensities in early-onset bipolar disorder prospectively.

MR-guided focused ultrasound liquid biopsy enriches circulating biomarkers in patients with brain tumors.

BACKGROUND: Liquid biopsy is promising for early detection, monitoring of response, and recurrence of cancer. The blood-brain barrier (BBB) limits the shedding of biomarker, such as cell-free DNA (cfDNA), into the blood from brain tumors, and their detection by conventional assays. Transcranial MR-guided focused ultrasound (MRgFUS) can safely and transiently open the BBB, providing an opportunity for less-invasive access to brain pathology. We hypothesized that MRgFUS can enrich the signal of circulating brain-derived biomarkers to aid in liquid biopsy. METHODS: Nine patients were treated in a prospective single-arm, open-label trial to investigate serial MRgFUS and adjuvant temozolomide combination in patients with glioblastoma (NCT03616860). Blood samples were collected as an exploratory measure within the hours before and after sonication, with control samples from non-brain tumor patients undergoing BBB opening (BBBO) alone (NCT03739905). RESULTS: Brain regions averaging 7.8 ± 6.0 cm3 (range 0.8-23.1 cm3) were successfully treated within 111 ± 39 minutes without any serious adverse events. We found MRgFUS acutely enhanced plasma cfDNA (2.6 ± 1.2-fold, P < .01, Wilcoxon signed-rank test), neuron-derived extracellular vesicles (3.2 ± 1.9-fold, P < .01), and brain-specific protein S100b (1.4 ± 0.2-fold, P < .01). Further comparison of the cfDNA methylation profiles suggests a signature that is disease- and post-BBBO-specific, in keeping with our hypothesis. We also found cfDNA-mutant copies of isocitrate dehydrogenase 1 (IDH1) increased, although this was in only one patient known to harbor the tumor mutation. CONCLUSIONS: This first-in-human proof-of-concept study shows MRgFUS enriches the signal of circulating brain-derived biomarkers, demonstrating the potential of the technology to support liquid biopsy for the brain.