Automated Quality Evaluation Index for Arterial Spin Labeling Derived Cerebral Blood Flow Maps.

BACKGROUND: Arterial spin labeling (ASL) derived cerebral blood flow (CBF) maps are prone to artifacts and noise that can degrade image quality. PURPOSE: To develop an automated and objective quality evaluation index (QEI) for ASL CBF maps. STUDY TYPE: Retrospective. POPULATION: Data from N = 221 adults, including patients with Alzheimer's disease (AD), Parkinson's disease, and traumatic brain injury. FIELD STRENGTH/SEQUENCE: Pulsed or pseudocontinuous ASL acquired at 3 T using non-background suppressed 2D gradient-echo echoplanar imaging or background suppressed 3D spiral spin-echo readouts. ASSESSMENT: The QEI was developed using N = 101 2D CBF maps rated as unacceptable, poor, average, or excellent by two neuroradiologists and validated by 1) leave-one-out cross validation, 2) assessing if CBF reproducibility in N = 53 cognitively normal adults correlates inversely with QEI, 3) if iterative discarding of low QEI data improves the Cohen's d effect size for CBF differences between preclinical AD (N = 27) and controls (N = 53), 4) comparing the QEI with manual ratings for N = 50 3D CBF maps, and 5) comparing the QEI with another automated quality metric. STATISTICAL TESTS: Inter-rater reliability and manual vs. automated QEI were quantified using Pearson's correlation. P < 0.05 was considered significant. RESULTS: The correlation between QEI and manual ratings (R = 0.83, CI: 0.76-0.88) was similar (P = 0.56) to inter-rater correlation (R = 0.81, CI: 0.73-0.87) for the 2D data. CBF reproducibility correlated negatively (R = -0.74, CI: -0.84 to -0.59) with QEI. The effect size comparing patients and controls improved (R = 0.72, CI: 0.59-0.82) as low QEI data was discarded iteratively. The correlation between QEI and manual ratings (R = 0.86, CI: 0.77-0.92) of 3D ASL was similar (P = 0.09) to inter-rater correlation (R = 0.78, CI: 0.64-0.87). The QEI correlated (R = 0.87, CI: 0.77-0.92) significantly better with manual ratings than did an existing approach (R = 0.54, CI: 0.30-0.72). DATA CONCLUSION: Automated QEI performed similarly to manual ratings and can provide scalable ASL quality control. EVIDENCE LEVEL: 2 TECHNICAL EFFICACY: Stage 1.

Coronavirus Disease (COVID-19)-Related Disseminated Leukoencephalopathy: A Retrospective Study of Findings on Brain MRI.

Among 2820 inpatients with coronavirus disease (COVID-19), 59 (2.1%) underwent brain MRI. Of them, six (10.2%) had MRI findings suspicious for COVID-19-related disseminated leukoencephalopathy (CRDL), which is characterized by extensive confluent or multifocal white matter lesions (with characteristics and locations atypical for other causes), microhemorrhages, diffusion restriction, and enhancement. CRDL is an uncommon but important differential consideration in patients with neurologic manifestations of COVID-19.

Histopathology-validated machine learning radiographic biomarker for noninvasive discrimination between true progression and pseudo-progression in glioblastoma.

BACKGROUND: Imaging of glioblastoma patients after maximal safe resection and chemoradiation commonly demonstrates new enhancements that raise concerns about tumor progression. However, in 30% to 50% of patients, these enhancements primarily represent the effects of treatment, or pseudo-progression (PsP). We hypothesize that quantitative machine learning analysis of clinically acquired multiparametric magnetic resonance imaging (mpMRI) can identify subvisual imaging characteristics to provide robust, noninvasive imaging signatures that can distinguish true progression (TP) from PsP. METHODS: We evaluated independent discovery (n = 40) and replication (n = 23) cohorts of glioblastoma patients who underwent second resection due to progressive radiographic changes suspicious for recurrence. Deep learning and conventional feature extraction methods were used to extract quantitative characteristics from the mpMRI scans. Multivariate analysis of these features revealed radiophenotypic signatures distinguishing among TP, PsP, and mixed response that compared with similar categories blindly defined by board-certified neuropathologists. Additionally, interinstitutional validation was performed on 20 new patients. RESULTS: Patients who demonstrate TP on neuropathology are significantly different (P < .0001) from those with PsP, showing imaging features reflecting higher angiogenesis, higher cellularity, and lower water concentration. The accuracy of the proposed signature in leave-one-out cross-validation was 87% for predicting PsP (area under the curve [AUC], 0.92) and 84% for predicting TP (AUC, 0.83), whereas in the discovery/replication cohort, the accuracy was 87% for predicting PsP (AUC, 0.84) and 78% for TP (AUC, 0.80). The accuracy in the interinstitutional cohort was 75% (AUC, 0.80). CONCLUSION: Quantitative mpMRI analysis via machine learning reveals distinctive noninvasive signatures of TP versus PsP after treatment of glioblastoma. Integration of the proposed method into clinical studies can be performed using the freely available Cancer Imaging Phenomics Toolkit.

Multiparametric magnetic resonance imaging in the assessment of anti-EGFRvIII chimeric antigen receptor T cell therapy in patients with recurrent glioblastoma.

EGFRvIII targeted chimeric antigen receptor T (CAR-T) cell therapy has recently been reported for treating glioblastomas (GBMs); however, physiology-based MRI parameters have not been evaluated in this setting. Ten patients underwent multiparametric MRI at baseline, 1, 2 and 3 months after CAR-T therapy. Logistic regression model derived progression probabilities (PP) using imaging parameters were used to assess treatment response. Four lesions from "early surgery" group demonstrated high PP at baseline suggestive of progression, which was confirmed histologically. Out of eight lesions from remaining six patients, three lesions with low PP at baseline remained stable. Two lesions with high PP at baseline were associated with large decreases in PP reflecting treatment response, whereas other two lesions with high PP at baseline continued to demonstrate progression. One patient didn't have baseline data but demonstrated progression on follow-up. Our findings indicate that multiparametric MRI may be helpful in monitoring CAR-T related early therapeutic changes in GBM patients.

Three-dimensional echo planar spectroscopic imaging for differentiation of true progression from pseudoprogression in patients with glioblastoma.

Accurate differentiation of true progression (TP) from pseudoprogression (PsP) in patients with glioblastomas (GBMs) is essential for planning adequate treatment and for estimating clinical outcome measures and future prognosis. The purpose of this study was to investigate the utility of three-dimensional echo planar spectroscopic imaging (3D-EPSI) in distinguishing TP from PsP in GBM patients. For this institutional review board approved and HIPAA compliant retrospective study, 27 patients with GBM demonstrating enhancing lesions within six months of completion of concurrent chemo-radiation therapy were included. Of these, 18 were subsequently classified as TP and 9 as PsP based on histological features or follow-up MRI studies. Parametric maps of choline/creatine (Cho/Cr) and choline/N-acetylaspartate (Cho/NAA) were computed and co-registered with post-contrast T1 -weighted and FLAIR images. All lesions were segmented into contrast enhancing (CER), immediate peritumoral (IPR), and distal peritumoral (DPR) regions. For each region, Cho/Cr and Cho/NAA ratios were normalized to corresponding metabolite ratios from contralateral normal parenchyma and compared between TP and PsP groups. Logistic regression analyses were performed to obtain the best model to distinguish TP from PsP. Significantly higher Cho/NAA was observed from CER (2.69 ± 1.00 versus 1.56 ± 0.51, p = 0.003), IPR (2.31 ± 0.92 versus 1.53 ± 0.56, p = 0.030), and DPR (1.80 ± 0.68 versus 1.19 ± 0.28, p = 0.035) regions in TP patients compared with those with PsP. Additionally, significantly elevated Cho/Cr (1.74 ± 0.44 versus 1.34 ± 0.26, p = 0.023) from CER was observed in TP compared with PsP. When these parameters were incorporated in multivariate regression analyses, a discriminatory model with a sensitivity of 94% and a specificity of 87% was observed in distinguishing TP from PsP. These results indicate the utility of 3D-EPSI in differentiating TP from PsP with high sensitivity and specificity.

Differentiation of brain infection from necrotic glioblastoma using combined analysis of diffusion and perfusion MRI.

BACKGROUND: Accurate differentiation of brain infections from necrotic glioblastomas (GBMs) may not always be possible on morphologic MRI or on diffusion tensor imaging (DTI) and dynamic susceptibility contrast perfusion-weighted imaging (DSC-PWI) if these techniques are used independently. PURPOSE: To investigate the combined analysis of DTI and DSC-PWI in distinguishing brain injections from necrotic GBMs. STUDY TYPE: Retrospective. POPULATION: Fourteen patients with brain infections and 21 patients with necrotic GBMs. FIELD STRENGTH/SEQUENCE: 3T MRI, DTI, and DSC-PWI. ASSESSMENT: Parametric maps of mean diffusivity (MD), fractional anisotropy (FA), coefficient of linear (CL), and planar anisotropy (CP) and leakage corrected cerebral blood volume (CBV) were computed and coregistered with postcontrast T1 -weighted and FLAIR images. All lesions were segmented into the central core and enhancing region. For each region, median values of MD, FA, CL, CP, relative CBV (rCBV), and top 90th percentile of rCBV (rCBVmax ) were measured. STATISTICAL TESTS: All parameters from both regions were compared between brain infections and necrotic GBMs using Mann-Whitney tests. Logistic regression analyses were performed to obtain the best model in distinguishing these two conditions. RESULTS: From the central core, significantly lower MD (0.90 × 10-3 ± 0.44 × 10-3 mm2 /s vs. 1.66 × 10-3 ± 0.62 × 10-3 mm2 /s, P = 0.001), significantly higher FA (0.15 ± 0.06 vs. 0.09 ± 0.03, P < 0.001), and CP (0.07 ± 0.03 vs. 0.04 ± 0.02, P = 0.009) were observed in brain infections compared to those in necrotic GBMs. Additionally, from the contrast-enhancing region, significantly lower rCBV (1.91 ± 0.95 vs. 2.76 ± 1.24, P = 0.031) and rCBVmax (3.46 ± 1.41 vs. 5.89 ± 2.06, P = 0.001) were observed from infective lesions compared to necrotic GBMs. FA from the central core and rCBVmax from enhancing region provided the best classification model in distinguishing brain infections from necrotic GBMs, with a sensitivity of 91% and a specificity of 93%. DATA CONCLUSION: Combined analysis of DTI and DSC-PWI may provide better performance in differentiating brain infections from necrotic GBMs. LEVEL OF EVIDENCE: 1 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2019;49:184-194.

Neuroimaging Findings in US Government Personnel With Possible Exposure to Directional Phenomena in Havana, Cuba.

IMPORTANCE: United States government personnel experienced potential exposures to uncharacterized directional phenomena while serving in Havana, Cuba, from late 2016 through May 2018. The underlying neuroanatomical findings have not been described. OBJECTIVE: To examine potential differences in brain tissue volume, microstructure, and functional connectivity in government personnel compared with individuals not exposed to directional phenomena. DESIGN, SETTING, AND PARTICIPANTS: Forty government personnel (patients) who were potentially exposed and experienced neurological symptoms underwent evaluation at a US academic medical center from August 21, 2017, to June 8, 2018, including advanced structural and functional magnetic resonance imaging analytics. Findings were compared with imaging findings of 48 demographically similar healthy controls. EXPOSURES: Potential exposure to uncharacterized directional phenomena of unknown etiology, manifesting as pressure, vibration, or sound. MAIN OUTCOMES AND MEASURES: Potential imaging-based differences between patients and controls with regard to (1) white matter and gray matter total and regional brain volumes, (2) cerebellar tissue microstructure metrics (eg, mean diffusivity), and (3) functional connectivity in the visuospatial, auditory, and executive control subnetworks. RESULTS: Imaging studies were completed for 40 patients (mean age, 40.4 years; 23 [57.5%] men; imaging performed a median of 188 [range, 4-403] days after initial exposure) and 48 controls (mean age, 37.6 years; 33 [68.8%] men). Mean whole brain white matter volume was significantly smaller in patients compared with controls (patients: 542.22 cm3; controls: 569.61 cm3; difference, -27.39 [95% CI, -37.93 to -16.84] cm3; P < .001), with no significant difference in the whole brain gray matter volume (patients: 698.55 cm3; controls: 691.83 cm3; difference, 6.72 [95% CI, -4.83 to 18.27] cm3; P = .25). Among patients compared with controls, there were significantly greater ventral diencephalon and cerebellar gray matter volumes and significantly smaller frontal, occipital, and parietal lobe white matter volumes; significantly lower mean diffusivity in the inferior vermis of the cerebellum (patients: 7.71 × 10-4 mm2/s; controls: 8.98 × 10-4 mm2/s; difference, -1.27 × 10-4 [95% CI, -1.93 × 10-4 to -6.17 × 10-5] mm2/s; P < .001); and significantly lower mean functional connectivity in the auditory subnetwork (patients: 0.45; controls: 0.61; difference, -0.16 [95% CI, -0.26 to -0.05]; P = .003) and visuospatial subnetwork (patients: 0.30; controls: 0.40; difference, -0.10 [95% CI, -0.16 to -0.04]; P = .002) but not in the executive control subnetwork (patients: 0.24; controls: 0.25; difference: -0.016 [95% CI, -0.04 to 0.01]; P = .23). CONCLUSIONS AND RELEVANCE: Among US government personnel in Havana, Cuba, with potential exposure to directional phenomena, compared with healthy controls, advanced brain magnetic resonance imaging revealed significant differences in whole brain white matter volume, regional gray and white matter volumes, cerebellar tissue microstructural integrity, and functional connectivity in the auditory and visuospatial subnetworks but not in the executive control subnetwork. The clinical importance of these differences is uncertain and may require further study.

Neurological Manifestations Among US Government Personnel Reporting Directional Audible and Sensory Phenomena in Havana, Cuba.

Importance: From late 2016 through August 2017, US government personnel serving on diplomatic assignment in Havana, Cuba, reported neurological symptoms associated with exposure to auditory and sensory phenomena. Objective: To describe the neurological manifestations that followed exposure to an unknown energy source associated with auditory and sensory phenomena. Design, Setting, and Participants: Preliminary results from a retrospective case series of US government personnel in Havana, Cuba. Following reported exposure to auditory and sensory phenomena in their homes or hotel rooms, the individuals reported a similar constellation of neurological symptoms resembling brain injury. These individuals were referred to an academic brain injury center for multidisciplinary evaluation and treatment. Exposures: Report of experiencing audible and sensory phenomena emanating from a distinct direction (directional phenomena) associated with an undetermined source, while serving on US government assignments in Havana, Cuba, since 2016. Main Outcomes and Measures: Descriptions of the exposures and symptoms were obtained from medical record review of multidisciplinary clinical interviews and examinations. Additional objective assessments included clinical tests of vestibular (dynamic and static balance, vestibulo-ocular reflex testing, caloric testing), oculomotor (measurement of convergence, saccadic, and smooth pursuit eye movements), cognitive (comprehensive neuropsychological battery), and audiometric (pure tone and speech audiometry) functioning. Neuroimaging was also obtained. Results: Of 24 individuals with suspected exposure identified by the US Department of State, 21 completed multidisciplinary evaluation an average of 203 days after exposure. Persistent symptoms (>3 months after exposure) were reported by these individuals including cognitive (n = 17, 81%), balance (n = 15, 71%), visual (n = 18, 86%), and auditory (n = 15, 68%) dysfunction, sleep impairment (n = 18, 86%), and headaches (n = 16, 76%). Objective findings included cognitive (n = 16, 76%), vestibular (n = 17, 81%), and oculomotor (n = 15, 71%) abnormalities. Moderate to severe sensorineural hearing loss was identified in 3 individuals. Pharmacologic intervention was required for persistent sleep dysfunction (n = 15, 71%) and headache (n = 12, 57%). Fourteen individuals (67%) were held from work at the time of multidisciplinary evaluation. Of those, 7 began graduated return to work with restrictions in place, home exercise programs, and higher-level work-focused cognitive rehabilitation. Conclusions and Relevance: In this preliminary report of a retrospective case series, persistent cognitive, vestibular, and oculomotor dysfunction, as well as sleep impairment and headaches, were observed among US government personnel in Havana, Cuba, associated with reports of directional audible and/or sensory phenomena of unclear origin. These individuals appeared to have sustained injury to widespread brain networks without an associated history of head trauma.

Assignment Confidence in Localization of the Hand Motor Cortex: Comparison of Structural Imaging With Functional MRI.

OBJECTIVE: The purpose of this study was to assign confidence levels to structural MRI and functional MRI (fMRI) for localization of the primary motor cortex. MATERIALS AND METHODS: Ninety-one fMRI studies with at least one motor task (178 hemispheres) were identified. Three anatomic assessments were used to localize the primary motor cortex: relation between the superior frontal sulcus and precentral sulcus; cortical thickness; and configuration of the precentral knob. In 105 hemispheres, interreader agreement was assessed for two investigators with different experience levels. Confidence ratings from 0 to 5 (0, no confidence; 5, 100% confidence) were assigned for fMRI and each anatomic localization method. RESULTS: Cortical thickness had the highest confidence rating (mean, 4.90 ± 0.47 [SD]) with only one failure. The relation between the superior frontal sulcus and precentral sulcus had the lowest confidence rating (4.33 ± 0.91) with three failures. The greatest statistical significance was observed for the cortical thickness and superior frontal sulcus-precentral sulcus methods (post hoc Bonferroni test, p < 0.001). Confidence rating scores were significantly higher for the cortical thickness sign than for fMRI results (4.72 ± 0.54) for a single motor task (post hoc Bonferroni test, p = 0.006); however, the mean confidence rating for fMRI improved to 4.87 ± 0.36 when additional motor tasks were performed. Interreader differences were least for the cortical thickness sign (paired t test, t = 4.25, p < 0.001). CONCLUSION: Cortical thickness is a better anatomic landmark than fMRI localization for assigning confidence regarding localization of the primary motor cortex; however, localization of motor function is more specific when combined with fMRI findings. Multiple techniques can be used to increase confidence in identifying the hand motor cortex.

Pattern analysis of dynamic susceptibility contrast-enhanced MR imaging demonstrates peritumoral tissue heterogeneity.

PURPOSE: To augment the analysis of dynamic susceptibility contrast material-enhanced magnetic resonance (MR) images to uncover unique tissue characteristics that could potentially facilitate treatment planning through a better understanding of the peritumoral region in patients with glioblastoma. MATERIALS AND METHODS: Institutional review board approval was obtained for this study, with waiver of informed consent for retrospective review of medical records. Dynamic susceptibility contrast-enhanced MR imaging data were obtained for 79 patients, and principal component analysis was applied to the perfusion signal intensity. The first six principal components were sufficient to characterize more than 99% of variance in the temporal dynamics of blood perfusion in all regions of interest. The principal components were subsequently used in conjunction with a support vector machine classifier to create a map of heterogeneity within the peritumoral region, and the variance of this map served as the heterogeneity score. RESULTS: The calculated principal components allowed near-perfect separability of tissue that was likely highly infiltrated with tumor and tissue that was unlikely infiltrated with tumor. The heterogeneity map created by using the principal components showed a clear relationship between voxels judged by the support vector machine to be highly infiltrated and subsequent recurrence. The results demonstrated a significant correlation (r = 0.46, P < .0001) between the heterogeneity score and patient survival. The hazard ratio was 2.23 (95% confidence interval: 1.4, 3.6; P < .01) between patients with high and low heterogeneity scores on the basis of the median heterogeneity score. CONCLUSION: Analysis of dynamic susceptibility contrast-enhanced MR imaging data by using principal component analysis can help identify imaging variables that can be subsequently used to evaluate the peritumoral region in glioblastoma. These variables are potentially indicative of tumor infiltration and may become useful tools in guiding therapy, as well as individualized prognostication.

Artificial intelligence-based locoregional markers of brain peritumoral microenvironment.

In malignant primary brain tumors, cancer cells infiltrate into the peritumoral brain structures which results in inevitable recurrence. Quantitative assessment of infiltrative heterogeneity in the peritumoral region, the area where biopsy or resection can be hazardous, is important for clinical decision making. Here, we derive a novel set of Artificial intelligence (AI)-based markers capturing the heterogeneity of tumor infiltration, by characterizing free water movement restriction in the peritumoral region using Diffusion Tensor Imaging (DTI)-based free water volume fraction maps. We leverage the differences in the peritumoral region of metastasis and glioblastomas, the former consisting of vasogenic versus the latter containing infiltrative edema, to extract a voxel-wise deep learning-based peritumoral microenvironment index (PMI). Descriptive characteristics of locoregional hubs of uniformly high PMI values are then extracted as AI-based markers to capture distinct aspects of infiltrative heterogeneity. The proposed markers are utilized to stratify patients' survival and IDH1 mutation status on a population of 275 adult-type diffuse gliomas (CNS WHO grade 4). Our results show significant differences in the proposed markers between patients with different overall survival and IDH1 mutation status (t test, Wilcoxon rank sum test, linear regression; p < 0.01). Clustering of patients using the proposed markers reveals distinct survival groups (logrank; p < 10-5, Cox hazard ratio = 1.82; p < 0.005). Our findings provide a panel of markers as surrogates of infiltration that might capture novel insight about underlying biology of peritumoral microstructural heterogeneity, providing potential biomarkers of prognosis pertaining to survival and molecular stratification, with applicability in clinical decision making.

Tractography-Based Surgical Targeting for Thalamic Deep Brain Stimulation: A Comparison of Probabilistic vs Deterministic Fiber Tracking of the Dentato-Rubro-Thalamic Tract.

BACKGROUND: The ventral intermediate (VIM) thalamic nucleus is the main target for the surgical treatment of refractory tremor. Initial targeting traditionally relies on atlas-based stereotactic targeting formulas, which only minimally account for individual anatomy. Alternative approaches have been proposed, including direct targeting of the dentato-rubro-thalamic tract (DRTT), which, in clinical settings, is generally reconstructed with deterministic tracking. Whether more advanced probabilistic techniques are feasible on clinical-grade magnetic resonance acquisitions and lead to enhanced reconstructions is poorly understood. OBJECTIVE: To compare DRTT reconstructed with deterministic vs probabilistic tracking. METHODS: This is a retrospective study of 19 patients with essential tremor who underwent deep brain stimulation (DBS) with intraoperative neurophysiology and stimulation testing. We assessed the proximity of the DRTT to the DBS lead and to the active contact chosen based on clinical response. RESULTS: In the commissural plane, the deterministic DRTT was anterior (P < 10-4) and lateral (P < 10-4) to the DBS lead. By contrast, although the probabilistic DRTT was also anterior to the lead (P < 10-4), there was no difference in the mediolateral dimension (P = .5). Moreover, the 3-dimensional Euclidean distance from the active contact to the probabilistic DRTT was smaller vs the distance to the deterministic DRTT (3.32 ± 1.70 mm vs 5.01 ± 2.12 mm; P < 10-4). CONCLUSION: DRTT reconstructed with probabilistic fiber tracking was superior in spatial proximity to the physiology-guided DBS lead and to the empirically chosen active contact. These data inform strategies for surgical targeting of the VIM.

The University of Pennsylvania glioblastoma (UPenn-GBM) cohort: advanced MRI, clinical, genomics, & radiomics.

Glioblastoma is the most common aggressive adult brain tumor. Numerous studies have reported results from either private institutional data or publicly available datasets. However, current public datasets are limited in terms of: a) number of subjects, b) lack of consistent acquisition protocol, c) data quality, or d) accompanying clinical, demographic, and molecular information. Toward alleviating these limitations, we contribute the "University of Pennsylvania Glioblastoma Imaging, Genomics, and Radiomics" (UPenn-GBM) dataset, which describes the currently largest publicly available comprehensive collection of 630 patients diagnosed with de novo glioblastoma. The UPenn-GBM dataset includes (a) advanced multi-parametric magnetic resonance imaging scans acquired during routine clinical practice, at the University of Pennsylvania Health System, (b) accompanying clinical, demographic, and molecular information, (d) perfusion and diffusion derivative volumes, (e) computationally-derived and manually-revised expert annotations of tumor sub-regions, as well as (f) quantitative imaging (also known as radiomic) features corresponding to each of these regions. This collection describes our contribution towards repeatable, reproducible, and comparative quantitative studies leading to new predictive, prognostic, and diagnostic assessments.

Toxicity after AAV delivery of RNAi expression constructs into nonhuman primate brain.

RNA interference (RNAi) for spinocerebellar ataxia type 1 can prevent and reverse behavioral deficits and neuropathological readouts in mouse models, with safety and benefit lasting over many months. The RNAi trigger, expressed from adeno-associated virus vectors (AAV.miS1), also corrected misregulated microRNAs (miRNA) such as miR150. Subsequently, we showed that the delivery method was scalable, and that AAV.miS1 was safe in short-term pilot nonhuman primate (NHP) studies. To advance the technology to patients, investigational new drug (IND)-enabling studies in NHPs were initiated. After AAV.miS1 delivery to deep cerebellar nuclei, we unexpectedly observed cerebellar toxicity. Both small-RNA-seq and studies using AAVs devoid of miRNAs showed that this was not a result of saturation of the endogenous miRNA processing machinery. RNA-seq together with sequencing of the AAV product showed that, despite limited amounts of cross-packaged material, there was substantial inverted terminal repeat (ITR) promoter activity that correlated with neuropathologies. ITR promoter activity was reduced by altering the miS1 expression context. The surprising contrast between our rodent and NHP findings highlight the need for extended safety studies in multiple species when assessing new therapeutics for human application.

Enhanced Fiber Tractography Using Edema Correction: Application and Evaluation in High-Grade Gliomas.

BACKGROUND: A limitation of diffusion tensor imaging (DTI)-based tractography is peritumoral edema that confounds traditional diffusion-based magnetic resonance metrics. OBJECTIVE: To augment fiber-tracking through peritumoral regions by performing novel edema correction on clinically feasible DTI acquisitions and assess the accuracy of the fiber-tracks using intraoperative stimulation mapping (ISM), task-based functional magnetic resonance imaging (fMRI) activation maps, and postoperative follow-up as reference standards. METHODS: Edema correction, using our bi-compartment free water modeling algorithm (FERNET), was performed on clinically acquired DTI data from a cohort of 10 patients presenting with suspected high-grade glioma and peritumoral edema in proximity to and/or infiltrating language or motor pathways. Deterministic fiber-tracking was then performed on the corrected and uncorrected DTI to identify tracts pertaining to the eloquent region involved (language or motor). Tracking results were compared visually and quantitatively using mean fiber count, voxel count, and mean fiber length. The tracts through the edematous region were verified based on overlay with the corresponding motor or language task-based fMRI activation maps and intraoperative ISM points, as well as at time points after surgery when peritumoral edema had subsided. RESULTS: Volume and number of fibers increased with application of edema correction; concordantly, mean fractional anisotropy decreased. Overlay with functional activation maps and ISM-verified eloquence of the increased fibers. Comparison with postsurgical follow-up scans with lower edema further confirmed the accuracy of the tracts. CONCLUSION: This method of edema correction can be applied to standard clinical DTI to improve visualization of motor and language tracts in patients with glioma-associated peritumoral edema.

Unenhanced dynamic MR angiography: high spatial and temporal resolution by using true FISP-based spin tagging with alternating radiofrequency.

PURPOSE: To present an unenhanced four-dimensional time-resolved dynamic magnetic resonance (MR) angiography technique with true fast imaging with steady-state precession-based spin tagging with alternating radiofrequency (STAR), also called TrueSTAR. MATERIALS AND METHODS: This study received Institutional Review Board approval and was HIPAA compliant. Informed consent was obtained from all study subjects. In eight healthy volunteers, the spatial and temporal resolution of the TrueSTAR technique were optimized. In another six healthy volunteers, the contrast-to-noise ratio (CNR) and signal-to-noise ratio (SNR) of the TrueSTAR dynamic MR angiography images were compared with those acquired by using a standard Look-Locker echo-planar technique by using the Wilcoxon signed rank test. Finally, one patient with an arteriovenous malformation (AVM) was studied by using this technique. RESULTS: The SNR and CNR of the TrueSTAR dynamic MR angiography images were 29% and 39% higher, respectively, compared with those acquired by using a standard Look-Locker echo-planar imaging sequence (both P = .028). In the AVM patient, TrueSTAR dynamic MR angiography delineated the dynamic course of labeled blood flowing through feeding arteries into the nidus and draining veins. CONCLUSION: The results suggest that TrueSTAR is a promising unenhanced dynamic MR angiography technique for clinical evaluation of cerebrovascular disorders such as AVM, steno-occlusive disease, and aneurysm.

Noninvasive measurement of cerebral blood flow and blood oxygenation using near-infrared and diffuse correlation spectroscopies in critically brain-injured adults.

BACKGROUND: This study assesses the utility of a hybrid optical instrument for noninvasive transcranial monitoring in the neurointensive care unit. The instrument is based on diffuse correlation spectroscopy (DCS) for measurement of cerebral blood flow (CBF), and near-infrared spectroscopy (NIRS) for measurement of oxy- and deoxy-hemoglobin concentration. DCS/NIRS measurements of CBF and oxygenation from frontal lobes are compared with concurrent xenon-enhanced computed tomography (XeCT) in patients during induced blood pressure changes and carbon dioxide arterial partial pressure variation. METHODS: Seven neurocritical care patients were included in the study. Relative CBF measured by DCS (rCBF(DCS)), and changes in oxy-hemoglobin (DeltaHbO(2)), deoxy-hemoglobin (DeltaHb), and total hemoglobin concentration (DeltaTHC), measured by NIRS, were continuously monitored throughout XeCT during a baseline scan and a scan after intervention. CBF from XeCT regions-of-interest (ROIs) under the optical probes were used to calculate relative XeCT CBF (rCBF(XeCT)) and were then compared to rCBF(DCS). Spearman's rank coefficients were employed to test for associations between rCBF(DCS) and rCBF(XeCT), as well as between rCBF from both modalities and NIRS parameters. RESULTS: rCBF(DCS) and rCBF(XeCT) showed good correlation (r (s) = 0.73, P = 0.010) across the patient cohort. Moderate correlations between rCBF(DCS) and DeltaHbO(2)/DeltaTHC were also observed. Both NIRS and DCS distinguished the effects of xenon inhalation on CBF, which varied among the patients. CONCLUSIONS: DCS measurements of CBF and NIRS measurements of tissue blood oxygenation were successfully obtained in neurocritical care patients. The potential for DCS to provide continuous, noninvasive bedside monitoring for the purpose of CBF management and individualized care is demonstrated.

Emerging Techniques in Imaging of Glioma Microenvironment.

Magnetic resonance imaging (MRI) has been the cornerstone of imaging of brain tumors in the past 4 decades. Conventional MRI remains the workhorse for neuro-oncologic imaging, not only for basic information such as location, extent, and navigation but also able to provide information regarding proliferation and infiltration, angiogenesis, hemorrhage, and more. More sophisticated MRI sequences have extended the ability to assess and quantify these features; for example, permeability and perfusion acquisitions can assess blood-brain barrier disruption and angiogenesis, diffusion techniques can assess cellularity and infiltration, and spectroscopy can address metabolism. Techniques such as fMRI and diffusion fiber tracking can be helpful in diagnostic planning for resection and radiation therapy, and more sophisticated iterations of these techniques can extend our understanding of neurocognitive effects of these tumors and associated treatment responses and effects. More recently, MRI has been used to go beyond such morphological, physiological, and functional characteristics to assess the tumor microenvironment. The current review highlights multiple recent and emerging approaches in MRI to characterize the tumor microenvironment.