In normal rat, intraventricularly administered insulin-like growth factor-1 is rapidly cleared from CSF with limited distribution into brain

BACKGROUND: Putatively active drugs are often intraventricularly administered to gain direct access to brain and circumvent the blood-brain barrier. A few studies on the normal central nervous system (CNS) have shown, however, that the distribution of materials after intraventricular injections is much more limited than presumed and their exit from cerebrospinal fluid (CSF) is more rapid than generally believed. In this study, we report the intracranial distribution and the clearance from CSF and adjacent CNS tissue of radiolabeled insulin-like growth factor-1 after injection into one lateral ventricle of the normal rat brain. METHODS: Under barbiturate anesthesia, (125)I-labeled insulin-like growth factor-1 (IGF-1) was injected into one lateral ventricle of normal Sprague-Dawley rats. The subsequent distribution of IGF-1 through the cerebrospinal fluid (CSF) system and into brain, cerebral blood vessels, and systemic blood was measured over time by gamma counting and quantitative autoradiography (QAR). RESULTS: Within 5 min of infusion, IGF-1 had spread from the infused lateral ventricle into and through the third and fourth ventricles. At this time, 25% of the infused IGF-1 had disappeared from the CSF-brain-meningeal system; the half time of this loss was 12 min. The plasma concentration of cleared IGF-1 was, however, very low from 2 to 9 min and only began to rise markedly after 20 min. This delay between loss and gain plus the lack of radiotracer in the cortical subarachnoid space suggested that much of the IGF-1 was cleared into blood via the cranial and/or spinal nerve roots and their associated lymphatic systems rather than periventricular tissue and arachnoid villi. Less than 10% of the injected radioactivity remained in the CSF-brain system after 180 min. The CSF and arteries and arterioles within the subarachnoid cisterns were labeled with IGF-1 within 10 min. Between 60 and 180 min, most of the radioactivity within the cranium was retained within and around these blood vessels and by periaqueductal gray matter. Tissue profiles at two sites next to ventricular CSF showed that IGF-1 penetrated less than 1.25 mm into brain tissue and appreciable (125)I-activity remained at the tissue-ventricular CSF interface after 180 min. CONCLUSION: Our findings suggest that entry of IGF-1 into normal brain parenchyma after lateral ventricle administration is limited by rapid clearance from CSF and brain and slow movement, apparently by diffusion, into the periventricular tissue. Various growth factors and other neuroactive agents have been reported to be neuroprotective within the injured brain after intraventricular administration. It is postulated that the delivery of such factors to neurons and glia in the injured brain may be facilitated by abnormal CSF flow. These several observations suggest that the flow of CSF and entrained solutes may differ considerably between normal and abnormal brain and even among various neuropathologies

A Prospective Safety Trial of Atorvastatin Treatment to Assess Rebleeding after Spontaneous Intracerebral Hemorrhage: A Serial MRI Investigation

AIM: This study was designed to determine any rebleeding after atorvastatin treatment following spontaneous intracerebral hemorrhage (ICH) in a prospective safety trial. PATIENTS: Atorvastatin (80 mg/day) therapy was initiated in 6 patients with primary ICH with admission Glasgow Coma Score (GCS) \u3e5 within 24 hours of ictus and continued for 7 days, with the dose tapered and treatment terminated over the next 5 days. Patients were studied longitudinally by multiparametric magnetic resonance imaging (MRI) at three time points: acute (3 to 5 days), subacute (4 to 6 weeks) and chronic (3 to 4 months). Imaging sequences included T1, T2-weighted imaging (T2WI), diffusion tensor imaging (DTI) and contrast-enhanced MRI measures of cerebral perfusion, blood volume and blood-brain barrier (BBB) permeability. Susceptibility weighted imaging (SWI) was used to identify primary ICH and to check for secondary rebleeding. Final outcome was assessed using Glasgow Outcome Score (GOS) at 3-4 months. RESULTS: Mean admission GCS was 13.2±4.0 and mean GOS at 3 months was 4.5±0.6. Hemorrhagic lesions were segmented into core and rim areas. Mean lesion volumes decreased significantly between the acute and chronic study time points (p=0.008). Average ipsilateral hemispheric tissue loss at 3 to 4 months was 11.4±4.6 cm3. MRI showed acutely reduced CBF (p=0.004) and CBV (p=0.002) in the rim, followed by steady normalization. Apparent diffusion coefficient of water (ADC) in the rim demonstrated no alterations at any of the time points (p\u3e0.2). The T2 values were significantly elevated in the rim acutely (p=0.02), but later returned to baseline. The ICH core showed sustained low CBF and CBV values concurrent with a small reduction in ADC acutely, but significant ADC elevation at the end suggestive of irreversible injury. CONCLUSION: Despite the presence of a small, probably permanent, cerebral lesion in the ICH core, no patients exhibited post-treatment rebleeding. These data suggest that larger, Phase 2 trials are warranted to establish long term clinical safety of atorvastatin in spontaneous ICH

Direct regional microvascular monitoring and assessment of blood brain barrier function following cerebral ischemia-reperfusion injury

Evans Blue (EB) is often used to evaluate Blood-Brain Barrier Damage (BBB) in cerebral ischemia, frequently by dye extraction. Herein we present a method that allows assessing regional brain microvasculature, distribution of EB and Fluorescent Isothiocyanate-Labeled Red Blood Cells (FITC-RBCs) in a rat model of acute cerebral Ischemia-Reperfusion (I-R). Wistar rats were subjected to 3 h of middle cerebral artery occlusion and then reperfused. At ~2.5 h of reperfusion, BBB opening was assessed by contrast enhanced magnetic resonance imaging. It was followed by injections of EB and FITC-RBCs that circulated for either 5 or 20 min. Regional microvasculature and tracer distributions were assessed by laser scanning confocal microscopy. Microvascular networks in stroke-affected regions networks were partially damaged with apparent EB extravasation. Brain regions were affected in the following order: preoptic area (PoA)\u3estriatum (Str)\u3ecortex (Ctx). EB leakage increased with circulation time in Str. Cells around the leakage sites sequestered EB. An inverse correlation was observed between low CBF rates recorded during MCA occlusion and post-reperfusion EB extravasation patterns. Accordingly, this approach provided data on brain regional microvascular status, extravascular tracer distribution and its cellular uptake. It may be useful to evaluate model-dependent variations in vascular injury and efficacy of putative vascular protective drugs in stroke

An Unsupervised Autoencoder Developed from Dynamic Contrast-Enhanced (DCE)-MRI Datasets for Classification of Acute Tumor Response in an Animal Model

Purpose/Objective(s): Recent studies have shown that vascular parameters of brain tumors derived from DCE-MRI may act as potential biomarkers for radiation-induced acute effects. However, accurate characterization of the spatial regions affected by radiation therapy (RT) remains challenging. Here, we introduce an unsupervised adaptive model for classification and ranking of the RT-affected regions in an animal model of cerebral U-251n tumors. Materials/Methods: Twenty-three immune-compromised-RNU rats were implanted with human U251n cancer cells to form an orthotopic glioma (IACUC #1509). For each rat, 28 days after implantation, two DCE-MRI studies (Dual Gradient Echo, DGE, FOV: 32 × 32 mm2, TR/(TE1-TE2) = 24 ms/(2 ms-4 ms), flip angle = 18°, 400 acquisitions, 1.55 sec interval with Magnevist contrast agent, CA injection at ∼ 24 sec) were performed 24h apart using a 7T MRI scanner. A single 20 Gy stereotactic radiation exposure was performed before the second MRI, which was acquired 1-6.5 hrs after RT. DCE-MRI analysis was done using a model selection technique to distinguish three different brain regions as follows: Normal vasculature (Model 1: No leakage, only plasma volume, vp, is estimated), leaky tumor tissues with no back-flux to the vasculature (Model 2: vp and forward volumetric transfer constant, Ktrans, are estimated), and leaky tumor tissues with back-flux (Model 3: vp, Ktrans, and interstitial volume fraction, ve, are estimated). Normalized time traces of DCE-MRI information (24 pre, and 24 post-RT for each rat, total of 64108 training datasets) of tumors and their soft surrounding normal tissues were extracted from the 3 different model regions. To eliminate high-dimensional data similarity, an unsupervised autoencoder (AE) was trained to map out the model-derived data into a feature space (latent variables, N=10). For each model, the pre and post RT latent variables were compared (by appropriate tests of significance: ANOVA/Welch, CI=95%) to reveal RT-discriminant features. Pearson correlation coefficients were used to compare the decoded data to rank the effect of RT on different models. Results: The time trace of DCE-MRI information of rat brain in normal (Model 1, non-leaky) and highly permeable (Model 3) regions are less impacted by RT (Higher correlation between pre and post RT: r= 0.8518, p\u3c0.0001 and r= 0.9040, p\u3c0.0001 for Model 1 and Model 3, respectively) compared to the peritumoral regions pertaining to Model 2 (r= 0.8077, p\u3c0.0001). Conclusion: This pilot study suggests that among different brain regions, peritumoral zones (infiltrative tumor borders with enhanced rim) are highly affected by RT. Spatial assessment of RT-affected brain regions can play a key role in optimization of treatment planning in cancer patients, but presents a challenging task in conventional DCE-MRI. This study represents an important step toward classification and ranking the RT-affected brain spatial regions according to their vascular response following hypofractionated RT

Dynamic contrast enhanced (DCE) MRI estimation of vascular parameters using knowledge-based adaptive models

We introduce and validate four adaptive models (AMs) to perform a physiologically based Nested-Model-Selection (NMS) estimation of such microvascular parameters as forward volumetric transfer constant, K(trans), plasma volume fraction, v(p), and extravascular, extracellular space, v(e), directly from Dynamic Contrast-Enhanced (DCE) MRI raw information without the need for an Arterial-Input Function (AIF). In sixty-six immune-compromised-RNU rats implanted with human U-251 cancer cells, DCE-MRI studies estimated pharmacokinetic (PK) parameters using a group-averaged radiological AIF and an extended Patlak-based NMS paradigm. One-hundred-ninety features extracted from raw DCE-MRI information were used to construct and validate (nested-cross-validation, NCV) four AMs for estimation of model-based regions and their three PK parameters. An NMS-based a priori knowledge was used to fine-tune the AMs to improve their performance. Compared to the conventional analysis, AMs produced stable maps of vascular parameters and nested-model regions less impacted by AIF-dispersion. The performance (Correlation coefficient and Adjusted R-squared for NCV test cohorts) of the AMs were: 0.914/0.834, 0.825/0.720, 0.938/0.880, and 0.890/0.792 for predictions of nested model regions, v(p), K(trans), and v(e), respectively. This study demonstrates an application of AMs that quickens and improves DCE-MRI based quantification of microvasculature properties of tumors and normal tissues relative to conventional approaches

Cerebral microcirculation in glioblastoma: A major determinant of diagnosis, resection, and drug delivery

Glioblastoma (GBM) is the most common primary brain tumor with a dismal prognosis. Current standard of treatment is safe maximal tumor resection followed by chemotherapy and radiation. Altered cerebral microcirculation and elevated blood-tumor barrier (BTB) permeability in tumor periphery due to glioma-induced vascular dysregulation allow T1 contrast-enhanced visualization of resectable tumor boundaries. Newer tracers that label the tumor and its vasculature are being increasingly used for intraoperative delineation of glioma boundaries for even more precise resection. Fluorescent 5-aminolevulinic acid (5-ALA) and indocyanine green (ICG) are examples of such intraoperative tracers. Recently, magnetic resonance imaging (MRI)-based MR thermometry is being employed for laser interstitial thermal therapy (LITT) for glioma debulking. However, aggressive, fatal recurrence always occurs. Postsurgical chemotherapy is hampered by the inability of most drugs to cross the blood-brain barrier (BBB). Understanding postsurgical changes in brain microcirculation and permeability is crucial to improve chemotherapy delivery. It is important to understand whether any microcirculatory indices can differentiate between true recurrence and radiation necrosis. LITT leads to peri-ablation BBB opening that persists for several weeks. Whether it can be a conduit for chemotherapy delivery is yet to be explored. This review will address the role of cerebral microcirculation in such emerging ideas in GBM diagnosis and therapy

MR‐guided laser interstitial thermal therapy in the treatment of recurrent intracranial meningiomas

OBJECTIVE: Recurrent meningiomas can prove problematic for treatment, especially if anaplastic, as options are limited primarily to surgery and radiation therapy. Laser interstitial thermal therapy (LITT) is a minimally invasive technique for achieving immediate cytoreduction. This study seeks to determine the utility of LITT in the setting of recurrent meningiomas. MATERIALS AND METHODS: Patients undergoing LITT for tumor treatment at our institution between November 2014 and February 2016 were identified. Those with biopsy-confirmed meningiomas were reviewed with attention to ablation volume, survival, demographic data, and complications. Data from imaging performed at set intervals post-operatively were available for all. RESULTS: Four patients were identified, three of whom had successful treatment with a total of four ablations. The one case that did not result in a successful ablation was due to problems with stereotactic placing of the laser catheter. One patient had a grade 1 meningioma, with the other two being Grade 3. Immediate ablation volumes averaged 75% of preoperative tumor volume and increased to 97% at 2 weeks before dropping to 65% at 3 months. One patient had acute hemiparesis with speech difficulty, which resolved after 6 months. At date of last follow-up, two of three had progression at an average of nine weeks, and one had no progression at 28 weeks. CONCLUSION: LITT appeared to be a potentially viable treatment for recurrent meningiomas. Ablation volumes increased over time, but not beyond the initial meningioma volume. Larger studies are needed to better determine complications and outcomes. Lasers Surg. Med. 51:245-250, 2019. © 2018 Wiley Periodicals, Inc

Voxel-by-voxel distribution pattern of estimates of vascular volume and that of blood-to-brain forward volume transfer constant are different in experimental embolic stroke

Background and Purpose: Changes in vascular indices such as blood-to-brain forward volume transfer constant (Ktrans) and plasma distribution volume (vp) are considered as potential predictors of impending hemorrhage in acute stroke. However, few studies have reported their spatial distributions and variability within a given stroke lesion. This study examined the voxel-by-voxel distributions of vp and Ktrans within a region of interest (ROI) and the overall mean for the entire ROI to investigate their possible inherent variability.Methods: Male Wistar rats (~300 g; N=6) were subjected to embolic occlusion of the middle cerebral artery for 2 h followed by treatment with recombinant tissue plasminogen activator (rTPA) treatment for thrombolysis. Measurements of vp and Ktrans were made in the ischemic lesion after rTPA infusion using dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI). Data were generated using two approaches. In the first, voxel-by-voxel values of moments about the mean viz., median and skewness. In the second, values were summed across the ROI producing a mean and standard deviation. Differences between the two means were assessed by t-tests and significance inferred at p\u3c=0.05.Results: The voxel-by-voxel estimates of vp were larger (0.025+0.008) than the summed mean (0.016+0.005), the difference being marginally significant (p=0.05). A positive skew value of 1.88 was obtained for the data and accordingly the median value (0.019) was lower than the mean. In contrast, voxel -based estimate of Ktrans (0.002+0.001) was not different from the summed mean (0.002+0.001; p\u3e0.05). The median value for Ktrans (0.002) was not significantly different from the mean (p\u3e0.05) suggesting a more uniform distribution of the data across the voxels with a very low skewness (0.05).Conclusions: These observations suggest that the voxel-by-voxel distributions can be dissimilar for the different indices of vascular injury within a given ischemic lesion. Such variations may be representative of varying degrees of damage and, consequently, may also represent the effects of a putative treatment. Understanding the tissue pathology determining these variations can assist in employing them as biomarkers of injury and response to treatment.(C) 2015 American Heart Association, Inc