Objective The aim of this study was to measure the flux of amyloid-β (Aβ) across the human cerebral capillary bed in order to determine if transport into the blood is a significant mechanism of clearance for Aβ produced in the central nervous system (CNS). Methods Time-matched blood samples were simultaneously collected from a cerebral vein (including the sigmoid sinus, inferior petrosal sinus, and the internal jugular vein), femoral vein, and radial artery of patients undergoing Inferior Petrosal Sinus Sampling (IPSS). For each plasma sample, Aβ concentration was assessed by three assays and the venous to arterial Aβ concentration ratios were determined. Results Aβ concentration was increased by ~7.5% in venous blood leaving the CNS capillary bed compared to arterial blood, indicating efflux from the CNS into the peripheral blood (p < 0.0001). There was no difference in peripheral venous Aβ concentration compared to arterial blood concentration. Interpretation Our results are consistent with clearance of CNS-derived Aβ into the venous blood supply with no increase from a peripheral capillary bed. Modeling these results suggests that direct transport of Aβ across the blood-brain barrier accounts for ~25% of Aβ clearance, and reabsorption of cerebrospinal fluid Aβ accounts for ~25% of the total CNS Aβ clearance in humans.

BACKGROUND:Surgical treatments for deep-seated intracranial lesions have been limited by morbidities associated with resection. Real-time magnetic resonance imaging–guided focused laser interstitial thermal therapy (LITT) offers a minimally invasive surgical treatment option for such lesions.OBJECTIVE:To review treatments and results of patients treated with LITT for intracranial lesions at Washington University School of Medicine.METHODS:In a review of 17 prospectively recruited LITT patients (34-78 years of age; mean, 59 years), we report demographics, treatment details, postoperative imaging characteristics, and peri- and postoperative clinical courses.RESULTS:Targets included 11 gliomas, 5 brain metastases, and 1 epilepsy focus. Lesions were lobar (n = 8), thalamic/basal ganglia (n = 5), insular (n = 3), and corpus callosum (n = 1). Mean target volume was 11.6 cm3, and LITT produced 93% target ablation. Patients with superficial lesions had shorter intensive care unit stays. Ten patients experienced no perioperative morbidities. Morbidities included transient aphasia, hemiparesis, hyponatremia, deep venous thrombosis, and fatal meningitis. Postoperative magnetic resonance imaging showed blood products within the lesion surrounded by new thin uniform rim of contrast enhancement and diffusion restriction. In conjunction with other therapies, LITT targets often showed stable or reduced local disease. Epilepsy focus LITT produced seizure freedom at 8 months. Preliminary overall median progression-free survival and survival from LITT in tumor patients were 7.6 and 10.9 months, respectively. However, this small cohort has not been followed for a sufficient length of time, necessitating future outcomes studies.CONCLUSION:Early peri- and postoperative clinical data demonstrate that LITT is a safe and viable ablative treatment option for intracranial lesions, and may be considered for select patients.ABBREVIATION:LITT, laser interstitial thermal therapy

BackgroundPoor central nervous system penetration of cytotoxic drugs due to the blood brain barrier (BBB) is a major limiting factor in the treatment of brain tumors. Most recurrent glioblastomas (GBM) occur within the peritumoral region. In this study, we describe a hyperthemic method to induce temporary disruption of the peritumoral BBB that can potentially be used to enhance drug delivery.MethodsTwenty patients with probable recurrent GBM were enrolled in this study. Fourteen patients were evaluable. MRI-guided laser interstitial thermal therapy was applied to achieve both tumor cytoreduction and disruption of the peritumoral BBB. To determine the degree and timing of peritumoral BBB disruption, dynamic contrast-enhancement brain MRI was used to calculate the vascular transfer constant (Ktrans) in the peritumoral region as direct measures of BBB permeability before and after laser ablation. Serum levels of brain-specific enolase, also known as neuron-specific enolase, were also measured and used as an independent quantification of BBB disruption.ResultsIn all 14 evaluable patients, Ktrans levels peaked immediately post laser ablation, followed by a gradual decline over the following 4 weeks. Serum BSE concentrations increased shortly after laser ablation and peaked in 1–3 weeks before decreasing to baseline by 6 weeks.ConclusionsThe data from our pilot research support that disruption of the peritumoral BBB was induced by hyperthemia with the peak of high permeability occurring within 1–2 weeks after laser ablation and resolving by 4–6 weeks. This provides a therapeutic window of opportunity during which delivery of BBB-impermeant therapeutic agents may be enhanced.Trial RegistrationClinicalTrials.gov NCT01851733