PURPOSE: Focused ultrasound-induced blood-brain barrier (BBB) opening is a promising method for neurotherapeutic delivery. The standard for quantifying induced BBB permeability is the Ktrans$$ {K}^{\mathrm{trans}} $$ parameter, which reflects both permeability and plasma flow. The influence of plasma flow can be eliminated by estimating the PS parameter. However, this parameter has been largely unexplored in this application. This study aims to compare permeability estimates based on Ktrans$$ {K}^{\mathrm{trans}} $$ and PS in focused ultrasound-induced BBB opening experiments. METHODS: We used the extended Tofts model (ETM) and the two-compartment exchange model (2CXM) to estimate Ktrans$$ {K}^{\mathrm{trans}} $$ and PS parameters, respectively. Permeability estimates were compared using simulated concentration curves, simulated DCE-MRI data, and real datasets. We explored the influence of spatially-regularized model fitting on the results. RESULTS: For opened BBB, Ktrans$$ {K}^{\mathrm{trans}} $$ was minimally influenced by plasma flow under the tested conditions. However, fitting the ETM often introduced outliers in Ktrans$$ {K}^{\mathrm{trans}} $$ estimates in regions with closed BBB. The 2CXM outperformed the ETM at high signal-to-noise ratios, but its higher complexity led to lower precision at low signal-to-noise ratios. Both these issues were successfully compensated by spatially-regularized model fitting. CONCLUSION: Both Ktrans$$ {K}^{\mathrm{trans}} $$ and PS seem to be eligible options for the quantification of BBB opening, and the correct choice depends on the specifics of the acquired DCE-MRI data. Additionally, spatial regularization has demonstrated its importance in enhancing the accuracy and reproducibility of results for both models.

• MeSH
• Blood-Brain Barrier * diagnostic imaging   metabolism   radiation effects   MeSH
• Contrast Media MeSH
• Humans MeSH
• Magnetic Resonance Imaging * methods   MeSH
• Brain diagnostic imaging   MeSH
• Permeability MeSH
• Computer Simulation MeSH
• Image Processing, Computer-Assisted methods   MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Comparative Study MeSH

• MeSH
• Diagnosis, Differential MeSH
• Blood-Brain Barrier diagnostic imaging   physiology   MeSH
• Humans MeSH
• Cerebrospinal Fluid * chemistry   cytology   diagnostic imaging   physiology   MeSH
• Cerebrovascular Circulation physiology   MeSH
• Neurologic Examination methods   MeSH
• Neuroinflammatory Diseases diagnostic imaging   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Review MeSH

Disruption of the blood-brain barrier (BBB) is a key feature of various brain disorders. To assess its integrity a parametrization of dynamic magnetic resonance imaging (DCE MRI) with a contrast agent (CA) is broadly used. Parametrization can be done quantitatively or semi-quantitatively. Quantitative methods directly describe BBB permeability but exhibit several drawbacks such as high computation demands, reproducibility issues, or low robustness. Semi-quantitative methods are fast to compute, simply mathematically described, and robust, however, they do not describe the status of BBB directly but only as a variation of CA concentration in measured tissue. Our goal was to elucidate differences between five semi-quantitative parameters: maximal intensity (Imax), normalized permeability index (NPI), and difference in DCE values between three timepoints: baseline, 5 min, and 15 min (delta5-0, delta15-0, delta15-5) and two quantitative parameters: transfer constant (Ktrans) and an extravascular fraction (Ve). For the purpose of comparison, we analyzed DCE data of four patients 12-15 days after the stroke with visible CA enhancement. Calculated parameters showed abnormalities spatially corresponding with the ischemic lesion, however, findings in individual parameters morphometrically differed. Ktrans and Ve were highly correlated. Delta5-0 and delta15-0 were prominent in regions with rapid CA enhancement and highly correlated with Ktrans. Abnormalities in delta15-5 and NPI were more homogenous with less variable values, smoother borders, and less detail than Ktrans. Moreover, only delta15-5 and NPI were able to distinguish vessels from extravascular space. Our comparison provides important knowledge for understanding and interpreting parameters derived from DCE MRI by both quantitative and semi-quantitative methods.

• MeSH
• Blood-Brain Barrier * diagnostic imaging   MeSH
• Contrast Media MeSH
• Humans MeSH
• Magnetic Resonance Imaging methods   MeSH
• Brain Diseases * MeSH
• Reproducibility of Results MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH

Thanks to the widespread use and safety profile of donepezil (1) in the treatment of Alzheimer's disease (AD), one of the most widely adopted multi-target-directed ligand (MTDL) design strategies is to modify its molecular structure by linking a second fragment carrying an additional AD-relevant biological property. Herein, supported by a proposed combination therapy of 1 and the quinone drug idebenone, we rationally designed novel 1-based MTDLs targeting Aβ and oxidative pathways. By exploiting a bioisosteric replacement of the indanone core of 1 with a 1,4-naphthoquinone, we ended up with a series of highly merged derivatives, in principle devoid of the "physicochemical challenge" typical of large hybrid-based MTDLs. A preliminary investigation of their multi-target profile identified 9, which showed a potent and selective butyrylcholinesterase inhibitory activity, together with antioxidant and antiaggregating properties. In addition, it displayed a promising drug-like profile.

• MeSH
• Acetylcholinesterase chemistry   metabolism   MeSH
• Alzheimer Disease drug therapy   MeSH
• Amyloid beta-Peptides antagonists & inhibitors   metabolism   MeSH
• Antioxidants chemistry   metabolism   pharmacology   MeSH
• Cholinesterase Inhibitors chemistry   metabolism   pharmacology   therapeutic use   MeSH
• Donepezil chemistry   metabolism   pharmacology   therapeutic use   MeSH
• Blood-Brain Barrier diagnostic imaging   metabolism   MeSH
• Indans chemistry   MeSH
• Humans MeSH
• Ligands * MeSH
• Cell Line, Tumor MeSH
• Neuroprotective Agents chemistry   metabolism   pharmacology   therapeutic use   MeSH
• Oxidative Stress drug effects   MeSH
• Protein Aggregates drug effects   MeSH
• Drug Design MeSH
• Cell Survival drug effects   MeSH
• Structure-Activity Relationship MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH

Rationale: The blood-brain barrier (BBB) is a major obstacle for drug delivery to the brain. Sonopermeation, which relies on the combination of ultrasound and microbubbles, has emerged as a powerful tool to permeate the BBB, enabling the extravasation of drugs and drug delivery systems (DDS) to and into the central nervous system (CNS). When aiming to improve the treatment of high medical need brain disorders, it is important to systematically study nanomedicine translocation across the sonopermeated BBB. To this end, we here employed multimodal and multiscale optical imaging to investigate the impact of DDS size on brain accumulation, extravasation and penetration upon sonopermeation. Methods: Two prototypic DDS, i.e. 10 nm-sized pHPMA polymers and 100 nm-sized PEGylated liposomes, were labeled with fluorophores and intravenously injected in healthy CD-1 nude mice. Upon sonopermeation, computed tomography-fluorescence molecular tomography, fluorescence reflectance imaging, fluorescence microscopy, confocal microscopy and stimulated emission depletion nanoscopy were used to study the effect of DDS size on their translocation across the BBB. Results: Sonopermeation treatment enabled safe and efficient opening of the BBB, which was confirmed by staining extravasated endogenous IgG. No micro-hemorrhages, edema and necrosis were detected in H&E stainings. Multimodal and multiscale optical imaging showed that sonopermeation promoted the accumulation of nanocarriers in mouse brains, and that 10 nm-sized polymeric DDS accumulated more strongly and penetrated deeper into the brain than 100 nm-sized liposomes. Conclusions: BBB opening via sonopermeation enables safe and efficient delivery of nanomedicine formulations to and into the brain. When looking at accumulation and penetration (and when neglecting issues such as drug loading capacity and therapeutic efficacy) smaller-sized DDS are found to be more suitable for drug delivery across the BBB than larger-sized DDS. These findings are valuable for better understanding and further developing nanomedicine-based strategies for the treatment of CNS disorders.

• MeSH
• Fluorescent Dyes administration & dosage   MeSH
• Blood-Brain Barrier diagnostic imaging   metabolism   MeSH
• Drug Delivery Systems methods   MeSH
• Liposomes administration & dosage   MeSH
• Microbubbles MeSH
• Brain diagnostic imaging   MeSH
• Mice, Nude MeSH
• Mice MeSH
• Nanomedicine methods   MeSH
• Brain Diseases drug therapy   MeSH
• Optical Imaging methods   MeSH
• Ultrasonography methods   MeSH
• Animals MeSH
• Check Tag
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH

Epilepsy is chronic neurological disease characterized by occurrence of spontaneous recurrent seizures affecting approximately 1% of people. One of the most common causes of epilepsy in adults is a stroke. The precise mechanism of development of vascular epilepsy is not known, and thus no reliable biomarker of postischemic epileptogenesis currently exists. Blood-brain barrier (BBB) impairment is phenomenon observed in several pathologies including stroke after which epilepsy often develops. Blood components such as albumin or thrombin have been experimentally shown to possess the capacity to increase excitability which results in seizures and epileptogenesis. We hypothesize that severity of the BBB breakdown during first weeks after the stroke can be used as a biomarker of postischemic epileptogenesis. This paper describes free MATLAB based software /Gd-Tracker/ and methodology developed for assessment of BBB permeability from magnetic resonance (MR) scans based on statistical voxel to voxel comparison of sequences with and without Gd-DTPA contrast. This software allows to evaluate extent and magnitude of impaired BBB region and thus serve as a tool for visualization and quantification of BBB breakdown.

• MeSH
• Stroke diagnostic imaging   MeSH
• Gadolinium DTPA administration & dosage   MeSH
• Epilepsy diagnostic imaging   etiology   MeSH
• Blood-Brain Barrier * diagnostic imaging   MeSH
• Capillary Permeability MeSH
• Contrast Media pharmacokinetics   MeSH
• Humans MeSH
• Image Enhancement instrumentation   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Research Support, Non-U.S. Gov't MeSH