Brain Compartments Research Articles

Borrelia Invasion of Brain Pyramidal Neurons and Biofilm Borrelia Plaques in Neuroborreliosis Dementia with Alzheimer’s Phenotype

Dementia in Lyme borreliosis complex has been reported, mainly in post-mortem studies without available antemortem evidence of active borrelia infection. Blanc in 2014 studied living patients with Lyme neuroborreliosis dementia and several dementia phenotype illnesses including an Alzheimer’s Phenotype. Herein we report an additional case study of a longitudinal evolution of European neuroborreliosis over eight years from tick bite to mild cognitive disease, to advanced dementia to death with a brain Alzheimer’s disease phenotype and concurrent borrelia deposits in brain Alzheimer’s disease sites at autopsy. Intrathecal borrelia specific antibodies were detected by commercial diagnostic laboratories (antemortem). Molecular autopsy tissue imaging was completed with borrelia specific DNA probes and an immunomicroscopic detection histopathology method. Results: Autopsy showed intact spirochetes, fragmented spirochetes, deposits of borrelia-specific proteins inside plaque lesions and inside of neurons, and borrelia DNA deposits in plaque and neuronal sites. Pure Alzheimer’s disease (without Lewy bodies) was a routine neuropathological finding. CSF evidence for a brain compartment immune response is established here. Intrathecal antibodies to infection presented as oligoclonal total CSF IgG bands (n=twelve increase to n=13 bands) and separate borrelia IgG western blot band analysis in cerebrospinal fluids (seven diagnostic borrelia CSF antibody bands). Blood western blot disclosed triple borrelia species infection; burgdorferi European type (eighteen bands), garinii (twelve bands) and afzelii (eighteen bands). Total borrelia IgG antibodies in blood during life were two hundred-fold higher than normal range. Western blot of cerebrospinal fluid prior to death disclosed 7 protein bands which were not represented in simultaneous blood western blot studies, further validating the intrathecal fingerprint of a separate brain compartment immune response to neuroborreliosis infection. Conclusion: Borrelia protein antigenic stimulation of intrathecal borrelia antibodies was caused by resident deposits of spirochetal protein deposits in plaques, in diseased neurons, and in neuropil brain sites, and in intact brain spirochetes. Deposits of borrelia proteins inside neurons and brain phagocytes and in neuropil sites (invasosomes) confirm remnants of chronic brain infection.

Exocyst-mediated membrane trafficking of the lissencephaly-associated ECM receptor dystroglycan is required for proper brain compartmentalization.

To assemble a brain, differentiating neurons must make proper connections and establish specialized brain compartments. Abnormal levels of cell adhesion molecules disrupt these processes. Dystroglycan (Dg) is a major non-integrin cell adhesion receptor, deregulation of which is associated with dramatic neuroanatomical defects such as lissencephaly type II or cobblestone brain. The previously established Drosophila model for cobblestone lissencephaly was used to understand how Dg is regulated in the brain. During development, Dg has a spatiotemporally dynamic expression pattern, fine-tuning of which is crucial for accurate brain assembly. In addition, mass spectrometry analyses identified numerous components associated with Dg in neurons, including several proteins of the exocyst complex. Data show that exocyst-based membrane trafficking of Dg allows its distinct expression pattern, essential for proper brain morphogenesis. Further studies of the Dg neuronal interactome will allow identification of new factors involved in the development of dystroglycanopathies and advance disease diagnostics in humans.

Risk of Brain Herniation After Craniotomy With Preoperative Lumbar Spinal Drainage: A Single-Surgeon Experience of 365 Patients Among 3000 Major Cranial Cases.

Lumbar spinal drainage (LSD) can significantly facilitate brain relaxation and improve ease of surgical goals for a variety of neurosurgical indications. Although rapid drainage of large volumes of spinal fluid can theoretically produce shifts in brain compartments and herniation syndromes, the clinical significance of this phenomenon when LSD is used immediately before craniotomy is unclear. To report a large single-surgeon consecutive experience with symptomatic brain herniation after lumbar drainage before craniotomy. Included were 365 patients who underwent LSD with either lumbar drain or lumbar puncture for a variety of different neurosurgical pathologies between 2008 and 2018 immediately before craniotomy. We reviewed the surgical indications, craniotomy location, approach, type of LSD, presence of postoperative brain herniation on imaging, type of herniation, clinical symptoms, lesion pathology, and 30-d modified Rankin Scale score for each patient. There was no patient who suffered from the development of new or worsening symptomatic or radiological brain herniation directly related to use of immediate preoperative LSD. This included 204 supratentorial and 161 infratentorial procedures. Surgical indications included 188 tumors, 5 aneurysms, 37 arteriovenous malformations, 2 revascularization procedures, 97 microvascular decompressions, 10 optic nerve decompressions requiring extradural clinoidectomy for tumor removal, and 26 "other" pathologies. Brain herniation did not occur postoperatively with the use of immediate preoperative LSD in our series, regardless of craniotomy location, pathology, extent of mass effect, or approach. Our experience suggests that LSD is a potentially safe preoperative adjunct that can be used to facilitate surgical objectives.

Development of a Blood-Brain Barrier Permeability Assay Using Human Induced Pluripotent Stem Cell Derived Brain Endothelial Cells.

The development of translational and predictive models in vitro for assessing blood-brain barrier (BBB) delivery has become an important requirement in preclinical testing of CNS-targeting therapeutics. Here we describe a directed monolayer differentiation strategy to generate a population of brain endothelial-like cells (BECs) from human induced pluripotent stem cell (iPSC) with robust BBB properties. To generate BBB permeability assays, the BECs are seeded as a monolayer on a semipermeable Transwell insert placed inside a companion plate to generate a two-compartment Transwell model. The BECs provide a BBB-like separation between the luminal (blood) and abluminal (brain) compartments to assess BBB permeability of CNS-targeting therapeutics.

Correlation of the Brain Compartments in the Attention Deficit and Hyperactivity Disorder Calculated by the Method of Virtual Electrodes from Magnetic Encephalography Data

New method to study the correlation of the human brain compartments based on the magnetic encephalography data analysis was proposed. The time series for the correlation analysis are generated by the method of virtual electrodes. First, the multichannel time series of the subject with confirmed attention deficit and hyperactivity disorder are transformed into the functional tomogram - spatial distribution of the magnetic field sources structure on the discrete grid. This structure is provided by the inverse problem solution for all elementary oscillations, found by the Fourier transform. Each frequency produces the elementary current dipole located in the node of the 3D grid. The virtual electrode includes the part of space, producing the activity under study. The time series for this activity is obtained by the summation of the spectral power of all sources, covered by the virtual electrode. To test the method, in this article we selected ten basic compartments of the brain, including frontal lobe, parietal lobe, occipital lobe and others. Each compartment was included in the virtual electrode, obtained from the subjects' MRI. We studied the correlation between compartments in the frequency bands, corresponding to four brain rhythms: theta, alpha, beta, and gamma. The time series for each electrode were calculated for the period of 300 seconds. The correlation coefficient between power series was calculated on the 1 second epoch and then averaged. The results were represented as matrices. The method can be used to study correlations of the arbitrary parts of the brain in any spectral band.

Primary Central Nervous System Lymphomas: A Diagnostic Overview of Key Histomorphologic, Immunophenotypic, and Genetic Features.

Primary central nervous system lymphoma (PCNSL) is a rare form of extranodal non-Hodgkin lymphoma that primarily arises in the brain, spinal cord, leptomeninges, and vitreoretinal compartment of the eye. The term is sometimes used interchangeably with primary central nervous system diffuse large B-cell lymphoma (PCNS DLBCL) because DLBCL comprises a great majority (90–95%) of PCNSL. Although rare, other types of lymphomas can be seen in the central nervous system (CNS), and familiarity with these entities will help their recognition and further workup in order to establish the diagnosis. The latter is especially important in the case of PCNSL where procurement of diagnostic specimen is often challenging and yields scant tissue. In this review, we will discuss the most common types of primary lymphomas that can be seen in the CNS with emphasis on the diagnostic histomorphologic, immunophenotypic, and molecular genetic features. The differential diagnostic approach to these cases and potential pitfalls will also be discussed.

In Situ Surface Modification of Microfluidic Blood-Brain-Barriers for Improved Screening of Small Molecules and Nanoparticles.

Here, we have developed and evaluated a microfluidic-based human blood-brain-barrier (μBBB) platform that models and predicts brain tissue uptake of small molecule drugs and nanoparticles (NPs) targeting the central nervous system. By using a photocrosslinkable copolymer that was prepared from monomers containing benzophenone and N-hydroxysuccinimide ester functional groups, we were able to evenly coat and functionalize μBBB chip channels in situ, providing a covalently attached homogenous layer of extracellular matrix proteins. This novel approach allowed the coculture of human endothelial cells, pericytes, and astrocytes and resulted in the formation of a mimic of cerebral endothelium expressing tight junction markers and efflux proteins, resembling the native BBB. The permeability coefficients of a number of compounds, including caffeine, nitrofurantoin, dextran, sucrose, glucose, and alanine, were measured on our μBBB platform and were found to agree with reported values. In addition, we successfully visualized the receptor-mediated uptake and transcytosis of transferrin-functionalized NPs. The BBB-penetrating NPs were able to target glioma cells cultured in 3D in the brain compartment of our μBBB. In conclusion, our μBBB was able to accurately predict the BBB permeability of both small molecule pharmaceuticals and nanovectors and allowed time-resolved visualization of transcytosis. Our versatile chip design accommodates different brain disease models and is expected to be exploited in further BBB studies, aiming at replacing animal experiments.

Transient structural MRI patterns correlate with the motor functions in preterm infants

AimTo explore the relationships between transient structural brain patterns on MRI at preterm and at term-equivalent age (TEA) as a predictor of general movements (GMs) and motor development at 1-year corrected age (CA) in very preterm infants. MethodsIn this prospective study, 30 very preterm infants (median = 28wks; 16 males) had structural magnetic resonance imaging (MRI) at preterm (median = 31wks + 6d) and at TEA (median = 40wks) and neuromotor assessments. The quality of GMs was assessed by Prechtl’s general movements assessment and a detailed analysis of the motor repertoire was performed by calculating a motor optimality score (MOS), both at term age and at 3 months post-term. Motor development at 1-year CA was evaluated with the Infant Motor Profile (IMP). Associations between qualitative MRI findings and neuromotor scores were investigated. ResultsAbnormal GMs and low motor performance at 1-year CA were associated with the poor visibility of transient structural pattern, that is with sagittal strata. InterpretationTransient structural MRI pattern, sagittal strata, at preterm age is related to the quality of GMs and later motor development in preterm infants. This transient fetal brain compartment may be considered as a component of neurobiological basis for early neuromotor behavior, as expressed by GMs.

Comparison of Bone Graft Storage Effectiveness Between Cryopreservation and Subcutaneous in Patients Conducted Craniectomy Decompression

Abstract
 Decompression craniectomy is a surgical method used for immediate reduction of intracranial pressure. Repair of cranial bone defects to protect the brain and reconstruct the original cranial brain compartment is called a cranioplasty. In this study researchers will conduct research and compare storage of bone graft in the freezer with a temperature of -20 ° C and subcutaneous to the risk of infection. The research design used was paired clinical trials. Clinical tests were in open label form. The analysis of significance using the Mann Whitnay test showed that the value of p = 0.381. This means that there is no significant difference between the storage group in the subcutie and the storage group in the Cryopreservation (p> 0.05). The analysis of significance using the McNemar test showed that the p value = 0.003. This means that there is a significant relationship between the storage group in the subcutie and the storage group in the Cryopreservation (p <0.05).

Obesity and muscle may have synergic effect more than independent effects on brain volume in community-based elderly.

To evaluate the individual and combined effects of obesity and muscle mass on brain volume in a community-dwelling healthy older population. One thousand two hundred nine participants (M:F = 574:635, mean age 63.6 ± 6.9years) were included. The cross-sectional area of visceral fat (VF), the height-adjusted appendicular skeletal muscle mass (ASM/height2), and the ratio of thigh muscle to visceral fat (TM/VF) represented obesity, muscle mass, and their integrated value, respectively. Linear regression analysis was performed to establish associations between 215 brain compartment volumes and VF, ASM/height2, and TM/VF after adjusting for covariates. On regression analysis, TM/VF had a positive correlation to the volumes of temporal lobe and cerebellum. TM/VF was associated with volumes of 10 subcompartments. TM/VF was positively correlated with the volumes of left entorhinal cortex, right temporal pole and inferior temporal gyrus related to cognition (p< 0.05, respectively), and the volumes of cerebellum and right pallidum related to movement (p< 0.05, respectively). However, VF had a negative correlation to temporal lobe volume and ASM/height2 had no significant correlation to any of the brain lobes. VF and ASM/height2 were correlated with volumes of 5 subcompartments and one subcompartment, respectively, CONCLUSIONS: TM/VF reflects the integrated effect of obesity and muscle mass and is associated with the volume of more brain regions compared to indices of obesity or muscle mass alone. The positive effect of muscle mass and the negative effect of obesity change the volumes of brain regions related to cognition and movement which were not significantly affected by obesity or muscle mass alone. • If obesity and muscle mass were considered together, we could find more significant brain volume changes which were not found in obesity or muscle alone. • The ratio of thigh muscle to visceral fat was positively correlated with the volumes of entorhinal cortex, temporal pole, and inferior temporal gyrus related to cognition. • The ratio of thigh muscle to visceral fat was positively correlated with the volumes of cerebellum and pallidum related to movement.

Automated identification of the mouse brain\u2019s spatial compartments from in situ sequencing data

BackgroundNeuroanatomical compartments of the mouse brain are identified and outlined mainly based on manual annotations of samples using features related to tissue and cellular morphology, taking advantage of publicly available reference atlases. However, this task is challenging since sliced tissue sections are rarely perfectly parallel or angled with respect to sections in the reference atlas and organs from different individuals may vary in size and shape and requires manual annotation. With the advent of in situ sequencing technologies and automated approaches, it is now possible to profile the gene expression of targeted genes inside preserved tissue samples and thus spatially map biological processes across anatomical compartments.ResultsHere, we show how in situ sequencing data combined with dimensionality reduction and clustering can be used to identify spatial compartments that correspond to known anatomical compartments of the brain. We also visualize gradients in gene expression and sharp as well as smooth transitions between different compartments. We apply our method on mouse brain sections and show that a fully unsupervised approach can computationally define anatomical compartments, which are highly reproducible across individuals, using as few as 18 gene markers. We also show that morphological variation does not always follow gene expression, and different spatial compartments can be defined by various cell types with common morphological features but distinct gene expression profiles.ConclusionWe show that spatial gene expression data can be used for unsupervised and unbiased annotations of mouse brain spatial compartments based only on molecular markers, without the need of subjective manual annotations based on tissue and cell morphology or matching reference atlases.

Brain-homing CD4+ T cells display glucocorticoid-resistant features in MS.

ObjectiveTo study whether glucocorticoid (GC) resistance delineates disease-relevant T helper (Th) subsets that home to the CNS of patients with early MS.MethodsThe expression of key determinants of GC sensitivity, multidrug resistance protein 1 (MDR1/ABCB1) and glucocorticoid receptor (GR/NR3C1), was investigated in proinflammatory Th subsets and compared between natalizumab-treated patients with MS and healthy individuals. Blood, CSF, and brain compartments from patients with MS were assessed for the recruitment of GC-resistant Th subsets using fluorescence-activated cell sorting (FACS), quantitative polymerase chain reaction (qPCR), immunohistochemistry, and immunofluorescence.ResultsAn MS-associated Th subset termed Th17.1 showed a distinct GC-resistant phenotype as reflected by high MDR1 and low GR expression. This expression ratio was further elevated in Th17.1 cells that accumulated in the blood of patients with MS treated with natalizumab, a drug that prevents their entry into the CNS. Proinflammatory markers C-C chemokine receptor 6, IL-23R, IFN-γ, and GM-CSF were increased in MDR1-expressing Th17.1 cells. This subset predominated the CSF of patients with early MS, which was not seen in the paired blood or in the CSF from patients with other inflammatory and noninflammatory neurologic disorders. The potential of MDR1-expressing Th17.1 cells to infiltrate brain tissue was confirmed by their presence in MS white matter lesions.ConclusionThis study reveals that GC resistance coincides with preferential CNS recruitment of pathogenic Th17.1 cells, which may hamper the long-term efficacy of GCs in early MS.

Passage of uranium through human cerebral microvascular endothelial cells: influence of time exposure in mono- and co-culture in vitro models

Purpose Depleted uranium (DU) has several civilian and military applications. The effects of this emerging environmental pollutant on human health raise some concerns. Previous experimental studies have shown that uranium (U) exposure can disturb the central nervous system. A small quantity of U reaches the brain via the blood, but the effects on the blood-brain barrier (BBB) remain unclear. Materials and methods In the present work, two cell culture models were exposed to DU for different times to study its cytotoxicity, paracellular permeability and extracellular concentration of U. The well-known immortalized human cerebral microvascular endothelial cells, hCMEC/D3, were cultured on the filter in the first model. In the second model, human primary cells of pericytes were cultured under the filter to understand the influence of cell environment after U exposure. Results The results show that U is not cytotoxic to hCMEC/D3 cells or pericytes until 500 µM (1.6 Bq.L−1). In addition, acute or chronic low-dose exposure of U did not disturb permeability and was conserved in both cell culture models. However, U is able to reach the brain compartment. During the first hours of exposure, the passage of U to the abluminal compartment was significantly reduced in the presence of pericytes. Electronic microscopy studies evidenced the formation of needlelike structures, like urchin-shaped precipitates, from 1 h of exposure. Analytical microscopy confirmed the U composition of these precipitates. Interestingly, precipitated U was detected only in endothelial cells and not in pericytes. U was localized in multilamellar or multivesicular bodies along the endo-lysosomal pathway, suggesting the involvement of these traffic vesicles in U sequestration and/or elimination. Conclusions We show for the first time the in vitro passage of U across a human cerebral microvascular endothelial cells, and the intracellular localization of U precipitates without any cytotoxicity or modification of paracellular permeability. The difference between the results obtained with monolayers and co-culture models with pericytes illustrates the need to use complex in vitro models in order to mimic the neurovascular unit. Further in vivo studies should be performed to better understand the passage of U across the blood-brain barrier potentially involved in behavioral consequences.

Oxidoreductase Activities in Oxyphilic Tissues of the Black Sea Ruff Scorpaena porcus under Short-term Hydrogen Sulfide Loading

Hydrogen sulfide can both exert a toxic effect and function as a signaling molecule in various physiological processes. Under conditions of experimental short-term hydrogen sulfide loading (HSL), activities of oxidoreductases (enzymes of energy metabolism and antioxidant defense)—malate dehydrogenase (MDH, 1.1.1.37), lactate dehydrogenase (LDH, 1.1.1.27) and catalase (1.11.1.6) were analyzed in oxyphilic tissues (brain, heart, gills) of the Black Sea sea ruff Scorpaena porcus Linnaeus, 1758. Two groups of fish were exposed for 5 min to different concentrations of sodium sulfide (37 and 75 µM Na2S) used as a hydrogen sulfide donor. High MDH and LDH activities were simultaneously detected in the brain structures and heart chambers, reflecting a similar potential of energy metabolism in these tissues, while enhanced LDH activity in the brain indicated anaerobization of the energy metabolism pathways. Differences in oxydoreductase activities were found between the first and fourth branchial arches, heart atrium and ventricle, as well as between different brain compartments. Under HSL, the gills exhibited some signs of hypoxemia (increasing darkening of the lamellae as the Na2S concentration moved upward) and metabolic depression. At a low Na2S concentration, HSL did not cause significant changes in oxidoreductase activities in the brain and heart, while upon a 2-fold increase in the Na2S concentration these changes became more pronounced. In the key oxyphilic structures (anterior brain compartments, heart ventricle) intense HSL led to a simultaneous increase in LDH and MDH activities, which was due to the ability of MDH to participate in anaerobic processes. The less O2-sensitive structures (medulla oblongata and heart atrium) exhibited almost no changes in MDH and LDH activities even in response to high-intensity HSL, suggesting a different mode of energy metabolism in these tissues. Under intense HSL, the oxidoreductases in the heart ventricles and anterior brain compartments demonstrated responses, which were similar to those under hypoxia/anoxia.

Thalamic and neocortical differences in the relationship between the time course of delta and sigma power during NREM sleep in humans.

Sleep spindles and slow waves are the hallmarks of non-rapid eye movement (NREM) sleep and are produced by the dynamic interplay between thalamic and cortical regions. Several studies in both human and animal models have focused their attention on the relationship between electroencephalographic (EEG) spindles and slow waves during NREM, using the power in the sigma and delta bands as a surrogate for the production of spindles and slow waves. A typical report is an overall inverse relationship between the time course of sigma and delta power as measured by a single correlation coefficient both within and across NREM episodes. Here we analysed stereotactically implanted intracerebral electrode (Stereo-EEG [SEEG]) recordings during NREM simultaneously acquired from thalamic and from several neocortical sites in six neurosurgical patients. We investigated the relationship between the time course of delta and sigma power and found that, although at the cortical level it shows the expected inverse relationship, these two frequency bands follow a parallel time course at the thalamic level. Both these observations were consistent across patients and across different cortical as well as thalamic regions. These different temporal dynamics at the neocortical and thalamic level are discussed, considering classical as well as more recent interpretations of the neurophysiological determinants of sleep spindles and slow waves. These findings may also help understanding the regulatory mechanisms of these fundamental sleep EEG graphoelements across different brain compartments.

Compartment and cell-type specific hypoxia responses in the developing Drosophila brain.

ABSTRACTEnvironmental factors such as the availability of oxygen are instructive cues that regulate stem cell maintenance and differentiation. We used a genetically encoded biosensor to monitor the hypoxic state of neural cells in the larval brain of Drosophila. The biosensor reveals brain compartment and cell-type specific levels of hypoxia. The values correlate with differential tracheolation that is observed throughout development between the central brain and the optic lobe. Neural stem cells in both compartments show the strongest hypoxia response while intermediate progenitors, neurons and glial cells reveal weaker responses. We demonstrate that the distance between a cell and the next closest tracheole is a good predictor of the hypoxic state of that cell. Our study indicates that oxygen availability appears to be the major factor controlling the hypoxia response in the developing Drosophila brain and that cell intrinsic and cell-type specific factors contribute to modulate the response in an unexpected manner.This article has an associated First Person interview with the first author of the paper.

Abstract 3026: Evaluation of brain pharmacokinetics (PK) and tumor growth inhibition of PARP inhibitors in mouse xenograft models using semi-mechanistic PK/pharmacodynamic (PD) modeling

Abstract OBJECTIVE: The PARP inhibitors rucaparib, niraparib, olaparib, and veliparib have shown remarkable antitumor activity against various cancer types. We evaluated the brain penetration of PARP inhibitors in mice and the anti-tumor effects of selected PARP inhibitors in orthotopic and intracranial BRCA1-mutant triple-negative breast cancer (TNBC) MDA-MB-436 mouse models. PK/PD models were used to characterize the systemic/brain PK and tumor growth inhibition. METHODS: In non-tumor-bearing NOD-SCID female mice, plasma concentrations were determined at selected time points following an oral dose of 2, 5, 15, 50, or 150 mg rucaparib. The antitumor efficacy of rucaparib (2, 5, 15, 50, or 150 mg BID for 28 days) was evaluated in the MDA-MB-436 orthotopic model. In addition, a single dose of rucaparib (150 mg), niraparib (50 mg), olaparib (150 mg), or veliparib (150 mg) was given to male CD-1 mice; plasma, brain, and cerebrospinal fluid (CSF) concentrations of these compounds were determined at various time points. Intracranial efficacy was evaluated in luciferase-expressing MDA-MB-436 tumors following treatment of rucaparib (150 mg BID) or niraparib (50 mg QD) for 57 days. Tumor burden was evaluated using bioluminescence measurements. Semi-mechanistic PK and tumor growth inhibition models were developed to evaluate systemic, brain, and CSF concentration-time profiles for all 4 PARP inhibitors, and to evaluate tumor inhibition for rucaparib and niraparib using NONMEM software. RESULTS: All of the PARP inhibitors showed limited brain penetration in mice with an intact blood-brain barrier. However, rucaparib and niraparib demonstrated antitumor efficacy in a BRCA1-mutant, intracranial, TNBC mouse model. Brain and CSF concentrations were modeled as separate physiologically relevant compartments with PARP inhibitors being able to distribute to both brain and CSF compartments from the systemic compartment following oral administration. The model characterized plasma, brain, and CSF drug concentrations simultaneously. A modified Simeoni model with a 1st-order tumor growth rate adequately described the dose-dependent tumor inhibition at different doses of rucaparib in the orthotopic tumor model. The effects of brain tumor inhibition by rucaparib and niraparib were sufficiently described by a simpler model with a 1st-order tumor growth rate and a 2nd-order tumor inhibition rate that was proportional to brain drug concentrations. CONCLUSIONS: Systemic and brain concentrations, as well as orthotopic and intracranial tumor inhibition data, following oral administration in mice, were adequately described using semi-mechanistic models. Further studies are warranted to understand the intracranial distribution and antitumor activity of PARP inhibitors. Citation Format: Michelle Liao, Feng Jin, Minh Nguyen, Liliane Robillard, Andrew D. Simmons, Thomas C. Harding, Jim J. Xiao. Evaluation of brain pharmacokinetics (PK) and tumor growth inhibition of PARP inhibitors in mouse xenograft models using semi-mechanistic PK/pharmacodynamic (PD) modeling [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3026.

Ocular pathology in NeuroAIDS – An autopsy study

The central nervous system (CNS) and the eye are involved in Human immunodeficiency virus related disease. Although, optic nerve is considered an extension of the CNS, it has not been systematically evaluated to determine if infections of brain can extend into the eye or vice versa. The brain and posterior compartment of eyeball retrieved at autopsy of patients succumbing to NeuroAIDS, were evaluated with Hematoxylin & Eosin, special stains and immunohistochemistry for infective pathogens. Multiplex PCR was performed in vitreous, CSF and serum for simultaneous detection of bacterial, viral, and protozoal opportunistic infections. Ocular involvement in NeuroAIDS was seen in 93.7% (15/16) with opportunistic infection being the most common 62.5% (10/16); with toxoplasma optic neuropathy in 5 (50%), Cryptococcal optic neuritis in 3 (30%), and Cytomegalovirus chorioretinitis in 2 (20%). Concordance between ocular and CNS pathology was seen in 50% of cases. CSF PCR was more sensitive than PCR in vitreous for detecting ocular infections in posterior compartment of eye.

Ultrabright Fluorescent Polymeric Nanoparticles with a Stealth Pluronic Shell for Live Tracking in the Mouse Brain.

Visualizing single organic nanoparticles (NPs) in vivo remains a challenge, which could greatly improve our understanding of the bottlenecks in the field of nanomedicine. To achieve high single-particle fluorescence brightness, we loaded polymer poly(methyl methacrylate)-sulfonate (PMMA-SO3H) NPs with octadecyl rhodamine B together with a bulky hydrophobic counterion (perfluorinated tetraphenylborate) as a fluorophore insulator to prevent aggregation-caused quenching. To create NPs with stealth properties, we used the amphiphilic block copolymers pluronic F-127 and F-68. Fluorescence correlation spectroscopy and Förster resonance energy transfer (FRET) revealed that pluronics remained at the NP surface after dialysis (at one amphiphile per 5.5 nm2) and prevented NPs from nonspecific interactions with serum proteins and surfactants. In primary cultured neurons, pluronics stabilized the NPs, preventing their prompt aggregation and binding to neurons. By increasing dye loading to 20 wt % and optimizing particle size, we obtained 74 nm NPs showing 150-fold higher single-particle brightness with two-photon excitation than commercial Nile Red-loaded FluoSpheres of 39 nm hydrodynamic diameter. The obtained ultrabright pluronic-coated NPs enabled direct single-particle tracking in vessels of mice brains by two-photon intravital microscopy for at least 1 h, whereas noncoated NPs were rapidly eliminated from the circulation. Following brain injury or neuroinflammation, which can open the blood-brain barrier, extravasation of NPs was successfully monitored. Moreover, we demonstrated tracking of individual NPs from meningeal vessels until their uptake by meningeal macrophages. Thus, single NPs can be tracked in animals in real time in vivo in different brain compartments and their dynamics visualized with subcellular resolution.

Pharmacokinetic and pharmacodynamic analyses of cocaine and its metabolites in behaviorally divergent inbred mouse strains.

Cocaine (COC) is a psychostimulant with a high potential for abuse and addiction. Risk for COC use disorder is driven, in part, by genetic factors. Animal models of addiction-relevant behaviors have proven useful for studying both genetic and nongenetic contributions to drug response. In a previous study, we examined initial locomotor sensitivity to COC in genetically diverse inbred mouse strains. That work highlighted the relevance of pharmacokinetics (PK) in initial locomotor response to COC but was limited by a single dose and two sampling points. The objective of the present study was to characterize the PK and pharmacodynamics of COC and its metabolites (norcocaine and benzoylecgonine) in six inbred mouse strains (I/LnJ, C57BL/6J, FVB/NJ, BTBR T+ tf/J, LG/J and LP/J) that exhibit extreme locomotor responses to cocaine. Mice were administered COC at one of four doses and concentrations of cocaine, norcocaine and benzoylecgonine were analyzed in both plasma and brain tissue at 5 different time points. Initial locomotor sensitivity to COC was used as a pharmacodynamic endpoint. We developed an empirical population PK model that simultaneously characterizes cocaine, norcocaine and benzoylecgonine in plasma and brain tissues. We observed interstrain variability occurring in the brain compartment that may contribute to pharmacodynamic differences among select strains. Our current work paves the way for future studies to explore strain-specific pharmacokinetic differences and identify factors other than PK that are responsible for the diverse behavioral response to COC across these inbred mouse strains.