Brain Perfusion Studies Research Articles

A Fatal Case of Powassan Virus Encephalitis

The Powassan virus (POWV) is part of the Flaviviridae family. It is mainly transmitted via tickbite but can rarely be spread person-to-person through blood transfusions. Initial symptoms include fever, headache, and vomiting. It can cause severe symptoms, including confusion, aphasia, and seizures. Approximately 1 out of 10 people with severe disease die. From 2010 to 2020, 194 Powassan virus cases have been reported to the Center for Disease Control (CDC), with 22 of them resulting in death. In this case report, we discuss a 39-year-old female who presented with fever, myalgia, and confusion. During her hospitalization, she developed tonic-clonic seizures, which required sedation and intubation. A central venous catheter was inserted due to poor intravenous access, and in the process of placing it, the provider sustained a needle stick injury. The patient was eventually diagnosed with POWV encephalitis and transferred to a higher level of care, where a brain perfusion study showed an absence of brain flow consistent with brain death. After a discussion with the family, the decision was made to extubate the patient terminally. The provider who sustained the needle stick injury reported no concerning symptoms two years after the event.

Evaluation of Whole Brain Intravoxel Incoherent Motion (IVIM) Imaging.

Intravoxel Incoherent Motion (IVIM) imaging provides non-invasive perfusion measurements, eliminating the need for contrast agents. This work explores the feasibility of IVIM imaging in whole brain perfusion studies, where an isotropic 1 mm voxel is widely accepted as a standard. This study follows the validity of a time-limited, precise, segmentation-ready whole-brain IVIM protocol suitable for clinical reality. To assess the influence of SNR on the estimation of S0, f, D*, and D IVIM parameters, a series of measurements and simulations were performed in MATLAB for the following three estimation techniques: segmented grid search, segmented curve fitting, and one-step curve fitting, utilizing known "ground truth" and noised data. Scanner-specific SNR was estimated based on a healthy subject IVIM MRI study in a 3T scanner. Measurements were conducted for 25.6 × 25.6 × 14.4 cm FOV with a 256 × 256 in-plane resolution and 72 slices, resulting in 1 × 1 × 2 mm voxel size. Simulations were performed for 36 SNR levels around the measured SNR value. For a single voxel grid, the search algorithm mean relative error Ŝ0, f^, D^*, and D^ of at the expected SNR level were 5.00%, 81.91%, 76.31%, and 18.34%, respectively. Analysis has shown that high-resolution IVIM imaging is possible, although there is significant variation in both accuracy and precision, depending on SNR and the chosen estimation method.

Is brain perfusion correlated to switching mood states and cognitive impairment in bipolar disorder type I? A longitudinal study using perfusion imaging approach.

Type I Bipolar disorder (BD-I) is a neuropsychiatric disorder characterized by manic or mixed-featured episodes, impaired cognitive functioning, and persistent work and social functioning impairment. This study aimed to investigate within-subject; (i) differences in brain perfusion using Single-photon emission computed tomography (SPECT) between manic and euthymic states in BD-I patients; (ii) explore potential associations between altered brain perfusion and cognitive status; and (iii) examine the relationship between cerebral perfusion and mania symptom ratings. Seventeen adult patients diagnosed with BD-I in a manic episode were recruited, and clinical assessments, cognitive tests, and brain perfusion studies were conducted at baseline (mania state) and a follow-up visit 6 months later. The results showed cognitive impairment during the manic episode, which persisted during the euthymic state at follow-up. However, no significant changes in brain perfusion were observed between the manic and euthymic states. During mania, trends toward decreased perfusion in the left cerebellum and right superior parietal lobule were noted. Additionally, trends indicated a higher perfusion imbalance in the left superior and middle frontal gyrus during mania and the right superior and middle frontal gyrus during euthymia. No significant correlations existed between brain perfusion, mania symptom ratings, and cognitive performance, indicating that symptomatology might represent more than neural hemodynamics. These findings suggest that cognitive impairment may persist in BD-I patients and highlight the need for therapeutic interventions targeting cognitive deficits. More extensive studies with extended follow-up periods are warranted further to investigate brain perfusion and cognitive functioning in BD-I patients.

Prevalence of Stroke in Patient Presenting to Emergency Department (ED) With Dizziness Base on Brain Computed Tomography (CT)

Objectives: Dizziness is a common acute emergency complain which can present in isolation. Diagnosing a stroke in patient complains of dizziness only is major challenge to the practicing emergency physician as this symptom nor sensitive neither specific. The purpose of this study was to measure the prevalence of stroke as a diagnosis in patient who present to the emergency department with dizziness base on brain CT. Methods: This is Retrospective, Cross sectional study was carried out at the Armed Force Hospital (adult ED) in Muscat, Oman, from between August 2019 -August 2020. All patients who underwent head CT during this period where review both indication and the CT finding. Result: out of 1000 CT brain request, 115 patients meet the inclusion criteria, and 13 patients from the inclusion criteria have stroke with isolated dizziness. 80% of brain CT was normal, while 11% showed acute stroke. Conclusion: patient present with dizziness carry the risk to have stroke and head CT brain can help in diagnosis. Adding further imaging, such as, brain perfusion study and MRI can lower the chance of missing stroke case in isolated dizziness presentation.

CARD27: The Effect of Permissive Hypertension on Cerebral Perfusion in VAD Patients with Embolic Stroke

Study: This study aims to investigate the effect of permissive hypertension, a deliberate rise in Mean Arterial Pressure (MAP), on cerebral perfusion in Left Ventricular Assist Device (LVAD) patients with embolic stroke. Methods: A previously published Lumped Parameter Model (LPM) of the human circulation, including pulmonary and systemic circulation, as well as all four cardiac chambers and an LVAD, is divided into circulation of the upper and lower body. The upper circulation is further divided into extracranial and intracranial vessels to study brain perfusion as a function of MAP, as well as peripheral and intracranial resistance. Actual LVAD H-Q characteristic curves model the instantaneous LVAD response to a rise in MAP and the differential increase in resistance between the intracranial region suffering a stroke and the remaining circulation. The resulting changes in intracranial flow rate as MAP increases and vascular resistance is altered are analyzed. Increased resistance in intracranial vasculature is incorporated into a model of a typical embolic stroke, and its influence on cerebral perfusion is studied for a range of LVAD speeds and MAP values. Results: In LVAD patients with embolic stroke, intracranial flow significantly decreases as MAP is allowed to rise. These findings are robust at any LVAD speed, consistent with a significant reduction in LVAD flow with increased afterload. This counterintuitive result of permissive hypertension in LVAD patients is captured by the LPM model of embolic stroke, whereby the increase in intracranial resistance decreases cerebral perfusion even further via a decrease in total cardiac output associated with the increase in MAP. Third-generation LVADs are known to be afterload sensitive. Our results show that a mere increase in MAP from 70 to 80 mmHg decreases cerebral blood flow by a commensurate 15%, thus increasing infarct size, which is quite deleterious (see Fig. 1). Our study confirms there is no role for permissive hypertension in LVAD patients with embolic stroke. Figure 1. Cranial flow rate (Qcranial) as a function of MAP for no embolism (purple) and embolism (teal) cases and for 2400 RPM (circles) and 2800 RPM (squares) LVAD speeds.

Neuroimaging in Glucocerebrosidase-Associated Parkinsonism: A Systematic Review.

BackgroundMutations in the GBA gene cause Gaucher's disease (GD) and constitute the most frequent genetic risk factor for idiopathic Parkinson's disease (iPD). Nonmanifesting carriers of GBA mutations/variants (GBA‐NMC) constitute a potential PD preclinical population, whereas PD patients carrying some GBA mutations/variants (GBA‐PD) have a higher risk of a more aggressive disease course. Different neuroimaging techniques are emerging as potential biomarkers in PD and have been used to study GBA‐associated parkinsonism.ObjectiveThe aim is to critically review studies applying neuroimaging to GBA‐associated parkinsonism.MethodsLiterature search was performed using PubMed and EMBASE databases (last search February 7, 2022). Studies reporting neuroimaging findings in GBA‐PD, GD with and without parkinsonism, and GBA‐NMC were included.ResultsThirty‐five studies were included. In longitudinal studies, GBA‐PD patients show a more aggressive disease than iPD at both structural magnetic resonance imaging and 123‐fluoropropylcarbomethoxyiodophenylnortropane single‐photon emission computed tomography. Fluorodeoxyglucose‐positron emission tomography and brain perfusion studies reported a greater cortical involvement in GBA‐PD compared to iPD. Overall, contrasting evidence is available regarding GBA‐NMC for imaging and clinical findings, although subtle differences have been reported compared with healthy controls with no mutations.ConclusionsAlthough results must be interpreted with caution due to limitations of the studies, in line with previous clinical observations, GBA‐PD showed a more aggressive disease progression in neuroimaging longitudinal studies compared to iPD. Cognitive impairment, a “clinical signature” of GBA‐PD, seems to find its neuroimaging correlate in the greater cortical burden displayed by these patients as compared to iPD. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society

Cerebral Perfusion and Sensory Testing Results Differ in Interstitial Cystitis/Bladder Pain Syndrome Patients with and without Fibromyalgia: A Site-Specific MAPP Network Study.

PurposeFibromyalgia is a common co-morbidity in patients with interstitial cystitis/bladder pain syndrome. Quantitative sensory testing measures and regional cerebral blood flow measures have been noted to differ from healthy controls in both subjects with fibromyalgia and those with interstitial cystitis when studied independently. The present study examined such measures in subjects with the diagnosis of interstitial cystitis both with and without the co-diagnosis of fibromyalgia to determine whether differences in these measures may be associated with co-morbidity.Patients and MethodsFemale subjects with the diagnosis of interstitial cystitis with (n = 15) and without (n = 19) the co-diagnosis of fibromyalgia as well as healthy control subjects (n = 41) underwent quantitative sensory testing. A subset of these patients (9 with and 9 without fibromyalgia) underwent brain perfusion studies using arterial spin labeled functional magnetic resonance imaging. An analysis was performed of absolute regional cerebral blood flow of regions-of-interest when experiencing a full bladder compared with an empty bladder.ResultsSubjects with both interstitial cystitis and fibromyalgia were more hypersensitive than those without fibromyalgia as well as healthy controls in most sensory measures except heat. Subjects with interstitial cystitis, but no fibromyalgia, differed from healthy controls only in toleration of the ischemic forearm task. Other co-morbidities were more common in those subjects with both interstitial cystitis and fibromyalgia. Bladder fullness was associated with significantly greater whole brain gray matter blood flow in subjects with interstitial cystitis and fibromyalgia when compared with that of subjects with interstitial cystitis without fibromyalgia. Examination of regional cerebral blood flow in individual regions-of-interest demonstrated statistically significant differences between the subjects with interstitial cystitis with and those without fibromyalgia bilaterally in the thalamus, amygdala and hippocampus, as well as the right prefrontal cortex and greater responsiveness to changes in bladder fullness in the insula.ConclusionQuantitative sensory testing and brain perfusion data support that there are two phenotypes of interstitial cystitis patients, which can be differentiated by a co-diagnosis of fibromyalgia. This may affect responsiveness to treatment and suggest the utility of stratifying interstitial cystitis patients according to their co-morbidities.

Neurochemical Features of Rem Sleep Behaviour Disorder.

Dopaminergic deficiency, shown by many studies using functional neuroimaging with Single Photon Emission Computerized Tomography (SPECT) and Positron Emission Tomography (PET), is the most consistent neurochemical feature of rapid eye movement (REM) sleep behaviour disorder (RBD) and, together with transcranial ultrasonography, and determination of alpha-synuclein in certain tissues, should be considered as a reliable marker for the phenoconversion of idiopathic RBD (iRBD) to a synucleopathy (Parkinson’s disease –PD- or Lewy body dementia -LBD). The possible role in the pathogenesis of RBD of other neurotransmitters such as noradrenaline, acetylcholine, and excitatory and inhibitory neurotransmitters; hormones such as melatonin, and proinflammatory factors have also been suggested by recent reports. In general, brain perfusion and brain glucose metabolism studies have shown patterns resembling partially those of PD and LBD. Finally, the results of structural and functional MRI suggest the presence of structural changes in deep gray matter nuclei, cortical gray matter atrophy, and alterations in the functional connectivity within the basal ganglia, the cortico-striatal, and the cortico-cortical networks, but they should be considered as preliminary.

Alcoholic pontine myelinolysis: beware the stroke mimic

Central pontine myelinolysis (CPM), often referred to as osmotic demyelination syndrome, is most commonly seen in the setting of rapid correction of hyponatraemia. Although imaging is the key to diagnosis, conventional CT and MRI findings often lag the clinical manifestations and characteristic MRI changes may be delayed by up to 14 days.We present a case of a 45-year-old female with an extensive history of alcohol misuse and malnutrition who presented with left hemiparesis, initially suspected to be a stroke. This was following a recent hospital admission when she was managed for Wernicke’s encephalopathy and treated with electrolyte and vitamin replacement. As part of a “code stroke” protocol, CT was initially performed. The initial non-contrast CT brain and CT angiogram of the intracranial arteries were normal, but a CT brain perfusion study demonstrated increased pontine blood flow. A subsequent MRI of the brain confirmed CPM, which was congruent with her clinical course.This case highlights the importance of osmotic demyelination as a stroke mimic. CPM should be considered in alcoholic patients with neurological impairment regardless of serum sodium. To our knowledge, this is the first published case which illustrates CT perfusion changes in CPM. MRI, however, remains essential for diagnosis.

Value of Vascular and Non-Vascular Pattern on Computed Tomography Perfusion in Patients With Acute Isolated Aphasia.

Acute onset aphasia may be due to stroke but also to other causes, which are commonly referred to as stroke mimics. We hypothesized that, in patients with acute isolated aphasia, distinct brain perfusion patterns are related to the cause and the clinical outcome. Herein, we analyzed the prognostic yield and the diagnostic usefulness of computed tomography perfusion (CTP) in patients with acute isolated aphasia. From a single-center registry, we selected a cohort of 154 patients presenting with acute isolated aphasia who had a whole-brain CTP study available. We collected the main clinical and radiological data. We categorized brain perfusion studies on CTP into vascular and nonvascular perfusion patterns and the cause of aphasia as ischemic stroke, transient ischemic attack, stroke mimic, and undetermined cause. The primary clinical outcome was the persistence of aphasia at discharge. We analyzed the sensitivity, specificity, positive and negative predictive values of perfusion patterns to predict complete clinical recovery and ischemic stroke on follow-up imaging. The cause of aphasia was an ischemic stroke in 58 patients (38%), transient ischemic attack in 3 (2%), stroke mimic in 68 (44%), and undetermined in 25 (16%). CTP showed vascular and nonvascular perfusion pattern in 62 (40%) and 92 (60%) patients, respectively. Overall, complete recovery occurred in 116 patients (75%). A nonvascular perfusion pattern predicted complete recovery (sensitivity 75.9%, specificity 89.5%, positive predictive value 95.7%, and negative predictive value 54.8%), and a vascular perfusion pattern was highly predictive of ischemic stroke (sensitivity 94.8%, specificity 92.7%, positive predictive value 88.7%, and negative predictive value 96.7%). The 3 patients with ischemic stroke without a vascular perfusion pattern fully recovered at discharge. CTP has prognostic value in the workup of patients with acute isolated aphasia. A nonvascular pattern is associated with higher odds of full recovery and may prompt the search for alternative causes of the symptoms.

Dynamic cerebral perfusion parameters and magnetic nanoparticle accumulation assessed by AC biosusceptometry.

Cerebral blood flow (CBF) assessment is mainly performed by scintigraphy, computed tomography (CT) and magnetic resonance imaging (MRI). New approaches to assess the CBF through the passage of magnetic nanoparticles (MNPs) to blood-brain barrier (BBB) are convenient to help decrease the use of ionizing radiation and unleash the required MRI schedule in clinics. The development of nanomedicine and new biomedical devices, such as the magnetic particle imaging (MPI), enabled new approaches to study dynamic brain blood flow. In this paper, we employed MNPs and the alternating current biosusceptometry (ACB) to study the brain perfusion. We utilized the mannitol, before the MNPs, injection to modulate the BBB permeability and study its effects on the circulation time of the MNPs in the brain of rats. Also, we characterized a new ACB sensor to increase the systems' applicability to study the MNPs' accumulation, especially in the animals' brain. Our data showed that the injection of mannitol increased the circulation time of MNPs in the brain. Also, the mannitol increased the accumulation of MNPs in the brain. This paper suggests the use of the ACB as a tool to study brain perfusion and accumulation of MNPs in studies of new nano agents focused on the brain diagnostics and treatment.

Abnormal brain functional connectivity coupled with hypoperfusion measured by Resting-State fMRI: An additional contributing factor for cognitive impairment in patients with Alzheimer's disease

The contribution of hypoperfusion to abnormal functional connectivity in Alzheimer's disease (AD) and mild cognitive impairment (MCI) remains unclear. In this study, we investigated the potential association between brain perfusion and functional connectivity (FC), and its effects on the cognitive impairment among AD, MCI, and normal controls (NC). One-time acquisition of resting-state functional magnetic resonance imaging (rs-fMRI) was used to study brain perfusion and FC. Compared to the NC, the perfusion in the left temporal lobe showed significantly lower in AD, and bilateral hypoperfusion in the frontal lobe showed in MCI. Using these hypoperfusion areas as seed regions, we found that FC between the left inferior temporal gyrus and medial frontal-cingulate regions in AD patients was significantly lower than that in NCs. The FC between the right medial superior frontal gyrus and left parietal lobe in MCI patients was significantly higher than that in NCs. Additionally, the FC between the right medial superior frontal gyrus and the left superior parietal gyrus were found to be correlated significantly and negatively with mini-mental state examination (MMSE) scores in MCI patients. In conclusion, hypoperfusion may affect cognitive states via abnormal FC as an additional factor contributing to cognitive impairment.

Oxidative stress-induced activation of Abl and Src kinases rapidly induces P-glycoprotein internalization via phosphorylation of caveolin-1 on tyrosine-14, decreasing cortisol efflux at the blood–brain barrier

Exposure of the brain to high levels of glucocorticoids during ischemia–reperfusion induces neuronal cell death. Oxidative stress alters blood–brain barrier (BBB) function during ischemia–reperfusion, and so we hypothesized that it might impair P-glycoprotein (P-gp)-mediated efflux transport of glucocorticoids at the BBB. Therefore, the purpose of this study was to clarify the molecular mechanism of this putative decrease of P-gp-mediated efflux function. First, we established that H2O2 treatment of a human in vitro BBB model (hCMEC/D3) reduced both P-gp efflux transport activity and protein expression on the plasma membrane within 20 min. These results suggested that the rapid decrease of efflux function might be due to internalization of P-gp. Furthermore, H2O2 treatment markedly increased tyrosine-14-phosphorylated caveolin-1, which is involved in P-gp internalization. A brain perfusion study in rats showed that cortisol efflux at the BBB was markedly decreased by H2O2 administration, and inhibitors of Abl kinase and Src kinase, which phosphorylate tyrosine-14 in caveolin-1, suppressed this decrease. Overall, these findings support the idea that oxidative stress-induced activation of Abl kinase and Src kinase induces internalization of P-gp via the phosphorylation of tyrosine-14 in caveolin-1, leading to a rapid decrease of P-gp-mediated cortisol efflux at the BBB.

Tc-99m ECD brain perfusion single-photon emission computed tomography in Parry–Romberg syndrome

We report a 15-year-old girl referred to our department for a brain perfusion study with a diagnosis of Parry–Romberg syndrome with left hemifacial atrophy and left enophthalmos. In the presence of a normal magnetic resonance imaging, Tc-99m ECD brain perfusion revealed left temporal lobe hypoperfusion with preserved perfusion in rest of the cortical and subcortical regions and both cerebellar hemispheres.

Changes of cortical perfusion in the early phase of subarachnoid bleeding in a rat model and the role of intracranial hypertension.

Brain perfusion is reduced early after subarachnoid hemorrhage (SAH) due to intracranial hypertension and early vasospasm. The contribution of these two mechanisms is unknown. By performing a prophylactic decompressive craniectomy (DC) in a rat model of SAH we aimed to study brain perfusion after the component of intracranial hypertension has been eliminated. We used 2x2 factorial design, where rats received either decompressive craniectomy or sham operation followed by injection of 250 microl of blood or normal saline into prechiasmatic cistern. The cortical perfusion has been continually measured by laser speckle-contrast analysis for 30 min. Injection of blood caused a sudden increase of intracranial pressure (ICP) and drop of cerebral perfusion, which returned to baseline within 6 min. DC effectively prevented the rise of ICP, but brain perfusion after SAH was significantly lower and took longer to normalize compared to non-DC animals due to increased cerebral vascular resistance, which lasted throughout 30 min experimental period. Our findings suggest that intracranial hypertension plays dominant role in the very early hypoperfusion after SAH whilst the role of early vasospasm is only minor. Prophylactic DC effectively maintained cerebral perfusion pressure, but worsened cerebral perfusion by increased vascular resistance.

Multiple boli arterial spin labeling for high signal-to-noise rodent brain perfusion imaging.

A systematic method is proposed for optimizing a promising preclinical arterial spin labeling (ASL) sequence based on the use of a train of adiabatic radiofrequency pulses labeling successive boli of blood water. The sequence optimization is performed and evaluated using brain imaging experiments in mice and in rats. It involves the investigation of several parameters, ranging from the number of adiabatic pulses and labeling duration to the properties of the adiabatic hyperbolic secant pulses (ie, amplitude and frequency modulation). Species-dependent parameters are identified, allowing for robust fast optimization protocols to be introduced. The resulting optimized multiple boli ASL (mbASL) sequence provides with significantly higher average signal-to-noise ratios (SNR) per voxel volume than currently encountered in ASL studies (278 mm-3 in mice and 172 mm-3 in rats). Comparing with the commonly used flow-sensitive alternating inversion recovery technique (FAIR), mbASL-to-FAIR SNR ratios reach 203% for mice and 725% for rats. When properly optimized, mbASL can offer a robust, high SNR ASL alternative for rodent brain perfusion studies Magn Reson Med 79:1020-1030, 2018. © 2017 International Society for Magnetic Resonance in Medicine.

Radiation-Induced Skin Injuries to Patients: What the Interventional Radiologist Needs to Know

For a long time, radiation-induced skin injuries were only encountered in patients undergoing radiation therapy. In diagnostic radiology, radiation exposures of patients causing skin injuries were extremely rare. The introduction of fast multislice CT scanners and fluoroscopically guided interventions (FGI) changed the situation. Both methods carry the risk of excessive high doses to the skin of patients resulting in skin injuries. In the early nineties, several reports of epilation and skin injuries following CT brain perfusion studies were published. During the same time, several papers reported skin injuries following FGI, especially after percutaneous coronary interventions and neuroembolisations. Thus, CT and FGI are of major concern regarding radiation safety since both methods can apply doses to patients exceeding 5 Gy (National Council on Radiation Protection and Measurements threshold for substantial radiation dose level). This paper reviews the problem of skin injuries observed after FGI. Also, some practical advices are given how to effectively avoid skin injuries. In addition, guidelines are discussed how to deal with patients who were exposed to a potentially dangerous radiation skin dose during medically justified interventional procedures.

Pyrilamine-sensitive proton-coupled organic cation (H+/OC) antiporter for brain-specific drug delivery

Blood-brain barrier (BBB) represents the greatest challenge that hampers therapeutic molecules entering the brain. Here, we described a novel brain-specific delivery strategy targeting to pyrilamine-sensitive H+/OC antiporter to facilitate therapeutic molecules cross the BBB and penetrate into the brain. In this study, four cyclic tertiary amines were selected as the brain-targeting moieties to modify naproxen (NP), a non-steroidal anti-inflammatory drug. The obtained NP conjugates displayed cell uptake efficiencies over 144-fold higher than that of unmodified NP in endothelial cells. The cell uptake process of the conjugates was primarily driven by pyrilamine-sensitive H+/OC antiporter in a pH-dependent, Na+-independent, and membrane potential-independent pathway, which could be further inhibited by pyrilamine, propranolol, and imipramine. Moreover, the NP conjugates showed significantly higher AUC0−t and Cmax in the brain compared with unmodified NP, and significantly higher accumulation than NP in the in situ brain perfusion study. Also, the conjugates showed superior neuroprotective effect in vitro and in vivo. Thus, the chemical modification of therapeutics with a cyclic tertiary amine moiety represents a promising and efficient strategy for brain-specific drug delivery via pyrilamine-sensitive H+/OC antiporter.

Applying x-ray micro-tomography to learning and memory

Metabolic processes and neural pathways such as those for glucose metabolism and olfaction in insects are similar to, and in some cases identical to, those found in vertebrates. In particular, the peripheral architecture of the insect and mammalian olfactory system is surprisingly similar. Thus one insect, the western honeybee (Apis mellifera), has become a model organism for the investigation of olfactory signal processing in the brain. A. Mellifera has superior abilities to identify, classify, learn and remember odoriferous environmental chemicals. The use of x-ray MicroCT imaging for the non-invasive study of insects (termed diagnostic radioentomology ‘DR’) is increasing. This experiment was conducted as a ‘proof of principle’ study to identify whether DR scanning live insects (honeybees) can be used to non-invasively examine learning and memory with respect to brain architecture and function. A bench-top MicroCT scanner was used to scan live bees. To enhance tissue differentiation, radiographic contrast was injected directly into the haemolymph. Brain volume was measured using BeeView software. Gross brain architecture was visualised in 2D and 3D projections. Scanning of live bees enabled minimally-invasive imaging of physiological processes for the first time such as passage of contrast from gut to haemolymph as well as preliminary brain perfusion studies. In particular, the learning and memory neuropils in the antennal lobes were assessed by measuring changes in antennal lobe volumes. Future experiments will correlate neuropil volume changes with classic PER learning and memory studies. One advantage of using an insect model is that multiple experiments can be conducted without the need for lengthy ethics approvals that apply to vertebrate experiments. The advantage of using live insects is that longitudinal studies can be performed on individuals therefore reducing, to a great extent, the inherent inter-cohort errors which occur. Once proof of principles is established in the insect model, experiments such as these can easily be extended to vertebrates.

Plasma protein binding limits the blood brain barrier permeation of the pyrethroid insecticide, deltamethrin.

Previous pharmacokinetic studies of deltamethrin (DLM) have revealed that brain levels of this highly lipophilic pyrethroid insecticide are only 15-20% of plasma levels. Experiments were performed to assess determinants limiting CNS access including plasma protein binding and the efflux transporter, P-gp. A human brain microvascular endothelial cell line, hCMEC/D3, was utilized as a model in vitro system to evaluate blood-brain barrier (BBB) permeation. Incubation of DLM with a series of human serum albumin (HSA) concentrations showed that unbound (fu) DLM ranged from 80% with 0.01% HSA to ∼20% at the physiologically-relevant 4% HSA. A positive correlation (R=0.987) was seen between fu and cellular uptake. Concentration-dependent uptake of DLM in 0.01% HSA was non-linear and was reduced at 4°C and by the P-gp inhibitor cyclosporine (CSA), indicative of a specific transport process. Cellular accumulation of [(3)H]-paclitaxel, a P-glycoprotein (P-gp) substrate, was increased by CSA but not by DLM, suggesting that DLM is neither a substrate nor an inhibitor of P-gp. The concentration-dependent uptake of DLM from 4% HSA was linear and not significantly impacted by temperature or CSA. In situ brain perfusion studies monitoring brain association of DLM at 0.01% and 4% HSA confirmed the aforementioned in vitro findings. This study demonstrates that brain uptake of DLM under normal physiological conditions appears to be a passive, non-saturable process, limited by the high protein binding of the pyrethroid.