Pathogenesis Of Brain Disorders Research Articles

An in-depth review of the function of RNA-binding protein FXR1 in neurodevelopment.

FMR1 autosomal homolog 1 (FXR1) is an RNA-binding protein that belongs to the Fragile X-related protein (FXR) family. FXR1 is critical for development, as its loss of function is intolerant in humans and results in neonatal death in mice. Although FXR1 is expressed widely including the brain, functional studies on FXR1 have been mostly performed in cancer cells. Limited studies have demonstrated the importance of FXR1 in the brain. In this review, we will focus on the roles of FXR1 in brain development and pathogenesis of brain disorders. We will summarize the current knowledge in FXR1 in the context of neural biology, including structural features, isoform diversity and nomenclature, expression patterns, post-translational modifications, regulatory mechanisms, and molecular functions. Overall, FXR1 emerges as an important regulator of RNA metabolism in the brain, with strong implications in neurodevelopmental and psychiatric disorders.

An In Vivo High-Resolution Human Brain Atlas of Synaptic Density.

Synapses are fundamental to the function of the central nervous system and are implicated in a number of brain disorders. Despite their pivotal role, a comprehensive imaging resource detailing the distribution of synapses in the human brain has been lacking until now. Here, we employ high-resolution PET neuroimaging in healthy humans (17F/16M) to create a 3D atlas of the synaptic marker Synaptic Vesicle glycoprotein 2A (SV2A). Calibration to absolute density values (pmol/ml) was achieved by leveraging postmortem human brain autoradiography data. The atlas unveils distinctive cortical and subcortical gradients of synapse density that reflect functional topography and hierarchical order from core sensory to higher-order integrative areas-a distribution that diverges from SV2A mRNA patterns. Furthermore, we found a positive association between IQ and SV2A density in several higher-order cortical areas. This new resource will help advance our understanding of brain physiology and the pathogenesis of brain disorders, serving as a pivotal tool for future neuroscience research.

High lactic acid levels in the brain contribute to the generation of focal slowing on the electroencephalogram.

Focal slowing on the EEG is often associated with structural pathology of the brain. Despite the clinical significance of focal slowing, the actual electrochemical mechanisms underlying this EEG phenomenon are still poorly understood. This paper briefly reviews the role of lactate in the pathogenesis of brain disorders that are primarily related to focal EEG slowing. An attempt is made to trace the hypothetical link between this EEG pattern and focal cerebral tissue lactacidosis.

Advances in brain epitranscriptomics research and translational opportunities.

Various chemical modifications of all RNA transcripts, or epitranscriptomics, have emerged as crucial regulators of RNA metabolism, attracting significant interest from both basic and clinical researchers due to their diverse functions in biological processes and immense clinical potential as highlighted by the recent profound success of RNA modifications in improving COVID-19 mRNA vaccines. Rapid accumulation of evidence underscores the critical involvement of various RNA modifications in governing normal neural development and brain functions as well as pathogenesis of brain disorders. Here we provide an overview of RNA modifications and recent advancements in epitranscriptomic studies utilizing animal models to elucidate important roles of RNA modifications in regulating mammalian neurogenesis, gliogenesis, synaptic formation, and brain function. Moreover, we emphasize the pivotal involvement of RNA modifications and their regulators in the pathogenesis of various human brain disorders, encompassing neurodevelopmental disorders, brain tumors, psychiatric and neurodegenerative disorders. Furthermore, we discuss potential translational opportunities afforded by RNA modifications in combatting brain disorders, including their use as biomarkers, in the development of drugs or gene therapies targeting epitranscriptomic pathways, and in applications for mRNA-based vaccines and therapies. We also address current limitations and challenges hindering the widespread clinical application of epitranscriptomic research, along with the improvements necessary for future progress.

Impact of the gut microbiome on nicotine's motivational effects and glial cells in the ventral tegmental area in male mice.

A link between gut dysbiosis and the pathogenesis of brain disorders has been identified. A role for gut bacteria in drug reward and addiction has been suggested but very few studies have investigated their impact on brain and behavioral responses to addictive drugs so far. In particular, their influence on nicotine's addiction-like processes remains unknown. In addition, evidence shows that glial cells shape the neuronal activity of the mesolimbic system but their regulation, within this system, by the gut microbiome is not established. We demonstrate that a lack of gut microbiota in male mice potentiates the nicotine-induced activation of sub-regions of the mesolimbic system. We further show that gut microbiota depletion enhances the response to nicotine of dopaminergic neurons of the posterior ventral tegmental area (pVTA), and alters nicotine's rewarding and aversive effects in an intra-VTA self-administration procedure. These effects were not associated with gross behavioral alterations and the nicotine withdrawal syndrome was not impacted. We further show that depletion of the gut microbiome modulates the glial cells of the mesolimbic system. Notably, it increases the number of astrocytes selectively in the pVTA, and the expression of postsynaptic density protein 95 in both VTA sub-regions, without altering the density of the astrocytic glutamatergic transporter GLT1. Finally, we identify several sub-populations of microglia in the VTA that differ between its anterior and posterior sub-parts, and show that they are re-organized in conditions of gut microbiota depletion. The present study paves the way for refining our understanding of the pathophysiology of nicotine addiction.

Pattern of TAAR5 Expression in the Human Brain Based on Transcriptome Datasets Analysis.

Trace amine-associated receptors (TAAR) recognize organic compounds, including primary, secondary, and tertiary amines. The TAAR5 receptor is known to be involved in the olfactory sensing of innate socially relevant odors encoded by volatile amines. However, emerging data point to the involvement of TAAR5 in brain functions, particularly in the emotional behaviors mediated by the limbic system which suggests its potential contribution to the pathogenesis of neuropsychiatric diseases. TAAR5 expression was explored in datasets available in the Gene Expression Omnibus, Allen Brain Atlas, and Human Protein Atlas databases. Transcriptomic data demonstrate ubiquitous low TAAR5 expression in the cortical and limbic brain areas, the amygdala and the hippocampus, the nucleus accumbens, the thalamus, the hypothalamus, the basal ganglia, the cerebellum, the substantia nigra, and the white matter. Altered TAAR5 expression is identified in Down syndrome, major depressive disorder, or HIV-associated encephalitis. Taken together, these data indicate that TAAR5 in humans is expressed not only in the olfactory system but also in certain brain structures, including the limbic regions receiving olfactory input and involved in critical brain functions. Thus, TAAR5 can potentially be involved in the pathogenesis of brain disorders and represents a valuable novel target for neuropsychopharmacology.

Identifying associations among genomic, proteomic and imaging biomarkers via adaptive sparse multi-view canonical correlation analysis.

To uncover the genetic underpinnings of brain disorders, brain imaging genomics usually jointly analyzes genetic variations and imaging measurements. Meanwhile, other biomarkers such as proteomic expressions can also carry valuable complementary information. Therefore, it is necessary yet challenging to investigate the underlying relationships among genetic variations, proteomic expressions, and neuroimaging measurements, which stands a chance of gaining new insights into the pathogenesis of brain disorders. Given multiple types of biomarkers, using sparse multi-view canonical correlation analysis (SMCCA) and its variants to identify the multi-way associations is straightforward. However, due to the gradient domination issue caused by the naive fusion of multiple SCCA objectives, SMCCA is suboptimal. In this paper, we proposed two adaptive SMCCA (AdaSMCCA) methods, i.e. the robustness-aware AdaSMCCA and the uncertainty-aware AdaSMCCA, to analyze the complicated associations among genetic, proteomic, and neuroimaging biomarkers. We also imposed a data-driven feature grouping penalty to the genetic data with aim to uncover the joint inheritance of neighboring genetic variations. An efficient optimization algorithm, which is guaranteed to converge, was provided. Using two state-of-the-art SMCCA as benchmarks, we evaluated robustness-aware AdaSMCCA and uncertainty-aware AdaSMCCA on both synthetic data and real neuroimaging, proteomics, and genetic data. Both proposed methods obtained higher associations and cleaner canonical weight profiles than comparison methods, indicating their promising capability for association identification and feature selection. In addition, the subsequent analysis showed that the identified biomarkers were related to Alzheimer's disease, demonstrating the power of our methods in identifying multi-way bi-multivariate associations among multiple heterogeneous biomarkers.

Gut microbiota and its impact on neuropsychiatric disorders

Introduction: Over the last few decades, the interest of microbiota- gut – brain axis has increased. It is thought to have an impact on the overall health of the host. Gut microbiota and central nervous system can communicate in different ways. The connection between them is especially interesting in case of neuropsychiatric diseasesThe aim of the study: The purpose of this systemic review was to collect and analyse current data of the association between gut microbiota and neuropsychitric disorders, specifically schizophrenia and bipolar disorderMaterial and method: Standard criteria were used to review the literature data. The search of articles in the PubMed and Google Scholar database was carried out using the following keywords: gut microbiota, dysbiosis, schizophrenia, bipolar disorderDescription of the state of knowledge: Dysregulation of microbiota is a potential factor in pathogenesis of brain disorders. Gut microbiome is thought to be an important part of not only normal brain development, but also modulation of host physiological systems. Studies show that the composition of microbiota in psychiatric diseases including schizophrenia and bipolar disorder differs from healthy individuals. Many environmental factors can change the composition of microbiota and therefore potentially contribute to the development of many disorders, including neuropsychiatric disorders.Summary: Microbiota is a potential factor contributing to the onset or modulating the course of many illnessis, including brain disorders The subject of imbalanced microbiota composition give hope for finding etiology or improving treatment of many disorders. However, it still requires more studies.

The Potential Role of Dysfunctions in Neuron-Microglia Communication in the Pathogenesis of Brain Disorders.

The bidirectional communication between neurons and microglia is fundamental for the proper functioning of the central nervous system (CNS). Chemokines and clusters of differentiation (CD) along with their receptors represent ligand-receptor signalling that is uniquely important for neuron – microglia communication. Among these molecules, CX3CL1 (fractalkine) and CD200 (OX-2 membrane glycoprotein) come to the fore because of their cell-type-specific localization. They are principally expressed by neurons when their receptors, CX3CR1 and CD200R, respectively, are predominantly present on the microglia, resulting in the specific axis which maintains the CNS homeostasis. Disruptions to this balance are suggested as contributors or even the basis for many neurological diseases.In this review, we discuss the roles of CX3CL1, CD200 and their receptors in both physiological and pathological processes within the CNS. We want to underline the critical involvement of these molecules in controlling neuron – microglia communication, noting that dysfunctions in their interactions constitute a key factor in severe neurological diseases, such as schizophrenia, depression and neurodegeneration-based conditions.

Gastrodin attenuates proliferation and inflammatory responses in activated microglia through Wnt/β-catenin signaling pathway

Microglia contribute to the regulation of neuroinflammation and play an important role in the pathogenesis of brain disorders. Thus, regulation of neuroinflammation triggered by activation of microglia has become a promising therapeutic strategy. Here, we investigated the beneficial effects of Gastrodin in activated microglia and analyzed the underlying molecular mechanisms. Microglia activation was regulated by Gastrodin not only in terms of microglia population size but also production of inflammatory mediators. Gastrodin inhibited the expression of inducible nitric oxide synthase (iNOS), tumor necrosis factor-α (TNF-α), cyclin-D1 and Ki67 in lipopolysaccharide (LPS)-stimulated BV-2 or primary microglia. Gastrodin also suppressed the expression of iNOS and Ki67 in activated microglia in three-day-old LPS-injected postnatal rats. In addition, the present results have shown that Gastrodin inhibited LPS-induced phosphorylation of glycogen synthase kinase-3β (GSK-3β) at Ser 9 and β-catenin activity. We further extended our investigation to determine whether Wnt/β-catenin signaling pathway was involved in the anti-inflammatory and anti-proliferation function of Gastrodin. β-Catenin antagonist (XAV939) was used to block LPS-mediated upregulation of iNOS, TNF-α, cyclin-D1, nitric oxide (NO) and the number of cells in the G2/M+S phase of cell cycle. Moreover, treatment with LiCl, a special Wnt/β-catenin pathway agonist significantly blocked Gastrodin-mediated down-regulation of iNOS, TNF-α, cyclin-D1, NO and the number of cells in the G2/M+S phase of cell cycle in LPS-stimulated BV-2 microglia. Taken together, the present results suggested that Gastrodin mediated anti-inflammatory and anti-proliferation effects in activated microglia by modulating the Wnt/β-catenin signaling pathway.

Maternal immune activation-induced PPARγ-dependent dysfunction of microglia associated with neurogenic impairment and aberrant postnatal behaviors in offspring

Maternal infection during pregnancy is an important factor involved in the pathogenesis of brain disorders in the offspring. Mounting evidence from maternal immune activation (MIA) animals indicates that microglial priming may contribute to neurodevelopmental abnormalities in the offspring. Because peroxisome proliferator-activated receptor gamma (PPARγ) activation exerts neuroprotective effects by regulating neuroinflammatory response, it is a pharmacological target for treating neurogenic disorders. We investigated the effect of PPARγ-dependent microglial activation on neurogenesis and consequent behavioral outcomes in male MIA-offspring. Pregnant dams on gestation day 18 received Poly(I:C) (1, 5, or 10 mg/kg; i.p.) or the vehicle. The MIA model that received 10 mg/kg Poly(I:C) showed significantly increased inflammatory responses in the maternal serum and fetal hippocampus, followed by cognitive deficits, which were highly correlated with hippocampal neurogenesis impairment in prepubertal male offspring. The microglial population in hippocampus increased, displayed decreased processes and larger soma, and had a higher expression of the CD11b, which is indicative of the M1 phenotype (classical activation). Activation of the PPARγ pathway by pioglitazone in the MIA offspring rescued the imbalance of the microglial activation and ameliorated the MIA-induced suppressed neurogenesis and cognitive impairments and anxiety behaviors. In an in vitro experiment, PPARγ-induced M2 microglia (alternative activation) promoted the proliferation and differentiation of neural precursor cells. These results indicated that the MIA-induced long-term changes in microglia phenotypes were associated with hippocampal neurogenesis and neurobehavioral abnormalities in offspring. Modulation of the microglial phenotypes was associated with a PPARγ-mediated neuroprotective mechanism in the MIA offspring and may serve as a potential therapeutic approach for prenatal immune activation-induced neuropsychiatric disorders.

Ropivacaine Protects against Memory Impairment and Hippocampal Damage in a Rat Neurodegeneration Model

Background: Ropivacaine, a long-acting amide local anesthetic agent, has been demonstrated to inhibit glutamatergic transmission. Glutamate neurotoxicity plays a pivotal role in the pathogenesis of brain disorders. The purpose of this study is to investigate the neuroprotective effect of ropivacaine against brain damage induced by kainic acid (KA), an analogue of glutamate. Methods: Rats were injected with ropivacaine (0.4 or 2 mg/kg, intraperitoneal) 30 min before KA treatment (15 mg/kg, intraperitoneal). KA-induced memory impairment was evaluated using the Morris water maze test. Extracellular hippocampal glutamate levels were assessed using high-performance liquid chromatography. Neuronal death was verified using Fluoro-Jade B and neutral red staining, and apoptosis was determined through terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL). Western blotting was conducted to assay the levels of activated (cleaved) caspase-3 and the phosphorylation of different mitogen-activated protein kinases (MAPKs). ­Results: Ropivacaine pretreatment effectively prevented KA-induced memory impairment. KA-induced elevations of ­glutamate release in rat hippocampi were inhibited by pretreatment with ropivacaine. Histopathological and TUNEL staining analyzes showed that ropivacaine inhibited KA-induced neuronal death and apoptosis in the hippocampal CA3 region. KA-induced caspase-3 activation and MAPKs phosphorylation in the hippocampus were also reduced by ropivacaine pretreatment. Conclusions: This study ­demonstrates that ropivacaine executes a protective action against KA-induced neuronal damage and apoptosis in vivo. Protective effects may be caused by glutamate level reduction, caspase-3 activation suppression, and MAPKs phosphorylation reduction. Our findings indicate that ropivacaine can benefit prevention or treatment of glutamate excitotoxicity-related neurodegenerative diseases.

The Blood-Brain Barrier and the EphR/Ephrin System: Perspectives on a Link Between Neurovascular and Neuropsychiatric Disorders.

Interactions among endothelial cells (EC) forming blood vessels and their surrounding cell types are essential to establish the blood-brain barrier (BBB), an integral part of the neurovascular unit (NVU). Research on the NVU has recently seen a renaissance to especially understand the neurobiology of vascular and brain pathologies and their frequently occurring comorbidities. Diverse signaling molecules activated in the near proximity of blood vessels trigger paracellular pathways which regulate the formation and stabilization of tight junctions (TJ) between EC and thereby influence BBB permeability. Among regulatory molecules, the erythropoietin-producing-hepatocellular carcinoma receptors (EphR) and their Eph receptor-interacting signals (ephrins) play a pivotal role in EC differentiation, angiogenesis and BBB integrity. Multiple EphR-ligand interactions between EC and other cell types influence different aspects of angiogenesis and BBB formation. Such interactions additionally control BBB sealing properties and thus the penetration of substances into the brain parenchyma. Thus, they play critical roles in the healthy brain and during the pathogenesis of brain disorders. In this mini-review article, we aim at integrating the constantly growing literature about the functional roles of the EphR/ephrin system for the development of the vascular system and the BBB and in the pathogenesis of neurovascular and neuropsychiatric disorders. We suggest the hypothesis that a disrupted EphR/ephrin signaling at the BBB might represent an underappreciated molecular hub of disease comorbidity. Finally, we propose the possibility that the EphR/ephrin system bears the potential of becoming a novel target for the development of alternative therapeutic treatments, focusing on such comorbidities.

Assessment of Blood-brain Barrier Permeability by Intravenous Infusion of FITC-labeled Albumin in a Mouse Model of Neurodegenerative Disease

Disruption of blood-brain barrier (BBB) integrity is a common feature for different neurological and neurodegenerative diseases. Although the interplay between perturbed BBB homeostasis and the pathogenesis of brain disorders needs further investigation, the development and validation of a reliable procedure to accurately detect BBB alterations may be crucial and represent a useful tool for potentially predicting disease progression and developing targeted therapeutic strategies. Here, we present an easy and efficient procedure for evaluating BBB leakage in a neurodegenerative condition like that occurring in a preclinical mouse model of Huntington disease, in which defects in the permeability of BBB are clearly detectable precociously in the disease. Specifically, the high molecular weight fluorescein isothiocyanate labelled (FITC)-albumin, which is able to cross the BBB only when the latter is impaired, is acutely infused into a mouse jugular vein and its distribution in the vascular or parenchymal districts is then determined by fluorescence microscopy. Accumulation of green fluorescent-albumin in the brain parenchyma functions as an index of aberrant BBB permeability and, when quantitated by using Image J processing software, is reported as Green Fluorescence Intensity.

Assessment of Blood-brain Barrier Permeability by Intravenous Infusion of FITC-labeled Albumin in a Mouse Model of Neurodegenerative Disease.

Disruption of blood-brain barrier (BBB) integrity is a common feature for different neurological and neurodegenerative diseases. Although the interplay between perturbed BBB homeostasis and the pathogenesis of brain disorders needs further investigation, the development and validation of a reliable procedure to accurately detect BBB alterations may be crucial and represent a useful tool for potentially predicting disease progression and developing targeted therapeutic strategies. Here, we present an easy and efficient procedure for evaluating BBB leakage in a neurodegenerative condition like that occurring in a preclinical mouse model of Huntington disease, in which defects in the permeability of BBB are clearly detectable precociously in the disease. Specifically, the high molecular weight fluorescein isothiocyanate labelled (FITC)-albumin, which is able to cross the BBB only when the latter is impaired, is acutely infused into a mouse jugular vein and its distribution in the vascular or parenchymal districts is then determined by fluorescence microscopy. Accumulation of green fluorescent-albumin in the brain parenchyma functions as an index of aberrant BBB permeability and, when quantitated by using Image J processing software, is reported as Green Fluorescence Intensity.

Angiographic evidence of proliferative retinopathy predicts neuropsychiatric morbidity in diabetic patients

IntroductionDiabetic retinopathy (DR) is a common vasculopathy categorized as either non-proliferative (NPDR) or proliferative (PDR),characterized by dysfunctional blood-retinal barrier (BRB) and diagnosed using fluorescein angiography (FA). Since the BRB is similar in structure and function to the blood-brain barrier (BBB) and BBB dysfunction plays a key role in the pathogenesis of brain disorders, we hypothesized that PDR, the severe form of DR, is likely to mirror BBB damage and to predict a worse neuropsychiatric outcome. MethodsA retrospective cohort study was conducted among subjects with diabetes (N=2982) with FA-confirmed NPDR (N=2606) or PDR (N=376). Incidence and probability to develop brain pathologies and mortality were investigated in a 10-year follow-up study. We used Kaplan–Meier, Cox and logistic regression analyses to examine association between DR severity and neuropsychiatric morbidity adjusting for confounders. ResultsPatients with PDR had significantly higher rates of all-cause brain pathologies (P<0.001), specifically stroke (P=0.005), epilepsy (P=0.006) and psychosis (P=0.024), and a shorter time to develop any neuropsychiatric event (P<0.001) or death (P=0.014) compared to NPDR. Cox adjusted hazard ratio for developing all-cause brain impairments was higher for PDR (HR=1.37, 95% CI 1.16–1.61, P<0.001) which was an independent predictor for all-cause brain impairments (OR 1.30, 95% CI 1.04–1.64, P=0.022), epilepsy (OR 2.16, 95% CI 1.05–4.41, P=0.035) and mortality (HR=1.35, 95% CI 1.06–1.70, P=0.014). ConclusionsThis is the first study to confirm that angiography-proven microvasculopathy identifies patients at high risk for neuropsychiatric morbidity and mortality.

The gray area between synapse structure and function—Gray's synapse types I and II revisited

On the basis of ultrastructural parameters, the concept was formulated that asymmetric Type I and symmetric Type II synapses are excitatory and inhibitory, respectively. This "functional Gray synapses concept" received strong support from the demonstration of the excitatory neurotransmitter glutamate in Type I synapses and of the inhibitory neurotransmitter γ-aminobutyric acid in Type II synapses, and is still frequently used in modern literature. However, morphological and functional evidence has accumulated that the concept is less tenable. Typical features of synapses like shape and size of presynaptic vesicles and synaptic cleft and presence of a postsynaptic density (PsD) do not always fit the postulated (excitatory/inhibitory) function of Gray's synapses. Furthermore, synapse function depends on postsynaptic receptors and associated signal transduction mechanisms rather than on presynaptic morphology and neurotransmitter type. Moreover, the notion that many synapses are difficult to classify as either asymmetric or symmetric has cast doubt on the assumption that the presence of a PsD is a sign of excitatory synaptic transmission. In view of the morphological similarities of the PsD in asymmetric synapses with membrane junctional structures such as the zonula adherens and the desmosome, asymmetric synapses may play a role as links between the postsynaptic and presynaptic membrane, thus ensuring long-term maintenance of interneuronal communication. Symmetric synapses, on the other hand, might be sites of transient communication as takes place during development, learning, memory formation, and pathogenesis of brain disorders. Confirmation of this idea might help to return the functional Gray synapse concept its central place in neuroscience.

Non-coding RNA as a trigger of neuropathologic disorder phenotypes in transgenic Drosophila

At most, many protein-misfolding diseases develop as environmentally induced sporadic disorders. Recent studies indicate that the dynamic interplay between a wide repertoire of noncoding RNAs and the environment play an important role in brain development and pathogenesis of brain disorders. To elucidate this new issue, novel animal models which reproduce the most prominent disease manifestations are required. For this, transgenic Drosophila strains were constructed to express small highly structured, non-coding RNA under control of a heat shock promoter. Expression of the RNA induced formation of intracellular aggregates revealed by Thioflafin T in embryonic cell culture and Congo Red in the brain of transgenic flies. Also, this strongly perturbed the brain control of locomotion monitored by the parameters of sound production and memory retention of young 5-day-old males. This novel model demonstrates that expression of non-coding RNA alone is sufficient to trigger neuropathology.

Small RNAs in Human Brain Development and Disorders

Small RNA is a variable and abundant type of non-coding RNAs in brain. The function of these RNAs is mainly unknown. A specific class of small RNA, microRNA, is dynamically regulated in neurogenesis and in embryo brain development. The genes for synaptic formation and some mental retardation disorders are putative targets for microRNA predicted by computational algorithms. The molecular pathways for mental development, common forms of autisms, schizophrenia, and affective disorders have yet to be elucidated. The hypothesis proposed here is that small regulatory RNAs, specifically microRNAs, play a role in human brain development and pathogenesis of brain disorders, especially of neurodevelopmental conditions. Pilot tests using comprehensive arrays of microRNAs demonstrate that microRNAs derived from postmortem human brains are applicable for microRNA expression profiling. The abundant expression of many regulatory small RNAs in human brain implies their biological role that must be tested by functional assays in neurons and by genetic and comparative expression profiling.

2 [ 18 F]F‐A85380: PET imaging of brain nicotinic acetylcholine receptors and whole body distribution in humans

Noninvasive imaging of nicotinic acetylcholine receptors (nAChRs) in the human brain in vivo is critical for elucidating the role of these receptors in normal brain function and in the pathogenesis of brain disorders. Here we report the first in vivo visualization of human brain areas containing nAChRs by using PET and 2-[18F]fluoro-3-(2(S)azetidinylmethoxy)pyridine (2-[18F]FA). We acquired scans from six healthy non-smoking volunteers after i.v. bolus administration of 2-[18F]FA (1.6 MBq/kg or 0.043 +/- 0.002 mCi/kg). This dose was sufficient for visualizing nAChRs in the thalamus up to 5 h after injection. There were no adverse effects associated with administration of no-carrier-added 2-[18F]FA (1.3-10 pmol/kg). Consistent with the distribution of nAChRs in human brain, accumulated radioactivity was greatest in thalamus, intermediate in the midbrain, pons, cerebellum, and cortex; and least in white matter. As approximately 90% of the injected radioactivity was eliminated via the urine (biological half-life ca. 4 h), the urinary bladder wall received the highest radiation dose. The estimate of radiation dose equivalent to the urinary bladder wall (ca. 180 +/- 30 mSv/MBq or 0.7 rem/mCi with a 2.4 h void interval) suggests that multiple studies could be performed in a single subject. The results predict that quantitative PET imaging of nAChRs in human brain with 2-[18F]FA is feasible.