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Study Objectives: The purpose of this study was to investigate the effects of neck myoclonus (NM) on sleep quality and daytime sleepiness in patients with narcolepsy (NT) and to further explore possible underlying mechanisms., Methods: We included 72 patients with narcolepsy type 1 (NT1), 34 patients with narcolepsy type 2 (NT2) and 33 healthy controls. Patients underwent questionnaires, lumbar puncture procedure, polysomnography, and multiple sleep latency test (MSLT). Healthy controls underwent polysomnography and questionnaires. Orexin-A levels in the cerebrospinal fluid (CSF) were analyzed by radioimmunoassay. Three catecholamines, including dopamine, norepinephrine and epinephrine, in the CSF were measured by high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS)., Results: Both the NT1 and NT2 groups displayed a higher level of NM incidence rate and index compared to the control group in PSG. NT1 displayed greater MSLT REM--NM incidence rate and index than NT2. NM were often associated with arousal or awakening and body movements, which had a prominent influence on sleep quality in both narcoleptic patients and controls. There was a positive correlation between the NM index and the Pittsburgh Sleep Quality Index (PSQI), Stanford Sleepiness Scale (SSS) and Ullanlinna Narcolepsy Scale (UNS) scores in NT1 patients. In MSLT of NT1 patients, REM-NM index were positively correlated with the CSF dopamine levels, and there were elevated dopamine levels but reduced orexin-A levels in patients with REM-NM., Conclusion: NM incidence rate and index were high in patients with narcolepsy, which had a huge effect on sleep quality and aggravated daytime sleepiness. NM should be considered pathological and viewed as a new sleep-related movement disorder. Orexin-A and dopamine may be involved in the development of NM., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

The synucleinopathies Parkinson disease (PD), multiple system atrophy (MSA), and the Lewy body form of pure autonomic failure (PAF) entail intra-cytoplasmic deposition of the protein alpha-synuclein and pathogenic catecholaminergic neurodegeneration. Cerebrospinal fluid (CSF) levels of catecholamines and their metabolites are thought to provide a "neurochemical window" on central catecholaminergic innervation and can identify specific intra-neuronal dysfunctions in synucleinopathies. We asked whether there are CSF concentration gradients for catechols such as 3,4-dihydroxyphenylacetic acid (DOPAC), the main neuronal metabolite of dopamine, and if so whether the gradients influence neurochemical differences among synucleinopathies. In a retrospective cohort study, we reviewed data about concentrations of catechols in the first, sixth, and twelfth 1-mL aliquots from 33 PD, 28 MSA, and 15 PAF patients and 41 controls. There were concentration gradients for DOPAC, dopamine, norepinephrine, and 3,4-dihydroxyphenylglycol (the main neuronal metabolite of norepinephrine) and gradients in the opposite direction for 5-S-cysteinyldopa and 5-S-cysteinyldopamine. In all 3 aliquots, CSF DOPAC was low in PD and MSA compared with controls (p < 0.0001 each) and normal in PAF. Synucleinopathies differ in CSF catechols regardless of concentration gradients. Concentration gradients for 5-S-cysteinyl derivatives in opposite directions from the parent catechols may provide biomarkers of spontaneous oxidation in the CSF space., (Published 2024. This article is a U.S. Government work and is in the public domain in the USA. Journal of Neurochemistry published by John Wiley & Sons Ltd on behalf of International Society for Neurochemistry.)

Background: Depression is known as the "mental cold" and is also considered a major cause of disability worldwide. It is estimated that over 300 million people worldwide suffer from severe depression, equivalent to 4.4% of the world's population. The monoamine hypothesis of depression predicts the underlying pathophysiological mechanisms of depression, but in-depth research has failed to find convincing evidence., Method: In this study, we will dynamically and strictly quantitatively monitor the concentration changes of monoamine transmitters in the cerebrospinal fluid (CSF) of macaques, based on our previous work. In the experiment, timed and quantitative collection of CSF samples from macaques was performed and the concentration of monoamine transmitters was determined., Result: The results showed that after 2 months of chronic stress, the concentrations of high vanillin acid (HVA) and 3,4-dihydroxy-phenylacetic acid were significantly higher in the maternal separation (MS) group, whereas there was no significant difference in dopamine and 5-hydroxyindoleacetic acid., Conclusion: This study is the first to observe the long-term dynamic relationship between early adversity, chronic stress, adolescent depression, and CSF monoamine concentrations. The research suggests that MS and chronic stress play an undeniable role in the pathogenesis of depression and that concentrations of HVA and dihydroxyphenylacetic acid are likely to serve as early markers of depressive-like symptoms in macaques., (© 2024 The Author(s). Brain and Behavior published by Wiley Periodicals LLC.)

Background: Potential biomarkers for neuropsychiatric disorders are cerebrospinal fluid (CSF) monoamines and their corresponding precursors and metabolites. During CSF sampling, CSF flows towards the lumbar sampling site from more cranial regions. To compare the results of studies in which different CSF volumes were acquired, it is important to know if ventricular-lumbar concentration gradients exist. This has only been addressed for a few biogenic amines, and almost exclusively in neurologically unwell patients due to the burden of a lumbar puncture (necessary to obtain CSF). The aim of our study was to determine if concentration gradients exist for routinely measured CSF constituents and biogenic amines in neurologically healthy patients. We applied a novel ultrasensitive liquid chromatography mass spectrometry (LC-MS/MS) method for the simultaneous quantification of multiple monoamines, precursors and metabolites in CSF and plasma., Methods: CSF and blood samples were collected from twenty neurologically healthy patients undergoing spinal anaesthesia. Ten mL of lumbar CSF was collected in five consecutive two mL fractions. We determined leucocyte and erythrocyte counts, glucose, albumin and protein concentrations and quantified monoamines, precursors and metabolites on each of the fractions using LC-MS/MS., Results: In twenty patients (60% male; median age: 46 years), dopamine, DOPAC, 3-MT, HVA, noradrenaline, normetanephrine and 5-HIAA concentrations increased from the first to the last CSF fraction (all p < 0.001). CSF adrenaline concentrations were below the detection limit, whereas serotonin measurements were regarded as unreliable. Albumin and total protein levels decreased significantly across CSF fractions., Conclusions: A ventricular-lumbar CSF concentration gradient existed for most of the investigated analytes. This is a novel finding for dopamine, noradrenaline, 3-MT and normetanephrine. These results contribute to the understanding of the neurobiology and underline the importance of standardized procedures for CSF handling to allow comparisons between studies., (© 2023. The Author(s).)

Cerebrospinal fluid-contacting (CSF-c) neurons line the central canal of the spinal cord and a subtype of CSF-c neurons expressing somatostatin, forms a homeostatic pH regulating system. Despite their importance, their intricate spatial organization is poorly understood. The function of another subtype of CSF-c neurons expressing dopamine is also investigated. Imaging methods with a high spatial resolution (5-10 nm) are used to resolve the synaptic and ciliary compartments of each individual cell in the spinal cord of the lamprey to elucidate their signalling pathways and to dissect the cellular organization. Here, light-sheet and expansion microscopy resolved the persistent ventral and lateral organization of dopamine- and somatostatin-expressing CSF-c neuronal subtypes. The density of somatostatin-containing dense-core vesicles, resolved by stimulated emission depletion microscopy, was shown to be markedly reduced upon each exposure to either alkaline or acidic pH and being part of a homeostatic response inhibiting movements. Their cilia symmetry was unravelled by stimulated emission depletion microscopy in expanded tissues as sensory with 9 + 0 microtubule duplets. The dopaminergic CSF-c neurons on the other hand have a motile cilium with the characteristic 9 + 2 duplets and are insensitive to pH changes. This novel experimental workflow elucidates the functional role of CSF-c neuron subtypes in situ paving the way for further spatial and functional cell-type classification., Competing Interests: EJ, JA, GC, SE, BR, SG No competing interests declared, IT Reviewing Editor, eLife, (© 2022, Jalalvand et al.)

An SU-8 probe with an array of nine, individually addressable gold microband electrodes (100 μm long, 4 μm wide, separated by 4-μm gaps) was photolithographically fabricated and characterized for detection of low concentrations of chemicals in confined spaces and in vivo studies of biological tissues. The probe's shank (6 mm long, 100 μm wide, 100 μm thick) is flexible, but exhibits sufficient sharpness and rigidity to be inserted into soft tissue. Laser micromachining was used to define probe geometry by spatially revealing the underlying sacrificial aluminum layer, which was then etched to free the probes from a silicon wafer. Perfusion with fluorescent nanobeads showed that, like a carbon fiber electrode, the probe produced no noticeable damage when inserted into rat brain, in contrast to damage from an inserted microdialysis probe. The individual addressability of the electrodes allows single and multiple electrode activation. Redox cycling is possible, where adjacent electrodes serve as generators (that oxidize or reduce molecules) and collectors (that do the opposite) to amplify signals of small concentrations without background subtraction. Information about electrochemical mechanisms and kinetics may also be obtained. Detection limits for potassium ferricyanide in potassium chloride electrolyte of 2.19, 1.25, and 2.08 μM and for dopamine in artificial cerebral spinal fluid of 1.94, 1.08, and 5.66 μM for generators alone and for generators and collectors during redox cycling, respectively, were obtained., (© 2021. Springer-Verlag GmbH Germany, part of Springer Nature.)

Repeated administration of psychostimulants, such as amphetamine, is associated with a progressive increased sensitivity to some of the drug's effects, but tolerance towards others. We hypothesized that these adaptations in part could be linked to differential effects by amphetamine on dopaminergic signaling in striatal subregions. To test this theory, acute and long-lasting changes in dopaminergic neurotransmission were assessed in the nucleus accumbens (nAc) and the dorsomedial striatum (DMS) following amphetamine exposure in Wistar rats. By means of in vivo microdialysis, dopamine release induced by local administration of amphetamine was monitored in nAc and DMS of amphetamine naïve rats, and in rats subjected to five days of systemic amphetamine administration (2.0 mg/kg/day) followed by two weeks of withdrawal. In parallel, ex vivo electrophysiology was conducted to outline the effect of acute and repeated amphetamine exposure on striatal neurotransmission. The data shows that amphetamine increases dopamine in a concentration-dependent and subregion-specific manner. Furthermore, repeated administration of amphetamine followed by abstinence resulted in a selective decrease in baseline dopamine in the nAc, and a potentiation of the relative dopamine elevation after systemic amphetamine in the same area. Ex vivo electrophysiology demonstrated decreased excitatory neurotransmission in brain slices from amphetamine-treated animals, and a nAc selective shift in the responsiveness to the dopamine D2-receptor agonist quinpirole. These selective effects on dopamine signaling seen in striatal subregions after repeated drug exposure may partially explain why tolerance develops to the rewarding effects, but not towards the psychosis inducing properties of amphetamine., (Copyright © 2021 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

The synucleinopathies Parkinson's disease (PD), multiple system atrophy (MSA), and pure autonomic failure (PAF) are characterized by intra-cytoplasmic deposition of the protein alpha-synuclein and by catecholamine depletion. PAF, which manifests with neurogenic orthostatic hypotension (nOH) and no motor signs of central neurodegeneration, can evolve into PD+nOH. The cerebrospinal fluid (CSF) levels of catecholamine metabolites may indicate central catecholamine deficiency in these synucleinopathies, but the literature is inconsistent and incomplete. In this retrospective cohort study we reviewed data about CSF catecholamines, the dopamine metabolites 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), and the norepinephrine metabolites 3,4-dihydroxyphenylglycol (DHPG) and 3-methoxy-4-hydroxyphenylglycol (MHPG). The compounds were measured in 36 patients with PD, 37 patients with MSA, and 19 patients with PAF and in 38 controls. Compared to the control group, the PD, MSA, and PAF groups had decreased CSF MHPG (p < .0001 each by Dunnett's post hoc test), DHPG (p = .004; p < .0001; p < .0001) and norepinephrine (p = .017; p = .0003; p = .044). CSF HVA and DOPAC were decreased in PD (p < .0001 each) and MSA (p < .0001 each) but not in PAF. The three synucleinopathies therefore have in common in vivo evidence of central noradrenergic deficiency but differ in the extents of central dopaminergic deficiency-prominent in PD and MSA, less apparent in PAF. Data from putamen 18 F-DOPA and cardiac 18 F-dopamine neuroimaging in the same patients, post-mortem tissue catecholamines in largely separate cohorts, and review of the neuropathology literature fit with these distinctions. The results suggest a 'norepinephrine first' ascending pathogenetic sequence in synucleinopathies, with degeneration of pontine locus ceruleus noradrenergic neurons preceding the loss of midbrain substantia nigra dopaminergic neurons., (© 2021 The Authors. This article is a U.S.Government work and is in the public domain in the USA.)

Background and Purpose: Ongoing neuropathic pain is one of the most challenging clinical problems which have detrimental effects on a patient's life quality. Conventional therapies for chronic neuropathic pain majorly includes centrally acting analgesics. Unfortunately, the unceasing use of these drugs results in adverse effects, such as CNS in-coordination, respiratory depression and substance use disorder. DALDA ([D-Arg 2 , Lys 4 ]-Dermorphin-(1-4)-amide), a peripherally acting opioid have been shown to possess potent analgesic activity without causing CNS toxicities in nerve-injured rats. However, the mechanism(s) underpinning DALDA induced-attenuation of ongoing neuropathic pain is yet to identify [1]., Experimental Design: In this study, we have measured the in-silico ligand-receptor binding affinity of DALDA against potential inflammatory targets by utilizing glide module of schrödinger software. Effect of DALDA on oxido-inflammatory stress was evaluated in LPS-induced C6 glial cells. In-vitro studies were followed by the behavioral assessments, where effect of DALDA was measured in chronic constriction injured rats. To examine the effect of DALDA on dopaminergic neurotransmission, cerebrospinal fluid of nerve-injured rats was assessed using LC-MS/QToF (Liquid Chromatography-Mass spectrometry/ Quadrapole time of flight Analyzer)., Results: DALDA has shown a good binding affinity with chemokine receptor type-2 (CCR2), chemokine CX3C receptor 1 (CX3CR1) and purinergic receptor (P2×4), major receptor subtypes involved in pain and inflammation. Findings from the in-vitro studies suggest that DALDA possesses potent anti-oxidant activity leading to inhibition of p38-MAPK pathway [1]. Moreover, the subcutaneous administration of DALDA leads to dose-dependent attenuation of thermal and mechanical hypersensitivity along with inhibition of neuroinflammatory mediators in serum and spinal cord of nerve-injured rats. Most importantly, DALDA treated neuropathic rats showed a preference for the DALDA-treated chamber, which was attenuated on pre-treatment with dopaminergic receptor antagonist, flupenthixol. LC-MS analysis further confirms the enhanced dopaminergic transmission in the brain of DALDA-treated neuropathic rats., Conclusion: Our findings suggest that DALDA mediated attenuation of ongoing neuropathic pain may be associated with a decrease in spinal neuroinflammatory signalling and subsequent increase in the brain dopamine level; may serve a potential therapeutic for the treatment of ongoing neuropathic pain., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Microglia as an important type of innate immune cell in the brain have been considered as an effective therapeutic target for the treatment of central nervous degenerative diseases. Herein, we report cell membrane coated novel biomimetic Cu 2- x Se-PVP-Qe nanoparticles (denoted as CSPQ@CM nanoparticles, where PVP is poly(vinylpyrrolidone), Qe is quercetin, and CM is the cell membrane of neuron cells) for effectively targeting and modulating microglia to treat Parkinson's disease (PD). The CSPQ nanoparticles exhibit multienzyme activities and could effectively scavenge the reactive oxygen species and promote the polarization of microglia into the anti-inflammatory M2-like phenotype to relieve neuroinflammation. We reveal that biomimetic CSPQ@CM nanoparticles targeted microglia through the specific interactions between the membrane surface vascular cells adhering to molecule-1 and α4β1 integrin expressed by microglia. They could significantly improve the symptoms of PD mice to result in an excellent therapeutic efficacy, as evidenced by the recovery of their dopamine level in cerebrospinal fluid, tyrosine hydroxylase, and ionized calcium binding adapter protein 1 to normal levels. Our work demonstrates the great potential of these robust biomimetic nanoparticles in the targeted treatment of PD and other central nervous degenerative diseases.

Importance: This study evaluated nilotinib safety and its effects on biomarkers as a potential disease-modifying drug in Parkinson disease., Objectives: To assess nilotinib effects on safety and pharmacokinetics and measure the change in exploratory biomarkers in patients with moderately severe Parkinson disease., Design, Setting, and Participants: This was a single-center, phase 2, randomized, double-blind, placebo-controlled trial with 300 patients approached in clinic; of these, 200 declined to participate, 100 were screened, 25 were excluded, and 75 were randomized 1:1:1 into placebo; nilotinib, 150-mg; or nilotinib, 300-mg groups. Recruitment started on May 17, 2017, and ended April 28, 2018, and follow-up ended August 10, 2019. Parkinson disease was confirmed according to the UK Brain Bank diagnostic criteria and symptoms were stabilized with use of optimal levodopa and/or dopamine agonists and other medications used in Parkinson disease., Interventions: Nilotinib vs placebo, administered orally once daily for 12 months followed by a 3-month washout period., Main Outcomes and Measures: It was hypothesized that nilotinib is safe and can be detected in the cerebrospinal fluid, where it alters exploratory biomarkers via inhibition of Abelson tyrosine kinase and potentially improves clinical outcomes., Results: Of the 75 patients included in the study, 55 were men (73.3%); mean (SD) age was 68.4 (8.2) years. Doses of 150 or 300 mg of nilotinib were reasonably safe, although more serious adverse events were detected in the nilotinib (150 mg: 6 [24%]; 300 mg: 12 [48%]) vs placebo (4 [16%]) groups. The 150-mg nilotinib group showed an increase in cerebrospinal fluid levels of the dopamine metabolites homovanillic acid (159.80nM; 90% CI, 7.04-312.60nM; P = .04) and 3,4-dihydroxyphenylacetic acid (4.87nM; 90% CI, 1.51-8.23nM; P = .01), and the 300-mg nilotinib group showed an increase in 3,4-dihydroxyphenylacetic acid (7.52nM; 90% CI, 2.35-12.69nM; P = .01). The nilotinib 150-mg but not the nilotinib 300-mg group demonstrated a reduction of α-synuclein oligomers (-0.04 pg/mL; 90% CI, -0.08 to 0.01 pg/mL; P = .03). A significant reduction of hyperphosphorylated tau levels was seen in the nilotinib 150-mg (-10.04 pg/mL; 90% CI, -17.41 to -2.67 pg/mL; P = .01) and nilotinib 300-mg (-12.05 pg/mL; 90% CI, -19.21 to -4.90 pg/mL; P = .01) groups., Conclusions and Relevance: In this study, nilotinib appeared to be reasonably safe and detectable in the cerebrospinal fluid. Exploratory biomarkers were altered in response to nilotinib. Taken together, these data will guide the development of a phase 3 study to investigate the effects of nilotinib therapy in patients with Parkinson disease., Trial Registration: ClinicalTrials.gov identifier: NCT02954978.

Dopamine (DA), as one of the central neurotransmitters, plays an important role in many physiological and pathological processes. Detection of DA is critical to diagnose and monitor some neurological diseases. In this work, a novel on-off ratiometric electrochemical sensor with molecularly imprinted polymers (MIPs) as target molecule recognizer has been developed for selective and accurate detection of DA. Nanoporous gold (NPG) was electrodeposited on bare gold electrode, which not only benefited the output signal amplification, but also provided enlarged surface for immobilization of polythionine (pThi) and MIPs. Oxidation of DA and pThi served as response signal and internal reference signal, respectively. The oxidation peak currents of DA at +0.12 V increased with increasing the concentration of DA, while the peak currents of pThi at -0.2 V decreased simultaneously. Due to the specificity from MIPs and the built-in correction from pThi, the fabricated sensor showed excellent performance in view of selectivity and reproducibility. It's worth to mention that even if the surface area and morphology of working electrode underwent huge variation deliberately, the assay deviation among these ratiometric sensors was largely reduced around 10 times. The proposed sensor demonstrated a broad dynamic range of 0.3-100 μM, as well as a low detection limit of 0.1 μM (S/N = 3). Moreover, superior anti-interfering ability toward DA detection was obtained despite the presence of interferents at high concentration in artificial cerebrospinal fluid (aCSF). Therefore, this work is expected to provide an alternative pathway for constructing ratiometric electrochemical sensor and offer reliable determination of small molecules with high selectivity and stability., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Surface plasmon resonance (SPR) based dopamine sensor is realized using the state-of-art technique of molecular imprinting over an optical fiber substrate. Polypyrrole (PPy) is depicted as an effective polymer for the imprinting of dopamine through a green synthesis approach. Sensitivity of the probe is enhanced by the augmenting effect of surface imprinting of dopamine in polypyrrole over multiwalled carbon nanotubes (MWCNTs). To ensure the permselectivity of the probe towards dopamine molecules, a cation exchange polymer, nafion, is utilized as a membrane over imprinted sites to reduce the interference from anionic analytes like ascorbic acid and uric acid at physiological pH. The probe is characterized for a wide range of dopamine concentration from 0 to 10 -5 M in artificial cerebrospinal fluid. Various probe parameters are varied to maximize the sensitivity of the sensor. The sensor possesses 18.9 pM as the limit of detection (LOD) which is lowest of those reported in the literature. The manifestation of sensing probe over an optical fiber along with the improved LOD makes the approach highly advantageous in terms of stability, repeatability, online remote monitoring, fast response, and miniaturization for its in vivo/in vitro applications in clinical sensing of dopamine., (Copyright © 2019 Elsevier B.V. All rights reserved.)

The authors describe an electrochemical dopamine sensor that is based on the use of electrochemically co-reduced graphene oxide (Er-GO) and gold nanoparticles (AuNPs) on an indium-tin oxide (ITO) electrode. The synergistic effects of Er-GO and Er-AuNPs promote electron transport in the modified ITO. This results in an excellent performance for voltammetric sensing of dopamine (DA). Under the optimum conditions and a typical working potential of -0.05 V (vs. Ag/AgCl), the ITO electrode has a linear response in the 0.02-200 μM DA concentration range and a low detection limit of 15 nM. The sensor also showed a good selectivity over ascorbic acid and uric acid. The feasibility of the method was studied by analyzing DA in cerebrospinal fluid of rats. Graphical abstract Schematic presentation of one-step electrochemical co-reduction of graphene oxide (GO) and gold nanoparticles (AuNPs) on an ITO electrode for voltammetric sensing of dopamine.

Non-human primates have become one of the most important model animals for the investigation of brain diseases because they share a wide-range of genetics and social similarities with human beings. Naturally-evoked depression models in macaques may offer a full spectrum of similarity to human depression states, but they require validation and corroboration of specific phenotypes to depression-associated states before they can be used in research into more effective interventions. It is reported here that depressed cynomolgus monkeys developed in the natural condition display higher levels of typical depressive-like huddling behavior than healthy monkeys. Moreover, these depressed macaques presented other key phenotypes linked to depression, including low levels of cerebrospinal fluid monoamine neurotransmitters and their metabolites, increased passive states, reduced positive behaviors and disrupted nocturnal sleep. When subjected to an acute subanesthetic dose of ketamine, the depressed monkeys responded substantially in rapid and sustained antidepressant-like ways, which demonstrated decreased huddling behavior, an elevated interest in exploration activities and sleep improvement. Taken together, this naturally-evoked depression monkey model was systematically validated for ecological, face, construct and predictive validities. This model will serve as a qualified platform for studying depression in the future., (Copyright © 2018. Published by Elsevier B.V.)

Huntington's disease (HD) is a severe neurological disease leading to psychiatric symptoms, motor impairment and cognitive decline. The disease is caused by a CAG expansion in the huntingtin (HTT) gene, but how this translates into the clinical phenotype of HD remains elusive. Using liquid chromatography mass spectrometry, we analyzed the metabolome of cerebrospinal fluid (CSF) from premanifest and manifest HD subjects as well as control subjects. Inter-group differences revealed that the tyrosine metabolism, including tyrosine, thyroxine, L-DOPA and dopamine, was significantly altered in manifest compared with premanifest HD. These metabolites demonstrated moderate to strong associations to measures of disease severity and symptoms. Thyroxine and dopamine also correlated with the five year risk of onset in premanifest HD subjects. The phenylalanine and the purine metabolisms were also significantly altered, but associated less to disease severity. Decreased levels of lumichrome were commonly found in mutated HTT carriers and the levels correlated with the five year risk of disease onset in premanifest carriers. These biochemical findings demonstrates that the CSF metabolome can be used to characterize molecular pathogenesis occurring in HD, which may be essential for future development of novel HD therapies.

Dopamine (DA), a catecholamine neurotransmitter, is considered to be an important indicator for mental diseases detection in the clinic. In this study, a novel fluorescent sensing platform consisting of the ficin-H 2 O 2 -tyramine system for determining DA in cerebrospinal fluids (CSF) was established. The proposed method is based on the fact that ficin, a mimetic peroxidase, can catalyze H 2 O 2 decomposition into OH radicals, which can oxidize non-fluorescent tyramine into fluorescent dityramine. When DA was introduced, DA can compete with tyramine for OH and resulting in the oxidation reaction of tyramine inhibited along with the fluorescence intensity of the system decreased, which provides a unique strategy for fluorescence detection of DA. Under optimal conditions, the fluorescence intensity decreased linearly with the DA level over a wide concentration range from 0.05 to 12.0 μM (R 2  = 0.995) with a detection limit of 46 nM (3σ/k). More importantly, the proposed sensing approach exhibits high sensitivity, good selectivity and has been successfully applied to DA sensing in complex biological samples, which made it hold great potential for DA determination in chemical and biological analytical applications., (Copyright © 2018 Elsevier B.V. All rights reserved.)

In vivo monitoring of the neurotransmitter dopamine can potentially improve the diagnosis of neurological disorders and elucidate their underlying biochemical mechanisms. While electrochemical sensors can detect unlabeled dopamine molecules, their sensing performance is dramatically reduced by electrochemical currents generated by other, interfering molecules (e.g., uric acid) in the biological environment. To overcome this caveat, the surface of the sensor is often modified with electrocatalytic materials, which are encapsulated inside a polymeric film; however, the effect of the encapsulating film on the sensing performance of the electrode has not been systematically studied. This study characterizes the effect of loading carbon nanotubes (CNTs) onto a chitosan film on the electrochemical sensing performance of dopamine in the presence of uric acid. Higher CNT loading increases the diffusion and electron transfer rate coefficients of the sensor and, in the presence of uric acid, provides better sensitivity (3.00µALµmol -1 for 1.75% CNT loading, vs 0.01µALµmol -1 for 1% loading) but a poorer limit-of-detection (2.00µmolL -1 vs 1.00, respectively), as reported here for the first time. These findings can help optimize the sensitivity and the limit-of-detection of electrochemical sensors in complex biofluids to enable an in vivo monitoring of dopamine and other redox-active molecules., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Background: Consistent with nigrostriatal dopamine depletion, low cerebrospinal fluid (CSF) concentrations of 3,4-dihydroxyphenylacetic acid (DOPAC), the main neuronal metabolite of dopamine, characterize Parkinson's disease (PD) even in recently diagnosed patients. Whether low CSF levels of DOPAC or DOPA, the precursor of dopamine, identify pre-clinical PD in at-risk healthy individuals has been unknown., Methods: Participants in the intramural NINDS PDRisk study entered information about family history of PD, olfactory dysfunction, dream enactment behavior, and orthostatic hypotension at a protocol-specific website. After at least 3 risk factors were confirmed by on-site screening, 26 subjects had CSF sampled for levels of catechols and were followed for at least 3 years., Results: Of 26 PDRisk subjects, 4 were diagnosed with PD (Pre-Clinical PD group); 22 risk-matched (mean 3.2 risk factors) subjects remained disease-free after a median of 3.7 years (No-PD group). The Pre-Clinical PD group had lower initial DOPA and DOPAC levels than did the No-PD group (p = 0.0302, p = 0.0190). All 3 subjects with both low DOPA (<2.63 pmol/mL) and low DOPAC (<1.22 pmol/mL) levels, based on optimum cut-off points using the minimum distance method, developed PD, whereas none of 14 subjects with both normal DOPA and DOPAC levels did so (75% sensitivity at 100% specificity, p = 0.0015 by 2-tailed Fisher's exact test)., Conclusions: In people with multiple PD risk factors, those with low CSF DOPA and low CSF DOPAC levels develop clinical disease during follow-up. We suggest that neurochemical biomarkers of central dopamine deficiency identify the disease in a pre-clinical phase., (Published by Elsevier Ltd.)

It is a challenge to develop a robust sensor for simple, rapid operation and sensitive detection of neurotransmitters in complex specimens. Herein, ferric citrate functionalized gold nanoparticles (CA-Fe III /Au NPs) are utilized to develop a facile sensor based on surface-enhanced resonance Raman spectroscopy (SERRS) for sensitive detection of dopamine (DA). The sensor is prepared by decorating the acupuncture needle with Au NPs, which enables sufficient surface-enhanced Raman spectroscopy enhancement. The CA-Fe III structure is highly sensitive and selective for DA due to the formation of the CA-Fe III -DA resonant structure; this indicates the advantages of capturing, carrying, and separating DA molecules from complicated samples in a simple operation. Furthermore, the practical application of the fabricated sensor is validated by the detection of DA in pretreated serum and cerebrospinal fluid of acupuncture-treated mice with detection limits of 0.1 and 2.5 nm DA, respectively. The developed active acupuncture needle sensor has potential benefits for sensitive detection and qualitative identification of DA molecules from biological samples., (© 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Levodopa (l-DOPA, l-3,4-dihydroxyphenylalanine) is the most effective drug in the symptomatic treatment of Parkinson's disease (PD), but chronic use initiates a maladaptive process leading to l-DOPA-induced dyskinesia (LID). Risk factors for early onset LID include younger age, more severe disease at baseline and higher daily l-DOPA dose, but biomarkers to predict the risk of motor complications are not yet available. Here, we investigated whether CSF levels of catecholamines and its metabolites are altered in PD patients with LID [PD-LID, n = 8)] as compared to non-dyskinetic PD patients receiving l-DOPA (PD-L, n = 6), or not receiving l-DOPA (PD-N, n = 7) as well as non-PD controls (n = 16). PD patients were clinically assessed using the Unified Parkinson's Disease Rating Scale and Unified Dyskinesia Rating Scale and CSF was collected after overnight fasting and 1-2 h after oral intake of l-DOPA or other anti-Parkinson medication. CSF catecholamines and its metabolites were analyzed by HPLC with electrochemical detection. We observed (i) decreased levels of dihydroxyphenylacetic acid (DOPAC) and homovanillic acid in PD patients not receiving l-DOPA (ii) higher dopamine (DA) levels in PD-LID as compared to controls (iii) higher DA/l-DOPA and lower DOPAC/DA ratio's in PD-LID as compared to PD-L and (iv) an age-dependent increase of DA and decrease of DOPAC/DA ratio in controls. These results suggest increased DA release from non-DA cells and deficient DA re-uptake in PD-LID. Monitoring DA and DOPAC in CSF of l-DOPA-treated PD patients may help identify patients at risk of developing LID., (© 2017 International Society for Neurochemistry.)

We showed previously that higher levels in CSF dopamine in HIV patients are associated with the presence of the dopamine transporter (DAT) 10/10-repeat allele which was also detected more frequently in HIV-infected individuals compared to uninfected subjects. In the current study, we investigated further whether other genetic dopamine (DA)-related polymorphisms may be related with changes in CSF DA levels and frequency of HIV infection in HIV-infected subjects. Specifically, we studied genetic polymorphisms of brain-derived neurotrophic factor, catechol-O-methyltransferase, and dopamine receptors DRD2, DRD3, and DRD4 genetic polymorphisms in uninfected and HIV-infected people in two different ethnical groups, a German cohort (Caucasian, 72 individuals with HIV infection and 22 individuals without HIV infection) and a South African cohort (Xhosan, 54 individuals with HIV infection and 19 individuals without HIV infection). We correlated the polymorphisms with CSF DA levels, HIV dementia score, CD4 + T cell counts, and HIV viral load. None of the investigated DA-related polymorphisms was associated with altered CSF DA levels, CD4 + T cell count, viral load, and HIV dementia score. The respective allele frequencies were equally distributed between HIV-infected patients and controls. Our findings do not show any influence of the studied genetic polymorphisms on CSF DA levels and HIV infection. This is in contrast to what we found previously for the DAT 3'UTR VNTR and highlights the specific role of the DAT VNTR in HIV infection and disease.

Since the last two decades, protein conjugated fluorescent gold nanoclusters (NCs) owe much attention in the field of medical and nanobiotechnology due to their excellent photo stability characteristics. In this paper, we reported stable, nontoxic and red fluorescent emission BSA-Au NCs for selective detection of L-dopamine (DA) in cerebrospinal fluid (CSF). The evolution was probed by various instrumental techniques such as UV-vis spectroscopy, High resolution transmission electron microscopy (HTEM), X-ray photoelectron spectroscopy (XPS), X-ray diffraction (XRD), Fourier transform infrared spectroscopy (FTIR), photoluminescence spectroscopy (PL). The synthesised BSA-Au NCs were showing 4-6 nm with high fluorescent ~8% Quantum yield (QY). The fluorescence intensity of BSA-Au NCs was quenched upon the addition of various concentrations of DA via an electron transfer mechanism. The decrease in BSA-Au NCs fluorescence intensity made it possible to determine DA in PBS buffer and the spiked DA in CSF in the linear range from 0 to 10 nM with the limit of detection (LOD) 0.622 and 0.830 nM respectively. Best of our knowledge, as-prepared BSA-Au NCs will gain possible strategy and good platform for biosensor, drug discovery, and rapid disease diagnosis such as Parkinson's and Alzheimer diseases.

Methamphetamine (MA) is an illicit psychostimulant that stimulates the release of catecholamines from sympathetic nerve terminals and is widely abused worldwide. Since catechol-O-methyltransferase (COMT) metabolizes catecholamines and mediates adrenergic, noradrenergic, and dopaminergic signaling responses, we investigated the effects of the COMT polymorphisms rs4633 and rs4680 on cerebrospinal fluid (CSF) catecholamine concentrations in autopsies of subjects who died of drug intoxication. 28 MA abusers and 22 fatal psychotropic drug intoxication cases were evaluated. No correlations were identified between rs4633 or rs4680 polymorphisms and CSF concentrations of adrenaline (Adr), noradrenaline (Nad), or dopamine (DA) in fatal psychotropic cases. However, among MA abusers, DA concentrations in the CSF were significantly higher in those with the T allele (CT and TT) of rs4633 than in CC genotype carriers (p=0.004). Moreover, among MA abusers, DA concentrations were significantly higher in those with the A allele (GA and AA) of rs4680 than in GG genotype carriers (p=0.017). In subsequent haplotype analyses of MA abusers, a strong correlation was identified between two COMT haplotypes and CSF DA concentrations (p=0.002). However, the CSF concentrations of Adr and Nad were not associated with COMT genotypes or haplotypes. The present results indicate that rs4633 and rs4680 polymorphisms influence CSF DA concentrations and MA toxicity in MA abusers., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Aims: Bladder dysfunction is frequent during the course of multiple sclerosis (MS), observed in up to 75% of patients. Urinary symptomatology can be a feature of the first episode of MS in a minority of cases, and most often shows characteristics of an overactive bladder (OAB), with voiding symptoms seen less frequently, often in combination with OAB. The neural control of micturition is complex, involving systems located in the brain, spinal cord, and periphery, and implicating central noradrenergic, serotonergic, and dopaminergic activities. Urinary disorders are also linked to anxiety and depression, conditions connected to hypothalamus-pituitary-adrenal axis activity. In this study we aimed to investigate neurochemical and neuroendocrine correlates of bladder dysfunction in early MS., Methods: We included 101 patients at first demyelinating episode suggestive of MS that were drug-free at assessment. We evaluated the presence of urinary symptomatology and estimated CSF levels of the main metabolites of noradrenaline, serotonin, and dopamine, as well CSF-ACTH and serum cortisol., Results: In total, 15 patients (15%) reported urinary dysfunction suggestive of OAB. Four of these had coexistent voiding symptomatology. The serotonin metabolite 5-HIAA was significantly reduced (P = 0.017) in patients with OAB syndrome, while there were no differences in the metabolites of noradrenaline (MHPG) and of dopamine (HVA). Additionally, significantly lower serum cortisol (P = 0.009) and borderline lower CSF-ACTH (P = 0.08) were found in patients with OAB., Conclusions: MS patients with OAB syndrome at the first demyelinating episode show reductions in central serotonergic activity and stress hormones. Whether the same changes persist at later disease stages remains to be investigated. Neurourol. Urodynam. 35:955-958, 2016. © 2015 Wiley Periodicals, Inc., (© 2015 Wiley Periodicals, Inc.)

A composite electrode with a sandwich structure combining the properties of silver nanoparticles and a titania photoactive layer was used for the electroanalytical detection, by differential pulse voltammetry, of three neurotransmitters: dopamine, norepinephrine, and serotonin. The three analytes were determined at low detection limits (around 0.03 μM) also in the presence of conventional interferents, such as uric and ascorbic acids. The fouling of the electrode surface was overcome by irradiating the device with UVA light, restoring the initial sensor sensitivity. Dopamine, norepinephrine, and serotonin were determined also in simulated biological matrices: liquor (artificially reproduced cerebrospinal fluid) and serum. Moreover, the contemporaneous detection of dopamine and norepinephrine in simulated human urine solutions was also demonstrated, representing the first step towards clinical applications of the proposed methodology. Graphical abstract The photo-renewable electroanalytical sensor.

Introduction: There is intense interest in identifying cerebrospinal fluid (CSF) biomarkers of Parkinson's disease (PD), both for early diagnosis and to track effects of putative treatments. Nigrostriatal dopamine depletion characterizes PD. Predictably, CSF levels of 3,4-dihydroxyphenylacetic acid (DOPAC), the main neuronal metabolite of dopamine, are decreased in PD, even in patients with recent onset of the movement disorder. Whether low CSF DOPAC is associated specifically with parkinsonism has been unclear. In the neuronal cytoplasm dopamine undergoes not only enzymatic oxidation to form DOPAC but also spontaneous oxidation to form 5-S-cysteinyl-dopamine (Cys-DA). Theoretically, oxidative stress or decreased activity of aldehyde dehydrogenase (ALDH) in the residual nigrostriatal dopaminergic neurons would increase CSF Cys-DA levels with respect to DOPAC levels. PD, parkinsonian multiple system atrophy (MSA-P), and pure autonomic failure (PAF) are synucleinopathies; however, PAF does not entail parkinsonism. We examined whether an elevated Cys-DA/DOPAC ratio provides a specific biomarker of parkinsonism in synucleinopathy patients., Methods: CSF catechols were assayed in PD (n = 24), MSA-P (n = 32), PAF (n = 18), and control subjects (n = 32)., Results: Compared to controls, CSF DOPAC was decreased in PD and MSA-P (p < 0.0001 each). In both diseases Cys-DA/DOPAC ratios averaged more than twice control (0.14 ± 0.02 and 0.13 ± 0.02 vs. 0.05 ± 0.01, p < 0.0001 each), whereas in PAF the mean Cys-DA/DOPAC ratio was normal (0.05 ± 0.01)., Conclusions: CSF Cys-DA/DOPAC ratios are substantially increased in PD and MSA-P and are normal in PAF. Thus, in synucleinopathies an elevated CSF Cys-DA/DOPAC ratio seems to provide a specific biomarker of parkinsonism., (Published by Elsevier Ltd.)

Objectives: To investigate the demographic features, clinical features, and potential mechanism in patients with Parkinson disease (PD) with pure apathy., Method: A total of 145 patients with PD without depression and dementia and 30 age-matched controls were consecutively recruited. Patients with PD were evaluated by Apathy Scale (AS), scales for motor symptoms and quality of life. The levels of iron, oxidative and neuroinflammatory factors, α-synuclein oligomer, and dopamine in cerebrospinal fluid (CSF) from patients with PD and controls were detected by enzyme-linked immunosorbent assay, chemical colorimetric method, and high-performance liquid chromatography. Comparisons between PD with pure apathy and with no pure apathy groups and correlation between AS score and the levels of above factors were analyzed., Results: There were 64 (44.14%) cases in PD-apathy group. The PD-apathy group had older age, (97.81 ± 10.82) years versus (61.86 ± 10.80) years, and severer quality of life (P < .05). The PD-apathy and PD without apathy groups presented no remarkable differences in motor symptoms (P > .05). The levels of iron, hydroxyl radical (·OH), hydrogen peroxide (H2O2), and α-synuclein oligomer in CSF in PD-apathy group were significantly higher than that in PD without the apathy group (P < .05). In patients with PD, the AS score was positively correlated with the levels of iron, ·OH, H2O2 and α-synuclein oligomer in CSF (r = 19.838, .063, 1.046, and 0.498, respectively, P < .05). In PD-apathy group, iron level was positively correlated with ·OH level (r = .011, P < .05), and H2O2 level was positively correlated with α-synuclein oligomer level in CSF (r = .045, P < .05)., Conclusion: Patients with PD had high prevalence of pure apathy. Patients with PD having pure apathy had older age. Pure apathy reduced quality of life for patients without worsening motor function. Excessive iron and α-synuclein oligomer in brain commonly contributed to pure apathy of PD through potential mechanism of oxidative stress., (© The Author(s) 2016.)

Flow-gated capillary electrophoresis (CE) coupled with microdialysis has become an important tool for in vivo bioanalytical measurements because it is capable of performing rapid and efficient separations of complex biological mixtures thus enabling high temporal resolution in chemical monitoring. However, the limit of detection (LOD) is often limited to a micro- or nano-molar range while many important target analytes have picomolar or sub-nanomolar levels in brain and other tissues. To enhance the capability of flow-gated CE for catecholamine detection, a novel and simple on-line sample preconcentration method was developed exclusively for fluorescent derivatives of catecholamines that were fluorogenically derivatized with naphthalene-2,3-dicarboxaldehyde (NDA) in the presence of cyanide. The effective preconcentration coupled with the sensitive laser-induced fluorescence (LIF) detection lowered the LOD down to 20pM for norepinephrine (NE) and 50pM for dopamine (DA) at 3-fold of S/N ratio, and the signal enhancement was estimated to be over 100-fold relative to normal injection when standard analytes were dissolved in artificial cerebrospinal fluid (aCSF). The basic focusing principle is novel since the sample plug contains borate while the background electrolyte (BGE) is void of borate. This strategy took advantage of the complexation between diols and borate, through which one negative charge was added to the complex entity. The sample derivatization mixture was electrokinetically injected into a capillary via the flow-gated injection, and then NE and DA derivatives were selectively focused to a narrow zone by the reversible complexation. Separation of NE and DA derivatives was executed by incoming surfactants of cholate and deoxycholate mixed in the front BGE plug. This on-line preconcentration method was finally applied to the detection of DA in rat cerebrospinal fluid (CSF) via microdialysis and on-line derivatization. It is anticipated that the method would be valuable for in vivo monitoring of DA and NE in various brain regions of live animals on flow-gated CE or microchip platforms., (Published by Elsevier B.V.)

The role of the monoamines dopamine (DA) and serotonin (5HT) and the monoamine-metabolizing enzyme monoamine oxidase A (MAOA) have been repeatedly implicated in studies of alcohol use and dependence. Genetic investigations of MAOA have yielded conflicting associations between a common polymorphism (MAOA-LPR) and risk for alcohol abuse. The present study provides direct comparison of tissue-specific MAOA expression and the level of alcohol consumption. We analyzed rhesus macaque MAOA (rhMAOA) expression in blood from males before and after 12 months of alcohol self-administration. In addition, nucleus accumbens core (NAc core) and cerebrospinal fluid (CSF) were collected from alcohol access and control (no alcohol access) subjects at the 12-month time point for comparison. The rhMAOA expression level in the blood of alcohol-naive subjects was negatively correlated with subsequent alcohol consumption level. The mRNA expression was independent of rhMAOA-LPR genotype and global promoter methylation. After 12 months of alcohol use, blood rhMAOA expression had decreased in an alcohol dose-dependent manner. Also after 12 months, rhMAOA expression in the NAc core was significantly lower in the heavy drinkers, as compared with control subjects. The CSF measured higher levels of DA and lower DOPAC/DA ratios among the heavy drinkers at the same time point. These results provide novel evidence that blood MAOA expression predicts alcohol consumption and that heavy alcohol use is linked to low MAOA expression in both the blood and NAc core. Together, the findings suggest a mechanistic link between dampened MAOA expression, elevated DA and alcohol abuse.

Objective: To investigate whether propiverine has a noradrenaline re-uptake inhibitor and whether it acts on the lumbosacral cord or the urethral wall. In addition, we aimed to examine the effect of propiverine on leak point pressure in rats., Methods: A total of 72 female and 30 male rats were used to examine the following: (i) the change of leak point pressure caused by intravenous agents in rats with vaginal distention; (ii) the change of leak point pressure caused by intrathecal agents in rats with vaginal distention; (iii) the noradrenaline re-uptake inhibitor action of propiverine; and (iv) catecholamine levels in the bladder wall, urethral wall, cerebrospinal fluid and plasma after oral administration of propiverine., Results: Intravenous injection of propiverine, imipramine and duloxetine increased the leak point pressure in rats with vaginal distention. Intrathecal naftopidil decreased the leak point pressure, whereas subsequent intravenous propiverine restored the leak point pressure to the level before intrathecal naftopidil in rats with vaginal distention. Propiverine acted like a noradrenaline re-uptake inhibitor, increasing noradrenaline and/or dopamine levels in the plasma, cerebrospinal fluid, and urethral wall perfusion fluid., Conclusion: Propiverine inhibits noradrenaline re-uptake, as well as having antimuscarinic and Ca-antagonist actions. The inhibition of noradrenaline re-uptake by propiverine mainly occurs at the urethral level and partially in the central nervous system, and might stimulate the smooth muscle of the bladder neck and proximal urethra through α1-adrenergic receptors, as well as stimulating the striated muscle of the urethra and pelvic floor by activation of spinal motoneurons. Therefore, propiverine might be effective for both stress and urge incontinence., (© 2015 The Japanese Urological Association.)

Metabolites of cerebrospinal biogenic amines (dopamine and serotonin)are an important tool in clinical research and diagnosis of children with neurotransmitter disorders. In this article we focused on finding relationships between the concentration of biogenic amine metabolites, age, and gender. We analyzed 148 samples from children with drug resistant seizures of unknown etiology and children with mild stable encephalopathy aged 0-18 years. A normal profile of biogenic amineswas found in 107 children and those children were enrolled to the study group. The CSF samples were analyzed by HPLC with an electrochemical detector. The concentrations of the dopamine and serotonin metabolites homovanillic acid (HVA) and 5-hydroxyindoleacetic acid (5-HIAA), respectively, were high at birth, gradually decreasing afterward until the 18 years of age. Nevertheless, the HVA/5-HIAA ratio did not vary with age, except in the children below 1 year of age. In the youngest group we observed a strong relationship between the HVA/5-HIAA ratio and age (r = 0.69, p < 0.001). There were no statistical differences in the level of both dopamine and serotonin metabolites between boys and girls, although a tread toward lower HVA and 5-HIAA in the boys was noticeable. Significant inter-gender differences in the level of HVA and 5-HIAA were noted only in the age-group of 1-4 years, with 5-HIAA being higher in the girls than boys (p = 0.004). In conclusion, the study revealed that the concentration of biogenic amine metabolites is age and sex dependent.

Glutamate-related genes have been associated with schizophrenia, but the results have been ambiguous and difficult to replicate. Homovanillic acid (HVA), 5-hydroxyindoleacetic acid (5-HIAA) and 3-methoxy-4-hydroxyphenylglycol (MHPG) are the major degradation products of the monoamines dopamine, serotonin and noradrenaline, respectively, and their concentrations in the cerebrospinal fluid (CSF), mainly HVA, have been associated with schizophrenia. In the present study, we hypothesized that CSF HVA, 5-HIAA and MHPG concentrations represent intermediate phenotypes in the association between glutamate-related genes and psychosis. To test this hypothesis, we searched for association between 238 single nucleotide polymorphisms (SNPs) in ten genes shown to be directly or indirectly implicated in glutamate transmission and CSF HVA, 5-HIAA and MHPG concentrations in 74 patients with psychotic disease. Thirty-eight nominally significant associations were found. Further analyses in 111 healthy controls showed that 87% of the nominal associations were restricted to the patients with psychosis. Some of the psychosis-only-associated SNPs found in the d-amino acid oxidase activator (DAOA) and the kynurenine 3-monooxygenase (KMO) genes have previously been reported to be associated with schizophrenia. The present results suggest that CSF monoamine metabolite concentrations may represent intermediate phenotypes in the association between glutamate-related genes and psychosis., (Copyright © 2015 The Authors. Published by Elsevier Ireland Ltd.. All rights reserved.)

We report a new NMR relaxation time-based method for sensitive and selective dopamine detection using paramagnetic nanoparticles. The Fe(3+) species in the nanoparticles serves as both the contrast agent and the target recognition element. The results demonstrate that paramagnetic nanoparticles, similar to the more widely used superparamagnetic nanoparticles, can be integrated into relaxation based detection schemes while avoiding the aggregation problem commonly associated with superparamagnetic nanoparticles.

Background: Neurochemical studies have pointed to a modulatory role in human aggression for a variety of central neurotransmitters and neuromodulators such as cytokines. While animal studies of cytokines suggest an aggression-facilitating role for central cytokines, especially for interleukin-1β and other cytokines, no cerebrospinal fluid studies of cytokines have yet been reported in regard to human aggression., Methods: Basal lumbar cerebrospinal fluid samples were obtained from 38 physically healthy subjects with DSM-5 Personality Disorder and assayed for cerebrospinal fluid interleukin-6 (log IL-6) and cerebrospinal fluid soluble IL-1 Receptor II protein in the context of their relationship with measures of aggression., Results: Cerebrospinal fluid soluble interleukin-1 Receptor II (r=.35, r(2) = .12, P= .03), but not log interleukin-6 (r = -.05, r(2) = .00, P= .76), levels were positively correlated with a composite measure of aggression. Adding relevant covariates, including cerebrospinal fluid levels of serotonin and dopamine metabolites, to the statistical model doubled the strength of this relationship (partial r = .54, r(2) = .29, P= .002). No relationship was seen with history of suicidal behavior or with any measure of impulsivity, negative affectivity, or of general dimensions of personality., Conclusion: These data suggest a positive relationship between at least one inflammatory cytokine in the central nervous system and aggression in human subjects. This finding adds to the complex picture of the central neurochemistry of impulsive aggression in human subjects., (© The Author 2015. Published by Oxford University Press on behalf of CINP.)

Background: Vagus nerve stimulation (VNS) is an established treatment for refractory epilepsy in humans, but the precise mechanism of action (MOA), predictive responsive factors and the optimal stimulation parameters remain to be elucidated., Objective: We aimed to investigate the effect of two rapid cycling VNS paradigms on CSF monoamine levels and the seizure threshold in the canine pentylenetetrazole (PTZ) model., Methods: Eight Beagle dogs, implanted with a VNS Therapy(®) System, participated in a cross-over study. Levels of serotonin (5HT), norepinephrine (NE) and dopamine (DA) were quantified in the CSF after 1 h of sham, standard and microburst VNS with a wash-out period of 1 month. One week after the CSF experiment, the PTZ seizure threshold was determined after the same stimulation paradigm. As a positive control, the PTZ seizure threshold was determined after a single oral dose of phenobarbital., Results: Rapid cycling standard and microburst VNS caused a significant increase of NE levels in the CSF (P = 0.03 and P = 0.02 respectively). No significant changes in 5HT or DA levels were detected. Rapid cycling standard and microburst VNS did not cause significant changes in the PTZ seizure threshold compared to sham., Conclusions: VNS induces an increase of NE in the canine brain, which supports previous findings indicating that VNS influences the locus coeruleus-NE (LC/NE) system. Importantly, this study demonstrates that this increase in NE is measurable in the CSF. One hour of VNS did not affect seizure threshold in the canine PTZ model. Therefore, the role of NE in the antiepileptic effect of VNS in dogs remains to be elucidated., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Background: Homovanillic acid (HVA), 5-hydroxyindoleacetic acid (5-HIAA) and 3-methoxy-4-hydroxyphenylglycol (MHPG) are the major monoamine metabolites in the central nervous system (CNS). Their cerebrospinal fluid (CSF) concentrations, reflecting the monoamine turnover rates in CNS, are partially under genetic influence and have been associated with schizophrenia. We have hypothesized that CSF monoamine metabolite concentrations represent intermediate steps between single nucleotide polymorphisms (SNPs) in genes implicated in monoaminergic pathways and psychosis., Methods: We have searched for association between 119 SNPs in genes implicated in monoaminergic pathways [tryptophan hydroxylase 1 (TPH1), TPH2, tyrosine hydroxylase (TH), DOPA decarboxylase (DDC), dopamine beta-hydroxylase (DBH), catechol-O-methyltransferase (COMT), monoamine oxidase A (MAOA) and MAOB] and monoamine metabolite concentrations in CSF in 74 patients with psychotic disorder., Results: There were 42 nominally significant associations between SNPs and CSF monoamine metabolite concentrations, which exceeded the expected number (20) of nominal associations given the total number of tests performed. The strongest association (p = 0.0004) was found between MAOB rs5905512, a SNP previously reported to be associated with schizophrenia in men, and MHPG concentrations in men with psychotic disorder. Further analyses in 111 healthy individuals revealed that 41 of the 42 nominal associations were restricted to patients with psychosis and were absent in healthy controls., Conclusions: The present study suggests that altered monoamine turnover rates in CNS reflect intermediate steps in the associations between SNPs and psychosis.

Object: The biogenic amines (dopamine, epinephrine, norepinephrine, and serotonin) are involved in the regulation of multiple neuronal functions, and changes in monoamine concentrations in the CSF have been detected in several disorders. The aim of the present study was to investigate the role of biogenic amines in the ventricular CSF of children suffering from posterior fossa tumors and their possible correlation with tumor histology and cognitive functioning., Methods: Twenty-two children with posterior fossa tumors who were treated surgically at Children's Hospital "Agia Sofia" were studied. Patients ranged in age from 5.5 to 15 years. The study population included patients who suffered from hydrocephalus and were treated by ventriculoperitoneal shunt placement. During the operation for shunt placement, a CSF sample was obtained for the assessment of 3-methoxy-4-hydroxyphenylglycol (MHPG), homovanillic acid (HVA), and 5-hydroxyindoleacetic acid (5-HIAA). Simultaneously, a blood sample was also obtained for assessment of the same metabolites in the serum. The concentration of vanillylmandelic acid (VMA) was evaluated in 24-hour urine samples in 11 patients. Cerebrospinal fluid from a control group of children was also studied. Executive functions were assessed using the short form of the Wechsler Intelligence Scale for Children (WISC)., Results: Twelve patients suffered from astrocytomas, 9 from medulloblastomas, and 1 from an ependymoma. The MHPG concentration in CSF was significantly higher in patients with astrocytomas compared with patients with medulloblastomas. Twenty-four-hour urine samples of VMA were significantly higher in patients with astrocytomas compared with patients with medulloblastomas. The MHPG concentration in CSF was negatively correlated with the verbal scale of the WISC and there was a trend toward a significant negative correlation with the total WISC score. Homovanillic acid in CSF was positively correlated with the performance scale of the WISC. There was a significant correlation between HVA and MHPG levels in CSF. The CSF concentration of 5-HIAA was significantly correlated with the HVA concentration in serum. Twenty-four-hour urine VMA samples were statistically significantly correlated with HVA concentration in both CSF and serum, with MHPG in CSF, and with 5-HIAA in serum., Conclusions: This study showed that children with posterior fossa tumors have differences in the levels of monoamine metabolites in CSF. Further studies with a larger number of patients are obviously needed to verify these observations as well as studies to correlate the monoamine metabolite levels with the neuropsychological and behavioral findings in children with posterior fossa tumors.

The dopaminergic neural system is a crucial part of the brain responsible for many of its functions including mood, arousal, and other roles. Dopamine is the key neurotransmitter of this system, and a determination of its level presents a demanding task needed for a deeper understanding of the processes, even pathological, involving this brain part. In this work, we present a method for a fast analysis of dopamine levels in samples of cerebrospinal fluid and mouse striatum. The method is based on a nanocomposite composed of magnetite and silver nanoparticles, whose surface is modified with iron nitriloacetic acid (Fe-NTA)-a dopamine-selective compound. The magnetic properties of this nanocomposite enable simple separation of targeted molecules from a complex matrix while the silver acts as a platform for surface-enhanced Raman scattering (SERS). Silver and magnetite nanoparticles are joined by carboxymethyl chitosan, useful in biological environments and enhancing the sensitivity due to the presence of carboxyl groups. This system reveals a good stability and reproducibility. Moreover, rapid and simple quantitative experiments show an improvement in the detection of dopamine levels in biological assays at low femtomolar concentrations. The comparative data performed with clinical samples of mouse striatum show that the developed magnetic SERS is a strong alternative to conventional high-performance liquid chromatography-mass spectrometry (HPLC-MS) with even several superior aspects including faster and cheaper analysis and no necessity of sample preconcentration or derivatization.

Aim: Dopamine is used as an inotropic medication in preterm infants. The preterm human blood brain barrier (BBB) is permeable to intravascular dopamine, and the impact of exogenous dopamine on the preterm brain remains unknown. The preterm lamb model may be suitable for studying the cerebral impact of dopamine therapy whether its BBB permeability is similar to preterm human infants. We aimed to examine BBB permeability to exogenous dopamine in the preterm lamb, by measuring dopamine levels in the cerebrospinal fluid (CSF)., Methods: Nine preterm foetal lambs (125-130 days, term = 147 days) were given either dopamine at 10 μg/kg/min (dopamine, n = 4) or saline (control, n = 5). CSF, and plasma samples were taken for dopamine assay., Results: The median (range) baseline CSF dopamine level for the combined control and dopamine groups (n = 9) was 0.10(0.03-0.16) ng/mL, and baseline plasma dopamine was 0.30(0.13-0.84) ng/mL. The dopamine lambs showed increase in CSF dopamine to 3.91(1.87-11.35) ng/mL with plasma dopamine increased to 14.2 (9.1-57.9) ng/mL. No change was found in the control lambs., Conclusion: In the preterm lamb, the BBB permeability and pharmacokinetics to dopamine infusion are similar to findings in the preterm human infant, supporting applicability of the preterm lamb model for studying effects of dopamine infusion in the preterm human brain., (©2013 Foundation Acta Paediatrica. Published by John Wiley & Sons Ltd.)

A dual-template imprinted polymer film containing dispersed multiwalled carbon nanotubes was exploited in the fabrication of a typical, reproducible, and rugged carbon ceramic electrode, adopting "surface grafting from" approach for the growth of a nanometer thin coating on its surface. For this, chloro groups were first introduced at the exterior surface of silica-carbon composite electrode through sol-gel modification using (3-chloropropyl)-trimethoxysilane, followed by an iniferter (sodium diethyl dithiocarbamate) initiated photopolymerization of functional monomer (2,4,6-trisacrylamido-1,3,5-triazine), mixed templates (ascorbic acid and dopamine), and cross-linker (ethylene glycol dimethacrylate), in the presence of multiwalled carbon nanotubes. The modified sensor was validated for the simultaneous analysis of ascorbic acid and dopamine in aqueous, blood serum, cerebrospinal fluid, and pharmaceutical samples, using differential pulse anodic stripping voltammetric technique. The oxidation peak potentials for both analytes were found to be well apart approximately by 300 mV, which was large enough to allow selective and sensitive analysis of one in the presence of other, without any cross reactivity, interferences and false-positives. The detection limits realized by the proposed sensor, under optimized conditions, were found to be as low as 2.24 ng mL(-1) for ascorbic acid and 0.21 ng mL(-1) for dopamine (S/N=3). Such stringent limits could be considered suitable for the primitive diagnosis of several chronic diseases, in clinical settings., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Boron-doped diamond (BDD) films are excellent electrode materials, whose electrochemical activity for some analytes can be tuned by controlling their surface termination, most commonly either to predominantly hydrogen or oxygen. This tuning can be accomplished by e.g. suitable cathodic or anodic electrochemical pretreatments. Recently, it has been shown that amorphous carbon nitride (a-CNx) films may present electrochemical characteristics similar to those of BDD, including the influence of surface termination on their electrochemical activity toward some analytes. In this work, we report for the first time a complete electroanalytical method using an a-CNx electrode. Thus, an a-CNx film deposited on a stainless steel foil by DC magnetron sputtering is proposed as an alternative electrode for the simultaneous determination of dopamine (DA) and ascorbic acid (AA) in synthetic biological samples by square-wave voltammetry. The obtained results are compared with those attained using a BDD electrode. For both electrodes, a same anodic pretreatment in 0.1 mol L(-1) KOH was necessary to attain an adequate and equivalent separation of the DA and AA oxidation potential peaks of about 330 mV. The detection limits obtained for the simultaneous determination of these analytes using the a-CNx electrode were 0.0656 μmol L(-1) for DA and 1.05 μmol L(-1) for AA, whereas with the BDD electrode these values were 0.283 μmol L(-1) and 0.968 μmol L(-1), respectively. Furthermore, the results obtained in the analysis of the analytes in synthetic biological samples were satisfactory, attesting the potential application of the a-CNx electrode in electroanalysis., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Dysfunction of dopaminergic neurotransmission has been implicated in HIV infection. We showed previously increased dopamine (DA) levels in CSF of therapy-naïve HIV patients and an inverse correlation between CSF DA and CD4 counts in the periphery, suggesting adverse effects of high levels of DA on HIV infection. In the current study including a total of 167 HIV-positive and negative donors from Germany and South Africa (SA), we investigated the mechanistic background for the increase of CSF DA in HIV individuals. Interestingly, we found that the DAT 10/10-repeat allele is present more frequently within HIV individuals than in uninfected subjects. Logistic regression analysis adjusted for gender and ethnicity showed an odds ratio for HIV infection in DAT 10/10 allele carriers of 3.93 (95% CI 1.72-8.96; p = 0.001, Fishers exact test). 42.6% HIV-infected patients harbored the DAT 10/10 allele compared to only 10.5% uninfected DAT 10/10 carriers in SA (odds ratio 6.31), whereas 68.1 versus 40.9%, respectively, in Germany (odds ratio 3.08). Subjects homozygous for the 10-repeat allele had higher amounts of CSF DA and reduced DAT mRNA expression but similar disease severity compared with those carrying other DAT genotypes. These intriguing and novel findings show the mutual interaction between DA and HIV, suggesting caution in the interpretation of CNS DA alterations in HIV infection solely as a secondary phenomenon to the virus and open the door for larger studies investigating consequences of the DAT functional polymorphism on HIV epidemiology and progression of disease.

Chronic exposure to interferon (IFN)-alpha, an innate immune cytokine, produces high rates of behavioral disturbances, including depression and fatigue. These effects may be mediated by the actions of IFN-alpha on dopamine (DA) metabolism in the basal ganglia. Diminished conversion of phenylalanine (Phen) to tyrosine (Tyr), the primary amino acid precursor of DA, has been associated with inflammation, and may reflect decreased activity of the enzyme phenylalanine-hydroxylase (PAH). This study investigated the peripheral Phen/Tyr ratio in relation to cerebrospinal fluid (CSF) concentrations of DA and its metabolites in subjects treated with IFN-alpha plus ribavirin for hepatitis C and controls awaiting IFN-alpha therapy. Plasma Phen/Tyr ratios were significantly increased in IFN-alpha-treated subjects (n=25) compared to controls (n=9), and were negatively correlated with CSF DA (r=-0.59, df=15, p<0.05) and its metabolite, homovanillic acid (r=-0.67, df=15, p<0.01), and positively correlated with fatigue (r=0.44, df=23, p<.05) in IFN-alpha-treated patients but not controls. Given the role of tetrahydrobiopterin (BH4) in the PAH conversion of Phen to Tyr, CSF concentrations of BH4 and its inactive oxidized form, dihydrobiopterin (BH2), were examined along with CSF interleukin (IL)-6 in a subset of patients. BH2 concentrations were significantly increased in IFN-alpha-treated patients (n=12) compared to controls (n=7), and decreased CSF BH4 concentrations correlated with increased CSF IL-6 (r=-0.57, df=12, p<0.05). These results indicate that IFN-alpha is associated with decreased peripheral conversion of Phen to Tyr, which in turn is associated with reduced DA in the brain as well as fatigue. These alterations may be related to oxidation of BH4 secondary to IFN-alpha-induced activation of a CNS inflammatory response., (Copyright © 2012 Elsevier Inc. All rights reserved.)

To clarify endocrine responses to psychological stressors in cattle, the effects of isolation from familiar peers on plasma prolactin (PRL) and cortisol (CORT) concentrations, and the effect of 3,4-dihydroxy-L-phenylalanine (L-DOPA), a precursor of dopamine (DA), on stress-induced PRL secretion were determined in Holstein steers. First, the potency of peripheral L-DOPA administration on attenuation of central DA levels was confirmed. Cerebrospinal fluid (CSF) collected from a chronic cannula in the third ventricle and plasma were sampled 1 h before and 3 h after intravenous injection of L-DOPA (100 mg/head). DA concentrations in CSF increased just after L-DOPA injection with subsequent decrease in PRL secretion. Injection of L-DOPA increased CORT secretion. Second, one experimental steer was isolated in its stall by removing its peers for 2 h with or without- pre-injection of L-DOPA. The concentration of PRL was elevated by isolation treatment, whereas the effect of isolation on CORT concentration could not be detected. The increase in PRL concentration after isolation was abolished by pre-injection of L-DOPA. These results suggest that PRL responds to isolation and that DA neurons in the central nervous system may regulate stress-induced PRL secretion in steers., (© 2013 Japanese Society of Animal Science.)

Aim: To determine the prevalence of dopaminergic abnormalities in 1388 children with neurological disorders, and to analyse their clinical, neuroradiological, and electrophysiological characteristics., Method: We studied biogenic amines in 1388 cerebrospinal fluid (CSF) samples from children with neurological disorders (mean age 3y 10mo, SD 4y 5mo; 712 males, 676 females. Correlations among CSF homovanillic acid (HVA) values and other biochemical, clinical, neuroradiological, and electrophysiological parameters were analysed., Results: Twenty-one patients with primary dopaminergic deficiencies were identified. Of the whole sample, 20% showed altered HVA. We report neurological diseases with abnormal CSF HVA values such as pontocerebellar hypoplasia, perinatal asphyxia, central nervous system infections, mitochondrial disorders, and other genetic diseases. Overlapping HVA levels between primary and secondary dopamine deficiencies were observed. Prevalence of low CSF HVA levels was significantly higher in neonatal patients (χ(2) =84.8, p<0.001). Abnormalities in white matter were associated with low CSF HVA (odds ratio 2.3, 95% confidence interval 1.5-3.5)., Interpretation: HVA abnormalities are observed in various neurological diseases, but some are probably an unspecific finding. No clear limits for CSF HVA values pointing towards primary diseases can be stated. We report several neurological diseases showing HVA alterations. No neuroimaging traits were associated with low HVA values, except for white matter abnormalities., (© The Authors. Developmental Medicine & Child Neurology © 2013 Mac Keith Press.)

Objective: Neurotransmitter systems participate in the regulation of food intake, and their activities are expected to influence eating behavior., Design and Methods: We investigated possible associations between body mass index (BMI) and central noradrenaline, serotonin, and dopamine activities, as reflected by the cerebrospinal fluid levels of their main metabolites methoxyhydroxyphenylglycol (MHPG), 5-hydroxyindoleacetic acid (5-HIAA), and homovanillic acid (HVA), respectively. We studied 192 subjects (111 males, 81 females) admitted to neurologic clinic for diagnostic investigations that included CSF analysis, and were found not to suffer from any major neurological disease. Subjects were categorized in three groups, namely in lower, in the two middle, and in upper BMI quartiles, the limits calculated separately for males and females., Results: No differences were found in MHPG levels between groups, while subjects in the upper BMI quartile showed significantly elevated levels of 5-HIAA and HVA compared to the levels of subjects in lower and middle quartiles., Conclusions: The results provide evidence that in overweight subjects there are enhanced demands in serotoninergic and dopaminergic signaling for their reward system that may lead to increased motivation for food consumption. The implication of reward centers in eating behavior supports the hypothesis of common mechanisms in obesity and drug addiction., (Copyright © 2012 The Obesity Society.)

This paper reports a combination of molecularly imprinted stir bar sorptive extraction and complementary molecularly imprinted polymer-sensor for the analysis of dopamine as a biomarker of several neurodegenerative diseases occurred at ultra trace level. This exploited iniferter initiated polymerization via "surface grafting-from" approach onto magnetic stir bar (for sorptive extraction) and multiwalled carbon nanotubes-ceramic electrode (for detection). Such hyphenation helped dual pre-concentration of dopamine in aqueous, biological and pharmaceutical samples. This enabled high sensitivity to achieve the stringent limit [limit of detection: 4.9ngL(-1), RSD=2.4%, S/N=3, cerebrospinal fluid] of clinical detection, without any problems of non-specific contributions and cross-reactivity., (Copyright © 2013 Elsevier Inc. All rights reserved.)

The electrochemical behavior of dopamine was examined under redox cycling conditions in the presence and absence of a high concentration of the interferent ascorbic acid at a coplanar, microelectrode array where the area of the generator electrodes was larger than that of the collector electrodes. Redox cycling converts a redox species between its oxidized and reduced forms by application of suitable potentials on a set of closely located generator and collector electrodes. It allows signal amplification and discrimination between species that undergo reversible and irreversible electron transfer. Microfabrication was used to produce 18 individually addressable, 4-μm-wide gold band electrodes, 2 mm long, contained in an array having an interelectrode spacing of 4 μm. Because the array electrodes are individually addressable, each can be selectively biased to produce an overall optimal electrochemical response. Four adjacent microbands were shorted together to serve as the collector, and were flanked on each side by seven microbands shorted as the generator (a ratio of 1:3.5 of electroactive area, respectively). This configuration achieved a detection limit of 0.454 ± 0.026 μM dopamine at the collector in the presence of 100 μM ascorbic acid in artificial cerebrospinal fluid buffer, concentrations that are consistent with physiological levels. Enhancement by surface modification of the microelectrode array to achieve this detection limit was unnecessary. The results suggest that the redox cycling method may be suitable for in vivo quantification of transients and basal levels of dopamine in the brain without background subtraction.