Cerebrospinal Fluid Neurotransmitter Research Articles

Ameliorative influence of Baijin Pills on lithium-pilocarpine-induced epilepsy in mice: role of oxidative stress, neurotransmitters and multidrug resistant transporters

BackgroundOxidative stress, imbalance of neurotransmitters and multidrug resistant transporters play pivotal roles in the development and treatment of seizures. Classical formula Baijin Pills (BJP) has been used to treat brain damage caused by epilepsy for thousands of years. However, little information on the anti-seizure effects of BJP has been reported so far. PurposeTo investigate the effects of BJP on Lithium-pilocarpine- induced seizures and its role in the regulation of oxidative stress and neurotransmission. Study DesignThe present study elucidates the anti-epileptic effects and mechanisms of action of BJP, using a mouse model of Lithium-pilocarpine- induced seizures. MethodsThe antiepileptic effect of BJP was tested by fear conditioning test of mice model. Nissl staining showed neural loss and apoptosis in the hippocampus seizure mice and BJP treatment. Immunohistochemistry analysis of Bcl-2 and Bax inflected anti-apoptotic effects of BJP. The chemical colorimetric method was utilized to determine the effects of BJP on oxidative stress. The levels of excitatory and inhibitory neurotransmitters in cerebrospinal fluid (CSF) were detected by ELISA. Whole-cell votage-clamp recording was made to detect currents of receptor gated channels. ResultsWe found that BJP can significantly improve the cognitive disorders of epileptic mice, prolonged the latency of seizures and reduced the duration of epilepsy. BJP also effectively ameliorate neural injury in the hippocampus, up-regulated Bcl-2 protein level whereas decreased Bax expression. Moreover, the levels of SOD, GSH as well as γ-aminobutyric acid (GABA) were increased, while the levels of MDA, aminomethyl phosphonic acid (AMPA) and N-Methyl-D-aspartic acid (NMDA) were decreased in the hippocampus with BJP treatment. Patch clamp recording showed that BJP had no significant effect on the current induced by GABA, NMDA and AMPA in acutely isolated mice hippocampal neurons. Furthermore, BJP inhibited the expression of P-gp, MRP1 and MDR1 protein. ConclusionsOur study provides the first experimental basis that BJP can exert anti-seizure effects by attenuating oxidative stress, regulating neurotransmission and inhibit drug-resistant associated proteins. BJP may be developed as a drug candidate to treat epilepsy in clinical practice.

Cerebrospinal fluid levels of 5-HIAA and dopamine in people with HIV and depression.

Depression is a common illness in people with HIV (PWH) and is associated with substantial morbidity and mortality. The mechanisms that underpin depression in PWH remain incompletely elucidated, and more research is therefore needed to develop effective treatments. One hypothesis is that neurotransmitter levels may be altered. These levels could be influenced by the chronic inflammation and viral persistence that occurs in PWH. We examined a panel of cerebrospinal fluid (CSF) neurotransmitters in PWH on suppressive antiretroviral therapy (ART), many of whom had a current depression diagnosis. CSF monoamine neurotransmitters and their metabolites were measured from participants in studies at the Emory Center for AIDS Research (CFAR). Only participants on stable ART with suppressed HIV RNA from both plasma and CSF were analyzed. Neurotransmitter levels were measured with high-performance liquid chromatography (HPLC). Neurotransmitters and their metabolites included dopamine (DA), homovanillic acid (HVA, a major metabolite of dopamine), serotonin (5-HT), 5-hydroxyindole-3-acetic acid (5-HIAA, a major metabolite of serotonin), and 4-hydroxy-3-methoxyphenylglycol (MHPG, a major metabolite of norepinephrine). Multivariable logistic regression was used to evaluate factors associated with depression. There were 79 PWH with plasma and CSF HIV RNA levels < 200 copies/mL at the time of the visit, and 25 (31.6%) carried a current diagnosis of depression. Participants with depression were significantly older (median age 53years versus 47years, P = 0.014) and were significantly less likely to be African American (48.0% versus 77.8%, P = 0.008). Participants with depression had significantly lower dopamine levels (median 0.49ng/mL versus 0.62ng/mL, P = 0.03) and significantly lower 5-HIAA levels (median 12.57ng/mL versus 15.41ng/mL, P = 0.015). Dopamine and 5-HIAA were highly correlated. In the multivariable logistic regression models, lower 5-HIAA was significantly associated with the depression diagnosis when accounting for other significant demographic factors. The associations between lower 5-HIAA, lower dopamine, and depression in PWH suggest that altered neurotransmission may contribute to these comorbid conditions. However, the effects of antidepressants on neurotransmitters cannot be ruled out as a factor in the 5-HIAA results.

Magnetic ionic liquid-based liquid-liquid microextraction followed by ultra-performance liquid chromatography coupled with triple-quadrupole tandem mass spectrometry for simultaneous determination of neurotransmitters in human cerebrospinal fluid and plasma

A green, efficient and easy sample pretreatment method of magnetic ionic liquid-based liquid-liquid microextraction (MIL-based LLME) combined with a sensitive, rapid and precise analytical method of ultra-performance liquid chromatography coupled with triple-quadrupole tandem mass spectrometry (UPLC-QqQ/MS2) was developed to simultaneously - determining of neurotransmitters (NTs) in biosamples. Two magnetic ionic liquids (MILs), [P6,6,6,14]3[GdCl6] and [P6,6,6,14]2[CoCl4] tested, and the latter was selected as the extraction solvent due to its advantages of visual recognition, paramagnetic behavior and higher extraction efficiency. Facile magnetic separation of MIL containing analytes from matrix was realized by applying external magnetic field without rather than centrifugation. Experimental parameters that would influence the extraction efficiency, including type and amount of MIL, extraction time, speed of the vortex process, salt concentration, and environmental pH, were optimized obtained. The proposed method was successfully applied to the simultaneous extraction and determination of 20 NTs in human cerebrospinal fluid and plasma samples. Excellent analytical performance indicates the broad potential of this method for clinical diagnosis and therapy of neurological diseases.

Pathological α-synuclein accumulation, CSF metabolites changes and brain microstructures in cynomolgus monkeys treated with 6-hydroxydopamine

The lack of evidence indicating the accumulation of phosphorylated α-synuclein (P-α-syn), a neuropathological hallmark of Parkinson disease (PD), limits the application of 6-OHDA animal models. In cynomolgus monkeys received unilateral 6-hydroxydopamine (6-OHDA) injection, we identified nigrostriatal dysfunction related behavioral defects, such as the increase of PD score, decrease of locomotor activities, and exhibition of typical rotations. We found the dopaminergic neurons were significantly reduced and had fragmented morphology in substantia nigra (SN). Furthermore, insoluble P-α-syn aggregates were observed. The P-α-syn aggregates were extracellular distributed and had typical morphology of inclusion. Immunofluorescence staining showed that the P-α-syn colocalized with ubiquitin (Ub) and p62. We also found there were more actived astrocytes and microglial in SN and striatum, reflecting neuroinflammations increase in nigrostriatal pathway. At last, to determine the long-term consequence of dopamine (DA) neuron loss induced by 6-OHDA injection, the changes of cerebrospinal fluid (CSF) neurotransmitters over time as well as the brain microstructure alternations were examined. The dopamine-related metabolites were decreased after 6-OHDA injection reflecting dopaminergic neuron loss. The levels of γ-aminobutyric acid (GABA) and acetylcholine (Ach) showed an increasing trend but not significant. By diffusion tensor Magnetic Resonance Imaging (MRI) image scans, the fractional anisotropy (FA) value in the ipsilateral SN and caudate was found to reduce, which indicated neural fiber injury. Therefore, these results suggested that α-syn pathology might participate in process of 6-OHDA injuring DA neurons, and may expand the application of 6-OHDA monkeys on investigations into the pathogenesis of PD.

Monoamine neurotransmitters in early epileptic encephalopathies: New insights into pathophysiology and therapy

AimTo study neurotransmitter status in children with early epileptic and developmental and epileptic encephalopathy (DEE) and to explore the clinical response to dopaminergic and serotoninergic therapies in a group of patients.MethodTwo hundred and five patients (111 males [54.1.%] and 94 females [45.9%], mean age 10 months at the onset of epilepsy [SD 1 year 1 month], range 0–3 year) with epileptic encephalopathy/DEE were recruited, including those with West syndrome, Ohtahara syndrome, early myoclonic encephalopathy, epilepsy of infancy with migrating focal seizures, myoclonic encephalopathy in non‐progressive disorders, infantile spasms, Doose syndrome, Lennox–Gastaut syndrome, Landau–Kleffner syndrome, and those unclassified. Cerebrospinal fluid (CSF) neurotransmitter studies and patients' medical records were reviewed. Additionally, we present clinical data of 10 patients with low CSF neurotransmitter levels who received dopaminergic/serotoninergic treatments.ResultsAbnormal neurotransmitter values were identified in 68 (33%) patients. 5‐Hydroxyindoleacetic acid (5‐HIAA) deficit was the most prevalent alteration (91%). Low CSF 5‐HIAA levels were significantly higher in 1‐ to 3‐year‐old children. A negative significant correlation was found between 5‐HIAA levels and epilepsy duration before CSF study (Spearman's ρ=−0.191, p=0.007). Abnormalities in deep grey matter were associated with low levels of CSF homovanillic acid and 5‐HIAA. Ten patients with low CSF neurotransmitter levels received dopamine and/or serotonin therapies. Six of them showed initial decrease of seizure frequency and severity and maintained improvement in some neurodevelopmental skills.InterpretationA considerable number of patients showed neurotransmitter abnormalities. Age at seizure onset and duration of epilepsy before CSF study were the principal factors related to neurotransmitter depletion. Early monoamine supplementation would seem advisable as a neuroprotective strategy.What this paper adds 5‐Hydroxyindoleacetic acid homeostasis is especially vulnerable in patients with epileptic encephalopathy/developmental and epileptic encephalopathy. Age of seizure onset and duration of epilepsy are determinants of neurotransmitter depletion.

Approaches for diagnosis and treatment in neurotransmitter disorders of childhood.

Neurotransmitter disorders are a group of neurometabolic syndromes caused by disturbances of neurotransmitter metabolism. The primary aim of this retrospective study is to present patients with disturbances of monoamine neurotransmitter metabolism. Cerebrospinal fluid (CSF) neurotransmitter measurements and genetic analysis were performed on five patients. Five patients who had various movement disorders and motor and cognitive disabilities were included. Four patients were diagnosed with sepiapterin reductase (SR) deficiency, and one was diagnosed with aromatic L-amino acid decarboxylase (AADC) deficiency. Different treatment responses appeared in patients with SR and AADC deficiency. The responses to drug treatment ranged from good to weak in our patients. The diagnosis process is challenging in patients with SR and AADC deficiency, which present similar clinical features to other neurological and metabolic diseases. Investigations of neurotransmitters in CSF and analysis of related genes are essential to differentiate disturbances of monoamine neurotransmitter metabolism from other neurometabolic diseases. For patients with monoamine neurotransmitter disorders, drugs that target these disturbances should be combined as necessary to produce the appropriate response.

Parkinson's Disease With Depression: The Correlations Between Neuroinflammatory Factors and Neurotransmitters in Cerebrospinal Fluid.

Background: To explore the changes of neuroinflammatory factors in cerebrospinal fluid (CSF) and their correlation with monoamine neurotransmitters in Parkinson’s disease (PD) with depression (PD-D) patients.Methods: Neuroinflammatory factors and neurotransmitters in CSF were measured and compared between PD with no depression (PD-ND) and PD-D groups. The relationship between PD-D and neuroinflammatory factors was studied by binary logistic regression equation, and the related factors of PD-D were adjusted. The correlations of the levels of neuroinflammatory factors and neurotransmitters in PD-D group were analyzed.Results: The levels of tumor necrosis factor (TNF)-α in CSF from PD-D group were significantly higher and there were no significant differences in the levels of interleukin-1β, prostaglandin (PG) E2, hydrogen peroxide (H2O2), and nitric oxide (NO). The 24-item Hamilton Depression Scale (HAMD-24) score was positively correlated with the level of TNF-α in CSF. Binary logistic regression showed that the OR of CSF TNF-α level was 1.035 (95% CI 1.002–1.069). The level of dopamine (DA) in CSF of PD-D group was significantly lower than that in PD-ND group. TNF-α level was negatively correlated with DA level in CSF from PD patients (r = −0.320, P = 0.003).Conclusions: Neuroinflammatory factors, especially TNF-α, may play an important role in PD-D. It may cause damage to DA neurons and lead to the depletion of DA, which is related to the occurrence and development of PD-D.

Association of Cigarette Smoking with Sleep Disturbance and Neurotransmitters in Cerebrospinal Fluid.

BackgroundCigarette smoking has shown to be associated with sleep disturbance, especially prolonged sleep onset latency (SOL). Cigarette smoking stimulates the release of dopamine (DA) and serotonin (5-HT), which might promote awakening and inhibit rapid eye movement sleep. Dopamine transporter (DAT) and serotonin transporter play a key role in the reuptake of DA and 5-HT from the synaptic cleft into presynaptic neurons. However, the relationship among cigarette smoking, sleep disturbance and neurotransmitters has never been investigated in human cerebrospinal fluid (CSF).MethodsA total of 159 Chinese male subjects (81 active smokers and 78 non-smokers) who would undergo lumbar puncture before the surgery of anterior cruciate ligament reconstruction were recruited and 5mL-CSF samples were collected incidentally. CSF levels of DA, DAT, 5-HT, and serotonin transporter were measured using radioimmunoassay and ELISA. Sociodemographic data and the Pittsburgh Sleep Quality Index (PSQI) scale were collected before surgery.ResultsPSQI global scores, SOL, and CSF DA levels were significantly higher in active smokers compared to non-smokers (2.00 [1.00–4.75] scores vs 4.00 [3.00–6.00] scores, p = 0.001; 10.00 [5.00–15.00] minutes vs 15.00 [10.00–30.00] minutes, p = 0.002; 87.20 [82.31–96.06]ng/mL vs 107.45 [92.78–114.38] ng/mL, p < 0.001), while CSF DAT levels were significantly lower in active smokers (0.35 [0.31–0.39] ng/mL vs 0.29 [0.26–0.34] ng/mL, p < 0.001).ConclusionCigarette smoking was indeed associated with sleep disturbance, shown by prolonged SOL, higher DA levels and lower DAT levels in CSF of active smokers.

SAT-382 Pyridoxal 5’-Phosphate Cerebrospinal Fluid Abnormalities in Hyopophosphatasia Before and After Enzyme Replacement Therapy

Introduction: Hypophosphatasia (HPP) is an inborn error of metabolism due to deficiency of tissue non-specific alkaline phosphatase (TNSALP), characterized by a wide range of skeletal and neurological symptoms. Little is known about the mechanism of neurologic involvement, but it may result from inefficient hydrolysis of vitamin B6 (pyridoxal 5’-phosphate, PLP), which is involved in neurotransmitter synthesis and is markedly elevated in HPP. However, it remains unknown what PLP levels are in the cerebrospinal fluid (CSF) of patients with HPP. We report two cases: (1) one with pre- and post-treatment CSF PLP levels and (2) one with pre-treatment CSF PLP and neurotransmitter levels. Case 1: A 30-year-old woman with extensive fracture history presented with seizure-like activity. Laboratory evaluation while on no B6 supplementation was notable for low ALP (14 U/L, ref: 40-150), high plasma PLP (362 mcg/L, ref: 5-50), and high CSF PLP (16 mcg/L), with a low CSF/plasma PLP ratio (0.04, ref: 0.1-0.7[1]). Genetic testing showed a pathogenic variant of TNSALP (Het c.1133A>T, p.Asp378Val, rs 121918008). After initiation of enzyme replacement therapy (ERT), her plasma and CSF PLP levels normalized to 6.3 and 1.4 mcg/L, respectively, with a ratio of 0.23. She reported improvement in energy level and seizure-like activity after several months of ERT. Case 2: A 34-year-old man with no history of skeletal pathology presented with diffuse musculoskeletal pain, weakness, and loss of sensory function attributed to generalized peripheral neuropathy. Laboratory evaluation while on no B6 supplementation was notable for low ALP (23 U/L), high plasma PLP (496 mcg/L), and high CSF PLP (17 mcg/L) with a low CSF/plasma ratio (0.03). CSF neurotransmitter levels were also low, including 5-hydroxyindoleacetic acid (40 nmol/L, ref: 67-140) and homovanillic acid (115 nmol/L, ref: 145-324). Genetic testing showed heterozygous expression of a catastrophic frameshift mutation of TNSALP (c.662del, p.Gly221Valfs*56). ERT is being considered at this time. Conclusions: We report the novel findings that in these patients with HPP:1. CSF PLP levels are markedly elevated, though to a much lesser extent than plasma levels. Elevated CSF/plasma ratios suggest that transport of PLP and its metabolites across the blood brain barrier may be impaired in HPP.2. Decreased CSF neurotransmitter levels, as seen in our patient, may contribute to neurologic symptoms of HPP.3. Enzyme replacement therapy normalized both CSF and plasma PLP in case 1. Further studies are needed to understand how these changes affect patient symptoms and prognosis.Citation:1. Albersen, M., et al., Vitamin B-6 vitamers in human plasma and cerebrospinal fluid. Am J Clin Nutr, 2014. 100(2): p. 587-92

Analysis of 5-hydroxytryptamine and its related indoles in cerebrospinal fluid of leukemic children by gas chromatography-mass spectrometry

Abstract Background It is meaningful to quantify some neurotransmitters in cerebrospinal fluid (CSF) for pathology and clinical diagnosis. The objective of this study was to develop a rapid and reliable method for detecting 5-hydroxyindole ethanol (5-HTOL), 5-hydroxyindole acetic acid (5-HIAA), 5-hydroxytryptophan (5-HTP) and 5-hydroxytryptamine (5-HT) in CSF by gas chromatography-mass spectrometry (GC-MS), and explore the clinical significance of the levels of these neurotransmitters in CSF from acute lymphoblastic leukemia (ALL). Methods The levels of 5-HTOL, 5-HIAA, 5-HTP and 5-HT in CSF from children with ALL and a control (CON) group were examined by the proposed GC-MS method. Results The GC-MS method showed good sensitivity and accuracy. 5-HT and 5-HIAA contents in the ALL group were significantly lower than those in the CON group (p &lt; 0.01), while there was no significant difference in 5-HTP and 5-HTOL contents between the two groups (p &gt; 0.05). Conclusions This sensitive and reliable method could be used in studies focusing on clinical pathogenesis of ALL.

Correlation Between Salivary, Platelet and Central Serotonin Levels in Children.

Serotonin (5-HT) is a neurotransmitter synthesized in both the central nervous system (CNS) and in enterochromaffin cells of the gut. 5-HT biosynthesis is separate between the periphery and the CNS. Any observed correlations between centrally and peripherally measured 5-HT remain to be elucidated. Previous efforts have looked for a noninvasive marker of central serotonin, including serotonin in whole blood, plasma, platelets, saliva, and urine; however, results are conflicting. Finding a noninvasive marker for central serotonin turnover that can be used for diagnosis and therapeutic monitoring in patients with primary neurotransmitter deficiencies. Inclusion criterion was all children presenting with neurological symptoms whose clinical investigations included lumbar puncture (LP) for cerebrospinal fluid (CSF) collection and neurotransmitter metabolite analysis, were recruited. For central serotonin turnover, the serotonin metabolite 5-hydroxyindoleacetic acid (5HIAA) was used. Bivariate correlation between the serotonin levels in CSF (5HIAA), platelets, and saliva was calculated. Twenty-six patients (aged 6 months to 15 years) with various neurologic presentations had LP for CSF collection and neurotransmitter metabolite analysis as part of their clinical care. An additional salivary and blood sample was obtained at the same time. Eighteen patients had suitable samples for quantitative measure of serotonin. There was no correlation between platelet serotonin and CSF 5HIAA levels (Pearson's coefficient of correlation - PCC: 0.010) or between salivary serotonin and CSF 5HIAA (PCC: 0.258). There was a strong negative correlation between salivary and platelet serotonin (PCC: -0.679). Our findings suggest that salivary serotonin measurement is not a suitable noninvasive marker for measuring central serotonin turnover.

Cerebrospinal fluid neurotransmitter levels and central nervous system depression in a rat drug overdose model

A neuropsychiatric drug overdose impairs physiological function via central nervous system (CNS) depression. In drug-related deaths, only the drug concentration can currently provide information regarding CNS depression in victims. In this study, using a drug overdose model, we investigated the ability of neurotransmitters in the cerebrospinal fluid (CSF) to serve as biomarkers for CNS depression. Four groups of rats were orally administered diazepam (200 mg/kg) and/or phenobarbital (100 mg/kg) or vehicle. In a hot plate test performed to assess physiological impairment, drug-administered animals showed prolongation of the response latency. Serum drug concentrations were also sufficient to observe the effect of drug overdose. The levels of benzoyl-derivatized neurotransmitters were measured using liquid chromatography–tandem mass spectrometry (LC-MS/MS) analysis. Noradrenaline, adrenaline, serotonin, melatonin, phosphoethanolamine, and histamine levels in the CSF decreased as the response latencies in the hot plate test increased. These reduced CSF neurotransmitter levels may represent physiological dysfunction through CNS depression.

Expanding the Phenotype: Neurodevelopmental Disorder, Mitochondrial, With Abnormal Movements and Lactic Acidosis, With or Without Seizures (NEMMLAS) due to WARS2 Biallelic Variants, Encoding Mitochondrial Tryptophanyl-tRNA Synthase

WARS2 encodes a tryptophanyl tRNA synthetase, which is involved in mitochondrial protein synthesis. Biallelic mutations in WARS2 are rare and have been associated with a spectrum of clinical presentations, including neurodevelopmental disorder with abnormal movements, lactic acidosis with or without seizures (NEMMLAS). Here we present the case of an 8-year-old girl with ataxia and parkinsonism with periventricular white matter abnormalities on magnetic resonance imaging (MRI) and global developmental delay. The initial investigations revealed an elevated lactate level. Extensive metabolic testing, including a muscle biopsy, was inconclusive. Cerebrospinal fluid (CSF) neurotransmitter levels were low; however, a trial of levodopa was unremarkable. The chromosomal microarray and initial ataxia gene panel was normal. Zinc supplementation for a heterozygous variant of unknown significance in the CP gene on the ataxia exome panel was not effective in treating her symptoms. Reanalysis of the ataxia exome panel highlighted biallelic mutations in WARS2, which lead to the diagnosis of neurodevelopmental disorder, mitochondrial, with abnormal movements and lactic acidosis, with or without seizures (NEMMLAS). This lead to parental genetic testing, redirected therapy, and helped to expand the symptomology of this rare condition. Here we emphasize the importance of imminent and repeat expanded genetic testing to ensure early diagnosis and treatment for rare pediatric disorders. The patient is being trialed on a mitochondrial cocktail in an attempt to compensate for defects in mitochondrial protein synthesis associated with this variant. Longitudinal monitoring of disease manifestation will help establish the currently unknown natural history of this condition.

An Investigation on the Clinical Features and Neurochemical Changes in Parkinson's Disease With Depression.

Objective: To investigate the clinical features and neurochemical changes in Parkinson's disease with depression (PD-D).Methods: A total of 478 PD patients were divided into PD-D and PD patients without depression (PD-ND) groups according to the 24-item Hamilton Depression Rating Scale (HAMD) score. Demographic variables, motor and non-motor symptoms and activities of daily living were evaluated. The independent influencing factors of PD-D were investigated via binary logistic regression analysis. The levels of neurotransmitters in cerebrospinal fluid (CSF) were measured and their correlations with HAMD score were analyzed.Results: The proportion of PD-D was 59.0%, of which 76.95, 20.92, and 2.13% had mild, moderate, and severe depression, respectively. Anxiety/somatization was the most prevalent sub-factor of HAMD in PD-D. The scores of UPDRS III, postural instability/gait difficulty (PIGD) type and the scores of 14-item Hamilton Anxiety Scale (HAMA) and 14-item Chalder Fatigue Scale (FS) were independently associated with PD-D. The levels of dopamine (DA) and 5-hydroxytryptamine (5-HT) were all significantly reduced in PD-D group compared with those in PD-ND group. HAMD scores were negatively correlated with the DA levels in CSF.Conclusions: PD patients have a high proportion of depression, mainly of mild and moderate levels. The profile of depression in PD population is subtly different from that of the general population. Motor symptoms, PIGD type, anxiety and fatigue are the significant influencing factors of PD-D. Compared to 5-HT, DA may play a more important role in PD-D.

Inherited Disorders of Neurotransmitters: Classification and Practical Approaches for Diagnosis and Treatment.

Neurotransmitter deficiencies are rare neurological disorders with clinical onset during childhood. The disorders are caused by genetic defects in the enzymes involved in synthesis, degradation, or transport of neurotransmitters or by defects in the cofactor biosynthesis such as tetrahydrobiopterin (BH4). With the newly described DNAJC12 deficiency, a chaperon-associated neurotransmitter disorder, the pathophysiological spectrum has been broadened. All deficiencies result in a lack of monoamine neurotransmitters, especially dopamine and its products, with a subset leading to decreased levels of serotonin. Symptoms can occur already in the neonatal period. Classical signs are hypotonia, movement disorders, autonomous dysregulations, and impaired development. Diagnosis depends on quantitative detection of neurotransmitters in cerebrospinal fluid, since peripheral markers in blood or urine are less reliable. Treatment is based on supplementation of the missing neurotransmitter precursors or restoring deficient cofactors for endogenous enzymatic synthesis. In recent years, knowledge about this orphan group of diseases increased substantially among clinicians. However, the difficult task of integrating clinical symptoms and laboratory values still leads to a critical delay in diagnosis and therapy for patients. This review aims at enhancing the understanding of neurotransmitter disorders and should help practicing clinicians to choose useful diagnostic steps on the way to a valid diagnosis.

Spectrum of movement disorders and neurotransmitter abnormalities in paediatric POLG disease

ObjectivesTo describe the spectrum of movement disorders and cerebrospinal fluid (CSF) neurotransmitter profiles in paediatric patients with POLG disease.MethodsWe identified children with genetically confirmed POLG disease, in whom CSF neurotransmitter analysis had been undertaken. Clinical data were collected retrospectively. CSF neurotransmitter levels were compared to both standardised age-related reference ranges and to non-POLG patients presenting with status epilepticus.ResultsForty-one patients with POLG disease were identified. Almost 50% of the patients had documented evidence of a movement disorder, including non-epileptic myoclonus, choreoathetosis and ataxia. CSF neurotransmitter analysis was undertaken in 15 cases and abnormalities were seen in the majority (87%) of cases tested. In many patients, distinctive patterns were evident, including raised neopterin, homovanillic acid and 5-hydroxyindoleacetic acid levels.ConclusionsChildren with POLG mutations can manifest with a wide spectrum of abnormal movements, which are often prominent features of the clinical syndrome. Underlying pathophysiology is probably multifactorial, and aberrant monoamine metabolism is likely to play a role.

A Case of Homozygous Disruption of P450 Side-Chain Cleavage ( CYP11A1 ): Cerebral MRI and CSF Neurotransmitter Findings

Mitochondrial cytochrome P450 side-chain cleavage enzyme (P450scc, CYP11A1 ) is the initiating enzyme of steroidogenesis and converts cholesterol to pregnenolone. Here we describe neurological, cerebral magnetic resonance imaging (MRI), and cerebrospinal fluid (CSF) findings in a patient with a homozygous disruption of P450scc. Free γ-aminobutyric acid (GABA) and glutamate levels were measured in the patient’s CSF and control samples from 10 subjects by mean of high performance liquid chromatography with electrochemical detection. In the CSF, patient’s free GABA levels were significantly reduced in comparison to control values. Cerebral MRI revealed multiple supratentorial located T2 lesions in the periventricular and peritrigonal white matter without gadolinium enhancement or diffusion restriction of lesions. Both MRI and CSF neurotransmitter findings in our patient with P450scc deficiency were comparable to those found in multiple sclerosis. J Neurol Res. 2018;8(1-2):13-15 doi: https://doi.org/10.14740/jnr467w

No major influence of regular tobacco smoking on cerebrospinal fluid monoamine metabolite concentrations in patients with psychotic disorder and healthy individuals

Metabolism of the monoamines dopamine, serotonin and noradrenaline, is altered in the central nervous system of people with schizophrenia, and their major metabolites homovanillic acid (HVA), 5-hydroxyindoleacetic acid (5-HIAA) and 3-methoxy-4-hydroxyphenylglycol (MHPG), respectively, have been intensively studied as indirect measures of these neurotransmitters in cerebrospinal fluid (CSF). Regular tobacco smoking has been shown to alter neurotransmitter metabolism in the brain and studies have found CSF monoamine metabolite concentrations to be substantially lower in smokers. However, few studies investigating these monoamines in CSF have controlled for regular tobacco smoking. We investigated if regular tobacco smoking influences CSF HVA, 5-HIAA and MHPG concentrations in patients treated for psychotic disorders (n = 69) and healthy non-psychotic human volunteers (n = 200). After lumbar puncture CSF samples were analyzed with mass fragmentography. CSF HVA, 5-HIAA and MHPG concentrations did not significantly differ between smokers and non-smokers neither in patients, nor in healthy subjects, whereas back-length predicted HVA and 5-HIAA and antipsychotic medication MHPG concentrations. The results indicate that regular tobacco smoking has no significant effect on monoamine metabolite concentrations in CSF. This suggests that lack of controlling for regular tobacco smoking should not substantially violate the results in studies of the major monoamine metabolites in CSF.

Secondary Abnormal CSF Neurotransmitter Metabolite Profiles in a Pediatric Tertiary Care Centre.

Secondary neurotransmitter deficiencies have been reported in several reviews. Our primary aim was to assess the relationship among epilepsy, antiseizure medications, and specific neurotransmitter abnormalities. We also evaluated movement disorders and brain abnormalities via magnetic resonance imaging scans in patients with secondary neurotransmitter defects. This is a retrospective case series of 376 patients who underwent neurotransmitter analysis at BC Children's Hospital between 2009 and 2013, for a variety of neurological presentations. The biochemical genetics laboratory database was interrogated for results of cerebrospinal fluid neurotransmitter analyses. Clinical data for patients with abnormal results were collected from the hospital charts. Statistical analysis included one-way analysis of variance, chi-square, and a two-way contingency table. Abnormal neurotransmitter values were identified in 67 (17.8%) patients, two (0.53%) of which were attributable to a congenital neurotransmitter disorder and 11 (16.9%) secondary to other genetic diagnoses. Of 64 patients with secondary abnormal neurotransmitter values, 38 (59%) presented with epilepsy and 20 (31%) with movement disorders. A combination of epilepsy and movement disorder was less frequent. Acknowledging the limitations of this retrospective chart review, we conclude that, in our cohort, in addition to patients with movement disorders, a considerable number of patients with epilepsy and epileptic encephalopathy also showed secondary neurotransmitter mono-amine abnormalities. There is no clear relation, however, between clinical phenotype and type of neurotransmitter affected. In addition, no association was identified between the type of antiseizure medications and affected neurotransmitter type. We outline the need for prospective studies to further enrich our understanding of the relation between epilepsy and neurotransmitters with a focus on improving treatments and patient outcomes.

Restless legs syndrome in Parkinson disease: Clinical characteristics, abnormal iron metabolism and altered neurotransmitters

Relationships among clinical characteristics, iron metabolism and neurotransmitters in Parkinson disease (PD) patients with restless legs syndrome (RLS) remains unclear. We divided 218 patients into PD with and with no RLS (PD-RLS and PD-NRLS) groups by RLS-rating scale (RLS-RS) score. Motor and non-motor symptoms were rated by related scales. Iron and related proteins, and neurotransmitters in cerebrospinal fluid (CSF) and serum were measured. PD-RLS frequency was 40.37%. PD-RLS group had longer duration, higher stage and scores of motor symptoms, depression, anxiety, sleep disorders, fatigue and apathy, and increased transferrin and decreased iron, ferritin, dopamine (DA) and 5-hydroxytryptamine (5-HT) in CSF. In CSF of PD-RLS group, RLS-RS score was positively correlated with transferrin level and negatively correlated with iron and ferritin levels; RLS-RS score was negatively correlated with DA and 5-HT levels; transferrin level was negatively correlated with DA and 5-HT levels, and ferritin level was positively correlated with DA level. In serum, PD-RLS group had decreased iron and transferrin levels, which were negatively correlated with RLS-RS score. PD-RLS was common and severer in motor and some non-motor symptoms. Iron deficiency induced by its metabolism dysfunctions in peripheral and central systems might cause PD-RLS through decreasing brain DA and 5-HT.