Cerebrospinal Fluid 5-hydroxyindoleacetic Acid Research Articles

Cerebrospinal fluid monoamine levels in central disorders of hypersomnolence.

Whether the cause of daytime sleepiness in narcolepsy type 1 (NT1) is a direct consequence of the loss of orexin (ORX) neurons or whether low orexin reduces the efficacy of the monoaminergic systems to promote wakefulness is unclear. The neurobiology underlying sleepiness in other central hypersomnolence disorders, narcolepsy type 2 (NT2), and idiopathic hypersomnia (IH), is currently unknown. Eleven biogenic amines including the monoaminergic neurotransmitters and their metabolites and five trace amines were measured in the cerebrospinal fluid (CSF) of 94 drug-free subjects evaluated at the French National Reference Center for Narcolepsy: 39 NT1(orexin-deficient) patients, 31 patients with objective sleepiness non orexin-deficient (NT2 and IH), and 24 patients without objective sleepiness. Three trace amines were undetectable in the sample: tryptamine, octopamine, and 3-iodothyronamine. No significant differences were found among the three groups for quantified monoamines and their metabolites in crude and adjusted models; however, CSF 5-hydroxyindoleacetic acid (5-HIAA) levels tended to increase in NT1 compared to other patients after adjustment. Most of the biomarkers were not associated with ORX-A levels, clinical or neurophysiological parameters, but a few biomarkers (e.g. 3-methoxy-4-hydroxyphenylglycol and norepinephrine) correlated with daytime sleepiness and high rapid eye movement (REM) sleep propensity. We found no striking differences among CSF monoamines, their metabolites and trace amine levels, and few associations between them and key clinical or neurophysiological parameters in NT1, NT2/IH, and patients without objective sleepiness. Although mostly negative, these findings are a significant contribution to our understanding of the neurobiology of hypersomnolence in these disorders that remain mysterious and deserve further exploration.

Maternal neglect and the serotonin system are associated with daytime sleep in infant rhesus monkeys.

Environmental and biological factors contribute to sleep development during infancy. Parenting plays a particularly important role in modulating infant sleep, potentially via the serotonin system, which is itself involved in regulating infant sleep. We hypothesized that maternal neglect and serotonin system dysregulation would be associated with daytime sleep in infant rhesus monkeys. Subjects were nursery-reared infant rhesus macaques (n = 287). During the first month of life, daytime sleep-wake states were rated bihourly (0800-2100). Infants were considered neglected (n = 16) if before nursery-rearing, their mother repeatedly failed to retrieve them. Serotonin transporter genotype and concentrations of cerebrospinal fluid 5-hydroxyindoleacetic acid (5-HIAA) were used as markers of central serotonin system functioning. t tests showed that neglected infants were observed sleeping less frequently, weighed less, and had higher 5-HIAA than non-neglected nursery-reared infants. Regression revealed that serotonin transporter genotype moderated the relationship between 5-HIAA and daytime sleep: in subjects possessing the Ls genotype, there was a positive correlation between 5-HIAA and daytime sleep, whereas in subjects possessing the LL genotype there was no association. These results highlight the pivotal roles that parents and the serotonin system play in sleep development. Daytime sleep alterations observed in neglected infants may partially derive from serotonin system dysregulation.

Cerebrospinal fluid biogenic amines depletion and brain atrophy in adult patients with phenylketonuria.

Biogenic amines synthesis in phenylketonuria (PKU) patients with high phenylalanine (Phe) concentration is thought to be impaired due to inhibition of tyrosine and tryptophan hydroxylases and competition with amino acids at the blood-brain barrier. Dopamine and serotonin deficits might explain brain damage and progressive neuropsychiatric impairment in adult PKU patients. Ten early treated adult PKU patients (mean age 38.2 years) and 15 age-matched controls entered the study. Plasma and cerebrospinal fluid (CSF) Phe, 5-hydroxyindoleacetic acid (5-HIAA), 5-hydroxytryptophan (5-HTP), 3,4-dihydroxy-l-phenylalanine (l-DOPA) and homovanillic acid (HVA) were analyzed. Voxel-based morphometry statistical nonparametric mapping was used to test the age-corrected correlation between gray matter atrophy and CSF biogenic amines levels. 5-HIAA and 5-HTP were significantly reduced in PKU patients compared to controls. Significant negative correlations were found between CSF 5-HIAA, HVA, and 5-HTP and Phe levels. A decrease in 5-HIAA and 5-HTP concentrations correlated with precuneus and frontal atrophy, respectively. Lower HVA levels correlated with occipital atrophy. Biogenic amines deficits correlate with specific brain atrophy patterns in adult PKU patients, in line with serotonin and dopamine projections. These findings may support a more rigorous Phe control in adult PKU to prevent neurotransmitter depletion and accelerated brain damage due to aging.

Cerebrospinal fluid monoamine metabolite concentrations in depressive disorder: A meta-analysis of historic evidence

Altered monoaminergic functions have been implicated in the pathophysiology of depressive disorder. However, previously reported cerebrospinal fluid (CSF) monoamine metabolite concentrations in major depression have been inconsistent. We performed a meta-analysis of historic evidence to determine whether CSF monoamine metabolite levels were different between patients with depression and normal controls, and could be used as depression biomarkers. Relevant studies that investigated CSF 5-hydroxyindoleacetic acid (5-HIAA), homovanillic acid (HVA), and 3-methoxy-4-hydroxyphenylglycol (MHPG) levels in patients with depression and normal controls were identified in PubMed, Web of Science, PsycINFO, and Embase databases through September 5, 2017, using a synonymous search for depression, CSF, normal, control, and each monoamine metabolite name, and in the reference lists of the acquired articles. Obtained records were individually scrutinized for eligibility. Our search strategy identified 26 studies, including our own. We employed random effects modeling and adopted “Hedges's g” as an index of effect size. In the meta-analyses, no significant difference was observed in CSF 5-HIAA or MHPG levels between patients with depressive disorder and controls. In contrast, CSF HVA was significantly decreased in patients with depression (Hedges's g = −0.30, P = 0.0000025), and these results remained significant after patients with bipolar disorder were excluded (Hedges's g = −0.37, P = 0.000061). In the meta-regression, sex was significantly associated with the Hedges's g of CSF HVA (Q = 4.41, P = 0.036). This meta-analysis revealed that only CSF HVA, and not 5-HIAA or MHPG, levels were decreased in depressive disorder. The reduction in the CSF HVA concentration in patients with depression may guide future studies on depression and serve as a useful biomarker of depressive disorder.

Monoaminergic Markers Across the Cognitive Spectrum of Lewy Body Disease.

Lewy body disorders, including Parkinson's disease (PD), Parkinson's disease dementia (PDD) and dementia with Lewy bodies (DLB), are characterized by profound central and peripheral monoaminergic dysfunction. To investigate whether these alterations depend on dementia status, we measured cerebrospinal fluid (CSF) and serum monoamine and metabolite levels across subgroups of the cognitive spectrum, and evaluated their marker potential afterwards. In total, 153 subjects were included, of which 43 healthy controls (HC), 28 PD patients with normal cognition (PD-NC), 26 patients with PD and mild cognitive impairment (PD-MCI), 18 PDD patients, and 38 DLB patients. The levels of monoamines and metabolites in paired CSF and serum samples were analyzed applying reversed-phase high-performance liquid chromatography with electrochemical detection. Firstly, when comparing subgroups, CSF 3-methoxy-4-hydroxyphenylglycol (MHPG) levels were found lowest in HC and PD-NC groups and significantly higher in PDD/DLB patients. In addition, CSF 5-hydroxyindoleacetic acid (5-HIAA) levels differed significantly between HC and PD-MCI/PDD, and DLB patients (P≤0.001), but not between HC and PD-NC patients. Secondly, when performing logistic regression, it was shown that particularly CSF/serum MHPG levels and the serum MHPG to noradrenaline (NA) ratio effectively differentiated between HC and (non-)pooled PD subgroups (AUC = 0.914-0.956), and PDD and DLB patients (AUC = 0.822), respectively. Furthermore, CSF 5-HIAA was the most discriminative parameter to differentiate between PD-NC and PD-MCI (AUC = 0.808), and, PD-NC and PDD subgroups (AUC = 0.916). Our data revealed that especially alterations of the noradrenergic neurotransmitter system could distinguish between Lewy body disorder subtypes, pinpointing CSF/serum MHPG and NA as potential stage markers across the cognitive spectrum.

Maternal Cerebrospinal Fluid Glutamate in Response to Variable Foraging Demand: Relationship to Cerebrospinal Fluid Serotonin Metabolites in Grown Offspring

Background Maternal response to allostatic overload during infant rearing may alter neurobiological measures in grown offspring, potentially increasing susceptibility to mood and anxiety disorders. We examined maternal cerebrospinal fluid (CSF) glutamate response during exposure to variable foraging demand (VFD), a bonnet macaque model of allostatic overload, testing whether activation relative to baseline predicted concomitant CSF elevations of the stress neuropeptide, corticotropin-releasing factor. We investigated whether VFD-induced activation of maternal CSF glutamate affects maternal–infant attachment patterns and offspring CSF 5-hydroxyindoleacetic acid concentrations. Methods Mother–infant dyads were exposed to the “VFD stressor,” a paradigm in which mothers experience 16 weeks of foraging uncertainty while rearing their infant offspring. Through staggering the infant age of VFD onset, both a cross-sectional design and a longitudinal design were used. Maternal CSF glutamate and glutamine concentrations post-VFD exposure were cross-sectionally compared to maternal VFD naive controls. Proportional change in concentrations of maternal glutamate (and glutamine), a longitudinal measure, was evaluated in relation to VFD-induced elevations of CSF corticotropin-releasing factor. The former measure was related to maternal–infant proximity scores obtained during the final phases of VFD exposure. Maternal glutamatergic response to VFD exposure was used as a predictor variable for young adolescent offspring CSF metabolites of serotonin, dopamine, and norepinephrine. Results Following VFD exposure, maternal CSF glutamate concentrations correlated positively with maternal CSF CRF concentrations. Activation relative to baseline of maternal CSF glutamate concentrations following VFD exposure correlated directly with a) increased maternal-infant proximity during the final phases of VFD and b) offspring CSF concentrations of monoamine metabolites including 5-hydroxyindoleacetic acid, which was elevated relative to controls. Conclusions Activation of maternal CSF glutamate in response to VFD-induced allostasis is directly associated with elevations of maternal CSF corticotropin-releasing factor. Maternal CSF glutamate alterations induced by VFD potentially compromise serotonin neurotransmission in grown offspring, conceivably modeling human vulnerability to treatment-resistant mood and anxiety disorders.

Elevated cerebrospinal fluid 5-hydroxyindoleacetic acid in macaques following early life stress and inverse association with hippocampal volume: preliminary implications for serotonin-related function in mood and anxiety disorders.

Background: Early life stress (ELS) is cited as a risk for mood and anxiety disorders, potentially through altered serotonin neurotransmission. We examined the effects of ELS, utilizing the variable foraging demand (VFD) macaque model, on adolescent monoamine metabolites. We sought to replicate an increase in cerebrospinal fluid (CSF) 5-hydroxyindoleacetic acid (5-HIAA) observed in two previous VFD cohorts. We hypothesized that elevated cisternal 5-HIAA was associated with reduced neurotrophic effects, conceivably due to excessive negative feedback at somatodendritic 5-HT1A autoreceptors. A putatively decreased serotonin neurotransmission would be reflected by reductions in hippocampal volume and white matter (WM) fractional anisotropy (FA).Methods: When infants were 2–6 months of age, bonnet macaque mothers were exposed to VFD. We employed cisternal CSF taps to measure monoamine metabolites in VFD (N = 22) and non-VFD (N = 14) offspring (mean age = 2.61 years). Metabolites were correlated with hippocampal volume obtained by MRI and WM FA by diffusion tensor imaging in young adulthood in 17 males [10 VFD (mean age = 4.57 years)].Results: VFD subjects exhibited increased CSF 5-HIAA compared to non-VFD controls. An inverse correlation between right hippocampal volume and 5-HIAA was noted in VFD- but not controls. CSF HVA and MHPG correlated inversely with hippocampal volume only in VFD. CSF 5-HIAA correlated inversely with FA of the WM tracts of the anterior limb of the internal capsule (ALIC) only in VFD.Conclusions: Elevated cisternal 5-HIAA in VFD may reflect increased dorsal raphe serotonin, potentially inducing excessive autoreceptor activation, inducing a putative serotonin deficit in terminal fields. Resultant reductions in neurotrophic activity are reflected by smaller right hippocampal volume. Convergent evidence of reduced neurotrophic activity in association with high CSF 5-HIAA in VFD was reflected by reduced FA of the ALIC.

Serotonin Metabolites in the Cerebrospinal Fluid in Sudden Infant Death Syndrome

Forensic biomarkers are needed in sudden infant death syndrome (SIDS) to help identify this group among other sudden unexpected deaths in infancy. Previously, we reported multiple serotonergic (5-HT) abnormalities in nuclei of the medulla oblongata that help mediate protective responses to homeostatic stressors. As a first step toward their assessment as forensic biomarkers of medullary pathology, here we test the hypothesis that 5-HT-related measures are abnormal in the cerebrospinal fluid (CSF) of SIDS infants compared with those of autopsy controls. Levels of CSF 5-hydroxyindoleacetic acid (5-HIAA) and homovanillic acid (HVA), the degradative products of 5-HT and dopamine, respectively, were measured by high-performance liquid chromatography in 52 SIDS and 29 non-SIDS autopsy cases. Tryptophan (Trp) and tyrosine (Tyr), the substrates of 5-HT and dopamine, respectively, were also measured. There were no significant differences in 5-HIAA, Trp, HVA, or Tyr levels between the SIDS and non-SIDS groups. These data preclude the use of 5-HIAA, HVA, Trp, or Tyr measurements as CSF autopsy biomarkers of 5-HT medullary pathology in infants who have died suddenly and unexpectedly. They do, however, provide important information about monoaminergic measurements in human CSF at autopsy and their developmental profile in infancy that is applicable to multiple pediatric disorders beyond SIDS.

Sertraline effects on cerebrospinal fluid monoamines and species-typical socioemotional behavior of female cynomolgus monkeys

Although widely prescribed, little is known about the effects of selective serotonin reuptake inhibitors (SSRIs) on social behavior and cerebrospinal fluid (CSF) monoamines in female primates. The objective of this study was to determine the effects of sertraline on agonistic and affiliative behavior. Twenty-one adult female cynomolgus monkeys were housed in small, stable social groups, trained to participate in oral dosing, and began a 5-week cumulative dose-response study. Serial doses of 0, 5, 10, 15, and 20 mg/kg of sertraline were administered orally for 1 week each. Behavior was recorded daily during 10-min observations before and 4 h after dosing. On the seventh day of dosing, circulating sertraline/desmethylsertraline and CSF monoamines/metabolites were determined 4 h after the last dose. At 20 mg/kg, circulating sertraline/desmethylsertraline was in the therapeutic range. CSF 5-hydroxyindole acetic acid decreased by 33 % (p < 0.05). Overall aggression, submission, locomotion, and time alone decreased, whereas affiliative behaviors (body contact, grooming) increased (all p values <0.05). Effects of sertraline on aggression and submission were social status-dependent, reducing aggression in dominants and submission in subordinates. A clinically relevant oral dose of sertraline resulted in CSF metabolite changes similar to those observed in patients and altered the socioemotional behavior of female monkeys. Changes in CSF 5-HT and dopamine are novel observations that may be sex-specific. The robust effects of sertraline on aggression and affiliation may explain the efficacy of SSRIs on a range of human behavioral pathologies that share the characteristics of increased aggression and decreased sociality.

The serotonin transporter gene is a substrate for age and stress dependent epigenetic regulation in rhesus macaque brain: Potential roles in genetic selection and Gene × Environment interactions

In humans, it has been demonstrated that the serotonin transporter linked polymorphic region (5-HTTLPR) genotype moderates risk in the face of adversity. One mechanism by which stress could interact with genotype is via epigenetic modifications. We wanted to examine whether stress interacted with genotype to predict binding of a histone 3 protein trimethylated at lysine 3 (H3K4me3) that marks active promoters. The brains (N = 61) of male rhesus macaques that had been reared in the presence or absence of stress were archived and the hippocampusi dissected. Chromatin immunoprecipitation was performed with an antibody against H3K4me3 followed by sequencing on a SolexaG2A. The effects of age, genotype (5-HTTLPR long/long vs. short), and stress exposure (peer-reared vs. mother-reared) on levels of H3K4me3 binding were determined. We found effects of age and stress exposure. There was a decline in H3K4me3 from preadolescence to postadolescence and lower levels in peer-reared monkeys and no effects of genotype. When we controlled for age, however, we found that there were effects of 5-HTTLPR genotype and rearing condition on H3K4me3 binding. In a larger sample, we observed that cerebrospinal fluid 5-hydroxyindoleacetic acid levels were subject to interactive effects among age, rearing history, and genotype. Genes containing both genetic selection and epigenetic regulation may be particularly important in stress adaptation and development. We find evidence for selection at the solute carrier family C6 member 4 gene and observe epigenetic reorganization according to genotype, stress, and age. These data suggest that developmental stage may moderate effects of stress and serotonin transporter genotype in the emergence of alternative adaptation strategies and in the vulnerability to developmental or psychiatric disorders.

Cerebrospinal fluid 5-hydroxyindolacetic acid correlates directly with negative affective intensity, but not affective lability, in human subjects

Centrally acting monoamines have long been thought to be associated with component traits of behavior and emotion and are potential biological mediators of psychopathology. In this study we tested the hypothesis that centrally acting monoamines would be associated with measures of affective instability (i.e. affective intensity and affective lability) in healthy and personality disordered human subjects. In total, 57 adult subjects including 19 psychiatrically healthy volunteers and 38 personality disordered individuals were assessed for affective instability with the affective intensity measure (AIM) and the Affective Lability Scale (ALS). Samples of cerebrospinal fluid (CSF) were collected for assay of 5-hydroxyindoleacitic acid (5-HIAA), homovanillic acid (HVA) and 3-methoxy-4-hydroxy-phenylglycol (MHPG). CSF 5-HIAA concentration correlated directly with overall AIM score and, specifically, with the AIM Negative Intensity score, in all subjects and in personality disordered subjects. This result was not affected but the addition of aggression scores or life history of mood disorder to the model. Neither CSF HVA nor MHPG were found to uniquely correlate with either AIM or ALS measure. Higher Affective Intensity scores, Negative Intensity scores, specifically, are directly correlated with higher basal levels of CSF 5-HIAA. This relationship was independent of aggression, life history of mood disorder and general personality traits.

Effects of early life stress on drinking and serotonin system activity in rhesus macaques: 5-hydroxyindoleacetic acid in cerebrospinal fluid predicts brain tissue levels

Early childhood stress is a risk factor for the development of substance-abuse disorders. A nonhuman primate model of early life stress, social impoverishment through nursery-rearing rather than mother-rearing, has been shown to produce increased impulsive and anxiety-like behaviors, cognitive and motor deficits, and increased alcohol consumption. These behavioral changes have been linked to changes in cerebrospinal fluid (CSF) levels of 5-hydroxyindoleacetic acid (5-HIAA), a serotonin (5-HT) metabolite. The effects of different rearing conditions on ethanol drinking and three measures of 5-HT function in the central nervous system were evaluated, including CSF 5-HIAA levels and tissue levels of 5-HT and 5-HIAA in brain samples. Brain samples were taken from the dorsal caudate, putamen, substantia nigra (SN) pars reticulata, SN pars compacta and hippocampus. There was a clear effect of rearing condition on the 5-HT system. Overall 5-HIAA and 5-HIAA/5-HT ratio measures of 5-HT turnover were significantly lower in nursery reared compared to mother-reared animals. In addition, there was a strong within-subject correlation between CSF and brain tissue 5-HIAA levels. Ethanol drinking was greater in nursery reared monkeys, consistent with previous results. These findings show that CSF 5-HIAA measurements can be used to predict brain 5-HT activity that may be involved in behavioral outcomes such as anxiety and alcohol consumption. Thus, CSF sampling may provide a minimally invasive test for neurochemical risk factors related to alcohol abuse.

Deficient serotonin neurotransmission and depression-like serotonin biomarker alterations in tryptophan hydroxylase 2 (Tph2) loss-of-function mice

Probably the foremost hypothesis of depression is the 5-hydroxytryptamine (5-HT, serotonin) deficiency hypothesis. Accordingly, anomalies in putative 5-HT biomarkers have repeatedly been reported in depression patients. However, whether such anomalies in fact reflect deficient central 5-HT neurotransmission remains unresolved. We employed a naturalistic model of 5-HT deficiency, the tryptophan hydroxylase 2 (Tph2) R439H knockin mouse, to address this question. We report that Tph2 knockin mice have reduced basal and stimulated levels of extracellular 5-HT (5-HT(Ext)). Interestingly, cerebrospinal fluid (CSF) 5-hydroxyindoleacetic acid (5-HIAA) and fenfluramine-induced plasma prolactin levels are markedly diminished in the Tph2 knockin mice. These data seemingly confirm that low CSF 5-HIAA and fenfluramine-induced plasma prolactin reflects chronic, endogenous central nervous system (CNS) 5-HT deficiency. Moreover, 5-HT(1A) receptor agonist-induced hypothermia is blunted and frontal cortex 5-HT(2A) receptors are increased in the Tph2 knockin mice. These data likewise parallel core findings in depression, but are usually attributed to anomalies in the respective receptors rather than resulting from CNS 5-HT deficiency. Further, 5-HT(2A) receptor function is enhanced in the Tph2 knockin mice. In contrast, 5-HT(1A) receptor levels and G-protein coupling is normal in Tph2 knockin mice, indicating that the blunted hypothermic response relates directly to the low 5-HT(Ext). Thus, we show that not only low CSF 5-HIAA and a blunted fenfluramine-induced prolactin response, but also blunted 5-HT(1A) agonist-induced hypothermia and increased 5-HT(2A) receptor levels are bona fide biomarkers of chronic, endogenous 5-HT deficiency. Potentially, some of these biomarkers could identify patients likely to have 5-HT deficiency. This could have clinical research utility or even guide pharmacotherapy.

Dystrobrevin-binding protein 1 gene ( DTNBP1) variants associated with cerebrospinal fluid homovanillic acid and 5-hydroxyindoleacetic acid concentrations in healthy volunteers

The dystrobrevin binding protein-1 ( DTNBP1) gene encodes dysbindin-1, a protein involved in neurodevelopmental and neurochemical processes related mainly to the monoamine dopamine. We investigated possible associations between eleven DTNBP1 polymorphisms and cerebrospinal fluid (CSF) concentrations of the major dopamine metabolite homovanillic acid (HVA), the major serotonin metabolite 5-hydroxyindoleacetic acid (5-HIAA), and the major noradrenaline metabolite 3-methoxy-4-hydroxyphenylglycol (MHPG) in healthy human subjects ( n = 132). Two polymorphisms, rs2619538 and rs760666, were nominally associated with CSF HVA and 5-HIAA concentrations, whereas a third polymorphism, rs909706, showed association only with HVA. After correction for multiple testing only the associations between rs2619538 and HVA and 5-HIAA concentrations remained significant. No significant association was found between any of the investigated DTNBP1 polymorphisms and CSF MHPG concentrations. The results suggest that genetic variation in DTNBP1 gene affects the regulation of dopamine and serotonin turnover in the central nervous system of healthy volunteers.

Clinical and molecular characterisation of hereditary dopamine transporter deficiency syndrome: an observational cohort and experimental study

SummaryBackgroundDopamine transporter deficiency syndrome is the first identified parkinsonian disorder caused by genetic alterations of the dopamine transporter. We describe a cohort of children with mutations in the gene encoding the dopamine transporter (SLC6A3) with the aim to improve clinical and molecular characterisation, reduce diagnostic delay and misdiagnosis, and provide insights into the pathophysiological mechanisms.Methods11 children with a biochemical profile suggestive of dopamine transporter deficiency syndrome were enrolled from seven paediatric neurology centres in the UK, Germany, and the USA from February, 2009, and studied until June, 2010. The syndrome was characterised by detailed clinical phenotyping, biochemical and neuroradiological studies, and SLC6A3 mutation analysis. Mutant constructs of human dopamine transporter were used for in-vitro functional analysis of dopamine uptake and cocaine-analogue binding.FindingsChildren presented in infancy (median age 2·5 months, range 0·5–7) with either hyperkinesia (n=5), parkinsonism (n=4), or a mixed hyperkinetic and hypokinetic movement disorder (n=2). Seven children had been initially misdiagnosed with cerebral palsy. During childhood, patients developed severe parkinsonism-dystonia associated with an eye movement disorder and pyramidal tract features. All children had raised ratios of homovanillic acid to 5-hydroxyindoleacetic acid in cerebrospinal fluid, of range 5·0–13·2 (normal range 1·3–4·0). Homozygous or compound heterozygous SLC6A3 mutations were detected in all cases. Loss of function in all missense variants was recorded from in-vitro functional studies, and was supported by the findings of single photon emission CT DaTSCAN imaging in one patient, which showed complete loss of dopamine transporter activity in the basal nuclei.InterpretationDopamine transporter deficiency syndrome is a newly recognised, autosomal recessive disorder related to impaired dopamine transporter function. Careful characterisation of patients with this disorder should provide novel insights into the complex role of dopamine homoeostasis in human disease, and understanding of the pathophysiology could help to drive drug development.FundingBirmingham Children's Hospital Research Foundation, Birth Defects Foundation Newlife, Action Medical Research, US National Institutes of Health, Wellchild, and the Wellcome Trust.

Early death and CSF monoamine metabolites in schizophrenia spectrum psychosis

Introduction: Patients with schizophrenia have higher rates of mortality than the general population. Lower concentrations of the cerebrospinal fluid (CSF) monoamine metabolites homovanillic acid (HVA) and 5-hydroxyindoleacetic acid (5-HIAA) have been associated with suicidal, aggressive and impulsive behavior. Mortality has been suggested as a measure of impulsivity and a relationship between early death and lower concentrations of CSF monoamine metabolites has been reported but the studies are few with short periods of follow-up and small numbers. Aim: The objective of this study was to investigate a relationship between early death and concentrations of CSF 5-HIAA and HVA. Methods: Three hundred and eighty-five inpatients with schizophrenia spectrum psychosis were lumbar punctured in a standardized manner and followed for a median of 26 years. Patients were searched to identify those who had died. Causes of death were obtained from the Causes of Death Register. Results: During the time of follow-up, 97 patients died. Schizophrenia spectrum psychosis patients died at an earlier age from both natural and unnatural causes of death. No significant associations were found between CSF 5-HIAA and HVA concentrations and non-suicidal death. Attempted suicide was not a risk factor for non-suicidal death at younger age. Conclusion: Patients with schizophrenia spectrum psychosis die at an earlier age from both natural and unnatural causes of death. Attempted suicide is not a risk factor for non-suicidal death at younger age. Low concentrations of CSF HVA and 5-HIAA were not a risk factor for non-suicidal death at younger age in schizophrenia spectrum psychosis.

Central Nervous System Serotonin and Clustering of Hostility, Psychosocial, Metabolic, and Cardiovascular Endophenotypes in Men

To use measures of cerebrospinal fluid (CSF) 5-hydroxyindoleacetic acid (5HIAA) and genotype of a functional polymorphism of the monoamine oxidase A gene promoter (MAOA-uVNTR) to study the role of central nervous system (CNS) serotonin in clustering of hostility, other psychosocial, metabolic and cardiovascular endophenotypes. In 86 healthy male volunteers, we evaluated CSF levels of the primary serotonin metabolite 5HIAA and MAOA-uVNTR genotype for association with a panel of 29 variables assessing hostility, other psychosocial, metabolic, and cardiovascular endophenotypes. The correlations of 5HIAA with these endophenotypes in men with more active MAOA-uVNTR alleles were significantly different from those of men with less active alleles for 15 of the 29 endophenotypes. MAOA-uVNTR genotype and CSF 5HIAA interacted to explain 20% and 22% of the variance, respectively, in scores on one factor wherein high scores reflected a less healthy psychosocial profile and a second factor wherein high score reflected increased insulin resistance, body mass index, blood pressure and hostility. In men with less active alleles, higher 5HIAA was associated with more favorable profiles of hostility, other psychosocial, metabolic and cardiovascular endophenotypes; in men with more active alleles, higher 5HIAA was associated with less favorable profiles. These findings indicate that, in men, indices of CNS serotonin function influence the expression and clustering of hostility, other psychosocial, metabolic and cardiovascular endophenotypes that have been shown to increase risk of developing cardiovascular disease. The findings are consistent with the hypothesis that increased CNS serotonin is associated with a more favorable psychosocial/metabolic/cardiovascular profile, whereas decreased CNS serotonin function is associated with a less favorable profile.

Tryptophan hydroxylase gene 1 ( TPH1) variants associated with cerebrospinal fluid 5-hydroxyindole acetic acid and homovanillic acid concentrations in healthy volunteers

Tryptophan hydroxylase (TPH) is the rate-limiting enzyme in serotonin synthesis. We investigated possible relationships between five TPH1 gene polymorphisms and cerebrospinal fluid (CSF) concentrations of the major serotonin metabolite 5-hydroxyindoleacetic acid (5-HIAA), the major dopamine metabolite homovanillic acid (HVA), and the major norepinephrine metabolite 3-methoxy-4-hydroxyphenylglycol (MHPG) in healthy volunteers ( n = 132). The G-allele of the TPH1 rs4537731 (A-6526G) polymorphism was associated with 5-HIAA and HVA, but not MHPG concentrations. None of the other four TPH1 polymorphisms (rs211105, rs1800532, rs1799913 and rs7933505) were significantly associated with any of the monoamine metabolite concentrations. Two (rs4537731G/rs211105T/rs1800532C/rs1799913C/rs7933505G and rs4537731A/rs211105T/rs1800532C/rs1799913C/rs7933505G) of five common TPH1 five-allele haplotypes were associated with 5-HIAA and HVA concentrations in opposite directions. None of the common haplotypes was associated with MHPG concentrations in the CSF. The results suggest that TPH1 gene variation participates in the regulation of serotonin and dopamine turnover rates in the central nervous system of healthy human subjects.

Cerebrospinal fluid 5-hydroxyindolacetic acid and homovanillic acid: reciprocal relationships with impulsive aggression in human subjects

While the relationship between cerebrospinal fluid 5-HIAA (CSF 5-HIAA) and aggression is typically reported as inverse, studies of some groups of aggressive individuals demonstrate a positive (or no) relationship, between these two variables. It is possible that simultaneous examination of both CSF 5-HIAA and CSF homovanillic acid (HVA), which co-vary in human subjects may clarify differences in reported findings in different groups of aggressive individuals. CSF 5-HIAA and CSF HVA concentrations were simultaneously examined in 60 healthy human subjects (40 with personality disorder and 20 healthy controls) and were correlated with measures of aggression and impulsivity. CSF 5-HIAA concentrations correlated positively, and CSF HVA concentrations correlated inversely, with a composite measure of impulsive aggression in all subjects as well as in the personality disordered subjects. The CSF 5-HIAA findings are consistent with those demonstrating reduced post-synaptic 5-HT receptor responsiveness to 5-HT agent challenge and suggest differences in the pathophysiology between different groups of subjects with aggressive behavior, particularly with regard to severity of aggressive behavior.

CSF neurochemicals during tryptophan depletion in individuals with remitted depression and healthy controls

The purpose of this study was to examine the differential effects of acute tryptophan (TRP) depletion vs. sham condition on plasma, cerebrospinal fluid (CSF) biochemical parameters, and mood in the following three subject groups: (1) nine antidepressant-free individuals with remitted depression, (2) eight paroxetine-treated individuals with recently remitted depression, and (3) seven healthy controls. Plasma TRP decreased during TRP depletion and increased during sham condition (p<.01). CSF TRP and 5-hydroxyindoleacetic acid were lower during TRP depletion than sham condition (p<.01 each). During TRP depletion, CSF TRP correlated significantly with the plasma sum of large neutral amino acids (SigmaLNAA) (R=-.52, p=.01), but did not significantly correlate with plasma TRP (R=.15, p=.52). The correlation between CSF TRP and ratio of TRP to SigmaLNAA was R=.41 and p=.06 during TRP depletion, and R=-.44 and p=.04 during sham condition. A negative correlation trend was observed between CSF-TRP levels and peak Hamilton Depression Rating Scale scores during TRP depletion in patients recovered from depression (R=-.45, p=.07), but not in healthy controls (R=-.01, p=.98). CSF neuropeptide Y was higher during TRP depletion than sham condition (t=1.75, p<.10). These results illustrate the importance of assessing plasma SigmaLNAA when using the TRP depletion paradigm. The use of a single CSF sampling technique although practical may result in data acquisition limitations.