Correlations between serotonin impairments and clinical indices in multiple system atrophy.

BACKGROUND AND PURPOSE: Multiple system atrophy (MSA) is a neurodegenerative disease with characteristic motor and autonomic symptoms. Impaired brain serotonergic innervation can be associated with various clinical indices of MSA; however, the relationship between clinical symptoms and cerebrospinal fluid (CSF) levels of 5-hydroxyindole acetic acid (5-HIAA), a main serotonin metabolite, has not been fully elucidated. METHODS: To compare CSF 5-HIAA levels between patients with MSA and healthy controls, we included 33 controls and 69 MSA patients with either predominant parkinsonian or cerebellar ataxia subtypes. CSF 5-HIAA levels were measured using high-performance liquid chromatography. Additionally, we investigated correlations between CSF 5-HIAA and various clinical indices in 34 MSA patients. RESULTS: CSF 5-HIAA levels were significantly lower in MSA patients than in controls (p < 0.0001). Probable MSA patients had lower CSF 5-HIAA levels than possible MSA patients (p < 0.001). In MSA patients, CSF 5-HIAA levels were inversely correlated with scores in Parts 1, 2, and 4 of the Unified Multiple System Atrophy Rating Scale, and with systolic and diastolic blood pressure in Part 3. Structural equation modeling revealed significant paths between serotonin and clinical symptoms, and significance was highest for activities of daily living, walking, and body sway. CONCLUSIONS: Serotonin dysfunction, as assessed by CSF 5-HIAA levels, may implicate greater MSA severity.

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 53 years versus 47 years, 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 0.49 ng/mL versus 0.62 ng/mL, P = 0.03) and significantly lower 5-HIAA levels (median 12.57 ng/mL versus 15.41 ng/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.

Exploring the aging process of cognitively healthy adults by analyzing cerebrospinal fluid metabolomics using liquid chromatography-tandem mass spectrometry.

BACKGROUND: During biological aging, significant metabolic dysregulation in the central nervous system may lead to cognitive decline and neurodegeneration. However, the metabolomics of the aging process in cerebrospinal fluid (CSF) has not been thoroughly explored. METHODS: In this cohort study of CSF metabolomics using liquid chromatography-mass spectrometry (LC-MS), fasting CSF samples collected from 92 cognitively unimpaired adults aged 20-87 years without obesity or diabetes were analyzed. RESULTS: We identified 37 metabolites in these CSF samples with significant positive correlations with aging, including cysteine, pantothenic acid, 5-hydroxyindoleacetic acid (5-HIAA), aspartic acid, and glutamate; and two metabolites with negative correlations, asparagine and glycerophosphocholine. The combined alterations of asparagine, cysteine, glycerophosphocholine, pantothenic acid, sucrose, and 5-HIAA showed a superior correlation with aging (AUC = 0.982). These age-correlated changes in CSF metabolites might reflect blood-brain barrier breakdown, neuroinflammation, and mitochondrial dysfunction in the aging brain. We also found sex differences in CSF metabolites with higher levels of taurine and 5-HIAA in women using propensity-matched comparison. CONCLUSIONS: Our LC-MS metabolomics of the aging process in a Taiwanese population revealed several significantly altered CSF metabolites during aging and between the sexes. These metabolic alterations in CSF might provide clues for healthy brain aging and deserve further exploration.

Cerebrospinal Fluid Concentrations of Neurotransmitters in a Greek Pediatric Reference Population.

BACKGROUND: Biogenic amines and pterins analysis in cerebrospinal fluid (CSF) are reliable biomarkers for the diagnosis of inherited disorders of monoamine neurotransmitters. OBJECTIVE: The objectives of this study were the establishment of reference values of CSF biogenic amine metabolites in a cohort of Greek children, the detection of primary defects of biogenic amine metabolism, and the assessment of biogenic amine metabolites in children with different neurological disorders. METHODS: CSF biogenic amine metabolites and pterins (biopterin and neopterin) were analyzed using high-performance liquid chromatography with electrochemical and fluorescence detection. Three hundred sixty-three samples were analyzed: 60 infants and children with no history of neurological disorder, 6 with inherited disorders of monoamine neurotransmitters, and 297 with diverse neurological disorders. RESULTS: Reference values were stratified into six age groups. A strong correlation between homovanillic acid (HVA) and 5-hydroxyindoleacetic acid (5HIAA) levels with age was detected (p < 0.001). Two patients were diagnosed with a defect of the biogenic amine synthetic pathway and three with a defect of tetrahydrobiopterin cofactor production. HVA and 5HIAA abnormalities were detected within different groups of neurological disorders, but none followed a specific pattern of HVA and 5HIAA abnormalities. CONCLUSION: In the current study, Greek reference values of biogenic amines and pterins in CSF are presented. Five new patients with inherited monoamine neurotransmitter disorders are described. Nonspecific secondary biogenic amine disturbances can be seen in patients with different neurological disorders.

Cerebrospinal Fluid Pterins, Pterin-Dependent Neurotransmitters, and Mortality in Pediatric Cerebral Malaria.

BACKGROUND: Cerebral malaria (CM) pathogenesis remains incompletely understood. Having shown low systemic levels of tetrahydrobiopterin (BH4), an enzymatic cofactor for neurotransmitter synthesis, we hypothesized that BH4 and BH4-dependent neurotransmitters would likewise be low in cerebrospinal fluid (CSF) in CM. METHODS: We prospectively enrolled Tanzanian children with CM and children with nonmalaria central nervous system conditions (NMCs). We measured CSF levels of BH4, neopterin, and BH4-dependent neurotransmitter metabolites, 3-O-methyldopa, homovanillic acid, and 5-hydroxyindoleacetate, and we derived age-adjusted z-scores using published reference ranges. RESULTS: Cerebrospinal fluid BH4 was elevated in CM (n = 49) compared with NMC (n = 51) (z-score 0.75 vs -0.08; P < .001). Neopterin was increased in CM (z-score 4.05 vs 0.09; P < .001), and a cutoff at the upper limit of normal (60 nmol/L) was 100% sensitive for CM. Neurotransmitter metabolite levels were overall preserved. A higher CSF BH4/BH2 ratio was associated with increased odds of survival (odds ratio, 2.94; 95% confidence interval, 1.03-8.33; P = .043). CONCLUSION: Despite low systemic BH4, CSF BH4 was elevated and associated with increased odds of survival in CM. Coma in malaria is not explained by deficiency of BH4-dependent neurotransmitters. Elevated CSF neopterin was 100% sensitive for CM diagnosis and warrants further assessment of its clinical utility for ruling out CM in malaria-endemic areas.

Sex and race differences of cerebrospinal fluid metabolites in healthy individuals.

INTRODUCTION: Analyses of cerebrospinal fluid (CSF) metabolites in large, healthy samples have been limited and potential demographic moderators of brain metabolism are largely unknown. OBJECTIVE: Our objective in this study was to examine sex and race differences in 33 CSF metabolites within a sample of 129 healthy individuals (37 African American women, 29 white women, 38 African American men, and 25 white men). METHODS: CSF metabolites were measured with a targeted electrochemistry-based metabolomics platform. Sex and race differences were quantified with both univariate and multivariate analyses. Type I error was controlled for by using a Bonferroni adjustment (0.05/33 = .0015). RESULTS: Multivariate Canonical Variate Analysis (CVA) of the 33 metabolites showed correct classification of sex at an average rate of 80.6% and correct classification of race at an average rate of 88.4%. Univariate analyses revealed that men had significantly higher concentrations of cysteine (p < 0.0001), uric acid (p < 0.0001), and N-acetylserotonin (p = 0.049), while women had significantly higher concentrations of 5-hydroxyindoleacetic acid (5-HIAA) (p = 0.001). African American participants had significantly higher concentrations of 3-hydroxykynurenine (p = 0.018), while white participants had significantly higher concentrations of kynurenine (p < 0.0001), indoleacetic acid (p < 0.0001), xanthine (p = 0.001), alpha-tocopherol (p = 0.007), cysteine (p = 0.029), melatonin (p = 0.036), and 7-methylxanthine (p = 0.037). After the Bonferroni adjustment, the effects for cysteine, uric acid, and 5-HIAA were still significant from the analysis of sex differences and kynurenine and indoleacetic acid were still significant from the analysis of race differences. CONCLUSION: Several of the metabolites assayed in this study have been associated with mental health disorders and neurological diseases. Our data provide some novel information regarding normal variations by sex and race in CSF metabolite levels within the tryptophan, tyrosine and purine pathways, which may help to enhance our understanding of mechanisms underlying sex and race differences and potentially prove useful in the future treatment of disease.

Long-term clinical outcome of 6-pyruvoyl-tetrahydropterin synthase-deficient patients.

INTRODUCTION: 6-Pyruvoyl-tetrahydropterin synthase deficiency (PTPSd) is a rare autosomal recessive disorder of synthesis of biogenic amines, which is characterized by variable neurological impairment and hyperphenylalaninemia. We aimed to assess the long-term clinical outcome of this disorder and the factors affecting it. METHODS: At total of 28 PTPSd patients (aged 19.9 ±â€¯10.9 years) underwent clinical (neurological and psychiatric) and neuropsychological assessment (BRIEF, VABS-II, and IQ). Based on CSF homovanillic (HVA) and 5-hydroxyindolacetic acid (5-HIAA) and pterin concentrations at diagnosis, patients were classified as having either a severe [SF; low level of CSF, HVA, and 5-HIAA with altered neopterin/biopterin (Neo/Bio)] or mild form (MF; normal HVA and 5-HIAA with altered Neo/Bio) of PTPSd. RESULTS: Approximately 36% of patients had MF PTPSd. At the last examination, 43% of patients had movement disorders (2 MF, 10 SF), 43% of patients had variable degrees of intellectual disability (SF only), 39% met the criteria for a psychiatric disorder (3 MF, 9 SF). Applying a linear regression model, we found that HVA and phenylalanine levels at birth had a significant influence on IQ, BRIEF, and VABS-II variability. Lastly, 5-HIAA further contributed to VABS-II variability. The disease showed a self-limiting clinical course and its treatment, although delayed, is effective in improving the neurological status. CONCLUSIONS: Neurodevelopmental impairment due to PTPSd shows a self-limiting course. A continuous improvement in the neurological condition has been observed in patients receiving treatment, even when delayed. The severity of brain biogenic amine depletion at diagnosis predicts neurological and psychiatric outcomes.

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.

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

BACKGROUND: 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. AIM: Finding a noninvasive marker for central serotonin turnover that can be used for diagnosis and therapeutic monitoring in patients with primary neurotransmitter deficiencies. METHODS: 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. RESULTS: 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). CONCLUSION: Our findings suggest that salivary serotonin measurement is not a suitable noninvasive marker for measuring central serotonin turnover.

Comparison of the levels of the serotonin metabolite, 5-hydroxyindole acetic acid, in cerebrospinal fluid from patients with and without premature ejaculation.

INTRODUCTION: Premature ejaculation (PE) is a significant problem as it can cause a loss of sexual self-confidence and a significant deterioration in quality of life. The frequency of PE varies between 9% and 27%. In the current study, we aimed to compare the levels of the serotonin metabolite 5HIAA (5 hydroxyindole acetic acid) in the cerebrospinal fluid (CSF) of patients with and without PE according to IELT (intravaginal ejaculation latency time) in order to investigate the relationship of PE with CSF 5HIAA levels. MATERIALS AND METHODS: A total of 60 male patients were included in the study who were planning to undergo surgery under spinal anesthesia, 30 in the patient (PE) group (all of the included patients had an IELT of <1min) and 30 in the control group (patients had an IELT of >1min). Levels of CSF 5HIAA were measured. RESULTS: There was a significant negative correlation between IELT and the 5HIAA variables in all patients (r=-0.322, p=0.012). Although the average 5HIAA levels (nmol/L) were higher in the patient group (86.80±28.33) than in the control group (76.44±35.91), this difference was not significant (p=0.22). DISCUSSION: Results of the current study bring new and different perspectives to the explanation of PE pathophysiology. There is a need for more specific and genetic studies to determine the best treatment for this common disorder.

Sampling issues of cerebrospinal fluid and plasma monoamines: Investigation of the circadian rhythm and rostrocaudal concentration gradient.

Biomarkers for neurodegenerative dementias offer interesting prospects regarding diagnosis and disease monitoring. Monoamines such as dopamine, (nor)adrenaline, serotonin (5-hydroxytryptamine or 5-HT), and their respective metabolites homovanillic acid (HVA) and 3,4-dihydroxyphenylacetic acid, 3-methoxy-4-hydroxyphenylglycol (MHPG), and 5-hydroxyindoleacetic acid (5-HIAA), were shown to be altered in dementia, including Alzheimer's disease (AD). Biomarker research is hampered by potential confounds including the influence of time of day and volume of cerebrospinal fluid (CSF) collected. Therefore, the possibility of a circadian rhythm in CSF and plasma, and the presence of a rostrocaudal concentration gradient (RCG) in CSF for aforementioned monoamines/metabolites, were investigated. Circadian rhythmicity was assessed using reversed-phase ultra-high performance liquid chromatography with electrochemical detection (RP-UHPLC-ECD) to measure monoamine/metabolite concentrations in 271 paired CSF and plasma samples, successively collected over a period of 30 h and derived from eight healthy subjects. Plasma samples were also analyzed for melatonin, serving as positive control analyte, using ELISA. The RCG examination entailed RP-UHPLC-ECD analyses on five consecutive CSF samples derived from 10 patients with AD and 10 non-AD/control subjects. Besides a diurnal rhythm for melatonin, we found a similar rhythmicity for plasma HVA, with acrophases occurring between 02:00 and 06:00 h, in four out of seven subjects. Three and two subjects showed a circadian rhythm for CSF HVA and 5-HIAA, respectively. No rhythmicity was observed in any other compound. We found that only CSF MHPG, HVA and 5-HIAA levels differed across CSF fractions, and that these changes in 5-HIAA levels varied in the AD versus non-AD/control group. Positive correlations between CSF volume and HVA and 5-HIAA levels, indicative of a RCG, were also observed. Such a RCG could not be detected for the other monoamines/metabolites. Our results stress the importance of standardizing sampling procedures of biological fluids with respect to time of day, volume and number of samples.

Spectrum of movement disorders and neurotransmitter abnormalities in paediatric POLG disease.

OBJECTIVES: To describe the spectrum of movement disorders and cerebrospinal fluid (CSF) neurotransmitter profiles in paediatric patients with POLG disease. METHODS: We 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. RESULTS: Forty-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. CONCLUSIONS: Children 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.

Cerebrospinal fluid 5-HIAA concentrations correlate with cardiac uptake of 123I-MIBG during myocardial scintigraphy in drug naïve Parkinson's disease.

We examined the correlations between cerebrospinal fluid (CSF) concentrations of homovanillic acid (HVA) and 5-hydroxyindole acetic acid (5-HIAA) and imaging assessment scores, using 123I-Ioflupane SPECT and 123I-MIBG myocardial scintigraphy in 23 drug naïve PD patients. The CSF 5-HIAA concentration correlated with the H/M ratio of the delayed image (r = 0.458, p < 0.05) and the washout rate (r = - 0.642, p < 0.01) of 123I-MIBG myocardial scintigraphy. These correlations suggest some unclarified pathophysiological links between the central serotonergic and cardiac sympathetic systems.

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.

Poor evidence for putative abnormalities in cerebrospinal fluid neurotransmitters in patients with depression versus healthy non-psychiatric individuals: A systematic review and meta-analyses of 23 studies.

BACKGROUND: Although investigated for decades, surprisingly no systematic review has ever been published on monoamines concentrations in cerebrospinal fluid (CSF) in major depressive disorder (MDD) versus healthy individuals (HC). METHODS: We did a systematic review and meta-analyses according to the PRISMA Statement based on comprehensive database searches for studies on CSF biomarkers of monoamines and their precursor and/or metabolites, and glutamine, glutamate and GABA in MDD versus HC. Risk of bias was systematically assessed. RESULTS: A total of 23 studies were included. Statistically significantly decreased levels between MDD and HC were found regarding CSF 5-HIAA (n = 2/13 (15%)), HVA (n = 2/11 (18%)), MHPG (n = 1/8 (13%)), and GABA (n = 2/4 (50%)), while increased levels were reported regarding NE (n = 1/2 (50%)), MHPG (n = 1/8 (13%)) and DOPEG (n = 1/1 (100%)). A majority of the studies found no statistically significant differences between MDD and HC regarding CSF 5-HIAA, HVA, NE, MHPG, glutamine, glutamate and GABA. Meta-analyses showed: 5-HIAA (-3.85, -8.89, 1.19, 0.14), HVA (-18.02, -30.99, -5.04, 0.01), MHPG (0.11, -2.96, 3.17, 0.95) and GABA (-33.20, -51.79, -14.62, 0.00) (mean difference, lower 95% CL, upper 95% CL, p-value). Most studies were influenced by risk of bias mainly due to small sample sizes, and not considering potential confounders as age, gender, severity of depression, body height and position during lumbar puncture, analytics of biomarkers and medication. CONCLUSION: The evidence for CSF 5-HIAA, HVA, NE, MHPG, DOPEG and GABA being related to the pathophysiology of MDD is poor. Future controlled studies of monoamines or metabolites should validate the null i.e., that the concentrations of these compounds are not abnormal in MDD.

Biomarkers in cerebrospinal fluid of patients with bipolar disorder versus healthy individuals: A systematic review.

BACKGROUND: The pathophysiological processes of bipolar disorder (BD) may be detectable by the use of cerebrospinal fluid (CSF) biomarkers. AIM: We aimed for the first time to review studies of CSF biomarkers in patients with BD compared to healthy control individuals (HC). We investigated the effect of diagnosis, age, gender, clinical state, medication, technical characteristics of tests, fasting state and, cognitive function if applicable. METHOD: We did a systematic review according to the PRISMA Statement based on comprehensive database searches for studies on cerebrospinal biomarkers in patients with bipolar disorder versus HC. Risk of bias was systematically assessed. RESULTS: The search strategy identified 410 studies of which thirty-four fulfilled the inclusion criteria. A total of 117 unique biomarkers were investigated, out of which 11 were evaluated in more than one study. Forty biomarkers showed statistically significant differences between BD and HC in single studies. Only the findings of elevated homovanillic acid and 5-hydroxy-indoleacetic acid were replicated across studies. Most studies had a cross sectional design and were influenced by risk of bias mainly due to small sample size, lack of data on mood state at the time of the CSF puncture and not considering potential confounders including age, gender, diagnoses, BMI, life style factors such as smoking, and psychotropic medication. CONCLUSION: Specific monoamine CSF biomarkers may be related to the pathophysiology of BD. Future studies must aim at increasing the level of evidence by validating the positive findings in prospective studies with stringent methodology.

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.

Monoaminergic Markers Across the Cognitive Spectrum of Lewy Body Disease.

BACKGROUND: 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. OBJECTIVE: 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. METHODS: 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. RESULTS: 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). CONCLUSIONS: 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.

Seasonality of cerebrospinal fluid monoamine metabolite concentrations and their associations with meteorological variables in humans.

Seasonal variations in neurotransmitter parameters have been previously reported in humans. However, these studies have involved small sample sizes and have not examined possible relationships with meteorological variables. We compared cerebrospinal fluid (CSF) concentrations of the major monoamine neurotransmitter metabolites (5-HIAA, HVA, and MHPG) in 188 healthy controls (80 men, 108 women) in relationship to age, sex, BMI, and available meteorological variables. All subjects had a lumbar puncture (LP) performed at 9 a.m. after overnight stay. Meteorological data for the day prior to LP were obtained from the National Climatic Association and included the photoperiod, percent sunshine, temperature (max, min, mean), barometric pressure, relative humidity, amount of precipitation and sky cover. Results revealed differences across seasons and cross-seasons for CSF 5-HIAA (p ≤ .05), with post-hoc differences emerging between spring versus summer and fall and between x-spring and x-summer (p ≤ .05). Differences were also found across seasons for CSF HVA (p ≤ .05) with post-hoc differences between spring versus fall. CSF 5-HIAA was significantly inversely correlated with maximum (r = -.28, p ≤ .02), minimum (r = -.24, p ≤ .04), and mean temperature (r = -.28, p ≤ .02) in men. In women, 5-HIAA (r = -.22, p ≤ .02) and HVA (r = -.28, p ≤ .003) were significantly correlated with relative humidity. These data confirm previous findings of variations in serotonin and dopamine metabolites across the year and highlight possible underlying mechanisms involving meteorological changes, which may result in alterations in neurophysiology and behavior.