CSF 5-HIAA Research Articles

Sex differences of cerebrospinal fluid biomarkers in Alzheimer’s disease

AbstractBackgroundAlzheimer’s disease (AD) is more common in women than in men. Thus, to investigate the sex‐specific mechanism is important to understand the pathogenesis of AD. We examined the sex differences in levels of CSF biomarkers (tau, ptau‐181, Aβ42, HVA and 5HIAA) in AD.MethodThe subjects of this study consisted of clinically diagnosed 386 patients with AD (age 75.9±8.4 years, 237 women and 149 men). The clinical diagnosis was made based on the AD diagnostic criteria (NIA/AA, McKhann GM, et al., Alzheimers Dement 2011; 7: 263‐269). The CSF samples were obtained by lumbar puncture after informed consent was obtained. The levels of CSF tau, ptau‐181 and Aβ42 were measured by ELISA (Fujirebio, Belgium) according to the manufacturer’s protocol. The levels of CSF HVA and 5HIAA were measured by HPLC. We compared the levels of CSF biomarkers between women and men.ResultAge, the levels of CSF tau, ptau‐181 and Aβ42 showed no sex differences. The levels of CSF HVA (ng/ml) were 32.6±19.3 in women and 25.9±14.4 in men. The levels of 5HIAA were 19.1±11.7 in women and 14.8±7.7 in men. The levels of CSF HVA and 5HIAA were significantly higher in women than those in men (t‐test, HVA: p<0.001, 5HIAA: p<0.001).It has been reported that women have higher values of HVA and 5HIAA among normal subjects, due to higher monoamine oxidase (MAO) activity in women. The MAO‐A and MAO‐B genes are located on the X chromosome, and are controlled by XCI (X‐chromosome inactivation). However, the MAO genes may escape XCL MAO‐B has also been reported to be γ‐secretase associated protein and regulate neuronal amyloid β‐peptide levels. Thus, increased MAO‐B activity may be one of the reasons why AD is more common in women.ConclusionBoth CSF levels of HVA and 5HIAA were significantly higher in women in AD, presumably due to increased MAO activity.

Updated Parkinson's disease motor subtypes classification and correlation to CSF HVA and 5-HIAA levels (P3-11.005)

<h3>Objective:</h3> To update a motor subtypes classification using the MDS-UPDRS and determine if CSF neurotransmitter profiles (HVA and 5-HIAA) are different between MDS-UPDRS subtypes in a cohort from the Parkinson9s Progression Marker Initiative (PPMI). <h3>Background:</h3> Schiess <i>et al</i> designed a UPDRS motor classification of Parkinson9s Disease (PD) that has been widely used, but in the last decade, the field has moved towards the use of the MDS-UPDRS. <h3>Design/Methods:</h3> UPDRS and MDS-UPDRS scores were collected for 20 PD patients. Akinetic-rigid (AR), Tremor-dominant (TD), and Mixed (MX) subtypes were calculated using a UPDRS formula, and a new ratio was developed for MDS-UPDRS. This new formula was subsequently applied to 95 PD patients from the PPMI dataset, and subtyping was correlated to neurotransmitter levels. Data were analyzed using receiver operating characteristic models and ANOVA. <h3>Results:</h3> Compared to previous UPDRS classifications, the new MDS-UPDRS AR/TD ratios produced significantly different areas under the curves (AUC). The optimal sensitivity and specificity cutoff scores were ≥0.82 for TD, ≤0.71 for AR classifications and Mixed &gt;0.71 and &lt;0.82. Analysis of variance showed significant differences in 5-HIAA levels between the HC and AR group. Logistic models utilizing neurotransmitter levels and MDS-UPDRS motor scores showed significant AUCs for MDS-UPDRS classifications. <h3>Conclusions:</h3> This MDS-UPDRS motor subtype classification system provides a method to transition from the original UPDRS to the newer MDS-UPDRS and offers a reliable and quantifiable tool for monitoring disease progression that is supported by neurotransmitter levels. <b>Disclosure:</b> Dr. Suescun has nothing to disclose. Dr. Adams has stock in Medtronic. Dr. Block has nothing to disclose. Dr. Tharp has nothing to disclose. The institution of Prof. Ellmore has received research support from NIMH. Dr. Schiess has nothing to disclose.

CSF P-Tau181 and Other Biomarkers in Patients With Neuronal Intranuclear Inclusion Disease.

CSF tau phosphorylated at threonine 181 (p-tau181) is a widely used biomarker for Alzheimer disease (AD) and has recently been regarded to reflect β-amyloid and/or p-tau deposition in the AD brain. Neuronal intranuclear inclusion disease (NIID) is a neurodegenerative disease characterized by intranuclear inclusions in neurons, glial cells, and other somatic cells. Symptoms include dementia, neuropathy, and others. CSF biomarkers were not reported. The objective of this study was to investigate whether CSF biomarkers including p-tau181 are altered in patients with NIID. This was a retrospective observational study. CSF concentrations of p-tau181, total tau, amyloid-beta 1-42 (Aβ42), monoamine metabolites homovanillic acid (HVA), and 5-hydroxyindole acetic acid (5-HIAA) were compared between 12 patients with NIID, 120 patients with Alzheimer clinical syndrome biologically confirmed based on CSF biomarker profiles, and patients clinically diagnosed with other neurocognitive disorders (dementia with Lewy bodies [DLB], 24; frontotemporal dementia [FTD], 13; progressive supranuclear palsy [PSP], 21; and corticobasal syndrome [CBS], 13). Amyloid PET using Pittsburgh compound B (PiB) was performed in 6 patients with NIID. The mean age of patients with NIID, AD, DLB, FTD, PSP, and CBS was 71.3, 74.6, 76.8, 70.2, 75.5, and 71.9 years, respectively. CSF p-tau181 was significantly higher in NIID (72.7 ± 24.8 pg/mL) compared with DLB, PSP, and CBS and was comparable between NIID and AD. CSF p-tau181 was above the cutoff value (50.0 pg/mL) in 11 of 12 patients with NIID (91.7%). Within these patients, only 2 patients showed decreased CSF Aβ42, and these patients showed negative or mild local accumulation in PiB PET, respectively. PiB PET scans were negative in the remaining 4 patients tested. The proportion of patients with increased CSF p-tau181 and normal Aβ42 (A-T+) was significantly higher in NIID (75%) compared with DLB, PSP, and CBS (4.2%, 4.8%, and 7.7%, respectively). CSF HVA and 5-HIAA concentrations were significantly higher in patients with NIID compared with disease controls. CSF p-tau181 was increased in patients with NIID without amyloid accumulation. Although the deposition of p-tau has not been reported in NIID brains, the molecular mechanism of tau phosphorylation or secretion of p-tau may be altered in NIID.

Long-term neurological and psychiatric outcomes in patients with aromatic l-amino acid decarboxylase deficiency

Introductionl-amino acid decarboxylase deficiency (AADCD) is an ultrarare autosomal recessive defect of biogenic amine synthesis that presents with early-onset encephalopathy progressing to severe neurological impairment and intellectual disability. We aimed to explore neurocognitive and behavioral profiles associated with AADCD and possible factors predicting outcome in more detail. MethodsNine AADCD patients (23.2 ± 10.3 years; range 8–40) underwent systematic clinical and neuropsychological assessment. Diagnostic levels of CSF 5-hydroxyindolacetic acid (5-HIAA) and homovanillic acid (HVA), and DDC genotype (as ascertained by American College of Medical Genetics and Genomics grading) were included in the data analysis. ResultsAll AADCD patients were affected by intellectual disability and psychiatric disorders. Movement disorders included parkinsonism-dystonia, dysarthria, and oculogyric crises. CSF 5-HIAA and HVA levels at diagnosis had a significant influence on adaptive behavior and executive function performance. Patients homozygous for DDC pathogenetic variants showed lower CSF 5-HIAA and HVA levels and higher Unified Parkinson's Disease Rating Scale scores. The disease showed a self-limiting clinical course with partial improvement under pharmacological treatment (B6 and dopamine mimetic drugs). ConclusionsPatients with AADCD suffer from neuropsychological and psychopathological impairment, which may be improved but not reversed under the present therapeutic approach. However, cognitive functioning should be specifically examined in order to avoid its underestimation on the basis of movement disorder severity. Genotype and biogenic amine level at diagnosis have an important prognostic value.

Cerebrospinal fluid monoamine metabolite concentrations in suicide attempt: A meta-analysis.

The purpose of this meta-analysis was to critically examine the data from individual studies on CSF neurotransmitter metabolites to see whether there were consistencies in the results of the comparison of suicide attempters and psychiatric controls and of the comparison of attempted suicides using violent versus nonviolent methods. Systematic literature search across different electronic databases using PubMed/Google Scholar/EMBASE/Cochrane library was conducted for studies that reported concentration of CSF-neurotransmitter metabolites: 5-hydroxyindoleacetic acid (5-HIAA), homovanillic acid (HVA) and 3-methoxy-4-hydroxy phenylglycol (MHPG) in suicide attempters, from January'1981 to November'2020. Standardized mean differences (SMDs) and corresponding 95 % confidence interval (CIs) were deduced for outcome measures. I2 statistics were used to assess heterogeneity within studies. Data were analyzed using STATA software. A total of 36 studies (N = 1987 attempted suicide and N = 1235 psychiatry control) were included for the meta-analysis. We found CSF levels of all the 3 metabolites i.e. 5-HIAA (SMD= -0.43; 95 %CI: -0.61, -0.24), HVA (SMD= -0.16; 95 %CI: -0.33, -0.00) and MHPG (SMD= -0.33; 95 %CI: -0.71, -0.05) were lower in suicide attempters. While the findings were consistent for 5-HIAA, they were inconsistent for the HVA and MHPG. CSF levels of 5-HIAA (SMD= -0.66; 95 %; CI: -1.01, -0.31), HVA (SMD= -0.14; 95 %CI: -0.45, 0.16) and MHPG (SMD= -0.12; 95 %CI: -0.56, 0.31) were significantly lower in violent suicide attempters than non-violent attempters. No significant publication bias found in any study. We found a significant association between lower levels of CSF 5-HIAA in suicide attempters, particularly the violent ones, compared to psychiatric controls, whereas findings from CSF HVA and MHPG were inconsistent.

Early Rearing Conditions Affect Monoamine Metabolite Levels During Baseline and Periods of Social Separation Stress: A Non-human Primate Model (Macaca mulatta).

A variety of studies show that parental absence early in life leads to deleterious effects on the developing CNS. This is thought to be largely because evolutionary-dependent stimuli are necessary for the appropriate postnatal development of the young brain, an effect sometimes termed the “experience-expectant brain,” with parents providing the necessary input for normative synaptic connections to develop and appropriate neuronal survival to occur. Principal among CNS systems affected by parental input are the monoamine systems. In the present study, N = 434 rhesus monkeys (233 males, 201 females) were reared in one of two conditions: as mother-reared controls (MR; n = 269) or without adults with 24-h access to same-aged peers (PR; n = 165). When subjects were six-months-old, they underwent a separation paradigm involving 4, sequential, four-day social separations from their mothers or peers, with each separation followed by three-day reunions with their mothers or their peers. Prior to the separation paradigm, baseline cisternal CSF samples were obtained, as well as at the end of each the four social separations, and after final separation, during a recovery period. CSF was assayed for concentrations of monoamine metabolites and a blood sample was genotyped for the serotonin transporter (5-HTT) genotype. Replicating earlier landmark findings, PR subjects with the s allele exhibited lower baseline concentrations of the serotonin metabolite 5-hydroxyindoleacetic acid (5-HIAA), when compared to PR subjects homozygous for the L allele. MR subjects were undifferentiated by genotype. PR subjects exhibited lower CSF 5-HIAA concentrations during baseline, but higher CSF 5-HIAA during social separations, when compared to MR subjects. There were rearing effects for the dopamine metabolite homovanillic acid (HVA) and for the norepinephrine metabolite 3-methoxy-4-hydroxyphenylglycol (MHPG), with PR subjects showing higher HVA and lower MHPG when compared to MR subjects. These findings indicate that there are long-term deficits in the response of monoamines following early maternal absence. The results of this study confirm and extend earlier findings that early parental absence has deleterious consequences for the development of the monoamine systems, and that these consequences are modulated by the 5-HTT genotype.

Oxidative Stress, Folate Receptor Autoimmunity, and CSF Findings in Severe Infantile Autism.

Background Biomarkers such as oxidative stress, folate receptor alpha (FRα) autoimmunity, and abnormal brain serotonin turnover are common in autism. Methods Oxidative stress biomarkers with pro- and antioxidants were measured in the severe form of infantile autism (n = 38) and controls (n = 24). Children and parents had repeated testing for serum FR autoantibodies, spinal fluid dopamine and serotonin metabolites, pterins, and N5-methyltetrahydrofolate (MTHF). Statistical analysis assessed correlations between variables. Genetic analysis included the SLC6A4 and SLC29A4 genes encoding synaptic serotonin reuptake proteins. Results Compared to controls, the autism group showed a significant increase in oxidative DNA damage in lymphocytes, plasma ceruloplasmin and copper levels with a high copper/zinc ratio, thiol proteins, and superoxide dismutase (SOD) activity. Vitamin C levels were significantly diminished. In most autistic patients, the vitamin A (64%) and D (70%) levels were low. Serum FR autoantibodies fluctuating over 5–7 week periods presented in 68% of all autistic children, 41% of parents vs. 3.3% of control children and their parents. CSF showed lowered serotonin 5-hydroxyindole acetic acid (5HIAA) metabolites in 13 (34%), a low 5HIAA to HVA (dopamine metabolite) ratio in 5 (13%), low 5HIAA and MTHF in 2 (5%), and low MTHF in 8 patients (21%). A known SLC6A4 mutation was identified only in 1 autistic child with low CSF 5HIAA and a novel SLC29A4 mutation was identified in identical twins. Low CSF MTHF levels among only 26% of subjects can be explained by the fluctuating FR antibody titers. Two or more aberrant pro-oxidant and/or antioxidant factors predisposed to low CSF serotonin metabolites. Three autistic children having low CSF 5HIAA and elevated oxidative stress received antioxidative supplements followed by CSF 5HIAA normalisation. Conclusion In autism, we found diverse combinations for FR autoimmunity and/or oxidative stress, both amenable to treatment. Parental and postnatal FR autoantibodies tend to block folate passage to the brain affecting folate-dependent pathways restored by folinic acid treatment, while an abnormal redox status tends to induce reduced serotonin turnover, corrected by antioxidant therapy. Trial Registration. The case-controlled study was approved in 2008 by the IRB at Liège University (Belgian Number: B70720083916). Lay Summary. Children with severe infantile autism frequently have serum folate receptor autoantibodies that block the transport of the essential vitamin folate across the blood-brain barrier to the brain. Parents are often asymptomatic carriers of these serum folate receptor autoantibodies, which in mothers can block folate passage across the placenta to their unborn child. This folate deficiency during the child's intrauterine development may predispose to neural tube defects and autism. Oxidative stress represents a condition with the presence of elevated toxic oxygen derivatives attributed to an imbalance between the formation and protection against these toxic reactive oxygen derivatives. Oxidative stress was found to be present in autistic children where these reactive oxygen derivatives can cause damage to DNA, which changes DNA function and regulation of gene expression. In addition, excessive amounts of these toxic oxygen derivatives are likely to damage the enzyme producing the neuromessenger serotonin in the brain, diminished in about 1/3 of the autistic children. Testing children with autism for oxidative stress and its origin, as well as testing for serum folate receptor autoantibodies, could open new approaches towards more effective treatments.

The effects of fluoxetine on socioemotional behavior in female rhesus monkeys is influenced by social status

BackgroundChronic adverse social experience is a major environmental variable linked to multiple psychiatric disorders. The use of social subordination in nonhuman primates represents a translational model of chronic psychosocial stress. While social dominance is associated with a resistance to a range of stressors and social subordination produces stress‐susceptible phenotypes, the neural mechanisms that underlie status‐induced differences in susceptibility remain unclear. The current study assessed the effects of increasing serotonin (5HT) activity by administering fluoxetine on rates of socioemotional behavior (including agonistic, affiliative, and anxiety‐like behaviors) in female rhesus monkeys. We hypothesized that fluoxetine would increase rates of aggression in dominant but not subordinate animals.MethodsSubjects were gonadally intact adult female rhesus monkeys (n=14) housed in small social groups of four to six females each (6 dominant and 8 subordinate females). Using a counterbalanced design, subjects received both a 14‐day treatment with fluoxetine (SC dose of 2.8 mg/kg/day) and vehicle (50% polyethylene glycol in sterile saline) separated by a three‐week washout period. Behavioral observations were collected every two days using a standard monkey ethogram during each treatment, and CSF samples were collected at the end of each treatment for assessment of central 5‐hydroxyindoleacetic (5HIAA).ResultsThe amount of aggression directed at group mates was influenced by a status by treatment interaction (p=0.05, η2=0.27), with fluoxetine enhancing aggression in dominant females and decreasing aggression in subordinate females. As expected, subordinate females emitted significantly higher rates of submission behavior than did dominant females and this was unaffected by treatment (p=0.001). Affiliation emitted towards others was influenced by a status by treatment interaction (p=0.05, η2=0.27), as fluoxetine treatment decreased affiliation emitted in dominant females and increased it in subordinates. Anxiety‐like behavior was also influenced by a status by treatment interaction (p=0.011), as anxiety‐like behaviors were reduced only in subordinate females by fluoxetine treatment (p=0.012). CSF 5HIAA concentrations were reduced by fluoxetine (p&lt;0.001) regardless of social status.ConclusionThe data show that increased 5HT activity following fluoxetine treatment in female monkeys alters socioemotional behavior in a status‐dependent manner. Notably, subordinate females are less aggressive and more affiliative during fluoxetine treatment. Future studies include determining whether these effects of fluoxetine are sex dependent and whether subordinate males respond similarly to subordinate females.Support or Funding InformationThis research was supported by an NIMH grant MH110212.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Clinical and Biochemical Correlations of Aggression in Young Patients with Mental Disorders

Hyperdopaminergia has been identified at impulsive or psychotic patients, the polymorphism of COMT or other enzymes that metabolize dopamine could be involved. The deficiencies of the serotoninergic system in suicidal behaviour has been mentioned by many studies that indicate the reduction of 5-HT, 5-HIAA in CSF or 5-HTT polymorphism. Young patients with psychotic or depression symptoms manifest, frequently, aggressive and self-harm behaviour. Besides the association between the young age and the aggressivity of the patients with serious mental disorders, our study shows gender differences and this matter is sustained by hormonal factors. The study was conducted at the Gheorghe Preda Psychiatric Hospital in Sibiu. The study comprises 52 patients aged between 18 and 35 who were diagnosed with the diagnosis of Schizophrenia, Bipolar Affective Disorder, Depressive Episode and Major depressive disorder according to the DSM-5 criteria. Evaluation of the severity of psychiatric and depressive symptomathology were assessed with Brief Psychiatric Rating Scale and Beck Depression Inventory; aggression and self-aggression in the patients with Schizophrenia, respectively with Bipolar disorder, depressive episode and Major depression disorder were assessed with Buss Perry Aggression Questionnaire and Suicide Intent Scale. Regarding the severity of aggression in the young patients from our study (Buss Perry scale score), male gender is higher than female gender: higher percentages in males (35% and 10%) than in females (16 and 0%). Determining aggression in schizophrenia is possible due to COMT polymorphism that lead to impulsivity or psychotic symptoms. The study show a significant positive correlation between the severity of symptoms of schizophrenia and aggression. From the analysis of the severity of depression in young patients (SIS score) it is noted that its severity is higher in the female gender. Women had higher scores of moderate depression (58%) and severe (26%) than men (37 and 25%, respectively). This relationships could be possible due to the polymorphism of the gene encoding the 5-HTT serotonin transporter related with serotonin deficiency.The study do not show a significant positive correlation between the severity of the depressive symptomatology and the degree of the suicide intent.

CSF Apolipoprotein E in attempted suicide

BackgroundCholesterol and cholesterol metabolism, involved in continued neural plasticity, has been associated to suicide and suicidal behavior. Apolipoprotein E (ApoE) plays an important role in the cholesterol metabolism. The purpose of this study was to investigate whether ApoE in cerebrospinal fluid was related to severity of suicidal behavior as measured by number of earlier suicide attempts, reversibility/interruptabilty and violent method of suicide attempt. MethodsCSF ApoE and 5-hydroxyindolacetic acid (5-HIAA) were measured in 42 medication free suicide attempters. Earlier suicide attempts and the reversibility of suicide attempt method were assessed with the Suicide Intent Scale (SIS) and the Freeman Scale. Suicide attempts were classified according to violence of method. ResultsCSF ApoE levels significantly negatively correlated to the scores on Freeman Reversibility and there was a trend for lower CSF ApoE levels in suicide attempters using a violent method. Patients with at least one earlier suicide attempt (repeaters) showed a trend for higher CSF ApoE levels compared to suicide attempters debuting with suicidal behavior at inclusion in the study. The correlation between CSF ApoE and 5-HIAA was not significant. LimitationsThe main limitations to this study were a relatively small sample size and lack of a healthy control group. ConclusionIrreversible suicide attempts, representing a high risk for completed suicide, may be associated with lower level of ApoE in CSF.

0048 CEREBRAL SEROTONIN EXPRESSION PREDICTS DAYTIME SLEEP AND SLEEP DEVELOPMENT IN INFANT RHESUS MONKEYS

Cerebral serotonin expression and sleep share a complex and as yet unclear association in early development. Though serotonin is linked with sleep-wake patterns in early childhood, whether this association emerges during infancy remains to be discovered. We hypothesized that the developing serotonergic system will be associated with the development of sleep-wake patterns. We investigated the associations between cerebral serotonin expression and sleep development during the first month of life in 152 nursery-reared infant rhesus macaques (Macaca mulatta). Cerebral serotonin expression was determined using cerebrospinal fluid serotonin metabolite 5-hydroxyindoleacetic acid (CSF 5-HIAA) concentrations, relative to weight, sampled at 2 and 4 weeks post-birth. Sleep-wake states were rated by trained observers every two hours from 0800-2000 hours. Sleep-wake states were scored as awake=1, drowsy=2, or asleep=3. For analyses, daytime sleep-wake states were averaged across the 7 days prior to each CSF sampling. Paired-samples t-test, Wilcoxon signed ranks test, and Spearman’s ρ were utilized to explore associations between time points, averages, and change scores (week 4 minus week 2) for both CSF 5-HIAA and sleep-wake states. Daytime sleep (t(239)=17.27, p<.001) and CSF 5-HIAA (Z = -9.9, p<.001) decreased significantly from week 2 to week 4. Higher CSF 5-HIAA was associated with more daytime sleep during the first month of development (ρ=.25, p=.003). Lower week 2 CSF 5-HIAA predicted greater reductions in sleep from week 2-week 4 (ρ=.16, p=.05). Greater reductions in CSF 5-HIAA from week 2 to week 4 predicted lower sleep at week 4 (ρ=-.18, p =.03). These important findings are among the first to demonstrate that, from birth, daytime sleep-wake patterns are predicted by cerebral serotonin expression. Considering the link between serotonin, sleep, and mood disorders later in life, these results have exciting implications for improving sleep with serotonin interventions. This research was supported by the Laboratory of Comparative Ethology at the National Institute of Child Health & Human Development, National Institute of Health.

OPRM1 genotype interacts with serotonin system dysfunction to predict alcohol-heightened aggression in primates.

Although the notion that alcohol promotes violence is widespread, not all individuals are aggressive while intoxicated. Genetic variation could be a contributing factor to individual differences in alcohol-heightened aggression. The present study examines the effects of OPRM1C77G genotype on responses to threat in rhesus macaques under normal conditions and following alcohol administration. Prior studies have shown that a low CSF level of 5-HIAA is a trait marker for individuals prone to escalated aggression. We wanted to examine whether the predictive value for this marker on aggression was moderated by OPRM1 genotype. Animals were administered alcohol (BAC 100-200 mg%), were provoked by a human intruder, and aggressive responses were recorded. Factor analysis was performed to generate aggressive response factors, which were then used as dependent variables for ANOVA, with OPRM1 genotype and CSF 5-HIAA as independent variables. Factor analysis generated three factors ('Threatening', 'Distance Decreasing' and 'High Intensity'). We found that High Intensity aggression was increased among carriers of the OPRM1 G allele, especially among individuals with low CSF levels of 5-HIAA. Aggression in the non-intoxicated state was predicted by 5-HIAA, but not by genotype. This study demonstrates that OPRM1 genotype predicts alcohol-heightened aggression in rhesus macaques with low CSF levels of 5-HIAA. Because OPRM1 variation predicts similar effects on alcohol response and behavior in humans and macaques, this study could suggest a role for OPRM1 genotype in alcohol-heightened aggression in humans. If so, it may be that compounds that block this receptor could reduce alcohol-associated violence in selected patient populations.

Dietary tryptophan depletion in humans using a simplified two amino acid formula – a pilot study

BackgroundAcute tryptophan depletion (ATD) is a well-established dietary method in translational brain research used to briefly lower central nervous serotonin (5-hydroxytryptamine (5-HT)) synthesis. A simplified two amino acid ATD formula (ATDPHE/LEU) was developed while reducing the overall amount of amino acids (AAs), with the objective of administration especially in children and adolescents in future studies.ObjectiveThis study investigated tryptophan (TRP) influx rates across the blood-brain barrier (BBB) after dietary ATDPHE/LEU administration relative to the ATD Moja-De protocol that has been established for use in children and adolescents.DesignSeventy-two healthy adults (50% females) were randomized into four groups and administered ATD Moja-De, its TRP-balanced control condition (BAL), ATDPHE/LEU, or its respective control mixture (BALPHE/LEU) in a counterbalanced, double-blind, between-subjects design. Blood samples were collected at baseline and at hourly intervals for 6 h after AA intake. Questionnaires about mood, taste, and challenge tolerance were completed at fixed time points.ResultsBoth challenge mixtures significantly reduced central nervous TRP influx as calculated by Michaelis–Menten kinetics relative to baseline and the respective control conditions with only mild and comparable side effects. A greater decline in TRP influx over the BBB after ATDPHE/LEU administration when compared with ATD Moja-De was detected without group effects for taste, challenge tolerance, and mood. There was unintended initial short increase in plasma TRP concentrations observed after ATDPHE/LEU intake, and a possible redistribution between free and protein-bound TRP triggered by protein synthesis stimulated by the ingested AAs may account for this finding. Moreover, a decline in TRP influx after BALPHE/LEU administration over a 6-h period was observed, and the large amount of PHE in the BALPHE/LEU mixture may be a possible explanation for this particular phenomenon, which could have led to an unexpected increase in displacement of TRP at the BBB in this control condition.ConclusionsThis pilot study provides preliminary evidence for the possibility of lowering TRP influx as calculated by Michaelis–Menten kinetics into the brain by using a simplified ATD protocol in humans. The simplified composition of only two AAs, the lower overall AA amount, and the appropriate tolerance are characteristics of the newly developed ATDPHE/LEU protocol. Future studies focusing on the effects of the ATDPHE/LEU protocol and its respective control condition on CSF 5-HIAA concentrations, as well as neurochemical studies in rodents, are needed to further validate this newly developed AA mixture before definite conclusions about its usability in ATD-related research in humans, its specificity, and additional effects can be made.

Commentary: Clinical Correlates of Raphe Serotonergic Dysfunction in Early Parkinson's Disease.

Growing and clinical evidence supports the conclusion that Parkinson’s Disease (PD) is a complex multisystem disorder not exclusively affecting the dopaminergic circuits. In fact, the dopaminergic neuronal loss does not cover all the clinical aspects of PD. Therefore, different non-dopaminergic neurotransmitter systems have been invoked as playing a role in the PD clinical picture. Principally, the inefficiency of serotonergic circuitry has been demonstrated in PD animal models, as well as in post-mortem and in vivo human studies. In the recent article published in Brain, Zahi Qamhawi and colleagues interrogated 123I-FP-CIT single-photon emission computed tomography documenting raphe serotonergic dysfunction in a large group of early PD patients compared to a subset of possible PD patients without evidence of dopaminergic deficit (SWEDD) and a population of healthy controls (1). This paper combined an accurate clinical evaluation with a sophisticated neuroimaging protocol and documented in PD patients a mean raphe serotonin (5-HT) transporter availability significantly lower than both SWEDD patients and controls. These findings, achieved in a large cohort of PD patients, enforced previous autoptic examinations documenting serotonergic neurons loss due to Lewy body pathology in the raphe nuclei of PD patients (2). Accordingly, neuroimaging studies have shown the progressive 5-HT transporter availability reduction in the raphe nuclei as PD pathology progresses (3–5). It is well accepted that concentration of 5-HT and its metabolite 5-hydroxyindolacetic acid (5-HIAA) in CSF reflects the serotonergic metabolism and turnover in the CNS (6, 7). We performed a case-control study investigating CSF levels of 5-HT and 5-HIAA in a cohort of PD patients, after a 3-day dopaminergic therapy withdrawal and in absence of serotonergic agents (8). We demonstrated the significant reduction of CSF 5-HT and 5-HIAA concentrations in PD patients compared to controls. We also found the significant reduction of CSF 5-HT and 5-HIAA in the PD population with respect to Alzheimer’s Disease patients (8), thus highlighting that the impairment of serotonergic system could represent a specific effect of synuclein-mediated neurodegeneration (8). As a matter of fact, novel experimental studies in alpha-synuclein (α-syn) mouse model of PD showed the impairment of serotonergic system owing to the intracellular accumulation of α-syn in serotonergic neurons coupled with the reduction of 5-HT levels in lower brainstem (9). Based on the clinical presentation, Qamhawi and collegues divided PD patients into two subgroups corresponding to patients with and without resting tremor. Remarkably, patients with tremor had lower mean raphe 5-HT transporter availability than patients unaffected by tremor. Since tremor amplitude, constancy, and severity negatively correlated with raphe 5-HT transporter availability in the whole PD cohort, authors suggested that the serotonergic system inefficiency could be responsible for parkinsonian tremor. This finding was consistent with previous studies detecting an association between 5-HT receptor availability in the raphe nuclei and severity of parkinsonian tremor (10). However, in our CSF study, we found no differences in CSF 5-HT and 5-HIAA levels between tremor dominant and non-tremor dominant patients. This discrepancy could be ascribed to the fact that Qamhawi and collegues studied de novo early PD patients, whereas we investigated patients with higher Hoehn and Yahr stage and greater motor disability at the Unified PD Rating Scale-motor section. It could be of interest to evaluate in follow-up studies how the serotonergic transmission damage may influence PD motor symptoms along with the progression of the disease. Concurrently, the reliability of the proposed difference in raphe 5-HT transporter availability found by Qamhawi and coworkers in early PD patients should be also analyzed in more advanced PD patients. Remarkably, Qamhawi and coauthors documented that raphe 5-HT transporter availability did not correlate with PD non-motor symptoms, such as fatigue, depression, and sleep-wake cycle disturbances. In agreement with this finding, we did not identify mutual interplays linking CSF 5-HT and 5-HIAA concentrations to depression, apathy, and sleep disturbances. Although our report sustained Qamhawi and coworkers results, literature proposes controversial data regarding the involvement of serotonergic pathways breakage in the pathophysiology of PD non-motor symptoms (11), thus requiring further investigations. All considering, we suppose that the reduced 5-HT transporter availability, as shown by Qamhawi and collegues, and the 5-HT synthesis, metabolism, and turnover impairment, resulting in reduced CSF levels of 5-HT and 5-HIAA (8) may both contribute to the serotonergic transmission dysfunction evident in PD. Hence, serotonin circuitry inefficiency could represent the fitting partner of the dopaminergic deficit in PD.

MG-142 Improved motor function with 5-hydroxytryptophan in a family with systemic serotonin deficiency, hemiplegic migraines and neurodegenerative course

Background Serotonin’s role is multiple: controlling mood and sleep, modifying vascular resistance, modulating spinal segmental reflexes and nociception amongst others. Case report We present a family with three affected siblings, presenting with hemiplegic migraines, spinal cord atrophy, progressive lower limb weakness and spasticity, who were found to have profoundly low CSF 5HIAA levels (25, 14, 18 nmol/L, ref 87–189) and low platelet serotonin levels. Their motor function and strength greatly improved with 5-hydroxytrypotphan (5HTP)/carbidopa treatment. Platelet serotonin transporter function was diminished, and cytoskeletal aggregates were proven to keep membrane proteins in the non-soluble fractions. Whole exome sequencing revealed a novel variant in SRRM2 gene, supporting alternative splicing of many target genes. This protein is a component of the spliceosome and has multiple functions in the splicing process. It also plays an important role in pre-mRNA splicing and has a role in cell migration. Alternative splicing increases the complexity of mammalian transcriptomes since nearly all mammalian genes express multiple pre-mRNA isoforms. Full transcriptome analysis comparing RNA expression in two affected and one unaffected sibling revealed multiple differences in levels of RNA expression and splicing. Conclusion Improvement of motor function with 5HTP/carbidopa proves yet another important role of serotonin as a signalling molecule probably through its action on G-protein coupled receptors.

Revisiting the serotonin-aggression relation in humans: a meta-analysis.

The inverse relation between serotonin and human aggression is often portrayed as "reliable," "strong," and "well established" despite decades of conflicting reports and widely recognized methodological limitations. In this systematic review and meta-analysis, we evaluate the evidence for and against the serotonin deficiency hypothesis of human aggression across 4 methods of assessing serotonin: (a) cerebrospinal fluid levels of 5-hydroxyindoleacetic acid (CSF 5-HIAA), (b) acute tryptophan depletion, (c) pharmacological challenge, and (d) endocrine challenge. Results across 175 independent samples and over 6,500 total participants were heterogeneous, but, in aggregate, revealed a small, inverse correlation between serotonin functioning and aggression, anger, and hostility (r = -.12). Pharmacological challenge studies had the largest mean weighted effect size (r = -.21), and CSF 5-HIAA studies had the smallest (r = -.06). Potential methodological and demographic moderators largely failed to account for variability in study outcomes. Notable exceptions included year of publication (effect sizes tended to diminish with time) and self- versus other-reported aggression (other-reported aggression was positively correlated to serotonin functioning). We discuss 4 possible explanations for the pattern of findings: unreliable measures, ambient correlational noise, an unidentified higher order interaction, and a selective serotonergic effect. Finally, we provide 4 recommendations for bringing much needed clarity to this important area of research: acknowledge contradictory findings and avoid selective reporting practices; focus on improving the reliability and validity of serotonin and aggression measures; test for interactions involving personality and/or environmental moderators; and revise the serotonin deficiency hypothesis to account for serotonin's functional complexity.

CSF 5-HIAA, cortisol and DHEAS levels in suicide attempters

The serotonin system and the hypothalamic–pituitary–adrenal (HPA) axis are involved in the biological vulnerability to suicidal behaviour. Altered levels of dehydroepiandrosterone (DHEA) and its sulphate ester DHEAS have been reported in neuropsychiatric conditions. The aim of this study was to investigate CSF levels of 5-Hydroxyindoleacetic acid (5-HIAA) and CSF and plasma levels of cortisol and DHEAS in 28 medication free suicide attempters and 19 healthy volunteers. Another aim was to investigate the relationship between neuroendocrine measures and childhood trauma in suicide attempters. As the study design includes a longitudinal part, we investigated whether CSF cortisol, 5-HIAA or DHEAS would predict subsequent suicide. We hypothesized higher cortisol levels in suicide attempters and lower CSF 5-HIAA levels and higher cortisol levels in suicide victims. Suicide attempters had higher CSF and plasma cortisol levels compared to healthy volunteers. Male suicide attempters had higher CSF DHEAS levels and female suicide attempters had lower CSF 5-HIAA levels compared to male and female healthy volunteers respectively. Exposure to interpersonal violence as a child showed a negative correlation with CSF cortisol/DHEAS ratio adjusted for age, gender and depression severity in a regression analysis. Suicide victims tended to have low CSF 5-HIAA and high CSF cortisol. Abused suicide victims had higher CSF cortisol compared to suicide victims with low exposure to interpersonal violence as a child. The results underlie the important role of the serotonergic system and HPA axis in suicidal behaviour and suggest that CSF DHEAS may be elevated in male suicide attempters.

Autosomal dominant tauopathy with parkinsonism and central hypoventilation

Frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17T) can show various clinical phenotypes.1 We describe Japanese siblings with the intronic 10 + 14 splice site mutation of the microtubule-associated protein tau (MAPT) gene, showing parkinsonism, depression, weight loss, and central hypoventilation with reduced serotonin concentration suggested by low 5-hydroxyindole acetic acid (5-HIAA) in CSF. These clinical and biochemical features are just shared by Perry syndrome,2–4 although neither DCTN1 gene mutation nor TDP-43 proteinopathy was found. ### Case reports. A Japanese woman (III-5) (figure, A) developed clumsiness, tremor of the upper limbs, appetite loss, and apathy at age 44. She had lost 14 kilograms of body weight during 10 months. Mask-like face, hypophonic voice, bradykinesia, and muscle rigidity with predominance on the right side were observed. Deep tendon reflexes were hyperactive, especially in the right extremities with the Babinski sign. Despite levodopa treatment, her parkinsonism progressed and memory loss, disorientation, and cyanosis became apparent. Blood tests, EKG, and chest X-ray were not remarkable. Arterial blood gases showed reduced oxygen (60.3 Torr) and increased carbon dioxide (55.5 Torr). CSF analysis showed reduced 5-HIAA (5.6 ng/mL [normal 28.5 ± 7.2 ng/mL]). Brain MRI demonstrated mild atrophy in the brainstem tegmentum. Polysomnography revealed central hypoventilation with hypoxia. Although memory loss, disorientation, and …

Cutaneous magnetic stimulation reduces rat chronic pain via activation of the supra-spinal descending pathway.

Recent studies have demonstrated that magnetic stimulation (MS) can induce cellular responses such as Ca(2+) influx into the cultured neurons and glia, leading to increased intracellular phosphorylation. We have demonstrated previously that MS reduces rat neuropathic pain associated with the prevention of neuronal degeneration. Thus, we aimed to elucidate the actions of MS in relation to modulation of spinal neuron-glia and the descending inhibitory system in chronic pain. The male SD rats intrathecally implanted with catheters were subjected to sciatic nerve ligation (CCI). MS is a low power apparatus characterized by two different frequencies, 2 KHz and 83 MHz. Rats were given MS to the skin (injured sciatic nerve) for 10 min from the seventh day after CCI. The paw withdrawal latency (PWL) evoked by thermal stimuli was measured for 14 days after CCI. Immunohistochemistry for Iba-1 or GFAP was performed after 4% paraformaldehyde fixation (microscopic analysis). We employed microdialysis for measuring CSF 5-HIAA as a reflection of 5-HT release by MS stimulation. Following CCI, rats showed a decrease in PWL after CCI, and the decrease continued until the 14th day. With MS treatment, the decrease in PWL was reduced during the 10-14 day after CCI. Injection of JNK-1 inhibitors on the 14th day antagonized the analgesic effect of MS. MS also eliminated the CCI-induced decrease in GFAP immunoreactivity. Moreover, MS evoked spinal 5-HT release reflected by increase in spinal 5-HIAA level. Thus, we demonstrate that a novel magnetic stimulator used cutaneously can ameliorate chronic pain by not only preventing abnormal spinal neuron-glia interaction, but also through the activation of the supra-spinal descending inhibitory system.

Autism associated with low 5-hydroxyindolacetic acid in CSF and the heterozygous SLC6A4 gene Gly56Ala plus 5-HTTLPR L/L promoter variants

The known Gly56Ala mutation in the serotonin transporter SERT (or 5-HTT), encoded by the SLC6A4 gene, causes increased serotonin reuptake and has been associated with autism and rigid–compulsive behavior. We report a patient with macrocephaly from birth, followed by hypotonia, developmental delay, ataxia and a diagnosis of atypical autism (PDD-NOS) in retrospect at the age of 4½ years. Low levels of the serotonin end-metabolite 5-hydroxyindolacetic acid (5HIAA) in CSF were detected, and SLC6A4 gene analysis revealed the heterozygous Gly56Ala alteration and the homozygous 5-HTTLPR L/L promoter variant. These changes are reported to be responsible for elevated SERT activity and expression, suggesting that these alterations were responsible in our patient for low serotonin turnover in the central nervous system (CNS). Daily treatment with 5-hydroxytryptophan (and carbidopa) led to clinical improvement and normalization of 5HIAA, implying that brain serotonin turnover normalized. We speculate that the mutated 56Ala SERT transporter with elevated expression and basal activity for serotonin re-uptake is accompanied with serotonin accumulation within pre-synaptic axons and their vesicles in the CNS, resulting in a steady-state of lowered serotonin turnover and degradation by monoamine-oxidase (MAO) enzymes in pre-synaptic or neighboring cells.