CSF Monoamine Research Articles

Associations of plasma interleukin-6 with plasma and cerebrospinal fluid monoamine biosynthetic pathway metabolites in treatment-resistant depression

Abstract Background Current research suggests that depression is associated with several changes in the immune system, including alterations in inflammatory cytokines, the hypothalamic-pituitary-adrenal axis, and downstream effects on neurotransmitters. Specifically, plasma interleukin-6 (IL-6) is elevated in depressed individuals compared to non-depressed controls, and these same inflammatory processes may be implicated in treatment resistant depression (TR-MDD). IL-6 has also been theorized to affect central monoamine pathway metabolites. Few studies have assessed the relationship of IL-6 and plasma/CSF monoamine biosynthetic pathway metabolites and symptomatic correlates of depression. Methods We analyzed plasma IL-6 levels in an outpatient treatment-resistant depressed cohort (n = 67) and healthy control cohort (n = 40). We also assessed relationship of plasma IL-6 with plasma/CSF monoamine pathway metabolites and symptomatic correlates of depression. Results Higher levels of plasma IL-6 were found in the TR-MDD cohort compared to the control cohort. Plasma IL-6 correlated with plasma serotonin levels among all participants, although there was no association of plasma IL-6 and plasma serotonin in the TR-MDD cohort on subgroup analysis. No correlations were found between plasma IL-6 and plasma/CSF monoamine breakdown products, depressive symptomatology, or suicidality. Limitations Our analysis was a post-hoc analysis and we were not able to exhaustively control for confounds of IL-6 levels, such as sleep or stress. Conclusion The findings of the current study extend current evidence that plasma IL-6 levels are elevated in TR-MDD, after adjusting for body mass index. Additionally, plasma IL-6 and serotonin regulation may vary between healthy and TR-MDD populations. Lastly, our study finds no association between plasma IL-6 and CSF monoamine pathway metabolites, suggesting that further research is needed to elucidate the association of IL-6 and depression.

The effect of vagus nerve stimulation on CSF monoamines and the PTZ seizure threshold in dogs.

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

Paroxysmal exercise-induced dystonia due to GLUT1 mutation can be responsive to levodopa: a case report

Dear Sirs,Paroxysmal exercise-induced dyskinesia (PED) is a disor-der characterized by brief episodes of dystonia or choreausually lasting a few minutes [1]. Invariably, the movementdisorder affects the part of the body which is exercised.Less than 30 % of PED cases are due to a mutation in theSLC2A1 gene encoding for the glucose transporter type 1(GLUT1) [2–4]. This disorder is difficult to treat, and anumber of drugs have been proven unhelpful [5]. Recently,ketogenic diet has been suggested to be useful [6]. How-ever, such diet is difficult to follow and long-term com-pliance is poor [6]; also, it has been reported to worsen theattacks in some patients [7]. Hence, there is a need for othersymptomatic treatments. Here we report a case of PEDassociated with a GLUT1 mutation where the patientresponded dramatically to levodopa.This 47-year-old gentleman, with no family history forany neurological disorder, developed his first symptomsduring childhood, with dystonic attacks affecting mainlyhis legs after physical exercise. The attacks lasted20–165 min and occurred daily on average. He had nofurther symptoms in between attacks. The neurologicalexamination was normal interictally. A number of inves-tigations, including routine blood tests, brain CT scan andMRI, and dopamine transporter SPECT were normal.Cerebrospinal fluid to blood glucose ratio was consistentwith GLUT1 deficiency (ratio = 0.45; normal values[0.60 [2, 3]). He was therefore tested and found positivefor a previously reported mutation (p.R333Q) in theSLC2A1 gene.Our patient refused treatment with ketogenic diet (whichshould be considered the first-line option [5]) and preferredto try pharmacological approaches. Trials with oxazepam,diazepam, carbamazepine, clonazepam, sodium valproate,and acetazolamide were completely unhelpful. Finally, weempirically treated him with levodopa to reach a dose of800 mg daily. Since being on this dose of levodopa, hemarkedly improved, with a reduction of both frequency andintensity of the attacks. At some stage, he spontaneouslyreduced the levodopa to 200 mg daily, making his condi-tion much worse with frequent and severe episodes.Therefore, he went back to 800 mg daily; since then, he hashad only one minor episode over 6 months.Pathophysiological underpinnings of PED are not yetestablished. However, there are some suggestions thatdopamine can be involved in the pathogenesis of PED.Firstly, from a phenomenological perspective, dyskinesiasassociated with GLUT1 affect the legs and somehowresemble diphasic dyskinesias of Parkinson’s disease(which are usually seen during low dopaminergic states)and respond to high dose of levodopa, unlike what happenswith peak dose dyskinesias. Secondly, CSF analysis ofpterins and monoamine metabolites before and after anattack in a patient with PED has given evidence that theremight be an altered dopaminergic transmission whichcontributes to the clinical appearance of the abnormal

Widening Phenotypic Spectrum of AADC Deficiency, a Disorder of Dopamine and Serotonin Synthesis.

Aromatic amino acid decarboxylase deficiency presents with prominent extrapyramidal and autonomic features and CSF monoamine deficiency with increased 3-O-methyldopa, a by-product of accumulated L-DOPA. Less than 100 cases have been identified. The disease is typically associated with a severe phenotype and worse prognosis in females. Gene transfer technology has been implemented using an adeno-associated virus encoding AADC in the putamen bilaterally. We describe the phenotype/genotype in a cohort of five cases showing a heterogeneous phenotype and variably intact response to pharmacologic therapy. Five patients (age range 2-10 years, mean 5 years, 3M/2F) with confirmed AADC deficiency are described. Four (3M/1F) have had improvement on combinations of dopaminergic agonists, MAO inhibitors, pyridoxine/P5P, and folinic acid. Each presented with hypotonia, decreased voluntary movement, dystonia, irritability, and oculogyric crises. Two (1M/1F) are independently ambulatory and are not dependent on gastrostomy tube feedings; the 9-year-old girl is reading single words. One female has a severe phenotype including recurrent hypoglycemic events associated with bradycardia, although the latter have resolved with chronic anticholinergic therapy. One Taiwanese boy had the common homozygous mutation, and otherwise we describe five new DDC mutations. We report a wider phenotypic spectrum including intact response to pharmacologic management and milder outcome in a female, as well as five new mutations. Four of five patients have improved on combination therapy including a dopamine agonist, MAO inhibitor, pyridoxal-5'-phosphate, and folinic acid. The advent of viral-mediated gene therapy in AADC deficiency renders expanded knowledge of the outcome increasingly important.

Is multi-infarct dementia representative of vascular dementias? A retrospective study

Multi-infarct dementia (MID) indicates a dementia disorder primarily caused by multiple cerebral infarcts. Since other pathogenetic mechanisms cause vascular dementia we evaluated clinical, CT scan and CSF neurochemical parameters of 134 MID and 67 PVD (probable vascular dementia) patients. We found no differences with regard to the presence of major risk factors. Only TIA/stroke episodes and focal neurological signs were significantly more frequent in MID than in PVD cases, an anticipable result on the basis of MID definition. CT scan findings showed a prevalence of subcortical with respect to cortical lesions in both groups, with a higher frequency in MID patients. Subjects with deep infarcts more frequently showed TIA/stroke episodes and diabetes mellitus. No differences were detectable in CSF monoamine metabolite levels. We conclude that in the majority of vascular dementias subcortical damage seems to have a major pathogenetic role.

No Association of COMT Val158Met Polymorphism with Suicidal Behavior or CSF Monoamine Metabolites in Mood Disorders

The Met allele of the Catechol-O-Methyltransferase (COMT) gene functional polymorphism (COMT-V158M) is associated with lower enzymatic activity than the Val allele and is reported to be associated with aggression, depression, and suicidal behavior. Since depression and impulsive-aggressive behavior may mediate risk for suicidal behavior, we assessed the association of this polymorphism with suicidal behavior. Clinical (impulsive aggression) and biological (CSF monoamine metabolites) endophenotypes were tested as potential mediators of the effect of genotype on suicide risk. Subjects with mood disorders (N = 486) and healthy volunteers (N = 119), all European Caucasian, were genotyped for COMT-V158M and assessed for DSM IV diagnoses, lifetime suicidal behavior, lifetime impulsivity, hostility, and aggression. CSF monoamine metabolites were assayed in a sub-sample of mood disorder patients (N = 111). We found no association between genotype and mood disorder diagnosis or with reported history of suicide attempt in mood disorder subjects. There was no association between genotype and lethality or method of suicide attempt, or with aggressive/impulsive traits. Further, there was no difference in monoamine metabolites by genotype. The COMT-V158M polymorphism was not associated with suicidal behavior in a Caucasian sample of mood disorder subjects, or with possible clinical or biological endophenotypes.

No association between a TPH2 promoter polymorphism and mood disorders or monoamine turnover

Tryptophan hydroxylase (TPH) is the rate-limiting enzyme in serotonin synthesis. TPH2 is a recently discovered isoform that is expressed predominantly in serotonin neurons. Associations are reported of TPH2 polymorphisms with MDD, bipolar disorder and suicidal behavior. This study examines a single nucleotide polymorphism in the putative promoter region of the TPH2 gene. One hundred nine bipolar, 324 major depressive disorder, and 130 healthy volunteers were genotyped for the rs4131347 (-C8347G) promoter SNP. Association was assessed with diagnosis, suicide attempt status, severity of psychopathology and cerebrospinal fluid monoamine metabolite levels of 5-HIAA, HVA, and MHPG. General linear models and logistic regression tested the effect of genotype*childhood abuse interactions on psychopathology severity and suicide attempt. There was no association between genotype and either mood disorder, suicide attempt status, psychopathology severity or CSF monoamine metabolite levels. No association was detected between the rs4131347 (-C8347G) SNP in the promoter region of the TPH2 gene and mood disorders, suicidal behavior or monoamine function.

Cerebrospinal fluid monoamine metabolite levels in human newborn infants born in winter differ from those born in summer

An earlier study has shown significant differences in the CSF monoamine metabolite levels in adults born during different seasons of the year. We study here the relationship between season of birth and CSF monoamine metabolite levels in 283 newborn febrile infants without neurological abnormalities, with an age distribution ranging from birth to about 3 months, adjusting for the confounding variables age and time at lumbar puncture, weight at birth, estimated gestational age at birth, gender, race, and medicaid status. Each of the three metabolite levels as well as their ratios HVA/5-HIAA and 5-HIAA/MHPG showed significant month-of-birth variations, but not the ratio HVA/MHPG. For HVA and MHPG levels, the maximum was obtained around the winter birth months November-December, whereas for 5-HIAA level, the maximum was obtained around the summer birth months June-July. The correlations between HVA and 5-HIAA were, in general, significantly positive within the different birth seasons and races. Among summer-born Caucasian infants, MHPG was significantly positively correlated with HVA and with 5-HIAA, whereas among winter-born Black infants, MHPG was significantly positively correlated with HVA. Season of birth is an unspecific environmental factor that may be proxy for several possible seasonally varying environmental circumstances such as the length of photoperiod, temperature, infections, nutrition, stress and lifestyle. Studies relating season of birth to monoaminergic turnover at different stages of life may yield important clues about the gestational and perinatal origins of neurodevelopment.

Influence of parenting style on the offspring's behaviour and CSF monoamine metabolite levels in crossfostered and noncrossfostered female rhesus macaques

We investigated the association between variation in parenting style and the offspring's behaviour and CSF monoamine metabolite (5-HIAA, HVA, and MHPG) levels in rhesus monkeys. Study subjects were 25 two-year-old females reared by their biological mothers and 15 same-aged females that were crossfostered at birth and reared by unrelated mothers. Subjects that were rejected more by their mothers in the first 6 months of life engaged in more solitary play and had lower CSF concentrations of 5-HIAA than subjects that were rejected less. The relation between these variables was generally similar in crossfostered and noncrossfostered females. CSF levels of 5-HIAA were negatively correlated with rates of scratching, a behavioural indicator of anxiety. These results suggest that that early exposure to high rates of maternal rejection can result in higher anxiety later in life, and that this effect may be mediated by serotonergic mechanisms. Variation in maternal protectiveness did not affect offspring behaviour and neither protectiveness nor rejection affected CSF levels of HVA and MHPG. CSF levels of MHPG, however, were negatively correlated with solitary play behaviour and avoidance of other individuals, suggesting that individuals with lower CSF MHPG were more fearful and socially phobic than those with higher CSF MHPG. Taken together, these findings suggest that individual differences in anxiety and fearfulness in young rhesus monkeys are accounted for, at least in part, by variation in CSF levels of monoamine metabolites, and that the development of brain monoamine systems, particularly serotonin, can be affected by early exposure to variable maternal behaviour.

Relationships among CSF monoamine metabolite levels, alcohol sensitivity, and alcohol‐related aggression in rhesus macaques

AbstractA relationship between alcohol intake and aggressive behavior has been demonstrated in both associational and laboratory studies. Among the factors that contribute to aggression during intoxication are a history of violence and the level of alcohol‐induced stimulation. In humans, excessive alcohol intake and alcoholism are predicted by decreased sensitivity, or a low level of response (LOR), to alcohol. In addition, aggressive behavior, LOR, and alcoholism have been attributed to CNS serotonergic dysfunction. Given that they are both related to diminished CNS serotonin, in this study we wanted to determine whether a low LOR to alcohol would be associated with aggression during intoxication in rhesus macaques. Adolescent rhesus macaques (N=115) received an intravenous dose of ethanol (2.2g/kg) and were scored for their levels of response for 30 minutes. Following provocation by an investigator, animals were then scored for aggressive behaviors (lunges, open‐mouth threats, stares, head‐bobs, and barks) for five minutes. At the approximate age of five years, animals were entered into a free‐access alcohol consumption study, during which they were allowed voluntary access for one hour/day, four days/week to aspartame‐sweetened alcohol or vehicle. Alcohol intake for each subject was determined using a computerized collar, which was detected by a station system that measured individual subject consumption rates. Data were analyzed using regression analyses and t‐tests. Decreased sensitivity to alcohol, alcohol‐induced increases in CSF MHPG, and pre‐alcohol CSF levels of 5–HIAA were associated independently with aggression during intoxication (r= −0.32, P= 0.0006 , r = − 0.29, P=0.01, and r= −0.21, P=0.02, respectively). High rates of alcohol‐related aggression predicted future alcohol consumption (r=0.27, p=0.004), even after controlling for rearing condition and monoamine metabolite concentrations, previously shown in these animals to predict alcohol consumption. By investigating the relationships between LOR, central catecholamine reactivity and function, and alcohol‐induced aggression in alcohol‐naïve nonhuman primates, this report provides evidence that alcohol‐induced stimulation and neurotransmitter‐linked predisposition to impulsive aggression independently contribute to aggression during intoxication. This paper further emphasizes the importance of the nonhuman primate model for studying susceptibility to alcohol‐related aggression and alcoholism, because variables such as prior exposure to alcohol are difficult to control in human subjects. Aggr. Behav. 29:288–301, 2003. © 2003 Wiley‐Liss, Inc.

New evidence for an association between the CSF HVA:5-HIAA ratio and psychopathic traits

Objectives: To replicate the relation between the CSF HVA:5-HIAA ratio and psychopathic traits previously reported in a pilot group of 22 perpetrators of violent crimes. Methods: CSF monoamine metabolite concentrations...

Homocysteine, folate, methylation, and monoamine metabolism in depression

OBJECTIVESPrevious studies suggest that folate deficiency may occur in up to one third of patients with severe depression, and that treatment with the vitamin may enhance recovery of the mental...

Season of birth associated with the age and method of suicide

A recent study reported season of birth variation in CSF levels of 5-HIAA and HVA, with low 5-m for February to April and high HVA for October to January (Chotai & Asberg, 1999). We therefore analysed data on all completed suicides during 1952–1993 in the county of Västerbotten in northern Sweden (1466 cases), regarding these birth seasons in relation to suicide method and sociodemographic variables. Those with suicide age under 45 years were more likely than older suicides to have been born during February to April, significantly so compared to October to January. This was more pronounced for the later birth-year cohort (born in 1931 or later). Those who preferred hanging rather than poisoning or petrol gases were significantly more likely born during February to April. Those who preferred poisoning rather than hanging were significantly more likely born during October to January, particularly for the later birth-year cohort. The results regarding suicide method were somewhat more pronounced for males. The results of the study are compatible with a hypothesis of season of birth variation in CSF monoamine metabolites.

CSF Monoamine Metabolite and Beta Endorphin Levels in Recently Detoxified Alcoholics and Healthy Controls

CSF Monoamine Metabolite and Beta Endorphin Levels in Recently Detoxified Alcoholics and Healthy Controls

Season of birth associated with the age and method of suicide

A recent study reported season of birth variation in CSF levels of 5-HIAA and HVA, with low 5-HIAA for February to April and high HVA for October to January (Chotai & Asberg, 1999). We therefore analysed data on all completed suicides during 1952--1993 in the county of Vasterbotten in northern Sweden (1466 cases), regarding these birth seasons in relation to suicide method and sociodemographic variables. Those with suicide age under 45 years were more likely than older suicides to have been born during February to April, significantly so compared to October to January. This was more pronounced for the later birth-year cohort (born in 1931 or later). Those who preferred hanging rather than poisoning or petrol gases were significantly more likely born during February to April. Those who preferred poisoning rather than hanging were significantly more likely born during October to January, particularly for the later birth-year cohort. The results regarding suicide method were somewhat more pronounced for males. The results of the study are compatible with a hypothesis of season of birth variation in CSF monoamine metabolites.

Cerebrospinal Fluid Monoamine Metabolites and Glucose Metabolism in Posttraumatic Aggression

This pilot study was conducted to determine if aggressive, post brain-injured patients have abnormal glucose metabolism or abnormal CSF monoamine metabolite concentrations as compared with non-aggressive, post brain-injured controls. Subjects with a history of traumatic brain injury underwent a lumbar puncture and glucose tolerance test after a three-week medication wash-out period. Monoamine metabolite concentrations and glucose nadirs were compared between aggressive and control subjects. There were no statistical differences between the aggressive (n = 4) and control (n = 6) group with respect to age (28.5 +/- 15.7 versus 28.0 +/- 10.8), weight (72.5 kg +/- 14.1 versus 67.7 kg +/- 10.1) or number of months since brain injury (31.8 +/- 26.1 versus 33.3 +/- 23.3). There were no significant differences between the two groups in glucose nadirs following oral glucose challenge or in levels of CSF monoamine metabolite concentrations of 5-hydroxyindoleacetic acid (5-HIAA), homovanillic acid (HVA), or 3-methoxy-4-hydroxyphenylglycol (MHPG), although a trend toward significance was noted between the MHPG groups (higher MHPG within aggressive group). The preliminary data suggest that glucose metabolism and CSF monoamine metabolite concentrations do not differ significantly from aggressive subjects to controls in persons with brain injury. Follow-up prospective studies with larger sample sizes are needed to evaluate these preliminary findings.

Natural killer cell activity and csf monoamine metabolites in suicide attempters

The aim of this study was to investigate markers of serotonin and immune function in suicidal patients. Cytotoxic activity of natural killer cells (NK) and CD16 lymphocytes were studied in 28 suicide attempters and 26 healthy controls, and related in patients to 5-hydroxyindoleacetic acid (5-HIAA) in cerebrospinal fluid (CSF). Patients with CSF 5-HIAA below the median had significantly lower NK cell activity than other patients. CD 16 cell frequency was significantly lower in patients than in controls, and patients also tended to have lower NK cell cytotoxicity than healthy controls. There were no statistically significant correlations between 4-hydroxy-3methoxyphenyl glycol (HMPG), homovanillic acid (HVA), CSF cortisol and NK cell activity. The results support the hypothesis of compromised immune function in suicidal patients with evidence of disordered serotonin function.

Cerebrospinal fluid amines and higher-lethality suicide attempts in depressed inpatients

Previous studies have found that not all suicide attempters with major depression have reduced serotonergic activity based on low cerebrospinal fluid 5-hydroxyindoleacetic acid (CSF- 5-HIAA) levels. In this study we hypothesized that serotonergic function is lower in depressed patients who have carried out high-lethality suicide attempts resulting in more medical damage, which might explain differences in serotonergic activity among depressed suicide attempters. We assessed the relationship of CSF 5-HIAA and other amine metabolites to the most lethal lifetime suicide attempt in 22 drug-free inpatients with major depression. CSF 5-HIAA levels were lower in depressed patients with a history of a high-lethality or well-planned suicide attempt compared to depressed patients with a history of only low-lethality suicide attempt(s). Other CSF monoamine metabolites did not correlate with suicidal behavior. Low serotonergic activity may correlate with a predisposition to more lethal suicide attempts in major depression.

Brain MRI, lumbar CSF monoamine concentrations, and clinical descriptors of patients with spinocerebellar ataxia mutations.

To serially assess changes in lumbar CSF biogenic amines, radiographic characteristics, and neurological signs in 34 patients with dominantly inherited ataxia. Mutational analysis was used to identify genetic subgroups. Annual assessment of lumbar CSF monoamine metabolites using a gas chromatographic/mass spectrometric method and morphometric measurements of the cerebellum, pons, and the cervical spinal cord on MRI were analysed for each patient and compared with normal controls. Patients with CAG trinucleotide repeat expansions on chromosome 6p (mutSCA1) and chromosome 14q (mutSCA3) had only about one half the normal concentrations of lumbar CSF homovanillic acid (HVA) whereas, 5-hydroxyindoleacetic acid (5-HIAA) concentrations were similar to those in age matched normal subjects. The HVA and 5-HIAA concentrations in clinically similar patients without mutSCA1 or mutSCA3 were normal. One year after the first study, HVA concentrations were reduced by a mean of 22% regardless of the patient's SCA mutation. Abnormalities on MRI were consistent with a spinopontine atrophy in patients with mutSCA3, spinopontocerebellar atrophy in patients with mutSCA1, and "pure" cerebellar atrophy in patients without these mutations. Quantitative MRI measurements were not useful in monitoring progression of disease but lumbar CSF HVA concentrations and total scores on a revised version of the ataxia clinical rating scale seemed to progress in parallel.

437. - CSF monoamine metabolites in alcoholics with and without nicotine addiction

437. - CSF monoamine metabolites in alcoholics with and without nicotine addiction