Cerebrospinal Fluid Tryptophan Research Articles

Tryptophan metabolism determines outcome in tuberculous meningitis: a targeted metabolomic analysis.

Cellular metabolism is critical for the host immune function against pathogens, and metabolomic analysis may help understand the characteristic immunopathology of tuberculosis. We performed targeted metabolomic analyses in a large cohort of patients with tuberculous meningitis (TBM), the most severe manifestation of tuberculosis, focusing on tryptophan metabolism. We studied 1069 Indonesian and Vietnamese adults with TBM (26.6% HIV-positive), 54 non-infectious controls, 50 with bacterial meningitis, and 60 with cryptococcal meningitis. Tryptophan and downstream metabolites were measured in cerebrospinal fluid (CSF) and plasma using targeted liquid chromatography-mass spectrometry. Individual metabolite levels were associated with survival, clinical parameters, CSF bacterial load and 92 CSF inflammatory proteins. CSF tryptophan was associated with 60-day mortality from TBM (hazard ratio [HR] = 1.16, 95% confidence interval [CI] = 1.10-1.24, for each doubling in CSF tryptophan) both in HIV-negative and -positive patients. CSF tryptophan concentrations did not correlate with CSF bacterial load nor CSF inflammation but were negatively correlated with CSF interferon-gamma concentrations. Unlike tryptophan, CSF concentrations of an intercorrelating cluster of downstream kynurenine metabolites did not predict mortality. These CSF kynurenine metabolites did however correlate with CSF inflammation and markers of blood-CSF leakage, and plasma kynurenine predicted death (HR 1.54, 95% CI = 1.22-1.93). These findings were mostly specific for TBM, although high CSF tryptophan was also associated with mortality from cryptococcal meningitis. TBM patients with a high baseline CSF tryptophan or high systemic (plasma) kynurenine are at increased risk of death. These findings may reveal new targets for host-directed therapy. This study was supported by National Institutes of Health (R01AI145781) and the Wellcome Trust (110179/Z/15/Z and 206724/Z/17/Z).

Metabolomic Signature of Diabetic Kidney Disease in Cerebrospinal Fluid and Plasma of Patients with Type 2 Diabetes Using Liquid Chromatography-Mass Spectrometry

Diabetic kidney disease (DKD) is the major cause of end stage renal disease in patients with type 2 diabetes mellitus (T2DM). The subtle metabolic changes in plasma and cerebrospinal fluid (CSF) might precede the development of DKD by years. In this longitudinal study, CSF and plasma samples were collected from 28 patients with T2DM and 25 controls, during spinal anesthesia for elective surgery in 2017. These samples were analyzed using liquid chromatography-mass spectrometry (LC-MS) in 2017, and the results were correlated with current DKD in 2017, and the development of new-onset DKD, in 2021. Comparing patients with T2DM having new-onset DKD with those without DKD, revealed significantly increased CSF tryptophan and plasma uric acid levels, whereas phosphatidylcholine 36:4 was lower. The altered metabolites in the current DKD cases were uric acid and paraxanthine in the CSF and uric acid, L-acetylcarnitine, bilirubin, and phosphatidylethanolamine 38:4 in the plasma. These metabolic alterations suggest the defective mitochondrial fatty acid oxidation and purine and phospholipid metabolism in patients with DKD. A correlation analysis found CSF uric acid had an independent positive association with the urine albumin-to-creatinine ratio. In conclusion, these identified CSF and plasma biomarkers of DKD in diabetic patients, might be valuable for monitoring the DKD progression.

Improving host-directed therapy for tuberculous meningitis by linking clinical and multi-omics data

There is a clear need to improve host-directed therapy for tuberculous meningitis (TBM), the most severe and deadly manifestation of tuberculosis. Corticosteroids represent the only host-directed therapy of proven benefit in TBM, yet their effect is modest, the mechanism by which they reduce mortality is unknown, and there is evidence for heterogeneity in their effect. Novel therapeutic approaches are therefore urgently needed. Cellular metabolism is critical for the function of immune cells; through unbiased metabolomics we recently found that high concentrations of cerebrospinal fluid (CSF) tryptophan are associated with increased mortality in Indonesian TBM patients, and that CSF tryptophan concentrations are under strong genetic regulation. Many questions remain. How exactly is tryptophan metabolism altered during TBM? How does it correlate with inflammation, immunopathology, and response to corticosteroids? How is tryptophan metabolism genetically regulated? What is the effect of HIV co-infection on tryptophan metabolism before and during TBM treatment?The ULTIMATE project addresses these questions by integrating data and specimens from large patient studies and clinical trials evaluating the effects of corticosteroids in Vietnam and Indonesia. Through its powerful and unbiased approach, ULTIMATE aims to identify which TBM patients benefit from corticosteroids and if novel therapeutic targets, such as the tryptophan pathway, could be targeted.

A novel, robust method for quantification of multiple kynurenine pathway metabolites in the cerebrospinal fluid.

Aim:Kynurenine metabolites are potential modulators of psychiatric disease. We aimed to develop a highly sensitive biochemical analysis of cerebrospinal fluid (CSF) tryptophan (TRP) metabolites, to investigate the stability of metabolites and to confirm our previous findings of aberrant CSF quinolinic acid (QUIN) and picolinic acid (PIC) in suicide attempters using this method.Methodology & results:Ten CSF TRP metabolites were analyzed with ultraperformance LC–MS/MS. The method showed small intra- and interassay variation. Metabolites were stable following freeze–thaw cycles. A decreased CSF PIC/QUIN ratio was found in suicide attempters.Conclusion:The feasibility of reliably determining CSF TRP metabolites were demonstrated, including separation of the two isomers PIC and nicotinic acid (NA) and the finding of a reduced PIC/QUIN ratio replicated in suicide attempters.

The Relationships among Tryptophan, Kynurenine, Indoleamine 2,3-Dioxygenase, Depression, and Neuropsychological Performance.

It has been suggested that the metabolic enzyme indoleamine 2,3-dioxygenase (IDO) is a biological mediator of inflammation related to the psychopathology of depression, with a Kynurenine (KYN) increase in the Tryptophan (TRP) metabolic pathway, resulting in reduced Serotonin. In this study, we examined KYN, TRP, and the ratio of KYN to TRP concentrations × 103 (KT Ratio) in serum and cerebrospinal fluid (CSF) in (a) a group of depressed patients and (b) a control group of patients referred to a neurologic outpatient clinic for whom no specific diagnosis could be established. The KT Ratio is considered an index that represents IDO. The participants were examined with the Beck Depression Inventory II (BDI-II), the Montgomery Aasberg Depression Rating Scale (MADRS), and a neuropsychological test battery. We found no significant differences between the two study groups with respect to TRP, KYN, or KT Ratio in serum or CSF. Differences in neuropsychological performance between the two patient groups could be seen in the following tests: Animal Fluency, Digit Symbol, the DKEFS Color-Interference Test (Naming Part), Trail Making Test A and B, and the Grooved Pegboard Non-dominant Hand. KYN in serum correlated highly with KYN in CSF. KYN in serum correlated significantly with both age and gender. When analyzing males and females separately, we found that women had a lower level of TRP in both serum (Mann–Whitney U-test: TRP in Serum; p = 0.001) and CSF (Mann–Whitney U-test: TRP in CSF; p = 0.003). Women had a lower level of KYN in serum (p = 0.029) than men did. Age was positively associated with KYN. KYN in CSF correlated only with age, however; there were no gender differences. No significant relationship was seen between BDI-II and MADRS on the one hand, and KYN and TRP on the other. KYN in CSF as the KT Ratio in both serum and CSF was associated with neuropsychological performance. Thus, we suggest that KYN and KT Ratio are related more strongly to neuropsychological performance than to affective symptoms in depression.

Kynurenic acid and psychotic symptoms and personality traits in twins with psychiatric morbidity

Increased cytokines and kynurenic acid (KYNA) levels in cerebrospinal fluid (CSF) have been reported in patients with schizophrenia and bipolar disorder. The aim of the present study was to investigate cytokines and kynurenines in the CSF of twin pairs discordant for schizophrenia or bipolar disorder and to study these CSF markers in relation to psychotic symptoms and personality traits. CSF levels of tryptophan (TRP), KYNA, quinolinic acid (QUIN), interleukin (IL)−6, IL-8 and tumor necrosis factor-alpha (TNF-α) were analyzed in 23 twins with schizophrenia or bipolar disorder, and in their not affected co-twins. Ratings of psychotic symptoms and personality traits were made using the Scales for Assessment of Negative and Positive symptoms, the Structured Clinical Interview for DSM-IV - Axis II Disorders, and the Schizotypal Personality Questionnaire - Brief. A total score for psychotic symptoms and personality traits was constructed for analysis. CSF KYNA was associated with the score for psychotic symptom and personality traits. TNF-α and IL-8 were associated, and the intra-pair differences scores of TNF-α and IL-8 were highly correlated. Intraclass correlations indicated genetic influences on CSF KYNA, TRP, IL-8 and TNF-α. The association between KYNA and psychotic symptoms further supports a role of KYNA in psychotic disorders.

Effects of chronic administration of tryptophan with or without concomitant fluoxetine in depression-related and anxiety-like behaviors on adult rat

Depression and anxiety play an important role in decreasing quality of life worldwide. Since tryptophan is a serotonin precursor and low levels of serotonin seems to be related to depression, the effect of oral tryptophan has been investigated for possible potentiation of the action of antidepressant drugs. We investigated the effects of chronically administered tryptophan (50mg/kg/day, p.o.) with or without concomitant fluoxetine (10mg/kg/day, s.c.) on adult rats regarding depression-related and anxiety-like behaviors. Tryptophan levels in cerebrospinal fluid (CSF) were measured 4h after a single administration of daily dosages of chronic treatments. We found that tryptophan increased depressive-related behavior, but did not alter anxiety-like behavior. However, fluoxetine decreased depression-related behavior and was anxiogenic. Tryptophan with concomitant fluoxetine did not alter anxiety-like behavior. Moreover, our data suggests that the antidepressant effect of fluoxetine was not enhanced by concomitant administration of tryptophan, which could be associated with increased levels of tryptophan in CSF. Further investigations are needed to elucidate the related mechanisms.

Blood Chemistry, Hematology and Tryptophan Level in Cerebral Malaria Children

Cerebral malaria is a deadly complication of P. falciparum infection, yet its pathogenesis remains incompletely understood. The blood chemistry, hematology, protein and tryptophan levels in the cerebrospinal fluid (CSF) of cerebral malaria children were investigated. Fifteen children (2.44 +/- 0.25 yr) diagnosed with cerebral malaria were used for this study. The control subjects consist of healthy and malaria-free children (2.50 +/- 0.16 yr). Two ml of blood were collected from each child between 0830 h and 0930 h. Blood chemistry and hematological parameters were analyzed using 2 ml each of Synchron CX5 auto-analyzer. The cerebrospinal fluid (CSF) was collected from the children using the lumbar puncture method, by inserting a sterile needle between the 4th and 5th lumbar vertebrae collected into sterile tubes. The CSF tryptophan, plasma and CSF protein concentrations and CSF protein concentration were determined. There were no significant (p > 0.01) differences in the plasma protein, glucose and CSF glucose levels of the cerebral malaria children as compared with the control. The packed cell volume (PCV) of the cerebral malaria children hemoglobin (Hb) levels were significantly (p < 0.01) lower as compared to control, but were significantly higher in CSF tryptophan and erythrocyte sedimentation rate (ESR) of cerebral malaria children were observed. Results of the study showed that cerebral malaria affected the CSF protein level, ESR, Hb and PCV, but do not affect plasma protein, glucose and CSF glucose concentrations. Data of the present study indicate that CSF protein, tryptophan, ESR, Hb and PCV could be used as possible markers in the diagnosis of cerebral malaria.

The Kynurenine Pathway and Inflammation in Amyotrophic Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is a progressive and fatal motor neuron disease of unknown pathogenesis. The kynurenine pathway (KP), activated during neuroinflammation, is emerging as a possible contributory factor in ALS. The KP is the major route for tryptophan (TRP) catabolism. The intermediates generated can be either neurotoxic, such as quinolinic acid (QUIN), or neuroprotective, such as picolinic acid (PIC), an important endogenous chelator. The first and inducible enzyme of the pathway is indoleamine 2,3-dioxygenase (IDO). The present study aimed to characterize the expression of the KP in cerebrospinal fluid (CSF), serum and central nervous system (CNS) tissue of ALS patients. Using high performance liquid chromatography, we analysed the levels of TRP and kynurenine (KYN), and, with gas chromatography/mass spectrometry, the levels of PIC and QUIN, in the CSF and serum of ALS patients and control subjects. Immunohistochemistry was employed to determine the expression of QUIN, IDO and human leukocyte antigen-DR (HLA-DR) in sections of brain and spinal cord from ALS patients. There were significantly increased levels of CSF and serum TRP (P < 0.0001), KYN (P < 0.0001) and QUIN (P < 0.05) and decreased levels of serum PIC (P < 0.05) in ALS samples. There was a significant increase in activated microglia expressing HLA-DR (P < 0.0001) and increased neuronal and microglial expression of IDO and QUIN in ALS motor cortex and spinal cord. We show the presence of neuroinflammation in ALS and provide the first strong evidence for the involvement of the KP in ALS. These data point to an inflammation-driven excitotoxic-chelation defective mechanism in ALS, which may be amenable to inhibitors of the KP.

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

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

Serial cerebrospinal fluid tryptophan and 5-hydroxy indoleacetic acid concentrations in healthy human subjects

The role of the serotonergic system in the pathogenesis of behavioral disorders such as depression, alcoholism, obsessive-compulsive disorder, and violence is not completely understood. Measurement of the concentration of neurotransmitters and their metabolites in cerebrospinal fluid (CSF) is considered among the most valid, albeit indirect, methods of assessing central nervous system function in man. However, most studies in humans have measured lumbar CSF concentrations only at single time points, thus not taking into account rhythmic or episodic variations in levels of neurotransmitters, precursors, or metabolites. We have continuously sampled lumbar CSF via subarachnoid catheter in 12 healthy volunteers, aged 20–65 years. One ml (every 10 min) CSF samples were collected at a rate of 0.1ml/min for 24-hour (h), and the levels of tryptophan (TRP) and 5-hydroxy indoleacetic acid (5-HIAA) were measured. Variability across all 12 subjects was significantly greater (P < 0.0001) than the variability seen in repeated analysis of a reference CSF sample for both 5-HIAA (32.0% vs 7.9%) and TRP (25.4% vs 7.0%), confirming the presence of significant biological variability during the 24-hr period examined. This variability could not be explained solely by meal related effects. Cosinor analysis of the 24-hr TRP concentrations from all subjects revealed a significant diurnal pattern in CSF TRP levels, whereas the 5-HIAA data were less consistent. These studies indicate that long-term serial CSF sampling reveals diurnal and biological variability not evident in studies based on single CSF samples.

Intraspinal Pressure Influences CSF Disposition of Tryptophan and 5-HIAA

Cerebrospinal fluid (CSF) concentrations of monoamine compounds are influenced by factors such as age, gender, height, body weight, tapping time, and atmospheric pressure. We have now examined the role of intraspinal pressure. Thirteen male volunteers underwent lumbar puncture in the right decubitus position without preceding strict bed rest. The intraspinal pressure was recorded, and monoamine precursors, transmitters, and metabolites were analyzed in two consecutively collected CSF fractions. Tryptophan in 12 ml of CSF and the 5-hydroxyindoleacetic acid concentration ratio [fraction II (7–12 ml CSF)/fraction I (0–6 ml CSF)] correlated with the intraspinal pressure. Hypothetically, the intraspinal pressure may be a confounding factor for a correct interpretation of CSF tryptophan and 5-hydroxyindoleacetic acid concentrations, and this is an issue that has to be addressed in future CSF studies.

Depressive Symptoms in Hypothyroid Disorder with some Observations on Biochemical Correlates

Lumbar punctures and ratings of depressive symptoms were done in hypothyroid patients before and during L-thyroxine therapy. Before treatment, the most prominent symptoms were concentration difficulties, lassitude, and reduced sexual interest. All patients suffered from sleep disturbances. Suicidal thoughts did not occur at all. Inner tension was negatively correlated with the anxiogenic cholecystokinin tetrapeptide (CCK-4) in the cerebrospinal fluid (CSF), while reduced sexual interest was negatively correlated with CSF tryptophan. Furthermore, failing memory correlated negatively with T3 as well as T4 in serum. A positive correlation was found between failing memory and serum TSH. All patients improved significantly during treatment. No biochemical correlates were found. In conclusion, hypothyroidism is associated with major depressive symptoms. CSF CCK-4 and tryptophan, as well as serum thyroid hormones, may constitute biochemical correlates for some of these symptoms.

Cerebrospinal fluid concentrations of tryptophan and 5-hydroxyindoleacetic acid in Macaca mulatta: diurnal variations and response to chronic changes in dietary protein intake.

In rats, dietary protein is known to influence brain tryptophan (TRP) concentrations and serotonin (5HT) synthesis. However, few studies have examined this relationship in primates (including humans). We therefore studied the effect in monkeys of changes in chronic protein intake on plasma and cerebrospinal fluid (CSF) concentrations of TRP and 5-hydroxyindoleacetic acid (5HIAA), the principal 5HT metabolite. Juvenile male monkeys (Macacca mulatta) consumed for sequential 4-week periods diets differing in protein content (approximately 23%-->approximately 16%--> approximately 10%-->approximately 6% protein [%-energy/day]). Each day, food was presented as a morning meal of fruit, and an afternoon meal consisting of a pelleted, commercial diet and fruit. During week 4 on each diet, blood and CSF were sampled diurnally via indwelling catheters. Plasma and CSF TRP varied diurnally and with dietary protein content. On all diets, CSF TRP declined modestly in the morning, and increased in the afternoon; the magnitude of the increments varied directly with dietary protein content. Diurnal variations were absent for CSF 5HIAA; however, CSF 5HIAA varied directly with chronic dietary protein content. We conclude that dietary protein content can chronically influence CSF TRP concentrations in monkeys. The variation in CSF 5HIAA suggests chronic protein intake may influence serotonin synthesis and turnover, perhaps via changes in TRP concentrations.

Effects of acute tryptophan depletion on plasma and cerebrospinal fluid tryptophan and 5-hydroxyindoleacetic acid in normal volunteers.

Brain serotonin synthesis and metabolism (turnover), as indicated by CSF concentrations of 5-hydroxyindoleacetic acid (5-HIAA), may depend on plasma concentrations of the essential amino acid L-tryptophan (TRP). We investigated the biochemical effects of acute plasma TRP depletion (ATD) in normal volunteers undergoing a 36-h CSF collection via lumbar drain. Six subjects who were in good health were put on a low-TRP diet (160 mg/day) 24 h before lumbar puncture; this diet was continued for the first 22 h of the CSF collection. At hour 22, subjects ingested a TRP-deficient 15-amino acid drink shown previously to deplete plasma TRP. Total plasma TRP, free plasma TRP, and CSF TRP subsequently decreased 86.3, 86.5, and 92.3%, respectively. CSF 5-HIAA decreased by 32.8%. Plasma total and free TRP concentrations were both decreased at approximately 2 h following ingestion of the TRP-free amino acid drink and were lowest approximately 6 h after ATD; CSF TRP and 5-HIAA were decreased at 2.5 h and approximately 4 h after ATD, respectively. CSF TRP was lowest 8.0 h later. CSF 5-HIAA continued to decrease 14 h after the TRP-deficient amino acid drink was given.

Tryptophan depletion during continuous CSF sampling in healthy human subjects.

The tryptophan (TRP) depletion paradigm has been employed to investigate mood and behavioral effects of acutely lowering plasma TRP, and presumably brain serotonin (5-hydroxytryptamine [5-HT]) levels through administration of a special diet and/or amino acid drink. Our goal was to test the assumption that a corresponding fall in central levels of TRP and 5-HT (measured by its major metabolite, 5-hydroxyindoleacetic acid [5-HIAA]) occurs during the standard execution of this method in healthy adult subjects. Three males and two females completed the protocol, which included a one-day low-TRP diet and a TRP-free amino acid drink. Lumbar puncture was performed, with placement of an indwelling catheter connected to a peristaltic pump and fraction collector. Cerebrospinal fluid (CSF) was sampled continuously for a 13.5-hour period (before, during, and after the drink), with fractions removed every 15 minutes. Plasma samples were simultaneously obtained. CSF TRP levels and plasma TRP levels were highly correlated, falling a mean of 92% and 85% from baseline, respectively. CSF nadirs were reached several hours after plasma nadirs. CSF 5-HIAA decreased modestly (24% to 40%, mean 31% change from baseline), with lowest concentrations observed 8-12 hours after the amino acid drink. These data suggest that TRP depletion results in substantial declines in central 5-HT turnover.

Assessment of diurnal variation of cerebrospinal fluid tryptophan and 5-hydroxyindoleacetic acid in healthy human females.

The role of serotonin (5-HT) in the pathogenesis and treatment of major neuropsychiatric disorders, including mood and anxiety disorders, continues to be the subject of extensive research. Previous studies examining central 5-HT functioning measured cerebrospinal fluid (CSF) levels of 5-hydroxyindoleacetic acid (5-HIAA) by using single or multiple lumbar punctures. A number of investigators have demonstrated the feasibility of continuous CSF sampling via an indwelling lumbar catheter to study CSF neurochemistry in healthy subjects and patients with neuropsychiatric illness. Four healthy female volunteers, aged 21-34 years, underwent continuous CSF sampling. CSF was collected at a constant rate of 1 ml every 10 minutes over a 30-hour period, with levels of tryptophan (TRP) and 5-HIAA measured every hour. Plasma was also obtained hourly for TRP determination. The results of this study indicate that CSF 5-HIAA, CSF TRP, and plasma TRP levels showed variation over time, but failed to show diurnal fluctuation. Intra-individual coefficients of variation determined for CSF 5-HIAA, CSF TRP, and plasma TRP ranged from 9.2 to 14.9%, 8.8 to 14.6%, and 14.7 to 19.0%, respectively. Continuous CSF sampling is safe and feasible in humans, and may prove useful for studies of central 5-HT neurotransmission in neuropsychiatric illness.

A preliminary study of tryptophan depletion on tics, obsessive-compulsive symptoms, and mood in Tourette's syndrome

Tourette's syndrome (TS) is a chronic neuropsychiatric disorder of childhood onset characterized by motor and phonic tics that wax and wane in severity, as well as by symptoms of obsessive-compulsive disorder (OCD) (Pauls and Leckman 1986; Leckman et a1 1992). There have been conflicting reports regarding altered tryptophan (TRP) metabolism and abnormalities in the serotonin (5-HT) system in TS. In one study of 7 TS subjects and 10 normal controls, no group differences in whole blood TRP were seen (Dursun et a1 1994); however, in two larger studies, whole blood TRP was lower in the TS group (Leckman et a1 1984; Comings 1990). Cerebrospinal fluid (CSF) levels of TRP have also been reported to be slightly but nonsignificantly lower in TS subjects, while within the TS group, CSF TRP was inversely related to tic severity (Leckman et a1 1995). Finally, a postmortem study found lower TS group mean levels of 5-HT and 5-hydroxy indoleacetic acid (5-HIAA), the major metabolite of 5-HT, in nearly all subcortical brain regions examined (Anderson et a1 1992). A role for altered TRP metabolism or underactivity of the brain 5-HT system in the pathophysiology of TS is also suggested by the emergence of transient motor tics in a patient with OCD participating in an acute TRP depletion study (Goodman WK, personal communication). In addition, there is a report of the successful treatment of stimulant-induced tics with oral TRP (Chandler et a1 1989). We therefore elected to systematically study the effects of acute TRP depletion in a group of subjects with TS.

Cracking the riddle of cancer anorexia

During tumor growth, anorexia and reduced food intake are among the major causes leading to malnutrition and eventually cachexia, which negatively affect patients' outcome. Consistent evidence from our laboratories in rats and humans indicates a key role for ventromedial hypothalamic (VMH) serotonergic system in the development of cancer anorexia. Thus, we postulated that during cancer, increased plasma tryptophan levels (the precursor of serotonin) lead to increased cerebrospinal fluid tryptophan concentrations and increased VMH serotonin synthesis, which then mediates the occurrence of anorexia. However, recent data strongly suggest that factors other than tryptophan supplied to the central nervous system might be involved in the pathogenesis of reduced food intake during tumor growth. Particularly, a significant role appears to be played by interleukin-1 (IL-1). We recently showed that IL-1 infusion in normal rats causes changes in food intake and its determinants, meal number and meal size, similar to those characterizing cancer anorexia, thus supporting the involvement of this cytokine in the development of anorexia. Interestingly, IL-1 and the VMH serotonergic system appear to be closely linked: peripherally infused IL-1 increases brain tryptophan and serotonin concentrations, while intracerebrally infused IL-1 increases neuronal firing rate and serotonin release. We therefore hypothesize that during tumor growth, increased production/secretion of IL-1 occurs, which facilitates the tryptophan supply to the brain. IL-1 can then also act on the VHM itself, where IL-1 receptors exist, to increase its neuronal activity and serotonin release. In other words, we believe that centrally acting IL-1 increases hypothalamic neuronal firing rate and serotonin release, while peripherally acting IL-1 is critical in supplying the hypothalamus with the precursor, tryptophan, in order to maintain the high rate of serotonin synthesis. Also, additional factors recently proposed as mediators of anorexia (including neuropeptide Y and nitric oxide) appear to be part of the hypothesized pathogenic mechanism.

Early-Onset Alcoholics Have Lower Cerebrospinal Fluid 5-Hydroxyindoleacetic Acid Levels Than Late-Onset Alcoholics

We investigated the interrelationships of age at onset of excessive alcohol consumption, family history of alcoholism, psychiatric comorbidity, and cerebrospinal fluid monoamine metabolite concentrations in abstinent, treatment-seeking alcoholics. We studied 131 recently abstinent alcoholics. Supervised abstinence was maintained on a research ward at the National Institutes of Health Clinical Center for a minimum of 3 weeks. All alcoholics received a low-monoamine diet for a minimum of 3 days before lumbar puncture. Lumbar punctures were performed in the morning after an overnight fast. Monamine metabolites and tryptophan in cerebrospinal fluid were quantified with liquid chromatography by means of electrochemical detection. Psychiatric diagnoses were established from blind-rated Schedule for Affective Disorders and Schizophrenia-Lifetime version interviews administered by a research social worker. Severity and age at onset of excessive alcohol consumption were documented with a structured lifetime drinking history questionnaire and with selected alcoholism screening questionnaires (CAGE and Michigan Alcoholism Screening Test). Family history of alcoholism was obtained from the probands. A majority of the treatment-seeking, primarily white male alcoholics had a lifetime history of psychiatric disorders other than alcoholism. None fulfilled criteria for antisocial personality disorder. Early-onset alcoholics (onset of excessive consumption before 25 years of age) had a more severe course of alcoholism and lower mean cerebrospinal fluid 5-hydroxyindoleacetic acid concentration than late-onset alcoholics. Patients who reported both parents to be alcoholics had particularly low mean cerebrospinal fluid 5-hydroxyindoleacetic acid, homovanillic acid, and tryptophan concentrations. Among treatment-seeking alcoholics, early age at onset is generally associated with a more severe course of alcoholism and lower cerebrospinal fluid 5-hydroxyindoleacetic acid concentration.