Lack of seasonal variation in pediatric lumbar cerebrospinal fluid neurotransmitter metabolite concentrations

Seasonal variation of cerebrospinal fluid (CSF) monoamines, particularly 5-hydroxyindoleacetic acid (5-HIAA) and homovanillic acid (HVA) has been reported for psychiatrically ill and normal adults. Circannual variability was examined for a group of 72 children (mean age = 159.4 +/- 40.3 (SD), range 77-238 months), with a primary diagnosis of obsessive-compulsive disorder (OCD) or disruptive behavior disorder (DBD) (attention deficit disorder, oppositional disorder and/or conduct disorder), from whom CSF had been obtained systematically. There were no seasonal differences in mean concentrations of 3-methoxy-4-hydroxyphenylglycol (MHPG), HVA, or 5-HIAA, either for the group as a whole, for the separate diagnostic (OCD vs DBD) categories or for the pre-pubertal subgroup. Log-corrected HVA concentrations for the Tanner IV and V subgroup differed by season with summer concentrations less than those of fall (P = 0.06) and winter (P = 0.005). The results suggest that pubertal changes may play a role in any expression of circannual variability.     

Different neurotransmitter metabolite concentrations in CSF samples from inpatient and outpatient normal volunteers

Cerebrospinal fluid concentrations of the neurotransmitter metabolites 5-hydroxyindoleacetic acid (5HIAA), homovanillic acid (HVA), 3,4-dihydroxyphenylacetic acid (DOPAC) and 3-methoxy-4-hydroxyphenylglycol (MHPG) were compared in two groups of healthy volunteer subjects. One group (outpatient) was composed of 27 subjects who were transported to the outpatient clinic on the day of the lumbar puncture (LP). The other group (inpatient) was composed of 10 subjects who were admitted to the NIMH Research Ward on the evening prior to the LP. After statistical adjustment for age, height, sex and season in which LP was performed the inpatient group had significantly higher concentrations of both 5HIAA and HVA (P less than 0.005 and P less than 0.05, respectively) than the outpatient group. The difference in DOPAC concentration approached significance (P = 0.056), but there was no difference in MHPG concentration between the groups. This result indicates the need for strict control of environment in studies of CSF monoamines and their metabolites.     

Intercorrelations among monoamine metabolite concentrations in human lumbar CSF are not due to a shared acid transport system.

Intercorrelations among homovanillic acid (HVA), 5-hydroxyindoleacetic acid (5-HIAA), and 3-methoxy-hydroxy-phenylglycol (MHPG) concentrations in lumbar cerebrospinal fluid (CSF) were examined before and after blockade of the acid transport system by probenecid in 59 psychiatric inpatients. The three compounds remained intercorrelated despite acid transport blockade, suggesting that the common transport system does not account for their covariance. Other possibilities to explain the interrelationship among these compounds are discussed.     

Lesch-Nyhan syndrome: CSF neurotransmitter abnormalities

Serial determinations of spinal fluid homovanillic acid (HVA) and 5-hydroxyindoleacetic acid (5-HIAA) were made in four patients with the Lesch-Nyhan syndrome over a 5-year period. Control spinal fluids for age-matched comparison were obtained from 194 neurologic and nonneurologic pediatric patients. A rapid decline in control spinal fluid HVA and 5-HIAA occurs over the first 3 years of life (50 and 60%, respectively), and a more gradual decline persists throughout adolescence. The Lesch-Nyhan subjects have similar age-related changes in their spinal fluid neurotransmitter levels. Sequential 5-HIAA determinations from the four Lesch-Nyhan boys fall within the control range. The Lesch-Nyhan HVA levels are lower than the mean value for the age-matched control group in 18 of 19 samples. Ten of 19 determinations fell below the control range. Our findings provide evidence for altered CNS dopamine metabolism in the Lesch-Nyhan syndrome.     

CSF neurotransmitter markers in Alzheimer's disease

CSF neurotransmitter markers may reflect neurochemical alterations in Alzheimer's disease (AD). The best studied neurochemical deficit in AD is that of acetylcholine. Both acetylcholinesterase and butyrylcholinesterase activity have been reported to be reduced in some but not all studies of AD CSF. Studies of monoamine metabolites have also been controversial but most authors have found reduced concentrations of CSF HVA, lesser reductions in HIAA and no change in MHPG. CSF GABA concentrations have been found to be reduced in AD. Studies of CSF neuropeptides in AD have shown reduced concentrations of somatostatin and vasopressin, normal concentrations of vasoactive intestinal polypeptide and either normal or decreased concentrations of beta-endorphin and corticotropin releasing factor. Although no individual CSF neurochemical markers are specific for AD it may be possible to develop a profile of several neurochemical markers which will have enhanced specificity.     

A longitudinal assessment of CSF monoamine metabolite and plasma cortisol concentrations in young rhesus monkeys.

Twenty-two rhesus macaques were studied longitudinally from infancy to early adolescence in order to assess the effects of developmental change, experimental history, gender, and individual variation on the response of the catecholaminergic, serotonergic, and adrenocortical systems to separation-induced stress. Experimental effects were assessed by comparing subjects reared for the first 6 months of life either with their mothers or in peer groups. Developmental changes in response to repeated separation stress were assessed by subjecting the monkeys to four sequential 4-day social separations when they were 6 and 18 months old. At both ages, prior to, and on the last day of the first and fourth separations, cerebrospinal fluid (CSF) was obtained from the cisterna magna to assess monoamine metabolite concentrations, and blood samples were collected to assess plasma cortisol concentrations. Blood samples were also obtained on the first day of each separation at each age. Age-related declines were found in both homovanillic acid (HVA) and 5-hydroxyindoleacetic acid (5-HIAA) concentrations for all subjects. Social separation consistently increased CSF 3-methoxy-4-hydroxyphenolglycol (MHPG) over baseline levels, but decreased HVA concentrations, whereas 5-HIAA levels increased following the first, but not the fourth separation. Plasma cortisol increased rapidly immediately after separation and remained higher than baseline on day 4 of both the first and fourth separation. Independent of age and experimental condition, peer-rearing increased CSF MHPG and plasma cortisol concentrations. During year 1, peer-rearing also produced diminished CSF 5-HIAA concentrations in female monkeys relative to female mother-reared monkeys, but increased male peer-reared monkeys' concentrations relative to mother-reared males. Interindividual differences were highly stable, with significant correlations both within and between years for each of the three metabolites and cortisol.     

Tryptophan hydroxylase and catechol-O-methyltransferase gene polymorphisms: relationships to monoamine metabolite concentrations in CSF of healthy volunteers

Concentrations of monoamine metabolites (MM) in lumbar cerebrospinal fluid (CSF) have been used extensively as indirect estimates of monoamine turnover in the brain. We investigated possible relationships between DNA polymorphisms in the tryptophan hydroxylase (TPH) and catechol-O-methyltransferase (COMT) genes and CSF concentrations of 5-hydroxyindoleacetic acid (5-HIAA), homovanillic acid (HVA), and 3-methoxy-4-hydroxyphenylglycol (MHPG) in healthy volunteers (n = 66). Lower CSF 5-HIAA levels were found in men with the TPH U allele (p = 0.005), but not in women. A similar but less significant pattern was observed for CSF HVA. No relationship was found between the TPH polymorphism and CSF MHPG. COMT genotypes did not relate significantly to MM concentrations. The results suggest that TPH genotypes participate differentially in the regulation of serotonin turnover rate under presumed steady state in the central nervous system of men. Due to the uncertain functional relevance of the DNA polymorphism investigated and the many calculations performed, the results should be interpreted with caution until replicated.     

GABA and amino acid concentrations in lumbar CSF in patients with treated and untreated epilepsy

Lumbar free CSF GABA and amino acid concentrations were measured in 43 patients with newly diagnosed untreated epilepsy and 26 patients with chronic drug-resistant epilepsy. The results were compared with those from 51 control patients. No differences in free CSF GABA concentration could be detected between patients with epilepsy, either treated or untreated, and controls. Untreated patients with primary generalised epilepsy and partial seizures had similar free CSF GABA concentrations. These results would not support the hypothesis that patients with epilepsy have a global disturbance of GABA function. CSF taurine, asparagine, aspartate, glycine and alanine were significantly reduced in patients with epilepsy compared to the control population.     

Determinants of lumbar CSF protein concentration

Objective To determine factors influencing the wide variation of protein concentration in lumbar cerebrospinal fluid (CSF). Methods Patient variables with potential influence on spinal CSF flow and resorption were measured in different patient settings and compared with albumin and IgG CSF/serum quotients. Results In patients whose diagnostic lumbar puncture produces normal CSF the albumin quotient increased with body mass index (r = 0.408), abdominal circumference (r = 0.399), and body weight (r = 0.317), age-corrected with partial correlation. Body motion before lumbar puncture showed only marginal influence on albumin quotient. In patients with radiculography the albumin quotient decreased with iodine contrast medium elimination from spinal subarachnoid space (r = -0.598) and increased with narrowing of lumbosacral spinal canal (r = 0.515). Conclusion Correlation of albumin quotient with body mass index and related variables may be mediated by spinal CSF resorption, which should be impaired in overweight patients with elevated venous pressure. Negative correlation of albumin quotient with iodine resorption from spinal CSF supports this assumption. Correlation of albumin quotient with narrowing of lumbosacral canal should be due to slowed spinal CSF flow which does increase protein concentration. Tested variables explain part of variation of CSF protein concentration. Other variables like blood-CSF barrier permeability and pulsatile spinal CSF flow should have additional influence. Received: 5 September 2001 Received in revised form: 6 February 2002 Accepted: 7 February 2002     

Interacting neurotransmitter systems. A non-experimental approach to the 5HIAA-HVA correlation in human CSF

The repeatedly observed strong positive correlation between 5-hydroxyindoleacetic acid (5HIAA) and homovanillic acid (HVA) in human cerebrospinal fluid (CSF) prompted an investigation to see if conclusions concerning possible interactions between brain serotonin and dopamine turnover could be reached from human CSF concentrations of these acid metabolites. CSF data from patients with depressive disorders diagnosed according to the RDC from Sweden (n = 140) and from the National Institute of Mental Health (n = 35) were used to test structural hypotheses by two statistical approaches--LISREL analysis and logistic regression. Results from both men and women were unequivocal: 5HIAA "controls" HVA, interpretable as a regulatory action of serotonin turnover on dopamine turnover. In women, only 5HIAA was affected by age, height and body size (higher in elderly, short and stout women); no similar relationships were seen in males. The concept of a serotonergic regulation of dopamine turnover was tested on brain punch analyses of serotonin and dopamine and their metabolites in two sets of dogs in a large number of brain areas. Results confirm a facilatory effect of serotonin on indices of dopamine turnover in many brain regions, especially brain stem and hypothalamus. The animal data validate the data analytic approach in humans.     

Monoamine metabolite concentrations in lumbar cerebrospinal fluid of patients with histologically verified Alzheimer''s dementia.

Concentrations of 3-methoxy-4-hydroxyphenylglycol (MHPG), 5-hydroxy indoleacetic acid (5-HIAA) and homovanillic acid (HVA) were determined in lumbar cerebrospinal fluid (CSF) from control subjects and patients of both presenile and senile age with histologically verified Alzheimer's dementia. CSF HVA increased with age in control but not in Alzheimer patients. HVA and 5-HIAA in the CSF of presenile Alzheimer patients was lower than that of age matched control subjects.     

Isoniazid-induced alteration of CSF neurotransmitter amino acids in Huntington's disease

During a randomized, double-blind, crossover, placebo-controlled clinical trial of isoniazid (plus pyridoxine) in Huntington's disease (HD), amino acids and related amino compounds were measured in both cerebrospinal fluid (CSF) and plasma utilizing a newly developed high-performance liquid chromatography ion-exchange/fluorometric assay method. Results showed that isoniazid (plus pyridoxine) significantly elevated the mean (+/- S.E.M.) levels of gamma-aminobutyric acid, aspartate, asparagine, homocarnosine, ornithine, histidine, alpha-aminobutyric acid, isoleucine, leucine and alanine in CSF and the levels of beta-alanine in both CSF and plasma. These alterations can be traced to inhibition of decarboxylation and transamination reactions requiring the cofactor pyridoxal phosphate and may be related to the observed equivocal clinical response in the HD patients. The differential influence of isoniazid on plasma and CSF amino acid profiles suggests that alterations of CNS amino acid metabolism may be reflected in CSF, and that isoniazid-induced alterations of amino acid metabolism in the CNS differ from those in the periphery.     

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

OBJECTIVES: To serially assess changes in lumbar CSF biogenic amines, radiographic characteristics, and neurological signs in 34 patients with dominantly inherited ataxia. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.     

HTR2C Cys23Ser polymorphism in relation to CSF monoamine metabolite concentrations and DSM-III-R psychiatric diagnoses.

BACKGROUND: Heritable variation in brain monoaminergic activity has been suggested to lead to interindividual differences in vulnerability to alcoholism, and many other behavioral disorders. We evaluated if a functional Cys23Ser polymorphism in the 5-HT2C receptor gene, the principal serotonin receptor in the brain, contributes to variation in serotonin, norepinephrine and dopamine activity, as indexed by their major metabolite concentrations in cerebrospinal fluid (CSF). Genotype-monoamine metabolite concentration associations were subsequently correlated to risk for alcoholism. METHODS: The study sample consisted of unrelated Finnish males, including 214 alcoholic, violent offenders and 222 population controls who were interviewed using the Structured Clinical Interview for DSM-III-R, blind rated for psychiatric diagnoses and typed for the HTR2C Cys23Ser polymorphism. CSF concentrations of 5-hydroxyindoleacetic acid (5-HIAA), the major metabolite of serotonin, 3-methoxy-4-hydroxyphenylethyleneglycol (MHPG), the major metabolite of norepinephrine, and homovanillic acid (HVA), the major metabolite of dopamine were available from 195 individuals. RESULTS: The major finding in this study was that HTR2C CysSer23 significantly contributed to CSF MHPG concentrations (p = .012). Higher concentrations of CSF MHPG were observed both in alcoholic violent offenders and population controls with HTR2C Ser23 genotype. Despite the association of Cys23Ser to CSF MHPG, HTR2C genotype was not associated with alcoholism, nor with other psychiatric disorders present in this sample. CONCLUSIONS: We conclude that a functional HTR2C Cys23Ser polymorphism contributes to the interindividual genetic variation of CSF MHPG explaining 3% of the total variance. This finding suggests that 5-HT2C receptors are involved in the regulation of norepinephrine turnover in humans; however, HTR2C Cys23Ser does not appear to contribute to the risk of alcoholism, or its contribution to this complex and heterogenous disorder is too small to be detected by a sample of this size and structure.     

Seasonal variations of lithium plasma levels

The aim of this study was to investigate the seasonal time course of lithium blood levels. We analyzed lithium plasma and red blood cell (RBC) levels in 186 subjects affected by bipolar (n=134) and major depressive (n=52) disorder, with stable oral dosage, followed in our lithium clinic for an average of 36 months. We observed a significant elevation of lithium plasma levels in summer with a more marked variation among early-onset subjects, bipolar subtype, and females. Lithium levels in plasma peaked in summer, and levels in RBC showed a trend in the same direction. Possible stratification factors such as presence of affected relatives or psychotic features did not significantly influence results. In conclusion, we observed a significant variation of lithium plasma levels according to seasons. If confirmed, this finding could have both clinical and research implications.