Metabolites In CSF Research Articles

Low lumbar CSF levels of homovanillic acid and 5-hydroxyindoleacetic acid in multiple system atrophy with autonomic failure.

Low lumbar CSF concentrations of homovanillic acid (HVA) and 5-hydroxyindoleacetic acid (5-HIAA) in patients with multiple system atrophy attended by autonomic failure (MSA) reflect decreased activity in central dopaminergic and serotonergic pathways. These neurochemical changes are consistent with the neuropathological involvement in MSA and distinguish such patients from those with pure autonomic failure who have normal CSF metabolite levels.

Neuroendocrine Aspects of Suicidal Behavior

To assess biologic risk factors in suicidal behavior accurately, it is necessary to distinguish prospective from retrospective design. The former studies are more likely to elicit information concerning possible risk factors in suicide, whereas the latter may be better indicators of biologic traits. In both types of investigations, measures taken close to the suicide attempt are more likely to reflect the biologic state of the individual at the time of the behavior. Although the abnormalities present in suicidal individuals are not entirely clear, most evidence to date suggests an overactivity of the hypothalamic-pituitary-adrenal axis and a dysregulation of both serotonin and adrenergic metabolism. These systems are interrelated. Both animal and human studies have established that a multivariate biologic approach is necessary to the understanding of the pathophysiology of suicide.

Neuroendocrine Aspects of Suicidal Behavior

To assess biologic risk factors in suicidal behavior accurately, it is necessary to distinguish prospective from retrospective designs. The former studies are more likely to elicit information concerning possible risk factors in suicide, whereas the latter may be better indicators of biologic traits. In both types of investigations, measures taken close to the suicide attempt are more likely to reflect the biologic state of the individual at the time of the behavior. Although the abnormalities present in suicidal individuals are not entirely clear, most evidence to date suggests an overactivity of the hypothalamic-pituitary-adrenal axis and a dysregulation of both serotonin and adrenergic metabolism. These systems are interrelated. Both animal and human studies have established that a multivariate biologic approach is necessary to the understanding of the pathophysiology of suicide.

Biological markers in dementia

As biopsies are not usually carried out in the diagnosis of dementia disorders, biological markers for dementia must be searched for in the body fluids. Although no changes are found in the concentrations of active amines and minor metabolites of the monoamines in CSF, the major metabolites, homovanillic acid (HVA) and 5-hydroxyindolacetic acid (5-HIAA), are significantly reduced in patients with Alzheimer's disease (AD) and senile dementia of Alzheimer type (SDAT). The findings from CSF concur with postmortem brain tissue investigations in demented patients. Significant correlations are found between reduced concentrations of monoamine metabolites in CSF and behavioural disturbances as rated by the GBS-scale. Neuroendocrinological studies in dementia show that there is a pathological response to the dexamethasone suppression test in patients with AD, SDAT and multi-infarction dementia (MID). Also, when assessing the postsynaptic NA-sensitivity by giving clonidine, a blunted growth hormone response was recorded. The challenge with the thyrotropin-releasing hormone (TRH) gives a blunted TSH-response in demented patients. It is of interest that there are considerable similarities between neuroendocrinal disturbances in melancholia and in dementia disorders. The investigation of blood is also of value in the diagnosis of dementia disorders. In an investigation of 155 patients admitted to a hospital for suspected dementia it was found that 23% of the patients with late onset primary dementia (SDAT) had low concentrations of vitamin B12, in the blood, high MAO-activity in the platelets and normal concentrations of HVA in CSF.

Comparison of ketamine, physical restraint, halothane and pentobarbital: Lack of influence on serotonergic measures in monkeys and rats

The consequences of the use of ketamine for immobilization have been examined on the concentration of whole blood serotonin, concentrations of neurotransmitters and metabolites in CSF and brain, and specific binding of ligands related to neurotransmitters in brain. Vervet monkeys ( Cercopithecus aethiops sabaeus) were examined under conditions which compared ketamine with physical restraint and with halothane. It was found that ketamine, used acutely in monkeys for restraint, had no influence on the concentration of serotonin in whole blood or the concentration of 5-hydroxyindoleacetic acid or homovanillic acid in the CSF. In rats, untreated animals were compared with those treated with ketamine alone, or in conjunction with pentobarbital. Treatment with ketamine had no influence on the specific binding of ketanserin, imipramine, prazosin or dihydroalprenolol in brain of rat, nor any influence on the concentrations of serotonin, 5-hydroxyindoleacetic acid, norepinephrine, epinephrine, dopamine, or dihydroxyphenylacetic acid in brain. A moderately increased concentration of homovanillic acid was observed in several areas of the brain of the rat after ketamine alone or paired with pentobarbital.

Serotonergic activity and disinhibitory psychopathy in alooholism

Evidence exists of an increased risk for alcoholism in those individuals with some form of disinhibitory behavioral disturbance such as impulsivity, low frustration tolerance, attention span deficits, impersistance, sociopathy, hyperactivity and stimulus-seeking behavior. Studies have also linked alcohol abuse with aggression and criminality. Aggressive and impulsive individuals have been shown to have low levels of the major CSF metabolite of serotonin, 5-hydroxyindoleacetic acid. Interestingly, abstinent alcoholic men, and non-alcoholic first-degree relatives have been shown to have similar decrement. Alcoholism may therefore be part of a spectrum of disinhibitory psychopathy which is characterized by reduced central serotonergic activity, and has a familial or genetic component.

Effects of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) on catecholamines and metabolites in primate brain and CSF

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) administration is able to produce nigrostriatal damage and motor disabilities in primates similar to those seen in Parkinson's disease. Two months after MPTP treatment in African Green monkeys, significant depletions of dopamine (DA) and/or homovanillic acid (HVA) were found in the dorsal ventral tegmental area, and septum, but not in the ventral part of the ventral tegmental area or nucleus accumbens. However, DA losses were greater at all examined sites in the striatum. In putamen and caudate nucleus the decreases in DA and HVA appeared more marked dorsolaterally than ventromedially. After MPTP treatment the ratio HVA/DA was elevated in the septum and all striatal regions; in the striatum the increases in ratio were greater in the dorsolateral than in the ventromedial samples. NE concentration was not significantly altered by MPTP in the mesolimbic system. In control animals the HVA concentration and the ratio HVA/DA were higher in the putamen than in the caudate nucleus. A longitudinal study showed that CSF HVA and 3-methoxy-4-hydroxyphenylglycol were reduced by MPTP and remained below baseline level for 12 months after MPTP treatment. This biochemical study indicates that in the monkey MPTP is able to induce selective damage within both the nigrostriatal and mesolimbic DA systems.

Dietary folate and biogenic amines in the CNS.

Abnormal biogenic amine biosynthesis has been observed in humans and animals with endogenous and exogenous disturbances in folate metabolism. In an attempt to study this interaction biochemically, rats were depleted or repleted with folate for 10 weeks. Folate levels in depleted animals in serum and CSF correlated with stores in liver and brain, respectively. In depleted or repleted animals, there was no significant effect on biogenic amine metabolism in the CNS, as determined by quantitation of biogenic amines in brain and their respective metabolites in brain and CSF. These results are contrary to studies by other investigators. We suspect, however, that specific genetic defects in folate metabolism do result in impaired biogenic amine metabolism and probably at the level of disturbed biopterin cofactor functions.

Discrimination of idiopathic pain syndromes from neurogenic pain syndromes and healthy volunteers by means of clinical rating, personality traits, monoamine metabolites in CSF, serum cortisol, platelet MAO and urinary melatonin

The aim of the present study was to investigate the discriminative power of a series of variables (including determination of depressive symptomatology by means of a visual analogue scale, determination of personality traits by means of the Karolinska Scales of Personality, determination of monoamine metabolites in CSF, platelet MAO activities, serum cortisol before and after dexamethasone suppression and urinary melatonin) in differentiating chronic pain patients from healthy subjects, and patients with idiopathic pain syndromes from patients with neurogenic pain syndromes. Separately each of the measures gave a significant but often low contribution to the discrimination, while a combination of several measures gave a complete discrimination both between healthy subjects and patients with chronic pain syndromes and between patients with idiopathic and neurogenic pain syndromes, respectively.

Dihydropteridine reductase deficiency: Clinical, biochemical and therapeutic aspects

Inborn errors of biopterin metabolism are detected in 1–3% of patients with hyperphenylalaninaemia and appear to result from a deficiency of dihydropteridine reductase (DHPR, EC 1.6.99.7) (Kaufmann et al, 1975) or dihydrobiopterin synthetase (Bartholome etal., 1977) or GPT-cyclohydrolase (EC 3.5.4.16) (Nieder- wieser et al1982). In addition to hyperphenylalaninaemia, most infants and children with congenital defects of biopterin metabolism have decreased levels of neurotransmitter metabolites in CSF.

Cognitive enhancement in Korsakoff's psychosis by clonidine: A comparison with l-Dopa and Ephedrine

Each of three catecholamine agonist medications (clonidine, L-dopa, and ephedrine) and placebo were administered for 2-week trials to a group of amnesics with Korsakoff's psychosis following a double-blind, counterbalanced design. During the last 3 days of each treatment, patients were given a battery of neuropsychological tests to determine the effects of the drugs on memory and related cognitive processes. Only clonidine had a significant effect on measures of anterograde amnesia, and this response was restricted to the same psychometric measures that improved with clonidine in an earlier study (McEntee and Mair 1980). Each of the medications affected performance on some measures of attention. None of the treatments had any effect on measures of retrograde amnesia or digit-symbol substitution. There appears to be a significant negative correlation between the amnestic effects of clonidine and the concentration of the primary noradrenergic metabolite in lumbar CSF (as measured prior to the initial drug trial).

Changes of monoamine metabolites in cisternal CSF in conscious and freely moving rats after reserpine administration

Changes of monoamine metabolites in cisternal CSF in conscious and freely moving rats after reserpine administration

Tofisopam and midazolam: differences in clinical effects and in changes of CSF monoamine metabolites.

The effect of two repeated oral doses of 100 mg tofisopam 15 mg midazolam and placebo on the concentrations of monoamine metabolites (MHPG, 5-HIAA, HVA) in lumbar CSF were studied in general surgical patients operated on under spinal analgesia (n = 12 in each group). Midazolam, but not tofisopam, improved the quality of sleep the night before surgery. Both active agents reduced preoperative anxiety of the patients, but tofisopam was without subjective sedative action. In the placebo group, in contrast to the active drug groups, there was a slight positive correlation between the MHPG concentration and degree of anxiety before surgery. The only significant difference in the monoamine metabolites in lumbar CSF was found in the concentrations of HVA between tofisopam and placebo treated patients. The lower HVA concentrations suggest that the curious 3,4-benzodiazepine derivative, tofisopam, modifies central dopaminergic activity.

Study of dopamine turnover by monitoring the decline of dopamine metabolites in rat CSF after alpha-methyl-p-tyrosine.

CSF was continuously withdrawn from the third ventricle of anesthetized rats. CSF 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), and 5-hydroxyindoleacetic acid concentrations were determined every 15 min by liquid chromatography coupled with electrochemical detection. Acute tyrosine hydroxylase inhibition [with alpha-methyl-p-tyrosine (alpha-MPT)] induced an exponential decline in levels of DOPAC and HVA in CSF. The decline in DOPAC and HVA concentrations was identical in CSF and forebrain but was much slower in the striatum, suggesting that CSF metabolites of 3,4-dihydroxyphenylethylamine (dopamine) reflect whole forebrain metabolites. The decay in CSF DOPAC and HVA levels after dopamine synthesis inhibition was also used as an in vivo index of forebrain dopamine turnover after various pharmacological treatments. Haloperidol pretreatment accelerated this decay, confirming the increase in brain dopamine turnover induced by neuroleptics. After reserpine pretreatment (15 h before), alpha-MPT produced a very sharp decay in levels of DOPAC and HVA. This result indicates that the residual dopamine that cannot be stored after reserpine treatment is very rapidly renewed and metabolized. Nomifensine strongly diminished the slope of DOPAC and HVA level decreases after alpha-MPT, a result which can be explained either by a slower dopamine turnover or by the involvement of storage dopamine pools. These results exemplify the use of monitoring the decay of dopamine metabolites after alpha-MPT administration in the study of the pharmacological action of drugs on the central nervous system of the rat.

CSF monoamine metabolite levels in Alzheimer's and Parkinson's disease.

Levels of the monoamine metabolites homovanillic acid (HVA), 5-hydroxyindoleacetic acid (5-HIAA), and 3-methoxy-4-hydroxyphenylglycol (MHPG) were measured in lumbar CSF from 32 patients with a clinical diagnosis of Alzheimer's disease (AD) and from 21 patients with Parkinson's disease (PD). The baseline CSF metabolite values did not differ significantly between the two groups of patients, although HVA levels were lowest in patients with PD and in the more severely demented patients with AD. Levels of all three metabolites increased significantly in both patient groups during probenecid administration, but HVA levels were significantly higher in patients with AD than in patients with PD. Within the AD group, those with the most severe dementia had the greatest rise in MHPG levels. Alterations in monoamine metabolite levels in the CSF detected during probenecid administration aid in the differential diagnosis of neurodegenerative diseases such as AD.

Measurement of 5-HIAA levels in ventricular CSF (by LCEC) and in striatum (byin vivo voltammetry) during pharmacological modifications of serotonin metabolism in the rat

The relationship between the concentrations of 5-hydroxyindoleacetic acid (5-HIAA) in the CSF and in the striatum has been evaluated in the rat by measuring the levels of this metabolite in ventricular CSF (by liquid chromatography coupled with electrochemical detection) and in the striatal extracellular fluid (by in vivo voltammetry) after administration of inhibitors of serotonin synthesis or degradation. Pargyline, NSD 1015 and alpha-propyldopacetamide all caused an exponential decline of 5-HIAA in both CSF and striatum. For a given drug, the rate constants for 5-HIAA disappearance were identical in the CSF and in the striatal extracellular fluid. These results confirm the view that CSF 5-HIAA may serve as a good index of brain serotonin turnover.

Possible Neurohumoral Mechanisms in CNS Stimulation for Pain Suppression

Improved knowledge about biochemical mechanisms underlying pain suppression by CNS electric stimulation is one condition for the further advancement of this form of treatment. In 6 patients treated with PVG stimulation and in 14 with spinal cord stimulation the concentration of substance P-like immunoreactivity in lumbar CSF increased significantly following stimulation. However, these changes may be unspecific and not directly related to the suppression of pain. Measurements of somatostatin, cholecystokinin, vasoactive intestinal polypeptide, neurotensin and monoamine metabolites in CSF showed no changes related to stimulation and the ensuing pain relief. Possible reasons for these negative findings are discussed.

Concentrations of cefotaxime and the desacetyl metabolite in serum and CSF of patients with meningitis.

Thirty-two cases of meningitis (20 caused by Gram-positive or -negative cocci, 7 by Gram-negative bacilli or listeria, and 5 with aseptic meningitis) received cefotaxime, 2 g 8-hourly, in addition to routine therapy. The concentrations of cefotaxime and its desacetyl metabolite in serum and CSF were determined by a high pressure liquid chromotography. Mean concentration of cefotaxime in CSF ranged from 0.8 mg/l (aseptic meningitis), to 6.4 mg/l (Gram-negative and listeria meningitis), and from 0.5 to 5.4 mg/l for the metabolite. The concentrations of both cefotaxime and the derivative demonstrated a correlation with the degree of inflammation (i.e., cell count and protein concentration) and were higher at 3 h after an infusion of antibiotic than at one and two hours. The concentration showed no marked decline on day 10 when signs of inflammation had largely resolved. The concentrations of both the parent compound and the metabolite 3 h after the infusion suggest that, considering the activity and half life of both the dosing might be spaced at 6-8 h intervals.

CSF and urinary biogenic amines and metabolites in depression and mania. A controlled, univariate analysis.

Levels of 5-hydroxyindoleacetic acid (5-HIAA), homovanillic acid (HVA), and 3-methoxy-4-hydroxyphenylglycol (MHPG) in the CSF, and norepinephrine (NE), epinephrine (E), vanillylmandelic acid, normetanephrine, metanephrine, and MHPG in the urine, were measured in 151 hospitalized patients with affective disorders and in 80 healthy controls following a two-week drug-free period. Unipolar and bipolar depressed subjects differed only in NE and E levels. Compared with controls, depressed subjects had higher CSF MHPG levels, women had higher 5-HIAA levels, and men had lower HVA levels. All urinary metabolites were elevated in depression and mania, with the exception of MHPG. The patterns of NE-E differences discriminated among the forms of affective disorders. These data suggest an imbalance of monoamine transmission in depression, characterized by the hyperactive sympathetic nervous system and adrenal medulla. However, MHPG may not be the measure of choice to reflect this imbalance, necessitating measurement of total body monoamine output.

Carbamazepine and its -10,11-epoxide metabolite in plasma and CSF. Relationship to antidepressant response.

Levels of carbamazepine and its -10,11-epoxide metabolite were measured in plasma and CSF of affectively ill patients treated only with carbamazepine for an average of 33 days at an average dosage of 1,055 mg/day. The CSF levels of carbamazepine were 2.06 micrograms/mL (ie, 31% of plasma levels, which equaled 6.55 micrograms/mL); CSF -10,11-epoxide concentrations averaged 0.91 micrograms/mL in 18 subjects (63% of those found in plasma). Carbamazepine levels in plasma or CSF were not related to degree of antidepressant or antimanic response. In contrast, concentrations of the -10,11-epoxide metabolite were correlated with the degree of antidepressant response. This preliminary study suggests the possibility that the -10,11-epoxide metabolite of carbamazepine may be related to the degree of clinical efficacy in affectively ill patients and may thus possess active psychotropic properties in man in addition to its reported anticonvulsant effects in animals.