CSF GABA Research Articles

KCNQ2 mutations: genotype-phenotype association beyond epilepsy

Background: KCNQ2 abnormalities were described in infants with benign familial neonatal seizures (BFNS) and epileptic encephalopathy (EE). Associated features possibly include abnormal neuroimaging findings such as hypomyelination and/or T2 high signal of basal ganglia. Methods: This report describes 4 infants carrying different heterozygous KCNQ2 variants and 2 infants with 20q13.33 deletions encompassing KCNQ2 gene. Results: The different KCNQ2 mutations led to EE in 3 patients and included a novel de novo missense variant, p.Arg201Cys/c.601C>T, in an infant with severe EE and global developmental delay, hyperkinetic movement disorder, autonomic dysfunction with chronic hypoventilation, apnea, low GABA levels in CSF, and hypomyelination. She died at age 3 years of respiratory failure. One patient with BFNS and normal MRI has a previously reported c.508delG frame shift mutation in KCNQ2. Of the two de novo 22q13.33 deletions (1.2Mb versus 254.1 Kb) the larger caused a more severe phenotype, including focal epilepsy from infancy until 4 years, moderate developmental delay and diffuse brain volume loss. Conclusions: Along with varied epilepsy phenotypes and neuroimaging findings KCNQ abnormalities were associated with severe autonomic dysfunction and reduced CSF GABA levels. This might have further treatment implications, besides that the altered potassium channel function itself presents a therapeutic target.

Manifestations respiratoires au cours du syndrome ‘DRESS’ : cohorte rétrospective et revue de la littérature

Recently we have developed a simple and sensitive assay for the measurement of GABA in fluids and tissues by high performance liquid chromatography [16]. The only sample preparation required is deproteinization and usually 100 μl of CSF is all that is required for a reliable determination of OABA. We have measured GABA CSF levels in patients with various neurological disorders as well as in a few control specimens. The control values, around 300 nM, agree with published results. Patients with Parkinson's disease or Huntington's chorea had CSF GABA levels ranging from 26–150 nM with occasional high values and are in general agreement with those reported by Enna et al. [7]. Cerebrospinal fluid GABA levels in patients with myoclonus, stroke, dystonia and other miscellaneous neurological disorders ranged from 50–600 nM, without any recognizable pattern. From the results obtained thus far, low levels of CSF GABA are not necessarily limited to patients with Huntington's chorea or Parkinson's disease.

Free and conjugated CSF and plasma GABA in Huntington's chorea.

Free and conjugated GABA concentrations were measured in CSF and plasma from 28 patients with manifest Huntington's chorea (HC) and 30 age- and sex-matched controls. GABA was determined by ion-exchange chromatography with fluorimetric detection (IE/F). Free and conjugated CSF GABA was significantly decreased in prolonged HC with advanced disease states and was suggested practicable as an additional diagnostic tool. However, in younger patients (less than 40 yrs) with a short period of HC (less than 2 yrs) an overlap with the age-matched normal range indicated GABA measurement inadequate to early diagnosis nor predictive for offspring at risk. An age-dependent decrease of conjugated CSF GABA was observed in patients and controls. The more pronounced decrease in patients might reflect the neurodegenerative feature of HC.

Fluoxetine Partly Exerts its Actions Through GABA: A Neurochemical Evidence

Fluoxetine, as a serotonin re-uptake inhibitor augments serotonin concentration within the synapse by inhibiting the serotonin transporter. The contribution of amino acids has also been shown in depression. We hypothesized that fluoxetine exerts its actions at least in part by intervening brain signaling operated by amino acid transmitters. Therefore the aim of this study is to supply neurochemical evidence that fluoxetine produces changes in amino acids in cerebrospinal fluid of rats. Sprague-Dawley rats were anesthetized and concentric microdialysis probes were implanted stereotaxically into the right lateral ventricle. Intraperitoneal fluoxetine (2.5 or 5 mg/kg) or physiological saline was administered and the probes were perfused with artificial cerebrospinal fluid at a rate of 1 mul/min. In the chronic fluoxetine group, the rats were treated daily with oral fluoxetine solution or inert syrup for 3 weeks. The microdialysis probes were placed on the 21st day and perfused the next day. Fluoxetine was ineffective in changing the cerebrospinal fluid GABA levels at the dose of 2.5 mg/kg but produced a significant increase in the perfusates following injection of 5 mg/kg of fluoxetine (P < 0.05). Oral fluoxetine administration (5 mg/kg) for 21 days also elevated the CSF GABA levels by approximately 2-fold (P < 0.05). L: -glutamic acid levels were not affected in all groups. These neurochemical findings show that fluoxetine, a selective serotonin re-uptake inhibitor affects brain GABA levels indirectly, and our results suggest that acute or chronic effects may be involved in beneficial and/or adverse effects of the drug.

GABAergic Contributions to the Pathophysiology of Depression and the Mechanism of Antidepressant Action

Increasing evidence suggests that abnormalities in amino neurotransmission are associated with the neurobiology of depression. Preclinical studies demonstrate that GABA modulating agents are active in commonly used rodent behavioral models of antidepressant activity, and that chronic administration of antidepressant drugs induces marked changes in GABAergic function. In humans, depressed patients have lower plasma, CSF and brain GABA concentrations than non-depressed comparison subjects. The recent discovery that several anticonvulsant and GABA-mimetic agents possess mood stabilizing and antidepressant properties has further increased interest in these findings. This review outlines the existing literature investigating the possible involvement of GABA in the neurobiology of depression and briefly highlights how this information may afford new targets for antidepressant drug development.

P.1.g.001 Increased CSF cholecystokinin, NPY and GABA levels in pathological gambling

P.1.g.001 Increased CSF cholecystokinin, NPY and GABA levels in pathological gambling

Pyridoxal phosphat (vitamine B6) responsive West syndrome – follow up over 12 years

The West syndrome, known since 1841 is one of the most therapeutically resistant and unfavourable epilepsies of the first months of life. First line drug for treatment is vitamine B6. A response is really a 'lucky shot'. Long term follow up of neuropsychological outcome in these children is not available up to now. We report the course over 12 years on a boy with a vitamine B6 sensible West syndrome. He is the 2nd child of healthy parents, pregnancy and birth were normal. At the age of 6 months West syndrome of idiopathic origin started with typical seizures and hypsarrhythmia in the EEG. CSF GABA concentration before vitamine B6 (300mg/kg/body weight) was 8 pmol/ml (normal range 54–184 pmol/ml).

303. Measurement of human cortical GABA synthesis in vivo

Studies of GABA receptors and CSF GABA levels have implicated the GABAergic system in mood disorders. Recently H magnetic resonance spectroscopy (MRS) has shown that cortical GABA is changed in unipolar depression. The mechanism of the changes is unknown and may hold clues for clinical effects and treatments. GABA synthesis may be reduced, or GABA turnover may be elevated by GABAergic overstimulation, reaching new, lower steady-state levels. Key to evaluating these possibilities is the ability to measure the synthesis of cortical GABA in humans in vivo. C MRS was used to detect the incorporation of the non-radioactive isotope C in GABA, glutamate, and glutamate during a 90-minute infusion of [1-C]glucose in three healthy volunteers. The GABA C2 time course was fitted with a single exponential function after removing the contribution from natural abundance labeling of the co-resonant N-acetylaspartate C3, showing that 2.4 6 2.1% (mean 6 s.d.) of the GABA pool is degraded and replaced per minute. Given a GABA concentration of 1.48 mmol g in healthy controls obtained from previous H MRS studies (Sanacora et al., Arch Psych 56:1043), the rate of synthesis of GABA was estimated to be 0.035 mmol min g, which is ;4% of the rate of the cortical tricarboxylic acid cycle. While more studies will more precisely define the rate, the results demonstrate the possibility of direct measurements of GABA synthesis in mood disorders.

Impairment of GABAergic transmission in depression: new insights from neuroimaging studies.

Several lines of evidence suggest that abnormalities in GABAergic neurotransmission are associated with the neurobiology of depression. Animal studies demonstrate that GABA agonists and antagonists can modulate commonly used behavioral models of depression and that chronic administration of antidepressant drugs induce marked changes in GABAergic function. In humans, depressed patients have lower plasma and CSF GABA concentrations than nondepressed comparison subjects. The recent discovery that several anticonvulsant and GABA-mimetic agents possess mood stabilizing and antidepressant properties has further increased interest in these findings. Novel imaging techniques now allow investigation of the GABAergic contribution to affective disorder pathophysiology. Through the techniques of PET, SPECT, and MRS, GABAergic function can be evaluated in vivo. Preliminary studies employing these techniques are finding new evidence suggesting that GABAergic abnormalities are associated with stress, anxiety, and depression. This article reviews the existing literature investigating the possible involvement of GABA in the neurobiology of depression and briefly highlights how these novel neuroimaging techniques can be used to further assess this hypothesis.

GABA and brain abnormalities in schizophrenia

Some recent autopsy studies indicate that γ-aminobutyric acid (GABA) function is decreased in brain areas that involve some of the well-described structural changes observed in schizophrenia. The current study examined the relationship between CSF and plasma GABA levels and brain structural measures in schizophrenia. Sixty-two drug-free, physically healthy male patients with schizophrenia (DSM-IIIR) were evaluated for plasma and CSF GABA, as well as brain structural measures on CT scans. Plasma levels of GABA were associated with prefrontal sulcal widening and VBRs, but not global sulcal widening in the schizophrenic patients. CSF GABA measures were not associated with brain structural measures, but were associated with age and age of onset. The significant relationship between plasma GABA, but not CSF GABA, and specific brain morphology measures in schizophrenic patients suggests that if GABA transmission is impaired in schizophrenia, it is a local, but not global, phenomenon.

Neurotransmitter amino acids in cerebrospinal fluid of patients with Parkinson's disease

We measured the CSF and plasma levels of glutamate, glutamine, aspartate (only in plasma), asparagine, glutamine, glycine and GABA in 31 patients with Parkinson's disease and in 45 matched controls. We used an ion-exchange chromatography method. When compared to controls, PD patients had similar CSF levels of glutamate, glutamine, asparagine, and glycine higher CSF GABA levels higher plasma levels of glutamine, asparagine, and glycine, and lower plasma levels of aspartate. The CSF levels of the amino acids measured were not correlated with the clinical features of PD. Our results that CSF GABA levels are not decreased in PD as previously suggested.

Schizotypal features in relatives of schizophrenic patients with and without a family history of schizophrenia

Some recent autopsy studies indicate that γ-aminobutyric acid (GABA) function is decreased in brain areas that involve some of the well-described structural changes observed in schizophrenia. The current study examined the relationship between CSF and plasma GABA levels and brain structural measures in schizophrenia. Sixty-two drug-free, physically healthy male patients with schizophrenia (DSM-IIIR) were evaluated for plasma and CSF GABA, as well as brain structural measures on CT scans. Plasma levels of GABA were associated with prefrontal sulcal widening and VBRs, but not global sulcal widening in the schizophrenic patients. CSF GABA measures were not associated with brain structural measures, but were associated with age and age of onset. The significant relationship between plasma GABA, but not CSF GABA, and specific brain morphology measures in schizophrenic patients suggests that if GABA transmission is impaired in schizophrenia, it is a local, but not global, phenomenon.

Vigabatrin: rational treatment for chronic epilepsy.

Vigabatrin is a selective, irreversible suicide inhibitor of GABA transaminase and thus increases brain and CSF GABA. In 33 adult patients with long standing refractory epilepsy on treatment with one or two standard anti-convulsant drugs, the addition of vigabatrin up to 3g daily for eight weeks was associated with a 48.2% reduction in seizure frequency. Twenty patients who had exhibited a 50% or more reduction in frequency of one or more seizure types entered an eight week double-blind placebo controlled phase. Patients on vigabatrin maintained a 54.7% reduction of seizure frequency, whereas those on placebo showed an 18.6% increase in seizure frequency, a highly significant difference between the two groups. In the open phase, seven patients were withdrawn due to unacceptable and reversible adverse events. The commonest side effects were drowsiness, depression and mood instability, and headaches. Vigabatrin is a potentially valuable new treatment for chronic epilepsy, especially partial seizures with or without secondary generalisation.

Clinical relevance of measuring GABA concentrations in cerebrospinal fluid

Determination of GABA concentrations in human cerebrospinal fluid can be used to assess GABAergic activity in the central nervous system. As CSF free GABA concentrations may vary with age, sex, CSF fraction, and collection and storage conditions, careful attention to these factors are necessary to allow interpretation of results. Longitudinal studies to investigate the influence of pharmacological agents on CSF GABA have proven especially useful to define clinical biochemical activity and have been utilized to attribute the anti-epileptic action of vigabatrin, a selective inhibitor of GABA-transaminase, to its effects on brain GABA metabolism.

Review: Normal and abnormal central nervous system GABA metabolism in childhood

The metabolism and function of central nervous system GABA is briefly reviewed. Hereditary disorders of the GABA metabolism presenting in childhood are discussed with particular emphasis on the recently identified succinic semialdehyde dehydrogenase deficiency and GABA-transaminase deficiency, and on diseases associated with low CSF GABA which await further unravelling. Low CSF GABA concentrations are not always associated with convulsions. A separate section is devoted to the CSF as a tool in the diagnosis of these disorders. Finally, we present a few diagnostic and therapeutic guidelines.

CSF GABA in depressed patients and normal controls

CSF GABA in depressed patients and normal controls

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.

Disappearance of neonatal seizures and low CSF GABA levels after treatment with vitamin B 6

In an infant with neonatal seizures, CSF GABA levels were determined before and after treatment with vitamin B 6. Before onset of treatment, the level of GABA in CSF was very low (13 pmol/ml). Injection of vitamin B 6 blocked the seizures immediately. When GABA level in CSF was again analysed after continued treatment with vitamin B 6, a value of 127 pmol/ml was determined, which is within the normal concentration range in children. The data substantiate previous findings in brain tissue from a patient with vitamin B 6-dependent seizures, and strongly indicate that impairment of central GAB Aergic activity was the cause of the seizures.

Recent advances in infantile spasms research in Finland.

AbstractData on incidence, etiology, therapy and prognosis of infantile spasms are reviewed. Infants with infantile spasms have a lower CSF GABA concentration than other epileptics. In a large proportion of cases the etiological factors of infantile spasms can now be elucidated with some certainty. Especially, the new neuroradiological and virological methods have enabled a more accurate diagnosis. There have been changes in the etiological pattern over the years. The optimal dosage and duration of ACTH or glucocorticoid therapy have not been established. In the Finnish study the large ACTH doses (120–160 IE) generally used in many Nordic European countries did not carry a better prognosis than the smaller doses (20–40 IE). Therapeutic response showed no correlation with the Cortisol secretion rate but the infants who responded well had a high dehydroepiandrosterone‐androstenedione concentration ratio. Side‐effects of ACTH therapy are relatively common and more common with large doses than with smaller ones. The most common side‐effects are infections and arterial hypertension. There were disturbances of calcium and phosphate metabolism during ACTH therapy. Severe nephrocalcinosis was seen in some infants at autopsy. Fluid disturbances were common at termination of ACTH therapy. ACTH therapy causes adrenal hyporesponsiveness. The therapy should be modified to improve the prognosis.

CSF GABA in euthymic manie-depressive patients and controls

CSF GABA in euthymic manie-depressive patients and controls