Amino Acids In Cerebrospinal Fluid Research Articles

Excitatory Amino Acids in Cerebrospinal Fluid of Patients with Acute Head Injuries

The excitatory amino acids (EAAs) glutamate (Glu) and aspartate (Asp) play a role in the pathogenesis of postischemic and posttraumatic brain insult. The changes of EAAs in cerebrospinal fluid (CSF) of patients with traumatic brain injury are incompletely understood. We used reversed-phase HPLC with precolumn derivatization with o-phthalaldehyde and fluorescence detection to measure Glu and Asp in CSF of 42 patients with acute head injury and 9 control adults without neurologic diseases. We assessed the Glasgow Coma Scale (GCS) on admission, the main lesion patterns on computed tomography (CT) scan within 24 h post trauma, and the Glasgow Outcome Scale (GOS) 3 months post injury. The mean concentrations of Glu and Asp in CSF in the brain-injured group were significantly higher than those of the control group (Glu, P <0.001; Asp, P <0.05). In patients admitted within 24 h after severe injury (n = 13), peak Glu values appeared within 48 h in 11 patients (85%), and the mean value remained higher than control values at day 7 (P <0.02). The concentrations of EAAs were higher in patients with severe injuries (GCS < or =8) than in those with milder injuries (Glu, P <0.001; Asp, P <0.05). GCS and peak EAAs correlated negatively (Glu, rs = -0.5706, P <0.001; Asp, rs = -0.5503, P <0.001). The patients with focal brain contusion on initial CT scan (n = 8) had a significantly lower peak Glu value than the patients with other patterns (n = 8-15; P <0.02 to 0.001). The peak value of EAAs in the poor-outcome group (including severe disability, vegetative state, and death) was significantly higher than in the good-outcome group (good recovery and moderate disability; Glu, P <0.001; Asp, P <0.01); GOS was closely correlated to the EAA values (Glu, rs = 0.5737, P <0.001; Asp, rs = 0.5470, P <0.001). The EAA concentrations in CSF increase after acute head injury and remain higher for at least 1 week post injury in severely injured patients. The more severe the trauma, the more obvious the excitotoxicity induced by EAAs and the worse the outcome.

Little change in cerebrospinal fluid amino acids in subtypes of multiple sclerosis compared with acute polyradiculoneuropathy

Levels of free amino acids were determined in randomised, blinded samples of cerebrospinal fluid (CSF) from patients with relapsing-remitting or chronic progressive multiple sclerosis (MS), all in the active phase of disease. The levels were compared with amino acid amounts in patients with an acute polyradiculoneuropathy (Guillain–Barré syndrome (GBS)) and a control population of patients with no known neurological disease or deficit. The data did not indicate any significant changes in amino acid levels between MS subgroups. The only significant differences between MS patients and controls were a modest reduction in glutamate and a slight increase in taurine, but the changes were so small that the biological relevance is dubious. These results contrasted with the marked increases for many amino acids in CSF from patients with acute polyradiculoneuropathy compared with controls. The amino acid profile in cerebrospinal fluid (CSF) does not appear to provide evidence of differential pathology in multiple sclerosis (MS). The increase in hydrophobic amino acids and lysine in CSF from patients with acute polyradiculoneuropathy is consistent with transudation over the blood–CSF barrier following an infection. The increases in glutamine and alanine may reflect increased nitrogen removal from brain.

Treatment of pediatric traumatic brain injury: A broad path to a narrow gate

Treatment of pediatric traumatic brain injury: A broad path to a narrow gate

Transport of nutrients across the choroid plexus

A brief outline is given first of the early history of the ventricles and the strange ideas of their functions from Galen to the enlightenment of the Renaissance with the work of Versalius. This is followed by a description of the histology of the choroid plexuses (CP) and discussion on the functions of the choroid plexus and on the composition of cerebrospinal fluid (CSF). The methods of measuring the rate of secretion of CSF will be outlined and the possible nutritive functions of the choroid plexuses will be considered. The role of the choroid plexuses in the control of the concentration of glucose and amino acids in CSF will be compared with data from in vitro experiments to that from the isolated vascularly perfused choroid plexuses. The handling of peptides and proteins by the CP and the synthesis of these molecules by this tissue is then discussed and the effects of lead on the synthesis of transthyretin by this tissue. Finally, reference will be made to the extensive neuro-endocrine role of the CP and efflux systems across the tissue for lipid soluble molecules. Microsc. Res. Tech. 52:38–48, 2001. © 2001 Wiley-Liss, Inc.

Metabolic factors affecting the reproductive axis in male sheep

Changes in food intake affect the reproductive axis in both sexes, and the nutritional signals involved and the sites that receive those signals are now beginning to be unravelled. Our studies have focussed on the mature male sheep, a model in which high food intake stimulates GnRH-LH pulse frequency for only 10-20 days but continues to promote testicular growth over several months. Different signals and different target organs seem to be responsible for these short- and long-term responses. Short-term dietary treatments lead to changes in blood concentrations of glucose, fatty acids, insulin and leptin, and concentrations of glucose, insulin, leptin and some amino acids in cerebrospinal fluid. It seems unlikely that amino acids affect GnRH-LH secretion directly in sheep. Intracerebroventricular infusions of insulin specifically increase LH pulse frequency, but intravenous, intra-abomasal or intracerebroventricular infusions of glucose have no effect, despite their effects on cerebrospinal fluid insulin concentrations. The addition of fatty acids to the diet also increases LH pulse frequency, but does not affect the concentrations of insulin or leptin in the cerebrospinal fluid. It appears that acute responses to changes in nutrition involve a range of alternative pathways, possibly including interactions among insulin, leptin and energy substrates. Effects of long-term dietary treatments on testicular size are only partly dependent on the GnRH-LH system (that is, on brain control) and so must also depend on other, as yet unknown, pathways. Concepts of 'metabolic sensing and integration' are being developed from the basis of existing knowledge of the central control of appetite and reproduction.

Metabolic factors affecting the reproductive axis in male sheep

Changes in food intake affect the reproductive axis in both sexes, and the nutritional signals involved and the sites that receive those signals are now beginning to be unravelled. Our studies have focussed on the mature male sheep, a model in which high food intake stimulates GnRH-LH pulse frequency for only 10-20 days but continues to promote testicular growth over several months. Different signals and different target organs seem to be responsible for these short- and long-term responses. Short-term dietary treatments lead to changes in blood concentrations of glucose, fatty acids, insulin and leptin, and concentrations of glucose, insulin, leptin and some amino acids in cerebrospinal fluid. It seems unlikely that amino acids affect GnRH-LH secretion directly in sheep. Intracerebroventricular infusions of insulin specifically increase LH pulse frequency, but intravenous, intra-abomasal or intracerebroventricular infusions of glucose have no effect, despite their effects on cerebrospinal fluid insulin concentrations. The addition of fatty acids to the diet also increases LH pulse frequency, but does not affect the concentrations of insulin or leptin in the cerebrospinal fluid. It appears that acute responses to changes in nutrition involve a range of alternative pathways, possibly including interactions among insulin, leptin and energy substrates. Effects of long-term dietary treatments on testicular size are only partly dependent on the GnRH-LH system (that is, on brain control) and so must also depend on other, as yet unknown, pathways. Concepts of 'metabolic sensing and integration' are being developed from the basis of existing knowledge of the central control of appetite and reproduction.

L-glutamate, L-arginine and L-citrulline levels in cerebrospinal fluid of Parkinson's disease, multiple system atrophy, and Alzheimer's disease patients.

Alterations in neuronal nitric oxide (NO) production may play a role in the pathophysiology of Parkinson's disease (PD) Alzheimer's disease (AD), and multiple system atrophy (MSA). The biosynthesis of NO is dependent on the availability of L-arginine, the substrate for NO-synthase (NOS), and on L-glutamate, which stimulates NO synthesis via the NMDA receptor. In this process L-citrulline is formed. We measured the levels of these amino acids in cerebrospinal fluid (CSF) of 108 PD patients, 12 AD patients, 15 MSA patients and 21 healthy subjects. A slight but statistically significant elevation of CSF L-citrulline was found in MSA patients, while CSF L-glutamate was found to be significantly decreased in AD patients. We found no significant changes in L-arginine levels. Although the relation between the CSF levels of these amino acids and neuronal NO production is still unclear, our findings suggest that AD is associated with a decrease in NO synthesis.

Transport of nutrients across the choroid plexus.

A brief outline is given first of the early history of the ventricles and the strange ideas of their functions from Galen to the enlightenment of the Renaissance with the work of Versalius. This is followed by a description of the histology of the choroid plexuses (CP) and discussion on the functions of the choroid plexus and on the composition of cerebrospinal fluid (CSF). The methods of measuring the rate of secretion of CSF will be outlined and the possible nutritive functions of the choroid plexuses will be considered. The role of the choroid plexuses in the control of the concentration of glucose and amino acids in CSF will be compared with data from in vitro experiments to that from the isolated vascularly perfused choroid plexuses. The handling of peptides and proteins by the CP and the synthesis of these molecules by this tissue is then discussed and the effects of lead on the synthesis of transthyretin by this tissue. Finally, reference will be made to the extensive neuro-endocrine role of the CP and efflux systems across the tissue for lipid soluble molecules.

Increased cerebrospinal fluid glycine: a biochemical marker for a leukoencephalopathy with vanishing white matter.

Recently, a new disease entity has been defined: the disease of vanishing white matter. This leukoencephalopathy has an autosomal-recessive mode of inheritance. No cause or biochemical marker is known. We studied cerebrospinal fluid amino acids in five patients with the disease and found a consistent, moderate elevation of cerebrospinal fluid glycine in all. The ratio of cerebrospinal fluid to plasma glycine was elevated in four patients, in two patients reaching the level considered diagnostic for nonketotic hyperglycinemia. The activity of the glycine cleavage system was found to be normal in lymphoblasts in two patients. The elevation of cerebrospinal fluid glycine in the disease of vanishing white matter is either caused by a primary disturbance of glycine metabolism or is secondary to excitotoxic brain damage.

Glycine and other neurotransmitter amino acids in cerebrospinal fluid in perinatal asphyxia and neonatal hypoxic‐ischaemic encephalopathy

The aim of this study was to evaluate the concentrations of neurotransmitter amino acids in the cerebrospinal fluid (CSF) of asphyctic newborns, and to establish whether these concentrations are related to the degree of hypoxic‐ischaemic encephalopathy (HIE). Levels of glutamate, aspartate, glycine and taurine in CSF were measured in 48 full‐term newborns during the first 2 d of life. Thirty‐nine of these newborns had birth asphyxia and were divided into three groups: 11 without HIE, 19 with mild HIE and 9 with moderate HIE. None suffered from severe HIE. They were compared with a control group of 9 non‐hypoxic newborns. Determinations of the amino acids in CSF were made by chromatography and expressed as μmol/1 (mean ± SD). CSF glycine value was related to erythrocyte count, and CSF taurine value was related to its plasmatic level. Levels of CSF glycine were related to the severity of HIE (p= 0.020): control (12.08 ± 4.04 μmol/1), without HIE (12.49 ± 4.04 μmol/1), mild HIE (12.14 ± 3.83 μmol/1), and moderate HIE (19.1 ± 10.08 μmol/1; p&lt;0.05 versus mild HIE), even after removing the influence of red cells in CSF.

Involvement of microglia in cerebrospinal fluid glutamate increase in SIV-infected rhesus monkeys (Macaca mulatta).

Cerebrospinal fluid (CSF) samples were collected from 24 uninfected and 24 SIV251 MPBMC-infected rhesus monkeys during early infection and from 6 animals in a longitudinal design up to 7 months postinfection to investigate excitatory and inhibitory amino acid neurotransmitter levels. During the early infection period CSF amino acid concentrations of infected animals were not significantly different from those of uninfected animals. However, long-term studies demonstrated that gamma-aminobutyric acid (GABA) concentrations were decreased while glutamate concentrations were increased late in infection compared with the preinfection values of the same animals. Moreover, we showed that the source of increased glutamate in animals with AIDS is, at least partially, microglial cells. Our data support the hypothesis that excitotoxicity is involved in immunodeficiency virus-induced neurological disease and propose microglia as a contributor to excitotoxic damage.

Analysis of CSF amino acids in young patients with generalised refractory epilepsy during an add-on study with lamotrigine.

The effect of add-on administration of lamotrigine (1-12 mg/kg per day, 2-12 months) on the levels of neurotransmission related amino acids including gamma-aminobutyric acid (GABA), glutamate, aspartate, glycine and antiepileptic drugs (AEDs) in lumbar cerebrospinal fluid (CSF) was studied in 22 children and young adults with generalised therapy resistant epilepsy. Two lumbar punctures were performed, one prior to, and one following a mean of 5 months (2-12 months) of lamotrigine treatment. Lamotrigine decreased seizure incidence and severity in 12 of the 22 patients without influencing CSF GABA, glutamate, aspartate or glycine levels. Lamotrigine did not alter the concentrations of AEDs in CSF or plasma. However, CSF GABA levels were 86% higher in those patients also treated with gamma-vinyl-GABA (vigabatrin, GVG) compared with patients treated with other combinations and this was not altered by co-medication with lamotrigine. The proposed mechanism of action of lamotrigine, namely that it may inhibit glutamate release in the CNS, is not reflected by changes in CSF glutamate levels. The present findings indicate that CSF GABA, glutamate, aspartate and glycine levels may not be useful as in vivo neurochemical markers in young patients responding to the therapeutic dose of lamotrigine used in this study.

Glutamate and taurine are increased in ventricular cerebrospinal fluid of severely brain-injured patients.

Glutamate contributes to secondary brain damage, resulting in cell swelling and brain edema. Under in vitro conditions, increased extracellular levels of the amino acid taurine reflect glutamate-induced osmotic cell swelling. In vivo, increases in cerebrospinal fluid (CSF) taurine could, therefore, unmask glutamate-mediated cytotoxic edema formation and possibly differentiate it from vasogenic edema. To test this hypothesis, ventricular CSF glutamate and taurine levels were measured in 28 severely brain-injured patients on days 1, 5, and 14 after trauma. Posttraumatic changes in CSF amino acids were investigated in regard to extent of tissue damage and alterations in brain edema as estimated by computerized tomography. On day 1, CSF glutamate and taurine levels were significantly increased in patients with subdural or epidural hematomas (8+/-0.8/71+/-12 microM), contusions (21+/-4.1/122+/-18 microM), and generalized brain edema (13+/-3.2/80+/-15 microM) compared to lumbar control CSF (1.3+/-0.1/12+/-1 microM; p < 0.001). CSF amino acids, however, did not reflect edema formation and resolution as estimated by computerized tomography. CSF taurine correlated positively with glutamate, eventually depicting glutamate-induced cell swelling. However, parallel neuronal release of taurine with its inhibitory function cannot be excluded. Thus, the sensitivity of taurine in unmasking cytotoxic edema formation is weakened by the inability in defining its origin and function under the conditions chosen in the present study. Overall, persisting pathologic ventricular CSF glutamate and taurine levels are highly suggestive of ongoing glial and neuronal impairment in humans following severe traumatic brain injury.

Infantile spasm: the effect of corticotropin (ACTH) on the free amino acid profile in cerebrospinal fluid

Increased excitatory amino acid neurotransmission has been implicated in the pathogenesis of infantile spasm. In this study we studied the profile of free amino acids in cerebrospinal fluid (CSF) from 16 patients with infantile spasm before corticotropin (ACTH) treatment. After 10 weeks ACTH therapy the profile of amino acids in CSF was studied once more in eight of the patients. Eleven patients were in the symptomatic group, and five in the cryptogenic group. Increased aspartate levels were measured in CSF following ACTH therapy ( P<0.05). It was concluded that aspartate might have an important role in hypothalamic–hypophyseal axis in patients with infantile spasm.

Stability of Neuroactive Amino Acids in Cerebrospinal Fluid under Various Conditions of Processing and Storage

Free amino acids (AAs) are widely distributed within the central nervous system and play an important role as transmitters of synaptic excitation and/or modulators of synaptic function (1). Because the content of free AAs in cerebrospinal fluid (CSF) has been demonstrated to correlate with brain AA content (2), a reliable measurement of CSF AA concentrations is a potentially useful tool for investigating central nervous system function. Changes in concentrations of AAs with known excitatory function, e.g., aspartate (ASP) and glutamate (GLU), or putative inhibitory function, e.g., glycine (GLY) and taurine (TAU), play an important role in the physiopathology of several neuropsychiatric disorders (3). Varying AA concentrations have been found in the CSF in controls and in neurological disorders. Increased, decreased, and unchanged concentrations of GLU have been observed in the CSF of epileptic patients (4)(5)(6). Initial studies provided evidence for increased concentrations of GLU and ASP in the CSF of patients with amyotrophic lateral sclerosis (7)(8); however, subsequent studies reported CSF concentrations of ASP and GLU that were more than an order of magnitude lower (9). These discrepancies have been explained as the effects of different analytical methods or as the result of a …

Infantile Epileptic Encephalopathy (Ohtahara Syndrome) and Migrational Disorder

A case of early infantile epileptic encephalopathy (EIEE) with suppression-bursts (Ohtahara syndrome) associated with a diffuse cerebral migrational and maturation disorder evident on microscopic examination is reported. Although virtually all reported cases of EIEE are secondary to a congenital or acquired structural malformation of cortical development, EIEE is sometimes identified only by detailed neuropathologic examination, as confirmed by this case report. In addition to the malformation of cortical development, the patient demonstrated an absence of gamma-aminobutyric acid in the cerebrospinal fluid. All children with EIEE should be thoroughly examined by magnetic resonance imaging, cerebrospinal fluid amino acid level determination, and detailed postmortem neuropathologic examination.

Cerebrospinal fluid levels of amino acids in infants and young children with chronic renal failure.

Chronic renal failure (CRF) is associated, especially in young children, with delayed cognitive development of unknown origin. As cerebrospinal fluid (CSF) reflects the composition of the extracellular fluid of the brain, not only plasma but also CSF amino acids concentrations were determined in 8 infants (age 2-8 months) and 3 children (age 26, 32 and 56 months) with CRF (creatinine clearance 13 +/- 9 ml/min/ 1.73 m2). In three of these children investigations were repeated after six weeks of CAPD treatment. In the infants, a significant decrease was found in CSF of alpha-aminobutyric acid, valine, isoleucine, leucine, tyrosine, tryptophane, histidine and n-zeta-methyl-1-lysine, whereas there was a significant increase of 3-methylhistidine. In plasma serine, valine, leucine, tyrosine and histidine were significantly decreased, whereas there was a significant increase of aspartic acid, citrulline, and 3-methylhistidine. These abnormalities remained constant after the start of CAPD except for the normalization in CSF and plasma of 3-methylhistidine. These data indicate a generalized disturbance of amino acids in young children with CRF. An abnormal substrate is offered to the neurons and astroglia in children with CRF.

Alanyl-Aminopeptidase Activity Decrease in Cerebrospinal Fluid of Alzheimer Patients

We analyzed the amino acid concentrations and aminopeptidase activities in plasma and the cerebrospinal fluid (CSF) of Alzheimer patients. Correlations were calculated between these parameters and the degree of cognitive impairment, duration of the disease and age. In comparison with a control group, no changes were found in the levels of amino acids in CSF or plasma of Alzheimer patients. Alanyl-aminopeptidase activity was significantly lower in the CSF of Alzheimer patients, whereas no differences in CSF were detected as regards the remaining aminopeptidases. The plasma/CSF ratio for aminopeptidase activities was higher in AD patients than in controls, although the difference was only significant for alanyl-aminopeptidase. Amino acid ratios did not show this general tendency. The correlations between plasma aspartate and glutamate concentrations and the stage of the disease, measured with the Mini Mental State Examination, were studied. Changes in aminopeptidase activities and their role in protein dysfunction underlying Alzheimer disease are discussed.

Selective alterations of cerebrospinal fluid amino acids in dogs with congenital portosystemic shunts.

Numerous studies suggest that modifications in concentrations of both excitatory and inhibitory amino acids are implicated in the pathophysiology of portal-systemic encephalopathy (PSE), a neuropsychiatric disorder associated with chronic liver disease in humans. In this study, amino acid levels were measured by High Performance Liquid Chromatography (HPLC) in Cerebrospinal Fluid (CSF) of 10 dogs (age range: 3 mo.- 3 yr 4 mo.) exhibiting a congenital portal-systemic shunt, either intra or extra-hepatic, and 8 age-matched control dogs who showed no signs of hepatic or neurologic disorders. Dogs with congenital shunts manifested signs of encephalopathy such as disorientation, head pressing, vocalization, depression, seizures and coma. CSF from dogs with congenital shunts contained significantly increased amounts of glutamate (2 to 3-fold increase, p<0.01), glutamine (6-fold increase, p<0.05) and aromatic amino acids (phenylalanine, tyrosine and tryptophan) compared to CSF of control dogs. Concentrations of GABA and branched chain amino acids (valine, leucine, isoleucine) were within normal limits. Modifications of brain glutamate (an excitatory amino acid) as well as tryptophan (the precursor of serotonin) could contribute to the neurological syndrome characteristic of congenital PSE in dogs.

Changes in the concentration of amino acids in serum and cerebrospinal fluid of patients with Parkinson's disease

The concentrations of sixteen amino acids have been measured in the serum and cerebrospinal fluid (CSF) of patients with Parkinson's disease and compared with those of control subjects. The levels of most amino acids were not different between the two groups, but the level of glutamate in CSF was decreased significantly, while the level of glutamine was increased. The results may be consistent with an alteration of glutamate neurotransmission in Parkinson's disease.