Cerebrospinal Fluid Serine Research Articles

Cerebrospinal fluid amino acids glycine, serine, and threonine in nonketotic hyperglycinemia.

Nonketotic hyperglycinemia (NKH) is caused by deficient glycine cleavage enzyme activity and characterized by elevated brain glycine. Metabolism of glycine is connected enzymatically to serine through serine hydroxymethyltransferase and shares transporters with serine and threonine. We aimed to evaluate changes in serine and threonine in NKH patients, and relate this to clinical outcome severity. Age‐related reference values were developed for cerebrospinal fluid (CSF) serine and threonine from 274 controls, and in a cross‐sectional study compared to 61 genetically proven NKH patients, categorized according to outcome. CSF d‐serine and l‐serine levels were stereoselectively determined in seven NKH patients and compared to 29 age‐matched controls. In addition to elevated CSF glycine, NKH patients had significantly decreased levels of CSF serine and increased levels of CSF threonine, even after age‐adjustment. The CSF serine/threonine ratio discriminated between NKH patients and controls. The CSF glycine/serine aided in discrimination between severe and attenuated neonates with NKH. Over all ages, the CSF glycine, serine and threonine had moderate to fair correlation with outcome classes. After age‐adjustment, only the CSF glycine level provided good discrimination between outcome classes. In untreated patients, d‐serine was more reduced than l‐serine, with a decreased d/l‐serine ratio, indicating a specific impact on d‐serine metabolism. We conclude that in NKH the elevation of glycine is accompanied by changes in l‐serine, d‐serine and threonine, likely reflecting a perturbation of the serine shuttle and metabolism, and of one‐carbon metabolism. This provides additional guidance on diagnosis and prognosis, and opens new therapeutic avenues to be explored.

Differential effects on blood and cerebrospinal fluid immune protein markers and kynurenine pathway metabolites from aerobic physical exercise in healthy subjects

Mounting evidence shows that physical exercise modulates systemic inflammation. However, its effect on cerebrospinal fluid (CSF) immune-marker profiles in man are largely unknown. We here report a study on healthy subjects (n = 27, males = 12, mean age 28.7, range 22–52) allocated to either an acute exercise setting over four consecutive days, or a training intervention over 4 weeks. Paired plasma and CSF samples collected at baseline, after 7 days of exercise abstention, and the day after completion of the exercise interventions, were analyzed for protein inflammation markers using a multiplex proximity extension assay and neurotransmitters and kynurenine pathway (KP) metabolites using liquid chromatography, respectively. Routine cell counts, and albumin, immunoglobulin G and neurofilament light chain concentrations in CSF remained unchanged in both paradigms, while several inflammatory proteins became upregulated after acute exercise. However, only changes in three CSF (vascular endothelial growth factor-A, interleukin-7 and matrix metalloproteinase-10) and 12 plasma proteins reached significance levels after adjustment for multiple comparisons and exclusion of less stable proteins. Similarly, KP metabolites only changed among participants after acute exercise, while neurotransmitter levels, except for increased CSF serine, remained stable. Both in plasma and CSF changes in KP metabolites and inflammatory proteins correlated, suggesting that these processes are functionally linked. These findings suggest that acute aerobic physical exercise affects immune markers and KP metabolites systemically and in the CSF.

C.04.03 Relevance of study design for the effectiveness of long-acting injectable antipsychotics in schizophrenia

Serine and other amino acids that function as coagonists at the N-methyl-d-aspartate receptor (NMDAR) have been extensively investigated in schizophrenia (SCZ). However, studies comparing amino acid levels in body fluids of SCZ patients with healthy controls have yielded inconsistent results. We therefore conducted a meta-analysis (search: May 9, 2013) of serine, l-serine, d-serine, glycine, alanine, proline, and aspartate levels in blood and cerebrospinal fluid (CSF) obtained from adult SCZ patients and healthy controls. Standardized differences of means (SDMs) were computed, and heterogeneity, subgroup, sensitivity, and publication bias analyses were conducted. Blood serine levels were found to be significantly higher in SCZ patients compared to healthy controls (SDM = 0.280 (0.021–0.540), p = 0.034; N = 1671 subjects), whereas CSF serine, l-serine, d-serine, glycine, alanine, proline, and aspartate levels did not differ. Stratification by sex suggested that the case–control difference in blood serine levels particularly applies to male subjects. These results provide support for blood serine level aberrations in SCZ patients and warrant further research to disentangle the involvement of serine with SCZ in both sexes.

An update on serine deficiency disorders

Serine deficiency disorders are caused by a defect in one of the three synthesising enzymes of the L-serine biosynthesis pathway. Serine deficiency disorders give rise to a neurological phenotype with psychomotor retardation, microcephaly and seizures in newborns and children or progressive polyneuropathy in adult patients. There are three defects that cause serine deficiency of which 3-phosphoglycerate dehydrogenase (3-PGDH) deficiency, the defect affecting the first step in the pathway, has been reported most frequently. The other two disorders in L-serine biosynthesis phosphoserine aminotransferase (PSAT) deficiency and phosphoserine phosphatase (PSP) deficiency have been reported only in a limited number of patients. The biochemical hallmarks of all three disorders are low concentrations of serine in cerebrospinal fluid and plasma. Prompt recognition of affected patients is important, since serine deficiency disorders are treatable causes of neurometabolic disorders. The use of age-related reference values for serine in CSF and plasma can be of great help in establishing a correct diagnosis of serine deficiency, in particular in newborns and young children.

Multicentre age-related reference intervals for cerebrospinal fluid serine concentrations: Implications for the diagnosis and follow-up of serine biosynthesis disorders

The disorders of serine biosynthesis are a group of inborn errors of metabolism characterised by congenital microcephaly, seizures and severe psychomotor retardation. Although these disorders are rare the prompt recognition of serine deficiency is important as these disorders are treatable. The diagnosis is based on decreased concentrations of serine in cerebrospinal fluid (CSF). It has previously been reported that CSF serine concentrations are inversely associated with age. However, accurate age-related reference intervals have not been generated which has contributed to cases not being identified. In a multicentre study involving 9 different laboratories a total of 424 CSF serine results were obtained. Regression based analyses were performed to calculate age-specific reference intervals. Lower reference intervals for subjects aged 1week, 1month, 6months, 1year, 3years and 15years were 35.0, 31.0, 26.0, 24.0, 21.0 and 17.0μmol/L respectively. Assessment of CSF serine concentrations in 11 patients (aged 1day to 13years) previously diagnosed with disorders of serine biosynthesis (serine concentrations ranging from 5 to 18μmol/L) were clearly decreased compared to our age-related reference intervals and would have correctly identified all cases, thus enabling prompt treatment. However, if age had not been taken into consideration a reference interval of 12.6–69.4μmol/L would be obtained for the combined data set and would have resulted in 2 cases being missed. In conclusion, appropriate age-related reference intervals for CSF serine should be used to diagnose patients with inborn errors of serine biosynthesis.

Simultaneous Analysis of d- and l-Serine in Cerebrospinal Fluid by Use of HPLC

D-Serine is a coagonist for the glycine-binding site of the N-methyl-D-aspartate receptors and has been implicated in various neuropsychiatric functions such as learning, memory, and nociception, as well as schizophrenia and Alzheimer disease. We developed an HPLC method for D- and L-serine in cerebrospinal fluid (CSF). The dabsylated racemic serine peak, automatically collected using a previously reported HPLC separation process for CSF amino acids, was desalted and subjected to a chiral resolution HPLC step with a Sumichiral column using an ultraviolet-visible detector. The limits of quantification (signal-to-noise ratio = 10) for D- and L-serine were 0.8 and 1.3 micromol/L, respectively. The mean imprecision values (CVs) for within-day measurements of D- and L-serine were 2.1% and 1.8%, respectively, and for between-day were 6.2% and 6.6%. Mean recovery of CSF serine (sum of D-serine + L-serine) applied to the Sumichiral column was 87%. The mean (SD) d-serine concentrations in 45 CSF samples obtained from 16 patients with chronic pain due to degenerative osteoarthritis of the knees, 16 with postherpetic neuralgia, and 13 with no pain were, respectively, 3.97 (0.44), 1.85 (0.21), and 2.72 (0.32) micromol/L. D- and L-serine can be quantified with ultraviolet-visible detection of dabsyl derivatives. The dabsyl derivatives are stable and allow duplicate analysis of CSF samples in multisample runs.

Reference data for cerebrospinal fluid and the utility of amino acid measurement for the diagnosis of inborn errors of metabolism

Cerebrospinal fluid (CSF) amino acid analysis is fundamental to the investigation of several inherited metabolic diseases, particularly those presenting with unexplained seizures. CSF glycine measurement is often crucial to the diagnosis of glycine encephalopathy (GE), low CSF serine concentrations are characteristic of 3-phosphoglycerate dehydrogenase deficiency (3-PGDD) and the presence of sulphocysteine is pathognomonic of sulphite oxidase deficiency (SOD), and a vital clue to molybdenum cofactor deficiency (MCD). Limited information is available in the literature on reference values of amino acids in CSF during infancy and CSF samples from healthy individuals are not easily obtained. In order to establish paediatric CSF amino acid reference ranges, we performed a retrospective analysis of all quantitative CSF amino acid data collected in our laboratory over a five-year period. Amino acid analysis was performed using ion-exchange chromatography on a Biochrom-20 amino acid analyser with ninhydrin detection. CSF samples were collected from infants undergoing investigation for unexplained seizures. About 18 of the 95 samples received were excluded from the reference data-set; one was from a patient in whom a diagnosis of GE was confirmed by enzyme analysis, one was from a patient with CSF sulphocysteine of 19 micromol/L in whom a diagnosis of SOD was confirmed by enzyme analysis; the remaining 16 were clearly bloodstained (n = 4) or xanthochromic (n = 12). Frequency of distribution analysis revealed that concentration values for each amino acid demonstrated a right-skewed distribution which was not normalized by log transformation. Data were therefore analysed using non-parametric descriptive statistics and reference ranges were defined by the 2.5th and 97.5th centile limits. Our reference data were derived from 77 CSF samples taken from 77 infants. Median CSF glycine concentration was 9 micromol/L with a reference range of 3-19 micromol/L. For serine, the median CSF concentration was 52 micromol/L with a reference range of 25-105 micromol/L. Sulphocysteine was not normally present in detectable quantities (<1 micromol/L).

Change in the concentrations of amino acids in CSF and serum of patients with essential tremor.

The concentrations of amino acids in the cerebrospinal fluid (CSF) (n = 20) and serum (n = 20) taken from patients with essential tremor were measured by HPLC and compared with those of controls (n = 10). Reduced concentrations of some amino acids (asparagine, glutamine, glycine, threonine, isoleucine, leucine) were observed in serum taken from patients with tremor. Significant increases were detected in the concentrations of glutamate (p < 0.001) and aspartate (p < 0.01). The general tendency of the changes in CSF and serum was similar; although the highest differences were observed in amino acid concentrations in the serum of patients with essential tremor. Opposite shifts of some amino acids were detected, in the concentrations of aspartate, serine, tyrosine, leucine, and isoleucine, which may indicate the independence of the changes in the serum from those in the CSF. This study raises the possibility that a genetically determined metabolic disorder is involved in the etiology of essential tremor that appears peripherally and, partly, centrally. The slight increase in the concentration of glutamate together with the reduced levels of GABA, glycine, and serine in CSF may form the neurochemical basis of the central oscillation observed in essential tremor.

Concentrations of glycine and serine in cerebrospinal fluid during disturbed consciousness; a study of the therapeutic effect of thyrotropin-releasing hormone on the consciousness level.

The concentrations of aliphatic amino acids (glycine, serine, valine, threonine, alanine, leucine, isoleucine) in lumbar cerebrospinal fluid from patients with consciousness disturbances and normal controls were measured. Thyrotropin-releasing hormone (TRH) was administered to patients and the changes of levels of consciousness and amino acid concentrations were followed before and after TRH administration. The concentrations of glycine and serine from patients were significantly higher than those from controls; they returned to the control values with improvement of consciousness disturbances. The influence of TRH upon these amino acid concentrations was not observed. These results suggest that within the central nervous system, an alteration of the level of consciousness is associated with a distortion of glycine and serine metabolism and that TRH itself has no influence upon these amino acid concentrations.