Monoamine metabolites in ventricular CSF of children with posterior fossa tumors: correlation with tumor histology and cognitive functioning

Clinical article

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Object

The biogenic amines (dopamine, epinephrine, norepinephrine, and serotonin) are involved in the regulation of multiple neuronal functions, and changes in monoamine concentrations in the CSF have been detected in several disorders. The aim of the present study was to investigate the role of biogenic amines in the ventricular CSF of children suffering from posterior fossa tumors and their possible correlation with tumor histology and cognitive functioning.

Methods

Twenty-two children with posterior fossa tumors who were treated surgically at Children's Hospital “Agia Sofia” were studied. Patients ranged in age from 5.5 to 15 years. The study population included patients who suffered from hydrocephalus and were treated by ventriculoperitoneal shunt placement. During the operation for shunt placement, a CSF sample was obtained for the assessment of 3-methoxy-4-hydroxyphenylglycol (MHPG), homovanillic acid (HVA), and 5-hydroxyindoleacetic acid (5-HIAA). Simultaneously, a blood sample was also obtained for assessment of the same metabolites in the serum. The concentration of vanillylmandelic acid (VMA) was evaluated in 24-hour urine samples in 11 patients. Cerebrospinal fluid from a control group of children was also studied. Executive functions were assessed using the short form of the Wechsler Intelligence Scale for Children (WISC).

Results

Twelve patients suffered from astrocytomas, 9 from medulloblastomas, and 1 from an ependymoma. The MHPG concentration in CSF was significantly higher in patients with astrocytomas compared with patients with medulloblastomas. Twenty-four-hour urine samples of VMA were significantly higher in patients with astrocytomas compared with patients with medulloblastomas. The MHPG concentration in CSF was negatively correlated with the verbal scale of the WISC and there was a trend toward a significant negative correlation with the total WISC score. Homovanillic acid in CSF was positively correlated with the performance scale of the WISC. There was a significant correlation between HVA and MHPG levels in CSF. The CSF concentration of 5-HIAA was significantly correlated with the HVA concentration in serum. Twenty-four-hour urine VMA samples were statistically significantly correlated with HVA concentration in both CSF and serum, with MHPG in CSF, and with 5-HIAA in serum.

Conclusions

This study showed that children with posterior fossa tumors have differences in the levels of monoamine metabolites in CSF. Further studies with a larger number of patients are obviously needed to verify these observations as well as studies to correlate the monoamine metabolite levels with the neuropsychological and behavioral findings in children with posterior fossa tumors.

Abbreviations used in this paper:5-HIAA = 5-hydroxyindoleacetic acid; HVA = homovanillic acid; MHPG = 3-methoxy-4-hydroxyphenylglycol; VMA = vanillylmandelic acid; WISC = Wechsler Intelligence Scale for Children.

Abstract

Object

The biogenic amines (dopamine, epinephrine, norepinephrine, and serotonin) are involved in the regulation of multiple neuronal functions, and changes in monoamine concentrations in the CSF have been detected in several disorders. The aim of the present study was to investigate the role of biogenic amines in the ventricular CSF of children suffering from posterior fossa tumors and their possible correlation with tumor histology and cognitive functioning.

Methods

Twenty-two children with posterior fossa tumors who were treated surgically at Children's Hospital “Agia Sofia” were studied. Patients ranged in age from 5.5 to 15 years. The study population included patients who suffered from hydrocephalus and were treated by ventriculoperitoneal shunt placement. During the operation for shunt placement, a CSF sample was obtained for the assessment of 3-methoxy-4-hydroxyphenylglycol (MHPG), homovanillic acid (HVA), and 5-hydroxyindoleacetic acid (5-HIAA). Simultaneously, a blood sample was also obtained for assessment of the same metabolites in the serum. The concentration of vanillylmandelic acid (VMA) was evaluated in 24-hour urine samples in 11 patients. Cerebrospinal fluid from a control group of children was also studied. Executive functions were assessed using the short form of the Wechsler Intelligence Scale for Children (WISC).

Results

Twelve patients suffered from astrocytomas, 9 from medulloblastomas, and 1 from an ependymoma. The MHPG concentration in CSF was significantly higher in patients with astrocytomas compared with patients with medulloblastomas. Twenty-four-hour urine samples of VMA were significantly higher in patients with astrocytomas compared with patients with medulloblastomas. The MHPG concentration in CSF was negatively correlated with the verbal scale of the WISC and there was a trend toward a significant negative correlation with the total WISC score. Homovanillic acid in CSF was positively correlated with the performance scale of the WISC. There was a significant correlation between HVA and MHPG levels in CSF. The CSF concentration of 5-HIAA was significantly correlated with the HVA concentration in serum. Twenty-four-hour urine VMA samples were statistically significantly correlated with HVA concentration in both CSF and serum, with MHPG in CSF, and with 5-HIAA in serum.

Conclusions

This study showed that children with posterior fossa tumors have differences in the levels of monoamine metabolites in CSF. Further studies with a larger number of patients are obviously needed to verify these observations as well as studies to correlate the monoamine metabolite levels with the neuropsychological and behavioral findings in children with posterior fossa tumors.

Neurotransmitters and neuromodulators are molecules from different chemical classes that transmit signals between cells. Among them, the biogenic amines—namely serotonin, epinephrine, norepinephrine, and dopamine—control a variety of neural functions within the CNS.5 The major metabolites of the biogenic amines—3-methoxy-4-hydroxyphenylglycol (MHPG) for norepinephrine, homovanillic acid (HVA) for dopamine, and 5-hydroxyindoleacetic acid (5-HIAA) for serotonin—can be detected in the CSF and provide important information about the turnover of their parent monoamines in the brain.5 The concentration of monoamine metabolites in the CSF of patients with brain tumors has been used in the past to provide clues about the tumor's histological type and its response to treatment.2,3

In a previous study we found that children with posterior fossa tumors suffer more frequently from somatic concerns, aggressiveness, anxiety, and internalizing disorders compared with controls; however, no difference was found with respect to intelligence scores.19 In this study, we investigated the role of biogenic amines in the CSF of children suffering from posterior fossa tumors and their possible correlation with tumor histology and cognitive functioning.

Methods

Study Population

We studied 22 children with posterior fossa tumors, ranging in age from 5.5 to 15 years, who were treated surgically at Children's Hospital “Agia Sofia” over a 5-year period (2005–2010). All of these patients suffered from obstructive hydrocephalus and were treated using ventriculoperitoneal shunt placement. In 19 cases the shunt was placed before tumor removal, and in 3 cases after tumor excision. During the operation for shunt placement, a CSF sample was obtained for the assessment of monoamine metabolites. Simultaneously, a blood sample was also obtained for assessment of the same metabolites in serum. The concentration of vanillylmandelic acid (VMA) was evaluated in a 24-hour urine sample in 11 patients. Some of these patients were included in a previous study.19 During this same time period, the levels of the above metabolites were measured in the CSF of 22 children via lumbar puncture; these children ranged in age from 12 days to 10 years, were hospitalized, and suffered mostly from benign viral infections. These patients served as a control group. The study was approved by our institutional review board and a written informed consent form was obtained from the child's parents or caregivers.

Chemical Analysis

The metabolites of the neurotransmitters (5-HIAA, HVA, and MHPG) were analyzed by ion pair high-performance liquid chromatography (Series 1050, Hewlett Packard Isocratic pump) with electrochemical detection (Coulochem II, ESA) in the biochemical laboratory of our institution. The detection procedure has been described in detail by Hyland.11 Cerebrospinal fluid monoamines vary according to age. Table 1 depicts the normal levels of CSF monoamines according to age.

TABLE 1:

Normal levels of monoamine concentrations in the CSF of patients according to age*

MonoamineNeonates<1 Yr1–4 Yrs5–10 Yrs11–16 Yrs>16 Yrs
5-HIAA (nmol/L)144–800114–336105–29988–17874–16366–141
HVA (nmol/L)300–1000295–932211–871144–801133–551115–448
MHPG (nmol/L)98–16851–11247–8139–7339–7328–60

Levels are higher in infants and gradually decrease until 16 years of age.

Neuropsychological Assessment

Executive functions were assessed using the short form of the Wechsler Intelligence Scale for Children (WISC) consisting of the subtests “Information” and “Similarities” for the verbal scale and “Block Design” for the performance scale.13 It has been found that these 3 subtests give a valid total IQ with a correlation coefficient of 0.67. In patients with brain tumors the WISC was completed 4.6 days (range 2–8 days) after shunt placement.

Statistical Analysis

We used Pearson's correlation coefficient to compare the values of neurotransmitter metabolite concentrations in CSF, plasma, and urine of the patients and the scores of each scale of the WISC neuropsychological tests. We investigated the intercorrelation between the above values. The Fisher exact test (nonparametric criterion) was used to compare the values of metabolite concentrations in CSF between the patients and controls. We used the Mann-Whitney U-test to compare the values of monoamine metabolites in the CSF of patients and age-matched controls and between astrocytomas and medulloblastomas. Continuous data are expressed as means ± SDs. A 2-sided p value < 0.05 was considered statistically significant.

Results

We assessed 22 patients and 22 controls (Tables 2 and 3). Twelve patients suffered from astrocytoma (2 with WHO Grade I, 10 with WHO Grade II), 9 from medulloblastoma, and 1 from ependymoma.

TABLE 2:

Metabolites of neurotransmitters in the CSF of patients with posterior fossa tumors

Case No.Age (yrs), SexHistology (Grade)5-HIAAHVAMHPG
16.1, Mastrocytoma (II)11229852
26, Mmedulloblastoma10430846
315.5, Fastrocytoma (II)16530763
45.3, Mependymoma13815568
513.6, Mastrocytoma (I)177156789
66.7, Fastrocytoma (II)21016571
714.1, Mastrocytoma (II)15644266
87.3, Mmedulloblastoma23860559
94.9, Mastrocytoma (II)27348865
1014.3, Fastrocytoma (II)14756476
1110, Mastrocytoma (II)29638648
127.1, Mastrocytoma (II)7410941
1312.1, Mmedulloblastoma10320160
146.8, Fastrocytoma (I)14417649
1513.1, Mastrocytoma (II)30737364
1610.6, Mmedulloblastoma18325453
1710, Fmedulloblastoma14826447
186.3, Fmedulloblastoma21037856
195.5, Fmedulloblastoma19831742
205.9, Fastrocytoma (II)28451756
219.8, Mmedulloblastoma12841655
2211.6, Mmedulloblastoma17147647
TABLE 3:

Metabolites of neurotransmitters in the CSF of controls

Case No.Age (yrs), SexDisease5-HIAAHVAMHPG
110, Manemia22554453
24.6, Fhigh fever18534756
310, Mpneumonia30556228
45.6, Fvirosis20542048
51.7, Mhigh fever29341458
61, Fhigh fever25542436
70.3, Fgastroenteritis20839540
81, Mhigh fever30042642
90.5, Mhigh fever31060453
101.8, Mhigh fever15529438
110.8, Mhigh fever29043028
120.2, Mhigh fever22052839
130.2, Fhigh fever20040453
140.2, Furinary infection31360041
150.1, Murinary infection29351562
160.1, Fhigh fever19635027
170.05, Fhigh fever408714123
180.1, Ffebrile seizures21438586
190.05, Mhigh fever18037543
200.05, Mhigh fever21044531
210.1, Furinary infection32563944
220.05, Mhigh fever38059573
TABLE 4:

Statistically significant relationships between monoamine metabolites

Relationshipr Valuep Value
HVA (CSF) – MHPG (CSF)0.620.002
HVA (CSF) – HVA (serum)0.600.003
HVA (serum) – 5-HIAA (CSF)0.460.03
VMA – HVA (CSF)0.750.008
VMA – HVA (serum)0.730.011
VMA – MHPG (CSF)0.720.012
VMA – 5-HIAA (serum)0.740.01

In 14 cases the caregivers consented and the patients underwent a neuropsychological evaluation using the WISC test. No significant difference was found in the age and WISC scores between patients who completed the test and controls (p = 0.4 and p = 0.94, respectively). In 70.6% of patients and in 29.4% of controls, the level of 5-HIAA in CSF was higher than normal (p = 0.031, Fisher exact test). The MHPG levels in CSF were lower than normal in all control subjects but in none of the patients; this difference was statistically significant (p = 0.0001; Fisher exact test). There was a statistical trend of increased HVA concentration in the CSF of the patients compared with age-matched controls (p = 0.06). The MHPG concentration in CSF was significantly higher in patients with astrocytomas compared with patients with medulloblastomas (p = 0.01). Twenty-four-hour urine concentration of VMA was significantly higher in patients with astrocytomas than in those with medulloblastomas (p = 0.042). The MHPG concentration in CSF was negatively correlated with the verbal scale of the WISC (r = −0.67, p = 0.009) and there was a trend toward a significant negative correlation with the total WISC scores (r = −0.49, p = 0.073). Homovanillic acid in CSF was positively correlated with the performance scale of the WISC (r = 0.55, p = 0.041).

There was a significant correlation between HVA and MHPG concentrations in CSF (r = 0.62, p = 0.002; Table 4). There was also a significant correlation between the HVA concentration in serum and in CSF (r = 0.60, p = 0.003). The CSF concentration of 5-HIAA was significantly correlated with the HVA concentration in serum (r = 0.46, p = 0.03). The 24-hour urine concentrations of VMA in 11 of the patients were statistically significantly correlated with the HVA concentrations in CSF (r = 0.75, p = 0.008) and serum (r = 0.73, p = 0.011), with MHPG in CSF (r = 0.72, p = 0.012), and with 5-HIAA in serum (r = 0.74, p = 0.01).

Discussion

In the present study we found that the MHPG concentration in CSF and 24-hour urine concentrations of VMA were higher in astrocytomas compared with medulloblastomas. The MHPG concentration in CSF was negatively correlated with the verbal scale of the WISC, while the HVA concentration in CSF was positively correlated with the performance scale of the WISC.

The biogenic amines (dopamine, epinephrine, norepinephrine, and serotonin) are produced by a biological process and are involved in the regulation of multiple neuronal functions such as regulation of motor coordination, reward-driven learning, arousal, processing of sensory input, memory, appetite, emotional stability, sleep, mood, vomiting, social behavior, and the secretion of anterior pituitary and other hormones.10 Changes in monoamine concentrations in CSF have been detected in major mental disorders.13 For the assessment of the overall functioning of catecholamine and serotonin neurotransmitter pathway within the CNS, the levels of the end products of dopamine (HVA), norepinephrine (MHPG), and serotonin (5-HIAA) in the CSF are measured.12 The measurement of biogenic amines and their metabolites in urine, blood plasma, and CSF is used for the assessment of mental illness and neurological disorders.5

Measured values of monoamine metabolites in the CSF reflect average concentrations accumulated from all brain regions, and in the case of CSF obtained via lumbar puncture, the regional changes that occur within the spinal cord.10 The examination of the ventricular CSF in humans is possible only during certain neurosurgical operations or at necropsy. Thus, lumbar puncture is the most important diagnostic method for the study of monoamine metabolite concentrations, and the findings in lumbar CSF are considered to be similar to those in ventricular CSF.14 Hyland et al. found that the effect of age was independent of the length (height) of the child and therefore unlikely to reflect decreasing concentrations of CSF monoamine metabolites along the spinal canal with increasing size.11,13 The levels of MHPG in ventricular and lumbar CSF and their determination may provide some evidence about the function of catecholamines at important receptor sites in affective disorders, according to Gordon and Oliver.7 Fink et al.,6 using PET in healthy persons, found a significant lateralization in the serotonin-1A receptor distribution in the superior and middle frontal gyrus, the triangular part of the inferior frontal gyrus, the superior temporal gyrus, and the Rolandic operculum. These findings suggested a relationship between serotoninergic organization and language representation in lateralized brain functions.6

Constantino and Murphy reported a circadian influence in the concentration of monoamine metabolites in the CSF of infants and a trend toward lower sociability among 9-month-olds whose newborn 5-HIAA levels were in the lower levels.4 In our study we collected CSF only from children who were operated on during the morning hours. Also, the WISC tests were always performed in the morning. Bareggi et al. reported that alterations of the monoamine metabolites in ventricular CSF can be found in patients with intracranial tumors.2 Higher HVA concentration levels in ventricular CSF can be found in patients who suffer from tumors in the area of the third or fourth ventricles, or in aqueducts that produced either stasis or reduction of CSF flow.2 The present study also showed a trend toward increased HVA concentration in patients with brain tumors compared with controls. All tumors in the present study were located in the posterior fossa.

Dopamine is a neuromodulator that alters the responses of target neurons to other neurotransmitters. In this study, the level of HVA in CSF was positively correlated with the performance scale of the WISC. According to Haller et al., noradrenaline is involved in arousal and attention, learning and memory in socially relevant stimuli, as well as in pain perception.9 In the present study, MHPG concentration in CSF was negatively correlated with the verbal scale of the WISC. Serotonin acts as neurotransmitter-neuromodulator in the CNS in concert with other neurotransmitters. No significant correlation between 5-HIAA levels and tumor type or cognitive functioning was found in the present study. Ashcroft et al. reported a defect in the synthesis or release of serotonin in depressed patients, while in their 6 patients with brain tumors, the concentration of 5-HIAA in the ventricular CSF was increased.1

Bostrom and Mirkin3 calculated the catecholamine metabolites in lumbar CSF of patients with intracranial neuroectodermal tumors and found a significant increase in the concentration of HVA. They proposed that because the neuroectodermal tumors have a common origin with the sympathetic nervous system, these tumors may synthesize catecholamines and form corresponding amine metabolites.3 In this study the concentration of 5-HIAA in the CSF of patients was increased in 70.6%, compared with 29.4% of the controls (p = 0.031). Some of these patients were included in a previous study and they demonstrated the presence of anxiety, aggressiveness, internalizing, and self-concern symptoms compared with controls. These symptoms perhaps produce alterations in activity of the central serotoninergic system, and as a result, the increased concentration of 5-HIAA in the CSF of our patients. The fact that increased 5-HIAA levels were found in controls might be explained by the anxiety that hospitalization produces. This condition may increase the activity of monoaminergic neurons in the CNS and might explain the increase of 5-HIAA in the CSF concentration. Guthrie et al. found that the 5-HIAA and HVA concentrations in CSF were significantly higher in inpatient than in outpatient normal volunteers.8 Bostrom and Mirkin also found a trend toward increased concentration of HVA in ventricular CSF of patients who suffered from neuroectodermal and glial tumors of the posterior fossa compared with age-matched controls.3 We found increased concentration of MHPG in the CSF of patients who suffered from astrocytomas compared with those who suffered from medulloblastomas. According to Sparrow and Davis, the information subtest of the verbal Wechsler scale included items that attempted to measure long-term memory.18 Sheline et al.17 reported that CSF levels of MHPG were inversely correlated with cognitive function in a sample of patients over the age of 55 years who suffered from dementia of the Alzheimer's type. They did not find any similar correlation between cognitive function and concentrations of HVA and 5-HIAA in CSF.17 The present study showed that the MHPG concentration in CSF was negatively correlated with verbal scale of the WISC. Nonetheless, Sheline et al. found a significant correlation between MHPG and both 5-HIAA and HVA concentrations in the CSF, suggesting that each monoaminergic system can affect the others.17 In our study we also found a significant correlation between MHPG and HVA in CSF but not between MHPG and 5-HIAA. We assessed the concentrations of monoamine metabolites in the CSF and blood (plasma), and 24-hour urine concentrations of VMA in our patients, and we correlated the results with their scores on the neurobehavioral and neuropsychological tests. We also compared the concentration of each metabolite to the other. We found a positive correlation between the performance scale of the WISC (with which the function of the right brain hemisphere is assessed) and the HVA levels in the CSF. There was also a positive correlation between the HVA concentration in both the CSF and the plasma samples. The concentration of 5-HIAA in the CSF was correlated significantly with the HVA concentration from the samples obtained from the plasma. The urine concentrations of VMA were correlated significantly with HVA in CSF, MHPG in CSF, HVA in plasma, and 5-HIAA in plasma.

In this study the patients were assessed neuropsychologically with the short form of the WISC during the preoperative period. We found a negative relationship between the concentration of MHPG in the ventricular CSF and the verbal scale of the WISC. The finding that controls had lower than normal MHPG levels might be derived from the fact that controls consisted of children who suffered mostly from benign viral infections. According to Constantino and Murphy, some viruses may influence the monoamine system and affect the interpretation of monoamine metabolite levels in affected infants.4

Due to previous research we included in the verbal scale the subtests of Information, Similarities, Vocabulary, and Digit Span, which examine cognitive function, and from them, memory. The role of the closed loops between the cerebellum, basal ganglia, and areas of the brain cortex (frontal, subfrontal, prefrontal, parietal, and temporal) is significant in the development of cognitive and behavioral function.18 Tumors of the posterior fossa (mainly tumors of the cerebellum) perhaps influence the noradrenergic system through the above loops and the result is the negative correlation between MHPG in CSF and the verbal scale of the WISC.

Recently, neurotransmitters and their receptors have been implicated in medulloblastoma biology. Agonists and antagonists of neurotransmitter signaling have been demonstrated to block proliferation of neurospheres and medulloblastoma spheroids. Thus, involvement of neurotransmitter signaling raises the possibility of exploiting neuroactive drugs in cancer therapy.15 Sengupta et al. found high levels of γ-aminobutyric acid A receptor α-5 (GABRA5), expression in a particularly aggressive molecular subtype of medulloblastoma. Using a highly specific A5/γ-aminobutyric acid-α (A5/GABA-A) receptor agonist, the authors managed to significantly decrease medulloblastoma cell survival through the induction of apoptosis.16

Conclusions

The present study demonstrated that children with posterior fossa tumors have differences in the concentration of monoamine metabolites in CSF. Alterations in monoamine metabolites correlated with the cognitive function of these patients. This might be an important finding because brain tumor treatments produce negative consequences in the cognitive development of children, in terms of decreased IQs. Thus, further studies with larger numbers of patients are obviously needed to verify our observations, as well as studies to correlate the levels of monoamine metabolites with the neuropsychological and behavioral findings in children with posterior fossa tumors.

Disclosure

The authors report no conflict of interest concerning the materials or methods used in this study or the findings specified in this paper.

Author contributions to the study and manuscript preparation include the following. Conception and design: Alexiou, Varela, Alevizopoulos. Acquisition of data: Varela, Liakopoulou, Papakonstantinou. Analysis and interpretation of data: all authors. Drafting the article: Alexiou, Varela, Papakonstantinou. Critically revising the article: all authors. Reviewed submitted version of manuscript: all authors. Approved the final version of the manuscript on behalf of all authors: Alexiou. Statistical analysis: Pitsouni. Administrative/technical/material support: Alexiou, Liakopoulou, Pitsouni. Study supervision: Varela, Alevizopoulos.

References

  • 1

    Ashcroft GWCrawford TBEccleston DSharman DFMacDougall EJStanton JB: 5-hydroxyindole compounds in the cerebrospinal fluid of patients with psychiatric or neurological diseases. Lancet 288:104910521966

  • 2

    Bareggi SRPorta MCollice MCalderini GFerrara MMorselli PL: Monoamine acid metabolites in ventricular CSF of patients with brain tumours. Acta Neurochir (Wien) 35:1611701976

  • 3

    Bostrom BMirkin BL: Elevation of cerebrospinal fluid catecholamine metabolites in patients with intracranial tumors of neuroectodermal origin. J Clin Oncol 5:109010971987

  • 4

    Constantino JNMurphy DL: Monoamine metabolites in ‘leftover’ newborn human cerebrospinal fluid—a potential resource for biobehavioral research. Psychiatry Res 65:1291421996

  • 5

    Davis BA: Biogenic amines and their metabolites in body fluids of normal, psychiatric and neurological subjects. J Chromatogr A 466:892181989

  • 6

    Fink MWadsak WSavli MStein PMoser UHahn A: Lateralization of the serotonin-1A receptor distribution in language areas revealed by PET. Neuroimage 45:5986052009

  • 7

    Gordon EKOliver J: 3-Methoxy-4-hydroxyphenylethylene glycol in human cerebrospinal fluid. Clin Chim Acta 35:1451501971

  • 8

    Guthrie SKBerrettini WRubinow DRNurnberger JIBartko JJLinnoila M: Different neurotransmitter metabolite concentrations in CSF samples from inpatient and outpatient normal volunteers. Acta Psychiatr Scand 73:3153211986

  • 9

    Haller JMakara GBKruk MR: Catecholaminergic involvement in the control of aggression: hormones, the peripheral sympathetic, and central noradrenergic systems. Neurosci Biobehav Rev 22:85971998

  • 10

    Hyland K: Clinical utility of monoamine neurotransmitter metabolite analysis in cerebrospinal fluid. Clin Chem 54:6336412008

  • 11

    Hyland K: The lumbar puncture for diagnosis of pediatric neurotransmitter diseases. Ann Neurol 54:Suppl 6S13S172003

  • 12

    Hyland K: Neurochemistry and defects of biogenic amine neurotransmitter metabolism. J Inherit Metab Dis 22:3533631999

  • 13

    Hyland KSurtees RAHeales SJBowron AHowells DWSmith I: Cerebrospinal fluid concentrations of pterins and metabolites of serotonin and dopamine in a pediatric reference population. Pediatr Res 34:10141993

  • 14

    Malm JKristensen BEkstedt JWester P: CSF concentration gradients of monoamine metabolites in patients with hydrocephalus. J Neurol Neurosurg Psychiatry 57:102610331994

  • 15

    Mercola M: Chemical probes of neural stem cell self-renewal. Nat Chem Biol 3:2462472007

  • 16

    Sengupta SWeeraratne SDPhallen JSun HRallapalli SArmani V: Leveraging expression of A5/GABA-A receptor in medulloblastoma as a novel therapeutic target. Neuro Oncol 14:Suppl 1i1052012. (Abstract)

  • 17

    Sheline YIMiller KBardgett MECsernansky JG: Higher cerebrospinal fluid MHPG in subjects with dementia of the Alzheimer type. Relationship with cognitive dysfunction. Am J Geriatr Psychiatry 6:1551611998

  • 18

    Sparrow SSDavis SM: Recent advances in the assessment of intelligence and cognition. J Child Psychol Psychiatry 41:1171312000

  • 19

    Varela MLiakopoulou MAlexiou GAPitsouni DAlevizopoulos GA: Presurgical neuropsychological and behavioral evaluation of children with posterior fossa tumors. Clinical article. J Neurosurg Pediatr 8:5485532011

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Article Information

Address correspondence to: George Alexiou, M.D., Aetideon 52, Holargos, Attikis 11561, Greece. email: alexiougrg@yahoo.gr.

Please include this information when citing this paper: published online February 21, 2014; DOI: 10.3171/2014.1.PEDS13425.

© AANS, except where prohibited by US copyright law.

Headings

References

1

Ashcroft GWCrawford TBEccleston DSharman DFMacDougall EJStanton JB: 5-hydroxyindole compounds in the cerebrospinal fluid of patients with psychiatric or neurological diseases. Lancet 288:104910521966

2

Bareggi SRPorta MCollice MCalderini GFerrara MMorselli PL: Monoamine acid metabolites in ventricular CSF of patients with brain tumours. Acta Neurochir (Wien) 35:1611701976

3

Bostrom BMirkin BL: Elevation of cerebrospinal fluid catecholamine metabolites in patients with intracranial tumors of neuroectodermal origin. J Clin Oncol 5:109010971987

4

Constantino JNMurphy DL: Monoamine metabolites in ‘leftover’ newborn human cerebrospinal fluid—a potential resource for biobehavioral research. Psychiatry Res 65:1291421996

5

Davis BA: Biogenic amines and their metabolites in body fluids of normal, psychiatric and neurological subjects. J Chromatogr A 466:892181989

6

Fink MWadsak WSavli MStein PMoser UHahn A: Lateralization of the serotonin-1A receptor distribution in language areas revealed by PET. Neuroimage 45:5986052009

7

Gordon EKOliver J: 3-Methoxy-4-hydroxyphenylethylene glycol in human cerebrospinal fluid. Clin Chim Acta 35:1451501971

8

Guthrie SKBerrettini WRubinow DRNurnberger JIBartko JJLinnoila M: Different neurotransmitter metabolite concentrations in CSF samples from inpatient and outpatient normal volunteers. Acta Psychiatr Scand 73:3153211986

9

Haller JMakara GBKruk MR: Catecholaminergic involvement in the control of aggression: hormones, the peripheral sympathetic, and central noradrenergic systems. Neurosci Biobehav Rev 22:85971998

10

Hyland K: Clinical utility of monoamine neurotransmitter metabolite analysis in cerebrospinal fluid. Clin Chem 54:6336412008

11

Hyland K: The lumbar puncture for diagnosis of pediatric neurotransmitter diseases. Ann Neurol 54:Suppl 6S13S172003

12

Hyland K: Neurochemistry and defects of biogenic amine neurotransmitter metabolism. J Inherit Metab Dis 22:3533631999

13

Hyland KSurtees RAHeales SJBowron AHowells DWSmith I: Cerebrospinal fluid concentrations of pterins and metabolites of serotonin and dopamine in a pediatric reference population. Pediatr Res 34:10141993

14

Malm JKristensen BEkstedt JWester P: CSF concentration gradients of monoamine metabolites in patients with hydrocephalus. J Neurol Neurosurg Psychiatry 57:102610331994

15

Mercola M: Chemical probes of neural stem cell self-renewal. Nat Chem Biol 3:2462472007

16

Sengupta SWeeraratne SDPhallen JSun HRallapalli SArmani V: Leveraging expression of A5/GABA-A receptor in medulloblastoma as a novel therapeutic target. Neuro Oncol 14:Suppl 1i1052012. (Abstract)

17

Sheline YIMiller KBardgett MECsernansky JG: Higher cerebrospinal fluid MHPG in subjects with dementia of the Alzheimer type. Relationship with cognitive dysfunction. Am J Geriatr Psychiatry 6:1551611998

18

Sparrow SSDavis SM: Recent advances in the assessment of intelligence and cognition. J Child Psychol Psychiatry 41:1171312000

19

Varela MLiakopoulou MAlexiou GAPitsouni DAlevizopoulos GA: Presurgical neuropsychological and behavioral evaluation of children with posterior fossa tumors. Clinical article. J Neurosurg Pediatr 8:5485532011

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