Impaired histaminergic neurotransmission in children with narcolepsy type 1.

OBJECTIVE: Narcolepsy is a sleep disorder characterized in humans by excessive daytime sleepiness and cataplexy. Greater than fifty percent of narcoleptic patients have an onset of symptoms prior to the age of 18. Current general agreement considers the loss of hypothalamic hypocretin (orexin) neurons as the direct cause of narcolepsy notably cataplexy. To assess whether brain histamine (HA) is also involved, we quantified the cerebrospinal fluid (CSF) levels of HA and tele-methylhistamine (t-MeHA), the direct metabolite of HA between children with orexin-deficient narcolepsy type 1 (NT1) and controls. METHODS: We included 24 children with NT1 (12.3 ± 3.6 years, 11 boys, 83% cataplexy, 100% HLA DQB1*06:02) and 21 control children (11.2 ± 4.2 years, 10 boys). CSF HA and t-MeHA were measured in all subjects using a highly sensitive liquid chromatographic-electrospray/tandem mass spectrometric assay. CSF hypocretin-1 values were determined in the narcoleptic patients. RESULTS: Compared with the controls, NT1 children had higher CSF HA levels (771 vs 234 pmol/L, P < 0.001), lower t-MeHA levels (879 vs 1924 pmol/L, P < 0.001), and lower t-MeHA/HA ratios (1.1 vs 8.2, P < 0.001). NT1 patients had higher BMI z-scores (2.7 ± 1.6 vs 1.0 ± 2.3, P = 0.006) and were more often obese (58% vs 29%, P = 0.05) than the controls. Multivariable analyses including age, gender, and BMI z-score showed a significant decrease in CSF HA levels when the BMI z-score increased in patients (P = 0.007) but not in the controls. No association was found between CSF HA, t-MeHA, disease duration, age at disease onset, the presence of cataplexy, lumbar puncture timing, and CSF hypocretin levels. CONCLUSIONS: Narcolepsy type 1 children had a higher CSF HA level together with a lower t-MeHA level leading to a significant decrease in the t-MeHA/HA ratios. These results suggest a decreased HA turnover and an impairment of histaminergic neurotransmission in narcoleptic children and support the use of a histaminergic therapy in the treatment against narcolepsy.

Temporal Changes in the Cerebrospinal Fluid Level of Hypocretin-1 and Histamine in Narcolepsy.

Study Objectives: To follow the temporal changes of cerebrospinal fluid (CSF) biomarker levels in narcoleptic patients with unexpected hypocretin level at referral. Methods: From 2007 to 2015, 170 human leukocyte antigen (HLA) DQB1*06:02-positive patients with primary narcolepsy and definite (n = 155, 95 males, 60 females, 36 children) or atypical cataplexy (n = 15, 4 males, 3 children) were referred to our center. Cerebrospinal hypocretin deficiency was found in 95.5% and 20% of patients with definitive and atypical cataplexy, respectively. CSF hypocretin-1 (n = 6) and histamine/tele-methylhistamine (n = 5) levels were assessed twice (median interval: 14.4 months) in four patients with definite and in two with atypical cataplexy and hypocretin level greater than 100 pg/mL at baseline. Results: CSF hypocretin levels decreased from normal/intermediate to undetectable levels in three of the four patients with definite cataplexy and remained stable in the other (>250 pg/mL). Hypocretin level decreased from 106 to 27 pg/mL in one patient with atypical cataplexy, and remained stable in the other (101 and 106 pg/mL). CSF histamine and tele-methylhistamine levels remained stable, but for one patient showing increased frequency of cataplexy and a strong decrease (-72.5%) of tele-methylhistamine levels several years after disease onset. No significant association was found between relative or absolute change in hypocretin level and demographic/clinical features. Conclusions: These findings show that in few patients with narcolepsy with cataplexy, symptoms and CSF marker levels can change over time. In these rare patients with cataplexy without baseline hypocretin deficiency, CSF markers should be monitored over time with potential for immune therapies in early stages to try limiting hypocretin neuron loss.

Cerebrospinal fluid levels of orexin-A and histamine, and sleep profile within the Alzheimer process.

To better understand how sleep/wake dysregulation affects Alzheimer's disease (AD), we compared the cerebrospinal fluid (CSF) orexin and histamine/tele-methylhistamine (HA/t-MHA) levels of 82 patients (41 probable-AD-high level of evidence, 41 mild cognitive impairment MCI-due-to-AD), 24 other neurologic disorders (OND) and 24 controls. We determined the relationships between these biomarkers, the CSF AD biomarkers concentrations, and the clinical sleep profile. CSF orexin-A but not HA/t-MHA levels were higher in MCI and AD than OND and controls. CSF orexin-A is correlated to CSF amyloid-ß42in MCI and AD, independently of age, gender, MMSE, total-tau/phosphorylated-tau, HA or sleep parameters. Nighttime sleep duration was longer in MCI and AD patients than controls. In MCI, nighttime sleep duration negatively correlated with CSF amyloid-ß42 and MMSE. To conclude, CSF orexin-A but not HA/t-HMA was upregulated in AD and correlated with amyloid-ß42 level. Our data suggested a change in the sleep-wake pattern at an early stage of the disease that needs further investigation to deeply explain the mechanistic interplay between sleep and Alzheimer.

Preliminary results on CSF biomarkers for hypothalamic dysfunction in Kleine-Levin syndrome.

OBJECTIVE: To measure CSF biomarkers of hypothalamic dysfunction in patients with typical Kleine-Levin syndrome (KLS) during symptomatic and asymptomatic periods. PATIENTS/METHODS: Two patients with typical KLS were admitted during symptomatic and asymptomatic periods to a research Sleep Disorders Center. Cerebrospinalfluid (CSF) hypocretin-1, histamine (HA), and its major metabolite tele-methylhistamine (t-MHA) levels were measured in two KLS patients in and out of episode. RESULTS: CSF biomarkers of hypothalamic dysfunction measured in two KLS patients in and out of episode revealed low hypocretin levels (within the narcolepsy-cataplexy range) during a hypersomnia episode in the more severe patient, and a 42% decrease (although within normal range) in the second patient. CSF HA and t-MHA measurements in and out of episode revealed a two-fold in-episode decrease in HA in the more severe patient, with no significant change for the second patient, nor for t-MHA levels. CONCLUSION: We reported reversible changes in CSF hypothalamic biomarkers in a typical patient with KLS that reinforces the hypothesis that in some patients KLS episodes may be caused by recurrent functional alterations of the hypothalamus.

Addressing the need for biomarker liquid chromatography/mass spectrometry assays: a protocol for effective method development for the bioanalysis of endogenous compounds in cerebrospinal fluid.

RATIONALE: Research on disorders of the central nervous system (CNS) has shown that an imbalance in the levels of specific endogenous neurotransmitters may underlie certain CNS diseases. These alterations in neurotransmitter levels may provide insight into pathophysiology, but can also serve as disease and pharmacodynamic biomarkers. To measure these potential biomarkers in vivo, the relevant sample matrix is cerebrospinal fluid (CSF), which is in equilibrium with the brain's interstitial fluid and circulates through the ventricular system of the brain and spinal cord. Accurate analysis of these potential biomarkers can be challenging due to low CSF sample volume, low analyte levels, and potential interferences from other endogenous compounds. METHODS: A protocol has been established for effective method development of bioanalytical assays for endogenous compounds in CSF. Database searches and standard-addition experiments are employed to qualify sample preparation and specificity of the detection thus evaluating accuracy and precision. RESULTS: This protocol was applied to the study of the histaminergic neurotransmitter system and the analysis of histamine and its metabolite 1-methylhistamine in rat CSF. CONCLUSIONS: The protocol resulted in a specific and sensitive novel method utilizing pre-column derivatization ultra high performance liquid chromatography/tandem mass spectrometry (UHPLC/MS/MS), which is also capable of separating an endogenous interfering compound, identified as taurine, from the analytes of interest.

High-performance liquid chromatographic determination of histamine in biological samples: the cerebrospinal fluid challenge--a review.

Histamine, a neurotransmitter crucially involved in a number of basic physiological functions, undergoes changes in neuropsychiatric disorders. Detection of histamine in biological samples such as cerebrospinal fluid (CSF) is thus of clinical importance. The most commonly used method for measuring histamine levels is high performance liquid chromatography (HPLC). However, factors such as very low levels of histamine, the even lower CSF-histamine and CSF-histamine metabolite levels, especially in certain neuropsychiatric diseases, rapid formation of histamine metabolites, and other confounding elements during sample collection, make analysis of CSF-histamine and CSF-histamine metabolites a challenging task. Nonetheless, this challenge can be met, not only with respect to HPLC separation column, derivative reagent, and detector, but also in terms of optimizing the CSF sample collection. This review aims to provide a general insight into the quantitative analyses of histamine in biological samples, with an emphasis on HPLC instruments, methods, and hyphenated techniques, with the aim of promoting the development of an optimal and practical protocol for the determination of CSF-histamine and/or CSF-histamine metabolites.

Normal cerebrospinal fluid histamine and tele-methylhistamine levels in hypersomnia conditions.

STUDY OBJECTIVES: To determine the activity of cerebral histaminergic system evaluated by CSF levels of histamine (HA) and tele-methylhistamine (t-MHA), its major metabolite, and their relationships with hypocretin-1 levels in a large population of patients with hypersomnia and neurological conditions. DESIGN: sensitive liquid chromatographic-electrospray/tandem mass spectrometric assay was developed for the simultaneous quantification of CSF HA and t-MHA. SETTING: ata were collected and CSF hypocretin-1 levels were measured using radioimmunoassay at the Sleep Disorders Center, Montpellier, France. CSF HA and t-MHA were measured in Bioprojet-Biotech, France PARTICIPANTS: One hundred fourteen unrelated patients with a suspicion of central hypersomnia underwent one night of polysomnography followed by the multiple sleep latency test. Sleep disorders were diagnosed clinically and using sleep studies: narcolepsy-cataplexy NC (n = 56), narcolepsy without cataplexy NwC (n = 27), idiopathic hypersomnia IH (n = 11), secondary narcolepsy (n = 3), and unspecified hypersomnia Uns EDS (n = 17). Fifty neurological patients without daytime sleepiness were included as controls. MEASUREMENTS AND RESULTS: No between-hypersomnia group differences were found for CSF HA levels (median 708.62 pM extreme range [55.92-3335.50] in NC; 781.34 [174.08-4391.50] in NwC; 489.42 [177.45-906.70] in IH, and 1155.40 [134.80-2736.59] in Uns EDS) or for t-MHA levels. No association was found between CSF HA, t-MHA, or HA + t-MHA, sleepiness, treatment intake, and frequency of cataplexy. A slight negative correlation was found between age and HA levels. Further adjustment for the age revealed no significant HA levels difference between hypersomnia patients and controls. CONCLUSION: CSF histamine and tele-methylhistamine did not significantly differ between patients with narcolepsy-cataplexy and other etiologies of non-hypocretin-1 deficient central hypersomnias; these measurements, therefore, are not useful in assessing the etiology or severity of centrally mediated hypersomnia.

Development and validation of a sample stabilization strategy and a UPLC-MS/MS method for the simultaneous quantitation of acetylcholine (ACh), histamine (HA), and its metabolites in rat cerebrospinal fluid (CSF).

A UPLC-MS/MS assay was developed and validated for simultaneous quantification of acetylcholine (ACh), histamine (HA), tele-methylhistamine (t-mHA), and tele-methylimidazolacetic acid (t-MIAA) in rat cerebrospinal fluid (CSF). The biological stability of ACh in rat CSF was investigated. Following fit-for-purpose validation, the method was applied to monitor the drug-induced changes in ACh, HA, t-mHA, and t-MIAA in rat CSF following administration of donepezil or prucalopride. The quantitative method utilizes hydrophilic interaction chromatography (HILIC) Core-Shell HPLC column technology and a UPLC system to achieve separation with detection by positive ESI LC-MS/MS. This UPLC-MS/MS method does not require extraction or derivatization, utilizes a stable isotopically labeled internal standard (IS) for each analyte, and allows for rapid throughput with a 4 min run time. Without an acetylcholinesterase (AChE) inhibitor present, ACh was found to have 1.9±0.4 min in vitro half life in rat CSF. Stability studies and processing modification, including the use of AChE inhibitor eserine, extended this half life to more than 60 min. The UPLC-MS/MS method, including stabilization procedure, was validated over a linear concentration range of 0.025-5 ng/mL for ACh and 0.05-10 ng/mL for HA, t-mHA, and t-MIAA. The intra-run precision and accuracy for all analytes were 1.9-12.3% CV and -10.2 to 9.4% RE, respectively, while inter-run precision and accuracy were 4.0-16.0% CV and -5.3 to 13.4% RE, respectively. By using this developed and validated method, donepezil caused increases in ACh levels at 0.5, 1, 2, and 4h post dose as compared to the corresponding vehicle group, while prucalopride produced approximately 1.6- and 3.1-fold increases in the concentrations of ACh and t-mHA at 1h post dose, respectively, compared to the vehicle control. Overall, this methodology enables investigations into the use of CSF ACh and HA as biomarkers in the study of these neurotransmitter systems and related drug discovery efforts.

Histamine and tele-methylhistamine quantification in cerebrospinal fluid from narcoleptic subjects by liquid chromatography tandem mass spectrometry with precolumn derivatization.

An ultra-performance liquid chromatography tandem mass spectrometry (UPLC™-MS/MS) assay was developed for the simultaneous analysis of histamine, its major metabolite tele-methylhistamine, and an internal standard (N-tele-(R)-α-dimethylhistamine) from human cerebrospinal fluid (CSF) samples. The method involves derivatization of primary amines with 4-bromobenzenesulfonyl chloride and subsequent analysis by reversed phase liquid chromatography with mass spectrometry detection and positive electrospray ionization. The separation of derivatized biogenic amines was achieved within 3.5 min on an Acquity® BEH C(18) column by elution with a linear gradient of acetonitrile/water/formic acid (0.1%). The assay was linear in the concentration range of 50-5000 pM for each amine (5.5-555 pg/ml for histamine and 6.25-625 pg/ml for tele-methylhistamine). For repeatability and precision determination, coefficients of variation (CVs) were less than 11.0% over the tested concentration ranges, within acceptance criteria. Thus, the developed method provides the rapid, easy, highly sensitive, and selective requirement to quantify these amines in human CSF. No significant difference was found in the mean ± standard error levels of these amines between a group of narcoleptic patients (histamine=392 ± 64 pM, tele-methylhistamine=2431 ± 461 pM, n=7) and of neurological control subjects (histamine=402 ± 72 pM, tele-methylhistamine=2209 ± 463 pM, n=32).

CSF levels of the histamine metabolite tele-methylhistamine are only slightly decreased in Alzheimer's disease.

Neuropathological studies have reported a strong neurofibrillary degeneration of the tuberomamillary nucleus, the region of origin of histamine neurons, in Alzheimer's disease (AD). Histaminergic neurons enhance cognition and memory, suggesting that their degeneration may contribute to the cognitive decline of AD. Besides neurons, the brain histaminergic system comprises mast cells and microglia that can also produce histamine. The level of activity of this histaminergic system in AD remained unknown. In the present study, we have measured the levels of the main histamine metabolite in brain, tele-methylhistamine (t-MeHA), an index of histaminergic system activity, in the cerebrospinal fluid (CSF) of 97 non-AD (controls) and 91 AD patients, males or females. t-MeHA levels in CSF of controls tended to be higher, although non-significantly, in females than in males. t-MeHA levels of controls and AD significantly increased with age (1.66 ± 0.13, 2.04 ± 0.12, and 2.76 ± 0.12 pmol/ml at 40, 60 and 80 years, respectively). In spite of the strong degeneration of histamine neurons in the disease, t-MeHA levels in CSF were only slightly decreased in AD compared to controls (2.14 ± 0.10 vs 2.76 ± 0.13 pmol/ml, -22%, p < 0.01). This decrease was similar whatever the age, and was slightly higher in females than in males. The increase observed with age, and the limited magnitude of the decrease in AD even at late stages may result from the compensatory activation of spared neurons, as well as the neuroinflammation-induced activation of microglia occurring in senescence and AD.

The relationship between urine excretion and biogenic amines and their metabolites in cerebrospinal fluid of schizophrenic patients.

Concentrations of norepinephrine and metabolites of biogenic amines were measured in lumbar cerebrospinal fluid of 30 patients with chronic schizophrenia, nine of whom were polyuric. The mean level of norepinephrine was two-fold higher (p < or = 0.025) in polyuric patients than in patients whose excretion of urine was within the normal range. CSF levels of histamine's primary metabolite, tele-methylhistamine, an index of brain histaminergic activity, were positively correlated (p < 0.005) with daily urine volume. These results are consistent with the known influence of norepinephrine and histamine on fluid regulation and suggest that norepinephrine and histamine may be involved in psychogenic polydipsia-polyuria in schizophrenic patients.

Histamine in cerebrospinal fluid of children with febrile convulsions.

Febrile convulsions (FC) are frequent acute neurologic disturbances of childhood. The cellular and neurochemical mechanisms causing FC are unclear. Among other mechanisms, the CNS histamine (HA) has been suggested to participate in seizure control and thermoregulation. We evaluated the possible role of HA in regulation of FC by measuring HA and tele-methylhistamine (t-MH) concentrations in the cerebrospinal fluid (CSF) of children with FC. The study group consisted of 35 children treated for acute FC in the hospital. The control groups consisted of (a) feverish children without seizures (n = 23), (b) convulsive children without fever (n = 7), and (c) children with neither fever nor convulsions (n = 21). HA was assayed by high-performance liquid chromatography (HPLC) with fluorescence detection, and t-MH was measured by gas chromatography-mass spectrometry. CSF HA concentration in the group of febrile children without seizures was significantly higher (0.69 +/- 0.16 pmol/ml, mean +/- SE) than in children with FC (0.36 +/- 0.07 pmol/ml, p < 0.05, analysis of variance, ANOVA). HA concentration was 0.37 +/- 0.18 pmol/ml in the group of nonfebrile convulsive children and 0.36 +/- 0.08 pmol/ml in the nonfebrile nonconvulsive group. No statistical differences in t-MH were detected between groups. The increased susceptibility to seizures during fever may be connected to the lack of increase in CSF HA in the FC group. The data support the hypothesis that the central histaminergic neuron system may be involved in inhibition of seizures associated with febrile illnesses in childhood.

Elevated mast cell tryptase in cerebrospinal fluid of multiple sclerosis patients.

Multiple sclerosis (MS) lesions are associated with infiltration of T lymphocytes and macrophages that appear to mediate myelin destruction and gliosis (scarring). Mast cells are located perivascularly in the brain, are juxtaposed to neurons, and have been shown to secrete vasoactive and inflammatory mediators in response to neuropeptides and direct nerve stimulation. Mast cells have been previously identified in MS lesions, are activated by myelin basic protein, and can participate in the regulation of blood-brain barrier permeability, as well as in myelin destruction. Here, cerebrospinal fluid from MS patients and controls with other neurologic diseases was assayed for histamine, its major metabolite methylhistamine, and the specific mast cell marker tryptase. Histamine and methylhistamine were not elevated in MS. However, the mast cell specific proteolytic enzyme tryptase was significantly elevated in MS, suggesting that mast cell activation may be involved in the pathophysiology of this disease.

Histamine metabolites in cerebrospinal fluid of patients with chronic schizophrenia: their relationships to levels of other aminergic transmitters and ratings of symptoms.

Levels of the histamine metabolites, tele-methylhistamine (t-MH) and tele-methylimidazoleacetic acid (t-MIAA), and metabolites of other aminergic transmitters and of norepinephrine were measured in cerebrospinal fluid of 36 inpatients with chronic schizophrenia and eight controls. The mean t-MH level from controls was nearly identical to the levels seen previously in healthy volunteers. Compared with controls, the mean level of t-MH in the schizophrenic patients was 2.6-fold higher (p = 0.006); 21 of the patients had levels exceeding the range of controls. There was no significant difference (p > 0.05) in levels of other analytes, although the levels of t-MH correlated significantly with those of t-MIAA, homovanillic acid, 3,4-dihydroxyphenylacetic acid, norepinephrine, 3-methoxy-4-hydroxyphenylglycol and 5-hydroxyindoleacetic acid. The difference in levels of t-MH were not attributable to medication, since those taking (n = 10) or withdrawn from (n = 26) neuroleptic drugs had nearly the same mean levels of t-MH; each group had higher levels than controls (ANOVA: p < 0.05). Patients with or without tardive dyskinesia showed no significant differences in means of any analyte. Only levels of t-MH among those with schizophrenia correlated with positive symptom scores on the Psychiatric Symptom Assessment Scale (rs = 0.45, p < 0.02). The elevated levels of t-MH in cerebrospinal fluid, which represent histamine that was released and metabolized, suggest increased central histaminergic activity in patients with chronic schizophrenia.

Diurnal and age-related changes in cerebrospinal fluid tele-methylhistamine levels during infancy and childhood.

Histamine is a neurotransmitter participating in many physiological functions and behavior, including control of arousal and modulation of the circadian rhythms. Diurnal variation in cerebrospinal fluid (CSF) levels of tele-methylhistamine (t-MH), the main histamine metabolite, has been detected in several animal studies. In humans, such changes have not been described. Little is known on the development of histaminergic neurons in human brain. In children, the levels of CSF t-MH are not known. Therefore, we have measured the concentrations of CSF t-MH in 81 children, age ranging from 3 months to 14.6 years. t-MH levels were higher in infants, and near adult values were measured in adolescents, the relation between CSF t-MH and age being; CSF t-MH = -0.217 years + 7.31 (n = 81, r = 0.26, p = 0.021). The mean t-MH concentration was higher during the daytime (7.07 +/- 0.46 pmol/ml, mean +/- SEM) than in the night (5.35 +/- 0.60 pmol/ml, p = 0.0019, ANOVA). The results show a development change in the concentration of t-MH during childhood and a difference in t-MH levels between the daytime and night indicating a more active metabolism of brain HA in the waking period.

The effects of morphine, morphine plus scopolamine, midazolam and promethazine on cerebrospinal fluid histamine concentration and postoperative analgesic consumption.

The effects of morphine (0.14 mg/kg), morphine (0.14 mg/kg plus scopolamine (0.042 mg/kg), midazolam (0.015 mg/kg) and promethazine (0.08 mg/kg) on cerebrospinal fluid histamine (CSF-HA) and CSF-methylhistamine were investigated in 44 healthy patients. CSF-HA was determined by HPLC. CSF-HA was found to be increased after all premedications with great individual variation (range 0.07-7.4 pmol/ml). The highest values were found in the promethazine group (1.83 +/- 2.2 (SD) pmol/ml and the lowest in the control group (0.63 +/- 0.42 pmol/ml). Measurable concentrations of CSF-methylhistamine were found in 13 patients without correlation with HA. Postoperative need for analgesics was reduced in all premedicated groups. A significant correlation existed between HA and need for postoperative analgesics in the morphine plus scopolamine group. It is concluded that the histamine system plays a role in central nociception.

Rostral-caudal concentration gradients of histamine metabolites in human cerebrospinal fluid.

The metabolites of histamine, tele-methylhistamine (t-MH) and tele-methylimidazoleacetic acid (t-MIAA), have a large concentration gradient between cisternal and lumbar CSF in the rhesus monkey. The possibility of a t-MH and/or t-MIAA gradient in man was studied in sequential samples of CSF withdrawn from the lumbar space from a healthy male. The mean levels of t-MH and t-MIAA in the 14-16 ml segment of CSF from 6 male volunteers was also measured. pros-Methylimidazoleacetic acid (p-MIAA), an endogenous isomer of t-MIAA that is not derived from histamine, was also measured. Levels of t-MH, t-MIAA and p-MIAA were measured by gas chromatography-mass spectrometry. With increasing volumes of CSF removed, t-MH and t-MIAA levels increased linearly (p less than 0.01) when plotted against the midpoints of each volume segment. Levels of t-MH and t-MIAA from the volunteers showed little variation; the means of the levels were within 15% of the respective regression lines of the points from the single subject. In contrast, p-MIAA levels showed no gradient (p greater than 0.6) in serially removed CSF; the individual levels in CSF from the volunteers on unrestricted diets varied widely, suggestive of a dietary influence on p-MIAA levels in the CNS. The concentration gradient of histamine metabolites in CSF confirms the rostral-caudal gradient observed in monkey and argues against plasma or spinal cord as major sources of these metabolites.(ABSTRACT TRUNCATED AT 250 WORDS)

Diurnal fluctuation in levels of histamine metabolites in cerebrospinal fluid of rhesus monkey.

In samples of ventricular cerebrospinal fluid (CSF) that were collected from a conscious, restrained rhesus monkey at intervals of 30 90 min, levels of the histamine metabolites, tele-methylhistamine (t-MH) and tele-methylimidazoleacetic acid (t-MIAA), were determined by gas chromatography-mass spectrometry. Levels of t-MH and t-MIAA each showed time-related fluctuations. Peak and trough concentrations of t-MIAA, the product of t-MH, paralleled, but lagged about 2 h behind, the levels of t-MH. Within the first 3 h of illumination, metabolite levels increased more than 3-fold; they fell sharply within the first 3 h of darkness. Mean levels of t-MH and t-MIAA were significantly higher during periods of illumination than of darkness. Fluctuations in the levels of pros-methylimidazoleacetic acid (p-MIAA), an endogenous isomer of t-MIAA that is not a histamine metabolite, were markedly different from those of t-MH or t-MIAA; p-MIAA levels peaked only at the middle of the dark period. The time-related fluctuations in levels of t-MH and t-MIAA, but not p-MIAA, are similar to the daily rhythmic changes observed in monkey CSF for the levels of other central neurotransmitters and peptide neurohormones.

Elevated levels of histamine metabolites in cerebrospinal fluid of aging, healthy humans.

The metabolites of histamine, tele-methylhistamine (t-MH) and tele-methylimidazoleacetic acid (t-MIAA), were measured in lumbar cerebrospinal fluid of healthy, normal volunteers aged 20-31 (n = 4) and 60-72 (n = 8) by gas chromatography-mass spectrometry. Mean levels (pmol/ml) of t-MH, t-MIAA and the sum of t-MH and t-MIAA (2.9, 6.4 and 9.4, respectively) were significantly higher in CSF from older subjects than from younger subjects (1.1, 4.5 and 5.5, respectively). Another older subject had yet higher levels of metabolites (6.7, 15.1 and 21.8, respectively). The sum of the levels of the known metabolites of histamine in brain, i.e. t-MH and t-MIAA, did not overlap between the younger and older subjects. The levels of pros-methylimidazoleacetic acid, an endogenous isomer of t-MIAA that is not derived from metabolism of histamine, did not differ significantly between the two groups. These findings contrast with results of similar studies of metabolites of other aminergic transmitters in showing elevated levels of metabolites of histamine in cerebrospinal fluid with increasing age.