Cerebrospinal Fluid Melatonin Levels Research Articles

Blast Exposure Dysregulates Nighttime Melatonin Synthesis and Signaling in the Pineal Gland: A Potential Mechanism of Blast-Induced Sleep Disruptions.

Blast-induced traumatic brain injury (bTBI) frequently results in sleep-wake disturbances. However, limited studies have investigated the molecular signaling mechanisms underlying these sleep disturbances, and potentially efficacious therapies are lacking. We investigated the levels of melatonin and genes involved in melatonin synthesis pathway in the pineal glands of Sprague Dawley rats exposed to single and tightly coupled repeated blasts during the night and daytime. Rats were exposed to single and tightly coupled repeated blasts using an advanced blast simulator. The plasma, cerebrospinal fluid (CSF), and pineal gland were collected at 6 h, 24 h, or 1 month postblast at two different time points: one during the day (1000 h) and one at night (2200 h). Differential expressions of genes involved in pineal melatonin synthesis were quantified using quantitative real-time polymerase chain reaction (qRT-PCR). Plasma and CSF melatonin levels were assessed using a commercial melatonin ELISA kit. The plasma and CSF melatonin levels showed statistically significant decreases at 6 h and 24 h in the blast-exposed rats euthanized in the night (in dim light), with no significant alterations noted in rats euthanized in the morning (daylight) at all three-time points. Blast-exposed rats showed statistically significant decreases in Tph1, Aanat, Asmt, and Mtnr1b mRNA levels, along with increased Tph2 mRNA, in the pineal gland samples collected at night at 6 h and 24 h. No significant changes in the mRNA levels of these genes were noted at 1 month. These findings imply that the melatonin circadian rhythm is disrupted following blast exposure, which may be a factor in the sleep disturbances that blast victims frequently experience.

Neural glymphatic system: Clinical implications and potential importance of melatonin

The central nervous system was thought to lack a lymphatic drainage until the recent discovery of the neural glymphatic system. This highly specialized waste disposal network includes classical lymphatic vessels in the dura that absorb fluid and metabolic by-products and debris from the underlying cerebrospinal fluid (CSF) in the subarachnoid space. The subarachnoid space is continuous with the Virchow-Robin peri-arterial and peri-vascular spaces which surround the arteries and veins that penetrate into the neural tissue, respectively. The dural lymphatic vessels exit the cranial vault via an anterior and a posterior route and eventually drain into the deep cervical lymph nodes. Aided by the presence of aquaporin 4 on the perivascular endfeet of astrocytes, nutrients and other molecules enter the brain from peri-arterial spaces and form interstitial fluid (ISF) that baths neurons and glia before being released into peri-venous spaces. Melatonin, a pineal-derived secretory product which is in much higher concentration in the CSF than in the blood, is believed to follow this route and to clear waste products such as amyloid-β from the interstitial space. The clearance of amyloid-β reportedly occurs especially during slow wave sleep which happens concurrently with highest CSF levels of melatonin. Experimentally, exogenously-administered melatonin defers amyloid-β buildup in the brain of animals and causes its accumulation in the cervical lymph nodes. Clinically, with increased age CSF melatonin levels decrease markedly, co-incident with neurodegeneration and dementia. Collectively, these findings suggest a potential association between the loss of melatonin, decreased glymphatic drainage and neurocognitive decline in the elderly.

Serum Daytime Melatonin Levels Reflect Cerebrospinal Fluid Melatonin Levels in Alzheimer's Disease but Are Not Correlated with Cognitive Decline.

Background:Nocturnal cerebrospinal fluid (CSF) and blood melatonin levels are altered in Alzheimer’s disease (AD). However, literature remains inconclusive on daytime blood melatonin levels. A positive correlation between melatonin levels and Mini-Mental State Examination (MMSE) scores in AD subjects has been evidenced following cross-sectional analyses. Whereas a correlation between serum and spinal CSF melatonin has been shown in healthy volunteers, an equal investigation in AD patients still has to be undertaken.Objective:1) To evaluate whether serum melatonin levels correlate with spinal CSF melatonin levels in AD. 2) To compare daytime CSF and serum melatonin levels between patients with AD dementia, mild cognitive impairment due to AD, and healthy controls, and to evaluate whether melatonin can affect cognitive decline in AD.Methods:Subjects with AD and healthy controls included in two existing cohorts, of whom a CSF and serum sample was available at the neurobiobank and had at least 6 months of neuropsychological follow-up, were included in the present study. Melatonin concentrations were measured with liquid chromatography-mass spectrometry.Results:Daytime serum melatonin levels correlated with spinal CSF melatonin levels in AD (r = 0.751, p < 0.001). No significant differences regarding daytime melatonin levels were found between patients and controls. No correlations were observed between daytime melatonin levels and MMSE score changes.Conclusion:Daytime serum melatonin accurately reflects CSF melatonin levels in AD, raising the possibility to assess melatonin alterations by solely performing blood sampling if also confirmed for night-time values. However, daytime melatonin levels are not associated with changes of cognitive impairment.

Evaluation of human pineal gland acetylserotonin O-methyltransferase immunoreactivity in suicide: A preliminary study.

Disorders of the serotonergic system are especially known to be present in the neurobiology of suicidal behavior. Studies investigating melatonin levels show that changes in pineal gland functions may also play a role in the pathogenesis of suicide. However, to our knowledge, there are no studies evaluating the activity of pinealocytes responsible for melatonin synthesis in suicide. This preliminary study aimed to investigate the relationship among pinealocyte, acetylserotonin O-methyltransferase (ASMT) immunoreactivity, and suicide. Samples of pineal gland, cerebrospinal fluid, blood, and urine were obtained from 21 suicide and 21 non-suicide cases on which medicolegal autopsies were performed. Expression of ASMT in human pineal gland was evaluated by immunohistochemical methods. A scoring system was used to define the anti-ASMT-positive staining in the sections. Enzyme-linked immunosorbent assays were employed to assess serum and cerebrospinal fluid melatonin levels and blood and urine noradrenaline levels. The ASMT-immunopositive pinealocyte count was observed to be lower in suicide cases compared to the non-suicide cases. With the exception of two cases (with moderate staining), all graded scores were 3 (strong staining) in non-suicide group, whereas scores were 1 (mild staining) or 2 (moderate staining) in the suicide group. Melatonin levels in the blood were lower among the suicide victims. These results support decreased pineal gland activity in suicide. However, further studies are needed to assess whether these changes are related to a psychiatric disorder.

Preoperative CSF Melatonin Concentrations and the Occurrence of Delirium in Older Hip Fracture Patients: A Preliminary Study.

BackgroundDelirium is characterized by disturbances in circadian rhythm. Melatonin regulates our circadian rhythm. Our aim was to compare preoperative cerebrospinal fluid (CSF) melatonin levels in patients with and without postoperative delirium.MethodsProspective cohort study with hip fracture patients ≥ 65 years who were acutely admitted to the hospital for surgical treatment and received spinal anaesthesia. CSF was collected after cannulation, before administering anaesthetics. Melatonin was measured by radioimmunoassay (RIA). Data on delirium was obtained from medical and nursing records. Nurses screened every shift for delirium using the Delirium Observation Screening Scale (DOSS). If the DOSS was ≥3, a psychiatrist was consulted to diagnose possible delirium using the DSM-IV criteria. At admission, demographic data, medical history, and information on functional and cognitive status was obtained.ResultsSeventy-six patients met the inclusion criteria. Sixty patients were included in the analysis. Main reasons for exclusion were technical difficulties, insufficient CSF or exogenous melatonin use. Thirteen patients (21.7%) experienced delirium during hospitalisation. Baseline characteristics did not differ between patients with and without postoperative delirium. In patients with and without postoperative delirium melatonin levels were 12.88 pg/ml (SD 6.3) and 11.72 pg/ml (SD 4.5) respectively, p-value 0.47. No differences between patients with and without delirium were found in mean melatonin levels in analyses stratified for cognitive impairment or age.ConclusionPreoperative CSF melatonin levels did not differ between patients with and without postoperative delirium. This suggests that, if disturbances in melatonin secretion occur, these might occur after surgery due to postoperative inflammation.

Differential melatonin alterations in cerebrospinal fluid and serum of patients with major depressive disorder and bipolar disorder

BackgroundMelatonin, which plays an important role for regulation of circadian rhythms and the sleep/wake cycle has been linked to the pathophysiology of major depressive and bipolar disorder. Here we investigated melatonin levels in cerebrospinal fluid (CSF) and serum of depression and bipolar patients to elucidate potential differences and commonalities in melatonin alterations across the two disorders. MethodsUsing enzyme-linked immunosorbent assays, CSF and serum melatonin levels were measured in 108 subjects (27 healthy volunteers, 44 depressed and 37 bipolar patients). Covariate adjusted multiple regression analysis was used to investigate group differences in melatonin levels. ResultsIn CSF, melatonin levels were significantly decreased in bipolar (P<0.001), but not major depressive disorder. In serum, we observed a significant melatonin decrease in major depressive (P=0.003), but not bipolar disorder. No associations were found between serum and CSF melatonin levels or between melatonin and measures of symptom severity or sleep disruptions in either condition. ConclusionThis study suggests the presence of differential, body fluid specific alterations of melatonin levels in bipolar and major depressive disorder. Further, longitudinal studies are required to explore the disease phase dependency of melatonin alterations and to mechanistically explore the causes and consequences of site-specific alterations.

Endogenous Melatonin Increases in Cerebrospinal Fluid of Patients after Severe Traumatic Brain Injury and Correlates with Oxidative Stress and Metabolic Disarray

Oxidative stress plays a significant role in secondary damage after severe traumatic brain injury (TBI); and melatonin exhibits both direct and indirect antioxidant effects. Melatonin deficiency is deleterious in TBI animal models, and its administration confers neuroprotection, reducing cerebral oedema, and improving neurobehavioural outcome. This study aimed to measure the endogenous cerebrospinal fluid (CSF) and serum melatonin levels post-TBI in humans and to identify relationships with markers of oxidative stress via 8-isoprostaglandin-F2alpha (isoprostane), brain metabolism and neurologic outcome. Cerebrospinal fluid and serum samples of 39 TBI patients were assessed for melatonin, isoprostane, and various metabolites. Cerebrospinal fluid but not serum melatonin levels were markedly elevated (7.28+/-0.92 versus 1.47+/-0.35 pg/mL, P<0.0005). Isoprostane levels also increased in both CSF (127.62+/-16.85 versus 18.28+/-4.88 pg/mL, P<0.0005) and serum (562.46+/-50.78 versus 126.15+/-40.08 pg/mL (P<0.0005). A strong correlation between CSF melatonin and CSF isoprostane on day 1 after injury (r=0.563, P=0.002) suggests that melatonin production increases in conjunction with lipid peroxidation in TBI. Relationships between CSF melatonin and pyruvate (r=0.369, P=0.049) and glutamate (r=0.373, P=0.046) indicate that melatonin production increases with metabolic disarray. In conclusion, endogenous CSF melatonin levels increase after TBI, whereas serum levels do not. This elevation is likely to represent a response to oxidative stress and metabolic disarray, although further studies are required to elucidate these relationships.

Ventricular cerebrospinal fluid melatonin concentrations investigated with an endoscopic technique

The role of melatonin in humans still remains unclear. Uncertainties persist about its effects on neurophysiology regarding its levels in human cerebrospinal fluid (CSF), as the bulk of knowledge on this subject mainly derives from studies conducted on animals. In this study, CSF was micro-sampled with a simple, new method from each cerebral ventricle of patients undergoing neuroendoscopy for hydrocephalus. Our purpose was to measure CSF melatonin levels and determine possible differences in its concentration among various significant areas in the cerebral ventricles (e.g. pineal recess, pituitary recess, lateral ventricle, fourth ventricle) and lumbar cistern. From 2002 to 2004, 10 hydrocephalic patients were operated on using a neuroendoscopic technique. The CSF specimens were investigated for melatonin concentrations (free plus protein-bound) after deproteinization; the measurement technique was high-performance liquid chromatography. The preliminary data obtained with this endoscopic micro-sampling technique (applied to humans for the first time) suggest that melatonin is more concentrated within the ventricles and its highest concentration is found in the third ventricle (IIIv), although the difference detected between the CSF of the IIIv and that of the pineal recess was not significant.

Molecular changes underlying reduced pineal melatonin levels in Alzheimer disease: alterations in preclinical and clinical stages.

A disturbed sleep-wake rhythm is common in Alzheimer disease (AD) patients and correlated with decreased melatonin levels and a disrupted circadian melatonin rhythm. Melatonin levels in the cerebrospinal fluid are decreased during the progression of AD neuropathology (as determined by the Braak stages), already in cognitively intact subjects with the earliest AD neuropathology (Braak stages I-II) (preclinical AD). To investigate the molecular mechanisms behind the decreased melatonin levels, we measured monoamines and mRNA levels of enzymes of the melatonin synthesis and its noradrenergic regulation in pineal glands from 18 controls, 33 preclinical AD subjects, and 25 definite AD patients. Pineal melatonin levels were highly correlated with cerebrospinal fluid melatonin levels. The circadian melatonin rhythm disappeared because of decreased nocturnal melatonin levels in both the preclinical AD and AD patients. Also the circadian rhythm of beta(1)-adrenergic receptor mRNA disappeared in both patient groups. The precursor of melatonin, serotonin was stepwise depleted during the course of AD, as indicated by the up-regulated monoamine oxidase A mRNA and activity (5-hydroxyindoleacetic acid:serotonin ratio). We conclude that a dysfunction of noradrenergic regulation and the depletion of serotonin by increased monoamine oxidase A result in the loss of melatonin rhythm already in preclinical AD.

Early neuropathological Alzheimer's changes in aged individuals are accompanied by decreased cerebrospinal fluid melatonin levels.

Neuropathology is the most reliable criterion for diagnosing Alzheimer's disease (AD). A well-established system for staging the spread of neuropathological changes in AD is available. The clinical use of a biomarker that reflects the neuropathological change occurring in brain tissue has not yet been established. Melatonin is a product that plays not only a major role in the regulation of the circadian rhythms but may also exert neuroprotective effects in AD. Melatonin levels were determined in ventricular postmortem cerebrospinal fluid (CSF) of 121 subjects. Braak staging and a modified Braak staging for cortex (MBSC) were used to evaluate the severity of AD neuropathology. The present study revealed that not only the Braak stages of AD, but also the MBSC were negatively correlated with CSF melatonin levels. By using MBSC, we now demonstrate for the first time that CSF melatonin levels were significantly decreased in the aged individuals with early neuropathological changes in the temporal cortex, where the AD process starts. Those individuals that did not have any neurofibrillary tangle (NFT) or neuritic plaque (NP) in the temporal cortex, had much higher melatonin levels (287 +/- 68 and 280 +/- 64 pg/mL, respectively) than those individuals that had a few NFTs and NPs (82 +/- 4 and 39 +/- 8 pg/mL, respectively) in the temporal cortex. These results suggest that the decrease in CSF melatonin levels may be an early event in the development of AD possibly occurring even before the clinical symptoms.

High melatonin concentrations in third ventricular cerebrospinal fluid are not due to Galen vein blood recirculating through the choroid plexus.

Melatonin has been implicated in several neurotropic effects, but few studies have investigated the bioavailability of melatonin in the brain. The discovery of periventricular sites of action adjacent to the third ventricle forced us to investigate the dynamics of cerebrospinal fluid (CSF) melatonin release and the source of this melatonin. Our first study demonstrated unequivocally that third ventricle CSF melatonin, like jugular plasma melatonin, accurately reflects the duration of the night and is rapidly suppressed by light. However, third ventricle CSF melatonin levels are 20-fold higher than nocturnal plasma concentrations. A further study showed that melatonin increased in plasma before third ventricle CSF, raising the possibility that melatonin is taken up from the blood after recirculation through the Galen vein. However, a final experiment suggested strongly that CSF melatonin is released directly into the third ventricle, as melatonin levels in the lateral ventricle were 7-fold lower than those in the third ventricle. Our study raises the possibility that there may be two compartments of melatonin affecting physiological functioning: the first in plasma acting on peripheral organs, and the second in the CSF affecting neurally mediated functions at a much higher concentration of this pineal indoleamine.

Decreased melatonin levels in postmortem cerebrospinal fluid in relation to aging, Alzheimer's disease, and apolipoprotein E-epsilon4/4 genotype.

Sleep disruption, nightly restlessness, sundowning, and other circadian disturbances are frequently seen in Alzheimer's disease (AD) patients. Changes in the suprachiasmatic nucleus and pineal gland are thought to be the biological basis for these behavioral disturbances. Melatonin is the main endocrine message for circadian rhythmicity from the pineal. To determine whether melatonin production was affected in AD, melatonin levels were determined in the cerebrospinal fluid (CSF) of 85 patients with AD (mean age, 75 +/- 1.1 yr) and in 82 age-matched controls (mean age, 76 +/- 1.4 yr). Ventricular postmortem CSF was collected from clinically and neuropathologically well defined AD patients and from control subjects without primary neurological or psychiatric disease. In old control subjects (>80 yr of age), CSF melatonin levels were half of those in control subjects of 41-80 yr of age [176 +/- 58 (n = 29) and 330 +/- 66 (n = 53) pg/mL, respectively; P = 0.016]. We did not find a diurnal rhythm in CSF melatonin levels in control subjects. In AD patients the CSF melatonin levels were only one fifth (55 +/- 7 pg/mL) of those in control subjects (273 +/- 47 pg/mL; P = 0.0001). There was no difference in the CSF melatonin levels between the presenile (42 +/- 11 pg/mL; n = 21) and the senile (59 +/- 8 pg/mL; n = 64; P = 0.35) AD patients. The melatonin level in AD patients expressing apolipoprotein E-epsilon3/4 (71 +/- 11 pg/mL) was significantly higher than that in patients expressing apolipoprotein E-epsilon4/4 (32 +/- 8 pg/ml; P = 0.02). In the AD patients no significant correlation was observed between age of onset or duration of AD and CSF melatonin levels. In the present study, a dramatic decrease in the CSF melatonin levels was found in old control subjects and even more so in AD patients. Whether supplementation of melatonin may indeed improve behavioral disturbances in AD patients should be investigated.

Melatonin concentrations in the sudden infant death syndrome

To examine a possible relationship between pineal function and the sudden infant death syndrome (SIDS), samples of whole blood, ventricular cerebrospinal fluid (CSF) and/or vitreous humor (VH) were obtained at autopsy from 68 infants (45 male, 23 female) whose deaths were attributed to either SIDS ( n = 32, 0.5–5.0 months of age; mean ± S.E.M., 2.6 ± 0.2 months) or other causes (non-SIDS, n = 36, 0.3–8.0 months of age 4.3 ± 0.3 months). The melatonin concentrations were measured by radioimmunoassay. A significant correlation was observed for melatonin levels in different body fluids from the same individual. After adjusting for age differences, CSF melatonin levels were significantly lower among the SIDS infants (91 ± 29 pmol/l; n = 32) than among those dying of other causes (180 ± 27; n = 35, P < 0.05). A similar, but non-significant trend was also noted in blood (97 ± 23, n = 30 vs. 144 ± 22 pmol/l, n = 33) and vitreous humor (68 ± 21, n = 10 vs. 81 ± 17 pmol/l, n = 15). These differences do not appear to be explainable in terms of the interval between death and autopsy, gender, premortem infection or therapeutic measures instituted prior to death. Diminished melatonin production may be characteristic of SIDS and could represent and impairment in the maturation of physiologic circadian organization.

Melatonin in the blood and cerebrospinal fluid of the green sea turtle (Chelonia mydas).

Abstract A melatonin radioimmunoassay was validated for the green sea turtle. A pronounced diurnal rhythm of melatonin content was evident in both serum and cerebrospinal fluid (CSF). In immature turtles, CSF melatonin levels paralleled those in serum but were always significantly lower. Despite the close anatomical juxtaposition of the sea turtle's large pineal gland to the brain, our data suggest that the primary route of secretion into the CSF is through the peripheral vasculature via the choroid plexus. Light exposure reduced serum melatonin titers. Adult females that were either mating or nesting exhibited the lowest serum melatonin levels we measured for this species.

Melatonin concentration in cerebrospinal fluid, peripheral plasma and plasma of the confluens sinuum of the rat.

A procedure is described for collection of blood from the confluens sinuum of the rat. Melatonin concentration, measured by RIA, in plasma of the confluens was found to be significantly higher than that in peripheral plasma. Melatonin levels in cerebrospinal fluid of the cisterna magna were always lower than those in plasma and exhibited no significant changes which paralleled those occurring in plasma with darkness. It is concluded that, in the rat, the major route of secretion of melatonin by the pineal gland is into the blood of the confluens sinuum.

MELATONIN CONCENTRATION IN HUMAN BLOOD AND CEREBROSPINAL FLUID: TO STRESS.

In 35 daytime paired blood and cerebrospinal fluid (CSF) samples from 15 patients, melatonin levels in CSF were undetectable or detectable but not higher than blood levels. During pneumoencephalography in 6 patients, no significant elevation of blood melatonin levels was observed, whereas cortisol concentration increased.