Cerebrospinal fluid protein reactions during non-neurological surgery

OBJECTIVE: To study changes in cerebrospinal fluid (CSF) protein markers of blood-CSF barrier integrity and immunological reactions during surgical stress. SUBJECTS AND METHODS: Thirty-five patients without neurological or psychiatric disorders undergoing knee replacements had CSF and serum samples drawn from spinal and arterial catheters before, 3 h after and the morning after surgery. RESULTS: Serum albumin decreased during surgery and CSF albumin decreased during and after surgery, and, as a consequence, the CSF/serum albumin ratio decreased significantly during the study period, especially after the intervention. In contrast, CSF concentrations of beta-2-microglobuline (beta2M) increased significantly during surgery and remained high. The CSF general marker beta-trace protein (betaTP) remained unchanged. CONCLUSIONS: Central nervous system protein reactions to a non-neurological surgical intervention include sharply decreased permeability of albumin into the CSF and signs of intrathecal inflammatory activity.     

Serial neurochemical measurement of cerebrospinal fluid during the human sexual response cycle

Recent studies examining the neuroendocrine response pattern underlying the human sexual response cycle revealed transient activation of the sympathoadrenal system and a substantial, long-lasting increase in plasma prolactin concentrations following orgasm in men and women. Prolactin has been discussed as being part of a feedback mechanism that signals centers in the central nervous system, such as the dopaminergic system controlling sexual arousal. To further elucidate the central role of neuropeptides, biogenic monoamines and neurotransmitters in human sexual behavior, a serial cerebrospinal fluid (CSF)-sampling technique was implemented using a previously established experimental paradigm for sexual activity in a laboratory setting. In parallel with peripheral endocrine measures, lumbar CSF was drawn via an indwelling spinal catheter during the sexual response cycle in 10 healthy males and 10 age-matched controls, and analysed for prolactin, oxytocin, biogenic monoamines and/or their metabolites as well as inhibitory and excitatory neurotransmitter concentrations. Parallel to raised peripheral sympathetic activity, norepinephrine also increased in CSF during audiovisual, masturbation-induced sexual arousal and orgasm, and remained elevated for the remainder of the session (F(4,72) = 8.79, P = 0.000). In contrast, none of the other measures, in particular prolactin and dopamine or its metabolites, reflected significant alteration. In conclusion, the human sexual response cycle is characterized by an increase in sympathetic activity in plasma and CSF, and by pronounced secretion of plasma prolactin after orgasm. However, alterations in dopaminergic or peptidergic activity are not found in lumbar CSF, possibly due to local and restricted release in diencephalic and mesencephalic brain regions.     

Effect of Yishen Qiqiao Fang on dopamine content in serum and cerebrospinal fluid of patients in persistent vegetative statec

BACKGROUND: It has been demonstrated that the attack of persistent vegetative state is associated with the damaged neuron, which produces dopamine, and nervous pathway, the reduce of dopamine or malfunction of dopamine. OBJECTIVE: To observe the effect of self-made traditional Chinese medicine (TCM) Yishen Qiqiao Fang, which has the functions of supplementing qi and nourishing blood, resolving phlegm by promoting blood circulation, restoring consciousness and inducing resuscitation, on the contents of dopamine in serum and cerebrospinal fluid of patients in persistent vegetative state. DESIGN: An open randomized controlled clinical trial. SETTINGS: Nanjing University of Traditional Chinese Medicine, Nanjing Zijin Hospital. PARTICIPANTS: Thirty-eight inpatients of persistent vegetative state were selected from the Department of Neurology, Nanjing Zijin Hospital from August 2005 to November 2006. The patients were diagnosed according to the diagnostic standards set by the summary of a meeting for specialists in Nanjing. Informed contents were obtained from their relatives. According to the order of admission, the enrolled patients were divided into control group (n =20) and TCM treated group (n =20). METHODS: In the control group, the patients were treated with routine treatments for the symptoms. In the TCM treated group, the patients were treated with Yishen Qiqiao Fang besides the same treatments in the control group. TCM dispensing granules: each bag of mongolian milkvetch root, Chinese angelica and peach seed equaled to 10 g crude drug respectively; each bag of grassleaf sweetflag rhizome and dahurian angelica root equaled to 6 g crude drug respectively; Musk 0.05 g. The daily dosage for adults: 4 bags of mongolian milkvetch root, 2 bags of Chinese angelica, 0.05 g musk, 1 bag of peach seed, 2 bags of grassleaf sweetflag rhizome and 2 bags of dahurian angelica root, which should be given though nasal feeding or gastrostogavage before breakfast and supper every day, the course lasted for 2 months. The contents of dopamine in serum and cerebrospinal fluid were determined with enzyme immunoassay analyzer before and after treatment in both groups. MAIN OUTCOME MEASURES: Contents of dopamine in serum and cerebrospinal fluid before and after treatment in both groups. RESULTS: Totally 38 patients of persistent vegetative state were enrolled, 33 of them were involved in the final analysis of results, and the other 5 missed. The contents of dopamine in serum and cerebrospinal fluid had no obvious differences between the two groups both before and after treatment (P > 0.05). In the control group, the contents of dopamine in serum and cerebrospinal fluid had no obvious differences before and after treatment (P > 0.05). In the TCM treated group, the contents of dopamine in serum and cerebrospinal fluid after treatment were obviously higher than those before treatment (t =2.174, 2.485, P < 0.05). CONCLUSION: Yishen Qiqiao Fang can significantly increase the contents of dopamine in serum and cerebrospinal fluid of patients in persistent vegetative state, which may be one of the mechanisms for ameliorating persistent vegetative state.     

Effects of citalopram, a synthetic serotonin uptake inhibitor, on indoleamine and catecholamine concentrations in the cerebrospinal fluid of freely moving rats

Summary We studied changes in the concentrations of 5-hydroxytryptamine (5-HT), other indoleamines, and catecholamines in the cerebrospinal fluid (CSF) of freely-moving rats that had been administered citalopram, ±1-[3-(Dimethylamino)propyl)-1-(4-fluorophenyl)-1, 3-dihydro-5-isobenzofurancarbonitrile hydrobromide), a selective inhibitor of 5-HT uptake. In a microdialysis experiment, the intracerebral extracellular free 5-HT increased significantly, peaking 60 to 90 min after citalopram (30 mg/kg p.o.) was administerd. The 5-HT concentrations in CSF from the cisterna magna increased significantly, reaching a maximum 6 hours after a single dose of citalopram (30 mg/kg p.o.) was given. Six hours after this dose, the CSF 5-HT concentration in the cisterna magna was significantly increased, and the 5-hydroxyindoleacetic acid (5-HIAA) concentration was significantly decreased. There were non-significant changes in the other indoleamines (tryptophan, 5-hydroxytryptophan, and kynurenine) and in the catecholamines (dopamine, homovanillic acid, normetanephrine, and 3-methoxy-4-hydroxyphenethyleneglycol). The 5-HT/tryptophan ratio was correlated significantly with the kynurenine/tryptophan ratio before treatment with citalopram (r=0.81, p=0.051), indicative that there is coordination of the serotonin and kynurenine pathways in normal rats. In the animals posttreatment there was no such correlation, suggesting that the changes in 5-HT are independent of the kynurenine system at least within the 6 hours postreatment. These CSF results appear to reflect selective inhibition of 5-HT uptake in brain tissues by citalopram that is not associated with changes in catecholamines.     

Forearm vascular conductance during mental stress is related to the heart rate response

The forearm vasodilator response to mental stress is multifactorial and widely variable among individuals. We evaluated the association between the heart rate and forearm vascular conductance (FVC) responses to a color word test in 101 healthy adults. We found a striking correlation between heart rate and FVC (r = 0.66, P < 0.001), which remained significant when controlling for subject characteristics, blood pressure, and catecholamines. This suggests that the mechanical stimulation is one of the key factors that contribute to the increase in FVC during mental stress.     

Disproportionate increases in locomotor activity in response to hormonal and photic stimuli following regional neurochemical depletions of serotonin

The role of forebrain serotonin in behavior-related energy output was assessed in two locomotor activity tests conducted 3 and 6 months after bilateral, intrahypothalamic microinfusion of the serotonin neurotoxin, 5,7-dihydroxytryptamine (5,7-DHT). The serotonin-depleted animals exhibited a long-lasting and stable increase in energy expenditure as locomotor activity. This increased activity was investigated at the behavioral level by relating the hyperactivity to estrous cycle, photoperiod and body weight. Although the serotonin depletion-induced hyperactivity occurred in all photoperiod and estrous cycle stages, its magnitude was disproportionately increased during light and estrus. This hyperactivity could not be related to decreases in body weight because the serotonin-depleted animals weighed significantly more than the control animals. These animals responded to the weight loss that normally accompanies wheel running by increasing their activity to the same proportion as the other groups.The neuroanatomical and neurochemical substrate of the increased locomotor activity was investigated with a regional neurochemical assay for serotonin, dopamine and norepinephrine. This assay revealed that the toxin had no effect on dopamine or norepinephrine in any structure analyzed; however, serotonin was depleted in the hippocampus, septum and, to a lesser degree, in the hypothalamus. Serotonin levels were negatively correlated with overall activity. The magnitude of the disproportionate increase in activity during light and estrus was negatively correlated with hippocampal serotonin level. These results indicate that forebrain depletions of serotonin differentially affect the control of activity exerted by the phases of the photoperiod and estrous cycle. However, the modulation of activity levels by decreases in body weight remains intact.     

Implementation of a new CSF dynamic device: a multicenter feasibility study in 562 patients

Malm J, Sundström N, Cesarini KG, Edsbagge M, Kristensen B, Leijon G, Eklund A. Implementation of a new CSF dynamic device: a multicenter feasibility study in 562 patients.
Acta Neurol Scand: 2012: 125: 199–205.
© 2011 John Wiley & Sons A/S. Objectives – The cerebrospinal fluid (CSF) infusion test is frequently used when selecting hydrocephalus patients for shunt surgery. Very little has been reported regarding adverse events. We present a prospective feasibility study. Methods – Standardized devices for measuring CSF dynamics were built and 562 patients investigated: Needles were placed by lumbar puncture (LP). An automatic CSF infusion protocol was performed. Course of events during the investigation as well as adverse events were registered. Results – Preoperative evaluation of normal‐pressure hydrocephalus was the most common indication (63%), followed by evaluation of shunt function (23%) and intracranial pressure recordings (14%). The LP was successfully performed in all but nine cases with 24 patients (4.3%) reporting major discomfort. Ringer infusion was performed in 474 investigations, and a valid measurement of the outflow resistance was received in 439 (93%). During the infusion phase, 17 (4%) patients reported severe headache. Infusion volume was significantly higher in patients having subjective symptoms during the infusion phase compared with those without adverse events. During 269 preoperative CSF tap tests, six (2%) patients had severe headache. Post‐investigational headache was reported by 83 (15%) patients at the 24‐h follow‐up. No serious adverse events were observed. Conclusion – Infusion testing was safe and without serious adverse events with a high rate of successful procedures. The investigation was associated with expected mild to moderate discomfort.     

Normal dopaminergic and serotonergic metabolites in cerebrospinal fluid and blood of restless legs syndrome patients.

Cerebrospinal fluid (CSF) and blood obtained from 22 untreated or scarcely treated patients with moderate to severe restless legs syndrome (RLS; mean age, 58.6 +/- 13 years) and 11 control subjects (mean age, 56.6 +/- 12.9 years) were investigated for biogenic amines between 6:00 and 8:00 PM. We did not find any significant differences in the CSF concentrations of homovanillic acid, 3-ortho- methyl-dopa, levodopa, 5-hydroxytryptophan, 5-hydroxyindoleacetic acid, tetrahydrobiopterin, dihydrobiopterin, 5-methyltetrahydrofolate, and neopterin. In addition, serotonin in whole blood and plasma activity of aromatic amino acid decarboxylase were all normal. Our results suggest that dopaminergic and serotonergic release is not substantially affected in RLS.     

Altered behavioral and neurochemical response to stress in benzodiazepine-withdrawn rats

Rats chronically treated with diazepam (DZM) (2 mg/kg/day i.p.) for 21 days, were subsequently tested at 24, 48, 72 and 96 h after the last injection in the elevated plus-maze. When compared with their respective controls, withdrawn animals showed an anxiogenic response since they exhibited a significant decrease in the % of time spent in the open arms, and a reduction in open and total arms entries at 24 and 48 h following the last benzodiazepine administration. No other behavioral differences were observed in the remaining groups. Ninety-six hours following DZM withdrawal, when the anxiogenic response was no longer evident, withdrawn rats showed a significant decrease in immobility time when exposed to a forced-swim test (FST). GABA stimulation of chloride uptake in cortical tissue was measured in BDZ-withdrawn rats or vehicle-treated animals with or without exposure to the FST. An enhanced chloride uptake following GABA stimulation was observed in vehicle-treated rats following the swimming trial. However, similar values of chloride uptake were found among rats withdrawn from DZM at 96 h either exposed or not to the FST and vehicle-treated animals without prior stress exposure. These findings show that BDZ withdrawal alters the neurochemical and behavioral response to a subsequent stressful experience. These lines of evidence may indicate that BZD withdrawal reduced the ability to develop an adaptive response to stress.     

Relationship between platelet MAO activity and concentrations of 5-HIAA and HVA in cerebrospinal fluid in chronic pain patients

Summary Platelet monoamine oxidase (MAO) activity and concentrations of 5-HIAA and HVA in the cerebrospinal fluid (CSF) were estimated in a series of 54 chronic pain patients. Platelet MAO activity was found to correlate, positively to CSF concentrations of 5-HIAA and HVA, which had been adjusted in order to eliminate the influence of age and body height. However, only the correlation with 5-HIAA reached a significant level. When partial correlations were sought, only the positive correlation between platelet MAO activity and CSF 5-HIAA remained. The results support the notion that platelet MAO ia a biological marker for some trait dependent property of the central serotonergic system.Supported in part by grants from the Swedish Medical Research Council (grants No. 166, 4145 and 5740).     

Long-term effects of repeated methylamphetamine administration on monoamine neurons in the rhesus monkey brain

Previous studies indicate that the repeated administration of D-methylamphetamine (MA) produces a long-lasting depletion of dopamine (DA), norepinephrine (NE) and serotonin (5-hydroxytryptamine, 5-HT) in various brain regions of a number of species. The objectives of the present study were: (1) to establish a short, subcutaneous injection regimen which would reliably produce the neuronal alterations; (2) to evaluate MA-induced NE depletions produced by this new regimen; and (3) to determine whether central MA-induced neuronal changes are reflected in changes in cerebrospinal fluid monoamine metabolite concentrations. It was observed that high doses of MA administered (s.c.) over a 2-week period to rhesus monkeys produced decreases in DA and 5-HT, but not NE levels, in various brain regions. The decrease in caudate DA levels was accompanied by a decrease in the number of DA uptake sites, a decrease in the level of homovanillic acid (HVA) and an increase in DA turnover. This decrease in brain DA was also accompanied by a decrease in the cerebrospinal fluid concentration of HVA.     

Seasonal variation of serotonin turnover in human cerebrospinal fluid,depressive symptoms and the role of the 5-HTTLPR

Studying monoaminergic seasonality is likely to improve our understanding of neurobiological mechanisms underlying season-associated physiological and pathophysiological behavior. Studies of monoaminergic seasonality and the influence of the serotonin-transporter-linked polymorphic region (5-HTTLPR) on serotonin seasonality have yielded conflicting results, possibly due to lack of power and absence of multi-year analyses. We aimed to assess the extent of seasonal monoamine turnover and examined the possible involvement of the 5-HTTLPR. To determine the influence of seasonality on monoamine turnover, 5-hydroxyindoleacetic acid (5-HIAA) and homovanillic acid (HVA) were measured in the cerebrospinal fluid of 479 human subjects collected during a 3-year period. Cosine and non-parametric seasonal modeling were applied to both metabolites. We computed serotonin (5-HT) seasonality values and performed an association analysis with the s/l alleles of the 5-HTTLPR. Depressive symptomatology was assessed using the Beck Depression Inventory-II. Circannual variation in 5-HIAA fitted a spring-peak cosine model that was significantly associated with sampling month (P=0.0074). Season of sampling explained 5.4% (P=1.57 × 10⁻⁷) of the variance in 5-HIAA concentrations. The 5-HTTLPR s-allele was associated with increased 5-HIAA seasonality (standardized regression coefficient=0.12, P=0.020, N=393). 5-HIAA seasonality correlated with depressive symptoms (Spearman''s rho=0.13, P=0.018, N=345). In conclusion, we highlight a dose-dependent association of the 5-HTTLPR with 5-HIAA seasonality and a positive correlation between 5-HIAA seasonality and depressive symptomatology. The presented data set the stage for follow-up in clinical populations with a role for seasonality, such as affective disorders.     

Decreased cerebrospinal fluid cGMP levels in patients with amyotrophic lateral sclerosis

Summary. The role of cyclic guanosine 5 monophosphate (cGMP) in neurodegeneration of motor neurons in amyotrophic lateral sclerosis (ALS) is still controversial. The aim of this study was to measure levels of cGMP in cerebrospinal fluid (CSF) of patients with ALS, and to investigate whether there is a relationship between CSF cGMP levels and clinical parameters of the disease. The study involved 30 ALS and 20 control group patients. The CSF cGMP was measured by the enzyme-linked immunosorbent assay. The results showed that levels of CSF cGMP were significantly decreased in the group of ALS patients compared to controls and did not depend on clinical state of ALS patients, type of ALS onset, or the duration of the disease. Decreased levels of CSF cGMP observed in this study may suggest the role of cGMP in neurodegeneration in ALS. The CSF cGMP cannot be a marker of the disease activity.     

Amitriptyline: sex-dependent effect on sympathetic response and anxiety in rats submitted to early maternal separation and variable chronic stress in adulthood

The aim of the present study was to determine the effects of chronic treatment with the antidepressant amitriptyline on sympathetic nervous system activity and anxiety in male and female rats submitted to maternal separation (MS) and variable chronic stress (VCS). We observed that the treatment with amitriptyline produced a significant increase in norepinephrine (NE) plasma levels in non-maternally separated (NMS), non-stressed (NVCS) males in relation to vehicle-treated males, whereas in females the antidepressant produced a significant decrease in epinephrine (E) and NE when compared to the vehicle-treated group. In NMS/VCS males, amitriptyline produced a significant increase in the time spent on the open arms (TIME) in relation to the vehicle-treated group. In NMS/VCS females, amitriptyline produced a significant increase in TIME when compared to males. MS/VCS females showed a significant increase in the number of entries into the open arms (ENTRIES) in relation to males with the same treatment. This result suggests that there is a dimorphic response in coping with physical or emotional stressful situations and that amitriptyline acts in a differential way, being more effective in females.     

Modification of protein transfer across blood/cerebrospinal fluid barrier in response to altered plasma protein composition during development

A developmentally regulated protein-specific transfer mechanism across choroid plexus epithelial cells has previously been proposed to contribute to the characteristically high concentration of protein in cerebrospinal fluid (CSF) in the immature brain. Here we demonstrate that this mechanism is sensitive to protein variations in plasma resulting in changed numbers of transferring cells for individual proteins and altered transfer into the CSF. Pups of Monodelphis domestica at postnatal day (P)9, P65 and P110 were injected intraperitoneally with either adult Monodelphis plasma or exogenous bovine fetuin. Samples of CSF, blood and brain were collected from terminally anaesthetized animals 3-48 h later. The concentration of total protein was measured and levels of albumin, hemopexin, α-fetoprotein and bovine fetuin were estimated by western blotting. Numbers of lateral ventricular choroid plexus cells positive for total and individual plasma proteins were counted in paraffin sections of brains stained with appropriate antibodies. Following intraperitoneal injections, the content of proteins in the CSF increased at all three ages, but the concentration increased only in the CSF of older animals. The total numbers of plexus cells positive for plasma protein did not change significantly, but cells positive for individual proteins did. Fetuin was detected in all protein-positive cells, but apparently displaced α-fetoprotein and, to a lesser degree, hemopexin. The results indicate that protein transfer across the blood/CSF barrier appears to be regulated by a molecular recognition mechanism that is probably saturable but may not be as specific for individual proteins as previously suggested.     

Melatonin, pituitary function and stress in humans

(1) The nocturnal rise in plasma melatonin concentration continued through two cycles with continuous light occlusion by blindfolds in normal subjects. A daytime nap did not disturb the rhythm. (2) The plasma melatonin rhythm was present in patients with pituitary-adrenal and pituitary-gonadal failure, but appeared diminished or absent in patients bearing lesions at different points in the pineal afferent pathway. (3) In other patients and subjects who showed normal response of cortisol, growth hormone or prolactin after stimuli including hypoglycemia, pneumoencephalography, exercise or administration of -dopa during the daytime, there was no stimulation of plasma melatonin concentration. (4) Melatonin was not correlated with prolactin in blood or cerebrospinal fluid of patients with a wide range of plasma prolactin levels. (5) The adult human melatonin rhythm is relatively independent from pituitary, gonadal, and adrenal function, but may rely on a neural pathway similar to that controlling the rhythm in lower animals. The human melatonin rhythm may represent the output of a stable oscillator with a signal relatively free from acute perturbation by sleep, darkness, or stress sufficient to cause changes in other hormones.     

Paraclinical tests in acute-onset optic neuritis: basal data and results of a short follow-up

Up to now it is still doubtful whether there is a real risk of developing multiple sclerosis (MS) after initial monosymptomatic optic neuritis (ON). In this study we evaluated 43 patients with isolated acute-onset ON, in order to demonstrate the presence of oligoclonal bands (OBs) in the cerebrospinal fluid (CSF) and any additional clinically silent central nervous system (CNS) lesions. All examinations were performed from 5 days to 4 months (mean 43 days), from the onset of visual disturbances. Brain magnetic resonance imaging (MRI) detected white matter areas with increased signal in 21 patients (49%), while somatosensory and brainstem auditory evoked potentials revealed CNS abnormalities in only 5 patients (12%). OBs were present in the CSF of 20 patients (46%). Visual evoked potentials were abnormal in 39 patients (91%). Seven out of the 37 patients (19%) with at least one year follow-up, (mean duration of the follow-up = 32 months, range = 12-74), developed clinically definite MS (CDMS). All 7 patients had positive brain MRI and 6 had positive CSF examination at the basal evaluation. Our data suggest that MRI and CSF-OBs are the most reliable means of identifying patients with isolated ON who subsequently develop CDMS. They may therefore have a predictive value in defining MS risk.     

Effect of oestradiol on the responses of regional brain serotonin to stress in the ovariectomized rat

Summary The effect of oestradiol on the response of regional brain 5-hydroxytryptamine (serotonin, 5-HT) to 24 hours electrical footshock was investigated in ovariectomized rats. The stress applied four weeks after ovariectomy induced significant decreases in 5-HT concentrations in the fronto-parietal brain cortex (Bc), hippocampus (Hipp), striatum (CP), medial-basal hypothalamus (MBH) and the preoptic-anterior hypothalamic area (PAHA). Pretreatment with oestradiol prevented the footshock-induced decreases in 5-HT in the Hipp, CP, MBH and the PAHA. It was concluded that oestradiol may prevent stress-induced response of regional brain 5-HT in ovariectomized rats. An interaction between oestradiol and brain 5-HT is proposed in the control of the course of the oestrous cycles in stressful situations.