Differential abnormalities of cerebrospinal fluid dopaminergic versus noradrenergic indices in synucleinopathies.

The synucleinopathies Parkinson's disease (PD), multiple system atrophy (MSA), and pure autonomic failure (PAF) are characterized by intra-cytoplasmic deposition of the protein alpha-synuclein and by catecholamine depletion. PAF, which manifests with neurogenic orthostatic hypotension (nOH) and no motor signs of central neurodegeneration, can evolve into PD+nOH. The cerebrospinal fluid (CSF) levels of catecholamine metabolites may indicate central catecholamine deficiency in these synucleinopathies, but the literature is inconsistent and incomplete. In this retrospective cohort study we reviewed data about CSF catecholamines, the dopamine metabolites 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), and the norepinephrine metabolites 3,4-dihydroxyphenylglycol (DHPG) and 3-methoxy-4-hydroxyphenylglycol (MHPG). The compounds were measured in 36 patients with PD, 37 patients with MSA, and 19 patients with PAF and in 38 controls. Compared to the control group, the PD, MSA, and PAF groups had decreased CSF MHPG (p < .0001 each by Dunnett's post hoc test), DHPG (p = .004; p < .0001; p < .0001) and norepinephrine (p = .017; p = .0003; p = .044). CSF HVA and DOPAC were decreased in PD (p < .0001 each) and MSA (p < .0001 each) but not in PAF. The three synucleinopathies therefore have in common in vivo evidence of central noradrenergic deficiency but differ in the extents of central dopaminergic deficiency-prominent in PD and MSA, less apparent in PAF. Data from putamen 18 F-DOPA and cardiac 18 F-dopamine neuroimaging in the same patients, post-mortem tissue catecholamines in largely separate cohorts, and review of the neuropathology literature fit with these distinctions. The results suggest a 'norepinephrine first' ascending pathogenetic sequence in synucleinopathies, with degeneration of pontine locus ceruleus noradrenergic neurons preceding the loss of midbrain substantia nigra dopaminergic neurons.

Associations between CSF cortisol and CSF norepinephrine in cognitively normal controls and patients with amnestic MCI and AD dementia.

OBJECTIVE: This study evaluated the effects of Alzheimer disease (AD) on the relationship between the brain noradrenergic system and hypothalamic pituitary adrenocortical axis (HPA). Specifically, relationships between cerebrospinal fluid (CSF) norepinephrine (NE) and CSF cortisol were examined in cognitively normal participants and participants with AD dementia and amnestic mild cognitive impairment (aMCI). We hypothesized that there would a positive association between these 2 measures in cognitively normal controls and that this association would be altered in AD. METHODS: Four hundred twenty-one CSF samples were assayed for NE and cortisol in controls (n = 305), participants with aMCI (n = 22), and AD dementia (n = 94). Linear regression was used to examine the association between CSF cortisol and NE, adjusting for age, sex, education, and body mass index. RESULTS: Contrary to our hypothesis, CSF cortisol and NE levels were not significantly associated in controls. However, higher cortisol levels were associated with higher NE levels in AD and aMCI participants. Regression coefficients ± standard errors for the change in cortisol per 100-pg/mL increase in NE are as follows: controls 0.0 ± 0.2, P = 1.0; MCI, 1.4 ± 0.7, P = .14; and AD 1.1 ± 0.4, P = .032. Analysis with MCI and AD participants combined strengthened statistical significance (1.2 ± 0.3, P = .007). CONCLUSIONS: Enhanced responsiveness of the HPA axis to noradrenergic stimulatory regulation in AD and disruption of the blood brain barrier may contribute to these findings. Because brainstem noradrenergic stimulatory regulation of the HPA axis is substantially increased by both acute and chronic stress, these findings are also consistent with AD participants experiencing higher levels of acute and chronic stress.

Cerebrospinal fluid levels of catecholamines and its metabolites in Parkinson's disease: effect of l-DOPA treatment and changes in levodopa-induced dyskinesia.

Levodopa (l-DOPA, l-3,4-dihydroxyphenylalanine) is the most effective drug in the symptomatic treatment of Parkinson's disease (PD), but chronic use initiates a maladaptive process leading to l-DOPA-induced dyskinesia (LID). Risk factors for early onset LID include younger age, more severe disease at baseline and higher daily l-DOPA dose, but biomarkers to predict the risk of motor complications are not yet available. Here, we investigated whether CSF levels of catecholamines and its metabolites are altered in PD patients with LID [PD-LID, n = 8)] as compared to non-dyskinetic PD patients receiving l-DOPA (PD-L, n = 6), or not receiving l-DOPA (PD-N, n = 7) as well as non-PD controls (n = 16). PD patients were clinically assessed using the Unified Parkinson's Disease Rating Scale and Unified Dyskinesia Rating Scale and CSF was collected after overnight fasting and 1-2 h after oral intake of l-DOPA or other anti-Parkinson medication. CSF catecholamines and its metabolites were analyzed by HPLC with electrochemical detection. We observed (i) decreased levels of dihydroxyphenylacetic acid (DOPAC) and homovanillic acid in PD patients not receiving l-DOPA (ii) higher dopamine (DA) levels in PD-LID as compared to controls (iii) higher DA/l-DOPA and lower DOPAC/DA ratio's in PD-LID as compared to PD-L and (iv) an age-dependent increase of DA and decrease of DOPAC/DA ratio in controls. These results suggest increased DA release from non-DA cells and deficient DA re-uptake in PD-LID. Monitoring DA and DOPAC in CSF of l-DOPA-treated PD patients may help identify patients at risk of developing LID.

Neurochemical and neuroendocrine correlates of overactive bladder at first demyelinating episode.

AIMS: Bladder dysfunction is frequent during the course of multiple sclerosis (MS), observed in up to 75% of patients. Urinary symptomatology can be a feature of the first episode of MS in a minority of cases, and most often shows characteristics of an overactive bladder (OAB), with voiding symptoms seen less frequently, often in combination with OAB. The neural control of micturition is complex, involving systems located in the brain, spinal cord, and periphery, and implicating central noradrenergic, serotonergic, and dopaminergic activities. Urinary disorders are also linked to anxiety and depression, conditions connected to hypothalamus-pituitary-adrenal axis activity. In this study we aimed to investigate neurochemical and neuroendocrine correlates of bladder dysfunction in early MS. METHODS: We included 101 patients at first demyelinating episode suggestive of MS that were drug-free at assessment. We evaluated the presence of urinary symptomatology and estimated CSF levels of the main metabolites of noradrenaline, serotonin, and dopamine, as well CSF-ACTH and serum cortisol. RESULTS: In total, 15 patients (15%) reported urinary dysfunction suggestive of OAB. Four of these had coexistent voiding symptomatology. The serotonin metabolite 5-HIAA was significantly reduced (P = 0.017) in patients with OAB syndrome, while there were no differences in the metabolites of noradrenaline (MHPG) and of dopamine (HVA). Additionally, significantly lower serum cortisol (P = 0.009) and borderline lower CSF-ACTH (P = 0.08) were found in patients with OAB. CONCLUSIONS: MS patients with OAB syndrome at the first demyelinating episode show reductions in central serotonergic activity and stress hormones. Whether the same changes persist at later disease stages remains to be investigated. Neurourol. Urodynam. 35:955-958, 2016. © 2015 Wiley Periodicals, Inc.

Photo-renewable electroanalytical sensor for neurotransmitters detection in body fluid mimics.

A composite electrode with a sandwich structure combining the properties of silver nanoparticles and a titania photoactive layer was used for the electroanalytical detection, by differential pulse voltammetry, of three neurotransmitters: dopamine, norepinephrine, and serotonin. The three analytes were determined at low detection limits (around 0.03 µM) also in the presence of conventional interferents, such as uric and ascorbic acids. The fouling of the electrode surface was overcome by irradiating the device with UVA light, restoring the initial sensor sensitivity. Dopamine, norepinephrine, and serotonin were determined also in simulated biological matrices: liquor (artificially reproduced cerebrospinal fluid) and serum. Moreover, the contemporaneous detection of dopamine and norepinephrine in simulated human urine solutions was also demonstrated, representing the first step towards clinical applications of the proposed methodology. Graphical abstract The photo-renewable electroanalytical sensor.

Propiverine increases urethral wall catecholamine levels and bladder leak point pressure in rats.

OBJECTIVE: To investigate whether propiverine has a noradrenaline re-uptake inhibitor and whether it acts on the lumbosacral cord or the urethral wall. In addition, we aimed to examine the effect of propiverine on leak point pressure in rats. METHODS: A total of 72 female and 30 male rats were used to examine the following: (i) the change of leak point pressure caused by intravenous agents in rats with vaginal distention; (ii) the change of leak point pressure caused by intrathecal agents in rats with vaginal distention; (iii) the noradrenaline re-uptake inhibitor action of propiverine; and (iv) catecholamine levels in the bladder wall, urethral wall, cerebrospinal fluid and plasma after oral administration of propiverine. RESULTS: Intravenous injection of propiverine, imipramine and duloxetine increased the leak point pressure in rats with vaginal distention. Intrathecal naftopidil decreased the leak point pressure, whereas subsequent intravenous propiverine restored the leak point pressure to the level before intrathecal naftopidil in rats with vaginal distention. Propiverine acted like a noradrenaline re-uptake inhibitor, increasing noradrenaline and/or dopamine levels in the plasma, cerebrospinal fluid, and urethral wall perfusion fluid. CONCLUSION: Propiverine inhibits noradrenaline re-uptake, as well as having antimuscarinic and Ca-antagonist actions. The inhibition of noradrenaline re-uptake by propiverine mainly occurs at the urethral level and partially in the central nervous system, and might stimulate the smooth muscle of the bladder neck and proximal urethra through α1-adrenergic receptors, as well as stimulating the striated muscle of the urethra and pelvic floor by activation of spinal motoneurons. Therefore, propiverine might be effective for both stress and urge incontinence.

Effects of duloxetine on norepinephrine and serotonin transporter activity in healthy subjects.

Duloxetine selectively inhibits the serotonin (5-HT) and norepinephrine (NE) transporters (5-HTT and NET, respectively), as demonstrated in vitro and in preclinical studies; however, transporter inhibition has not been fully assessed in vivo at the approved dose of 60 mg/d. Here, the in vivo effects of dosing with duloxetine 60 mg once daily for 11 days in healthy subjects were assessed in 2 studies: (1) centrally (n = 11), by measuring concentrations of 5-hydroxyindoleacetic acid, 3,4-dihydroxyphenylglycol (DHPG), and NE in cerebrospinal fluid, and (2) versus escitalopram 20 mg/d (n = 32) in a 2-period crossover study by assessing the ΔDHPG/ΔNE ratio in plasma during orthostatic testing and by pharmacokinetic/pharmacodynamic modeling of reuptake inhibition using subjects' serum in cell lines expressing cloned human 5-HTT or NET. At steady state, duloxetine significantly reduced concentrations of DHPG and 5-hydroxyindoleacetic acid (P < 0.05), but not NE, in cerebrospinal fluid; DHPG was also decreased in plasma and urine. The ΔDHPG/ΔNE ratio in plasma decreased significantly more with duloxetine than escitalopram (65% and 21%, respectively; P < 0.0001). Ex vivo reuptake inhibition of 5-HTT was comparable (EC50 = 44.5 nM) for duloxetine and escitalopram, but duloxetine inhibited NET more potently (EC50 = 116 nM and 1044 nM, respectively). Maximal predicted reuptake inhibition for 5-HTT was 84% for duloxetine and 80% for escitalopram, and that for NET was 67% and 14%, respectively. In summary, duloxetine significantly affected 5-HT and NE turnover in the central nervous system and periphery; these effects presumably occurred via inhibition of reuptake by the 5-HTT and NET, as indicated by effects on functional reuptake inhibition ex vivo.

Polymorphisms in genes implicated in dopamine, serotonin and noradrenalin metabolism suggest association with cerebrospinal fluid monoamine metabolite concentrations in psychosis.

BACKGROUND: Homovanillic acid (HVA), 5-hydroxyindoleacetic acid (5-HIAA) and 3-methoxy-4-hydroxyphenylglycol (MHPG) are the major monoamine metabolites in the central nervous system (CNS). Their cerebrospinal fluid (CSF) concentrations, reflecting the monoamine turnover rates in CNS, are partially under genetic influence and have been associated with schizophrenia. We have hypothesized that CSF monoamine metabolite concentrations represent intermediate steps between single nucleotide polymorphisms (SNPs) in genes implicated in monoaminergic pathways and psychosis. METHODS: We have searched for association between 119 SNPs in genes implicated in monoaminergic pathways [tryptophan hydroxylase 1 (TPH1), TPH2, tyrosine hydroxylase (TH), DOPA decarboxylase (DDC), dopamine beta-hydroxylase (DBH), catechol-O-methyltransferase (COMT), monoamine oxidase A (MAOA) and MAOB] and monoamine metabolite concentrations in CSF in 74 patients with psychotic disorder. RESULTS: There were 42 nominally significant associations between SNPs and CSF monoamine metabolite concentrations, which exceeded the expected number (20) of nominal associations given the total number of tests performed. The strongest association (p = 0.0004) was found between MAOB rs5905512, a SNP previously reported to be associated with schizophrenia in men, and MHPG concentrations in men with psychotic disorder. Further analyses in 111 healthy individuals revealed that 41 of the 42 nominal associations were restricted to patients with psychosis and were absent in healthy controls. CONCLUSIONS: The present study suggests that altered monoamine turnover rates in CNS reflect intermediate steps in the associations between SNPs and psychosis.

Antinociceptive effect of intrathecal microencapsulated human pheochromocytoma cell in a rat model of bone cancer pain.

Human pheochromocytoma cells, which are demonstrated to contain and release met-enkephalin and norepinephrine, may be a promising resource for cell therapy in cancer-induced intractable pain. Intrathecal injection of alginate-poly (l) lysine-alginate (APA) microencapsulated human pheochromocytoma cells leads to antinociceptive effect in a rat model of bone cancer pain, and this effect was blocked by opioid antagonist naloxone and alpha 2-adrenergic antagonist rauwolscine. Neurochemical changes of cerebrospinal fluid are in accordance with the analgesic responses. Taken together, these data support that human pheochromocytoma cell implant-induced antinociception was mediated by met-enkephalin and norepinephrine secreted from the cell implants and acting at spinal receptors. Spinal implantation of microencapsulated human pheochromocytoma cells may provide an alternative approach for the therapy of chronic intractable pain.

Antagonism of orexin receptors significantly lowers blood pressure in spontaneously hypertensive rats.

In normal rats, central administration of orexin or exposure to certain forms of stress can induce significant increases in blood pressure and sympathetic nerve activity, which can be blocked by orexin receptor antagonists. The resting blood pressure is, however, unaffected by such antagonists, but is significantly lower in rodents with total loss of orexin, such as prepro-orexin knockout mice and orexin neuron-ablated orexin/ataxin-3 transgenic rats. We hypothesize that orexin is involved in the pathophysiology and maintenance of high blood pressure in the spontaneously hypertensive rat (SHR), a model of primary hypertension. To test this hypothesis, we measured orexin-A mRNA expression in the rostral ventrolateral medulla and antagonized both orexin receptors using an orally administered potent dual orexin receptor antagonist, almorexant, in SHRs and normotensive Wistar-Kyoto rats. In SHRs, there was a strong trend towards an increased orexin-A mRNA expression in the rostral ventrolateral medulla, and blocking orexin receptors markedly lowered blood pressure (from 182/152 ± 5/6 to 149/119 ± 9/8 mmHg; P < 0.001), heart rate (P < 0.001), sympathetic vasomotor tone (P < 0.001) and the noradrenaline levels in cerebrospinal fluid and plasma (P < 0.002). The significant antihypertensive effects of almorexant were observed in wakefulness and non-rapid eye movement sleep during both dark and light phases of the diurnal cycle only in SHRs. Blocking orexin receptors had no effect on blood pressure and sympathetic tone in normotensive Wistar-Kyoto rats. Our study links the orexin system to the pathogenesis of high blood pressure in SHRs and suggests that modulation of the orexin system could be a potential target in treating some forms of hypertension.

Association between sympathetic response, neurogenic cardiomyopathy, and venous thromboembolization in patients with primary subarachnoid hemorrhage.

INTRODUCTION: Sympathetic activation promotes hemostasis, and subarachnoid hemorrhage (SAH) is associated with pronounced sympathetic activation. This investigation will assess whether catecholaminergic activity relates to venous thrombotic events in patients with acute SAH. METHODS: Observational study of consecutive SAH grade 3-5 patients requiring ventriculostomy insertion who did not undergo open surgical treatment of cerebral aneurysm. Cerebrospinal fluid (CSF) samples were obtained within 48 h of hemorrhage for assay of catecholamines, which were related to occurrence of deep venous thrombosis (DVT) and pulmonary embolization (PE). RESULTS: Of the 92 subjects, mean age was 57 years, 76% were female, and 57% Caucasian; 11% experienced lower extremity (LE) DVT, 12% developed upper extremity (UE) or LE DVT, and 23% developed any DVT/PE. Mean time to occurrence of UE/LE DVT was 7.8 days (+/-5.9 days), and mean time to development of PE was 8.8 days (+/-5.4 days). In hazards analysis models, independent predictors of LE DVT included neurogenic cardiomyopathy (NC) [HR 4.97 (95%CI 1.32-18.7)], norepinephrine/3,4-dihydroxyphenylglycol ratio (NE/DHPG) [3.81 (2.04-7.14)], NE [5.91 (2.14-16.3)], and dopamine (DA) [2.27 (1.38-3.72)]. Predictors of UE/LE DVT included NC [5.78 (1.70-19.7)], cerebral infarction [4.01 (1.18-13.7)], NE [3.58 (1.40-9.19)], NE/DHPG [3.38 (1.80-6.33)] and DA [2.01 (1.20-3.35)]. Predictors of DVT/PE included Hunt-Hess grade (H/H) [3.02 (1.19-7.66)], NE [2.56 (1.23-5.37)] and 3,4-dihydroxyphenylalanine (DOPA) [3.49 (1.01-12.0)]. CONCLUSIONS: In severe SAH, central sympathetic activity and clinical manifestations of (nor)adrenergic activity relate to the development of venous thromboemboli. Catecholamine activation may promote hemostasis, or may represent a biomarker for venous thromboses.

Concentration gradients of monoamines, their precursors and metabolites in serial lumbar cerebrospinal fluid of neurologically healthy patients determined with a novel LC-MS/MS technique.

BACKGROUND: Potential biomarkers for neuropsychiatric disorders are cerebrospinal fluid (CSF) monoamines and their corresponding precursors and metabolites. During CSF sampling, CSF flows towards the lumbar sampling site from more cranial regions. To compare the results of studies in which different CSF volumes were acquired, it is important to know if ventricular-lumbar concentration gradients exist. This has only been addressed for a few biogenic amines, and almost exclusively in neurologically unwell patients due to the burden of a lumbar puncture (necessary to obtain CSF). The aim of our study was to determine if concentration gradients exist for routinely measured CSF constituents and biogenic amines in neurologically healthy patients. We applied a novel ultrasensitive liquid chromatography mass spectrometry (LC-MS/MS) method for the simultaneous quantification of multiple monoamines, precursors and metabolites in CSF and plasma. METHODS: CSF and blood samples were collected from twenty neurologically healthy patients undergoing spinal anaesthesia. Ten mL of lumbar CSF was collected in five consecutive two mL fractions. We determined leucocyte and erythrocyte counts, glucose, albumin and protein concentrations and quantified monoamines, precursors and metabolites on each of the fractions using LC-MS/MS. RESULTS: In twenty patients (60% male; median age: 46 years), dopamine, DOPAC, 3-MT, HVA, noradrenaline, normetanephrine and 5-HIAA concentrations increased from the first to the last CSF fraction (all p < 0.001). CSF adrenaline concentrations were below the detection limit, whereas serotonin measurements were regarded as unreliable. Albumin and total protein levels decreased significantly across CSF fractions. CONCLUSIONS: A ventricular-lumbar CSF concentration gradient existed for most of the investigated analytes. This is a novel finding for dopamine, noradrenaline, 3-MT and normetanephrine. These results contribute to the understanding of the neurobiology and underline the importance of standardized procedures for CSF handling to allow comparisons between studies.

Cerebrospinal fluid neurotransmitter changes during the perioperative period in patients undergoing total knee replacement: a randomized trial.

BACKGROUND: Total knee replacement (TKR) is of enormous benefit to patients with osteoarthritis of the knee; however, the acute postoperative pain can be severe and difficult to manage. The role of major spinal cord neurotransmitters in this acute postoperative period is not clear, although there are a few studies in humans. We performed the first prospective clinical study undertaken to delineate the changes in the spinal neurotransmitters after a surgery such as TKR. Furthermore, we also determined whether antihyperalgesic drugs at clinically acceptable doses modulate spinal neurotransmitter concentrations in patients during the perioperative period. METHODS: All patients had a spinal needle placed in the lumbar region and cerebrospinal fluid (CSF) obtained for baseline measurement of the neurotransmitters. An intrathecal catheter was then placed for spinal anesthesia for standard TKR and for continuous spinal postoperative analgesia. The spinal catheter was also used postoperatively to sample CSF at 2, 4, 8, 12, 24, and 32 hours after catheter placement. CSF samples were assayed for norepinephrine, substance P, calcitonin gene-related peptide (CGRP), and glutamate concentrations. SF-36 (36-item Short Form Health Survey) was measured preoperatively. Numerical rating scale (NRS) pain scores and intrathecal analgesic consumption were recorded postsurgery at 4-hour intervals for 32 hours. We performed a randomized, placebo-controlled, double-blind trial with 3 drug groups (n = 16 per group): placebo; single-dose pregabalin (150 mg administered before surgery); and multidose pregabalin (150 mg administered presurgery and 12 and 24 hours later), to determine the effect of an antihyperalgesic drug such as pregabalin on spinal neurotransmitters. RESULTS: Forty-eight patients were randomly assigned to the 3 perioperative treatment groups, and multiple CSF samples were successfully obtained from 44 patients. Before surgery, increased bodily pain (from preoperative SF-36 measure) was correlated with increased CSF norepinephrine concentration (P = 0.044). Compared with presurgery values, norepinephrine levels were lower in the placebo group at the 2- and 4-hour time points (P < 0.005) whereas in the single and multidose groups, the reduction (P < 0.001) continued until 12 and 24 hours, respectively. Substance P CSF levels had an early peak value (at 2 hours) in all 3 groups, and then returned to baseline. Compared with baseline value, the CGRP CSF levels only decreased at the 32-hour time point in the placebo group, but in both pregabalin groups, CGRP levels decreased over the 4- to 32-hour period. In the placebo group only, CSF glutamate decreased over 4 to 32 hours compared with presurgery values. However, there was no difference in the CSF neurotransmitter concentrations among the 3 treatment groups over the 32-hour sampling period. In the placebo group, the early NRS pain score area under the curve, AUC [0-12 hours], was positively correlated (R = 0.67, P = 0.0088) with the CSF norepinephrine concentration AUC [12-24 hours], but none of the other neurotransmitters was correlated with the NRS. None of the CSF neurotransmitter concentrations correlated with postoperative analgesic consumption. CONCLUSION: In the perioperative period, the concentration changes of the 4 spinal neurotransmitters have a distinct time course. CSF substance P seems to increase very rapidly with surgical intervention, whereas the CSF norepinephrine concentration tends to decrease. At clinical doses, pregabalin does not seem to modulate these spinal neurotransmitter concentrations.

Determinants of central sympathetic activation in spontaneous primary subarachnoid hemorrhage.

BACKGROUND: Subarachnoid hemorrhage (SAH) has been associated with pronounced acute sympathetic activation. The purpose of this investigation is to identify demographic, clinical, radiological, and anatomical features of SAH that relate to sympathetic activation. METHODS: Observational study of consecutive Grades 3-5 SAH patients requiring ventriculostomy and undergoing endovascular aneurysmal obliteration. All patients underwent cerebrospinal fluid (CSF) sampling within 48 h of SAH onset, and samples were assayed for various catecholamine compounds and metabolites. Univariate analyses were performed to identify variables associated with catecholamine levels, and to correlate linearity among catecholamine compounds and metabolites. Variables demonstrating a possible association and variables of interest were entered into linear regression models to determine predictors of catecholamine elevations. RESULTS: Of the 102 patients, mean age was 58 years and 74% were female; 42% were Hunt-Hess (H/H) grade 4/5, 61% had a computed tomography (CT) score of 3/4, 57% had anterior cerebral or communicating artery (ACA/ACom) aneursysms, and 23% had aneurysms in the posterior circulation. In the univariate analysis, age, gender, H/H grade, CT score, and aneurysm location demonstrated various associations with catecholamine levels, and substantial positive correlations existed between the various catecholamine compounds and metabolites. Linear regression analyses revealed H/H grade to be an independent predictor of elevated CSF epinephrine (EPI), 3,4-dihydroxyphenylalanine (DOPA) and 3,4-dihydroxyphenyl acetic acid (DOPAC) levels, and of the norepinephrine/3,4-dihydroxyphenylglycol (NE/DHPG) ratio (p < 0.05 for all analyses). Female gender independently predicted increased dopamine (DA) and DOPAC levels (p < 0.05 for two analyses), as well as possibly DOPA levels (p < 0.1). Age, CT score and aneurysm location demonstrated only inconsistent associations and trends. CONCLUSIONS: Central sympathetic activation relates to clinical severity and female gender. No definitive associations were found for age, hemorrhage amount, or aneurysm location.

Evidence for involvement of central noradrenergic activity in crying proneness.

Crying as a response to emotionally-charged situations varies greatly among individuals, genders, and cultures. Information on the neural systems involved in crying behavior comes mainly from studies of pathological laughing and crying in patients after brain injury. The authors assessed crying proneness (CPR) as expressed by the score on the "crying easily" item of the SCL-90 questionnaire in 65 men and 105 women subjects in whom lumbar puncture was performed for diagnostic reasons. None of the subjects showed pathological laughing or crying. The authors estimated the levels of the main metabolites of noradrenaline (MHPG), serotonin (5-HIAA), and dopamine (HVA) in CSF, and searched for associations to CPR score. Subjects with high CPR showed significantly lower MHPG levels than subjects with low CPR, and no differences in 5-HIAA or HVA levels. Higher frequencies of women were found in the subgroups with high CPR. The "crying easily" score was positively associated with the Interpersonal Sensitivity subscale of the SCL-90 questionnaire in female but not in male subjects, indicating the cultural dimension of crying behavior, while it was not associated with the Depression subscale score. It is suggested that central noradrenergic mechanisms control the threshold for tear production in normal crying behavior.

CSF catecholamine profile in subarachnoid hemorrhage patients with neurogenic cardiomyopathy.

BACKGROUND: Patients experiencing apoplectic intracranial processes may develop neurogenic cardiomyopathy (NC). The purpose of this research is to determine whether cerebrospinal fluid (CSF) catecholamine levels are elevated in subarachnoid hemorrhage (SAH) patients with NC when compared to those without NC. METHODS: Observational study of consecutive grades 3-5 SAH patients requiring ventriculostomy. All patients underwent CSF sampling for catecholamine levels, and transthoracic echocardiography (TTE) to assess for NC, within 48 h of SAH onset. Univariate analyses were performed to identify clinical and laboratory variables associated with NC. Clinical variables associated with NC in the univariate analysis were entered into logistic regression models along with the candidate catecholamine variables to identify predictors of NC. RESULTS: The study group contained 100 patients--mean age of study subjects was 58 years, 73% were female, and 15% developed NC. NC patients were more likely to have a worse clinical grade than patients without NC (80 vs. 34%, P = 0.001). NC patients possessed greater DOPA levels (5.83 vs. 4.60 nmol/l, P = 0.044), and a trend toward greater noradrenergic activity as determined by NE/DHPG ratio (0.3799 vs. 0.2519, P = 0.073). Multivariate analysis identified worse clinical grade (OR 7.09, P = 0.005) and possibly NE levels (OR 1.005, P = 0.057) as independent predictors of NC. Bivariate analysis reinforced the findings for NE (OR 1.006, P = 0.022), and also identified DOPA levels (OR 1.001, P = 0.034) and NE/DHPG (OR 22.18, P = 0.019) as predictors of NC. CONCLUSIONS: SAH patients with NC tend to have greater CSF catecholamine levels than those without NC. However, the development of NC may also be related to factors not evaluated by our study.

Elevated Norepinephrine Metabolism Gauges Alzheimer's Disease-Related Pathology and Memory Decline.

The noradrenergic (NE) locus coeruleus (LC) is vulnerable to hyperphosphorylated tau, and dysregulated NE-metabolism is linked to greater tau and disease progression. We investigated whether elevated NE-metabolism alone predicts memory decline or whether concomitant presence of tau and amyloid-ß is required. Among 114 memory clinic participants, time trends (max. six years) showed dose-response declines in learning across groups with elevated NE-metabolite 3-methoxy-4-hydroxyphenylethyleneglycol (MHPG) with no, one, or two Alzheimer's disease biomarkers; and no decline in the low MHPG group. Elevated MHPG is required and sufficient to detect learning declines, supporting a pathophysiologic model including the LC-NE system contributing to initial Alzheimer's disease-related processes.

Cerebrospinal Fluid Norepinephrine and Neurocognition in HIV and Methamphetamine Dependence.

OBJECTIVE: HIV disease and methamphetamine (METH) dependence share overlapping mechanisms of neurotoxicity that preferentially compromise monoamine-rich frontostriatal circuitry. However, norepinephrine (NE) function is poorly understood in HIV and METH dependence. We evaluated associations between cerebrospinal fluid (CSF) NE and HIV, METH dependence, and neurocognition. METHODS: Participants included 125 adults, stratified by HIV serostatus (HIV+/HIV-) and recent METH dependence (METH+/METH-), who underwent comprehensive neurocognitive testing and lumbar puncture. CSF NE was assayed using high-performance liquid chromatography. Multivariable regression modelled NE as a function of HIV, METH, and their interaction, adjusting for demographic and clinical factors. Pearson correlations examined relationships between NE and demographically-adjusted neurocognitive domain scores. RESULTS: HIV significantly interacted with METH (P < 0.001) such that compared with HIV-/METH-, CSF NE was markedly elevated in the single risk-groups (HIV+/METH-: d = 0.96; HIV-/METH+: d = 0.79) and modestly elevated in the dual-risk group (HIV+/METH+: d = 0.48). This interaction remained significant after adjustment for lifetime depression, antidepressant use, and race/ethnicity. In the full sample, higher NE levels significantly correlated with worse global function (r = -0.19), learning (r = -0.23), and delayed recall (r = -0.18). Similar relationships between higher NE and worse neurocognition were detected in the METH- groups (ie, HIV-/METH- and HIV+/METH-) and in the virally-suppressed persons HIV+ subgroup, but not in the METH+ groups (ie, HIV-/METH+, HIV+/METH+). DISCUSSION: HIV and METH independently, but not additively, relate to noradrenergic excess in the central nervous system, and perturbations to noradrenergic function may represent a pathophysiological mechanism of HIV-related neurocognitive dysfunction. Consistent with prior reports that noradrenergic excess compromises hippocampal and prefrontal function, higher NE related to worse neurocognition, even among successfully treated persons with HIV. Pharmacological and psychosocial interventions that stabilize NE function may improve neurocognition in persons with HIV.

Effects of botulinum toxin A on endometriosis­associated pain and its related mechanism.

Endometriosis (EMS) is a common disease in women aged 25­45 years, and pain is the main clinical symptom. The primary clinical treatment is surgical excision and drug therapy targeting the ectopic lesions, but these have not been very effective. Botulinum neurotoxin serotype A (BTX­A) has been reported to be useful in the treatment of pain in a variety of diseases. Based on this, the aim of the present study was to explore the therapeutic effect and mechanism of BTX­A on EMS. A model of nerve injury induced by oxygen glucose deprivation (OGD) was constructed in PC12 cells and EMS mice. Model cells and mice were treated with different concentrations of BTX­A to observe the changes in pain behavior, to detect cell viability and the secretion of norepinephrine (NE) and methionine enkephalin (M­EK) in cells and the spinal cord, and to evaluate the expression of apoptosis­related molecules in spinal cord nerves. The results revealed that BTX­A significantly reduced the amount of writhing in model mice, enhanced the activity of PC12 OGD cells, increased the secretion of NE and M­EK in model cells and the spinal cord of mice, and decreased the apoptosis of neural cells in the spinal cord of the model mice. Therefore, it was hypothesized that BTX­A may alleviate the pain induced by EMS by increasing the secretion of analgesic substances and promoting the repair of nerve injury. The present study provided a theoretical basis for the treatment of pain induced by EMS.

Essential hypertension: central and peripheral norepinephrine.

The concentration of norepinephrine in cerebrospinal fluid from patients with essential hypertension is higher than that from healthy normal volunteers, but the concentrations of norepinephrine in plasma from these groups are similar. This finding indicates that central nervous system noradrenergic hyperactivity occurs in essential hypertension but apparently is not reflected in abnormal function of the peripheral sympathetic nervous system in these patients.