Cerebrospinal Fluid Dopamine Research Articles

Clinical features and mechanisms of neck myoclonus in narcolepsy

Study objectivesThe purpose of this study was to investigate the effects of neck myoclonus (NM) on sleep quality and daytime sleepiness in patients with narcolepsy (NT) and to further explore possible underlying mechanisms. MethodsWe included 72 patients with narcolepsy type 1 (NT1), 34 patients with narcolepsy type 2 (NT2) and 33 healthy controls. Patients underwent questionnaires, lumbar puncture procedure, polysomnography, and multiple sleep latency test (MSLT). Healthy controls underwent polysomnography and questionnaires. Orexin-A levels in the cerebrospinal fluid (CSF) were analyzed by radioimmunoassay. Three catecholamines, including dopamine, norepinephrine and epinephrine, in the CSF were measured by high-performance liquid chromatography–tandem mass spectrometry (HPLC–MS/MS). ResultsBoth the NT1 and NT2 groups displayed a higher level of NM incidence rate and index compared to the control group in PSG. NT1 displayed greater MSLT REM–-NM incidence rate and index than NT2. NM were often associated with arousal or awakening and body movements, which had a prominent influence on sleep quality in both narcoleptic patients and controls. There was a positive correlation between the NM index and the Pittsburgh Sleep Quality Index (PSQI), Stanford Sleepiness Scale (SSS) and Ullanlinna Narcolepsy Scale (UNS) scores in NT1 patients. In MSLT of NT1 patients, REM–NM index were positively correlated with the CSF dopamine levels, and there were elevated dopamine levels but reduced orexin-A levels in patients with REM–NM. ConclusionNM incidence rate and index were high in patients with narcolepsy, which had a huge effect on sleep quality and aggravated daytime sleepiness. NM should be considered pathological and viewed as a new sleep-related movement disorder. Orexin-A and dopamine may be involved in the development of NM.

Clinical features and neurobiochemical mechanisms of olfactory dysfunction in patients with Parkinson disease.

This study aimed to investigate clinical features, influencing factors and neurobiochemical mechanisms of olfactory dysfunction (OD) in Parkinson disease (PD). Total 39 patients were divided into thePD with OD (PD-OD) and PD with no OD (PD-nOD) groups according to overall olfactory function, including threshold, discrimination and identification, assessed by Sniffin' Sticks test. Motor functionand non-motor symptoms were rated by multiple scales. Dopamine, acetylcholine, norepinephrine and 5-hydroxytryptamine levels in cerebrospinal fluid (CSF) were measured. We found that thePD-OD group showed significantly lower score of Montreal Cognitive Assessment Scale, higher scores of rapid eye movement sleep behavior disorder (RBD) Screening Questionnaire and Epworth Sleepiness Scale than thePD-nOD group (p < 0.05). RBD Screening Questionnaire score was independently associated with the scores of overall olfactory function and discrimination (p < 0.05). Dopamine and acetylcholine levels in CSF from thePD-OD group was significantly lower than that from thePD-nOD group (p < 0.05). Dopamine and acetylcholine levels in CSF were significantly and positively correlated with the scores of overall olfactory function, threshold, discrimination and identification in PD patients (p < 0.05). RBD Screening Questionnaire score was significantly and negatively correlated with acetylcholine level in CSF in PD patients with poor olfactory detection (p < 0.05). This investigation reveals that PD-OD is associated with cognitive impairment, probable RBD and excessive daytime sleepiness. PD-OD is correlated with the decreased levels of dopamine and acetylcholine in CSF. RBD is an independent influencing factor of overall olfactory function and discrimination, and thedecreased acetylcholine level in CSF may be the common neurobiochemical basis of RBD and OD in PD patients.

CSF dopamine is elevated in first-episode psychosis and associates to symptom severity and cognitive performance.

The hypothesis of dopamine dysfunction in psychosis has evolved since the mid-twentieth century. However, clinical support from biochemical analysis of the transmitter in patients is still missing. The present study assessed dopamine and related metabolites in the cerebrospinal fluid (CSF) of first-episode psychosis (FEP) subjects. Forty first-episode psychosis subjects and twenty healthy age-matched volunteers were recruited via the Karolinska Schizophrenia Project, a multidisciplinary research consortium that investigates the pathophysiology of schizophrenia. Psychopathology, disease severity, and cognitive performance were rated as well as cerebrospinal fluid concentrations of dopamine and related metabolites were measured using a sensitive high-pressure liquid chromatography assay. CSF dopamine was reliably detected in 50% of healthy controls and in 65% of first-episode psychosis subjects and significantly higher in first-episode psychosis subjects compared to age-matched healthy controls. No difference in CSF dopamine levels was observed between drug-naive subjects and subjects with short exposure to antipsychotics. The dopamine concentrations were positively associated with illness severity and deficits in executive functioning. Dopamine dysfunction has long been considered a cornerstone of the pathophysiology of schizophrenia, although biochemical support for elevated brain dopamine levels has been lacking. The results of the present study, showing that FEP subjects have increased CSF dopamine levels that correlate to disease symptoms, should fill the knowledge gap in this regard.

Accelerated high frequency rTMS induces time-dependent dopaminergic alterations: a DaTSCAN brain imaging study in healthy beagle dogs.

The neurobiological effects of repetitive transcranial magnetic stimulation are believed to run in part through the dopaminergic system. Accelerated high frequency rTMS (aHF-rTMS), a new form of stimuli delivery, is currently being tested for its usefulness in treating human and canine mental disorders. However, the short-and long-term neurobiological effects are still unclear, including the effects on the dopaminergic system. In aHF-rTMS, multiple sessions are delivered within 1 day instead of one session per day, not only to accelerate the time to response but also to increase clinical efficacy. To gain more insight into the neurobiology of aHF-rTMS, we investigated whether applying five sessions in 1 day has direct and/or delayed effects on the dopamine transporter (DAT), and on dopamine metabolites of cerebrospinal fluid (CSF) in beagles. Thirteen beagles were randomly divided into two groups: five active stimulation sessions (n = 9), and 5 sham stimulation sessions (n = 4). Using DaTSCAN, DAT binding indices (BI) were obtained at baseline, after 1 day, 1 month, and 3 months post stimulation. CSF samples were collected after each scan. Active aHF-rTMS significantly reduced striatal DAT BI 1 day post-active stimulation session (p < 0.01), and the effect lasted to 1 month (p < 0.01). No significant DAT BI change was found in sham group. No significant changes in dopamine metabolites of CSF were found. Although no significant effects on CSF dopamine metabolites were observed, five sessions of active aHF-rTMS significantly decreased striatal DAT BI after 1 day and up to 1 month post stimulation, indicating immediate and delayed effects on the brain dopaminergic system. Our findings in healthy beagles further substantiate the assumption that (a)HF-rTMS affects the brain dopaminergic system and it may pave the way to apply (a)HF-rTMS treatment in behaviorally disturbed dogs.

Cerebrospinal fluid catecholamines in Alzheimer\u2019s disease patients with and without biological disease

Noradrenergic and dopaminergic neurons are involved in cognitive functions, relate to behavioral and psychological symptoms in dementia and are affected in Alzheimer’s disease (AD). Amyloid plaques (A), neurofibrillary tangles (T) and neurodegeneration (N) hallmarks the AD neuropathology. Today, the AT(N) pathophysiology can be assessed through biomarkers. Previous studies report cerebrospinal fluid (CSF) catecholamine concentrations in AD patients without biomarker refinement. We explored if CSF catecholamines relate to AD clinical presentation or neuropathology as reflected by CSF biomarkers. CSF catecholamines were analyzed in AD patients at the mild cognitive impairment (MCI; n = 54) or dementia stage (n = 240) and in cognitively unimpaired (n = 113). CSF biomarkers determined AT status and indicated synaptic damage (neurogranin). The AD patients (n = 294) had higher CSF noradrenaline and adrenaline concentrations, but lower dopamine concentrations compared to the cognitively unimpaired (n = 113). AD patients in the MCI and dementia stage of the disease had similar CSF catecholamine concentrations. In the CSF neurogranin positively associated with noradrenaline and adrenaline but not with dopamine. Adjusted regression analyses including AT status, CSF neurogranin, age, gender, and APOEε4 status verified the findings. In restricted analyses comparing A+T+ patients to A−T− cognitively unimpaired, the findings for CSF adrenaline remained significant (p < 0.001) but not for CSF noradrenaline (p = 0.07) and CSF dopamine (p = 0.33). There were no differences between A+T+ and A−T− cognitively unimpaired. Thus, we find alterations in CSF catecholamines in symptomatic AD and the CSF adrenergic transmitters to increase simultaneously with synaptic damage as indexed by CSF neurogranin.

Lab-In-A-Syringe: A Novel Electrochemical Biosensor for On-Site and Real-Time Monitoring of Dopamine in Freely Behaving Mice.

There is a growing demand for real-time analysis and sampling of biofluids on a single low-cost platform in ultralow fluid volumes with robustness. In this study, a microfluidic sensor was developed, manufactured through an additive manufacturing technique, and used for dopamine (DA) measurements. We implemented a biosensing system using pencil graphites (PGEs) integrated into a three-dimensional (3D) printed microfluidic syringe-type device (μSyringe). The amperometry technique was used to monitor the current changes associated with the electrooxidation of DA. The sensing signal was stable and linear in a concentration range of DA between the limit of quantification (0.1 nM) and the upper limit of linearity (500 nM). The μSyringe sensing device is simple, robust, and stable, making it suitable for real-time measurement of DA in cerebrospinal fluid (CSF) from freely moving mice.

Safety, target engagement, and biomarker effects of bosutinib in dementia with Lewy bodies.

IntroductionBosutinib, a dual Abelson/Src inhibitor, was investigated in individuals with dementia with Lewy bodies (DLB).MethodsA single site, randomized, double‐blind, placebo‐controlled study of the effects of oral bosutinib, 100 mg once daily for 12 weeks on primary safety and pharmacokinetics and secondary biomarker outcomes.ResultsTwenty‐six participants were randomized and included male and female (12:1) in the bosutinib arm and all male (13) in the placebo arm. The average age was 72.9 ± 8.1 (year ± standard deviation). There were no serious adverse events and no dropouts. Bosutinib was measured in the cerebrospinal fluid (CSF) and inhibited Abelson. Bosutinib reduced CSF alpha‐synuclein and dopamine catabolism.DiscussionBosutinib is safe and well tolerated and penetrates the blood–brain barrier to inhibit Abelson and reduce CSF alpha‐synuclein and dopamine catabolism, suggesting that bosutinib (100 mg) may be at or near the lowest effective dose in DLB. These results will guide adequately powered studies to determine the efficacy of a dose range of bosutinib and longer treatment in DLB.Highlights Bosutinib is a dual Abl/Src inhibitor that penetrates the blood brain barrierBosutinib is safe and tolerated in individuals with dementia with Lewy bodiesBosutinib engages its target via inhibition of Abl and SrcBosutinib reduces CSF alpha‐synuclein and attenuates breakdown of dopamineBosutinib improves activities of daily living in dementia with Lewy bodies

Fibroblast growth factor 21 associating with serotonin and dopamine in the cerebrospinal fluid predicts impulsivity in healthy subjects

BackgroundImpulsivity is more commonly reported in subjects with mental disorders compared to healthy subjects, suggesting a potential application of impulsivity in predicting impulsivity-related mental disorders. However, no biomarker of impulsivity available so far. This study explored the association between cerebrospinal fluid (CSF) fibroblast growth factor 21 (FGF21), a key hormonal mediator of the stress response, and impulsivity in healthy subjects.MethodsA total of 126 healthy persons subjected to surgery of anterior cruciate ligament were recruited in the present study. The impulsiveness of the subjects was evaluated by the Chinese version of the Barratt Impulsiveness Scale (BIS)-11 before surgery. CSF and blood samples of the subjects were collected before spinal anesthesia for surgery. The levels of FGF21, serotonin and dopamine in CSF and the level of FGF21 in blood of the subjects were measured by ELISA using commercial kits.ResultsNegative correlations were found between BIS-11 total score and either FGF21, serotonin or dopamine in CSF. However, BIS-11 total score was not correlated with FGF21 in blood. In addition, FGF21 was positively correlated with serotonin and dopamine in CSF, respectively. Multivariable linear regression models indicated that the decrease of FGF21 level associating with the decrease of serotonin and dopamine level in CSF contributed to the higher impulsivity. Furthermore, receiver operating characteristic curve (ROC) analysis indicated an important role of CSF FGF21 predicting high impulsivity.ConclusionsFGF21, serotonin and dopamine in CSF associate with impulsivity in opposite directions. The decrease of CSF FGF21 is related to higher impulsivity, and indicate that CSF FGF21 may predict impulsivity in healthy subjects.

Gene therapy restores dopamine transporter expression and ameliorates pathology in iPSC and mouse models of infantile parkinsonism.

Most inherited neurodegenerative disorders are incurable, and often only palliative treatment is available. Precision medicine has great potential to address this unmet clinical need. We explored this paradigm in dopamine transporter deficiency syndrome (DTDS), caused by biallelic loss-of-function mutations in SLC6A3, encoding the dopamine transporter (DAT). Patients present with early infantile hyperkinesia, severe progressive childhood parkinsonism, and raised cerebrospinal fluid dopamine metabolites. The absence of effective treatments and relentless disease course frequently leads to death in childhood. Using patient-derived induced pluripotent stem cells (iPSCs), we generated a midbrain dopaminergic (mDA) neuron model of DTDS that exhibited marked impairment of DAT activity, apoptotic neurodegeneration associated with TNFα-mediated inflammation, and dopamine toxicity. Partial restoration of DAT activity by the pharmacochaperone pifithrin-μ was mutation-specific. In contrast, lentiviral gene transfer of wild-type human SLC6A3 complementary DNA restored DAT activity and prevented neurodegeneration in all patient-derived mDA lines. To progress toward clinical translation, we used the knockout mouse model of DTDS that recapitulates human disease, exhibiting parkinsonism features, including tremor, bradykinesia, and premature death. Neonatal intracerebroventricular injection of human SLC6A3 using an adeno-associated virus (AAV) vector provided neuronal expression of human DAT, which ameliorated motor phenotype, life span, and neuronal survival in the substantia nigra and striatum, although off-target neurotoxic effects were seen at higher dosage. These were avoided with stereotactic delivery of AAV2.SLC6A3 gene therapy targeted to the midbrain of adult knockout mice, which rescued both motor phenotype and neurodegeneration, suggesting that targeted AAV gene therapy might be effective for patients with DTDS.

Catecholamine activity in delirium with and without pre‐existing dementia

AbstractBackgroundDelirium “acute confusion” is an unpleasant but common complication of acute illness in the aged population associated with prolonged hospitalization. Dementia is a substantial risk factor for delirium that may be apparent already in preclinical Alzheimer’s disease, but a delirium is also a risk factor for dementia. Effective agents for preventing and treating delirium are therefore searched. This include administration of antipsychotics targeting anticipated excessive dopaminergic activity in delirium and alpha‐2‐receptor (α2) agonists reducing noradrenergic activity. Data of noradrenergic and dopaminergic activity in delirium is however limited. We therefore aimed to characterize the cerebrospinal fluid (CSF) levels of dopamine and noradrenaline (norepinephrine) in delirium, with or without pre‐existing dementia.MethodCSF levels of dopamine and noradrenaline were determined by high‐performance‐liquid‐chromatography (HPLC) in: 1) cognitively healthy (controls; n=122) 2) Hip fracture patients (n=118) with and without delirium and pre‐fracture dementia 3) Patients with delirium precipitated by another medical condition (n=26). Non‐parametric statistical analyzes were applied.ResultPatients with delirium following a hip fracture and another medical condition had lower CSF dopamine levels relative to hip fracture patients without delirium and controls respectively. Stratified analyzes of hip fracture patients according to dementia status and separating patients with delirium before and after surgery showed differences in the two stratas. Interestingly there was a trend for higher levels of noradrenaline in incident delirium among those without pre‐fracture dementia, but there were few patients in this group (n=7).ConclusionThe lower levels of dopamine in CSF in delirium align with recent meta‐analyzes not recommending use of antipsychotics. Further evaluation of α2‐agonists for delirium prevention, in particular in those without pre‐existing dementia is supported, although the data should be reproduced in larger studies.

Parkinson's Disease With Depression: The Correlations Between Neuroinflammatory Factors and Neurotransmitters in Cerebrospinal Fluid.

Background: To explore the changes of neuroinflammatory factors in cerebrospinal fluid (CSF) and their correlation with monoamine neurotransmitters in Parkinson’s disease (PD) with depression (PD-D) patients.Methods: Neuroinflammatory factors and neurotransmitters in CSF were measured and compared between PD with no depression (PD-ND) and PD-D groups. The relationship between PD-D and neuroinflammatory factors was studied by binary logistic regression equation, and the related factors of PD-D were adjusted. The correlations of the levels of neuroinflammatory factors and neurotransmitters in PD-D group were analyzed.Results: The levels of tumor necrosis factor (TNF)-α in CSF from PD-D group were significantly higher and there were no significant differences in the levels of interleukin-1β, prostaglandin (PG) E2, hydrogen peroxide (H2O2), and nitric oxide (NO). The 24-item Hamilton Depression Scale (HAMD-24) score was positively correlated with the level of TNF-α in CSF. Binary logistic regression showed that the OR of CSF TNF-α level was 1.035 (95% CI 1.002–1.069). The level of dopamine (DA) in CSF of PD-D group was significantly lower than that in PD-ND group. TNF-α level was negatively correlated with DA level in CSF from PD patients (r = −0.320, P = 0.003).Conclusions: Neuroinflammatory factors, especially TNF-α, may play an important role in PD-D. It may cause damage to DA neurons and lead to the depletion of DA, which is related to the occurrence and development of PD-D.

Association of Cigarette Smoking with Sleep Disturbance and Neurotransmitters in Cerebrospinal Fluid.

BackgroundCigarette smoking has shown to be associated with sleep disturbance, especially prolonged sleep onset latency (SOL). Cigarette smoking stimulates the release of dopamine (DA) and serotonin (5-HT), which might promote awakening and inhibit rapid eye movement sleep. Dopamine transporter (DAT) and serotonin transporter play a key role in the reuptake of DA and 5-HT from the synaptic cleft into presynaptic neurons. However, the relationship among cigarette smoking, sleep disturbance and neurotransmitters has never been investigated in human cerebrospinal fluid (CSF).MethodsA total of 159 Chinese male subjects (81 active smokers and 78 non-smokers) who would undergo lumbar puncture before the surgery of anterior cruciate ligament reconstruction were recruited and 5mL-CSF samples were collected incidentally. CSF levels of DA, DAT, 5-HT, and serotonin transporter were measured using radioimmunoassay and ELISA. Sociodemographic data and the Pittsburgh Sleep Quality Index (PSQI) scale were collected before surgery.ResultsPSQI global scores, SOL, and CSF DA levels were significantly higher in active smokers compared to non-smokers (2.00 [1.00–4.75] scores vs 4.00 [3.00–6.00] scores, p = 0.001; 10.00 [5.00–15.00] minutes vs 15.00 [10.00–30.00] minutes, p = 0.002; 87.20 [82.31–96.06]ng/mL vs 107.45 [92.78–114.38] ng/mL, p < 0.001), while CSF DAT levels were significantly lower in active smokers (0.35 [0.31–0.39] ng/mL vs 0.29 [0.26–0.34] ng/mL, p < 0.001).ConclusionCigarette smoking was indeed associated with sleep disturbance, shown by prolonged SOL, higher DA levels and lower DAT levels in CSF of active smokers.

Electrochemically reduced graphene oxide and gold nanoparticles onan indium tin oxide electrode for voltammetric sensing of dopamine.

The authors describe an electrochemical dopamine sensor that is based on the use of electrochemically co-reduced graphene oxide (Er-GO) and gold nanoparticles (AuNPs) on an indium-tin oxide (ITO) electrode. The synergistic effects of Er-GO and Er-AuNPs promote electron transport in the modified ITO. This results in an excellent performance for voltammetric sensing of dopamine (DA). Under the optimum conditions and a typical working potential of -0.05V (vs. Ag/AgCl), the ITO electrode has a linear response in the 0.02-200μM DA concentration range and a low detection limit of 15nM. The sensor also showed a good selectivity over ascorbic acid and uric acid. The feasibility of the method was studied by analyzing DA in cerebrospinal fluid of rats. Graphical abstract Schematic presentation of one-step electrochemical co-reduction of graphene oxide (GO) and gold nanoparticles (AuNPs) on anITO electrode for voltammetric sensing of dopamine.

VNTR polymorphism in the monoamine oxidase A promoter region and cerebrospinal fluid catecholamine concentrations in forensic autopsy cases

Monoamine oxidase A (MAOA) plays important roles in the metabolism of catecholamines and modulates adrenergic, noradrenergic, and dopaminergic signaling. A polymorphic promoter variable number tandem repeat (VNTR) locus (MAOA-uVNTR) is located approximately 1.2 kb upstream from MAOA exon 1. Functional studies revealed that MAOA-uVNTR affects gene expression. In the present study, we examined the frequencies of MAOA-uVNTR alleles in Japanese autopsy cases, in which amphetamines or psychotropic drugs were not detected. In total, 87 males and 35 females were evaluated and investigated for the possible effect of MAOA-uVNTR polymorphisms on cerebrospinal fluid (CSF) catecholamine concentrations. In males, there was no significant association between MAOA-uVNTR polymorphisms and CSF adrenaline (Adr), noradrenaline (Nad), or dopamine (DA) levels. In contrast, females who were homozygous for the 3-repeat allele (i.e., 3/3 genotype carriers) had higher CSF levels of Adr (p = 0.024) and DA (p = 0.035) than individuals who were heterozygous or homozygous for the 4-repeat allele (3/4 and 4/4, respectively). We found no significant association between MAOA-uVNTR polymorphisms and CSF Nad levels in females. Thus, the results of the present study indicated that MAOA-uVNTR polymorphism influences CSF Adr and DA levels in females.

DRD2/ANKK1 gene polymorphisms in forensic autopsies of methamphetamine intoxication fatalities.

Dopamine D2 receptor/ankyrin repeat and kinase domain containing 1 (DRD2/ANKK1) gene polymorphisms have been associated with responses to psychotropic drugs and addiction. We analyzed two DRD2/ANKK1 polymorphisms, Taq1A and -141C Ins/Del, in 37 fatal methamphetamine (MA) intoxication cases and 235 control cases in which MA and psychotropic drugs were not detected. The association among polymorphism, cause of death, and cerebrospinal fluid (CSF) dopamine concentration was evaluated. The Taq1A polymorphism distribution in the fatal MA intoxication cases differed from in the controls (P = 0.030) with a significantly high A1/A1 + A1/A2 genotype frequency. No significant associations were observed between -141C Ins/Del polymorphisms and MA intoxication cases or between DRD2/ANKK1 polymorphisms and CSF dopamine concentrations. Our findings suggest that the DRD2/ANKK1 Taq1A polymorphism is associated with susceptibility to fatal MA intoxication.

Quantitative SERS Detection of Dopamine in Cerebrospinal Fluid by Dual-Recognition-Induced Hot Spot Generation

Reliable profiling of the extracellular dopamine (DA) concentration in the central nervous system is essential for a deep understanding of its biological and pathological functions. However, quantitative determination of this neurotransmitter remains a challenge because of the extremely low concentration of DA in the cerebrospinal fluid (CSF) of patients. Herein, on the basis of the specific recognition of boronate toward diol and N-hydroxysuccinimide ester toward the amine group, a simple and highly sensitive strategy was presented for DA detection by using surface-enhanced Raman scattering (SERS) spectroscopy as a signal readout. This was realized by first immobilizing 3,3'-dithiodipropionic acid di( N-hydroxysuccinimide ester) on gold thin film surfaces to capture DA, followed by introducing 3-mercaptophenylboronic acid (3-MPBA)-functionalized silver nanoparticles to generate numerous plasmonic "hot spots" with the nanoparticle-on-mirror geometry. Such a dual-recognition mechanism not only avoids complicated bioelement-based manipulations but also efficiently decreases the background signal. With the direct use of the recognition probe 3-MPBA as a Raman reporter, the "signal-on" SERS method was employed to quantify the concentration of DA from 1 pM to 1 μM with a detection limit of 0.3 pM. Moreover, our dual-recognition-directed SERS assay exhibited a high resistance to cerebral interference and was successfully applied to monitoring of DA in CSF samples of patients.

Restless legs syndrome in Parkinson disease: Clinical characteristics, abnormal iron metabolism and altered neurotransmitters

Relationships among clinical characteristics, iron metabolism and neurotransmitters in Parkinson disease (PD) patients with restless legs syndrome (RLS) remains unclear. We divided 218 patients into PD with and with no RLS (PD-RLS and PD-NRLS) groups by RLS-rating scale (RLS-RS) score. Motor and non-motor symptoms were rated by related scales. Iron and related proteins, and neurotransmitters in cerebrospinal fluid (CSF) and serum were measured. PD-RLS frequency was 40.37%. PD-RLS group had longer duration, higher stage and scores of motor symptoms, depression, anxiety, sleep disorders, fatigue and apathy, and increased transferrin and decreased iron, ferritin, dopamine (DA) and 5-hydroxytryptamine (5-HT) in CSF. In CSF of PD-RLS group, RLS-RS score was positively correlated with transferrin level and negatively correlated with iron and ferritin levels; RLS-RS score was negatively correlated with DA and 5-HT levels; transferrin level was negatively correlated with DA and 5-HT levels, and ferritin level was positively correlated with DA level. In serum, PD-RLS group had decreased iron and transferrin levels, which were negatively correlated with RLS-RS score. PD-RLS was common and severer in motor and some non-motor symptoms. Iron deficiency induced by its metabolism dysfunctions in peripheral and central systems might cause PD-RLS through decreasing brain DA and 5-HT.

BIOLOGICAL FLUID MONOAMINE LEVELS TO EXPLORE THE NEUROCHEMICAL CONTINUUM BETWEEN FRONTOTEMPORAL DEMENTIA AND AMYOTROPHIC LATERAL SCLEROSIS

Behavioral variant frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) are early-onset debilitating diseases with genetic and clinicopathological commonalities, and are hypothesized to be part of a disease continuum alongside FTD-ALS. Although serotonergic and dopaminergic disturbances were recently identified in brain and spinal cord of ALS patients, information about neurochemical status of these disorders in body fluids remains scarce. Furthermore, few studies have compared neurochemical parameters directly between FTD and ALS. No FDA-approved disease-modifying drug therapies are available for FTD, nor ALS, with the sole exception of riluzole. An unmet medical need thus exists for both conditions, necessitating the identification of new pharmacological targets or the establishment of biomarkers for early disease detection. We retrospectively analyzed paired cerebrospinal fluid (CSF) – serum samples from 40 FTD, 26 ALS, 4 FTD-ALS and 40 age-matched control subjects using reversed-phase ultra-high-performance liquid chromatography with electrochemical detection. Levels of serotonergic, dopaminergic and (nor) adrenergic compounds were measured for all samples. Statistically significant differences in monoamine concentrations were predominantly present between FTD and age-matched control subjects, with significantly increased CSF (P<0.001) and serum (P<0.001) dopamine (DA) concentrations in FTD subjects. In contrast, levels of 3,4-dihydroxyphenylacetic acid (DOPAC) (P=0.008 for CSF; P=0.003 for serum) and DOPAC/DA ratios (P<0.001 for CSF; P<0.001 for serum), indicative for dopaminergic turnover, were lowered in latter patients. A similar pattern was observed between the ALS and age-matched control group, despite insignificant differences for DOPAC/DA ratios and DOPAC levels in CSF and serum, respectively. Concerning the (nor)adrenergic system, a significant increase in CSF MHPG concentrations was identified in FTD compared to age-matched control subjects (P=0.006). No dissimilarities could be detected in any of the monoaminergic compounds between FTD and ALS patients. Given the dopaminergic differences in CSF and serum samples in the age-matched control group compared to FTD and ALS groups, we hypothesize that both may be characterized by a dopaminergic disturbance. Furthermore, since no monoaminergic differences could be identified between patients, such neurodegenerative disorders do not only seem to belong to a genetic and clinicopathological continuum, but are likely to share a similar neurochemical pathophysiology as well.

Homovanillic acid in CSF of mild stage Parkinson's disease patients correlates with motor impairment

In Parkinson's disease (PD), several efforts have been spent in order to find biochemical parameters able to identify the progression of the pathological processes at the basis of the disease. It is already known that advanced PD patients manifesting dyskinesia are featured by the high homovanillic acid (HVA)/dopamine (DA) ratio, suggesting the increased turnover of DA in these patients. Less clear is whether similar changes affect mild and moderate stages of the disease (between 1 and 2.5 of Hoehn & Yahr –H&Y- stage). Hence, here we tested whether cerebrospinal fluid (CSF) concentrations of DA and its major metabolites, either 3,4-dihydroxyphenylacetic acid (DOPAC) or HVA, correlate with motor performance in mild and moderate PD patients. CSF samples were collected after 2 days of anti-PD drugs washout, via lumbar puncture (LP) performed 130 min following administration of oral levodopa (LD) dose (200 mg). LP timing was determined in light of our previous tests clarifying that 2 h after oral LD administration CSF DA concentration reaches a plateau, which was un-respective of PD stage or duration. DA, DOPAC and HVA were assayed by high performance liquid chromatography in a group of 19 patients, distributed in two groups on the basis of the H&Y stage with a cut-off of 1.5. In these PD patients, HVA was correlated with DOPAC (R = 0,56, p < 0,01) and both HVA and DOPAC CSF levels increased in parallel with the motor impairment. More importantly, HVA correlated with motor impairment measured by the Unified Parkinson's Disease Score –III (UPDRS) (R = 0.61; p < 0.0001).The present findings showed the early alteration of the DA pre-synaptic machinery, as documented by the progressive increase of CSF HVA concentrations, which also correlated with PD motor impairment. Therefore, we suggest the potential use of measuring the CSF HVA level as a possible biomarker of PD stage changes in order to monitor the effectiveness of PD-modifying pharmacological therapies.

Association between cerebrospinal fluid dopamine concentrations and catechol-O-methyltransferase gene polymorphisms in forensic autopsy cases of methamphetamine abusers

Methamphetamine (MA) is an illicit psychostimulant that stimulates the release of catecholamines from sympathetic nerve terminals and is widely abused worldwide. Since catechol-O-methyltransferase (COMT) metabolizes catecholamines and mediates adrenergic, noradrenergic, and dopaminergic signaling responses, we investigated the effects of the COMT polymorphisms rs4633 and rs4680 on cerebrospinal fluid (CSF) catecholamine concentrations in autopsies of subjects who died of drug intoxication. 28 MA abusers and 22 fatal psychotropic drug intoxication cases were evaluated. No correlations were identified between rs4633 or rs4680 polymorphisms and CSF concentrations of adrenaline (Adr), noradrenaline (Nad), or dopamine (DA) in fatal psychotropic cases. However, among MA abusers, DA concentrations in the CSF were significantly higher in those with the T allele (CT and TT) of rs4633 than in CC genotype carriers (p=0.004). Moreover, among MA abusers, DA concentrations were significantly higher in those with the A allele (GA and AA) of rs4680 than in GG genotype carriers (p=0.017). In subsequent haplotype analyses of MA abusers, a strong correlation was identified between two COMT haplotypes and CSF DA concentrations (p=0.002). However, the CSF concentrations of Adr and Nad were not associated with COMT genotypes or haplotypes. The present results indicate that rs4633 and rs4680 polymorphisms influence CSF DA concentrations and MA toxicity in MA abusers.