NEUROTRANSMITTER MEASURES IN THE CEREBROSPINAL FLUID OF PATIENTS WITH ALZHEIMER\u27S DISEASE: A REVIEW

Background: Alzheimer\u27s disease (AD) is a severe neurodegenerative disorder characterized by progressive cognitive and functional decline, as well as by a variety of neuropsychiatric and psychological symptoms and behavioral dysfunctions. Various studies proposed the role of different neurotransmitter systems not only in AD-related cognitive, but also psychotic symptoms and behavioral and emotional deficits. Due to the close proximity, pathological neurochemical changes in brain occurring in AD are likely to be reflected in the cerebrospinal fluid (CSF). The purpose of this review is to provide a summary of the CSF neurotransmitter correlates of AD in order to get further insights into the potential role of altered neurotransmitters in the pathophysiology of AD and to offer novel AD biomarkers. Methods: PubMed and MEDLINE data bases were searched for English-language articles by using "Alzheimer\u27s disease", "CSF" and "neurotransmitter" as primary terms. No time or article type constraints were applied. Moreover, the lists of references were searched manually for additional articles. Results: Changes in various correlates of cholinergic, monoaminergic and amino acid neurotransmitter systems, as well as neuropeptides, have been observed in CSF of AD patients. However, as the results of these studies have been controversial, the importance of CSF neurotransmitter parameters as potential biomarkers in AD remains quite unclear. The observed discrepancies could be bypassed by implementation of new sensitive methods, such as novel proteomics approaches that include protein separation techniques, mass spectroscopy and targeted multiplex panels of specific analytes. Conclusion: Although no individual CSF neurotransmitter correlate was demonstrated as suitable biomarker of AD, a combined profile of several CSF neurochemical parameters might show enhanced sensitivity and specificity and thus contribute to earlier and more accurate diagnosis of AD, crucial for application of effective treatments

The role of serotonergic system at the interface of aggression and suicide

Alterations in serotonin (5-HT) neurochemistry have been implicated in the aetiology of all major neuropsychiatric disorders, ranging from schizophrenia to mood and anxiety-spectrum disorders. This review will focus on the mulifaceted implications of 5-HT-ergic dysfunctions in the pathophysiology of aggressive and suicidal behaviours. After a brief overview of the anatomical distribution of the 5-HT-ergic system in the key brain areas that govern aggression and suicidal behaviours, the implication of 5-HT markers (5-HT receptors, transporter as well as synthetic and metabolic enzymes) in these conditions is discussed. In this regard, particular emphasis is placed on the integration of pharmacological and genetic evidence from animal studies with the findings of human experimental and genetic association studies. Traditional views postulated an inverse relationship between 5-HT and aggression and suicidal behaviours; however, ample evidence has shown that this perspective may be overly simplistic, and that such pathological manifestations may reflect alterations in 5-HT homeostasis due to the interaction of genetic, environmental and gender-related factors, particularly during early critical developmental stages. The development of animal models that may capture the complexity of such interactions promises to afford a powerful tool to elucidate the pathophysiology of impulsive aggression and suicidability, and find new effective therapies for these conditions

REMISSION IS NOT ASSOCIATED WITH DRD2 RS1800497 AND DAT1 RS28363170 GENETIC VARIANTS IN MALE SCHIZOPHRENIC PATIENTS AFTER 6-MONTHS MONOTHERAPY WITH OLANZAPINE

Background: Symptomatic remission is an achievable goal in the treatment of schizophrenia. The type of antipsychotic medication and particular genetic variants of the dopaminergic system might be associated with remission. Potential pharmacogenetic markers of the treatment response to antipsychotic medication are missing. This study assessed the possible association between dopamine receptor type 2 (DRD2 rs1800497) and dopamine transporter (DAT1 rs28363170) gene variants with symptomatic remission in schizophrenia. Subjects and methods: Olanzapine (5-20 mg/d) monotherapy was administered for 6 months to 150 male Caucasian subjects with schizophrenia. Remission was evaluated according to "Remission in Schizophrenia Working Group" criteria. Genotyping was performed by PCR-RFLP. Results: Symptomatic remission was found in 31% of patients. DRD2 rs1800497 and DAT1 rs28363170 gene variants were not significantly associated with symptomatic remission. The limitations are a relatively small sample size of patients with schizophrenia (N=150), especially of group with symptomatic remission (N=45). However, the study had moderate but adequate sample sizes for most of the comparisons. Only two dopaminergic polymorphisms were analyzed, and plasma concentration of olanzapine was not determined. Conclusion: These results revealed a lack of association between DRD2 rs1800497 and DAT1 rs28363170 genetic variants and symptomatic remission in male patients treated with olanzapine, suggesting that these genetic variants could not be used to predict symptomatic remission to olanzapine monotherapy. Negative results should be further confirmed or rejected in the larger samples, including haplotype analyses, to detect clinically useful and easy obtainable pharmacogenetic markers that might predict therapeutic response or remission in schizophrenia

Association Study of a Functional Catechol-O-Methyltransferase Polymorphism and Cognitive Function in Patients with Dementia

A functional catechol-o-methyltransferase (COMT Val158/108Met) polymorphism, a valine (Val) to methionine (Met) substitution, has been associated with cognitive processing in the normal brain, older age, mild cognitive impairment and in various dementias. COMT is involved in the breakdown of dopamine and other catecholamines, especially in the frontal cortex; hence the carriers of Met allele, with the lower enzymatic activity, are expected to perform better on particular neuro-cognitive tests. The study included 46 patients with dementia and 65 healthy older subjects. The neurological status was assessed, using the Mini Mental Status Examination (MMSE), and the batery of different neurological tests. In DNA samples COMT polymorphism was genotyped. Patients with dementia exhibited significant genotype-induced differences in scores for MMSE, Visual Association Test (VAT) duration of numbers test, VAT time of response to numbers test, VAT average response to numbers test and WPLCR/PPLR unanswered. Carriers of Met/Met genotype had significantly lower scores of MMSE, significantly longer time to respond to VAT duration of numbers test, VAT time of response to numbers test and VAT average response to numbers test, and significantly greater number of unanswered questions to WPLCR/PPLR when compared to Met/Val or Val/Val genotypes. Our preliminary data showed significantly impaired performance in several neuro-cognitive tests in carriers of Met/Met genotype in patients with dementia compared to either Met/Val or Val/Val genotype carriers. Although Met/Met genotype with more dopamine available in the frontal cortex should be associated with better neuro-cognitive test results than Met/Val or Val/Val genotype, our data on patients with dementia did not confirm this hypothesis. Further study on larger sample of patients is needed to clarify the role of COMT polymorphism in cognitive functions

Monoaminergic and histaminergic strategies and treatments in brain diseases

The monoaminergic systems are the target of several drugs for the treatment of mood, motor and cognitive disorders as well as neurological conditions. In most cases, advances have occurred through serendipity, except for Parkinson's disease where the pathophysiology led almost immediately to the introduction of dopamine restoring agents. Extensive neuropharmacological studies first showed that the primary target of antipsychotics, antidepressants, and anxiolytic drugs were specific components of the monoaminergic systems. Later, some dramatic side effects associated with older medicines were shown to disappear with new chemical compounds targeting the origin of the therapeutic benefit more specifically. The increased knowledge regarding the function and interaction of the monoaminergic systems in the brain resulting from in vivo neurochemical and neurophysiological studies indicated new monoaminergic targets that could achieve the efficacy of the older medicines with fewer side-effects. Yet, this accumulated knowledge regarding monoamines did not produce valuable strategies for diseases where no monoaminergic drug has been shown to be effective. Here, we emphasize the new therapeutic and monoaminergic-based strategies for the treatment of psychiatric diseases. We will consider three main groups of diseases, based on the evidence of monoamines involvement (schizophrenia, depression, obesity), the identification of monoamines in the diseases processes (Parkinson's disease, addiction) and the prospect of the involvement of monoaminergic mechanisms (epilepsy, Alzheimer's disease, stroke). In most cases, the clinically available monoaminergic drugs induce widespread modifications of amine tone or excitability through neurobiological networks and exemplify the overlap between therapeutic approaches to psychiatric and neurological conditions. More recent developments that have resulted in improved drug specificity and responses will be discussed in this review.peer-reviewe

The lack of effect of ziprasidone on platelet serotonin concentration in schizophrenic patients

Rationale Ziprasidone is an atypical antipsychotic, with the unique multireceptor-binding profile. If affects multiple serotonergic (5-HT) receptors, inhibits 5-HT transporter (5-HTT) and inhibits synaptic 5-HT reuptake. These effects might be responsible for the antidepressant effect of ziprasidone. Objectives Since there is a lack of in vivo data on the effects of ziprasidone on 5-HT concentration in humans, the aim of the study was to investigate the effect of ziprasidone treatment on platelet 5-HT concentration in patients with schizophrenia or schizoaffective disorders. Methods In and open-label study, the effect of ziprasidone (average dose of 109 mg/day) on platelet 5-HT concentration (determined fluorimetrically) was evaluated at baseline and after 7 and 28 days of treatment in 21 male and female patients with schizophrenia or schizoaffective disorders. Results Ziprasidone treatment for 7 or 28 days did not significantly change baseline platelet 5-HT concentration in male and female schizophrenic patients. Platelet 5-HT concentration was not correlated with gender, age and smoking status of patients. Conclusions There was a lack of effect of ziprasidone treatment on platelet 5-HT concentration in male and female schizophrenic patients. Although the clinical effects of ziprasidone were evident after 28 days of treatment, and ziprasidone has the highest potency among atypical antipsychotics to block 5-HTT, our data did not confirm the hypothesis that ziprasidone treatment decreases platelet 5-HT concentration, at least not in the doses used in our study

Platelet serotonin in combat related posttraumatic stress disorder with psychotic symptoms

Background: Combat-related posttraumatic stress disorder (PTSD) is severe form of PTSD, frequently associated with psychotic symptoms. Platelet serotonin (5-hydroxytryptamine, 5-HT) was used as a peripheral 5-HT marker to identify particular symptoms in PTSD. ----- Methods: Platelet 5-HT was determined fluorimetrically in 67 war veterans with combat related PTSD. 36 combat exposed veterans who did not develop PTSD, 35 veterans with PTSD complicated with psychotic features. PTSD diagnosis of current and chronic PTSD, and clinical symptoms of PTSD and psychoses were assessed according to DSM-IV criteria, using the Clinician Administrated PTSD Scale, and Positive and Negative Syndrome Scale (PANSS). ----- Results: Platelet 5-HT concentration was significantly higher in veterans with psychotic PTSD than in veterans with non-psychotic PTSD, veterans without PTSD, or in control subjects. Platelet 5-HT was significantly positively correlated with the positive symptoms in PANSS subscale, and with the symptoms of delusions within PANSS positive subscale. ----- Limitations: The results were obtained on peripheral 5-HT marker, i.e. platelet 5-HT concentration. ----- Conclusions: Since the delusions are the core psychotic symptoms occurring in our psychotic PTSD patients, the result of the increased platelet 5-HT concentration, associated with delusions, indicate that platelet 5-HT might be used as a trait marker of psychotic symptoms in PTSD, but not as a state marker for PTSD. reserved

Platelet serotonin concentration and monoamine oxidase type B activity in female patients in early, middle and late phase of Alzheimer’s disease

Alzheimer’s disease (AD) is a progressive, neurodegenerative disorder with unclear etiology. Cognitive impairment in AD might be associated with altered serotonergic system. The aim of the study was to determine platelet serotonin (5-HT) concentrations and platelet monoamine oxidase type B (MAO-B) activity in patients with different severity of AD. Platelet 5-HT concentrations and MAO-B activity were determined spectrofluorimetrically in 74 female patients with AD (NINCDS-ADRDA, DSM-IV-TR criteria), subdivided according to the Mini Mental State Examination (MMSE) scores in three groups with a) 23 patients in early (MMSE scores 19-24), b) 23 patients in middle (MMSE 10-18), and c) 28 patients in late (MMSE 0-9) phase of AD, and in 49 age-matched healthy women. Platelet 5-HT concentrations and MAO-B activity were similar between all patients with AD and healthy subjects, but were significantly lower in patients in the late phase of AD than in other phases of AD, and in healthy controls. The significant correlations were found between MMSE scores and platelet 5-HT concentrations, MAO-B activity and age. Lower platelet 5-HT concentration and MAO-B activity in the late phase of AD suggested that these markers might indicate severity and/or clinical progress of AD

Platelet serotonin and serum lipids in psychotic mania

BACKGROUND: The role of serotonergic system and lipid status in the etiology of mania and its subtypes is not clear. The aims of the study were to determine platelet serotonin (5-HT) concentration, platelet monoamine oxidase (MAO) activity, and serum total cholesterol, high-density lipoprotein cholesterol (HDL), low-density lipoprotein cholesterol (LDL) and triglycerides (TG) in patients with psychotic and nonpsychotic subtypes of mania and in healthy control subjects. - - - - - METHODS: The serum lipids, platelet 5-HT and MAO were determined in 40 (17 psychotic, 23 nonpsychotic) drug free male inpatients with type I bipolar affective disorder, current episode mania (DSM-IV criteria), and in 32 healthy male subjects. - - - - - RESULTS: Platelet 5-HT levels in manic patients were similar to the values in healthy controls. Serum cholesterol and LDL values were significantly lower in manic patients than in healthy controls. Patients with psychotic features had increased platelet 5-HT concentrations and decreased levels of cholesterol and LDL as compared to the nonpsychotic manic patients and healthy controls. There was no significant difference in age, body mass index, platelet MAO activity, serum levels of TG and HDL between psychotic and nonpsychotic manic patients and healthy subjects. - - - - - LIMITATION: Data on physical activity, dietary habits and alcohol consumption before hospitalization were not collected. - - - - - CONCLUSION: The results of the present study suggest that biological differences between subtypes of mania might depend upon the presence of the psychotic symptoms. Our data confirm our previous results showing the increased platelet 5-HT concentration in psychotic disorders across the different diagnoses