CSF Levels Of Homovanillic Acid Research Articles

Long-term neurological and psychiatric outcomes in patients with aromatic l-amino acid decarboxylase deficiency

Introductionl-amino acid decarboxylase deficiency (AADCD) is an ultrarare autosomal recessive defect of biogenic amine synthesis that presents with early-onset encephalopathy progressing to severe neurological impairment and intellectual disability. We aimed to explore neurocognitive and behavioral profiles associated with AADCD and possible factors predicting outcome in more detail. MethodsNine AADCD patients (23.2 ± 10.3 years; range 8–40) underwent systematic clinical and neuropsychological assessment. Diagnostic levels of CSF 5-hydroxyindolacetic acid (5-HIAA) and homovanillic acid (HVA), and DDC genotype (as ascertained by American College of Medical Genetics and Genomics grading) were included in the data analysis. ResultsAll AADCD patients were affected by intellectual disability and psychiatric disorders. Movement disorders included parkinsonism-dystonia, dysarthria, and oculogyric crises. CSF 5-HIAA and HVA levels at diagnosis had a significant influence on adaptive behavior and executive function performance. Patients homozygous for DDC pathogenetic variants showed lower CSF 5-HIAA and HVA levels and higher Unified Parkinson's Disease Rating Scale scores. The disease showed a self-limiting clinical course with partial improvement under pharmacological treatment (B6 and dopamine mimetic drugs). ConclusionsPatients with AADCD suffer from neuropsychological and psychopathological impairment, which may be improved but not reversed under the present therapeutic approach. However, cognitive functioning should be specifically examined in order to avoid its underestimation on the basis of movement disorder severity. Genotype and biogenic amine level at diagnosis have an important prognostic value.

Genetic influences on response to novel objects and dimensions of personality in Papio baboons.

Behavioral variation within and between populations and species of the genus Papio has been studied extensively, but little is known about the genetic causes of individual- or population-level differences. This study investigates the influence of genetic variation on personality (sometimes referred to as temperament) in baboons and identifies a candidate gene partially responsible for the variation in that phenotype. To accomplish these goals, we examined individual variation in response to both novel objects and an apparent novel social partner (using a mirror test) among pedigreed baboons (n = 578) from the Southwest National Primate Research Center. We investigated the frequency and duration of individual behaviors in response to novel objects and used multivariate factor analysis to identify trait-like dimensions of personality. Exploratory factor analysis identified two distinct dimensions of personality within this population. Factor 1 accounts for 46.8 % of the variance within the behavioral matrix, and consists primarily of behaviors related to the "boldness" of the subject. Factor 2 accounts for 18.8 % of the variation, and contains several "anxiety" like behaviors. Several specific behaviors, and the two personality factors, were significantly heritable, with the factors showing higher heritability than most individual behaviors. Subsequent analyses show that the behavioral reactions observed in the test protocol are associated with animals' social behavior observed later in their home social groups. Finally we used linkage analysis to map quantitative trait loci for the measured phenotypes. Single nucleotide polymorphisms in a positional candidate gene (SNAP25) are associated with variation in one of the personality factors, and CSF levels of homovanillic acid and 3-methoxy-4-hydroxyphenylglycol. This study documents heritable variation in personality among baboons and suggests that sequence variation in SNAP25 may influence differences in behavior and neurochemistry in these nonhuman primates.

Levels of HVA, 5-HIAA, and MHPG in the CSF of vascular parkinsonism compared to Parkinson’s disease and controls

The neurochemical abnormalities underlying vascular parkinsonism (VP) have not been well characterised. A better understanding may help to optimize pharmacological interventions. Since VP patients generally have a poorer response to l-Dopa than Parkinson's disease (PD) patients, we investigated whether levels of relevant CSF neurotransmitter metabolites may be differentially altered in VP and PD and assessed the potential of neurotransmitter metabolites as biomarkers. We compared CSF levels of homovanillic acid (HVA), 5-hydroxyindolacetic acid, and 3-methoxy-4-hydroxyphenylethyleneglycol, in 16 VP patients, 57 PD patients and 60 non-neurological controls. We found that levels of HVA were reduced in PD compared with both VP and controls but did not differ significantly between VP and controls indicating that dopamine deficiency was less pronounced in VP.

P3-078: Prominent reduction in cerebrospinal fluid homovanillic acid and 5-hydroxyindole acetic acid levels in dementia with Lewy bodies

One of the most distinct pathologic features in the brains of dementia with Lewy bodies (DLB) patients is the prominent loss of nigrostriatal dopaminergic neurons similar to that in the brains of Parkinson's disease (PD) patients. CSF levels of homovanillic acid (HVA) and 5-hydroxyindole acetic acid (5-HIAA) are decreased in PD patients. In the present study, we measured the CSF levels of HVA and 5-HIAA in DLB patients and compared with those of Alzheimer's disease (AD) patients. Seventy-six patients with PD (73.9 ± 6.8 years, mean±SD), 22 patients with DLB (76.0 ± 6.5 years, including 6 pathologically confirmed cases), 215 patients with AD (76.9 ± 7.3 years) and 38 normal control subjects (76.8 ± 6.5 years) were examined. After informed consent was obtained, CSF samples were collected from the patients by lumbar puncture. CSF levels of HVA and 5-HIAA were measured by HPLC system equipped with 16 electrochemical sensors (CEAS Model 5500, ESA, Bedford, MA, USA). CSF HVA levels were 15.8 ± 8.1 ng/ml (mean±SD) in the PD group, 8.0 ± 5.2 ng/ml in the DLB group, 22.1±13.3 ng/ml in the AD group and 35.2 ± 15.0 ng/ml in the control group. CSF 5-HIAA levels were 12.5 ± 7.2 ng/ml (mean±SD) in the PD group, 8.1 ± 7.9 ng/ml in the DLB group, 17.6±11.5 ng/ml in the AD group and 30.6 ± 13.9 ng/ml in the control group. CSF levels of HVA and 5HIAA were lower in the DLB, PD and AD groups than those in the control group (p<0.001, ANOVA). CSF levels of HVA and 5HIAA in the DLB and PD groups were much lower than those in the AD group (DLB: p<0.01, PD: p<0.05, ANOVA). We demonstrated a prominent reduction in CSF HVA and 5-HIAA levels in DLB patients. The analysis of CSF HVA and 5HIAA levels may be useful in distinguishing DLB patients from AD patients.

A case of 6-pyruvoyl-tetrahydropterin synthase deficiency demonstrates a more significant correlation of l-Dopa dosage with serum prolactin levels than CSF homovanillic acid levels

6-Pyruvoyl-tetrahydropterin synthase (PTPS) deficiency is a tetrahydrobiopterin (BH4) deficiency that presents as hyperphenylalaninemia. Administration of the neurotransmitter precursors l-Dopa/carbidopa and 5-hydroxytryptophan (5HTP), as well as BH4, is necessary for treatment. It has been reported that serum prolactin levels are elevated in patients with PTPS deficiency indicating that inhibition of prolactin secretion by dopamine is insufficient and is negatively correlated with the CSF level of HVA. Here, we present a case of PTPS deficiency which showed a more significant correlation of dosage of l-Dopa/carbidopa with serum prolactin levels than with CSF HVA levels. Combined treatment of BH4, l-Dopa/carbidopa, and 5HTP was started as the CSF neopterin/biopterin ratio (N/B ratio 7.54, control 0.46–1.59) and serum prolactin level (36.79 ng/ml, control <15) were elevated. The dosage of l-Dopa/carbidopa was adjusted in the range of 9.08–10.5 mg/kg/day. The CSF level of HVA stayed within normal limits using these dosages of l-Dopa/carbidopa, and there was no correlation between dose given and HVA level ( R = 0.230, p = 0.71). On the other hand, even in this relatively small dosing range, the serum prolactin level showed significant negative correlation with the dosage of l-Dopa/carbidopa ( R = 0.645, p = 0.023). The patient did not show any neurological symptoms even when the serum prolactin level was elevated. From these results, we suggest that the serum prolactin level may be a more sensitive marker than the CSF HVA level to guide the dose adjustment of l-Dopa/carbidopa in the management of patients with PTPS deficiency.

Transcription factor AP-2beta genotype, striatal dopamine D2 receptor density and cerebrospinal fluid monoamine metabolite concentrations in humans.

Transcription factor AP-2beta has been suggested to influence brain monoaminergic systems by regulating target genes. In order to explore a possible functional role, AP-2beta genotype was analysed in relation to striatal dopamine D2 receptor density determined in vivo by positron emission tomography in human subjects (n = 52). The AP-2beta genotype was also analysed in relation to cerebrospinal fluid (CSF) concentrations of homovanillic acid (HVA), 3-methoxy-4-hydroxy-phenylglycol (MHPG) and 5-hydroxyindoleacetic acid (5-HIAA) in healthy human subjects (n = 90). There was no association between the AP-2beta genotype and measures of dopamine receptor density, or CSF 5-HIAA concentrations. However, AP-2beta genotype was associated with CSF-levels of HVA (in women) and MHPG. These data may suggest a functional involvement of AP-2beta in the dopaminergic system, but should be interpreted with caution until replicated.

A review of biochemical and molecular genetic aspects of tyrosine hydroxylase deficiency including a novel mutation (291delC).

An overview is given of the current knowledge on the human tyrosine hydroxylase gene and on the biochemical aspects of diagnosing defects in this gene. Diagnostic biochemical findings are described in four cases of genetically confirmed tyrosine hydroxylase deficiency. Decreased CSF levels of homovanillic acid (HVA) and 3-methoxy-4-hydroxyphenylethyleneglycol (MHPG), together with normal pterin and CSF tyrosine and 5-hydroxyindoleacetic acid (5-HIAA) concentrations are the diagnostic hallmarks of tyrosine hydroxylase deficiency. At the metabolite level the diagnosis can only be made reliably in CSF. Strict adherence to a standardized lumbar puncture protocol and adequate reference values are essential for diagnosis of this 'new' treatable neurometabolic disorder. Measurements of HVA, vanillylmandelic acid (VMA) or catecholamines in urine are not relevant for diagnosing tyrosine hydroxylase deficiency. The diagnosis should be considered in all children with unexplained hypokinesia and other extrapyramidal symptoms. Three of our patients are homozygous for a mutation in exon 6 (698G > A) of the tyrosine hydroxylase gene and one patient was compound heterozygous for the same mutation and a novel truncating mutation in exon 3 (291delC).

Susceptibility to neuroleptic malignant syndrome in Parkinson's disease.

To determine susceptibility to neuroleptic malignant syndrome (NMS) in patients with PD in relation to central monoamine metabolism. CSF levels of homovanillic acid (HVA), 3-methoxy-4-hydroxy phenyletilene glycol (MHPG), and 5-hydroxyindole acetic acid (5-HIAA) were assayed in 98 PD patients (mean age, 77.2 years), including 11 patients with a prior NMS-like episode, by high-performance liquid chromatography with electrochemical detection. Patients with a previous NMS-like episode had worse parkinsonian disability as measured by Hoehn & Yahr scale (3.7 +/- 0.8 versus 3.0 +/- 1.1; p = 0.038) and lower CSF HVA levels (20.9 +/- 17.3 versus 44.7 +/- 22.2 ng/mL; p = 0.001) compared to those without, despite similar age, disease duration, and daily dosages of antiparkinsonian drugs between groups. Logistic regression analysis showed that the CSF HVA level (p = 0.008), but not 5-HIAA level (p = 0.621), was significantly and independently related to NMS, and that the MHPG level (p = 0.070) was tendentially associated with the disorder. Odds ratios (95% confidence intervals) corresponding to 10 ng/mL increment in CSF HVA, MHPG, and 5-HIAA levels were 0.30 (0.13 to 0.73), 4.03 (0.89 to 18.2) and 1.29 (0.47 to 3.58), respectively. Central dopaminergic and possible noradrenergic activity contributes to NMS development in an elderly population of PD patients. Measuring CSF levels of monoamine metabolites may provide a means for identifying NMS susceptibility in PD patients.

Decreased CSF levels of homovanillic acid in ALS patients

Levels of homovanillic acid (MVA) were measured in lumbar cerebrospinal fluid from 24 patients affected by amyotrophic lateral sclerosis (ALS) and compared with those found in 11 patients with Parkinson's disease (PD) and 10 patients with lumbar disc herniations who served as controls. Mean HVA levels were significantly decreased in ALS and PD patients. These findings are consistent with impairment of central dopaminergic systems in ALS as well as suggesting degeneration of neuroanatomical structures other than motor neurons.

Rapid-onset dystonia-parkinsonism.

We studied a large family with a previously undescribed, autosomal dominant dystonia-parkinsonism syndrome. We chose to call the disorder "rapid-onset dystonia-parkinsonism" (RDP) based on the unusually rapid evolution of signs and symptoms. Affected individuals developed dystonia and parkinsonism between 14 and 45 years of age. The onset was acute in six individuals with the abrupt onset of symptoms over the course of several hours, and subacute in four others who had evolution over several days or weeks. Thereafter, progression of symptoms was usually very slow. Two had intermittent focal dystonia without parkinsonism, and one obligate gene carrier was asymptomatic at 68 years. CSF levels of homovanillic acid were decreased in the two individuals tested, but dopaminergic therapy provided only slight benefit. The DYT1 gene responsible for early-onset, generalized idiopathic torsion dystonia in Jewish and some non-Jewish families has been mapped to chromosome 9q34. Linkage analysis with three markers near the DYT1 gene showed several obligate recombinations, excluding DYT1 as a candidate gene for RDP. We believe RDP is unique and should be classified separately from other forms of hereditary dystonia-parkinsonism.

The dopamine-serotonin relationship in clozapine response

The effects of clozapine on the dopamine and serotonin systems may underlie its atypical pharmacologic and clinical profile. To examine this hypothesis, we measured dopamine and serotonin plasma and cerebrospinal (CSF) metabolites and the relationship of these values to treatment response in 19 neuroleptic refractory and intolerant schizophrenic patients. Only a small change in the CSF and plasma homovanillic acid (HVA) and 5-hydroxyindoleacetic acid (5HIAA) levels was found. However, the pretreatment CSF HVA/5HIAA ratio and, to a lesser extent, the CSF HVA level predicted treatment response. These results suggest that the modest relationship between HVA and 5-HIAA and treatment response supports the involvement of both neurotransmitters in the pathophysiology of schizophrenia.

Increased cerebrospinal fluid dopamine and 3,4-dihydroxyphenylacetic acid levels in Huntington's disease: evidence for an overactive dopaminergic brain transmission.

Levels of dopamine (DA), 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), noradrenaline (NA), 3-methoxy-4-hydroxyphenylglycol (MHPG), and 5-hydroxyindoleacetic acid (5-HIAA) in the CSF of patients with Huntington's disease (HD) were measured by HPLC. CSF DA, DOPAC, and MHPG levels were found to be increased in HD patients. Levels of HVA, 5-HIAA, and NA in the CSF of HD patients did not differ from those of controls. Changes in CSF DA and DOPAC levels were consistent with previous findings of increased DA tissue content in some brain areas of patients with HD. These results suggest that CSF DOPAC levels could be a more reliable index of overactive dopaminergic brain systems in HD than CSF HVA levels.

Relationship between Growth Hormone Responses to Apomorphine and CSF Homovanillic Acid Levels in Dementia of the Alzheimer Type

The possible relationship between growth hormone (GH) responses to the dopamine (DA) agonist apomorphine (APO; 0.24 mg i.v.) and CSF concentrations of the monoamine metabolites was investigated in 15 patients with dementia of the Alzheimer type (DAT). A significant negative correlation was found between the CSF concentrations of homovanillic acid (HVA) and the maximum APO-stimulated serum GH levels. Assuming that CSF HVA reflects central DA release and the GH response to APO reflects postsynaptic DA D&lt;sub&gt;2&lt;/sub&gt; receptor function, this finding suggests that low DA release is associated with upregulation of DA D&lt;sub&gt;2&lt;/sub&gt; in DAT.

Cerebrospinal fluid catecholamine metabolites in HIV‐infected patients

Twenty-eight HIV-seropositive individuals--11 asymptomatic cases, 8 with lymphadenopathy syndrome (LAS), and 9 with AIDS--were investigated. Clinical staging of the AIDS dementia complex was done in the 9 AIDS patients. The catecholamine metabolites 3-methoxy-4-hydroxyphenylglycol (MHPG) and homovanillic acid (HVA) in CSF were determined in all the HIV patients and in 20 healthy volunteers. The CSF MHPG levels did not differ significantly between healthy subjects and HIV-infected patients at any stage of the infection. The CSF concentrations of HVA differed between the groups only during the AIDS stage. The mean CSF HVA value in the AIDS patients was 42% lower than in the healthy subjects and significantly lower than in any other stage of HIV infection (P less than .01). Patients with signs of the AIDS dementia complex had reduced CSF HVA levels, but there was no clear relationship between HVA concentration and stage of the AIDS dementia complex.

Cerebrospinal Fluid and Plasma Monoamine Metabolites and Their Relation to Psychosis

The relationship between central (cerebrospinal fluid [CSF]) and peripheral (plasma) monoaminergic metabolites and psychotic symptoms was examined in 22 drug-free schizophrenic inpatients. The CSF homovanillic acid levels did not differ significantly between patients and normal controls (n = 33). The CSF homovanillic acid levels, however, were negatively correlated with ratings of psychosis and positive symptoms, and the CSF homovanillic acid and 5-hydroxyindoleacetic acid levels correlated negatively with individual deficit symptoms. Stepwise and hierarchical multiple-regression analysis revealed that among monoaminergic measures, only the CSF and plasma homovanillic acid levels contributed significantly to the total Brief Psychiatric Rating Scale and positive symptom variance with negative and positive partial correlations, respectively. Levels of CSF 3-methoxy-4-hydroxyphenylglycol, but not of CSF norepinephrine, were significantly elevated in the schizophrenic patients compared with controls, and plasma 3-methoxy-4-hydroxyphenylglycol levels were positively correlated with negative symptoms. We discuss the potential implications of these findings for a model of dopaminergic dysfunction in schizophrenia involving distinct cortical and subcortical contributions.

Low lumbar CSF levels of homovanillic acid and 5-hydroxyindoleacetic acid in multiple system atrophy with autonomic failure.

Low lumbar CSF concentrations of homovanillic acid (HVA) and 5-hydroxyindoleacetic acid (5-HIAA) in patients with multiple system atrophy attended by autonomic failure (MSA) reflect decreased activity in central dopaminergic and serotonergic pathways. These neurochemical changes are consistent with the neuropathological involvement in MSA and distinguish such patients from those with pure autonomic failure who have normal CSF metabolite levels.

The significance of homovanillic acid and 3,4-dihydroxyphenylacetic acid concentrations in human lumbar cerebrospinal fluid.

The concentrations of the acidic dopamine (DA) catabolites homovanillic acid (HVA) and 3,4-dihydroxyphenylacetic acid (DOPAC) measured in human CSF are supposed to reflect the "turnover" of DA in the brain. The notion of "turnover" is, however, not synonymous with impulse nerve activity in the dopaminergic systems. Significant amounts of DOPAC and HVA could, indeed, be demonstrated in brain structures wherein dopaminergic innervation has not been documented. It must also be noted that DA is not only a neurotransmitter itself, but also a precursor of norepinephrine and epinephrine. Furthermore, in lumbar CSF, levels of biogenic amine catabolites partially reflect metabolism in the spinal cord and may have limited relevance to neurotransmission in the brain. To elucidate these points further, we determined the concentrations of DOPAC and HVA in 22 areas of six human brains and eight levels of six human spinal cords. The data were correlated with the concentration of DA. Quantitative determinations were done using HPLC with electrochemical detection, after solvent and ion-pair extraction. In this study, significant amounts of both DOPAC and HVA were demonstrated in brain structures not previously associated with dopaminergic innervation. The relatively lower DA concentration in these structures suggests that in these regions, the DOPAC and HVA concentrations are unrelated to dopaminergic neurotransmission. The possible role of capillary walls and glial cells in the catabolism of DA must be further evaluated. The demonstration of DOPAC and HVA in the spinal cord is another argument against the hypothesis that CSF levels of HVA and DOPAC reflect closely the activity of the dopaminergic systems in the brain.

Enhancement of Brain Dopamine Metabolism by Tyrosine During Immobilisation: An In Vivo Study Using Repeated Cerebrospinal Fluid Sampling in Conscious Rats

Central dopamine (DA) and 5-hydroxytryptamine (5-HT) metabolism was monitored in conscious, freely moving rats by determination of levels of the DA metabolites 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) and the 5-HT metabolite 5-hydroxyindoleacetic acid (5-HIAA) in CSF samples withdrawn repeatedly from the cisterna magna and treated with acid to hydrolyse DOPAC and HVA conjugates. The effect of tyrosine on DA metabolism was investigated. Time courses of metabolite concentrations in individual rats in a quiet room showed that tyrosine (20, 50, or 200 mg/kg i.p.) was without significant effect; brain changes were essentially in agreement. However, the increases of CSF DOPAC and HVA levels that occurred on immobilisation for 2 h were further enhanced by tyrosine (200 mg/kg). The associated increases of 5-HIAA level were unaffected. The corresponding increases of DA metabolite concentrations in the brains of immobilised rats given tyrosine were less marked than the CSF changes and only reached significance for "rest of brain" DOPAC. The CSF studies revealed large interindividual variation in the magnitude and duration of the effects of immobilisation on transmitter amine metabolism. These results may help toward the elucidation of possible relationships between the neurochemical and behavioural effects of stress.

Reduced CSF concentrations of homovanillic acid and homovanillic acid to 5-hydroxyindoleacetic acid ratios in depressed patients: relationship to suicidal behavior and dexamethasone nonsuppression

Depressed patients who had attempted suicide (N = 19) had significantly lower CSF homovanillic acid (HVA) levels than patients who had not attempted suicide (N = 8) and control subjects (N = 41). Intergroup levels of 5-hydroxyindoleacetic acid (5-HIAA) were not significantly different. The ratio of CSF HVA to CSF 5-HIAA was significantly lower in both patient groups than in control subjects, and patients who had attempted suicide had CSF HVA/5-HIAA ratios that were nearly 50% those of the control subjects. The combinations of nonsuppression on the dexamethasone suppression test and either a low CSF HVA level or a low CSF HVA/5-HIAA ratio were significantly more common among patients who had attempted suicide than among those who had not.

Correlates of lateral ventricular size in chronic schizophrenia, II: biological measures

CSF homovanillic acid levels showed a significant negative correlation with ventricle-brain ratios (VBRs) in a group of drug-free chronic schizophrenic male veterans, while CSF 5-hydroxyindoleacetic acid levels showed a similar, nearly significant trend. The response of plasma human growth hormone to 0.75 mg of apomorphine also demonstrated a significant negative correlation with VBR in this group, but other measures of central neurotransmitter activity were unrelated to ventricular size.