Cerebrospinal Fluid Homovanillic Acid Research Articles

Physiological predictors of reproductive outcome and mother-infant behaviors in captive rhesus macaque females (Macaca mulatta).

Previous research has shown that offspring of females with low cerebrospinal fluid (CSF) 5-hydroxyindoleacetic acid (5-HIAA) concentrations are less likely to survive the first year of life than are offspring of females with high CSF 5-HIAA concentrations. In addition, studies of free-ranging rhesus macaque males have suggested that individuals with low CSF 5-HIAA concentrations suffer reduced reproductive success relative to their high serotonin counterparts. We examined CSF concentrations of the monoamine metabolites 5-HIAA and homovanillic acid (HVA), and plasma cortisol concentrations as predictors of first-time adult reproductive potential, maternal behavior, and overall social interactions in two groups of captive female rhesus macaques and their first offspring. Repeated CSF and blood samples were obtained from adult females in two social groups, and focal observations were performed for both new mothers and infants during the first month following parturition. We found that the reproductively aged nulliparous females who failed to give birth to their first offspring showed significantly lower CSF 5-HIAA concentrations than those females who gave birth. Among those females that gave birth to offspring, females with low CSF 5-HIAA concentrations and females with high plasma cortisol concentrations were overly protective and restrictive with their infants. CSF HVA concentration was not associated with reproductive output, social behavior, aggression, or mother-infant interactions in this sample of rhesus macaque females. We conclude that low CNS serotonin activity and high stress, measured by high plasma cortisol, are correlated with reduced reproductive success and patterns of high maternal restrictiveness in young adult female rhesus macaques.

Self-rated childhood emotional neglect and CSF monoamine indices in abstinent cocaine-abusing adults: possible implications for suicidal behavior

Non-human primate studies suggest that early environmental influences may have an enduring effect on central serotonin function. Therefore, it was decided to examine in humans whether childhood trauma might be related to cerebrospinal fluid (CSF) concentrations of the serotonin metabolite 5-hydroxyindoleacetic acid (5-HIAA) as an adult. A total of 29 withdrawn cocaine-dependent patients completed the Childhood Trauma Questionnaire. They also had a lumbar puncture for determination of CSF concentrations of 5-HIAA. CSF concentrations of the dopamine metabolite homovanillic acid (HVA) were also determined. Childhood emotional neglect scores showed significant negative correlations with CSF levels of 5-HIAA and HVA, and patients with emotional neglect scores above the median had significantly lower CSF 5-HIAA and HVA levels than patients with emotional neglect scores at or below the median. These findings suggest the possibility that childhood trauma may have an effect on central monoamine function as an adult.

In-use stability of monoamine metabolites in human cerebrospinal fluid

Cerebrospinal fluid (CSF) concentrations of the monoamine metabolites homovanillic acid (HVA) and 5-hydroxyindolacetic acid (5-HIAA) are commonly used to provide information about central nervous system (CNS) dopaminergic and serotonergic activity. However, little attention has been given to the effects of sample handling on the concentrations of these compounds in human CSF. Using high-performance liquid chromatography (HPLC) with electrochemical detection, we observed that, in CSF stored at −80°C, concentrations of the serotonin metabolite 5-HIAA and the dopamine metabolite HVA remained unchanged through six 1-h and six 24-h freeze–thaw cycles. Exposure to bright room light (3 h, 1230 lux) resulted in a 5-HIAA concentration that was 96.3±2.0% of the initial and an HVA concentration that was 98.8±1.03% of initial. The pH of the CSF significantly increased during both freeze–thaw series and while maintained on ice (4°C). These results demonstrate the in-use stability of 5-HIAA and HVA in human CSF under commonly-encountered laboratory conditions.

Biogenic amine metabolites and thiamine in cerebrospinal fluid in heredo-degenerative ataxias.

The aims of the present study were: i) to measure levels of the dopamine metabolite homovanillic acid (HVA), the serotonin metabolite 5-hydroxindoleacetic acid (5HIAA) and precursor tryptophan, as well as the noradrenaline metabolite 3-methoxy-4-hydroxyphenylethylene glycol (MHPG) and thiamine in the cerebrospinal fluid (CSF) of patients with Friedreich's ataxia (FA), olivopontocerebellar atrophy (OPCA), and the autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSAC), as compared with sex- and age-matched control subjects. CSF amine related compound levels and thiamine results were compared in 40 FA, 44 OPCA and nine ARSAC patients with those of 94 sex- and age-matched subjects. Neuroimaging (CT scans and single photon emission computed tomographies i.e. SPECT) were carried out in all patients and controls. Genetic studies were conducted on OPCA patients. CSF amine related compounds were measured by high performance liquid chromatography, whereas CSF thiamine levels were measured by a microbiological method. FA patients had significantly lower CSF HVA, 5HIAA and thiamine values than control patients and a trend for lower MHPG levels. In OPCA patients, CSF HVA, MHPG and thiamine values were markedly lower whereas CSF 5HIAA values showed only a trend towards lower levels; in ARSAC patients only thiamine and HVA CSF values were lower than those in control subjects. After presenting the relationships between neurochemical findings on one side, the degree of ataxia, the degree of cerebellar atrophy and the SPECT findings on the other, the authors concluded that replacement and neuroprotective clinical trials in these patients would have to include two or three drugs because the neurotransmitter deficiencies are multiple.

Influence of mutation type and X chromosome inactivation on Rett syndrome phenotypes

We screened 71 sporadic and 7 familial Rett syndrome (RTT) patients for MECP2 mutations by direct sequencing and determined the pattern of X chromosome inactivation (XCI) in 39 RTT patients. We identified 23 different disease-causing MECP2 mutations in 54 of 71 (76%) sporadic patients and in 2 of 7 (29%) familial cases. We compared electrophysiological findings, cerebrospinal fluid neurochemistry, and 13 clinical characteristics between patients carrying missense mutations and those carrying truncating mutations. Thirty-one of 34 patients (91%) with classic RTT had random XCI. Nonrandom XCI was associated with milder phenotypes, including a mitigated classic RTT caused by a rare early truncating mutation. Patients with truncating mutations have a higher incidence of awake respiratory dysfunction and lower levels of cerebrospinal fluid homovanillic acid. Scoliosis is more common in patients with missense mutations. These data indicate that different MECP2 mutations have similar phenotypic consequences, and random XCI plays an important role in producing the full phenotypic spectrum of classic RTT. The association of early truncating mutations with nonrandom XCI, along with the fact that chimeric mice lacking methyl-CpG-binding protein 2 (MeCP2) function die during embryogenesis, supports the notion that RTT is caused by partial loss of MeCP2 function.

Plasma total cholesterol concentrations do not predict cerebrospinal fluid neurotransmitter metabolites: implications for the biophysical role of highly unsaturated fatty acids

Low concentrations of a metabolite of serotonin found in cerebrospinal fluid (CSF), 5-hydroxyindolacetic acid (5-HIAA), are strongly associated with suicidal and violent behaviors. Although lowering of plasma total cholesterol has been suggested to increase mortality from suicide and violence by decreasing concentrations of CSF 5-HIAA via changes in membrane biophysical properties, highly unsaturated fatty acids may play a more important role. Violent and nonviolent comparison groups, early- and late-onset alcoholics, and healthy comparison subjects were studied to control for alcohol use and predisposition to violence. Fasting plasma total cholesterol and CSF were assayed under stringently controlled conditions. When all groups were combined (n = 234), plasma cholesterol concentrations had a weak positive correlation with CSF 5-HIAA (r = 0.18, P < 0.01). However, age correlated with both plasma total cholesterol and CSF 5-HIAA concentrations. When age was included in multiple regression models, the correlation between cholesterol and CSF 5-HIAA concentrations was not significant. Cholesterol correlated weakly with CSF 5-HIAA concentrations only in late-onset alcoholics after age was controlled for, but the relation was not significant after correction for multiple testing. CSF homovanillic acid did not correlate with plasma total cholesterol in any group. Plasma total cholesterol had no apparent relation to CSF neurotransmitter metabolites in any group of subjects. Highly unsaturated essential fatty acids, which are also critical determinants of membrane biophysical properties and may be linked to brain serotonin concentrations, should also be considered in studies examining the effect of lowering fat intake on the incidence of suicide and violence.

Altered CSF 5-HIAA Disposition in Pathologic Male Gamblers

Previous reports concerning the cerebrospinal fluid (CSF) of pathologic gamblers have described disturbed norepinephrine and dopamine (but not serotonin) functioning in the central nervous system. We analyzed neurotransmitter metabolites in two consecutive 6-mL samples of CSF obtained from 10 pathologic male gamblers punctured at the L4-5 level following 8 hours of fasting along with strict bed rest. Data were compared with those for healthy male controls. In conformity with findings in healthy male controls, we found gradients in CSF 5-hydroxyindoleacetic acid (5-HIAA) and homovanillic acid (HVA), but not 4-hydroxy-3-methoxyphenyl glycol (HMPG). Expressing the CSF concentrations as nmol x L-1 x min-1 of tapping time (an estimate of the mass flow through the needle), the levels of 5-HIAA and HMPG (but not HVA) were found to be significantly lower in gamblers. Levels of 5-HIAA and HVA showed a significant correlation in gamblers but not in healthy controls. Taking tapping time into account, the CSF levels of HMPG and 5-HIAA were significantly lower in gamblers. We concluded that, in light of previous CSF findings of disturbed norepinephrine and dopamine function, altered indolamine function cannot be fully ruled out.

The effect of lumbar puncture stress on dopamine and serotonin metabolites in human cerebrospinal fluid

In order to examine concentrations of cerebrospinal fluid (CSF) neurochemicals, the technique of lumbar puncture is typically used. However, the effect of the intrinsic stress of undergoing a lumbar puncture on CSF monoamine concentrations in humans has not yet been established. We used lumbar puncture followed 3 h later by continuous CSF sampling to examine the effect of lumbar puncture on levels of the dopamine and serotonin metabolites homovanillic acid (HVA) and 5-hydroxyindoleacetic acid (5-HIAA), respectively. Additionally, we examined the effect of lumbar puncture on the CSF HVA to 5-HIAA ratio. Immediately post lumbar puncture, CSF concentrations of HVA and 5-HIAA were, respectively, only 51 and 54% of the mean levels detected hours later. However, the HVA to 5-HIAA ratio remained stable during lumbar puncture. While HVA and 5-HIAA levels in CSF obtained via lumbar puncture reflect highly variable responses to the stress of the procedure, the ratio of these metabolites is unaffected.

Psychiatric aspects of therapy with corticosteroids in asthma

Dopamine activity, mediated by the catecholaminergic neurotransmitter dopamine, is prominent in the human brain and has been implicated in schizophrenia. Dopamine targets five different receptors and is then degraded to its major metabolite homovanillic acid (HVA). We hypothesized that genes encoding dopamine receptors may be associated with cerebrospinal fluid (CSF) HVA concentrations in patients with psychotic disorder.We searched for association between 67 single nucleotide polymorphisms (SNPs) in the five dopamine receptor genes i.e., DRD1, DRD2, DRD3, DRD4 and DRD5, and the CSF HVA concentrations in 74 patients with psychotic disorder. Nominally associated SNPs were also tested in 111 healthy controls.We identified a locus, located downstream DRD1 gene, where four SNPs, rs11747728, rs11742274, rs265974 and rs11747886, showed association with CSF HVA concentrations in psychotic patients. The associations between rs11747728, which is a regulatory region variant, and rs11742274 with HVA remained significant after correction for multiple testing. These associations were restricted to psychotic patients and were absent in healthy controls. The results suggest that the DRD1 gene is implicated in the pathophysiology of psychosis and support the dopamine hypothesis of schizophrenia.

Psychomotor performance and monoamine function in bipolar and unipolar affective disorders

Background: Affective disorders are associated with prominent psychomotor abnormalities that may be related to changes in arousal or motivation due to altered catecholamine function.Methods: We investigated relationships between performance on psychomotor tests of motor speed (reaction time and tapping speed) and visual tracking (trail making and dot placement) and catecholamine system function including cerebrospinal fluid (CSF) or urinary concentrations of catecholamines or their metabolites. Subjects were medicine-free inpatients with unipolar depression or with manic, depressive, or mixed episodes of bipolar disorder, and healthy controls matched by gender and stratified by age.Results: Unipolar and bipolar depressed patients were impaired in motor speed, dexterity, and visual tracking, whereas manic and mixed patients did not differ from controls. Tapping speed correlated positively with CSF 3-methoxy-4-hydroxyphenylglycol in healthy controls and with CSF homovanillic acid in bipolar depressed subjects. Increased catecholamine function correlated with slowing in all other measures for patients with bipolar disorder. Relationships between catecholamines and psychomotor function were weaker in unipolar depressed subjects. Psychomotor function was related to severity of depression in bipolar, but not in unipolar, patients.Conclusions: These data suggest that catecholamine systems are associated with increased arousal and psychomotor impairment in patients with bipolar disorder. Similar behavioral changes have different neurotransmitter relationships in unipolar disorder.

髄液中神経伝達物質，アミノ酸およびフリーラジカル関連物質の脳血管障害患者における変化

Acetylcholinesterase (AChE), choline, monoamine and its metabolite, amino acid and superoxide dismutase (SOD) levels were measured in cerebrospinal fluid (CSF) in patients with cerebrovascular diseases. Patients were classified into the following four groups; controls: normal subjects without neurological disease, group A: cerebral hemorrhage, group B: cerebral infarction, group C: patients with mental impairment, including those in groups A and B, and a low score on Hasegawa's Dementia Rating Scale. CSF AChE level of groups A, B and C was decreased significantly, while choline concentration from patients showed a increase compared with that of control cases. CSF alanine concentration showed a tendency to increase, while glycine and glutamate tended to decrease. CSF epinephrine, norepinephrine or 3-methoxy-4-hydroxyphenylethylen glycol concentrations of groups A, B and C did not exhibit a significant difference from that in control cases. Some cases with cerebrovascular diseases showed low concentrations of both CSF 5-hydroxyindole acetic acid and homovanillic acid. However, dihydroxyphenyl acetic acid concentration was higher than in control cases. The CSF SOD level was not significantly from that in control cases. The changes in neurochemical substances in the CSF support their use as markers of cerebrovascular disease-related change.

PET imaging of the pre-synaptic dopamine uptake sites in rapid-onset dystonia-parkinsonism (RDP).

Rapid-onset dystonia-parkinsonism (RDP) is a genetic movement disorder characterized by abrupt onset over hours to days of bradykinesia, postural instability, dysphagia, dysarthria, and severe dystonic spasms with decreased levels of the dopamine metabolite, homovanillic acid (HVA), in cerebrospinal fluid (CSF). We imaged the dopamine re-uptake system with [O-methyl-11C]beta-CFT ([11C]beta-CFT) in three severely affected individuals with RDP and four patients with idiopathic Parkinson's disease (IPD). Results were compared with those of age-matched normal volunteers. Positron emission tomography images from those patients with IPD demonstrated a dramatic reduction in the volume of distribution of [11C]beta-CFT whereas patients with RDP showed slightly elevated values. The data suggest that patients with RDP do not have a decrease in the number of dopamine re-uptake sites. Our findings suggest that, unlike the situation in IPD, low CSF HVA concentrations seen in RDP patients are not the result of degeneration of striatal dopamine terminals or loss of dopamine re-uptake sites.

PET imaging of the pre‐synaptic dopamine uptake sites in rapid‐onset dystonia‐parkinsonism (RDP)

BACKGROUND Rapid-onset dystonia-parkinsonism (RDP) is a genetic movement disorder characterized by abrupt onset over hours to days of bradykinesia, postural instability, dysphagia, dysarthria, and severe dystonic spasms with decreased levels of the dopamine metabolite, homovanillic acid (HVA), in cerebrospinal fluid (CSF). METHODS We imaged the dopamine re-uptake system with [O-methyl-11C]β-CFT ([11C]β-CFT) in three severely affected individuals with RDP and four patients with idiopathic Parkinson's disease (IPD). Results were compared with those of age-matched normal volunteers. RESULTS Positron emission tomography images from those patients with IPD demonstrated a dramatic reduction in the volume of distribution of [11C]β-CFT whereas patients with RDP showed slightly elevated values. CONCLUSIONS The data suggest that patients with RDP do not have a decrease in the number of dopamine re-uptake sites. Our findings suggest that, unlike the situation in IPD, low CSF HVA concentrations seen in RDP patients are not the result of degeneration of striatal dopamine terminals or loss of dopamine re-uptake sites.

Biochemical hallmarks of tyrosine hydroxylase deficiency

We report the biochemical hallmarks of tyrosine hydroxylase deficiency with emphasis on reliable diagnostic strategies of four new cases of an inborn error of tyrosine hydroxylase (TH). Three of our patients from different parts of the Netherlands were found homozygous for a mutation in exon 6 (G698A) of the TH gene, and one patient was found compound heterozygous for the same mutation and an additional mutation in exon 3. The first clinical symptoms of hypokinesia, rigidity of arms and legs and axial hypotonia, developed between 3 and 7 months of age. Cerebrospinal fluid investigations revealed a characteristic metabolite constellation in every case: low homovanillic acid (HVA) and 3-methoxy-4-hydroxyphenylethyleneglycol concentrations in the presence of normal reference range 5-hydroxyindolacetic acid concentrations. Strict adherence to a standardized lumbar puncture protocol and adequate age-related reference values are essential for diagnosis of this "new" treatable neurometabolic disorder. Urinary measurements of HVA, vanillylmandelic acid, and catecholamines can lead to false-negative conclusions. All patients showed a remarkable clinical improvement on a low dose of L-dihydroxyphenylalanine/ (S)-2-(3,4-dihydroxybenzyl)-2-hydrazinpropionic acid. During treatment, cerebrospinal fluid HVA, and 3-methoxy-4-hydroxy-phenylethyleneglycol increased substantially.

Role of serotonin in obsessive-compulsive disorder

Serotonin may play a role in the pathophysiology of obsessive-compulsive disorder (OCD) because of the anti-obsessional effect of selective serotonin reuptake inhibitors (SSRIs). The literature is reviewed on knowledge of the role of serotonergic neurons in brain function, studies on monoamine metabolites in cerebrospinal fluid (CSF), various stress neuropeptides, neuroendocrine and behavioural challenge after administration of direct and indirect serotomimetic compounds, and neuroanatomical data on brain circuits organising behaviour. In most of the OCD cases analysed, CSF 5-hydroxyindoleacetic acid and homovanillic acid concentrations do not significantly differ from age-corrected controls. However, a relationship appears to exist between pre-treatment levels of these metabolites and clinical response to drugs acting on the serotonin transporter. Abnormalities in CSF arginine vasopressin, corticotropin-releasing hormone, oxytocin and somatostatin levels have been reported in OCD. Long-term treatment with high-doses of clomipramine, fluvoxamine, and fluoxetine tend to correct these neuropeptide abnormalities. We hypothesise that continuous treatment with SSRIs alters serotonin turnover and neuropeptide expression patterns in OCD-entertaining functional forebrain/midbrain circuits.

Polymorphisms in the dopamine, serotonin, and norepinephrine transporter genes and their relationships to monoamine metabolite concentrations in CSF of healthy volunteers

Concentrations of monoamine metabolites (MM) in lumbar cerebrospinal fluid (CSF) have been used extensively as indirect estimates of monoamine turnover in the brain. We investigated the possible relationships between DNA polymorphisms in the dopamine transporter (DAT), serotonin transporter (SERT), and norepinephrine transporter (NET) genes and CSF concentrations of homovanillic acid (HVA), 5-hydroxyindoleacetic acid (5-HIAA), and 3-methoxy-4-hydroxyphenylglycol (MHPG) in healthy volunteers ( n=66). The DAT polymorphism was not significantly associated with any of the monoamine metabolites, but a tendency for relationship with 5-HIAA was found in women. For both of the two SERT polymorphisms investigated, a functional promoter polymorphism and an intronic polymorphism without known function, significant relationships were found with CSF MHPG levels. No relationship was found between the SERT polymorphisms and CSF HVA and 5-HIAA. The NET polymorphism was associated with CSF MHPG levels but not with HVA and 5-HIAA concentrations. The results suggest that SERT and NET genotypes may participate differentially in the regulation of the norepinephrine turnover rate under presumed steady-state conditions in the central nervous system. As only limited data so far indicate interactions between the serotonin and norepinephrine systems in the brain, and the NET polymorphism investigated is not known to be of functional significance, the results should be interpreted with caution until replicated.

Monoaminergic effects of high-dose corticotropin in corticotropin-responsive pediatric opsoclonus-myoclonus.

Children with the opsoclonus-myoclonus syndrome (OMS) usually respond to corticotropin (adrenocorticotrophic hormone, ACTH) treatment but the mechanism of benefit is unknown. We previously showed that both cerebrospinal fluid (CSF) homovanillic acid (HVA) and 5-hydroxyindole-acetic acid (5-HIAA) concentrations are low in pediatric OMS. In this study, we measured levels of CSF Dopa, catecholamines, deaminated metabolites of catecholamines, as well as HVA and 5-HIAA in eight patients before and during treatment with ACTH. All the children were ACTH-responsive with 50-70% improvement in multiple clinical features of OMS. ACTH treatment reduced the HVA concentration in every child by a mean of 21% (p < 0.001). Treatment with ACTH was associated with significant correlations between dopaminergic markers such as HVA, dihydroxyphenylacetic acid (DOPAC), and Dopa. There were no significant changes in the CSF concentrations of the noradrenergic markers norepinephrine (NE) and dihydroxyphenylglycol (DHPG), or the serotonergic marker 5-HIAA. The only child with a marked inflammatory pattern in CSF, which was reversed by ACTH, was atypical for a large increase in NE and decrease in 5-HIAA during ACTH treatment. Beneficial effects of ACTH in OMS are not associated with normalization of HVA or 5-HIAA levels. The pattern of decreased HVA and unchanged DOPAC levels could reflect decreased extraneuronal uptake of catecholamines (which steroids inhibit) or decreased 0-methylation of catecholamines in nonneuronal cells.

Cerebrospinal fluid homovanillic acid levels are not reduced in early corticobasal degeneration

To investigate the contribution of nigral degeneration to the development of parkinsonism in the early stages of corticobasal degeneration (CBD), we measured the cerebrospinal fluid (CSF) levels of homovanillic acid (HVA) in patients with early CBD ( n=5), and compared the levels with those in patients with early Parkinson's disease ( n=11) and in normal subjects ( n=13). The mean CSF HVA level in the early CBD group (33.1±6.0 ng/ml) did not differ significantly from that in the control group (37.1±12.7 ng/ml), whereas that in the early Parkinson's disease group (19.0±7.6 ng/ml) was reduced significantly ( P<0.001). This result suggests that neuronal cell loss in the substantia nigra and presynaptic nigrostriatal dopaminergic neuron dysfunction are mild in the early stages of CBD.

Higher Cerebrospinal Fluid MHPG in Subjects With Dementia of the Alzheimer Type: Relationship With Cognitive Dysfunction

The authors sought to determine the relationships between cerebrospinal fluid (CSF) levels of three neurotransmitter monoamine metabolites and cognitive function. CSF was collected from subjects with dementia of the Alzheimer's type ([DAT] n = 28) and control subjects (n = 10) for determination of CSF 5-hydroxyindole acetic acid (5-HIAA), 3-methoxy-4-hydroxy-phenylglycol (MHPG), and homovanillic acid (HVA) levels. All subjects underwent systematic assessment to determine cognitive function. Subjects with DAT had higher concentrations of CSF MHPG. In the overall sample, cognitive function was inversely correlated with CSF levels of MHPG but not with 5-HIAA or HVA. Within the DAT sample, these correlations did not achieve significance.

Central levodopa metabolism in Parkinson's disease after administration of stable isotope-labeled levodopa.

We report the use of a new stable isotope-labeled form of levodopa (LD) to examine in vivo central LD metabolism in Parkinson's disease (PD). Eight patients representing a wide spectrum of disease severity were administered 50 mg of carbidopa orally followed in 1 hour by an intravenous bolus of 150 mg of stable isotope-labeled LD (ring-1',2',3',4',5',6'-(13)C6). Serial blood samples were taken every 30 to 60 minutes and a lumbar puncture was performed 6 hours after the infusion. The average percentage of labeled homovanillic acid (HVA) in lumbar cerebrospinal fluid (CSF) was 54% (SD, 9%; range, 34-67%). The mean CSF labeled HVA concentration was 34.7 ng/ml (SD, 20.2 ng/ml; range, 11.3-67.9 ng/ml). Area under the curve for labeled serum LD closely predicted CSF labeled HVA concentrations (r = 0.747, p = 0.033). Labeled CSF HVA levels did not significantly correlate with either quality or duration of response to the labeled LD dose. In a similar manner, labeled CSF HVA concentrations were not influenced by duration of disease or previous daily LD dosage. These findings support the hypothesis that levodopa-induced benefit in PD is not severely limited by a defect in central levodopa metabolism.