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.

Cerebrospinal fluid-based kinetic biomarkers of axonal transport in monitoring neurodegeneration.

Progress in neurodegenerative disease research is hampered by the lack of biomarkers of neuronal dysfunction. We here identified a class of cerebrospinal fluid-based (CSF-based) kinetic biomarkers that reflect altered neuronal transport of protein cargo, a common feature of neurodegeneration. After a pulse administration of heavy water (2H2O), distinct, newly synthesized 2H-labeled neuronal proteins were transported to nerve terminals and secreted, and then appeared in CSF. In 3 mouse models of neurodegeneration, distinct 2H-cargo proteins displayed delayed appearance and disappearance kinetics in the CSF, suggestive of aberrant transport kinetics. Microtubule-modulating pharmacotherapy normalized CSF-based kinetics of affected 2H-cargo proteins and ameliorated neurodegenerative symptoms in mice. After 2H2O labeling, similar neuronal transport deficits were observed in CSF of patients with Parkinson's disease (PD) compared with non-PD control subjects, which indicates that these biomarkers are translatable and relevant to human disease. Measurement of transport kinetics may provide a sensitive method to monitor progression of neurodegeneration and treatment effects.

Impact of manganese on and transfer across blood-brain and blood-cerebrospinal fluid barrier in vitro.

Manganese occupational and dietary overexposure has been shown to result in specific clinical central nervous system syndromes, which are similar to those observed in Parkinson disease. To date, modes of neurotoxic action of Mn are still to be elucidated but are thought to be strongly related to Mn accumulation in brain and oxidative stress. However, the pathway and the exact process of Mn uptake in the brain are yet not fully understood. Here, two well characterized primary porcine in vitro models of the blood-brain and the blood-cerebrospinal fluid (CSF) barrier were applied to assess the transfer of Mn in the brain while monitoring its effect on the barrier properties. Thus, for the first time effects of MnCl(2) on the integrity of these two barriers as well as Mn transfer across the respective barriers are compared in one study. The data reveal a stronger Mn sensitivity of the in vitro blood-CSF barrier compared with the blood-brain barrier. Very interestingly, the negative effects of Mn on the structural and functional properties of the highly Mn-sensitive blood-CSF barrier were partly reversible after incubation with calcium. In summary, both the observed stronger Mn sensitivity of the in vitro blood-CSF barrier and the observed site-directed, most probably active, Mn transport toward the brain facing compartment, reveal that, in contrast to the general assumption in literature, after oral Mn intake the blood-CSF barrier might be the major route for Mn into the brain.

MPP+ analogs acting on mitochondria and inducing neuro-degeneration.

This review focuses on the mechanisms of action and the injurious effect of complex I inhibitors, of which 1-methyl-4-phenylpyridinium ion (MPP(+)) is a well studied example. These compounds can be divided into two groups, i.e. competitive inhibitors with respect to ubiquinone, such as piericidine A, and non-competitive inhibitors such as rotenone. Complex I inhibitors such as MPP(+) have been reported to induce anatomical, behavioral, and biochemical changes similar to those seen in Parkinson's disease, which is characterized by nigrostriatal dopaminergic neuro-degeneration. Spectroscopic analyses and structure-activity relationship studies have indicated that the V-shaped structure of the rotenone molecule is critical for binding to the rotenone binding site on complex I. Many isoquinoline derivatives, some of them endogenous, are also complex I inhibitors. Many lines of evidence show that complex I inhibitors elicit neuronal cell death. Recently, it was reported that chronic and systemic exposure to low-dose rotenone reproduces the features of Parkinson's disease. This work further focused attention on compounds acting on mitochondria, such as MPP(+). In Guadeloupe, the French West Indies, patients with atypical parkinsonism or progressive supranuclear palsy are frequently encountered. These diseases seem to be associated with ingestion of tropical herbal teas or tropical fruits of the Annonaceae family, which contain complex I inhibitors such as benzylisoquinoline derivatives and acetogenins. Complex I inhibitors may not simply result in reactive oxygen species generation or ATP exhaustion, but may influence complex downstream signal transduction processes. An understanding of these changes would throw light on the ways in which complex I inhibitors induce a wide range of abnormalities.

Chronic exposure to MPTP as a primate model of progressive parkinsonism: a pilot study with a free radical scavenger.

The development of a validated primate model of progressive parkinsonism is a critical step in the evaluation of drugs that might halt or slow progression of Parkinson's disease. In this pilot study, we gradually exposed 14 cynomolgus monkeys to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), at a weekly dose of 0.5 mg/kg s.c. for 10 weeks, to determine their probability of not reaching a predetermined endpoint on a disability scale by Kaplan-Meier analysis. Four other MPTP-exposed animals were coadministered the potent free radical scavenger 7-hydroxy-1-[4-(3-methoxyphenyl)-1-piperazinyl]acetylamino-2,2,4,6- tetramethylindan (OPC-14117) as a single oral daily dose of 0.6 g/kg, starting 2 weeks before MPTP initiation. The risk of reaching endpoint by week 10 was 79% and mean time before reaching endpoint was 6 weeks. Global motor activity, recorded in a subset of animals using a portable activity monitor, declined following the first MPTP dose and never recovered. Several cerebrospinal fluid indices of central monoamine metabolism collected by suboccipital puncture at 0, 5, and 10 weeks, including HVA, DOPAC, and tetrahydrobiopterin but not MHPG, were found to be "trait" markers for MPTP exposure, whereas CSF DOPAC and tetrahydrobiopterin constituted potential "state" markers for reaching endpoint. The antioxidant OPC-14117 did not protect against MPTP-induced parkinsonism. Further attempts to validate this incremental model of neurotoxin-induced parkinsonism as a predictor of patient responses to putative neuroprotective agents appear warranted.

1-Benzyl-1,2,3,4-tetrahydroisoquinoline as a parkinsonism-inducing agent: a novel endogenous amine in mouse brain and parkinsonian CSF.

1-Benzyl-1,2,3,4-tetrahydroisoquinoline (1BnTIQ) was detected as a novel endogenous amine in mouse brain and parkinsonian CSF by using the gas chromatography-selected ion-monitoring method. The level of 1BnTIQ was very high in CSF of some parkinsonian patients compared with that of controls with other neurological diseases, the mean value being three times higher (parkinsonians: 1.17 +/- 0.35 ng/ml of CSF, n = 18; vs. controls: 0.40 +/- 0.10 ng/ml of CSF, n = 11; mean +/- SEM, not significantly different). The pole test, a toxicological examination to evaluate behavior abnormalities related to Parkinson's disease, was used to examine the pharmacological effect of 1BnTIQ in mice. Repeated administration of 1BnTIQ induced behavior abnormalities, which pretreatment with 1-methyl-1,2,3,4-tetrahydroisoquinoline could prevent. We suggest that 1BnTIQ may be related to the idiopathic Parkinson's disease.

CSF somatostatin increase in patients with early parkinsonian syndrome.

Somatostatin-like immunoreactivity levels (SLI) in cerebrospinal fluid (CSF) were determined in twenty-three patients with untreated parkinsonian syndrome (15 with Idiopathic Parkinson's disease (IPD) and 8 with other forms of parkinsonism) at the moment of clinical diagnosis (mean duration of disease 1.1 +/- 0.2 years), and in 26 subjects without neurological symptoms. None of the IPD patients had a diagnosis of dementia at the moment of inclusion in the study. CSF-SLI content was found to be significantly higher in patients with parkinsonian syndrome (107.9 +/- 9.8 pg/ml) than in control subjects (73.5 +/- 8.4 pg/ml). The increase was also significant when controls were compared with IPD patients. In addition, a positive correlation between SLI and homovanillic acid was found in CSF of all patients. A test of learning memory was used to evaluate the mental state of patients and a significant increase in CSF-somatostatin levels was observed in patients with Idiopathic Parkinson's disease and severe affectation of memory. These results indicate that in the early steps of untreated parkinsonian syndrome, somatostatin concentration in cerebrospinal fluid may increase, probably due to the neurodegenerative depletion of somatostatin from striatal or cortical neurons.

Dopa-responsive dystonia simulating cerebral palsy.

Five patients presented in infancy or early childhood with various combinations of pyramidal and extrapyramidal signs with normal cognitive function. Their perinatal courses were unremarkable. In each patient, initial impressions listed by several examiners included spastic diplegia or cerebral palsy. Later in each course, either extrapyramidal features or progression suggested dopa-responsive dystonia. In 4 of the 5 children, cerebrospinal fluid was obtained and disclosed reduced levels of biopterin, neopterin, and homovanillic acid in all 4. Levodopa therapy resulted in prompt improvement with normal function returning within 6 months. The disappearance of the "spasticity," extensor plantar responses, and extrapyramidal signs, following levodopa therapy, confirmed the diagnosis of doparesponsive dystonia in these patients. Three had apparently sporadic disease; the other 2 were siblings with an affected paternal grandmother. Three had onset in infancy with delayed sitting and walking before the appearance of overt dystonia; infantile onset is infrequent in dopa-responsive dystonia. The other 2 had normal milestones, but developed gait disorders with prominent imbalance in early childhood. The diagnosis of dopa-responsive dystonia should be considered in children with unexplained or atypical "cerebral palsy."

6-[18F]fluoro-L-dopa and cerebral blood flow in unilaterally MPTP-treated monkeys.

Intravenous administration of 15O-labeled water and 6-[18F]-L-fluorodopa were used to assess abnormal striatal activity in monkeys after long-term recovery of unilateral lesions of the dopaminergic nigro-striatal system induced by the neurotoxin MPTP. PET data were examined in relation to behavioral and biological parameters. Cerebral blood flow and 6-[18F]-L-DOPA uptake were found to be significantly reduced in the lesioned striatum, compared to the unaffected side and to normal controls. There was no correlation between cerebral blood flow and any of the behavioral parameters. The uptake rate constant of 18F-DOPA from blood to striatum and the ratios of striatum to occipital areas were highly correlated to the concentrations of homovanillic acid in the cerebrospinal fluid of the same animals but not to the rotational behavior. This MPTP-induced model of striatal dopamine deficiency in primates presents similarities with idiopathic Parkinson's disease and may be used to evaluate the effects of dopaminergic lesions and transplants on brain function.

Cinnarizine-induced parkinsonism in primates.

We describe the production of an experimental model of parkinsonism induced by cinnarizine (CNZ) in three healthy sylvanna monkeys. The drug produced a severe but reversible parkinsonism in all animals. After discontinuation of CNZ, all animals recovered but the oldest one was akinetic for 6 weeks. CNZ produced a persistent reduction in HVA and 5-HIAA levels in the CSF. Our data suggest a predominant presynaptic effect on DA and 5-HT neurons; and could account for the longstanding parkinsonism induced by calcium antagonist in some patients as well as the depression observed in these subjects.

Acute parkinsonian syndrome with demyelinating leukoencephalopathy in bone marrow transplant recipients.

A syndrome of rigidity, bradykinesia, spasticity, and often myoclonus and dementia developed acutely in 5 patients who had undergone successful engraftment of bone marrow transplants for the treatment of various hematologic diseases. Magnetic resonance imaging demonstrated widespread changes in white matter; brain biopsy disclosed mild demyelination associated with active phagocytosis of myelin. One patient, who was not treated, remains severely demented. Patients treated with very high-dose methylprednisolone had complete clinical recovery.

[An experimental study on the contents of enkephalins in the cerebrospinal fluid in rabbits with unilateral destructive lesions produced in the substantia nigra and their relation to the regulation of MIF-1].

The changes of the contents of enkephalins in cerebrospinal fluid (CSF) and the action of MIF-1 in rabbit experimental models of Parkinson's disease were studied. In the experiment, the rabbits received injection of 6-hydroxydopamine (6-OH DA) into the unilateral substantia nigra. The contents of Met-enkephalin (MEK) and Leuenkephalin (LEK) in the CSF of the fourth ventricles of the normal control rabbits and those with destructive lesions in the substantia nigra were determined with radio-immunoassay. The concentrations of MEK and LEK in CSF of the rabbit models increased markedly to 14.3 and 28.2 folds in the controls respectively. The increased enkephalin content in CSF could be reduced to the normal level by intravenous administration of MIF-I. The results indicated that the action of MIF-I may be one of the important factors in alleviating the symptoms of parkinsonian patients.

Myoclonic encephalopathy due to bismuth salts: treatment with dimercaprol and analysis of CSF transmitters.

Two cases of myoclonic encephalopathy due to bismuth salts intoxication are reported. In both, treatment with dimercaprol led to clinical recovery. This therapy was shown to enhance bismuth clearance. We also present data on the CSF metabolites dopamine, norepinephrine and serotonin of one patient.

Cerebrospinal fluid homovanillic acid and hypokinetic side effects of neuroleptics.

Eleven psychotic patients treated with neuroleptics for 1 month showed a relatively poor response, more side effects, and a no-tolerance pattern with respect to cerebrospinal fluid (CSF) homovanillic acid (HVA). Within this group the severity of neuroleptic catatonia and Parkinsonian side effects was positively associated with an increase in CSF HVA turnover during the treatment period.

Comparative neurochemical investigation of tardive dyskinesia and neuroleptic-induced chronic parkinsonism.

Cerebrospinal fluid (CSF) homovanillic acid (HVA), cyclic adenosine 3', 5'-monophosphate (cAMP), and serum prolactin were measured in schizophrenic male patients with tardive dyskinesia (TD) and in those exhibiting the symptoms of chronic neuroleptic parkinsonism (P). The patients (nine TD and eight P) were chronic paranoid schizophrenics. Levels of HVA in CSF were found to be significantly higher in the TD group. Normal prolactin levels were observed in both groups and are indicative of tolerance developed in the hypothalamic tuberoinfundibular dopaminergic system.

[Value of the probenecid test in the diagnosis and treatment of parkinson disease]. / Apport du test au probenecid dans le diagnostic et le traitement de la maladie de Parkinson.

Forty-five patients presenting a parkinsonian syndrome, accompanied in some cases by depressive and/or confusional signs, were subjected to neurological and neurobiochemical investigation involving a probenecid test (estimate of central turnover of dopamine by determination of homovanillic acid in cerebrospinal fluid before and after an oral dose of probenecid). Patients were classified in two groups on the basis of the benefit procured by dopa therapy as estimated at least one year after treatment. The probenecid test revealed a sharp drop in turnover of dopamine in the dopasensitive group. Furthermore, in this group the dopamine turnover was not related to sex, age, duration of the parkinsonian syndrome or clinical severity. In contrast, there seemed to be a correlation between dopamine turnover and optimum dosage of l-DOPA. Lastly, the study showed that, beyond the diagnosis of dopasensitivity, the test was useful for patient follow-up. The test profile in cases of excess dopatherapy is described.

CSF-changes of HVA and 5-HIAA during intermittent and continuous Parkinson therapy with particular regard to prodipin application.

The influence of prodipin, a putative dopamine releasing compound, on the concentration of homovanillic acid (HVA) and 5-hydroxyindoleacetic acid (5-HIAA) in the spinal liquor of 28 patients with Parkinson's disease was investigated. The patients were divided into three groups. In group 1 the combined antiparkinson therapy was interrupted, and 20 mg prodipin was infused. In group 2 and 3 the therapy was continued, while an additional 20 mg of prodipin was administered by infusion only to group 3. 4 Liquor-samples were obtained from each patient: 1 basic value and three additional samples 5, 8 and 24 hours after administration of 2 g probenecid. The base concentration of HVA was 15 ng/ml and this was not increased by probenecid in group 1; the concentration of 5-HIAA was 11.6 ng/ml and this was doubled by probenecid to 22.9 ng/ml. The HVA concentration increased to a maximum of 28.9 ng/ml during continued therapy (group 2); the elevated 5-HIAA remained unchanged. Prodipin does not cause an alteration in metabolite concentration in cases of interrupted therapy (group 1), but leads, in the case of continued therapy, to a 1.8-fold increase in HVA, and a 1.6-fold increase in 5-HIAA (group 3).

CSF homovanillic acid: an index of dopaminergic activity.

Although CSF HVA is derived from brain DA metabolism the value of its determination as an index of brain DA turnover and dopaminergic activity is limited, as other factors can affect CSF concentrations. These include the partitioning of HVA between different routes of elimination from the brain, the rates of transport from CSF to blood and from the lateral ventricle to the lumbar sac, CSF space volumes, and methodologic problems. The uses and limitations of CSF HVA determination is illustrated by findings in Parkinson's disease, Huntington's chorea, motor neuron disease, disseminated sclerosis, and hepatic coma. Finally, preliminary results on the effect on CSF HVA of the DA agonist CB 154 are described.