Dopamine agonists in Parkinson's disease.

The main pathologic hallmark of Parkinson's disease is a degeneration of the dopaminergic cells in the substantia nigra, pars compacta and--to a lesser extent--in the ventral tegmental area. Striatal dopamine concentrations are significantly reduced before clinical symptoms become apparent. Recent neuroanatomic and function studies have revealed that the nigrostriatal dopaminergic projection is only one of the neuronal elements integrated into extensive basal ganglia-thalamocortical circuits that are intimately involved in the regulation of motor activity. The possibilities for therapeutic intervention at the level of the different dopamine receptor subtypes and their effect on the regulation of motor behavior will be briefly reviewed. Dopamine precursors are considered to provide the best symptomatic treatment, whereas dopamine agonists, although less effective, might be important in slowing the progression of the disease. Our results with pergolide as monotherapy and in combination therapy in patients with Parkinson's disease also are discussed.

Olanzapine in the treatment of dopaminomimetic psychosis in patients with Parkinson's disease.

We studied the effect of olanzapine (1 to 15 mg/d) in 15 nondemented parkinsonian patients with drug-induced psychosis. Psychotic symptoms decreased significantly during treatment, and there was no worsening of extrapyramidal symptoms. These results suggest that olanzapine is a well-tolerated and effective treatment for drug-induced psychosis in nondemented patients with Parkinson's disease.

Whole blood monoamine oxidase activity in Parkinson's disease and multiple system atrophy patients.

Monoamine oxidase type B (MAO-B), which catalyses the breakdown of dopamine (DA) in human brain, is said to be involved in the pathophysiology of Parkinson's disease (PD). Activity of MAO-B in PD has been measured in platelets isolated from blood samples in different studies, with contradictory results, possibly due to the differences in substrate used or to differences in platelet isolation. Therefore we measured MAO activity in whole blood, which is almost identical to MAO-B activity in platelets, in 25 drug-naive PD patients, 25 treated PD patients, 9 multiple system atrophy (MSA) patients and 20 controls, using a spectrofluorimetric method with kynuramin as a substrate. No statistically significant differences between groups were found, nor any correlation with the severity or duration of the disease.

Decreased cerebrospinal fluid nitrate levels in Parkinson's disease, Alzheimer's disease and multiple system atrophy patients.

Nitric oxide (NO) is a recently discovered endogenous mediator of vasodilatation, neurotransmission, and macrophage cytotoxicity. NO is thought to have a function in memory and in long-term potentiation. At high concentrations NO is neurotoxic and may play a role in neurodegeneration. NO is formed from L-arginine by the enzyme NO synthase (NOS), for which tetrahydrobiopterin (BH4) is a necessary co-factor. Alzheimer's disease (AD) and, to a lesser degree, Parkinson's disease (PD) are thought to be associated with increased microglial activity, suggesting that NO production may be increased. Alternatively, in circumstances of reduced levels of intracellular L-arginine or BH4, NO production is diminished and neurotoxic oxygen radicals may be produced. Since BH4 is decreased in AD and PD brains, these diseases may be associated with decreased NO production. We investigated these two alternatives by measuring the NO degradation products nitrite and nitrate in cerebrospinal fluid (CSF) of PD (n = 103), AD (n = 13), and multiple system atrophy (MSA; n = 14) patients and controls (n = 20). We found for all patient groups, compared with controls, significantly decreased levels of nitrate, but not nitrite. This finding seems to indicate a decreased NO production of the central nervous system (CNS) in these neurodegenerative disorders.

Serum alpha 1-antichymotrypsin is not a useful marker for Alzheimer's disease or dementia in Parkinson's disease.

We measured serum alpha 1-antichymotrypsin (ACT) levels in patients with Alzheimer's disease (AD), Parkinson's disease (PD), Multiple System Atrophy (MSA) and age-matched controls to evaluate whether serum ACT levels in AD patients were elevated and whether ACT levels in PD patients with dementia differed from those in PD or AD. None of the patient groups displayed an increase in ACT levels. We conclude that serum ACT is not useful as a marker, nor in AD nor in dementia in PD.

L-glutamate, L-arginine and L-citrulline levels in cerebrospinal fluid of Parkinson's disease, multiple system atrophy, and Alzheimer's disease patients.

Alterations in neuronal nitric oxide (NO) production may play a role in the pathophysiology of Parkinson's disease (PD) Alzheimer's disease (AD), and multiple system atrophy (MSA). The biosynthesis of NO is dependent on the availability of L-arginine, the substrate for NO-synthase (NOS), and on L-glutamate, which stimulates NO synthesis via the NMDA receptor. In this process L-citrulline is formed. We measured the levels of these amino acids in cerebrospinal fluid (CSF) of 108 PD patients, 12 AD patients, 15 MSA patients and 21 healthy subjects. A slight but statistically significant elevation of CSF L-citrulline was found in MSA patients, while CSF L-glutamate was found to be significantly decreased in AD patients. We found no significant changes in L-arginine levels. Although the relation between the CSF levels of these amino acids and neuronal NO production is still unclear, our findings suggest that AD is associated with a decrease in NO synthesis.

Subclinical dopaminergic dysfunction in asymptomatic Parkinson's disease patients' relatives with a decreased sense of smell.

By the time a clinical diagnosis of Parkinson's disease (PD) is made, a significant loss of dopaminergic neurons has already occurred. Identifying patients in the period between the presumed onset of dopaminergic cell loss and the appearance of clinical parkinsonism may be of major importance in the development of effective neuroprotective treatment strategies. In an effort to develop a feasible strategy to detect preclinical PD, a combination of olfactory processing tasks, including odor detection, odor identification, and odor discrimination was used to select groups of hyposmic and normosmic individuals from a total of 250 relatives (parents, siblings, or children) of subjects with PD. Single photon emission computed tomography (SPECT) with [123I]beta-CIT as a dopamine transporter ligand was used to assess nigrostriatal dopaminergic function in 25 hyposmic and 23 normosmic relatives of PD patients. An abnormal reduction in striatal dopamine transporter binding was found in 4 out of 25 hyposmic relatives of PD patients, two of whom subsequently developed clinical parkinsonism, and in none of the 23 normosmic relatives. These observations demonstrate that subclinical reductions in dopamine transporter binding can be detected in asymptomatic relatives of sporadic PD patients by means of [123I]beta-CIT and SPECT. The results further indicate that olfactory deficits may precede clinical motor signs in PD.