Presynaptic nigro-striatal function in a group of Alzheimer’s disease patients with parkinsonism: evidence from a dopamine transporter imaging study

Summary. The occurrence of parkinsonism in Alzheimers disease (AD) is quite common, however the molecular and neurochemical changes underlying such extrapyramidal features in AD have been not fully understood. Post-mortem as well as in vivo imaging study have produced conflicting results as regards the existence of dopaminergic changes in AD. Aim of the present study was to investigate in vivo the nigro-striatal dopaminergic function in a group of AD patients with parkinsonism. Thirteen patients with AD and extrapyramidal features not related to past neuroleptic use (AD-P) underwent SPECT with ¹²³I-FP-CIT, a ligand of dopamine transporter, and the data were compared with those obtained in 15 patients with Diffuse Lewy Body Dementia (DLBD), 20 patients with Parkinsons disease (PD), and 8 healthy elderly controls. The analysis of the data was performed by regions-of-interest approach and calculations of the striatal-to-non specific (occipital lobes) radioactivity ratios were made. The ¹²³I-FP-CIT striatal uptake in patients with AD-P was similar to that obtained in the control population. Both the DLBD and PD groups showed significantly lower ¹²³I-FP-CIT uptake in all striatal areas with respect to AD-P and control groups (p<0.005). The lack of dopamine transporter changes in our series of AD-P patients can indicate that dopaminergic presynaptic function is preserved in this population and that different dopaminergic changes such as postsynaptic ones, or different neurotransmitter alterations might underlie the extrapyramidal features in AD.     

Efficacy of boron neutron capture therapy on liver metastases of colon adenocarcinoma: optical and ultrastructural study in the rat

The effect of neutron boron capture therapy (BNCT) was studied in rat tumor liver cells after induction of the liver metastases by splenic inoculation of cells from DHA/K12/TRb line. Ten days following the treatment, the BPA was injected into rats and therefore the animals were sacrificed, the liver was exposed to neutron irradiation and processed. In some experiments the liver was reimplanted (after irradiation) in syngenic animals and studied 3 days later, following sacrifice. Samples of tissue obtained from metastasised and non-metastasised areas of the liver parenchyma, before and after the neutron irradiation, were examined in light microscopy and electron microscopy. The analysis pointed out damages induced by the neutron treatment in single tumor cells mostly localised in the synusoidal blood stream. Debris and apoptotic cells were sometimes observed in the neoplastic nodules before treatment, while the tumor cell death (apoptosis) increased in the tumor cells following BNCT treatment. An intense scavenger activity of Kupffer cells after irradiation was accompanied by a strong acid phosphatase reaction detectable in wide cytoplasmic areas. In the liver parenchyma of reimplanted animals, the presence of large collagen bundles spread among the hepatocytes was observed at electron microscopy.     

A study on the release mechanism of drugs from hydrophilic partially coated perforated matrices

Partially coated perforated systems (PCPS) based on low-viscosity hydroxypropyl methylcellulose (HPMC) as the polymeric material were formerly designed, prepared and evaluated in terms of in vitro behaviour. These systems proved to afford the pursued linear release with model drugs (metoprolol tartrate and benfluorex) of different solubility. To the aim of exploring the mechanisms concurring in the definition of zero-order kinetics, studies of drug release, polymer dissolution and medium penetration were performed on PCPS and constant release area systems (CRAS). According to the obtained results, PCPS release kinetics has to be mainly attributed to the progressive outward erosion of the core and to the related variation of the release area. The special geometry of the system, in fact, involves a gradual increase in the release surface, which allows the diffusional path lengthening to be offset. By properly selecting the shape and dimensions of the device as well as the physico-chemical characteristics of the hydrophilic polymer, the advantage of a zero-order release kinetics with programmable rate can be achieved.     

Clinical pharmacokinetics of cabergoline

Cabergoline is a synthetic ergoline dopamine agonist with a high affinity for D(2) receptors indicated for use in both early and advanced Parkinson's disease and in hyperprolactinaemic disorders.Following oral administration, peak plasma concentrations of cabergoline are reached within 2-3 hours. Over the 0.5-7mg dose range, cabergoline shows linear pharmacokinetics in healthy adult volunteers and parkinsonian patients. Cabergoline is moderately bound (around 40%) to human plasma proteins in a concentration-independent manner; concomitant administration of highly protein-bound drugs is unlikely to affect its disposition. The absolute bioavailability of cabergoline is unknown.Cabergoline is extensively metabolised by the liver, predominantly via hydrolysis of the acylurea bond of the urea moiety. Cytochrome P450-mediated metabolism appears to be minimal. The major metabolites identified thus far do not contribute to the therapeutic effect of cabergoline. A significant fraction of the administered dose undergoes a first-pass effect. Less than 4% is excreted unchanged in the urine. The elimination half-life of cabergoline estimated from urinary data of healthy subjects ranges between 63 and 109 hours. Mild to moderate renal and hepatic impairment, administration of food and the use of concomitant antiparkinsonian medications, such as levodopa and selegiline, have no effect on the pharmacokinetics of cabergoline.The pharmacokinetic properties of cabergoline allow once daily administration in patients with Parkinson's disease and twice weekly administration in patients with hyperprolactinaemia, making this drug advantageous over other dopaminergic agents in term of both therapeutic compliance and better symptom control.     

SSRIs do not worsen Parkinson's disease: evidence from an open-label, prospective study

Selective serotonin reuptake inhibitors (SSRIs) have been reported to be useful in the treatment of depression in patients with Parkinson's disease (PD). However, a few reports have suggested that SSRIs may worsen parkinsonian motor symptomatology and extrapyramidal side effects have been reported in depressed patients treated with SSRIs. So far, no prospective trial comparing the effects of different SSRIs in depressed patients with PD has been performed. The aim of the present study was to assess the effects of four SSRIs (citalopram, fluoxetine, fluvoxamine, and sertraline) on motor performance and their efficacy on depression in a group of patients with PD. Sixty-two consecutive nondemented, nonfluctuating, depressed patients with PD were included in four treatment groups (15 patiens received citalopram, 16 fluoxetine, 16 fluvoxamine, and 15 sertraline). The evaluation of extrapyramidal and depressive symptomatology was performed with use of the Unified Parkinson's Disease Rating Scale (UPDRS), Beck Depression Inventory, and Hamilton Depression Rating Scale at baseline and after 1, 3, and 6 months. Fifty-two patients completed the study. UPDRS scores were not significantly modified by the add-on therapy with each of the SSRIs studied. A significant improvement in depressive symptoms from baseline to the end of the trial was obtained with all SSRIs (Beck and Hamilton scores improving; p < 0.05 according to an analysis of variance). Our findings suggest that SSRIs do not significantly worsen extrapyramidal symptomatology and may ameliorate depression in patients with PD.     

Chromosome and oxidative damage biomarkers in lymphocytes of Parkinson's disease patients.

As cancer development usually results from exposure to several environmental risk factors in interaction with the genetic susceptibility of the host, it could be of interest to investigate if neurodegeneration, as occurs in Parkinson's disease (PD) patients can be attributed at least partially, to environmental risk factors. There is growing evidence that oxidative stress could play a significant role as a risk factor in the aetiology and pathogenesis of neurodegenerative diseases, emphasising the need for new individual and human-based approaches. The aim of our research is to explore the relation between chromosome instability and oxidative stress biomarkers in Parkinson's disease using a variety of strategies. We determined peripheral markers for oxidative damage in PD by testing for spontaneous and induced chromosomal damage, DNA strand breaks, oxidised pyrimidines and altered purines both in peripheral blood and cultured lymphocytes. We also measured glutathione S-transferase activity in the plasma of patients and controls. Compared to healthy controls, PD patients show higher frequencies of micronuclei (17.2 +/- 4.8 vs. 9.0 +/- 3.4, p < 0.001) and a significant increase in the levels of single strand breaks (SSB). Significant differences were also obtained in the distribution of oxidised purine bases between the two groups. Preliminary data obtained by fluorescence in situ hybridization analysis showed that the percentage of centromere negative micronuclei is higher than that of centromere positive micronuclei. Glutathione S-transferase activity in plasma from PD patients and controls was also measured and the enzymatic activity in PD patients was lower than in healthy controls.     

Predictive value of nigrostriatal dysfunction in isolated tremor: A clinical and SPECT study

The overlap among tremor disorders is wide and complex because essential tremor patients may present resting tremor coexisting with postural tremor, while postural may coexist with resting tremor in Parkinson's disease. We investigated dopamine transporter binding in 61 subjects presenting with isolated atypical tremors defined as unilateral either postural, resting, or mixed (i.e. resting and postural) tremor, without rigidity or bradykinesia, by means of 123I‐FPCIT SPECT imaging at baseline. Patients were followed‐up clinically for 28.4 ± 7.2 months. Twenty‐five patients with baseline normal SPECT continued to present only tremor at follow‐up. Among 36 patients with abnormal SPECT, 23 (64%) developed PD, while the remaining 13 continued to present only tremor at follow‐up. The value of 123I‐FPCIT SPECT in predicting the evolution to PD was very high in a way independent from the first clinical presentation of tremor (Rest tremor, P = 0.015; Mixed tremor, P = 0.015; Postural tremor, P = 0.039; chi‐square test). Our data suggest that the clinical presentation of isolated tremors is insufficient to allow a precise early‐stage diagnosis, whereas the detection of presynaptic nigrostriatal dopaminergic dysfunction could lead to diagnosis of atypical tremor disorders at a very early stage. We suggest this disorder to be labeled as “isolated tremor with dopaminergic presynaptic dysfunction.” © 2008 Movement Disorder Society     

Platelet monoamine oxidase B activity in parkinsonian patients.

Monoamine oxidase B (MAO B) plays a pivotal role in N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) induced Parkinsonism. An increased MAO B activity in platelets of patients with idiopathic Parkinson's disease (PD) is reported in this study. The possibility that high MAO B activity may represent a trait of vulnerability for PD by enhancing the neurotoxic effects of environmental compounds is discussed.     

Phylogenetic relationships within the oliveirai complex (Hemiptera:Reduviidae:Triatominae).

The oliveirai complex is actually composed of nine related species of Triatominae that occur in the Pantanal ecosystem of Mato Grosso, Brazil. In order to confirm their specific status and infer their phylogenetic relationships, we performed a genetic and morphometric comparison concerning seven of the nine species of the complex. Isoenzyme analysis provided broadly similar phylogenetic information to that derived from discriminant analysis of size-free variables. The derived trees reveal two main species groups, one composed of three closed species (T. jurbergi, T. matogrossensis and T. vandae), and another one subdivided into two different pairs, the T. guazu-T. williami pair and the T. klugi-T. oliveirai pair. The results call the specific status of T. guazu and T. williami into question, support the possibility that the other analyzed species represent distinct taxa and query the existence of the oliveirai complex.