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We used qualitative visual assessment and semiquantitative measures of striatal DAT binding using [123I]FP-CIT-SPET in 85 patients with Parkinson's disease (PD). We compared these two assessments and their correlation with PD clinical progression. SPET imaging was visually classified by a nuclear medicine physician as normal or abnormal pattern grade I, II and III, in relation to a different degree of radioligand reduction uptake. Nineteen patients presented abnormal grade I (group 1), 53 grade II (group 2) and 13 grade III (group 3). The UPDRS III motor score, the H-Y score, the rigidity and bradykinesia subscores were significantly different among the three groups. Post hoc analysis showed that all values of these clinical parameters were higher in group 3 than in 2 and 1. All clinical indices were also significantly higher in group 2 than in group 1. This means that groups 3 and 2 were clinically more severely affected. No significant differences among the 3 groups were observed for age or duration of disease. Values of the mean striatum uptake were also significantly different among the three groups. Post hoc analysis revealed significantly lower values of the mean striatum uptake in group 3 with respect to groups 2 and 1; values were also significantly lower in group 2 than in group 1. We conclude that our findings of good consistency between visual and semi-quantitative assessment may help simplify the evaluation of striatal DAT binding in PD in a clinical routine setting. [ABSTRACT FROM AUTHOR]

We briefly summarise biochemical anomalies of serotonin, norepinephrine, glutamic and aspartic acids, the main neurotransmitters of inhibitory and excitatory neuronal circuitries, found in primary headaches and their relationship with pathogenesis of migraine and cluster headache (CH). In addition, the high levels of circulating tyramine, octopamine and synephrine (elusive amines), recently reported in both migraine types and CH, are discussed in relation to the other “classic” amines findings. In particular it is suggested how abnormal levels of elusive amines may participate in the pathophysiology of migraine and CH acting through their specific trace amine receptors and a and ß receptors. The possible hypothesis that emerges from the analysis of these biochemical findings is that an imbalance of systems, with opposite neurophysiological functions related to the pain and other yet unknown functions, may constitute the biochemical phenotype of migraine with and without aura, and CH. [ABSTRACT FROM AUTHOR]

Migraine with aura (MwA) sufferers, at times, need specific treatments. This is the case when the auras are frequent, prolonged and cause anxiety and distress. Abnormal release of glutamate, which may trigger auras, and abnormal platelet behaviour, which constitutes a possible predisposing factor to MwA, are possible targets for MwA-specific prophylactic therapy. Here we present results obtained using lamotrigine (two open trials), an agent known to inhibit glutamate release, and picotamide, an antiplatelet drug, in the prophylactic treatment of MwA sufferers. Lamotrigine significantly reduced the frequency of MwA attacks, and picotamide together with lamotrigine reduced the duration and/or the occurrence of auras. In comparison to lamotrigine, the therapy with picotamide may have some advantages such as the use of the therapeutic dose from the first day of treatment (lamotrigine needs one month or more to reach such a dose) and the possibility to prevent cerebral ischaemic events and migraine stroke, a rare but severe complication of MwA attacks. [ABSTRACT FROM AUTHOR]

Frailty is an aging-related pathology, defined as a state of increased vulnerability to stressors, leading to a limited capacity to meet homeostatic demands. Extracellular microRNAs (miRNAs) were proposed as potential biomarkers of various disease conditions, including age-related pathologies. The primary objective of this study was to identify blood miRNAs that could serve as potential biomarkers and candidate mechanisms of frailty. Using the Fried index, we enrolled 22 robust and 19 frail subjects. Blood and urine samples were analysed for several biochemical parameters. We observed that sTNF-R was robustly upregulated in the frail group, indicating the presence of an inflammatory state. Further, by RNA-seq, we profiled 2654 mature miRNAs in the whole blood of the two groups. Expression levels of selected differentially expressed miRNAs were validated by qPCR, and target prediction analyses were performed for the dysregulated miRNAs. We identified 2 miRNAs able to significantly differentiate frail patients from robust subjects. Both miR-101-3p and miR-142-5p were found to be downregulated in the frail vs. robust group. Finally, using bioinformatics targets prediction tools, we explored the potential molecular mechanisms and cellular pathways regulated by the two miRNAs and potentially involved in frailty.

Background: Oxidative stress may be the cause or effect of several pathogenetic processes such as neurodegenerative diseases. The aim of this paper was to evaluate the diagnostic efficacy in Parkinson's disease (PKD) of a panel of oxidative stress markers selected from the many proposed by the most recent literature., Methods: 23 molecules including both plasma and urinary oxidative markers such total radical oxygen species, homocysteine, biological antioxidant potential, glutathione, superoxide dismutase, uric acid, total bilirubin, iron, ferritin, coenzyme Q10, 3-nitrotyrosine, total lipoperoxides, 4-hydroxy-nonenal, and 8-hydroxy-deoxy-guanosine were determined both in PKD and aged control subjects. For each analyte and group, the respective reference intervals were determined. Statistical analysis was used to assess the existence of significant differences between intervals in order to indicate which markers can better characterize PKD and distinguish it from the control population., Results: Some parameters were different in both groups when compared to those observed in younger subjects, supporting the hypothesis that aging is associated with an increase of oxidative stress. A peculiar increase of oxidative damage on nucleic acids was found in PKD, as well as a less efficient turnover of the DNA and an increase of protein peroxidation., Conclusions: Our results demonstrate that in PKD there is an increase of oxidative attack on nucleic acids and that the protein nitration is a characteristic phenomenon. These observations are in good agreement with the hypothesis that in PKD oxidative damage occurs that counter-regulatory systems attempt to balance, but inefficiently.

The Movement Disorder Society-sponsored revision of the Unified Parkinson's Disease Rating Scale (MDS-UPDRS) has been available in English since 2008. As part of this process, the MDS-UPDRS organizing team developed guidelines for development of official non-English translations. We present here the formal process for completing officially approved non-English versions of the MDS-UPDRS and specifically focus on the first of these versions in Italian. The MDS-UPDRS was translated into Italian and tested in 377 native-Italian speaking PD patients. Confirmatory and exploratory factor analyses determined whether the factor structure for the English-language MDS-UPDRS could be confirmed in data collected using the Italian translation. To be designated an 'Official MDS translation,' the Comparative Fit Index (CFI) had to be ≥0.90 relative to the English-language version. For all four parts of the Italian MDS-UPDRS, the CFI, in comparison with the English-language data, was ≥0.94. Exploratory factor analyses revealed some differences between the two datasets, however these differences were considered to be within an acceptable range. The Italian version of the MDS-UPDRS reaches the criterion to be designated as an Official Translation and is now available for use. This protocol will serve as outline for further validation of this in multiple languages.

Background: Oxidative stress may be directly or indirectly involved in the pathogenesis of Parkinson's disease (PD). 8-hydroxy-2'deoxyguanosine (8-OHdG) is the major product of DNA oxidative damage but its determination in plasma or urine may have controversial significance. The concentration of 8-OHdG not only depends on its oxidation rate but also on the efficacy of the DNA repairing systems., Methods: We studied the ratio between 8-OHdG and 2-dG (the corresponding not hydroxylated base 2'-deoxyguanosine) in plasma and urine as a marker of oxydative stress in PD. This enabled the determination of the real DNA damage in terms of oxidation rate regardless of the efficacy of the DNA repairing mechanisms., Results: We optimized two different analytical methods: one for 8-OHdG and the other for 2-dG, both based on a common preliminary solid-phase extraction step (SPE) followed by two different HPLC analytical separations with electrochemical detection (HPLC-ED). The reliability of these methods was confirmed by analysing plasma and urine samples collected in parkinsonian patients and in age-matched healthy control subjects., Conclusions: In urine samples, the measurement of 8-OHdG alone as well as the ratio 8-OHdG/2-dG were significantly different in healthy controls and PD patients. In plasma samples, only the ratio 8-OHdG/2-dG was significantly higher in PD compared to healthy controls showing that the ratio 8-OHdG/2-dG is a reliable diagnostic tool in studies on DNA oxydative damage.

Recent evidence suggests that trace amines such as tyramine and octopamine, alternative products of tyrosine metabolism (an aminoacid parent of dopamine and noradrenaline), play a role in the homeostasis of the extrapyramidal system. However, the relevance of these trace amines in the pathogenesis of Parkinson's disease is still largely unknown. Here, we assessed the plasma levels of octopamine and noradrenaline in three sub-groups of PD patients, namely de novo, non-fluctuating and fluctuating patients, versus age-matched control subjects. We show that octopamine is detectable in plasma of all subjects, the mean levels of which are significantly lower in PD patients, including de novo patients, when compared to controls (p<0.001). Unlike this, no changes in plasmatic noradrenaline levels were found in the de novo patients, but only in plasma of fluctuating and non-fluctuating PD patients. These findings raise the possibility that Parkinson's disease is firstly characterized by abnormalities of tyrosine decarboxylase, rather than tyrosine hydroxylase, enzyme activity. Given the role of this enzyme in the production of trace amines, circulating octopamine levels may hold promise as a biomarker of early Parkinson's disease., ((c) 2010 Elsevier Ireland Ltd. All rights reserved.)

Objective: In many parkinsonian patients with fluctuating disease the early morning levodopa dose is more effective than the following dose on the same day. In this study we investigated whether the poor responsiveness to the early afternoon dose of levodopa depends only on peripheral and central levodopa pharmacokinetics or also on pharmacodynamic factors., Methods: Ten parkinsonian patients experiencing postprandial drug-resistant off periods received two boluses of apomorphine by subcutaneous injection at 8 am and 3 pm on two nonconsecutive days. On day 2, therapy was stopped at 11 am. For each bolus we determined time to on, duration of the on state, magnitude of benefit, and levodopa and apomorphine plasma levels at baseline and immediately after patients reached the on state., Results: The mean duration of on phases was significantly shorter and the apomorphine plasma level needed to reach the on state was significantly higher in the afternoon than in the morning (P<0.01 by paired t test)., Conclusions: This study suggest that there is a change in responsiveness to dopaminergic stimulation during the day. The less effective dopaminergic response in afternoon depends on pharmacodynamic factors and not only on peripheral and central levodopa pharmacokinetic.

The authors investigated the long-duration response to levodopa in advanced Parkinson's disease. Eight patients with advanced Parkinson's disease disabled by severe ON/OFF fluctuations treated by chronic daytime subcutaneous apomorphine infusion with supplemental oral levodopa were studied. On day 1, oral levodopa was withdrawn at 4:00 pm and on the following morning subcutaneous apomorphine infusion was continued at the same rate without levodopa therapy. While receiving apomorphine alone, seven of the eight patients turned ON, and their usual dyskinesias returned. The ON phase persisted for 60 to 100 minutes (mean, 185.7 minutes) but then, despite continued, constant-rate apomorphine infusion to stabilize plasma levels, switched to an OFF phase. The authors conclude that the clinical effect of apomorphine is sustained by levodopa long-duration response. This effect is probably the result of postsynaptic mechanisms. In patients with advanced Parkinson's disease, the long-duration response to levodopa is present although slightly diminished.

Background: Paroxetine has demonstrated efficacy in depression and anxiety disorders, including generalized anxiety disorder (GAD). This 32-week study evaluated the maintained efficacy and safety of paroxetine in GAD by assessing the potential for relapse after discontinuation of medication., Method: Adults (N = 652) with DSM-IV GAD and a Clinical Global Impressions-Severity of Illness (CGI-S) score > or = 4 received paroxetine (20-50 mg/day) for 8 weeks. Patients whose CGI-S score had decreased by at least 2 points to < or = 3 at week 8 were randomly assigned to double-blind treatment with paroxetine (N = 278) or placebo (N = 288) for a further 24 weeks. The primary efficacy parameter was the proportion of patients relapsing (an increase in CGI-S score of at least 2 points to a score < or = 4 or withdrawal resulting from lack of efficacy) during double-blind treatment., Results: Significantly fewer paroxetine than placebo patients relapsed during the 24-week double-blind phase (10.9% vs. 39.9%; p <.001). Placebo patients were almost 5 times more likely to relapse than paroxetine patients (estimated hazard ratio = 0.213 [95% CI = 0.1 to 0.3]; p <.001). Statistical significance in favor of paroxetine was demonstrated for all secondary efficacy parameters, including functional status. Twice as many paroxetine patients as placebo patients (73%) achieved remission. Paroxetine was well tolerated, with no unexpected adverse events reported., Conclusion: Paroxetine was found to be effective and well tolerated for both the short- and long-term treatment of DSM-IV GAD. Continued treatment with paroxetine significantly reduced the potential for relapse of GAD symptoms.

The nature of sleep is one of the major sources of dissatisfaction with the quality of life among patients with Parkinson's disease (PD). Difficult sleep maintenance (light and fragmented sleep) and difficulties with sleep initiation are the earliest and most frequent sleep disorders observed in these patients. Sleep disorders are also common in the normal elderly population, suggesting that normal aging may play a role in the etiology of sleep disorders in PD. Factor et al. examined the frequency of various sleep disorders in PD and compared them to those of normal elderly subjects. Sleep fragmentation and spontaneous daytime dozing occurred much more frequently in PD patients than in controls. Sleep fragmentation in PD may be due to an increased skeletal muscle activity, disturbed breathing and REM/non-REM variations of the dopaminergic receptor sensitivity. In parkinsonian patients who developed motor fluctuations (on-off phenomenon, wearing-off) during the day, other common sleep-related motor complaints including nocturnal akinesia, dystonia and painful cramps are observed. In a double-blind cross-over study, we compared the efficacy of a single dose of a chronic release formulation of levodopa/carbidopa (Sinemet CR) with that of a placebo in improving sleep-related motor disturbances in a group of 40 fluctuating PD patients. Sinemet CR significantly improved nocturnal akinesia and increased the hours of sleep in this group of patients. Initiation and maintenance of sleep are problems that may not be solved with antiparkinsonian treatment.

A single dose of levodopa (L-DOPA) reduces motor disability in Parkinson's disease (PD) for a few hours, a short-duration effect. However, there are suggestions that L-DOPA may also produce a long-duration benefit of some days. In the present study, we examined the long-duration action of L-DOPA by observing the time taken to achieve maximum stable benefit after starting a constant dose of sinemet-CR (sinemet-CR) (200 g L-DOPA/50 mg carbidopa) twice daily in nine newly diagnosed patients, and the time taken to deteriorate back to baseline after stopping treatment. A single dose of sinemet-CR (200 mg L-DOPA/50 mg carbidopa) had little obvious short-duration action on the Unified PD Rating Scale (UPDRS) motor scores in the majority of patients, either before starting chronic sinemet-CR therapy (200 mg L-DOPA/50 mg carbidopa, b.i.d.) or after chronic treatment. However, all patients gradually improved on chronic sinemet-CR therapy, taking 9.3 +/- 1.8 days to achieve maximum response. On stopping chronic sinemet-CR treatment, it took 6.8 +/- 3.0 days for the same patients to deteriorate back to baseline motor disability. In similar experiments, the time taken to deteriorate back to baseline after stopping treatment with the directly acting dopamine agonist ropinirole (9-21 mg daily) in eight other de novo patients with PD was found to be 6.2 +/- 1.7 days. The long-duration effect of L-DOPA and ropinirole may, therefore, be due to some slowly evolving postsynaptic pharmacodynamic change in the central nervous system (CNS). Loss of this long-duration action may be responsible for the emergence of motor fluctuations on chronic L-DOPA therapy.

Patients with advanced Parkinson's disease often develop severe fluctuations and dyskinesias while receiving long-term levodopa therapy. These complications can prove increasingly difficult to control. Here we review our strategies for coping with such problems. These include establishing the best rational schedule of levodopa treatment, optimizing levodopa absorption, the use of oral dopaminergic agonists, and the use of subcutaneous injections or infusions of apomorphine or lisuride. The problems of severe dyskinesias, sleep disturbances, psychotoxicity, and urinary difficulties also are considered. Finally, the role of new surgical procedures to treat Parkinson's disease is reviewed.

The pharmacological management of Parkinson's disease (PD) can be complicated by psychiatric disorders induced by antiparkinsonian drugs. The reduction or withdrawal of levodopa (l-dopa) and other drugs commonly used in the treatment of PD may attenuate the psychosis but exacerbate motor impairment and disability. Melperone is an atypical antipsychotic drug showing in vivo a greater relative affinity for the 5-HT2 than the D2 receptors. A two-year study to assess the clinical efficacy and the safety of melperone in the management of iatrogenic psychosis in 30 parkinsonian patients was carried out. Neurological evaluation was performed with patients in the "off" and in the "on" state using the motor examination of the Unified Parkinson's Disease Rating Scale (UPDRS). Time spent in "on" state was evaluated using the self-evaluation diary of daily life. To assess psychiatric disturbances the modified version of the Brief Psychiatric Rating Scale (BPRS) was used. The mean BPRS score was significantly reduced when comparing baseline with individual examinations; no statistically significant differences were found between subsequent examinations. UPDRS motor score and time spent in "on" state during daily life showed no statistically significant differences when comparing baseline with subsequent examinations. Two patients dropped out because of excessive sedation problems but in the remaining 28 patients melperone proved to be optimally tolerated.

Thirty-four patients with idiopathic fluctuating Parkinson's disease and early afternoon "delayed on" or severely resistant "off" periods, in spite of long-term antiparkinsonian therapy, were studied. The first afternoon levodopa administration was substituted with an equimolar dosage of the liquid formulation levodopa methyl ester (LDME). The major end-points for efficacy were latency to "on" and duration of "on" periods. The patients were divided into five subgroups according to their baseline treatment and they were evaluated monthly for 6 months using the Unified Parkinson's Disease Rating Scale. The patients completed weekly self-evaluation using an "on-off" chart. LDME was well tolerated by all the patients. A statistically significant reduction in latency to "on" was observed in all patients. The clinical effect of LDME remained stable during the treatment period (repeat measures ANOVA). The more rapid clinical effect of LDME and its stable and predictable antiparkinsonian activity represents a new and useful approach for treating patients with complicated Parkinson's disease.