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Background and purpose Depressed mood is a common psychiatric problem associated with Parkinson's disease ( PD), and studies have suggested a benefit of rasagiline treatment. Methods ACCORDO (see the [Appendix A]) was a 12-week, double-blind, placebo-controlled trial to evaluate the effects of rasagiline 1 mg/day on depressive symptoms and cognition in non-demented PD patients with depressive symptoms. The primary efficacy variable was the change from baseline to week 12 in depressive symptoms measured by the Beck Depression Inventory ( BDI- IA) total score. Secondary outcomes included change from baseline to week 12 in cognitive function as assessed by a comprehensive neuropsychological battery; Parkinson's disease quality of life questionnaire ( PDQ-39) scores; Apathy Scale scores; and Unified Parkinson's Disease Rating Scale ( UPDRS) subscores. Results One hundred and twenty-three patients were randomized. At week 12 there was no significant difference between groups for the reduction in total BDI- IA score (primary efficacy variable). However, analysis at week 4 did show a significant difference in favour of rasagiline (marginal means difference ± SE: rasagiline −5.46 ± 0.73 vs. placebo −3.22 ± 0.67; P = 0.026). There were no significant differences between groups on any cognitive test. Rasagiline significantly improved UPDRS Parts I ( P = 0.03) and II ( P = 0.003) scores versus placebo at week 12. Post hoc analyses showed the statistical superiority of rasagiline versus placebo in the UPDRS Part I depression item ( P = 0.04) and PDQ-39 mobility ( P = 0.007) and cognition domains ( P = 0.026). Conclusions Treatment with rasagiline did not have significant effects versus placebo on depressive symptoms or cognition in PD patients with moderate depressive symptoms. Although limited by lack of correction for multiple comparisons, post hoc analyses signalled some improvement in patient-rated cognitive and depression outcomes. [ABSTRACT FROM AUTHOR]

ABSTRACT Levodopa is effective for the motor symptoms of Parkinson's disease (PD), but is associated with motor fluctuations and dyskinesia. Many patients require add-on therapy to improve motor fluctuations without exacerbating dyskinesia. The objective of this Phase III, multicenter, double-blind, placebo-controlled, parallel-group study was to evaluate the efficacy and safety of safinamide, an α-aminoamide with dopaminergic and nondopaminergic mechanisms, as add-on to l-dopa in the treatment of patients with PD and motor fluctuations. Patients were randomized to oral safinamide 100 mg/day (n = 224), 50 mg/day (n = 223), or placebo (n = 222) for 24 weeks. The primary endpoint was total on time with no or nontroublesome dyskinesia (assessed using the Hauser patient diaries). Secondary endpoints included off time, Unified Parkinson's Disease Rating Scale (UPDRS) Part III (motor) scores, and Clinical Global Impression-Change (CGI-C). At week 24, mean ± SD increases in total on time with no or nontroublesome dyskinesia were 1.36 ± 2.625 hours for safinamide 100 mg/day, 1.37 ± 2.745 hours for safinamide 50 mg/day, and 0.97 ± 2.375 hours for placebo. Least squares means differences in both safinamide groups were significantly higher versus placebo. Improvements in off time, UPDRS Part III, and CGI-C were significantly greater in both safinamide groups versus placebo. There were no significant between-group differences for incidences of treatment-emergent adverse events (TEAEs) or TEAEs leading to discontinuation. The addition of safinamide 50 mg/day or 100 mg/day to l-dopa in patients with PD and motor fluctuations significantly increased total on time with no or nontroublesome dyskinesia, decreased off time, and improved parkinsonism, indicating that safinamide improves motor symptoms and parkinsonism without worsening dyskinesia. © 2013 International Parkinson and Movement Disorder Society [ABSTRACT FROM AUTHOR]

To evaluate the effects of 25-Hz deep brain stimulation of the nucleus tegmenti pedunculopontini (PPTg) on brain metabolic activity. Six patients with Parkinson's disease (PD) who had bilateral stereotactic implantation of PPTg at least 12 months prior to evaluation were included in our study. All underwent, in separate sessions, 18-FDG-PET in core assessment programme for intra-cerebral transplantation as well as motor evaluation [Unified Parkinson's disease rating scale (UPDRS) - section III] and a battery of cognitive testing. PPTg-ON (low bipolar contacts, 25 Hz) promoted a significant increase of glucose utilization in bilateral prefrontal areas including dorsolateral prefrontal cortex (DLPFC, BA9), orbito-frontal cortex (BA47), anterior cingulate (BA 25-32), superior frontal gyrus (BA 10) and supramarginal gyrus (BA40); a significant increase of uptake and consumption of FDG also occurred in the left ventral striatum, left subgyral (BA 46), right insula (BA 13) and right superior temporal gyrus (BA 22). PPTg-ON was associated with a significant decrease of glucose utilization in the left cerebellar anterior lobe (culmen) and right cerebellar posterior lobe (declive). In the same patients, PPTg-ON improved delayed recall ( P < 0.05) and executive functions whilst the UPDRS revealed a modest (−21%) and variable treatment effect. Low frequency stimulation of PPTg, a sub-region of the pedunculopontine nucleus complex, causes a minor motor benefit but a peculiar profile of cognitive improvement associated with a significant increase in FDG consumption in both prefrontal areas and mono-lateral ventral striatum. These data are consistent with multiple limbic and/or associative domains modulated by PPTg stimulation in our patients with PD. [ABSTRACT FROM AUTHOR]

Entacapone is a COMT inhibitor used in Parkinson's disease (PD) patients, as an adjunctive therapy tol-dopa in order to prolong its bioavailability and thus its clinical effect. However, previous studies reported entacapone-inducedl-dopa to have lowerCmax and delayedtmax values, coupled with a delayed onset of the clinical effect, possibly suggesting an interference between the two drugs. The aim of our study was to evaluate whether a delayed entacapone administration in association with standardl-dopa/carbidopa, may in some subjects improve the entacapone effects onl-dopa AUC and thus on the clinical‘on time’ duration.Twenty-eight idiopathic advanced PD patients were blindly evaluated in three different test days, following administration of carbidopa/l-dopa or carbidopa/l-dopa plus co-administered entacapone or plus entacapone administered with 30 min of delay.The AUC, the‘on time’ and UPDRS score of the whole group were improved by both modalities of entacapone administration. Anex postanalysis showed that the delayed entacapone administration produced a significant improvement in a subgroup of 10 non-responding patients to the co-administration.We suggest that the delayed administration should be attempted in the subjects not improved by entacapone co-administration. [ABSTRACT FROM AUTHOR]

In Parkinson’s disease (PD) patients, internal globus pallidus (GPi) stimulation has been reported to produce good effects on abnormal involuntary movements (AIM); less improvement has been observed in extrapyramidal symptoms. We assessed the effect of monopolar dorsal (uppermost), ventral (lowest) and bipolar (uppermost vs. lowest) bilateral globus pallidus stimulation by quadripolar electrode on extrapyramidal symptoms and AIM induced by a dose of apomorphine. Six PD patients were studied in OFF therapy condition after surgery without stimulation (STIM OFF) and during stimulation (STIM ON) with the three different modalities. All patients were evaluated by the unified Parkinson’s disease rating scale, section III (UPDRS) and by the AIM. Our results show that all three bilateral GPi stimulation modalities reduce the UPDRS score (between 49.7 and 31.5%), although the bipolar and lowest stimulation are the most effective. Similarly, bipolar and lowest stimulation were also the most effective in reducing the occurrence and intensity of the apomorphine-induced AIM. On the contrary, uppermost stimulation (UP ON) produced an AIM occurrence similar to that observed in the OFF stimulus condition. We suggest that bilateral GPi stimulation is an useful procedure to ameliorate extrapyramidal signs of advanced PD patients; however, it produces an antidyskinetic effect only if the ventral or the entire GPi is stimulated. On the contrary, the UP ON, most probably located in the external globus pallidus (GPe), does not modify the AIM occurrence. [ABSTRACT FROM AUTHOR]

Background and purpose: Transcranial direct current stimulation (TDCS) is a potential tool to improve motor deficits in chronic stroke patients. Safety and efficacy of this procedure in acute stroke patients have not yet been addressed. Methods: We performed in our stroke unit a single-centre randomized, double-blind, sham-controlled study to investigate safety and efficacy of anodal TDCS of the affected hemisphere in acute stroke patients. The second day from stroke onset, 50 acute stroke patients received either five-daily sessions of anodal (n = 25) at 2 mA for 20 min or sham TDCS (n = 25) to the ipsilesional primary motor cortex (M1). Motor deficit was assessed by the short form of the Fugl-Meyer motor scale (FM) and overall neurological deficit by the National Institute of Health Stroke Scale (NIHSS) at onset, at 5 days after stroke and after 3 months. Results: No side effects were detected during either TDCS or sham. In both groups, there was a significant improvement in NIHSS and FM scores, which did not significantly differ when comparing TDCS and sham. Conclusions: Five-daily sessions of anodal TDCS to the ipsilesional M1 appear to be safe in acute stroke patients but do not improve clinical outcome. [ABSTRACT FROM AUTHOR]

A letter to the editor about the influence of pedunculopontine nucleus stimulation on rapid eye movement sleep in parkinson's disease is presented.

Background: CagA-positive Helicobacter pylori infection has been found to be associated with a first-ever atherosclerotic stroke. The aim of this study was to investigate whether these strains represent an independent risk factor for recurrent atherosclerotic stroke., Materials and Methods: We performed a longitudinal study of patients with a first-ever large vessels stroke and resulted positive at H. pylori serology. Patients had clinical examination 1 month after the acute event, and were subsequently visited or contacted by telephone up to 3 years at 6-month intervals. Sera obtained at the time of enrollment were frozen and analyzed for the presence of anti-CagA antibodies at the end of the study. The primary outcome event was any fatal or nonfatal stroke after the index stroke., Results: One hundred seventy H. pylori-positive patients were included (n = 68 CagA positive and n = 102 CagA negative). No significant difference regarding age and other stroke risk factors was detected. According to Kaplan-Meier survival analysis, CagA-positive patients showed a significantly higher risk for stroke recurrence than CagA-negative ones (45.6% vs 17.6%; p < .001). Difference in the rate of recurrent stroke between the two groups persisted after Cox regression analysis taking into account possible confounding factors (hazard ratio = 3.5; 95% CI = 1.9-6.4; p < .001)., Conclusions: Infection with H. pylori CagA-positive strains increases the risk of recurrent atherosclerotic stroke. Seropositivity determination should be performed in order to identify high-risk patients requiring a strict clinical surveillance, and the possible beneficial effect of eradication therapy should be evaluated.

Recent data suggest a potential role of pedunculopontine nucleus (PPN) electrical stimulation in improving gait and posture in Parkinson's disease. Because the PPN receives fibres from the subthalamic nucleus (STN), we investigated the effects of STN-high-frequency stimulation (HFS) on PPN neuronal activity in intact rats and in rats bearing either an ibotenate lesion of the entopeduncular nucleus (EP) or a lesion of the substantia nigra (SN). The main response of PPN neurons to STN single-shock stimulations in the three experimental groups was a short latency (4.5 +/- 2.1 ms) and brief (15.3 +/- 6.5 ms) excitation. This response was maintained during 1-5 s of STN-HFS (130 Hz, 60 micros, 100-1000 microA). In EP-lesioned rats the percentage (75.0%) of PPN neurons showing a modulation of activity following STN-HFS was significantly higher compared with that observed in intact (39.7%) and in SN-lesioned rats (35.4%). Furthermore, in EP-lesioned rats the most frequent response of PPN neurons following STN-HFS was a 5-20 s excitation, which was present in 76.6% of responsive neurons in comparison to 15.4% and 9.1% of neurons responsive in intact and in 6-hydroxydopamine-lesioned rats, respectively. Neurons responsive to STN-HFS in the three experimental groups showed either a sharp positively skewed distribution of interspike intervals or multisecond oscillations in autocorrelograms. The results support that STN-HFS modulates the PPN through a balance of excitatory and inhibitory influences, which may be independent from the dopaminergic nigral neurons. In the absence of inhibitory EP fibres, the direct excitatory influence exerted by the STN on the PPN appears to predominate.

To understand the events underlying the clinical efficacy of deep brain stimulation (DBS) of the subthalamic nucleus (STN), electrophysiological recordings and microdialysis evaluations were carried out in the substantia nigra pars reticulata (SNr), one of the two basal ganglia (BG) nuclei targeted by STN output, in patients with Parkinson's disease (PD). Clinically effective STN-DBS caused a significant increase of the SNr firing rate. The poststimulus histogram (PSTH) showed an excitation peak at 1.92-3.85 ms after the STN stimulus. The spontaneous discharge of SNr neurons was driven at the frequency of the stimulation (130 Hz), as shown in the autocorrelograms (AutoCrl). The fast Fourier transform (FFT) analysis showed a peak at 130 Hz, and a less pronounced second one at 260 Hz. Accordingly, in the distribution of the interspike intervals (ISIs), the mode was earlier, and skewness more asymmetric. Biochemically, the increased excitatory driving from the STN was reflected by a clear-cut increase in cyclic guanosine 3',5'-monophosphate (cGMP) levels in the SNr. These results indicate that the beneficial effect of DBS in PD patients is paralleled with a stimulus-synchronized activation of the STN target, SNr. Our findings suggest that, during STN-DBS, a critical change towards a high-frequency oscillatory discharge occurs.