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The effect of dopamine agonists (DAs) on cognition in Parkinson's disease (PD) is not yet completely established. Previous papers reported a worsening effect on some cognitive functions with some DAs, but not with others, suggesting that DAs may differently affect cognition in PD patients according to their pharmacological characteristics. We set out to test the effect of rotigotine and cabergoline on cognitive functions in a group of forty non-demented early-mild PD patients (HY2). Subjects were randomly divided into two groups and evaluated in a randomized cross-over study using neuropsychological tests; at the same time, motor function was monitored under three different treatment conditions: DA (rotigotine or cabergoline), L-dopa, and off therapy. Rotigotine and cabergoline were chosen because while they share a mixed D1 and D2 receptor profile, the former is non-ergolinic and the latter ergolinic. No significant differences were found in cognitive function between the basal condition and the DA treatments. On the basis of the present data, which we compare with previous findings regarding pramipexole IR and pergolide, we hypothesize that combined stimulation of both dopamine receptor families, as occurs with rotigotine, cabergoline, L-dopa and pergolide, may preserve cognitive functions more than pure D2 family stimulation.

Background and Purpose— DP-b99, a lipophilic moderate-affinity chelator of zinc, was postulated to improve recovery after acute ischemic stroke. We evaluated the safety and therapeutic effects of DP-b99 in patients with acute hemispheric ischemic stroke. Methods— The Membrane-Activated Chelator Stroke Intervention trial was a randomized, double-blind, placebo-controlled, multicenter, parallel-group trial of intravenous DP-b99 administered for 4 consecutive days (NCT00893867). Acute ischemic stroke patients within 9 hours of onset, but untreated by alteplase, with a baseline National Institutes of Health Stroke Scale score of 10 to 16, and evidence of language dysfunction, visual field defect, and neglect were eligible. The primary efficacy analysis compared distributions of functional status measured by modified Rankin score in the intent-to-treat population of patients with any post-treatment outcome, adjusted for initial severity. Functional and neurological recovery were secondary measures. Home time was an exploratory end point. Results— Enrollment terminated at n=446 after the planned interim analysis determined futility; follow-up continued. Final modified Rankin score distributions were equal between DP-b99 and placebo-treated groups ( P =0.10; P adj adjusted for baseline age and National Institutes of Health Stroke Scale=0.21). Fewer patients recovered to modified Rankin score ≤1 in the DP-b99–treated group (45/218; 20.6%) than after placebo (63/219; 28.8%) ( P =0.05; P adj =0.10). Similarly, fewer patients attained National Institutes of Health Stroke Scale ≤1 after DP-b99 (42/218; 19.3%) than placebo (56/219; 25.6%; P =0.10; P adj =0.26). Mortality was similar between DP-b99 and placebo intent-to-treat groups (36/218; 16.5% vs 33/219; 15.1%; P =0.68). Home time was unchanged by treatment (median 36 vs 36.5 days; P =0.25). Conclusions— Despite encouraging preclinical and phase II trial data, DP-b99 shows no evidence of efficacy in treating human ischemic stroke.

Assessing the frequency of Wearing-Off (WO) in Parkinson's disease (PD) patients, and its impact on Quality of Life (QoL). METHODS: Consecutive ambulatory patients, who were on dopaminergic treatment for ≥ 1 year, were included in this multicentre, observational cross-sectional study. In a single visit, WO was diagnosed based on neurologist assessment as well as using the validated Italian version of a patient self-rated 19-question Wearing-Off Questionnaire (WOQ-19); WO was defined for scores ≥ 2. QoL was evaluated by the 8-item Parkinson's Disease Questionnaire (PDQ-8). RESULTS: 617 subjects were included, with a mean anti-Parkinson treatment duration of 6.6 ± 4.6 years, 87.2% were on levodopa treatment. Neurologists identified presence of WO in 351 subjects (56.9%), whereas 415 subjects (67.3%) were identified by the self-administered WOQ-19. In patients with a

Non-motor symptoms are gaining relevance in Parkinson's disease (PD) management but little is known about their progression and contribution to deterioration of quality of life. We followed prospectively 707 PD patients (62 % males) for 2 years. We assessed non-motor symptoms referred to 12 different domains, each including 1-10 specific symptoms, as well as motor state (UPDRS), general cognition, and life quality. HoehnYahr (HY) stage was used to categorize patient status (I-II mild; III moderate; IV-V severe). We found that individual non-motor symptoms had variable evolution over the 2-year follow-up with sleep, gastrointestinal, attention/memory and skin disturbances (hyperhidrosis and seborrhea) becoming more prevalent and psychiatric, cardiovascular, and respiratory disorders becoming less prevalent. Development of symptoms in the cardiovascular, apathy, urinary, psychiatric, and fatigue domains was associated with significant life-quality worsening (p0.0045, alpha with Bonferroni correction). During the observation period, 123 patients (17 %) worsened clinically while 584 were rated as stable. There was a fivefold greater increase in UPDRS motor score in worse compared with stable patients over 24 months (p0.0001 vs. baseline both in stable and worse group). The total number of reported non-motor symptoms increased over 24 months in patients with motor worsening compared to stable ones (p0.001). Thirty-nine patients died (3.4 % of patients evaluable at baseline) with mean age at death of 74 years. Deceased patients were older, had significantly higher HY stage and motor score, and reported a greater number of non-motor symptoms at baseline. In conclusion, overall non-motor symptom progression does not follow motor deterioration, is symptom-specific, and only development of specific domains negatively impacts quality of life. These results have consequences for drug studies targeting non-motor features.

Rationale Intravenous (i.v.) thrombolysis with recombinant tissue-Plasminogen Activator (rt-PA) (alteplase) within three hours from symptom onset is the only approved treatment of pharmacological revascularization in acute ischaemic stroke. However, the current license limits the use of rt-PA to patients aged ≤80 years due to the lack of evidence of safety and efficacy of this treatment in the elderly from randomized clinical trials. This article describes the design of the Thrombolysis in Elderly Stroke Patients in Italy (TESPI) trial planned to fill the lack of controlled data on i.v. thrombolysis in this age category of stroke patients. Aims To collect efficacy and safety data on i.v. alteplase (rt-PA) in patients aged more than 80 years, to demonstrate that the treatment of these patients within three hours of symptoms onset of an acute ischaemic stroke with i.v. rt-PA, compared to patients receiving standard treatment (according to the national guidelines), will result in an improved clinical outcome with a favourable benefit/risk ratio. Design TESPI is a prospective, multicenter, national, open-label, controlled (non-treated group as control), randomized, parallel group trial with blinded evaluation of outcome in patients older than 80 years treated with i.v. rt-PA within three hours after ischaemic stroke onset. The randomization procedure assigns patients to the treatment group with IV alteplase (0.9 mg/kg of body weight) or to standard treatment group with a 1 : 1 basis. A three-month follow-up, when applicable, is performed by a blind assessor. Six hundred patients will be enrolled (300 patients per arm) The study period has been planned to be of three years. Study Outcomes The primary efficacy end-point is the disability at day 90, dichotomized as a favourable outcome (modified Rankin Scale 0–2) or unfavourable outcome (modified Rankin Scale 3–6). The main primary safety end-point is symptomatic intracerebral haemorrhage defined as any hemorrhage at the 22–36 h post-treatment scan combined with neurological deterioration leading to an increase of one or more points at the National Institutes of Health Stroke Scale. The TESPI trial, with the protocol number FARM65KNKY, is registered in the European Union Drug Regulating Authorities Clinical Trials database with the number 2007-006177-88 and in the Stroke Trials Registry of the Washington University Internet Stroke Center.

Heterozygous rare variants in the PINK1 gene, as well as in other genes causing autosomal recessive parkinsonism, have been reported both in patients and healthy controls. Their pathogenic significance is uncertain, but they have been suggested to represent risk factors to develop Parkinson disease (PD). The few large studies that assessed the frequency of PINK1 heterozygotes in cases and controls yielded controversial results, and the phenotypic spectrum is largely unknown. We retrospectively analyzed the occurrence of PINK1 heterozygous rare variants in over 1100 sporadic and familial patients of all onset ages and in 400 controls. Twenty patients and 6 controls were heterozygous, with frequencies (1.8% vs. 1.5%) not significantly different in the two groups. Clinical features of heterozygotes were indistinguishable to those of wild-type patients, with mean disease onset 10 years later than in carriers of two mutations but worse disease progression. A meta-analysis indicated that, in PINK1 heterozygotes, the PD risk is only slightly increased with a non significant odds ratio of 1.62. These findings suggest that PINK1 heterozygous rare variants play only a minor susceptibility role in the context of a multifactorial model of PD. Hence, their significance should be kept distinct from that of homozygous/compound heterozygous mutations, that cause parkinsonism inherited in a mendelian fashion. © 2008 Wiley-Liss, Inc.

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 (P0.05) 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.

Pathological oscillations characterize the firing discharge of different basal ganglia (BG) stations in rat models of Parkinson's disease. Most recent literature focused on the prominence of the beta frequency band in awake rats. Yet, in 6-hydroxydopamine-lesioned animals, the firing discharge of the globus pallidus (GP) and the substantia nigra reticulata are in phase with urethane-induced slow wave cortical activity. The neuronal basis of this pathological synergy at low frequency is widely debated. In order to understand the role of substantia nigra pars compacta (SNc) signalling in the development of pathological synchronization, we performed a pharmacological inactivation of the medial forebrain bundle (MFB) through tetrodotoxin (TTX), which led to a dramatic, but reversible, reduction of the dopamine content in the striatum. This procedure caused a significant contralateral akinesia, detectable as soon as anaesthesia vanished, and lasting about 3-4 h. We sought to determine the electrophysiological counterpart of this transient Parkinsonian-like hypokinetic syndrome. Hence, we obtained the electrocorticogram (ECoG) and single unit recordings from GP and subthalamic nucleus (STN) in normal rats before and after the TTX injection in MFB. Intriguingly, the TTX-mediated inactivation of MFB induced a fast developing coherence between cortex and GP and a significant increase of the cortex/STN synchronization. The intra-GP iontophoretic delivery of haloperidol or the GABA(A) receptor antagonist bicuculline induced a short term cortex/GP synchronization. Strikingly, STN inactivation by local muscimol reversed both haloperidol- and TTX-mediated coherence between cortex and GP. Our data show that an abnormal cortical/BG synchronization, at low frequency, can be reproduced also without SNc neuronal loss and striatal cytoarchitectonic alterations. In addition, our results, which represent an acute and reversible Parkinsonism based upon impaired cable properties, seem compatible with the interpretation of acute changes of the functional interplay between cortex and the STN-GP pathway as a key factor mechanism underlying the fast deep brain stimulation-induced acute Off-On transitions.

The intra-laminar (IL) thalamic complex, composed of centromedian (CM) and parafascicular (Pf) nucleus, is a strategic crossroad for the activity of the basal ganglia and is recently regaining its position has a putative neurosurgical target for Parkinsonian syndromes. The multi-target approach we have encouraged since the late nineties has allowed the combined implantation of a standard target (the subthalamic nucleus-STN or the internal pallidus-GPi) plus an innovative one (CM/Pf) in well-identified Parkinson's disease (PD) patients; hence, it is possible to study, in the same PD patients, the specific target-mediated effects on different clinical signs. Here, we focus on the potential usefulness of implanting the CM/Pf complex when required in the management of contra-lateral tremor (resistant to standard deep brain stimulation-DBS - in STN - , n=2) and disabling involuntary movements, partially responsive to GPi-DBS (n=6). When considering global UPDRS scores, CM/Pf-DBS ameliorate extra-pyramidal symptoms but not as strongly as STN (or GPi) does. Yet, CM/Pf acts very powerfully on tremor and contributes to the long-term management of l-Dopa-induced involuntary movements. The lack of cognitive deficits and psychic impairment associated with the improvement of their quality of life, in our small cohort of CM/Pf implanted patients, reinforces the notion of CM/Pf as a safe and attractive area for surgical treatment of advanced PD, possibly affecting not only motor but also associative functions.

PRIAMO (PaRkinson And non Motor symptOms) is an epidemiology study aimed to assess the prevalence and incidence of non-motor symptoms (NMS) in patients with parkinsonism. PRIAMO consists of two phases: (1) a transversal assessment of the prevalence of NMS and (2) a longitudinal observation with two follow-up visits at 12 and 24 months to establish the incidence of NMS. A secondary aim of PRIAMO is to study the relationship between NMS and quality of life. Patients with parkinsonism have been evaluated in 59 Neurology Centres widely distributed throughout Italy. PRIAMO has analysed a total of 1307 patients (out of 1325 initially enrolled). We expect that PRIAMO will substantially help to quantify the burden of NMS in patients with parkinsonism.