M. Onofrj

Peripheral cytokines profile in Parkinson's disease

Higher levels of proinflammatory cytokines are found in Parkinsons disease (PD) patients brains and inflammation is thought to be a major contributor to the neurodegeneration. During the inflammatory process, microglial release of proinflammatory cytokines act on the endothelium of blood-brain barrier (BBB) cells to stimulate upregulation of adhesion molecules. Consequently, this upregulation leads to the recruitment of passing T cells and monocytes, which express the counter receptors, that then go on to release more cytokines [Whitton, P.S., 2007. Inflammation as a causative factor in the aetiology of Parkinsons disease, Br. J. Pharmacol. 50, 963-976; Kortekaas, R., Leenders, K.L., Van Oostrom, J.C., Vaalburg, W., Bart, J., Willemsen, A.T., Hendrikse, N.H., 2005. Blood-brain barrier dysfunction in parkinsonian midbrain in vivo, Ann. Neurol. 57, 176-179]. In addition, a systemic inflammatory response results in the production of cytokines which circulate in the blood and communicate with neurons within the brain. Thus, a central inflammatory reaction interacts with peripheral blood mononuclear cells (PBMCs) modulating immune activity. The present study investigates levels of production and expression of cyto/chemokines by PBMCs in PD patients. Basal and LPS-induced levels of MCP-1, RANTES, MIP-1alpha, IL-8, IFNgamma, IL-1beta and TNFalpha were significantly higher in PD patients than in HC subjects (p<0.001), as determined by RT-PCR and Elisa methods. Cyto/chemokine levels were significantly correlated with UPDRS III and H/Y stage (p<0.001). The Pearsons correlation coefficient (R) was also used to assess the strength of the relationship between NF-kappaBp65 levels and all studied cyto/chemokines and between NF-kappaBp65, UPDRS III and H/Y score in PD patients. The overall results strengthen and extend the knowledge of the peripheral dysregulation in the cytokine network associated with PD.

EEG comparisons in early Alzheimer's disease, dementia with Lewy bodies and Parkinson's disease with dementia patients with a 2-year follow-up

EEG abnormalities have been reported for both dementia with Lewy bodies (DLB) and Alzheimers disease (AD). Although it has been suggested that variations in mean EEG frequency are greater in the former, the existence of meaningful differences remains controversial. No evidence is as yet available for Parkinsons disease with dementia (PDD). The aim of this study was to evaluate whether EEG abnormalities can discriminate between DLB, AD and PDD in the earliest stages of dementia and to do this 50 DLB, 50 AD and 40 PDD patients with slight cognitive impairment at first visit (MMSE > or = 20) were studied. To improve clinical diagnostic accuracy, special emphasis was placed on identifying cognitive fluctuations and REM-sleep behaviour disorder. EEG variability was assessed by mean frequency analysis and compressed spectral arrays (CSA) in order to detect changes over time from different scalp derivations. Patients initial diagnoses were revised at a 2-year follow-up visit with neuroimaging evaluation. Initial diagnoses were confirmed in 36 DLB, 40 AD and 35 PDD patients. The most relevant group differences were observed between the AD and DLB patients in EEGs from posterior derivations (P<0.001). Dominant frequencies were 8.3 +/- 0.6 Hz for the AD group and 7.4 +/- 1.6 Hz for the DLB group, in which most of the patients (88%) exhibited a frequency band of 5.6-7.9 Hz. Dominant frequency variability also differed between the AD (1.1 +/- 0.4 Hz) and DLB groups (1.8 +/- 1.2 Hz, P<0.001). Of note, less than a half (46%) of the patients with PDD exhibited the EEG abnormalities seen in those with DLB. Graded according to the presence of alpha activity, five different patterns were identified on EEG CSA from posterior derivations. A pattern with dominant alpha bands was observed in patients with AD alone while, in those with DLB and PDD, the degree to which residual alpha and 5.6-7.9 bands appeared was related to the presence and severity of cognitive fluctuations. At follow-up, EEG abnormalities from posterior leads were seen in all subjects with DLB and in three-quarters of those with PDD. Of interest, in four patients initially labelled as having AD, in whom the occurrence of fluctuations and/or REM-sleep behaviour disorder during the 2-year follow-up had made the diagnosis of AD questionable, the initial EEG was characterized by the features observed in the DLB group. If revised consensus criteria for DLB diagnosis are properly applied (i.e. emphasizing the diagnostic weight of fluctuations and REM sleep behaviour disorder), EEG recording may act to support discrimination between AD and DLB at the earliest stages of dementia, since characteristic abnormalities may even precede the appearance of distinctive clinical features.

Incidence of RBD and hallucination in patients affected by Parkinson's disease: 8-year follow-up

Abstract. We describe the 8-years follow-up of 80 patients affected by idiopathic, L-dopa-responsive Parkinsons disease. All patients were evaluated at baseline and during the follow-up with visual evoked potential, P300 event related potentials and polysomnography. The patients and their relatives compiled sleep and hallucination questionnaires. Statistical analysis was performed to evaluate if visual abnormalities, abnormal P300 recordings or sleep disturbances were linked to the development and hallucinations. Our results show that abnormal vision and abnormal P300 did not correlate with the incidence of hallucinations. However, the presence of REM sleep behavioral disorder (RBD) was significantly related to the development of hallucinations,independently of age, gender or duration of disease but dependent on the amount of dopaminoagonist treatment.

Agomelatine versus venlafaxine XR in the treatment of anhedonia in major depressive disorder: a pilot study

Abstract The primary aim of the present study was to compare the effects of agomelatine (AGO) and venlafaxine XR (VLX) on anhedonia in patients with major depressive disorder. Secondary end points were to test its antidepressant and anxiolytic efficacy. Sixty patients were enrolled and randomly assigned to two different treatments: AGO (25-50 mg/d; n = 30 subjects) or VLX (75-150 mg/d, n = 30 subjects). Psychopathological assessment was performed at baseline and after 8 weeks of treatment with the Snaith Hamilton Rating Scale (SHAPS), the Hamilton Depression Rating Scale, the Hamilton Anxiety Rating Scale, and the Clinical Global Impression for anhedonia, depression, anxiety, and global improvement, respectively. Both groups showed a significant reduction in time for the SHAPS, the Hamilton Depression Rating Scale, and the Hamilton Anxiety Rating Scale. A significant between-group difference was observed for SHAPS scores: patients treated with AGO showed a more relevant reduction compared with that in VLX-treated patients. Moreover, only patients treated with AGO showed a statistically significant improvement in Clinical Global Impression scores. In this study, AGO showed significantly greater efficacy on anhedonia and similar antidepressant efficacy to the serotonin-norepinephrine reuptake inhibitor VLX in patients with major depressive disorder during an 8-week treatment period. Anhedonia has been considered a potential trait marker related to vulnerability for depression. Therefore, the efficacy of AGO on this dimension holds particular importance in the treatment of patients with anhedonic features.

Acute akinesia or akinetic crisis in Parkinson's disease.

Abstract.In 22 patients with idiopathic Parkinson’s disease wenobserved a sudden worsening of motor symptoms and severenakinesia during hospitalization because of infectious diseases,nbone fractures, surgery for gastrointestinal tract diseases, andniatrogenic causes. Of these patients, 12 recovered completely, 6nhad a partial recovery, and 4 died. Treatments includednsubcutaneous apomorphine/lisuride infusion and dantreolene (withna creatine phosphokinase level higher than 200 IU). In allnpatients a definite refractoriness to therapy was shown with antransient lack of response to apomorphine.

Recurrent and fatal akinetic crisis in genetic‐mitochondrial parkinsonisms

Akinetic crisis (AC) is the most severe and possibly lethal complication of parkinsonism. It occurs with an incidence of 3‰ Parkinsons disease patients per year, but it is not known whether genetically determined parkinsonism is more or less susceptible to this complication.

Protracted benefit from paradoxical kinesia in typical and atypical parkinsonisms

Paradoxical kinesia (PK) is the sudden resolution of a previously stabilized akinesia in an advanced idiopathic Parkinson’s disease (IPD) patient facing an immediate threat. We are reporting the effect of PK, as a consequence of a life threatening event (earthquake), in a group of 14 patients with parkinsonism and dementia in Hoehn/Yahr (H/Y) stage 3–5. All the patients presented an extraordinary motor response during the earthquake that has recently stricken the Italian city of L’Aquila. All of them were able to safely escape unaided and, in some cases, to assist their families, despite they suffered before from severe night time akinesia and gait difficulties with postural instability requiring assistance. In five patients, the improvement of motor disabilities, particularly of freezing, lasted for 2–5xa0months.

Long half-life and prolonged-release dopamine receptor agonists: a review of ropinirole prolonged-release studies

Our review summarizes the five main studies conducted to evaluate the efficacy and pharmacokinetics of ropinirole prolonged release (PR) in Parkinsons disease (PD). The PR formulation was developed with Geomatrix coating technology in order to obtain constant pharmacokinetics throughout 24 hours. The areas under the curve were not significantly different from those observed with similar doses of ropinirole immediate-release (IR) formulation, administered 3 times a day, but concentration fluctuations were less for ropinirole PR (2-fold vs 5-fold). The efficacy study of the PR versus IR formulations showed non-inferiority of the PR formulation, similar tolerability and feasibility of overnight switches, and indicated that the optimal doses of ropinirole in patients with de novo PD is in the range of 8-12 mg/day. The efficacy study in PD patients with motor fluctuations treated with L-dopa showed that adding ropinirole PR significantly reduced off time and increased on time in comparison with placebo. The study with ropinirole as an add-on to L-dopa showed a reduced incidence of dyskinesias.

Cefixime-induced nonconvulsive status epilepticus

Nonconvulsive status epilepticus (NCSE) is an epileptic condition lasting >30xa0min, clinically manifested by an altered mental state and associated with continuous epileptiform activity on the electroencephalogram. NCSE is a common yet still under recognized condition and delay in diagnosis and treatment may be associated with increased mortality as well as cognitive/behavioral consequences. We described an epileptic female patient assuming carbamazepine (900xa0mg/day) and levetiracetam (3,000xa0mg/day), seizure free for more than 10xa0years, who developed NCSE during cefixime treatment, a third-generation cephalosporin compound that along with penicillins is classified within the b-lactam class of antibiotics. In our report we outline the importance and the difficulty to choose secure antibiotic treatment in epileptic patients, we discuss the possible mechanisms by which cephalosporins induce neurotoxicity and the need to stress family components questioning about new drugs assumed. Finally we highlight the value of the EEG recording to diagnose NCSE and treat it adequately and promptly.

Multimodal EEG-MRI in the differential diagnosis of Alzheimer's disease and dementia with Lewy bodies.

Differential diagnosis of Alzheimers disease (AD) and dementia with Lewy bodies (DLB) remains challenging; currently the best discriminator is striatal dopaminergic imaging. However this modality fails to identify 15–20% of DLB cases and thus other biomarkers may be useful. It is recognised electroencephalography (EEG) slowing and relative medial temporal lobe preservation are supportive features of DLB, although individually they lack diagnostic accuracy. Therefore, we investigated whether combined EEG and MRI indices could assist in the differential diagnosis of AD and DLB. Seventy two participants (21 Controls, 30 AD, 21 DLB) underwent resting EEG and 3 T MR imaging. Six EEG classifiers previously generated using support vector machine algorithms were applied to the present dataset. MRI index was derived from medial temporal atrophy (MTA) ratings. Logistic regression analysis identified EEG predictors of AD and DLB. A combined EEG-MRI model was then generated to examine whether there was an improvement in classification compared to individual modalities. For EEG, two classifiers predicted AD and DLB (model: χ2 = 22.1, df = 2, p < 0.001, Nagelkerke R2 = 0.47, classification = 77% (AD 87%, DLB 62%)). For MRI, MTA also predicted AD and DLB (model: χ2 = 6.5, df = 1, p = 0.01, Nagelkerke R2 = 0.16, classification = 67% (77% AD, 52% DLB). However, a combined EEG-MRI model showed greater prediction in AD and DLB (model: χ2 = 31.1, df = 3, p < 0.001, Nagelkerke R2 = 0.62, classification = 90% (93% AD, 86% DLB)). While suggestive and requiring validation, diagnostic performance could be improved by combining EEG and MRI, and may represent an alternative to dopaminergic imaging.