Trial of Prasinezumab in Early-Stage Parkinson's Disease.

BACKGROUND: Aggregated α-synuclein plays an important role in the pathogenesis of Parkinson's disease. The monoclonal antibody prasinezumab, directed at aggregated α-synuclein, is being studied for its effect on Parkinson's disease. METHODS: In this phase 2 trial, we randomly assigned participants with early-stage Parkinson's disease in a 1:1:1 ratio to receive intravenous placebo or prasinezumab at a dose of 1500 mg or 4500 mg every 4 weeks for 52 weeks. The primary end point was the change from baseline to week 52 in the sum of scores on parts I, II, and III of the Movement Disorder Society-sponsored revision of the Unified Parkinson's Disease Rating Scale (MDS-UPDRS; range, 0 to 236, with higher scores indicating greater impairment). Secondary end points included the dopamine transporter levels in the putamen of the hemisphere ipsilateral to the clinically more affected side of the body, as measured by 123I-ioflupane single-photon-emission computed tomography (SPECT). RESULTS: A total of 316 participants were enrolled; 105 were assigned to receive placebo, 105 to receive 1500 mg of prasinezumab, and 106 to receive 4500 mg of prasinezumab. The baseline mean MDS-UPDRS scores were 32.0 in the placebo group, 31.5 in the 1500-mg group, and 30.8 in the 4500-mg group, and mean (±SE) changes from baseline to 52 weeks were 9.4±1.2 in the placebo group, 7.4±1.2 in the 1500-mg group (difference vs. placebo, -2.0; 80% confidence interval [CI], -4.2 to 0.2; P = 0.24), and 8.8±1.2 in the 4500-mg group (difference vs. placebo, -0.6; 80% CI, -2.8 to 1.6; P = 0.72). There was no substantial difference between the active-treatment groups and the placebo group in dopamine transporter levels on SPECT. The results for most clinical secondary end points were similar in the active-treatment groups and the placebo group. Serious adverse events occurred in 6.7% of the participants in the 1500-mg group and in 7.5% of those in the 4500-mg group; infusion reactions occurred in 19.0% and 34.0%, respectively. CONCLUSIONS: Prasinezumab therapy had no meaningful effect on global or imaging measures of Parkinson's disease progression as compared with placebo and was associated with infusion reactions. (Funded by F. Hoffmann-La Roche and Prothena Biosciences; PASADENA ClinicalTrials.gov number, NCT03100149.).

Brain functional connectivity during the first day of coma reflects long-term outcome.

OBJECTIVE: In patients with disorders of consciousness (DOC), properties of functional brain networks at rest are informative of the degree of consciousness impairment and of long-term outcome. Here we investigate whether connectivity differences between patients with favorable and unfavorable outcome are already present within 24 h of coma onset. METHODS: We prospectively recorded 63-channel electroencephalography (EEG) at rest during the first day of coma after cardiac arrest. We analyzed 98 adults, of whom 57 survived beyond unresponsive wakefulness. Functional connectivity was estimated by computing the 'debiased weighted phase lag index' over epochs of five seconds duration. We evaluated the network's topological features, including clustering coefficient, path length, modularity and participation coefficient and computed their variance over time. Finally, we estimated the predictive value of these topological features for patients' outcomes by splitting the patient sample in training and test datasets. RESULTS: Group-level analysis revealed lower clustering coefficient, higher modularity and path length variance in patients with favorable compared to those with unfavorable outcomes (p < 0.01). Within all features, the path length variance in the network provided the best positive predictive value (PPV) for favorable outcome and specificity for unfavorable outcome in the test dataset (PPV: 0.83, p < 0.01; specificity: 0.86, p < 0.01) with above-chance negative predictive value and accuracy. Of note, the exclusion of patients with epileptiform activity (20 in total) eliminates all false positive predictions (n = 6) for path length variance. INTERPRETATION: Topological features of functional connectivity differ as a function of long-term outcome in patients on the first day of coma. These differences are not interpretable in terms of consciousness levels as all patients were in a deep unconscious state. The time variance of path length is informative of comatose patients' outcome, as patients with favorable outcome exhibit a richer repertoire of path length than those with unfavorable outcomes.

Electroencephalography-based power spectra allow coma outcome prediction within 24 h of cardiac arrest.

BACKGROUND: Outcome prediction in comatose patients following cardiac arrest remains challenging. Here, we assess the predictive performance of electroencephalography-based power spectra within 24 h from coma onset. METHODS: We acquired electroencephalography (EEG) from comatose patients (n = 138) on the first day of coma in four hospital sites in Switzerland. Outcome was categorised as favourable or unfavourable based on the best state within three months. Data were split in training and test sets. We evaluated the predictive performance of EEG power spectra for long term outcome and its added value to standard clinical tests. RESULTS: Out of 138 patients, 80 had a favourable outcome. Power spectra comparison between favourable and unfavourable outcome in the training set yielded significant differences at 5.2-13.2 Hz and above 21 Hz. Outcome prediction based on power at 5.2-13.2 Hz was accurate in training and test sets. Overall, power spectra predicted patients' outcome with maximum specificity and positive predictive value: 1.00 (95% with CI: 0.94-1.00 and 0.89-1.00, respectively). The combination of power spectra and reactivity yielded better accuracy and sensitivity (0.81, 95% CI: 0.71-0.89) than prediction based on power spectra alone. CONCLUSIONS: On the first day of coma following cardiac arrest, low power spectra values around 10 Hz, typically linked to impaired cortico-thalamic structural connections, are highly specific of unfavourable outcome. Peaks in this frequency range can predict long-term outcome.

Electromyographic reactivity measured with scalp-EEG contributes to prognostication after cardiac arrest.

AIM: To assess whether stimulus-induced modifications of electromyographic activity observed on scalp EEG have a prognostic value in comatose patients after cardiac arrest. METHODS: 184 adult patients from a multi-centric prospective register who underwent an early EEG after cardiac arrest were included. Auditory and somatosensory stimulation was performed during EEG-recording. EEG reactivity (EEG-R) and EMG reactivity (EMG-R) were retrospectively assessed visually by board-certified electroencephalographers, and compared with clinical outcome (cerebral performance category, CPC) at three months. A favorable functional outcome was defined as CPC 1-2, an unfavorable outcome as CPC 3-5. RESULTS: Both EEG-R and EMG-R were predictors for good outcome (EEG-R accuracy 72% (95%-CI 66-79), sensitivity 86% (78-93), specificity 60% (50-69); EMG-R accuracy 65% (58-72), sensitivity 61% (51-75), specificity 69% (60-78)). When reactivity was defined as EEG-R and/or EMG-R, the accuracy was 73% (67-70), the sensitivity 94% (90-99), and the specificity 53% (43-63). CONCLUSION: Taking EMG into account when assessing reactivity of EEG seems to reduce false negative predictions for identifying patients with favorable outcome after cardiac arrest.

Oscillatory brain dynamics supporting impaired Stroop task performance in schizophrenia-spectrum disorder.

The Stroop color-word interference task, prompting slower response to color-incongruent than to congruent items, is often used to study neural mechanisms of inhibitory control and dysfunction in schizophrenia-spectrum disorders. Inconsistent findings of an augmented Stroop effect limit identification of relevant dysfunctional mechanism(s) in schizophrenia. The present study sought to advance understanding of normal and impaired neural oscillatory dynamics by distinguishing interference detection and response preparation during the Stroop task in schizophrenia-spectrum disorders via analysis of behavioral performance and 4-7 Hz (theta) and 10-30 Hz (alpha/beta) EEG oscillations in 40 patients (SZ) and 27 healthy comparison participants (HC). SZ responded more slowly and showed less dorsal anterior cingulate (dACC) theta enhancement during INC trials, less enhancement of dACC-sensorimotor cortex connectivity (theta phase synchrony) during INC trials, more alpha/beta suppression though less enhancement of that suppression during INC trials, and slower post-response alpha/beta rebound than did HC. Reaction time distributions showed larger group and Stroop effects during the 25% of trials with the slowest responses. Poorer theta phase coherence in patients indicates impaired communication between regions associated with interference processing (dACC) and response preparation (sensorimotor cortex). Results suggest a failure cascade in which compromised behavioral Stroop effects are driven at least in part by dysfunctional interference processing (less theta power increase) prompting dysfunctional motor response preparation (less alpha/beta power suppression). Inconsistent Stroop effects in past studies of schizophrenia may result from differing task parameters sampling different degrees of Stroop task difficulty.

Neural network communication facilitates verbal working memory.

Oscillatory brain activity in the theta, alpha, and gamma frequency ranges has been associated with working memory (WM). In addition to alpha and theta activity associated with WM retention, and gamma band activity with item encoding, activity in the alpha band is related to the deployment of attention resources and information. The present study sought to specify distinct roles of neuromagnetic 4-7 Hz theta, 9-13 Hz alpha, and 50-70 Hz gamma power modulation and communication in fronto-parietal networks during cued, hemifield-specific item presentation in a modified Sternberg verbal WM task in 14 student volunteers. Lateralized posterior alpha and gamma power during encoding suggest a preparatory role of alpha oscillations. Bilateral alpha power increases during maintenance reflect information retention for the non-lateralized probe response. Lateralized alpha power increase during encoding was apparently driven by a monotonic increase in fronto-parietal 6 Hz phase, suggesting a mechanism facilitating WM encoding and successful performance.

Verbal working memory-related neural network communication in schizophrenia.

Impaired working memory (WM) in schizophrenia is associated with reduced hemodynamic and electromagnetic activity and altered network connectivity within and between memory-associated neural networks. The present study sought to determine whether schizophrenia involves disruption of a frontal-parietal network normally supporting WM and/or involvement of another brain network. Nineteen schizophrenia patients (SZ) and 19 healthy comparison subjects (HC) participated in a cued visual-verbal Sternberg task while dense-array EEG was recorded. A pair of item arrays each consisting of 2-4 consonants was presented bilaterally for 200 ms with a prior cue signaling the hemifield of the task-relevant WM set. A central probe letter 2,000 ms later prompted a choice reaction time decision about match/mismatch with the target WM set. Group and WM load effects on time domain and time-frequency domain 11-15 Hz alpha power were assessed for the cue-to-probe time window, and posterior 11-15 Hz alpha power and frontal 4-8 Hz theta power were assessed during the retention period. Directional connectivity was estimated via Granger causality, evaluating group differences in communication. SZ showed slower responding, lower accuracy, smaller overall time-domain alpha power increase, and less load-dependent alpha power increase. Midline frontal theta power increases did not vary by group or load. Network communication in SZ was characterized by temporal-to-posterior information flow, in contrast to bidirectional temporal-posterior communication in HC. Results indicate aberrant WM network activity supporting WM in SZ that might facilitate normal load-dependent and only marginally less accurate task performance, despite generally slower responding.

Deficient attention modulation of lateralized alpha power in schizophrenia.

Modulation of 8-14 Hz (alpha) activity in posterior brain regions is associated with covert attention deployment in visuospatial tasks. Alpha power decrease contralateral to to-be-attended stimuli is believed to foster subsequent processing, such as retention of task-relevant input. Degradation of this alpha-regulation mechanism may reflect an early stage of disturbed attention regulation contributing to impaired attention and working memory commonly found in schizophrenia. The present study tested this hypothesis of early disturbed attention regulation by examining alpha power modulation in a lateralized cued delayed response task in 14 schizophrenia patients (SZ) and 25 healthy controls (HC). Participants were instructed to remember the location of a 100-ms saccade-target cue in the left or right visual hemifield in order to perform a delayed saccade to that location after a retention interval. As expected, alpha power decrease during the retention interval was larger in contralateral than ipsilateral posterior regions, and SZ showed less of this lateralization than did HC. In particular, SZ failed to show hemifield-specific alpha modulation in posterior right hemisphere. Results suggest less efficient modulation of alpha oscillations that are considered critical for attention deployment and item encoding and, hence, may affect subsequent spatial working memory performance.