Natural Compounds as Pharmaceuticals: The Key Role of Cytochromes P450 Reactivity.

The design of drugs from natural products is a re-emerging area due to the need for bioactive compounds. The exploitation of natural products and their derivatives obtained by biocatalysis is in line with the higher attention given today to new sustainable technologies that better preserve the environment (green chemistry). The research field of cytochromes P450 (CYPs) is continuously providing new enzymes and mutants that produce metabolites suitable for late-stage functionalization for new potential drugs. This review provides an overview of the exploitation of CYPs as biocatalysts in drug synthesis. Additionally, recent progress in protein and metabolic engineering is provided to show how these enzymes offer a toolbox that can be combined with other biocatalytic or chemical processes to build new platforms for the green production of new drugs.

Safety of magnetic resonance imaging in patients with cardiac implantable electronic devices and abandoned or epicardial leads: a systematic review and meta-analysis.

AIMS: Persistent reluctance to perform magnetic resonance imaging (MRI) in patients with abandoned and/or epicardial leads of cardiac implantable electronic devices is related to in vitro studies reporting tip heating. While there is a plethora of data on the safety of MRI in conditional and non-conditional implantable devices, there is a clear lack of safety data in patients with abandoned and/or epicardial leads. METHODS AND RESULTS: Relevant literature was identified in Medline and CINAHL using the key terms 'magnetic resonance imaging' AND 'abandoned leads' OR 'epicardial leads'. Secondary literature and cross-references were supplemented. For reporting guidance, the Preferred Reporting Items for Systematic reviews and Meta-Analyses 2020 was used. International Prospective Register of Systematic Reviews (PROSPERO) registration number 465530. Twenty-one publications with a total of 656 patients with 854 abandoned and/or epicardial leads and 929 MRI scans of different anatomical regions were included. No scan-related major adverse cardiac event was documented, although the possibility of under-reporting of critical events in the literature should be considered. Furthermore, no severe device dysfunction or severe arrhythmia was reported. Mainly transient lead parameter changes were observed in 2.8% in the subgroup of patients with functional epicardial leads. As a possible correlate of myocardial affection, subjective sensations occurred mainly in the subgroup with abandoned epicardial leads (4.0%), but no change in myocardial biomarkers was observed. CONCLUSION: Existing publications did not report any relevant adverse events for MRI in patients with abandoned and/or epicardial leads if performed according to strict safety guidelines. However, a more rigorous risk-benefit calculation should be made for patients with epicardial leads.

Review on the current long-term, limited lead electroencephalograms.

In the last century, 10-20 lead EEG recordings became the gold standard of surface EEG recordings, and the 10-20 system provided comparability between international studies. With the emergence of advanced EEG sensors, that may be able to record and process signals in much more compact units, this additional sensor technology now opens up opportunities to revisit current ambulatory EEG recording practices and specific patient populations, and even electrodes that are embedded into the head surface. Here, we aim to provide an overview of current limited sensor long-term EEG systems. We performed a literature review using Pubmed as a database and included the relevant articles. The review identified several systems for recording long-term ambulatory EEGs. In general, EEGs recorded with these modalities can be acquired in ambulatory and home settings, achieve good sensitivity with low false detection rates, are used for automatic seizure detection as well as seizure forecasting, and are well tolerated by patients, but each of them has advantages and disadvantages. Subcutaneous, subgaleal, and subscalp electrodes are minimally invasive and provide stable signals that can record ultra--long-term EEG and are in general less noisy than scalp EEG, but they have limited spatial coverage and require anesthesia, a surgical procedure and a trained surgeon to be placed. Behind and in the ear electrodes are discrete, unobtrusive with a good sensitivity mainly for temporal seizures but might miss extratemporal seizures, recordings could be obscured by muscle artifacts and bilateral ictal patterns might be difficult to register. Finally, recording systems using electrodes in a headband can be easily and quickly placed by the patient or caregiver, but have less spatial coverage and are more prone to movement because electrodes are not attached. Overall, limited EEG recording systems offer a promising opportunity to potentially record targeted EEG with focused indications for prolonged periods, but further validation work is needed.

Value of q waves in lateral and left precordial leads in patients with left bundle branch block to predict the response to cardiac resynchronization therapy.

BACKGROUND: The cardiac resynchronization therapy (CRT) non-response rate can reach 30% in heart failure (HF) patients with left bundle branch block (LBBB). This study aimed to evaluate the value of baseline q waves in leads I, V5, or V6 in predicting response to CRT in patients with HF and LBBB. METHODS: Patients with HF (left ventricular ejection fraction ≤35%) and LBBB receiving CRT implantation were retrospectively enrolled. Baseline characteristics and electrocardiogram parameters, including lateral and left precordial q waves were evaluated. Non-response to CRT was defined as the improvement of left ventricular ejection fraction (LVEF) < 5% at a 6-month follow-up. RESULTS: A total of 132 patients (mean age 63.0 ± 10.4 years, 94 [71.2%] male) were included. Among them, 32 patients with q waves in leads I, V5, or V6 were classified into the qLBBB (+) group, and the rest without q waves in these leads were defined as the qLBBB (-) group. The CRT non-response rate in the qLBBB (+) group was markedly higher than that in the qLBBB (-) group (68.8% vs. 33.3%, p < .001). Multivariable logistic regression analysis revealed that the presence of baseline q waves in leads I, V5, or V6 remained significantly associated with a higher rate of CRT non-response in patients with HF and LBBB (odds ratio: 4.8, 95% confidence interval: 1.5-15.0, p = .007). CONCLUSION: Any q wave in leads I, V5, or V6 was an independent predictive factor for CRT non-response in patients with HF and LBBB.

General Algorithm Applicability in Determining DBS Lead Orientation: Adapting 2D and 3D X-Ray Techniques for SenSightTM Leads.

INTRODUCTION: With recent advancements in deep brain stimulation (DBS), directional leads featuring segmented contacts have been introduced, allowing for targeted stimulation of specific brain regions. Given that manufacturers employ diverse markers for lead orientation, our investigation focuses on the adaptability of the 2017 techniques proposed by the Cologne research group for lead orientation determination. METHODS: We tailored the two separate 2D and 3D X-ray-based techniques published in 2017 and originally developed for C-shaped markers, to the dual-marker of the Medtronic SenSight™ lead. In a retrospective patient study, we evaluated their feasibility and consistency by comparing the degree of agreement between the two methods. RESULTS: The Bland-Altman plot showed favorable concordance without any noticeable systematic errors. The mean difference was 0.79°, with limits of agreement spanning from 21.4° to -19.8°. The algorithms demonstrated high reliability, evidenced by an intraclass correlation coefficient of 0.99 (p < 0.001). CONCLUSION: The 2D and 3D algorithms, initially formulated for discerning the circular orientation of a C-shaped marker, were adapted to the marker of the Medtronic SenSight™ lead. Statistical analyses revealed a significant level of agreement between the two methods. Our findings highlight the adaptability of these algorithms to different markers, achievable through both low-dose intraoperative 2D X-ray imaging and standard CT imaging.

Directional deep brain stimulation in the management of Parkinson's disease: efficacy and constraints-an analytical appraisal.

Deep brain stimulation (DBS) is a widely employed treatment for Parkinson's disease. However, conventional DBS utilizing ring-shaped leads can often result in undesirable side effects by stimulating nearby brain structures, thus limiting its effectiveness. To address this issue, a novel DBS electrode was developed to allow for directional stimulation, avoiding neighboring structures. This literature review aims to analyze the disparities between conventional and directional DBS and discuss the benefits and limitations associated with this innovative electrode design, focusing on the stimulation-induced side effects it can or cannot mitigate. A comprehensive search was conducted in MEDLINE/PubMed, ScienceDirect, and EBSCO databases using the Boolean search criteria: "Deep brain stimulation" AND "Parkinson" AND "Directional." Following the application of inclusion and exclusion criteria, the selected articles were downloaded for full-text reading. Subsequently, the results were organized and analyzed to compose this article. Numerous studies have demonstrated that directional DBS effectively reduces side effects associated with brain stimulation, prevents the stimulation of non-targeted structures, and expands the therapeutic window, among other advantages. However, it has been observed that directional DBS may be more challenging to program and requires higher energy consumption. Furthermore, there is a lack of standardization among different manufacturers of directional DBS electrodes. Various stimulation-induced side effects, including dysarthria, dyskinesia, paresthesias, and symptoms of pyramidal tract activation, have been shown to be mitigated with the use of directional DBS. Moreover, directional electrodes offer a wider therapeutic window and a reduced incidence of undesired effects, requiring the same or lower minimum current for symptom relief compared to conventional DBS. The utilization of directional leads in DBS offers numerous advantages over conventional electrodes without significant drawbacks for patients undergoing directional DBS therapy.

Tall R waves across the precordial leads.

We here present a case of tall R waves in V1-V3, with normal R waves in V4-V6, due to a rare clinical entity. The differential diagnosis of such condition is reviewed. ECG clues are provided to guide the diagnosis. A simple diagnostic test is ordered to confirm the diagnosis.

Modifying the trajectory of epicardial leads can substantially reduce MRI-induced RF heating in pediatric patients with a cardiac implantable electronic device at 1.5T.

PURPOSE: After epicardial cardiac implantable electronic devices are implanted in pediatric patients, they become ineligible to receive MRI exams due to an elevated risk of RF heating. We investigated whether simple modifications in the trajectories of epicardial leads could substantially and reliably reduce RF heating during MRI at 1.5 T, with benefits extending to abandoned leads. METHODS: Electromagnetic simulations were performed to assess RF heating of two common 35-cm epicardial lead trajectories exhibiting different degrees of coupling with MRI incident electric fields. Experiments in anthropomorphic phantoms implanted with commercial cardiac implantable electronic devices confirmed the findings. Both electromagnetic simulations and experimental measurements were performed using head-first and feet-first positioning and various landmarks. Transfer function approach was used to assess the performance of suggested modifications in realistic body models. RESULTS: Simulations (head-first, chest landmark) of a 35-cm epicardial lead with a trajectory where the excess length of the lead was looped and placed on the inferior surface of the heart showed an 87-fold reduction in the 0.1 g-averaged specific absorption rate compared with the lead where the excess length was looped on the anterior surface. Repeated experiments with a commercial epicardial device confirmed this. For fully implanted systems following low-specific absorption rate trajectories, there was a 16-fold reduction in the average temperature rise and a 28-fold reduction for abandoned leads. The transfer function method predicted a 7-fold reduction in the RF heating in 336 realistic scenarios. CONCLUSION: Surgical modification of epicardial lead trajectory can substantially reduce RF heating at 1.5 T, with benefits extending to abandoned leads.

RF-induced heating for active implantable medical devices in dual parallel leads configurations at 1.5 T MRI.

PURPOSE: The Radiofrequency (RF)-induced heating for an active implantable medical device (AIMD) with dual parallel leads is evaluated in this paper. The coupling effects between dual parallel leads are studied via simulations and experiments methods. The global transfer function technique is used to assess the RF-induced heating for dual-lead AIMDs inside four human body models. METHODS: RF-induced heating for spinal cord stimulator systems with 60 and 90 cm length leads are studied at three parallel dual-lead configurations (closely spaced, 8 mm spaced, and 40 mm spaced) and a single-lead configuration. The global transfer function method is used to develop the AIMD models of different configurations and is used for lead-tip heating assessments inside human body models. RESULTS: In simulation studies, the peak 1g specific absorption rate/temperatrue rises of dual parallel leads systems is lower than those from the single-lead system. In experimental American Society for Testing and Materials phantom studies, the temperature rises for the single-lead AIMD system can be 2.4 times higher than that from dual-lead AIMD systems. For the spinal cord stimulator systems used in the study, the statistical analysis shows the RF-induced heating of dual-lead configurations are also lower than those from the single-lead configuration inside all four human body models. CONCLUSION: For the AIMD system in this study, it shows that the coupling effects between the dual parallel leads of AIMD systems can reduce RF-induced heating. The global transfer function for different spatial distance dual-lead configurations can potentially provide a method for the RF-induced heating evaluation for dual-lead AIMD systems.

Rationale for and use of the lumenless 3830 pacing lead.

Most currently available pacing and defibrillation leads utilize a stylet-based design that facilitates implantation. This has advantages, but also increases the lead diameter and adds the potential for metal fatigued-based conductor failure. A systematic literature search was conducted, and the authors add their twenty-year experience with this lead design. The global experience with lumenless leads was reviewed both for "standard" positioning and with conduction system pacing. Methods for both placement and system modification are reviewed. Lumenless leads have the potential to improve the durability of endocardial pacing and facilitate conduction system pacing.

A survival analysis of bipolar steroid-eluting and unipolar nonsteroid-eluting epicardial leads.

INTRODUCTION: Epicardial pacemakers are known as an alternative for endocardial pacemakers in some cases such as heart block, and complex congenital heart diseases. Considering recent advances and improvement of epicardial lead subtypes, it is essential to investigate the long-term function of them. In this study, we aimed to assess the sensing and pacing characteristics, and survival of bipolar steroid-eluting and unipolar nonsteroid-eluting epicardial pacemakers. METHODS: We conducted an entirely concentrated search on the documents of all patients who had undergone epicardial lead implantation in the Shaheed Rajaie Cardiovascular, Medical & Research Center during 2015-2018. Implant, and follow-up data were extracted. Kaplan-Meier analysis and Weibull regression hazards model were applied for the survival analysis. RESULTS: Eighty-nine leads were implanted for 77 patients. Of the total leads, 52.81%, 53.93%, and 47.19% were implanted in children (under 18-year-old), females, and patients with congenital heart diseases, respectively. Bipolar steroid-eluting leads comprised 33.71% of 89 leads. The pacing threshold of unipolar nonsteroid-eluting leads that were implanted on the left ventricle and right atrium increased significantly during the follow-up to greater records than bipolar steroid-eluting leads. Survival analysis also revealed that bipolar steroid-eluting leads are significantly better in 48-month survival (Weibull hazard ratio [HR]: 0.13 (95% confidence interval [CI]: 0.02-0.99), p = .049). Age, ventricular location of the lead, and acute pacing characteristics were not associated with survival. CONCLUSIONS: Bipolar steroid-eluting epicardial leads have an acceptable survival compared with unipolar nonsteroid-eluting, without a significant difference regarding patients age. Therefore, they could be an excellent alternative for endocardial ones.

Long-term performance of single-connector (DF4) implantable defibrillator leads.

AIMS: Single-connector (DF4) defibrillator leads have become the predominantly implanted transvenous implantable cardioverter-defibrillator lead. However, data on their long-term performance are derived predominantly from manufacturer product performance reports. METHODS AND RESULTS: We reviewed medical records in 5289 patients with DF4 leads between 2011 and 2023 to determine the frequency of lead-related abnormalities. We defined malfunction as any single or combination of electrical abnormalities requiring revision including a sudden increase (≥2×) in stimulation threshold, a discrete jump in high-voltage impedance, or sensing of non-physiologic intervals or noise. We documented time to failure, predictors of failure, and management strategies. Mean follow-up after implant was 4.15 ± 3.6 years (median = 3.63), with 37% of leads followed for >5 years. A total of 80 (1.5%) leads demonstrated electrical abnormalities requiring revision with an average time to failure of 4 ± 2.8 years (median = 3.5). Of the leads that malfunctioned, 62/80 (78%) were extracted and replaced with a new lead and in the other 18 cases, malfunctioned DF4 leads were abandoned, and a new lead implanted. In multivariable models, younger age at implant (OR 1.03 per year; P < 0.001) and the presence of Abbott/St. Jude leads increased the risk of malfunction. CONCLUSION: DF4 defibrillator leads demonstrate excellent longevity with >98.3% of leads followed for at least 5 years still functioning normally. Younger age at implant and lead manufacturer are associated with an increased risk of DF4 lead malfunction. The differences in lead survival between manufacturers require further investigation.

Variations in Determining Actual Orientations of Segmented Deep Brain Stimulation Leads Using the DiODe Algorithm: A Retrospective Study Across Different Lead Designs and Medical Institutions.

INTRODUCTION: Directional deep brain stimulation (DBS) leads have become widely used in the past decade. Understanding the asymmetric stimulation provided by directional leads requires precise knowledge of the exact orientation of the lead in respect to its anatomical target. Recently, the DiODe algorithm was developed to automatically determine the orientation angle of leads from the artifact on postoperative computed tomography (CT) images. However, manual DiODe results are user-dependent. This study analyzed the extent of lead rotation as well as the user agreement of DiODe calculations across the two most common DBS systems, namely, Boston Scientific's Vercise and Abbott's Infinity, and two independent medical institutions. METHODS: Data from 104 patients who underwent an anterior-facing unilateral/bilateral directional DBS implantation at either Northwestern Memorial Hospital (NMH) or Albany Medical Center (AMC) were retrospectively analyzed. Actual orientations of the implanted leads were independently calculated by three individual users using the DiODe algorithm in Lead-DBS and patients' postoperative CT images. The deviation from the intended orientation and user agreement were assessed. RESULTS: All leads significantly deviated from the intended 0° orientation (p < 0.001), regardless of DBS lead design (p < 0.05) or institution (p < 0.05). However, the Boston Scientific leads showed an implantation bias toward the left at both institutions (p = 0.014 at NMH, p = 0.029 at AMC). A difference of 10° between at least two users occurred in 28% (NMH) and 39% (AMC) of all Boston Scientific and 76% (NMH) and 53% (AMC) of all Abbott leads. CONCLUSION: Our results show that there is a significant lead rotation from the intended surgical orientation across both DBS systems and both medical institutions; however, a bias toward a single direction was only seen in the Boston Scientific leads. Additionally, these results raise questions into the user error that occurs when manually refining the orientation angles calculated with DiODe.

Design, biological evaluation, and molecular modelling insights of cupressic acid derivatives as promising anti-inflammatory agents.

The major labdanes in the oleogum resin of Araucaria heterophylla (Salisb.) Franco, 13-epi-cupressic acid (1) and acetyl-13-epi-cupressic acid (2) were used to prepare seven new (3-9), along with one known (10) derivatives. RAW264.7 cells were used to evaluate the anti-inflammatory activity of the derivatives (1-10) via measuring the level of COX-2 expression and IL-6. Pre-treated RAW264.7 cells with 1-10 (except for derivative 7) at 25 µM for 24h exhibited downregulation of COX-2 expression in response to LPS stimulation. Moreover, pre-treatment with compounds 1, 2, or 3 significantly attenuated the LPS-stimulated IL-6 level in RAW264.7 cells (p < 0.05). A docking study was conducted against phospholipase A2 (PLA2), a crucial enzyme in initiating the inflammatory cascade. The significant structural features of compounds (1-10) as PLA2 inhibitors included the carbonyl group at C-4 (free or substituted) and the hydrophobic diterpenoid skeleton. This study suggested 13-epi-cupressic acid as a scaffold for new anti-inflammatory agents.

Unlocking the Potential of Octocoral-Derived Secondary Metabolites against Neutrophilic Inflammatory Response.

Inflammation is a critical defense mechanism that is utilized by the body to protect itself against pathogens and other noxious invaders. However, if the inflammatory response becomes exaggerated or uncontrollable, its original protective role is not only demolished but it also becomes detrimental to the affected tissues or even to the entire body. Thus, regulating the inflammatory process is crucial to ensure that it is resolved promptly to prevent any subsequent damage. The role of neutrophils in inflammation has been highlighted in recent decades by a plethora of studies focusing on neutrophilic inflammatory diseases as well as the mechanisms to regulate the activity of neutrophils during the overwhelmed inflammatory process. As natural products have demonstrated promising effects in a wide range of pharmacological activities, they have been investigated for the discovery of new anti-inflammatory therapeutics to overcome the drawbacks of current synthetic agents. Octocorals have attracted scientists as a plentiful source of novel and intriguing marine scaffolds that exhibit many pharmacological activities, including anti-inflammatory effects. In this review, we aim to provide a summary of the neutrophilic anti-inflammatory properties of these marine organisms that were demonstrated in 46 studies from 1995 to the present (April 2023). We hope the present work offers a comprehensive overview of the anti-inflammatory potential of octocorals and encourages researchers to identify promising leads among numerous compounds isolated from octocorals over the past few decades to be further developed into anti-inflammatory therapeutic agents.

Machine learning models of 6-lead ECGs for the interpretation of left ventricular hypertrophy (LVH).

BACKGROUND: Left Ventricular Hypertrophy (LVH) is closely linked to the cardiovascular disease prognosis, and thus, timely diagnosis improves outcomes. Diagnosis is challenging due to dependency on doctor's visits and a 12­lead ECG. In addition, the interpretation of LVH from ECGs is challenging due to variability of ECG measurements, body habitus, electrode positioning, several LVH ECG criteria and EP mechanisms. The aims of this study are to evaluate different big data-driven machine learning models for ECG LVH interpretation based on limb leads only, and to compare the performance of an ECG parameter-based statistical model with a deep learning-based model. METHODS AND DATA: The first two models are binary class Random Forest (RF) models, an ensemble learning method which constructs many decision trees at training time and predicts the class chosen by the greatest number of trees at inference time. One random forest is trained using the following five features: lead aVL R-wave amplitude, lead I, II, aVL ST segment amplitude, and QRS duration. The second RF model uses 54 features across all limb leads, including the five features used by the smaller model. The second type of model is a multi-class deep neural network (DNN) which takes median beats of 6 limb leads arranged in Cabrera sequence as input. The signal preprocessing included forming median beats, filtering with a 40-Hz lowpass filter, and down-sampling to 125 Hz. The DNN models consist of 1 lead-formation convolutional layer, 5 downsampling convolutional resnet blocks with skip connections, and 3 fully connected layers. The training dataset consisted of 1 million 10-s 12­lead ECGs, and an independent test dataset consisted of 250,000 10-s ECGs from the Mayo Clinic. RESULTS: The five-parameter RF model has the prediction performance of Area Under the Receiver-Operator Curve (AUC) 0.78, and the larger RF model had AUC of 0.83. The DNN model for ECG LVH detection achieves AUC 0.92 using only the limb leads, compared to an AUC of 0.98 for the full 12­lead DNN. CONCLUSION: The study shows that machine learning models trained only on limb leads achieve promising results with potential to add clinical value to early detection mechanisms. We also observe that the RF model splits parameters by thresholds known to be characteristic of LVH, and that the DNN model can automatically detect morphology differences from 6 limb lead ECGs. This will be meaningful for expanding the capabilities of potential electrical LVH detection in mobile 6­lead ECG devices.

Smartwatch: Looking beyond what you see.

BACKGROUND: The clinical utility of the Apple Inc.® smartwatch in scenarios beyond detecting atrial fibrillation has been debated. Although the device has the capability to record electrocardiograms (ECG) and detect arrhythmias, voltage limitations hinder its accuracy in measuring real voltage when recording precordial leads. This limitation poses challenges for its clinical use in diagnosing ischemia and screening cardiomyopathies. This review aims to analyze the ECG recording capacity of the Apple Watch, investigate the reasons for voltage limitations, and explore alternative approaches for its use in these clinical scenarios. METHODS: A comprehensive literature review was conducted to examine the ECG recording capacity of the Apple Watch and the limitations encountered when recording precordial leads. Data in CSV format files were analyzed to gain insights into the underlying causes of voltage limitations. RESULTS: The Apple Watch demonstrates effectiveness in detecting cardiac arrhythmias such as atrial fibrillation using photoplethysmography and ECG recording. However, voltage limitations during precordial lead recordings impede accurate voltage measurement, thereby limiting its clinical utility. Analysis of the data stored in the CSV files revealed that these voltage limitations are primarily attributed to the presentation format. Exploring alternative approaches for data processing could potentially overcome this challenge. CONCLUSIONS: This review highlights the potential for addressing voltage limitations through alternative data processing approaches. Further research is necessary to identify suitable alternatives that enable the Apple Watch to be effectively utilized in these clinical scenarios.

A proposal for better visualization of Aslanger pattern.

In the context of reporting a case of a patient with Aslanger pattern, the application of additional leads in the frontal plane is proposed to facilitate the recognition of this condition - indicating occlusive myocardial infarction - as eligible for the current ST-segment elevation myocardial infarction (STEMI) criteria and consequently for immediate reperfusion strategy recommendation.

Amyloid and tau-PET in early-onset AD: Baseline data from the Longitudinal Early-onset Alzheimer's Disease Study (LEADS).

INTRODUCTION: We aimed to describe baseline amyloid-beta (Aß) and tau-positron emission tomograrphy (PET) from Longitudinal Early-onset Alzheimer's Disease Study (LEADS), a prospective multi-site observational study of sporadic early-onset Alzheimer's disease (EOAD). METHODS: We analyzed baseline [18F]Florbetaben (Aß) and [18F]Flortaucipir (tau)-PET from cognitively impaired participants with a clinical diagnosis of mild cognitive impairment (MCI) or AD dementia aged < 65 years. Florbetaben scans were used to distinguish cognitively impaired participants with EOAD (Aß+) from EOnonAD (Aß-) based on the combination of visual read by expert reader and image quantification. RESULTS: 243/321 (75.7%) of participants were assigned to the EOAD group based on amyloid-PET; 231 (95.1%) of them were tau-PET positive (A+T+). Tau-PET signal was elevated across cortical regions with a parietal-predominant pattern, and higher burden was observed in younger and female EOAD participants. DISCUSSION: LEADS data emphasizes the importance of biomarkers to enhance diagnostic accuracy in EOAD. The advanced tau-PET binding at baseline might have implications for therapeutic strategies in patients with EOAD. HIGHLIGHTS: 72% of patients with clinical EOAD were positive on both amyloid- and tau-PET. Amyloid-positive patients with EOAD had high tau-PET signal across cortical regions. In EOAD, tau-PET mediated the relationship between amyloid-PET and MMSE. Among EOAD patients, younger onset and female sex were associated with higher tau-PET.

Intraoperative Local Field Potential Beta Power and Three-Dimensional Neuroimaging Mapping Predict Long-Term Clinical Response to Deep Brain Stimulation in Parkinson Disease: A Retrospective Study.

BACKGROUND: Directional deep brain stimulation (DBS) leads allow a fine-tuning control of the stimulation field, however, this new technology could increase the DBS programming time because of the higher number of the possible combinations used in directional DBS than in standard nondirectional electrodes. Neuroimaging leads localization techniques and local field potentials (LFPs) recorded from DBS electrodes implanted in basal ganglia are among the most studied biomarkers for DBS programing. OBJECTIVE: This study aimed to evaluate whether intraoperative LFPs beta power and neuroimaging reconstructions correlate with contact selection in clinical programming of DBS in patients with Parkinson disease (PD). MATERIALS AND METHODS: In this retrospective study, routine intraoperative LFPs recorded from all contacts in the subthalamic nucleus (STN) of 14 patients with PD were analyzed to calculate the beta band power for each contact. Neuroimaging reconstruction obtained through Brainlab Elements Planning software detected contacts localized within the STN. Clinical DBS programming contact scheme data were collected after one year from the implant. Statistical analysis evaluated the diagnostic performance of LFPs beta band power and neuroimaging data for identification of the contacts selected with clinical programming. We evaluated whether the most effective contacts identified based on the clinical response after one year from implant were also those with the highest level of beta activity and localized within the STN in neuroimaging reconstruction. RESULTS: LFPs beta power showed a sensitivity of 67%, a negative predictive value (NPV) of 84%, a diagnostic odds ratio (DOR) of 2.7 in predicting the most effective contacts as evaluated through the clinical response. Neuroimaging reconstructions showed a sensitivity of 62%, a NPV of 77%, a DOR of 1.20 for contact effectivity prediction. The combined use of the two methods showed a sensitivity of 87%, a NPV of 87%, a DOR of 2.7 for predicting the clinically more effective contacts. CONCLUSIONS: The combined use of LFPs beta power and neuroimaging localization and segmentations predict which are the most effective contacts as selected on the basis of clinical programming after one year from implant of DBS. The use of predictors in contact selection could guide clinical programming and reduce time needed for it.