Almudena Sánchez-Gómez

Activating mutations at the leucine-rich repeat kinase 2 (LRRK2) gene are the most frequent genetic cause of Parkinson's Disease (PD). Using in-depth mass-spectrometry, here we analysed the impact of LRRK2 mutations on the proteome and phospho-proteome of skin fibroblasts from a large LRRK2 clinical cohort from Spain. The cohort encompassed G2019S LRRK2-associated PD (L2PD) (n=15), G2019S LRRK2 non-manifesting carriers (L2NMCs) (n=13), idiopathic PD (iPD) (n=12), and control subjects (n=14) (total n=54). The proteome analysis revealed 89 differential proteins in G2019S L2PD (58 down/ 31 up) and 168 in G2019S L2NMCs (127 down / 41 up) compared to controls. Most of these proteome changes involved deficits in proteins related to mitochondrial energy and ribosomal protein synthesis. At the phospho-proteome level, we identified 394 differential phospho-sites in G2019S L2PD (188 hyper / 206 hypo), 367 in G2019S L2NMCs (215 hyper / 152 hypo), and 428 in iPD (214 hyper / 214 hypo) compared with controls. These phospho-proteomic changes included hyper-phosphorylated proteins associated with the mTOR and Rho GTPase pathways. Notably, the top hyper-phosphorylated hit in G2019S carriers was pThr37/46 4E-BP1, a key effector of the mTOR pathway controlling protein synthesis, and this protein was also deregulated in iPD. In summary, our study uncovers peripheral deregulation of mTOR phospho-signalling associated with LRRK2 mutations, which is related to deficits in mitochondrial and ribosomal proteins, and affects converging pathways altered in iPD.

Background: Deep brain stimulation has become the standard of care for refractory Parkinson's disease. Neuroimaging advances have led to image‐based targeting of the subthalamic nucleus under general anaesthesia (GA), an approach that renders unnecessary microelectrode recording and stimulation tests under local anaesthesia and conscious sedation (CS). We aimed to compare procedures and incidents related to each anaesthetic approach.Methods: Retrospective descriptive comparison of deep brain stimulation under CS versus G. We collected patient and procedure data (e.g., comorbidities, difficult airway criteria, intraoperative monitoring, duration of surgery, hospitalization and motor outcomes) and reviewed intraoperative and postoperative haemodynamic, neurologic and surgery‐related incidents.Results: Seventy‐eight procedures were analysed, 36 in the CS group (47.4%) and 42 in the GA group (52.6%). One‐third of the patients were women, and the median age was 62 years (range, 33–75). In total, 23 patients experienced at least one perioperative incident, 19 (24.4%) in the CS group and 4 (5.1%) in the GA group (p < .001), even though the GA group included higher‐risk patients (p < .05). Fourteen patients (17.9%) presented disorientation/agitation, 12 in the CS group (p < .01). The median duration of the surgery was 5.2 h (range, 3.5–9.2 h) in the CS group, split into two sessions, and 4.6 h (range, 4.1–5.2 h) in the GA group (p < .001). The median (interquartile range [IQR]) hospital stay was also longer in the CS group, at 7.5 days (IQR 6.75–10), compared to 3 days (IQR 3–4) in the GA group (p < .0001). Pre‐ and postoperative movement disorder evaluations for 38 of the 78 patients (49%) showed significantly improved scores after surgery. No differences were found between the two groups either before (p = .41) or after (p = .52) the surgery.Conclusions: Deep brain stimulation under GA was associated with fewer perioperative incidents, shorter surgeries and shorter hospital stays.Editorial Comment: Patients with Parkinson's disease who are refractory to standard drug therapy may benefit from the implantation of deep‐brain stimulating electrodes. In this report, imaging‐guided electrode implantation under general anaesthesia was associated with fewer adverse perioperative events as well as shorter procedure times, compared to implantation guided by intraoperative electrode recording and stimulation under conscious sedation. Since imaging‐ and stimulation‐guided implantation confers equal long‐term benefits to motor function, the results from the current study suggest that general anaesthesia and imaging‐guided implantation represent an overall quality improvement for these patients.

Background: Recently, robotic arms have been incorporated into electrodes for deep brain stimulation (DBS). Objectives: This study aimed to determine the accuracy of brain electrode placement, initial clinical efficacy, and safety profile of the robotic arm Neuromate (Renishaw) compared to a stereotactic frame in movement disorders. Methods: This study involved two retrospective cohorts: one patient was operated on using a stereotactic frame and the other with a robotic arm. This study was conducted at Barcelona Hospital Clinic. Results: Seventy-seven patients were included, of whom 30 underwent surgery using the robot and 47 using a stereotactic frame. There was a significant improvement in the anatomical-radiological accuracy of brain electrode implantation assisted by the robotic arm, measured using radial error (robot: 1.01 ± 0.5 mm vs. frame: 1.32 ± 0.6 mm, P: 0.03). The postoperative improvement percentage of the Unified Parkinson’s Disease Rating Scale at 3 months was similar in both groups (robot: 71.4 ± 18 vs. frame: 72.6% ± 17, P: 0.82). There were no significant differences in the perioperative complications (robot: 4% vs. frame: 4.3%, P: 0.93) or in the adverse reactions related to brain stimulation and medical treatment (robot: 18% vs. frame: 25%, P: 0.53). Conclusions: The use of the robotic arm Neuromate improved the anatomical-radiological accuracy in the placement of DBS electrodes for movement disorders compared with the stereotactic frame. Both systems (robotic and stereotactic frame) exhibited similar initial clinical efficacies and safety profiles.

Deep brain stimulation (DBS) is an effective treatment for patients with Parkinson’s disease (PD). However, some patients may not respond optimally to clinical programming adjustments. Advances in DBS technology have led to more complex and time-consuming programming. Image-guided programming (IGP) could optimize and improve programming leading to better clinical outcomes in patients for whom DBS programming is not ideal due to sub-optimal response. We conducted a prospective single-center study including 31 PD patients with subthalamic nucleus (STN) DBS and suboptimal responses refractory to clinical programming. Programming settings were adjusted according to the volumetric reconstruction of the stimulation field using commercial postoperative imaging software. Clinical outcomes were assessed at baseline and at 3-month follow-up after IGP, using motor and quality of life (QoL) scales. Additionally, between these two assessment points, follow-up visits for fine-tuning amplitude intensity and medication were conducted at weeks 2, 4, 6, and 9. After IGP, twenty-six patients (83.9%) experienced motor and QoL improvements, with 25.8% feeling much better and 38.7% feeling moderately better according to the patient global impression scale. Five patients (16.1%) had no clinical or QoL changes after IGP. The MDS-UPDRS III motor scale showed a 21.9% improvement and the DBS-IS global score improved by 41.5%. IGP optimizes STN-DBS therapy for PD patients who are experiencing suboptimal clinical outcomes. These findings support using IGP as a standard tool in clinical practice, which could save programming time and improve patients’ QoL.

Background: Impulse control disorders (ICDs) are commonly developed among patients who take dopamine agonist drugs as a treatment for Parkinson disease (PD). Gambling disorder and hypersexuality are more frequent in male patients with PD, with a prevalence over 4% in dopamine agonists users. Although impulsive-compulsive behaviors are related to antiparkinsonian medication, and even though ICD symptomatology, such as hypersexuality, often subsides when the dopaminergic dose is reduced, sometimes ICD persists in spite of drug adjustment. Consequently, a multidisciplinary approach should be considered to address these comorbidities and to explore new forms of complementary interventions, such as serious games or therapies adapted to PD. Objective: The aim of this study is to present the case of a patient with ICD (ie, hypersexuality) triggered by dopaminergic medication for PD. A combined intervention was carried out using cognitive behavioral therapy (CBT) for ICD adapted to PD, plus an intervention using a serious game—e-Estesia—whose objective is to improve emotion regulation and impulsivity. The aim of the combination of these interventions was to reduce the harm of the disease. Methods: After 20 CBT sessions, the patient received the e-Estesia intervention over 15 sessions. Repeated measures, before and after the combined intervention, were administered to assess emotion regulation, general psychopathology, and emotional distress and impulsivity. Results: After the intervention with CBT techniques and e-Estesia, the patient presented fewer difficulties to regulate emotion, less emotional distress, and lower levels of impulsivity in comparison to before the treatment. Moreover, the frequency and severity of the relapses also decreased. Conclusions: The combined intervention—CBT and a serious game—showed positive results in terms of treatment outcomes.

Type-2 diabetes (T2D) and glucose metabolic imbalances have been linked to neurodegenerative diseases, including Parkinson’s disease (PD). To detect potential effects of different glucose levels on gene expression, by RNA-seq we analyzed the transcriptome of dermal fibroblasts from idiopathic PD (iPD) patients, LRRK2-associated PD (L2PD) patients, and healthy controls (total n = 21 cell lines), which were cultured at two different glucose concentrations (25 and 5 mM glucose). In PD patients we identified differentially expressed genes (DEGs) that were related to biological processes mainly involving the plasmatic cell membrane, the extracellular matrix, and also neuronal functions. Such pathway deregulation was largely similar in iPD or L2PD fibroblasts. Overall, the gene expression changes detected in this study were associated with PD independently of glucose concentration.