Advanced Parkinson's Disease Research Articles

Non-invasive, continuous oral delivery of solid levodopa-carbidopa for management of Parkinson's disease.

When short plasma half-life drugs act only briefly, they require frequent or continuous administration. We report the engineering of a non-invasive oral drug delivery system for long-term, continuous administration of these drugs. Their non-invasive, long-term, continuous administration at daily doses exceeding 100 mg has, for many years, been considered an insurmountable challenge. We show that over 1200 mg/day of 4:1 levodopa-carbidopa (LD-CD) can be non-invasively and continuously extruded when formulated as a semisolid paste, loaded with 63%w/w of the solid drugs. The drug delivery system comprises a reusable orthodontic retainer with a co-molded pocket into which the patient inserts after each meal a new 1 mL propellant-driven, prefilled, disposable, drug delivery extruder. The paste is delivered to the lingual side of the teeth where it is mixed with saliva and swallowed. As reported elsewhere, a 15-day, 16 patient open label clinical trial of the drug delivery system continuously extruding LD-CD paste significantly reduces the variability of the plasma LD concentration and alleviates symptoms of advanced Parkinson's disease (PD) as compared to LD-CD tablets.

Respiratory Dysfunction and Abnormal Hypoxic Ventilatory Response in Mild to Moderate Parkinson's Disease.

Respiratory dysfunction is an important contributor to morbidity and mortality in advanced Parkinson's disease (PD), but it is unclear what parameters are sensitive to diagnose and monitor respiratory dysfunction across disease phases. We aimed to characterize respiratory dysfunction in mild to moderate PD. In 20 individuals without cardiopulmonary comorbidity, pulmonary and inspiratory muscle function testing were performed ON-medication. Subsequently, the acute ventilatory response to hypoxia (HVR) was assessed by gradually decreasing FIO2 from 0.209 (room air) to 0.127, which was compared to eight age- and sex-matched healthy controls under arterial blood gas monitoring. Lastly, on different days, the same 20 individuals with PD underwent six blinded exposures to 45-min normobaric hypoxia at FiO2 0.163 and 0.127 or placebo OFF-medication to assess breathing responses. At rest, individuals with greatest PD severity had a lower tidal volume (pairwise comparisons: 0.59 vs. 0.74, P = 0.038-0.050) and tended to have a higher breathing frequency (17.7 vs. 14.4, P = 0.076), despite normal pulmonary function. A 45-min exposure to hypoxia induced a significantly lower acute HVR in individuals with PD compared to controls (-0.0489 vs. 0.133 L.min/%, P = 0.0038). Acute HVR was reduced regardless of disease severity. Subacute HVR in individuals with milder disease tended to be higher compared to those with more advanced disease (P = 0.079). Respiratory dysfunction is present in individuals with PD, including those with relatively mild disease severity, and is characterized by altered breathing patterns at rest, as well as a lower HVR, despite normal pulmonary and inspiratory muscle function testing.

Directional Subthalamic Deep Brain Stimulation Better Improves Gait and Balance Disorders in Parkinson's Disease Patients: A Randomized Controlled Study.

To investigate the effects of directional subthalamic deep brain stimulation (STN-dDBS) on gait and balance disorders, including freezing of gait (FOG), in patients with advanced Parkinson's disease (PD). We included 10 participants who underwent STN-DBS and presented severe preoperative FOG, in a randomized, double-blind, crossover study. We used segmented DBS electrodes to investigate whether directing the predicted volume of tissue activated (VTA) to overlap the central STN preferentially improved gait and balance disorders compared to directional DBS applied in the more posterior STN (sensorimotor). We also assessed non-directional (ring-mode) STN-DBS. Our primary outcome was gait and balance control measured using instrumented gait recordings. Each patient had a pre-operative structural and diffusion-weighted imaging to model individual VTAs and to examine cortico-subthalamic connectivity. We used linear mixed-effects models to contrast the effects of central STN-dDBS, posterior STN-dDBS, and ring-mode STN-DBS. Central STN-dDBS produced significantly better improvement in gait and balance control compared to posterior STN-dDBS (p = 0.027), with fewer FOG episodes (p < 0.001). Conversely, ring-mode STN-DBS resulted in worsened postural control compared to central STN-dDBS (p = 0.009). The cortico-subthalamic connectivity with the STN VTAs involved mostly primary sensorimotor, premotor, and medial frontal cortices, with a higher overall cortico-STN connectivity with ring-mode STN-DBS. Central STN-dDBS represents the best option to improve gait and balance disorders in PD patients, including FOG. Our findings raise the possibility of reprogramming STN-DBS toward the central area in selected patients with disabling FOG and/or postural instability after surgery. ANN NEUROL 2024.

Effectiveness and safety of levodopa-entacapone-carbidopa infusion in Parkinson disease: A real-world data study.

Levodopa-entacapone-carbidopa intestinal gel (LECIG) infusion is a recently developed device-aided therapy for advanced Parkinson disease (PD) patients. The aim of this study was to report real-world evidence about the effectiveness, tolerability, and safety of LECIG in PD patients. A multicenter observational retrospective study of the first patients who initiated LECIG in Spain was performed. All neurologists with an experience of at least two patients treated until 30 March 2024 were invited to participate. Data about effectiveness and safety from the medical records (V0, pre-LECIG; V1, initiation of LECIG; V2, post-LECIG follow-up) with a total of 246 variables were collected. Seventy-three PD patients (61.6% males, 70.1 ± 9.1 years old) from 21 Spanish centers with a mean disease duration of 14.4 ± 6.3 years (range = 5-31) were included. Twenty-six patients (35.6%) were switched directly from levodopa-carbidopa intestinal gel. The mean exposure to LECIG was 177.3 ± 110.5 days (range = 7-476). The mean daily OFF time decreased from 5.2 ± 3 (pre-LECIG) to 1.9 ± 1.8 (post-LECIG; n = 66, p < 0.0001). Global improvement was observed in >85% of the patients. No significant change was detected in the levodopa equivalent daily dose from V0 to V2. Only 7% received 24-h infusion, and 24.7% required more than one cartridge per day at V2. Thirty-four patients (46.6%) had at least one adverse event related to LECIG and/or the device system. Five patients (6.8%) discontinued LECIG. LECIG was safe and effective in advanced PD patients.

Prescription trends in Japanese advanced Parkinson's disease patients with non-motor symptoms: J-FIRST.

Non-motor symptoms (NMS) are important factors when selecting treatments for patients with advanced Parkinson's disease (PD). We sought to elucidate the prescribing practices for advanced PD patients with NMS in Japanese clinical practice. We examined the prescription rates and doses of anti-PD drugs, and the use of non-steroidal anti-inflammatory drugs (NSAIDs) in post hoc analyses of a 52-week observational study of 996 PD patients with wearing-off on levodopa-containing therapy and ≥1 NMS. Dopamine agonists were the most frequently prescribed drugs combined with levodopa-containing drugs, followed by entacapone, zonisamide, istradefylline, selegiline, and amantadine. The daily dose of levodopa-containing drugs, rotigotine, entacapone, istradefylline, and droxidopa, and the levodopa-equivalent dose increased during the observation period. In a subgroup analysis of patients stratified by NMS status (improved/unchanged/deteriorated), the deteriorated group had higher prescription rates of entacapone and istradefylline, whereas the improved group had higher prescription rates of NSAIDs and zonisamide at Week 52. Prescriptions varied by geographical region for anti-PD drugs and by NMS status for NSAIDs. There were significant changes in the prescriptions and dosing of selected anti-PD drugs, especially newer drugs. Anti-PD drug and NSAID prescriptions also varied by changes in NMS status and geographic region.

Nocturnal continuous subcutaneous infusion of apomorphine in advanced Parkinson's disease: a series of 37 cases

Multiple factors can cause sleep disturbances in Parkinson's disease. The quality of sleep and therefore of life is usually improved with continuous dopaminergic stimulation therapies, such as continuous subcutaneous infusion of apomorphine. We present an observational retrospective study of patients at our centre with advanced Parkinson's disease, treated with continuous infusion of apomorphine, with treatment extended to nights, between 2011 and 2022. We collected data from 37 patients, and evaluated the indication for nocturnal treatment, efficacy, safety and reasons for withdrawal. Fifty percent of patients began nocturnal treatment for motor complications, 19% for non-motor complications and 31% for both. The most common non-motor symptoms were sleep fragmentation and disturbances, neuropathic pain, psychiatric symptoms and intense nocturia. Twenty of the 37 patients (54%) were continuing treatment at the end of the study follow-up, 16 (43%) discontinued the infusion, and one (3%) was lost to follow-up. The adverse reactions that led to termination of the infusion were severe nodules (two), dopaminergic psychosis (one) and a positive Coombs test with/without anaemia (one). Four patients terminated the nocturnal infusions while continuing the daytime infusions due to suboptimal adaptation to the device. Patients whose symptoms improved without any significant adverse effects continued the treatment. Continuous infusion of apomorphine during the night was an effective and safe treatment in our series.

Deep brain stimulation for Parkinson's disease: bibliometric analysis of the top 100 cited literature.

Deep Brain Stimulation (DBS) has been widely applied and accepted in the treatment of neurological and psychiatric disorders. Despite numerous studies exploring the effects of DBS on the progression of neurodegenerative diseases and the treatment of advanced Parkinson's disease (PD), there is a limited number of articles summarizing this research. The purpose of this study is to investigate the current trends, hot topics, and potential in research surrounding DBS therapy for PD, as well as to anticipate the challenges of such research. We searched the Web of Science Core Collection database (WoSCC) for DBS research literature related to PD published from January 2014 to January 2024, utilized CiteSpace, VOS viewer, the bibliometric online analysis platform, Scimago Graphica, Microsoft Excel 2021, and R software version 4.2.3 for data analysis. And we conducted quantitative research on publications, citations, journals, authors, countries, institutions, keywords, and references, visualized the results in network graphs. From 2014 to 2024, papers from 39 journals from 11 countries were among the top 100 cited. Most papers were published in Neurology, with the highest average citations per paper in Nature Neuroscience. The United States (US) contributed the most publications, followed by the United Kingdom (UK) and Germany. In terms of total publications, University College London (UCL) contributed the most papers. The primary classifications of articles were Clinical Neurology, Neurosciences, and Surgery. The top five keywords were subthalamic nucleus, DBS, PD, medical therapy, and basal ganglia. Cluster analysis indicates that DBS research focus on improving quality of life and applying computational models. Through bibliometric analysis, researchers could quickly and clearly understand the hotspots and boundaries of their research field, thus guiding their research direction and scope to improve research efficiency and the quality of outcomes. Although studies indicate that DBS is currently a crucial method for treating advanced PD, in the long run, creating a personalized, low-cost treatment regimen with precise targeting and long-term efficacy poses a challenge.

Pain Fluctuations in Parkinson's Disease and Their Association with Motor and Non-Motor Fluctuations.

Pain fluctuations are a characteristic phenomenon in advanced Parkinson's disease (PD), but their temporal association with motor and non-motor symptom (NMS) fluctuations remains largely enigmatic. Moreover, data on their importance for disease severity perception and health-related quality-of-life (hr-QoL) is limited. To dissect pain fluctuations with respect to pain type and frequency patterns, and their association with motor and non-motor fluctuations. Prospective observational cohort study in advanced PD assessing symptom fluctuations by simultaneous hourly ratings using the PD Home diary (Off, On, Dyskinetic state), a pain diary (assessing 9 pain types) and a non-motor diary (10 key NMS) based on validated instruments. Forty-seven out of 55 eligible participants with fluctuating PD (51% men, median age 65, median disease duration 10 years) had sufficient datasets (>95% of hours) from 2 consecutive days. Pain was reported in 35% of waking hours with clear circadian rhythm peaking in early morning Off periods and clustering during motor Off state (49% of Off state hours with pain). Main NMS co-fluctuating with pain were "Fatigue" and "Inner Restlessness". Simultaneous assessment of global disease severity by participants revealed that pain was associated with worse disease severity only in motor On and Dyskinetic state but not in Off state, which translated into significant correlations of daily pain times with hr-QoL only during motor On and Dyskinetic state. Aside from treating motor Off periods, specific recognition of pain particularly during motor On and Dyskinetic state comprises an important aspect for disease management in advanced PD.

A prediction model for the walking and balance milestone in Parkinson's disease

BackgroundWalking and balance impairments, represented by freezing of gait and falls, are significant contributors to disability in advanced Parkinson's disease (PD) patients. However, the composite measure of the Walking and Balance Milestone (WBMS) has not been thoroughly investigated. MethodsThis study included 606 early-stage PD patients from the Parkinson's Progression Markers Initiative (PPMI) database, with a disease duration of less than 2 years and no WBMS at baseline. Patients were divided into a model development cohort (70 %) and a validation cohort (30 %) according to the enrollment site. Longitudinal follow-up data over a period of 12 years were analyzed. ResultsAmong all 606 patients, the estimated probability of being WBMS-free at the 5th and 10th year was 88 % and 60 %, respectively. Five clinical variables (Age, Symbol Digit Modalities Test (SDMT), postural instability and gait difficulty (PIGD) score, Movement Disorder Society-Unified Parkinson's Disease Rating Scale Part I (MDS-UPDRS-I) score, and REM Sleep Behavior Disorder (RBD) were used to construct the Cox predictive model. The C-index of the model was 0.75 in the development cohort and 0.76 in the validation cohort. By optimizing the PIGD and MDS-UPDRS-I variables, an easy-to-use model was achieved with comparable predictive performance. ConclusionA predictive model based on five baseline clinical measures (Age, SDMT, PIGD score, MDS-UPDRS-I score, RBD) could effectively estimate the risk of the WBMS in early PD patients. This model is valuable for prognostic counseling and clinical intervention trials for gait and balance impairment.

AIMP2 accumulation in brain leads to cognitive deficits and blood secretion in Parkinson’s disease

BackgroundPropagation of neuronal α-synuclein aggregate pathology to the cortex and hippocampus correlates with cognitive impairment in Parkinson’s disease (PD) dementia and dementia with Lewy body disease. Previously, we showed accumulation of the parkin substrate aminoacyl-tRNA synthetase interacting multifunctional protein-2 (AIMP2) in the temporal lobe of postmortem brains of patients with advanced PD. However, the potential pathological role of AIMP2 accumulation in the cognitive dysfunction of patients with PD remains unknown.MethodsWe performed immunofluorescence imaging to examine cellular distribution and accumulation of AIMP2 in brains of conditional AIMP2 transgenic mice and postmortem PD patients. The pathological role of AIMP2 was investigated in the AIMP2 transgenic mice by assessing Nissl-stained neuron counting in the hippocampal area and Barnes maze to determine cognitive functions. Potential secretion and cellular uptake of AIMP2 was monitored by dot blot analysis and immunofluorescence. The utility of AIMP2 as a new PD biomarker was evaluated by dot blot and ELISA measurement of plasma AIMP2 collected from PD patients and healthy control followed by ROC curve analysis.ResultsWe demonstrated that AIMP2 is toxic to the dentate gyrus neurons of the hippocampus and that conditional AIMP2 transgenic mice develop progressive cognitive impairment. Moreover, we found that neuronal AIMP2 expression levels correlated with the brain endothelial expression of AIMP2 in both AIMP2 transgenic mice and in the postmortem brains of patients with PD. AIMP2, when accumulated, was released from the neuronal cell line SH-SY5Y cells. Secreted AIMP2 was taken up by human umbilical vein endothelial cells. Consistent with the fact that AIMP2 can be released into the extracellular space, we showed that AIMP2 transgenic mice have higher levels of plasma AIMP2. Finally, ELISA-based assessment of AIMP2 in plasma samples from patients with PD and controls, and subsequent ROC curve analysis proved that high plasma AIMP2 expression could serve as a reliable molecular biomarker for PD diagnosis.ConclusionsThe pathological role in the hippocampus and the cell-to-cell transmissibility of AIMP2 provide new therapeutic avenues for PD treatment, and plasma AIMP2 combined with α-synuclein may improve the accuracy of PD diagnosis in the early stages.

Unraveling the interplay of β-amyloid pathology and Parkinson's disease progression: Insights from autopsy-confirmed patients

BackgroundParkinson's disease (PD) is a prevalent neurodegenerative disorder that manifests with both motor and non-motor symptoms, with α-synuclein misfolding recognized as a key contributor. Cognitive decline in advanced PD stages prompts interest in amyloid deposition, a hallmark of Alzheimer's disease (AD), as a potential factor. This study explores the impact of β-amyloid (Aβ) pathology in PD patients on disease progression, aiming to elucidate the role of Aβ in PD development and progression. MethodsThis study included autopsy-confirmed PD patients with post-mortem analyses from the Parkinson's Progression Markers Initiative. Comprehensive clinical assessments, including demographic data, clinical features, CSF markers, and neuroimaging, were conducted. Statistical analyses assessed differences between groups based on the severity of AD neuropathological changes. ResultsAll 16 PD participants exhibited severe Lewy body pathology, with 75 % displaying AD neuropathological changes. At baseline, PD patients with severe or moderate AD neuropathological changes had a lower Aβ42 levels (p = 0.022) and Aβ42/tau ratio (p = 0.001). Longitudinal follow-up data indicated that individuals with severe or moderate AD neuropathological changes exhibited a more rapid decline in MOCA score and BJLOT score, along with a quicker increase in MDS-UPDRS Ⅲ score. ConclusionsThe study underscores the presence of severe Aβ pathology in PD, suggesting a role in accelerated disease progression. Cross-seeding between Aβ and α-synuclein may contribute to rapid clinical symptom progression. Further research is needed for a comprehensive understanding of neurodegenerative disease complexities and exploring potential therapeutic interventions targeting protein aggregation.

12492 Clinical Resolution Of Parkinsonism And Dementia Following Radio Frequency Ablation Of A Parathyroid Adenoma

Abstract Disclosure: P. Finny: None. T. George: None. A.K. Francis: None. Background: Parkinsonism is a rare neurological manifestation of primary hyperparathyroidism. Radiofrequency ablation (RFA) of parathyroid adenomas is a novel treatment modality. Clinical Case: A 78 year old lady presented to our Emergency department with hypercalcemic encephalopathy. She had long standing Diabetes mellitus, Bronchial asthma and Parkinsonism with dementia for the past 14 years. She was bed bound with dependence on carers for activities of daily living (ADL). She had been diagnosed elsewhere in 2018 to have primary hyperparathyroidism due to a right inferior parathyroid adenoma and had a right hemithyroidectomy with a failed parathyroidectomy. She was being managed with Cinacalcet 60 mg daily for the past 4 years. Prior to this admission she had discontinued Cinacalcet for a few days. Her initial serum calcium was 15.3 mg/dl (8.7-10.7), phosphorus 1.80 mg/dl (2.5-4.5) and PTH 451 pg/ml (15- 88). She was aggressively treated with intravenous normal saline hydration followed by Furosemide injection. Then she was given Calcitonin injections subcutaneously and IV Zoledronic acid infusion. Her calcium dropped to 11.8 mg/dl within 48 hours of admission, and her sensorium improved. Imaging studies showed no visible parathyroid adenoma on ultrasound, but the 4D CT scan of the neck revealed a left inferior parathyroid adenoma of size 1.1 x 1.2 cm. This was concordant on the Technetium 99m Sestamibi scan. Her MRI Brain showed bilateral globus pallidus calcification. In view of her multiple comorbidities making her a poor candidate for general anaesthesia, non-surgical options were considered. A percutaneous ultrasound guided RFA of the left parathyroid adenoma was successfully performed. Post procedure the PTH dropped from 321 pg/ml to 54.9 pg/ml within 24 hours. The calcium, phosphorus and PTH remained normal. Her Parkinsonism and dementia significantly improved and we could wean her off the anti- parkinsonian and anti-psychotic medication. She became ambulant and regained her cognitive functions. This clinical and biochemical remission was maintained over the next 22 months of follow up. Conclusion: RFA is a novel therapeutic option in treating parathyroid adenomas among surgically unfit patients. Reversal of advanced Parkinsonism following correction of chronic hypercalcemia led to this patient regaining a good quality of life. 4D CT scan of the neck is useful in localizing the parathyroid adenoma when there is discordance between the ultrasound and Sestamibi scan.

Therapy for advanced stages of Parkinson's disease

The search and analysis of data on treatment options of advanced stages of Parkinson's disease from various scientific sources on biomedical research PubMed in the Medline, Russian scientific electronic library CyberLeninka databases are summarized in the article. A comparison of data was performed to highlight the main directions of modern approaches to the treatment of advanced stages of Parkinson's disease. To treat the disease at a late stage with pronounced motor fluctuations in the form of “off” symptoms and painful dyskinesias during the “on” period, invasive and non-invasive high-tech methods of treatment are used. The most relevant method of treatment for Parkinson's disease in patients with a long history of the disease and side symptoms of traditional medicinal methods of correction are the use of Duodopa - levodopa/carbidopa intestinal gel (LCIG). It is important to note that the increased "on" period can allow people with advanced Parkinson's disease to raise motor activity, thereby improving their independence in daily activities from other people.

Continuous Subcutaneous Foslevodopa-Foscarbidopa in Parkinson's Disease: A Mini-Review of Current Scope and Future Outlook.

Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by motor and non-motor symptoms, primarily because of the impairment of dopaminergic neurons. Long-term use of levodopa, the standard PD treatment, often results in fluctuating therapeutic effects and dyskinesia, necessitating alternative therapies. This review aims to synthesize current insights and clinical experiences with foslevodopa-foscarbidopa, focusing on its pharmacokinetics, efficacy, and safety profile, to evaluate its potential in transforming PD therapy. A systematic literature search was conducted up to November 2023 using databases PubMed, Web of Science, and Cochrane Library. The search yielded eight eligible articles, including pharmacological studies, case reports, observational studies, and controlled trials. No language restrictions were applied. Foslevodopa and foscarbidopa, as prodrugs of levodopa and carbidopa, exhibited excellent chemical stability and solubility, facilitating continuous subcutaneous infusion. Clinical trials demonstrated that these prodrugs maintain stable levodopa levels, thereby addressing the limitations of oral levodopa therapy. Phase 1 and 3 studies indicated significant improvements in motor function and quality of life in advanced PD patients. However, a higher incidence of treatment-emergent adverse events, mainly infusion site reactions, was observed compared to oral therapies. Foslevodopa-foscarbidopa emerges as a promising alternative for advanced PD treatment, offering sustained symptom control. Its efficacy in managing motor fluctuations and dyskinesia makes it a viable option in the PD therapeutic spectrum. Future research should focus on long-term safety, economic impact, and broader accessibility. Foslevodopa-foscarbidopa is now commercially distributed in many countries in Europe and in Japan.

Application of multimodal deep learning and multi-instance learning fusion techniques in predicting STN-DBS outcomes for Parkinson's disease patients

Parkinson's Disease (PD) is a progressive neurodegenerative disorder with substantial impact on patients' quality of life. Subthalamic nucleus deep brain stimulation (STN-DBS) is an effective treatment for advanced PD, but patient responses vary, necessitating predictive models for personalized care. Recent advancements in medical imaging and machine learning offer opportunities to enhance predictive accuracy, particularly through deep learning and multi-instance learning (MIL) techniques. This retrospective study included 127 PD patients undergoing STN-DBS. Medical records and imaging data were collected, and patients were categorized based on treatment outcomes. Advanced segmentation models were trained for automated region of interest (ROI) delineation. A novel 2.5D deep learning approach incorporating multi-slice representation was developed to extract detailed ROI features. Multi-instance learning fusion techniques integrated predictions across multiple slices, combining radiomics and deep learning features to enhance model performance. Various machine learning algorithms were evaluated, and model robustness was assessed using cross-validation and hyperparameter optimization. The MIL model achieved an area under the curve (AUC) of 0.846 for predicting STN-DBS outcomes, surpassing the radiomics model's AUC of 0.825. Integration of MIL and radiomics features in the DLRad model further improved discriminative ability to an AUC of 0.871. Calibration tests showed good model reliability, and decision curve analysis demonstrated clinical utility, affirming the model's predictive advantage. This study demonstrates the efficacy of integrating MIL, radiomics, and deep learning techniques to predict STN-DBS outcomes in PD patients. The multimodal fusion approach enhances predictive accuracy, supporting personalized treatment planning and advancing patient care.

Exploring the Role of Reactive Oxygen Species in the Pathogenesis and Pathophysiology of Alzheimer's and Parkinson's Disease and the Efficacy of Antioxidant Treatment.

Alzheimer's (AD) and Parkinson's Disease (PD) are life-altering diseases that are characterised by progressive memory loss and motor dysfunction. The prevalence of AD and PD is predicted to continuously increase. Symptoms of AD and PD are primarily mediated by progressive neuron death and dysfunction in the hippocampus and substantia nigra. Central features that drive neurodegeneration are caspase activation, DNA fragmentation, lipid peroxidation, protein carbonylation, amyloid-β, and/or α-synuclein formation. Reactive oxygen species (ROS) increase these central features. Currently, there are limited therapeutic options targeting these mechanisms. Antioxidants reduce ROS levels by the induction of antioxidant proteins and direct neutralisation of ROS. This review aims to assess the effectiveness of antioxidants in reducing ROS and neurodegeneration. Antioxidants enhance major endogenous defences against ROS including superoxide dismutase, catalase, and glutathione. Direct neutralisation of ROS by antioxidants protects against ROS-induced cytotoxicity. The combination of Indirect and direct protective mechanisms prevents ROS-induced α-synuclein and/or amyloid-β formation. Antioxidants ameliorate ROS-mediated oxidative stress and subsequent deleterious downstream effects that promote apoptosis. As a result, downstream harmful events including neuron death, dysfunction, and protein aggregation are decreased. The protective effects of antioxidants in human models have yet to directly replicate the success seen in cell and animal models. However, the lack of diversity in antioxidants for clinical trials prevents a definitive answer if antioxidants are protective. Taken together, antioxidant treatment is a promising avenue in neurodegenerative disease therapy and subsequent clinical trials are needed to provide a definitive answer on the protective effects of antioxidants. No current treatment strategies have significant impact in treating advanced AD and PD, but new mimetics of endogenous mitochondrial antioxidant enzymes (Avasopasem Manganese, GC4419 AVA) may be a promising innovative option for decelerating neurodegenerative progress in the future at the mitochondrial level of OS.

A Patient-Centered Perspective on Changes in Personal Characteristics After Deep Brain Stimulation

Deep brain stimulation (DBS) results in improvements in motor function and quality of life in patients with Parkinson disease (PD), which might impact a patient's perception of valued personal characteristics. Prior studies investigating whether DBS causes unwanted changes to oneself or one's personality have methodological limitations that should be addressed. To determine whether DBS is associated with changes in characteristics that patients with PD identify as personally meaningful. This cohort study assessed changes in visual analog scale (VAS) ratings reflecting the extent to which patients with PD manifested individually identified personal characteristics before and 6 and 12 months after DBS at a large academic medical center from February 21, 2018, to December 9, 2021. The VAS findings were tailored to reflect the top 3 individually identified personal characteristics the patient most feared losing. The VASs were scored from 0 to 10, with 0 representing the least and 10 the most extreme manifestation of the trait. Change scores were examined at the individual level. Content analysis was used to code the qualitative data. Qualitative and quantitative analyses were performed from January 12, 2019 (initial qualitative coding), to December 15, 2023. Deep brain stimulation. The primary outcome variable was the mean VAS score for the top 3 personal characteristics. The secondary outcome was the incidence of meaningful changes on the patients' top 3 characteristics at the individual level. Fifty-two of 54 dyads of patients with PD and their care partners (96.3%) were recruited from a consecutive series approved for DBS (36 patients [69.2%] were male and 45 care partners [86.5%] were female; mean [SD] age of patients, 61.98 [8.55] years). Two patients and 1 care partner were lost to follow-up. Increases in the mean VAS score (indicative of greater manifestation of [ie, positive changes in] specific characteristics) were apparent following DBS for ratings of both the patients (Wald χ2 = 16.104; P < .001) and care partners (Wald χ2 = 6.746; P < .001) over time. The slopes of the changes for both the patient and care partners were correlated, indicating agreement in observed changes over time. The individual level analyses indicated that scores for most patients and care partners remained the same or increased. In this cohort study, participants reported greater (more positive) manifestations of individually identified, valued characteristics after DBS. These findings may be relevant to informing decision-making for patients with advanced PD who are considering DBS.

The effect of subthalamic nucleus deep brain stimulation on speech performance: a prospective clinical and tractography study.

Speech changes significantly impact the quality of life for Parkinson's disease (PD) patients. Deep Brain Stimulation (DBS) of the Subthalamic Nucleus (STN) is a standard treatment for advanced PD, but its effects on speech remain unclear. This study aimed to investigate the relationship between STN-DBS and speech changes in PD patients using comprehensive clinical assessments and tractography. Forty-seven PD patients underwent STN-DBS, with preoperative and 3-month postoperative assessments. Speech analyses included acoustic measurements, auditory-perceptual evaluations, and fluency-intelligibility tests. On the other hand, structures within the volume tissue activated (VTA) were identified using MRI and DTI. The clinical and demographic data and structures associated with VTA (Corticospinal tract, Internal capsule, Dentato-rubro-thalamic tract, Medial forebrain bundle, Medial lemniscus, Substantia nigra, Red nucleus) were compared with speech analyses. The majority of patients (36.2-55.4% good, 29.7-53.1% same) exhibited either improved or unchanged speech quality following STN-DBS. Only a small percentage (8.5-14.9%) experienced deterioration. Older patients and those with worsened motor symptoms postoperatively were more likely to experience negative speech changes (p < 0.05). Interestingly, stimulation of the right Substantia Nigra correlated with improved speech quality (p < 0.05). No significant relationship was found between other structures affected by VTA and speech changes. This study suggests that STN-DBS does not predominantly negatively impact speech in PD patients, with potential benefits observed, especially in younger patients. These findings underscore the importance of individualized treatment approaches and highlight the need for further long-term studies to optimize therapeutic outcomes and better understand the effects of STN-DBS on speech.

Body image appearance in Parkinson's disease patients on device aided therapies.

Parkinson's disease patients may experience altered body image perception. Advanced Parkinson's disease (aPD) with motor complications often requires surgical and device-aided treatments (DAT), such as levodopa-carbidopa intestinal gel (LCIG) and deep brain stimulation (DBS). Understanding body image perception is crucial when managing these devices. This study aims to explore body image perception in aPD patients, hypothesizing a link between DAT and body image perception. We performed a cross-sectional study including non-demented aPD patients with and without DAT and age- and sex-matched controls. Participants were assessed using the Appearance Schemas Inventory-Revised (ASI-R), including Motivational Salience (MS) and Self-Evaluative Salience (SES) scores. Additional data included age, education, BMI, comorbidities, pharmacotherapy, and psychopathologies. PD patients were also evaluated with UPDRS, Hoehn and Yahr scales and LEDD calculation. 70 aPD and 36 controls were enrolled. No differences in ASI-R scores were found between PD patients and controls, but women with PD had significantly lower MS scores than controls (16.1 ± 5.6 vs 19.7 ± 5.8; p = 0.023). Among aPD patients, those on DAT had longer disease duration, higher Hoehn and Yahr, and lower UPDRS IV scores. The lowest MS was observed in women on LCIG (12.7 ± 3.3; p = 0.001). This study shows low MS ratings driven by female gender and LCIG treatment. Women on LCIG show reduced attention and management of their appearance. This may be influenced by cultural, environmental, and biological factors. Prospective research is needed to understand the impact of DAT on body image.

Efficacy of subthalamic deep brain stimulation programming strategies for gait disorders in Parkinson's disease: a systematic review and meta-analysis.

Patients with advanced Parkinson's disease often suffer from severe gait and balance problems, impacting quality of live and persisting despite optimization of standard therapies. The aim of this review was to systematically review the efficacy of STN-DBS programming techniques in alleviating gait disturbances in patients with advanced PD. Searches were conducted in PubMed, Embase, and Lilacs databases, covering studies published until May 2024. The review identified 36 articles that explored five distinct STN-DBS techniques aimed at addressing gait and postural instability in Parkinson's patients: low-frequency stimulation, ventral STN stimulation for simultaneous substantia nigra activation, interleaving, asymmetric stimulation and a short pulse width study. Among these, 21 articles were included in the meta-analysis, which revealed significant heterogeneity among studies. Notably, low-frequency STN-DBS demonstrated positive outcomes in total UPDRS-III score and FOG-Q, especially when combined with dopaminergic therapy. The most favorable results were found for low-frequency STN stimulation. The descriptive analysis suggests that unconventional stimulation approaches may be viable for gait problems in patients who do not respond to standard therapies.