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Introduction: Despite the effectiveness of exercise-based interventions on symptom management and disease progression, many people with Parkinson's Disease (PwPD) do not exercise regularly. In line with the ubiquitous use of digital health technology, the MoveONParkinson digital solution was developed, comprising a Web Platform and a Mobile App with a Conversational Agent (CA). The interface features were designed based on the principles of Social Cognitive Theory with the goal of fostering behavior change in PwPD for sustained exercise participation and improved disease management. Methods: Using a mixed methods approach, this study aimed to collect feedback, assess the acceptability of the Mobile App and the Web Platform, and evaluate the usability of the latter. Quantitative data, which included questionnaire responses and the System Usability Scale (SUS) scores, were analyzed using descriptive statistics, heatmaps, and correlation matrices. Qualitative data, comprising semi-structured and thinking-aloud interview transcripts, were subjected to an inductive thematic analysis. A total of 28 participants were involved in the study, comprising 20 physiotherapists (average age: 34.50 ± 10.4), and eight PwPD (average age: 65.75 ± 8.63; mean Hoehn & Yahr: 2.0 (± 0.76)). Results: Three main themes emerged from the thematic analysis of the interviews, namely: Self-management (Theme 1), User Engagement (Theme 2), and Recommendations (Theme 3). The assessment of the Mobile App and the CA (mean score: 4.42/5.0 ± 0.79) suggests that PwPD were able to navigate this interface without notable difficulties. The mean SUS score of 79.50 (± 12.40%) with a 95% confidence interval ranging from 73.70 to 85.30, reveal good usability. Discussion: These findings indicate a high level of acceptability of the MoveONParkinson digital solution, serving as a foundation for assessing its impact on exercise engagement and, subsequently, its influence on symptom management and quality of life of PwPD.

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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.

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BACKGROUND: Deep Brain Stimulation (DBS) is FDA-approved for several movement disorders; such as Parkinson's disease, dystonia, and neuropsychiatric disorders. There are various reports of Body mass index (BMI) changes following different DBS targets in various disorders. AIM: A comprehensive systematic review and meta-analysis were conducted to investigate the impact of DBS on patients' Body Mass Index (BMI) and provide an in-depth overview of its underlying mechanisms. MATERIALS AND METHODS: We conducted research according to PRISMA guidelines. Our study assessed comprehensively electronic databases, including Pubmed, Scopus, Embase, web of science, and the Cochrane Library, up to May 2024. The random-effect model analysis was performed by the Comprehensive Meta-analysis software (CMA) version 3.0. As well, Cochran's Q test was used to determine the statistical heterogeneity of included studies. RESULT: This systematic review ultimately included 49 studies, 46 of which entered the meta-analysis. The total number of patients was 1478, consisting of Parkinson's disease (PD), dystonia, and the obsessive compulsive disorder (OCD) patients. The most common DBS target was subthalamic nucleus, followed by globus pallidus internus (GPi). Our meta-analysis depicted the BMI of participants significantly mount after DBS electrode implantation (SMD = -0.542, 95%CI: -0.678 to -0.406, and P-value < 0.001). However, moderate to high heterogeneity was detected among the studies (I2 = 67.566%). Additionally, the Daily energy intake (DEI) of patients significantly decreased after DBS (SMD: 0.457, 95%CI; 0.205 to 0.709, and P-value < 0.001). CONCLUSION: STN and GPi DBS can lead to weight gain through distinct central pathways in various movement and neuropsychiatric disorders, posing a potential risk for obesity, insulin resistance, and metabolic syndrome.

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BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

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Alpha-synuclein (αSyn) forms pathologic aggregates in Parkinson's disease (PD) and is implicated in mechanisms underlying neurodegeneration. While pathologic αSyn has been extensively studied, there is currently no method to evaluate αSyn within the brains of living patients. Patients with PD are often treated with deep brain stimulation (DBS) surgery in which surgical instruments are in direct contact with neuronal tissue; herein, we describe a method by which tissue is collected from DBS surgical instruments in PD and essential tremor (ET) patients and demonstrate that αSyn is detected. 24 patients undergoing DBS surgery for PD (17 patients) or ET (7 patients) were enrolled; from patient samples, 81.2 ± 44.8 µg of protein (n = 15), on average, was collected from surgical instruments. Light microscopy revealed axons, capillaries, and blood cells as the primary components of purified tissue (n = 3). ELISA assay further confirmed the presence of neuronal and glial tissue in DBS samples (n = 4). Further analysis was conducted using western blot, demonstrating that multiple αSyn antibodies are reactive in PD (n = 5) and ET (n = 3) samples; truncated αSyn (1-125 αSyn) was significantly increased in PD (n = 5) compared to ET (n = 3), in which αSyn misfolding is not expected (0.64 ± 0.25 vs. 0.25 ± 0.12, P = 0.046), thus showing that multiple forms of αSyn can be detected from living PD patients with this method.

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OBJECTIVE: MR-guided focused ultrasound (MRgFUS) thalamotomy is an incisionless neurosurgical treatment for patients with medically refractory essential tremor and tremor-dominant Parkinson's disease. A low skull density ratio (SDR) < 0.40 is a known risk factor for treatment failure. The aim of this study was to identify useful sonication strategies for patients with a low SDR < 0.40 by modifying the standard sonication protocol using maximum high-energy sonication while minimizing the number of sonications. METHODS: The authors retrospectively analyzed the effects of modified MRgFUS sonication on low-SDR tremor patients. All patients underwent head CT scans to calculate their SDR. The SDR threshold for MRgFUS thalamotomy was 0.35. The patients in the early series underwent the standard sonication protocol targeting the ventral intermediate nucleus contralateral to the treated hand side. The patients with a low SDR < 0.40 in the late series underwent a modified sonication protocol, in which the number of alignment sonications was minimized and high-energy treatment sonication (> 36,000 J) was used. The authors evaluated the lesion volume the following day and tremor improvement and adverse events 3 and 12 months after the procedure. The sonication patterns between low-SDR patients treated using different sonication protocols were examined using Fisher's exact test. ANOVA was used to examine the lesion volume and tremor improvement in high- and low-SDR patients treated using different sonication protocols. RESULTS: Among 41 patients with an SDR < 0.40, 14 underwent standard sonication and 27 underwent modified sonication. Fewer alignment sonications and high-energy treatment sonications were used in the modified sonication group compared with the standard group (p < 0.001). The duration of modified sonication was significantly shorter than that of standard sonication (p < 0.001). The lesion volume and tremor improvement significantly differed among the high- and low-SDR groups with different sonication protocols (p < 0.001). Low-SDR patients treated using modified sonication protocols had comparable lesion volume and tremor improvement to the high-SDR group. The modified sonication protocol did not significantly increase adverse intraprocedural and postprocedural events. CONCLUSIONS: Minimizing alignment sonications and applying high-energy sonication in early treatment help to create an optimal lesion volume and control tremor in low-SDR patients.

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In orchestrating cell signaling, facilitating plasma membrane repair, supervising protein secretion, managing waste elimination, and regulating energy consumption, lysosomes are indispensable guardians that play a crucial role in preserving intracellular homeostasis. Neurons are terminally differentiated post-mitotic cells. Neuronal function and waste elimination depend on normal lysosomal function. Converging data suggest that lysosomal dysfunction is a critical event in the etiology of Parkinson's disease (PD). Mutations in Glucosylceramidase Beta 1 (GBA1) and leucine-rich repeat kinase 2 (LRRK2) confer an increased risk for the development of parkinsonism. Furthermore, lysosomal dysfunction has been observed in the affected neurons of sporadic PD (sPD) patients. Given that lysosomal hydrolases actively contribute to the breakdown of impaired organelles and misfolded proteins, any compromise in lysosomal integrity could incite abnormal accumulation of proteins, including α-synuclein, the major component of Lewy bodies in PD. Clinical observations have shown that lysosomal protein levels in cerebrospinal fluid may serve as potential biomarkers for PD diagnosis and as signs of lysosomal dysfunction. In this review, we summarize the current evidence regarding lysosomal dysfunction in PD and discuss the intimate relationship between lysosomal dysfunction and pathological α-synuclein. In addition, we discuss therapeutic strategies that target lysosomes to treat PD.

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PURPOSE: To describe the effects of subthalamic nucleus deep brain stimulation (STN-DBS) on the speech of Spanish-speaking Parkinson's disease (PD) patients during the first year of treatment. METHODS: The speech measures (SMs): maximum phonation time, acoustic voice measures, speech rate, speech intelligibility measures, and oral diadochokinesis rates of nine Colombian idiopathic PD patients (four females and five males; age = 63 ± 7 years; years of PD = 10 ± 7 years; UPDRS-III = 57 ± 6; H&Y = 2 ± 0.3) were studied in OFF and ON medication states before and every three months during the first year after STN-DBS surgery. Praat software and healthy native listeners' ratings were used for speech analysis. Statistical analysis tried to find significant differences in the SMs during follow-up (Friedman test) and between medication states (Wilcoxon paired test). Also, a pre-surgery variation interval (PSVI) of reference for every participant and SM was calculated to make an individual analysis of post-surgery variation. RESULTS: Non-significative post-surgery or medication state-related differences in the SMs were found. Nevertheless, individually, based on PSVIs, the SMs exhibited: no variation, inconsistent or consistent variation during post-surgery follow-up in different combinations, depending on the medication state. CONCLUSION: As a group, participants did not have a shared post-surgery pattern of change in any SM. Instead, based on PSVIs, the SMs varied differently in every participant, which suggests that in Spanish-speaking PD patients, the effects of STN-DBS on speech during the first year of treatment could be highly variable.

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OBJECTIVE: Optimized deep brain stimulation (DBS) is fast becoming a therapy of choice for the treatment of Parkinson's disease (PD). However, the post-operative optimization (aimed at maximizing patient clinical benefits and minimizing adverse effects) of all possible DBS parameter settings using the standard-of-care clinical protocol requires numerous clinical visits, which substantially increases the time to optimization per patient (TPP), patient cost burden and limit the number of patients who can undergo DBS treatment. The TPP is further elongated in electrodes with stimulation directionality or in diseases with latency in clinical feedback. In this work, we proposed a deep learning and fMRI-based pipeline for DBS optimization that can potentially reduce the TPP from ~1 year to a few hours during a single clinical visit. METHODS AND PROCEDURES: We developed an unsupervised autoencoder (AE)-based model to extract meaningful features from 122 previously acquired blood oxygenated level dependent (BOLD) fMRI datasets from 39 a priori clinically optimized PD patients undergoing DBS therapy. The extracted features are then fed into multilayer perceptron (MLP)-based parameter classification and prediction models for rapid DBS parameter optimization. RESULTS: The AE-extracted features of optimal and non-optimal DBS were disentangled. The AE-MLP classification model yielded accuracy, precision, recall, F1 score, and combined AUC of 0.96 ± 0.04, 0.95 ± 0.07, 0.92 ± 0.07, 0.93 ± 0.06, and 0.98 respectively. Accuracies of 0.79 ± 0.04, 0.85 ± 0.04, 0.82 ± 0.05, 0.83 ± 0.05, and 0.70 ± 0.07 were obtained in the prediction of voltage, frequency, and x-y-z contact locations, respectively. CONCLUSION: The proposed AE-MLP models yielded promising results for fMRI-based DBS parameter classification and prediction, potentially facilitating rapid semi-automated DBS parameter optimization. Clinical and Translational Impact Statement-A deep learning-based pipeline for semi-automated DBS parameter optimization is presented, with the potential to significantly decrease the optimization duration per patient and patients' financial burden while increasing patient throughput.

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BACKGROUND: Stem cell-based therapy is a promising strategy for treating Parkinson's disease (PD) characterized by the loss of dopaminergic neurons. Recently, induced neural stem cell-derived dopaminergic precursor cells (iNSC-DAPs) have been emerged as a promising candidate for PD cell therapy because of a lower tumor-formation ability. Designer receptors exclusively activated by designer drugs (DREADDs) are useful tools for examining functional synaptic connections with host neurons. METHODS: DREADD knock-in human iNSCs to express excitatory hM3Dq and inhibitory hM4Di receptors were engineered by CRISPR. The knock-in iNSCs were differentiated into midbrain dopaminergic precursor cells (DAPs) and transplanted into PD mice. The various behavior test such as the Apomorphine-induced rotation test, Cylinder test, Rotarod test, and Open field test were assessed at 4, 8, or 12 weeks post-transplantation with or without the administration of CNO. Electrophysiology were performed to assess the integrated condition and modulatory function to host neurons. RESULTS: DREADD expressing iNSCs were constructed with normal neural stem cells characteristics, proliferation ability, and differentiation potential into dopaminergic neuorns. DAPs derived from DREADD expressing iNSC showed matched function upon administration of clozapine N-oxide (CNO) in vitro. The results of electrophysiology and behavioral tests of transplanted PD mouse models revealed that the grafts established synaptic connections with downstream host neurons and exhibited excitatory or inhibitory modulation in response to CNO in vivo. CONCLUSION: iNSC-DAPs are a promising candidate for cell replacement therapy for Parkinson's disease. Remote DREADD-dependent activation of iNSC-DAP neurons significantly enhanced the beneficial effects on transplanted mice with Parkinson's disease.

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Parkinson's disease (PD) and essential tremor are two major causes of pathological tremor among people over 60 years old. Due to the side effects and complications of traditional tremor management methods such as medication and deep brain surgery, non invasive tremor suppression methods have become more popular in recent years. Functional electrical stimulation (FES) is one of the methods used to reduce tremor in several studies. However, the effect of different FES parameters on tremor suppression and discomfort level, including amplitude, the number of pulses in each stimulation burst, frequency, and pulse width is yet to be studied for longer stimulation durations. Therefore, in this work, experiments were performed on 14 participants with PD to evaluate the effect of thirty seconds of out-of-phase electrical stimulation on wrist tremor at rest. Trials were conducted by varying the stimulation amplitude and the number of pulses while keeping the frequency and pulse width constant. Each test was repeated three times for each participant. The results showed an overall tremor suppression for 11 out of 14 participants and no average positive effects for three participants. It is concluded that despite the effectiveness of FES in tremor suppression, each set of FES parameters showed different suppression levels among participants due to the variability of tremor over time. Thus, for this method to be effective, an adaptive control system would be required to tune FES parameters in real time according to changes in tremor during extended stimulation periods.

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Objective.Cryogel microcarriers made of poly(ethylene glycol) diacrylate and 3-sulfopropyl acrylate have the potential to act as delivery vehicles for long-term retention of neurotrophic factors (NTFs) in the brain. In addition, they can potentially enhance stem cell-derived dopaminergic (DAergic) cell replacement strategies for Parkinson's disease (PD), by addressing the limitations of variable survival and poor differentiation of the transplanted precursors due to neurotrophic deprivation post-transplantation in the brain. In this context, to develop a proof-of-concept, the aim of this study was to determine the efficacy of glial cell line-derived NTF (GDNF)-loaded cryogel microcarriers by assessing their impact on the survival of, and reinnervation by, primary DAergic grafts after intra-striatal delivery in Parkinsonian rat brains.Approach.Rat embryonic day 14 ventral midbrain cells were transplanted into the 6-hydroxydopamine-lesioned striatum either alone, or with GDNF, or with unloaded cryogel microcarriers, or with GDNF-loaded cryogel microcarriers.Post-mortem, GDNF and tyrosine hydroxylase immunostaining were used to identify retention of the delivered GDNF within the implanted cryogel microcarriers, and to identify the transplanted DAergic neuronal cell bodies and fibres in the brains, respectively.Main results.We found an intact presence of GDNF-stained cryogel microcarriers in graft sites, indicating their ability for long-term retention of the delivered GDNF up to 4 weeks in the brain. This resulted in an enhanced survival (1.9-fold) of, and striatal reinnervation (density & volume) by, the grafted DAergic neurons, in addition to an enhanced sprouting of fibres within graft sites.Significance.This data provides an important proof-of-principle for the beneficial effects of neurotrophin-loaded cryogel microcarriers on engraftment of cells in the context of cell replacement therapy in PD. For clinical translation, further studies will be needed to assess the impact of cryogel microcarriers on the survival and differentiation of stem cell-derived DAergic precursors in Parkinsonian rat brains.

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Parkinson's disease (PD) is the second most common neurodegenerative disease. The development of PD is closely linked to genetic and environmental factors, with GBA1 variants being the most common genetic risk. Mutations in the GBA1 gene lead to reduced activity of the coded enzyme, glucocerebrosidase, which mediates the development of PD by affecting lipid metabolism (especially sphingolipids), lysosomal autophagy, endoplasmic reticulum, as well as mitochondrial and other cellular functions. Clinically, PD with GBA1 mutations (GBA1-PD) is characterized by particular features regarding the progression of symptom severity. On the therapeutic side, the discovery of the relationship between GBA1 variants and PD offers an opportunity for targeted therapeutic interventions. In this review, we explore the genotypic and phenotypic correlations, etiologic mechanisms, biomarkers, and therapeutic approaches of GBA1-PD and summarize the current state of research and its challenges.

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BACKGROUND: The burgeoning field of regenerative medicine has significantly advanced with recent findings on biotherapies using human platelet lysates (HPLs), derived from clinical-grade platelet concentrates (PCs), for treating brain disorders. These developments have opened new translational research avenues to explore the neuroprotective effects of platelet-extracellular vesicles (PEVs). Their potential in managing neurodegenerative conditions like traumatic brain injury (TBI) and Parkinson's disease (PD) warrants further exploration. We aimed here to characterize the composition of a PEV preparation isolated from platelet concentrate (PC) supernatant, and determine its neuroprotective potential and neurorestorative effects in cellular and animal models of TBI and PD. METHODS: We isolated PEVs from the supernatant of clinical-grade PC collected from healthy blood donors utilizing high-speed centrifugation. PEVs were characterized by biophysical, biochemical, microscopic, and LC-MS/MS proteomics methods to unveil biological functions. Their functionality was assessed in vitro using SH-SY5Y neuronal cells, LUHMES dopaminergic neurons, and BV-2 microglial cells, and in vivo by intranasal administration in a controlled cortical impact (CCI)-TBI model using 8-weeks-old male C57/BL6 mice, and in a PD model induced by MPTP in 5-month-old male C57/BL6 mice. RESULTS: PEVs varied in size from 50 to 350 nm, predominantly around 200 nm, with concentrations ranging between 1010 and 1011/mL. They expressed specific platelet membrane markers, exhibited a lipid bilayer by cryo-electron microscopy and, importantly, showed low expression of pro-coagulant phosphatidylserine. LC-MS/MS indicated a rich composition of trophic factors, including neurotrophins, anti-inflammatory agents, neurotransmitters, and antioxidants, unveiling their multifaceted biological functions. PEVs aided in the restoration of neuronal functions in SH-SY5Y cells and demonstrated remarkable neuroprotective capabilities against erastin-induced ferroptosis in dopaminergic neurons. In microglial cells, they promoted anti-inflammatory responses, particularly under inflammatory conditions. In vivo, intranasally delivered PEVs showed strong anti-inflammatory effects in a TBI mouse model and conserved tyrosine hydroxylase expression of dopaminergic neurons of the substantia nigra in a PD model, leading to improved motor function. CONCLUSIONS: The potential of PEV-based therapies in neuroprotection opens new therapeutic avenues for neurodegenerative disorders. The study advocates for clinical trials to establish the efficacy of PEV-based biotherapies in neuroregenerative medicine.

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Introduction: Subthalamic nucleus deep brain stimulation (STN-DBS) is a proven treatment modality for Parkinson's disease (PD), reducing dyskinesia and time spent in the "OFF" state. This study evaluates the long-term outcomes of STN-DBS in PD patients up to 10 years post-surgery in Singapore. Method: We conducted a retrospective review of Movement Disorders Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) scores, activities of daily living (ADLs), disease milestones, dopaminergic drug prescriptions, and adverse events in patients before and after STN-DBS surgery. Results: A total of 94 PD patients who underwent bilateral STN-DBS were included. STN-DBS reduced time in the "OFF" state by 36.9% at 1 year (P=0.034) and 40.9% at 5 years (P=0.006). Time with dyskinesia did not significantly change. Levodopa equivalent daily dose was reduced by 35.1% by 5 years (P<0.001). MDS-UPDRS-II and III scores increased from 5 years post-DBS by 40.5% and 35.4%, respectively. Independence in ADLs decreased, though not significantly. The prevalence of frequent falls increased at 5 years. Surgery- and device-related adverse events were uncommon and generally mild. Conclusion: STN-DBS provides sustained relief from motor complications and reduced medication requirements in PD patients in Singapore. This study highlights STN-DBS as an effective treatment option, significantly enhancing the quality of life for those with PD.

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OBJECTIVE: Early morning OFF (EMO) is one of the first motor complications to manifest and frequently signals the onset of additional motor complications in Parkinson's Disease (PD). Although EOM are frequently observed in patients with PD and many caregivers must help with their motor inability, the treatment is still unsatisfactory. The majority of research that has been conducted on the wearing-off state of patients with PD has focused on daytime symptoms; evening and early morning symptoms have received much less attention.This study aimed to review the clinical perspectives of current therapies for EMO. MATERIALS AND METHODS: We reviewed the searching relevant publications from the key words such as morning off. A total of 456 publications were identified and we reviewed 21 clinical trials as well as other relevant clinical studies and reviews. RESULTS: EMO are frequently disregarded or undervalued, which could have resulted in unintentional risks, inadequate management, and an increased burden of care. Oral medication is still the primary medical intervention for EMO. However, new developments in non-oral medications and advanced formulations aim to reduce the delay in experiencing the benefits of oral levodopa due to gastrointestinal problems. CONCLUSIONS: The current therapies for EMO could be helpful in selecting a limited practical treatment. Advancements in non-oral medications and oral formulations hold promise for improving efficacy in EMO.

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Parkinson's disease (PD), a prevalent neurodegenerative condition, manifests predominantly through the degeneration of nigrostriatal dopaminergic (DA) pathways, culminating in a notable depletion of striatal dopamine. This pathophysiological process critically impairs the DA-mediated regulation of motor behaviors within the basal ganglia circuitry, particularly impacting various subtypes of striatal medium spiny neurons. Recent advancements in neuroscientific research have illuminated the pivotal role of D2-dopamine receptor expressing medium spiny neurons (D2-MSNs) plasticity in coordinating motor control in PD. Intriguingly, aerobic exercise emerges as a potent therapeutic intervention, capable of preventing or improving motor impairments. This ameliorative effect is mediated through the modulation of DA receptor activity and the consequent activation of downstream extracellular signal-regulated kinase (Erk) signaling pathway. This article meticulously reviewed the intricate regulatory mechanisms governing the structural and functional plasticity of striatal D2-MSNs in the context of PD. It particularly emphasized the transformative impact of aerobic exercise on motor deficits in PD, attributing this effect to the modulation of striatal D2-MSNs.

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Orthostatic hypotension (OH) is the most common manifestation of cardiovascular autonomic dysfunction in Parkinson's disease. In this viewpoint, we discuss five practical questions regarding OH in Parkinson's disease: 1) How common is the problem? 2) Why should people with Parkinson's disease and providers care about OH? 3) What are the symptoms of OH? 4) How to confirm a diagnosis of OH? And 5) How to treat OH? OH is an important non-motor symptom of Parkinson's disease for which we have available treatments to significantly mitigate morbidity and possibly positively impact the disease course.

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