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Parkinson's disease (PD) is a neurodegenerative disorder resulting from the loss of dopamine-producing neurons in the brain, causing motor symptoms like tremors and stiffness. Although current treatments like medication and deep brain stimulation can alleviate symptoms, they don't address the root cause of neuron loss. Therefore, cell replacement therapy emerges as a promising treatment strategy. However, the generation of engraftable dopaminergic (DA) cells in clinically relevant quantities is still a challenge. Recent advances in cell reprogramming technologies open up vast possibilities to produce patient-specific cells of a desired type in therapeutic quantities. The main cell reprogramming strategies involve the enforced expression of individual or sets of genes through viral transduction or transfection, or through small molecules, known as the chemical approach, which is a much easier and safer method. In our previous studies, using a small molecule approach (combinations of epigenetic modifiers and SMAD inhibitors such asDorsomorphin and SB431542), we have been able to generate DA progenitors from human mesenchymal stem cells (hMSCs). The aim of this study was to further improve the method for the generation of DA progenitors and to test their therapeutic effect in an animal model of Parkinson's. The results showed that the addition of an autophagy enhancer (AE) to our DA cell induction protocol further increased the yield of DA progenitor cells. The results also showed that DA progenitors transplanted into the mouse model of PD survived, integrated, and improved PD motor symptoms. These data suggest that chemically-produced DA cells can be very promising and safe cellular therapeutics for PD., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Deep brain stimulation of the subthalamic nucleus (STN-DBS) is a successful treatment option in Parkinson's disease (PD) for different motor and non-motor symptoms, but has been linked to postoperative cognitive impairment., Aim: Since both dopaminergic and norepinephrinergic neurotransmissions play important roles in symptom development, we analysed STN-DBS effects on dopamine and norepinephrine availability in different brain regions and morphological alterations of catecholaminergic neurons in the 6-hydroxydopamine PD rat model., Methods: We applied one week of continuous unilateral STN-DBS or sham stimulation, respectively, in groups of healthy and 6-hydroxydopamine-lesioned rats to quantify dopamine and norepinephrine contents in the striatum, olfactory bulb and dentate gyrus. In addition, we analysed dopaminergic cell counts in the substantia nigra pars compacta and area tegmentalis ventralis and norepinephrinergic neurons in the locus coeruleus after one and six weeks of STN-DBS., Results: In 6-hydroxydopamine-lesioned animals, one week of STN-DBS did not alter dopamine levels, while striatal norepinephrine levels were decreased. However, neither one nor six weeks of STN-DBS altered dopaminergic neuron numbers in the midbrain or norepinephrinergic neuron counts in the locus coeruleus. Dopaminergic fibre density in the dorsal and ventral striatum also remained unchanged after six weeks of STN-DBS. In healthy animals, one week of STN-DBS resulted in increased dopamine levels in the olfactory bulb and decreased contents in the dentate gyrus, but had no effects on norepinephrine availability., Conclusions: STN-DBS modulates striatal norepinephrinergic neurotransmission in a PD rat model. Additional behavioural studies are required to investigate the functional impact of this finding., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: Severe dysphagia poses a significant challenge for clinicians regarding feeding tube choices, practices, and timing due to a lack of evidence-based guidance., Objectives: To assess national clinical practices and opinions on gastrostomy use in patients with atypical parkinsonian syndromes (APS) across the UK., Methods: Online survey was administered to clinicians and allied health professionals regarding availability of services, current use, perceived advantages, and problems associated with gastrostomy insertion., Results: We received responses from 47 respondents across 12 UK centers, including 44 clinicians specialized in APS. Consensus was observed regarding primary indications for gastrostomy insertion and circumstances justifying avoidance of the procedure. Limitations in recommending gastrostomy due to insufficient evidence on safety and outcomes, survival and quality of life were identified. Widespread agreement on delays in gastrostomy discussions was highlighted as a challenge in optimizing patient care, together with variability in current practices and concerns over the lack of a standardized gastrostomy pathway, emphasizing the need for further research to address existing evidence gaps., Conclusion: This multi-center survey highlights agreement among clinicians on key aspects of indication, challenges, and limitations such as delayed decision-making and the absence of standardized pathways regarding the timing, method, and overall approach to gastrostomy insertion in APS. This study identified next steps to facilitate a more structured approach to future research toward a consensus on best practices for gastrostomy in APS. Addressing these challenges is crucial for enhancing patient outcomes and overall care quality in APS., (© 2024 The Author(s). Movement Disorders Clinical Practice published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.)

Background: Although care of Parkinsonism (PKM) is assumed to be optimally provided by movement disorder neurologists within an interdisciplinary clinic model, there is a paucity of published data to support this., Objectives: To investigate the impact of movement disorder neurologist care of individuals with Parkinsonism (PKM)., Methods: A retrospective exposure design was adopted using administrative data. Incident PKM individuals were identified in billing claims. A nine-year exposure period to movement disorder neurologist, general neurologist and non-neurologist care was calculated based on the billing codes. Regression models were used to test the association of provider exposure on time to death and long-term care (LTC) admission. Linear models were used to test varying provider exposure and hospital admissions, hospital days and emergency department visits., Results: 1914 incident individuals were identified. There was no difference in PKM mortality, emergency visits, hospital admissions, or hospital days between providers, however exposure to general neurology and non-neurology care was associated with a significantly higher risk of admission to LTC compared to movement disorder neurologist care (HR 1.43; 95% CI 1.09-1.87 for general neurology (p-value = 0.0089); HR 1.61; 95% CI 1.25-2.05 for non-neurology (p-value = 0.0002), respectively., Conclusion: Movement disorder neurologist care is associated with a lower risk of admission to LTC over general neurologist care in individuals with PKM., Competing Interests: Declaration of competing interest The author group has no competing interest in regard to this manuscript. No AI was used during the creation of this submission. Financial disclosures are individually listed in each author's declaration. There is no conflict of interest relating to those mentioned that pertain to the content within this submission., (Crown Copyright © 2024. Published by Elsevier Ltd. All rights reserved.)

Cognitive impairment in Parkinson's disease is considered an indicator of the prodromal stages of this condition, occurring prior to the onset of classic and pathognomonic motor symptoms. Among other factors, neuroinflammation is increasingly recognized as a potential mediator of this neurodegenerative process, and glial cells are directly involved. However, the use of neurotrophic factors is associated with neuroprotection and cognitive improvements. Among all those factors, insulin-like growth factor 1 (IGF-1) has attracted considerable attention. In this study, we aimed to investigate the effect of IGF-1 gene therapy in an early animal model of 6-hydroxidopamine (6-OHDA)- induced parkinsonism. For this purpose, we employed male Wistar rats. The animals were first divided into two groups according to the bilateral injection into de Caudate Putamen unit (CPu):(a) VEH group (vehicle solution) and (b) 6-OHDA group (neurotoxic solution). After that, the animals in each group were divided, according to the bilateral injection into the dorsal hippocampus, in a control group (who received a control virus RAd-DSRed) and an experimental group (who received a therapeutic virus (RAd-IGF1). After three weeks of exposure to 6-OHDA, our study showed that IGF-1 gene therapy improved cognitive deficits related to short-term and spatial working memory, it also increased expression levels of tyrosine hydroxylase in the CPu. In addition, the therapy resulted in significant changes in several parameters (area, perimeter, roundness, ramification, and skeleton ́s analyses) related to microglia and astrocyte phenotypes, particularly in the CPu and dorsal hippocampal areas. Our data support the use of IGF-1 as a therapeutic molecule for future gene transfer interventions, that will contribute to a better understanding of the mechanisms correlating cognitive function and inflammatory process., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Inc.)

Background: High-frequency repeated transcranial magnetic stimulation (rTMS) stimulating the primary motor cortex (M1) is an alternative, adjunctive therapy for improving the motor symptoms of Parkinson's disease (PD). However, whether the high frequency of rTMS positively correlates to the improvement of motor symptoms of PD is still undecided. By controlling for other parameters, a disease animal model may be useful to compare the neuroprotective effects of different high frequencies of rTMS., Objective: The current exploratory study was designed to compare the protective effects of four common high frequencies of rTMS (5, 10, 15, and 20 Hz) and iTBS (a special form of high-frequency rTMS) and explore the optimal high-frequency rTMS on an animal PD model., Methods: Following high frequencies of rTMS application (twice a week for 5 weeks) in a MPTP/probenecid-induced chronic PD model, the effects of the five protocols on motor behavior as well as dopaminergic neuron degeneration levels were identified. The underlying molecular mechanisms were further explored., Results: We found that all the high frequencies of rTMS had protective effects on the motor functions of PD models to varying degrees. Among them, the 10, 15, and 20 Hz rTMS interventions induced comparable preservation of motor function through the protection of nigrostriatal dopamine neurons. The enhancement of brain-derived neurotrophic factor (BDNF), dopamine transporter (DAT), and vesicular monoamine transporter 2 (VMAT-2) and the suppression of TNF-α and IL-1β in the nigrostriatum were involved in the process. The efficacy of iTBS was inferior to that of the above three protocols. The effect of 5 Hz rTMS protocol was weakest., Conclusions: Combined with the results of the present study and the possible side effects induced by rTMS, we concluded that 10 Hz might be the optimal stimulation frequency for preserving the motor functions of PD models using rTMS treatment., (© 2024 The Author(s). Brain and Behavior published by Wiley Periodicals LLC.)

DNAJC6 encodes auxilin, a co-chaperone protein involved in clathrin-mediated endocytosis (CME) at the presynaptic terminal. Biallelic mutations in DNAJC6 cause a complex, early-onset neurodegenerative disorder characterized by rapidly progressive parkinsonism-dystonia in childhood. The disease is commonly associated with additional neurodevelopmental, neurological and neuropsychiatric features. Currently, there are no disease-modifying treatments for this condition, resulting in significant morbidity and risk of premature mortality. To investigate the underlying disease mechanisms in childhood-onset DNAJC6 parkinsonism, we generated induced pluripotent stem cells (iPSC) from three patients harbouring pathogenic loss-of-function DNAJC6 mutations and subsequently developed a midbrain dopaminergic neuronal model of disease. When compared to age-matched and CRISPR-corrected isogenic controls, the neuronal cell model revealed disease-specific auxilin deficiency as well as disturbance of synaptic vesicle recycling and homeostasis. We also observed neurodevelopmental dysregulation affecting ventral midbrain patterning and neuronal maturation. To explore the feasibility of a viral vector-mediated gene therapy approach, iPSC-derived neuronal cultures were treated with lentiviral DNAJC6 gene transfer, which restored auxilin expression and rescued CME. Our patient-derived neuronal model provides deeper insights into the molecular mechanisms of auxilin deficiency as well as a robust platform for the development of targeted precision therapy approaches., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Introduction: Gait and mobility impairment are pivotal signs of parkinsonism, and they are particularly severe in atypical parkinsonian disorders including multiple system atrophy (MSA) and progressive supranuclear palsy (PSP). A pilot study demonstrated a significant improvement of gait in patients with MSA of parkinsonian type (MSA-P) after physiotherapy and matching home-based exercise, as reflected by sensor-based gait parameters. In this study, we aim to investigate whether a gait-focused physiotherapy (GPT) and matching home-based exercise lead to a greater improvement of gait performance compared with a standard physiotherapy/home-based exercise programme (standard physiotherapy, SPT)., Methods and Analysis: This protocol was deployed to evaluate the effects of a GPT versus an active control undergoing SPT and matching home-based exercise with regard to laboratory gait parameters, physical activity measures and clinical scales in patients with Parkinson's disease (PD), MSA-P and PSP. The primary outcomes of the trial are sensor-based laboratory gait parameters, while the secondary outcome measures comprise real-world derived parameters, clinical rating scales and patient questionnaires. We aim to enrol 48 patients per disease group into this double-blind, randomised-controlled trial. The study starts with a 1 week wearable sensor-based monitoring of physical activity. After randomisation, patients undergo a 2 week daily inpatient physiotherapy, followed by 5 week matching unsupervised home-based training. A 1 week physical activity monitoring is repeated during the last week of intervention., Ethics and Dissemination: This study, registered as 'Mobility in Atypical Parkinsonism: a Trial of Physiotherapy (Mobility_APP)' at clinicaltrials.gov (NCT04608604), received ethics approval by local committees of the involved centres. The patient's recruitment takes place at the Movement Disorders Units of Innsbruck (Austria), Erlangen (Germany), Lausanne (Switzerland), Luxembourg (Luxembourg) and Bolzano (Italy). The data resulting from this project will be submitted to peer-reviewed journals, presented at international congresses and made publicly available at the end of the trial., Trial Registration Number: NCT04608604., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is a well-established treatment for the motor symptoms of Parkinson's disease (PD). While PD is primarily characterized by motor symptoms such as tremor, rigidity, and bradykinesia, it also involves a range of non-motor symptoms, and anxiety is one of the most common. The relationship between PD and anxiety is complex and can be a result of both pathological neural changes and the psychological and emotional impacts of living with a chronic progressive condition. Managing anxiety in PD is critical for improving the patients' quality of life. However, patients undergoing STN DBS can occasionally experience increased anxiety., Methods: This study investigates changes in risk-avoidant behavior following STN DBS in a pre-motor animal model of PD under chronic and acute unilateral high frequency stimulation., Results: No significant changes in risk-avoidant behaviors were observed in rats who underwent STN DBS compared with sham stimulation controls. Chronic stimulation prevented sensitization in the elevated zero maze., Conclusions: These results suggest that unilateral stimulation of the STN may have minimal effects on risk-avoidant behaviors in PD. However, additional research is required to fully understand the mechanisms responsible for changes in anxiety during STN DBS for PD., Competing Interests: The authors declare no conflict of interest., (© 2024 The Author(s). Published by IMR Press.)

Transcranial direct current stimulation (tDCS) is increasingly being used for Parkinson's disease (PD); however, the evaluation of its clinical impact remains complex owing to the heterogeneity of patients and treatments. Therefore, we used a unilateral 6-hydroxydopamine-induced PD rat model to investigate whether anodal tDCS of the primary motor cortex (M1) alleviates PD motor deficits. Before tDCS treatment, unilateral PD rats preferentially used the forelimb ipsilateral to the lesion in the exploratory cylinder test and showed reduced locomotor activity in the open field test. In addition, PD-related clumsy forelimb movements during treadmill walking were detected using deep learning-based video analysis (DeepLabCut). When the 5-day tDCS treatment began, the forelimb-use asymmetry was ameliorated gradually, and locomotor activity increased to pre-lesion levels. tDCS treatment also normalized unnatural forelimb movement during walking and restored a balanced gait. However, these therapeutic effects were rapidly lost or gradually disappeared when the tDCS treatment was terminated. Histological analysis at the end of the experiment revealed that the animals had moderately advanced PD, with 40-50% of dopamine neurons and fibers preserved on the injured side compared with those on the intact side. Although it remains a challenge to elucidate the neural mechanisms of the transient improvement in motor function induced by tDCS, the results of this study provide evidence that tDCS of the M1 produces positive behavioral outcomes in PD animals and provides the basis for further clinical research examining the application of tDCS in patients with PD., Competing Interests: Conflicts of interest The authors declare no conflict of interest., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background: Parkinson's disease (PD) is a neurodegenerative disease that leads to progressive disability. Cost studies have mainly explored the early stages of the disease, whereas late-stage patients are underrepresented., Objective: The aim is to evaluate the resource utilization and costs of PD management in people with late-stage disease., Methods: The Care of Late-Stage Parkinsonism (CLaSP) study collected economic data from patients with late-stage PD and their caregivers in five European countries (France, Germany, the Netherlands, UK, Sweden) in a range of different settings. Patients were eligible to be included if they were in Hoehn and Yahr stage >3 in the on state or Schwab and England stage at 50% or less. In total, 592 patients met the inclusion criteria and provided information on their resource utilization. Costs were calculated from a societal perspective for a 3-month period. A least absolute shrinkage and selection operator approach was utilized to identify the most influential independent variables for explaining and predicting costs., Results: During the 3-month period, the costs were €20,573 (France), €19,959 (Germany), €18,319 (the Netherlands), €25,649 (Sweden), and €12,156 (UK). The main contributors across sites were formal care, hospitalization, and informal care. Gender, age, duration of the disease, Unified Parkinson's Disease Rating Scale 2, the EQ-5D-3L, and the Schwab and England Scale were identified as predictors of costs., Conclusion: Costs in this cohort of individuals with late-stage PD were substantially higher compared to previously published data on individuals living in earlier stages of the disease. Resource utilization in the individual sites differed in part considerably among these three parameters mentioned. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society., (© 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.)

Neurological disorders such as Parkinsonism cause serious socio-economic problems as there are, at present, only therapies that treat their symptoms. The well-established hallmark alpha-synuclein (SYN) is enriched in the inclusion bodies characteristic of Parkinsonism. We discovered a prominent partner of SYN, termed Tubulin Polymerization Promoting Protein (TPPP), which has important physiological and pathological activities such as the regulation of the microtubule network and the promotion of SYN aggregation. The role of TPPP in Parkinsonism is often neglected in research, which we here attempt to remedy. In the normal brain, SYN and TPPP are expressed endogenously in neurons and oligodendrocytes, respectively, whilst, at an early stage of Parkinsonism, soluble hetero-associations of these proteins are found in both cell types. The cell-to-cell transmission of these proteins, which is central to disease progression, provides a unique situation for specific drug targeting. Different strategies for intervention and for the discovery of biomarkers include (i) interface targeting of the SYN-TPPP hetero-complex; (ii) proteolytic degradation of SYN and/or TPPP using the PROTAC technology; and (iii) depletion of the proteins by miRNA technology. We also discuss the potential roles of SYN and TPPP in the phenotype stabilization of neurons and oligodendrocytes.

Parkinson's disease (PD) is one of the most common neurodegenerative diseases worldwide. Currently applied therapeutic protocols are limited to improve the motor functions of patients. Therefore, seeking alternative regimes with better therapeutic impact is crucial. This study aims to validate the therapeutic impact of mesenchymal stem cell injection using two delivery methods, intracranial administration and intravenous administration, on rotenone (ROT)-induced PD model in rats. Our work included behavioral, biochemical, histological, and molecular investigations. Open field test (OFT) and rotarod tests were applied. Important oxidative stress, antioxidant and proinflammatory markers were monitored. Substantia Nigra and Striatum tissues were examined histologically and the molecular expression of DOPA decarboxylase, Tyrosine hydroxylase, and α-synuclein in neurons in these tissues were investigated. Our results showed that MSC grafting improved motor and memory impairments and oxidative stress status that were observed after ROT administration. Additionally, BM-MSCs application restored SOD and CAT activities and the levels of DA, L-Dopa, IL6, IL1β, and TNFα. Moreover, MSC grafting overwhelmed the pathological changes induced by ROT and normalized the expression of Tyrosine hydroxylase, DOPA decarboxylase, and α-synuclein towards the control values in the Nigral and Striatal tissues of male rats. Conclusively, both administration routes improved motor function, protection of the nigrostriatal system, and improved striatal dopamine release. The observed beneficial effect of applying MSCs suggests potential benefits in clinical applications. No significant differences in the outcomes of the treatment would favor a certain way of MSC application over the other. However, the intravenous delivery method seems to be safer and more feasible compared to the intrastriatal method., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Essawy Essawy et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Here, we introduce the magneto-mechanical-genetic (MMG)-driven wireless deep brain stimulation (DBS) using magnetic nanostructures for therapeutic benefits in the mouse model of Parkinson's disease (PD). Electrical DBS of the subthalamic nucleus (STN) is an effective therapy for mitigating Parkinson's motor symptoms. However, its broader application is hampered by the requirement for implanted electrodes and the lack of anatomical and cellular specificity. Using the nanoscale magnetic force actuators (m-Torquer), which deliver torque force under rotating magnetic fields to activate pre-encoded Piezo1 ion channels on target neurons, our system enables wireless and STN-specific DBS without implants, addressing key unmet challenges in the DBS field. In both late- and early-stage PD mice, MMG-DBS significantly improved locomotor activity and motor balance by 2-fold compared to untreated PD mice. Moreover, MMG-DBS enabled sustained therapeutic effects. This approach provides a non-invasive and implant-free DBS with cellular targeting capability for the effective treatment of Parkinsonian symptoms.

Introduction: The aim of the study was to present a narrative review of the literature on the management of lower urinary tract symptoms (LUTS) in patients presenting Parkinsonian disorders (PD)., Material and Methods: We carried out a literature search in PubMed and Embase database, without time restriction. We used keywords and free-text words around "Parkinsonian disorders" AND "lower urinary tracts symptoms" without language restriction. We focused mainly on papers less than 10 years old. We included all studies evaluating LUTS in patients with PD., Results: For the diagnostic management, authors emphasized the importance of differentiating Parkinson's disease with symptoms of bladder overactivity from multiple system atrophy with symptoms of bladder hypoactivity. Urodynamic evaluation was noted as the key element of diagnostic management. The therapeutic management proposed was symptomatic, based on functional urology techniques for the treatment of LUTS, both with drugs (especially anticholinergics) or surgery (intradetrusor injections of botulinum toxin, neuromodulation). Moreover, it was pointed out that it is always necessary to take into account the existence of a possible associated uropathy (prostate adenoma or pelvic prolapse)., Conclusion: Urodynamic evaluation is the cornerstone of diagnostic management of LUTS in patients with PD. Therapeutic management is above all symptomatic and must be done in a collegial way involving the urologist, neurologist, gynecologist, and physical medicine and rehabilitation physician., (Copyright © 2023 Elsevier Masson SAS. All rights reserved.)

Introduction: Gait impairments in Parkinson's disease (PD) are treated with dopaminergic medication or deep-brain stimulation (DBS), although the magnitude of the response is variable between individuals. Computer vision-based approaches have previously been evaluated for measuring the severity of parkinsonian gait in videos, but have not been evaluated for their ability to identify changes within individuals in response to treatment. This pilot study examines whether a vision-based model, trained on videos of parkinsonism, is able to detect improvement in parkinsonian gait in people with PD in response to medication and DBS use., Methods: A spatial-temporal graph convolutional model was trained to predict MDS-UPDRS-gait scores in 362 videos from 14 older adults with drug-induced parkinsonism. This model was then used to predict MDS-UPDRS-gait scores on a different dataset of 42 paired videos from 13 individuals with PD, recorded while ON and OFF medication and DBS treatment during the same clinical visit. Statistical methods were used to assess whether the model was responsive to changes in gait in the ON and OFF states., Results: The MDS-UPDRS-gait scores predicted by the model were lower on average (representing improved gait; p = 0.017, Cohen's d = 0.495) during the ON medication and DBS treatment conditions. The magnitude of the differences between ON and OFF state was significantly correlated between model predictions and clinician annotations (p = 0.004). The predicted scores were significantly correlated with the clinician scores (Kendall's tau-b = 0.301, p = 0.010), but were distributed in a smaller range as compared to the clinician scores., Conclusion: A vision-based model trained on parkinsonian gait did not accurately predict MDS-UPDRS-gait scores in a different PD cohort, but detected weak, but statistically significant proportional changes in response to medication and DBS use. Large, clinically validated datasets of videos captured in many different settings and treatment conditions are required to develop accurate vision-based models of parkinsonian gait., (© 2023. The Author(s).)

Background: Excessive glutamatergic transmission in the striatum is implicated in Parkinson's disease (PD) progression. Astrocytes maintain glutamate homeostasis, protecting from excitotoxicity through the glutamate-aspartate transporter (GLAST), whose alterations have been reported in PD. Noninvasive brain stimulation using intermittent theta-burst stimulation (iTBS) acts on striatal neurons and glia, inducing neuromodulatory effects and functional recovery in experimental parkinsonism., Objective: Because PD is associated with altered astrocyte function, we hypothesized that acute iTBS, known to rescue striatal glutamatergic transmission, exerts regional- and cell-specific effects through modulation of glial functions., Methods: 6-Hydroxydopamine-lesioned rats were exposed to acute iTBS, and the areas predicted to be more responsive by a biophysical, hyper-realistic computational model that faithfully reconstructs the experimental setting were analyzed. The effects of iTBS on glial cells and motor behavior were evaluated by molecular and morphological analyses, and CatWalk and Stepping test, respectively., Results: As predicted by the model, the hippocampus, cerebellum, and striatum displayed a marked c-FOS activation after iTBS, with the striatum showing specific morphological and molecular changes in the astrocytes, decreased phospho-CREB levels, and recovery of GLAST. Striatal-dependent motor performances were also significantly improved., Conclusion: These data uncover an unknown iTBS effect on astrocytes, advancing the understanding of the complex mechanisms involved in TMS-mediated functional recovery. Data on numerical dosimetry, obtained with a degree of anatomical details never before considered and validated by the biological findings, provide a framework to predict the electric-field induced in different specific brain areas and associate it with functional and molecular changes. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society., (© 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.)

The subthalamic nucleus (STN) is a common target for deep brain stimulation (DBS) treatments of Parkinsonian motor symptoms. According to the dominant model, the STN output can suppress movement by enhancing inhibitory basal ganglia (BG) output via the indirect pathway, and disrupting STN output using DBS can restore movement in Parkinson's patients. But the mechanisms underlying STN DBS remain poorly understood, as previous studies usually relied on electrical stimulation, which cannot selectively target STN output neurons. Here, we selectively stimulated STN projection neurons using optogenetics and quantified behavior in male and female mice using 3D motion capture. STN stimulation resulted in movements with short latencies (10-15 ms). A single pulse of light was sufficient to generate movement, and there was a highly linear relationship between stimulation frequency and kinematic measures. Unilateral stimulation caused movement in the ipsiversive direction (toward the side of stimulation) and quantitatively determined head yaw and head roll, while stimulation of either STN raises the head (pitch). Bilateral stimulation does not cause turning but raised the head twice as high as unilateral stimulation of either STN. Optogenetic stimulation increased the firing rate of STN neurons in a frequency-dependent manner, and the increased firing is responsible for stimulation-induced movements. Finally, stimulation of the STN's projection to the brainstem mesencephalic locomotor region was sufficient to reproduce the behavioral effects of STN stimulation. These results question the common assumption that the STN suppresses movement, and instead suggest that STN output can precisely specify action parameters via direct projections to the brainstem. SIGNIFICANCE STATEMENT Our results question the common assumption that the subthalamic nucleus (STN) suppresses movement, and instead suggest that STN output can precisely specify action parameters via direct projections to the brainstem., (Copyright © 2023 the authors.)

Dysphagia is a clinically relevant problem in Parkinson's disease as well as in atypical Parkinsonian syndromes, such as multiple system atrophy and diseases from the spectrum of 4‑repeat tauopathies, which affect most patients to a varying degree in the course of their disease. This results in relevant restrictions in daily life due to impaired intake of food, fluids, and medication with a subsequent reduction in quality of life. This article not only gives an overview of the pathophysiological causes of dysphagia in the various Parkinson syndromes, but also presents screening, diagnostic and treatment procedures that have been investigated for the different diseases., (© 2023. The Author(s), under exclusive licence to Springer Medizin Verlag GmbH, ein Teil von Springer Nature.)

Competing Interests: Declaration of competing interest VVH, BKS, SP, KN, NK, BM, PKP, and RY have no financial disclosures or any conflicts of interest to report relevant to this article.

In Parkinson's disease (PD), reduced dopamine levels in the basal ganglia have been associated with altered neuronal firing and motor dysfunction. It remains unclear whether the altered firing rate or pattern of basal ganglia neurons leads to parkinsonism-associated motor dysfunction. In the present study, we show that increased histaminergic innervation of the entopeduncular nucleus (EPN) in the mouse model of PD leads to activation of EPN parvalbumin (PV) neurons projecting to the thalamic motor nucleus via hyperpolarization-activated cyclic nucleotide-gated (HCN) channels coupled to postsynaptic H 2 R. Simultaneously, this effect is negatively regulated by presynaptic H 3 R activation in subthalamic nucleus (STN) glutamatergic neurons projecting to the EPN. Notably, the activation of both types of receptors ameliorates parkinsonism-associated motor dysfunction. Pharmacological activation of H 2 R or genetic upregulation of HCN2 in EPN PV neurons, which reduce neuronal burst firing, ameliorates parkinsonism-associated motor dysfunction independent of changes in the neuronal firing rate. In addition, optogenetic inhibition of EPN PV neurons and pharmacological activation or genetic upregulation of H 3 R in EPN-projecting STN Glu neurons ameliorate parkinsonism-associated motor dysfunction by reducing the firing rate rather than altering the firing pattern of EPN PV neurons. Thus, although a reduced firing rate and more regular firing pattern of EPN PV neurons correlate with amelioration in parkinsonism-associated motor dysfunction, the firing pattern appears to be more critical in this context. These results also confirm that targeting H 2 R and its downstream HCN2 channel in EPN PV neurons and H 3 R in EPN-projecting STN Glu neurons may represent potential therapeutic strategies for the clinical treatment of parkinsonism-associated motor dysfunction.

Due to the heterogeneous clinical presentation, people with Parkinsonism (PwP) develop individual healthcare needs as their disease progresses. However, because of limited health resources during the COVID-19 pandemic, many patients were put at risk of inadequate care. All this occurred in the context of inequitable healthcare provision within societies, especially for such vulnerable populations. This study aimed to investigate factors influencing satisfaction and unmet need for healthcare among PwP during the COVID-19 pandemic in Germany. Analyses relied on an anonymous online survey with a 49-item questionnaire. We aimed at describing access to health services before and during the early stages of the pandemic. To this end, a generalized linear model was used to derive significant predictors and a stepwise regression to subsummarize the main factors of perceived inadequate care. In total, 551 questionnaires showed that satisfaction with Parkinsonism-related care decreased significantly during the pandemic ( p  < 0.001). In particular, factors such as lower educational level, lower perceived expertise of healthcare providers, less confidence in remote care, difficulties in obtaining healthcare, and restricted access to care before the pandemic but also lower densities of neurologists at residence and less ability to overcome barriers were indicative of higher odds to perceive unmet needs ( p  < 0.05). The results unveil obstacles contributing to reduced access to healthcare during the COVID-19 pandemic for PwP. These findings enable considerations for improved provision of healthcare services to PwP., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 van Munster, Printz, Crighton, Mestre, Pedrosa and iCARE-PD Consortium.)

Atypical parkinsonian syndromes are neurodegenerative conditions, characterised by rapid disease progression and shorter life expectancy compared to idiopathic Parkinson's disease. These conditions inflict substantial physical and psychosocial burden on patients and their families; hence, there is a clear rationale for a palliative care approach from diagnosis. An interdisciplinary care model has been shown to improve symptom burden, quality of life and engagement with advance care planning, in a heterogeneous group of neurodegenerative conditions. In this update, we summarise how the landscape for treating these patients has changed and the questions that still need to be resolved., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany.)

Induced pluripotent stem cells (iPS cells) are considered a promising source of cell-based therapy for the treatment of Parkinson's disease (PD). Recent studies have shown forebrain GABA interneurons have crucial roles in many psychiatric disorders, and secondary changes in the GABA system play a directly effect on the pathogenesis of PD. Here, we first describe an efficient differentiation procedure of GABA progenitors (MiPSC-iGABAPs) from miniature-swine iPSCs through two major developmental stages. Then, the MiPSC-iGABAPs were stereotactically transplanted into the right medial forebrain bundle (MFB) of 6-hydroxydopamine (OHDA)-lesioned PD model rats to confirm their feasibility for the neural transplantation as a donor material. Furthermore, the grafted MiPSC-iGABAPs could survive and migrate from the graft site into the surrounding brain tissue including striatum (ST) and substantia nigra (SN) for at least 32 weeks, and significantly improved functional recovery of PD rats from their parkinsonian behavioral defects. Histological studies showed that the grafted cells could migrate and differentiate into various neurocytes, including GABAergic, dopaminergic neurons, and glial cells in vivo, and many induced dopaminergic neurons extended dense neurites into the host striatum. Moreover, over 50% of the grafted MiPSC-iGABAPs could express GABA, and these GABAergic neurons might be responsible for modifying the balance of excitatory and inhibitory signals in the striatum to promote behavioral recovery. Thus, the present study confirmed that the MiPSC-iGABAPs can be used as an attractive donor material for the neural grafting to remodel basal ganglia circuitry in neurodegenerative diseases, avoiding tumorigenicity of iPSCs and the nonproliferative and nondifferentiated potential of mature neurons., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Little is known about the burden of parkinsonism and Parkinson's disease (PD) in Latin America. Better understanding of health service use and clinical outcomes in PD is needed to improve its prognosis., Objective: The aim of the study was to estimate the burden of parkinsonism and PD in six Latin American countries., Methods: 12,865 participants aged 65 years and older from the 10/66 population-based cohort study were analysed. Baseline assessments were conducted in 2003-2007 and followed-up 4 years later. Parkinsonism and PD were defined using current clinical criteria or self-reported diagnosis. Logistic regression models assessed the association between parkinsonism/PD with baseline health service use (community-based care or hospitalisation in the last 3 months) and Cox proportional hazards regression models with incident dependency (subjective assessment by interviewer based on informant interview) and mortality. Separate analyses for each country were combined via fixed effect meta-analysis., Results: At baseline, the prevalence of parkinsonism and PD was 7.9% (n = 934) and 2.6% (n = 317), respectively. Only parkinsonism was associated with hospital admission at baseline (OR 1.89, 95% CI 1.30-2.74). Among 7,296 participants without dependency at baseline, parkinsonism (HR 2.34, 95% CI 1.81-3.03) and PD (2.10, 1.37-3.24) were associated with incident dependency. Among 10,315 participants with vital status, parkinsonism (1.73, 1.50-1.99) and PD (1.38, 1.07-1.78) were associated with mortality. The Higgins I2 tests showed low to moderate levels of heterogeneity across countries., Conclusions: Our findings show that older people with parkinsonism or PD living in Latin America have higher risks of developing dependency and mortality but may have limited access to health services.

The development of the closed-loop deep brain stimulator (DBS) for clinical trials requires verification of its safety and effectiveness in a large animal model. Due to the financial and ethical challenges of using non-human primates, it is reasonable to use an alternative large animal model. It was reported that minipigs are suitable for the establishment of the MPTP-induced parkinsonian model. However, there is currently no evidence of whether beta oscillations, the symptom-related biomarker, exist in the subthalamic nucleus (STN) of the parkinsonian minipig model. This study was to verify whether the beta oscillations could be recorded in the STN of the parkinsonian minipig model. Parkinsonism was induced by injections of the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Through a protocol involving up to nine subcutaneous or intramuscular injections, delivering a cumulative dose of 8-10 mg/kg MPTP, the minipigs developed notable movement disturbance. By stereotactic surgery and microelectrode recording, beta oscillations were recorded in the STN of the MPTP-injected minipigs. Immunohistochemistry of the tyrosine hydroxylase (TH) was performed in the substantia nigra pars compacta (SNc) of each animal. Compared with the control animal injected with saline, the TH-positive cells in the SNc were significantly reduced in the MPTP-injected minipigs. This study showed that beta oscillations could be recorded in the STN of the MPTP-induced parkinsonian minipig model. This large animal model is suitable as an alternative pre-clinical model for developing closed-loop DBS in the future., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier B.V. All rights reserved.)

To date, the diagnoses of Parkinson syndromes are based on clinical examination. Therefore, these specific diagnoses are made, when the neuropathological process is already advanced. However, disease modification or neuroprotection, is considered to be most effective before marked neurodegeneration has occurred. In recent years, early clinical or prodromal stages of Parkinson syndromes came into focus. Moreover, subtypes of distinct diseases will allow predictions of the individual course of the diseases more precisely. Thereby, patients will be enrolled into clinical trials with more specific disease entities and endpoints. Furthermore, novel fluid and imaging biomarkers that allow biochemical diagnoses are under development. These will lead to earlier diagnoses and earlier therapy in the future as consequence. Furthermore, therapeutic approaches will take the underlying neuropathological process of neurodegenerative Parkinson syndromes more specific into account. Specifically, future therapies will target the aggregation of aggregation-prone proteins such as alpha-synuclein and tau, the degradation of pathological aggregates, and the spreading of pathological protein aggregates throughout the brain. Many of these approaches are already in (pre)clinical development. In addition, anti-inflammatory approaches are in development. Furthermore, drug-repurposing is a feasible approach to shorten the developmental process of new drugs., (© 2022. The Author(s).)

Background: Telemedicine for patients with parkinsonism is feasible, cost-effective and satisfactory. However, the feasibility of this modality of care for this subpopulation is not known in real-life scenarios of developing countries like Brazil., Objective: To evaluate the feasibility of telemedicine for patients with parkinsonism in a developing country., Methods: A cross-sectional study with patients with parkinsonism treated in the Brazilian public healthcare system. We included 130 patients, who were contacted by telephone; those who could be reached underwent a structured interview for data collection. The primary outcomes were the feasibility of teleconsultations and video consultations, but we also performed a logistic regression regarding the feasibility of a video consultation and associated factors., Results: Telemedicine was feasible and accepted by 69 (53.08%) patients regarding teleconsultations and by 50 (38.5%) patients regarding video consultations. Teleconsultations were feasible for 80.2%, and video consultations were feasible for 58.1% of the patients reachable through telephone calls. Having a higher family income was positively correlated with the feasibility for a video consultation while a negative association was observed regarding being married or in a stable union and having a low level of schooling., Conclusions: A significant proportion of patients with parkinsonism in a developing country are unreachable, unwilling, or unable to participate in telemedicine. Among the reachable patients, feasibility is higher but still lower than what is reported in studies in developed countries. Family income, level of schooling, and marital status were associated with the feasibility of video consultations., Competing Interests: The authors have no conflict of interests to declare., (Academia Brasileira de Neurologia. This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/).)

Background: Telemedicine (TM) consultations have shown to be feasible for the management of neurological conditions including movement disorders. In contrast, satisfaction with such consultations have been less studied., Objective: To assess the satisfaction of persons with a movement disorder with a TM consultation in comparison to previous experiences in face-to-face visits., Subjects and Methods: A cross-sectional multicenter study was carried out. Persons with a diagnosis of a movement disorder underwent a TM consultation. After the consultation concluded, a satisfaction survey was sent for the subject to fill out anonymously. The survey included ease of use-related items, setup-related items, and quality-of-service-related items., Results: A total of 175 survey responses were received (response rate of 71.4%), all of which were included for analysis. A total of 102 subjects considered that the TM consultation involved much less time in comparison to their previous experience with face-to-face visits. Overall, 96% reported to be satisfied with the consultation. In addition, 92% were satisfied or very satisfied with the neurologist ability to communicate recommendations. Furthermore, 93.7% indicated that the consultation was valuable, and 90.9% considered that they would recommend teleconsultation to another patient., Conclusion: Patients with a diagnosis of a movement disorder consider TM as a convenient and potential tool for health services with a high level of satisfaction., Competing Interests: None

The subthalamic nucleus (STN) is one of the best targets for therapeutic deep brain stimulation (DBS) to control motor symptoms in Parkinson's disease. However, the precise circuitry underlying the effects of STN-DBS remains unclear. To understand how electrical stimulation affects STN projection neurons, we used a retrograde viral vector (AAV-retro-hSyn-eGFP) to label STN neurons projecting to the substantia nigra pars reticulata (SNr) (STN-SNr neurons) or the globus pallidus interna (GPi) (STN-GPi neurons) in mice, and performed whole-cell patch-clamp recordings from these projection neurons in ex vivo brain slices. We found that STN-SNr neurons exhibited stronger responses to depolarizing stimulation than STN-GPi neurons. In most STN-SNr and STN-GPi neurons, inhibitory synaptic inputs predominated over excitatory inputs and electrical stimulation at 20-130 Hz inhibited these neurons in the short term; its longer-term effects varied. 6-OHDA lesion of the nigrostriatal dopaminergic pathway significantly reduced inhibitory synaptic inputs in STN-GPi neurons, but did not change synaptic inputs in STN-SNr neurons; it enhanced short-term electrical-stimulation-induced inhibition in STN-SNr neurons but reversed the effect of short-term electrical stimulation on the firing rate in STN-GPi neurons from inhibitory to excitatory; in both STN-SNr and STN-GPi neurons, it increased the inhibition but attenuated the enhancement of firing rate induced by long-term electrical stimulation. Our results suggest that STN-SNr and STN-GPi neurons differ in their synaptic inputs, their responses to electrical stimulation, and their modification under parkinsonian conditions; STN-GPi neurons may play important roles in both the pathophysiology and therapeutic treatment of Parkinson's disease., (© 2021. The Author(s), under exclusive licence to CPS and SIMM.)

Background: Although various motor manifestations can be seen in patients with cerebrospinal fluid (CSF) disorders, such as hydrocephalus or intracranial hypotension, the clinical presentation with parkinsonism is not clearly elucidated., Methods: We searched the literature for studies describing the occurrence of parkinsonism in subjects with normal pressure hydrocephalus (NPH), obstructive hydrocephalus, and intracranial hypotension. We analyzed the clinical presentation (particularly with respect to bradykinesia, rigidity, rest tremor, and gait disturbance/postural instability) as well as the response to treatment., Results: Parkinsonism was most commonly reported in NPH patients. Although gait disturbance/postural instability is a well-known motor symptom of NPH, other cardinal signs include upper limb involvement or asymmetric presentation. As for obstructive hydrocephalus, parkinsonism was mainly observed in subjects with aqueductal stenosis and more often after shunt surgery. Patients with NPH or obstructive hydrocephalus rarely improved with levodopa therapy, while most subjects only improved with shunt surgery. Although the mechanism is still controversial, a functional involvement of nigrostriatal pathway has been hypothesized based on imaging studies and case reports. Brain imaging is also helpful for atypical cases of intracranial hypotension presenting with parkinsonism. Parkinsonism improved after treatment in such cases as well., Conclusions: Studies exploring the relationship between CSF disorders and parkinsonism are mainly descriptive and their quality is generally poor. However, considering that these disorders can be treated, clinicians' awareness of the differential diagnosis is important and future studies better exploring the underlying pathophysiological mechanisms are warranted. This article is part of the Special Issue "Parkinsonism across the spectrum of movement disorders and beyond" edited by Joseph Jankovic, Daniel D. Truong and Matteo Bologna., (Copyright © 2021 Elsevier B.V. All rights reserved.)