The Role of MicroRNAs in Progressive Supranuclear Palsy-A Systematic Review.

Progressive supranuclear palsy (PSP) is a rare, neurodegenerative movement disorder. Together with multiple system atrophy (MSA), Dementia with Lewy bodies (DLB), and corticobasal degeneration (CBD), PSP forms a group of atypical parkinsonisms. The latest diagnostic criteria, published in 2017 by the Movement Disorders Society, classify PSP diagnosis into defined, probable, and possible categories based on clinical examination. However, no single test is specific and sensitive for this disease. Microribonucleic acids (miRNAs) are promising molecules, particularly in the case of diseases that lack appropriate diagnostic and treatment tools, which supports exploring their role in PSP. We aimed to systematically review the current knowledge about the role of miRNAs in PSP. This study was registered in the Open Science Framework Registry, and the protocol is available online. Primary original studies, both clinical and preclinical, written in English and assessing miRNAs in PSP were included. Systematic reviews, meta-analyses, reviews, case reports, letters to editors, commentaries, conference abstracts, guidelines/statements, expert opinions, preprints, and book chapters were excluded. The following five databases were searched: Embase, Medline Ultimate, PubMed, Scopus, and Web of Science. Each database was last searched on 18 June 2024. Eventually, nine original studies relevant to the discussed area were included. The risk of bias was not assessed. The selected research suggests that miRNAs may be considered promising biomarkers in PSP. However, the exact involvement of miRNAs in the pathogenesis of PSP is still to be determined. Several microRNAs were found to be dysregulated in patients with PSP. This applies to both brain tissue and fluids like cerebrospinal fluid CSF or blood. Several miRNAs were found that could potentially be helpful in differentiating among PSP patients, PD patients, and healthy individuals. Although some correlations and alterations have already been found, this field requires much more research. MicroRNAs are exciting and promising small molecules, and their investigation into many diseases, including PSP, may lead to significant discoveries.

Unilateral gamma knife thalamotomy for tremor safety and efficacy in multimodal assessment: a prospective case-control study with two-year follow-up.

INTRODUCTION: Unilateral gamma knife thalamotomy (GKT) is a treatment option for pharmacoresistant tremor of various aetiologies. There have been to date no randomised controlled trials performed to assess its safety and efficacy. Our aim was to summarise a two-year multimodal observation of patients with tremor caused by Parkinson's Disease (PD) or essential tremor (ET). MATERIAL AND METHODS: 23 patients with PD (n = 12) or ET (n = 11) were included. They underwent assessments before, V0 (n = 23), and 12 months, V12 (n = 23), and 24 months, V24 (n = 15), after unilateral GKT. Patients were assessed with psychological tests and acoustic voice analysis. Tremor assessment was performed with a digitising table using the Fahn-Tolosa-Marin rating scale (FTMRS). The Unified Parkinson's Disease rating scale part III (UPDRS-III) was also used in the PD group. Gait and balance was assessed using clinical tests, stabilometric platform, and treadmill. RESULTS: No side effects were observed in a two-year follow-up. There was no notable deterioration observed in the patients' psychological evaluation, speech, or assessment of gait and balance. The scores were significantly lower (p = 0.01) in parts A and B of FTMRS one year after GKT. In post hoc analysis, the scores did not differ significantly between V0 and V24. In FTMRS part C (activities of daily living), no significant change was observed. There was no significant difference in total UPDRS part III score or in score of UPDRS part III domains 3 and 4 ('tremor at rest' and 'action and postural tremor of hands') between measurements. CONCLUSIONS: UGKT may be a safe treatment modality if performed in an experienced centre. Tremor reduction may diminish over time, and UGKT did not lead to cognitive, gait or speech deterioration in a long-term observation.

Machine Learning and Eye Movements Give Insights into Neurodegenerative Disease Mechanisms.

Humans are a vision-dominated species; what we perceive depends on where we look. Therefore, eye movements (EMs) are essential to our interactions with the environment, and experimental findings show EMs are affected in neurodegenerative disorders (ND). This could be a reason for some cognitive and movement disorders in ND. Therefore, we aim to establish whether changes in EM-evoked responses can tell us about the progression of ND, such as Alzheimer's (AD) and Parkinson's diseases (PD), in different stages. In the present review, we have analyzed the results of psychological, neurological, and EM (saccades, antisaccades, pursuit) tests to predict disease progression with machine learning (ML) methods. Thanks to ML algorithms, from the high-dimensional parameter space, we were able to find significant EM changes related to ND symptoms that gave us insights into ND mechanisms. The predictive algorithms described use various approaches, including granular computing, Naive Bayes, Decision Trees/Tables, logistic regression, C-/Linear SVC, KNC, and Random Forest. We demonstrated that EM is a robust biomarker for assessing symptom progression in PD and AD. There are navigation problems in 3D space in both diseases. Consequently, we investigated EM experiments in the virtual space and how they may help find neurodegeneration-related brain changes, e.g., related to place or/and orientation problems. In conclusion, EM parameters with clinical symptoms are powerful precision instruments that, in addition to their potential for predictions of ND progression with the help of ML, could be used to indicate the different preclinical stages of both diseases.

Glymphatic System and Mitochondrial Dysfunction as Two Crucial Players in Pathophysiology of Neurodegenerative Disorders.

Neurodegenerative diseases are a complex problem affecting millions of people around the world. The pathogenesis is not fully understood, but it is known that both insufficiency of the glymphatic system and mitochondrial disorders affect the development of pathology. It appears that these are not just two independent factors that coexist in the processes of neurodegeneration, but that they often interact and drive each other. Bioenergetics disturbances are potentially associated with the accumulation of protein aggregates and impaired glymphatic clearance. Furthermore, sleep disorders characteristic of neurodegeneration may impair the work of both the glymphatic system and the activity of mitochondria. Melatonin may be one of the elements linking sleep disorders with the function of these systems. Moreover, noteworthy in this context is the process of neuroinflammation inextricably linked to mitochondria and its impact not only on neurons, but also on glia cells involved in glymphatic clearance. This review only presents possible direct and indirect connections between the glymphatic system and mitochondria in the process of neurodegeneration. Clarifying the connection between these two areas in relation to neurodegeneration could lead to the development of new multidirectional therapies, which, due to the complexity of pathogenesis, seems to be worth considering.

Clinical Phenotypes of Progressive Supranuclear Palsy-The Differences in Interleukin Patterns.

Progressive supranuclear palsy (PSP) is an atypical parkinsonian syndrome based on tau pathology; its clinical phenotype differs, but PSP with Richardson's syndrome (PSP-RS) and the PSP parkinsonism predominant (PSP-P) variant remain the two most common manifestations. Neuroinflammation is involved in the course of the disease and may cause neurodegeneration. However, an up-to-date cytokine profile has not been assessed in different PSP phenotypes. This study aimed to evaluate possible differences in neuroinflammatory patterns between the two most common PSP phenotypes. Serum and cerebrospinal fluid (CSF) concentrations of interleukin-1 beta (IL-1ß) and IL-6 were analyzed using enzyme-linked immunosorbent assay (ELISA) kits in 36 study participants-12 healthy controls and 24 patients with a clinical diagnosis of PSP-12 PSP-RS and 12 PSP-P. Disease duration among PSP patients ranged from three to six years. All participants underwent basic biochemical testing, and neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) values were calculated. Due to a lack of neuropathological examinations, as all patients remain alive, total tau levels were assessed in the CSF. Tau levels were significantly higher in the PSP-P and PSP-RS groups compared to the healthy controls. The lowest concentrations of serum and CSF interleukins were observed in PSP-RS patients, whereas PSP-P patients and healthy controls had significantly higher interleukin concentrations. Furthermore, there was a significant correlation between serum IL-6 levels and PLR in PSP-RS patients. The results indicate the existence of distinct neuroinflammatory patterns or a neuroprotective role of increased inflammatory activity, which could cause the differences between PSPS phenotypes and clinical course. The causality of the correlations described requires further studies to be confirmed.

Cathepsin B p.Gly284Val Variant in Parkinson's Disease Pathogenesis.

Parkinson's disease (PD) is generally considered a sporadic disorder, but a strong genetic background is often found. The aim of this study was to identify the underlying genetic cause of PD in two affected siblings and to subsequently assess the role of mutations in Cathepsin B (CTSB) in susceptibility to PD. A typical PD family was identified and whole-exome sequencing was performed in two affected siblings. Variants of interest were validated using Sanger sequencing. CTSB p.Gly284Val was genotyped in 2077 PD patients and 615 unrelated healthy controls from the Czech Republic, Ireland, Poland, Ukraine, and the USA. The gene burden analysis was conducted for the CTSB gene in an additional 769 PD probands from Mayo Clinic Florida familial PD cohort. CTSB expression and activity in patient-derived fibroblasts and controls were evaluated by qRT-PCR, western blot, immunocytochemistry, and enzymatic assay. The CTSB p.Gly284Val candidate variant was only identified in affected family members. Functional analysis of CTSB patient-derived fibroblasts under basal conditions did not reveal overt changes in endogenous expression, subcellular localization, or enzymatic activity in the heterozygous carrier of the CTSB variant. The identification of the CTSB p.Gly284Val may support the hypothesis that the CTSB locus harbors variants with differing penetrance that can determine the disease risk.

Carbohydrate metabolism and lipid profile in patients with Parkinson's disease with subthalamic deep brain stimulation.

AIM OF THE STUDY: Assessment of potential effect of subthalamic nucleus deep brain stimulation (STN-DBS) on glucose metabolism in patients with Parkinson's disease (PD). CLINICAL RATIONALE FOR THE STUDY: Although a valuable alternative to pharmacotherapy in advanced PD, STN-DBS is thought to negatively affect the cardiometabolic profile of patients (including body mass, lipid profile). Exacerbation of glucose metabolism dysregulation after DBS could therefore be assumed. MATERIAL AND METHODS: Two groups of patients with Parkinson's disease were included: 20 treated pharmacologically (PHT) and 20 newly qualified for STN-DBS (DBS) - with the first assessment prior to surgery, and the second 11 months after surgery on average. Body mass index (BMI), plasma concentrations of total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol (HDL-C), triglycerides (TG) and glucose levels during a three-point oral glucose tolerance test were measured three times (median intervals between visits 12 and 14 months respectively). RESULTS: Significant differences between the two groups were noted with respect to changes in BMI, and serum concentration of TG and HDL-C over the course of the study. In the DBS group, a significant increase in BMI (26.42 vs. 27.24 kg/m2, p = 0.03) and TG level (103.8 vs. 142.8 mg/dL, p < 0.001) with a simultaneous decrease in HDL-C level (54.4 vs. 46 mg/dL, p < 0.01) was observed. Mean glucose level after oral glucose administration was lower in the DBS than in the PHT group (147.4 vs. 120.2 mg/dL, p = 0.03 after one hour and 109.9 vs. 82.3 mg/dL, p < 0.01 after two hours) during the second visit. Also inter-visit changes in fasting glucose levels (8.4 mg/dL in the PHT group and -5.8 mg/dL in the DBS group, p = 0.02) differed over the study duration. CONCLUSIONS: Our observations are similar to previous ones indicating less favourable changes in BMI and some lipid fractions in patients treated surgically. Interestingly, such a trend was not observed for glucose metabolism parameters, suggesting that mechanisms other than simple body mass changes are involved in early biochemical changes after STN-DBS in PD patients. CLINICAL IMPLICATIONS: The metabolic consequences of DBS require further investigation as an additional factor potentially affecting the outcome of therapy, and routine patient follow-up should not be limited to neurological and psychological assessments.

Movement disorders associated with chromosomal aberrations diagnosed in adult patients.

INTRODUCTION: Chromosomal aberrations are rare but important causes of various movement disorders. In cases of movement disorders associated with dysmorphic features, multiorgan involvement and/or intellectual disability, the identification of causative chromosomal aberrations should be considered. AIM OF THE STUDY: The purpose of this article was to summarise clinical findings in six patients with dystonia and two with parkinsonism and identified chromosomal aberrations in a single-centre prospective study. MATERIALS AND METHODS: 15 adult patients with dystonia or parkinsonism were referred to array comparative genomic hybridisation (aCGH) testing from our Department of Neurology between 2014 and 2019. Additionally, one patient had a karyotype examination. Detailed clinical, psychological and radiological diagnostics were performed in each case. RESULTS: Chromosomal aberrations were identified in six patients with dystonia and two with parkinsonism. Two patients were identified with aberrations associated with de Grouchy syndrome. We also reported generalised dystonia in patients with deletion in 3q26.31 and duplication in 3p26.3, as well as dystonia and hypoacusis in a patient with duplication in Xq26.3. One patient was diagnosed with duplication in 21q21.1. Early-onset parkinsonism was a manifestation of deletion in the 2q24.1 region. Late onset parkinsonism was also present in the patient with the most severe aberrations (duplication 1q21.1q44; deletion 10p15.3p15.1; deletion 10q11.21). CONCLUSIONS: Dystonia and parkinsonism are possible manifestations of chromosomal aberrations. Chromosomal aberrations should be excluded in patients with early-onset movement disorders and concomitant dysmorphic features and/or intellectual disability. It is important to include this cause of movement disorders in future classifications. aCGH can be a valuable diagnostic tool in the evaluation of movement disorder aetiology.

"New methods of assessing autonomic disorders in Parkinson disease patients: skin-galvanic reaction".

The aim of this study was to assess quantitatively sweating in PD patients. In the study, the galvanic-skin reaction (GSR) was used. The GSR was tested using eSense Skin Reaction device. The results show that sweating in patients with Parkinson's disease on drugs (PD ON) and control patients is similar, while patients with PD without levodopa (PD OFF) have higher perspiration.

A Multimodal Approach to the Quantification of Kinetic Tremor in Parkinson's Disease.

Parkinson's disease results in motor impairment that deteriorates patients' quality of life. One of the symptoms negatively interfering with daily activities is kinetic tremor which should be measured to monitor the outcome of therapy. A new instrumented method of quantification of the kinetic tremor is proposed, based on the analysis of circles drawn on a digitizing tablet by a patient. The aim of this approach is to obtain a tremor scoring equivalent to that performed by trained clinicians. Models are trained with the least absolute shrinkage and selection operator (LASSO) method to predict the tremor scores on the basis of the parameters computed from the patients' drawings. Signal parametrization is derived from both expert knowledge and the response of an artificial neural network to the raw data, thus the approach was named multimodal. The fitted models are eventually combined into model ensembles that provide aggregated scores of the kinetic tremor captured in the drawings. The method was verified with a set of clinical data acquired from 64 Parkinson's disease patients. Automated and objective quantification of the kinetic tremor with the presented approach yielded promising results, as the Pearson's correlations between the visual ratings of tremor and the model predictions ranged from 0.839 to 0.890 in the best-performing models.

Evaluating reflexive saccades and UDPRS as markers of Deep Brain Stimulation and Best Medical Treatment improvements in Parkinson's disease patients: a prospective controlled study.

INTRODUCTION: To date, there has been no clear evidence regarding the evaluation of saccades as a monitoring tool of motor impairment in Parkinson's disease (PD) Subthalamic Nucleus Deep Brain Stimulation (STN-DBS) patients. The aim of this study was to evaluate the long-term impact of STN-DBS and pharmacological treatment on reflexive saccades' (RS) parameters and UPDRS alterations. MATERIAL AND METHODS: The DBS group consisted of 20 PD patients who underwent bilateral STN-DBS. The Postoperative (POP) group consisted of 14 post-DBS patients. The Best Medical Therapy (BMT) group consisted of 20 patients on pharmacotherapy only. RS parameters and the UPDRS scale were measured during three visits in four phases of treatment (i.e. BMT-ON/OFF, DBS-ON/OFF). RESULTS: The significant UPDRS III and UPDRS. Total improvements were observed in all three study groups (p < 0.05), but RS latency improvement was stated only in the DBS group in the DBS-ON phase (p < 0.05). A significant correlation between RS latency increase and UPDRS III score worsening was found in all study groups, with the most evident effect in the UPDRS III ON phase (p < 0.05). CONCLUSION: RS parameters correlated with UPDRS III outcomes during the postoperative period in DBS-STN patients. Therefore, saccadic evaluation may be a good biomarker of the patient's response to surgical and/or pharmacological treatment.

Difficulties in the diagnosis of four repeats (4R) tauopathic parkinsonian syndromes.

Corticobasal Degeneration Degeneration (CBD) and Progressive Supranuclear Palsy (PSP) are types of four repeats (4R) tauopathies, which are associated to parkinsonian syndromes. The aim of the work is to analyze cases of patients of the Department of Neurology, overlapping of syndromes related to both pathologies and to show that most likely CBS and PSP are not lineary related to their commonly associated syndromes i.e. adequately corticobasal syndromes and progressive supranuclear palsy syndromes. In the context of each patient factors in favor of most likely CBS, PSP or both diseases are discussed and analyzed using contemporary criteria. This work discusses multidimensional aspect of the examination of five patient aged 64 to 83 - 4 females and 1 male with 4R tauopathies and difficulties in distinguishing both diseases. The duration of the disease varied from 1 to 5 years. Each patient after neurological examination was assessed using magnetic resonance imaging (MRI) and psychological test. Examination of all patients was extended using single photon emission computer tomography (SPECT) to reveal the usefulness of this tool in differentiation of diseases was done. The outcome of this examination was verified with prior clinical manifestation of patients and morphological abnormalities in magnetic resonance imaging. Autopsies were not conducted.

The patient with mild diencephalic-mesencephalic junction dysplasia - Case report and review of literature.

Diencephalic-mesencephalic junction dysplasia (DMJD) is very rare congenital brain malformation. We present a 66-years-old man with mild cognitive impairment, dysarthria, deafness, gait abnormality, and involuntary movements of the trunk. The first symptoms, psychomotor excitation and anxiety begun when he was over thirty years old however the symptoms gradually intensified and slowly progressed. The magnetic resonance imaging scans showed partial DMJD. According to recent date it represented type-B of the malformation with relatively mild phenotype in relation to the previously described in literature type-A. To the best of our knowledge this is the first description of an adult patient diagnosed with DMJD anomaly.

Multimodal Learning and Intelligent Prediction of Symptom Development in Individual Parkinson's Patients.

We still do not know how the brain and its computations are affected by nerve cell deaths and their compensatory learning processes, as these develop in neurodegenerative diseases (ND). Compensatory learning processes are ND symptoms usually observed at a point when the disease has already affected large parts of the brain. We can register symptoms of ND such as motor and/or mental disorders (dementias) and even provide symptomatic relief, though the structural effects of these are in most cases not yet understood. It is very important to obtain early diagnosis, which can provide several years in which we can monitor and partly compensate for the disease's symptoms, with the help of various therapies. In the case of Parkinson's disease (PD), in addition to classical neurological tests, measurements of eye movements are diagnostic. We have performed measurements of latency, amplitude, and duration in reflexive saccades (RS) of PD patients. We have compared the results of our measurement-based diagnoses with standard neurological ones. The purpose of our work was to classify how condition attributes predict the neurologist's diagnosis. For n = 10 patients, the patient age and parameters based on RS gave a global accuracy in predictions of neurological symptoms in individual patients of about 80%. Further, by adding three attributes partly related to patient 'well-being' scores, our prediction accuracies increased to 90%. Our predictive algorithms use rough set theory, which we have compared with other classifiers such as Naïve Bayes, Decision Trees/Tables, and Random Forests (implemented in KNIME/WEKA). We have demonstrated that RS are powerful biomarkers for assessment of symptom progression in PD.

Small intestine dysfunction in Parkinson's disease.

The aim of this study was to assess the small bowel transit time in patients with Parkinson's disease (PD). Ten patients with PD with no gastrointestinal complaints and ten healthy control subjects were investigated using single photon emission computed tomography fused with computed tomography after swallowing of a specially prepared capsule containing technetium 99m, which allowed visualization of the passage in the intestines. Preliminary results show that the small intestine passage in PD patients was prolonged compared to controls.

Glymphatic System Pathology and Neuroinflammation as Two Risk Factors of Neurodegeneration.

The key to the effective treatment of neurodegenerative disorders is a thorough understanding of their pathomechanism. Neurodegeneration and neuroinflammation are mutually propelling brain processes. An impairment of glymphatic system function in neurodegeneration contributes to the progression of pathological processes. The question arises as to how neuroinflammation and the glymphatic system are related. This review highlights the direct and indirect influence of these two seemingly independent processes. Protein aggregates, a characteristic feature of neurodegeneration, are correlated with glymphatic clearance and neuroinflammation. Glial cells cannot be overlooked when considering the neuroinflammatory processes. Astrocytes are essential for the effective functioning of the glymphatic system and play a crucial role in the inflammatory responses in the central nervous system. It is imperative to acknowledge the significance of AQP4, a protein that exhibits a high degree of polarization in astrocytes and is crucial for the functioning of the glymphatic system. AQP4 influences inflammatory processes that have not yet been clearly delineated. Another interesting issue is the gut-brain axis and microbiome, which potentially impact the discussed processes. A discussion of the correlation between the functioning of the glymphatic system and neuroinflammation may contribute to exploring the pathomechanism of neurodegeneration.

Cannabidiol usage, efficacy, and side effects: analyzing the impact of health conditions, medications, and cannabis use in a cross-sectional online pilot study.

Background: Products containing cannabidiol (CBD) are attracting attention because of their potential therapeutic benefits and positive impacts on well-being and mental health. Although additional research is needed to understand their effectiveness in treating mental disorders, cross-sectional studies may help identify the factors influencing CBD use patterns. This study examined the impact of variables such as health status, medication use, medical supervision, gender, age, and cannabis use on CBD consumption patterns. Materials and methods: A self-selected sample (n =267) of current or former CBD users was recruited via social media and participated in an online survey designed to collect data on basic demographics, health status, cannabis use, and CBD usage patterns. Results: The sample (n = 267) consisted of 68.5% women with an average age of 30.21 years, of which 25.8% reported diagnosed psychiatric disorders and 49.4% reported cannabis use. The top five reasons for using CBD were self-reported stress (65.3%), sleep problems (51.7%), overall improvement in well-being (52.5%), improved mood (44.9%), and anxiety relief (40.9%). Our findings suggest that individuals with psychiatric disorders and those taking psychotropic medications are more likely to use CBD to relieve stress and anxiety. Overall, nearly 70% of the individuals found CBD products to be effective. Sublingual administration was more popular among non-cannabis users, while cannabis users preferred smoking and vaping to CBD administration. Conclusion: Our results indicate that individuals using CBD for health and wellness reasons believe that it has potential health benefits. Further research using rigorous longitudinal designs is needed to delve deeper into the effectiveness of low-dose CBD and to better understand the therapeutic potential of CBD.

The significance of glial cell line-derived neurotrophic factor analysis in Progressive Supranuclear Palsy.

Progressive Supranuclear Palsy (PSP) is an atypical parkinsonism. Major subtypes of the disease: PSP-Richardson's Syndrome (PSP-RS) and PSP Parkinsonism Predominant (PSP-P) vary in clinical features, the pathomechanism remains unexplored. The aim of this work is to analyze the relevance of glial cell line-derived neurotrophic factor (GDNF) evaluation in the serum and cerebrospinal fluid (CSF) in PSP subtypes and to verify its significance as a possible factor in the in vivo examination. Authors assessed the concentration of GDNF in the serum and CSF of 12 patients with PSP-RS, 12 with PSP-P and 12 controls. Additionally authors evaluated patients using Unified Parkinson's Disease Rating Scale-III part (UPDRS-III), Frontal Assessment Battery (FAB) and Magnetic Resonance Imaging (MRI). The evaluation revealed significantly increased concentrations of GDNF in the CSF among PSP-RS patients and substantially increased concentrations of GDNF in the serum in PSP-P. Though the GDNF concentrations differentiated PSP subtypes, no correlations between with clinical factors were observed however certain correlations with atrophic changes in MRI were detected. GDNF is a factor which may impact the pathogenesis of PSP. Possible implementation of GDNF as a therapeutic factor could be a perspective in the search for therapy in this currently incurable disease.

Impact of Physical Exercise on Levodopa Therapy Across Parkinson's Disease Stages.

Background: Levodopa is the gold standard of treatment in Parkinson's disease (PD). Its clinical effect changes as the disease progresses. Wearing off is a frequent first manifestation of motor fluctuations. Some patients with advanced PD report faster wearing off after physical exercise. Objective: The aim was to assess if pharmacokinetics of levodopa is influenced by physical exercise in patients with different disease advancement. Methods: 22 patients with PD (12 untreated with levodopa and 10 with motor fluctuations) and 7 healthy controls (HC) were included. Plasma samples were collected at 9 fixed timepoints following administration of levodopa/benserazide 200/50 mg for two days: rest day and standardized physical exercise day. Clinical assessment with Unified Parkinson Disease Rating Scale part III (UPDRS III) was performed in fixed timepoints. Liquid chromatography-tandem mass spectrometry was used to measure levodopa concentrations. Results: No differences between the HC, levodopa naïve and advanced PD groups were observed regarding selected pharmacokinetic parameters. In advanced PD and HC no differences in pharmacokinetic parameters of levodopa with and without effort were observed. In levodopa naïve PD group higher mean residence time after rest than after exercise (168.9±48.3 min vs. 145.5±50.8 min; p = 0.026) was observed. In advanced PD group higher UPDRS III score (14.45±5.5 versus 20.9±6.1 points, p = 0.04) was observed after exercise. Conclusions: The deterioration of motor status of advanced PD patients after physical effort is not reflected by changes in pharmacokinetics but rather mediated by central mechanisms.

Microglia and Stem Cells for Ischemic Stroke Treatment-Mechanisms, Current Status, and Therapeutic Challenges.

Ischemic stroke is one of the major causes of death and disability. Since the currently used treatment option of reperfusion therapy has several limitations, ongoing research is focusing on the neuroprotective effects of microglia and stem cells. By exerting the bystander effect, secreting exosomes and forming biobridges, mesenchymal stem cells (MSCs), neural stem cells (NSCs), induced pluripotent stem cells (iPSCs), and multilineage-differentiating stress-enduring cells (Muse cells) have been shown to stimulate neurogenesis, angiogenesis, cell migration, and reduce neuroinflammation. Exosome-based therapy is now being extensively researched due to its many advantageous properties over cell therapy, such as lower immunogenicity, no risk of blood vessel occlusion, and ease of storage and modification. However, although preclinical studies have shown promising therapeutic outcomes, clinical trials have been associated with several translational challenges. This review explores the therapeutic effects of preconditioned microglia as well as various factors secreted in stem cell-derived extracellular vesicles with their mechanisms of action explained. Furthermore, an overview of preclinical and clinical studies is presented, explaining the main challenges of microglia and stem cell therapies, and providing potential solutions. In particular, a highlight is the use of novel stem cell therapy of Muse cells, which bypasses many of the conventional stem cell limitations. The paper concludes with suggestions for directions in future neuroprotective research.