Extracellular vesicles in neurodegenerative, mental, and other neurological disorders: Perspectives into mechanisms, biomarker potential, and therapeutic implications.

Extracellular vesicles (EVs) are produced, secreted, and targeted by most human cells, including cells that compose nervous system tissues. EVs carry several types of biomolecules, such as lipids, proteins and microRNA, and can function as signaling agents in physiological and pathological processes. In this chapter, we will focus on EVs and their cargo secreted by brain cells, especially neurons and glia, and how these aspects are affected in pathological conditions. The chapter covers neurodegenerative disorders, including Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis, as well as several psychiatric disorders, namely schizophrenia, autism spectrum disorder and major depressive disorder. This chapter also addresses other types of neurological dysfunctions, epilepsy and traumatic brain injury. EVs can cross the blood brain barrier, and thus brain EVs may be detected in more accessible peripheral tissue, such as circulating blood. Alterations in EV composition and contents can therefore impart valuable clues into the molecular etiology of these disorders, and serve biomarkers regarding disease prevalence, progression and treatment. EVs can also be used to carry drugs and biomolecules into brain tissue, considered as a promising drug delivery agent for neurological diseases. Therefore, although this area of research is still in its early development, it offers great potential in further elucidating and in treating neurological disorders.

History of symptoms consistent with REM sleep behavior disorder in a population with Parkinson's Disease.

REM Sleep Behavioral Disorder (RBD) is a parasomnia marked by the maintenance of muscle tone during REM sleep. Evidence has placed RBD as one of the possible prodromal stages of Parkinson's Disease (PD), but data on the proportion of people with PD who have had symptoms of RBD are limited. This study aimed to investigate the history of symptoms compatible with RBD in a population with PD. The sample was composed by 73 patients with clinically diagnosed PD being followed up at a reference outpatient setting, compared to 73 age- and sex-matched individuals with no PD. The evaluation of symptoms compatible with RBD was performed using the Brazilian version of the RBD Screening Questionnaire (RBDSQ). The prevalence of symptoms compatible with RBD was 65 % for PD and 10.09 % for controls. The RBDSQ score was significantly higher in the PD group (6.03 ± 0.35) in comparison to the control group (2.38 ± 0.23). The odds ratio for presenting previous RBD-compatible symptoms was 12.09 in favor of positive PD cases. PD diagnosis has the following diagnostic properties in relation to presenting RBD symptoms: sensitivity of 0.65, specificity of 0.86, positive predictive value of 0.82 and negative predictive value of 0.71. In conclusion, the proportion of PD patients showing RBD symptoms is high, corroborating the expected neuroprogression of the disease on a case-control design comprising outpatient PD cases. Clinical practitioners should include evaluations of RBD-compatible symptoms during the PD assessment and, if positive, forward to a sleep specialist.

Hepatitis C virus infection and Parkinson's disease: insights from a joint sex-stratified BioOptimatics meta-analysis.

Hepatitis C virus (HCV) infection poses a significant public health challenge and often leads to long-term health complications and even death. Parkinson's disease (PD) is a progressive neurodegenerative disorder with a proposed viral etiology. HCV infection and PD have been previously suggested to be related. This work aimed to identify potential biomarkers and pathways that may play a role in the joint development of PD and HCV infection. Using BioOptimatics-bioinformatics driven by mathematical global optimization-, 22 publicly available microarray and RNAseq datasets for both diseases were analyzed, focusing on sex-specific differences. Our results revealed that 19 genes, including MT1H, MYOM2, and RPL18, exhibited significant changes in expression in both diseases. Pathway and network analyses stratified by sex indicated that these gene expression changes were enriched in processes related to immune response regulation in females and immune cell activation in males. These findings suggest a potential link between HCV infection and PD, highlighting the importance of further investigation into the underlying mechanisms and potential therapeutic targets involved.

Automatic selection model to identify neurodegenerative diseases.

Objective: This study evaluates machine learning algorithms' effectiveness in classifying Parkinson's disease and Huntington's disease based on biomarker data obtained non-invasively from patients and healthy controls. Methods: Datasets containing biomarker data (x, y, and z values of accelerometers) from sensors were collected from Parkinson's disease, Huntington's disease patients, and healthy controls. An automatic selection model method was implemented for disease classification, using a unique Mexican database of human gait biomarkers, which we consider the only one of its kind. Random forest, random subspace method, and K-star algorithms were employed, with parameters optimized through an automated model selection. Results: The study achieved a 0.893 precision rate for Parkinson's disease and Huntington's disease using the random subspace method. The findings underscore the potential of machine learning techniques in medical diagnosis, particularly in neurological disorders. Conclusion: The automatic selection model method demonstrated efficacy in classifying Parkinson's disease and Huntington's disease based on non-invasive biomarker data. This research contributes to advancing non-invasive diagnostic approaches in neurological disorders, highlighting the significance of machine learning in healthcare.

Parkinson biomarker determination with an Au microflower-enhanced electrochemical immunosensor using non-Faradaic capacitance measurements.

This work comprehends the development and characterization of a carbon black-based electrode modified with Au microflowers to increase its effect as a capacitance biosensor for the determination of PARK7/DJ-1. Due to its high surface-to-volume ratio and biocompatibility, Au particles are suitable for antibody binding, and by monitoring surface capacitance, it is possible to identify the immune-pair interaction. Au microflowers allowed the adequate immobilization of Parkinsonian-related proteins: PARK7/DJ-1 and its antibody. The protein is associated with several antioxidant mechanisms, but its abnormal concentrations or mutations can be the cause of the loss of dopaminergic neurons, leading to Parkinson's disease. The device was characterized by scanning electron microscopy and cyclic voltammetry, revealing the flower-like structures and the electrochemically-interest enhancements they provide, such as increased heterogeneous electron transfer rate coefficient and electroactive area. The self-assembled monolayers of different molecules were optimized with the aid of 22 central composite experiments and a linear calibration curve was obtained between 0.700 and 120 ng mL-1 of PARK7/DJ-1, with a limit of detection of 0.207 ng mL-1. The data confirms that the addition of Au microflowers enhanced the electrochemical signal of the device, as well as allowed for the determination of an early stage Parkinson's disease biomarker with appreciable analytical performance.

Complex Exercises Improve Cognition in People With Parkinson's Disease and Freezing of Gait.

BACKGROUND: Evidence has suggested that cognitive decline may be a risk factor for freezing of gait (FOG) in Parkinson's disease (PD). Complex and challenging exercises have been suggested as potential rehabilitation strategies to decrease FOG severity and improve cognition; however, it is unknown whether improvement in cognition would explain decreased FOG severity following exercise. OBJECTIVE: In this secondary analysis, we evaluated the effects of the adapted resistance training with instability (ARTI-complex and challenging exercises) compared with traditional motor rehabilitation (TMR-without challenging exercises) on cognitive function in people with FOG of PD. We also verified whether cognitive improvement explains the decrease in FOG previously published. METHODS: Participants were randomized to either the experimental group (ARTI, n = 17) or the active control group (TMR, n = 15). Both training groups exercised 3 times a week for 12 weeks (80-90 minute each session). FOG severity (FOG ratio from inertial sensors during a 360° turning-in-place task), frontal lobe function (Frontal Assessment Battery [FAB]), global cognition (Montreal Cognitive Assessment [MoCA]), and attention and psychomotor speed (Digit Symbol Substitution Test [DSST]) were evaluated before and after interventions. RESULTS: Only the ARTI group improved FAB, MoCA, and DSST scores at posttraining. In addition, ARTI was more effective than TMR in improving FAB scores at posttraining. The changes in FAB scores explained the changes in FOG ratio following ARTI (R2 = .43, P < .01). CONCLUSIONS: This pilot study suggests that ARTI, a complex and challenging training, improves cognition in people with FOG of PD. Improvements in frontal lobe function with ARTI help explain decreased FOG severity.

Absence of pretaporter restrains features of the parkin phenotype in Drosophila.

BACKGROUND: Scientific research based on model organisms can help to understand the biology of Parkinson's Disease, the second most prevalent neurodegenerative disease. Drosophila melanogaster mutant for the gene parkin, homologous to human's PARK2, exhibit well-characterized phenotypes including loss of dopaminergic neurons, lower survival and motor defects. Through the transcriptomic analysis of an exceptional case of reversible neurodegeneration in Drosophila, our group identified that the gene pretaporter, homologous to TXNDC5 of humans, was downregulated in the reversal phase. Here, we explore the hypothesis that the lack of expression of pretaporter will restrain phenotypes observed in Drosophila parkin mutants. METHODS: After establishing by immunochemistry that Pretaporter is expressed in PPL1 dopaminergic neurons, we constructed pretaporter-parkin double mutants flies to investigate the hypothesis through immunohistochemistry, survival and climbing assays. CONCLUSIONS: It was found that the loss-of-function mutation in pretaporter significatively restrains the phenotype caused by the loss-of-function mutation in parkin in several key aspects: it abolished the loss of PPL1 neurons normally seen in parkin mutant flies, promoted their survival in both sexes and reduced the decay in motor ability in parkin female flies. We propose that the absence of Pretaporter in parkin mutant flies prevents the death of dopaminergic neurons by rendering them resistant to Draper-mediated-phagocytosis.

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

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

The GBA1 K198E Variant Is Associated with Suppression of Glucocerebrosidase Activity, Autophagy Impairment, Oxidative Stress, Mitochondrial Damage, and Apoptosis in Skin Fibroblasts.

Parkinson's disease (PD) is a multifactorial, chronic, and progressive neurodegenerative disorder inducing movement alterations as a result of the loss of dopaminergic (DAergic) neurons of the pars compacta in the substantia nigra and protein aggregates of alpha synuclein (α-Syn). Although its etiopathology agent has not yet been clearly established, environmental and genetic factors have been suggested as the major contributors to the disease. Mutations in the glucosidase beta acid 1 (GBA1) gene, which encodes the lysosomal glucosylceramidase (GCase) enzyme, are one of the major genetic risks for PD. We found that the GBA1 K198E fibroblasts but not WT fibroblasts showed reduced catalytic activity of heterozygous mutant GCase by -70% but its expression levels increased by 3.68-fold; increased the acidification of autophagy vacuoles (e.g., autophagosomes, lysosomes, and autolysosomes) by +1600%; augmented the expression of autophagosome protein Beclin-1 (+133%) and LC3-II (+750%), and lysosomal-autophagosome fusion protein LAMP-2 (+107%); increased the accumulation of lysosomes (+400%); decreased the mitochondrial membrane potential (∆Ψm) by -19% but the expression of Parkin protein remained unperturbed; increased the oxidized DJ-1Cys106-SOH by +900%, as evidence of oxidative stress; increased phosphorylated LRRK2 at Ser935 (+1050%) along with phosphorylated α-synuclein (α-Syn) at pathological residue Ser129 (+1200%); increased the executer apoptotic protein caspase 3 (cleaved caspase 3) by +733%. Although exposure of WT fibroblasts to environmental neutoxin rotenone (ROT, 1 µM) exacerbated the autophagy-lysosomal system, oxidative stress, and apoptosis markers, ROT moderately increased those markers in GBA1 K198E fibroblasts. We concluded that the K198E mutation endogenously primes skin fibroblasts toward autophagy dysfunction, OS, and apoptosis. Our findings suggest that the GBA1 K198E fibroblasts are biochemically and molecularly equivalent to the response of WT GBA1 fibroblasts exposed to ROT.

Thermal Facial Profile and Orofacial Myofunctional Aspects in Movement Disorder Patients: Comparison Between Parkinson Disease and Spinocerebellar Ataxia Type 3.

OBJECTIVE: To evaluate the orofacial myofunctional characteristics, masticatory performance and facial thermal profile in individuals with Parkinson disease (PD) and spinocerebellar ataxia (SCA3), comparing with healthy control ones. METHOD: Seventy-two participants aged between 30 and 85 years were evaluated and divided into PD, SCA3 and control groups. The assessments included clinical evaluation using the Orofacial Myofunctional Evaluation with Scores protocol (orofacial structures, mastication, swallowing and breathing aspects), masticatory performance assessed with a colour-changeable chewing gum and infrared thermography. The Kruskal-Wallis, one-way ANOVA and Wilcoxon tests were applied. RESULTS: With the exception of face and tongue, a difference was seen in the cheek, maxillomandibular relationship, lips, mentalis muscle and palate appearance and posture between patients and healthy control participants. Orofacial mobility, swallowing and masticatory function also scored higher in the control group. The SCA3 and PD groups required more time to eat the test-food and showed greater facial temperature asymmetries than the control one (p < 0.05). Masticatory performance measured by chewing gum did not differ. CONCLUSION: Facial temperature asymmetries, swallowing and masticatory function scores and the time needed by the SCA3 and PD groups to eat the test-food were different from healthy participants, drawing attention to the impaired orofacial functions in patients with neurodegenerative disorders.

Single-domain magnetic particles with motion behavior under electromagnetic AC and DC fields are a fatal cargo in Metropolitan Mexico City pediatric and young adult early Alzheimer, Parkinson, frontotemporal lobar degeneration and amyotrophic lateral sclerosis and in ALS patients.

Metropolitan Mexico City (MMC) children and young adults exhibit overlapping Alzheimer and Parkinsons' diseases (AD, PD) and TAR DNA-binding protein 43 pathology with magnetic ultrafine particulate matter (UFPM) and industrial nanoparticles (NPs). We studied magnetophoresis, electron microscopy and energy-dispersive X-ray spectrometry in 203 brain samples from 14 children, 27 adults, and 27 ALS cases/controls. Saturation isothermal remanent magnetization (SIRM), capturing magnetically unstable FeNPs ~ 20nm, was higher in caudate, thalamus, hippocampus, putamen, and motor regions with subcortical vs. cortical higher SIRM in MMC ≤ 40y. Motion behavior was associated with magnetic exposures 25-100 mT and children exhibited IRM saturated curves at 50-300 mT associated to change in NPs position and/or orientation in situ. Targeted magnetic profiles moving under AC/AD magnetic fields could distinguish ALS vs. controls. Motor neuron magnetic NPs accumulation potentially interferes with action potentials, ion channels, nuclear pores and enhances the membrane insertion process when coated with lipopolysaccharides. TEM and EDX showed 7-20 nm NP Fe, Ti, Co, Ni, V, Hg, W, Al, Zn, Ag, Si, S, Br, Ce, La, and Pr in abnormal neural and vascular organelles. Brain accumulation of magnetic unstable particles start in childhood and cytotoxic, hyperthermia, free radical formation, and NPs motion associated to 30-50 µT (DC magnetic fields) are critical given ubiquitous electric and magnetic fields exposures could induce motion behavior and neural damage. Magnetic UFPM/NPs are a fatal brain cargo in children's brains, and a preventable AD, PD, FTLD, ALS environmental threat. Billions of people are at risk. We are clearly poisoning ourselves.

Natural Compounds That Activate the KEAP1/Nrf2 Signaling Pathway as Potential New Drugs in the Treatment of Idiopathic Parkinson's Disease.

Recently, a single-neuron degeneration model has been proposed to understand the development of idiopathic Parkinson's disease based on (i) the extremely slow development of the degenerative process before the onset of motor symptoms and during the progression of the disease and (ii) the fact that it is triggered by an endogenous neurotoxin that does not have an expansive character, limiting its neurotoxic effect to single neuromelanin-containing dopaminergic neurons. It has been proposed that aminochrome is the endogenous neurotoxin that triggers the neurodegenerative process in idiopathic Parkinson's disease by triggering mitochondrial dysfunction, oxidative stress, neuroinflammation, dysfunction of both lysosomal and proteasomal protein degradation, endoplasmic reticulum stress and formation of neurotoxic alpha-synuclein oligomers. Aminochrome is an endogenous neurotoxin that is rapidly reduced by flavoenzymes and/or forms adducts with proteins, which implies that it is impossible for it to have a propagative neurotoxic effect on neighboring neurons. Interestingly, the enzymes DT-diaphorase and glutathione transferase M2-2 prevent the neurotoxic effects of aminochrome. Natural compounds present in fruits, vegetables and other plant products have been shown to activate the KEAP1/Nrf2 signaling pathway by increasing the expression of antioxidant enzymes including DT-diaphorase and glutathione transferase. This review analyzes the possibility of searching for natural compounds that increase the expression of DT-diaphorase and glutathione transferase through activation of the KEAP1/Nrf2 signaling pathway.

Associations between cognitive screening performance and motor symptoms in Parkinson's disease:a systematic review and meta-analysis.

Although the most prominent symptoms of Parkinson's disease (PD) are those impacting movement, cognitive dysfunction is prevalent and often presents early in the disease process. Individuals with cognitive symptoms of PD often complete cognitive screening, making it important to identify factors associated with cognitive screening performance to ensure prompt and accurate detection of cognitive impairments. Objective: Despite a body of research examining relationships between motor symptoms and cognitive dysfunction in PD, no prior study has undertaken a systematic review of the magnitude of the relationship between motor symptoms and cognitive screening performance in PD. Methods: This study was a systematic review and meta-analysis of the relationship between cognitive screening performance, as assessed by the Montreal Cognitive Assessment (MoCA), and motor symptoms of PD. After the systematic screening, 20 studies were included, and meta-regressions using mixed-effects models were conducted. Results: Motor symptoms across included studies were relatively mild, but average MoCA scores were at the established cutoff for risk of dementia in PD. The average disease duration was 5 years. Consistent with hypotheses, more severe motor symptoms were associated with lower MoCA scores (r=-0.22 (95%CI -0.29 to -0.16), p<0.001), indicating worse cognitive functioning. Conclusion: The results indicate a significant negative correlation between MoCA performance and motor symptoms of PD. Average MoCA scores captured early disease-stage cognitive impairment when motor symptoms remained relatively mild. Serial screening for cognitive impairment beginning early in the disease course may be of benefit to ensure that cognitive dysfunction is detected as it arises.

Embora os sintomas mais proeminentes da doença de Parkinson (DP) sejam aqueles que afetam o movimento, a disfunção cognitiva é prevalente e muitas vezes se apresenta no início do processo da doença. Indivíduos com sintomas cognitivos de DP frequentemente realizam triagem cognitiva, tornando importante identificar os fatores associados ao desempenho da triagem cognitiva para garantir a detecção rápida e precisa de deficiências cognitivas. Objetivo: Apesar de um conjunto de pesquisas examinar as relações entre sintomas motores e disfunção cognitiva na DP, nenhum trabalho anterior realizou uma revisão sistemática da magnitude da relação entre sintomas motores e desempenho na triagem cognitiva na DP. Métodos: O presente estudo foi uma revisão sistemática e meta-análise da relação entre o desempenho da triagem cognitiva, avaliada pela Avaliação Cognitiva de Montreal (Montreal Cognitive Assessment ­ MoCA), e os sintomas motores da DP. Após triagem sistemática, 20 estudos foram incluídos e foram realizadas meta-regressões utilizando modelos de efeitos mistos. Resultados: Os sintomas motores nos estudos incluídos foram relativamente leves, mas as pontuações médias do MoCA estavam no ponto de corte estabelecido para o risco de demência na DP. A duração média da doença foi de 5 anos. Consistente com as hipóteses, sintomas motores mais graves foram associados a pontuações mais baixas no MoCA, r=-0,22 (IC95% -0,29 to -0,16), p<0,001), indicando pior funcionamento cognitivo. Conclusão: Os resultados indicam uma correlação negativa significativa entre o desempenho no MoCA e os sintomas motores da DP. As pontuações médias do MoCA capturaram o comprometimento cognitivo em estágio inicial da doença, quando os sintomas motores permaneceram relativamente leves. O rastreio em série do comprometimento cognitivo que começa no início do curso da doença pode ser benéfico para garantir que a disfunção cognitiva seja detectada à medida que surge.

Molecular Alterations in Core Subunits of Mitochondrial Complex I and Their Relation to Parkinson's Disease.

Among the myriad of neurodegenerative diseases, mitochondrial dysfunction represents a nexus regarding their pathogenic processes, in which Parkinson's disease (PD) is notable for inherent vulnerability of the dopaminergic pathway to energy deficits and oxidative stress. Underlying this dysfunction, the occurrence of defects in complex I (CI) derived from molecular alterations in its subunits has been described in the literature. However, the mechanistic understanding of the processes mediating the occurrence of mitochondrial dysfunction mediated by CI deficiency in PD remains uncertain and subject to some inconsistencies. Therefore, this review analyzed existing evidence that may explain the relationship between molecular alterations in the core subunits of CI, recognized for their direct contribution to its enzymatic performance, and the pathogenesis of PD. As a result, we discussed 47 genetic variants in the 14 core subunits of CI, which, despite some discordant results, were predominantly associated with varying degrees of deficiency in complex enzymatic activity, as well as defects in supercomplex biogenesis and CI itself. Finally, we hypothesized about the relationship of the described alterations with the pathogenesis of PD and offered some suggestions that may aid in the design of future studies aimed at elucidating the relationship between such alterations and PD.

Association between cognitive performance and manual dexterity in patients with Parkinson's disease.

INTRODUCTION: Parkinson's disease (PD) is a progressive neurological condition resulting from the degeneration of dopaminergic neurons in the substantia nigra. Impaired manual dexterity and cognitive impairment are common symptoms and are often associated with recurrent adverse events in this population. OBJECTIVE: To verify the association between cognitive performance and manual dexterity in people with PD. METHODS: This is a cross-sectional observational study, with 29 participants, who underwent cognitive and manual dexterity assessments, and the following tools were used: Trail Making Test, box and block test (BBT), Learning Test of Rey and Nine Hole Peg Test. Descriptive statistics for clinical and demographic data were performed using mean and standard deviation, and data normality was assessed using the Shapiro-Wilk test. Spearman's nonparametric test was used to determine the correlation between variables. RESULTS: Our findings revealed significant associations between cognitive performance and manual dexterity. The nine-hole peg test positively correlated with TMT-Part A and Part B, establishing a relationship between manual dexterity and cognitive functions such as attention and mental flexibility. On the other hand, BBT showed an inverse relationship with TMT-Part B, indicating that longer time on this task was associated with lower manual dexterity. CONCLUSION: Fine manual dexterity had a significant correlation with visual search skills and motor speed, while gross motor dexterity had a negative correlation with cognitive skills. No significant results were demonstrated regarding the interaction between manual dexterity and memory.

SUMOylation modulates mitochondrial dynamics in an in vitro rotenone model of Parkinson's disease.

SUMOylation is a post-translational modification essential for various biological processes. SUMO proteins bind to target substrates in a three-step enzymatic pathway, which is rapidly reversible by the action of specific proteases, known as SENPs. Studies have shown that SUMOylation is dysregulated in several human disorders, including neurodegenerative diseases that are characterized by the progressive loss of neurons, mitochondrial dysfunction, deficits in autophagy, and oxidative stress. Considering the potential neuroprotective roles of SUMOylation, the aim of this study was to investigate the effects of SENP3 knockdown in H4 neuroglioma cells exposed to rotenone, an in vitro model of cytotoxicity that mimics dopaminergic loss in Parkinson's disease (PD). The current data show that SENP3 knockdown increases SUMO-2/3 conjugates, which is accompanied by reduced levels of the mitochondrial fission protein Drp1 and increased levels of the mitochondrial fusion protein OPA1. Of high interest, SENP3 knockdown prevented rotenone-induced superoxide production and cellular death. Taken together, these findings highlight the importance of SUMOylation in maintaining mitochondrial homeostasis and the neuroprotective potential of this modification in PD.

Experimental Periodontitis Worsens Dopaminergic Neuronal Degeneration.

AIM: To investigate the hypothesis supporting the link between periodontitis and dopaminergic neuron degeneration. MATERIALS AND METHODS: Adult male Wistar rats were used to induce dopaminergic neuronal injury with 6-hydroxydopamine (6-OHDA) neurotoxin and experimental periodontitis via ligature placement. Motor function assessments were conducted before and after periodontitis induction in controls and 6-OHDA-injury-induced rats. Tissue samples from the striatum, jaw and blood were collected for molecular analyses, encompassing immunohistochemistry of tyrosine hydroxylase, microglia and astrocyte, as well as micro-computed tomography, to assess alveolar bone loss and for the analysis of striatal oxidative stress and plasma inflammatory markers. RESULTS: The results indicated motor impairment in 6-OHDA-injury-induced rats exacerbated by periodontitis, worsening dopaminergic striatal degeneration. Periodontitis alone or in combination with 6-OHDA-induced lesion was able to increase striatal microglia, while astrocytes were increased by the combination only. Periodontitis increased striatal reactive oxygen species levels and plasma tumour necrosis factor-alpha levels in rats with 6-OHDA-induced lesions and decreased the anti-inflammatory interleukin-10. CONCLUSIONS: This study provides original insights into the association between periodontitis and a neurodegenerative condition. The increased inflammatory pathway associated with both 6-OHDA-induced dopaminergic neuron lesion and periodontal inflammatory processes corroborates that the periodontitis-induced systemic inflammation may aggravate neuroinflammation in Parkinson's-like disease, potentially hastening disease progression.

Magnetic resonance-guided focused ultrasound ventral intermediate thalamotomy for Tremor-Dominant Parkinson's disease: a systematic review and meta-analysis.

INTRODUCTION: Tremor-dominant Parkinson's Disease (TDPD) has a slower neurological decline compared to other phenotypes of the disease, but significantly impacts daily activities and is often less responsive to standard medications. Magnetic Resonance-guided Focused Ultrasound (MRgFUS) lesioning of the Ventral Intermediate (VIM) nucleus of the thalamus may alleviate symptoms for these patients. METHODS: A systematic review and meta-analysis of English-language studies from PubMed, Cochrane, and Embase were conducted, assessing the efficacy and safety of MRgFUS VIM thalamotomy in TDPD patients. Tremor scores were evaluated using the Clinical Scale Rating for Tremor and the Movement Disorders Society - Unified Parkinson's Disease Rating Scale (MDS-UPDRSIII). Neuropsychological outcomes were measured using the Parkinson Disease Questionnaire (PDQ) and the Montreal Cognitive Assessment. This analysis adhered to Cochrane and PRISMA guidelines. RESULTS: Thirteen studies with 211 patients were included. MDS-UPDRSIII scores showed significant improvement at 1, 6, and 12 months post-MRgFUS, respectively: (MD -8.92 points, 95% CI: -15.44 to -2.40, p < 0.01; MD -7.39 points, 95% CI: -11.47 to -3.30, p < 0.01; MD -10.66 points, 95% CI: -16.89 to -4.43, p < 0.01). PDQ scores at baseline compared to 6 months post-treatment also indicated a significant improvement (SMD - 0.86, 95% CI: -1.21 to -0.50, p < 0.01). Neurological adverse events were generally mild and transient, with gait instability and sensory deficits being the most common. CONCLUSION: This meta-analysis demonstrates significant improvements in tremor and neuropsychological outcomes following MRgFUS VIM thalamotomy in TDPD patients, with adverse events being typically mild and transient.

NMDA receptor remodeling and nNOS activation in mice after unilateral striatal injury with 6-OHDA.

Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by selective dopaminergic loss. Non dopaminergic neurotransmitters such as glutamate are also involved in PD progression. NMDA receptor/postsynaptic density protein 95 (PSD-95)/neuronal nitric oxide synthase (nNOS) activation is involved in neuronal excitability in PD. Here, we are focusing on the evaluating these post-synaptic protein levels in the 6-OHDA model of PD. Adult male C57BL/6 mice subjected to unilateral striatal injury with 6-OHDA were assessed at 1-, 2-, or 4-weeks post-lesion. Animals were subjected to an apomorphine-induced rotation test followed by the analysis of protein content, synaptic structure, and NOx production. All biochemical analysis was performed comparing the control versus lesioned sides of the same animal. 6-OHDA mice exhibited contralateral rotation activity, difficulties in coordinating movements, and changes in Iba-1 and glial fibrillary acidic protein (GFAP) expression during the whole period. At one week of survival, the mice showed a shift in NMDA composition, favoring the GluN2A subunit and increased PSD95 and nNOS expression and NOx formation. After two-weeks, a decrease in the total number of synapses was observed in the lesioned side. However, the number of excitatory synapses was increased with a higher content of GluN1 subunit and PSD95. After four weeks, NMDA receptor subunits restored to control levels. Interestingly, NOx formation in the serum increased. This study reveals, for the first time, the temporal course of behavioral deficits and glutamatergic synaptic plasticity through NMDAr subunit shift. Together, these data demonstrate that dopamine depletion leads to a fine adaptive response over time, which can be used for further studies of therapeutic management adjustments with the progression of PD.

Treating activated regulatory T cells with pramipexole protects human dopaminergic neurons from 6-OHDA-induced degeneration.

BACKGROUND: Parkinson's disease (PD) is a chronic neurodegenerative disorder characterized by the loss of dopaminergic neurons in the substantia nigra, which promotes a sustained inflammatory environment in the central nervous system. Regulatory T cells (Tregs) play an important role in the control of inflammation and might play a neuroprotective role. Indeed, a decrease in Treg number and function has been reported in PD. In this context, pramipexole, a dopaminergic receptor agonist used to treat PD symptoms, has been shown to increase peripheral levels of Treg cells and improve their suppressive function. The aim of this work was to determine the effect of pramipexole on immunoregulatory Treg cells and its possible neuroprotective effect on human dopaminergic neurons differentiated from human embryonic stem cells. METHODS: Treg cells were sorted from white blood cells of healthy human donors. Assays were performed with CD3/CD28-activated and non-activated Treg cells treated with pramipexole at concentrations of 2 or 200 ng/mL. These regulatory cells were co-cultured with in vitro-differentiated human dopaminergic neurons in a cytotoxicity assay with 6-hydroxydopamine (6-OHDA). The role of interleukin-10 (IL-10) was investigated by co-culturing activated IL-10-producing Treg cells with neurons. To further investigate the effect of treatment on Tregs, gene expression in pramipexole-treated, CD3/CD28-activated Treg cells was determined by Fluidigm analysis. RESULTS: Pramipexole-treated CD3/CD28-activated Treg cells showed significant protective effects on dopaminergic neurons when challenged with 6-OHDA. Pramipexole-treated activated Treg cells showed neuroprotective capacity through mechanisms involving IL-10 release and the activation of genes associated with regulation and neuroprotection. CONCLUSION: Anti-CD3/CD28-activated Treg cells protect dopaminergic neurons against 6-OHDA-induced damage. In addition, activated, IL-10-producing, pramipexole-treated Tregs also induced a neuroprotective effect, and the supernatants of these co-cultures promoted axonal growth. Pramipexole-treated, activated Tregs altered their gene expression in a concentration-dependent manner, and enhanced TGFß-related dopamine receptor regulation and immune-related pathways. These findings open new perspectives for the development of immunomodulatory therapies for the treatment of PD.