The therapeutic use of clonal neural stem cells in experimental Parkinson´s disease.

BACKGROUND: Parkinson´s disease (PD), the second most common neurodegenerative disease in the world, is characterized by the death or impairment of dopaminergic neurons (DAn) in the substantia nigra pars compacta and dopamine depletion in the striatum. Currently, there is no cure for PD, and treatments only help to reduce the symptoms of the disease, and do not repair or replace the DAn damaged or lost in PD. Cell replacement therapy (CRT) seeks to relieve both pathological and symptomatic PD manifestations and has been shown to have beneficial effects in experimental PD models as well as in PD patients, but an apt cell line to be used in the treatment of PD has yet to be established. The purpose of this study was to examine the effects of the transplantation of hVM1 clone 32 cells, a bankable line of human neural stem cells (hNSCs), in a PD mouse model at four months post-transplant. METHODS: Adult (five month-old) C57BL/6JRccHsd male mice were injected with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine and subsequently transplanted with hVM1 clone 32 cells, or buffer, in the left striatum. Four months post-transplant, behavioral effects were explored using the open field and paw print tests, and histological analyses were performed. RESULTS: Transplantation of hVM1 clone 32 cells rescued dopaminergic nigrostriatal populations in adult Parkinsonian mice. Motor and neurological deterioration were observed in buffer-treated mice, the latter of which had a tendency to improve in hNSC-transplanted mice. Detection of mast cell migration to the superficial cervical lymph nodes in cell-transplanted mice denoted a peripheral effect. Transplantation of hNSCs also rescued neuroblast neurogenesis in the subgranular zone, which was correlated with dopaminergic recovery and is indicative of local recovery mechanisms. CONCLUSIONS: In this proof-of-concept study, the transplantation of hVM1 clone 32 cells provided neuroprotection in adult Parkinsonian mice by restoring the dopaminergic nigrostriatal pathway and hippocampal neurogenesis, demonstrating the efficacy of cell replacement therapy as a treatment for PD.

Emerging Gene Therapies for Alzheimer's and Parkinson's Diseases: An Overview of Clinical Trials and Promising Candidates.

Gene therapy as a disease-modifying therapeutic approach for neurodegenerative diseases, such as Alzheimer's disease (AD) and Parkinson's disease (PD), is a promising avenue. Promising results in the preclinical studies involving rodents and nonhuman primates utilizing gene therapy have led to multiple clinical trials evaluating various genes of interest for AD and PD. In AD, clinical trials are assessing gene therapy involving brain-derived neurotrophic factor (BDNF) and other targets such as apolipoprotein E2 (APOE2) and human telomerase reverse transcriptase (hTERT). In PD, clinical trials are evaluating gene therapy delivering neurotrophic factors, such as glial cell line-derived neurotrophic factor (GDNF). Additionally, gene therapy delivering enzymes aromatic L-amino acid decarboxylase (AADC) and glutamic acid decarboxylase (GAD) are also being evaluated for PD. All these trials primarily utilized adeno-associated virus (AAV) to deliver the above transgene of interest. This review summarizes the current clinical trials involving gene therapy for AD and PD. It also discusses the challenges and opportunities associated with the gene therapy approach in AD and PD and ongoing developments related to increasing the safety and efficacy of the gene therapy for long-term outcomes, which include evaluation of various serotypes and administration routes. This comprehensive review emphasizes translating preclinical findings into clinical trials, further directions, and the potential for this promising therapeutic approach to alleviate neurodegenerative disease.

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.

An Alternative Approach for the Rehabilitation of a Complete Denture Patient With Parkinson's Disease.

Parkinson's disease (PD) affects one to two out of every 1,000 individuals. PD, being age-related, is affecting a percentage of those over and around the sixth decade. Lewy bodies containing α-synuclein and a reduction in dopaminergic neurons in the substantia nigra, which impairs the region's capacity to promote voluntary movements, are the main neuropathological findings. The three main symptoms of PD are stiffness, bradykinesia, and tremor. Treatment of edentulous conditions in patients with PD becomes a challenge due to decreased neuromuscular coordination and decreased mobility. This case report outlines a 64-year-old male patient with complete edentulism suffering from PD. Complete denture fabrication was done using the concepts of the neutral zone and denture characterization. Significantly, it not only improves the stability of the dentures but also establishes good denture aesthetics.

Prevalence, Impact, and Screening Methods of Sarcopenia in Japanese Patients With Parkinson's Disease: A Prospective Cross-Sectional Study.

INTRODUCTION: Sarcopenia is a skeletal muscle disease manifesting as low muscle mass and impaired muscle function. It has been reported that sarcopenia correlates with a low quality of life (QOL) and an increased risk of falls in patients with Parkinson's disease (PD). Nevertheless, few studies have investigated the prevalence, impact, and screening methods of sarcopenia in Japanese patients with PD. METHODS: Sarcopenia was diagnosed based on the Asian Working Group for Sarcopenia 2019 consensus. We compared demographic characteristics, severity of PD, levodopa equivalent daily dose, QOL, fatigue, impulsive and compulsive behaviors, body mass index (BMI), calf circumference, skeletal muscle mass index (SMI), handgrip strength, a 4-meter gait speed, a five-time sit-to-stand test (FTSST), short physical performance battery, and SARC-F questionnaire scores between sarcopenia and non-sarcopenia groups. Furthermore, to investigate the best tool for screening sarcopenia in PD, the sensitivity and specificity of calf circumference, handgrip strength, FTSST, and SARC-F questionnaire were compared. RESULTS: The prevalence of sarcopenia in PD was 31.9% (15/47). The sarcopenia group showed significantly higher age (77.3 ± 5.12 versus 70.3 ± 8.17, p = 0.0042), lower BMI (19.3 ± 2.99 versus 23.3 ± 3.18, p = 0.0002), higher rate of decreased calf circumference (86.6% versus 34.3%, p = 0.0013) and SMI (100% versus 6.25%, p < 0.0001), and worse FTSST (15.5 ± 5.57 versus 12.0 ± 4.12, p = 0.0219). The other parameters were not significantly different. Among screening tools, calf circumference had the highest sensitivity (86%) and specificity (65%). All screening tools had higher sensitivity and specificity in men than in women. The SARC-F questionnaire was not useful in distinguishing sarcopenia but was significantly correlated with the Movement Disorder Society-sponsored revision of the Unified Parkinson's Disease Rating Scale Part 3 (r = 0.41, p = 0.0037) and the 39-item Parkinson's Disease QOL Scale (r = 0.71, p < 0.0001). CONCLUSION: This study investigated the characteristics of PD patients with sarcopenia in Japan. Calf circumference was found to be the most useful tool for screening sarcopenia in PD. Handgrip strength and FTSST also showed high sensitivities, particularly in men. Conversely, the SARC-F questionnaire is not suitable for diagnosing sarcopenia in PD.

Combined Pimavanserin and Maintenance Electroconvulsive Therapy: A Novel Approach to Parkinson's Disease Psychosis.

Parkinson's disease (PD) is among the most common neurodegenerative diseases. Parkinson's disease psychosis (PDP) is a potential psychiatric manifestation of PD that is associated with increased morbidity and mortality. The treatment of PD with concomitant PDP is challenging as standard-of-care medication to improve motor symptoms can cause or exacerbate PDP. In this case report, we present an atypical presentation of a 70-year-old female who developed PDP only four years after her initial PD diagnosis, much earlier than the established average. Treatment was particularly complex as her PDP symptoms were refractory to PD medication reduction and oral antipsychotics, yet her PD motor symptoms were well controlled with a deep brain stimulator (DBS). We discuss a combination of pimavanserin and maintenance electroconvulsive therapy (ECT) as a safe and efficacious treatment modality which has led to remission of her PDP while DBS continues to provide adequate management of her PD symptoms. This case improves upon the early recognition of PDP and outlines a unique treatment modality not well described in the literature. This is the only case that demonstrates the efficacy of combining pimavanserin and ECT for refractory PDP in a patient with a DBS.

Monotherapy with infusion therapies - useful or not?

Infusion pump-based therapies are an effective treatment option for patients with advanced Parkinson´s disease. Achieving monotherapy with infusion-based therapies could simplify the treatment regimen, provide better medication adherence, reduce adverse events and drug interactions. This review presents the literature data on the efficacy, safety, and achievability of monotherapy with all available infusion-based therapies, including apomorphine, levodopa-carbidopa-intestinal gel (LCIG), levodopa-entacapone-carbidopa intestinal gel (LECIG), and foslevodopa-foscarbidopa (LDp/CDp). In summary, monotherapy is achievable and effective in most patients on intestinal levodopa infusion therapy and in some patients on apomorphine infusion. There is a need for further investigation of monotherapy compared to polytherapy, especially in new pump treatment options (LECIG and LDp/CDp). Future research should reveal which patients on infusion-based therapies could benefit from monotherapy, including identification of potential baseline predictors of achieving monotherapy in patients treated with specific infusion-based therapies.

Study protocol of the HessenKohorte2042: a prospective, longitudinal cohort study characterising quality of life in people with Parkinson's disease and their caregivers using a bio-psycho-social approach.

INTRODUCTION: Quality of life (QoL) is of paramount importance as an outcome to monitor and guide therapies for people with Parkinson's disease (PwPD). In particular, due to the heterogeneous symptoms that PwPD may experience during their disease course, QoL can deteriorate not only in patients but also in their caregivers, with a variety of psychosocial consequences. However, there is a lack of longitudinal studies that explore how QoL evolves over time and what factors are significant. Furthermore, holistic approaches that consider bio-psycho-social determinants are rare. In the worst cases, these gaps can lead to suboptimal care and therefore unmet needs for patients and their caregivers, resulting in unnecessary symptom burden and increased healthcare costs for society. METHODS AND ANALYSIS: This prospective, longitudinal study will follow 1000 PwPD along with their caregivers for 20 years, with up to 40 semi-annual assessments. Patient data and sample collection will include clinical assessments, self-reported outcome measures focusing on QoL, biospecimen collection and MRI. Caregiver burden will be systematically assessed through self-administered questionnaires. The use of digitised surveys will allow efficient data collection and convenient assessment at home. Our primary objective is to attain a holistic understanding of QoL in PwPD and establish a tool to measure it. The secondary objective is to explore the psycho-social and biological variables associated with QoL of patients and caregivers over the progression of the disease. This will provide key information for diagnostic and prognostic prediction, therapeutic patient stratification and adaptation of therapy in the future. ETHICS AND DISSEMINATION: The study was approved by the local ethics committee of the University Hospital of Marburg (study number: 209/19). The results will be disseminated by means of publication in peer-reviewed journals, international conference contributions, annual patient meetings and a dedicated website. TRIAL REGISTRATION NUMBER: German Clinical Trials Register (DRKS00023598).

Efectos sobre los procesos cognitivos del entrenamiento basado en doble tarea en personas con enfermedad de Parkinson: una revisión sistemática / Effects on cognitive processes of dual-task training in people with Parkinson’s disease: a systematic review

Introducción: La doble tarea es una intervención no farmacológica en personas con condiciones neurodegenerativas, utilizada en la enfermedad de Parkinson (EP), principalmente para favorecer el desempeño motor. El objetivo de esta revisión es reunir la evidencia actual sobre cómo el entrenamiento de doble tarea afecta a los procesos cognitivos en personas que presenten EP. Material y métodos. Se desarrolló una revisión sistemática, aplicando las directrices de PRISMA, incluyendo artículos obtenidos en las bases de datos de PubMed, Web of Science, Science Direct y Springer Link. La calidad metodológica se evaluó mediante PEDro y ROBINS-I. Resultados: Doce artículos cumplieron con los criterios de inclusión y exclusión: nueve de ellos corresponden a ensayos controlados aleatorizados y los tres restantes fueron estudios no aleatorizados. Se identificaron mejoras en la atención y las funciones ejecutivas, aunque la diversidad en enfoques y duración dificulta llegar a conclusiones definitivas. Conclusiones: Es crucial expandir la investigación, estandarizando los programas de intervención. Del mismo modo, es importante llevar a cabo estudios longitudinales y controlados aleatorizados en muestras representativas que permitan llegar a conclusiones aplicables a otros contextos.(AU)

Introduction: Dual-tasking is a non-pharmacological intervention in people with neurodegenerative conditions, and is used in Parkinson’s disease (PD), primarily to enhance motor performance. The aim of this review is to compile the current evidence on how dual-task training affects cognitive processes in people with PD. Material and methods: A systematic review was undertaken, applying PRISMA guidelines, which included articles obtained from the PubMed, Web of Science, Science Direct and Springer Link databases. Methodological quality was assessed using PEDro and ROBINS-I. Results: Twelve articles met the inclusion and exclusion criteria: nine of them were randomized controlled trials, and the remaining three were non-randomized studies. Improvements in attention and executive functions were identified, although the diversity of approaches and duration means that reaching definitive conclusions is difficult. Conclusions: Increased research and standardized intervention programmes are essential. Longitudinal and randomized controlled studies in representative samples which provide conclusions that are applicable to other contexts are also important.(AU)

Immunomodulation as a Treatment for Parkinson´s Disease in Current Trials: A Systematic Review and Meta-Analysis

ABSTRACT Background: Immunomodulatory drugs and immunotherapies are being evaluated in clinical trials for the treatment of neuroinflammation, as the latter is an essential mechanism for the development and progression of Parkinson´s disease. Objective: The objective of the study is to review recent evidence on the evaluation of immunomodulators in randomized controlled clinical trials measuring improvement of motor symptoms. Methods: A meta-analysis of Movement Disorder Society-Unified Parkinson´s disease Rating Scale (MDS-UPDRS III) scores extracted from seven articles selected after an online search of PubMed, Cochrane Library, and Clarivate's Web of Science for randomized controlled clinical trials published between 2000 and July 2023 was performed. The selected articles reported clinical trials evaluating the effects of specific immunomodulators or treatments with known effects on the immune system and inflammation. MDS-UPDRS III scores were reported in these studies, and the results of the placebo groups were compared with those of the treatment groups. Results: A total of 590 patients treated with immunomodulators and 622 patients treated with placebo were included. A test for heterogeneity yielded an I2 value > 50%. The mean standard difference for change in MDS-UPDR III score was −0.46 (CI [95%] = −0.90 - −0.02, p < 0.01). No significant differences were found in the change in mean MDS-UPDR III score between the treatment and placebo groups; however, two studies showed a trend toward separation from the mean. Conclusion: The immunomodulatory treatments included in this study showed no efficacy in improving motor symptoms in Parkinson´s disease patients. Further clinical trials with larger patient populations are needed.

Sublingual apomorphine in the treatment of Parkinson's disease.

Advanced Parkinson´s disease (PD) is often complicated by fluctuations of disability depending on plasma levels of levodopa. For most patients OFF phases with worsening of tremor and immobility, but also pain, depression, autonomic symptoms are troublesome. While adjustments of levodopa administrations can relief such fluctuations for some time, "on demand" therapies become more and more important. These "on demand" therapies should provide fast and efficacious relief. During the past years, new options for on demand therapies in PD-associated OFF episodes have been developed, including new formulations of levodopa and apomorphine to provide fast and readily accessible on demand treatment. In this narrative review, the challenges of the treatment of PD-associated fluctuations and OFF states are addressed, with a special focus on sublingual apomorphine (SL-APO) including the results from recent clinical trials.

Efficacy and safety of acupuncture therapy for Parkinson's disease with neuropsychiatric symptoms: protocol for a systematic review and meta-analysis.

INTRODUCTION: Neuropsychiatric symptoms (NPS) are common non-motor symptoms among patients with Parkinson's disease (PD) and significantly impact their overall quality of life detrimentally. Several studies have reported the clinical effect of acupuncture therapy in treating NPS in PD. Therefore, the objective of this systematic review is to evaluate the potential inclusion of acupuncture therapy as an integral component of complementary treatment for PD with NPS. METHODS AND ANALYSIS: From their inception until 1 December 2023, we will search eight databases, including PubMed, Cochrane Library, Embase, Web of Science, China National Knowledge Infrastructure, China Science Periodical Database, Chinese Citation Database and China Biology Medicine disc for randomised controlled trials examining the effectiveness of acupuncture for PD with NPS. Literature screening and data extraction will be carried out independently by the authors. RevMan V.5.3 software will be used for meta-analysis, while the Cochrane risk-of-bias tool will assess the potential for bias. ETHICS AND DISSEMINATION: This systematic review protocol does not require ethical approval because it does not include private information or data of participants. This article will be published in a peer-reviewed journal. PROSPERO REGISTRATION NUMBER: CRD42022324494.

Role of virtual reality in examining the effect of fear of falling (FOF) on postural stability in individuals without and with Parkinson's disease in Egypt: a mixed-methods feasibility study protocol.

BACKGROUND: Falls are common in older people and individuals with neurological conditions. Parkinson's disease (PD) is known for postural instability causing mobility disabilities, falls and reduced quality of life. The fear of falling (FOF), a natural response to unstable balance, can worsen postural control problems. Evaluating FOF relies largely on affected persons' subjective accounts due to limited objective assessment methods available. The aim of this mixed-methods feasibility study is to develop an assessment method for FOF while in motion and walking within virtual environments. This study will assess a range of FOF-related responses, including cognitive factors, neuromuscular response and postural stability. METHODS AND ANALYSIS: This feasibility study will consist of four phases: the first two phases will include people without PD, while the other two will include people diagnosed with PD. Participants will be assessed for direct and indirect responses to real life, as well as virtual environment walking scenarios that may induce FOF. Data from questionnaires, different neurophysiological assessments, movement and gait parameters, alongside evaluations of usability and acceptability, will be collected. Semistructured interviews involving both participants and research assistants shall take place to elicit their experiences throughout different phases of the assessments undertaken. Demographic data, the scores of assessment scales, as well as feasibility, usability and acceptability of the measurement methods, will be illustrated via descriptive statistics. Movement and gait outcomes, together with neurophysiological data, will be extracted and calculated. Exploring relationships between different factors in the study will be achieved using a regression model. Thematic analysis will be the approach used to manage qualitative data. ETHICS AND DISSEMINATION: This feasibility study was approved by the Ethics Committee of the Faculty of Physical Therapy, Kafr El Sheikh University, Egypt (number: P.T/NEUR/3/2023/46). The results of this study will be published in a peer-reviewed journal. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov Registry (NCT05931692).

Effects of physiotherapy and home-based training in parkinsonian syndromes: protocol for a randomised controlled trial (MobilityAPP).

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.

Cognitive dysfunction characteristics of multiple sclerosis with aging.

BACKGROUND: We aimed to investigate the characteristics of cognitive impairment in older people with multiple sclerosis (MS). METHODS: Cross-sectional study that included participants that were examined with a common and comprehensive neuropsychological protocol. The subjects were matched by sociodemographic variables and the following groups were generated for comparisons: young MS versus healthy controls (HC) (n = 246), old MS versus HC (n = 198), young MS vs old MS (n = 226), MS vs Alzheimer's disease (AD)(n = 70), and MS vs Parkinson's disease (PD) (n = 62). The ICCoDiMS criteria were used to define cognitive impairment in MS. RESULTS: Cognitive impairment was more frequent in young than old patients (70.8 % vs 52.2 %). Attention and speed processing is the most frequent cognitive domain impaired in MS (54.9 % of young MS vs 32.7 % of old MS). The frequency of impairment in attention/processing speed (54.9 % vs 32.7 %) and episodic memory (27.9 % vs 14.3) was higher in the young group than in the old group. There were no statistically significant differences in the distribution of impairment in executive function (46.0 % vs 35.3 %), visuospatial (17.9 % vs 9.5 %), and language (12.4 % vs 17.7 %). In those patients meeting the criteria for cognitive impairment, young MS patients showed lower performance in attention/processing speed tests. Conversely, old MS patients showed lower performance in episodic memory, verbal fluency, and planning. There were no differences in the correlations between SDMT and other neuropsychological tests in young and old patients, which suggests similar cognitive processes underlying SDMT performance in both groups. There were differences between old MS and prodromal AD, especially in episodic memory, while the cognitive profile of old MS was largely shared with PD. CONCLUSIONS: Our study found that the cognitive profile of MS is defined by a characteristic impairment in attention and processing speed, which is present during the lifespan. The impairment in processing speed is less prominent in old age, whereas the impairment of other cognitive functions becomes more relevant. These findings suggest potential differences in the pathophysiological processes associated with cognitive impairment between young and old ages that warrant further investigation.

Physical Exercise-Induced Activation of NRF2 and BDNF as a Promising Strategy for Ferroptosis Regulation in Parkinson's Disease.

Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by the loss of dopaminergic neurons in the substantia nigra. Ferroptosis, an iron-dependent form of regulated cell death, may contribute to the progression of PD owing to an unbalanced brain redox status. Physical exercise is a complementary therapy that can modulate ferroptosis in PD by regulating the redox system through the activation of nuclear factor (erythroid-derived 2)-like 2 (NRF2) and brain-derived neurotrophic factor (BDNF) signaling. However, the precise effects of physical exercise on ferroptosis in PD remain unclear. In this review, we explored how physical exercise influences NRF2 and BDNF signaling and affects ferroptosis in PD. We further investigated relevant publications over the past two decades by searching the PubMed, Web of Science, and Google Scholar databases using keywords related to physical exercise, PD, ferroptosis, and neurotrophic factor antioxidant signaling. This review provides insights into current research gaps and demonstrates the necessity for future research to elucidate the specific mechanisms by which exercise regulates ferroptosis in PD, including the assessment of different exercise protocols and their long-term effects. Ultimately, exploring these aspects may lead to the development of improved exercise interventions for the better management of patients with PD.

Nigrostriatal degeneration determines dynamics of glial inflammatory and phagocytic activity.

Glial cells are key players in the initiation of innate immunity in neurodegeneration. Upon damage, they switch their basal activation state and acquire new functions in a context and time-dependent manner. Since modulation of neuroinflammation is becoming an interesting approach for the treatment of neurodegenerative diseases, it is crucial to understand the specific contribution of these cells to the inflammatory reaction and to select experimental models that recapitulate what occurs in the human disease. Previously, we have characterized a region-specific activation pattern of CD11b+ cells and astrocytes in the α-synuclein overexpression mouse model of Parkinson´s disease (PD). In this study we hypothesized that the time and the intensity of dopaminergic neuronal death would promote different glial activation states. Dopaminergic degeneration was induced with two administration regimens of the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), subacute (sMPTP) and chronic (cMPTP). Our results show that in the sMPTP mouse model, the pro-inflammatory phenotype of striatal CD11b+ cells was counteracted by an anti-inflammatory astrocytic profile. In the midbrain the roles were inverted, CD11b+ cells exhibited an anti-inflammatory profile and astrocytes were pro-inflammatory. The overall response generated resulted in decreased CD4 T cell infiltration in both regions. Chronic MPTP exposure resulted in a mild and prolonged neuronal degeneration that generated a pro-inflammatory response and increased CD4 T cell infiltration in both regions. At the onset of the neurodegenerative process, microglia and astrocytes cooperated in the removal of dopaminergic terminals. With time, only microglia maintained the phagocytic activity. In the ventral midbrain, astrocytes were the main phagocytic mediators at early stages of degeneration while microglia were the major phagocytic cells in the chronic state. In this scenario, we questioned which activation pattern recapitulates better the features of glial activation in PD. Glial activation in the cMPTP mouse model reflects many pathways of their corresponding counterparts in the human brain with advanced PD. Altogether, our results point toward a context-dependent cooperativity of microglia/myeloid cells and astrocytes in response to neuronal damage and the relevance of selecting the right experimental models for the study of neuroinflammation.

Remote neuropsychological assessment of patients with neurological disorders and injuries-a study protocol for a cross-sectional case-control validation study.

INTRODUCTION: There are great potential benefits of being able to conduct neuropsychological assessments remotely, especially for hard-to-reach or less mobile patient groups. Such tools need to be equivalent to standard tests done in the clinic and also easy to use in a variety of clinical populations. METHODS AND ANALYSIS: This study protocol describes a cross-sectional study aimed at validating the newly developed digitalized neuropsychological test battery Mindmore Remote in patients with neurological disorders and injuries. Diagnoses comprise traumatic brain injury, stroke, Parkinson's disease, multiple sclerosis, brain tumour and epilepsy. 50 patients in each patient group will be included. In addition, 50 healthy controls will be recruited. All participants will undergo both testing with Mindmore Remote at home and traditional neuropsychological assessment face-to-face in a randomised order. The primary outcome is the association between tests from the Mindmore Remote battery and their equivalent traditional neuropsychological tests. Further, bias between methods and differences between groups will also be investigated. ETHICS AND DISSEMINATION: The study protocol has been approved by the Swedish Ethical Review Authority (2022-06230-01) and adheres to the declaration of Helsinki. All participants will be given oral and written information about the study and sign informed consent forms before entering the study. All participants are informed that they can terminate their participation in the study at any given time, without giving any explanation, and participating in the study or not will not affect their care at the clinic. Neither authors nor personnel involved in the research project are affiliated with Mindmore AB. The results from the study will be published in peer-reviewed scientific journals and presented at national and international conferences on the topic. TRIAL REGISTRATION NUMBER: NCT05819008.