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.

Human serum-derived α-synuclein auto-antibodies mediate NMDA receptor-dependent degeneration of CNS neurons.

BACKGROUND: Presence of autoantibodies against α-synuclein (α-syn AAb) in serum of the general population has been widely reported. That such peripheral factors may be involved in central nervous system pathophysiology was demonstrated by detection of immunoglobulins (IgGs) in cerebrospinal fluid and brain of Parkinson's disease (PD) patients. Thus, blood-borne IgGs may reach the brain parenchyma through an impaired blood-brain barrier (BBB). FINDINGS: The present study aims to evaluate the patho-physiological impact of α-syn AAbs on primary brain cells, i.e., on spontaneously active neurons and on astrocytes. Exposure of neuron-astrocyte co-cultures to human serum containing α-syn AAbs mediated a dose-dependent reduction of spontaneous neuronal activity, and subsequent neurodegeneration. Removal specifically of α-syn AAbs from the serum prevented neurotoxicity, while purified, commercial antibodies against α-syn mimicked the neurodegenerative effect. Mechanistically, we found a strong calcium flux into neurons preceding α-syn AAbs-induced cell death, specifically through NMDA receptors. NMDA receptor antagonists prevented neurodegeneration upon treatment with α-syn (auto)antibodies. α-syn (auto)antibodies did not affect astrocyte survival. However, in presence of α-syn, astrocytes reacted to α-syn antibodies by secretion of the chemokine RANTES. CONCLUSION: These findings provide a novel basis to explain how a combination of BBB impairment and infiltration of IgGs targeting synuclein may contribute to neurodegeneration in PD and argue for caution with α-syn immunization therapies for treatment of PD.

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.

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.

NFKB1 variants were associated with the risk of Parkinson´s disease in male.

The NF-κB pathway is involved in the pathogenesis of neurological disorders that have inflammation as a hallmark, including Parkinson's disease (PD). Our objective was to determine whether common functional variants in the NFKB1, NFKBIA and NFKBIZ genes were associated with the risk of PD. A total of 532 Spanish PD cases (61% male; 38% early-onset, ≤ 55 years) and 300 population controls (50% ≤55 years) were genotyped for the NFKB1 rs28362491 and rs7667496, NFKBIA rs696, and NFKBIZ rs1398608 polymorphisms. We compared allele and genotype frequencies between early and late-onset, male and female, and patient's vs. controls. We found that the two NFKB1 alleles were significantly associated with PD in our population (p = 0.01; total patients vs. controls), without difference between Early and Late onset patients. The frequencies of the NFKB1 variants significantly differ between male and female patients. Compared to controls, male patients showed a significantly higher frequency of rs28362491 II (p = 0.02, OR = 1.52, 95%CI = 1.10-2.08) and rs28362491 C (p = 0.003, OR = 1.62, 95%CI = 1.18-2.22). The two NFKB1 variants were in strong linkage disequilibrium and the I-C haplotype was significantly associated with the risk of PD among male (p = 0.002). In conclusion, common variants in the NF-kB genes were associated with the risk of developing PD in our population, with significant differences between male and female. These results encourage further studies to determine the involvement of the NF-kB components in the pathogenesis of Parkinson´s disease.

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.

Parkinson´s disease cardiovascular symptoms: A new complex functional and structural insight.

BACKGROUND: The known impairments of the cardiovascular system in Parkinson´s disease (PD) are caused by autonomic dysfunction and manifested mainly in postural hypotension, chronotropic insufficiency, and reduced heart rate variability. Other dysfunctions, mainly stress response, arrhythmia occurrence, and heart morphology changes, are still the subject of research. OBJECTIVES: To assess the heart rate and blood pressure reaction during exercise, advanced measurements of heart volumes and mass using cardiac magnetic resonance (CMR), and occurrence of arrhythmias in PD patients. METHODS: Thirty PD patients (19 men, mean age 57.5 years) without known cardiac comorbidities underwent bicycle ergometry, electrocardiogram Holter monitoring and CMR. Exercise and CMR parameters were compared with controls (24 subjects for ergometry, 20 for CMR). RESULTS: PD patients had lower baseline systolic blood pressure (SBP) (117.8 vs. 128.3 mmHg, p < 0.01), peak SBP (155.8 vs. 170.8 mmHg, p < 0.05), and lower heart rate increase (49.7 vs. 64.3 beats per minute, p < 0.01). PD patients had higher indexed left and right ventricular end-diastolic volumes (68.5 vs. 57.3, p = 0.003 and 73.5 vs. 61.0 mL/m2 , respectively) and also indexed left and right ventricular end-systolic volumes (44.1 vs. 39.0, p = 0.013 and 29.0 vs. 22.0 mL/m2 , p = 0.013, respectively). A high prevalence of atrial fibrillation (8 subjects, 26.7%) was found. CONCLUSIONS: This novel study combining functional and structural approaches showed that PD is linked with weaker blood pressure and heart rate reaction during exercise, increased myocardial mass and heart volumes compared to controls, and a high prevalence of atrial fibrillation.

An examination of anxiety and its influence on health-related quality of life in Parkinson's disease using the geriatric anxiety scale: a cross-sectional study.

BACKGROUND: Anxiety is one of the most common but often overlooked mood-related nonmotor symptoms in people with Parkinson's disease (PD). To improve the well-being of people with PD, it is important to understand the impact of anxiety in PD, especially its association with depressive and motor symptoms and its impact on health-related quality of life (HRQoL). METHODS: 91 people with PD were assessed between June 2017 and June 2018. Anxiety was measured using the Geriatric Anxiety Scale (GAS) and its cognitive, somatic, and affective subscales. HRQoL was assessed using the Parkinson's Disease Questionnaire 39 (PDQ-39). Moreover, sociodemographic information, depressive symptoms, cognition, motor and nonmotor symptoms were assessed. Descriptive statistics, regression analyses, and path analyses were performed to understand predictors of anxiety and its influence on HRQoL. RESULTS: Of the 91 people with PD, 35 (38.5%) experienced anxiety. Anxiety symptoms in these individuals primarily manifest as somatic sensations. Anxiety, motor, and depressive symptoms are interlinked but contribute individually to HRQoL. Beyond motor symptoms, cognitive and affective aspects of anxiety impact HRQoL. While anxiety and depression overlap, the somatic and cognitive aspects of anxiety play a significant role in determining HRQoL in addition to depressive symptoms. CONCLUSION: Our study used the GAS and its three subscales to shed light on the connections between anxiety, depression, and motor impairment in people with PD. Although anxiety is linked to depression and motor symptoms, it independently affects the HRQoL of people with PD. Thus, it is crucial to adopt a comprehensive diagnostic approach that detects and considers the impact of anxiety on HRQoL in PD.

Neurological gait assessment.

Gait disorders are a common feature of neurological disease. The gait examination is an essential part of the neurological clinical assessment, providing valuable clues to a myriad of causes. Understanding how to examine gait is not only essential for neurological diagnosis but also for treatment and prognosis. Here, we review aspects of the clinical history and examination of neurological gait to help guide gait disorder assessment. We focus particularly on how to differentiate between common gait abnormalities and highlight the characteristic features of the more prevalent neurological gait patterns such as ataxia, waddling, steppage, spastic gait, Parkinson's disease and functional gait disorders. We also offer diagnostic clues for some unusual gait presentations, such as dystonic, stiff-person and choreiform gait, along with red flags that help differentiate atypical parkinsonism from Parkinson's disease.

Cognitive behavioural therapy for neurologists.

In neurological practice, we take pride in accurate diagnosis and using neuroscience to develop novel disease-modifying therapies, but we sometimes neglect symptom management and the treatment of distress. Most patients with neurological disorders report that their mental health needs are not being met. Of the many forms of psychological therapy, cognitive behavioural therapy (CBT) is the most likely to be available to our patients. This article sets out to answer the following questions: (1) What is CBT? (2) What will patients experience if they have CBT? (3) Is CBT effective for people with neurological disorders? (4) Who is most suitable for CBT? (5) How and where can a neurologist refer their patients for CBT? (6) Can we as neurologists use aspects of the CBT model in our own consultations?

Parkinson's disease patients' perspective on telephone visits during the COVID-19 pandemic.

Telemedicine is a promising modality to provide specialized care in periods when attendance is challenged, as recently observed during the Coronavirus disease 2019 (COVID-19) pandemic. We aimed to evaluate the satisfaction with telemedicine visits in a group of Parkinson´s disease (PD) patients during the COVID-19 pandemic, as well as to identify demographic or clinical factors associated with higher telemedicine satisfaction. Retrospective cohort study of PD patients who attended telemedicine visits at Centro Hospitalar de Lisboa Ocidental, from March 1, 2020 until March 31, 2021. An eleven-question telephone survey was used to assess satisfaction with telemedicine visits. Patients' answers were dichotomized into "satisfied" or "not satisfied" to study the factors associated with satisfaction with telemedicine. Mann-Whitney U for continuous variables and chi-square tests for categorical variables were performed to compare data between the two groups. Linear regression was used to study the factors associated with being satisfied with telemedicine. A total of 111 patients (87%) accepted to participate in this survey. The majority (n = 74.67%) reported being satisfied with telemedicine visits. Patients preferred a combination of in-person and telemedicine visits (n = 43.39%). Male gender (p < 0.001) and employed patients (p < 0.001) were associated with higher satisfaction. In the linear regression, therapeutic changes deemed clear (p < 0.014) and considering the absence of neurological examination non-detrimental (p < 0.001) were associated with a higher degree of satisfaction with telemedicine. Most patients are satisfied with telemedicine visits, even in urgent implementation due to the COVID-19 pandemic. Moreover, telemedicine does not pose a hurdle to a paradigm shift away from conventional in-person appointments.

Effects of rasagiline combined with levodopa and benserazide hydrochloride on motor function and homocysteine and IGF-1 levels in elderly patients with Parkinson's disease.

BACKGROUND: During the course of their illness, people with Parkinson's disease may see changes in their insulin-like growth factor (IGF-1) and serum homocysteine (Hcy) indices. In this study, patients with intermediate to severe Parkinson's disease were examined for how Resagiline and levodopa and benserazide hydrochloride affected their motor performance, serum levels of homocysteine (Hcy), and insulin-like growth factor (IGF-1). METHODS: From June 2020 to December 2021, a total of 100+ cases of Parkinson's patients over 60 years old in the middle and late stages of Parkinson's were seen in the outpatient and inpatient departments of the Third People's Hospital of Chengdu City and had a detailed observation record, and according to the inclusion criteria, the patients who met the criteria were randomly grouped into a clinical observation group and a control group. The subjects in the control group received only levodopa and benserazide hydrochloride treatment, while the observation group was treated with Resagiline in combination with the clinical control group. The total treatment observation period was 1 year for both groups, and the motor function and serum Hcy and IGF-1 indexes of both groups were compared after the end of treatment. RESULTS: We randomly and evenly grouped 64 patients who met the requirements of the inclusion criteria into a clinical observation group and a control group, each with 32 patients, from among 168 patients over 60 years of age with detailed observation records in the middle and late stages of Parkinson's. After the 1-year observation period, we found that the total effective rate after treatment in the clinical observation group (93.75%) and significantly higher than that in the control group (68.75%) (P < 0.05); after 1 year of treatment, the UPDRS score decreased in both groups, and the observation group was significantly lower than the control group (P < 0.05); after treatment, serum Hcy decreased and IGF-1 increased in both groups, and the observation group was higher than the control group mean values (P < 0.05). CONCLUSIONS: In patients with Parkinson's disease who are in the middle and late stages of the disease, the administration of Resagiline combined with levodopa and benserazide hydrochloride can significantly lower the body's serum Hcy level, significantly raise IGF-1 levels, and significantly improve motor function in patients with Parkinson's disease. It can also have significant therapeutic effects.

Effects of curcumin to counteract levodopa-induced toxicity in zebrafish.

Parkinson's disease (PD) is a neurodegenerative disorder characterized by motor dysfunction due to the death of dopaminergic neurons in the substantia nigra pars compacta. Currently, treatment of PD has focused on increasing dopamine levels, using a dopamine precursor, levodopa (L-DOPA) or stimulation of dopaminergic receptors. Prolonged use of L-DOPA is associated with the occurrence of motor complications and dyskinesia, attributed to neurotoxic effects of this drug. The aim of this study was to investigate the effects of curcumin (CUR), a lipophilic polyphenol, to counteract L-DOPA induced toxicity. Zebrafish larvae were pre-treated with CUR (0.05 µM) or vehicle dimethyl sulfoxide (DMSO) for 24 hr and subsequently exposed to L-DOPA (1 mM) or vehicle. Immediately and 24 hr after L-DOPA exposure, spontaneous swimming and dark/light behavioral tests were performed. In addition, levels of reactive oxygen species (ROS) and lipid peroxidation products were determined at the end of treatment. CUR significantly improved the motor impairment induced by 24 hr L-DOPA treatment, and reduced levels of ROS and lipoperoxidation products in zebrafish larvae. In conclusion, our results suggest that CUR acts as a neuroprotector against toxicity initiated by L-DOPA. Evidence suggests the observed effects of CUR are associated with its antioxidant properties.

Motor and non-motor improvements following short-term multidisciplinary day-clinic care in Parkinson´s disease.

BACKGROUND: Inpatient as well as outpatient care does often not meet PD-patients' individual needs. INTRODUCTION: Day-clinic concepts encompassing a multidisciplinary team as well as therapy adjustments accompanying everyday demands aim at filling this gap. METHODS: This is a retrospective study on short-term effects of a 3 week multidisciplinary rehabilitation program in patients with Parkinson´s disease (PD) embedded in a specialized movement disorder day-clinic. We analyzed short-term outcome of motor and non-motor symptoms (NMS) in 143 PD-patients (mean age 65.3 ± 11.9 years; Hoehn-and-Yahr-score 2.6 ± 0.7) after 3 weeks with 7.4 ± 1.8 active days of interdisciplinary day-care treatment. Participants attended the day-clinic in groups of five patients at a time. Improvements were evaluated by comparison of standardized physical therapy assessments, disease specific scores for motor symptoms (MDS-UPDRS III), mood (BDI), quality of life (PDQ39, SF36), sleep (PDSS, ESS), impulsiveness (QUIP), apathy (SAS), cognition (MMST), as well as change in medication before and directly after the intervention. RESULTS: MDS-UPDRS motor score improved significantly by 22.9 ± 21.5% (p < 0.001) and was accompanied by a significant reduction of imbalance, immobility, and weakness ranging between 6% and 17% in standardized physical therapy tests. In addition, all disease-specific non-motor scales improved significantly. CONCLUSIONS: A multidisciplinary day-clinic approach can support benefit on motor, non-motor symptoms and QoL in PD-patients. Given the increase in PD incidence and prevalence as well as the significant treatment effects shown here, more day-clinic treatment opportunities ought to be implemented to improve PD treatment adapted to everyday challenges while still reducing costs to the health care system.

Systematic quantitative assessment of motor function in clinically isolated REM sleep behaviour disorder: A diagnostic window into early alpha-synucleinopathies.

Mild motor abnormalities can herald the beginning of Parkinson´s disease but their diagnostic value is limited by multifactorial ageing-related influences on motor function. We characterized mild motor abnormalities in different motor domains by conducting a systematic motor assessment in 20 patients with clinically isolated REM sleep behaviour disorder (iRBD) without parkinsonian motor signs and 20 healthy controls. We addressed the influence of lifestyle factors and age on motor function, which needs to be distinguished from neurodegenerative motor features, and assessed the diagnostic value of innovative and established quantitative motor tests in iRBD. Patients with iRBD showed abnormalities in perceptual motor speed (falling stick test), trunk movement coordination (bend, twist and touch test) and dynamic balance (line walk test) without alterations in simple motor speed (alternate tap test), dexterity (grooved pegboard), static balance (force plate) and gait (timed up and go test). The falling stick test showed the highest diagnostic accuracy in identifying subjects with RBD (ROC-AUC 0.85, p ≤ 0.001). Multivariate analysis revealed physical activity and age as additional determinants of motor test performance. iRBD comprises a wide spectrum of mild motor abnormalities which cannot be verified by established tests for motor speed, gait and balance. The falling stick test, an innovative screening test for perceptual motor speed, provides high diagnostic potential in identifying subjects with subclinical neurodegenerative symptoms before parkinsonian motor signs become apparent. Normative data for physical activity and age need to be obtained to ensure correct interpretation of motor test results in prodromal Parkinson-related disease.

Enforced dimerization between XBP1s and ATF6f enhances the protective effects of the UPR in models of neurodegeneration.

Alteration to endoplasmic reticulum (ER) proteostasis is observed in a variety of neurodegenerative diseases associated with abnormal protein aggregation. Activation of the unfolded protein response (UPR) enables an adaptive reaction to recover ER proteostasis and cell function. The UPR is initiated by specialized stress sensors that engage gene expression programs through the concerted action of the transcription factors ATF4, ATF6f, and XBP1s. Although UPR signaling is generally studied as unique linear signaling branches, correlative evidence suggests that ATF6f and XBP1s may physically interact to regulate a subset of UPR target genes. In this study, we designed an ATF6f/XBP1s fusion protein termed UPRplus that behaves as a heterodimer in terms of its selective transcriptional activity. Cell-based studies demonstrated that UPRplus has a stronger effect in reducing the abnormal aggregation of mutant huntingtin and α-synuclein when compared to XBP1s or ATF6 alone. We developed a gene transfer approach to deliver UPRplus into the brain using adeno-associated viruses (AAVs) and demonstrated potent neuroprotection in vivo in preclinical models of Parkinson's disease and Huntington's disease. These results support the concept in which directing UPR-mediated gene expression toward specific adaptive programs may serve as a possible strategy to optimize the beneficial effects of the pathway in different disease conditions.

Efficacy and evaluation of therapeutic exercises on adults with Parkinson's disease: a systematic review and network meta-analysis.

BACKGROUND: Exercises are an effective treatment in Parkinson's disease (PD), but there is still controversy over which types should be used. We aimed to compare and rank the types of exercise that improve PD symptoms by quantifying information from randomised controlled trials. METHODS: We performed a systematic review and network meta-analysis and searched PubMed, MEDLINE, Embase, PsycINFO, Cochrane Central Register of Controlled Trials (CENTRAL), Web of Science, and China National Knowledge Infrastructure (CNKI) from their inception date to June 30, 2022. We included randomized controlled trials of 24 types of exercise for the interventional treatment of adults (≥ 50 years old) with PD. Effect size measures were standardized mean differences (SMDs) with 95% credible intervals (CrIs). The confidence of evidence was examined using Confidence in Network Meta-Analysis (CINeMA). RESULTS: We identified 10 474 citations and included 250 studies involving 13 011 participants. Results of NMA showed that power training (PT) had the best benefits for motor symptoms compared with the control group (CON), with SMDs (95% CrI) (-1.46, [-2.18 to -0.74]). Body weight support treadmill training (BWS_TT) showed the best improvement in balance (1.55, [0.72 to 2.37]), gait velocity (1.15 [0.57 to 1.31]) and walking distance (1.96, [1.18 to 2.73]), and robotic assisted gait training (RA_GT) had the most benefits for freezing of gait (-1.09, [-1.80 to -0.38]). For non-motor symptoms, Dance showed the best benefits for depression (-1.71, [-2.79 to -0.73]). Only Yoga significantly reduced anxiety symptom compared with CON (-0.53, [0.96 to -0.11]). Only resistance training (RT) significantly enhanced sleep quality and cognition (-1.42, [-2.60 to -0.23]; 0.51, [0.09 to 0.94]). For muscle strength, PT showed the best advance (1.04, [0.64 to 1.44]). For concern of falling, five types of exercise were more effective than CON. CONCLUSIONS: There is low quality evidence that PT, Yoga, BWS_TT, Dance, and RT are the most effective treatments, pending outcome of interest, for adults with PD. TRIAL REGISTRATION: PROSPERO (CRD42021220052).

Wearable Immersive Virtual Reality Device for Promoting Physical Activity in Parkinson's Disease Patients.

Parkinson's disease (PD) is a neurological disorder that usually appears in the 6th decade of life and affects up to 2% of older people (65 years and older). Its therapeutic management is complex and includes not only pharmacological therapies but also physiotherapy. Exercise therapies have shown good results in disease management in terms of rehabilitation and/or maintenance of physical and functional capacities, which is important in PD. Virtual reality (VR) could promote physical activity in this population. We explore whether a commercial wearable head-mounted display (HMD) and the selected VR exergame could be suitable for people with mild-moderate PD. In all, 32 patients (78.1% men; 71.50 ± 11.80 years) were a part of the study. Outcomes were evaluated using the Simulator Sickness Questionnaire (SSQ), the System Usability Scale (SUS), the Game Experience Questionnaire (GEQ post-game module), an ad hoc satisfaction questionnaire, and perceived effort. A total of 60 sessions were completed safely (without adverse effects (no SSQ symptoms) and with low scores in the negative experiences of the GEQ (0.01-0.09/4)), satisfaction opinions were positive (88% considered the training "good" or "very good"), and the average usability of the wearable HMD was good (75.16/100). Our outcomes support the feasibility of a boxing exergame combined with a wearable commercial HMD as a suitable physical activity for PD and its applicability in different environments due to its safety, usability, low cost, and small size. Future research is needed focusing on postural instability, because it seems to be a symptom that could have an impact on the success of exergaming programs aimed at PD.

Altered Cortical Palmitoylation Induces Widespread Molecular Disturbances in Parkinson's Disease.

The relationship between Parkinson's disease (PD), the second-most common neurodegenerative disease after Alzheimer's disease, and palmitoylation, a post-translational lipid modification, is not well understood. In this study, to better understand the role of protein palmitoylation in PD and the pathways altered in this disease, we analyzed the differential palmitoyl proteome (palmitome) in the cerebral cortex of PD patients compared to controls (n = 4 per group). Data-mining of the cortical palmitome from PD patients and controls allowed us to: (i) detect a set of 150 proteins with altered palmitoylation in PD subjects in comparison with controls; (ii) describe the biological pathways and targets predicted to be altered by these palmitoylation changes; and (iii) depict the overlap between the differential palmitome identified in our study with protein interactomes of the PD-linked proteins α-synuclein, LRRK2, DJ-1, PINK1, GBA and UCHL1. In summary, we partially characterized the altered palmitome in the cortex of PD patients, which is predicted to impact cytoskeleton, mitochondrial and fibrinogen functions, as well as cell survival. Our study suggests that protein palmitoylation could have a role in the pathophysiology of PD, and that comprehensive palmitoyl-proteomics offers a powerful approach for elucidating novel cellular pathways modulated in this neurodegenerative disease.

Pathological laughter and crying in neurological disorders: recognition and treatment.

Pathological laughter and crying is a disabling symptom complex associated with damage to various central nervous system pathways that control the reflex motor component of emotional expression. Many underlying conditions-including neurodegenerative diseases, CNS inflammation, vascular lesions and traumatic brain injury-can be associated with disinhibition of emotional reflex control. This suggests a disruption of anatomical and functional networks, rather than any specific unifying pathological process. There is a wide differential diagnosis, including depression, dementia and other forms of behavioural disturbance. Diagnostic criteria and rating scales can help with clinical assessments and facilitate clinical trials. There is now good-quality evidence for a combination of dextromethorphan and quinidine, with weaker evidence for tricyclic and selective serotonin reuptake inhibitor antidepressants. Pathological laughter and crying is disabling and underdiagnosed but potentially treatable, and its wider recognition is important.