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Literature indicates a potential association between dairy consumption and risk of Parkinson´s disease (PD), especially among men, yet the results remain inconclusive. We investigated this association in a large prospective European cohort. Dietary and non-dietary data was collected from 183,225 participants of the EPIC-for-Neurodegenerative-Diseases (EPIC4ND) cohort, a sub-cohort of the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. Crude and multivariable-adjusted Cox proportional hazards models were employed to examine potential associations between baseline dietary intake of dairy, calcium and vitamin D with incident PD risk. No relationship was observed between dairy consumption (HR 1.07, 95% CI 0.82–1.39), individual dairy products (milk: HR 0.95, 95% CI 0.73–1.23; yogurt: HR 1.03, 95% CI 0.82–1.29; cheese: HR 1.13, 95% CI 0.85–1.51), or vitamin D (HR 1.08, 95% CI 0.80–1.45) with PD risk. However, we observed a risk-increasing association with higher calcium intakes (HR 1.33, 95% CI 1.00-1.78, p for trend = 0.031), which was more pronounced in men (HR 1.50, 95% CI 1.00-2.25, p for trend = 0.044) and in ever smokers (HR 1.64, 95% CI 1.06–2.53, p for trend = 0.014). No compelling evidence was found for an association between dairy products or vitamin D intake and PD risk indicating a potentially limited relevance of dairy intake in PD risk than previously described. Our observations of a positive association between dietary calcium intake and PD risk in men and in ever smokers require further validation. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Abstract 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.

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Abstract 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. Graphical abstract

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. [ABSTRACT FROM AUTHOR]

Background: Zonisamide (ZNS) has shown some efficacy in motor symptoms of PD; however, more evidence is lacking, and its effects on nonmotor symptoms (NMSs) and quality of life (QoL) remain to be investigated. This randomized double-blinded placebo-controlled crossover study investigated the effect of ZNS on motor and NMS symptoms and QoL in advanced PD. Methods: PD patients with Hoehn and Yahr stage ≥ 2 ("On" state) and at least 2 h off time daily were randomized to groups: ZNS 25 mg, ZNS 50 mg and placebo. Groups were assessed at baseline and at the 1- and 3-month follow-ups. The primary endpoint was the change in the total MDS-UPDRS III "On", while the secondary endpoint was the change in the total and parts I and IV MDS-UPDRS, Nonmotor Symptoms Scale and Parkinson's disease questionnaire-39 at the final assessment. Results: Sixty-nine patients were assessed for efficacy at the 1-month follow-up, and 58 patients were assessed at the 3-month follow-up. The primary endpoint showed significant improvement in the ZNS 25 mg group compared to the placebo group (p = 0.009). At the final assessment, the ZNS 25 mg group showed significant improvement of total and part VI MDS-UPDRS, bradykinesia, tremor and functional impact of fluctuations compared to placebo. There was no change in dyskinesia, NMSs, QoL or side effects except for sedation. Conclusion: ZNS has a favourable effect on motor symptoms in patients with wearing off as adjunctive therapy with other dopaminergic drugs, with no exacerbation of dyskinesia and a limited impact on NMSs and QoL. Trial registration: Clinicaltrials.gov, NCT04182399, in 24/11/2019. [ABSTRACT FROM AUTHOR]

Abstract 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.

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Neurodegenerative diseases are caused by the progressive loss of specific neurons. The exact mechanisms of action of these diseases are unknown, and many studies have focused on pathways related to abnormal accumulation and processing of proteins, mitochondrial dysfunction, and oxidative stress leading to apoptotic death. However, a growing body of evidence indicates that aberrant cell cycle re-entry plays a major role in the pathogenesis of neurodegeneration. The activation of the cell cycle in mature neurons could be promoted by several signaling mechanisms, including c-Jun N-terminal kinases, p38 mitogen-activated protein kinases, and mitogen-activated protein kinase/extracellular signal-regulated kinase cascades; post-translational modifications such as Tau-phosphorylation; and DNA damage response. In all these events, implicated Cdk5, a proline-directed serine/threonine protein kinase, seems to be responsible for several cellular processes in neurons including axon growth, neurotransmission, synaptic plasticity, neuronal migration, and maintenance of neuronal survival. However, under pathological conditions, Cdk5 dysregulation may lead to cell cycle re-entry in post-mitotic neurons. Thus, Cdk5 hyperactivation, by its physiologic activator p25, hyper-phosphorylates downstream substrates related to neurodegenerative diseases. This review summarizes factors such as oxidative stress, DNA damage response, signaling pathway disturbance, and Ubiquitin proteasome malfunction contributing to cell cycle re-entry in post-mitotic neurons. It also describes how all these factors are linked to a greater or lesser extent with Cdk5. Thus, it offers a global vision of the function of cell cycle-related proteins in mature neurons with a focus on Cdk5 and how this protein contributes to the development of Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, and Huntington’s disease by cell cycle activation.

Since the discovery of the presynaptic protein α-synuclein (aSyn) as a central player in Parkinson's disease (PD), several key questions on the function of the protein in neurodegeneration processes remain unclear, including: is there a synergy between dopamine metabolism and the formation of toxic aSyn species in neurons? What is the role of aSyn in the immunological system? Herein, the authors revisit the intricate pathways related to dopamine metabolism and how it impacts on aSyn aggregation/function. Additionally, they discuss the importance of aSyn in the immune response to viral infections as well as the current findings on the possible protective role of certain virus vaccines against PD and other neuropathologies. The physiological function of aSyn seems to cover different pathways, such as immune response against infections and a neuroprotective role, besides the already-established regulation of synaptic vesicle trafficking. Clinical studies with monoclonal antibodies against aSyn aggregates have shown disappointing results in patients with early-stage PD. Alternatively, we could consider, as immunological target, specific neurotoxic oligomers of aSyn formed in the presence of dopamine metabolites, such as DOPAL. Nevertheless, the crucial question remains as to whether removing these protein deposits will affect the clinical course of the disease. [ABSTRACT FROM AUTHOR]

Curcumin (CUR) is a bioactive compound that has been proposed for the treatment of various neurodegenerative diseases. However, its use is limited due to its low solubility in aqueous media and chemical instability under physiological conditions. Herein, we propose a strategy to overcome these limitations by using PAMAM dendrimers of generation 4.5 (DG4.5). Using a combination of biophysical techniques together with in vitro models, we demonstrate that CUR-DG4.5 complexes: (i) increased the solubility and stability of CUR via internalization into dendrimer's pockets and interaction with terminal carboxylic groups; (ii) showed in vitro biocompatibility and increased CUR uptake; (iii) presented DPPH radical scavenging activity and in vitro inhibition of H2O2-induced stress; and (iv) interfere with α-synuclein aggregation. In conclusion, this work lays the foundation to use curcumin-loaded PAMAM dendrimers of generation 4.5 as nanodrugs capable of reducing oxidative stress and inhibiting α-synuclein aggregation to treat synucleinopathies.

Acoustic myography (AMG) noninvasively probes muscle activity. We explored whether AMG captures abnormal motor activity in patients with Parkinson's disease (PD) and how this activity is modulated by antiparkinsonian medication. Twenty patients with PD underwent AMG of the biceps, triceps, extensor carpi radialis longus, and adductor policis muscles of the more affected arm during active and passive movements, using a mobile AMG device (CURO, Denmark). AMG and assessment of motor symptoms were performed in a pragmatic off‐medication state, as well as one and 3 h after oral intake of 200 mg levodopa. Three AMG parameters were calculated using the CURO analysis system. Motor efficiency was expressed by the E‐score, muscle fiber recruitment by the temporal T‐score, spatial summation by the S‐score, and S/T ratio. Twenty age‐ and sex‐matched healthy subjects served as controls. Group mean values were statistically compared using unpaired two‐tailed adjusted t‐test and ANOVA with Tukey´s correction for multiple comparison (p ≤ 0.05). For the biceps and extensor carpi radialis longus muscles, the active movement S:T ratio was lower in PD relative to healthy controls. The E‐score was also lower during active and passive flexion/extension movements in the off‐medication state. No significant between‐group differences in the AMG scores were noted for the triceps muscle during active or passive movements. The active S:T ratio and the E‐score during active elbow flexion and extension may offer a useful means to quickly assess abnormal motor activity and the effect of drug treatment in PD. [ABSTRACT FROM AUTHOR]

The incidence of hospitalizations of Parkinson´s disease (PD) in Spain suffered a steady rise from 1997 to 2012. However, data on the trends during the following decade (2010–2019) are lacking. Hospital admissions with a primary and secondary diagnosis of PD were selected using the Spanish National Hospital Discharge Database (SNHDD) for the period 2010–2019. The primary endpoint was the incidence of hospitalizations and in-hospital mortality, stratified in biannual periods. The incidence of PD hospitalizations increased progressively over time from 81.25 cases in 2010–2011 to 94.82 cases in 2018–2019 per 100,000 inhabitants. Male sex, age and comorbidity also increased progressively in PD inpatients. PD as a comorbid condition presented a higher increment (annual percentage of change, APC +1.71%, p < 0.05) than PD as the main reason of hospitalization (APC +1.26%, p < 0.05). In the multivariate regression model, factors associated with mortality were male sex (OR = 1.15, 95% CI 1.01–1.35), age (>80 years, OR = 12.76, 95% CI 3.96–29.64) and comorbidity (Charlson index ≥ 2, OR 1.77, 95% CI 1.69–1.85). Adjusted mortality by age, sex, comorbidity and diagnostic position remained stable. In conclusion, PD hospitalizations in Spain have increased, with a parallel increment in mean age, male sex and higher comorbidities. However, adjusted mortality remains unchanged. The burden of this disease may increase the complexity and costs of hospital care in the future. [ABSTRACT FROM AUTHOR]

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Abstract Acoustic myography (AMG) noninvasively probes muscle activity. We explored whether AMG captures abnormal motor activity in patients with Parkinson's disease (PD) and how this activity is modulated by antiparkinsonian medication. Twenty patients with PD underwent AMG of the biceps, triceps, extensor carpi radialis longus, and adductor policis muscles of the more affected arm during active and passive movements, using a mobile AMG device (CURO, Denmark). AMG and assessment of motor symptoms were performed in a pragmatic off‐medication state, as well as one and 3 h after oral intake of 200 mg levodopa. Three AMG parameters were calculated using the CURO analysis system. Motor efficiency was expressed by the E‐score, muscle fiber recruitment by the temporal T‐score, spatial summation by the S‐score, and S/T ratio. Twenty age‐ and sex‐matched healthy subjects served as controls. Group mean values were statistically compared using unpaired two‐tailed adjusted t‐test and ANOVA with Tukey´s correction for multiple comparison (p ≤ 0.05). For the biceps and extensor carpi radialis longus muscles, the active movement S:T ratio was lower in PD relative to healthy controls. The E‐score was also lower during active and passive flexion/extension movements in the off‐medication state. No significant between‐group differences in the AMG scores were noted for the triceps muscle during active or passive movements. The active S:T ratio and the E‐score during active elbow flexion and extension may offer a useful means to quickly assess abnormal motor activity and the effect of drug treatment in PD.

Objective: To synthesize evidence from systematic reviews on the effects of qigong, tai chi, and yoga in people with neurological diseases. Methods: A systematic search was conducted in PubMed, PsycINFO, Embase, CINAHL and Cochrane Library until September 2022. Methodological quality was assessed using the AMSTAR 2 tool. A qualitative synthesis of included reviews and meta-analyses was performed. Citation matrices and the corrected covered area were used to explore the overlap of randomized controlled trials among reviews. Results: Nineteen systematic reviews (containing 74 trials and 80 meta-analyses) in people with Parkinson’s disease (PD) or stroke were included. The critical domains of the AMSTAR 2 were not satisfied in more than half of the reviews, and only 4 evaluated the certainty of the evidence. The overlap was very high (21.7%) and high (11%) for tai chi studies in PD and stroke, respectively. In people with PD, qigong, yoga, and tai chi can improve balance, with tai chi being beneficial to increase functional mobility. For stroke patients, tai chi was better than controls to enhance motor function and independence, but not for health-related quality of life and quality of sleep. Findings on balance, walking ability and depression were inconclusive in stroke population. Conclusions: Qigong, tai chi, and yoga appear to be effective to improve balance performance in people with PD. Tai chi practice enhances motor function and independency in stroke patients.

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Oxidative stress is strongly involved in the pathogenesis of neurodegenerative diseases, like Parkinson´s disease (PD). Particularly, an excess of reactive oxygen species (ROS) released by the cells promotes an oxidative stress condition, which is a main cause of tissue injury leading to nervous system dysfunction. In this work, the antioxidant, neuroprotective and anti-inflammatory activities of different fractions from the brown seaweed Bifurcaria bifurcata are presented and related with their chemical profile. The antioxidant capacity was evaluated by the Folin-Ciocalteu method, 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging activity, ferric reducing antioxidant power (FRAP) and oxygen radical absorbance capacity (ORAC) assays. Neuroprotective capacity was evaluated to prevent neurological cell death mediated by the neurotoxin 6-hydroxydopamine (6-OHDA) on SH-SY5Y cells, and their anti-inflammatory effects on RAW 264.7 macrophages. The ethyl acetate fractions (100 µg mL−1) exhibited significant antioxidant and neuroprotective activities in the in vitro models assayed. Furthermore, two of the most polar fractions obtained with methanol and water also evidenced a significant neuroprotective potential. Bifurcaria bifurcata fractions treatment decreased ROS production, mitochondrial dysfunction, and Caspase-3 activity. Regarding the anti-inflammatory potential, five fractions (100 µg mL−1) inhibited nitric oxide (NO) production and reduced the interleukin – 6 (IL-6) and tumor necrosis factor (TNF-α) levels. Mannitol, identified as the major component of the most bioactive fraction, protected SH-SY5Y cells against the 6-OHDA neurotoxicity mediating ROS generation mitigation, mitochondrial dysfunction, and DNA damage, together with the Caspase-3 activity inhibition. Results suggest that B. bifurcata is a relevant source of neuroprotective agents, with particular interest for preventive therapeutics. [ABSTRACT FROM AUTHOR]

Background: Parkinson's disease (PD) affects millions of people worldwide, but only 5-10% of patients suffer from a monogenic form of the disease with Mendelian inheritance. SNCA, the gene encoding for the protein alpha-synuclein (aSyn), was the first to be associated with familial forms of PD and, since then, several missense variants and multiplications of the SNCA gene have been established as rare causes of autosomal dominant forms of PD., Aim and Methods: A patient carrying aSyn missense mutation and his family members were studied. We present the clinical features, genetic testing - whole exome sequencing (WES), and neuropathological findings. The functional consequences of this aSyn variant were extensively investigated using biochemical, biophysical, and cellular assays., Results: The patient exhibited a complex neurodegenerative disease that included generalized myocloni, bradykinesia, dystonia of the left arm and apraxia. WES identified a novel heterozygous SNCA variant (cDNA 40G>A; protein G14R). Neuropathological examination showed extensive atypical aSyn pathology with frontotemporal lobar degeneration (FTLD) and nigral degeneration pattern with abundant ring-like neuronal inclusions, and few oligodendroglial inclusions. Sanger sequencing confirmed the SNCA variant in the healthy, elderly parent of the patient patient suggesting incomplete penetrance. NMR studies suggest that the G14R mutation induces a local structural alteration in aSyn, and lower thioflavin T binding in in vitro fibrillization assays. Interestingly, the G14R aSyn fibers display different fibrillar morphologies as revealed by cryo-electron microscopy. Cellular studies of the G14R variant revealed increased inclusion formation, enhanced membrane association, and impaired dynamic reversibility of serine-129 phosphorylation., Summary: The atypical neuropathological features observed, which are reminiscent of those observed for the G51D aSyn variant, suggest a causal role of the SNCA variant with a distinct clinical and pathological phenotype, which is further supported by the properties of the mutant aSyn, compatible with the strain hypothesis of proteinopathies., Competing Interests: Conflict of interests The authors have no relevant conflicts of interest to disclose related to the article.

Background: Intracellular deposition of alpha‐synuclein (α‐syn) as Lewy bodies and Lewy neurites is a central event in the pathogenesis of Parkinson's disease (PD) and other α‐synucleinopathies. Transgenic mouse models overexpressing human α‐syn, are useful research tools in preclinical studies of pathogenetic mechanisms. Such mice develop α‐syn inclusions as well as neurodegeneration with a topographical distribution that varies depending on the choice of promoter and which form of α‐syn that is overexpressed. Moreover, they display motor symptoms and cognitive disturbances that to some extent resemble the human conditions. Purpose: One of the main motives for assessing behavior in these mouse models is to evaluate the potential of new treatment strategies, including their impact on motor and cognitive symptoms. However, due to a high within‐group variability with respect to such features, the behavioral studies need to be applied with caution. In this review, we discuss how to make appropriate choices in the experimental design and which tests that are most suitable for the evaluation of PD‐related symptoms in such studies. Methods: We have evaluated published results on two selected transgenic mouse models overexpressing wild type (L61) and mutated (A30P) α‐syn in the context of their validity and utility for different types of behavioral studies. Conclusions: By applying appropriate behavioral tests, α‐syn transgenic mouse models provide an appropriate experimental platform for studies of symptoms related to PD and other α‐synucleinopathies. [ABSTRACT FROM AUTHOR]

Abstract Background Intracellular deposition of alpha‐synuclein (α‐syn) as Lewy bodies and Lewy neurites is a central event in the pathogenesis of Parkinson's disease (PD) and other α‐synucleinopathies. Transgenic mouse models overexpressing human α‐syn, are useful research tools in preclinical studies of pathogenetic mechanisms. Such mice develop α‐syn inclusions as well as neurodegeneration with a topographical distribution that varies depending on the choice of promoter and which form of α‐syn that is overexpressed. Moreover, they display motor symptoms and cognitive disturbances that to some extent resemble the human conditions. Purpose One of the main motives for assessing behavior in these mouse models is to evaluate the potential of new treatment strategies, including their impact on motor and cognitive symptoms. However, due to a high within‐group variability with respect to such features, the behavioral studies need to be applied with caution. In this review, we discuss how to make appropriate choices in the experimental design and which tests that are most suitable for the evaluation of PD‐related symptoms in such studies. Methods We have evaluated published results on two selected transgenic mouse models overexpressing wild type (L61) and mutated (A30P) α‐syn in the context of their validity and utility for different types of behavioral studies. Conclusions By applying appropriate behavioral tests, α‐syn transgenic mouse models provide an appropriate experimental platform for studies of symptoms related to PD and other α‐synucleinopathies.

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Parkinson´s disease is the most important neuromotor pathology due to the prominent loss of dopaminergic neurons in the substantia nigra pars compacta. There is an inherent deficiency of dopamine in Parkinson´s disease, which is aggravated when neuroinflammatory processes are present. Several biomolecules are interesting candidates for the regulation of inflammation and possible neuroprotection, such as valerenic acid, one of the main components of Valeriana officinalis. A 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine hydrochloride (MPTP)-induced mouse model of Parkinson's disease was developed to evaluate the motor effects of valerenic acid. The evaluation was carried out with four tests (an invert screen test for muscle strength, cross beam test, open field mobility test and lifting on hind legs test). Subsequently, the neuroinflammatory process was evaluated through ELISA of pro-inflammatory cytokines (IL-1β, IL-6, TNF-α and IFN-γ). The decreases in the inflammatory and neurodegenerative processes were evaluated by Western blot and immunohistochemistry analyses of the tissues, which included an evaluation of the tyrosine hydroxylase and GFAP proteins. Finally, the predicted mechanism of action of valerenic acid was supported by molecular docking calculations with the 5-HT5A receptor. The results indicate that the use of valerenic acid as a co-treatment decreases the neuroinflammation in Parkinson's disease induced by MPTP and provides evidence of a decrease in the evaluated pro-inflammatory cytokines and in the amount of GFAP in the mesencephalic area. Valerenic acid prevents neuroinflammation in a Parkinson's disease mouse model, which might reflect the neuroprotection of dopaminergic neurons with the recovery of motor ability.

Introduction: The aim of the present study was to examine the frequency of self-reported sleep problems and their associated factors in a large cohort of PD patients. Methods: PD patients and controls, recruited from 35 centers of Spain from the COPPADIS cohort were included in this cross-sectional study. Sleep problems were assessed by the Spanish version of the Parkinson's disease Sleep Scale version 1 (PDSS-1). An overall score below 82 or a score below 5 on at least 1 item was defined as sleep problems. Results: The frequency of sleep problems was nearly double in PD patients compared to controls: 65.8% (448/681) vs 33.5% (65/206) (p < 0.0001). Mean total PDSS score was lower in PD patients than controls: 114.9 ± 28.8 vs 132.8 ± 16.3 (p < 0.0001). Quality of life (QoL) was worse in PD patients with sleep problems compared to those without: PDQ-39SI, 19.3 ± 14 vs 13 ± 11.6 (p < 0.0001); EUROHIS-QoL8, 3.7 ± 0.5 vs 3.9 ± 0.5 (p < 0.0001). Non-motor symptoms burden (NMSS; OR = 1.029; 95%CI 1.015–1.043; p < 0.0001) and impulse control behaviors (QUIP-RS; OR = 1.054; 95%CI 1.009–1.101; p = 0.018) were associated with sleep problems after adjustment for age, gender, disease duration, daily equivalent levodopa dose, H&Y, UPDRS-III, UPDRS-IV, PD-CRS, BDI-II, NPI, VAS-Pain, VAFS, FOGQ, and total number of non-antiparkinsonian treatments. Conclusion: Sleep problems were frequent in PD patients and were related to both a worse QoL and a greater non-motor symptoms burden in PD. These findings call for increased awareness of sleep problems in PD patients. [ABSTRACT FROM AUTHOR]

Tino Prell,1,2 Denise Schaller,1 Caroline Perner,1,3 Gabriele Helga Franke,4 Otto W Witte,1,2 Albrecht Kunze,1 Julian Grosskreutz1,2 1Department of Neurology, Jena University Hospital, Jena, Germany; 2Center for Healthy Aging, Jena University Hospital, Jena, Germany; 3Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, USA; 4University of Applied Sciences, Psychology of Rehabilitation, Stendal, Germany Purpose: Adherence to medication can be assessed by various self-report questionnaires. One could hypothesize that survey respondents tend to answer questions in a manner that will be viewed favorably by others. We aimed to answer if anonymous and nonanonymous responses to a questionnaire on medication adherence differ.Patients and methods: Adherence was assessed with the German Stendal Adherence with Medication Score (SAMS), which includes 18 questions with responses based on a 5-point Likert scale. Anonymous data from 40 subjects were collected during a symposium for patients with Parkinson’s disease (PD), and nonanonymous data were obtained from 40 outpatient-clinic PD patients at the Department of Neurology.Results: The two groups (anonymous self-reported questionnaire and nonanonymous) did not differ in terms of demographical characteristics and the SAMS sum score. However, anonymously collected data showed significant higher scoring for the item 6 (“Do you forget your medications?”) than the data collected nonanonymously (P=0.017). All other items of the SAMS did not significantly differ between both groups.Conclusion: Overall assessment of adherence does not depend on whether the patient remains anonymous or not. There seems to be no relevant social desirability bias in nonanonymous responses. Keywords: self-report, adherence questionnaire, Parkinson’s disease, anonymous, nonadherence

Cerebral deposition of abnormally aggregated α-synuclein (αSyn) is a neuropathological hallmark of Parkinson's disease (PD). PD-associated αSyn (αSynPD) aggregates can act as proteinaceous nuclei ("seeds") able of self-templated propagation. Since this is strikingly reminiscent to properties of proteinaceous infectious particles (prions), lessons learned from prion diseases suggest to test whether transferred αSynPD can propagate and induce neurological impairments or disease in a new host. Two studies that addressed this question provided divergent results. Intracerebral (i.c.) injection of Lewy body extracts from PD patients caused cerebral αSyn pathology, as well as nigrostriatal neurodegeneration, of wild-type mice and macaques, with the mice also showing motor impairments (Recasens et al. 2014, Ann Neurol 75:351–362). In contrast, i.c. transmission of homogenates from PD brains did not stimulate, after "> 360" days post-injection (dpi), pathological αSyn conversion or clinical symptoms in transgenic TgM83+/− mice hemizygously expressing mutated (A53T) human αSyn (Prusiner et al. 2015, PNAS 112:E5308–E5317). To advance the assessment of possible αSynPD hazards by providing further data, we examined neuropathological and clinical effects upon i.c. transmission of brain, stomach wall and muscle tissue as well as blood from PD patients in TgM83+/− mice up to 612 dpi. This revealed a subtle, yet distinctive stimulation of localized αSyn aggregation in the somatodendritic compartment and dystrophic neurites of individual or focally clustered cerebral neurons after challenge with brain and stomach wall homogenates. No such effect was observed with transmitted blood or homogenized muscle tissue. The detected stimulation of αSyn aggregation was not accompanied by apparent motor impairments or overt neurological disease in TgM83+/− mice. Our study substantiated that transmitted αSynPD seeds, including those from the stomach wall, are able to propagate in new mammalian hosts. The consequences of such propagation and potential safeguards need to be further investigated. [ABSTRACT FROM AUTHOR]

Background: Parkinson´s disease (PD) has a large phenotypic variability, which may, at least partly, be genetically driven including alterations of gene products. Candidates might not only be proteins associated with disease risk but also pathways that play a role in aging. Objective: To evaluate phenotype‐modifying effects of genetic variants in Klotho, a longevity gene. Methods: We analyzed two longitudinal cohorts: one local cohort comprising 459 PD patients who underwent genotyping for the KL‐VS haplotype in Klotho including a subgroup of 125 PD patients and 50 healthy controls who underwent biochemical cerebrospinal fluid (CSF) analyses of Klotho and fibroblast growth factor 23 as well as vitamin D metabolites. The second cohort comprised 297 patients from the Parkinsonʼs Progression Markers Initiative (PPMI) for validation of genetic−clinical findings. Results: PD patients carrying the KL‐VS haplotype demonstrated a shorter interval between PD onset and onset of cognitive impairment (both cohorts) and higher Unified Parkinson´s Disease Rating Scale part III (UPDRS III) scores (PPMI). CSF protein levels of Klotho and fibroblast growth factor 23 were lower in PD patients irrespective of gender compared to controls. Moreover, low CSF levels of Klotho were associated with higher scores in the UPDRS III and Hoehn and Yahr Scale. Conclusions: Our results indicate that genetic variants in Klotho together with its corresponding CSF protein profiles are associated with aspects of disease severity in PD. These findings suggest that pathways associated with aging might be targets for future biomarker research in PD. [ABSTRACT FROM AUTHOR]

Introduction: The subthalamic nucleus (STN) is known to be involved in the pathophysiology of Parkinson´s disease and by reducing its abnormal activity, normal output of basal ganglia can be restored along with improvement in PD cardinal motor features. Deep brain stimulation of the STN is currently the main surgical procedure for PD with motor complications, but lesioning can be an alternative. Areas covered: Here, the authors systematically review the current evidence regarding subthalamotomy both with radiofrequency and, more recently, with focused ultrasound (FUS) for the treatment of PD. Expert opinion: Unilateral subthalamotomy for the treatment of PD motor features can be considered a viable option in asymmetric patients, particularly with FUS which allows a minimally invasive safe and effective ablation of the STN. Risk of inducing dyskinesia (i.e., hemichorea/ballism) may be strikingly reduced when lesions enlarge dorsally to impinge on pallidothalamic fibers. [ABSTRACT FROM AUTHOR]

Parkinson's disease (PD) is characterized by a degeneration of nigrostriatal dopaminergic neurons that results in a hypercholinergic state in the striatum. This hypercholinergic state contributes to the clinical signs of PD. However, the mechanisms that underlie this state remain unknown. Cholinergic interneurons (ChIs) are the main source of acetylcholine in the striatum. Many studies have highlighted the importance of their normal physiological activity to guarantee a normal motor control and goal‐directed behaviour. Moreover, recent studies with optogenetic and chemogenetic approaches have shown that reducing ChIs activity ameliorates parkinsonian symptoms and modifies L‐dopa induced dyskinesia in PD animal models. Here, we review the described alterations in ChIs physiology that may contribute to a hypercholinergic state in PD. The best‐established finding is an increase of ChIs intrinsic membrane excitability after dopaminergic denervation of striatum. Understanding the molecular basis of ChIs dysfunction in PD could help to develop new therapeutic tools to restore their normal activity and decrease parkinsonian symptoms, improving life quality of PD patients. [ABSTRACT FROM AUTHOR]

The enzyme glutathione transferase M2-2, expressed in human astrocytes, increases its expression in the presence of aminochrome and catalyzes the conjugation of aminochrome, preventing its toxic effects. Secretion of the enzyme glutathione transferase M2-2 from U373MG cells, used as a cellular model for astrocytes, has been reported, and the enzyme is taken up by neuroblastoma SYSH-S7 cells and provide protection against aminochrome. The present study provides evidence that glutathione transferase M2-2 is released in exosomes from U373MG cells, thereby providing a means for intercellular transport of the enzyme. With particular relevance to Parkinson disease and other degenerative conditions, we propose a new mechanism by which astrocytes may protect dopaminergic neurons against the endogenous neurotoxin aminochrome. [ABSTRACT FROM AUTHOR]

Abstract Introduction Bradyphrenia is a key cognitive feature in Parkinson's disease (PD). There is no consensus on whether information processing speed is impaired or not beyond motor performance. Objective This study aims to explore which perceptual, motor, or cognitive components of information processing are involved in the slowdown affecting cognitive performance. Methods The study included 48 patients with PD (age: 63, 3 ± 8, 18; HY I‐III; UPDRS 15,46 ± 7,76) and 53 healthy controls (age: 60,09 ± 12,83). Five reaction time (RT) tasks were administered to all participants. The average RT in each of the tasks and the percentage of correct answers were measured. Patients with PD were in "ON state" at the time of the evaluation. Perceptual, motor, and cognitive components were isolated by means of a series of ANCOVAs. Results As expected, the motor component was slowed down in patients with PD. Moreover, while patients with PD showed slower RT than controls in all tasks, differences between groups did not exponentially increase with the increasing task complexity. ANCOVA analyses also revealed that the perceptual and sustained alert component resulted to be slowed down, with no differences being found in any of the remaining isolated cognitive components (i.e., response strategy‐inhibition, decisional, visual search, or interference control). Conclusions The results revealed that slowness of information processing in PD was mainly associated with an impaired processing speed of the motor and perceptual‐alertness components analyzed. The results may help designing new neurorehabilitation strategies, focusing on the improvement of perceptual and alertness mechanisms.

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.

A contribution of α‐Synuclein (α‐Syn) to etiology of Parkinson´s disease (PD) and Dementia with Lewy bodies (DLB) is currently undisputed, while the impact of the closely related β‐Synuclein (β‐Syn) on these disorders remains enigmatic. β‐Syn has long been considered to be an attenuator of the neurotoxic effects of α‐Syn, but in a rodent model of PD β‐Syn induced robust neurodegeneration in dopaminergic neurons of the substantia nigra. Given that dopaminergic nigral neurons are selectively vulnerable to neurodegeneration in PD, we now investigated if dopamine can promote the neurodegenerative potential of β‐Syn. We show that in cultured rodent and human neurons a dopaminergic neurotransmitter phenotype substantially enhanced β‐Syn‐induced neurodegeneration, irrespective if dopamine is synthesized within neurons or up‐taken from extracellular space. Nuclear magnetic resonance interaction and thioflavin‐T incorporation studies demonstrated that dopamine and its oxidized metabolites 3,4‐dihydroxyphenylacetaldehyde (DOPAL) and dopaminochrome (DCH) directly interact with β‐Syn, thereby enabling structural and functional modifications. Interaction of DCH with β‐Syn inhibits its aggregation, which might result in increased levels of neurotoxic oligomeric β‐Syn. Since protection of outer mitochondrial membrane integrity prevented the additive neurodegenerative effect of dopamine and β‐Syn, such oligomers might act at a mitochondrial level similar to what is suggested for α‐Syn. In conclusion, our results suggest that β‐Syn can play a significant pathophysiological role in etiology of PD through its interaction with dopamine metabolites and thus should be re‐considered as a disease‐relevant factor, at least for those symptoms of PD that depend on degeneration of nigral dopaminergic neurons. [ABSTRACT FROM AUTHOR]

Introduction: Bradyphrenia is a key cognitive feature in Parkinson's disease (PD). There is no consensus on whether information processing speed is impaired or not beyond motor performance. Objective: This study aims to explore which perceptual, motor, or cognitive components of information processing are involved in the slowdown affecting cognitive performance. Methods: The study included 48 patients with PD (age: 63, 3 ± 8, 18; HY I‐III; UPDRS 15,46 ± 7,76) and 53 healthy controls (age: 60,09 ± 12,83). Five reaction time (RT) tasks were administered to all participants. The average RT in each of the tasks and the percentage of correct answers were measured. Patients with PD were in "ON state" at the time of the evaluation. Perceptual, motor, and cognitive components were isolated by means of a series of ANCOVAs. Results: As expected, the motor component was slowed down in patients with PD. Moreover, while patients with PD showed slower RT than controls in all tasks, differences between groups did not exponentially increase with the increasing task complexity. ANCOVA analyses also revealed that the perceptual and sustained alert component resulted to be slowed down, with no differences being found in any of the remaining isolated cognitive components (i.e., response strategy‐inhibition, decisional, visual search, or interference control). Conclusions: The results revealed that slowness of information processing in PD was mainly associated with an impaired processing speed of the motor and perceptual‐alertness components analyzed. The results may help designing new neurorehabilitation strategies, focusing on the improvement of perceptual and alertness mechanisms. [ABSTRACT FROM AUTHOR]

The medical procedures for disease diagnostics are significantly demanding and time-consuming. Data mining methods can accelerate this process and assist doctors in making decisions in complex situations. In case of Parkinson´s disease (PD), the diagnostics of the initial disease stage is the primary issue since the symptoms are not so unambiguous and easily observable. Therefore, this article is focused on determining the actual stage of PD based on the data recording signals of patient´s speech using decision trees (C4.5, C5.0 and CART). Methods such as RandomForest, Bagging and Boosting were also employed to improve the existing classification models. Estimation of model accuracy was achieved by using k-fold cross-validation and validation with omission of one record (Leave-one-out). In addition, experiments were also performed to remove collinearity in data by computing the Variance inflation factor (VIF) in order to increase the accuracy of the models.

Abstract The combination of genetics and genomics in Parkinson´s disease has recently begun to unveil molecular mechanisms possibly underlying disease onset and progression. In particular, catabolic processes such as autophagy have been increasingly gaining relevance as post-mortem evidence and experimental models suggested a participation in neurodegeneration and alpha-synuclein Lewy body pathology. In addition, familial Parkinson´s disease linked to LRRK2 and alpha-synuclein provided stronger correlation between etiology and alterations in autophagy. More detailed cellular pathways are proposed and genetic risk factors that associate with idiopathic Parkinson´s disease provide further clues in dissecting contributions of single players. Nevertheless, the fine-tuning of these processes remains elusive, as the initial stages of the pathways are not yet clarified. In this review, we collect literature evidence pointing to autophagy as the common, downstream target of Parkinsonian dysfunctions and augment current knowledge on the factors that direct the subsequent steps. Cell and molecular biology evidence indicate that p38 signaling underlies neurodegeneration and autoptic observations suggest a participation in neuropathology. Moreover, alpha-synuclein and LRRK2 also appear involved in the p38 pathway with additional roles in the regulation of GTPase signaling. Small GTPases are critical modulators of p38 activation and thus, their functional interaction with aSyn and LRRK2 could explain much of the detailed mechanics of autophagy in Parkinson´s disease. We propose a novel hypothesis for a more comprehensive working model where autophagy is controlled by upstream pathways, such as GTPase-p38, that have been so far underexplored in this context. In addition, etiological factors (LRRK2, alpha-synuclein) and risk loci might also combine in this common mechanism, providing a powerful experimental setting to dissect the cause of both familial and idiopathic disease.

Background: The presence of subjective cognitive complaints (SCC) as a predictor of cognitive impairment in Parkinson´s disease (PD) has shown conflicting results. Most previous studies only assessed complaints in the memory domain. We investigate the association of SCCs across cognitive domains with development of mild cognitive impairment (PD‐MCI) and dementia (PDD) in PD and to assess agreement between SCCs and objective cognitive impairments in this population. Methods: This is a retrospective analysis of a prospective cohort study. Participants were enrolled at six North‐American movement disorders centers. They underwent neuropsychological and non‐cognitive clinical evaluations, including the modified Neurobehavioral Inventory to elicit SCC (rated by each patient and independently by their close contact (CC)). Associations between SCCs and development of future cognitive impairment were assessed. Agreement between SCCs and objective impairment within the same domain was also calculated. Results: Of 138 included PD patients, 42% fulfilled criteria for PD‐MCI. None of the NBI items predicted development of cognitive impairment after one and two years in PD with normal cognition. In PD‐MCI patients, SCCs related to attention predicted dementia at year one. CC ratings of SCCs related to memory and language problems predicted PDD in PD‐MCI patients. According to CC reported patients' complaints, there was a significant agreement between SCCs and objective cognitive test scores on attention. Conclusions: Eliciting SCCs including cognitive domains other than memory is crucial for a complete evaluation, including both patient and CC report. Memory, language, and especially attention SCCs in PD‐MCI may predict progression to dementia. [ABSTRACT FROM AUTHOR]

Background and Purpose: l-DOPA-induced dyskinesia (LID) is considered a major complication in the treatment of Parkinson's disease (PD). Buspirone (5-HT1A partial agonist) have shown promising results in the treatment of PD and LID, however no 5-HT-based treatment has been approved in PD. The present study was aimed to investigate how the substantia nigra pars reticulata (SNr) is affected by buspirone and whether it is a good target to study 5-HT antidyskinetic treatments.Experimental Approach: Buspirone was studied using in vivo single-unit, electrocorticogram, local field potential recordings along with microdialysis and immunohistochemistry in naïve/sham, 6-hydroxydopamine (6-OHDA)-lesioned or 6-OHDA-lesioned and l-DOPA-treated (6-OHDA/l-DOPA) rats.Key Results: Local buspirone inhibited SNr neuron activity in all groups. However, systemic buspirone reduced burst activity in 6-OHDA-lesioned rats (with or without l-DOPA treatment), whereas 8-OH-DPAT, a full 5-HT1A agonist induced larger inhibitory effects in sham animals. Neither buspirone nor 8-OH-DPAT markedly modified the low-frequency oscillatory activity in the SNr or synchronization within the SNr with the cortex. In addition, local perfusion of buspirone increased GABA and glutamate release in the SNr of naïve and 6-OHDA-lesioned rats but no effect in 6-OHDA/l-DOPA rats. In the 6-OHDA/l-DOPA group, increased 5-HT transporter and decreased 5-HT1A receptor expression was found.Conclusions and Implications: The effects of buspirone in SNr are influenced by dopamine loss and l-DOPA treatment. The present results suggest that the regulation of burst activity of the SNr induced by DA loss may be a good target to test new drugs for the treatment of PD and LID. [ABSTRACT FROM AUTHOR]