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Pregabalin is an anti-epileptic drug approved for the treatment of neuropathic pain and focal-onset seizures. In a few cases, pregabalin was associated with parkinsonism. We present a case of a 48-year-old female who had hypertension and was on losartan 50 mg/daily. Her general practitioner prescribed pregabalin 150 mg/daily for fibromyalgia-related pain. The subject doubled the dosage without medical advice. After 5 days of the increased dosage, she started to experience difficulty and slowness in movement associated with resting tremors. Neuroimaging, electrodiagnostic studies, and laboratory exams were unremarkable. Secondary parkinsonism was suspected, so pregabalin was discontinued. The subject fully recovered within 7 days. To the authors' knowledge, only 6 cases of pregabalin-induced parkinsonism were reported in the literature. Pregabalin discontinuation was the most common management. All individuals fully recovered after pregabalin withdrawal. The mechanism of pregabalin-induced parkinsonism is not fully understood. [ABSTRACT FROM AUTHOR]

Neurodegenerative disorder refers to malfunctioning of neurons their degradation leading to death of neurons. Among various neurodegenerative disorders APHD (Alzheimer's, Parkinson's, and Huntington's Disease) are particularly concerning due to their progressive and debilitating nature. The therapeutic agent used for treatment and management of APHD often show unsatisfactory clinical outcome owing to poor solubility and limited permeability across blood brain barrier (BBB). The nose-to brain delivery can overcome this BBB challenge as it can transport drug directly to brain though olfactory pathways bypassing BBB. Additionally, the nanotechnology has emerged as a cutting-edge methodology to address this issue and specifically mucoadhesive micro/nanoemulsion can improve the overall performance of the drug when administered intranasally. Beyond the therapy neurotechnology has emerged as are revolutionary AI-driven BCI (Brain computer interface) aimed to restore independence in patients with function loss due to neuron degeneration/death. A promising BCI Neuralink has been recently explored for clinical trials and results revealed that a quadriplegia bearing person with implanted Neuralink chip was able to perform few normal functions of daily routine such as playing online games, text messaging, reading, and learning foreign languages online through accessing the particular websites. This review will discuss the fundamental concepts of neurodegeneration, application of micro/nanoemulsion through intranasal route and integration of neurotechnology for the management and treatment of APHD. [ABSTRACT FROM AUTHOR]

Numerous challenges hinder the development of neuroprotective treatments for Parkinson's disease, with a regularly identified issue being the lack of clinically relevant animal models. Viral vector overexpression of α‐synuclein is widely considered the most relevant model; however, this has been limited by high variability and inconsistency. One potential method of optimisation is pairing it with a secondary insult such as FN075, a synthetic molecule demonstrated to accelerate α‐synucleinopathy. Thus, the aim of this study was to investigate if sequential infusion of adeno‐associated virus (AAV)‐α‐synuclein and FN075 into the rat brain can replicate α‐synucleinopathy, nigrostriatal pathology and motor dysfunction associated with Parkinson's disease. Rats received a unilateral injection of AAV‐α‐synuclein (or AAV‐green fluorescent protein) into two sites in the substantia nigra, followed 4 weeks later by unilateral injection of FN075 (or vehicle) into the striatum. Animals underwent behavioural testing every 4 weeks until sacrifice at 20 weeks, followed by immunohistochemistry assessment post‐mortem. As anticipated, AAV‐α‐synuclein led to extensive overexpression of human α‐synuclein throughout the nigrostriatal pathway, as well as elevated levels of phosphorylated and aggregated forms of the protein. However, the sequential administration of FN075 into the striatum did not exacerbate any of the α‐synuclein pathology. Furthermore, despite the extensive α‐synuclein pathology, neither administration of AAV‐α‐synuclein nor FN075, alone or in combination, was sufficient to induce dopaminergic degeneration or motor deficits. In conclusion, this approach did not replicate the key characteristics of Parkinson's disease, and further studies are required to create more representational models for testing of novel compounds and treatments for Parkinson's disease. [ABSTRACT FROM AUTHOR]

Understanding what matters to people with Parkinson's and their family is essential to derive relevant clinical outcome measures and guide clinical care. The purpose of this study was to explore what is important to people with Parkinson's disease vs. family over time. A qualitative content-analysis of online survey data collected by Parkinson's UK was conducted to identify types and frequencies of important symptoms and impacts of Parkinson's for people with the disease vs. family of people with Parkinson's. Independent T-tests were used to identify significance of between group differences for patients vs. family at < 2, 2–5, 6–10, 11–20, > 20-year durations. ANOVA was used to assess for within group differences by disease duration. We found that symptom priority changed significantly over time with longer disease duration. Tremor was reported less often later on, whereas mobility, dyskinesias, gait and speech/communication symptoms gained priority. In general, patients identified movement-related symptoms (e.g., walking, bradykinesia) as the most bothersome at all durations while family more strongly prioritized the physical and psychosocial impacts of disease (e.g., mobility, safety, interpersonal interactions, independence, and family impact). We conclude that important differences exist between family and patient perspectives of what matters and change over time with longer duration of disease. [ABSTRACT FROM AUTHOR]

Glucocerebrosidase (GBA1) variants constitute numerically the most common known genetic risk factor for Parkinson's disease (PD) and are distributed worldwide. Access to GBA1 genotyping varies across the world and even regionally within countries. Guidelines for GBA1 variant counseling are evolving. We review the current knowledge of the link between GBA1 and PD, and discuss the practicalities of GBA1 testing. Lastly, we provide a consensus for an approach to counseling people with GBA1 variants, notably the communication of PD risk. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society. [ABSTRACT FROM AUTHOR]

AbstractPurposeMaterials and methodsResultsConclusionsThe lockdown and social distancing measures introduced as a result of the COVID-19 pandemic impacted the ability of people with Parkinson’s to engage in normal health management practices. This led to documented reductions in psychological wellbeing. The aim of the present review was to identify factors associated with the psychological wellbeing of people with Parkinson’s during the acute stage of the pandemic.Five academic databases (PsycINFO, MEDLINE, Embase, CINAHL, and Web of Science) were searched and 23 articles were identified using pre-defined inclusion and exclusion criteria. The findings are stratified by risk factor and analysed using a narrative synthesis.Worsening of motor symptoms, poor motor-related daily living experiences and motor symptoms during “off time” (when symptom suppressing medication has worn off) as well as less physical activity emerged as the most consistent risk factors of worsened or poorer psychological wellbeing. A deviation from pre-pandemic risk factors was identified, with age and gender not identified as consistent risk factors.The implications of this review are not limited to preparing for future pandemics but can also be applied to more common concerns with comparable contextual characteristics such as yearly flu outbreaks, social isolation, and economic uncertainty. [ABSTRACT FROM AUTHOR]

Background: Parkinson's disease (PD), a prevalent neurodegenerative condition affecting more than seven million individuals globally, manifests through the loss of dopaminergic neurons, leading to diverse motor and non-motor symptoms. This comprehensive review aims to explore PD's multifaceted nature, covering its introduction, prevalence patterns, pathophysiology, diagnostic challenges, and varied treatment strategies. Genetic and environmental influences on prevalence, brain region degeneration, Lewy body formation, and early-stage diagnostic difficulties are key focus areas. The review emphasizes the necessity of personalized approaches, innovative clinical criteria-, and subtype categorizations for effective management. Objective: This review aims to provide a holistic understanding of Parkinson's disease, contributing to improved insights for both individuals and healthcare professionals. By consolidating knowledge on PD's various facets, it seeks to facilitate informed decision-making for better management and enhanced quality of life. Methods: A thorough review of research literature, including studies, trials, and historical perspectives, was done. It covers prevalence, causes, diagnosis, and treatment options, including both traditional and herbal remedies, alongside conventional approaches. Results: The review reveals the complex interplay of genetic predisposition, environmental factors, and the neurodegenerative mechanisms underlying PD. It underscores the challenges of early-stage diagnosis and the wide array of treatment options available, emphasizing the need for personalized care. Conclusion: Understanding Parkinson's disease in its entirety is crucial for effective management. By presenting a comprehensive overview, this review advocates for a holistic approach, integrating diverse treatments and individualized strategies, thereby offering valuable guidance for improved quality of life in PD patients. [ABSTRACT FROM AUTHOR]

Parkinson's disease is a neurological disorder characterized by motor and non-motor symptoms. Assessment methods, despite the many years of existence of the disease, lack individualized visualization. On the other hand, virtual reality promises immersion and realism. In this paper, we develop an integrated system for visualizing the gestures of Parkinson's disease patients in a virtual reality environment. With this application, clinicians will have information about the unique motor patterns and challenges they must address in each individual patient's case, while the collected data can travel and be easily and instantly visualized in any location. At the beginning of this research, the current terms of immersive technologies in conjunction with data visualization and Parkinson's disease are described. Through an extensive systematic literature review, the technological developments in the field of Parkinson's data visualization are presented. The findings of the review lead to the experimental procedure and implementation of the application. The conclusions drawn from this work fuel future extensions on the contribution of immersive technologies to various diseases. [ABSTRACT FROM AUTHOR]

The purpose of this study was to examine teaching strategies utilized by instructors within a dance class for individuals with Parkinson’s, and to describe ways in which dancers respond to the teaching strategies utilized; both through the lens of physical literacy. Dance instructors offer important insight into the content design and facilitation of these classes for individuals with Parkinson’s so they can experience the physical, psychological, and social benefits of dancing. Observations of nine dance classes (occurring online and via hybrid format) were conducted. Data was analyzed using reflexive thematic analysis and five themes were created: (1) Tuning in and connecting dancers with their bodies; (2) Creating a fun, low-pressure, and responsive environment; (3) Designing opportunities for dancers to be creative during class; (4) Overcoming challenges and feeling successful; (5) Connecting and dancing together. Dance classes led by adaptable, encouraging, and responsive instructors offer joyful and motivating dancing experiences for individuals with Parkinson’s. These findings paint a picture of specific pedagogical strategies and behaviours utilized by dance instructors to support expressions of physical literacy within classes for individuals with Parkinson’s. [ABSTRACT FROM AUTHOR]

Aim: Neurological manifestations are common in patients with chronic liver diseases. This study aimed to depict the association between liver cirrhosis and Parkinson's disease (PD) and propose a clinically relevant diagnostic scheme. Methods: We examined patients' medical records with PD and chronic liver impairment secondary to cirrhosis or liver metastases for temporal correlations between liver insult and Parkinsonian signs. Results: Thirty-five individuals with PD and chronic liver impairment were included due to either cirrhosis or liver metastases. In all 22 patients with PD and liver metastases, the diagnosis of PD preceded the diagnosis of cancer. Conversely, patients with cirrhosis were often diagnosed with liver impairment before diagnosing PD. Age at diagnosis did not account for this difference. Conclusions: This study reinforces the potential clinical association between cirrhosis and PD. We also provide a diagnostic scheme that may guide therapeutic interventions and prognostic assessments. [ABSTRACT FROM AUTHOR]

Chronic sialorrhea is a condition characterized by excessive drooling, often associated with neurological and neuromuscular disorders such as Parkinson's disease, cerebral palsy, and stroke. Despite its prevalence, it remains underdiagnosed and poorly understood, leading to a lack of comprehensive data on patient demographics, clinical characteristics, and treatment patterns. This study aimed to help fill these existing gaps by analyzing real-world data using Optum's de-identified Clinformatics® Data Mart Database. Patients were required to have a diagnosis indicative of sialorrhea plus evidence of sialorrhea treatment between 1/1/2007 and 5/31/2022. Two cohorts were analyzed: patients with evidence of newly diagnosed sialorrhea and associated treatment, and sialorrhea patients initiating incobotulinumtoxinA. Clinical characteristics, comorbidities, symptoms, and treatment utilization were described before and after diagnosis and incobotulinumtoxinA initiation. No formal statistical comparisons were performed. Patients were predominantly aged 65 or older, male, and non-Hispanic white. Parkinson's disease and cerebral palsy were the most common comorbidities among adults and children, respectively. Treatment patterns suggest that anticholinergics are more commonly used than botulinum toxin therapy. The findings offer valuable information for improving diagnosis and treatment approaches and suggest a need for further research into treatment effectiveness, safety, and disease burden. [ABSTRACT FROM AUTHOR]

Melanin is a crucial pigment in melanomagenesis. Its fluorescence in human tissue is exceedingly weak but can be detected through advanced laser spectroscopy techniques. The spectral profile of melanin fluorescence distinctively varies among melanocytes, nevomelanocytes, and melanoma cells, with melanoma cells exhibiting a notably "red" fluorescence spectrum. This characteristic enables the diagnosis of melanoma both in vivo and in histological samples. Neuromelanin, a brain pigment akin to melanin, shares similar fluorescence properties. Its fluorescence can also be quantified with high spectral resolution using the same laser spectroscopic methods. Documented fluorescence spectra of neuromelanin in histological samples from the substantia nigra substantiate these findings. Our research reveals that the spectral behavior of neuromelanin fluorescence mirrors that of melanin in melanomas. This indicates that the typical red fluorescence is likely influenced by the microenvironment around (neuro)melanin, rather than by direct pigment interactions. Our ongoing studies aim to further explore this distinctive "red" fluorescence. We have observed this red fluorescence spectrum in post-mortem measurements of melanin in benign nevus. The characteristic red spectrum is also evident here (unlike the benign nevus in vivo), suggesting that hypoxia may contribute to this phenomenon. Given the central role of hypoxia in both melanoma development and treatment, as well as in fundamental Parkinson's disease mechanisms, this study discusses strategies aimed at reinforcing the hypothesis that red fluorescence from (neuro)melanin serves as an indicator of hypoxia. [ABSTRACT FROM AUTHOR]

Following reports of low striatal dopamine content in Parkinson's disease, levodopa was shown to rapidly reverse hypokinesis, establishing the model of disease as one of dopamine deficiency. Dopaminergic therapy became standard of care, yet it failed to reverse the disease, suggesting the understanding of disease was incomplete. The literature suggests the potential for toxicity of dopamine and its metabolites, perhaps more relevant given the recent evidence for elevated cytosolic dopamine levels in the dopaminergic neurons of people with Parkinson's. To understand the relevance of these data, multiple investigations are reviewed that tested dopamine reduction therapy as an alternative to dopaminergic agents. The data from use of an inhibitor of dopamine synthesis in experimental models suggest that such an approach could reverse disease pathology, which suggests that cytosolic dopamine excess is a primary driver of disease. These data support clinical investigation of dopamine reduction therapy for Parkinson's disease. Doing so will determine whether these experimental models are predictive and this treatment strategy is worth pursuing further. If clinical data are positive, it could warrant reconsideration of our disease model and treatment strategies, including a shift from dopaminergic to dopamine reduction treatment of the disease. [ABSTRACT FROM AUTHOR]

Abstract Understanding what matters to people with Parkinson’s and their family is essential to derive relevant clinical outcome measures and guide clinical care. The purpose of this study was to explore what is important to people with Parkinson’s disease vs. family over time. A qualitative content-analysis of online survey data collected by Parkinson’s UK was conducted to identify types and frequencies of important symptoms and impacts of Parkinson’s for people with the disease vs. family of people with Parkinson’s. Independent T-tests were used to identify significance of between group differences for patients vs. family at 20-year durations. ANOVA was used to assess for within group differences by disease duration. We found that symptom priority changed significantly over time with longer disease duration. Tremor was reported less often later on, whereas mobility, dyskinesias, gait and speech/communication symptoms gained priority. In general, patients identified movement-related symptoms (e.g., walking, bradykinesia) as the most bothersome at all durations while family more strongly prioritized the physical and psychosocial impacts of disease (e.g., mobility, safety, interpersonal interactions, independence, and family impact). We conclude that important differences exist between family and patient perspectives of what matters and change over time with longer duration of disease.

Background and Objectives: Parkinson disease (PD), which is a neurodegenerative disorder, includes several gastrointestinal symptoms that are similar to those of Celiac disease (CD). However, the presence of celiac antibodies in PD patients has not yet been studied. Our aim in this study is to compare anti-transglutaminase (ATA) and antigliadin antibodies (AGA) as well as gastrointestinal symptoms and nutrition habits between patients with Parkinson's disease (PD) and healthy controls. Methods and Study Design: Serum AGA IgG and IgA and the ATA antibodies IgA and IgG were studied in 102 PD patients and 91 healthy controls. Gastrointestinal symptoms, specifically constipation, were investigated using the gastrointestinal system rating scale (GSRS) and the constipation rating scale (CRS). Dietary habits were also investigated and compared between the groups. Results: No significant differences were found between the two groups in terms of celiac antibodies. As expected, the hypokinetic GSRS and CRS scores were significantly higher in the PD group (p<0.001). Dietary habits, especially carbohydrate-rich diets, had a negative impact on gastrointestinal symptoms in the PD patients. Conclusions: Studies have suggested a connection between PD and CD, which infers a probable non-celiac gluten intolerance and the need to offer PD patients an elimination diet. However, the results of our study did not support any link between celiac antibodies and PD. Notwithstanding, the negative impact of a carbohydrate-rich diet in PD patients still leaves a question regarding gluten sensitivity in these patients. [ABSTRACT FROM AUTHOR]

Aim: Neurological manifestations are common in patients with chronic liver diseases. This study aimed to depict the association between liver cirrhosis and Parkinson’s disease (PD) and propose a clinically relevant diagnostic scheme. Methods: We examined patients’ medical records with PD and chronic liver impairment secondary to cirrhosis or liver metastases for temporal correlations between liver insult and Parkinsonian signs. Results: Thirty-five individuals with PD and chronic liver impairment were included due to either cirrhosis or liver metastases. In all 22 patients with PD and liver metastases, the diagnosis of PD preceded the diagnosis of cancer. Conversely, patients with cirrhosis were often diagnosed with liver impairment before diagnosing PD. Age at diagnosis did not account for this difference. Conclusions: This study reinforces the potential clinical association between cirrhosis and PD. We also provide a diagnostic scheme that may guide therapeutic interventions and prognostic assessments.

Abstract Background Dyspnea is considered a silent threat to people diagnosed with Parkinson’s disease and may be a common concern in patients, however, little is known about how it affects quality of life. This study explored the experiences of independently mobile people who are affected by dyspnea in daily life. Methodology This was a cross-sectional mixed methods study that included an online questionnaire and semi-structured interviews. The participants were included if they were diagnosed with Parkinson’s disease; had a self-reported Hoehn and Yahr Score I, II or III; were mobilizing independently; and were Arabic speakers. Participants were excluded if they had any other musculoskeletal, cardiac, respiratory, or neurological diseases; or were previous or current smokers; or had been previously hospitalized due to respiratory complications. Results A total of 117 participants completed the Arabic version of the Dyspnea-12 Questionnaire. Dyspnea was reported in all participants and that it had an adverse effect on their quality of life, especially during activities of daily living. Additionally, participants reported a lack of knowledge about pulmonary rehabilitation and were unaware of the availability and potential benefits of participation in programs. Conclusion Dyspnea was reported in people in the early stages (Hoehn and Yahr Stages I, II, and III) of Parkinson’s disease, and may benefit from routine assessment of lung function, dyspnea management and participation in pulmonary rehabilitation.

Abstract Background Parkinson’s disease is characterized by dopamine-responsive symptoms as well as aggregation of α-synuclein protofibrils. New diagnostic methods assess α-synuclein aggregation characteristics from cerebrospinal fluid (CSF) and recent pathophysiologic mechanisms suggest that CSF circulation disruptions may precipitate α-synuclein retention. Here, diffusion-weighted MRI with low-to-intermediate diffusion-weightings was applied to test the hypothesis that CSF motion is reduced in Parkinson’s disease relative to healthy participants. Methods Multi-shell diffusion weighted MRI (spatial resolution = 1.8 × 1.8 × 4.0 mm) with low-to-intermediate diffusion weightings (b-values = 0, 50, 100, 200, 300, 700, and 1000 s/mm2) was applied over the approximate kinetic range of suprasellar cistern fluid motion at 3 Tesla in Parkinson’s disease (n = 27; age = 66 ± 6.7 years) and non-Parkinson’s control (n = 32; age = 68 ± 8.9 years) participants. Wilcoxon rank-sum tests were applied to test the primary hypothesis that the noise floor-corrected decay rate of CSF signal as a function of b-value, which reflects increasing fluid motion, is reduced within the suprasellar cistern of persons with versus without Parkinson’s disease and inversely relates to choroid plexus activity assessed from perfusion-weighted MRI (significance-criteria: p

The synaptojanin-1 (SYNJ1) gene is known to be important for dopamine-related disorders. Recent evidence has demonstrated that Synj1 deficient mice (Synj1+/-) have impairments in dopaminergic synaptic vesicular recycling. However, less is known about how Synj1 deficits affect the mesolimbic system, reward processing, and motivated behavior. To examine the role of the Synj1 gene in motivated behavior, we subjected male and female Synj1+/- and Synj1+/+ mice to a battery of behavioral tests evaluating hedonic responses, effortful responding, and responses to psychomotor stimulants. We observed that Synj1+/- mice exhibit few differences in reward processing and motivated behavior, with normal hedonic responses and motivated responding for sucrose. However, male but not female Synj1+/- demonstrated an attenuated conditioned place preference for cocaine that could not be attributed to deficits in spatial memory. To further understand the dopamine signaling underlying the attenuated response to cocaine in these mutant mice, we recorded nucleus accumbens dopamine in response to cocaine and observed that Synj1+/- male and female mice took longer to reach peak dopamine release following experimenter-administered cocaine. However, female mice also showed slower decay in accumbens dopamine that appear to be linked to differences in cocaine-induced DAT responses. These findings demonstrate that SYNJ1 deficiencies result in abnormal mesolimbic DA signaling which has not previously been demonstrated. Our work also highlights the need to develop targeted therapeutics capable of restoring deficits in DAT function, which may be effective for reversing the pathologies associated with Synj1 mutations. [ABSTRACT FROM AUTHOR]

Background: For the past five years, our annual reports have been tracking the clinical development of new drug-based therapies for the neurodegenerative condition of Parkinson's disease (PD). These reviews have followed the progress both of "symptomatic treatments" (ST – improves/reduces symptoms of the condition) and "disease-modifying treatments" (DMT – attempts to delay/slow progression by addressing the underlying biology of PD). Efforts have also been made to further categorize these experimental treatments based on their mechanisms of action and class of drug. Methods: A dataset of clinical trials for drug therapies in PD using trial data downloaded from the ClinicalTrials.gov online registry was generated. A breakdown analysis of all the studies that were active as of January 31st, 2024, was conducted. This analysis involved categorizing the trials based on both the mechanism of action (MOA) and the drug target. Results: There were 136 active Phase 1–3 trials evaluating drug therapies for PD registered on ClinicalTrials.gov, as of January 31, 2024. Of these trials, 76 (56%) were classified as ST trials and 60 (44%) were designated DMT. More than half (58%) of the trials were in Phase 2 testing stage, followed by Phase 1 (30%) and Phase 3 (12%). 35 of the trials were registered since our last report, with the remaining 101 trials appearing in at least one earlier report. Conclusions: The drug development pipeline for PD remains in a robust state with a wide variety of approaches being developed and evaluated in Phase 1 and 2. Yet again, however, only a limited number of DMTs are transitioning to Phase 3. Plain Language Summary: The development of new medical therapies, particularly for neurodegenerative conditions, is a long process that involves multiple phases of testing before a treatment is approved for use in a doctor's clinic. The first phase assesses the short-term safety of a drug – most often in healthy volunteers but sometimes in people affected by the disease. The second phase explores the short-term safety and preliminary efficacy of the agent in people affected by the disease of interest, and the third phase investigates long-term safety and efficacy in a large group of people affected by the disease. For a disease like Parkinson's disease, where the causes of the condition are not well understood, drugs targeting different biological pathways need to be tested to determine which ones may be useful in treating the symptoms, and which could be administered to slow down or stop the progression of the condition. Here, we provide an annual report on the current landscape of both these clinical testing efforts. In total, we reviewed 136 active studies evaluating therapies for Parkinson's disease registered on a clinical trial database called 'ClinicalTrials.gov'. Of these trials, approximately 55% were testing experimental symptomatic treatments, while the rest were focused on slowing down disease progression. More than half (58%) of the studies were in the second phase of clinical testing (short-term safety and preliminary efficacy), but only three studies were found to be testing treatments to stop the progression of Parkinson's in the Phase 3 testing. We concluded that the drug development pipeline for Parkinson's is robust, but more progress needs to be made with late-stage testing of treatments to slow the disease. [ABSTRACT FROM AUTHOR]

Background: People with Parkinson's disease (PD) have an increased risk of dementia, yet patients and clinicians frequently avoid talking about it due to associated stigma, and the perception that "nothing can be done about it". However, open conversations about PD dementia may allow people with the condition to access treatment and support, and may increase participation in research aimed at understanding PD dementia. Objectives: To co‐produce information resources for patients and healthcare professionals to improve conversations about PD dementia. Methods: We worked with people with PD, engagement experts, artists, and a PD charity to open up these conversations. 34 participants (16 PD; 6 PD dementia; 1 Parkinsonism, 11 caregivers) attended creative workshops to examine fears about PD dementia and develop information resources. 25 PD experts contributed to the resources. Results: While most people with PD (70%) and caregivers (81%) shared worries about cognitive changes prior to the workshops, only 38% and 30%, respectively, had raised these concerns with a healthcare professional. 91% of people with PD and 73% of caregivers agreed that PD clinicians should ask about cognitive changes routinely through direct questions and perform cognitive tests at clinic appointments. We used insights from the creative workshops, and input from a network of PD experts to co‐develop two open‐access resources: one for people with PD and their families, and one for healthcare professionals. Conclusion: Using artistic and creative workshops, co‐learning and striving for diverse voices, we co‐produced relevant resources for a wider audience to improve conversations about PD dementia. [ABSTRACT FROM AUTHOR]

Background Excessive daytime sleepiness (EDS) is one of the most frequent nonmotor symptoms in Parkinson's disease (PD); however, the pathogenesis of EDS is unclear, and there is a lack of information on plasma biomarkers for EDS in PD. We aimed to investigate the plasma biomarkers of EDS in a large PD cohort. Methods A total of 159 PD patients were included in the prospective cohort study and followed up annually for 3 years. Plasma biomarkers including glial fibrillary acidic protein, amyloid-beta, p-tau181, and neurofilament light chain (NfL), were measured using an ultrasensitive single-molecule array (Simoa) technology at each visit. EDS was evaluated using the Epworth Sleepiness Scale (ESS). Results The frequency of EDS in PD increased from 15.1% at baseline to 25.0% after 3 years. The mean ESS scores increased from 5.1 (standard deviation [ SD ]: 4.8) at baseline to 6.1 (SD : 5.5) at the third year of follow-up. At baseline, compared with patients with PD without EDS, those with EDS were more likely to be male, had poorer cognitive performance, and more severe motor and nonmotor symptoms. The adjusted generalized estimating equations models showed that higher plasma NfL levels (OR: 1.047 [1.002–1.094], p  = .042) were associated with EDS during follow-ups. The adjusted linear mixed-effects model showed that higher plasma NfL levels (β 0.097 [0.012–0.183], p  = .026) were associated with ESS scores during follow-ups. Conclusions Higher plasma NfL levels were associated with EDS in PD, indicating an association between neuro-axonal degeneration and EDS in PD. [ABSTRACT FROM AUTHOR]

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Objectives: The purpose of this retrospective study is to further the limited body of evidence regarding the effects of a group-based boxing intervention for those with Parkinson's disease (PD). Design: A retrospective cohort study was performed analyzing data collected on outcome measures at 6-month intervals up to 2 years. Individuals participated in the standardized "Rock Steady Boxing" (RSB) program for up to 24 months. Every 6 months, measures were taken of balance (Fullerton Advanced Balance [FAB] Scale), functional mobility (Timed-Up and Go [TUG]), lower extremity strength (30-second Chair Stand [30CST]), and gait speed (10 Meter Walk Test [10MWT]). Methods: Statistical significance (P <.05) was determined by a two-tailed t test. Data were collected from RSB-affiliated programs at 4 locations across the southeastern United States. Current and/or past participants in RSB with baseline and at least one subsequent outcome measure were included, resulting in 68 participants (54 male, 14 female, and mean age of 71.2 years ± 8.56 standard deviation). Results: Statistically significant improvements in FAB scale, TUG, and 30CST over time were found at both 6- and 12-month time points. Significant changes continued through 18 months for FAB and 30CST. No significant changes in 10MWT were observed; however, a moderate effect size was observed at the 1-year point. Conclusions: Participants with PD were able to achieve statistically significant improvements in standard measures of functional mobility, balance, and strength within the timeline of this study. Limitations include the retrospective nature, an inability to monitor adherence, and lack of control over pharmaceutical or other interventions. [ABSTRACT FROM AUTHOR]

The prevalence of Parkinson's disease has rapidly increased over the last decade. This editorial discusses our current understanding of the pathophysiological basis for the condition, with a particular focus on the potential role of α-synuclein, and the consequent implications this has for both the development of new investigations and disease-modifying therapies. Specifically, the article discusses the development of a new diagnostic test for cerebrospinal fluid α-synuclein, the development of a new staging system for Parkinson's disease, which takes into account the α-synuclein, genetic and neuro-imaging status, and the results of two recently completed clinical trials, using monoclonal antibodies wherein α-synuclein is the principal target. We also discuss the increasing awareness of the importance of non-motor symptoms in Parkinson's disease including hyposmia, rapid eye movement sleep behaviour disorder, and autonomic and cognitive symptoms. [ABSTRACT FROM AUTHOR]

Parkinson's disease is a neurological illness that slowly impairs a small number of neurons in the substantia nigra, a part of the brain. Dopamine, a substance (neurotransmitter) that disseminates signals to different regions of the brain and, when it functions correctly, coordinates smooth and balanced muscular activity, is typically produced by these cells. One-hand tremor is frequently the first sign of Parkinson's disease. Loss of balance, stiffness, and delayed mobility are further symptoms. Proteins including catechol-O-methyltransferase and dopamine D3 receptors were taken into consideration as prospective therapeutic targets in this study. Two ligand-based pharmacophore models were generated with the help of compounds used for Parkinson's disease which have structural similarity, screened from the first 16 compounds found in the drug bank. In the second case, 9 compounds that have similar structure to the compound istradefylline were selected. Based on docking score, intermolecular interactions, ADME (absorption, distribution, metabolism, and excretion) features, pharmacophore, and toxicity investigations, the inhibitors among the chosen compounds were found. Additionally, the chosen inhibitor underwent a 100 nanosecond molecular dynamics simulation with the two protein targets to determine its stability and binding affinity. The compound 3,4-Bis(1,3,5,6-heptatetraenyloxy) benzaldehyde was identified to be the most promising lead molecule in this analysis due to its better binding affinity, better pharmacophore properties, and greater stability. Hence, by targeting both specified proteins, the compound 3,4-Bis(1,3,5,6-heptatetraenyloxy) benzaldehyde should be beneficial against Parkinson's disease. [ABSTRACT FROM AUTHOR]

The brain is the most complex organ in the human body and, as such, its study entails great challenges (methodological, theoretical, etc.). Nonetheless, there is a remarkable amount of studies about the consequences of pathological conditions on its development and functioning. This bibliographic review aims to cover mostly findings related to changes in the physical distribution of neurons and their connections—the connectome—both structural and functional, as well as their modelling approaches. It does not intend to offer an extensive description of all conditions affecting the brain; rather, it presents the most common ones. Thus, here, we highlight the need for accurate brain modelling that can subsequently be used to understand brain function and be applied to diagnose, track, and simulate treatments for the most prevalent pathologies affecting the brain. [ABSTRACT FROM AUTHOR]

Although the effect of spirituality in chronic disease has been discussed in recent years, little is known about spirituality and spiritual beliefs in Parkinson's disease. In this scoping review, the databases PubMed, Scopus and Web of Science were searched and initially identified 914 studies. A total of nine studies satisfied the inclusion criteria. It was found age, gender, education level, emotional changes, region of onset of Parkinson's disease, severity of symptoms, quality of life, religion affiliation and acceptance of Parkinson's disease influence spirituality in people with Parkinson's disease. In this context, future studies should focus on the relationship between Parkinson's disease and spirituality. [ABSTRACT FROM AUTHOR]

Background: Motor complications are well recognized in Parkinson's disease (PD), but their reported prevalence varies and functional impact has not been well studied. Objectives: To quantify the presence, severity, impact and associated factors for motor complications in PD. Methods: Analysis of three large prospective cohort studies of recent‐onset PD patients followed for up to 12 years. The MDS‐UPDRS part 4 assessed motor complications and multivariable logistic regression tested for associations. Genetic risk score (GRS) for Parkinson's was calculated from 79 single nucleotide polymorphisms. Results: 3343 cases were included (64.7% male). Off periods affected 35.0% (95% CI 33.0, 37.0) at 4–6 years and 59.0% (55.6, 62.3) at 8–10 years. Dyskinesia affected 18.5% (95% CI 16.9, 20.2) at 4–6 years and 42.1% (38.7, 45.5) at 8–10 years. Dystonia affected 13.4% (12.1, 14.9) at 4–6 years and 22.8% (20.1, 25.9) at 8–10 years. Off periods consistently caused greater functional impact than dyskinesia. Motor complications were more common among those with higher drug doses, younger age at diagnosis, female gender, and greater dopaminergic responsiveness (in challenge tests), with associations emerging 2–4 years post‐diagnosis. Higher Parkinson's GRS was associated with early dyskinesia (0.026 ≤ P ≤ 0.050 from 2 to 6 years). Conclusions: Off periods are more common and cause greater functional impairment than dyskinesia. We confirm previously reported associations between motor complications with several demographic and medication factors. Greater dopaminergic responsiveness and a higher genetic risk score are two novel and significant independent risk factors for the development of motor complications. [ABSTRACT FROM AUTHOR]

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Parkinson's disease (PD) refers to a degenerative disease of the dopaminergic neurons of the substantia nigra pars compacta in the brain. It is considered a disabling disorder affecting many people. Its symptoms mainly include bradykinesia, rigidity, tremor, postural instability, and gait disability. Its effects are very wide covering large spectrum of people especially with old age. Its duration may last long years due to its degenerative nature. It has not only obvious and noxious motor manifestations, but also it has unmanifested disorders or dysfunctions including painful symptoms, depression, and the cognitive decline. All these features complete the whole image of disability in patients with PD. The most popular pathway is simply found in a slow fashion for most of patients. its effects causes the societies to suffer greatly with burdens in most sectors. Physiotherapy including excises and motor learning and training principles have good effects in deterioration of symptoms and improvement of the whole condition. Future research should focus on the best treatment methods especially using technology, in the management of PD. [ABSTRACT FROM AUTHOR]

Background: Parkinson's disease is characterized by dopamine-responsive symptoms as well as aggregation of α-synuclein protofibrils. New diagnostic methods assess α-synuclein aggregation characteristics from cerebrospinal fluid (CSF) and recent pathophysiologic mechanisms suggest that CSF circulation disruptions may precipitate α-synuclein retention. Here, diffusion-weighted MRI with low-to-intermediate diffusion-weightings was applied to test the hypothesis that CSF motion is reduced in Parkinson's disease relative to healthy participants. Methods: Multi-shell diffusion weighted MRI (spatial resolution = 1.8 × 1.8 × 4.0 mm) with low-to-intermediate diffusion weightings (b-values = 0, 50, 100, 200, 300, 700, and 1000 s/mm2) was applied over the approximate kinetic range of suprasellar cistern fluid motion at 3 Tesla in Parkinson's disease (n = 27; age = 66 ± 6.7 years) and non-Parkinson's control (n = 32; age = 68 ± 8.9 years) participants. Wilcoxon rank-sum tests were applied to test the primary hypothesis that the noise floor-corrected decay rate of CSF signal as a function of b-value, which reflects increasing fluid motion, is reduced within the suprasellar cistern of persons with versus without Parkinson's disease and inversely relates to choroid plexus activity assessed from perfusion-weighted MRI (significance-criteria: p < 0.05). Results: Consistent with the primary hypothesis, CSF decay rates were higher in healthy (D = 0.00673 ± 0.00213 mm2/s) relative to Parkinson's disease (D = 0.00517 ± 0.00110 mm2/s) participants. This finding was preserved after controlling for age and sex and was observed in the posterior region of the suprasellar cistern (p < 0.001). An inverse correlation between choroid plexus perfusion and decay rate in the voxels within the suprasellar cistern (Spearman's-r=-0.312; p = 0.019) was observed. Conclusions: Multi-shell diffusion MRI was applied to identify reduced CSF motion at the level of the suprasellar cistern in adults with versus without Parkinson's disease; the strengths and limitations of this methodology are discussed in the context of the growing literature on CSF flow. [ABSTRACT FROM AUTHOR]

Most individuals with Parkinson's disease experience cognitive decline. Mounting evidence suggests this is partially caused by cholinergic denervation due to α-synuclein pathology in the cholinergic basal forebrain. Alpha-synuclein deposition causes inflammation, which can be measured with free water fraction, a diffusion MRI-derived metric of extracellular water. Prior studies have shown an association between basal forebrain integrity and cognition, cholinergic levels and cognition, and basal forebrain volume and acetylcholine, but no study has directly investigated whether basal forebrain physiology mediates the relationship between acetylcholine and cognition in Parkinson's disease. We investigated the relationship between these variables in a cross-sectional analysis of 101 individuals with Parkinson's disease. Cholinergic levels were measured using fluorine-18 fluoroethoxybenzovesamicol (18F-FEOBV) PET imaging. Cholinergic innervation regions of interest included the medial, lateral capsular and lateral perisylvian regions and the hippocampus. Brain volume and free water fraction were quantified using T1 and diffusion MRI, respectively. Cognitive measures included composites of attention/working memory, executive function, immediate memory and delayed memory. Data were entered into parallel mediation analyses with the cholinergic projection areas as predictors, cholinergic basal forebrain volume and free water fraction as mediators and each cognitive domain as outcomes. All mediation analyses controlled for age, years of education, levodopa equivalency dose and systolic blood pressure. The basal forebrain integrity metrics fully mediated the relationship between lateral capsular and lateral perisylvian acetylcholine and attention/working memory, and partially mediated the relationship between medial acetylcholine and attention/working memory. Basal forebrain integrity metrics fully mediated the relationship between medial, lateral capsular and lateral perisylvian acetylcholine and free water fraction. For all mediations in attention/working memory and executive function, the free water mediation was significant, while the volume mediation was not. The basal forebrain integrity metrics fully mediated the relationship between hippocampal acetylcholine and delayed memory and partially mediated the relationship between lateral capsular and lateral perisylvian acetylcholine and delayed memory. The volume mediation was significant for the hippocampal and lateral perisylvian models, while free water fraction was not. Free water fraction in the cholinergic basal forebrain mediated the relationship between acetylcholine and attention/working memory and executive function, while cholinergic basal forebrain volume mediated the relationship between acetylcholine in temporal regions in memory. These findings suggest that these two metrics reflect different stages of neurodegenerative processes and add additional evidence for a relationship between pathology in the basal forebrain, acetylcholine denervation and cognitive decline in Parkinson's disease. [ABSTRACT FROM AUTHOR]

Summary: Isolated rapid eye movement (REM) sleep behaviour disorder (iRBD) is a sleep disorder that is characterised by dream enactment episodes during REM sleep. It is the strongest known predictor of α‐synuclein‐related neurodegenerative disease (αNDD), such that >80% of people with iRBD will eventually develop Parkinson's disease, dementia with Lewy bodies, or multiple system atrophy in later life. More research is needed to understand the trajectory of phenoconversion to each αNDD. Only five 'gold standard' prevalence studies of iRBD in older adults have been undertaken previously, with estimates ranging from 0.74% to 2.01%. The diagnostic recommendations for video‐polysomnography (vPSG) to confirm iRBD makes prevalence studies challenging, as vPSG is often unavailable to large cohorts. In Australia, there have been no iRBD prevalence studies, and little is known about the cognitive and motor profiles of Australian people with iRBD. The Island Study Linking Ageing and Neurodegenerative Disease (ISLAND) Sleep Study will investigate the prevalence of iRBD in Tasmania, an island state of Australia, using validated questionnaires and home‐based vPSG. It will also explore several cognitive, motor, olfactory, autonomic, visual, tactile, and sleep profiles in people with iRBD to better understand which characteristics influence the progression of iRBD to αNDD. This paper details the ISLAND Sleep Study protocol and presents preliminary baseline results. [ABSTRACT FROM AUTHOR]

The CRISPR (Clustered Regulatory Interspaced Short Palindromic Repeats) -- Cas9 (CRISPR Associated) system has become the most widely used gene editing tool due to its simplicity and efficiency. Advances in iPSC (induced pluripotent stem cell) technology have resulted in the development of hiPSCs (human iPSC) that can be differentiated into any cell of choice while ensuring that the modified cells retain patient-specific genetic information. The CRISPR-Cas system and hiPSCs have opened new avenues for gene therapy and treatment of previously incurable diseases by transplanting or replacing damaged or mutated cells with patient-specific, healthy, normally functioning cells. However, the success of these techniques has been limited in the case of neurodegenerative diseases, as recovery entails the restoration of motor skills and cognitive abilities, including the patient's memory. This paper discusses the symptoms and genetic causes of three neurodegenerative diseases, namely Alzheimer's, Huntington's, and Parkinson's diseases, along with the latest advances in applying the CRISPR-Cas9 system and hiPSCs in identifying their genetic causes, modeling, and validating them while also briefly touching upon the challenges in the application of gene-editing techniques to brain cells and the introduction of corrected healthy differentiated cells derived from hiPSCs into the brain leading to relatively slow progress in finding permanent cures of neurodegenerative diseases compared to diseases affecting other organs. [ABSTRACT FROM AUTHOR]

Sake may potentially halt the progression of Parkinson's disease due to its properties, yet no studies have explored its effects. This preliminary study aimed to assess the impact of sake supplementation on Parkinson's disease using a zebrafish model. Sixty fish were divided into six groups: control, rotenone (ROT), and groups administered rotenone along with sake at concentrations of 25, 50, 75, and 100 mg/L (25S, 50S, 75S, and 100S). After 28 days of treatment, behavioral responses and the activities of catalase (CAT), superoxide dismutase (SOD), reduced glutathione (GSH), and glutathione-S-transferase (GST), as well as the expressions of TNF-α, IL-1β, and COX-2, were evaluated. The results indicated that rotenone administration significantly reduced crossing number (P = 0.001), entries in the top area (P = 0.001), and time spent in the top area (P = 0.001). It also markedly increased levels of TBARS and SH compared to the control group (P = 0.001). Rotenone significantly decreased CAT, SOD, and GSH activities while increasing GST levels. Furthermore, it upregulated the expressions of TNF-α (P = 0.001), IL-1β (P = 0.001), and COX-2 (P = 0.001). Supplementation with sake, particularly at higher doses, reversed the adverse effects of rotenone on behavioral, oxidative, and inflammatory responses. In conclusion, sake shows promise for preventing Parkinson's disease pending further clinical studies.

Effective engagement with stakeholders is key in health-care research and intervention development. There is currently a lack of evidence relating to the involvement of co-producers with Parkinson’s-related communication difficulties. This article provides a critical reflection on co-producing a novel speech and language therapy intervention (Better Conversations with Parkinson’s) with people living with Parkinson’s who have an interest in, or lived experience of, communication difficulties. Evaluation is based on qualitative comments and survey responses from patient and public involvement group members, documentation and outputs from the patient and public involvement group, and reflection using the Public Involvement Impact Assessment Framework. The co-production group, research team and organisation highly valued the expertise and collaboration as equal partners gained through co-production. Key enablers included skilled facilitation and adequate time and funding. Consideration should be given to the format of participation (online or face-to-face), recruitment strategies and the role of patient and public involvement, in order to improve access to underserved groups and strengthen the voice of public and patient involvement members. Co-production with people living with Parkinson’s and communication difficulties allowed the creation of a more credible, relevant intervention which responds to the needs of key stakeholders, and it was a positive experience with personal benefits for those involved. We propose offering a flexible choice of co-production methods to accommodate the differing experiences of patient and public involvement members with Parkinson’s and communication difficulties.

The amyloid aggregation of alpha-synuclein within the brain is associated with the pathogenesis of Parkinson's disease (PD) and other related synucleinopathies, including multiple system atrophy (MSA). Alpha-synuclein aggregates are a major therapeutic target for treatment of these diseases. We identify two small molecules capable of disassembling preformed alpha-synuclein fibrils. The compounds, termed CNS-11 and CNS-11g, disaggregate recombinant alpha-synuclein fibrils in vitro, prevent the intracellular seeded aggregation of alpha-synuclein fibrils, and mitigate alpha-synuclein fibril cytotoxicity in neuronal cells. Furthermore, we demonstrate that both compounds disassemble fibrils extracted from MSA patient brains and prevent their intracellular seeding. They also reduce in vivo alpha-synuclein aggregates in C. elegans. Both compounds also penetrate brain tissue in mice. A molecular dynamics-based computational model suggests the compounds may exert their disaggregating effects on the N terminus of the fibril core. These compounds appear to be promising therapeutic leads for targeting alpha-synuclein for the treatment of synucleinopathies.

Background and Aim: Parkinson's disease is a prevalent neurodegenerative disorder characterized by the degeneration of dopaminergic neurons and the presence of catalepsy. This study aimed to investigate the effects of 12 weeks of aerobic training and food restriction on dopaminergic and catalepsy neurons in the brain tissue of Parkinson's disease model of rats. Methods: In this experimental study, 40 male Wistar rats aged 2-3 months were randomly divided into five groups (n=8): healthy control (C), Parkinson's disease model (P), Parkinson's disease model + aerobic training (P+T), Parkinson's disease model + food restriction (P+FR), and Parkinson's disease model + aerobic training + food restriction (P+T+FR). The aerobic training regimen consisted of three months with five sessions per week at an intensity of 75-80% of maximum oxygen consumption. The food restriction group received approximately 11 grams of food daily. Catalepsy was assessed using the rod test, while dopaminergic neurons were quantified through brain sectioning and microscopic counting. Results: The P+T+FR group exhibited a significant increase in dopaminergic neuron count compared to the C, P, P+T, and P+FR groups (P=0.001). Furthermore, a significant reduction in catalepsy was observed in the P+T+RF group compared to the P group (P=0.001). Conclusion: The combination of three months of aerobic training and food restriction resulted in improvements in dopaminergic neuron count and reduced catalepsy in a rat model of Parkinson's disease. These findings suggest that aerobic training and food restriction could serve as potential complementary interventions for Parkinson's disease treatment, alongside pharmacological approaches, warranting further investigation in this area.

Abstract Parkinson’s disease (PD) is a prevalent neurodegenerative disorder affecting millions of elderly individuals worldwide. Clinically, PD is diagnosed based on the presentation of motoric symptoms. Other methods such as F-DOPA PET scan or α-Synuclein detection from the cerebral spinal fluid are either too expensive or invasive for routine use. Omics platforms such as transcriptomics, proteomics, and metabolomics may identify PD biomarkers from blood, which can reduce cost and increase efficiency. However, there are many biological moieties being measured and issues with false positives/negatives. It is also unknown which omics platform offers most useful information. Therefore, it is important to assess the reliability of these omics studies. Here, we shortlisted and analysed nearly 80 published reports across transcriptomics, proteomics and metabolomics in search of overlapping blood-based biomarkers for PD. The top biomarkers were reported across 29%, 42% and 12.5% of shortlisted papers in transcriptomics, proteomics and metabolomics respectively. These percentages increased to 42%, 60% and 50% accordingly when studies were grouped by specific blood subtypes for analysis, demonstrating the need for test kits to be blood-subtype specific. Following systematic analyses, we propose six novel PD biomarkers: two mRNAs (Whole blood, WB) – Arg1 and SNCA, two proteins (Plasma EV) – SNCA and APOA1, and two metabolites (WB) – 8-OHdG and uric acid for further validation. While these proposed biomarkers are useful, they are also snapshots, representing subsets of larger pathways of origin where the different omics levels corroborate. Indeed, identifying the interconnections across different biological layers can strengthen contextual reasoning, which in turn, would give rise to better quality biomarkers. Knowledge integration across the omics spectrum revealed consistent aberrations on the same neuroinflammation pathway, showcasing the value of integrative (i)-omics agreements for increasing confidence of biomarker selection. We believe that our findings could pave the way for identifying reproducible PD biomarkers, with potential for clinical deployment. Graphical Abstract Six Proposed blood-based biomarkers. Seventy-nine publications across transcriptomics, proteomics and metabolomics were shortlisted and analysed for reported biomarkers. The proposed biomarkers are SNCA, APOA1, Arg1, 8-OHdG and Uric acid.

Abstract Ivermectin (IVM) is a commonly prescribed antiparasitic treatment with pharmacological effects on invertebrate glutamate ion channels resulting in paralysis and death of invertebrates. However, it can also act as a modulator of some vertebrate ion channels and has shown promise in facilitating L-DOPA treatment in preclinical models of Parkinson’s disease. The pharmacological effects of IVM on dopamine terminal function were tested, focusing on the role of two of IVM’s potential targets: purinergic P2X4 and nicotinic acetylcholine receptors. Ivermectin enhanced electrochemical detection of dorsal striatum dopamine release. Although striatal P2X4 receptors were observed, IVM effects on dopamine release were not blocked by P2X4 receptor inactivation. In contrast, IVM attenuated nicotine effects on dopamine release, and antagonizing nicotinic receptors prevented IVM effects on dopamine release. IVM also enhanced striatal cholinergic interneuron firing. L-DOPA enhances dopamine release by increasing vesicular content. L-DOPA and IVM co-application further enhanced release but resulted in a reduction in the ratio between high and low frequency stimulations, suggesting that IVM is enhancing release largely through changes in terminal excitability and not vesicular content. Thus, IVM is increasing striatal dopamine release through enhanced cholinergic activity on dopamine terminals.

ABSTRACTPINK1, mutated in familial forms of Parkinson’s disease, initiates mitophagy following mitochondrial depolarization. However, it is difficult to monitor this pathway physiologically in mice as loss of PINK1 does not alter basal mitophagy levels in most tissues. To further characterize this pathway in vivo, we used mito-QC mice in which loss of PINK1 was combined with the mitochondrial-associated POLGD257A mutation. We focused on skeletal muscle as gene expression data indicates that this tissue has the highest PINK1 levels. We found that loss of PINK1 in oxidative hindlimb muscle significantly reduced mitophagy. Of interest, the presence of the POLGD257A mutation, while having a minor effect in most tissues, restored levels of muscle mitophagy caused by the loss of PINK1. Although our observations highlight that multiple mitophagy pathways operate within a single tissue, we identify skeletal muscle as a tissue of choice for the study of PINK1-dependant mitophagy under basal conditions.

Ivermectin (IVM) is a commonly prescribed antiparasitic treatment with pharmacological effects on invertebrate glutamate ion channels resulting in paralysis and death of invertebrates. However, it can also act as a modulator of some vertebrate ion channels and has shown promise in facilitating L-DOPA treatment in preclinical models of Parkinson's disease. The pharmacological effects of IVM on dopamine terminal function were tested, focusing on the role of two of IVM's potential targets: purinergic P2X4 and nicotinic acetylcholine receptors. Ivermectin enhanced electrochemical detection of dorsal striatum dopamine release. Although striatal P2X4 receptors were observed, IVM effects on dopamine release were not blocked by P2X4 receptor inactivation. In contrast, IVM attenuated nicotine effects on dopamine release, and antagonizing nicotinic receptors prevented IVM effects on dopamine release. IVM also enhanced striatal cholinergic interneuron firing. L-DOPA enhances dopamine release by increasing vesicular content. L-DOPA and IVM co-application further enhanced release but resulted in a reduction in the ratio between high and low frequency stimulations, suggesting that IVM is enhancing release largely through changes in terminal excitability and not vesicular content. Thus, IVM is increasing striatal dopamine release through enhanced cholinergic activity on dopamine terminals. [ABSTRACT FROM AUTHOR]

There is a critical need for accessible neuropsychological testing for basic research and translational studies worldwide. Traditional in-person neuropsychological studies are inherently difficult to conduct because testing requires the recruitment and participation of individuals with neurological conditions. Consequently, studies are often based on small sample sizes, are highly time-consuming, and lack diversity. To address these challenges, in the last decade, the utilization of remote testing platforms has demonstrated promising results regarding the feasibility and efficiency of collecting patient data online. Herein, we tested the validity and generalizability of remote administration of the Montreal Cognitive Assessment (MoCA) test. We administered the MoCA to English and Hebrew speakers from three different populations: Parkinson's disease, Cerebellar Ataxia, and healthy controls via video conferencing. First, we found that the online MoCA scores do not differ from traditional in-person studies, demonstrating convergent validity. Second, the MoCA scores of both our online patient groups were lower than controls, demonstrating construct validity. Third, we did not find differences between the two language versions of the remote MoCA, supporting its generalizability to different languages and the efficiency of collecting binational data (USA and Israel). Given these results, future studies can utilize the remote MoCA, and potentially other remote neuropsychological tests to collect data more efficiently across multiple different patient populations, language versions, and nations. [ABSTRACT FROM AUTHOR]