D2/D3 Receptor Agonism: Paving the Way for a New Therapeutic Target for Taste Disorders in Parkinson's Disease and Other Conditions?

Chemosensory (i.e., olfaction and taste) dysfunction is common in neurodegenerative (e.g., Parkinson's disease, Alzheimer's disease, and dementia), psychiatric (e.g., depression, bipolar disorders, other conditions), and postinfectious (i.e., long COVID) diseases and in the elderly. Despite its impact on patients' quality of life, no established treatment for taste disorders exists so far. A recent report on the effect of pramipexole, a D2/D3 agonist, on taste performance in healthy participants provides support for a new potential therapeutic target for taste dysfunction to be tested in future randomized, placebo-controlled, clinical trials across several populations reporting gustatory symptoms.

Adopting a multidisciplinary telemedicine intervention for fall prevention in Parkinson's disease. Protocol for a longitudinal, randomized clinical trial.

BACKGROUND: Approximately 40-70% of people with Parkinson's disease (PD) fall each year, causing decreased activity levels and quality of life. Current fall-prevention strategies include the use of pharmacological and non-pharmacological therapies. To increase the accessibility of this vulnerable population, we developed a multidisciplinary telemedicine program using an Information and Communication Technology (ICT) platform. We hypothesized that the risk for falling in PD would decrease among participants receiving a multidisciplinary telemedicine intervention program added to standard office-based neurological care. OBJECTIVE: To determine the feasibility and cost-effectiveness of a multidisciplinary telemedicine intervention to decrease the incidence of falls in patients with PD. METHODS: Ongoing, longitudinal, randomized, single-blinded, case-control, clinical trial. We will include 76 non-demented patients with idiopathic PD with a high risk of falling and limited access to multidisciplinary care. The intervention group (n = 38) will receive multidisciplinary remote care in addition to standard medical care, and the control group (n = 38) standard medical care only. Nutrition, sarcopenia and frailty status, motor, non-motor symptoms, health-related quality of life, caregiver burden, falls, balance and gait disturbances, direct and non-medical costs will be assessed using validated rating scales. RESULTS: This study will provide a cost-effectiveness assessment of multidisciplinary telemedicine intervention for fall reduction in PD, in addition to standard neurological medical care. CONCLUSION: In this challenging initiative, we will determine whether a multidisciplinary telemedicine intervention program can reduce falls, as an alternative intervention option for PD patients with restricted access to multidisciplinary care. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04694443.

An equation to calculate UPDRS motor severity for online and rural assessments of Parkinson's.

OBJECTIVE: Management of PD has largely been affected by COVID-19. Due to the restrictions posed by COVID-19, there has been a shift from in-person to online forms of assessment. This presents a challenge as not all motor symptoms can be assessed virtually. Two of the four cardinal symptoms of PD (rigidity and postural instability) cannot be assessed virtually using the gold-standard Unified Parkinson's Disease Rating Scale (UPDRS-III). As a result, an accurate total motor severity score can not be computed from the remaining subsections. Recently, one study stated that in order for accurate scores to be calculated, only three sections could be absent. Virtually, six sections are unable to be evaluated with online assessments. This inability to compute a total motor severity score may result in poor disease management. Thus, in this study a regression equation was developed to predict total motor severity scores from partial scores. METHODS: Total motor severity scores (UPDRS-III) from N = 234 individuals with idiopathic Parkinson's were retrospectively analyzed. In order to conduct a linear regression analysis predictor and outcome variables were created. The variables were then used for the linear regression. The equation was then tested on an independent data set N = 1168. RESULTS: The regression analysis resulted in the equation to predict total motor symptom severity of PD. CONCLUSIONS: In conclusion, the developed equation will be very useful for outreach in rural communities, as well as the continued remote management of PD during COVID-19 and beyond.

Clinical perception and management of Parkinson's disease during the COVID-19 pandemic: A Canadian experience.

BACKGROUND: The COVID-19 pandemic has necessitated the social isolation of the population and the rapid implementation of remote care for patients with neurodegenerative diseases. The objective of this study was to explore the perceived impact of confinement in patients with Parkinson's disease and document the effects of gender and living environment. METHODS: We recruited two cohorts from the Canadian provinces of Québec and Alberta, which differed in the dynamics of COVID-19 spreading at the time of the study, and administered a questionnaire on the perceived effects of confinement on daily living and disease management. RESULTS: The data reveals that approximately half of the patients experienced a change in one or more clinical symptoms, with differences observed between gender (e.g. day-to-day changes in slowness in men, aggravated headaches in women) and geographic location (e.g. increased depression in Alberta but reduced sleep quality in Québec). Furthermore, participants identifying as women or living in Alberta implemented more frequently home or online exercise. Lastly, high levels of satisfaction with phone or video consultations did not translate into a sustained interest to pursue this mode of healthcare. CONCLUSIONS: This study suggests that COVID-19-related confinement affected Parkinson's disease manifestation and management. Patients also reported varying levels of interest to continue remote care. A number of differences reported in our study were seemingly related to gender and living environment.

The Interplay Among Epilepsy, Parkinson's Disease and Inflammation: Revisiting the Link through Ca2+/cAMP Signalling.

BACKGROUND: Robust evidence has described that Parkinson´s disease (PD) is associated with an increased risk for developing epileptic seizures. In fact, an interplay between PD and epilepsy has been of interest for many years. An emerging hypothesis is that inflammation could link both diseases. OBJECTIVE: Bearing in mind the experience of our group in the field of Ca2+/cAMP signalling pathways, this article discussed, beyond inflammation, the role of these signalling pathways in this link between PD and epilepsy. METHODS: Publications involving Ca2+/cAMP signalling pathways, PD, and epilepsy (alone or combined) were collected by searching PubMed and EMBASE. RESULTS: The comprehension of the interplay between PD and epilepsy could improve the drug therapy. In addition, a Ca2+ signalling dyshomeostasis due to Coronavirus disease 2019 (COVID-19), an emerging and rapidly evolving situation, has been reported. CONCLUSION: Thus, this article also debated recent findings about therapeutics involving Ca2+ channel blockers for preventing Ca2+ signalling dyshomeostasis due to COVID-19, including the correlation among COVID-19, epilepsy, and PD.

Prolonged Dysphagia After a COVID-19 Infection in a Patient With Parkinson Disease.

ABSTRACT: Coronavirus disease 2019 might have an impact on patients with Parkinson disease because of the neuroinvasive potential. Herein, we report the case of a patient with Parkinson disease who developed severe and prolonged oropharyngeal dysphagia after a coronavirus disease 2019 infection. A 73-yr-old male patient with Parkinson disease was diagnosed with coronavirus disease 2019 and admitted to a tertiary care hospital. Before hospitalization, he was assessed at Hoehn and Yahr stage 4 and showed no symptoms of dysphagia. After admission, the patient gradually recovered; however, he was fed through a nasogastric tube. A videofluoroscopic swallowing study revealed a severe oropharyngeal dysphagia with a severely delayed oral phase. Therefore, he underwent percutaneous gastrostomy tube insertion. After discharge, although he received swallowing therapy for 4 mos, he still had severe dysphagia, which made him dependent on enteral feeding. We speculate that the impact of coronavirus disease 2019 on dopaminergic and nondopaminergic mechanisms could lead to the development of dysphagia in this patient. The present case suggests that clinicians must have a high index of suspicion without dismissing the possibility of dysphagia and subsequent aspiration pneumonia in coronavirus disease 2019 patients with Parkinson disease.

Impact of the COVID-19 Pandemic on the Quality of Life of Patients with Parkinson's Disease and Their Caregivers: A Single-Center Survey in Tochigi Prefecture.

BACKGROUND: The coronavirus disease 2019 (COVID-19) pandemic has negatively affected the mental health of the general population. OBJECTIVE: We investigated the determinants of quality of life (QOL) in Parkinson's disease (PD) patients during the COVID-19 pandemic. METHODS: Impacts of lifestyle changes due to the COVID-19 pandemic on 100 patients with PD and their caregivers/spouses were assessed. The Hospital Anxiety and Depression Scale was used to assess anxiety and depression. The physical component summary (PCS) and mental component summary (MCS) scores of the short form (SF)-8 were used to evaluate health-related QOL. RESULTS: Regarding health-related QOL, physical function, role physical, general health, vitality and the PCS score were significantly worse in PD patients than in caregivers. Worsening of PD-related symptoms, increased stress, and decreased physical activity were observed in 29.0%, 37.0% and 44.0% of PD patients, respectively. Sixteen patients (16.0%) experienced problems with hospital access, but none reported medication shortages. Strong concerns about COVID-19 were reported by 47.0% of caregivers and 50.0% of PD patients. In PD patients, increased gait disturbance and rigidity, disease severity, smoking, the levodopa equivalent dose and decreased body weight predicted a worse PCS score; anxiety, depression, female sex, stress and long disease duration predicted a worse MCS score. In caregivers, age and smoking contributed to a worse PCS score; depression, stress and worsening patient mood contributed to a worse MCS score. CONCLUSION: We report the negative impacts of the COVID-19 pandemic on health-related QOL and its determinants in PD patients and their caregivers.

Negative Effects of COVID-19 Stay-at-Home Mandates on Physical Intervention Outcomes: A Preliminary Study.

BACKGROUND: Due to the COVID-19 pandemic, beneficial physical intervention classes for individuals with Parkinson's disease (PD) were cancelled. OBJECTIVE: To understand effects of the COVID-19 stay-at-home mandate and the inability to participate in recommended and structured physical interventions as a consequence of these mandates, specifically designed mobile assessments were used that collected both self-reporting information and objective task-based metrics of neurocognitive functions to assess symptom changes for individuals with PD. METHODS: Self-reporting questionnaires focusing on overall quality of life (e.g., when individuals typically feel at their best, changes in activity levels, and symptom progression) were given to all individuals (n = 28). In addition, mobile-based neurocognitive assessments were administered to a subset of the population (n = 8) to quantitatively assess changes due to COVID-19 restrictions. RESULTS: The highest self-reported factors in which individuals denoted feeling their best were after exercise (67.86%) and being in a comfortable and supportive environment (60.71%). Objective measures found overall duration of physical activity during the stay-at-home mandate decreased significantly (p = 0.022). With the lack of overall activity, 82.14%of individuals self-reported having at least one symptom that worsened moderately or higher. Further testing, using mobile-based assessments, showed average completion times of functional tasks increased, taking about 2.1 times longer, while accuracy metrics showed overall degradation. CONCLUSION: Although the COVID-19 stay-at-home mandate was intended to help protect individuals at high risk from coming into contact with the virus, it also prevented individuals from receiving recommended supervised exercise interventions resulting in significant negative effects in social well-being and across motor and speech neurocognitive tasks for individuals with PD.

Automated Computer Vision Assessment of Hypomimia in Parkinson Disease: Proof-of-Principle Pilot Study.

BACKGROUND: Facial expressions require the complex coordination of 43 different facial muscles. Parkinson disease (PD) affects facial musculature leading to "hypomimia" or "masked facies." OBJECTIVE: We aimed to determine whether modern computer vision techniques can be applied to detect masked facies and quantify drug states in PD. METHODS: We trained a convolutional neural network on images extracted from videos of 107 self-identified people with PD, along with 1595 videos of controls, in order to detect PD hypomimia cues. This trained model was applied to clinical interviews of 35 PD patients in their on and off drug motor states, and seven journalist interviews of the actor Alan Alda obtained before and after he was diagnosed with PD. RESULTS: The algorithm achieved a test set area under the receiver operating characteristic curve of 0.71 on 54 subjects to detect PD hypomimia, compared to a value of 0.75 for trained neurologists using the United Parkinson Disease Rating Scale-III Facial Expression score. Additionally, the model accuracy to classify the on and off drug states in the clinical samples was 63% (22/35), in contrast to an accuracy of 46% (16/35) when using clinical rater scores. Finally, each of Alan Alda's seven interviews were successfully classified as occurring before (versus after) his diagnosis, with 100% accuracy (7/7). CONCLUSIONS: This proof-of-principle pilot study demonstrated that computer vision holds promise as a valuable tool for PD hypomimia and for monitoring a patient's motor state in an objective and noninvasive way, particularly given the increasing importance of telemedicine.

The Intersection of Parkinson's Disease, Viral Infections, and COVID-19.

The Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), the causative agent of human COVID-19, not only causes flu-like symptoms and gut microbiome complications but a large number of infected individuals also experience a host of neurological symptoms including loss of smell and taste, seizures, difficulty concentrating, decreased alertness, and brain inflammation. Although SARS-CoV-2 infections are not more prevalent in Parkinson's disease patients, a higher mortality rate has been reported not only associated with older age and longer disease duration, but also through several mechanisms, such as interactions with the brain dopaminergic system and through systemic inflammatory responses. Indeed, a number of the neurological symptoms seen in COVID-19 patients, as well as the alterations in the gut microbiome, are also prevalent in patients with Parkinson's disease. Furthermore, biochemical pathways such as oxidative stress, inflammation, and protein aggregation have shared commonalities between Parkinson's disease and COVID-19 disease progression. In this review, we describe and compare the numerous similarities and intersections between neurodegeneration in Parkinson's disease and RNA viral infections, emphasizing the current SARS-CoV-2 global health crisis.

Video-Based Analyses of Parkinson's Disease Severity: A Brief Review.

Remote and objective assessment of the motor symptoms of Parkinson's disease is an area of great interest particularly since the COVID-19 crisis emerged. In this paper, we focus on a) the challenges of assessing motor severity via videos and b) the use of emerging video-based Artificial Intelligence (AI)/Machine Learning techniques to quantitate human movement and its potential utility in assessing motor severity in patients with Parkinson's disease. While we conclude that video-based assessment may be an accessible and useful way of monitoring motor severity of Parkinson's disease, the potential of video-based AI to diagnose and quantify disease severity in the clinical context is dependent on research with large, diverse samples, and further validation using carefully considered performance standards.

Environmental Nanoparticles, SARS-CoV-2 Brain Involvement, and Potential Acceleration of Alzheimer's and Parkinson's Diseases in Young Urbanites Exposed to Air Pollution.

Alzheimer's and Parkinson's diseases (AD, PD) have a pediatric and young adult onset in Metropolitan Mexico City (MMC). The SARS-CoV-2 neurotropic RNA virus is triggering neurological complications and deep concern regarding acceleration of neuroinflammatory and neurodegenerative processes already in progress. This review, based on our MMC experience, will discuss two major issues: 1) why residents chronically exposed to air pollution are likely to be more susceptible to SARS-CoV-2 systemic and brain effects and 2) why young people with AD and PD already in progress will accelerate neurodegenerative processes. Secondary mental consequences of social distancing and isolation, fear, financial insecurity, violence, poor health support, and lack of understanding of the complex crisis are expected in MMC residents infected or free of SARS-CoV-2. MMC residents with pre-SARS-CoV-2 accumulation of misfolded proteins diagnostic of AD and PD and metal-rich, magnetic nanoparticles damaging key neural organelles are an ideal host for neurotropic SARS-CoV-2 RNA virus invading the body through the same portals damaged by nanoparticles: nasal olfactory epithelium, the gastrointestinal tract, and the alveolar-capillary portal. We urgently need MMC multicenter retrospective-prospective neurological and psychiatric population follow-up and intervention strategies in place in case of acceleration of neurodegenerative processes, increased risk of suicide, and mental disease worsening. Identification of vulnerable populations and continuous effort to lower air pollution ought to be critical steps.

Broader Insights into Understanding Tumor Necrosis Factor and Neurodegenerative Disease Pathogenesis Infer New Therapeutic Approaches.

Proinflammatory cytokines such as tumor necrosis factor (TNF), with its now appreciated key roles in neurophysiology as well as neuropathophysiology, are sufficiently well-documented to be useful tools for enquiry into the natural history of neurodegenerative diseases. We review the broader literature on TNF to rationalize why abruptly-acquired neurodegenerative states do not exhibit the remorseless clinical progression seen in those states with gradual onsets. We propose that the three typically non-worsening neurodegenerative syndromes, post-stroke, post-traumatic brain injury (TBI), and post cardiac arrest, usually become and remain static because of excess cerebral TNF induced by the initial dramatic peak keeping microglia chronically activated through an autocrine loop of microglial activation through excess cerebral TNF. The existence of this autocrine loop rationalizes post-damage repair with perispinal etanercept and proposes a treatment for cerebral aspects of COVID-19 chronicity. Another insufficiently considered aspect of cerebral proinflammatory cytokines is the fitness of the endogenous cerebral anti-TNF system provided by norepinephrine (NE), generated and distributed throughout the brain from the locus coeruleus (LC). We propose that an intact LC, and therefore an intact NE-mediated endogenous anti-cerebral TNF system, plus the DAMP (damage or danger-associated molecular pattern) input having diminished, is what allows post-stroke, post-TBI, and post cardiac arrest patients a strong long-term survival advantage over Alzheimer's disease and Parkinson's disease sufferers. In contrast, Alzheimer's disease and Parkinson's disease patients remorselessly worsen, being handicapped by sustained, accumulating, DAMP and PAMP (pathogen-associated molecular patterns) input, as well as loss of the LC-origin, NE-mediated, endogenous anti-cerebral TNF system. Adrenergic receptor agonists may counter this.

Design of a virtual longitudinal observational study in Parkinson's disease (AT-HOME PD).

OBJECTIVE: The expanding power and accessibility of personal technology provide an opportunity to reduce burdens and costs of traditional clinical site-centric therapeutic trials in Parkinson's disease and generate novel insights. The value of this approach has never been more evident than during the current COVID-19 pandemic. We sought to (1) establish and implement the infrastructure for longitudinal, virtual follow-up of clinical trial participants, (2) compare changes in smartphone-based assessments, online patient-reported outcomes, and remote expert assessments, and (3) explore novel digital markers of Parkinson's disease disability and progression. METHODS: Participants from two recently completed phase III clinical trials of inosine and isradipine enrolled in Assessing Tele-Health Outcomes in Multiyear Extensions of Parkinson's Disease trials (AT-HOME PD), a two-year virtual cohort study. After providing electronic informed consent, individuals complete annual video visits with a movement disorder specialist, smartphone-based assessments of motor function and socialization, and patient-reported outcomes online. RESULTS: From the two clinical trials, 226 individuals from 42 states in the United States and Canada enrolled. Of these, 181 (80%) have successfully downloaded the study's smartphone application and 161 (71%) have completed patient-reported outcomes on the online platform. INTERPRETATION: It is feasible to conduct a large-scale, international virtual observational study following the completion of participation in brick-and-mortar clinical trials in Parkinson's disease. This study, which brings research to participants, will compare established clinical endpoints with novel digital biomarkers and thereby inform the longitudinal follow-up of clinical trial participants and design of future clinical trials.

Sparse Adaptive Graph Convolutional Network for Leg Agility Assessment in Parkinson's Disease.

Motor disorder is a typical symptom of Parkinson's disease (PD). Neurologists assess the severity of PD motor symptoms using the clinical rating scale, i.e., MDS-UPDRS. However, this assessment method is time-consuming and easily affected by the perception difference of assessors. In the recent outbreak of coronavirus disease 2019, telemedicine for PD has become extremely urgent for clinical practice. To solve these problems, we developed an automated and objective assessment method of the leg agility task in the MDS-UPDRS using videos and a graph neural network. In this study, a sparse adaptive graph convolutional network (SA-GCN) was proposed to achieve fine-grained quantitative assessment of skeleton sequences extracted from videos. Specifically, the sparse adaptive graph convolutional unit with a prior knowledge constraint was proposed to perform adaptive spatial modeling of physical and logical dependency for skeleton sequences, thus achieving the sparse modeling of the discriminative spatial relationships. Subsequently, a temporal context module was introduced to construct the remote context dependency in the temporal dimension, hence determining the global changes of the task. A multi-domain attention learning module was also developed to integrate the static spatial features and dynamic temporal features, and then to emphasize the salient feature selection in the channel domain, thereby capturing the multi-domain fine-grained information. Finally, the evaluation results using a dataset with 148 patients and 870 samples confirmed the effectiveness and reliability of our scheme, and the method outperformed other related state-of-the-art methods. Our contactless method provides a new potential tool for automated PD assessment and telemedicine.

Effects of COVID-19 on Parkinson's Disease Clinical Features: A Community-Based Case-Control Study.

The impact of coronavirus disease 2019 (COVID-19) on clinical features of Parkinson's disease (PD) has been poorly characterized so far. Of 141 PD patients resident in Lombardy, we found 12 COVID-19 cases (8.5%), whose mean age and disease duration (65.5 and 6.3 years, respectively) were similar to controls. Changes in clinical features in the period January 2020 to April 2020 were compared with those of 36 PD controls matched for sex, age, and disease duration using the clinical impression of severity index for PD, the Movement Disorders Society Unified PD Rating Scale Parts II and IV, and the nonmotor symptoms scale. Motor and nonmotor symptoms significantly worsened in the COVID-19 group, requiring therapy adjustment in one third of cases. Clinical deterioration was explained by both infection-related mechanisms and impaired pharmacokinetics of dopaminergic therapy. Urinary issues and fatigue were the most prominent nonmotor issues. Cognitive functions were marginally involved, whereas none experienced autonomic failure. © 2020 International Parkinson and Movement Disorder Society.