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.

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.