Impact of COVID­19 infection in patients with neurodegenerative diseases with particular focus on Alzheimer's and Parkinson's disease.

Neurodegenerative disorders (NDD) are chronic neurological diseases characterized by loss and/or damage to neurons along with the myelin sheath, and patients are at higher risk of severe infection with the SARS­CoV­2. A comprehensive literature search was performed using relevant terms and inclusion­exclusion criteria. Recent articles, subjects older than 50 years, and articles written in the English language were included, whereas letters to the editor and articles related to pregnant women were excluded from the review study. COVID­19 appears to damage angiotensin­II receptors which cause natural killer cells to lose the ability to clear virus­infected cells, owing to worse outcomes in patients with NDD. COVID­19 can worsen the symptoms of Alzheimer's disease. In addition, COVID­19 worsens drug­responsive motor symptoms in Parkinson's disease (PD) and other symptoms like fatigue and urinary complaints. Vitamin D is essential in decreasing pro­inflammatory and increasing anti­inflammatory cytokines in ongoing COVID­19 infections and reducing angiotensin receptors and, hence, decreasing COVID­19 infection severity. Telemedicine shows promise for patients with NDD but is yet to overcome legal issues and personal barriers. COVID­19 has a significant effect on neurodegenerative conditions, which appears partly to the nature of the NDD and the neuro­invasive capabilities of the SARS­CoV­2. The protective role of vitamin D in patients with NDD further supports this hypothesis. Modifications in current health care, like the telemedicine platform, are required to address the increased risk of serious infection in this population. Further studies will be required to clarify conflicting reports in many fields.

Deep brain stimulation in Parkinson's disease: state of the art and future perspectives.

For more than 30 years, Deep Brain Stimulation (DBS) has been a therapeutic option for Parkinson's disease (PD) treatment. However, this therapy is still underutilized mainly due to misinformation regarding risks and clinical outcomes. DBS can ameliorate several motor and non-motor symptoms, improving patients' quality of life. Furthermore, most of the improvement after DBS is long-lasting and present even in advanced PD. Adequate patient selection, precise electric leads placement, and correct DBS programming are paramount for good surgical outcomes. Nonetheless, DBS still has many limitations: axial symptoms and signs, such as speech, balance and gait, do not improve to the same extent as appendicular symptoms and can even be worsened as a direct or indirect consequence of surgery and stimulation. In addition, there are still unanswered questions regarding patient's selection, surgical planning and programming techniques, such as the role of surgicogenomics, more precise imaging-based lead placement, new brain targets, advanced programming strategies and hardware features. The net effect of these innovations should not only be to refine the beneficial effect we currently observe on selected symptoms and signs but also to improve treatment resistant facets of PD, such as axial and non-motor features. In this review, we discuss the current state of the art regarding DBS selection, implant, and programming, and explore new advances in the DBS field.

Covid-19 and Parkinson's disease: Nursing care, vaccination and impact on advanced therapies.

The Coronavirus Disease 2019 (Covid-19) pandemic has created many challenges for the Parkinson's Disease (PD) care service delivery, which has been established over the past decades. The need for rapid adjustments to the new conditions has highlighted the role of technology, which can act as an enabler both in patient-facing aspects of care, such as clinical consultations, as well as in professional development and training. The Parkinson's Disease Nurse Specialists (PNSs) play a vital role in the effective management of people with PD (PwP). Maintaining optimum functionality and availability of device aided therapies is essential in order to ensure patients' quality of life. PwP are particularly recommended to use vaccination as a basic protection from the virus. The long-term consequences of this pandemic on PwP are highly uncertain, and education, support and reassurance of patients and their families may help ease their burden.

Long-term safety, discontinuation and mortality in an Italian cohort with advanced Parkinson's disease on levodopa/carbidopa intestinal gel infusion.

INTRODUCTION: Levodopa/carbidopa intestinal gel (LCIG) is an effective treatment in patients with advanced Parkinson's disease (PD) with consolidated evidence of clinical efficacy. However, only few studies have assessed long-term safety, causes of discontinuation, mortality, and relative predictors. METHODS: We conducted a retrospective analysis of 79 PD patients treated with LCIG between 2005 and 2020 in two Italian Neurological Centers, recording all adverse events (AEs), including weight loss (WL). Kaplan-Meier curve was used to estimate the time to discontinuation and survival. Cox proportional hazard model was employed to identify predictors of discontinuation and mortality, while Pearson's correlation was used to analyze predictors of WL. RESULTS: The average follow-up was 47.7 ± 40.5 months and the median survival from disease onset was 25 years. There were three cases of polyradiculoneuropathy Guillain-Barre syndrome-like, all occurred in the early years of LCIG treatment. Twenty-five patients died (32%), 18 on LCIG (including one suicide) and seven after discontinuation. The mean WL was 3.62 ± 7.5 kg, which correlated with levodopa dose at baseline (p = 0.002), levodopa equivalent daily dose (LEDD) baseline (p = 0.017) and off-duration (p = 0.0014), but not dyskinesia. Peristomal complications emerged as a negative predictor of discontinuation (p = 0.008). CONCLUSIONS: LCIG has a relatively satisfactory long-term safety profile and efficacy and a relatively low rate of discontinuation. Peristomal complications may represent a predictor of longer duration of therapy. According to the mortality analysis, LCIG patients show a long lifespan. Delaying the initiation of LCIG does not affect the sustainability of LCIG therapy.

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.

Clozapine Use in a Movement Disorder Clinic.

BACKGROUND: Clozapine is an effective antipsychotic for Parkinson's disease (PD) that does not worsen motor function and can improve tremor. It is approved for PD psychosis in Europe and Australia. OBJECTIVE: The aim of this study was to report on the use of clozapine in a movement disorder clinic. METHODS: We report on patients monitored during the COVID-19 pandemic in clinic over a 7-month period. RESULTS: Sixty-five patients were seen, of whom 50 had PD. Thirty-one were treated for psychosis, 18 for refractory tremor and 1 for levodopa dyskinesias. The remainder had psychotic symptoms with dementia with Lewy bodies (n = 2) or other movement disorders. Four had clozapine discontinued because of sedation and 1 for agranulocytosis. Three had clozapine temporarily halted because of granulocytopenia but were rechallenged successfully. CONCLUSIONS: When comparing clozapine use in this clinic as compared with others, we deduce that clozapine is likely significantly underutilized in the United States.

Parkinson's Disease Drug Therapies in the Clinical Trial Pipeline: 2022 Update.

BACKGROUND: As the international community dealt with the ongoing COVID-19 pandemic, important progress continued to be made in the development of new drug-based therapies for the neurodegenerative condition of Parkinson's disease (PD) in 2021. This progress included both "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), which can be categorised further based on their mechanisms of action and class of drug. OBJECTIVE: This report continues previous efforts to provide an overview of the pharmacological therapies - both ST and DMT - in clinical trials for PD during 2021- 2022, with the aim of creating greater awareness and involvement in the clinical trial process. We also hope to stimulate collaboration amongst all stakeholders, including industry, academia, advocacy organizations, and most importantly patient community. METHODS: We conducted a review of clinical trials of drug therapies for PD using trial data obtained from the ClinicalTrials.gov and World Health Organisation (WHO) registries, and performed a breakdown analysis of studies that were active as of January 31st 2022. We also assessed active drug development projects that had completed one clinical phase but were yet to start the next. RESULTS: There was a total of 147 clinical trials registered on the ClinicalTrials.gov website as active during the period of analysis. Of these trials, 91 (62%)were investigating STs, while 56 (38%)focused on DMTs. Approximately 1/3 of the studies (34.7%; 51 trials) were in Phase 1, while over half of the trials were in Phase 2 (50.3%; 74 trials). Only 15% (22 trials) of the studies were in Phase 3, of which only 3 trials were evaluating DMTs. Novel therapeutics (42%)were the most common type of agents being tested across all phases of testing, followed by repurposed agents (34%)and reformulations (20%). CONCLUSION: Despite significant global health constraints, the development of new drug-based therapies for PD continued in 2021. Hopefully with a shift towards a post-pandemic world in which COVID-19 is better managed, we will see an increase in the number of clinical trials focused on drug development for PD. The need for more Phase 3 studies for DMTs remains acute.

Parkinson's Disease and the COVID-19 Pandemic.

Studies focusing on the relationship between severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), coronavirus disease 2019 (COVID-19), and Parkinson's disease (PD) have provided conflicting results. We review the literature to investigate: 1) Are PD patients at higher risk for contracting COVID-19 and are there specific contributing factors to that risk? 2) How does COVID-19 affect PD symptoms? 3) How does COVID-19 present in PD patients? 4) What are the outcomes in PD patients who contract COVID-19? 5) What is the impact of COVID-19 on PD care? 6) Does COVID-19 increase the risk of developing PD? A literature search was performed from 1979 to 2020 using the terms: 'Parkinson's disease' and 'parkinsonism' combined with: 'COVID-19'; 'SARS-CoV-2' and 'coronavirus'. It does not appear that PD is a specific risk factor for COVID-19. There is evidence for direct/indirect effects of SARS-CoV-2 on motor/non-motor symptoms of PD. Although many PD patients present with typical COVID-19 symptoms, some present atypically with isolated worsening of parkinsonian symptoms, requiring increased anti-PD therapy and having worse outcomes. Mortality data on PD patients with COVID-19 is inconclusive (ranging from 5.2%to 100%). Patients with advanced PD appear to be particularly vulnerable. Single cases of acute hypokinetic-rigid syndrome have been described but no other convincing data has been reported. The rapidity with which COVID-19 has swept across the globe has favored the proliferation of studies which lack scientific rigor and the PD literature has not been immune. A coordinated effort is required to assimilate data and answer these questions in larger PD cohorts.

Impact of Coronavirus Disease 2019 Pandemic on Parkinson's Disease: A Cross-Sectional Survey of 568 Spanish Patients.

BACKGROUND: The aim of this study was to know the impact of the coronavirus disease 2019 (COVID-19) pandemic on Spanish patients with Parkinson's disease (PD). METHODS: This is a descriptive, observational, cross-sectional study. An anonymous online survey with 95 questions was distributed among patients. Responses were collected from 11 May 2020 to 20 July 2020. RESULTS: Of a total of 570 questionnaires received, 568 (99.6%) were considered valid for the analysis (mean age, 63.5 ± 12.5 years; 53% females). A total of 553 patients (97.4%) were aware of the COVID-19 pandemic and 68.8% were concerned about it; 95.6% took preventive measures. A total of 484 patients (85.2%) had no contact with cases of COVID-19, and only 15 (2.6%) had confirmed COVID-19. Although up to 72.7% remained active during confinement, 65.7% perceived a worsening of their symptoms. CONCLUSIONS: Spanish patients with PD perceived the COVID-19 pandemic with concern and responsibility. More than half experienced worsening of their symptoms during confinement. © 2020 International Parkinson and Movement Disorder Society.

Targeting COVID-19 in Parkinson's Patients: Drugs Repurposed.

The last couple of months have witnessed the world in a state of virtual standstill. The SARS-CoV-2 virus has overtaken the globe to economic and social lockdown. Many patients with COVID-19 have compromised immunity, especially in an aged population suffering from Parkinson 's disease (PD). Alteration in dopaminergic neurons and deficiency of dopamine in PD patients are the most common symptoms affecting 1% population above the age of 60 years. The compromised immune system and inflammatory manifestation in PD patients make them an easy target. The most common drugs under trial for COVID-19 are remdesivir, favipiravir, chloroquine and hydroxychloroquine, azithromycin along with adjunct drugs like amantadine with some monoclonal antibodies. Presently, clinically US FDA approved drugs in PD include Levodopa, catechol-O-methyl transferase (COMT) inhibitors, (Entacapone and Tolcapone), dopamine agonists (Bromocriptine, Ropinirole, Pramipexole, and Rotigotine), monoamine oxidase B (MAO-B) inhibitors (Selegiline and Rasagiline), amantadine and antimuscarinic drugs. The drugs have established mechanisms of action on PD patients with known pharmacodynamics and pharmacokinetic properties along with dose and adverse effects. Conclusion and relevance of this review focus on the drugs that can be tried on PD patients with SAR CoV-2 infection, in particular, amantadine that has been approved by all the developed countries as a common drug possessing both antiviral properties by downregulation of CTSL, lysosomal pathway disturbance and change in pH necessary to uncoat the viral proteins and anti- Parkinson properties. To deal with the significant prognostic adverse effect of SARS-CoV-2 on PD, the present-day treatment options, clinical presentation and various mechanisms are the need of the hour.

The Impact of COVID-19 on Access to Parkinson's Disease Medication.

BACKGROUND: Many countries have implemented drastic measures to fight the COVID-19 pandemic. Restrictions and diversion of resources may have negatively affected patients with Parkinson's disease (PD). Our aim was to examine whether COVID-19 had an impact on access to PD medication by region and income. METHODS: This study was conducted as part of a survey sent to members of the Movement Disorders Society focusing on access to PD medication globally. RESULTS: Of 346 responses, 157 (45.4%) agreed that COVID-19 had affected access to PD medication, while 189 (54.6%) disagreed. 22.8% of high-income and 88.9% of low-income countries' respondents agreed that access to PD medication was affected by COVID-19. 59% of all 'yes' respondents reported increased disability of patients as an impact. CONCLUSIONS: Access to PD medication is likely to have been affected by COVID-19 and result in deterioration of patients' symptomatic control. Resource-poor countries appear to be disproportionately affected compared to more affluent countries. © 2020 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.