Digital health technologies and Alzheimer's disease clinical trials: might decentralized clinical trials increase participation by people with cognitive impairment?

BACKGROUND: Therapeutic trials in Alzheimer's disease (AD) face many obstacles-particularly with regard to screening and recruitment. DISCUSSION: Decentralized clinical trials (DCTs) are being developed in other diseases and appear to be of value for overcoming these difficulties. The use of remote visits offers hope of broader recruitment and thus a reduction in inequalities due to age, geography, and ethnicity. Furthermore, it might be easier to involve primary care providers and caregivers in DCTs. However, further studies are needed to determine the feasibility of DCTs in AD. A mixed-model DCT might constitute the first step towards completely remote trials in AD and should be assessed first.

[Cerebrolysin in the treatment of cognitive impairment]. / Tserebrolizin v lechenii kognitivnykh narushenii.

Cognitive impairment is one of the most important problems of modern health care. Currently, according to WHO, more than 55 million people worldwide are living with dementia. Dementia is one of the leading causes of disability and addiction among older people worldwide. Even more significant is the number of patients with mild cognitive impairment who have an increased risk of progression to dementia compared to people of the same age without cognitive impairment. The number of patients with cognitive impairment has also increased due to the consequences of COVID-19. It is necessary to use drugs that not only improve cognitive functions, but also slow down their progression. One of these drugs is cerebrolysin, the effectiveness of which has been confirmed in various types of cognitive impairment. Cerebrolysin, being a preparation from the brain of a pig, belongs to the group of biological drugs. In the production of Cerebrolysin very strict measures are taken to comply with the technology, which ensures the quality and identity of the product from batch to batch. The experience of many years of clinical use of Cerebrolysin testifies not only to its high efficiency, but also to its safety. It should be taken into account that similar substances can be developed in relation to biological products - biosimilars or biosimilars, which can be considered comparable only in case of equivalent pharmacokinetic parameters, efficacy and safety.

Natural and Semi-Synthetic Flavonoid Anti-SARS-CoV-2 Agents for the Treatment of Long COVID-19 Disease and Neurodegenerative Disorders of Cognitive Decline.

The aim of this review is to highlight the beneficial attributes of flavonoids, a diverse family of widely-distributed polyphenolic phytochemicals that have beneficial cell and tissue protective properties. Phytochemicals are widely distributed in plants, herbs and shrubs used in traditional complimentary medical formulations for centuries. The bioactive components that convey beneficial medicinal effects in these complex herbal preparations are now being identified using network pharmacology and molecular docking procedures that identify their molecular targets. Flavonoids have anti-oxidant, anti-inflammatory, antiviral, antibacterial and anti-cancer properties that have inspired the development of potent multifunctional derivatised flavonoids of improved efficacy. The antiviral properties of flavonoids and the emergence of the severe acute respiratory syndrome (SARS-CoV-2) pandemic has resulted in a resurgence of interest in phytochemicals in the search for efficacious compounds that can prevent viral infection or replication, with many promising plant compounds identified. Promising semi-synthetic flavonoid derivatives have also been developed that inhibit multiple pathological neurodegenerative processes; these offer considerable promise in the treatment of diseases of cognitive decline. Clinical trials are currently being undertaken to evaluate the efficacy of dietary supplements rich in flavonoids for the treatment of virally-mediated diseases. Such trials are expected to identify flavonoids with cell and tissue protective properties that can be harnessed in biomedical applications that may serve as supportive adjunctive procedures to conventional anti-viral drug therapies against diseases such as COVID-19.

[Neurological disorders in the postcovid period]. / Nevrologicheskie narusheniya v postkovidnom periode.

The consequences of COVID-19 include a wide range of neurological, emotional and cognitive impairments. The pathogenesis of postcovid disorders is complex and has not been fully studied. The article discusses the pathogenesis and clinical manifestations of neuropostocoid. A hypothesis is formulated about the possible role of circumventricular organs in its formation. The main directions of treatment of patients with postcovid disorders are proposed.

Alleviation of Post-COVID-19 Cognitive Deficits by Treatment with EGb 761®: A Case Series.

BACKGROUND Cognitive symptoms persisting longer than 3 months after infection, such as memory loss, or difficulties concentrating, have been reported in up to one-third of patients after COVID-19. Evidence-based therapeutic interventions to treat post-COVID-19 symptoms (also called "Long-COVID symptoms") have not yet been established, and the treating physicians must rely on conjecture to help patients. Based on its mechanism of action and its efficacy in treating cognitive impairment, as well as its good tolerability, the Ginkgo biloba special extract EGb 761 has been suggested as a remedy to alleviate cognitive post-COVID-19 symptoms. In many studies, EGb 761 has been demonstrated to protect endothelial cells, to have potent anti-inflammatory effects, and to enhance neuroplasticity. CASE REPORT Here, we report for the first time the application of EGb 761 in the therapy of post-COVID-19-related cognitive deficits. Three women and 2 men, aged 26 to 59 years (average age 34.6 years), presented with concentration and attention deficits, cognitive deficiencies, and/or fatigue 9-35 weeks after infection. A daily dose of 2×80 mg of EGb 761 did not cause any detectable adverse effects, and it substantially improved or completely restored cognitive deficits and, when initially present, also other symptoms, such as fatigue and hyposmia, within an observation period of up to 6 months. CONCLUSIONS Our observations support the hypothesis that EGb 761 might be a low-risk treatment option for post-COVID-19 patients with cognitive symptoms. Moreover, we derive recommendations for randomized controlled clinical trials to confirm efficacy in that indication.

Metformin alleviates prolonged isoflurane inhalation induced cognitive decline via reducing neuroinflammation in adult mice.

With the widespread use of volatile anesthetic agents in the prolonged sedation for COVID-19 pneumonia and ARDS, there is an urgent need to investigate the effects and treatments of lengthy low-concentration inhaled anesthetics exposure on cognitive function in adults. Previous studies showed that general anesthetics dose- and exposure length-dependently induced neuroinflammatory response and cognitive decline in neonatal and aging animals. The anti-diabetes drug metformin has anti-neuroinflammation effects by modulating microglial polarization and inhibiting astrocyte activation. In this study, we demonstrated that the inhalation of 1.3% isoflurane (a sub-minimal alveolar concentration, sub-MAC) for 6 h impaired recognition of novel objects from Day 1 to Day3 in adult mice. Prolonged sub-MAC isoflurane exposure also triggered typically reactive microglia and A1-like astrocytes in the hippocampus of adult mice on Day 3 after anesthesia. In addition, prolonged isoflurane inhalation switched microglia into a proinflammatory M1 phenotype characterized by elevated CD68 and iNOS as well as decreased arginase-1 and IL-10. Metformin pretreatment before anesthesia enhanced cognitive performance in the novel object test. The positive cellular modifications promoted by metformin pretreatment included the inhibition of reactive microglia and A1-like astrocytes and the polarization of microglia into M2 phenotype in the hippocampus of adult mice. In conclusion, prolonged sub-MAC isoflurane exposure triggered significant hippocampal neuroinflammation and cognitive decline in adult mice which can be alleviated by metformin pretreatment via inhibiting reactive microglia and A1-like astrocytes and promoting microglia polarization toward anti-inflammatory phenotype in the hippocampus.

Targeting impaired nutrient sensing with repurposed therapeutics to prevent or treat age-related cognitive decline and dementia: A systematic review.

BACKGROUND: Dementia is a debilitating syndrome that significantly impacts individuals over the age of 65 years. There are currently no disease-modifying treatments for dementia. Impairment of nutrient sensing pathways has been implicated in the pathogenesis of dementia, and may offer a novel treatment approach for dementia. AIMS: This systematic review collates all available evidence for Food and Drug Administration (FDA)-approved therapeutics that modify nutrient sensing in the context of preventing cognitive decline or improving cognition in ageing, mild cognitive impairment (MCI), and dementia populations. METHODS: PubMed, Embase and Web of Science databases were searched using key search terms focusing on available therapeutics such as 'metformin', 'GLP1', 'insulin' and the dementias including 'Alzheimer's disease' and 'Parkinson's disease'. Articles were screened using Covidence systematic review software (Veritas Health Innovation, Melbourne, Australia). The risk of bias was assessed using the Cochrane Risk of Bias tool v 2.0 for human studies and SYRCLE's risk of bias tool for animal studies. RESULTS: Out of 2619 articles, 114 were included describing 31 different 'modulation of nutrient sensing pathway' therapeutics, 13 of which specifically were utilized in human interventional trials for normal ageing or dementia. Growth hormone secretagogues improved cognitive outcomes in human mild cognitive impairment, and potentially normal ageing populations. In animals, all investigated therapeutic classes exhibited some cognitive benefits in dementia models. While the risk of bias was relatively low in human studies, this risk in animal studies was largely unclear. CONCLUSIONS: Modulation of nutrient sensing pathway therapeutics, particularly growth hormone secretagogues, have the potential to improve cognitive outcomes. Overall, there is a clear lack of translation from animal models to human populations.

Editorial: Targets for Disease-Modifying Therapies in Alzheimer's Disease, Including Amyloid ß and Tau Protein.

Current treatments for patients with Alzheimer's disease aim to improve behavioral, cognitive, and non-cognitive symptoms. There have been no new drug approvals for preventing or treating Alzheimer's disease for more than two decades. Drug development in Alzheimer's disease aims to identify disease-modifying therapies that will delay or slow the clinical course of this disease. More than 50% of the current Alzheimer's disease drug pipeline now involves immunotherapies or oral small molecule agents. The most promising disease-modifying drug targets are amyloid ß and tau protein. In June 2021, aducanumab, a humanized recombinant monoclonal antibody to amyloid ß, was the first potential disease-modifying therapy approved by the US Food and Drug Administration (FDA) to treat Alzheimer's disease and mild cognitive impairment. Accelerated approval of aducanumab was based on the results of only one of two phase 3 clinical trials. Several clinical trials of targeted disease-modifying immunotherapies to the tau protein and amyloid ß that commenced before the current COVID-19 pandemic have been delayed. This Editorial aims to provide an update on past, present, and future disease-modifying therapies in Alzheimer's disease, including targeted therapies for amyloid ß and tau protein.

[Endothelial dysfunction in COVID- 19 and cognitive impairment]. / Endotelial'naya disfunktsiya pri COVID-19 i kognitivnye narusheniya.

Endothelial dysfunction is an important mechanism underlying multiple organ and systems failure in COVID-19. The development of endothelial dysfunction in COVID-19 can disrupt organ perfusion and cause a procoagulant state, leading to both macro- and microvascular thrombotic events. Cognitive impairment is a common complication of COVID-19 that develop in acute and delayed periods and is not directly related to the severity of the underlying disease. Treatment of endothelial dysfunction in patients with COVID-19 should take into account the leading pathogenetic factors of its development and with the development of neurological, including cognitive, disorders should include neuroprotective drugs. One of these drugs is actovegin, which has been shown to be effective in improving endothelial function, microcirculation and cognition.

Long-COVID syndrome-associated brain fog and chemofog: Luteolin to the rescue.

COVID-19 leads to severe respiratory problems, but also to long-COVID syndrome associated primarily with cognitive dysfunction and fatigue. Long-COVID syndrome symptoms, especially brain fog, are similar to those experienced by patients undertaking or following chemotherapy for cancer (chemofog or chemobrain), as well in patients with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) or mast cell activation syndrome (MCAS). The pathogenesis of brain fog in these illnesses is presently unknown but may involve neuroinflammation via mast cells stimulated by pathogenic and stress stimuli to release mediators that activate microglia and lead to inflammation in the hypothalamus. These processes could be mitigated by phytosomal formulation (in olive pomace oil) of the natural flavonoid luteolin.

[Poststroke motor and cognitive impairments: clinical features and current approaches to rehabilitation]. / Postinsul'tnye dvigatel'nye i kognitivnye narusheniya: klinicheskie osobennosti i sovremennye podkhody k reabilitatsii.

Stroke is one of the most common neurological diseases with high morbidity, disability and mortality, which is an urgent medical and social problem. Clinically, stroke, depending on its nature and location, causes a wide range of neurological disorders, including movement disorders, as well as a variety of cognitive and neuropsychiatric disorders. There is an emerging need for new approaches to manage patients with cerebrovascular diseases during the pandemic of COVID-19. Rehabilitation measures for the correction of motor and cognitive impairments are very diverse. The use of drugs stimulating the production of neurotrophic factors is considered as a promising direction of pharmacotherapy. Cerebrolysin promotes significant regression of motor and cognitive impairments in the acute and recovery period of ischemic stroke. Based on the data of clinical studies, Cerebrolysin is included in the guidelines for the rehabilitation of patients with stroke in Canada and Germany.

The Effects of COVID-19 Home Confinement in Dementia Care: Physical and Cognitive Decline, Severe Neuropsychiatric Symptoms and Increased Caregiving Burden.

PURPOSE: This study aims to analyze home confinement impact on individuals with neurocognitive disorders (NCD) through informal caregiver's perspective and examine how it has affected caregiving burden. METHODS: Thirty-six caregivers (64.94 ± 13.54 years, 41.7% female) of individuals with NCD (74.28 ± 6.76 years, 66.7% female) selected from the Body & Brain exercise program were interviewed over the phone. The following instruments were used: Barthel Index (BI) to assess care recipients' ability to function independently on activities of daily living (ADL), the Neuropsychiatric Inventory (NPI) to evaluate neuropsychiatric symptoms, and the CarerQol-7D/ CarerQol-VAS to determine caregiver subjective burden/well-being. RESULTS: Pre and post-confinement comparisons showed that care recipients significantly declined their independence in ADL (p = 0.003) and increased NPI total score (MD = 5.72; 95% CI: 1.19 to 10.25, p = 0.015). As for caregivers, results also showed an increased caregiving burden (MD = -0.17; 95% CI: -0.27 to -0.08; p = 0.001) and a decline in their well-being (p = 0.015). DISCUSSION: COVID-19 crisis sheds light on how imperative it is to find solutions and design contingency plans for future crisis, in order to ensure properly sustained support to dementia caregiving dyads and mitigate caregivers' burden.

Adamantanes might be protective from COVID-19 in patients with neurological diseases: multiple sclerosis, parkinsonism and cognitive impairment.

Facing the outbreak of coronavirus disease 2019 (COVID-19) pandemic, there is an urgent need to find protective or curable drugs to prevent or to stop the course of the coronavirus SARS-CoV-2 infection. Recent evidence accumulates that adamantanes, widely used in different neurological diseases, could be repurposed for COVID-19. We hereby report on a questionnaire-based study performed to assess severity of COVID-19 in patients suffering from multiple sclerosis (n=10), Parkinson's disease (n=5) or cognitive impairment (n=7). In all patients infection with SARS-CoV-2 was confirmed by rtPCR of nasopharyngeal swabs. They were receiving treatment with either amantadine (n=15) or memantine (n=7) in stable registered doses. All of them had two-week quarantine since documented exposure and none of them developed clinical manifestations of infectious disease. They also did not report any significant changes in neurological status in the course of primary nervous system disease. Above results warrant further studies on protective effects of adamantanes against COVID-19 manifestation, especially in subjects suffering from neurological disease.