Cholinesterase Inhibitor Donepezil Research Articles

Pharmacological Approaches and Herbal Interventions for Alzheimer's Disease

Abstract: This comprehensive review extensively examines the utilization of herbal remedies and pharmacological techniques for managing Alzheimer's disease (AD). It delves deeply into the active constituents and modes of operation of diverse herbal medications such as Withania somnifera, Bacopa monnieri, Ginkgo biloba, and Curcuma longa, emphasizing their qualities in reducing inflammation, acting as antioxidants, and safeguarding neural tissue. Additionally, it assesses conventional pharmaceuticals like cholinesterase inhibitors (Donepezil, rivastigmine) and memantine, investigating their mechanisms of action and potential adverse effects. The study also encompasses non-pharmacological therapies like interventions aimed at cognition, physical exercise, and methods of stimulating the brain, all of which exhibit potential in enhancing cognitive capacity and neural adaptability. Furthermore, it delves into the amalgamation of therapies to tackle numerous facets of AD pathology. In essence, this review furnishes valuable insights into alternative strategies for managing AD, underscoring the potential of herbal interventions in enhancing cognitive function and addressing the underlying issues of AD. Additionally, it presents a fresh avenue for exploring the collaborative impacts of combining conventional pharmaceuticals with herbal remedies.

The impact of long-course chemoradiotherapy on the myenteric plexus, neuromuscular functions and responses to prokinetic drugs in the human rectum.

The long-term effects of chemoradiotherapy on human rectum are poorly understood. The aims were to investigate changes in inflammatory status, myenteric neuron numbers/phenotype, neuromuscular functions and prokinetic drug efficacy. Macroscopically normal proximal-to-mid rectum was obtained from 21 patients undergoing surgery for bowel cancer, 98days (range: 63-350) after concurrent capecitabine and pelvic radiotherapy, and 19 patients without chemoradiotherapy. Inflammatory status was measured by H&E, CD45 staining and qPCR. Myenteric neurons were examined by immunohistochemistry. Neuromuscular functions and drug efficacy were studied using exogenous agents and electrical field stimulation (EFS) to activate intrinsic nerves. Inflammation was not detected. Numbers of myenteric ganglia/neurons were unchanged (11.7±2.4 vs. 10.3±2.2 neurons/mm myenteric plexus with/without chemoradiotherapy) as were the numbers of cholinergic/nitrergic neurons. EFS stimulated cholinergic and nitrergic neurons so the contractile response of the muscle was the sum of both but dominated by cholinergic (causing contraction) or less often, nitrergic activity (relaxation), followed, after termination of EFS, by neuronally mediated contraction. Inhibition of nitric oxide synthase (by L-NAME 300μM) more clearly defined EFS-evoked contractions. The 5-HT4 agonist prucalopride 10μM and the cholinesterase inhibitor donepezil 1µM, respectively increased and greatly increased the composite contractile response to EFS (measured as 'area-under-the curve') and the contractions isolated by L-NAME (respectively, by 22±14% and 334±87%; n=11/8). After chemoradiotherapy, nitrergic-mediated muscle relaxations occurred more often during EFS (in 29.8±6.1% preparations vs. 12.6±5.1% without chemoradiotherapy, n=21/18). With L-NAME, the ability of prucalopride to facilitate EFS-evoked contraction was lost and that of donepezil approximately halved (contractions increased by 132±36%; n=8). Several months after chemoradiotherapy, the rectum was not inflamed and myenteric neuron numbers/phenotype unchanged. However, nitrergic activity was increased relative to cholinergic activity, and prokinetic-like drug activity was lost or greatly reduced. Thus, chemoradiotherapy causes long-term changes in neuromuscular functions and markedly reduces the efficacy of drugs for treating constipation.

Systematic Review on Pathology and Drug Efficacy Clinical Trials (1973-2023) for Cognitive Impairment and Alzheimer’s Dementia

Rationale: The systematic review evaluates the results of last fifty years (1973-2023) of clinical trials on pathology and treatment for cognitive impairment including Alzheimer’s dementia (AD dementia). Objectives: Alzheimer’s dementia is a growing public health concern worldwide. The systematic review analyzes the disease confirming pathological findings presented by modern imaging techniques MRI/ PET. In addition, we analyze the success of fifty years of therapeutic advancements of the neurological disabilities and count on the safe drugs to treat clinical conditions of AD dementia. Findings: We followed the PRISMA guidelines to determine the inclusion and exclusion criteria for the selection of clinical records collected from the NCBI databases. We analyzed the drug efficacy results on the three aspects of the AD brain: (a) morphological deformation of the choroid plexus and hippocampus; (b) senile plaques with amyloid beta42 (Abeta42) including hyperintensities of neurons; and (c) inhibitory action of acetylcholinesterase enzyme. The pathological findings include detection of Abeta42 plaques in cerebral cortex and retention ability of trial drugs in cerebrospinal fluid versus blood plasma of AD patients in the context of disease progression and treatment efficacy. The clinical trial records demonstrated evidence of genetic susceptibility factor(s) clustered in European populations. The susceptibility is also found due to mutations in the presenilin-1 gene and expression of the ApoEε-allele among the population. The clinical records demonstrate moderate efficacy of cholinesterase inhibitors Donepezil and Rivastigmine in improving cognition. The antibodies aducanumab, donanemab, and lecanemab show low to moderate success in removing plaques and reducing plasma Abeta burden. Conclusion: The cholinesterase inhibitors demonstrate moderate success in improving cognition. However, the overall efficacy of antibody treatment was poor. The findings suggest a need for new generation drugs which can clear plaques and improve cognition for AD.

Systematic Overview: AD Pathology and Recent Pharmacological Advances

This systematic review provides a comprehensive analysis of Alzheimer’s Disease (AD) pathology and its pharmacological advancements. Population aging over last decades render AD becoming more prevalent, indicating a significant sociological and economic burden. Yet, due to the complexity of the brain structure, the researchers must understand AD’s multifactorial pathology and progression mechanisms in order to find an effective treatment. The review will primarily examine the classical amyloid-β hypothesis and tau protein’s involvement, exploring their interplay in neuronal degeneration. Additionally, it also examines the emerging theories of neuroinflammation, prion-like proteins and vascular damages as crucial contributors to AD pathology. Recently, several FDA-approved non-curative drugs have been reported to reduce amyloid-β plaque and/or enhance cognitive function. Consequently, beyond analyzing AD’s pathological hypotheses, critically assessments on recent pharmacological advances using monoclonal antibodies (Aducanumab), cholinesterase inhibitors (Donepezil) and NMDA antagonists (Memantine) are used as examples to compare their clinical efficacies and controversies. Discussion on other factors including ethical considerations, personalized medicine and the transformation of treatment paradigms are included. By identifying a paradigm shift towards a multi-targeted approach which integrates pharmacological and non-pharmacological interventions, this review underscores the necessities of ethical concerns and patient-centred treatments. Thus, this review aims to present an academic consolidation of current knowledge and stimulate further interdisciplinary research, promoting innovation in AD treatment.

Research and progress of focused ultrasound in the treatment of Alzheimer's disease.

Alzheimer's disease is one of the most common degenerative diseases of the central nervous system, with progressive cognitive and memory impairment and decreased ability of daily life as the cardinal symptoms, influencing the life quality of patients severely. There are currently approximately 46 million people living with Alzheimer's disease worldwide, and the number is expected to triple by 2050, which will pose a huge challenge for healthcare. At present, the Food and Drug Administration of the United States has approved five main drugs for the clinical treatment of Alzheimer's disease, which are cholinesterase inhibitors tacrine, galantamine, capalatine and donepezil, and N-methyl-d-aspartate receptor antagonist memantine, although these drugs have shown good efficacy in clinical trials, the actual clinical effect is less effective due to the existence of blood brain barrier. With the continuous development of ultrasound technology in recent years, focused ultrasound, as a non-invasive treatment technique, may target ultrasound energy to the deep brain for treatment without damaging the surrounding tissue. For the past few years, some studies could use focused ultrasound combined with microvesicles to induce blood brain barrier opening and targeted drug delivery to treat Alzheimer's disease, providing new opportunities for the treatment of Alzheimer's disease. This article reviews the application research and progress of focused ultrasound in the treatment of Alzheimer's disease, in order to provide new directions and ideas for the treatment of Alzheimer's disease.

Cholinesterase inhibitors and falls, syncope and injuries in patients with cognitive impairment: a systematic review and meta-analysis.

Cholinesterase inhibitors are commonly used to treat patients with neurocognitive disorders, who often have an elevated risk of falling. Effective use of these medications requires a thoughtful assessment of risks and benefits. To provide an update on previous reviews and determine the association between cholinesterase inhibitors and falls, syncope, fracture and accidental injuries in patients with neurocognitive disorders. Embase, MEDLINE, Cochrane Central Register of Controlled Trials, Cumulative Index of Nursing and Allied Health Literature and AgeLine were systematically searched through March 2023 to identify all randomised controlled trials of cholinesterase inhibitors (donepezil, galantamine, rivastigmine) in patients with cognitive impairment. Corresponding authors were contacted for additional data necessary for meta-analysis. Inclusion criteria consisted of adults ≥19years, with a diagnosis of dementia, Parkinson's disease, mild cognitive impairment or traumatic brain injury. Data were extracted in duplicate for the aforementioned primary outcomes and all outcomes were analysed using random-effects meta-analysis. Fifty three studies (30 donepezil, 14 galantamine, 9 rivastigmine) were included providing data on 25, 399 patients. Cholinesterase inhibitors, compared to placebo, were associated with reduced risk of falls (risk ratio [RR] 0.84 [95% confidence interval [CI] = 0.73-0.96, P = 0.009]) and increased risk of syncope (RR 1.50 [95% CI = 1.02-2.21, P = 0.04]). There was no association with accidental injuries or fractures. In patients with neurocognitive disorders, cholinesterase inhibitors were associated with decreased risk of falls, increased risk of syncope and no association with accidental trauma or fractures. These findings will help clinicians better evaluate risks and benefits of cholinesterase inhibitors.

Dementia Diagnosis and Alternate Treatment: A Recent Update on Treatment Options

Dementia is a global health burden identified by the World Health Organization in its global action plan on the public health response to dementia 2017-2025. Our study aims to determine the efficacy of treatment options in Alzheimer’s disease and related dementia (ADRD). The initiation of dementia treatment has consistently posed a significant dilemma for healthcare professionals, necessitating careful consideration when selecting the appropriate group of medications to commence therapy, considering the specific type of treatment required. To conduct our study, we searched PubMed Central and the Cochrane database to identify comparative trials that compared different dementia treatment options. Our objective was to evaluate the effectiveness of various treatment approaches across different types of dementia. In total, we reviewed over 40 papers that provided valuable insights into the comparative outcomes of these treatment options. In our analysis, we have found mild to moderate cognitive dysfunction (MMSE 19 to 26) and newly diagnosed Alzheimer's disease can be treated with a trial of Cholinesterase inhibitors (Donepezil, Galantamine, and Rivastigmine); choice can be based on clinician and/or patient preference, as efficacy is similar. Moderate to advanced dementia (MMSE 10 to 18): Memantine (10 mg twice daily) is a suggested option with Cholinesterase inhibitors. In conclusion, it is evident that the available options for dementia medication are inherently limited, while the resources allocated to evaluate further treatment alternatives remain constrained. As a result, there is an urgent need to prioritize additional research and comprehensive assessment in this field.

SARS-CoV-2 S1 protein causes brain inflammation by reducing intracerebral acetylcholine production

Neurological complications that occur in SARS-CoV-2 infection, such as olfactory dysfunction, brain inflammation, malaise, and depressive symptoms, are thought to contribute to long COVID. However, in autopsies of patients who have died from COVID-19, there is normally no direct evidence that central nervous system damage is due to proliferation of SARS-CoV-2. For this reason, many aspects of the pathogenesis mechanisms of such symptoms remain unknown. Expressing SARS-CoV-2 S1 protein in the nasal cavity of mice was associated with increased apoptosis of the olfactory system and decreased intracerebral acetylcholine production. The decrease in acetylcholine production was associated with brain inflammation, malaise, depressive clinical signs, and decreased expression of the cytokine degrading factor ZFP36. Administering the cholinesterase inhibitor donepezil to the mice improved brain inflammation, malaise and depressive clinical signs. These findings could contribute to the elucidation of the pathogenesis mechanisms of neurological complications associated with COVID-19 and long COVID.

The therapeutic effect of Zhenbao pills on behavioral changes in zebrafish caused by aluminum chloride

Zhenbao pill (ZBP) is a type of traditional Mongolian medicine that contains 241 ingredients such as flavonoids, anthraquinones, triterpenoids, sterols, and Calculus bovis, which are mainly used for treating neurological diseases in clinical practice. In this study, we established an Alzheimer’s disease (AD)-mimetic symptomatic zebrafish model by AlCl3 treatment and investigated the therapeutic effect of ZBP on the AD-mimetic zebrafish model. The results revealed that AlCl3 treatment led to behavioral impairment, induced apoptotic cell (body) in the brain, increased acetylcholinesterase (AChE) activity, and decreased the ACh content in zebrafish. After treatment with ZBP, 16 μg/mL ZBP could alleviate the behavioral disorder of zebrafish larvae. This effect was found superior to the effect of the cholinesterase inhibitor donepezil hydrochloride. The analysis of transcriptomics data revealed that ZBP mainly acted on apoptosis, the p53 signaling pathway, and the enrichment of the AChE-associated pathway. Furthermore, the overexpression of AChE RNA produced similar AD-mimetic disorders, whereas AChE-gene knockdown (AChE-MO) decreased the AChE activity and alleviated the AD-mimetic symptoms. These results suggested that ZBP is a potential cholinergic-enhancing drug, which can be used for the treatment of AD in the future.

Inhibition of Th17 cells by donepezil ameliorates experimental lung fibrosis and pulmonary hypertension.

Rationale: Pulmonary hypertension (PH) secondary to lung fibrosis belongs to WHO Group III, one of the most common subgroups of PH; however, it lacks effective treatment options. Cholinesterase inhibitor donepezil (DON) has been shown to effectively improve Group I PH. However, its effects on Group III PH are unknown. Methods: A lung fibrosis-induced PH mouse model was constructed using a single intratracheal instillation of bleomycin (BLM), after which DON was administered daily. Pulmonary artery and right ventricle (RV) remodeling were evaluated at the end of the study. Lung tissue in each group was analyzed using RNA sequencing, and the results were further verified with datasets from patients with PH. The mechanisms underlying DON-induced effects on PH were verified both in vivo and in vitro. Results: DON effectively improved pulmonary artery and RV remodeling in the BLM-induced mouse model. Transcriptomic profiles of lung tissue indicated that the expression of inflammatory and fibrotic genes was significantly changed in this process. In the animal model and patients with PH, T helper 17 lymphocytes (Th17) were the most common inflammatory cells infiltrating the lung tissue. DON significantly inhibited lung fibroblast activation; thus, preventing lung fibrosis and reducing the inflammatory response and Th17 cell infiltration in the BLM-induced lung tissue. In addition, Th17 cells could activate lung fibroblasts by secreting IL17A, and DON-mediated inhibition of Th17 cell differentiation was found to depend on the α7nAchR-JAK2-STAT3 pathway. Conclusion: DON can alleviate lung fibrosis and PH in an experimental mouse model. It inhibited pro-inflammatory Th17 cell differentiation, which is dependent on a cholinergic receptor pathway, thereby regulating fibroblast activation.

Multi-targeted anti-inflammatory drugs for the treatment of neurological disorders.

Multi-targeted anti-inflammatory drugs for the treatment of neurological disorders.

Interventions for preventing falls in Parkinson's disease.

Interventions for preventing falls in Parkinson's disease.

Phosphoproteomic of the acetylcholine pathway enables discovery of the PKC-β-PIX-Rac1-PAK cascade as a stimulatory signal for aversive learning

Acetylcholine is a neuromodulator critical for learning and memory. The cholinesterase inhibitor donepezil increases brain acetylcholine levels and improves Alzheimer’s disease (AD)-associated learning disabilities. Acetylcholine activates striatal/nucleus accumbens dopamine receptor D2-expressing medium spiny neurons (D2R-MSNs), which regulate aversive learning through muscarinic receptor M1 (M1R). However, how acetylcholine stimulates learning beyond M1Rs remains unresolved. Here, we found that acetylcholine stimulated protein kinase C (PKC) in mouse striatal/nucleus accumbens. Our original kinase-oriented phosphoproteomic analysis revealed 116 PKC substrate candidates, including Rac1 activator β-PIX. Acetylcholine induced β-PIX phosphorylation and activation, thereby stimulating Rac1 effector p21-activated kinase (PAK). Aversive stimulus activated the M1R-PKC-PAK pathway in mouse D2R-MSNs. D2R-MSN-specific expression of PAK mutants by the Cre-Flex system regulated dendritic spine structural plasticity and aversive learning. Donepezil induced PAK activation in both accumbal D2R-MSNs and in the CA1 region of the hippocampus and enhanced D2R-MSN-mediated aversive learning. These findings demonstrate that acetylcholine stimulates M1R-PKC-β-PIX-Rac1-PAK signaling in D2R-MSNs for aversive learning and imply the cascade’s therapeutic potential for AD as aversive learning is used to preliminarily screen AD drugs.

Targeting the Beta-2-Adrenergic Receptor and the Risk of Developing Alzheimer's Disease: A Retrospective Inception Cohort Study.

Background:Animal studies suggested that β2-Adrenergic receptors (β2AR) may be a potential target for the treatment of Alzheimer’s disease (AD).Objective:This retrospective inception cohort study aimed to assess the association between antagonists and agonists of the β2AR and the risk of starting treatment for AD in older adults.Methods:A retrospective inception cohort study was conducted among older adults who initiated either non-selective βAR antagonists or selective β2AR agonists using the University Groningen IADB.nl prescription database (study period 1994–2019). For each exposed cohort, two reference cohorts (A and B) were matched on age at index date. The main outcome was defined as at least two prescriptions for cholinesterase inhibitors (rivastigmine, galantamine, and donepezil) and/or memantine. Cox proportional hazard regression models were used to estimate hazard ratios (HR).Results:The risk of developing AD was elevated among patients exposed to non-selective βAR antagonists (A: aHR 3.303, 95% CI 1.230–8.869, B: aHR 1.569, 95% CI 0.560–4.394) and reduced among patients exposed to selective β2AR agonists (A: aHR 0.049, 95% CI 0.003–0.795, B: aHR 0.834, 95% CI 0.075–9.273) compared to reference patients.Conclusion:These findings suggest that exposure to non-selective βAR antagonists is associated with an increased risk for developing AD whereas there may be a decreased risk for developing AD after exposure to selective β2AR agonists.

Association Between the Cholinesterase Inhibitor Donepezil and the Cholinergic Precursor Choline Alphoscerate in the Treatment of Depression in Patients with Alzheimer's Disease.

Background:Depressive symptoms are common in Alzheimer’s disease (AD) patients and are associated with an increased functional decline. Selective serotonin reuptake inhibitor antidepressants showed a limited efficacy.Objective:The purpose of this work was to evaluate if a higher brain cholinergic stimulation induced by the association between the acetylcholinesterase inhibitor donepezil and the cholinergic precursor choline alphoscerate has any effect on depression in AD patients.Methods:Patients were selected among those recruited in the ASCOMALVA (association between the cholinesterase inhibitor donepezil and the cholinergic precursor choline alphoscerate in AD) trial. Depressive symptoms were investigated in 90 AD patients through the neuropsychiatric inventory at baseline and after 3, 6, 9, 12, 18, and 24 months of treatment. Patients were randomized in a group association therapy (45 subjects) receiving donepezil 10 mg plus choline alphoscerate 1,200 mg/day, and a group monotherapy (45 subjects) receiving donepezil 10 mg/day plus placebo. Based on the results of the MMSE at the recruitment patients were divided into 3 groups: severely impaired (score < 15); moderately impaired (score 19-16); mild-moderately impaired (score 24-20).Results:Depression symptoms were significantly lower (p < 0.05) in patients treated with donepezil plus choline alphoscerate compared to patients treated with donepezil alone. Subjects of the group having mild to moderate cognitive impairment were those more sensitive to the association treatment.Conclusion:Depression symptoms of AD patients in the mild to moderate stage probably could to benefit of a stronger cholinergic stimulation induced by associating donepezil with the cholinergic precursor choline alphoscerate.

Management of psychiatric disorders in patients with cancer.

Management of psychiatric disorders in patients with cancer.

Alzheimer’s Disease Therapy, and the Effects of Genetic Polymorphisms on Its Efficacy and Safety

Alzheimer’s disease (AD) continues to be a significant health burden worldwide as the global population is getting older and health care costs are escalating. AD is a heterogeneous condition having diverse phenotypes and genotypes, which is a major challenge in understanding disease etiopathogenesis. The difficulty in understanding the intricacies of the disease has led to recurrent failure of therapeutic agents in clinical trials resulting in an extremely slow and low success in the new drug discovery process for the AD. Currently approved agents for AD therapy are acetyl cholinesterase inhibitors (AchEIs) (donepezil, galantamine and rivastigmine) and n-methyl d-aspartate (NMDA) antagonist (memantine) that provide symptomatic relief only. However, extensive inter-individual variability in drug responsiveness is observed. ‘Pharmacogenomics’ which refers to how the genome of a patient might affect the treatment response to a drug, appears to play an important role in this inter-individual variability. By bringing pharmacogenomics profile of patients on AD therapy into consideration, it might be possible to gain maximum benefits from available treatments in terms of safety, therapeutic optimization and minimizing adverse effects. The purpose of this review is to provide better understanding of AD pathogenesis, challenges of current AD therapy and insight into the role of genetic polymorphism in drug response with focus on available therapeutic options in AD.

Muscarinic signaling regulates voltage-gated potassium channel KCNQ2 phosphorylation in the nucleus accumbens via protein kinase C for aversive learning.

The nucleus accumbens (NAc) plays critical roles in emotional behaviors, including aversive learning. Aversive stimuli such as an electric foot shock increase acetylcholine (ACh) in the NAc, and muscarinic signaling appears to increase neuronal excitability and aversive learning. Muscarinic signaling inhibits the voltage-dependent potassium KCNQ current which regulates neuronal excitability, but the regulatory mechanism has not been fully elucidated. Phosphorylation of KCNQ2 at threonine 217 (T217) and its inhibitory effect on channel activity were predicted. However, whether and how muscarinic signaling phosphorylates KCNQ2 in vivo remains unclear. Here, we found that PKC directly phosphorylated KCNQ2 at T217 in vitro. Carbachol and a muscarinic M1 receptor (M1R) agonist facilitated KCNQ2 phosphorylation at T217 in NAc/striatum slices in a PKC-dependent manner. Systemic administration of the cholinesterase inhibitor donepezil, which is commonly used to treat dementia, and electric foot shock to mice induced the phosphorylation of KCNQ2 at T217 in the NAc, whereas phosphorylation was suppressed by an M1R antagonist. Conditional deletion of Kcnq2 in the NAc enhanced electric foot shock induced aversive learning. Our findings indicate that muscarinic signaling induces the phosphorylation of KCNQ2 at T217 via PKC activation for aversive learning.

Masitinib in mild to moderate Alzheimer’s disease: Results from study AB09004

AbstractBackgroundMasitinib is a small molecule drug targeting KIT, LYN, FYN and CSF1R. Proof‐of‐concept that masitinib slowed cognitive decline in Alzheimer's disease (AD) was previously demonstrated [doi:10.1186/alzrt75; doi:10.3233/JAD‐200466]. Study AB09004 assessed oral masitinib administered as an add‐on therapy to standard care for the treatment of mild to moderate AD.MethodPhase 2B/3 study AB09004 comprised two independent, double‐blinded, placebo‐controlled, sub‐studies: masitinib at 4.5mg/kg/day versus placebo (randomized 1:1), and a titrated masitinib dose of 6.0 mg/kg/day versus matched placebo (randomized 2:1). Eligible patients that had a clinical diagnosis of AD with baseline mini‐mental state examination (MMSE) score ≥12–≤25, and had received a stable dose of cholinesterase inhibitor (donepezil, rivastigmine or galantamine) and/or memantine for ≥6 months, were treated for 24 weeks. Primary endpoint was overall change from baseline at week‐24 (analysis of covariance model) in the Alzheimer's Disease Assessment Scale‐Cognitive Subscale (ADAS‐Cog) or the Alzheimer's Disease Cooperative Study Activities of Daily Living (ADCS‐ADL) score. The study was successful if a significant improvement was reached on either ADAS‐Cog or ADCS‐ADL at a 2.5% level of statistical significance, in either sub‐study.ResultMasitinib (4.5mg/kg/day) (n=182, median (age=73 years, MMSE=19, ADCS‐ADL=55.0, ADAS‐Cog=25.5)) showed significant benefit over placebo (n=176, median (age=73 years, MMSE=19, ADCS‐ADL=53.5, ADAS‐Cog=24.8)) with a least‐squares mean difference in ADAS‐Cog from baseline (δCog) of ‐1.46 versus 0.69, respectively, and corresponding least‐squares mean difference between groups (ΔCog) of ‐2.15 (97.5%CI[‐3.48,‐0.81]);p=0.0003. All ADAS‐Cog sensitivity analyses were convergent with the primary outcome, including the conservative jump‐to‐reference approach with ΔCog of ‐1.89 (95%CI[‐3.06,‐0.72];p=0.0016). Considering ADCS‐ADL, δADL was 1.01 for masitinib (4.5mg/kg/day) versus ‐0.81 for placebo, with a ΔADL of 1.82 (97.5%CI[‐0.15,3.79]);p=0.038. Safety was consistent with the known profile for masitinib. The proportion of patients presenting at least one adverse event (AE) or severe AE was respectively, 87.0% and 26.5% for masitinib (4.5mg/kg/day, n=185) versus 77.5% and 19.3% for placebo (pooled, n=280). Efficacy results from the titrated masitinib 6.0 mg/kg/day sub‐study were inconclusive and no new safety signal was observed.ConclusionMasitinib (4.5mg/kg/day), a tyrosine kinase inhibitor targeting mast cell and microglia activity, may provide a new treatment option for mild to moderate AD.

Controlling the past, owning the present, and future: cholinergic modulation decreases semantic perseverations in a person with post-stroke aphasia

ABSTRACT Background Perseverations in speech production tasks represent a pervasive symptom of chronic aphasia. Semantic perseverations (SPs) are defined as repetitive and unconscious production of specific linguistic forms previously produced, heard, or seen which share semantic relatedness with the target word. Neurochemically, SPs have been attributed to weakened activation of the target word due to the depletion of neurotransmitter systems (acetylcholine and dopamine) occurring in the context of activation of semantic competitors. Aims The present pilot study seeks to evaluate the effectiveness of a cholinergic enhancing drug combined with speech language therapy in reducing SPs and other non-perseverative semantic errors in a person with chronic post-stroke aphasia. Methods & Procedures Combined therapy of the cholinesterase inhibitor donepezil and conventional speech-language therapy (SLT) (2 hours/week) over 16 weeks was administered to a woman with chronic fluent post-stroke aphasia showing high rate of semantic errors. Aphasia and SPs assessments were performed at four different time-points across the study: at baseline, after donepezil 5 mg, donepezil 10 mg, and after 4-weeks of washout. The changes induced by the treatments on the occurrence of SPs and semantic paraphasias during a picture naming task were evaluated. By using a specific statistical methodology, we performed a fine-grained analysis of the frequency of SPs and their temporal course at the different time-points to dissect changes induced by the treatment. Results At baseline, there were significantly more SPs than expected by a random distribution, whereas a marked reduction of these errors was found in the three following evaluations. A significant reduction in aphasia severity was also found with high donepezil doses and this improvement maintained after a 4-week washout period. Everyday communication improved with low doses of donepezil. Conclusion Our findings suggest that decreased activity of the cholinergic system may exert a permissive role for the production of SPs and highlight the importance of combining cholinergic agents with speech-language therapy to reduce SPs in aphasia at the time that other language deficits are also improved.