piperidines and Cognitive-Dysfunction

Topics: Alzheimer Disease; Amyloid beta-Peptides; Biomarkers; Cholinesterase Inhibitors; Cognitive Dysfunction; Dementia; Disease Progression; Donepezil; Education, Medical, Continuing; Galantamine; Humans; Indans; Lewy Body Disease; Nootropic Agents; Peptide Fragments; Phenylcarbamates; Piperidines; Positron-Emission Tomography; Reference Standards; Rivastigmine; tau Proteins; Tomography, Emission-Computed, Single-Photon

Survivors of childhood cancer frequently experience cancer-related cognitive dysfunction, commonly months to years after treatment for pediatric brain tumors, acute lymphoblastic leukemia (ALL), or tumors involving the head and neck. Risk factors for cancer-related cognitive dysfunction include young age at diagnosis, treatment with cranial irradiation, use of parenteral or intrathecal methotrexate, female sex, and pre-existing comorbidities. Limiting use and reducing doses and volume of cranial irradiation while intensifying chemotherapy have improved survival and reduced the severity of cognitive dysfunction, especially in leukemia. Nonetheless, problems in core functional domains of attention, processing speed, working memory and visual-motor integration continue to compromise quality of life and performance. We review the epidemiology, pathophysiology and assessment of cancer-related cognitive dysfunction, the impact of treatment changes for prevention, and the broad strategies for educational and pharmacological interventions to remediate established cognitive dysfunction following childhood cancer. The increased years of life saved after childhood cancer warrants continued study toward the prevention and remediation of cancer-related cognitive dysfunction, using uniform assessments anchored in functional outcomes.

Topics: Adolescent; Adult; Age Factors; Antimetabolites, Antineoplastic; Attention; Benzhydryl Compounds; Brain Neoplasms; Central Nervous System Stimulants; Child; Child, Preschool; Cognitive Dysfunction; Comorbidity; Cranial Irradiation; Donepezil; Early Intervention, Educational; Education, Special; Head and Neck Neoplasms; Human Growth Hormone; Humans; Indans; Infant; Injections, Spinal; Memory, Short-Term; Methotrexate; Methylphenidate; Modafinil; Neoplasms; Neurosurgical Procedures; Nootropic Agents; Patient Education as Topic; Piperidines; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Psychomotor Performance; Quality of Life; Radiotherapy Dosage; Risk Factors; Severity of Illness Index; Sex Factors; Survivors; Thinking; Wakefulness-Promoting Agents; Young Adult

The constitutional isomers and tautomers of oxadiazolones, as well as their mono- and disulfur analogues, were calculated at the B3LYP/aug-cc-pVDZ level. Four groups of 30 molecules each were considered: oxadiazolone, oxadiazolthione, thiadiazolone, and thiadiazolthione isomers. The compounds were categorized into six groups according to permutations of three heteroatoms in the five-membered ring. Additionally, each of the constitutional isomer was considered to have five tautomers conserving stable five-membered ring: two NH tautomers, two rotameric OH (or SH) forms and one CH. La trombocitosis es un hallazgo casual frecuente en pediatría. En niños, predominan las formas secundarias, siendo las infecciones su causa más prevalente. Se distinguen 4 grados de trombocitosis en función del número de plaquetas; en la forma extrema, se supera el 1.000.000/mm. Endoscopic thrombin injection was similar to glue injection in achieving successful hemostasis of AGVH. However, a higher incidence of complications may be associated with glue injection.

Topics: Acetaminophen; Administration, Oral; Adolescent; Adsorption; Adult; Allyl Compounds; Amylopectin; Amylose; Anaerobiosis; Animals; Anti-Bacterial Agents; Anura; Arginase; Arthritis, Rheumatoid; Asthma; Atmosphere; B-Lymphocytes; Basic Helix-Loop-Helix Transcription Factors; Bioelectric Energy Sources; Biofilms; Biofuels; Biomarkers; Biopolymers; Bioreactors; Brain; Brain Injuries, Traumatic; Breast Neoplasms; Calibration; Carbon Tetrachloride; Caspase 3; Catalysis; Catechin; Cations; Cattle; CD4-Positive T-Lymphocytes; CD8-Positive T-Lymphocytes; Cell Body; Cell Line, Tumor; Cell Plasticity; Chemical and Drug Induced Liver Injury; Chemistry Techniques, Synthetic; China; Chitosan; Chloride Channels; Chromatography, High Pressure Liquid; Chromosome Mapping; Cognition; Cognitive Dysfunction; Cohort Studies; Colitis, Ulcerative; Colloids; Coloring Agents; Congresses as Topic; Correlation of Data; Crystallization; Cyanoacrylates; Cyclohexane Monoterpenes; Cyprinidae; Cytochrome P-450 CYP1A1; Death, Sudden; Dent Disease; Dietary Supplements; Diffusion Magnetic Resonance Imaging; Disease Models, Animal; Disease Progression; Disease Resistance; Disulfides; Drug Monitoring; Drug Stability; Ecotoxicology; Electricity; Electrodes; Endocytosis; Environmental Exposure; Environmental Monitoring; Enzyme Inhibitors; Epithelial-Mesenchymal Transition; Esophageal and Gastric Varices; Esters; Fagopyrum; Female; Ferrosoferric Oxide; Flame Retardants; Flavobacteriaceae; Flow Cytometry; Follow-Up Studies; Formoterol Fumarate; Fusarium; Garlic; Gastrointestinal Hemorrhage; Gene Expression; Genes, Plant; Genetic Markers; Glial Fibrillary Acidic Protein; Gliosis; Global Health; Glutathione Transferase; Glycine max; Gum Arabic; Hemostasis, Endoscopic; Hepatocytes; Hippocampus; Humans; Hydrogen-Ion Concentration; Illinois; Immunoglobulin G; Indoleamine-Pyrrole 2,3,-Dioxygenase; Infant, Newborn; Infant, Small for Gestational Age; Injections, Intraperitoneal; Interleukin-4; Iowa; Iron; Ki-67 Antigen; Kidney; Kinetics; Kynurenine; Lakes; Levofloxacin; Lipid Peroxidation; Lipids; Liver; Liver Cirrhosis, Experimental; Magnetic Fields; Magnetic Iron Oxide Nanoparticles; Male; Manure; Maze Learning; Memory, Short-Term; Metal Nanoparticles; Metals, Heavy; Methane; Mice; Mice, Inbred C57BL; Mice, Knockout; Michigan; Microalgae; Microbial Consortia; Mitochondria; Models, Animal; Models, Chemical; Models, Neurological; Molecular Structure; Molecular Weight; Mutation; Myeloid-Derived Suppressor Cells; NADPH Oxidase 2; Neoplasm Recurrence, Local; Neurites; Neurons; Neuroprotective Agents; NF-kappa B; NIH 3T3 Cells; Nitric Oxide Synthase Type II; Nitrogen; Ohio; Ointments; Ontario; Organelle Biogenesis; Organophosphates; Organophosphorus Compounds; Oxidative Stress; Palladium; Particle Size; Pectins; Phenotype; Phytotherapy; Piperidines; Placenta; Plant Diseases; Plant Extracts; Polymers; Polymorphism, Genetic; Polyphenols; Powders; Pregnancy; Pregnancy Trimester, First; Prospective Studies; Protein Kinase Inhibitors; Protein Structure, Secondary; Proteins; Pyridines; Pyrimidines; Rats, Wistar; Real-Time Polymerase Chain Reaction; Receptors, Aryl Hydrocarbon; Receptors, Chemokine; Receptors, Formyl Peptide; Receptors, Lipoxin; Recovery of Function; Recurrence; Reference Standards; Reference Values; Reproducibility of Results; Respiratory Function Tests; Retrospective Studies; Risk; Sensitivity and Specificity; Sewage; Signal Transduction; Sodium Glutamate; Soil; Solanum tuberosum; Solubility; Solutions; Spectroscopy, Fourier Transform Infrared; Spectrum Analysis; Spermatozoa; STAT3 Transcription Factor; Sulfamethoxazole; Tea; Temperature; Thermodynamics; Thrombin; Treatment Outcome; Triazoles; United States; Viscosity; Waste Disposal, Fluid; Wastewater; Water; Water Pollutants, Chemical; Water Purification; White Matter; Wisconsin; X-Ray Diffraction; Zea mays

Cognitive enhancers, including cholinesterase inhibitors and memantine, are used to treat dementia, but their effectiveness for mild cognitive impairment is unclear. We conducted a systematic review to examine the efficacy and safety of cognitive enhancers for mild cognitive impairment.. Our eligibility criteria were studies of the effects of donepezil, rivastigmine, galantamine or memantine on mild cognitive impairment reporting cognition, function, behaviour, global status, and mortality or harms. We identified relevant material by searching electronic databases (e.g., MEDLINE, Embase), the references of included studies, trial registries and conference proceedings, and by contacting experts. Two reviewers independently screened the results of the literature search, abstracted data and appraised risk of bias using the Cochrane risk-of-bias tool.. We screened 15,554 titles and abstracts and 1384 full-text articles. Eight randomized clinical trials and 3 companion reports met our inclusion criteria. We found no significant effects of cognitive enhancers on cognition (Mini-Mental State Examination: 3 randomized clinical trials [RCTs], mean difference [MD] 0.14, 95% confidence interval [CI] -0.22 to 0.50; Alzheimer's Disease Assessment Scale - cognition subscale: 3 RCTs, standardized MD -0.07, 95% CI-0.16 to 0.01]) or function (Alzheimer's Disease Cooperative Study activities of daily living inventory: 2 RCTs, MD 0.30, 95% CI -0.26 to 0.86). Cognitive enhancers were associated with higher risks of nausea, diarrhea and vomiting than placebo.. Cognitive enhancers did not improve cognition or function among patients with mild cognitive impairment and were associated with a greater risk of gastrointestinal harms. Our findings do not support the use of cognitive enhancers for mild cognitive impairment.

Topics: Cholinesterase Inhibitors; Cognitive Dysfunction; Donepezil; Galantamine; Humans; Indans; Memantine; Nootropic Agents; Phenylcarbamates; Piperidines; Rivastigmine; Treatment Outcome

In randomized clinical trials, adverse events (AEs) are reported for the drug under evaluation and compared with the placebo group. Patients who receive placebo treatment report a high frequency of AEs, but little is understood about the nature of these. No study has yet analyzed the level of cognitive impairment as a crucial aspect for the AEs reported by patients.. The rates of AEs reported by patients with mild cognitive impairment (MCI) and Alzheimer's disease (AD) in the placebo arms of donepezil trials were compared using a systematic review approach. PubMed was searched with the terms "MCI and donepezil" as well as "AD and donepezil" from January 1989 to December 2010. Nineteen studies fulfilled the selection criteria (3 MCI, n = 783; 16 AD, n = 2,059).. An overall comparison of 81 categories of AEs in the placebo arm of MCI versus AD trials showed that patients in AD trials experienced a significantly higher number of AEs than patients in MCI trials (p < 0.001).. This is the first study showing that AD patients may be at a greater risk of developing AEs than MCI patients. This may be related to a greater presence of somatic comorbidity predisposing them to express emotional distress as physical symptoms and/or to AD patients being frailer and therefore more susceptible to AEs. The phenomena we observed may be interpreted in terms of the "nocebo effect".

Topics: Aged; Alzheimer Disease; Cognitive Dysfunction; Donepezil; Humans; Indans; Nootropic Agents; Piperidines; Placebos; Randomized Controlled Trials as Topic

Cholinergic neurotransmission regulates neuroinflammation in Parkinson disease (PD).. The authors conducted a delayed-start study of donepezil for cognitive decline in non-demented PD patients. The study consisted of a 96-week randomized placebo-controlled double-blind phase 1, followed by a 24-week donepezil extension phase 2. The primary outcome measure was a change in the Mini-Mental State Examination (MMSE) at week 120.. Cognitive function deteriorated in ε4 carriers, but not in non-carriers, and early-start donepezil may postpone cognitive decline in the former.

Topics: Alzheimer Disease; Cholinesterase Inhibitors; Cognitive Dysfunction; Donepezil; Double-Blind Method; Humans; Indans; Parkinson Disease; Piperidines; Treatment Outcome

Post-operative cognitive dysfunction (POCD) is frequent in patients older than 60 years undergoing major non-cardiac surgery, and increases both morbidity and mortality. Anesthetic drugs may exert neurotoxic effects and contribute to the genesis of POCD. The hypothesis of the POCD-ELA trial was that closed-loop target-controlled infusion of propofol and remifentanil could reduce the occurrence of POCD by decreasing the risk of excessive depth of anesthesia and the dose of anesthetic drugs.. We designed a single-center, single-blind, randomized, controlled, parallel trial and aim to include 204 patients aged >60 years undergoing elective major non-cardiac surgery. Patients will be randomized to receive closed-loop versus manual target-controlled infusion of propofol and remifentanil guided by bispectral index monitoring. Cognitive assessment will be performed the day before surgery (baseline) and within 72 hours after surgery, using a battery of validated neuropsychological tests. The primary outcome is the incidence of POCD within 72 hours after surgery. POCD is defined as a Z-score value > 1.96 for at least 2 different tests or a Z-score composite value >1.96. The calculation of the Z-score is based on data from an age-matched control population who did not undergo surgery or general anesthesia.. This study was approved by the Ethics Committee (Comité de Protection des Personnes Est-II) and authorized by the French Health Products Agency (Agence Nationale de Sécurité des Médicaments, Saint-Denis, France). The University Hospital of Besancon is the trial sponsor and the holder of all data and publication rights. Results of the study will be submitted for publication in a peer-review international medical journal and for presentation in abstract (oral or poster) in international peer-reviewed congresses.. The trial is registered with ClinicalTrials.gov (Identifier: NCT02841423, principal investigator: Prof Emmanuel Samain, date of registration: July 22, 2016). Last amendment of protocol: version 8.0 April 2018.

Topics: Aged; Aged, 80 and over; Anesthesia, Closed-Circuit; Anesthetics, Intravenous; Cognitive Dysfunction; Elective Surgical Procedures; Female; Humans; Male; Middle Aged; Neuropsychological Tests; Piperidines; Postoperative Complications; Propofol; Remifentanil; Research Design; Single-Blind Method

Electro-acupuncture is a burgeoning treatment using the needle inserting into the body acupoints and the low-frequency pulse current being electrified by an electric acupuncture machine. This study was designed to evaluate the effects of preconditioning of electro-acupuncture on postoperative cognitive dysfunction in elderly.Ninety patients scheduled spine surgery were randomly assigned into 2 groups using a random number table: control group (group C) and electro-acupuncture group (group EA). In group EA, electro-acupuncture was applied on Baihui, Dazhui, and Zusanli acupoints 30 minutes before anesthesia. At 0 minute before treatment of electro-acupuncture, 1 hour after skin incision and surgery completed (T1-3), blood samples were taken for detection of interleukin (IL)-6, IL-10, and S100β by enzyme-linked immunosorbent assay. The total dose of remifentanil and propofol during surgery were recorded. Mini-Mental State Examination was applied to evaluate the cognitive function of patients at 1 day before surgery and 7th and 30th day after surgery.The results showed that compared with group C, score of MMSE increased after surgery, the serum concentration of IL-6, IL-10, and S100β decreased at 1 hour after skin incision, and surgery completed in group EA. Moreover, the total dose of remifentanil and propofol reduced during surgery in group EA.The present study suggests that preconditioning of electro-acupuncture could improve the postoperative cognitive function, and the reduction of inflammatory reaction and brain injury may be involved in the mechanism.

Topics: Aged; Anesthetics, Intravenous; Biomarkers; Cognitive Dysfunction; Electroacupuncture; Female; Humans; Interleukin-10; Interleukin-6; Male; Mental Status Schedule; Operative Time; Orthopedic Procedures; Piperidines; Postoperative Complications; Preoperative Care; Propofol; Remifentanil; S100 Calcium Binding Protein beta Subunit; Spine; Treatment Outcome

We determined the value of hippocampus (Hp) and basal forebrain (BF) volumes for predicting cognitive decline and treatment response in a double-blind, randomized, placebo-controlled phase 4 trial at 28 academic centers (France) in patients with amnestic mild cognitive impairment (MCI) receiving Donepezil 10 mg daily or placebo over 12 months, and 6 months open label follow-up. Outcome measures were the rates of global and domain specific cognitive decline as non-primary efficacy endpoint. The intention-to-treat (ITT) sample analyzed comprised 215 cases. Baseline Hp volume was a significant predictor of rates of change in global cognitive function in linear mixed effects models. This effect was independent of treatment. BF volume was not associated with rates of global or domain specific cognitive decline. Rates of delayed free recall decline were higher in MCI cases treated with donepezil compared to placebo. Only Hp, but not BF volume was a useful predictor of cognitive decline in suspected prodromal AD patients. Both Hp and BF volumes were poor predictors of treatment response, questioning previous approaches on predicting treatment response without placebo control.. clinicalTrials.gov Identifier NCT00403520.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Cognitive Dysfunction; Cross-Sectional Studies; Disease Progression; Donepezil; Double-Blind Method; Female; Follow-Up Studies; Humans; Indans; Magnetic Resonance Imaging; Male; Nootropic Agents; Piperidines; Predictive Value of Tests; Prodromal Symptoms; Treatment Outcome

Genetic heterogeneity in amnestic mild cognitively impaired (aMCI) subjects could lead to variations in progression rates and response to cholinomimetic agents. Together with the apolipoprotein E4 (APOE-ɛ4) gene, butyrylcholinesterase (BCHE) has become recently one of the few Alzheimer's disease (AD) susceptibility genes with distinct pharmacogenomic properties.. To validate candidate genes (APOE/BCHE) which display associations with age of onset of AD and donepezil efficacy in aMCI subjects.. Using the Petersen et al. (2005) study on vitamin E and donepezil efficacy in aMCI, we contrasted the effects of BCHE and APOE variants on donepezil drug response using the Alzheimer's Disease Assessment Score-Cognition (ADAS-Cog) scale. Independently, we assessed the effects of APOE/BCHE genotypes on age of onset and cortical choline acetyltransferase activity in autopsy-confirmed AD and age-matched control subjects.. Statistical analyses revealed a significant earlier age of onset in AD for APOE-ɛ4, BCHE-K*, and APOE-ɛ4/BCHE-K* carriers. Among the carriers of APOE-ɛ4 and BCHE-K*, the benefit of donepezil was evident at the end of the three-year follow-up. The responder's pharmacogenomic profile is consistent with reduced brain cholinergic activity measured in APOE-ɛ4 and BCHE-K* positive subjects.. APOE-ɛ4 and BCHE-K* positive subjects display an earlier age of onset of AD, an accelerated cognitive decline and a greater cognitive benefits to donepezil therapy. These results clearly emphasize the necessity of monitoring potential pharmacogenomic effects in this population of subjects, and suggest enrichment strategies for secondary prevention trials involving prodromal AD subjects.

Topics: Age of Onset; Aged; Aged, 80 and over; Alzheimer Disease; Apolipoprotein E4; Butyrylcholinesterase; Cholinesterase Inhibitors; Cognitive Dysfunction; Disease Progression; Donepezil; Double-Blind Method; Female; Humans; Indans; Male; Piperidines; Quebec; Treatment Outcome

Cortical thinning, previously identified during prodromal stages of Alzheimer's disease (AD), is a "candidate" biomarker implemented in AD clinical therapy trials. We investigated the effect of donepezil treatment on cortical thickness in mild cognitively impaired subjects with the amnestic syndrome of the hippocampal type, a prodromal at-risk group for progression to AD dementia.. Data were from a longitudinal analysis of a community-based multicenter suspected prodromal AD cohort diagnosed by the Free and Cued Selective Reminding Test (81 donepezil vs 92 placebo) enrolled in a double-blind, randomized, placebo-controlled parallel group design using donepezil (10 mg/day). The study started in November 2006 and concluded in August 2010. All subjects underwent 2 brain structural magnetic resonance imaging (MRI) scans, at baseline and at the end of the trial. Structural MRI images had been processed using the automated pipeline for longitudinal segmentation and surface reconstruction implemented in FreeSurfer. The primary outcome measure of this post hoc study was the annualized percentage change (APC) of cortical thickness.. The donepezil group exhibited reduced APC cortical thinning compared to placebo in the rostral anterior cingulate (right: P = .048; left: P = .032), the orbitofrontal (right: P = .012; left: P < .048), and the right inferior frontal (P = .022) cortices and in the right insula (P = .010). These results were not statistically significant after Bonferroni correction likely due to insufficient power for cortical thickness measurements in the study group powered for the predefined hippocampus outcome.. Our findings support the hypothesis that cortical thickness is a reliable candidate surrogate outcome in early predementia AD trials. In addition, donepezil treatment may have an impact on cortical structure/morphology in areas innervated by the medial and lateral cholinergic pathways.. ClinicalTrials.gov identifier: NCT00403520.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Amnesia; Cerebral Cortex; Cognitive Dysfunction; Disease Progression; Donepezil; Double-Blind Method; Female; Humans; Indans; Longitudinal Studies; Magnetic Resonance Imaging; Male; Nootropic Agents; Outcome Assessment, Health Care; Piperidines; Prodromal Symptoms

Little is known about the utility of plasma amyloid beta (Aβ) in clinical trials of Alzheimer's disease (AD).. We analyzed longitudinal plasma samples from two large multicenter clinical trials: (1) donezepil and vitamin E in mild cognitive impairment (n = 405, 24 months) and (2) simvastatin in mild to moderate AD (n = 225, 18 months).. Baseline plasma Aβ was not related to cognitive or clinical progression. We observed a decrease in plasma Aβ40 and 42 among apolipoprotein E epsilon 4 (APOE ε4) carriers relative to noncarriers in the mild cognitive impairment trial. Patients treated with simvastatin showed a significant increase in Aβ compared with placebo. We found significant storage time effects and considerable plate-to-plate variation.. We found no support for the utility of plasma Aβ as a prognostic factor or correlate of cognitive change. Analysis of stored specimens requires careful standardization and experimental design, but plasma Aβ may prove useful in pharmacodynamic studies of antiamyloid drugs.

Topics: Aged; Alzheimer Disease; Amyloid beta-Peptides; Apolipoprotein E4; Biomarkers; Blood Chemical Analysis; Cognitive Dysfunction; Disease Progression; Donepezil; Female; Heterozygote; Humans; Indans; Longitudinal Studies; Male; Nootropic Agents; Peptide Fragments; Piperidines; Severity of Illness Index; Simvastatin; Vitamin E

To observe the intervention effect of nourishing Xin and Shen method (NXSM) on the cognitive function of mild cognitive impairment due to subcortical small vessel disease (MCI-SSVD).. All 54 MCI-SSVD patients came from Department of Traditional Chinese Medicine, Affiliated Union Hospital of Fujian Medical University from June 2010 to August 2013. They were randomly assigned to the treatment group (28 cases) and the control group (26 cases). Another 33 volunteers were recruited as a healthy control group. On the basis of targeting risk factors of blood vessels, MCI-SSVD patients were treated respectively with NXSM and donepezil hydrochloride, with the therapeutic course of 12 weeks. Neuropsychological scales [mini-mental state examination (MMSE) and Montreal cognitive assessment (MoCA)], and Chinese medical dementia syndrome scales were performed in all subjects, and results were compared among groups or intra-group before and after treatment.. MMSE and MoCA scores of the two treatment groups decreased more, when compared with those of the healthy control group (P < 0.05). In particular, MoCA score was significantly decreased (P < 0.01). MMSE and MoCA scores of the two treatment groups increased more after treatment than before treatment (P < 0.05). But there was no statistical difference in MMSE or MOCA score after treatment between the two groups (P > 0.05). Chinese medical dementia syndrome scales decreased more significantly in the treatment group, when compared with before treatment (P < 0.01). But there was no statistical difference in Chinese medical dementia syndrome scales in the control group between before and after treatment (P > 0.05). Visual spatial and executive function scores or delayed recall scores of the two treatment groups increased more, when compared with the same group before treatment (P < 0.05, P < 0.01).. NXSM could effectively improve cognitive functions of MCI-SSVD.

Topics: Alzheimer Disease; Biomedical Research; Cognition; Cognitive Dysfunction; Dementia; Donepezil; Drugs, Chinese Herbal; Humans; Indans; Neuropsychological Tests; Piperidines

Changes in brain-derived neurotrophic factor (BDNF) level are implicated in the pathophysiology of cognitive decline in depression and neurodegenerative disorders in older adults. We aimed to evaluate the longitudinal association over two years between BDNF and persistent cognitive decline in individuals with remitted late-life depression and Mild Cognitive Impairment (LLD + MCI) compared to either individuals with remitted LLD and no cognitive decline (LLD + NCD) or never-depressed, cognitively normal, elderly control participants. We additionally evaluated the effect of double-blind, placebo-controlled donepezil treatment on BDNF levels in all of the remitted LLD participants (across the levels of cognitive function). We included 160 elderly participants in this study (72 LLD + NCD, 55 LLD + MCI and 33 never-depressed cognitively normal elderly participants). At the same visits, cognitive assessments were conducted and blood sampling to determine serum BDNF levels were collected at baseline assessment and after one and two years of follow-up. We utilized repeated measure, mixed effect models to assess: (1) the effects of diagnosis (LLD + MCI, LLD + NCD, and controls), time, and their interaction on BDNF levels; and (2) the effects of donepezil treatment (donepezil vs. placebo), time, baseline diagnosis (LLD + MCI vs. LLD + NCD), and interactions between these contrasts on BDNF levels. We found a significant effect of time on BDNF level (p = 0.02) and a significant decline in BDNF levels over 2 years of follow-up in participants with LLD + MCI (p = 0.004) and controls (p = 0.04). We found no effect of donepezil treatment on BDNF level. The present results suggest that aging is an important factor related to decline in BDNF level. Clinicaltrials.gov Identifier: NCT00177671.

Topics: Aged; Aged, 80 and over; Antidepressive Agents; Brain-Derived Neurotrophic Factor; Cognitive Dysfunction; Depression; Donepezil; Enzyme-Linked Immunosorbent Assay; Female; Humans; Indans; Linear Models; Longitudinal Studies; Male; Piperidines; Time Factors

The constitutional isomers and tautomers of oxadiazolones, as well as their mono- and disulfur analogues, were calculated at the B3LYP/aug-cc-pVDZ level. Four groups of 30 molecules each were considered: oxadiazolone, oxadiazolthione, thiadiazolone, and thiadiazolthione isomers. The compounds were categorized into six groups according to permutations of three heteroatoms in the five-membered ring. Additionally, each of the constitutional isomer was considered to have five tautomers conserving stable five-membered ring: two NH tautomers, two rotameric OH (or SH) forms and one CH. La trombocitosis es un hallazgo casual frecuente en pediatría. En niños, predominan las formas secundarias, siendo las infecciones su causa más prevalente. Se distinguen 4 grados de trombocitosis en función del número de plaquetas; en la forma extrema, se supera el 1.000.000/mm. Endoscopic thrombin injection was similar to glue injection in achieving successful hemostasis of AGVH. However, a higher incidence of complications may be associated with glue injection.

Topics: Acetaminophen; Administration, Oral; Adolescent; Adsorption; Adult; Allyl Compounds; Amylopectin; Amylose; Anaerobiosis; Animals; Anti-Bacterial Agents; Anura; Arginase; Arthritis, Rheumatoid; Asthma; Atmosphere; B-Lymphocytes; Basic Helix-Loop-Helix Transcription Factors; Bioelectric Energy Sources; Biofilms; Biofuels; Biomarkers; Biopolymers; Bioreactors; Brain; Brain Injuries, Traumatic; Breast Neoplasms; Calibration; Carbon Tetrachloride; Caspase 3; Catalysis; Catechin; Cations; Cattle; CD4-Positive T-Lymphocytes; CD8-Positive T-Lymphocytes; Cell Body; Cell Line, Tumor; Cell Plasticity; Chemical and Drug Induced Liver Injury; Chemistry Techniques, Synthetic; China; Chitosan; Chloride Channels; Chromatography, High Pressure Liquid; Chromosome Mapping; Cognition; Cognitive Dysfunction; Cohort Studies; Colitis, Ulcerative; Colloids; Coloring Agents; Congresses as Topic; Correlation of Data; Crystallization; Cyanoacrylates; Cyclohexane Monoterpenes; Cyprinidae; Cytochrome P-450 CYP1A1; Death, Sudden; Dent Disease; Dietary Supplements; Diffusion Magnetic Resonance Imaging; Disease Models, Animal; Disease Progression; Disease Resistance; Disulfides; Drug Monitoring; Drug Stability; Ecotoxicology; Electricity; Electrodes; Endocytosis; Environmental Exposure; Environmental Monitoring; Enzyme Inhibitors; Epithelial-Mesenchymal Transition; Esophageal and Gastric Varices; Esters; Fagopyrum; Female; Ferrosoferric Oxide; Flame Retardants; Flavobacteriaceae; Flow Cytometry; Follow-Up Studies; Formoterol Fumarate; Fusarium; Garlic; Gastrointestinal Hemorrhage; Gene Expression; Genes, Plant; Genetic Markers; Glial Fibrillary Acidic Protein; Gliosis; Global Health; Glutathione Transferase; Glycine max; Gum Arabic; Hemostasis, Endoscopic; Hepatocytes; Hippocampus; Humans; Hydrogen-Ion Concentration; Illinois; Immunoglobulin G; Indoleamine-Pyrrole 2,3,-Dioxygenase; Infant, Newborn; Infant, Small for Gestational Age; Injections, Intraperitoneal; Interleukin-4; Iowa; Iron; Ki-67 Antigen; Kidney; Kinetics; Kynurenine; Lakes; Levofloxacin; Lipid Peroxidation; Lipids; Liver; Liver Cirrhosis, Experimental; Magnetic Fields; Magnetic Iron Oxide Nanoparticles; Male; Manure; Maze Learning; Memory, Short-Term; Metal Nanoparticles; Metals, Heavy; Methane; Mice; Mice, Inbred C57BL; Mice, Knockout; Michigan; Microalgae; Microbial Consortia; Mitochondria; Models, Animal; Models, Chemical; Models, Neurological; Molecular Structure; Molecular Weight; Mutation; Myeloid-Derived Suppressor Cells; NADPH Oxidase 2; Neoplasm Recurrence, Local; Neurites; Neurons; Neuroprotective Agents; NF-kappa B; NIH 3T3 Cells; Nitric Oxide Synthase Type II; Nitrogen; Ohio; Ointments; Ontario; Organelle Biogenesis; Organophosphates; Organophosphorus Compounds; Oxidative Stress; Palladium; Particle Size; Pectins; Phenotype; Phytotherapy; Piperidines; Placenta; Plant Diseases; Plant Extracts; Polymers; Polymorphism, Genetic; Polyphenols; Powders; Pregnancy; Pregnancy Trimester, First; Prospective Studies; Protein Kinase Inhibitors; Protein Structure, Secondary; Proteins; Pyridines; Pyrimidines; Rats, Wistar; Real-Time Polymerase Chain Reaction; Receptors, Aryl Hydrocarbon; Receptors, Chemokine; Receptors, Formyl Peptide; Receptors, Lipoxin; Recovery of Function; Recurrence; Reference Standards; Reference Values; Reproducibility of Results; Respiratory Function Tests; Retrospective Studies; Risk; Sensitivity and Specificity; Sewage; Signal Transduction; Sodium Glutamate; Soil; Solanum tuberosum; Solubility; Solutions; Spectroscopy, Fourier Transform Infrared; Spectrum Analysis; Spermatozoa; STAT3 Transcription Factor; Sulfamethoxazole; Tea; Temperature; Thermodynamics; Thrombin; Treatment Outcome; Triazoles; United States; Viscosity; Waste Disposal, Fluid; Wastewater; Water; Water Pollutants, Chemical; Water Purification; White Matter; Wisconsin; X-Ray Diffraction; Zea mays

The importance of the cholinergic system for cognitive function has been well documented in animal and human studies. The objective of this study was to elucidate the cognitive and functional connectivity changes associated with enhanced acetylcholine levels. We hypothesized that older adults with mild memory deficits would show behavioral and functional network enhancements with an acetylcholinesterase inhibitor treatment (donepezil) when compared to a placebo control group.. We conducted a 3-month, double-blind, placebo-controlled study on the effects of donepezil in 27 older adults with mild memory deficits. Participants completed a delayed recognition memory task. Functional magnetic resonance imaging (fMRI) scans were collected at baseline prior to treatment and at 3-month follow-up while subjects were on a 10mg daily dose of donepezil or placebo.. Donepezil treatment significantly enhanced the response time for face and scene memory probes when compared to the placebo group. A group-by-visit interaction was identified for the functional network connectivity of the left fusiform face area (FFA) with the hippocampus and inferior frontal junction, such that the treatment group showed increased connectivity over time when compared to the placebo group. Additionally, the enhanced functional network connectivity of the FFA and hippocampus significantly predicted memory response time at 3-month follow-up in the treatment group.. These findings suggest that increased cholinergic transmission improves goal-directed neural processing and cognitive ability and may serve to facilitate communication across functionally-connected attention and memory networks. Longitudinal fMRI is a useful method for elucidating the neural changes associated with pharmacological modulation and is a potential tool for monitoring intervention efficacy in clinical trials.

Topics: Aged; Aged, 80 and over; Brain; Cholinesterase Inhibitors; Cognitive Dysfunction; Donepezil; Double-Blind Method; Female; Humans; Indans; Longitudinal Studies; Male; Middle Aged; Nerve Net; Photic Stimulation; Piperidines; Reaction Time; Up-Regulation

Episodic memory encoding of a verbal message depends upon initial registration, which requires sustained auditory attention followed by deep semantic processing of the message. Motivated by previous data demonstrating modulation of auditory cortical activity during sustained attention to auditory stimuli, we investigated the response of the human auditory cortex during encoding of sentences to episodic memory. Subsequently, we investigated this response in patients with mild cognitive impairment (MCI) and probable Alzheimer's disease (pAD).. Using functional magnetic resonance imaging, 31 healthy participants were studied. The response in 18 MCI and 18 pAD patients was then determined, and compared to 18 matched healthy controls. Subjects heard factual sentences, and subsequent retrieval performance indicated successful registration and episodic encoding.. The healthy subjects demonstrated that suppression of auditory cortical responses was related to greater success in encoding heard sentences; and that this was also associated with greater activity in the semantic system. In contrast, there was reduced auditory cortical suppression in patients with MCI, and absence of suppression in pAD. Administration of a central cholinesterase inhibitor (ChI) partially restored the suppression in patients with pAD, and this was associated with an improvement in verbal memory.. Verbal episodic memory impairment in AD is associated with altered auditory cortical function, reversible with a ChI. Although these results may indicate the direct influence of pathology in auditory cortex, they are also likely to indicate a partially reversible impairment of feedback from neocortical systems responsible for sustained attention and semantic processing.

Topics: Adult; Aged; Aged, 80 and over; Alzheimer Disease; Attention; Auditory Cortex; Auditory Perceptual Disorders; Cognitive Dysfunction; Donepezil; Female; Humans; Indans; Limbic System; Magnetic Resonance Imaging; Male; Memory Disorders; Memory, Episodic; Mental Recall; Middle Aged; Nootropic Agents; Piperidines; Verbal Learning; Young Adult

It is important to detect and prevent Alzheimer disease (AD) at its early stage. Constituting the early stage sign of AD, amnestic mild cognitive impairment (aMCI) has drawn much attention. Studies have shown that donepezil could reduce the AD assessment scale-cognitive subscale (ADAS-Cog) score in MCI patients and improve the patient's attention and speed of response; however, it also has many side effects. Therefore, the authors aim to explore the effects of Chinese herbal medicine for treating aMCI.. To explore the clinical efficacy and safety of Chinese medicine for tonifying the kidney, and resolving phlegm and blood stasis in the treatment of aMCI.. This clinical trial used randomized, double-blind, double-dummy and parallel-controlled design. According to the randomized, double-blind principle, some aMCI patients were randomly divided into Chinese medicine group and donepezil group. Other patients who did not receive any treatment were enrolled as the control. Patients in the Chinese medicine group received oral administration of Chinese medicine, 1 bag/dose, two doses per day, while patients in the donepezil group received donepezil hydrochloride, 5mg/day. Twelve weeks were allocated as the trial period.. After 12 weeks, the Chinese medicine group patients, the donepezil group patients and those patients who did not receive any treatment were accessed using the scores of ADAS-Cog and mini-mental status examination (MMSE).. The ADAS-Cog and MMSE scores of the Chinese medicine group and the donepezil group were both improved from baseline (P=0.001, P=0.000), but the non-treatment group showed no change from baseline (P=0.151, P=0.125); furthermore, there was no significant difference between the Chinese medicine group and the donepezil group. The attention function of the Chinese medicine group was better than baseline (P=0.015), but no change was seen in the donepezil group (P=0.085) at the 12th week. Safety data showed that the occurrence of insomnia, nausea and diarrhea was greater in the donepezil group than in the Chinese medicine group (P=0.002, P=0.005, P=0.000), and both treatments had no influence in participants' vital signs and laboratory examination results.. Both Chinese medicine and donepezil can improve global cognition in patients with aMCI after 12 weeks of treatment. Chinese medicine can also improve attention function and some clinical symptoms in patients with aMCI. Furthermore, Chinese medicine is safe for aMCI patients. Further study is necessary to explore the long-term effect of Chinese medicine for aMCI.

Topics: Adult; Aged; Aged, 80 and over; Alzheimer Disease; Cognitive Dysfunction; Donepezil; Double-Blind Method; Drugs, Chinese Herbal; Female; Humans; Indans; Male; Middle Aged; Phytotherapy; Piperidines; Treatment Outcome

A magnetic resonance imaging (MRI) study was conducted as part of an intervention study in subjects with amnestic mild cognitive impairment (aMCI) to assess donepezil's treatment effect on brain atrophy. Adults with aMCI were randomly assigned to double-blind treatment with 10 mg/day donepezil hydrochloride or placebo for 48 weeks. Brain MRI scans were acquired at baseline and endpoint. The primary outcome measure was annualized percentage change (APC) in hippocampal volume; the main secondary outcome measure was APC in whole brain volumes. An analysis of variance (ANOVA) model including terms for treatment, site, and age was used to compare the treatment groups. APCs for hippocampal volumes were not significantly different between treatment groups. There were significant differences favoring the donepezil group for total (p = 0.001), ventricular region (p = 0.0002), and cortical region (p = 0.003) whole brain volumes. Although the primary MRI outcome measure was negative, the main secondary MRI outcome measure showed a positive result. These findings suggest a treatment effect of donepezil on brain atrophy in aMCI.

Topics: Aged; Aged, 80 and over; Brain; Cognitive Dysfunction; Donepezil; Double-Blind Method; Female; Humans; Indans; Magnetic Resonance Imaging; Male; Middle Aged; Piperidines; Single-Blind Method

Alzheimer's disease (AD) is an age-related neurodegenerative disease, which characterized by deposition of amyloid-β (Aβ) plaques, neurofibrillary tangles, neuronal loss, and accompanied by neuroinflammation. Neuroinflammatory processes are well acknowledged to contribute to the progression of AD pathology. Histamine H3 receptor (H3R) is a presynaptic autoreceptor regulating histamine release via negative feedback way. Recently, studies show that H3R are highly expressed not only in neurons but also in microglia and astrocytes. H3R antagonist has been reported to have anti-inflammatory efficacy. However, whether inhibition of H3R is responsible for the anti-neuroinflammation in glial cells and neuroprotection on APPswe, PSEN1dE9 (APP/PS1 Tg) mice remain unclear. In this study, we found that inhibition of H3R by thioperamide reduced the gliosis and induced a phenotypical switch from A1 to A2 in astrocytes, and ultimately attenuated neuroinflammation in APP/PS1 Tg mice. Additionally, thioperamide rescued the decrease of cyclic AMP response element-binding protein (CREB) phosphorylation and suppressed the phosphorylated P65 nuclear factor kappa B (p-P65 NF-κB) in APP/PS1 Tg mice. H89, an inhibitor of CREB signaling, abolished these effects of thioperamide to suppress gliosis and proinflammatory cytokine release. Lastly, thioperamide alleviated the deposition of amyloid-β (Aβ) and cognitive dysfunction in APP/PS1 mice, which were both reversed by administration of H89. Taken together, these results suggested the H3R antagonist thioperamide improved cognitive impairment in APP/PS1 Tg mice via modulation of the CREB-mediated gliosis and inflammation inhibiting, which contributed to Aβ clearance. This study uncovered a novel mechanism involving inflammatory regulating behind the therapeutic effect of thioperamide in AD.

Topics: Alzheimer Disease; Animals; Brain; Cognitive Dysfunction; Gliosis; Male; Mice; Mice, Transgenic; Neuroinflammatory Diseases; Neuroprotective Agents; Piperidines

Dysfunction of the cholinergic basal forebrain (BF) neurotransmitter system, including cholinergic axon denervation of the cortex, plays an important role in cognitive decline and dementia. A validated method to directly quantify cortical cholinergic terminal integrity enables exploration of the involvement of this system in diverse cognitive profiles associated with dementia, particularly at a prodromal stage. In this study, we used the radiotracer [

Topics: Alzheimer Disease; Amyloid beta-Peptides; Basal Forebrain; Cholinergic Agents; Cognitive Dysfunction; Dementia; Humans; Magnetic Resonance Imaging; Piperidines; Positron-Emission Tomography

There is an urgent need to understand and reverse cognitive impairment. The lack of appropriate animal models combined with the limited knowledge of pathophysiological mechanisms makes the development of new cognition-enhancing drugs complex. Scopolamine is a pharmacologic agent which impairs cognition and functional imaging in a wide range of animal species, similarly to what is seen in cognitive impairment in humans.. In this study, using a functional ultrasound (fUS) neuroimaging technique, we monitored the impact of donepezil (DPZ), a potent acetylcholinesterase inhibitor and first-line treatment in patients with mild to moderate Alzheimer's disease, in a scopolamine-induced mouse model.. We demonstrated that despite its low impact on the cerebral blood volume (CBV) signal, scopolamine injection produced an overall decrease in functional connectivity between various brain areas. In addition, we revealed that DPZ induced a strong decrease in CBV signal without causing a difference in functional connectivity.. Finally, our work highlighted that DPZ counteracted the impact of scopolamine on functional connectivity changes and confirmed the interest of using pharmaco-fUS imaging on cognitive disorders, both in frequent and rare neurological disorders.

Topics: Acetylcholinesterase; Alzheimer Disease; Animals; Cognitive Dysfunction; Donepezil; Humans; Indans; Mice; Piperidines; RNA-Binding Protein FUS; Scopolamine

Little is known about the effects of endocrine-disrupting chemicals (EDCs) and the combination of memantine and donepezil on the pathogenesis of cognitive impairment. Here, we aimed to identify in silico the molecular mechanisms of the combination of memantine and donepezil that combat cognitive impairment induced by nine common EDCs using GeneMania, AutoDock Vina, Metascape, SwissADME, MIENTURNET, and miRNAsong. We observed that the mixture of memantine and donepezil had therapeutic effects on mixed EDC-induced cognitive impairment via five genes (TNF, ACHE, BAX, IL1B, and CASP3). With ACHE and TNF, donepezil and memantine both had a high docking score, respectively. The predominant connections among five mutual genes were physical interactions (77.6%). The major pathways associated with memantine and donepezil countering cognitive impairment generated by mixed EDCs were discovered to be "AGE-RAGE signaling pathway in diabetic complications," "pro-survival signaling of neuroprotectin D1," and "non-alcoholic fatty liver disease." The miRNAs and transcription factors implicated in memantine and donepezil protecting against mixed EDCs were hsa-miR-128-3p and hsa-miR-34a-5p, NFKB1, NFKB2, IRF8, and E2F4. The sponges' tertiary structure predictions for two major miRNAs were provided. The physicochemical and pharmacokinetic properties of memantine and donepezil highlighted the need for a therapeutic combination of these medications to treat cognitive impairment.

Topics: Alzheimer Disease; Cholinesterase Inhibitors; Cognitive Dysfunction; Donepezil; Humans; Indans; Memantine; MicroRNAs; Piperidines

Severe cholinergic degeneration is known to occur in Parkinson's disease (PD) and is thought to play a primary role in the cognitive decline associated with this disease. Although cholinergic losses occur in all patients with PD, cognitive performance remains normal for many of them, suggesting compensatory mechanisms in those.. This exploratory study aimed at verifying if normal cognition in PD may involve distinctive features of the brain cholinergic systems.. Following extensive neuropsychological screening in 25 patients with PD, 12 were selected and evenly distributed between a cognitively normal (PD-CN) group, and a mild cognitive impairment (PD-MCI) group. Each group was compared with matched healthy volunteers (HV) on standardized cognitive scales (MoCA, PDCRS), and PET imaging with [. [. These findings suggest a compensatory upregulation of the hippocampal cholinergic innervation in PD-CN, which might underly normal cognitive performances in spite of cortical cholinergic denervation in other regions.

Topics: Aged; Cholinergic Agents; Cognition; Cognitive Dysfunction; Female; Hippocampus; Humans; Male; Middle Aged; Parkinson Disease; Piperidines; Positron-Emission Tomography; Radioactive Tracers

Circulating adiponectin (APN) levels decrease with age and obesity. On the other hand, a reduction in APN levels is associated with neurodegeneration and neuroinflammation. We previously showed that aged adiponectin knockout (APN

Topics: Administration, Oral; Aged; Alzheimer Disease; Amyloid beta-Peptides; Animals; Cognitive Dysfunction; Disease Models, Animal; Humans; Mice; Mice, Transgenic; Piperidines

Endotoxin-induced neuroinflammation plays a crucial role in the pathogenesis and progression of various neurodegenerative diseases. A growing body of evidence supports that incretin-acting drugs possess various neuroprotective effects that can improve learning and memory impairments in Alzheimer's disease models. Thus, the present study aimed to investigate whether alogliptin, a dipeptidyl peptidase-4 inhibitor, has neuroprotective effects against lipopolysaccharide (LPS)-induced neuroinflammation and cognitive impairment in mice as well as the potential mechanisms underlying these effects.. Mice were treated with alogliptin (20 mg/kg/d; p.o.) for 14 days, starting 1 day prior to intracerebroventricular LPS injection (8 μg/μL in 3 μL).. Alogliptin treatment alleviated LPS-induced cognitive impairment as assessed by Morris water maze and novel object recognition tests. Moreover, alogliptin reversed LPS-induced increases in toll-like receptor 4 and myeloid differentiation primary response 88 protein expression, nuclear factor-κB p65 content, and microRNA-155 gene expression. It also rescued LPS-induced decreases in suppressor of cytokine signaling gene expression, cyclic adenosine monophosphate (cAMP) content, and phosphorylated cAMP response element binding protein expression in the brain.. The present study sheds light on the potential neuroprotective effects of alogliptin against intracerebroventricular LPS-induced neuroinflammation and its associated memory impairment via inhibition of toll-like receptor 4/ myeloid differentiation primary response 88/ nuclear factor-κB signaling, modulation of microRNA-155/suppressor of cytokine signaling-1 expression, and enhancement of cAMP/phosphorylated cAMP response element binding protein signaling.

Topics: Animals; Behavior, Animal; Cognitive Dysfunction; Dipeptidyl-Peptidase IV Inhibitors; Disease Models, Animal; Lipopolysaccharides; Male; Mice; MicroRNAs; Myeloid Differentiation Factor 88; Neuroinflammatory Diseases; Neuroprotective Agents; NF-kappaB-Inducing Kinase; Piperidines; Protein Serine-Threonine Kinases; Signal Transduction; Suppressor of Cytokine Signaling 1 Protein; Toll-Like Receptor 4; Uracil

Dysfunction of cholinergic system plays an important role in disease associated with cognitive blockage, such as Alzheimer's disease (AD). Central administration of scopolamine, an antagonist of acetylcholine receptor, could induce memory impairment in mice. Endocannabinoid system was also implicated in AD, as two peptides agonists of cannabinoid 1 receptor (CB1R), (m)RVD-hemopressin (α) (RVD) and (m)VD-hemopressin (α) (VD) have been reported to inhibit the AD-relating impairment in animal and cell models. More than one-third of the cholinergic cells expressed CB1R, so we speculated that RVD and VD might have ability to inhibit the memory-impairing effect of scopolamine. Our results showed RVD and VD ameliorated the memory toxicity of scopolamine, and the effects of the two peptides could be blocked by CB1R antagonists hemopressin (Hp) and AM251 in novel object and object location recognition tasks in mice. This study suggested that RVD and VD might be potential compounds for the treatment of the disease associated with impairment of cholinergic system.

Topics: Alzheimer Disease; Animals; Cognitive Dysfunction; Disease Models, Animal; Endocannabinoids; Hemoglobins; Humans; Memory Disorders; Mice; Oligopeptides; Peptide Fragments; Piperidines; Pyrazoles; Receptor, Cannabinoid, CB1; Scopolamine

Alzheimer's disease (AD) is an age-related neurodegenerative disease, and the imbalance between production and clearance of β-amyloid (Aβ) is involved in its pathogenesis. Autophagy is an intracellular degradation pathway whereby leads to removal of aggregated proteins, up-regulation of which may be a plausible therapeutic strategy for the treatment of AD. Histamine H3 receptor (H3R) is a presynaptic autoreceptor regulating histamine release via negative feedback way. Our previous study showed that thioperamide, as an antagonist of H3R, enhances autophagy and protects against ischemic injury. However, the effect of thioperamide on autophagic function and Aβ pathology in AD remains unknown. In this study, we found that thioperamide promoted cognitive function, ameliorated neuronal loss, and Aβ pathology in APP/PS1 transgenic (Tg) mice. Interestingly, thioperamide up-regulated autophagic level and lysosomal function both in APP/PS1 Tg mice and in primary neurons under Aβ-induced injury. The neuroprotection by thioperamide against AD was reversed by 3-MA, inhibitor of autophagy, and siRNA of Atg7, key autophagic-related gene. Furthermore, inhibition of activity of CREB, H3R downstream signaling, by H89 reversed the effect of thioperamide on promoted cell viability, activated autophagic flux, and increased autophagic-lysosomal proteins expression, including Atg7, TFEB, and LAMP1, suggesting a CREB-dependent autophagic activation by thioperamide in AD. Taken together, these results suggested that H3R antagonist thioperamide improved cognitive impairment in APP/PS1 Tg mice via modulation of the CREB-mediated autophagy and lysosomal pathway, which contributed to Aβ clearance. This study uncovered a novel mechanism involving autophagic regulating behind the therapeutic effect of thioperamide in AD.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Animals; Autophagy; Cell Death; Cell Survival; Cells, Cultured; Cognition; Cognitive Dysfunction; Cyclic AMP Response Element-Binding Protein; Hippocampus; Humans; Male; Mice, Inbred C57BL; Mice, Transgenic; Models, Biological; Neurons; Neuroprotective Agents; Piperidines; Presenilin-1; Up-Regulation

Neurofibromatosis type 1 (NF1), a genetically determined neurodevelopmental disorder and tumor syndrome, is associated with cognitive impairments, including in executive function and sleep-related problems. Consistent with the human data, NF1 heterozygous (Het) mice show impaired spatial learning and memory in the water maze and extinction of contextual fear memory. It is not clear whether neurological phenotypes might depend on the parental carrier. In this study, we compared the behavioral and cognitive performance of NF1 Het and wild-type litter mates with either the father (PC) or the mother (MC) as the NF1 carrier on a F1 C57BL/66/129SvJ background. The behavioral and cognitive phenotypes and responsiveness to Alk inhibition in heterozygous NF1 offspring depended on whether the parental carrier was maternal or paternal. Alk inhibition (20 mg/kg) increased activity levels during the dark period in NF1 Het PC, but not MC, mice. In the water maze, NF1 Het PC, but not MC, mice showed reduced cognitive flexibility and impaired ability to locate the third hidden platform location, which was improved by Alk inhibition (3.6 mg/kg). Consistent with reduced cognitive flexibility, WT, but not NF1, mice showed better performance in the third than second water maze probe trial. Finally, Alk inhibition (10 mg/kg) increased baseline activity of NF1 MC, but not PC, mice during the fear conditioning test. Thus, the effective dose depends on the behavioral test and genotype but indicates that in NF1 patients cognitive flexibility might be particularly sensitive to Alk inhibition.

Topics: Anaplastic Lymphoma Kinase; Animals; Antineoplastic Agents; Behavior, Animal; Carbazoles; Cognition; Cognitive Dysfunction; Dose-Response Relationship, Drug; Enzyme Inhibitors; Fear; Female; Genotype; Heterozygote; Male; Maze Learning; Mice; Mice, Inbred C57BL; Neurofibromatosis 1; Neurofibromin 1; Parents; Piperidines

Topics: Administration, Oral; Animals; Biphenyl Compounds; Cognitive Dysfunction; Disease Models, Animal; Maze Learning; Mice; Mice, Inbred C57BL; Mice, Transgenic; Molecular Structure; Neurons; Neuroprotective Agents; Piperidines; Synaptic Transmission

Alzheimer's disease (AD) is a complex neurological disorder with contributions from genetic and environmental factors. High-resolution metabolomics (HRM) has the potential to identify novel endogenous and environmental factors involved in AD. Previous metabolomics studies have identified circulating metabolites linked to AD, but lack of replication and inconsistent diagnostic algorithms have hindered the generalizability of these findings. Here we applied HRM to identify plasma metabolic and environmental factors associated with AD in two study samples, with cerebrospinal fluid (CSF) biomarkers of AD incorporated to achieve high diagnostic accuracy.. Liquid chromatography-mass spectrometry (LC-MS)-based HRM was used to identify plasma and CSF metabolites associated with AD diagnosis and CSF AD biomarkers in two studies of prevalent AD (Study 1: 43 AD cases, 45 mild cognitive impairment [MCI] cases, 41 controls; Study 2: 50 AD cases, 18 controls). AD-associated metabolites were identified using a metabolome-wide association study (MWAS) framework.. An MWAS meta-analysis identified three non-medication AD-associated metabolites in plasma, including elevated levels of glutamine and an unknown halogenated compound and lower levels of piperine, a dietary alkaloid. The non-medication metabolites were correlated with CSF AD biomarkers, and glutamine and the unknown halogenated compound were also detected in CSF. Furthermore, in Study 1, the unknown compound and piperine were altered in MCI patients in the same direction as AD dementia.. In plasma, AD was reproducibly associated with elevated levels of glutamine and a halogen-containing compound and reduced levels of piperine. These findings provide further evidence that exposures and behavior may modify AD risks.

Topics: Aged; Aged, 80 and over; Alkaloids; Alzheimer Disease; Benzodioxoles; Biomarkers; Chromatography, Liquid; Cognitive Dysfunction; Female; Glutamine; Humans; Male; Mass Spectrometry; Metabolome; Metabolomics; Middle Aged; Piperidines; Polyunsaturated Alkamides

Adult neurogenesis in hippocampus dentate gyrus (DG) is associated with the etiology on the early stage of Alzheimer's disease (AD). Factors that affect adult hippocampal neurogenesis have been shown to contribute to the neuropathology of AD. Adiponectin, a peptide hormone secreted by adipocytes, plays a critical role in insulin sensitizing, anti-inflammatory, and anti-diabetic effects in peripheral tissues. We previously showed that AdipoRon, as an agonist of adiponectin, promotes neurite outgrowth under ischemia. However, the role of AdipoRon on neural stem cells (NSCs) proliferation and cognitive dysfunction in the early stage of AD remains unknown. In this study, we investigated the role of AdipoRon on cognitive dysfunction and deficits of NSCs proliferation in AD. The in vivo study showed that AdipoRon improved either cognitive dysfunction or impaired NSCs proliferation in hippocampus DG region in APP/PS1 transgenic (Tg) mice. In addition, AdipoRon treatment also suppressed the β-amyloid (Aβ) deposition and inhibited β-secretase 1(BACE1) expression in both cortex and hippocampus of APP/PS1 Tg mice. The in vitro study further suggested that AdipoRon significantly alleviated Aβ-induced cell viability and neuronal morphology in primary neurons. Both AdipoR1 silencing and compound C, inhibitor of AMPK, completely abolished the effect of AdipoRon. Interestingly, AdipoRon also protected the dissipation of the ΔΨm caused by Aβ toxicity in primary neurons, which was reversed by compound C. In NE-4C NSCs, AdipoRon significantly promoted the Aβ-induced impaired cell proliferation through AdipoR1/AMPK/CREB pathway. Furthermore, inhibition of AMPK by compound C also reversed the promotive effects of AdipoRon on cognition and proliferation of NSCs of APP/PS1 Tg mice, suggesting a AMPK-dependent mechanism by AdipoRon in AD in vivo. Taken together, these results suggested that AdipoRon alleviated the cognitive dysfunction of AD mice, inhibited the Aβ deposition by inhibiting BACE1 expression and promoted the impaired hippocampal NSCs proliferation on the early stage in vivo. The mechanisms involved activation of AdipoR1/AMPK pathway. Therefore, AdipoRon might be a potential candidate for the treatment of AD on the early stage.

Topics: Alzheimer Disease; AMP-Activated Protein Kinases; Animals; Cell Proliferation; Cognition; Cognitive Dysfunction; Disease Models, Animal; Hippocampus; Mice; Mice, Transgenic; Neural Stem Cells; Piperidines; Receptors, Adiponectin; Signal Transduction

Kelch-like ECH-associated protein (Keap1)-nuclear factor erythroid-2-related factor 2 (Nrf2) protein-protein interaction has become an important drug target for the treatment of Alzheimer's disease. In this study, we found a novel piperine derivative (HJ22) synthesized by our group with great ability to bind to Keap-1 and activate Keap1-Nrf2-ARE signaling pathway in vitro, driving us to investigate the beneficial effects of HJ22 on ibotenic acid (IBO)-induced neurological disorders in rats and underlying mechanisms. Interestingly, HJ22 significantly ameliorated IBO-induced cognitive impairment in Morris water maze, Y-maze and passive avoidance tests. Moreover, HJ22 significantly attenuated cholinergic dysfunction and neuronal morphological changes via inhibiting apoptotic cell death induced by IBO. Notably, HJ22 inhibited the interaction between Keap1 and Nrf2, and subsequently up-regulated nuclear Nrf2 expression, thereby inhibiting oxidative stress and Thioredoxin-interacting protein (TXNIP)-mediated Nod-like receptor protein 3 (NLRP3) inflammasome activation. These findings demonstrated that HJ22 exhibited potent therapeutic effects against IBO-induced cognitive impairment by alleviating cholinergic damage, oxidative stress, apoptosis and neuroinflammation, which might be partly attributed to its inhibitory activity on Keap1-Nrf2 protein-protein interaction.

Topics: Alkaloids; Animals; Apoptosis; Benzodioxoles; Cells, Cultured; Cognitive Dysfunction; Disease Models, Animal; Humans; Ibotenic Acid; Inflammasomes; Inflammation; Kelch-Like ECH-Associated Protein 1; Neurons; NF-E2-Related Factor 2; Oxidative Stress; Piperidines; Polyunsaturated Alkamides; Protein Binding; Protein Interaction Domains and Motifs; Rats; Rats, Sprague-Dawley

Elucidating the relationship between neuronal metabolism and the integrity of the cholinergic system is prerequisite for a profound understanding of cholinergic dysfunction in Alzheimer's disease. The cholinergic system can be investigated specifically using positron emission tomography (PET) with [

Topics: Acetates; Acetylcholinesterase; Aged; Aged, 80 and over; Alzheimer Disease; Cognitive Dysfunction; Female; Fluorodeoxyglucose F18; Humans; Male; Middle Aged; Piperidines; Positron-Emission Tomography; Radiopharmaceuticals

We previously reported that centrally acting non-narcotic antitussives, including tipepidine, inhibit G-protein-coupled inwardly rectifying potassium (GIRK) channel-activated currents of neurons. In addition, when administered at a cough suppressant dose, the drugs ameliorated the symptoms of various models of intractable brain disease in rodents. In the current study, we investigated whether tipepidine causes recovery from schizophrenia-like cognitive dysfunction, which was induced by MK-801 (0.2 mg/kg, i.p.) in mice. We also examined the effect of tipepidine and clozapine co-administration on the dysfunction. Moreover, we studied whether clozapine inhibits GIRK channel activated currents in single brain neurons using the patch-clamp technique. Tipepidine elicited recovery from MK-801-induced cognitive impairment in the novel objective recognition test and Y-maze test. Further, co-administration of tipepidine and clozapine, at subthreshold doses of each drug, improved MK-801-induced cognitive impairment in the novel objective recognition test. Clozapine (3 × 10

Topics: Animals; Antidepressive Agents; Antitussive Agents; Clozapine; Cognitive Dysfunction; Disease Models, Animal; Dizocilpine Maleate; Dopaminergic Neurons; G Protein-Coupled Inwardly-Rectifying Potassium Channels; Male; Mice; Patch-Clamp Techniques; Piperidines; Rats; Rats, Wistar; Schizophrenia; Ventral Tegmental Area

Intellectual disability is the most limiting hallmark of Down syndrome, for which there is no gold-standard clinical treatment yet. The endocannabinoid system is a widespread neuromodulatory system involved in multiple functions including learning and memory processes. Alterations of this system contribute to the pathogenesis of several neurological and neurodevelopmental disorders. However, the involvement of the endocannabinoid system in the pathogenesis of Down syndrome has not been explored before. We used the best-characterized preclinical model of Down syndrome, the segmentally trisomic Ts65Dn model. In male Ts65Dn mice, cannabinoid type-1 receptor (CB1R) expression was enhanced and its function increased in hippocampal excitatory terminals. Knockdown of CB1R in the hippocampus of male Ts65Dn mice restored hippocampal-dependent memory. Concomitant with this result, pharmacological inhibition of CB1R restored memory deficits, hippocampal synaptic plasticity and adult neurogenesis in the subgranular zone of the dentate gyrus. Notably, the blockade of CB1R also normalized hippocampal-dependent memory in female Ts65Dn mice. To further investigate the mechanisms involved, we used a second transgenic mouse model overexpressing a single gene candidate for Down syndrome cognitive phenotypes, the dual specificity tyrosine-phosphorylation-regulated kinase 1A (DYRK1A). CB1R pharmacological blockade similarly improved cognitive performance, synaptic plasticity and neurogenesis in transgenic male Dyrk1A mice. Our results identify CB1R as a novel druggable target potentially relevant for the improvement of cognitive deficits associated with Down syndrome.

Topics: Animals; Brain; Cannabinoid Receptor Antagonists; Cognition; Cognitive Dysfunction; Disease Models, Animal; Down Syndrome; Female; Male; Mice; Mice, Transgenic; Neurogenesis; Phenotype; Piperidines; Pyrazoles; Receptor, Cannabinoid, CB1; Rimonabant

The multitarget-directed strategy offers an effective and promising paradigm to treat the complex neurodegenerative disorder, such as Alzheimer's disease (AD). Herein, a series of N-benzylpiperidine analogs (17-31 and 32-46) were designed and synthesized as multi-functional inhibitors of acetylcholinesterase (AChE) and β-secretase-1 (BACE-1) with moderate to excellent inhibitory activities. Among the tested inhibitors, 25, 26, 40, and 41 presented the most significant and balanced inhibition against both the targets. Compounds 40 and 41 exhibited high brain permeability in the PAMPA-BBB assay, significant displacement of propidium iodide from the peripheral anionic site (PAS) of AChE, and were devoid of neurotoxicity towards SH-SY5Y neuroblastoma cell lines up to the maximum tested concentration of 80 μM. Meanwhile, both these compounds inhibited self- and AChE-induced Aβ aggregation in thioflavin T assay, which was also re-affirmed by morphological characterization of Aβ aggregates using atomic force microscopy (AFM). Moreover, 40 and 41 ameliorated the scopolamine-induced cognitive impairment in elevated plus and Y-maze experiments. Ex vivo and biochemical analysis established the brain AChE inhibitory potential and antioxidant properties of these compounds. Further, improvement in Aβ

Topics: Alzheimer Disease; Amyloid Precursor Protein Secretases; Animals; Aspartic Acid Endopeptidases; Blood-Brain Barrier; Cell Line, Tumor; Cholinesterase Inhibitors; Cognitive Dysfunction; Drug Design; Humans; Mice; Piperidines; Protein Aggregation, Pathological; Structure-Activity Relationship

In early Alzheimer's disease, which initially presents with progressive loss of short-term memory, neurodegeneration especially affects cholinergic neurons of the basal forebrain. Pharmacotherapy of Alzheimer's disease therefore often targets the cholinergic system. In contrast, cholinergic pharmacotherapy of mild cognitive impairment is debated since its efficacy to date remains controversial. We here investigated the relationship between cholinergic treatment effects and the integrity of the cholinergic system in mild cognitive impairment due to Alzheimer's disease. Fourteen patients with high likelihood of mild cognitive impairment due to Alzheimer's disease and 16 age-matched cognitively normal adults performed an episodic memory task during functional magnetic resonance imaging under three conditions: (i) without pharmacotherapy; (ii) with placebo; and (iii) with a single dose of rivastigmine (3 mg). Cortical acetylcholinesterase activity was measured using PET with the tracer 11C-N-methyl-4-piperidyl acetate (MP4A). Cortical acetylcholinesterase activity was significantly decreased in patients relative to controls, especially in the lateral temporal lobes. Without pharmacotherapy, mild cognitive impairment was associated with less memory-related neural activation in the fusiform gyrus and impaired deactivation in the posterior cingulate cortex, relative to controls. These differences were attenuated under cholinergic stimulation with rivastigmine: patients showed increased neural activation in the right fusiform gyrus but enhanced deactivation of the posterior cingulate cortex under rivastigmine, compared to placebo. Conversely, controls showed reduced activation of the fusiform gyrus and reduced deactivation of the posterior cingulate under rivastigmine, compared to placebo. In both groups, the change in neural activation in response to rivastigmine was negatively associated with local acetylcholinesterase activity. At the behavioural level, an analysis of covariance revealed a significant group × treatment interaction in episodic memory performance when accounting for hippocampal grey matter atrophy and function. Our results indicate that rivastigmine differentially affects memory-related neural activity in patients with mild cognitive impairment and cognitively normal, age-matched adults, depending on acetylcholinesterase activity as a marker for the integrity of the cortical cholinergic system. Furthermore, hippocampal integrity showed an indepe

Topics: Acetates; Acetylcholinesterase; Aged; Aged, 80 and over; Alzheimer Disease; Case-Control Studies; Cerebral Cortex; Cholinergic Agents; Cognitive Dysfunction; Female; Humans; Magnetic Resonance Imaging; Male; Mental Status Schedule; Middle Aged; Neuropsychological Tests; Oxygen; Piperidines; Positron-Emission Tomography; Rivastigmine

The purpose of the study was to explore the therapeutic potential of Betulinic acid (BA) in streptozotocin (STZ) induced memory damage in experimental rats.. STZ (3mg/kg bilaterally) as intracerebroventrical (icv) route was administered on day 1 and 3 in rats. Donepezil (5mg/kg/day po), used as standard, and BA (5, 10 and 15mg/kg/day po) were administered after 1h of 1st STZ infusion up to 21days. Object recognition task (ORT) for non-spatial, Morris water maze (MWM) for spatial and locomotor activity were performed to evaluate behavioral changes in rats. On 22nd day, animals were decapitated and hippocampus was separated to perform biochemical (AChE, LPO, GSH, nitrite), neuroinflammatory (TNF-α, IL-1β, and IL-6), neurotransmitters (NTs) (dopamine, norepinephrine and serotonin) analysis.. STZ infusion significantly impaired memory as observed in MWM and ORT, increased oxidative stress, pro-inflammatory cytokine's level and altered NTs level. Moreover, BA demonstrated a neuroprotective effect in a dose-dependent manner. BA dose dependently (5, 10 and 15mg/kg) significantly restore STZ induced memory changes and pathological abnormalities in rat brain.. The findings of the current study suggests that BA protect rat brain from STZ induced neuronal damage via acting through multiple mechanisms and would be used to curb cognitive decline associated with neurodegenerative disorders especially AD.

Topics: Acetylcholinesterase; Animals; Betulinic Acid; Cognitive Dysfunction; Disease Models, Animal; Donepezil; Glutathione; Hippocampus; Indans; Inflammation; Injections, Intraventricular; Male; Maze Learning; Memory; Memory Disorders; Neuroprotective Agents; Neurotransmitter Agents; Oxidative Stress; Pentacyclic Triterpenes; Piperidines; Rats; Rats, Wistar; Streptozocin; Triterpenes

Cerebral ischemic stroke is associated with a high rate of incidence, prevalence and mortality globally. Carotid artery stenosis, which is mainly caused by atherosclerosis plaque, results in chronic cerebral hypoperfusion and predominantly increases the risk of ischemic stroke. In the present study, we used bilateral common carotid artery stenosis (BCAS) model by placing microcoils of 0.18 mm diameter encompassing both common carotid arteries respectively, to mimic the pathogenesis of carotid artery atherosclerosis and intensively explore the pathology. We found that BCAS injury for 1 month impaired spatial cognitive functions significantly, and inhibited synaptic plasticity, including hippocampal long-term potentiation (LTP) inhibition, dendritic spine density reduction and synaptic associative proteins disorder. BCAS-induced cerebral hypoperfused mice treated with 1-(1-propanoylpiperidin-4-yl)-3-[4-(trifluoromethoxy)phenyl]urea (TPPU), a potent soluble epoxide hydrolase (sEH) inhibitor, exhibited amelioration of cognitive dysfunction and improved synaptic plasticity. The neural protective effects of TPPU on BCAS-induced cerebral hypoperfusion might due to activation of neuregulin-1 (NRG1)/ErbB4 signaling, and triggered PI3K-Akt pathways subsequently. Our results suggested that sEH inhibition could exert multi-target protective effects and alleviate spatial cognitive dysfunctions after chronic cerebral hypoperfusion in mice.

Topics: Animals; Brain; Carotid Stenosis; Cognitive Dysfunction; Disease Models, Animal; Epoxide Hydrolases; Male; Mice, Inbred C57BL; Neuregulin-1; Nootropic Agents; Phenylurea Compounds; Piperidines; Random Allocation; Receptor, ErbB-4; Signal Transduction; Tissue Culture Techniques

Heterozygous Neurofibromatosis 1 (NF1) loss of function mutations are found in 90% of patients with neurofibromatosis, a syndrome associated with disabling cognitive impairment. Drosophila studies have demonstrated a genetic interaction between Anaplastic Lymphoma Kinase (Alk) and NF1 in cognitive performance. In addition, pharmacologic inhibition of Alk improves cognitive performance in heterozygous NF1 mutant flies. In this study, we tested whether pharmacological inhibition of Alk in heterozygous NF1 mutant mice attenuates or rescues cognitive impairments. Cognitive impairment of spatial memory retention observed in heterozygous NF1 mutant mice was rescued by the Alk inhibitor. These data support the hypothesis that inhibition of Alk may cognitively benefit patients with Neurofibromatosis 1.

Topics: Anaplastic Lymphoma Kinase; Animals; Carbazoles; Cognitive Dysfunction; Disease Models, Animal; Female; Male; Maze Learning; Memory Disorders; Mice, Inbred C57BL; Mice, Knockout; Neurofibromatosis 1; Nootropic Agents; Piperidines; Protein Kinase Inhibitors; Receptor Protein-Tyrosine Kinases; Spatial Memory; Swimming

Topics: Acetaminophen; Aged; Aged, 80 and over; Automobile Driving; Cognition Disorders; Cognitive Dysfunction; Colonic Neoplasms; Delirium; Dementia; Donepezil; Early Detection of Cancer; Estrogen Replacement Therapy; Female; Geriatrics; Humans; Indans; Male; Neuropsychological Tests; Nootropic Agents; Oxycodone; Piperidines; Urinary Incontinence; Watchful Waiting

The therapy of complex neurodegenerative diseases requires the development of multitarget-directed drugs (MTDs). Novel indole derivatives with inhibitory activity towards acetyl/butyrylcholinesterases and monoamine oxidases A/B as well as the histamine H

Topics: Animals; Antioxidants; Blood-Brain Barrier; Cholinesterase Inhibitors; Cognitive Dysfunction; Drug Design; Histamine H3 Antagonists; Humans; Indoles; Ligands; Mice; Monoamine Oxidase Inhibitors; Neurodegenerative Diseases; Neuroprotective Agents; Piperidines

Anticholinergic challenge can induce odor identification impairment that indicates Alzheimer's disease pathology.. To determine if decline in odor identification ability with anticholinergic challenge can predict improvement with donepezil, a cholinesterase inhibitor (ChEI), in patients with mild cognitive impairment (MCI).. At baseline, the University of Pennsylvania Smell identification Test (UPSIT) was administered before and after an anticholinergic atropine nasal spray challenge. Donepezil was started at 5 mg daily, increased to 10 mg daily if tolerated, and then the dose was kept constant for 52 weeks. Main outcomes were change in Selective Reminding Test (SRT) total immediate recall and ADAS-Cog total score from baseline to 26 and 52 weeks.. In 37 participants, mean age 70.4 (SD 9.8) y, greater atropine-induced decrease in UPSIT score at baseline was associated with greater improvement in SRT total recall score from baseline to 26 and 52 weeks (p < 0.03). This effect remained after adjusting for time, age, education, gender, APOE ɛ4 status, and baseline cognitive score (p < 0.05). Decrease in UPSIT score was associated with global improvement (CIBIC-plus) over 52 weeks (p < 0.02). After excluding patients with congential anosmia, increase in UPSIT score from 0 to 8 weeks showed a trend-level association with improvement on the ADAS-Cog (p = 0.07).. Anticholinergic challenge-induced odor identification decline was associated with cognitive improvement, and short-term improvement in odor identification tended to predict longer term cognitive improvement. These simple inexpensive strategies have the potential to improve selection of patients with MCI for ChEI treatment.

Topics: Aged; Atropine; Cholinesterase Inhibitors; Cognitive Dysfunction; Donepezil; Female; Humans; Indans; Male; Memory; Muscarinic Antagonists; Neuropsychological Tests; Odorants; Olfaction Disorders; Olfactory Perception; Pattern Recognition, Physiological; Piperidines; Prognosis; Psychotropic Drugs; Treatment Outcome

Stress occurs in everyday life and persistence of it causes memory loss. Bioflavonoids like quercetin are reported to have poor bioavailability and limited therapeutic potential against stress induced neurological disorders. Therefore, the present study is an attempt to elucidate the therapeutic potency of combination of quercetin with piperine; a bioavailability enhancer against chronic unpredictable stress (CUS)-induced behavioral and biochemical alterations. Laca mice were subjected to a series of stressful events for a period of 28 days. Quercetin (20, 40 and 80 mg/kg, p.o.), piperine (20 mg/kg, p.o.) and their combinations were administered daily 30 min before CUS procedure. Piracetam (100 mg/kg, i.p.) served as a standard control. CUS caused impaired spatial navigation in Morris water maze test and poor retention in elevated plus maze task. Further, there was significant increase in brain oxidative stress markers and neuro-inflammation (TNF-α). This was coupled with marked rise in acetylcholinesterase and serum corticosterone levels. Co-administration of piperine with quercetin significantly elevated their potential to restore these behavioral, biochemical and molecular changes associated with mouse model of CUS. These results suggest that piperine enhances the neuroprotective effects of quercetin against CUS-induced oxidative stress, neuro-inflammation and memory deficits.

Topics: Alkaloids; Animals; Behavior, Animal; Benzodioxoles; Biological Availability; Chronic Disease; Cognitive Dysfunction; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Therapy, Combination; Male; Mice, Inbred Strains; Neurogenic Inflammation; Oxidative Stress; Piperidines; Polyunsaturated Alkamides; Quercetin; Stress, Psychological

Falls are a leading cause of death in the elderly and, in a majority of patients with Parkinson's disease (PD), the leading levodopa-insensitive cause of hospitalization and long-term care. Falling in PD has been attributed to degeneration of forebrain cholinergic neurons that, in interaction with striatal dopamine losses, impairs the cognitive control of balance, gait, and movement. We previously established an animal model of these dual cholinergic-dopaminergic losses ("DL rats") and a behavioral test system (Michigan Complex Motor Control Task, MCMCT) to measure falls associated with traversing dynamic surfaces and distractors. Because the combined treatment of the acetylcholinesterase inhibitor donepezil and the 5-HT

Topics: Animals; Benzylamines; Cholinesterase Inhibitors; Cognition; Cognitive Dysfunction; Corpus Striatum; Donepezil; Dopamine; Female; Gait; Indans; Indoles; Male; Parkinson Disease; Piperidines; Postural Balance; Rats, Sprague-Dawley; Receptors, Serotonin

Donepezil is an acetylcholinesterase inhibitor frequently prescribed for the treatment of mild cognitive impairment (MCI) though not approved by the Food and Drug Administration for this indication. In Alzheimer's disease, butyrylcholinesterase (BChE) activity increases with disease progression and may replace acetylcholinesterase function. The most frequent polymorphism of BChE is the K-variant, which is associated with lower acetylcholine-hydrolyzing activity. BChE-K polymorphism has been studied in Alzheimer's disease progression and donepezil therapy, and has led to contradictory results.. To determine whether BChE-K genotype predicts response to donepezil in MCI.. We examined the association between BChE-K genotype and changes in cognitive function using the data collected during the ADCS vitamin E/donepezil clinical trial in MCI.. We found significant interactions between BChE-K genotype and the duration of donepezil treatment, with increased changes in MMSE and CDR-SB scores compared to the common allele in MCI subjects treated during the 3-year trial. We found faster MMSE decline and CDR-SB rise in BChE-K homozygous individuals treated with donepezil compared to the untreated. We observed similar interactions between BChE-K genotype and steeper changes in MMSE and CDR-SB scores in APOE4 carriers treated with donepezil compared to controls.. BChE-K polymorphisms are associated with deleterious changes in cognitive decline in MCI patients treated with donepezil for 3 years. This indicates that BChE-K genotyping should be performed to help identify subsets of subjects at risk for donepezil therapy, like those carrying APOE4. BChE-K and APOE4 carriers should not be prescribed off-label donepezil therapy for MCI management.

Topics: Aged; Aged, 80 and over; Apolipoprotein E4; Butyrylcholinesterase; Cholinesterase Inhibitors; Cognitive Dysfunction; Disease Progression; Donepezil; Female; Gene Frequency; Genotype; Humans; Indans; Longitudinal Studies; Male; Mental Status Schedule; Middle Aged; Neuropsychological Tests; Outcome Assessment, Health Care; Pharmacognosy; Piperidines; Polymorphism, Single Nucleotide; Time Factors

The dyshomeostasis of transition metal ions, accumulation of amyloid-β (Aβ) senile plaques and neuroinflammatory response found in the brain of patients with Alzheimer's disease (AD) have been suggested to be involved in AD pathogenesis. Novel compounds capable of targeting metal-Aβ species and neuroinflammation would be valuable. AD-35 is such a patented small-molecule compound derived from innovative modification of the chemical structure of donepezil. This compound could moderately inhibit acetylcholinesterase and metal-induced Aβ aggregation in vitro and showed disassembly of Aβ aggregates. The effects of AD-35 on cognitive impairments and neuroinflammatory changes caused by intracerebroventricular injection of Aβ25-35 were studied in rats. Compared to sham group, Aβ25-35 injection significantly led to learning and memory deficits, astrocyte activation, and pro-inflammatory cytokines releases (TNF-α and IL-1β). Further studies indicated that the phosphorylation of extracellular signal-regulated kinase was involved in astrocyte activation and pro-inflammatory cytokines production. Oral administration of AD-35 could markedly attenuate Aβ25-35 injection-induced astrocyte activation, pro-inflammatory cytokines TNF-α and IL-1β release, and memory deficits. On the contrary, donepezil only showed inhibition of IL-1β production, but failed to block astrocyte activation and TNF-α production. These results showed that AD-35 would be a novel multi-mechanism drug for the prevention and/or treatment of AD.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Astrocytes; Brain; Cell Line, Tumor; Cholinesterase Inhibitors; Cognitive Dysfunction; Disease Models, Animal; Donepezil; Humans; Indans; Interleukin-1beta; Male; Memory Disorders; Nootropic Agents; Peptide Fragments; Piperidines; Protein Aggregation, Pathological; Random Allocation; Rats, Sprague-Dawley; Tumor Necrosis Factor-alpha

In Alzheimer's disease (AD), white matter lesions (WMLs) are associated with an increased risk of progression from mild cognitive impairment (MCI) to dementia, while memory deficits have, at least in part, been linked to a cholinergic deficit. We investigated the relationship between WML load assessed with the Scheltens scale, cerebral acetylcholinesterase (AChE) activity measured with [

Topics: Acetates; Acetylcholinesterase; Aged; Aged, 80 and over; Aging; Alzheimer Disease; Cognitive Dysfunction; Female; Humans; Male; Memory; Middle Aged; Neuropsychological Tests; Piperidines; Positron-Emission Tomography; White Matter

The treatment of depression in old age is complicated by frequent co-morbidity with cognitive impairment. Anti-dementia drugs have some efficacy to improve cognitive performance and there is an inconsistent literature regarding the effect of such drugs on depressive symptoms. Here, we have investigated whether anti-dementia drugs would have antidepressant-like and pro-cognitive effects in a well-validated animal model of depression and cognitive impairment, chronic mild stress (CMS).. Rats were subjected to CMS for a total of 8 weeks. After 2 weeks, subgroups of stressed and non-stressed animals were treated daily, for 5 weeks followed by 1 week of drug withdrawal, with vehicle, imipramine (10 mg/kg), rivastigmine (2 mg/kg), donepezil (0.3 mg/kg) or memantine (5 mg/kg). Sucrose intake was tested weekly, and animals were also tested in the elevated plus maze (at week 7) and in an object recognition task (at weeks 7 and 8).. CMS decreased sucrose intake, had an anxiogenic effect in the elevated plus maze, and impaired performance in the object recognition test. Imipramine, rivastigmine and donepezil normalized performance in all three tests. Memantine had anxiolytic and pro-cognitive effects, but did not reverse CMS-induced anhedonia.. The fact that all three anti-dementia drugs reversed CMS-induced cognitive impairment and that cholinesterase inhibitors, but not memantine, have antidepressant-like effects in this model suggest that different mechanisms may underlie CMS-induced anhedonia and cognitive impairment. We discuss the clinical implications of these findings.

Topics: Anhedonia; Animals; Antidepressive Agents; Cholinesterase Inhibitors; Cognitive Dysfunction; Depressive Disorder; Disease Models, Animal; Donepezil; Indans; Male; Nootropic Agents; Piperidines; Rats; Rats, Wistar; Recognition, Psychology; Rivastigmine; Stress, Psychological

The impact of CYP2D6 and CYP3A4 polymorphism on the steady-state plasma concentrations and therapeutic outcome of donepezil monotherapy and combination therapy in Alzheimer's disease (AD) patients.. A total of 38 patients for donepezil and 17 patients for donepezil and memantine therapy, aged ≥ 55 years, were recruited meeting inclusion and exclusion criteria. Polymerase chain reaction-restriction fragment length polymorphism was performed. The liquid chromatography-tandem mass spectrometry method was used for estimation of drug levels of donepezil and memantine.. Significant allele frequency was observed for CYP2D6*3 polymorphism in patients on donepezil monotherapy and combination therapy. Significant allele frequency for CYP2D6*4 was observed in the patients on donepezil monotherapy.. CYP2D6 polymorphism, though not significant, might partially be involved in the plasma concentration of AD drug.

Topics: Aged; Alleles; Alzheimer Disease; Cholinesterase Inhibitors; Chromatography, High Pressure Liquid; Cognitive Dysfunction; Cytochrome P-450 CYP2D6; Cytochrome P-450 CYP3A; Diagnostic and Statistical Manual of Mental Disorders; DNA; Donepezil; Dopamine Agents; Drug Therapy, Combination; Female; Genotype; Humans; Indans; India; Male; Memantine; Middle Aged; Neuropsychological Tests; Nootropic Agents; Piperidines; Polymorphism, Genetic; Tandem Mass Spectrometry; Treatment Outcome

To report a case of mania associated with the titration of donepezil in an elderly patient.. A 400-bed academic acute care psychiatric facility.. A 70-year-old male with a history of paranoid schizophrenia, alcohol dependence, and mild cognitive impairment was admitted after concerns that he was responding to internal stimuli and exhibited increased disorganization. The patient was initiated on quetiapine, titrated to 500 mg at bedtime, to address disorganization, hallucinations, and poor sleep. After improvement of psychotic symptoms and assessment of cognitive function, donepezil 5 mg daily was initiated and titrated to 10 mg daily after two weeks. Days following the increase of donepezil to 10 mg daily, the patient exhibited symptoms of mania and became hyperverbal with elevated mood and agitation. A decreased need for sleep with an increase in cleaning activities throughout the day was noted. Donepezil was suspected to have induced the new symptoms and was discontinued. Following discontinuation, the manic symptoms completely resolved over a two-week period.. The titration of donepezil was associated with the onset of mania. Previous trials involving off-label donepezil use in patients with bipolar disorder, but not schizophrenia, have reported the development of manic symptoms. Although rare, there is mounting evidence that donepezil is associated with the emergence of mania. Clinicians should be aware of this potential side effect in all patients treated with donepezil.

Topics: Aged; Bipolar Disorder; Cholinesterase Inhibitors; Cognitive Dysfunction; Donepezil; Humans; Indans; Male; Nootropic Agents; Piperidines

Episodic memory retrieval is reliant upon cognitive control systems, of which 2 have been identified with functional neuroimaging: a cingulo-opercular salience network (SN) and a frontoparietal executive network (EN). In Alzheimer's disease (AD), pathology is distributed throughout higher-order cortices. The hypotheses were that this frontoparietal pathology would impair activity associated with verbal memory recall; and that central cholinesterase inhibition (ChI) would modulate this, improving memory recall.. Functional magnetic resonance imaging was used to study normal participants and 2 patient groups: mild cognitive impairment (MCI) and AD. Activity within the EN and SN was observed during free recall of previously heard sentences, and related to measures of recall accuracy.. In normal subjects, trials with reduced recall were associated with greater activity in both the SN and EN. Better recall was associated with greater activity in medial regions of the default mode network. By comparison, AD patients showed attenuated responses in both the SN and EN compared with either controls or MCI patients, even after recall performance was matched between groups. Following ChI, AD patients showed no modulation of activity within the SN, but increased activity within the EN. There was also enhanced activity within regions associated with episodic and semantic memory during less successful recall, requiring greater cognitive control.. The results indicate that in AD, impaired responses of cognitive control networks during verbal memory recall are partly responsible for reduced recall performance. One action of symptom-modifying treatment is partially to reverse the abnormal function of frontoparietal cognitive control and temporal lobe memory networks.

Topics: Adult; Aged; Aged, 80 and over; Alzheimer Disease; Cholinesterase Inhibitors; Cognitive Dysfunction; Donepezil; Executive Function; Female; Frontal Lobe; Functional Neuroimaging; Humans; Indans; Magnetic Resonance Imaging; Male; Mental Recall; Middle Aged; Parietal Lobe; Piperidines; Speech Perception; Young Adult

The clinical expression of Alzheimer's disease (AD) occurs as neuropathology exceeds the brain "reserve capacity." A possible association between the cholinergic system and reserve is suggested by preclinical observations that the cholinergic system allows cortical plasticity and by clinical observations of variable responses to cholinergic treatments depending on the patient's educational level. The aim of this study was to investigate the association of reserve proxies, that is, education and occupation, with acetylcholinesterase (AChE) activity, measured voxelwise by [(11)C]-MP4A and positron emission tomography (PET), in 9 healthy controls (HC), 7 patients with early probable AD, and 9 subjects with mild cognitive impairment (MCI) at the time of PET imaging, who progressed to AD at follow-up (prodromal AD). The analysis of prodromal and early AD showed positive correlations between education and AChE activity in the hippocampus, bilaterally, and between occupation and AChE activity in the right posterior cingulate gyrus. The significant correlation between AChE activity in structures belonging to the memory network and reserve proxies suggests that the brain reserve in AD is associated with a preserved/stimulated cholinergic neurotransmission.

Topics: Acetates; Acetylcholine; Aged; Aged, 80 and over; Alzheimer Disease; Carbon Isotopes; Cognitive Dysfunction; Cognitive Reserve; Educational Status; Employment; Female; Fluorodeoxyglucose F18; Humans; Male; Mental Status Schedule; Middle Aged; Piperidines; Positron-Emission Tomography; Radiography; Statistics, Nonparametric; Tomography Scanners, X-Ray Computed

We report the case of a 74-year-old woman who presented with amnesia and positive serum anticholinergic activity (SAA), which disappeared after treatment with the cholinesterase inhibitor donepezil for 1 year. Her only other regular medications were topical glaucoma preparations. We suggest that mental stress, mild cognitive impairment and Alzheimer's disease pathology combined to generate SAA in this patient. We also consider that SAA may have subsequently become negative because of upregulation of acetylcholine production by donepezil, and because the patient's other medications and physical condition (including glaucoma) remained unchanged during the 1-year period.

Topics: Aged; Amnesia; Cholinesterase Inhibitors; Cognitive Dysfunction; Donepezil; Female; Humans; Indans; Nootropic Agents; Piperidines

Non-invasive approaches for positron emission tomography (PET) parametric imaging of acetylcholinesterase (AChE) activity have been developed and applied to the investigation of dementia, mainly Alzheimer's disease (AD), but also dementia with Lewy bodies (DLB), not including, however, patients in the early disease stage. The few cholinergic PET studies on mild cognitive impairment (MCI) did not provide clinical follow-up. One limitation of the methods used so far is the relatively low sensitivity in measuring subcortical or deep cortical structures, which might represent specific disease markers. Here we assessed AChE activity with [11C]-MP4A and PET by a maximum a posteriori Bayesian method (MAPB) based on a 2-tissue compartment-3-rate-constant reference region model. 30 subjects were included: 10 multi-domain amnestic MCI (aMCI) with a follow up of 2 years, 7 probable AD (pAD), 4 DLB subjects, and 9 healthy controls. Regions of interest and voxel-based statistical parametric mapping analyses revealed significant and widespread AChE reductions in several cortical regions and in the hippocampus in all pAD subjects and aMCI subjects who progressed to AD (converters). Noteworthy, hippocampal AChE activity correlated significantly with long-term verbal and non-verbal memory in both aMCI converters and pAD. The pattern was more heterogeneous in early DLB patients, with only 2 out of 4 cases showing a severe or intermediate reduction of AChE activity. The comparable AChE reductions in pAD and aMCI converters indicate the presence of a widespread impairment of the cholinergic system already in the MCI phase. A more variable degree of cholinergic dysfunction is present in early DLB.

Topics: Acetates; Acetylcholinesterase; Aged; Aged, 80 and over; Amnesia; Bayes Theorem; Carbon Radioisotopes; Cognitive Dysfunction; Female; Humans; Lewy Body Disease; Male; Middle Aged; Piperidines; Positron-Emission Tomography

Mild cognitive impairment (MCI) is defined as 'a condition between a normal state and dementia indicated by a cognitive decline in comparison to previous results'. MCI groups as a whole are not necessarily in the prodromal stage of dementia. However, when patients are notified of their condition, communication must be cautious and account for the patient's personality, mental status, and examination findings. Hurriedly notifying patients may give the incorrect impression that they will certainly have dementia in the future and cause worry or emotional tension. The efficacy of pharmacotherapy and non-pharmacotherapy, such as cognitive function training, in preventing dementia in MCI patients has not yet been confirmed. As no particular types of intervention are currently shown to be effective for MCI, it is believed that periodically monitoring patients and providing lifestyle guidance, while also treating lifestyle-related diseases, is an appropriate treatment strategy for those with MCI.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Cholinesterase Inhibitors; Cognitive Dysfunction; Combined Modality Therapy; Donepezil; Health Behavior; Humans; Indans; Japan; Life Style; Middle Aged; Nootropic Agents; Patient Education as Topic; Physician-Patient Relations; Piperidines; Treatment Outcome; Truth Disclosure

To evaluate the cost effectiveness of genetic screening for the apolipoprotein (APOE) ε4 allele in combination with preventive donepezil treatment in comparison with the standard of care for amnestic mild cognitive impairment (AMCI) patients in Canada.. We performed a cost-effectiveness analysis using a Markov model with a societal perspective and a time horizon of 30 years. For each strategy, we calculated quality-adjusted life-years (QALYs), using utilities from the literature. Costs were also based on the literature and, when appropriate, Ontario sources. One-way and probabilistic sensitivity analyses were performed. Expected value of perfect information (EVPI) analysis was conducted to explore the value of future research.. The base case results in our exploratory study suggest that the combination of genetic testing and preventive donepezil treatment resulted in a gain of 0.027 QALYs and an incremental cost of $1,015 (in 2009 Canadian dollars [Can$]), compared with the standard of care. The incremental cost-effectiveness ratio (ICER) for the base case was Can$38,016 per QALY. The ICER was sensitive to the effectiveness of donepezil in slowing the rate of progression to Alzheimer's disease (AD), utility in AMCI patients, and AD and donepezil treatment costs. EVPI analysis showed that additional information on these parameters would be of value.. Using presently available clinical evidence, this exploratory study illustrates that genetic testing combined with preventive donepezil treatment for AMCI patients may be economically attractive. Since our results were based on a secondary post hoc analysis, our study alone is insufficient to warrant recommending APOE genotyping in AMCI patients. Future research on the effectiveness of preventive donepezil as a targeted therapy is recommended.

Topics: Aged; Aged, 80 and over; Amnesia; Canada; Case-Control Studies; Chemoprevention; Cognitive Dysfunction; Cost-Benefit Analysis; Donepezil; Genetic Testing; Humans; Indans; Markov Chains; Molecular Targeted Therapy; Nootropic Agents; Piperidines; Precision Medicine; Quality-Adjusted Life Years; Severity of Illness Index; Standard of Care

A wearable camera that takes pictures automatically, SenseCam, was used to generate images for rehearsal, promoting consolidation and retrieval of memories for significant events in a patient with memory retrieval deficits. SenseCam images of recent events were systematically reviewed over a 2-week period. Memory for these events was assessed throughout and longer-term recall was tested up to 6 months later. A written diary control condition followed the same procedure. The SenseCam review procedure resulted in significantly more details of an event being recalled, with twice as many details recalled at 6 months follow up compared to the written diary method. Self-report measures suggested autobiographical recollection was triggered by the SenseCam condition but not by reviewing the written diary. Emotional and social wellbeing questionnaires indicated improved confidence and decreased anxiety as a result of memory rehearsal using SenseCam images. We propose that SenseCam images provide a powerful boost to autobiographical recall, with secondary benefits for quality of life.

Topics: Cholinesterase Inhibitors; Cognitive Dysfunction; Cues; Donepezil; Environmental Monitoring; Female; Humans; Image Processing, Computer-Assisted; Indans; Medical Records; Memory Disorders; Memory, Episodic; Mental Recall; Microcomputers; Middle Aged; Nootropic Agents; Photography; Piperidines; Quality of Life; Self Report; Self-Help Devices