Update on Cognitive Enhancers Among the Older Adult Population: A Clinical Review.

PURPOSE OF REVIEW: The purpose of this review is to identify key classes of medications that are used for the treatment of older adults with neurocognitive disorders. RECENT FINDINGS: Clinical factors play a critical role in the prescribing of these medication classes for the treatment of dementia. The variation in prescribing trends is determined by the presence of medical and psychiatric comorbidities commonly occurring in older adults and is based on the consideration of potential interactions between pharmacotherapies for the comorbidities and for the dementia. Six medication classes currently exist to address the neurocognitive aspect of dementia, with varying pharmacokinetic and pharmacodynamic profiles. We review these six classes in this report and provide a provision of clinical insights regarding the use of these agents. While literature exists on the safety and efficacy of individual medication options for the treatment of dementia in the older adult population, further research is needed to provide clearer guidance regarding the specific use of these agents in clinical practice.

The Atypical Dopamine Transporter Inhibitor CE-158 Enhances Dopamine Neurotransmission in the Prefrontal Cortex of Male Rats: A Behavioral, Electrophysiological, and Microdialysis Study.

BACKGROUND: Dopamine plays a key role in several physiological functions such as motor control, learning and memory, and motivation and reward. The atypical dopamine transporter inhibitor S,S stereoisomer of 5-(((S)-((S)-(3-bromophenyl)(phenyl)methyl)sulfinyl)methyl)thiazole (CE-158) has been recently reported to promote behavioral flexibility and restore learning and memory in aged rats. METHODS: Adult male rats were i.p. administered for 1 or 10 days with CE-158 at the dose of 1 or 10 mg/kg and tested for extracellular dopamine in the medial prefrontal cortex by means of intracerebral microdialysis and single unit cell recording in the same brain area. Moreover, the effects of acute and chronic CE-158 on exploratory behavior, locomotor activity, prepulse inhibition, working memory, and behavioral flexibility were also investigated. RESULTS: CE-158 dose-dependently potentiated dopamine neurotransmission in the medial prefrontal cortex as assessed by intracerebral microdialysis. Moreover, repeated exposure to CE-158 at 1 mg/kg was sufficient to increase the number of active pyramidal neurons and their firing frequency in the same brain area. In addition, CE-158 at the dose of 10 mg/kg stimulates exploratory behavior to the same extent after acute or chronic treatment. Noteworthy, the chronic treatment at both doses did not induce any behavioral alterations suggestive of abuse potential (e.g., motor behavioral sensitization) or pro-psychotic-like effects such as disruption of sensorimotor gating or impairments in working memory and behavioral flexibility as measured by prepulse inhibition and Y maze. CONCLUSIONS: Altogether, these findings confirm CE-158 as a promising pro-cognitive agent and contribute to assessing its preclinical safety profile in a chronic administration regimen for further translational testing.

Immunomodulation through vaccination as a promising therapeutic strategy to mitigate malaria-related neurocognitive sequelae.

Malaria, an ancient infectious parasitic disease, is caused by protozoa of the genus Plasmodium, whose erythrocytic cycle is accompanied by fever, headache, sweating and chills and a systemic inflammation that can progress to severe forms of disease, including cerebral malaria. Approximately 25% of survivors of this syndrome develop sequelae that may include neurological, neurocognitive, behavioral alterations and poor school performance. Furthermore, some outcomes have also been recorded following episodes of non-severe malaria, which correspond to the most common clinical form of the disease worldwide. There is a body of evidence that neuroinflammation, due to systemic inflammation, plays an important role in the neuropathogenesis of malaria culminating in these cognitive dysfunctions. Preclinical studies suggest that vaccination with type 2 immune response elicitors, such as the tetanus-diphtheria (Td) vaccine, may exert a beneficial immunomodulatory effect by alleviating neuroinflammation. In this viewpoint article, vaccination is proposed as a therapy approach to revert or mitigate neurocognitive deficits associated with malaria.

Oral intake of carboxy alkyl ester improves attention: A randomized double-blind cross-over placebo-controlled study.

OBJECTIVE: To test the null hypothesis that oral intake of the dietary supplement carboxy alkyl ester (CAE) would have no effect on attention as revealed by mean rapid visual information processing (RVIP) scores. METHODS: In a randomized double-blind cross-over placebo-controlled trial, healthy participants (age 19-66 years) of both sexes were randomly assigned to consume 700 mg of CAE or 700 mg of placebo. They received baseline attention testing via the RVIP task. Then they consumed CAE or placebo followed by RVIP testing. Participants were then given a washout period where they did not consume CAE or placebo. Afterward, individuals who initially consumed CAE were given the placebo and those who initially consumed the placebo were given CAE. Finally, all participants were tested again via RVIP. RESULTS: A priori statistical computation revealed that 30-day oral intake of CAE improved mean RVIP test scores (t = 2.4, p < .05) relative to that at baseline, which resulted in a rejection of the null hypothesis. CONCLUSIONS: Daily oral intake of the CAE dietary supplement may boost attention and further research is now needed to confirm this observation.

Event-related potential (P300): the effects of levetiracetam in cognitive performance.

BACKGROUND: The current study is a reanalysis in the time domain of EEG data collection in healthy adults during an oddball paradigm using levetiracetam (LEV) vs. placebo acute administration. Specifically, the event-related potential (ERP) technique provides a tool for exploring the EEG responses to a specific event/stimulus. One of the ERP components widely studied is the P300 component, which is associated with the last stage of information processing and a general measurement of "cognitive efficiency." METHODS: The sample was composed of thirteen healthy right-handed individuals randomized to participate under two conditions: LEV and placebo. Electrophysiological measures were collected before and after drug intake. We explored the oddball paradigm, which is commonly used with healthy individuals to investigate the stages of information processing. RESULTS: The electrophysiological results showed a main effect of condition on P300 amplitude for the frontal (F3, Fz, F4), central (C3, Cz, C4), and parietal electrodes (P3, Pz, P4). The post hoc comparisons (Scheffé's test) demonstrated the significant differences between electrodes. Regarding P300 latency, all regions represented a main effect of condition. A P300 latency reduction was observed during LEV condition compared with placebo. CONCLUSION: Our study observed the ERP component-P300-through the variation of its amplitude and latency to evaluate a supposed higher CNS efficiency when participants were under the LEV effect. Our findings sustain this premise, mainly due to reducing in P300 latency for the LEV condition, supporting the neural efficiency hypothesis.

ß-hydroxybutyric acid attenuates oxidative stress and improves markers of mitochondrial function in the HT-22 hippocampal cell line.

Ketone bodies have been the topic of research for their possible therapeutic neurotropic effects in various neurological diseases such as Parkinson's disease, dementia, and seizures. However, continuing research on ketone bodies as a prophylactic agent for decreasing the risk for various neurodegenerative diseases is currently required. In this paper, hippocampal HT-22 cells were treated with ß-hydroxybutyric acid at different doses to elucidate the neurotropic effects. In addition, markers of oxidative stress, mitochondrial function, and apoptosis were investigated. As a result, the ketone body (ß-hydroxybutyric acid) showed a significant increase in hippocampal neuronal viability at a moderate dose. Results show that ß-hydroxybutyric acid exhibited antioxidant effect by decreasing prooxidant oxidative stress markers such as reactive oxygen species, nitrite content, and increasing glutathione content leading to decreased lipid peroxidation. Results show that ß-hydroxybutyric acid improved mitochondrial functions by increasing Complex-I and Complex-IV activities and showing that ß-hydroxybutyric acid significantly reduces caspase-1 and caspase-3 activities. Finally, using computational pharmacokinetics and molecular modeling software, we validated the pharmacokinetic effects and pharmacodynamic (N-Methyl-D-aspartic acid and acetylcholinesterase) interactions of ß-hydroxybutyric acid. The computational studies demonstrate that ß-hydroxybutyric acid can interact with N-Methyl-D-aspartic acid receptor and cholinesterase enzyme (the prime pharmacodynamic targets for cognitive impairment) and further validates its oral absorption, distribution into the central nervous system. Therefore, this work highlights the neuroprotective potential of ketone bodies in cognitive-related neurodegenerative diseases.

Mass Spectrometry Imaging Shows Modafinil, A Student Study Drug, Changes the Lipid Composition of the Fly Brain.

Modafinil, a widely used psychoactive drug, has been shown to exert a positive impact on cognition and is used to treat sleep disorders and hyperactivity. Using time-of-flight secondary ion mass spectrometric imaging, we studied the changes of brain lipids of Drosophila melanogaster induced by modafinil to gain insight into the functional mechanism of modafinil in the brain. We found that upon modafinil treatment, the abundance of phosphatidylcholine and sphingomyelin species in the central brain of Drosophila is significantly decreased, whereas the levels of phosphatidylethanolamine and phosphatidylinositol in the brains show significant enhancement compared to the control flies. The alteration of brain lipids caused by modafinil is consistent with previous studies about cognition-related drugs and offers a plausible mechanism regarding the action of modafinil in the brain as well as a potential target for the treatment of certain disorders.

Ginkgo biloba special extract LI 1370 improves dual-task walking in patients with MCI: a randomised, double-blind, placebo-controlled exploratory study.

BACKGROUND: In patients with mild cognitive impairment (MCI), gait instability, particularly in dual-task situations, has been associated with impaired executive function and an increased fall risk. Ginkgo biloba extract (GBE) could be an effective mean to improve gait stability. AIMS: This study investigated the effect of GBE on spatio-temporal gait parameters of MCI patients while walking under single and dual-task conditions. METHODS: Fifty patients aged 50-85 years with MCI and associated dual-task-related gait impairment participated in this randomised, double-blind, placebo-controlled, exploratory phase IV drug trial. Intervention group (IG) patients received GBE (Symfona® forte 120 mg) twice-daily for 6 months while control group (CG) patients received placebo capsules. A 6-month open-label phase with identical GBE dosage followed. Gait was quantified at months 0, 3, 6 and 12. RESULTS: After 6 months, dual-task-related cadence increased in the IG compared to the CG (p = 0.019, d = 0.71). No significant changes, but GBE-associated numerical non-significant trends were found after 6-month treatment for dual-task-related gait velocity and stride time variability. DISCUSSION: Findings suggest that 120 mg of GBE twice-daily for at least 6 months may improve dual-task-related gait performance in patients with MCI. CONCLUSIONS: The observed gait improvements add to the understanding of the self-reported unspecified improvements among MCI patients when treated with standardised GBE.

Attitudes Toward Cognitive Enhancer Use Among New Zealand Tertiary Students.

BACKGROUND: Cognitive enhancement is the use of prescription stimulant medicines by healthy individuals for nonmedical use in academic settings. Commonly used cognitive enhancers (CEs) include methylphenidate, amphetamines, and modafinil. To understand the motivation to use CEs, it is important to look beyond prevalence and explore the extent to which attitudes, beliefs, and intentions predict the decision to use CEs. OBJECTIVE: The study aimed to investigate what factors explain the decision to use CEs among tertiary students in New Zealand, using the Theory of Planned Behaviour (TPB). METHODS: Students from the Schools of Pharmacy, Nursing, Medicine, Law, and Accounting at a university in New Zealand were invited to complete a paper-based questionnaire. The questionnaire elicited students' attitudes, subjective norms, and perceived control toward illicit use of CEs using TPB. An exploratory factor analysis was conducted. RESULTS: Response rate was 88.6% (442/499). Students who perceived CE use to be socially and ethically acceptable were more likely to use CEs (odds ratio, OR: 1.56, 95% confidence interval, 95% CI: 1.153-2.105, p = 0.004). Students who were concerned about the health impact of CE use were less likely to use CEs (OR: 0.54, 95% CI: 0.492-0.826, p = 0.001). Students who believed that CE use was approved were more likely to use them (OR: 1.648, CI: 1.193-2.278, p = 0.002). CONCLUSION: This research supports the notion that the decision to use CEs is not just an autonomous choice that occurs in isolation. Attitudes on the ethical and social acceptability of CE use were more likely to drive the decision to use CEs. The study provides the impetus for an integrative discussion by health care professionals and academics on the impact of attitudes, social norms, and advocates on the decision to use CEs.

PKR Inhibition Rescues Memory Deficit and ATF4 Overexpression in ApoE ε4 Human Replacement Mice.

Sporadic Alzheimer's disease (AD) is an incurable neurodegenerative disease with clear pathological hallmarks, brain dysfunction, and unknown etiology. Here, we tested the hypothesis that there is a link between genetic risk factors for AD, cellular metabolic stress, and transcription/translation regulation. In addition, we aimed at reversing the memory impairment observed in a mouse model of sporadic AD. We have previously demonstrated that the most prevalent genetic risk factor for AD, the ApoE4 allele, is correlated with increased phosphorylation of the translation factor eIF2α. In the present study, we tested the possible involvement of additional members of the eIF2α pathway and identified increased mRNA expression of negative transcription factor ATF4 (aka CREB2) both in human and a mouse model expressing the human ApoE4 allele. Furthermore, injection of a PKR inhibitor rescued memory impairment and attenuated ATF4 mRNA increased expression in the ApoE4 mice. The results propose a new mechanism by which ApoE4 affects brain function and further suggest that inhibition of PKR is a way to restore ATF4 overexpression and memory impairment in early stages of sporadic AD. Significance statement: ATF4 mRNA relative quantities are elevated in ApoE4 allele carriers compared with noncarrier controls. This is true also for the ApoE ε4 human replacement mice. ApoE4 mice injected with PKR inhibitor (PKRi) demonstrate a significant reduction in ATF4 expression levels 3 h after one injection of PKRi. Treatment of ApoE4 human replacement mice with the PKRi before learning rescues the memory impairment of the ApoE4 AD model mice. We think that these results propose a new mechanism by which ApoE4 affects brain function and suggest that inhibition of PKR is a way to restore memory impairment in early stages of sporadic AD.

Neural effects of methylphenidate and nicotine during smooth pursuit eye movements.

INTRODUCTION: Nicotine and methylphenidate are putative cognitive enhancers in healthy and patient populations. Although they stimulate different neurotransmitter systems, they have been shown to enhance performance on overlapping measures of attention. So far, there has been no direct comparison of the effects of these two stimulants on behavioural performance or brain function in healthy humans. Here, we directly compare the two compounds using a well-established oculomotor biomarker in order to explore common and distinct behavioural and neural effects. METHODS: Eighty-two healthy male non-smokers performed a smooth pursuit eye movement task while lying in an fMRI scanner. In a between-subjects, double-blind design, subjects either received placebo (placebo patch and capsule), nicotine (7mg nicotine patch and placebo capsule), or methylphenidate (placebo patch and 40mg methylphenidate capsule). RESULTS: There were no significant drug effects on behavioural measures. At the neural level, methylphenidate elicited higher activation in left frontal eye field compared to nicotine, with an intermediate response under placebo. DISCUSSION: The reduced activation of task-related regions under nicotine could be associated with more efficient neural processing, while increased hemodynamic response under methylphenidate is interpretable as enhanced processing of task-relevant networks. Together, these findings suggest dissociable neural effects of these putative cognitive enhancers.

Dissecting structure-activity-relationships of crebinostat: Brain penetrant HDAC inhibitors for neuroepigenetic regulation.

Targeting chromatin-mediated epigenetic regulation has emerged as a potential avenue for developing novel therapeutics for a wide range of central nervous system disorders, including cognitive disorders and depression. Histone deacetylase (HDAC) inhibitors have been pursued as cognitive enhancers that impact the regulation of gene expression and other mechanisms integral to neuroplasticity. Through systematic modification of the structure of crebinostat, a previously discovered cognitive enhancer that affects genes critical to memory and enhances synaptogenesis, combined with biochemical and neuronal cell-based screening, we identified a novel hydroxamate-based HDAC inhibitor, here named neurinostat, with increased potency compared to crebinostat in inducing neuronal histone acetylation. In addition, neurinostat was found to have a pharmacokinetic profile in mouse brain modestly improved over that of crebinostat. This discovery of neurinostat and demonstration of its effects on neuronal HDACs adds to the available pharmacological toolkit for dissecting the molecular and cellular mechanisms of neuroepigenetic regulation in health and disease.

Selective serotonin re-uptake inhibitors potentiate gene blunting induced by repeated methylphenidate treatment: Zif268 versus Homer1a.

There is a growing use of psychostimulants, such as methylphenidate (Ritalin; dopamine re-uptake inhibitor), for medical treatments and as cognitive enhancers in the healthy. Methylphenidate is known to produce some addiction-related gene regulation. Recent findings in animal models show that selective serotonin re-uptake inhibitors (SSRIs), including fluoxetine, can potentiate acute induction of gene expression by methylphenidate, thus indicating an acute facilitatory role for serotonin in dopamine-induced gene regulation. We investigated whether repeated exposure to fluoxetine, in conjunction with methylphenidate, in adolescent rats facilitated a gene regulation effect well established for repeated exposure to illicit psychostimulants such as cocaine-blunting (repression) of gene inducibility. We measured, by in situ hybridization histochemistry, the effects of a 5-day repeated treatment with methylphenidate (5 mg/kg), fluoxetine (5 mg/kg) or a combination on the inducibility (by cocaine) of neuroplasticity-related genes (Zif268, Homer1a) in the striatum. Repeated methylphenidate treatment alone produced minimal gene blunting, while fluoxetine alone had no effect. In contrast, fluoxetine added to methylphenidate robustly potentiated methylphenidate-induced blunting for both genes. This potentiation was widespread throughout the striatum, but was most robust in the lateral, sensorimotor striatum, thus mimicking cocaine effects. For illicit psychostimulants, blunting of gene expression is considered part of the molecular basis of addiction. Our results thus suggest that SSRIs, such as fluoxetine, may increase the addiction liability of methylphenidate.

The diffusion of performance and image-enhancing drugs (PIEDs) on the internet: the abuse of the cognitive enhancer piracetam.

INTRODUCTION: Performance and image-enhancing drugs (PIEDs), also known as "lifestyle drugs," are increasingly sold on the Internet to enhance cognitive as well as sexual, muscular, attentive, and other natural capacities. Our analysis focuses on the misuse of the cognitive enhancer piracetam. METHODS: A literature review was carried out in PsychInfo and Pubmed database. Considering the absence of peer-reviewed data, review of additional sources of unstructured information from the Internet was carried out between February 2012 and July 2013. Additional searches were conducted using the Global Public Health Intelligence Network (GPHIN), a secure Internet-based early warning system developed by Health Canada and the World Health Organization (WHO), which monitors media reports in six languages, Arabic, Chinese, English, French, Russian, and Spanish. RESULTS: Piracetam is sold via illicit online pharmacies with no need of prescription at low prices. Buyers, mainly healthy individuals, purchase the product to enhance study- and work-related performances as well as for recreational purposes. Its nonmedical use is often associated with the occurrence of side effects such as hallucinations, psychomotor agitation, dysphoria, tiredness, dizziness, memory loss, headache, and severe diarrhoea; moreover, several users declared to have neither felt any cognitive improvement nor psychedelic effects. CONCLUSIONS: This is a new and fast-growing trend of abuse that needs to be extensively monitored and studied also by using near real-time and unstructured sources of information such as Internet news and online reports in order to acquire rapid knowledge and understanding. Products sold online might be counterfeits and this enhances related health risks.

Age-related decline of various cognitive functions in well-experienced male rats treated with the putative anti-aging compound (2R)-1-(1-benzofuran-2-yl)-N-propylpentane-2-amine ((-)BPAP).

Aging-associated cognitive disorders lack proper medication. To meet this need translation-wise, modification of the animal models is also required. In the present study, effect of the putative anti-aging compound (2R)-1-(1-benzofuran-2-yl)-N-propylpentane-2-amine ((-)BPAP, a deprenyl derivative) on age-related cognitive decline was investigated in experienced, aged Long-Evans rats. During their lifetime, animals had acquired knowledge in various cognitive assays. Their performance in these tests was then parallel followed from the age of 27 months until their death meanwhile half of them were treated with BPAP. Cognitive performance in various tasks showed different sensitivities/resistances to age-related impairment. Pot jumping performance (motor skill-learning) started to impair first, at 21 months of age, followed by decreasing performance in five-choice serial reaction time task (attention) at 26 months. Navigation performance in Morris water maze (spatial learning) started to decline at 31 months. Performance in a cooperation task (social cognition) started to decline the latest, at 34 months. Our findings suggest that in this process, the primary factor was the level of motivation to be engaged with the task and not losing the acquired knowledge. The average lifespan of the tested rat population was 36 months. BPAP could not improve the cognitive performance; neither could it prolong lifespan. A possible reason might be that dietary restriction and lifelong cognitive engagement had beneficial effects on cognitive capabilities and lifespan creating a "ceiling effect" for further improvement. The results confirmed that experienced animals provide a translationally relevant model to study age-related cognitive decline and measure the effect of putative anti-aging compounds.

Potentiation of prefrontal cortex dopamine function by the novel cognitive enhancer d-govadine.

Cognitive impairment is a debilitating feature of psychiatric disorders including schizophrenia, mood disorders and substance use disorders for which there is a substantial lack of effective therapies. d-Govadine (d-GOV) is a tetrahydroprotoberberine recently shown to significantly enhance working memory and behavioural flexibility in several prefrontal cortex (PFC)-dependent rodent tasks. d-GOV potentiates dopamine (DA) efflux in the mPFC and not the nucleus accumbens, a unique pharmacology that sets it apart from many dopaminergic drugs and likely contributes to its effects on cognitive function. However, specific mechanisms involved in the preferential effects of d-GOV on mPFC DA function remain to be determined. The present study employs brain dialysis in male rats to deliver d-GOV into the mPFC or ventral tegmental area (VTA), while simultaneously sampling DA and norepinephrine (NE) efflux in the mPFC. Intra-PFC delivery or systemic administration of d-GOV preferentially potentiated medial prefrontal DA vs NE efflux. This differential effect of d-GOV on the primary catecholamines known to affect mPFC function further underscores its specificity for the mPFC DA system. Importantly, the potentiating effect of d-GOV on mPFC DA was disrupted when glutamatergic transmission was blocked in either the mPFC or the VTA. We hypothesize that d-GOV acts in the mPFC to engage the mesocortical feedback loop through which prefrontal glutamatergic projections activate a population of VTA DA neurons that specifically project back to the PFC. The activation of a PFC-VTA feedback loop to elevate PFC DA efflux without affecting mesolimbic DA release represents a novel approach to developing pro-cognitive drugs.

Cognition and gut microbiota in schizophrenia spectrum and mood disorders: A systematic review.

FRILEUX, M., BOLTRI M. and al. Cognition and Gut microbiota in schizophrenia spectrum and mood disorders: a Systematic Review. NEUROSCI BIOBEHAV REV (1) 2024 Schizophrenia spectrum disorders and major mood disorders are associated with cognitive impairments. Recent studies suggest a link between gut microbiota composition and cognitive functioning. Here, we review the relationship between gut microbiota and cognition in these disorders. To do this, we conducted a systematic review, searching Cochrane Central Register of Controlled Trials, EBSCOhost, Embase, Pubmed, Scopus, and Web of Science. Studies were included if they investigated the relationship between gut microbiota composition and cognitive function through neuropsychological assessments in patients with bipolar, depressive, schizophrenia spectrum, and other psychotic disorders. Ten studies were identified. Findings underscore a link between gut dysbiosis and cognitive impairment. This relationship identified specific taxa (Haemophilus, Bacteroides, and Alistipes) as potential contributors to bolstered cognitive performance. Conversely, Candida albicans, Toxoplasma gondii, Streptococcus and Deinococcus were associated with diminished performance on cognitive assessments. Prebiotics and probiotics interventions were associated with cognitive enhancements, particularly executive functions. These results emphasize the role of gut microbiota in cognition, prompting further exploration of the underlying mechanisms paving the way toward precision psychiatry.

New insights in the development of positive allosteric modulators of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors belonging to 3,4-dihydro-2H-1,2,4-benzothiadiazine 1,1-dioxides: Introduction of (mono/difluoro)methyl groups at the 2-position of the thiadiazine ring.

Positive allosteric modulators of the AMPA receptors (AMPAR PAMs) have been proposed as new drugs for the management of various neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, attention deficit hyperactivity disorder, depression, and schizophrenia. The present study explored new AMPAR PAMs belonging to 3,4-dihydro-2H-1,2,4-benzothiadiazine 1,1-dioxides (BTDs) characterized by the presence of a short alkyl substituent at the 2-position of the heterocycle and by the presence or absence of a methyl group at the 3-position. The introduction of a monofluoromethyl or a difluoromethyl side chain at the 2-position instead of the methyl group was examined. 7-Chloro-4-cyclopropyl-2-fluoromethyl-3,4-dihydro-4H-1,2,4-benzothiadiazine 1,1-dioxide (15e) emerged as the most promising compound associating high in vitro potency on AMPA receptors, a favorable safety profile in vivo and a marked efficacy as a cognitive enhancer after oral administration in mice. Stability studies in aqueous medium suggested that 15e could be considered, at least in part, as a precursor of the corresponding 2-hydroxymethyl-substituted analogue and the known AMPAR modulator 7-chloro-4-cyclopropyl-3,4-dihydro-4H-1,2,4-benzothiadiazine 1,1-dioxide (3) devoid of an alkyl group at the 2-position.

CCCDTD5 recommendations on the deprescribing of cognitive enhancers in dementia.

INTRODUCTION: Cognitive enhancers (ie, cholinesterase inhibitors and memantine) can provide symptomatic benefit for some individuals with dementia; however, there are circumstances in which the risks of continuing treatment may potentially outweigh benefits. The decision to deprescribe cognitive enhancers must consider each patient's preferences, treatment indications, current clinical status and symptoms, prognosis, and dementia type. METHODS: The 5th Canadian Consensus Conference on the Diagnosis and Treatment of Dementia (CCCDTD5) established a subcommittee of experts to review current evidence on the deprescribing of cognitive enhancers. The questions answered by this group included: When should cognitive enhancers be deprescribed in persons with dementia and mild cognitive impairment? How should cognitive enhancers be deprescribed? And, what clinical factors should be considered when deprescribing cognitive enhancers? RESULTS: Patient and care-partner preferences should be incorporated into all decisions to deprescribe cognitive enhancers. Cognitive enhancers should be discontinued in individuals without ongoing evidence of benefit or when the indication for cognitive enhancer use was inappropriate (eg, mild cognitive impairment). Deprescribing should occur gradually and cognitive enhancers should be reinitiated if patients' cognition or function deteriorates. Cognitive enhancers should be continued in individuals whose neuropsychiatric symptoms improve in response to treatment. Clinicians should not deprescribe cognitive enhancers in individuals with significant neuropsychiatric symptoms until symptoms have stabilized. CONCLUSION: CCCDTD5 deprescribing recommendations provide evidence-informed recommendations related to cognitive enhancer deprescribing that will facilitate shared decision making among patients, care partners, and clinicians.

Therapeutic effects of crude extracts of Bacopa floribunda on beta-amyloid 1-42-induced Alzheimer's disease via suppression of dyslipidemia, systemic inflammation and oxidative stress in male Wistar Rats.

Aims: Bacopa floribunda (BF), an African traditional plant and its species have been widely used as brain tonic for memory enhancement. It has also been reported to help relieve anxiety and some psychological disorders. This study aimed to investigate the mechanisms of action of BF on Amyloid beta (Aß) 1-42 peptides induced cognitive deficit in male Wistar rats. Main methods: A total of 48 healthy male wistar rats were used for this study. Some groups were pre-treated with 200 mg/kg of BF extracts before a single bilateral injection of Aß 1-42 while some were post-treated with BF for 21 days after Aß1-42 exposure. Cognitive performance was evaluated using Y-Maze and Novel Object recognition tests. After treatments, hippocampal homogenates were assayed for the levels of Acetylcholinesterase, Na-K/ATPase activities, glutamate and Aß1-42 concentrations among others. Key findings: It was observed that Aß1-42 caused cognitive impairment and BF extracts especially the ethanol extract was able to significantly (p < 0.05) reverse almost all the perturbations including lipid imbalance caused by Aß1-42 assault mainly at the post-treatment level. Significance: Administration of ethanol and aqueous extracts of BF mitigated the hazardous effect of Aß1-42 observed in the blood plasma and hippocampal homogenates. In this context, we conclude that BF is an efficient cognitive enhancer that can help alleviate some symptoms associated with Alzheimer's disease.