Current Alzheimer research最新文献

The accumulation of amyloid-β (Aβ) is the main event related to Alzheimer's disease (AD) progression. Over the years, several disease-modulating approaches have been reported, but without clinical success. The amyloid cascade hypothesis evolved and proposed essential targets such as tau protein aggregation and modulation of β-secretase (β-site amyloid precursor protein cleaving enzyme 1 - BACE-1) and γ-secretase proteases. BACE-1 cuts the amyloid precursor protein (APP) to release the C99 fragment, giving rise to several Aβ peptide species during the subsequent γ-secretase cleavage. In this way, BACE-1 has emerged as a clinically validated and attractive target in medicinal chemistry, as it plays a crucial role in the rate of Aβ generation. In this review, we report the main results of candidates in clinical trials such as E2609, MK8931, and AZD-3293, in addition to highlighting the pharmacokinetic and pharmacodynamic-related effects of the inhibitors already reported. The current status of developing new peptidomimetic, non-peptidomimetic, naturally occurring, and other class inhibitors are demonstrated, considering their main limitations and lessons learned. The goal is to provide a broad and complete approach to the subject, exploring new chemical classes and perspectives.

Background: Neuropsychiatric symptoms (NPS) in patients with Alzheimer's disease (AD) worsened during the COVID-19 lockdowns, but their progression thereafter is unknown. We present the first longitudinal study tracking them before, during, and after restrictions.

Objectives: To describe the effect of the COVID-19 mandatory lockdowns on Cognitive and Neuropsychiatric symptoms in patients with Mild Cognitive Impairment (MCI) and Alzheimer's Disease (AD).

Methods: Cohort of 48 patients with amnestic MCI and 38 with AD in Lima, Peru. They received three rounds of cognitive (RUDAS, CDR, M@T), behavioral (NPI), and functional (ADCS-ADL) assessments. We assessed the change in score means across the time points and for each domain of NPS and tracked the changes in individual patients.

Results: RUDAS declined 0.9 (SD 1.0) from baseline to lockdown and 0.7 (SD 1.0) after restrictions. M@T declined 1.0 (SD 1.5) from baseline to lockdown and 1.4 (SD 2.0) after restrictions. CDR worsened in 72 patients (83.72%) from baseline to post-lockdown. NPI worsened by 10 (SD 8.3) from baseline to lockdown but improved by 4.8 (SD 6.4) after restrictions. Proportionally, 81.3% of all patients had worsened NPS during the lockdowns, but only 10.7% saw an increase thereafter. Improvement was statistically significant for specific NPS domains except hallucinations, delusions, and appetite changes. Anxiety, irritability, apathy, and disinhibition returned to baseline levels.

Conclusion: Following confinement, cognition continued to decline, but NPS demonstrated either stability or improvement. This highlights the role modifiable risk factors may have on the progression of NPS.

Background: Identifying individuals with mild cognitive impairment (MCI) who are at increased risk of Alzheimer's Disease (AD) in cognitive screening is important for early diagnosis and prevention of AD.

Objective: This study aimed at proposing a screening strategy based on landmark models to provide dynamic predictive probabilities of MCI-to-AD conversion according to longitudinal neurocognitive tests.

Methods: Participants were 312 individuals who had MCI at baseline. The longitudinal neurocognitive tests were the Mini-Mental State Examination, Alzheimer Disease Assessment Scale-Cognitive 13 items, Rey Auditory Verbal Learning Test immediate, learning, and forgetting, and Functional Assessment Questionnaire. We constructed three types of landmark models and selected the optimal landmark model to dynamically predict 2-year probabilities of conversion. The dataset was randomly divided into training set and validation set at a ratio of 7:3.

Results: The FAQ, RAVLT-immediate, and RAVLT-forgetting were significant longitudinal neurocognitive tests for MCI-to-AD conversion in all three landmark models. We considered Model 3 as the final landmark model (C-index = 0.894, Brier score = 0.040) and selected Model 3c (FAQ and RAVLT-forgetting as neurocognitive tests) as the optimal landmark model (C-index = 0.898, Brier score = 0.027).

Conclusion: Our study shows that the optimal landmark model with a combination FAQ and RAVLTforgetting is feasible to identify the risk of MCI-to-AD conversion, which can be implemented in cognitive screening.

Introduction: The present study has examined microglial and astrocyte activation in association with neuronal degeneration in an animal model using an injection of amyloid-beta peptide Aβ_1-42 (Aβ₄₂) plus fibrinogen into rat hippocampus.

Methods: The combination of stimuli is suggested as a novel and potent perturbation to induce gliosis and the production of glial-derived neurotoxic factors in an animal model exhibiting a leaky BBB (blood-brain barrier). Specifically, Aβ₄₂ + fibrinogen stimulation elevated levels of COX-2 (cyclooxygenase-2) and iNOS (inducible nitric oxide synthase) with a considerable extent of neuronal loss associated with microglia and astrocyte activation.

Results: Treatment of injected rats with the broad spectrum anti-inflammatory agent, minocycline or the iNOS inhibitor, 1400 W inhibited gliosis, reduced levels of COX-2 and iNOS, and demonstrated efficacy for neuroprotection.

Conclusion: The findings suggest the utility of combining amyloid beta peptide plus fibrinogen as a potent and understudied neuroinflammatory stimulus for the induction of glial-derived neurotoxic factors in BBB-compromised AD brain.

Background and objectives: Neuropsychiatric symptoms (NPS), including psychotic symptoms (hallucinations, illusions, delusions), agitation/aggression, and depressed mood, are common in individuals with Alzheimer's disease (AD) and predict poorer outcomes, including faster disease progression. We aimed to evaluate associations between NPS and cognition and dependence in a multi-ethnic sample of community-dwelling older adults with AD.

Methods: Predictors 3 (P3) is a cohort study of AD disease courses recruiting older adults aged 65 and above residing in upper Manhattan. A total of 138 of 293 participants had probable AD at the study baseline. We fit linear mixed models to examine longitudinal associations of time-varying NPS (psychotic symptoms, agitation/aggression, and depressed mood) with dependence and cognition, adjusted for race-ethnicity, sex, education, age, clinical dementia rating score, APOE-ε4, and comorbidity burden; separate interaction models were fit for age, Hispanic ethnicity, and sex.

Results: Psychotic symptoms were associated with faster rates of increasing dependence and declining cognition over time, agitation/aggression with faster rates of declining cognition, and depressed mood with faster rates of increasing dependence. Among psychotic symptoms, delusions, but not hallucinations or illusions, were associated with worse outcome trajectories. Depressed mood predicted an accelerated increase in dependence in males but not females.

Conclusion: Our results confirm and extend prior results in clinic-based samples. The presence of NPS was associated with worse trajectories of dependence and cognition in this muti-ethnic sample of older adults with AD. Importantly, sex modified the association between depressed mood and dependence. Our results on NPS as predictors of differential AD progression in a community-dwelling, ethnically diverse sample serve to better inform the clinical care of patients and the future development of AD therapies.

Beyond the time-honoured targeting of protein misfolding and aggregation, Alzheimer's disease needs new, innovative therapeutic directions. When exploring alternative druggable mechanisms, multifaceted in vitro and in vivo data demonstrate that immune system dysfunction is a pivotal driver of Alzheimer's disease progression. In pursuing neuroimmunological targets, a major but often under-discussed consideration regards the issue of whether innate or adaptive immunity (or both) within the neuroimmune network should be the centre of focus when devising immunotherapeutic approaches to Alzheimer's. This perspective article briefly reviews current data, concluding that while both innate and adaptive immunity contributes to the immunopathology of Alzheimer's, the proinflammatory microglia and cytokines of innate immunity will provide higher yield targets with a greater likelihood of efficacy. Although it seems paradoxical to focus on a rapid, short-lived aspect of immunity when seeking approaches to a quintessentially chronic brain disease, accumulating evidence affords ample data to support the target-rich cascade of innate immunity for the development of much-needed new diagnostics and therapeutics.

Background: Self-imagination refers to a mnemonic strategy of imagining oneself at a scene related to a cue.

Objective: We tested the effect of self-imagination on memory recall in Alzheimer's disease (AD) Methods: Individuals with AD and healthy controls were invited to perform two conditions. In the control (i.e., semantic elaboration) condition, participants were asked to define to which semantic category (e.g., dance) words (e.g., waltz) belong. However, in a self-imagining condition, participants were asked to imagine themselves in a scene related to the stimuli (e.g., dancing waltz). Both conditions were followed by two free memory tests with two different intervals (20 seconds vs. 20 minutes).

Results: Analysis showed a beneficial effect of self-imagination for the 20-second but not for the 20- minute recall in AD participants and controls.

Conclusion: Clinicians can incorporate our findings when assessing, especially when trying to rehabilitate, episodic memory in AD.

The lack of effective treatments for cognitive decline in older adults has led to an interest in the possibility that lifestyle interventions can help to prevent changes in mental functioning and reduce the risk for dementia. Multiple lifestyle factors have been related to risk for decline, and multicomponent intervention studies suggest that changing older adults' behaviors can have a positive impact on their cognition. How to translate these findings into a practical model for clinical use with older adults, however, is not clear. In this Commentary, we propose a shared decision-making model to support clinicians' efforts to promote brain health in older persons. The model organizes risk and protective factors into three broad groups based on their mechanism of action and provides older persons with basic information to allow them to make evidence- and preference-based choices in choosing goals for effective brain health programs. A final component includes basic instruction in behavior change strategies such as goal setting, self-monitoring, and problem-solving. The implementation of the model will support older persons' efforts to develop a personally relevant and effective brainhealthy lifestyle that may help to reduce their risk for cognitive decline.