Journal of Alzheimer's Disease最新文献

Background: Impaired social behavior in mild cognitive impairment (MCI) represents an important burden for caregivers and its presence is associated with increased risk of conversion to dementia. Social cognition provides a relevant framework for investigating functional and social outcomes of these patients but is still based on a very narrow number of domains and lacks robust connection to clinical outcomes.

Objective: The present study aims to investigate social trait inference, our ability to form judgements about others, in MCI patients and how it relates to functional outcomes.

Methods: We used Signal Detection Theory's measures of sensitivity and bias in perceiving facial trustworthiness.

Results: We found that increasing education level decreased the difference in sensitivity between MCI patients and controls. Importantly, we found that higher impairment in activities of daily living was associated with perceiving others as less trustworthy. In controls, lower cognitive integrity was also related to perceiving others as less trustworthy.

Conclusions: Our results have important implications for the understanding of changes in social perception in MCI. Education may have a protective role in delaying the onset of impairment in social trait inference. Also, we show evidence that the age-associated positivity bias depends on higher cognitive integrity. Our results have implications for patient care and provide additional characterization of social perception in these patients.

BackgroundAcetyl tributyl citrate (ATBC), an eco-friendly plasticizer, exhibits poorly characterized neurotoxic effects.ObjectiveWe integrated network toxicology, machine learning, and molecular docking to elucidate molecular mechanisms underlying the link between ATBC exposure and Alzheimer's disease (AD) pathogenesis.MethodsPotential action targets of ATBC were screened from ChEMBL, TargetNet, and SwissTarget Prediction databases; disease-associated targets were derived from differential expression analysis of GEO datasets. Overlapping candidates underwent protein-protein interaction network construction (STRING) and subsequent Gene Ontology (GO)/Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses. Machine learning employing SHAP prioritized pivotal targets, while molecular docking and dynamics simulations validated binding affinities.ResultsWe identified 68 shared targets, of which five were designated as critical (CCKBR, RAF1, GABRG2, STS, RAPGEF3). GO enrichment revealed that ATBC compromises neuronal function and synaptic plasticity by perturbing glial cell differentiation, synaptic transmission, benzodiazepine receptor activity, and serine/threonine kinase activity. KEGG analysis implicated neuroactive ligand-receptor interactions, calcium, FoxO, and PI3K-Akt signaling pathways. Molecular simulations confirmed stable compound-target binding.ConclusionsThis integrative computational approach elucidates mechanisms underlying plasticizer-associated neurotoxicity in AD, establishing a framework for investigating neurological impacts of environmental contaminants.

BackgroundBoth sleep duration and traits significantly influence cognitive health, making it crucial to identify optimal sleep patterns for preventing dementia.ObjectiveTo investigate the mutual effects of sleep duration and sleep traits on dementia risk.MethodsThis prospective study analyzed data from 359,505 participants in the UK Biobank, with baseline data collected between 2006-2010. Sleep patterns were assessed by constructing composite indicators through pairwise combinations of self-reported sleep duration and traits, including ease of getting up in the morning, chronotype, napping, daytime dozing, and use of sleep-related medications. The association between sleep patterns and dementia incidence was evaluated using Cox proportional hazards models during a mean follow-up period of 13.63 years.ResultsDuring the follow-up, 5123 participants developed dementia. In fully adjusted models, both short (≤6 h) and long (≥9 h) sleep durations, along with unfavorable sleep traits (hard or easy getting up, morning chronotype, habitual napping, dozing, sleep-related medications use), were significantly associated with increased dementia risk (p < 0.05). Notably, long sleep duration combined with evening chronotype (HR = 1.45, 95%CI: 1.15-1.83), habitual dozing (HR = 1.57, 95%CI: 1.18-2.09), or hypnotic use (HR = 2.71, 95%CI: 1.77-4.13) exhibited the highest risks compared to optimal sleep duration with corresponding alternative sleep traits. Similarly, short sleep duration combined with habitual napping carried the highest risk of dementia (HR = 1.54, 95%CI: 1.27-1.88).ConclusionsBoth sleep duration and traits are associated with dementia risk, particularly when abnormal duration interacts with unfavorable traits. These findings underscore the necessity of incorporating comprehensive sleep pattern assessments into dementia prevention strategies.

BackgroundDeaf individuals continue to face complex challenges in both accessing healthcare and obtaining information about dementia. Despite this, research into their perceptions of dementia and the need of tailored awareness programs remains limited. In response, a dementia awareness program specially designed for Deaf communities is being developed as part of the Erasmus+ project "DeSign".ObjectiveThis study provides the groundwork for that initiative by exploring (a) what Deaf individuals in Austria, Germany, and Greece know and how they perceive dementia, (b) the current challenges in accessing information and healthcare, and (c) their preferences for the design of specialized, accessible dementia awareness courses.MethodsSix semi-structured focus groups (two per country) were held in the respective national sign languages with 4-14 Deaf participants, including dementia experts, family caregivers, and general community members. Data were analyzed using inductive content analysis.ResultsDeaf participants from the general population demonstrated significant gaps in dementia knowledge, including misconceptions about early signs, causes, and risk factors. Dementia-related information in sign language was described as nearly non-existent. Participants highlighted the need for tailored awareness courses, covering dementia basics, as well as information on available specialized healthcare services and resources in their country. The preferred format for such a course should be delivered in sign language and incorporate culturally appropriate methods of information sharing.ConclusionsTailored awareness courses in sign language are crucial to address knowledge gaps and improve access to information for Deaf communities. This study provides the groundwork for developing such courses within the Erasmus+ project.*DeSign: Raising Awareness for Dementia in Deaf Older Adults in Europe.

BackgroundPeople living with dementia can develop resistive behavior during eating and drinking, complicating food and fluid intake.ObjectiveThis study aimed to explore how relatives and healthcare professionals navigate care decisions, and to identify possible ethical dilemmas related to decision making and the impact on all involved.MethodsA qualitative multiple case study was conducted, nested in a prospective study. We identified cases where resistive behavior was observed in a person with dementia. We aimed at interviewing at least one relative and three healthcare professionals closely involved with a specific case. The interviews were transcribed verbatim and analyzed thematically.ResultsA total of sixteen cases were eligible, of which five cases were included. Four cases concerned people residing in a nursing home, and one person was living at home. Three themes were identified from a total of sixteen interviews: 1) fundamental tension between autonomy and adequate nutrition, 2) understanding the person with dementia and the resistive behavior, and 3) solutions: searching for a personalized approach. This study contributes to the understanding of decision making in situations involving resistive behavior that adversely affects the intake of food and fluids.ConclusionsThe findings emphasize the importance of a personalized approach that balances autonomy, quality of life, and adequate nutrition to provide the best care for people with dementia. The perspectives elicited in this study can help multidisciplinary teams to navigate this complex decision-making process.

BackgroundAlzheimer's disease (AD) patients frequently present to emergency departments (EDs) with complex comorbidities that complicate triage and management. Yet, little is known about how these multimorbidity patterns have evolved over time.ObjectiveTo identify temporal shifts in comorbidity-based phenotypes among older adults with AD visiting EDs between 2007 and 2022 using unsupervised clustering methods.MethodsWe analyzed ED visits for adults aged ≥60 with an AD diagnosis from the Nationwide Emergency Department Sample (NEDS) for the years 2007, 2012, 2017, and 2022. Using ICD-9/10 codes, we mapped diagnoses to 30 clinically relevant comorbidities per year and applied the k-means clustering method to identify subgroups based on diagnostic co-occurrence. Heatmaps summarized cluster compositions across timepoints.ResultsOver 15 years, four stable but evolving comorbidity clusters emerged in each year. Earlier cohorts (2007-2012) were dominated by cardiovascular and respiratory clusters (e.g., CHF, CAD, respiratory failure), while more recent cohorts (2017-2022) showed increased prevalence of nonspecific, frailty-related presentations (e.g., fatigue, GERD, general symptoms). Despite rising ED utilization among older adults, the proportion of visits documenting AD declined from 2.59% in 2007 to 1.34% in 2022, potentially reflecting shifts in coding, outpatient management, and diagnostic overshadowing by acute symptoms.ConclusionsThe comorbidity landscape of AD-related ED visits is changing, with a shift toward vaguer syndromes and complex multimorbidity. These findings underscore the need for dementia-aware triage strategies and dynamic phenotyping tools to improve emergency care for cognitively impaired older adults.

BackgroundPatients with Alzheimer's disease and related dementias (ADRD) have an increased risk for delirium and subsequent complications. Rating delirium severity in the presence of co-occurring dementia is challenging due to overlapping features of delirium and ADRD. The multi-site prospective Better ASsessment of ILlness (BASIL)-II study will develop and validate a new delirium severity instrument for use in patients with and without ADRD.ObjectiveDescribe an expert panel process used to rate delirium severity.MethodsClinical assessors conducted standardized cognitive tests. A separate panel of experts independently reviewed assessors' reports, rated delirium severity using a 0-10 scale, and assigned dementia diagnoses using DSM-5 criteria. Panel agreement was defined using a priori criteria. Cases without agreement after initial review were discussed as a group and re-rated using a modified Delphi approach until achieving consensus.ResultsPatients (N = 488) were on average 79 years old, 58% female, and 75% White. After initial review, 80% of cases were in agreement for delirium severity. Kappa was 0.86 (95% CI, 0.78, 0.82) before expert panel discussion and 0.90 (95%CI, 0.89, 0.92) after consensus. Final delirium severity ratings were no delirium (48%); subsyndromal (22%), mild-moderate (25%), or severe (6%). Disagreement in delirium severity was associated with ADRD (OR 3.02), nursing home setting (2.63), and vision impairment (2.42).ConclusionsThis rigorous process provides confidence that delirium severity can be rated accurately in patients with and without ADRD. We will use this expert panel adjudication to provide the reference standard for validation of a future delirium severity instrument.

BackgroundAlthough multi-task handwriting analysis has the potential to improve early detection of Alzheimer's disease (AD), the educational bias inherent in its text-based tasks poses a significant obstacle to its widespread adoption across different regions.ObjectiveUsing the clock drawing test, we aim to design a deep neural network to extract features from static images and process signals to achieve high-precision recognition of early AD.MethodsEarly Detection of Alzheimer's Disease based on Leveraging Multimodal Features of the clock-drawing test (EDADLMF) is proposed. Firstly, to utilize the behavioral features inherent in the clock drawing test task, we propose a Dual Stream Clock Drawing Feature Extraction module,which employs a convolutional neural networks to capture the spatial features of static clock face images, while concurrently employing a multi-layer perceptron to map low-dimensional process signal into a high-dimensional feature space. Furthermore, we propose a Feature Fusion module with the Squeeze-and-Excitation attention mechanism to adaptively enhance key features and fuses complementary information from different modalities. Thirdly, to enhance the model's focus on hard-to-classify samples, a PolyLoss function is introduced to assign greater weights to difficult samples.ResultsComparative experiments on benchmark demonstrated that EDADLMF outperforms the compaired methods on accuracy (92.59%), precision (93.65%), recall (92.65%), and F1-score (92.59%), and the case study indicates that the developed prototype system has well effectiveness.ConclusionsThe clock drawing test, combined with process signals and image data, exhibits better screening accuracy and could serve as a practical alternative to initial MRI scans.

BackgroundGene dysregulation is one of the key mechanisms that link pathological abnormalities to cognitive impairment in Alzheimer's disease (AD), the most prevalent neurodegenerative disorder. Our transcriptomic analysis of large-scale postmortem AD human prefrontal cortex (PFC) data revealed that complement genes, a key player in modulating tissue homeostasis and immune surveillance, were prominently upregulated.ObjectiveThe goal of this study is to reveal key transcriptional regulators that contribute to the elevation of complement genes in AD.MethodsTranscriptomic and epigenomic analyses, molecular, biochemical and immunocytochemical assays, and in vivo gene manipulation, were used.ResultsOur epigenomic analysis identified ADNP (activity-dependent neuroprotective protein), a chromatin regulator strongly linked to intellectual disability, as one of the top-ranking transcription factors regulating complement genes. ADNP and its partner HP1γ (Heterochromatin protein 1) were found to be significantly diminished in postmortem AD human PFC. Reduced Adnp expression was also found in PFC of a familial AD mouse model, 5xFAD. Knockdown of Adnp in mice led to the significantly increased levels of complement genes, reminiscent to complement gene elevation in postmortem AD humans and 5xFAD mice. Furthermore, human induced pluripotent stem cell-derived neuronal cultures from AD patients exhibited astrocyte activation, ADNP/HP1γ reduction, and complement gene increase. Manipulation of ADNP levels led to bidirectional changes in complement gene expression.ConclusionsThese data suggest that the diminished ADNP in AD could lead to chromatin dysregulation because of disrupted transcriptional repression, which contributes to the elevation of complement genes. It provides a novel upstream epigenetic modifier for gene dysregulation in AD.

Growing interest in noninvasive neuromodulation posits 40 Hz sensory stimulation as a potential intervention for Alzheimer's disease. Early studies suggested that 40 Hz visual flicker entrains gamma activity and reduces amyloid pathology; however, later work found either absent entrainment or even increased amyloid burden, revealing strong dependence on disease stage, network integrity, and stimulation parameters. Initial clinical investigations suggest that 40 Hz stimulation is safe, well-tolerated, and capable of modulating cortical network dynamics and improving cognition, despite limited effects on amyloid burden. These findings suggest a shift from molecular pathology to network plasticity as the primary target of gamma stimulation.