Journal of Alzheimer's Disease最新文献

Background: Plasma biomarkers have recently emerged for the diagnosis, assessment, and disease monitoring of Alzheimer's disease (AD), but have yet to be fully validated in preclinical AD. In addition to AD pathologic plasma biomarkers (amyloid-β (Aβ) and phosphorylated tau (p-tau) species), a proteomic panel can discriminate between symptomatic AD and cognitively unimpaired older adults in a dementia clinic population.

Objective: Examine the added value of a plasma proteomic panel, validated in symptomatic AD, over standard AD pathologic plasma biomarkers and demographic and genetic (apolipoprotein (APOE) ɛ4 status) risk factors in detecting preclinical AD.

Methods: 125 cognitively unimpaired older adults (mean age = 66 years) who completed Aβ PET and plasma draw were analyzed using multiple regression with Aβ PET status (positive versus negative) as the outcome to determine the best fit for predicting preclinical AD. Model 1 included age, education, and gender. Model 2 and 3 added predictors APOE ɛ4 status (carrier versus non-carrier) and AD pathologic blood biomarkers (Aβ_42/40 ratio, p-tau181), respectively. Random forest modeling established the 5 proteomic markers from the proteomic panel that best predicted Aβ PET status, and these markers were added in Model 4.

Results: The best model for predicting Aβ PET status included age, years of education, APOE ɛ4 status, Aβ_42/40 ratio, and p-tau181. Adding the top 5 proteomic markers did not significantly improve the model.

Conclusions: Proteomic markers in plasma did not add predictive value to standard AD pathologic plasma biomarkers in predicting preclinical AD in this sample.

Background: Evidence on associations of remnant cholesterol (RC) and its variability with cognitive function is still lacking.

Objective: To explore the association of RC and its variability with cognitive function.

Methods: Participants were recruited from a population-based cohort, the China Health and Retirement Longitudinal Study (CHARLS). Cognitive function was assessed by a standardized questionnaire from CHARLS, with domains of episodic memory and mental intactness. A linear mixed effects model was used to analyze the association of RC with cognitive function, along with its variability (calculated as standard deviation [SD], coefficient of variation [CV], variability independent of the mean [VIM]), with results expressed as β (95%CI). Potential subgroup differences in the association of RC and its variability with cognitive function were also explored.

Results: 4234 participants were eventually included, with mean (SD) age of 57.4 (8.0) years. Each 10 mg/dL increase in RC was associated with 0.053 (95%CI: 0.096, 0.009) points, 0.021 (95%CI: 0.042, 0.000) points, 0.032 (95%CI: 0.064, 0.001) points decrease in global cognitive function, episodic memory, and mental intactness scores, respectively. Compared with the first tertile (T1) group of RC variability (calculated as SD, VIM), T3 showed a lower level in global cognition and episodic memory after multivariate adjustment. The potential modification effects of educational level on RC and its variability in relation to cognitive function were also identified.

Conclusions: Among Chinese middle-aged and older adults, higher RC level were associated with worse cognitive function. Greater RC variability was also associated with worse cognitive performance, especially in memory function.

Post-translational modifications (PTMs) of proteins play a significant role in normal protein function but can also be instrumental in disease pathogenesis. One critical yet under-studied PTM in disease is ubiquitination. Ubiquitin chain addition and substrate specificity are determined by a large spectrum of ubiquitin-ligating and -modifying enzymes, E3 ligases, whose expression levels and activities are tightly regulated in a cell-specific manner. While most ubiquitin chains can target proteins for proteasomal degradation, ubiquitination can contribute to other functions within the cell, including protein localization, protein activity, endocytosis, transcription, and autophagy. One E3 ligase, UBE3A, has garnered much attention because of its involvement in learning and memory, as well as its association with neurodevelopmental autism spectrum disorders (ASDs). However, more recent findings have suggested a potential involvement of UBE3A in neurodegenerative proteinopathies, where reduced UBE3A levels can lead to an enhanced rate of aggregate formation and cell death. Here, we review the literature on UBE3A in neurodevelopment, function, and neurodegenerative diseases and demonstrate that UBE3A could play a critical role in disease progression and cognitive function.

Background: Alterations in factors involved in cholesterol homeostasis are critical in Alzheimer's disease (AD), but the stage of occurrence, their specific association, and a possible relationship with the APOE4 genotype are not clarified.

Objective: We aimed to quantify and correlate specific lipid factors in patients with different degrees of cognitive decline, namely patients with AD and patients with mild cognitive impairment due to AD (MCI-AD), carriers or non-carriers of the APOE4 genotype.

Methods: We evaluated Proprotein Convertase Subtilisin/Kexin type 9 (PCSK9), cholesterol and the oxidative metabolites 24-, 25-, 27-hydroxycholesterol (HC) in the cerebrospinal fluid (CSF) and serum of AD (n = 28) and MCI-AD (n = 27) patients.

Results: CSF and serum PCSK9 and lipids were similar, except for higher serum PCSK9 and triglycerides in MCI-AD compared to AD. In CSF, AD APOE4 carriers showed higher PCSK9 and 24-HC (+61.3%, p = 0.027 and +32.7%, p = 0.037), compared to non-carriers. There was a negative association between CSF PCSK9 and 27-HC in AD (r = -0.444, p = 0.049) and, exclusively among AD APOE4 carriers, a negative association between CSF PCSK9 and 24-HC (r = -0.786, p = 0.028). A positive correlation was observed between CSF and serum PCSK9 in AD (r = 0.520, p = 0.004), driven by APOE4 carriers (r = 0.544, p = 0.038), suggesting PCSK9 exchange between brain and periphery. A positive correlation was detected between serum and CSF 27-HC (r = 0.465, p = 0.039) in AD. None of these results were found in MCI-AD patients.

Conclusions: PCSK9 and 24-HC might be specific markers of ApoE4-associated lipid alterations in AD, possibly contributing to clinical progression in the AD continuum.

Background: The neurodegenerative diseases like Alzheimer's disease (AD) can result in progressive decline in both cognitive functions and motor skills, which have critical need for accurate early diagnosis. However, current diagnosis approaches primarily rely on timely clinical magnetic resonance imaging (MRI) scans, which impede widely application for potential patients. Leveraging handwriting as a diagnostic tool offers significant potential for identifying AD in its early stages.

Objective: This study aims to develop an efficient, rapid, and accurate method for early diagnosis of AD by utilizing handwriting analysis, a promising avenue due to its association with compromised motor skills in neurodegenerative diseases.

Methods: We propose a novel methodology that leverages self-attention mechanisms for the early diagnosis of AD. Our approach integrates data from 25 distinct handwriting tasks available in the DARWIN (Diagnosis AlzheimeR WIth haNdwriting) dataset.

Results: The Self-Attention model achieved an accuracy of 94.3% and an F1-score of 94.5%, outperforming other state-of-the-art models, including traditional machine learning and deep learning approaches. Specially, the Self-Attention model surpassed the previous best model, the convolutional neural networks, by approximately 4% in both accuracy and F1-score. Additionally, the model demonstrated superior precision (94.7%), sensitivity (94.5%), and specificity (94.1%), indicating high reliability and excellent identification of true positive and true negative cases, which is crucial in medical diagnostics.

Conclusions: Handwriting analysis, powered by self-attention mechanisms, offers significant potential as a diagnostic tool for identifying AD in its early stages, providing an effective alternative to traditional MRI-based diagnosis.

Background: Effect of education attainment and nutritional status on the development of cognitive impairment in Chinese elderly has not been reported.

Objective: To investigate the role of education and nutrition in preventing cognitive impairment in the hospitalized Chinese elderly.

Methods: Cognitive function was examined using the scoring system of Mini-Mental State Examination (MMSE) domains performed under instruction of Physicians of Geriatrics. Generalized linear mixed-effect regression was used for analyzing the association of demographic factors (age and gender), socioeconomic factors (education attainment and monthly income), as well as health-related factors (nutritional status, comorbidity, anxiety, and depression) and MMSE scores.

Results: Total 246 hospitalized Chinese elders were enrolled into this study. Of them, 96 participants were 60-70 years old, 65 participants were 71-80 years old, and 85 of them were 81 years or older. Of the examined factors, we found that age, education attainment, and nutritional status were significantly associated with the outcome of MMSE scores, while monthly income and health condition (comorbidity, anxiety, and depression) were not significantly associated with MMSE score. Furthermore, education attainment was significantly associated with majority of the MMSE domains, including orientation, registration, attention and calculation, recall, and most of language sub-domains.

Conclusion: Education attainment and nutritional status were significantly associated with MMSE scores in the hospitalized Chinese elderly. Higher education and better nutritional status are protective factors for the development of cognitive impairment in the hospitalized elderly Chinese population.

Background: The aging global population is increasing the attention to cognitive decline in older individuals.

Objective: This study sought to examine the potential link between the neutrophil percentage-to-albumin ratio (NPAR) and cognitive function.

Methods: We analyzed data from the National Health and Nutrition Examination Survey 2011-2014 using multivariate logistic regression and smooth curve fitting, to investigate the correlation between NPAR and cognitive performance. Restricted cubic spline analysis assessed the linear relationship with high-risk cognitive dysfunction, while piecewise linear regression identified thresholds. Subgroup analyses confirmed the consistency and reliability of our findings.

Results: Our study included data from 2759 individuals aged >60 years. NPAR showed a significant correlation with Consortium to Establish a Registry for Alzheimer's Disease (CERAD) word learning score, CERAD delayed recall score, total z-score and a high risk of cognitive dysfunction. Furthermore, there were statistically significant trends in the changes in CERAD word learning, digit symbol substitution test, and CERAD delayed recall scores as the NPAR quartile increased, these trends were inverted U-shaped. When the NPAR exceeded 14.57, there was a positive association with the likelihood of a high risk of cognitive impairment. The link between NPAR and cognitive performance was notably stronger in individuals with moderate body mass index and those aged 73-80 years.

Conclusions: A strong link was observed between the NPAR and cognitive function. NPAR may serve as a tool to identify individuals at increased risk of cognitive decline.