Review
Kevin R Nash, Umesh K Jinwal, Krishna Moorthi Bhat (Handling Associate Editor: Heng Du)
UBE3A: Bridging the gap between neurodevelopment, neural function, and neurodegenerative woes
Abstract: 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.
Review
Narimene Beder, Mourad Belkhelfa, Hakim Leklou
Involvement of inflammasomes in the pathogenesis of Alzheimer’s disease
Abstract: Alzheimer's disease (AD) is a neurodegenerative disease with a long preclinical and prodromal stage near 20 years. The neuropathological hallmarks of AD include amyloid plaques, neurofibrillary tangles, and neuroinflammation, those lead to neuronal and synaptic loss. Important fact, oxidative stress participates in the AD development by promoting amyloid-β deposition, tau hyperphosphorylation. However, the inflammatory response and pyroptotic death are mediated by the aberrant expression of NLRP inflammasome activated caspase-1, which leads to cleavage pro-inflammatory cytokines such as pro-interleukin-1β and pro-IL-18. IL-1β, TNF-α, and IL-6 which amplify the neuroinflammation loop, are produce by activated microglia and astrocytes, that can serve as early diagnostic markers or therapeutic targets in AD. In this review, we summarize our current understanding of the role of inflammasome in the pathogenesis of AD, highlighting key issues that need to be addressed to improve the development of new therapies.
Commentary
Yicheng Lin, Sheng-Han Kuo
The emerging role of the cerebellum in neurodegeneration linked to cognitive impairment
Abstract: The cerebellum has been largely overlooked in Alzheimer’s disease, despite increasing evidence implicating its cognitive capacities and functional networks, which interacts with cerebral cortex to subserve cognition. A study by Lin et al. has indicated that the cerebellum is part of the integrated network in amnestic mild cognitive impairment (aMCI), a prodromal state of Alzheimer's disease. The aMCI patients exhibited weaker cerebello-parietal functional connectivity but stronger cerebellar coupling with precuneus cortex, posterior cingulate gyrus, and caudate nucleus. These alterations in cerebello-cortical connectivity correlated with cognitive performance, suggesting a dynamic change of cerebello-cortical network related to cognitive change in aMCI.
Commentary
Sulekha Anand, Peter J Bayley, James O Clifford Jr, J Wesson Ashford
New tablet-based screening tool for assessment of cognitive decline in Nigeria
Abstract: We comment on the importance of the novel tablet-based screening tool for cognitive decline recently studied in Nigeria by Ogbuagu et al. TabCAT-BHA was administered on an iPad in urban and rural settings and was found to be a sensitive and culturally appropriate tool for assessing cognitive function and impairment. With accuracy, portability, speed, and ease of use, this study shows that such tests, computerized or online, have the potential to improve the screening of cognitive decline in diverse countries such as Nigeria, to facilitate early treatment and improved care and quality of life.
Jian-Guo Li, Alessandro Leone, Maurizio Servili, Domenico Praticò (Handling Associate Editor: Patrizia Mecocci)
Extra virgin olive oil beneficial effects on memory, synaptic function, and neuroinflammation in a mouse model of Down syndrome
Abstract: Background: Clinical and preclinical studies have shown that extra virgin olive oil (EVOO), a major component of the Mediterranean diet, has beneficial effects on brain aging and cognition. Individuals with Down syndrome develop age-dependent cognitive decline and synaptic dysfunction. However, whether EVOO intake is beneficial in Down syndrome is not known. Objective: In this study, by implementing a mouse model of Down syndrome, we aimed to investigate the effect that chronic administration of EVOO has on memory, synaptic function, and neuroinflammation. Methods: Starting at 4 months of age Ts65dn mice were randomized to receive EVOO for 5 months in their diet, after which they were tested for learning and memory impairment. After euthanasia, synaptic function was measured in freshly obtained hippocampal slices, whereas brain tissues were assessed for inflammatory biomarkers. Results: Compared with controls, mice receiving EVOO had a significant improvement in learning and spatial memory. Additionally, field potential recordings showed that treated mice had an improvement in synaptic function. Finally, array analysis showed that EVOO modulated the expression levels of several inflammatory biomarkers. Conclusions: Chronic administration of EVOO to a mouse model of Down syndrome has beneficial effects on memory impairments, synaptic function deficits and neuroinflammation. Our findings provide additional support for the potential therapeutic effects of EVOO also in individuals with Down syndrome.
Hanrui Liu, Lili Luo, Juan Xia, Xiaonan Wang, Yanxia Luo (Handling Associate Editor: Maria Vassilaki)
Remnant cholesterol and cognitive function: Evidence from the China Health and Retirement Longitudinal Study
Abstract: 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: 4,234 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.
Jessica Grothe, Alexander Pabst, Susanne Röhr, Steffi G Riedel-Heller, Melanie Luppa
Social isolation and social cognition: a cross-sectional analysis
Abstract: Background: The impact of social isolation on social cognition is not entirely clear. Objective: The aim of the study is to investigate the association between social isolation and social cognition. Methods: In a population-based sample of 83 individuals aged 50+ years without dementia, we assessed the relationship between social isolation (measured by the Lubben Social Network Scale - LSNS-6) and performance on emotional recognition (measured by the Emotion Recognition Task (ERT)) and on Theory of Mind (ToM) abilities (measured by the Reading the Mind in the Eyes Test (RMET)), two core aspects of social cognition. Results: No significant association was found between social isolation and ToM abilities for both the unadjusted and adjusted models. Similarly, no significant association was observed between social isolation and emotion recognition. Conclusions: Further research is needed to understand the complex correlation between social relationships and cognitive health, particularly in different cognitive domains, adopting a life course perspective.
Lubnaa Abdullah, Fan Zhang, James Hall, Sid O’Bryant
Neurofilament light and cognition in community-dwelling non-Hispanic Blacks
Abstract: Background: No large-scale characterizations of neurofilament light chain (NfL) and cognitive outcomes have been conducted in community-dwelling non-Hispanic Blacks. Objective: This study aims to enhance the application of blood biomarkers, in particular NfL, to ethno-racially diverse communities. We assess the association of NfL with cognitive outcomes, hypothesizing that NfL can identify cognitive changes regardless of diagnostic category. Methods: Baseline data were analyzed among n = 283 non-Hispanic Blacks (NHB)from the multi-ethnic Health and Aging Brain Study- Health Disparities (HABS-HD). Plasma NfL was measured on the Simoa platform. Linear regression models were conducted, covarying for age, gender, and education. Results: The majority of study participants (72%) were cognitively unimpaired (CU), with 21% having mild cognitive impairment (MCI), and 6.7% with Alzheimer’s disease (AD). In adjusted models among the entire sample, significant associations existed between NfL and Trails A (p < 0.0001), Trails B (p < 0.0001), phonemic (FAS) and semantic (Animals) fluency (p = 0.03), and Symbol Digit Substitution (p < 0.001). When separated by diagnostic classification, significant associations were removed for functions involving executive functions for all diagnostic groups. Higher levels of NfL were positively associated with cognitive diagnosis, older age, and less education. Conclusions: Plasma NfL levels are significantly associated with measures of executive functioning, which elucidate NfL as a non-specific marker of neurodegeneration associated with efficiency of brain functions involving attention, processing, and generativity. NfL may be a sensitive measure for the detection of alterations in cognitive processing before the onset of phenotypic functional changes of neurodegeneration.
Lucía Fernández-Romero*, Florentina Morello-García*, Robert Laforce Jr, Cristina Delgado-Alonso, Alfonso Delgado-Álvarez, María José Gil-Moreno, Monica Lavoie, Jorge Matias-Guiu, Fernando Cuetos, Jordi A Matias-Guiu *These authors contributed equally to this work.
Comparative accuracy of Mini-Linguistic State Examination, Addenbrooke’s Cognitive Examination, and Depistage Cognitif de Quebec for the diagnosis of primary progressive aphasia
Abstract: Background: Clinical diagnosis in primary progressive aphasia (PPA) is challenging. Recently, emphasis has been placed on the importance of screening evaluation. Three different screening tests that use different strategies based on the assessment of language (Mini-Linguistic State Examination, MLSE) or different cognitive domains (Addenbrooke's Cognitive Examination, ACE-III and Dépistage Cognitif de Québec, DCQ) have been proposed and independently validated. These tests aim to detect PPA and classify into the three main variants (non-fluent (nfvPPA), semantic (svPPA) and logopenic (lvPPA)). Objective: This study aims to evaluate and compare the diagnostic capacity of these three instruments in detecting PPA and distinguishing between PPA variants. Methods: A cross-sectional study including 43 patients with PPA (nfvPPA (n=19), svPPA (n=8), and lvPPA (n=16)) and 21 cognitively unimpaired controls was conducted. Clinical diagnoses were established based on an extensive multidisciplinary assessment including neuropsychological assessment, FDG-PET, MRI, and CSF biomarkers. Both PPA patients and controls completed the three tests (MLSE, ACE-III, and DCQ). Results: Internal consistency was excellent for the three tests. The area under the curve for the diagnosis of PPA was 0.950 for MLSE, 0.953 for ACE-III, and 0.933 for DCQ. Correlations between the three tests were high. The MLSE, ACE-III, and DCQ tests obtained adequate levels of discrimination between the variants of PPA, with accuracies between 76-79%. Conclusions: This study confirms the validity of ACE-III, MLSE, and DCQ for the diagnosis of PPA and its variants. This suggests that detailed assessment of linguistic characteristics (MLSE) and non-linguistic features (DCQ, ACE-III) are relevant for the diagnosis and classification of PPA.
Zihao Zhang*, Zehu Sheng*, Jiayao Liu, Dandan Zhang, Hao Wang, Lanyang Wang, Yangke Zhu, Lingzhi Ma, Lan Tan *These authors have contributed equally to this work.
The association of the triglyceride-glucose index with Alzheimer's disease and its potential mechanisms
Abstract: Background: The correlation between Alzheimer's disease (AD) and the glucose-triglyceride (TyG) index remains undetermined. Objective: This study aimed to investigate the relationship between the TyG index and AD, as well as the relationship between the TyG index and cerebrospinal fluid (CSF) AD biomarkers and cognition. Methods: Six hundred twenty-eight non-dementia participants were included. The TyG index, pathological markers, and cognitive measures were studied using multiple linear regression. Also calculated using a multivariate Cox regression model were the hazard ratio (HR) and its 95% confidence interval (CI). Ten thousand bootstrap iterative causal mediation analyses were performed to investigate the potential mediating effect of AD pathology on cognition. Results: The TyG index was linked to CSF AD biomarkers (βAβ42 = 0.880; βTau = -0.674; βpTau = -0.884; βAβ42/pTau = 1.764; βAβ42/Tau = 1.554; βpTau/Tau = -0.210) and cognitive measurements (βMEM = 0.570; βEF = 0.535; βADAS11 = -0.789). Mediation analysis revealed that the TyG index may influence cognition via CSF AD biomarkers, including Aβ42, tau, and pTau. Furthermore, each 1-unit increase in TyG index was associated with a 29.5% reduction in the risk of incident AD. Conclusions: A delayed rate of cognitive decline and a reduced risk of AD were found to be correlated with higher levels of the TyG index, but this does not mean increasing TyG index levels is beneficial for health. Through AD pathology, the TyG index may influence AD and cognitive changes.
Haley Leclerc, Athene KW Lee, Zachary J Kunicki, Jessica Alber (Handling Associate Editor: Ines Baldeiras)
Added value of inflammatory plasma biomarkers to pathologic biomarkers in predicting preclinical Alzheimer’s disease
Abstract: 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-ꞵ (Aꞵ) 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 Aꞵ PET and plasma draw were analyzed using multiple regression with Aꞵ 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 (Aꞵ42/40 ratio, p-tau181), respectively. Random forest modeling established the 5 proteomic markers from the proteomic panel that best predicted Aꞵ PET status, and these markers were added in Model 4. Results: The best model for predicting Aꞵ PET status included age, years of education, APOE ɛ4 status, Aꞵ42/40 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.
Zhenxiang Gao, Ian Dorney, Pamela B Davis, David C Kaelber, Rong Xu
Association between selective serotonin reuptake inhibitors and mortality following COVID-19 among patients with Alzheimer’s disease
Abstract: Background: Recent research suggests that selective serotonin reuptake inhibitors (SSRIs) may reduce mortality in COVID-19 patients; however, research into their benefits for elderly Alzheimer’s disease (AD) patients remains limited. Objective: To investigate the relationship between SSRIs therapy and the mortality risk after COVID-19 infection in elderly patients with and without AD. Methods: This retrospective cohort study leveraged a large database containing over 100 million electronic health records in the US from the TriNetX platform to compare the hazard rates of mortality after COVID-19 infection in elderly AD patients prescribed SSRIs versus propensity-score matched individuals prescribed other antidepressants. This study was also conducted in separate cohorts of patients without AD to compare the findings. Results: When compared with non-SSRI antidepressants, SSRIs were associated with lower risk for mortality after COVID-19 infection in elderly patients without AD over early, middle, and later stages of the pandemic with HRs of 0.84 (95% CI: 0.75–0.93), 0.86 (95% CI: 0.79–0.93), and 0.77 (95% CI: 0.71–0.33), respectively. When comparing SSRIs with non-SSRI antidepressants for mortality risk following COVID-19 among patients with AD, HRs of 0.95 (95% CI: 0.71-1.27), 0.80 (95% CI: 0.61-1.06), and 0.99 (95% CI: 0.75-1.32), were found respectively. Conclusions: Our findings suggest that the use of SSRIs is significantly associated with reduced mortality risk following COVID-19 in elderly patients without AD compared to other antidepressants. While a lower mortality risk was also observed among AD patients, the association was not statistically significant.
Lilah M Besser, Anthony J Fuentes, Jessica N Zhang, Deirdre M O’Shea, James E Galvin (Handling Associate Editor: Gabrielle Britton)
Intersectionality of gender with social determinants of health and asymptomatic Alzheimer’s disease neuropathology
Abstract: Background: Women comprise approximately two-thirds of Alzheimer’s disease cases. Objective: This is the first known study to investigate the role of intersectionality between gender and other social determinants of health (SDOH) in the presentation of cognitive symptoms (i.e., being asymptomatic or symptomatic) among those with pathologically confirmed Alzheimer’s disease. Methods: We studied 3,107 individuals with Alzheimer’s disease neuropathology (ADNP) confirmed at autopsy. Asymptomatic ADNP was defined as the absence of a clinical diagnosis of mild cognitive impairment (MCI) or dementia before death (versus symptomatic: diagnosis of MCI/dementia). SDOH included gender, education, ethnoracial group, living alone, and primary language. Multivariable logistic regression tested associations between SDOH and asymptomatic ADNP (versus symptomatic); models were also stratified by gender. Results: Women, Hispanics, those living alone, and more educated individuals were found to have higher odds of asymptomatic ADNP. Non-English speakers had lower odds of asymptomatic ADNP. Both women and men had higher odds of asymptomatic ADNP if Hispanic or living alone. In only women, non-English speakers had lower odds while in only men, more education was associated with higher odds of asymptomatic ADNP. Conclusions: Gender, education, ethnicity, primary language, and living alone, and intersectionality of gender with primary language, may differentially influence MCI and dementia diagnosis prior to death among those with underlying ADNP. These findings emphasize the need for future Alzheimer’s disease research to prioritize social determinants of brain health including their intersectionality with gender and how to inform targeted interventions.
Noelia Calvo, G Peggy McFall, Shreeyaa Ramana, Michelle Galper, Esme Fuller-Thomson, Roger A Dixon, Gillian Einstein
Associated risk and resilience factors of Alzheimer disease in women with early bilateral oophorectomy: Data from the UK Biobank
Abstract: Background: Bilateral oophorectomy (BO) confers immediate estradiol loss. We examined prevalence and predictors of Alzheimer’s disease (AD) in women with early BO comparing their odds ratios of AD to those of women with spontaneous menopause (SM). Methods: A cohort from UK Biobank (n = 34,603) included women aged 60+ at baseline with and without AD who had early BO or SM. AD was determined based on AD related ICD-10 or ICD-9 code. We used logistic regression to model the association of menopause type with AD. Model predictors included age, education, age at menopause, hormone therapy (HT), APOE4, body mass index (BMI), cancer history, and smoking history. Results: Those with early BO had four times the odds of developing AD (OR = 4.12, 95% CI [2.02, 8.44]) compared to those with SM. APOE4 (OR = 4.29, 95% CI [2.43, 7.56]), and older age (OR = 1.16, 95% CI [1.05, 1.28]) were associated with increased odds of AD in the BO group. Greater years of education were associated with reduced odds of AD for both BO (OR = 0.91, 95% CI [0.85, 0.98]), and SM (OR = 0.95, 95% CI [0.90, 1.00]), while ever use of HT was associated with decreased odds of AD only for the BO group (OR = 0.43, 95% CI [0.23, 0.82]). Conclusions: Women with early BO, particularly with an APOE4 allele, are at high risk of AD. Women with early BO who use HT and those with increased education have lower odds of developing AD.
Sajid Ullah Khan, Abdullah Albanyan, Mohsin Bilal, Shahid Ullah
A genetic programming Rician noise reduction and explainable deep learning model for Alzheimer’s diseases severity prediction
Abstract: Background: Degradation of magnetic resonance imaging (MRI) remains a challenging issue, with noise being a key damaging component introduced due to a variety of environmental and mechanical factors. Objective: The aim of this research work is to addresses the issue of noise reduction and to predict Alzheimer’s disease detection efficiently. Methods: First, we present a genetic programming (GP) technique for reducing Rician noise in MRI images to pre-process the dataset. To effectively reduce Rician noise, this GP approach combines a Feature Extraction component, GP Optimal Expression, and an Optimum Removal Estimation component. In the second phase, we design and develop an explainable Deep Learning framework. This framework uses a local data-driven interpretation technique based on SHAP values to investigate the relationship between the neural network's estimated AD diagnosis and the input MRI images. In addition, we handle class distribution by combining an oversampling strategy with a minority approach. Several assessment metrics are used to analyze the performance of our proposed model. Results: The proposed method is tested on a variety of medical samples, and the results are compared to those obtained using other comparable approaches. We also test and compare our model to three cutting-edge models: DenseNet169, VGGNet15, and Inceptionv3. Conclusions: The empirical results show that our proposed model outperforms others, particularly in handling basic structures with limited spectral features, lower computational complexity, and less overfitting. This research worked addressed Rician noise issue in MRI images and predict AD severity prediction using explainable deep learning framework.
Zhao Gao, Tianjiong Luo, Chenyu Ye, Kun Cheng, Lichao Qian, Qingqing Cai, Qiong Zhou, Hui Fang, Guancheng Zhang, Shenyan Cai, Ming Shi, Ye Ji, Letian Zhao, Yilin Zhu, Weifeng Guo
Education attainment and nutritional status in the prevention of cognitive impairment in the hospitalized Chinese elderly
Abstract: 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.
Di Fan*, Tingfan Wang*, Jinxian Xiang, Yiping Bai, Liling Zhang, Xiaobin Wang (Handling Associate Editor: Youjie Zeng) *These authors contributed equally to this work.
Neutrophil percentage-to-albumin ratio is associated with cognitive function in adults aged over 60 years: An analysis of data from the NHANES 2011-2014
Abstract: 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 2,759 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.
Bianca Papotti*, Marcella Palumbo*, Maria Pia Adorni, Lisa Elviri, Annalisa Chiari, Manuela Tondelli, Roberta Bedin, Enrica Baldelli, Giulia Lancellotti, Maria Giovanna Lupo, Nicola Ferri, Marco Bertolotti, Franco Bernini, Chiara Mussi, Francesca Zimetti (Handling Associate Editor: Irundika Dias) *These authors contributed equally to this work.
Influence of APOE4 genotype on PCSK9-lipids association in cerebrospinal fluid and serum of patients in the Alzheimer’s disease continuum
Abstract: 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.
Lei Kang, Xiaolei Zhang, Jitian Guan, Kai Huang, Renhua Wu
Early Alzheimer’s disease diagnosis via handwriting with self-attention mechanisms
Abstract: 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.
Laura Serra, Sabrina Bonarota, Carlotta Di Domenico, Giulia Caruso, Giovanni Giulietti, Martina Rizzuti, Martina Assogna, Marta Rodini, Lucia Mencarelli, Francesco Di Lorenzo, Giacomo Koch, Lucia Fadda, Carlo Caltagirone, Marco Bozzali
The funnel effect of reserves prompted by leisure activities across the Alzheimer’s disease continuum
Abstract: Background: The mechanisms of reserves have been hypothesized to explain inconsistencies between accumulation of neuropathological damage and clinical manifestations. Leisure activities are believed to promote reserves. Objective: This study evaluates whether cognitive, social, and physical leisure activities performed over lifespan predict current cognitive functioning in normal aging and the Alzheimer's disease (AD) continuum. Methods: Thirty-five AD, 24 amnestic mild cognitive impairment (aMCI) patients, 21 individuals with subjective cognitive complaint (SCD), and 25 controls underwent a questionnaire developed to quantify leisure activities in different life periods, the Addenbrooke’s Cognitive Examination-Revised (ACE-R), and T1-weighted 3T-MRI scans for brain volumetrics and cortical thickness quantification. Partial/total leisure activities’ scores and demographic and brain variables were entered as predictors, while ACE-R scores as dependent variables in linear regression analyses. Results: Current level of cognition was predicted by 1) social and physical activities performed in middle age and current cognitive activity in AD; 2) cognitive and social activities performed in middle age, current age and cortical thickness in aMCI; 3) recreational activities the set of lifetime, current age, and brain features in SCD; 4) education and the set of lifetime leisure activities over lifespan in controls. Conclusions: This study shows a funnel effect due to gradual reduction of stimulatory activities in the transition from healthy aging to AD. Reserve indices taking into account different types of stimulatory activities allow to capture even smallest residual effects of reserves accumulated over lifespan, until their complete depletion at advanced AD stages. These results may help target tailored interventions during normal and pathological aging.
Chongcheng Xi*, Jie Zhang*, Haihui Liu*, Jia Xing, Yiyun Ding, Wei Wei, Le Wang, Zhenzhu Liu *These authors contributed equally to this work.
Can early gut microbiota screening reduce the incidence of cognitive impairment? A Mendelian randomization study
Abstract: Background: Gastrointestinal symptoms are now detected early in the clinical course of many dementia patients, and studies of the microbiome-gut-brain axis have confirmed bidirectional interactions between the gut and the brain. However, the causal relationship between gut microbiota and cognitive impairment has not been fully established. Therefore, this study conducted a bidirectional Mendelian randomization study to elucidate the potential causal relationship of gut microbiota to cognitive impairment. Objective: Using Mendelian randomization to identify gut flora with a genetic causal effect on the development of cognitive impairment. Methods: This study utilized publicly available genome-wide association study summary data to perform MR analysis, with gut microbiota as the exposure and various cognitive function indicators as well as scores for Alzheimer's disease as outcomes. This study selected single nucleotide polymorphisms as instrumental variables based on p-values, F-statistics, and r2. Bidirectional Mendelian randomization was conducted using methods such as IVW, MR-Egger, simple mode, and weighted mode to assess the causal relationship. Concurrently, this study carried out Cochran's Q test, MR-Egger intercept test, and leave-one-out analysis to identify potential heterogeneity and horizontal pleiotropy. Results: This study identified a total of 31 gut microbes that have a causal relationship with cognitive impairment, which include 1 phylum, 4 classes, 3 orders, 2 families, and 21 genera. Conclusions: This study unveiled specific gut microbiota associated with cognitive impairment, offering new insights and approaches for the prevention and treatment of cognitive impairment through gut microbiota.
Jordi A Matias-Guiu, José Álvarez-Sabín, Enrique Botia, Ignacio Casado-Naranjo, Mar Castellanos, Ana Frank, Cristina Íñiguez, María Dolores Jiménez-Hernández, Félix Javier Jiménez-Jiménez, José-Miguel Láinez, Ester Moral, David A Pérez-Martínez, Alfredo Rodríguez-Antigüedad, Nuria Ruiz-Lavilla, Tomás Segura, Pedro J Serrano-Castro, Jorge Matias-Guiu
Perceptions of key informant neurologists before implementing anti-amyloid drugs in the Spanish departments of neurology
Abstract: Background: A deep knowledge of the healthcare system and the organization of neurology departments is important for planning and optimizing changes to facilitate the successful implementation of anti-amyloid antibodies treatments. Objective: We aimed to assess the necessary changes prior to introducing these therapies in our setting. Methods: We conducted a key informant survey among heads of departments of neurology from 16 hospitals in Spain. The questionnaire comprised questions about changes in the organization and functioning of the departments of neurology with the introduction of anti-amyloid drugs, changes in diagnosis and patient care, use of diagnostic techniques, patients, families and public information, resources allocation, and research. Results: Sixteen key informants completed the survey. They strongly agreed that the introduction of anti-amyloid drugs will impact the functioning of neurology services, especially in hospitals with dementia units. Consensus was reached regarding referring all Alzheimer’s disease patients eligible for therapy to dementia units. There was also agreement on the need to expand the neurology services, day hospital units, extend visit durations, and hire more professionals, especially neurologists, neuropsychologists, and nuclear medicine physicians. Furthermore, consensus was achieved on increasing the use of MRI, amyloid PET, cerebrospinal fluid biomarkers, APOE genotyping, and the necessity of advancing blood biomarkers and tau tracers. Conclusions: Our study highlights the need for extensive changes within Spanish neurological departments to effectively integrate anti-amyloid antibodies. Implementing these changes is essential for the timely and equitable adoption of novel therapies.
Vanesa Jurasova, Ross Andel, Alzbeta Katonova, Raena Nolan, Zuzana Lacinova, Tereza Kolarova, Vaclav Matoska, Martin Vyhnalek, Jakub Hort
Is KIBRA polymorphism associated with memory performance and cognitive impairment in Alzheimer’s disease?
Abstract: Background: Genetic variations in a common single nucleotide polymorphism in the ninth intron of the KIBRA gene have been linked to memory performance and risk of Alzheimer's disease (AD). Objective: We examined the risk of AD related to presence of KIBRA T allele (versus CC homozygote) and to memory performance. The role of established genetic risk factors APOE ε4 and BDNF Met was also considered. Methods: Participants were cognitively healthy individuals (n=19), participants with amnestic mild cognitive impairment (aMCI) due to AD (n=99) and AD dementia (n=37) from the Czech Brain Aging Study. Binary and multinomial logistic regressions compared odds of belonging to a certain diagnostic category and multivariate linear regressions assessed associations with memory. Results: KIBRA T allele was associated with increased AD dementia risk (odds ratio [OR]=5.98, p=0.012) compared to KIBRA CC genotype. In APOE ε4 negative individuals, KIBRA T allele was associated with a greater risk of both aMCI due to AD (OR=6.68, p=0.038) and AD dementia (OR=15.75, p=0.009). In BDNF Met positive individuals, the KIBRA T allele was associated with a greater risk of AD dementia (OR=10.98, p=0.050). In AD dementia, the association between KIBRA T allele and better memory performance approached significance (β=0.42; p=0.062). The link between possessing the KIBRA T allele and better memory reached statistical significance only among BDNF Met carriers (β=1.21, p=0.027). Conclusions: Findings suggest that KIBRA T allele may not fully protect against AD dementia but could potentially delay progression of post-diagnosis cognitive deficits.
Kazunari Ishii, Takahiro Yamada, Kohei Hanaoka, Hayato Kaida, Yasuyuki Kojita, Atsushi Kono, Kazushi Hanada, Kazumasa Saigoh, Shizuka Sakuta, Mamoru Hashimoto, Takashi Kato, Akinori Nakamura, for BATON Study Group
Regional differences in glucose metabolic decline and tau deposition in the Alzheimer’s continuum brain
Abstract: Background: Alzheimer's disease (AD) is characterized by the accumulation of amyloid-β and tau proteins, leading to neurofibrillary tangles. A biomarker-based diagnostic method called the ATN system categorizes AD pathology into amyloid-β (A), tau (T), and neurodegeneration (N). The relationship between regional tau deposition and reduced glucose metabolism in the preclinical AD stage is not well understood. Objective: We presented voxel-by-voxel metabolic/tau deposition ratio (MTR) images to investigate the effects of tau deposition on metabolism in AD brains on a stage-by-stage basis. Methods: We selected 174 subjects who underwent 3D-MRI, FDG-PET, amyloid PET, and tau PET scans. MTR images were created by normalizing FDG-PET toMK6240 PET images. Voxel-wise comparisons among 63 cognitively normal amyloid-negative (CNA) subjects, 49 subjects with AD dementia (ADD), 23 subjects with mild cognitive impairment due to AD (MCA), and 39 preclinical AD (PRC) subjects were conducted. Results: There was reduced glucose metabolism in ADD and MCA groups compared to CNA, predominantly in parietotemporal areas. Tau deposition was observed in wider areas in ADD and restricted to the medial temporal lobes in MCA. MTR exhibited significant reductions in broader regions in ADD and MCA, indicating simultaneous glucose metabolism decrease and tau deposition. At the MCA and PRC stages, glucose metabolism impairment and tau deposition were shown in separate regions by FDG PET and tau PET, respectively, while MTR images showed impairment in both regions. Conclusions: Our findings suggest that MTR imaging provides insights into AD pathophysiology by simultaneously assessing glucose metabolism and tau deposition. In the early stage of the AD continuum (MCA and PRC), metabolic decline and tau deposition occur independently in different brain regions.
Yingxin Zhao, Alejandro Villasante-Tezanos, Ernesto G Miranda-Morales, Miguel A Pappolla, Xiang Fang
Discovery of novel metabolic biomarkers in blood serum for diagnosis of Alzheimer's disease
Abstract: Background: Blood metabolites have emerged as promising candidates in the search for biomarkers for Alzheimer's disease (AD), as evidence shows that various metabolic derangements contribute to neurodegeneration in AD. Objective: We aim to identify metabolic biomarkers for AD diagnosis. Methods: We conducted an in-depth analysis of the serum metabolome of AD patients and age, sex-matched cognitively unimpaired older adults using ultra-high-performance liquid chromatography-high resolution mass spectrometry. The biomarkers associated with AD were identified using machine learning algorithms. Results: Using the discovery dataset and support vector machine (SVM) algorithm, we identified a panel of 14 metabolites predicting AD with a 1.00 area under the curve (AUC) of receiver operating characteristic (ROC). The SVM model was tested against the verification dataset using an independent cohort and retained high predictive accuracy with a 0.97 AUC. Using the random forest (RF) algorithm, we identified a panel of 13 metabolites that predicted AD with a 0.96 AUC when tested against the verification dataset. Conclusions: These findings pave the way for an efficient, blood-based diagnostic test for AD, holding promise for clinical screenings and diagnostic procedures
