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Abstract Alzheimer’s disease (AD) is a progressive disease leading to cognitive decline, and to prevent it, researchers seek to diagnose mild cognitive impairment (MCI) early. Particularly, non-amnestic MCI (naMCI) is often mistaken for normal aging as the representative symptom of AD, memory decline, is absent. Subjective cognitive decline (SCD), an intermediate step between normal aging and MCI, is crucial for prediction or early detection of MCI, which determines the presence of AD spectrum pathology. We developed a computer-based cognitive task to classify the presence or absence of AD pathology and stage within the AD spectrum, and attempted to perform multi-stage classification through electroencephalography (EEG) during resting and memory encoding state. The resting and memory-encoding states of 58 patients (20 with SCD, 10 with naMCI, 18 with aMCI, and 10 with AD) were measured and classified into four groups. We extracted features that could reflect the phase, spectral, and temporal characteristics of the resting and memory-encoding states. For the classification, we compared nine machine learning models and three deep learning models using Leave-one-subject-out strategy. Significant correlations were found between the existing neurophysiological test scores and performance of our computer-based cognitive task for all cognitive domains. In all models used, the memory-encoding states realized a higher classification performance than resting states. The best model for the 4-class classification was cKNN. The highest accuracy using resting state data was 67.24%, while it was 93.10% using memory encoding state data. This study involving participants with SCD, naMCI, aMCI, and AD focused on early Alzheimer’s diagnosis. The research used EEG data during resting and memory encoding states to classify these groups, demonstrating the significance of cognitive process-related brain waves for diagnosis. The computer-based cognitive task introduced in the study offers a time-efficient alternative to traditional neuropsychological tests, showing a strong correlation with their results and serving as a valuable tool to assess cognitive impairment with reduced bias.

Alzheimer's disease (AD) is a progressive disease leading to cognitive decline, and to prevent it, researchers seek to diagnose mild cognitive impairment (MCI) early. Particularly, non-amnestic MCI (naMCI) is often mistaken for normal aging as the representative symptom of AD, memory decline, is absent. Subjective cognitive decline (SCD), an intermediate step between normal aging and MCI, is crucial for prediction or early detection of MCI, which determines the presence of AD spectrum pathology. We developed a computer-based cognitive task to classify the presence or absence of AD pathology and stage within the AD spectrum, and attempted to perform multi-stage classification through electroencephalography (EEG) during resting and memory encoding state. The resting and memory-encoding states of 58 patients (20 with SCD, 10 with naMCI, 18 with aMCI, and 10 with AD) were measured and classified into four groups. We extracted features that could reflect the phase, spectral, and temporal characteristics of the resting and memory-encoding states. For the classification, we compared nine machine learning models and three deep learning models using Leave-one-subject-out strategy. Significant correlations were found between the existing neurophysiological test scores and performance of our computer-based cognitive task for all cognitive domains. In all models used, the memory-encoding states realized a higher classification performance than resting states. The best model for the 4-class classification was cKNN. The highest accuracy using resting state data was 67.24%, while it was 93.10% using memory encoding state data. This study involving participants with SCD, naMCI, aMCI, and AD focused on early Alzheimer's diagnosis. The research used EEG data during resting and memory encoding states to classify these groups, demonstrating the significance of cognitive process-related brain waves for diagnosis. The computer-based cognitive task introduced in the study offers a time-efficient alternative to traditional neuropsychological tests, showing a strong correlation with their results and serving as a valuable tool to assess cognitive impairment with reduced bias. [ABSTRACT FROM AUTHOR]

Background: Research into the neurobiological underpinnings of learning and memory has demonstrated the cognitive-enhancing effects associated with diverse classes of phosphodiesterase (PDE) inhibitors. Specific PDE inhibitors have been identified to improve neuronal communication through selective inhibition of PDE activity. Roflumilast, a PDE4 inhibitor, has demonstrated efficacy in enhancing episodic memory in healthy adults and elderly participants with pronounced memory impairment, indicative of amnestic mild cognitive impairment (aMCI). In alignment with these findings, the present protocol aims to provide a proof of concept phase II of the potential of roflumilast to aid patients diagnosed with (a)MCI or mild Alzheimer's disease (AD) dementia. Methods: The study will be conducted according to a double-blind, randomized placebo-controlled, between-subjects design. Participants with (a)MCI and mild AD dementia will be recruited through the Memory Clinic at the Maastricht University Medical Centre + (MUMC +) in Maastricht, the Netherlands, alongside outreach through regional hospitals, and social media. The study will have three arms: placebo, 50 μg roflumilast, and 100 μg roflumilast, with a treatment duration of 24 weeks. The primary outcome measure will focus on the assessment of episodic memory, as evaluated through participants' performance on the 15-word Verbal Learning Task (VLT). Our secondary objectives are multifaceted, including an exploration of various cognitive domains. In addition, insights into the well-being and daily functioning of participants will be investigated through interviews with both the participants and their (informal) caregivers, we are interested in the well-being and daily functioning of the participants. Discussion: The outcomes of the present study aim to elucidate the significance of the PDE4 inhibition mechanism as a prospective therapeutic target for enhancing cognitive function in individuals with (a)MCI and mild AD dementia. Identifying positive effects within these patient cohorts could extend the relevance of this treatment to encompass a broader spectrum of neurological disorders. Trial registration: The Medical Ethics Committee of MUMC + granted ethics approval for the 4th version of the protocol on September 10th, 2020. The trial was registered at the European Drug Regulatory Affairs Clinical Trials (EudraCT) registered on the 19th of December 2019 (https://www.clinicaltrialsregister.eu/ctr-search/trial/2019-004959-36/NL) and ClinicalTrial.gov (NCT04658654, https://clinicaltrials.gov/study/NCT04658654?intr=roflumilast&cond=mci&rank=1) on the 8th of December 2020. The Central Committee on Research Involving Human Subjects (CCMO) granted approval on the 30th of September 2020. [ABSTRACT FROM AUTHOR]

Orientation is a fundamental cognitive faculty and the bedrock of the neurologic examination. Orientation is defined as the alignment between an individual's internal representation and the external world in the spatial, temporal, and social domains. While spatial disorientation is a recognized hallmark of Alzheimer's disease (AD), little is known about disorientation beyond space in AD. This study aimed to explore disorientation in spatial, temporal, and social domains along the AD continuum. Fifty‐one participants along the AD continuum performed an ecological orientation task in the spatial, temporal, and social domains while undergoing functional MRI. Disorientation in AD followed a three‐way association between orientation domain, brain region, and disease stage. Specifically, patients with early amnestic mild cognitive impairment exhibited spatio‐temporal disorientation and reduced brain activity in temporoparietal regions, while patients with AD dementia showed additional social disorientation and reduced brain activity in frontoparietal regions. Furthermore, patterns of hypoactivation overlapped different subnetworks of the default mode network, patterns of fluorodeoxyglucose hypometabolism, and cortical atrophy characteristic of AD. Our results suggest that AD may encompass a disorder of orientation, characterized by a biphasic process manifesting as early spatio‐temporal and late social disorientation. As such, disorientation may offer a unique window into the clinicopathological progression of AD. Significance statement: Despite extensive research into Alzheimer's disease (AD), its core cognitive deficit remains a matter of debate. In this study, we investigated whether orientation, defined as the ability to align internal representations with the external world in spatial, temporal, and social domains, constitutes a core cognitive deficit in AD. To do so, we used PET‐fMRI imaging to collect behavioral, functional, and metabolic data from 51 participants along the AD continuum. Our findings suggest that AD may constitute a disorder of orientation, characterized by an early spatio‐temporal disorientation and followed by late social disorientation, manifesting in task‐evoked and neurodegenerative changes. We propose that a profile of disorientation across multiple domains offers a unique window into the progression of AD and as such could greatly benefit disease diagnosis, monitoring, and evaluation of treatment response. [ABSTRACT FROM AUTHOR]

Background: The aim is to compare the plasma levels of hyaluronic acid (HA) which is closely related to inflammation and vascular changes and arterial stiffness (AS) related values in patients with Alzheimer's disease (AD), amnestic type mild cognitive impairment (aMCI), and normal cognitive functions (NCF). Methods: Ninety participants were categorized into three groups, patients with AD, MCI, and NCF. Arterial stiffness measurement in the nephrology outpatient clinic, and storage and analysis of plasma samples in the biochemistry laboratory. Results: Of the 90 patients, 32 had NCF, 32 had aMCI, and 26 had AD. Between groups, there was no difference in HA, pulse wave velocity, and augmentation index. The HA level had no statistically significant correlation with any of the other variables. Conclusions: Plasma HA levels will not be useful in the diagnosis of AD. More comprehensive studies with larger number of patients are needed. [ABSTRACT FROM AUTHOR]

A simple screening test to identify the early stages of Alzheimer's disease (AD) is urgently needed. We investigated whether odor identification impairment can be used to differentiate between stages of the A/T/N classification (amyloid, tau, neurodegeneration) in individuals with amnestic mild cognitive impairment or AD and in healthy controls. We collected data from 132 Japanese participants visiting the Toranomon Hospital dementia outpatient clinic. The odor identification scores correlated significantly with major neuropsychological scores, regardless of apolipoprotein E4 status, and with effective cerebrospinal fluid (CSF) biomarkers [amyloid β 42 (Aβ42) and the Aβ42/40 and phosphorylated Tau (p-Tau)/Aβ42 ratios] but not with ineffective biomarkers [Aβ40 and the p-Tau/total Tau ratio]. A weak positive correlation was observed between the corrected odor identification score (adjusted for age, sex, ApoE4 and MMSE), CSF Aβ42, and the Aβ42/40 ratio. The odor identification score demonstrated excellent discriminative power for the amyloidogenesis stage , according to the A/T/N classification, but was unsuitable for differentiating between the p-Tau accumulation and the neurodegeneration stages. After twelve odor species were analyzed, a version of the score comprising only four odors—India ink, wood, curry, and sweaty socks—proved highly effective in identifying AD amyloidogenesis, showing promise for the screening of preclinical AD. [ABSTRACT FROM AUTHOR]

Background and aims: Amnestic mild cognitive impairment (aMCI) is the most common subtype of MCI, which carries a significantly high risk of transitioning to Alzheimer's disease. Recently, increasing attention has been given to remnant cholesterol (RC), a non-traditional and previously overlooked risk factor. The aim of this study was to explore the association between plasma RC levels and aMCI. Methods: Data were obtained from Brain Health Cognitive Management Team in Wuhan (https://hbtcm.66nao.com/admin). A total of 1,007 community-dwelling elders were recruited for this project. Based on ten tools including general demographic data, cognitive screening and some exclusion scales, these participants were divided into the aMCI (n = 401) and normal cognitive groups (n = 606). Physical examinations were conducted on all participants, with clinical indicators such as blood pressure, blood sugar, and blood lipids collected. Results: The aMCI group had significantly higher RC levels compared to the normal cognitive group (0.64 ± 0.431 vs. 0.52 ± 0.447 mmol/L, p<0.05). Binary logistics regression revealed that occupation (P<0.001, OR = 0.533, 95%CI: 0.423-0.673) and RC (p = 0.014, OR = 1.477, 95% CI:1.081-2.018) were associated factors for aMCI. Partial correlation analysis, after controlling for occupation, showed a significant negative correlation between RC levels and MoCA scores (r = 0.059, p = 0.046), as well as Naming scores (r = 0.070, p = 0.026). ROC curve analysis demonstrated that RC levels had an independent predictive efficacy in predicting aMCI (AUC = 0.580, 95%CI: 0.544 ~ 0.615, P <0.001). Conclusion: Higher RC levels were identified as an independent indicator for aMCI, particularly in the naming cognitive domain among older individuals. Further longitudinal studies are necessary to validate the predictive efficacy of RC. [ABSTRACT FROM AUTHOR]

Objectives: Subjective cognitive decline (SCD) and amnestic mild cognitive impairment (aMCI) are considered as the spectrum of preclinical Alzheimer's disease (AD), with abnormal brain network connectivity as the main neuroimaging feature. Repetitive transcranial magnetic stimulation (rTMS) has been proven to be an effective non-invasive technique for addressing neuropsychiatric disorders. This study aims to explore the potential of targeted rTMS to regulate effective connectivity within the default mode network (DMN) and the executive control network (CEN), thereby improving cognitive function. Methods: This study included 86 healthy controls (HCs), 72 SCDs, and 86 aMCIs. Among them, 10 SCDs and 11 aMCIs received a 2-week rTMS course of 5-day, once-daily. Cross-sectional analysis with the spectral dynamic causal model (spDCM) was used to analyze the DMN and CEN effective connectivity patterns of the three groups. Afterwards, longitudinal analysis was conducted on the changes in effective connectivity patterns and cognitive function before and after rTMS for SCD and aMCI, and the correlation between them was analyzed. Results: Cross-sectional analysis showed different effective connectivity patterns in the DMN and CEN among the three groups. Longitudinal analysis showed that the effective connectivity pattern of the SCD had changed, accompanied by improvements in episodic memory. Correlation analysis indicated a negative relationship between effective connectivity from the left angular gyrus (ANG) to the anterior cingulate gyrus and the ANG.R to the right middle frontal gyrus, with visuospatial and executive function, respectively. In patients with aMCI, episodic memory and executive function improved, while the effective connectivity pattern remained unchanged. Conclusion: This study demonstrates that PCUN-targeted rTMS in SCD regulates the abnormal effective connectivity patterns in DMN and CEN, thereby improving cognition function. Conversely, in aMCI, the mechanism of improvement may differ. Our findings further suggest that rTMS is more effective in preventing or delaying disease progression in the earlier stages of the AD spectrum. [ABSTRACT FROM AUTHOR]

Background: The Montreal Cognitive Assessment (MoCA) is one of the most widely-used cognitive screening instruments and has been translated into several different languages and dialects. Although the original validation study suggested to use a cutoff of ≤26, subsequent studies have shown that lower cutoff values may yield fewer false-positive indications of cognitive impairment. The aim of this study was to summarize the diagnostic accuracy and mean difference of the MoCA when comparing cognitively unimpaired (CU) older adults to those with amnestic mild cognitive impairment (aMCI). Methods: PubMed and EMBASE databases were searched from inception to 22 February 2022. Meta-analyses for area under the curve (AUC) and standardized mean difference (SMD) values were performed. Results: Fifty-five observational studies that included 17,343 CU and 8,413 aMCI subjects were selected for inclusion. Thirty-nine studies were used in the AUC analysis while 44 were used in the SMD analysis. The overall AUC value was 0.84 (95% CI: 0.81, 0.87) indicating good diagnostic accuracy and a large effect size was noted for the SMD analysis (Hedge’s g  =  1.49, 95% CI: 1.33, 1.64). Both analyses had high levels of between-study heterogeneity. The median cutoff score for identifying aMCI was <24. Discussion and conclusion: The MoCA has good diagnostic accuracy for detecting aMCI across several different languages. The findings of this metaanalysis also support the use of 24 as the optimal cutoff when the MoCA is used to screen for suspected cognitive impairment. [ABSTRACT FROM AUTHOR]

Metacognition, the ability to monitor and regulate cognitive processes, is essential for individuals with Mild Cognitive Impairment (MCI) to accurately identify their deficits and effectively manage them. However, previous studies primarily focused on memory awareness in MCI, neglecting other domains affected in daily life. This study aimed to investigate how individuals with MCI perceive their abilities to handle various cognitively challenging situations representing real-life scenarios and their use of compensatory strategies. Thus 100 participants were recruited, including 50 with amnestic MCI with multiple deficits (aMCI) and 50 cognitively healthy controls (HC) matched in age and education. Participants completed three metacognitive scales assessing self-perceived efficacy in everyday life scenarios and one scale evaluating use of cognitive strategies. Results indicated that aMCI participants reported significantly lower self-efficacy in memory and divided-shifted attention scenarios compared to HC. Surprisingly, no significant group differences were found in the self-reports about the use of cognitive strategies. This suggests a potential gap in understanding or applying effective strategies for compensating cognitive deficits. These findings emphasize the importance of cognitive training programs targeting metacognitive knowledge enhancement and practical use of cognitive strategies that could enhance the quality of life for individuals with MCI. [ABSTRACT FROM AUTHOR]

Background: The relationship between periodontitis and Alzheimer's disease (AD) has attracted more attention recently, whereas profiles of subgingival microbiomes and gingival crevicular fluid (GCF) metabolic signatures in AD patients have rarely been characterized; thus, little evidence exists to support the oral-brain axis hypothesis. Therefore, our study aimed to characterize both the microbial community of subgingival plaque and the metabolomic profiles of GCF in patients with AD and amnestic mild cognitive impairment (aMCI) for the first time. Methods: This was a cross-sectional study. Clinical examinations were performed on all participants. The microbial community of subgingival plaque and the metabolomic profiles of GCF were characterized using the 16S ribosomal RNA (rRNA) gene high-throughput sequencing and liquid chromatography linked to tandem mass spectrometry (LC–MS/MS) analysis, respectively. Results: Thirty-two patients with AD, 32 patients with aMCI, and 32 cognitively normal people were enrolled. The severity of periodontitis was significantly increased in AD patients compared with aMCI patients and cognitively normal people. The 16S rRNA gene sequencing results showed that the relative abundances of 16 species in subgingival plaque were significantly correlated with cognitive function, and LC–MS/MS analysis identified a total of 165 differentially abundant metabolites in GCF. Moreover, multiomics Data Integration Analysis for Biomarker discovery using Latent cOmponents (DIABLO) analysis revealed that 19 differentially abundant metabolites were significantly correlated with Veillonella parvula, Dialister pneumosintes, Leptotrichia buccalis, Pseudoleptotrichia goodfellowii, and Actinomyces massiliensis, in which galactinol, sn-glycerol 3-phosphoethanolamine, D-mannitol, 1 h-indole-1-pentanoic acid, 3-(1-naphthalenylcarbonyl)- and L-iditol yielded satisfactory accuracy for the predictive diagnosis of AD progression. Conclusions: This is the first combined subgingival microbiome and GCF metabolome study in patients with AD and aMCI, which revealed that periodontal microbial dysbiosis and metabolic disorders may be involved in the etiology and progression of AD, and the differential abundance of the microbiota and metabolites may be useful as potential markers for AD in the future. [ABSTRACT FROM AUTHOR]

This document is a special issue of the International Journal of Molecular Sciences that focuses on the role of apoptosis and cellular senescence in cancer and aging. It explains that apoptosis and senescence are cellular responses to irreversible dysfunctions caused by cellular damage, and their functions change over time. In the early stages of life, they function as tumor suppression mechanisms, but later in life, they become destructive and promote aging. The document also discusses the role of cellular senescence in neurodegenerative diseases like Alzheimer's and its potential link to cancer. It concludes by highlighting the need to understand the delicate balance between apoptosis and cellular senescence for the development of future anti-cancer and aging strategies. [Extracted from the article]

Objective: Dementia is a significant public health concern, and mild cognitive impairment (MCI) serves as a transitional stage between normal aging and dementia. Among the various types of MCI, amnestic MCI (aMCI) has been identified as having a higher likelihood of progressing to Alzheimer's dimension. However, limited research has been conducted on the prevalence of aMCI in China. Therefore, the objective of this study is to investigate the prevalence of aMCI, examine its cognitive characteristics, and identify associated risk factors. Methods: In this cross-sectional study, we investigated a sample of 368 older adults aged 60 years and above in the urban communities of Chengdu, China. The participants underwent a battery of neuropsychological assessments, including the Mini-Mental State Examination (MMSE), the Clinical Dementia Rating (CDR), Auditory Verbal Learning Test (AVLT), Wechsler's Logical Memory Task (LMT), Boston Naming Test (BNT) and Trail Making Test Part A (TMT-A). Social information was collected by standard questionnaire. Multiple logistic regression analysis was utilized to screen for the risk and protective factors of aMCI. Results: The data analysis included 309 subjects with normal cognitive function and 59 with aMCI, resulting in a prevalence of 16.0% for aMCI. The average age of participants was 69.06 ± 7.30 years, with 56.0% being females. After controlling for age, gender and education, the Spearman partial correlation coefficient between various cognitive assessments and aMCI ranged from -0.52 for the long-term delayed recall scores in AVLT to 0.19 for the time-usage scores in TMT-A. The results indicated that all cognitive domains, except for naming scores (after semantic cue of BNT) and error quantity (in TMT-A), showed statistically significant associations with aMCI. Furthermore, the multiple logistic regression analysis revealed that older age (OR = 1.044, 95%CI: 1.002~1.087), lower educational level, and diabetes (OR = 2.450, 95%CI: 1.246~4.818) were risk factors of aMCI. Conclusion: This study found a high prevalence of aMCI among older adults in Chengdu, China. Individuals with aMCI exhibited lower cognitive function in memory, language, and executive domains, with long-term delayed recall showing the strongest association. Clinicians should prioritize individuals with verbal learning and memory difficulties, especially long-term delayed recall, in clinical practice. [ABSTRACT FROM AUTHOR]

Introduction: Gait disorders and gait-related cognitive tests were recently linked to future Alzheimer’s Disease (AD) dementia diagnosis in amnestic Mild Cognitive Impairment (aMCI). This study aimed to evaluate the predictive power of gait disorders and gait-related neuropsychological performances for future AD diagnosis in aMCI through machine learning (ML). Methods: A sample of 253 aMCI (stable, converter) individuals were included. We explored the predictive accuracy of four predictors (gait profile plus MMSE, DSST, and TMT-B) previously identified as critical for the conversion from aMCI to AD within a 36-month follow-up. Supervised ML algorithms (Support Vector Machine [SVM], Logistic Regression, and k-Nearest Neighbors) were trained on 70% of the dataset, and feature importance was evaluated for the best algorithm. Results: The SVM algorithm achieved the best performance. The optimized training set performance achieved an accuracy of 0.67 (sensitivity = 0.72; specificity = 0.60), improving to 0.70 on the test set (sensitivity = 0.79; specificity = 0.52). Feature importance revealed MMSE as the most important predictor in both training and testing, while gait type was important in the testing phase. Discussion: We created a predictive ML model that is capable of identifying aMCI at high risk of AD dementia within 36 months. Our ML model could be used to quickly identify individuals at higher risk of AD, facilitating secondary prevention (e.g., cognitive and/or physical training), and serving as screening for more expansive and invasive tests. Lastly, our results point toward theoretically and practically sound evidence of mind and body interaction in AD. [ABSTRACT FROM AUTHOR]

This research evaluated the modified RCTU score, derived from amyloid PET scans, for predicting the progression from amnestic Mild Cognitive Impairment (aMCI) to Alzheimer's Disease (AD). aMCI patients underwent baseline evaluations, including amyloid PET. AD conversion was identified through neuropsychological tests after observation. The RCTU was modified by segmenting frontal, parietal, and temporal lobes into left and right, resulting in seven areas. Scores from both modified and conventional RCTU were analyzed and compared. Among 45 patients, 12 progressed to AD (over 17.8 ± 6.8 months). AD converters showed higher scores in modified RCTU scores. Modified RCTU score had strong correlations with amyloid SUVR (r > 0.7). Modified RCTU sum score was the significant covariate of AD conversion. Modified RCTU could determine the asymmetry of amyloid deposits. We demonstrated that symmetric deposits of amyloid showed a higher risk for AD conversion when analyzed using modified RCTU. The modified RCTU score is a promising method for predicting AD conversion, correlating strongly with amyloid SUVR. [ABSTRACT FROM AUTHOR]

Background: Elevated amyloid-β (Aβ) on positron emission tomography (PET) scan is used to aid diagnosis of Alzheimer's disease (AD), but many prior studies have focused on patients with a typical AD phenotype such as amnestic mild cognitive impairment (MCI). Little is known about whether elevated Aβ on PET scan predicts rate of cognitive and functional decline among those with MCI or dementia that is clinically less typical of early AD, thus leading to etiologic uncertainty. Objective: We aimed to investigate whether elevated Aβ on PET scan predicts cognitive and functional decline over an 18-month period in those with MCI or dementia of uncertain etiology. Methods: In 1,028 individuals with MCI or dementia of uncertain etiology, we evaluated the association between elevated Aβ on PET scan and change on a telephone cognitive status measure administered to the participant and change in everyday function as reported by their care partner. Results: Individuals with either MCI or dementia and elevated Aβ (66.6% of the sample) showed greater cognitive decline compared to those without elevated Aβ on PET scan, whose cognition was relatively stable over 18 months. Those with either MCI or dementia and elevated Aβ were also reported to have greater functional decline compared to those without elevated Aβ, even though the latter group showed significant care partner-reported functional decline over time. Conclusions: Elevated Aβ on PET scan can be helpful in predicting rates of both cognitive and functional decline, even among cognitively impaired individuals with atypical presentations of AD. [ABSTRACT FROM AUTHOR]

Background: Individuals with amnestic mild cognitive impairment (aMCI), especially for those with multidomain cognitive deficits, should be clinically examined for determining risk of developing Alzheimer's disease. English-speakers with aMCI exhibit language impairments mostly at the lexical–semantic level. Given that the language processing of Mandarin Chinese is different from that of alphabetic languages, whether previous findings for English-speakers with aMCI can be generalized to Mandarin Chinese speakers with aMCI remains unclear. Objective: This study examined the multifaceted language functions of Mandarin Chinese speakers with aMCI and compared them with those without cognitive impairment by using a newly developed language test battery. Methods: Twenty-three individuals with aMCI and 29 individuals without cognitive impairment were recruited. The new language test battery comprises five language domains (oral production, auditory and reading comprehension, reading aloud, repetition, and writing). Results: Compared with the controls, the individuals with aMCI exhibited poorer performance in the oral production and auditory and reading comprehension domains, especially on tests involving effortful lexical and semantic processing. Moreover, the aMCI group made more semantic naming errors compared with their counterparts and tended to experience difficulty in processing items belonging to the categories of living objects. Conclusions: The pattern identified in the present study is similar to that of English-speaking individuals with aMCI across multiple language domains. Incorporating language tests involving lexical and semantic processing into clinical practice is essential and can help identify early language dysfunction in Mandarin Chinese speakers with aMCI. [ABSTRACT FROM AUTHOR]

Background: Mild cognitive impairment (MCI) is considered to be the borderline of cognitive changes associated with aging and very early dementia. Cognitive functions in MCI can improve, remain stable or progress to clinically probable AD. Quantitative electroencephalography (qEEG) can become a useful tool for using the analytical techniques to quantify EEG patterns indicating cognitive impairment. Objective: The aim of our study was to assess spectral and connectivity analysis of the EEG resting state activity in amnestic MCI (aMCI) patients in comparison with healthy control group (CogN). Methods: 30 aMCI patients and 23 CogN group, matched by age and education, underwent equal neuropsychological assessment and EEG recording, according to the same protocol. Results: qEEG spectral analysis revealed decrease of global relative beta band power and increase of global relative theta and delta power in aMCI patients. Whereas, decreased coherence in centroparietal right area considered to be an early qEEG biomarker of functional disconnection of the brain network in aMCI patients. In conclusion, the demonstrated changes in qEEG, especially, the coherence patterns are specific biomarkers of cognitive impairment in aMCI. Conclusions: Therefore, qEEG measurements appears to be a useful tool that complements neuropsychological diagnostics, assessing the risk of progression and provides a basis for possible interventions designed to improve cognitive functions or even inhibit the progression of the disease. [ABSTRACT FROM AUTHOR]

The aim of the present study was to examine how a person with amnestic mild cognitive impairment perceives the phenomenon of deception. Amnestic mild cognitive impairment (aMCI) usually represents the prodromal phase of Alzheimer's disease (AD), with patients showing memory impairment but with normal activities of daily living. It was expected that aMCI patients would face difficulties in the attribution and interpretation of deceptive behavior due to deficits regarding their diagnosis. The main sample of the study consisted of 76 older adults who were patients of a daycare center diagnosed with aMCI. A sample of 55 highly educated young adults was also examined in the same experiment to qualitatively compare their performance with that of aMCI patients. Participants were assigned a scenario where a hypothetical partner (either a friend or a stranger) was engaged in a task in which the partner could lie to boost their earnings at the expense of the participant. The results showed that aMCI patients, even if they understood that something was going wrong, did not invest in interpretations of potential deception and tended to avoid searching for confirmative information related to the hypothetical lie of their partner compared to highly educated young adults. It seems that aMCI patients become somehow "innocent", and this is discussed in terms of cognitive impairment and/or socioemotional selectivity. [ABSTRACT FROM AUTHOR]

Objective: To explore the relationship between age, education, sex, and ApoE4 (+) status to brain volume among a cohort with amnestic mild cognitive impairment (aMCI). Method: One hundred and twenty-three participants were stratified into Hispanic (n = 75) and White non-Hispanic (WNH, N = 48). Multiple linear regression analyses were conducted with age, education, sex, and ApoE4 status as predictor variables and left and right combined MRI volumes of the hippocampus, parahippocampus, and entorhinal cortex as dependent variables. Variations in head sizes were corrected by normalization with a total intracranial volume measurement. Results: Bonferroni-corrected results indicated that when controlling for ApoE4 status, education, and age, sex was a significant predictor of hippocampal volume among the Hispanic group (β =.000464, R 2 =.196, p <.01) and the WNH group (β =.000455, R 2 =.195, p <.05). Education (β =.000028, R 2 =.168, p <.01) and sex (β =.000261, R 2 =.168, p <.01) were significant predictors of parahippocampal volume among the Hispanic MCI group when controlling for the effects of ApoE4 status and age. One-way ANCOVAs comparing hippocampal and parahippocampal volume between males and females within groups revealed that females had significantly larger hippocampal volumes (p <.05). Hispanic females had significantly larger hippocampal (p <.001) and parahippocampal (p <.05) volume compared to males. No sex differences in parahippocampal volume were noted among WNHs. Conclusions: Biological sex, rather than ApoE4 status, was a greater predictor of hippocampal volume among Hispanic and WNH females. These findings add to the mixed literature on sex differences in dementia research and highlight continued emphasis on ethnic populations to elucidate on neurodegenerative disparities. [ABSTRACT FROM AUTHOR]

Introduction: Alzheimer's disease (AD) is the most common type of dementia. Amnestic mild cognitive impairment (aMCI), a pre-dementia stage is an important stage for early diagnosis and intervention. This study aimed to investigate the diagnostic value of qEEG, APOA-I, and APOE ɛ4 allele in aMCI and AD patients and found the correlation between qEEG (Delta + Theta)/(Alpha + Beta) ratio (DTABR) and different cognitive domains. Methods: All participants were divided into three groups: normal controls (NCs), aMCI, and AD, and all received quantitative electroencephalography (qEEG), neuropsychological scale assessment, apolipoprotein epsilon 4 (APOE ɛ4) alleles, and various blood lipid indicators. Different statistical methods were used for different data. Results: The cognitive domains except executive ability were all negatively correlated with DTABR in different brain regions while executive ability was positively correlated with DTABR in several brain regions, although without statistical significance. The consequences confirmed that the DTABR of each brain area were related to MMSE, MoCA, instantaneous memory, and the language ability (p < 0.05), and the DTABR in the occipital area was relevant to all cognitive domains (p < 0.01) except executive function (p = 0.272). Also, occipital DTABR was most correlated with language domain when tested by VFT with a moderate level (r = 0.596, p < 0.001). There were significant differences in T3, T5, and P3 DTABR between both AD and NC and aMCI and NCs. As for aMCI diagnosis, the maximum AUC was achieved when using T3 combined with APOA-I and APOE ε4 (0.855) and the maximum AUC was achieved when using T5 combined with APOA-I and APOE ε4 (0.889) for AD diagnosis. Conclusion: These findings highlight that APOA-I, APOE ɛ4, and qEEG play an important role in aMCI and AD diagnosis. During AD continuum, qEEG DTABR should be taken into consideration for the early detection of AD risk. [ABSTRACT FROM AUTHOR]

Background: Amnestic mild cognitive impairment (aMCI) is a transitional state between normal aging and dementia, and identifying early biomarkers is crucial for disease detection and intervention. Functional magnetic resonance imaging (fMRI) has the potential to identify changes in neural activity in MCI. Methods: We investigated neural activity changes in the visual network of the aMCI patients (n:20) and healthy persons (n:17) using resting‐state fMRI and visual oddball task fMRI. We used independent component analysis to identify regions of interest and compared the activity between groups using a false discovery rate correction. Results: Resting‐state fMRI revealed increased activity in the areas that have functional connectivity with the visual network, including the right superior and inferior lateral occipital cortex, the right angular gyrus and the temporo‐occipital part of the right middle temporal gyrus (p‐FDR = 0.008) and decreased activity in the bilateral thalamus and caudate nuclei, which are part of the frontoparietal network in the aMCI group (p‐FDR = 0.002). In the visual oddball task fMRI, decreased activity was found in the right frontal pole, the right frontal orbital cortex, the left superior parietal lobule, the right postcentral gyrus, the right posterior part of the supramarginal gyrus, the right superior part of the lateral occipital cortex, and the right angular gyrus in the aMCI group. Conclusion: Our results suggest the alterations in the visual network are present in aMCI patients, both during resting‐state and task‐based fMRI. These changes may represent early biomarkers of aMCI and highlight the importance of assessing visual processing in cognitive impairment. However, future studies with larger sample sizes and longitudinal designs are needed to confirm these findings. [ABSTRACT FROM AUTHOR]

INTRODUCTION: Visual search impairment is a potential cognitive marker for Alzheimer's disease (AD) and amnestic mild cognitive impairment (aMCI). The aim of this study is to compare eye movements during visual tracking in AD and aMCI patients versus healthy controls (HCs). METHODS: A prospective cohort study included 32 AD and 37 aMCI patients, and 33 HCs. Each participant was asked to look at the target object in a visual stimulus containing one target and eight distractors, and eye movements were recorded with EyeLink 1000 Plus. RESULTS: AD patients had fewer fixations and shorter target fixation duration than aMCI patients and HCs. Fixation durations were also shorter in aMCI patients compared to HCs. Also, AD patients were more fixated on distractors than HCs. DISCUSSION: Our findings revealed that visual search is impaired in the early stages of AD and even aMCI, highlighting the importance of addressing visual processes in the Alzheimer's continuum. Highlights: AD patients looked to distractors more and longer than the target compared to aMCI patients and older healthy individuals.aMCI patients had an impaired visual search pattern compared to healthy controls, just like patients with AD.The visual search task differentiated AD and aMCI patients from healthy individuals without dementia. [ABSTRACT FROM AUTHOR]

Background: Developing biomarkers for early stage AD patients is crucial. Glucose metabolism measured by 18F-FDG PET is the most common biomarker for evaluating cellular energy metabolism to diagnose AD. Arterial spin labeling (ASL) MRI can potentially provide comparable diagnostic information to 18F-FDG PET in patients with neurodegenerative disorders. However, the conclusions about the diagnostic performance of AD are still controversial between 18F-FDG PET and ASL. This study aims to compare quantitative cerebral blood flow (CBF) and glucose metabolism measured by 18F-FDG PET diagnostic values in patients with Alzheimer's disease (AD) and amnestic mild cognitive impairment (aMCI) using integrated PET/MR. Results: Analyses revealed overlapping between decreased regional rCBF and 18F-FDG PET SUVR in patients with AD compared with NC participants in the bilateral parietotemporal regions, frontal cortex, and cingulate cortex. Compared with NC participants, patients with aMCI exclusively demonstrated lower 18F-FDG PET SUVR in the bilateral temporal cortex, insula cortex, and inferior frontal cortex. Comparison of the rCBF in patients with aMCI and NC participants revealed no significant difference (P > 0.05). The ROC analysis of rCBF in the meta-ROI could diagnose patients with AD (AUC, 0.87) but not aMCI (AUC, 0.61). The specificity of diagnosing aMCI has been improved to 75.56% when combining rCBF and 18F-FDG PET SUVR. Conclusion: ASL could detect similar aberrant patterns of abnormalities compared to 18F-FDG PET in patients with AD compared with NC participants but not in aMCI. The diagnostic efficiency of 18F-FDG-PET for AD and aMCI patients remained higher to ASL. Our findings support that applying 18F-FDG PET may be preferable for diagnosing AD and aMCI. Key points: Hypometabolic brain areas are more widespread in patients with AD and aMCI than hypoperfused brain areas. 18F-FDG PET provides superior diagnostic performance over ASL for patients with AD and aMCI. After comprehensive consideration, PET alone is recommended for the diagnosis of AD and aMCI patients. [ABSTRACT FROM AUTHOR]

Background: Mild behavioral impairment (MBI) has been commonly reported in early Alzheimer's disease (AD) but rarely using biomarker-defined samples. It is also unclear whether genetic polymorphisms influence MBI in such individuals. We thus aimed to examine the association between the cognitive status of participants (amnestic mild cognitive impairment (aMCI-AD) vs cognitively normal (CN) older adults) and MBI severity. Within aMCI-AD, we further examined the association between APOE and BDNF risk genetic polymorphisms and MBI severity. Methods: We included 62 aMCI-AD participants and 50 CN older adults from the Czech Brain Aging Study. The participants underwent neurological, comprehensive neuropsychological examination, APOE and BDNF genotyping, and magnetic resonance imaging. MBI was diagnosed with the Mild Behavioral Impairment Checklist (MBI-C), and the diagnosis was based on the MBI-C total score ≥ 7. Additionally, self-report instruments for anxiety (the Beck Anxiety Inventory) and depressive symptoms (the Geriatric Depression Scale-15) were administered. The participants were stratified based on the presence of at least one risk allele in genes for APOE (i.e., e4 carriers and non-carriers) and BDNF (i.e., Met carriers and non-carriers). We used linear regressions to examine the associations. Results: MBI was present in 48.4% of the aMCI-AD individuals. Compared to the CN, aMCI-AD was associated with more affective, apathy, and impulse dyscontrol but not social inappropriateness or psychotic symptoms. Furthermore, aMCI-AD was related to more depressive but not anxiety symptoms on self-report measures. Within the aMCI-AD, there were no associations between APOE e4 and BDNF Met and MBI-C severity. However, a positive association between Met carriership and self-reported anxiety appeared. Conclusions: MBI is frequent in aMCI-AD and related to more severe affective, apathy, and impulse dyscontrol symptoms. APOE and BDNF polymorphisms were not associated with MBI severity separately; however, their combined effect warrants further investigation. [ABSTRACT FROM AUTHOR]

Patients with amnestic mild cognitive impairment (aMCI) are at a higher risk of converting to Alzheimer's disease. The aim of this study was to examine the potential use of Verbal Fluency (VF) measures as markers for predicting the conversion to dementia. At baseline, 61 aMCI, aged 65 to 80 years, underwent a comprehensive neuropsychological assessment, including phonemic (PVF) and semantic verbal fluency (SVF) tasks. After 18 months, 14 individuals with aMCI had progressed to a diagnosis of dementia. The findings revealed that aMCI-converter group had lower Mini Mental State Examination and Rey Auditory Verbal Learning Task scores than aMCI-no converter and produced fewer clusters in both VF tasks and a lower number of switches in PVF at baseline (p < 0.05). According to receiver operating characteristic curve analysis, the number of clusters in PVF had the highest predictive value (AUC = 0.80) with a threshold of 5.510 for identifying aMCI-converter at baseline. Additionally, participants with higher levels of education exhibited more clusters and switches in VF tasks (p < 0.05). These results suggest that qualitative measures of VF could serve as neuropsychological markers for predicting cognitive decline in individuals with aMCI. Furthermore, the study highlights the potential influence of the education level on cognitive performance in neuropsychological tasks. [ABSTRACT FROM AUTHOR]

The objective of this study was to find variables that showed significant associations with cognitive decline and memory loss in visual, auditory, olfactory, and balance functions. Seventysix elderly people aged 65 or older participated in the experiment, received the aforementioned functions' assessments, and underwent cognitive screening. Participants were divided into the normal cognitive (NC) and lower cognitive (LC) groups on the basis of cognitive function test scores, and the LC group was divided into the lower-MIS and normal-MIS groups on the basis of memory index scores (MISs). The LC group had less balance, hearing, and olfactory functions than the NC group, and the lower-MIS group had less visual and auditory functions than the normal-MIS group. The performance of the classification model made of variables was evaluated as the area under the receiver operating characteristic curve. The performance was shown to be good. Therefore, this study can be the basis for the development of tools for the early diagnosis of dementia and the creation of a smart environment. [ABSTRACT FROM AUTHOR]

Background: Studies have suggested that levetiracetam may help improve cognitive function in patients with epilepsy. Recently, its efficacy in improving cognitive function was reported in patients with amnestic mild cognitive impairment, schizophrenia, and Alzheimer's disease. However, the specific cognitive domains affected and the degree of evidence supporting these effects remain unclear. This systematic review and meta-analysis aimed to explore the effects of levetiracetam on different cognitive domains. Methods: This meta-analysis was conducted following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 guidelines. We defined our inclusion criteria for the systematic review as: (1) randomized placebo-controlled trials (RCTs) involving human subjects, (2) double-blinded RCTs, and (3) RCTs evaluating the quantitative differences in cognitive function between levetiracetam and placebo. We excluded: (1) non-RCT studies, (2) open-label studies, and (3) RCTs lacking cognitive assessments for either intervention. Two authors independently searched electronic databases, including PubMed, Embase, Cochrane CENTRAL, and ClinicalTrials.gov, from inception until 2 July 2023. The methodological quality of the included studies was assessed using the Cochrane risk of bias tool. Meta-analytic techniques were applied to examine the impact of levetiracetam on cognitive domain tests, with Hedges' g facilitating the comparison with placebo. The domains analyzed comprised multi-domain, executive function, processing speed, working memory, verbal memory/learning (verbal ML), visuospatial memory/learning (visuospatial ML), and language. We used odds ratios to compare the incidence of treatment-emergent adverse events between the groups, including somnolence, fatigue, dizziness, headache, irritability, and cognitive adverse events. Results: A random-effects model was utilized to perform a meta-analysis of 16 RCTs including 545 participants. Compared with a placebo, levetiracetam was associated with improved executive function [Hedges'g = − 0.390, 95% confidence interval (CI) = − 0.609 to − 0.172, p < 0.001, I2 = 24.0%]. Subgroup analysis showed that levetiracetam outperformed placebo in patients without epilepsy (Hedges' g = − 0.419, 95% CI = − 0.647 to − 0.191, p < 0.001, I2 = 26.2%). Meanwhile, low-dose levetiracetam showed a moderate favorable effect over placebo (Hedges' g = −0.544, 95% CI = − 1.085 to − 0.003, p = 0.049, I2 = 65.3%). In patients without epilepsy, low-dose levetiracetam was associated with improved executive function (Hedges'g = − 0.544, 95% CI = − 1.085 to − 0.003, p = 0.049, I2 = 65.3%). Concurrently, levetiracetam was associated with more frequent somnolence than a placebo (odds ratio = 4.654, 95% CI = 1.533 to 14.124, p = 0.007, I2 = 32.9%). Potential publication bias was observed in the executive function domain. Conclusions: This exploratory study suggests that levetiracetam might improve executive function in specific populations. However, the diversity in study populations and potential publication bias warrant caution. [ABSTRACT FROM AUTHOR]

HIV-associated neurocognitive disorders (HAND) remain prevalent despite viral suppression on antiretroviral therapy (ART). Older people with HIV (PWH) are also at risk for amnestic mild cognitive impairment (aMCI) and Alzheimer's disease (AD). β-amyloid (Aβ) and Tau biomarkers are associated with aMCI/AD, but their relationship to HAND is unclear. Given the role of extracellular vesicles (EVs) in age-related neurological disorders, we investigated soluble and EV-associated Aβ42, total Tau, NFL, GFAP, ICAM-1, VCAM-1, and CRP in relation to cognitive impairment in PWH. Plasma and CSF EVs were isolated from 184 participants (98 PWH on ART and 86 HIV− controls). Biomarkers were measured using Meso Scale Discovery assays. The median age of PWH was 53 years, and 52% were diagnosed with mild forms of HAND. PWH had increased plasma NFL (p = 0.04) and CSF Aβ42 (p = 0.0003) compared with HIV− controls but no significant difference in Tau or EV-associated forms of these markers. CSF EV Aβ42 was decreased (p = 0.0002) and CSF EV Tau/Aβ42 ratio was increased (p = 0.001) in PWH with HAND vs. no HAND, while soluble forms of these markers showed no significant differences. Decreased CSF EV Aβ42 (p < 0.0001) and an increased CSF EV Tau/Aβ42 ratio (p = 0.0003) were associated with lower neurocognitive T scores in age-adjusted models; an optimal model included both CSF EV Aβ42 and plasma NFL. Levels of soluble, but not EV-associated, ICAM-1, VCAM-1, and CRP were increased in PWH with HAND vs. no HAND (p < 0.05). These findings suggest that decreased Aβ42 and an increased Tau/Aβ42 ratio in CSF EVs are associated with cognitive impairment in older PWH, and these EV-associated biomarkers may help to distinguish aMCI/AD from HIV-related cognitive disorders in future studies. [ABSTRACT FROM AUTHOR]

The Montreal Cognitive Assessment (MoCA) rating scale is frequently used to assess cognitive impairments in amnestic mild cognitive impairment (aMCI) and Alzheimer's disease (AD). The aims of this study were to a) evaluate the construct validity of the MoCA and its subdomains or whether the MoCA can be improved by feature reduction, and b) develop a short version of the MoCA (MoCA-Brief) for the Thai population. We recruited 181 participants, namely 60 healthy controls, 61 aMCI, and 60 AD patients. The construct reliability of the original MoCA was not optimal and could be improved by deleting one subdomain (Naming) and five items, namely Clock Circle, Lion, Digit Forward, Repeat 2nd Sentence, and Place, which showed inadequate loadings on their latent vectors. To construct the MoCA-Brief, the reduced model underwent further reduction and feature selection based on model quality data of the outer models. We produced a MoCA-Brief rating scale comprising five items, namely Clock Time, Subtract 7, Fluency, Month, and Year. The first latent vector extracted from these five indicators showed adequate construct validity with an Average Variance Extracted of 0.599, composite reliability of 0.822, Cronbach's alpha of 0.832 and rho A of 0.833. The MoCA-Brief factor score showed a strong correlation with the total MoCA score (r = 0.98, p < 0.001) and shows adequate concurrent, test-retest, and inter-rater validity. The construct validity of the MoCA may be improved by deleting five items. The new MoCA-Brief rating scale deserves validation in independent samples and especially in other countries. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is currently an incurable neurodegenerative disorder and is the most common etiological cause of dementia. Consequently, it has severe burden on its patients and on their caregivers and represents a global health concern. Clinical investigations have indicated that a dysregulation of peripheral T cell immune homeostasis may be involved in the pathogenesis of AD, as well as in the early stages of AD, characterized by mild cognitive impairment (MCI). However, the characteristics and concomitant feasibility of the use of T‐cell receptor (TCR) typing for disease diagnosis remains largely unknown. We employed a high‐throughput sequencing and multidimensional bioinformatics analyses for the identification of TCR repertoires present in peripheral blood samples of 10 patients with amnestic MCI (aMCI), 10 patients with AD, and 10 healthy controls (HCs). Based on the characteristics of the TCR repertoires in the amount and diversity of combinations of V–J, the spectrum of immune defense, and differentially expressed genes (DEGs), single and specific TCR profiles were observed in the patient samples of aMCI and AD compared to profiles of HCs. In particular, the diversity of TCR clonotypes manifested a pattern of "decreased first and then increased" pattern during the progression from aMCI to AD, a pattern that was not observed in HC samples. Additionally, a total of 46 and 35 amino acid CDR3 sequences with consistent and reverse expressive abundance with diversity of TCR clonotypes were identified, respectively. Taken together, we provide novel and essential preliminary evidence demonstrating the presence of diversity of T cell repertoires from differentially expressed V–J gene segments and amino acid clonotypes using peripheral blood samples from patients with AD, aMCI, and from HC. Such findings have the potential to reveal potential mechanisms through which aMCI progresses to AD and provide a reference for the future development of immune‐related diagnoses and therapies for AD. [ABSTRACT FROM AUTHOR]

Background: Apolipoprotein E (ApoE) ε4 carriers have a higher risk of developing Alzheimer's disease (AD) and show brain atrophy and cognitive decline even before diagnosis. Objective: To predict ApoE ε4 status using gray matter volume (GMV) obtained from magnetic resonance imaging images and demographic data with machine learning (ML) methods. Methods: We recruited 74 participants (25 probable AD, 24 amnestic mild cognitive impairment, and 25 cognitively normal older people) with known ApoE genotype (22 ApoE ε4 carriers and 52 noncarriers) and scanned them with three‐dimensional (3D) T1‐weighted (T1W) and 3D double inversion recovery (DIR) sequences. We extracted GMV from regions of interest related to AD pathology and used them as features along with age and mini–mental state examination (MMSE) scores to train different ML models. We performed both receiver operating characteristic curve analysis and the prediction analysis of the ApoE ε4 carrier with different ML models. Results: The best model of ML analyses was a cubic support vector machine (SVM3) that used age, the MMSE score, and DIR GMVs at the amygdala, hippocampus, and precuneus as features (AUC =.88). This model outperformed models using T1W GMV or demographic data alone. Conclusion: Our results suggest that brain atrophy with DIR GMV and cognitive decline with aging can be useful biomarkers for predicting ApoE ε4 status and identifying individuals at risk of AD progression. [ABSTRACT FROM AUTHOR]

Lipid metabolism and oxidative stress are key mechanisms in Alzheimer's disease (AD). The link between plasma lipid metabolites and oxidative stress in AD patients is poorly understood. This study was to identify markers that distinguish AD and amnestic mild cognitive impairment (aMCI) from NC, and to reveal potential links between lipid metabolites and oxidative stress. We performed non‐targeted lipid metabolism analysis of plasma from patients with AD, aMCI, and NC using LC–MS/MS. The plasma malondialdehyde (MDA), glutathione peroxidase (GSH‐Px), and superoxide dismutase (SOD) levels were assessed. We found significant differences in lipid metabolism between patients with AD and aMCI compared to those in NC. AD severity is associated with lipid metabolites, especially TG (18:0_16:0_18:0) + NH4, TG (18:0_16:0_16:0) + NH4, LPC(16:1e)‐CH3, and PE (20:0_20:4)‐H. SPH (d16:0) + H, SPH (d18:1) + H, and SPH (d18:0) + H were high‐performance markers to distinguish AD and aMCI from NC. The AUC of three SPHs combined to predict AD was 0.990, with specificity and sensitivity as 0.949 and 1, respectively; the AUC of three SPHs combined to predict aMCI was 0.934, with specificity and sensitivity as 0.900, 0.981, respectively. Plasma MDA concentrations were higher in the AD group than in the NC group (p = 0.003), whereas plasma SOD levels were lower in the AD (p < 0.001) and aMCI (p = 0.045) groups than in NC, and GSH‐Px activity were higher in the AD group than in the aMCI group (p = 0.007). In addition, lipid metabolites and oxidative stress are widely associated. In conclusion, this study distinguished serum lipid metabolism in AD, aMCI, and NC subjects, highlighting that the three SPHs can distinguish AD and aMCI from NC. Additionally, AD patients showed elevated oxidative stress, and there are complex interactions between lipid metabolites and oxidative stress. [ABSTRACT FROM AUTHOR]

Abstract Background Visual attention‐related processes that underlie visual search behavior are impaired in both the early stages of Alzheimer's disease (AD) and amnestic mild cognitive impairment (aMCI), which is considered a risk factor for AD. Although traditional computer‐based array tasks have been used to investigate visual search, information on the visual search patterns of AD and MCI patients in real‐world environments is limited. Aim The objective of this study was to evaluate the differences in visual search behaviors among individuals with AD, aMCI, and healthy controls (HCs) in real‐world scenes. Materials and Methods A total of 92 participants were enrolled, including 28 with AD, 32 with aMCI, and 32 HCs. During the visual search task, participants were instructed to look at a single target object amid distractors, and their eye movements were recorded. Results The results indicate that patients with AD made more fixations on distractors and fewer fixations on the target, compared to patients with aMCI and HC groups. Additionally, AD patients had longer fixation durations on distractors and spent less time looking at the target than both patients with aMCI and HCs. Discussion These findings suggest that visual search behavior is impaired in patients with AD and can be distinguished from aMCI and healthy individuals. For future studies, it is important to longitudinally monitor visual search behavior in the progression from aMCI to AD. Conclusion Our study holds significance in elucidating the interplay between impairments in attention, visual processes, and other underlying cognitive processes, which contribute to the functional decline observed in individuals with AD and aMCI.

Abstract Objective To explore the functional connectivity (FC) characteristics of the episodic memory network (EMN) in amnestic mild cognitive impairment (aMCI) patients with different levels of executive function (EF). Methods This study included 76 participants from the Alzheimer's Disease Neuroimaging Initiative database, comprising 23 healthy controls (HCs) and 53 aMCI patients. Based on EF levels, aMCI patients were categorized into aMCI‐highEF and aMCI‐lowEF groups. Cognitive function scores, pathological markers (cerebrospinal fluid β‐amyloid, total tau protein, phosphorylated tau protein, AV45‐PET, and FDG‐PET), and functional magnetic resonance imaging were collected and compared among the three groups. Seed‐based FC analysis was used to examine differences in the EMN among the groups, and partial correlation analysis was employed to investigate the relationship between changes in FC and cognitive function scores as well as pathological markers. Results Compared to the aMCI‐highEF group, the aMCI‐lowEF group exhibited more severe cognitive impairment, decreased cerebral glucose metabolism, and elevated AV45 levels. Significant FC differences in the left superior temporal gyrus (STG) of the EMN were observed among the three groups. Post hoc analysis revealed that the aMCI‐lowEF group had increased FC in the left STG compared to the HCs and aMCI‐highEF groups, with statistically significant differences. Correlation analysis showed a significant negative correlation between the differences in FC in the left STG of aMCI‐highEF and aMCI‐lowEF groups and Rey Auditory Verbal Learning Test forgetting scores. Receiver operator characteristic curve analysis indicated an area under the curve of 0.741 for distinguishing between aMCI‐highEF and aMCI‐lowEF groups based on FC of left STG, with a sensitivity of 0.808 and a specificity of 0.667. Conclusion aMCI‐lowEF exhibits characteristic changes in FC within the EMN, providing theoretical support for the role of EF in mediating EMN alterations and, consequently, impacting episodic memory function.

Abstract Background Microbiota-gut-brain axis interacts with one another to regulate brain functions. However, whether the impacts of gut dysbiosis on limbic white matter (WM) tracts contribute to the neuropsychiatric symptoms (NPS) in patients with amyloid-positive amnestic mild cognitive impairment (aMCI+), have not been explored yet. This study aimed to investigate the mediation effects of limbic WM integrity on the association between gut microbiota and NPS in patients with aMCI+. Methods Twenty patients with aMCI + and 20 healthy controls (HCs) were enrolled. All subjects underwent neuropsychological assessments and their microbial compositions were characterized using 16S rRNA Miseq sequencing technique. Amyloid deposition inspected by positron emission tomography imaging and limbic WM tracts (i.e., fornix, cingulum, and uncinate fasciculus) detected by diffusion tensor imaging were additionally measured in patients with aMCI+. We employed a regression-based mediation analysis using Hayes’s PROCESS macro in this study. Results The relative abundance of genera Ruminococcus and Lactococcus was significantly decreased in patients with aMCI + versus HCs. The relative abundance of Ruminococcus was negatively correlated with affective symptom cluster in the aMCI + group. Notably, this association was mediated by WM integrity of the left cingulate gyrus. Conclusions Our findings suggest Ruminococcus as a potential target for the management of affective impairments in patients with aMCI+.

Patients with amyloid-negative amnestic mild cognitive impairment (MCI) have a conversion rate of approximately 10% to dementia within 2 years. We aimed to investigate whether brain age is an important factor in predicting conversion to dementia in patients with amyloid-negative amnestic MCI. We conducted a retrospective cohort study of patients with amyloid-negative amnestic MCI. All participants underwent detailed neuropsychological evaluation, brain magnetic resonance imaging (MRI), and [18F]-florbetaben positron emission tomography. Brain age was determined by the volumetric assessment of 12 distinct brain regions using an automatic segmentation software. During the follow-up period, 38% of the patients converted from amnestic MCI to dementia. Further, 73% of patients had a brain age greater than their actual chronological age. When defining 'survival' as the non-conversion of MCI to dementia, these groups differed significantly in survival probability (p = 0.036). The low-educated female group with a brain age greater than their actual age had the lowest survival rate among all groups. Our findings suggest that the MRI-based brain age used in this study can contribute to predicting conversion to dementia in patients with amyloid-negative amnestic MCI. [ABSTRACT FROM AUTHOR]

Background: Not only gray matter lesions (GMLs) but also white matter lesions (WMLs) can play important roles in the pathology of Alzheimer's disease (AD). The progression of cognitive impairment (CI) and behavioral and psychological symptoms of dementia (BPSD) might be caused by a concerted effect of both GML and WML. Objective: This study aimed to investigate the association between GML and WML and how they are involved in the symptoms of CI and BPSD in dementia patients by means of imaging technology. Methods: Patients in our memory clinic, who were diagnosed with AD-type dementia or amnestic mild cognitive impairment (aMCI) and had undergone both single-photon emission computed tomography (SPECT) and brain MRI, were consecutively enrolled (n = 156; 61 males and 95 females; 79.8 ± 7.4 years old). Symptoms of CI and BPSD were obtained from patients' medical records. For the analysis of GMLs and WMLs, SPECT data and MRI T1-weighted images were used, respectively. This study followed the Declaration of Helsinki, and all procedures were approved by the institutional ethics committee. Results: According to a multivariate analysis, disorientation and disturbed attention demonstrated a relationship between the precuneus and WMLs in both hemispheres. Hyperactivity in BPSD showed multiple correlations between GMLs on both sides of the frontal cortex and WMLs. Patients with aMCI presented more multiple correlations between GMLs and WMLs compared with those with AD-type dementia regarding dementia symptoms including BPSD. Conclusion: The interaction between GMLs and WMLs may vary depending on the symptoms of CI and BPSD. Hyperactivity in BPSD may be affected by the functional relationship between GMLs and WMLs in the left and right hemispheres. The correlation between GMLs and WMLs may be changing in AD-type dementia and aMCI. [ABSTRACT FROM AUTHOR]

Background: Alzheimer’s disease (AD) and amnestic mild cognitive impairment (aMCI) are characterized by abnormal functional connectivity (FC) of defaultmode network (DMN), salience network (SN), and central executive network (CEN). Static FC (sFC) and dynamic FC (dFC) combined with triple network model can better study the dynamic and static changes of brain networks, and improve its potential diagnostic value in the diagnosis of AD spectrum disorders. Methods: Dierences in sFC values and dFC variability patterns among the three brain networks of the three groups (53 AD patients, 40 aMCI patients, and 40 NCs) were computed by ANOVA using Gaussian Random Field theory (GRF) correction. The correlation between FC values (sFC values and dFC variability) in the three networks and cognitive scores (MMSE and MoCA) in AD and aMCI groups was analyzed separately. Results: Within the DMN network, there were significant dierences of sFC values in right/left medial superior frontal gyrus and dFC variability in left opercular part inferior frontal gyrus and right dorsolateral superior frontal gyrus among the three groups. Within the CEN network, there were significant dierences of sFC values in left superior parietal gyrus. Within the SN network, there were significant dierences of dFC variability in right Cerebelum_7b and left opercular part inferior frontal gyrus. In addition, there was a significant negative correlation between FC values (sFC values of CEN and dFC variability of SN) and MMSE and MoCA scores. Conclusion: It suggests that sFC, dFC combined with triple network model can be considered as potential biomarkers for AD and aMCI. [ABSTRACT FROM AUTHOR]

Background: Neuroimaging studies have demonstrated alterations in hippocampal volume and hippocampal subfields among individuals with amnestic mild cognitive impairment (aMCI). However, research on using hippocampal subfield volume modeling to differentiate aMCI from normal controls (NCs) is limited, and the relationship between hippocampal volume and overall cognitive scores remains unclear. Methods: We enrolled 50 subjects with aMCI and 44 NCs for this study. Initially, a univariate general linear model was employed to analyze differences in the volumes of hippocampal subfields. Subsequently, two sets of dimensionality reduction methods and four machine learning techniques were applied to distinguish aMCI from NCs based on hippocampal subfield volumes. Finally, we assessed the correlation between the relative volumes of hippocampal subfields and cognitive test variables (Mini-Mental State Examination (MMSE) and Montreal Cognitive Assessment Scale (MoCA)). Results: Significant volume differences were observed in several hippocampal subfields, notably in the left hippocampus. Specifically, the volumes of the hippocampal tail, subiculum, CA1, presubiculum, molecular layer, GC-ML-DG, CA3, CA4, and fimbria differed significantly between the two groups. The highest area under the curve (AUC) values for left and right hippocampal machine learning classifiers were 0.678 and 0.701, respectively. Moreover, the volumes of the left subiculum, left molecular layer, right subiculum, right CA1, right molecular layer, right GC-ML-DG, and right CA4 exhibited the strongest and most consistent correlations with MoCA scores. Conclusion: Hippocampal subfield volume may serve as a predictive marker for aMCI. These findings underscore the sensitivity of hippocampal subfield volume to overall cognitive performance. [ABSTRACT FROM AUTHOR]

Background: Amnestic mild cognitive impairment (aMCI) is considered a prodromal phase of Alzheimer's disease (AD). However, little is known about the neuropsychological characteristic at pre-MCI stage. This study aimed to investigate which neuropsychological tests could significantly predict aMCI from a seven-year longitudinal cohort study. Methods: The present study included 123 individuals with baseline cognitive normal (NC) diagnosis and a 7-year follow-up visit. All the subjects were from the China Longitudinal Aging Study (CLAS) study. Participants were divided into two groups, non-converter and converter based on whether progression to aMCI at follow-up. All participants underwent standardized comprehensive neuropsychological tests, including the mini-mental state examination (MMSE), Montreal Cognitive Assessment (MoCA), auditory verbal learning test (AVLT), the digital span test, the verbal fluency test, the visual recognition test, the WAIS picture completion task, and WAIS block design. Logistic regression analysis was used to evaluate the predictive power of baseline cognitive performance for the transformation of amnestic mild cognitive impairment. Receiver operating characteristic (ROC) curve was used to test the most sensitive test for distinguishing different groups. Results: Between the non-converter group and converter group, there were significant differences in the baseline scores of AVLT-delayed recall (AVLT-DR) (8.70 ± 3.61 vs. 6.81 ± 2.96, p = 0.001) and WAIS block design (29.86 ± 7.07 vs. 26.53 ± 8.29, p = 0.041). After controlling for gender, age, and education level, converter group showed lower baseline AVLT-DR than non-converter group, while no significant difference was found in WAIS block design. Furthermore, converter group had lower AVLT-DR score after controlling for somatic disease. The area under the curve of regression equation model was 0.738 (95%CI:0.635–0.840), with a sensitivity 83.9%, specificity of 63.6%. Conclusions: Our results proved the value of delayed recall of AVLT in predicting conversion to aMCI. Early and careful checking of the cognitive function among older people should be emphasized. [ABSTRACT FROM AUTHOR]

Background: Mild memory impairment, termed amnestic mild cognitive impairment (aMCI), is associated with rapid progression towards dementia in Parkinson's disease (PD). Studies have shown hyperactivation of hippocampal DG/CA3 subfields during an episodic memory task as a biomarker of aMCI related to Alzheimer's disease. This project investigates the feasibility of a trial to establish the efficacy of a repurposed antiepileptic drug, levetiracetam, in low doses as a putative treatment to target DG/CA3 hyperactivation and improve episodic memory deficits in aMCI in PD. Based on previous work, it is hypothesized that levetiracetam will normalize DG/CA3 overactivation in PD-aMCI participants and improve memory performance. Methods: Twenty-eight PD-aMCI participants, 28 PD participants without memory impairment (PD-nMI), and 28 healthy controls will be recruited. PD-aMCI participants will undertake a 12-week randomized, placebo-controlled, double-blind cross-over trial with a 14-day treatment of 125 mg levetiracetam or placebo twice daily, separated by a 4-week washout period. After each treatment period, participants will complete an episodic memory task designed to tax hippocampal subregion-specific function during high-resolution functional magnetic resonance imaging (fMRI). PD-nMI and healthy controls will undergo the fMRI protocol only, to compare baseline DG/CA3 subfield activity. Results: Episodic memory task performance and functional activation in the DG/CA3 subfield during the fMRI task will be primary outcome measures. Global cognition, PD severity, and adverse events will be measured as secondary outcomes. Recruitment, eligibility, and study completion rates will be explored as feasibility outcomes. Conclusions: This study, the first of its kind, will establish hippocampal subregion functional impairment and proof of concept of levetiracetam as an early therapeutic option to reduce dementia risk in PD. Trial registration: ClinicalTrials.gov, NCT04643327. Registered on 25 November 2020. [ABSTRACT FROM AUTHOR]

Background: Apolipoprotein E (APOE) is the most recognized risk gene for cognitive decline and clinical progression of late-onset Alzheimer's disease (AD); nonetheless, its association with neuropsychiatric symptoms (NPSs) remains inconclusive. Objective: To investigate the association of APOE ɛ4 with NPSs and explore nutritional status and cognition as joint mediators of this association. Methods: Between June 2021 and October 2022, patients with amnestic mild cognitive impairment (aMCI) or AD were recruited from the Chinese Imaging, Biomarkers, and Lifestyle Study. NPSs were assessed using the Neuropsychiatric Inventory, while global cognition and nutritional status were evaluated using the Mini-Mental State Examination (MMSE) and Mini-Nutritional Assessment (MNA), respectively. Simple mediation and multiple chain mediation models were developed to examine the mediating effects of the MNA and MMSE scores on the relationship between APOE ɛ4 and specific neuropsychiatric symptom. Results: Among 310 patients, 229 (73.87%) had NPSs, and 110 (35.48%) carried APOE ɛ4. Patients with APOE ɛ4 were more likely to have hallucinations (p = 0.014), apathy (p = 0.008), and aberrant motor activity (p = 0.018). MNA and MMSE scores mediated the association between APOE ɛ4 and hallucinations (17.97% and 37.13%, respectively), APOE ɛ4 and apathy (30.73% and 57.72%, respectively), and APOE ɛ4 and aberrant motor activity (17.82% and 34.24%), respectively. Chain-mediating effects of MNA and MMSE scores on the association of APOE ɛ4 with hallucinations, apathy, and aberrant motor activity after adjusting for confounding factors were 6.84%, 11.54%, and 6.19%, respectively. Conclusion: Nutritional status and cognition jointly mediate the association between APOE ɛ4 and neuropsychiatric symptoms in patients with aMCI or AD. [ABSTRACT FROM AUTHOR]

Introduction: Memory and discourse production are closely related in healthy populations. A few studies in people with amnestic mild cognitive impairment and people with dementia (PWD) suggested similar links, although empirical evidence is insufficient to inform emerging intervention design and natural language processing research. Fine-grained discourse assessment is needed to understand their complex relationship in PWD. Methods: Spoken samples from 104 PWD were elicited using personal narrative and sequential picture description and assessed using Main Concept Analysis and other content-based analytic methods. Discourse and memory performance data were analyzed in bivariate correlation and linear multiple regression models to determine the relationship between discourse production and episodic autobiographical memory and verbal short-term memory (vSTM). Results: Global coherence was a significant predictor of episodic autobiographical memory, explaining over half of the variance. Both episodic autobiographical memory and vSTM were positively correlated with global coherence and informativeness, and negatively with empty speech indices. Discussion: Coherence in personal narrative may be supported by episodic autobiographical memory and vice versa, suggesting potential mechanism of interventions targeting personhood through conversation. Indices of global coherence, informativeness, and empty speech can be used as markers of memory functions in PWD. [ABSTRACT FROM AUTHOR]