Search Results (53)

Background/Objectives: Sleep disturbances are increasingly implicated in age-related cognitive decline and may contribute to heterogeneity in cognitive and social–cognitive functioning in Mild Cognitive Impairment (MCI). Nevertheless, it remains unclear whether longitudinal actigraphy-derived sleep parameters predict social cognition, including theory of mind (ToM), across amnestic (aMCI) and non-amnestic (naMCI) MCI subtypes. This study examined longitudinal trajectories of cognitive control and ToM in individuals with aMCI and naMCI and healthy older adults, and investigated whether actigraphy-derived sleep indices prospectively predict subsequent cognitive control and higher-order social cognition across these groups. Methods: A total of 179 participants (46 healthy controls, 75 aMCI, 58 naMCI) were assessed across three waves over approximately 16–20 months. Actigraphy-derived sleep indices were obtained using wrist actigraphy. Cognitive control was assessed with Delis–Kaplan Executive Function System subtests, whereas ToM was evaluated through tasks involving non-literal language comprehension, metaphor and proverb interpretation, higher-order mentalizing, and emotion recognition. Longitudinal trajectories were examined using mixed-design ANOVAs, and prospective sleep effects were tested using longitudinal path models. Results: Both cognitive control and ToM declined over time in the MCI groups, whereas healthy controls showed relative stability. Subtype differences in cognitive control emerged primarily in higher-order planning and rule-monitoring processes, with naMCI showing greater impairment. ToM revealed a clearer and more consistent gradient (healthy controls > aMCI > naMCI), particularly in higher-order inferential tasks. Among the actigraphy-derived sleep indices, only TST prospectively predicted later ToM performance, whereas prospective associations with cognitive control were limited and inconsistent. Conclusions: Reduced sleep duration was prospectively associated with poorer subsequent performance in higher-order social cognition, independently of the executive-control measures examined. These findings highlight phenotypic heterogeneity across MCI subtypes and suggest that objectively measured sleep duration may serve as a clinically relevant longitudinal marker of social–cognitive vulnerability. Future studies are needed to determine whether interventions targeting sleep duration are associated with improved social–cognitive outcomes. Full article

Background: Amnestic mild cognitive impairment (aMCI) is considered a transitional state between normal aging and dementia, often without visible abnormalities on standard brain magnetic resonance (MR) images. The aim of the study was to analyze both microstructural and functional brain abnormalities using advanced MR techniques. Methods: The study included 27 patients with aMCI and an age-matched control group (CG) of 25 healthy subjects. All MR studies were performed on a 3T MR scanner (Philips, Ingenia) with a 32-channel head and neck coil using volumetric 3D T1 sequences, followed by a resting-state functional MRI (rs-fMRI) sequence. Volumetric analysis was performed using the Destrieux atlas to assess potential structural differences between groups. Seed-to-voxel functional connectivity analyses were conducted using the bilateral hippocampi and both anterior and posterior divisions of the parahippocampal gyri as seed regions. Results: Compared to healthy controls, reduced cortical thickness was observed in aMCI subjects in the temporal regions, frontal and orbitofrontal areas, limbic areas, parietal and sensorimotor cortices, as well as occipito-temporal regions. Additionally, significantly increased functional connectivity was observed between bilateral medial temporal lobe (MTL) regions and the right thalamus. Conclusions: Cortical thinning in various brain regions along with the increased functional connectivity between the MTL regions and the right thalamus may reflect potential compensatory mechanisms in response to initial subtle degenerative changes, emphasizing the importance of using both functional and structural imaging to detect early changes in aMCI patients. Full article

Background/Objectives: Circadian rhythm disruption is linked to cognitive decline, yet it remains unclear how behavioral and physiological rhythm markers are differently associated with cognition in amnestic mild cognitive impairment (aMCI). The primary aim of this study was to compare sleep–wake timing, rest–activity rhythm (RAR), and dim light melatonin onset (DLMO) between patients with aMCI and cognitively normal controls. Exploratory analyses further examined their associations with domain-specific cognitive performance. Methods: Eighteen aMCI patients and 21 cognitively normal controls (NC) enrolled. Cognitive function was assessed using the Korean version of the Consortium to Establish a Registry for Alzheimer’s Disease Neuropsychological Battery (CERAD-K). Participants underwent 5-day actigraphy to assess sleep–wake timing and non-parametric RAR variables, including interdaily stability (IS), intradaily variability (IV), and relative amplitude (RA). DLMO was determined from hourly salivary melatonin samples collected over five hours before sleep onset under dim-light conditions. Group comparisons of circadian markers were conducted as the primary analyses, and generalized linear models were used for exploratory analyses of associations between circadian markers and cognitive outcomes. Results: Groups did not significantly differ in sleep–wake timing, RAR parameters and DLMO. Sleep–wake timing variables and DLMO were not significantly associated with cognitive performance. Higher IS was associated with better visuospatial memory and executive function, whereas higher RA was associated with poorer verbal memory among aMCI patients. Conclusions: Although sleep–wake timing and melatonin phase did not differ between groups nor predict cognitive performance, higher daily rhythm stability was linked to better non-verbal memory and executive functioning. In contrast, high RA may relate to poorer verbal memory in aMCI, suggesting that elevated RA may not reflect true circadian robustness required for optimal cognition. Full article

Background: Frontal lobe involvement represents an important but heterogeneously expressed feature across neurodegenerative and vascular cognitive disorders. While frontal atrophy has been described in Alzheimer’s disease (AD), detailed volumetric assessment of frontal subregions across Alzheimer’s disease, amnestic mild cognitive impairment (aMCI), and vascular dementia (VaD) remains insufficiently characterized. The aim of this study was to evaluate frontal lobe and frontal subregional volumetric alterations across these diagnostic groups using automated MRI-based volumetry. Methods: This cross-sectional study included 120 participants divided into four groups: AD, VaD, aMCI, and cognitively healthy controls (n = 30 per group). All participants underwent standardized neuropsychological assessment and 3T brain MRI. Automated volumetric analysis of the frontal lobe and its subregions was performed using the Vol2Brain pipeline. Group differences in total intracranial volume–adjusted frontal volumes were assessed using analysis of covariance, controlling for age and sex, followed by Bonferroni-corrected post hoc comparisons. False discovery rate (FDR) correction was applied across subregional comparisons. Results: A significant main effect of diagnostic group was observed for total frontal lobe volume, with lower adjusted volumes in patients with AD compared with aMCI and cognitively healthy controls. After correction for multiple comparisons, only total frontal lobe volume remained statistically significant. At the nominal level, group differences were observed in several frontal subregions, predominantly involving prefrontal and orbitofrontal areas. However, these findings did not survive FDR correction and should be interpreted as exploratory. No consistent frontal volumetric pattern was observed in VaD. Receiver operating characteristic analysis demonstrated moderate discriminatory ability of total frontal lobe volume for distinguishing AD from cognitively healthy controls. Conclusions: Automated MRI-based volumetry revealed global frontal lobe reduction in Alzheimer’s disease, whereas subregional findings were exploratory after correction for multiple testing. Frontal volumetric measures did not demonstrate a characteristic pattern in VaD. Global frontal volume may provide complementary structural information within clinically define cognitive disorders. Full article

Background/Objectives: Identifying pathological distinctions among mild cognitive impairment (MCI) subtypes is important for differentiating dementia. The purpose of this study is to investigate subtype-specific structural alterations in amnestic MCI (aMCI) and non-amnestic MCI (naMCI) and evaluate their potential as imaging biomarkers for subtype classification. Methods: T1 and DTI MRI data from two independent cohorts were analyzed, including a discovery dataset (58 aMCI, 35 naMCI, and 95 NC) and a replication dataset (61 aMCI, 39 naMCI, and 67 NC). Surface-based morphometry and automated fiber quantification (AFQ) were used to examine cortical thickness and white matter microstructure. Mediation models were used to explore the links between brain structure and cognitive outcomes. A logistic regression model was applied to evaluate classification performance. Results: The aMCI exhibited right hippocampal atrophy. In the naMCI, reduced cortical thickness was observed in the right anterior cingulate cortex (rACC) and opercular inferior frontal gyrus, along with increased fractional anisotropy (FA) in the right inferior fronto-occipital fasciculus (IFOF). These alterations were linked to domain-specific cognitive deficits. Moreover, partial mediation effects of IFOF FA values were observed in the link between rACC thickness and cognitive outcomes. Furthermore, these structural alterations effectively distinguished between aMCI and naMCI, showing stable performance across independent datasets (Accuracy = 0.821, AUC = 0.904). Conclusions: Our findings reveal distinct structural alterations across MCI subtypes, providing deeper insight into the heterogeneous mechanisms of dementia and supporting the potential of imaging markers for the diagnosis of MCI subtypes. Full article

Background/Objectives: Amnestic mild cognitive impairment (aMCI) represents a transitional stage between normal aging and dementia, constituting a critical intervention window for Alzheimer’s disease (AD). As a non-invasive intervention, neurofeedback training (NFT) has demonstrated potential in ameliorating cognitive deficits and clinical symptoms in aMCI patients; however, its mechanistic effects on functional brain connectivity remain inadequately elucidated. Methods: This study employed low- and high-order functional analytical approaches to comprehensively investigate the effects of NFT on dynamic brain functional networks in aMCI. Results: Our findings revealed that following NFT, aMCI patients exhibited enhanced connectivity strength, global efficiency, and nodal characteristics within the delta band, whereas connectivity was generally attenuated in the theta, alpha, and beta bands. Dynamic network analysis indicated increased entropy in short-time windows. Cognitive assessments showed a significant short-term improvement in MoCA scores among 92.9% of participants. Conclusions: These results suggest that NFT effectively remodels brain network activity patterns in aMCI patients, thereby facilitating cognitive improvement. These findings provide preliminary insights into the brain network mechanisms underlying NFT-mediated cognitive enhancement in aMCI. Full article

Background/Objectives: Sleep disturbances are increasingly recognized as dynamic biomarkers of cognitive decline; however, longitudinal and multimodal studies directly comparing amnestic (aMCI) and non-amnestic mild cognitive impairment (naMCI) remain limited. Methods: In a three-wave longitudinal design (~24 months), 179 older adults (46 healthy controls [HCs], 75 aMCI, 58 naMCI; mean age = 70.2 years, education = 12.3 years) were assessed with actigraphy and validated questionnaires (Athens Insomnia Scale, Pittsburgh Sleep Quality Index, STOP-BANG). Mixed ANOVAs and structural equation modeling tested group, time and mediation effects. Results: Subjective measures revealed a progressive worsening of insomnia and sleep quality in MCI, with naMCI exhibiting the steepest decline, while HCs remained largely stable. STOP-BANG trajectories indicated increasing sleep-disordered breathing risk across groups, most pronounced in naMCI. Objective indices corroborated these findings: total sleep time (TST) and sleep efficiency (SE) declined significantly in MCI, especially naMCI, while wake after sleep onset (WASO) increased longitudinally. By the third assessment, naMCI consistently showed the shortest TST and lowest SE. Mediation analyses identified SE as a central predictor of future subjective complaints, with indirect contributions from WASO and PSQI. Conclusions: Longitudinal trajectories, rather than cross-sectional comparisons, best differentiated MCI subtypes. NaMCI demonstrated the most aggressive deterioration in both objective and subjective sleep measures, highlighting its heightened vulnerability to sleep dysregulation and potential relevance for neurodegenerative progression. Clinically, sustained monitoring of SE, TST, and sleep-disordered breathing risk may provide prognostic value and inform early, targeted interventions in at-risk populations. Full article

Background: This study examined the impact of amnestic mild cognitive impairment (aMCI) on dynamic changes in cerebrocortical oxygen saturation (ScO₂) and O₂ extraction during acute, moderately intense, normobaric hypoxia and reoxygenation in elderly adults (71 ± 6 years old). Methods: Thirty-two aMCI and thirty-five control subjects participated. Inspired and expired fractions of O₂ and CO₂ (mass spectrometry), arterial O₂ saturation (SaO₂) and prefrontal ScO₂ (near-infrared spectroscopy), heart rate, tidal volume and breathing frequency were monitored while subjects breathed hypoxic air (fractional inspired O₂ 0.10) for 3–5 min (aMCI: 4.5 ± 0.7 min; control: 4.5 ± 0.6 min) and recovered on room air. Values at the pre-hypoxia baseline, the first and last min of hypoxia and the first min of recovery were compared within and between groups using two-factor ANOVA. Results: Despite a similar baseline SaO₂ in aMCI (97.2 ± 1.6%) and control (97.3 ± 1.3%) subjects, prefrontal ScO₂ was lower (p < 0.05) in the aMCI subjects in both the left (67.0 ± 1.7% vs. 69.6 ± 4.5%) and right (66.8 ± 4.6% vs. 69.4 ± 4.1%) hemispheres. Hypoxia similarly decreased SaO₂ and ScO₂ in both groups (last min hypoxia, aMCI vs. control subjects: SaO₂ 76.6 ± 5.3% vs. 77.4 ± 6.1%, left prefrontal ScO₂ 54.0 ± 4.9% vs. 55.2 ± 6.4%, right prefrontal ScO₂ 56.0 ± 4.3% vs. 58.2 ± 4.4%). Upon the resumption of room-air breathing, ScO₂ recovered at similar rates in aMCI and control subjects. Conclusions: Although it produced a greater deoxygenation in the left vs. the right prefrontal cortex, acute, normobaric, moderate hypoxia was well tolerated by elderly adults, even those with aMCI. Dynamic changes in cerebral oxygenation during hypoxia and recovery were unaltered by aMCI. Brief, moderate hypoxia does not impose more intense cerebrocortical oxygen depletion in elderly adults with aMCI, despite pre-hypoxic cerebrocortical oxygenation below that of their non-MCI counterparts. Full article

Background/Objectives: Rest–activity rhythm (RAR) disturbances can contribute to aging and dementia via metabolic dysregulation. Hydroxycholesterol (OH) is thought to mediate the link between hypercholesterolemia and neurodegeneration. This study compared sleep and RAR parameters between amnestic mild cognitive impairment (aMCI) patients and normal controls (NCs), and examined their associations with plasma 27-OH levels, reflecting peripheral cholesterol metabolism. Methods In total, 18 aMCI patients (76.6 ± 6.1 years) and 21 NCs (70.4 ± 6.7 years) underwent five-day actigraphy and dim light melatonin onset assessment. Plasma 27-OH levels were measured via high-performance liquid chromatography-mass spectrometry. Generalized linear models (GLMs) were used to analyze the relationships between sleep, RAR, and 27-OH levels. Results: The aMCI group had significantly lower 27-OH levels and 27-OH/total cholesterol ratios (p < 0.05). GLM revealed that longer sleep onset latency (SOL) was associated with higher 27-OH levels in aMCI, distinguishing them from NCs. Additionally, in aMCI, longer SOL, lower sleep efficiency (SE), and higher fragmentation index (FI) were associated with an increased 27-OH/total cholesterol ratio (p < 0.05). Higher relative amplitude of RAR was linked to lower 27-OH levels across groups (p < 0.01), but RAR parameters showed no significant association with the 27-OH/total cholesterol ratio. Sleep disturbances, including prolonged SOL, reduced SE, and increased FI, were associated with altered peripheral cholesterol oxygenation in aMCI. Conclusions: Greater RAR amplitude correlated with lower 27-OH levels, regardless of cognitive status. These findings suggest that peripheral cholesterol oxygenation in aMCI is related to both sleep disturbances and circadian rhythm dysregulation, highlighting their role in cholesterol metabolism and neurodegeneration. Full article

Background: Physical activity (PA) has been shown to prevent Alzheimer’s disease (AD) by reducing amyloid accumulation, lowering inflammatory factors, and increasing hippocampal grey matter. While high lifetime PA engagement is associated with a reduced risk of AD, the relationship between specific types of PA and early-stage AD remains unclear. As AD primarily affects cognitive function before physical capabilities, PA engagement—an important factor in PA—needs further investigation. Objectives: This study explores the potential association between current participation in open-skill sports (OSSs) versus closed-skill sports (CSSs) and early-stage AD. Methods: The sample (N = 128) included a cognitively healthy (HC, n = 78) group and an Alzheimer’s disease (AD) group, combining amnestic mild cognitive impairment due to AD patients (n = 22) and early-stage Alzheimer’s dementia patients (n = 28), reflecting the continuum of progression from aMCI to dAD (n = 50). PA was assessed with the Physical Activity Scale for the Elderly questionnaire, specifically focusing on PA within the last seven days. The statistical analyses included Mann–Whitney U tests and backwards stepwise logistic regression models. Results: Key predictors of group classification (AD vs. NC) included sex, high frequency of PA, and high duration of PA, each for the last seven days. Participation in OSS was significantly associated with medium PA frequency, high PA duration, both within the last seven days, and age, but not with diagnostic status. No statistically significant differences in PA levels (OSSs or CSSs) executed within the last seven days were observed between the AD and HC groups. Conclusions: Participation in OSSs or CSSs within the last seven days was only a marginally significant predictor of AD vs. HC status, and a diagnosis of AD was not predictive of OSS participation within the last seven days. Given the protective role of PA in AD, future research should aim to identify specific PA types that effectively support cognitive health in older adults with early cognitive decline. Full article

Background/Objectives: The interplay between the gut microbiome (GMB) and neurovascular function in neurodegeneration is unclear. The goal of this proof-of-concept, cross-sectional study is to identify relationships between the GMB, neurovascular functioning, and cognition in amnestic mild cognitive impairment (aMCI), the prototypical prodromal symptomatic stage of Alzheimer’s disease (AD). Methods: Participants (n = 14 aMCI and 10 controls) provided fecal samples for GMB sequencing (16S and shotgun metagenomics), underwent MRI, and completed cognitive testing. Cerebral vascular reactivity (CVR), cerebral blood flow (CBF), and arterial transit time (ATT) were assessed. Statistical analyses evaluated the relationships between discriminatory taxa, cerebrovascular metrics, and cognition. Results: Sequencing revealed differentially abundant bacterial and viral taxa distinguishing aMCI from controls. Spearman correlations revealed that bacteria known to induce inflammation were negatively associated with CVR, CBF, and cognition, and positively associated with ATT. A reciprocal pattern emerged for the association of taxa with gut health. Conclusions: Our results provide preliminary evidence that pro-inflammatory gut bacterial and viral taxa are associated with neurovascular dysfunction and cognitive impairment in prodromal AD, highlighting their potential as candidate microbial biomarkers and targets for early intervention. Full article

In amnestic mild cognitive impairment (aMCI), neuroinflammation evolves during disease progression, affecting microglial function and potentially accelerating the pathological process. Currently, no effective treatment exists, leading to explorations of various symptomatic approaches, though few target the underlying physiological mechanisms. Modulating inflammatory processes may be critical in slowing disease progression. Cognitive stimulation (CS) and transcranial direct current stimulation (tDCS) applied to the left dorsolateral prefrontal cortex (l-DLPFC) show promise, but the results are heterogeneous. Thus, a randomized, double-blind, placebo-controlled clinical trial is currently underway. The first-stage results were examined after three weeks of intervention in two groups: active tDCS combined with CS and sham tDCS combined with CS. Twenty-two participants underwent two assessments: T0 (baseline) and T1 (after 15 sessions of tDCS, active or sham, and 9 sessions of CS). The results demonstrated that CS improved cognition, increased brain-derived neurotrophic factor (BDNF) levels, and reduced peripheral proinflammatory cytokine levels (interleukin IL-6 and chemokine CX3CL1) in serum. This decrease in IL-6 may promote microglial proliferation and survival as a modulatory effect response, while the increase in BDNF might suggest a regulatory mechanism in microglia–neuron interaction responses. However, tDCS did not enhance the cognitive or modulatory effects of CS, suggesting that longer interventions might be required to achieve substantial benefits. Full article

Background: There is a paucity of evidence on the association between genetic propensity for hippocampal atrophy with cognitive outcomes. Therefore, we examined the relationship of the polygenic risk score for hippocampal atrophy (PRShp) with the incidence of amnestic mild cognitive impairment (aMCI) and Alzheimer’s disease (AD) as well as the rates of cognitive decline. Methods: Participants were drawn from the population-based HELIAD cohort. Comprehensive neuropsychological assessments were performed at baseline and at follow-up. PRShp was derived from the summary statistics of a large genome-wide association study for hippocampal volume. Cox proportional hazards models as well as generalized estimating equations (GEEs) were used to evaluate the association of PRShp with the combined incidence of aMCI/AD and cognitive changes over time, respectively. All models were adjusted for age, sex, education, and apolipoprotein E (APOE) genotype. Results: Our analysis included 618 older adults, among whom 73 developed aMCI/AD after an average follow-up of 2.96 ± 0.8 years. Each additional SD of PRShp elevated the relative hazard for incident aMCI/AD by 46%. Participants at the top quartile of PRShp had an almost three times higher risk of converting to aMCI/AD compared to the lowest quartile group. Higher PRShp scores were also linked to steeper global cognitive and memory decline. The impact of PRShp was greater among women and younger adults. Conclusions: Our findings support the association of PRShp with aMCI/AD incidence and with global cognitive and memory decline over time. The PRS association was sex- and age-dependent, suggesting that these factors should be considered in genetic modelling for AD. Full article

Background/Objectives: The study examined the relationships between specific Theory-of-Mind (ToM) dimensions, cognitive planning, and sleep duration in aging adults. Methods: The sample included 179 participants, comprising 46 cognitively healthy individuals, 75 diagnosed with amnestic Mild Cognitive Impairment (aMCI), and 58 with non-amnestic (naMCI). The mean age of the participants was 70.23 years (SD = 4.74), with a mean educational attainment of 12.35 years (SD = 3.22) and gender distribution of 53 men and 126 women. ToM assessment included tasks measuring the understanding and interpretation of non-literal speech, proverbs and metaphors, as well as an emotion-recognition test. For cognitive planning, a Tower Test was utilized. Sleep duration was measured using actigraphy. Results: We identified significant differences in various ToM tasks’ performance between the groups, particularly in non-literal speech tasks and third-order ToM stories. The HC group consistently outperformed both MCI groups in these tasks, with aMCI showing higher performance than naMCI. Mediation analysis applied to examine potential direct and indirect effects of sleep duration on ToM tasks indicated that total sleep time had significant indirect effects through cognitive planning—mainly as rule violation total score—on specific ToM aspects. Hence, besides the effects of MCI pathologies and especially of naMCI, sleep duration seems also to be associated with ToM performance in aging via specific executive functioning decrements. Conclusions: The findings underscore the social implications of ToM deficits due to MCI and/or sleep duration decrease, particularly in naMCI older adults, as they can seriously impair their social interactions. Targeted interventions could improve emotional understanding, communication, and overall quality of life. Full article

Background: Alzheimer’s disease (AD) dementia and mild cognitive impairment (MCI) are currently underdiagnosed in the community, and early detection of cognitive deficits is crucial for timely intervention. FACEmemory^®, the first completely self-administered online memory test with voice recognition, has been launched as an accessible tool to detect such deficits. This study aims to investigate the neuropsychological associations between FACEmemory subscores and cognitive composites derived from traditional paper-and-pencil neuropsychological tests and to develop an optimal algorithm using FACEmemory data and demographics to discriminate cognitively healthy (CH) individuals from those with MCI. Methods: A total of 669 participants (266 CH, 206 non-amnestic MCI [naMCI], and 197 amnestic MCI [aMCI]) were included. Multiple linear regression analyses were conducted using a cognitive composite as the dependent variable and FACEmemory subscores and demographic data (age, sex, and schooling) as independent variables. Machine learning models were compared to identify an optimal algorithm for distinguishing between CH and MCI (whole MCI, aMCI, and naMCI). Results: Multiple regression analyses showed associations between FACEmemory scores and the domains of memory (ρ = 0.67), executive functions (ρ = 0.63), visuospatial/visuoperceptual abilities (ρ = 0.55), language (ρ = 0.43), praxis (ρ = 0.52), and attention (ρ = 0.31). An optimal algorithm distinguished between CH and aMCI, achieving a FACEmemory cutoff score of 44.5, with sensitivity and specificity values of 0.81 and 0.72, respectively. Conclusions: FACEmemory is a promising online tool for identifying early cognitive impairment, particularly aMCI. It may contribute to addressing the underdiagnosis of MCI and dementia in the community and in promoting preventive strategies. Full article