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This study explored the effect of different dual-task (DT) training programs on DT interference in adults with intellectual disability. Center-of-pressure (CoP) mean velocity in single-task (ST) and cognitive-DT conditions and the Timed Up-and-Go Test (TUGT) during ST, cognitive-DT, and motor-DT conditions were assessed before and after intervention in a cognitive–motor training group, a motor–motor training group, and a control group. Before training, CoP mean velocity and TUGT time increased (p <.001) in DT compared with the ST condition. After training, the CoP mean velocity values remained unchanged (p =.07) in DT compared with the ST condition among the cognitive–motor training group. Furthermore, compared with the ST condition, no increase (p = 1) was reported in the TUGT time during the cognitive-DT condition for the cognitive–motor training group and during the motor-DT for the motor–motor training group (p =.12). The effect of DT training on DT interference depends on the training modality. [ABSTRACT FROM AUTHOR]

The aim of this systematic review, meta-analysis, and meta-regression was to examine the effects of virtual reality–based training on global cognition and executive function compared with conventional training or information-based treatment in older adults, regardless of cognitive level. A systematic literature search was conducted using four databases. A total of 31 randomized controlled trials were identified. Pooled effect sizes were calculated, the risk of bias was assessed, and evidence was graded. The primary analyses showed a small but statistically significant effect of virtual reality–based training compared with control on global cognition (Hedges' g 0.42, 95% confidence interval [0.17, 0.68], I2 = 70.1%, n = 876, 20 randomized controlled trials, low evidence) and executive function (Hedges' g 0.35, 95% confidence interval [0.06, 0.65], I2 = 68.4%, n = 810, 16 randomized controlled trials, very low evidence). Meta-regression yielded inconclusive results. Virtual reality–based training may be more effective than control in improving cognition in older adults; however, more high-quality studies are needed. [ABSTRACT FROM AUTHOR]

Early stages of Alzheimer's disease (AD) are associated with volume reductions in specific subregions of the medial temporal lobe (MTL). Using a manual segmentation method-the Olsen-Amaral-Palombo (OAP) protocol-previous work in healthy older adults showed that reductions in grey matter volumes in MTL subregions were associated with lower scores on the Montreal Cognitive Assessment (MoCA), suggesting atrophy may occur prior to diagnosis of mild cognitive impairment, a condition that often progresses to AD. However, current "gold standard" manual segmentation methods are labour intensive and time consuming. Here, we examined the utility of Automatic Segmentation of Hippocampal Subfields (ASHS) to detect volumetric differences in MTL subregions of healthy older adults who varied in cognitive status as determined by the MoCA. We trained ASHS on the OAP protocol to create the ASHS-OAP atlas and then examined how well automated segmentation replicated manual segmentation. Volumetric measures obtained from the ASHS-OAP atlas were also contrasted against those from the ASHS-PMC atlas, a widely used atlas provided by the ASHS team. The pattern of volumetric results was similar between the ASHS-OAP atlas and manual segmentation for anterolateral entorhinal cortex and perirhinal cortex, suggesting that ASHS-OAP is a viable alternative to current manual segmentation methods for detecting group differences based on cognitive status. Although ASHS-OAP and ASHS-PMC produced varying volumes for most regions of interest, they both identified early signs of neurodegeneration in CA2/CA3/DG and identified marginal differences in entorhinal cortex. Our findings highlight the utility of automated segmentation methods but still underscore the need for a unified and harmonized MTL segmentation atlas.

Study objectivesInsomnia symptoms are prevalent along the trajectory of Alzheimer's disease (AD), but the neurobiological underpinning of their interaction is poorly understood. Here, we assessed structural and functional brain measures within and between the default mode network (DMN), salience network, and central executive network (CEN).MethodsWe selected 320 participants from the ADNI database and divided them by their diagnosis: cognitively normal (CN), Mild Cognitive Impairment (MCI), and AD, with and without self-reported insomnia symptoms. We measured the gray matter volume (GMV), structural covariance (SC), degrees centrality (DC), and functional connectivity (FC), testing the effect and interaction of insomnia symptoms and diagnosis on each index. Subsequently, we performed a within-group linear regression across each network and ROI. Finally, we correlated observed abnormalities with changes in cognitive and affective scores.ResultsInsomnia symptoms were associated with FC alterations across all groups. The AD group also demonstrated an interaction between insomnia and diagnosis. Within-group analyses revealed that in CN and MCI, insomnia symptoms were characterized by within-network hyperconnectivity, while in AD, within- and between-network hypoconnectivity was ubiquitous. SC and GMV alterations were nonsignificant in the presence of insomnia symptoms, and DC indices only showed network-level alterations in the CEN of AD individuals. Abnormal FC within and between DMN and CEN hubs was additionally associated with reduced cognitive function across all groups, and increased depressive symptoms in AD.ConclusionsWe conclude that patients with clinical AD present with a unique pattern of insomnia-related functional alterations, highlighting the profound interaction between both conditions.

INTRODUCTION: Speech-based testing shows promise for sensitive and scalable objective screening for Alzheimers disease (AD), but research to date offers limited evidence of generalizability. METHODS: Data were taken from the AMYPRED (Amyloid Prediction in Early Stage Alzheimers Disease from Acoustic and Linguistic Patterns of Speech) studies (N = 101, N = 46 mild cognitive impairment [MCI]) and Alzheimers Disease Neuroimaging Initiative 4 (ADNI4) remote digital (N = 426, N = 58 self-reported MCI, mild AD or dementia) and in-clinic (N = 57, N = 13 MCI) cohorts, in which participants provided audio-recorded responses to automated remote story recall tasks in the Storyteller test battery. Text similarity, lexical, temporal, and acoustic speech feature sets were extracted. Models predicting early AD were developed in AMYPRED and tested out of sample in the demographically more diverse cohorts in ADNI4 (> 33% from historically underrepresented populations). RESULTS: Speech models generalized well to unseen data in ADNI4 remote and in-clinic cohorts. The best-performing models evaluated text-based metrics (text similarity, lexical features: area under the curve 0.71-0.84 across cohorts). DISCUSSION: Speech-based predictions of early AD from Storyteller generalize across diverse samples. HIGHLIGHTS: The Storyteller speech-based test is an objective digital prescreener for Alzheimers Disease Neuroimaging Initiative 4 (ADNI4). Speech-based models predictive of Alzheimers disease (AD) were developed in the AMYPRED (Amyloid Prediction in Early Stage Alzheimers Disease from Acoustic and Linguistic Patterns of Speech) sample (N = 101). Models were tested out of sample in ADNI4 in-clinic (N = 57) and remote (N = 426) cohorts. Models showed good generalization out of sample. Models evaluating text matching and lexical features were most predictive of early AD.

BACKGROUND: About one-third of older adults aged 65 years and older often have mild cognitive impairment or dementia. Acoustic and psycho-linguistic features derived from conversation may be of great diagnostic value because speech involves verbal memory and cognitive and neuromuscular processes. The relative decline in these processes, however, may not be linear and remains understudied. OBJECTIVE: This study aims to establish associations between cognitive abilities and various attributes of speech and natural language production. To date, the majority of research has been cross-sectional, relying mostly on data from structured interactions and restricted to textual versus acoustic analyses. METHODS: In a sample of 71 older (mean age 83.3, SD 7.0 years) community-dwelling adults who completed qualitative interviews and cognitive testing, we investigated the performance of both acoustic and psycholinguistic features associated with cognitive deficits contemporaneously and at a 1-2 years follow up (mean follow-up time 512.3, SD 84.5 days). RESULTS: Combined acoustic and psycholinguistic features achieved high performance (F1-scores 0.73-0.86) and sensitivity (up to 0.90) in estimating cognitive deficits across multiple domains. Performance remained high when acoustic and psycholinguistic features were used to predict follow-up cognitive performance. The psycholinguistic features that were most successful at classifying high cognitive impairment reflected vocabulary richness, the quantity of speech produced, and the fragmentation of speech, whereas the analogous top-ranked acoustic features reflected breathing and nonverbal vocalizations such as giggles or laughter. CONCLUSIONS: These results suggest that both acoustic and psycholinguistic features extracted from qualitative interviews may be reliable markers of cognitive deficits in late life.

Both navigation abilities and gait can be affected by the atrophy in the medial temporal cortex. This study aimed to determine whether navigation abilities could differentiate seniors with and without medial temporal lobe atrophy who complained about their cognitive status. The participants, classified to either the medial temporal atrophy group (n = 23) or the control group (n = 22) underwent neuropsychological assessment and performed a spatial navigation task while their gait parameters were recorded. The study showed no significant differences between the two groups in memory, fluency, and semantic knowledge or typical measures of navigating abilities. However, gait parameters, particularly the propulsion index during certain phases of the navigation task, distinguished between seniors with and without medial temporal lobe lesions. These findings suggest that the gait parameters in the navigation task may be a valuable tool for identifying seniors with cognitive complaints and subtle medial temporal atrophy. [ABSTRACT FROM AUTHOR]

This pragmatic review synthesises the current understanding of prodromal dementia with Lewy bodies (pDLB) and prodromal Alzheimers disease (pAD), including clinical presentations, neuropsychological profiles, neuropsychiatric symptoms, biomarkers, and indications for disease management. The core clinical features of dementia with Lewy bodies (DLB)-parkinsonism, complex visual hallucinations, cognitive fluctuations, and REM sleep behaviour disorder are common prodromal symptoms. Supportive clinical features of pDLB include severe neuroleptic sensitivity, as well as autonomic and neuropsychiatric symptoms. The neuropsychological profile in mild cognitive impairment attributable to Lewy body pathology (MCI-LB) tends to include impairment in visuospatial skills and executive functioning, distinguishing it from MCI due to AD, which typically presents with impairment in memory. pDLB may present with cognitive impairment, psychiatric symptoms, and/or recurrent episodes of delirium, indicating that it is not necessarily synonymous with MCI-LB. Imaging, fluid and other biomarkers may play a crucial role in differentiating pDLB from pAD. The current MCI-LB criteria recognise low dopamine transporter uptake using positron emission tomography or single photon emission computed tomography (SPECT), loss of REM atonia on polysomnography, and sympathetic cardiac denervation using meta-iodobenzylguanidine SPECT as indicative biomarkers with slowing of dominant frequency on EEG among others as supportive biomarkers. This review also highlights the emergence of fluid and skin-based biomarkers. There is little research evidence for the treatment of pDLB, but pharmacological and non-pharmacological treatments for DLB may be discussed with patients. Non-pharmacological interventions such as diet, exercise, and cognitive stimulation may provide benefit, while evaluation and management of contributing factors like medications and sleep disturbances are vital. There is a need to expand research across diverse patient populations to address existing disparities in clinical trial participation. In conclusion, an early and accurate diagnosis of pDLB or pAD presents an opportunity for tailored interventions, improved healthcare outcomes, and enhanced quality of life for patients and care partners.

IntroductionData-driven neuropsychological methods can identify mild cognitive impairment (MCI) subtypes with stronger associations to dementia risk factors than conventional diagnostic methods.MethodsCluster analysis used neuropsychological data from participants without dementia (mean age = 71.6 years) in the National Alzheimer's Coordinating Center (NACC) Uniform Data Set (n = 26,255) and the "normal cognition" subsample (n = 16,005). Survival analyses examined MCI or dementia progression.ResultsFive clusters were identified: "Optimal" cognitively normal (oCN; 13.2%), "Typical" CN (tCN; 28.0%), Amnestic MCI (aMCI; 25.3%), Mixed MCI-Mild (mMCI-Mild; 20.4%), and Mixed MCI-Severe (mMCI-Severe; 13.0%). Progression to dementia differed across clusters (oCN

Sex disparities in serum bile acid (BA) levels and Alzheimer's disease (AD) prevalence have been established. However, the precise link between changes in serum BAs and AD development remains elusive. Here, authors quantitatively determined 33 serum BAs and 58 BA features in 4 219 samples collected from 1 180 participants from the Alzheimer's Disease Neuroimaging Initiative. The findings revealed that these BA features exhibited significant correlations with clinical stages, encompassing cognitively normal (CN), early and late mild cognitive impairment, and AD, as well as cognitive performance. Importantly, these associations are more pronounced in men than women. Among participants with progressive disease stages (n = 660), BAs underwent early changes in men, occurring before AD. By incorporating BA features into diagnostic and predictive models, positive enhancements are achieved for all models. The area under the receiver operating characteristic curve improved from 0.78 to 0.91 for men and from 0.76 to 0.83 for women for the differentiation of CN and AD. Additionally, the key findings are validated in a subset of participants (n = 578) with cerebrospinal fluid amyloid-beta and tau levels. These findings underscore the role of BAs in AD progression, offering potential improvements in the accuracy of AD prediction.

IntroductionReproductive health history may contribute to cognitive aging and risk for Alzheimer's disease, but this is understudied among Hispanic/Latina women.MethodsParticipants included 2126 Hispanic/Latina postmenopausal women (44 to 75 years) from the Study of Latinos-Investigation of Neurocognitive Aging. Survey linear regressions separately modeled the associations between reproductive health measures (age at menarche, history of oral contraceptive use, number of pregnancies, number of live births, age at menopause, female hormone use at Visit 1, and reproductive span) with cognitive outcomes at Visit 2 (performance, 7-year change, and mild cognitive impairment [MCI] prevalence).ResultsYounger age at menarche, oral contraceptive use, lower pregnancies, lower live births, and older age at menopause were associated with better cognitive performance. Older age at menarche was protective against cognitive change. Hormone use was linked to lower MCI prevalence.DiscussionSeveral aspects of reproductive health appear to impact cognitive aging among Hispanic/Latina women.

Leisure walking has been found to be positively associated with increased mental health. However, the benefits of leisure walking of varying intensities on the mental health of older adults (>50 years old) with mild cognitive impairment are not clear. This study employed 2020 Health and Retirement Study data to investigate the benefits of leisure walking for three groups based on levels of participation (low, mid, and high). We conducted a multivariate analysis of covariance (n = 834) to examine the group mean differences (MDs). The respondents in the high and mid groups presented higher life satisfaction and happiness than those in the low group. The high group had lower loneliness and stress scores than those in the low and mid groups. These findings indicate that older adults with mild cognitive impairment gained more mental health benefits and life satisfaction through moderate and vigorous leisure walking than through light leisure walking. [ABSTRACT FROM AUTHOR]

Inflammation is an important factor in Alzheimer's disease (AD). An NMR measurement in plasma, glycoprotein acetyls (GlycA), captures the overall level of protein production and glycosylation implicated in systemic inflammation. With its additional advantage of reducing biological variability, GlycA might be useful in monitoring the relationship between peripheral inflammation and brain changes relevant to AD. However, the associations between GlycA and these brain changes have not been fully evaluated. Here, we performed Spearman's correlation analyses to evaluate these associations cross-sectionally and determined whether GlycA can inform AD-relevant longitudinal measurements among participants in the Alzheimer's Disease Neuroimaging Initiative (n = 1506), with additional linear models and stratification analyses to evaluate the influences of sex or diagnosis status and confirm findings from Spearman's correlation analyses. We found that GlycA was elevated in AD patients compared to cognitively normal participants. GlycA correlated negatively with multiple concurrent regional brain volumes in females diagnosed with late mild cognitive impairment (LMCI) or AD. Baseline GlycA level was associated with executive function decline at 3-9 year follow-up in participants diagnosed with LMCI at baseline, with similar but not identical trends observed in the future decline of memory and entorhinal cortex volume. Results here indicated that GlycA is an inflammatory biomarker relevant to AD pathogenesis and that the stage of LMCI might be relevant to inflammation-related intervention.

The aging population of the world is increasing at an unprecedented rate which is expected to lead to a corresponding unparalleled increase in age related diseases. Of particular concern are the large number of older adults expected to develop Alzheimers disease (AD), which will require extraordinary local, national and worldwide healthcare resources. In this context, innovative interventions are needed urgently to delay AD onset and thereby give our healthcare systems time to prepare and provide meaningful care to our aging populations. This focused review discusses the crucial role of frontal gamma oscillations as a therapeutic target to delay or ameliorate cognitive decline in AD. Frontal gamma oscillations, including from prefrontal cortical areas, serve as a biomarker for working memory and other cognitive functions, and their impairment is observed before clinical symptoms manifest. This review evaluates evidence from animal models and human subjects to highlight the correlation between gamma wave abnormalities and cognitive deterioration. Furthermore, the review summarizes 11 clinical studies using neuromodulation techniques designed to stimulate gamma oscillations in mild cognitive impairment (MCI) and AD patients, including transcranial electrical stimulation, transcranial magnetic stimulation, and rhythmic sensory stimulation. These interventions have shown promise in mitigating early-stage cognitive decline, as evidenced by improved performance on memory tests, increased gamma oscillatory responses, and some have even shown reduced brain atrophy. These early studies suggest that treatments that strengthen frontal gamma oscillatory responses through neuromodulation are a promising approach to delay cognitive decline, that may serve as an adjunct to other therapies or as a standalone treatment in some populations.

BackgroundHypertension can have deleterious effects on cognitive function; however, few studies have examined its effects on cognition among Hispanics/Latinos.ObjectiveTo assess associations between hypertension status with 1) change in cognitive performance, and 2) having mild cognitive impairment (MCI) among diverse Hispanics/Latinos.MethodsThis population-based, prospective cohort, multisite study included Hispanic/Latino adults aged 45 to 72 years in enrolled in the Hispanic Community Health Study/Study of Latinos at Visit 1 (2008-2011; mean age of 63.40±8.24 years), and the Study of Latinos-Investigation of Neurocognitive Aging at Visit 2 (2016-2018), with a mean follow-up duration of 7 years (n = 6,173). Hypertension status was assessed at both visits: normotension (no hypertension), incident hypertension (only at Visit 2), and persistent hypertension (at both visits). We examined change in cognitive performance and having MCI (only assessed at Visit 2) relative to hypertension status and adjusted for demographics and cardiovascular disease risk factors.ResultsCompared to normotension, persistent hypertension was associated with significantly increased decline in verbal fluency (β= -0.08; CI = [-0.16;-0.01]; p

BACKGROUND: Unsupervised online cognitive assessments have demonstrated promise as an efficient and scalable approach for evaluating cognition in aging, and Alzheimers disease and related dementias. OBJECTIVES: The aim of this study was to evaluate the feasibility, usability, and construct validity of the Paired Associates Learning task from the Cambridge Neuropsychological Test Automated Battery® in adults enrolled in the Brain Health Registry. DESIGN, SETTING, PARTICIPANTS, MEASUREMENTS: The Paired Associates Learning task was administered to Brain Health Registry participants in a remote, unsupervised, online setting. In this cross-sectional analysis, we 1) evaluated construct validity by analyzing associations between Paired Associates Learning performance and additional participant registry data, including demographics, self- and study partner-reported subjective cognitive change (Everyday Cognition scale), self-reported memory concern, and depressive symptom severity (Patient Health Questionnaire-9) using multivariable linear regression models; 2) determined the predictive value of Paired Associates Learning and other registry variables for identifying participants who self-report Mild Cognitive Impairment by employing multivariable binomial logistic regressions and calculating the area under the receiver operator curve; 3) investigated feasibility by looking at task completion rates and statistically comparing characteristics of task completers and non-completers; and 4) evaluated usability in terms of participant requests for support from BHR related to the assessment. RESULTS: In terms of construct validity, in participants who took the Paired Associates Learning for the first time (N=14,528), worse performance was associated with being older, being male, lower educational attainment, higher levels of self- and study partner-reported decline, more self-reported memory concerns, greater depressive symptom severity, and self-report of Mild Cognitive Impairment. Paired Associates Learning performance and Brain Health Registry variables together identified those with self-reported Mild Cognitive Impairment with moderate accuracy (areas under the curve: 0.66-0.68). In terms of feasibility, in a sub-sample of 29,176 participants who had the opportunity to complete Paired Associates Learning for the first time in the registry, 14,417 started the task. 11,647 (80.9% of those who started) completed the task. Compared to those who did not complete the task at their first opportunity, those who completed were older, had more years of education, more likely to self-identify as White, less likely to self-identify as Latino, less likely to have a subjective memory concern, and more likely to report a family history of Alzheimers disease. In terms of usability, out of 8,395 received requests for support from BHR staff via email, 4.4% (n=374) were related to PAL. Of those, 82% were related to technical difficulties. CONCLUSIONS: Our findings support moderate feasibility, good usability, and construct validity of cross-sectional Paired Associates Learning in an unsupervised online registry, but also highlight the need to make the assessment more inclusive and accessible to individuals from ethnoculturally and socioeconomically diverse communities. A future, improved version could be a scalable, efficient method to assess cognition in many different settings, including clinical trials, observational studies, healthcare, and public health.

BACKGROUND: Anatomic total shoulder arthroplasty (ATSA) and reverse total shoulder arthroplasty (RTSA) reliably alleviate pain and restore shoulder function for a variety of indications. However, these procedures are not well-studied in patients with neurocognitive impairment. Therefore, the purpose of this study was to investigate whether patients with dementia or mild cognitive impairment (MCI) have increased odds of surgical or medical complications following arthroplasty. METHODS: The PearlDiver database was queried from 2010 through October 2021 to identify a cohort of patients who underwent either ATSA or RTSA and had a minimum 2-year follow-up. Current Procedural Terminology and International Classification of Diseases codes were used to stratify this cohort into three groups: (1) patients with dementia, (2) patients with MCI, and (3) patients with neither condition. Surgical and medical complication rates were compared among these three groups. RESULTS: The overall prevalence of neurocognitive impairment among patients undergoing total shoulder arthroplasty was 3.0% in a cohort of 92,022 patients. Patients with dementia had increased odds of sustaining a periprosthetic humerus fracture (odds ratio [OR] = 1.46, P

INTRODUCTION: Virtually all people with Down syndrome (DS) develop neuropathology associated with Alzheimers disease (AD). Atrophy of the hippocampus and entorhinal cortex (EC), as well as elevated plasma concentrations of neurofilament light chain (NfL) protein, are markers of neurodegeneration associated with late-onset AD. We hypothesized that hippocampus and EC gray matter loss and increased plasma NfL concentrations are associated with memory in adults with DS. METHODS: T1-weighted structural magnetic resonance imaging (MRI) data were collected from 101 participants with DS. Hippocampus and EC volume, as well as EC subregional cortical thickness, were derived. In a subset of participants, plasma NfL concentrations and modified Cued Recall Test scores were obtained. Partial correlation and mediation were used to test relationships between medial temporal lobe (MTL) atrophy, plasma NfL, and episodic memory. RESULTS: Hippocampus volume, left anterolateral EC (alEC) thickness, and plasma NfL were correlated with each other and were associated with memory. Plasma NfL mediated the relationship between left alEC thickness and memory as well as hippocampus volume and memory. DISCUSSION: The relationship between MTL gray matter and memory is mediated by plasma NfL levels, suggesting a link between neurodegenerative processes underlying axonal injury and frank gray matter loss in key structures supporting episodic memory in people with DS.

Background: Mild cognitive impairment (MCI) is a heterogeneous diagnostic entity, without a clear prognosis, often accompanied by psychiatric symptomatology and physical frailty. Objective: Understanding the heterogeneity within MCI is a critical step in improving the early detection of cognitive decline and developing effective interventions. Methods: Cross-sectional multivariate latent mixture analyses of data from patients evaluated between 2015 and 2019, who were routinely entered into a multidisciplinary database for research purposes. A sample of 538 community-dwelling older adults drawn from a large academic medical center, referred from within the Department of Neurology (63.7% Female, Mage = 67.8, SDage = 10.6). Participants completed comprehensive neuropsychological assessments, psychiatric symptom measures, and frailty evaluations. Results: Latent profile analyses supported five profiles of cognitive impairment: At-Risk, Pre-MCI, Amnestic MCI, Multiple Domain MCI, and Major Cognitive Impairment. The inclusion of concomitant psychiatric symptoms and frailty criteria revealed two additional profiles: Psychiatric/Frail, without cognitive impairments, and Multiple Cognitive Domains/Psychiatric/Frail. Critically, 55% of those classified as Healthy based on cognitive data alone were reclassified. Significant profile-wise differences emerged across auxiliary variables of brief cognitive screening, sociodemographics, and medical and psychosocial risk. Conclusions: Results highlight heterogeneity represented by neurologic patients referred for neuropsychological evaluation that include key physical and emotional symptoms known to increase the risk of cognitive decline. Findings are in alignment with more recent research suggesting that the traditional paradigm cognitive impairment may need to be expanded to improve diagnostic accuracy and to develop more tailored, precision-driven interventions. [ABSTRACT FROM AUTHOR]

Background: Distinguishing between mild cognitive impairment (MCI) and early dementia requires both neuropsychological and functional assessment that often relies on caregivers' insights. Contacting a patient's caregiver can be time-consuming in a physician's already-filled workday. Objective: To assess the utility of a brief, machine learning (ML)-enabled digital cognitive assessment, the Digital Clock and Recall (DCR), for detecting functional dependence. Methods: We evaluated whether the DCR can help identify individuals at risk of functional deficits as measured by the informant-rated Functional Activities Questionnaire (FAQ) in older individuals including cognitively unimpaired, MCI, and dementia likely due to Alzheimer's disease. Results: The DCR scaled well with FAQ scores, and ML classifiers trained on multimodal DCR features demonstrated strong performance in predicting functional impairment on a held-out test set. Differences in FAQ scores between DCR-predicted classes were comparable across key demographic groups. Conclusions: The DCR can streamline the clinical decision-making, triage, and intervention planning associated with functional impairment in primary care. [ABSTRACT FROM AUTHOR]

Background: Semantic and short-term episodic memory are impaired in some brain disorders including Alzheimer's disease. Objective: Development and validation of an almost self-administered, but cognitively demanding four-minute test identifying very mild cognitive impairment (vMCI). Methods: The innovative hedgehog PICture Naming and Immediate Recall (PICNIR) consisted of two parts. The first task was to write down the names of 20 black-and-white pictures to evaluate long-term semantic memory and language. The second task involves immediate recall and writing the names of as many previously named pictures as possible in one minute. The PICNIR is assessed using the number of naming errors (NE) and correctly recalled picture names (PICR). The PICNIR and a neuropsychological battery were administered to 190 elderly individuals living independently in the community. They were divided into those with vMCI (n = 43 with Montreal Cognitive Assessment (MoCA) 24 ± 3 points) and sociodemographically matched cognitively normal (CN) individuals (n = 147 with MoCA 26 ± 3). Both subgroups had predicted mean Mini-Mental State Examination scores of 28–29 points. Results: Compared to CN, vMCI participants made more NE (0.3 ± 0.6 versus 0.6 ± 0.9; p = 0.02) and recalled fewer PICR (8.9 ± 2.2 versus 6.8 ± 2.2; p < 0.000001). Discriminative validity was satisfactory using the area under the ROC curve (AUC): 0.76 for PICR, 0.74 for MoCA, 0.67 for MoCA-five-word recall, and 0.59 for NE. The AUCs of PICR and MoCA were comparable and larger than those of MoCA five-point recall or NE. Logical Memory scores, RAVLT scores, Digit symbol, and animal fluency correlated with PICR. Conclusions: The picture-based PICNIR is an ultra-brief, sensitive cognitive test valid for assessing very mild cognitive impairment. Its effectiveness should be validated for other languages and cultures. [ABSTRACT FROM AUTHOR]

SMOC1 has emerged as one of the most significant and consistent new biomarkers of early Alzheimer's disease (AD). Recent studies show that SMOC1 is one of the earliest changing proteins in AD, with levels in the cerebrospinal fluid increasing many years before symptom onset. Despite this clear association with disease, little is known about the role of SMOC1 in AD or its function in the brain. Therefore, the aim of this study was to examine the distribution of SMOC1 in human AD brain tissue and to determine if SMOC1 influenced amyloid beta (Aβ) aggregation. The distribution of SMOC1 in human brain tissue was assessed in 3 brain regions (temporal cortex, hippocampus, and frontal cortex) using immunohistochemistry in a cohort of 73 cases encompassing advanced AD, mild cognitive impairment (MCI), preclinical AD, and cognitively normal controls. The Aβ- and phosphorylated tau-interaction with SMOC1 was assessed in control, MCI, and advanced AD human brain tissue using co-immunoprecipitation, and the influence of SMOC1 on Aβ aggregation kinetics was assessed using Thioflavin-T assays and electron microscopy. SMOC1 strongly colocalized with a subpopulation of amyloid plaques in AD (43.8 ± 2.4%), MCI (32.8 ± 5.4%), and preclinical AD (28.3 ± 6.4%). SMOC1 levels in the brain strongly correlated with plaque load, irrespective of disease stage. SMOC1 also colocalized with a subpopulation of phosphorylated tau aggregates in AD (9.6 ± 2.6%). Co-immunoprecipitation studies showed that SMOC1 strongly interacted with Aβ in human MCI and AD brain tissue and with phosphorylated tau in human AD brain tissue. Thioflavin-T aggregation assays showed that SMOC1 significantly delayed Aβ aggregation in a dose-dependent manner, and electron microscopy confirmed that the Aβ fibrils generated in the presence of SMOC1 had an altered morphology. Overall, our results emphasize the importance of SMOC1 in the onset and progression of AD and suggest that SMOC1 may influence pathology development in AD. [ABSTRACT FROM AUTHOR]

Background: A few studies have suggested that light at night (LAN) exposure, i.e. lighting during night hours, may increase dementia risk. We evaluated such association in a cohort of subjects diagnosed with mild cognitive impairment (MCI). Methods: We recruited study participants between 2008 and 2014 at the Cognitive Neurology Clinic of Modena Hospital, Northern Italy and followed them for conversion to dementia up to 2021. We collected their residential history and we assessed outdoor artificial LAN exposure at subjects' residences using satellite imagery data available from the Visible Infrared Imaging Radiometer Suite (VIIRS) for the period 2014–2022. We assessed the relation between LAN exposure and cerebrospinal fluid biomarkers. We used a Cox-proportional hazards model to compute the hazard ratio (HR) of dementia with 95% confidence interval (CI) according to increasing LAN exposure through linear, categorical, and non-linear restricted-cubic spline models, adjusting by relevant confounders. Results: Out of 53 recruited subjects, 34 converted to dementia of any type and 26 converted to Alzheimer's dementia. Higher levels of LAN were positively associated with biomarkers of tau pathology, as well as with lower concentrations of amyloid β1−42 assessed at baseline. LAN exposure was positively associated with dementia conversion using linear regression model (HR 1.04, 95% CI 1.01–1.07 for 1-unit increase). Using as reference the lowest tertile, subjects at both intermediate and highest tertiles of LAN exposure showed increased risk of dementia conversion (HRs 2.53, 95% CI 0.99–6.50, and 3.61, 95% CI 1.34–9.74). In spline regression analysis, the risk linearly increased for conversion to both any dementia and Alzheimer's dementia above 30 nW/cm2/sr of LAN exposure. Adding potential confounders including traffic-related particulate matter, smoking status, chronic diseases, and apolipoprotein E status to the multivariable model, or removing cases with dementia onset within the first year of follow-up did not substantially alter the results. Conclusion: Our findings suggest that outdoor artificial LAN may increase dementia conversion, especially above 30 nW/cm2/sr, although the limited sample size suggests caution in the interpretation of the results, to be confirmed in larger investigations. [ABSTRACT FROM AUTHOR]

[Display omitted] • Significant hippocampal volume reduction found in MCI and AD patients. • No causal link between hippocampal volume reduction and Alzheimer's disease. • Subfield-specific hippocampal changes in MCI advance understanding of AD. This study investigates the association between cognitive dysfunction and hippocampal volumes in Alzheimer's Disease (AD) and Mild Cognitive Impairment (MCI) using Mendelian randomization. A meta -analysis of 503 healthy controls, 562 MCI patients, and 389 CE patients revealed significant reductions in hippocampal and subregion volumes in MCI and AD compared to controls. While various subregions showed volume reductions, no causal relationship between hippocampal volume and AD was established through Mendelian randomization analysis. In conclusion, significant volume reductions were observed in MCI and AD patients, highlighting the complexity of the relationship between hippocampal volume and cognitive impairment. [ABSTRACT FROM AUTHOR]

Background: To establish simple screening tests to suspect Alzheimer's disease (AD) pathology, the clinical sign "head-turning sign" (HTS), which is a patient's behavior of turning their head towards their partner to seek assistance with questions posed by the examiner during the interview, and the simple screening questionnaire for dementia named "Neucop-Q" were validated in participants diagnosed with amyloid and tau positron emission tomography (PET). Methods: We enrolled 155 patients: 47 cognitive normal, 36 with mild cognitive impairment, 64 with dementia, and 8 with psychiatric disorders. All participants underwent Neucop-Q [three questions: Consciousness/self-awareness of cognitive disabilities (C) normal/impaired (nor/imp), Pleasure/pastime (P) nor/imp, and News/knowledge on current topics (N) nor/imp] and amyloid/tau PET. Additionally, we measured plasma amyloid β (Aβ) 42/40 ratio, phosphorylated tau 181 (pTau181), glial fibrillary acidic protein (GFAP), and neurofilament light (NFL) levels and compared with HTS and Neucop-Q results. Results: The specificity and positive predictive value (PPV) of HTS positivity (HTSpos) were the highest (amyloid PET: 0.930 and 0.870, tau PET: 0.944 and 0.957, respectively), while Cimp and Nimp had a high negative predictive value (NPV) for amyloid PET (negativity) (0.750 and 0.725). Pimp showed high specificity for predicting non-AD tau positivity among non-AD participants without amyloid PET positivity (0.854). To validate these findings with PET results, we examined the correlation between well-established AD blood biomarkers and results obtained from these screening tests. HTSpos, Cimp, and Nimp were strongly associated with Aβ42/40 ratio (P < 0.0001, P = 0.0022, and P = 0.001), pTau181 (P < 0.0001, P = 0.0095, and P = 0.001), GFAP (P = 0.0372, P = 0.0088, and P = 0.0002), and amyloid PET Centiloid (P < 0.0001, P = 0.0210, and P = 0.0006), whereas Pimp increased neuroinflammation (GFAP; P = 0.0061) and was associated with non-AD tauopathy. The combination of Neucop-Q questions showed that Cimp/Pnor/Nimp subjects have the highest specificity and PPV (0.972 and 0.833) and were strongly associated with Aβ42/40 ratio (P = 0.0006), pTau181 (P = 0.0006), and amyloid PET Centiloid (P < 0.0001). Conclusion: HTSpos, Cimp, and Nimp have diagnostic utility in suspecting MCI due to AD and AD, and Pimp has diagnostic value in non-AD tauopathy. HTSpos, Cimp, and Nimp were associated with biomarkers of Aβ pathology. HTS and Neucop-Q may serve as powerful first-line screening in memory clinics. Trial registration: UMIN Clinical Trials Registry (UMIN-CTR) under registration numbers 000032027 (Registration date: 2018/03/31) and 000030248 (Registration date: 2018/01/01). [ABSTRACT FROM AUTHOR]

Background Methods Results Conclusions The associations between community‐wide social determinants of health and mild cognitive impairment (MCI) among individuals warrant investigation.Among 2830 dementia‐free individuals aged 65+ years in a community‐based US study, we examined cross‐sectional associations of MCI (Clinical Dementia Rating = 0.5) with the following potential social determinants of health: at the census tract or block group level obtained from public sources: neighborhood disadvantage (Area Deprivation Index, ADI), air pollution with fine particulate matter (PM2.5), greenspace, Walkability Index, ambulatory healthcare availability per square mile, homicide rate; and at the individual participant level, birth/schooling in a southern US state.Unadjusted logistic regression models found higher odds ratios (OR, 95% CI) for MCI with higher ADI (1.01, 1.003–1.02), higher PM2.5 (1.16, 1.07–1.26), higher homicide rate (1.007, 1.001–1.012), lesser greenspace (0.99, 0.90–0.99), and southern schooling (2.06, 1.6–3.54). Adjusting for age, race, sex, and educational level, ADI remained statistically significant (1.04, 1.01–1.06), while PM2.5 and Southern state schooling interacted significantly with race and were more strongly affected in Black participants than in White participants.In this cohort, several community‐wide social/environmental factors were associated with MCI. While clinicians should continue to encourage older adults to modify their individual risk factors, policy changes are needed to mitigate social determinants of health in the community. [ABSTRACT FROM AUTHOR]

Design: This is a retrospective cohort study. Setting: The study was conducted at the Instituto de Neurociencias de la Junta de Beneficencia de Guayaquil, a primary neuroscience institute in Ecuador. Participants: The study evaluated 425 participants diagnosed with Mild Cognitive Impairment (MCI) or dementia, out of which 272 individuals (mean age = 75 years; 164 female) presenting specific medical conditions were selected for analysis. Measurements: Data were collected on demographics, medical history, and neuropsychological assessment using the Neuropsi scale. Conditions such as Type 2 Diabetes Mellitus, hypertension, obesity, and history of traumatic brain injury were specifically noted. Results: Latent Class Analysis identified three distinct classes of patients: Unspecified Cognitive Deterioration, Dementia, and MCI. The three-class model provided the best fit, revealing varied morbidity patterns and highlighting the influence of vascular and metabolic conditions on cognitive decline. Notably, similarities in hypertension and diabetes prevalence between Dementia and MCI classes suggested shared risk factors. The study also found no significant age differences between the classes, indicating that age alone might not be the primary determinant in the progression of cognitive decline. Conclusions: The study underscores the complexity of dementia and MCI in an ageing Ecuadorian population, with vascular health playing a crucial role in cognitive impairment. These findings advocate for a holistic approach in managing dementia and MCI, emphasising the importance of addressing cardiovascular and metabolic health alongside neurocognitive care. The distinct morbidity patterns identified offer insights into tailored intervention strategies, highlighting the need for comprehensive, multidisciplinary care in dementia management. [ABSTRACT FROM AUTHOR]

Diagnosing Alzheimer's disease (AD) in its prodromal stage is a significantly crucial area of research. Approximately 50% of individuals within the well-known Mild Cognitive Impairment (MCI) cohort are estimated to progress to AD, and the factors influencing conversion remain unknown. Gaining insights into the disease evolution can enhance support strategies and potentially slow down the pathology. Utilizing the Alzheimer's Disease Neuroimaging Initiative (ADNI) database, our objective is to construct a framework for distinguishing between Normal Controls (NC) and different stages of Alzheimer's Disease (AD), encompassing Earlier Mild Cognitive Impairment (EMCI), Later Mild Cognitive Impairment (LMCI), and AD patients. In pursuit of this objective, we preprocessed Diffusion Tensor and Magnetic Resonance brain images from 237 subjects, generating corresponding brain connectivity maps. Notably, we introduce an innovative linearity assessment method that utilizes the Ordinary Least Squares (OLS) linear regression model to identify and select relevant features for classification. This approach effectively identifies features with strong linear relationships to the target variable. Our method's superiority is demonstrated through a comparative analysis with the traditional SelectKBest approach. By integrating this feature selection strategy with a Logistic Regression model, our study achieves both efficient and highly accurate classification outcomes, highlighting the effectiveness of the proposed method. In a four-class classification scenario, the model attained an accuracy of 66 % ± 0.06 . In binary classification, the results were equally impressive, with an area under the curve of 0.68 ± 0.10 % for CN vs. EMCI discrimination, 99 ± 0.02 % for distinguishing LMCI from adjacent classes CN and EMCI, and 0.79 % ± 0.08 for discriminating AD from healthy subjects. Additionally, the calculation of Pearson's correlation coefficient has been employed to identify cortical regions affected by changes, explore the nature of fiber disconnection propagation from one stage to another, and establish the traceability of the interference origin between stages. The summarized results reveal an apparent flow of white matter disruption from the right to the left hemisphere. [ABSTRACT FROM AUTHOR]

Background: Optical coherence tomography (OCT) enables high-resolution imaging of ocular structures in health and disease. Choroid thickness (CT) is a key vascular retinal parameter that can be assessed by OCT and might be relevant in the evaluation of the vascular component of cognitive decline. We aimed to investigate CT changes in a large cohort of individuals cognitive unimpaired (CU), with mild cognitive impairment due to Alzheimer's (MCI-AD), mild cognitive impairment due to cerebrovascular disease (MCI-Va), Alzheimer's disease dementia (ADD), and vascular dementia (VaD). Methods: Clinical, demographical, ophthalmological and OCT data from the Neuro-ophthalmological Research at Fundació ACE (NORFACE) project were analyzed. CT was assessed in the macula across nine Early Treatment Diabetic Retinopathy Study (ETDRS) quadrants, average thickness, total volume, and subfoveal choroidal thickness. Differences of CT among the five diagnostic groups were assessed in a multivariate regression model, adjusting for demographic and cardiovascular risk factors and OCT image quality. A comparison between manual and automatic CT measurements in a subset of participants was also performed. Results: The study cohort comprised 1,280 participants: 301 CU, 196 MCI-AD, 112 MCI-Va, 578 ADD, and 93 VaD. CT was significantly increased in individuals with cognitive impairment compared to those CU, particularly in the VaD and MCI-Va groups and in the peripheral ETDRS regions. No significant differences were found in inner superior, center and subfoveal choroidal thickness. The interaction of sex and diagnosis had no effect in differentiating CT. Mini-Mental State Examination (MMSE) scores were not correlated to CT. Manual and automated CT measurements showed good reliability. Discussion: Our findings indicated that peripheral choroidal thickening, especially in patients with cerebrovascular disease, may serve as a potential choroidal biomarker for cognitive decline and suggest different pathogenic pathways in AD and VaD. Further research is required to explore CT as a reliable ocular biomarker for cognitive impairment. [ABSTRACT FROM AUTHOR]

AbstractAimMethodsResultsConclusionsTo investigate the influence of cognitive functions on the effectiveness of Lee Silverman Voice Treatment (LSVT)® BIG therapy on motor symptoms, gait speed, activities of daily living (ADLs), and quality of life (QOL) in people with Parkinson’s disease (PD).This retrospective, single-center cohort study included 20 people with PD (PwPD) with mild cognitive impairment (PD-MCI group) or without (PD-NC group) (n = 10 each).In the PD-NC group, all assessments improved significantly. Similarly, the PD-MCI group showed significant improvements in the total Movement Disorder Society‐sponsored revision of the Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) Part III, 10-meter walking test, and total MDS-UPDRS Part II. However, the Parkinson’s Disease Questionnaire summary index showed a trend toward improvement that did not reach statistical significance.LSVT® BIG therapy may improve motor symptoms, gait speed, and ADLs in PwPD, regardless of the presence or absence of MCI. [ABSTRACT FROM AUTHOR]

Diabetes is associated with cognitive impairment, but the underlying mechanism remains unclear. Methylglyoxal (MGO), a precursor to advanced glycation endproducts (AGEs), is elevated in diabetes and linked to microvascular dysfunction. In this study, overexpression of the MGO‐detoxifying enzyme glyoxalase 1 (Glo1) was used in a mouse model of diabetes to explore whether MGO accumulation in diabetes causes cognitive impairment. Diabetes was induced with streptozotocin. Fasting blood glucose, cognitive function, cerebral blood flow, neurovascular coupling (NVC), Glo1 activity, MGO and AGEs were assessed. In diabetes, MGO‐derived hydroimidazolone‐1 increased in the cortex, and was decreased in Glo1‐overexpressing mice compared to controls. Visuospatial memory was decreased in diabetes, but not in Glo1/diabetes. NVC response time was slightly increased in diabetes, and normalised in the Glo1‐overexpressing group. No impact of diabetes or Glo1 overexpression on blood–brain barrier integrity or vascular density was observed. Diabetes induced a mild visuospatial memory impairment and slightly reduced NVC response speed and these effects were mitigated by Glo1. This study shows a link between MGO‐related AGE accumulation and cerebrovascular/cognitive functions in diabetes. Modulation of the MGO–Glo1 pathway may be a novel intervention strategy in patients with diabetes who have cerebrovascular complications. Key points: Diabetes is associated with an increased risk of stroke, cognitive decline, depression and Alzheimer's disease, but the underlying mechanism remains unclear.Methylglyoxal (MGO), a highly reactive by‐product of glycolysis, plays an important role in the development of diabetes‐associated microvascular dysfunction in the periphery and is detoxified by the enzyme glyoxalase 1.Diabetes reduced visuospatial memory in mice and slowed the neurovascular coupling response speed, which was improved by overexpression of glyoxalase 1.MGO formation and MGO‐derived advanced glycation endproduct (AGE) accumulation in the brain of diabetic mice are associated with a slight reduction in neurovascular coupling and mild cognitive impairment.The endogenous formation of MGO, and the accumulation of MGO‐derived AGEs, might be a potential target in reducing the risk of vascular cognitive impairment in people with diabetes. [ABSTRACT FROM AUTHOR]

ObjectiveMethodsResultsConclusionThis study aimed to investigate the effects of a long-term intervention with β-lactolin, a tetrapeptide (sequence: glycine-threonine-tryptophan-tyrosine) derived from milk, on cognitive performance in individuals with mild cognitive impairment (MCI).A randomized, double-blind, placebo-controlled trial was conducted. We recruited 48 participants aged 50 years or older with the Japanese version of the Mini-Mental State Examination (MMSE-J) score of 24–28 and a Clinical Dementia Rating (CDR) score of 0.5. Participants were administered β-lactolin (1.8 mg daily) or placebo for 24 weeks. The primary outcomes were the MMSE-J and the Japanese version of the Montreal Cognitive Assessment (MoCA-J) scores for cognitive function.A total of 422 individuals were screened, 48 of whom were included in this study. The MMSE-J and MoCA-J scores showed no significant differences between the groups. In the intra-group comparison of the MoCA-J delayed recall score, a significant difference was observed in the β-lactolin group after 12 and 24 weeks of intervention (p = 0.0256, p = 0.0175, respectively). Furthermore, the subgroup analysis stratified for females only showed a significant difference in MoCA-J total score in the β-lactolin group after 24 weeks of intervention (p = 0.0253).β-lactolin intake does not significantly improve cognitive function in MCI in an inter-group comparison; nevertheless, the MoCA-J delayed recall score was significantly improved in the β-lactolin group. The number of participants was lower than planned, limiting the confirmation of the effectiveness of β-lactolin on MCI. This report demonstrated the effect size of β-lactolin intervention in MCI, contributing insights for future research. [ABSTRACT FROM AUTHOR]

Background: The unprecedented increase in the older population and ever-increasing incidence of dementia are leading to a "silver tsunami" in upcoming decades. To combat multimorbidity and maintain daily activities, elderly people face a high prevalence of polypharmacy. However, how these medications affect dementia-related pathology, such as Alzheimer's β-amyloid (Aβ) fibrils formation, remains unknown. In the present study, we aimed to analyze the medication profiles of Alzheimer's disease (AD; n = 124), mild cognitive impairment (MCI; n = 114), and non-demented (ND; n = 228) patients to identify highly prevalent drugs and to determine the effects of those drugs on Aβ fibrils formation. Methods: Study subjects (≥ 65 years) were recruited from an academic geriatric practice that heavily focuses on memory disorders. The disease state was defined based on the score of multiple cognitive assessments. Individual medications for each subject were listed and categorized into 10 major drug classes. Statistical analysis was performed to determine the frequency of individual and collective drug classes, which are expressed as percentages of the respective cohorts. 10 µM monomeric β-amyloid (Aβ) 42 and fibrillar Aβ (fAβ) were incubated for 6–48 h in the presence of 25 µM drugs. fAβ was prepared with a 1:10 ratio of Aβ42 to Aβ40. The amount of Aβ fibrils was monitored using a thioflavin T (Th-T) assay. Neuronal cells (N2A and SHSY-5Y) were treated with 25 µM drugs, and cell death was measured using a lactose dehydrogenase (LDH) assay. Results: We noticed a high prevalence (82–90%) of polypharmacy and diverse medication profiles including anti-inflammatory (65–77%), vitamin and mineral (64–72%), anti-cholesterol (33–41%), anti-hypersensitive (35–39%), proton pump inhibitor (23–34%), anti-thyroid (9–21%), anti-diabetic (5–13%), anti-constipation (9–11%), anti-coagulant (10–13%), and anti-insomnia (9–20%) drugs in the three cohorts. Our LDH assay with 18 highly prevalent drug components showed toxic effects of Norvasc, Tylenol, Colace, and Plavix on N2A cells, and of vitamin D and Novasc on SH-SY5Y cells. All these drugs except Colace significantly reduced the amount of Aβ fibril when incubated with Aβ42 for a short period (6 h). However, Lipitor, vitamin D, Levothyroxine, Prilosec, Flomax, and Norvasc prominently reduce the amount of fibrils when incubated with monomeric Aβ42 for a longer period (48 h). Furthermore, our disaggregation study with fAβ showed consistent results for cholecalciferol (vitamin D), omeprazole (Prilosec), clopidogrel hydrogensulfate (Flomax), levothyroxine, and amlodipine (Norvasc). The chemical structures of these four efficient molecules contain polyphenol components, a characteristic feature of the structures of polyphenolic inhibitors of Aβ fibrillation. Conclusion: A higher polypharmacy incidence was observed in an elderly population of 228 ND, 114 MCI, and 124 AD patients. We found that several highly recommended drug components, including vitamin D3, Levothyroxine, Prilosec, Flomax, and Norvasc, efficiently reduce the amount of fibrils formed by monomeric Aβ42 and existing preformed Aβ fibrils in vitro. However, only Levothyroxine was able to prevent Aβ-mediated toxicity to SH-SY5Y cells. Our study suggested that these drugs likely function as polyphenolic inhibitors of Aβ. [ABSTRACT FROM AUTHOR]

Background: Alzheimer's disease (AD) is characterized by the accumulation of amyloid-β and tau proteins, leading to neurofibrillary tangles. A biomarker-based diagnostic method called the ATN system categorizes AD pathology into amyloid-β (A), tau (T), and neurodegeneration (N). The relationship between regional tau deposition and reduced glucose metabolism in the preclinical AD stage is not well understood. Objective: We presented voxel-by-voxel metabolic/tau deposition ratio (MTR) images to investigate the effects of tau deposition on metabolism in AD brains on a stage-by-stage basis. Methods: We selected 174 subjects who underwent 3D-MRI, FDG-PET, amyloid PET, and tau PET scans. MTR images were created by normalizing FDG-PET toMK6240 PET images. Voxel-wise comparisons among 63 cognitively normal amyloid-negative (CNA) subjects, 49 subjects with AD dementia (ADD), 23 subjects with mild cognitive impairment due to AD (MCA), and 39 preclinical AD (PRC) subjects were conducted. Results: There was reduced glucose metabolism in ADD and MCA groups compared to CNA, predominantly in parietotemporal areas. Tau deposition was observed in wider areas in ADD and restricted to the medial temporal lobes in MCA. MTR exhibited significant reductions in broader regions in ADD and MCA, indicating simultaneous glucose metabolism decrease and tau deposition. At the MCA and PRC stages, glucose metabolism impairment and tau deposition were shown in separate regions by FDG PET and tau PET, respectively, while MTR images showed impairment in both regions. Conclusions: Our findings suggest that MTR imaging provides insights into AD pathophysiology by simultaneously assessing glucose metabolism and tau deposition. In the early stage of the AD continuum (MCA and PRC), metabolic decline and tau deposition occur independently in different brain regions. [ABSTRACT FROM AUTHOR]

Background: A deep knowledge of the healthcare system and the organization of neurology departments is important for planning and optimizing changes to facilitate the successful implementation of anti-amyloid antibodies treatments. Objective: We aimed to assess the necessary changes prior to introducing these therapies in our setting. Methods: We conducted a key informant survey among heads of departments of neurology from 16 hospitals in Spain. The questionnaire comprised questions about changes in the organization and functioning of the departments of neurology with the introduction of anti-amyloid drugs, changes in diagnosis and patient care, use of diagnostic techniques, patients, families and public information, resources allocation, and research. Results: Sixteen key informants completed the survey. They strongly agreed that the introduction of anti-amyloid drugs will impact the functioning of neurology services, especially in hospitals with dementia units. Consensus was reached regarding referring all Alzheimer's disease patients eligible for therapy to dementia units. There was also agreement on the need to expand the neurology services, day hospital units, extend visit durations, and hire more professionals, especially neurologists, neuropsychologists, and nuclear medicine physicians. Furthermore, consensus was achieved on increasing the use of MRI, amyloid PET, cerebrospinal fluid biomarkers, APOE genotyping, and the necessity of advancing blood biomarkers and tau tracers. Conclusions: Our study highlights the need for extensive changes within Spanish neurological departments to effectively integrate anti-amyloid antibodies. Implementing these changes is essential for the timely and equitable adoption of novel therapies. [ABSTRACT FROM AUTHOR]

Background: Alterations in factors involved in cholesterol homeostasis are critical in Alzheimer's disease (AD), but the stage of occurrence, their specific association, and a possible relationship with the APOE4 genotype are not clarified. Objective: We aimed to quantify and correlate specific lipid factors in patients with different degrees of cognitive decline, namely patients with AD and patients with mild cognitive impairment due to AD (MCI-AD), carriers or non-carriers of the APOE4 genotype. Methods: We evaluated Proprotein Convertase Subtilisin/Kexin type 9 (PCSK9), cholesterol and the oxidative metabolites 24-, 25-, 27-hydroxycholesterol (HC) in the cerebrospinal fluid (CSF) and serum of AD (n = 28) and MCI-AD (n = 27) patients. Results: CSF and serum PCSK9 and lipids were similar, except for higher serum PCSK9 and triglycerides in MCI-AD compared to AD. In CSF, AD APOE4 carriers showed higher PCSK9 and 24-HC (+61.3%, p = 0.027 and +32.7%, p = 0.037), compared to non-carriers. There was a negative association between CSF PCSK9 and 27-HC in AD (r = −0.444, p = 0.049) and, exclusively among AD APOE4 carriers, a negative association between CSF PCSK9 and 24-HC (r = −0.786, p = 0.028). A positive correlation was observed between CSF and serum PCSK9 in AD (r = 0.520, p = 0.004), driven by APOE4 carriers (r = 0.544, p = 0.038), suggesting PCSK9 exchange between brain and periphery. A positive correlation was detected between serum and CSF 27-HC (r = 0.465, p = 0.039) in AD. None of these results were found in MCI-AD patients. Conclusions: PCSK9 and 24-HC might be specific markers of ApoE4-associated lipid alterations in AD, possibly contributing to clinical progression in the AD continuum. [ABSTRACT FROM AUTHOR]

Background: Women comprise approximately two-thirds of Alzheimer's disease cases. Objective: This is the first known study to investigate the role of intersectionality between gender and other social determinants of health (SDOH) in the presentation of cognitive symptoms (i.e., being asymptomatic or symptomatic) among those with pathologically confirmed Alzheimer's disease. Methods: We studied 3107 individuals with Alzheimer's disease neuropathology (ADNP) confirmed at autopsy. Asymptomatic ADNP was defined as the absence of a clinical diagnosis of mild cognitive impairment (MCI) or dementia before death (versus symptomatic: diagnosis of MCI/dementia). SDOH included gender, education, ethnoracial group, living alone, and primary language. Multivariable logistic regression tested associations between SDOH and asymptomatic ADNP (versus symptomatic); models were also stratified by gender. Results: Women, Hispanics, those living alone, and more educated individuals were found to have higher odds of asymptomatic ADNP. Non-English speakers had lower odds of asymptomatic ADNP. Both women and men had higher odds of asymptomatic ADNP if Hispanic or living alone. In only women, non-English speakers had lower odds while in only men, more education was associated with higher odds of asymptomatic ADNP. Conclusions: Gender, education, ethnicity, primary language, and living alone, and intersectionality of gender with primary language, may differentially influence MCI and dementia diagnosis prior to death among those with underlying ADNP. These findings emphasize the need for future Alzheimer's disease research to prioritize social determinants of brain health including their intersectionality with gender and how to inform targeted interventions. [ABSTRACT FROM AUTHOR]

Background: No large-scale characterizations of neurofilament light chain (NfL) and cognitive outcomes have been conducted in community-dwelling non-Hispanic Blacks. Objective: This study aims to enhance the application of blood biomarkers, in particular NfL, to ethno-racially diverse communities. We assess the association of NfL with cognitive outcomes, hypothesizing that NfL can identify cognitive changes regardless of diagnostic category. Methods: Baseline data were analyzed among n = 283 non-Hispanic Blacks (NHB) from the multi-ethnic Health and Aging Brain Study- Health Disparities (HABS-HD). Plasma NfL was measured on the Simoa platform. Linear regression models were conducted, covarying for age, gender, and education. Results: The majority of study participants (72%) were cognitively unimpaired (CU), with 21% having mild cognitive impairment (MCI), and 6.7% with Alzheimer's disease (AD). In adjusted models among the entire sample, significant associations existed between NfL and Trails A (p < 0.0001), Trails B (p < 0.0001), phonemic (FAS) and semantic (Animals) fluency (p = 0.03), and Symbol Digit Substitution (p < 0.001). When separated by diagnostic classification, significant associations were removed for functions involving executive functions for all diagnostic groups. Higher levels of NfL were positively associated with cognitive diagnosis, older age, and less education. Conclusions: Plasma NfL levels are significantly associated with measures of executive functioning, which elucidate NfL as a non-specific marker of neurodegeneration associated with efficiency of brain functions involving attention, processing, and generativity. NfL may be a sensitive measure for the detection of alterations in cognitive processing before the onset of phenotypic functional changes of neurodegeneration. [ABSTRACT FROM AUTHOR]

Early detection and accurate diagnosis of brain morphological abnormalities are essential for the effective management and treatment of Alzheimer's disease (AD) and mild cognitive impairment (MCI). Structural magnetic resonance imaging (MRI) is a powerful support tool to aid in disease diagnosis and prediction. In this research study, we present an innovative approach to predict Alzheimer's disease (AD) and mild cognitive impairment (MCI) using MRI data, which integrates regional interest (ROI)-based methodology and deep learning within a comprehensible framework. The proposed method involves dividing the brain into 138 predetermined sections based on anatomical information. Next, we apply three-dimensional vision transformers (3D-ViTs) to each ROI individually, harnessing the power of deep learning. To improve prediction accuracy, we employ a deep belief network (DBN) as an ensemble learning model. Evaluating our approach on the baseline structural MRI dataset obtained from the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort, and comparing it against five other competing models, we demonstrate its performance across four binary classification tasks and a three-class classification test (AD vs MCI vs CN (Cognitively Normal)). The proposed system outperforms existing models and provides interpretable insights into the brain regions that significantly contribute to solving each classification problem. Our findings align with the existing body of literature and hold promise for guiding future research directions in this domain. [ABSTRACT FROM AUTHOR]

ABSTRACT To complement the conventional area under the ROC curve (AUC) which cannot fully describe the diagnostic accuracy of some non‐standard biomarkers, we introduce a transformed ROC curve and its associated transformed AUC (TAUC) in this article, and show that TAUC can relate the original improper biomarker to a proper biomarker after a non‐monotone transformation. We then provide nonparametric estimation of the non‐monotone transformation and TAUC, and establish their consistency and asymptotic normality. We conduct extensive simulation studies to assess the performance of the proposed TAUC method and compare with the traditional methods. Case studies on real biomedical data are provided to illustrate the proposed TAUC method. We are able to identify more important biomarkers that tend to escape the traditional screening method. [ABSTRACT FROM AUTHOR]

Background: Previous studies have demonstrated widespread brain neurodegeneration in Alzheimer's disease (AD). However, the neurobiological and pathogenic substrates underlying this structural atrophy across the AD spectrum remain largely understood. Methods: In this study, we obtained structural MRI data from ADNI datasets, including 83 participants with early-stage cognitive impairments (EMCI), 83 with late-stage mild cognitive impairments (LMCI), 83 with AD, and 83 with normal controls (NC). Our goal was to explore structural atrophy across the full clinical AD spectrum and investigate the genetic mechanism using gene expression data from the Allen Human Brain Atlas. Results: As a result, we identified significant volume atrophy in the left thalamus, left cerebellum, and bilateral middle frontal gyrus across the AD spectrum. These structural changes were positively associated with the expression levels of genes such as ABCA7, SORCS1, SORL1, PILRA, PFDN1, PLXNA4, TRIP4, and CD2AP, while they were negatively associated with the expression levels of genes such as CD33, PLCG2, APOE, and ECHDC3 across the clinical AD spectrum. Further gene enrichment analyses revealed that the positively associated genes were mainly involved in the positive regulation of cellular protein localization and the negative regulation of cellular component organization, whereas the negatively associated genes were mainly involved in the positive regulation of iron transport. Conclusion: Overall, these results provide a deeper understanding of the biological mechanisms underlying structural changes in prodromal and clinical AD. [ABSTRACT FROM AUTHOR]

Background: Mild cognitive impairment (MCI) is generally considered to have a high risk of progression to Alzheimer's disease. Our study aimed to investigate the abnormal functional connectivity (FC) in prefrontal cortex (PFC) in patients with MCI and explore the relationship between the observed changes and cognitive function. Methods: Sixty-seven patients with MCI and 71 healthy individuals were recruited for this study. All participants underwent the Montreal Cognitive Assessment (MoCA) and functional near-infrared spectroscopy (fNIRS) examinations. Results: Compared with healthy controls (HC), the patients with MCI exhibited significantly lower MoCA scores (p < 0.001). Through FC analysis, an enhanced subnetwork was observed in the right prefrontal cortex of the MCI group, covering four pairs of channel connections: CH12-CH15, CH12-CH16, CH13-CH15, and CH13-CH16. Moreover, the FC values of these four channel pairs and the education duration were significantly correlated with MoCA scores. Subsequently, a multiple linear regression model was performed to observe the independent factors of cognition decline, serving the education duration and the average FC values of subnetwork as independent variables and the MoCA scores as the dependent variable. The regression model showed a total of 25.7% explanation power (adjusted R2 = 0.257, F = 24.723, p < 0.001). Conclusion: Our study suggested that the enhanced subnetwork within the right PFC may be involved in the pathophysiology of MCI and serve as a potential target for the treatment of MCI. [ABSTRACT FROM AUTHOR]

Objective: Cerebrospinal fluid biomarkers are challenging to use for diagnosing mild cognitive impairment (MCI) in large populations, and there is an urgent need for new blood biomarkers. The aim of this study is to investigate whether astrocyte activation is correlated with hippocampal atrophy, and to assess the potential of glial fibrillary acidic protein (GFAP) as a biomarker for diagnosing MCI among community-dwelling older individuals. Methods: This cross-sectional study included 107 older adults. The levels of GFAP in serum were measured, and the volumetric assessment of gray matter within hippocampal subregions was conducted using Voxel-Based Morphometry (VBM). The relationship between hippocampal subregion volume and blood biomarkers were analyzed using partial correlation. The effectiveness of blood biomarkers in differentiating MCI was assessed using a receiver operating characteristic (ROC) curve. Results: We found that serum GFAP levels were significantly elevated in the MCI group compared to the cognitively normal (CN) group. Additionally, individuals with MCI exhibited a reduction gray matter volume in specific hippocampal subregions. Notably, the right dentate gyrus (DG) and right cornu ammonis (CA) subregions were found to be effective for distinguishing MCI patients from CN individuals. Serum levels of GFAP demonstrate a sensitivity of 65.9% and a specificity of 75.6% in differentiating patients with MCI from CN individuals. Conclusion: Specific atrophy within hippocampal subregions has been observed in the brains of community-dwelling elderly individuals. Elevated levels of circulating GFAP may serve as a sensitive peripheral biomarker indicative of hippocampal-specific cognitive alterations in patients with MCI. [ABSTRACT FROM AUTHOR]

Background: Mild cognitive impairment (MCI) is a growing concern among older adults, with limited effective pharmacological treatments available. Despite the potential of herbal medicine and acupuncture in managing MCI, there is a lack of research on their long-term effects on cognitive function and brain activity in clinical practice settings. This study aimed to address this gap by exploring the effects of a community-based program integrating herbal medicine and acupuncture on cognitive function and neural responses in older individuals with MCI. Methods: Nineteen individuals were enrolled from a pool of 250 individuals registered in the 2021 Busan Dementia Prevention & Care Program. Participants with MCI received herbal medicine, acupuncture, and pharmacopuncture treatments over a 6-month period. The Montreal Cognitive Assessment (MoCA) was administered at baseline and after 3 and 6 months to evaluate cognitive function. Functional near-infrared spectroscopy (fNIRS) was used to measure prefrontal cortex activity during cognitive task performance, including verbal fluency, Stroop color and word, and digit span backward tests. Results: Seventeen participants (13 female; mean age, 69.5 years) with MCI completed the study. Following the 6-month intervention, they exhibited a significant increase in the MoCA total score over time [F(2.32) =10.59, p < 0.0001]. Additionally, the deoxygenated hemoglobin beta coefficient in the left frontopolar prefrontal cortex significantly decreased during the Stroop task after the intervention. Conclusion: The Dementia Prevention & Care Program, which integrates herbal medicine and acupuncture, may enhance cognitive function in individuals with MCI. Moreover, the observed changes in prefrontal cortex activity after completion of the program suggest a need for further investigation of the underlying mechanisms. [ABSTRACT FROM AUTHOR]

Introduction: Insomnia is associated with mild cognitive impairment, although the mechanisms of this impairment are not well-understood. Timing of slow-wave and rapid eye movement sleep may help explain cognitive impairments common in insomnia. This investigation aimed to determine whether cognitive changes following continuous theta-burst stimulation (cTBS) are attributable to active stimulation, polysomnographic parameters of sleep, or both. Method: Data presented here are part of a pilot clinical trial aiming to treat insomnia by targeting a node in the default mode network using an inhibitory 40-s (cTBS). A double-blind counterbalanced sham-controlled crossover design was conducted. Participants (N = 20) served as their own controls on two separate in-laboratory visits—one with active cTBS and the other with sham cTBS. Each visit included cognitive assessments before and after stimulation and following a night of sleep in the lab monitored with polysomnography. Results: Slow wave sleep duration influenced working memory in the active cTBS condition, with shorter duration predicting improvements in working memory post sleep (B = −0.003, p = 0.095). Onset latency to rapid eye movement sleep predicted subsequent working memory, regardless of treatment condition (B = −0.001, p = 0.040). Results suggest that changes in attention and processing speed were primarily due to slow wave sleep onset (B = −0.001, p = 0.017) and marginally predicted by slow wave sleep duration (B = 0.002, p = 0.081) and sleep efficiency (B = 0.006, p = 0.090). Conclusions: Findings emphasize the important role that timing of slow-wave and rapid eye movement sleep have on information processing. Future work using larger sample sizes and more stimulation sessions is needed to determine optimal interactions between timing and duration of slow wave and rapid eye movement throughout the sleep period. Clinical trial registration: This study is registered on ClinicalTrials.gov (NCT04953559). https://clinicaltrials.gov/study/NCT04953559?locStr=Arizona&country=United%20States&state=Arizona&cond=insomnia&intr=tms%20&rank=1 [ABSTRACT FROM AUTHOR]

Background: Mild cognitive impairment (MCI) may lead to difficulty maintaining postural stability and balance during locomotion. This heightened susceptibility to falls is particularly evident during tasks such as obstacle negotiation, which demands efficient motor planning and reallocation of attentional resources. This study proposed a multi-objective optimal control (MOOC) technique to assess the changes in motor control strategies during obstacle negotiation in older people affected by amnestic MCI. Methods: Motion data from 12 older adults with MCI and 12 controls when crossing obstacles were measured using a motion capture system, and used to obtain the control strategy of obstacle-crossing as the best compromise between the conflicting objectives of the MOOC problem, i.e., minimising mechanical energy expenditure and maximising foot-obstacle clearance. Comparisons of the weighting sets between groups and obstacle heights were performed using a two-way analysis of variance with a significance level of 0.05. Results: Compared to the controls, the MCI group showed significantly lower best-compromise weightings for mechanical energy expenditure but greater best-compromise weightings for both heel- and toe-obstacle clearances. This altered strategy involved a trade-off, prioritising maximising foot-obstacle clearance at the expense of increased mechanical energy expenditure. The MCI group could successfully navigate obstacles with a normal foot-obstacle clearance but at the cost of higher mechanical energy expenditure. Conclusions: MCI alters the best-compromise strategy between minimising mechanical energy expenditure and maximising foot-obstacle clearances for obstacle-crossing in older people. These findings provide valuable insights into how MCI impacts motor tasks and offer potential strategies for mitigating fall risks in individuals with MCI. Moreover, this approach could serve as an assessment tool for early diagnosis and a more precise evaluation of disease progression. It may also have applications for individuals with impairments in other cognitive domains. [ABSTRACT FROM AUTHOR]

Background: Advance research directives (ARDs) provide a promising way to involve individuals with mild cognitive impairment (MCI) in research decisions before they lose the capacity to consent. At the same time, the views of people with MCI on ARDs are underexplored. This study assesses the perceptions of people with MCI and family members on the benefits and challenges associated with ARDs. Aims: The aim of this study was to investigate the perspectives of individuals with MCI and family members of individuals with MCI on ARDs. We focus specifically on willingness to participate in nontherapeutic research, understanding of ARDs and the ethical considerations involved. Methods: Thirteen open-ended, face-to-face interviews were conducted using a semi-structured format. Seven interviews were conducted with individuals with MCI, and six with family members of individuals with MCI. The narratives were transcribed verbatim and qualitative content analysis was carried out. Results: Research participation and ARDs were viewed positively, largely based on altruistic motives and the desire to contribute to society. The participants recognized the potential advantages of ARDs in reducing the decision-making burden on family members and maintaining personal autonomy. They also highlighted challenges in comprehending ARDs and navigating the complexities surrounding potential conflicts between current preferences versus preferences described in an ARD. Conclusions: ARDs were predominantly seen as valuable instruments that enable individuals with MCI to participate in research. This study provides insights into the reasons why affected individuals are interested in drafting ARDs. These insights can guide the development of supportive interventions that are tailored to assist individuals with MCI and their families in navigating ARD processes. [ABSTRACT FROM AUTHOR]