Effectiveness of a mobile application for independent computerized cognitive training in patients with mild cognitive impairment: study protocol for the NeNaE Study, a randomized controlled trial.

BACKGROUND: Mild cognitive impairment (MCI) involves cognitive decline beyond typical age-related changes, but without significant daily activity disruption. It can encompass various cognitive domains as the causes of MCI are diverse. MCI as well as frequent comorbid neuropsychiatric conditions like depression and anxiety affect individuals' quality of life. Early interventions are essential, and computerized cognitive training (cCT) is an established treatment method. This paper presents the protocol for the NeuroNation MED Effectiveness Study, evaluating the self-administered mobile cCT intervention ("NeuroNation MED") in individuals with MCI to assess training effects on cognitive domains, health competence, neuropsychiatric symptoms, psychological well-being, and the general application usability. METHODS: This study protocol presents a single-blinded multicenter randomized controlled trial that will be carried out in six study centers in Germany and Luxembourg. We included adults with MCI (existing F06.7 ICD-10-GM diagnosis and TICS ≥ 21 and ≤ 32). The intervention group will use a mobile, multi-domain cCT ("NeuroNation MED") for 12 weeks. Meanwhile, the wait list control group will receive standard medical care or no care. The eligibility of volunteers will be determined through a telephone screening. After completion of the baseline examination, patients will be randomly assigned to one of the experimental conditions in a 2:1 ratio. In total, 286 participants will be included in this study. The primary outcome is the change of cognitive performance measured by the index score of the screening module of the Neuropsychological Assessment Battery. Secondary outcomes are changes in the Cognitive Failures Questionnaire, Hospital Anxiety and Depression Scale, Health-49, Health Literacy Questionnaire, among others. All of the primary and secondary outcomes will be assessed at baseline and after the 12-week post-allocation period. Furthermore, the intervention group will undergo an assessment of the System Usability Scale, and the training data of the NeuroNation MED application will be analyzed. DISCUSSION: This study aims to assess the effectiveness of a mobile self-administered cCT in enhancing cognitive abilities among individuals diagnosed with MCI. Should the findings confirm the effectiveness of the NeuroNation MED app, it may confer possible benefits for the care management of patients with MCI, owing to the accessibility, cost-effectiveness, and home-based setting it provides. Specifically, the cCT program could provide patients with personalized cognitive training, educational resources, and relaxation techniques, enabling participants to independently engage in cognitive training sessions at home without further supervision. TRIAL REGISTRATION: German Clinical Trials Register DRKS00025133. Registered on November 5, 2021.

Obstructive Sleep Apnea Among Patients with Mild Cognitive Impairment.

Background: Obstructive sleep apnea (OSA) is associated with cognitive disorders, but little is known about prevalence of co-occurring OSA and mild cognitive impairment (MCI) as well as about co-occurring OSA and Alzheimer's disease (AD). Pathophysiological models integrating OSA, cognitive deficits and neurodegeneration remain speculative. Findings in this area could contribute to the knowledge about pathophysiological processes in cognitive disorders and neurodegenerative processes, be helpful for the diagnosis of cognitive disorders and provide approaches for the treatment of cognitive disorders. Objective: Examining the prevalence of OSA and patterns of cognitive deficits as well as AD biomarker profiles associated with OSA in a cohort of 104 MCI patients. Methods: Assessments used include: respiratory polygraphy, The Consortium to Establish a Registry for Alzheimer's Disease Neuropsychological Battery (CERAD NB), Tau, phosphoTau181, amyloid-ß-1-42/1-40, 18F-fluorodeoxyglucose positron emission tomography (F18-FDG-PET). Results: Prevalence of OSA of any severity: 58,7% (Apnea Hypopnea Index (AHI)≥5/h), OSA in a moderate-to-severe extent (AHI≥15/h): 25%. Only 13.1% of MCI patients with OSA reported daytime sleepiness. MCI-OSA patients showed no specific neuropsychological pattern. Presence of OSA was not associated with specific AD biomarker profiles in the whole study group besides a positive association between AD positivity in an AD biomarker sub cohort. Conclusions: OSA is highly prevalent in patients with MCI. It might often remain undiagnosed as only a small number of MCI-OSA patients report daytime sleepiness. OSA could contribute to MCI symptoms and even to AD pathology. Further research is needed to validate these findings and to investigate possible pathophysiological relationships between OSA and MCI as well as between OSA and AD.

Embodied Spatial Navigation Training in Mild Cognitive Impairment: A Proof-of-Concept Trial.

Background: Egocentric and allocentric spatial memory impairments affect the navigation abilities of older adults with mild cognitive impairment (MCI). Embodied cognition research hints that specific aids can be implemented into virtual reality (VR) training to enhance spatial memory. Objective: In this study, we preliminarily tested 'ANTaging', an embodied-based immersive VR training for egocentric and allocentric memory, compared to treatment as usual (TAU) spatial training in MCI. Methods: MCI patients were recruited for this controlled trial. A cognitive battery was administered at pre-test, after ten sessions of ANTaging or TAU intervention, and at 3-month follow-up (FU). The primary outcomes were spatial cognition tests (Corsi supra-span, CSS; Manikin test, MT). VR egocentric and allocentric performance was also collected. Results: We found that ANTaging significantly improved MT scores at FU compared to TAU. CSS slightly improved in both groups. Concerning secondary outcomes, auditory-verbal forgetting significantly improved at post-test in the ANTaging but not TAU group and significantly declined at FU in the TAU but not in the ANTaging group. Global cognition significantly improved at FU for TAU and remained stable for ANTaging. Other tests showed no improvement or deterioration. Clinical significance showed that ANTaging is effective for CSS. Virtual egocentric and allocentric memory performance improved across ANTaging sessions. Conclusions: ANTaging holds the potential to be superior for improving spatial cognition in MCI compared to TAU. Embodied cognition research provides insights for designing effective spatial navigation rehabilitation in aging.

Improving the DSM-5 approach to cognitive impairment: Developmental prosopagnosia reveals the need for tailored diagnoses.

The Diagnostic Statistical Manual of Mental Disorders (DSM-5) recommends diagnosing neurocognitive disorders (i.e., cognitive impairment) when a patient scores beyond - 1 SD below neurotypical norms on two tests. I review how this approach will fail due to cognitive tests' power limitations, validity issues, imperfect reliabilities, and biases, before summarizing their resulting negative consequences. As a proof of concept, I use developmental prosopagnosia, a condition characterized by difficulties recognizing faces, to show the DSM-5 only diagnoses 62-70% (n1 = 61, n2 = 165) versus 100% (n1 = 61) through symptoms alone. Pooling the DSM-5 missed cases confirmed the presence of group-level impairments on objective tests, which were further evidenced through meta-analyses, thus validating their highly atypical symptoms. These findings support a paradigm shift towards bespoke diagnostic approaches for distinct cognitive impairments, including a symptom-based method when validated effective. I reject dogmatic adherence to the DSM-5 approach to neurocognitive disorders, and underscore the importance of a data driven, transdiagnostic approach to understanding patients' subjective cognitive impairments. This will ultimately benefit patients, their families, clinicians, and scientific progress.

Effectiveness of dairy products to protect against cognitive decline in later life: a narrative review.

As the world's population ages the prevalence of age-related health concerns is increasing, including neurodegeneration disorders such as mild cognitive impairment, vascular dementia and Alzheimer's disease. Diet is a key modifiable risk factor for the development of neurodegeneration, likely due to gut-brain axis interactions related to neuroinflammation. Analyses of dietary patterns identified dairy as being part of a cognitively healthy diet; however, its contribution to cognitive outcomes is difficult to discern. This narrative review evaluates the literature to determine whether there is sufficient evidence that the consumption of dairy products helps to maintain cognitive function in later life. A search using the terms (dairy OR milk OR cheese OR yogurt OR yogurt) AND ("mild cognitive impairment" OR dementia OR "Alzheimer's disease") identified 796 articles. After screening and sorting, 23 observational studies and 6 intervention studies were identified. The results of the observational studies implied that the relationship between total dairy consumption and cognitive outcomes is inverse U-shaped, with moderate consumption (1-2 servings per day) being the most beneficial. The analysis of the intake of different types of dairy products indicated that fermented products, particularly cheese, were most likely responsible for the observed benefits. The experimental studies all used dairy-derived peptides produced during fermentation as the dietary intervention, and the results indicated that these could be an effective treatment for early-stage cognitive impairment. Further experimental studies with whole dairy products, particularly fermented dairy, are needed to determine whether the regular consumption of these foods should be recommended to maximize the likelihood of healthy cognitive aging.

Effects of folic acid supplementation on cognitive function and inflammation in elderly patients with mild cognitive impairment: A systematic review and meta-analysis of randomized controlled trials.

OBJECT: The aim was to assess the effect of folic acid supplementation on cognitive function and inflammatory cytokines in elderly patients with mild cognitive impairment. METHODS: From its inception until February 2024, four databases including Web of Science were searched. Two researchers independently screened the literature, assessed the quality, extracted data, and conducted a meta-analysis using RevMan. RESULTS: The systematic review included seven studies (with a total of 1102 participants, mean age 65-80 years), seven of which were appropriate for meta-analysis. Although a small number of studies found relatively large heterogeneity, the majority of studies showed significant benefit from folic acid supplementation, including the FSIQ (823 individuals, standardized mean difference [SMD] = 8.36, 95 % confidence interval [CI] = 0.79 - 1.08), Arithmetic (823 individuals, SMD = 0.17, 95 % CI = -0.03-0.31), Information, SMD = 1.73, 95 % CI 0.41-3.05), Digit Span (823 individuals, SMD = 0.17, 95 % CI = -0.03 - 0.31), Block Design (823 individuals, SMD = 0.26, 95 % CI 0.03-0.49), Picture Completion (823 individuals, SMD = 0.27, 95 % CI = -0.15 - 0.69) and Picture Arrangement (823 individuals, SMD = -0.12, 95 % CI = -0.26 - 0.01). Finally, folic acid supplementation had a significant effect on the reduction of most inflammatory cytokines, blood biomarkers of Alzheimer's disease, and Hcy. CONCLUSIONS: Folic acid supplementation seems to have a positive impact on cognitive function in older adults with mild cognitive impairment, but further evidence of its effectiveness in improving inflammatory cytokines is needed from high-quality studies.

Prevalence of sleep disturbances in people with mild cognitive impairment: A systematic review and meta-analysis.

This review was performed to determine sleep disturbance prevalence in individuals with mild cognitive impairment (MCI). The MEDLINE, Embase, Cochrane Library, CINAHL, PsycINFO, and Web of Science databases were systematically searched from inception to January 20, 2024. Fifty-two studies fulfilling the eligibility criteria were included. However, six of these studies were excluded from data synthesis due to poor methodological quality. The subjective sleep disturbance prevalence among all individuals with MCI was 35.8 % (95 % CI: 31.9-39.7) across 44 studies, and the objective sleep disturbance prevalence was 46.3 % (95 % CI: 36.3-56.3) across 6 studies. Five studies examined TST and WASO, while three assessed SE. Among all potential objective assessments of sleep disturbance prevalence, only TST, WASO, and SE could be meta-analyzed in MCI because of the limited number of studies available. The estimated sleep disturbance prevalence differed significantly according to measurement method, geographical region, and research design. However, the data source did not significantly influence prevalence estimates. In meta-regression analysis, publication year, participant age, percentage of females, and study quality did not predict prevalence. As subjective and objective sleep disturbances are common in people with MCI, effective intervention strategies should be developed to alleviate them.

Association of dual task gait performance with cognitive outcomes among older adults: Piloting an inexpensive, portable assessment platform.

Motor assessment has emerged as complementary evidence for the detection of late life cognitive disorders. Clinicians lack inexpensive, accurate, and portable tools for this purpose. To fill this void, the current study piloted measures from the Mizzou Point-of-care Assessment System a multimodal sensor platform. We examined the ability of these motor function measures to distinguish neurocognitive status and assessed their associations with cognitive performance. Data came from 42 older adults, including 16 with mild cognitive impairment (MCI). Participants performed dual task gait, pairing walking with serial subtraction by sevens, along with aa neuropsychological test battery. T-tests revealed that individuals with MCI demonstrated slower stride times (d = .55) and shorter stride lengths (d = .98) compared to healthy older adults. Results from hierarchical regression showed that stride time and stride length predicted cognitive performance across several domains, after controlling for cognitive status and demographics. Cognitive status moderated this relationship for global cognition and attention, wherein gait measures were significantly related to these outcomes for the cognitively normal group, but not the MCI group. Evidence from the current study provided preliminary support that MPASS measures demonstrate expected associations with cognitive performance and can distinguish amongst those with and without cognitive impairment.

The effects of different types of exercises on cognition in older persons with mild cognitive impairment: A systematic review and meta-analysis.

PURPOSE: This systematic review with meta-analysis aims to analyze the effects of different types of exercise on cognition, neuroprotective and neuroinflammatory blood markers in older adults with mild cognitive impairment (MCI). METHODS: Relevant studies were identified using PubMED, SPORTDiscuss, Web of Science, Scopus, and PsycInfo databases. Methodological quality assessment of the studies was done with modified Downs and Black checklist. Data obtained from the included studies was analyzed using Comprehensive Meta-Analysis 4.0 software and results were reported using the random effects method. RESULTS: A total of twenty-three studies were identified. The findings were summarized as change in cognitive function after the exercise interventions in general and after each type of exercise. On average, the exercise intervention revealed an effect size (ES): 1.165; 0.741 to 1.589 (95% Confidence Interval (CI); p < 0.001); aerobic exercise ES: 1.442; 0.624 to 2.260 (95 %CI); p = 0.001; Multimodal ES: 0,856; 0.366 to 1.346 (95 % CI); p = 0.001 and resistance exercise ES: 1.229; 0.339 to 2.120 (95 % CI); p = 0.007. In addition, we observed significant small ES: -0.475; -0.817 to -0.134 (95 %CI); p = 0.006, I2= 0 %; τ2 = 0 of exercise effects on Tumor Necrosis Factor-α (TNF-α) and non-significant large ES:0.952; -0.238 to 2.142 (95 %CI); p = 0.117 on Brain Derived Neurotrophic Factor (BDNF) in persons with MCI. CONCLUSION: The present study revealed the existence of a large positive effect of overall exercise intervention on cognitive function and a small effect on TNF-α in old people with MCI. Additionally, this study demonstrates that aerobic and resistance exercises had similar larger positive effects and were better than multimodal exercise on increasing cognition in older persons with MCI.

Compared to exercise, the effects of exercise combined with cognitive training in people with mild cognitive impairment: a network meta-analysis.

OBJECTIVES: The study aimed to evaluate the relative effectiveness of exercise combined with cognitive training (E&CT) in improving cognitive function compared to exercise alone. METHOD: PubMed, Embase, Cochrane Central Register of Controlled Trials, SPORTDiscus, and OpenGrey were systematically searched. Additional screenings were performed by reviewing citations of relevant articles. Studies were included if they met inclusion criteria. Both pairwise and network meta-analyses were performed using a random effects model in Stata 15.0. RESULTS: Totally, 46 trials from 54 literature (n = 2846) were eligible for inclusion in the meta-analysis. The network meta-analysis indicated that exercise alone was more efficacious than E&CT in improving global cognition and multicomponent exercise exhibited the highest likelihood (SUCRA value= 89.0%) of being the most effective type. Regarding memory function, E&CT presented greater potential than exercise alone, with the interactive modality ranking first (SUCRA value = 88.4%). Multicomponent exercise was identified as the top intervention for enhancing executive function. The overall quality of the included studies was rated as moderate, and the certainty of evidence ranged from low to high. CONCLUSION: Multicomponent exercise emerged as the optimal intervention for improving global cognition and executive function. Nevertheless, for memory function, the interactive modality of E&CT demonstrated the highest probability of being the most effective choice.

Pattern of heterogeneity in normal brain ageing: screening for mild cognitive impairment and its risk of progression with a radiomics model.

PURPOSE: This study aimed to develop a normal brain ageing model based on magnetic resonance imaging and radiomics, therefore identifying radscore, an imaging indicator representing white matter heterogeneity and exploring the significance of radscore in detecting people's cognitive changes. METHODS: Three hundred sixty cognitively normal (CN) subjects from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database and 105 CN subjects from the Parkinson's Progression Markers Initiative database were used to develop the model. In ADNI, 230 mild cognitive impairment (MCI) subjects were matched with 230 CN old-aged subjects to evaluate their heterogeneity difference. One hundred four MCI subjects with 48 months of follow-up were divided into low and high heterogeneity groups. Kaplan-Meier survival curve analysis was used to observe the importance of heterogeneity results for predicting MCI progression. RESULTS: The area under the receiver operating characteristic curve of the model in the training, internal test and external test sets was 0.7503, 0.7512 and 0.7514, respectively. There was a significantly positive correlation between age and radscore of CN subjects (r = 0.501; P < .001). The radscore of MCI subjects was significantly higher than that of matched CN subjects (P < .001). The median radscore ratios of MCI to CN from four age groups (66-70y, 71-75y, 76-80y and 81-85y) were 1.611, 1.760, 1.340 and 1.266, respectively. The probability to progression of low and high heterogeneity groups had a significant difference (P = .002). CONCLUSION: When radscore is significantly higher than that of normal ageing, it is necessary to alert the possibility of cognitive impairment and deterioration.

Spontaneous cerebrovascular reactivity at rest in older adults with and without mild cognitive impairment and memory deficits.

Background: Older adults with mild cognitive impairment (MCI) exhibit deficits in cerebrovascular reactivity (CVR), suggesting CVR is a biomarker for vascular contributions to MCI. This study examined if spontaneous CVR is associated with MCI and memory impairment. Methods: 161 older adults free of dementia or major neurological/psychiatric disorders were recruited. Participants underwent clinical interviews, cognitive testing, venipuncture for Alzheimer's biomarkers, and brain MRI. Spontaneous CVR was quantified during 5 minutes of rest. Results: Whole brain CVR was negatively associated with age, but not MCI. Lower CVR in the parahippocampal gyrus (PHG) was found in participants with MCI and was linked to worse memory performance on memory tests. Results remained significant after adjusting for Alzheimer's biomarkers and vascular risk factors. Conclusion: Spontaneous CVR deficits in the PHG are observed in older adults with MCI and memory impairment, indicating medial temporal microvascular dysfunction's role in cognitive decline.

Abnormal white matter integrity of anterior-inferior hypothalamus in mild cognitive impairment patients with depression symptoms.

BACKGROUND: The hypothalamus is a key brain structure involved in the pathogenesis of depression, and its abnormal activity is considered an important pathological mechanism for the formation of depression. The presence of abnormalities in the white matter integrity of hypothalamic subregions in mild cognitive impairment with depressive symptoms (D-MCI) remains unknown. METHODS: In this study, we used diffusion tensor imaging (DTI) to explore the white matter integrity of hypothalamic subregions in D-MCI. On a 3 T magnetic resonance imaging scanner, we collected DTI data from 63 subjects. The subjects included 20 healthy controls (HC), 23 MCI patients without depression (nD-MCI), and 20 patients with D-MCI. The differences in DTI metrics of hypothalamic subregions of the three groups were compared using analysis of variance and post hoc t-tests. We looked at the relationship between clinical variables and DTI metrics in hypothalamus subregions using Pearson correlation analysis. RESULTS: Compared with nD-MCI and HC groups, D-MCI group showed increased fractional anisotropy (FA) in anterior-inferior hypothalamus. There was a weak negative correlation between FA values in the anterior-inferior hypothalamus and depression scores in D-MCI patients. CONCLUSIONS: Our findings suggest that depressive symptoms in MCI patients are associated with abnormal white matter integrity in the anterior-inferior hypothalamus.

A randomized, double-blind, placebo-controlled study of Cistanche tubulosa and Ginkgo biloba extracts for the improvement of cognitive function in middle-aged and elderly people.

Mild cognitive impairment poses an increasing challenge to middle-aged and elderly populations. Traditional Chinese medicinal herbs like Cistanche tubulosa and Ginkgo biloba (CG) have been proposed as potential agents to improve cognitive and memory functions. A randomized controlled trial involving 100 Chinese middle-aged and elderly participants was conducted to investigate the potential synergistic effects of CG on cognitive function in individuals at risk of neurodegenerative diseases. Over 90 days, both CG group and placebo group received two tablets daily, with each pair of CG tablets containing 72 mg echinacoside and 27 mg flavonol glycosides. Cognitive functions were assessed using multiple scales and blood biomarkers were determined at baseline, Day 45, and Day 90. The CG group exhibited significant improvements in the scores of Mini-Mental State Examination (26.5 at baseline vs. 27.1 at Day 90, p < 0.001), Montreal Cognitive Assessment (23.4 at baseline vs. 25.3 at Day 90, p < 0.001), and World Health Organization Quality of Life (81.6 at baseline vs. 84.2 at Day 90, p < 0.001), all surpassing scores in placebo group. Notably, both the Cognitrax matrix test and the Wechsler Memory Scale-Revised demonstrated enhanced memory functions, including long-term and delayed memory, after CG intervention. Moreover, cognitive-related blood biomarkers, including total tau, pT181, pS199, pT231, pS396, and thyroid-stimulating hormone, significantly decreased, whereas triiodothyronine and free triiodothyronine significantly increased. No treatment-related adverse events were reported, and routine blood and urine tests remained stable. These findings indicated that CG supplementation could potentially serve as an effective supplementary solution for enhancing cognitive and memory functions.

Predicting the Conversion from Mild Cognitive Impairment to Alzheimer's Disease Using Graph Frequency Bands and Functional Connectivity-Based Features.

Accurate prediction of the progression from mild cognitive impairment (MCI) to Alzheimer's disease (AD) is crucial for disease management. Machine learning techniques have demonstrated success in classifying AD and MCI cases, particularly with the use of resting-state functional magnetic resonance imaging (rs-fMRI) data.This study utilized three years of rs-fMRI data from the ADNI, involving 142 patients with stable MCI (sMCI) and 136 with progressive MCI (pMCI). Graph signal processing was applied to filter rs-fMRI data into low, middle, and high frequency bands. Connectivity-based features were derived from both filtered and unfiltered data, resulting in a comprehensive set of 100 features, including global graph metrics, minimum spanning tree (MST) metrics, triadic interaction metrics, hub tendency metrics, and the number of links. Feature selection was enhanced using particle swarm optimization (PSO) and simulated annealing (SA). A support vector machine (SVM) with a radial basis function (RBF) kernel and a 10-fold cross-validation setup were employed for classification. The proposed approach demonstrated superior performance, achieving optimal accuracy with minimal feature utilization. When PSO selected five features, SVM exhibited accuracy, specificity, and sensitivity rates of 77%, 70%, and 83%, respectively. The identified features were as follows: (Mean of clustering coefficient, Mean of strength)/Radius/(Mean Eccentricity, and Modularity) from low/middle/high frequency bands of graph. The study highlights the efficacy of the proposed framework in identifying individuals at risk of AD development using a parsimonious feature set. This approach holds promise for advancing the precision of MCI to AD progression prediction, aiding in early diagnosis and intervention strategies.

Mild cognitive impairment and microbiota: what is known and future perspectives.

Mild cognitive impairment (MCI) is a heterogeneous condition definable as the intermediate clinical state between normal aging and dementia. As a pre-dementia condition, there is a recent growing interest in the identification of non-invasive markers able to predict the progression from MCI to a more advanced stage of the disease. Previous evidence showed the close link between gut microbiota and neurodegenerative diseases, such as Alzheimer's (AD) and Parkinson's disease (PD). Conversely, the actual relationship between gut microbiota and MCI is yet to be clarified. In this work, we provide an overview about the current knowledge regarding the role of gut microbiota in the context of MCI, also assessing the potential for microbiota-targeted therapies. Through the review of the most recent studies focusing on this topic, we found evidence of an increase of Bacteroidetes at phylum level and Bacteroides at genus level in MCI subjects with respect to healthy controls and patients with AD. Despite such initial evidence, the definitive identification of a typical microbiota profile associated with MCI is still far from being achieved. These preliminary results, however, are growingly encouraging research on the role of gut microbiota modulation in improving the cognitive status of pre-dementia subjects. To date, few studies evaluated the role of probiotics in MCI subjects, and they showed favorable results, although still biased by small sample size, heterogeneity of study design and short follow-up.

Neurovascular coupling, functional connectivity, and cerebrovascular endothelial extracellular vesicles as biomarkers of mild cognitive impairment.

INTRODUCTION: Mild cognitive impairment (MCI) is a prodromal stage of dementia. Understanding the mechanistic changes from healthy aging to MCI is critical for comprehending disease progression and enabling preventative intervention. METHODS: Patients with MCI and age-matched controls (CN) were administered cognitive tasks during functional near-infrared spectroscopy (fNIRS) recording, and changes in plasma levels of extracellular vesicles (EVs) were assessed using small-particle flow cytometry. RESULTS: Neurovascular coupling (NVC) and functional connectivity (FC) were decreased in MCI compared to CN, prominently in the left-dorsolateral prefrontal cortex (LDLPFC). We observed an increased ratio of cerebrovascular endothelial EVs (CEEVs) to total endothelial EVs in patients with MCI compared to CN, correlating with structural MRI small vessel ischemic damage in MCI. LDLPFC NVC, CEEV ratio, and LDLPFC FC had the highest feature importance in the random Forest group classification. DISCUSSION: NVC, CEEVs, and FC predict MCI diagnosis, indicating their potential as markers for MCI cerebrovascular pathology. HIGHLIGHTS: Neurovascular coupling (NVC) is impaired in mild cognitive impairment (MCI). Functional connectivity (FC) compensation mechanism is lost in MCI. Cerebrovascular endothelial extracellular vesicles (CEEVs) are increased in MCI. CEEV load strongly associates with cerebral small vessel ischemic lesions in MCI. NVC, CEEVs, and FC predict MCI diagnosis over demographic and comorbidity factors.

Nanoscale flow cytometry-based quantification of blood-based extracellular vesicle biomarkers distinguishes MCI and Alzheimer's disease.

INTRODUCTION: Accurate testing for Alzheimer's disease (AD) represents a crucial step for therapeutic advancement. Currently, tests are expensive and require invasive sampling or radiation exposure. METHODS: We developed a nanoscale flow cytometry (nFC)-based assay of extracellular vesicles (EVs) to screen biomarkers in plasma from mild cognitive impairment (MCI), AD, or controls. RESULTS: Circulating amyloid beta (Aß), tau, phosphorylated tau (p-tau)181, p-tau231, p-tau217, p-tauS235, ubiquitin, and lysosomal-associated membrane protein 1-positive EVs distinguished AD samples. p-tau181, p-tau217, p-tauS235, and ubiquitin-positive EVs distinguished MCI samples. The most sensitive marker for AD distinction was p-tau231, with an area under the receiver operating characteristic curve (AUC) of 0.96 (sensitivity 0.95/specificity 1.0) improving to an AUC of 0.989 when combined with p-tauS235. DISCUSSION: This nFC-based assay accurately distinguishes MCI and AD plasma without EV isolation, offering a rapid approach requiring minute sample volumes. Incorporating nFC-based measurements in larger populations and comparison to "gold standard" biomarkers is an exciting next step for developing AD diagnostic tools. HIGHLIGHTS: Extracellular vesicles represent promising biomarkers of Alzheimer's disease (AD) that can be measured in the peripheral circulation. This study demonstrates the utility of nanoscale flow cytometry for the measurement of circulating extracellular vesicles (EVs) in AD blood samples. Multiple markers including amyloid beta, tau, phosphorylated tau (p-tau)181, p-tau231, p-tau217, and p-tauS235 accurately distinguished AD samples from healthy controls. Future studies should expand blood and cerebrospinal fluid-based EV biomarker development using nanoflow cytometry approaches.

Role of Metalloproteinases in Diabetes-associated Mild Cognitive Impairment.

Diabetes has been linked to an increased risk of mild cognitive impairment (MCI), a condition characterized by a subtle cognitive decline that may precede the development of dementia. The underlying mechanisms connecting diabetes and MCI involve complex interactions between metabolic dysregulation, inflammation, and neurodegeneration. A critical mechanism implicated in diabetes and MCI is the activation of inflammatory pathways. Chronic low-grade inflammation, as observed in diabetes, can lead to the production of pro-inflammatory cytokines such as tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), interleukin-1 beta (IL-1ß), and interferon-gamma (IFNγ), each of which can exacerbate neuroinflammation and contribute to cognitive decline. A crucial enzyme involved in regulating inflammation is ADAM17, a disintegrin, and metalloproteinase, which can cleave and release TNF-α from its membrane-bound precursor and cause it to become activated. These processes, in turn, activate additional inflammation-related pathways, such as AKT, NF-κB, NLP3, MAPK, and JAK-STAT pathways. Recent research has provided novel insights into the role of ADAM17 in diabetes and neurodegenerative diseases. ADAM17 is upregulated in both diabetes and Alzheimer's disease, suggesting a shared mechanism and implicating inflammation as a possible contributor to much broader forms of pathology and pointing to a possible link between inflammation and the emergence of MCI. This review provides an overview of the different roles of ADAM17 in diabetes-associated mild cognitive impairment diseases. It identifies mechanistic connections through which ADAM17 and associated pathways may influence the emergence of mild cognitive impairment.

Prolonged ventricular repolarization associated with mild cognitive impairment and white matter hyperintensities: a cross-sectional study.

Prolonged ventricular repolarization has been associated with cardiovascular disease. We sought to investigate the association of prolonged ventricular repolarization with mild cognitive impairment (MCI) and the potential underlying neuropathological mechanisms in older adults. This cross-sectional study included 4328 dementia-free participants (age ≥ 65 years; 56.8% female) in the baseline examination of the Multidomain INterventions to delay dementia and Disability in rural China; of these, 989 undertook structural brain magnetic resonance imaging (MRI) scans. QT, QTc, JT, JTc, and QRS intervals were derived from 12-lead electrocardiograph. MCI, amnestic MCI (aMCI), and non-amnestic MCI (naMCI) were defined following the Petersen's criteria. Volumes of gray matter (GM), white matter, cerebrospinal fluid, total white matter hyperintensities (WMH), periventricular WMH (PWMH), and deep WMH (DWMH) were automatically estimated. Data were analyzed using logistic and general linear regression models. Prolonged QT, QTc, JT, and JTc intervals were significantly associated with an increased likelihood of MCI and aMCI, but not naMCI (p < 0.05). In the MRI subsample, QT, QTc, JT, and JTc intervals were significantly associated with larger total WMH and PWMH volumes (p < 0.05), but not with DWMH volume. Statistical interactions were detected, such that prolonged QT and JT intervals were significantly associated with reduced GM volume only among participants with coronary heart disease or without APOE ε4 allele (p < 0.05). Prolonged ventricular repolarization is associated with MCI and cerebral microvascular lesions in a general population of older adults. This underlies the importance of cognitive assessments and brain MRI examination among older adults with prolonged QT interval.