Extracellular vesicle biomarkers of Alzheimer's disease associated with sub-clinical cognitive decline in late middle age.
Ontology highlight
ABSTRACT: Introduction
Neuronal extracellular vesicle (nEV) tau and insulin signaling biomarkers may detect preclinical Alzheimer's disease and age-associated cognitive decline.Methods
This case-control study used repeated serum samples from 73 cognitively declining and 73 stable Wisconsin Registry for Alzheimer's Prevention participants (62.4 ± 6.3 years old). We immunocaptured nEVs; measured tau and insulin signaling biomarkers; and examined biomarker differences by group, their performance in group classification in training and test datasets (97, 49 individuals, respectively), and whether they predict cognitive performance change.Results
Declining compared to stable individuals showed higher baseline total, p231-, and p181-tau with older age and higher annualized change for p-IR and p-IGF-1R. Combining biomarkers classified decliners with 94% area under the curve (AUC), 86.0% sensitivity and 86.7% specificity, in training data, and 75% AUC, 71.4% sensitivity, and 77.3% specificity, in test data. Insulin biomarkers predicted cognitive performance change prospectively.Discussion
Combining nEV biomarkers can identify individuals with age-associated cognitive decline.
SUBMITTER: Eren E
PROVIDER: S-EPMC7984100 | biostudies-literature |
REPOSITORIES: biostudies-literature
Similar Datasets
Project description:This study investigated differences in retrospective cognitive trajectories between amyloid and tau PET biomarker stratified groups in initially cognitively unimpaired participants sampled from the Wisconsin Registry for Alzheimer's Prevention. One hundred and sixty-seven initially unimpaired individuals (baseline age 59 ± 6 years; 115 females) were stratified by elevated amyloid-β and tau status based on 11C-Pittsburgh compound B (PiB) and 18F-MK-6240 PET imaging. Mixed effects models were used to determine if longitudinal cognitive trajectories based on a composite of cognitive tests including memory and executive function differed between biomarker groups. Secondary analyses investigated group differences for a variety of cross-sectional health and cognitive tests, and associations between 18F-MK-6240, 11C-PiB, and age. A significant group × age interaction was observed with post hoc comparisons indicating that the group with both elevated amyloid and tau pathophysiology were declining approximately three times faster in retrospective cognition compared to those with just one or no elevated biomarkers. This result was robust against various thresholds and medial temporal lobe regions defining elevated tau. Participants were relatively healthy and mostly did not differ between biomarker groups in health factors at the beginning or end of study, or most cognitive measures at study entry. Analyses investigating association between age, MK-6240 and PiB indicated weak associations between age and 18F-MK-6240 in tangle-associated regions, which were negligible after adjusting for 11C-PiB. Strong associations, particularly in entorhinal cortex, hippocampus and amygdala, were observed between 18F-MK-6240 and global 11C-PiB in regions associated with Braak neurofibrillary tangle stages I-VI. These results suggest that the combination of pathological amyloid and tau is detrimental to cognitive decline in preclinical Alzheimer's disease during late middle-age. Within the Alzheimer's disease continuum, middle-age health factors likely do not greatly influence preclinical cognitive decline. Future studies in a larger preclinical sample are needed to determine if and to what extent individual contributions of amyloid and tau affect cognitive decline. 18F-MK-6240 shows promise as a sensitive biomarker for detecting neurofibrillary tangles in preclinical Alzheimer's disease.
| S-EPMC6935717 | biostudies-literature
Project description:BackgroundInsulin resistance is implicated in Alzheimer's disease (AD), whereas intranasal insulin is an experimental treatment in clinical trials. We previously proposed insulin signaling mediators in plasma neuronal-enriched extracellular vesicles (EVs) as biomarkers of brain insulin resistance.ObjectiveWe sought to demonstrate the capacity of neuronal-enriched EV biomarkers to demonstrate target engagement in response to intranasal insulin and their ability to track treatment-associated cognitive changes in AD.MethodsWe isolated neuronal-enriched EVs from plasma samples of participants with amnestic mild cognitive impairment or probable AD involved in a 4-month duration placebo-controlled clinical trial of 20 or 40 IU intranasal insulin. We measured insulin signaling mediators as biomarkers and examined treatment-associated changes and their relationship with cognitive performance (ADAS-Cog).ResultsThere were no EV biomarker changes from baseline in any of the treatment groups. In participants treated with 20 IU insulin, EV biomarkers of insulin resistance (pS312-IRS-1, pY-IRS-1) showed strong positive correlations with ADAS-Cog changes, especially in ApoE ɛ4 non-carriers.ConclusionNeuronal EV biomarkers of insulin resistance (pS312-IRS-1, pY-IRS-1) were associated with cognitive changes in response to low dose intranasal insulin suggesting engagement of the insulin cascade in neurons of origin.
| S-EPMC6668911 | biostudies-literature
Project description:Age-related changes in cognition are partially mediated by the presence of neuropathology and neurodegeneration. This manuscript evaluates the degree to which biomarkers of Alzheimer's disease, (AD) neuropathology and longitudinal changes in brain structure, account for age-related differences in cognition. Data from the AD Neuroimaging Initiative (n = 1012) were analyzed, including individuals with normal cognition and mild cognitive impairment. Parallel process mixed effects regression models characterized longitudinal trajectories of cognitive variables and time-varying changes in brain volumes. Baseline age was associated with both memory and executive function at baseline (p's < 0.001) and change in memory and executive function performances over time (p's < 0.05). After adjusting for clinical diagnosis, baseline, and longitudinal changes in brain volume, and baseline levels of cerebrospinal fluid biomarkers, age effects on change in episodic memory and executive function were fully attenuated, age effects on baseline memory were substantially attenuated, but an association remained between age and baseline executive function. Results support previous studies that show that age effects on cognitive decline are fully mediated by disease and neurodegeneration variables but also show domain-specific age effects on baseline cognition, specifically an age pathway to executive function that is independent of brain and disease pathways.
| S-EPMC5710827 | biostudies-literature
Project description:Sepsis is a life-threatening condition with high hospital mortality. Elevated mortality has also been observed in patients after hospital discharge, associated with post sepsis syndrome (PSS), causing systemic impairments and reduced life quality. The etiology of PSS is still not completely known but certainly involves inflammation. Extracellular vesicles (EV) are recognized as a notable mechanism of intercellular communication in inflammatory processes. It has been reported that EV microRNA (miRNA) production patterns during the acute phase of the disease may persist until after sepsis resolution and are associated with PSS. Methods: We employed mass spectrometry and qPCR to characterize the protein and miRNA composition of plasma-derived EVs of 35 patients during sepsis-related hospitalization and after discharge (post-sepsis) for up to three years. Findings: Fifteen differentially expressed EVs miRNAs (DEMiRs) were identified in septic patients compared to the control group. Predictive analyses revealed that these DEMiRs could influence inflammation by modulating pathways mediated by the activation of NF-κB, STAT3, and TLR4. Thirteen miRNAs (-15b-5p, -16-5p, -20a-5p, -25-3p, -27a-3p, -29a-3p, -30d-5p, -93-5p, -146a-5p, -148a -3p, -191-5p, -195-5p, -223-3p) were downregulated in the death group compared to the survivor group and are candidates for serving as prognostic markers of survival in the Intensive Care Unit. The expression of 11 miRNAs (-15b-5p, -16-5p, -21-5p, -25-3p, -27a-3p, -29a-3p, -30d-5p, -93-5p, -146a-5p -195- 5p and -223-3p) was lower one year after ICU discharge than the control group. Interpretation: The miRNAs identified in the present study represent potential biomarkers for the survival prognosis of post-sepsis patients.
2022-08-03 | GSE210335 | GEO
Project description:With ever-increasing elder populations, age-related cognitive decline, which is characterized as a gradual decline in cognitive capacity in the aging process, has turned out to be a mammoth public health concern. Since genetic information has become increasingly important to explore the biological mechanisms of cognitive decline, the search for genetic biomarkers of cognitive aging has received much attention. There is growing evidence that single-nucleotide polymorphisms (SNPs) within the ADAMTS9, BDNF, CASS4, COMT, CR1, DNMT3A, DTNBP1, REST, SRR, TOMM40, circadian clock, and Alzheimer's diseases-associated genes may contribute to susceptibility to cognitive aging. In this review, we first illustrated evidence of the genetic contribution to disease susceptibility to age-related cognitive decline in recent studies ranging from approaches of candidate genes to genome-wide association studies. We then surveyed a variety of association studies regarding age-related cognitive decline with consideration of gene-gene and gene-environment interactions. Finally, we highlighted their limitations and future directions. In light of advances in precision medicine and multi-omics technologies, future research in genomic medicine promises to lead to innovative ideas that are relevant to disease prevention and novel drugs for cognitive aging.
| S-EPMC5702307 | biostudies-literature
Project description:We tested association of nine late-onset Alzheimer's disease (LOAD) risk variants from genome-wide association studies (GWAS) with memory and progression to mild cognitive impairment (MCI) or LOAD (MCI/LOAD) in older Caucasians, cognitively normal at baseline and longitudinally evaluated at Mayo Clinic Rochester and Jacksonville (n>2000). Each variant was tested both individually and collectively using a weighted risk score. APOE-e4 associated with worse baseline memory and increased decline with highly significant overall effect on memory. CLU-rs11136000-G associated with worse baseline memory and incident MCI/LOAD. MS4A6A-rs610932-C associated with increased incident MCI/LOAD and suggestively with lower baseline memory. ABCA7-rs3764650-C and EPHA1-rs11767557-A associated with increased rates of memory decline in subjects with a final diagnosis of MCI/LOAD. PICALM-rs3851179-G had an unexpected protective effect on incident MCI/LOAD. Only APOE-inclusive risk scores associated with worse memory and incident MCI/LOAD. The collective influence of the nine top LOAD GWAS variants on memory decline and progression to MCI/LOAD appears limited. Discovery of biologically functional variants at these loci may uncover stronger effects on memory and incident disease.
| S-EPMC4268433 | biostudies-literature
Project description:Identifying older adults at risk of cognitive decline represents a challenge as Alzheimer's disease (AD) modifying therapies move toward preclinical stages.To investigate the relationship between AD biomarkers and subsequent change in cognition in a cohort of cognitively intact older adults.84 cognitively normal subjects (mean age 72.0 years, 59% women) were recruited through the Massachusetts Alzheimer's Disease Research Center and the Harvard Aging Brain Study and followed over 3 years. Measurements of amyloid-? 1-42 (A?42), total Tau (t-Tau), and Tau phosphorylated at threonine 181 (p-Tau181) in the cerebrospinal fluid (CSF) at study entry were available in all cases. Baseline brain MRI, FDG-PET, and PiB-PET data were available in the majority of participants. Relationship between baseline AD biomarkers and longitudinal change in cognition was assessed using Cox proportional hazard regression and linear mixed models.14% participants increased their global Clinical Dementia Rating (CDR) score from 0 to 0.5 during follow-up. A CDR score increase was associated with higher baseline CSF t-Tau and p-Tau181, higher global cortical PiB retention, and lower hippocampal volume. The combination of high CSF t-Tau and low A?42 or low hippocampal volume was more strongly related to cognitive outcome than each single biomarker. Higher CSF t-Tau was the only biomarker associated with subsequent decline in MMSE score.Baseline CSF t-Tau and p-Tau181, in vivo amyloid load, and hippocampal volume were all independently associated with future decline in cognition. The discriminatory ability of these biomarkers to predict risk of cognitive decline, however, was only modest.
| S-EPMC5773095 | biostudies-literature
Project description:IntroductionThe presence of multiple cardiometabolic diseases (CMDs) has been linked to increased dementia risk, but the combined influence of CMDs on cognition and brain structure across the life course is unclear.MethodsIn the UK Biobank, 46,562 dementia-free participants completed a cognitive test battery at baseline and a follow-up visit 9 years later, at which point 39,306 also underwent brain magnetic resonance imaging. CMDs (diabetes, heart disease, and stroke) were ascertained from medical records. Data were analyzed using age-stratified (middle age [< 60] versus older [≥ 60]) mixed-effects models and linear regression.ResultsA higher number of CMDs was associated with significantly steeper global cognitive decline in older (β = -0.008; 95% confidence interval: -0.012, -0.005) but not middle age. Additionally, the presence of multiple CMDs was related to smaller total brain volume, gray matter volume, white matter volume, and hippocampal volume and larger white matter hyperintensity volume, even in middle age.DiscussionCMDs are associated with cognitive decline in older age and poorer brain structural health beginning already in middle age.HighlightsWe explored the association of CMDs with cognitive decline and brain MRI measures.CMDs accelerated cognitive decline in older (≥60y) but not middle (<60) age.CMDs were associated with poorer brain MRI parameters in both middle and older age.Results highlight the connection between CMDs and cognitive/brain aging.
| S-EPMC11002777 | biostudies-literature
Project description:Community dwelling older individuals from the North Florida region were examined for health status and a comprehensive neuropsychological battery, including the Montreal Cognitive Assessment (MoCA), was performed on each participant. A subpopulation (58 females and 39 males) met the criteria for age (60-89) and no evidence of mild cognitive impairment, with a MoCA score ?23. Despite the stringent criteria for participation, MoCA scores were negatively correlated within the limited age range. Extracellular microvesicles were isolated from the plasma and samples were found to be positive for the exosome marker CD63, with an enrichment of particles within the size range for exosomes. miRNA was extracted and examined using next generation sequencing with a stringent criterion (average of ?10 counts per million reads) resulting in 117 miRNA for subsequent analysis. Characterization of expression confirmed pervious work concerning the relative abundance and overall pattern of expression of miRNA in plasma. Correlation analysis indicated that most of the miRNAs (74 miRNAs) were positively correlated with age (p <0.01). Multiple regression was employed to identify the relationship of miRNA expression and MoCA score, accounting for age. MoCA scores were negatively correlated with 13 miRNAs. The pattern of expression for cognition-related miRNA did not match that previously described for Alzheimer's disease. Enrichment analysis was employed to identify miRNA-gene interactions to reveal possible links to brain function.
| S-EPMC5632661 | biostudies-literature
Project description:In this paper, we explore the utility of resting-state EEG measures as potential biomarkers for the detection and assessment of cognitive decline in mild cognitive impairment (MCI) and Alzheimer's disease (AD). Neurophysiological biomarkers of AD derived from EEG and FDG-PET, once characterized and validated, would expand the set of existing diagnostic molecular biomarkers of AD pathology with associated biomarkers of disease progression and neural dysfunction. Since symptoms of AD often begin to appear later in life, successful identification of EEG-based biomarkers must account for age-related neurophysiological changes that occur even in healthy individuals. To this end, we collected EEG data from individuals with AD (n = 26), MCI (n = 53), and cognitively normal healthy controls stratified by age into three groups: 18-40 (n = 129), 40-60 (n = 62) and 60-90 (= 55) years old. For each participant, we computed power spectral density at each channel and spectral coherence between pairs of channels. Compared to age matched controls, in the AD group, we found increases in both spectral power and coherence at the slower frequencies (Delta, Theta). A smaller but significant increase in power of slow frequencies was observed for the MCI group, localized to temporal areas. These effects on slow frequency spectral power opposed that of normal aging observed by a decrease in the power of slow frequencies in our control groups. The AD group showed a significant decrease in the spectral power and coherence in the Alpha band consistent with the same effect in normal aging. However, the MCI group did not show any significant change in the Alpha band. Overall, Theta to Alpha ratio (TAR) provided the largest and most significant differences between the AD group and controls. However, differences in the MCI group remained small and localized. We proposed a novel method to quantify these small differences between Theta and Alpha bands' power using empirically derived distributions of spectral power across the time domain as opposed to averaging power across time. We defined Power Distribution Distance Measure (PDDM) as a distance measure between probability distribution functions (pdf) of Theta and Alpha power. Compared to average TAR, using PDDF enhanced the statistical significance, the effect size, and the spatial distribution of significant effects in the MCI group. We designed classifiers for differentiating individual MCI and AD participants from age-matched controls. The classification performance measured by the area under ROC curve after cross-validation were AUC = 0.85 and AUC = 0.6, for AD and MCI classifiers, respectively. Posterior probability of AD, TAR, and the proposed PDDM measure were all significantly correlated with MMSE score and neuropsychological tests in the AD group.
| S-EPMC7864432 | biostudies-literature