Similar Datasets
Project description:Transcriptional regulation loss disturbs the brain function and indicates detrimental clinical outcomes of Alzheimer's disease
| PRJNA529858 | ENA
Project description:Alzheimer's disease (AD) causes alterations of brain network structure and function. The latter consists of connectivity changes between oscillatory processes at different frequency channels. We proposed a multi-layer network approach to analyze multiple-frequency brain networks inferred from magnetoencephalographic recordings during resting-states in AD subjects and age-matched controls. Main results showed that brain networks tend to facilitate information propagation across different frequencies, as measured by the multi-participation coefficient (MPC). However, regional connectivity in AD subjects was abnormally distributed across frequency bands as compared to controls, causing significant decreases of MPC. This effect was mainly localized in association areas and in the cingulate cortex, which acted, in the healthy group, as a true inter-frequency hub. MPC values significantly correlated with memory impairment of AD subjects, as measured by the total recall score. Most predictive regions belonged to components of the default-mode network that are typically affected by atrophy, metabolism disruption and amyloid-β deposition. We evaluated the diagnostic power of the MPC and we showed that it led to increased classification accuracy (78.39%) and sensitivity (91.11%). These findings shed new light on the brain functional alterations underlying AD and provide analytical tools for identifying multi-frequency neural mechanisms of brain diseases.
| S-EPMC5589939 | biostudies-literature
Project description:IntroductionMitochondrial dysfunction is observed in Alzheimer's disease (AD). However, the relationship between functional mitochondrial deficits and AD pathologies is not well established in human subjects.MethodsPost-mortem human brain tissue from 11 non-demented (ND) and 12 AD subjects was used to examine mitochondrial electron transport chain (ETC) function. Data were analyzed by neuropathology diagnosis and Apolipoprotein E (APOE) genotype. Relationships between AD pathology and mitochondrial function were determined.ResultsAD subjects had reductions in brain cytochrome oxidase (COX) function and complex II Vmax. APOE ε4 carriers had COX, complex II and III deficits. AD subjects had reduced expression of Complex I-III ETC proteins, no changes were observed in APOE ε4 carriers. No correlation between p-Tau Thr 181 and mitochondrial outcomes was observed, although brains from non-demented subjects demonstrated positive correlations between Aβ concentration and COX Vmax.DiscussionThese data support a dysregulated relationship between brain mitochondrial function and Aβ pathology in AD.
| S-EPMC9329272 | biostudies-literature
Project description:INTRODUCTION:Effectiveness of Alzheimer's disease (AD) treatments is commonly evaluated with coprimary outcomes; cognition with function to ensure clinical meaningfulness of a cognitive effect. METHODS:We reviewed the literature for functional outcomes in mild AD or mild cognitive impairment (MCI) patients (distinct from combined mild-moderate/severe AD) treated with approved AD drugs. Cognitive and functional treatment differences in mild AD patients in solanezumab EXPEDITION/EXPEDITION2 studies were compared across time. RESULTS:Seven publications provided MCI/mild AD functional outcomes, one of which reported a significant functional treatment effect. Secondary analyses of EXPEDITION studies suggested a smaller functional effect of solanezumab relative to cognition. An increasing effect of solanezumab over 18 months was shown for cognition and function. DISCUSSION:Function as the sole measure to demonstrate clinical meaningfulness of cognitive effects in mild AD may have limitations. For disease-modifying treatments, point differences on cognitive and functional scales should be qualified with duration of treatment.
| S-EPMC4879645 | biostudies-other
Project description:BackgroundMicroglia, the brain's principal immune cell, are increasingly implicated in Alzheimer's disease (AD), but the molecular interfaces through which these cells contribute to amyloid beta (Aβ)-related neurodegeneration are unclear. We recently identified microglial contributions to the homeostatic and disease-associated modulation of perineuronal nets (PNNs), extracellular matrix structures that enwrap and stabilize neuronal synapses, but whether PNNs are altered in AD remains controversial.MethodsExtensive histological analysis was performed on male and female 5xFAD mice at 4, 8, 12, and 18 months of age to assess plaque burden, microgliosis, and PNNs. Findings were validated in postmortem AD tissue. The role of neuroinflammation in PNN loss was investigated via LPS treatment, and the ability to prevent or rescue disease-related reductions in PNNs was assessed by treating 5xFAD and 3xTg-AD model mice with colony-stimulating factor 1 receptor (CSF1R) inhibitor PLX5622 to deplete microglia.FindingsUtilizing the 5xFAD mouse model and human cortical tissue, we report that PNNs are extensively lost in AD in proportion to plaque burden. Activated microglia closely associate with and engulf damaged nets in the 5xFAD brain, and inclusions of PNN material are evident in mouse and human microglia, while aggrecan, a critical PNN component, deposits within human dense-core plaques. Disease-associated reductions in parvalbumin (PV)+ interneurons, frequently coated by PNNs, are preceded by PNN coverage and integrity impairments, and similar phenotypes are elicited in wild-type mice following microglial activation with LPS. Chronic pharmacological depletion of microglia prevents 5xFAD PNN loss, with similar results observed following depletion in aged 3xTg-AD mice, and this occurs despite plaque persistence.InterpretationWe conclude that phenotypically altered microglia facilitate plaque-dependent PNN loss in the AD brain.FundingThe NIH (NIA, NINDS) and the Alzheimer's Association.
| S-EPMC7399129 | biostudies-literature
Project description:Eighteen-month-long randomized, placebo-controlled clinical trials are common for phase II and phase III drug development for Alzheimer's disease (AD). Yet, no 18-month trial has shown statistically significant outcomes favoring the test drug. We examined characteristics and underlying assumptions of these trials by assessing the placebo groups.We searched the clinicaltrials.gov registry for randomized, placebo-controlled clinical trials for AD of at least 18-month duration and extracted demographic, clinical, and trials characteristics, and change in main outcomes from the placebo groups. We obtained additional information from presentations, abstracts, publications, and sponsors.Of 23 trials identified, 11 were completed and had baseline data available; nine had follow-up data available; 17 were phase III. General inclusion criteria were very similar except that minimum Mini-Mental State Examination (MMSE) scores varied from 12 to 20. Sample sizes ranged from 402 to 1,684 for phase III trials and 80 to 400 for phase II. Cholinesterase inhibitor use was from 53% to 100%, and memantine use was from 13.5% to 78%. The AD Assessment Scale-cognitive (ADAS-cog) was the co-primary outcome in all trials; and activities of daily living, global severity, or global change ratings were the other co-primaries. APOE epsilon4 genotype carriers ranged from 58% to 67%; mean baseline ADAS-cog was 17.8 to 24.2. ADAS-cog worsening in the placebo groups during 18 months ranged from 4.34 to 9.10, with standard deviations from 8.17 to 9.39, increasing during 18 months.Inclusion criteria are essentially similar to earlier 6-month and 12-month trials in which cholinesterase inhibitors were not allowed, as were mean ADAS-cog rates of change. Yet increasing variability and relatively little change overall in the ADAS-cog placebo groups, eg, about 25% of patients do not worsen by more than 1 point, might make it more unlikely than previously assumed that a modestly effective drug can be reliably recognized, especially when the drug might work only to attenuate decline in function and not to improve function. These observations would be strengthened by pooling individual trials data, and pharmaceutical sponsors should participate in such efforts.
| S-EPMC3321732 | biostudies-literature
Project description:Juvenile neuronal ceroid lipofuscinosis (JNCL) is a fatal childhood-onset neurodegenerative disorder caused by mutations in ceroid lipofuscinosis neuronal-3 (CLN3), a hydrophobic transmembrane protein of unresolved function. Previous studies indicate blood-brain barrier (BBB) defects in JNCL, and our earlier report showed prominent Cln3 expression in mouse brain endothelium. Here we find that CLN3 is necessary for normal trafficking of the microdomain-associated proteins caveolin-1, syntaxin-6, and multidrug resistance protein 1 (MDR1) in brain endothelial cells. Correspondingly, CLN3-null cells have reduced caveolae, and impaired caveolae- and MDR1-related functions including endocytosis, drug efflux, and cell volume regulation. We also detected an abnormal blood-brain barrier response to osmotic stress in vivo. Evaluation of the plasma membrane with fluorescent sphingolipid probes suggests microdomain destabilization and enhanced fluidity in CLN3-null cells. In further work we found that application of the glycosphingolipid lactosylceramide to CLN3-deficient cells rescues protein transport and caveolar endocytosis. Last, we show that CLN3 localizes to the trans-Golgi network (TGN) and partitions with buoyant microdomain fractions. We propose that CLN3 facilitates TGN-to-plasma membrane transport of microdomain-associated proteins. Insult to this pathway may underlie BBB dysfunction and contribute to JNCL pathogenesis.
| S-EPMC3828460 | biostudies-literature
Project description:Alzheimer's disease (AD) biomarkers and stroke risk factors independently predict cognitive impairment, likely through independent disease pathways. However, limited work has sought to describe the dynamic interplay between these important risk factors. This article evaluated the interaction between stroke risk and AD biomarkers on hippocampal volume and cognitive performance. We first evaluated the interaction between stroke risk factors and AD biomarkers using data from the Alzheimer's Disease Neuroimaging Initiative (ADNI, n = 1202). We then extended our findings to an independent autopsy data set from the National Alzheimer's Coordinating Center (NACC, n = 1122) using measures of AD pathology. Stroke risk was quantified using the Framingham Stroke Risk Profile. In ADNI, stroke risk interacted with tau and amyloid levels in relation to baseline and longitudinal cognitive performance. Similarly, in NACC, stroke risk interacted with amyloid and tau positivity on cognitive performance. The effect of stroke risk factors on cognition was strongest in the absence of AD biomarkers or neuropathology, providing additional evidence that AD biomarkers and stroke risk factors relate to cognition through independent pathways.
| S-EPMC4523400 | biostudies-literature
Project description:Resting state functional connectivity (rs-fMRI) is impaired early in persons who subsequently develop Alzheimer's disease (AD) dementia. This impairment may be leveraged to aid investigation of the pre-clinical phase of AD. We developed a model that predicts brain age from resting state (rs)-fMRI data, and assessed whether genetic determinants of AD, as well as beta-amyloid (Aβ) pathology, can accelerate brain aging. Using data from 1340 cognitively unimpaired participants between 18-94 years of age from multiple sites, we showed that topological properties of graphs constructed from rs-fMRI can predict chronological age across the lifespan. Application of our predictive model to the context of pre-clinical AD revealed that the pre-symptomatic phase of autosomal dominant AD includes acceleration of functional brain aging. This association was stronger in individuals having significant Aβ pathology.
| S-EPMC8429427 | biostudies-literature
Project description:Quantify region-dependent fluctuations on a proteome-wide scale, performing integrative analysis of the proteome and phosphoproteome across AD stages in EC and FC.
2022-02-16 | PXD021645 | Pride