Altered microRNA profiles in cerebrospinal fluid exosome in Parkinson disease and Alzheimer disease.
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ABSTRACT:
SUBMITTER: Gui Y
PROVIDER: S-EPMC4741914 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Human cerebrospinal fluid (CSF) contains diverse lipid particles, including lipoproteins that are distinct from their plasma counterparts and contain apolipoprotein (apo) E isoforms, apoJ, and apoAI, and extracellular vesicles, which can be detected by annexin V binding. The aim of this study was to develop a method to quantify CSF particles and evaluate their relationship to aging and neurodegenerative diseases. We used a flow cytometric assay to detect annexin V-, apoE-, apoAI-, apoJ-, and amyloid (A) ?42-positive particles in CSF from 131 research volunteers who were neurologically normal or had mild cognitive impairment (MCI), Alzheimer disease (AD) dementia, or Parkinson disease. APOE ?4/?4 participants had CSF apoE-positive particles that were more frequently larger but at an 88% lower level versus those in APOE ?3/?3 or APOE ?3/?4 patients; this finding was reproduced in conditioned medium from mouse primary glial cell cultures with targeted replacement of apoE. Cerebrospinal fluid apoE-positive and ?-amyloid (A?42)-positive particle concentrations were persistently reduced one-third to one-half in middle and older age subjects; apoAI-positive particle concentration progressively increased approximately 2-fold with age. Both apoAI-positive and annexin V-positive CSF particle levels were reduced one-third to one-half in CSF of MCI and/or AD dementia patients versus age-matched controls. Our approach provides new methods to investigate CNS lipid biology in relation to neurodegeneration and perhaps develop new biomarkers for diagnosis or treatment monitoring.
| S-EPMC4471879 | biostudies-literature
Project description:BackgroundAltered proteome profiles have been reported in both postmortem brain tissues and body fluids of subjects with Alzheimer disease (AD), but their broad relationships with AD pathology, amyloid pathology, and tau-related neurodegeneration have not yet been fully explored. Using a robust automated MS-based proteomic biomarker discovery workflow, we measured cerebrospinal fluid (CSF) proteomes to explore their association with well-established markers of core AD pathology.MethodsCross-sectional analysis was performed on CSF collected from 120 older community-dwelling adults with normal (n?=?48) or impaired cognition (n?=?72). LC-MS quantified hundreds of proteins in the CSF. CSF concentrations of ?-amyloid 1-42 (A?1-42), tau, and tau phosphorylated at threonine 181 (P-tau181) were determined with immunoassays. First, we explored proteins relevant to biomarker-defined AD. Then, correlation analysis of CSF proteins with CSF markers of amyloid pathology, neuronal injury, and tau hyperphosphorylation (i.e., A?1-42, tau, P-tau181) was performed using Pearson's correlation coefficient and Bonferroni correction for multiple comparisons.ResultsWe quantified 790 proteins in CSF samples with MS. Four CSF proteins showed an association with CSF A?1-42 levels (p value ??0.05 with correlation coefficient (R)???0.38). We identified 50 additional CSF proteins associated with CSF tau and 46 proteins associated with CSF P-tau181 (p value ??0.05 with R???0.37). The majority of those proteins that showed such associations were brain-enriched proteins. Gene Ontology annotation revealed an enrichment for synaptic proteins and proteins originating from reelin-producing cells and the myelin sheath.ConclusionsWe used an MS-based proteomic workflow to profile the CSF proteome in relation to cerebral AD pathology. We report strong evidence of previously reported CSF proteins and several novel CSF proteins specifically associated with amyloid pathology or neuronal injury and tau hyperphosphorylation.
| S-EPMC6052524 | biostudies-literature
Project description:ImportanceIncreasing evidence suggests an important role of liver function in the pathophysiology of Alzheimer disease (AD). The liver is a major metabolic hub; therefore, investigating the association of liver function with AD, cognition, neuroimaging, and CSF biomarkers would improve the understanding of the role of metabolic dysfunction in AD.ObjectiveTo examine whether liver function markers are associated with cognitive dysfunction and the "A/T/N" (amyloid, tau, and neurodegeneration) biomarkers for AD.Design, setting, and participantsIn this cohort study, serum-based liver function markers were measured from September 1, 2005, to August 31, 2013, in 1581 AD Neuroimaging Initiative participants along with cognitive measures, cerebrospinal fluid (CSF) biomarkers, brain atrophy, brain glucose metabolism, and amyloid-β accumulation. Associations of liver function markers with AD-associated clinical and A/T/N biomarkers were assessed using generalized linear models adjusted for confounding variables and multiple comparisons. Statistical analysis was performed from November 1, 2017, to February 28, 2019.ExposuresFive serum-based liver function markers (total bilirubin, albumin, alkaline phosphatase, alanine aminotransferase, and aspartate aminotransferase) from AD Neuroimaging Initiative participants were used as exposure variables.Main outcomes and measuresPrimary outcomes included diagnosis of AD, composite scores for executive functioning and memory, CSF biomarkers, atrophy measured by magnetic resonance imaging, brain glucose metabolism measured by fludeoxyglucose F 18 (18F) positron emission tomography, and amyloid-β accumulation measured by [18F]florbetapir positron emission tomography.ResultsParticipants in the AD Neuroimaging Initiative (n = 1581; 697 women and 884 men; mean [SD] age, 73.4 [7.2] years) included 407 cognitively normal older adults, 20 with significant memory concern, 298 with early mild cognitive impairment, 544 with late mild cognitive impairment, and 312 with AD. An elevated aspartate aminotransferase (AST) to alanine aminotransferase (ALT) ratio and lower levels of ALT were associated with AD diagnosis (AST to ALT ratio: odds ratio, 7.932 [95% CI, 1.673-37.617]; P = .03; ALT: odds ratio, 0.133 [95% CI, 0.042-0.422]; P = .004) and poor cognitive performance (AST to ALT ratio: β [SE], -0.465 [0.180]; P = .02 for memory composite score; β [SE], -0.679 [0.215]; P = .006 for executive function composite score; ALT: β [SE], 0.397 [0.128]; P = .006 for memory composite score; β [SE], 0.637 [0.152]; P < .001 for executive function composite score). Increased AST to ALT ratio values were associated with lower CSF amyloid-β 1-42 levels (β [SE], -0.170 [0.061]; P = .04) and increased amyloid-β deposition (amyloid biomarkers), higher CSF phosphorylated tau181 (β [SE], 0.175 [0.055]; P = .02) (tau biomarkers) and higher CSF total tau levels (β [SE], 0.160 [0.049]; P = .02) and reduced brain glucose metabolism (β [SE], -0.123 [0.042]; P = .03) (neurodegeneration biomarkers). Lower levels of ALT were associated with increased amyloid-β deposition (amyloid biomarkers), and reduced brain glucose metabolism (β [SE], 0.096 [0.030]; P = .02) and greater atrophy (neurodegeneration biomarkers).Conclusions and relevanceConsistent associations of serum-based liver function markers with cognitive performance and A/T/N biomarkers for AD highlight the involvement of metabolic disturbances in the pathophysiology of AD. Further studies are needed to determine if these associations represent a causative or secondary role. Liver enzyme involvement in AD opens avenues for novel diagnostics and therapeutics.
| S-EPMC6669786 | biostudies-literature
Project description:There is a clear need to develop biomarkers for Parkinson disease (PD) diagnosis, differential diagnosis of Parkinsonian disorders, and monitoring disease progression. We and others have demonstrated that a decrease in DJ-1 and/or ?-synuclein in the cerebrospinal fluid (CSF) is a potential index for Parkinson disease diagnosis, but not for PD severity.Using highly sensitive and quantitative Luminex assays, we measured total tau, phosphorylated tau, amyloid beta peptide 1-42 (A?(1-42)), Flt3 ligand, and fractalkine levels in CSF in a large cohort of PD patients at different stages as well as healthy and diseased controls. The utility of these 5 markers was evaluated for disease diagnosis and severity/progression correlation alone, as well as in combination with DJ-1 and ?-synuclein. The major results were further validated in an independent cohort of cross-sectional PD patients as well as in PD cases with CSF samples collected longitudinally.The results demonstrated that combinations of these biomarkers could differentiate PD patients not only from normal controls but also from patients with Alzheimer disease (AD) and multiple system atrophy. Particularly, with CSF Flt3 ligand, PD could be clearly differentiated from multiple system atrophy, a disease that overlaps with PD clinically, with excellent sensitivity (99%) and specificity (95%). In addition, we identified CSF fractalkine/A?(1-42) that positively correlated with PD severity in cross-sectional samples as well as with PD progression in longitudinal samples.We have demonstrated that this panel of 7 CSF proteins could aid in Parkinson disease diagnosis, differential diagnosis, and correlation with disease severity and progression.
| S-EPMC3117674 | biostudies-literature
Project description:Recent demonstrations that the secretion, uptake, and interneuronal transfer of tau can be modulated by disease-associated tau modifications suggest that secretion may be an important element in tau-induced neurodegeneration. Here, we show that much of the tau secreted by M1C cells occurs via exosomal release, a widely characterized mechanism that mediates unconventional secretion of other aggregation-prone proteins (?-synuclein, prion protein, and ?-amyloid) in neurodegenerative disease. Exosome-associated tau is also present in human CSF samples and is phosphorylated at Thr-181 (AT270), an established phosphotau biomarker for Alzheimer disease (AD), in both M1C cells and in CSF samples from patients with mild (Braak stage 3) AD. A preliminary analysis of proteins co-purified with tau in secreted exosomes identified several that are known to be involved in disease-associated tau misprocessing. Our results suggest that exosome-mediated secretion of phosphorylated tau may play a significant role in the abnormal processing of tau and in the genesis of elevated CSF tau in early AD.
| S-EPMC3281682 | biostudies-literature
Project description:Evidence supporting the hypothesis that reduced cerebrospinal fluid (CSF) clearance is involved in the pathophysiology of Alzheimer disease (AD) comes primarily from rodent models. However, unlike rodents, in which predominant extracranial CSF egress is via olfactory nerves traversing the cribriform plate, human CSF clearance pathways are not well characterized. Dynamic PET with 18F-THK5117, a tracer for tau pathology, was used to estimate the ventricular CSF time-activity as a biomarker for CSF clearance. We tested 3 hypotheses: extracranial CSF is detected at the superior turbinates; CSF clearance is reduced in AD; and CSF clearance is inversely associated with amyloid deposition. Methods: Fifteen subjects, 8 with AD and 7 normal control volunteers, were examined with 18F-THK5117. Ten subjects additionally underwent 11C-Pittsburgh compound B (11C-PiB) PET scanning, and 8 were 11C-PiB-positive. Ventricular time-activity curves of 18F-THK5117 were used to identify highly correlated time-activity curves from extracranial voxels. Results: For all subjects, the greatest density of CSF-positive extracranial voxels was in the nasal turbinates. Tracer concentration analyses validated the superior nasal turbinate CSF signal intensity. AD patients showed ventricular tracer clearance reduced by 23% and 66% fewer superior turbinate CSF egress sites. Ventricular CSF clearance was inversely associated with amyloid deposition. Conclusion: The human nasal turbinate is part of the CSF clearance system. Lateral ventricle and superior nasal turbinate CSF clearance abnormalities are found in AD. Ventricular CSF clearance reductions are associated with increased brain amyloid depositions. These data suggest that PET-measured CSF clearance is a biomarker of potential interest in AD and other neurodegenerative diseases.
| S-EPMC5577629 | biostudies-literature
Project description:Clinical diagnosis of Alzheimer's disease (AD) prior to the age of 65 years is classified as young-onset (YOAD), whereas diagnosis after the age of 65 years is considered late-onset (LOAD). Although rare autosomal mutations more commonly associate with YOAD, most YOAD and LOAD cases are sporadic. YOAD and LOAD share amyloid and tau pathology, but many YOAD patients show increased disease severity and rate of progression. The current study examined the microRNA (miRNA) expression profile from exosomes isolated from the cerebrospinal fluid (CSF) of YOAD patients with biomarker-confirmed AD. Results uncovered miR-16-5p, miR-125b-5p, miR-451a, and miR-605-5p as differentially expressed in the CSF-derived exosomes of YOAD patients when compared with healthy controls (HC). In a cohort of LOAD patients, miR-125b-5p, miR-451a, and miR-605-5p were similarly altered in expression, but miR-16-5p showed similar expression to control. Analysis of the mRNA targets of these miRNAs revealed transcripts enriched in biological processes relevant to the post-mortem posterior cingulate cortex transcriptome in YOAD from a previously published microarray study, including those related to neuron projections, synaptic signaling, metabolism, apoptosis, and the immune system. Hence, these miRNAs represent novel targets for uncovering disease mechanisms and for biomarker development in both YOAD and LOAD.
| S-EPMC6208843 | biostudies-literature
Project description:ImportanceIndividuals in the presymptomatic stage of Alzheimer disease (AD) are increasingly being targeted for AD secondary prevention trials. How early during the normal life span underlying AD pathologies begin to develop, their patterns of change over time, and their relationship with future cognitive decline remain to be determined.ObjectiveTo characterize the within-person trajectories of cerebrospinal fluid (CSF) biomarkers of AD over time and their association with changes in brain amyloid deposition and cognitive decline in cognitively normal middle-aged individuals.Design, setting, and participantsAs part of a cohort study, cognitively normal (Clinical Dementia Rating [CDR] of 0) middle-aged research volunteers (n = 169) enrolled in the Adult Children Study at Washington University, St Louis, Missouri, had undergone serial CSF collection and longitudinal clinical assessment (mean, 6 years; range, 0.91-11.3 years) at 3-year intervals at the time of analysis, between January 2003 and November 2013. A subset (n = 74) had also undergone longitudinal amyloid positron emission tomographic imaging with Pittsburgh compound B (PiB) in the same period. Serial CSF samples were analyzed for β-amyloid 40 (Aβ40), Aβ42, total tau, tau phosphorylated at threonine 181 (P-tau181), visinin-like protein 1 (VILIP-1), and chitinase-3-like protein 1 (YKL-40). Within-person measures were plotted according to age and AD risk defined by APOE genotype (ε4 carriers vs noncarriers). Linear mixed models were used to compare estimated biomarker slopes among middle-age bins at baseline (early, 45-54 years; mid, 55-64 years; late, 65-74 years) and between risk groups. Within-person changes in CSF biomarkers were also compared with changes in cortical PiB binding and progression to a CDR higher than 0 at follow-up.Main outcomes and measuresChanges in Aβ40, Aβ42, total tau, P-tau181, VILIP-1, and YKL-40 and, in a subset of participants, changes in cortical PiB binding.ResultsWhile there were no consistent longitudinal patterns in Aβ40 (P = .001-.97), longitudinal reductions in Aβ42 were observed in some individuals as early as early middle age (P ≤ .05) and low Aβ42 levels were associated with the development of cortical PiB-positive amyloid plaques (area under receiver operating characteristic curve = 0.9352; 95% CI, 0.8895-0.9808), especially in mid middle age (P < .001). Markers of neuronal injury (total tau, P-tau181, and VILIP-1) dramatically increased in some individuals in mid and late middle age (P ≤ .02), whereas the neuroinflammation marker YKL-40 increased consistently throughout middle age (P ≤ .003). These patterns were more apparent in at-risk ε4 carriers (Aβ42 in an allele dose-dependent manner) and appeared to be associated with future cognitive deficits as determined by CDR.Conclusions and relevanceLongitudinal CSF biomarker patterns consistent with AD are first detectable during early middle age and are associated with later amyloid positivity and cognitive decline. Such measures may be useful for targeting middle-aged, asymptomatic individuals for therapeutic trials designed to prevent cognitive decline.
| S-EPMC4570860 | biostudies-literature
Project description:Asthma is characterized by increased airway narrowing in response to nonspecific stimuli. The disorder is influenced by both environmental and genetic factors. Exosomes are nanosized vesicles of endosomal origin released from inflammatory and epithelial cells that have been implicated in asthma. In this study we characterized the microRNA (miRNA) content of exosomes in healthy control subjects and patients with mild intermittent asthma both at unprovoked baseline and in response to environmental challenge.To investigate alterations in bronchoalveolar lavage fluid (BALF) exosomal miRNA profiles due to asthma, and following subway air exposure.Exosomes were isolated from BALF from healthy control subjects (n = 10) and patients with mild intermittent asthma (n = 10) after subway and control exposures. Exosomal RNA was analyzed by using microarrays containing probes for 894 human miRNAs, and selected findings were validated with quantitative RT-PCR. Results were analyzed by using multivariate modeling.The presence of miRNAs was confirmed in exosomes from BALF of both asthmatic patients and healthy control subjects. Significant differences in BALF exosomal miRNA was detected for 24 miRNAs with a subset of 16 miRNAs, including members of the let-7 and miRNA-200 families, providing robust classification of patients with mild nonsymptomatic asthma from healthy subjects with 72% cross-validated predictive power (Q(2) = 0.72). In contrast, subway exposure did not cause any significant alterations in miRNA profiles.These studies demonstrate substantial differences in exosomal miRNA profiles between healthy subjects and patients with unprovoked, mild, stable asthma. These changes might be important in the inflammatory response leading to bronchial hyperresponsiveness and asthma.
| S-EPMC4013392 | biostudies-literature
Project description:Tau gene has been consistently associated with the risk of Parkinson disease in recent genome wide association studies. In addition, alterations of the levels of total tau, phosphorylated tau [181P], and amyloid beta 1-42 in cerebrospinal fluid have been reported in patients with sporadic Parkinson disease and asymptomatic carriers of leucine-rich repeat kinase 2 mutations, in patterns that clearly differ from those typically described for patients with Alzheimer disease. To further determine the potential roles of these molecules in Parkinson disease pathogenesis and/or in tracking the disease progression, especially at early stages, the current study assessed all three proteins in 403 Parkinson disease patients enrolled in the DATATOP (Deprenyl and tocopherol antioxidative therapy of parkinsonism) placebo-controlled clinical trial, the largest cohort to date with cerebrospinal fluid samples collected longitudinally. These initially drug-naive patients at early disease stages were clinically evaluated, and cerebrospinal fluid was collected at baseline and then at endpoint, defined as the time at which symptomatic anti-Parkinson disease medications were determined to be required. General linear models were used to test for associations between baseline cerebrospinal fluid biomarker levels or their rates of change and changes in the Unified Parkinson Disease Rating Scale (total or part III motor score) over time. Robust associations among candidate markers are readily noted. Baseline levels of amyloid beta were weakly but negatively correlated with baseline Unified Parkinson Disease Rating Scale total scores. Baseline phosphorylated tau/total tau and phosphorylated tau/amyloid beta were significantly and negatively correlated with the rates of the Unified Parkinson Disease Rating Scale change. While medications (deprenyl and/or tocopherol) did not appear to alter biomarkers appreciably, a weak but significant positive correlation between the rate of change in total tau or total tau/amyloid beta levels and the change of the Unified Parkinson Disease Rating Scale was observed. Notably, these correlations did not appear to be influenced by APOE genotype. These results are one of the very first pieces of evidence suggesting that tau and amyloid beta are critically involved in early Parkinson disease progression, potentially by a different mechanism than that in Alzheimer disease, although their applications as Parkinson disease progression markers will likely require the addition of other proteins.
| S-EPMC3796193 | biostudies-literature