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INTRODUCTION: Alzheimer's disease (AD) trial participants are often screened for eligibility by brain amyloid positron emission tomography/cerebrospinal fluid (PET/CSF), which is inefficient as many are not amyloid positive. Use of blood-based biomarkers may reduce screen failures. METHODS: We recruited 755 non-Hispanic White, 115 Hispanic, 112 non-Hispanic Black, and 19 other minority participants across groups of cognitively normal (n = 417), mild cognitive impairment (n = 312), or mild AD (n = 272) participants. Plasma amyloid beta (Aß)40, Aß42, Aß42/Aß40, total tau, phosphorylated tau (p-tau)181, and p-tau217 were measured; amyloid PET/CSF (n = 956) determined amyloid positivity. Clinical, blood biomarker, and ethnicity/race differences associated with amyloid status were evaluated. RESULTS: Greater impairment, older age, and carrying an apolipoprotein E (apoE) ε4 allele were associated with greater amyloid burden. Areas under the receiver operating characteristic curve for amyloid status of plasma Aß42/Aß40, p-tau181, and p-tau217 with amyloid positivity were ≥ 0.7117 for all ethnoracial groups (p-tau217, ≥0.8128). Age and apoE ε4 adjustments and imputation of biomarker values outside limit of quantitation provided small improvement in predictive power. DISCUSSION: Blood-based biomarkers are highly associated with amyloid PET/CSF results in diverse populations enrolled at clinical trial sites. HIGHLIGHTS: Amyloid beta (Aß)42/Aß40, phosphorylated tau (p-tau)181, and p-tau 217 blood-based biomarkers predicted brain amyloid positivity. P-tau 217 was the strongest predictor of brain amyloid positivity. Biomarkers from diverse ethnic, racial, and clinical cohorts predicted brain amyloid positivity. Community-based populations have similar Alzheimer's disease (AD) biomarker levels as other populations. A prescreen process with blood-based assays may reduce the number of AD trial screen failures.
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Enfermedad de Alzheimer , Disfunción Cognitiva , Humanos , Enfermedad de Alzheimer/líquido cefalorraquídeo , Péptidos beta-Amiloides/líquido cefalorraquídeo , Proteínas tau/líquido cefalorraquídeo , Disfunción Cognitiva/diagnóstico , Disfunción Cognitiva/líquido cefalorraquídeo , Encéfalo , Tomografía de Emisión de Positrones , Biomarcadores/líquido cefalorraquídeoRESUMEN
INTRODUCTION: Plasma biomarkers of Alzheimer's disease and related dementias predict global cognitive performance and decline over time; it remains unclear how they associate with changes in different dementia syndromes affecting distinct cognitive domains. METHODS: In a prospective study with repeated assessments of a randomly selected population-based cohort (n = 787, median age 73), we evaluated performance and decline in different cognitive domains over up to 8 years in relation to plasma concentrations of amyloid beta 42/40 (Aß42/40) ratio, phosphorylated tau181 (p-tau181), neurofilament light chain (NfL), and glial fibrillary acidic protein (GFAP). RESULTS: Cross-sectionally, memory showed the strongest associations with p-tau181, and attention, executive, and visuospatial functions with NfL. Longitudinally, memory decline was distinguishable with all biomarker profiles dichotomized according to data-driven cutoffs, most efficiently with Aß42/40. GFAP and Aß42/40 were the best discriminators of decline patterns in language and visuospatial functions, respectively. DISCUSSION: These relatively non-invasive tests may be beneficial for clinical screening after replication in other populations and validation through neuroimaging or cerebrospinal fluid analysis. HIGHLIGHTS: We performed a prospective study with up to 8 years of repeated domain-specific cognitive assessments and baseline plasma Alzheimer's disease and related dementias biomarker measurements in a randomly selected population-based cohort. We considered distinct growth curves of trajectories of different cognitive domains and survival bias induced by missing data by adding quadratic time and applying joint modeling technique. Cross-sectionally, memory showed the strongest associations with plasma phosphorylated tau181, while attention, executive, and visuospatial functions were most strongly associated with neurofilament light chain. Longitudinally, memory and visuospatial declines were most efficiently distinguished by dichotomized amyloid beta 42/40 profile among all plasma biomarkers, while language was by dichotomized glial fibrillary acidic protein. These relatively non-invasive tests may be beneficial for clinical screening; however, they will need replication in other populations and validation through neuroimaging and/or cerebrospinal fluid assessments.
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Enfermedad de Alzheimer , Péptidos beta-Amiloides , Biomarcadores , Disfunción Cognitiva , Proteínas de Neurofilamentos , Proteínas tau , Humanos , Biomarcadores/sangre , Femenino , Masculino , Enfermedad de Alzheimer/sangre , Anciano , Péptidos beta-Amiloides/sangre , Péptidos beta-Amiloides/líquido cefalorraquídeo , Proteínas tau/sangre , Proteínas tau/líquido cefalorraquídeo , Disfunción Cognitiva/sangre , Estudios Prospectivos , Estudios Transversales , Proteínas de Neurofilamentos/sangre , Fragmentos de Péptidos/sangre , Fragmentos de Péptidos/líquido cefalorraquídeo , Proteína Ácida Fibrilar de la Glía/sangre , Estudios Longitudinales , Pruebas Neuropsicológicas/estadística & datos numéricos , Persona de Mediana Edad , Cognición/fisiología , Anciano de 80 o más AñosRESUMEN
We have previously developed a unique 8-amino acid Aß42 oligomer-Interacting Peptide (AIP) as a novel anti-amyloid strategy for the treatment of Alzheimer's disease. Our lead candidate has successfully progressed from test tubes (i.e., in vitro characterization of protease-resistant D-AIP) to transgenic flies (i.e., in vivo rescue of human Aß42-mediated toxicity via D-AIP-supplemented food). In the present study, we examined D-AIP in terms of its stability in multiple biological matrices (i.e., ex-vivo mouse plasma, whole blood, and liver S9 fractions) using MALDI mass spectrometry, pharmacokinetics using a rapid and sensitive LC-MS method, and blood brain barrier (BBB) penetrance in WT C57LB/6 mice. D-AIP was found to be relatively stable over 3 h at 37 °C in all matrices tested. Finally, label-free MALDI imaging showed that orally administered D-AIP can readily penetrate the intact BBB in both male and female WT mice. Based upon the favorable stability, pharmacokinetics, and BBB penetration outcomes for orally administered D-AIP in WT mice, we then examined the effect of D-AIP on amyloid "seeding" in vitro (i.e., freshly monomerized versus preaggregated Aß42). Complementary biophysical assays (ThT, TEM, and MALDI-TOF MS) showed that D-AIP can directly interact with synthetic Aß42 aggregates to disrupt primary and/or secondary seeding events. Taken together, the unique mechanistic and desired therapeutic potential of our lead D-AIP candidate warrants further investigation, that is, testing of D-AIP efficacy on the altered amyloid/tau pathology in transgenic mouse models of Alzheimer's disease.
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Enfermedad de Alzheimer , Péptidos beta-Amiloides , Encéfalo , Fragmentos de Péptidos , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/patología , Péptidos beta-Amiloides/farmacocinética , Péptidos beta-Amiloides/farmacología , Animales , Encéfalo/metabolismo , Femenino , Masculino , Ratones , Ratones Transgénicos , Fragmentos de Péptidos/farmacocinética , Fragmentos de Péptidos/farmacologíaRESUMEN
INTRODUCTION: This study investigated the comparability of cerebrospinal fluid (CSF) cutoffs for Elecsys immunoassays for amyloid beta (Aß)42/Aß40 or Aß42/phosphorylated tau (p-tau)181 and the effects of measurement variability when predicting Alzheimer's disease (AD)-related outcomes (i.e., Aß-positron emission tomography [PET] visual read and AD neuropathology). METHODS: We studied 750 participants (BioFINDER study, Alzheimer's Disease Neuroimaging Initiative [ADNI], and University of California San Francisco [UCSF]). Youden's index was used to identify cutoffs and to calculate accuracy (Aß-PET visual read as outcome). Using longitudinal variability in Aß-negative controls, we identified a gray zone around cut-points where the risk of an inconsistent predicted outcome was >5%. RESULTS: For Aß42/Aß40, cutoffs across cohorts were <0.059 (BioFINDER), <0.057 (ADNI), and <0.058 (UCSF). For Aß42/p-tau181, cutoffs were <41.90 (BioFINDER), <39.20 (ADNI), and <46.02 (UCSF). Accuracy was ≈90% for both Aß42/Aß40 and Aß42/p-tau181 using these cutoffs. Using Aß-PET as an outcome, 8.7% of participants fell within a gray zone interval for Aß42/Aß40, compared to 4.5% for Aß42/p-tau181. Similar findings were observed using a measure of overall AD neuropathologic change (7.7% vs. 3.3%). In a subset with CSF and plasma Aß42/40, the number of individuals within the gray zone was ≈1.5 to 3 times greater when using plasma Aß42/40. DISCUSSION: CSF Aß42/p-tau181 was more robust to the effects of measurement variability, suggesting that it may be the preferred Elecsys-based measure in clinical practice and trials.
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Enfermedad de Alzheimer , Humanos , Enfermedad de Alzheimer/patología , Péptidos beta-Amiloides/líquido cefalorraquídeo , Biomarcadores/líquido cefalorraquídeo , Fragmentos de Péptidos/líquido cefalorraquídeo , Proteínas tau/líquido cefalorraquídeo , Inmunoensayo , Tomografía de Emisión de PositronesRESUMEN
INTRODUCTION: It is uncertain whether subjective cognitive decline (SCD) in individuals who seek medical help serves the identification of the initial symptomatic stage 2 of the Alzheimer's disease (AD) continuum. METHODS: Cross-sectional and longitudinal data from the multicenter, memory clinic-based DELCODE study. RESULTS: The SCD group showed slightly worse cognition as well as more subtle functional and behavioral symptoms than the control group (CO). SCD-A+ cases (39.3% of all SCD) showed greater hippocampal atrophy, lower cognitive and functional performance, and more behavioral symptoms than CO-A+. Amyloid concentration in the CSF had a greater effect on longitudinal cognitive decline in SCD than in the CO group. DISCUSSION: Our data suggests that SCD serves the identification of stage 2 of the AD continuum and that stage 2, operationalized as SCD-A+, is associated with subtle, but extended impact of AD pathology in terms of neurodegeneration, symptoms and clinical progression.
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Enfermedad de Alzheimer , Disfunción Cognitiva , Humanos , Enfermedad de Alzheimer/patología , Péptidos beta-Amiloides , Estudios Transversales , Disfunción Cognitiva/diagnóstico , Cognición , Biomarcadores , Proteínas tauRESUMEN
INTRODUCTION: We examined the association between cerebrospinal fluid (CSF)-derived biomarkers of Alzheimer's disease and neuropsychiatric symptoms (NPS) in older non-demented adults. METHODS: We included 784 persons (699 cognitively unimpaired, 85 with mild cognitive impairment) aged ≥ 50 years who underwent CSF amyloid beta (Aß42), hyperphosphorylated tau 181 (p-tau), and total tau (t-tau) as well as NPS assessment using Beck Depression and Anxiety Inventories (BDI-II, BAI), and Neuropsychiatric Inventory Questionnaire (NPI-Q). RESULTS: Lower CSF Aß42, and higher t-tau/Aß42 and p-tau/Aß42 ratios were associated with BDI-II and BAI total scores, clinical depression (BDI-II ≥ 13), and clinical anxiety (BAI ≥ 10), as well as NPI-Q-assessed anxiety, apathy, and nighttime behavior. DISCUSSION: CSF Aß42, t-tau/Aß42, and p-tau/Aß42 ratios were associated with NPS in community-dwelling individuals free of dementia. If confirmed by a longitudinal cohort study, the findings have clinical relevance of taking into account the NPS status of individuals with abnormal CSF biomarkers.
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Enfermedad de Alzheimer , Disfunción Cognitiva , Humanos , Anciano , Enfermedad de Alzheimer/líquido cefalorraquídeo , Péptidos beta-Amiloides/líquido cefalorraquídeo , Estudios Longitudinales , Proteínas tau/líquido cefalorraquídeo , Envejecimiento , Biomarcadores/líquido cefalorraquídeo , Disfunción Cognitiva/diagnóstico , Fragmentos de Péptidos/líquido cefalorraquídeoRESUMEN
INTRODUCTION: Approximately 40% of dementia cases could be delayed or prevented acting on modifiable risk factors including hypertension. However, the mechanisms underlying the hypertension-dementia association are still poorly understood. METHODS: We conducted a cross-sectional analysis in 2048 patients from the MEMENTO cohort, a French multicenter clinic-based study of outpatients with either isolated cognitive complaints or mild cognitive impairment. Exposure to hypertension was defined as a combination of high blood pressure (BP) status and antihypertensive treatment intake. Pathway associations were examined through structural equation modeling integrating extensive collection of neuroimaging biomarkers and clinical data. RESULTS: Participants treated with high BP had significantly lower cognition compared to the others. This association was mediated by higher neurodegeneration and higher white matter hyperintensities load but not by Alzheimer's disease (AD) biomarkers. DISCUSSION: These results highlight the importance of controlling hypertension for prevention of cognitive decline and offer new insights on mechanisms underlying the hypertension-dementia association. HIGHLIGHTS: Paths of hypertension-cognition association were assessed by structural equation models. The hypertension-cognition association is not mediated by Alzheimer's disease biomarkers. The hypertension-cognition association is mediated by neurodegeneration and leukoaraiosis. Lower cognition was limited to participants treated with uncontrolled blood pressure. Blood pressure control could contribute to promote healthier brain aging.
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Enfermedad de Alzheimer , Disfunción Cognitiva , Hipertensión , Humanos , Enfermedad de Alzheimer/metabolismo , Estudios Transversales , Tomografía de Emisión de Positrones , Imagen por Resonancia Magnética , Cognición/fisiología , Disfunción Cognitiva/metabolismo , Biomarcadores , Péptidos beta-Amiloides/metabolismoRESUMEN
The oligomeric form of the peptide amyloid beta 42 (Abeta42) contributes to the development of synaptic abnormalities and cognitive impairments associated with Alzheimer's disease (AD). To date, there is a gap in knowledge regarding how Abeta42 alters the elementary parameters of GABAergic synaptic function. Here we found that Abeta42 increased the frequency and amplitude of miniature GABAergic currents as well as the amplitude of evoked inhibitory postsynaptic currents. When we focused on paired pulse depression (PPD) to establish whether GABA release probability was affected by Abeta42, we did not observe any significant change. On the other hand, a more detailed investigation of the presynaptic effects induced by Abeta42 by means of multiple probability fluctuation analysis and cumulative amplitude analysis showed an increase in both the size of the readily releasable pool responsible for synchronous release and the number of release sites. We further explored whether ryanodine receptors (RyRs) contributed to exacerbating these changes by stabilizing the interaction between RyRs and the accessory protein calstabin. We observed that the RyR-calstabin interaction stabilizer S107 restored the synaptic parameters to values comparable to those measured in control conditions. In conclusion, our results clarify the mechanisms of potentiation of GABAergic synapses induced by Abeta42. We further suggest that RyRs are involved in the control of synaptic activity during the early stage of AD onset and that their stabilization could represent a new therapeutical approach for AD treatment. KEY POINTS: Accumulation of the peptide amyloid beta 42 (Abeta42) is a key characteristic of Alzheimer's disease (AD) and causes synaptic dysfunctions. To date, the effects of Abeta42 accumulation on GABAergic synapses are poorly understood. The findings reported here suggest that, similarly to what is observed on glutamatergic synapses, Abeta42 modifies GABAergic synapses by targeting ryanodine receptors and causing calcium dysregulation. The GABAergic impairments can be restored by the ryanodine receptor-calstabin interaction stabilizer S107. Based on this research, RyRs stabilization may represent a novel pharmaceutical strategy for preventing or delaying AD.
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Enfermedad de Alzheimer , Péptidos beta-Amiloides , Humanos , Péptidos beta-Amiloides/metabolismo , Canal Liberador de Calcio Receptor de Rianodina/metabolismo , Rianodina/farmacología , Enfermedad de Alzheimer/metabolismo , Hipocampo/fisiología , Neuronas/metabolismo , Sinapsis/fisiología , Transmisión Sináptica/fisiologíaRESUMEN
Amyloid beta (Aß) peptides are a major contributor to Alzheimer's disease. They occur in differing lengths, each of which forms a multitude of assembly types. The most toxic soluble oligomers are formed by Aß42; some of which have antiparallel ß-sheets. Previously, our group proposed molecular models of Aß42 hexamers in which the C-terminus third of the peptide (S3) forms an antiparallel 6-stranded ß-barrel that is surrounded by an antiparallel barrel formed by the more polar N-terminus (S1) and middle (S2) portions. These hexamers were proposed to act as seeds from which dodecamers, octadecamers, both smooth annular protofibrils (sAPFs) and beaded annular protofibrils (bAPFs), and transmembrane channels form. Since then, numerous aspects of our models have been supported by experimental findings. Recently, NMR-based structures have been proposed for Aß42 tetramers and octamers, and NMR studies have been reported for oligomers composed of ~32 monomers. Here we propose a range of concentric ß-barrel models and compare their dimensions to image-averaged electron micrographs of both bAPFs and sAPFs of Aß42. The smaller oligomers have 6, 8, 12, 16, and 18 monomers. These beads string together to form necklace-like bAPFs. These bAPRs gradually morph into sAPFs in which a S3 ß-barrel is shielded on one or both sides by ß-barrels formed from S1 and S2 segments.
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Péptidos beta-Amiloides , Fragmentos de Péptidos , Amiloide/química , Péptidos beta-Amiloides/química , Proteínas Amiloidogénicas , Humanos , Fragmentos de Péptidos/químicaRESUMEN
ApoE4, the strongest genetic risk factor for Alzheimer's disease (AD), has been shown to be associated with both beta-amyloid (Aß) and tau pathology, with the strongest evidence for effects on Aß, while the association between ApoE4 and tau pathology remains inconsistent. This study aimed to investigate the associations between ApoE4 with CSF Aß42, total tau (t-tau), phospho-tau181 (p-tau), and with the progression of decline in a large cohort of MCI subjects, both progressors to AD and other dementias, as well as non-progressors. We analyzed associations of CSF Aß42, p-tau and t-tau with ApoE4 allele frequency cross-sectionally and longitudinally over 3 years of follow-up in 195 individuals with a diagnosis of MCI-stable, MCI-AD converters and MCI progressing to other dementias from the German Dementia Competence Network. In the total sample, ApoE4 carriers had lower concentrations of CSF Aß42, and increased concentrations of t-tau and p-tau compared to non-carriers in a gene dose-dependent manner. Comparisons of these associations stratified by MCI-progression groups showed a significant influence of ApoE4 carriership and diagnostic group on all CSF biomarker levels. The effect of ApoE4 was present in MCI-stable individuals but not in the other groups, with ApoE4 + carriers having decreased CSF Aß 42 levels, and increased concentration of t-tau and p-tau. Longitudinally, individuals with abnormal t-tau and Aß42 had a more rapid progression of cognitive and clinical decline, independently of ApoE4 genotype. Overall, our results contribute to an emerging framework in which ApoE4 involves mechanisms associated with both CSF amyloid-ß burden and tau aggregation at specific time points in AD pathogenesis.
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Enfermedad de Alzheimer , Disfunción Cognitiva , Enfermedad de Alzheimer/patología , Péptidos beta-Amiloides/líquido cefalorraquídeo , Apolipoproteína E4/genética , Biomarcadores/líquido cefalorraquídeo , Disfunción Cognitiva/diagnóstico , Genotipo , Humanos , Fragmentos de Péptidos/líquido cefalorraquídeo , Proteínas tau/líquido cefalorraquídeoRESUMEN
INTRODUCTION: This report details the approach taken to providing a dataset allowing for analyses on the performance of recently developed assays of amyloid beta (Aß) peptides in plasma and the extent to which they improve the prediction of amyloid positivity. METHODS: Alzheimer's Disease Neuroimaging Initiative plasma samples with corresponding amyloid positron emission tomography (PET) data were run on six plasma Aß assays. Statistical tests were performed to determine whether the plasma Aß measures significantly improved the area under the receiver operating characteristic curve for predicting amyloid PET status compared to age and apolipoprotein E (APOE) genotype. RESULTS: The age and APOE genotype model predicted amyloid status with an area under the curve (AUC) of 0.75. Three assays improved AUCs to 0.81, 0.81, and 0.84 (P < .05, uncorrected for multiple comparisons). DISCUSSION: Measurement of Aß in plasma contributes to addressing the amyloid component of the ATN (amyloid/tau/neurodegeneration) framework and could be a first step before or in place of a PET or cerebrospinal fluid screening study. HIGHLIGHTS: The Foundation of the National Institutes of Health Biomarkers Consortium evaluated six plasma amyloid beta (Aß) assays using Alzheimer's Disease Neuroimaging Initiative samples. Three assays improved prediction of amyloid status over age and apolipoprotein E (APOE) genotype. Plasma Aß42/40 predicted amyloid positron emission tomography status better than Aß42 or Aß40 alone.
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BACKGROUND: Canine cognitive dysfunction syndrome (CCDS) is a progressive neurodegenerative disorder found in senior dogs. Due to the lack of biological markers, CCDS is commonly underdiagnosed. The aim of this study was to identify potential plasma biomarkers using proteomics techniques and to increase our understanding of the pathogenic mechanism of the disease. Plasma amyloid beta 42 (Aß42) has been seen to be a controversial biomarker for CCDS. Proteomics analysis was performed for protein identification and quantification. RESULTS: Within CCDS, ageing, and adult dogs, 87 proteins were identified specific to Canis spp. in the plasma samples. Of 87 proteins, 48 and 41 proteins were changed in the ageing and adult groups, respectively. Several distinctly expressed plasma proteins identified in CCDS were involved in complement and coagulation cascades and the apolipoprotein metabolism pathway. Plasma Aß42 levels considerably overlapped within the CCDS and ageing groups. In the adult group, the Aß42 level was low compared with that in the other groups. Nevertheless, plasma Aß42 did not show a correlation with the Canine Cognitive Dysfunction Rating scale (CCDR) score in the CCDS group (p = 0.131, R2 = 0.261). CONCLUSIONS: Our present findings suggest that plasma Aß42 does not show potential for use as a diagnostic biomarker in CCDS. The nano-LC-MS/MS data revealed that the predictive underlying mechanism of CCDS was the co-occurrence of inflammation-mediated acute phase response proteins and complement and coagulation cascades that partly functioned by apolipoproteins and lipid metabolism. Some of the differentially expressed proteins may serve as potential predictor biomarkers along with Aß42 in plasma for improved CCDS diagnosis. Further study in larger population-based cohort study is required in validation to define the correlation between protein expression and the pathogenesis of CCDS.
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Disfunción Cognitiva/diagnóstico , Enfermedades de los Perros/diagnóstico , Proteoma , Envejecimiento , Péptidos beta-Amiloides/sangre , Animales , Biomarcadores/sangre , Proteínas Sanguíneas/análisis , Disfunción Cognitiva/sangre , Enfermedades de los Perros/sangre , Perros , Femenino , Masculino , TailandiaRESUMEN
INTRODUCTION: Obstructive sleep apnea (OSA) is associated with Alzheimer's disease (AD) biomarkers in cognitively normal (CN) and mild cognitive impaired (MCI) participants. However, independent and combined effects of OSA, amyloid beta (Aß) and tau-accumulation on AD time-dependent progression risk is unclear. METHODS: Study participants grouped by biomarker profile, as described by the A/T/N scheme, where "A" refers to aggregated Aß, "T" aggregated tau, and "N" to neurodegeneration, included 258 CN (OSA-positive [OSA+] [A+TN+ n = 10, A+/TN- n = 6, A-/TN+ n = 10, A-/TN- n = 6 and OSA-negative [OSA-] [A+TN+ n = 84, A+/TN- n = 11, A-/TN+ n = 96, A-/TN- n = 36]) and 785 MCI (OSA+ [A+TN+ n = 35, A+/TN- n = 15, A-/TN+ n = 25, A-/TN- n = 16] and OSA- [A+TN+ n = 388, A+/TN- n = 28, A-/TN+ n = 164, A-/TN- n = 114]) older-adults from the Alzheimer's Disease Neuroimaging Initiative cohort. Cox proportional hazards regression models estimated the relative hazard of progression from CN-to-MCI and MCI-to-AD, among baseline OSA CN and MCI patients, respectively. Multi-level logistic mixed-effects models with random intercept and slope investigated the synergistic associations of self-reported OSA, Aß, and tau burden with prospective cognitive decline. RESULTS: Independent of TN-status (CN and MCI), OSA+/Aß+ participants were approximately two to four times more likely to progress to MCI/AD (P < .001) and progressed 6 to 18 months earlier (P < .001), compared to other participants combined (ie, OSA+/Aß-, OSA-/Aß+, and OSA-/Aß-). Notably, OSA+/Aß- versus OSA-/Aß- (CN and MCI) and OSA+/TN- versus OSA-/TN- (CN) participants showed no difference in the risk and time-to-MCI/AD progression. Mixed effects models demonstrated OSA synergism with Aß (CN and MCI [ß = 1.13, 95% confidence interval (CI), 0.74 to 1.52, and ß = 1.18, 95%CI, 0.82 to 1.54]) respectively, and with tau (MCI [ß = 1.31, 95% CI, 0.87 to 1.47]), P < .001 for all. DISCUSSION: OSA acts in synergism with Aß and with tau, and all three acting together result in synergistic neurodegenerative mechanisms especially as Aß and tau accumulation becomes increasingly abnormal, thus leading to shorter progression time to MCI/AD in CN and MCI-OSA patients, respectively.
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The concentration effect of dielectrophoresis (DEP) enables detection of biomolecules with high sensitivity. In this study, microstructures were patterned between the interdigitated microelectrodes (IMEs) to increase the concentration effect of DEP. The microstructures increased the electric field gradient ( ∇ | E 2 | ) between the IMEs to approximately 6.61-fold higher than in the bare IMEs with a gap of 10 µm, resulting in a decreased optimal voltage to concentrate amyloid beta 42 (Aß42, from 0.8 Vpp to 0.5 Vpp) and tau-441 (from 0.9 Vpp to 0.6 Vpp) between the IMEs. Due to the concentration effect of DEP, the impedance change in the optimal condition was higher than the values in the reference condition at 2.64-fold in Aß42 detection and at 1.59-fold in tau-441 detection. This concentration effect of DEP was also verified by counting the number of gold (Au) particles which conjugated with the secondary antibody. Finally, an enhanced concentration effect in the patterned IMEs was verified by measuring the impedance change depending on the concentration of Aß42 and tau-441. Our results suggest that microstructures increase the concentration effect of DEP, leading to enhanced sensitivity of the IMEs.
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Homodimeric chalcone based 11C-PET radiotracer, 11C-(Chal)2DEA-Me, was synthesized, and binding affinity toward beta amyloid (Aß) was evaluated. The computational studies revealed multiple binding of the tracer at the recognition sites of Aß fibrils. The bivalent ligand 11C-(Chal)2DEA-Me displayed higher binding affinity compared to the corresponding monomer, 11C-Chal-Me, and classical Aß agents. The radiolabeling yield with carbon-11 was 40-55% (decay corrected) with specific activity of 65-90 GBq/µmol. A significant ( p < 0.0001) improvement in the binding affinity of 11C-(Chal)2DEA-Me with synthetic Aß42 aggregates over the monomer, 11C-Chal-Me, demonstrates the utility of the bivalent approach. The PET imaging and biodistribution data displayed suitable brain pharmacokinetics of both ligands with higher brain uptake in the case of the bivalent ligand. Metabolite analysis of healthy ddY mouse brain homogenates exhibited high stability of the radiotracers in the brain with >93% intact tracer at 30 min post injection. Both chalcone derivatives were fluorescent in nature and demonstrated significant changes in the emission properties after binding with Aß42. The preliminary analysis indicates high potential of 11C-(Chal)2DEA-Me as in vivo Aß42 imaging tracer and highlights the significance of the bivalent approach to achieve a higher biological response for detection of early stages of amyloidosis.
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Péptidos beta-Amiloides/metabolismo , Radioisótopos de Carbono/metabolismo , Chalcona/metabolismo , Amiloidosis/metabolismo , Animales , Encéfalo/metabolismo , Colorantes Fluorescentes/metabolismo , Ligandos , Masculino , Ratones , Tomografía de Emisión de Positrones/métodos , Unión Proteica , Distribución TisularRESUMEN
Alzheimer's disease (AD) is the most prevalent neurodegenerative disease and a worldwide health challenge. Different therapeutic approaches are being developed to reverse or slow the loss of affected neurons. Another plausible therapeutic way that may complement the studies is to increase the survival of existing neurons by mobilizing the existing neural stem/progenitor cells (NSPCs) - i.e. "induce their plasticity" - to regenerate lost neurons despite the existing pathology and unfavorable environment. However, there is controversy about how NSPCs are affected by the unfavorable toxic environment during AD. In this review, we will discuss the use of stem cells in neurodegenerative diseases and in particular how NSPCs affect the AD pathology and how neurodegeneration affects NSPCs. In the end of this review, we will discuss how zebrafish as a useful model organism with extensive regenerative ability in the brain might help to address the molecular programs needed for NSPCs to respond to neurodegeneration by enhanced neurogenesis.
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Enfermedad de Alzheimer/metabolismo , Células-Madre Neurales/citología , Células-Madre Neurales/metabolismo , Enfermedad de Alzheimer/patología , Péptidos beta-Amiloides/metabolismo , Animales , Humanos , Neurogénesis/fisiología , Fragmentos de Péptidos/metabolismo , Pez CebraRESUMEN
INTRODUCTION: Brain insulin resistance and deficiency is a consistent feature of Alzheimer's disease (AD). Insulin resistance can be mediated by the surface expression of the insulin receptor (IR). Cleavage of the IR generates the soluble IR (sIR). METHODS: We measured the levels of sIR present in cerebrospinal fluid (CSF) from individuals along the AD diagnostic spectrum from two cohorts: Seattle (n = 58) and the Consortium for the Early Identification of Alzheimer's Disease-Quebec (CIMA-Q; n = 61). We further investigated the brain cellular contribution for sIR using human cell lines. RESULTS: CSF sIR levels were not statistically different in AD. CSF sIR and amyloid beta (Aß)42 and Aß40 levels significantly correlated as well as CSF sIR and cognition in the CIMA-Q cohort. Human neurons expressing the amyloid precursor protein "Swedish" mutation generated significantly greater sIR and human astrocytes were also able to release sIR in response to both an inflammatory and insulin stimulus. DISCUSSION: These data support further investigation into the generation and role of sIR in AD. Highlights: Cerebrospinal fluid (CSF) soluble insulin receptor (sIR) levels positively correlate with amyloid beta (Aß)42 and Aß40.CSF sIR levels negatively correlate with cognitive performance (Montreal Cognitive Assessment score).CSF sIR levels in humans remain similar across Alzheimer's disease diagnostic groups.Neurons derived from humans with the "Swedish" mutation in which Aß42 is increased generate increased levels of sIR.Human astrocytes can also produce sIR and generation is stimulated by tumor necrosis factor α and insulin.
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BACKGROUND: To determine whether Lewy body dementia (LBD) patients with likely copathology of Alzheimer's disease (AD) exhibit greater neuropsychiatric symptom (NPS) compared to those without likely AD-type copathology. METHODS: We enrolled 69 individuals diagnosed with Lewy body dementia (LBD), comprising both dementia with Lewy bodies (DLB) (n = 36) and Parkinson's disease dementia (PDD) (n = 33). These participants had accessible cerebrospinal fluid (CSF) markers related to Alzheimer's disease (AD) and cognitive data. We assessed CSF levels of ß-amyloid 42 (Aß42), phosphorylated tau (p-tau), and total tau (t-tau). Employing autopsy-validated CSF thresholds (t-tau/Aß42 ratio > 0.3, n = 69), we categorized individuals into LBD with AD pathology (LBD + AD, n = 31) and LBD without apparent AD co-pathology (LBD - AD, n = 38). Moreover, the Hamilton Depression Scale (HAMD24), Hamilton Anxiety Scale (HAMA14), and Neuropsychiatric Inventory Questionnaire (NPI-Q) was used to assess the NPS. Spearman correlations were utilized to explore links between NPS and CSF marker profiles. RESULTS: In terms of neuropsychiatric symptoms, LBD + AD patients demonstrated notably elevated levels of depressive symptoms (HAMD24) in comparison to LBD - AD patients (P < 0.001). However, based on PDD and DLB groups, no significant variations were noted in the neuropsychiatric symptoms(Pï¼0.05). Moreover, CSF-derived biomarkers of Aß42, and t-tau/Aß42 were also associated with HAMD24 total scores in the LBD + AD subsample (P < 0.05). CONCLUSION: There is an association between AD pathological markers and the NPS of LBD. The biologically based classification of LBD may be more advantageous in elucidating clinical heterogeneity than clinically defined syndromes.
Asunto(s)
Enfermedad de Alzheimer , Péptidos beta-Amiloides , Biomarcadores , Enfermedad por Cuerpos de Lewy , Proteínas tau , Humanos , Enfermedad por Cuerpos de Lewy/líquido cefalorraquídeo , Enfermedad por Cuerpos de Lewy/psicología , Enfermedad por Cuerpos de Lewy/patología , Femenino , Enfermedad de Alzheimer/líquido cefalorraquídeo , Enfermedad de Alzheimer/patología , Enfermedad de Alzheimer/psicología , Masculino , Anciano , Péptidos beta-Amiloides/líquido cefalorraquídeo , Proteínas tau/líquido cefalorraquídeo , Biomarcadores/líquido cefalorraquídeo , Persona de Mediana Edad , Fragmentos de Péptidos/líquido cefalorraquídeo , Anciano de 80 o más Años , Enfermedad de Parkinson/líquido cefalorraquídeo , Enfermedad de Parkinson/psicología , Enfermedad de Parkinson/patología , Pruebas NeuropsicológicasRESUMEN
Introduction: Beta-amyloid accumulation in the brain appears to be a key initiating event in Alzheimer's disease (AD), and factors associated with increased deposition of beta-amyloid are of great interest. Enhanced deposition of amyloid-ß peptides is due to an imbalance between their production and elimination. Previous studies show that diminished levels of CSF amyloid beta 42 (Aß42) is a biomarker in AD; however, the role of serum Aß42 in AD is contradictory. BMI and obesity have been reported to be related to increased serum Aß42 levels. Therefore, we aimed to investigate the relation between metabolic syndrome (MetS), its clinical measures (abdominal obesity, high glucose, high triglyceride, low high-density lipoprotein cholesterol level, and hypertension), and serum Aß42 levels. Methods: A total of 1261 subjects, aged 18-89 years in Chengdu, China, were enrolled from January 2020 to January 2021 to explore the correlation of serum Aß42 levels with body mass index (BMI), blood lipids, and blood pressure. Furthermore, as the risk of MetS is closely related to age, 1,212 participants (N = 49 with age ≥ 80 years old were excluded) were analyzed for the correlation of serum Aß42 level and MetS clinical measures. Results: The results showed that log-transformed serum Aß42 level was positively correlated with BMI (R = 0.29; p < 0.001), log-transformed triglyceride (R = 0.14; p < 0.001), and diastolic blood pressure (DBP) (R = 0.12; p < 0.001) and negatively correlated with high-density lipoprotein (HDL-c) (R = -0.18; p < 0.001). After adjusting for age, sex, and other covariates, elevated serum Aß42 level was correlated with higher values of BMI (ßmodel1 = 2.694, ßmodel2 = 2.703) and DBP (ßmodel1 = 0.541, ßmodel2 = 0.546) but a lower level of HDL-c (ßmodel2 = -1.741). Furthermore, serum Aß42 level was positively correlated with MetS and its clinical measures, including BMI and DBP, and negatively correlated with HDL-c level in the Han Chinese population. However, the level of serum Aß42 did not show a significant correlation with high glucose or high triglyceride. Discussion: These observations indicate that MetS and its components are associated with higher levels of serum Aß42 and hence limit the potential of serum Aß42 as a suitable diagnostic biomarker for AD. As such, we recommend serum Aß42 serve as a direct risk biomarker for MetS rather than for AD.