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OBJECTIVE: In Alzheimer's disease, hyperphosphorylated tau is associated with formation of insoluble paired helical filaments that aggregate as neurofibrillary tau tangles and are associated with neuronal loss and cognitive symptoms. Dual orexin receptor antagonists decrease soluble amyloid-ß levels and amyloid plaques in mouse models overexpressing amyloid-ß, but have not been reported to affect tau phosphorylation. In this randomized controlled trial, we tested the acute effect of suvorexant, a dual orexin receptor antagonist, on amyloid-ß, tau, and phospho-tau. METHODS: Thirty-eight cognitively unimpaired participants aged 45 to 65 years were randomized to placebo (N = 13), suvorexant 10 mg (N = 13), and suvorexant 20 mg (N = 12). Six milliliters of cerebrospinal fluid were collected via an indwelling lumbar catheter every 2 hours for 36 hours starting at 20:00. Participants received placebo or suvorexant at 21:00. All samples were processed and measured for multiple forms of amyloid-ß, tau, and phospho-tau via immunoprecipitation and liquid chromatography-mass spectrometry. RESULTS: The ratio of phosphorylated-tau-threonine-181 to unphosphorylated-tau-threonine-181, a measure of phosphorylation at this tau phosphosite, decreased ~10% to 15% in participants treated with suvorexant 20 mg compared to placebo. However, phosphorylation at tau-serine-202 and tau-threonine-217 were not decreased by suvorexant. Suvorexant decreased amyloid-ß ~10% to 20% compared to placebo starting 5 hours after drug administration. INTERPRETATION: In this study, suvorexant acutely decreased tau phosphorylation and amyloid-ß concentrations in the central nervous system. Suvorexant is approved by the US Food and Drug Administration to treatment insomnia and may have potential as a repurposed drug for the prevention of Alzheimer's disease, however, future studies with chronic treatment are needed. ANN NEUROL 2023;94:27-40.
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Doença de Alzheimer , Camundongos , Animais , Humanos , Doença de Alzheimer/diagnóstico , Fosforilação , Proteínas tau/metabolismo , Peptídeos beta-Amiloides/metabolismo , Sistema Nervoso Central/metabolismo , Antagonistas dos Receptores de Orexina/farmacologia , Antagonistas dos Receptores de Orexina/uso terapêuticoRESUMO
INTRODUCTION: Sleep deprivation increases cerebrospinal fluid (CSF) amyloid beta (Aß) and tau levels; however, sleep's effect on Aß and tau in plasma is unknown. METHODS: In a cross-over design, CSF Aß and tau concentrations were measured in five cognitively normal individuals who had blood and CSF collected every 2 hours for 36 hours during sleep-deprived and normal sleep control conditions. RESULTS: Aß40, Aß42, unphosphorylated tau threonine181 (T181), unphosphorylated tau threonine-217 (T217), and phosphorylated T181 (pT181) concentrations increased â¼35% to 55% in CSF and decreased â¼5% to 15% in plasma during sleep deprivation. CSF/plasma ratios of all Alzheimer's disease (AD) biomarkers increased during sleep deprivation while the CSF/plasma albumin ratio, a measure of blood-CSF barrier permeability, decreased. CSF and plasma Aß42/40, pT181/T181, and pT181/Aß42 ratios were stable longitudinally in both groups. DISCUSSION: These findings show that sleep loss alters some plasma AD biomarkers by lowering brain clearance mechanisms and needs to be taken into account when interpreting individual plasma AD biomarkers but not ratios.
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Doença de Alzheimer , Distúrbios do Início e da Manutenção do Sono , Transtornos do Sono-Vigília , Humanos , Doença de Alzheimer/líquido cefalorraquidiano , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Privação do Sono , Proteínas tau/líquido cefalorraquidiano , Sono , Biomarcadores/líquido cefalorraquidiano , Fragmentos de Peptídeos/líquido cefalorraquidianoRESUMO
Sleep disturbances are associated with future risk of Alzheimer disease. Disrupted sleep increases soluble amyloid ß, suggesting a mechanism for sleep disturbances to increase Alzheimer disease risk. We tested this response in humans using indwelling lumbar catheters to serially sample cerebrospinal fluid while participants were sleep-deprived, treated with sodium oxybate, or allowed to sleep normally. All participants were infused with 13 C6 -leucine to measure amyloid ß kinetics. We found that sleep deprivation increased overnight amyloid ß38, amyloid ß40, and amyloid ß42 levels by 25 to 30% via increased overnight amyloid ß production relative to sleeping controls. These findings suggest that disrupted sleep increases Alzheimer disease risk via increased amyloid ß production. Ann Neurol 2018;83:197-204.
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Peptídeos beta-Amiloides/líquido cefalorraquidiano , Sono/fisiologia , Adulto , Doença de Alzheimer/líquido cefalorraquidiano , Anestésicos/farmacologia , Ritmo Circadiano , Feminino , Humanos , Cinética , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Testes Neuropsicológicos , Fragmentos de Peptídeos/líquido cefalorraquidiano , Projetos Piloto , Transtornos do Sono-Vigília/líquido cefalorraquidiano , Oxibato de Sódio/farmacologiaRESUMO
The risk of Alzheimer's disease (AD) is highly dependent on apolipoprotein-E (apoE) genotype. The reasons for apoE isoform-selective risk are uncertain; however, both the amounts and structure of human apoE isoforms have been hypothesized to lead to amyloidosis increasing the risk for AD. To address the hypothesis that amounts of apoE isoforms are different in the human CNS, we developed a novel isoform-specific method to accurately quantify apoE isoforms in clinically relevant samples. The method utilizes an antibody-free enrichment step and isotope-labeled physiologically relevant lipoprotein particle standards produced by immortalized astrocytes. We applied this method to a cohort of well characterized clinical samples and observed the following findings. The apoE isoform amounts are not different in cerebrospinal fluid (CSF) from young normal controls, suggesting that the amount of apoE isoforms is not the reason for risk of amyloidosis prior to the onset of advanced age. We did, however, observe an age-related increase in both apoE isoforms. In contrast to normal aging, the presence of amyloid increased apoE3, whereas apoE4 was unchanged or decreased. Importantly, for heterozygotes, the apoE4/apoE3 isoform ratio was increased in the CNS, although the reverse was true in the periphery. Finally, CSF apoE levels, but not plasma apoE levels, correlated with CSF ß-amyloid levels. Collectively, these findings support the hypothesis that CNS and peripheral apoE are separate pools and differentially regulated. Furthermore, these results suggest that apoE mechanisms for the risk of amyloidosis and AD are related to an interaction between apoE, aging, and the amount of amyloid burden.
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Amiloidose/sangue , Amiloidose/líquido cefalorraquidiano , Apolipoproteína E3/análise , Apolipoproteína E4/análise , Biomarcadores/análise , Encéfalo/metabolismo , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/sangue , Doença de Alzheimer/líquido cefalorraquidiano , Doença de Alzheimer/diagnóstico , Sequência de Aminoácidos , Amiloidose/diagnóstico , Astrócitos/citologia , Astrócitos/metabolismo , Estudos de Casos e Controles , Células Cultivadas , Demência/sangue , Demência/líquido cefalorraquidiano , Demência/diagnóstico , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Adulto JovemRESUMO
INTRODUCTION: Cerebrospinal fluid analysis and other measurements of amyloidosis, such as amyloid-binding positron emission tomography studies, are limited by cost and availability. There is a need for a more practical amyloid ß (Aß) biomarker for central nervous system amyloid deposition. METHODS: We adapted our previously reported stable isotope labeling kinetics protocol to analyze the turnover kinetics and concentrations of Aß38, Aß40, and Aß42 in human plasma. RESULTS: Aß isoforms have a half-life of approximately 3 hours in plasma. Aß38 demonstrated faster turnover kinetics compared with Aß40 and Aß42. Faster fractional turnover of Aß42 relative to Aß40 and lower Aß42 and Aß42/Aß40 concentrations in amyloid-positive participants were observed. DISCUSSION: Blood plasma Aß42 shows similar amyloid-associated alterations as we have previously reported in cerebrospinal fluid, suggesting a blood-brain transportation mechanism of Aß. The stability and sensitivity of plasma Aß measurements suggest this may be a useful screening test for central nervous system amyloidosis.
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Peptídeos beta-Amiloides/sangue , Amiloidose/sangue , Fragmentos de Peptídeos/sangue , Idoso , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Amiloidose/líquido cefalorraquidiano , Amiloidose/diagnóstico por imagem , Área Sob a Curva , Biomarcadores/sangue , Biomarcadores/líquido cefalorraquidiano , Cromatografia Líquida , Humanos , Imunoprecipitação , Marcação por Isótopo , Cinética , Espectrometria de Massas , Fragmentos de Peptídeos/líquido cefalorraquidiano , Estudos Prospectivos , Curva ROC , Método Simples-CegoRESUMO
OBJECTIVE: Age is the single greatest risk factor for Alzheimer's disease (AD), with the incidence doubling every 5 years after age 65. However, our understanding of the mechanistic relationship between increasing age and the risk for AD is currently limited. We therefore sought to determine the relationship between age, amyloidosis, and amyloid-beta (Aß) kinetics in the central nervous system (CNS) of humans. METHODS: Aß kinetics were analyzed in 112 participants and compared to the ages of participants and the amount of amyloid deposition. RESULTS: We found a highly significant correlation between increasing age and slowed Aß turnover rates (2.5-fold longer half-life over five decades of age). In addition, we found independent effects on Aß42 kinetics specifically in participants with amyloid deposition. Amyloidosis was associated with a higher (>50%) irreversible loss of soluble Aß42 and a 10-fold higher Aß42 reversible exchange rate. INTERPRETATION: These findings reveal a mechanistic link between human aging and the risk of amyloidosis, which may be owing to a dramatic slowing of Aß turnover, increasing the likelihood of protein misfolding that leads to deposition. Alterations in Aß kinetics associated with aging and amyloidosis suggest opportunities for diagnostic and therapeutic strategies. More generally, this study provides an example of how changes in protein turnover kinetics can be used to detect physiological and pathophysiological changes and may be applicable to other proteinopathies.
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Envelhecimento/metabolismo , Peptídeos beta-Amiloides/metabolismo , Amiloidose/metabolismo , Sistema Nervoso Central/metabolismo , Fragmentos de Peptídeos/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Envelhecimento/patologia , Amiloidose/patologia , Sistema Nervoso Central/patologia , Feminino , Humanos , Cinética , Masculino , Pessoa de Meia-IdadeRESUMO
BACE, a ß-secretase, is an attractive potential disease-modifying therapeutic strategy for Alzheimer's disease (AD) as it results directly in the decrease of amyloid precursor protein (APP) processing through the ß-secretase pathway and a lowering of CNS amyloid-ß (Aß) levels. The interaction of the ß-secretase and α-secretase pathway-mediated processing of APP in the rhesus monkey (nonhuman primate; NHP) CNS is not understood. We hypothesized that CNS inhibition of BACE would result in decreased newly generated Aß and soluble APPß (sAPPß), with increased newly generated sAPPα. A stable isotope labeling kinetics experiment in NHPs was performed with a (13)C6-leucine infusion protocol to evaluate effects of BACE inhibition on CNS APP processing by measuring the kinetics of sAPPα, sAPPß, and Aß in CSF. Each NHP received a low, medium, or high dose of MBI-5 (BACE inhibitor) or vehicle in a four-way crossover design. CSF sAPPα, sAPPß, and Aß were measured by ELISA and newly incorporated label following immunoprecipitation and liquid chromatography-mass spectrometry. Concentrations, kinetics, and amount of newly generated APP fragments were calculated. sAPPß and sAPPα kinetics were similar, but both significantly slower than Aß. BACE inhibition resulted in decreased labeled sAPPß and Aß in CSF, without observable changes in labeled CSF sAPPα. ELISA concentrations of sAPPß and Aß both decreased and sAPPα increased. sAPPα increased by ELISA, with no difference by labeled sAPPα kinetics indicating increases in product may be due to APP shunting from the ß-secretase to the α-secretase pathway. These results provide a quantitative understanding of pharmacodynamic effects of BACE inhibition on NHP CNS, which can inform about target development.
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Secretases da Proteína Precursora do Amiloide/líquido cefalorraquidiano , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Precursor de Proteína beta-Amiloide/líquido cefalorraquidiano , Sistema Nervoso Central/metabolismo , Secretases da Proteína Precursora do Amiloide/metabolismo , Peptídeos beta-Amiloides/metabolismo , Precursor de Proteína beta-Amiloide/metabolismo , Animais , Isótopos de Carbono/metabolismo , Linhagem Celular Tumoral , Sistema Nervoso Central/efeitos dos fármacos , Estudos Cross-Over , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/farmacologia , Humanos , Imunoprecipitação , Leucina/metabolismo , Macaca mulatta , Espectrometria de Massas , Neuroblastoma , Fragmentos de Peptídeos , TransfecçãoRESUMO
OBJECTIVE: The aim of this study was to measure the flux of amyloid-ß (Aß) across the human cerebral capillary bed to determine whether transport into the blood is a significant mechanism of clearance for Aß produced in the central nervous system (CNS). METHODS: Time-matched blood samples were simultaneously collected from a cerebral vein (including the sigmoid sinus, inferior petrosal sinus, and the internal jugular vein), femoral vein, and radial artery of patients undergoing inferior petrosal sinus sampling. For each plasma sample, Aß concentration was assessed by 3 assays, and the venous to arterial Aß concentration ratios were determined. RESULTS: Aß concentration was increased by â¼7.5% in venous blood leaving the CNS capillary bed compared to arterial blood, indicating efflux from the CNS into the peripheral blood (p < 0.0001). There was no difference in peripheral venous Aß concentration compared to arterial blood concentration. INTERPRETATION: Our results are consistent with clearance of CNS-derived Aß into the venous blood supply with no increase from a peripheral capillary bed. Modeling these results suggests that direct transport of Aß across the blood-brain barrier accounts for â¼25% of Aß clearance, and reabsorption of cerebrospinal fluid Aß accounts for â¼25% of the total CNS Aß clearance in humans. Ann Neurol 2014;76:837-844.
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Peptídeos beta-Amiloides/sangue , Barreira Hematoencefálica/metabolismo , Sistema Nervoso Central/metabolismo , Adulto , Biomarcadores/sangue , Biomarcadores/metabolismo , Encéfalo/metabolismo , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Transporte Proteico/fisiologiaRESUMO
Importance: Phase 3 trials of successful antiamyloid therapies in Alzheimer disease (AD) have demonstrated improved clinical efficacy in people with less severe disease. Plasma biomarkers will be essential for efficient screening of participants in future primary prevention clinical trials testing antiamyloid therapies in cognitively unimpaired (CU) individuals with initially low brain ß-amyloid (Aß) levels who are at high risk of accumulating Aß. Objective: To investigate if combining plasma biomarkers could be useful in predicting subsequent development of Aß pathology in CU individuals with subthreshold brain Aß levels (defined as Aß levels <40 Centiloids) at baseline. Design, Setting, and Participants: This was a longitudinal study including Swedish BioFINDER-2 (enrollment 2017-2022) and replication in 2 independent cohorts, the Knight Alzheimer Disease Research Center (Knight ADRC; enrollment 1988 and 2019) and Swedish BioFINDER-1 (enrollment 2009-2015). Included for analysis was a convenience sample of CU individuals with baseline plasma phosphorylated tau 217 (p-tau217) and Aß42/40 assessments and Aß assessments with positron emission tomography (Aß-PET) or cerebrospinal fluid (CSF) Aß42/40. Data were analyzed between April 2023 and May 2024. Exposures: Baseline plasma levels of Aß42/40, p-tau217, the ratio of p-tau217 to nonphosphorylated tau (%p-tau217), p-tau231, and glial fibrillary acidic protein (GFAP). Main Outcomes and Measures: Cross-sectional and longitudinal PET and CSF measures of brain Aß pathology. Results: This study included 495 (BioFINDER-2), 283 (Knight ADRC), and 205 (BioFINDER-1) CU participants. In BioFINDER-2, the mean (SD) age was 65.7 (14.4) with 261 females (52.7%). When detecting abnormal CSF Aß-status, a combination of plasma %p-tau217 and Aß42/40 showed better performance (area under the curve = 0.949; 95% CI, 0.929-0.970; P <.02) than individual biomarkers. In CU participants with subthreshold baseline Aß-PET, baseline plasma %p-tau217 and Aß42/40 levels were significantly associated with baseline Aß-PET (n = 384) and increases in Aß-PET over time (n = 224). Associations of plasma %p-tau217 and Aß42/40 and their interaction with baseline Aß-PET (%p-tau217: ß = 2.77; 95% CI, 1.84-3.70; Aß42/40: ß = -1.64; 95% CI, -2.53 to -0.75; %p-tau217 × Aß42/40: ß = -2.14; 95% CI, -2.79 to -1.49; P < .001) and longitudinal Aß-PET (%p-tau217: ß = 0.67; 95% CI, 0.48-0.87; Aß42/40: ß = -0.33; 95% CI, -0.51 to -0.15; %p-tau217 × Aß42/40: ß = -0.31; 95% CI, -0.44 to -0.18; P < .001) were also significant in the models combining the 2 baseline biomarkers as predictors. Similarly, baseline plasma p-tau217 and Aß42/40 were independently associated with longitudinal Aß-PET in Knight ADRC (%p-tau217: ß = 0.71; 95% CI, 0.26-1.16; P = .002; Aß42/40: ß = -0.74; 95% CI, -1.26 to -0.22; P = .006) and longitudinal CSF Aß42/40 in BioFINDER-1 (p-tau217: ß = -0.0003; 95% CI, -0.0004 to -0.0001; P = .01; Aß42/40: ß = 0.0004; 95% CI, 0.0002-0.0006; P < .001) in CU participants with subthreshold Aß levels at baseline. Plasma p-tau231 and GFAP did not provide any clear independent value. Conclusions and Relevance: Results of this cohort study suggest that combining plasma p-tau217and Aß42/40 levels could be useful for predicting development of Aß pathology in people with early stages of subthreshold Aß accumulation. These biomarkers might thus facilitate screening of participants for future primary prevention trials.
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Alzheimer's disease biomarkers are crucial to understanding disease pathophysiology, aiding accurate diagnosis and identifying target treatments. Although the number of biomarkers continues to grow, the relative utility and uniqueness of each is poorly understood as prior work has typically calculated serial pairwise relationships on only a handful of markers at a time. The present study assessed the cross-sectional relationships among 27 Alzheimer's disease biomarkers simultaneously and determined their ability to predict meaningful clinical outcomes using machine learning. Data were obtained from 527 community-dwelling volunteers enrolled in studies at the Charles F. and Joanne Knight Alzheimer Disease Research Center at Washington University in St Louis. We used hierarchical clustering to group 27 imaging, CSF and plasma measures of amyloid beta, tau [phosphorylated tau (p-tau), total tau t-tau)], neuronal injury and inflammation drawn from MRI, PET, mass-spectrometry assays and immunoassays. Neuropsychological and genetic measures were also included. Random forest-based feature selection identified the strongest predictors of amyloid PET positivity across the entire cohort. Models also predicted cognitive impairment across the entire cohort and in amyloid PET-positive individuals. Four clusters emerged reflecting: core Alzheimer's disease pathology (amyloid and tau), neurodegeneration, AT8 antibody-associated phosphorylated tau sites and neuronal dysfunction. In the entire cohort, CSF p-tau181/Aß40lumi and Aß42/Aß40lumi and mass spectrometry measurements for CSF pT217/T217, pT111/T111, pT231/T231 were the strongest predictors of amyloid PET status. Given their ability to denote individuals on an Alzheimer's disease pathological trajectory, these same markers (CSF pT217/T217, pT111/T111, p-tau/Aß40lumi and t-tau/Aß40lumi) were largely the best predictors of worse cognition in the entire cohort. When restricting analyses to amyloid-positive individuals, the strongest predictors of impaired cognition were tau PET, CSF t-tau/Aß40lumi, p-tau181/Aß40lumi, CSF pT217/217 and pT205/T205. Non-specific CSF measures of neuronal dysfunction and inflammation were poor predictors of amyloid PET and cognitive status. The current work utilized machine learning to understand the interrelationship structure and utility of a large number of biomarkers. The results demonstrate that, although the number of biomarkers has rapidly expanded, many are interrelated and few strongly predict clinical outcomes. Examining the entire corpus of available biomarkers simultaneously provides a meaningful framework to understand Alzheimer's disease pathobiological change as well as insight into which biomarkers may be most useful in Alzheimer's disease clinical practice and trials.
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BACKGROUND: In MAPT (Multidomain Alzheimer Preventive Trial), a cognitive effect of multidomain intervention (MI) was showed in non-demented subjects with positive amyloid PET. However, screening eligible patients for multidomain intervention by PET is difficult to generalize in real-world settings. METHODS: MAPT study was a 3-year, randomized, placebo-controlled trial followed by a 2-year observational and optional extension. All participants were non-demented and randomly assigned (1:1:1:1) to the MI plus omega 3, MI plus placebo, omega 3 alone, or placebo alone group. The objectives were to assess the cognitive effect of MAPT interventions (omega 3 supplementation, MI, combined intervention) in non-demented subjects according to amyloid blood status at 12, 36, and 60 months. In this subgroup analysis (n = 483), amyloid status was defined by plasma Aß42/40 ratio (cutoff ≤ 0.0107). The primary outcome measure was the change in cognitive composite score after a 1, 3, and 5-year clinical follow-up. RESULTS: The intention-to-treat (ITT) population included 483 subjects (161 positive and 322 negative amyloid participants based on plasma Aß42/40 ratio). In the positive amyloid ITT population, we showed a positive effect of MI plus omega 3 on the change in composite cognitive score in 12 (raw p = .0350, 0.01917, 95% CI = [0.0136 to 0.3699]) and 36 months (raw p = .0357, 0.2818, 95% CI = [0.0190 to 0.5446]). After correction of multiple comparisons and adjustments, these differences were not significant (adjusted p = .1144 and .0690). In the per-protocol positive amyloid group (n = 154), we observed a significant difference between the combined intervention and placebo groups at 12 (p = .0313, 0.2424, 0.0571 to 0.4276) and 36 months (p = .0195, 0.3747, 0.1055 to 0.6439) persisting after adjustment. In the ITT and per-protocol analyses, no cognitive effect was observed in the positive and negative amyloid group at 60-month visit. CONCLUSIONS: These findings suggest a benefit of MI plus omega 3 in positive blood amyloid subjects. This promising trend needs to be confirmed before using blood biomarkers for screening in preventive trials. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01513252 .
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Doença de Alzheimer , Ácidos Graxos Ômega-3 , Humanos , Doença de Alzheimer/tratamento farmacológico , Ácidos Graxos Ômega-3/farmacologia , Ácidos Graxos Ômega-3/uso terapêutico , Projetos de Pesquisa , Amiloide , CogniçãoRESUMO
Introduction: Continuous measures of amyloid burden as measured by positron emission tomography (PET) are being used increasingly to stage Alzheimer's disease (AD). This study examined whether cerebrospinal fluid (CSF) and plasma amyloid beta (Aß)42/Aß40 could predict continuous values for amyloid PET. Methods: CSF Aß42 and Aß40 were measured with automated immunoassays. Plasma Aß42 and Aß40 were measured with an immunoprecipitation-mass spectrometry assay. Amyloid PET was performed with Pittsburgh compound B (PiB). The continuous relationships of CSF and plasma Aß42/Aß40 with amyloid PET burden were modeled. Results: Most participants were cognitively normal (427 of 491 [87%]) and the mean age was 69.0 ± 8.8 years. CSF Aß42/Aß40 predicted amyloid PET burden until a relatively high level of amyloid accumulation (69.8 Centiloids), whereas plasma Aß42/Aß40 predicted amyloid PET burden until a lower level (33.4 Centiloids). Discussion: CSF Aß42/Aß40 predicts the continuous level of amyloid plaque burden over a wider range than plasma Aß42/Aß40 and may be useful in AD staging. Highlights: Cerebrospinal fluid (CSF) amyloid beta (Aß)42/Aß40 predicts continuous amyloid positron emission tomography (PET) values up to a relatively high burden.Plasma Aß42/Aß40 is a comparatively dichotomous measure of brain amyloidosis.Models can predict regional amyloid PET burden based on CSF Aß42/Aß40.CSF Aß42/Aß40 may be useful in staging AD.
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Cerebrospinal fluid (CSF) amyloid-ß peptide (Aß)42/Aß40 and the concentration of tau phosphorylated at site 181 (p-tau181) are well-established biomarkers of Alzheimer's disease (AD). The present study used mass spectrometry to measure concentrations of nine phosphorylated and five nonphosphorylated tau species and phosphorylation occupancies (percentage phosphorylated/nonphosphorylated) at ten sites. In the present study we show that, in 750 individuals with a median age of 71.2 years, CSF pT217/T217 predicted the presence of brain amyloid by positron emission tomography (PET) slightly better than Aß42/Aß40 (P = 0.02). Furthermore, for individuals with positive brain amyloid by PET (n = 263), CSF pT217/T217 was more strongly correlated with the amount of amyloid (Spearman's ρ = 0.69) than Aß42/Aß40 (ρ = -0.42, P < 0.0001). In two independent cohorts of participants with symptoms of AD dementia (n = 55 and n = 90), CSF pT217/T217 and pT205/T205 were better correlated with tau PET measures than CSF p-tau181 concentration. These findings suggest that CSF pT217/T217 and pT205/T205 represent improved CSF biomarkers of amyloid and tau pathology in AD.
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Doença de Alzheimer , Humanos , Idoso , Doença de Alzheimer/diagnóstico , Proteínas tau/líquido cefalorraquidiano , Fosforilação , Fragmentos de Peptídeos/líquido cefalorraquidiano , Amiloide , Biomarcadores/líquido cefalorraquidianoRESUMO
The extracellular buildup of amyloid beta (Aß) plaques in the brain is a hallmark of Alzheimer's disease (AD). Detection of Aß pathology is essential for AD diagnosis and for identifying and recruiting research participants for clinical trials evaluating disease-modifying therapies. Currently, AD diagnoses are usually made by clinical assessments, although detection of AD pathology with positron emission tomography (PET) scans or cerebrospinal fluid (CSF) analysis can be used by specialty clinics. These measures of Aß aggregation, e.g. plaques, protofibrils, and oligomers, are medically invasive and often only available at specialized medical centers or not covered by medical insurance, and PET scans are costly. Therefore, a major goal in recent years has been to identify blood-based biomarkers that can accurately detect AD pathology with cost-effective, minimally invasive procedures.To assess the performance of plasma Aß assays in predicting amyloid burden in the central nervous system (CNS), this review compares twenty-one different manuscripts that used measurements of 42 and 40 amino acid-long Aß (Aß42 and Aß40) in plasma to predict CNS amyloid status. Methodologies that quantitate Aß42 and 40 peptides in blood via immunoassay or immunoprecipitation-mass spectrometry (IP-MS) were considered, and their ability to distinguish participants with amyloidosis compared to amyloid PET and CSF Aß measures as reference standards was evaluated. Recent studies indicate that some IP-MS assays perform well in accurately and precisely measuring Aß and detecting brain amyloid aggregates.
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Doença de Alzheimer , Humanos , Doença de Alzheimer/diagnóstico por imagem , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Placa Amiloide/diagnóstico por imagem , Fragmentos de Peptídeos/líquido cefalorraquidiano , Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Amiloide , Proteínas Amiloidogênicas , Biomarcadores/líquido cefalorraquidiano , Tomografia por Emissão de Pósitrons/métodosRESUMO
BACKGROUND AND OBJECTIVES: To determine the diagnostic accuracy of a plasma Aß42/Aß40 assay in classifying amyloid PET status across global research studies using samples collected by multiple centers that utilize different blood collection and processing protocols. METHODS: Plasma samples (n = 465) were obtained from 3 large Alzheimer disease (AD) research cohorts in the United States (n = 182), Australia (n = 183), and Sweden (n = 100). Plasma Aß42/Aß40 was measured by a high precision immunoprecipitation mass spectrometry (IPMS) assay and compared to the reference standards of amyloid PET and CSF Aß42/Aß40. RESULTS: In the combined cohort of 465 participants, plasma Aß42/Aß40 had good concordance with amyloid PET status (receiver operating characteristic area under the curve [AUC] 0.84, 95% confidence interval [CI] 0.80-0.87); concordance improved with the inclusion of APOE ε4 carrier status (AUC 0.88, 95% CI 0.85-0.91). The AUC of plasma Aß42/Aß40 with CSF amyloid status was 0.85 (95% CI 0.78-0.91) and improved to 0.93 (95% CI 0.89-0.97) with APOE ε4 status. These findings were consistent across the 3 cohorts, despite differences in protocols. The assay performed similarly in both cognitively unimpaired and impaired individuals. DISCUSSION: Plasma Aß42/Aß40 is a robust measure for detecting amyloid plaques and can be utilized to aid in the diagnosis of AD, identify those at risk for future dementia due to AD, and improve the diversity of populations enrolled in AD research and clinical trials. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that plasma Aß42/Aß40, as measured by a high precision IPMS assay, accurately diagnoses brain amyloidosis in both cognitively unimpaired and impaired research participants.
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Doença de Alzheimer , Doença de Alzheimer/diagnóstico por imagem , Peptídeos beta-Amiloides , Biomarcadores , Humanos , Fragmentos de Peptídeos , Placa Amiloide , Tomografia por Emissão de PósitronsRESUMO
Importance: Blood-based tests for brain amyloid-ß (Aß) pathology are needed for widespread implementation of Alzheimer disease (AD) biomarkers in clinical care and to facilitate patient screening and monitoring of treatment responses in clinical trials. Objective: To compare the performance of plasma Aß42/40 measured using 8 different Aß assays when detecting abnormal brain Aß status in patients with early AD. Design, Setting, and Participants: This study included 182 cognitively unimpaired participants and 104 patients with mild cognitive impairment from the BioFINDER cohort who were enrolled at 3 different hospitals in Sweden and underwent Aß positron emission tomography (PET) imaging and cerebrospinal fluid (CSF) and plasma collection from 2010 to 2014. Plasma Aß42/40 was measured using an immunoprecipitation-coupled mass spectrometry developed at Washington University (IP-MS-WashU), antibody-free liquid chromatography MS developed by Araclon (LC-MS-Arc), and immunoassays from Roche Diagnostics (IA-Elc); Euroimmun (IA-EI); and Amsterdam University Medical Center, ADx Neurosciences, and Quanterix (IA-N4PE). Plasma Aß42/40 was also measured using an IP-MS-based method from Shimadzu in 200 participants (IP-MS-Shim) and an IP-MS-based method from the University of Gothenburg (IP-MS-UGOT) and another immunoassay from Quanterix (IA-Quan) among 227 participants. For validation, 122 participants (51 cognitively normal, 51 with mild cognitive impairment, and 20 with AD dementia) were included from the Alzheimer Disease Neuroimaging Initiative who underwent Aß-PET and plasma Aß assessments using IP-MS-WashU, IP-MS-Shim, IP-MS-UGOT, IA-Elc, IA-N4PE, and IA-Quan assays. Main Outcomes and Measures: Discriminative accuracy of plasma Aß42/40 quantified using 8 different assays for abnormal CSF Aß42/40 and Aß-PET status. Results: A total of 408 participants were included in this study. In the BioFINDER cohort, the mean (SD) age was 71.6 (5.6) years and 49.3% of the cohort were women. When identifying participants with abnormal CSF Aß42/40 in the whole cohort, plasma IP-MS-WashU Aß42/40 showed significantly higher accuracy (area under the receiver operating characteristic curve [AUC], 0.86; 95% CI, 0.81-0.90) than LC-MS-Arc Aß42/40, IA-Elc Aß42/40, IA-EI Aß42/40, and IA-N4PE Aß42/40 (AUC range, 0.69-0.78; P < .05). Plasma IP-MS-WashU Aß42/40 performed significantly better than IP-MS-UGOT Aß42/40 and IA-Quan Aß42/40 (AUC, 0.84 vs 0.68 and 0.64, respectively; P < .001), while there was no difference in the AUCs between IP-MS-WashU Aß42/40 and IP-MS-Shim Aß42/40 (0.87 vs 0.83; P = .16) in the 2 subcohorts where these biomarkers were available. The results were similar when using Aß-PET as outcome. Plasma IPMS-WashU Aß42/40 and IPMS-Shim Aß42/40 showed highest coefficients for correlations with CSF Aß42/40 (r range, 0.56-0.65). The BioFINDER results were replicated in the Alzheimer Disease Neuroimaging Initiative cohort (mean [SD] age, 72.4 [5.4] years; 43.4% women), where the IP-MS-WashU assay performed significantly better than the IP-MS-UGOT, IA-Elc, IA-N4PE, and IA-Quan assays but not the IP-MS-Shim assay. Conclusions and Relevance: The results from 2 independent cohorts indicate that certain MS-based methods performed better than most of the immunoassays for plasma Aß42/40 when detecting brain Aß pathology.
Assuntos
Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/análise , Encéfalo/patologia , Fragmentos de Peptídeos/análise , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/diagnóstico por imagem , Biomarcadores/análise , Encéfalo/diagnóstico por imagem , Estudos Transversais , Feminino , Humanos , Imunoensaio/métodos , Masculino , Espectrometria de Massas/métodos , Pessoa de Meia-Idade , Tomografia por Emissão de PósitronsRESUMO
In vivo gold standard for the ante-mortem assessment of brain ß-amyloid pathology is currently ß-amyloid positron emission tomography or cerebrospinal fluid measures of ß-amyloid42 or the ß-amyloid42/ß-amyloid40 ratio. The widespread acceptance of a biomarker classification scheme for the Alzheimer's disease continuum has ignited interest in more affordable and accessible approaches to detect Alzheimer's disease ß-amyloid pathology, a process that often slows down the recruitment into, and adds to the cost of, clinical trials. Recently, there has been considerable excitement concerning the value of blood biomarkers. Leveraging multidisciplinary data from cognitively unimpaired participants and participants with mild cognitive impairment recruited by the multisite biomarker study of Alzheimer's Disease Neuroimaging Initiative, here we assessed to what extent plasma ß-amyloid42/ß-amyloid40, neurofilament light and phosphorylated-tau at threonine-181 biomarkers detect the presence of ß-amyloid pathology, and to what extent the addition of clinical information such as demographic data, APOE genotype, cognitive assessments and MRI can assist plasma biomarkers in detecting ß-amyloid-positivity. Our results confirm plasma ß-amyloid42/ß-amyloid40 as a robust biomarker of brain ß-amyloid-positivity (area under curve, 0.80-0.87). Plasma phosphorylated-tau at threonine-181 detected ß-amyloid-positivity only in the cognitively impaired with a moderate area under curve of 0.67, whereas plasma neurofilament light did not detect ß-amyloid-positivity in either group of participants. Clinical information as well as MRI-score independently detected positron emission tomography ß-amyloid-positivity in both cognitively unimpaired and impaired (area under curve, 0.69-0.81). Clinical information, particularly APOE ε4 status, enhanced the performance of plasma biomarkers in the detection of positron emission tomography ß-amyloid-positivity by 0.06-0.14 units of area under curve for cognitively unimpaired, and by 0.21-0.25 units for cognitively impaired; and further enhancement of these models with an MRI-score of ß-amyloid-positivity yielded an additional improvement of 0.04-0.11 units of area under curve for cognitively unimpaired and 0.05-0.09 units for cognitively impaired. Taken together, these multi-disciplinary results suggest that when combined with clinical information, plasma phosphorylated-tau at threonine-181 and neurofilament light biomarkers, and an MRI-score could effectively identify ß-amyloid+ cognitively unimpaired and impaired (area under curve, 0.80-0.90). Yet, when the MRI-score is considered in combination with clinical information, plasma phosphorylated-tau at threonine-181 and plasma neurofilament light have minimal added value for detecting ß-amyloid-positivity. Our systematic comparison of ß-amyloid-positivity detection models identified effective combinations of demographics, APOE, global cognition, MRI and plasma biomarkers. Promising minimally invasive and low-cost predictors such as plasma biomarkers of ß-amyloid42/ß-amyloid40 may be improved by age and APOE genotype.
RESUMO
INTRODUCTION: Blood-based assays to measure brain amyloid beta (Aß) deposition are an attractive alternative to the cerebrospinal fluid (CSF)-based assays currently used in clinical settings. In this study, we examined different blood-based assays to measure Aß and how they compare among centers and assays. METHODS: Aliquots from 81 plasma samples were distributed to 10 participating centers. Seven immunological assays and four mass-spectrometric methods were used to measure plasma Aß concentrations. RESULTS: Correlations were weak for Aß42 while Aß40 correlations were stronger. The ratio Aß42/Aß40 did not improve the correlations and showed weak correlations. DISCUSSION: The poor correlations for Aß42 in plasma might have several potential explanations, such as the high levels of plasma proteins (compared to CSF), sensitivity to pre-analytical sample handling and specificity, and cross-reactivity of different antibodies. Different methods might also measure different pools of plasma Aß42. We, however, hypothesize that greater correlations might be seen in future studies because many of the methods have been refined during completion of this study.
RESUMO
BACKGROUND: Concentrations of soluble amyloid-ß (Aß) oscillate with the sleep-wake cycle in the interstitial fluid of mice and cerebrospinal fluid (CSF) of humans. Further, the concentration of Aß in CSF increases during sleep deprivation. Stress and disruption of the circadian clock are additional mechanisms hypothesized to increase CSF Aß levels. Cortisol is a marker for stress and has an endogenous circadian rhythm. Other factors such as glucose and lactate have been associated with changes in sleep-wake activity and/or Aß. OBJECTIVE: In this exploratory study, we used samples collected in a previous study to examine how sleep deprivation affects Aß, cortisol, lactate, and glucose in plasma and CSF from healthy middle-aged adults (Nâ=â11). METHODS: Eleven cognitively normal participants without evidence of sleep disturbance were randomized to sleep deprivation or normal sleep control. All participants were invited to repeat the study. Cortisol, lactate, glucose, and Aß were measured in 2-h intervals over a 36-h period in both plasma and CSF. All concentrations were normalized to the mean prior to calculating mesor, amplitude, acrophase, and other parameters. RESULTS: One night of sleep deprivation increases the overnight concentration of Aß in CSF approximately 10%, but does not significantly affect cortisol, lactate, or glucose concentrations in plasma or CSF between the sleep-deprived and control conditions. CONCLUSION: These data suggest that sleep deprivation-related changes in CSF Aß are not mediated by stress or circadian disruption as measured by cortisol.