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1.
Alzheimers Dement ; 20(1): 376-387, 2024 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-37639492

RESUMEN

INTRODUCTION: Accumulating evidence indicates disproportionate tau burden and tau-related clinical progression in females. However, sex differences in plasma phosphorylated tau (p-tau)217 prediction of subclinical cognitive and brain changes are unknown. METHODS: We measured baseline plasma p-tau217, glial fibrillary acidic protein (GFAP), and neurofilament light (NfL) in 163 participants (85 cognitively unimpaired [CU], 78 mild cognitive impairment [MCI]). In CU, linear mixed effects models examined sex differences in plasma biomarker prediction of longitudinal domain-specific cognitive decline and brain atrophy. Cognitive models were repeated in MCI. RESULTS: In CU females, baseline plasma p-tau217 predicted verbal memory and medial temporal lobe trajectories such that trajectories significantly declined once p-tau217 concentrations surpassed 0.053 pg/ml, a threshold that corresponded to early levels of cortical amyloid aggregation in secondary amyloid positron emission tomography analyses. CU males exhibited similar rates of cognitive decline and brain atrophy, but these trajectories were not dependent on plasma p-tau217. Plasma GFAP and NfL exhibited similar female-specific prediction of medial temporal lobe atrophy in CU. Plasma p-tau217 exhibited comparable prediction of cognitive decline across sex in MCI. DISCUSSION: Plasma p-tau217 may capture earlier Alzheimer's disease (AD)-related cognitive and brain atrophy hallmarks in females compared to males, possibly reflective of increased susceptibility to AD pathophysiology.


Asunto(s)
Enfermedad de Alzheimer , Disfunción Cognitiva , Adulto , Humanos , Femenino , Masculino , Proteínas tau/metabolismo , Enfermedad de Alzheimer/metabolismo , Encéfalo/metabolismo , Tomografía de Emisión de Positrones , Atrofia/metabolismo , Biomarcadores , Péptidos beta-Amiloides/metabolismo
2.
Alzheimers Dement ; 20(2): 1166-1174, 2024 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-37920945

RESUMEN

INTRODUCTION: We set out to identify tau PET-positive (A+T+) individuals among amyloid-beta (Aß) positive participants using plasma biomarkers. METHODS: In this cross-sectional study we assessed 234 participants across the AD continuum who were evaluated by amyloid PET with [18 F]AZD4694 and tau-PET with [18 F]MK6240 and measured plasma levels of total tau, pTau-181, pTau-217, pTau-231, and N-terminal tau (NTA-tau). We evaluated the performances of plasma biomarkers to predict tau positivity in Aß+ individuals. RESULTS: Highest associations with tau positivity in Aß+ individuals were found for plasma pTau-217 (AUC [CI95% ] = 0.89 [0.82, 0.96]) and NTA-tau (AUC [CI95% ] = 0.88 [0.91, 0.95]). Combining pTau-217 and NTA-tau resulted in the strongest agreement (Cohen's Kappa = 0.74, CI95%  = 0.57/0.90, sensitivity = 92%, specificity = 81%) with PET for classifying tau positivity. DISCUSSION: The potential for identifying tau accumulation in later Braak stages will be useful for patient stratification and prognostication in treatment trials and in clinical practice. HIGHLIGHTS: We found that in a cohort without pre-selection pTau-181, pTau-217, and NTA-tau showed the highest association with tau PET positivity. We found that in Aß+ individuals pTau-217 and NTA-tau showed the highest association with tau PET positivity. Combining pTau-217 and NTA-tau resulted in the strongest agreement with the tau PET-based classification.


Asunto(s)
Enfermedad de Alzheimer , Humanos , Proteínas tau , Estudios Transversales , Péptidos beta-Amiloides , Biomarcadores , Tomografía de Emisión de Positrones
3.
Alzheimers Dement ; 20(3): 2240-2261, 2024 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-38170841

RESUMEN

INTRODUCTION: The pace of innovation has accelerated in virtually every area of tau research in just the past few years. METHODS: In February 2022, leading international tau experts convened to share selected highlights of this work during Tau 2022, the second international tau conference co-organized and co-sponsored by the Alzheimer's Association, CurePSP, and the Rainwater Charitable Foundation. RESULTS: Representing academia, industry, and the philanthropic sector, presenters joined more than 1700 registered attendees from 59 countries, spanning six continents, to share recent advances and exciting new directions in tau research. DISCUSSION: The virtual meeting provided an opportunity to foster cross-sector collaboration and partnerships as well as a forum for updating colleagues on research-advancing tools and programs that are steadily moving the field forward.


Asunto(s)
Enfermedad de Alzheimer , Tauopatías , Humanos , Proteínas tau
4.
Alzheimers Dement ; 19(11): 4967-4977, 2023 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-37078495

RESUMEN

INTRODUCTION: Plasma biomarkers are promising tools for Alzheimer's disease (AD) diagnosis, but comparisons with more established biomarkers are needed. METHODS: We assessed the diagnostic performance of p-tau181 , p-tau217 , and p-tau231 in plasma and CSF in 174 individuals evaluated by dementia specialists and assessed with amyloid-PET and tau-PET. Receiver operating characteristic (ROC) analyses assessed the performance of plasma and CSF biomarkers to identify amyloid-PET and tau-PET positivity. RESULTS: Plasma p-tau biomarkers had lower dynamic ranges and effect sizes compared to CSF p-tau. Plasma p-tau181 (AUC = 76%) and p-tau231 (AUC = 82%) assessments performed inferior to CSF p-tau181 (AUC = 87%) and p-tau231 (AUC = 95%) for amyloid-PET positivity. However, plasma p-tau217 (AUC = 91%) had diagnostic performance indistinguishable from CSF (AUC = 94%) for amyloid-PET positivity. DISCUSSION: Plasma and CSF p-tau217 had equivalent diagnostic performance for biomarker-defined AD. Our results suggest that plasma p-tau217 may help reduce the need for invasive lumbar punctures without compromising accuracy in the identification of AD. HIGHLIGHTS: p-tau217 in plasma performed equivalent to p-tau217 in CSF for the diagnosis of AD, suggesting the increased accessibility of plasma p-tau217 is not offset by lower accuracy. p-tau biomarkers in plasma had lower mean fold-changes between amyloid-PET negative and positive groups than p-tau biomarkers in CSF. CSF p-tau biomarkers had greater effect sizes than plasma p-tau biomarkers when differentiating between amyloid-PET positive and negative groups. Plasma p-tau181 and plasma p-tau231 performed worse than p-tau181 and p-tau231 in CSF for AD diagnosis.


Asunto(s)
Enfermedad de Alzheimer , Humanos , Enfermedad de Alzheimer/diagnóstico , Punción Espinal , Proteínas Amiloidogénicas , Plasma , Biomarcadores , Proteínas tau , Péptidos beta-Amiloides
5.
Alzheimers Dement ; 2022 Jul 12.
Artículo en Inglés | MEDLINE | ID: mdl-35820077

RESUMEN

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.

6.
Alzheimers Dement ; 17(9): 1452-1464, 2021 09.
Artículo en Inglés | MEDLINE | ID: mdl-33792144

RESUMEN

INTRODUCTION: This study sought to discover and replicate plasma proteomic biomarkers relating to Alzheimer's disease (AD) including both the "ATN" (amyloid/tau/neurodegeneration) diagnostic framework and clinical diagnosis. METHODS: Plasma proteins from 972 subjects (372 controls, 409 mild cognitive impairment [MCI], and 191 AD) were measured using both SOMAscan and targeted assays, including 4001 and 25 proteins, respectively. RESULTS: Protein co-expression network analysis of SOMAscan data revealed the relation between proteins and "N" varied across different neurodegeneration markers, indicating that the ATN variants are not interchangeable. Using hub proteins, age, and apolipoprotein E ε4 genotype discriminated AD from controls with an area under the curve (AUC) of 0.81 and MCI convertors from non-convertors with an AUC of 0.74. Targeted assays replicated the relation of four proteins with the ATN framework and clinical diagnosis. DISCUSSION: Our study suggests that blood proteins can predict the presence of AD pathology as measured in the ATN framework as well as clinical diagnosis.


Asunto(s)
Enfermedad de Alzheimer , Péptidos beta-Amiloides/sangre , Biomarcadores/sangre , Proteínas Sanguíneas , Proteómica , Proteínas tau/sangre , Anciano , Enfermedad de Alzheimer/sangre , Enfermedad de Alzheimer/patología , Apolipoproteína E4/sangre , Apolipoproteína E4/genética , Disfunción Cognitiva/sangre , Disfunción Cognitiva/patología , Europa (Continente) , Femenino , Humanos , Masculino , Persona de Mediana Edad
7.
J Nucl Cardiol ; 21(3): 553-62, 2014 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-24627345

RESUMEN

INTRODUCTION: Rupture of unstable atherosclerotic plaque that leads to stroke and myocardial infarction may be induced by macrophage infiltration and neovessel formation. A tracer that selectively binds to integrin αvß3 a protein expressed by macrophages and neovascular endothelium may identify rupture prone plaque. METHODS: (18)F-labeled "R-G-D" containing tripeptide (Flotegatide), a click chemistry derived radiotracer that binds to integrin αvß3 was injected in ApoE knockout mice fed a high fat diet. Uptake of Flotegatide by atherosclerotic plaque was visualized by micro-PET, autoradiography, and correlated to histologic markers of inflammation and angiogenesis. RESULTS: We found that Flotegatide preferentially binds to aortic plaque in an ApoE knockout mouse model of atherosclerosis. The tracer's uptake is strongly associated with presence of histologic markers for macrophage infiltration and integrin expression. There is a weaker but detectable association between Flotegatide uptake and presence of an immunohistochemical marker for neovascularization. DISCUSSION: We hypothesize that Flotegatide may be a useful tracer for visualization of inflamed plaque in clinical subjects with atherosclerosis and may have potential for detecting vulnerable plaque.


Asunto(s)
Aterosclerosis/diagnóstico por imagen , Aterosclerosis/metabolismo , Modelos Animales de Enfermedad , Integrina alfaVbeta3/metabolismo , Imagen Molecular/métodos , Oligopéptidos/farmacocinética , Animales , Apolipoproteínas E/genética , Biomarcadores/metabolismo , Femenino , Radioisótopos de Flúor/farmacocinética , Ratones , Ratones Noqueados , Tomografía de Emisión de Positrones/métodos , Radiofármacos/farmacocinética , Reproducibilidad de los Resultados , Sensibilidad y Especificidad
8.
Proc Natl Acad Sci U S A ; 108(35): 14620-5, 2011 Aug 30.
Artículo en Inglés | MEDLINE | ID: mdl-21873245

RESUMEN

Hypoxia has been shown to be an important microenvironmental parameter influencing tumor progression and treatment efficacy. Patient guidance for hypoxia-targeted therapy requires evaluation of tumor oxygenation, preferably in a noninvasive manner. The aim of this study was to evaluate and validate the uptake of [(18)F]HX4, a novel developed hypoxia marker for PET imaging. A heterogeneous accumulation of [(18)F]HX4 was found within rat rhabdomyosarcoma tumors that was significantly (P < 0.0001) higher compared with the surrounding tissues, with temporal increasing tumor-to-blood ratios reaching a plateau of 7.638 ± 0.926 and optimal imaging properties 4 h after injection. [(18)F]HX4 retention in normal tissues was found to be short-lived, homogeneous and characterized by a fast progressive temporal clearance. Heterogeneity in [(18)F]HX4 tumor uptake was analyzed based on 16 regions within the tumor according to the different orthogonal planes at the largest diameter. Validation of heterogeneous [(18)F]HX4 tumor uptake was shown by a strong and significant relationship (r = 0.722; P < 0.0001) with the hypoxic fraction as calculated by the percentage pimonidazole-positive pixels. Furthermore, a causal relationship with tumor oxygenation was established, because combination treatment of nicotinamide and carbogen resulted in a 40% reduction (P < 0.001) in [(18)F]HX4 tumor accumulation whereas treatment with 7% oxygen breathing resulted in a 30% increased uptake (P < 0.05). [(18)F]HX4 is therefore a promising candidate for noninvasive detection and evaluation of tumor hypoxia at a macroscopic level.


Asunto(s)
Hipoxia de la Célula , Radioisótopos de Flúor , Imidazoles , Neoplasias Experimentales/metabolismo , Tomografía de Emisión de Positrones/métodos , Radiofármacos , Triazoles , Animales , Biomarcadores , Masculino , Nitroimidazoles/farmacología , Ratas
9.
Commun Biol ; 7(1): 528, 2024 May 04.
Artículo en Inglés | MEDLINE | ID: mdl-38704445

RESUMEN

Neuronal dysfunction and cognitive deterioration in Alzheimer's disease (AD) are likely caused by multiple pathophysiological factors. However, mechanistic evidence in humans remains scarce, requiring improved non-invasive techniques and integrative models. We introduce personalized AD computational models built on whole-brain Wilson-Cowan oscillators and incorporating resting-state functional MRI, amyloid-ß (Aß) and tau-PET from 132 individuals in the AD spectrum to evaluate the direct impact of toxic protein deposition on neuronal activity. This subject-specific approach uncovers key patho-mechanistic interactions, including synergistic Aß and tau effects on cognitive impairment and neuronal excitability increases with disease progression. The data-derived neuronal excitability values strongly predict clinically relevant AD plasma biomarker concentrations (p-tau217, p-tau231, p-tau181, GFAP) and grey matter atrophy obtained through voxel-based morphometry. Furthermore, reconstructed EEG proxy quantities show the hallmark AD electrophysiological alterations (theta band activity enhancement and alpha reductions) which occur with Aß-positivity and after limbic tau involvement. Microglial activation influences on neuronal activity are less definitive, potentially due to neuroimaging limitations in mapping neuroprotective vs detrimental activation phenotypes. Mechanistic brain activity models can further clarify intricate neurodegenerative processes and accelerate preventive/treatment interventions.


Asunto(s)
Enfermedad de Alzheimer , Péptidos beta-Amiloides , Encéfalo , Proteínas tau , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/fisiopatología , Humanos , Proteínas tau/metabolismo , Péptidos beta-Amiloides/metabolismo , Encéfalo/metabolismo , Encéfalo/diagnóstico por imagen , Encéfalo/patología , Masculino , Femenino , Anciano , Imagen por Resonancia Magnética , Persona de Mediana Edad , Tomografía de Emisión de Positrones , Modelos Neurológicos , Biomarcadores/sangre , Anciano de 80 o más Años , Electroencefalografía , Neuronas/metabolismo
10.
Alzheimers Dement ; 9(6): 666-76, 2013 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-23411393

RESUMEN

OBJECTIVE: We wished to develop a highly selective positron emission tomography (PET) imaging agent targeting PHF-tau in human Alzheimer's disease (AD) brains. METHODS: To screen potential tau binders, human AD brain sections were used as a source of native paired helical filament (PHF)-tau and Aß rather than synthetic tau aggregates or Aß fibrils generated in vitro to measure the affinity and selectivity of [(18)F]T807 to tau and Aß. Brain uptake and biodistribution of [(18)F]T807 in mice were also tested. RESULTS: In vitro autoradiography results show that [(18)F]T807 exhibits strong binding to PHF-tau-positive human brain sections. A dissociation constant (Kd) of [(18)F]T807 (14.6 nM) was measured using brain sections from the frontal lobe of AD patients. A comparison of autoradiography and double immunohistochemical staining of PHF-tau and Aß on adjacent sections demonstrated that [(18)F]T807 binding colocalized with immunoreactive PHF-tau pathology, but did not highlight Aß plaques. In vivo studies in mice demonstrated that [(18)F]T807 was able to cross the blood-brain barrier and washed out quickly. CONCLUSIONS: [(18)F]T807 demonstrates high affinity and selectivity to PHF-tau as well as favorable in vivo properties, making this a promising candidate as an imaging agent for AD.


Asunto(s)
Enfermedad de Alzheimer/diagnóstico , Encéfalo/diagnóstico por imagen , Radioisótopos de Flúor , Proteínas tau/química , Proteínas tau/efectos de los fármacos , Anciano , Anciano de 80 o más Años , Péptidos beta-Amiloides/metabolismo , Animales , Autorradiografía , Encéfalo/patología , Estudios de Casos y Controles , Femenino , Humanos , Masculino , Ratones , Ratones Transgénicos , Persona de Mediana Edad , Tomografía de Emisión de Positrones , Unión Proteica/efectos de los fármacos , Unión Proteica/genética , Distribución Tisular , Proteínas tau/genética
11.
bioRxiv ; 2023 Jul 20.
Artículo en Inglés | MEDLINE | ID: mdl-37502947

RESUMEN

Neuronal dysfunction and cognitive deterioration in Alzheimer's disease (AD) are likely caused by multiple pathophysiological factors. However, evidence in humans remains scarce, necessitating improved non-invasive techniques and integrative mechanistic models. Here, we introduce personalized brain activity models incorporating functional MRI, amyloid-ß (Aß) and tau-PET from AD-related participants (N=132). Within the model assumptions, electrophysiological activity is mediated by toxic protein deposition. Our integrative subject-specific approach uncovers key patho-mechanistic interactions, including synergistic Aß and tau effects on cognitive impairment and neuronal excitability increases with disease progression. The data-derived neuronal excitability values strongly predict clinically relevant AD plasma biomarker concentrations (p-tau217, p-tau231, p-tau181, GFAP). Furthermore, our results reproduce hallmark AD electrophysiological alterations (theta band activity enhancement and alpha reductions) which occur with Aß-positivity and after limbic tau involvement. Microglial activation influences on neuronal activity are less definitive, potentially due to neuroimaging limitations in mapping neuroprotective vs detrimental phenotypes. Mechanistic brain activity models can further clarify intricate neurodegenerative processes and accelerate preventive/treatment interventions.

12.
Nat Aging ; 3(9): 1079-1090, 2023 09.
Artículo en Inglés | MEDLINE | ID: mdl-37653254

RESUMEN

Cost-effective strategies for identifying amyloid-ß (Aß) positivity in patients with cognitive impairment are urgently needed with recent approvals of anti-Aß immunotherapies for Alzheimer's disease (AD). Blood biomarkers can accurately detect AD pathology, but it is unclear whether their incorporation into a full diagnostic workflow can reduce the number of confirmatory cerebrospinal fluid (CSF) or positron emission tomography (PET) tests needed while accurately classifying patients. We evaluated a two-step workflow for determining Aß-PET status in patients with mild cognitive impairment (MCI) from two independent memory clinic-based cohorts (n = 348). A blood-based model including plasma tau protein 217 (p-tau217), age and APOE ε4 status was developed in BioFINDER-1 (area under the curve (AUC) = 89.3%) and validated in BioFINDER-2 (AUC = 94.3%). In step 1, the blood-based model was used to stratify the patients into low, intermediate or high risk of Aß-PET positivity. In step 2, we assumed referral only of intermediate-risk patients to CSF Aß42/Aß40 testing, whereas step 1 alone determined Aß-status for low- and high-risk groups. Depending on whether lenient, moderate or stringent thresholds were used in step 1, the two-step workflow overall accuracy for detecting Aß-PET status was 88.2%, 90.5% and 92.0%, respectively, while reducing the number of necessary CSF tests by 85.9%, 72.7% and 61.2%, respectively. In secondary analyses, an adapted version of the BioFINDER-1 model led to successful validation of the two-step workflow with a different plasma p-tau217 immunoassay in patients with cognitive impairment from the TRIAD cohort (n = 84). In conclusion, using a plasma p-tau217-based model for risk stratification of patients with MCI can substantially reduce the need for confirmatory testing while accurately classifying patients, offering a cost-effective strategy to detect AD in memory clinic settings.


Asunto(s)
Enfermedad de Alzheimer , Péptidos beta-Amiloides , Humanos , Flujo de Trabajo , Tomografía Computarizada por Rayos X , Proteínas Sanguíneas , Enfermedad de Alzheimer/diagnóstico
13.
JAMA Neurol ; 80(2): 188-199, 2023 02 01.
Artículo en Inglés | MEDLINE | ID: mdl-36508198

RESUMEN

Importance: The recent proliferation of phosphorylated tau (p-tau) biomarkers has raised questions about their preferential association with the hallmark pathologies of Alzheimer disease (AD): amyloid-ß plaques and tau neurofibrillary tangles. Objective: To determine whether cerebrospinal fluid (CSF) and plasma p-tau biomarkers preferentially reflect cerebral ß-amyloidosis or neurofibrillary tangle aggregation measured with positron emission tomography (PET). Design, Setting, and Participants: This was a cross-sectional study of 2 observational cohorts: the Translational Biomarkers in Aging and Dementia (TRIAD) study, with data collected between October 2017 and August 2021, and the Alzheimer's Disease Neuroimaging Initiative (ADNI), with data collected between September 2015 and November 2019. TRIAD was a single-center study, and ADNI was a multicenter study. Two independent subsamples were derived from TRIAD. The first TRIAD subsample comprised individuals assessed with CSF p-tau (p-tau181, p-tau217, p-tau231, p-tau235), [18F]AZD4694 amyloid PET, and [18F]MK6240 tau PET. The second TRIAD subsample included individuals assessed with plasma p-tau (p-tau181, p-tau217, p-tau231), [18F]AZD4694 amyloid PET, and [18F]MK6240 tau PET. An independent cohort from ADNI comprised individuals assessed with CSF p-tau181, [18F]florbetapir PET, and [18F]flortaucipir PET. Participants were included based on the availability of p-tau and PET biomarker assessments collected within 9 months of each other. Exclusion criteria were a history of head trauma or magnetic resonance imaging/PET safety contraindications. No participants who met eligibility criteria were excluded. Exposures: Amyloid PET, tau PET, and CSF and plasma assessments of p-tau measured with single molecule array (Simoa) assay or enzyme-linked immunosorbent assay. Main Outcomes and Measures: Associations between p-tau biomarkers with amyloid PET and tau PET. Results: A total of 609 participants (mean [SD] age, 66.9 [13.6] years; 347 female [57%]; 262 male [43%]) were included in the study. For all 4 phosphorylation sites assessed in CSF, p-tau was significantly more closely associated with amyloid-PET values than tau-PET values (p-tau181 difference, 13%; 95% CI, 3%-22%; P = .006; p-tau217 difference, 11%; 95% CI, 3%-20%; P = .003; p-tau231 difference, 15%; 95% CI, 5%-22%; P < .001; p-tau235 difference, 9%; 95% CI, 1%-19%; P = .02) . These results were replicated with plasma p-tau181 (difference, 11%; 95% CI, 1%-22%; P = .02), p-tau217 (difference, 9%; 95% CI, 1%-19%; P = .02), p-tau231 (difference, 13%; 95% CI, 3%-24%; P = .009), and CSF p-tau181 (difference, 9%; 95% CI, 1%-21%; P = .02) in independent cohorts. Conclusions and Relevance: Results of this cross-sectional study of 2 observational cohorts suggest that the p-tau abnormality as an early event in AD pathogenesis was associated with amyloid-ß accumulation and highlights the need for careful interpretation of p-tau biomarkers in the context of the amyloid/tau/neurodegeneration, or A/T/(N), framework.


Asunto(s)
Enfermedad de Alzheimer , Disfunción Cognitiva , Humanos , Masculino , Femenino , Anciano , Enfermedad de Alzheimer/líquido cefalorraquídeo , Estudios Transversales , Proteínas tau/líquido cefalorraquídeo , Tomografía de Emisión de Positrones , Péptidos beta-Amiloides/líquido cefalorraquídeo , Biomarcadores
14.
Nat Med ; 29(7): 1775-1781, 2023 07.
Artículo en Inglés | MEDLINE | ID: mdl-37248300

RESUMEN

An unresolved question for the understanding of Alzheimer's disease (AD) pathophysiology is why a significant percentage of amyloid-ß (Aß)-positive cognitively unimpaired (CU) individuals do not develop detectable downstream tau pathology and, consequently, clinical deterioration. In vitro evidence suggests that reactive astrocytes unleash Aß effects in pathological tau phosphorylation. Here, in a biomarker study across three cohorts (n = 1,016), we tested whether astrocyte reactivity modulates the association of Aß with tau phosphorylation in CU individuals. We found that Aß was associated with increased plasma phosphorylated tau only in individuals positive for astrocyte reactivity (Ast+). Cross-sectional and longitudinal tau-positron emission tomography analyses revealed an AD-like pattern of tau tangle accumulation as a function of Aß only in CU Ast+ individuals. Our findings suggest astrocyte reactivity as an important upstream event linking Aß with initial tau pathology, which may have implications for the biological definition of preclinical AD and for selecting CU individuals for clinical trials.


Asunto(s)
Enfermedad de Alzheimer , Disfunción Cognitiva , Humanos , Enfermedad de Alzheimer/patología , Péptidos beta-Amiloides , Astrocitos/patología , Biomarcadores , Estudios Transversales , Tomografía de Emisión de Positrones , Proteínas tau
15.
Nat Aging ; 3(10): 1210-1218, 2023 10.
Artículo en Inglés | MEDLINE | ID: mdl-37749258

RESUMEN

The mechanisms by which the apolipoprotein E ε4 (APOEε4) allele influences the pathophysiological progression of Alzheimer's disease (AD) are poorly understood. Here we tested the association of APOEε4 carriership and amyloid-ß (Aß) burden with longitudinal tau pathology. We longitudinally assessed 94 individuals across the aging and AD spectrum who underwent clinical assessments, APOE genotyping, magnetic resonance imaging, positron emission tomography (PET) for Aß ([18F]AZD4694) and tau ([18F]MK-6240) at baseline, as well as a 2-year follow-up tau-PET scan. We found that APOEε4 carriership potentiates Aß effects on longitudinal tau accumulation over 2 years. The APOEε4-potentiated Aß effects on tau-PET burden were mediated by longitudinal plasma phosphorylated tau at threonine 217 (p-tau217+) increase. This longitudinal tau accumulation as measured by PET was accompanied by brain atrophy and clinical decline. Our results suggest that the APOEε4 allele plays a key role in Aß downstream effects on the aggregation of phosphorylated tau in the living human brain.


Asunto(s)
Enfermedad de Alzheimer , Péptidos beta-Amiloides , Apolipoproteína E4 , Heterocigoto , Humanos , Enfermedad de Alzheimer/diagnóstico por imagen , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/metabolismo , Péptidos beta-Amiloides/genética , Péptidos beta-Amiloides/metabolismo , Imagen por Resonancia Magnética , Tomografía de Emisión de Positrones , Proteínas tau/genética , Apolipoproteína E4/genética , Alelos
16.
Alzheimers Res Ther ; 14(1): 67, 2022 05 14.
Artículo en Inglés | MEDLINE | ID: mdl-35568889

RESUMEN

BACKGROUND: Recent advances in disease-modifying treatments highlight the need for accurately identifying individuals in early Alzheimer's disease (AD) stages and for monitoring of treatment effects. Plasma measurements of phosphorylated tau (p-tau) are a promising biomarker for AD, but different assays show varying diagnostic and prognostic accuracies. The objective of this study was to determine the clinical performance of a novel plasma p-tau217 (p-tau217) assay, p-tau217+Janssen, and perform a head-to-head comparison to an established assay, plasma p-tau217Lilly, within two independent cohorts. METHODS: The study consisted of two cohorts, cohort 1 (27 controls and 25 individuals with mild-cognitive impairment [MCI]) and cohort 2 including 147 individuals with MCI at baseline who were followed for an average of 4.92 (SD 2.09) years. Receiver operating characteristic analyses were used to assess the performance of both assays to detect amyloid-ß status (+/-) in CSF, distinguish MCI from controls, and identify subjects who will convert from MCI to AD dementia. General linear and linear mixed-effects analyses were used to assess the associations between p-tau and baseline, and annual change in Mini-Mental State Examination (MMSE) scores. Spearman correlations were used to assess the associations between the two plasma measures, and Bland-Altmann plots were examined to assess the agreement between the assays. RESULTS: Both assays showed similar performance in detecting amyloid-ß status in CSF (plasma p-tau217+Janssen AUC = 0.91 vs plasma p-tau217Lilly AUC = 0.89), distinguishing MCI from controls (plasma p-tau217+Janssen AUC = 0.91 vs plasma p-tau217Lilly AUC = 0.91), and predicting future conversion from MCI to AD dementia (plasma p-tau217+Janssen AUC = 0.88 vs p-tau217Lilly AUC = 0.89). Both assays were similarly related to baseline (plasma p-tau217+Janssen rho = -0.39 vs p-tau217Lilly rho = -0.35), and annual change in MMSE scores (plasma p-tau217+Janssenr = -0.45 vs p-tau217Lillyr = -0.41). Correlations between the two plasma measures were rho = 0.69, p < 0.001 in cohort 1 and rho = 0.70, p < 0.001 in cohort 2. Bland-Altmann plots revealed good agreement between plasma p-tau217+Janssen and plasma p-tau217Lilly in both cohorts (cohort 1, 51/52 [98%] within 95%CI; cohort 2, 139/147 [95%] within 95%CI). CONCLUSIONS: Taken together, our results indicate good diagnostic and prognostic performance of the plasma p-tau217+Janssen assay, similar to the p-tau217Lilly assay.


Asunto(s)
Enfermedad de Alzheimer , Disfunción Cognitiva , Enfermedad de Alzheimer/psicología , Péptidos beta-Amiloides , Biomarcadores , Disfunción Cognitiva/psicología , Progresión de la Enfermedad , Humanos , Pronóstico , Proteínas tau
17.
Alzheimers Dement (Amst) ; 14(1): e12307, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-35415202

RESUMEN

Introduction: We evaluated a new Simoa plasma assay for phosphorylated tau (P-tau) at aa217 enhanced by additional p-tau sites (p217+tau). Methods: Plasma p217+tau levels were compared to 18F-NAV4694 amyloid beta (Aß) positron emission tomography (PET) and 18F-MK6240 tau PET in 174 cognitively impaired (CI) and 223 cognitively unimpaired (CU) participants. Results: Compared to Aß- CU, the plasma levels of p217+tau increased 2-fold in Aß+ CU and 3.5-fold in Aß+ CI. In Aß- the p217+tau levels did not differ significantly between CU and CI. P217+tau correlated with Aß centiloids P = .67 (CI, P = .64; CU, P = .45) and tau SUVRMT P = .63 (CI, P = .69; CU, P = .34). Area under curve (AUC) for Alzheimer's disease (AD) dementia versus Aß- CU was 0.94, for AD dementia versus other dementia was 0.93, for Aß+ versus Aß- PET was 0.89, and for tau+ versus tau- PET was 0.89. Discussion: Plasma p217+tau levels elevate early in the AD continuum and correlate well with Aß and tau PET.

18.
Biomed Microdevices ; 13(1): 231-42, 2011 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-21072595

RESUMEN

We present numerical modeling and experimental studies of flow optimization inside a batch microfluidic micro-reactor used for synthesis of human-scale doses of Positron Emission Tomography (PET) tracers. Novel techniques are used for mixing within, and eluting liquid out of, the coin-shaped reaction chamber. Numerical solutions of the general incompressible Navier Stokes equations along with time-dependent elution scalar field equation for the three dimensional coin-shaped geometry were obtained and validated using fluorescence imaging analysis techniques. Utilizing the approach presented in this work, we were able to identify optimized geometrical and operational conditions for the micro-reactor in the absence of radioactive material commonly used in PET related tracer production platforms as well as evaluate the designed and fabricated micro-reactor using numerical and experimental validations.


Asunto(s)
Técnicas Analíticas Microfluídicas/instrumentación , Microtecnología/métodos , Tomografía de Emisión de Positrones , Trazadores Radiactivos , Indicadores y Reactivos/química , Modelos Teóricos
19.
Alzheimers Dement (Amst) ; 13(1): e12204, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-34095436

RESUMEN

INTRODUCTION: Diagnosis of Alzheimer's disease (AD) based on amyloid beta (A), pathologic tau (T), and neurodegeneration (N) biomarkers in peripheral fluids promises to accelerate clinical trials and intercept disease earlier. METHODS: Qualification of a Simoa plasma p217+tau assay was performed, followed by clinical utility evaluation in a cohort of 227 subjects with broad A and T spectrum. RESULTS: The p217+tau plasma assay was accurate, precise, dilution linear, and highly sensitive. All measured samples were within linear range of the assay, presented higher concentration in AD versus healthy controls (P < .0001), and plasma and cerebrospinal fluid levels correlated (r2 = 0.35). The plasma p217+tau results were predictive of central T and A status (area under the curve = 0.90 and 0.90, respectively) with low false +/- rates. DISCUSSION: The assay described here exhibits good technical performance and shows potential as a highly accurate peripheral biomarker for A or T status in AD and cognitively normal subjects.

20.
J Cereb Blood Flow Metab ; 41(12): 3302-3313, 2021 12.
Artículo en Inglés | MEDLINE | ID: mdl-34259071

RESUMEN

The [18F]-JNJ-64326067-AAA ([18F]-JNJ-067) tau tracer was evaluated in healthy older controls (HCs), mild cognitive impairment (MCI), Alzheimer's disease (AD), and progressive supranuclear palsy (PSP) participants. Seventeen subjects (4 HCs, 5 MCIs, 5 ADs, and 3 PSPs) received a [11C]-PIB amyloid PET scan, and a tau [18F]-JNJ-067 PET scan 0-90 minutes post-injection. Only MCIs and ADs were amyloid positive. The simplified reference tissue model, Logan graphical analysis distribution volume ratio, and SUVR were evaluated for quantification. The [18F]-JNJ-067 tau signal relative to the reference region continued to increase to 90 min, indicating the tracer had not reached steady state. There was no significant difference in any bilateral ROIs for MCIs or PSPs relative to HCs; AD participants showed elevated tracer relative to controls in most cortical ROIs (P < 0.05). Only AD participants showed elevated retention in the entorhinal cortex. There was off-target signal in the putamen, pallidum, thalamus, midbrain, superior cerebellar gray, and white matter. [18F]-JNJ-067 significantly correlated (p < 0.05) with Mini-Mental State Exam in entorhinal cortex and temporal meta regions. There is clear binding of [18F]-JNJ-067 in AD participants. Lack of binding in HCs, MCIs and PSPs suggests [18F]-JNJ-067 may not bind to low levels of AD-related tau or 4 R tau.


Asunto(s)
Enfermedad de Alzheimer , Encéfalo , Radioisótopos de Flúor/administración & dosificación , Isoquinolinas/administración & dosificación , Tomografía de Emisión de Positrones , Piridinas/administración & dosificación , Radiofármacos/administración & dosificación , Proteínas tau/metabolismo , Anciano , Anciano de 80 o más Años , Enfermedad de Alzheimer/diagnóstico por imagen , Enfermedad de Alzheimer/metabolismo , Encéfalo/diagnóstico por imagen , Encéfalo/metabolismo , Femenino , Humanos , Masculino
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