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OBJECTIVE: A clock relating amyloid positron emission tomography (PET) to time was used to estimate the timing of biomarker changes in sporadic Alzheimer disease (AD). METHODS: Research participants were included who underwent cerebrospinal fluid (CSF) collection within 2 years of amyloid PET. The ages at amyloid onset and AD symptom onset were estimated for each individual. The timing of change for plasma, CSF, imaging, and cognitive measures was calculated by comparing restricted cubic splines of cross-sectional data from the amyloid PET positive and negative groups. RESULTS: The amyloid PET positive sub-cohort (n = 118) had an average age of 70.4 ± 7.4 years (mean ± standard deviation) and 16% were cognitively impaired. The amyloid PET negative sub-cohort (n = 277) included individuals with low levels of amyloid plaque burden at all scans who were cognitively unimpaired at the time of the scans. Biomarker changes were detected 15-19 years before estimated symptom onset for CSF Aß42/Aß40, plasma Aß42/Aß40, CSF pT217/T217, and amyloid PET; 12-14 years before estimated symptom onset for plasma pT217/T217, CSF neurogranin, CSF SNAP-25, CSF sTREM2, plasma GFAP, and plasma NfL; and 7-9 years before estimated symptom onset for CSF pT205/T205, CSF YKL-40, hippocampal volumes, and cognitive measures. INTERPRETATION: The use of an amyloid clock enabled visualization and analysis of biomarker changes as a function of estimated years from symptom onset in sporadic AD. This study demonstrates that estimated years from symptom onset based on an amyloid clock can be used as a continuous staging measure for sporadic AD and aligns with findings in autosomal dominant AD. ANN NEUROL 2024;95:951-965.
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Enfermedad de Alzheimer , Péptidos beta-Amiloides , Biomarcadores , Tomografía de Emisión de Positrones , Humanos , Enfermedad de Alzheimer/sangre , Enfermedad de Alzheimer/líquido cefalorraquídeo , Enfermedad de Alzheimer/diagnóstico por imagen , Enfermedad de Alzheimer/diagnóstico , Femenino , Masculino , Biomarcadores/líquido cefalorraquídeo , Biomarcadores/sangre , Anciano , Péptidos beta-Amiloides/líquido cefalorraquídeo , Péptidos beta-Amiloides/sangre , Persona de Mediana Edad , Fragmentos de Péptidos/líquido cefalorraquídeo , Fragmentos de Péptidos/sangre , Anciano de 80 o más Años , Estudios Transversales , Factores de Tiempo , Edad de Inicio , Estudios de Cohortes , Progresión de la Enfermedad , Proteína 1 Similar a Quitinasa-3/líquido cefalorraquídeo , Proteína 1 Similar a Quitinasa-3/sangre , Disfunción Cognitiva/líquido cefalorraquídeo , Disfunción Cognitiva/sangre , Placa Amiloide/diagnóstico por imagen , Placa Amiloide/patologíaRESUMEN
OBJECTIVE: Identifying cerebrospinal fluid measures of the microtubule binding region of tau (MTBR-tau) species that reflect tau aggregation could provide fluid biomarkers that track Alzheimer's disease related neurofibrillary tau pathological changes. We examined the cerebrospinal fluid (CSF) MTBR-tau species in dominantly inherited Alzheimer's disease (DIAD) mutation carriers to assess the association with Alzheimer's disease (AD) biomarkers and clinical symptoms. METHODS: Cross-sectional and longitudinal CSF from 229 DIAD mutation carriers and 130 mutation non-carriers had sequential characterization of N-terminal/mid-domain phosphorylated tau (p-tau) followed by MTBR-tau species and tau positron emission tomography (tau PET), other soluble tau and amyloid biomarkers, comprehensive clinical and cognitive assessments, and brain magnetic resonance imaging of atrophy. RESULTS: CSF MTBR-tau species located within the putative "border" region and one species corresponding to the "core" region of aggregates in neurofibrillary tangles (NFTs) increased during the presymptomatic stage and decreased during the symptomatic stage. The "border" MTBR-tau species were associated with amyloid pathology and CSF p-tau; whereas the "core" MTBR-tau species were associated stronger with tau PET and CSF measures of neurodegeneration. The ratio of the border to the core species provided a continuous measure of increasing amounts that tracked clinical progression and NFTs. INTERPRETATION: Changes in CSF soluble MTBR-tau species preceded the onset of dementia, tau tangle increase, and atrophy in DIAD. The ratio of 4R-specific MTBR-tau (border) to the NFT (core) MTBR-tau species corresponds to the pathology of NFTs in DIAD and change with disease progression. The dynamics between different MTBR-tau species in the CSF may serve as a marker of tau-related disease progression and target engagement of anti-tau therapeutics. ANN NEUROL 2023;93:1158-1172.
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Enfermedad de Alzheimer , Disfunción Cognitiva , Humanos , Enfermedad de Alzheimer/diagnóstico por imagen , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/metabolismo , Estudios Transversales , Proteínas tau/metabolismo , Disfunción Cognitiva/diagnóstico por imagen , Disfunción Cognitiva/genética , Disfunción Cognitiva/líquido cefalorraquídeo , Péptidos beta-Amiloides/metabolismo , Tomografía de Emisión de Positrones/métodos , Atrofia/patología , Biomarcadores/líquido cefalorraquídeo , Progresión de la Enfermedad , Microtúbulos/metabolismo , Microtúbulos/patologíaRESUMEN
INTRODUCTION: Amyloid PET scans provide individuals with mild cognitive impairment (MCI) information about their risk of progressing to Alzheimer's dementia (AD). Given the wide-ranging implications of this information, best practice guidelines are needed to support researchers and clinicians disclosing these high-stakes test results. To inform the development of such guidelines, this analysis aims to describe questions and concerns raised during the disclosure of amyloid PET results in the context of MCI. METHODS: Qualitative description was performed to analyze (n = 34) transcripts of audio-recorded amyloid PET results disclosure sessions involving MCI care dyads. The analysis focused on characterizing the frequency and nature of questions raised during an open question-and-answer (Q&A) period following the return of scan results using a standardized protocol. RESULTS: Nearly all (n = 32/34) dyads posed questions during Q&A. Questions fell within six main categories with the most common being requests for clarification regarding AD/MCI, and next steps given the result. Questions were interspersed with comments reflecting the need for emotional support. Independently administered assessments of comprehension of results showed that, following the disclosure and Q&A, 31/32 participants with MCI and 31/31 care partners scored ≥4 on a 5-point scale. The number of questions asked by care partners during Q&A positively correlated with their level of comprehension (n = 31, Spearman's r = 0.370, p = 0.040). DISCUSSION: This analysis highlights the value of providing opportunities for patients and their family members to ask questions upon learning patients' brain amyloid status. Disclosing clinicians should be prepared to provide clarification, resources, and support to patients and families during the return of amyloid PET results.
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Enfermedad de Alzheimer , Disfunción Cognitiva , Humanos , Enfermedad de Alzheimer/diagnóstico por imagen , Revelación , Amiloide/metabolismo , Disfunción Cognitiva/diagnóstico por imagen , Disfunción Cognitiva/psicología , Encéfalo/metabolismo , Tomografía de Emisión de Positrones/métodosRESUMEN
Longitudinal data from clinical trials are commonly analyzed using mixed models for repeated measures (MMRM) when the time variable is categorical or linear mixed-effects models (ie, random effects model) when the time variable is continuous. In these models, statistical inference is typically based on the absolute difference in the adjusted mean change (for categorical time) or the rate of change (for continuous time). Previously, we proposed a novel approach: modeling the percentage reduction in disease progression associated with the treatment relative to the placebo decline using proportional models. This concept of proportionality provides an innovative and flexible method for simultaneously modeling different cohorts, multivariate endpoints, and jointly modeling continuous and survival endpoints. Through simulated data, we demonstrate the implementation of these models using SAS procedures in both frequentist and Bayesian approaches. Additionally, we introduce a novel method for implementing MMRM models (ie, analysis of response profile) using the nlmixed procedure.
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Teorema de Bayes , Ensayos Clínicos como Asunto , Simulación por Computador , Modelos Estadísticos , Humanos , Estudios Longitudinales , Ensayos Clínicos como Asunto/métodos , Dinámicas no Lineales , Modelos de Riesgos Proporcionales , Interpretación Estadística de DatosRESUMEN
Neurofilament light chain, a putative measure of neuronal damage, is measurable in blood and CSF and is predictive of cognitive function in individuals with Alzheimer's disease. There has been limited prior work linking neurofilament light and functional connectivity, and no prior work has investigated neurofilament light associations with functional connectivity in autosomal dominant Alzheimer's disease. Here, we assessed relationships between blood neurofilament light, cognition, and functional connectivity in a cross-sectional sample of 106 autosomal dominant Alzheimer's disease mutation carriers and 76 non-carriers. We employed an innovative network-level enrichment analysis approach to assess connectome-wide associations with neurofilament light. Neurofilament light was positively correlated with deterioration of functional connectivity within the default mode network and negatively correlated with connectivity between default mode network and executive control networks, including the cingulo-opercular, salience, and dorsal attention networks. Further, reduced connectivity within the default mode network and between the default mode network and executive control networks was associated with reduced cognitive function. Hierarchical regression analysis revealed that neurofilament levels and functional connectivity within the default mode network and between the default mode network and the dorsal attention network explained significant variance in cognitive composite scores when controlling for age, sex, and education. A mediation analysis demonstrated that functional connectivity within the default mode network and between the default mode network and dorsal attention network partially mediated the relationship between blood neurofilament light levels and cognitive function. Our novel results indicate that blood estimates of neurofilament levels correspond to direct measurements of brain dysfunction, shedding new light on the underlying biological processes of Alzheimer's disease. Further, we demonstrate how variation within key brain systems can partially mediate the negative effects of heightened total serum neurofilament levels, suggesting potential regions for targeted interventions. Finally, our results lend further evidence that low-cost and minimally invasive blood measurements of neurofilament may be a useful marker of brain functional connectivity and cognitive decline in Alzheimer's disease.
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Enfermedad de Alzheimer , Disfunción Cognitiva , Conectoma , Humanos , Estudios Transversales , Filamentos Intermedios , Imagen por Resonancia Magnética/métodos , Encéfalo/diagnóstico por imagen , Cognición , Red Nerviosa/diagnóstico por imagenRESUMEN
INTRODUCTION: Estimating treatment effects as time savings in disease progression may be more easily interpretable than assessing the absolute difference or a percentage reduction. In this study, we investigate the statistical considerations of the existing method for estimating time savings and propose alternative complementary methods. METHODS: We propose five alternative methods to estimate the time savings from different perspectives. These methods are applied to simulated clinical trial data that mimic or modify the Clinical Dementia Rating Sum of Boxes progression trajectories observed in the Clarity AD lecanemab trial. RESULTS: Our study demonstrates that the proposed methods can generate more precise estimates by considering two crucial factors: (1) the absolute difference between treatment arms, and (2) the observed progression rate in the treatment arm. DISCUSSION: Quantifying treatment effects as time savings in disease progression offers distinct advantages. To provide comprehensive estimations, it is important to use various methods. HIGHLIGHTS: We explore the statistical considerations of the current method for estimating time savings. We proposed alternative methods that provide time savings estimations based on the observed absolute differences. By using various methods, a more comprehensive estimation of time savings can be achieved.
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Prior authorization criteria for Federal Drug Administration (FDA) approved immunotherapeutics, among the class of anti-amyloid monoclonal antibodies (mAbs), established by state drug formulary committees, are tailored for adults with late-onset Alzheimer's disease. This overlooks adults with Down syndrome (DS), who often experience dementia at a younger age and with different diagnostic assessment outcomes. This exclusion may deny DS adults access to potential disease-modifying treatments. To address this issue, an international expert panel convened to establish adaptations of prescribing criteria suitable for DS patients and parameters for access to Centers for Medicare & Medicaid Services (CMS) registries. The panel proposed mitigating disparities by modifying CMS and payer criteria to account for younger onset age, using alternative language and assessment instruments validated for cognitive decline in the DS population. The panel also recommended enhancing prescribing clinicians' diagnostic capabilities for DS and initiated awareness-raising activities within healthcare organizations. These efforts facilitated discussions with federal officials, aimed at achieving equity in access to anti-amyloid immunotherapeutics, with implications for national authorities worldwide evaluating these and other new disease-modifying therapeutics for Alzheimer's disease.
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Síndrome de Down , Humanos , Estados Unidos , Enfermedad de Alzheimer/tratamiento farmacológico , Adulto , Anticuerpos Monoclonales/uso terapéutico , Inmunoterapia/métodosRESUMEN
The National Institute on Aging and the Alzheimer's Association convened three separate work groups in 2011 and single work groups in 2012 and 2018 to create recommendations for the diagnosis and characterization of Alzheimer's disease (AD). The present document updates the 2018 research framework in response to several recent developments. Defining diseases biologically, rather than based on syndromic presentation, has long been standard in many areas of medicine (e.g., oncology), and is becoming a unifying concept common to all neurodegenerative diseases, not just AD. The present document is consistent with this principle. Our intent is to present objective criteria for diagnosis and staging AD, incorporating recent advances in biomarkers, to serve as a bridge between research and clinical care. These criteria are not intended to provide step-by-step clinical practice guidelines for clinical workflow or specific treatment protocols, but rather serve as general principles to inform diagnosis and staging of AD that reflect current science. HIGHLIGHTS: We define Alzheimer's disease (AD) to be a biological process that begins with the appearance of AD neuropathologic change (ADNPC) while people are asymptomatic. Progression of the neuropathologic burden leads to the later appearance and progression of clinical symptoms. Early-changing Core 1 biomarkers (amyloid positron emission tomography [PET], approved cerebrospinal fluid biomarkers, and accurate plasma biomarkers [especially phosphorylated tau 217]) map onto either the amyloid beta or AD tauopathy pathway; however, these reflect the presence of ADNPC more generally (i.e., both neuritic plaques and tangles). An abnormal Core 1 biomarker result is sufficient to establish a diagnosis of AD and to inform clinical decision making throughout the disease continuum. Later-changing Core 2 biomarkers (biofluid and tau PET) can provide prognostic information, and when abnormal, will increase confidence that AD is contributing to symptoms. An integrated biological and clinical staging scheme is described that accommodates the fact that common copathologies, cognitive reserve, and resistance may modify relationships between clinical and biological AD stages.
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INTRODUCTION: Increasing evidence suggests that amyloid reduction could serve as a plausible surrogate endpoint for clinical and cognitive efficacy. The double-blind phase 3 DIAN-TU-001 trial tested clinical and cognitive declines with increasing doses of solanezumab or gantenerumab. METHODS: We used latent class (LC) analysis on data from the Dominantly Inherited Alzheimer Network Trials Unit 001 trial to test amyloid positron emission tomography (PET) reduction as a potential surrogate biomarker. RESULTS: LC analysis categorized participants into three classes: amyloid no change, amyloid reduction, and amyloid growth, based on longitudinal amyloid Pittsburgh compound B PET standardized uptake value ratio data. The amyloid-no-change class was at an earlier disease stage for amyloid amounts and dementia. Despite similar baseline characteristics, the amyloid-reduction class exhibited reductions in the annual decline rates compared to the amyloid-growth class across multiple biomarker, clinical, and cognitive outcomes. DISCUSSION: LC analysis indicates that amyloid reduction is associated with improved clinical outcomes and supports its use as a surrogate biomarker in clinical trials. HIGHLIGHTS: We used latent class (LC) analysis to test amyloid reduction as a surrogate biomarker. Despite similar baseline characteristics, the amyloid-reduction class exhibited remarkably better outcomes compared to the amyloid-growth class across multiple measures. LC analysis proves valuable in testing amyloid reduction as a surrogate biomarker in clinical trials lacking significant treatment effects.
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Enfermedad de Alzheimer , Humanos , Enfermedad de Alzheimer/diagnóstico por imagen , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/genética , Amiloide , Péptidos beta-Amiloides , Proteínas Amiloidogénicas , Biomarcadores , Método Doble Ciego , Análisis de Clases Latentes , Tomografía de Emisión de Positrones/métodosRESUMEN
INTRODUCTION: Studies suggest distinct differences in the development, presentation, progression, and response to treatment of Alzheimer's disease (AD) between females and males. We investigated sex differences in cognition, neuroimaging, and fluid biomarkers in dominantly inherited AD (DIAD). METHODS: Three hundred twenty-five mutation carriers (55% female) and one hundred eighty-six non-carriers (58% female) of the Dominantly Inherited Alzheimer Network Observational Study were analyzed. Linear mixed models and Spearman's correlation explored cross-sectional sex differences in cognition, cerebrospinal fluid (CSF) biomarkers, Pittsburgh compound B positron emission tomography (11 C-PiB PET) and structural magnetic resonance imaging (MRI). RESULTS: Female carriers performed better than males on delayed recall and processing speed despite similar hippocampal volumes. As the disease progressed, symptomatic females revealed higher increases in MRI markers of neurodegeneration and memory impairment. PiB PET and established CSF AD markers revealed no sex differences. DISCUSSION: Our findings suggest an initial cognitive reserve in female carriers followed by a pronounced increase in neurodegeneration coupled with worse performance on delayed recall at later stages of DIAD.
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Enfermedad de Alzheimer , Humanos , Femenino , Masculino , Enfermedad de Alzheimer/diagnóstico por imagen , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/líquido cefalorraquídeo , Péptidos beta-Amiloides/líquido cefalorraquídeo , Estudios Transversales , Caracteres Sexuales , Tomografía de Emisión de Positrones , Mutación/genética , BiomarcadoresRESUMEN
INTRODUCTION: Amyloid beta and tau pathology are the hallmarks of sporadic Alzheimer's disease (AD) and autosomal dominant AD (ADAD). However, Lewy body pathology (LBP) is found in ≈ 50% of AD and ADAD brains. METHODS: Using an α-synuclein seed amplification assay (SAA) in cerebrospinal fluid (CSF) from asymptomatic (n = 26) and symptomatic (n = 27) ADAD mutation carriers, including 12 with known neuropathology, we investigated the timing of occurrence and prevalence of SAA positive reactivity in ADAD in vivo. RESULTS: No asymptomatic participant and only 11% (3/27) of the symptomatic patients tested SAA positive. Neuropathology revealed LBP in 10/12 cases, primarily affecting the amygdala or the olfactory areas. In the latter group, only the individual with diffuse LBP reaching the neocortex showed α-synuclein seeding activity in CSF in vivo. DISCUSSION: Results suggest that in ADAD LBP occurs later than AD pathology and often as amygdala- or olfactory-predominant LBP, for which CSF α-synuclein SAA has low sensitivity. HIGHLIGHTS: Cerebrospinal fluid (CSF) real-time quaking-induced conversion (RT-QuIC) detects misfolded α-synuclein in ≈ 10% of symptomatic autosomal dominant Alzheimer's disease (ADAD) patients. CSF RT-QuIC does not detect α-synuclein seeding activity in asymptomatic mutation carriers. Lewy body pathology (LBP) in ADAD mainly occurs as olfactory only or amygdala-predominant variants. LBP develops late in the disease course in ADAD. CSF α-synuclein RT-QuIC has low sensitivity for focal, low-burden LBP.
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Enfermedad de Alzheimer , Cuerpos de Lewy , alfa-Sinucleína , Humanos , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/patología , Enfermedad de Alzheimer/líquido cefalorraquídeo , alfa-Sinucleína/líquido cefalorraquídeo , alfa-Sinucleína/genética , Femenino , Masculino , Persona de Mediana Edad , Cuerpos de Lewy/patología , Anciano , Mutación , Encéfalo/patología , Péptidos beta-Amiloides/líquido cefalorraquídeo , Péptidos beta-Amiloides/metabolismo , Progresión de la EnfermedadRESUMEN
Carriers of mutations responsible for dominantly inherited Alzheimer disease provide a unique opportunity to study potential imaging biomarkers. Biomarkers based on routinely acquired clinical MR images, could supplement the extant invasive or logistically challenging) biomarker studies. We used 1104 longitudinal MR, 324 amyloid beta, and 87 tau positron emission tomography imaging sessions from 525 participants enrolled in the Dominantly Inherited Alzheimer Network Observational Study to extract novel imaging metrics representing the mean (µ) and standard deviation (σ) of standardized image intensities of T1-weighted and Fluid attenuated inversion recovery (FLAIR) MR scans. There was an exponential decrease in FLAIR-µ in mutation carriers and an increase in FLAIR and T1 signal heterogeneity (T1-σ and FLAIR-σ) as participants approached the symptom onset in both supramarginal, the right postcentral and right superior temporal gyri as well as both caudate nuclei, putamina, thalami, and amygdalae. After controlling for the effect of regional atrophy, FLAIR-µ decreased and T1-σ and FLAIR-σ increased with increasing amyloid beta and tau deposition in numerous cortical regions. In symptomatic mutation carriers and independent of the effect of regional atrophy, tau pathology demonstrated a stronger relationship with image intensity metrics, compared with amyloid pathology. We propose novel MR imaging intensity-based metrics using standard clinical T1 and FLAIR images which strongly associates with the progression of pathology in dominantly inherited Alzheimer disease. We suggest that tau pathology may be a key driver of the observed changes in this cohort of patients.
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Enfermedad de Alzheimer , Humanos , Enfermedad de Alzheimer/diagnóstico por imagen , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/complicaciones , Péptidos beta-Amiloides , Imagen por Resonancia Magnética/métodos , Tomografía de Emisión de Positrones , Biomarcadores , Atrofia , Proteínas tauRESUMEN
OBJECTIVE: To determine the characteristics of participants with amyloid-related imaging abnormalities (ARIA) in a trial of gantenerumab or solanezumab in dominantly inherited Alzheimer disease (DIAD). METHODS: 142 DIAD mutation carriers received either gantenerumab SC (n = 52), solanezumab IV (n = 50), or placebo (n = 40). Participants underwent assessments with the Clinical Dementia Rating® (CDR®), neuropsychological testing, CSF biomarkers, ß-amyloid positron emission tomography (PET), and magnetic resonance imaging (MRI) to monitor ARIA. Cross-sectional and longitudinal analyses evaluated potential ARIA-related risk factors. RESULTS: Eleven participants developed ARIA-E, including 3 with mild symptoms. No ARIA-E was reported under solanezumab while gantenerumab was associated with ARIA-E compared to placebo (odds ratio [OR] = 9.1, confidence interval [CI][1.2, 412.3]; p = 0.021). Under gantenerumab, APOE-É4 carriers were more likely to develop ARIA-E (OR = 5.0, CI[1.0, 30.4]; p = 0.055), as were individuals with microhemorrhage at baseline (OR = 13.7, CI[1.2, 163.2]; p = 0.039). No ARIA-E was observed at the initial 225 mg/month gantenerumab dose, and most cases were observed at doses >675 mg. At first ARIA-E occurrence, all ARIA-E participants were amyloid-PET+, 60% were CDR >0, 60% were past their estimated year to symptom onset, and 60% had also incident ARIA-H. Most ARIA-E radiologically resolved after dose adjustment and developing ARIA-E did not significantly increase odds of trial discontinuation. ARIA-E was more frequently observed in the occipital lobe (90%). ARIA-E severity was associated with age at time of ARIA-E. INTERPRETATION: In DIAD, solanezumab was not associated with ARIA. Gantenerumab dose over 225 mg increased ARIA-E risk, with additional risk for individuals APOE-É4(+) or with microhemorrhage. ARIA-E was reversible on MRI in most cases, generally asymptomatic, without additional risk for trial discontinuation. ANN NEUROL 2022;92:729-744.
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Enfermedad de Alzheimer , Humanos , Enfermedad de Alzheimer/diagnóstico por imagen , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/genética , Estudios Transversales , Péptidos beta-Amiloides , Amiloide , Biomarcadores , Apolipoproteínas ERESUMEN
PURPOSE: Pittsburgh Compound-B (11C-PiB) and 18F-florbetapir are amyloid-ß (Aß) positron emission tomography (PET) radiotracers that have been used as endpoints in Alzheimer's disease (AD) clinical trials to evaluate the efficacy of anti-Aß monoclonal antibodies. However, comparing drug effects between and within trials may become complicated if different Aß radiotracers were used. To study the consequences of using different Aß radiotracers to measure Aß clearance, we performed a head-to-head comparison of 11C-PiB and 18F-florbetapir in a Phase 2/3 clinical trial of anti-Aß monoclonal antibodies. METHODS: Sixty-six mutation-positive participants enrolled in the gantenerumab and placebo arms of the first Dominantly Inherited Alzheimer Network Trials Unit clinical trial (DIAN-TU-001) underwent both 11C-PiB and 18F-florbetapir PET imaging at baseline and during at least one follow-up visit. For each PET scan, regional standardized uptake value ratios (SUVRs), regional Centiloids, a global cortical SUVR, and a global cortical Centiloid value were calculated. Longitudinal changes in SUVRs and Centiloids were estimated using linear mixed models. Differences in longitudinal change between PET radiotracers and between drug arms were estimated using paired and Welch two sample t-tests, respectively. Simulated clinical trials were conducted to evaluate the consequences of some research sites using 11C-PiB while other sites use 18F-florbetapir for Aß PET imaging. RESULTS: In the placebo arm, the absolute rate of longitudinal change measured by global cortical 11C-PiB SUVRs did not differ from that of global cortical 18F-florbetapir SUVRs. In the gantenerumab arm, global cortical 11C-PiB SUVRs decreased more rapidly than global cortical 18F-florbetapir SUVRs. Drug effects were statistically significant across both Aß radiotracers. In contrast, the rates of longitudinal change measured in global cortical Centiloids did not differ between Aß radiotracers in either the placebo or gantenerumab arms, and drug effects remained statistically significant. Regional analyses largely recapitulated these global cortical analyses. Across simulated clinical trials, type I error was higher in trials where both Aß radiotracers were used versus trials where only one Aß radiotracer was used. Power was lower in trials where 18F-florbetapir was primarily used versus trials where 11C-PiB was primarily used. CONCLUSION: Gantenerumab treatment induces longitudinal changes in Aß PET, and the absolute rates of these longitudinal changes differ significantly between Aß radiotracers. These differences were not seen in the placebo arm, suggesting that Aß-clearing treatments may pose unique challenges when attempting to compare longitudinal results across different Aß radiotracers. Our results suggest converting Aß PET SUVR measurements to Centiloids (both globally and regionally) can harmonize these differences without losing sensitivity to drug effects. Nonetheless, until consensus is achieved on how to harmonize drug effects across radiotracers, and since using multiple radiotracers in the same trial may increase type I error, multisite studies should consider potential variability due to different radiotracers when interpreting Aß PET biomarker data and, if feasible, use a single radiotracer for the best results. TRIAL REGISTRATION: ClinicalTrials.gov NCT01760005. Registered 31 December 2012. Retrospectively registered.
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Enfermedad de Alzheimer , Humanos , Enfermedad de Alzheimer/diagnóstico por imagen , Enfermedad de Alzheimer/tratamiento farmacológico , Péptidos beta-Amiloides/metabolismo , Tomografía de Emisión de Positrones/métodos , Compuestos de Anilina , Glicoles de Etileno , Encéfalo/metabolismoRESUMEN
The temporal evolutions and relative orderings of Alzheimer disease biomarkers, including CSF amyloid-ß42 (Aß42), Aß40, total tau (Tau) and phosphorylated tau181 (pTau181), standardized uptake value ratio (SUVR) from the molecular imaging of cerebral fibrillar amyloid-ß with PET using the 11C-Pittsburgh Compound-B (PiB), MRI-based hippocampal volume and cortical thickness and cognition have been hypothesized but not yet fully tested with longitudinal data for all major biomarker modalities among cognitively normal individuals across the adult lifespan starting from 18 years. By leveraging a large harmonized database from 8 biomarker studies with longitudinal data from 2609 participants in cognition, 873 in MRI biomarkers, 519 in PET PiB imaging and 475 in CSF biomarkers for a median follow-up of 5-6 years, we estimated the longitudinal trajectories of all major Alzheimer disease biomarkers as functions of baseline age that spanned from 18 to 103 years, located the baseline age window at which the longitudinal rates of change accelerated and further examined possible modifying effects of apolipoprotein E (APOE) genotype. We observed that participants 18-45 years at baseline exhibited learning effects on cognition and unexpected directions of change on CSF and PiB biomarkers. The earliest acceleration of longitudinal change occurred for CSF Aß42 and Aß42/Aß40 ratio (with an increase) and for Tau, and pTau181 (with a decrease) at the next baseline age interval of 45-50 years, followed by an accelerated increase for PiB SUVR at the baseline age of 50-55 years and an accelerated decrease for hippocampal volume at the baseline age of 55-60 years and finally by an accelerated decline for cortical thickness and cognition at the baseline age of 65-70 years. Another acceleration in the rate of change occurred at the baseline age of 65-70 years for Aß42/Aß40 ratio, Tau, pTau181, PiB SUVR and hippocampal volume. Accelerated declines in hippocampal volume and cognition continued after 70 years. For participants 18-45 years at baseline, significant increases in Aß42 and Aß42/Aß40 ratio and decreases in PiB SUVR occurred in APOE É4 non-carriers but not carriers. After age 45 years, APOE É4 carriers had greater magnitudes than non-carriers in the rates of change for all CSF biomarkers, PiB SUVR and cognition. Our results characterize the temporal evolutions and relative orderings of Alzheimer disease biomarkers across the adult lifespan and the modification effect of APOE É4. These findings may better inform the design of prevention trials on Alzheimer disease.
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Enfermedad de Alzheimer , Humanos , Adulto , Adolescente , Adulto Joven , Persona de Mediana Edad , Anciano , Anciano de 80 o más Años , Enfermedad de Alzheimer/genética , Longevidad , Proteínas tau , Tomografía de Emisión de Positrones , Péptidos beta-Amiloides , Biomarcadores , Apolipoproteínas E/genética , Fragmentos de Péptidos , Estudios LongitudinalesRESUMEN
The extent to which the pathophysiology of autosomal dominant Alzheimer's disease corresponds to the pathophysiology of 'sporadic' late onset Alzheimer's disease is unknown, thus limiting the extrapolation of study findings and clinical trial results in autosomal dominant Alzheimer's disease to late onset Alzheimer's disease. We compared brain MRI and amyloid PET data, as well as CSF concentrations of amyloid-ß42, amyloid-ß40, tau and tau phosphorylated at position 181, in 292 carriers of pathogenic variants for Alzheimer's disease from the Dominantly Inherited Alzheimer Network, with corresponding data from 559 participants from the Alzheimer's Disease Neuroimaging Initiative. Imaging data and CSF samples were reprocessed as appropriate to guarantee uniform pipelines and assays. Data analyses yielded rates of change before and after symptomatic onset of Alzheimer's disease, allowing the alignment of the â¼30-year age difference between the cohorts on a clinically meaningful anchor point, namely the participant age at symptomatic onset. Biomarker profiles were similar for both autosomal dominant Alzheimer's disease and late onset Alzheimer's disease. Both groups demonstrated accelerated rates of decline in cognitive performance and in regional brain volume loss after symptomatic onset. Although amyloid burden accumulation as determined by PET was greater after symptomatic onset in autosomal dominant Alzheimer's disease than in late onset Alzheimer's disease participants, CSF assays of amyloid-ß42, amyloid-ß40, tau and p-tau181 were largely overlapping in both groups. Rates of change in cognitive performance and hippocampal volume loss after symptomatic onset were more aggressive for autosomal dominant Alzheimer's disease participants. These findings suggest a similar pathophysiology of autosomal dominant Alzheimer's disease and late onset Alzheimer's disease, supporting a shared pathobiological construct.
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Enfermedad de Alzheimer , Amiloidosis , Humanos , Enfermedad de Alzheimer/diagnóstico por imagen , Enfermedad de Alzheimer/genética , Péptidos beta-Amiloides , Imagen por Resonancia Magnética/métodos , BiomarcadoresRESUMEN
BACKGROUND: Comparisons of late-onset Alzheimer's disease (LOAD) and autosomal dominant AD (ADAD) are confounded by age. METHODS: We compared biomarkers from cerebrospinal fluid (CSF), magnetic resonance imaging, and amyloid imaging with Pittsburgh Compound-B (PiB) across four groups of 387 cognitively normal participants, 42 to 65 years of age, in the Dominantly Inherited Alzheimer Network (DIAN) and the Adult Children Study (ACS) of LOAD: DIAN mutation carriers (MCs) and non-carriers (NON-MCs), and ACS participants with a positive (FH+) and negative (FH-) family history of LOAD. RESULTS: At baseline, MCs had the lowest age-adjusted level of CSF Aß42 and the highest levels of total and phosphorylated tau-181, and PiB uptake. Longitudinally, MC had similar increase in PiB uptake to FH+, but drastically faster decline in hippocampal volume than others, and was the only group showing cognitive decline. DISCUSSION: Preclinical ADAD and LOAD share many biomarker signatures, but cross-sectional and longitudinal differences may exist.
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Enfermedad de Alzheimer , Adulto , Humanos , Persona de Mediana Edad , Enfermedad de Alzheimer/diagnóstico por imagen , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/líquido cefalorraquídeo , Péptidos beta-Amiloides/líquido cefalorraquídeo , Biomarcadores/líquido cefalorraquídeo , Cognición , Estudios Transversales , Padres , Tomografía de Emisión de PositronesRESUMEN
INTRODUCTION: The identification of multiple genetic risk factors for Alzheimer's disease (AD) suggests that many pathways contribute to AD onset and progression. However, the metabolomic and lipidomic profiles in carriers of distinct genetic risk factors are not fully understood. The metabolome can provide a direct image of dysregulated pathways in the brain. METHODS: We interrogated metabolomic signatures in the AD brain, including carriers of pathogenic variants in APP, PSEN1, and PSEN2 (autosomal dominant AD; ADAD), APOE É4, and TREM2 risk variant carriers, and sporadic AD (sAD). RESULTS: We identified 133 unique and shared metabolites associated with ADAD, TREM2, and sAD. We identified a signature of 16 metabolites significantly altered between groups and associated with AD duration. DISCUSSION: AD genetic variants show distinct metabolic perturbations. Investigation of these metabolites may provide greater insight into the etiology of AD and its impact on clinical presentation. HIGHLIGHTS: APP/PSEN1/PSEN2 and TREM2 variant carriers show distinct metabolic changes. A total of 133 metabolites were differentially abundant in AD genetic groups. ß-citrylglutamate is differentially abundant in autosomal dominant, TREM2, and sporadic AD. A 16-metabolite profile shows differences between Alzheimer's disease (AD) genetic groups. The identified metabolic profile is associated with duration of disease.
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Enfermedad de Alzheimer , Humanos , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/patología , Precursor de Proteína beta-Amiloide/genética , Encéfalo/patología , Heterocigoto , Lipidómica , Mutación , Presenilina-1/genéticaRESUMEN
BACKGROUND: Glial fibrillary acidic protein (GFAP) is a promising candidate blood-based biomarker for Alzheimer's disease (AD) diagnosis and prognostication. The timing of its disease-associated changes, its clinical correlates, and biofluid-type dependency will influence its clinical utility. METHODS: We evaluated plasma, serum, and cerebrospinal fluid (CSF) GFAP in families with autosomal dominant AD (ADAD), leveraging the predictable age at symptom onset to determine changes by stage of disease. RESULTS: Plasma GFAP elevations appear a decade before expected symptom onset, after amyloid beta (Aß) accumulation and prior to neurodegeneration and cognitive decline. Plasma GFAP distinguished Aß-positive from Aß-negative ADAD participants and showed a stronger relationship with Aß load in asymptomatic than symptomatic ADAD. Higher plasma GFAP was associated with the degree and rate of neurodegeneration and cognitive impairment. Serum GFAP showed similar relationships, but these were less pronounced for CSF GFAP. CONCLUSION: Our findings support a role for plasma GFAP as a clinical biomarker of Aß-related astrocyte reactivity that is associated with cognitive decline and neurodegeneration. HIGHLIGHTS: Plasma glial fibrillary acidic protein (GFAP) elevations appear a decade before expected symptom onset in autosomal dominant Alzheimer's disease (ADAD). Plasma GFAP was associated to amyloid positivity in asymptomatic ADAD. Plasma GFAP increased with clinical severity and predicted disease progression. Plasma and serum GFAP carried similar information in ADAD, while cerebrospinal fluid GFAP did not.
Asunto(s)
Enfermedad de Alzheimer , Humanos , Enfermedad de Alzheimer/metabolismo , Péptidos beta-Amiloides/metabolismo , Biomarcadores/líquido cefalorraquídeo , Cognición , Proteína Ácida Fibrilar de la Glía , Tomografía de Emisión de Positrones , Proteínas tau/líquido cefalorraquídeoRESUMEN
INTRODUCTION: As the number of biomarkers used to study Alzheimer's disease (AD) continues to increase, it is important to understand the utility of any given biomarker, as well as what additional information a biomarker provides when compared to others. METHODS: We used hierarchical clustering to group 19 cross-sectional biomarkers in autosomal dominant AD. Feature selection identified biomarkers that were the strongest predictors of mutation status and estimated years from symptom onset (EYO). Biomarkers identified included clinical assessments, neuroimaging, cerebrospinal fluid amyloid, and tau, and emerging biomarkers of neuronal integrity and inflammation. RESULTS: Three primary clusters were identified: neurodegeneration, amyloid/tau, and emerging biomarkers. Feature selection identified amyloid and tau measures as the primary predictors of mutation status and EYO. Emerging biomarkers of neuronal integrity and inflammation were relatively weak predictors. DISCUSSION: These results provide novel insight into our understanding of the relationships among biomarkers and the staging of biomarkers based on disease progression.