RESUMEN
INTRODUCTION: The Centiloid scale was developed to harmonise the quantification of ß-amyloid (Aß) PET images across tracers, scanners, and processing pipelines. However, several groups have reported differences across tracers and scanners even after centiloid conversion. In this study, we aim to evaluate the impact of different pre and post-processing harmonisation steps on the robustness of longitudinal Centiloid data across three large international cohort studies. METHODS: All Aß PET data in AIBL (N = 3315), ADNI (N = 3442) and OASIS3 (N = 1398) were quantified using the MRI-based Centiloid standard SPM pipeline and the PET-only pipeline CapAIBL. SUVR were converted into Centiloids using each tracer's respective transform. Global Aß burden from pre-defined target cortical regions in Centiloid units were quantified for both raw PET scans and PET scans smoothed to a uniform 8 mm full width half maximum (FWHM) effective smoothness. For Florbetapir, we assessed the performance of using both the standard Whole Cerebellum (WCb) and a composite white matter (WM)+WCb reference region. Additionally, our recently proposed quantification based on Non-negative Matrix Factorisation (NMF) was applied to all spatially and SUVR normalised images. Correlation with clinical severity measured by the Mini-Mental State Examination (MMSE) and effect size, as well as tracer agreement in 11C-PiB-18F-Florbetapir pairs and longitudinal consistency were evaluated. RESULTS: The smoothing to a uniform resolution partially reduced longitudinal variability, but did not improve inter-tracer agreement, effect size or correlation with MMSE. Using a Composite reference region for 18F-Florbetapir improved inter-tracer agreement, effect size, correlation with MMSE, and longitudinal consistency. The best results were however obtained when using the NMF method which outperformed all other quantification approaches in all metrics used. CONCLUSIONS: FWHM smoothing has limited impact on longitudinal consistency or outliers. A Composite reference region including subcortical WM should be used for computing both cross-sectional and longitudinal Florbetapir Centiloid. NMF improves Centiloid quantification on all metrics examined.
Asunto(s)
Enfermedad de Alzheimer , Péptidos beta-Amiloides , Enfermedad de Alzheimer/diagnóstico por imagen , Compuestos de Anilina , Estudios Transversales , Humanos , Estudios Longitudinales , Tomografía de Emisión de Positrones/métodosRESUMEN
The Alzheimer's Association International Conference held its sixth Satellite Symposium in Sydney, Australia in 2019, highlighting the leadership of Australian researchers in advancing the understanding of and treatment developments for Alzheimer's disease (AD) and other dementias. This leadership includes the Australian Imaging, Biomarker, and Lifestyle Flagship Study of Ageing (AIBL), which has fueled the identification and development of many biomarkers and novel therapeutics. Two multimodal lifestyle intervention studies have been launched in Australia; and Australian researchers have played leadership roles in other global studies in diverse populations. Australian researchers have also played an instrumental role in efforts to understand mechanisms underlying vascular contributions to cognitive impairment and dementia; and through the Women's Healthy Aging Project have elucidated hormonal and other factors that contribute to the increased risk of AD in women. Alleviating the behavioral and psychological symptoms of dementia has also been a strong research and clinical focus in Australia.
Asunto(s)
Envejecimiento/fisiología , Enfermedad de Alzheimer/epidemiología , Investigación Biomédica , Progresión de la Enfermedad , Síntomas Prodrómicos , Enfermedad de Alzheimer/diagnóstico , Enfermedad de Alzheimer/tratamiento farmacológico , Australia/epidemiología , Biomarcadores/sangre , Biomarcadores/líquido cefalorraquídeo , Biomarcadores/metabolismo , Disfunción Cognitiva/diagnóstico , Disfunción Cognitiva/tratamiento farmacológico , Humanos , Estilo de Vida , Tomografía de Emisión de PositronesRESUMEN
INTRODUCTION: The evidence for characteristics of persons with subjective cognitive decline (SCD) associated with amyloid positivity is limited. METHODS: In 1640 persons with SCD from 20 Amyloid Biomarker Study cohort, we investigated the associations of SCD-specific characteristics (informant confirmation, domain-specific complaints, concerns, feelings of worse performance) demographics, setting, apolipoprotein E gene (APOE) ε4 carriership, and neuropsychiatric symptoms with amyloid positivity. RESULTS: Between cohorts, amyloid positivity in 70-year-olds varied from 10% to 76%. Only older age, clinical setting, and APOE ε4 carriership showed univariate associations with increased amyloid positivity. After adjusting for these, lower education was also associated with increased amyloid positivity. Only within a research setting, informant-confirmed complaints, memory complaints, attention/concentration complaints, and no depressive symptoms were associated with increased amyloid positivity. Feelings of worse performance were associated with less amyloid positivity at younger ages and more at older ages. DISCUSSION: Next to age, setting, and APOE ε4 carriership, SCD-specific characteristics may facilitate the identification of amyloid-positive individuals.
Asunto(s)
Amiloidosis , Disfunción Cognitiva , Humanos , Amiloide , Proteínas Amiloidogénicas , Apolipoproteína E4/genética , Biomarcadores , Encéfalo/metabolismo , Disfunción Cognitiva/genética , Disfunción Cognitiva/psicología , Tomografía de Emisión de PositronesRESUMEN
PURPOSE: Previous studies have shown that Aß-amyloid (Aß) likely promotes tau to spread beyond the medial temporal lobe. However, the Aß levels necessary for tau to spread in the neocortex is still unclear. METHODS: Four hundred sixty-six participants underwent tau imaging with [18F]MK6420 and Aß imaging with [18F]NAV4694. Aß scans were quantified on the Centiloid (CL) scale with a cut-off of 25 CL for abnormal levels of Aß (A+). Tau scans were quantified in three regions of interest (ROI) (mesial temporal (Me); temporoparietal neocortex (Te); and rest of neocortex (R)) and four mesial temporal region (entorhinal cortex, amygdala, hippocampus, and parahippocampus). Regional tau thresholds were established as the 95%ile of the cognitively unimpaired A- subjects. The prevalence of abnormal tau levels (T+) along the Centiloid continuum was determined. RESULTS: The plots of prevalence of T+ show earlier and greater increase along the Centiloid continuum in the medial temporal area compared to neocortex. Prevalence of T+ was low but associated with Aß level between 10 and 40 CL reaching 23% in Me, 15% in Te, and 11% in R. Between 40 and 70 CL, the prevalence of T+ subjects per CL increased fourfold faster and at 70 CL was 64% in Me, 51% in Te, and 37% in R. In cognitively unimpaired, there were no T+ in R below 50 CL. The highest prevalence of T+ were found in the entorhinal cortex, reaching 40% at 40 CL and 80% at 60 CL. CONCLUSION: Outside the entorhinal cortex, abnormal levels of cortical tau on PET are rarely found with Aß below 40 CL. Above 40 CL prevalence of T+ accelerates in all areas. Moderate Aß levels are required before abnormal neocortical tau becomes detectable.
Asunto(s)
Enfermedad de Alzheimer , Proteínas tau , Amiloide , Péptidos beta-Amiloides , Humanos , Imagen por Resonancia Magnética , Tomografía de Emisión de PositronesRESUMEN
OBJECTIVES: The criteria for objective memory impairment in mild cognitive impairment (MCI) are vaguely defined. Aggregating the number of abnormal memory scores (NAMS) is one way to operationalise memory impairment, which we hypothesised would predict progression to Alzheimer's disease (AD) dementia. METHODS: As part of the Australian Imaging, Biomarkers and Lifestyle Flagship Study of Ageing, 896 older adults who did not have dementia were administered a psychometric battery including three neuropsychological tests of memory, yielding 10 indices of memory. We calculated the number of memory scores corresponding to z ≤ -1.5 (i.e., NAMS) for each participant. Incident diagnosis of AD dementia was established by consensus of an expert panel after 3 years. RESULTS: Of the 722 (80.6%) participants who were followed up, 54 (7.5%) developed AD dementia. There was a strong correlation between NAMS and probability of developing AD dementia (r = .91, p = .0003). Each abnormal memory score conferred an additional 9.8% risk of progressing to AD dementia. The area under the receiver operating characteristic curve for NAMS was 0.87 [95% confidence interval (CI) .81-.93, p < .01]. The odds ratio for NAMS was 1.67 (95% CI 1.40-2.01, p < .01) after correcting for age, sex, education, estimated intelligence quotient, subjective memory complaint, Mini-Mental State Exam (MMSE) score and apolipoprotein E ϵ4 status. CONCLUSIONS: Aggregation of abnormal memory scores may be a useful way of operationalising objective memory impairment, predicting incident AD dementia and providing prognostic stratification for individuals with MCI.
Asunto(s)
Enfermedad de Alzheimer , Disfunción Cognitiva , Anciano , Enfermedad de Alzheimer/complicaciones , Australia , Disfunción Cognitiva/diagnóstico , Disfunción Cognitiva/etiología , Progresión de la Enfermedad , Humanos , Pruebas NeuropsicológicasRESUMEN
Executive function (EF) is a set of cognitive capabilities considered essential for successful daily living, and is negatively affected by ageing and neurodegenerative conditions. Underpinning EF performance are functional nodes in the executive control network (ECN), while the structural connectivity underlying this network is not well understood. In this paper, we evaluated the structural white matter tracts that interconnect the ECN and investigated their relationship to the EF performance. Using high-angular resolution diffusion MRI data, we performed tractography analysis of structural connectivity in a cognitively normal cohort (n = 140), specifically targeting the connectivity between ECN nodes. Our data revealed the presence of a strongly-connected "structural core" of the ECN comprising three components: interhemispheric frontal connections, a fronto-parietal subnetwork and fronto-striatal connections between right dorsolateral prefrontal cortex and right caudate. These pathways were strongly correlated with EF performance (p = .003). Post-hoc analysis of subregions within the significant ECN connections showed that these effects were driven by a highly specific subset of interconnected cortical regions. The structural core subnetwork of the functional ECN may be an important feature crucial to a better future understanding of human cognition and behaviour.
Asunto(s)
Función Ejecutiva/fisiología , Red Nerviosa/diagnóstico por imagen , Red Nerviosa/fisiología , Adolescente , Adulto , Anciano , Mapeo Encefálico , Cognición , Estudios de Cohortes , Conectoma , Imagen de Difusión por Resonancia Magnética , Imagen de Difusión Tensora , Femenino , Lóbulo Frontal/diagnóstico por imagen , Lóbulo Frontal/fisiología , Humanos , Masculino , Persona de Mediana Edad , Neostriado/diagnóstico por imagen , Neostriado/fisiología , Vías Nerviosas , Pruebas Neuropsicológicas , Lóbulo Parietal/diagnóstico por imagen , Lóbulo Parietal/fisiología , Sustancia Blanca/diagnóstico por imagen , Sustancia Blanca/fisiología , Adulto JovenRESUMEN
ABSTRACTBackground:This study investigated the characteristics of subjective memory complaints (SMCs) and their association with current and future cognitive functions. METHODS: A cohort of 209 community-dwelling individuals without dementia aged 47-90 years old was recruited for this 3-year study. Participants underwent neuropsychological and clinical assessments annually. Participants were divided into SMCs and non-memory complainers (NMCs) using a single question at baseline and a memory complaints questionnaire following baseline, to evaluate differential patterns of complaints. In addition, comprehensive assessment of memory complaints was undertaken to evaluate whether severity and consistency of complaints differentially predicted cognitive function. RESULTS: SMC and NMC individuals were significantly different on various features of SMCs. Greater overall severity (but not consistency) of complaints was significantly associated with current and future cognitive functioning. CONCLUSIONS: SMC individuals present distinctive features of memory complaints as compared to NMCs. Further, the severity of complaints was a significant predictor of future cognition. However, SMC did not significantly predict change over time in this sample. These findings warrant further research into the specific features of SMCs that may portend subsequent neuropathological and cognitive changes when screening individuals at increased future risk of dementia.
Asunto(s)
Cognición , Disfunción Cognitiva/diagnóstico , Evaluación Geriátrica/métodos , Trastornos de la Memoria , Pruebas Neuropsicológicas , Anciano , Autoevaluación Diagnóstica , Femenino , Humanos , Vida Independiente/estadística & datos numéricos , Masculino , Trastornos de la Memoria/diagnóstico , Trastornos de la Memoria/epidemiología , Trastornos de la Memoria/psicología , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Pronóstico , Índice de Severidad de la Enfermedad , Australia Occidental/epidemiologíaRESUMEN
BACKGROUND: Given the long preclinical disease course of Alzheimer disease (AD) pathology, novel treatments may be more efficacious if administered before the emergence of dementia. Thus, accurate prediction of who will develop AD dementia is of key importance in selecting individuals for trials of treatment and may become crucial for future selection of patients for therapy. METHODS: As part of the Australian Imaging, Biomarkers and Lifestyle Flagship Study of Ageing, 901 individuals who did not have dementia were recruited. We assigned individuals according to Petersen criteria and Winblad criteria for Mild Cognitive Impairment (MCI) at baseline. We then stratified individuals with amnestic MCI into 2 groups according to the severity of their memory impairment on baseline neuropsychological assessment. Incident diagnosis of AD dementia was established by consensus of an expert panel at 36 months. RESULTS: At 36 months, 725 (80.5%) participants were followed up, 54 (7.4%) of whom developed AD dementia. Subjects with amnestic MCI according to Petersen criteria were more likely to develop AD dementia [positive predictive value; PPV, 24.1%; 95% confidence interval (CI), 18.4-30.6] than healthy controls (PPV, 1.0%; 95% CI, 0.3-2.3). Winblad criteria were also effective, with multiple domain amnestic MCI being most accurate at predicting AD dementia (PPV, 47.3%; 95% CI, 33.7-61.2). Finally, more severe amnestic impairment below the median was useful for predicting the development of AD dementia in single domain amnestic MCI (PPV, 28.1%; 95% CI, 17.0-41.5) and in multiple domain amnestic MCI (PPV, 65.7%; 95% CI, 47.8-80.9). CONCLUSIONS: Memory impairment per se, impairment in multiple cognitive domains and severity of memory impairment were all associated with greater risk of developing AD dementia in this sample. Characterizing the severity of memory impairment may provide prognostic stratification within Petersen or Winblad taxonomies of amnestic MCI.
Asunto(s)
Amnesia/diagnóstico , Disfunción Cognitiva/diagnóstico , Demencia/diagnóstico , Progresión de la Enfermedad , Índice de Severidad de la Enfermedad , Anciano , Enfermedad de Alzheimer/diagnóstico , Australia , Biomarcadores , Femenino , Humanos , Masculino , Pruebas Neuropsicológicas/estadística & datos numéricos , Estudios Prospectivos , Factores de RiesgoRESUMEN
INTRODUCTION: Our objective was to investigate the effect of sex on cognitive decline within the context of amyloid ß (Aß) burden and apolipoprotein E genotype. METHODS: We analyzed sex-specific effects on Aß-positron emission tomography, apolipoprotein, and rates of change on the Preclinical Alzheimer Cognitive Composite-5 across three cohorts, such as the Alzheimer's Disease Neuroimaging Initiative, Australian Imaging, Biomarker and Lifestyle, and Harvard Aging Brain Study (n = 755; clinical dementia rating = 0; age (standard deviation) = 73.6 (6.5); female = 55%). Mixed-effects models of cognitive change by sex, Aß-positron emission tomography, and apolipoprotein ε4 were examined with quadratic time effects over a median of 4 years of follow-up. RESULTS: Apolipoprotein ε4 prevalence and Aß burden did not differ by sex. Sex did not directly influence cognitive decline. Females with higher Aß exhibited faster decline than males. Post hoc contrasts suggested that females who were Aß and apolipoprotein ε4 positive declined faster than their male counterparts. DISCUSSION: Although Aß did not differ by sex, cognitive decline was greater in females with higher Aß. Our findings suggest that sex may play a modifying role on risk of Alzheimer's disease-related cognitive decline.
Asunto(s)
Enfermedad de Alzheimer/epidemiología , Péptidos beta-Amiloides/metabolismo , Apolipoproteína E4/genética , Disfunción Cognitiva/epidemiología , Anciano , Anciano de 80 o más Años , Enfermedad de Alzheimer/diagnóstico por imagen , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/metabolismo , Encéfalo/diagnóstico por imagen , Encéfalo/metabolismo , Disfunción Cognitiva/diagnóstico por imagen , Disfunción Cognitiva/genética , Disfunción Cognitiva/metabolismo , Estudios de Cohortes , Progresión de la Enfermedad , Femenino , Humanos , Masculino , Síntomas Prodrómicos , Factores de Riesgo , Factores SexualesRESUMEN
Alzheimer's disease is defined by the presence of ß-amyloid plaques and neurofibrillary tau tangles potentially preceding clinical symptoms by many years. Previously only detectable post-mortem, these pathological hallmarks are now identifiable using biomarkers, permitting an in vivo definitive diagnosis of Alzheimer's disease. 18F-flortaucipir (previously known as 18F-T807; 18F-AV-1451) was the first tau positron emission tomography tracer to be introduced and is the only Food and Drug Administration-approved tau positron emission tomography tracer (Tauvid™). It has been widely adopted and validated in a number of independent research and clinical settings. In this review, we present an overview of the published literature on flortaucipir for positron emission tomography imaging of neurofibrillary tau tangles. We considered all accessible peer-reviewed literature pertaining to flortaucipir through 30 April 2022. We found 474 relevant peer-reviewed publications, which were organized into the following categories based on their primary focus: typical Alzheimer's disease, mild cognitive impairment and pre-symptomatic populations; atypical Alzheimer's disease; non-Alzheimer's disease neurodegenerative conditions; head-to-head comparisons with other Tau positron emission tomography tracers; and technical considerations. The available flortaucipir literature provides substantial evidence for the use of this positron emission tomography tracer in assessing neurofibrillary tau tangles in Alzheimer's disease and limited support for its use in other neurodegenerative disorders. Visual interpretation and quantitation approaches, although heterogeneous, mostly converge and demonstrate the high diagnostic and prognostic value of flortaucipir in Alzheimer's disease.
RESUMEN
BACKGROUND: Maximizing the efficiency to screen amyloid-positive individuals in asymptomatic and non-demented aged population using blood-based biomarkers is essential for future success of clinical trials in the early stage of Alzheimer's disease (AD). In this study, we elucidate the utility of combination of plasma amyloid-ß (Aß)-related biomarkers and tau phosphorylated at threonine 217 (p-tau217) to predict abnormal Aß-positron emission tomography (PET) in the preclinical and prodromal AD. METHODS: We designed the cross-sectional study including two ethnically distinct cohorts, the Japanese trial-ready cohort for preclinica and prodromal AD (J-TRC) and the Swedish BioFINDER study. J-TRC included 474 non-demented individuals (CDR 0: 331, CDR 0.5: 143). Participants underwent plasma Aß and p-tau217 assessments, and Aß-PET imaging. Findings in J-TRC were replicated in the BioFINDER cohort including 177 participants (cognitively unimpaired: 114, mild cognitive impairment: 63). In both cohorts, plasma Aß(1-42) (Aß42) and Aß(1-40) (Aß40) were measured using immunoprecipitation-MALDI TOF mass spectrometry (Shimadzu), and p-tau217 was measured with an immunoassay on the Meso Scale Discovery platform (Eli Lilly). RESULTS: Aß-PET was abnormal in 81 participants from J-TRC and 71 participants from BioFINDER. Plasma Aß42/Aß40 ratio and p-tau217 individually showed moderate to high accuracies when detecting abnormal Aß-PET scans, which were improved by combining plasma biomarkers and by including age, sex and APOE genotype in the models. In J-TRC, the highest AUCs were observed for the models combining p-tau217/Aß42 ratio, APOE, age, sex in the whole cohort (AUC = 0.936), combining p-tau217, Aß42/Aß40 ratio, APOE, age, sex in the CDR 0 group (AUC = 0.948), and combining p-tau217/Aß42 ratio, APOE, age, sex in the CDR 0.5 group (AUC = 0.955), respectively. Each subgroup results were replicated in BioFINDER, where the highest AUCs were seen for models combining p-tau217, Aß42/40 ratio, APOE, age, sex in cognitively unimpaired (AUC = 0.938), and p-tau217/Aß42 ratio, APOE, age, sex in mild cognitive impairment (AUC = 0.914). CONCLUSIONS: Combination of plasma Aß-related biomarkers and p-tau217 exhibits high performance when predicting Aß-PET positivity. Adding basic clinical information (i.e., age, sex, APOE ε genotype) improved the prediction in preclinical AD, but not in prodromal AD. Combination of Aß-related biomarkers and p-tau217 could be highly useful for pre-screening of participants in clinical trials of preclinical and prodromal AD.
Asunto(s)
Péptidos beta-Amiloides , Biomarcadores , Encéfalo , Tomografía de Emisión de Positrones , Proteínas tau , Humanos , Péptidos beta-Amiloides/sangre , Péptidos beta-Amiloides/metabolismo , Femenino , Masculino , Proteínas tau/sangre , Anciano , Tomografía de Emisión de Positrones/métodos , Biomarcadores/sangre , Estudios Transversales , Encéfalo/diagnóstico por imagen , Encéfalo/metabolismo , Anciano de 80 o más Años , Estudios de Cohortes , Fosforilación , Persona de Mediana Edad , Enfermedad de Alzheimer/sangre , Enfermedad de Alzheimer/diagnóstico por imagen , Enfermedad de Alzheimer/diagnóstico , Fragmentos de Péptidos/sangre , Disfunción Cognitiva/sangre , Disfunción Cognitiva/diagnóstico por imagen , Disfunción Cognitiva/diagnósticoRESUMEN
This systematic review examines the prevalence, underlying mechanisms, cohort characteristics, evaluation criteria, and cohort types in white matter hyperintensity (WMH) pipeline and implementation literature spanning the last two decades. Following Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines, we categorized WMH segmentation tools based on their methodologies from January 1, 2000, to November 18, 2022. Inclusion criteria involved articles using openly available techniques with detailed descriptions, focusing on WMH as a primary outcome. Our analysis identified 1007 visual rating scales, 118 pipeline development articles, and 509 implementation articles. These studies predominantly explored aging, dementia, psychiatric disorders, and small vessel disease, with aging and dementia being the most prevalent cohorts. Deep learning emerged as the most frequently developed segmentation technique, indicative of a heightened scrutiny in new technique development over the past two decades. We illustrate observed patterns and discrepancies between published and implemented WMH techniques. Despite increasingly sophisticated quantitative segmentation options, visual rating scales persist, with the SPM technique being the most utilized among quantitative methods and potentially serving as a reference standard for newer techniques. Our findings highlight the need for future standards in WMH segmentation, and we provide recommendations based on these observations.
RESUMEN
Alzheimer's disease (AD) is a complex genetic disease, and variants identified through genome-wide association studies (GWAS) explain only part of its heritability. Epistasis has been proposed as a major contributor to this 'missing heritability', however, many current methods are limited to only modelling additive effects. We use VariantSpark, a machine learning approach to GWAS, and BitEpi, a tool for epistasis detection, to identify AD associated variants and interactions across two independent cohorts, ADNI and UK Biobank. By incorporating significant epistatic interactions, we captured 10.41% more phenotypic variance than logistic regression (LR). We validate the well-established AD loci, APOE, and identify two novel genome-wide significant AD associated loci in both cohorts, SH3BP4 and SASH1, which are also in significant epistatic interactions with APOE. We show that the SH3BP4 SNP has a modulating effect on the known pathogenic APOE SNP, demonstrating a possible protective mechanism against AD. SASH1 is involved in a triplet interaction with pathogenic APOE SNP and ACOT11, where the SASH1 SNP lowered the pathogenic interaction effect between ACOT11 and APOE. Finally, we demonstrate that VariantSpark detects disease associations with 80% fewer controls than LR, unlocking discoveries in well annotated but smaller cohorts.
Asunto(s)
Enfermedad de Alzheimer , Humanos , Enfermedad de Alzheimer/genética , Estudio de Asociación del Genoma Completo , Epistasis Genética , Aprendizaje Automático , Polimorfismo de Nucleótido Simple , Apolipoproteínas E/genética , Predisposición Genética a la Enfermedad , Proteínas Adaptadoras Transductoras de Señales/genéticaRESUMEN
BACKGROUND: Astrocyte reactivity is an early event along the Alzheimer's disease (AD) continuum. Plasma glial fibrillary acidic protein (GFAP), posited to reflect astrocyte reactivity, is elevated across the AD continuum from preclinical to dementia stages. Monoamine oxidase-B (MAO-B) is also elevated in reactive astrocytes observed using 18F-SMBT-1 PET in AD. OBJECTIVE: The objective of this study was to evaluate the association between the abovementioned astrocyte reactivity biomarkers. METHODS: Plasma GFAP and Aß were measured using the Simoa® platform in participants who underwent brain 18F-SMBT-1 and Aß-PET imaging, comprising 54 healthy control (13 Aß-PET+ and 41 Aß-PET-), 11 mild cognitively impaired (3 Aß-PET+ and 8 Aß-PET-) and 6 probable AD (5 Aß-PET+ and 1 Aß-PET-) individuals. Linear regressions were used to assess associations of interest. RESULTS: Plasma GFAP was associated with 18F-SMBT-1 signal in brain regions prone to early Aß deposition in AD, such as the supramarginal gyrus (SG), posterior cingulate (PC), lateral temporal (LT) and lateral occipital cortex (LO). After adjusting for age, sex, APOE É4 genotype, and soluble Aß (plasma Aß42/40 ratio), plasma GFAP was associated with 18F-SMBT-1 signal in the SG, PC, LT, LO, and superior parietal cortex (SP). On adjusting for age, sex, APOE É4 genotype and insoluble Aß (Aß-PET), plasma GFAP was associated with 18F-SMBT-1 signal in the SG. CONCLUSION: There is an association between plasma GFAP and regional 18F-SMBT-1 PET, and this association appears to be dependent on brain Aß load.
Asunto(s)
Enfermedad de Alzheimer , Disfunción Cognitiva , Humanos , Enfermedad de Alzheimer/metabolismo , Péptidos beta-Amiloides/metabolismo , Astrocitos/metabolismo , Proteína Ácida Fibrilar de la Glía/metabolismo , Disfunción Cognitiva/genética , Encéfalo/diagnóstico por imagen , Encéfalo/metabolismo , Tomografía de Emisión de Positrones/métodos , Biomarcadores/metabolismo , Apolipoproteínas E/metabolismo , Proteínas tau/metabolismoRESUMEN
The concept of age acceleration, the difference between biological age and chronological age, is of growing interest, particularly with respect to age-related disorders, such as Alzheimer's Disease (AD). Whilst studies have reported associations with AD risk and related phenotypes, there remains a lack of consensus on these associations. Here we aimed to comprehensively investigate the relationship between five recognised measures of age acceleration, based on DNA methylation patterns (DNAm age), and cross-sectional and longitudinal cognition and AD-related neuroimaging phenotypes (volumetric MRI and Amyloid-ß PET) in the Australian Imaging, Biomarkers and Lifestyle (AIBL) and the Alzheimer's Disease Neuroimaging Initiative (ADNI). Significant associations were observed between age acceleration using the Hannum epigenetic clock and cross-sectional hippocampal volume in AIBL and replicated in ADNI. In AIBL, several other findings were observed cross-sectionally, including a significant association between hippocampal volume and the Hannum and Phenoage epigenetic clocks. Further, significant associations were also observed between hippocampal volume and the Zhang and Phenoage epigenetic clocks within Amyloid-ß positive individuals. However, these were not validated within the ADNI cohort. No associations between age acceleration and other Alzheimer's disease-related phenotypes, including measures of cognition or brain Amyloid-ß burden, were observed, and there was no association with longitudinal change in any phenotype. This study presents a link between age acceleration, as determined using DNA methylation, and hippocampal volume that was statistically significant across two highly characterised cohorts. The results presented in this study contribute to a growing literature that supports the role of epigenetic modifications in ageing and AD-related phenotypes.
Asunto(s)
Enfermedad de Alzheimer , Envejecimiento/genética , Enfermedad de Alzheimer/diagnóstico por imagen , Enfermedad de Alzheimer/genética , Péptidos beta-Amiloides , Australia , Estudios Transversales , Epigénesis Genética , Hipocampo/diagnóstico por imagen , HumanosRESUMEN
Importance: Plasma biomarkers of Alzheimer disease may be useful as minimally invasive pharmacodynamic measures of treatment outcomes. Objective: To analyze the association of donanemab treatment with plasma biomarkers associated with Alzheimer disease. Design, Setting, and Participants: TRAILBLAZER-ALZ was a randomized, double-blind, placebo-controlled clinical trial conducted from December 18, 2017, to December 4, 2020, across 56 sites in the US and Canada. Exploratory biomarkers were prespecified with the post hoc addition of plasma glial fibrillary acidic protein and amyloid-ß. Men and women aged 60 to 85 years with gradual and progressive change in memory function for at least 6 months were included. A total of 1955 participants were assessed for eligibility. Key eligibility criteria include Mini-Mental State Examination scores of 20 to 28 and elevated amyloid and intermediate tau levels. Interventions: Randomized participants received donanemab or placebo every 4 weeks for up to 72 weeks. The first 3 doses of donanemab were given at 700 mg and then increased to 1400 mg with blinded dose reductions as specified based on amyloid reduction. Main Outcomes and Measures: Change in plasma biomarker levels after donanemab treatment. Results: In TRAILBLAZER-ALZ, 272 participants (mean [SD] age, 75.2 [5.5] years; 145 [53.3%] female) were randomized. Plasma levels of phosphorylated tau217 (pTau217) and glial fibrillary acidic protein were significantly lower with donanemab treatment compared with placebo as early as 12 weeks after the start of treatment (least square mean change difference vs placebo, -0.04 [95% CI, -0.07 to -0.02]; P = .002 and -0.04 [95% CI, -0.07 to -0.01]; P = .01, respectively). No significant differences in plasma levels of amyloid-ß 42/40 and neurofilament light chain were observed between treatment arms at the end of treatment. Changes in plasma pTau217 and glial fibrillary acidic protein were significantly correlated with the Centiloid percent change in amyloid (Spearman rank correlation coefficient [R] = 0.484 [95% CI, 0.359-0.592]; P < .001 and R = 0.453 [95% CI, 0.306-0.579]; P < .001, respectively) following treatment. Additionally, plasma levels of pTau217 and glial fibrillary acidic protein were significantly correlated at baseline and following treatment (R = 0.399 [95% CI, 0.278-0.508], P < .001 and R = 0.393 [95% CI, 0.254-0.517]; P < .001, respectively). Conclusions and Relevance: Significant reductions in plasma biomarkers pTau217 and glial fibrillary acidic protein compared with placebo were observed following donanemab treatment in patients with early symptomatic Alzheimer disease. These easily accessible plasma biomarkers might provide additional evidence of Alzheimer disease pathology change through anti-amyloid therapy. Usefulness in assessing treatment response will require further evaluation. Trial Registration: ClinicalTrials.gov Identifier: NCT03367403.
Asunto(s)
Enfermedad de Alzheimer , Masculino , Femenino , Humanos , Anciano , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/diagnóstico , Proteína Ácida Fibrilar de la Glía , Péptidos beta-Amiloides , Biomarcadores , Plasma , Método Doble Ciego , Anticuerpos Monoclonales/uso terapéuticoRESUMEN
Reactive gliosis, characterized by reactive astrocytes and activated microglia, contributes greatly to neurodegeneration throughout the course of Alzheimer disease (AD). Reactive astrocytes overexpress monoamine oxidase B (MAO-B). We characterized the clinical performance of 18F-(S)-(2-methylpyrid-5-yl)-6-[(3-fluoro-2-hydroxy)propoxy]quinoline (18F-SMBT-1), a novel MAO-B PET tracer as a potential surrogate marker of reactive astrogliosis. Methods: Seventy-seven participants-53 who were elderly and cognitively normal, 7 with mild cognitive impairment, 7 with AD, and 10 who were young and cognitively normal-were recruited for the different aspects of the study. Older participants underwent 3-dimensional magnetization-prepared rapid gradient-echo MRI and amyloid-ß, tau, and 18F-SMBT-1 PET. To ascertain 18F-SMBT-1 selectivity to MAO-B, 9 participants underwent 2 18F-SMBT-1 scans, before and after receiving 5 mg of selegiline twice daily for 5 d. To compare selectivity, 18F-THK5351 studies were also conducted before and after selegiline. Amyloid-ß burden was expressed in centiloids. 18F-SMBT-1 outcomes were expressed as SUV, as well as tissue ratios and binding parameters using the subcortical white matter as a reference region. Results: 18F-SMBT-1 showed robust entry into the brain and reversible binding kinetics, with high tracer retention in basal ganglia, intermediate retention in cortical regions, and the lowest retention in cerebellum and white matter, which tightly follows the known regional brain distribution of MAO-B (R 2 = 0.84). More than 85% of 18F-SMBT-1 signal was blocked by selegiline across the brain, and in contrast to 18F-THK5351, no residual cortical activity was observed after the selegiline regimen, indicating high selectivity for MAO-B and low nonspecific binding. 18F-SMBT-1 also captured the known MAO-B increases with age, with an annual rate of change (â¼2.6%/y) similar to the in vitro rates of change (â¼1.9%/y). Quantitative and semiquantitative measures of 18F-SMBT-1 binding were strongly associated (R 2 > 0.94), suggesting that a simplified tissue-ratio approach could be used to generate outcome measures. Conclusion: 18F-SMBT-1 is a highly selective MAO-B tracer, with low nonspecific binding, high entry into the brain, and reversible kinetics. Moreover, 18F-SMBT-1 brain distribution matches the reported in vitro distribution and captures the known MAO-B increases with age, suggesting that 18F-SMBT-1 can potentially be used as a surrogate marker of reactive astrogliosis. Further validation of these findings with 18F-SMBT-1 will require examination of a much larger series, including participants with mild cognitive impairment and AD.
Asunto(s)
Enfermedad de Alzheimer , Quinolinas , Anciano , Enfermedad de Alzheimer/metabolismo , Aminopiridinas , Péptidos beta-Amiloides , Gliosis , Humanos , Monoaminooxidasa/metabolismo , Tomografía de Emisión de Positrones/métodos , Radiofármacos/metabolismo , SelegilinaRESUMEN
BACKGROUND: Tau deposition in the mesial temporal lobe (MTL) in the absence of amyloid-ß (Aß-) occurs with aging. The tau PET tracer 18F-MK6240 has low non-specific background binding so is well suited to exploration of early-stage tau deposition. The aim of this study was to investigate the associations between MTL tau, age, hippocampal volume (HV), cognition, and neocortical tau in Aß- cognitively unimpaired (CU) individuals. METHODS: One hundred and ninety-nine Aß- participants (Centiloid < 25) who were CU underwent 18F-MK6240 PET at age 75 ± 5.2 years. Tau standardized uptake value ratio (SUVR) was estimated in mesial temporal (Me), temporoparietal (Te), and rest of the neocortex (R) regions and four Me sub-regions. Tau SUVR were analyzed as continuous variables and compared between high and low MTL SUVR groups. RESULTS: In this cohort with a stable clinical classification of CU for a mean of 5.3 years prior to and at the time of tau PET, MTL tau was visually observed in 9% of the participants and was limited to Braak stages I-II. MTL tau was correlated with age (r = 0.24, p < 0.001). Age contributed to the variance in cognitive scores but MTL tau did not. MTL tau was not greater with subjective memory complaint, nor was there a correlation between MTL tau and Aß Centiloid value, but high tau was associated with smaller HV. Participants with MTL tau had higher tau SUVR in the neocortex but this was driven by the cerebellar reference region and was not present when using white matter normalization. CONCLUSIONS: In an Aß- CU cohort, tau tracer binding in the mesial temporal lobe was age-related and associated with smaller hippocampi, but not with subjective or objective cognitive impairment.
Asunto(s)
Enfermedad de Alzheimer , Disfunción Cognitiva , Anciano , Anciano de 80 o más Años , Péptidos beta-Amiloides/metabolismo , Humanos , Tomografía de Emisión de Positrones , Proteínas tau/metabolismoRESUMEN
Longitudinal observational cohort studies are being conducted worldwide to understand cognition, biomarkers, and the health of the aging population better. Cross-cohort comparisons and networks of registries in Alzheimer's disease (AD) foster scientific exchange, generate insights, and contribute to the evolving clinical science in AD. A scientific working group was convened with invited investigators from established cohort studies in AD, in order to form a research collaboration network as a resource to address important research questions. The Connecting Cohorts to Diminish Alzheimer's Disease (CONCORD-AD) collaboration network was created to bring together global resources and expertise, to generate insights and improve understanding of the natural history of AD, to inform design of clinical trials in all disease stages, and to plan for optimal patient access to disease-modifying therapies once they become available. The network brings together expertise and data insights from 7 cohorts across Australia, Europe, and North America. Notably, the network includes populations recruited through memory clinics as well as population-based cohorts, representing observations from individuals across the AD spectrum. This report aims to introduce the CONCORD-AD network, providing an overview of the cohorts involved, reporting the common assessments used, and describing the key characteristics of the cohort populations. Cohort study designs and baseline population characteristics are compared, and available cognitive, functional, and neuropsychiatric symptom data, as well as the frequency of biomarker assessments, are summarized. Finally, the challenges and opportunities of cross-cohort studies in AD are discussed.
Asunto(s)
Enfermedad de Alzheimer , Redes de Comunicación de Computadores , Cooperación Internacional , Anciano , Biomarcadores , Cognición , Estudios de Cohortes , Humanos , Estudios Observacionales como AsuntoRESUMEN
BACKGROUND: In Alzheimer's disease, heterogeneity has been observed in the postmortem distribution of tau neurofibrillary tangles. Visualizing the topography of tau in vivo may facilitate clinical trials and clinical practice. OBJECTIVE: This study aimed to investigate whether tau distribution patterns that are limited to mesial temporal lobe (MTL)/limbic regions, and those that spare MTL regions, can be visually identified using 18F-MK6240, and whether these patterns are associated with different demographic and cognitive profiles. METHODS: Tau 18F-MK6240 PET images of 151 amyloid-ß positive participants with mild cognitive impairment (MCI) and dementia were visually rated as: tau negative, limbic predominant (LP), MTL-sparing, and Typical by two readers. Groups were evaluated for differences in age, APOE É4 carriage, hippocampal volumes, and cognition (MMSE, composite memory and non-memory scores). Voxel-wise contrasts were also performed. RESULTS: Visual rating resulted in 59.6% classified as Typical, 17.9% as MTL-sparing, 9.9% LP, and 12.6% as tau negative. Intra-rater and inter-rater reliability was strong (Cohen's kappa values of 0.89 and 0.86 respectively). Tracer retention in a "hook"-like distribution on sagittal sequences was observed in the LP and Typical groups. The visually classified MTL-sparing group had lower APOE É4 carriage and relatively preserved hippocampal volumes. Higher MTL tau was associated with greater amnestic cognitive impairment. High cortical tau was associated with greater impairments on non-memory domains of cognition, and individuals with high cortical tau were more likely to have dementia than MCI. CONCLUSION: Tau distribution patterns can be visually identified using 18F-MK6240 PET and are associated with differences in APOE É4 carriage, hippocampal volumes, and cognition.