Disentangling relationships between Alzheimer's disease plasma biomarkers and established biomarkers in patients of tertiary memory clinics.

Background: Several plasma biomarkers for Alzheimer's disease (AD) have demonstrated diagnostic and analytical robustness. Yet, contradictory results have been obtained regarding their association with standard diagnostic markers of AD. This study aims to investigate the specific relationship between the AD biomarkers currently used in clinical practice and the plasma biomarkers.

Tau PET positivity predicts clinically relevant cognitive decline driven by Alzheimer's disease compared to comorbid cases; proof of concept in the ADNI study.

β-amyloid (Aβ) pathology is not always coupled with Alzheimer's disease (AD) relevant cognitive decline. We assessed the accuracy of tau PET to identify Aβ(+) individuals who show prospective disease progression. 396 cognitively unimpaired and impaired individuals with baseline Aβ and tau PET and a follow-up of ≥ 2 years were selected from the Alzheimer's Disease Neuroimaging Initiative dataset.

Imaging Neuroinflammation: Quantification of Astrocytosis in a Multitracer PET Approach.

The recent progress in the development of in vivo biomarkers is rapidly changing how neurodegenerative diseases are conceptualized and diagnosed and how clinical trials are designed today. Alzheimer's disease (AD) - the most common neurodegenerative disorder - is characterized by a complex neuropathology involving the deposition of extracellular amyloid-β (Aβ) plaques and intracellular neurofibrillary tangles (NFTs) of hyperphosphorylated tau proteins, accompanied by the activation of glial cells, i.e.

Tracking reactive astrogliosis in autosomal dominant and sporadic Alzheimer's disease with multi-modal PET and plasma GFAP.

Background: Plasma assays for the detection of Alzheimer's disease neuropathological changes are receiving ever increasing interest. The concentration of plasma glial fibrillary acidic protein (GFAP) has been suggested as a potential marker of astrocytes or recently, amyloid-β burden, although this hypothesis remains unproven. We compared plasma GFAP levels with the astrocyte tracer C-Deuterium-L-Deprenyl (C-DED) in a multi-modal PET design in participants with sporadic and Autosomal Dominant Alzheimer's disease.

Profiling of plasma biomarkers in the context of memory assessment in a tertiary memory clinic.

Plasma biomarkers have shown promising performance in research cohorts in discriminating between different stages of Alzheimer's disease (AD). Studies in clinical populations are necessary to provide insights on the clinical utility of plasma biomarkers before their implementation in real-world settings. Here we investigated plasma biomarkers (glial fibrillary acidic protein (GFAP), tau phosphorylated at 181 and 231 (pTau181, pTau231), amyloid β (Aβ) 42/40 ratio, neurofilament light) in 126 patients (age = 65 ± 8) who were admitted to the Clinic for Cognitive Disorders, at Karolinska University Hospital.

Astrocyte Signature in Alzheimer's Disease Continuum through a Multi-PET Tracer Imaging Perspective.

Reactive astrogliosis is an early event in the continuum of Alzheimer's disease (AD). Current advances in positron emission tomography (PET) imaging provide ways of assessing reactive astrogliosis in the living brain. In this review, we revisit clinical PET imaging and in vitro findings using the multi-tracer approach, and point out that reactive astrogliosis precedes the deposition of Aβ plaques, tau pathology, and neurodegeneration in AD.

Blood β-synuclein is related to amyloid PET positivity in memory clinic patients.

Introduction: β-synuclein is an emerging blood biomarker to study synaptic degeneration in Alzheimer´s disease (AD), but its relation to amyloid-β (Αβ) pathology is unclear.

Methods: We investigated the association of plasma β-synuclein levels with flutemetamol positron emission tomography (PET) in patients with AD dementia (n = 51), mild cognitive impairment (MCI-Aβ+ n = 18, MCI- Aβ- n = 30), non-AD dementias (n = 22), and non-demented controls (n = 5).

Results: Plasma β-synuclein levels were higher in Aβ+ (AD dementia, MCI-Aβ+) than in Aβ- subjects (non-AD dementias, MCI-Aβ-) with good discrimination of Aβ+ from Aβ- subjects and prediction of Aβ status in MCI individuals.

Crossover of Work Engagement: The Moderating Role of Agreeableness.

Work engagement can cross over from one individual to another, and this process may depend on several factors, such as the work context or individual differences. With this study, we argue that agreeableness, one of the Big five personality measures that characterized empathetic, can be instrumental in the crossover process. Specifically, we hypothesize that agreeableness can facilitate this process so that engagement of an actor can more easily cross over to their partner when either of them or both have high agreeableness.

Alzheimer's disease profiled by fluid and imaging markers: tau PET best predicts cognitive decline.

For early detection of Alzheimer's disease, it is important to find biomarkers with predictive value for disease progression and clinical manifestations, such as cognitive decline. Individuals can now be profiled based on their biomarker status for Aβ42 (A) or tau (T) deposition and neurodegeneration (N). The aim of this study was to compare the cerebrospinal fluid (CSF) and imaging (PET/MR) biomarkers in each ATN category and to assess their ability to predict longitudinal cognitive decline.

Assessment of Tau Pathology as Measured by 18F-THK5317 and 18F-Flortaucipir PET and Their Relation to Brain Atrophy and Cognition in Alzheimer's Disease.

Background: In Alzheimer's disease (AD), the abnormal aggregation of hyperphosphorylated tau leads to synaptic dysfunction and neurodegeneration. Recently developed tau PET imaging tracers are candidate biomarkers for diagnosis and staging of AD.

Objective: We aimed to investigate the discriminative ability of 18F-THK5317 and 18F-flortaucipir tracers and brain atrophy at different stages of AD, and their respective associations with cognition.

Clinical validity of increased cortical binding of tau ligands of the THK family and PBB3 on PET as biomarkers for Alzheimer's disease in the context of a structured 5-phase development framework.

Purpose: The research community has focused on defining reliable biomarkers for the early detection of the pathological hallmarks of Alzheimer's disease (AD). In 2017, the Geneva AD Biomarker Roadmap initiative adapted the framework for the systematic validation of oncological biomarkers to AD, with the aim to accelerate their development and implementation in clinical practice. The aim of this work was to assess the validation status of tau PET ligands of the THK family and PBB3 as imaging biomarkers for AD, based on the Biomarker Roadmap methodology.

The strategic biomarker roadmap for the validation of Alzheimer's diagnostic biomarkers: methodological update.

Background: The 2017 Alzheimer's disease (AD) Strategic Biomarker Roadmap (SBR) structured the validation of AD diagnostic biomarkers into 5 phases, systematically assessing analytical validity (Phases 1-2), clinical validity (Phases 3-4), and clinical utility (Phase 5) through primary and secondary Aims. This framework allows to map knowledge gaps and research priorities, accelerating the route towards clinical implementation. Within an initiative aimed to assess the development of biomarkers of tau pathology, we revised this methodology consistently with progress in AD research.

Comparison of subtyping methods for neuroimaging studies in Alzheimer's disease: a call for harmonization.

Biological subtypes in Alzheimer's disease, originally identified on neuropathological data, have been translated to biomarkers such as structural magnetic resonance imaging and positron emission tomography, to disentangle the heterogeneity within Alzheimer's disease. Although there is methodological variability across studies, comparable characteristics of subtypes are reported at the group level. In this study, we investigated whether group-level similarities translate to individual-level agreement across subtyping methods, in a head-to-head context.

Regional Disconnection in Alzheimer Dementia and Amyloid-Positive Mild Cognitive Impairment: Association Between EEG Functional Connectivity and Brain Glucose Metabolism.

The disconnection hypothesis of Alzheimer's disease (AD) is supported by growing neuroimaging and neurophysiological evidence of altered brain functional connectivity in cognitively impaired individuals. Brain functional modalities such as [F]fluorodeoxyglucose positron-emission tomography ([F]FDG-PET) and electroencephalography (EEG) measure different aspects of synaptic functioning, and can contribute to understanding brain connectivity disruptions in AD. This study investigated the relationship between cortical glucose metabolism and topographical EEG measures of brain functional connectivity in subjects along AD continuum.

[F]THK5317 imaging as a tool for predicting prospective cognitive decline in Alzheimer's disease.

Cross-sectional studies have indicated potential for positron emission tomography (PET) in imaging tau pathology in Alzheimer's disease (AD); however, its prognostic utility remains unproven. In a longitudinal, multi-modal, prognostic study of cognitive decline, 20 patients with a clinical biomarker-based diagnosis in the AD spectrum (mild cognitive impairment or dementia and a positive amyloid-beta PET scan) were recruited from the Cognitive Clinic at Karolinska University Hospital. The participants underwent baseline neuropsychological assessment, PET imaging with [F]THK5317, [C]PIB and [F]FDG, magnetic resonance imaging, and in a subgroup cerebrospinal fluid (CSF) sampling, with clinical follow-up after a median 48 months (interquartile range = 32:56).

Cross-interaction of tau PET tracers with monoamine oxidase B: evidence from in silico modelling and in vivo imaging.

Purpose: Several tracers have been designed for tracking the abnormal accumulation of tau pathology in vivo. Recently, concerns have been raised about the sources of off-target binding for these tracers; inconclusive data propose binding for some tracers to monoamine oxidase B (MAO-B).

Methods: Molecular docking and dynamics simulations were used to estimate the affinity and free energy for the binding of several tau tracers (FDDNP, THK523, THK5105, THK5317, THK5351, T807 [aka AV-1451, flortaucipir], T808, PBB3, RO-948, MK-6240, JNJ-311 and PI-2620) to MAO-B.

Clinical impact of [F]flutemetamol PET among memory clinic patients with an unclear diagnosis.

Purpose: To investigate the impact of amyloid PET with [F]flutemetamol on diagnosis and treatment management in a cohort of patients attending a tertiary memory clinic in whom, despite extensive cognitive assessment including neuropsychological testing, structural imaging, CSF biomarker analysis and in some cases [F]FDG PET, the diagnosis remained unclear.

Methods: The study population consisted of 207 patients with a clinical diagnosis prior to [F]flutemetamol PET including mild cognitive impairment (MCI; n = 131), Alzheimer's disease (AD; n = 41), non-AD (n = 10), dementia not otherwise specified (dementia NOS; n = 20) and subjective cognitive decline (SCD; n = 5).

Results: Amyloid positivity was found in 53% of MCI, 68% of AD, 20% of non-AD, 20% of dementia NOS, and 60% of SCD patients.

Optimal timing of tau pathology imaging and automatic extraction of a reference region using dynamic [F]THK5317 PET.

[F]THK5317 is a PET tracer for in-vivo imaging of tau associated with Alzheimer's disease (AD). This work aimed to evaluate optimal timing for standardized uptake value ratio (SUVR) measures with [F]THK5317 and automated generation of SUVR-1 and relative cerebral blood flow (R) parametric images. Nine AD patients and nine controls underwent 90 min [F]THK5317 scans.

Tau PET imaging in neurodegenerative tauopathies-still a challenge.

The accumulation of pathological misfolded tau is a feature common to a collective of neurodegenerative disorders known as tauopathies, of which Alzheimer's disease (AD) is the most common. Related tauopathies include progressive supranuclear palsy (PSP), corticobasal syndrome (CBS), Down's syndrome (DS), Parkinson's disease (PD), and dementia with Lewy bodies (DLB). Investigation of the role of tau pathology in the onset and progression of these disorders is now possible due the recent advent of tau-specific ligands for use with positron emission tomography (PET), including first- (e.

Longitudinal tau and metabolic PET imaging in relation to novel CSF tau measures in Alzheimer's disease.

Purpose: Studies comparing CSF and PET tau biomarkers have included only commercial CSF assays examining specific phosphorylation sites (e.g. threonine 181, P-tau) and mid-domain tau (i.

Longitudinal association between astrocyte function and glucose metabolism in autosomal dominant Alzheimer's disease.

Purpose: The spatial resolution of F-fluorodeoxyglucose PET does not allow the specific cellular origin of its signal to be determined, but it is commonly accepted that transport and trapping of F-fluorodeoxyglucose reflects neuronal glucose metabolism. The main frameworks for the diagnosis of Alzheimer's disease suggest that hypometabolism measured with F-fluorodeoxyglucose PET is a biomarker of neuronal injury and neurodegeneration. There is preclinical evidence to suggest that astrocytes contribute, at least partially, to the in vivo F-fluorodeoxyglucose PET signal.

Data driven diagnostic classification in Alzheimer's disease based on different reference regions for normalization of PiB-PET images and correlation with CSF concentrations of Aβ species.

Positron emission tomography (PET) neuroimaging with the Pittsburgh Compound_B (PiB) is widely used to assess amyloid plaque burden. Standard quantification approaches normalize PiB-PET by mean cerebellar gray matter uptake. Previous studies suggested similar pons and white-matter uptake in Alzheimer's disease (AD) and healthy controls (HC), but lack exhaustive comparison of normalization across the three regions, with data-driven diagnostic classification.

Spatial Normalization of F-Flutemetamol PET Images Using an Adaptive Principal-Component Template.

Though currently approved for visual assessment only, there is evidence to suggest that quantification of amyloid-β (Aβ) PET images may reduce interreader variability and aid in the monitoring of treatment effects in clinical trials. Quantification typically involves a regional atlas in standard space, requiring PET images to be spatially normalized. Different uptake patterns in Aβ-positive and Aβ-negative subjects, however, make spatial normalization challenging.

Tau positron emission tomography imaging in tauopathies: The added hurdle of off-target binding.

Ligands targeting tau for use with positron emission tomography have rapidly been developed during the past several years, enabling the in vivo study of tau pathology in patients with Alzheimer's disease and related non-Alzheimer's disease tauopathies. Several candidate compounds have been developed, showing good in vitro characteristics with respect to their ability to bind tau deposits; off-target binding, however, has also been observed. In this short commentary, we briefly summarize the available in vivo and in vitro evidence pertaining to their off-target binding and discuss the different approaches that are needed for the future development of tau positron emission tomography tracers.