Brain Functional Flexibility and its Relationship to the Preclinical Stage of Alzheimer’s Disease.

Background: Characterizing pathological and functional features of the preclinical stage of Alzheimer’s Disease (AD) is essential as Amyloid beta (Aβ) and tau, the pathological hallmarks of AD, start to accumulate years prior to the onset of clinical symptoms. Whether Aβ and/or tau are related to the brain’s ability to functionally reconfigure in time (functional flexibility) remains unclear despite its important role in behavior and cognition.

Method: We included 233 cognitively unimpaired individuals with family history of AD from the PREVENT‐AD cohort who underwent both Positron Emission Tomography (PET) and functional Magnetic Resonance Imaging (fMRI).

Longitudinal change of cerebral amyloid and tau and its association with plasma biomarkers in preclinical Alzheimer's disease.

Background: For medical purposes, amyloid‐beta (Aβ) and tau biomarkers are typically dichotomized into positive (+) and negative (‐) status to define individuals with Alzheimer’s disease (AD) pathology. Nevertheless, such AD proteinopathies start accumulating years before reaching clinically‐defined abnormality thresholds. We examined longitudinal change in PET Aβ and tau in cognitively unimpaired (CU) individuals; then we explored their baseline plasma levels and demographic characteristics.

Autoradiographic comparison of [11C]PiB and [18F]NAV4694 in post‐mortem human brain tissue.

Background: To evaluate the in vitro binding properties of [C]PiB and [F]NAV4694 head‐to‐head in post‐mortem human brain tissue.

Method: Autoradiography was used to assess uptake of [C]PiB and [F]NAV4694 in control (CN) and Alzheimer’s disease (AD) autopsy‐confirmed brain tissues. The study focuses on the analysis of the prefrontal cortex, inferior parietal cortex, posterior cingulate cortex and hippocampus sections in 11 CN and 11 AD cases.

Inflammation in the white matter relates to core Alzheimer's disease pathophysiological processes.

Background: In‐vivo PET imaging studies have demonstrated neuroinflammation (microglia reactivity) in the neocortex of Alzheimer’s disease (AD) patients. However, the extent and implication of microglia reactivity in white matter regions remains unclear. Here, we explored microglia reactivity in white matter using PET imaging of the translocator protein (TSPO) in relation to core AD biomarkers (amyloid, tau, and astrogliosis), microstructural damage, and cognitive decline.

APOEε4 drives microglial activation in the medial temporal cortex in individuals across the AD spectrum.

Background: Microglial activation is an early phenomenon in Alzheimer’s disease (AD) that may occur prior to and independently of amyloid‐β (Aβ) aggregation. Compelling experimental evidence suggests that the apolipoprotein E ε4 (ε4) allele may be a culprit of early microglial activation in AD. However, it is unclear whether the ε4 genotype is associated with microglial reactivity in the living human brain.

A‐T+ PET participants in preclinical AD: Clinical progression and concordance with fluid markers.

Background: Amyloid‐negative tau‐positive PET (A‐T+) participants have been reported in several studies. We assessed the prevalence and characteristics of A‐T+ participants in a cohort of cognitively unimpaired individuals with a first‐degree family history of Alzheimer’s disease (AD) dementia.

Method: We studied 252 participants from the longitudinal PREVENT‐AD cohort (mean cognitive follow‐up = 3.

Plasma p‐tau217 outperforms [F]FDG‐PET in identifying biological Alzheimer’s disease in atypical and early‐onset dementia.

Background: Biomarkers promise to significantly improve the differential diagnosis of Alzheimer’s disease (AD). Plasma biomarkers, such as phosphorylated tau (p‐tau), have shown potential in diagnosing AD with high accuracy. Unlike the widely‐used [18 F]FDG‐PET diagnostic biomarker in clinical practice, plasma p‐tau is specific to AD and can provide an affordable and scalable diagnostic tool.

Longitudinal association between synaptic dysfunction and Alzheimer’s disease pathology in preclinical Alzheimer’s disease.

Background: Synapse loss in Alzheimer’s disease (AD) is correlates closely with cognitive impairment. Recent evidence suggests that synapse loss is promoted by amyloid‐beta, leading in turn to the spread of tau pathology. We sought to assess: 1) the association in positron emission tomography (PET) between several cerebrospinal fluid (CSF) synaptic biomarkers and amyloid and tau burden, as well as their annual change; and 2) the potential clinical utility of these synaptic biomarkers in preclinical AD.

Using a Bayesian workflow approach to define the optimal level of anatomy/functionality voxels clustering for the prediction of tau propagation and cortical loss in Alzheimer’s disease.

Background: Tau aggregates in Alzheimer’s disease (AD) induce loss of synapses and neurons, leading to cognitive impairment. Predicting tau and neurodegeneration temporal evolution could be used for prognostication and for assessing results of therapeutic trials. Tau PET and MRI volumetry are reliable markers of disease stage, but cost and radiation protection considerations limit research measurement frequency, lowering the accuracy of disease progression modeling.

The role of biofluid markers in predicting near‐term cognitive impairment.

Background: PET biomarkers have proven valuable for identifying cognitively unimpaired (CU) individuals at‐risk of near‐term clinical progression. Given the increasing interest in plasma biomarkers to detect Alzheimer’s pathology, we assessed levels of amyloid (Aβ) and tau (p‐tau217 and p‐tau181) biomarkers in plasma (A+T+) in CU individuals as predictors of clinical progression to mild cognitive impairment (MCI). We then repeated these analyses using cerebrospinal fluid (CSF) and PET biomarkers.

Sleep, Alzheimer pathology and risk of clinical progression in cognitively unimpaired older adults.

Background: Increasing evidence suggests a link between sleep and Alzheimer disease’s (AD) pathology and cognitive decline. We investigated whether sleep disturbances might be accompanied by faster AD pathology accumulation and/or cognitive decline before the onset of cognitive symptoms.

Method: We investigated cross‐sectional and longitudinal associations between sleep quality, AD pathology and cognition in 220 participants from the PREVENT‐AD cohort.

Using a Bayesian workflow approach to define the optimal level of anatomy/functionality voxels clustering for the prediction of tau propagation and cortical loss in Alzheimer's disease.

Background: Tau aggregates in Alzheimer’s disease (AD) induce loss of synapses and neurons, leading to cognitive impairment. Predicting tau and neurodegeneration temporal evolution could be used for prognostication and for assessing results of therapeutic trials. Tau PET and MRI volumetry are reliable markers of disease stage, but cost and radiation protection considerations limit research measurement frequency, lowering the accuracy of disease progression modeling.

Longitudinal association between synaptic dysfunction and Alzheimer's disease pathology in preclinical Alzheimer's disease.

Background: Synapse loss in Alzheimer’s disease (AD) is correlates closely with cognitive impairment. Recent evidence suggests that synapse loss is promoted by amyloid‐beta, leading in turn to the spread of tau pathology. We sought to assess: 1) the association in positron emission tomography (PET) between several cerebrospinal fluid (CSF) synaptic biomarkers and amyloid and tau burden, as well as their annual change; and 2) the potential clinical utility of these synaptic biomarkers in preclinical AD.

Brain Functional Flexibility and its Relationship to the Preclinical Stage of Alzheimer’s Disease.

Background: Characterizing pathological and functional features of the preclinical stage of Alzheimer’s Disease (AD) is essential as Amyloid beta (Aß) and tau, the pathological hallmarks of AD, start to accumulate years prior to the onset of clinical symptoms. Whether Aß and/or tau are related to the brain’s ability to functionally reconfigure in time (functional flexibility) remains unclear despite its important role in behavior and cognition.

Method: We included 233 cognitively unimpaired individuals with family history of AD from the PREVENT‐AD cohort who underwent both Positron Emission Tomography (PET) and functional Magnetic Resonance Imaging (fMRI).

A‐T+ PET participants in preclinical AD: Clinical progression and concordance with fluid markers.

Background: Amyloid‐negative tau‐positive PET (A‐T+) participants have been reported in several studies. We assessed the prevalence and characteristics of A‐T+ participants in a cohort of cognitively unimpaired individuals with a first‐degree family history of Alzheimer’s disease (AD) dementia.

Method: We studied 252 participants from the longitudinal PREVENT‐AD cohort (mean cognitive follow‐up = 3.

The role of biofluid markers in predicting near‐term cognitive impairment.

Background: PET biomarkers have proven valuable for identifying cognitively unimpaired (CU) individuals at‐risk of near‐term clinical progression. Given the increasing interest in plasma biomarkers to detect Alzheimer’s pathology, we assessed levels of amyloid (Aß42/40) and tau (p‐tau217 and p‐tau181) biomarkers in plasma (A+T+plasma) in CU individuals as predictors of clinical progression to mild cognitive impairment (MCI). We then repeated these analyses using cerebrospinal fluid (CSF) and PET biomarkers.

Inflammation in the white matter relates to core Alzheimer's disease pathophysiological processes.

Background: In‐vivo PET imaging studies have demonstrated neuroinflammation (microglia reactivity) in the neocortex of Alzheimer’s disease (AD) patients. However, the extent and implication of microglia reactivity in white matter regions remains unclear. Here, we explored microglia reactivity in white matter using PET imaging of the translocator protein (TSPO) in relation to core AD biomarkers (amyloid, tau, and astrogliosis), microstructural damage, and cognitive decline.

Comparison of Plasma p-tau217 and [F]FDG-PET for Identifying Alzheimer Disease in People With Early-Onset or Atypical Dementia.

Background And Objectives: To compare the diagnostic performance of an immunoassay for plasma concentrations of phosphorylated tau (p-tau) 217 with visual assessments of fluorine-18 fluorodeoxyglucose [F]FDG-PET in individuals who meet appropriate use criteria for Alzheimer dementia (AD) biomarker assessments.

Methods: We performed a retrospective analysis of individuals with early-onset (age <65 years at onset) and/or atypical dementia (features other than memory at onset), who were evaluated at a tertiary care memory clinic. All participants underwent measurements of CSF biomarkers (Aβ42, p-tau181, and total tau levels), as well as [F]FDG-PET scans, amyloid-PET scans, and plasma p-tau217 quantifications.

Plasma phosphorylated tau181 outperforms [F] fluorodeoxyglucose positron emission tomography in the identification of early Alzheimer disease.

Background And Purpose: This study was undertaken to compare the performance of plasma p-tau181 with that of [F]fluorodeoxyglucose (FDG) positron emission tomography (PET) in the identification of early biological Alzheimer disease (AD).

Methods: We included 533 cognitively impaired participants from the Alzheimer's Disease Neuroimaging Initiative. Participants underwent PET scans, biofluid collection, and cognitive tests.

Cryo-EM structure of Alzheimer's disease tau filaments with PET ligand MK-6240.

Positron Emission Tomography (PET) ligands have advanced Alzheimer's disease (AD) diagnosis and treatment. Using autoradiography and cryo-EM, we identify AD brain tissue with elevated tau burden, purify filaments, and determine the structure of second-generation high avidity PET ligand MK-6240 at 2.31 Å resolution, which bound at a 1:1 ratio within the cleft of tau paired-helical filament (PHF), engaging with glutamine 351, lysine 353, and isoleucine 360.

Tau follows principal axes of functional and structural brain organization in Alzheimer's disease.

Alzheimer's disease (AD) is a brain network disorder where pathological proteins accumulate through networks and drive cognitive decline. Yet, the role of network connectivity in facilitating this accumulation remains unclear. Using in-vivo multimodal imaging, we show that the distribution of tau and reactive microglia in humans follows spatial patterns of connectivity variation, the so-called gradients of brain organization.

Public transit mobility as a leading indicator of COVID-19 transmission in 40 cities during the first wave of the pandemic.

Background: The rapid global emergence of the COVID-19 pandemic in early 2020 created urgent demand for leading indicators to track the spread of the virus and assess the consequences of public health measures designed to limit transmission. Public transit mobility, which has been shown to be responsive to previous societal disruptions such as disease outbreaks and terrorist attacks, emerged as an early candidate.

Methods: We conducted a longitudinal ecological study of the association between public transit mobility reductions and COVID-19 transmission using publicly available data from a public transit app in 40 global cities from March 16 to April 12, 2020.

Plasma p-tau217 predicts cognitive impairments up to ten years before onset in normal older adults.

Importance: Positron emission tomography (PET) biomarkers are the gold standard for detection of Alzheimer amyloid and tau . Such imaging can identify cognitively unimpaired (CU) individuals who will subsequently develop cognitive impartment (CI). Plasma biomarkers would be more practical than PET or even cerebrospinal fluid (CSF) assays in clinical settings.