Dynamic Amyloid and Metabolic Signatures of Delayed Recall Performance within the Clinical Spectrum of Alzheimer's Disease.

Associations between pathophysiological events and cognitive measures provide insights regarding brain networks affected during the clinical progression of Alzheimer's disease (AD). In this study, we assessed patients' scores in two delayed episodic memory tests, and investigated their associations with regional amyloid deposition and brain metabolism across the clinical spectrum of AD. We assessed the clinical, neuropsychological, structural, and positron emission tomography (PET) baseline measures of participants from the Alzheimer's Disease Neuroimaging Initiative.

[C]Martinostat PET analysis reveals reduced HDAC I availability in Alzheimer's disease.

Alzheimer's disease (AD) is characterized by the brain accumulation of amyloid-β and tau proteins. A growing body of literature suggests that epigenetic dysregulations play a role in the interplay of hallmark proteinopathies with neurodegeneration and cognitive impairment. Here, we aim to characterize an epigenetic dysregulation associated with the brain deposition of amyloid-β and tau proteins.

Preclinical longitudinal assessment of KG207-M as a disease-modifying Alzheimer's disease therapeutic.

biomarker abnormalities provide measures to monitor therapeutic interventions targeting amyloid-β pathology as well as its effects on downstream processes associated with Alzheimer's disease pathophysiology. Here, we applied an longitudinal study design combined with imaging and cerebrospinal fluid biomarkers, mirroring those used in human clinical trials to assess the efficacy of a novel brain-penetrating anti-amyloid fusion protein treatment in the McGill-R-Thy1-APP transgenic rat model. The bi-functional fusion protein consisted of a blood-brain barrier crossing single domain antibody (FC5) fused to an amyloid-β oligomer-binding peptide (ABP) via Fc fragment of mouse IgG (FC5-mFc2a-ABP).

Neuropsychiatric symptoms are early indicators of an upcoming metabolic decline in Alzheimer's disease.

Background: Neuropsychiatric symptoms (NPS) are increasingly recognized as early non-cognitive manifestations in the Alzheimer's disease (AD) continuum. However, the role of NPS as an early marker of pathophysiological progression in AD remains unclear. Dominantly inherited AD (DIAD) mutation carriers are young individuals who are destined to develop AD in future due to the full penetrance of the genetic mutation.

Amyloid-beta modulates the association between neurofilament light chain and brain atrophy in Alzheimer's disease.

Neurofilament light chain (NFL) measurement has been gaining strong support as a clinically useful neuronal injury biomarker for various neurodegenerative conditions. However, in Alzheimer's disease (AD), its reflection on regional neuronal injury in the context of amyloid pathology remains unclear. This study included 83 cognitively normal (CN), 160 mild cognitive impairment (MCI), and 73 AD subjects who were further classified based on amyloid-beta (Aβ) status as positive or negative (Aβ+ vs Aβ-).

Topographical distribution of Aβ predicts progression to dementia in Aβ positive mild cognitive impairment.

Introduction: Abnormal brain amyloid beta (Aβ) is typically assessed in vivo using global concentrations from cerebrospinal fluid and positron emission tomography (PET). However, it is unknown whether the assessment of the topographical distribution of Aβ pathology can provide additional information to identify, among global Aβ positive individuals, those destined for dementia.

Methods: We studied 260 amnestic mild cognitive impairment (MCI) subjects who were Aβ-PET positive with [F]florbetapir.

Mild behavioral impairment is associated with β-amyloid but not tau or neurodegeneration in cognitively intact elderly individuals.

Introduction: Mild behavioral impairment (MBI) is characterized by the emergence of neuropsychiatric symptoms in elderly persons. Here, we examine the associations between MBI and Alzheimer's disease (AD) biomarkers in asymptomatic elderly individuals.

Methods: Ninety-six cognitively normal elderly individuals underwent MRI, [ F]AZD4694 β-amyloid-PET, and [ F]MK6240 tau-PET.

Rasagiline, a monoamine oxidase B inhibitor, reduces in vivo [F]THK5351 uptake in progressive supranuclear palsy.

Background: [F]THK5351 is a tau positron emission tomography tracer that has shown promise in quantifying tau distribution in tauopathies such as Alzheimer's disease (AD) and progressive supranuclear palsy (PSP). However, the interpretation of [F]THK5351 uptake has been shown to be confounded by high monoamine oxidase B (MAO-B) availability across the brain in AD.

Objectives: To test the hypothesis that the MAO-B inhibitor, rasagiline reduces [F]THK5351 uptake in PSP.

Aβ-induced vulnerability propagates via the brain's default mode network.

The link between brain amyloid-β (Aβ), metabolism, and dementia symptoms remains a pressing question in Alzheimer's disease. Here, using positron emission tomography ([F]florbetapir tracer for Aβ and [F]FDG tracer for glucose metabolism) with a novel analytical framework, we found that Aβ aggregation within the brain's default mode network leads to regional hypometabolism in distant but functionally connected brain regions. Moreover, we found that an interaction between this hypometabolism with overlapping Aβ aggregation is associated with subsequent cognitive decline.

Regional Amyloid-β Load and White Matter Abnormalities Contribute to Hypometabolism in Alzheimer's Dementia.

We investigated the association between amyloid-β deposition and white matter (WM) integrity as a determinant of brain glucose hypometabolism across the Alzheimer's disease (AD) spectrum. We assessed ninety-six subjects (27 cognitively normal, 49 mild cognitive impairment, and 20 AD dementia) who underwent [F]FDG and [F]Florbetapir positron emission tomography (PET) as well as magnetic resonance imaging (MRI) with diffusion tensor imaging. Among the regions with reduced fractional anisotropy (FA) in the AD group, we selected a voxel of interest in the angular bundle bilaterally for subsequent analyses.

In vivo quantification of neurofibrillary tangles with [F]MK-6240.

Background: Imaging agents capable of quantifying the brain's tau aggregates will allow a more precise staging of Alzheimer's disease (AD). The aim of the present study was to examine the in vitro properties as well as the in vivo kinetics, using gold standard methods, of the novel positron emission tomography (PET) tau imaging agent [F]MK-6240.

Methods: In vitro properties of [F]MK-6240 were estimated with autoradiography in postmortem brain tissues of 14 subjects (seven AD patients and seven age-matched controls).

variant mitigates Alzheimer disease pathophysiology in vivo and postmortem.

Objective: To verify whether polymorphisms are associated with amyloid-β (Aβ) pathology across the spectrum of clinical Alzheimer disease using in vivo and postmortem data from 2 independent cohorts.

Methods: A candidate-gene approach tested the association between 5 genes (28 single nucleotide polymorphisms) and Aβ load measured in vivo by the global [F]florbetapir PET standardized uptake value ratio (SUVR) in 338 Alzheimer's Disease Neuroimaging Initiative participants. Significant results were then tested using plasma Aβ and CSF Aβ and Aβ/phosphorylated tau (Aβ/p-tau) ratio in the same cohort.

Anosognosia predicts default mode network hypometabolism and clinical progression to dementia.

Objective: To identify the pathophysiologic mechanisms and clinical significance of anosognosia for cognitive decline in mild cognitive impairment.

Methods: We stratified 468 patients with amnestic mild cognitive impairment into intact and impaired awareness groups, determined by the discrepancy between the patient and the informant score on the Everyday Cognition questionnaire. Voxel-based linear regression models evaluated the associations between self-awareness status and baseline β-amyloid load, measured by [F]florbetapir, and the relationships between awareness status and regional brain glucose metabolism measured by [F]fluorodeoxyglucose at baseline and at 24-month follow-up.

Amyloid and tau signatures of brain metabolic decline in preclinical Alzheimer's disease.

Purpose: We aimed to determine the amyloid (Aβ) and tau biomarker levels associated with imminent Alzheimer's disease (AD) - related metabolic decline in cognitively normal individuals.

Methods: A threshold analysis was performed in 120 cognitively normal elderly individuals by modelling 2-year declines in brain glucose metabolism measured with [F]fluorodeoxyglucose ([F]FDG) as a function of [F]florbetapir Aβ positron emission tomography (PET) and cerebrospinal fluid phosphorylated tau biomarker thresholds. Additionally, using a novel voxel-wise analytical framework, we determined the sample sizes needed to test an estimated 25% drugeffect with 80% of power on changes in FDG uptake over 2 years at every brain voxel.

Multimodal Imaging in Rat Model Recapitulates Alzheimer's Disease Biomarkers Abnormalities.

Imaging biomarkers are frequently proposed as endpoints for clinical trials targeting brain amyloidosis in Alzheimer's disease (AD); however, the specific impact of amyloid-β (Aβ) aggregation on biomarker abnormalities remains elusive in AD. Using the McGill-R-Thy1-APP transgenic rat as a model of selective Aβ pathology, we characterized the longitudinal progression of abnormalities in biomarkers commonly used in AD research. Middle-aged (9-11 months) transgenic animals (both male and female) displayed mild spatial memory impairments and disrupted cingulate network connectivity measured by resting-state fMRI, even in the absence of hypometabolism (measured with PET [F]FDG) or detectable fibrillary amyloidosis (measured with PET [F]NAV4694).

Identifying incipient dementia individuals using machine learning and amyloid imaging.

Identifying individuals destined to develop Alzheimer's dementia within time frames acceptable for clinical trials constitutes an important challenge to design studies to test emerging disease-modifying therapies. Although amyloid-β protein is the core pathologic feature of Alzheimer's disease, biomarkers of neuronal degeneration are the only ones believed to provide satisfactory predictions of clinical progression within short time frames. Here, we propose a machine learning-based probabilistic method designed to assess the progression to dementia within 24 months, based on the regional information from a single amyloid positron emission tomography scan.

Neuropsychiatric symptoms predict hypometabolism in preclinical Alzheimer disease.

Objective: To identify regional brain metabolic dysfunctions associated with neuropsychiatric symptoms (NPS) in preclinical Alzheimer disease (AD).

Methods: We stratified 115 cognitively normal individuals into preclinical AD (both amyloid and tau pathologies present), asymptomatic at risk for AD (either amyloid or tau pathology present), or healthy controls (no amyloid or tau pathology present) using [F]florbetapir PET and CSF phosphorylated tau biomarkers. Regression and voxel-based regression models evaluated the relationships between baseline NPS measured by the Neuropsychiatric Inventory (NPI) and baseline and 2-year change in metabolism measured by [F]fluorodeoxyglucose (FDG) PET.

Monoamine oxidase B inhibitor, selegiline, reduces F-THK5351 uptake in the human brain.

Background: F-THK5351 is a quinoline-derived tau imaging agent with high affinity to paired helical filaments (PHF). However, high levels of F-THK5351 retention in brain regions thought to contain negligible concentrations of PHF raise questions about the interpretation of the positron emission tomography (PET) signals, particularly given previously described interactions between quinolone derivatives and monoamine oxidase B (MAO-B). Here, we tested the effects of MAO-B inhibition on F-THK5351 brain uptake using PET and autoradiography.

Synergistic interaction between amyloid and tau predicts the progression to dementia.

Introduction: Recent literature proposes that amyloid β (Aβ) and phosphorylated tau (p-tau) synergism accelerates biomarker abnormalities in controls. Yet, it remains to be answered whether this synergism is the driving force behind Alzheimer disease (AD) dementia.

Methods: We stratified 314 mild cognitive impairment individuals using [F]florbetapir positron emission tomography Aβ imaging and cerebrospinal fluid p-tau.

VoxelStats: A MATLAB Package for Multi-Modal Voxel-Wise Brain Image Analysis.

In healthy individuals, behavioral outcomes are highly associated with the variability on brain regional structure or neurochemical phenotypes. Similarly, in the context of neurodegenerative conditions, neuroimaging reveals that cognitive decline is linked to the magnitude of atrophy, neurochemical declines, or concentrations of abnormal protein aggregates across brain regions. However, modeling the effects of multiple regional abnormalities as determinants of cognitive decline at the voxel level remains largely unexplored by multimodal imaging research, given the high computational cost of estimating regression models for every single voxel from various imaging modalities.

Imaging Alzheimer's disease pathophysiology with PET.

Alzheimer's disease (AD) has been reconceptualised as a dynamic pathophysiological process characterized by preclinical, mild cognitive impairment (MCI), and dementia stages. Positron emission tomography (PET) associated with various molecular imaging agents reveals numerous aspects of dementia pathophysiology, such as brain amyloidosis, tau accumulation, neuroreceptor changes, metabolism abnormalities and neuroinflammation in dementia patients. In the context of a growing shift toward presymptomatic early diagnosis and disease-modifying interventions, PET molecular imaging agents provide an unprecedented means of quantifying the AD pathophysiological process, monitoring disease progression, ascertaining whether therapies engage their respective brain molecular targets, as well as quantifying pharmacological responses.

Epistasis analysis links immune cascades and cerebral amyloidosis.

Background: Several lines of evidence suggest the involvement of neuroinflammatory changes in Alzheimer's disease (AD) pathophysiology such as amyloidosis and neurodegeneration. In fact, genome-wide association studies (GWAS) have shown a link between genes involved in neuroinflammation and AD. In order to further investigate whether interactions between candidate genetic variances coding for neuroinflammatory molecules are associated with brain amyloid β (Aβ) fibrillary accumulation, we conducted an epistasis analysis on a pool of genes associated with molecular mediators of inflammation.

White matter abnormalities and structural hippocampal disconnections in amnestic mild cognitive impairment and Alzheimer's disease.

The purpose of this project was to evaluate white matter degeneration and its impact on hippocampal structural connectivity in patients with amnestic mild cognitive impairment, non-amnestic mild cognitive impairment and Alzheimer's disease. We estimated white matter fractional anisotropy, mean diffusivity and hippocampal structural connectivity in two independent cohorts. The ADNI cohort included 108 subjects [25 cognitively normal, 21 amnestic mild cognitive impairment, 47 non-amnestic mild cognitive impairment and 15 Alzheimer's disease].