Decreased meta-memory is associated with early tauopathy in cognitively unimpaired older adults

The ability to accurately judge memory efficiency (meta-memory monitoring) for newly learned (episodic) information, is decreased in older adults and even worse in Alzheimer's disease (AD), whereas no differences have been found for semantic meta-memory. The pathological substrates of this phenomenon are poorly understood. Here, we examine the association between meta-memory monitoring for episodic and semantic information to the two major proteinopathies in AD: amyloid (Aβ) and tau pathology in a group of cognitively unimpaired older adults. All participants underwent multi-tracer PET and meta-memory monitoring was assessed using a feeling-of-knowing (FOK) task for non-famous (episodic) and famous (semantic) face-name pairs. Whole brain voxel-wise correlations between meta-memory and PET data were conducted (controlling for memory), as well as confirmatory region-of-interest analyses. Participants had reduced episodic FOK compared to semantic FOK. Decreased episodic FOK was related to tauopathy in the medial temporal lobe regions, including the entorhinal cortex and temporal pole, whereas decreased semantic FOK was related to increased tau in regions associated with the semantic knowledge network. No association was found with Aβ-pathology. Alterations in the ability to accurately judge memory efficiency (in the absence of memory decline) may be a sensitive clinical indicator of AD pathophysiology in the pre-symptomatic phase

On the mechanisms governing gas penetration into a tokamak plasma during a massive gas injection

A new 1D radial fluid code, IMAGINE, is used to simulate the penetration of gas into a tokamak plasma during a massive gas injection (MGI). The main result is that the gas is in general strongly braked as it reaches the plasma, due to mechanisms related to charge exchange and (to a smaller extent) recombination. As a result, only a fraction of the gas penetrates into the plasma. Also, a shock wave is created in the gas which propagates away from the plasma, braking and compressing the incoming gas. Simulation results are quantitatively consistent, at least in terms of orders of magnitude, with experimental data for a D 2 MGI into a JET Ohmic plasma. Simulations of MGI into the background plasma surrounding a runaway electron beam show that if the background electron density is too high, the gas may not penetrate, suggesting a possible explanation for the recent results of Reux et al in JET (2015 Nucl. Fusion 55 093013)

Lower novelty-related locus coeruleus function is associated with A beta-related cognitive decline in clinically healthy individuals

Animal and human imaging research reported that the presence of cortical Alzheimer's Disease's (AD) neuropathology, beta-amyloid and neurofibrillary tau, is associated with altered neuronal activity and circuitry failure, together facilitating clinical progression. The locus coeruleus (LC), one of the initial subcortical regions harboring pretangle hyperphosphorylated tau, has widespread connections to the cortex modulating cognition. Here we investigate whether LC's in-vivo neuronal activity and functional connectivity (FC) are associated with cognitive decline in conjunction with beta-amyloid. We combined functional MRI of a novel versus repeated face-name paradigm, beta-amyloid-PET and longitudinal cognitive data of 128 cognitively unimpaired older individuals. We show that LC activity and LC-FC with amygdala and hippocampus was higher during novelty. We also demonstrated that lower novelty-related LC activity and LC-FC with hippocampus and parahippocampus were associated with steeper beta-amyloid-related cognitive decline. Our results demonstrate the potential of LC's functional properties as a gauge to identify individuals at-risk for AD-related cognitive decline.Older individuals exhibiting diminished function of the locus coeruleus while learning new information show faster cognitive decline that is typical for Alzheimer's disease

Lower novelty-related locus coeruleus function is associated with A beta-related cognitive decline in clinically healthy individuals

Animal and human imaging research reported that the presence of cortical Alzheimer's Disease's (AD) neuropathology, beta-amyloid and neurofibrillary tau, is associated with altered neuronal activity and circuitry failure, together facilitating clinical progression. The locus coeruleus (LC), one of the initial subcortical regions harboring pretangle hyperphosphorylated tau, has widespread connections to the cortex modulating cognition. Here we investigate whether LC's in-vivo neuronal activity and functional connectivity (FC) are associated with cognitive decline in conjunction with beta-amyloid. We combined functional MRI of a novel versus repeated face-name paradigm, beta-amyloid-PET and longitudinal cognitive data of 128 cognitively unimpaired older individuals. We show that LC activity and LC-FC with amygdala and hippocampus was higher during novelty. We also demonstrated that lower novelty-related LC activity and LC-FC with hippocampus and parahippocampus were associated with steeper beta-amyloid-related cognitive decline. Our results demonstrate the potential of LC's functional properties as a gauge to identify individuals at-risk for AD-related cognitive decline.Older individuals exhibiting diminished function of the locus coeruleus while learning new information show faster cognitive decline that is typical for Alzheimer's disease

Identifying Sensitive Measures of Cognitive Decline at Different Clinical Stages of Alzheimer's Disease

Copyright © INS. Published by Cambridge University Press, 2020.Objective: Alzheimer's disease (AD) studies are increasingly targeting earlier (pre)clinical populations, in which the expected degree of observable cognitive decline over a certain time interval is reduced as compared to the dementia stage. Consequently, endpoints to capture early cognitive changes require refinement. We aimed to determine the sensitivity to decline of widely applied neuropsychological tests at different clinical stages of AD as outlined in the National Institute on Aging-Alzheimer's Association (NIA-AA) research framework. Method: Amyloid-positive individuals (as determined by positron emission tomography or cerebrospinal fluid) with longitudinal neuropsychological assessments available were included from four well-defined study cohorts and subsequently classified among the NIA-AA stages. For each stage, we investigated the sensitivity to decline of 17 individual neuropsychological tests using linear mixed models. Results: 1103 participants (age = 70.54 ± 8.7, 47% female) were included: n = 120 Stage 1, n = 206 Stage 2, n = 467 Stage 3 and n = 309 Stage 4. Neuropsychological tests were differentially sensitive to decline across stages. For example, Category Fluency captured significant 1-year decline as early as Stage 1 (β =-.58, p <.001). Word List Delayed Recall (β =-.22, p <.05) and Trail Making Test (β = 6.2, p <.05) became sensitive to 1-year decline in Stage 2, whereas the Mini-Mental State Examination did not capture 1-year decline until Stage 3 (β =-1.13, p <.001) and 4 (β =-2.23, p <.001). Conclusions: We demonstrated that commonly used neuropsychological tests differ in their ability to capture decline depending on clinical stage within the AD continuum (preclinical to dementia). This implies that stage-specific cognitive endpoints are needed to accurately assess disease progression and increase the chance of successful treatment evaluation in AD

Defining the Lowest Threshold for Amyloid-PET to Predict Future Cognitive Decline and Amyloid Accumulation

IntroductionAs clinical trials move toward earlier intervention, we sought to redefine the beta-amyloid (A beta)-PET threshold based on the lowest point in a baseline distribution that robustly predicts future A beta accumulation and cognitive decline in 3 independent samples of clinically normal individuals.MethodsSequential A beta cutoffs were tested to identify the lowest cutoff associated with future change in cognition (Preclinical Alzheimer Cognitive Composite [PACC]) and A beta-PET in clinically normal participants from the Harvard Aging Brain Study (n = 342), Australian Imaging, Biomarker and Lifestyle study of aging (n = 157), and Alzheimer's Disease Neuroimaging Initiative (n = 356).ResultsWithin samples, cutoffs derived from future A beta-PET accumulation and PACC decline converged on the same inflection point, beyond which trajectories diverged from normal. Across samples, optimal cutoffs fell within a short range (Centiloid 15-18.5).DiscussionThese optimized thresholds can help to inform future research and clinical trials targeting early A beta. Threshold convergence raises the possibility of contemporaneous early changes in A beta and cognition

Comparing PET and MRI Biomarkers Predicting Cognitive Decline in Preclinical Alzheimer Disease

Objective To compare how structural MRI, fluorodeoxyglucose (FDG), and flortaucipir (FTP) PET signals predict cognitive decline in high-amyloid vs low-amyloid participants with the goal of determining which biomarker combination would result in the highest increase of statistical power for prevention trials. Methods In this prospective cohort study, we analyzed data from clinically normal adults from the Harvard Aging Brain Study with MRI, FDG, FTP, and Pittsburgh compound B (PiB)-PET acquired within a year and prospective cognitive evaluations over a mean 3-year follow-up. We focused analyses on predefined regions of interest: inferior temporal, isthmus cingulate, hippocampus, and entorhinal cortex. Cognition was assessed with the Preclinical Alzheimer's Cognitive Composite. We evaluated the association between biomarkers and cognitive decline using linear mixed-effect models with random intercepts and slopes, adjusting for demographics. We generated power curves simulating prevention trials. Results Data from 131 participants (52 women, age 73.98 +/- 8.29 years) were analyzed in the study. In separate models, most biomarkers had a closer association with cognitive decline in the high-PiB compared to the low-PiB participants. A backward stepwise regression including all biomarkers demonstrated that only neocortical PiB, entorhinal FTP, and entorhinal FDG were independent predictors of subsequent cognitive decline. Power analyses revealed that using both high PiB and low entorhinal FDG as inclusion criteria reduced 3-fold the number of participants needed in a hypothetical trial compared to using only high PiB. Discussion In preclinical Alzheimer disease, entorhinal hypometabolism is a strong and independent predictor of subsequent cognitive decline, making FDG a potentially useful biomarker to increase power in clinical trials. Classification of Evidence This study provides Class II evidence that in people with preclinical Alzheimer disease, entorhinal hypometabolism identified by FDG-PET is predictive of subsequent cognitive decline

Decreased meta-memory is associated with early tauopathy in cognitively unimpaired older adults

The ability to accurately judge memory efficiency (meta-memory monitoring) for newly learned (episodic) information, is decreased in older adults and even worse in Alzheimer's disease (AD), whereas no differences have been found for semantic meta-memory. The pathological substrates of this phenomenon are poorly understood. Here, we examine the association between meta-memory monitoring for episodic and semantic information to the two major proteinopathies in AD: amyloid (Aβ) and tau pathology in a group of cognitively unimpaired older adults. All participants underwent multi-tracer PET and meta-memory monitoring was assessed using a feeling-of-knowing (FOK) task for non-famous (episodic) and famous (semantic) face-name pairs. Whole brain voxel-wise correlations between meta-memory and PET data were conducted (controlling for memory), as well as confirmatory region-of-interest analyses. Participants had reduced episodic FOK compared to semantic FOK. Decreased episodic FOK was related to tauopathy in the medial temporal lobe regions, including the entorhinal cortex and temporal pole, whereas decreased semantic FOK was related to increased tau in regions associated with the semantic knowledge network. No association was found with Aβ-pathology. Alterations in the ability to accurately judge memory efficiency (in the absence of memory decline) may be a sensitive clinical indicator of AD pathophysiology in the pre-symptomatic phase

In vivo and neuropathology data support locus coeruleus integrity as indicator of Alzheimer's disease pathology and cognitive decline

Several autopsy studies recognize the locus coeruleus (LC) as the initial site of hyperphosphorylated TAU aggregation, and as the number of LC neurons harboring TAU increases, TAU pathology emerges throughout the cortex. By conjointly using dedicated MRI measures of LC integrity and TAU and amyloid PET-imaging, we aimed to address the question whether in vivo LC measures relate to initial cortical patterns of Alzheimer’s disease (AD) fibrillar proteinopathies or cognitive dysfunction in 174 cognitively unimpaired and impaired older individuals with longitudinal cognitive measures. To guide our interpretations, we verified these associations in autopsy data from 1524 Religious Orders Study and Rush Memory and Aging Project and 2145 National Alzheimer’s Coordinating Center cases providing three different LC measures (pigmentation, tangle density and neuronal density), Braak staging, beta-amyloid and longitudinal cognitive measures. Lower LC integrity was associated with elevated TAU deposition in the entorhinal cortex among unimpaired individuals, consistent with postmortem correlations between LC tangle density and successive Braak staging. LC pigmentation ratings correlated with LC neuronal density but not with LC tangle density, and were particularly worse at advanced Braak stages. In the context of elevated beta-amyloid, lower LC integrity and greater cortical tangle density were associated with greater TAU burden beyond the medial temporal lobe and retrospective memory decline. These findings support neuropathologic data in which early LC TAU accumulation relates to disease progression, and identify LC integrity as a promising indicator of initial AD-related processes and subtle changes in cognitive trajectories of preclinical AD