Quantification of white matter cellularity and damage in preclinical and early symptomatic Alzheimer\u27s disease

Interest in understanding the roles of white matter (WM) inflammation and damage in the pathophysiology of Alzheimer disease (AD) has been growing significantly in recent years. However, in vivo magnetic resonance imaging (MRI) techniques for imaging inflammation are still lacking. An advanced diffusion-based MRI method, neuro-inflammation imaging (NII), has been developed to clinically image and quantify WM inflammation and damage in AD. Here, we employed NII measures in conjunction with cerebrospinal fluid (CSF) biomarker classification (for β-amyloid (Aβ) and neurodegeneration) to evaluate 200 participants in an ongoing study of memory and aging. Elevated NII-derived cellular diffusivity was observed in both preclinical and early symptomatic phases of AD, while disruption of WM integrity, as detected by decreased fractional anisotropy (FA) and increased radial diffusivity (RD), was only observed in the symptomatic phase of AD. This may suggest that WM inflammation occurs earlier than WM damage following abnormal Aβ accumulation in AD. The negative correlation between NII-derived cellular diffusivity and CSF Aβ42 level (a marker of amyloidosis) may indicate that WM inflammation is associated with increasing Aβ burden. NII-derived FA also negatively correlated with CSF t-tau level (a marker of neurodegeneration), suggesting that disruption of WM integrity is associated with increasing neurodegeneration. Our findings demonstrated the capability of NII to simultaneously image and quantify WM cellularity changes and damage in preclinical and early symptomatic AD. NII may serve as a clinically feasible imaging tool to study the individual and composite roles of WM inflammation and damage in AD. Keywords: Inflammation, White matter damage, Diffusion basis spectrum imaging, Neuro-inflammation imaging, Cerebrospinal fluid, Preclinical Alzheimer disease, Early symptomatic Alzheimer disease, Magnetic resonance imagin

Tau and atrophy: domain-specific relationships with cognition.

BackgroundLate-onset Alzheimer's disease (AD) is characterized by primary memory impairment, which then progresses towards severe deficits across cognitive domains. Here, we report how performance in cognitive domains relates to patterns of tau deposition and cortical thickness.MethodsWe analyzed data from 131 amyloid-β positive participants (55 cognitively normal, 46 mild cognitive impairment, 30 AD) of the Alzheimer's Disease Neuroimaging Initiative who underwent magnetic resonance imaging (MRI), flortaucipir (FTP) positron emission tomography, and neuropsychological testing. Surface-based vertex-wise and region-of-interest analyses were conducted between FTP and cognitive test scores, and between cortical thickness and cognitive test scores.ResultsFTP and thickness were differentially related to cognitive performance in several domains. FTP-cognition associations were more widespread than thickness-cognition associations. Further, FTP-cognition patterns reflected cortical systems that underlie different aspects of cognition.ConclusionsOur findings indicate that AD-related decline in domain-specific cognitive performance reflects underlying progression of tau and atrophy into associated brain circuits. They also suggest that tau-PET may have better sensitivity to this decline than MRI-derived measures of cortical thickness

Tau PET and multimodal brain imaging in patients at risk for chronic traumatic encephalopathy.

ObjectiveTo characterize individual and group-level neuroimaging findings in patients at risk for Chronic Traumatic Encephalopathy (CTE).MethodsEleven male patients meeting criteria for Traumatic Encephalopathy Syndrome (TES, median age: 64) underwent neurologic evaluation, 3-Tesla MRI, and PET with [18F]-Flortaucipir (FTP, tau-PET) and [11C]-Pittsburgh compound B (PIB, amyloid-PET). Six patients underwent [18F]-Fluorodeoxyglucose-PET (FDG, glucose metabolism). We assessed imaging findings at the individual patient level, and in group-level comparisons with modality-specific groups of cognitively normal older adults (CN). Tau-PET findings in patients with TES were also compared to a matched group of patients with mild cognitive impairment or dementia due to Alzheimer's disease (AD).ResultsAll patients with TES sustained repetitive head injury participating in impact sports, ten in American football. Three patients met criteria for dementia and eight had mild cognitive impairment. Two patients were amyloid-PET positive and harbored the most severe MRI atrophy, FDG hypometabolism, and FTP-tau PET binding. Among the nine amyloid-negative patients, tau-PET showed either mildly elevated frontotemporal binding, a "dot-like" pattern, or no elevated binding. Medial temporal FTP was mildly elevated in a subset of amyloid-negative patients, but values were considerably lower than in AD. Voxelwise analyses revealed a convergence of imaging abnormalities (higher FTP binding, lower FDG, lower gray matter volumes) in frontotemporal areas in TES compared to controls.ConclusionsMildly elevated tau-PET binding was observed in a subset of amyloid-negative patients at risk for CTE, in a distribution consistent with CTE pathology stages III-IV. FTP-PET may be useful as a biomarker of tau pathology in CTE but is unlikely to be sensitive to early disease stages

Bayesian latent time joint mixed-effects model of progression in the Alzheimer's Disease Neuroimaging Initiative.

IntroductionWe characterize long-term disease dynamics from cognitively healthy to dementia using data from the Alzheimer's Disease Neuroimaging Initiative.MethodsWe apply a latent time joint mixed-effects model to 16 cognitive, functional, biomarker, and imaging outcomes in Alzheimer's Disease Neuroimaging Initiative. Markov chain Monte Carlo methods are used for estimation and inference.ResultsWe find good concordance between latent time and diagnosis. Change in amyloid positron emission tomography shows a moderate correlation with change in cerebrospinal fluid tau (ρ = 0.310) and phosphorylated tau (ρ = 0.294) and weaker correlation with amyloid-β 42 (ρ = 0.176). In comparison to amyloid positron emission tomography, change in volumetric magnetic resonance imaging summaries is more strongly correlated with cognitive measures (e.g., ρ = 0.731 for ventricles and Alzheimer's Disease Assessment Scale). The average disease trends are consistent with the amyloid cascade hypothesis.DiscussionThe latent time joint mixed-effects model can (1) uncover long-term disease trends; (2) estimate the sequence of pathological abnormalities; and (3) provide subject-specific prognostic estimates of the time until onset of symptoms

Prediction of Cognitive Decline in Healthy Older Adults using fMRI

Few studies have examined the extent to which structural and functional MRI, alone and in combination with genetic biomarkers, can predict future cognitive decline in asymptomatic elders. This prospective study evaluated individual and combined contributions of demographic information, genetic risk, hippocampal volume, and fMRI activation for predicting cognitive decline after an 18-month retest interval. Standardized neuropsychological testing, an fMRI semantic memory task (famous name discrimination), and structural MRI (sMRI) were performed on 78 healthy elders (73% female; mean age = 73 years, range = 65 to 88 years). Positive family history of dementia and presence of one or both apolipoprotein E (APOE) ε4 alleles occurred in 51.3% and 33.3% of the sample, respectively. Hippocampal volumes were traced from sMRI scans. At follow-up, all participants underwent a repeat neuropsychological examination. At 18 months, 27 participants (34.6%) declined by at least 1 SD on one of three neuropsychological measures. Using logistic regression, demographic variables (age, years of education, gender) and family history of dementia did not predict future cognitive decline. Greater fMRI activity, absence of an APOE ε4 allele, and larger hippocampal volume were associated with reduced likelihood of cognitive decline. The most effective combination of predictors involved fMRI brain activity and APOE ε4 status. Brain activity measured from task-activated fMRI, in combination with APOE ε4 status, was successful in identifying cognitively intact individuals at greatest risk for developing cognitive decline over a relatively brief time period. These results have implications for enriching prevention clinical trials designed to slow AD progression

Evaluation of neurodegenerative diseases with [18F]flortaucipir : comparison of visual reads with tau PET quantification and cerebrospinal fluid analysis

Contexte & objectifs: L’avènement de biomarqueurs in vivo pour la maladie d’Alzheimer a révolutionné la recherche clinique dans ce domaine. Nous avons comparé le taux de positivité pour le biomarqueur tau (statut-T) dérivé de l’interprétation visuelle des études TEP au [18F]flortaucipir (FTP), de l’analyse quantitative du FTP et de la mesure de la protéine Tau phosphorylée en position 281 (PTau181) dans le liquide céphalorachidien (LCR). Méthodologie: Nous avons inclus 351 participants avec divers diagnostics cliniques provenant de trois cohortes ayant subi une étude TEP au FTP ainsi qu’une mesure du PTau181 dans un délai de 18 mois. Le statut-T a été dérivé de : (1) l’interprétation visuelle à l’aveugle du FTP par deux observateurs; (2) la quantification SUVR (standardized uptake value ratio) du FTP d’une région d’intérêt composite temporale (seuil : SUVR ≥ 1.27) ; (3) la concentration dans le LCR de Elecsys® Phospho-Tau (181P) (Roche Diagnostics) (seuil : PTau181 ≥ 24.5 pg/ml). Résultats: L’interprétation visuelle du FTP a entraîné le plus haut taux de T+, alors que les T+ par quantification SUVR augmentaient progressivement des sujets cognitivement normaux (CN) vers les sujets avec troubles cognitifs légers (TCL) et ceux avec démence de type Alzheimer (DA). Le taux de T+ par PTau181 était intermédiaire à ceux de l’analyse visuelle et quantitative du FTP pour les CN, similaire à la quantification SUVR pour les TCL et plus faible chez les DA. La concordance entre le statut-T par paire de modalité fluctuait de 68% à 76% et variait selon le diagnostic, étant plus élevé chez les DA. L’interprétation visuelle du FTP offrait la plus haute sensibilité (0.96) pour discriminer entre les sujets avec TCL ou DA amyloïde-positifs des sujets CN et non-Alzheimer, mais une spécificité plus faible (0.60). La spécificité était la plus élevée avec la quantification SUVR (0.91) avec une sensibilité de 0.89, alors que la sensibilité (0.73) et la spécificité (0.72) étaient de même niveau pour le PTau181 dans le LCR. Conclusion: Le choix d’un biomarqueur tau pourrait varier selon le stade de la maladie et les objectifs de recherche visant à maximiser la sensibilité ou la spécificité. L’interprétation visuelle des TEP tau augmente la sensibilité en comparaison avec la quantification seule, en particulier dans les stades précoces de la maladie.Background & purpose: The advent of in vivo biomarkers for Alzheimer’s disease (AD) pathology has transformed clinical research in this field. The purpose of this study is to compare rates of tau biomarker positivity (T-status) per the 2018 AD Research Framework derived from [18F]flortaucipir (FTP) PET visual assessment, FTP quantification, and cerebrospinal fluid (CSF) phosphorylated Tau-181 (PTau181) concentration. Methods: We included 351 subjects with varying clinical diagnoses from three cohorts with available FTP PET and CSF PTau181 within 18 months. T-status was derived from: (1) FTP blinded visual assessment by two raters; (2) FTP standardized uptake value ratio (SUVR) quantification from a temporal meta-ROI (threshold: SUVR ≥ 1.27); (3) Elecsys® Phospho-Tau (181P) CSF (Roche Diagnostics) concentrations (threshold: PTau181 ≥ 24.5 pg/ml). Results: FTP visual reads yielded the highest rates of T+, while T+ by SUVR increased progressively from cognitively normal (CN) through mild cognitive impairment (MCI) and to AD dementia. T+ designation by CSF PTau181 was intermediate between FTP visual reads and SUVR values in CN, similar to SUVR in MCI, and lower in AD dementia. Concordance in T- status between modality pairs ranged from 68% to 76% and varied by clinical diagnosis, being highest in patients with AD dementia. In discriminating Aβ+ MCI and AD subjects from healthy controls and non-AD participants, FTP visual assessment was the most sensitive (0.96) but the least specific (0.60) approach. Specificity was highest with FTP SUVR (0.91) with a sensitivity of 0.89. Sensitivity (0.73) and specificity (0.72) were balanced for PTau181. Conclusion: The choice of a tau biomarker may differ by disease stage and research goals that seek to maximize sensitivity or specificity. Visual interpretations of tau PET enhance sensitivity compared to quantification alone, particularly in early disease stages

Regional association of pCASL-MRI with FDG-PET and PiB-PET in people at risk for autosomal dominant Alzheimer's disease.

Autosomal dominant Alzheimer's disease (ADAD) is a small subset of Alzheimer's disease that is genetically determined with 100% penetrance. It provides a valuable window into studying the course of pathologic processes that leads to dementia. Arterial spin labeling (ASL) MRI is a potential AD imaging marker that non-invasively measures cerebral perfusion. In this study, we investigated the relationship of cerebral blood flow measured by pseudo-continuous ASL (pCASL) MRI with measures of cerebral metabolism (FDG PET) and amyloid deposition (Pittsburgh Compound B (PiB) PET). Thirty-one participants at risk for ADAD (age 39 ± 13 years, 19 females) were recruited into this study, and 21 of them received both MRI and FDG and PiB PET scans. Considerable variability was observed in regional correlations between ASL-CBF and FDG across subjects. Both regional hypo-perfusion and hypo-metabolism were associated with amyloid deposition. Cross-sectional analyses of each biomarker as a function of the estimated years to expected dementia diagnosis indicated an inverse relationship of both perfusion and glucose metabolism with amyloid deposition during AD development. These findings indicate that neurovascular dysfunction is associated with amyloid pathology, and also indicate that ASL CBF may serve as a sensitive early biomarker for AD. The direct comparison among the three biomarkers provides complementary information for understanding the pathophysiological process of AD

Functional Magnetic Resonance Imaging of Semantic Memory as a Presymptomatic Biomarker of Alzheimer’s Disease Risk

Extensive research efforts have been directed toward strategies for predicting risk of developing Alzheimer\u27s disease (AD) prior to the appearance of observable symptoms. Existing approaches for early detection of AD vary in terms of their efficacy, invasiveness, and ease of implementation. Several non-invasive magnetic resonance imaging strategies have been developed for predicting decline in cognitively healthy older adults. This review will survey a number of studies, beginning with the development of a famous name discrimination task used to identify neural regions that participate in semantic memory retrieval and to test predictions of several key theories of the role of the hippocampus in memory. This task has revealed medial temporal and neocortical contributions to recent and remote memory retrieval, and it has been used to demonstrate compensatory neural recruitment in older adults, apolipoprotein E ε4 carriers, and amnestic mild cognitive impairment patients. Recently, we have also found that the famous name discrimination task provides predictive value for forecasting episodic memory decline among asymptomatic older adults. Other studies investigating the predictive value of semantic memory tasks will also be presented. We suggest several advantages associated with the use of semantic processing tasks, particularly those based on person identification, in comparison to episodic memory tasks to study AD risk. Future directions for research and potential clinical uses of semantic memory paradigms are also discussed. This article is part of a Special Issue entitled: Imaging Brain Aging and Neurodegenerative disease

Obstructive sleep apnea severity affects amyloid burden in cognitively normal elderly a longitudinal study

Recent evidence suggests that Obstructive Sleep Apnea (OSA) may be a risk factor for developing Mild Cognitive Impairment and Alzheimer’s disease. However, how sleep apnea affects longitudinal risk for Alzheimer’s disease is less well understood.Postprint (author's final draft