Evidence suggesting common mechanisms underlie contralateral and ipsilateral negative BOLD responses in the human visual cortex.

The task-evoked positive BOLD response (PBR) to a unilateral visual hemi-field stimulation is often accompanied by robust and sustained contralateral as well as ipsilateral negative BOLD responses (NBRs) in the visual cortex. The signal characteristics and the neural and/or vascular mechanisms that underlie these two types of NBRs are not completely understood. In this paper, we investigated the properties of these two types of NBRs. We first demonstrated the linearity of both NBRs with respect to stimulus duration. Next, we showed that the hemodynamic response functions (HRFs) of the two NBRs were similar to each other, but significantly different from that of the PBR. Moreover, the subject-wise expressions of the two NBRs were tightly coupled to the degree that the correlation between the two NBRs was significantly higher than the correlation between each NBR and the PBR. However, the activation patterns of the two NBRs did not show a high level of interhemispheric spatial similarity, and the functional connectivity between them was not different than the interhemispheric functional connectivity between the NBRs and PBR. Finally, while attention did modulate both NBRs, the attention-related changes in their HRFs were similar. Our findings suggest that the two NBRs might be generated through common neural and/or vascular mechanisms involving distal/deep brain regions that project to the two hemispheres.

Landmark-guided region-based spatial normalization for functional magnetic resonance imaging.

As the size of the neuroimaging cohorts being increased to address key questions in the field of cognitive neuroscience, cognitive aging, and neurodegenerative diseases, the accuracy of the spatial normalization as an essential preprocessing step becomes extremely important. Existing spatial normalization methods have poor accuracy particularly when dealing with the highly convoluted human cerebral cortex and when brain morphology is severely altered (e.g., aging populations). To address this shortcoming, we propose a novel spatial normalization technique that takes advantage of the existing surface-based human brain parcellation to automatically identify and match regional landmarks. To simplify the nonlinear whole brain registration, the identified landmarks of each region and its counterpart are registered independently with topology-preserving deformation. Next, the regional warping fields are combined by an inverse distance weighted interpolation technique to have a global warping field for the whole brain. To ensure that the final warping field is topology-preserving, we used simultaneously forward and reverse maps with certain symmetric constraints to yield bijectivity. We have evaluated our proposed solution using both simulated and real (structural and functional) human brain images. Our evaluation shows that our solution can enhance structural correspondence compared to the existing methods. Such improvement also increases the sensitivity and specificity of the functional imaging studies, reducing the required number of subjects and subsequent study costs. We conclude that our proposed solution can effectively substitute existing substandard spatial normalization methods to deal with the demand of large cohorts which is now common in clinical and aging studies.

Patterns of tau pathology identified with 18 F-MK-6240 PET imaging.

INTRODUCTION: Positron emission tomography (PET) imaging for neurofibrillary tau allows investigation of the in vivo spatiotemporal progression of Alzheimer's disease (AD) pathology. We evaluated the suitability of 18 F-MK-6240 in a clinical sample and determined the relationships among 18 F-MK-6240 binding, age, cognition, and cerebrospinal fluid (CSF)-based AD biomarkers. METHODS: Participants (n = 101, 72 ± 9 years, 52% women) underwent amyloid PET, tau PET, structural T1-weighted magnetic resonance imaging, and neuropsychological evaluation. Twenty-one participants had lumbar puncture for CSF measurement of amyloid beta (Aß)42 , tau, and phosphorylated tau (p-tau). RESULTS: 18 F-MK-6240 recapitulated Braak staging and correlated with CSF tau and p-tau, normalized to Aß42 . 18 F-MK-6240 negatively correlated with age across Braak regions in amyloid-positive participants, consistent with greater tau pathology in earlier onset AD. Domain-specific, regional patterns of 18 F-MK-6240 binding were associated with reduced memory, executive, and language performance, but only in amyloid-positive participants. DISCUSSION: 18 F-MK-6240 can approximate Braak staging across the AD continuum and provide region-dependent insights into biomarker-based AD models.

Attenuation of motion artifacts in fMRI using discrete reconstruction of irregular fMRI trajectories (DRIFT).

PURPOSE: Numerous studies report motion as the most detrimental source of noise and artifacts in fMRI. Current motion correction methods fail to completely address the motion problem. Retrospective techniques such as spatial realignment can correct for between-volume misalignment but fail to address within volume contamination and spin-history artifacts. Prospective motion correction can prevent spin-history artifacts but currently cannot update the gradients fast enough to remove k-space filling artifacts, calling for a hybrid approach to fully address these problems. THEORY AND METHODS: Motion can be mathematically formulated into the MR signal equation to describe the motion artifacts at their origin in k-space. From these equations, it is demonstrated that different motions have different effects on the signal. A novel motion correction algorithm is designed from these equations to remove motion-induced artifacts directly in k-space, discrete reconstruction of irregular fMRI trajectory (DRIFT). This method is evaluated rigorously using fMRI simulations and data from a rotating phantom inside the scanner. RESULTS: The results indicate that although some motion types have negligible effects on the MR signal, others produce catastrophic and lasting artifacts even after motion cessation. In simulation, DRIFT is able to remove motion artifacts in the absence of spin history. In a phantom scan, DRIFT significantly attenuates the motion artifacts in the fMRI data. CONCLUSION: Neither prospective nor retrospective motion correction methods could completely remove the motion artifacts from the fMRI data. However, DRIFT, as a retrospective technique, when combined with prospective motion correction, can eliminate a significant portion of motion artifacts.

fMRI-guided white matter connectivity in fluid and crystallized cognitive abilities in healthy adults.

This study examined within-subject differences among three fluid abilities that decline with age: reasoning, episodic memory and processing speed, compared with vocabulary, a crystallized ability that is maintained with age. The data were obtained from the Reference Ability Neural Network (RANN) study from which 221 participants had complete behavioral data for all 12 cognitive tasks, three per ability, along with fMRI and diffusion weighted imaging data. We used fMRI task activation to guide white matter tractography, and generated mean percent signal change in the regions associated with the processing of each ability along with diffusion tensor imaging measures, fractional anisotropy (FA) and mean diffusivity (MD), for each cognitive ability. Qualitatively brain regions associated with vocabulary were more localized and lateralized to the left hemisphere whereas the fluid abilities were associated with brain activations that were more distributed across the brain and bilaterally situated. Using continuous age, we observed smaller correlations between MD and age for white matter tracts connecting brain regions associated with the vocabulary ability than that for the fluid abilities, suggesting that vocabulary white matter tracts were better maintained with age. Furthermore, after multiple comparisons correction and accounting for age, education, and sex, the mean percent signal change for episodic memory showed positive associations with behavioral performance. Overall, the vocabulary ability may be better maintained with age due to the more localized brain regions involved, which places smaller reliance on long distance white matter tracts for signal transduction. These results support the hypothesis that functional activation and white matter structures underlying the vocabulary ability contribute to the ability's greater resistance against aging.

Between-network Functional Connectivity Is Modified by Age and Cognitive Task Domain.

Research on the cognitive neuroscience of aging has identified myriad neurocognitive processes that are affected by the aging process, with a focus on identifying neural correlates of cognitive function in aging. This study aimed to test whether internetwork connectivity among six cognitive networks is sensitive to age-related changes in neural efficiency and cognitive functioning. A factor analytic connectivity approach was used to model network interactions during 11 cognitive tasks grouped into four primary cognitive domains: vocabulary, perceptual speed, fluid reasoning, and episodic memory. Results showed that both age and task domain were related to internetwork connectivity and that some of the connections among the networks were associated with performance on the in-scanner tasks. These findings demonstrate that internetwork connectivity among several cognitive networks is not only affected by aging and task demands but also shows a relationship with task performance. As such, future studies examining internetwork connectivity in aging should consider multiple networks and multiple task conditions to better measure dynamic patterns of network flexibility over the course of cognitive aging.

Brain biomarkers and cognition across adulthood.

Understanding the associations between brain biomarkers (BMs) and cognition across age is of paramount importance. Five hundred and sixty-two participants (19-80 years old, 16 mean years of education) were studied. Data from structural T1, diffusion tensor imaging, fluid-attenuated inversion recovery, and resting-state functional magnetic resonance imaging scans combined with a neuropsychological evaluation were used. More specifically, the measures of cortical, entorhinal, and parahippocampal thickness, hippocampal and striatal volume, default-mode network and fronto-parietal control network, fractional anisotropy (FA), and white matter hyperintensity (WMH) were assessed. z-Scores for three cognitive domains measuring episodic memory, executive function, and speed of processing were computed. Multiple linear regressions and interaction effects between each of the BMs and age on cognition were examined. Adjustments were made for age, sex, education, intracranial volume, and then, further, for general cognition and motion. BMs were significantly associated with cognition. Across the adult lifespan, slow speed was associated with low striatal volume, low FA, and high WMH burden. Poor executive function was associated with low FA, while poor memory was associated with high WMH burden. After adjustments, results were significant for the associations: speed-FA and WMH, memory-entorhinal thickness. There was also a significant interaction between hippocampal volume and age in memory. In age-stratified analyses, the most significant associations for the young group occurred between FA and executive function, WMH, and memory, while for the old group, between entorhinal thickness and speed, and WMH and speed, executive function. Unique sets of BMs can explain variation in specific cognitive domains across adulthood. Such results provide essential information about the neurobiology of aging.

Dynamic Patterns of Brain Structure-Behavior Correlation Across the Lifespan.

Although the brain/behavior correlation is one of the premises of cognitive neuroscience, there is still no consensus about the relationship between brain measures and cognitive function, and only little is known about the effect of age on this relationship. We investigated the age-associated variations on the spatial patterns of cortical thickness correlates of four cognitive domains. We showed that the spatial distribution of the cortical thickness correlates of each cognitive domain is distinctive and depicts varying age-association differences across the adult lifespan. Specifically, the present study provides evidence that distinct cognitive domains are associated with unique structural patterns in three adulthood periods: Early, middle, and late adulthood. These findings suggest a dynamic interaction between multiple neural substrates supporting each cognitive domain across the adult lifespan.

ß-Amyloid Deposition Is Associated with Decreased Right Prefrontal Activation during Task Switching among Cognitively Normal Elderly.

The accumulation of ß-amyloid (Aß) peptides, a pathological hallmark of Alzheimer's disease (AD), has been associated with functional alterations, often in an episodic memory system with a particular emphasis on medial temporal lobe function. The topography of Aß deposition, however, largely overlaps with frontoparietal control (FPC) regions implicated in cognitive control that has been shown to be impaired in early mild AD. To understand the neural mechanism underlying early changes in cognitive control with AD, we examined the impact of Aß deposition on task-evoked FPC activation using functional magnetic resonance imaging (fMRI) in humans. Forty-three young and 62 cognitively normal older adults underwent an fMRI session during an executive contextual task in which task difficulty varied: single (either letter case or vowel/consonant judgment task) vs dual (switching between letter case and vowel/consonant decisions) task. Older subjects additionally completed (18)F-florbetaben positron emission tomography scans and were classified as either amyloid positive (Aß+) or negative (Aß-). Consistent with previous reports, age-related increases in brain activity were found in FPC regions commonly identified across groups. For both task conditions, Aß-related increases in brain activity were found compared with baseline activity. For higher cognitive control load, however, Aß+ elderly showed reduced task-switching activation in the right inferior frontal cortex. Our findings suggest that with Aß deposition, brain activation in the cognitive control region reaches a maximum with lower control demand and decreases with higher control demand, which may underlie early impairment in cognitive control with AD progression. SIGNIFICANCE STATEMENT: The accumulation of ß-amyloid (Aß) peptides, a pathological hallmark of Alzheimer's disease, spatially overlaps with frontoparietal control (FPC) regions implicated in cognitive control, but the impact of Aß deposition on FPC regions is largely unknown. Using functional magnetic resonance imaging with a task-switching task, we found Aß-related increases in FPC regions compared with baseline activity. For higher cognitive control load, however, Aß-related hypoactivity was found in the right inferior frontal cortex, a region highly implicated in cognitive control. The findings suggest that with Aß deposition, task-related brain activity may reach a plateau early and undergo downstream pathways of neural dysfunction, which may relate to the early impairment of cognitive control seen in the progression of Aß pathology.

Cognitive neuroscience neuroimaging repository for the adult lifespan.

With recent advances in neuroimaging technology, it is now possible to image human brain function in vivo, which revolutionized the cognitive neuroscience field. However, like any other newly developed technique, the acquisition of neuroimaging data is costly and logistically challenging. Furthermore, studying human cognition requires acquiring a large amount of neuroimaging data, which might not be feasible to do by every researcher in the field. Here, we describe our group's efforts to acquire one of the largest neuroimaging datasets that aims to investigate the neural substrates of age-related cognitive decline, which will be made available to share with other investigators. Our neuroimaging repository includes up to 14 different functional images for more than 486 subjects across the entire adult lifespan in addition to their 3 structural images. Currently, data from 234 participants have been acquired, including all 14 functional and 3 structural images, which is planned to increased to 375 participants in the next few years. A complete battery of neuropsychological tests was also administered to all participants. The neuroimaging and accompanying psychometric data will be available through an online and easy-to-use data sharing website.

BOLD neurovascular coupling does not change significantly with normal aging.

Studies of cognitive function that compare the blood oxygenation level dependent (BOLD) signal across age groups often require the assumption that neurovascular coupling does not change with age. Tests of this assumption have produced mixed results regarding the strength of the coupling and its relative time course. Using deconvolution, we found that age does not have a significant effect on the time course of the hemodynamic impulse response function or on the slope of the BOLD versus stimulus duration relationship. These results suggest that in cognitive studies of healthy aging, group differences in BOLD activation are likely due to age-related changes in cognitive-neural interactions and information processing rather than to impairments in neurovascular coupling. Hum Brain Mapp 38:3538-3551, 2017. © 2017 Wiley Periodicals, Inc.

Brain atrophy can introduce age-related differences in BOLD response.

Use of functional magnetic resonance imaging (fMRI) in studies of aging is often hampered by uncertainty about age-related differences in the amplitude and timing of the blood oxygenation level dependent (BOLD) response (i.e., hemodynamic impulse response function (HRF)). Such uncertainty introduces a significant challenge in the interpretation of the fMRI results. Even though this issue has been extensively investigated in the field of neuroimaging, there is currently no consensus about the existence and potential sources of age-related hemodynamic alterations. Using an event-related fMRI experiment with two robust and well-studied stimuli (visual and auditory), we detected a significant age-related difference in the amplitude of response to auditory stimulus. Accounting for brain atrophy by circumventing spatial normalization and processing the data in subjects' native space eliminated these observed differences. In addition, we simulated fMRI data using age differences in brain morphology while controlling HRF shape. Analyzing these simulated fMRI data using standard image processing resulted in differences in HRF amplitude, which were eliminated when the data were analyzed in subjects' native space. Our results indicate that age-related atrophy introduces inaccuracy in co-registration to standard space, which subsequently appears as attenuation in BOLD response amplitude. Our finding could explain some of the existing contradictory reports regarding age-related differences in the fMRI BOLD responses. Hum Brain Mapp 38:3402-3414, 2017. © 2017 Wiley Periodicals, Inc.

Selective association between cortical thickness and reference abilities in normal aging.

A previous study of reference abilities and cortical thickness reported that association between reference abilities and cortical thickness summarized over large ROIs suppressed was suppressed after controlling for mean cortical thickness and global cognition. In this manuscript, we showed that preserving detailed spatial patterns of cortical thickness can identify reference-ability-specific association besides the association explained by global cognition and mean cortical thickness. We identified associations between cortical thickness and 3 cognitive reference abilities after controlling for mean thickness, global cognition, and linear chronological age: (1) memory, (2) perceptual speed, and (3) vocabulary. Global cognition was correlated with mean overall thickness but also was found to have a regionally specific pattern of associations. Nonlinear associations between cortical thickness and cognition were not observed, neither were nonlinear age effects. Age-by-thickness interactions were also absent. This implies that all thickness-cognition relations and age associations are independent of age and that consequently no age range is inherently special, since brain-behavioral findings are invariant across the whole age range.

White matter tract covariance patterns predict age-declining cognitive abilities.

UNLABELLED: Previous studies investigating the relationship of white matter (WM) integrity to cognitive abilities and aging have either focused on a global measure or a few selected WM tracts. Ideally, contribution from all of the WM tracts should be evaluated at the same time. However, the high collinearity among WM tracts precludes systematic examination of WM tracts simultaneously without sacrificing statistical power due to stringent multiple-comparison corrections. Multivariate covariance techniques enable comprehensive simultaneous examination of all WM tracts without being penalized for high collinearity among observations. METHOD: In this study, Scaled Subprofile Modeling (SSM) was applied to the mean integrity of 18 major WM tracts to extract covariance patterns that optimally predicted four cognitive abilities (perceptual speed, episodic memory, fluid reasoning, and vocabulary) in 346 participants across ages 20 to 79years old. Using expression of the covariance patterns, age-independent effects of white matter integrity on cognition and the indirect effect of WM integrity on age-related differences in cognition were tested separately, but inferences from the indirect analyses were cautiously made given that cross-sectional data set was used in the analysis. RESULTS: A separate covariance pattern was identified that significantly predicted each cognitive ability after controlling for age except for vocabulary, but the age by WM covariance pattern interaction was not significant for any of the three abilities. Furthermore, each of the patterns mediated the effect of age on the respective cognitive ability. A distinct set of WM tracts was most influential in each of the three patterns. The WM covariance pattern accounting for fluid reasoning showed the most number of influential WM tracts whereas the episodic memory pattern showed the least number. CONCLUSION: Specific patterns of WM tracts make significant contributions to the age-related differences in perceptual speed, episodic memory, and fluid reasoning but not vocabulary. Other measures of brain health will need to be explored to reveal the major influences on the vocabulary ability.

Making cognitive latent variables manifest: distinct neural networks for fluid reasoning and processing speed.

Cognitive psychologists posit several specific cognitive abilities that are measured with sets of cognitive tasks. Tasks that purportedly tap a specific underlying cognitive ability are strongly correlated with one another, whereas performances on tasks that tap different cognitive abilities are less strongly correlated. For these reasons, latent variables are often considered optimal for describing individual differences in cognitive abilities. Although latent variables cannot be directly observed, all cognitive tasks representing a specific latent ability should have a common neural underpinning. Here, we show that cognitive tasks representing one ability (i.e., either perceptual speed or fluid reasoning) had a neural activation pattern distinct from that of tasks in the other ability. One hundred six participants between the ages of 20 and 77 years were imaged in an fMRI scanner while performing six cognitive tasks, three representing each cognitive ability. Consistent with prior research, behavioral performance on these six tasks clustered into the two abilities based on their patterns of individual differences and tasks postulated to represent one ability showed higher similarity across individuals than tasks postulated to represent a different ability. This finding was extended in the current report to the spatial resemblance of the task-related activation patterns: The topographic similarity of the mean activation maps for tasks postulated to reflect the same reference ability was higher than for tasks postulated to reflect a different reference ability. Furthermore, for any task pairing, behavioral and topographic similarities of underlying activation patterns are strongly linked. These findings suggest that differences in the strengths of correlations between various cognitive tasks may be because of the degree of overlap in the neural structures that are active when the tasks are being performed. Thus, the latent variable postulated to account for correlations at a behavioral level may reflect topographic similarities in the neural activation across different brain regions.

The Reference Ability Neural Network Study: motivation, design, and initial feasibility analyses.

We introduce and describe the Reference Ability Neural Network Study and provide initial feasibility data. Based on analyses of large test batteries administered to individuals ranging from young to old, four latent variables, or reference abilities (RAs) that capture the majority of the variance in age-related cognitive change have been identified: episodic memory, fluid reasoning, perceptual speed, and vocabulary. We aim to determine whether spatial fMRI networks can be derived that are uniquely associated with the performance of each reference ability. We plan to image 375 healthy adults (50 per decade from age 20 to 50; 75 per decade from age 50 to 80) while performing a set of 12 cognitive tasks. Data on 174 participants are reported here. Three tasks were grouped a priori into each of the four reference ability domains. We first assessed to what extent both cognitive task scores and activation patterns readily show convergent and discriminant validity, i.e. increased similarity between tasks within the same domain and decreased similarity between tasks between domains, respectively. Block-based time-series analysis of each individual task was conducted for each participant via general linear modeling. We partialled activation common to all tasks out of the imaging data. For both test scores and activation topographies, we then calculated correlations for each of 66 possible pairings of tasks, and compared the magnitude of correlation of tasks within reference ability domains to that of tasks between domains. For the behavioral data, globally there were significantly stronger inter-task correlations within than between domains. When examining individual abilities, 3 of the domains also met these criteria but memory reached only borderline significance. Overall there was greater topographic similarity within reference abilities than between them (p<0.0001), but when examined individually, statistical significance was reached only for episodic memory and perceptual speed. We then turned to a multivariate technique, linear indicator regression analysis, to derive four unique linear combinations of Principal Components (PC) of imaging data that were associated with each RA. We investigated the ability of the identified PCs to predict the reference domain associated with the activation of individual subjects for individual tasks. Median accuracy rates for associating component task activation with a particular reference ability were quite good: memory: 82%; reasoning: 87%; speed: 84%; vocabulary: 77%. These results demonstrate that even using basic GLM analysis, the topography of activation of tasks within a domain is more similar than tasks between domains. The follow-up regression analyses suggest that all tasks with each RA rely on a common network, unique to that RA. Our ultimate goal is to better characterize these RA neural networks and then study how their expression changes across the age span. Our hope is that by focusing on these networks associated with key features of cognitive aging, as opposed to task-related activation associated with individual tasks, we will be able to advance our knowledge regarding the key brain changes that underlie cognitive aging.

APOE ε4 and risk for Alzheimer's disease: do regionally distributed white matter hyperintensities play a role?

BACKGROUND: We previously demonstrated that parietal lobe white matter hyperintensities (WMH) increase the risk for Alzheimer's disease (AD). Here, we examined whether individuals with apolipoprotein E gene (APOE ε4) have increased parietal WMH volume. METHODS: Participants were from the Washington Heights-Inwood Columbia Aging Project (WHICAP; n = 694, 47 with dementia) in northern Manhattan and the Etude Santé Psychologique Prévalence Risques et Traitement study (ESPRIT; n = 539, 8 with dementia) in Montpellier. The association between regional WMH and APOE ε4 was examined separately in each group and then in a combined analysis. RESULTS: In WHICAP, ε4 carriers had higher WMH volume particularly in parietal and occipital lobes. In ESPRIT, ε4 carriers had elevated WMH particularly in parietal and temporal lobes. In the combined analysis, ε4 carriers had higher WMH in parietal and occipital lobes. Increased WMH volume was associated with increased frequency of dementia irrespective of APOE ε4 status; those with the ε4 were more likely to have dementia if they also had increased parietal WMH. CONCLUSIONS: APOE ε4 is associated with increased parietal lobe WMH.

Pulsatility analysis of the circle of Willis.

Purpose: To evaluate the phenomenological significance of cerebral blood pulsatility imaging in aging research. Methods: N = 38 subjects from 20 to 72 years of age (24 females) were imaged with ultrafast MRI with a sampling rate of 100 ms and simultaneous acquisition of pulse oximetry data. Of these, 28 subjects had acceptable MRI and pulse data, with 16 subjects between 20 and 28 years of age, and 12 subjects between 61 and 72 years of age. Pulse amplitude in the circle of Willis was assessed with the recently developed method of analytic phase projection to extract blood volume waveforms. Results: Arteries in the circle of Willis showed pulsatility in the MRI for both the young and old age groups. Pulse amplitude in the circle of Willis significantly increased with age (p = 0.01) but was independent of gender, heart rate, and head motion during MRI. Discussion and conclusion: Increased pulse wave amplitude in the circle of Willis in the elderly suggests a phenomenological significance of cerebral blood pulsatility imaging in aging research. The physiologic origin of increased pulse amplitude (increased pulse pressure vs. change in arterial morphology vs. re-shaping of pulse waveforms caused by the heart, and possible interaction with cerebrospinal fluid pulsatility) requires further investigation.

In vivo tau is associated with change in memory and processing speed, but not reasoning, in cognitively unimpaired older adults.

The relationship between tau deposition and cognitive decline in cognitively healthy older adults is still unclear. The tau PET tracer 18F-MK-6240 has shown favorable imaging characteristics to identify early tau deposition in aging. We evaluated the relationship between in vivo tau levels (18F-MK-6240) and retrospective cognitive change over 5 years in episodic memory, processing speed, and reasoning. For tau quantification, a set of regions of interest (ROIs) was selected a priori based on previous literature: (1) total-ROI comprising selected areas, (2) medial temporal lobe-ROI, and (3) lateral temporal lobe-ROI and cingulate/parietal lobe-ROI. Higher tau burden in most ROIs was associated with a steeper decline in memory and speed. There were no associations between tau and reasoning change. The novelty of this finding is that tau burden may affect not only episodic memory, a well-established finding but also processing speed. Our finding reinforces the notion that early tau deposition in areas related to Alzheimer's disease is associated with cognitive decline in cognitively unimpaired individuals, even in a sample with low amyloid-ß pathology.

Remote Associations Between Tau and Cortical Amyloid-ß Are Stage-Dependent.

Background: Histopathologic studies of Alzheimer's disease (AD) suggest that extracellular amyloid-ß (Aß) plaques promote the spread of neurofibrillary tau tangles. However, these two proteinopathies initiate in spatially distinct brain regions, so how they interact during AD progression is unclear. Objective: In this study, we utilized Aß and tau positron emission tomography (PET) scans from 572 older subjects (476 healthy controls (HC), 14 with mild cognitive impairment (MCI), 82 with mild AD), at varying stages of the disease, to investigate to what degree tau is associated with cortical Aß deposition. Methods: Using multiple linear regression models and a pseudo-longitudinal ordering technique, we investigated remote tau-Aß associations in four pathologic phases of AD progression based on tau spread: 1) no-tau, 2) pre-acceleration, 3) acceleration, and 4) post-acceleration. Results: No significant tau-Aß association was detected in the no-tau phase. In the pre-acceleration phase, the earliest stage of tau deposition, associations emerged between regional tau in medial temporal lobe (MTL) (i.e., entorhinal cortex, parahippocampal gyrus) and cortical Aß in lateral temporal lobe regions. The strongest tau-Aß associations were found in the acceleration phase, in which tau in MTL regions was strongly associated with cortical Aß (i.e., temporal and frontal lobes regions). Strikingly, in the post-acceleration phase, including 96% of symptomatic subjects, tau-Aß associations were no longer significant. Conclusions: The results indicate that associations between tau and Aß are stage-dependent, which could have important implications for understanding the interplay between these two proteinopathies during the progressive stages of AD.