Certified normal: Alzheimer's disease biomarkers and normative estimates of cognitive functioning

Hassenstab, Jason; Chasse, Rachel; Grabow, Perri; Benzinger, Tammie L.S.; Fagan, Anne M.; Xiong, Chengjie; Jasielec, Mateusz S.; Grant, Elizabeth; Morris, John C.

doi:10.1016/j.neurobiolaging.2016.03.014

Cited by 50 publications

(50 citation statements)

References 61 publications

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“…The only procedure that may allow an actual refutation should necessarily rely on the use of amyloid deposition markers to rule out the influence of prodromal or even preclinical AD cases. Consequently, this is a very important (see [77-79]) but not the only limitation of our study. The sample was relatively small, particularly the control-low group (see also the reduced number of younger APOE4 carriers), limiting the generalization of the present results.…”

Section: Discussionmentioning

confidence: 97%

APOE ε4 Genotype and Cognitive Reserve Effects on the Cognitive Functioning of Healthy Elders

López

Turrero

Delgado

et al. 2017

Dement Geriatr Cogn Disord

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Aim: To test the association between cognitive performance and APOE genotype, and to assess potential modifications of this association by sociodemographic and neuroanatomical factors in a sample of 74 healthy elders. Methods: Firstly, we explored the isolated role of the APOE ɛ4 genotype (i.e., APOE4) in different neuropsychological tests, and then the effects of its interaction with sociodemographic (i.e., age, gender, and educational level) and neuroanatomical (i.e., hippocampal volumes) variables. Subsequently, we performed the same analyses after dividing the sample into two subgroups according to their Mini-Mental State Examination scores (control-high group ≥29 and control-low group < 29). Results: In the whole group, APOE4 carriers exhibited a significantly poorer execution in several cognitive domains including global cognitive functioning, episodic memory, verbal fluency, and naming. This effect was more noticeable in older and less educated subjects. The separated analyses revealed that APOE4 carriers in the control-low group exhibited lower scores in global cognitive functioning and episodic memory, while no effects were observed in the control-high group. Neither gender nor hippocampal volumes showed a significant interaction effect with APOE genotype. Conclusions: Current results point out that APOE4 genotype influences healthy aged cognition, although factors such age or educational attainment seem to modulate its effects.

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Section: Discussionmentioning

confidence: 97%

APOE ε4 Genotype and Cognitive Reserve Effects on the Cognitive Functioning of Healthy Elders

López

Turrero

Delgado

et al. 2017

Dement Geriatr Cogn Disord

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“…Previous SuperAger findings combined with our own finding of biomarker differences among Optimal versus Typical Memory Performers and Optimal Maintainers versus Non-Maintainers suggests that a certain proportion of what is considered “normal age-related decline” is in fact potentially pathological. In vivo imaging of amyloid and more recently tau, provides an unprecedented opportunity to improve normative data by incorporating biomarker-corrected normative data (Hassenstab et al, 2016). …”

Section: Discussionmentioning

confidence: 99%

Neuroimaging markers associated with maintenance of optimal memory performance in late-life

et al. 2017

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Background Age-related memory decline has been well-documented; however, some individuals reach their 8th–10th decade while maintaining strong memory performance. Objective To determine which demographic and biomarker factors differentiated top memory performers (aged 75+, top 20% for memory) from their peers and whether top memory performance was maintained over 3 years. Methods Clinically normal adults (n = 125, CDR = 0; age: 79.5 ± 3.57 years) from the Harvard Aging Brain Study underwent cognitive testing and neuroimaging (amyloid PET, MRI) at baseline and 3-year follow-up. Participants were grouped into Optimal (n = 25) vs. Typical (n = 100) performers using performance on 3 challenging memory measures. Non-parametric tests were used to compare groups. Results There were no differences in age, sex, or education between Optimal vs. Typical performers. The Optimal group performed better in Processing Speed (p = 0.016) and Executive Functioning (p < 0.001). Optimal performers had larger hippocampal volumes at baseline compared with Typical Performers (p = 0.027) but no differences in amyloid burden (p = 0.442). Twenty-three of the 25 Optimal performers had longitudinal data and16 maintained top memory performance while 7 declined. Non-Maintainers additionally declined in Executive Functioning but not Processing Speed. Longitudinally, there were no hippocampal volume differences between Maintainers and Non-Maintainers, however Non-Maintainers exhibited higher amyloid burden at baseline in contrast with Maintainers (p = 0.008). Conclusions Excellent memory performance in late life does not guarantee protection against cognitive decline. Those who maintain an optimal memory into the 8th and 9th decades may have lower levels of AD pathology.

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“…In-depth descriptions have been published elsewhere (Aschenbrenner et al, 2015a; Johnson et al, 2009). Tests of memory and attention were selected as both have previously shown to be sensitive to preclinical levels of pathology (Aschenbrenner et al, 2015a, 2015b; Hassenstab et al, 2016; Monsell et al, 2014)…”

Section: Methodsmentioning

confidence: 99%

AV-1451 PET imaging of tau pathology in preclinical Alzheimer disease: Defining a summary measure

et al. 2017

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Utilizing [18F]-AV-1451 tau positron emission tomography (PET) as an Alzheimer disease (AD) biomarker will require identification of brain regions that are most important in detecting elevated tau pathology in preclinical AD. Here, we utilized an unsupervised learning, data-driven approach to identify brain regions whose tau PET is most informative in discriminating low and high levels of [18F]-AV-1451 binding. 84 cognitively normal participants who had undergone AV-1451 PET imaging were used in a sparse k-means clustering with resampling analysis to identify the regions most informative in dividing a cognitively normal population into high tau and low tau groups. The highest-weighted FreeSurfer regions of interest (ROIs) separating these groups were the entorhinal cortex, amygdala, lateral occipital cortex, and inferior temporal cortex, and an average SUVR in these four ROIs was used as a summary metric for AV-1451 uptake. We propose an AV-1451 SUVR cut-off of 1.25 to define high tau as described by imaging. This spatial distribution of tau PET is a more widespread pattern than that predicted by pathological staging schemes. Our data-derived metric was validated first in this cognitively normal cohort by correlating with early measures of cognitive dysfunction, and with disease progression as measured by β-amyloid PET imaging. We additionally validated this summary metric in a cohort of 13 Alzheimer disease patients, and showed that this measure correlates with cognitive dysfunction and β-amyloid PET imaging in a diseased population.

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Certified normal: Alzheimer's disease biomarkers and normative estimates of cognitive functioning

Cited by 50 publications

References 61 publications

<b><i>APOE</i></b> ε4 Genotype and Cognitive Reserve Effects on the Cognitive Functioning of Healthy Elders

<b><i>APOE</i></b> ε4 Genotype and Cognitive Reserve Effects on the Cognitive Functioning of Healthy Elders

Neuroimaging markers associated with maintenance of optimal memory performance in late-life

AV-1451 PET imaging of tau pathology in preclinical Alzheimer disease: Defining a summary measure

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