Regional amyloid accumulation and cognitive decline in initially amyloid-negative adults

Farrell, Michelle E.; Chen, Xi; Rundle, Melissa M.; Chan, Micaela Y.; Wig, Gagan S.; Park, Denise C.

doi:10.1212/wnl.0000000000006469

Cited by 88 publications

(88 citation statements)

References 49 publications

(61 reference statements)

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“…These Cohen's kappa was used to determine the degree of concordance between visual assessment and the six different thresholds BP ND binding potential, GMM Gaussian mixture modelling, SUVr standardized uptake value ratio previous studies found that individuals in the subthreshold range can be on the path to further neurodegeneration (i.e. atrophy, tau pathology, hypometabolism) [38,41], and are at risk of further amyloid accumulation, cognitive decline and clinical progression [25,26,39]. In the present study, we defined the grey zone making use of two thresholds obtained in a data-driven way.…”

Section: Discussionmentioning

confidence: 99%

Grey zone amyloid burden affects memory function: the SCIENCe project

Ebenau

Verfaillie

Bosch

et al. 2020

Eur J Nucl Med Mol Imaging

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Purpose To determine thresholds for amyloid beta pathology and evaluate associations with longitudinal memory performance with the aim to identify a grey zone of early amyloid beta accumulation and investigate its clinical relevance. Methods We included 162 cognitively normal participants with subjective cognitive decline from the SCIENCe cohort (64 ± 8 years, 38% F, MMSE 29 ± 1). Each underwent a dynamic [ 18 F] florbetapir PET scan, a T1-weighted MRI scan and longitudinal memory assessments (RAVLT delayed recall, n = 655 examinations). PET scans were visually assessed as amyloid positive/ negative. Additionally, we calculated the mean binding potential (BP ND) and standardized uptake value ratio (SUVr 50-70) for an a priori defined composite region of interest. We determined six amyloid positivity thresholds using various data-driven methods (resulting thresholds: BP ND 0.19/0.23/0.29; SUVr 1.28/1.34/1.43). We used Cohen's kappa to analyse concordance between thresholds and visual assessment. Next, we used quantiles to divide the sample into two to five subgroups of equal numbers (median, tertiles, quartiles, quintiles), and operationalized a grey zone as the range between the thresholds (0.19-0.29 BP ND / 1.28-1.43 SUVr). We used linear mixed models to determine associations between thresholds and memory slope. Results As determined by visual assessment, 24% of 162 individuals were amyloid positive. Concordance with visual assessment was comparable but slightly higher for BP ND thresholds (range kappa 0.65-0.70 versus 0.60-0.63). All thresholds predicted memory decline (range beta − 0.29 to − 0.21, all p < 0.05). Analyses in subgroups showed memory slopes gradually became steeper with higher amyloid load (all p for trend < 0.05). Participants with a low amyloid burden benefited from a practice effect (i.e. increase in memory), whilst high amyloid burden was associated with memory decline. Memory slopes of individuals in the grey zone were intermediate. Conclusion We provide evidence that not only high but also grey zone amyloid burden subtly impacts memory function. Therefore, in case a binary classification is required, we suggest using a relatively low threshold which includes grey zone amyloid pathology.

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Section: Discussionmentioning

confidence: 99%

Grey zone amyloid burden affects memory function: the SCIENCe project

Ebenau

Verfaillie

Bosch

et al. 2020

Eur J Nucl Med Mol Imaging

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“…In previous studies, preclinical AD has often been defined by abnormal levels of A β biomarkers (e.g., using positron emission tomography, PET), typically using thresholds associated with quite advanced A β pathology 3 . We suggest that such overt changes are preceded by subthreshold changes that occur within the normal range of the biomarkers, but which may still have meaningful biological and clinical effects 4–7 . A focus on biomarker positivity at conservative thresholds may therefore result in misleadingly late estimates for when preclinical AD starts.…”

Section: Introductionmentioning

confidence: 92%

The A4 study: β‐amyloid and cognition in 4432 cognitively unimpaired adults

Insel

Donohue

Sperling

et al. 2020

Ann Clin Transl Neurol

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Objective: To clarify the preclinical stage of Alzheimer's disease by estimating when b-amyloid accumulation first becomes associated with changes in cognition. Methods: Here we studied a large group (N = 4432) of cognitively unimpaired individuals who were screened for inclusion in the A4 trial (age 65-85) to assess the effect of subthreshold levels of b-amyloid on cognition and to identify which cognitive domains first become affected. Results: b-amyloid accumulation was linked to significant cognitive dysfunction in cognitively unimpaired participants with subthreshold levels of b-amyloid in multiple measures of memory (Logical Memory Delayed Recall, P = 0.03; Free and Cued Selective Reminding Test, P < 0.001), the Preclinical Alzheimer's Cognitive Composite (P = 0.01), and was marginally associated with decreased executive function (Digit Symbol Substitution, P = 0.07). Significantly, decreased cognitive scores were associated with suprathreshold levels of b-amyloid, across all measures (P < 0.05). The Free and Cued Selective Reminding Test, a list recall memory test, appeared most sensitive to b-amyloid -related decreases in average cognitive scores, outperforming all other cognitive domains, including the narrative recall memory test, Logical Memory. Interpretation: Clinical trials for cognitively unimpaired b-amyloid-positive individuals will include a large number of individuals where mechanisms downstream from b-amyloid pathology are already activated. These findings have implications for primary and secondary prevention of Alzheimer's disease. 776

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“…The neuritic plaques and A␤ are consistent components of AD pathology [14], which is the predominant cause of dementia. However, the distribution pattern of A␤ pathology, which is found at least as early and diffusely in the neocortex as the tau pathology, is found first in most regions of the neocortex [15] but is generally not or much less related to cognitive changes than the tau pathology [16][17][18]. With a slowly progressing condition, mild cognitive impairment is a transition from normal cognition that precedes dementia, and is very poorly described [19].…”

Section: Introductionmentioning

confidence: 99%

Putative Survival Advantages in Young Apolipoprotein ɛ4 Carriers are Associated with Increased Neural Stress

Smith

Ashford

Perfetti³

2019

JAD

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Inheritance of a single copy of the apolipoprotein E (APOE) 4 allele increases risk of Alzheimer's disease (AD) by 3-4-fold, with homozygosity associated with a 12-16-fold increase in risk, relative to 3 allele homozygosity. There is a decreased risk associated with the APOE 2 allele. The pathological consequence of APOE genotype has led to intense efforts to understand the mechanistic basis of the interplay between APOE status and loss of synapses. Numerous 4 allele-related associations have been reported with the potential relevance of these associations to the pathogenesis of AD unknown at this time. In primarily young subjects, we have reviewed a representative body of literature on 4 allele-associations related to the following: cardiovascular responses; impacts on reproduction and fetal development; co-morbidities; resistance to infectious disease; responses to head injury; biochemical differences possibly related to neural stress; and brain structure-function differences. In addition, the literature on the association between the 4 allele and cognitive performance has been reviewed comprehensively. The weight-of-the-evidence supports the hypothesis that possession of the ancestral 4 allele in youth is associated with improved fitness during fetal development, infancy, and youth relative to the more recently appearing 3 allele, at the expense of decreased fitness in old age, which is substantially improved by the 3 allele. However, possession of the 4 allele is also associated with higher levels of synaptic macromolecular turnover, which likely stresses basic cellular neuroplasticity mechanisms. Clinical trials of potential AD therapeutics should consider APOE status as an enrollment criterion. conceptualization of AD pathology dates from 1968 when Blessed et al. showed in elderly individuals that the NFTs correlated with the severity of the dementia, though the neuritic plaques, which contain cerebral amyloid-␤ (A␤), did not [2]. A major advance in understanding AD pathology was the demonstration that AD pathology predominantly affects the posterior-temporal, inferior parietal, posterior cingulate, and medial temporal region [3], with a characteristic pattern of progression beginning in the entorhinal cortex involving neurofibrillary (NF)

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Regional amyloid accumulation and cognitive decline in initially amyloid-negative adults

Cited by 88 publications

References 49 publications

Grey zone amyloid burden affects memory function: the SCIENCe project

Grey zone amyloid burden affects memory function: the SCIENCe project

The A4 study: β‐amyloid and cognition in 4432 cognitively unimpaired adults

Putative Survival Advantages in Young Apolipoprotein ɛ4 Carriers are Associated with Increased Neural Stress

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