Longitudinal relationships among biomarkers for Alzheimer disease in the Adult Children Study

Xiong, Chengjie; Jasielec, Mateusz S.; Weng, Hua; Benzinger, Tammie L.S.; Head, Denise; Hassenstab, Jason; Grant, Elizabeth; Sutphen, Courtney L.; Buckles, Virginia; Moulder, Krista L.; Morris, John C.

doi:10.1212/wnl.0000000000002593

Cited by 44 publications

(66 citation statements)

References 37 publications

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“…This result further supports using baseline amyloid burden such as PiB PET as an important biomarker inclusion for secondary prevention trials in AD [1,3], and as a principle component of the newly proposed AD diagnostic criteria [28,29]. Also it has been reported that low baseline CSF Ab 42 leads to significant cognitive decline [7,30], this pattern was consistent in our results. In addition, the rate of change in CSF Ab 42 did not significantly predict the rate of cognitive decline, which is similar to the lack of correlation in previous reports [7].…”

Section: Discussionsupporting

confidence: 91%

“…Consistent with previous reports [4][5][6], we found that higher cerebral amyloid deposition at baseline predicted longitudinal cognitive decline; however, the individual rate of change in amyloid did not. Xiong et al [7] previously evaluated the correlation between the change in amyloid deposition and the change in cognition in sporadic AD and concluded that the correlation was not significant, which is indirectly validated by our result in that the former does not predict the latter. For both cerebral amyloid deposition and CSF Ab 42 , the baseline value is more informative than the longitudinal change in predicting the cognitive decline.…”

Section: Discussionsupporting

confidence: 82%

“…Future research should also directly analyze a sporadic AD cohort and include subgroup analyses for age and ethnic groups to evaluate whether or not our findings replicate. Second, our cognitive composite score is composed of tests that are different from those used in previous studies [4–9]; therefore, caution is needed to interpret the discrepancies in various findings, which may be due to the relative sensitivity of various cognitive tests. Third, there are challenges to interpret the findings when using z‐scores—primarily, the loss of meaningfulness of the raw score and its standard deviation, magnifying small changes, not reflecting the reality of memory declines [36].…”

Section: Discussionmentioning

confidence: 99%

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Simultaneously evaluating the effect of baseline levels and longitudinal changes in disease biomarkers on cognition in dominantly inherited Alzheimer's disease

Wang

Xiong

McDade

et al. 2018

A&D Transl Res & Clin Interv

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IntroductionAs the role of biomarkers is increasing in Alzheimer's disease (AD) clinical trials, it is critical to use a comprehensive temporal biomarker profile that reflects both baseline and longitudinal assessments to establish a more precise association between the change in biomarkers and change in cognition. Because age of onset of dementia symptoms is highly predictable, and there are relatively few age-related comorbidities, the Dominantly Inherited Alzheimer Network autosomal dominant AD population affords a unique opportunity to investigate these relationships in a well-characterized population.MethodsA novel joint statistical model was used to simultaneously evaluate how a comprehensive AD biomarker profile predicts change in cognition using amyloid positron emission tomography (PET), CSF Aβ42, CSF total tau and Ptau181, cortical metabolism using [F-18] fluorodeoxyglucose–PET, and hippocampal volume from participants enrolled in the Dominantly Inherited Alzheimer Network (n = 262) with mean (SD) duration of follow-up of 2.7 (1.2) years.ResultsBaseline amyloid PET levels and CSF biomarkers were associated with change in cognition in contrast to the rate of change of brain metabolism and hippocampal volume, which predicted change in cognition.ConclusionsThis study suggests that the baseline value of amyloid PET and CSF Aβ42 measures may be useful for screening participants for AD trials; however, brain hippocampus atrophy and hypometabolism are only useful as repeated longitudinal assessments for tracking cognition and disease progression. This suggests that measures of amyloid plaques predict future cognitive decline, but only longitudinal measures of neurodegeneration correlate with cognitive decline. The novel statistical model used in this study can be easily applied to any pair of outcomes and has potential to be widely used by the AD research community.

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Section: Discussionsupporting

confidence: 91%

Section: Discussionsupporting

confidence: 82%

Section: Discussionmentioning

confidence: 99%

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Simultaneously evaluating the effect of baseline levels and longitudinal changes in disease biomarkers on cognition in dominantly inherited Alzheimer's disease

Wang

Xiong

McDade

et al. 2018

A&D Transl Res & Clin Interv

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“…A large portion of similar elderly adults as in this study has been reported to have "preclinical AD," 29 which indicates the absence of dementia symptoms in spite of AD neuropathological change in the brain. Accumulating biomarker evidence for a temporal cascade of changes in CSF biomarkers and PET amyloid uptakes 14,15 also supports the concept of preclinical AD with amyloid beta (Aβ) accumulation in the brain as a very early neuropathological process in AD. Neurofibrillary tangles and neuronal death, however, appear to begin during the preclinical phase of AD, but represent a closer event to the cognitive changes.…”

Section: Discussionmentioning

confidence: 82%

Complex interactions underlie racial disparity in the risk of developing Alzheimer's disease dementia

Xiong

Luo

Coble

et al. 2020

Alzheimer's & Dementia

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Introduction We aim to determine racial disparities and their modifying factors in risk for Alzheimer's disease (AD) dementia among cognitively normal individuals 65 years or older. Methods Longitudinal data from the National Alzheimer's Coordinating Center Uniform Data Set on 1229 African Americans (AAs) and 6679 whites were analyzed for the risk of AD using competing risk models with death as a competing event. Results Major AD risk factors modified racial differences which, when statistically significant, occurred only with older age among APOE ε4 negative individuals, but also with younger age among APOE ε4 positive individuals. The racial differences favored AAs among individuals with body mass index (BMI) < 30, but whites among individuals with a high BMI (≥ 30), and were additionally modified by sex, education, hypertension, and smoking status. Conclusions The presence, direction, and relative magnitude of racial disparity for AD represent an interactive function of major AD and cerebrovascular risk factors.

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“…Different covariance matrices for the random effects and different residual variances were assumed between tracers. These models can handle missing, unbalanced, and unevenly spaced longitudinal data and have been used in previous studies of AD [30]. These analyses were done using Proc Mixed, SAS 9.4.…”

Section: Methodsmentioning

confidence: 99%

Comparison of Pittsburgh compound B and florbetapir in cross‐sectional and longitudinal studies

Su¹,

Flores

Wang

et al. 2019

Alz & Dem Diag Ass & Dis Mo

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101

124

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Introduction Quantitative in vivo measurement of brain amyloid burden is important for both research and clinical purposes. However, the existence of multiple imaging tracers presents challenges to the interpretation of such measurements. This study presents a direct comparison of Pittsburgh compound B–based and florbetapir-based amyloid imaging in the same participants from two independent cohorts using a crossover design. Methods Pittsburgh compound B and florbetapir amyloid PET imaging data from three different cohorts were analyzed using previously established pipelines to obtain global amyloid burden measurements. These measurements were converted to the Centiloid scale to allow fair comparison between the two tracers. The mean and inter-individual variability of the two tracers were compared using multivariate linear models both cross-sectionally and longitudinally. Results Global amyloid burden measured using the two tracers were strongly correlated in both cohorts. However, higher variability was observed when florbetapir was used as the imaging tracer. The variability may be partially caused by white matter signal as partial volume correction reduces the variability and improves the correlations between the two tracers. Amyloid burden measured using both tracers was found to be in association with clinical and psychometric measurements. Longitudinal comparison of the two tracers was also performed in similar but separate cohorts whose baseline amyloid load was considered elevated (i.e., amyloid positive). No significant difference was detected in the average annualized rate of change measurements made with these two tracers. Discussion Although the amyloid burden measurements were quite similar using these two tracers as expected, difference was observable even after conversion into the Centiloid scale. Further investigation is warranted to identify optimal strategies to harmonize amyloid imaging data acquired using different tracers.

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Longitudinal relationships among biomarkers for Alzheimer disease in the Adult Children Study

Cited by 44 publications

References 37 publications

Simultaneously evaluating the effect of baseline levels and longitudinal changes in disease biomarkers on cognition in dominantly inherited Alzheimer's disease

Simultaneously evaluating the effect of baseline levels and longitudinal changes in disease biomarkers on cognition in dominantly inherited Alzheimer's disease

Complex interactions underlie racial disparity in the risk of developing Alzheimer's disease dementia

Comparison of Pittsburgh compound B and florbetapir in cross‐sectional and longitudinal studies

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