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A harmonized longitudinal biomarkers and cognition database for assessing the natural history of preclinical Alzheimer's disease from young adulthood and for designing prevention trials.

ABSTRACT: INTRODUCTION:Large longitudinal biomarkers database focusing on middle age is needed for Alzheimer's disease (AD) prevention. METHODS:Data for cerebrospinal fluid analytes, molecular imaging of cerebral fibrillar ?-amyloid with positron emission tomography, magnetic resonance imaging-based brain structures, and clinical/cognitive outcomes were harmonized across eight AD biomarker studies. Statistical power was estimated. RESULTS:The harmonized database included 7779 participants with clinical/cognitive data: 3542 were 18?65 years at the baseline, 5865 had longitudinal cognitive data for a median of 4.7 years, 2473 participated in the cerebrospinal fluid studies (906 had longitudinal data), 2496 participated in the magnetic resonance imaging studies (1283 had longitudinal data), and 1498 participated in the positron emission tomography amyloid studies (849 had longitudinal data). The database provides adequate power for detecting early biomarker changes, and demonstrates the feasibility of AD prevention trials on middle-aged individuals. DISCUSSION:The harmonized database is an optimum resource to design AD prevention trials decades before symptomatic onset.

SUBMITTER: Xiong C

PROVIDER: S-EPMC6874758 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature

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A harmonized longitudinal biomarkers and cognition database for assessing the natural history of preclinical Alzheimer's disease from young adulthood and for designing prevention trials.

Xiong Chengjie C Luo Jingqin J Agboola Folasade F Li Yan Y Albert Marilyn M Johnson Sterling C SC Koscik Rebecca L RL Masters Colin L CL Soldan Anja A Villemagne Victor L VL Li Qiao-Xin QX McDade Eric M EM Fagan Anne M AM Massoumzadeh Parinaz P Benzinger Tammie T Hassenstab Jason J Bateman Randall J RJ Morris John C JC

Alzheimer's & dementia : the journal of the Alzheimer's Association 20190907 11

<h4>Introduction</h4>Large longitudinal biomarkers database focusing on middle age is needed for Alzheimer's disease (AD) prevention.<h4>Methods</h4>Data for cerebrospinal fluid analytes, molecular imaging of cerebral fibrillar β-amyloid with positron emission tomography, magnetic resonance imaging-based brain structures, and clinical/cognitive outcomes were harmonized across eight AD biomarker studies. Statistical power was estimated.<h4>Results</h4>The harmonized database included 7779 partici ...[more]

PMID: 31506247

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Project description:BACKGROUND:There is growing interest in identifying sensitive composite cognitive tests to serve as primary endpoints in preclinical Alzheimer's disease (AD) treatment trials. We reported previously a composite cognitive test score sensitive to tracking preclinical AD decline up to 5?years prior to clinical diagnosis. Here we expand upon and refine this work, empirically deriving a composite cognitive test score sensitive to tracking preclinical AD decline up to 11?years prior to diagnosis and suitable for use as a primary endpoint in a preclinical AD trial. METHODS:This study used a longitudinal approach to maximize sensitivity to tracking progressive cognitive decline in people who progressed to the clinical stages of AD (n =?868) compared to those who remained cognitively unimpaired during the same time period (n =?989), thereby correcting for normal aging and practice effects. Specifically, we developed the Alzheimer's Prevention Initiative Preclinical Composite Cognitive test (APCC) to measure very early longitudinal cognitive decline in older adults with preclinical AD. Data from three cohorts from Rush University were analyzed using a partial least squares (PLS) regression model to identify optimal composites within different time periods prior to diagnosis, up to 11?years prior to diagnosis. The mean-to-standard deviation ratio (MSDRs) is an indicator of sensitivity to change and was used to inform the final calculation of the composite score. RESULTS:The optimal composite, the APCC, is calculated: 0.26*Symbol Digit Modalities +?2.24*MMSE Orientation to Time?+?2.14*MMSE Orientation to Place +?0.53*Logical Memory Delayed Recall +?1.36* Word List-Delayed Recall +?0.68*Judgment of Line Orientation +?1.39*Raven's Progressive Matrices Matrices (subset of 9 items from A and B). The MSDR of the APCC in a population of preclinical AD individuals who eventually progress to cognitive impairment, compared to those who remained cognitively unimpaired during the same time period, was -?1.10 over 1 year. CONCLUSIONS:The APCC is an empirically derived composite cognitive test score with high face validity that is sensitive to preclinical AD decline up to 11?years prior to diagnosis of the clinical stages of AD. The components of the APCC are supported by theoretical understanding of cognitive decline that occurs during preclinical AD. The APCC was used as a primary outcome in the API Generation Program trials.

Project description:IntroductionA number of studies have reported an association between peripheral hearing impairment, central auditory processing and Alzheimer's disease (AD) and its preclinical stages. Both peripheral hearing impairment and central auditory processing disorders are observed many years prior to the clinical manifestation of AD symptoms, hence, providing a long window of opportunity to investigate potential interventions against neurodegenerative processes. This paper outlines the protocol for a systematic review of studies examining the central auditory processing functions in AD and its preclinical stages, investigated through behavioural (clinical assessments that require active participation) central auditory processing tests.Methods and analysisWe will use the keywords and Medical Subject Heading terms to search the following electronic databases: MEDLINE, PsychINFO, PubMed, Scopus, EMBASE and CINAHL Plus. Studies including assessments of central auditory function in adults diagnosed with dementia, AD and its preclinical stages that were published before 8 May 2019 will be reviewed. This review protocol will be reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Protocols guidelines. Data analysis and search results will be reported in the full review. This manuscript has designed the protocols for a systematic review that will identify the behavioural clinical central auditory processing measures that are sensitive to the changes in auditory function in adults with AD and its preclinical stages. Such assessments may subsequently help to design studies to examine the potential impact of hearing and communication rehabilitation of individuals at risk of AD.Ethics and disseminationEthical approval is not required as this manuscript only reports the protocols for conducting a systematic review as primary data will only be reviewed and not be collected. The results of this systematic review will be disseminated through publication and in scientific conferences.Prospero registration numberCRD42017078272.

Project description:BackgroundSubjective cognitive decline (SCD), non-amnestic mild cognitive impairment (naMCI), and amnestic mild cognitive impairment (aMCI) are regarded to be at high risk of converting to Alzheimer's disease (AD). Amplitude of low-frequency fluctuations (ALFF) can reflect functional deterioration while diffusion tensor imaging (DTI) is capable of detecting white matter integrity. Our study aimed to investigate the structural and functional alterations to further reveal convergence and divergence among SCD, naMCI, and aMCI and how these contribute to cognitive deterioration.MethodsWe analyzed ALFF under slow-4 (0.027-0.073 Hz) and slow-5 (0.01-0.027 Hz) bands and white matter fiber integrity among normal controls (CN), SCD, naMCI, and aMCI groups. Correlation analyses were further utilized among paired DTI alteration, ALFF deterioration, and cognitive decline.ResultsFor ALFF calculation, ascended ALFF values were detected in the lingual gyrus (LING) and superior frontal gyrus (SFG) within SCD and naMCI patients, respectively. Descended ALFF values were presented mainly in the LING, SFG, middle frontal gyrus, and precuneus in aMCI patients compared to CN, SCD, and naMCI groups. For DTI analyses, white matter alterations were detected within the uncinate fasciculus (UF) in aMCI patients and within the superior longitudinal fasciculus (SLF) in naMCI patients. SCD patients presented alterations in both fasciculi. Correlation analyses revealed that the majority of these structural and functional alterations were associated with complicated cognitive decline. Besides, UF alterations were correlated with ALFF deterioration in the SFG within aMCI patients.ConclusionsSCD shares structurally and functionally deteriorative characteristics with aMCI and naMCI, and tends to convert to either of them. Furthermore, abnormalities in white matter fibers may be the structural basis of abnormal brain activation in preclinical AD stages. Combined together, it suggests that structural and functional integration may characterize the preclinical AD progression.

Dataset Information

A harmonized longitudinal biomarkers and cognition database for assessing the natural history of preclinical Alzheimer's disease from young adulthood and for designing prevention trials.

Publications

A harmonized longitudinal biomarkers and cognition database for assessing the natural history of preclinical Alzheimer's disease from young adulthood and for designing prevention trials.

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