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Integration and relative value of biomarkers for prediction of MCI to AD progression: spatial patterns of brain atrophy, cognitive scores, APOE genotype and CSF biomarkers.

Abstract

This study evaluates the individual, as well as relative and joint value of indices obtained from magnetic resonance imaging (MRI) patterns of brain atrophy (quantified by the SPARE-AD index), cerebrospinal fluid (CSF) biomarkers, APOE genotype, and cognitive performance (ADAS-Cog) in progression from mild cognitive impairment (MCI) to Alzheimer's disease (AD) within a variable follow-up period up to 6 years, using data from the Alzheimer's Disease Neuroimaging Initiative-1 (ADNI-1). SPARE-AD was first established as a highly sensitive and specific MRI-marker of AD vs. cognitively normal (CN) subjects (AUC = 0.98). Baseline predictive values of all aforementioned indices were then compared using survival analysis on 381 MCI subjects. SPARE-AD and ADAS-Cog were found to have similar predictive value, and their combination was significantly better than their individual performance. APOE genotype did not significantly improve prediction, although the combination of SPARE-AD, ADAS-Cog and APOE ε4 provided the highest hazard ratio estimates of 17.8 (last vs. first quartile). In a subset of 192 MCI patients who also had CSF biomarkers, the addition of Aβ1-42, t-tau, and p-tau181p to the previous model did not improve predictive value significantly over SPARE-AD and ADAS-Cog combined. Importantly, in amyloid-negative patients with MCI, SPARE-AD had high predictive power of clinical progression. Our findings suggest that SPARE-AD and ADAS-Cog in combination offer the highest predictive power of conversion from MCI to AD, which is improved, albeit not significantly, by APOE genotype. The finding that SPARE-AD in amyloid-negative MCI patients was predictive of clinical progression is not expected under the amyloid hypothesis and merits further investigation.

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  • Authors+Show Affiliations

    ,

    Section of Biomedical Image Analysis, Department of Radiology, and Center for Biomedical Image Computing and Analytics, University of Pennsylvania, Philadelphia, PA, USA.

    ,

    Department of Pathology & Laboratory Medicine, Institute on Aging, Center for Neurodegenerative Disease Research, University of Pennsylvania School of Medicine, Philadelphia, PA, USA.

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    Department of Biostatistics and Epidemiology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.

    ,

    Memory Center, University of Pennsylvania, Philadelphia, PA, USA ; Section of Biomedical Image Analysis, Department of Radiology, and Center for Biomedical Image Computing and Analytics, University of Pennsylvania, Philadelphia, PA, USA.

    ,

    Department of Biostatistics and Epidemiology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.

    ,

    Section of Biomedical Image Analysis, Department of Radiology, and Center for Biomedical Image Computing and Analytics, University of Pennsylvania, Philadelphia, PA, USA.

    ,

    Section of Biomedical Image Analysis, Department of Radiology, and Center for Biomedical Image Computing and Analytics, University of Pennsylvania, Philadelphia, PA, USA.

    ,

    Section of Biomedical Image Analysis, Department of Radiology, and Center for Biomedical Image Computing and Analytics, University of Pennsylvania, Philadelphia, PA, USA.

    ,

    Department of Pathology & Laboratory Medicine, Institute on Aging, Center for Neurodegenerative Disease Research, University of Pennsylvania School of Medicine, Philadelphia, PA, USA.

    ,

    Department of Pathology & Laboratory Medicine, Institute on Aging, Center for Neurodegenerative Disease Research, University of Pennsylvania School of Medicine, Philadelphia, PA, USA.

    ,

    Section of Biomedical Image Analysis, Department of Radiology, and Center for Biomedical Image Computing and Analytics, University of Pennsylvania, Philadelphia, PA, USA.

    Source

    NeuroImage. Clinical 4: 2014 pg 164-73

    MeSH

    Aged
    Aged, 80 and over
    Alzheimer Disease
    Amyloid beta-Peptides
    Apolipoproteins E
    Atrophy
    Biomarkers
    Brain
    Cognitive Dysfunction
    Disease Progression
    Female
    Genotype
    Humans
    Longitudinal Studies
    Magnetic Resonance Imaging
    Male
    Neuropsychological Tests
    Peptide Fragments
    Psychiatric Status Rating Scales
    ROC Curve
    tau Proteins

    Pub Type(s)

    Journal Article
    Research Support, N.I.H., Extramural
    Research Support, Non-U.S. Gov't

    Language

    eng

    PubMed ID

    24371799

    Citation

    Da, Xiao, et al. "Integration and Relative Value of Biomarkers for Prediction of MCI to AD Progression: Spatial Patterns of Brain Atrophy, Cognitive Scores, APOE Genotype and CSF Biomarkers." NeuroImage. Clinical, vol. 4, 2014, pp. 164-73.
    Da X, Toledo JB, Zee J, et al. Integration and relative value of biomarkers for prediction of MCI to AD progression: spatial patterns of brain atrophy, cognitive scores, APOE genotype and CSF biomarkers. Neuroimage Clin. 2014;4:164-73.
    Da, X., Toledo, J. B., Zee, J., Wolk, D. A., Xie, S. X., Ou, Y., ... Davatzikos, C. (2014). Integration and relative value of biomarkers for prediction of MCI to AD progression: spatial patterns of brain atrophy, cognitive scores, APOE genotype and CSF biomarkers. NeuroImage. Clinical, 4, pp. 164-73. doi:10.1016/j.nicl.2013.11.010.
    Da X, et al. Integration and Relative Value of Biomarkers for Prediction of MCI to AD Progression: Spatial Patterns of Brain Atrophy, Cognitive Scores, APOE Genotype and CSF Biomarkers. Neuroimage Clin. 2014;4:164-73. PubMed PMID: 24371799.
    * Article titles in AMA citation format should be in sentence-case
    TY - JOUR T1 - Integration and relative value of biomarkers for prediction of MCI to AD progression: spatial patterns of brain atrophy, cognitive scores, APOE genotype and CSF biomarkers. AU - Da,Xiao, AU - Toledo,Jon B, AU - Zee,Jarcy, AU - Wolk,David A, AU - Xie,Sharon X, AU - Ou,Yangming, AU - Shacklett,Amanda, AU - Parmpi,Paraskevi, AU - Shaw,Leslie, AU - Trojanowski,John Q, AU - Davatzikos,Christos, AU - ,, Y1 - 2013/11/28/ PY - 2013/09/20/received PY - 2013/11/20/revised PY - 2013/11/22/accepted PY - 2013/12/28/entrez PY - 2013/12/29/pubmed PY - 2013/12/29/medline KW - Amyloid KW - Biomarkers of AD KW - Cerebrospinal fluid KW - Dementia KW - Early Alzheimer's disease KW - Magnetic resonance imaging KW - Mild cognitive impairment SP - 164 EP - 73 JF - NeuroImage. Clinical JO - Neuroimage Clin VL - 4 N2 - This study evaluates the individual, as well as relative and joint value of indices obtained from magnetic resonance imaging (MRI) patterns of brain atrophy (quantified by the SPARE-AD index), cerebrospinal fluid (CSF) biomarkers, APOE genotype, and cognitive performance (ADAS-Cog) in progression from mild cognitive impairment (MCI) to Alzheimer's disease (AD) within a variable follow-up period up to 6 years, using data from the Alzheimer's Disease Neuroimaging Initiative-1 (ADNI-1). SPARE-AD was first established as a highly sensitive and specific MRI-marker of AD vs. cognitively normal (CN) subjects (AUC = 0.98). Baseline predictive values of all aforementioned indices were then compared using survival analysis on 381 MCI subjects. SPARE-AD and ADAS-Cog were found to have similar predictive value, and their combination was significantly better than their individual performance. APOE genotype did not significantly improve prediction, although the combination of SPARE-AD, ADAS-Cog and APOE ε4 provided the highest hazard ratio estimates of 17.8 (last vs. first quartile). In a subset of 192 MCI patients who also had CSF biomarkers, the addition of Aβ1-42, t-tau, and p-tau181p to the previous model did not improve predictive value significantly over SPARE-AD and ADAS-Cog combined. Importantly, in amyloid-negative patients with MCI, SPARE-AD had high predictive power of clinical progression. Our findings suggest that SPARE-AD and ADAS-Cog in combination offer the highest predictive power of conversion from MCI to AD, which is improved, albeit not significantly, by APOE genotype. The finding that SPARE-AD in amyloid-negative MCI patients was predictive of clinical progression is not expected under the amyloid hypothesis and merits further investigation. SN - 2213-1582 UR - https://www.unboundmedicine.com/medline/citation/24371799/Integration_and_relative_value_of_biomarkers_for_prediction_of_MCI_to_AD_progression:_spatial_patterns_of_brain_atrophy_cognitive_scores_APOE_genotype_and_CSF_biomarkers_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S2213-1582(13)00158-7 DB - PRIME DP - Unbound Medicine ER -