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Different pathways to Alzheimer’s disease? atrophy, hypometabolism, and beta-amyloid deposition in diagnostic groups at increased risk

  • Miranka Wirth
    Affiliations
    Ecole Pratique des Hautes Etudes, UMR-S1077, Caen, France

    CHU de Caen, U1077, Caen, France

    Inserm-EPHE-UCBN U1077, Caen, France

    Université de Caen Basse-Normandie, UMR-S1077, Caen, France
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  • Alexandre Bejanin
    Affiliations
    Ecole Pratique des Hautes Etudes, UMR-S1077, Caen, France

    CHU de Caen, U1077, Caen, France

    Inserm-EPHE-UCBN U1077, Caen, France

    Université de Caen Basse-Normandie, UMR-S1077, Caen, France
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  • Eider M. Arenaza-Urquijo
    Affiliations
    Ecole Pratique des Hautes Etudes, UMR-S1077, Caen, France

    CHU de Caen, U1077, Caen, France

    Inserm-EPHE-UCBN U1077, Caen, France

    Université de Caen Basse-Normandie, UMR-S1077, Caen, France
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  • Julie Gonneaud
    Affiliations
    Ecole Pratique des Hautes Etudes, UMR-S1077, Caen, France

    CHU de Caen, U1077, Caen, France

    Inserm-EPHE-UCBN U1077, Caen, France

    Université de Caen Basse-Normandie, UMR-S1077, Caen, France
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  • Renaud La Joie
    Affiliations
    Ecole Pratique des Hautes Etudes, UMR-S1077, Caen, France

    CHU de Caen, U1077, Caen, France

    Inserm-EPHE-UCBN U1077, Caen, France

    Université de Caen Basse-Normandie, UMR-S1077, Caen, France
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  • Brigitte Landeau
    Affiliations
    Ecole Pratique des Hautes Etudes, UMR-S1077, Caen, France

    CHU de Caen, U1077, Caen, France

    Inserm-EPHE-UCBN U1077, Caen, France

    Université de Caen Basse-Normandie, UMR-S1077, Caen, France
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  • Audrey Perrotin
    Affiliations
    Ecole Pratique des Hautes Etudes, UMR-S1077, Caen, France

    CHU de Caen, U1077, Caen, France

    Inserm-EPHE-UCBN U1077, Caen, France

    Université de Caen Basse-Normandie, UMR-S1077, Caen, France
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  • Florence Mézenge
    Affiliations
    Ecole Pratique des Hautes Etudes, UMR-S1077, Caen, France

    CHU de Caen, U1077, Caen, France

    Inserm-EPHE-UCBN U1077, Caen, France

    Université de Caen Basse-Normandie, UMR-S1077, Caen, France
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  • Vincent de La Sayette
    Affiliations
    Ecole Pratique des Hautes Etudes, UMR-S1077, Caen, France

    CHU de Caen, U1077, Caen, France

    Inserm-EPHE-UCBN U1077, Caen, France

    Université de Caen Basse-Normandie, UMR-S1077, Caen, France

    Service de Neurologie, CHU de Caen, Caen, France
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  • Béatrice Desgranges
    Affiliations
    Ecole Pratique des Hautes Etudes, UMR-S1077, Caen, France

    CHU de Caen, U1077, Caen, France

    Inserm-EPHE-UCBN U1077, Caen, France

    Université de Caen Basse-Normandie, UMR-S1077, Caen, France
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  • Gaël Chételat
    Affiliations
    Ecole Pratique des Hautes Etudes, UMR-S1077, Caen, France

    CHU de Caen, U1077, Caen, France

    Inserm-EPHE-UCBN U1077, Caen, France

    Université de Caen Basse-Normandie, UMR-S1077, Caen, France
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      Background

      Existing findings of Alzheimer’s disease (AD)-typical atrophy without concurrent β-amyloid (Aβ) burden suggest that β-amyloidosis might not be the only entrance point to AD pathogenesis. The present study aimed to characterize AD-pathological mechanisms in at-risk diagnostic groups, namely, cognitively normal (CN) older APOE4 carriers and patients with subjective cognitive decline (SCD) and mild cognitive impairment (MCI). Brain regions showing characteristic variation in the relative degree of Aβ deposition, glucose hypometabolism, and gray-matter atrophy were previously identified in AD patients (La Joie et al., 2012). Here, we used a similar approach to detect AD-typical patterns in biomarker expression within each diagnostic group.

      Methods

      Structural MRI, 18F-fluorodeoxyglucose PET and 18F-florbetapir PET data were collected from Aβ-negative/neurodegeneration-negative CN controls (n=41, 66±8 years), CN APOE4 carriers (n=17, 64±9 years), and patients with SCD (n=16, 69±7 years), MCI (n=30, 73±7 years) and AD (n=22, 69±9 years). For each imaging modality, standardized age-adjusted maps were computed using the controls as reference group. Relative degrees of biomarker expression were assessed in each diagnostic group via voxel-wise inter-modality comparisons of standardized maps. In addition, discriminatory power of AAL ROIs preferentially sensitive to Aβ deposition, hypometabolism, or atrophy (as derived in AD patients) was examine.

      Results

      In the MCIs voxel-wise analyses detected AD-typical patterns in the relative degree of biomarker expressions (Figure 1a). In SCD only predominant medial-temporal atrophy was recovered (Figure 1b), while CN APOE4 carriers showed greater degree of Aβ deposition (Figure 1c). Confirming these findings, MCI patients were discriminated from controls by Aβ deposition-, hypometabolism-, and atrophy-predominant ROIs. Only the atrophy-predominant ROI distinguished SCD patients, and only the Aβ deposition-predominant ROI discriminated CN APOE4 carriers.

      Conclusions

      MCI patients exhibit regional variation in the relative degree of Aβ deposition, hypometabolism, and atrophy typically seen in AD, although less extended and pronounced. SCD appears to reflect pathological mechanisms linked to atrophy in the absence of Aβ deposition. CN APOE4 carriers predominately harbor Aβ pathology without AD-typical patterns of atrophy or hypometabolism. Our findings suggest that Aβ and non-Aβ pathways could emerge first in different at-risk groups and converge in prodromal AD.
      Figure thumbnail fx1
      Figure 1Voxel-wise intra-modality comparisons between regional degrees of atrophy, hypermetabolism and amyloid deposition in diagnostic groups with 1A. Mild Cognitive Impairment (MCI), 1B. Subjective Memory Decline (SCD), 1C. CN APOE4 carriers as well as 0. AD patients (for visual comparison). Contrast maps were displayed on the left hemisphere thresholded at t -values of p < 0.001 uncorrected, k = 20.