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Original Investigation |

Role of β-Amyloidosis and Neurodegeneration in Subsequent Imaging Changes in Mild Cognitive Impairment

David S. Knopman, MD1,2; Clifford R. Jack Jr, MD2,3; Emily S. Lundt, MS4; Heather J. Wiste, BA4; Stephen D. Weigand, MS4; Prashanthi Vemuri, PhD1; Val J. Lowe, MD3; Kejal Kantarci, MD3; Jeffrey L. Gunter, PhD3; Matthew L. Senjem, MS3; Michelle M. Mielke, PhD1,5; Mary M. Machulda, PhD6; Rosebud O. Roberts, MBChB1,5; Bradley F. Boeve, MD1,2; David T. Jones, MD1,2,3; Ronald C. Petersen, MD, PhD1,2,5
[+] Author Affiliations
1Department of Neurology, Mayo Clinic and Foundation, Rochester, Minnesota
2Mayo Clinic Alzheimer’s Disease Research Center, Mayo Clinic and Foundation, Rochester, Minnesota
3Department of Radiology, Mayo Clinic and Foundation, Rochester, Minnesota
4Division of Biomedical Statistics and Informatics, Department of Health Sciences Research, Mayo Clinic and Foundation, Rochester, Minnesota
5Division of Epidemiology, Department of Health Sciences Research, Mayo Clinic and Foundation, Rochester, Minnesota
6Division of Psychology, Department of Psychiatry, Mayo Clinic and Foundation, Rochester, Minnesota
JAMA Neurol. 2015;72(12):1475-1483. doi:10.1001/jamaneurol.2015.2323.
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Importance  To understand how a model of Alzheimer disease pathophysiology based on β-amyloidosis and neurodegeneration predicts the regional anatomic expansion of hypometabolism and atrophy in persons with mild cognitive impairment (MCI).

Objective  To define the role of β-amyloidosis and neurodegeneration in the subsequent progression of topographic cortical structural and metabolic changes in MCI.

Design, Setting, and Participants  Longitudinal, observational study with serial brain imaging conducted from March 28, 2006, to January 6, 2015, using a population-based cohort. A total of 96 participants with MCI (all aged >70 years) with serial imaging biomarkers from the Mayo Clinic Study of Aging or Mayo Alzheimer’s Disease Research Center were included. Participants were characterized initially as having elevated or not elevated brain β-amyloidosis (A+ or A−) based on 11C-Pittsburgh compound B positron emission tomography. They were further characterized initially by the presence or absence of neurodegeneration (N+ or N−), where the presence of neurodegeneration was defined by abnormally low hippocampal volume or hypometabolism in an Alzheimer disease–like pattern on 18fluorodeoxyglucose (FDG)–positron emission tomography.

Main Outcomes and Measures  Regional FDG standardized uptake value ratio (SUVR) and gray matter volumes in medial temporal, lateral temporal, lateral parietal, and medial parietal regions.

Results  In the primary regions of interest (ROI), the A+N+ group (n = 45) had lower FDG SUVR at baseline compared with the A+N− group (n = 17) (all 4 ROIs; P < .001). The A+N+ group also had lower FDG SUVR at baseline (all 4 ROIs; P < .01) compared with the A−N− group (n = 12). The A+N+ group had lower medial temporal gray matter volume at baseline (P < .001) compared with either the A+N− group or A−N− group. The A+N+ group showed large longitudinal declines in FDG SUVR (P < .05 for medial temporal, lateral temporal, and medial parietal regions) and gray matter volumes (P < .05 for medial temporal and lateral temporal regions) compared with the A−N+ group (n = 22). The A+N+ group also showed large longitudinal declines compared with the A−N− group on FDG SUVR (P < .05 for medial temporal and lateral parietal regions) and gray matter volumes (all 4 ROIs; P < .05) compared with the A+N− group. The A−N+ group did not show declines in FDG SUVR or gray matter volume compared with the A+N− or A−N− groups.

Conclusions and Relevance  Persons with MCI who were A+N+ demonstrated volumetric and metabolic worsening in temporal and parietal association areas, consistent with the expectation that the MCI stage in the Alzheimer pathway heralds incipient isocortical involvement. The A−N+ group, those with suspected non-Alzheimer pathophysiology, lacked a distinctive longitudinal volumetric or metabolic profile.

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Figure 1.
Primary Cortical Regions of Interest

The spatial extent of the 4 primary regions of interest is displayed overlaid on our custom template brain using 6 representative axial slices. Red indicates lateral parietal; green, medial parietal; blue, lateral temporal; and pink, medial temporal.

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Figure 2.
Baseline 18Fluorodeoxyglucose (FDG) Standardized Uptake Value Ratio (SUVR) and Gray Matter (GM) Volumes by Group

Baseline FDG SUVR (A) and baseline GM volume (B) estimates with 95% CI estimates (orange lines) and 84% CI estimates (dark lines) by biomarker group for primary regions of interest (ROIs): medial temporal, medial parietal, lateral temporal, and lateral parietal. The 84% CI allows for visual comparisons between groups where any amount of overlap indicates a lack of significance at the 0.05 level. Estimates are from a linear mixed model for a participant aged 80 years. Statistical tests: FDG: for comparison of A+N+ with A+N−, P < .001 for all 4 ROIs. For comparison of A+N+ with A−N−, medial temporal, P = .002; medial parietal, P = .01; lateral temporal, P = .003; and lateral parietal, P = .01. For comparison of A−N+ with the A+N− group, P < .01 for all 4 ROIs. For comparison of A−N+ with the A−N− group, P < .01 for all 4 ROIs except the medial temporal (P = .06). Gray matter volume: for comparison of A+N+ with both A−N− and A+N− groups for medial temporal, P < .001; for comparison of A+N+ with the A−N+ group for medial temporal, P = .05. All other medial temporal contrasts were not significant. Other 3 ROIs: all contrasts not significant. A+ and A− indicate having and not having elevated β-amyloidosis, respectively, and N+ and N−, presence and absence of neurodegeneration, respectively.

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Figure 3.
Annual Percentage Change in 18Fluorodeoxyglucose (FDG) Standardized Uptake Value Ratio (SUVR) and Gray Matter (GM) Volumes by Group

Estimated annual percentage change for FDG SUVR (A) and GM volume (B) with 95% CIs (orange lines) and 84% CIs (dark lines) by biomarker group for primary regions of interest: medial temporal, medial parietal, lateral temporal, and lateral parietal. The 84% CI allows for visual comparisons between groups where any amount of overlap indicates a lack of significance at the 0.05 level. Estimates are from a linear mixed model for a participant aged 80 years. Statistical tests: FDG value by region of interest for comparison of A+N+ vs A−N+: lateral temporal, P = .03; medial temporal, P = .007; medial parietal, P = .04; and lateral parietal, P = .09. For comparison of A+N+ vs A−N−: lateral temporal, P = .12; medial temporal, P = .004; medial parietal, P = .08; and lateral parietal, P = .02. All other contrasts are not significant. Gray matter volume: for comparison of A+N+ vs A−N+: lateral temporal, P = .005; medial temporal, P = .02; medial parietal, P = .12; and lateral parietal, P = .06. For comparison of A+N+ vs A−N−: lateral temporal, P = .006; medial temporal, P ≤ .001; medial parietal, P = .03; and lateral parietal, P = .02. All other contrasts are not significant. A+ and A− indicate having and not having elevated β-amyloidosis, respectively, and N+ and N−, presence and absence of neurodegeneration, respectively.

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Figure 4.
Summary Regression Plots for the 4 Primary Regions of Interest for 18Fluorodeoxyglucose (FDG) Standardized Uptake Value Ratio (SUVR) and Gray Matter (GM) Volume

Regression plots for the 4 primary regions of interest showing trajectories of FDG SUVR (A-D) and GM (E-H) over time for the 4 biomarker-defined groups for a hypothetical man aged 80 years. The time scale was limited to 2 years for illustrative purposes. See Figure 1 and Figure 2 for confidence intervals of baseline values and slopes. A+ and A− indicate having and not having elevated β-amyloidosis, respectively, and N+ and N−, presence and absence of neurodegeneration, respectively.

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