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Original Investigation |

Selective Worsening of Brain Injury Biomarker Abnormalities in Cognitively Normal Elderly Persons With β-Amyloidosis

David S. Knopman, MD1,2; Clifford R. Jack, Jr, MD1,3; Heather J. Wiste, BA4; Stephen D. Weigand, MS4; Prashanthi Vemuri, PhD3; Val J. Lowe, MD3; Kejal Kantarci, MD3; Jeffrey L. Gunter, PhD3; Matthew L. Senjem, MS3; Michelle M. Mielke, PhD5; Rosebud O. Roberts, MBBCh2,5; Bradley F. Boeve, MD1,2; Ronald C. Petersen, MD, PhD1,2,5
[+] Author Affiliations
1Mayo Clinic Alzheimer’s Disease Research Center, Mayo Clinic and Foundation, Rochester, Minnesota
2Department of Neurology, Mayo Clinic and Foundation, Rochester, Minnesota
3Department of Radiology, Mayo Clinic and Foundation, Rochester, Minnesota
4Department of Health Sciences Research, Mayo Clinic and Foundation, Rochester, Minnesota
5Division of Epidemiology, Department of Health Sciences Research, Mayo Clinic and Foundation, Rochester, Minnesota
JAMA Neurol. 2013;70(8):1030-1038. doi:10.1001/jamaneurol.2013.182.
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Importance  The appearance of β-amyloidosis and brain injury biomarkers in cognitively normal (CN) persons is thought to define risk for the future development of cognitive impairment due to Alzheimer disease (AD), but their interaction is poorly understood.

Objective  To test the hypothesis that the joint presence of β-amyloidosis and brain injury biomarkers would lead to more rapid neurodegeneration.

Design  Longitudinal cohort study.

Setting  Population-based Mayo Clinic Study of Aging.

Participants  One hundred ninety-one CN persons (median age, 77 years; range, 71-93 years) in the Mayo Clinic Study of Aging who underwent magnetic resonance, fludeoxyglucose F 18 (FDG) positron emission tomography (PET), and Pittsburgh Compound B (PiB) PET imaging at least twice 15 months apart. Participants were grouped according to the recommendations of the National Institute on Aging–Alzheimer Association preclinical AD criteria based on the presence of β-amyloidosis, defined as a PiB PET standardized uptake value ratio (SUVr) greater than 1.5, alone (stage 1) or with brain injury (stage 2 + 3), defined as hippocampal atrophy or FDG hypometabolism. We also studied a group of patients with mild cognitive impairment (n = 17) or dementia (n = 9) from the Mayo Clinic Study of Aging or the Mayo Alzheimer Center with similar follow-up times who had undergone comparable imaging and had a PiB PET SUVr greater than 1.5.

Main Outcomes and Measures  Rate of change of cortical volume on volumetric magnetic resonance images and rate of change of glucose metabolism on FDG PET scan results.

Results  There were 25 CN participants with both high PiB retention and low hippocampal volume or FDG hypometabolism at baseline (preclinical AD stages 2 + 3). On follow-up scans, the preclinical AD stage 2 + 3 participants had greater loss of medial temporal lobe volume and greater glucose hypometabolism in the medial temporal lobe compared with the other CN groups. The changes were similar to those in the cognitively impaired participants. Extratemporal regions did not show similar changes.

Conclusions and Relevance  Higher rates of medial temporal neurodegeneration occur in CN individuals who, on their initial scans, had abnormal levels of both β-amyloid and brain injury biomarkers. Although preclinical AD is currently only a research topic, the description of its brain structural changes will be critical for trials designed to prevent or forestall dementia due to AD.

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Figures

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Figure 1.
Annualized Rate of Change in Hippocampal Volume

Annualized rate of change in hippocampal volume in cognitively normal, mild cognitive impairment (MCI) due to Alzheimer disease (AD), and dementia due to AD groups. The preclinical AD stages 2 + 3 group differed significantly in gray matter volume loss from stage 0 (P = .001), preclinical AD stage 1 (P = .005), and suspected non-AD pathophysiology (sNAP) (P = .003) groups. The boxes indicate the 25th and 75th percentile. The line within the box represents the median value. Vertical lines extending from the boxes are extended out to the data point furthest from the box that is within 1.5 times the interquartile range, defined as the 75th percentile minus the 25th percentile.

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Figure 2.
Annualized Rate of Change in Gray Matter (GM) Volume

Annualized rate of change in GM volume in selected cortical regions in the cognitively normal groups. The preclinical Alzheimer disease (preclinAD) stages 2 + 3 group differed significantly from the stage 0 (P = .004 medial temporal; P = .008 lateral temporal) and suspected non-AD pathophysiology (sNAP) (P = .03 medial temporal; P = .02 lateral temporal) groups in GM loss in both the medial temporal region of interest (ROI) and the lateral temporal ROI. For the medial temporal ROI, the preclinAD stages 2 + 3 group also differed significantly from the preclinAD stage 1 group (P = .02). The individual regions included in the medial temporal ROI included the hippocampus, parahippocampal gyrus, entorhinal cortex, and the amygdala. The individual regions in the lateral temporal ROI included the superior temporal gyrus (mid- and polar portions), middle temporal gyrus (mid- and polar portions), inferior temporal gyrus, Heschl gyrus, and fusiform gyrus. Graph elements are defined in the legend to Figure 1.

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Figure 3.
Annualized Rate of Change in Glucose Metabolic Rate

Annualized rate of change in glucose metabolic rate from fludeoxyglucose F 18 positron emission tomography (FDG PET). Rate of change is shown for the Alzheimer disease (AD) signature composite regions of interest (angular gyrus, posterior cingulate, and inferior temporal) in the cognitively normal groups, mild cognitive impairment (MCI) due to AD, and dementia due to AD groups. There were no significant group differences among the cognitively normal groups. Graph elements are defined in the legend to Figure 1. sNAP indicates suspected non-AD pathophysiology; SUVr, standardized uptake value ratio.

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Figure 4.
Annualized Rate of Change in Glucose Metabolic Rate in the Cognitively Normal Groups

Annualized rate of change in glucose metabolic rate from fludeoxyglucose F 18 positron emission tomography (FDG PET) in selected cortical regions in the cognitively normal groups. The preclinical Alzheimer disease (AD) stages 2 + 3 group differed significantly from stage 0 (P = .02) and suspected non-AD pathophysiology (sNAP) (P = .01) groups in glucose hypometabolism in the medial temporal regions of interest (hippocampus, parahippocampal gyrus, entorhinal cortex, and the amygdala) and showed a trend toward a difference from preclinical AD stage 1. Graph elements are defined in the legend to Figure 1. SUVr indicates standardized uptake value ratio.

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