• David S Knopman, Clifford R Jack, Heather J Wiste, Stephen D Weigand, Prashanthi Vemuri, Val J Lowe, Kejal Kantarci, Jeffrey L Gunter, Matthew L Senjem, Michelle M Mielke, Rosebud O Roberts, Bradley F Boeve, and Ronald C Petersen.
• Mayo Clinic Alzheimer's Disease Research Center, Mayo Clinic and Foundation, Rochester, Minnesota 55905, USA. knopman@mayo.edu
• JAMA Neurol. 2013 Aug 1; 70 (8): 1030-8.

ImportanceThe 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.ObjectiveTo test the hypothesis that the joint presence of β-amyloidosis and brain injury biomarkers would lead to more rapid neurodegeneration. DESIGN Longitudinal cohort study.SettingPopulation-based Mayo Clinic Study of Aging.ParticipantsOne 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 MeasuresRate of change of cortical volume on volumetric magnetic resonance images and rate of change of glucose metabolism on FDG PET scan results.ResultsThere 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 RelevanceHigher 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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