Elizabeth C Mormino1, Rebecca A Betensky2, Trey Hedden3, Aaron P Schultz4, Rebecca E Amariglio5, Dorene M Rentz5, Keith A Johnson6, Reisa A Sperling6. 1. Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston. 2. Department of Biostatistics, Harvard School of Public Health, Boston, Massachusetts. 3. Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, Charlestown4Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston. 4. Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston3Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, Charlestown. 5. Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston5Center for Alzheimer Research and Treatment, Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts. 6. Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston4Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston5Center for Alzheimer Research and Treatment, Department of Neurology, Brigham a.
Abstract
IMPORTANCE: Assessing the ability of Alzheimer disease neuroimaging markers to predict short-term cognitive decline among clinically normal (CN) individuals is critical for upcoming secondary prevention trials using cognitive outcomes. OBJECTIVE: To determine whether neuroimaging markers of β-amyloid (Aβ) and neurodegeneration (ND) are independently or synergistically associated with longitudinal cognitive decline in CN individuals. DESIGN, SETTING, AND PARTICIPANTS: Academic medical center longitudinal natural history study among 166 CN individuals (median age, 74 years; 92 women). MAIN OUTCOMES AND MEASURES: The Aβ status was determined with Pittsburgh Compound B-positron emission tomography, while ND was assessed using 2 a priori measures, hippocampus volume (magnetic resonance imaging) and glucose metabolism (positron emission tomography with fludeoxyglucose F 18), extracted from Alzheimer disease-vulnerable regions. Based on imaging markers, CN individuals were categorized into the following preclinical Alzheimer disease stages: stage 0 (Aβ-/ND-), stage 1 (Aβ(+)/ND-), stage 2 (Aβ(+)/ND(+)), and suspected non-Alzheimer disease pathology (Aβ-/ND(+)). Cognition was assessed with a composite of neuropsychological tests administered annually. RESULTS: The Aβ(+) CN individuals were more likely to be classified as ND+: 59.6% of Aβ(+) CN individuals were ND(+), whereas 31.9% of Aβ- CN individuals were ND(+) (odds ratio, 3.14; 95% CI, 1.44-7.02; P = .004). In assessing longitudinal cognitive performance, practice effects were evident in CN individuals negative for both Aβ and ND, whereas diminished practice effects were observed in CN individuals positive for either Aβ or ND. Decline over time was observed only in CN individuals positive for both Aβ and ND, and decline in this group was significantly greater than that in all other groups (P < .001 for all). A significant interaction term between Aβ and ND confirmed that this decline was greater than the additive contributions of Aβ and ND (P = .04). CONCLUSIONS AND RELEVANCE: The co-occurrence of Aβ and ND accelerates cognitive decline in CN individuals. Therefore, both factors are important to consider in upcoming secondary prevention trials targeting CN individuals at high risk for progression to the symptomatic stages of Alzheimer disease.
IMPORTANCE: Assessing the ability of Alzheimer disease neuroimaging markers to predict short-term cognitive decline among clinically normal (CN) individuals is critical for upcoming secondary prevention trials using cognitive outcomes. OBJECTIVE: To determine whether neuroimaging markers of β-amyloid (Aβ) and neurodegeneration (ND) are independently or synergistically associated with longitudinal cognitive decline in CN individuals. DESIGN, SETTING, AND PARTICIPANTS: Academic medical center longitudinal natural history study among 166 CN individuals (median age, 74 years; 92 women). MAIN OUTCOMES AND MEASURES: The Aβ status was determined with Pittsburgh Compound B-positron emission tomography, while ND was assessed using 2 a priori measures, hippocampus volume (magnetic resonance imaging) and glucose metabolism (positron emission tomography with fludeoxyglucose F 18), extracted from Alzheimer disease-vulnerable regions. Based on imaging markers, CN individuals were categorized into the following preclinical Alzheimer disease stages: stage 0 (Aβ-/ND-), stage 1 (Aβ(+)/ND-), stage 2 (Aβ(+)/ND(+)), and suspected non-Alzheimer disease pathology (Aβ-/ND(+)). Cognition was assessed with a composite of neuropsychological tests administered annually. RESULTS: The Aβ(+) CN individuals were more likely to be classified as ND+: 59.6% of Aβ(+) CN individuals were ND(+), whereas 31.9% of Aβ- CN individuals were ND(+) (odds ratio, 3.14; 95% CI, 1.44-7.02; P = .004). In assessing longitudinal cognitive performance, practice effects were evident in CN individuals negative for both Aβ and ND, whereas diminished practice effects were observed in CN individuals positive for either Aβ or ND. Decline over time was observed only in CN individuals positive for both Aβ and ND, and decline in this group was significantly greater than that in all other groups (P < .001 for all). A significant interaction term between Aβ and ND confirmed that this decline was greater than the additive contributions of Aβ and ND (P = .04). CONCLUSIONS AND RELEVANCE: The co-occurrence of Aβ and ND accelerates cognitive decline in CN individuals. Therefore, both factors are important to consider in upcoming secondary prevention trials targeting CN individuals at high risk for progression to the symptomatic stages of Alzheimer disease.
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