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摘要
IMPORTANCE Criteria for preclinical Alzheimer disease (AD) propose beta-amyloid (A beta) plaques to initiate neurodegeneration within AD-affected regions. However, some cognitively normal older individuals harbor neural injury similar to patients with AD, without concurrent A beta burden. Such findings challenge the proposed sequence and suggest that A beta-independent precursors underlie AD-typical neurodegenerative patterns. OBJECTIVE To examine relationships between A beta and non-A beta factors as well as neurodegeneration within AD regions in cognitively normal older adults. The study quantified neurodegenerative abnormalities using imaging biomarkers and examined cross-sectional relationships with A beta deposition; white matter lesions (WMLs), a marker of cerebrovascular disease; and cognitive functions. DESIGN, SETTING, AND PARTICIPANTS Cross-sectional study in a community-based convenience sample of 72 cognitively normal older individuals (mean [SD] age, 74.9 [5.7] years; 48 women; mean [SD] 17.0 [1.9] years of education) of the Berkeley Aging Cohort. INTERVENTION Each individual underwent a standardized neuropsychological test session, magnetic resonance imaging, and positron emission tomography scanning. MAIN OUTCOMES AND MEASURES For each individual, 3 AD-sensitive neurodegeneration biomarkers were measured: hippocampal volume, glucose metabolism, and gray matter thickness, the latter 2 sampled from cortical AD-affected regions. To quantify neurodegenerative abnormalities, each biomarker was age adjusted, dichotomized into a normal or abnormal status (using cutoff thresholds derived from an independent AD sample), and summarized into 0, 1, or more than 1 abnormal neurodegenerative biomarker. Degree and topographic patterns of neurodegenerative abnormalities were assessed and their relationships with cognitive functions, WML volume, and A beta deposition (quantified using carbon 11-labeled Pittsburgh compound B positron emission tomography). RESULTS Of our cognitively normal elderly individuals, 40% (n = 29) displayed at least 1 abnormal neurodegenerative biomarker, 26%(n = 19) of whom had no evidence of elevated Pittsburgh compound B retention. In those people who were classified as having abnormal cortical thickness, degree and topographic specificity of neurodegenerative abnormalities were similar to patients with AD. Accumulation of neurodegenerative abnormalities was related to poor memory and executive functions as well as larger WML volumes but not elevated Pittsburgh compound B retention. CONCLUSIONS AND RELEVANCE Our study confirms that a substantial proportion of cognitively normal older adults harbor neurodegeneration, without A beta burden. Associations of neurodegenerative abnormalities with cerebrovascular disease and cognitive performance indicate that neurodegenerative pathology can emerge through non-A beta pathways within regions most affected by AD.
- 出版日期2013-12
