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From the Departments of Pathology (D.I., O.P., G.R., J.C.T.), Division of Neuropathology, Neurology (J.C.T.), and Mental Health (P.Z.), Johns Hopkins University, Baltimore, MD; Departments of Pathology, Neurology, and Alzheimer’s Disease Center (W.R.M.), Sanders-Brown Center on Aging, University of Kentucky, Lexington; and Department of Laboratory Medicine and Pathology (M.G.), University of Minnesota, Minneapolis.
Address correspondence and reprint requests to Dr. Juan C. Troncoso, Division of Neuropathology, Department of Pathology, Johns Hopkins University, School of Medicine, Ross Building 558, 720 Rutland Avenue, Baltimore, MD 21205 troncoso{at}jhmi.edu
Background: It is common to find substantial Alzheimer disease (AD) lesions, i.e., neuritic β-amyloid plaques and neurofibrillary tangles, in the autopsied brains of elderly subjects with normal cognition assessed shortly before death. We have termed this status asymptomatic AD (ASYMAD). We assessed the morphologic substrate of ASYMAD compared to mild cognitive impairment (MCI) in subjects from the Nun Study. In addition, possible correlations between linguistic abilities in early life and the presence of AD pathology with and without clinical manifestations in late life were considered.
Methods: Design-based stereology was used to measure the volumes of neuronal cell bodies, nuclei, and nucleoli in the CA1 region of hippocampus (CA1). Four groups of subjects were compared: ASYMAD (n = 10), MCI (n = 5), AD (n = 10), and age-matched controls (n = 13). Linguistic ability assessed in early life was compared among all groups.
Results: A significant hypertrophy of the cell bodies (+44.9%), nuclei (+59.7%), and nucleoli (+80.2%) in the CA1 neurons was found in ASYMAD compared with MCI. Similar differences were observed with controls. Furthermore, significant higher idea density scores in early life were observed in controls and ASYMAD group compared to MCI and AD groups.
Conclusions: 1) Neuronal hypertrophy may constitute an early cellular response to Alzheimer disease (AD) pathology or reflect compensatory mechanisms that prevent cognitive impairment despite substantial AD lesions; 2) higher idea density scores in early life are associated with intact cognition in late life despite the presence of AD lesions.
Abbreviations: ACG = anterior cingulate gyrus; AD = Alzheimer disease; ADL = activities of daily living; ASYMAD = asymptomatic Alzheimer disease; BLSA = Baltimore Longitudinal Study of Aging; CERAD = Consortium to Establish a Registry for Alzheimer’s Disease; H-E = hematoxylin-eosin; MCI = mild cognitive impairment; MMSE = Mini-Mental State Examination; NFT = neurofibrillary tangles; NP = neuritic plaques; PCG = posterior cingulate gyrus; PVC = primary visual cortex.
e-Pub ahead of print on July 8, 2009, at www.neurology.org.
Supported by the Johns Hopkins University Alzheimer’s Disease Research Center (NIH grant P50AG05146), the Nun Study (NIA grants: R01AG09862, K04AG00553), the University of Kentucky Alzheimer’s Disease Center (NIH grant AG028383), the Abercrombie Foundation, and the Kleberg Foundation.
Disclosure: The authors report no disclosures.
Received November 25, 2008. Accepted in final form May 11, 2009.
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