The Journal of Neuroscience, August 24, 2005 • 25(34):7709–7717 • 7709 Neurobiology of Disease Molecular, Structural, and Functional Characterization of Alzheimer’s Disease: Evidence for a Relationship between Default Activity, Amyloid, and Memory Randy L. Buckner,1,2,3,4,5 Abraham Z. Snyder,3,6 Benjamin J. Shannon,5 Gina LaRossa,3 Rimmon Sachs,3 Anthony F. Fotenos,5 Yvette I. Sheline,3,7 William E. Klunk,9 Chester A. Mathis,9 John C. Morris,6,8 and Mark A. Mintun3 1Howard Hughes Medical Institute, 2Department of Psychology, 3Mallinckrodt Institute of Radiology, 4Department of Anatomy and Neurobiology, 5Division of Biology and Biomedical Sciences, and Departments of 6Neurology, 7Psychiatry, and 8Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri 63105, and 9Department of Neurology, University of Pittsburgh and Western Psychiatric Institute and Clinic, Pittsburgh, Pennsylvania 15312 Alzheimer’s disease (AD) and antecedent factors associated with AD were explored using amyloid imaging and unbiased measures of longitudinal atrophy in combination with reanalysis of previous metabolic and functional studies. In total, data from 764 participants were compared across five in vivo imaging methods. Convergence of effects was seen in posterior cortical regions, including posterior cingulate, retrosplenial, and lateral parietal cortex. These regions were active in default states in young adults and also showed amyloid deposition in older adults with AD. At early stages of AD progression, prominent atrophy and metabolic abnormalities emerged in these posterior cortical regions; atrophy in medial temporal regions was also observed. Event-related functional magnetic resonance imaging studies further revealed that these cortical regions are active during successful memory retrieval in young adults. One possibility is that lifetime cerebral metabolism associated with regionally specific default activity predisposes cortical regions to AD-related changes, including amyloid deposition, metabolic disruption, and atrophy. These cortical regions may be part of a network with the medial temporal lobe whose disruption contributes to memory impairment. Key words: amyloid; PIB; memory; MCI; parietal cortex; FDG-PET; fMRI; human; prefrontal cortex; hippocampus Introduction demonstrate medial temporal atrophy (for review, see Jack and Alzheimer’s disease (AD) is the most prevalent dementing disor- Petersen, 2000). der in older adults. AD is pathologically defined by the presence Given the coexistence of pathology and atrophy in the MTL, it 18 of amyloid (A␤) aggregations (plaques) and tau pathology (neu- is puzzling that [ F]-2-fluoro-2-deoxy-D-glucose positron rofibrillary tangles) (Khachaturian, 1985; Mirra et al., 1991; Na- emission tomography (FDG-PET)-measured hypometabolism is tional Institute on Aging, 1997). Histological studies suggest that most prominent in temporoparietal and retrosplenial association tau pathology is prominent in the medial temporal lobe (MTL) cortex (Friedland et al., 1983; Herholz, 1995; Reiman et al., 1996). early in the disease and progresses outward; amyloid has a Nondemented individuals, genetically at risk for late-onset AD, broader cortical distribution that includes but is not especially also show these metabolic differences (Reiman et al., 1996). An prominent in MTL (Braak and Braak, 1991, 1997; Price et al., open question is how patterns of metabolic disruption relate to 1991). Profound cell loss is also observed in the hippocampal structural atrophy and underlying neuropathology. One possibil- formation (Hyman et al., 1984; Price et al., 1991; Go´mez-Isla et ity is that metabolic effects in posterior cortical regions represent al., 1996). Consistent with this pathology, in vivo magnetic reso- the secondary consequences of MTL pathology. Posterior cortical nance imaging (MRI) structural measures in early-stage AD regions are densely interconnected with the MTL (Insausti et al., 1987; Vogt et al., 1992; Suzuki and Amaral, 1994; Meguro et al., 1999; Morris et al., 1999; Kobayashi and Amaral, 2003). Another Received May 29, 2005; revised July 11, 2005; accepted July 11, 2005. possibility is that these cortical regions are directly affected by ThisworkwassupportedbyNationalInstituteonAgingGrantsP50AG05681andP01AG03991,theMallinckrodt pathology resulting in atrophy early in the disease (Buckner, Institute of Radiology, the Alzheimer’s Association, the James S. McDonnell Foundation, and the Howard Hughes 2004). Here we revisit this issue using anatomic procedures sen- Medical Institute. We thank the Washington University Alzheimer’s Disease Research Center, including Mary Coats, Amy Buckley, Elizabeth Grant, and Martha Storandt. Marcus Raichle and David Holtzman provided valuable discus- sitive to longitudinal cortical atrophy (Fox et al., 2001) in patients sion. Robert Mach, Carmen Dence, and Song Yoon Lee synthesized [ 11C]PIB and its precursor. David Van Essen with early-stage AD and individuals at the cusp of clinically ex- provided Caret software, and Karl Herholz generously provided FDG-PET data. pressed AD, in conjunction with mapping amyloid deposition Correspondence should be addressed to Dr. Randy L. Buckner, Howard Hughes Medical Institute at Washington using the recently developed amyloid-imaging tracer [ 11C]Pitts- University, Campus Box 1125, One Brookings Drive, St. Louis, MO 63105. E-mail: [email protected]. DOI:10.1523/JNEUROSCI.2177-05.2005 burgh Compound-B (PIB) (Klunk et al., 2004). To foreshadow Copyright © 2005 Society for Neuroscience 0270-6474/05/257709-09$15.00/0 the results, there is correlation in posterior cortical regions be- 7710 • J. Neurosci., August 24, 2005 • 25(34):7709–7717 Buckner et al. • Default Activity in AD Table 1. Data types integrated in the present study Table 2. PIB amyloid imaging sample Default activity, H2O-PET Updated meta-analysis of nine published PET Nondemented AD studies [data from Shulman et al. (1997b)] n 810 Amyloid deposition, PIB-PET New data Male/female 5/3 7/3 Structural atrophy, MRI New data Age (years) 76.8 75.2 Glucose metabolism, FDG-PET Multicenter data from Herholz et al. (2002) Education (years) 16.4 13.4 Retrieval success effect, fMRI Meta-analysis of data CDR (n) 0 (8) 0.5(7),1(3) MMSE 29.0 25.0 tween amyloid deposition, atrophy, and hypometabolism, sug- CDR 0, No dementia; CDR 0.5, 1, and 2, very mild, mild, and moderate dementia, respectively. Numbers in paren- gesting a network that is directly disrupted in early-stage AD. theses within CDR rows indicate the number of participants with each CDR. The present analyses also explore early life risk factors for AD based on the study of default mode activity in young adults. Al- humans (Kung et al., 2002; Shoghi-Jadid et al., 2002; Mathis et al., 2003). though PET and functional MRI (fMRI) imaging most often seek Here we used [ 11C]PIB (Klunk et al., 2001; Mathis et al., 2002; Klunk et to identify areas of increased activity related to specific active al., 2004) to image amyloid in a sample of AD participants and age- tasks (e.g., speaking, classifying a stimulus, etc.), many published matched controls. These images map regions of amyloid deposition. functional imaging studies note regions that are more active dur- Participants. Eighteen older participants were enrolled from the lon- gitudinal sample of the Washington University Alzheimer’s Disease Re- ing rest or in the passive control condition compared with the search Center and screened to exclude neurological illness, psychoactive active task condition (Shulman et al., 1997b; Mazoyer et al., 2001; medications, and medical conditions that might produce cognitive im- McKiernan et al., 2003). The consistency of this observation has pairment. The presence or absence of dementia and, when present, its led to the hypothesis of a “default” mode of human cognition severity was classified based on the Clinical Dementia Rating (CDR) (Gusnard and Raichle, 2001). Here we demonstrate a remarkable (Morris, 1993). Eight participants were nondemented, and 10 were very correlation between default activity patterns in cortical regions in mild to mildly demented with AD. The clinical diagnosis of AD in our young adults and the topography of amyloid deposition in elderly sample, even in its very mildest stages, has been validated by neuropatho- AD patients. This correspondence raises the possibility of a rela- logical examination (Berg et al., 1998; Morris et al., 2001). All partici- tionship between activity patterns in early adulthood and later pants consented in accordance with the Washington University Human amyloid deposition. Of additional interest, the default activity Studies Committee guidelines. Table 2 presents sample characteristics. Imaging methods. Images of amyloid deposition were acquired on a pattern also correlates with posterior networks involved in mem- 961 ECAT PET scanner (Siemens, Erlangen, Germany) while partici- ory retrieval, suggesting that memory may be affected promi- pants rested with eyes closed. A catheter was placed in the antecubital nently in AD because memory systems are modulated as part of vein. Head position was such that the cantho-meatal line was ϳ1.0 cm default cognitive modes. above, and parallel to, the lowest imaging plane. A transmission scan was obtained to correct for attenuation. Imaging used 8–18 mCi of [ 11C]PIB Materials and Methods and a 60 min dynamic PET scan in three-dimensional (3-D) mode (septa Overview. Five imaging methods were compared (Table 1). We obtained