Lack of association between 11C-PiB and longitudinal brain atrophy in non-demented older individuals☆
Introduction
Alzheimer's disease (AD) is characterized by neuropathological changes (Alzheimer, 1906, Alzheimer, 1907, Braak and Braak, 1991, Braak and Braak, 1998) in combination with clinico-pathological features, and represents the culmination of a process that evolves over decades (Godbolt et al., 2004, Thal and Braak, 2005, Torack, 1979, Troncoso et al., 1998). The definitive diagnosis of AD still requires post-mortem confirmation of neuropathological hallmarks – amyloid-β plaques (Aβ) and neurofibrillary tangles.
The preeminent explanation of AD pathogenesis, the ‘amyloid cascade theory’, suggests that Aβ is at the root of neurodegeneration, subsequent brain atrophy, cognitive impairment and ultimately dementia (Hardy and Selkoe, 2002.). It has become evident, through prospective longitudinal studies with autopsy data, that neuropathological changes precede neurodegeneration, atrophy, and clinical symptoms by perhaps decades (Bennett et al., 2006, Price and Morris, 1999), with clinical impairments becoming detectable much later after substantial neurodegeneration has taken place (Morris and Price, 2001).
The advent of radiotracers for amyloid imaging (Mintun, 2005, Nordberg, 2008) presents an opportunity to investigate prospective changes in amyloid deposition in vivo. The best validated of these radiotracers to date is the PET ligand known as Pittsburgh Compound B (11C-PiB; {N-methyl-11C} 2-(4′-methylaminophenyl)-6-hydroxybenzothiazole). 11C-PiB detects almost a twofold increase in tracer retention in AD cases compared to non-demented older individuals (Klunk et al., 2004), has a topographical distribution (Rowe et al., 2007) that parallels autopsy findings (Braak and Braak, 1991), shows promise in discriminating individuals with mild cognitive impairment (MCI) who progress vs. those who remain stable, and provides some utility for differential diagnosis of dementia, particularly AD from frontotemporal (Ng et al., 2007).
Brain atrophy, presumably a direct result of neurodegeneration, is a fundamental, although not a specific, feature of AD and has been extensively characterized antemortem by magnetic resonance imaging (MRI; Kantarci and Jack, 2004). Recently we reported that over a 10-year interval those with mild cognitive impairment (MCI) show accelerated changes in the volumes of the whole brain, ventricular cerebrospinal fluid, temporal gray matter, and orbito-frontal and temporal association cortices, including the hippocampus, compared to older, non-demented individuals (Driscoll et al., 2009). Accelerated change associated with MCI was detected against a background of widespread age-related regional volume loss, suggesting that cognitive impairment is associated with a unique pattern of structural vulnerability.
In the present report, we investigate whether amyloid burden, measured by 11C-PiB, is associated with rates of brain atrophy in the preceding years. Based on our structural findings (Driscoll et al., 2009), we predict that the same regions that distinguish between non-demented and those with cognitive impairment, such as frontal and temporal association cortices for example, will exhibit steeper volume declines in association with higher 11C-PiB burden.
Section snippets
Participants
The sample consists of 57 non-demented, highly educated, community-dwelling individuals (M (age) = 78.7 ± 6.2; age range 64–86; 90% Caucasian), who were prospectively followed through the neuroimaging (NI) sub-study of the Baltimore Longitudinal Study of Aging (BLSA; Resnick et al., 2000). They were ascertained from the initial 61 BLSA-NI participants consecutively assessed with [11C]PiB from June 2005 to March 2007, after excluding 2 participants with clinical stroke, 1 with a brain injury and 1
Statistical analyses
We employed linear mixed models, which estimated cross-sectional and longitudinal effects simultaneously to investigate the association between amyloid burden, measured by mean cortical DVR, and longitudinal changes in select regional brain volumes. The models are fit using PROC MIXED in SAS v9.1 (SAS Institute Inc., Cary, NC). Brain volume data were longitudinal, with annual measurements from 1994 through 2003. PiB was measured once, obtained between year 2005 and 2006.
We used regional brain
Results
Mixed-model results for global and regional volumes with cortical DVR score as a continuous variable are summarized in Table 2. In this sample, volume decline accompanied by ventricular CSF increase (p = 0.001) was evident for all brain regions investigated (p ≤ 0.001). Main effects of PiB (mean cortical DVR) on regional brain volumes were not significant (p > 0.1). We also found no interactions between mean cortical PiB burden and interval, indicating no significant effects of mean cortical DVR on
Discussion
The main goal of the present study was to examine the relationships between amyloid burden measured with 11C-PiB and trajectories of regional brain volume changes. Consistent with our findings of structural brain changes in the complete BLSA neuroimaging sample (Driscoll et al., 2009), we found significant age-related regional brain atrophy in this sub-sample of non-demented, community-dwelling older individuals who underwent PiB-PET imaging and were prospectively followed and extensively
Acknowledgments
We thank the staff of the PET facility at Johns Hopkins University and the neuroimaging staff of the BLSA project National Institute on Aging (NIA) for their assistance. Dr. Driscoll had full access to the data in the study and takes responsibility for the integrity of the data and the accuracy of the analysis. This research was supported in part by the Intramural Research Program of the NIH, National Institute on Aging (NIA), and N01-AG-3-2124 and K24 DA00412 (DFW). A portion of that support
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GE Healthcare holds a license agreement with the University of Pittsburgh based on the PIB technology described in this manuscript. Dr. Klunk and Dr. Mathis are co-inventors of PIB and, as such, have a financial interest in this license agreement.
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Address: NIH Biomedical Research Center, 251 Bayview Blvd, Room 4B317, Baltimore, MD 21224, United States.