Abstract of online articleIncreased fMRI signal with age in familial Alzheimer's disease mutation carriers
Introduction
Previous studies using functional magnetic resonance imaging (fMRI) to evaluate Alzheimer's disease (AD) risk have demonstrated that during memory tasks, nondemented older adults having increased genetic risk for AD showed differences in brain activity compared with those without such a risk (Bondi et al., 2005, Bookheimer et al., 2000, Filippini et al., 2009, Fleisher et al., 2005, Johnson et al., 2006, Lind et al., 2006, Xu et al., 2009). These studies have focused almost exclusively on the contributions to brain activity of allele ε4 of apolipoprotein E (APOE4), the genetic influence that has most consistently been shown to confer an increased risk of developing late onset AD across numerous studies (Bertram and Tanzi, 2008). However, although possession of an APOE4 allele increases the risk of developing AD at a younger age, the allele is neither necessary nor sufficient to cause the disease (Corder et al., 1993). Therefore, without later determining which subjects eventually develop AD, it is not possible to determine which APOE genotype-related differences are related to incipient AD in healthy adults and which are intrinsic to APOE4 without regard to AD processes.
Rare, early onset (typically before age 60), familial forms of AD exist, which are caused by mutations in one of three genes: presenilin 1 (PSEN1), presenilin 2 (PSEN2), and amyloid precursor protein (APP). For carriers of these mutations, AD onset is governed by a fully-penetrant autosomal dominant inheritance (Bertram and Tanzi, 2008). Additionally, in such familial Alzheimer's disease (FAD), although age of onset may vary between families, it has been shown to be similar within families (Fox et al., 1997, Murrell et al., 2006). Therefore, for presymptomatic carriers of these mutations, it is possible to predict approximately when disease symptoms will begin. This certainty provides an excellent model for identifying the earliest AD-related changes prospectively. Differences between mutation carriers and noncarriers that are also seen in APOE4+ subjects performing a similar task may be evidence of AD-related processes that transcend gene polymorphism. Correlation of those variations with the number of years until expected age of disease symptoms in FAD mutation carriers would provide further support that the changes were associated with AD processes.
We compared the brain activity of nondemented adults carrying mutations in PSEN1 or APP with the brain activity of their family members who did not carry such a mutation as they performed a nonassociative novelty encoding task. Although mutations in PSEN1 and APP may have different effects on the brain, our goal was to identify functional brain patterns that generalized to prodromal AD without being specific to any one polymorphism. Also, the small number of subjects at risk for the individual mutation types makes meaningful comparisons more challenging. We therefore considered mutation carriers as a group regardless of mutation. The novelty encoding task we used engages regions of the hippocampus and surrounding cortex (Zeineh et al., 2000), and various similar tasks have been shown to be sensitive to differences in APOE genotype in cognitively intact adults (Bondi et al., 2005, Filippini et al., 2009, Johnson et al., 2006, Trivedi et al., 2006). Of these studies, two used tasks most similar to ours in that they involved the encoding of novel pictures (Bondi et al., 2005, Filippini et al., 2009) without the element of recognition decisions found in some other studies (Johnson et al., 2006, Trivedi et al., 2006). We hypothesized that our results would be most similar to those in a picture novelty encoding study of older (Bondi et al., 2005) rather than younger (Filippini et al., 2009) adults who, like our subjects, were presumably closer to AD onset in those destined to develop the disease. Specifically, we hypothesized that PSEN1 and APP mutation carriers in our study would show increased fMRI activity while viewing novel versus repeated images compared with mutation noncarriers. We further hypothesized that this increased activity would occur among regions that, in older APOE4+ subjects, had shown greater fMRI activity during the task in prior studies. These regions included parts of the temporal lobe (the fusiform and parahippocampal gyri and the hippocampus), the superior parietal lobule, and the medial and middle frontal gyri (Bondi et al., 2005). We anticipated that differences would be most striking in the temporal lobe, which is known to be affected early by Alzheimer's disease changes (Braak and Braak, 1995).
Section snippets
Subjects
Subjects were 26, cognitively intact or mildly cognitively impaired first-degree relatives of PSEN1 or APP mutation-carriers (age 19–46; mean 31.6 years) (Table 1). Cognitively intact subjects were those who did not meet the definition of AD or mild cognitive impairment (MCI) as defined below. Each underwent extensive clinical, cognitive, biochemical, and imaging evaluations. Subjects were cognitively intact except for five subjects who had MCI (Petersen, 2004). MCI was defined as those
Results
Using a normal approximation of a two-tailed Mann-Whitney test with a threshold of p < 0.05, mutation carriers and noncarriers were not significantly different in MMSE, CASI, or CDR score, sex, familial gene mutated, age, relative age, or possession of APOE4 (Table 1).
When all subjects were considered together, fMRI activity during novel pictures exceeded fMRI activity during previously viewed pictures in broad regions of the brain including areas important to episodic memory (such as the
Discussion
We found that when nondemented adults carrying fully-penetrant autosomal dominant Alzheimer's disease mutations approached the familial age of disease diagnosis, they showed greater fMRI activity in the fusiform and middle temporal gyri compared with mutation carriers who were further from the familial age of disease diagnosis. The fusiform gyrus is important in object processing (Tyler et al., 2004) and has been shown previously to be engaged during novelty encoding (Yamaguchi et al., 2004),
Disclosure statement
There were no actual or potential conflicts of interest that could inappropriately bias the authors work on this project.
Study procedures were approved by the Institutional Review Boards at UCLA and the National Institute of Neurology and Neurosurgery in Mexico City. All subjects signed written, informed consent.
Acknowledgements
This study was supported by PHS K08 AG-22228, California DHS #04-35522, UC MEXUS, and the Shirley and Jack Goldberg Trust. Further support for this study came from Alzheimer's Disease Research Center Grant P50 AG-16570 from the National Institute on Aging, General Clinical Research Centers Program M01-RR00865, and an Alzheimer's Disease Research Center of California grant, the Sidell Kagan Foundation, and the Easton Consortium for Alzheimer's Disease Drug Discovery and Biomarkers. MNB was
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Present address: SDSU/UCSD Joint Doctoral Program in Clinical Psychology, San Diego, CA, USA.