Cerebral perfusion and oxygenation differences in Alzheimer's disease risk
Introduction
Both the apolipoprotien E ɛ4 allele (APOE4) and a family history of dementia are associated with increased risk of Alzheimer's disease (AD) and subsequent presence of neurofibrillary tangles and amyloid plaques in the brain (Fratiglioni et al., 1993, Corder et al., 1998, Corder et al., 2004, Ghebremedhin et al., 1998). In fact, having a family history of dementia is additive to the risk of having a copy of the APOE4 allele (Cupples et al., 2004), and has been shown to be independently associated with functional imaging activations in the medial temporal lobe (MTL) (Bassett et al., 2006, Johnson et al., 2006). For this reason, imaging studies attempting to identify differences associated with AD risk often stratify by these factors. Blood oxygenation level dependent (BOLD) functional magnetic resonance imaging (fMRI) has demonstrated distinctions in medial temporal lobe activations during memory tasks based on presence or absence of APOE4 (Bookheimer et al., 2000, Bondi et al., 2004, Han et al., 2006) and family history (Fleisher et al., 2005, Johnson et al., 2006). In addition, fluorodeoxyglucose positron emission tomography (FDG PET) has shown decreased glucose metabolism in the medial temporal and parietal lobes of those with the APOE4 gene many decades prior to the typical age of AD onset (Reiman et al., 1996, Reiman et al., 2004). fMRI studies looking at differences in the BOLD response based on Alzheimer's disease risk factors have shown varying results. Depending on age and the memory task used, some studies have demonstrated increased BOLD signal in the MTL associated with AD risk (Bookheimer et al., 2000, Fleisher et al., 2005). Yet, others have reported reduced BOLD signal response associated with AD risk during encoding (Bondi et al., 2005, Johnson et al., 2006, Trivedi et al., 2006). However, in people with Alzheimer's disease the BOLD response in the MTL during a memory task is consistently decreased, compared to normal controls (Dickerson et al., 2005). In addition, imaging studies using arterial spin labeling (ASL) show decreased resting perfusion in AD and mild cognitive impairment (MCI) (Alsop et al., 2000, Johnson et al., 2005, Xu et al., 2007), as well as decreased perfusion response to encoding in the MTL in those with MCI. (Xu et al., 2007) Taken together, these findings suggest an underlying pathological process that may be observed with functional imaging prior to the clinical onset of dementia.
The BOLD response is often interpreted as an indirect measure of underlying neuronal activity. In this regard, increases in BOLD signal in the MTL in elderly persons at increased risk for AD and MCI have been frequently interpreted as a neuronal stress response to underlying cholinergic system degeneration at the earliest stages of disease (Bookheimer et al., 2000, Bondi et al., 2005, Dickerson et al., 2005). However, the BOLD response relies on many other factors including the baseline perfusion state, vascular compliance, cerebral blood volume, and the coupling relationships between these measures (Buxton et al., 2004, Iadecola, 2004, Iannetti and Wise, 2007). For example, increases in baseline cerebral blood flow (CBF) by use of vasodilators significantly decreases the amplitude of the BOLD response irrespective of task performance (Brown et al., 2003, Stefanovic et al., 2006). There is evidence that these neurovascular relationships may be altered in AD pathology, with increased vascular resistance (Bateman et al., 2006) and differences in coupling of the vascular response to neuronal activity (Iadecola, 2004, Zlokovic, 2005, Girouard and Iadecola, 2006). Therefore group differences in activation BOLD signal, in many cases, may be entirely due to differences in the cerebral perfusion states, not necessarily representative of increased neuronal activity or oxygen consumption. A better understanding of the underlying vascular response and resting blood flow state is necessary for understanding BOLD fMRI signal in AD risk.
Pulsed arterial spin labeling (pASL) is an MRI technique that can simultaneously measure cerebral blood flow and BOLD changes during a functional task. Coupled with its ability to measure baseline cerebral blood flow, pASL is a powerful tool for evaluating the underlying physiologic changes associated with the BOLD response, and hence aid in interpreting factors related to neuronal oxygen utilization (Wong et al., 1998, Obata et al., 2004, Uludag et al., 2004). A recent report demonstrated the utility of these techniques for evaluating the relationship between BOLD and perfusion responses in the MTL during memory performance (Restom et al., 2007). They concluded that the BOLD response and related oxygen utilization in the MTL during memory acquisition can be better understood when changes in cerebral blood flow are accounted for. Use of combined functional perfusion and BOLD imaging has not been previously reported in the evaluation of AD risk. Therefore, in this study we evaluated middle aged, cognitively normal, subjects with and without the APOE4 allele, and with and without a family history of dementia. We acquired, simultaneous, medial temporal lobe BOLD and perfusion response during associative encoding, as well as resting perfusion levels.
Section snippets
Study population
Thirty-eight healthy right-handed volunteers, 50–65 years of age, were evaluated. Twenty-five had a significant family history of dementia in a first degree relative, 13 did not. All participants were drawn from a larger group of normal control participants currently active in the University of San Diego (UCSD) Alzheimer's Disease Research Center, from the UCSD student, staff and faculty population, as well as the general San Diego community by means of advertisement.
All potential participants
Results
Twenty-five subjects had a significant family history of dementia in a first degree relative, whereas 13 did not. After enrollment and APOE4 testing, we further stratified the groups into “High” and “Low” risk groups. Thirteen participants had both a positive family history and at least one copy of the APOE ɛ4 gene (high risk group). Ten had no family history of dementia and no copies of the APOE ɛ4 gene (low risk group). These groups did not significantly differ by age, education,
Discussion
This study demonstrates that functional arterial spin labeling can detect signal differences in the medial temporal lobes of people with differential risk for Alzheimer's disease. In this cognitively normal, middle aged, cohort we found decreased fractional changes in medial temporal lobe cerebral blood flow and BOLD signal during associative encoding in those at increased risk for AD. However, evaluation of resting state cerebral blood perfusion revealed that the high risk group also had
Disclosure statement
No authors of this manuscript have any actual or potential conflicts of interest including any financial, personal or other relationships with other people or organizations within 3 years of beginning the work submitted that could inappropriately influence (bias) their work. The author's institutions do not have contracts relating to this research through which it or any other organization may stand to gain financially now or in the future. Nor does any author have any other agreements of
Acknowledgement
This research was funded by a National Institute on Aging grant: k23 AG024062.
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