We found that in older, cognitively intact adults, fMRI activation during a verbal memory task was higher in several task-related brain regions in participants who had higher sBP&BMI, even within the normal ranges of these variables. These regions included frontal lobe, temporal lobe, precuneus, and posterior cingulate cortex. Our whole brain results are in keeping with a recent study focusing solely on medial temporal lobe that similarly found increased fMRI signal in older adults having increased risk for stroke (Bangen et al., 2007
In our study, the frontal regions that correlated with sBP&BMI were left-lateralized during encoding, in keeping with the well-known hemispheric encoding/retrieval asymmetry (HERA) model (Tulving et al., 1994
). Unlike during encoding, the correlated activations we saw in the frontal lobe during retrieval were bilateral, and so did not display the typical lateralized pattern described by the HERA model. However, the frontal activation bilaterality during retrieval is consistent with the hemispheric asymmetry reduction in older adults (HAROLD) model, which describes reduced frontal asymmetry of activation in older adults (Cabeza et al., 1997
; Cabeza, 2002
). Similarly, in our study, sBP&BMI was correlated with medial temporal activation during retrieval, but not during encoding, although memory encoding has reliably elicited medial temporal lobe (MTL) activity previously (Wagner et al., 2005
). In aging populations, however, lack of MTL activation during encoding has been documented (Grady et al., 1995
), as found in the current study.
Our results suggest that increased cardiovascular risk is associated with changes in brain function during a memory task even within the normal ranges of sBP and BMI, before memory ability is altered, and independent of hippocampal volume. These findings raise interesting questions about what are acceptable levels of cardiovascular risk and to what extent such related changes to brain activation are reversible.
Various studies in past years have examined brain function at rest by performing meta-analyses across PET or fMRI studies and comparing regions that deactivate during the active condition across a number of tasks. As a result of these studies, a network of brain regions has emerged that is more active during the resting state than during the test condition. This network has reliably included precuneus, posterior cingulate, inferior parietal lobule, anterior cingulate, DLPFC, and medial frontal regions (Mazoyer et al., 2001
; McKiernan et al., 2003
; Shulman et al., 1997
), regions that in the current study all showed more activity during the memory task than during the control task in participants with higher sBP&BMI. Therefore, it is possible that the perceived increases in activation we found with higher sBP&BMI actually relate to greater reduction of activity during the control task, in other words, a reduced resting state in those areas.
Hypertension and obesity are both risk factors for coronary artery disease, and possibly cerebrovascular disease as well (Isozumi, 2004
). Additionally, hypertension has been associated with reduced regional cerebral blood flow in healthy adults at rest (Meyer et al., 1985
; Sinha et al., 2005
). One previous study that used 15
O-water tracer PET to measure regional cerebral blood flow found that hypertensive participants had reduced overall cerebral blood flow compared with normotensive participants (Jennings, 2003
). However, unlike in the current study, the authors of that study found that during a memory task, blood flow in posterior parietal cortex was depressed compared with normotensive participants who activated readily in that area (Jennings, 2003
). The current study, however, largely includes normotensive and non-obese participants, while the previous study compared hypertensive and normotensive participants. One possible model that would accommodate both studies involves a linear regional decrease in blood flow at rest due to mild arterial changes as sBP increases through a normal range, but a compensatory increase in blood velocity during the task such that available oxygen then mirrors that seen in participants having lower sBP&BMI. The result would be an overall apparent increase in regional activity in those with more cardiovascular risk. Such compensatory effects have been proposed in cognitive aging literature previously (Bondi et al., 2005
; Bookheimer et al., 2000
; Dickerson et al., 2004
; Garrido et al., 2002
; Johnson et al., 2000
). With further increases in sBP, however, the arterial changes frequently associated with hypertension (such as hardening and plaque deposits) might decrease regional blood flow to the extent that compensation can no longer occur in those same regions, even during the task, and net signal change appears small, as shown previously (Jennings, 2003
Parietal and posterior cingulate cortices are among the first regions to show signs of hypometabolism or hypoperfusion in AD (Ishii et al., 1997
; Johnson et al., 2005
; Minoshima et al., 1997
; Mosconi et al., 2004
; Salmon et al., 2005
). In normal, healthy older adults, genetic risk for AD is also associated with blood flow and glucose metabolism changes in these same brain regions, suggesting that changes occur prior to onset of the disease (Drzezga et al., 2005
; Reiman et al., 2004
; Small, 1996
). We have no way of knowing which, if any, of our subjects will eventually decline cognitively, but the overlap in areas of differential activation in both vascular risk and AD risk suggests a possible vehicle by which the two types of risk might interact in some older adults, as shown in many studies between high midlife sBP or BMI and later AD risk (Gustafson et al., 2003
; Kivipelto et al., 2002
; Launer et al., 2000
; Skoog et al., 1996
; Swan et al., 1998
; Wu et al., 2003
; Yamada et al., 2003
). If a decreased resting state does indeed underlie our results, the link between vascular health and risk for AD found in some past studies may be explained by an overlap of areas associated with AD risk and vascular health risk. Vascular health-related decreases in resting state activity occurring in regions that are later depressed by AD could compound AD effects, perhaps making symptoms evident at an earlier age. The task we used in the current study includes control activity and the task activity, but no true “resting state” periods. Because any activity during our control task is necessarily compared with activity during the memory task, it is not possible to separate the effects of each in order to determine whether resting state activity was, in fact, correlated with vascular risk factors.
Finally, it is possible that rather than being specific to cardiovascular risk or to AD risk, the overlapping patterns of fMRI activation seen with cardiovascular risk in this study and previously with genetic risk for AD (Bondi et al., 2005
; Bookheimer et al., 2000
) are indicators of compensation for challenges to the memory processes in general, which may or may not be progressive. Such compensation for cognitive decline may be characterized initially by increased recruitment of brain regions to augment cognitive resources. Only future longitudinal study will help to elucidate these relationships.
Our participants were recruited by UCLA’s Memory and Aging Clinic. Volunteers having a family history of dementia are naturally drawn to these studies, and in this current group of thirty participants, only ten had no known direct family history of AD (parent, grandparent, or sibling). Because of this, our results may be generalizable only to those with an increased risk for AD. However, a recent study including subjects who largely were not known to have increased AD risk found increased fMRI activity in medial temporal lobe with increased stroke risk (Bangen et al., 2007
), suggesting that, in that region at least, the results are not specific to those with increased AD risk. Future whole brain studies having AD risk that is more representative of the general population than the current study are necessary to determine whether all of these results apply to the population at large.
We did not find a significant correlation between sBP&BMI and fMRI activity in primary sensory cortex, such as auditory or primary visual cortices, although both regions were engaged during the task. We did, however, see correlations between this measure and fMRI activity in motor cortex. It is therefore unclear how specific our results were to memory processes. Future studies that covary vascular health measures with fMRI activity using motor and sensory processing tasks would test this question more directly.
One goal of this study was to examine the relationships between vascular health risks and fMRI activity during a memory task across a mostly healthy range of vascular risk factors. We found that the correlations between sBP&BMI and fMRI activity were not driven solely by vascularly at risk outliers, but were evident across participants in the healthy ranges of sBP and BMI as well. This suggests that in these brain regions, sBP and BMI interact with fMRI activity as continuous variables. Therefore, separating participants into vascular risk versus no risk may mask such effects, as participants on either side of this somewhat arbitrary boundary would almost certainly be similar to one another.
We did not find a significant correlation between total cholesterol and fMRI activity during the memory task. It is possible that the effect of cholesterol is not distributed continuously as are the effects of sBP and BMI. Alternately, the brain response may have been more sensitive to the individual components of total cholesterol (HDL and LDL), which were not available to us. Lastly, caution must be taken in interpreting our cholesterol results since some of our subjects had their cholesterol tested without first having fasted, which may have affected the results.
Our results demonstrate that even within the normal range, certain vascular health risks in older, cognitively intact adults are correlated with increased fMRI activity during a memory task in regions similar to those showing greater activity in adults having increased AD risk. This study raises the question of how vascular risk and cognition may be associated, and provides a starting point for future studies aimed at investigating these relationships further.