Increasing age is associated with reduced episodic memory functions including encoding, and a host of cerebral changes including reduced WM integrity, reduced CBF, reduced glucose metabolism in frontal and temporal lobes, reduced volume in MTL and prefrontal regions critical for episodic memory, and alterations in the cerebrovascular system (D’Esposito, Deouell, & Gazzaley, 2003
). Age is also the largest single risk factor for AD and is associated with a number of other neurodegenerative diseases and cerebrovascular disease. Functional MRI studies have revealed age-related changes in brain activation during a variety of cognitive tasks including episodic memory tasks (see Persson & Nyberg, 2006
for review). In the present study we examined age-related changes in brain activation across the adult lifespan in a large sample of cognitively healthy individuals between the ages of 18 and 83 years using an episodic encoding paradigm found to yield robust activity in the MTL, and a metacognitive self-appraisal paradigm that results in robust activity in posterior cingulate and medial frontal and subcortical regions important for metacognitive executive functions. The sample was enriched with subjects at risk for AD, enabling us to determine whether risk factors influenced the effect of aging.
D’Esposito et al. (2003)
have suggested that age-related changes in the blood-oxygenation level dependent (BOLD) fMRI signal are more difficult to interpret because of changes in the cerebrovascular system (e.g., altered neurovascular coupling) that might influence accurate measurement of the BOLD signal. For example, normal aging is associated with increased incidence of several conditions that might influence the BOLD signal such as chronic cerebral ischemia, atherosclerosis, small vessel disease, reduced resting blood flow, and changes in specific neurotransmitter systems. In order to study these decoupling changes prospectively, it is necessary to identify asymptomatic people at risk for AD and follow them longitudinally with imaging exams including perfusion imaging and BOLD, which are sensitive to change. Such work is underway in our laboratory.
4.1 Episodic Encoding
In a series of previous studies using the same task, we have demonstrated reduced brain activity in the MTL in individuals with certain risk factors for AD including individuals with AMCI (Johnson et al., 2006a
), middle-aged individuals with a positive parental history of AD (Johnson et al., 2006b
), and carriers of the APOE e4 allele (Trivedi et al., 2006
). In the present study, we observed significant age-related declines in fMRI activation bilaterally in ventral temporal lobe regions important for object identification and the hippocampus during episodic memory encoding in a large sample of cognitively healthy adults.
The results of the analyses restricted to the 148 participants in the AD risk factor analysis indicated there were several locations in the medial and ventral temporal lobe that were related to task activation, but there was no significant interaction between age and FH or APOE risk factors. At a more liberal threshold we found that APOE e4 carriers who were also FH+ displayed age-related increases in fMRI activation in the right hippocampus. In conjunction with our prior results, these results suggest that FH status continues to exert an effect but appears to be separate from the effects of age (in the age range that we studied), while APOE may interact with age.
The effect of APOE on the brain response is still unclear in both the direction of the effect and its potential meaning. Few if any fMRI studies have examined the interaction between age and APOE in a large sample. Studies of the effect of APOE alone have provided mixed results. Lind et al. (2006)
found that APOE e4 carriers (age range: 49 – 74 years) displayed reduced activation in the left inferior parietal cortex, bilateral anterior cingulate cortex, and the right hippocampus during a novel versus familiar word encoding paradigm (see also Trivedi et al., 2006
). In contrast, other studies have reported increased activation in elderly APOE e4 carriers (mean age > 75 years) using a verbal paired-associate paradigm (Han et al., 2006
) and a novel versus familiar picture encoding paradigm (Bondi, Houston, Eyler, & Brown, 2005
), though the APOE4 positive subjects also performed significantly better on neuropsychological tests of encoding. The meaning of increased signal with risk has been hypothesized to reflect a compensatory mechanism or mechanisms. Others have suggested an alternative hypothesis (Mondadori et al., 2006
) involving an interaction with age, where a beneficial effect may be present early in life and deleterious effect in late life. These hypotheses now require more clarification with operational criteria for further direct testing and validation, and characterization of the temporal profile over the lifespan.
Prior fMRI studies of age-related changes in brain activity during episodic memory have also yielded conflicting data. Several studies have reported reduced activation in elderly relative to young individuals in certain brain areas important for episodic memory function, such as the prefrontal cortex and MTL (e.g., Grady et al., 1995
; Logan, Sanders, Snyder, Morris, & Buckner, 2002
; Stebbins et al., 2002
). In contrast, other studies have reported greater activity in these same regions in older individuals during episodic memory tasks (Cabeza, Anderson, Locantore, & McIntosh, 2002
; Grady, Bernstein, Beig, & Siegenthaler, 2002
; Gutchess et al., 2005
; Morcom, Good, Frackowiak, & Rugg, 2003
). One recent study examined age-related changes in brain activity in three groups of individuals aged 20-30 years, 40-60 years, and 65-87 years. These authors reported linear increases in fMRI activation in the medial frontal and parietal regions at both encoding and recognition, whereas activation in the dorsolateral prefrontal cortex was found to linearly decrease with age (Grady, Springer, Hongwanishkul, McIntosh, & Winocur, 2006
). The results of the present study indicate that FH status and APOE genotype do not strongly affect age-related changes in brain activation using the episodic encoding paradigm employed in this study. More studies are needed to clarify the conflicting data regarding age-related changes in brain activity during episodic memory function.
It is important to note that laboratories using fMRI to investigate aging and risk-factors for AD have used episodic memory tasks which vary along several experimental (e.g., task difficulty, task timing, use of a ‘resting state’ baseline, or different statistical analysis techniques) and clinical (e.g., alterations in cerebral hemodynamics and energy metabolism, age, degree of cognitive impairment, and other health characteristics) dimensions that may influence the accurate measurement of task-related changes in the BOLD hemodynamic response. In addition, a recent fMRI study of paired-associate encoding and recall by Celone et al. (2006) emphasizes the possibility that the effect of disease severity may be nonlinear.
Methodological and clinical variability limits the extent to which one study can be generalized to another. Large studies are needed in which these factors can be modeled or manipulated experimentally, possibly using a non-parametric approach similar to the one employed in this study. FMRI studies of cognitive operations are prone to the same problems and issues as any other neuropsychological test when applied to patient groups or individuals with risk factors for disease. Therefore, a psychometric approach would also be useful if fMRI is to be successfully used to examine functional changes in the brain during episodic memory or on other cognitive tasks in the elderly or individuals with risk factors for AD.
4.2. Meta-cognitive self-appraisal
The most prominent cognitive deficit in AMCI is a robust impairment in episodic encoding and memory that typically progresses to other aspects of cognitive function. However, awareness of cognitive dysfunction in individuals with AD and AMCI is often quite variable, ranging from clear insight and marked concern about cognitive difficulties to frank anosognosia (i.e., a patient’s unawareness of deficits resulting from brain disease or injury) (Vogel, Hasselbalch, Gade, Ziebell, & Waldemar, 2005
; Vogel et al., 2004
). Previous findings from our laboratory indicate that individuals with AMCI display reduced brain activation in medial prefrontal and posterior cingulate regions (Ries et al., 2007
) using the same meta-cognitive self-appraisal task used in the present study. Ries et al. (2007)
also found that activation of both medial prefrontal and posterior cingulate regions in individuals with AMCI was strongly related with level of insight into cognitive difficulties (indexed by a discrepancy score between patient and informant ratings of cognitive decline in each AMCI participant, i.e., the informant questionnaire on cognitive decline in the elderly (Jorm, Christensen, Korten, Jacomb, & Henderson, 2000
) such that individuals with poor insight also displayed the least amount of brain activation in these cortical midline structures. Importantly, this relationship existed even after controlling for extent of memory impairment.
In the present study, we sought to determine if fMRI activation in metacognitive regions such as the prefrontal cortex and posterior cingulate gyrus were modulated by risk factors for AD in cognitively healthy individuals. We found that increasing age was associated with reduced activity in the medial prefrontal cortex. By contrast, we also found that increasing age was associated with increased activity in the lateral parietal cortex, amygdala, orbitofrontal cortex, and basal forebrain across 203 individuals. In the follow-up analysis, restricted to the 150 participants with known AD risk factor status, we failed to demonstrate any evidence that these age-related changes in brain activation during self-appraisal were modulated by APOE genotype or FH status. Although, activity in certain brain regions such as the medial prefrontal cortex appears to decline over the lifespan, other brain regions such as the lateral parietal cortex appear to exhibit an increase in brain activity over the lifespan. These results only generalize to cognitively healthy people, a different pattern will likely be observed in symptomatic participants along the AD continuum.
There are several limitations to the present study. First, the FH status and APOE genotype were not available for all subjects. Therefore, we were not able to determine the influence of these variables across the entire lifespan. Second, the risk factor of parental FH is quite vague and likely comprises unidentified genes and environmental factors. Only 10% of the FH+ individuals had parents with autopsy confirmed AD, whereas a consensus diagnostic conference using published DSM-IV and NINDS-ADRDA criteria was used for the remaining FH+ individuals. Although not likely to have a significant effect on the results, our FH+ cohort may have been contaminated with subjects whose demented parents did not actually have AD pathology. Third, we cannot exclude the possibility that the FH- group may have contained persons whose parents may eventually develop AD. Finally, the design of this study was cross-sectional. It will be more informative to examine rates of change within individuals and these studies are underway in our laboratory.
Although risk factors such as FH and APOE have previously been shown to affect neural activation, the results of this study indicate that age-related changes in brain activation during episodic encoding and metacognitive appraisals are not strongly modulated by FH status or APOE genotype. We found age-related declines in brain activation in the ventral temporal lobes and the hippocampus during novel picture encoding and we showed that these regions were affected by AD risk factors (), and we provided limited evidence for an interaction between APOE genotype and age. We also found evidence for age-related declines in the medial prefrontal cortex during metacognitive self-appraisal and age-related increases in brain activation in the parietal cortex, orbital cortex and amygdala. There was no evidence that these age-related changes in brain activation during SA were modulated by FH status or APOE genotype. Given the current state of the literature, we suggest that future functional imaging studies in this area adopt psychometric methods familiar to neuropsychologists with large sample sizes and normative data. We also suggest that future studies involve a longitudinal component so that endpoints of AD status can be included in statistical models of early AD brain changes, thereby improving internal validity. Other imaging modalities such as perfusion and amyloid imaging should also be utilized in examining the early brain changes that occur prior to the onset of clinical AD.