This study presents an investigation of brain activation in asymptomatic offspring of autopsy-confirmed late-onset familial AD cases, in response to a spatial cognitive challenge. We report evidence that subjects in this high-risk sample are capable of performing as well on this task as their matched controls, but are activating specific cerebral loci to a greater extent. Familial risk status appears to be associated with increased activation in the parietal region as hypothesized, as well as the insula and frontal regions during mental rotation, providing further evidence that genetic risk for AD is associated with modifications in brain function, and that increased activation, especially in the prefrontal cortex, seems to be part of compensatory network.
There is some recent evidence that patients with AD perform poorly on mental rotation tasks, which may be due to pathologic changes in the parietal lobe that manifest as deficits in spatial processing.18
However, changes in cerebral blood flow as a function of cognitive load may be a characteristic preclinical marker in cases where AD symptoms have not yet manifested. While there has been report of decreased activation among individuals at risk for AD, our results are consistent with the majority of findings from other neuroimaging studies that report increases in brain activation in individuals at risk for AD, in spite of normal cognitive performance.19-24
These findings lend further support to the hypothesis that increased brain activation acts in a compensatory fashion to bring performance on cognitive challenges to the baseline of healthy controls. Additional neural resources may be required to complete the task in order to compensate for neuronal loss.25,26
Increased activation in the inferior and middle frontal gyri (Brodmann areas 47 and 10) in at-risk subjects may be part of a prefrontal compensatory network, previously implicated in functional imaging research with AD cases.25,27
A recent investigation also found that the right inferior pre-frontal lobe was activated to a higher extent in patients with AD than controls in response to a subtraction task, compared to various other regions with decreased activation.28
It is possible that prefrontal compensatory mechanisms are not task specific and respond similarly with increased neural activity to a variety of cognitive challenges.29
It has been proposed that distributed interactions between the parietal and frontal regions represent circuitry related to spatial attention.29
Thus increased activation in the frontal lobe, a brain region that does not usually show early pathology in AD, may reflect decreased functioning within the circuit. Further research is needed to elucidate the role of the prefrontal cortex in modulating cognitive performance in cases where the primary processing cortices are compromised.
Activation in the superior parietal lobule (SPL) in response to a mental rotation task has been extensively documented.11,30-33
Increased SPL activation during rotation was expected in this high-risk sample, and illustrates that individuals at risk for AD recruit more neural resources in the parietal lobe to resolve this spatial cognitive challenge than healthy controls.
Increased activation in the insula in the at-risk sample was a somewhat unexpected finding. Although its exact involvement in this type of task is unclear, previous research using similar tasks has demonstrated activation in the insular cortex with PET and fMRI.30,34
There is some recent evidence suggesting that the insula may be involved in spatial attention to mental representations. A recent fMRI study, using a spatial attention and working memory task to test whether it is possible to shift attention to locations within mental representation in working memory, found brain regions that were specific to the orienting of spatial attention, including the posterior parietal cortex, the insula, and the lateral and medial frontal cortices.35
This suggests that the insula may play an auxiliary role in mental rotation, one that deals with the orienting of attention. The absence of increased insula activity when the at-risk group is examined independently suggests they have a sustained increase in insular activity across all conditions. This further supports the notion that the heightened insular activity may reflect the orienting of spatial attention. Further, structural MRI and cerebral volumetry studies of AD report local gray matter loss in the insula.36-39
Thus it is possible that overactivation in the insula makes up for mild neuronal loss in the same area. Finally, although increased insular activation has been associated with elevated anxiety,40
that does not provide an explanation for the activation seen in the current study. Clearly this heightened insular activation requires further investigation.
This study lends support to the hypothesis that asymptomatic individuals at risk for familial late-onset AD recruit more widespread neural activity than healthy individuals to resolve a spatial cognitive challenge. This provides further evidence that genetic risk for AD is associated with modifications in brain function, and that increased activation, especially in the prefrontal cortex, seems to be part of a compensatory network.