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This study was undertaken to examine differential functional MRI patterns in those at genetic risk for Alzheimer disease (AD), specifically investigating parietal lobe activation, a brain region with changes noted in the early stages of AD.
This study uses functional MRI to investigate blood oxygenation level dependent changes in the parietal lobe in a high-risk sample of 18 asymptomatic offspring of autopsy-confirmed AD cases, compared to 15 matched controls. The cognitive activation paradigm was a mental rotation task, which requires individuals to rotate three-dimensional cube stimuli to judge their similarity.
We found no differences in either reaction time or performance accuracy between groups. However, the at-risk individuals showed increases in activation in the right superior parietal lobule (BA 7), the right insula (BA 13), the right middle frontal gyrus (BA 10), and the right inferior frontal gyrus (BA 47).
We present evidence for a compensatory mechanism for those at increased risk for Alzheimer disease (AD). This study examines and confirms parietal changes with increased risk for late-onset AD, despite normal cognitive performance. Added to the previous findings from this group, these results demonstrate the sensitivity of functional imaging measures to brain changes that are not yet reflected in cognitive performance, which may ultimately serve as an important indicator of disease.
Since pathologic changes most likely start years or even decades before the manifestation of clinical symptoms in Alzheimer disease (AD), functional brain imaging of unaffected offspring of confirmed AD cases provides a means of studying the earliest brain changes associated with risk for the disease. From functional studies of mildly affected patients with AD, several brain regions demonstrate changes early in the disease process. The question is whether functional alterations are evident prior to the development of clinical symptoms and prove predictive of conversion to AD. The medial temporal lobe (MTL), a region critical for memory function, is implicated early in the course of AD. Our group has now shown increased activation in the MTL among asymptomatic individuals at elevated risk for AD using an episodic memory paradigm.1 Further, it appears that distinct patterns of activation among those at risk are associated with genetic findings reported by our group.2-4 In addition to changes in the MTL, results of positron emission tomography (PET) studies in patients with early AD reveal significant cerebral glucose hypometabolism in parietal cortical regions,5-7 positing the parietal lobes as yet another locus where functional changes may precede clinical symptoms.
The purpose of the present study, therefore, was to assess parietal changes in an asymptomatic sample that is at genetic risk for late-onset AD (by having one autopsy-confirmed affected parent, and at least one more affected first-degree relative), using fMRI. For this purpose, we chose a task involving mental rotation (also known as mental imagery). Mental rotation has been frequently studied in perception and cognition research.8 In functional imaging studies, tasks involving mental rotation demonstrate robust and consistent activation in the parietal cortex.9-13 We hypothesized that individuals at familial risk for AD would demonstrate increased activation in parietal regions compared to a matched sample of healthy controls during performance of this task. We also hypothesized that these brain changes would be present before changes in cognitive performance are evident.
At-risk participants in this study are enrolled in an ongoing study of preclinical disease markers in a sample of individuals at genetic risk for development of late-onset AD. These individuals come from families initially enrolled at Johns Hopkins University as part of the NIMH Alzheimer's Disease Genetics Initiative. Those enrolled have a parent with autopsy-confirmed AD and at least one additional first-degree relative with a clinical diagnosis of probable AD, are at least 50 years of age, and are free of memory impairment, memory complaints, or treatment for cognitive impairments. Control participants, also free of memory impairment, cognitive complaint, or treatment, screened negative for the presence of a first-degree relative with AD or suspected dementia. A full description of this study, which has been approved by the Johns Hopkins Institutional Review Board, can be found in our previous publication.1 Included here are data from a subset of the overall sample, 18 right-handed at-risk and 15 right-handed control subjects, matched on age, sex, and education, who completed the fMRI task outlined below. Prior to scanning, individuals completed measures of anxiety and depression.14,15 In addition, all participants were administered a cognitive battery which included the Mini-Mental State Examination and the North American Adult Reading Test from which estimated IQs were computed.16,17 All participants provided written informed consent.
Data were acquired on a 1.5 Tesla Philips Intera-NT system (Philips Medical Systems, Best, The Netherlands) at the F.M. Kirby Functional Imaging Research Center (Kennedy Krieger Institute, Baltimore, MD). The system is equipped with Galaxy gradients (66 mT/m at 110 mT/m/sec). A sagittal localizer scan was collected to pinpoint the exact location of the brain. Functional scans were collected using echoplanar imaging (EPI) and a blood oxygenation level dependent (BOLD) technique with repetition time (TR) = 1,500 msec, echo time (TE) = 39 msec, flip angle = 90 degrees, field of view (FOV) 240 mm2 in the xy plane, and matrix size = 64 × 64. Twenty-seven axial slices were acquired with a 3.5 mm thickness and an interslice gap of 0.5 mm (used to reduce the possibility of obtaining artifacts in the images due to incomplete echo digitization) oriented parallel to the anterior-posterior commissure line. Functional scanning was performed in a single session with 300 time points. Total functional acquisition time was 7.5 minutes. A high-resolution whole-brain anatomic scan was also obtained using a T1-weighted, three-dimensional magnetization prepared rapid acquisition gradient echo sequence with the following parameters: TR = 8.6 msec, TE = 3.9 msec, FOV = 240 mm, flip angle = 8 degrees, matrix size = 256 × 256, slice thickness = 1.5 mm, 124 slices.
Participants were presented with a mental rotation challenge, using three-dimensional cube stimuli. Participants viewed the stimuli in pairs and were instructed to press one button if the two stimuli were either the same or could be rotated to look the same (congruent), and to press the other button if the two objects were different or could not be rotated to look the same (incongruent). Trials that involved rotation used a 20-, 40-, or 90-degree rotation (randomly assigned), to prevent subjects from developing a degree-specific mapping strategy. The incongruent stimulus pairs appeared as mirror images of each other, upon completing the required rotation. The different stimulus pairs were identical to each other, except one of the stimuli was missing a cube (figure 1). The task was programmed using the E-prime programming environment (E-prime 1.1; Psychology Software Tools, Inc., Pittsburgh, PA). The task consisted of 80 trials with unique stimuli, evenly divided among “same,” “different,” “congruent,” and “incongruent” stimulus types. Twenty additional null event trials (fixation) were interspersed throughout the task. The stimulus order was completely randomized and interstimulus intervals were jittered between 5, 6, and 7 seconds. All subjects underwent a computerized practice session with similar stimuli before scanning, with practice sessions continuing until the participant demonstrated task comprehension. The instructions were explained again once the participant was inside the scanner. Behavioral responses were recorded using an MR-compatible serial response button box.
Data preprocessing was conducted on a Windows XP Professional workstation. Statistical Parametric Mapping (SPM99, Wellcome Department of Imaging Neuroscience, University College, London, UK) was used, under the MATLAB 6.1 (The Mathworks, Sherborn, MA) programming environment. Slice timing correction was conducted using an intermediate slice (#13) as the reference slice, and sinc-interpolation. Motion correction was conducted using a six-parameter affine transformation (three translations and three rotations in x, y, and z axes), followed by reslicing using a “windowed” sinc-interpolation. Twelve parameter affine transformation and nonlinear deformation using 7 × 8 × 7 basis functions and medium nonlinear regularization were conducted to warp each subject's data into standard stereotaxic space. Template space was defined by SPM's standard EPI template (Montreal Neurologic Institute, McGill University, Montreal, Canada). Data were resliced to isotropic voxels (2 mm3) using trilinear interpolation, and spatially smoothed with a full-width at half-maximum isotropic Gaussian kernel of 8 mm3.
A voxel-based general linear model was fit to each subject's time series, within the framework of Statistical Parametric Mapping (SPM99). Data were modeled as event-related, and convolved with SPM's canonical hemodynamic response function to account for the lag between stimulation and the BOLD signal. The model was estimated using SPM's standard ordinary least squares. Stimulus onset times and corresponding reaction times were used to define two conditions, ROTATION and NO-ROTATION. The former condition consisted of the trials in which subjects were required to perform a mental rotation (whether it was a match or a non-match), whereas the latter consisted of trials in which they were required to match the stimuli without rotation (same or different). The contrast of interest subtracted activation during the NO-ROTATION condition from the ROTATION condition, in order to isolate task-relevant activation (i.e., rotation) from task-irrelevant activation (i.e., motor, visual).
Analysis of within-group activation using one-sample t tests was conducted to determine the individual group activation patterns and ensure the task produced the expected parietal lobe activation in both groups.
In addition, a two-group comparison was conducted to compare the at-risk group with the control group using an analysis of covariance, to control for possible confounding effects of age, sex, handedness, education, anxiety, depression, and APOEe4 status. Voxel-wise threshold for inference and visualization was set to p = 0.001, uncorrected, with a cluster-extent threshold of k = 20 voxels. The coordinates of voxels that survived the statistical threshold were produced in MNI space and converted to Talairach space to facilitate anatomic labeling, which was conducted using the Talairach Daemon software with an adaptive gray matter search range of 5mm3. Labels were manually checked with the Talairach and Tournoux atlas.
Behavioral data recorded from the task included mean reaction time and accuracy for each of the task conditions. These scores were compared using an independent samples t test in SPSS version 15.0 (Statistical Package for Social Sciences; SPSS Inc., Chicago, IL).
The at-risk and control participants did not differ in age, education, gender, or APOE4 status, nor were there any significant differences in cognition, anxiety, or depression (table 1). Analysis of within-group activation using one-sample t tests revealed the expected task-related activation in the parietal lobes in both groups. However, the at-risk group showed much more extensive activation. Controls showed uni-lateral activation in the superior temporal, superior frontal, and parietal lobes when contrasting the non-rotate and rotate trials. The at-risk group showed a greater degree of activation in these regions as well as others including the occipital lobe (table 2, figure e-1 on the Neurology® Web site at www.neurology.org).
The two-group analysis of covariance, with age, sex, handedness, education, anxiety, depression, and ApoE ε4 as covariates, revealed significantly increased activation in the right inferior frontal gyrus (BA 47), the right middle frontal gyrus (BA 10), the right insula (BA 13), and the right superior parietal lobule (BA 7) in the at-risk group compared to the control group. Talairach coordinates and statistical values are presented in table 3 and images in figure 2. The reverse comparison did not show any decreased activation in the at-risk group compared to the controls. Comparison of the groups' behavioral data revealed no significant differences in performance. Reaction time and accuracy were similar between groups during all task conditions, demonstrating the task was being performed at comparable levels (table e-1).
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.
Funding for this work was provided by the National Institute on Aging, NIH (PI: Susan Bassett; AG16324).
Disclosure: The authors report no conflicts of interest.
Supplemental data at www.neurology.org