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Logo of nihpaAbout Author manuscriptsSubmit a manuscriptNIH Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
 
J Am Geriatr Soc. Author manuscript; available in PMC Jul 15, 2013.
Published in final edited form as:
PMCID: PMC3711192
NIHMSID: NIHMS308081
MRI Volume of the Angular Gyri Predicts Financial Skill Deficits in Patients with Amnestic Mild Cognitive Impairment
H. Randall Griffith, Ph.D.,1,2,4 Christopher C. Stewart, M.S.,2 Luke E. Stoeckel, Ph.D.,2,5 Ozioma C. Okonkwo, Ph.D.,6 Jan A. den Hollander, Ph.D.,3 Roy C. Martin, Ph.D.,1,4 Katherine Belue, B.S.,1,4 Jacquelynn N. Copeland, B.S.,2 Lindy E. Harrell, M.D., Ph.D.,1,4,7 John C. Brockington, M.D.,1,4 David G. Clark, M.D.,1,4,7 and Daniel C. Marson, J.D., Ph.D.1,4
1Department of Neurology, University of Alabama at Birmingham, USA
2Department of Psychology, University of Alabama at Birmingham, USA
3Department of Cardiology, University of Alabama at Birmingham, USA
4Alzheimer's Disease Research Center, University of Alabama at Birmingham, USA
5Department of Psychiatry, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
6Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
7Birmingham Regional Veterans Affairs Medical Center, Birmingham, AL, USA
Author Contributions: All the authors contributed toward manuscript design, data analysis, preparation and writing of the paper.
Corresponding Author: H. Randall Griffith, Ph.D., ABPP-CN; SC 650, 1530 3rd Ave. S., Birmingham, AL 35294-0017, rlgriffith/at/uabmc.edu, Phone (205) 934-2334; Fax (205) 975-3094.
OBJECTIVES
Persons with amnestic mild cognitive impairment (MCI) have demonstrated subtle impairments in IADLs including financial abilities, although the underlying brain changes related to these IADL impairments is poorly understood. The purpose of this investigation was to better understand how brain atrophy in MCI as measured by MRI volumetrics could impact IADLs such as financial abilities.
DESIGN
Controlled, matched sample, cross-sectional analysis regressing MRI volumetrics with financial performance measures.
SETTING
University medical and research center.
PARTICIPANTS
Thirty-eight MCI patients and 28 older adult controls.
MEASUREMENTS
MRI volumetric measurement of the hippocampi, angular gyri, precunei, and medial frontal lobes. Participants also completed neuropsychological tests and the Financial Capacity Instrument (FCI).
RESULTS
We performed correlations between FCI scores and MRI volumes in the MCI group. Patients with MCI performed significantly below controls on the FCI and had significantly smaller hippocampi. Among MCI patients, performance on the FCI was moderately correlated with angular gyri and precunei volumes. Regression models demonstrated that angular gyri volumes were predictive of FCI scores. Tests of mediation showed that the relationship of angular gyri volume with FCI score was partially mediated by measures of arithmetic and possibly attention.
CONCLUSION
Impaired financial abilities in amnestic MCI correspond with volume of the angular gyri as mediated by arithmetic knowledge. The findings suggest that early neuropathology within the lateral parietal region in MCI leads to a breakdown of cognitive abilities that impact everyday financial skills. The findings have implications for diagnosis and clinical care of patients with MCI and AD.
Keywords: magnetic resonance imaging, mild cognitive impairment, financial capacity, angular gyrus, hippocampus, precuneus
Mild cognitive impairment (MCI) is a clinical construct that denotes the transitional phase between normal cognitive aging and Alzheimer's disease (AD)1. Diagnostic criteria for MCI indicate that these patients have “generally intact” activities of daily living2, although investigations of instrumental activities of daily life (IADLs) in MCI have revealed mild impairments in both informant reported IADLs3 and laboratory-assessed IADLs4, 5. By definition, IADLs such as financial capacity6, medication management, and driving are the skills that are necessary for independent living and autonomy of older adults in this society. Financial capacity comprises a broad range of conceptual, pragmatic, and judgment abilities, ranging from basic (e.g. identifying and counting coins and currency) to more complex skills (e.g. paying bills, managing a bank statement, and exercising financial judgment)7. Declines in financial capacity are some of the earliest IADL changes noted in cognitive aging and dementia8.
Our group has systematically investigated financial capacity deficits in the amnestic variant of MCI as well as in patients with AD. Patients with amnestic MCI have been shown to be impaired on the Financial Capacity Instrument (FCI), a direct assessment measure of financial capacity, specifically on domains measuring financial concepts, bank statement management, financial judgment, and bill payment4, all of which represent relatively complex aspects of financial capacity. The neurocognitive predictors of financial abilities in patients with amnestic MCI include measures of attention9, visuomotor tracking9, and written arithmetic ability10.
The presence of complex IADL deficits in MCI suggests that brain networks underlying the neurocognitive underpinnings of daily activities are becoming non-functional in the context of brain changes that occur in amnestic MCI. Brain changes are observable on PET, structural MRI, and fMRI in patients with amnestic MCI, and these neuroimaging markers are often indicative of neuropathological changes related to AD11. For instance, the importance of arithmetic to financial abilities suggests that pathology within the angular gyrus may be related to declines in financial capacity12; attention and executive function as predictors of financial abilities could implicate pathology within the midline cortical regions such as the posterior cingulate/precuneus and medial superior frontal lobes1316. Although measures of episodic memory are not primary predictors of FCI performance in amnestic MCI patients9, 10, the prominence of hippocampal/medial temporal lobe pathology in these patients17 suggests that atrophy of these regions may also play a role in cognitive and mental status declines affecting FCI performance.
An important gap in neurodegenerative disease research is the identification of links between brain changes, cognitive change, and changes in IADLs; this gap exists despite advances in neuroimaging and in the assessment of IADLs. Only a few studies have attempted to use brain imaging techniques to examine how brain changes in AD and MCI can influence the everyday functional abilities of older adults1822. Unfortunately, such studies have generally relied on informant report of IADLs rather than direct-assessment measurements. The reliance on informant report is concerning as studies have suggested that informant ratings of IADLs may be unreliable23, 24.
Of the available neuroimaging technologies, structural MRI volumetrics is a potentially useful tool to examine IADL changes in MCI as it is sensitive to atrophy in patients with MCI25, is correlated with cognitive function in MCI26, and has generally good correspondence with AD pathology at autopsy11, 27.
The current study investigates MRI volumetrics of four structures suspected to play a role in financial abilities in persons with amnestic MCI: the medial prefrontal lobes, the hippocampi, the medial parietal/precunei, and the angular gyri. As discussed below, these structures were chosen because they are brain regions known to be affected in MCI and AD, and given their prior association with cognitive abilities that could influence financial abilities. We sought to identify which regions contribute to FCI performance, in patients with amnestic MCI. We additionally sought to explore the neurocognitive mechanism(s) that might mediate the relationships of brain atrophy to FCI performance in patients with amnestic MCI.
Participants
Sixty-six participants were included in this study, of which 38 patients had amnestic MCI and 28 were age-matched healthy older adult controls. Patients with amnestic MCI were community-dwelling older adults who presented for clinical evaluation to the UAB Memory Disorders Clinic, a tertiary care outpatient clinic. They were subsequently recruited into the UAB Alzheimer's Disease Research Center (ADRC) and an associated study of functional change in amnestic MCI (Cognitive Observations in Seniors, or “COINS”). All participants underwent a research assessment comprised of neurological evaluation, neuropsychological testing, capacity testing, and laboratory blood work. The diagnosis of amnestic MCI was made in a consensus diagnostic conference using original Mayo criteria2. Informant or patient report of subjective memory impairment was determined through clinical examination as well as an informant interview conducted separately from the patient's ADRC exam. Neuropsychological tests used to fulfill criteria for amnestic MCI included the Wechsler Memory Scale-Revised Edition (WMSR) Logical Memory28, the California Verbal Learning Test II (CVLT-II)29, DRS Memory, and 10/36 Spatial Recall. Impairment was determined by the ADRC neuropsychologists in reference to appropriate age-based norms and clinical judgment regarding change from prior/premorbid level of function. Overall cognition was assessed through performance on the Dementia Rating Scale-2 (DRS-2)30 and the Mini-Mental State Examination (MMSE)31. Activities of daily living (for diagnostic purposes) were assessed by informant report using a standardized interview format relevant to MCI and early AD.
At the time this study began, the UAB ADRC was using the original Mayo criteria for amnestic MCI2. Retrospective examination of the frequency of cognitive impairment in our ADRC amnestic MCI cohort revealed that approximately 2/3 of the participants would likely meet criteria for amnestic MCI - multiple cognitive domains involved32.
Exclusion criteria for the amnestic MCI group included a diagnosis of exclusively non-amnestic MCI, evidence of another neurodegenerative disease, history of stroke, another chronic debilitating neurological illness (i.e., MS or cerebral palsy), severe organ disease, autoimmune disease, cancer (except skin cancer), alcoholism, or a terminal condition with less than 12 months to live. Participants were also excluded if they had untreated major depression or any other severe psychiatric disorder.
Control participants were 28 volunteers recruited from the community into the ADRC through newspaper advertisements or health fairs. These participants underwent ADRC neurological evaluation and neuropsychological testing to ensure the absence of medical and psychiatric conditions that could compromise cognition, and well characterized as cognitively normal following ADRC diagnostic consensus conference. Controls in the ADRC also met the exclusion criteria listed above for amnestic MCI participants.
All participants gave informed consent according to UAB Institutional Review Board guidelines.
Financial Capacity Instrument (FCI)
The FCI is a standardized psychometric instrument developed to directly assess the financial abilities and performance of older adults4, 33. The FCI assesses financial abilities based upon a three-level conceptual model of the financial capacity construct: specific financial abilities, broader financial activities, and overall financial capacity4, 33. The development, reliability, and validation of the instrument have been described elsewhere33. Participants were administered the FCI by a trained technician who then scored performance on the items based upon standardized criteria. In this study, only the FCI domains of financial conceptual knowledge (Domain 2), bank statement management (Domain 5), financial judgment (Domain 6), and bill payment (Domain 7) were used because of prior evidence demonstrating that these domains discriminate best between healthy controls and amnestic MCI patients4, 9. Participants' scores on these domains were summed to create an abbreviated FCI Total Score. The prior experience of our participants with the financial skills measured by the FCI was determined by self-report and/or informant report. This information was then used to correct for lack of prior experience in any applicable financial tasks and domains following our previously described method4.
Neuropsychological Tests
Each participant was administered a battery of neuropsychological tests by a trained technician. From this battery, we selected the following measures for inclusion in this study because of their prior association with FCI performance in MCI9, 10:
Attention was measured by the Wechsler Memory Scale - Third Edition (WMS-III) Spatial Span subtest34.
Visuomotor tracking was measured by Trail-Making Test A35.
Arithmetic ability was measured by the Wide-Range Achievement Test - Third Edition (WRAT-3) Arithmetic subtest36.
The raw scores from these measures were used in the statistical analyses.
MRI Acquisition and Data Processing
MRI images were obtained using a Philips Intera 3 Tesla MRI system with a quadrature TR head coil to measure gray matter volumes from our regions of interest (ROI). These imaging sequences consisted of 1) multi-slice sagittal, axial, and coronal T1 FFE scout sequences acquired using TR/TE=11.1/4.6 ms, 256 × 128 resolution, and 10 mm slice thickness (for the purpose of image alignment) and 2) multi-slice sagittal T1 FFE acquired using TR/TE=9.3/4.6 ms, 240 × 240 resolution, and 2 mm slice thickness.
After the MRI images were obtained, they were transferred to a workstation running SPM5 (www.fil.ion.ucl.ac.uk/spm/software/spm5). Tissue segmentation was derived in SPM5 and involved segmentation/normalization/modulation of the brain and smoothing of the resulting gray and white matter images37. The T1 image set was first skull stripped and the origin of each scan manually set to the anterior commissure. Next, a combined normalization/segmentation process was implemented on the scan using the prior probability templates provided with the SPM5 program. These tissue probability maps are modified versions of the ICBM Tissue Probabilistic Atlases. The results of this modulated segmentation/normalization process are gray matter, white matter, and CSF images for each subject normalized to the same stereotactic space37. Finally, gray and white matter images were smoothed using an 8 mm Gaussian kernel.
We first used voxel-based morphometry (VBM) to explore the predictive ability of brain voxels within the MCI group upon FCI scores. Voxel-level data were then analyzed for clusters associated with FCI score, with a threshold of 10 voxels per cluster. Associations were then corrected for multiple comparisons, with significance set at P < 0.00025. Voxel clusters that predicted FCI score variance past this threshold were identified by the MNI coordinate system38.
The ROI for volumetric analyses were then identified using an automated pickatlas routine in SPM5. This method is based upon an anatomical parcellation of the MNI MRI Single-subject brain38 and has the advantage of requiring no trained user interface to reliably obtain volumetric masks from any of 45 cortical and subcortical ROI (each hemisphere) after modulated MRI images are segmented and normalized in SPM5. Similar methods have been shown to have good reliability with manual traces of the hippocampus in patients with dementia39. Based upon this method, we derived bilateral volumes of the following ROI (see Figure 1):
Superior Frontal Gyri, Medial - this region was defined on the medial aspect of the frontal cortex and included all of the superior frontal gyrus to a posterior border of the supplementary motor area and cingulate, with an inferior border at the line of the anterior-posterior commisure, at which point the orbital portion of the superior frontal gyri occurs38.
Hippocampi - this region consisted of the gray matter in the region of the temporal ventricular horns including the dentate gyrus, uncus, and hippocampus proper, limited caudally by the parahippocampal ramus of the collateral fissure38.
Precunei - this region is defined on the medial cortical surface of both hemispheres with posterior boundaries of the parietooccipital sulcus, dorsally by the marginal sulcus, and ventrally by the subparietal sulcus38.
Angular Gyri - this region was defined anteriorly by the angular sulcus and caudally at the occipitoparietal line38.
Figure 1
Figure 1
Regions of interest as derived by SPM for volumetric analysis. Regions are labeled.
All ROI were derived for both hemispheres. Given that asymmetries were not observed in these structures at the group level, hemispheric ROI volumes were summed to obtain a bilateral ROI volumes, a procedure that also effectively reduced the number of statistical tests performed. We adjusted for the influence of sex and age on MRI volumes using multiple regression analyses based on the control participants40. The regression equations were then applied to the volumes of MCI participants and the predicted variance was removed from the observed volumes. The result is a residual score that removes variance due to body size and aging. The z-score transformations of adjusted volumes were then computed based upon the control group's mean adjusted volumes.
Statistical Analyses
Demographic data were compared using independent samples t tests or Chi-square (for categorical data). Group differences on neuropsychological, FCI, and MRI measures were tested using independent samples t tests. Within the MCI patient group, we first ran Pearson correlations to examine the associations among neuropsychological test scores, MRI volumes, and FCI performance (approximating a 5-1 subject-to-variable ratio). VBM analyses were then conducted as previously described above. We then performed a forward stepwise multiple regression (probability of F to enter = .05; probability of F to remove = .10) to determine which of the four MRI volumes best predicted FCI Total Score. This stepwise multiple regression was subsequently repeated with an initial predictor block entered to account for overall cognition (MMSE score) and demographic variables prior to the stepwise block. Finally, models of mediation using MRI volume(s) as the predictor variable(s), FCI score as the dependent variable, and neuropsychological variables as the mediator(s) were investigated using the method described by Sobel41. A two-tailed alpha level of .05 was adopted for all analyses.
Demographics, dementia staging, and clinical characteristics
Demographics, dementia staging, and clinical characteristics are presented in Table 1. As expected, our matched samples showed no significant differences in terms of age, education, race, or gender. Staging using the Clinical Dementia Rating (CDR)42 scale was different: all MCI patients had CDR scores = 0.5 and all controls had CDR = 0.0. Almost 40% of the MCI patients were taking a cholinesterase inhibitor for memory loss.
Table 1
Table 1
Demographics and Study Measures in Controls and MCI Patients
Neuropsychological Performance
Neuropsychological test performance is also shown in Table 1. Controls performed significantly above MCI patients on the MMSE, Spatial Span, and Trails A. There was a trend observed (P = .069) towards lower performance on WRAT-3 Arithmetic in the amnestic MCI patients.
Financial Performance
Comparison of FCI score performance is also shown in Table 1. Variance was not equal between groups (Levene's Test = 21.86, P < .001). We thus applied a t value that does not assume equality of variances. Comparison of the FCI Total Score demonstrated that controls performed significantly better than patients with amnestic MCI.
VBM Analysis
The regression of brain voxels onto FCI scores showed a positive association with one cluster of voxels with maxima located at MNI coordinates −54, −48, 44 (uncorrected P = .015) (posterior parietal cortex in the area of the angular gyrus), although this association became a trend and did not reach significance when the multiple-comparison correction was applied (corrected P = .081) (see Figure 2). A second cluster of voxels with maxima located at 18, 12, −24 (right ventral frontal region) showed a trend prior to correction (P = .053), although after correction this finding did not approach significance (corrected P = .262).
Figure 2
Figure 2
Results of voxel-based morphometry analysis of FCI scores in amnestic MCI patients. A) The cluster with maxima at coordinates −54, −48, 44 on the glass brain projection (P = .081 corrected) (the second cluster was not significant after (more ...)
MRI Volumes
MRI volumes from the four ROIs are displayed in Table 2. The hippocampi were significantly smaller bilaterally in amnestic MCI patients compared to controls. A trend was observed (P = .064) towards smaller medial frontal lobe volume in the amnestic MCI patients. The percentage of MCI patients with adjusted z-score volumes below −1 SD was greatest in the hippocampi (47%), followed by angular gyri (34%), and then the medial frontal (29%) and precunei (29%).
Table 2
Table 2
Volumes of Regions of Interest in Controls and MCI Patients
Neuropsychological test, MRI volume, and FCI correlations
Table 3 shows the correlations among the neuropsychological tests, MRI volumes, and the FCI Total as obtained within the MCI group. MRI volumes were highly correlated with each other (significant r values ranging from .48 to .80) and also showed correlations with neuropsychological variables. The medial frontal lobe volume was correlated with WRAT-3 Arithmetic. Angular gyri volume was correlated with WMS-III Spatial Span and Arithmetic. The precunei was correlated with Spatial Span, Trails A, and Arithmetic. The hippocampi volume showed no correlations with neuropsychological test scores within our amnestic MCI group.
Table 3
Table 3
Correlations among Neuropsychological Tests, MRI Volume Regions of Interest, and FCI Score in Amnestic MCI Patients
The FCI score showed correlations with all three of the neuropsychological variables (r values ranging from −.56 to .74). The FCI score was correlated with the angular gyri ROI (see Figure 3), but not with the other three ROIs.
Figure 3
Figure 3
Scatterplot demonstrating the correlation between the FCI score and adjusted angular gyri volume.
Regression models
Two stepwise regressions were computed to determine the key predictors of the FCI score. The first stepwise regression was computed to determine the key MRI volume predictor of FCI score, with all four ROI considered for the regression. The regression entered the angular gyri ROI, and explained 19% of the variance in FCI scores: F (1, 36) = 8.44, P < .01.
As demographic variables and overall mental status could help explain variability in FCI scores within our patient group, we performed a regression analysis of FCI score that first force-entered MMSE score, age, education, and sex in one block, and subsequently entered the four MRI volumes in a second stepwise block. After the initial block was force-entered, the angular gyri was the only ROI that met entry criteria for the model, uniquely accounting for 12% change in the variance above and beyond the covariate block: F (1, 32) = 7.61, P < .05.
Tests of mediation
Both the Spatial Span measure and WRAT Arithmetic met the initial assumptions for mediation43. As detailed above, angular gyri volume was correlated with both neuropsychological measures and the neuropsychological measures were in turn correlated with FCI score.
The first mediator model tested whether the relationship of angular gyri volume to FCI score is mediated by the Spatial Span score. The Sobel equation was computed with the unstandardized coefficients of the correlation of angular gyri volume with Spatial Span (B = .88, SE = .38) and the correlation of Spatial Span with FCI score, when angular gyri volume is also accounted for (B = 2.63, SE = .78)41. The test statistic (1.93) just missed our significance level (P = .054); the Beta for the relationship of angular gyri volume with FCI score changed from .44 to .26 (P = .07) after accounting for Spatial Span score, suggesting a partial mediation.
The second mediator model tested whether the relationship of angular gyri volume to FCI score is mediated by the Arithmetic score. The Sobel equation was computed with the unstandardized coefficients of the correlation of angular gyri volume with Arithmetic (B = 1.36, SE = .64) and the correlation of Arithmetic with FCI score, when angular gyri volume is also accounted for (B = 2.18, SE = .38). The test statistic (1.99) was significant (P < .05), indicating that the relationship of angular gyri volume with FCI score is carried by the Arithmetic score; the Beta for the relationship of angular gyri volume with FCI score changed from .44 to .17 (P = .18) after accounting for Arithmetic score, indicating a partial mediation.
There are three main findings of interest from this study. First, MRI volume of the angular gyri, one of the posterior cortical regions known to be implicated in the early neuropathology of AD, was moderately correlated with a direct assessment measure of financial abilities in patients with amnestic MCI. Second, angular gyri volume was shown to be a unique predictor of financial abilities after accounting for overall mental status and demographic variables. Third, the relationship of angular gyri volume with financial abilities was shown to be partially mediated by arithmetic ability. These findings have implications for understanding the pathway by which early declines in financial abilities can occur in amnestic MCI patients.
To our knowledge, the current study is one of the first to link brain measures in areas other than the hippocampus with IADLs in patients with amnestic MCI, demonstrating that structural brain measures are sensitive not only to cognitive and clinical impairments but also to emerging deficits in cognitively demanding IADLs such as financial capacity. Patients with amnestic MCI are known to experience brain volume changes that have implications for cognitive function and prognosis. Hippocampal atrophy in amnestic MCI corresponds to memory impairment26 and disease progression25, and is predictive of risk of later “conversion” to AD44. However, volumetric abnormalities also occur in other cortical regions in patients with MCI, such as the posterior cingulate45 and angular gyrus46, 47. Our data generally correspond with these prior findings: the hippocampal volumes were significantly smaller in amnestic MCI compared to controls. While the other ROIs did not reach significance, they were smaller in patients compared to controls in all instances, and in the case of the angular gyrus over 1/3 of the MCI patients showed emerging volumetric abnormalities (values below −1 SD).
Furthermore, these data suggest that angular gyri volume, and the neural networks that it is a part of, is a specific neurocognitive substrate by which financial capacity is influenced. The first evidence supporting our conclusion is that, despite high intercorrelations among the volumetric ROI in our sample, other brain volumes including the hippocampus were meagerly correlated with FCI performance, whereas the angular gyri volume showed a reasonably robust correlation. An exploratory VBM analysis showed a strong trend for a cluster of voxels located in the posterior parietal cortex in the area of the angular gyrus to predict FCI scores. Additionally, regression demonstrated that the volumetric predictor of FCI in our MCI patient sample was angular gyri volume. The third evidence in support of a specific relationship between angular gyri volume and FCI performance is the more stringent regression model that accounted for overall mental status, age, education, and sex (factors that would plausibly influence performance on financial abilities). Despite adjustment for these covariates, the angular gyri volume remained a key predictor of FCI performance, uniquely accounting for 12% of variance in scores. It could be argued that the relationship of MRI volumes with financial abilities and IADLs is simply a proxy for the effects of global cognitive change on IADLs. However, our data suggest that there is a specific relationship between financial abilities and angular gyri volume in patients with amnestic MCI.
Another key finding is the demonstration that arithmetic abilities, and to some extent attention, mediate the relationship of angular gyri volume with financial abilities in patients with amnestic MCI. The amnestic MCI patients in this study were impaired relative to the matched controls on performance of the FCI, consistent with our prior reports4, 9. The Arithmetic score was the primary neurocognitive predictor of overall financial abilities in a prior study using a larger amnestic MCI sample and the full FCI instrument10. Our findings add further confirmation of the importance of arithmetic ability to financial abilities by demonstrating the link with brain volumetrics of the angular gyri. Prior studies have demonstrated a role for the angular gyri in calculation abilities4850, and a recent study linked regional metabolic abnormalities of the angular gyri with dyscalculia in AD12. Our data add to the literature by demonstrating an association between angular gyri volume and calculation ability in amnestic MCI patients, and extending this finding to everyday financial tasks. Attention is also possibly a mediator of the relationship of the angular gyri volume with FCI in our patients. In a prior study, an attention composite score that included Spatial Span was predictive of FCI domain scores in MCI patients9. Posterior lateral cortical regions such as the angular gyri have been implicated in attention deficits in patients with AD13.
Brain structures that show changes in early AD and MCI, such as the angular gyrus and posterior cingulate, are components of larger neural networks that are responsible for neurocognitive processes51, 52. In turn, changes in these neurocognitive processes likely result in impairment in complex daily activities. One such critical network that has received increasing attention is the default mode network, in which abnormalities have been detected in patients with AD53 and MCI54. This network has been implicated in executive function55, memory56, and goal directed behavior57, and as such is likely a primary neural system mediating cognitive functions subserving complex daily activities. Thus, the current findings are an initial effort to identify brain structures that underlie neural network degradation associated with changes in complex daily activities.
One potential issue to address is the amount of overlap between the FCI and the WRAT-3 Arithmetic score. Both measures are strongly correlated (.74) and the Arithmetic measure predicted 55% of the variance in FCI scores. The financial domains measured by this version of the FCI were financial conceptual knowledge, bank statement management, financial judgment, and bill payment. Of these, only the financial conceptual knowledge domain directly involves calculations (i.e., figuring percentages on tax). The other domains assess abilities such as demonstrating knowledge regarding financial affairs (i.e., bank statements, bills, taxes), locating information on bank statements and bills, organizing bills, and exercising financial judgment in fraud scenarios. In an exploratory analysis of correlations with domain- and task-level performance on the FCI, we found that angular gyri volume is correlated with both conceptual tasks as well as pragmatic tasks requiring calculation (data not shown). Certainly, application of written arithmetic problems such as those measured by the WRAT-3 requires not only calculation abilities but conceptual knowledge regarding calculations (i.e. division, fractions, percentages), visual scanning, and working memory (for instance, see the correlation of Arithmetic scores with Spatial Span in Table 3). We previously reported that performance on WRAT-3 Arithmetic was impaired in patients with AD, who showed a variety of errors such as operation substitution (addition rather than subtraction) that indicate possible degradation of semantic knowledge regarding calculations, as well as digit substitution and other inattentive errors58. One possible implication is that the angular gyri are important not only for performance of calculations, as well as reading and writing50, 59, but also for knowledge of mathematic operations and financial concepts as well. Such a supposition would certainly require further study.
Our study represents one of the first to directly link structural brain measures in amnestic MCI with a direct-assessment measure of financial abilities. A grossly neglected area of research has been investigations of the neuroanatomical basis of changes in IADLs in older adults using neuroimaging. Only a few such studies have been reported, and none to our knowledge with a clinically-diagnosed population of amnestic MCI patients. In one study MRI volumes of cortical gray matter and the hippocampus were predictive of contemporaneous clinician ratings of IADLs based upon caregiver interview in healthy individuals and patients with AD18. Another study using an informant-based rating of IADLs (IQCODE) examined the correspondence of these ratings with hippocampal volume and white matter hyperintensities in a mixed group of English and Spanish speakers, some of whom were cognitively impaired based upon psychometrically-defined thresholds21. The uniqueness of the current study compared to these other reports is the focus on direct assessment of a specific IADL, investigation of several ROIs, and study of a clinically-diagnosed group of patients with amnestic MCI. Additionally, our focus on MRI volumes within the MCI group likely influenced the lack of findings in the hippocampus, as both prior studies included imaging data from cognitively normal individuals in their statistical analyses. Other authors have indicated that hippocampal volumes in patients with AD may fail to correspond with behavioral measures as an artifact of the extensiveness of hippocampal atrophy and more widespread effects to other brain regions60. Such factors may plausibly be at play in patients with MCI as well.
The clinical and future research implications of the current findings are grounded in the importance of understanding IADL changes for clinicians and families. Decline of IADLs is the phenomenological “face” of dementia to patients with AD and their families, as they typically require increasing oversight and engagement of family members in the care of these patients. Changes in IADLs such as financial capacity moreover have public health significance, as such changes can be important markers of disease progression in MCI and are a crucial diagnostic criterion for clinically detecting conversion to dementia. Although it has been increasingly appreciated that cognitive changes in MCI can lead to changes in IADLs, we do not yet understand how neurodegeneration of key neural pathways lead to deficits and declines in IADLs. Such knowledge would be important for researchers to develop comprehensive models of IADL declines and will assist in early identification and care as well as inform diagnosis and support instrument development.
Limitations of the current study should be acknowledged. Our approach to volumetric analysis may not correspond directly with volumetrics derived from manually traced volumes, and results obtained using such methods may not be directly comparable. Other findings have suggested that SPM-based approaches have high correspondence with manual tracing39. Persons with amnestic MCI in this study are undergoing longitudinal follow-up as part of their participation in the UAB ADRC. As the current paper is a cross-sectional study, the ultimate clinical and neuropathological status of these participants is unknown. Our Center's observed rates of conversion to AD from amnestic MCI is consistent with the conventional annualized 15% rate of risk61, indicating that a majority of the participants in this study will likely clinically manifest AD in the future. Correspondence of findings in a sample of mild AD patients would also be desirable.
In conclusion, we present findings supporting a relationship between MRI brain volumes and IADL deficits in patients with amnestic MCI. Financial abilities showed a robust relationship with volume of the angular gyri, and this relationship was partially mediated by a measure of arithmetic abilities and possibly also by attention. These findings hold promise for further investigation of IADL declines in amnestic MCI and mild AD using neuroimaging techniques in order to increase our knowledge of how brain atrophy and corresponding pathology and cognitive change may place these patients at high risk for changes in complex daily activities such as financial capacity.
ACKNOWLEDGMENT
This study was funded by grants from the National Institute on Aging (Alzheimer's Disease Research Center - 1P50 AG16582-10: Marson, PI); (1R01 AG021927-05: Marson, PI) & Alzheimer's of Central Alabama (Griffith, PI).
Sponsor's Role: None
Footnotes
Conflict of Interest: The editor in chief has reviewed the conflict of interest checklist provided by the authors and has determined that the authors have no financial or any other kind of personal conflicts with this paper.
The authors report no conflicts of interest.
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