Alzheimer Disease: Bondi MW

Han SD, Bangen KJ, Bondi MW. · Department of Psychology, Loyola University Chicago, Chicago, Ill., USA. · Dement Geriatr Cogn Disord. · Pubmed #19088472 links to  free full text

Abstract: There has been a recent proliferation of functional magnetic resonance imaging (fMRI) studies that interpret between-group or within-group differences in brain response patterns as evidence for compensatory neural recruitment. However, it is currently a challenge to determine whether these observed differences are truly attributable to compensatory neural recruitment or whether they are indicative of some other cognitive or physiological process. Therefore, the need for a standardized set of criteria for interpreting whether differences in brain response patterns are compensatory in nature is great. Focusing on studies of aging and potentially prodromal Alzheimer's disease conditions (genetic risk, mild cognitive impairment), we critically review the functional neuroimaging literature purporting evidence for compensatory neural recruitment. Finally, we end with a comprehensive model set of criteria for ascertaining the degree to which a 'compensatory' interpretation may be supported. This proposed model addresses significant brain region, activation pattern, and behavioral performance considerations, and is therefore termed the Region-Activation-Performance model (RAP model).

Salmon DP, Bondi MW. · Department of Neurosciences, University of California, San Diego, California 92093, USA. · Annu Rev Psychol. · Pubmed #18616392 No free full text.

Abstract: Neuropsychological studies show that cognitive deficits associated with Alzheimer's disease (AD) are distinct from age-associated cognitive decline. Quantitative and qualitative differences are apparent across many cognitive domains, but are especially obvious in episodic memory (particularly delayed recall), semantic knowledge, and some aspects of executive functions. The qualitatively distinct pattern of deficits is less salient in very old AD patients than in younger AD patients. Although decline in episodic memory is usually the earliest cognitive change that occurs prior to the development of the AD dementia syndrome, asymmetry in cognitive abilities may also occur in this "preclinical" phase of the disease and predict imminent dementia. Discrete patterns of cognitive deficits occur in AD and several neuropathologically distinct age-associated neurodegenerative disorders. Knowledge of these differences helps to clinically distinguish among various causes of dementia and provides useful models for understanding brain-behavior relationships that mediate cognitive abilities affected in various neurodegenerative diseases.

Bondi MW, Jak AJ, Delano-Wood L, Jacobson MW, Delis DC, Salmon DP. · Department of Psychiatry, University of California San Diego, La Jolla, CA, USA. · Neuropsychol Rev. · Pubmed #18347989 No free full text.

Abstract: A wealth of evidence demonstrates that a prodromal period of Alzheimer's disease (AD) exists for some years prior to the appearance of significant cognitive and functional declines required for the clinical diagnosis. This prodromal period of decline is characterized by a number of different neuropsychological and brain changes, and reliable identification of individuals prior to the development of significant clinical symptoms remains a top priority of research. In this review we provide an overview of those neuropsychological changes. In particular, we examine specific domains of cognition that appear to be negatively affected during the prodromal period of AD, and we review newer analytic strategies designed to examine cognitive asymmetries or discrepancies between higher-order cognitive functions versus fundamental skills. Finally, we provide a critical examination of the clinical concept of Mild Cognitive Impairment and offer suggestions for an increased focus on the impact of cerebrovascular disease (CVD) and CVD risk during the prodromal period of AD.

Wierenga CE, Bondi MW. · Department of Psychiatry, University of California San Diego, La Jolla, California, USA. · Neuropsychol Rev. · Pubmed #17476598 links to  free full text

Abstract: A growing body of evidence suggests that a preclinical phase of Alzheimer's disease (AD) exists several years or more prior to the overt manifestation of clinical symptoms and is characterized by subtle neuropsychological and brain changes. Identification of individuals prior to the development of significant clinical symptoms is imperative in order to have the greatest treatment impact by maintaining cognitive abilities and preserving quality of life. Functional magnetic resonance imaging (fMRI) offers considerable promise as a non-invasive tool for detecting early functional brain changes in asymptomatic adults. In fact, evidence to date indicates that functional brain decline precedes structural decline in preclinical samples. Therefore, fMRI may offer the unique ability to capture the dynamic state of change in the degenerating brain. This review examines the clinical utility of blood oxygen level dependent (BOLD) fMRI in those at risk for AD as well as in early AD. We provide an overview of fMRI findings in at-risk groups by virtue of genetic susceptibility or mild cognitive decline followed by an appraisal of the methodological issues concerning the diagnostic usefulness of fMRI in early AD. We conclude with a discussion of future directions and propose that BOLD-fMRI in combination with cerebral blood flow or diffusion techniques will provide a more complete accounting of the neurovascular changes that occur in preclinical AD and thus improve our ability to reliably detect early brain changes prior to disease onset.

Twamley EW, Ropacki SA, Bondi MW. · Department of Psychiatry, University of California-San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA. · J Int Neuropsychol Soc. · Pubmed #16961952 links to  free full text

Abstract: Alzheimer's disease (AD) is a common, devastating form of dementia. With the advent of promising symptomatic treatment, the importance of recognizing AD at its very earliest stages has increased. We review the extant neuropsychological and neuroimaging literature on preclinical AD, focusing on longitudinal studies of initially nondemented individuals and cross-sectional investigations comparing at-risk with normal individuals. We systematically reviewed 91 studies of neuropsychological functioning, structural neuroimaging, or functional neuroimaging in preclinical AD. The neuropsychological studies indicated that preclinical AD might be characterized by subtle deficits in a broad range of neuropsychological domains, particularly in attention, learning and memory, executive functioning, processing speed, and language. Recent findings from neuroimaging research suggest that volume loss and cerebral blood flow or metabolic changes, particularly in the temporal lobe, may be detected before the onset of dementia. There exist several markers of a preclinical period of AD, in which specific cognitive and biochemical changes precede the clinical manifestations. The preclinical indicators of AD reflect early compromise of generalized brain integrity and temporal lobe functioning in particular.

Houston WS, Delis DC, Lansing A, Jacobson MW, Cobell KR, Salmon DP, Bondi MW. · University of Iowa, Department of Neurology, Division of Cognitive Neuroscience, Iowa City, Iowa 52242-1053, USA. · J Int Neuropsychol Soc. · Pubmed #16519265 No free full text.

Abstract: Recent studies have reported cognitive asymmetries in patients with Alzheimer's disease (AD) and in individuals with apolipoprotein E epsilon4 (APOE epsilon4) genotype who are in the preclinical phase of AD. This increased frequpncy of cognitive asymmetry, typically defined as a significant discrepancy (in either direction) between verbal and spatial abilities, often occurs despite an absence of differences on traditional measures of central tendency (i.e., mean test scores). We prospectively studied the relationship between APOE genotype and two modality-specific executive-function tasks: The Verbal Fluency and Design Fluency tests of the Delis-Kaplan Executive Function System (D-KEFS) in 52 normal functioning older adult participants who were grouped according to the presence (n=24) or absence (n=28) of the APOE e4 allele. Nondemented older adults with the APOE epsilon4 allele demonstrated a greater frequency of cognitive asymmetric profile on the new switching conditions of the Verbal and Design Fluency measures than the APOE non-epsilon4 individuals. This study further supports the utility of assessing cognitive asymmetry for the detection of subtle cognitive differences in individuals at-risk for AD, and suggests that dual-task executive function tests (i.e., fluency plus switching) may serve as a useful preclinical marker of AD.

Lineweaver TT, Salmon DP, Bondi MW, Corey-Bloom J. · Department of Psychology, Butler University, Indianapolis, Indiana 46208, USA. · J Int Neuropsychol Soc. · Pubmed #15686606 No free full text.

Abstract: The ability to spatially rotate a mental image was compared in patients with Alzheimer's disease (AD; n = 18) and patients with Huntington's disease (HD; n = 18). Compared to their respective age-matched normal control (NC) group, the speed, but not the accuracy, of mental rotation abnormally decreased with increasing angle of orientation for patients with HD. In contrast, the accuracy, but not the speed, of rotation abnormally decreased with increasing angle of orientation for patients with AD. Additional analyses showed that these unique patterns of performance were not attributable to different speed/accuracy trade-off sensitivities. This double dissociation suggests that the distinct brain regions affected in the two diseases differentially contribute to speed and accuracy of mental rotation. Specifically, the slowing exhibited by HD patients may be mediated by damage to the basal ganglia, whereas the spatial manipulation deficit of AD patients may reflect pathology in parietal and temporal lobe association cortices important for visuospatial processing.

Bondi MW, Houston WS, Salmon DP, Corey-Bloom J, Katzman R, Thal LJ, Delis DC. · VA San Diego Healthcare System, San Diego, California 92161, USA. · J Int Neuropsychol Soc. · Pubmed #12901784 links to  free full text

Abstract: The profiles of neuropsychological deficits associated with Alzheimer's disease (AD) in Young-Old (M age and 70) and Very-Old (M age > 80) patients were compared, along with possible modifying effects of apolipoprotein E (APOE) genotype on these profiles. A comprehensive battery of neuropsychological tests was administered to the two AD patient groups (Young-Old: n = 33; Very-Old: n = 48) and their respective age-matched normal control (NC) groups who remained free of dementia on follow-up examinations over a 1 to 10 year period (Young-Old: n = 43; Very-Old: n = 36). AD and NC groups did not differ in education levels or gender distributions. Young-Old AD and Very-Old AD groups were comparable in education, gender, dementia severity, and disease duration. Results showed that both AD groups achieved comparable raw scores on all the neuropsychological measures. However, when scores were standardized on the basis of performance of their respective NC groups (i.e., age-corrected z scores), Very-Old AD patients significantly outperformed Young-Old AD patients on tests of executive functions, visuospatial skills, and delayed memory. Furthermore, the relationship between age and memory and executive function deficits in AD was modified by APOE genotype. These data suggest that the profile of neuropsychological deficits associated with AD in the Very-Old lacks the disproportionate saliency of episodic memory and executive function deficits typical of the Young-Old.

Jacobson MW, Delis DC, Bondi MW, Salmon DP. · Department of Veterans Affairs Medical Center, San Diego, California 92161, USA. · Neuropsychology. · Pubmed #11949704 No free full text.

Abstract: Attempts to identify cognitive markers of a preclinical phase of Alzheimer's disease (AD) have yielded inconsistent findings. The problem may stem in part from methodologies that are insensitive to potential subgroups within the at-risk, preclinical AD population (PCAD). The present study investigated the utility of asymmetric cognitive profiles in identifying individuals at risk for AD. Twenty elderly adults who were later diagnosed with AD (PCAD) and 20 matched control participants were compared on measures of cognitive asymmetry derived from difference scores on tests of verbal and visuospatial ability. Although both groups performed similarly on the individual tests, comparisons using difference scores revealed significantly larger discrepancies between naming and visuoconstruction skills in the PCAD group. The PCAD group also had a higher frequency of asymmetric cognitive profiles relative to a normative group.

Bondi MW, Salmon DP, Galasko D, Thomas RG, Thal LJ. · San Diego Veterans Affairs Medical Center and Department of Psychiatry and School of Medicine, University of California, 92161, USA. · Psychol Aging. · Pubmed #10403716 No free full text.

Abstract: Nondemented older adults genotyped for the Apolipoprotein E (ApoE) epsilon4 allele (n = 43) were neuropsychologically compared to participants without a copy of the epsilon4 allele (n = 90). At baseline, the groups did not differ on age, education, gender, or global cognitive status. ApoE-epsilon4 participants demonstrated significantly poorer mean performances on delayed recall, but no significant group differences emerged on attention, language, constructional skills, psychomotor speed, or executive function. Significantly more ApoE-epsilon4 participants developed probable or questionable Alzheimer's disease (AD) compared with non-epsilon4 participants, suggesting that the group differences resulted from a preponderance of preclinical AD cases within the epsilon4 group and not from a direct influence of ApoE genotype on cognition. Cox proportional hazards analysis, adjusting for age, years of education, and global cognitive status, revealed that ApoE-epsilon4 allele status and measures of recall performance were significant and independent predictors of conversion to AD. Results support the importance of specific episodic memory changes and possession of the ApoE-epsilon4 allele in the preclinical detection of AD.

Stout JC, Bondi MW, Jernigan TL, Archibald SL, Delis DC, Salmon DP. · Department of Psychiatry, University of California, San Diego, and Veterans Affairs Medical Center, USA. · Neuropsychology. · Pubmed #10353370 No free full text.

Abstract: Twenty-seven research participants with dementia of the Alzheimer type were studied with the California Verbal Learning Test (D. C. Delis, J. H. Kramer, E. Kaplan, & B. A. Ober, 1987) and standardized volume measures of the mesial temporal cortical gray matter, neocortical gray matter, thalamus, and caudate nuclei, from magnetic resonance imaging. A pattern of atrophic brain changes in the mesial temporal lobes (MTL) and the thalamus, with relatively less severe atrophy in the neocortical gray matter, was associated with poorer learning of the word list. Similar patterns of brain atrophy were observed for measures of delayed recall and recognition hits. However, for delayed recall, neither contribution was statistically significant, and for recognition hits, MTL was only at the trend level for significance. These results provide evidence that the verbal memory deficit of Alzheimer's disease (AD) is associated not only with the mesial temporal limbic cortex, thought to be the site of earliest and most severe pathology in AD, but also with damage in the thalamus.

Stricker NH, Schweinsburg BC, Delano-Wood L, Wierenga CE, Bangen KJ, Haaland KY, Frank LR, Salmon DP, Bondi MW. · New Mexico VA Healthcare System, USA. · Neuroimage. · Pubmed #19100839 No free full text.

Abstract: The retrogenesis model of Alzheimer's disease (AD) posits that white matter (WM) degeneration follows a pattern that is the reverse of myelogenesis. Using diffusion tensor imaging (DTI) to test this model, we predicted greater loss of microstructural integrity in late-myelinating WM fiber pathways in AD patients than in healthy older adults, whereas differences in early-myelinating WM fiber pathways were not expected. We compared 16 AD patients and 14 demographically-matched healthy older adults with a whole-brain approach via tract-based spatial statistics (TBSS), and a region of interest (ROI) approach targeting early-myelinating (posterior limb of internal capsule, cerebral peduncles) and late-myelinating (inferior longitudinal fasciculus [ILF], superior longitudinal fasciculus [SLF]) fiber pathways. Permutation-based voxelwise analysis supported the retrogenesis model. There was significantly lower fractional anisotropy (FA) in AD patients compared to healthy older adults in late-myelinating but not early-myelinating pathways. These group differences appeared to be driven by loss of myelin integrity based on our finding of greater radial diffusion in AD than in healthy elderly. ROI analyses were generally in agreement with whole-brain findings, with significantly lower FA and increased radial diffusion in the ILF in the AD group. Consistent with the retrogenesis model, AD patients showed demonstrable changes in late-myelinating WM fiber pathways. Given greater change in the ILF than the SLF, wallerian degeneration secondary to cortical atrophy may also be a contributing mechanism. Knowledge of the pattern of WM microstructural changes in AD and its underlying mechanisms may contribute to earlier detection and intervention in at-risk groups.

Bloss CS, Delis DC, Salmon DP, Bondi MW. · San Diego State University and University of California, San Diego, Joint Doctoral Program in Clinical Psychology, San Diego, CA, USA. · Biol Psychiatry. · Pubmed #18722591 No free full text.

Abstract: BACKGROUND: The epsilon4 allele of the apolipoprotein E gene (APOE-epsilon4) and a family history (+FH) of Alzheimer's disease (AD) are both risk factors for the development of AD. Although studies to identify a preclinical phase of AD have led to evidence of APOE-epsilon4- and +FH-related differences in brain and cognitive functioning in healthy adults, the relative influence of these factors in children is unknown. METHODS: To investigate this issue, school-age children (n = 109) received standardized achievement tests, the Rey-Osterrieth Complex Figure Test (Copy Condition; RCFT-CC), assessment of family medical history, and buccal swab testing to determine their APOE genotype. RESULTS: Analyses revealed that, relative to children without these risk factors, children who possess both an APOE-epsilon4 allele and a +FH of AD and/or significant memory problems (MP) obtained lower scores on nearly every cognitive test administered. CONCLUSIONS: Findings suggest that when both AD risk factors are present, cognition may be adversely affected as early as childhood. Thus, risk factors for a disorder of pathological aging (i.e., AD) may have implications for the etiology of certain types of learning difficulties in children.

Han SD, Bondi MW. · Department of Psychology, Loyola University Chicago, Chicago, IL, USA. · Alzheimers Dement. · Pubmed #18631975 No free full text.

Abstract: The association between the apolipoprotein E epsilon4 allele and Alzheimer's disease (AD) is well-established. Functional neuroimaging research has supported a compensatory mechanism recruitment hypothesis whereby nondemented epsilon4 participants use additional cognitive resources to buffer against episodic memory declines in older age, a mechanism that is presumably associated with encroaching disease. However, recent studies have implicated a beneficial effect associated with the epsilon4 allele early in the life span. These studies suggest a revised hypothesis whereby epsilon4 persons perform better on cognitive measures early in the life span and then show greater recruitment of brain regions during performance to compensate for declines in older age caused by preclinical AD.

Fine EM, Delis DC, Wetter SR, Jacobson MW, Jak AJ, McDonald CR, Braga JC, Thal LJ, Salmon DP, Bondi MW. · Veterans Affairs San Diego Healthcare System, San Diego, CA 92161, USA. · Am J Geriatr Psychiatry. · Pubmed #18448849 No free full text.

Abstract: OBJECTIVES: Cognitive-discrepancy analysis has been shown to be a useful technique for detecting subtle cognitive deficits in normal-functioning elderly individuals who are genetically at-risk for Alzheimer disease (AD). However, studies that have used cognitive-discrepancy measures to date have used retrospective or cross-sectional designs, and the utility of this approach to predict cognitive decline has not been examined in a prospective investigation. DESIGN: Longitudinal study. SETTING: San Diego, CA, Veterans Administration Hospital. PARTICIPANTS: Twenty-four normal-functioning elderly individuals participated in the study, with 16 subjects exhibiting no change in their Dementia Rating Scale (DRS) scores over an 1-year period (Stable Group), and 8 subjects exhibiting a decline in DRS scores over the 1-year period (Decline group). MEASUREMENTS: A cognitive-discrepancy measure isolating cognitive switching was computed that contrasted performance on a new higher-level task of executive functioning (a Stroop/Switching measure) relative to a composite measure of lower-level Stroop conditions. RESULTS: a) In the year before their cognitive changes, the Decline group exhibited a significantly larger cognitive-discrepancy (Stroop/Switching versus lower-level Stroop conditions) score compared with a control (Stable) group; and b) the cognitive-discrepancy measure was superior to APOE genotype in predicting DRS decline. CONCLUSION: Cognitive-discrepancy analysis isolating a component executive function ability not only seems to be a useful tool for identifying individuals at risk for cognitive deficits, but also shows promise in predicting individuals who may show subtle cognitive decline over time.

Fine EM, Delis DC, Wetter SR, Jacobson MW, Hamilton JM, Peavy G, Goldstein J, McDonald C, Corey-Bloom J, Bondi MW, Salmon DP. · Psychology Service (116B)-Delis Lab, Veterans Affairs San Diego Healthcare System, 3350 La Jolla Village Drive, San Diego, CA 92161, USA. · J Clin Exp Neuropsychol. · Pubmed #18415887 No free full text.

Abstract: The present study compared the performance of individuals with Huntington's disease (HD) and Alzheimer's disease (AD) on three types of California Verbal Learning Test-Second Edition (CVLT-II) recognition discriminability indices (RDI): Source, Novel, and Total. The HD and AD groups did not differ significantly on Source RDI (all 16 targets versus the 16 previously presented, List B, distractors). However, HD patients performed significantly better than AD patients on Total RDI (all 16 targets versus all 32 distractors) and Novel RDI (all 16 targets versus 16 new distractors). Implications of these findings on the differentiation of the memory disorders associated with HD and AD are discussed.

Delano-Wood L, Houston WS, Emond JA, Marchant NL, Salmon DP, Jeste DV, Thal LJ, Bondi MW. · VA San Diego Healthcare System, San Diego, CA 92161, USA. · Int J Geriatr Psychiatry. · Pubmed #18058831 links to  free full text

Abstract: OBJECTIVE: The association between the APOE epsilon4 allele and depression was investigated in a retrospective study of 323 AD patients. METHODS: Patients were divided into demographically comparable groups based on the presence or absence of depression. RESULTS: Results showed that the frequency of APOE epsilon4 allele was significantly higher in the depressed vs non-depressed AD patients (72% and 58%, respectively), and an interaction revealed that women possessing the APOE epsilon4 allele were almost four times more likely to be depressed than those without the epsilon4 allele. CONCLUSION: Results are consistent with recent suggestions that the APOE epsilon4 genotype may be over-represented among depressed women with AD and highlight the need for additional research investigating the links between APOE genotype, mood, and gender.

Mickes L, Wixted JT, Fennema-Notestine C, Galasko D, Bondi MW, Thal LJ, Salmon DP. · Department of Psychology, University of California, San Diego, CA 92093-0109, USA. · Neuropsychology. · Pubmed #17983283 No free full text.

Abstract: Previous research suggests that patients with Alzheimer's disease exhibit cognitive impairment in the years preceding a clinical diagnosis. Memory impairments are particularly pronounced, but the relative degree to which other cognitive functions are impaired and the speed with which they decline during the preclinical years remains unclear. The authors report a detailed neuropsychological evaluation of 11 patients over the course of 3 years up to and including the 1st year of nonnormal diagnosis. The results suggest that performance falls off rapidly in all areas of cognitive functioning but that abilities thought to be subserved by the medial and lateral temporal lobes (episodic and semantic memory, respectively) appear to be substantially more impaired than those abilities thought to be subserved by the frontal lobes.

Bischoff-Grethe A, Ozyurt IB, Busa E, Quinn BT, Fennema-Notestine C, Clark CP, Morris S, Bondi MW, Jernigan TL, Dale AM, Brown GG, Fischl B. · Laboratory of Cognitive Imaging, Department of Psychiatry, University of California, San Diego, La Jolla, USA. · Hum Brain Mapp. · Pubmed #17295313 links to  free full text

Abstract: Due to the increasing need for subject privacy, the ability to deidentify structural MR images so that they do not provide full facial detail is desirable. A program was developed that uses models of nonbrain structures for removing potentially identifying facial features. When a novel image is presented, the optimal linear transform is computed for the input volume (Fischl et al. [2002]: Neuron 33:341-355; Fischl et al. [2004]: Neuroimage 23 (Suppl 1):S69-S84). A brain mask is constructed by forming the union of all voxels with nonzero probability of being brain and then morphologically dilated. All voxels outside the mask with a nonzero probability of being a facial feature are set to 0. The algorithm was applied to 342 datasets that included two different T1-weighted pulse sequences and four different diagnoses (depressed, Alzheimer's, and elderly and young control groups). Visual inspection showed none had brain tissue removed. In a detailed analysis of the impact of defacing on skull-stripping, 16 datasets were bias corrected with N3 (Sled et al. [1998]: IEEE Trans Med Imaging 17:87-97), defaced, and then skull-stripped using either a hybrid watershed algorithm (Ségonne et al. [2004]: Neuroimage 22:1060-1075, in FreeSurfer) or Brain Surface Extractor (Sandor and Leahy [1997]: IEEE Trans Med Imaging 16:41-54; Shattuck et al. [2001]: Neuroimage 13:856-876); defacing did not appreciably influence the outcome of skull-stripping. Results suggested that the automatic defacing algorithm is robust, efficiently removes nonbrain tissue, and does not unduly influence the outcome of the processing methods utilized; in some cases, skull-stripping was improved. Analyses support this algorithm as a viable method to allow data sharing with minimal data alteration within large-scale multisite projects.

Wetter SR, Delis DC, Houston WS, Jacobson MW, Lansing A, Cobell K, Salmon DP, Bondi MW. · Veterans Affairs San Diego Healthcare System, California, USA. · Neuropsychol Dev Cogn B Aging Neuropsychol Cogn. · Pubmed #16887786 No free full text.

Abstract: Demonstrations of memory changes in those at risk for Alzheimer's disease by the presence of the APOE e4 allele have been inconsistent to date. The present study went beyond traditional analyses of central tendency (i.e., group differences on mean test scores) and also conducted distribution analyses to search for subtle cognitive differences in subgroups of normal-functioning elderly persons with the APOE e4 genotype. The results of the study revealed that (a) the e4 and non-e4 groups failed to differ in terms of their mean scores on tests of memory and verbal skills; and (b) relative to the non-e4 group, the e4 subjects had significantly greater heterogeneity of variance on the memory measures but not on fundamental verbal skills. Logistic regression analyses indicated that the discrepancy in scores on the memory measures was a significant predictor of genotype group membership (82% correct classification rate). Implications of these findings for the detection of a preclinical phase of AD are discussed.

Fleisher AS, Houston WS, Eyler LT, Frye S, Jenkins C, Thal LJ, Bondi MW. · Department of Neurosciences, University of California, San Diego, La Jolla 92037, USA. · Arch Neurol. · Pubmed #16344346 links to  free full text

Abstract: BACKGROUND: Functional magnetic resonance imaging plays a promising role in the preclinical characterization of Alzheimer disease (AD) for use in early diagnosis and in preventive drug trials. OBJECTIVE: To determine whether functional magnetic resonance imaging can reliably distinguish risk groups for AD among cognitively normal middle-aged adults. DESIGN: Cross-sectional case-control study. SETTING: University of California, San Diego, Alzheimer Disease Research Center participants and San Diego community volunteers. PARTICIPANTS: Twenty cognitively normal individuals (10 high risk and 10 low risk), aged 58 to 65 years, were divided into 2 groups based on the presence or absence of the apolipoprotein E epsilon4 allele and a positive family history of AD. MAIN OUTCOME MEASURES: Word pairs were presented in a blocked design alternating between conditions of novel pairs, repeated pairs, and fixation. Whole-brain differences in blood oxygenation level-dependent brain responses between conditions were compared across risk groups. RESULTS: Compared with the low-risk group, the high-risk group showed many areas of differential blood oxygenation level-dependent response in regions commonly associated with AD pathology (eg, the left medial temporal lobe). Furthermore, different patterns of association between left medial temporal lobe activity and memory performance were demonstrated. CONCLUSIONS: Results support a theory of up-regulation in neuronal memory systems in people at risk for AD many years before the typical age at disease onset. They further demonstrate that functional magnetic resonance imaging is a viable technique to identify persons at risk for AD.

Moore AB, Bondi MW, Salmon DP, Murphy C. · San Diego State University/University of California, San Diego Joint Doctoral Program in Clinical Psychology, San Diego, CA 92120-4913, USA. · Neuropsychology. · Pubmed #16060818 No free full text.

Abstract: Patients with Alzheimer's disease (AD) demonstrate slowed acquisition of the conditioned response (CR) in eyeblink classical conditioning paradigms (EBCC), although it is unknown how early in the course of the disease CR acquisition is affected. This study investigated whether changes in the rate of CR acquisition were apparent in nondemented older adults at greater genetic risk for developing AD (i.e., carriers of the apolipoprotein E [APOE] epsilon 4 allele). Both epsilon 4+ and epsilon 4- participants demonstrated CR acquisition to auditory and olfactory CSs; however, rate of acquisition to the olfactory CS was significantly slower in epsilon 4+ persons. Both groups acquired the CR to an auditory CS at the same rate. Results support olfactory compromise in the earliest stages of the AD disease process. ((c) 2005 APA, all rights reserved).

Jacobson MW, Delis DC, Bondi MW, Salmon DP. · Department of Veterans Affairs Medical Center, San Diego, CA 92161, USA. · J Clin Exp Neuropsychol. · Pubmed #15903153 No free full text.

Abstract: Some studies of elderly individuals with the ApoE-e4 genotype noted subtle deficits on tests of attention such as the WAIS-R Digit Span subtest, but these findings have not been consistently reported. One possible explanation for the inconsistent results could be the presence of subgroups of e4+ individuals with asymmetric cognitive profiles (i.e., significant discrepancies between verbal and visuospatial skills). Comparing genotype groups with individual, modality-specific tests might obscure subtle differences between verbal and visuospatial attention in these asymmetric subgroups. In this study, we administered the WAIS-R Digit Span and WMS-R Visual Memory Span subtests to 21 nondemented elderly e4+ individuals and 21 elderly e4- individuals matched on age, education, and overall cognitive ability. We hypothesized that a) the e4+ group would show a higher incidence of asymmetric cognitive profiles when comparing Digit Span/Visual Memory Span performance relative to the e4- group; and (b) an analysis of individual test performance would fail to reveal differences between the two subject groups. Although the groups' performances were comparable on the individual attention span tests, the e4+ group showed a significantly larger discrepancy between digit span and spatial span scores compared to the e4- group. These findings suggest that contrast measures of modality-specific attentional skills may be more sensitive to subtle group differences in at-risk groups, even when the groups do not differ on individual comparisons of standardized test means. The increased discrepancy between verbal and visuospatial attention may reflect the presence of "subgroups" within the ApoE-e4 group that are qualitatively similar to asymmetric subgroups commonly associated with the earliest stages of AD.

Bondi MW, Houston WS, Eyler LT, Brown GG. · University of California San Diego and VA San Diego Healthcare System, 3350 La Jolla Village Drive, San Diego, CA 92161, USA. · Neurology. · Pubmed #15699382 links to  free full text

Abstract: OBJECTIVE: To determine whether APOE genotype influences brain response and whether nonverbal stimuli generate findings comparable with those of previous studies that used verbal stimuli. The relationship between APOE genotype and blood oxygenation level dependent (BOLD) brain response was examined during a picture-encoding task in nondemented older adults. METHODS: Twenty nondemented participants with normal episodic memory function were divided into two groups based on the presence (n = 10) or absence (n = 10) of the APOE epsilon4 allele. Picture learning was completed during functional MRI in a blocked design alternating between experimental (novel pictures) and control (repeated picture) conditions. RESULTS: Nondemented older adults with an APOE epsilon4 allele showed greater magnitude and extent of BOLD brain response during learning of new pictures relative to their matched epsilon3 counterparts. Different patterns and directions of association between hippocampal activity and learning and memory performance were also demonstrated. CONCLUSIONS: The results suggest that brain response differences are not due to poorer general memory abilities, differential atrophy, or brain response during control conditions, but instead appear to be directly influenced by APOE genotype. Results are consistent with a compensatory hypothesis wherein older adults at genetic risk for Alzheimer disease by virtue of the APOE epsilon4 allele appear to require additional cognitive effort to achieve comparable performance levels on tests of episodic memory encoding.

Delis DC, Jacobson M, Bondi MW, Hamilton JM, Salmon DP. · Psychology Service, Department of Veterans Affairs Medical Center, San Diego, California 92161, USA. · J Int Neuropsychol Soc. · Pubmed #14632252 No free full text.

Abstract: For nearly a century, the primary method employed by psychologists to define and test the validity of constructs evaluated by assessment instruments has been shared-variance techniques such as intervariable correlations or factor analysis with large normative or mixed clinical samples. To illustrate the shortcomings of this approach, we conducted (1) correlational analyses of immediate- and delayed-memory measures separately in normal participants and in homogeneous samples of patients with either Alzheimer's disease or Huntington's disease; and (2) factor analysis of immediate and delayed-recall and recognition measures in a large, homogeneous sample of patients with Alzheimer's disease. The findings revealed that cognitive measures that share variance in the intact brain-thereby giving the facade of assessing a unitary construct-can dissociate and contribute to unique variance in the damaged brain, but only if the pathology occurs in brain regions known to disrupt vital cognitive processes tapped by those measures. The results illustrate that shared-variance procedures applied to normal or mixed clinical populations can mask some of the most vital cognitive constructs, such as the classic distinction between short- and long-term memory. Implications of these findings for research and clinical practice are discussed.