Wes S. Houston

fMRI evidence of compensatory mechanisms in older adults at genetic risk for Alzheimer disease

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 ε4 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 ε4 allele showed greater magnitude and extent of BOLD brain response during learning of new pictures relative to their matched ε3 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 ε4 allele appear to require additional cognitive effort to achieve comparable performance levels on tests of episodic memory encoding.

Verbal paired-associate learning by APOE genotype in non-demented older adults: fMRI evidence of a right hemispheric compensatory response☆

Previous studies of episodic memory report a greater extent of blood-oxygenation-level-dependent (BOLD) response in non-demented older adults with the apolipoprotein E epsilon-4 (APOE epsilon4) allele than in those without the allele. We conducted a functional MRI study to investigate whether APOE genotype is related to brain response to verbal paired-associate encoding and consolidation, particularly in the right hemisphere, among non-demented older adults. Structurally segmented volumes and BOLD response were measured in 13 non-epsilon4 and 12 epsilon4 subjects. The epsilon4 group displayed greater activation than the non-epsilon4 group in multiple right hemisphere regions for previously encoded word pairs relative to fixation. Activation within manually outlined hippocampal regions of interest also displayed genotype-specific dissociations consistent with whole brain analyses. Furthermore, this differential BOLD response occurred in the presence of equivalent behavioral and neuropsychological performances as well as comparable hippocampal and overall structural segmentation volumes between groups. Results implicate a widely distributed and interconnected network of right hemisphere brain regions that may be involved in compensating for APOE epsilon4-related deficiencies associated with verbal episodic memory encoding and consolidation.

Differential Cross-Sectional and Longitudinal Impact of APOE Genotype on Hippocampal Volumes in Nondemented Older Adults

Background/Aims: Because of conflicting findings across studies, we sought to better determine the relationship between apolipoprotein E (APOE) genotype, hippocampal volume, and cognitive performance in nondemented older adults. Methods: Two groups ofolder adults, as determined by their APOE Ε4 allele status, received structural MRI and comprehensive neuropsychological testing on two occasions separated on average by 17 months. Results: Cross-sectional comparisons by APOE group revealed no differences in hippocampal volumes, although longitudinal percent reduction in hippocampal volume was significantly greater for those possessing the APOE Ε4 allele. Relationship between hippocampal volumes and memory performance was strongly impacted by diagnosis of mild cognitive impairment. Conclusions: APOE Ε4 allele appears to significantly impact rate of volume loss over time in the hippocampus in nondemented older adults, and detailed cognitive characterization of the sample is necessary to reliably interpret the relationship between cognition and brain structure.

Apolipoprotein E and traumatic brain injury in a military population: evidence of a neuropsychological compensatory mechanism?

Objective: Although research has implicated the apolipoprotein E (APOE) epsilon-4 genotype as having a negative effect on neuropsychological outcomes following traumatic brain injury (TBI), the potentially negative role of the ε4 allele on TBI outcomes has recently been challenged. In light of this debate, the present study served to examine the role of APOE genotype on neuropsychological outcomes approximately 1 month following mild to moderate TBI in a military population. Because of the well documented role of the APOE-ε4 allele in increasing the risk of Alzheimer’s disease, we predicted that persons with the APOE-ε4 genotype would display relatively greater deficits in cognition than their non-ε4 counterparts. Methods: 78 participants were consecutively recruited following a mild to moderate TBI and were divided into two groups based on the presence or absence of an APOE ε4 allele. Groups were comparable on demographic characteristics and psychosocial outcomes. Participants were administered a comprehensive neuropsychological battery. Results: Analyses revealed comparable performances on most neuropsychological measures and better performances by ε4 carriers on select measures of attention, executive functioning and episodic memory encoding. Furthermore, differences remained after accounting for the effects of TBI severity. Conclusions: Evidence from these analyses supports current literature refuting the notion of relatively poorer neuropsychological functioning associated with the APOE-ε4 genotype among young adult participants shortly following mild or moderate brain injury. Neuropsychological performance differences by APOE genotype following TBI are discussed in terms of the importance of considering severity of injury, timing of postinjury assessment and possible neurocognitive compensatory mechanisms.

Repetition and the arcuate fasciculus.

According to the traditional model of language organization, repetition deficits arise following damage to the arcuate fasciculus of the dominant hemisphere (conduction aphasia). Conduction aphasia may result from lesions that spare the arcuate fasciculus. However, these patients have atypical language organization. We describe a man with normal language architecture who underwent a resection of the anterior portion of his arcuate fasciculus and retained his ability to repeat words and sentences. We propose that the arcuate fasciculus is not necessary for speech repetition by the lexical route.

Executive function asymmetry in older adults genetically at-risk for Alzheimer's disease: Verbal versus design fluency

Recent studies have reported cognitive asymmetries in patients with Alzheimers 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.

Creativity Lost: The Importance of Testing Higher-Level Executive Functions in School-Age Children and Adolescents

In school settings, students are typically evaluated using group achievement tests, IQ scales, and college entrance exams that focus more on rote-verbal skills (e.g., vocabulary, mathematical facts) than on higher level executive functions (e.g., abstract thinking, problem solving). However, recent neuropsychological findings suggest that rote-knowledge skills and executive functions are divergent cognitive domains that can be dissociated in both adults with frontal lesions and children with neurodevelopmental disorders. New correlational findings obtained from 470 children and adolescents provide additional support for the divergent nature of these cognitive domains and the existence of subgroups of students who exhibit either strengths in abstract, creative thinking with relative weaknesses in rote-verbal skills or vice versa. The results suggest that current school assessment practices may result in academic roadblocks for those students who have strengths in abstract, creative thinking but whose relative weaknesses in rote-verbal skills may hinder their ability to take college entrance exams.

Deficits in inhibition and flexibility are associated with the APOE-E4 allele in nondemented older adults.

This prospective study of nondemented older adults at genetic risk for AD and other types of dementia (i.e., APOE e4 allele) utilized a new Stroop test that includes a dual executive-function condition requiring both response inhibition and cognitive switching. Results indicated that, relative to non-e4 subjects, the e4 group committed more errors, but only on the new Inhibition/Switching condition. In addition, error-rate variance on this task was more heterogeneous for the e4 compared to the non-e4 group, and errors rates correlated significantly with global cognitive status (i.e., DRS scores) for the e4 group but not for the non-e4 group. These findings suggest that vulnerability to errors in response inhibition and cognitive flexibility is present in persons at risk for AD and may signal early emergence of executive dysfunction in preclinical AD. The association between these subtle executive-function deficits and the overall cognitive functioning of at-risk individuals provides further evidence of their utility as a possible preclinical marker of AD. Preparation of this article was supported in part by a Veterans Administration Merit Review Grant (DD), a VA Career Development Award (MJ) and by National Institute on Aging Grants RO1 AG12674 (MB) and P50 AG05131 (UCSD ADRC; DS).

Neuropsychological deficits associated with Alzheimer's disease in the very-old: discrepancies in raw vs. standardized scores.

The profiles of neuropsychological deficits associated with Alzheimers 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.

Asymmetries in Global-Local Processing Ability in Elderly People With the Apolipoprotein E-ε4 Allele.

Previous studies have identified cognitive asymmetries in elderly people at increased risk for Alzheimers disease (AD) by comparing standardized neuropsychological tests of verbal and spatial abilities in both preclinical AD and apolipoprotein epsilon4+ elderly groups. This prospective study investigated cognitive asymmetries within a single test by comparing cognitively intact elderly (with and without the epsilon4+ allele) on a learning and memory measure that uses global and local visuospatial stimuli. Both groups demonstrated comparable overall learning and recall. But the epsilon4+ group had a significantly larger discrepancy between their global and local learning scores and had a greater proportion of individuals with more than a one standard deviation difference between their immediate recall of the global and local elements, relative to the epsilon4- group. These findings build on previous studies identifying subgroups of elderly people at greater risk for AD who often demonstrate increased cognitive asymmetries relative to groups without significant risk factors.