Clinical, cognitive, and genetic predictors of change in job status following traumatic brain injury in a military population.

OBJECTIVE: Traumatic brain injury (TBI) is a risk associated with military duty, and residual effects from TBI may adversely affect a service member's ability to complete duties. It is, therefore, important to identify factors associated with a change in job status following TBI in an active military population. On the basis of previous research, we predicted that apolipoprotein E (APOE) genotype may be 1 factor. DESIGN: Cohort study of military personnel who sustained a mild to moderate TBI. SETTING: Military medical clinics. PATIENTS OR OTHER PARTICIPANTS: Fifty-two military participants were recruited through the Defense and Veterans Brain Injury Center, affiliated with Naval Medical Center San Diego and the Defense and Veterans Brain Injury Center Concussion Clinic located at the First Marine Division at Camp Pendleton. INTERVENTION(S): A multivariate statistical classification approach called optimal data analysis allowed for consideration of APOE genotype alongside cognitive, emotional, psychosocial, and physical functioning. MAIN OUTCOME MEASURE(S): APOE genotype, neuropsychological, psychosocial, and clinical outcomes. RESULTS: We identified a model of factors that was associated with a change in job status among military personnel who experienced a mild or moderate TBI. CONCLUSIONS: Factors associated with a change in job status are different when APOE genotype is considered. We conclude that APOE genotype may be an important genetic factor in recovery from mild to moderate head injury.

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 epsilon4 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-epsilon4 allele in increasing the risk of Alzheimer's disease, we predicted that persons with the APOE-epsilon4 genotype would display relatively greater deficits in cognition than their non-epsilon4 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 epsilon4 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 epsilon4 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-epsilon4 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.

Heterogeneity in verbal memory: a marker of preclinical Alzheimer's disease?

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.

Identification of Alzheimer disease risk by functional magnetic resonance imaging.

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.

Treatment adherence in cognitive processing therapy for combat-related PTSD with history of mild TBI.

OBJECTIVE: This retrospective study examined treatment adherence in Cognitive Processing Therapy (CPT) for combat-related posttraumatic stress disorder (PTSD) in Veterans of Operation Enduring Freedom (OEF) and Operation Iraqi Freedom (OIF) with and without history of mild traumatic brain injury (mTBI). METHOD: Medical record review of consecutive referrals to an outpatient PTSD clinic identified veterans diagnosed with combat-related PTSD who began treatment with CPT. The sample (N = 136) was grouped according to positive (n = 44) and negative (n = 92) mTBI history. Groups were compared in terms of presenting symptoms and treatment adherence. RESULTS: The groups were not different on a pretreatment measure of depression, but self-reported and clinician-rated PTSD symptoms were higher in veterans with history of mTBI. The treatment completion rate was greater than 61% in both groups. The number of sessions attended averaged 9.6 for the PTSD group and 7.9 for the mTBI/PTSD group (p = .05). IMPLICATIONS: Given the lack of marked group differences in treatment adherence, these initial findings suggest that standard CPT for PTSD may be a tolerable treatment for OEF/OIF veterans with a history of PTSD and mTBI as well as veterans with PTSD alone.

Comparison of the traditional recall-based versus a new list-based method for computing semantic clustering on the California Verbal Learning Test: evidence from Alzheimer's disease.

For over 50 years, cognitive psychologists and neuropsychologists have relied almost exclusively on a method for computing semantic clustering on list-learning tasks (recall-based formula) that was derived from an outdated assumption about how learning occurs. A new procedure for computing semantic clustering (list-based formula) was developed for the CVLT-II to correct the shortcomings of the traditional method. In the present study we compared the clinical utility of the traditional recall-based method versus the new list-based method using results from the original CVLT administered to 87 patients with Alzheimer's disease and 86 matched normal control participants. Logistic regression and score distribution analyses indicated that the new list-based method enhances the detection of differences in semantic-clustering ability between the groups.

APOE genotype predicts depression in women with Alzheimer's disease: a retrospective study.

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.

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 epsilon4 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 epsilon4 allele. Relationship between hippocampal volumes and memory performance was strongly impacted by diagnosis of mild cognitive impairment. CONCLUSIONS: APOE epsilon4 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.

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.

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 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.

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 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.

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.

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

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.