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1.  Asymmetry in Auditory and Spatial Attention Span in Normal Elderly Genetically At Risk for Alzheimer's Disease 
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.
PMCID: PMC3080769  PMID: 15903153
The Clinical neuropsychologist  2009;24(1):70-79.
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on a method for computing semantic clustering on list-learning tasks (recall-based formula) that was derived from an outdated assumption about how learning occurs.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.
PMCID: PMC3084534  PMID: 19894184
Learning; Memory; Neuropsychology; CVLT
3.  Brain substrates of learning and retention in mild cognitive impairment diagnosis and progression to Alzheimerâs disease 
Neuropsychologia  2009;48(5):1237-1247.
Understanding the underlying qualitative features of memory deficits in mild cognitive impairment (MCI) can provide critical information for early detection of Alzheimerâs disease (AD). This study sought to investigate the utility of both learning and retention measures in (a) the diagnosis of MCI, (b) predicting progression to AD, and (c) examining their underlying brain morphometric correlates. A total of 607 participants were assigned to three MCI groups (high learning-low retention; low learning-high retention; low learning-low retention) and one control group (high learning-high retention) based on scores above or below a 1.5 SD cutoff on learning and retention indices of the Rey Auditory Verbal Learning Test. Our results demonstrated that MCI individuals with predominantly a learning deficit showed a widespread pattern of gray matter loss at baseline, whereas individuals with a retention deficit showed more focal gray matter loss. Moreover, either learning or retention measures provided good predictive value for longitudinal clinical outcome over two years, although impaired learning had modestly better predictive power than impaired retention. As expected, impairments in both measures provided the best predictive power. Thus, the conventional practice of relying solely on the use of delayed recall or retention measures in studies of amnestic MCI misses an important subset of older adults at risk of developing AD. Overall, our results highlight the importance of including learning measures in addition to retention measures when making a diagnosis of MCI and for predicting clinical outcome.
PMCID: PMC2851550  PMID: 20034503
Amnestic MCI; Early detection; Episodic memory; Longitudinal outcome; MR morphometry
4.  Cognitive Discrepancies Versus APOE Genotype as Predictors of Cognitive Decline in Normal-Functioning Elderly Individuals: A Longitudinal Study 
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.
Longitudinal study.
San Diego, CA, Veterans Administration Hospital.
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).
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.
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.
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.
PMCID: PMC3050584  PMID: 18448849
Cognitive discrepancies; aging; Alzheimer disease; executive functioning
5.  Neuropsychological Contributions to the Early Identification of Alzheimer’s Disease 
Neuropsychology review  2008;18(1):73-90.
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.
PMCID: PMC2882236  PMID: 18347989
Neuropsychological contributions; Alzheimer’s disease; Prodromal expression; Mild Cognitive Impairment; Apolipoprotein E; Cerebrovascular; Very-Old
6.  The emergence of cognitive discrepancies in preclinical Alzheimer's disease: A six-year case study 
Neurocase  2009;15(4):278-293.
We present neuropsychological data from an 81-year-old individual who was followed over a six-year period, initially as a healthy control participant. She performed above age-adjusted cutoff scores for impairment on most neuropsychological tests, including learning and memory measures, until the final assessment when she received a diagnosis of probable Alzheimer's disease (AD). Despite generally normal scores on individual cognitive tests, her cognitive profile revealed increasingly large cognitive discrepancies when contrasting verbal versus visuospatial tasks, and complex versus basic-level tasks. The present case provides intriguing evidence that cognitive-discrepancy measures could improve our ability to detect subtle changes in cognition at the earliest, preclinical stages of AD.
PMCID: PMC2875065  PMID: 19382039
Alzheimer's disease; Neuropsychology; Cognition; Discrepancy; Preclinical
7.  Identifying the “source” of recognition memory deficits in patients with Huntington's disease or Alzheimer's disease: Evidence from the CVLT-II 
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.
PMCID: PMC2864091  PMID: 18415887
8.  Are Empirically-Derived Subtypes of Mild Cognitive Impairment Consistent with Conventional Subtypes? 
Given the importance of identifying dementia prodromes for future treatment efforts, we examined two methods of diagnosing mild cognitive impairment (MCI) and determined whether empirically-derived MCI subtypes of these diagnostic methods were consistent with one another as well as with conventional MCI subtypes (i.e., amnestic, non-amnestic, single-domain, multi-domain). Participants were diagnosed with MCI using either conventional Petersen/Winblad criteria (n = 134; >1.5 SDs below normal on one test within a cognitive domain) or comprehensive neuropsychological criteria developed by Jak et al. (2009) (n = 80; >1 SD below normal on two tests within a domain), and the resulting samples were examined via hierarchical cluster and discriminant function analyses. Results showed that neuropsychological profiles varied depending on the criteria used to define MCI. Both criteria revealed an Amnestic subtype, consistent with prodromal Alzheimer’s disease (AD), and a Mixed subtype that may capture individuals in advanced stages of MCI. The comprehensive criteria uniquely yielded Dysexecutive and Visuospatial subtypes, whereas the conventional criteria produced a subtype that performed within normal limits, suggesting its susceptibility to false positive diagnostic errors. Whether these empirically-derived MCI subtypes correspond to dissociable neuropathologic substrates and represent reliable prodromes of dementia will require additional follow-up.
PMCID: PMC3742806  PMID: 23552486
Mild cognitive impairment; Amnestic MCI; Non-amnestic MCI; Dementia; Cluster analysis; Neuropsychology
9.  Which Neuropsychological Tests Predict Progression to Alzheimer’s Disease in Hispanics? 
Neuropsychology  2013;27(3):343-355.
To investigate which neuropsychological tests predict eventual progression to Alzheimer’s disease (AD) in both Hispanic and non-Hispanic individuals. Although our approach was exploratory, we predicted that tests that underestimate cognitive ability in healthy aging Hispanics might not be sensitive to future cognitive decline in this cultural group.
We compared first-year data of 22 older adults (11 Hispanic) who were diagnosed as cognitively normal but eventually developed AD (decliners), to 60 age- and education-matched controls (27 Hispanic) who remained cognitively normal. To identify tests that may be culturally biased in our sample, we compared Hispanic with non-Hispanic controls on all tests and asked which tests were sensitive to future decline in each cultural group.
Compared to age-, education-, and gender-matched non-Hispanic controls, Hispanic controls obtained lower scores on tests of language, executive function, and some measures of global cognition. Consistent with our predictions, some tests identified non-Hispanic, but not Hispanic, decliners (vocabulary, semantic fluency). Contrary to our predictions, a number of tests on which Hispanics obtained lower scores than non-Hispanics nevertheless predicted eventual progression to AD in both cultural groups (e.g., Boston Naming Test [BNT], Trails A and B).
Cross-cultural variation in test sensitivity to decline may reflect greater resistance of medium difficulty items to decline and bilingual advantages that initially protect Hispanics against some aspects of cognitive decline commonly observed in non-Hispanics with preclinical AD. These findings highlight a need for further consideration of cross-cultural differences in neuropsychological test performance and development of culturally unbiased measures.
PMCID: PMC3740167  PMID: 23688216
preclinical Alzheimer’s disease; Spanish–English bilingual; Hispanic; verbal fluency; object naming
10.  Effect of mild cognitive impairment and APOE genotype on resting cerebral blood flow and its association with cognition 
Using whole-brain pulsed arterial spin labeling magnetic resonance imaging, resting cerebral blood flow (CBF) was measured in 20 mild cognitive impairment (MCI; 11 ɛ3 and 9 ɛ4) and 40 demographically matched cognitively normal (CN; 27 ɛ3 and 13 ɛ4) participants. An interaction of apolipoprotein (APOE) genotype (ɛ3 and ɛ4) and cognitive status (CN and MCI) on quantified gray-matter CBF corrected for partial volume effects was found in the left parahippocampal and fusiform gyri (PHG/FG), right middle frontal gyrus, and left medial frontal gyrus. In the PHG/FG, CBF was elevated for CN ɛ4 carriers but decreased for MCI ɛ4 carriers. The opposite pattern was seen in frontal regions: CBF was decreased for CN ɛ4 carriers but increased for MCI ɛ4 carriers. Cerebral blood flow in the PHG/FG was positively correlated with verbal memory for CN ɛ4 adults (r=0.67, P=0.01). Cerebral blood flow in the left medial frontal gyrus was positively correlated with verbal memory for MCI ɛ4 adults (r=0.70, P=0.05). Findings support dynamic pathophysiologic processes in the brain associated with Alzheimer's disease risk and indicate that cognitive status and APOE genotype have interactive effects on CBF. Correlations between CBF and verbal memory suggest a differential neurovascular compensatory response in posterior and anterior cortices with cognitive decline in ɛ4 adults.
PMCID: PMC3421098  PMID: 22549621
apolipoprotein E; arterial spin labeling; cognition; mild cognitive impairment
11.  Partially Overlapping Mechanisms of Language and Task Control in Young and Older Bilinguals 
Psychology and aging  2012;27(4):959-974.
The current study tested the hypothesis that bilinguals rely on domain-general mechanisms of executive control to achieve language control by asking if linguistic and nonlinguistic switching tasks exhibit similar patterns of aging-related decline. Thirty young and 30 aging bilinguals completed a cued language-switching task and a cued color-shape switching task. Both tasks demonstrated significant aging effects, but aging-related slowing and the aging-related increase in errors were significantly larger on the color-shape than on the language task. In the language task, aging increased language-switching costs in both response times and errors, and language-mixing costs only in response times. In contrast, the color-shape task exhibited an aging-related increase in costs only in mixing errors. Additionally, a subset of the older bilinguals could not do the color-shape task, but were able to do the language task, and exhibited significantly larger language-switching costs than matched controls. These differences, and some subtle similarities, in aging effects observed across tasks imply that mechanisms of nonlinguistic task and language control are only partly shared and demonstrate relatively preserved language control in aging. More broadly, these data suggest that age deficits in switching and mixing costs may depend on task expertise, with mixing deficits emerging for less-practiced tasks and switching deficits for highly practiced, possibly “expert” tasks (i.e., language).
PMCID: PMC3494773  PMID: 22582883
aging; bilingualism; language switching; task switching; executive control
12.  Yes/No Versus Forced-Choice Recognition Memory in Mild Cognitive Impairment and Alzheimer’s Disease: Patterns of Impairment and Associations with Dementia Severity 
The Clinical neuropsychologist  2012;26(7):1201-1216.
Memory tests are sensitive to early identification of Alzheimer’s disease (AD) but less useful as the disease advances. However, assessing particular types of recognition memory may better characterize dementia severity in later stages of AD. We sought to examine patterns of recognition memory deficits in individuals with AD and mild cognitive impairment (MCI). Memory performance and global cognition data were collected from participants with AD (n=37), MCI (n=37), and cognitively intact older adults (normal controls, NC; n=35). One-way analyses of variance (ANOVAs) examined differences between groups on yes/no and forced-choice recognition measures. Individuals with amnestic MCI performed worse than NC and nonamnestic MCI participants on yes/no recognition, but were comparable on forced-choice recognition. AD patients were more impaired across yes/no and forced-choice recognition tasks. Individuals with mild AD (≥120 Dementia Rating Scale, DRS) performed better than those with moderate-to-severe AD (<120 DRS) on forced-choice recognition, but were equally impaired on yes/no recognition. There were differences in the relationships between learning, recall, and recognition performance across groups. Although yes/no recognition testing may be sensitive to MCI, forced-choice procedures may provide utility in assessing severity of anterograde amnesia in later stages of AD. Implications for assessment of insufficient effort and malingering are also discussed.
PMCID: PMC3482270  PMID: 23030301
Recognition memory; Alzheimer’s disease; Mild cognitive impairment; Dementia severity; Neuropsychology
13.  fMRI evidence of compensatory mechanisms in older adults at genetic risk for Alzheimer disease 
Neurology  2005;64(3):501-508.
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.
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.
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.
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.
PMCID: PMC1761695  PMID: 15699382
14.  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 < 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.
PMCID: PMC1621043  PMID: 12901784
Aging; Alzheimer's disease; Neuropsychology; Apolipoprotein E; Very-old
15.  Assessment of Alzheimer’s Disease Risk with Functional Magnetic Resonance Imaging: An Arterial Spin Labeling Study 
Functional magnetic resonance imaging (fMRI) of older adults at risk for Alzheimer’s disease (AD) by virtue of their cognitive (i.e., mild cognitive impairment [MCI]) and/or genetic (i.e., apolipoprotein E [APOE] ε4 allele) status demonstrate divergent brain response patterns during memory encoding across studies. Using arterial spin labeling MRI, we examined the influence of AD risk on resting cerebral blood flow (CBF) as well as the CBF and blood oxygenation level dependent (BOLD) signal response to memory encoding in the medial temporal lobes (MTL) in 45 older adults (29 cognitively normal [14 APOE ε4 carriers and 15 noncarriers]; 16 MCI [8 APOE ε4 carriers, 8 noncarriers]). Risk groups were comparable in terms of mean age, years of education, gender distribution, and vascular risk burden. Individuals at genetic risk for AD by virtue of the APOE ε4 allele demonstrated increased MTL resting state CBF relative to ε4 noncarriers, whereas individuals characterized as MCI showed decreased MTL resting state CBF relative to their cognitively normal peers. For percent change CBF, there was a trend toward a cognitive status by genotype interaction. In the cognitively normal group, there was no difference in percent change CBF based on APOE genotype. In contrast, in the MCI group, APOE ε4 carriers demonstrated significantly greater percent change in CBF relative to ε4 noncarriers. No group differences were found for BOLD response. Findings suggest that abnormal resting state CBF and CBF response to memory encoding may be early indicators of brain dysfunction in individuals at risk for developing AD.
PMCID: PMC3443702  PMID: 22531427
Apolipoprotein E; cerebral blood flow; functional; hippocampus; magnetic resonance imaging; memory; mild cognitive impairment
16.  Intraindividual Variability in HIV Infection: Evidence for Greater Neurocognitive Dispersion in Older HIV Seropositive Adults 
Neuropsychology  2011;25(5):645-654.
Both the prevalence and incidence of HIV infection among older adults are on the rise. Older adults are at increased risk of HIV-associated neurocognitive disorders, which has historically been characterized as an inconsistent or “spotty” pattern of deficits. Dispersion is a form of intraindividual variability (IIV) that is defined as within-person variability in performance across domains and has been associated with poorer neurocognitive functioning and incipient decline among healthy older adults. To our knowledge, no studies have yet examined dispersion in an aging HIV-infected sample.
For the current study we examined the hypothesis that age and HIV infection have synergistic effects on dispersion across a battery of clinical and experimental cognitive tasks. Our well-characterized sample comprised 126 HIV-seropositive individuals (HIV+) and 40 HIV-seronegative comparison individuals (HIV−), all of whom were administered a comprehensive neuropsychological battery.
Consistent with our hypothesis, an age by HIV serostatus interaction was observed, with the older HIV+ group demonstrating a higher level of dispersion relative to older HIV− and younger HIV+ individuals, even when potentially confounding demographic and medical factors were controlled.
Our results demonstrate that older HIV+ adults produce greater dispersion, or intraindividual variability in performance across a range of tests, which may be reflective of cognitive dyscontrol to which this population is vulnerable, perhaps driven by the combined effects of aging and HIV infection on prefrontostriatal systems.
PMCID: PMC3158302  PMID: 21574712
HIV; aging; neuropsychological assessment; variability
17.  Antemortem Pulse Pressure Elevation Predicts Cerebrovascular Disease in Autopsy-Confirmed Alzheimer’s Disease 
Journal of Alzheimer's Disease  2012;30(3):595-603.
Elevated pulse pressure (PP) is associated with cognitive decline and increased risk of Alzheimer’s disease (AD) in older adults, although the mechanisms behind these associations remain unclear. To address this question, we examined whether antemortem late-life PP elevation predicted vascular or AD pathology in autopsy-confirmed AD patients. Sixty-five elderly patients (mean age 74.2 years) clinically diagnosed with possible or probable AD underwent neuropsychological testing and blood pressure examinations. Postmortem histopathological measures of cerebrovascular disease (CVD) and AD neuropathology were later obtained on these same patients. We expected that antemortem PP elevation, but not standard blood pressure measures such as systolic or diastolic blood pressure, would predict the autopsy-based presence of CVD, and possibly AD pathology, in elderly AD patients. Results demonstrated that antemortem PP elevation was associated with the presence and severity of CVD at autopsy. For every 5 mmHg increase in antemortem PP there was an estimated 36% increase in the odds of having CVD at autopsy. Additionally, PP accounted for 12% of variance in CVD severity. No significant associations were present for cerebral amyloid angiopathy or Braak and Braak staging of the severity of AD pathology. Other standard blood pressure measures also did not significantly predict neuropathology. The association between antemortem PP and CVD at autopsy suggests that in older adults with AD, PP elevation may increase the risk of CVD. These findings may have treatment implications since some antihypertensive medications specifically address the pulsatile component of blood pressure (e.g., renin-angiotensin system inhibitors, calcium channel blockers).
PMCID: PMC3370943  PMID: 22451309
Alzheimer’s disease; blood pressure; cerebrovascular disease; pulse pressure
18.  Posterior Cingulum White Matter Disruption and Its Associations with Verbal Memory and Stroke Risk in Mild Cognitive Impairment 
Journal of Alzheimer's Disease  2012;29(3):589-603.
Medial temporal lobe and temporoparietal brain regions are among the earliest neocortical sites to undergo pathophysiologic alterations in Alzheimer’s disease (AD), although the underlying white matter changes in these regions is less well known. We employed diffusion tensor imaging to evaluate early alterations in regional white matter integrity in participants diagnosed with mild cognitive impairment (MCI). The following regions of interests (ROIs) were examined: 1) anterior cingulum (AC); 2) posterior cingulum (PC); 3) genu of the corpus callosum; 4) splenium of the corpus callosum; and 5) as a control site for comparison, posterior limb of the internal capsule. Forty nondemented participants were divided into demographically-similar groups based on cognitive status (MCI: n = 20; normal control: n = 20), and fractional anisotropy (FA) estimates of each ROI were obtained. MCI participants showed greater posterior white matter (i.e., PC, splenium) but not anterior white matter (i.e., AC, genu) changes, after adjusting for age, stroke risk, and whole brain volume. FA differences of the posterior white matter were best accounted for by changes in radial but not axial diffusivity. PC FA was also significantly positively correlated with hippocampal volume as well as with performance on tests of verbal memory, whereas stroke risk was significantly correlated with genu FA and was unrelated to PC FA. When investigating subtypes of our MCI population, amnestic MCI participants showed lower PC white matter integrity relative to those with non-amnestic MCI. Findings implicate involvement of posterior microstructural white matter degeneration in the development of MCI-related cognitive changes and suggest that reduced FA of the PC may be a candidate neuroimaging marker of AD risk.
PMCID: PMC3341099  PMID: 22466061
Aging; diffusion tensor imaging; memory; mild cognitive impairment; posterior cingulum; white matter
19.  An examination of the age-prospective memory paradox in HIV-infected adults 
The age-prospective memory (PM) paradox asserts that, despite evidence of age-associated PM deficits on laboratory tasks, older adults perform comparably to (or better than) young adults on naturalistic PM tasks. This study examined the age-PM paradox in older HIV-infected individuals, who represent a growing epidemic and may be at heightened risk for adverse neurocognitive and everyday functioning outcomes. Participants included 88 older (50+ years) and 53 younger (≤40 years) HIV-infected individuals as well as 54 older and 59 younger seronegative adults who completed both laboratory and naturalistic time-based PM tasks. Similar interactions were observed in both the seropositive and the seronegative samples, such that the older participants demonstrated significantly lower laboratory-based PM than the younger groups, but not on the naturalistic PM trial. Secondary analyses within the HIV+ sample revealed that naturalistic task success was indirectly associated with greater self-reported use of PM-based and external compensatory strategies in the daily lives of older, but not younger, HIV+ adults. Study findings suggest that, although older HIV-infected adults exhibit moderate PM deficits on laboratory measures versus their younger counterparts, such impairments are paradoxically not evident on ecologically relevant naturalistic PM activities in daily life, perhaps related to effective utilization compensatory strategies.
PMCID: PMC3327134  PMID: 21992453
Episodic memory; Aging; Neuropsychological assessment; AIDS dementia complex; Cognition
20.  Are self-reported symptoms of executive dysfunction associated with objective executive function performance following mild to moderate traumatic brain injury? 
Background and objective
We examined the relationship between self-reported pre- and post-injury changes in executive dysfunction, apathy, disinhibition, and depression, and performance on neuropsychological tests of executive function, attention/processing speed, and memory in relation to mood levels and effort test performance in individuals in the early stages of recovery from mild to moderate traumatic brain injury (TBI).
Participants were 71 noncombat military personnel who were in a semiacute stage of recovery (<3 months post injury) from mild to moderate TBI. Pre- and post-TBI behaviors were assessed with the Frontal Systems Behavior Scale (FrSBe; Grace & Malloy, 2001) and correlated with levels of depressive symptoms, effort test performance, and performance on objective measures of attention, executive function, and memory.
Self-reported symptoms of executive dysfunction generally failed to predict performance on objective measures of executive function and memory, although they predicted poorer performance on measures of attention/processing speed. Instead, higher levels of depressive symptomatology best predicted poorer performance on measures of executive function and memory. However, the relationship between memory performance and TBI symptoms was no longer significant when effort performance was controlled.
Our findings suggest that, among individuals in early recovery from mild to moderate TBI, self-reported depressive symptoms, rather than patients’ cognitive complaints, are associated with objective executive function. However, self-reported cognitive complaints may be associated with objectively measured inattention and slow processing speed.
PMCID: PMC3325052  PMID: 21958432
Traumatic brain injury; Neuropsychology; Cognition; Behavior; Depression
21.  Clinical, Cognitive, and Genetic Predictors of Change in Job Status Following Traumatic Brain Injury in a Military Population 
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.
Cohort study of military personnel who sustained a mild to moderate TBI.
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.
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.
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.
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.
PMCID: PMC3319716  PMID: 19158597
apolipoprotein E; military; neurocognition; optimal data analysis; traumatic brain injury
22.  Age-Related Influences of Prior Sleep on Brain Activation during Verbal Encoding 
Disrupted sleep is more common in older adults (OLD) than younger adults (YOUNG), often co-morbid with other conditions. How these sleep disturbances affect cognitive performance is an area of active study. We examined whether brain activation during verbal encoding correlates with sleep quantity and quality the night before testing in a group of healthy OLD and YOUNG. Twenty-seven OLD (ages 59–82) and 27 YOUNG (ages 19–36) underwent one night of standard polysomnography. Twelve hours post-awakening, subjects performed a verbal encoding task while undergoing functional magnetic resonance imaging. Analyses examined the group (OLD vs. YOUNG) by prior sleep quantity (total sleep time, TST) or quality (sleep efficiency, SE) interaction on cerebral activation, controlling for performance. Longer TST promoted higher levels of activation in the bilateral anterior parahippocampal in OLD and lower activation levels in the left anterior parahippocampus in YOUNG. Greater SE promoted higher activation levels in the left posterior parahippocampus and right inferior frontal gyrus in YOUNG, but not in OLD. The roles of these brain regions in verbal encoding suggest, in OLD, longer sleep duration may be linked to the ability to engage in functional compensation during cognitive challenges. By contrast, in YOUNG, shorter sleep duration may necessitate functional compensation to maintain cognitive performance, similar to what is seen following acute sleep deprivation. Additionally, in YOUNG, better sleep quality may improve semantic retrieval processes, thereby aiding encoding.
PMCID: PMC3318226  PMID: 22493590
aging; sleep; fMRI; cerebral activation; cognitive performance; verbal encoding
23.  Verbal Serial List Learning in Mild Cognitive Impairment: A Profile Analysis of Interference, Forgetting, and Errors 
Using cluster analysis Libon et al. (2010) found three verbal serial list-learning profiles involving delay memory test performance in patients with mild cognitive impairment (MCI). Amnesic MCI (aMCI) patients presented with low scores on delay free recall and recognition tests; mixed MCI (mxMCI) patients scored higher on recognition compared to delay free recall tests; and dysexecutive MCI (dMCI) patients generated relatively intact scores on both delay test conditions. The aim of the current research was to further characterize memory impairment in MCI by examining forgetting/savings, interference from a competing word list, intrusion errors/perseverations, intrusion word frequency, and recognition foils in these three statistically determined MCI groups compared to normal control (NC) participants. The aMCI patients exhibited little savings, generated more highly prototypic intrusion errors, and displayed indiscriminate responding to delayed recognition foils. The mxMCI patients exhibited higher saving scores, fewer and less prototypic intrusion errors, and selectively endorsed recognition foils from the interference list. dMCI patients also selectively endorsed recognition foils from the interference list but performed similarly compared to NC participants. These data suggest the existence of distinct memory impairments in MCI and caution against the routine use of a single memory test score to operationally define MCI.
PMCID: PMC3315271  PMID: 21880171
Mild cognitive impairment; MCI; Declarative memory; Executive control; Philadelphia (repeatable) Verbal Learning Test; P(r)VLT; Cluster analysis; Boston Process Approach
24.  Dysexecutive Functioning in Mild Cognitive Impairment: Derailment in Temporal Gradients 
Libon et al. (2010) provided evidence for three statistically determined clusters of patients with mild cognitive impairment (MCI): amnesic (aMCI), dysexecutive (dMCI), and mixed (mxMCI). The current study further examined dysexecutive impairment in MCI using the framework of Fuster's (1997) derailed temporal gradients, that is, declining performance on executive tests over time or test epoch. Temporal gradients were operationally defined by calculating the slope of aggregate letter fluency output across 15-s epochs and accuracy indices for initial, middle, and latter triads from the Wechsler Memory Scale-Mental Control subtest (Boston Revision). For letter fluency, slope was steeper for dMCI compared to aMCI and NC groups. Between-group Mental Control analyses for triad 1 revealed worse dMCI performance than NC participants. On triad 2, dMCI scored lower than aMCI and NCs; on triad 3, mxMCI performed worse versus NCs. Within-group Mental Control analyses yielded equal performance across all triads for aMCI and NC participants. mxMCI scored lower on triad 1 compared to triads 2 and 3. dMCI participants also performed worse on triad 1 compared to triads 2 and 3, but scored higher on triad 3 versus triad 2. These data suggest impaired temporal gradients may provide a useful heuristic for understanding dysexecutive impairment in MCI.
PMCID: PMC3315354  PMID: 22014116
Mild cognitive impairment; Single domain mild cognitive impairment; Multiple domain mild cognitive impairment; Alzheimer's disease; The Titanic Effect; Executive control
25.  Specific Measures of Executive Function Predict Cognitive Decline in Older Adults 
Decline in executive function has been noted in the prodromal stage of Alzheimer’s disease (AD) and may presage more global cognitive declines. In this prospective longitudinal study, five measures of executive function were used to predict subsequent global cognitive decline in initially nondemented older adults. Of 71 participants, 15 demonstrated significant decline over a 1-year period on the Dementia Rating Scale (Mattis, 1988) and the remaining participants remained stable. In the year before decline, the decline group performed significantly worse than the no-decline group on two measures of executive function: the Color-Word Interference Test (CWIT; inhibition/switching condition) and Verbal Fluency (VF; switching condition). In contrast, decliners and non-decliners performed similarly on measures of spatial fluency (Design Fluency switching condition), spatial planning (Tower Test), and number-letter switching (Trail Making Test switching condition). Furthermore, the CWIT inhibition-switching measure significantly improved the prediction of decline and no-decline group classification beyond that of learning and memory measures. These findings suggest that some executive function measures requiring inhibition and switching provide predictive utility of subsequent global cognitive decline independent of episodic memory and may further facilitate early detection of dementia.
PMCID: PMC3314335  PMID: 22115028
Executive functions; Global cognition; Switching; Prodromal Alzheimer’s disease; Mild cognitive impairment; Prediction

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