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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
2.  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.
doi:10.1080/13554790902729465
PMCID: PMC2875065  PMID: 19382039
Alzheimer's disease; Neuropsychology; Cognition; Discrepancy; Preclinical
3.  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 
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.
doi:10.1080/13854040903002232
PMCID: PMC3084534  PMID: 19894184
Learning; Memory; Neuropsychology; CVLT
4.  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.
doi:10.1016/j.neuropsychologia.2009.12.024
PMCID: PMC2851550  PMID: 20034503
Amnestic MCI; Early detection; Episodic memory; Longitudinal outcome; MR morphometry
5.  Cognitive Discrepancies Versus APOE Genotype as Predictors of Cognitive Decline in Normal-Functioning Elderly Individuals: A Longitudinal Study 
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.
doi:10.1097/JGP.0b013e3181629957
PMCID: PMC3050584  PMID: 18448849
Cognitive discrepancies; aging; Alzheimer disease; executive functioning
6.  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.
doi:10.1007/s11065-008-9054-1
PMCID: PMC2882236  PMID: 18347989
Neuropsychological contributions; Alzheimer’s disease; Prodromal expression; Mild Cognitive Impairment; Apolipoprotein E; Cerebrovascular; Very-Old
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.
doi:10.1080/13803390701531912
PMCID: PMC2864091  PMID: 18415887
8.  Subjective Cognitive Complaints Contribute to Misdiagnosis of Mild Cognitive Impairment 
Subjective cognitive complaints are a criterion for the diagnosis of mild cognitive impairment (MCI), despite their uncertain relationship to objective memory performance in MCI. We aimed to examine self-reported cognitive complaints in subgroups of the Alzheimer’s Disease Neuroimaging Initiative (ADNI) MCI cohort to determine whether they are a valuable inclusion in the diagnosis of MCI or, alternatively, if they contribute to misdiagnosis. Subgroups of MCI were derived using cluster analysis of baseline neuropsychological test data from 448 ADNI MCI participants. Cognitive complaints were assessed via the Everyday Cognition (ECog) questionnaire, and discrepancy scores were calculated between self- and informant-report. Cluster analysis revealed Amnestic and Mixed cognitive phenotypes as well as a third Cluster-Derived Normal subgroup (41.3%), whose neuropsychological and cerebrospinal fluid (CSF) Alzheimer’s disease (AD) biomarker profiles did not differ from a “robust” normal control group. This cognitively intact phenotype of MCI participants overestimated their cognitive problems relative to their informant, whereas Amnestic MCI participants with objective memory impairment underestimated their cognitive problems. Underestimation of cognitive problems was associated with positive CSF AD biomarkers and progression to dementia. Overall, there was no relationship between self-reported cognitive complaints and objective cognitive functioning, but significant correlations were observed with depressive symptoms. The inclusion of self-reported complaints in MCI diagnostic criteria may cloud rather than clarify diagnosis and result in high rates of misclassification of MCI. Discrepancies between self- and informant-report demonstrate that overestimation of cognitive problems is characteristic of normal aging while underestimation may reflect greater risk for cognitive decline.
doi:10.1017/S135561771400068X
PMCID: PMC4172502  PMID: 25156329
Mild cognitive impairment; Awareness; Cluster analysis; Diagnostic errors; Neuropsychology; Dementia; Alzheimer disease
9.  White Matter Integrity in Veterans With Mild Traumatic Brain Injury: Associations With Executive Function and Loss of Consciousness 
Objective
We investigated using diffusion tensor imaging (DTI) and the association between white matter integrity and executive function (EF) performance in postacute mild traumatic brain injury (mTBI). In addition, we examined whether injury severity, as measured by loss of consciousness (LOC) versus alterations in consciousness (AOC), is related to white matter microstructural alterations and neuropsychological outcome.
Participants
Thirty Iraq and Afghanistan War era veterans with a history of mTBI and 15 healthy veteran control participants.
Results
There were no significant overall group differences between control and mTBI participants on DTI measures. However, a subgroup of mTBI participants with EF decrements (n = 13) demonstrated significantly decreased fractional anisotropy of prefrontal white matter, corpus callosum, and cingulum bundle structures compared with mTBI participants without EF decrements (n = 17) and control participants. Participants having mTBI with LOC were more likely to evidence reduced EF performances and disrupted ventral prefrontal white matter integrity when compared with either mTBI participants without LOC or control participants.
Conclusions
Findings suggest that altered white matter integrity contributes to reduced EF in subgroups of veterans with a history of mTBI and that LOC may be a risk factor for reduced EF as well as associated changes to ventral prefrontal white matter.
doi:10.1097/HTR.0b013e31828a1aa4
PMCID: PMC4300196  PMID: 23640539
diffusion tensor imaging; executive functions; traumatic brain injury; white matter
10.  Neuropsychological Criteria for Mild Cognitive Impairment Improves Diagnostic Precision, Biomarker Associations, and Progression Rates 
We compared two methods of diagnosing mild cognitive impairment (MCI): conventional Petersen/Winblad criteria as operationalized by the Alzheimer’s Disease Neuroimaging Initiative (ADNI) and an actuarial neuropsychological method put forward by Jak and Bondi designed to balance sensitivity and reliability. 1,150 ADNI participants were diagnosed at baseline as cognitively normal (CN) or MCI via ADNI criteria (MCI: n = 846; CN: n = 304) or Jak/Bondi criteria (MCI: n = 401; CN: n = 749), and the two MCI samples were submitted to cluster and discriminant function analyses. Resulting cluster groups were then compared and further examined for APOE allelic frequencies, cerebrospinal fluid (CSF) Alzheimer’s disease (AD) biomarker levels, and clinical outcomes. Results revealed that both criteria produced a mildly impaired Amnestic subtype and a more severely impaired Dysexecutive/Mixed subtype. The neuropsychological Jak/Bondi criteria uniquely yielded a third Impaired Language subtype, whereas conventional Petersen/Winblad ADNI criteria produced a third subtype comprising nearly one-third of the sample that performed within normal limits across the cognitive measures, suggesting this method’s susceptibility to false positive diagnoses. MCI participants diagnosed via neuropsychological criteria yielded dissociable cognitive phenotypes, significant CSF AD biomarker associations, more stable diagnoses, and identified greater percentages of participants who progressed to dementia than conventional MCI diagnostic criteria. Importantly, the actuarial neuropsychological method did not produce a subtype that performed within normal limits on the cognitive testing, unlike the conventional diagnostic method. Findings support the need for refinement of MCI diagnoses to incorporate more comprehensive neuropsychological methods, with resulting gains in empirical characterization of specific cognitive phenotypes, biomarker associations, stability of diagnoses, and prediction of progression. Refinement of MCI diagnostic methods may also yield gains in biomarker and clinical trial study findings because of improvements in sample compositions of ‘true positive’ cases and removal of ‘false positive’ cases.
doi:10.3233/JAD-140276
PMCID: PMC4133291  PMID: 24844687
Alzheimer’s disease; Alzheimer’s Disease Neuroimaging Initiative; biomarker; cluster analysis; dementia; mild cognitive impairment; neuropsychology; progression
11.  Cortical and Subcortical Cerebrovascular Resistance Index in Mild Cognitive Impairment and Alzheimer's Disease 
Background
Reduced regional cerebral blood flow (rCBF) is a well-established finding in Alzheimer's disease (AD), although fewer studies have examined the role of increased regional cerebrovascular resistance. By calculating the ratio of mean arterial pressure to rCBF, it is possible to estimate an index of regional cerebrovascular resistance (CVRi) that may be a sensitive measure of occult cerebrovascular disease.
Objective
To compare probable AD patients to mild cognitive impairment (MCI) and normal control (NC) participants on CVRi, the ratio of mean arterial pressure to rCBF.
Methods
Eighty-one participants (12 AD, 23 MCI, 46 NC) were compared on CVRi using voxel-wise analyses. Region-of-interest analyses examined correlations between subcortical CVRi and both cognition and white matter lesion (WML) volume.
Results
Voxel-wise analyses revealed CVRi elevation in AD relative to NCs (subcortical, medial temporal, posterior cingulate, precuneus, inferior parietal, superior temporal) and MCI (subcortical, posterior cingulate). MCI participants exhibited intermediate CVRi values within cortical and medial temporal areas. Significant CVRi clusters were larger and more widespread than those of parallel CBF analyses. Among MCI and AD participants, subcortical CVRi elevation was associated with lower Dementia Rating Scale score (r = −0.52, p = 0.001, for both thalamus and caudate), and caudate CVRi correlated with WML volume (r = 0.45, p = 0.001).
Conclusions
Cortical and subcortical CVRi is elevated in AD, particularly within the caudate and thalamus, where it is associated with decreased cognitive performance and increased WMLs. Findings suggest CVRi may play a role in cognitive decline and cerebrovascular disease in MCI and AD.
doi:10.3233/JAD-130086
PMCID: PMC4089500  PMID: 23666173
Alzheimer's disease; cerebral blood flow; cerebrovascular resistance; mild cognitive impairment
12.  Pulse pressure is associated with Alzheimer biomarkers in cognitively normal older adults 
Neurology  2013;81(23):2024-2027.
Objective:
The current study examined the association between pulse pressure (PP) and CSF-based biomarkers for Alzheimer disease, including β-amyloid 1–42 (Aβ1–42) and phosphorylated tau (P-tau) protein, in cognitively normal older adults.
Methods:
One hundred seventy-seven cognitively normal, stroke-free older adult participants (aged 55–100 years) underwent blood pressure assessment for determination of PP (systolic − diastolic blood pressure) and lumbar puncture for measurement of CSF Aβ1–42 and P-tau. Pearson correlations and multiple linear regression, controlling for age, sex, APOE genotype, and body mass index, evaluated the relationship between PP and Alzheimer disease biomarkers.
Results:
PP elevation was associated with increased P-tau (r = 0.23, p = 0.002), reduced Aβ1–42 (r = −0.19, p = 0.01), and increased P-tau to Aβ1–42 ratio (r = 0.27, p < 0.001). After controlling for covariates, PP remained associated with P-tau (β = 0.18, p = 0.0196) and P-tau to Aβ1–42 ratio (β = 0.0016, p < 0.001) but was no longer associated with Aβ1–42 (β = −0.1, p = 0.35). Post hoc multivariate analyses indicated that increased PP was associated with all biomarkers in younger participants (aged 55–70 years) (Aβ1–42: p = 0.050; P-tau: p = 0.003; P-tau to Aβ ratio: p = 0.0007) but not older participants (aged 70–100 years).
Conclusions:
PP elevation is associated with increased CSF P-tau and decreased Aβ1–42 in cognitively normal older adults, suggesting that pulsatile hemodynamics may be related to amyloidosis and tau-related neurodegeneration. The relationship between PP and CSF biomarkers is age-dependent and observed only in participants in the fifth and sixth decades of life.
doi:10.1212/01.wnl.0000436935.47657.78
PMCID: PMC3854831  PMID: 24225352
13.  Mild Cognitive Impairment: A Concept and Diagnostic Entity in Need of Input from Neuropsychology 
This virtual issue consists of studies previously published in the Journal of the International Neuropsychological Society and selected on the basis of their content related to one of the most highly researched concepts in behavioral neurology and neuropsychology over the past decade: mild cognitive impairment (MCI). The reliance on cognitive screening measures, staging-based rating scales, and limited neuropsychological testing in diagnosing MCI across most research studies may miss individuals with subtle cognitive declines or mis-diagnose MCI in those who are otherwise cognitively normal on a broader neuropsychological battery of tests. The assembled articles highlight the perils of relying on these conventional criteria for MCI diagnosis and reveal how the reliability of diagnosis is improved when sound neuropsychological approaches are adopted. When these requirements are met, we illustrate with a second series of articles that neuropsychological measures associate strongly with biomarkers and often reflect pathology beyond or instead of typical AD distributions. The final set of articles reveal that people with MCI demonstrate mild but identifiable functional difficulties, and a challenge for neuropsychology is how to incorporate this information to better define MCI and distinguish it from early dementia. Neuropsychology is uniquely positioned to improve upon the state of the science in MCI research and practice by providing critically important empirical information on the specific cognitive domains affected by the predominant neurodegenerative disorders of late life as well as on the diagnostic decision-making strategies used in studies. When such efforts to more comprehensively assess neuropsychological functions are undertaken, better characterizations of spared and impaired cognitive and functional abilities result and lead to more convincing associations with other biomarkers as well as to prediction of clinical outcomes.
doi:10.1017/S1355617714000010
PMCID: PMC4039178  PMID: 24490866
Mild cognitive impairment; Alzheimer’s disease; Neuropsychology; Episodic memory; Semantic memory; Executive functions; Neuroimaging; Magnetic resonance imaging; Functional MRI; Diffusion tensor imaging; Cerebrospinal fluid; Biomarkers; Activities of daily living; Functional capacity
14.  APOE genotype modifies the relationship between midlife vascular risk factors and later cognitive decline 
Vascular risk factors have been associated with cognitive decline, however, it remains unclear whether apolipoprotein E (APOE) genotype modifies this relationship. We aimed to further elucidate these relationships and extend previous findings by examining data from a more comprehensive cognitive assessment than used in prior studies. 1,436 participants from the prospective Framingham Offspring Cohort Study underwent health examination from 1991-1995, followed by a baseline neuropsychological assessment (1999-2003) and a repeat neuropsychological assessment approximately eight years later (2004-2009). Multivariate linear regression analyses were performed to examine the relationship between midlife vascular risk factors, presence of the APOE ε4 allele, and cognitive change. APOE genotype significantly modified the associations between both midlife hypertension and cardiovascular disease and decline in language abilities as well as midlife diabetes and decline in verbal memory, attention, and visuospatial abilities. Associations between increased midlife vascular risk burden and greater cognitive decline were observed among APOE ε4 carriers but not non-carriers. The present findings revealed a subgroup at increased risk for cognitive decline (APOE ε4 carriers with midlife exposure to vascular risk factors) and suggest that treatment of vascular risk factors during midlife may reduce the risk of cognitive impairment later in life, particularly among APOE ε4 carriers.
doi:10.1016/j.jstrokecerebrovasdis.2013.03.013
PMCID: PMC3849195  PMID: 23601373
Apolipoprotein E; Cognition; Vascular Risk; Aging; Diabetes; Hypertension; Cardiovascular Disease
15.  Interactive effects of vascular risk burden and advanced age on cerebral blood flow 
Vascular risk factors and cerebral blood flow (CBF) reduction have been linked to increased risk of cognitive impairment and Alzheimer's disease (AD); however the possible moderating effects of age and vascular risk burden on CBF in late life remain understudied. We examined the relationships among elevated vascular risk burden, age, CBF, and cognition. Seventy-one non-demented older adults completed an arterial spin labeling MR scan, neuropsychological assessment, and medical history interview. Relationships among vascular risk burden, age, and CBF were examined in a priori regions of interest (ROIs) previously implicated in aging and AD. Interaction effects indicated that, among older adults with elevated vascular risk burden (i.e., multiple vascular risk factors), advancing age was significantly associated with reduced cortical CBF whereas there was no such relationship for those with low vascular risk burden (i.e., no or one vascular risk factor). This pattern was observed in cortical ROIs including medial temporal (hippocampus, parahippocampal gyrus, uncus), inferior parietal (supramarginal gyrus, inferior parietal lobule, angular gyrus), and frontal (anterior cingulate, middle frontal gyrus, medial frontal gyrus) cortices. Furthermore, among those with elevated vascular risk, reduced CBF was associated with poorer cognitive performance. Such findings suggest that older adults with elevated vascular risk burden may be particularly vulnerable to cognitive change as a function of CBF reductions. Findings support the use of CBF as a potential biomarker in preclinical AD and suggest that vascular risk burden and regionally-specific CBF changes may contribute to differential age-related cognitive declines.
doi:10.3389/fnagi.2014.00159
PMCID: PMC4083452  PMID: 25071567
aging; vascular risk factors; arterial spin labeling; cognition
16.  Interaction of Age and APOE Genotype on Cerebral Blood Flow at Rest 
We investigated the impact of APOE genotype on cerebral blood flow (CBF) in older and younger adults. Forty cognitively normal older adults (16 ε4 carriers, 24 non-ε4 carriers) and 30 younger adults (15 ε4 carriers, 15 non-ε4 carriers) completed a resting-state whole-brain pulsed arterial spin labeling magnetic resonance scan. Main effects of aging were demonstrated wherein older adults had decreased gray matter CBF corrected for partial volume effects compared to younger adults in widespread brain regions. Main effects of APOE genotype were also observed wherein ε4 carriers displayed greater CBF in the left lingual gyrus and precuneus than non-carriers. An interaction between age and APOE genotype in the left anterior cingulate cortex (ACC) was characterized by reduced CBF in older ε4 carriers and increased CBF in young ε4 carriers. Increased CBF in the left ACC resulting from the interaction of age group and APOE genotype was positively correlated with executive functioning in young ε4 adults (r = 0.61, p = 0.04). Results demonstrate APOE genotype differentially impacts cerebrovascular function across the lifespan and may modify the relationship between CBF and cognition. Findings may partially support suggestions that the gene exerts antagonistic pleiotropic effects.
doi:10.3233/JAD-121897
PMCID: PMC4124882  PMID: 23302659
Aging; antagonistic pleiotropy; apolipoprotein E; cerebral blood flow; cerebrovascular function
17.  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.
doi:10.1017/S1355617713000313
PMCID: PMC3742806  PMID: 23552486
Mild cognitive impairment; Amnestic MCI; Non-amnestic MCI; Dementia; Cluster analysis; Neuropsychology
18.  Effect of Knowledge of APOE Genotype on Subjective and Objective Memory Performance in Healthy Older Adults 
The American journal of psychiatry  2014;171(2):201-208.
Objective
The knowledge that one carries the apolipoprotein E (APOE) ε4 allele risk factor for Alzheimer’s disease was recently found to have little short-term psychological risk. The authors investigated the impact of knowledge of carrying the risk allele on subjective ratings of memory and objective memory test performance of older adults.
Method
Using a nested case-control design, the authors administered objective verbal and visual memory tests and self-rating scales of memory function to 144 cognitively normal older adults (ages 52–89) with known APOE genotype who knew (ε4+, N=25; ε4−, N=49) or did not know (ε4+, N=25; ε4−, N=45) their genotype and genetic risk for Alzheimer’s disease prior to neuropsychological evaluation.
Results
Significant genotype-by-disclosure interaction effects were observed on several memory rating scales and tests of immediate and delayed verbal recall. Older adults who knew their ε4+ genotype judged their memory more harshly and performed worse on an objective verbal memory test than did ε4+ adults who did not know. In contrast, older adults who knew their ε4− genotype judged their memory more positively than did ε4− adults who did not know, but these groups did not differ in objective memory test performance.
Conclusions
Informing older adults that they have an APOE genotype associated with an increased risk of Alzheimer’s disease can have adverse consequences on their perception of their memory abilities and their performance on objective memory tests. The patient’s knowledge of his or her genotype and risk of Alzheimer’s disease should be considered when evaluating cognition in the elderly.
doi:10.1176/appi.ajp.2013.12121590
PMCID: PMC4037144  PMID: 24170170
19.  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.
doi:10.1136/jnnp.2006.108183
PMCID: PMC2117544  PMID: 17287237
20.  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.
doi:10.1080/13854046.2012.728626
PMCID: PMC3482270  PMID: 23030301
Recognition memory; Alzheimer’s disease; Mild cognitive impairment; Dementia severity; Neuropsychology
21.  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.
doi:10.3233/JAD-2012-120292
PMCID: PMC3443702  PMID: 22531427
Apolipoprotein E; cerebral blood flow; functional; hippocampus; magnetic resonance imaging; memory; mild cognitive impairment
22.  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).
doi:10.3233/JAD-2012-111697
PMCID: PMC3370943  PMID: 22451309
Alzheimer’s disease; blood pressure; cerebrovascular disease; pulse pressure
23.  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.
doi:10.3233/JAD-2012-102103
PMCID: PMC3341099  PMID: 22466061
Aging; diffusion tensor imaging; memory; mild cognitive impairment; posterior cingulum; white matter
24.  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).
Method
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.
Results
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.
Conclusions
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.
doi:10.1080/13803395.2011.553587
PMCID: PMC3325052  PMID: 21958432
Traumatic brain injury; Neuropsychology; Cognition; Behavior; Depression
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.
doi:10.1017/S1355617711001524
PMCID: PMC3314335  PMID: 22115028
Executive functions; Global cognition; Switching; Prodromal Alzheimer’s disease; Mild cognitive impairment; Prediction

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