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1.  Normative Data in Women Age 85 and Older: Verbal Fluency, Digit Span, and the CVLT-II Short Form 
The Clinical neuropsychologist  2012;26(1):18-30.
Individuals age 85 years and above (i.e., the oldest old) represent the fastest growing segment of the U.S. population and are at increased risk of developing dementia. This represents an important challenge for the clinical neuropsychologist, as the extant normative data on neuropsychological measures remains relatively limited for this age group. Therefore, the aim of the present study was to characterize the performance effects of age and education in a large, well-characterized sample of women between the ages of 85 and 95 years on the CVLT-II Short Form (Delis et al., 2000), verbal fluency tasks, and the WAIS-III Digit Span Test (Wechsler, 1997). In order to minimize the likelihood that women with an incipient neurodegenerative process were included in the final normative sample, we applied regression-based change scores to identify and exclude women who evidenced a statistically significant decline on a global cognitive screening measure over a 20 year interval. The results of our analysis indicate varying influence of age and education on these measures and we provide tables with descriptive statistics stratified by both age and education. Findings from the present normative study are discussed within the context of “robust” longitudinal normative data.
doi:10.1080/13854046.2011.639310
PMCID: PMC3927723  PMID: 22224509
oldest old; normative data; CVLT
2.  Depressive Symptoms in Oldest-Old Women: Risk of Mild Cognitive Impairment and Dementia 
Objectives
Increasing evidence suggests that depression is a risk factor for cognitive impairment, but it is unclear if this is true among the oldest old. We determined whether elevated depressive symptoms predicted five-year incident mild cognitive impairment (MCI) or dementia, and neuropsychological test performance among oldest-old women.
Design
Prospective
Setting
Three study sites
Participants
302 women ≥85 years (mean, 87 ±2)
Measurements
Depressive symptoms were measured with the 15-item Geriatric Depression Scale (GDS); scores ≥6 indicated elevated symptoms. Five years later, participants completed neuropsychological testing and clinical cognitive status was adjudicated.
Results
In analyses of MCI vs. normal cognition, 70% of women with GDS ≥6 at baseline developed MCI vs. 37% with GDS <6. After adjustment for age, education, alcohol and benzodiazepine use, and study site, GDS ≥6 remained independently associated with much greater likelihood of developing MCI (multivariable odds ratio (MOR) = 3.71, 95% confidence interval (CI) 1.30, 10.59). In analyses of dementia vs. normal cognition, 65% of women with GDS ≥6 developed dementia compared to 37% of those with GDS <6 (MOR = 3.15, 95% CI 1.03, 9.65). Only 19% of women with GDS ≥6 had normal cognitive status five years later, compared to 46% of those with GDS <6 (MOR = 0.28, 95% CI 0.11, 0.73). Women with elevated depressive symptoms had worse scores on tests of global cognition and working memory.
Conclusion
Elevated depressive symptoms are an important risk factor for cognitive disorders and lower cognitive performance among women living to their ninth and tenth decades.
doi:10.1097/JGP.0b013e318235b611
PMCID: PMC3326212  PMID: 22015706
oldest-old; women; depression; mild cognitive impairment; dementia
3.  Body Mass and White Matter Integrity: The Influence of Vascular and Inflammatory Markers 
PLoS ONE  2013;8(10):e77741.
High adiposity is deleteriously associated with brain health, and may disproportionately affect white matter integrity; however, limited information exists regarding the mechanisms underlying the association between body mass (BMI) and white matter integrity. The present study evaluated whether vascular and inflammatory markers influence the relationship between BMI and white matter in healthy aging. We conducted a cross-sectional evaluation of white matter integrity, BMI, and vascular/inflammatory factors in a cohort of 138 healthy older adults (mean age: 71.3 years). Participants underwent diffusion tensor imaging, provided blood samples, and participated in a health evaluation. Vascular risk factors and vascular/inflammatory blood markers were assessed. The primary outcome measure was fractional anisotropy (FA) of the genu, body, and splenium (corpus callosum); exploratory measures included additional white matter regions, based on significant associations with BMI. Regression analyses indicated that higher BMI was associated with lower FA in the corpus callosum, cingulate, and fornix (p<.001). Vascular and inflammatory factors influenced the association between BMI and FA. Specifically, BMI was independently associated with the genu [β=-.21; B=-.0024; 95% CI, -.0048 to -.0000; p=.05] and cingulate fibers [β=-.39; B=-.0035; 95% CI,-.0056 to -.0015; p<.001], even after controlling for vascular/inflammatory risk factors and blood markers. In contrast, BMI was no longer significantly associated with the fornix and middle/posterior regions of the corpus callosum after controlling for these markers. Results partially support a vascular/inflammatory hypothesis, but also suggest a more complex relationship between BMI and white matter characterized by potentially different neuroanatomic vulnerability.
doi:10.1371/journal.pone.0077741
PMCID: PMC3797689  PMID: 24147070
4.  Anti-saccade performance predicts executive function and brain structure in normal elders 
Objective
To assess the neuropsychological and anatomical correlates of anti-saccade (AS) task performance in normal elders.
Background
The AS task correlates with neuropsychological measures of executive function and frontal lobe volume in neurological diseases, but has not been studied in a well-characterized normal elderly population. Because executive dysfunction can indicate an increased risk for cognitive decline in cognitively normal elders, we hypothesized that AS performance might be a sensitive test of age-related processes that impair cognition.
Method
The percentage of correct AS responses was evaluated in forty-eight normal elderly subjects and compared with neuropsychological test performance using linear regression analysis and gray matter volume measured on MRI scans using voxel-based morphometry.
Results
The percentage of correct AS responses was associated with measures of executive function, including modified trails, design fluency, Stroop inhibition, abstraction, and backward digit span, and correlated with gray matter volume in two brain regions involved in inhibitory control: the left inferior frontal junction and the right supplementary eye field. The association of AS correct responses with neuropsychological measures of executive function was strongest in individuals with fewer years of education.
Conclusions
The AS task is sensitive to executive dysfunction and frontal lobe structural alterations in normal elders.
doi:10.1097/WNN.0b013e318223f6c6
PMCID: PMC3775477  PMID: 21697711
anti-saccade; normal aging; executive function; frontal lobe; cognitive reserve
5.  Validating the Chinese version of the Verbal Learning Test for screening Alzheimer’s disease 
Episodic memory tasks are one of the most sensitive tools to discriminate Alzheimer’s disease (AD). This study aimed to validate a shorter version verbal memory test that will efficiently assess Chinese elderly with memory complaints. One hundred and eighty-five elderly with normal cognition (NC) and 217 AD patients were evaluated. Each participant received the Chinese Version Verbal Learning Test (CVVLT) consisting of 9 two-character nouns with 4 learning trials, 2 delayed recalls in 30 seconds and 10 minutes, and a word recognition test. In the NC elderly, age and sex had significant effects on recall scores in CVVLT, while education level showed an inverse correlation with 3 different patterns of errors made during the learning, recall, and recognition trials. AD patients had lower scores across all recall tests. In those with lower educational level, NC elderly had higher perseveration errors than AD patients. The cutoff value between the AD and NC groups in the 10-minute recall was 4/5 for those aged >75 years and 5/6 for those aged <75 years. This study has good validity in discriminating AD participants and the data here can help in diagnosing AD and mild cognitive impairment using the CVVLT.
doi:10.1017/S1355617709991184
PMCID: PMC3767760  PMID: 20003579
Chinese Verbal Learning Test; education; memory; dementia; cutoff value; validation
6.  Inflammation and clinical presentation in neurodegenerative disease: a volatile relationship 
Neurocase  2012;19(2):182-200.
A proposed immune mechanism that potentially modifies or exacerbates neurodegenerative disease presentation in older adults has received considerable attention in the past decade, with recent studies demonstrating a strong link between pro-inflammatory markers and neurodegeneration. The overarching aim of the following review is to synthesize recent research that supports a possible relationship between inflammation and clinical features of neurodegenerative diseases, including risk of development, cognitive and clinical correlates, and progression of the specified diseases. Specific emphasis is placed on providing a temporal context for the association between inflammation and neurodegeneration.
doi:10.1080/13554794.2011.654227
PMCID: PMC3733377  PMID: 22515699
Inflammation; Cognition; Neuropsychology; Neurodegenerative disease; Alzheimer’s
7.  Longitudinal MRI and Cognitive Change in Healthy Elderly 
Neuropsychology  2007;21(4):412-418.
Cross-sectional studies of normal aging indicate an association between memory and hippocampal volume, and between executive functioning and subcortical-frontal circuits. Much less is known, however, about the relationship between longitudinal MRI changes and cognitive decline. The authors hypothesized that longitudinal change in memory would be best predicted by change in hippocampal volumes, whereas change in executive functioning would be best predicted by cortical atrophy and progression of MRI markers of cerebrovascular disease. For this study, 50 healthy elderly subjects underwent structural MRI and cognitive testing at baseline and again at follow-up, with a mean follow-up interval of 45 months. Volumetric MRI measures were hippocampus, cortical gray matter, white matter signal hyperintensity (WMSH), and lacunae. Neuropsychological measures were psychometrically robust composite scores of episodic memory (MEM) and executive functioning (EXEC). Hierarchical multiple regression indicated that a decrease in hippocampus was associated with a decline in MEM, whereas decreased cortical gray matter and increased WMSH were independently associated with a decline in EXEC. Results suggest that in normal aging, cognitive functioning declines as cortical gray matter and hippocampus decrease, and WMSH increases. The association between WMSH and EXEC further highlights the cognitive sequealae associated with cerebrovascular disease in normal elderly.
doi:10.1037/0894-4105.21.4.412
PMCID: PMC2780018  PMID: 17605574
normal aging; memory; executive function; hippocampal volumes; white matter signal hyperintensity
8.  Dissociations in Hippocampal and Frontal Contributions to Episodic Memory Performance 
Neuropsychology  2005;19(6):799-805.
The hippocampus and frontal lobes both contribute to episodic memory performance. In the present study, the authors evaluated the relative contributions of hippocampus, frontal lobes, anterior temporal cortex, and posterior cortex to memory performance in neurodegenerative patients and normal older controls. Subjects (n = 42) were studied with structural MRI and a memory paradigm that measured delayed recall, semantic clustering during recall, recognition discriminability, and recognition response bias. Data were analyzed with multiple regression. Consistent with the authors’ hypotheses, hippocampal volumes were the best predictor of delayed recall and recognition discriminability, whereas frontal volumes were the best predictor of semantic clustering and response bias. Smaller frontal volumes were associated with less semantic clustering during recall and a more liberal response bias. Results indicate that hippocampal and frontal contributions to episodic memory can be dissociated, with the hippocampus more important for memory accuracy, and frontal structures more important for strategic processing and decision making.
doi:10.1037/0894-4105.19.6.799
PMCID: PMC1851935  PMID: 16351355
memory; hippocampus; frontal lobes; organization; response bias
9.  Neuropsychological correlates of dominance, warmth, and extraversion in neurodegenerative disease 
Introduction
Changes in personality differ qualitatively and quantitatively between patients with different neurodegenerative diseases, likely due to divergent patterns of regional neurodegeneration. Regional damage to circuits underlying various cognitive and emotional functions have been associated with interpersonal traits like dominance, extraversion, and warmth in patients with neurodegenerative diseases, suggesting that personality may in part be mediated by these more basic neuropsychological functions. In this study, we hypothesized that different combinations of cognitive, neuropsychiatric, and emotional measures would predict different interpersonal traits in patients with neurodegenerative diseases.
Methods
A battery of cognitive, neuropsychiatric, and emotional measures was administered to 286 patients with various neurodegenerative diseases such as Alzheimer’s disease, behavioral variant frontotemporal dementia, semantic dementia, and progressive supranuclear palsy, and informants described patients’ dominance, extraversion, and warmth using the Interpersonal Adjective Scales (IAS) personality questionnaire. Regression modeling was performed to identify which neuropsychological factors uniquely predicted current personality, controlling for age, gender, and premorbid personality.
Results
Social dominance covaried with patients’ capacity for cognitive control and verbal fluency. Conversely, warmth did not rely on these executive or verbal skills, but covaried primarily with patients’ capacity for emotional responsiveness. Extraversion, representing a blend of dominance and warmth, demonstrated an intermediate degree of relationship to both executive/verbal and emotional functions.
Conclusions
These findings suggest that different personality traits are partly subserved by specific cognitive and emotional functions in neurodegenerative disease patients. While this study was performed in the context of brain damage, the results raise the question of whether individual differences in these neuropsychological abilities may also underlie variability in normal personality.
doi:10.1016/j.cortex.2011.03.001
PMCID: PMC3132224  PMID: 21470601
personality; neurodegenerative disease; cognition; emotion
10.  The Frontal-Anatomic Specificity of Design Fluency Repetitions and their Diagnostic Relevance for Behavioral Variant Frontotemporal Dementia 
On tests of design fluency, an examinee draws as many different designs as possible in a specified time limit while avoiding repetition. The neuroanatomical substrates and diagnostic group differences of design fluency repetition errors and total correct scores were examined in 110 individuals diagnosed with dementia, 53 with mild cognitive impairment (MCI), and 37 neurologically healthy controls. The errors correlated significantly with volumes in the right and left orbitofrontal cortex (OFC), the right and left superior frontal gyrus, the right inferior frontal gyrus, and the right striatum, but did not correlate with volumes in any parietal or temporal lobe regions. Regression analyses indicated that the lateral OFC may be particularly crucial for preventing these errors, even after excluding patients with behavioral variant frontotemporal dementia (bvFTD) from the analysis. Total correct correlated more diffusely with volumes in the right and left frontal and parietal cortex, the right temporal cortex, and the right striatum and thalamus. Patients diagnosed with bvFTD made significantly more repetition errors than patients diagnosed with MCI, Alzheimer’s disease, semantic dementia, progressive supranuclear palsy or corticobasal syndrome. In contrast, total correct design scores did not differentiate the dementia patients. These results highlight the frontal-anatomic specificity of design fluency repetitions. In addition, the results indicate that the propensity to make these errors supports the diagnosis of bvFTD.
doi:10.1017/S1355617712000604
PMCID: PMC3620020  PMID: 22835330
Perseveration; Orbitofrontal; Neuropsychology; Executive Function; Dementia; Process Approach
12.  Patterns of Brain Atrophy in Clinical Variants of Frontotemporal Lobar Degeneration 
Background/Aims
The clinical syndromes of frontotemporal lobar degeneration include behavioral variant frontotemporal dementia (bvFTD) and semantic (SV-PPA) and nonfluent variants (NF-PPA) of primary progressive aphasia. Using magnetic resonance imaging (MRI), tensor-based morphometry (TBM) was used to determine distinct patterns of atrophy between these three clinical groups.
Methods
Twenty-seven participants diagnosed with bvFTD, 16 with SV-PPA, and 19 with NF-PPA received baseline and follow-up MRI scans approximately 1 year apart. TBM was used to create three-dimensional Jacobian maps of local brain atrophy rates for individual subjects.
Results
Regional analyses were performed on the three-dimensional maps and direct comparisons between groups (corrected for multiple comparisons using permutation tests) revealed significantly greater frontal lobe and frontal white matter atrophy in the bvFTD relative to the SV-PPA group (p < 0.005). The SV-PPA subjects exhibited significantly greater atrophy than the bvFTD in the fusiform gyrus (p = 0.007). The NF-PPA group showed significantly more atrophy in the parietal lobes relative to both bvFTD and SV-PPA groups (p < 0.05). Percent volume change in ventromedial prefrontal cortex was significantly associated with baseline behavioral symptomatology.
Conclusion
The bvFTD, SV-PPA, and NF-PPA groups displayed distinct patterns of progressive atrophy over a 1-year period that correspond well to the behavioral disturbances characteristic of the clinical syndromes. More specifically, the bvFTD group showed significant white matter contraction and presence of behavioral symptoms at baseline predicted significant volume loss of the ventromedial prefrontal cortex.
doi:10.1159/000345523
PMCID: PMC3609420  PMID: 23306166
Frontotemporal dementia; Primary progressive aphasia; Longitudinal study; Magnetic resonance imaging; Tensor-based morphometry; White matter
13.  Predicting regional neurodegeneration from the healthy brain functional connectome 
Neuron  2012;73(6):1216-1227.
Summary
Neurodegenerative diseases target large-scale neural networks. Four competing mechanistic hypotheses have been proposed to explain network-based disease patterning: nodal stress, transneuronal spread, trophic failure, and shared vulnerability. Here, we used task-free fMRI to derive the healthy intrinsic connectivity patterns seeded by brain regions vulnerable to any of five distinct neurodegenerative diseases. These data enabled us to investigate how intrinsic connectivity in health predicts region-by-region vulnerability to disease. For each illness, specific regions emerged as critical network “epicenters” whose normal connectivity profiles most resembled the disease-associated atrophy pattern. Graph theoretical analyses in healthy subjects revealed that regions with higher total connectional flow and, more consistently, shorter functional paths to the epicenters, showed greater disease-related vulnerability. These findings best fit a transneuronal spread model of network-based vulnerability. Molecular pathological approaches may help clarify what makes each epicenter vulnerable to its targeting disease and how toxic protein species travel between networked brain structures.
doi:10.1016/j.neuron.2012.03.004
PMCID: PMC3361461  PMID: 22445348
fMRI; neurodegeneration; network; functional connectivity; Alzheimer’s disease; frontotemporal dementia
14.  Processing Speed Delays Contribute to Executive Function Deficits in Individuals with Agenesis of the Corpus Callosum 
Corpus callosum malformation and dysfunction are increasingly recognized causes of cognitive and behavioral disability. Individuals with agenesis of the corpus callosum (AgCC) offer unique insights regarding the cognitive skills that depend specifically upon callosal connectivity. We examined the impact of AgCC on cognitive inhibition, flexibility, and processing speed using the Color-Word Interference Test (CWIT) and Trail Making Test (TMT) from the Delis-Kaplan Executive Function System. We compared 36 individuals with AgCC and IQs within the normal range to 56 matched controls. The AgCC cohort was impaired on timed measures of inhibition and flexibility; however, group differences on CWIT Inhibition, CWIT Inhibition/Switching and TMT Number-Letter Switching appear to be largely explained by slow performance in basic operations such as color naming and letter sequencing. On CWIT Inhibition/Switching, the AgCC group was found to commit significantly more errors which suggests that slow performance is not secondary to a cautious strategy. Therefore, while individuals with agenesis of the corpus callosum show real deficits on tasks of executive function, this impairment appears to be primarily a consequence of slow cognitive processing. Additional studies are needed to investigate the impact of AgCC on other aspects of higher order cortical function.
doi:10.1017/S1355617712000045
PMCID: PMC3605885  PMID: 22390821
Absence of the corpus callosum; Human information processing; Inhibition; Stroop Paradigm; Trail Making Test; Cognition
15.  KNOW THYSELF: REAL WORLD BEHAVIORAL CORRELATES OF SELF-APPRAISAL ACCURACY 
The Clinical neuropsychologist  2011;25(5):741-756.
Accurate appraisal of one’s own abilities is one metacognitive skill considered to be an important factor affecting learning and behavior in childhood. The present study measured self-appraisal accuracy in children using tasks of executive function, and investigated relations between self-appraisal and informant ratings of real world behaviors measured by the BRIEF. We examined self-appraisal accuracy on fluency tasks in 91 children ages 10-17. More accurate self-appraisal was correlated with fewer informant ratings of real world behavior problems in inhibition and shifting, independent of actual performance. Findings suggest that self-appraisal represents cognitive processes that are at least partially independent of other functions putatively dependent on the frontal lobes, and these self-appraisal-specific processes have unique implications for optimal daily function.
doi:10.1080/13854046.2011.569759
PMCID: PMC3586194  PMID: 21547852
Self Assessment; Self Concept; Awareness; Child Behavior; Executive Function; Meta-cognition
16.  Coronary Artery Disease is Associated with Cognitive Decline Independent of MRI Changes in Cognitively Normal Elderly 
BACKGROUND/OBJECTIVES
White matter hyperintensities (WMH) and silent brain infarcts (SBI) have been associated with both vascular factors and cognitive decline. We examined among cognitively normal elderly, whether vascular factors predict cognitive decline and whether these associations are mediated by MRI measures of subclinical vascular brain injury.
DESIGN
Prospective multi-site longitudinal study of subcortical ischemic vascular diseases
SETTING
Memory and aging centers in California
PARTICIPANTS
We studied 74 participants who were cognitively normal at entry and received at least 2 neuropsychological evaluations and 2 MRI exams over an average follow-up of 6.9 years.
MEASUREMENTS
Item response theory was used to create composite scores of global, verbal memory, and executive functioning. Volumetric MRI measures included WMH, SBI, hippocampus, and cortical gray matter (CGM). We used linear mixed effects models to examine the associations between vascular factors, MRI measures, and cognitive scores.
RESULTS
History of coronary artery disease (CAD) was associated with greater declines in global, verbal memory, and executive cognition. The CAD associations remained after controlling for changes in WMH, SBI, hippocampal and CGM volumes.
CONCLUSION
History of CAD may be a surrogate marker for clinically significant atherosclerosis which also affects the brain. Structural MRI measures of WMH and SBI do not fully capture the potential adverse effects of atherosclerosis on the brain. Future longitudinal studies of cognition should incorporate direct measures of atherosclerosis in cerebral arteries, as well as more sensitive neuroimaging measures.
doi:10.1111/j.1532-5415.2011.03839.x
PMCID: PMC3302932  PMID: 22283410
cognitively normal elderly; coronary artery disease; cognitive decline; MRI
17.  Executive functions and the down-regulation and up-regulation of emotion 
Cognition & emotion  2011;26(1):103-118.
This study examined the relationship between individual differences in executive functions (EF; assessed by measures of working memory, Stroop, trail making, and verbal fluency) and ability to down-regulate and up-regulate responses to emotionally evocative film clips. To ensure a wide range of EF, 48 participants with diverse neurodegenerative disorders and 21 older neurologically normal aging participants were included. Participants were exposed to three different movie clips that were designed to elicit a mix of disgust and amusement. While watching the films they were either instructed to watch, down-regulate, and up-regulate their visible emotional responses. Heart-rate and facial behaviors were monitored throughout. Emotion regulatory ability was operationalized as changes in heart-rate and facial behavior in the down- and up-regulation conditions, controlling for responses in the watch condition. Results indicated that higher verbal fluency scores were related to greater ability to regulate emotion in both the down-regulation and up-regulation conditions. This finding remained significant even after controlling for age and general cognitive functioning. No relationships were found between emotion regulation and the other EF measures. We believe these results derive from differences among EF measures, with verbal fluency performance best capturing the complex sequence of controlled planning, activation, and monitoring required for successful emotion regulation. These findings contribute to our understanding of emotion-cognition interaction, suggesting a link between emotion-regulatory abilities and individual differences in complex executive functions.
doi:10.1080/02699931.2011.557291
PMCID: PMC3155745  PMID: 21432634
emotion regulation; executive functions; emotional behavior; Stroop; trail making; verbal fluency; working memory; FTLD; AD; cognition-emotion interaction; cognitive influences on emotion
18.  C-Reactive Protein is Related to Memory and Medial Temporal Brain Volume in Older Adults 
Brain, behavior, and immunity  2011;26(1):103-108.
Recent research suggests a central role for inflammatory mechanisms in cognitive decline that may occur prior to evidence of neurodegeneration. Limited information exists, however, regarding the relationship between low-grade inflammation and cognitive function in healthy older adults. This study examined the relation between inflammation, verbal memory consolidation, and medial temporal lobe volumes in a cohort of older community-dwelling subjects. Subjects included 141 functionally intact, community dwelling older adults with detectable (n = 76) and undetectable (n= 65) levels of C-reactive protein. A verbal episodic memory measure was administered to all subjects, and measures of delayed recall and recognition memory were assessed. A semiautomated parcellation program was used to analyze structural MRI scans. On the episodic memory task, analysis of covariance revealed a significant CRP group by memory recall interaction, such that participants with detectable levels of CRP evidenced worse performance after a delay compared to those with undetectable levels of CRP. Individuals with detectable CRP also demonstrated lower performance on a measure of recognition memory. Imaging data demonstrated smaller left medial temporal lobe volumes in the detectable CRP group as compared with the undetectable CRP group. These findings underscore a potential role for inflammation in cognitive aging as a modifiable risk factor.
doi:10.1016/j.bbi.2011.07.240
PMCID: PMC3221922  PMID: 21843630
inflammation; memory; aging; cognition; temporal lobe; c-reactive protein; cytokines
19.  Gender Modulates the APOE ε4 Effect in Healthy Older Adults: Convergent Evidence from Functional Brain Connectivity and Spinal Fluid Tau Levels 
The Journal of Neuroscience  2012;32(24):8254-8262.
We examined whether the effect of APOE genotype on functional brain connectivity is modulated by gender in healthy older human adults. Our results confirm significantly decreased connectivity in the default mode network in healthy older APOE ε4 carriers compared to ε3 homozygotes. More importantly, further testing revealed a significant interaction between APOE genotype and gender in the precuneus, a major default mode hub. Female ε4 carriers showed significantly reduced default mode connectivity compared to either female ε3 homozygotes or male ε4 carriers, whereas male ε4 carriers differed minimally from male ε3 homozygotes. An additional analysis in an independent sample of healthy elderly using an independent marker of Alzheimer’s disease, i.e. spinal fluid levels of tau, provided corresponding evidence for this gender by APOE interaction. Taken together, these results converge with previous work showing a higher prevalence of the ε4 allele among women with Alzheimer’s disease and, critically, demonstrate that this interaction between APOE genotype and gender is detectable in the preclinical period.
doi:10.1523/JNEUROSCI.0305-12.2012
PMCID: PMC3394933  PMID: 22699906
20.  Let's Inhibit Our Excitement: The Relationships Between Stroop, Behavioral Disinhibition, and the Frontal Lobes 
Neuropsychology  2011;25(5):655-665.
Objective
The Stroop is a frequently used neuropsychological test, with poor performance typically interpreted as indicative of disinhibition and frontal lobe damage. This study tested those interpretations by examining relationships between Stroop performance, behavioral disinhibition, and frontal lobe atrophy.
Method
Participants were 112 well-characterized patients with mild cognitive impairment or dementia, recruited through UCSF's Memory and Aging Center. Participants received comprehensive dementia evaluations including structural MRI, neuropsychological testing, and informant interviews. Freesurfer, a semi-automated parcellation program, was used to analyze 1.5T MRI scans. Behavioral disinhibition was measured using the Disinhibition scale of the Neuropsychiatric Inventory. The sample (n=112) mean age was 65.40 (SD=8.60) years, education was 16.64 (SD=2.54) years, and MMSE was 26.63 (SD=3.32). Hierarchical linear regressions were used for data analysis.
Results
Controlling for age, MMSE, and Color Naming performance, Stroop performance was not significantly associated with behavioral disinhibition (β=0.01, ΔR2=0.01, p=0.29). Hierarchical regressions controlling for age, MMSE, Color Naming, intracranial volume, and temporal and parietal lobes, examined whether left hemisphere or right hemisphere regions predict Interference speed. Bilaterally, parietal lobes were the brain region in which atrophy best predicted poorer Stroop (left: β=0.0004, ΔR2=0.02, p=0.002; right: β=0.0004, ΔR2=0.02, p=0.002). Of frontal regions, only dorsolateral prefrontal cortex atrophy predicted poorer Stroop (β=0.001, ΔR2=0.01, p=0.03); left and right anterior cingulate cortex (ACC) atrophy predicted better Stroop (left: β=−0.003, ΔR2=0.01, p=0.02; right: β=−0.004, ΔR2=0.01, p=0.02).
Conclusions
These findings suggest Stroop performance is a poor measure of behavioral disinhibition and frontal lobe atrophy even among a relatively high-risk population.
doi:10.1037/a0023863
PMCID: PMC3158285  PMID: 21574716
Stroop; disinhibition; MRI; frontal; neuropsychological
21.  Sensitivity of revised diagnostic criteria for the behavioural variant of frontotemporal dementia 
Brain  2011;134(9):2456-2477.
Based on the recent literature and collective experience, an international consortium developed revised guidelines for the diagnosis of behavioural variant frontotemporal dementia. The validation process retrospectively reviewed clinical records and compared the sensitivity of proposed and earlier criteria in a multi-site sample of patients with pathologically verified frontotemporal lobar degeneration. According to the revised criteria, ‘possible’ behavioural variant frontotemporal dementia requires three of six clinically discriminating features (disinhibition, apathy/inertia, loss of sympathy/empathy, perseverative/compulsive behaviours, hyperorality and dysexecutive neuropsychological profile). ‘Probable’ behavioural variant frontotemporal dementia adds functional disability and characteristic neuroimaging, while behavioural variant frontotemporal dementia ‘with definite frontotemporal lobar degeneration’ requires histopathological confirmation or a pathogenic mutation. Sixteen brain banks contributed cases meeting histopathological criteria for frontotemporal lobar degeneration and a clinical diagnosis of behavioural variant frontotemporal dementia, Alzheimer’s disease, dementia with Lewy bodies or vascular dementia at presentation. Cases with predominant primary progressive aphasia or extra-pyramidal syndromes were excluded. In these autopsy-confirmed cases, an experienced neurologist or psychiatrist ascertained clinical features necessary for making a diagnosis according to previous and proposed criteria at presentation. Of 137 cases where features were available for both proposed and previously established criteria, 118 (86%) met ‘possible’ criteria, and 104 (76%) met criteria for ‘probable’ behavioural variant frontotemporal dementia. In contrast, 72 cases (53%) met previously established criteria for the syndrome (P < 0.001 for comparison with ‘possible’ and ‘probable’ criteria). Patients who failed to meet revised criteria were significantly older and most had atypical presentations with marked memory impairment. In conclusion, the revised criteria for behavioural variant frontotemporal dementia improve diagnostic accuracy compared with previously established criteria in a sample with known frontotemporal lobar degeneration. Greater sensitivity of the proposed criteria may reflect the optimized diagnostic features, less restrictive exclusion features and a flexible structure that accommodates different initial clinical presentations. Future studies will be needed to establish the reliability and specificity of these revised diagnostic guidelines.
doi:10.1093/brain/awr179
PMCID: PMC3170532  PMID: 21810890
behavioural variant frontotemporal dementia; diagnostic criteria; frontotemporal lobar degeneration; FTD; pathology
22.  Double Dissociation in the Anatomy of Socioemotional Disinhibition and Executive Functioning in Dementia 
Neuropsychology  2011;25(2):249-259.
Objective
To determine if socioemotional disinhibition and executive dysfunction are related to dissociable patterns of brain atrophy in neurodegenerative disease. Previous studies have indicated that behavioral and cognitive dysfunction in neurodegenerative disease are linked to atrophy in different parts of the frontal lobe, but these prior studies did not establish that these relationships were specific, which would best be demonstrated by a double dissociation.
Method
Subjects included 157 patients with neurodegenerative disease. A semi-automated parcellation program (Freesurfer) was used to generate regional cortical volumes from structural MRI scans. Regions of interest (ROIs) included anterior cingulate cortex (ACC), orbitofrontal cortex (OFC), middle frontal gyrus (MFG) and inferior frontal gyrus (IFG). Socioemotional disinhibition was measured using the Neuropsychiatric Inventory. Principal component analysis including three tasks of executive function (EF; verbal fluency, Stroop Interference, modified Trails) was used to generate a single factor score to represent EF.
Results
Partial correlations between ROIs, disinhibition, and EF were computed after controlling for total intracranial volume, MMSE, diagnosis, age, and education. Brain regions significantly correlated with disinhibition (ACC, OFC, IFG, and temporal lobes) and EF (MFG) were entered into separate hierarchical regressions to determine which brain regions predicted disinhibition and EF. OFC was the only brain region to significantly predict disinhibition and MFG significantly predicted executive functioning performance. A multivariate general linear model demonstrated a significant interaction between ROIs and cognitive-behavioral functions.
Conclusions
These results support a specific association between orbitofrontal areas and behavioral management as compared to dorsolateral areas and EF.
doi:10.1037/a0021681
PMCID: PMC3075812  PMID: 21381829
Brain behaviour and relationships; prefrontal; emotion regulation; executive control
23.  Perioperative Cognitive Decline in the Aging Population 
Mayo Clinic Proceedings  2011;86(9):885-893.
Elderly patients who have an acute illness or who undergo surgery often experience cognitive decline. The pathophysiologic mechanisms that cause neurodegeneration resulting in cognitive decline, including protein deposition and neuroinflammation, also play a role in animal models of surgery-induced cognitive decline. With the aging of the population, surgical candidates of advanced age with underlying neurodegeneration are encountered more often, raising concerns that, in patients with this combination, cognitive function will precipitously decline postoperatively. This special article is based on a symposium that the University of California, San Francisco, convened to explore the contributions of surgery and anesthesia to the development of cognitive decline in the aged patient. A road map to further elucidate the mechanisms, diagnosis, risk factors, mitigation, and treatment of postoperative cognitive decline in the elderly is provided.
doi:10.4065/mcp.2011.0332
PMCID: PMC3257991  PMID: 21878601
24.  Cognitive Training Changes Hippocampal Function in Mild Cognitive Impairment: A Pilot Study 
Journal of Alzheimer's Disease  2011;26(Suppl 3):349-357.
A randomized pilot experiment examined the neural substrates of response to cognitive training in participants with mild cognitive impairment (MCI). Participants performed exercises previously demonstrated to improve verbal memory and an active control group performed other computer activities. An auditory-verbal fMRI task was conducted before and after the two-month training program. Verbal memory scores improved significantly and left hippocampal activation increased significantly in the experimental group (gains in 5 of 6 participants) relative to the control group (reductions in all 6 participants). Results suggest that the hippocampus in MCI may retain sufficient neuroplasticity to benefit from cognitive training.
doi:10.3233/JAD-2011-0009
PMCID: PMC3277842  PMID: 21971474
MRI; dementia; cognition; MCI; mild cognitive impairment; fMRI; functional MRI; cognitive training; hippocampus; medial temporal lobe
25.  Distinct Neuroanatomical Substrates and Cognitive Mechanisms of Figure Copy Performance in Alzheimer’s Disease and Behavioral Variant Frontotemporal Dementia 
Neuropsychologia  2010;49(1):43-48.
Figure copy is the most common method of visual spatial assessment in dementia evaluations, but performance on this test may be multifactorial. We examined the neuroanatomical substrates of figure copy performance in 46 patients with Alzheimer’s disease (AD) and 48 patients with the behavioral variant of Frontotemporal dementia (bvFTD). A group of 94 neurologically healthy controls were studied for comparison. In AD, poor figure copy correlated significantly with right parietal cortex volumes but not with right dorsolateral prefrontal cortex volumes, whereas in bvFTD, figure copy performance correlated significantly with right dorsolateral prefrontal cortex volumes and there was only a trend with right parietal cortex volumes. The cognitive processes associated with figure copy performance also differed by diagnostic group such that figure copy was associated with spatial perception and attention in AD and with spatial planning and working memory in bvFTD. Spatial planning accounted for unique variance in the figure copy performance of bvFTD even after accounting for spatial perception, attention, and working memory. These results suggest that figure copy performance in AD and bvFTD is not anatomically-specific and is differentially impacted by bottom-up and top-down aspects of visual spatial processing. Alternative methods of visual spatial assessment for dementia evaluations are proposed.
doi:10.1016/j.neuropsychologia.2010.10.026
PMCID: PMC3005024  PMID: 21029744
Visuospatial; Parietal; Prefrontal; Dementia; Neurodegenerative; Neuropsychological Assessment; Visuoconstruction

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