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1.  Vascular risk and Aβ interact to reduce cortical thickness in AD vulnerable brain regions 
Neurology  2014;83(1):40-47.
Objective:
The objective of this study was to define whether vascular risk factors interact with β-amyloid (Aβ) in producing changes in brain structure that could underlie the increased risk of Alzheimer disease (AD).
Methods:
Sixty-six cognitively normal and mildly impaired older individuals with a wide range of vascular risk factors were included in this study. The presence of Aβ was assessed using [11C]Pittsburgh compound B–PET imaging, and cortical thickness was measured using 3-tesla MRI. Vascular risk was measured with the Framingham Coronary Risk Profile Index.
Results:
Individuals with high levels of vascular risk factors have thinner frontotemporal cortex independent of Aβ. These frontotemporal regions are also affected in individuals with Aβ deposition, but the latter show additional thinning in parietal cortices. Aβ and vascular risk were found to interact in posterior (especially in parietal) brain regions, where Aβ has its greatest effect. In this way, the negative effect of Aβ in posterior regions is increased by the presence of vascular risk.
Conclusion:
Aβ and vascular risk interact to enhance cortical thinning in posterior brain regions that are particularly vulnerable to AD. These findings give insight concerning the mechanisms whereby vascular risk increases the likelihood of developing AD and supports the therapeutic intervention of controlling vascular risk for the prevention of AD.
doi:10.1212/WNL.0000000000000550
PMCID: PMC4114172  PMID: 24907234
2.  Coronary risk correlates with cerebral amyloid deposition 
Neurobiology of Aging  2011;33(9):1979-1987.
This study investigated the hypothesis that vascular risk factors are amyloidogenic. Participants were 43 persons, most with normal cognition or mild cognitive impairment. Vascular risk was quantified using the Framingham Coronary Risk Profile score (FCRP). Cerebral amyloid was measured by 11C-PIB PET and quantified with a Global PIB index, which is the average of distribution volume ratios in selected cortical regions of interest. In a bivariate model FCRP accounted for 16% of the variance in PIB index (p < .008) and the positive association remained significant controlling for age and sex. The effect of FCRP was independent of APOE genotype, which was also associated as expected with PIB. Carotid intima-media thickness was not associated with PIB index. Effects of individual FCRP component risk factors, cholesterol and glycemic status on PIB index were all non-significant, suggesting an aggregate effect of risk factors. Although this is a correlational observation it may represent a causal relationship as there are multiple, plausible, amyloidogenic mechanisms of vascular risk factors.
doi:10.1016/j.neurobiolaging.2011.10.002
PMCID: PMC3371309  PMID: 22078485
vascular risk factors; coronary risk factors; cerebral amyloid; Mild Cognitive Impairment; Normal Aging; Alzheimer’s disease
3.  Cortical thickness mediates the effect of β-amyloid on episodic memory 
Neurology  2014;82(9):761-767.
Objective:
To investigate the associations among β-amyloid (Aβ), cortical thickness, and episodic memory in a cohort of cognitively normal to mildly impaired individuals at increased risk of vascular disease.
Methods:
In 67 subjects specifically recruited to span a continuum of cognitive function and vascular risk, we measured brain Aβ deposition using [11C] Pittsburgh compound B–PET imaging and cortical thickness using MRI. Episodic memory was tested using a standardized composite score of verbal memory, and vascular risk was quantified using the Framingham Coronary Risk Profile index.
Results:
Increased Aβ was associated with cortical thinning, notably in frontoparietal regions. This relationship was strongest in persons with high Aβ deposition. Increased Aβ was also associated with lower episodic memory performance. Cortical thickness was found to mediate the relationship between Aβ and memory performance. While age had a marginal effect on these associations, the relationship between Aβ and cortical thickness was eliminated after controlling for vascular risk except when examined in only Pittsburgh compound B–positive subjects, in whom Aβ remained associated with thinner cortex in precuneus and occipital lobe. In addition, only the precuneus was found to mediate the relationship between Aβ and memory after controlling for vascular risk.
Conclusion:
These results suggest strong links among Aβ, cortical thickness, and memory. They highlight that, in individuals without dementia, vascular risk also contributes to cortical thickness and influences the relationships among Aβ, cortical thickness, and memory.
doi:10.1212/WNL.0000000000000170
PMCID: PMC3945649  PMID: 24489134
4.  Demographic Predictors of Cognitive Change in Ethnically Diverse Older Persons 
Psychology and aging  2013;28(3):633-645.
The purpose of this study was to evaluate how demographic variables relate to cognitive change and address whether cross-sectional demographic effects on cognitive tests are mirrored in differences in longitudinal trajectories of cognitive decline. We hypothesized that race and ethnicity, education, and language of test administration would relate to cross-sectional status and that the rate of cognitive decline would differ among African Americans, Hispanics, and Caucasians, across levels of educational attainment, and according to linguistic background. Participants were 404 educationally, ethnically, and cognitively diverse older adults enrolled in an ongoing longitudinal study of cognition. Mixed-effects regression analysis was used to measure baseline status and longitudinal change in episodic memory, executive functioning, and semantic memory. Results showed that ethnicity and education were strongly associated with baseline scores, but were, at most, weakly associated with change in cognition over time after accounting for confounding variables. There was evidence that the episodic-memory scores of Spanish-speaking Hispanic participants with limited education underestimated their true abilities in the initial evaluation, which may reflect lack of familiarity with the testing environment. These results—consistent with other reports in the literature—suggest that cross-sectional effects of demographic variables on cognitive-test scores result from differences in life experiences that directly influence test performance and do not indicate greater disease effects on cognition in minorities and those with limited education.
doi:10.1037/a0031645
PMCID: PMC3778107  PMID: 23437898
cognitive change; African Americans; Hispanics; ethnic differences; dementia
5.  Cognitive Activities During Adulthood Are More Important than Education in Building Reserve 
Cognitive reserve is thought to reflect life experiences. Which experiences contribute to reserve and their relative importance is not understood. Subjects were 652 autopsied cases from the Rush Memory and Aging Project and the Religious Orders Study. Reserve was defined as the residual variance of the regressions of cognitive factors on brain pathology and was captured in a latent variable that was regressed on potential determinants of reserve. Neuropathology variables included Alzheimer’s disease markers, Lewy bodies, infarcts, microinfarcts, and brain weight. Cognition was measured with six cognitive domain scores. Determinants of reserve were socioeconomic status (SES), education, leisure cognitive activities at age 40 (CA40) and at study enrollment (CAbaseline) in late life. The four exogenous predictors of reserve were weakly to moderately inter-correlated. In a multivariate model, all except SES had statistically significant effects on Reserve, the strongest of which were CA40 (β= .31) and CAbaseline (β= .28). The Education effect was negative in the full model (β= −.25). Results suggest that leisure cognitive activities throughout adulthood are more important than education in determining reserve. Discrepancies between cognitive activity and education may be informative in estimating late life reserve.
doi:10.1017/S1355617711000014
PMCID: PMC3498078  PMID: 23131600
Cognitive reserve; Alzheimer’s disease; Cerebrovascular disorders; Aging; Neuropsychological test battery; Multivariate analysis
6.  The Aging Brain and Cognition 
JAMA neurology  2013;70(4):488-495.
Importance
β-Amyloid (Aβ) deposition and vascular brain injury (VBI) frequently co-occur and are both associated with cognitive decline in aging. Determining whether a direct relationship exists between them has been challenging. We sought to understand VBI’s influence on cognition and clinical impairment, separate from and in conjunction with pathologic changes associated with Alzheimer disease (AD).
Objective
To examine the relationship between neuroimaging measures of VBI and brain Aβ deposition and their associations with cognition.
Design and Setting
A cross-sectional study in a community- and clinic-based sample recruited for elevated vascular disease risk factors.
Participants
Clinically normal (mean age, 77.1 years [N=30]), cognitively impaired (mean age, 78.0 years [N=24]), and mildly demented (mean age, 79.8 years [N=7]) participants.
Interventions
Magnetic resonance imaging, Aβ (Pitts-burgh Compound B–positron emission tomographic [PiB-PET]) imaging, and cognitive testing.
Main Outcome Measures
Magnetic resonance images were rated for the presence and location of infarct (34 infarct-positive participants, 27 infarct-negative participants) and were used to quantify white matter lesion volume. The PiB-PET uptake ratios were used to create a PiB index by averaging uptake across regions vulnerable to early Aβ deposition; PiB positivity (29 PiB-positive participants, 32 PiB-negative participants) was determined from a data-derived threshold. Standardized composite cognitive measures included executive function and verbal and nonverbal memory.
Results
Vascular brain injury and Aβ were independent in both cognitively normal and impaired participants. Infarction, particularly in cortical and subcortical gray matter, was associated with lower cognitive performance in all domains (P<.05 for all comparisons). Pittsburgh Compound B positivity was neither a significant predictor of cognition nor interacted with VBI.
Conclusions and Relevance
In this elderly sample with normal cognition to mild dementia, enriched for vascular disease, VBI was more influential than Aβ in contemporaneous cognitive function and remained predictive after including the possible influence of Aβ. There was no evidence that VBI increases the likelihood of Aβ deposition. This finding highlights the importance of VBI in mild cognitive impairment and suggests that the impact of cerebrovascular disease should be considered with respect to defining the etiology of mild cognitive impairment.
doi:10.1001/2013.jamaneurol.405
PMCID: PMC3771392  PMID: 23400560
7.  Everyday Cognition in older adults 
The recently developed Everyday Cognition scales (ECog) measure multiple cognitively-relevant functional domains (e.g. Everyday Memory, Everyday Language, Everyday Visuospatial abilities and three everyday executive domains). The present study further evaluated the validity of the ECog by examining its relationship with objective measures of neuropsychological function, and neurobiological markers of disease as reflected by structural neuroimaging. Participants included 474 older adults (244 normals, 142 with MCI, 88 with dementia). The neuropsychological domains measured were episodic memory, semantic memory, spatial ability, and executive functioning. Brain MRI volumes included total brain (BV), hippocampus (HC) and dorsolateral prefrontal cortex (DLPFC). Neuropsychological measures of episodic memory and executive function were most consistently related to the ECog domains; spatial abilities had a specific relationship to the Everyday Visuospatial ECog domain. HC and BV volumes were related to most ECog domains, while DLPFC volume was independently related to two everyday executive domains (Everyday Planning and Everyday Organization). The pattern of associations varied somewhat as a function of diagnosis. Episodic memory and HC had more consistent associations with the ECog domains in older adults with MCI/dementia than in cognitively normal elderly.
doi:10.1017/S1355617712001609
PMCID: PMC3818105  PMID: 23369894
Activities of daily living; Instrumental Activities of daily living; Functional abilities; MCI; Dementia; Neuroimaging; Episodic memory; Executive function
8.  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
9.  Criterion-referenced validity of a neuropsychological test battery: Equivalent performance in elderly Hispanics and Non-Hispanic Whites 
This study examined the validity of the Spanish and English Neuropsychological Assessment Scales (SENAS) in comparison with clinical diagnosis of normal cognition versus cognitive impairment, not demented (CIND) versus demented in elderly Hispanics and Whites. Relationships between SENAS scales and diagnosis were essentially the same in Hispanics and Whites. Verbal memory measures were most strongly related, with more than 35% of the variance in these measures accounted for by diagnosis independent of effects of education, age, gender, and language. Diagnosis accounted for more than 10% of the variance (19% on average) in 11 of the 17 measures examined in this study. Logistic regressions showed that verbal memory was important both for distinguishing normal from CIND and CIND from demented. Object naming improved discrimination of CIND from demented beyond that of verbal memory alone. These results provide evidence of equivalent validity across Hispanics and Whites.
doi:10.1017/S1355617705050745
PMCID: PMC3771317  PMID: 16212690
Neuropsychological assessment; Ethnic groups; Cognitive impairment; Dementia; Early diagnosis; Cognition
10.  Different mechanisms of episodic memory failure in mild cognitive impairment 
Neuropsychologia  2005;43(11):1688-1697.
Mild cognitive impairment (MCI), defined as episodic memory impairment beyond what is expected in normal aging, is often associated with hippocampal atrophy (HA) and may represent incipient Alzheimer’s disease. However, recent studies suggest that MCI is very heterogeneous and multiple etiologies likely exist. One possibility is small vessel cerebrovascular disease (CVD). Specifically, we hypothesized that white matter hyperintensities(WMH),an MRI marker for CVD, would lead to impairments in executive control processes critical for working memory that may, in turn, result in episodic memory impairment. To test this hypothesis, we examined a group of subjects clinically diagnosed with MCI and used MRI to further subcategorize individuals as either MCI with severe white matter hyperintensities (MCI-WMH) or MCI with severe hippocampal atrophy (MCI-HA). MCI-WMH, MCI-HA, and matched control subjects each performed a battery of working memory and episodic memory tasks. Results showed that MCI-HA and MCI-WMH were equally impaired on the episodic memory task relative to controls, but MCI-WMH were additionally impaired on tests tapping verbal and spatial working memory abilities and attentional control processes. These results suggest that CVD and hippocampal dysfunction are associated with distinct neuropsychological profiles. Although both syndromes are associated with episodic memory deficits, CVD is additionally associated with working memory and executive control deficits. © 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.neuropsychologia.2005.01.003
PMCID: PMC3771323  PMID: 16009250
Aging; Dementia; White matter hyperintensities; Working memory; Cerebrovascular disease; Hippocampus
11.  Cerebrovascular disease, beta-amyloid and cognition in aging 
Neurobiology of Aging  2011;33(5):1006.e25-1006.e36.
The present study evaluated cerebrovascular disease (CVD), β-amyloid (Aβ), and cognition in clinically normal elderly adults. Fifty-four participants underwent MRI, PIB-PET imaging, and neuropsychological evaluation. High white matter hyperintensity burden and/or presence of infarct defined CVD status (CVD−: N = 27; CVD+: N = 27). PIB-PET ratios of Aβ deposition were extracted using Logan plotting (cerebellar reference). Presence of high levels of Aβ in prespecified regions determined PIB status (PIB−: N = 33; PIB+: N = 21). Executive functioning and episodic memory were measured using composite scales. CVD and Aβ, defined as dichotomous or continuous variables, were unrelated to one another. CVD+ participants showed lower executive functioning (P = 0.001) when compared to CVD− individuals. Neither PIB status nor amount of Aβ affected cognition (Ps ≥ .45), and there was no statistical interaction between CVD and PIB on either cognitive measure. Within this spectrum of normal aging CVD and Aβ aggregation appear to be independent processes with CVD primarily affecting cognition.
doi:10.1016/j.neurobiolaging.2011.10.001
PMCID: PMC3274647  PMID: 22048124
PIB; cerebrovascular disease; episodic memory; executive functioning; cognition
12.  Cognitive decline in the elderly: an analysis of population heterogeneity 
Age and Ageing  2011;40(6):684-689.
Background: studies of cognitive ageing at the group level suggest that age is associated with cognitive decline; however, there may be individual differences such that not all older adults will experience cognitive decline.
Objective: to evaluate patterns of cognitive decline in a cohort of older adults initially free of dementia.
Design, setting and subjects: elderly Catholic clergy members participating in the Religious Orders Study were followed for up to 15 years. Cognitive performance was assessed annually.
Methods: performance on a composite global measure of cognition was analysed using random effects models for baseline performance and change over time. A profile mixture component was used to identify subgroups with different cognitive trajectories over the study period.
Results: from a sample of 1,049 participants (mean age 75 years), three subgroups were identified based on the distribution of baseline performance and change over time. The majority (65%) of participants belonged to a slow decline class that did not experience substantial cognitive decline over the observation period [−0.04 baseline total sample standard deviation (SD) units/year]. About 27% experienced moderate decline (−0.19 SD/year), and 8% belonged to a class experiencing rapid decline (−0.57 SD/year). A subsample analysis revealed that when substantial cognitive decline does occur, the magnitude and rate of decline is correlated with neuropathological processes.
Conclusions: in this sample, the most common pattern of cognitive decline is extremely slow, perceptible on a time scale measured by decades, not years. While in need of cross validation, these findings suggest that cognitive changes associated with ageing may be minimal and emphasise the importance of understanding the full range of age-related pathologies that may diminish brain function.
doi:10.1093/ageing/afr101
PMCID: PMC3199215  PMID: 21890481
aged; 80 and over; cognition disorders; longitudinal study; elderly
13.  The Measurement of Everyday Cognition (ECog): Development and validation of a short form 
Background
This study describes the development and validation of a shortened version of the Everyday Cognition scales (ECog) (1), an informant-rated questionnaire designed to detect cognitive and functional decline.
Methods
External, convergent and divergent validity, and internal consistency were examined. Data was derived from informant ratings of 907 participants who were cognitively normal, had mild cognitive impairment (MCI) or dementia.
Results
Twelve items were included in the short version (ECog-12). The ECog-12 correlated with established functional measures and neuropsychological scores, only weakly with age and education, and demonstrated high internal consistency. The ECog-12 showed excellent discrimination between the dementia and normal groups (AUC = .95, CI = .94-.97) and showed promise in discriminating normal older adults from those with any cognitive impairment (i.e. MCI or dementia). Discrimination between MCI and normals was poor.
Conclusions
The ECog-12 shows promise as a clinical tool for assisting clinicians in identifying individuals with dementia.
doi:10.1016/j.jalz.2011.02.007
PMCID: PMC3211103  PMID: 22055976
Alzheimer’s disease; mild cognitive impairment; assessment of cognition; functional assessment
14.  Vascular risk factors and Alzheimer's disease: are these risk factors for plaques and tangles or for concomitant vascular pathology that increases the likelihood of dementia? An evidence-based review 
Recent epidemiologic studies have noted that risk factors for atherosclerosis (for example, diabetes mellitus, hypertension, and hyperlipidemia) are associated with increased risk of incident Alzheimer's disease (AD). In this evidence-based review, we frame the proposition as a question: are vascular risk factors also risk factors for plaques and tangles or just for concomitant vascular pathology that increases the likelihood of dementia? To date, no representative, prospective studies with autopsy (evidence level A) show significant positive associations between diabetes mellitus, hypertension, or intracranial atherosclerosis and plaques or tangles. Some prospective, representative, epidemiologic studies (evidence level B) show associations between diabetes, hypertension, hyperlipidemia, and aggregated risk factors with clinically diagnosed incident AD. However, the strength of association diminishes in the following order: vascular dementia (VaD) > AD + VaD > AD. This pattern is arguably more consistent with the hypothesis that atherosclerosis promotes subclinical vascular brain injury, thereby increasing the likelihood of dementia and in some cases making symptoms present earlier. Several autopsy studies from AD brain banks (evidence level C) have observed positive associations between intracranial atherosclerosis and severity of plaques and tangles. However, these studies may reflect selection bias; these associations are not confirmed when cases are drawn from non-dementia settings. We conclude that, at the present time, there is no consistent body of evidence to show that vascular risk factors increase AD pathology.
doi:10.1186/alzrt98
PMCID: PMC3471388  PMID: 22182734
15.  Neuropathological Associates of Multiple Cognitive Functions in Two Community-Based Cohorts of Older Adults 
Studies of neuropathology-cognition associations are not common and have been limited by small sample sizes, long intervals between autopsy and cognitive testing, and lack of breadth of neuropathology and cognition variables. This study examined domain-specific effects of common neuropathologies on cognition using data (N = 652) from two large cohort studies of older adults. We first identified dimensions of a battery of 17 neuropsychological tests, and regional measures of Alzheimer’s disease (AD) neuropathology. We then evaluated how cognitive factors were related to dimensions of AD and additional measures of cerebrovascular and Lewy Body disease, and also examined independent effects of brain weight. All cognitive domains had multiple neuropathology determinants that differed by domain. Neocortical neurofibrillary tangles were the strongest predictors of most domains, while medial temporal tangles showed a weaker relationship with episodic memory. Neuritic plaques had relatively strong effects on multiple domains. Lewy bodies and macroscopic infarcts were associated with all domains, while microscopic infarcts had more limited associations. Brain weight was related to all domains independent of specific neuropathologies. Results show that cognition is complexly determined by multiple disease substrates. Neuropathological variables and brain weight contributed approximately a third to half of the explained variance in different cognitive domains.
doi:10.1017/S1355617710001426
PMCID: PMC3376403  PMID: 21092373
Latent variable analysis; Confirmatory factor analysis; Neuropathology; MIMIC; Cerebrovascular disease; Neuropsychological test battery
16.  Measurement Invariance of Neuropsychological Tests in Diverse Older Persons 
Neuropsychology  2011;25(2):260-269.
Objective
Comparability of meaning of neuropsychological test results across ethnic, linguistic, and cultural groups is important for clinicians challenged with assessing increasing numbers of older ethnic minorities. We examined the dimensional structure of a neuropsychological test battery in linguistically and demographically diverse older adults.
Method
The Spanish and English Neuropsychological Assessment Scales (SENAS), developed to provide psychometrically sound measures of cognition for multi-ethnic and multilingual applications, was administered to a community dwelling sample of 760 Caucasians, 443 African Americans, 451 English-speaking Hispanics, and 882 Spanish-speaking Hispanics. Cognitive function spanned a broad range from normal to mildly impaired to demented. Multiple group confirmatory factor analysis (CFA) was used to examine equivalence of the dimensional structure for the SENAS across the groups defined by language and ethnicity.
Results
Covariance among 16 SENAS tests was best explained by five cognitive dimensions corresponding to episodic memory, semantic memory/language, spatial ability, attention/working memory, and verbal fluency. Multiple group CFA supported a common dimensional structure in the diverse groups. Measures of episodic memory showed the most compelling evidence of measurement equivalence across groups. Measurement equivalence was observed for most but not all measures of semantic memory/language and spatial ability. Measures of attention/working memory defined a common dimension in the different groups, but results suggest that scores are not strictly comparable across groups.
Conclusions
These results support the applicability of the SENAS for use with multi-ethnic and bilingual older adults, and more broadly, provide evidence of similar dimensions of cognition in the groups represented in the study.
doi:10.1037/a0021090
PMCID: PMC3058248  PMID: 21381830
Neuropsychological Assessment; Measurement Equivalence; Ethnicity; English; Spanish
17.  Measuring cognitive reserve based on the decomposition of episodic memory variance 
Brain  2010;133(8):2196-2209.
In later adulthood brain pathology becomes common and trajectories of cognitive change are heterogeneous. Among the multiple determinants of late-life cognitive course, cognitive reserve has been proposed as an important factor that modifies or buffers the impact of brain pathology on cognitive function. This article presents and investigates a novel method for measuring and investigating such factors. The core concept is that in a population where pathology is common and variably present, ‘reserve’ may be defined as the difference between the cognitive performance predicted by an individual's level of pathology and that individual's actual performance. By this definition, people whose measured cognitive performance is better than predicted by pathology have high reserve, whereas those who perform worse than predicted have low reserve. To test this hypothesis, we applied a latent variable model to data from a diverse ageing cohort and decomposed the variance in a measure of episodic memory into three components, one predicted by demographics, one predicted by pathology as measured by structural MRI and a ‘residual’ or ‘reserve’ term that included all remaining variance. To investigate the plausibility of this approach, we then tested the residual component as an operational measure of reserve. Specific predictions about the effects of this putative reserve measure were generated from a general conceptual model of reserve. Each was borne from the results. The results show that the current level of reserve, as measured by this decomposition approach, modifies rates of conversion from mild cognitive impairment to dementia, modifies rates of longitudinal decline in executive function and, most importantly, attenuates the effect of brain atrophy on cognitive decline such that atrophy is more strongly associated with cognitive decline in subjects with low reserve than in those with high reserve. Decomposing the variance in cognitive function scores offers a promising new approach to the measure and study of cognitive reserve.
doi:10.1093/brain/awq154
PMCID: PMC3139935  PMID: 20591858
cognitive ageing; mild cognitive impairment; dementia; neuropsychological tests; longitudinal change; cognitive reserve
18.  Recruitment of a Community-Based Cohort for Research on Diversity and Risk of Dementia 
We describe the history, development, and success of the recruitment and screening procedures used by researchers at the University of California, Davis Alzheimer's Disease Center (UCD ADC) to facilitate minority enrollment in research. After an initial, unsuccessful approach with satellite clinics in minority neighborhoods, the ADC shifted to an active community outreach approach. Multiple strategies were implemented to remove barriers to research participation such as providing transportation to clinical appointments and offering in-home cognitive screening. Considerable resources were directed towards hiring and training bicultural and bilingual individuals with knowledge of the target populations, both as recruiters and staff involved in clinical assessment. Implementation of these methods resulted in a dramatic increase in the number of ethnic minorities enrolled (and retained) in research protocols, including protocols that are complex and longitudinal. Diversity was achieved on other variables as well; years of education in the cohort ranges from 0 – 21, with 26% having 8 years or less. The community screen identified candidates for an in depth clinical evaluation and enrollment in longitudinal research, and we examined factors that predicted a positive response to invitation for the clinical evaluation. Individuals with a broader fund of knowledge were more likely to participate independent of other variables including ethnicity and education. When diversity is an important goal active outreach is far more efficacious than clinic-based and advertising-based approaches to recruitment.
doi:10.1097/WAD.0b013e3181c1ee01
PMCID: PMC2946798  PMID: 20625273
minority recruitment; minority enrollment; bilingual; bicultural; community screen; longitudinal
19.  Diagnosing Depression in Alzheimer Disease With the National Institute of Mental Health Provisional Criteria 
Objective
To compare the rates of depression in Alzheimer Disease (AD) determined using National Institute of Mental Health (NIMH) provisional criteria for depression in AD (NIMH-dAD) to those determined using other established depression assessment tools.
Design
Descriptive longitudinal cohort study.
Setting
The Alzheimer’s Disease Research Centers of California.
Participants
A cohort of 101 patients meeting NINDS-ADRDA criteria for possible/probable AD, intentionally selected to increase the frequency of depression at baseline.
Measurements
Depression was diagnosed at baseline and after 3 months using NIMH-dAD criteria and the Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) Axis I Disorders. Depressive symptoms also were assessed with the Cornell Scale for Depression in Dementia (CSDD), the Geriatric Depression Scale (GDS), and the Neuropsychiatric Inventory Questionnaire.
Results
The baseline frequency of depression using NIMH-dAD criteria (44%) was higher than that obtained using DSM-IV criteria for major depression (14%; Z = −5.50, df = 101, p <0.001) and major or minor depression (36%; Z = −2.86, df = 101, p = 0.021) or using established cut-offs for the CSDD (30%; Z = −2.86, df = 101, p = 0.004) or GDS (33%; Z = −2.04, df = 101, p = 0.041). The NIMH-dAD criteria correctly identified all patients meeting DSM-IV criteria for major depression, and correlated well with DSM-IV criteria for major or minor depression (κ = 0.753, p <0.001), exhibiting 94% sensitivity and 85% specificity. The higher rates of depression found with NIMH-dAD criteria derived primarily from its less stringent requirements for the frequency and duration of symptoms. Remission rates at 3 months were similar across instruments.
Conclusions
The NIMH-dAD criteria identify a greater proportion of AD patients as depressed than several other established tools.
doi:10.1097/JGP.0b013e318165dbae
PMCID: PMC2989660  PMID: 18515691
20.  Progression of Mild Cognitive Impairment to Dementia in Clinic- vs Community-Based Cohorts 
Archives of neurology  2009;66(9):1151-1157.
Background
Mild cognitive impairment is increasingly recognized as an important public health problem associated with increased risk of developing dementia. Annual conversion rates, however, vary across different studies with clinic samples showing higher rates of conversion than community-based samples.
Objectives
To establish whether the rates of conversion from mild cognitive impairment to dementia differed according to recruitment source and, if so, to investigate factors that might explain this discrepancy.
Design
Rates and predictors of conversion were examined in a prospective longitudinal study at a single center.
Setting
Among the participants, 46% were recruited from a clinical setting and 54% were recruited directly through community outreach.
Participants
One hundred eleven individuals with mild cognitive impairment were followed up longitudinally for an average of 2.4 years (range, 0.5–4.0 years).
Main Outcome Measures
Conversion from mild cognitive impairment to dementia.
Results
During the follow-up period, 28 individuals progressed to dementia with a mean (SD) time to conversion of 2.19 (0.72) years. The clinic sample had an annual conversion rate of 13%, whereas the community sample had an annual conversion rate of 3%. In a Cox proportional hazards model, clinic recruitment source alone was associated with an increased hazard of incident dementia (hazard ratio=3.50; 95% confidence interval, 1.31–9.18; P=.01). When other variables were added to the model, only baseline functional impairment as measured by the Clinical Dementia Rating Scale (and no demographic, cognitive, or neuroimaging variables or mild cognitive impairment subtype) accounted for the differences in conversion rates across the 2 cohorts.
Conclusions
These findings add to the growing literature to suggest that the degree of functional impairment at baseline is an important predictor of conversion to dementia and may help explain differences in findings between epidemiological and clinic-based studies.
doi:10.1001/archneurol.2009.106
PMCID: PMC2863139  PMID: 19752306
21.  Computer-Based Cognitive Training for Mild Cognitive Impairment: Results from a Pilot Randomized, Controlled Trial 
We performed a pilot randomized, controlled trial of intensive, computer-based cognitive training in 47 subjects with mild cognitive impairment (MCI). The intervention group performed exercises specifically designed to improve auditory processing speed and accuracy for 100 minutes/day, 5 days/week for 6 weeks; the control group performed more passive computer activities (reading, listening, visuospatial game) for similar amounts of time. Subjects had a mean age of 74 years and 60% were men; 77% successfully completed training. On our primary outcome, Repeatable Battery for Assessment of Neuropsychological Status (RBANS) total scores improved 0.36 standard deviations (SD) in the intervention group (p=0.097) compared to 0.03 SD in the control group (p=0.88) for a non-significant difference between the groups of 0.33 SD (p=0.26). On 12 secondary outcome measures, most differences between the groups were not statistically significant. However, we observed a pattern in which effect sizes for verbal learning and memory measures tended to favor the intervention group while effect sizes for language and visuospatial function measures tended to favor the control group, which raises the possibility that these training programs may have domain-specific effects. We conclude that intensive, computer-based mental activity is feasible in subjects with MCI and that larger trials are warranted.
doi:10.1097/WAD.0b013e31819c6137
PMCID: PMC2760033  PMID: 19812460
human; aged; cognition; cognitive rehabilitation; memory; neuropsychological tests; randomized controlled trial; mild cognitive impairment
22.  Longitudinal Changes in Memory and Executive Functioning are Associated with Longitudinal Change in Instrumental Activities of Daily Living in older adults 
The Clinical neuropsychologist  2008;23(3):446-461.
Impaired everyday function is a diagnostic criterion for dementia, and a determinant of healthcare utilization and caregiver burden. Although many previous studies have demonstrated a cross-sectional relationships between cognition (particularly executive functions and memory) and everyday function in older adults, very little is known about longitudinal relationships between these domains. This study examined the association between longitudinal change in episodic memory (MEM) and executive functioning (EXEC) and change in everyday function. Participants were a cognitively heterogeneous group of 100 elderly persons including those with normal cognition, as well as those with mild cognitive impairment and dementia. They were followed for an average of five years. Random effects modeling showed that change in both MEM and EXEC were independently associated with rate of change in informant-rated instrumental activities of daily living (IADLs), even after controlling for age, education, and gender. Findings indicate that declines in MEM and EXEC over time make unique and independent contributions to declines in older adults’ ability to function in daily life.
doi:10.1080/13854040802360558
PMCID: PMC2881703  PMID: 18821181
Memory; Executive functioning; Everyday Function; dementia; Alzheimer’s disease
23.  MCI is Associated With Deficits in Everyday Functioning 
The purpose of the present study was to examine the types of impairments in everyday function that accompany mild cognitive impairment (MCI). Data for this study was collected from 434 individuals consecutively evaluated at a university-based Alzheimer’s Center. A total of 96 participants were diagnosed with MCI, 105 were cognitively normal, and 233 had dementia. Informant ratings of participants’ abilities were obtained across different functional domains reflecting everyday abilities related to memory, language, visual spatial abilities, planning, organization, and divided attention. As expected, the demented group was significantly more impaired than the healthy control and MCI groups across all of the functional domains. The MCI group also showed significantly more functional impairment relative to healthy controls in all of the functional domains. Examination of the effect sizes as a measure of the magnitude of functional impairment in the MCI groups relative to controls showed that the greatest degree of impairment occurred within the Everyday Memory domain. The current findings suggest that individuals with MCI demonstrate deficits in a wide range of everyday functions but that the magnitude of these changes is greatest for those functional abilities that rely heavily on memory.
doi:10.1097/01.wad.0000213849.51495.d9
PMCID: PMC2880610  PMID: 17132965
mild cognitive impairment (MCI); dementia; functional impairment
24.  Cognitive and neuroimaging predictors of instrumental activities of daily living 
Impaired ability to conduct daily activities is a diagnostic criterion for dementia and a determinant of healthcare services utilization and caregiver burden. What predicts decline in instrumental activities of daily living (IADLs) is not well understood. This study examined measures of episodic memory, executive function, and MRI brain volumes in relation to baseline IADLs and as predictors of rate of IADL change. Participants were 124 elderly persons with cognitive function between normal and moderate dementia both with and without significant small vessel cerebrovascular disease. Random effects modeling showed that baseline memory and executive function (EXEC) were associated with baseline IADL scores, but only EXEC was independently associated with rate of change in IADLs. Whereas hippocampal and cortical gray matter volumes were significantly associated with baseline IADL scores, only hippocampal volume was associated with IADL change. In a model including cognitive and neuroimaging predictors, only EXEC independently predicted rate of decline in IADL scores. These findings indicate that greater executive dysfunction at initial assessment is associated with more rapid decline in IADLs. Perhaps executive function is particularly important with respect to maintaining IADLs. Alternatively, executive dysfunction may be a sentinel event indicating widespread cortical involvement and poor prognosis.
doi:10.1017/S1355617707070853
PMCID: PMC2877031  PMID: 17521485
Alzheimer’s disease; Vascular dementia; Memory; Everyday function; Neuroimaging; Frontal lobe
25.  The Measurement of Everyday Cognition (ECog): Scale Development and Psychometric Properties 
Neuropsychology  2008;22(4):531-544.
This article describes the development and validation of an instrument to assess cognitively mediated functional abilities in older adults, Everyday Cognition (ECog). The ECog is an informant-rated questionnaire comprised of multiple subscales. Confirmatory factor analysis (CFA) was used to examine its factor structure. Convergent validity was evaluated by comparing it to established measures of everyday function. External validity was evaluated by comparing ECog results across different clinical groups [cognitively normal, mild cognitive impairment (MCI), dementia]. CFA supported a seven-factor model including one global factor and six domain-specific factors (Everyday Memory, Language, Visuospatial Abilities, Planning, Organization, and Divided attention). The ECog correlated with established measures of functional status and global cognition, but only weakly with age and education. The clinical groups performed differently in each domain. In addition to the global factor, the Everyday Memory factor independently differentiated MCI from Normal, while the Everyday Language domain differentiated Dementia from MCI. Different subtypes of MCI also showed different patterns. Results suggest the ECog shows promise as a useful tool for the measurement of general and domain-specific everyday functions in the elderly.
doi:10.1037/0894-4105.22.4.531
PMCID: PMC2877034  PMID: 18590364
functional impairment; everyday function; aging; instrument validation; factor analysis

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