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1.  Longitudinal relationships between Alzheimer’s disease progression and psychosis, depressed mood and agitation/aggression 
Objectives
Behavioral and psychological symptoms of dementia (BPSD) are prevalent in Alzheimer’s disease (AD) and are related to poor outcomes such as nursing home placement. No study has examined the impact of individual BPSD on dependence, a clinically important feature that reflects changing patient needs and their impact on caregivers. The current study characterized independent cross-sectional and longitudinal relationships between three BPSD (i.e., psychosis, depressed mood, and agitation/aggression), cognition, and dependence to better understand the interplay between these symptoms over time.
Design
The Predictors Study measured changes in BPSD, cognition, and dependence in AD patients every six months. Cross-sectional and longitudinal relationships between individual BPSD, cognition, and dependence over six years were characterized using multivariate latent growth curve modeling. This approach characterizes independent changes in multiple outcome measures over time.
Setting
Four memory clinics in the United States and Europe.
Participants
517 patients with probable Alzheimer’s disease.
Measurements
Columbia University Scale for Psychopathology, modified Mini-Mental State Exam, Dependence Scale.
Results
Both psychosis and depressed mood at study entry were associated with worse subsequent cognitive decline. Independent of cognitive decline, initial psychosis was associated with worse subsequent increases in dependence. Rates of increase in agitation/aggression separately correlated with rates of declines in both cognition and independence.
Conclusions
Although purely observational, findings support the poor prognosis associated with psychosis and depression in AD. Results also show that agitation/aggression tracks declines in cognition and independence independently over time. Targeted intervention for individual BPSD, particularly psychosis, could have broad impacts on not only patient well-being, but also care costs and family burden.
doi:10.1016/j.jagp.2013.03.014
PMCID: PMC3858495  PMID: 23871118
dementia; statistical modeling; depression
2.  Olfactory deficits predict cognitive decline and Alzheimer dementia in an urban community 
Neurology  2015;84(2):182-189.
Objective:
To determine the predictive utility of baseline odor identification deficits for future cognitive decline and the diagnosis of Alzheimer disease (AD) dementia.
Methods:
In a multiethnic community cohort in North Manhattan, NY, 1,037 participants without dementia were evaluated with the 40-item University of Pennsylvania Smell Identification Test (UPSIT). In 757 participants, follow-up occurred at 2 years and 4 years.
Results:
In logistic regression analyses, lower baseline UPSIT scores were associated with cognitive decline (relative risk 1.067 per point interval; 95% confidence interval [CI] 1.040, 1.095; p < 0.0001), and remained significant (relative risk 1.065 per point interval; 95% CI 1.034, 1.095; p < 0.0001) after including covariates. UPSIT, but not Selective Reminding Test–total immediate recall, predicted cognitive decline in participants without baseline cognitive impairment. During follow-up, 101 participants transitioned to AD dementia. In discrete time survival analyses, lower baseline UPSIT scores were associated with transition to AD dementia (hazard ratio 1.099 per point interval; 95% CI 1.067, 1.131; p < 0.0001), and remained highly significant (hazard ratio 1.072 per point interval; 95% CI 1.036, 1.109; p < 0.0001) after including demographic, cognitive, and functional covariates.
Conclusions:
Impairment in odor identification was superior to deficits in verbal episodic memory in predicting cognitive decline in cognitively intact participants. The findings support the cross-cultural use of a relatively inexpensive odor identification test as an early biomarker of cognitive decline and AD dementia. Such testing may have the potential to select/stratify patients in treatment trials of cognitively impaired patients or prevention trials in cognitively intact individuals.
doi:10.1212/WNL.0000000000001132
PMCID: PMC4336090  PMID: 25471394
3.  Reconsidering harbingers of dementia: Progression of parietal lobe white matter hyperintensities predicts Alzheimer's disease incidence 
Neurobiology of aging  2014;36(1):27-32.
Accumulating evidence implicates small vessel cerebrovascular disease, visualized as white matter hyperintensities (WMH) on T2-weighted MRI, in the pathogenesis and diagnosis of Alzheimer's disease (AD). Cross-sectional volumetric measures of WMH, particularly in the parietal lobes, are associated with increased risk of AD. In the current study, we sought to determine whether the longitudinal regional progression of WMH predicts incident AD above-and-beyond traditional radiological markers of neurodegeneration (i.e., hippocampal atrophy, cortical thickness). Three hundred three non-demented older adults (mean age = 79.24±5.29) received high-resolution MRI at baseline and then again 4.6 years (SD=1.01) later. Over the follow-up interval 26 participants progressed to AD. Using structural equation modeling (SEM), we calculated latent difference scores of parietal/non-parietal WMH, hippocampus volumes, and cortical thickness values in AD-related regions. Within the SEM framework, we determined whether baseline or change scores or both predicted AD conversion, while controlling for several time-invariant relevant variables. Smaller baseline hippocampus volume, change in hippocampus volume (i.e., atrophy), higher baseline parietal lobe WMH, and increasing parietal lobe WMH volume but not WMH in other regions or measures of cortical thickness, independently predicted progression to AD. The findings provide strong evidence that regionally accumulating WMH, in addition to degenerative changes in the medial temporal lobe, predict AD onset in addition to hallmark neurodegenerative changes typically associated with AD.
doi:10.1016/j.neurobiolaging.2014.07.019
PMCID: PMC4268124  PMID: 25155654
4.  The Reference Ability Neural Network Study: Motivation, Design, and Initial Feasibility Analyses 
NeuroImage  2014;103:139-151.
We introduce and describe the Reference Ability Neural Network Study and provide initial feasibility data. Based on analyses of large test batteries administered to individuals ranging from young to old, four latent variables, or reference abilities (RAs) that capture the majority of the variance in age-related cognitive change have been identified: episodic memory, fluid reasoning, perceptual speed, and vocabulary. We aim to determine whether spatial fMRI networks can be derived that are uniquely associated with the performance of each reference ability.
We plan to image 375 healthy adults (50 per decade from age 20 to 50; 75 per decade from age 50 to 80) while performing a set of 12 cognitive tasks. Data on 174 participants are reported here. Three tasks were grouped a priori into each of the four reference ability domains.
We first assessed to what extent both cognitive task scores and activation patterns readily show convergent and discriminant validity, i.e. increased similarity between tasks within the same domain and decreased similarity between tasks between domains, respectively. Block-based time-series analysis of each individual task was conducted for each participant via general linear modeling. We partialled activation common to all tasks out of the imaging data. For both test scores and activation topographies, we then calculated correlations for each of 66 possible pairings of tasks, and compared the magnitude of correlation of tasks within reference ability domains to that of tasks between domains. For the behavioral data, globally there were significantly stronger inter-task correlations within than between domains. When examining individual abilities, 3 of the domains also met these criteria but memory reached only borderline significance. Overall there was greater topographic similarity within reference abilities than between them (p<0.0001), but when examined individually, statistical significance was reached only for episodic memory and perceptual speed.
We then turned to a multivariate technique, linear indicator regression analysis, to derive four unique linear combinations of Principal Components (PC) of imaging data that were associated with each RA. We investigated the ability of the identified PCs to predict the reference domain associated with the activation of individual subjects for individual tasks. Median accuracy rates for associating component task activation with a particular reference ability were quite good: memory: 82%; reasoning: 87%; speed: 84%; vocabulary: 77%.
These results demonstrate that even using basic GLM analysis, the topography of activation of tasks within a domain is more similar than tasks between domains. The follow-up regression analyses suggest that all tasks with each RA rely on a common network, unique to that RA. Our ultimate goal is to better characterize these RA neural networks and then study how their expression changes across the age span. Our hope is that by focusing on these networks associated with key features of cognitive aging, as opposed to task-related activation associated with individual tasks, we will be able to advance our knowledge regarding the key brain changes that underlie cognitive aging.
doi:10.1016/j.neuroimage.2014.09.029
PMCID: PMC4312259  PMID: 25245813
Cognitive aging; fMRI; convergent/discriminant validity
5.  The Prevalence of Mild Cognitive Impairment in Diverse Geographical and Ethnocultural Regions: The COSMIC Collaboration 
PLoS ONE  2015;10(11):e0142388.
Background
Changes in criteria and differences in populations studied and methodology have produced a wide range of prevalence estimates for mild cognitive impairment (MCI).
Methods
Uniform criteria were applied to harmonized data from 11 studies from USA, Europe, Asia and Australia, and MCI prevalence estimates determined using three separate definitions of cognitive impairment.
Results
The published range of MCI prevalence estimates was 5.0%–36.7%. This was reduced with all cognitive impairment definitions: performance in the bottom 6.681% (3.2%–10.8%); Clinical Dementia Rating of 0.5 (1.8%–14.9%); Mini-Mental State Examination score of 24–27 (2.1%–20.7%). Prevalences using the first definition were 5.9% overall, and increased with age (P < .001) but were unaffected by sex or the main races/ethnicities investigated (Whites and Chinese). Not completing high school increased the likelihood of MCI (P ≤ .01).
Conclusion
Applying uniform criteria to harmonized data greatly reduced the variation in MCI prevalence internationally.
doi:10.1371/journal.pone.0142388
PMCID: PMC4634954  PMID: 26539987
6.  Social Cognition in Alzheimer’s disease: A separate construct contributing to dependence 
The extent to which social cognitive changes reflect a discrete constellation of symptoms dissociable from general cognitive changes in Alzheimer’s disease (AD) is unclear. Moreover, whether social cognitive symptoms contribute to disease severity and progression is unknown. The current multicenter study investigated cross-sectional and longitudinal associations between social cognition, general cognition, and dependence in 517 participants with Probable AD. Participants were followed every 6-months for 5.5 years. Results from multivariate latent growth curve models adjusted for sex, age, education, depression, and recruitment site revealed that social cognition and general cognition were unrelated cross-sectionally and over time. However, baseline levels of each were independently related to dependence, and change values of each were independently related to change in dependence. These findings highlight the separability of social and general cognition in AD. Results underscore the relevance of considering social cognition when modeling disease and estimating clinical outcomes related to patient disability.
doi:10.1016/j.jalz.2013.12.021
PMCID: PMC3980672  PMID: 24656839
Alzheimer’s disease; social cognition; cognition; dependence
7.  APOE-ε4 and risk for Alzheimer’s disease: Do regionally distributed white matter hyperintensities play a role? 
Background
We previously demonstrated that parietal lobe white matter hyperintensities (WMH) increase risk for Alzheimer’s disease (AD). Here, we examined whether individuals with APOE*4have increased parietal WMH volume.
Methods
Participants were from the Washington Heights-Inwood Columbia Aging Project (WHICAP; n=694, 47 with dementia) in northern Manhattan and the Etude Santé Psychologique Prévalence Risques et Traitement study (ESPRIT; n=539, 8 with dementia) in Montpellier. The association between regional WMH and APOE*4 was examined separately in each group and then in a combined analysis.
Results
In WHICAP, ε4 carriers had higher WMH volume particularly in parietal and occipital lobes. In ESPRIT, ε4 carriers had elevated WMH particularly in parietal and temporal lobes. In the combined analysis, ε4 carriers had higher WMH in parietal and occipital lobes. Increased WMH volume was associated with increased frequency of dementia irrespective of APOE*4 status; those with the ε4 were more likely to have dementia if they also had increased parietal WMH.
Conclusions
APOE*4 is associated with increased parietal lobe WMH.
doi:10.1016/j.jalz.2014.07.155
PMCID: PMC4252241  PMID: 25304991
APOE; Alzheimer disease; white matter hyperintensities
8.  Functional connectivity of the posterior hippocampus is more dominant as we age 
Cognitive neuroscience  2014;5(0):150-159.
The role of the hippocampus in memory is dependent on its interaction with distributed brain areas. Anterior and posterior hippocampus have different roles in memory processing, and are impacted differently by aging in terms of structural decline, however functional connectivity of these hippocampal regions in aging is not well understood.
Young (age 17-30) and aging (age 60-69) cognitively normal subjects underwent resting-state functional MRI revealing a shift from anterior hippocampus dominant hippocampus connectivity in younger age to posterior hippocampus dominant connectivity in aging subjects. We identified a subset of neocortical regions that are connected to the anterior hippocampus in younger adults but to the posterior hippocampus among older subjects, suggesting an age related reorganization of hippocampal networks supporting normal cognitive function. We also performed volumetric analysis which revealed no significant structural differences between groups. These findings provide evidence that “functional anatomy” which supports normal memory performance changes across the life span.
doi:10.1080/17588928.2014.975680
PMCID: PMC4237614  PMID: 25360889
9.  Cerebral microbleeds in a multiethnic elderly community: Demographic and clinical correlates 
Background
Microbleeds, small perivascular collections of hemosiderin manifested radiologically as hypointensities on gradient-echo magnetic resonance imaging (MRI), are important markers of small vessel pathology. Despite their clinical relevance, little is known about their prevalence and demographic correlates, particularly among ethnically diverse older adults. We examined demographic and clinical correlates of regional microbleeds in a multi-ethnic cohort and examined categorization schemes of microbleed distribution and severity.
Methods
Between 2005 and 2007, 769 individuals participated in a MRI study as part of the Washington Heights/Inwood Columbia Aging Project. Approximately four years later, 243 out of 339 participants (mean age=84.50) who returned for a repeat MRI had gradient-echo scans for microbleed assessment and comprised the sample. We examined the association of deep and lobar microbleeds with age, sex, education, vascular factors, cognitive status and markers of small vessel disease.
Results
Sixty-seven of the 243(27%) participants had at least one microbleed. Individuals with microbleeds were more likely to have a history of stroke than individuals without. When categorized as having either no microbleeds, microbleeds in deep regions only, in lobar regions only, and both deep and lobar microbleeds, hypertension, proportion of strokes, and white matter hyperintensity volume (WMH) increased monotonically across the four groups. Number of lobar microbleeds correlated with WMH volume and diastolic blood pressure.
Conclusions
Microbleeds in deep and lobar locations are associated with worse outcomes than microbleeds in either location alone, although presence of lobar microbleeds appears to be more clinically relevant.
doi:10.1016/j.jns.2014.07.024
PMCID: PMC4177942  PMID: 25091451
cerebral microbleeds; community; small-vessel disease; multi-ethnic; vascular risk factors; white matter hyperintensities; stroke
10.  Use and cost of hospitalization in dementia: longitudinal results from a community-based study 
Objectives
The aim of this study is to examine the relative contribution of functional impairment and cognitive deficits on risk of hospitalization and costs.
Methods
A prospective cohort of Medicare beneficiaries aged 65 and older who participated in the Washington Heights-Inwood Columbia Aging Project (WHICAP) were followed approximately every 18 months for over 10 years (1805 never diagnosed with dementia during study period, 221 diagnosed with dementia at enrollment). Hospitalization and Medicare expenditures data (1999–2010) were obtained from Medicare claims. Multivariate analyses were conducted to examine (1) risk of all-cause hospitalizations, (2) hospitalizations from ambulatory care sensitive (ACSs) conditions, (3) hospital length of stay (LOS), and (4) Medicare expenditures. Propensity score matching methods were used to reduce observed differences between demented and non-demented groups at study enrollment. Analyses took into account repeated observations within each individual.
Results
Compared to propensity-matched individuals without dementia, individuals with dementia had significantly higher risk for all-cause hospitalization, longer LOS, and higher Medicare expenditures. Functional and cognitive deficits were significantly associated with higher risks for hospitalizations, hospital LOS, and Medicare expenditures. Functional and cognitive deficits were associated with higher risks of for some ACS but not all admissions.
Conclusions
These results allow us to differentiate the impact of functional and cognitive deficits on hospitalizations. To develop strategies to reduce hospitalizations and expenditures, better understanding of which types of hospitalizations and which disease characteristics impact these outcomes will be critical.
doi:10.1002/gps.4222
PMCID: PMC4414886  PMID: 25351909
dementia; hospitalization; healthcare expenditures; longitudinal follow-up
11.  Alcohol intake and brain structure in a multiethnic elderly cohort 
Background & Aims
Evidence suggests that consuming light-to-moderate amounts of alcohol reduces the risk of dementia and is associated better cognitive function and less cardiovascular disease, relative to those consuming no or heavy alcohol. There are only minimal data on the association between alcohol and brain magnetic resonance imaging (MRI) markers. This study aimed to examine the association between alcohol and brain structure measured with MRI.
Methods
In this cross-sectional study, high-resolution structural MRI was collected on 589 multi-ethnic community residents of New York aged ≥65 with available alcohol intake assessments via a food frequency questionnaire. Total brain volume (TBV), white matter hyperintensity volume (WMHV), and presence of infarcts were derived from MRI scans with established methods. We examined the association of alcohol intake with these imaging markers using regression models adjusted for demographic, clinical, and vascular risk factors.
Results
Compared to non-drinking, light-to-moderate total alcohol (b=0.007, p=0.04) or wine (b= 0.008, p=0.05) intake, but not beer or liquor intake, was associated with larger TBV. Further analysis showed a dose-response association between alcohol (p-trend=0.03) or wine (p-trend=0.006)) and TBV. Overall, alcohol intake was not associated with WMHV or brain infarcts.
Conclusions
Our study suggests that among older adults in the community, light-to-moderate alcohol intake, in particular wine, is associated with larger TBV. These findings suggest that light to moderate alcohol consumption is potentially beneficial for brain aging, but replication is needed.
doi:10.1016/j.clnu.2013.08.004
PMCID: PMC4048329  PMID: 24011900
Alcohol; nutrition; magnetic resonance imaging (MRI); brain atrophy; cerebrovascular disease; neuroepidemiology
12.  Brain Amyloid Deposition and Longitudinal Cognitive Decline in Nondemented Older Subjects: Results from a Multi-Ethnic Population 
PLoS ONE  2015;10(7):e0123743.
Objective
We aimed to whether the abnormally high amyloid-β (Aβ) level in the brain among apparently healthy elders is related with subtle cognitive deficits and/or accelerated cognitive decline.
Methods
A total of 116 dementia-free participants (mean age 84.5 years) of the Washington Heights Inwood Columbia Aging Project completed 18F-Florbetaben PET imaging. Positive or negative cerebral Aβ deposition was assessed visually. Quantitative cerebral Aβ burden was calculated as the standardized uptake value ratio in pre-established regions of interest using cerebellar cortex as the reference region. Cognition was determined using a neuropsychological battery and selected tests scores were combined into four composite scores (memory, language, executive/speed, and visuospatial) using exploratory factor analysis. We examined the relationship between cerebral Aβ level and longitudinal cognition change up to 20 years before the PET scan using latent growth curve models, controlling for age, education, ethnicity, and Apolipoprotein E (APOE) genotype.
Results
Positive reading of Aβ was found in 41 of 116 (35%) individuals. Cognitive scores at scan time was not related with Aβ. All cognitive scores declined over time. Aβ positive reading (B = -0.034, p = 0.02) and higher Aβ burden in temporal region (B = -0.080, p = 0.02) were associated with faster decline in executive/speed. Stratified analyses showed that higher Aβ deposition was associated with faster longitudinal declines in mean cognition, language, and executive/speed in African-Americans or in APOE ε4 carriers, and with faster memory decline in APOE ε4 carriers. The associations remained significant after excluding mild cognitive impairment participants.
Conclusions
High Aβ deposition in healthy elders was associated with decline in executive/speed in the decade before neuroimaging, and the association was observed primarily in African-Americans and APOE ε4 carriers. Our results suggest that measuring cerebral Aβ may give us important insights into the cognitive profile in the years prior to the scan in cognitively normal elders.
doi:10.1371/journal.pone.0123743
PMCID: PMC4519341  PMID: 26221954
13.  Daytime Sleepiness and Sleep Inadequacy as Risk Factors for Dementia 
Background/Aims
To examine the association between self-reported sleep problems and incidence of dementia in community-dwelling elderly people.
Methods
1,041 nondemented participants over 65 years old were examined longitudinally. Sleep problems were estimated using the RAND Medical Outcomes Study Sleep Scale examining sleep disturbance, snoring, sleep short of breath or with a headache, sleep adequacy, and sleep somnolence. Cox regression analysis was used to examine the association between sleep problems and risk for incident dementia. Age, gender, education, ethnicity, APOE-ε4, stroke, heart disease, hypertension, diabetes, and depression were included as covariates.
Results
Over 3 years of follow-up, 966 (92.8%) participants remained nondemented, while 78 (7.2%) developed dementia. In unadjusted models, sleep inadequacy (‘Get the amount of sleep you need’) at the initial visit was associated with increased risk of incident dementia (HR = 1.20; 95% CI 1.02-1.42; p = 0.027). Adjusting for all the covariates, increased risk of incident dementia was still associated with sleep inadequacy (HR = 1.20; 95% CI 1.01-1.42; p = 0.040), as well as with increased daytime sleepiness (‘Have trouble staying awake during the day’) (HR = 1.24; 95% CI 1.00-1.54; p = 0.047).
Conclusion
Our results suggest that sleep inadequacy and increased daytime sleepiness are risk factors for dementia in older adults, independent of demographic and clinical factors.
doi:10.1159/000431311
PMCID: PMC4521063  PMID: 26273244
Dementia; Daytime sleepiness; Sleep adequacy; Elderly; Longitudinal study
14.  Subjective Word-Finding Difficulty Reduces Engagement in Social Leisure Activities in Alzheimer’s Disease 
Objectives
To assess the influence of subjective word-finding difficulty on Alzheimer’s disease (AD) patients’ likelihood of engaging in social leisure activities.
Design
Analysis of data collected from the second cohort of the Multicenter Study of Predictors of Disease Course in Alzheimer’s disease.
Setting
Four study sites in the U.S. and France.
Participants
Individuals diagnosed with mild to moderate AD (N = 236)
Measurements
On separate questionnaires, patients were asked to 1) report whether had trouble finding the right word when speaking (subjective word-finding difficulty), and 2) rate their frequency and enjoyment of both social and nonsocial leisure activities. Objective language measures included object naming and verbal fluency. Measures of dependence, depression, cognitive status, age, sex, and education were also included as covariates in regression analyses.
Results
Over half (52%) of the sample reported word-finding difficulty, and subjective complaints were correlated with poorer verbal fluency scores. Subjective word-finding difficulty was uniquely related to social activity measures. Endorsers of word-finding difficulty reported reduced frequency and enjoyment of social leisure activities, controlling for covariates. In contrast, engagement in nonsocial activities was associated with higher age and depression scores, but was not related to word-finding complaints. These results were corroborated by the caregivers’ reports, and occurred above and beyond the effect of objective word-finding ability.
Conclusion
AD patients who are aware of increasing word-finding failures are less likely to participate in and enjoy socially-oriented leisure activities. This finding may have significant implications for clinical and health outcomes in AD. A failure to evaluate subjective language complaints could result in social withdrawal symptoms, thereby threatening the patient’s quality of life as well as increasing caregiver burden. Importantly, reduced social interaction may ultimately exacerbate language symptoms over time.
doi:10.1111/jgs.12850
PMCID: PMC4238963  PMID: 24890186
subjective language complaints; Alzheimer’s disease; leisure activities
15.  Making Cognitive Latent Variables Manifest: Distinct Neural Networks for Fluid Reasoning and Processing Speed 
Journal of cognitive neuroscience  2014;27(6):1249-1258.
Cognitive psychologists posit several specific cognitive abilities that are measured with sets of cognitive tasks. Tasks that purportedly tap a specific underlying cognitive ability are strongly correlated with one another, whereas performances on tasks that tap different cognitive abilities are less strongly correlated. For these reasons, latent variables are often considered optimal for describing individual differences in cognitive abilities. Although latent variables cannot be directly observed, all cognitive tasks representing a specific latent ability should have a common neural underpinning. Here, we show that cognitive tasks representing one ability (i.e., either perceptual speed or fluid reasoning) had a neural activation pattern distinct from that of tasks in the other ability. One hundred six participants between the ages of 20 and 77 years were imaged in an fMRI scanner while performing six cognitive tasks, three representing each cognitive ability. Consistent with prior research, behavioral performance on these six tasks clustered into the two abilities based on their patterns of individual differences and tasks postulated to represent one ability showed higher similarity across individuals than tasks postulated to represent a different ability. This finding was extended in the current report to the spatial resemblance of the task-related activation patterns: The topographic similarity of the mean activation maps for tasks postulated to reflect the same reference ability was higher than for tasks postulated to reflect a different reference ability. Furthermore, for any task pairing, behavioral and topographic similarities of underlying activation patterns are strongly linked. These findings suggest that differences in the strengths of correlations between various cognitive tasks may be because of the degree of overlap in the neural structures that are active when the tasks are being performed. Thus, the latent variable postulated to account for correlations at a behavioral level may reflect topographic similarities in the neural activation across different brain regions.
doi:10.1162/jocn_a_00778
PMCID: PMC4416986  PMID: 25539045
16.  Functional Status in the Young–Old: Establishing a Working Prototype of an Extended-Instrumental Activities of Daily Living Scale 
Background.
Instrumental activities of daily living (IADLs) exhibit strong predictive power for the presence of dementia and mild cognitive impairment. However, IADLs are often less effective in younger cohorts or in healthy community-dwelling samples, presenting with large ceiling effects. This study aimed to construct an IADL scale with an extended range. An effort was made to incorporate leisure activity tasks that were more stimulating, and potentially more challenging, into a set of traditional IADLs.
Methods.
Beginning with a set of IADL and leisure activity items, nonparametric item response theory methodology was used to construct a scale with appropriate dimensionality, monotonicity, item discrimination power, and scalability within a large cohort of young–old (aged 65–75). Dimensionality was further scrutinized by principal component analysis of the residuals. The predictive validity of the resulting scale for poor cognitive performance was evaluated using logistic regression.
Results.
A reliable (ρ = .73) unidimensional construct was established, meeting the Mokken item response theory criteria of medium scalability. Excluding demented participants, the adjusted model proved sensitive to relatively subtle cognitive deficits; each additional task endorsed (nine-item scale) significantly decreased the odds of being in the bottom quarter of composite domains relating to processing speed (odds ratio = 0.73 [confidence interval: 0.56–0.97], p < .05) and visuospatial ability (odds ratio = 0.70 [confidence interval: 0.73–0.87], p < .01).
Conclusions.
A reliable extended-IADL scale was constructed meeting item response theory assumptions relating to unidimensionality, monotonicity, and invariant item ordering. The range of measurement extends well beyond traditional IADL scales. Finally, the scale appears to be sensitive to cognitive differences within the normal spectrum.
doi:10.1093/gerona/glt167
PMCID: PMC4049145  PMID: 24149431
Cognitive aging; Functional performance; Successful aging.
17.  Examining the association between late-life depressive symptoms, cognitive function, and brain volumes in the context of cognitive reserve 
Objective
The present study aimed to investigate whether cognitive reserve moderated the association between depressive symptoms and cognition, as well as brain volumes in a sample of older adults.
Methods
Non-demented participants (n = 3484) were selected from the Washington Heights/Hamilton Heights Inwood Columbia Aging Project (Northern Manhattan). A subsample of these participants without dementia (n = 703), who had brain imaging data, was also selected for a separate analysis. Depressive symptomatology was assessed with the 10-item Center for Epidemiologic Studies Depression Scale. Reading level and years of education were used as measures of cognitive reserve. Four distinct cognitive composite scores were calculated: executive function, memory, visual–spatial, and language.
Results
Multiple regression analysis revealed interaction effects between both measures of cognitive reserve and depressive symptoms on all the cognitive outcome measures except for visual–spatial ability. Those with greater reserve showed greater cognitive decrements than those with lower levels of reserve as depressive symptoms increased. A borderline interaction effect was revealed between reading level and depressive symptoms on total brain volumes. Those with lower reading scores showed greater volume loss as depressive symptoms increased than those with higher reading scores.
Conclusions
Our findings indicate that the association between late-life depressive symptoms and core aspects of cognition varies depending on one’s level of cognitive reserve. Those that had greater levels of education and/or reading ability showed a greater decrease in memory, executive, and language performances as depressive symptoms increased than those with lower years of education and reading ability.
doi:10.1002/gps.4192
PMCID: PMC4336836  PMID: 25145832
late life depressive symptoms; cognitive performance; cognitive reserve; brain volumes
18.  Functional network mediates age-related differences in reaction time: a replication and extension study 
Brain and Behavior  2015;5(5):e00324.
Introduction
A functional activation (i.e., ordinal trend) pattern was previously identified in both young and older adults during task-switching performance, the expression of which correlated with reaction time. The current study aimed to (1) replicate this functional activation pattern in a new group of fMRI activation data, and (2) extend the previous study by specifically examining whether the effect of aging on reaction time can be explained by differences in the activation of the functional activation pattern.
Method
A total of 47 young and 50 older participants were included in the extension analysis. Participants performed task-switching as the activation task and were cued by the color of the stimulus for the task to be performed in each block. To test for replication, two approaches were implemented. The first approach tested the replicability of the predictive power of the previously identified functional activation pattern by forward applying the pattern to the Study II data and the second approach was rederivation of the activation pattern in the Study II data.
Results
Both approaches showed successful replication in the new data set. Using mediation analysis, expression of the pattern from the first approach was found to partially mediate age-related effects on reaction time such that older age was associated with greater activation of the brain pattern and longer reaction time, suggesting that brain activation efficiency (defined as “the rate of activation increase with increasing task difficulty” in Neuropsychologia 47, 2009, 2015) of the regions in the Ordinal trend pattern directly accounts for age-related differences in task performance.
Discussion
The successful replication of the functional activation pattern demonstrates the versatility of the Ordinal Trend Canonical Variates Analysis, and the ability to summarize each participant's brain activation map into one number provides a useful metric in multimodal analysis as well as cross-study comparisons.
doi:10.1002/brb3.324
PMCID: PMC4389056  PMID: 25874162
Aging; functional magnetic resonance imaging; mediation; ordinal trend covariance analysis; study replication; task-switching
19.  Estimation and Validation of a Multi-Attribute Model of Alzheimer's Disease Progression 
Objectives
To estimate and validate a multi-attribute model of the clinical course of Alzheimer's Disease (AD) from mild AD to death in a high-quality prospective cohort study; to estimate the impact of hypothetical modifications to AD progression rates on costs associated with Medicare and Medicaid services.
Data and Methods
We estimated sex-specific longitudinal Grade of Membership (GoM) models for AD patients (103 males; 149 females) in the initial cohort of the Predictors Study (1989–2001) based on 80 individual measures obtained every six months for 10 years. We replicated these models for AD patients (106 males; 148 females) in the second Predictors Study cohort (1997–2007). Model validation required that the disease-specific transition parameters be identical for both Predictors Study cohorts. Medicare costs were estimated from the National Long Term Care Survey.
Results
Sex-specific models were validated using the second Predictors Study cohort with the GoM transition parameters constrained to the values estimated for the first Predictors Study cohort; 57–61 of the 80 individual measures contributed significantly to the GoM models. Simulated, cost-free interventions in the rate of progression of AD indicated that large potential cost offsets could occur for patients at the earliest stages of AD.
Conclusions
AD progression is characterized by a small number of parameters governing changes in large numbers of correlated indicators of AD severity. The analysis confirmed that the progression of AD represents a complex multidimensional physiological process that is similar across different study cohorts. The estimates suggested that there could be large cost offsets to Medicare and Medicaid from the slowing of AD progression among patients with mild AD. The methodology appears generally applicable in AD modeling.
doi:10.1177/0272989X10363479
PMCID: PMC4392765  PMID: 21183754
Clinical assessment; outcomes; staging of dementia
20.  Modeling Metabolic Syndrome and Its Association with Cognition: The Northern Manhattan Study 
Metabolic syndrome (MetS) is a clustering of vascular risk factors and is associated with increased risk of cardiovascular disease. Less is known about the relationship between MetS and cognition. We examined component vascular risk factors of MetS as correlates of different cognitive domains. The Northern Manhattan Study (NOMAS) includes 1290 stroke-free participants from a largely Hispanic multi-ethnic urban community. We used structural equation modeling (SEM) to model latent variables of MetS, assessed at baseline and an average of 10 years later, at which time participants also underwent a full cognitive battery. The two four-factor models, of the metabolic syndrome (blood pressure, lipid levels, obesity, and fasting glucose) and of cognition (language, executive function, psychomotor, and memory), were each well supported (CFI = 0.97 and CFI = 0.95, respectively). When the two models were combined, the correlation between metabolic syndrome and cognition was −.31. Among the metabolic syndrome components, only blood pressure uniquely predicted all four cognitive domains. After adjusting for age, gender, race/ethnicity, education, smoking, alcohol, and risk factor treatment variables, blood pressure remained a significant correlate of all domains except memory. In this stroke-free race/ethnically diverse community-based cohort, MetS was associated with cognitive function suggesting that MetS and its components may be important predictors of cognitive outcomes. After adjusting for sociodemographic and vascular risk factors, blood pressure was the strongest correlate of cognitive performance. Findings suggest MetS, and in particular blood pressure, may represent markers of vascular or neurodegenerative damage in aging populations.
doi:10.1017/S1355617714000861
PMCID: PMC4380272  PMID: 25382144
Cognition; Dementia; Hypertension; Aging; Metabolic syndrome; Cardiovascular; Vascular markers
21.  Functional network mediates age‐related differences in reaction time: a replication and extension study 
Brain and Behavior  2015;e00324.
Abstract
Introduction
A functional activation (i.e., ordinal trend) pattern was previously identified in both young and older adults during task‐switching performance, the expression of which correlated with reaction time. The current study aimed to (1) replicate this functional activation pattern in a new group of fMRI activation data, and (2) extend the previous study by specifically examining whether the effect of aging on reaction time can be explained by differences in the activation of the functional activation pattern.
Method
A total of 47 young and 50 older participants were included in the extension analysis. Participants performed task‐switching as the activation task and were cued by the color of the stimulus for the task to be performed in each block. To test for replication, two approaches were implemented. The first approach tested the replicability of the predictive power of the previously identified functional activation pattern by forward applying the pattern to the Study II data and the second approach was rederivation of the activation pattern in the Study II data.
Results
Both approaches showed successful replication in the new data set. Using mediation analysis, expression of the pattern from the first approach was found to partially mediate age‐related effects on reaction time such that older age was associated with greater activation of the brain pattern and longer reaction time, suggesting that brain activation efficiency (defined as “the rate of activation increase with increasing task difficulty” in Neuropsychologia 47, 2009, 2015) of the regions in the Ordinal trend pattern directly accounts for age‐related differences in task performance.
Discussion
The successful replication of the functional activation pattern demonstrates the versatility of the Ordinal Trend Canonical Variates Analysis, and the ability to summarize each participant's brain activation map into one number provides a useful metric in multimodal analysis as well as cross‐study comparisons.
doi:10.1002/brb3.324
PMCID: PMC4389056  PMID: 25874162
Aging; functional magnetic resonance imaging; mediation; ordinal trend covariance analysis; study replication; task‐switching
22.  Cerebral Blood Flow and Gray Matter Volume Covariance Patterns of Cognition in Aging 
Human brain mapping  2012;34(12):10.1002/hbm.22142.
Advancing age results in altered cognitive and neuroimaging-derived markers of neural integrity. Whether cognitive changes are the result of variations in brain measures remains unclear and relating the two across the lifespan poses a unique set of problems. It must be determined whether statistical associations between cognitive and brain measures truly exist and are not epiphenomenal due solely to their shared relationships with age. The purpose of this study was to determine whether cerebral blood flow (CBF) and gray matter volume (GMV) measures make unique and better predictions of cognition than age alone. Multivariate analyses identified brain-wide covariance patterns from 35 healthy young and 23 healthy older adults using MRI-derived measures of CBF and GMV related to three cognitive composite scores (i.e., memory, fluid ability, and speed/attention). These brain-cognitive relationships were consistent across the age range, and not the result of epiphenomenal associations with age and each imaging modality provided its own unique information. The CBF and GMV patterns each accounted for unique aspects of cognition and accounted for nearly all the age-related variance in the cognitive composite scores. The findings suggest that measures derived from multiple imaging modalities explain larger amounts of variance in cognition providing a more complete understanding of the aging brain.
doi:10.1002/hbm.22142
PMCID: PMC3812339  PMID: 22806997
aging; multiple modality imaging; cognitive decline; cerebral blood flow; gray matter volume; multivariate analysis
24.  Promising developments in neuropsychological approaches for the detection of preclinical Alzheimer’s disease: a selective review 
Recently published guidelines suggest that the most opportune time to treat individuals with Alzheimer’s disease is during the preclinical phase of the disease. This is a phase when individuals are defined as clinically normal but exhibit evidence of amyloidosis, neurodegeneration and subtle cognitive/behavioral decline. While our standard cognitive tests are useful for detecting cognitive decline at the stage of mild cognitive impairment, they were not designed for detecting the subtle cognitive variations associated with this biomarker stage of preclinical Alzheimer’s disease. However, neuropsychologists are attempting to meet this challenge by designing newer cognitive measures and questionnaires derived from translational efforts in neuroimaging, cognitive neuroscience and clinical/experimental neuropsychology. This review is a selective summary of several novel, potentially promising, approaches that are being explored for detecting early cognitive evidence of preclinical Alzheimer’s disease in presymptomatic individuals.
doi:10.1186/alzrt222
PMCID: PMC3978443  PMID: 24257331
25.  THE HETEROGENEOUS COURSE OF DEPRESSIVE SYMPTOMS FOR THE DEMENTIA CAREGIVER 
Caregiving may be burdensome to caregivers, negatively affecting health and impacting decisions to institutionalize patients. It is unclear how caregiver depression changes over longer periods or whether heterogeneous trajectories for caregivers are apparent. The goals of this article are to characterize the course of depressive symptoms among caregivers over time and to examine the impact of baseline patient and caregiver characteristics on these trajectories. Patients with dementia and their caregivers were followed every 6 months for up to 6 years or until death (n = 133). Growth mixture modeling identified trajectories of caregiver depression over time. Most caregivers had stable trajectories of symptoms, with a smaller subset showing evidence of wear-and-tear. Patient clinical characteristics had no impact on symptom course for caregivers. Future work should utilize a longitudinal perspective and consider that there may be heterogeneous trajectories for caregivers. Those caregivers who follow a wear-and-tear trajectory may require targeted interventions to improve outcomes.
PMCID: PMC4240506  PMID: 24956922

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