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1.  Use and cost of hospitalization in dementia: longitudinal results from a community-based study 
The aim of this study is to examine the relative contribution of functional impairment and cognitive deficits on risk of hospitalization and costs.
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.
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.
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.
PMCID: PMC4414886  PMID: 25351909
dementia; hospitalization; healthcare expenditures; longitudinal follow-up
2.  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.
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.
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.
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.
PMCID: PMC4048329  PMID: 24011900
Alcohol; nutrition; magnetic resonance imaging (MRI); brain atrophy; cerebrovascular disease; neuroepidemiology
3.  Brain Amyloid Deposition and Longitudinal Cognitive Decline in Nondemented Older Subjects: Results from a Multi-Ethnic Population 
PLoS ONE  2015;10(7):e0123743.
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.
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.
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.
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.
PMCID: PMC4519341  PMID: 26221954
4.  Subjective Word-Finding Difficulty Reduces Engagement in Social Leisure Activities in Alzheimer’s Disease 
To assess the influence of subjective word-finding difficulty on Alzheimer’s disease (AD) patients’ likelihood of engaging in social leisure activities.
Analysis of data collected from the second cohort of the Multicenter Study of Predictors of Disease Course in Alzheimer’s disease.
Four study sites in the U.S. and France.
Individuals diagnosed with mild to moderate AD (N = 236)
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.
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.
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.
PMCID: PMC4238963  PMID: 24890186
subjective language complaints; Alzheimer’s disease; leisure activities
5.  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.
PMCID: PMC4416986  PMID: 25539045
6.  Functional Status in the Young–Old: Establishing a Working Prototype of an Extended-Instrumental Activities of Daily Living Scale 
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.
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.
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).
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.
PMCID: PMC4049145  PMID: 24149431
Cognitive aging; Functional performance; Successful aging.
7.  Examining the association between late-life depressive symptoms, cognitive function, and brain volumes in the context of cognitive reserve 
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.
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.
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.
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.
PMCID: PMC4336836  PMID: 25145832
late life depressive symptoms; cognitive performance; cognitive reserve; brain volumes
8.  Functional network mediates age-related differences in reaction time: a replication and extension study 
Brain and Behavior  2015;5(5):e00324.
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.
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.
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.
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.
PMCID: PMC4389056  PMID: 25874162
Aging; functional magnetic resonance imaging; mediation; ordinal trend covariance analysis; study replication; task-switching
9.  Estimation and Validation of a Multi-Attribute Model of Alzheimer's Disease Progression 
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.
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.
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.
PMCID: PMC4392765  PMID: 21183754
Clinical assessment; outcomes; staging of dementia
10.  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.
PMCID: PMC4380272  PMID: 25382144
Cognition; Dementia; Hypertension; Aging; Metabolic syndrome; Cardiovascular; Vascular markers
11.  Functional network mediates age‐related differences in reaction time: a replication and extension study 
Brain and Behavior  2015;e00324.
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.
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.
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.
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.
PMCID: PMC4389056  PMID: 25874162
Aging; functional magnetic resonance imaging; mediation; ordinal trend covariance analysis; study replication; task‐switching
12.  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.
PMCID: PMC3812339  PMID: 22806997
aging; multiple modality imaging; cognitive decline; cerebral blood flow; gray matter volume; multivariate analysis
14.  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.
PMCID: PMC3978443  PMID: 24257331
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
16.  Long term associations between cholinesterase inhibitors and memantine use and health outcomes among patients with Alzheimer’s disease 
Randomized-controlled trials that examine the effects of Cholinesterase inhibitors (ChEI) and memantine on patient outcomes over long periods of time are difficult to conduct. Observational studies based on practice-based populations outside the context of controlled trials and open label extension studies that evaluate the effects of these medications over time are limited.
To examine in an observational study (1) relationships between ChEI and memantine use and functional and cognitive endpoints and mortality in AD patients, (2) relationships between other patient characteristics on these clinical endpoints, and (3) whether effects of the predictors change across time.
Multicenter, natural history study.
Three university-based AD centers in the US.
201 patients diagnosed with probable AD with modified Mini-Mental State Examination scores of 30 or higher at study entry followed annually for 6 years.
Discrete-time hazard analyses were used to examine relationships between ChEI and memantine use during the previous 6 months reported at each assessment and time to cognitive (Mini-Mental State Examination, MMSE≤10) and functional (Blessed Dementia Rating Scale, BDRS≥10) endpoints and mortality. Analyses controlled for clinical characteristics including baseline cognition, function, and comorbid conditions, and presence of extrapyramidal signs and psychiatric symptoms at each assessment interval. Demographic characteristics included baseline age, sex, education, and living arrangement at each assessment interval.
ChEI use was associated with delayed time in reaching functional endpoint and death. Memantine use was associated with delayed time to death. Different patient characteristics were associated with different clinical endpoints
Results suggest long term beneficial effects of ChEI and memantine on patient outcomes. As for all observational cohort study, observed relationships should not be interpreted as causal effects.
PMCID: PMC3633652  PMID: 23332671
Alzheimer’s disease; cholinesterase inhibitors; memantine; outcomes; longitudinal studies
17.  Change in body mass index before and after Alzheimer's disease onset 
Current Alzheimer research  2014;11(4):349-356.
A high body mass index (BMI) in middle-age or a decrease in BMI at late-age has been considered a predictor for the development of Alzheimer's disease (AD). However, little is known about the BMI change close to or after AD onset.
BMI of participants from three cohorts, the Washington Heights and Inwood Columbia Aging Project (WHICAP; population-based) and the Predictors Study (clinic-based), and National Alzheimer's Coordinating Center (NACC; clinic-based) were analyzed longitudinally. We used generalized estimating equations to test whether there were significant changes of BMI over time, adjusting for age, sex, education, race, and research center. Stratification analyses were run to determine whether BMI changes depended on baseline BMI status.
BMI declined over time up to AD clinical onset, with an annual decrease of 0.21 (p=0.02) in WHICAP and 0.18 (p=0.04) kg/m2 in NACC. After clinical onset of AD, there was no significant decrease of BMI. BMI even increased (b=0.11, p=0.004) among prevalent AD participants in NACC. During the prodromal period, BMI decreased over time in overweight(BMI ≥25 and <30) WHICAP participants or obese (BMI≥30) NACC participants. After AD onset, BMI tended to increase in underweight/normal weight (BMI<25) patients and decrease in obese patients in all three cohorts, although the results were significant in NACC study only.
Our study suggests that while BMI declines before the clinical AD onset, it levels off after clinical AD onset, and might even increase in prevalent AD. The pattern of BMI change may also depend on the initial BMI.
PMCID: PMC4026350  PMID: 24251397
Body mass index; weight; Alzheimer's disease; prospective study
18.  Efficiency, capacity, compensation, maintenance, plasticity: emerging concepts in cognitive reserve 
Trends in cognitive sciences  2013;17(10):10.1016/j.tics.2013.08.012.
Cognitive reserve (CR) is a concept meant to account for the frequent discrepancy between an individual’s measured level of brain pathology and her expected cognitive performance. It is particularly important within the context of aging and dementia, but has wider applicability to all forms of brain damage. As such, it has intimate links to related compensatory and neuroprotective concepts, as well as to the related notion of brain reserve. In this article, we introduce the concept of cognitive reserve and explicate its potential cognitive neural implementation. We conclude that cognitive reserve is compatible and complementary with many related concepts, but that each much draw sharper conceptual boundaries in order to truly explain preserved cognitive function in the face of aging or brain damage.
PMCID: PMC3840716  PMID: 24018144
cognitive reserve; aging; Alzheimer’s disease; imaging; epidemiology
19.  The hypercorrection effect in younger and older adults 
The hypercorrection effect, which refers to the finding that errors committed with high confidence are more likely to be corrected than are low confidence errors, has been replicated many times, and with both young adults and children. In the present study, we contrasted older with younger adults. Participants answered general-information questions, made confidence ratings about their answers, were given corrective feedback, and then were retested on questions that they had gotten wrong. While younger adults showed the hypercorrection effect, older adults, despite higher overall accuracy on the general-information questions and excellent basic metacognitive ability, showed a diminished hypercorrection effect. Indeed, the correspondence between their confidence in their errors and the probability of correction was not significantly greater than zero, showing, for the first time, that a particular participant population is selectively impaired on this error-correction task. These results potentially offer leverage both on the mechanisms underlying the hypercorrection effect and on reasons for older adults' memory impairments, as well as on memory functions that are spared.
PMCID: PMC3604148  PMID: 23241028
Hypercorrection; Memory; Confidence; Older Adults; Error Correction
20.  Quantifying Cognitive Reserve in Older Adults by Decomposing Episodic Memory Variance: Replication and Extension 
The theory of cognitive reserve attempts to explain why some individuals are more resilient to age-related brain pathology. Efforts to explore reserve have been hindered by measurement difficulties. Reed et al. (2010) proposed quantifying reserve as residual variance in episodic memory performance that remains after accounting for demographic factors and brain pathology (whole brain, hippocampal, and white matter hyperintensity volumes). This residual variance represents the discrepancy between an individual’s predicted and actual memory performance. The goals of the present study were to extend these methods to a larger, community-based sample and to investigate whether the residual reserve variable is explained by age, predicts longitudinal changes in language, and predicts dementia conversion independent of age. Results support this operational measure of reserve. The residual reserve variable was associated with higher reading ability, lower likelihood of meeting criteria for mild cognitive impairment, lower odds of dementia conversion independent of age, and less decline in language abilities over 3 years. Finally, the residual reserve variable moderated the negative impact of memory variance explained by brain pathology on language decline. This method has the potential to facilitate research on the mechanisms of cognitive reserve and the efficacy of interventions designed to impart reserve.
PMCID: PMC3777696  PMID: 23866160
Cognition; Aging; Mild cognitive impairment; Dementia; Statistical models; Magnetic resonance imaging
21.  Lessons from Epidemiologic Research about Risk Factors, Modifiers, and Progression of Late Onset Alzheimer’s Disease in New York City at Columbia University Medical Center 
Journal of Alzheimer's disease : JAD  2013;33(0 1):S447-S455.
This review summarizes the findings and importance of 12 articles from research at Columbia University in New York City that were among the most cited in the literature between 2006 and 2011. The 12 articles summarized in this review made important contributions to the field of Alzheimer’s disease in the last 5 years. Four of the articles established the Mediterranean diet as a food consumption pattern that may prevent Alzheimer’s disease in addition to physical activity. Two of the articles advanced our knowledge of predictors of conversion from mild cognitive impairment to dementia. Four of the articles provided important knowledge of risk factors for the progression of Alzheimer’s disease and its complications. Lastly, one of the articles laid the theoretical framework for the study of cognitive reserve, an important modifier of the manifestation of Alzheimer’s disease. These studies have advanced our knowledge about risk factors, modifiers, and progression of late onset Alzheimer’s disease.
PMCID: PMC4149254  PMID: 22836187
Alzheimer’s disease; conversion; diet; cognitive reserve; epidemiology; genes; mild cognitive impairment; predictors; progression; risk factors
22.  Cognitive Reserve: Implications for Assessment and Intervention 
The concept of reserve is used to explain the observation that some individuals function better than others in the presence of brain pathology. This paper reviews the concept of reserve from its theoretical basis to the implication of reserve for clinical practice. A distinction between brain reserve, referring to individual differences in the anatomic substrate, and cognitive reserve, referring to differences in the flexibility or adaptivity of cognitive networks, is useful. Epidemiologic evidence indicates that a set of life exposures including higher educational and occupational attainment, and engaging in leisure activities is associated with a lower risk of incident dementia, suggesting that these life exposures may enhance cognitive reserve. This provides a basis for controlled clinical studies can test specific exposures that may enhance reserve. The concept of cognitive reserve also has important implications for clinical practice in terms of diagnosis and prognosis.
PMCID: PMC3970779  PMID: 23941972
23.  Depressive Symptoms Precede Memory Decline, but Not Vice Versa, in Non-Demented Older Adults 
Numerous studies support an association between depression and increased risk of dementia. Because few studies have directly examined the temporal ordering of depression and memory decline in late life, it is not clear whether depressive symptoms typically precede and/or follow memory declines.
An autoregressive latent trajectory model examined the direction of the relationship between depressive symptoms and memory decline observed over 12 years.
Washington/Hamilton Heights Inwood Columbia Aging Project, a community-based longitudinal study of aging and dementia in Northern Manhattan.
2,425 initially non-demented older adults.
Memory composite scores were computed from three subscores of the Selective Reminding Test. Depressive symptoms were assessed with a 10-item version of the Center for Epidemiological Studies Depression Scale. Analyses controlled for age, sex, recruitment wave, education, Black race and Hispanic ethnicity measured at baseline, and chronic disease burden measured at each study visit.
Initial depressive symptoms predicted worse memory scores at the second study visit (B weight=−0.03; P=.003) as well as accelerated memory decline over the entire study period (B weight=−0.02; P=.03). Memory scores did not predict subsequent depressive symptoms.
These findings suggest that depressive symptoms precede memory decline, but not vice versa, in late life. This pattern of results is in line with hypotheses that depression is a prodrome of dementia and/or a causal contributor to memory decline. Clinicians should be aware that depressive symptoms may represent an early indicator not only of dementia, as reported previously, but also of memory decline more generally.
PMCID: PMC4123225  PMID: 25093232
Depression; episodic memory; statistical modeling
24.  Epidemiology of Alzheimer Disease 
The global prevalence of dementia has been estimated to be as high as 24 million, and is predicted to double every 20 years until at least 2040. As the population worldwide continues to age, the number of individuals at risk will also increase, particularly among the very old. Alzheimer disease is the leading cause of dementia beginning with impaired memory. The neuropathological hallmarks of Alzheimer disease include diffuse and neuritic extracellular amyloid plaques in brain that are frequently surrounded by dystrophic neurites and intraneuronal neurofibrillary tangles. The etiology of Alzheimer disease remains unclear, but it is likely to be the result of both genetic and environmental factors. In this review we discuss the prevalence and incidence rates, the established environmental risk factors, and the protective factors, and briefly review genetic variants predisposing to disease.
Alzheimer disease is the most frequent cause of dementia in Western societies. Advancing age and genetic and nongenetic antecedent factors (e.g., education and obesity) are thought to play important roles.
PMCID: PMC3405821  PMID: 22908189
25.  Metabolic syndrome and localization of white matter hyperintensities in the elderly population 
Metabolic syndrome (MetS) is defined as a clustering of metabolic disorders: abdominal obesity, dyslipidemia, hypertension, and hyperglycemia. Although specific components of MetS have been associated with white matter hyperintensities (WMH), less is known about the association between MetS as a whole and WMH, especially in normal aging. We aimed to: (1) investigate this association in a cohort of healthy elderly individuals, and (2) examine the relationship between MetS and the regional distribution of WMH, to further understanding of the relationship between MetS and structural brain changes.
Analyses were carried out on 308 participants (48.1% men, age: 71.0 ± 3.9 years) from the French longitudinal ESPRIT (Enquête de Santé Psychologique - Risques, Incidence et Traitement) study, who were free of cerebrovascular disease cognitive and functional impairment. Logistic regression models were used to examine the cross-sectional association between MetS (defined using the National Cholesterol Education Program–Adult Treatment Panel III criteria) and (1) WMH volumes, and (2) WMH volumes according to their localization in insulofrontal and temporoparietal regions.
After adjusting for potential confounders, participants with MetS had a twofold increased chance of presenting with high levels of WMH volume compared with those without (odds ratio [OR] = 2.74, 95% confidence interval [CI]: 1.25–6.03). MetS was specifically associated with an increase of temporoparietal WMH volumes, but no association was found between MetS and WMH localized in the insulofrontal region.
Our findings suggest that effective management of MetS may reduce WMH accumulation in brain areas already vulnerable to the aging process.
PMCID: PMC4108160  PMID: 22682962
Epidemiology; Observational study; Elderly; Metabolic syndrome; White matter hyperintensities; Alzheimer’s disease

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