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1.  Adverse Vascular Risk is Related to Cognitive Decline in Older Adults 
Journal of Alzheimer's disease : JAD  2015;44(4):1361-1373.
Cardiovascular disease (CVD) and related risk factors are associated with Alzheimer’s disease (AD). This association is less well-defined in normal cognition (NC) or prodromal AD (mild cognitive impairment (MCI)).
Cross-sectionally and longitudinally relate a vascular risk index to cognitive outcomes among elders free of clinical dementia.
3117 MCI (74±8 years, 56% female) and 6603 NC participants (72±8 years, 68% female) were drawn from the National Alzheimer’s Coordinating Center. A composite measure of vascular risk was defined using the Framingham Stroke Risk Profile (FSRP) score (i.e., age, systolic blood pressure, anti-hypertensive medication, diabetes, cigarette smoking, CVD history, atrial fibrillation). Ordinary linear regressions and generalized linear mixed models related baseline FSRP to cross-sectional and longitudinal cognitive outcomes, separately for NC and MCI, adjusting for age, sex, race, education, and follow-up time (in longitudinal models).
In NC participants, increasing FSRP was related to worse baseline global cognition, information processing speed, and sequencing abilities (p-values<0.0001) and a worse longitudinal trajectory on all cognitive measures (p-values<0.0001). In MCI, increasing FSRP correlated with worse longitudinal delayed memory (p=0.004). In secondary models using an age-excluded FSRP score, associations persisted in NC participants for global cognition, naming, information processing speed, and sequencing abilities.
An adverse vascular risk profile is associated with worse cognitive trajectory, especially global cognition, naming, and information processing speed, among NC elders. Future studies are needed to understand how effective management of CVD and related risk factors can modify cognitive decline to identify the ideal timeframe for primary prevention implementation.
PMCID: PMC4336578  PMID: 25471188
Blood pressure; diabetes mellitus; smoking; Framingham Stroke Risk Profile; stroke
2.  Inclusion of an informant yields strong associations between cognitive complaint and longitudinal cognitive outcomes in non-demented elders 
The relation between the source of cognitive complaint and objective cognitive performance is not well understood.
Examine self and informant cognitive complaint as predictors of objective cognitive and functional trajectory in non-demented elders.
Participants from the National Alzheimer’s Coordinating Center had a baseline diagnosis of normal cognition (NC; n=6133, 72±8 years, 68% female) or mild cognitive impairment (MCI; n=3010, 74±8 years, 55% female). Four independent groups defined cognitive complaint: no complaint, self-only complaint, informant-only complaint, or mutual complaint (both self and informant complaint). Linear mixed model regression analyses related complaint status (referent was no complaint) to cognitive and functional trajectories, adjusting for age, sex, race, education, and follow-up period.
Among NC participants, mutual complaint related to faster decline in global cognition (p<0.0001), language (all p-values<0.0001), processing speed (p=0.0002), and executive functioning (p=0.0006). Informant-only complaint related to faster decline in global cognition (p=0.0001) and processing speed (p=0.0001). Self-only complaint related to greater decline in immediate (p<0.0001) and delayed (p=0.0005) episodic memory. In MCI, mutual complaint related to faster decline in global cognition (p<0.0001), verbal episodic memory (all p-values<0.0001), language (all p-values<0.0001), and processing speed (all p-values<0.0006). Informant-only or self-only complaint associations with cognitive trajectory did not survive correction factor for multiple comparisons.
Cognitive complaint appears to have clinical significance, as it is related to declines in objective cognitive performance over time. Mutual complaint was associated with the worst cognitive trajectory in both NC and MCI elders, highlighting the importance of incorporating an informant into evaluation of elders whenever feasible.
PMCID: PMC4314962  PMID: 25061054
mild cognitive impairment; cognitive complaint; dementia; cognition; Alzheimer’s disease
3.  An Intervention to Enhance Alzheimer’s Disease Clinical Research Participation among Older African Americans 
Alzheimer’s disease (AD) rates are higher among African Americans than in other racial or ethnic groups. However, Black elders participate in research at lower rates than Whites.
The present study aimed to: (1) implement an informational protocol for African Americans elders and their loved ones about the benefits of clinical research and brain donation program participation in AD, and (2) quantitatively assess changes in knowledge, attitudes, and trust.
Participants included 52 African American participants from the Boston University Alzheimer’s Disease Center research registry (74 ± 8 years, 83% female) and 11 loved ones. Registry participants completed a pre- and post-group survey assessing brain donation knowledge, factors influencing brain donation, attitudes about medical research, and trust in medical researchers.
There were no significant changes in mean scores between the pre- and post-group surveys. However, post-group outcomes revealed that 69% of participants shared details from the protocol with loved ones, 27% expressed an interest in joining Center-sponsored studies, and 10% indicated an interest in changing their brain donation status.
The informational protocol implemented in this study is an effective method to encourage family discussions about brain donation and increase interest in other AD research studies. Longitudinal follow-up is necessary to assess the long-term implications of these groups on participation in a brain donation program.
PMCID: PMC4180494  PMID: 23648514
Black populations; brain autopsy; cognitive impairment; research enthusiasm
4.  Lower Cardiac Output Is Associated with Greater White Matter Hyperintensities in Older Adults with Cardiovascular Disease 
To preliminarily examine the association between cardiac output, a measure of systemic blood flow, and structural brain magnetic resonance imaging indices of white matter hyperintensities (WMHs).
University medical setting.
Thirty-six older adults without dementia with prevalent cardiovascular disease (aged 56–85).
Cardiac output, WMHs.
Partial correlations, adjusting for age and history of hypertension, yielded an inverse relationship between WMHs adjacent to subcortical nuclei and cardiac output (correlation coefficient = −0.48, P = .03); as cardiac output decreased, WMHs increased significantly. No significant associations were found between cardiac output and total WMHs or periventricular WMHs.
These preliminary data suggest that systemic blood flow, measured according to cardiac output, is inversely associated with WMHs adjacent to the subcortical nuclei. Cerebrovascular degeneration and the chronicity of hypoperfusion may exacerbate the susceptibility of white matter integrity to alterations in blood flow in older adults.
PMCID: PMC2721459  PMID: 17608877
systemic perfusion; aging; cardiovascular disease; MRI
5.  The source of cognitive complaints differentially predicts diagnostic conversion in non-demented older adults 
The objective of this study was to compare whether different sources of cognitive complaint (i.e., subjective and informant) predict diagnostic conversion in nondemented older adults.
Participants from the National Alzheimer’s Coordinating Center had a baseline diagnosis of normal cognition (NC; n=4414, 73±8 years, 69% female) or mild cognitive impairment (MCI; n=1843, 74±8 years, 52% female). Multinomial logistic regression related baseline cognitive complaint (no-complaint, self only, informant only, or both self-and informant) to diagnostic outcome (reversion, stable or conversion).
At follow-up, 14% of NC participants converted to MCI/dementia (3.5±1.8 years), and 41% of MCI participants converted to dementia (3.0±1.6 years). Among NC participants, self-complaint only (OR=2.1; 99%CI=1.5–2.9, p<0.001), informant-complaint only (OR=2.2; 99%CI=1.2–3.9, p<0.001), and both self-and informant-complaint (OR=4.2; 99%CI=2.9–6.0, p<0.001) were associated with diagnostic conversion, compared to no-complaint. Among participants with MCI—compared with no-complaint, informant-complaint only (OR, 2.2; 99% CI, 1.2–4.3, P = .002), and both self- and informant-complaint (OR, 2.9; 99% CI, 1.8–4.8; P < .001)—were associated with conversion.
Cognitive complaints are related to conversion among non-demented older adults. Complaint from both (i.e. mutual complaint) sources was most predictive of diagnostic outcome, followed by informant complaint, highlighting the need for obtaining informant corroboration to enhance prognosis and distinguish underlying pathological processes from normal cognitive aging. Self-complaint was inconsistently related to diagnostic outcome.
PMCID: PMC4064681  PMID: 23871264
Mild cognitive impairment; Alzheimer’s disease; cognitive complaints; prognosis; conversion
6.  Clinical research risk assessment among individuals with mild cognitive impairment 
To determine whether individuals with mild cognitive impairment (MCI) differ from cognitively normal (NC) elders on a risk assessment task and whether participants and their study partners evaluate risk/benefit similarly.
University medical setting.
Seventy-nine participants (NC n=40; MCI n=39), 60–90 years (73±7 years; 53% female) and 64 study partners (NC n=36; MCI n=28), 38–84 years (68±10 years; 67% female).
Participants and study partners completed a risk assessment task that involved ranking from least to most risk four hypothetical vignettes for memory loss research (brain autopsy, blood draw, oral medication, neurosurgery). Participants also completed decisional capacity for research and neuropsychological protocols.
MCI participants’ risk rankings differed from NC risk rankings (p<0.001) with MCI participants ranking brain autopsy higher and an oral medication trial lower. Demographic, decisional capacity, and neuropsychological variables could not explain MCI participant performances. Participants and their study partners had comparable risk assessment performance (p-values=1.0). MCI study partners performing similar to their MCI participant counterparts but different from NC study partners (p=0.002; i.e., ranking autopsy higher and oral medication lower).
Findings suggest individuals with MCI assess risk differently than NC peers by overestimating the risk (or underestimating the benefit) of brain autopsy and underestimating the risk (or overestimating the benefit) of oral medication. Study partners display a similar pattern. These observations may be secondary to MCI participants’ (and their study partners’) personal connection to the potential benefits of an experimental medication for memory loss.
PMCID: PMC3411922  PMID: 22549368
mild cognitive impairment; research ethics; research participation; study partners; research proxy
7.  Relation of Left Ventricular Ejection Fraction to Cognitive Aging (From the Framingham Heart Study) 
The American journal of cardiology  2011;108(9):1346-1351.
Heart failure is a risk factor for Alzheimer’s disease (AD) and cerebrovascular disease. In the absence of heart failure, we hypothesized that left ventricular ejection fraction (LVEF), an indicator of cardiac dysfunction, would be associated with pre-clinical brain magnetic resonance imaging (MRI) and neuropsychological markers of ischemia and AD in the community. Brain MRI, cardiac MRI, neuropsychological, and laboratory data were collected on 1114 Framingham Heart Study Offspring Cohort participants free from clinical stroke or dementia (40–89 years, 67±9; 54% women). Neuropsychological and neuroimaging markers of brain aging were related to cardiac MRI-assessed LVEF. In multivariable-adjusted linear regressions, LVEF was not associated with any brain aging variable (p-values>0.15). However, LVEF quintile analyses yielded several U-shape associations. Compared to the referent (Q2–Q4), the lowest quintile (Q1) LVEF was associated with a lower mean cognitive performance, including Visual Reproduction Delayed Recall (β= −0.27, p<0.001) and Hooper Visual Organization Test (β= −0.27, p<0.001). Compared to the referent, the highest quintile (Q5) LVEF values also were associated with lower mean cognitive performances, including Logical Memory Delayed Recall (β= −0.18, p=0.03), Visual Reproduction Delayed Recall (β= −0.17, p=0.03), Trail Making Test Part B-Part A (β= −0.22, p=0.02) and Hooper Visual Organization Test (Q5 β= −0.20, p=0.02). Findings were similar when analyses were repeated excluding prevalent cardiovascular disease. In conclusion, although our observational cross-sectional data cannot establish causality, they suggest a non-linear association between LVEF and measures of accelerated cognitive aging.
PMCID: PMC3204899  PMID: 21880293
8.  Inflammatory Markers and Neuropsychological Functioning: The Framingham Heart Study 
Neuroepidemiology  2011;37(1):21-30.
We hypothesized that inflammatory markers are cross-sectionally and longitudinally associated with neuropsychological indicators of early ischemia and Alzheimer's disease.
Framingham Offspring Study participants, free of clinical stroke or dementia (n = 1,878; 60 ± 9 years; 54% women), underwent neuropsychological assessment and ascertainment of 11 inflammatory markers. Follow-up neuropsychological assessments (6.3 ± 1.0 years) were conducted on 1,352 of the original 1,878 participants.
Multivariable linear regression related the inflammatory markers to cross-sectional performance and longitudinal change in neuropsychological performances. Secondary models included a twelfth factor, tumor necrosis factor-α (TNF-α), available on a subset of the sample (n = 1,393 cross-sectional; n = 1,213 longitudinal). Results suggest a few modest cross-sectional inflammatory and neuropsychological associations, particularly for tests assessing visual organization (C-reactive protein, p = 0.007), and a few modest relations between inflammatory markers and neuropsychological change, particularly for executive functioning (TNF-α, p = 0.004). Secondary analyses suggested that inflammatory markers were cross-sectionally (TNF-α, p = 0.004) related to reading performance.
Our findings are largely negative, but suggest that specific inflammatory markers may have limited associations with poorer cognition and reading performance among community-dwelling adults. Because of multiple testing concerns, our limited positive findings are offered as hypothesis generating and require replication in other studies.
PMCID: PMC3142099  PMID: 21757961
Memory; Executive functioning; Inflammation; Cognition; WRAT-3 reading
9.  A Life Course Model of Cognitive Activities, Socioeconomic Status, Education, Reading Ability, and Cognition 
To cross-sectionally quantify the contribution of proxy measures of cognitive reserve reflective of the lifespan, such as education, socioeconomic status (SES), reading ability, and cognitive activities, in explaining late-life cognition.
Prospective observational cohort study of aging.
Retirement communities across the Chicago metropolitan area.
Nine hundred fifty-one older adults free of clinical dementia in the Rush Memory and Aging Project (aged 79 ± 8, 74% female).
Baseline data on multiple life course factors included early-, mid-, and late-life participation in cognitive activities; early-life and adult SES; education; and reading ability (National Adult Reading Test; NART). Path analysis quantified direct and indirect standardized effects of life course factors on global cognition and five cognitive domains (episodic memory, semantic memory, working memory, visuospatial ability, perceptual speed).
Adjusting for age, sex, and race, education had the strongest association with global cognition, episodic memory, semantic memory, and visuospatial ability, whereas NART (followed by education) had the strongest association with working memory. Late-life cognitive activities had the strongest association with perceptual speed, followed by education.
These cross-sectional findings suggest that education and reading ability are the most-robust proxy measures of cognitive reserve in relation to late-life cognition. Additional research leveraging path analysis is warranted to better understand how these life course factors, reflecting the latent construct of cognitive reserve, affect abnormal cognitive aging.
PMCID: PMC3222272  PMID: 21797830
education; cognition; reading ability; cognitive reserve
10.  Perceptions, Knowledge, Incentives, and Barriers of Brain Donation Among African American Elders Enrolled in an Alzheimer's Research Program 
The Gerontologist  2010;51(1):28-38.
Purpose: To learn about African American older adults’ knowledge and perceptions of brain donation, factors that relate to participating or not participating in a brain donation research program, and methods to increase African American brain donation commitment rates in the context of an Alzheimer's disease (AD) research program. Design and Methods: African American older adults (n = 15) from the Boston University Alzheimer's Disease Core Center participant research registry enrolled in 1 of 2 focus groups of 90 min about brain donation. Seven participants were selected for a third follow-up focus group. Results: Focus group transcripts were analyzed using consensual qualitative research methods, and 8 overarching themes emerged: (a) perceptions of and misconceptions about brain donation procedures, (b) racial minorities in medical research, (c) racial disparities and discrimination in medical settings, (d) influence of religion and spirituality, (e) family perceptions of and involvement in donation, (f) family history of disease and desire to find a cure, (g) prior exposure to medical and research settings, and (h) culturally sensitive approaches to brain donation. Implications: Culturally relevant educational protocols need to be created for use with African American older adults. These protocols should include information about brain donation procedures, rates of AD among Black elders, and potential benefits of donation to Black communities; inclusion of religious figures, family, and peers in donation education and decisions; and methods to address mistrust, including cultural competence trainings for staff.
PMCID: PMC3106364  PMID: 20679141
AD; Brain donation; African American; Racial disparity
11.  Clinical Research Participation among Aging Adults Enrolled in an Alzheimer’s Disease Center Research Registry 
In light of our limited understanding of what motivates older adults to participate in clinical studies of Alzheimer’s disease (AD), the current study examines incentives and barriers to participating in AD clinical research among older adults. 235 participants enrolled in the Boston University Alzheimer’s Disease Center research registry (75 ± 8 years, range 58–99 years, 60% female), a longitudinal registry from which individuals are recruited into other clinical studies, completed a survey assessing registry participation satisfaction, religiousness, trust in healthcare institutions, and medical research attitudes. Most participants reported initially enrolling in the registry for societal benefit. Insufficient time was a commonly endorsed barrier to enrolling in other Center-approved studies, particularly among younger participants. Driving and a lack of transportation to the medical facility were also barriers, particularly for older participants. Transportation was the most popular incentive, followed by home-based visits (particularly for older participants and participants with less formal education) and compensation (particularly among respondents from racial/ethnic minority groups). Participation interest in other studies was associated with favorable medical research attitudes (r = 0.34, p = 0.00003) but not religiousness (r = −0.09 p = 0.21) or trust in healthcare institutions (r = 0.09, p = 0.17). Among older adults, societal benefit is a motivating factor for registry enrollment; however, participation in additional studies is hindered by insufficient time among younger participants and transportation barriers among older participants. Providing transportation, home-based visits, and modest compensation may improve participation rates. Furthermore, favorable attitudes toward medical research are strongly associated with interest in enrolling in additional studies and may serve as a beneficial outreach triage technique.
PMCID: PMC3178330  PMID: 21116048
Alzheimer’s disease; barriers; clinical research; incentives; participation
12.  Cardiac index is associated with brain aging: The Framingham Heart Study 
Circulation  2010;122(7):690-697.
Cardiac dysfunction is associated with neuroanatomic and neuropsychological changes in aging adults with prevalent cardiovascular disease (CVD), theoretically because systemic hypoperfusion disrupts cerebral perfusion, contributing to subclinical brain injury. We hypothesized that cardiac function, as measured by cardiac index, would be associated with pre-clinical brain magnetic resonance imaging (MRI) and neuropsychological markers of ischemia and Alzheimer’s disease in the community.
Methods and Results
Brain MRI, cardiac MRI, neuropsychological, and laboratory data were collected on 1504 Framingham Offspring Cohort participants free from clinical stroke, transient ischemic attack, or dementia (61±9 years; 54% women). Neuropsychological and brain MRI variables were related to cardiac MRI-assessed cardiac index (cardiac output/body surface area). In multivariable-adjusted models, cardiac index was positively related to total brain volume (P=0.03) and information processing speed (P=0.02) and inversely related to lateral ventricular volume (P=0.048). When participants with clinically prevalent CVD were excluded, the relation between cardiac index and total brain volume remained (P=0.02). Post-hoc comparisons revealed that participants in the bottom cardiac index tertile (values<2.54) and middle cardiac index tertile (values between 2.54 and 2.92) had significantly lower brain volumes (P=0.04) than participants in the top cardiac index tertile (values>2.92).
Although observational data cannot establish causality, our findings are consistent with the hypothesis that decreasing cardiac function, even at normal cardiac index levels, is associated with accelerated brain aging.
PMCID: PMC2929763  PMID: 20679552
brain; cardiac output; epidemiology; imaging; neuropsychology
13.  Factors Associated With African-American and White Elders’ Participation in a Brain Donation Program 
This study examined factors associated with brain donation program participation among African-American and White elders. By postal mail, participants were recruited from an Alzheimer’s research registry (all of whom had been invited to participate in the Center’s brain donation program) and asked to complete surveys assessing brain donation knowledge, trust in healthcare systems, and religiousness. African-American respondents completed a cultural mistrust inventory. Demographic, brain donation status, and literacy data (as assessed by the Wide Range Achievement Test-3 Reading subtest) were compiled from the respondents’ most recent registry visit. The survey response rate was 60% (n=184 White and n=49 Black respondents). Logistic regression, comparing religiousness, trust in healthcare institutions, and educational attainment, identified a single predictor (ie, religiousness) in the prediction of donation status among White respondents (P=0.008), whereas no predictors were observed for donation status among the Black respondents. Using all African-American donors and nondonors from the registry (n=68), comparisons revealed Wide Range Achievement Test-3 Reading score differences for African-American donors (46.8±5.9) and nondonors (42.8±8.4, P=0.02). Results suggest that increased religiousness is related to White elders’ decisions not to donate, whereas lower reading ability might be related to African-American participants’ decisions not to donate.
PMCID: PMC3010335  PMID: 20856099
African-American; brain donation; cultural mistrust; religiousness; research participation
14.  Cardiac Output as a Potential Risk Factor for Abnormal Brain Aging 
Heart failure has served as a clinically useful model for understanding how cardiac dysfunction is associated with neuroanatomic and neuropsychological changes in aging adults, theoretically because systemic hypoperfusion disrupts cerebral perfusion, contributing to clinical brain injury. This review summarizes more recent data suggesting that subtle cardiac dysfunction or low normal levels of cardiac function, as quantified by cardiac output, are related to cognitive and neuroimaging markers of abnormal brain aging in the absence of heart failure or severe cardiomyopathy. Additional work is required, but such associations suggest that reduced cardiac output may be a risk factor for Alzheimer’s disease (AD) and abnormal brain aging through the propagation or exacerbation of neurovascular processes, microembolism due to thrombosis, and AD neuropathological processes. Such mechanistic pathways are discussed in the context of a theoretical model that posits a direct pathway of injury between cardiac output and abnormal brain aging (i.e., reduced systemic blood flow disrupts cerebral blood flow homeostasis), contributing to clinical brain injury, independent of shared risk factors for both cardiac dysfunction and abnormal brain aging.
PMCID: PMC3041147  PMID: 20413856
Alzheimer’s disease; cardiac output; cardiovascular disease; cognition
15.  Object Perception Impairments Predict Instrumental Activities of Daily Living Dependence in Alzheimer's Disease 
This study examined the contribution of object perception and spatial localization to functional dependence among Alzheimer's disease (AD) patients. Forty patients with probable AD completed measures assessing verbal recognition memory, working memory, object perception, spatial localization, semantic knowledge, and global cognition. Primary caregivers completed a measure of activities of daily living (ADLs) that included instrumental and basic self-care subscales (i.e., IADLs and BADLs, respectively). Stepwise multiple regressions revealed that global cognition accounted for significant portions of variance among the ADL total, IADL, and BADL scores. However, when global cognition was removed from the model, object perception was the only significant cognitive predictor of the ADL total and IADL subscale scores, accounting for 18.5% and 19.3% of the variance, respectively. When considering multiple cognitive components simultaneously, object perception and the integrity of the inferotemporal cortex is important in the completion of functional abilities in general and IADLs in particular among AD patients.
PMCID: PMC2746422  PMID: 16822730
16.  Geriatric Performance on an Abbreviated Version of the Boston Naming Test 
Applied neuropsychology  2007;14(3):215-223.
Abbreviated neuropsychological protocols are increasingly utilized secondary to time-constraints within research and healthcare settings, yet normative data for these abbreviated instruments are lacking. We present geriatric performances and normative data for the Boston Naming Test 30-item even verion (BNT-30). Data were utilized from the BU-ADCC registry (n = 441, ages 55-98) and included 219 normal controls (NC), 155 participants with mild cognitive impairment (MCI), and 67 participants with Alzheimer’s disease (AD). The NC group (M = 28.7, SD = 1.8) significantly outperformed both MCI (M = 26.2, SD = 4.4) and AD (M = 22.1, SD = 4.8) groups, and the MCI group outperformed the AD group. Normative data generated for the NC participants revealed a significant between-group difference for sex (males M = 29.1, SD = 1.7; females M = 28.4, SD = 1.8) and race (White M = 28.8, SD = 1.7; African American M = 27.5, SD = 2.1). The racial disparity remained even after adjusting for education level (p = .002) and literacy (p < .001). ANOVAs for the NC group were non-significant for age but significant for education level (p = .001). Geriatric normative data therefore suggest that sex, race, and education are all associated with naming performance, and these variables should be taken into consideration when interpreting geriatric BNT-30 performance.
PMCID: PMC2741691  PMID: 17848132
Alzheimer’s disease; Boston Naming Test; geriatrics; language; lexical retrieval; mild cognitive impairment; neuropsychological measures; normative data
17.  Decisional Capacity for Research Participation in Individuals with Mild Cognitive Impairment 
To assess decisional capacity performance and the neuropsychological correlates of such performance to better understand higher-level instrumental activities of daily living in individuals with mild cognitive impairment (MCI).
Research center, medical center, or patient’s home.
Forty participants with MCI and 40 cognitively normal older controls (NCs) aged 60 to 90 (mean age ± standard deviation 73.3 ± 6.6; 54% female).
Capacity to provide informed consent for a hypothetical, but ecologically valid, clinical trial was assessed using the MacArthur Competence Assessment Tool for Clinical Research. Neuropsychological functioning was assessed using a comprehensive protocol.
Adjusted between-group comparisons yielded significant differences for most decisional capacity indices examined, including Understanding (P = .001; NC>MCI) and Reasoning (P = .002; NC>MCI). Post hoc analyses revealed that participants with MCI who were categorized as capable of providing informed consent according to expert raters had higher levels of education than those who were categorized as incapable.
The findings suggest that many individuals with MCI perform differently on a measure of decisional capacity than their NC peers and that participants with MCI who are incapable of providing informed consent on a hypothetical and complex clinical trial are less educated. These findings are consistent with prior studies documenting functional and financial skill difficulties in individuals with MCI.
PMCID: PMC2724182  PMID: 18482298
mild cognitive impairment; memory; executive function; cognition; decision analysis; informed consent
18.  Characterization of Activities of Daily Living in Individuals With Mild Cognitive Impairment 
To determine whether participants with mild cognitive impairment (MCI) differ from cognitively normal (NC) older adults on traditional and novel informant-based measures of activities of daily living (ADL) and to identify cognitive correlates of ADLs among participants with MCI.
University medical setting.
Seventy-seven participants (NC: N = 39; MCI: N = 38), 60 to 90 years old (73.5 ± 6.6 years; 53% female).
Neuropsychological and ADL measures.
Neuropsychological tests were administered to NC and MCI participants. Informants completed the Lawton and Brody Instrumental Activities of Daily Living and Physical Self-Maintenance Scale, including instrumental (IADL) and basic ADL (BADL) scales, as well as the Functional Capacities for Activities of Daily Living (FC-ADL), an error-based ADL measure.
No statistically or clinically significant between-group differences emerged for the BADL or IADL subscales. However, a robust difference was noted for the FC-ADL scale (MCI errors > NC errors; F(1,75) = 13.6, p <0.001; d = 0.84). Among MCI participants, correlations revealed that a measure of verbal learning was the only neuropsychological correlate of FC-ADL total score (r =-0.39, df = 36, p = 0.007). No neuropsychological measures were significantly associated with the IADL or BADL subscale score.
Traditional measures assessing global ADLs may not be sensitive to early functional changes related to MCI; however, error-based measures may capture the subtle evolving functional decline associated with MCI. Among MCI participants, early functional difficulties are associated with verbal learning performance, possibly secondary to the hallmark cognitive impairment associated with this cohort.
PMCID: PMC2682324  PMID: 18332397
Instrumental activities of daily living; MCI; memory; functional errors; neuropsychology
19.  Blood Pressure and Cognition Among Older Adults: A Meta-Analysis 
Hypertension has adverse effects on cognition, can alter cerebral vasculature integrity, and is associated with the pathogenesis of dementia. Using meta-analysis, we correlated blood pressure to multiple cognitive domains among older adults free of clinical stroke and dementia. We identified 230 studies indexed in PubMed and PsycINFO relating blood pressure and cognition. After applying exclusion criteria, we selected n = 12 articles with n = 4,076 participants (age range 43–91 years). Meta-analysis yielded an association between blood pressure and episodic memory (r = −.18, p < .001) and between blood pressure and global cognition (r = −.07, p < .001). When limiting analyses to studies adjusting for vascular covariates (n = 8, n = 2,141), blood pressure was modestly related to global cognition (r = −.11, p < .001), attention (r = .14, p = .002), and episodic memory (r = −.20, p < .001) with a trend for language (r = −.22, p = .07). Findings underscore the need to manage blood pressure as a key prevention method in minimizing abnormal cognitive aging prior to the onset of clinical dementia.
PMCID: PMC3807830  PMID: 23838685
Cardiovascular disease; Dementia; Learning and episodic memory; Executive functioning; Meta analysis
20.  Diagnostic Accuracy Statistics for Seven Neuropsychological Assessment Battery (NAB) Test Variables in the Diagnosis of Alzheimer’s Disease 
Applied neuropsychology. Adult  2012;19(2):10.1080/09084282.2011.643947.
Neuropsychological tests are useful for diagnosing Alzheimer’s disease (AD), yet for many tests, diagnostic accuracy statistics are unavailable. We present diagnostic accuracy statistics for seven variables from the Neuropsychological Assessment Battery (NAB) that were administered to a large sample of elderly adults (n = 276) participating in a longitudinal research study at a national AD Center. Tests included Driving Scenes, Bill Payment, Daily Living Memory, Screening Visual Discrimination, Screening Design Construction, and Judgment. Clinical diagnosis was made independent of these tests, and for the current study, participants were categorized as AD (n = 65) or non-AD (n = 211). Receiver operating characteristics curve analysis was used to determine each test’s sensitivity and specificity at multiple cut points, which were subsequently used to calculate positive and negative predictive values at a variety of base rates. Of the tests analyzed, the Daily Living Memory test provided the greatest accuracy in the identification of AD and the two Screening measures required a significant tradeoff between sensitivity and specificity. Overall, the seven NAB subtests included in the current study are capable of excellent diagnostic accuracy, but appropriate understanding of the context in which the tests are used is crucial for minimizing errors.
PMCID: PMC3857936  PMID: 23373577
21.  A fMRI Study of Verbal Working Memory, Cardiac Output, and Ejection Fraction in Elderly Patients with Cardiovascular Disease 
Brain imaging and behavior  2009;3(4):350-357.
Cardiovascular disease (CVD) is associated with cognitive deficits even in the absence of stroke. We examined the relationship between cardiac performance, as measured by cardiac output (CO) and ejection fraction (EF), and brain activity during a verbal working memory (VWM) task in elderly CVD patients who tend to be at increased risk for vascular cognitive impairments. Seventeen patients were recruited from a cohort participating in an ongoing prospective study examining the effects of CVD on cognitive function in the elderly. Participants were diagnosed with CVD (age 68±8) and completed a 2-back VWM task in a 1.5T fMRI paradigm. CO and EF were calculated from echocardiogram measures. Task-related activation was averaged in a priori regions of interest. The relationship between CO, EF, and 2-back-related activity was modeled using partial correlations (two-tailed p<.05) controlling for age and 2-back accuracy. All participants were globally cognitively intact as indicated by Mini-Mental Status Exam and Dementia Rating Scale scores. Mean accuracy on the 2-back was 78±9% while reaction time averaged 1,027±192 ms. Mean CO and EF values showed a large range (CO: 3.55 to 6.31; EF: 0.36 to 0.76) but average values were within the normal range. After controlling for age and 2-back accuracy, lower EF was related to decrease in left insula activity (r=0.61, p=0.03). There were trends for EF to be related to accuracy (r=0.47, p=0.09) and reaction time (r=−0.48, p=0.09). CO was also related to insula activity (r=0.60, p=0.04) and activity in the supplementary motor area activity (r=0.66, p=0.01). Cardiac performance was related to decreased efficiency in task related brain areas and tended to be related to performance on a VWM task in elderly patients with CVD. Results have implications for a line of investigation indicating that cardiac and systemic vascular indices could be used as proxy measures to examine mechanisms of cerebrovascular dysfunction in the elderly.
PMCID: PMC3514458  PMID: 23227137
Functional magnetic resonance imaging; FMRI; Functional neuroimaging; Verbal working memory; Cardiovascular disease; Heart disease; Ejection fraction; Cardiac output
22.  Conceptual and Measurement Challenges in Research on Cognitive Reserve 
Cognitive reserve, broadly conceived, encompasses aspects of brain structure and function that optimize individual performance in the presence of injury or pathology. Reserve is defined as a feature of brain structure and/or function that modifies the relationship between injury or pathology and performance on neuropsychological tasks or clinical outcomes. Reserve is challenging to study for two reasons. The first is: reserve is a hypothetical construct, and direct measures of reserve are not available. Proxy variables and latent variable models are used to attempt to operationalize reserve. The second is: in vivo measures of neuronal pathology are not widely available. It is challenging to develop and test models involving a risk factor (injury or pathology), a moderator (reserve) and an outcome (performance or clinical status) when neither the risk factor nor the moderator are measured directly. We discuss approaches for quantifying reserve with latent variable models, with emphasis on their application in the analysis of data from observational studies. Increasingly latent variable models are used to generate composites of cognitive reserve based on multiple proxies. We review the theoretical and ontological status of latent variable modeling approaches to cognitive reserve, and suggest research strategies for advancing the field.
PMCID: PMC3289742  PMID: 21411036
Cognitive reserve; Brain reserve; Latent variable; Aging; Cognition; Neuronal plasticity; Multivariate Analysis; Environment; Social Environment; Education; Social Class; Intelligence
23.  Medical student education program in Alzheimer’s disease: The PAIRS Program 
BMC Medical Education  2012;12:80.
As life expectancy increases, dementia incidence will also increase, creating a greater need for physicians well-trained to provide integrated geriatric care. However, research suggests medical students have limited knowledge or interest in pursuing geriatric or dementia care. The purpose of this study is to evaluate the PAIRS Program and its effectiveness in enhancing medical education as a service-learning activity and replication model for the Buddy ProgramTM.
Between 2007 and 2011, four consecutive classes of first year Boston University School of Medicine students (n = 45; 24 ± 3 years, 58% female, 53% White) participated in a year-long program in which they were paired with a patient with early-stage Alzheimer’s disease (AD). Assessments included pre- and post-program dementia knowledge tests and a post-program reflective essay.
Program completion was 100% (n = 45). A paired-sample t-test revealed a modest improvement in dementia knowledge post-program (p < 0.001). Using qualitative coding methods, 12 overarching themes emerged from the students’ reflective essays, such as observing care partner burden, reporting a human side to AD, reporting experiences from the program that will impact future clinical practice, and obtaining a greater understanding of AD.
Quantitative and qualitative findings suggest that the PAIRS Program can enhance the acquisition of knowledge, skills, and positive attitudes regarding geriatric healthcare in future generations of physicians, a skill set that is becoming increasingly relevant in light of the rapidly aging population. Furthermore, results suggest that The Buddy ProgramTM model can be successfully replicated.
PMCID: PMC3500260  PMID: 22906234
Experiential learning; Qualitative methods; Communication; Dementia; Alzheimer's disease; Medical education; Service learning
25.  Neuroimaging and Cardiac Correlates of Cognitive Function among Patients with Cardiac Disease 
In the present study, we examined the relationships between whole brain volume (WBV), subcortical hyperintensities (SH), indices of cardiac disease and cognitive function in nondemented cardiac patients with evidence of mild cerebrovascular disease. A total of 27 individuals with evidence of cardiac disease underwent neuropsychological examination, neuroimaging, and cardiac assessment. Cognition was assessed with the Dementia Rating Scale-2 (DRS). WBV and SH were quantified using a semi-automated thresholding program based on MRI. Correlational analyses revealed that WBV predicted performance on the overall DRS score, the attention subscale and the initiation/perseveration scale. SH were significantly associated with performance on the attention subscale, and the initiation/perseveration subscale. Regression analyses revealed that SH accounted for most of the variance in the initiation/perseveration scale, whereas WBV accounted for most of the variance in the attention scale. The only cardiac structural or functional variable related to the neurological indices was aortic diameter, which was strongly related to both neuroimaging variables, as well as performances on the DRS attention and initiation/perseveration subscales. Our results highlight the importance of overall brain parenchyma in determining cognitive status among patients at risk for cognitive decline and suggest that select indices of structural cardiac morphology may be related to the early phases of cerebrovascular disease and cognitive status.
PMCID: PMC3222237  PMID: 16006761
Cardiac disease; MRI; Cognition; Neuropsychology; Subcortical hyperintensities

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