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1.  The source of cognitive complaints differentially predicts diagnostic conversion in non-demented older adults 
Objective
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.
Methods
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).
Results
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.
Conclusions
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.
doi:10.1016/j.jalz.2013.02.007
PMCID: PMC4064681  PMID: 23871264
Mild cognitive impairment; Alzheimer’s disease; cognitive complaints; prognosis; conversion
2.  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.
doi:10.1093/geront/gnq063
PMCID: PMC3106364  PMID: 20679141
AD; Brain donation; African American; Racial disparity
3.  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.
doi:10.1080/09084282.2011.643947
PMCID: PMC3857936  PMID: 23373577
4.  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.
doi:10.1097/WAD.0b013e3181f3e059
PMCID: PMC3010335  PMID: 20856099
African-American; brain donation; cultural mistrust; religiousness; research participation
5.  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.
doi:10.3233/JAD-2010-100081
PMCID: PMC3041147  PMID: 20413856
Alzheimer’s disease; cardiac output; cardiovascular disease; cognition
6.  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.
doi:10.1080/13803390591001034
PMCID: PMC2746422  PMID: 16822730
7.  Clinical research risk assessment among individuals with mild cognitive impairment 
Objective
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.
Design
Cross-sectional.
Setting
University medical setting.
Participants
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).
Measurements
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.
Results
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).
Conclusion
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.
doi:10.1097/JGP.0b013e318252e5cb
PMCID: PMC3411922  PMID: 22549368
mild cognitive impairment; research ethics; research participation; study partners; research proxy
8.  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.
doi:10.1016/j.amjcard.2011.06.056
PMCID: PMC3204899  PMID: 21880293
9.  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.
doi:10.1017/S1355617710001748
PMCID: PMC3289742  PMID: 21411036
Cognitive reserve; Brain reserve; Latent variable; Aging; Cognition; Neuronal plasticity; Multivariate Analysis; Environment; Social Environment; Education; Social Class; Intelligence
10.  Inflammatory Markers and Neuropsychological Functioning: The Framingham Heart Study 
Neuroepidemiology  2011;37(1):21-30.
Background/Aims
We hypothesized that inflammatory markers are cross-sectionally and longitudinally associated with neuropsychological indicators of early ischemia and Alzheimer's disease.
Methods
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.
Results
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.
Conclusions
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.
doi:10.1159/000328864
PMCID: PMC3142099  PMID: 21757961
Memory; Executive functioning; Inflammation; Cognition; WRAT-3 reading
11.  Medical student education program in Alzheimer’s disease: The PAIRS Program 
BMC Medical Education  2012;12:80.
Background
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.
Methods
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.
Results
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.
Conclusions
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.
doi:10.1186/1472-6920-12-80
PMCID: PMC3500260  PMID: 22906234
Experiential learning; Qualitative methods; Communication; Dementia; Alzheimer's disease; Medical education; Service learning
12.  A Life Course Model of Cognitive Activities, Socioeconomic Status, Education, Reading Ability, and Cognition 
OBJECTIVES
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.
DESIGN
Prospective observational cohort study of aging.
SETTING
Retirement communities across the Chicago metropolitan area.
PARTICIPANTS
Nine hundred fifty-one older adults free of clinical dementia in the Rush Memory and Aging Project (aged 79 ± 8, 74% female).
MEASUREMENTS
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).
RESULTS
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.
CONCLUSIONS
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.
doi:10.1111/j.1532-5415.2011.03499.x
PMCID: PMC3222272  PMID: 21797830
education; cognition; reading ability; cognitive reserve
14.  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.
doi:10.1159/000086803
PMCID: PMC3222237  PMID: 16006761
Cardiac disease; MRI; Cognition; Neuropsychology; Subcortical hyperintensities
15.  Neuropsychological dysfunction in patients with end-stage pulmonary disease: lung transplant evaluation 
There has been a relative absence of studies that have examined the neuropsychological profiles of potential lung transplant candidates. Neuropsychological data are presented for 134 patients with end-stage pulmonary disease who were being evaluated as potential candidates for lung transplantation. Neuropsychological test results indicated that a significantly greater proportion of the patients exhibited impaired performances on a number of Selective Reminding Test (SRT) tasks as compared to the expected population frequency distributions for these measures. The highest frequencies of impairment were observed on the SRT’s Immediate Free Recall (46.43%), Long-term Retrieval (41.67%), and Consistent Long-term Retrieval (51.19%) variables. On the Minnesota Multiphasic Personality Inventory-2 (MMPI-2)/Minnesota Multiphasic Personality Inventory-Adolescent (MMPI-A), patients’ mean clinical profile revealed elevations on Scales 1 (Hypochondriasis) and 3 (Conversion Hysteria). This profile indicated that they were experiencing an array of symptomatology ranging from somatic complaints to lethargy and fatigue, and that they may have been functioning at a reduced level of efficiency. Findings are discussed in light of patients’ end-stage pulmonary disease and factors possibly contributing to their neuropsychological test performances. Implications for clinical practice and future research are also provided.
PMCID: PMC3219058  PMID: 14591451
Neuropsychology; Neurocognitive; Pulmonary disease; End-stage; Lung transplant
16.  Blood pressure variability and white matter hyperintensities in older adults with cardiovascular disease 
Blood pressure  2005;14(6):353-358.
The present study examined the relationship between multiple blood pressure (BP) indices and white matter hyperintensities (WMH) in a sample of 39 older adults with cardiovascular disease (CVD). Resting BP was measured using an automated monitor every 10 min for 2 h. WMH were quantified on FLAIR images and separate indices were generated for neocortical, periventricular and subcortical brain regions. Correlation analyses revealed systolic BP variability was related to neocortical and total WMH. A function of systolic BP variability and average diastolic pressure showed the strongest relationships, including significant correlation to neocortical, subcortical and total WMH. No BP index was related to WMH in periventricular regions. Exploratory analyses showed only the function of systolic BP variability and average diastolic pressure predicted total WMH, whereas as age, CVD conditions and psychosocial factors did not. These findings demonstrate BP variability is an important contributor to WMH in older adults with CVD and suggests it may have differential relationships to WMH in different brain regions. Additional studies are needed to examine the role of autoregulatory systems in the development of WMH, particularly those using beat-to-beat measures of BP.
doi:10.1080/08037050500364117
PMCID: PMC3215278  PMID: 16403689
Blood pressure; cardiovascular disease; cerebrovascular disease
17.  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.
doi:10.3233/JAD-2010-101536
PMCID: PMC3178330  PMID: 21116048
Alzheimer’s disease; barriers; clinical research; incentives; participation
18.  Cardiac index is associated with brain aging: The Framingham Heart Study 
Circulation  2010;122(7):690-697.
Background
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).
Conclusions
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.
doi:10.1161/CIRCULATIONAHA.109.905091
PMCID: PMC2929763  PMID: 20679552
brain; cardiac output; epidemiology; imaging; neuropsychology
19.  Atlas-derived perfusion correlates of white matter hyperintensities in patients with reduced cardiac output 
Neurobiology of aging  2009;32(1):133-139.
Reduced cardiac output is associated with increased white matter hyperintensities (WMH) and executive dysfunction in older adults, which may be secondary to relations between systemic and cerebral perfusion. This study preliminarily describes the regional distribution of cerebral WMH in the context of a normal cerebral perfusion atlas and aims to determine if these variables are associated with reduced cardiac output. Thirty-two participants (72 ± 8 years old, 38% female) with cardiovascular risk factors or disease underwent structural MRI acquisition at 1.5 T using a standard imaging protocol that included FLAIR sequences. WMH distribution was examined in common anatomical space using voxel-based morphometry and as a function of normal cerebral perfusion patterns by overlaying a single photon emission computed tomography (SPECT) atlas. Doppler echocardiogram data was used to dichotomize the participants on the basis of low (n = 9) and normal (n = 23) cardiac output. Global WMH count and volume did not differ between the low and normal cardiac output groups; however, atlas-derived SPECT perfusion values in regions of hyperintensities were reduced in the low versus normal cardiac output group (p < 0.001). Our preliminary data suggest that participants with low cardiac output have WMH in regions of relatively reduced perfusion, while normal cardiac output participants have WMH in regions with relatively higher regional perfusion. This spatial perfusion distribution difference for areas of WMH may occur in the context of reduced systemic perfusion, which subsequently impacts cerebral perfusion and contributes to subclinical or clinical microvascular damage.
doi:10.1016/j.neurobiolaging.2009.01.011
PMCID: PMC2889176  PMID: 19269713
Cardiovascular disease; SPECT; MRI; Perfusion; Cardiac output; White matter hyperintensities
20.  Vascular Health and Cognitive Function in Older Adults with Cardiovascular Disease 
Artery research  2008;2(1):35-43.
Background
We hypothesized that changes in vascular flow dynamics resulting from age and cardiovascular disease (CVD) would correlate to neurocognitive capacities, even in adults screened to exclude dementia and neurological disease. We studied endothelial-dependent as well as endothelial-independent brachial responses in older adults with CVD to study the associations of vascular responses with cognition. Comprehensive neurocognitive testing was used to discern which specific cognitive domain(s) correlated to the vascular responses.
Methods
Eighty-eight independent, community-dwelling older adults (70.02+7.67 years) with mild to severe CVD were recruited. Enrollees were thoroughly screened to exclude neurological disease and dementia. Flow-mediated (endothelial-dependent) and nitroglycerin-mediated (endothelial-independent) brachial artery responses were assessed using 2-d ultrasound. Cognitive functioning was assessed using comprehensive neuropsychological testing. Linear regression analyses were used to evaluate the relationships between the endothelial-dependent and endothelial-independent vascular flow dynamics and specific domains of neurocognitive function.
Results
Endothelial-dependent and endothelial-independent brachial artery responses both correlated with neurocognitive testing indices. The strongest independent relationship was between endothelial function and measures of attention-executive functioning.
Conclusions
Endothelial-dependent and endothelial-independent vascular responsiveness correlate with neurocognitive performance among older CVD patients, particularly in the attention-executive domain. While further study is needed to substantiate causal relationships, our data demonstrate that brachial responses serve as important markers of risk for common neurocognitive changes. Learning and behavior-modifying therapeutic strategies that compensate for such common, insidious neurocognitive limitations will likely improve caregiving efficacy.
doi:10.1016/j.artres.2008.01.001
PMCID: PMC3004172  PMID: 21179381
Cardiovascular Disease; vascular function; age; endothelium; neurocognitive performance
21.  Subjective Cognitive Complaints Relate to White Matter Hyperintensities and Future Cognitive Decline in Patients with Cardiovascular Disease 
Objective
Elderly patients with cardiovascular disease (CVD) often report cognitive difficulties including reduced cognitive processing speed and attention. On cross-sectional examination, such reports relate more closely to mood than to objective measures of cognitive performance, thus questioning the validity of subjective cognitive complaints as a marker of neurodegenerative processes. This study examined the longitudinal relationship between self-reported cognitive difficulties, depression, and performance on objective tests of global cognition in patients with CVD.
Participants and Methods
Forty-seven CVD patients (ages 55 to 85 years) completed a measure of perceived cognitive dysfunction (Cognitive Difficulties Scale), a medical history questionnaire, the Dementia Rating Scale (DRS), and the Beck Depression Inventory (BDI) at baseline and 12 months later. Baseline brain imaging was available on a small sub-sample (n = 17).
Results
Hierarchical linear regression revealed that increased report of cognitive difficulties at baseline was significantly associated with poorer DRS performance at follow-up (F(3, 43) = 4.45, p = .008, CDS partial r = −.30, p = .048), independent of age, education, baseline DRS and BDI scores. Greater perceived cognitive dysfunction at baseline also related to higher level of white matter lesions (r = .53, df = 15, p = .028).
Conclusions
Self-reported cognitive difficulties may reflect early changes in cognitive aging that are difficult to detect using global cognitive screening measures at a single time point. Yet, these perceived difficulties relate to objectively measured cognitive decline over time. Thus, they may provide important clinical information about early neurodegenerative processes that should be carefully monitored.
doi:10.1097/JGP.0b013e3181b208ef
PMCID: PMC2813459  PMID: 20104055
Subjective Cognitive Complaints; Cognition; Cardiovascular Diseases; Dementia Ratings Scale; White Matter Hyperintensities
22.  SELP 1087G/A Polymorphism is Associated with Neuropsychological Test Performance in Older Adults with Cardiovascular Disease 
Background and Purpose
There is growing evidence that the cell adhesion molecule P-selectin (SELP) contributes to the adverse vascular processes that promote cognitive impairment in individuals with cardiovascular disease. Previous research has shown that SELP genotypes moderate circulating levels of P-selectin and that coronary artery bypass graft (CABG) patients with the SELP 1087A allele were less likely to show post-operative cognitive decline and more likely to exhibit lower levels of C-reactive protein (CRP) than non-carriers. Thus, we expected that carriers of the 1087A allele (n = 43) would exhibit better cognitive functioning than persons with two 1087G alleles (n = 77) and that CRP levels would be important for this relationship.
Methods
120 older adults with diagnosed cardiovascular disease (CVD) were recruited from outpatient cardiology clinics. Each participant underwent a comprehensive neuropsychological test battery and a blood draw.
Results
Participants with the SELP 1087A allele performed more poorly on tests of attention [TMT-A: t(116)=3.20, p=.002], executive function [TMT-B: t(116)=2.89, p=.005], psychomotor speed [Digit-Symbol Coding: t(117)=2.54, p=.012], and memory [CVLT Discrimination: t(116)=2.05, p=.04]. There were no significant differences between the SELP genotype groups on demographic/medical variables or CRP levels.
Conclusions
Contrary to expectations, the present analyses showed that older CVD patients with the SELP 1087A allele performed more poorly on neuropsychological testing. Findings from the present study were counter to previous research with CABG candidates. Further work using neuroimaging and alternative measures of cardiovascular function is needed to clarify the mechanisms of this association.
doi:10.1161/STROKEAHA.109.553339
PMCID: PMC2752956  PMID: 19590054
P-selectin; Cognitive Function; Heart Disease
23.  Predicting cognitive decline and conversion to Alzheimer's disease in older adults using the NAB List Learning test 
To validate the Neuropsychological Assessment Battery (NAB) List Learning test as a predictor of future multi-domain cognitive decline and conversion to Alzheimer's disease (AD), participants from a longitudinal research registry at a national AD Center were, at baseline, assigned to one of three groups (control, mild cognitive impairment [MCI], or AD), based solely on a diagnostic algorithm for the NAB List Learning test (Gavett et al., 2009), and followed for 1–3 years. Rate of change on common neuropsychological tests and time to convert to a consensus diagnosis of AD were evaluated to test the hypothesis that these outcomes would differ between groups (AD>MCI>control). Hypotheses were tested using linear regression models (n = 251) and Cox proportional hazards models (n = 265). The AD group declined significantly more rapidly than controls on Mini-Mental Status Examination (MMSE), animal fluency, and Digit Symbol; and more rapidly than the MCI group on MMSE and Hooper Visual Organization Test. The MCI group declined more rapidly than controls on animal fluency and CERAD Trial 3. The MCI and AD groups had significantly shorter time to conversion to a consensus diagnosis of AD than controls. The predictive validity of the NAB List Learning algorithm makes it a clinically useful tool for the assessment of older adults.
doi:10.1017/S1355617710000421
PMCID: PMC2922010  PMID: 20374677
Memory; Dementia; Differential diagnosis; Aging; Neuropsychology; Neuropsychological tests
24.  Blood Pressure and Cognitive Function in Older adults with Cardiovascular Disease 
Background
Past studies link elevated blood pressure (BP) and BP variability to adverse neurocognitive changes in community samples. However, little is known about the relationship between BP indices and cognitive function in older CVD patients.
Methods
A total of 99 older adults with CVD completed a comprehensive neuropsychological test battery. Resting BP measurements were collected every 10 minutes for two hours during a separate cardiac assessment. Five BP indices were generated: average and standard deviation of systolic blood pressure, average and standard deviation of diastolic blood pressure, and a function of systolic variability and average diastolic pressure. We examined the relationship between these BP indices and cognitive function.
Results
Partial correlation adjusting for age and education revealed that the function of systolic variability and average diastolic pressure (systolic BP standard deviation divided by the average diastolic BP) was most closely related to test performance, showing significant associations to both Learning/Memory (r = 0.25) and Language functioning (r = 0.22). Systolic BP indices were also related to Language functioning (SBP avg, r = 0.22; SBP sd, r = 0.25), though diastolic BP indices were unrelated to performance in any cognitive domain.
Conclusions
The current findings indicate that BP is modestly related to cognitive function in older CVD patients. Contrary to expectations, greater BP variability was associated with better, not poorer, cognitive test performance. Such findings suggest that the relationship between BP and cognitive function is more complicated than typically hypothesized and requires further examination.
doi:10.3109/00207450903139713
PMCID: PMC2899480  PMID: 19916851
Blood Pressure; Cognitive Function; Heart Disease
25.  LEUKOARAIOSIS SEVERITY AND LIST-LEARNING IN DEMENTIA 
The Clinical neuropsychologist  2009;23(6):944-961.
In patients with dementia, leukoaraiosis (LA) was hypothesized to result in differential patterns of impairment on a verbal serial list-learning test. Using a visual rating scale, 144 dementia patients with ischemic scores <4 were re-categorized as having mild (n = 73), moderate (n = 44), or severe LA (n = 27). Mild LA was predicted to be associated with an amnestic list-learning profile, while severe LA was predicted to be associated with a dysexecutive profile. List-learning performances were standardized to a group of healthy older adults (n = 24). Analyses were conducted on a set of four factors derived from the list-learning paradigm, as well as error scores. Data indicate that LA severity is an important marker for understanding list learning in dementia.
doi:10.1080/13854040802681664
PMCID: PMC2866111  PMID: 19370451
Alzheimer’s disease; Vascular dementia; Binswanger’s disease; Subcortical dementia; Episodic memory; The Philadelphia (repeatable) Verbal Learning Test (PrVLT)

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