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1.  Midlife Cardiovascular Risk Impacts Executive Function: Framingham Offspring Study 
Introduction
Novel error scores and traditional indices of executive function (EF) were related to cardiovascular risk factors (CVRF) measured 10–15 years earlier.
Methods
From 1991–1995, the Framingham Stroke Risk Profile (FSRP), a composite score of cardiovascular risk, was ascertained in 1755 Framingham Offspring participants (54% women, mean age= 54 ± 9 years). Participants were administered EF tests: FAS and Animals Fluency tests, Trail Making Test B (TrB), and Digit Span-Backwards (DS-B) in 2005–2009. Linear and logistic regression were used to relate the FSRP and its components to both error responses and traditional scores.
Results
Consistent with previous findings, the FSRP and the individual components diabetes and sex were associated with several traditional measures of EF. Of interest were relationships between the FSRP score and TrB Total Errors (p=0.04), DS-B % Total Errors (p=0.02) and DS-B Capacity Score (p=0.03), and prevalent CVD related to making FAS Perseverations in the 75th percentile (p=0.03). By comparison, FSRP and CVD were not related to the traditional DS-B or FAS scores. Additionally, age was associated with higher Animals % Total Errors and % Perseverations among ApoE4+ individuals and with higher TrB Total Errors among ApoE4− individuals.
Conclusion
For those middle-aged and healthy, including those ApoE4+, CVRF are related to impairments in EF as ascertained by novel errors as well as traditional measures.
doi:10.1097/WAD.0b013e3182a715bc
PMCID: PMC3945114  PMID: 23995818
Neuropsychological assessment; Executive function; Mild cognitive impairment; ApolipoproteinE allele 4
2.  The Association between Executive Function and Mortality in Homebound Elders 
Objectives
To determine the association between executive function and mortality in homebound elders.
Design
Longitudinal study
Setting
Four homecare agencies in the Boston area.
Participants
One thousand one hundred and seventy-two homebound elders aged 60 and older and with 8 year follow-up for mortality.
Measurements
Different cognitive domains including executive, memory, and language functions were evaluated at baseline. Executive function was measured by the Trail-making Test B (Trails B), and the subjects were divided into 4 subgroups from the lowest to highest Trails B scores. The second cross-group analyses were used to compare those who were alive and those were deceased. Multivariate logistic regressions were used to determine whether there was an association between the level of Trails B scores and mortality.
Results
At baseline, 436 (37.2%) homebound elders had the maximum Trails B scores (≥ 300), which indicated slowest performance. At the 8-year follow up, we found that 381 (32.5%) participants had died. The elderly with the highest Trails B scores were more than twice as likely to die when compared to those with the lowest scores (0–99) (OR = 2.39, 95% CI, 1.27–4.52, p = .003) after adjusting for the confounders including medical comorbidities related to death. In contrast, the other cognitive domains including memory and language were not associated with mortality in the same model.
Conclusion
Many homebound elderly have multiple medical conditions, and executive function may be crucial for the elderly to take care of their medical conditions and affect the outcome of death.
PMCID: PMC3919053  PMID: 24479144
homebound elders; executive function; mortality
3.  APOE genotype modifies the relationship between midlife vascular risk factors and later cognitive decline 
Vascular risk factors have been associated with cognitive decline, however, it remains unclear whether apolipoprotein E (APOE) genotype modifies this relationship. We aimed to further elucidate these relationships and extend previous findings by examining data from a more comprehensive cognitive assessment than used in prior studies. 1,436 participants from the prospective Framingham Offspring Cohort Study underwent health examination from 1991-1995, followed by a baseline neuropsychological assessment (1999-2003) and a repeat neuropsychological assessment approximately eight years later (2004-2009). Multivariate linear regression analyses were performed to examine the relationship between midlife vascular risk factors, presence of the APOE ε4 allele, and cognitive change. APOE genotype significantly modified the associations between both midlife hypertension and cardiovascular disease and decline in language abilities as well as midlife diabetes and decline in verbal memory, attention, and visuospatial abilities. Associations between increased midlife vascular risk burden and greater cognitive decline were observed among APOE ε4 carriers but not non-carriers. The present findings revealed a subgroup at increased risk for cognitive decline (APOE ε4 carriers with midlife exposure to vascular risk factors) and suggest that treatment of vascular risk factors during midlife may reduce the risk of cognitive impairment later in life, particularly among APOE ε4 carriers.
doi:10.1016/j.jstrokecerebrovasdis.2013.03.013
PMCID: PMC3849195  PMID: 23601373
Apolipoprotein E; Cognition; Vascular Risk; Aging; Diabetes; Hypertension; Cardiovascular Disease
4.  Defining MCI in the Framingham Heart Study Offspring: Education vs. WRAT-based norms 
Alzheimer disease and associated disorders  2013;27(4):10.1097/WAD.0b013e31827bde32.
Introduction
Psychometric definitions of mild cognitive impairment (MCI) typically use cut-off levels set at 1.5 standard deviations below age- and education-adjusted norms, assuming that the education adjustment accounts for premorbid abilities. However, non-cognitive factors impact educational attainment, potentially leading to incorrect categorization as MCI. We examined whether using an adjustment based on reading performance (Wide Range Achievement Test [WRAT] Reading) improved MCI diagnostic accuracy.
Methods
935 Framingham Offspring (mean age 72 ± 5) underwent tests of Memory, Executive Function, Abstraction, Language, and Visuospatial Function as part of a neuropsychological test battery. Domain-specific test scores were regressed onto age and WRAT score, or education, to define MCI. Survival analyses were used to relate baseline MCI to incident dementia.
Results
The two MCI definitions differed most for the lowest and highest education groups. The WRAT definition was more strongly associated with incident dementia for all five tests. MCI-level Abstraction performance was associated with incident dementia using the WRAT definition (HR = 3.20, p = .033), but not the education definition (HR = 1.19, p = .814).
Discussion
The WRAT should be considered along with the standard measure of years of education, as it may be a better surrogate marker of premorbid abilities.
doi:10.1097/WAD.0b013e31827bde32
PMCID: PMC3626741  PMID: 23314066
Mild cognitive impairment; premorbid abilities; neuropsychological assessment; Alzheimer's disease; longitudinal
5.  Serum BDNF and VEGF levels are associated with Risk of Stroke and Vascular Brain Injury: Framingham Study 
Stroke; a journal of cerebral circulation  2013;44(10):10.1161/STROKEAHA.113.001447.
Background and Purpose
BDNF, a major neurotrophin and VEGF, an endothelial growth factor have a documented role in neurogenesis, angiogenesis and neuronal survival. In animal experiments they impact infarct size and functional motor recovery after an ischemic brain lesion. We sought to examine the association of serum BDNF and VEGF with the risk of clinical stroke or subclinical vascular brain injury in a community-based sample.
Methods
In 3440 stroke/TIA-free FHS participants (mean age 65±11yrs, 56%W), we related baseline BDNF and logVEGF to risk of incident stroke/TIA. In a subsample with brain MRI and with neuropsychological (NP) tests available (N=1863 and 2104, respectively; mean age 61±9yrs, 55%W, in each) we related baseline BDNF and logVEGF to log-white matter hyperintensity volume (lWMHV) on brain MRI, and to visuospatial memory and executive function tests.
Results
During a median follow-up of 10 years, 193 participants experienced incident stroke/TIA. In multivariable analyses adjusted for age-, sex- and traditional stroke risk factors, lower BDNF and higher logVEGF levels were associated with an increased risk of incident stroke/TIA (HR comparing BDNF Q1 versus Q2–4:1.47, 95%CI:1.09–2.00, p=0.012; and HR/SD increase in logVEGF:1.21, 95%CI:1.04–1.40, p=0.012). Persons with higher BDNF levels had less lWMHV (β±SE=−0.05±0.02; p=0.025), and better visual memory (β±SE=0.18±0.07; p=0.005).
Conclusions
Lower serum BDNF and higher VEGF concentrations were associated with increased risk of incident stroke/TIA. Higher levels of BDNF were also associated with less white matter hyperintensity and better visual memory. Our findings suggest that circulating BDNF and VEGF levels modify risk of clinical and subclinical vascular brain injury.
doi:10.1161/STROKEAHA.113.001447
PMCID: PMC3873715  PMID: 23929745
BDNF; VEGF; Risk; Stroke; Brain MRI; Subclinical
6.  Brain Imaging and Cognitive Predictors of Stroke and Alzheimer Disease in the Framingham Heart Study 
Background and purpose
Exposure to vascular risk factors has a gradual deleterious effect on brain MRI and cognitive measures. We explored whether a pattern of these measures exists that predicts stroke and Alzheimer’s disease (AD) risk.
Methods
A cognitive battery was administered to 1,679 dementia and stroke-free Framingham Offspring (age>55; mean=65.7±7.0) between 1999 and 2004; participants were also free of other neurological conditions that could affect cognition and >90% also had brain MRI examination. We related cognitive and MRI measures to risks of incident stroke and AD during up to 10 years of follow-up. As a secondary analysis, we explored these associations in the FHS Original cohort (mean age 67.5±7.3 and 84.8±3.3 at the cognitive assessment and MRI examination, respectively).
Results
A total of 55 Offspring participants sustained strokes and 31 developed AD. Offspring who scored <1.5 standard-deviations below predicted mean scores, for age and education, on an executive function test, had a higher risk of future stroke (HR=2.27;95%CI:1.06–4.85) and AD (3.60;95%CI:1.52–8.52); additional cognitive tests also predicted AD. Participants with low (<20%ile) total brain volume and high (>20%ile) white matter hyperintensity volume had a higher risk of stroke (HR=1.97;95%CI:1.03–3.77 and HR=2.74;95%CI:1.51–5.00, respectively) but not AD. Hippocampal volume at the bottom quintile predicted AD in the Offspring and Original cohorts (HR=4.41;95%CI:2.00–9.72 and HR=2.37;95%CI:1.12–5.00, respectively). A stepwise increase in stroke risk was apparent with increasing numbers of these cognitive and imagingmarkers.
Conclusions
Specific patterns of cognitive and brain structural measures observed even in early aging predict stroke risk and may serve as biomarkers for risk prediction.
doi:10.1161/STROKEAHA.113.000947
PMCID: PMC3974341  PMID: 23920020
stroke; Alzheimer’s disease; cognitive function; brain MRI
7.  Clinical subtypes of chronic traumatic encephalopathy: literature review and proposed research diagnostic criteria for traumatic encephalopathy syndrome 
The long-term consequences of repetitive head impacts have been described since the early 20th century. Terms such as punch drunk and dementia pugilistica were first used to describe the clinical syndromes experienced by boxers. A more generic designation, chronic traumatic encephalopathy (CTE), has been employed since the mid-1900s and has been used in recent years to describe a neurodegenerative disease found not just in boxers but in American football players, other contact sport athletes, military veterans, and others with histories of repetitive brain trauma, including concussions and subconcussive trauma. This article reviews the literature of the clinical manifestations of CTE from 202 published cases. The clinical features include impairments in mood (for example, depression and hopelessness), behavior (for example, explosivity and violence), cognition (for example, impaired memory, executive functioning, attention, and dementia), and, less commonly, motor functioning (for example, parkinsonism, ataxia, and dysarthria). We present proposed research criteria for traumatic encephalopathy syndrome (TES) which consist of four variants or subtypes (TES behavioral/mood variant, TES cognitive variant, TES mixed variant, and TES dementia) as well as classifications of ‘probable CTE’ and ‘possible CTE’. These proposed criteria are expected to be modified and updated as new research findings become available. They are not meant to be used for a clinical diagnosis. Rather, they should be viewed as research criteria that can be employed in studies of the underlying causes, risk factors, differential diagnosis, prevention, and treatment of CTE and related disorders.
doi:10.1186/s13195-014-0068-z
PMCID: PMC4288217  PMID: 25580160
8.  Relations of arterial stiffness and endothelial function to brain aging in the community 
Neurology  2013;81(11):984-991.
Objective:
To determine the association of arterial stiffness and pressure pulsatility, which can damage small vessels in the brain, with vascular and Alzheimer-type brain aging.
Methods:
Stroke- and dementia-free Framingham Offspring Study participants (n = 1,587, 61 ± 9 years, 45% male) underwent study of tonometric arterial stiffness and endothelial function (1998–2001) and brain MRI and cognition (1999–2002). We related carotid-femoral pulse wave velocity (CFPWV), mean arterial and central pulse pressure, and endothelial function to vascular brain aging by MRI (total cerebral brain volume [TCBV], white matter hyperintensity volume, silent cerebral infarcts) and vascular and Alzheimer-type cognitive aging (Trails B minus Trails A and logical memory-delayed recall, respectively).
Results:
Higher CFPWV was associated with lower TCBV, greater white matter hyperintensity volume, and greater prevalence of silent cerebral infarcts (all p < 0.05). Each SD greater CFPWV was associated with lower TCBV equivalent to 1.2 years of brain aging. Mean arterial and central pulse pressure were associated with greater white matter hyperintensity volume (p = 0.005) and lower TCBV (p = 0.02), respectively, and worse verbal memory (both p < 0.05). Associations of tonometry variables with TCBV and white matter hyperintensity volume were stronger among those aged 65 years and older vs those younger than 65 years (p < 0.10 for interaction). Brachial artery endothelial function was unrelated to MRI measures (all p > 0.05).
Conclusions:
Greater arterial stiffness and pressure pulsatility are associated with brain aging, MRI vascular insults, and memory deficits typically seen in Alzheimer dementia. Future investigations are warranted to evaluate the potential impact of prevention and treatment of unfavorable arterial hemodynamics on neurocognitive outcomes.
doi:10.1212/WNL.0b013e3182a43e1c
PMCID: PMC3888200  PMID: 23935179
9.  Neuropsychological Criteria for Mild Cognitive Impairment Improves Diagnostic Precision, Biomarker Associations, and Progression Rates 
We compared two methods of diagnosing mild cognitive impairment (MCI): conventional Petersen/Winblad criteria as operationalized by the Alzheimer’s Disease Neuroimaging Initiative (ADNI) and an actuarial neuropsychological method put forward by Jak and Bondi designed to balance sensitivity and reliability. 1,150 ADNI participants were diagnosed at baseline as cognitively normal (CN) or MCI via ADNI criteria (MCI: n = 846; CN: n = 304) or Jak/Bondi criteria (MCI: n = 401; CN: n = 749), and the two MCI samples were submitted to cluster and discriminant function analyses. Resulting cluster groups were then compared and further examined for APOE allelic frequencies, cerebrospinal fluid (CSF) Alzheimer’s disease (AD) biomarker levels, and clinical outcomes. Results revealed that both criteria produced a mildly impaired Amnestic subtype and a more severely impaired Dysexecutive/Mixed subtype. The neuropsychological Jak/Bondi criteria uniquely yielded a third Impaired Language subtype, whereas conventional Petersen/Winblad ADNI criteria produced a third subtype comprising nearly one-third of the sample that performed within normal limits across the cognitive measures, suggesting this method’s susceptibility to false positive diagnoses. MCI participants diagnosed via neuropsychological criteria yielded dissociable cognitive phenotypes, significant CSF AD biomarker associations, more stable diagnoses, and identified greater percentages of participants who progressed to dementia than conventional MCI diagnostic criteria. Importantly, the actuarial neuropsychological method did not produce a subtype that performed within normal limits on the cognitive testing, unlike the conventional diagnostic method. Findings support the need for refinement of MCI diagnoses to incorporate more comprehensive neuropsychological methods, with resulting gains in empirical characterization of specific cognitive phenotypes, biomarker associations, stability of diagnoses, and prediction of progression. Refinement of MCI diagnostic methods may also yield gains in biomarker and clinical trial study findings because of improvements in sample compositions of ‘true positive’ cases and removal of ‘false positive’ cases.
doi:10.3233/JAD-140276
PMCID: PMC4133291  PMID: 24844687
Alzheimer’s disease; Alzheimer’s Disease Neuroimaging Initiative; biomarker; cluster analysis; dementia; mild cognitive impairment; neuropsychology; progression
10.  APOE genotype and MRI markers of cerebrovascular disease 
Neurology  2013;81(3):292-300.
Objective:
We aimed to examine the association of APOE ε genotype with MRI markers of cerebrovascular disease (CVD): white matter hyperintensities, brain infarcts, and cerebral microbleeds.
Methods:
We performed a systematic review and meta-analysis of 42 cross-sectional or longitudinal studies identified in PubMed from 1966 to June 2012 (n = 29,965). This included unpublished data from 3 population-based studies: 3C-Dijon, Framingham Heart Study, and Sydney Memory and Ageing Study. When necessary, authors were contacted to provide effect estimates for the meta-analysis.
Results:
APOE ε4 carrier status and APOE ε44 genotype were associated with increasing white matter hyperintensity burden (sample size–weighted z score meta-analysis [meta]-p = 0.0034 and 0.0030) and presence of cerebral microbleeds (meta odds ratio [OR] = 1.24, 95% confidence interval [CI] [1.07, 1.43], p = 0.004, and 1.87 [1.26, 2.78], p = 0.002), especially lobar. APOE ε2 carrier status was associated with increasing white matter hyperintensity load (z score meta-p = 0.00053) and risk of brain infarct (meta OR = 1.41[1.09, 1.81], p = 0.008).
Conclusions:
APOE ε4 and APOE ε2 were associated with increasing burden in MRI markers for both hemorrhagic and ischemic CVD. While the association of APOE ε4 with an increased burden of CVD could be partly contributing to the relationship between APOE ε4 and AD, APOE ε2 was associated with MRI markers of CVD in the opposite direction compared to AD.
doi:10.1212/WNL.0b013e31829bfda4
PMCID: PMC3770168  PMID: 23858411
11.  Lexical retrieval in discourse: An early indicator of Alzheimer's dementia 
Clinical linguistics & phonetics  2013;27(12):905-921.
We examined the progression of lexical-retrieval deficits in individuals with neuropathologically determined Alzheimer's disease (AD; n = 23) and a comparison group without criteria for AD (n = 24) to determine whether linguistic changes were a significant marker of the disease. Our participants underwent multiple administrations of a neuropsychological battery, with initial administration occurring on average 16 years prior to death. The battery included the Boston Naming Test (BNT), a letter fluency task (FAS), and written description of the Cookie Theft Picture (CTP).
Repeated measures analysis revealed that the AD-group showed progressively greater decline in FAS and CTP lexical performance than the comparison group. Cross-sectional time-specific group comparisons indicated that the CTP differentiated performance between the two groups at 7–9 years prior to death and FAS and BNT only at 2–4 years. These results suggest that lexical-retrieval deficits in written discourse serve as an early indicator of AD.
doi:10.3109/02699206.2013.815278
PMCID: PMC4095845  PMID: 23985011
discourse; naming; early markers; neuropathology; Alzheimer's disease
12.  Serum Brain-Derived Neurotrophic Factor and the Risk for Dementia 
JAMA neurology  2014;71(1):55-61.
IMPORTANCE
In animal studies, brain-derived neurotrophic factor (BDNF) has been shown to impact neuronal survival and function and improve synaptic plasticity and long-term memory. Circulating BDNF levels increase with physical activity and caloric restriction, thus BDNF may mediate some of the observed associations between lifestyle and the risk for dementia. Some prior studies showed lower circulating BDNF in persons with Alzheimer disease (AD) compared with control participants; however, it remains uncertain whether reduced levels precede dementia onset.
OBJECTIVE
To examine whether higher serum BDNF levels in cognitively healthy adults protect against the future risk for dementia and AD and to identify potential modifiers of this association.
DESIGN, SETTING, AND PARTICIPANTS
Framingham Study original and offspring participants were followed up from 1992 and 1998, respectively, for up to 10 years. We used Cox models to relate BDNF levels to the risk for dementia and AD and adjusted for potential confounders. We also ran sensitivity analyses stratified by sex, age, and education, as well as related BDNF genetic variants to AD risk. This community-based, prospective cohort study involved 2131 dementia-free participants aged 60 years and older (mean [SD] age, 72 [7] years; 56% women).
MAIN OUTCOMES AND MEASURES
Ten-year incidence of dementia and AD.
RESULTS
During follow-up, 140 participants developed dementia, 117 of whom had AD. Controlling for age and sex, each standard-deviation increment in BDNF was associated with a 33% lower risk for dementia and AD (P = .006 and P = .01, respectively) and these associations persisted after additional adjustments. Compared with the bottom quintile, BDNF levels in the top quintile were associated with less than half the risk for dementia and AD (hazard ratio, 0.49; 95%CI, 0.28–0.85; P = .01; and hazard ratio, 0.46; 95%CI, 0.24–0.86; P = .02, respectively). These associations were apparent only among women, persons aged 80 years and older, and those with college degrees (hazard ratios for AD: 0.65, [95%CI, 0.50–0.85], P = .001; 0.63 [95%CI, 0.47–0.85], P = .002; and 0.27 [95%CI, 0.11–0.65], P = .003, respectively). Brain-derived neurotrophic factor genetic variants were not associated with AD risk.
CONCLUSIONS AND RELEVANCE
Higher serum BDNF levels may protect against future occurrence of dementia and AD. Our findings suggest a role for BDNF in the biology and possibly in the prevention of dementia and AD, especially in select subgroups of women and older and more highly educated persons.
doi:10.1001/jamaneurol.2013.4781
PMCID: PMC4056186  PMID: 24276217
13.  Association of Parental Stroke with Brain Injury and Cognitive Measures in Offspring – The Framingham Heart Study 
Background and purpose
Parental stroke has been related to an increased risk of stroke in the offspring. This study examines whether parental stroke is also associated with increased vascular brain injury and poorer cognitive performance among offspring free of clinical stroke.
Methods
Multivariable regression analyses were used to relate parental stroke to cross-sectional and change in brain magnetic resonance imaging measures and cognitive function among the offspring, with and without adjustment for vascular risk factors.
Results
Stroke- and dementia-free Framingham Offspring (n=1,297, age:61±9 years, 54% women) were studied. Parental stroke by age 65 years was associated with a higher baseline white matter hyperintensity volume (WMHV;β=0.17±0.08; p=0.027), and with lower visual memory performance (β =−0.80±0.34; p=0.017). During a 6 year follow-up, parental stroke was also associated with increase in WMHV (odds ratio [OR] = 1.87;95%CI:1.03–3.38) and decline in executive function (Trails B–A; OR=1.81;95%CI:1.06–3.09). The associations with WMHV and visual memory attenuated after additional adjustment for concomitant vascular risk factors.
Conclusions
Parental stroke by age 65 years is associated with increased vascular brain injury and lower memory in offspring equivalent to 3 and 7 years of brain aging, respectively. This may be partly attributed to inheritance of vascular risk factors.
doi:10.1161/STROKEAHA.112.680520
PMCID: PMC3752976  PMID: 23362080
stroke; cognitive function; brain MRI
14.  Apolipoprotein Epsilon 4 Allele Modifies Waist-to-Hip Ratio Effects on Cognition and Brain Structure 
This study aimed to determine whether relationships between obesity, as measured by waist-to-hip ratio (WHR), and cognition and brain structure were modified by the apolipoprotein epsilon 4 allele (apoE4). The sample included 1,969 stroke and dementia-free participants from the Framingham Offspring Cohort who underwent neuropsychological (NP) testing and structural Magnetic Resonance Imaging (MRI) between 1999–2002. WHR was categorized into sex-specific quartiles with those in Q4 representing central obesity. Multivariate linear regression estimated the relationships between Q4-WHR, cognitive and MRI measures; interaction terms examined modification of these relationships by the presence of apoE4. All analyses were cross sectional.
ApoE4 status significantly modified a number of associations. Specifically, we observed a significant negative relationship between Q4-WHR and a measure of executive function in the apoE4+ group but not in the apoE4− group. Similarly, we observed a stronger negative relationship between Q4-WHR and a measure of memory function for those in the apoE4+ group compared to those in the apoE4− group. Additionally, apoE4 status modified the relationship between Q4-WHR and two measures of structural brain integrity. First, a paradoxical finding of a negative association between WHR and frontal brain volume that was significant only for those in the apoE4- group, and a second finding that WHR was significantly associated with greater white matter hyperintensity volume only in the apoE4+ group.
These findings suggest that associations between central adiposity and both neuropsychological performance and underlying brain structure are highly complex and must be considered in the context of possible modifying genetic influences.
doi:10.1016/j.jstrokecerebrovasdis.2011.06.020
PMCID: PMC3613758  PMID: 21835633
waist-to-hip ratio; apoE4; metabolic syndrome; obesity; Alzheimer’s disease
15.  Risk estimations, risk factors and genetic variants associated with Alzheimer Disease in selected publications from the Framingham Heart Study 
Journal of Alzheimer's disease : JAD  2013;33(0 1):S439-S445.
The study of Alzheimer Disease (AD) in the Framingham Heart Study (FHS), a multi-generational, community-based population study, began nearly four decades ago. In this overview, we highlight findings from 7 prior publications that examined lifetime risk estimates for AD, environmental risk factors for AD, circulating and imaging markers of aging-related brain injury and explorations on the genetics underlying AD.
doi:10.3233/JAD-2012-129040
PMCID: PMC3672236  PMID: 22796871
Cohort Studies; Alzheimer's disease; Risk factors; Cerebrovascular Disorders; Genetic variation
16.  QUALITATIVE NEUROPSYCHOLOGICAL MEASURES: NORMATIVE DATA ON EXECUTIVE FUNCTIONING TESTS FROM THE FRAMINGHAM OFFSPRING STUDY 
Experimental aging research  2013;39(5):10.1080/0361073X.2013.839029.
Background/Study Context
Studies have found that executive functioning is affected early in the pathophysiological processes associated with Alzheimer’s disease and vascular dementia. There also exists a range of functioning on executive tasks during normal aging. Although qualitative data are commonly utilized in clinical practice for evaluating subtle changes in cognitive functioning and diagnostic discernment, it is not clear whether error responses used in clinical practice are also evident as normative behavior.
Methods
As part of an extensive battery of neuropsychological tests, executive functioning measures (i.e., Trail Making-B, Similarities and Verbal Fluency tests) were administered via standardized administration prescript. Regression analyses were used to determine associations between vascular aging indices and qualitative performance measures. Descriptive statistics are included for 1907 cognitively normal individuals.
Results
Results suggest that while qualitative errors do occur, they are relatively infrequent within a presumably cognitively normal sample. Error commission rates on executive functioning tests are significantly associated with both age and education.
Conclusion
Provided is a baseline profile of errors committed on tests of executive function across a range of age and educational levels. The normative datasets are included, stratified by age and educational achievement, for which to compare qualitative test performance of clinical and research populations.
doi:10.1080/0361073X.2013.839029
PMCID: PMC3836045  PMID: 24151914
17.  COSMIC (Cohort Studies of Memory in an International Consortium): An international consortium to identify risk and protective factors and biomarkers of cognitive ageing and dementia in diverse ethnic and sociocultural groups 
BMC Neurology  2013;13:165.
Background
A large number of longitudinal studies of population-based ageing cohorts are in progress internationally, but the insights from these studies into the risk and protective factors for cognitive ageing and conditions like mild cognitive impairment and dementia have been inconsistent. Some of the problems confounding this research can be reduced by harmonising and pooling data across studies. COSMIC (Cohort Studies of Memory in an International Consortium) aims to harmonise data from international cohort studies of cognitive ageing, in order to better understand the determinants of cognitive ageing and neurocognitive disorders.
Methods/Design
Longitudinal studies of cognitive ageing and dementia with at least 500 individuals aged 60 years or over are eligible and invited to be members of COSMIC. There are currently 17 member studies, from regions that include Asia, Australia, Europe, and North America. A Research Steering Committee has been established, two meetings of study leaders held, and a website developed. The initial attempts at harmonising key variables like neuropsychological test scores are in progress.
Discussion
The challenges of international consortia like COSMIC include efficient communication among members, extended use of resources, and data harmonisation. Successful harmonisation will facilitate projects investigating rates of cognitive decline, risk and protective factors for mild cognitive impairment, and biomarkers of mild cognitive impairment and dementia. Extended implications of COSMIC could include standardised ways of collecting and reporting data, and a rich cognitive ageing database being made available to other researchers. COSMIC could potentially transform our understanding of the epidemiology of cognitive ageing, and have a world-wide impact on promoting successful ageing.
doi:10.1186/1471-2377-13-165
PMCID: PMC3827845  PMID: 24195705
Cohort studies; Cognitive ageing; Data harmonisation; Dementia; International consortium; Mild cognitive impairment
18.  Lipoprotein phospholipase A2 (Lp-PLA2) and cerebral microbleeds (CMBs) in the Framingham Heart Study 
Background and Purpose
Cerebral microbleeds (CMBs) due to cerebral amyloid angiopathy generally occur in lobar regions, while those due to hypertensive vasculopathy are deep. Inflammation may be an underlying mechanism for CMB, with varying associations according to CMB location. Lipoprotein phospholipase-A2 (Lp-PLA2) is a circulating enzyme marker of vascular inflammation associated with risk of ischemic stroke and dementia. We hypothesized that higher Lp-PLA2 levels would be related to higher prevalence of CMBs, with possible regional specificity.
Methods
Framingham Offspring participants aged ≥65 years with available Lp-PLA2 measures and brain MRI were included. Logistic regression models were used to relate Lp-PLA2 activity and mass to presence of CMBs, adjusted for age, sex, medication use (aspirin, anticoagulants, and statins), systolic blood pressure, APOE, current smoking, and diabetes.
Results
819 participants (mean age 73 years; 53% women) were included; 106 (13%) had CMBs; 82 (10%) lobar and 27 (3%) deep. We did not observe significant associations of CMB and LpPLA2 measures in multivariable adjusted analyses. However, there was a significant interaction between APOE genotype and Lp-PLA2 activity in their relation to presence of deep CMBs (p-interaction=0.01). Among persons with APOE ε3/ε3, the OR for deep CMB was 0.95 [0.59–1.53; p=0.83], while among those with at least one ε2 or ε4 allele, OR=3.46 [1.43–8.36; p=0.006].
Conclusions
In our community-based sample of older adults, there was no significant association of Lp-PLA2 with total or lobar CMBs. The association of higher levels of Lp-PLA2 activity with deep CMBs among those with at least one APOE ε2 or ε4 allele merits replication.
doi:10.1161/STROKEAHA.112.656744
PMCID: PMC3544291  PMID: 22961963
19.  Are Empirically-Derived Subtypes of Mild Cognitive Impairment Consistent with Conventional Subtypes? 
Given the importance of identifying dementia prodromes for future treatment efforts, we examined two methods of diagnosing mild cognitive impairment (MCI) and determined whether empirically-derived MCI subtypes of these diagnostic methods were consistent with one another as well as with conventional MCI subtypes (i.e., amnestic, non-amnestic, single-domain, multi-domain). Participants were diagnosed with MCI using either conventional Petersen/Winblad criteria (n = 134; >1.5 SDs below normal on one test within a cognitive domain) or comprehensive neuropsychological criteria developed by Jak et al. (2009) (n = 80; >1 SD below normal on two tests within a domain), and the resulting samples were examined via hierarchical cluster and discriminant function analyses. Results showed that neuropsychological profiles varied depending on the criteria used to define MCI. Both criteria revealed an Amnestic subtype, consistent with prodromal Alzheimer’s disease (AD), and a Mixed subtype that may capture individuals in advanced stages of MCI. The comprehensive criteria uniquely yielded Dysexecutive and Visuospatial subtypes, whereas the conventional criteria produced a subtype that performed within normal limits, suggesting its susceptibility to false positive diagnostic errors. Whether these empirically-derived MCI subtypes correspond to dissociable neuropathologic substrates and represent reliable prodromes of dementia will require additional follow-up.
doi:10.1017/S1355617713000313
PMCID: PMC3742806  PMID: 23552486
Mild cognitive impairment; Amnestic MCI; Non-amnestic MCI; Dementia; Cluster analysis; Neuropsychology
20.  The Framingham Heart Study Clock Drawing Performance: Normative Data from the Offspring Cohort 
Experimental aging research  2013;39(1):80-108.
Background/Study Context
While the Clock Drawing Test (CDT) is a popular tool used to assess cognitive function, limited normative data on CDT performance exists. The objective of the current study was to provide normative data on an expanded version of previous CDT scoring protocols from a large community-based sample of middle to older adults (aged 43 to 91) from the Framingham Heart Study.
Methods
The CDT was administered to 1476 Framingham Heart Study Offspring Cohort participants using a scoring protocol that assigned error scores to drawn features. Total error scores were computed, as well as for subscales pertaining to outline, numeral placement, time-setting, center, and “other.”
Results
Higher levels of education were significantly associated with fewer errors for time-setting (Command: p<.001; Copy: p=.003), numerals (Command: p<.001) and “other” (Command: p<.001) subscales. Older age was significantly associated with more errors for time-setting (Command: p<.001; Copy: p=.003), numeral (Command: p<.001) and “other” (Command: p<.001) subscales. Significant differences were also found between education groups on the Command condition for all but the oldest age group (75+).
Conclusion
Results provide normative data on CDT performance within a community-based cohort. Errors appear to be more prevalent in older compared with younger individuals, and may be less prevalent in individuals who completed at least some college compared with those who did not. Future studies are needed to determine whether this expanded scoring system allows detection of preclinical symptoms of future risk for dementia.
doi:10.1080/0361073X.2013.741996
PMCID: PMC3612583  PMID: 23316738
Clock Drawing Test; Normal aging; Scoring methods; Neuropsychological tests; Dementia; Cognitive screening
21.  Multiple Biomarkers and Risk of Clinical and Subclinical Vascular Brain Injury: The Framingham Offspring Study 
Circulation  2012;125(17):2100-2107.
Background
Several biomarkers have been individually associated with vascular brain injury but no prior study has explored the simultaneous association of a biologically plausible panel of biomarkers with the incidence of stroke/TIA, and the prevalence of subclinical brain injury.
Methods and Results
In 3127 stroke-free Framingham Offspring (59±10 yrs, 54%F), we related a panel of 8 biomarkers assessing inflammation(C-reactive protein[CRP]), hemostasis(D-dimer and plasminogen activator inhibitor-1), neurohormonal activity(aldosterone-to renin ratio, B-type natriuretic peptide[BNP] and N-terminal pro-atrial natriuretic peptides) and endothelial function (homocysteine and urinary albumin/creatinine ratio[UACR]) measured at the 6th examination(1995–98) to risk of incident stroke/TIA. In a subset of 1901 participants with available brain MRI (1999–2005), we further related these biomarkers to total cerebral brain volume (TCBV), covert brain infarcts (CBI), and large white matter hyperintensity volume(LWMHV).
During a median follow-up of 9.2 years, 130 participants experienced incident stroke/TIA. In multivariable analyses adjusted for stroke risk factors, the biomarker panel was associated with incident stroke/TIA and with TCBV (p<0.05 for both), but not with CBI or LWMHV (p >0.05). In backwards elimination analyses higher log-BNP (hazards ratio [HR] 1.39/SD, p=0.002) and log-UACR (HR1.31/SD, p=0.004) were associated with increased risk of stroke/TIA and improved risk prediction over using the Framingham stroke risk profile alone; using <5%, 5–15% or >15% 10-year risk categories the net reclassification index was 0.109;p=0.037). Higher CRP (β=−0.21/SD,p=0.008), D-dimer(β==−0.18/SD,p=0.041), tHcy(β=−0.21/SD,p=0.005), and UACR(β=−0.15/SD,p=0.042) were associated with lower TCBV.
Conclusions
In a middle-aged community sample, we identified multiple biomarkers that were associated with clinical and subclinical vascular brain injury and could improve risk stratification.
doi:10.1161/CIRCULATIONAHA.110.989145
PMCID: PMC3427730  PMID: 22456473
biomarkers; epidemiology; magnetic resonance imaging; risk stratification; stroke prevention
22.  Common variants at 6q22 and 17q21 are associated with intracranial volume 
Nature genetics  2012;44(5):539-544.
During aging, intracranial volume remains unchanged and represents maximally attained brain size, while various interacting biological phenomena lead to brain volume loss. Consequently, intracranial volume and brain volume in late life reflect different genetic influences. Our genome-wide association study in 8,175 community-dwelling elderly did not reveal any genome-wide significant associations (p<5*10−8) for brain volume. In contrast, intracranial volume was significantly associated with two loci: rs4273712 (p=3.4*10−11), a known height locus on chromosome 6q22, and rs9915547, tagging the inversion on chromosome 17q21 (p=1.5*10−12). We replicated the associations of these loci with intracranial volume in a separate sample of 1,752 older persons (p=1.1*10−3 for 6q22 and p=1.2*10−3 for 17q21). Furthermore, we also found suggestive associations of the 17q21 locus with head circumference in 10,768 children (mean age 14.5 months). Our data identify two loci associated with head size, with the inversion on 17q21 also likely involved in attaining maximal brain size.
doi:10.1038/ng.2245
PMCID: PMC3618290  PMID: 22504418
23.  The Framingham Brain Donation Program: Neuropathology Along the Cognitive Continuum 
Current Alzheimer research  2012;9(6):673-686.
The Framingham Heart Study has enrolled 3 generations of participants, the Original cohort (Gen 1) enrolled in 1948, the Offspring cohort (Gen 2) enrolled in 1971 and the Third Generation enrolled in 2002. Participants have been undergoing prospective surveillance for incident stroke and dementia and embedded within this cohort is the voluntary Framingham Brain Donation Program that was begun in 1997. Participants who register to become brain donors have had one or more brain MR and cognitive test batteries administered. In addition, they undergo neurological evaluation as indicated, record review and post-mortem next-of-kin interview to determine the presence, type and extent of antemortem, clinical neurological diagnoses and to assign a retrospective Clinical Dementia Rating (CDR) Scale score. Between 1997 and 2009 there were 1806 deaths, 186 of which were among registered brain donors and of these 139 brains could be examined. 58% were deemed cognitively normal at death. We present results for 3 projects; the first was to examine the sensitivity and specificity of our clinical diagnosis against the gold standard of pathological AD in 59 persons who underwent detailed cognitive assessment in the two years prior to death; we observed a 77.3% sensitivity (2 persons with AD were diagnosed clinically as Lewy body dementia) and a 91.9% specificity. The second examined the correlation of regional Alzheimer-type pathology to cognitive status at death among 34 persons who were over the age of 75 and without any significant vascular or alternative neurodegenerative pathology and found that neurofibrillary tangle counts distinguished between persons who were controls, had mild cognitive impairment, mild or moderate dementia; tangles in dorsolateral frontal cortex best distinguished MCI and controls. The third project examined the extent and severity of vascular pathology, again in a larger sample of varying cognitive abilities and in a subsample of persons with either amnestic or non-amnestic MCI. We observed that an aggregate ischemic injury score was significantly higher in persons with a CDR score of 0.5 than in normal controls.
PMCID: PMC3622706  PMID: 22471865
Brain; autopsy; epidemiology; alzheimer's disease; brain ischemia
24.  Biomarkers for Insulin Resistance and Inflammation and the Risk for All-Cause Dementia and Alzheimer Disease 
Archives of neurology  2012;69(5):10.1001/archneurol.2011.670.
Objective
To investigate the contribution of biomarkers of glucose homeostasis (adiponectin, glucose, glycated albumin, and insulin levels) and inflammation (high-sensitivity C-reactive protein and lipoprotein-associated phospholipase A2 levels) to the risk of developing Alzheimer disease (AD) and all-cause dementia.
Design
Prospective cohort study.
Setting
Dementia-free Framingham Heart Study participants had sera measured for these biomarkers at the 19th biennial examination (1985–1988) and were followed up prospectively for the development of AD and all-cause dementia.
Participants
Eight hundred forty (541 women, median age of 76 years) subjects participated in the study.
Main Outcome Measures
We used sex-pooled and sex-specific multivariable Cox proportional hazards models adjusted for age, education, body mass index, recent change in weight, APOE ε4 allele status, and plasma docosahexaenoic acid levels to determine association of these biomarkers with the development of all-cause dementia and AD.
Results
Over a mean follow-up period of 13 years, 159 persons developed dementia (including 125 with AD). After adjustment for other risk factors, only adiponectin in women was associated with an increased risk of all-cause dementia (hazard ratio [HR], 1.29; 95% confidence interval [CI], 1.00–1.66; P=.054) and AD (HR, 1.33; 95% CI, 1.00–1.76; P=.050) per 1-SD increase in adiponectin level. Women with baseline adiponectin values more than the median had a higher risk of all-cause dementia (HR, 1.63; 95% CI, 1.03–2.56; P=.04) and AD (HR, 1.87; 95% CI, 1.13–3.10; P=.01) as compared with those with values less than the median.
Conclusion
In women, increased plasma adiponectin levels are an independent risk factor for the development of both all-cause dementia and AD.
doi:10.1001/archneurol.2011.670
PMCID: PMC3512190  PMID: 22213409
25.  Effects of systolic blood pressure on white-matter integrity in young adults in the Framingham Heart Study: a cross-sectional study 
Lancet neurology  2012;11(12):1039-1047.
Summary
Background
Previous studies have identified effects of age and vascular risk factors on brain injury in elderly individuals. We aimed to establish whether the effects of high blood pressure in the brain are evident as early as the fifth decade of life.
Methods
In an investigation of the third generation of the Framingham Heart Study, we approached all participants in 2009 to ask whether they would be willing to undergo MRI. Consenting patients underwent clinical assessment and cerebral MRI that included T1-weighted and diffusion tensor imaging to obtain estimates of fractional anisotropy, mean diffusivity, and grey-matter volumes. All images were coregistered to a common minimum deformation template for voxel-based linear regressions relating fractional anisotropy, mean diffusivity, and grey-matter volumes to age and systolic blood pressure, with adjustment for potential confounders.
Findings
579 (14·1%) of 4095 participants in the third-generation cohort (mean age 39·2 years, SD 8·4) underwent brain MRI between June, 2009 and June, 2010. Age was associated with decreased fractional anisotropy and increased mean diffusivity in almost all cerebral white-matter voxels. Age was also independently associated with reduced grey-matter volumes. Increased systolic blood pressure was linearly associated with decreased regional fractional anisotropy and increased mean diffusivity, especially in the anterior corpus callosum, the inferior fronto-occipital fasciculi, and the fibres that project from the thalamus to the superior frontal gyrus. It was also strongly associated with reduced grey-matter volumes, particularly in Brodmann’s area 48 on the medial surface of the temporal lobe and Brodmann’s area 21 of the middle temporal gyrus.
Interpretation
Our results suggest that subtle vascular brain injury develops insidiously during life, with discernible effects even in young adults. These findings emphasise the need for early and optimum control of blood pressure.
Funding
National Institutes of Health and National Heart, Lung, and Blood Institute; National Institute on Aging; and National Institute of Neurological Disorders and Stroke.
doi:10.1016/S1474-4422(12)70241-7
PMCID: PMC3510663  PMID: 23122892

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