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ABSTRACT: 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=1297, age, 61±9 years, 54% women) were studied. Parental stroke by age 65 years was associated with a higher baseline white matter hyperintensity volume (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 white matter hyperintensity volume (odds ratio [OR], 1.87; 95% confidence interval [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 white matter hyperintensity volume 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.
Stroke 01/2013; · 5.73 Impact Factor
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ABSTRACT: INTRODUCTION:: Psychometric definitions of mild cognitive impairment (MCI) typically use cut-off levels set at 1.5 SDs below age-adjusted and education-adjusted norms, assuming that the education adjustment accounts for premorbid abilities. However, noncognitive 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:: A total of 935 Framingham Offspring (mean age, 72±5 y) 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 2 MCI definitions differed most for the lowest and highest education groups. The WRAT definition was more strongly associated with incident dementia for all 5 tests. MCI level abstraction performance was associated with incident dementia using the WRAT definition (HR=3.20, P=0.033), but not the education definition (HR=1.19, P=0.814). 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.
Alzheimer disease and associated disorders 01/2013; · 2.88 Impact Factor
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Justin A Nyborn,
Jayandra J Himali,
Alexa S Beiser,
Sherral A Devine,
Yangchun Du,
Edith Kaplan,
Maureen K O'Connor,
William E Rinn,
Helen S Denison,
Sudha Seshadri,
Philip A Wolf, Rhoda Au
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ABSTRACT: Background/Study Context: Although the Clock Drawing Test (CDT) is a popular tool used to assess cognitive function, limited normative data on CDT performance exist. 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), numerals (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.
Experimental Aging Research 01/2013; 39(1):80-108. · 1.31 Impact Factor
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ABSTRACT: 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.
The Lancet Neurology 11/2012; · 23.46 Impact Factor
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José Rafael Romero,
Sarah R Preis,
Alexa S Beiser,
Charles Decarli,
Dong Young Lee,
Anand Viswanathan,
Emelia J Benjamin,
Joao Fontes, Rhoda Au,
Aleksandra Pikula,
Jimmy Wang,
Carlos S Kase,
Philip A Wolf,
Michael C Irrizary,
Sudha Seshadri
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ABSTRACT: Cerebral microbleeds (CMB) attributable to cerebral amyloid angiopathy generally occur in lobar regions, whereas those attributable 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 CMB, with possible regional specificity.
Framingham Offspring participants aged 65 years or older with available Lp-PLA2 measures and brain magnetic resonance imaging were included. Logistic regression models were used to relate Lp-PLA2 activity and mass to presence of CMB, adjusted for age, sex, medication use (aspirin, anticoagulants, and statins), systolic blood pressure, APOE, current smoking, and diabetes.
Eight-hundred nineteen participants (mean age, 73 years; 53% women) were included; 106 (13%) had CMB, 82 (10%) were lobar, and 27 (3%) were 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 CMB (P interaction=0.01). Among persons with APOE ε3/ε3, the odds ratio for deep CMB was 0.95 (confidence interval, 0.59-1.53; P=0.83), whereas among those with at least 1 ε2 or ε4 allele, odds ratio was 3.46 (confidence interval, 1.43-8.36; P=0.006).
In our community-based sample of older adults, there was no significant association of Lp-PLA2 with total or lobar CMB. The association of higher levels of Lp-PLA2 activity with deep CMB among those with at least 1 APOE ε2 or ε4 allele merits replication.
Stroke 09/2012; 43(11):3091-4. · 5.73 Impact Factor
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ABSTRACT: The study of Alzheimer's 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 seven 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. First, we describe estimations of the lifetime risk of AD. These estimates are distinguished from other measures of disease burden and have substantial public health implications. We then describe prospective studies of environmental AD risk factors: one examined the association between plasma levels of omega-3 fatty-acid and risk of incident AD, the other explored the association of diabetes to this risk in subsamples with specific characteristics. With evidence of inflammation as an underlying mechanism, we also describe findings from a study that compared the effects of serum cytokines and spontaneous production of peripheral blood mononuclear cell cytokines on AD risk. Investigating AD related endophenotypes increases sensitivity in identifying risk factors and can be used to explore pathophysiologic pathways between a risk factor and the disease. We describe findings of an association between large volume of white matter hyperintensities and a specific pattern of cognitive deficits in non-demented participants. Finally, we summarize our findings from two genetic studies: The first used genome-wide association (GWA) and family-based association methods to explore the genetic basis of cognitive and structural brain traits. The second is a large meta-analysis GWA study of AD, in which novel loci of AD susceptibility were found. Together, these findings demonstrate the FHS multi-directional efforts in investigating dementia and AD.
Journal of Alzheimer's disease: JAD 07/2012; · 3.74 Impact Factor
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M Arfan Ikram,
Myriam Fornage,
Albert V Smith,
Sudha Seshadri,
Reinhold Schmidt,
Stéphanie Debette,
Henri A Vrooman,
Sigurdur Sigurdsson,
Stefan Ropele,
H Rob Taal, [......],
Vincent W V Jaddoe,
Vilmundur Gudnason,
B Gwen Windham,
Philip A Wolf,
Cornelia M van Duijn,
Thomas H Mosley,
Helena Schmidt,
Lenore J Launer,
Monique M B Breteler,
Charles DeCarli
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ABSTRACT: 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 (GWAS) in 8,175 community-dwelling elderly persons did not reveal any associations at genome-wide significance (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-associated locus on chromosome 6q22, and rs9915547 (P = 1.5 × 10(-12)), localized to the inversion on chromosome 17q21. We replicated the associations of these loci with intracranial volume in a separate sample of 1,752 elderly persons (P = 1.1 × 10(-3) for 6q22 and 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 of 14.5 months). Our data identify two loci associated with head size, with the inversion at 17q21 also likely to be involved in attaining maximal brain size.
Nature Genetics 04/2012; 44(5):539-44. · 35.53 Impact Factor
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Joshua C Bis,
Charles DeCarli,
Albert Vernon Smith,
Fedde van der Lijn,
Fabrice Crivello,
Myriam Fornage,
Stephanie Debette,
Joshua M Shulman,
Helena Schmidt,
Velandai Srikanth, [......],
W T Longstreth,
Matthew A Brown,
David A Bennett,
Cornelia M van Duijn,
Thomas H Mosley,
Reinhold Schmidt,
Christophe Tzourio,
Lenore J Launer,
M Arfan Ikram,
Sudha Seshadri
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ABSTRACT: Aging is associated with reductions in hippocampal volume that are accelerated by Alzheimer's disease and vascular risk factors. Our genome-wide association study (GWAS) of dementia-free persons (n = 9,232) identified 46 SNPs at four loci with P values of <4.0 × 10(-7). In two additional samples (n = 2,318), associations were replicated at 12q14 within MSRB3-WIF1 (discovery and replication; rs17178006; P = 5.3 × 10(-11)) and at 12q24 near HRK-FBXW8 (rs7294919; P = 2.9 × 10(-11)). Remaining associations included one SNP at 2q24 within DPP4 (rs6741949; P = 2.9 × 10(-7)) and nine SNPs at 9p33 within ASTN2 (rs7852872; P = 1.0 × 10(-7)); along with the chromosome 12 associations, these loci were also associated with hippocampal volume (P < 0.05) in a third younger, more heterogeneous sample (n = 7,794). The SNP in ASTN2 also showed suggestive association with decline in cognition in a largely independent sample (n = 1,563). These associations implicate genes related to apoptosis (HRK), development (WIF1), oxidative stress (MSR3B), ubiquitination (FBXW8) and neuronal migration (ASTN2), as well as enzymes targeted by new diabetes medications (DPP4), indicating new genetic influences on hippocampal size and possibly the risk of cognitive decline and dementia.
Nature Genetics 04/2012; 44(5):545-51. · 35.53 Impact Factor
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Aleksandra Pikula,
Alexa S Beiser,
Charles DeCarli,
Jayandra J Himali,
Stephanie Debette, Rhoda Au,
Jacob Selhub,
Geoffrey H Toffler,
Thomas J Wang,
James B Meigs,
Margaret Kelly-Hayes,
Carlos S Kase,
Philip A Wolf,
Ramachandran S Vasan,
Sudha Seshadri
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ABSTRACT: 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/transient ischemic attack and the prevalence of subclinical brain injury.
In 3127 stroke-free Framingham offspring (age, 59±10 years; 54% female), we related a panel of 8 biomarkers assessing inflammation (C-reactive protein), hemostasis (D-dimer and plasminogen activator inhibitor-1), neurohormonal activity (aldosterone-to-renin ratio, B-type natriuretic peptide, and N-terminal proatrial natriuretic peptides), and endothelial function (homocysteine and urinary albumin/creatinine ratio) measured at the sixth examination (1995-1998) to risk of incident stroke/transient ischemic attack. In a subset of 1901 participants with available brain magnetic resonance imaging (1999-2005), we further related these biomarkers to total cerebral brain volume, covert brain infarcts, and large white-matter hyperintensity volume. During a median follow-up of 9.2 years, 130 participants experienced incident stroke/transient ischemic attack. In multivariable analyses adjusted for stroke risk factors, the biomarker panel was associated with incident stroke/transient ischemic attack and with total cerebral brain volume (P<0.05 for both) but not with covert brain infarcts or white-matter hyperintensity volume (P>0.05). In backward elimination analyses, higher log-B-type natriuretic peptide (hazard ratio, 1.39 per 1-SD increment; P=0.002) and log-urinary albumin/creatinine ratio (hazard ratio, 1.31 per 1-SD increment; P=0.004) were associated with increased risk of stroke/transient ischemic attack and improved risk prediction compared with the Framingham Stroke Risk Profile alone; when the <5%, 5% to 15%, or >15% 10-year risk category was used, the net reclassification index was 0.109 (P=0.037). Higher C-reactive protein (β=-0.21 per 1-SD increment; P=0.008), D-dimer (β=-0.18 per 1-SD increment; P=0.041), total homocysteine (β=-0.21 per 1-SD increment; P=0.005), and urinary albumin/creatinine ratio (β=-0.15 per 1-SD increment; P=0.042) were associated with lower total cerebral brain volume.
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.
Circulation 03/2012; 125(17):2100-7. · 14.74 Impact Factor
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ABSTRACT: 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 A(2) 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.
Archives of neurology 01/2012; · 6.31 Impact Factor
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M Arfan Ikram,
Myriam Fornage,
Albert V Smith,
Sudha Seshadri,
Reinhold Schmidt,
Stéphanie Debette,
Henri A Vrooman,
Sigurdur Sigurdsson,
Stefan Ropele,
H Rob Taal, [......],
Vincent W V Jaddoe,
Vilmundur Gudnason,
B Gwen Windham,
Philip A Wolf,
Cornelia M van Duijn,
Thomas H Mosley,
Helena Schmidt,
Lenore J Launer,
Monique M B Breteler,
Charles Decarli
Nature Genetics 01/2012; 44(6):732. · 35.53 Impact Factor
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ABSTRACT: To relate cancer since entry into the Framingham Heart Study with the risk of incident Alzheimer's disease and to estimate the risk of incident cancer among participants with and without Alzheimer's disease.
Community based prospective cohort study; nested age and sex matched case-control study.
Framingham Heart Study, USA.
1278 participants with and without a history of cancer who were aged 65 or more and free of dementia at baseline (1986-90).
Hazard ratios and 95% confidence intervals for the risks of Alzheimer's disease and cancer.
Over a mean follow-up of 10 years, 221 cases of probable Alzheimer's disease were diagnosed. Cancer survivors had a lower risk of probable Alzheimer's disease (hazard ratio 0.67, 95% confidence interval 0.47 to 0.97), adjusted for age, sex, and smoking. The risk was lower among survivors of smoking related cancers (0.26, 0.08 to 0.82) than among survivors of non-smoking related cancers (0.82, 0.57 to 1.19). In contrast with their decreased risk of Alzheimer's disease, survivors of smoking related cancer had a substantially increased risk of stroke (2.18, 1.29 to 3.68). In the nested case-control analysis, participants with probable Alzheimer's disease had a lower risk of subsequent cancer (0.39, 0.26 to 0.58) than reference participants, as did participants with any Alzheimer's disease (0.38) and any dementia (0.44).
Cancer survivors had a lower risk of Alzheimer's disease than those without cancer, and patients with Alzheimer's disease had a lower risk of incident cancer. The risk of Alzheimer's disease was lowest in survivors of smoking related cancers, and was not primarily explained by survival bias. This pattern for cancer is similar to that seen in Parkinson's disease and suggests an inverse association between cancer and neurodegeneration.
BMJ (Clinical research ed.). 01/2012; 344:e1442.
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Joshua C Bis,,
Charles DeCarli,,
Albert Vernon Smith,,
Fedde van der Lijn,,
Fabrice Crivello,,
Myriam Fornage,,
Stephanie Debette,,
Joshua M Shulman,,
Helena Schmidt,,
Velandai Srikanth,, [......],
W T Longstreth Jr,,
Matthew A Brown,,
David A Bennett,,
Cornelia M van Duijn,,
Thomas H Mosley,,
Reinhold Schmidt,,
Christophe Tzourio,,
Lenore J Launer,,
M Arfan Ikram,
Sudha Seshadri
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[hide abstract]
ABSTRACT: Aging is associated with reductions in hippocampal volume that are accelerated by Alzheimer's disease and vascular risk factors. Our genome-wide association study (GWAS) of dementia-free persons (n = 9,232) identified 46 SNPs at four loci with P values of <4.0 × 10 −7 . In two additional samples (n = 2,318), associations were replicated at 12q14 within MSRB3-WIF1 (discovery and replication; rs17178006; P = 5.3 × 10 −11) and at 12q24 near HRK-FBXW8 (rs7294919; P = 2.9 × 10 −11). Remaining associations included one SNP at 2q24 within DPP4 (rs6741949; P = 2.9 × 10 −7) and nine SNPs at 9p33 within ASTN2 (rs7852872; P = 1.0 × 10 −7); along with the chromosome 12 associations, these loci were also associated with hippocampal volume (P < 0.05) in a third younger, more heterogeneous sample (n = 7,794). The SNP in ASTN2 also showed suggestive association with decline in cognition in a largely independent sample (n = 1,563). These associations implicate genes related to apoptosis (HRK), development (WIF1), oxidative stress (MSR3B), ubiquitination (FBXW8) and neuronal migration (ASTN2), as well as enzymes targeted by new diabetes medications (DPP4), indicating new genetic influences on hippocampal size and possibly the risk of cognitive decline and dementia. Differences in hippocampal volume that appear with advancing age represent cumulative effects of early-life factors, life-course events and disease. Hippocampal atrophy is a recognized biological marker of Alzheimer's disease 1,2 ; however, it is influenced by various vascular and metabolic factors 3,4 . Because hippocampal volume is a heritable 5 , widely measurable trait that shows meaningful detectable changes throughout life, it is a suitable endophenotype for aging-related physio-logical processes and presymptomatic diseases, improving the power to detect genetic associations. We explored genetic influences on hippocampal volume by conduct-ing a cross-sectional genome-wide association analysis in the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium 6 among 9,232 dementia-free persons from 8 community-based studies whose mean age ranged from 56 to 84 years (weighted average of 67.1 years). Each study imputed to a common set of SNPs from the Phase 2 HapMap Centre d'Etude du Polymorphisme Humain (CEPH) Utah residents of Northern and Western European ancestry (CEU) population using genotype data from Illumina or Affymetrix arrays; additive genetic models associating total hippocampal volume and genotype dosage were fitted with adjustment for age, sex and familial relationships (if applicable; Supplementary Note); and genomic control was applied. Study-specific results were combined in an inverse variance–weighted meta-analysis. We then conducted in silico replication of associations that reached genome-wide significance and sought additional evidence for sug-gestive associations in a second-stage targeted meta-analysis of 2,318 subjects from two community-based studies: the Three City Study and an independent sample from the third expansion of the Rotterdam Study. Characteristics of the discovery and replication samples are given (Supplementary Table 1). A Manhattan plot of −log 10 (P values) from the discovery analysis is shown (Fig. 1), where P values for 46 SNPs at 4 loci (Supplementary Table 2) surpassed our replication threshold of P < 4.0 × 10 −7 corres-ponding to 1 expected false positive. Of these, 18 SNPs at 2 loci sur-passed a genome-wide significance threshold of P < 5.0 × 10 −8 : the 12q14 locus, which included WIF1, LEMD3 and MSRB3, and the 12q24 locus, which included HRK and FBXW8. We found evidence of replication (P < 0.01) for both associations. The remaining sug-gestive associations included SNPs at 2q24 within DPP4 and at 9p33 within ASTN2, which had consistent directions of association in the discovery and replication phases but did not attain genome-wide sig-nificance in a combined analysis. Estimates for each stage are shown (Table 1). Discovery GWAS results for the region around each signal were annotated with recombination rates and known genes (Fig. 2), and study-specific findings are shown (Fig. 3).
Nature Genetics 01/2012; 44(5):545-551. · 35.53 Impact Factor
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ABSTRACT: Choline is the precursor to the neurotransmitter acetylcholine. Loss of cholinergic neurons is associated with impaired cognitive function, particularly memory loss and Alzheimer disease (AD). Brain atrophy and white-matter hyperintensity (WMH) are also associated with impaired cognitive function and AD.
The objective was to determine whether a relation exists between dietary choline intake, cognitive function, and brain morphology in a large, nondemented community-based cohort.
A dementia-free cohort of 1391 subjects (744 women, 647 men; age range: 36-83 y; mean ± SD age: 60.9 ± 9.29 y) from the Framingham Offspring population completed a food-frequency questionnaire administered from 1991 to 1995 (exam 5; remote intake) and from 1998 to 2001 (exam 7; concurrent intake). Participants underwent neuropsychological evaluation and brain MRI at exam 7. Four neuropsychological factors were constructed: verbal memory (VM), visual memory (VsM), verbal learning, and executive function. MRI measures included WMH volume (WMHV).
Performance on the VM and VsM factors was better with higher concurrent choline intake in multivariable-adjusted models for VM (average change in neuropsychological factor per 1-unit change in choline = 0.60; 95% CI: 0.29, 0.91; P < 0.01) and VsM (0.66; 95% CI: 0.19, 1.13; P < 0.01). Remote choline intake was inversely related to log-transformed WMHV (average change in log WMHV per 1-unit change in choline = -0.05; 95% CI: -0.10, -0.01; P = 0.02). Furthermore, an inverse association was observed between remote higher choline intake and presence of large WMVH (OR: 0.56; 95% CI: 0.34, 0.92; P = 0.01).
In this community-based population of nondemented individuals, higher concurrent choline intake was related to better cognitive performance, whereas higher remote choline intake was associated with little to no WMHV.
American Journal of Clinical Nutrition 11/2011; 94(6):1584-91. · 6.67 Impact Factor
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ABSTRACT: Heart failure is a risk factor for Alzheimer's disease and cerebrovascular disease. In the absence of heart failure, it was hypothesized that left ventricular ejection fraction (LVEF), an indicator of cardiac dysfunction, would be associated with preclinical brain magnetic resonance imaging (MRI) and neuropsychological markers of ischemia and Alzheimer disease in the community. Brain MRI, cardiac MRI, neuropsychological, and laboratory data were collected from 1,114 Framingham Heart Study Offspring Cohort participants free from clinical stroke or dementia (aged 40 to 89 years, mean age 67 ± 9 years, 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-shaped associations. Compared to the referent (quintile 2 to 4), the lowest quintile (quintile 1) LVEF was associated with 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 (quintile 5) LVEF values also were associated with lower mean cognitive performance, 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 (β = -0.20, p = 0.02). Findings were similar when analyses were repeated excluding prevalent cardiovascular disease. In conclusion, although these observational cross-sectional data cannot establish causality, they suggest a nonlinear association between LVEF and measures of accelerated cognitive aging.
The American journal of cardiology 08/2011; 108(9):1346-51. · 3.58 Impact Factor
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Rhoda Au
Neurology 08/2011; 77(8):706-7. · 8.31 Impact Factor
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ABSTRACT: BACKGROUND: 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). METHODS: The sample included 1969 stroke- and dementia-free participants from the Framingham Offspring Cohort who underwent neuropsychological (NP) testing and structural magnetic resonance imaging (MRI) between 1999 and 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. RESULTS: 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. In addition, apoE4 status modified the relationship between Q4-WHR and 2 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. CONCLUSIONS: 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.
Journal of stroke and cerebrovascular diseases: the official journal of National Stroke Association 08/2011;
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ABSTRACT: 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.
Neuroepidemiology 07/2011; 37(1):21-30. · 2.31 Impact Factor
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ABSTRACT: Diabetic and prediabtic states, including insulin resistance, fasting hyperglycemia, and hyperinsulinemia, are associated with metabolic dysregulation. These components have been individually linked to increased risks of cognitive decline and Alzheimer's disease. We aimed to comprehensively relate all of the components of metabolic dysregulation to cognitive function and brain magnetic resonance imaging (MRI) in middle-aged adults.
Framingham Offspring participants who underwent volumetric MRI and detailed cognitive testing and were free of clinical stroke and dementia during examination 7 (1998-2001) constituted our study sample (n = 2,439; 1,311 women; age 61 ± 9 years). We related diabetes, homeostasis model assessment of insulin resistance (HOMA-IR), fasting insulin, and glycohemoglobin levels to cross-sectional MRI measures of total cerebral brain volume (TCBV) and hippocampal volume and to verbal and visuospatial memory and executive function. We serially adjusted for age, sex, and education alone (model A), additionally for other vascular risk factors (model B), and finally, with the inclusion of apolipoprotein E-ε4, plasma homocysteine, C-reactive protein, and interleukin-6 (model C).
We observed an inverse association between all indices of metabolic dysfunction and TCBV in all models (P < 0.030). The observed difference in TCBV between participants with and without diabetes was equivalent to approximately 6 years of chronologic aging. Diabetes and elevated glycohemoglobin, HOMA-IR, and fasting insulin were related to poorer executive function scores (P < 0.038), whereas only HOMA-IR and fasting insulin were inversely related to visuospatial memory (P < 0.007).
Metabolic dysregulation, especially insulin resistance, was associated with lower brain volumes and executive function in a large, relatively healthy, middle-aged, community-based cohort.
Diabetes care 06/2011; 34(8):1766-70. · 8.09 Impact Factor
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Myriam Fornage,
Stephanie Debette,
Joshua C Bis,
Helena Schmidt,
M Arfan Ikram,
Carole Dufouil,
Sigurdur Sigurdsson,
Thomas Lumley,
Anita L DeStefano,
Franz Fazekas, [......],
Eric Boerwinkle,
Bruce M Psaty,
Sudha Seshadri,
Christophe Tzourio,
Monique M B Breteler,
Thomas H Mosley,
Reinhold Schmidt,
W T Longstreth,
Charles DeCarli,
Lenore J Launer
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ABSTRACT: White matter hyperintensities (WMHs) detectable by magnetic resonance imaging are part of the spectrum of vascular injury associated with aging of the brain and are thought to reflect ischemic damage to the small deep cerebral vessels. WMHs are associated with an increased risk of cognitive and motor dysfunction, dementia, depression, and stroke. Despite a significant heritability, few genetic loci influencing WMH burden have been identified.
We performed a meta-analysis of genome-wide association studies (GWASs) for WMH burden in 9,361 stroke-free individuals of European descent from 7 community-based cohorts. Significant findings were tested for replication in 3,024 individuals from 2 additional cohorts.
We identified 6 novel risk-associated single nucleotide polymorphisms (SNPs) in 1 locus on chromosome 17q25 encompassing 6 known genes including WBP2, TRIM65, TRIM47, MRPL38, FBF1, and ACOX1. The most significant association was for rs3744028 (p(discovery) = 4.0 × 10(-9) ; p(replication) = 1.3 × 10(-7) ; p(combined) = 4.0 × 10(-15) ). Other SNPs in this region also reaching genome-wide significance were rs9894383 (p = 5.3 × 10(-9) ), rs11869977 (p = 5.7 × 10(-9) ), rs936393 (p = 6.8 × 10(-9) ), rs3744017 (p = 7.3 × 10(-9) ), and rs1055129 (p = 4.1 × 10(-8) ). Variant alleles at these loci conferred a small increase in WMH burden (4-8% of the overall mean WMH burden in the sample).
This large GWAS of WMH burden in community-based cohorts of individuals of European descent identifies a novel locus on chromosome 17. Further characterization of this locus may provide novel insights into the pathogenesis of cerebral WMH.
Annals of Neurology 06/2011; 69(6):928-39. · 11.09 Impact Factor
