Background and Purpose
This scientific statement provides an overview of the evidence on
vascular contributions to cognitive impairment and dementia. Vascular
contributions to cognitive impairment and dementia of later life are common.
Definitions of vascular cognitive impairment (VCI), neuropathology, basic
science and pathophysiological aspects, role of neuroimaging and vascular
and other associated risk factors, and potential opportunities for
prevention and treatment are reviewed. This statement serves as an overall
guide for practitioners to gain a better understanding of VCI and dementia,
prevention, and treatment.
Writing group members were nominated by the writing group co-chairs
on the basis of their previous work in relevant topic areas and were
approved by the American Heart Association Stroke Council Scientific
Statement Oversight Committee, the Council on Epidemiology and Prevention,
and the Manuscript Oversight Committee. The writing group used systematic
literature reviews (primarily covering publications from 1990 to May 1,
2010), previously published guidelines, personal files, and expert opinion
to summarize existing evidence, indicate gaps in current knowledge, and,
when appropriate, formulate recommendations using standard American Heart
Association criteria. All members of the writing group had the opportunity
to comment on the recommendations and approved the final version of this
document. After peer review by the American Heart Association, as well as
review by the Stroke Council leadership, Council on Epidemiology and
Prevention Council, and Scientific Statements Oversight Committee, the
statement was approved by the American Heart Association Science Advisory
and Coordinating Committee.
The construct of VCI has been introduced to capture the entire
spectrum of cognitive disorders associated with all forms of cerebral
vascular brain injury—not solely stroke—ranging from mild
cognitive impairment through fully developed dementia. Dysfunction of the
neurovascular unit and mechanisms regulating cerebral blood flow are likely
to be important components of the pathophysiological processes underlying
VCI. Cerebral amyloid angiopathy is emerging as an important marker of risk
for Alzheimer disease, microinfarction, microhemorrhage and macrohemorrhage
of the brain, and VCI. The neuropathology of cognitive impairment in later
life is often a mixture of Alzheimer disease and microvascular brain damage,
which may overlap and synergize to heighten the risk of cognitive
impairment. In this regard, magnetic resonance imaging and other
neuroimaging techniques play an important role in the definition and
detection of VCI and provide evidence that subcortical forms of VCI with
white matter hyperintensities and small deep infarcts are common. In many
cases, risk markers for VCI are the same as traditional risk factors for
stroke. These risks may include but are not limited to atrial fibrillation,
hypertension, diabetes mellitus, and hypercholesterolemia. Furthermore,
these same vascular risk factors may be risk markers for Alzheimer disease.
Carotid intimal-medial thickness and arterial stiffness are emerging as
markers of arterial aging and may serve as risk markers for VCI. Currently,
no specific treatments for VCI have been approved by the US Food and Drug
Administration. However, detection and control of the traditional risk
factors for stroke and cardiovascular disease may be effective in the
prevention of VCI, even in older people.
Vascular contributions to cognitive impairment and dementia are
important. Understanding of VCI has evolved substantially in recent years,
based on preclinical, neuropathologic, neuroimaging, physiological, and
epidemiological studies. Transdisciplinary, translational, and transactional
approaches are recommended to further our understanding of this entity and
to better characterize its neuropsychological profile. There is a need for
prospective, quantitative, clinical-pathological-neuroimaging studies to
improve knowledge of the pathological basis of neuroimaging change and the
complex interplay between vascular and Alzheimer disease pathologies in the
evolution of clinical VCI and Alzheimer disease. Long-term vascular risk
marker interventional studies beginning as early as midlife may be required
to prevent or postpone the onset of VCI and Alzheimer disease. Studies of
intensive reduction of vascular risk factors in high-risk groups are another
important avenue of research.
AHA Scientific Statements; vascular dementia; Alzheimer disease; risk factors; prevention; treatment
Brain-derived neurotrophic factor (BDNF) and its receptor tyrosine kinase B (TrkB) may influence brain reserve, the ability of the brain to tolerate pathological changes without significant decline in function. Here, we explore whether a specifically vulnerable population of human neurons shows a compensatory response to the neuropathological changes of Alzheimer disease (AD) and whether that response depends on an upregulation of the BDNF pathway. We observed increased neuronal TrkB expression associated with early AD pathology (Braak and Braak stages I–II) in hippocampal CA1 region samples from cognitively intact Framingham Heart Study subjects (n = 5) when compared to cognitively intact individuals with no neurofibrillary tangles (n = 4). Because BDNF/TrkB signaling affects memory formation and retention through modification of the actin cytoskeleton, we examined the expression of actin capping protein β2 (Capzb2), a marker of actin cytoskeleton reorganization. Capzb2 expression was also significantly increased in CA1 hippocampal neurons of cognitively intact subjects with early AD pathology. Our data suggest that increased expression of TrkB and Capzb2 accompanies adequate brain reserve in the initial stages of AD pathology. In subsequent stages of AD, the higher levels of TrkB and Capzb2 expression achieved may not be sufficient to prevent cognitive decline.
Alzheimer disease; Brain-derived neurotrophic factor (BDNF); Brain reserve; Capzb2; TrkB
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.
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.”
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+).
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.
Clock Drawing Test; Normal aging; Scoring methods; Neuropsychological tests; Dementia; Cognitive screening
Background/objective: Transient global amnesia (TGA) is a temporary amnestic syndrome characterized by lack of other focal neurological deficits. Cerebrovascular disease, migraine and seizures have been suggested as underlying mechanisms. TGA may be a risk factor for cerebrovascular or other neurological events. We studied the relation of TGA, vascular risk factors, brain magnetic resonance imaging (MRI) indices of subclinical ischemia and neurological events in a community-based sample.
Design/setting: A total of 12 TGA cases were ascertained using standard criteria by experienced neurologists, and matched to 41 stroke- and seizure-free controls. Vascular risk factors, brain MRI findings, and subsequent cerebrovascular or seizure events were compared in cases and controls.
Participants: Framingham Heart Study (FHS) original and offspring cohort participants were included.
Results: No significant differences between the groups were observed in the prevalence of vascular risk factors, or brain MRI measures. Few incident stroke/transient ischemic attacks (TIA) (one event among the cases and four in controls) or subsequent seizures occurred in either group. Head CT during the acute event (n = 11) and brain MRI (n = 7) were negative for acute abnormalities. Electroencephalograms (EEG) (n = 5) were negative for epileptiform activity. Extracranial vascular studies were negative for significant stenosis in all cases.
Conclusion: In our community-based study TGA was not related to traditional vascular risk factors, or cerebrovascular disease. However, our study is limited by small sample size and power, and larger studies are required to exclude an association.
transient global amnesia; cerebrovascular disease; stroke; TIA; Brain MRI
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.
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.
biomarkers; epidemiology; magnetic resonance imaging; risk stratification; stroke prevention
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.
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.
Brain; autopsy; epidemiology; alzheimer's disease; brain ischemia
Imputation has been widely used in genome-wide association studies (GWAS) to infer genotypes of un-genotyped variants based on the linkage disequilibrium in external reference panels such as the HapMap and 1000 Genomes. However, imputation has only rarely been performed based on family relationships to infer genotypes of un-genotyped individuals. Using 8998 Framingham Heart Study (FHS) participants genotyped with Affymetrix 550K SNPs, we imputed genotypes of same set of SNPs for additional 3121 participants, most of whom were never genotyped due to lack of DNA sample. Prior to imputation, 122 pedigrees were too large to be handled by the imputation software Merlin. Therefore, we developed a novel pedigree splitting algorithm that can maximize the number of genotyped relatives for imputing each un-genotyped individual, while keeping new sub-pedigrees under a pre-specified size. In GWAS of four phenotypes available in FHS (Alzheimer disease, circulating levels of fibrinogen, high-density lipoprotein cholesterol, and uric acid), we compared results using genotyped individuals only with results using both genotyped and imputed individuals. We studied the impact of applying different imputation quality filtering thresholds on the association results and did not found a universal threshold that always resulted in a more significant p-value for previously identified loci. However most of these loci had a lower p-value when we only included imputed genotypes with with ≥60% SNP- and ≥50% person-specific imputation certainty. In summary, we developed a novel algorithm for splitting large pedigrees for imputation and found a plausible imputation quality filtering threshold based on FHS. Further examination may be required to generalize this threshold to other studies.
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.
Prospective cohort study.
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.
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.
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.
In women, increased plasma adiponectin levels are an independent risk factor for the development of both all-cause dementia and AD.
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.
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.
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.
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.
National Institutes of Health and National Heart, Lung, and Blood Institute; National Institute on Aging; and National Institute of Neurological Disorders and Stroke.
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.
The heat shock protein (HSP) 70 family has been implicated in the pathology of Alzheimer’s disease (AD). In this study, we examined common genetic variations in the 80 genes encoding HSP70 and its co-chaperones. We conducted a study in a series of 462 patients and 5238 unaffected participants derived from the Rotterdam Study, a population-based study including 7983 persons aged 55 years and older. We genotyped a total of 12,053 Single Nucleotide Polymorphisms (SNPs) using the HumanHap550K Genotyping BeadChip from Illumina. Replication was performed in two independent cohort studies, the Framingham Heart study (FHS; N=806) and Cardiovascular Health Study (CHS; N=2150). When adjusting for multiple testing, we found a small but consistent, though not significant effect of rs12118313 located 32kb from PFDN2, with an OR of 1.19 (p-value from meta-analysis =0.003). However this SNP was in the intron of another gene, suggesting it is unlikely this SNP reflects the effect of PFDN2. In a formal pathway analysis we found nominally significant evidence for an association of BAG, DNAJA and prefoldin with AD. These findings corroborate with those of a study of 2032 AD patients and 5328 controls, in which several members of the prefoldin family showed evidence for association to AD. Our study did not reveal evidence for a genetic variant if the HSP70 family with a major effect on AD. However, our findings of the single SNP analysis and pathway analysis suggest that multiple genetic variants in prefoldin are associated with AD.
Heat-Shock Proteins; Alzheimer Disease; prefoldin; Genetic Association Studies
The genetic background of atrial fibrillation (AF) in whites and African Americans is largely unknown. Genes in cardiovascular pathways have not been systematically investigated.
Methods and Results
We examined a panel of approximately 50,000 common single nucleotide polymorphisms (SNPs) in 2,095 cardiovascular candidate genes and AF in three cohorts with participants of European (n=18,524; 2,260 cases) or African American descent (n=3,662; 263 cases) in the National Heart Lung and Blood Institute's Candidate Gene Association Resource. Results in whites were followed up in the German Competence Network for AF (n=906, 468 cases). The top result was assessed in relation to incident ischemic stroke in the Cohorts for Heart and Aging Research in Genomic Epidemiology Stroke Consortium (n= 19,602 whites, 1544 incident strokes). SNP rs4845625 in the IL6R gene was associated with AF (relative risk (RR) C allele, 0.90; 95% confidence interval (CI), 0.85–0.95; P=0.0005) in whites, but did not reach statistical significance in African Americans (RR, 0.86; 95% CI, 0.72–1.03; P=0.09). The results were comparable in the German AF Network replication, (RR, 0.71; 95% CI, 0.57–0.89; P=0.003). No association between rs4845625 and stroke was observed in whites. The known chromosome 4 locus near PITX2 in whites also was associated with AF in African Americans (rs4611994, hazard ratio, 1.40; 95% CI, 1.16–1.69; P=0.0005).
In a community-based cohort meta-analysis, we identified genetic association in IL6R with AF in whites. Additionally, we demonstrated that the chromosome 4 locus known from recent genome-wide association studies in whites is associated with AF in African Americans.
atrial fibrillation; single nucleotide polymorphism; epidemiology; cohort study; race/ethnicity
Multiple lines of evidence suggest that specific subtypes of age-related cataract (ARC) and Alzheimer disease (AD) are related etiologically. To identify shared genetic factors for ARC and AD, we estimated co-heritability of quantitative measures of cataract subtypes with AD-related brain MRI traits among 1,249 members of the Framingham Eye Study who had a brain MRI scan approximately ten years after the eye exam. Cortical cataract (CC) was found to be co-heritable with future development of AD and with several MRI traits, especially temporal horn volume (THV, ρ = 0.24, P<10−4). A genome-wide association study using 187,657 single nucleotide polymorphisms (SNPs) for the bivariate outcome of CC and THV identified genome-wide significant association with CTNND2 SNPs rs17183619, rs13155993 and rs13170756 (P<2.6×10−7). These SNPs were also significantly associated with bivariate outcomes of CC and scores on several highly heritable neuropsychological tests (5.7×10−9≤P<3.7×10−6). Statistical interaction was demonstrated between rs17183619 and APP SNP rs2096488 on CC (P = 0.0015) and CC-THV (P = 0.038). A rare CTNND2 missense mutation (G810R) 249 base pairs from rs17183619 altered δ-catenin localization and increased secreted amyloid-β1–42 in neuronal cell culture. Immunohistopathological analysis of lens tissue obtained from two autopsy-confirmed AD subjects and two non-AD controls revealed elevated expression of δ-catenin in epithelial and cortical regions of lenses from AD subjects compared to controls. Our findings suggest that genetic variation in delta catenin may underlie both cortical lens opacities in mid-life and subsequent MRI and cognitive changes that presage the development of AD.
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.
Memory; Executive functioning; Inflammation; Cognition; WRAT-3 reading
VEGF impacts angiogenesis, atherosclerosis and cancer. Although the heritability of circulating VEGF levels is high, little is known about its genetic underpinnings.
Our aim was to identify genetic variants associated with circulating VEGF levels using an unbiased genome-wide approach and explore their functional significance with gene expression and pathway analysis.
Methods and results
We undertook a genome-wide association study (GWAS) of serum VEGF levels in 3,527 participants of the Framingham Heart Study (FHS), with pre-planned replication in 1,727 participants from two independent samples, the STANISLAS Family Study (SFS) and the Prospective Investigation of the Vasculature in Uppsala Seniors study (PIVUS). One hundred and forty SNPs reached genome-wide significance (p<5×10−8). We found evidence of replication for the most significant associations in both replication datasets. In a conditional GWAS 4 SNPs mapping to 3 chromosomal regions were independently associated with circulating VEGF levels: rs6921438 and rs4416670 (6p21.1, p=6.11×10−506 and p=1.47×10−12), rs6993770 (8q23.1, p=2.50×10−16) and rs10738760 (9p24.2, p=1.96×10−34). A genetic score including these four SNPs explained 48% of the heritability of serum VEGF levels. Six of the SNPs that reached genome-wide significance in the GWAS were significantly associated with VEGF mRNA levels in PBMCs. Ingenuity pathway analyses showed found plausible biological links between VEGF and 2 novel genes in these loci (ZFPM2 and VLDLR).
Genetic variants explaining up to half the heritability of serum VEGF levels were identified. These new insights provide important clues to the pathways regulating circulating VEGF levels.
growth factors; genome-wide association study; gene expression; pathway analysis
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.
RESEARCH DESIGN AND METHODS
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.
The association between ischemic stroke and 2 single nucleotide polymorphisms (SNPs) on chromosome 12p13, rs12425791 and rs11833579 appears inconsistent across different samples. These SNPs are close to the ninjurin2 gene which may alter the risk of stroke by affecting brain response to ischemic injury. The purpose of this study was to investigate the association between these two SNPs and ischemic stroke risk, as well as prognostic outcomes in a Taiwanese sample.
We examined the relations of these two SNPs to the odds of new-onset ischemic stroke, ischemic stroke subtypes, and to the one year risk of stroke-related death or recurrent stroke following initial stroke in a case-control study. A total of 765 consecutive patients who had first-ever ischemic stroke were compared to 977 stroke-free, age-matched controls. SNPs were genotyped by Taqman fluorescent allelic discrimination assay. The association between ischemic stroke and SNPs were analyzed by multivariate logistic regression. Cox proportional hazard model was used to assess the effect of individual SNPs on stroke-related mortality or recurrent stroke.
There was no significant association between SNP rs12425791 and rs11833579 and ischemic stroke after multiple testing corrections. However, the marginal significant association was observed between SNP rs12425791 and large artery atherosclerosis under recessive model (OR, 2.30; 95%CI, 1.22-4.34; q-value = 0.062). Among the 765 ischemic stroke patients, 59 died or developed a recurrent stroke. After adjustment for age, sex, vascular risk factors and baseline stroke severity, Cox proportional hazard analysis indicated that the hazard ratios were 2.76 (95%CI, 1.34-5.68; q-value, 0.02) and 2.15 (95%CI, 1.15-4.02; q-value, 0.03) for individuals with homozygous variant allele of rs12425791 and rs11833579, respectively.
This is a precedent study that found genetic variants of rs12425791 and rs11833579 on chromosome 12p13 are independent predictors of stroke-related mortality or stroke recurrence in patients with incident ischemic stroke in Taiwan. Further study is needed to explore the details of the physiological function and the molecular mechanisms underlying the association of this genetic locus with ischemic stroke.
stroke; single nucleotide polymorphisms; survival
This article focuses on the effects of operational differences in case ascertainment on estimates of prevalence and incidence of cognitive impairment/dementia of the Alzheimer type. Experience and insights are discussed by investigators from the Framingham Heart Study, the East Boston Senior Health Project, the Chicago Health and Aging Project, the Mayo Clinic Study of Aging, the Baltimore Longitudinal Study of Aging, and the Aging, Demographics, and Memory Study. There is a general consensus that the single most important factor regulating prevalence estimates of Alzheimer’s disease (AD) is the severity of cognitive impairment used for case ascertainment. Studies that require a level of cognitive impairment in which persons are unable to provide self-care will have much lower estimates than studies aimed at identifying persons in the earliest stages of AD. There is limited autopsy data from the above-mentioned epidemiologic studies to address accuracy in the diagnosis of etiologic subtype, namely the specification of AD alone or in combination with other types of pathology. However, other community-based cohort studies show that many persons with mild cognitive impairment (MCI) meet pathologic criteria for AD, and a large minority of persons without dementia or MCI also meets pathologic criteria for AD, thereby suggesting that the number of persons who would benefit from an effective secondary prevention intervention is probably higher than the highest published prevalence estimates. Improved accuracy in the clinical diagnosis of AD is anticipated with the addition of molecular and structural biomarkers in the next generation of epidemiologic studies.
Alzheimer’s disease; Dementia; Mild cognitive impairment; Cognitive impairment not dementia; Diagnostic criteria; Population-based; Prevalence, Incidence
Magnetic resonance imaging (MRI) findings of large white matter hyperintensities (LWMH), decreased brain volume and silent cerebral infarcts (SCI) are subclinical indices of brain ischemia and aging. Although the pathophysiology of these findings remains uncertain, extracellular matrix (ECM) remodeling, a process regulated by matrix metalloproteinases (MMPs) and their inhibitors (TIMPs), may be implicated.
We evaluated the cross-sectional relations of circulating MMP-9 and TIMP-1 to these MRI indices in 583 stroke and dementia-free, Framingham Offspring participants (mean age 57 years, 58% women). Using multivariable regression MMP-9 (detectable versus non-detectable) and TIMP-1 (modeled as sex-specific quartiles) were related to LWMH (>1 S.D. above age-specific mean; yes/no), SCI (yes/no) and total brain volume (ratio of parenchymal to intracranial volume, TCBVr).
Mean TCBVr was 0.78 (S.D. 0.03), 13% of subjects had LWMH and 12% had SCI. Detectable MMP-9 was associated with higher prevalence of LWMH (OR 2.09, 95%confidence interval (CI) 1.00–4.37), but not with TCBVr. TIMP-1 was associated with a high prevalence of LWMH (OR for Q4 versus Q1–3: 1.83, 95%CI 1.06–3.18) and with lower mean TCBVr (Q4 associated with 0.17 S.D. units lower value relative to Q1–3; p = 0.04). Neither biomarker was associated with SCI.
Our findings are preliminary but if confirmed in further studies, suggest a pathophysiological role for the MMP/TIMP pathway in processes of brain ischemia and aging.
MMPs; Brain MRI; Framingham; Brain aging
Human longevity and healthy aging show moderate heritability (20–50%). We conducted a meta-analysis of genome-wide association studies from nine studies from the Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium for two outcomes: a) all-cause mortality and b) survival free of major disease or death. No single nucleotide polymorphism (SNP) was a genome-wide significant predictor of either outcome (p < 5 × 10−8). We found fourteen independent SNPs that predicted risk of death, and eight SNPs that predicted event-free survival (p < 10−5). These SNPs are in or near genes that are highly expressed in the brain (HECW2, HIP1, BIN2, GRIA1), genes involved in neural development and function (KCNQ4, LMO4, GRIA1, NETO1) and autophagy (ATG4C), and genes that are associated with risk of various diseases including cancer and Alzheimer’s disease. In addition to considerable overlap between the traits, pathway and network analysis corroborated these findings. These findings indicate that variation in genes involved in neurological processes may be an important factor in regulating aging free of major disease and achieving longevity.
Cardiac dysfunction is associated with neuroanatomic and neuropsychological changes in aging adults with prevalent cardiovascular disease (CVD), theoretically because systemic hypoperfusion disrupts cerebral perfusion, contributing to subclinical brain injury. We hypothesized that cardiac function, as measured by cardiac index, would be associated with pre-clinical brain magnetic resonance imaging (MRI) and neuropsychological markers of ischemia and Alzheimer’s disease in the community.
Methods and Results
Brain MRI, cardiac MRI, neuropsychological, and laboratory data were collected on 1504 Framingham Offspring Cohort participants free from clinical stroke, transient ischemic attack, or dementia (61±9 years; 54% women). Neuropsychological and brain MRI variables were related to cardiac MRI-assessed cardiac index (cardiac output/body surface area). In multivariable-adjusted models, cardiac index was positively related to total brain volume (P=0.03) and information processing speed (P=0.02) and inversely related to lateral ventricular volume (P=0.048). When participants with clinically prevalent CVD were excluded, the relation between cardiac index and total brain volume remained (P=0.02). Post-hoc comparisons revealed that participants in the bottom cardiac index tertile (values<2.54) and middle cardiac index tertile (values between 2.54 and 2.92) had significantly lower brain volumes (P=0.04) than participants in the top cardiac index tertile (values>2.92).
Although observational data cannot establish causality, our findings are consistent with the hypothesis that decreasing cardiac function, even at normal cardiac index levels, is associated with accelerated brain aging.
brain; cardiac output; epidemiology; imaging; neuropsychology
Previous studies have demonstrated an association between white matter hyperintensities (WMH) and cognitive performance primarily in Caucasian samples, limiting generalizability to other ethnic and racial groups. This study investigated the association of WMH and cognition in an ethnic and racial minority cohort (Omni) of the Framingham Heart Study and compared these results to the Caucasian (Offspring) cohort.
Quantitative brain MRI and neuropsychological evaluations were performed on stroke- and dementia-free participants. Cognitive assessment included verbal memory, visuospatial memory and organization, language, and executive functioning. Linear regression models were conducted to assess the association between WMH and cognitive function.
The Omni group presented with demographic factors that significantly differed from those of the Offspring group: they were younger, but had more stroke risk factors such as hypertension. In the Offspring group, WMH volume was significantly associated with poorer performance on tests of executive function and visual organization. No significant associations between WMH and cognitive measures were found in the Omni group, but no differences (significant interaction terms) were seen between the regression coefficients.
The Omni cohort had greater variability in factors that may mediate the association of WMH and cognition. More research is needed to investigate how stroke risk factors impact on the occurrence of WMH and its association with cognition in more diverse cohorts.
White matter hyperintensities; Cognition; Executive function; Framingham Heart Study; Magnetic resonance imaging; Cultural/ethnic diversity
Midlife obesity has been associated with an increased risk of dementia. The underlying mechanisms are poorly understood. Our aim was to examine the cross-sectional association of body mass index (BMI), waist circumference (WC), waist to hip ratio (WHR) and CT-based measures of subcutaneous (SAT) and visceral (VAT) adipose tissue with various MRI-markers of brain aging in middle-aged community adults.
Participants from the Framingham Offspring cohort were eligible if in addition to having measures of BMI, WC, WHR, SAT and VAT, they had undergone a volumetric brain MRI scan with measures of total brain volume (TCBV), temporal horn volume (THV), white matter hyperintensity volume (WMHV) and MRI-defined brain infarcts (BI). All analyses were adjusted for age, sex and time interval between abdominal CT and brain MRI.
In a sample of 733 community participants (mean age 60 years, 53% women), we observed an inverse association of BMI (estimate by standard deviation unit ± standard error =−0.27±0.12,p=0.02), WC (−0.30±0.12,p=0.01), WHR (−0.37±0.12,p=0.02), SAT (−0.23±0.11,p=0.04) and VAT (−0.36±0.12,p=0.002) with TCBV, independent of vascular risk factors. The association between VAT and TCBV was the strongest and most robust, and was also independent of BMI (−0.35±0.15,p=0.02) and insulin resistance (−0.32±0.13,p=0.01). When adjusting for C-reactive protein levels the associations were attenuated (−0.17±0.13,p=0.17 for VAT). No consistently significant association was observed between the anthropometric or CT-based abdominal fat measures and THV, WMHV or BI.
In middle-aged community participants we observed a significant inverse association of anthropometric and CT-based measures of abdominal, especially visceral, fat with total brain volume.
To determine if the presence of the apoE4 allele, a known risk factor for Alzheimer’s disease, interacts with cerebrovascular risk factors to produce a disproportionate impairment in neuropsychological performance and alterations in structural morphometry as measured by magnetic resonance imaging.
1,995 participants from the community based Framingham Offspring Cohort participants (mean age 61; 1,063 women) underwent neuropsychological testing and structural magnetic resonance imaging in 1999-2002.
Multivariate linear regression was used to estimate the relationships between Framingham Stroke Risk Profile scores, neuropsychological variables and magnetic resonance imaging measures; interaction terms were included to examine modification of these relationships by the presence of the apoE4 allele. All analyses were cross sectional.
We found significant interactions between the presence of the apoE4 allele and the top sex-specific quartile of the Stroke Risk Profile and their effects on verbal memory (p=<0.001), verbal organization (p=<0.001), non-verbal memory (p=0.015), as well as set shifting and complex attention (p=0.005). Systolic blood pressure was the only individual risk factor significantly linked to these cognitive measures. With the exception of lateral ventricular volume, there were no significant interactions between presence of apoE4, the top sex-specific quartile of the Stroke Risk Profile and any of the magnetic resonance imaging variables.
The apoE4 allele exacerbates the effects of cerebrovascular risk factors on neuropsychological function. This relationship appears to be driven by systolic blood pressure, suggesting that treatment of high systolic blood pressure could potentially reduce risk of cognitive impairment among those already at increased risk for Alzheimer’s disease.