Aleksandra Pikula

Common variants at 12q14 and 12q24 are associated with hippocampal volume

Aging is associated with reductions in hippocampal volume that are accelerated by Alzheimers 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.

Red blood cell omega-3 fatty acid levels and markers of accelerated brain aging

Objective: Higher dietary intake and circulating levels of docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) have been related to a reduced risk for dementia, but the pathways underlying this association remain unclear. We examined the cross-sectional relation of red blood cell (RBC) fatty acid levels to subclinical imaging and cognitive markers of dementia risk in a middle-aged to elderly community-based cohort. Methods: We related RBC DHA and EPA levels in dementia-free Framingham Study participants (n = 1,575; 854 women, age 67 ± 9 years) to performance on cognitive tests and to volumetric brain MRI, with serial adjustments for age, sex, and education (model A, primary model), additionally for APOE ϵ4 and plasma homocysteine (model B), and also for physical activity and body mass index (model C), or for traditional vascular risk factors (model D). Results: Participants with RBC DHA levels in the lowest quartile (Q1) when compared to others (Q2–4) had lower total brain and greater white matter hyperintensity volumes (for model A: β ± SE = −0.49 ± 0.19; p = 0.009, and 0.12 ± 0.06; p = 0.049, respectively) with persistence of the association with total brain volume in multivariable analyses. Participants with lower DHA and ω-3 index (RBC DHA+EPA) levels (Q1 vs Q2–4) also had lower scores on tests of visual memory (β ± SE = −0.47 ± 0.18; p = 0.008), executive function (β ± SE = −0.07 ± 0.03; p = 0.004), and abstract thinking (β ± SE = −0.52 ± 0.18; p = 0.004) in model A, the results remaining significant in all models. Conclusion: Lower RBC DHA levels are associated with smaller brain volumes and a “vascular” pattern of cognitive impairment even in persons free of clinical dementia.

Serum Brain-Derived Neurotrophic Factor and the Risk for Dementia: The Framingham Heart Study

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.

Parental Occurrence of Stroke and Risk of Stroke in Their Children The Framingham Study

Background— Data relating parental history of stroke to stroke risk in offspring remain surprisingly inconsistent, largely because of heterogeneity of study design and the absence of verified, as opposed to historical, data on parental stroke status. Methods and Results— We determined whether prospectively verified parental occurrence of stroke increased incident stroke risk among offspring in a community-based sample by studying 3443 stroke-free Framingham offspring (53% female; mean age, 48±14 years) with verified parental stroke status (by 65 years of age) who attended the first, third, fifth, and/or seventh offspring examinations and were followed up for up to 8 years after each baseline examination. Over up to 11 029 such person-observation periods (77 534 person-years), we documented 106 parental strokes by 65 years of age and 128 offspring strokes (74 parental and 106 offspring strokes were ischemic). Using multivariable Cox models adjusted for age, sex, sibship, and baseline stroke risk factors, we observed that parental stroke, both all stroke generally and ischemic stroke specifically, was associated with an increased risk of incident stroke of the same type in the offspring (hazard ratio, 2.79; 95% confidence interval, 1.68 to 4.66; P<0.001 for all stroke; and hazard ratio, 3.15; 95% confidence interval, 1.69 to 5.88; P<0.001 for ischemic stroke). This was true for both maternal and paternal stroke. Conclusions— Documented parental stroke by 65 years of age was associated with a 3-fold increase in risk of offspring stroke. This increased risk persisted after adjustment for conventional stroke risk factors. Thus, verified parental stroke may serve as a clinically useful risk marker of an individuals propensity to stroke.

Serum brain-derived neurotrophic factor and vascular endothelial growth factor levels are associated with risk of stroke and vascular brain injury framingham study

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.Background and Purpose— Brain-derived neurotrophic factor (BDNF), a major neurotrophin and vascular endothelial growth factor (VEGF) 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 Framingham Study participants (mean age, 65±11 years; 56% women) who were free of stroke/transient ischemic attack (TIA), we related baseline BDNF and logVEGF to risk of incident stroke/TIA. In a subsample with brain MRI and with neuropsychological tests available (n=1863 and 2104, respectively; mean age, 61±9 years, 55% women, in each), we related baseline BDNF and logVEGF to log-white matter hyperintensity volume 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 (hazard ratio comparing BDNF Q1 versus Q2–Q4, 1.47; 95% confidence interval, 1.09–2.00; P=0.012 and hazard ratio/SD increase in logVEGF, 1.21; 95% confidence interval, 1.04–1.40; P=0.012). Persons with higher BDNF levels had less log-white matter hyperintensity volume (&bgr;±SE=−0.05±0.02; P=0.025), and better visual memory (&bgr;±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.

Association of parental dementia with cognitive and brain MRI measures in middle-aged adults

Objectives: Studies of autosomal dominant Alzheimer disease (AD) have shown structural and cognitive changes in mutation carriers decades prior to clinical disease. Whether such changes are detectable in offspring of persons with sporadic dementia remains unknown. We related prospectively verified parental dementia to brain MRI and cognitive testing in the offspring, within a 2-generational community-based cohort. Methods: A total of 717 Framingham offspring (mean age: 59 ± 8 years) were studied. In multivariate analyses, we compared offspring with and without verified parental dementia (and AD) for 1) performance on tests of memory, abstract reasoning, and cognitive flexibility, and 2) volumetric brain MRI measures of total cerebral brain volume (TCBV), hippocampal volume (HV), and white matter hyperintensity volume (WMHV), assessed cross-sectionally and longitudinally. Results: When testing the association of parental dementia and AD with baseline cognitive performance, we observed an interaction of parental dementia and AD with APOE ε4 status (p < 0.002). In APOE ε4 carriers only (n = 165), parental dementia was associated with poorer scores on tests of verbal memory (beta = −1.81 ± 0.53, p < 0.001) and visuospatial memory (beta = −1.73 ± 0.47, p < 0.001). These associations were stronger for parental AD (beta = −1.97 ± 0.52, p < 0.001, beta = −1.95 ± 0.48, p < 0.001), equivalent to 14–16 years of brain aging. Among APOE ε4 carriers, offspring of participants with dementia were also more likely to show an annual decline in TCBV in the top quartile (odds ratio = 4.67 [1.26–17.30], p = 0.02). Regardless of APOE ε4 status, participants with parental dementia were more likely to be in the highest quartile of decline in executive function test scores (odds ratio = 1.61 [1.02–2.53], p = 0.04). Conclusions: Among middle-aged carriers of the APOE ε4 allele, parental dementia and Alzheimer disease were associated with poorer verbal and visuospatial memory and a higher rate of global brain atrophy.

Stroke prevention: modifying risk factors

Risk factor modification remains as the principal aspect of care for stroke prevention. Understanding of risk factors has advanced and several options are now available to treat modifiable risk factors. However, effective treatment remains a challenging task in clinical practice. Prevention begins with awareness of risk factors by patients and clinicians. Risk factor assessment along with overall stroke risk estimation should be part of evaluation of patients with stroke, and used with careful clinical judgment. In this review, we discuss the impact of modifiable traditional vascular risk factors on ischemic stroke, interventions for stroke prevention, and evidence for early treatment of risk factors where available, as well as areas of research progress. Emphasis should be put on the education of patients, the community, and medical personnel. Future research in the field of genetic determinants of vascular risk factors and stroke will increase our understanding of the underlying mechanisms of cerebrovascular disease and likely result in development of new therapies and individualized programs for stroke prevention.

Association of Plasma ADMA Levels With MRI Markers of Vascular Brain Injury: Framingham Offspring Study

Background and Purpose— Asymmetrical dimethylarginine (ADMA), an inhibitor of endothelial nitric oxide synthase, is a marker of endothelial dysfunction. Elevated circulating ADMA concentrations have been associated with systemic and carotid atherosclerosis, an elevated risk of developing stroke, and magnetic resonance imaging white-matter hyperintensities (WMHs). The relation of plasma ADMA to subclinical vascular brain injury has not been previously studied in a middle-aged, community-based sample. Methods— In 2013 stroke-free Framingham offspring (mean±SD age, 58±9.5 years; 53% women), we related baseline plasma ADMA levels (1995–1998) to subsequent brain magnetic resonance imaging measures (1999–2004) of subclinical vascular injury: presence of silent brain infarcts (SBIs) and large white-matter hyperintensity volumes (LWMHs; defined as >1 SD above the age-specific mean). Results— Prevalences of SBIs and LWMHs were 10.7% and 12.6%, respectively. In multivariable analyses adjusting for age, sex and traditional stroke risk factors, higher ADMA levels were associated with an increased risk of prevalent SBIs (odds ratio [OR] per 1-SD increase in ADMA=1.16; 95% CI, 1.01 to 1.33; P=0.04). We observed that participants in the upper 3 age-specific quartiles (Qs) of plasma ADMA values had an increased prevalence of SBIs (OR for Q2–Q4 vs Q1=1.43; 95% CI, 1.00 to 2.04; P<0.05). The prevalence of SBIs in Q1and Q2–Q4 was 8.3% and 11.6%, respectively. The prevalence of LWMHs did not differ according to ADMA concentrations. Conclusions— Higher plasma ADMA values were associated with an increased prevalence of SBIs, after adjustment for traditional stroke risk factors. Thus, ADMA may be a potentially useful new biomarker of subclinical vascular brain injury, which is an important correlate of vascular cognitive impairment and risk of stroke.

Insulin-like growth factor-1 and risk of Alzheimer dementia and brain atrophy

Objective: To relate serum insulin-like growth factor-1 (IGF-1) to risk of Alzheimer disease (AD) dementia and to brain volumes in a dementia-free community sample spanning middle and older ages. Methods: Dementia-free Framingham participants from generation 1 (n = 789, age 79 ± 4 years, 64% women) and generation 2 (n = 2,793, age 61 ± 9 years, 55% women; total = 3,582, age 65 ± 11 years, 57% women) had serum IGF-1 measured in 1990–1994 and 1998–2001, respectively, and were followed prospectively for incident dementia and AD dementia. Brain MRI was obtained in stroke- and dementia-free survivors of both generations 1 (n = 186) and 2 (n = 1,867) during 1999–2005. Baseline IGF-1 was related to risk of incident dementia using Cox models and to total brain and hippocampal volumes using linear regression in multivariable models adjusted for age, sex, APOE ε4, plasma homocysteine, waist-hip ratio, and physical activity. Results: Mean IGF-1 levels were 144 ± 60 μg/L in generation 1 and 114 ± 37 μg/L in generation 2. We observed 279 cases of incident dementia (230 AD dementia) over a mean follow-up of 7.4 ± 3.1 years. Persons with IGF-1 in the lowest quartile had a 51% greater risk of AD dementia (hazard ratio = 1.51, 95% confidence interval: 1.14–2.00; p = 0.004). Among persons without dementia, higher IGF-1 levels were associated with greater total brain volumes (β/SD increment in IGF-1 was 0.55 ± 0.24, p = 0.025; and 0.26 ± 0.06, p < 0.001, for generations 1 and 2, respectively). Conclusion: Lower serum levels of IGF-1 are associated with an increased risk of developing AD dementia and higher levels with greater brain volumes even among middle-aged community-dwelling participants free of stroke and dementia. Higher levels of IGF-1 may protect against subclinical and clinical neurodegeneration.

Serum BDNF and VEGF levels are associated with Risk of Stroke and Vascular Brain Injury: Framingham Study

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.Background and Purpose— Brain-derived neurotrophic factor (BDNF), a major neurotrophin and vascular endothelial growth factor (VEGF) 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 Framingham Study participants (mean age, 65±11 years; 56% women) who were free of stroke/transient ischemic attack (TIA), we related baseline BDNF and logVEGF to risk of incident stroke/TIA. In a subsample with brain MRI and with neuropsychological tests available (n=1863 and 2104, respectively; mean age, 61±9 years, 55% women, in each), we related baseline BDNF and logVEGF to log-white matter hyperintensity volume 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 (hazard ratio comparing BDNF Q1 versus Q2–Q4, 1.47; 95% confidence interval, 1.09–2.00; P=0.012 and hazard ratio/SD increase in logVEGF, 1.21; 95% confidence interval, 1.04–1.40; P=0.012). Persons with higher BDNF levels had less log-white matter hyperintensity volume (&bgr;±SE=−0.05±0.02; P=0.025), and better visual memory (&bgr;±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.