Showing papers by "Charles DeCarli published in 2016"
Yasser Iturria-Medina, Roberto C. Sotero1, Paule-Joanne Toussaint, José María Mateos-Pérez +311 more•Institutions (60)
TL;DR: Imaging results suggest that intra-brain vascular dysregulation is an early pathological event during disease development, suggesting early memory deficit associated with the primary disease factors.
Abstract: Multifactorial mechanisms underlying late-onset Alzheimer's disease (LOAD) are poorly characterized from an integrative perspective. Here spatiotemporal alterations in brain amyloid-β deposition, metabolism, vascular, functional activity at rest, structural properties, cognitive integrity and peripheral proteins levels are characterized in relation to LOAD progression. We analyse over 7,700 brain images and tens of plasma and cerebrospinal fluid biomarkers from the Alzheimer's Disease Neuroimaging Initiative (ADNI). Through a multifactorial data-driven analysis, we obtain dynamic LOAD-abnormality indices for all biomarkers, and a tentative temporal ordering of disease progression. Imaging results suggest that intra-brain vascular dysregulation is an early pathological event during disease development. Cognitive decline is noticeable from initial LOAD stages, suggesting early memory deficit associated with the primary disease factors. High abnormality levels are also observed for specific proteins associated with the vascular system's integrity. Although still subjected to the sensitivity of the algorithms and biomarkers employed, our results might contribute to the development of preventive therapeutic interventions.
786 citations
TL;DR: The data show that Gram-negative bacterial molecules are associated with AD neuropathology, consistent with the LPS-ischemia-hypoxia rat model that produces myelin aggregates that colocalize with Aβ and resemble amyloid-like plaques.
Abstract: Objective: We determined whether Gram-negative bacterial molecules are associated with Alzheimer disease (AD) neuropathology given that previous studies demonstrate Gram-negative Escherichia coli bacteria can form extracellular amyloid and Gram-negative bacteria have been reported as the predominant bacteria found in normal human brains Methods: Brain samples from gray and white matter were studied from patients with AD (n = 24) and age-matched controls (n = 18) Lipopolysaccharide (LPS) and E coli K99 pili protein were evaluated by Western blots and immunocytochemistry Human brain samples were assessed for E coli DNA followed by DNA sequencing Results: LPS and E coli K99 were detected immunocytochemically in brain parenchyma and vessels in all AD and control brains K99 levels measured using Western blots were greater in AD compared to control brains ( p 1-40/42 in amyloid plaques and with Aβ 1-40/42 around vessels in AD brains DNA sequencing confirmed E coli DNA in human control and AD brains Conclusions: E coli K99 and LPS levels were greater in AD compared to control brains LPS colocalized with Aβ 1-40/42 in amyloid plaques and around vessels in AD brain The data show that Gram-negative bacterial molecules are associated with AD neuropathology They are consistent with our LPS-ischemia-hypoxia rat model that produces myelin aggregates that colocalize with Aβ and resemble amyloid-like plaques
339 citations
TL;DR: The authors' APOE-stratified GWAS is the first to show GWS association for AD with SNPs in the chromosome 17q21.31 region, and the finding in the stage 1 sample that AD risk is significantly influenced by the interaction of APOE with TMEM106B (P=1·6 × 10−7) is noteworthy, because TMEM 106B variants have previously been associated with risk of frontotemporal dementia.
Abstract: APOE ɛ4, the most significant genetic risk factor for Alzheimer disease (AD), may mask effects of other loci. We re-analyzed genome-wide association study (GWAS) data from the International Genomics of Alzheimer's Project (IGAP) Consortium in APOE ɛ4+ (10 352 cases and 9207 controls) and APOE ɛ4- (7184 cases and 26 968 controls) subgroups as well as in the total sample testing for interaction between a single-nucleotide polymorphism (SNP) and APOE ɛ4 status. Suggestive associations (P<1 × 10(-4)) in stage 1 were evaluated in an independent sample (stage 2) containing 4203 subjects (APOE ɛ4+: 1250 cases and 536 controls; APOE ɛ4-: 718 cases and 1699 controls). Among APOE ɛ4- subjects, novel genome-wide significant (GWS) association was observed with 17 SNPs (all between KANSL1 and LRRC37A on chromosome 17 near MAPT) in a meta-analysis of the stage 1 and stage 2 data sets (best SNP, rs2732703, P=5·8 × 10(-9)). Conditional analysis revealed that rs2732703 accounted for association signals in the entire 100-kilobase region that includes MAPT. Except for previously identified AD loci showing stronger association in APOE ɛ4+ subjects (CR1 and CLU) or APOE ɛ4- subjects (MS4A6A/MS4A4A/MS4A6E), no other SNPs were significantly associated with AD in a specific APOE genotype subgroup. In addition, the finding in the stage 1 sample that AD risk is significantly influenced by the interaction of APOE with rs1595014 in TMEM106B (P=1·6 × 10(-7)) is noteworthy, because TMEM106B variants have previously been associated with risk of frontotemporal dementia. Expression quantitative trait locus analysis revealed that rs113986870, one of the GWS SNPs near rs2732703, is significantly associated with four KANSL1 probes that target transcription of the first translated exon and an untranslated exon in hippocampus (P ⩽ 1.3 × 10(-8)), frontal cortex (P ⩽ 1.3 × 10(-9)) and temporal cortex (P⩽1.2 × 10(-11)). Rs113986870 is also strongly associated with a MAPT probe that targets transcription of alternatively spliced exon 3 in frontal cortex (P=9.2 × 10(-6)) and temporal cortex (P=2.6 × 10(-6)). Our APOE-stratified GWAS is the first to show GWS association for AD with SNPs in the chromosome 17q21.31 region. Replication of this finding in independent samples is needed to verify that SNPs in this region have significantly stronger effects on AD risk in persons lacking APOE ɛ4 compared with persons carrying this allele, and if this is found to hold, further examination of this region and studies aimed at deciphering the mechanism(s) are warranted.
241 citations
TL;DR: Evidence is provided that basal forebrain pathology precedes and predicts both entorhinal pathology and memory impairment, challenging the widely held belief that AD has a cortical origin.
Abstract: There is considerable debate whether Alzheimer's disease (AD) originates in basal forebrain or entorhinal cortex. Here we examined whether longitudinal decreases in basal forebrain and entorhinal cortex grey matter volume were interdependent and sequential. In a large cohort of age-matched older adults ranging from cognitively normal to AD, we demonstrate that basal forebrain volume predicts longitudinal entorhinal degeneration. Models of parallel degeneration or entorhinal origin received negligible support. We then integrated volumetric measures with an amyloid biomarker sensitive to pre-symptomatic AD pathology. Comparison between cognitively matched normal adult subgroups, delineated according to the amyloid biomarker, revealed abnormal degeneration in basal forebrain, but not entorhinal cortex. Abnormal degeneration in both basal forebrain and entorhinal cortex was only observed among prodromal (mildly amnestic) individuals. We provide evidence that basal forebrain pathology precedes and predicts both entorhinal pathology and memory impairment, challenging the widely held belief that AD has a cortical origin.
220 citations
Hieab H.H. Adams1, Derrek P. Hibar2, Vincent Chouraki3, Vincent Chouraki4 +432 more•Institutions (110)
TL;DR: Variants for intracranial volume were also related to childhood and adult cognitive function, and Parkinson's disease, and were enriched near genes involved in growth pathways, including PI3K-AKT signaling.
Abstract: Intracranial volume reflects the maximally attained brain size during development, and remains stable with loss of tissue in late life. It is highly heritable, but the underlying genes remain largely undetermined. In a genome-wide association study of 32,438 adults, we discovered five previously unknown loci for intracranial volume and confirmed two known signals. Four of the loci were also associated with adult human stature, but these remained associated with intracranial volume after adjusting for height. We found a high genetic correlation with child head circumference (ρgenetic = 0.748), which indicates a similar genetic background and allowed us to identify four additional loci through meta-analysis (Ncombined = 37,345). Variants for intracranial volume were also related to childhood and adult cognitive function, and Parkinson's disease, and were enriched near genes involved in growth pathways, including PI3K-AKT signaling. These findings identify the biological underpinnings of intracranial volume and their link to physiological and pathological traits.
185 citations
TL;DR: Low physical activity is associated with a higher risk for dementia in older individuals, suggesting that a reduced risk of dementia and higher brain volumes may be additional health benefits of maintaining physical activity into old age.
Abstract: Author(s): Tan, Zaldy S; Spartano, Nicole L; Beiser, Alexa S; DeCarli, Charles; Auerbach, Sanford H; Vasan, Ramachandran S; Seshadri, Sudha | Abstract: BackgroundSeveral longitudinal studies found an inverse relationship between levels of physical activity and cognitive decline, dementia, and/or Alzheimer's disease (AD), but results have been inconsistent. We followed an older, community-based cohort for over a decade to examine the association of physical activity with the risk of incident dementia and subclinical brain MRI markers of dementia.MethodsThe physical activity index (PAI) was assessed in the Framingham Study Original and Offspring cohorts, aged 60 years or older. We examined the association between PAI and risk of incident all-cause dementia and AD in participants of both cohorts who were cognitively intact and had available PAI (n = 3,714; 54% women; mean age = 70±7 years). We additionally examined the association between PAI and brain MRI in the Offspring cohort (n = 1,987).ResultsOver a decade of follow-up, 236 participants developed dementia (188 AD). Participants in the lowest quintile of PAI had an increased risk of incident dementia compared with those in higher quintiles (hazard ratio [HR] = 1.50, 95% confidence interval [CI] = 1.04-1.97, p = .028) in a multivariable-adjusted model. Secondary analysis revealed that this relation was limited to participants who were apolipoprotein (APO)E e4 allele noncarriers (HR = 1.58, 95% CI = 1.08-2.32; p = .018) and strongest in participants aged 75 years or older. PAI was also linearly related to total brain and hippocampal volumes (β ± SE = 0.24±0.06; p l .01 and 0.004±0.001; p = .003, respectively).ConclusionLow physical activity is associated with a higher risk for dementia in older individuals, suggesting that a reduced risk of dementia and higher brain volumes may be additional health benefits of maintaining physical activity into old age.
138 citations
TL;DR: Examining the cross-sectional associations of aortic stiffness with cognitive function and markers of subclinical brain injury in the Framingham Heart Study Third Generation cohort concluded that aorti stiffening in young adulthood is associated with vascular cognitive impairment later in life.
Abstract: Aortic stiffness is associated with cognitive decline and cerebrovascular disease late in life, although these associations have not been examined in young adults. Understanding the effects of aortic stiffness on the brain at a young age is important both from a pathophysiological and public health perspective. The aim of this study was to examine the cross-sectional associations of aortic stiffness with cognitive function and brain aging in the Framingham Heart Study Third Generation cohort (47% men; mean age, 46 years). Participants completed the assessment of aortic stiffness (carotid-femoral pulse wave velocity), a neuropsychological test battery assessing multiple domains of cognitive performance and magnetic resonance imaging to examine subclinical markers of brain injury. In adjusted regression models, higher aortic stiffness was associated with poorer processing speed and executive function (Trail Making B-A; β±SE, -0.08±0.03; P<0.01), larger lateral ventricular volumes (β±SE, 0.09±0.03; P<0.01) and a greater burden of white-matter hyperintensities (β±SE, 0.09±0.03; P<0.001). When stratifying by age, aortic stiffness was associated with lateral ventricular volume in young adults (30-45 years), whereas aortic stiffness was associated with white-matter injury and cognition in midlife (45-65 years). In conclusion, aortic stiffness was associated with cognitive function and markers of subclinical brain injury in young to middle-aged adults. Prospective studies are needed to examine whether aortic stiffening in young adulthood is associated with vascular cognitive impairment later in life.
115 citations
TL;DR: In middle-aged and older adults without evidence of clinical stroke or dementia, elevated arterial stiffness and pressure pulsatility are associated with longitudinal progression of subclinical vascular brain injury and greater neurocognitive decline.
Abstract: Objective: We tested whether abnormal arterial stiffness and blood pressure would be associated with progression of brain aging measured by brain MRI and neurocognitive testing. Methods: Framingham Offspring Cohort participants (n = 1,223, 61 ± 9 years, 56% women) without previous stroke or dementia underwent applanation tonometry, brain MRI, and neurocognitive testing at examination 7 (1998–2001). Follow-up brain MRI and neurocognitive testing was performed at examination 8 (2005–2008, mean interval 6.4 ± 1.3 years). We related examination 7 inverse-transformed carotid-femoral pulse wave velocity (iCFPWV), central pulse pressure (CPP), and mean arterial pressure to changes in the following variables between examinations 7 and 8: total cerebral brain volume, white matter hyperintensity volume, and performance on executive function and abstraction tasks, the Trail Making Test, Parts B and A (ΔTrails B-A), and Similarities tests. Results: Higher baseline iCFPWV and CPP were associated with greater progression of neurocognitive decline (iCFPWV and ΔTrails B-A association: SD unit change in outcome variable per SD change in tonometry variable [β] ± SE = 0.10 ± 0.04, p = 0.019; CPP and ΔSimilarities association: −0.08 ± 0.03, p = 0.013). Higher mean arterial pressure, but not iCFPWV or CPP, was associated with increase in white matter hyperintensity volume ([β ± SE] 0.07 ± 0.03, p = 0.017). No tonometry measures were associated with change in cerebral brain volume. Conclusions: In middle-aged and older adults without evidence of clinical stroke or dementia, elevated arterial stiffness and pressure pulsatility are associated with longitudinal progression of subclinical vascular brain injury and greater neurocognitive decline. Treatments to reduce arterial stiffness may potentially reduce the progression of neurovascular disease and cognitive decline.
102 citations
TL;DR: Adherence to the American Heart Association’s ideal CVH factors and behaviors, particularly in midlife, may protect against cerebrovascular disease and dementia.
Abstract: Background and Purpose— The American Heart Association developed the ideal cardiovascular health (CVH) index as a simple tool to promote CVH; yet, its association with brain atrophy and dementia remains unexamined. Methods— Our aim was to investigate the prospective association of ideal CVH with vascular brain injury, including the 10-year risks of incident stroke and dementia, as well as cognitive decline and brain atrophy on magnetic resonance imaging, measured for ≈7 years. We studied 2750 stroke- and dementia-free Framingham Heart Study Offspring cohort participants (mean age, 62±9 years; 45% men). Ideal CVH was quantified on a 7-point scale with 1 point awarded for each of the following: nonsmoking status, ideal body mass index, regular physical activity, healthy diet, as well as optimum blood pressure, cholesterol, and fasting blood glucose. Both recent (baseline) and remote (6.9 years earlier) ideal CVH scores were examined. Results— Recent ideal CVH was associated with stroke (hazard ratio, 0.80; 95% confidence interval, 0.67–0.95), vascular dementia (hazard ratio, 0.49; 95% confidence interval, 0.30–0.81), frontal brain atrophy ( P =0.003), and cognitive decline on tasks measuring visual memory and reasoning ( P Conclusions— Adherence to the American Heart Association’s ideal CVH factors and behaviors, particularly in midlife, may protect against cerebrovascular disease and dementia.
98 citations
TL;DR: Among young healthy adults, higher aortic stiffness was associated with measures of reduced white matter and GM integrity in areas implicated in cognitive decline and Alzheimer’s disease.
Abstract: Background and Purpose—Previous work from the Framingham Heart Study suggests that brain changes because of arterial aging may begin in young adulthood and that such changes precede cognitive deficits. The objective of this study was to determine the association of arterial stiffness with measures of white matter and gray matter (GM) integrity in young adults. Methods—One thousand nine hundred three participants from the Framingham Heart Study Third Generation (mean age, 46±8.7 years) had complete tonometry measurements and brain magnetic resonance imaging (T1-weighted and diffusion tensor imaging). Tonometry measures included carotid-femoral pulse wave velocity, augmentation index, carotid-brachial pressure amplification, and central pulse pressure. Fractional anisotropy and GM density images were computed from diffusion tensor imaging and T1 images. Registration to a common anatomic template enabled voxel-based linear regressions relating measures of fractional anisotropy and GM to tonometry measures, a...
98 citations
TL;DR: Low vitamin D concentrations were associated with smaller hippocampal volume and poorer neuropsychological function and no association was found between vitamin D deficiency and incident all-cause dementia or clinically characterized Alzheimer's disease.
Abstract: Background
Identifying nutrition- and lifestyle-based risk factors for cognitive impairment and dementia may aid future primary prevention efforts.
TL;DR: The enthusiastic response means that cohorts from North America, Australasia, and the Asia Pacific Region are included, creating a truly global, collaborative, data sharing platform, linked to major national dementia initiatives.
Abstract: Dementia is a global problem and major target for health care providers. Although up to 45% of cases are primarily or partly due to cerebrovascular disease, little is known of these mechanisms or treatments because most dementia research still focuses on pure Alzheimer's disease. An improved understanding of the vascular contributions to neurodegeneration and dementia, particularly by small vessel disease, is hampered by imprecise data, including the incidence and prevalence of symptomatic and clinically “silent” cerebrovascular disease, long-term outcomes (cognitive, stroke, or functional), and risk factors. New large collaborative studies with long follow-up are expensive and time consuming, yet substantial data to advance the field are available. In an initiative funded by the Joint Programme for Neurodegenerative Disease Research, 55 international experts surveyed and assessed available data, starting with European cohorts, to promote data sharing to advance understanding of how vascular disease affects brain structure and function, optimize methods for cerebrovascular disease in neurodegeneration research, and focus future research on gaps in knowledge. Here, we summarize the results and recommendations from this initiative. We identified data from over 90 studies, including over 660,000 participants, many being additional to neurodegeneration data initiatives. The enthusiastic response means that cohorts from North America, Australasia, and the Asia Pacific Region are included, creating a truly global, collaborative, data sharing platform, linked to major national dementia initiatives. Furthermore, the revised World Health Organization International Classification of Diseases version 11 should facilitate recognition of vascular-related brain damage by creating one category for all cerebrovascular disease presentations and thus accelerate identification of targets for dementia prevention.
TL;DR: Serum DHA levels were associated with pathogenesis of cerebral amyloidosis and with preservation of entorhinal and hippocampal volumes and suggest an important role for DHA metabolism in brain amyloids deposition during the preclinical or early symptomatic stages of Alzheimer disease.
Abstract: Importance Higher dietary intake of the essential fatty acid docosahexaenoic (DHA) has been associated with better cognitive performance in several epidemiological studies. Animal and in vitro studies also indicate that DHA prevents amyloid deposition in the brain. Objective To determine the association between serum DHA levels, cerebral amyloidosis, and the volumes of brain areas affected by Alzheimer disease. Design, Settings, and Participants Cross-sectional analysis of serum DHA levels together with measures of amyloid deposition (Pittsburgh Compound B index), brain volumes, and neuropsychological testing scores from 61 participants in the Aging Brain Study. The study was conducted between June 2008 and May 2013, and the data were analyzed between October 2015 and April 2016. Linear models were adjusted for age, sex, years of education, and apolipoprotein E status. Main Outcomes and Measures Serum DHA levels with cerebral amyloidosis measured using PIB PET. Results Samples were available from 61 Aging Brain Study participants (41 women and 20 men) who underwent amyloid PET imaging. The mean (SD) age of the participants was 77 (6) years and ranged from 67 to 88 years. Serum DHA levels (percentage of total fatty acids) were 23% lower in participants with cerebral amyloidosis than those without (0.97 vs 1.25, P = .007) and were inversely correlated with brain amyloid load ( r = −0.32, P = .01) independent of age, sex, apolipoprotein E genotype, and years of education. Moreover, greater serum DHA levels were positively associated with brain volume in several subregions affected by AD, in particular the left subiculum ( r = 0.38, P = .005) and the left entorhinal volumes ( r = 0.51, P = .001). Serum DHA levels were also associated with nonverbal memory scores ( r = 0.28, P = .03). Conclusions and Relevance In this study, serum DHA levels were associated with pathogenesis of cerebral amyloidosis and with preservation of entorhinal and hippocampal volumes. These findings suggest an important role for DHA metabolism in brain amyloid deposition during the preclinical or early symptomatic stages of Alzheimer disease.
TL;DR: The results suggest that chrDS associated with progressive atrophy of frontal regions may represent an additional risk factor for conversion to dementia in MCI as opposite to representing typical prodromal AD symptomatology.
Abstract: Objective Investigate the association of chronic depressive symptomatology (chrDS) with cortical atrophy rates and conversion to Alzheimer dementia (AD) over 3 years in mild cognitive impairment (MCI). Methods In a multicenter, clinic-based study, MCI elderly participants were selected from the Alzheimer's Disease Neuroimaging Initiative repository, based on availability of both serial structural magnetic resonance imaging and chrDS endorsed on three depression-related items from the Neuropsychiatric Inventory Questionnaire (chrDS N = 32 or no depressive symptoms N = 62) throughout follow-up. Clinical and laboratory investigations were performed every 6 months during the first 2 years and yearly thereafter (median follow-up: 3 years; interquartile range: 1.5–4.0 years). Cortical atrophy rates in 16 predefined frontotemporoparietal regions affected in major depression and AD and the rate of incident AD at follow-up. Results ChrDS in a single domain amnestic MCI sample were associated with accelerated cortical atrophy in the frontal lobe and anterior cingulate but not with atrophy rates in temporomedial or other AD-affected regions. During follow-up, 38 participants (42.7%) developed AD. Participants with chrDS had 60% shorter conversion time to AD than those without depressive symptoms. This association remained significant in survival models adjusted for temporomedial atrophy rates and showed the same trend in models adjusted for frontal cortical atrophy rate, which all increased the risk of AD. Conclusion Our results suggest that chrDS associated with progressive atrophy of frontal regions may represent an additional risk factor for conversion to dementia in MCI as opposite to representing typical prodromal AD symptomatology.
TL;DR: Tests of walking speed and handgrip strength may serve as clinical markers of brain structure and function and may improve dementia risk prediction.
Abstract: Background Handgrip strength and gait speed are simple measures of physical capability and have been associated with current and future health outcomes. However, studies on their associations with brain structure and function in middle-aged adults are lacking. Objective To assess the relationship of fast-paced walking speed and handgrip strength with risk of dementia, Alzheimer's disease (AD), and stroke, as well as the cross-sectional associations with cognitive and brain magnetic resonance imaging (MRI) measures in a middle-aged community sample. Methods Framingham Offspring (n = 2,176; mean age 62, 54% female) had physical function, brain MRI, and cognitive evaluations between 1999 and 2005 and were followed-up for incident dementia AD and stroke until 11 years later. We related walking speed and handgrip strength to incident dementia, AD, and stroke using Cox models, and to brain and cognitive measures using multivariable linear and logistic regression. Models were adjusted for age, sex, education, and vascular risk factors. Results Slow walking and weak handgrip were associated with more than 2.5-fold increase in risk of AD. Weaker handgrip was associated with an increased risk of incident stroke (HR 1.74, 95% CI: 1.12-2.70/SDU, p = 0.01) in persons ≥65 years. Both measures were associated with lower total brain volume and poorer performance on tests of visual memory, language, executive function, and visuoperceptual function. Slower gait was also related to poorer verbal memory, and weaker handgrip to poorer abstraction. Conclusion Tests of walking speed and handgrip strength may serve as clinical markers of brain structure and function and may improve dementia risk prediction.
TL;DR: The apparent paradoxical association of carotid intima–media thickness progression with lower risk of CMB may reflect benefits of intensive vascular risk factor treatment among persons with higher cardiovascular risk and deserves further investigation.
Abstract: Background Carotid atherosclerosis is associated with subclinical ischemic cerebrovascular disease, but its role in hemorrhage‐prone small vessel disease—represented by cerebral microbleed (CMB)—is unclear, although vascular risk factors underlie both conditions. We hypothesized that persons with carotid atherosclerosis would have higher risk of CMB, particularly in deep regions.
Methods and Results We studied 1243 participants in the Framingham Offspring Study (aged 56.9±8.8 years; 53% women) with carotid ultrasound available on 2 occasions (1995–1998 and 2005–2008) prior to brain magnetic resonance imaging. Using multivariable logistic regression, we related baseline carotid stenosis, baseline intima–media thickness, and site‐specific carotid intima–media thickness progression (at internal and common carotid locations) to the prevalence and location (lobar or deep plus mixed) of CMB. In addition, we assessed effect modification by lipid levels and use of statin and antithrombotic medications. Carotid stenosis ≥25% (a marker of cerebrovascular atherosclerosis) was associated with presence of CMB overall (Odds Ratio 2.20, 95% CI 1.10–4.40) and at deep and mixed locations (odds ratio 3.60, 95% CI 1.23–10.5). Baseline carotid intima–media thickness was not associated with CMB. Progression of common carotid artery intima–media thickness among persons on hypertension treatment was associated with lower risk of deep and mixed CMB (odds ratio per SD 0.41, 95% CI 0.18–0.96).
Conclusions Cumulative vascular risk factor exposure may increase the risk of CMB, especially in deep regions. The apparent paradoxical association of carotid intima–media thickness progression with lower risk of CMB may reflect benefits of intensive vascular risk factor treatment among persons with higher cardiovascular risk and deserves further investigation. If replicated, the results may have potential implications for assessment of preventive and therapeutic interventions for subclinical cerebral hemorrhage.
TL;DR: CN individuals harboring cerebral amyloid had greater accrual of WMH over a 2-year period after accounting for hypertension and age, and the role of cerebralAmyloid burden in white-matter injury should thus be considered as a relevant factor when WMHs are detected clinically.
TL;DR: Investigation of the association between atrial fibrillation and brain volume measures on magnetic resonance imaging found prevalent AF was associated with lobar indexes of vascular brain aging but not with expected white matter changes.
TL;DR: Results showed that the combination of elevated β-amyloid and baseline hippocampal atrophy is associated with increased rates specific to the limbic circuit and splenium, pointing to accelerated atrophy of AD-vulnerable regions detectable at the preclinical stage.
TL;DR: These cross-sectional community-based data from a diverse urban sample show an association between elevated FGF23 and small vessel disease and magnetic resonance imaging–defined brain infarction in men, independent of chronic kidney disease.
Abstract: Background and Purpose—Elevated fibroblast growth factor 23 (FGF23) regulates phosphate homeostasis and is linked with mortality, cardiovascular events, and stroke. However, the role of FGF23 as a risk factor for subclinical cerebrovascular damage is unclear. Methods—We used multivariable linear and logistic regression to evaluate associations between FGF23, continuously and by quartiles, with white matter hyperintensity volume, expressed as percent intracranial volume (%ICV), and subclinical brain infarction (SBI) in a community-based stroke-free sample. Results—There were 1170 stroke-free Northern Manhattan Study (NOMAS) participants with FGF23 levels and quantitative magnetic resonance imaging data on white matter hyperintensity volume and SBI. Participants with FGF23 levels in the top quartile (range=85–1425 RU/mL) had greater white matter hyperintensity volume (β=0.19 %ICV; 95% CI, 0.04–0.33 %ICV; P=0.01) compared with those in the lowest quartile (range=15–49 RU/mL), adjusted for demographics, vascu...
TL;DR: The results suggest that lower CV fitness and exaggerated exercise BP and HR responses in middle-aged adults are associated with smaller brain volume nearly 2 decades later, which is an important step towards ensuring healthy brain aging.
Abstract: Objective: To determine whether poor cardiovascular (CV) fitness and exaggerated exercise blood pressure (BP) and heart rate (HR) were associated with worse brain morphology in later life. Methods: Framingham Offspring participants (n = 1,094, 53.9% female) free from dementia and CV disease (CVD) underwent an exercise treadmill test at a mean age of 40 ± 9 years. A second treadmill test and MRI scans of the brain were administered 2 decades later at mean age of 58 ± 8 years. Results: Poor CV fitness and greater diastolic BP and HR response to exercise at baseline were associated with a smaller total cerebral brain volume (TCBV) almost 2 decades later (all p p Conclusion: Our results suggest that lower CV fitness and exaggerated exercise BP and HR responses in middle-aged adults are associated with smaller brain volume nearly 2 decades later. Promotion of midlife CV fitness may be an important step towards ensuring healthy brain aging.
TL;DR: Preliminary evidences supporting that PICALM variations render protections by facilitating reserve capacities of posterior cingulate in non-demented elderly are provided.
Abstract: Phosphatidylinositolbinding clathrin assembly protein (PICALM) gene is one novel genetic player associated with late-onset Alzheimer's disease (LOAD), based on recent genome wide association studies (GWAS). However, how it affects AD occurrence is still unknown. Brain reserve hypothesis highlights the tolerant capacities of brain as a passive means to fight against neurodegenerations. Here, we took the baseline volume and/or thickness of LOAD-associated brain regions as proxies of brain reserve capacities and investigated whether PICALM genetic variations can influence the baseline reserve capacities and the longitudinal atrophy rate of these specific regions using data from Alzheimer's Disease Neuroimaging Initiative (ADNI) dataset. In mixed population, we found that brain region significantly affected by PICALM genetic variations was majorly restricted to posterior cingulate. In sub-population analysis, we found that one PICALM variation (C allele of rs642949) was associated with larger baseline thickness of posterior cingulate in health. We found seven variations in health and two variations (rs543293 and rs592297) in individuals with mild cognitive impairment were associated with slower atrophy rate of posterior cingulate. Our study provided preliminary evidences supporting that PICALM variations render protections by facilitating reserve capacities of posterior cingulate in non-demented elderly.
TL;DR: Aortic arch assessment by transthoracic echocardiography may help identify subjects at higher risk of subclinical cerebrovascular disease, who may benefit from aggressive stroke risk factors treatment.
Abstract: Background and Purpose—Aortic arch plaque (AAP) is a risk factor for ischemic stroke, but its association with subclinical cerebrovascular disease is not established. We investigated the associatio...
TL;DR: Higher exhaled CO was associated with a greater burden of subclinical cerebrovascular disease cross-sectionally and with increased risk of stroke/transient ischemic attack prospectively in the Framingham Offspring study.
Abstract: Background and Purpose— Exhaled carbon monoxide (CO) is associated with cardiometabolic traits, subclinical atherosclerosis, and cardiovascular disease, but its specific relations with stroke are unexplored. We related exhaled CO to magnetic resonance imaging measures of subclinical cerebrovascular disease cross-sectionally and to incident stroke/transient ischemic attack prospectively in the Framingham Offspring study. Methods— We measured exhaled CO in 3313 participants (age 59±10 years; 53% women), and brain magnetic resonance imaging was available in 1982 individuals (age 58±10 years; 54% women). Participants were analyzed according to tertiles of exhaled CO concentration. Results— In age- and sex-adjusted models, the highest tertile of exhaled CO was associated with lower total cerebral brain volumes, higher white-matter hyperintensity volumes, and greater prevalence of silent cerebral infarcts ( P P =0.04). In prospective analyses (mean follow-up 12.9 years), higher exhaled CO was associated with 67% (second tertile) and 97% (top tertile) increased incidence of stroke/transient ischemic attack relative to the first tertile that served as referent ( P Conclusions— In this large, community-based sample of individuals without clinical stroke/transient ischemic attack at baseline, higher exhaled CO was associated with a greater burden of subclinical cerebrovascular disease cross-sectionally and with increased risk of stroke/transient ischemic attack prospectively. Further investigation is necessary to explore the biological mechanisms linking elevated CO with stroke.
TL;DR: This study examined whether interarm differences in systolic blood pressure (IDSBP) ≥10 mm Hg were associated with the risk of incident dementia and subclinical brain injury.
Abstract: Introduction This study examined whether interarm differences in systolic blood pressure (IDSBP) ≥10 mm Hg were associated with the risk of incident dementia and subclinical brain injury. Methods Between 1992 and 1998, 2063 participants of the Framingham Heart Study underwent assessment of IDSBP with results related to the 10-year risk of incident dementia including clinically characterized Alzheimer's disease. Secondary outcomes included markers of subclinical brain injury on magnetic resonance imaging. Results High IDSBP were associated with a greater risk of incident dementia (hazard ratio [HR] 1.92; 95% confidence interval [CI], 1.09–3.40) and Alzheimer's disease (HR, 2.32; 95% CI, 1.29–4.18), but only in those who carried an apolipoprotein E ( APOE ) e4 allele. IDSBP also predicted lower total brain volumes and more prevalent silent brain infarcts in those who were APOE e4 positive. Discussion High IDSBP were associated with an increased risk of dementia, including clinical Alzheimer's disease, and subclinical brain injury in those who were APOE e4 positive.
17 Jun 2016
TL;DR: Wang et al. as mentioned in this paper investigated the role APOE e4 plays in moderating brain volume in cognitively normal Chinese older adults, compared to older white Americans, and found a significant interaction effect of carrying apolipoprotein E and being Chinese.
Abstract: Studying ethnically diverse groups is important for furthering our understanding of biological mechanisms of disease that may vary across human populations. The e4 allele of apolipoprotein E (APOE e4) is a well-established risk factor for Alzheimer’s disease (AD), and may confer anatomic and functional effects years before clinical signs of cognitive decline are observed. The allele frequency of APOE e4 varies both across and within populations, and the size of the effect it confers for dementia risk may be affected by other factors. Our objective was to investigate the role APOE e4 plays in moderating brain volume in cognitively normal Chinese older adults, compared to older white Americans. We hypothesized that carrying APOE e4 would be associated with reduced brain volume and that the magnitude of this effect would be different between ethnic groups. We performed whole brain analysis of structural MRIs from Chinese living in America (n = 41) and Shanghai (n = 30) and compared them to white Americans (n = 71). We found a significant interaction effect of carrying APOE e4 and being Chinese. The APOE e4xChinese interaction was associated with lower volume in bilateral cuneus and left middle frontal gyrus (Puncorrected<0.001), with suggestive findings in right entorhinal cortex and left hippocampus (Puncorrected<0.01), all regions that are associated with neurodegeneration in AD. After correction for multiple testing, the left cuneus remained significantly associated with the interaction effect (PFWE = 0.05). Our study suggests there is a differential effect of APOE e4 on brain volume in Chinese versus white cognitively normal elderly adults. This represents a novel finding that, if verified in larger studies, has implications for how biological, environmental and/or lifestyle factors may modify APOE e4 effects on the brain in diverse populations.
Erasmus University Rotterdam1, University of Cambridge2, National Institutes of Health3, Boston University4, University of Graz5, University of Washington6, University of Bordeaux7, Johns Hopkins University8, Leiden University Medical Center9, University of Mississippi Medical Center10, Rush University Medical Center11, University of Greifswald12, National University of Singapore13, University of Edinburgh14, University of Pittsburgh15, University of Texas Health Science Center at Houston16, Brigham and Women's Hospital17, University of California, Davis18, Greifswald University Hospital19
TL;DR: A novel meta-analytical approach, named partial derivatives meta-analysis, that is mathematically equivalent to using IPD, yet only requires the sharing of aggregate data is proposed, which yields identical results as pooled IPD analyses, but also allows post-hoc adjustments for covariates and stratification without the need for site-specific re-analysis.
Abstract: Joint analysis of data from multiple studies in collaborative efforts strengthens scientific evidence, with the gold standard approach being the pooling of individual participant data (IPD). However, sharing IPD often has legal, ethical, and logistic constraints for sensitive or high-dimensional data, such as in clinical trials, observational studies, and large-scale omics studies. Therefore, meta-analysis of study-level effect estimates is routinely done, but this compromises on statistical power, accuracy, and flexibility. Here we propose a novel meta-analytical approach, named partial derivatives meta-analysis, that is mathematically equivalent to using IPD, yet only requires the sharing of aggregate data. It not only yields identical results as pooled IPD analyses, but also allows post-hoc adjustments for covariates and stratification without the need for site-specific re-analysis. Thus, in case that IPD cannot be shared, partial derivatives meta-analysis still produces gold standard results, which can be used to better inform guidelines and policies on clinical practice.
TL;DR: Consistent with prior observations, all adiposity measures showed associations with more adverse brain MRI and NP measures, suggesting a global association of generalized adiposity.
Abstract: Background Perivascular fat may have direct effects on local vascularity. Neck fat is associated with carotid intimal thickness, a predictor of brain aging outcomes. This study investigated whether neck circumference, an estimation of neck fat, has unique associations with brain aging outcomes. Methods The study sample (n = 2082, 53.5% women, mean age 60.9 years) was derived from Framingham Heart Study participants with brain magnetic resonance imaging (MRI) and neuropsychological (NP) test measures. Multivariable-adjusted regressions examined cross-sectional associations of neck circumference with brain MRI and NP test measures. Models were also constructed with waist circumference and body mass index (BMI) as exposures. Results A 1 standard deviation (2.8 cm [women]; 2.9 cm [men]) increment in neck circumference was associated with lower total cerebral brain volume (β = −.22, P = .0006) and lower frontal brain volume (β = −.55, P Conclusions There were no unique associations between neck circumference and brain MRI or NP measures. Consistent with prior observations, all adiposity measures showed associations with more adverse brain MRI and NP measures, suggesting a global association of generalized adiposity.
Journal Article•
TL;DR: In the community-based, stroke-free middle-aged sample, elevated BDNF has a subtle, positive effect on WM microstructural integrity in specific tracts whose integrity was also found to be associated with preserved executive function, which can expand the understanding of the structural pathways in the brain implicated in BDNF mediated preservation of cognitive reserve and protection from vascular brain injury.
Abstract: Objective:
To relate circulating Brain Derived Neurotrophic Factor (BDNF) levels to measures of Fractional Anisotropy (FA) using Diffusion Tensor Imaging (DTI) in the Framingham Heart Study (FHS) Offspring cohort.
Background:
Previous work from FHS has related higher serum BDNF concentration with decreased risk of incident stroke and dementia and lower white matter hyperintensity burden. BDNF is also inducible by exercise, social contact and caloric restriction, factors that promote cognitive reserve. We now explore the spatial distribution of subtle white matter (WM) injury associated with serum BDNF and whether integrity of implicated tracts may relate with cognitive performance in domains previously associated with vascular risk factors and vascular brain injury.
Methods:
In 577 FHS Offspring (mean age 58.9±8.1 yrs; 40.9[percnt] W), we related, at voxel level, FA measures derived from DTI to BDNF levels using multivariate linear regression, adjusting for age, gender, intracranial volume (ICV) and time between clinical and MRI exams (Δt). We then used generalized linear models to relate integrity of tracts implicated in BDNF associations with performance in visuospatial memory and executive function domains, adjusting for age, gender, ICV, Δt and education.
Results:
Greater BDNF was independently associated with higher FA in voxels that covered 44 cc of the WM. WM tracts showing the most benefit included the corpus callosum (9.4cc) and the corona radiata (8.2cc). Preserved integrity of BDNF-related WM tracts, was also associated with better executive function, including in the superior longitudinal fasciculus (3.0 cc, p<0.05).
Conclusions:
In our community-based, stroke-free middle-aged sample, elevated BDNF has a subtle, positive effect on WM microstructural integrity in specific tracts whose integrity was also found to be associated with preserved executive function. These data can expand our understanding of the structural pathways in the brain implicated in BDNF mediated preservation of cognitive reserve and protection from vascular brain injury. Disclosure: Dr. Maillard has nothing to disclose. Dr. Satizabal has nothing to disclose. Dr. Beiser has nothing to disclose. Dr. Himali has nothing to disclose. Dr. Chen has nothing to disclose. Dr. Vasan has nothing to disclose. Dr. Seshadri has nothing to disclose. Dr. DeCarli has nothing to disclose.
TL;DR: PHFtau tangles and b-amyloid AD pathology burdens were related to specific regional hippocampal surface deformity, with differing patterns on the surface, providing support that specific patterns of hippocampal atrophy may be biomarkers for specific AD pathologies.
Abstract: of 2.7 years (See Table 1 for details). Significant relationships existed between higher global PHFtau tangle burden and inward surface deformity in CA1 and CA2-4+GD (Figure 1), between higher b-amyloid load and inward subiculum deformity (trend, Figure 2), with differing patterns along the hippocampal surface. No significant relationship between surface shape and TDP-43 pathology was observed. Conclusions:PHFtau tangles and b-amyloid AD pathology burdens were related to specific regional hippocampal surface deformity, with differing patterns on the surface. We did not find associations between TDP-43 inclusions and surface deformity. These findings provide support that specific patterns of hippocampal atrophy may be biomarkers for specific AD pathologies. These results need to be further validated in larger samples.