Higher brain BDNF gene expression is associated with slower cognitive decline in older adults.
ABSTRACT: OBJECTIVES:We tested whether brain-derived neurotrophic factor (BDNF) gene expression levels are associated with cognitive decline in older adults. METHODS:Five hundred thirty-five older participants underwent annual cognitive assessments and brain autopsy at death. BDNF gene expression was measured in the dorsolateral prefrontal cortex. Linear mixed models were used to examine whether BDNF expression was associated with cognitive decline adjusting for age, sex, and education. An interaction term was added to determine whether this association varied with clinical diagnosis proximate to death (no cognitive impairment, mild cognitive impairment, or dementia). Finally, we examined the extent to which the association of Alzheimer disease (AD) pathology with cognitive decline varied by BDNF expression. RESULTS:Higher brain BDNF expression was associated with slower cognitive decline (p < 0.001); cognitive decline was about 50% slower with the 90th percentile BDNF expression vs 10th. This association was strongest in individuals with dementia. The level of BDNF expression was lower in individuals with pathologic AD (p = 0.006), but was not associated with macroscopic infarcts, Lewy body disease, or hippocampal sclerosis. BDNF expression remained associated with cognitive decline in a model adjusting for age, sex, education, and neuropathologies (p < 0.001). Furthermore, the effect of AD pathology on cognitive decline varied by BDNF expression such that the effect was strongest for high levels of AD pathology (p = 0.015); thus, in individuals with high AD pathology (90th percentile), cognitive decline was about 40% slower with the 90th percentile BDNF expression vs 10th. CONCLUSIONS:Higher brain BDNF expression is associated with slower cognitive decline and may also reduce the deleterious effects of AD pathology on cognitive decline.
Project description:In Alzheimer's disease (AD), a single-nucleotide polymorphism in the gene encoding brain-derived neurotrophic factor (BDNF<sub>Val66Met</sub>) is associated with worse impact of primary AD pathology (beta-amyloid, A?) on neurodegeneration and cognitive decline, rendering BDNF<sub>Val66Met</sub> an important modulating factor of cognitive impairment in AD. However, the effect of BDNF<sub>Val66Met</sub> on functional networks that may underlie cognitive impairment in AD is poorly understood. Using a cross-validation approach, we first explored in subjects with autosomal dominant AD (ADAD) from the Dominantly Inherited Alzheimer Network (DIAN) the effect of BDNF<sub>Val66Met</sub> on resting-state fMRI assessed functional networks. In seed-based connectivity analysis of six major large-scale networks, we found a stronger decrease of hippocampus (seed) to medial-frontal connectivity in the BDNF<sub>Val66Met</sub> carriers compared to BDNF<sub>Val</sub> homozogytes. BDNF<sub>Val66Met</sub> was not associated with connectivity in any other networks. Next, we tested whether the finding of more pronounced decrease in hippocampal-medial-frontal connectivity in BDNF<sub>Val66Met</sub> could be also found in elderly subjects with sporadically occurring A?, including a group with subjective cognitive decline (N?=?149, FACEHBI study) and a group ranging from preclinical to AD dementia (N?=?114, DELCODE study). In both of these independently recruited groups, BDNF<sub>Val66Met</sub> was associated with a stronger effect of more abnormal A?-levels (assessed by biofluid-assay or amyloid-PET) on hippocampal-medial-frontal connectivity decreases, controlled for hippocampus volume and other confounds. Lower hippocampal-medial-frontal connectivity was associated with lower global cognitive performance in the DIAN and DELCODE studies. Together these results suggest that BDNF<sub>Val66Met</sub> is selectively associated with a higher vulnerability of hippocampus-frontal connectivity to primary AD pathology, resulting in greater AD-related cognitive impairment.
Project description: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-stage AD pathology (Braak and Braak stages I-II) in hippocampal CA1 region samples from cognitively intact Framingham Heart Study subjects (n = 5) when compared with 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 ?2 (Capzb2), a marker of actin cytoskeleton reorganization. Capzb2 expression was also significantly increased in CA1 hippocampal neurons of cognitively intact subjects with early-stage 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.
Project description:Neural stem cell (NSC) transplantation represents an unexplored approach for treating neurodegenerative disorders associated with cognitive decline such as Alzheimer disease (AD). Here, we used aged triple transgenic mice (3xTg-AD) that express pathogenic forms of amyloid precursor protein, presenilin, and tau to investigate the effect of neural stem cell transplantation on AD-related neuropathology and cognitive dysfunction. Interestingly, despite widespread and established Ass plaque and neurofibrillary tangle pathology, hippocampal neural stem cell transplantation rescues the spatial learning and memory deficits in aged 3xTg-AD mice. Remarkably, cognitive function is improved without altering Ass or tau pathology. Instead, the mechanism underlying the improved cognition involves a robust enhancement of hippocampal synaptic density, mediated by brain-derived neurotrophic factor (BDNF). Gain-of-function studies show that recombinant BDNF mimics the beneficial effects of NSC transplantation. Furthermore, loss-of-function studies show that depletion of NSC-derived BDNF fails to improve cognition or restore hippocampal synaptic density. Taken together, our findings demonstrate that neural stem cells can ameliorate complex behavioral deficits associated with widespread Alzheimer disease pathology via BDNF.
Project description:Using data (n = 60,775 women) from the Women's Health Initiative Clinical Trial (WHI CT)-a national study of postmenopausal women aged 50-79 years-we analyzed cross-sectional associations between the availability of different types of food outlets in the 1.5 miles surrounding a woman's residence, census tract neighborhood socioeconomic status (NSES), BMI, and blood pressure (BP). We simultaneously modeled NSES and food outlets using linear and logistic regression models, adjusting for multiple sociodemographic factors, population density and random effects at the tract and metropolitan statistical area (MSA) level. We found significant associations between NSES, availability of food outlets and individual-level measurements of BMI and BP. As grocery store/supermarket availability increased from the 10th to the 90th percentile of its distribution, controlling for confounders, BMI was lower by 0.30 kg/m(2). Conversely, as fast-food outlet availability increased from the 10th to the 90th percentile, BMI was higher by 0.28 kg/m(2). When NSES increased from the 10th to the 90th percentile of its distribution, BMI was lower by 1.26 kg/m(2). As NSES increased from the 10th to the 90th percentile, systolic and diastolic BP were lower by 1.11 mm Hg and 0.40 mm Hg, respectively. As grocery store/supermarket outlet availability increased from the 10th and 90th percentiles, diastolic BP was lower by 0.31 mm Hg. In this national sample of postmenopausal women, we found important independent associations between the food and socioeconomic environments and BMI and BP. These findings suggest that changes in the neighborhood environment may contribute to efforts to control obesity and hypertension.
Project description:OBJECTIVE:To compare fetal/infant mortality risk associated with each additional week of expectant management with the infant mortality risk of immediate delivery in growth-restricted pregnancies. METHODS:A retrospective cohort study was conducted of singleton, nonanomalous pregnancies from the 2005-2008 California Birth Registry comparing pregnancies affected and unaffected by growth restriction, defined using birth weights as a proxy for fetal growth restriction (FGR). Birth weights were subdivided as greater than the 90th percentile, between the 10th percentile and 90th percentile, and less than the 10th percentile. Cases greater than the 90th percentile were excluded from analysis. Cases less than the 10th percentile were considered to have FGR and were further subcategorized into <10th percentile, <5th percentile, and <3rd percentile. We compared the risk of infant death at each gestational age week against a composite risk representing the mortality risk of one additional week of expectant management. RESULTS:We identified 1,641,000 births, of which 110,748 (6.7%) were less than 10th percentile. The risk of stillbirth increased with gestational age with the risk of stillbirth at each week of gestation inversely proportional to growth percentile. The risks of fetal and infant mortality with expectant management outweighed the risk of infant death for all FGR categories analyzed beginning at 38 weeks. However, the absolute risks differed by growth percentiles, with the highest risks of infant death and stillbirth in the <3rd percentile cohort. At 39 weeks, absolute risks were low, although the number needed to deliver to prevent 1 death ranged from 413 for <3rd percentile to 2667 in unaffected pregnancies. CONCLUSION:At 38 weeks, the mortality risk of expectant management for one additional week exceeds the risk of delivery across all growth-restricted cohorts, despite variation in absolute risk by degree of growth restriction.
Project description:The glymphatic system is a brain-wide perivascular network that facilitates clearance of proteins, including amyloid β, from the brain interstitium through the perivascular exchange of cerebrospinal fluid and interstitial fluid. The astrocytic water channel aquaporin-4 (AQP4) is required for glymphatic system function, and impairment of glymphatic function in the aging brain is associated with altered AQP4 expression and localization. In human cortical tissue, alterations in AQP4 expression and localization are associated with Alzheimer's disease (AD) status and pathology. Although this suggests a potential role for AQP4 in the development or progression of AD, the relationship between of naturally occurring variants in the human AQP4 gene and cognitive function has not yet been evaluated.Using data from several longitudinal aging cohorts, we investigated the association between five AQP4 single-nucleotide polymorphisms (SNPs) and the rate of cognitive decline in participants with a diagnosis of AD.None of the five SNPs were associated with different rates of AD diagnosis, age of dementia onset in trial subjects. No association between AQP4 SNPs with histological measures of AD pathology, including Braak stage or neuritic plaque density was observed. However, AQP4 SNPs were associated with altered rates of cognitive decline after AD diagnosis, with two SNPS (rs9951307 and rs3875089) associated with slower cognitive decline and two (rs3763040 and rs3763043) associated with more rapid cognitive decline after AD diagnosis.These results provide the first evidence that variations in the AQP4 gene, whose gene product AQP4 is vital for glymphatic pathway function, may modulate the progression of cognitive decline in AD.
Project description:<b>Background and Aim:</b> The classification of weight gain during pregnancy and the somatic classification of neonates according to birth weight and duration of pregnancy can be done using percentile values. We aimed to compare such classifications using percentiles of the overall study population with classifications using percentiles that were calculated taking account of maternal height and weight. <b>Material and Methods:</b> Using data from the German Perinatal Survey (1995-2000, over 2.2 million singleton pregnancies) we classified weight gain during pregnancy as low (<?10th percentile), high (>?90th percentile), or medium (10th-90th percentile). Neonates were classified by birth weight as small for gestational age (SGA, <?10th percentile), large for gestational age (LGA, >?90th percentile), or appropriate for gestational age (AGA, 10th-90th percentile). Classifications were performed for 12 groups of women and their neonates formed according to maternal height and weight, either with the percentiles calculated from the total study population or with group-specific percentiles. <b>Results:</b> Using percentiles of the total study population there was large variability between the 12 groups in the proportions with low and high weight gain and in the proportions of SGA and LGA neonates. The variability was much lower when group-specific percentiles were used. <b>Conclusions:</b> Classifications of maternal weight gain during pregnancy and birth weight differ substantially, depending on whether percentiles calculated from the total study population or group-specific percentiles are used. The impact of using percentiles that take account of maternal anthropometric parameters for the medical care and health of neonates needs to be elucidated in future research.
Project description:To define robust resilience metrics by leveraging CSF biomarkers of Alzheimer disease (AD) pathology within a latent variable framework and to demonstrate the ability of such metrics to predict slower rates of cognitive decline and protection against diagnostic conversion.Participants with normal cognition (n = 297) and mild cognitive impairment (n = 432) were drawn from the Alzheimer's Disease Neuroimaging Initiative. Resilience metrics were defined at baseline by examining the residuals when regressing brain aging outcomes (hippocampal volume and cognition) on CSF biomarkers. A positive residual reflected better outcomes than expected for a given level of pathology (high resilience). Residuals were integrated into a latent variable model of resilience and validated by testing their ability to independently predict diagnostic conversion, cognitive decline, and the rate of ventricular dilation.Latent variables of resilience predicted a decreased risk of conversion (hazard ratio < 0.54, p < 0.0001), slower cognitive decline (? > 0.02, p < 0.001), and slower rates of ventricular dilation (? < -4.7, p < 2 × 10-15). These results were significant even when analyses were restricted to clinically normal individuals. Furthermore, resilience metrics interacted with biomarker status such that biomarker-positive individuals with low resilience showed the greatest risk of subsequent decline.Robust phenotypes of resilience calculated by leveraging AD biomarkers and baseline brain aging outcomes provide insight into which individuals are at greatest risk of short-term decline. Such comprehensive definitions of resilience are needed to further our understanding of the mechanisms that protect individuals from the clinical manifestation of AD dementia, especially among biomarker-positive individuals.
Project description:Alzheimer's disease (AD) is a neurodegenerative disease characterized by A?-induced pathology and progressive cognitive decline. The incidence of AD is growing globally, yet a prompt and effective remedy is not available. Aging is the greatest risk factor for AD. Brain aging proceeds with reduced vascularization, which can cause low oxygen (O2 ) availability. Accordingly, the question may be raised whether O2 availability in the brain affects AD pathology. We found that Tg-APP/PS1 mice treated with 100% O2 at increased atmospheric pressure in a chamber exhibited markedly reduced A? accumulation and hippocampal neuritic atrophy, increased hippocampal neurogenesis, and profoundly improved the cognitive deficits on the multiple behavioral test paradigms. Hyperoxygenation treatment increased the expression of BDNF, NT3, and NT4/5 through the upregulation of MeCP2/p-CREB activity in HT22 cells in vitro and in the hippocampus of mice. In contrast, siRNA-mediated inhibition of MeCP2 or TrkB neurotrophin receptors in the hippocampal subregion, which suppresses neurotrophin expression and neurotrophin action, respectively, blocked the therapeutic effects of hyperoxygenation on the cognitive impairments of Tg-APP/PS1 mice. Our results highlight the importance of the O2 -related mechanisms in AD pathology, which can be revitalized by hyperoxygenation treatment, and the therapeutic potential of hyperoxygenation for AD.
Project description:Alzheimer's disease (AD) is characterized clinically by progressive cognitive decline and pathologically by the accumulation of amyloid-? (A?) in the brain. Royal jelly (RJ), a secretion of honeybee hypopharyngeal and mandibular glands, has previously been shown to have anti-aging and neuromodulatory activities. In this study, we discovered that 3 months of RJ treatment substantially ameliorated behavioral deficits of APP/PS1 mice in the Morris Water Maze (MWM) test and step-down passive avoidance test. Our data also showed that RJ significantly diminished amyloid plaque pathology in APP/PS1 mice. Furthermore, RJ alleviated c-Jun N-terminal kinase (JNK) phosphorylation-induced neuronal apoptosis by suppressing oxidative stress. Importantly, hippocampal cyclic adenosine monophosphate (cAMP), p-PKA, p-CREB and BDNF levels were significantly increased in the APP/PS1 mice after RJ treatment, indicating that the cAMP/PKA/CREB/BDNF pathway might be related to the ameliorative effect of RJ on cognitive decline. Collectively, these results provide a scientific basis for using RJ as a functional food for targeting AD pathology.