Brain-Derived Neurotrophic Factor Val66Met and Blood Glucose: A Synergistic Effect on Memory

Age-related declines in episodic memory performance are frequently reported, but their mechanisms remain poorly understood. Although several genetic variants and vascular risk factors have been linked to mnemonic performance in general and age differences therein, it is unknown whether and how they modify age-related memory declines. To address that question, we investigated the effect of Brain-Derived Neurotrophic Factor (BDNF) Val66Met polymorphism that affects secretion of BDNF, and fasting blood glucose level (a vascular risk factor) on episodic memory in a sample of healthy volunteers (age 19–77). We found that advanced age and high-normal blood glucose levels were associated with reduced recognition memory for name-face associations and poorer prose recall. However, elevated blood glucose predicted lower memory scores only in carriers of the BDNF 66Met allele. The effect on associative memory was stronger than on free recall. These findings indicate that even low-level vascular risk can produce negative cognitive effects in genetically susceptible individuals. Alleviation of treatable vascular risks in such persons may have a positive effect on age-related cognitive declines

Volume of white matter hyperintensities in healthy adults: Contribution of age, vascular risk factors, and inflammation-related genetic variants

AbstractAging is associated with appearance of white matter hyperintensities (WMH) on MRI scans. Vascular risk and inflammation, which increase with age, may contribute to white matter deterioration and proliferation of WMH. We investigated whether circulating biomarkers and genetic variants associated with elevated vascular risk and inflammation are associated with WMH volume in healthy adults (144 volunteers, 44–77years of age). We examined association of WMH volume with age, sex, hypertension, circulating levels of total plasma homocysteine (tHcy), cholesterol (low-density lipoprotein), and C-reactive protein (CRP), and four polymorphisms related to vascular risk and inflammation: Apolipoprotein ε (ApoE ε2,3,4), Angiotensin-Converting Enzyme insertion/deletion (ACE I/D), methylenetetrahydrofolate reductase (MTHFR) C677T, C-reactive protein (CRP)-286C>A>T, and interleukin-1β (IL-1β) C-511T. We found that larger WMH volume was associated with advanced age, hypertension, and elevated levels of homocysteine and CRP but not with low-density lipoprotein levels. Homozygotes for IL-1β-511T allele and carriers of CRP-286T allele that are associated with increased inflammatory response had larger WMH than the other allelic combinations. Carriers of the APOE ε2 allele had larger frontal WMH than ε3 homozygotes and ε4 carriers did. Thus, in healthy adults, who are free of neurological and vascular disease, genetic variants that promote inflammation and elevated levels of vascular risk biomarkers can contribute to brain abnormalities. This article is part of a Special Issue entitled: Imaging Brain Aging and Neurodegenerative disease

BDNF Val66Met Polymorphism Influences Age Differences in Microstructure of the Corpus Callosum

Brain-derived neurotrophic factor (BDNF) plays an important role in neuroplasticity and promotes axonal growth, but its secretion, regulated by a BDNF gene, declines with age. The low-activity (met) allele of common polymorphism BDNF val66met is associated with reduced production of BDNF. We examined whether age-related reduction in the integrity of cerebral white matter (WM) depends on the BDNF val66met genotype. Forty-one middle-aged and older adults participated in the study. Regional WM integrity was assessed by fractional anisotropy (FA) computed from manually drawn regions of interest in the genu and splenium of the corpus callosum on diffusion tensor imaging scans. After controlling for effects of sex and hypertension, we found that only the BDNF 66met carriers displayed age-related declines in the splenium FA, whereas no age-related declines were shown by BDNF val homozygotes. No genotype-related differences were observed in the genu of the corpus callosum. This finding is consistent with a view that genetic risk for reduced BDNF affects posterior regions that otherwise are considered relatively insensitive to normal aging. Those individuals with a genetic predisposition for decreased BDNF expression may not be able to fully benefit from BDNF-based plasticity and repair mechanisms

Adult Age Differences and the Role of Cognitive Resources in Perceptual-Motor Skill Acquisition: Application of a Multilevel Negative Exponential Model

The effects of advanced age and cognitive resources on the course of skill acquisition are unclear, and discrepancies among studies may reflect limitations of data analytic approaches. We applied a multilevel negative exponential model to skill acquisition data from 80 trials (four 20-trial blocks) of a pursuit rotor task administered to healthy adults (19-80 years old). The analyses conducted at the single-trial level indicated that the negative exponential function described performance well. Learning parameters correlated with measures of task-relevant cognitive resources on all blocks except the last and with age on all blocks after the second. Thus, age differences in motor skill acquisition may evolve in 2 phases: In the first, age differences are collinear with individual differences in task-relevant cognitive resources; in the second, age differences orthogonal to these resources emerg

Neuroanatomical Correlates of Fluid Intelligence in Healthy Adults and Persons with Vascular Risk Factors

The main objective of this study was to examine the effects of regional brain changes on cognitive decline and the modifying influence of vascular risk (VR) factors. We present latent difference score analyses of associations among 5-year changes in 12 regional brain volumes and age-sensitive cognitive functions in 87 adults (32 with identifiable VR factors). We found reliable individual differences in volume change for 11 of the 12 brain regions but not in the cognitive measures that showed average longitudinal decline. Thus, associations between rates of change in fluid intelligence and brain volumes could not be assessed. We observed, however, that lower levels of fluid intelligence were associated with smaller prefrontal and hippocampal volumes. Lower fluid intelligence scores were also linked to greater longitudinal shrinkage of the entorhinal cortex (EC). After accounting for the effects of age, sex, and VR factors, the orbitofrontal cortex and the prefrontal white matter (PFw) volumes as well as the 5-year change in the EC volume predicted fluid intelligence level. VR was independently associated with smaller prefrontal volumes and lower fluid intelligence. Thus, prefrontal and medial-temporal systems may play different roles in age-related differences and changes in cognitive performanc

Brain reserve, cognitive reserve, compensation, and maintenance: operationalization, validity, and mechanisms of cognitive resilience

Significant individual differences in the trajectories of cognitive aging and in age-related changes of brain structure and function have been reported in the past half-century. In some individuals, significant pathological changes in the brain are observed in conjunction with relatively well-preserved cognitive performance. Multiple constructs have been invoked to explain this paradox of resilience, including brain reserve, cognitive reserve, brain maintenance, and compensation. The aim of this session of the Cognitive Aging Summit III was to examine the overlap and distinctions in definitions and measurement of these constructs, to discuss their neural and behavioral correlates and to propose plausible mechanisms of individual cognitive resilience in the face of typical age-related neural declines

Hippocampal Subfield Volumes: Age, Vascular Risk, and Correlation with Associative Memory

Aging and age-related diseases have negative impact on the hippocampus (HC), which is crucial for such age-sensitive functions as memory formation, maintenance, and retrieval. We examined age differences in hippocampal subfield volumes in 10 younger and 19 older adults, and association of those volumes with memory performance in the older participants. We manually measured volumes of HC regions CA1 and CA2 (CA1–2), sectors CA3 and CA4 plus dentate gyrus (CA3–4/DG), subiculum, and the entorhinal cortex using a contrast-optimized high-resolution PD-weighted MRI sequence. Although, as in previous reports, the volume of one region (CA1–2) was larger in the young, the difference was due to the presence of hypertensive subjects among the older adults. Among older participants, increased false alarm rate in an associative recognition memory task was linked to reduced CA3–4/DG volume. We discuss the role of the DG in pattern separation and the formation of discrete memory representations

Optimization and validation of automated hippocampal subfield segmentation across the lifespan

Automated segmentation of hippocampal (HC) subfields from magnetic resonance imaging (MRI) is gaining popularity, but automated procedures that afford high speed and reproducibility have yet to be extensively validated against the standard, manual morphometry. We evaluated the concurrent validity of an automated method for hippocampal subfields segmentation (automated segmentation of hippocampal subfields, ASHS; Yushkevich et al.,2015b) using a customized atlas of the HC body, with manual morphometry as a standard. We built a series of customized atlases comprising the entorhinal cortex (ERC) and subfields of the HC body from manually segmented images, and evaluated the correspondence of automated segmentations with manual morphometry. In samples with age ranges of 6–24 and 62–79 years, 20 participants each, we obtained validity coefficients (intraclass correlations, ICC) and spatial overlap measures (dice similarity coefficient) that varied substantially across subfields. Anterior and posterior HC body evidenced the greatest discrepancies between automated and manual segmentations. Adding anterior and posterior slices for atlas creation and truncating automated output to the ranges manually defined by multiple neuroanatomical landmarks substantially improved the validity of automated segmentation, yielding ICC above 0.90 for all subfields and alleviating systematic bias. We cross-validated the developed atlas on an independent sample of 30 healthy adults (age 31–84) and obtained good to excellent agreement: ICC (2) = 0.70–0.92. Thus, with described customization steps implemented by experts trained in MRI neuroanatomy, ASHS shows excellent concurrent validity, and can become a promising method for studying age-related changes in HC subfield volumes

Cardiovascular fitness associated with cognitive performance in heart failure patients enrolled in cardiac rehabilitation

Abstract Background Reduced cognitive function is common in persons with heart failure (HF). Cardiovascular fitness is a known contributor to cognitive function in many patient populations, but has only been linked to cognition based on estimates of fitness in HF. The current study examined the relationship between fitness as measured by metabolic equivalents (METs) from a standardized stress test and cognition in persons with HF, as well as the validity of office-based predictors of fitness in this population. Methods Forty-one HF patients enrolled in cardiac rehabilitation completed a standardized exercise stress test protocol, a brief neuropsychological battery, the 2-minute step test (2MST), and a series of medical history and self-report questionnaires. Results Maximum METs from stress testing demonstrated incremental predictive validity for attention (β = .41,p = .03), executive function (β = .37,p = .04), and memory domains (β = .46,p = .04). Partial correlations accounting for key medical and demographic characteristics revealed greater METs was associated with the 2MST (r(32) = .41,p = .02) but not with the Duke Activity Status Index (DASI) (r(32) = .24,p = .17). Conclusion The current findings indicate that better fitness levels measured by METs is independently associated with better cognitive function in older adults with HF. Results also showed that METs was closely associated with one office-based measure of fitness (2MST), but not another (DASI). Prospective studies are needed to clarify the mechanisms linking fitness and cognitive function in HF