Age-Related Hearing Loss, Cognitive Performance, and Metabolic Risk in Healthy Adults: A Seven-Year Longitudinal Study.

OBJECTIVES: Sensorineural hearing loss (presbycusis) affects up to half of the adults, is associated with cognitive decline. Whether this association reflects the cause, the consequence, or parallel processes driven by other factors remains unclear. Both presbycusis and cognition are linked to elevated metabolic risk, which in turn raises with age. METHOD: In a multioccasion longitudinal design, we used latent change score models with strong factorial invariance to assess the change in pure-tone threshold auditory function, fluid intelligence, metabolic risk, variability therein, and the dynamic relationships among the 3 domains. We examined, up to 4 times over more than 7 years, a sample of relatively healthy 687 adults (aged 18.17-83.25 years). RESULTS: We found that levels of auditory and cognitive functioning at time t-1 influence each other's subsequent change between times t-1 and t, even when controlling for the reciprocal effects of metabolic risk on both. Thus, auditory and cognitive functioning do not only decline in parallel in healthy adults, but also affect each other's trajectories. To the best of our knowledge, this is the first long-term study with such evidence. DISCUSSION: Our results are in accord with extant hypotheses about auditory-cognitive associations in old age (e.g., social isolation, cognitive load, increased inflammation, reduced gene expression, and other microvascular or neuropathological factors). They also echo previous reports underscoring the need for improving access to hearing aids and other rehabilitative services aimed at reducing hearing loss. If applied early in the aging process, such interventions may mitigate cognitive decline.

Changes in cerebral arterial pulsatility and hippocampal volume: a transcranial doppler ultrasonography study.

The physiological mechanisms of age-related cognitive decline remain unclear, in no small part due to the lack of longitudinal studies. Extant longitudinal studies focused on gross neuroanatomy and diffusion properties of the brain. We present herein a longitudinal analysis of changes in arterial pulsatility - a proxy for arterial stiffness - in two major cerebral arteries, middle cerebral and vertebral. We found that pulsatility increased in some participants over a relatively short period and these increases were associated with hippocampal shrinkage. Higher baseline pulsatility was associated with lower scores on a test of fluid intelligence at follow-up. This is the first longitudinal evidence of an association between increase in cerebral arterial stiffness over time and regional shrinkage.

Lost Dynamics and the Dynamics of Loss: Longitudinal Compression of Brain Signal Variability is Coupled with Declines in Functional Integration and Cognitive Performance.

Reduced moment-to-moment blood oxygen level-dependent (BOLD) signal variability has been consistently linked to advanced age and poorer cognitive performance, showing potential as a functional marker of brain aging. To date, however, this promise has rested exclusively on cross-sectional comparisons. In a sample of 74 healthy adults, we provide the first longitudinal evidence linking individual differences in BOLD variability, age, and performance across multiple cognitive domains over an average period of 2.5 years. As expected, those expressing greater loss of BOLD variability also exhibited greater decline in cognition. The fronto-striato-thalamic system emerged as a core neural substrate for these change-change associations. Preservation of signal variability within regions of the fronto-striato-thalamic system also cohered with preservation of functional integration across regions of this system, suggesting that longitudinal maintenance of "local" dynamics may require across-region communication. We therefore propose this neural system as a primary target in future longitudinal studies on the neural substrates of cognitive aging. Given that longitudinal change-change associations between brain and cognition are notoriously difficult to detect, the presence of such an association within a relatively short follow-up period bolsters the promise of brain signal variability as a viable, experimentally sensitive probe for studying individual differences in human cognitive aging.

Metabolic risk affects fluid intelligence changes in healthy adults.

Metabolic syndrome affects persons of all ages and has been associated with cognitive decline. In a sample of 221 healthy adults (18.57 to 85.33 years), assessed up to 3 times (over up to 6.33 years), we applied a second-order bivariate dual-change-score model with strong factorial invariance to estimate the effects of previous levels of metabolic risk (MR) and fluid intelligence (Gf) on subsequent changes in both constructs. The results indicated that MR levels affect subsequent changes in Gf, whereas Gf does not affect changes in MR. This suggests that control of MR may be related to the change in a person's cognitive status, making early intervention, starting in young adulthood, a promising approach. To our knowledge, this is the first long-term study with such evidence. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

Regional brain shrinkage and change in cognitive performance over two years: The bidirectional influences of the brain and cognitive reserve factors.

We examined relationships between regional brain shrinkage and changes in cognitive performance, while taking into account the influence of chronological age, vascular risk, Apolipoprotein E variant and socioeconomic status. Regional brain volumes and cognitive performance were assessed in 167 healthy adults (age 19-79 at baseline), 90 of whom returned for the follow-up after two years. Brain volumes were measured in six regions of interest (ROIs): lateral prefrontal cortex (LPFC), prefrontal white matter (PFw), hippocampus (Hc), parahippocampal gyrus (PhG), cerebellar hemispheres (CbH), and primary visual cortex (VC), and cognitive performance was evaluated in three domains: episodic memory (EM), fluid intelligence (Gf), and vocabulary (V). Average volume loss was observed in Hc, PhG and CbH, but reliable individual differences were noted in all examined ROIs. Average positive change was observed in EM and V performance but not in Gf scores, yet only the last evidenced individual differences in change. We observed reciprocal influences among neuroanatomical and cognitive variables. Larger brain volumes at baseline predicted greater individual gains in Gf, but differences in LPFC volume change were in part explained by baseline level of cognitive performance. In one region (PFw), individual change in volume was coupled with change in Gf. Larger initial brain volumes did not predict slower shrinkage. The results underscore the complex role of brain maintenance and cognitive reserve in adult development.

Path Complexity in Virtual Water Maze Navigation: Differential Associations with Age, Sex, and Regional Brain Volume.

Studies of human navigation in virtual maze environments have consistently linked advanced age with greater distance traveled between the start and the goal and longer duration of the search. Observations of search path geometry suggest that routes taken by older adults may be unnecessarily complex and that excessive path complexity may be an indicator of cognitive difficulties experienced by older navigators. In a sample of healthy adults, we quantify search path complexity in a virtual Morris water maze with a novel method based on fractal dimensionality. In a two-level hierarchical linear model, we estimated improvement in navigation performance across trials by a decline in route length, shortening of search time, and reduction in fractal dimensionality of the path. While replicating commonly reported age and sex differences in time and distance indices, a reduction in fractal dimension of the path accounted for improvement across trials, independent of age or sex. The volumes of brain regions associated with the establishment of cognitive maps (parahippocampal gyrus and hippocampus) were related to path dimensionality, but not to the total distance and time. Thus, fractal dimensionality of a navigational path may present a useful complementary method of quantifying performance in navigation.

Volume of the hippocampal subfields in healthy adults: differential associations with age and a pro-inflammatory genetic variant.

The hippocampus is one of the most age-sensitive brain regions, yet the mechanisms of hippocampal shrinkage remain unclear. Recent studies suggest that hippocampal subfields are differentially vulnerable to aging and differentially sensitive to vascular risk. Promoters of inflammation are frequently proposed as major contributors to brain aging and vascular disease but their effects on hippocampal subfields are unknown. We examined the associations of hippocampal subfield volumes with age, a vascular risk factor (hypertension), and genetic polymorphisms associated with variation in pro-inflammatory cytokines levels (IL-1ß C-511T and IL-6 C-174G) and risk for Alzheimer's disease (APOEε4) in healthy adult volunteers (N = 80; age = 22-82 years). Volumes of three hippocampal subfields, cornu ammonis (CA) 1-2, CA3-dentate gyrus, and the subiculum were manually measured on high-resolution magnetic resonance images. Advanced age was differentially associated with smaller volume of CA1-2, whereas carriers of the T allele of IL-1ß C-511T polymorphism had smaller volume of all hippocampal subfields than CC homozygotes did. Neither of the other genetic variants, nor diagnosis of hypertension, was associated with any of the measured volumes. The results support the notion that volumes of age-sensitive brain regions may be affected by pro-inflammatory factors that may be targeted by therapeutic interventions.

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

Aging 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, 44-77 years 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-1ß (IL-1ß) 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-1ß-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.

Effects of age, genes, and pulse pressure on executive functions in healthy adults.

Executive functions (EF) evidence significant age-related declines, but the mechanisms underpinning those changes are unclear. In this study, we focus on two potential sources of variation: a physiological indicator of vascular health, and genetic variants related to vascular functions. In a sample of healthy adults (n=158, ages 18-81), we examine the effects of age, pulse pressure, and two polymorphisms (comt val158met and ace insertion/deletion) on working memory and cognitive flexibility. Results indicate that in addition to often-replicated age differences, the alleles of two polymorphisms that promote vasoconstriction (comt val and ace D) and reduced availability of dopamine in neocortical synapses (comt val), negatively impact virtually all aspects of EF tasks that involve working memory. In some cases, suppression of cognitive performance is limited to men or necessitates a combination of both risk-associated alleles. After accounting for genetic and age-related variation, pulse pressure had no additional effect on EF. These findings suggest that in healthy adults, the effects of genetic risk factors significantly modulate the course of cognitive aging.

Aging, vascular risk, and cognition: blood glucose, pulse pressure, and cognitive performance in healthy adults.

Advanced age is associated with decline in many areas of cognition as well as increased frequency of vascular disease. Well-described risk factors for vascular disease, such as diabetes and arterial hypertension, have been linked to cognitive deficits beyond those associated with aging. To examine whether vascular health indices such as fasting blood glucose levels and arterial pulse pressure can predict subtle deficits in age-sensitive abilities, the authors studied 104 healthy adults (ages 18 to 78) without diagnoses of diabetes or hypertension. Whereas results revealed a classic pattern of age-related differences in cognition, preprandial blood glucose level and pulse pressure independently and differentially affected cognitive performance. High-normal blood glucose levels were associated with decreased delayed associative memory, reduced accuracy of working memory processing among women, and slower working memory processing among men. Elevated pulse pressure was associated with slower perceptual-motor processing. Results suggest that blood glucose levels and pulse pressure may be sensitive indicators of cognitive status in healthy adults; however, longitudinal research is needed to determine whether such relatively mild elevations in this select group predict age-related cognitive declines.

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.