Age-related Cognitive Decline Research Articles

Cross-sectional and Longitudinal Age-related Disintegration in Functional Connectivity: Reference Ability Neural Network Cohort.

Some theories of aging have linked age-related cognitive decline to a reduction in distinctiveness of neural processing. Observed age-related correlation increases among disparate cognitive tasks have supported the dedifferentiation hypothesis. We previously showed cross-sectional evidence for age-related correlation decreases instead, supporting an alternative disintegration hypothesis. In the current study, we extended our previous research to a longitudinal sample. We tested 135 participants (20-80 years) at two time points-baseline and 5-year follow-up-on a battery of 12 in-scanner tests, each tapping one of four reference abilities. We performed between-tasks correlations within domain (convergent) and between domain (discriminant) at both the behavioral and neural level, calculating a single measure of construct validity (convergent - discriminant). Cross-sectionally, behavioral construct validity was significantly different from chance at each time point, but longitudinal change was not significant. Analysis by median age split revealed that older adults showed higher behavioral validity, driven by higher discriminant validity (lower between-tasks correlations). Participant-level neural validity decreased over time, with convergent validity consistently greater than discriminant validity; this finding was also observed at the cross-sectional level. In addition, a disproportionate decrease in neural validity with age remained significant after controlling for demographic factors. Factors predicting longitudinal changes in global cognition (mean performance across all 12 tasks) included age, change in neural validity, education, and National Adult Reading Test (premorbid intelligence). Change in neural validity partially mediated the effect of age on change in global cognition. Our findings support the theory of age-related disintegration, linking cognitive decline to changes in neural representations over time.

Noncoding RNA Terc-53 and hyaluronan receptor Hmmr regulate ageing in mice.

One of the basic questions in the ageing field is whether there is fundamental difference between the ageing of lower invertebrates and mammals. A major difference between the lower invertebrates and mammals is the abundancy of noncoding RNAs, most of which are not conserved. We have previously identified a noncoding RNA Terc-53 that is derived from the RNA component of telomerase Terc. To study its physiological functions, we generated two transgenic mouse models overexpressing the RNA in wild-type and early-ageing Terc-/- backgrounds. Terc-53 mice showed age-related cognition decline and shortened life span, even though no developmental defects or physiological abnormality at early age was observed, indicating its involvement in normal ageing of mammals. Subsequent mechanistic study identified hyaluronan-mediated motility receptor (Hmmr) as the main effector of Terc-53. Terc-53 mediates the degradation of Hmmr, leading to an increase of inflammation in the affected tissues, accelerating organismal ageing. AAV-delivered supplementation of Hmmr in the hippocampus reversed the cognition decline in Terc-53 transgenic mice. Neither Terc-53 nor Hmmr has homologs in C. elegans. Neither do arthropods express hyaluronan (Stern 2017). These findings demonstrate the complexity of ageing in mammals, and open new paths for exploring noncoding RNA and Hmmr as means of treating age-related physical debilities and improving healthspan.

Edge-Community Entropy Is a Novel Neural Correlate of Aging and Moderator of Fluid Cognition.

Decreased neuronal specificity of the brain in response to cognitive demands (i.e., neural dedifferentiation) has been implicated in age-related cognitive decline. Investigations into functional connectivity analogs of these processes have focused primarily on measuring segregation of nonoverlapping networks at rest. Here, we used an edge-centric network approach to derive entropy, a measure of specialization, from spatially overlapping communities during cognitive task fMRI. Using Human Connectome Project Lifespan data (713 participants, 36-100 years old, 55.7% female), we characterized a pattern of nodal despecialization differentially affecting the medial temporal lobe and limbic, visual, and subcortical systems. At the whole-brain level, global entropy moderated declines in fluid cognition across the lifespan and uniquely covaried with age when controlling for the network segregation metric modularity. Importantly, relationships between both metrics (entropy and modularity) and fluid cognition were age dependent, although entropy's relationship with cognition was specific to older adults. These results suggest entropy is a potentially important metric for examining how neurological processes in aging affect functional specialization at the nodal, network, and whole-brain level.

In sickness and in health-Type I interferon and the brain.

Type I interferons (IFN-I) represent a group of pleiotropic cytokines renowned for their antiviral activity and immune regulatory functions. A multitude of studies have unveiled a critical role of IFN-I in the brain, influencing various neurological processes and diseases. In this mini-review, I highlight recent findings on IFN-I's effects on brain aging, Alzheimer's disease (AD) progression, and central nervous system (CNS) homeostasis. The multifaceted influence of IFN-I on brain health and disease sheds light on the complex interplay between immune responses and neurological processes. Of particular interest is the cGAS-STING-IFN-I axis, which extensively participates in brain aging and various forms of neurodegeneration. Understanding the intricate role of IFN-I and its associated pathways in the CNS not only advances our comprehension of brain health and disease but also presents opportunities for developing interventions to modify the process of neurodegeneration and prevent age-related cognitive decline.

Does the liver facilitate aging-related cognitive impairment: Conversation between liver and brain during exercise?

Liver, an important regulator of metabolic homeostasis, is critical for healthy brain function. In particular, age-related neurodegenerative diseases seriously reduce the quality of life for the elderly. As population aging progresses rapidly, unraveling the mechanisms that effectively delay aging has become critical. Appropriate exercise is reported to improve aging-related cognitive impairment. Whereascurrent studies focused on exploring the effect of exercise on the aging brain itself, ignoring the persistent effects of peripheral organs on the brain through the blood circulation. The aim of this paper is to summarize the communication and aging processes of the liver and brain and to emphasize the metabolic mechanisms of the liver-brain axis about exercise ameliorating aging-related neurodegenerative diseases. A comprehensive understanding of the potential mechanisms about exercise ameliorating aging is critical for improving adaptation to age-related brain changes and formulating effective interventions against age-related cognitive decline.

Memory, mood and associated neuroanatomy in individuals with steroid sulphatase deficiency (X-linked ichthyosis).

Steroid sulphatase (STS) cleaves sulphate groups from steroid hormones, and steroid (sulphate) levels correlate with mood and age-related cognitive decline. In animals, STS inhibition or deletion of the associated gene, enhances memory/neuroprotection and alters hippocampal neurochemistry. Little is known about the consequences of constitutive STS deficiency on memory-related processes in humans. We investigated self-reported memory performance (Multifactorial Memory Questionnaire), word-picture recall and recent mood (Kessler Psychological Distress Scale, K10) in adult males with STS deficiency diagnosed with the dermatological condition X-linked ichthyosis (XLI; n = 41) and in adult female carriers of XLI-associated genetic variants (n = 79); we compared results to those obtained from matched control subjects [diagnosed with ichthyosis vulgaris (IV, n = 98) or recruited from the general population (n = 250)]. Using the UK Biobank, we compared mood/memory-related neuroanatomy in carriers of genetic deletions encompassing STS (n = 28) and non-carriers (n = 34,522). We found poorer word-picture recall and lower perceived memory abilities in males with XLI and female carriers compared with control groups. XLI-associated variant carriers and individuals with IV reported more adverse mood symptoms, reduced memory contentment and greater use of memory aids, compared with general population controls. Mood and memory findings appeared largely independent. Neuroanatomical analysis only indicated a nominally-significantly larger molecular layer in the right hippocampal body of deletion carriers relative to non-carriers. In humans, constitutive STS deficiency appears associated with mood-independent impairments in memory but not with large effects on underlying brain structure; the mediating psychobiological mechanisms might be explored further in individuals with XLI and in new mammalian models lacking STS developmentally.

Time-Restricted Feeding Mitigates Age-Related Cognitive Decline: Impacts on Neurovascular Coupling and Blood-Brain Barrier

Vascular cognitive impairment (VCI) and age-related cognitive decline are mediated by alterations in microvascular function, cerebral blood flow (CBF), neurovascular coupling (NVC) responses and blood-brain barrier (BBB) permeability. The pathogenesis of VCI can be influenced by lifestyle factors like exercise, nutrition, and dietary habits. Time-restricted feeding (TRF) offers an accessible intervention that can be employed during aging. This study is aimed at investigating the cerebromicrovascular effects of TRF on NVC responses and BBB integrity in aged mice to explore potential novel interventions against the age-related loss of cognitive function. We hypothesized that TRF would improve NVC responses and BBB integrity during aging to prevent age-related cognitive decline. To test this hypothesis, 18-month-old C57BL/6 mice were placed on TRF regimen for 6 months, where they received ad libitum feeding for 6 hours each day. 6- and 24-month-old mice fed 24 hours/day ad libitum were used as controls. All three groups were subjected to cognitive tests including radial-arms water maze (RAWM). NVC was assessed by measuring CBF using last speckle contrast imaging while performing contralateral whisker stimulation, and BBB integrity was measured through extravasation of tracers in various sizes using intravital two-photon imaging. We found that aged mice had significant impairment in NVC responses. 6 months of TRF improved BBB integrity and rescued NVC responses, and significantly improved learning and spatial memory. This study emphasizes the importance of maintaining cerebromicrovascular integrity to promote healthy brain aging and cognitive health. The establishment of the mechanisms by which TRF exerts benefits during aging provides pertinent information to the future development of therapeutic strategies to prevent VCI. Stephenson Cancer Center, National Institute of Aging R03 AG070479, American Heart Association. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Novel, engineered fusogenic liposome-based anti-oxidant delivery system improves the blood-brain barrier integrity in aging

Vascular dysfunction plays a pivotal role in age-related cognitive decline and neurodegeneration. The aging process often leads to a loss of integrity in the blood-brain barrier (BBB), initiating neuroinflammation and contributing to a decline in cognitive function. In previous research, we demonstrated the potential of resveratrol (RSV), a natural polyphenol, to target cerebromicrovascular endothelial cells (CMVECs), effectively countering age-related oxidative stress and improving vascular function, both in vitro and in vivo. However, the limited bioavailability of resveratrol raised questions about its effectiveness concerning the BBB and neuroinflammation. Our study aimed to address this challenge by introducing a novel drug delivery system designed to enhance the effciency of polyphenol delivery. This innovative approach involved the use of fusogenic liposomes (FL) integrated with a bioengineered protein corona (PC) featuring specific apolipoprotein E (ApoE). Our central hypothesis posited that PC formation could be harnessed to directly target CMVECs and enhance liposomal uptake, with the ultimate objective of effectively delivering RSV to the brain's microvessels in aging subjects (ApoE-FL-RSV). Our investigation encompassed the characterization of ApoE-FL uptake by CMVECs, along with an analysis of its biodistribution and pharmacokinetics in vivo. Remarkably, our findings revealed a significant increase in ApoE-FL-RSV accumulation within CMVECs in vivo, compared to control FL uptake. We employed advanced in vivo multiphoton imaging to longitudinally monitor the effects of ApoE-FL-RSV on the BBB, which demonstrated a significant rejuvenation of the endothelial barrier function in aged mice treated with ApoE-FL-RSV. In light of these results, we concluded that the fusogenic liposomal delivery system holds promise as a viable pharmacological intervention for addressing age-related vascular cognitive impairment. AHA834339, RF1AG072295, R01AG055395, R01AG068295; R01AG070915, K01AG073614, R01NS100782, R01CA255840, and Presbyterian Health Foundation. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Heme oxidation of NO-receptor soluble guanylyl cyclase is an important contributor to cerebrovascular and cognitive dysfunctions

Introduction: Decreased cerebral blood flow (CBF) is one of the major hemodynamic alterations leading to neurodegeneration and age-related cognitive decline. Nitric Oxide (NO)-dependent vasomotor reactivity is central in regulating cerebrovascular hemodynamics and adequate brain blood perfusion. NO receptor Soluble Guanylyl Cyclase (sGC) is the primary mediator of NO-dependent vasodilation. Oxidative stress, often persisting in diseased vasculature, renders sGC insensitive to NO and impairs the NO signaling. The objective of our study was to investigate the role of sGC oxidation in regulation CBF and brain function. Hypothesis: Oxidative stress disrupts NO/cGMP signaling in brain by decreasing sGC activity via oxidation of sGC heme. Approach: To assess causal effect of sGC oxidation on NO signaling function we administered ODQ, a sGC-specific heme oxidizing agent, to simulate long-term effect of sGC oxidation in cerebral vasculature. Two groups of young wild-type male and female mice (4 months old C57BL/6) were treated intraperitoneally (IP) twice a week for one month with ODQ (20 mg/kg) or a solvent as control. Changes in cerebrovascular reactivity and memory function were assessed and compared in treated and control groups. Using a non-invasive pulsed Doppler ultrasound-based system we assessed the changes in blood flow velocity (PVF, % of baseline) in the mouse middle cerebral artery (MCA) of male and female groups. MCA vasodilation was induced by bolus IP injection of NO-donor sodium nitroprusside (SNP) or BAY 58-2667, an allosteric NO-independent sGC activator. Memory function was assessed by the Novel Object Recognition Task (NORT, RI, recognition index) in all experimental groups. Western blotting and densitometry assessed the expression of major sGC subunits (α1, α2 and β1) in cleared brain lysates from ODQ-treated and control groups. Results: We observed a significantly blunted vasodilative response to SNP (1 mg/kg) in ODQ-treated mice vs controls of both genders (PVF, max response at 2 min post-injection, males 73.9 ± 10.4% (n=7/7) vs 58.5 ± 8.6 %, p=0.01; females (n=6/6) 77.4 ± 10.6 % vs 61.9 ± 5.4 %, p=0.01). Changes in response to NO-donor were more pronounced in males than females. The difference in BAY 58-2667 response between ODQ-treated and control groups was not statistically significant. ODQ significantly reduced the long-term memory in males but not female, according to NORT (RI, males (n=7/7) 0.58 ± 0.13 vs 0.69 ± 0.05; p=0.01; females (n=6/6) ODQ 0.59 ± 0.17 vs 0.73 ± 0.1, p=0.13). No statistically significant difference in expression of sGC subunits between control and ODQ-treated (n= 4/4) of male and female groups was determined. Conclusions: ODQ treatment significantly impairs vasodilation response to NO-donor but not to NO-independent sGC activator in mice MCA. ODQ treatment negatively affects long-term memory function in male, but not female mice. ODQ treatment does not significantly affect the expression of sGC subunits. Together our data suggest that the oxidation of sGC heme moiety impairs the regulation of cerebral blood flow of both genders and impairs long-term memory function gender-specifically in young mice. This research was supported by National Institute of Health grants RAG071999A (Iraida Sharina), HL139838, and American Heart Association 23TPA1070711 (Emil Martin). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

The role of neuroendothelial cells in aging-related vascular cognitive impairment

Vascular cognitive impairment (VCI) is a growing health problem in many developed countries due to aging of its population. Aging-induced impairment of neurovascular coupling (NVC) responses and brain microvascular rarefaction have been implicated as major driving mechanisms in age-related cognitive decline. One of the cellular hallmarks of NVC involve the release of vasodilator nitric oxide (NO) by endothelial cells in response to mediators released from activated neurons. Recent studies from our group identified and characterized a novel, minority subtype of scattered ECs with endothelial and neuronal characteristics, hence the name neuroendothelial cell (NECs). NECs present a well-defined arteriovenous zonal localization exclusively in small resistance arterioles with the highest density in the brain followed by the kidney. Intravital multiphoton microscopy (MPM) of intact brain arterioles in vivo suggest that NECs play an important role in regulating blood flow to the brain and able to detect changes in systemic blood pressure, hypoxia and perhaps other metabolic changes in the local microenvironment. Our central hypothesis is that NECs are novel key players in blood flow autoregulation, vascular control of organ functions in both short-term (hemodynamics) and long-term (angiogenesis, tissue regeneration). We further hypothesize that the decrease in NEC density and function in aged subjects is a major player in the development of age-related cerebral microvascular pathologies and that augmenting NEC number and function in aged animals will provide therapeutic benefit. This study used a NEC specific comprehensive research toolbox including NEC-GFP transgenic mouse models and high-resolution single-cell based transcriptome analysis to establish the NEC specific molecular atlas in young adult (3 month of age) and aged (2 years of age) animals. Furthermore, transgenic animal models combined with serial intravital imaging of the same tissue volume over consecutive days was used to study changes in vascular endothelial cell composition in response to NEC stimuli in young adult and aged mice. Cell fate tracking studies of the Nos1-lineage combined with Nos1 immunostaining revealed that NECs represent a permanent cell type with terminal neuronal differentiation. Importantly, NEC density is reduced with aging in all organs including the brain. High resolution single-cell based transcriptome analysis of 100K endothelial cells isolated from mouse brain demonstrated that, in contrast to other ECs, NECs highly express several traditional (e.g., Nos1, Angpt1, Egfl8) and novel (e.g., Cytl1, MGP, Gkn3) tissue trophic factors that are known to play important roles in acute hemodynamic responses including NO mediated functional hyperemia, and in chronic settings in angiogenesis, aging, vascular (dys)function, and chronic vascular diseases. Furthermore, the expression of many of these factors were significantly reduced in NECs isolated from aged animals. In conclusion, the newly discovered NEC-specific molecular and signaling mechanisms may play a role in the age-related decrease in NVC capacity and microvascular rarefaction and may be targeted for therapeutic benefits in age related VCI. American Society of Nephrology Carl W. Gottschalk Research Scholar Grant. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Reversal of Soleus Muscle Atrophy in Older Adults: A Non-Volitional Exercise Intervention for a Changing Climate.

The World Health Organization recommends that older adults undertake at least 150 minutes of moderate intensity physical activity over the course of each week in order to maintain physical, mental, and social health. This goal turns out to be very difficult for most community dwelling older adults to achieve, due to both actual and perceived barriers. These barriers include personal health limitations, confinement issues, and self-imposed restrictions such as fear of injury. Climate change exacerbates the confinement issues and injury fears among the elderly. To assist older adults in obtaining the benefits of increased physical activity under increasingly challenging climate conditions, we propose a targeted non-volitional intervention which could serve as a complement to volitional physical activity. Exogenous neuro-muscular stimulation of the soleus muscles is a non-invasive intervention capable of significantly increasing cardiac output in sedentary individuals. Long-term daily use has been shown to improve sleep, reduce bone loss, and reverse age-related cognitive decline, all of which are significant health concerns for older adults. These outcomes support the potential benefit of exogenous neuro-muscular stimulation as a complementary form of physical activity which older adults may find convenient to incorporate into their daily life when traditional forms of exercise are difficult to achieve due to barriers to completing traditional physical activities as a result of in-home or in-bed confinement, perceptual risks, or real environmental risks such as those arising from climate change.

Time-Restricted Feeding Induces Beiging and Rejuvenates Adipose Tissue with Beneficial Effects on Cerebral Function in Old Mice

Adipose tissue, traditionally viewed as purely an energy reserve, has recently been unveiled as a critical endocrine organ. Through the secretion of bioactive molecules known as adipokines, adipose tissue plays a role in inter-organ communication, most notably with the brain to maintain metabolic homeostasis and cognitive function. Aberrant adipokine secretion or signaling, often exacerbated with aging, has emerged as a defining characteristic of dysfunctional adipose tissue. This dysregulation can lead to inflammatory conditions, potentially disrupting neural homeostasis and heightening the vulnerability of older individuals to cognitive impairments. This study investigated the capacity of time-restricted feeding (TRF) to promote beiging (induction of brown adipocytes positive for uncoupling protein 1(UCP1) within white adipose tissue depots) in aged mice, exploring its potential role in modulating adipokine profiles, attenuating inflammation, and mitigating age-associated cognitive decline. To test this hypothesis, we collected adipose tissue samples from 24-month-old mice that underwent 6 months of TRF and compared their profiles to both young and age-matched controls on an unrestricted (ad-lib) diet. Immunohistochemical analyses of brown adipose tissue (BAT), subcutaneous adipose tissue (SAT), and visceral adipose tissue (VAT) revealed a marked reduction in pro-inflammatory markers CD80 and F4/80hi across all adipose tissues. Notably, a shift towards an anti-inflammatory state was indicated by a pronounced increase in CD163 staining in the SAT and VAT. Additionally, the increased expression of UCP1, especially in BAT and SAT, pointed towards an enhanced thermogenic capacity, suggesting a potential metabolic advantage. This was further reinforced by an increase in electron transport chain (ETC) activity in all adipose tissues. These findings have powerful implications given the established links between systemic inflammation, disrupted adipokine signaling, and neurodegenerative conditions. The alleviated adipose inflammatory profiles measured in TRF mice not only underscore its potential metabolic benefits but also highlight its possible role in safeguarding cognitive health, especially in an aging demographic. Currently serum studies and RNA sequencing are being conducted to look at altered transcript production and to investigate the role of adipokines on the brain health of the aged TRF mice. Such insights pave the way for future research exploring dietary strategies to combat age-related cognitive decline. Stephenson Cancer Center, National Institute on Aging R03 AG070479, American Heart Association. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Small-molecule-induced epigenetic rejuvenation promotes SREBP condensation and overcomes barriers to CNS myelin regeneration

Remyelination failure in diseases like multiple sclerosis (MS) was thought to involve suppressed maturation of oligodendrocyte precursors; however, oligodendrocytes are present in MS lesions yet lack myelin production. We found that oligodendrocytes in the lesions are epigenetically silenced. Developing a transgenic reporter labeling differentiated oligodendrocytes for phenotypic screening, we identified a small-molecule epigenetic-silencing-inhibitor (ESI1) that enhances myelin production and ensheathment. ESI1 promotes remyelination in animal models of demyelination and enables de novo myelinogenesis on regenerated CNS axons. ESI1 treatment lengthened myelin sheaths in human iPSC-derived organoids and augmented (re)myelination in aged mice while reversing age-related cognitive decline. Multi-omics revealed that ESI1 induces an active chromatin landscape that activates myelinogenic pathways and reprograms metabolism. Notably, ESI1 triggered nuclear condensate formation of master lipid-metabolic regulators SREBP1/2, concentrating transcriptional co-activators to drive lipid/cholesterol biosynthesis. Our study highlights the potential of targeting epigenetic silencing to enable CNS myelin regeneration in demyelinating diseases and aging.

Choir singing is associated with enhanced structural connectivity across the adult lifespan.

The global ageing of populations calls for effective, ecologically valid methods to support brain health across adult life. Previous evidence suggests that music can promote white matter (WM) microstructure and grey matter (GM) volume while supporting auditory and cognitive functioning and emotional well-being as well as counteracting age-related cognitive decline. Adding a social component to music training, choir singing is a popular leisure activity among older adults, but a systematic account of its potential to support healthy brain structure, especially with regard to ageing, is currently missing. The present study used quantitative anisotropy (QA)-based diffusion MRI connectometry and voxel-based morphometry to explore the relationship of lifetime choir singing experience and brain structure at the whole-brain level. Cross-sectional multiple regression analyses were carried out in a large, balanced sample (N = 95; age range 21-88) of healthy adults with varying levels of choir singing experience across the whole age range and within subgroups defined by age (young, middle-aged, and older adults). Independent of age, choir singing experience was associated with extensive increases in WM QA in commissural, association, and projection tracts across the brain. Corroborating previous work, these overlapped with language and limbic networks. Enhanced corpus callosum microstructure was associated with choir singing experience across all subgroups. In addition, choir singing experience was selectively associated with enhanced QA in the fornix in older participants. No associations between GM volume and choir singing were found. The present study offers the first systematic account of amateur-level choir singing on brain structure. While no evidence for counteracting GM atrophy was found, the present evidence of enhanced structural connectivity coheres well with age-typical structural changes. Corroborating previous behavioural studies, the present results suggest that regular choir singing holds great promise for supporting brain health across the adult life span.

The Effects of Computerized Cognitive Training in Older Adults' Cognitive Performance and Biomarkers of Structural Brain Aging.

Cognitive training (CT) has been investigated as a means of delaying age-related cognitive decline in older adults. However, its impact on biomarkers of age-related structural brain atrophy has rarely been investigated, leading to a gap in our understanding of the linkage between improvements in cognition and brain plasticity. This study aimed to explore the impact of CT on cognitive performance and brain structure in older adults. One hundred twenty-four cognitively normal older adults recruited from 2 study sites were randomly assigned to either an adaptive CT (n = 60) or a casual game training (active control, AC, n = 64). After 10 weeks of training, CT participants showed greater improvements in the overall cognitive composite score (Cohen's d = 0.66, p < .01) with nonsignificant benefits after 6 months from the completion of training (Cohen's d = 0.36, p = .094). The CT group showed significant maintenance of the caudate volume as well as significant maintained fractional anisotropy in the left internal capsule and in left superior longitudinal fasciculus compared to the AC group. The AC group displayed an age-related decrease in these metrics of brain structure. Results from this multisite clinical trial demonstrate that the CT intervention improves cognitive performance and helps maintain caudate volume and integrity of white matter regions that are associated with cognitive control, adding to our understanding of the changes in brain structure contributing to changes in cognitive performance from adaptive CT. NCT03197454.

Superagers Resist Typical Age-Related White Matter Structural Changes.

Superagers are elderly individuals with the memory ability of people 30 years younger and provide evidence that age-related cognitive decline is not inevitable. In a sample of 64 superagers (mean age, 81.9; 59% women) and 55 typical older adults (mean age, 82.4; 64% women) from the Vallecas Project, we studied, cross-sectionally and longitudinally over 5 years with yearly follow-ups, the global cerebral white matter status as well as region-specific white matter microstructure assessment derived from diffusivity measures. Superagers and typical older adults showed no difference in global white matter health (total white matter volume, Fazekas score, and lesions volume) cross-sectionally or longitudinally. However, analyses of diffusion parameters revealed the better white matter microstructure in superagers than in typical older adults. Cross-sectional differences showed higher fractional anisotropy (FA) in superagers mostly in frontal fibers and lower mean diffusivity (MD) in most white matter tracts, expressed as an anteroposterior gradient with greater group differences in anterior tracts. FA decrease over time is slower in superagers than in typical older adults in all white matter tracts assessed, which is mirrored by MD increases over time being slower in superagers than in typical older adults in all white matter tracts except for the corticospinal tract, the uncinate fasciculus, and the forceps minor. The better preservation of white matter microstructure in superagers relative to typical older adults supports resistance to age-related brain structural changes as a mechanism underpinning the remarkable memory capacity of superagers, while their regional aging pattern is in line with the last-in-first-out hypothesis.

Normal or improved cardiovascular risk factors in IGF-I-deficient adults with growth hormone receptor deficiency

Human subjects with generalized growth hormone (GH) insensitivity due to GH receptor deficiency (GHRD)/Laron syndrome display a very low incidence of insulin resistance, diabetes, and cancer, as well as delayed age-related cognitive decline. However, the risk of cardiovascular disease (CVD) in these subjects is poorly understood. Here, we have assessed cardiovascular function, damage, and risk factors in GHRD subjects and their relatives. We measured markers of CVD in two phases: one in a cohort of 30 individuals (GHRD= 16, control relatives= 14) brought to USC (in Los Angeles, CA) and one in a cohort including additional individuals examined in Ecuador (where the subjects live) for a total of 44 individuals (GHRD= 21, control relatives= 23). Data were collected on GHRD and control groups living in similar geographical locations and sharing comparable environmental and socio-economic circumstances. Compared to controls, GHRD subjects displayed lower serum glucose, insulin, blood pressure, smaller cardiac dimensions, similar pulse wave velocity, lower carotid artery intima-media thickness, lower creatinine, and a non-significant but major reduction in the portion of subjects with carotid atherosclerotic plaques (7% GHRDs vs. 36%, Controls p= 0.1333) despite elevated low-density lipoprotein cholesterol levels. The current study indicates that individuals with GHRD have normal or improved levels of cardiovascular disease risk factors as compared to their relatives. This study was funded in part by NIH/NIA grant P01 AG034906 to V.D.L.

Effects of age and flight experience on prefrontal cortex activity in airline pilots: An fNIRS study

It is essential for airlines to have a deep understanding of the cognitive impact of aging among pilots. The current literature on executive function indicates that compensatory mechanisms in the brain may counteract age-related cognitive decline, at least up to certain task load levels. However, few studies have been administered to evaluate changes in aircrew competence as they age. The present study focuses on dorsolateral prefrontal cortex (DLPFC) activity as it is implicated in cognitive performance and working memory, which are associated with skill proficiency. We measured the DLPFC activity for airline pilots, including trainees, during maneuvering using a flight simulator. Our preliminary results indicated that only expert (aged) pilots demonstrated higher activity of the left DLPFC than the right one. However, for youth trainees, not only was the error rate high while using the flight simulator, but the activity of the DLFPC was also lower than that of the expert pilots, and there was no statistically significant difference between the left and right DLPFC. Although these findings partially differ from those reported in previous studies on age-related changes, it is evident that training as an airline pilot for over 20 years may affect such results. We believe that this noninvasive approach to objective quantification of skill will facilitate the development of effective assessment competence in aging.

Duration, numerosity and length processing in healthy ageing and Parkinson’s disease

People constantly process temporal, numerical, and length information in everyday activities and interactions with the environment. However, it is unclear whether quantity perception changes during ageing. Previous studies have provided heterogeneous results, sometimes showing an age-related effect on a particular quantity, and other times reporting no differences between young and elderly samples. However, three dimensions were never compared within the same study. Here, we conducted two experiments with the aim of investigating the processing of duration, numerosity and length in both healthy and pathological ageing. The experimental paradigm consisted of three bisection tasks in which participants were asked to judge whether the presented stimulus (i.e. a time interval, a group of dots, or a line) was more similar to the short/few or long/many standards. The first study recruited healthy young and elderly participants, while the second recruited healthy elderly participants and patients with Parkinson’s disease, a clinical condition commonly associated with temporal impairments. The results of both experiments showed that discrimination precision differed between domains in all groups, with higher precision in the numerosity task and lower sensitivity in judging duration. Furthermore, while discrimination abilities were affected in healthy elderly and, even more so, in Parkinson’s disease group, no domain-specific impairments emerged. According to our research, reduced discrimination precision might be explained by an alteration of a single system for all quantities or by an age-related general cognitive decline.

Evidence for age-related decline in spatial memory in a novel allocentric memory task

ABSTRACT Several studies report spatial memory decline in old age. However, few studies have examined whether old adults are specifically impaired in allocentric memory tasks (testing for object-to-object spatial location memory). Thus, the present study examined the effects of age on allocentric spatial memory using a novel landmark memory task. Young (18–25 years old) and old (65 years and older) participants watched 10 short videos that displayed 180-degree viewpoints of distinct real-world locations with landmark cues. After watching each video, participants saw a snapshot from the video and were asked whether a landmark cue previously viewed in the video was to the left or right of the snapshot view. Young adults outperformed old adults on the task. This age-related decline in spatial performance was similar for men and women. These findings support that spatial ability in an allocentric task is sensitive to age-related cognitive decline in men and women.