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Funder: Carl von Ossietzky Universität Oldenburg (3092), Age-related hearing loss typically affects the hearing of high frequencies in older adults. Such hearing loss influences the processing of spoken language, including higher-level processing such as that of complex sentences. Hearing aids may alleviate some of the speech processing disadvantages associated with hearing loss. However, little is known about the relation between hearing loss, hearing aid use, and their effects on higher-level language processes. This neuroimaging (fMRI) study examined these factors by measuring the comprehension and neural processing of simple and complex spoken sentences in hard-of-hearing older adults (n = 39). Neither hearing loss severity nor hearing aid experience influenced sentence comprehension at the behavioral level. In contrast, hearing loss severity was associated with increased activity in left superior frontal areas and the left anterior insula, but only when processing specific complex sentences (i.e. object-before-subject) compared to simple sentences. Longer hearing aid experience in a sub-set of participants (n = 19) was associated with recruitment of several areas outside of the core speech processing network in the right hemisphere, including the cerebellum, the precentral gyrus, and the cingulate cortex, but only when processing complex sentences. Overall, these results indicate that brain activation for language processing is affected by hearing loss as well as subsequent hearing aid use. Crucially, they show that these effects become apparent through investigation of complex but not simple sentences.

Age-related cognitive decline has been linked to alterations of the dopaminergic system and its subcortical trajectories. Recent work suggests a critical role of iron accumulation within the basal ganglia (BG) in verbal memory performance, and increased iron levels have been related to demyelination. However, the specificity of age-related iron increases with respect to cognitive functions remains unclear. Therefore, we investigated the interplay of age, cognitive performance, and structural integrity of the BG. In total, 79 healthy older participants underwent a broad cognitive assessment (fluid and crystallized intelligence, verbal and numeric memory, processing speed, executive functions) and structural MRI. As expected, performance in most cognitive tests had a negative relationship with age. Moreover, BG grey matter volume and magnetization transfer (MT, indicative of myelin) decreased, and R2* (indicative of iron) increased with age. Importantly, R2* and demyelination negatively correlated with verbal memory and executive functions. Within the SN/VTA, age correlated negatively with MT, but there was no clear evidence in favor of a relationship between behavior and R2* or MT. Our results suggest that age-related increases in iron and demyelination within the BG, which are part of a fronto-striatal network, not only impact on verbal memory but also executive functions.

It is difficult to draw conclusions about the effect of resistance exercises on information processing speed and inhibitory control from previous studies due to possible underestimations of maximal strength and the lack of information on the intervention programs. To address this issue, a familiarization of resistance exercise was introduced before the strength test, and the repetition-to-fatigue method was used to calculate the 1RM (one repetition max). A two-arm RCT was conducted to evaluate the cognitive effect of resistance exercise. Male adults aged 50–65 years old performed a single bout of multiple joint, structural barbell resistance exercises (back squat, press, and deadlift) with 75% 1RM * 5 repetitions * 3 sets with 2–3 min rest between sets and exercises or a stretching exercise session (active-control intervention). This type of resistance exercise improved the information processing speed measured by Stroop task reaction time (t(23) = − 2.313, p = .030, M = − 16 ms, 95% CI [− 30, − 2]) and decreased the conflict-related neural activity measured by event-related potential N2b in both congruent (t(20) = 2.674, p = .015, M = 2.290 μv, 95% CI [0.504, 4.075]) and incongruent (t(20) = 2.851, p = .018, M = 2.291 μv, 95% CI [0.439, 4.142]) conditions. Resistance exercise significantly improved information processing speed and decrease conflict-related neural activity, but did not change inhibitory control in older adults compared to active control.Trial registration: NCT04534374 (01/09/2020).

Episodic memory decline is an early marker of cognitive aging in human. Although controversial in animals and called “episodic-like memory”, several models have been successfully developed, however they rarely focused on ageing. While marmoset is an emerging primate model in aging science, episodic-like memory has never been tested in this species and importantly in aged marmosets. Here, we examined if the recall of the what-when and what-where building blocks of episodic-like memory declines in ageing marmosets. We developed a naturalistic approach using spontaneous exploration of real objects by young and old marmosets in the home cage. We implemented a three-trial task with 1 week inter-trial interval. Two different sets of identical objects were presented in sample trials 1 and 2, respectively. For the test trial, two objects from each set were presented in a former position and two in a new one. We quantified the exploratory behaviour and calculated discrimination indices in a cohort of 20 marmosets. Young animals presented a preserved memory for combined what-where, and what-when components of the experiment, which declined with aging. These findings lead one to expect episodic-like memory deficits in aged marmosets.

Dance is a complex sensorimotor activity with positive effects on physical fitness, cognition, and brain plasticity in the aging population. We explored whether individual levels of cognitive reserve (CR) proxied by education moderate dance intervention (DI)-induced plasticity assessed by resting-state functional connectivity (rs-FC) changes of the sensorimotor network (SMN), and between the dorsal attention network (DAN) and anterior default mode network (aDMN). Our cohort consisted of 99 subjects, randomly assigned to either a DI group who underwent a 6-month intervention (n = 49, Mage = 69.02 ± 5.40) or a control group (n = 50, Mage = 69.37 ± 6.10). Moderation analyses revealed that CR moderated DI-induced increases of the SMN rs-FC with significant changes observed in participants with ≥ 13 years of education (b = .05, t(64) = 3.20, p

Altres ajuts: Fondo Europeo de Desarrollo Regional (FEDER) Altres ajuts: Generalitat de Catalunya. Programa CERCA Altres ajuts: Instituto de Salud Carlos III (CIBERSAM i CIBERNED) Altres ajuts: Fundació "La Caixa" Altres ajuts: Grífols SA (GR@ACE project) Neuropsychiatric symptoms (NPS) have been recently addressed as risk factors of conversion to Alzheimer's disease (AD) and other dementia types in patients diagnosed with Mild Cognitive Impairment (MCI). Our aim was to determine profiles based on the prominent NPS in MCI patients and to explore the predictive value of these profiles on conversion to specific types of dementia. A total of 2137 MCI patients monitored in a memory clinic were included in the study. Four NPS profiles emerged (classes), which were defined by preeminent symptoms: Irritability, Apathy, Anxiety/Depression and Asymptomatic. Irritability and Apathy were predictors of conversion to dementia (HR = 1.43 and 1.56, respectively). Anxiety/depression class showed no risk effect of conversion when compared to Asymptomatic class. Irritability class appeared as the most discriminant neuropsychiatric condition to identify non-AD converters (i.e., frontotemporal dementia, vascular dementia, Parkinson's disease and dementia with Lewy Bodies). The findings revealed that consistent subgroups of MCI patients could be identified among comorbid basal NPS. The preeminent NPS showed to behave differentially on conversion to dementia, beyond AD. Therefore, NPS should be used as early diagnosis facilitators, and should also guide clinicians to detect patients with different illness trajectories in the progression of MCI.

We developed machine learning (ML) algorithms to predict abnormal tau accumulation among patients with prodromal AD. We recruited 64 patients with prodromal AD using the Alzheimer’s Disease Neuroimaging Initiative (ADNI) dataset. Supervised ML approaches based on the random forest (RF) and a gradient boosting machine (GBM) were used. The GBM resulted in an AUC of 0.61 (95% confidence interval [CI] 0.579–0.647) with clinical data (age, sex, years of education) and a higher AUC of 0.817 (95% CI 0.804–0.830) with clinical and neuropsychological data. The highest AUC was 0.86 (95% CI 0.839–0.885) achieved with additional information such as cortical thickness in clinical data and neuropsychological results. Through the analysis of the impact order of the variables in each ML classifier, cortical thickness of the parietal lobe and occipital lobe and neuropsychological tests of memory domain were found to be more important features for each classifier. Our ML algorithms predicting tau burden may provide important information for the recruitment of participants in potential clinical trials of tau targeting therapies.

Causal inference with observational longitudinal data and time-varying exposures is often complicated by time-dependent confounding and attrition. The G-computation formula is one approach for estimating a causal effect in this setting. The parametric modelling approach typically used in practice relies on strong modelling assumptions for valid inference and moreover depends on an assumption of missing at random, which is not appropriate when the missingness is missing not at random (MNAR) or due to death. In this work we develop a flexible Bayesian semi-parametric G-computation approach for assessing the causal effect on the subpopulation that would survive irrespective of exposure, in a setting with MNAR dropout. The approach is to specify models for the observed data using Bayesian additive regression trees, and then, use assumptions with embedded sensitivity parameters to identify and estimate the causal effect. The proposed approach is motivated by a longitudinal cohort study on cognition, health and ageing and we apply our approach to study the effect of becoming a widow on memory. We also compare our approach to several standard methods.

Human brain aging is a true spectrum across the population, ranging from minimal changes on the microscopic level to full-blown neurodegenerative disease with accumulation of pathology, neuronal loss, dysfunctional large-scale brain networks, and progressive functional decline. Although much is known about the individual mechanisms involved in brain aging, a convincing framework that ties these highly related processes together is lacking. Herein, using mathematical modeling, I sought to understand decline with brain aging by capturing the essential macro-level processes that shape how a brain changes over the lifetime. I develop ABC (Aging Brain Capital), a simple linear simultaneous-equation model that unites aspects of neuroscience, economics, and thermodynamics to explain the evolution of brain pathology and human brain capital, the infrastructure and processes that underlie brain function, over the lifespan. The results of this model suggest that aging-associated decline in brain function is inevitable, driven by the finite nature of the brain’s pathology-clearance capacity. Furthermore, age-related neurodegenerative diseases can be understood as part of this aging process, explaining the spectrum of pathology and neurodegeneration across the population. I demonstrate that several essential aspects of the pathogenesis of Alzheimer disease (AD) can be likewise explained in this framework incorporating amyloid-tau interaction, the emerging concept that amyloid pathology accelerates tau pathology. The conception of Alzheimer pathogenesis that I present not only explains and unifies the basis for familial AD, primary-age-related tauopathy (PART), and late-onset AD (LOAD), but also reconciles amyloid-centered, tau-centered, and synergistic models of AD. Finally, I describe the possible implications of these results for future therapeutic development across neurodegenerative disease.

International audience; Combining multisensory sources is crucial to interact with our environment, especially for older people who are facing sensory declines. Here, we examined the influence of textured sounds on haptic exploration of artificial textures in healthy younger and older adults by combining a tactile device (ultrasonic display) with synthetized textured sounds. Participants had to discriminate simulated textures with their right index while they were distracted by three disturbing, more or less textured sounds. These sounds were presented as a real-time auditory feedback based on finger movement sonification and thus gave the sensation that the sounds were produced by the haptic exploration. Finger movement velocity increased across both groups in presence of textured sounds (Rubbing or Squeaking) compared to a non-textured (Neutral) sound. While young adults had the same discrimination threshold, regardless of the sound added, the older adults were more disturbed by the presence of the textured sounds with respect to the Neutral sound. Overall, these findings suggest that irrelevant auditory information was taken into account by all participants, but was appropriately segregated from tactile information by young adults. Older adults failed to segregate auditory information, supporting the hypothesis of general facilitation of multisensory integration with aging.

Healthy ageing leads to changes in the brain that impact upon sensory and cognitive processing. It is not fully clear how these changes affect the processing of everyday spoken language. Prediction is thought to play an important role in language comprehension, where information about upcoming words is pre-activated across multiple representational levels. However, evidence from electrophysiology suggests differences in how older and younger adults use context-based predictions, particularly at the level of semantic representation. We investigate these differences during natural speech comprehension by presenting older and younger subjects with continuous, narrative speech while recording their electroencephalogram. We use time-lagged linear regression to test how distinct computational measures of (1) semantic dissimilarity and (2) lexical surprisal are processed in the brains of both groups. Our results reveal dissociable neural correlates of these two measures that suggest differences in how younger and older adults successfully comprehend speech. Specifically, our results suggest that, while younger and older subjects both employ context-based lexical predictions, older subjects are significantly less likely to pre-activate the semantic features relating to upcoming words. Furthermore, across our group of older adults, we show that the weaker the neural signature of this semantic pre-activation mechanism, the lower a subject’s semantic verbal fluency score. We interpret these findings as prediction playing a generally reduced role at a semantic level in the brains of older listeners during speech comprehension and that these changes may be part of an overall strategy to successfully comprehend speech with reduced cognitive resources.

Active Caspase-6 (Casp6) and Tau cleaved by Casp6 at amino acids 402 (Tau∆D402) and 421 (Tau∆D421) are present in early Alzheimer disease intraneuronal neurofibrillary tangles, which are made primarily of filamentous Tau aggregates. To assess whether Casp6 cleavage of Tau contributes to Tau pathology and Casp6-mediated age-dependent cognitive impairment, we generated transgenic knock-in mouse models that conditionally express full-length human Tau (hTau) 0N4R only (CTO) or together with human Casp6 (hCasp6) (CTC). Region-specific hippocampal and cortical hCasp6 and hTau expression were confirmed with western blot and immunohistochemistry in 2–25-month-old brains. Casp6 activity was confirmed with Tau∆D421 and Tubulin cleaved by Casp6 immunopositivity in 3–25-month-old CTC, but not in CTO, brains. Immunoprecipitated Tau∆D402 was detected in both CTC and CTO brains, but was more abundant in CTC brains. Intraneuronal hippocampal Tau hyperphosphorylation at S202/T205, S422, and T231, and Tau conformational change were absent in both CTC and CTO brains. A slight accumulation of Tau phosphorylated at S396/404 and S202 was observed in Cornu Ammonis 1 (CA1) hippocampal neuron soma of CTC compared to CTO brains. Eighteen-month-old CTC brains showed rare argentophilic deposits that increased by 25 months, whereas CTO brains only displayed them sparsely at 25 months. Tau microtubule binding was equivalent in CTC and CTO hippocampi. Episodic and spatial memory measured with novel object recognition and Barnes maze, respectively, remained normal in 3–25-month-old CTC and CTO mice, in contrast to previously observed impairments in ACL mice expressing equivalent levels of hCasp6 only. Consistently, the CTC and CTO hippocampal CA1 region displayed equivalent dendritic spine density and no glial inflammation. Together, these results reveal that active hCasp6 co-expression with hTau generates Tau cleavage and rare age-dependent argentophilic deposits but fails to induce cognitive deficits, neuroinflammation, and Tau pathology.

Dementia is related to the cellular accumulation of β-amyloid plaques, tau aggregates, or α-synuclein aggregates, or to neurotransmitter deficiencies in the dopaminergic and cholinergic pathways. Cellular and neurochemical changes are both involved in dementia pathology. However, the role of dopaminergic and cholinergic networks in metabolic connectivity at different stages of dementia remains unclear. The altered network organisation of the human brain characteristic of many neuropsychiatric and neurodegenerative disorders can be detected using persistent homology network (PHN) analysis and algebraic topology. We used 18F-fluorodeoxyglucose positron emission tomography (18F-FDG PET) imaging data to construct dopaminergic and cholinergic metabolism networks, and used PHN analysis to track the evolution of these networks in patients with different stages of dementia. The sums of the network distances revealed significant differences between the network connectivity evident in the Alzheimer’s disease and mild cognitive impairment cohorts. A larger distance between brain regions can indicate poorer efficiency in the integration of information. PHN analysis revealed the structural properties of and changes in the dopaminergic and cholinergic metabolism networks in patients with different stages of dementia at a range of thresholds. This method was thus able to identify dysregulation of dopaminergic and cholinergic networks in the pathology of dementia.

Previous studies have shown an association between cognitive decline and white matter integrity in aging. This led to the formulation of a “disconnection hypothesis” in the aging-brain, which states that the disruption in cortical network communication may explain the cognitive decline during aging. Although some longitudinal studies have already investigated the changes occurring in white matter microstructure, most focused on specific white matter tracts. Our study aims to characterize the longitudinal whole-brain signatures of white matter microstructural change during aging. Furthermore, we assessed the relationship between distinct longitudinal alterations in white matter integrity and cognition. White matter microstructural properties were estimated from diffusion magnetic resonance imaging, and cognitive status characterized from extensive neurocognitive testing. The same individuals were evaluated at two timepoints, with a mean interval time of 52.8 months (SD = 7.24) between first and last assessment. Our results show that age is associated with a decline in cognitive performance and a degradation in white matter integrity. Additionally, significant associations were found between diffusion measures and different cognitive dimensions (memory, executive function and general cognition). Overall, these results suggest that age-related cognitive decline is related to white matter alterations, and thus give support to the “disconnected hypothesis” of the aging brain.

Strong gradient systems can improve the signal-to-noise ratio of diffusion MRI measurements and enable a wider range of acquisition parameters that are beneficial for microstructural imaging. We present a comprehensive diffusion MRI dataset of 26 healthy participants acquired on the MGH-USC 3 T Connectome scanner equipped with 300 mT/m maximum gradient strength and a custom-built 64-channel head coil. For each participant, the one-hour long acquisition systematically sampled the accessible diffusion measurement space, including two diffusion times (19 and 49 ms), eight gradient strengths linearly spaced between 30 mT/m and 290 mT/m for each diffusion time, and 32 or 64 uniformly distributed directions. The diffusion MRI data were preprocessed to correct for gradient nonlinearity, eddy currents, and susceptibility induced distortions. In addition, scan/rescan data from a subset of seven individuals were also acquired and provided. The MGH Connectome Diffusion Microstructure Dataset (CDMD) may serve as a test bed for the development of new data analysis methods, such as fiber orientation estimation, tractography and microstructural modelling., Measurement(s)brain measurementTechnology Type(s)diffusion magnetic resonance imagingFactor Type(s)diffusion time • gradient strength • directionSample Characteristic - OrganismHomo sapiens Machine-accessible metadata file describing the reported data: 10.6084/m9.figshare.16910290

Memory loss is primarily caused by the accumulation of both brain plaques [(consisting of beta-amyloid protein (Aβ) 1–42)] and neurofibrillary tangles (consisting of paired helical and straight filaments containing tau protein). Neuroinflammation is the third key and important factor that leads to accelerated memory loss and eventual dementia. Brain plaques, tangles and inflammation is the trilogy mainly responsible for causing memory loss that has now been documented for over 20 years in the scientific literature. The present investigation used in vitro quantitative methods to directly compare the ability of major memory-support dietary supplements to reduce pre-formed Aβ 1–42 fibrils (21 supplements tested) and tau protein paired helical/straight filaments (13 supplements tested)—two of the three most important targets for memory loss. Additionally, 18 different manufacturers of cat’s claw (Uncaria tomentosa) were directly compared for their ability to inhibit/reduce Aβ 1–42 fibrils and/or tau paired helical/straight filaments based on recent findings that PTI-00703 cat’s claw is a specific and potent inhibitor/reducer of all three targets -brain plaques, tangles and inflammation (Snow et al. in Sci Rep 9:561, 2019). In the present investigation quantitative Thioflavin T fluorometry was used on a comparative weight-to-weight basis at increasing concentrations with ingredients tested from the actual capsules the consumer ingests. Major memory-support dietary supplements were directly compared for their ability to inhibit and disaggregate/reduce both Aβ 1–42 fibrils and/or tau paired helical/straight filaments. Dietary supplements touted to enhance memory comparatively tested included Prevagen, FOCUSfactor, PROCERA AVH, Alpha Brain, NAD+OVIM, BRAIN JUICE, Cebria, EXCELEROL, NOOCUBE, US Doctor’s Clinical Brain Power ADVANCED, healthycell pro, LUMONOL, Brain Awake, BRAIN ARMOR, brainMD (BRAIN & MEMORY POWER BOOST), Brain Support, Clarity (BRAIN HEALTH FORMULA), brainMD (NEUROVITE PLUS), neuriva (Original and Plus) and percepta. This is the first paper to actually comparatively test these memory-support supplements for their ability to reduce Aβ fibrils and tau protein tangles. Percepta (PTI-00703 cat’s claw and a specific oolong tea extract) was determined to be the most effective and potent memory support dietary supplement to disaggregate/disrupt Aβ 1–42 fibrils (range of 25–89%) and tau paired helical/straight filaments (range of 26–86%) at all 3–4 doses tested in comparison to other major memory-support dietary supplements tested. This was at least more than double (> 50%) for percepta reducing Aβ 1–42 fibrils and in comparison to the other 20 memory-support dietary supplements tested. The ranking order for memory-support supplement effects based on reducing Aβ 1–42 fibrils (Aβ 1–42: memory-support supplement at 1:0.1 weight-to-weight in a 3-day study) was percepta (69.6% reduction) >>> Alpha Brain (34.9% reduction) = US Doctor’s Clinical Brain Power ADVANCED (32.4%) = BRAIN JUICE (30.1%) = neuriva Plus (27%) = neuriva Original (27%) > NEUROVITE PLUS (22.9%) = NOOCUBE (19.9%) = EXCELEROL (17.3%) = healthycell pro (17.2%) > Prevagen (12.9%) > PROCERA AVH (6.5%) = FOCUSfactor (5.5%) > Cebria (0%) = Brain Awake (0%) = Brain Support (0%) = brainMD (BRAIN & MEMORY POWER BOOST) (0%) = NAD+OVIM (0%) = BRAIN ARMOR (0%) = LUMONOL (0%). The ranking order for memory support supplement effects on reducing tau paired helical/straight filaments (tau:memory supplement at 1:1 weight-to-weight at 3 days) was percepta (85.7% reduction) >>> neuriva Plus (57.9%) >> BRAIN JUICE (41.9%) = EXCELEROL (41.0%) = neuriva Original (38.4%) = US Doctor’s Clinical Brain Power ADVANCED (38.3%) = healthycell pro (37.6%) >> Alpha Brain (27.9%) >> NOOCUBE (17.6%) >> FOCUSfactor (8.7%) > Cebria (3.6%) = PROCERA AVH (0%) = Prevagen (0%). Congo red staining, Thioflavin S fluorescence, circular dichroism (CD) spectroscopy and electron microscopy confirmed the positive results observed with the supplement percepta. CD spectroscopy demonstrated that percepta caused a marked inhibition of beta-sheet secondary folding of tau protein into paired helical filaments. PTI-00703 cat’s claw (main ingredient in percepta) was also identified as the most potent cat’s claw bark powder (Uncaria tomentosa) to reduce and inhibit Aβ 1–42 fibrils and tau tangles in comparison to 17 other manufacturers of cat’s claw extracts. Although there are thousands of brain memory-support dietary supplements in the marketplace today, none of them have been directly compared and analyzed for their ability to reduce and/or inhibit two major targets of memory loss i.e. Aβ 1–42 fibrils and tau paired helical/straight filaments (major constituents of brain plaques and tangles). In our comparison studies, we show that percepta has the most potent ability to disaggregate/reduce Aβ 1–42 fibrils and tau protein paired helical/straight filaments as demonstrated by a variety of methods most likely due to the specific polyphenol content in PTI-00703 cat’s claw (i.e. polyphenols and proanthocyanidins) as we have previously shown (Snow et al. in Sci Rep 9:561, 2019). Memory-support dietary supplements tested that also contained polyphenols and/or cat’s claw in their product demonstrated some Aβ fibril and tau protein tangle reducing activity, but were much less effective than percepta. Percepta’s main ingredient, PTI-00703 cat’s claw, has previously been shown to reduce brain amyloid plaques and Aβ 1–42/40 insoluble/soluble levels in brain (in plaque-producing transgenic mice) with marked concurrent memory improvements (shown by Morris water maze testing) (Snow et al. in Sci Rep 9:561, 2019). The present investigation further confirms that percepta is one of the best dietary supplements that causes a marked reduction and inhibition of Aβ fibrils and tau tangle filaments -two important major targets for memory-support. In addition, PTI-00703 cat’s claw was the most effective cat’s claw (Uncaria tomentosa) ingredient for reducing /disaggregating and inhibiting Aβ 1–42 fibrils and tau protein paired helical/straight filaments in comparison to 17 other manufacturers of cat’s claw extracts tested.

In daily life, speech perception is usually accompanied by other tasks that tap into working memory capacity. However, the role of working memory on speech processing is not clear. The goal of this study was to examine how working memory load affects the timeline for spoken word recognition in ideal listening conditions. We used the "visual world" eye-tracking paradigm. The task consisted of spoken instructions referring to one of four objects depicted on a computer monitor (e.g., "point at the candle"). Half of the trials presented a phonological competitor to the target word that either overlapped in the initial syllable (onset) or at the last syllable (offset). Eye movements captured listeners' ability to differentiate the target noun from its depicted phonological competitor (e.g., candy or sandal). We manipulated working memory load by using a digit pre-load task, where participants had to retain either one (low-load) or four (high-load) spoken digits for the duration of a spoken word recognition trial. The data show that the high-load condition delayed real-time target discrimination. Specifically, a four-digit load was sufficient to delay the point of discrimination between the spoken target word and its phonological competitor. Our results emphasize the important role working memory plays in speech perception, even when performed by young adults in ideal listening conditions.

Although mindfulness-based stress reduction (MBSR) improves cognitive function, the mechanism is not clear. In this study, people aged 65 years and older were recruited from elderly communities in Chitose City, Japan, and assigned to a non-MBSR group or a MBSR group. Before and after the intervention, the Japanese version of the Montreal Cognitive Assessment (MoCA-J) was administered, and blood samples were collected. Then, neuron-derived extracellular vesicles (NDEVs) were isolated from blood samples, and microRNAs, as well as the target mRNAs, were evaluated in NDEVs. A linear mixed model analysis showed significant effects of the MBSR x time interaction on the MoCA-J scores, the expression of miRNA(miR)-29c, DNA methyltransferase 3 alpha (DNMT3A), and DNMT3B in NDEVs. These results indicate that MBSR can improve cognitive function by increasing the expression of miR-29c and decreasing the expression of DNMT3A, as well as DNMT3B, in neurons. It was also found that intracerebroventricular injection of miR-29c mimic into 5xFAD mice prevented cognitive decline, as well as neuronal loss in the subiculum area, by down-regulating Dnmt3a and Dnmt3b in the hippocampus. The present study suggests that MBSR can prevent neuronal loss and cognitive impairment by increasing the neuronal expression of miR-29c.

VO2max (maximal oxygen consumption), a validated measure of aerobic fitness, has been associated with better cerebral artery compliance and measures of brain morphology, such as higher cortical thickness (CT) in frontal, temporal and cingular cortices, and larger grey matter volume (GMV) of the middle temporal gyrus, hippocampus, orbitofrontal cortex and cingulate cortex. Single sessions of physical exercise can promptly enhance cognitive performance and brain activity during executive tasks. However, the immediate effects of exercise on macro-scale properties of the brain’s grey matter remain unclear. We investigated the impact of one session of moderate-intensity physical exercise, compared with rest, on grey matter volume, cortical thickness, working memory performance, and task-related brain activity in older adults. Cross-sectional associations between brain measures and VO2max were also tested. Exercise did not induce statistically significant changes in brain activity, grey matter volume, or cortical thickness. Cardiovascular fitness, measured by VO2max, was associated with lower grey matter blood flow in the left hippocampus and thicker cortex in the left superior temporal gyrus. Cortical thickness was reduced at post-test independent of exercise/rest. Our findings support that (1) fitter individuals may need lower grey matter blood flow to meet metabolic oxygen demand, and (2) have thicker cortex.

Therapeutic interventions have not yet been shown to demonstrate restorative effects for declining long-term memory (LTM) that affects many healthy older adults. We developed a virtual reality (VR) spatial wayfinding game (Labyrinth-VR) as a cognitive intervention with the hypothesis that it could improve detailed, high-fidelity LTM capability. Spatial navigation tasks have been used as a means to achieve environmental enrichment via exposure to and learning about novel and complex information. Engagement has been shown to enhance learning and has been linked to the vitality of the LTM system in the brain. In the current study, 48 older adults (mean age 68.7 ± 6.4 years) with average cognitive abilities for their age were randomly assigned to 12 h of computer game play over four weeks in either the Labyrinth-VR or placebo control game arms. Promptly before and after each participant’s treatment regimen, high-fidelity LTM outcome measures were tested to assess mnemonic discrimination and other memory measures. The results showed a post-treatment gain in high-fidelity LTM capability for the Labyrinth-VR arm, relative to placebo, which reached the levels attained by younger adults in another experiment. This novel finding demonstrates generalization of benefits from the VR wayfinding game to important, and untrained, LTM capabilities. These cognitive results are discussed in the light of relevant research for hippocampal-dependent memory functions.

Postoperative delirium is the most common complication among older adults undergoing major surgery. The pathophysiology of delirium is poorly understood, and no blood-based, predictive markers are available. We characterized the plasma metabolome of 52 delirium cases and 52 matched controls from the Successful Aging after Elective Surgery (SAGES) cohort (N = 560) of patients ≥ 70 years old without dementia undergoing scheduled major non-cardiac surgery. We applied targeted mass spectrometry with internal standards and pooled controls using a nested matched case-control study preoperatively (PREOP) and on postoperative day 2 (POD2) to identify potential delirium risk and disease markers. Univariate analyses identified 37 PREOP and 53 POD2 metabolites associated with delirium and multivariate analyses achieved significant separation between the two groups with an 11-metabolite prediction model at PREOP (AUC = 83.80%). Systems biology analysis using the metabolites with differential concentrations rendered “valine, leucine, and isoleucine biosynthesis” at PREOP and “citrate cycle” at POD2 as the most significantly enriched pathways (false discovery rate

Executive functions demonstrate variable developmental and aging profiles, with protracted development into early adulthood and declines in older age. However, relatively few studies have specifically included middle-aged adults in investigations of age-related differences in executive functions. This study explored the age-related differences in executive function from late childhood through to old age, allowing a more informed understanding of executive functions across the lifespan. Three hundred and fifty participants aged 10 to 86 years-old completed a battery of tasks assessing the specific roles of inhibitory control, working memory, cognitive flexibility, and planning. Results highlighted continued improvement in working memory capacity across adolescence and into young adulthood, followed by declines in both working memory and inhibitory control, beginning from as early as 30–40 years old and continuing into older age. Analyses of planning abilities showed continued improvement across adolescence and into young adulthood, followed by a decline in abilities across adulthood, with a small (positive) change in older age. Interestingly, a dissociation was found for cognitive flexibility; switch costs decreased, yet mixing costs increased across the lifespan. The results provide a description of the developmental differences in inhibitory control, working memory, cognitive flexibility and planning, above any effects of IQ or SES, and highlight the importance of including middle-aged adults in studies seeking to establish a more comprehensive picture of age-related differences in executive function.

Funder: Rural and Environment Science and Analytical Services Division; doi: http://dx.doi.org/10.13039/100011310, Epigenetic imprinting is important for neurogenesis and brain function. Hippocampal volumes and brain hyperintensities in late life have been associated with early life circumstances. Epigenetic imprinting may underpin these associations. Methylation was measured at 982 sites in 13 imprinted locations in blood samples from a longitudinal cohort by bisulphite amplicon sequencing. Hippocampal volumes and hyperintensities were determined at age 64y and 72y using MRI. Hyperintensities were determined in white matter, grey matter and infratentorial regions. Permutation methods were used to adjust for multiple testing. At 64y, H19/IGF2 and NESPAS methylation predicted hippocampal volumes. PEG3 predicted hyperintensities in hippocampal grey matter, and white matter. GNASXL predicted grey matter hyperintensities. Changes with age were predicted for hippocampal volume (MEST1, KvDMR, L3MBTL, GNASXL), white matter (MEST1, PEG3) and hippocampal grey matter hyperintensities (MCTS2, GNASXL, NESPAS, L3MBTL, MCTS2, SNRPN, MEST1). Including childhood cognitive ability, years in education, or socioeconomic status as additional explanatory variables in regression analyses did not change the overall findings. Imprinting methylation in multiple genes predicts brain structures, and their change over time. These findings are potentially relevant to the development of novel tests of brain structure and function across the life-course, strategies to improve cognitive outcomes, and our understanding of early influences on brain development and function.

Vascular contributions to cognitive impairment and dementia (VCID) include structural and functional blood vessel injuries linked to poor neurocognitive outcomes. Smoking might indirectly increase the likelihood of cognitive impairment by exacerbating vascular disease risks. Sex disparities in VCID have been reported, however, few studies have assessed the sex-specific relationships between smoking and memory performance and with contradictory results. We investigated the associations between sex, smoking, and cardiovascular disease with verbal learning and memory function. Using MindCrowd, an observational web-based cohort of ~ 70,000 people aged 18–85, we investigated whether sex modifies the relationship between smoking and cardiovascular disease with verbal memory performance. We found significant interactions in that smoking is associated with verbal learning performance more in women and cardiovascular disease more in men across a wide age range. These results suggest that smoking and cardiovascular disease may impact verbal learning and memory throughout adulthood differently for men and women.

Few studies have investigated the neuropsychological profile of Hearing Loss (HL) subjects and the effects of hearing-aid on cognitive decline. We investigated the neuropsychological profile of HL patients at baseline and compared the neuropsychological profiles of patients with and without hearing-aid at 6 month. Fifty-six HL patients and 40 healthy subjects (HC) underwent neuropsychological and behavioral examination and were compared at baseline. Changes at follow-up were compared between HL patients with (N = 25) and without (N = 31) hearing-aids. At baseline, significant differences between HL and HC were found in MOCA test, Raven's Coloured Progressive Matrices (CPM) and SF-36. Among mild-HL patients, patients with hearing-aid significantly improved on the Clock Drawing Test (CDT) as compared to patients without hearing-aid. Our findings indicate that hearing loss is associated with both a reduced efficiency of the global cognitive state and a worse quality of life as compared to HC, supporting the association between HL and cognitive impairment. Moreover, only patients with mild-HL shows some cognitive improvement after using hearing-aid, suggesting that rehabilitative strategies may be more effective to delay cognitive decline in such patients. However, we cannot exclude that hearing-aids may affect cognitive decline in more severe-HL, but a longer follow-up is needed.

Working memory (WM) is a fundamental cognitive function that typically declines with age. Previous studies have shown that targeted WM training has the potential to improve WM performance in older adults. In the present study, we investigated whether a multi-domain cognitive training program that was not designed to specifically target WM could improve the behavioral performance and affect the neural activity during WM retrieval in healthy older adults. We assigned healthy older participants (70–78 years old) from a local community into a training group who completed a 3-month multi-domain cognitive training and a control group who only attended health education lectures during the same period. Behavioral and electroencephalography (EEG) data were recorded from participants while performing an untrained delayed match or non-match to category task and a control task at a pre-training baseline session and a post-training follow-up session. Behaviorally, we found that participants in the training group showed a trend toward greater WM performance gains than participants in the control group. Event-related potential (ERP) results suggest that the task-related modulation of P3 during WM retrieval was significantly enhanced at the follow-up session compared with the baseline session, and importantly, this enhancement of P3 modulation was only significant in the training group. Furthermore, no training-related effects were observed for the P2 or N2 component during WM retrieval. These results suggest that the multi-domain cognitive training program that was not designed to specifically target WM is a promising approach to improve WM performance in older adults, and that training-related gains in performance are likely mediated by an enhanced modulation of P3 which might reflect the process of WM updating.

Males and females are subject to differences in cognitive processing strategies, i.e. the way males and females solve cognitive tasks. So far primarily reported for younger adults, this seems to be especially important in older adults, who also show sex differences in cognitive impairments. Therefore, the aim of the current study was to examine the older adult population with respect to cognitive profiles derived from a large variety of cognitive functions. Using an exploratory component analysis with consecutive confirmatory factor analysis in a sample of 676 older adults, neuropsychological performance data in a variety of cognitive domains was decomposed into cognitive components. A general cognitive profile based on the whole group fits unequally well on the two sexes. Importantly, cognitive profiles based on either males or females differ in terms of their composition of cognitive components, i.e. three components in males versus four components in females, with a generally better model fit in females. Thus, related to the established differences in processing styles between males and females the current study found a rather decomposed (or local) cognitive profile in females while males seem to show a holistic (or global) cognitive profile, with more interrelations between different cognitive functions.

Objective: To determine the effect of later-life formal education or learning on quality of life (QOL), wellbeing, mood, and cognition. Methods: A systematic literature review of interventional clinical trials and observational studies was conducted for adults aged ≥55 years who had undertaken formal education or learning programs. Outcome measures included physical activity, happiness, affective and behavioral symptoms, cognitive function, and QOL. Bias was assessed using funnel plots, Egger’s test, and leave1out analysis. Results: From 32 studies identified, we showed qualitative increases in cognitive function, life satisfaction, and self-confidence associated with learning. A meta-analysis revealed a significant pooled mean difference in MMSE scores (0.40, 95% confidence intervals = [0.12, 0.67]). Although there was a low risk of publication bias there was a high risk of sampling bias. Conclusion: Participation in formal education or learning contributed to increased wellbeing, QOL, healthy cognitive function, self-dependency, and a sense of belonging in older adults.

The concept of Mild Cognitive Impairment (MCI) is used to describe the early stages of Alzheimer’s disease (AD), and identification and treatment before further decline is an important clinical task. We selected longitudinal data from the ADNI database to investigate how well normal function (HC, n= 134) vs. conversion to MCI (cMCI, n= 134) and stable MCI (sMCI, n=333) vs. conversion to AD (cAD, n= 333) could be predicted from cognitive tests, and whether the predictions improve by adding information from magnetic resonance imaging (MRI) examinations. Features representing trajectories of change in the selected cognitive and MRI measures were derived from mixed effects models and used to train ensemble machine learning models to classify the pairs of subgroups based on a subset of the data set. Evaluation in an independent test set showed that the predictions for HC vs. cMCI improved substantially when MRI features were added, with an increase in $$F_1$$ F 1 -score from 60 to 77%. The $$F_1$$ F 1 -scores for sMCI vs. cAD were 77% without and 78% with inclusion of MRI features. The results are in-line with findings showing that cognitive changes tend to manifest themselves several years after the Alzheimer’s disease is well-established in the brain.

Social relationships are a central aspect of our everyday life, yet our ability to change established social relationships is an under-investigated topic. Here, we use the concept of cognitive mapping to investigate the plasticity of social relationships in younger and older adults. We describe social relationships within a ‘social space’, defined as a two-dimensional grid composed of the axis ‘power’ and ‘affiliation’, and investigate it using a 3D virtual environment with interacting avatars. We show that participants remap dimensions in ‘social space’ when avatars show conflicting behavior compared to consistent behavior and that, while older adults show similar updating behavior than younger adults, they show a distinct reduction in remapping social space. Our data provide first evidence that older adults show more rigid social behavior when avatars change their behavior in the dimensions of power and affiliation, which may explain age-related social behavior differences in everyday life.

Contains fulltext : 231770.pdf (Publisher’s version ) (Open Access) People often experience high level of distress during invasive interventions, which may exceed their coping abilities. This may be in particular evident when confronted with the suspicion of cancer. Taking the example of prostate biopsy sampling, we aimed at investigating the impact of an MRI guided prostate biopsy on the acute stress response and its mechanistic basis. We recruited 20 men with a clinical suspicion of prostate cancer. Immediately before an MRI guided biopsy procedure, we conducted fMRI in the same scanner to assess resting-state brain connectivity. Physiological and hormonal stress measures were taken during the procedure and associated with questionnaires, hair cortisol levels and brain measures to elucidate mechanistic factors for elevated stress. As expected, patients reported a stress-related change in affect. Decreased positive affect was associated with higher hair but not saliva cortisol concentration. Stronger use of maladaptive emotion regulation techniques, elevated depression scores and higher within-salience-network connectivity was associated with stronger increase in negative affect and/or decrease of positive affect during the procedure. While being limited in its generalization due to age, sample size and gender, our proof of concept study demonstrates the utility of real-life stressors and large-scale brain network measures in stress regulation research with potential impact in clinical practice.

Alzheimer’s disease (AD) has no proven causal and modifiable risk factors, or effective interventions. We report a phenome-wide association study (PheWAS) of genetic liability for AD in 334,968 participants of the UK Biobank study, stratified by age. We also examined the effects of AD genetic liability on previously implicated risk factors. We replicated these analyses in the HUNT study. PheWAS hits and previously implicated risk factors were followed up in a Mendelian randomization (MR) framework to identify the causal effect of each risk factor on AD risk. A higher genetic liability for AD was associated with medical history and cognitive, lifestyle, physical and blood-based measures as early as 39 years of age. These effects were largely driven by the APOE gene. The follow-up MR analyses were primarily null, implying that most of these associations are likely to be a consequence of prodromal disease or selection bias, rather than the risk factor causing the disease.

There is a growing literature on the impact of ethnicity on brain structure and function. Despite the regional heterogeneity in age-related changes and non-uniformity across brain morphometry measurements in the aging process, paucity of studies investigated the difference in cortical anatomy between the East Asian and Caucasian older adults. The present study aimed to compare cortical anatomy measurements, including cortical thickness, volume and surface area, between cognitively normal East Asian (n = 171) and Caucasian (n = 178) older adults, using surface-based morphometry and vertex-wise group analysis of high-dimensional structural magnetic resonance imaging (MRI) data. The East Asian group showed greater cortical thickness and larger cortical volume in the right superior temporal gyrus, postcentral gyrus, bilateral inferior temporal gyrus, and inferior parietal cortex. The Caucasian group showed thicker and larger cortex in the left transverse temporal cortex, lingual gyrus, right lateral occipital cortex, and precentral gyrus. Additionally, the difference in surface area was discordant with that in cortical thickness. Differences in brain structure between the East Asian and Caucasian might reflect differences in language and information processing, but further studies using standardized methods for assessing racial characteristics are needed. The research results represent a further step towards developing a comprehensive understanding of differences in brain structure between ethnicities of older adults, and this would enrich clinical research on aging and neurodegenerative diseases.

Memory performance results from plasticity, the ability to change with experience. We show that benefit from practice over a few trials, learning slope, is predictive of long-term recall and hippocampal volume across a broad age range and a long period of time, relates to memory training benefit, and is heritable. First, in a healthy lifespan sample (n = 1825, age 4–93 years), comprising 3483 occasions of combined magnetic resonance imaging (MRI) scans and memory tests over a period of up to 11 years, learning slope across 5 trials was uniquely related to performance on a delayed free recall test, as well as hippocampal volume, independent from first trial memory or total memory performance across the five learning trials. Second, learning slope was predictive of benefit from memory training across ten weeks in an experimental subsample of adults (n = 155). Finally, in an independent sample of male twins (n = 1240, age 51–50 years), learning slope showed significant heritability. Within-session learning slope may be a useful marker beyond performance per se, being heritable and having unique predictive value for long-term memory function, hippocampal volume and training benefit across the human lifespan.

Brain structure in later life reflects both influences of intrinsic aging and those of lifestyle, environment and disease. We developed a deep neural network model trained on brain MRI scans of healthy people to predict “healthy” brain age. Brain regions most informative for the prediction included the cerebellum, hippocampus, amygdala and insular cortex. We then applied this model to data from an independent group of people not stratified for health. A phenome-wide association analysis of over 1,410 traits in the UK Biobank with differences between the predicted and chronological ages for the second group identified significant associations with over 40 traits including diseases (e.g., type I and type II diabetes), disease risk factors (e.g., increased diastolic blood pressure and body mass index), and poorer cognitive function. These observations highlight relationships between brain and systemic health and have implications for understanding contributions of the latter to late life dementia risk.

Experimental sleep-wake disruption in rodents and humans causally modulates β-amyloid (Aβ) dynamics (e.g., [1–3]). This leads to the hypothesis that, beyond cross-sectional associations, impaired sleep structure and physiology could represent prospective biomarkers of the speed with which Aβ accumulates over time. Here, we test the hypothesis that initial baseline measures of non-rapid eye movement (NREM) sleep slow-wave activity (SWA) and sleep quality (efficiency) provide future forecasting sensitivity to the rate of Aβ accumulation over subsequent years. A cohort of clinically normal older adults was assessed using objective sleep polysomnography in combination with longitudinal tracking of Aβ accumulation with [(11)C]PiB positron emission tomography (PET) imaging. Both the proportion of NREM SWA below 1 Hz and the measure of sleep efficiency predicted the speed (slope) of subsequent Aβ deposition over time, and these associations remained robust when taking into account additional cofactors of interest (e.g., age, sex, sleep apnea). Moreover, these measures were specific, such that no other macro- and microphysiological architecture metrics of sleep demonstrated such sensitivity. Our data support the proposal that objective sleep markers could be part of a set of biomarkers that statistically forecast the longitudinal trajectory of cortical Aβ deposition in the human brain. Sleep may therefore represent a potentially affordable, scalable, repeatable, and non-invasive tool for quantifying of Aβ pathological progression, prior to cognitive symptoms of Alzheimer’s disease (AD).