Brain In Older Adults Research Articles

Brain phosphoproteomic analysis identifies diabetes-related substrates in Alzheimer's disease pathology in older adults.

Type 2 diabetes increases the risk of Alzheimer's disease (AD) dementia. Insulin signaling dysfunction exacerbates tau protein phosphorylation, a hallmark of AD pathology. However, the comprehensive impact of diabetes on patterns of AD-related phosphoprotein in the human brain remains underexplored. We performed tandem mass tag-based phosphoproteome profiling in post mortem human brain prefrontal cortex samples from 191 deceased older adults with and without diabetes and pathologic AD. Among 7874 quantified phosphosites, microtubule-associated protein tau (MAPT) phosphorylated at T529 and T534 (isoform 8 T212 and T217) were more abundant in AD and showed differential associations with diabetes. Network analysis of co-abundance patterns uncovered synergistic interactions between AD and diabetes, with one module exhibiting higher MAPT phosphorylation (15 MAPT phosphosites) and another displaying lower MAP1B phosphorylation (22 MAP1B phosphosites). This study offers phosphoproteomics insights into AD in diabetes, shedding light on mechanisms that can inform the development of therapeutics for dementia. The risk of Alzheimer's disease (AD) dementia is increased among older adults living with diabetes. The patterns of AD-related phosphoprotein in the human brain in older adults are differential among older adults living with diabetes. Microtubule-associated protein tau phosphorylated at T529 and T534 (isoform 8 T212 and T217) showed differential associations with diabetes. Phosphosite co-abundance networks of synergistic interactions between AD and diabetes were identified.

Effects of sleep quality on diurnal volumetric change of brain in older adults

Effects of sleep quality on diurnal volumetric change of brain in older adults

Comparing the Efficacy of Two Cognitive Screening Tools in Identifying Gray and White Matter Brain Damage among Older Adults.

Ageing is associated with structural changes in brain regions and functional decline in cognitive domains. Noninvasive tools for identifying structural damage in the brains of older adults are relevant for early treatment. This study aims to evaluate and compare the accuracy of the Mini-Mental State Examination (MMSE) and Montreal Cognitive Assessment (MoCA©) in identifying gray and white matter brain damage in older individuals with varying degrees of cognitive impairment. Ninety older adults (62 women) with an average age of 69 ± 7 years were enrolled and categorized as having no cognitive impairment (NCI), mild cognitive impairment (MCI), or moderate cognitive impairment (MoCI). Magnetic resonance imaging (MRI) was utilized to assess the number, volume, and distribution of brain damage. The Fazekas and Scheltens scales were applied to the brain MRIs, and inferential statistics were employed to compare variables among the groups. Cognitive impairment was observed in 56.7% of the participants (95% confidence interval (CI): 46.4-66.4%), with thirty-six older adults (40%) classified as MCI and 15 (17%) as MoCI. Cognitive impairment and medial temporal lobe (MTL) atrophy were found to be associated (p=0.001), exhibiting higher mean volume scales of the MTL atrophied area in the MoCI group (p < 0.001). The MMSE accurately revealed MTL atrophy based on the Scheltens (p < 0.05) and Fazekas (p < 0.05) scales. At the same time, the MoCA accurately identified periventricular white matter (PWM) abnormalities according to the Fazekas scale (p < 0.05). The MMSE and MoCA screening tools effectively identified gray and white matter brain damage in older adults with varying degrees of cognitive impairment. Lower MMSE scores are associated with MTL atrophy and lesions, and lower MoCA scores are related to PWM lesions. The concurrent use of MMSE and MoCA is recommended for assessing structural changes in distinct brain regions.

Cognitive Impairment in Nonagenarians: Potential Metabolic Mechanisms Revealed by the Synergy of In Silico Gene Expression Modeling and Pathway Enrichment Analysis.

Previous studies examining the molecular and genetic basis of cognitive impairment, particularly in cohorts of long-living adults, have mainly focused on associations at the genome or transcriptome level. Dozens of significant dementia-associated genes have been identified, including APOE, APOC1, and TOMM40. However, most of these studies did not consider the intergenic interactions and functional gene modules involved in cognitive function, nor did they assess the metabolic changes in individual brain regions. By combining functional analysis with a transcriptome-wide association study, we aimed to address this gap and examine metabolic pathways in different areas of the brain of older adults. The findings from our previous genome-wide association study in 1155 older adults, 179 of whom had cognitive impairment, were used as input for the PrediXcan gene prediction algorithm. Based on the predicted changes in gene expression levels, we conducted a transcriptome-wide association study and functional analysis using the KEGG and HALLMARK databases. For a subsample of long-living adults, we used logistic regression to examine the associations between blood biochemical markers and cognitive impairment. The functional analysis revealed a significant association between cognitive impairment and the expression of NADH oxidoreductase in the cerebral cortex. Significant associations were also detected between cognitive impairment and signaling pathways involved in peroxisome function, apoptosis, and the degradation of lysine and glycan in other brain regions. Our approach combined the strengths of a transcriptome-wide association study with the advantages of functional analysis. It demonstrated that apoptosis and oxidative stress play important roles in cognitive impairment.

Associations of subcortical shapes with age‐related neuropathologies in community‐based older adults

AbstractBackgroundAge‐related neuropathologies lead to substantial atrophy of subcortical brain regions. However, the effects of age‐related neuropathologies on the shape of subcortical brain structures are not well understood because a) definitive diagnosis of most neuropathologies is only possible at autopsy and b) multiple neuropathologies often coexist in the brain of older adults. The purpose of this work was to integrate ex‐vivo MRI and detailed neuropathologic examination in a large number of community‐based older adults.Method Participants and Data Cerebral hemispheres from 842 older adults participating in four longitudinal, clinical‐pathologic cohort studies of aging: the Rush Memory and Aging Project (MAP), the Religious Orders Study (ROS), the Minority Aging Research Study (MARS) and the Clinical Core (CC) of the Rush Alzheimer’s Disease Research Center (ADRC)1,2 (Fig.1) were included in this work. All hemispheres were imaged at room temperature while immersed in 4% formaldehyde solution using clinical 3T MRI scanners approximately 30 days postmortem. After ex‐vivo MRI, each hemisphere underwent detailed neuropathologic examination by a board‐certified neuropathologist (Fig.1). Ex‐vivo MRI and Shape Estimation The subcortical structures were segmented in ex‐vivo T2‐weighted MR images from all participants. Shape analysis was performed using SPHARM‐PDM3. For each subcortical structure, signed shape differences were computed from the average mesh for all vertices and all participants. Statistical Analysis Vertex‐wise linear regression was performed for each subcortical structure, modeling the signed shape difference at each vertex (dependent variable) as a function of neuropathologies (specifically amyloid‐β plaques, neurofibrillary tangles, limbic‐predominant age‐related TDP‐43 encephalopathy neuropathological change (LATE‐NC), Lewy bodies, arteriolosclerosis, atherosclerosis, gross and microscopic infarcts, and cerebral amyloid angiopathy), and controlling for age at death, sex, years of education, postmortem interval to fixation, postmortem interval to imaging, and scanner. The statistical analysis was conducted using PALM4 with family‐wise error rate correction.ResultThe results are shown in Figure 2. These findings for tangles and LATE‐NC were in good agreement with our previous work5,6. Finally, although MRI was conducted ex‐vivo, we expect the results to translate well to in‐vivo7.ConclusionThe differences in spatial patterns of the effects of various neuropathologies may contribute towards the development of tools for in‐vivo prediction of these neuropathologies.

Associations of subcortical shapes with age‐related neuropathologies in community‐based older adults

AbstractBackgroundAge‐related neuropathologies lead to substantial atrophy of subcortical brain regions. However, the effects of age‐related neuropathologies on the shape of subcortical brain structures are not well understood because a) definitive diagnosis of most neuropathologies is only possible at autopsy and b) multiple neuropathologies often coexist in the brain of older adults. The purpose of this work was to integrate ex‐vivo MRI and detailed neuropathologic examination in a large number of community‐based older adults.MethodParticipants and Data Cerebral hemispheres from 842 older adults participating in four longitudinal, clinical‐pathologic cohort studies of aging: the Rush Memory and Aging Project (MAP), the Religious Orders Study (ROS), the Minority Aging Research Study (MARS) and the Clinical Core (CC) of the Rush Alzheimer’s Disease Research Center (ADRC)1,2 (Fig.1) were included in this work. All hemispheres were imaged at room temperature while immersed in 4% formaldehyde solution using clinical 3T MRI scanners approximately 30 days postmortem. After ex‐vivo MRI, each hemisphere underwent detailed neuropathologic examination by a board‐certified neuropathologist (Fig.1). Ex‐vivo MRI and Shape Estimation The subcortical structures were segmented in ex‐vivo T2‐weighted MR images from all participants. Shape analysis was performed using SPHARM‐PDM3. For each subcortical structure, signed shape differences were computed from the average mesh for all vertices and all participants. Statistical Analysis Vertex‐wise linear regression was performed for each subcortical structure, modeling the signed shape difference at each vertex (dependent variable) as a function of neuropathologies (specifically amyloid‐ß plaques, neurofibrillary tangles, limbic‐predominant age‐related TDP‐43 encephalopathy neuropathological change (LATE‐NC), Lewy bodies, arteriolosclerosis, atherosclerosis, gross and microscopic infarcts, and cerebral amyloid angiopathy), and controlling for age at death, sex, years of education, postmortem interval to fixation, postmortem interval to imaging, and scanner. The statistical analysis was conducted using PALM4 with family‐wise error rate correction.ResultThe results are shown in Figure 2. These findings for tangles and LATE‐NC were in good agreement with our previous work5,6. Finally, although MRI was conducted ex‐vivo, we expect the results to translate well to in‐vivo7.ConclusionThe differences in spatial patterns of the effects of various neuropathologies may contribute towards the development of tools for in‐vivo prediction of these neuropathologies.

Neuroprotective Effect of Thiazolidine-2,4-dione Derivatives on Memory Deficits and Neuropathological Symptoms of Dementia on a Scopolamine-Induced Alzheimer's Model in Adult Male Wistar Rats.

Alzheimer's disease (AD) is a neurodegenerative disorder associated with a decline in memory deficits and neuropathological diagnosis with loss of cholinergic neurons in the brains of older adults. Based on these facts and an increasing number of involved people worldwide, this investigation aimed to study the improvement of memory and cognitive impairments via an anticholinergic approach of thiazolidine-2,4-diones (TZDs) in the scopolamine-induced model of Alzheimer type in adult male Wistar rats (n = 40). The results indicated data analysis obtained from in vivo and in vitro tests for (E)-5-(3-hydroxybenzylidene)-3-(2-oxo-2-phenylethyl)thiazolidine-2,4-dione (TZ3O) (2 and 4 mg/kg) with the meta-hydroxy group and (E)-5-(4-methoxybenzylidene)-3-(2-oxo-2-phenylethyl)thiazolidine-2,4-dione (TZ4M) (2 and 3 mg/kg) with the para-methoxy group showed a neuroprotective effect. TZ3O and TZ4M alleviated the scopolamine-induced cognitive decline of the Alzheimer model in adult male Wistar rats. These initial and noteworthy results could be assumed as a starting point for the evolution of new anti-Alzheimer agents.

New horizons in cognitive and functional impairment as a consequence of cerebral small vessel disease.

Cerebral small vessel disease (cSVD) is a frequent finding in imaging of the brain in older adults, especially in the concomitance of cardiovascular disease risk factors. Despite the well-established link between cSVD and (vascular) cognitive impairment (VCI), it remains uncertain how and when these vascular alterations lead to cognitive decline. The extent of acknowledged markers of cSVD is at best modestly associated with the severity of clinical symptoms, but technological advances increasingly allow to identify and quantify the extent and perhaps also the functional impact of cSVD more accurately. This will facilitate a more accurate diagnosis of VCI, against the backdrop of concomitant other neurodegenerative pathology, and help to identify persons with the greatest risk of cognitive and functional deterioration. In this study, we discuss how better assessment of cSVD using refined neuropsychological and comprehensive geriatric assessment as well as modern image analysis techniques may improve diagnosis and possibly the prognosis of VCI. Finally, we discuss new avenues in the treatment of cSVD and outline how these contemporary insights into cSVD can contribute to optimise screening and treatment strategies in older adults with cognitive impairment and multimorbidity.

Characterization of the transcriptome and TCR of brain and cerebrospinal fluid infiltrated CD8 +T cells in an Alzheimer’s disease mouse model

Abstract Alzheimer’s disease (AD) is a common form of dementia characterized by the accumulation of protein aggregates in the brain of older adults. It has been observed that CD8 +T cells, particularly CD8 +TEMRA cells, infiltrate the brain and cerebrospinal fluid (CSF) of AD patients. However, the precise role of these cells in the development and progression of AD is not well understood. In this study, we used single-cell RNA sequencing (scRNAseq) and single-cell T cell receptor sequencing (scTCRseq) to examine the CD8 +T cells in the brain and CSF of a mouse model of AD (5xFAD) and its wild-type (WT) littermate controls. The AD mice (age 40–70 weeks) used in our experiments have developed memory deficits. Our analysis revealed a significant increase in the number of CD8 +T cells in the brain and CSF of AD mice compared to WT controls (n=4, p&amp;lt;0.05). Furthermore, these cells displayed a distinct transcriptome profile characterized by increased expression of inflammatory pathways, compared to WT mice. Through TCR sequence analysis, we also observed significant clonal expansion of CD8 +T cells in AD mice compared to WT mice. These findings provide a starting point for further investigation into the role of infiltrating CD8 +T cells in the pathogenesis of AD in this mouse model.

Peripheral Regulation of Central Brain-Derived Neurotrophic Factor Expression through the Vagus Nerve.

The brain-derived neurotrophic factor (BDNF) is an extensively studied neurotrophin es sential for both developing the brain and maintaining adult brain function. In the adult hippocampus, BDNF is critical for maintaining adult neurogenesis. Adult hippocampal neurogenesis is involved not only in memory formation and learning ability, but also mood regulation and stress responses. Accordingly, decreased levels of BDNF, accompanied by low levels of adult neurogenesis, occurs in brains of older adults with impaired cognitive function and in those of patients with major depression disorder. Therefore, elucidating the mechanisms that maintain hippocampal BDNF levels is biologically and clinically important. It has been revealed that signalling from peripheral tissues contribute to the regulation of BDNF expression in the brain across the blood-brain barrier. Moreover, recent studies indicated evidence that neuronal pathways can also be a mechanism by which peripheral tissues signal to the brain for the regulation of BDNF expression. In this review, we give an overview of the current status in the regulation of central BDNF expression by peripheral signalling, with a special interest in the regulation of hippocampal BDNF levels by signals via the vagus nerve. Finally, we discuss the relationship between signalling from peripheral tissues and age-associated control of central BDNF expression.

L-DOPA enhances neural direction signals in younger and older adults

Previous studies indicate a role of dopamine in spatial navigation. Although neural representations of direction are an important aspect of spatial cognition, it is not well understood whether dopamine directly affects these representations, or only impacts other aspects of spatial brain function. Moreover, both dopamine and spatial cognition decline sharply during age, raising the question which effect dopamine has on directional signals in the brain of older adults. To investigate these questions, we used a double-blind cross-over L-DOPA/Placebo intervention design in which 43 younger and 37 older adults navigated in a virtual spatial environment while undergoing functional magnetic resonance imaging (fMRI). We studied the effect of L-DOPA, a dopamine precursor, on fMRI activation patterns that encode spatial walking directions that have previously been shown to lose specificity with age. This was done in predefined regions of interest, including the early visual cortex, retrosplenial cortex, and hippocampus. Classification of brain activation patterns associated with different walking directions was improved across all regions following L-DOPA administration, suggesting that dopamine broadly enhances neural representations of direction. No evidence for differences between regions was found. In the hippocampus these results were found in both age groups, while in the retrosplenial cortex they were only observed in younger adults. Taken together, our study provides evidence for a link between dopamine and the specificity of neural responses during spatial navigation. Significance StatementThe sense of direction is an important aspect of spatial navigation, and neural representations of direction can be found throughout a large network of space-related brain regions. But what influences how well these representations track someone’s true direction? Using a double-blind cross-over L-DOPA/Placebo intervention design, we find causal evidence that the neurotransmitter dopamine impacts the fidelity of direction selective neural representations in the human hippocampus and retrosplenial cortex. Interestingly, the effect of L-DOPA was either equally present or even smaller in older adults, despite the well-known age related decline of dopamine. These results provide novel insights into how dopamine shapes the neural representations that underlie spatial navigation.

Development of high quality T1-weighted and diffusion tensor templates of the older adult brain in a common space

High-quality T1-weighted (T1w) and diffusion tensor imaging (DTI) brain templates that are representative of the individuals under study enhance the accuracy of template-based neuroimaging investigations, and when they are also located in a common space they facilitate optimal integration of information on brain morphometry and diffusion characteristics. However, such multimodal templates have not been constructed for the brain of older adults. The purpose of this work was threefold: (A) to introduce an iterative method for construction of multimodal T1w and DTI templates that aims at maximizing the quality of each template separately as well as the spatial matching between templates, (B) to use this method to develop T1w and DTI templates of the older adult brain in a common space, and (C) to evaluate the performance of the method across iterations and compare it to the performance of state-of-the-art approaches based on multichannel registration. It was demonstrated that more iterations of the proposed method enhanced the characteristics and spatial matching of the resulting T1w and DTI templates. The templates of the older adult brain generated by the final iteration of the proposed method provided better delineation of brain structures, higher discriminability between tissues, and higher image sharpness near the cortex compared to templates generated with approaches employing multichannel registration. In addition, the spatial matching between the T1w and DTI templates constructed by the proposed method approximated the template alignment achieved with methods employing multichannel registration. Finally, when using the templates generated by the proposed method as references for spatial normalization of older adult T1w and DTI data, both the intra-modality inter-subject normalization precision and the inter-modality spatial matching were higher in most metrics than those achieved with templates constructed with other methods. Overall, the present work brought new insights into multimodal template construction, generated much-needed high quality T1w and DTI templates of the older adult brain in a common space, and conducted a thorough, quantitative evaluation of available multimodal template construction methods.

Neurodegenerative and Cerebrovascular Brain Pathologies Are Differentially Associated With Declining Grip Strength and Gait In Older Adults.

Understanding the pathological bases underlying the heterogeneity of motor decline in old age may lead to targeted treatments. We examined whether different brain pathologies are related to declining grip strength and gait function. We examined postmortem brains of older adults who underwent annual motor testing. Postmortem exam measured 6 neurodegenerative and 5 cerebrovascular disease (CVD) pathologies. Grip strength was measured twice bilaterally using a hand-held dynamometer, and gait function was a composite measure based on time and steps taken to walk 8 ft and perform a 360° turn twice. In separate linear mixed-effects models including all autopsied adults (N = 1 217), neurodegenerative pathologies including tau tangles, TDP-43, and nigral neuronal loss were associated with declining grip strength, but not CVD pathologies. In contrast, although both CVD and neurodegenerative pathologies were associated with declining gait function, CVD pathologies accounted for 75% of the variance of declining rate of gait function explained by brain pathologies and neurodegenerative pathologies accounted for 25%. These findings were unchanged in adults (n = 970) without a history of stroke. Restricting analyses to only adults without dementia (n = 661), CVD pathologies continued to account for the majority of the variance of declining gait. However, we failed to detect in this subgroup the variance of declining grip strength explained by neurodegenerative or CVD pathologies. Different pathologies accumulating in aging brains may contribute to the phenotypic heterogeneity of motor decline. Larger studies are needed in older adults without dementia to assess differences in the motor consequences of varied brain pathologies.

Evidence of cortical thickness increases in bilateral auditory brain structures following piano learning in older adults.

Morphological differences in the auditory brain of musicians compared to nonmusicians are often associated with life-long musical activity. Cross-sectional studies, however, do not allow for any causal inferences, and most experimental studies testing music-driven adaptations investigated children. Although the importance of the age at which musical training begins is widely recognized to impact neuroplasticity, there have been few longitudinal studies examining music-related changes in the brains of older adults. Using magnetic resonance imaging, we measured cortical thickness (CT) of 12 auditory-related regions of interest before and after 6 months of musical instruction in 134 healthy, right-handed, normal-hearing, musically-naive older adults (64-76 years old). Prior to the study, all participants were randomly assigned to either piano training or to a musical culture/music listening group. In five regions-left Heschl's gyrus, left planum polare, bilateral superior temporal sulcus, and right Heschl's sulcus-we found an increase in CT in the piano training group compared with the musical culture group. Furthermore, CT of the right Heschl's gyrus could be identified as a morphological substrate supporting speech in noise perception. The results support the conclusion that playing an instrument is an effective stimulator for cortical plasticity, even in older adults.

Cannabis Use and Resting State Functional Connectivity in the Aging Brain.

Several lines of evidence suggest that older adults (aged 65+) sharply increased their cannabis use over the last decade, highlighting a need to understand the effects of cannabis in this age group. Pre-clinical models suggest that cannabinoids affect the brain and cognition in an age-dependent fashion, having generally beneficial effects on older animals and deleterious effects on younger ones. However, there is little research on how cannabis affects the brains of older adults or how older adults differ from younger adults who use cannabis. Resting state functional connectivity (rsFC) measures provide sensitive metrics of age-related cognitive decline. Here we compared rsFC in older adults who are either regular users of cannabis or non-users. We found stronger connectivity between sources in the hippocampus and parahippocampal cortex, and targets in the anterior lobes of the cerebellum in older adult cannabis users relative to non-users. A similar pattern of strengthened connectivity between hippocampal and cerebellar structures was also present in 25–35 year old non-users in comparison to 60–88 year old non-users. These findings suggest that future studies should examine both the potential risks of cannabinoids, as well as a potential benefits, on cognition and brain health for older adults.

Trait Mindfulness Is Associated With Less Amyloid, Tau, and Cognitive Decline in Individuals at Risk for Alzheimer’s Disease

BackgroundMindfulness, defined as nonjudgmental awareness of the present moment, has been associated with an array of mental and physical health benefits. Mindfulness may also represent a protective factor for Alzheimer’s disease (AD). Here, we tested the potential protective effect of trait mindfulness on cognitive decline and AD pathology in older adults at risk for AD dementia. MethodsMeasures of trait mindfulness, longitudinal cognitive assessments, and amyloid-β (Aβ) and tau positron emission tomography scans were collected in 261 nondemented older adults with a family history of AD dementia from the PREVENT-AD (Pre-symptomatic Evaluation of Experimental or Novel Treatments for AD) observational cohort study. Multivariate partial least squares analyses were used to examine relationships between combinations of different facets of trait mindfulness and 1) cognitive decline, 2) Aβ, and 3) tau. ResultsHigher levels of mindful nonjudgment, describing, and nonreactivity were associated with less cognitive decline in attention, global cognition, and immediate and delayed memory. Higher levels of mindful nonjudgment and nonreactivity were related to less Aβ positron emission tomography signal in bilateral medial and lateral temporoparietal and frontal regions. Higher levels of mindful acting with awareness, describing, nonjudgment, and nonreactivity were associated with less tau positron emission tomography signal in bilateral medial and lateral temporal regions. ConclusionsTrait mindfulness was associated with less cognitive decline and less Aβ and tau in the brain in older adults at risk for AD dementia. Longitudinal studies examining the temporal relationship between trait mindfulness and AD markers, along with mindfulness intervention studies, will be important for further clarifying the potential protective benefits of mindfulness on AD risk.

Leukoaraiosis and Gray Matter Volume Alteration in Older Adults: The PROOF Study.

Background and Purpose: Leukoaraiosis, also called white matter hyperintensities (WMH), is frequently encountered in the brain of older adults. During aging, gray matter structure is also highly affected. WMH or gray matter defects are commonly associated with a higher prevalence of mild cognitive impairment. However, little is known about the relationship between WMH and gray matter. Our aim was thus to explore the relationship between leukoaraiosis severity and gray matter volume in a cohort of healthy older adults.Methods: Leukoaraiosis was rated in participants from the PROOF cohort using the Fazekas scale. Voxel-based morphometry was performed on brain scans to examine the potential link between WMH and changes of local brain volume. A neuropsychological evaluation including attentional, executive, and memory tests was also performed to explore cognition.Results: Out of 315 75-year-old subjects, 228 had punctuate foci of leukoaraiosis and 62 had begun the confluence of foci. Leukoaraiosis was associated with a decrease of gray matter in the middle temporal gyrus, in the right medial frontal gyrus, and in the left parahippocampal gyrus. It was also associated with decreased performances in memory recall, executive functioning, and depression.Conclusion: In a population of healthy older adults, leukoaraiosis was associated with gray matter defects and reduced cognitive performance. Controlling vascular risk factors and detecting early cerebrovascular disease may prevent, at least in part, dementia onset and progression.

Age-related differences in the role of the prefrontal cortex in sensory-motor training gains: A tDCS study

The ability to process multiple sources of information concurrently is particularly impaired as individuals age and such age-related increases in multitasking costs have been linked to impairments in response selection. Previous neuroimaging studies with young adults have implicated the left hemisphere prefrontal cortex (PFC) as a key neural substrate of response selection. In addition, several transcranial direct current stimulation (tDCS) studies have provided causal evidence implicating this region in response selection and multitasking operations. For example, Filmer et al. (2013b) demonstrated that typically observed response selection learning/training gains in young adults were disrupted via offline tDCS of left, but not right, PFC. Here, considering evidence of age-related structural and functional changes in the brains of older adults, we assessed if this pattern of response selection learning disruption via tDCS to the left PFC is observed in older adults, testing if this region remains a key response selection node as individuals age. In a pre-registered study with 58 older adults, we applied anodal, cathodal, and sham stimulation to left and right PFC, and measured performance as participants trained on low- and high-response selection load tasks. Active stimulation did not disrupt training in older adults as compared to younger adults from our previous study. The results highlight age-related differences in the casual neural substrates that subserve response selection and learning.

Chronic oxytocin administration in older men modulates functional connectivity during animacy perception.

While aging is associated with social-cognitive change and oxytocin plays a crucial role in social cognition, oxytocin's effects on the social brain in older age remain understudied. To date, no study has examined the effects of chronic intranasal oxytocin administration on brain mechanisms underlying animacy perception in older adults. Using a placebo-controlled, randomized, double-blinded design in generally healthy older men (mean age (SD) = 69(6); n = 17 oxytocin; n = 14 placebo), this study determined the effects of a four-week intranasal oxytocin administration (24 international units/twice a day) on functional MRI (fMRI) during the Heider-Simmel task. This passive-viewing animacy perception paradigm contains video-clips of simple shapes suggesting social interactions (SOCIAL condition) or exhibiting random trajectories (RANDOM condition). While there were no oxytocin-specific effects on brain fMRI activation during the SOCIAL compared to the RANDOM condition, pre-to-post intervention change in the SOCIAL-RANDOM difference in functional connectivity (FC) was higher in the oxytocin compared to the placebo group in a network covering occipital, temporal, and parietal areas, and the superior temporal sulcus, a key structure in animacy perception. These findings suggest oxytocin modulation of circuits involved in action observation and social perception. Follow-up analyses on this network's connections suggested a pre-to-post intervention decrease in the SOCIAL-RANDOM difference in FC among the placebo group, possibly reflecting habituation to repeated exposure to social cues. Chronic oxytocin appeared to counter this process by decreasing FC during the RANDOM and increasing it during the SOCIAL condition. This study advances knowledge about oxytocin intervention mechanisms in the social brain of older adults.

Assessing the Effect of Training on the Cognition and Brain of Older Adults: Protocol for a Three-Arm Randomized Double-Blind Controlled Trial (ACTOP).

BackgroundTo prevent age-related cognitive impairment, many intervention programs offer exercises targeting different central cognitive processes. However, the effects of different process-based training programs are rarely compared within equivalent experimental designs.ObjectiveUsing a randomized double-blind controlled trial, this project aims to examine and compare the impact of 2 process-based interventions, inhibition and updating, on the cognition and brain of older adults.MethodsA total of 90 healthy older adults were randomly assigned to 1 of 3 training conditions: (1) inhibition (Stroop-like exercises), (2) updating (N-back-type exercises), and (3) control active (quiz game exercise). Training was provided in 12 half-hour sessions over 4 weeks. First, the performance gain observed will be measured on the trained tasks. We will then determine the extent of transfer of gain on (1) untrained tasks that rely on the same cognitive process, (2) complex working memory (WM) measurements hypothesized to involve 1 of the 2 trained processes, and (3) virtual reality tasks that were designed to mimic real-life situations that require WM. We will assess whether training increases cortical volume given that the volume of the cortex is determined by cortical area and thickness in regions known to be involved in WM or changes task-related brain activation patterns measured with functional magnetic resonance imaging. Dose effects will be examined by measuring outcomes at different time points during training. We will also determine whether individual characteristics moderate the effect of training on cognitive and cerebral outcomes. Finally, we will evaluate whether training reduces the age-related deficit on transfer and brain outcomes, by comparing study participants to a group of 30 younger adults.ResultsThe project was funded in January 2017; enrollment began in October 2017 and data collection was completed in April 2019. Data analysis has begun in June 2020 and the first results should be published by the end of 2020 or early 2021.ConclusionsThe results of this study will help understand the relative efficacy of 2 attentional control interventions on the cognition and the brain of older adults, as well as the moderating role of individual characteristics on training efficiency and transfer.Trial RegistrationClinicalTrials.gov NCT03532113; https://clinicaltrials.gov/ct2/show/NCT03532113International Registered Report Identifier (IRRID)DERR1-10.2196/20430