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Aging is often accompanied by changes in brain structure and executive functions, particularly in tasks involving cognitive flexibility, such as task-switching. However, substantial individual differences in the degree of cognitive impairment indicate that some individuals can cope with brain changes more effectively than others, suggesting higher cognitive reserve (CR). This study identified a neural basis for CR by examining the longitudinal relationship between task-related brain activation, structural brain changes, and changes in cognitive performance during an executive task-switching paradigm including single and dual conditions. Fifty-two older individuals were assessed at baseline and followed up after five years. Structural brain changes related to task-switching performance were analyzed using elastic net regression. Task-related functional brain activation was measured using ordinal trends canonical variate analysis (OrT CVA), capturing patterns of activation increasing from single to dual conditions. A differential task-related expression score (dOrT) was calculated as the difference in pattern expression scores between single and dual conditions at baseline. A linear regression model tested whether dOrT moderated the impact of brain changes on changes in switch cost over five years. Results showed a significant interaction between changes in brain structure and dOrT activation on switch cost change, indicating a moderation effect of task-related activation. Higher dOrT buffered the impact of brain structural decline on switch costs, enabling older adults to better cope with age-related brain structural changes and preserve cognitive flexibility. These findings suggest that these task-related activation patterns represent a neural basis for CR., Competing Interests: Declaration of Competing Interest None., (Copyright © 2024 Elsevier Inc. All rights reserved.)

The deposition of amyloid-β (Aβ) protein in the human brain is a hallmark of Alzheimer's disease and is related to cognitive decline. However, the relationship between early Aβ deposition and future cognitive impairment remains poorly understood, particularly concerning its spatial distribution and network-level effects. Here, we employed a cross-validated machine learning approach and investigated whether integrating subject-specific brain connectome information with Aβ burden measures improves predictive validity for subsequent cognitive decline. Baseline regional Aβ pathology measures from positron emission tomography (PET) imaging predicted prospective cognitive decline. Incorporating structural connectome, but not functional connectome, information into the Aβ measures improved predictive performance. We further identified a neuropathological signature pattern linked to future cognitive decline, which was validated in an independent cohort. These findings advance our understanding of how Aβ pathology relates to brain networks and highlight the potential of network-based metrics for Aβ-PET imaging to identify individuals at higher risk of cognitive decline., Competing Interests: Competing interest statement The authors have declared no conflicts of interest for this manuscript.

Greater engagement in cognitively stimulating activities (CSA) during adulthood has been shown to protect against neurocognitive decline, but no studies have investigated whether CSA during childhood protects against effects of brain changes on cognition later in life. The current study tested the moderating role of childhood CSA in the relationships between brain structure and cognitive performance during adulthood. At baseline (N=250) and 5-year follow-up (N=204) healthy adults aged 20-80 underwent MRI to assess four structural brain measures and completed neuropsychological tests to measure three cognitive domains. Participants were categorized into low and high childhood CSA based on self-report questionnaires. Results of multivariable linear regressions analyzing interactions between CSA, brain structure, and cognition showed that higher childhood CSA was associated with a weaker relationship between cortical thickness and memory at baseline, and attenuated the effects of change in cortical thickness and brain volume on decline in processing speed over time. These findings suggest higher CSA during childhood may mitigate the effects of brain structure changes on cognitive function later in life., Competing Interests: Declaration of Competing Interest None., (Copyright © 2024. Published by Elsevier Inc.)

Cognitive reserve (CR) explains differential susceptibility of cognitive performance to neuropathology. However, as brain pathologies progress, cognitive decline occurs even in individuals with initially high CR. The interplay between the structural brain health (= level of brain reserve) and CR-related brain networks therefore requires further research. Our sample included 142 individuals aged 60-70 years. National Adult Reading Test intelligence quotient (NART-IQ) was our CR proxy. On an in-scanner Letter Sternberg task, we used ordinal trend (OrT) analysis to extract a task-related brain activation pattern (OrT slope) for each participant that captures increased expression with task load (one, three, and six letters). We assessed whether OrT slope represents a neural mechanism underlying CR by associating it with task performance and NART-IQ. Additionally, we investigated how the following brain reserve measures affect the association between NART-IQ and OrT slope: mean cortical thickness, total gray matter volume, and brain volumes proximal to the areas contained in the OrT patterns. We found that higher OrT slope was associated with better task performance and higher NART-IQ. Further, the brain reserve measures were not directly associated with OrT slope, but they affected the relationship between NART-IQ and OrT slope: NART-IQ was associated with OrT slope only in individuals with high brain reserve. The degree of brain reserve has an impact on how (and perhaps whether) CR can be implemented in brain networks in older individuals., (© 2024 The Authors. Human Brain Mapping published by Wiley Periodicals LLC.)

The relationship between tau deposition and cognitive decline in cognitively healthy older adults is still unclear. The tau PET tracer 18 F-MK-6240 has shown favorable imaging characteristics to identify early tau deposition in aging. We evaluated the relationship between in vivo tau levels ( 18 F-MK-6240) and retrospective cognitive change over 5 years in episodic memory, processing speed, and reasoning. For tau quantification, a set of regions of interest (ROIs) was selected a priori based on previous literature: (1) total-ROI comprising selected areas, (2) medial temporal lobe-ROI, and (3) lateral temporal lobe-ROI and cingulate/parietal lobe-ROI. Higher tau burden in most ROIs was associated with a steeper decline in memory and speed. There were no associations between tau and reasoning change. The novelty of this finding is that tau burden may affect not only episodic memory, a well-established finding but also processing speed. Our finding reinforces the notion that early tau deposition in areas related to Alzheimer's disease is associated with cognitive decline in cognitively unimpaired individuals, even in a sample with low amyloid-β pathology., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Genome-wide association studies have discovered common genetic variants associated with cognitive performance. Polygenic scores that summarize these discoveries explain up to 10% of the variance in cognitive test performance in samples of adults. However, the role these genetics play in cognitive aging is not well understood. We analyzed data from 168 cognitively healthy participants aged 23-77 years old, with data on genetics, neuropsychological assessment, and brain-imaging measurements from two large ongoing studies, the Reference Abilities Neural Networks, and the Cognitive Reserve study. We tested whether a polygenic index previously related to cognition (Cog PGI) would moderate the relationship between age and measurements of the cognitive domains extracted from a neuropsychological evaluation: fluid reasoning, memory, vocabulary, and speed of processing. We further explored the relationship of Cog PGI and age on cognition using Johnson-Neyman intervals for two-way interactions. Sex, education, and brain measures of cortical thickness, total gray matter volume, and white matter hyperintensity were considered covariates. The analysis controlled for population structure-ancestry. There was a significant interaction effect of Cog PGI on the association between age and the domains of memory (Standardized coefficient = -0.158, p -value = 0.022), fluid reasoning (Standardized coefficient = -0.146, p -value = 0.020), and vocabulary (Standardized coefficient = -0.191, p -value = 0.001). Higher PGI strengthened the negative relationship between age and the domains of memory and fluid reasoning while PGI weakened the positive relationship between age and vocabulary. Based on the Johnson-Neyman intervals, Cog PGI was significantly associated with domains of memory, reasoning, and vocabulary for younger adults. There is a significant moderation effect of genetic predisposition for cognition for the association between age and cognitive performance. Genetics discovered in genome-wide association studies of cognitive performance show a stronger association in young and midlife older adults.

Objectives: Age-related cognitive changes can be influenced by both brain maintenance (BM), which refers to the relative absence over time of changes in neural resources or neuropathologic changes, and cognitive reserve (CR), which encompasses brain processes that allow for better-than-expected behavioral performance given the degree of life-course-related brain changes. This study evaluated the effects of age, BM, and CR on longitudinal changes over 2 visits, 5 years apart, in 3 cognitive abilities that capture most of age-related variability., Methods: Participants included 254 healthy adults aged 20-80 years at recruitment. Potential BM was estimated using whole-brain cortical thickness and white matter mean diffusivity at both visits. Education and intelligence quotient (IQ; estimated with American National Adult Reading Test) were tested as moderating factors for cognitive changes in the 3 cognitive abilities., Results: Consistent with BM-after accounting for age, sex, and baseline performance-individual differences in the preservation of mean diffusivity and cortical thickness were independently associated with relative preservation in the 3 abilities. Consistent with CR-after accounting for age, sex, baseline performance, and structural brain changes-higher IQ, but not education, was associated with reduced 5-year decline in reasoning (β = 0.387, p = .002), and education was associated with reduced decline in speed (β = 0.237, p = .039)., Discussion: These results demonstrate that both CR and BM can moderate cognitive changes in healthy aging and that the 2 mechanisms can make differential contributions to preserved cognition., (© The Author(s) 2023. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Introduction: Aging negatively impacts the ability to rapidly and successfully switch between two or more tasks that have different rules or objectives. However, previous work has shown that the context impacts the extent of this age-related impairment: while there is relative age-related invariance when participants must rapidly switch back and forth between two simple tasks (often called "switch costs"), age-related differences emerge when the contexts changes from one in which only one task must be performed to one in which multiple tasks must be performed, but a trial-level switch is not required (e.g., task repeat trials within dual task blocks, often called "mixing costs"). Here, we explored these two kinds of costs behaviorally, and also investigated the neural correlates of these effects., Methods: Seventy-one younger adults and 175 older adults completed a task-switching experiment while they underwent fMRI brain imaging. We investigated the impact of age on behavioral performance and neural activity considering two types of potential costs: switch costs (dual-task switch trials minus dual-task non-switch trials), and mixing costs (dual-task non-switch minus single-task trials)., Results: We replicated previous behavioral findings, with greater age associated with mixing, but not switch costs. Neurally, we found age-related compensatory activations for switch costs in the dorsal lateral prefrontal cortex, pars opercularis, superior temporal gyrus, and the posterior and anterior cingulate, but age-related under recruitment for mixing costs in fronto-parietal areas including the supramarginal gyrus and pre and supplemental motor areas., Discussion: These results suggest an age-based dissociation between executive components that contribute to task switching., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Eich, Langfield, Sakhardande, Gazes, Habeck and Stern.)

Background: Amyloid deposition is a primary predictor of Alzheimer's disease (AD) and related neurodegenerative disorders. Retinal changes involving the structure and function of the ganglion cell layer are increasingly documented in both established and prodromal AD. Visual event-related potentials (vERP) are sensitive to dysfunction in the magno- and parvocellular visual systems, which originate within the retinal ganglion cell layer. The present study evaluates vERP as a function of amyloid deposition in aging, and in mild cognitive impairment (MCI)., Methods: vERP to stimulus-onset, motion-onset, and alpha-frequency steady-state (ssVEP) stimuli were obtained from 16 amyloid-positive and 41 amyloid-negative healthy elders and 15 MCI individuals and analyzed using time-frequency approaches. Social cognition was assessed in a subset of individuals using The Awareness of Social Inference Test (TASIT)., Results: Neurocognitively intact but amyloid-positive participants and MCI individuals showed significant deficits in stimulus-onset (theta) and motion-onset (delta) vERP generation relative to amyloid-negative participants (all p < .01). Across healthy elders, a composite index of these measures correlated highly (r =  - .52, p < .001) with amyloid standardized uptake value ratios (SUVR) and TASIT performance. A composite index composed of vERP measures significant differentiated amyloid-positive and amyloid-negative groups with an overall classification accuracy of > 70%., Discussion: vERP may assist in the early detection of amyloid deposition among older individuals without observable neurocognitive impairments and in linking previously documented retinal deficits in both prodromal AD and MCI to behavioral impairments in social cognition., (© 2023. The Author(s).)

Introduction: Healthy diet has been shown to alter brain structure and function and improve cognitive performance, and prior work from our group showed that Mediterranean diet (MeDi) moderates the effect of between-network resting-state functional connectivity (rsFC) on cognitive function in a cross-sectional sample of healthy adults. The current study aimed to expand on this previous work by testing whether MeDi moderates the effects of changes in between- and within-network rsFC on changes in cognitive performance over an average of 5 years., Methods: At baseline and 5-year follow up, 124 adults aged 20-80 years underwent resting state fMRI to measure connectivity within and between 10 pre-defined networks, and completed six cognitive tasks to measure each of four cognitive reference abilities (RAs): fluid reasoning (FLUID), episodic memory, processing speed and attention, and vocabulary. Participants were categorized into low, moderate, and high MeDi groups based on food frequency questionnaires (FFQs). Multivariable linear regressions were used to test relationships between MeDi, change in within- and between-network rsFC, and change in cognitive function., Results: Results showed that MeDi group significantly moderated the effects of change in overall between-network and within-network rsFC on change in memory performance. Exploratory analyses on individual networks revealed that interactions between MeDi and between-network rsFC were significant for nearly all individual networks, whereas the moderating effect of MeDi on the relationship between within-network rsFC change and memory change was limited to a subset of specific functional networks., Discussion: These findings suggest healthy diet may protect cognitive function by attenuating the negative effects of changes in connectivity over time. Further research is warranted to understand the mechanisms by which MeDi exerts its neuroprotective effects over the lifespan., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Gaynor, Varangis, Song, Gazes, Habeck, Stern and Gu.)

Objective: Greater physical activity (PA) could delay cognitive decline, yet the underlying mechanisms remain unclear. White matter hyperintensity (WMH) burden is one of the key brain pathologies that have been shown to predict faster cognitive decline at a late age. One possible pathway is that PA may help maintain cognition by mitigating the detrimental effects of brain pathologies, like WMH, on cognitive change. This study aims to examine whether PA moderates the association between WMH burden and cognitive change., Materials and Methods: This population-based longitudinal study included 198 dementia-free adults aged 20-80 years. Leisure-time physical activity (LTPA) was assessed by a self-reported questionnaire. Occupational physical activity (OPA) was a factor score measuring the physical demands of each job. Total physical activity (TPA) was operationalized as the average of z-scores of LTPA and OPA. Outcome variables included 5-year changes in global cognition and in four reference abilities (fluid reasoning, processing speed, memory, and vocabulary). Multivariable linear regression models were used to estimate the moderation effect of PA on the association between white matter hyperintensities and cognitive change, adjusting for age, sex, education, and baseline cognition., Results: Over approximately 5 years, global cognition ( p < 0.001), reasoning ( p < 0.001), speed ( p < 0.001), and memory ( p < 0.05) scores declined, and vocabulary ( p < 0.001) increased. Higher WMH burden was correlated with more decline in global cognition (Spearman's rho = -0.229, p = 0.001), reasoning (rho = -0.402, p < 0.001), and speed (rho = -0.319, p < 0.001), and less increase in vocabulary (rho = -0.316, p < 0.001). Greater TPA attenuated the association between WMH burden and changes in reasoning (β TPA^*WMH = 0.029, 95% CI = 0.006-0.052, p = 0.013), speed (β TPA^*WMH = 0.035, 95% CI = -0.004-0.065, p = 0.028), and vocabulary (β TPA^*WMH = 0.034, 95% CI = 0.004-0.065, p = 0.029). OPA seemed to be the factor that exerted a stronger moderation on the relationship between WMH burden and cognitive change., Conclusion: Physical activity may help maintain reasoning, speed, and vocabulary abilities in face of WMH burden. The cognitive reserve potential of PA warrants further examination., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Song, Gaynor, Gazes, Lee, Xu, Habeck, Stern and Gu.)

Past research suggests modifiable lifestyle factors impact structural and functional measures of brain health, as well as cognitive performance, but no study to date has tested the effect of diet on resting state functional connectivity (rsFC), and its relationship with cognition. The current study tested whether Mediterranean diet (MeDi) moderates the associations between internetwork rsFC and cognitive function. 201 cognitively intact adults 20-80 years old underwent resting state fMRI to measure rsFC among 10 networks, and completed 12 cognitive tasks assessing perceptual speed, fluid reasoning, episodic memory, and vocabulary. Food frequency questionnaires were used to categorize participants into low, moderate, and high MeDi adherence groups. Multivariable linear regressions were used to test associations between MeDi group, task performance, and internetwork rsFC. MeDi group moderated the relationship between rsFC and fluid reasoning for nine of the 10 functional networks' connectivity to all others: higher internetwork rsFC predicted lower fluid reasoning performance in the low MeDi adherence group, but not in moderate and high MeDi groups. Results suggest healthy diet may support cognitive ability despite differences in large-scale network connectivity at rest. Further research is warranted to understand how diet impacts neural processes underlying cognitive function over time., (© 2022. The Author(s).)

Current evidence on the impact of Mediterranean diet (MeDi) on white matter hyperintensity (WMH) trajectory is scarce. This study aims to examine whether greater adherence to MeDi is associated with less accumulation of WMH. This population-based longitudinal study included 183 cognitively intact adults aged 20−80 years. The MeDi score was obtained from a self-reported food frequency questionnaire; WMH was assessed by 3T MRI. Multivariable linear regression was used to estimate the effect of MeDi on WMH change. Covariates included socio-demographic factors and brain markers. Moderation effects by age, gender, and race/ethnicity were examined, followed by stratification analyses. Among all participants, WMH increased from baseline to follow-up (mean difference [follow-up-baseline] [standard deviation] = 0.31 [0.48], p < 0.001). MeDi adherence was negatively associated with the increase in WMH (β = −0.014, 95% CI = −0.026−−0.001, p = 0.034), adjusting for all covariates. The association between MeDi and WMH change was moderated by age (young group = reference, p-interaction[middle-aged × MeDi] = 0.075, p-interaction[older × MeDi] = 0.037). The association between MeDi and WMH change was observed among the young group (β = −0.035, 95% CI = −0.058−−0.013, p = 0.003), but not among other age groups. Moderation effects by gender and race/ethnicity did not reach significance. Greater adherence to MeDi was associated with a lesser increase in WMH over time. Following a healthy diet, especially at younger age, may help to maintain a healthy brain.

Cognitive Reserve (CR), according to a recent consensus definition of the NIH-funded Reserve and Resilience collaboratory, is constituted by any mechanism contributing to cognitive performance beyond, or interacting with, brain structure in the widest sense. To identity multivariate activation patterns fulfilling this postulate, we investigated a verbal Sternberg fMRI task and imaged 181 people with age coverage in the ranges 20-30 (44 participants) and 55-70 (137 participants). Beyond task performance, participants were characterized in terms of demographics, and neuropsychological assessments of vocabulary, episodic memory, perceptual speed, and abstract fluid reasoning. Participants studied an array of either one, three, or six upper-case letters for 3 s (=encoding phase), then a blank fixation screen was presented for 7 s (=maintenance phase), to be probed with a lower-case letter to which they responded with a differential button press whether the letter was part of the studied array or not (=retrieval phase). We focused on identifying maintenance-related activation patterns showing memory load increases in pattern score on an individual participant level for both age groups. We found such a pattern that increased with memory load for all but one person in the young participants ( p  < 0.001), and such a pattern for all participants in the older group ( p  < 0.001). Both patterns showed broad topographic similarities; however, relationships to task performance and neuropsychological characteristics were markedly different and point to individual differences in Cognitive Reserve. Beyond the derivation of group-level activation patterns, we also investigated the inter-subject spatial similarity of individual working memory rehearsal patterns in the older participants' group as a function of neuropsychological and task performance, education, and mean cortical thickness. Higher task accuracy and neuropsychological function was reliably associated with higher inter-subject similarity of individual-level activation patterns in older participants., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Habeck, Gazes and Stern.)

Financial decision-making (FDM) and awareness of the integrity of one's FDM abilities (or financial awareness) are both critical for preventing financial mistakes. We examined the white matter correlates of these constructs and hypothesized that the tracts connecting the temporal-frontal regions would be most strongly correlated with both FDM and financial awareness. Overall, 49 healthy older adults were included in the FDM analysis and 44 in the financial awareness analyses. The Objective Financial Competency Assessment Inventory was used to measure FDM. Financial awareness was measured by integrating metacognitive ratings into this inventory and was calculated as the degree of overconfidence or underconfidence. Diffusion tensor imaging data were processed with Tracts Constrained by Underlying Anatomy distributed as part of the FreeSurfer analytic suite, which produced average measures of fractional anisotropy and mean diffusivity in 18 white matter tracts along with the overall tract average. As expected, FDM showed the strongest negative associations with average mean diffusivity measure of the superior longitudinal fasciculus -temporal (SLFT; r = -.360, p = .011) and -parietal (r = -.351, p = .014) tracts. After adjusting for FDM, only the association between financial awareness and average mean diffusivity measure of the right SLFT (r = .310, p = .046) was significant. Overlapping white matter tracts were involved in both FDM and financial awareness. More importantly, these preliminary findings reinforce emerging literature on a unique role of right hemisphere temporal connections in supporting financial awareness., (© 2021 The Authors. Human Brain Mapping published by Wiley Periodicals LLC.)

Recent evidence suggests that being physically active can mitigate age-related white matter (WM) changes. In a randomized clinical trial, the effect of 6-month aerobic exercise (AE) or stretching/toning interventions on measures of WM microstructure (WMM) was assessed in a sample of 74 adults aged 20-67 years. Major WM pathways were reconstructed. No significant group-level change in WM tract microstructure following an AE training was observed. Without adjustment for multiple comparisons, an increase in fractional anisotropy (FA) and a decrease in mean diffusivity (MD) of the uncinate fasciculus were observed post-intervention in the AE group in comparison with the stretching group. In the AE group, a significant increase in cardiorespiratory fitness was measured but did not correlate with FA and MD change. The present results of this study are in accordance with similar studies in healthy adults that did not show significant benefit on WMM after participating in an AE program. Clinical Trial Registration: Clinicaltrials.gov identifier, NCT01179958., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Predovan, Gazes, Lee, Li, Sloan and Stern.)

Objective: The authors examined the effects of two common functional polymorphisms-brain-derived neurotrophic factor (BDNF) Val66Met and catechol- O -methyltransferase (COMT) Val158Met-on cognitive, neuropsychiatric, and motor symptoms and MRI findings in persons with frontotemporal lobar degeneration (FTLD) syndromes., Methods: The BDNF Val66Met and COMT Val158Met polymorphisms were genotyped in 174 participants with FTLD syndromes, including behavioral variant frontotemporal dementia, primary progressive aphasia, and corticobasal syndrome. Gray matter volumes and scores on the Delis-Kaplan Executive Function System, Mattis Dementia Rating Scale, Wechsler Memory Scale, and Neuropsychiatric Inventory were compared between allele groups., Results: The BDNF Met allele at position 66 was associated with a decrease in depressive symptoms (F=9.50, df=1, 136, p=0.002). The COMT Val allele at position 158 was associated with impairment of executive function (F=6.14, df=1, 76, p=0.015) and decreased bilateral volume of the head of the caudate in patients with FTLD (uncorrected voxel-level threshold of p<0.001). Neither polymorphism had a significant effect on motor function., Conclusions: These findings suggest that common functional polymorphisms likely contribute to the phenotypic variability seen in patients with FTLD syndromes. This is the first study to implicate BDNF polymorphisms in depressive symptoms in FTLD. These results also support an association between COMT polymorphisms and degeneration patterns and cognition in FTLD.

This study examined within-subject differences among three fluid abilities that decline with age: reasoning, episodic memory and processing speed, compared with vocabulary, a crystallized ability that is maintained with age. The data were obtained from the Reference Ability Neural Network (RANN) study from which 221 participants had complete behavioral data for all 12 cognitive tasks, three per ability, along with fMRI and diffusion weighted imaging data. We used fMRI task activation to guide white matter tractography, and generated mean percent signal change in the regions associated with the processing of each ability along with diffusion tensor imaging measures, fractional anisotropy (FA) and mean diffusivity (MD), for each cognitive ability. Qualitatively brain regions associated with vocabulary were more localized and lateralized to the left hemisphere whereas the fluid abilities were associated with brain activations that were more distributed across the brain and bilaterally situated. Using continuous age, we observed smaller correlations between MD and age for white matter tracts connecting brain regions associated with the vocabulary ability than that for the fluid abilities, suggesting that vocabulary white matter tracts were better maintained with age. Furthermore, after multiple comparisons correction and accounting for age, education, and sex, the mean percent signal change for episodic memory showed positive associations with behavioral performance. Overall, the vocabulary ability may be better maintained with age due to the more localized brain regions involved, which places smaller reliance on long distance white matter tracts for signal transduction. These results support the hypothesis that functional activation and white matter structures underlying the vocabulary ability contribute to the ability's greater resistance against aging., Competing Interests: Declaration of competing interest None., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: The neurophysiological mechanisms underlying cognitive dysfunction in primary hyperparathyroidism (PHPT) and the brain regions affected are not clear. We assessed neural activation during cognitive testing (matrix reasoning, paired associates, and logical memory) using functional MRI (fMRI) in 23 patients with PHPT and 23 healthy controls. A subset with PHPT was re-assessed 6 months post-parathyroidectomy (PTX)., Design: This is an observational study comparing neural activation by fMRI in patients with PHPT to normative controls. Postmenopausal women were studied at a tertiary referral center., Results: There were no between-group differences in cognitive task performance. Patients with PHPT had lower neural activation vs controls (max Z = 4.02, all P < 0.01) during matrix reasoning in brain regions involved in executive function (left frontal lobe (k = 57) and right medial frontal gyrus (k = 72)) and motor function (right precentral gyrus (k = 51)). During paired associates (verbal memory), those with PHPT had greater activation in the right inferior parietal lobule (language/mathematical operations; k = 65, P < 0.01). Greater activation in this region bilaterally correlated with higher PTH (k = 96, P < 0.01). Post-PTX, activation decreased during matrix reasoning, but in different regions than those affected pre-PTX., Conclusions: PHPT is associated with differences in task-related neural activation patterns, but no difference in cognitive performance. While this may indicate compensation to maintain the same cognitive function, there was no clear improvement in neural activation after PTX. Larger, longitudinal studies that include PHPT patients followed without surgery are needed to determine if PTX could prevent worsening of altered neural activation patterns in PHPT.

Early-life education (years of schooling) has been investigated in regards to cognition, health outcomes and mortality. It has been shown to confer cognitive reserve that might lessen the impact of brain pathology and its impact on cognitive and motor functioning in a variety of neurodegenerative diseases and, for instance, to influence electrical activity [Begum, T., Reza, F., Ahmed, I., & Abdullah, J. M. (2014). Influence of education level on design-induced N170 and P300 components of event related potentials in the human brain. J Integr Neurosci, 13(1), 71-88. doi:10.1142/S0219635214500058]. On the other hand, demonstrations of a direct association between education and brain-structural measures have been more equivocal and scant. The current study sought to identify univariate cortical-thickness patterns underlying education and general intelligence after adjusting for age, gender and possible in-scanner movement in 353 individuals aged 40 to 80. We followed up this idea with multivariate analyses as well. For univariate analyses, our analyses yielded no robust associations between education and general intelligence beyond confounding effects of gender, age and extraneous in-scanner movement. A subsequent multivariate analyses showed a relationship between education and regional cortical thickness with a robust pattern of negative as well as positive loadings in several right-sided brain areas, speaking to a subtle but robust distributed effect of education on cortical thickness. Cortical thickness variance that is the residual of this education-related pattern was shown to be positively associated with age and extraneous in-scanner movement. Our study thus presents a complex picture of the association of education with regional cortical thickness: education was associated with a distributed brain-wide pattern of positive as well as negative loadings with unaccounted residuals being larger for older participants. Focal regional associations beyond demographic and age covariates were not identified., Competing Interests: The authors have declared that no competing interests exist.

A key challenge in the field of cognitive neuroscience is to identify discriminable cognitive functions, and then map these functions to brain activity. In the current study, we set out to explore the relationships between performance arising from different cognitive tasks thought to tap different domains of cognition, and then to test whether these distinct latent cognitive abilities also are subserved by corresponding "latent" brain substrates. To this end, we tested a large sample of adults under the age of 40 on twelve cognitive tasks as they underwent fMRI scanning. Exploratory factor analysis revealed 4-factor model, dissociating tasks into processes corresponding to episodic memory retrieval, reasoning, speed of processing and vocabulary. An analysis of the topographic covariance patterns of the BOLD-response acquired during each task similarity also converged on four neural networks that corresponded to the 4 latent factors. These results suggest that distinct ontologies of cognition are subserved by corresponding distinct neural networks., Competing Interests: The authors have declared that no competing interests exist.

Background: There are currently no disease-targeted treatments for cognitive or behavioral symptoms in patients with behavioral variant frontotemporal dementia (bvFTD)., Objective: To determine the effect of tolcapone, a specific inhibitor of Catechol-O-Methyltransferase (COMT), in patients with bvFTD., Methods: In this randomized, double-blind, placebo-controlled, cross-over study at two study sites, we examined the effect of tolcapone on 28 adult outpatients with bvFTD. The primary outcome was reaction time on the N-back cognitive test. As an imaging outcome, we examined differences in the resting blood oxygen level dependent (BOLD) functional magnetic resonance imaging (fMRI) signal intensity between subjects on placebo versus tolcapone performing the N-back test. Secondary outcomes included measures of cognitive performance and behavioral disturbance using the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS), Neuropsychiatric Inventory-Questionnaire (NPI-Q), and Clinical Global Impressions scale (CGI)., Results: Tolcapone was well tolerated and no patients dropped out. The most frequent treatment-related adverse event during tolcapone treatment was elevated liver enzymes (21%). There were no significant differences between tolcapone treatment and placebo in the primary or imaging outcomes. However, there were significant differences between RBANS total scores (p < 0.01), NPI-Q total scores (p = 0.04), and CGI total scores (p = 0.035) between treatment conditions which were driven by differences between baseline and tolcapone conditions. Further, there was a trend toward significance between tolcapone and placebo on the CGI (p = 0.078)., Conclusions: Further study of COMT inhibition and related approaches with longer duration of treatment and larger sample sizes in frontotemporal lobar degeneration-spectrum disorders may be warranted.

Background: Frontotemporal dementia (FTD) is the second most common cause of early-onset neurodegenerative dementia. Several studies have focused on early imaging changes in FTD patients, but once subjects meet full criteria for FTD diagnosis, structural changes are generally widespread., Objective: This study aims to determine the earliest structural brain changes in asymptomatic MAPT MUTATION carriers., Methods: This is a cross-sectional multicenter study comparing global and regional brain volume and white matter integrity in a group of MAPT mutation preclinical carriers and controls. Participants belong to multiple generations of six families with five MAPT mutations. All participants underwent a medical examination, neuropsychological tests, genetic analysis, and a magnetic resonance scan (3T, scout, T1-weighted image followed by EPI (BOLD), MPRAGE, DTI, FLAIR, and ASL sequences)., Results: Volumes of five cortical and subcortical areas were strongly correlated with mutation status: temporal lobe (left amygdala, left temporal pole), cingulate cortex (left rostral anterior cingulate gyrus, right posterior cingulate), and the lingual gyrus in the occipital lobe. We did not find significant differences in whole brain volume, white matter hyperintensities volume, and white matter integrity using DTI analysis., Conclusion: Temporal lobe, cingulate cortex and the lingual gyrus seem to be early targets of the disease and may serve as biomarkers for FTD prior to overt symptom onset.

Background: Changes in sexual behaviors in frontotemporal dementia (FTD) are common and multifaceted, but not well characterized., Objective: To characterize changes in sexual behaviors and intimacy in FTD compared to corticobasal syndrome (CBS) and normal controls (NC), and to evaluate the neuroanatomical associations of these changes., Methods: Spouses of 30 FTD patients, 20 CBS patients, and 35 NC completed the Sexual Symptoms in Neurological Illness and Injury Questionnaire (SNIQ), which captures changes in sexual interest, inappropriate sexual behaviors, and prosocial sexual behaviors. 25 patients with FTD and 14 patients with CBS also received 18-flouorodeoxyglucose positron-emission topography (18FDG-PET) scans to determine the metabolic changes associated with these symptoms., Results: FTD patients showed a greater increase in inappropriate sexual behaviors than CBS patients [p = 0.009] and NC [p < 0.001] and a greater decrease in prosocial sexual behaviors than CBS patients [p = 0.026] and NC [p < 0.001]. Groups did not differ in change in sexual interest. Among both patient groups, the most common change was decreased prosocial sexual behaviors p < 0.01. Hypometabolism in Brodmann's Area 10 (BA10), within the right frontal pole, correlated with decreased prosocial sexual behaviors [p(FWE-corr) <0.05, k = 44]. No anatomical associations were found with other sexual changes., Conclusion: Decreased prosocial sexual behavior was associated with hypometabolism in BA 10, an area tied to social knowledge and theory of mind, supporting the idea that changes reflect social-cognitive deficits due to frontal dysfunction.

Microstructural and macrostructural white matter damage occurs frequently with aging, is associated with negative health outcomes, and can be imaged non-invasively as fractional anisotropy (FA) and white matter hyperintensities (WMH), respectively. The extent to which diminished microstructure precedes or results from macrostructural white matter damage is poorly understood. This study evaluated the hypothesis that white matter areas with normatively lower microstructure in young adults are most susceptible to develop WMH in older adults. Forty-nine younger participants (age = 25.8 ± 2.8 years) underwent diffusion-weighted imaging (DWI), and 557 older participants (age = 73.9 ± 5.7 years) underwent DWI and T2-weighted magnetic resonance imaging (MRI). In older adults, WMH had a mostly periventricular distribution with higher frequency in frontal regions. We found lower FA in areas of frank WMH compared to normal-appearing white matter (NAWM) in older adults. Then, to determine if areas of normatively lower white matter microstructure spatially overlap with areas that frequently develop macrostructural damage in older age, we created a WMH frequency map in which each voxel represented the percentage of older adults with a WMH in that voxel. We found lower normative FA in young adults with regions frequently segmented as WMH in older adults. We conclude that low white matter microstructure is observed in areas of white matter macrostructural damage, but white matter microstructure is also normatively low (i.e., at ages 20-30) in regions with high WMH frequency, prior to white matter macrostructural damage., (Copyright © 2019 Lao, Vorburger, Narkhede, Gazes, Igwe, Colón, Amarante, Guzman, Last, Habeck, Stern and Brickman.)

Both white and grey matter atrophy with age, but it is still unclear how decline in white matter relates to decline in grey matter, and how this relationship varies with age. In a group of healthy adults from 20 to 80 years old, divided into three age groups by tertiles, we cross-sectionally examined the white-to-grey matter associations in the fornix and the hippocampus, and tested if and how the fornix-to-hippocampus relationship differs across the age groups. Both structures were also tested as predictors for performance on a memory test, the Selective Reminding Task (SRT). Participants were imaged with T1-weighted magnetic resonance imaging (MRI) and diffusion-weighted imaging (DWI), from which the hippocampal volume, fractional anisotropy (FA), and mean diffusivity (MD) for the bilateral crus and body of the fornix were calculated. Our data showed that even after accounting for age, sex, and motion parameters, fornix integrity predicted hippocampal volume in the two older age groups (middle and old age) for the crus of the fornix, and only in the oldest age group for the body of the fornix. Furthermore, fornix integrity significantly predicted SRT performance, whereas hippocampal volume did not; this relationship was also observed only in the oldest age group, and absent in the two younger age groups. The age specificity of the relationships suggests that the fornix-to-hippocampus relationship only manifests once brain structures begin to atrophy in old age, and that fornix integrity is a more sensitive measure for episodic memory than is hippocampal volume.

Understanding the associations between brain biomarkers (BMs) and cognition across age is of paramount importance. Five hundred and sixty-two participants (19-80 years old, 16 mean years of education) were studied. Data from structural T1, diffusion tensor imaging, fluid-attenuated inversion recovery, and resting-state functional magnetic resonance imaging scans combined with a neuropsychological evaluation were used. More specifically, the measures of cortical, entorhinal, and parahippocampal thickness, hippocampal and striatal volume, default-mode network and fronto-parietal control network, fractional anisotropy (FA), and white matter hyperintensity (WMH) were assessed. z-Scores for three cognitive domains measuring episodic memory, executive function, and speed of processing were computed. Multiple linear regressions and interaction effects between each of the BMs and age on cognition were examined. Adjustments were made for age, sex, education, intracranial volume, and then, further, for general cognition and motion. BMs were significantly associated with cognition. Across the adult lifespan, slow speed was associated with low striatal volume, low FA, and high WMH burden. Poor executive function was associated with low FA, while poor memory was associated with high WMH burden. After adjustments, results were significant for the associations: speed-FA and WMH, memory-entorhinal thickness. There was also a significant interaction between hippocampal volume and age in memory. In age-stratified analyses, the most significant associations for the young group occurred between FA and executive function, WMH, and memory, while for the old group, between entorhinal thickness and speed, and WMH and speed, executive function. Unique sets of BMs can explain variation in specific cognitive domains across adulthood. Such results provide essential information about the neurobiology of aging., (© 2019 Wiley Periodicals, Inc.)

The concept of cognitive reserve (CR) can explain individual differences in susceptibility to cognitive or functional impairment in the presence of age or disease-related brain changes. Epidemiologic evidence indicates that CR helps maintain performance in the face of pathology across multiple cognitive domains. We therefore tried to identify a single, "task-invariant" CR network that is active during the performance of many disparate tasks. In imaging data acquired from 255 individuals age 20-80 while performing 12 different cognitive tasks, we used an iterative approach to derive a multivariate network that was expressed during the performance of all tasks, and whose degree of expression correlated with IQ, a proxy for CR. When applied to held out data or forward applied to fMRI data from an entirely different activation task, network expression correlated with IQ. Expression of the CR pattern accounted for additional variance in fluid reasoning performance over and above the influence of cortical thickness, and also moderated between cortical thickness and reasoning performance, consistent with the behavior of a CR network. The identification of a task-invariant CR network supports the idea that life experiences may result in brain processing differences that might provide reserve against age- or disease-related changes across multiple tasks., (Copyright © 2018 Elsevier Inc. All rights reserved.)

To better understand the impact of aging, along with other demographic and brain health variables, on the neural networks that support different aspects of cognitive performance, we applied a brute-force search technique based on Principal Components Analysis to derive 4 corresponding spatial covariance patterns (termed Reference Ability Neural Networks -RANNs) from a large sample of participants across the age range. 255 clinically healthy, community-dwelling adults, aged 20-77, underwent fMRI while performing 12 tasks, 3 tasks for each of the following cognitive reference abilities: Episodic Memory, Reasoning, Perceptual Speed, and Vocabulary. The derived RANNs (1) showed selective activation to their specific cognitive domain and (2) correlated with behavioral performance. Quasi out-of-sample replication with Monte-Carlo 5-fold cross validation was built into our approach, and all patterns indicated their corresponding reference ability and predicted performance in held-out data to a degree significantly greater than chance level. RANN-pattern expression for Episodic Memory, Reasoning and Vocabulary were associated selectively with age, while the pattern for Perceptual Speed showed no such age-related influences. For each participant we also looked at residual activity unaccounted for by the RANN-pattern derived for the cognitive reference ability. Higher residual activity was associated with poorer brain-structural health and older age, but -apart from Vocabulary-not with cognitive performance, indicating that older participants with worse brain-structural health might recruit alternative neural resources to maintain performance levels., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Previous DTI studies have reported associations between white matter integrity and performance on the Stroop interference task. The current study aimed to add to these studies of inhibitory control by investigating how the differences in age and in white matter integrity relate to Stroop performance, and to examine whether the effect of age on Stroop performance is mediated by white matter integrity. 179 healthy adults from 20 to 80 years old were recruited in the study. DTI data were processed through TRACULA and the mean fractional anisotropy (FA) of 18 major white matter tracts were extracted and used for statistical analysis. Correlation analysis showed a strong negative relationship between age and the Stroop interference score (I G ). Higher I G indicated better inhibitory control. Simple linear regression analyses indicated that most of the tracts showed negative relationships with age, and positive relationships with I G . Moderation effect of age on the relationship between FA and I G was tested on tracts that significantly predicted I G after multiple comparison corrections, but none of these moderations were significant. Then we tested if these tracts mediated the effect of age on I G and found significant indirect effects of age on I G through the FA of the left corticospinal tract and through the right inferior longitudinal fasciculus. Our results highlight the role of a number of major white matter tracts in the processes supporting the Stroop inhibitory performance and further pinpointed the lower white matter integrity of specific tracts as contributors to the decrease in inhibitory control ability associated with the Stroop test in older age., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Alternating between completing two simple tasks, as opposed to completing only one task, has been shown to produce costs to performance and changes to neural patterns of activity, effects which are augmented in old age. Cognitive conflict may arise from factors other than switching tasks, however. Sensorimotor congruency (whether stimulus-response mappings are the same or different for the two tasks) has been shown to behaviorally moderate switch costs in older, but not younger adults. In the current study, we used fMRI to investigate the neurobiological mechanisms of response-conflict congruency effects within a task switching paradigm in older (N=75) and younger (N=62) adults. Behaviorally, incongruency moderated age-related differences in switch costs. Neurally, switch costs were associated with greater activation in the dorsal attention network for older relative to younger adults. We also found that older adults recruited an additional set of brain areas in the ventral attention network to a greater extent than did younger adults to resolve congruency-related response-conflict. These results suggest both a network and an age-based dissociation between congruency and switch costs in task switching., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Healthy aging simultaneously affects brain structure, brain function, and cognition. These effects are often investigated in isolation ignoring any relationships between them. It is plausible that age related declines in cognitive performance are the result of age-related structural and functional changes. This straightforward idea is tested in within a conceptual research model of cognitive aging. The current study tested whether age-related declines in task-performance were explained by age-related differences in brain structure and brain function using a task-switching paradigm in 175 participants. Sixty-three young and 112 old participants underwent MRI scanning of brain structure and brain activation. The experimental task was an executive context dual task with switch costs in response time as the behavioral measure. A serial mediation model was applied voxel-wise throughout the brain testing all pathways between age group, gray matter volume, brain activation and increased switch costs, worsening performance. There were widespread age group differences in gray matter volume and brain activation. Switch costs also significantly differed by age group. There were brain regions demonstrating significant indirect effects of age group on switch costs via the pathway through gray matter volume and brain activation. These were in the bilateral precuneus, bilateral parietal cortex, the left precentral gyrus, cerebellum, fusiform, and occipital cortices. There were also significant indirect effects via the brain activation pathway after controlling for gray matter volume. These effects were in the cerebellum, occipital cortex, left precentral gyrus, bilateral supramarginal, bilateral parietal, precuneus, middle cingulate extending to medial superior frontal gyri and the left middle frontal gyri. There were no significant effects through the gray matter volume alone pathway. These results demonstrate that a large proportion of the age group effect on switch costs can be attributed to individual differences in gray matter volume and brain activation. Therefore, age-related neural effects underlying cognitive control are a complex interaction between brain structure and function. Furthermore, the analyses demonstrate the feasibility of utilizing multiple neuroimaging modalities within a conceptual research model of cognitive aging.

Objective: We examined the association of nutrient intake with microstructural white matter integrity, and the role of white matter integrity in the association between nutrient consumption and cognition., Methods: This cross-sectional analysis included 239 elderly (age ≥ 65 years) participants of a multiethnic cohort. White matter integrity was measured with fractional anisotropy (FA) from diffusion tensor magnetic resonance imaging. Nutrient patterns were derived from principal component analysis based on energy-adjusted intake of 24 selected nutrients. Generalized linear models were used to assess the association between nutrient patterns and mean FA of 26 white matter tracts. Mediation analysis was used to determine whether FA mediates the nutrient-cognition relationship. All models were adjusted for age at time of scan, gender, ethnicity, education, caloric intake, and apolipoprotein genotype., Results: Among the identified 6 nutrient patterns, 1 (nutrient pattern 6, characterized by high intakes of Ω-3 and Ω-6 polyunsaturated fatty acids and vitamin E) was positively associated with FA. Those with the highest tertile of nutrient pattern 6 score had a mean of 0.01 (p = 0.01) higher FA value than those with the lowest tertile, similar to the effect of a 10-year decrease in age (b for age = -0.001, p = 0.01). FA mediated the relationship between nutrient pattern 6 and memory, language, visuospatial and speed/executive function, and mean cognitive scores., Interpretation: Our study suggests that older adults consuming more polyunsaturated fatty acids and vitamin E rich foods had better white matter integrity, and that maintaining white matter microstructural integrity might be a mechanism for the beneficial role of diet on cognition. Ann Neurol 2016;79:1014-1025., (© 2016 American Neurological Association.)

Unlabelled: Previous studies investigating the relationship of white matter (WM) integrity to cognitive abilities and aging have either focused on a global measure or a few selected WM tracts. Ideally, contribution from all of the WM tracts should be evaluated at the same time. However, the high collinearity among WM tracts precludes systematic examination of WM tracts simultaneously without sacrificing statistical power due to stringent multiple-comparison corrections. Multivariate covariance techniques enable comprehensive simultaneous examination of all WM tracts without being penalized for high collinearity among observations., Method: In this study, Scaled Subprofile Modeling (SSM) was applied to the mean integrity of 18 major WM tracts to extract covariance patterns that optimally predicted four cognitive abilities (perceptual speed, episodic memory, fluid reasoning, and vocabulary) in 346 participants across ages 20 to 79years old. Using expression of the covariance patterns, age-independent effects of white matter integrity on cognition and the indirect effect of WM integrity on age-related differences in cognition were tested separately, but inferences from the indirect analyses were cautiously made given that cross-sectional data set was used in the analysis., Results: A separate covariance pattern was identified that significantly predicted each cognitive ability after controlling for age except for vocabulary, but the age by WM covariance pattern interaction was not significant for any of the three abilities. Furthermore, each of the patterns mediated the effect of age on the respective cognitive ability. A distinct set of WM tracts was most influential in each of the three patterns. The WM covariance pattern accounting for fluid reasoning showed the most number of influential WM tracts whereas the episodic memory pattern showed the least number., Conclusion: Specific patterns of WM tracts make significant contributions to the age-related differences in perceptual speed, episodic memory, and fluid reasoning but not vocabulary. Other measures of brain health will need to be explored to reveal the major influences on the vocabulary ability., (Copyright © 2015 Elsevier Inc. All rights reserved.)

The accumulation of amyloid-beta (Aβ) peptides, a pathologic hallmark of Alzheimer's disease, has been associated with functional alterations in cognitively normal elderly, most often in the context of episodic memory with a particular emphasis on the medial temporal lobes. The topography of Aβ deposition, however, highly overlaps with frontoparietal control (FPC) regions implicated in cognitive control/working memory. To examine Aβ-related functional alternations in the FPC regions during a working memory task, we imaged 42 young and 57 cognitively normal elderly using functional magnetic resonance imaging during a letter Sternberg task with varying load. Based on (18)F-florbetaben-positron emission tomography scan, we determined older subjects' amyloid positivity (Aβ+) status. Within brain regions commonly recruited by all subject groups during the delay period, age and Aβ deposition were independently associated with load-dependent frontoparietal hyperactivation, whereas additional compensatory Aβ-related hyperactivity was found beyond the FPC regions. The present results suggest that Aβ-related hyperactivation is not specific to the episodic memory system but occurs in the PFC regions as well., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Recent advances in neuroimaging have identified a large number of neural measures that could be involved in age-related declines in cognitive functioning. A popular method of investigating neural-cognition relations has been to determine the brain regions in which a particular neural measure is associated with the level of specific cognitive measures. Although this procedure has been informative, it ignores the strong interrelations that typically exist among the measures in each modality. An alternative approach involves investigating the number and identity of distinct dimensions within the set of neural measures and within the set of cognitive measures before examining relations between the 2 types of measures. The procedure is illustrated with data from 297 adults between 20 and 79 years of age with cortical thickness in different brain regions as the neural measures and performance on 12 cognitive tests as the cognitive measures. The results revealed that most of the relations between cortical thickness and cognition occurred at a general level corresponding to variance shared among different brain regions and among different cognitive measures. In addition, the strength of the thickness-cognition relation was substantially reduced after controlling the variation in age, which suggests that at least some of the thickness-cognition relations in age-heterogeneous samples may be attributable to the influence of age on each type of measure., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Cognitive psychologists posit several specific cognitive abilities that are measured with sets of cognitive tasks. Tasks that purportedly tap a specific underlying cognitive ability are strongly correlated with one another, whereas performances on tasks that tap different cognitive abilities are less strongly correlated. For these reasons, latent variables are often considered optimal for describing individual differences in cognitive abilities. Although latent variables cannot be directly observed, all cognitive tasks representing a specific latent ability should have a common neural underpinning. Here, we show that cognitive tasks representing one ability (i.e., either perceptual speed or fluid reasoning) had a neural activation pattern distinct from that of tasks in the other ability. One hundred six participants between the ages of 20 and 77 years were imaged in an fMRI scanner while performing six cognitive tasks, three representing each cognitive ability. Consistent with prior research, behavioral performance on these six tasks clustered into the two abilities based on their patterns of individual differences and tasks postulated to represent one ability showed higher similarity across individuals than tasks postulated to represent a different ability. This finding was extended in the current report to the spatial resemblance of the task-related activation patterns: The topographic similarity of the mean activation maps for tasks postulated to reflect the same reference ability was higher than for tasks postulated to reflect a different reference ability. Furthermore, for any task pairing, behavioral and topographic similarities of underlying activation patterns are strongly linked. These findings suggest that differences in the strengths of correlations between various cognitive tasks may be because of the degree of overlap in the neural structures that are active when the tasks are being performed. Thus, the latent variable postulated to account for correlations at a behavioral level may reflect topographic similarities in the neural activation across different brain regions.

Introduction: A functional activation (i.e., ordinal trend) pattern was previously identified in both young and older adults during task-switching performance, the expression of which correlated with reaction time. The current study aimed to (1) replicate this functional activation pattern in a new group of fMRI activation data, and (2) extend the previous study by specifically examining whether the effect of aging on reaction time can be explained by differences in the activation of the functional activation pattern., Method: A total of 47 young and 50 older participants were included in the extension analysis. Participants performed task-switching as the activation task and were cued by the color of the stimulus for the task to be performed in each block. To test for replication, two approaches were implemented. The first approach tested the replicability of the predictive power of the previously identified functional activation pattern by forward applying the pattern to the Study II data and the second approach was rederivation of the activation pattern in the Study II data., Results: Both approaches showed successful replication in the new data set. Using mediation analysis, expression of the pattern from the first approach was found to partially mediate age-related effects on reaction time such that older age was associated with greater activation of the brain pattern and longer reaction time, suggesting that brain activation efficiency (defined as "the rate of activation increase with increasing task difficulty" in Neuropsychologia 47, 2009, 2015) of the regions in the Ordinal trend pattern directly accounts for age-related differences in task performance., Discussion: The successful replication of the functional activation pattern demonstrates the versatility of the Ordinal Trend Canonical Variates Analysis, and the ability to summarize each participant's brain activation map into one number provides a useful metric in multimodal analysis as well as cross-study comparisons.

We introduce and describe the Reference Ability Neural Network Study and provide initial feasibility data. Based on analyses of large test batteries administered to individuals ranging from young to old, four latent variables, or reference abilities (RAs) that capture the majority of the variance in age-related cognitive change have been identified: episodic memory, fluid reasoning, perceptual speed, and vocabulary. We aim to determine whether spatial fMRI networks can be derived that are uniquely associated with the performance of each reference ability. We plan to image 375 healthy adults (50 per decade from age 20 to 50; 75 per decade from age 50 to 80) while performing a set of 12 cognitive tasks. Data on 174 participants are reported here. Three tasks were grouped a priori into each of the four reference ability domains. We first assessed to what extent both cognitive task scores and activation patterns readily show convergent and discriminant validity, i.e. increased similarity between tasks within the same domain and decreased similarity between tasks between domains, respectively. Block-based time-series analysis of each individual task was conducted for each participant via general linear modeling. We partialled activation common to all tasks out of the imaging data. For both test scores and activation topographies, we then calculated correlations for each of 66 possible pairings of tasks, and compared the magnitude of correlation of tasks within reference ability domains to that of tasks between domains. For the behavioral data, globally there were significantly stronger inter-task correlations within than between domains. When examining individual abilities, 3 of the domains also met these criteria but memory reached only borderline significance. Overall there was greater topographic similarity within reference abilities than between them (p<0.0001), but when examined individually, statistical significance was reached only for episodic memory and perceptual speed. We then turned to a multivariate technique, linear indicator regression analysis, to derive four unique linear combinations of Principal Components (PC) of imaging data that were associated with each RA. We investigated the ability of the identified PCs to predict the reference domain associated with the activation of individual subjects for individual tasks. Median accuracy rates for associating component task activation with a particular reference ability were quite good: memory: 82%; reasoning: 87%; speed: 84%; vocabulary: 77%. These results demonstrate that even using basic GLM analysis, the topography of activation of tasks within a domain is more similar than tasks between domains. The follow-up regression analyses suggest that all tasks with each RA rely on a common network, unique to that RA. Our ultimate goal is to better characterize these RA neural networks and then study how their expression changes across the age span. Our hope is that by focusing on these networks associated with key features of cognitive aging, as opposed to task-related activation associated with individual tasks, we will be able to advance our knowledge regarding the key brain changes that underlie cognitive aging., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Cognition is important for locomotion and gait decline increases the risk for morbidity, mortality, cognitive decline, and dementia. Yet, the neural correlates of gait are not well established, because most neuroimaging methods cannot image the brain during locomotion. Imagined gait protocols overcome this limitation. This study examined the behavioral and neural correlates of a new imagined gait protocol that involved imagined walking (iW), imagined talking (iT), and imagined walking-while-talking (iWWT). In Experiment 1, 82 cognitively-healthy older adults (M=80.45) walked (W), iW, walked while talking (WWT) and iWWT. Real and imagined walking task times were strongly correlated, particularly real and imagined dual-task times (WWT and iWWT). In Experiment 2, 33 cognitively-healthy older adults (M=73.03) iW, iT, and iWWT during functional magnetic resonance imaging. A multivariate Ordinal Trend (OrT) Covariance analysis identified a pattern of brain regions that: (1) varied as a function of imagery task difficulty (iW, iT and iWWT), (2) involved cerebellar, precuneus, supplementary motor and other prefrontal regions, and (3) were associated with kinesthetic imagery ratings and behavioral performance during actual WWT. This is the first study to compare the behavioral and neural correlates of imagined gait in single and dual-task situations, an issue that is particularly relevant to elderly populations. These initial findings encourage further research and development of this imagined gait protocol as a tool for improving gait and cognition among the elderly., (Copyright © 2014 Wiley Periodicals, Inc.)

Background: Disruption of the default-mode network (DMN) in healthy elders has been reported in many studies., Methods: In a group of 51 participants (25 young, 26 elder) we examined DMN connectivity in subjects' native space. In the native space method, subject-specific regional masks (obtained independently for each subject) are used to extract regional fMRI times series. This approach substitutes the spatial normalization and subsequent smoothing used in prevailing methods, affords more accurate spatial localization, and provides the power to examine connectivity separately in the two hemispheres instead of averaging regions across hemispheres., Results: The native space method yielded new findings which were not detectable by the prevailing methods. The most reliable and robust disruption in elders' DMN connectivity were found between supramarginal gyrus and superior-frontal cortex in the right hemisphere only. The mean correlation between these two regions in young participants was about 0.5, and dropped significantly to 0.04 in elders (P = 2.1 × 10(-5)). In addition, the magnitude of functional connectivity between these regions in the right hemisphere correlated with memory (P = 0.05) and general fluid ability (P = 0.01) in elder participants and with speed of processing in young participants (P = 0.008). These relationships were not observed in the left hemisphere., Conclusion: These findings suggest that analysis of DMN connectivity in subjects' native space can improve localization and power and that it is important to examine connectivity separately in each hemisphere.

The aim of this study was to investigate findings of positron emission tomography with 18F-fluorodeoxyglucose (18F-FDG PET) in normal subjects to clarify the effects of sex differences, aging, and cognitive reserve on cerebral glucose metabolism. Participants comprised 123 normal adults who underwent 18F-FDG PET and a neuropsychological battery. We used statistical parametric mapping (SPM8) to investigate sex differences, and aging effects. The effects of cognitive reserve on 18F-FDG uptake were investigated using years of education as a proxy. Finally, we studied the effect of cognitive reserve on the recruitment of glucose metabolism in a memory task by dichotomizing the data according to educational level. Our results showed that the overall cerebral glucose metabolism in females was higher than that in males, whereas male participants had higher glucose metabolism in the bilateral inferior temporal gyri and cerebellum than females. Age-related hypometabolism was found in anterior regions, including the anterior cingulate gyrus. These areas are part of the attentional system, which may decline with aging even in healthy elderly individuals. Highly educated subjects revealed focal hypermetabolism in the right hemisphere and lower recruitment of glucose metabolism in memory tasks. This phenomenon is likely a candidate for a neural substrate of cognitive reserve., (© 2013 Published by Elsevier Ireland Ltd.)

The effect of aging on functional network activation associated with task-switching was examined in 24 young (age=25.2±2.73 years) and 23 older adults (age=65.2±2.65 years) using functional magnetic resonance imaging (fMRI). The study goals were to (1) identify a network shared by both young and older adults, (2) identify additional networks in each age group, and (3) examine the relationship between the networks identified and behavioral performance in task-switching. Ordinal trend covariance analysis was used to identify the networks, which takes advantage of increasing activation with greater task demand to isolate the network of regions recruited by task-switching. Two task-related networks were found: a shared network that was strongly expressed by both young and older adults and a second network identified in the young data that was residualized from the shared network. Both networks consisted of regions associated with task-switching in previous studies including the middle frontal gyrus, the precentral gyrus, the anterior cingulate, and the superior parietal lobule. Not only was pattern expression of the shared network associated with reaction time in both age groups, the difference in the pattern expression across task conditions (task-switch minus single-task) was also correlated with the difference in RT across task conditions. On the contrary, expression of the young-residual network showed a large age effect such that older adults do not increase expression of the network with greater task demand as young adults do and correlation between expression and accuracy was significant only for young adults. Thus, while a network related to RT is preserved in older adults, a different network related to accuracy is disrupted., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Effects of dual-responding on tracking performance after 49-h of sleep deprivation (SD) were evaluated behaviorally and with functional magnetic resonance imaging (fMRI). Continuous visuomotor tracking was performed simultaneously with an intermittent color-matching visual detection task in which a pair of color-matched stimuli constituted a target and non-matches were non-targets. Tracking error means were binned time-locked to stimulus onset of the detection task in order to observe changes associated with dual-responding by comparing the error during targets and non-targets. Similar comparison was made with fMRI data. Our result showed that despite a significant increase in the overall tracking error post SD, from 20 pixels pre SD to 45 pixels post SD, error decreased to a minimum of about 25 pixels 0-6s after dual-response. Despite an overall reduced activation post SD, greater activation difference between targets and non-targets was found post SD in task-related regions, such as the left cerebellum, the left somatosensory cortex, the left extrastriate cortex, bilateral precuneus, the left middle frontal gyrus, and the left motor cortex. Our results suggest that dual-response helps to alleviate performance impairment usually associated with SD. The duration of the alleviation effect was on the order of seconds after dual-responding., (Copyright © 2012 Elsevier Inc. All rights reserved.)