KIBRA single nucleotide polymorphism is associated with hippocampal subfield volumes and cognition across development.

The hippocampus (Hc) consists of cytoarchitectonically and functionally distinct subfields: dentate gyrus (DG), cornu ammonis (CA1-3), and subiculum. In adults, a single nucleotide polymorphism (rs17070145, C→ T) in KIBRA, a gene encoding the eponymous (KIdney-BRAin) protein, is associated with variability in Hc subfield volumes and episodic memory. T-allele carriers have larger DG and CA volumes and better episodic memory compared to C-homozygotes. Little is known, however, about KIBRA's role in the development of the brain and cognition. In a sample of children, adolescents, and young adults (N = 176, ages 5- 25 years), we replicated the adult association between KIBRA T-allele and larger DG and CA volumes but observed no relationship between KIBRA rs17070145 polymorphism and episodic memory. We noted, however, that a general cognitive performance index (IQ) differed across the allelic groups, with the lowest scores among T-homozygotes and the highest among C-homozygotes. Thus, in this developmental sample, KIBRA appears to have opposing effects on regional brain volume and cognition. These influences of KIBRA SNP may stem from associations between developmental reduction in brain volume and gains in cognitive performance-a hypothesis to be tested in longitudinal studies.

Age-related differences in hippocampal subfield volumes across the human lifespan: A meta-analysis.

The human hippocampus (Hc) is critical for memory function across the lifespan. It is comprised of cytoarchitectonically distinct subfields: dentate gyrus (DG), cornu ammonis sectors (CA) 1-4, and subiculum, each of which may be differentially susceptible to neurodevelopmental and neurodegenerative mechanisms. Identifying age-related differences in Hc subfield volumes can provide insights into neural mechanisms of memory function across the lifespan. Limited evidence suggests that DG and CA3 volumes differ across development while other regions remain relatively stable, and studies of adulthood implicate a downward trend in all subfield volumes with prominent age effects on CA1. Due to differences in methods and limited sampling for any single study, the magnitude of age effects on Hc subfield volumes and their probable lifespan trajectories remain unclear. Here, we conducted a meta-analysis on cross-sectional studies (n = 48,278 participants, ages = 4-94 years) to examine the association between age and Hc subfield volumes in development (n = 11 studies), adulthood (n = 30 studies), and a combined lifespan sample (n = 41 studies) while adjusting estimates for sample sizes. In development, age was positively associated with DG and CA3-4 volumes, whereas in adulthood a negative association was observed with all subfield volumes. Notably, the observed age effects were not different across subfield volumes within each age group. All subfield volumes showed a nonlinear age pattern across the lifespan with DG and CA3-4 volumes showing a more distinct age trajectory as compared to the other subfields. Lastly, among all the study-level variables, only female percentage of the study sample moderated the age effect on CA1 volume: a higher female-to-male ratio in the study sample was linked to the greater negative association between age and CA1 volume. These results document that Hc subfield volumes differ as a function of age offering broader implications for constructing theoretical models of lifespan memory development.

Development and validation of a quality control procedure for automatic segmentation of hippocampal subfields.

Automatic segmentation methods for in vivo magnetic resonance imaging are increasing in popularity because of their high efficiency and reproducibility. However, automatic methods can be perfectly reliable and consistently wrong, and the validity of automatic segmentation methods cannot be taken for granted. Quality control (QC) by trained and reliable human raters is necessary to ensure the validity of automatic measurements. Yet QC practices for applied neuroimaging research are underdeveloped. We report a detailed QC and correction procedure to accompany our validated atlas for hippocampal subfield segmentation. We document a two-step QC procedure for identifying segmentation errors, along with a taxonomy of errors and an error severity rating scale. This detailed procedure has high between-rater reliability for error identification and manual correction. The latter introduces at maximum 3% error variance in volume measurement. All procedures were cross-validated on an independent sample collected at a second site with different imaging parameters. The analysis of error frequency revealed no evidence of bias. An independent rater with a third sample replicated procedures with high within-rater reliability for error identification and correction. We provide recommendations for implementing the described method along with hypothesis testing strategies. In sum, we present a detailed QC procedure that is optimized for efficiency while prioritizing measurement validity and suits any automatic atlas.

Instructing Use of an Effective Strategy Improves Recognition Memory in Healthy Adults.

OBJECTIVES: Age-related memory decrements correlate with metacognitive declines, including knowledge and deployment of effective mnemonic encoding strategies. However, whether imparting such strategy suffices for mitigating memory differences is unclear. METHOD: In a longitudinal study of 276 healthy adults aged 18-79 years, we tested associative and working memory, and assessed beliefs regarding mnemonic strategies. Testing was repeated every 2 years, 5 times. Starting with the third occasion, we instructed participants to use an effective mnemonic strategy (sentence generation). Using continuous-time dynamic modeling, we assessed changes in the item and associative recognition, intervention effects, and their relations with age, sex, meta-memory beliefs, working memory, and metabolic health. RESULTS: Younger age, better working memory, and stronger belief in effective mnemonic strategies predicted better recognition, whereas instructional intervention attenuated associative memory deficits, with some persistence over time. DISCUSSION: The present findings show merely imparting effective strategies holds promise for mitigating age-related associative memory deficits.

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

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

Test-retest and repositioning effects of white matter microstructure measurements in selected white matter tracts.

We used intra-class effect decomposition (ICED) to evaluate the reliability of myelin water fraction (MWF) and geometric mean T2 relaxation time (geomT2IEW) estimated from a multi-echo MRI sequence. Our evaluation addressed test-retest reliability, with and without participant re-positioning, for seven commonly assessed white matter tracts: anterior and posterior limbs of the internal capsule, dorsal and ventral branches of the cingulum, the inferior fronto-occipital fasciculus, the superior longitudinal fasciculus, and the fornix in 20 healthy adults. We acquired two back-to-back scans in a single session, and a third after a break and repositioning the participant in the scanner. For both indices and for all white matter tracts assessed, reliability for an immediate retest, and after the participant's repositioning in the scanner was high. Variance partitioning revealed that in addition to measurement noise, which was significant in all regions, repositioning contributed to unreliability mainly in longer association fibers. Hemispheric location did not significantly contribute to unreliability in any region of interest (ROI). Thus, despite non-negligible error of measurement, for all ROIs, MWF and geomT2IEW have good test-retest reliability, regardless of the hemispheric location and are, therefore, suitable for longitudinal investigations in healthy adults.

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

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

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

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

Hippocampal subfield volumetry from structural isotropic 1 mm3 MRI scans: A note of caution.

Spurred by availability of automatic segmentation software, in vivo MRI investigations of human hippocampal subfield volumes have proliferated in the recent years. However, a majority of these studies apply automatic segmentation to MRI scans with approximately 1 × 1 × 1 mm3 resolution, a resolution at which the internal structure of the hippocampus can rarely be visualized. Many of these studies have reported contradictory and often neurobiologically surprising results pertaining to the involvement of hippocampal subfields in normal brain function, aging, and disease. In this commentary, we first outline our concerns regarding the utility and validity of subfield segmentation on 1 × 1 × 1 mm3 MRI for volumetric studies, regardless of how images are segmented (i.e., manually or automatically). This image resolution is generally insufficient for visualizing the internal structure of the hippocampus, particularly the stratum radiatum lacunosum moleculare, which is crucial for valid and reliable subfield segmentation. Second, we discuss the fact that automatic methods that are employed most frequently to obtain hippocampal subfield volumes from 1 × 1 × 1 mm3 MRI have not been validated against manual segmentation on such images. For these reasons, we caution against using volumetric measurements of hippocampal subfields obtained from 1 × 1 × 1 mm3 images.

Microstructure of Human Corpus Callosum across the Lifespan: Regional Variations in Axon Caliber, Density, and Myelin Content.

The myeloarchitecture of the corpus callosum (CC) is characterized as a mosaic of distinct differences in fiber density of small- and large-diameter axons along the anterior-posterior axis; however, regional and age differences across the lifespan are not fully understood. Using multiecho T2 magnetic resonance imaging combined with multi-T2 fitting, the myelin water fraction (MWF) and geometric-mean of the intra-/extracellular water T2 (geomT2IEW) in 395 individuals (7-85 years; 41% males) were examined. The approach was validated where regional patterns along the CC closely resembled the histology; MWF matched mean axon diameter and geomT2IEW mirrored the density of large-caliber axons. Across the lifespan, MWF exhibited a quadratic association with age in all 10 CC regions with evidence of a positive linear MWF-age relationship among younger participants and minimal age differences in the remainder of the lifespan. Regarding geomT2IEW, a significant linear age × region interaction reflected positive linear age dependence mostly prominent in the regions with the highest density of small-caliber fibers-genu and splenium. In all, these two indicators characterize distinct attributes that are consistent with histology, which is a first. In addition, these results conform to rapid developmental progression of CC myelination leveling in middle age as well as age-related degradation of axon sheaths in older adults.

Age-related decline in executive function as a hallmark of cognitive ageing in primates: an overview of cognitive and neurobiological studies.

Executive function (EF) is a complex construct that reflects multiple higher-order cognitive processes such as planning, updating, inhibiting and set-shifting. Decline in these functions is a hallmark of cognitive ageing in humans, and age differences and changes in EF correlate with age-related differences and changes in association cortices, particularly the prefrontal areas. Here, we review evidence for age-related decline in EF and associated neurobiological changes in prosimians, New World and Old World monkeys, apes and humans. While EF declines with age in all primate species studied, the relationship of this decline with age-related alterations in the prefrontal cortex remains unclear, owing to the scarcity of neurobiological studies focusing on the ageing brain in most primate species. In addition, the influence of sex, vascular and metabolic risk, and hormonal status has rarely been considered. We outline several methodological limitations and challenges with the goal of producing a comprehensive integration of cognitive and neurobiological data across species and elucidating how ageing shapes neurocognitive trajectories in primates with different life histories, lifespans and brain architectures. Such comparative investigations are critical for fostering translational research and understanding healthy and pathological ageing in our own species. This article is part of the theme issue 'Evolution of the primate ageing process'.

Poor glucose regulation is associated with declines in well-being among older men, but not women.

Glucose regulation is a key aspect of healthy aging and has been linked to brain functioning and cognition. Here we examined the role of glucose regulation for within-person longitudinal trajectories of well-being. We applied growth models to data from the Berlin Aging Study II (N = 955), using insulin resistance as an index of glucoregulatory capacity. We found that poor glucose regulation (higher insulin resistance) was consistently associated with lower levels of well-being among older men but not women. Our study provides novel evidence for the relevance of glucose regulation for well-being among older men. (PsycINFO Database Record (c) 2020 APA, all rights reserved).

White-matter microstructural properties of the corpus callosum: test-retest and repositioning effects in two parcellation schemes.

We investigated test-retest reliability of two MRI-derived indices of white-matter microstructural properties in the human corpus callosum (CC): myelin water fraction (MWF) and geometric mean T2 relaxation time of intra/extracellular water (geomT2IEW), using a 3D gradient and multi spin-echo sequence in 20 healthy adults (aged 24-69 years, 10 men). For each person, we acquired two back-to-back acquisitions in a single session, and the third after a break and repositioning the participant in the scanner. We assessed the contribution of session-related variance to reliability, using intra-class effect decomposition (ICED) while comparing two CC parcellation schemes that divided the CC into five and ten regions. We found high construct-level reliability of MWF and geomT2IEW in all regions of both schemes, except the posterior body-a slender region with a smaller number of large myelinated fibers. Only in that region, we observed significant session-specific variance in the MWF, interpreted as an effect of repositioning in the scanner. The geomT2IEW demonstrated higher reliability than MWF across both parcellation schemes and all CC regions. Thus, in both CC parcellation approaches, MWF and geomT2IEW have good test-retest reliability and are, therefore, suitable for longitudinal investigations in healthy adults. However, the five-region scheme appears more appropriate for MWF, whereas both schemes are suitable for geomT2IEW studies. Given the lower reliability in the posterior body, which may reflect sensitivity to the repositioning of the participant in the scanner, caution should be exercised in interpreting differential findings in that region.

Brain reserve, cognitive reserve, compensation, and maintenance: operationalization, validity, and mechanisms of cognitive resilience.

Significant individual differences in the trajectories of cognitive aging and in age-related changes of brain structure and function have been reported in the past half-century. In some individuals, significant pathological changes in the brain are observed in conjunction with relatively well-preserved cognitive performance. Multiple constructs have been invoked to explain this paradox of resilience, including brain reserve, cognitive reserve, brain maintenance, and compensation. The aim of this session of the Cognitive Aging Summit III was to examine the overlap and distinctions in definitions and measurement of these constructs, to discuss their neural and behavioral correlates and to propose plausible mechanisms of individual cognitive resilience in the face of typical age-related neural declines.

Metabolic risk affects fluid intelligence changes in healthy adults.

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

Progress update from the hippocampal subfields group.

INTRODUCTION: Heterogeneity of segmentation protocols for medial temporal lobe regions and hippocampal subfields on in vivo magnetic resonance imaging hinders the ability to integrate findings across studies. We aim to develop a harmonized protocol based on expert consensus and histological evidence. METHODS: Our international working group, funded by the EU Joint Programme-Neurodegenerative Disease Research (JPND), is working toward the production of a reliable, validated, harmonized protocol for segmentation of medial temporal lobe regions. The working group uses a novel postmortem data set and online consensus procedures to ensure validity and facilitate adoption. RESULTS: This progress report describes the initial results and milestones that we have achieved to date, including the development of a draft protocol and results from the initial reliability tests and consensus procedures. DISCUSSION: A harmonized protocol will enable the standardization of segmentation methods across laboratories interested in medial temporal lobe research worldwide.

Assessing reliability in neuroimaging research through intra-class effect decomposition (ICED).

Magnetic resonance imaging has become an indispensable tool for studying associations of structural and functional properties of the brain with behavior in humans. However, generally recognized standards for assessing and reporting the reliability of these techniques are still lacking. Here, we introduce a new approach for assessing and reporting reliability, termed intra-class effect decomposition (ICED). ICED uses structural equation modeling of data from a repeated-measures design to decompose reliability into orthogonal sources of measurement error that are associated with different characteristics of the measurements, for example, session, day, or scanning site. This allows researchers to describe the magnitude of different error components, make inferences about error sources, and inform them in planning future studies. We apply ICED to published measurements of myelin content and resting state functional connectivity. These examples illustrate how longitudinal data can be leveraged separately or conjointly with cross-sectional data to obtain more precise estimates of reliability.

Functional Magnetic Resonance Spectroscopy: The "New" MRS for Cognitive Neuroscience and Psychiatry Research.

Proton magnetic resonance spectroscopy (1H MRS) is a well-established technique for quantifying the brain regional biochemistry in vivo. In most studies, however, the 1H MRS is acquired during rest with little to no constraint on behavior. Measured metabolite levels, therefore, reflect steady-state concentrations whose associations with behavior and cognition are unclear. With the recent advances in MR technology-higher-field MR systems, robust acquisition techniques and sophisticated quantification methods-1H MRS is now experiencing a resurgence. It is sensitive to task-related and pathology-relevant regional dynamic changes in neurotransmitters, including the most ubiquitous among them, glutamate. Moreover, high temporal resolution approaches allow tracking glutamate modulations at a time scale of under a minute during perceptual, motor, and cognitive tasks. The observed task-related changes in brain glutamate are consistent with new metabolic steady states reflecting the neural output driven by shifts in the local excitatory and inhibitory balance on local circuits. Unlike blood oxygen level differences-base functional MRI, this form of in vivo MRS, also known as functional MRS (1H fMRS), yields a more direct measure of behaviorally relevant neural activity and is considerably less sensitive to vascular changes. 1H fMRS enables noninvasive investigations of task-related glutamate changes that are relevant to normal and impaired cognitive performance, and psychiatric disorders. By targeting brain glutamate, this approach taps into putative neural correlates of synaptic plasticity. This review provides a concise survey of recent technological advancements that lay the foundation for the successful use of 1H fMRS in cognitive neuroscience and neuropsychiatry, including a review of seminal 1H fMRS studies, and the discussion of biological significance of task-related changes in glutamate modulation. We conclude with a discussion of the promises, limitations, and outstanding challenges of this new tool in the armamentarium of cognitive neuroscience and psychiatry research.

Fluid intelligence and gross structural properties of the cerebral cortex in middle-aged and older adults: A multi-occasion longitudinal study.

According to Parieto-Frontal Integration Theory (P-FIT, Jung and Haier, 2007), individual differences in a circumscribed set of brain regions account for variations in general intelligence (g). The components of g, fluid (Gf) and crystallized (Gc) reasoning, exhibit distinct trajectories of age-related change. Because the brain also ages differentially, we hypothesized that age-related cognitive and neural changes would be coupled. In a sample of healthy middle-aged and older adults, we examined changes in Gf (operationalized by Cattell Culture Fair Test) and Gc (indexed by two vocabulary tests) as well as in structural properties of 19 brain regions. We fitted linear mixed models to the data collected on 73 healthy adults who participated in baseline assessment, with 43 returning for at least one follow-up, and 16 of them contributing four repeated assessments over seven years. We observed age differences as well as longitudinal decline in Gf, contrasted to a lack of age differences and stability in Gc. Cortical thickness and cortical volume exhibited significant age differences and longitudinal declines, which were accelerated in P-FIT regions. Gf (but not Gc) was associated with cortical thickness, but no such relationship was found for cortical volume. Uniformity of cognitive change (lack of reliable individual differences) precluded examination of the coupling between cognitive and brain changes. Cortical shrinkage was greater in high-Gc individuals, whereas in participants with higher Gf cortical volume slower volume shrinkage was observed.

Pathways to Brain Aging and Their Modifiers: Free-Radical-Induced Energetic and Neural Decline in Senescence (FRIENDS) Model - A Mini-Review.

In this mini-review, we survey the extant literature on brain aging, with the emphasis on longitudinal studies of neuroanatomy, including regional brain volumes and white matter microstructure. We assess the impact of vascular, metabolic, and inflammatory risk factors on the trajectories of change in regional brain volumes and white matter properties, as well as the relationships between neuroanatomical and physiological changes and their influence on cognitive performance. We examine these findings in the context of current biological theories of aging and propose the means of integrating noninvasive measures - spectroscopic indices of brain energy metabolism and regional iron deposits - as valuable proxies for elucidating the basic neurobiology of human brain aging. In a brief summary of the recent findings pertaining to age-related changes in the brain structure and their impact on cognition, we discuss the role of vascular, metabolic, and inflammatory risk factors in shaping the trajectories of change. Drawing on the extant biological theories of aging and mindful of the brain's role as a disproportionately voracious energy consumer in mammals, we emphasize the importance of the fundamental bioenergetic mechanisms as drivers of age-related changes in brain structure and function. We sketch out a model that builds on the conceptualization of aging as an expression of cumulative cellular damage inflicted by reactive oxygen species and ensuing declines in energy metabolism. We outline the ways and means of adapting this model, Free-Radical-Induced Energetic and Neural Decline in Senescence (FRIENDS), to human aging and testing it within the constraints of noninvasive neuroimaging.