Relationships between apparent cortical thickness and working memory across the lifespan - Effects of genetics and socioeconomic status.

Working memory (WM) supports several higher-level cognitive abilities, yet we know less about factors associated with development and decline in WM compared to other cognitive processes. Here, we investigated lifespan changes in WM capacity and their structural brain correlates, using a longitudinal sample including 2358 magnetic resonance imaging (MRI) scans and WM scores from 1656 participants (4.4-86.4 years, mean follow-up interval 4.3 years). 8764 participants (9.0-10.9 years) with MRI, WM scores and genetic information from the Adolescent Brain Cognitive Development study were used for follow-up analyses. Results showed that both the information manipulation component and the storage component of WM improved during childhood and adolescence, but the age-decline could be fully explained by reductions in passive storage capacity alone. Greater WM function in development was related to apparent thinner cortex in both samples, also when general cognitive function was accounted for. The same WM-apparent thickness relationship was found for young adults. The WM-thickness relationships could not be explained by SNP-based co-heritability or by socioeconomic status. A larger sample with genetic information may be necessary to disentangle the true gene-environment effects. In conclusion, WM capacity changes greatly through life and has anatomically extended rather than function-specific structural cortical correlates.

Reliability and sensitivity of two whole-brain segmentation approaches included in FreeSurfer - ASEG and SAMSEG.

Accurate and reliable whole-brain segmentation is critical to longitudinal neuroimaging studies. We undertake a comparative analysis of two subcortical segmentation methods, Automatic Segmentation (ASEG) and Sequence Adaptive Multimodal Segmentation (SAMSEG), recently provided in the open-source neuroimaging package FreeSurfer 7.1, with regard to reliability, bias, sensitivity to detect longitudinal change, and diagnostic sensitivity to Alzheimer's disease. First, we assess intra- and inter-scanner reliability for eight bilateral subcortical structures: amygdala, caudate, hippocampus, lateral ventricles, nucleus accumbens, pallidum, putamen and thalamus. For intra-scanner analysis we use a large sample of participants (n = 1629) distributed across the lifespan (age range = 4-93 years) and acquired on a 1.5T Siemens Avanto (n = 774) and a 3T Siemens Skyra (n = 855) scanners. For inter-scanner analysis we use a sample of 24 participants scanned on the day with three models of Siemens scanners: 1.5T Avanto, 3T Skyra and 3T Prisma. Second, we test how each method detects volumetric age change using longitudinal follow up scans (n = 491 for Avanto and n = 245 for Skyra; interscan interval = 1-10 years). Finally, we test sensitivity to clinically relevant change. We compare annual rate of hippocampal atrophy in cognitively normal older adults (n = 20), patients with mild cognitive impairment (n = 20) and Alzheimer's disease (n = 20). We find that both ASEG and SAMSEG are reliable and lead to the detection of within-person longitudinal change, although with notable differences between age-trajectories for most structures, including hippocampus and amygdala. In summary, SAMSEG yields significantly lower differences between repeated measures for intra- and inter-scanner analysis without compromising sensitivity to changes and demonstrating ability to detect clinically relevant longitudinal changes.

Self-reported sleep relates to microstructural hippocampal decline in ß-amyloid positive Adults beyond genetic risk.

STUDY OBJECTIVES: A critical role linking sleep with memory decay and ß-amyloid (Aß) accumulation, two markers of Alzheimer's disease (AD) pathology, may be played by hippocampal integrity. We tested the hypotheses that worse self-reported sleep relates to decline in memory and intra-hippocampal microstructure, including in the presence of Aß. METHODS: Two-hundred and forty-three cognitively healthy participants, aged 19-81 years, completed the Pittsburgh Sleep Quality Index once, and two diffusion tensor imaging sessions, on average 3 years apart, allowing measures of decline in intra-hippocampal microstructure as indexed by increased mean diffusivity. We measured memory decay at each imaging session using verbal delayed recall. One session of positron emission tomography, in 108 participants above 44 years of age, yielded 23 Aß positive. Genotyping enabled control for APOE ε4 status, and polygenic scores for sleep and AD, respectively. RESULTS: Worse global sleep quality and sleep efficiency related to more rapid reduction of hippocampal microstructure over time. Focusing on efficiency (the percentage of time in bed at night spent asleep), the relation was stronger in presence of Aß accumulation, and hippocampal integrity decline mediated the relation with memory decay. The results were not explained by genetic risk for sleep efficiency or AD. CONCLUSIONS: Worse sleep efficiency related to decline in hippocampal microstructure, especially in the presence of Aß accumulation, and Aß might link poor sleep and memory decay. As genetic risk did not account for the associations, poor sleep efficiency might constitute a risk marker for AD, although the driving causal mechanisms remain unknown.

Poor Self-Reported Sleep is Related to Regional Cortical Thinning in Aging but not Memory Decline-Results From the Lifebrain Consortium.

We examined whether sleep quality and quantity are associated with cortical and memory changes in cognitively healthy participants across the adult lifespan. Associations between self-reported sleep parameters (Pittsburgh Sleep Quality Index, PSQI) and longitudinal cortical change were tested using five samples from the Lifebrain consortium (n = 2205, 4363 MRIs, 18-92 years). In additional analyses, we tested coherence with cell-specific gene expression maps from the Allen Human Brain Atlas, and relations to changes in memory performance. "PSQI # 1 Subjective sleep quality" and "PSQI #5 Sleep disturbances" were related to thinning of the right lateral temporal cortex, with lower quality and more disturbances being associated with faster thinning. The association with "PSQI #5 Sleep disturbances" emerged after 60 years, especially in regions with high expression of genes related to oligodendrocytes and S1 pyramidal neurons. None of the sleep scales were related to a longitudinal change in episodic memory function, suggesting that sleep-related cortical changes were independent of cognitive decline. The relationship to cortical brain change suggests that self-reported sleep parameters are relevant in lifespan studies, but small effect sizes indicate that self-reported sleep is not a good biomarker of general cortical degeneration in healthy older adults.

Self-reported Sleep Problems Related to Amyloid Deposition in Cortical Regions with High HOMER1 Gene Expression.

Sleep problems are related to the elevated levels of the Alzheimer's disease (AD) biomarker ß-amyloid (Aß). Hypotheses about the causes of this relationship can be generated from molecular markers of sleep problems identified in rodents. A major marker of sleep deprivation is Homer1a, a neural protein coded by the HOMER1 gene, which has also been implicated in brain Aß accumulation. Here, we tested whether the relationship between cortical Aß accumulation and self-reported sleep quality, as well as changes in sleep quality over 3 years, was stronger in cortical regions with high HOMER1 mRNA expression levels. In a sample of 154 cognitively healthy older adults, Aß correlated with poorer sleep quality cross-sectionally and longitudinally (n = 62), but more strongly in the younger than in older individuals. Effects were mainly found in regions with high expression of HOMER1. The anatomical distribution of the sleep-Aß relationship followed closely the Aß accumulation pattern in 69 patients with mild cognitive impairment or AD. Thus, the results indicate that the relationship between sleep problems and Aß accumulation may involve Homer1 activity in the cortical regions, where harbor Aß deposits in AD. The findings may advance our understanding of the relationship between sleep problems and AD risk.

Anterior and posterior hippocampus macro- and microstructure across the lifespan in relation to memory-A longitudinal study.

There is evidence for a hippocampal long axis anterior-posterior (AP) differentiation in memory processing, which may have implications for the changes in episodic memory performance seen across development and aging. The hippocampus shows substantial structural changes with age, but the lifespan trajectories of hippocampal sub-regions along the AP axis are not established. The aim of the present study was to test whether the micro- and macro-structural age-trajectories of the anterior (aHC) and posterior (pHC) hippocampus are different. In a single-center longitudinal study, 1,790 cognitively healthy participants, 4.1-93.4 years of age, underwent a total of 3,367 MRI examinations and 3,033 memory tests sessions over 1-6 time points, spanning an interval up to 11.1 years. T1-weighted scans were used to estimate the volume of aHC and pHC (macrostructure), and diffusion tensor imaging to measure mean diffusion (MD, microstructure) within each region. We found that the macro- and microstructural lifespan-trajectories of aHC and pHC were clearly distinguishable, with partly common and partly unique variance shared with age. aHC showed a protracted period of microstructural development, while pHC microstructural development as indexed by MD was more or less completed in early childhood. In contrast, pHC showed larger unique aging-related changes. An aHC-pHC difference was also observed for volume, with pHC changing relatively more with higher age. All regions showed age-dependent relationships with episodic memory. aHC micro- and macrostructure was significantly related to verbal memory independently of age, but the relationships were still strongest among the older participants. We suggest that memory processes supported by each sub-region improve or decline in concert with volumetric and microstructural changes in the same age-period. Future research should disentangle the lifespan relationship between changes in these structural properties and different memory processes, encoding versus retrieval in particular, as well as other cognitive functions depending on the hippocampal long-axis specialization.

CSF sTREM2 and Tau Work Together in Predicting Increased Temporal Lobe Atrophy in Older Adults.

Neuroinflammation may be a key factor in brain atrophy in aging and age-related neurodegenerative disease. The objective of this study was to test the association between microglial expression of soluble Triggering Receptor Expressed on Myeloid Cells 2 (sTREM2), as a measure of neuroinflammation, and brain atrophy in cognitively unimpaired older adults. Brain magnetic resonance imagings (MRIs) and cerebrospinal fluid (CSF) sTREM2, total tau (t-tau), phosphorylated181 tau (p-tau), and Aß42 were analyzed in 115 cognitively unimpaired older adults, classified according to the A/T/(N)-framework. MRIs were repeated after 2 (n = 95) and 4 (n = 62) years. High baseline sTREM2 was associated with accelerated cortical thinning in the temporal cortex of the left hemisphere, as well as bilateral hippocampal atrophy, independently of age, Aß42, and tau. sTREM2-related atrophy only marginally increased with biomarker positivity across the AD continuum (A-T- #x2292; A+T- #x2292; A+T+) but was significantly stronger in participants with a high level of p-tau (T+). sTREM2-related cortical thinning correlated significantly with areas of high microglial-specific gene expression in the Allen Human Brain Atlas. In conclusion, increased CSF sTREM2 was associated with accelerated cortical and hippocampal atrophy in cognitively unimpaired older participants, particularly in individuals with tau pathology. This suggests a link between neuroinflammation, neurodegeneration, and amyloid-independent tauopathy.

Self-reported sleep relates to hippocampal atrophy across the adult lifespan: results from the Lifebrain consortium.

OBJECTIVES: Poor sleep is associated with multiple age-related neurodegenerative and neuropsychiatric conditions. The hippocampus plays a special role in sleep and sleep-dependent cognition, and accelerated hippocampal atrophy is typically seen with higher age. Hence, it is critical to establish how the relationship between sleep and hippocampal volume loss unfolds across the adult lifespan. METHODS: Self-reported sleep measures and MRI-derived hippocampal volumes were obtained from 3105 cognitively normal participants (18-90 years) from major European brain studies in the Lifebrain consortium. Hippocampal volume change was estimated from 5116 MRIs from 1299 participants for whom longitudinal MRIs were available, followed up to 11 years with a mean interval of 3.3 years. Cross-sectional analyses were repeated in a sample of 21,390 participants from the UK Biobank. RESULTS: No cross-sectional sleep-hippocampal volume relationships were found. However, worse sleep quality, efficiency, problems, and daytime tiredness were related to greater hippocampal volume loss over time, with high scorers showing 0.22% greater annual loss than low scorers. The relationship between sleep and hippocampal atrophy did not vary across age. Simulations showed that the observed longitudinal effects were too small to be detected as age-interactions in the cross-sectional analyses. CONCLUSIONS: Worse self-reported sleep is associated with higher rates of hippocampal volume decline across the adult lifespan. This suggests that sleep is relevant to understand individual differences in hippocampal atrophy, but limited effect sizes call for cautious interpretation.

The Impact of MRI Features and Observer Confidence on the Treatment Decision-Making for Patients with Untreated Glioma.

In a blind, dual-center, multi-observer setting, we here identify the pre-treatment radiologic features by Magnetic Resonance Imaging (MRI) associated with subsequent treatment options in patients with glioma. Study included 220 previously untreated adult patients from two institutions (94 + 126 patients) with a histopathologically confirmed diagnosis of glioma after surgery. Using a blind, cross-institutional and randomized setup, four expert neuroradiologists recorded radiologic features, suggested glioma grade and corresponding confidence. The radiologic features were scored using the Visually AcceSAble Rembrandt Images (VASARI) standard. Results were retrospectively compared to patient treatment outcomes. Our findings show that patients receiving a biopsy or a subtotal resection were more likely to have a tumor with pathological MRI-signal (by T2-weighted Fluid-Attenuated Inversion Recovery) crossing the midline (Hazard Ratio; HR = 1.30 [1.21-1.87], P < 0.001), and those receiving a biopsy sampling more often had multifocal lesions (HR = 1.30 [1.16-1.64], P < 0.001). For low-grade gliomas (N = 50), low observer confidence in the radiographic readings was associated with less chance of a total resection (P = 0.002) and correlated with the use of a more comprehensive adjuvant treatment protocol (Spearman = 0.48, P < 0.001). This study may serve as a guide to the treating physician by identifying the key radiologic determinants most likely to influence the treatment decision-making process.

Volumetric and microstructural regional changes of the hippocampus underlying development of recall performance after extended retention intervals.

Performance on recall tests improves through childhood and adolescence, in part due to structural maturation of the medial temporal cortex. Although partly different processes support successful recall over shorter vs. longer intervals, recall is usually tested after less than an hour. The aim of the present study was to test whether there are unique developmental changes in recall performance using extended retention intervals, and whether these are related to structural maturation of sub-regions of the hippocampus. 650 children and adolescents from 4.1 to 24.8 years were assessed in total 962 times (mean interval ≈ 1.8 years). The California Verbal Learning Test (CVLT) and the Rey Complex Figure Test (CFT) were used. Recall was tested 30 min and ≈ 10 days after encoding. We found unique developmental effects on recall in the extended retention interval condition independently of 30 min recall performance. For CVLT, major improvements happened between 10 and 15 years. For CFT, improvement was linear and was accounted for by visuo-constructive abilities. The relationships did not show anterior-posterior hippocampal axis differences. In conclusion, performance on recall tests using extended retention intervals shows unique development, likely due to changes in encoding depth or efficacy, or improvements of long-term consolidation processes.

Prosocial behavior relates to the rate and timing of cortical thinning from adolescence to young adulthood.

Prosocial behavior, or voluntary actions that intentionally benefit others, relate to desirable developmental outcomes such as peer acceptance, while lack of prosocial behavior has been associated with several neurodevelopmental disorders. Mapping the biological foundations of prosociality may thus aid our understanding of both normal and abnormal development, yet how prosociality relates to cortical development is largely unknown. Here, relations between prosociality, as measured by the Strengths and Difficulties Questionnaire (self-report), and changes in thickness across the cortical mantle were examined using mixed-effects models. The sample consisted of 169 healthy individuals (92 females) aged 12-26 with repeated MRI from up to 3 time points, at approximately 3-year intervals (301 scans). In regions associated with social cognition and behavioral control, higher prosociality was associated with greater cortical thinning during early-to-middle adolescence, followed by attenuation of this process during the transition to young adulthood. Comparatively, lower prosociality was related to initially slower thinning, followed by comparatively protracted thinning into the mid-twenties. This study showed that prosocial behavior is associated with regional development of cortical thickness in adolescence and young adulthood. The results suggest that the rate of thinning in these regions, as well as its timing, may be factors related to prosocial behavior.

Maintained Frontal Activity Underlies High Memory Function Over 8 Years in Aging.

Aging is characterized by substantial average decline in memory performance. Yet contradictory explanations have been given for how the brains of high-performing older adults work: either by engagement of compensatory processes such as recruitment of additional networks or by maintaining young adults' patterns of activity. Distinguishing these components requires large experimental samples and longitudinal follow-up. Here, we investigate which features are key to high memory in aging, directly testing these hypotheses by studying a large sample of adult participants (n > 300) with fMRI during an episodic memory experiment where item-context relationships were implicitly encoded. The analyses revealed that low levels of activity in frontal networks-known to be involved in memory encoding-were associated with low memory performance in the older adults only. Importantly, older participants with low memory performance and low frontal activity exhibited a strong longitudinal memory decline in an independent verbal episodic memory task spanning 8 years back (n = 52). These participants were also characterized by lower hippocampal volumes and steeper rates of cortical atrophy. Altogether, maintenance of frontal brain function during encoding seems to be a primary characteristic of preservation of memory function in aging, likely reflecting intact ability to integrate information.

Continuity and Discontinuity in Human Cortical Development and Change From Embryonic Stages to Old Age.

The human cerebral cortex is highly regionalized, and this feature emerges from morphometric gradients in the cerebral vesicles during embryonic development. We tested if this principle of regionalization could be traced from the embryonic development to the human life span. Data-driven fuzzy clustering was used to identify regions of coordinated longitudinal development of cortical surface area (SA) and thickness (CT) (n = 301, 4-12 years). The principal divide for the developmental SA clusters extended from the inferior-posterior to the superior-anterior cortex, corresponding to the major embryonic morphometric anterior-posterior (AP) gradient. Embryonic factors showing a clear AP gradient were identified, and we found significant differences in gene expression of these factors between the anterior and posterior clusters. Further, each identified developmental SA and CT clusters showed distinguishable life span trajectories in a larger longitudinal dataset (4-88 years, 1633 observations), and the SA and CT clusters showed differential relationships to cognitive functions. This means that regions that developed together in childhood also changed together throughout life, demonstrating continuity in regionalization of cortical changes. The AP divide in SA development also characterized genetic patterning obtained in an adult twin sample. In conclusion, the development of cortical regionalization is a continuous process from the embryonic stage throughout life.

Waves of Maturation and Senescence in Micro-structural MRI Markers of Human Cortical Myelination over the Lifespan.

Seminal human brain histology work has demonstrated developmental waves of myelination. Here, using a micro-structural magnetic resonance imaging (MRI) marker linked to myelin, we studied fine-grained age differences to deduce waves of growth, stability, and decline of cortical myelination over the life-cycle. In 484 participants, aged 8-85 years, we fitted smooth growth curves to T1- to T2-weighted ratio in each of 360 regions from one of seven cytoarchitectonic classes. From the first derivatives of these generally inverted-U trajectories, we defined three milestones: the age at peak growth; the age at onset of a stable plateau; and the age at the onset of decline. Age at peak growth had a bimodal distribution comprising an early (pre-pubertal) wave of primary sensory and motor cortices and a later (post-pubertal) wave of association, insular and limbic cortices. Most regions reached stability in the 30-s but there was a second wave reaching stability in the 50-s. Age at onset of decline was also bimodal: in some right hemisphere regions, the curve declined from the 60-s, but in other left hemisphere regions, there was no significant decline from the stable plateau. These results are consistent with regionally heterogeneous waves of intracortical myelinogenesis and age-related demyelination.

A longitudinal study of computerized cognitive training in stroke patients - effects on cognitive function and white matter.

Background Computerized cognitive training is suggested to enhance attention and working memory functioning following stroke, but effects on brain and behavior are not sufficiently studied and longitudinal studies assessing brain and behavior relationships are scarce. Objective The study objectives were to investigate relations between neuropsychological performance post-stroke and white matter microstructure measures derived from diffusion tensor imaging (DTI), including changes after 6 weeks of working memory training. Methods In this experimental training study, 26 stroke patients underwent DTI and neuropsychological tests at 3 time points - before and after a passive phase of 6 weeks, and again after 6 weeks of working memory training (Cogmed QM). Fractional anisotropy (FA) was extracted from stroke-free brain areas to assess the white matter microstructure. Twenty-two participants completed the majority of training (≥18/25 sessions) and were entered into longitudinal analyses. Results Significant correlations between FA and baseline cognitive functions were observed (r = 0.58, p = 0.004), however, no evidence was found of generally improved cognitive functions following training or of changes in white matter microstructure. Conclusions While white matter microstructure related to baseline cognitive function in stroke patients, the study revealed no effect on cognitive functions or microstructural changes in white matter in relation to computerized working memory training.

Parallel but independent reduction of emotional awareness and corpus callosum connectivity in older age.

Differential functional specialization of the left and right hemispheres for linguistic and emotional functions, respectively, suggest that interhemispheric communication via the corpus callosum is critical for emotional awareness. Accordingly, it has been hypothesized that the age-related decline in callosal connectivity mediates the frequently demonstrated reduction in emotional awareness in older age. The present study tests this hypothesis in a sample of 307 healthy individuals between 20-89 years using combined structural and diffusion-tensor magnetic resonance imaging (MRI) of the corpus callosum. As assumed, inter-hemispheric connectivity (midsagittal callosal area and thickness, as well as fractional anisotropy, FA) and emotional awareness (i.e., increase in externally-oriented thinking, EOT; assessed with the Toronto Alexithymia Scale, TAS-20) were found to be reduced in older (> 60 years) compared to younger participants. Furthermore, relating callosal measures to emotional awareness, FA in the genu of the corpus callosum was found to be negatively correlated with EOT in male participants. Thus, "stronger" structural connectivity (higher FA) was related with higher emotional awareness (lower EOT). However, a formal mediation analysis did not support the notion that age-related decline in emotional awareness is mediated by the corpus callosum. Thus, the observed reduction of emotional awareness and callosal connectivity in older age likely reflects parallel but not inter-dependent processes.