Interrelating differences in structural and functional connectivity in the older adult's brain.

In the normal aging process, the functional connectome restructures and shows a shift from more segregated to more integrated brain networks, which manifests itself in highly different cognitive performances in older adults. Underpinnings of this reorganization are not fully understood, but may be related to age-related differences in structural connectivity, the underlying scaffold for information exchange between regions. The structure-function relationship might be a promising factor to understand the neurobiological sources of interindividual cognitive variability, but remain unclear in older adults. Here, we used diffusion weighted and resting-state functional magnetic resonance imaging as well as cognitive performance data of 573 older subjects from the 1000BRAINS cohort (55-85 years, 287 males) and performed a partial least square regression on 400 regional functional and structural connectivity (FC and SC, respectively) estimates comprising seven resting-state networks. Our aim was to identify FC and SC patterns that are, together with cognitive performance, characteristic of the older adults aging process. Results revealed three different aging profiles prevalent in older adults. FC was found to behave differently depending on the severity of age-related SC deteriorations. A functionally highly interconnected system is associated with a structural connectome that shows only minor age-related decreases. Because this connectivity profile was associated with the most severe age-related cognitive decline, a more interconnected FC system in older adults points to a process of dedifferentiation. Thus, functional network integration appears to increase primarily when SC begins to decline, but this does not appear to mitigate the decline in cognitive performance.

Differential predictability of cognitive profiles from brain structure in older males and females.

Structural brain imaging parameters may successfully predict cognitive performance in neurodegenerative diseases but mostly fail to predict cognitive abilities in healthy older adults. One important aspect contributing to this might be sex differences. Behaviorally, older males and females have been found to differ in terms of cognitive profiles, which cannot be captured by examining them as one homogenous group. In the current study, we examined whether the prediction of cognitive performance from brain structure, i.e. region-wise grey matter volume (GMV), would benefit from the investigation of sex-specific cognitive profiles in a large sample of older adults (1000BRAINS; N = 634; age range 55-85 years). Prediction performance was assessed using a machine learning (ML) approach. Targets represented a) a whole-sample cognitive component solution extracted from males and females, and b) sex-specific cognitive components. Results revealed a generally low predictability of cognitive profiles from region-wise GMV. In males, low predictability was observed across both, the whole sample as well as sex-specific cognitive components. In females, however, predictability differences across sex-specific cognitive components were observed, i.e. visual working memory (WM) and executive functions showed higher predictability than fluency and verbal WM. Hence, results accentuated that addressing sex-specific cognitive profiles allowed a more fine-grained investigation of predictability differences, which may not be observable in the prediction of the whole-sample solution. The current findings not only emphasize the need to further investigate the predictive power of each cognitive component, but they also emphasize the importance of sex-specific analyses in older adults.

Prediction of cognitive performance differences in older age from multimodal neuroimaging data.

Differences in brain structure and functional and structural network architecture have been found to partly explain cognitive performance differences in older ages. Thus, they may serve as potential markers for these differences. Initial unimodal studies, however, have reported mixed prediction results of selective cognitive variables based on these brain features using machine learning (ML). Thus, the aim of the current study was to investigate the general validity of cognitive performance prediction from imaging data in healthy older adults. In particular, the focus was with examining whether (1) multimodal information, i.e., region-wise grey matter volume (GMV), resting-state functional connectivity (RSFC), and structural connectivity (SC) estimates, may improve predictability of cognitive targets, (2) predictability differences arise for global cognition and distinct cognitive profiles, and (3) results generalize across different ML approaches in 594 healthy older adults (age range: 55-85 years) from the 1000BRAINS study. Prediction potential was examined for each modality and all multimodal combinations, with and without confound (i.e., age, education, and sex) regression across different analytic options, i.e., variations in algorithms, feature sets, and multimodal approaches (i.e., concatenation vs. stacking). Results showed that prediction performance differed considerably between deconfounding strategies. In the absence of demographic confounder control, successful prediction of cognitive performance could be observed across analytic choices. Combination of different modalities tended to marginally improve predictability of cognitive performance compared to single modalities. Importantly, all previously described effects vanished in the strict confounder control condition. Despite a small trend for a multimodal benefit, developing a biomarker for cognitive aging remains challenging.

Characterization of the angular gyrus in an older adult population: a multimodal multilevel approach.

The angular gyrus (AG) has been associated with multiple cognitive functions, such as language, spatial and memory functions. Since the AG is thought to be a cross-modal hub region suffering from significant age-related structural atrophy, it may also play a key role in age-related cognitive decline. However, the exact relation between structural atrophy of the AG and cognitive decline in older adults is not fully understood, which may be related to two aspects: First, the AG is cytoarchitectonically divided into two areas, PGa and PGp, potentially sub-serving different cognitive functions. Second, the older adult population is characterized by high between-subjects variability which requires targeting individual phenomena during the aging process. We therefore performed a multimodal (gray matter volume [GMV], resting-state functional connectivity [RSFC] and structural connectivity [SC]) characterization of AG subdivisions PGa and PGp in a large older adult population, together with relations to age, cognition and lifestyle on the group level. Afterwards, we switched the perspective to the individual, which is especially important when it comes to the assessment of individual patients. The AG can be considered a heterogeneous structure in of the older brain: we found the different AG parts to be associated with different patterns of whole-brain GMV associations as well as their associations with RSFC, and SC patterns. Similarly, differential effects of age, cognition and lifestyle on the GMV of AG subdivisions were observed. This suggests each region to be structurally and functionally differentially involved in the older adult's brain network architecture, which was supported by differential molecular and genetic patterns, derived from the EBRAINS multilevel atlas framework. Importantly, individual profiles deviated considerably from the global conclusion drawn from the group study. Hence, general observations within the older adult population need to be carefully considered, when addressing individual conditions in clinical practice.

Classification and prediction of cognitive performance differences in older age based on brain network patterns using a machine learning approach.

Age-related cognitive decline varies greatly in healthy older adults, which may partly be explained by differences in the functional architecture of brain networks. Resting-state functional connectivity (RSFC) derived network parameters as widely used markers describing this architecture have even been successfully used to support diagnosis of neurodegenerative diseases. The current study aimed at examining whether these parameters may also be useful in classifying and predicting cognitive performance differences in the normally aging brain by using machine learning (ML). Classifiability and predictability of global and domain-specific cognitive performance differences from nodal and network-level RSFC strength measures were examined in healthy older adults from the 1000BRAINS study (age range: 55-85 years). ML performance was systematically evaluated across different analytic choices in a robust cross-validation scheme. Across these analyses, classification performance did not exceed 60% accuracy for global and domain-specific cognition. Prediction performance was equally low with high mean absolute errors (MAEs ≥ 0.75) and low to none explained variance (R2 ≤ 0.07) for different cognitive targets, feature sets, and pipeline configurations. Current results highlight limited potential of functional network parameters to serve as sole biomarker for cognitive aging and emphasize that predicting cognition from functional network patterns may be challenging.