Early Age-Related Functional Connectivity Decline in High-Order Cognitive Networks

Resting state functional connectivity MRI (fcMRI) is widely used to investigate brain networks that exhibit correlated fluctuations. While fcMRI does not provide direct measurement of anatomic connectivity, accumulating evidence suggests it is sufficiently constrained by anatomy to allow the architecture of distinct brain systems to be characterized. fcMRI is particularly useful for characterizing large-scale systems that span distributed areas (e.g., polysynaptic cortical pathways, cerebro-cerebellar circuits, cortical-thalamic circuits) and has complementary strengths when contrasted with the other major tool available for human connectomics-high angular resolution diffusion imaging (HARDI). We review what is known about fcMRI and then explore fcMRI data reliability, effects of preprocessing, analysis procedures, and effects of different acquisition parameters across six studies (n = 98) to provide recommendations for optimization. Run length (2-12 min), run structure (1 12-min run or 2 6-min runs), temporal resolution (2.5 or 5.0 s), spatial resolution (2 or 3 mm), and the task (fixation, eyes closed rest, eyes open rest, continuous word-classification) were varied. Results revealed moderate to high test-retest reliability. Run structure, temporal resolution, and spatial resolution minimally influenced fcMRI results while fixation and eyes open rest yielded stronger correlations as contrasted to other task conditions. Commonly used preprocessing steps involving regression of nuisance signals minimized nonspecific (noise) correlations including those associated with respiration. The most surprising finding was that estimates of correlation strengths stabilized with acquisition times as brief as 5 min. The brevity and robustness of fcMRI positions it as a powerful tool for large-scale explorations of genetic influences on brain architecture. We conclude by discussing the strengths and limitations of fcMRI and how it can be combined with HARDI techniques to support the emerging field of human connectomics.

The ageing of the human brain is a cause of cognitive decline in the elderly and the major risk factor for Alzheimer's disease. The time in life when brain ageing begins is undefined. Here we show that transcriptional profiling of the human frontal cortex from individuals ranging from 26 to 106 years of age defines a set of genes with reduced expression after age 40. These genes play central roles in synaptic plasticity, vesicular transport and mitochondrial function. This is followed by induction of stress response, antioxidant and DNA repair genes. DNA damage is markedly increased in the promoters of genes with reduced expression in the aged cortex. Moreover, these gene promoters are selectively damaged by oxidative stress in cultured human neurons, and show reduced base-excision DNA repair. Thus, DNA damage may reduce the expression of selectively vulnerable genes involved in learning, memory and neuronal survival, initiating a programme of brain ageing that starts early in adult life.

Whereas some older adults show significant cognitive deficits, others perform as well as young adults. We investigated the neural basis of these different aging patterns using positron emission tomography (PET). In PET and functional MRI (fMRI) studies, prefrontal cortex (PFC) activity tends to be less asymmetric in older than in younger adults (Hemispheric Asymmetry Reduction in Old Adults or HAROLD). This change may help counteract age-related neurocognitive decline (compensation hypothesis) or it may reflect an age-related difficulty in recruiting specialized neural mechanisms (dedifferentiation hypothesis). To compare these two hypotheses, we measured PFC activity in younger adults, low-performing older adults, and high-performing older adults during recall and source memory of recently studied words. Compared to recall, source memory was associated with right PFC activations in younger adults. Low-performing older adults recruited similar right PFC regions as young adults, but high-performing older adults engaged PFC regions bilaterally. Thus, consistent with the compensation hypothesis and inconsistent with the dedifferentiation hypothesis, a hemispheric asymmetry reduction was found in high-performing but not in low-performing older adults. The results suggest that low-performing older adults recruited a similar network as young adults but used it inefficiently, whereas high-performing older adults counteracted age-related neural decline through a plastic reorganization of neurocognitive networks.