Striatal iron content is linked to reduced frontostriatal brain function under working memory load Abstract   Nonheme iron accumulation contributes to agerelated decline in brain structure and cognition via a cascade of oxidative stress and inflammation, although its effect on brain function is largely unexplored. Thus, we examine the impact of striatal iron on dynamic range of BOLD modulation to working memory load. Nxe2x80xafxe2x80xaf166 healthy adults (age 20xe2x80x9394) underwent cognitive testing and an imaging session including nback (0, 2, 3, and 4back fMRI), R2*weighted imaging, and pcASL to measure cerebral blood flow. A statistical model was constructed to predict voxelwise BOLD modulation by age, striatal iron content and an agexc2xa0xc3x97xc2xa0iron interaction, controlling for cerebral blood flow, sex, and task response time. A significant interaction between age and striatal iron content on BOLD modulation was found selectively in the putamen, caudate, and inferior frontal gyrus. Greater iron was associated with reduced modulation to difficulty, particularly in middleaged and younger adults with greater iron content. Further, ironrelated decreases in modulation were associated with poorer executive function in an agedependent manner. These results suggest that iron may contribute to differences in functional brain activation prior to older adulthood, highlighting the potential role of iron as an early factor contributing to trajectories of functional brain aging.

Cholinergic white matter pathways make a stronger contribution to attention and memory in normal aging than cerebrovascular health and nucleus basalis of Meynert Abstract   The integrity of the cholinergic system plays a central role in cognitive decline both in normal aging and neurological disorders including Alzheimerxe2x80x99s disease and vascular cognitive impairment. Most of the previous neuroimaging research has focused on the integrity of the cholinergic basal forebrain, or its subregion the nucleus basalis of Meynert (NBM). Tractography using diffusion tensor imaging data may enable modelling of the NBM white matter projections. We investigated the contribution of NBM volume, NBM white matter projections, small vessel disease (SVD), and age to performance in attention and memory in 262 cognitively normal individuals (39xe2x80x9377 years of age, 53% female). We developed a multimodal MRI pipeline for NBM segmentation and diffusionbased tracking of NBM white matter projections, and computed white matter hypointensities (WMhypo) as a marker of SVD. We successfully tracked pathways that closely resemble the spatial layout of the cholinergic system as seen in previous postmortem and DTI tractography studies. We found that high WMhypo load was associated with older age, male sex, and lower performance in attention and memory. A high WMhypo load was also associated with lower integrity of the cholinergic system above and beyond the effect of age. In a multivariate model, age and integrity of NBM white matter projections were stronger contributors than WMhypo load and NBM volume to performance in attention and memory. We conclude that the integrity of NBM white matter projections plays a fundamental role in cognitive aging. This and other modern neuroimaging methods offer new opportunities to reevaluate the cholinergic hypothesis of cognitive aging.