Characterization of Bold Variability Across the Adult Lifespan : Influence of Dopamine and Structural Integrity



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Recent empirical work examining the influence of age on BOLD variability, much of which employed age-group comparison methods, has yielded mixed results. Critically, the current work utilized a lifespan sample of 171 healthy adults (aged 20-94) and calculated mean of the squared successive differences (MSSD), a metric of BOLD variability, during a digit n-back task. Modulation of BOLD variability and mean BOLD variability increased across the adult lifespan. Modulatory effects of BOLD variability were observed in selective posterior regions whereby older adults demonstrated up-modulation of BOLD variability in response to difficulty. Modulatory effects of difficulty on BOLD variability were not present in other portions of the adult lifespan. Age-related increased mean BOLD variability was evident in widespread cortical and subcortical regions, however, no evidence for age-related decreased BOLD variability was observed. Greater age-related modulation of BOLD variability was associated with poorer cognitive function indexed by in-scanner n-back task accuracy and executive function (EF), while greater modulation of BOLD variability and mean BOLD variability demonstrated detrimental effects on working memory (WM). Mean BOLD variability additionally demonstrated a graded effect on n-back task accuracy across the lifespan whereby increased BOLD variability was associated with poorer performance in all but the oldest adults. Study 1 established a lifespan trajectory of BOLD variability in a large, healthy lifespan cohort of adults. Study 2 and Study 3 sought to leverage other known age-related phenomena including declining dopaminergic neuromodulation and reductions in structural integrity which occur reliably in older age, to elucidate alterations of BOLD variability observed across the adult lifespan. Single nucleotide polymorphisms (SNPs) allowed for the study of naturally occurring predisposition to greater or lower dopamine (DA) availability in prefrontal (COMTVal158Met) and striatal/extrastriatal regions (DRD2 C957T). Age-dependent differences in BOLD variability emerged between genotype groups for each polymorphism, providing support for the resource-modulation hypothesis. Further, polymorphism-related differences in BOLD variability had cognitive consequences such that in most cases greater BOLD variability was observed alongside poorer cognitive outcomes. Study 3 examined the relationship among prefrontal and striatal estimates of brain morphometry (volume and cortical thickness) and BOLD variability across the adult lifespan. Prefrontal brain morphometry demonstrated a relationship with prefrontal and subcortical MSSD with increasing age whereby greater prefrontal cortex integrity illustrated a relationship with lesser BOLD variability and this association became stronger with older age. Lastly, age-dependent synergistic effects on executive function emerged, whereby worse executive function across the lifespan was observed when prefrontal cortex thickness and subcortical volume was low and average at all levels of subcortical BOLD variability, however, this association became less detrimental when structural integrity was intact and BOLD variability was low or average. Taken together, this body of work builds upon the extant literature suggesting detrimental effects of increased BOLD variability across the adult lifespan. Further, the influential nature of predisposition to differential availability of DA and brain morphometry on the lifespan trajectory of BOLD variability offer further support for increased levels of BOLD variability as a potential marker of cognitive decline observed in older age.



Brain -- Aging, Short-term memory, Magnetic resonance imaging