Aging-Related Changes in Cognition and Cortical Integrity are Associated With Serum Expression of Candidate MicroRNAs for Alzheimer Disease.

Evidence has shown that microRNAs (miRNAs) are involved in molecular pathways responsible for aging and prevalent aging-related chronic diseases. However, the lack of research linking circulating levels of miRNAs to changes in the aging brain hampers clinical translation. Here, we have investigated if serum expression of brain-enriched miRNAs that have been proposed as potential biomarkers in Alzheimer's disease (AD) (miR-9, miR-29b, miR-34a, miR-125b, and miR-146a) are also associated with cognitive functioning and changes of the cerebral cortex in normal elderly subjects. Results revealed that candidate miRNAs were linked to changes in cortical thickness (miR-9, miR-29b, miR-34a, and miR-125b), cortical glucose metabolism (miR-29b, miR-125b, and miR-146a), and cognitive performance (miR-9, miR-34a, and miR-125b). While both miR-29b and miR-125b were related to aging-related structural and metabolic cortical changes, only expression levels of miR-125b were associated with patterns of glucose consumption shown by cortical regions that correlated with executive function. Together, these findings suggest that serum expression of AD-related miRNAs are biologically meaningful in aging and may play a role as biomarkers of cerebral vulnerability in late life.

Effects of PER3 clock gene polymorphisms on aging-related changes of the cerebral cortex.

Considerable evidence suggests that circadian rhythmicity is progressively disrupted in senescence. Among clock genes, Period3 (PER3) has been associated with circadian phenotypes, homeostatic regulation of sleep, and cognitive performance in young adults. However, the effects of PER3 genotype on aging-related changes in both cognitive function and cortical integrity remain largely unknown. To shed light into this issue, we have investigated differences in cognitive performance, patterns of cortical thickness, and cortical glucose consumption in normal elderly subjects homozygous carriers of the short (PER34/4, n = 32) and long repeat alleles (PER35/5, n = 32). Relationships between cognitive performance and cortical thickness/metabolism were further explored for each PER3 genotype. We found that PER35/5 carriers had poorer cognitive performance (attention, executive function, semantic memory, and verbal fluency) and lower cortical integrity (structural and functional) than PER34/4. PER35/5 further showed thinning of temporo-parietal areas, and reductions of glucose consumption in fronto-temporo-parietal regions bilaterally. Moreover, PER35/5 subjects exhibited significant correlations between decreased glucose metabolism in fronto-parietal regions and poorer cognitive flexibility, though only correlations with lower glucose consumption of the supramarginal gyrus distinguished PER35/5 from PER34/4 groups. Overall, these findings enhance our understanding on the gene-brain interaction in aging, and may have further implications for the detection of subclinical cognitive decline associated with PER3 genotypes in late life.

Sleep mediates the association between homocysteine and oxidative status in mild cognitive impairment.

Tremendous progress has been made over the last few years in understanding how sleep and amyloid-ß (Aß) cooperate to speed up the progression of Alzheimer's disease (AD). However, it remains unknown whether sleep deficits also interact with other risk factors that exacerbate the pathological cascade of AD. Based on evidence showing that higher levels of homocysteine (HCY) and sleep loss increase oxidative damage, we here investigate whether the relationship between HCY and total antioxidant capacity (TAC) is mediated by changes in objective sleep in healthy older (HO, N = 21) and mild cognitive impairment (MCI, N = 21) subjects. Results revealed that reduced TAC levels in MCI was significantly correlated with increased HCY, shorter sleep duration, lower sleep efficiency, and reduced volume of temporal regions. However, only the HCY-TAC association showed diagnostic value, and this relationship was mediated by poorer sleep quality in MCI patients. We further showed that HCY-related cerebral volume loss in MCI depended on the serial relationship between poorer sleep quality and lower TAC levels. These findings provide novel insights into how impaired sleep may contribute to maintain the relationship between HCY and oxidative stress in prodromal AD, and offer empirical foundations to design therapeutic interventions aimed to weaken this link.

Sleep deficits in mild cognitive impairment are related to increased levels of plasma amyloid-ß and cortical thinning.

Evidence suggests that amyloid-beta (Aß) depositions parallel sleep deficits in Alzheimer's disease (AD). However, it remains unknown whether impaired sleep and changes in plasma Aß levels are related in amnestic mild cognitive impairment (aMCI) subjects, and whether both markers are further associated with cortical thinning in canonical AD regions. To jointly address this issue, we investigated relationships between changes in physiological sleep and plasma Aß concentrations in 21 healthy old (HO) adults and 21 aMCI subjects, and further assessed whether these two factors were associated with cortical loss in each group. aMCI, but not HO subjects, showed significant relationships between disrupted slow-wave sleep (SWS) and increased plasma levels of Aß42. We also found that shortened rapid-eye movement (REM) sleep in aMCI correlated with thinning of the posterior cingulate, precuneus, and postcentral gyrus; whereas higher levels of Aß40 and Aß42 accounted for grey matter (GM) loss of posterior cingulate and entorhinal cortex, respectively. These results support preliminary relationships between Aß burden and altered sleep physiology observed in animal models of AD amyloidosis, and provide precise cortical correlates of these changes in older adults with aMCI. Taken together, these findings open new research avenues on the combined role of sleep, peripheral Aß levels and cortical integrity in tracking the progression from normal aging to early neurodegeneration.