Reply to Biskup et al. and Tu et al.: Sex differences in metabolic brain aging

Manu S. Goyal, Andrei G. Vlassenko, Marcus E. Raichle
2019 Proceedings of the National Academy of Sciences of the United States of America  
We greatly appreciate the interest and thoughtful insights into our study by both Biskup et al. (1) and Tu et al. (2). Their comments prompted us to further analyze the data published in our paper (3), as discussed below. Biskup et al. (1) first wonder whether our results might be due to the multiparametric nature of the dataset or, alternatively, could be related to a global difference in rationing between aerobic glycolysis (AG) and oxidative metabolism. We investigate this further by looking
more » ... at each metabolic parameter independently. First, generalized linear modeling reveals that sex-based differences in regional gray matter AG (adjusted for chronological age) correlate well with how much a region's AG varies with age (i.e., regions with higher AG in females are also those that lose the most AG with age, Pearson's r = 0.72), suggesting that more typical statistical analysis for AG alone reflects the results from our multiparametric machine learning model. Next, we investigated whether sex-based differences in metabolic brain age persist when calculated independently for AG, total glucose use (CMRGlc), oxygen consumption (CMRO 2 ), and cerebral blood flow (CBF). We again find that females (as test cases) have a significantly lower metabolic brain age than males (as training cases) for AG, CMRGlc, and CMRO 2 , independently, but not for CBF (females vs. males, t test: −5.3 y, P < 0.005; −5.1 y, P < 0.01; −4.5 y, P < 0.05; −0.2 y, P > 0.8; respectively; the first three results remain P < 0.05 when test-training cases are reversed). These results would suggest that sex differences in metabolic brain aging are a more general phenomenon. This is also reflected in prior studies; for example, it has been found that females undergo an aging transition in brain transcription patterns later than males (4), and brain age prediction based on structural MRI alone in an older cohort was also found to be younger in females than in males (5). Biskup et al. (1) also remark that females might be more vulnerable to neurodegeneration than males.
doi:10.1073/pnas.1904673116 pmid:31138715 pmcid:PMC6561185 fatcat:hcwoec5pnbde3obarfzd2gsdiy