Powell, D. K. | bioRxiv Science

bioRxiv2024

Differential Speed and Accuracy Trade-off in Working Memory Retrieval and Bilateral Precuneus between Older Men and Women

BackgroundDespite various hypotheses, including differences in longevity, hormones, genetics, and neuroanatomy, the reasons for the higher prevalence of Alzheimers disease in older women compared to men remain unclear. Emerging evidence suggests that the precuneus, a key region of the default mode network, is linked to internally focused processes like memory retrieval. This study examined sex differences in the relationship between precuneus volumes and working memory retrieval speed in cognitively normal older adults, hypothesizing that disparities in precuneus size and function contribute to reduced working memory performance in older women. MethodA cohort of participants (N=45; 25 women; Mage =77) from the University of Kentucky Alzheimers Disease Research Center completed the Bluegrass Working Memory Task while undergoing 3T Siemens magnetic resonance imaging scans. ResultApplying Spearman correlation analyses, the results revealed correlations between working memory accuracy and volumes in the left (r=-.43, p<.01) and right (r=-.36, p<.05) precuneus across all subjects. Sex difference analysis indicated a tendency for the accuracy of the memory task to correlate more frequently with the left precuneus in women (r= 0.54; p < 0.05) than in men. Similarly, volumes in the left precuneus displayed a significant negative correlation with reaction time in response to memory target (r = -0.426; p < 0.05) and memory distractor (r = -0.549; p < 0.01) in women. There is a sex difference in accuracy and speed trade-off. While men were faster in reaction time, women were better in the accuracy of the memory task. Particularly noteworthy was the consistent association in women, where neurocognitive measures (Trail A, r= -.50, p<.01; Trail B, r= -.06, p<.01) reliably correlated with volumes in the left precuneus--a relationship not observed in men. DiscussionOur findings suggest that the left precuneus volume is associated with processing speed and accuracy of working memory performance, especially in women. Given that the left precuneus plays a key role in supporting various aspects of cognition, including memory retrieval, our findings point to the potential of reaction time serving as a surrogate marker for fMRI in predicting cognitive decline, particularly when considering sex differences.

neuroscience↗

bioRxiv2020

Novel therapeutic targets to mitigate early neuronal dysfunction and cognitive deficits in tauopathy

Tauopathies are a group of more than twenty known disorders that involve progressive neurodegeneration, cognitive decline, and pathological tau accumulation. Current therapeutic strategies provide only limited, late-stage symptomatic treatment. This is partly due to lack of understanding of the molecular mechanisms linking tau and cellular dysfunction, especially during the early stages of disease progression. In this study, we treated early stage tau transgenic mice with a multi-target kinase inhibitor to identify novel substrates that contribute to cognitive impairment and exhibit therapeutic potential. Drug treatment significantly ameliorated brain atrophy and cognitive function as determined by behavioral testing and a sensitive imaging technique called manganese-enhanced magnetic resonance imaging (MEMRI) with quantitative R1 mapping. Surprisingly, these benefits occurred despite unchanged hyperphosphorylated tau levels. To elucidate the mechanism behind these improved cognitive outcomes, we performed quantitative proteomics to determine the altered protein network during this early stage in tauopathy and compare this model with the human AD proteome. We identified a cluster of preserved pathways shared with human tauopathy with striking potential for broad multi-target kinase intervention. We further report high confidence candidate proteins as novel therapeutically relevant targets for the treatment of tauopathy. One Sentence SummaryMulti-target kinase inhibition rescues cognitive function in early stage tauopathy mice and reverses proteomic shifts common to Alzheimers disease in humans.

neuroscience↗