Earliest Amyloid and Tau Deposition Modulate the Influence of Limbic Networks During Closed-loop Hippocampal Downregulation

Stavros Skouras; Jordi Torner; Patrik Andersson; Yury Koush; Carles Falcon; Carolina Minguillon; Karine Fauria; Francesc Alpiste; Kaj Blenow; Henrik Zetterberg; Juan D. Gispert; José L. Molinuevo

Disclosures

Brain. 2020;143(3):976-992. 

In This Article

Results

Amyloid-β42

Controlling for the effects of age, sex, number of APOE ε4 alleles, hippocampal volume, cognitive reserve and neurofeedback performance, CSF amyloid-β42 levels showed a significant positive correlation with EC in the ACC [Brodmann area (BA)24, BA32] and primary motor cortex (BA4) (Figure 2 and Table 3). Note that amyloid-β42 levels in CSF are inversely proportional to the extent of amyloid-β plaque accumulation in the brain (Strozyk et al., 2003; Grothe et al., 2017); i.e. abnormal amyloid-β42 biomarkers were related to low EC in the ACC and BA4.

Figure 2.

Correlation between eigenvector centrality during hippocampal downregulation and amyloid-β deposition. The effects of age, sex, number of APOE ε4 alleles, hippocampal volume, cognitive reserve and neurofeedback performance, were modelled and controlled (z > 2.326, P < 0.05 whole-brain corrected, 95% confidence interval). Note that CSF amyloid-β42 levels are inversely proportional to the extent of amyloid-β plaque deposition in the brain.

Phosphorylated-tau

Controlling for the effects of age, sex, number of APOE ε4 alleles, hippocampal volume, cognitive reserve and neurofeedback performance, p-tau levels in CSF showed a significant positive correlation with EC in the ACC (BA32, BA10) ventral striatum (caudate, nucleus accumbens, putamen) and left primary somatosensory cortex (BA2). CSF p-tau levels, also showed a significant negative correlation with EC in the posterior cingulate cortex, precuneus, cuneus and left frontal pole (BA9) (Figure 3 and Table 3).

Figure 3.

Correlation between eigenvector centrality during hippocampal downregulation and CSF p-tau levels. The effects of age, sex, number of APOE ε4 alleles, hippocampal volume, cognitive reserve and neurofeedback performance were modelled and controlled (z > 2.326, P < 0.05 whole-brain corrected, 95% confidence interval). Note that CSF p-tau levels are proportional to the presence of neurofibrillary tangles in the brain. These results suggest that Alzheimer's disease-characteristic EC differences in the ACC may occur earlier than previously believed.

Healthy Ageing

Controlling for the effects of sex, number of APOE ε4 alleles, hippocampal volume, cognitive reserve, neurofeedback performance and the CSF p-tau by amyloid-β42 ratio (Maddalena et al., 2003), age presented a significant negative correlation with EC in the midcingulate cortex, insula, primary somatosensory cortex (BA2) and inferior parietal lobule (BA40). Age also presented a significant positive correlation with EC in the inferior temporal gyri (Figure 4 and Table 3).

Figure 4.

Correlation between eigenvector centrality during hippocampal downregulation and age. The effects of sex, number of APOE ε4 alleles, hippocampal volume, cognitive reserve, neurofeedback performance, CSF amyloid-β42 and p-tau levels were modelled and controlled (z > 2.326, P < 0.05 whole-brain corrected, 95% confidence interval). In relation to Figure 3, these results show that EC in the cingulate and BA2 present the opposite patterns in healthy ageing.

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