Earliest amyloid and tau deposition modulate the influence of limbic networks during closed-loop hippocampal downregulation

Abstract

Research into hippocampal self-regulation abilities may help determine the clinical significance of hippocampal hyperactivity throughout the pathophysiological continuum of Alzheimer's disease. In this study, we aimed to identify the effects of amyloid-β peptide 42 (amyloid-β42) and phosphorylated tau on the patterns of functional connectomics involved in hippocampal downregulation. We identified 48 cognitively unimpaired participants (22 with elevated CSF amyloid-β peptide 42 levels, 15 with elevated CSF phosphorylated tau levels, mean age of 62.705 ± 4.628 years), from the population-based 'Alzheimer's and Families' study, with baseline MRI, CSF biomarkers, APOE genotyping and neuropsychological evaluation. We developed a closed-loop, real-time functional MRI neurofeedback task with virtual reality and tailored it for training downregulation of hippocampal subfield cornu ammonis 1 (CA1). Neurofeedback performance score, cognitive reserve score, hippocampal volume, number of apolipoprotein ε4 alleles and sex were controlled for as confounds in all cross-sectional analyses. First, using voxel-wise multiple regression analysis and controlling for CSF biomarkers, we identified the effect of healthy ageing on eigenvector centrality, a measure of each voxel's overall influence based on iterative whole-brain connectomics, during hippocampal CA1 downregulation. Then, controlling for age, we identified the effects of abnormal CSF amyloid-β42 and phosphorylated tau levels on eigenvector centrality during hippocampal CA1 downregulation. Across subjects, our main findings during hippocampal downregulation were: (i) in the absence of abnormal biomarkers, age correlated with eigenvector centrality negatively in the insula and midcingulate cortex, and positively in the inferior temporal gyrus; (ii) abnormal CSF amyloid-β42 (<1098) correlated negatively with eigenvector centrality in the anterior cingulate cortex and primary motor cortex; and (iii) abnormal CSF phosphorylated tau levels (>19.2) correlated with eigenvector centrality positively in the ventral striatum, anterior cingulate and somatosensory cortex, and negatively in the precuneus and orbitofrontal cortex. During resting state functional MRI, similar eigenvector centrality patterns in the cingulate had previously been associated to CSF biomarkers in mild cognitive impairment and dementia patients. Using the developed closed-loop paradigm, we observed such patterns, which are characteristic of advanced disease stages, during a much earlier presymptomatic phase. In the absence of CSF biomarkers, our non-invasive, interactive, adaptive and gamified neuroimaging procedure may provide important information for clinical prognosis and monitoring of therapeutic efficacy. We have released the developed paradigm and analysis pipeline as open-source software to facilitate replication studies.

Keywords: CA1; ECM; amyloid-β42; p-tau; rt-fMRI.

Figure 1

VR environment and neuroimaging pipeline. The VR neurofeedback paradigm developed for the study used principles of passive, sensory-aided, operant conditioning and featured 570 neurofeedback signals per session. To maintain a balanced perceptual experience across participants, task difficulty adapted to individual performance dynamically, aiming to drive CA1 activity in each participant to the minimum possible. Using previously acquired anatomical images, multi-atlas hippocampal subfield segmentation localized and segmented hippocampal subfield CA1, prior to real-time scanning. With every real-time functional volume, moment-to-moment changes in hippocampal CA1 activation effected inverse changes of velocity in VR. Offline statistical modelling was used to derive a measure of neurofeedback regulation performance and to perform EC mapping (i.e. to estimate how much influence each voxel exerts during hippocampal CA1 downregulation with neurofeedback). APOE = apolipoprotein genotype; Aβ42 = amyloid-β₄₂; BrainRes = brain reserve; CA1 = cornu ammonis 1; CogRes = cognitive reserve; fMRI = functional MRI; GLM = general linear model; NF = neurofeedback; p-tau = phosphorylated tau; ROI = region of interest; TIV = total intracranial volume.

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.

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.

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 Fig. 3, these results show that EC in the cingulate and BA2 present the opposite patterns in healthy ageing.