Cognitive decline in Autosomal Dominant Alzheimer’s Disease and its relation to TauPET and fMRI Complexity in the Hippocampus

Abstract

AbstractBackgroundIn recent years the neurofibrillary tangle pathology detected with tauPET imaging has been found to be closely related to cognitive decline in Alzheimer’s Disease. However, PET scans are expensive and involve radioactive tracers. We and others have proposed the complexity of rs‐fMRI using MultiScaleEntropy (MSE) as an index for neuronal function. Reduced entropy values have been associated with aging, APOEɛ4 genotype and cognitive function in AD. Here we hypothesize that the BOLD signal complexity is sensitive to tau‐related neuronal injury and cognitive decline in AD.MethodData (N=44, Table1) was obtained from the Estudio de la Enfermedad de Alzheimer en Jalisciences (EEAJ) study, which examines persons at‐risk for autosomal‐dominant AD. All subjects had T1, tauPET (18F‐AV1451) and two resting‐state fMRI scans. FMRI data underwent standard preprocessing before computing MSE. SUVR images were calculated with inferior cerebellum as reference region. Correlations between SUVR tauPET and MSE were calculated voxel‐wise including age, gender and gray ‐matter volume as covariates. Mediation effects in hippocampal clusters between MSE, tauPET and cognitive function (MMSE) were tested in SAS (95% confidence‐interval was estimated with 1000 bootstrapping samples).ResultWe observed gradually decreasing entropy and gradually increasing tauPET from NC to MCI and AD (Fig1). This inverse relationship was significant (p<0.05,corrected) in hippocampus, lateral temporal lobe and anterior cingulate cortex (Fig2). Mediator analysis revealed significant indirect (mediation) effects of PET to the association between MSE and MMSE (log‐transformed) in both hippocampi: Left: total 1.37 95%CI (0.6,2.14) indirect 0.86(0.27,1.85) and Right: total 1.49(0.66,2.31) indirect 1.04(0.48,1.84).ConclusionOur findings show that there is a statistically significant total effect between MSE and cognitive decline that is largely mediated by tauPET, with 63% and 70% of total effect for right and left hippocampus respectively. These results support the relevance of hippocampal tauopathy on cognitive decline. Moreover, complexity of rs‐fMRI is associated with both regional tau protein accumulation and cognitive decline, and thus could provide a safe and cost‐effective alternative marker for regional neuropathology and prediction of cognitive decline in AD.