Hypermetabolic Cerebellar Connectome in Alzheimer's Disease

Introduction: Regional hypermetabolism in Alzheimer's disease (AD), especially in the cerebellum, has been consistently observed but often neglected as an artefact produced by the commonly used proportional scaling procedure in the statistical parametric mapping. We hypothesize that the hypermetabolic regions are also important in disease pathology in AD.Methods: Using fluorodeoxyglucose (FDG)-positron emission tomography (PET) images from 88 AD subjects and 88 age-sex matched normal controls (NL) from the publicly available Alzheimer's Disease Neuroimaging Initiative database, we developed a general linear model-based classifier that differentiated AD patients from normal individuals (sensitivity = 87.50%, specificity = 82.95%). We constructed region-region group-wise correlation matrices and evaluated differences in network organization by using the graph theory analysis between AD and control subjects.Results: We confirmed that hypermetabolism found in AD is not an artefact by replicating it using white matter as the reference region. The role of the hypermetabolic regions has been further investigated by using the graph theory. The differences in betweenness centrality (BC) between AD and NL network were correlated with region weights of FDG PET-based AD classifier. In particular, the hypermetabolism in cerebellum was accompanied with higher BC. The brain regions with higher BC in AD network showed a progressive increase in FDG uptake over 2 years in prodromal AD patients (n = 39).Discussion: This study suggests that hypermetabolism found in AD may play an important role in forming the AD-related metabolic network. In particular, hypermetabolic cerebellar regions represent a good candidate for further investigation in altered network organization in AD. Impact statementCerebellar hypermetabolism is a commonly observed characteristic of Alzhiemer's disease (AD) neurodegeneration in neuroimaging studies. However, whether cerebellar hypermetabolism is relevant to disease progression or whether it is an artefact of proportional scaling is controversial. In this study, we developed a general linear model-based classifier for AD by using the white matter mean for image scaling. We demonstrate that cerebellar hypermetabolism is a robust neuroimaging feature of AD. Further, hypermetabolism in the cerebellum is associated with an increase in the betweenness centrality of this region, indicating an important role of the cerebellum in changes in brain connectivity during AD.