Significant Relationship Between Worsening Sleep and Declining Brain Metabolism in Areas Associated with Dementia

Introduction: Insomnia and other disturbances in circadian rhythm often emerge duringdisease progression in patients with dementia. We recently reported that subjects whohad worsening sleep over time had a clear worsening of both memory and brainmetabolism compared to subjects whose sleep improved over time, and metabolicdecline was particularly significant in the posterior cingulate cortex (PCC) (Alzheimer’sDement. 2023; 19(Suppl. 24):e082867), an area of the brain that metabolically declinesin the earliest stages of Alzheimer’s disease. Here we expand upon those initialfindings, reporting on results of voxel-based comprehensive statistical examinationsthrough brain PET volumes, corroborated by independent quantitative assessment ofchanges in 47 pre-defined standardized volumes of interest (sVOI).

Methods: A consecutive series of 2,005 cognitively normal and mildly impaired subjectsfrom more than 50 North American sites participating in the first three phases of theAlzheimer’s Disease Neuroimaging Initiative were studied. Changes in cognitionassessed through formal neuropsychological testing, and in regional cerebralmetabolism assessed through brain PET using the radiotracer [F-18]fluorodeoxyglucose(FDG), were examined. Statistical parametric mapping (SPM) of FDG-PET scan datawere used to perform paired t-test analyses to identify regions of declining cerebralmetabolism. Imaging data were quantitatively assessed by both sVOI analyses andstatistical parametric mapping (SPM) corrected for multiple comparisons by the FalseDiscovery Rate method.

Results: In this consecutive series of subjects, 211 were found to have had a change ininsomnia status during their participation: 83 who were documented to have insomnia atbaseline that was subsequently alleviated ("improving sleep"), and 128 who weredocumented to have no insomnia at baseline but developed it during the study period("worsening sleep"); of the 211, 62 (29%) underwent FDG-PET scans during bothbaseline insomnia and subsequent insomnia-free status, or both baseline normal sleepand subsequent insomnia status periods. A difference-of-difference analysis conductedby statistical parametric mapping demonstrated that the areas showing significantlygreater decline in the worsening sleep group compared to the improving sleep groupincluded the anterior temporal posterior and posterior cingulate areas. A paired analysisfor the worsening sleep group showed that the anterior temporal peri-insular regiondeclined very significantly even after multiple comparison correction (peak voxel t=5.49,p<0.0005; 1777 contiguous p<0.01 voxels, p<0.0005 corr.) on the right and (peak voxelt=5.23, p<0.0005; 1574 voxels, p<0.0005 corr.) on the left side of the brain. ThePCC/precuneus region also showed significant decline (peak voxel t=6.19, p<0.0005;5585 voxels; p<0.0005 corr.), as did the posterior temporal cortex (t=5.25, p<0.0005;2088 voxels; p<0.0005 corr.). Analyses by sVOI corroborated these differences anddemonstrated that the rate of decline in both of these areas was 25.3% and 24.2%faster per year over two years, respectively in the group with worsening sleep comparedto the improving sleep group.

Conclusions: Analyses of scans of regional cerebral metabolism, specifically in subjects withworsening sleep compared to those with improving sleep during ADNI enrollment,robustly demonstrated group-specific significant loss of metabolic activity in posteriorcingulate and anterior temporal cortical regions, brain areas associated withneurodegenerative dementing processes.