Predictive value of brain 18F-FDG PET neuroimaging in a mouse model of sudden death

Sudden unexpected death (SUD) is a major cause of mortality in neurological disorders, with poorly understood mechanisms and no reliable biomarkers. Brain–heart axis dysfunction has been implicated in SUD pathogenesis. Using the FUSΔ14 mouse model, we tested whether cerebral glucometabolism, assessed by ¹⁸F-FDG PET, reflects autonomic dysregulation and predicts SUD vulnerability.

¹⁸F-FDG PET/CT and ECG were acquired at 10 weeks of age (FUS ^Δ14/Δ14 n=12, FUS ^+/Δ14 n=14, FUS ^+/+ n=12). Heart rate variability was analyzed in time and frequency domains, brain uptake via volume-of-interest and voxel-wise approaches, and correlations assessed by Pearson’s analysis. A classification-tree model tested SUD predictability within the FUSΔ14/Δ14 group.

Female FUSΔ14/Δ14 mice showed reduced ¹⁸F-FDG uptake in basal forebrain septum, left amygdala, and brainstem, with increased uptake in hypothalamus and right midbrain, alongside cardiac size, metabolic and heart rate variability alterations. 50% experienced SUD; in this subgroup, PET showed cortical hypometabolism (insular, entorhinal) and hypermetabolism in hypothalamus, amygdala, septum, and brainstem. Although brainstem uptake was able to singlehandedly predict SUD in this particular FUS ^Δ14/Δ14 group (AUC=0.787±0.06), cross-validation also highlighted cortical metabolism as a relevant feature (UsageRate=0.38 and 0.44, respectively).

¹⁸F-FDG PET identifies region-specific metabolic signatures of brain–heart axis dysfunction linked to SUD, supporting its potential as a non-invasive biomarker for risk stratification.

Significance statement

Sudden unexpected death (SUD) is common in neurological disease, yet there are no reliable tools to identify patients at risk. Using a mouse model that mimics seizures and high mortality rate seen in sudden death conditions such as SUDEP, we show that brain-heart axis glucose metabolism, measured by PET imaging, is altered, revealing disturbances in the brain circuits that control heart rhythm. Animals that died unexpectedly displayed a distinct metabolic signature—reduced cortical activity paired with heightened activity in brainstem and structures involved in autonomic control. Exploratory analyses point to brainstem and cortical metabolism as important predictors of SUD risk. These findings position ¹⁸F-FDG PET as a candidate biomarker of brain–heart axis dysfunction, offering a path toward identifying vulnerable individuals.