Longitudinal Multi-tracer PET/CT for Monitoring the Progression of Diabetic Cardiac Autonomic Neuropathy: A Preclinical Study

Rationale and Objective This study utilized micro-positron emission tomography/computed tomography (micro-PET/CT) to track the longitudinal and dynamic progression of cardiac autonomic nerve injury in diabetic rats. Our objective was to map the precise timeline of neural damage relative to disease stages, defining a sensitive imaging window for the early diagnosis of diabetic cardiac autonomic neuropathy (DCAN). Materials and Methods Following streptozotocin induction of type 2 diabetes, rats underwent biweekly micro-PET/CT imaging for up to 17 weeks. Sympathetic and parasympathetic innervations were thoroughly evaluated using [ 11 C]C-MDA and [ 11 C]C-donepezil ([ 11 C]C-DNP), respectively. [ 11 C]C-triphenylmethylphosphonium ([ 11 C]C-TPMP) provided a perfusion baseline to characterize neuro-perfusion mismatches. Quantitative tracer uptake was correlated with histopathological remodeling and the myocardial expression of neurotrophic factors (NGF, GAP-43, CNTF) quantified via quantitative real-time polymerase chain reaction (RT-qPCR). Results Longitudinal PET/CT imaging unveiled a distinct chronological cascade of cardiac deterioration. Parasympathetic denervation ([ 11 C]C-DNP depletion) manifested first at week 6, followed by sympathetic denervation ([ 11 C]C-MDA deficit) at week 8. Conversely, myocardial perfusion deficits ([ 11 C]C-TPMP) remained absent until week 16, escalating to severe metabolic dysfunction by week 17. Histopathology confirmed progressive myocardial inflammation, while RT-qPCR indicated a late-stage, yet insufficient, compensatory upregulation of neurotrophic factors. Conclusion This multi-tracer longitudinal investigation establishes that parasympathetic denervation precedes sympathetic impairment during DCAN development, with both deficits predating microvascular and metabolic crises. These insights offer a critical, noninvasive diagnostic window for early DCAN detection and clinical monitoring.