Amyloid-linked trajectories of cerebral hypoperfusion and dopamine loss in dementia with Lewy bodies

Dementia with Lewy bodies (DLB) is clinically heterogeneous, and the evolutionary trajectories of cortical dysfunction, nigrostriatal dopaminergic degeneration, and amyloid accumulation, as well as the interactions among them, remain poorly understood. This study enrolled 83 patients with DLB who underwent dual-phase 18F-FP-CIT PET and 18F-FBB PET scans at initial assessment. Fifteen standardised imaging biomarkers capturing cerebral perfusion (early-phase 18F-FP-CIT PET images), striatal dopamine depletion (late-phase 18F-FP-CIT PET images), and amyloid burden (18F-FBB PET images) were entered into a Subtype and Stage Inference (SuStaIn) model. The SuStaIn analysis delineated two subtypes of DLB with distinct evolutionary trajectories: Subtype 1 (n = 37) was characterized by early amyloid accumulation, followed by cerebral hypoperfusion progressing from the posterior cingulate cortex to other cortical and limbic regions, and later diffuse striatal dopamine depletion; Subtype 2 (n = 36) initially presented with selective dopamine loss in the putamen, with subsequent dopaminergic deficits in other striatal subregions, followed by amyloid accumulation and cerebral hypoperfusion progressing from the precuneus to other cortical and limbic regions. The remaining 10 patients with DLB did not have sufficiently abnormal imaging findings to be categorized into a defined subtype (Subtype 0). Subtype 1 exhibited more severe Alzheimer's disease (AD)-like cortical atrophy and lower cingulate island sign ratios on early-phase 18F-FP-CIT PET images. Patients in Subtype 2 had a higher prevalence of rapid eye movement sleep behavior disorder and visual hallucinations than those in Subtype 1. In conclusion, we delineate two distinct multimodal imaging progression patterns in DLB: an early nigrostriatal dopamine depletion-linked trajectory with more typical DLB characteristics and an early amyloid deposition-linked trajectory characterised by an inverse cingulate island sign and AD-like cortical atrophy. These findings highlight the clinical and biological heterogeneity within DLB.