Rapidly progressive dementia with parkinsonism in the Italian CJD Registry: underlying pathology and clinical-biomarker clues for differential diagnosis

Objective: Rapidly progressive dementia with parkinsonism may result from prion diseases (PrDs) or other neurological disorders. We aimed to characterize underlying diagnoses in patients referred to the Italian Registry for Creutzfeldt-Jakob disease and related disorders with this presentation and to identify clinical and biomarker features useful for differential diagnosis. Methods: We identified 181 patients classified as definite PrD, RT-QuIC supported probable PrD or neuropathologically confirmed non-prion disease. Neuropathological examination was available in 148 patients. The main analysis compared definite/RT-QuIC-supported probable PrDs (n = 111) versus Lewy body disease (LBD; n = 39). Multiple logistic regression models were used to identify clinical predictors of PrD. Hierarchical logistic regression analysis assessed whether supportive biomarkers added diagnostic information beyond onset presentation. Results: Among neuropathologically confirmed non-prion cases, LBD was the most frequent diagnosis. Notably, 50% of autopsied non-prion cases met criteria for possible or probable PrD. At onset, cerebellar signs and cognitive decline progressing within 1 year were independently associated with PrD, whereas older age at onset favoured LBD in this cohort. During the disease course, cerebellar signs and visual disturbances were more strongly associated with PrD than LBD. Clinical features alone correctly classified only 21.4% of LBD cases. Supportive biomarkers improved discrimination, increasing correct LBD classification to 57.1%, with MRI and EEG findings providing the main independent contribution. Interpretation: In this cohort, PrDs and LBD were the main causes of rapidly progressive dementia with parkinsonism. Clinical assessment alone was insufficient to distinguish conditions, supporting an integrated approach combining clinical pattern, MRI, EEG and disease-specific molecular biomarkers.