Dissecting the Neuropathological Contributors to Rapidly Progressive Dementia

Background Most series exploring the causes of rapidly progressive dementia (RPD) rely on clinical diagnoses, with limited pathological confirmation. This approach may underestimate the contributions of Alzheimer disease and related dementias to RPD, recognizing challenges associated with extrapolating clinical phenotypes to neuropathological diagnoses. A clearer understanding of the neuropathological causes of RPD is needed to inform the diagnosis and treatment of patients. To meet this need, we determined the neuropathological causes of RPD within the Mayo Clinic neurodegenerative brain bank. Method Patients with disease duration <4.0 years (symptom‐onset to death due to dementia) were identified within the Mayo Clinic neurodegenerative brain bank (1998‐2020). Available clinical records were reviewed, and details extracted including demographics, family history, dominant symptoms/signs at onset, and common comorbidities (depression, psychoses, sleep disturbance). Neuropathological diagnoses were assigned following standard protocols. Result 310/8586 (3.6%) cases met RPD criteria. Relative to typically progressive cases, prion disease most commonly presented as RPD (74%, 32/43), followed by progressive supranuclear palsy/corticobasal degeneration (PSP/CBD: 7.5%, 142/1894), other frontotemporal lobar degeneration (FTLD: 5.7%, 32/561), Lewy body disease (LBD: 4.1%, 49/1202), and Alzheimer disease (AD: 1.8%, 48/2687). Average age‐at‐symptom onset was 69.5±10.4 years. Patients with rapidly progressive AD were older than others (p<0.01), except LBD. Patients with FTLD were younger than others (p<0.05), except prion disease. Average disease duration was 2.9±1.0 years: prion diseases had the most rapid disease course (1.6±1.3 years). Comorbid cerebrovascular disease (25.5%), and clinically symptomatic depression (41.3%), psychoses (37.1%) and sleep disturbances (39.4%) were common across groups. Only psychosis was associated with shorter disease duration (β=‐0.31 years, CI 95% [‐0.53, ‐0.082]; controlling for age‐at‐symptom onset). Conclusion Rapidly progressive neurodegenerative diseases accounted for 3.6% of cases in this neurodegenerative brain bank. Although prion disease commonly presented as RPD, atypical presentations of more prevalent neurodegenerative diseases accounted for most cases. Atypical (rapidly progressive) variants of typical neurodegenerative diseases warrant consideration in clinical practice.