Age-related Neurodegenerative Diseases Represent Common Causes of Rapidly Progressive Dementia: A Clinicopathological Study
Evelyn Lazar1, Nikoleta Tamvaka2, Owen Ross2, Nikhil Ghayal2, Shanu Roemer2, Neill Graff-Radford2, Dennis Dickson2, Gregory Day2
1Neurology, JFK Medical Center, 2Mayo Clinic Jacksonville
Objective:

To identify the neuropathological causes of rapidly progressive dementia (RPD) in a large neurodegenerative brain bank.

Background:

A clear understanding of the underlying causes of RPD is needed to prioritize diagnostic testing, enhance diagnostic accuracy, and improve clinical management; yet most studies of RPD rely on clinical diagnoses with limited neuropathological confirmation. This approach may underestimate the contributions of rapidly progressive presentations of common age-related neurodegenerative diseases to RPD.

Design/Methods:
Patients with <4 years from the onset of cognitive impairment to death were identified within the Mayo Clinic Neurodegenerative Brain Bank (1998-2025). Demographics, family history, dominant symptoms/signs at onset, and common comorbidities (e.g. depression, psychoses, sleep disturbance) were extracted from clinical records and neuropathological diagnoses assigned following standard protocols. 
Results:

408/11738 (3.5 %) cases met RPD criteria. Patients with prion disease commonly presented with RPD (71%, 40/56), followed by patients with progressive supranuclear palsy/corticobasal degeneration (PSP/CBD: 6.8%, 162/2362) and other forms of frontotemporal lobar degeneration (FTLD: 8.5%, 50/585), Lewy body disease (LBD: 4.4%, 78/1762), and Alzheimer disease (AD: 1.7%, 68/3807). Average age-at-symptom onset was 69.1±10.4 years and disease duration 2.9±1.0 years. Symptomatic duration was fastest in patients with RPD due to prion disease (1.4±1.2 years). Comorbid cerebrovascular disease was reported in 23.5% of cases but was not associated with symptomatic duration. Although depression, psychosis, and sleep disturbances were common across all neuropathological groups, depression was most common in patients with FTLD (58%, p<0.015), whereas psychosis (75.6%, p<0.001) and sleep disturbance (60.3%, p<0.35) were most frequent in patients with LBD.

Conclusions:

Rapidly progressive forms of neurodegenerative diseases accounted for 3.5% of cases in this neurodegenerative brain bank, with 87.7% of cases of RPD attributed to rapid presentations of common age-related neurodegenerative diseases. These findings highlight the need to consider neurodegenerative diseases in patients with RPD.

10.1212/WNL.0000000000217693
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