Patients presenting with faster-than-expected cognitive decline may have rapidly progressive dementia (RPD) or a condition that stabilizes or reverts to a more typical progression.¹ Early distinction between “true” RPD and non-RPD cases is critical, as true RPDs rapidly impair cognition and function, requiring timely patient management and intervention.¹ At the AAN Annual Meeting 2025, Dr. Yoav D. Piura from the Mayo Clinic Florida in the United States, presented findings on the clinical and diagnostic features associated with RPD to improve the recognition of at-risk patients.¹

The study prospectively enrolled 248 patients with suspected RPD at two tertiary centers (Mayo Clinic Florida and Washington University, St. Louis) between 2016 and 2023.¹ Two dementia specialists independently reviewed clinical data and established diagnoses based on published criteria.¹ RPD was defined as progression to dementia (global clinical dementia rating [CDR] ≥1) within one year or incapacitation (global CDR ≥2) within two years of symptom onset.¹ Clinical, brain imaging, electroencephalogram (EEG), and relevant biofluid markers (cerebrospinal fluid [CSF] and serum) were compared between RPD and non-RPD groups using univariate analysis, followed by multivariate logistic regression on variables with p<0.10 to identify factors independently associated with RPD.¹

The analysis provided insights into the clinical and diagnostic profiles of RPD versus non-RPD cases.¹ Baseline characteristics showed a mean age of symptom onset of 60.7±15.8 years, with 46% of patients being female.¹ The majority of cases had an underlying autoimmune/inflammatory cause (33%) or neurodegenerative cause (24%).¹ Ultimately, 185 patients (75%) met RPD criteria.¹ Compared with non-RPD patients, those with RPD were older (62.6 ± 14.4 vs. 55.0 ± 18.3 years; p<0.001) and were more likely to have Alzheimer’s disease (19.1% vs. 4.6%; p=0.008) or Creutzfeldt-Jakob disease (28.3% vs. 9.8%; p=0.003).¹ Regression analysis identified older age (OR: 1.34), history of Intensive care unit (ICU) admission (OR=3.30), and CSF protein >45mg/dl (OR=2.15) as independent predictors of “true” RPD.¹ Neurodegenerative diseases (OR=3.13; 95% CI: 1.40-7.31) and prion diseases (OR=4.67; 95% CI: 1.38-15.75) were also positively associated with RPD.¹ In contrast, non-RPD cases were often attributed to autoimmune/inflammatory causes (42.6%) or other etiologies such as psychiatric, neoplastic, or toxic/metabolic conditions (34.4%).¹

Further analysis explored early clinical feature clusters to assist in identifying specific causes of RPD.¹ Among patients with autoimmune encephalitis, faciobrachial dystonic seizures (FBDS) and mania were identified with >80% confidence, while in neurodegenerative disease, brain atrophy and Parkinsonism were associated with >60% confidence.¹ After adjusting for age, hallucinations (OR=2.86; 95% CI: 1.26-6.52) and a normal CSF white blood cell count (<5 cells/mm³; OR=2.07; 95% CI: 1.05-4.09) remained independently associated with RPD.¹ Certain findings, such as cortical visual loss (8.2%), advanced brain atrophy (14.7%), and periodic epileptiform discharges on EEG (71.9%) were exclusively observed in RPD cases.¹ Notably, patients with RPD developed severe dementia or died an average of six years earlier than non-RPD patients (3.0 years vs. 9.1 years; p=0.002).¹ Among those who underwent brain autopsy (n=38), neuropathologic findings were consistent with clinical diagnoses, supporting the reliability of clinical judgment without requiring tissue sampling.¹

In conclusion, features such as older age, seizures, visual agnosia, ICU admission, marked brain atrophy, periodic epileptiform discharges on EEG, and CSF pleocytosis or elevated protein were independently associated with true RPD.¹ Patients with underlying neurodegenerative or prion diseases were more likely to meet RPD criteria, and early recognition of specific clinical feature clusters may facilitate diagnosis.¹ Improving early identification of these patients can inform clinical care decisions and support enrollment in RPD research studies.¹

“Rapidly progressive dementia is an alarming neurological condition mediated by a plethora of causes that rapidly impair cognition and function"

Dr. Yoav D. Piura
the Mayo Clinic Florida,
United States