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

In an interview with Omnihealth Practice, Dr. Tan, Juen-Kiem, a neurology fellow from Malaysia with a special interest in cognitive and behavioral neurology, shared his valuable insights into the challenges of recognizing patients with RPD. 

Question 1: How would you define RPD, and how commonly is it encountered in clinical practice? 

Dr. Tan: RPD describes a form of cognitive decline that progresses much faster than typical dementias— often within a year or two, and in some cases, within just weeks or months. Rather than a single diagnosis, RPD is an umbrella term encompassing a variety of underlying conditions. Although often perceived as rare, RPD is more common than many realized. In my center, we typically encounter at least one new case each week. 

Question 2: What are the common causes of RPD, and why is early detection crucial? 

Dr. Tan: RPD has a wide range of etiologies, including prion diseases (such as Creutzfeldt-Jakob Disease), autoimmune encephalitis, vasculitis, infections, nutritional deficiencies, and certain genetic disorders. Many of these are potentially reversible if identified and treated early. Delays in recognition and intervention can lead to irreversible brain injury, for example, in inflammatory causes, where ongoing damage may result in infarction. In RPD, management follows the principle that" time is brain" as well. 

Question 3: What are the key diagnostic challenges in managing RPD, and how can early recognition be improved? 

Dr. Tan: Evaluation of RPD typically involves a thorough clinical history, neurological and systemic examination, imaging (typically MRI), EEG and lumbar puncture. However, there are significant barriers that need to be addressed, including limited access to advanced diagnostics, financial constraints, and patients’ reluctance toward more invasive tests like lumbar punctures. Moreover, specialized tests for autoimmune biomarkers or genetic causes are often sent overseas, leading to further delays. In many cases, especially when reversible causes are suspected, treatment must be initiated before definitive results are available, which adds to the complexity of management. 

A major challenge lies in the poor awareness of RPD among both the general public and healthcare professionals. Symptoms such as forgetfulness are often dismissed as part of normal aging, particularly in older adults, and with medical attention only sought after a significant decline or critical event. Even among clinicians, the early signs of RPD may be overlooked or misattributed. Therefore, accurate history-taking is essential, ideally from a reliable collateral source, as patients or caregivers may focus on the most dramatic event, missing the subtle but critical early symptoms. Since RPD is broadly defined by rapid progression from the first symptom within two years, pinpointing onset is pivotal. Greater public and professional awareness is key to improving early detection and timely intervention.