Brier, Matthew R.

ObjectiveTo improve the timely recognition of patients with treatment‐responsive causes of rapidly progressive dementia (RPD).MethodsA total of 226 adult patients with suspected RPD were enrolled in a prospective observational study and followed for up to 2 years. Diseases associated with RPD were characterized as potentially treatment‐responsive or non‐responsive, referencing clinical literature. Disease progression was measured using Clinical Dementia Rating® Sum‐of‐Box scores. Clinical and paraclinical features associated with treatment responsiveness were assessed using multivariable logistic regression. Findings informed the development of a clinical criterion optimized to recognize patients with potentially treatment‐responsive causes of RPD early in the diagnostic evaluation.ResultsA total of 155 patients met defined RPD criteria, of whom 86 patients (55.5%) had potentially treatment‐responsive causes. The median (range) age‐at‐symptom onset in patients with RPD was 68.9 years (range 22.0–90.7 years), with a similar number of men and women. Seizures, tumor (disease‐associated), magnetic resonance imaging suggestive of autoimmune encephalitis, mania, movement abnormalities, and pleocytosis (≥10 cells/mm3) in cerebrospinal fluid at presentation were independently associated with treatment‐responsive causes of RPD after controlling for age and sex. Those features at presentation, as well as age‐at‐symptom onset <50 years (ie, STAM3P), captured 82 of 86 (95.3%) cases of treatment‐responsive RPD. The presence of ≥3 STAM3P features had a positive predictive value of 100%.InterpretationSelected features at presentation reliably identified patients with potentially treatment‐responsive causes of RPD. Adaptation of the STAM3P screening score in clinical practice may minimize diagnostic delays and missed opportunities for treatment in patients with suspected RPD. ANN NEUROL 2024;95:237–248

AbstractBackground and purposeReal‐time quaking‐induced conversion (RT‐QuIC) assays offer a sensitive and specific means for detection of prions, although false negative results are recognized in clinical practice. We profile the clinical, laboratory, and pathologic features associated with false negative RT‐QuIC assays and extend these to frame the diagnostic approach to patients with suspected prion disease.MethodsA total of 113 patients with probable or definite prion disease were assessed at Mayo Clinic (Rochester, MN; Jacksonville, FL; Scottsdale, AZ) or Washington University School of Medicine (Saint Louis, MO) from 2013 to 2021. RT‐QuIC testing for prions was performed in cerebrospinal fluid (CSF) at the National Prion Disease Pathology Surveillance Center (Cleveland, OH).ResultsInitial RT‐QuIC testing was negative in 13 of 113 patients (sensitivity = 88.5%). RT‐QuIC negative patients were younger (median = 52.0 years vs. 66.1 years, p < 0.001). Other demographic and presenting features, and CSF cell count, protein, and glucose levels were similar in RT‐QuIC negative and positive patients. Frequency of 14‐3‐3 positivity (4/13 vs. 77/94, p < 0.001) and median CSF total tau levels were lower in RT‐QuIC negative patients (2517 vs. 4001 pg/mL, p = 0.020), and time from symptom onset to first presentation (153 vs. 47 days, p = 0.001) and symptomatic duration (710 vs. 148 days, p = 0.001) were longer.ConclusionsRT‐QuIC is a sensitive yet imperfect measure necessitating incorporation of other test results when evaluating patients with suspected prion disease. Patients with negative RT‐QuIC had lower markers of neuronal damage (CSF total tau and protein 14‐3‐3) and longer symptomatic duration of disease, suggesting that false negative RT‐QuIC testing associates with a more indolent course.

This scientific commentary refers to ‘Stage-specific links between plasma neurofilament light and imaging biomarkers of Alzheimer’s disease’, by Benedet et al. (doi:10.1093/brain/awaa342).