Piura, Yoav

AbstractBackgroundThe term rapidly progressive dementia (RPD) may be applied to patients with precipitous declines in cognitive function resulting in dementia within one year or complete incapacitation within two‐years of symptom onset. Although most patients present with subacute, progressive declines, selected patients develop complete incapacitation within seven days of symptom onset. The differential diagnosis and clinical characteristics of patients with abrupt‐onset dementia are not known.Method187 patients with RPD were prospectively enrolled from February 2016 to September 2023 in a study of RPD at Mayo Clinic (Jacksonville, Florida) and Washington University (Saint Louis, Missouri). Patients with ≤7 days from first symptom to onset of RPD were labelled as abrupt onset. Patient characteristics, results of investigations, and causes of abrupt‐onset dementia were further characterized. We further explored the causes of abrupt‐onset dementia in the extant literature to refine the differential diagnosis and approach to evaluation and management of these patients.ResultTwo patients in our study of RPD had abrupt‐onset RPD (2/187, 1.1%), attributed to autoimmune and vascular. An additional 63 cases were identified through comprehensive meta‐narrative review of the literature (40 publications). Causes of abrupt‐onset dementia include vascular, infectious, inflammatory, and toxic. Compromise of structures within the Papez circuit was a common unifying feature common across patients with varying etiologies, informing the localization of abrupt‐onset dementia. 20% cases had potentially treatment‐responsive causes of abrupt‐onset dementia.ConclusionCases of abrupt‐onset dementia are rare overall and associated with a limited differential diagnosis. Evaluation of patients with abrupt‐onset dementia should prioritize testing for vascular, autoimmune, infectious, and toxic causes. Early‐recognition of patients with potentially treatment‐responsive causes of dementia may promote earlier intervention leading to better outcomes in selected patients.

AbstractBackgroundPatients with the precipitous onset of cognitive symptoms (i.e., suspected rapid progressive dementia [RPD]) may continue to decline (true RPD) or may stabilize or improve (non‐RPD). Recognizing patients with RPD early in the disease course is important to support clinical care and enrollment in research.MethodPatients referred for the evaluation of suspected RPD were prospectively enrolled and followed for up to 2 years at Mayo Clinic in Florida (Jacksonville, FL; Jan‐2020 – Oct‐2023) and Washington University in St. Louis (Saint Louis, MO; Jun‐2016 – Dec‐2019). Clinical data were independently reviewed by two dementia specialists who established clinical diagnoses, referencing published criteria. Patients were diagnosed with RPD if they progressed to dementia (global Clinical Dementia Rating® [CDR] ≥1) within 1 year or incapacitation (CDR ≥2) within 2 years of symptom onset. Univariate statistics compared demographics, clinical details, and test results between patients with RPD and non‐RPD. Variables with p<0.1 were entered into a multivariate logistic regression model to identify factors associated with RPD.ResultOf 248 patients referred for suspected RPD, 187 (75.4%) met stated criteria for RPD. Patients with RPD were older (62.6±14.4 years vs 55.0±18.3 years; p<0.001), and more likely to be diagnosed with Alzheimer disease or related dementias (28.3% vs 9.8%; p = 0.003) or Creutzfeldt‐Jakob (19.1% vs 4.6%; p = 0.008). Non‐RPD cases were more often attributed to autoimmune/inflammatory disease (42.6% vs 29.4%, p = 0.061) or other causes (e.g., psychiatric, neoplasms, toxic/metabolic; 34.4% vs 16.6%, p = 0.006). After controlling for age, hallucinations (OR, 2.81; 95%CI: 1.21‐6.52), elevated CSF protein (OR, 2.43; 95%CI: 1.17‐5.03), and CSF white blood cell count <5 cells/mm3 (OR, 2.77; 95%CI: 1.32‐5.85) were independently associated with RPD. Cortical visual loss (15/183, 8.2%) and substantial brain atrophy on MRI (27/184, 14.7%) were specific to patients with RPD, representing additional distinguishing features.ConclusionHallucinations, cortical visual loss, substantial atrophy on MRI, elevated CSF protein, and normal CSF white blood cell count were independently associated with RPD. Early detection of these features in patients with suspected RPD may inform clinical care and enrollment in research studies of RPD.

AbstractObjectivePrion disease classically presents with rapidly progressive dementia, leading to death within months of diagnosis. Advances in diagnostic testing have improved recognition of patients with atypical presentations and protracted disease courses, raising key questions surrounding the relationship between patterns of neurodegeneration and survival. We assessed the contribution of fluorodeoxyglucose (FDG‐PET) imaging for this purpose.MethodsFDG‐PET were performed in 40 clinic patients with prion disease. FDG‐PET images were projected onto latent factors generated in an external dataset to yield patient‐specific eigenvalues. Eigenvalues were input into a clustering algorithm to generate data‐driven clusters, which were compared by survival time.ResultsMedian age at FDG‐PET was 65.3 years (range 23–85). Median time from FDG‐PET to death was 3.7 months (range 0.3–19.0). Four data‐driven clusters were generated, termed “Neocortical” (n = 7), “Transitional” (n = 12), “Temporo‐parietal” (n = 13), and “Deep nuclei” (n = 6). Deep nuclei and transitional clusters had a shorter survival time than the neocortical cluster. Subsequent analyses suggested that this difference was driven by greater hypometabolism of deep nuclei relative to neocortical areas. FDG‐PET‐patterns were not associated with demographic (age and sex) or clinical (CSF total‐tau, 14‐3‐3) variables.InterpretationGreater hypometabolism within deep nuclei relative to neocortical areas associated with more rapid decline in patients with prion disease and vice versa. FDG‐PET informs large‐scale network physiology and may inform the relationship between spreading pathology and survival in patients with prion disease. Future studies should consider whether FDG‐PET may enrich multimodal prion disease prognostication models.