プリオン病

Nationwide surveillance of Creutzfeldt-Jakob disease (CJD) and other human prion diseases is performed by the Australian National Creutzfeldt-Jakob Disease Registry (ANCJDR). National surveillance encompasses the period since 1 January 1970, with prospective surveillance occurring from 1 October 1993. Over this prospective surveillance period, considerable improvements have been developed in pre-mortem diagnostics in parallel with the delineation of new disease subtypes and heightened awareness of prion diseases in healthcare settings. Surveillance practices of the ANCJDR have evolved and adapted accordingly. This report summarises the activities of the ANCJDR during 2025. Since the ANCJDR began offering diagnostic cerebrospinal fluid (CSF) 14-3-3 protein testing in Australia in September 1997, the annual number of diagnostic test referrals has steadily increased. In 2025, there were 788 domestic CSF specimens referred for diagnostic testing; 92 persons with suspected human prion disease were formally added to the national register. As of 31 December 2025, more than half of the 84 initial case notifications for 2025 (44/84) remain classified as 'incomplete'; 35 cases have been confirmed as 'definite' or 'probable' prion disease; five cases were excluded. In 2025, most suspected human-prion-disease-related deaths in Australia (56%) underwent neuropathological examination. No cases of variant or iatrogenic CJD were identified in Australia during 2025.

BACKGROUND AND OBJECTIVES: Rapidly progressive Alzheimer disease and related dementias (rpADRD) is a clinically urgent syndrome characterized by accelerated deterioration. Because it is often confounded by acute etiologies, its definition remains poorly characterized. We aimed to evaluate rpADRD as a distinct clinical state, testing the hypothesis that it represents a clinical "phase transition" rather than a simple linear acceleration of typical neurodegenerative decline. Our objective was to define this transition threshold and quantify its impact on survival and disease trajectory. METHODS: We conducted a retrospective cohort study using longitudinal data from participants recruited across US Alzheimer's Disease Research Centers. We defined incident rpADRD as dementia development (global Clinical Dementia Rating [CDR] ≥1) within 1 year of symptom onset, or progression to moderate-to-severe impairment (global CDR ≥2) within 2 years. To isolate primary neurodegeneration, we excluded prion, infectious, metabolic, toxic, and autoimmune etiologies. We used time-dependent Cox regression, multistate modeling, and restricted cubic spline analyses to model nonlinear survival dynamics. RESULTS: The final analysis cohort included 2,307 participants (mean baseline age 78.9 years; 57.1% female). Over a mean follow-up of 7.3 years, 270 patients (11.7%) developed incident rpADRD. Patients transitioning to rpADRD were older than non-rpADRD patients (mean 80.0 vs 78.8 years). Crucially, the transition to rpADRD was strongly associated with increased subsequent mortality (hazard ratio = 4.03; 95% CI 3.53-4.61, p < 0.001). Multistate and spline modeling confirmed that this shift represents a distinct, nonlinear clinical phase transition rather than a linear exacerbation of functional decline. Furthermore, this critical tipping point was reliably preceded by an early cascade of neuropsychiatric symptoms. DISCUSSION: These findings validate a clinical "phase transition" model for rpADRD, demonstrating that survival decline is not merely a linear function of disease severity. Rather, rpADRD constitutes a distinct state of clinical homeostatic failure fundamentally shifting subsequent mortality risk, often predicted by early neuropsychiatric symptoms. Recognizing this nonlinear shift is vital for accurate prognostication and segregation of rapidly progressing phenotypes in trials. Major limitations include reliance on observational data, potential recall bias regarding symptom onset, and the exclusion of neuroimaging and fluid biomarkers because of high missingness.

Prion diseases, of which Creutzfeldt-Jakob disease is the most common, are fatal neurodegenerative disorders and are often rapidly progressive. They are associated with a significant palliative care burden for patients and families, ranging from prognostic uncertainty to complex symptom management to caregiver distress. Healthcare professionals face unique pressures when caring for these patients, which can include a lack of familiarity with this rare diagnosis and rapidly evolving symptom needs due to accelerated clinical deterioration. We convened a multidisciplinary panel of experts from around the UK, including palliative care doctors, general practitioners, physician and nurse specialists in prion diseases, and a lived experience representative to compile practical, consensus-based recommendations for managing prion diseases, much of which can also be applied to other rapidly progressive dementias. In this article, we examine the available evidence base for managing various aspects of prion diseases. Where evidence is limited, we suggest best practices informed by decades of our collective experiences.

Amyloids are traditionally associated with neurodegenerative and systemic diseases, yet it is now clear that they also perform essential physiological functions across kingdoms of life. Over the last decade, advances in cryogenic electron microscopy (cryo-EM) have enabled high-resolution structural characterization of functional amyloids, transforming our understanding of how the amyloid fold can be repurposed for biological activity. A landmark study in 2020 reported the cryo-EM structure of Orb2, a neuronal amyloid required for long-term memory persistence, establishing the first atomic view of a nuclear amyloid fibril. Subsequent structures of human RNA-binding proteins that form functional amyloids further expanded this paradigm. The structure of hnRNPDL-2 revealed how prion-like low-complexity domains can assemble into highly ordered, stable fibrils while keeping the necessary functionality for RNA metabolism. More recently, cryo-EM structures of the pigment-associated amyloid PMEL have provided insight into the molecular basis of melanosome biogenesis and pigmentation. In parallel, structural studies of bacterial functional amyloids, including the biofilm protein FapC, have uncovered architectures optimized for mechanical robustness and environmental resilience. Together, these pioneering studies reveal shared structural principles, alongside organism-specific adaptations that distinguish functional amyloids from their pathological counterparts.

Chronic wasting disease (CWD) is a fatal neurodegenerative disease caused by infectious prions affecting wild and captive cervids. Transmission occurs directly between hosts or indirectly through contact with prion-contaminated environments. Soils, particularly those rich in clay, are hypothesized to enhance prion stability, retention, and bioavailability. Accurate detection of prions is therefore important for understanding environmental transmission risks. Real-time quaking-induced conversion (RT-QuIC) is a sensitive assay used to detect PrPCWD in tissue, excreta, and environmental materials. However, RT-QuIC performance across soil textures has not been evaluated. This study assessed RT-QuIC sensitivity and specificity using laboratory-prepared soils spiked with CWD-positive brain homogenate or water controls under a standardized extraction method. Conditional on the extraction method used, results suggest that RT-QuIC performance depends on soil texture, and thus, an optimal time-to-threshold (TTT) cutoff required to balance sensitivity and specificity will also vary with soil texture. RT-QuIC exhibited higher sensitivity and moderate specificity in soils with low clay (<20%) and moderate to high silt content, whereas high-clay soils (>20%) with low to moderate silt content (2%-60%) reduced both sensitivity and specificity, and required shorter TTT cutoffs. These findings highlight the importance of accounting for soil texture in environmental CWD surveillance.