Development of prognostic models for survival and care status in sporadic Creutzfeldt-Jakob disease

Abstract

Sporadic Creutzfeldt-Jakob disease, the most common human prion disease, typically presents as a rapidly progressive dementia and has a highly variable prognosis. Despite this heterogeneity, clinicians need to give timely advice on likely prognosis and care needs. No prognostic models have been developed that predict survival or time to increased care status from the point of diagnosis. We aimed to develop clinically useful prognostic models with data from a large prospective observational cohort study. 537 patients were visited by mobile teams of doctors and nurses from the National Health Service National Prion Clinic within 5 days of notification of a suspected diagnosis of sporadic Creutzfeldt-Jakob disease, enrolled to the study between October 2008 and March 2020, and followed up until November 2020. Prediction of survival over 10-, 30- and 100- day periods was the main outcome. Escalation of care status over the same time periods was a secondary outcome for a subsample of 113 patients with low care status at initial assessment. 280 (52.1%) patients were female and the median age was 67.2 (interquartile range 10.5) years. Median survival from initial assessment was 24 days (range 0-1633); 414 patients died within 100 days (77%). Ten variables were included in the final prediction models: sex; days since symptom onset; baseline care status; PRNP codon 129 genotype; Medical Research Council Prion Disease Rating Scale, Motor and Cognitive Examination Scales; count of MRI abnormalities; Mini-Mental State Examination score and categorical disease phenotype. The strongest predictor was PRNP codon 129 genotype (odds ratio 6.65 for MM compared to MV polymorphism; 95% CI 3.02-14.68 for 30-day mortality). Of 113 patients with lower care status at initial assessment, 88 (78%) had escalated care status within 100 days, with a median of 35 days. Area under the curve for models predicting outcomes within 10, 30 and 100 days was 0.94, 0.92 and 0.91 for survival, and 0.87, 0.87 and 0.95 for care status escalation respectively. Models without PRNP codon 129 genotype, which is not immediately available at initial assessment, were also highly accurate. We have developed a model that can accurately predict survival and care status escalation in sporadic Creutzfeldt-Jakob disease patients using clinical, imaging and genetic data routinely available in a specialist national referral service. The utility and generalizability of these models to other settings could be prospectively evaluated when recruiting to clinical trials and providing clinical care.

Diagnostic and prognostic value of cerebrospinal fluid SNAP-25 and neurogranin in Creutzfeldt-Jakob disease in a clinical setting cohort of rapidly progressive dementias

“…In the present study, in line with recently proposed prognostic models [38,39], we carried out the survival analyses also considering clinical variables known to have a prognostic role in prion diseases such as age at LP, PRNP codon 129 genotype, and time between symptoms onset and LP. Consistent with previous observations [21], we found a significant association between CSF levels of SNAP-25 at LP and survival, even after accounting for covariates such as codon 129 genotype, age at LP, and time between symptoms onset and LP.…”

Genome wide association study of clinical duration and age at onset of sporadic CJD

“…The median clinical duration is usually reported as five months with a range of only a few weeks to several years (2). Ability to estimate the likely clinical duration could help with timely decisions about care (8).…”

“…Human epidemiological and genetic studies have identified factors that associate with survival time in sCJD(2, 8, 18, 19), including demography, prion protein genotype, molecular strain typing of protease-resistant prion protein by Western blot analysis, and a range of biofluid, tissue, imaging, and neurophysiological biomarkers(20). Many biomarkers simply measure the rate or extent of neuronal injury, loss, or dysfunction, or immune cell or glial responses, whereas genetic associations are implicitly causal of modified clinical phenotypes.…”