National Prion Clinic Research Articles

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

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. Five hundred and thirty-seven 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. Two hundred and eighty (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 methionine homozygous compared with methionine-valine heterozygous; 95% confidence interval 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.

Estimation of the number of inherited prion disease mutation carriers in the UK

Inherited prion diseases (IPD) are a set of rare neurodegenerative diseases that are always caused by mutation of the prion protein gene (PRNP). These are highly heterogeneous in clinical presentation and best described by the specific gene mutation, but traditionally include the canonical syndromes familial Creutzfeldt-Jakob disease, Gerstamann-Straussler-Scheinker syndrome, and fatal familial insomnia. In the UK, care of IPD patients and clinical PRNP sequencing have been carried out almost exclusively by the National Prion Clinic and affiliated laboratories since the disease gene was discovered in 1989. Using data obtained over 30 years (1990–2019), this study aimed to provide a greater understanding of the genetic prevalence of IPD using multiple complementary methods. A key source of bias in rare disorders is ascertainment, so we included an analysis based on capture-recapture techniques that may help to minimise ascertainment bias. 225 patients, with 21 different IPD mutations were identified, varying in frequency (with 8/21 mutations comprising over 90% observed cases), derived from 116 kindreds and 151 3-generation families. We estimated a total of 303 UK families (95% CI = 222, 384) segregate IPD mutations, 1091 (95% CI = 720, 1461) UK mutation carriers and a lifetime risk of approximately 1 in 60,000. Simpler methods of measuring prevalence based on extrapolation from the annual incidence of disease, and large scale genomic studies, result in similar estimates of prevalence. These estimates may be of value for planning preventive trials of therapeutics in IPD mutation carriers, prevention of prion disease transmission and provision of specialist services.

Characterization of Prion Disease Associated with a Two-Octapeptide Repeat Insertion.

Genetic prion disease accounts for 10–15% of prion disease. While insertion of four or more octapeptide repeats are clearly pathogenic, smaller repeat insertions have an unclear pathogenicity. The goal of this case series was to provide an insight into the characteristics of the 2-octapeptide repeat genetic variant and to provide insight into the risk for Creutzfeldt–Jakob disease in asymptomatic carriers. 2-octapeptide repeat insertion prion disease cases were collected from the National Prion Disease Pathology Surveillance Center (US), the National Prion Clinic (UK), and the National Creutzfeldt–Jakob Disease Registry (Australia). Three largescale population genetic databases were queried for the 2-octapeptide repeat insertion allele. Eight cases of 2-octapeptide repeat insertion were identified. The cases were indistinguishable from the sporadic Creutzfeldt–Jakob cases of the same molecular subtype. Western blot characterization of the prion protein in the absence of enzymatic digestion with proteinase K revealed that 2-octapeptide repeat insertion and sporadic Creutzfeldt–Jakob disease have distinct prion protein profiles. Interrogation of large-scale population datasets suggested the variant is of very low penetrance. The 2-octapeptide repeat insertion is at most a low-risk genetic variant. Predictive genetic testing for asymptomatic blood relatives is not likely to be justified given the low risk.

Diagnosing Sporadic Creutzfeldt-Jakob Disease by the Detection of Abnormal Prion Protein in Patient Urine

Creutzfeldt-Jakob disease (CJD) is a fatal neurodegenerative disorder associated with the accumulation of infectious abnormal prion protein through a mechanism of templated misfolding. A recent report has described the detection of abnormal prion protein in the urine of patients with variant CJD (vCJD) using protein misfolding by cyclic amplification, which was apparently absent in the more common sporadic form of CJD (sCJD). A noninvasive diagnostic test could improve early diagnosis of sCJD and, by screening donations, mitigate the potential risks of prion transmission through human urine-derived pharmaceuticals. Here, we describe the adaptation of the direct detection assay, developed originally as a blood test for vCJD, for the detection of disease-associated prion protein in urine samples from patients with sCJD. To determine the feasibility of sCJD diagnosis by adaptation of an established vCJD diagnostic blood test to urine. This retrospective, cross-sectional study included anonymized urine samples from healthy nonneurological control individuals (n = 91), patients with non-prion neurodegenerative diseases (n = 34), and patients with prion disease (n = 37) of which 20 had sCJD. Urine samples obtained during the Medical Research Council PRION-1 Trial, the National Prion Monitoring Cohort Study, and/or referred to the National Prion Clinic or Dementia Research Centre at the National Hospital for Neurology and Neurosurgery in the United Kingdom. Presence of sCJD infection determined by an assay that captures, enriches, and detects disease-associated prion protein isoforms. A total of 162 samples were analyzed, composed of 91 normal control individuals (51 male, 33 female, and 7 not recorded), 34 neurological disease control individuals (19 male and 15 female), and 37 with prion disease (22 male and 15 female). The assay's specificity for prion disease was 100% (95% CI, 97%-100%), with no false-positive reactions from 125 control individuals, including 34 from a range of neurodegenerative diseases. In contrast to a previous study, which used a different method, sensitivity to vCJD infection was low (7.7%; 95% CI, 0.2%-36%), with only 1 of 13 patients with positive test results, while sensitivity to sCJD was unexpectedly high at 40% (95% CI, 19%-64%). We determined 40% of sCJD urine sample results as positive. To our knowledge, this is the first demonstration of an assay that can detect sCJD infection in urine or any target analyte outside of the central nervous system. Urine detection could allow the development of rapid, molecular diagnostics for sCJD and has implications for other neurodegenerative diseases where disease-related assemblies of misfolded proteins might also be present in urine.

Neuronal antibodies in patients with suspected or confirmed sporadic Creutzfeldt-Jakob disease

ObjectivesThere have been reports of patients with antibodies to neuronal antigens misdiagnosed as sporadic Creutzfeldt-Jakob disease (sCJD). Conversely, low levels of antibodies to neuronal proteins have been reported in patients...

Population screening for variant Creutzfeldt-Jakob disease using a novel blood test: diagnostic accuracy and feasibility study.

Our study indicates a prototype blood-based variant Creutzfeldt-Jakob disease (vCJD) assay has sufficient sensitivity and specificity to justify a large study comparing vCJD prevalence in the United Kingdom with a bovine spongiform encephalopathy-unexposed population. In a clinical diagnostic capacity, the assay's likelihood ratios dramatically change an individual's pretest disease odds to posttest probabilities and can confirm vCJD infection. To determine the diagnostic accuracy of a prototype blood test for vCJD and hence its suitability for clinical use and for screening prion-exposed populations. Retrospective, cross-sectional diagnostic study of blood samples from national blood collection and prion disease centers in the United States and United Kingdom. Anonymized samples were representative of the US blood donor population (n = 5000), healthy UK donors (n = 200), patients with nonprion neurodegenerative diseases (n = 352), patients in whom a prion disease diagnosis was likely (n = 105), and patients with confirmed vCJD (n = 10). Presence of vCJD infection determined by a prototype test (now in clinical diagnostic use) that captures, enriches, and detects disease-associated prion protein from whole blood using stainless steel powder. The assay's specificity among the presumed negative American donor samples was 100% (95% CI, 99.93%-100%) and was confirmed in a healthy UK cohort (100% specificity; 95% CI, 98.2%-100%). Of potentially cross-reactive blood samples from patients with nonprion neurodegenerative diseases, no samples tested positive (100% specificity; 95% CI, 98.9%-100%). Among National Prion Clinic referrals in whom a prion disease diagnosis was likely, 2 patients with sporadic CJD tested positive (98.1% specificity; 95% CI, 93.3%-99.8%). Finally, we reconfirmed but could not refine our previous sensitivity estimate in a small blind panel of samples from unaffected individuals and patients with vCJD (70% sensitivity; 95% CI, 34.8%-93.3%). In conjunction with the assay's established high sensitivity (71.4%; 95% CI, 47.8%-88.7%), the extremely high specificity supports using the assay to screen for vCJD infection in prion-exposed populations. Additionally, the lack of cross-reactivity and false positives in a range of nonprion neurodegenerative diseases supports the use of the assay in patient diagnosis.

Behavioral and psychiatric symptoms in prion disease.

The prion diseases are rare neurodegenerative conditions that cause complex and highly variable neuropsychiatric syndromes, often with remarkably rapid progression. Prominent behavioral and psychiatric symptoms have been recognized since these diseases were first described. While research on such symptoms in common dementias has led to major changes in the way these symptoms are managed, evidence to guide the care of patients with prion disease is scarce. The authors review the published research and draw on more than 10 years' experience at the U.K. National Prion Clinic, including two large prospective clinical research studies in which more than 300 patients with prion disease have been followed up from diagnosis to death, with detailed observational data gathered on symptomatology and symptomatic treatments. The authors group behavioral and psychiatric symptoms into psychotic features, agitated features, and mood disorder and describe their natural history, showing that they spontaneously improve or resolve in many patients and are short-lived in many others because of rapid progression of global neurological disability. Diagnostic category, disease severity, age, gender, and genetic variation are or may be predictive factors. The authors review the observational data on pharmacological treatment of these symptoms in the U.K. clinical studies and make cautious recommendations for clinical practice. While nonpharmacological measures should be the first-line interventions for these symptoms, the authors conclude that there is a role for judicious use of pharmacological agents in some patients: antipsychotics for severe psychosis or agitation; benzodiazepines, particularly in the late stages of disease; and antidepressants for mood disorder.

MRI findings are often missed in the diagnosis of Creutzfeldt-Jakob disease.

BackgroundEstablishing a confident clinical diagnosis before an advanced stage of illness can be difficult in Creutzfeldt-Jakob disease (CJD) but unlike common causes of dementia, prion diseases can often be diagnosed by identifying characteristic MRI signal changes. However, it is not known how often CJD-associated MRI changes are identified at the initial imaging report, whether the most sensitive sequences are used, and what impact MRI-diagnosis has on prompt referral to clinical trial-like studies.MethodsWe reviewed the MRI scans of 103 patients with CJD referred to the National Prion Clinic since 2007 and reviewed the presence of CJD-associated changes, compared these findings with the formal report from the referring centre and reviewed the types of sequence performed.ResultsIn sCJD we found CJD-associated MRI changes in 83 of 91 cases (91% sensitivity). However, the referring centres documented CJD-associated MRI changes in 43 of the sCJD cases (47% sensitivity). The most common region not documented by referring centres was the cortex (23 of 68 sCJD cases), but there was a statistically significant discrepancy in all regions (p<0.0001). Patients in whom MRI abnormalities were missed by the referring hospital were more advanced at the time of recruitment to a clinical trial-like study (p=0.03).ConclusionsCJD-associated MRI changes are often not documented on the formal investigation report at the referring centre. This is important as delay makes enrolment to clinical trials futile because of highly advanced disease. If a diagnosis of CJD is suspected, even if the initial imaging is reported as normal, a specialist MRI review either by an experienced neuroradiologist or by a prion disease specialist unit could facilitate earlier diagnosis.

Exploring the carers experience of the symptoms of prion disease

BackgroundPrion diseases, also known as transmissible spongiform encephalopathies (TSE's) are a group of progressive neurodegenerative conditions for which there is no current treatment or cure. Human prion diseases include sporadic...

Counselling people with Creutzfeldt-Jakob Disease (CJD) and their families

This article gives an account of the counselling service for people with Creutzfeldt-Jakob Disease (CJD) at the National Prion Clinic which is based in the National Hospital for Neurology and Neurosurgery in the UK and aims to provide information, advocacy and support from diagnosis through bereavement for people with a diagnosis of Creutzfeldt-Jakob Disease (CJD) and their families.

POD01 Misleading MRI in two recent patients with variant Creutzfeldt–Jakob disease emphasises the importance of tissue diagnosis

As the vCJD outbreak evolves we are alert to possible changes in the clinicopathological phenotype, investigations and genetic analysis. MRI typically shows high signal in the pulvinar nucleus on T2W...

Heterozygosity at Polymorphic Codon 219 in Variant Creutzfeldt-Jakob Disease

Genetic variants of the prion protein gene (PRNP) strongly determine susceptibility to prion diseases. All tested patients with definite variant Creutzfeldt-Jakob disease (vCJD) are homozygous for methionine at a common polymorphism at codon 129. A further genetic polymorphism at codon 219, a common variant in several Asian populations, is considered protective against sporadic CJD. To report a finding of heterozygosity at codon 219 in 2 patients with vCJD. Case reports. MRC (Medical Research Council) Prion Unit and Department of Neurodegenerative Disease, University College London Institute of Neurology, and National Prion Clinic, National Hospital for Neurology and Neurosurgery. Patients Two patients with clinical and investigation findings consistent with the diagnoses of probable vCJD. Clinical and genetic findings. A 34-year-old man had a 15-month history of behavioral change progressing to ataxia, dysarthria, involuntary choreiform movements, and severe cognitive impairment. Cerebrospinal fluid analysis was positive for 14-3-3 protein, electroencephalography showed generalized slowing, and magnetic resonance imaging revealed thalamic high signal bilaterally, typical of vCJD. A 31-year-old woman had a 16-month history of cognitive decline, ataxia, involuntary choreiform movements, and myoclonic jerks. Magnetic resonance imaging showed bilateral pulvinar high signal. The diagnosis was confirmed by a tonsillar biopsy demonstrating abnormal prion protein deposition in a typical pattern for vCJD. PRNP sequencing showed a methionine homozygous codon 129 genotype and an E219K polymorphism in both patients. The E219K polymorphism is neutral or may even confer susceptibility to vCJD. The observations are interpretable in the context of the conformational selection model of prion replication. A barrier to prion disease transmission depends on the degree to which permitted pathologic conformations of the prion protein overlap between the inoculum and the host.

Seven‐year discordance in age at onset in monozygotic twins with inherited prion disease (P102L)

Neuropathology and Applied NeurobiologyVolume 35, Issue 4 p. 427-432 Seven-year discordance in age at onset in monozygotic twins with inherited prion disease (P102L) T. Webb, T. Webb National Prion Clinic, National Hospital for Neurology and Neurosurgery, MRC Prion Unit and Department of Neurodegenerative Disease, UCL Institute of Neurology,Search for more papers by this authorS. Mead, S. Mead National Prion Clinic, National Hospital for Neurology and Neurosurgery, MRC Prion Unit and Department of Neurodegenerative Disease, UCL Institute of Neurology,Search for more papers by this authorJ. Beck, J. Beck MRC Prion Unit and Department of Neurodegenerative Disease, UCL Institute of Neurology,Search for more papers by this authorJ. Uphill, J. Uphill MRC Prion Unit and Department of Neurodegenerative Disease, UCL Institute of Neurology,Search for more papers by this authorS. Pal, S. Pal National Prion Clinic, National Hospital for Neurology and Neurosurgery, MRC Prion Unit and Department of Neurodegenerative Disease, UCL Institute of Neurology,Search for more papers by this authorS. Hampson, S. Hampson National Prion Clinic, National Hospital for Neurology and Neurosurgery,Search for more papers by this authorJ. D. F. Wadsworth, J. D. F. Wadsworth MRC Prion Unit and Department of Neurodegenerative Disease, UCL Institute of Neurology,Search for more papers by this authorI. Dalmau Mena, I. Dalmau Mena MRC Prion Unit and Department of Neurodegenerative Disease, UCL Institute of Neurology,Search for more papers by this authorC. O'Malley, C. O'Malley MRC Prion Unit and Department of Neurodegenerative Disease, UCL Institute of Neurology,Search for more papers by this authorS. Wroe, S. Wroe National Prion Clinic, National Hospital for Neurology and Neurosurgery, MRC Prion Unit and Department of Neurodegenerative Disease, UCL Institute of Neurology,Search for more papers by this authorA. Schapira, A. Schapira and University Department of Clinical Neurosciences, Royal Free & University College Medical School, London, UK.Search for more papers by this authorS. Brandner, S. Brandner MRC Prion Unit and Department of Neurodegenerative Disease, UCL Institute of Neurology,Search for more papers by this authorJ. Collinge, J. Collinge National Prion Clinic, National Hospital for Neurology and Neurosurgery, MRC Prion Unit and Department of Neurodegenerative Disease, UCL Institute of Neurology,Search for more papers by this author T. Webb, T. Webb National Prion Clinic, National Hospital for Neurology and Neurosurgery, MRC Prion Unit and Department of Neurodegenerative Disease, UCL Institute of Neurology,Search for more papers by this authorS. Mead, S. Mead National Prion Clinic, National Hospital for Neurology and Neurosurgery, MRC Prion Unit and Department of Neurodegenerative Disease, UCL Institute of Neurology,Search for more papers by this authorJ. Beck, J. Beck MRC Prion Unit and Department of Neurodegenerative Disease, UCL Institute of Neurology,Search for more papers by this authorJ. Uphill, J. Uphill MRC Prion Unit and Department of Neurodegenerative Disease, UCL Institute of Neurology,Search for more papers by this authorS. Pal, S. Pal National Prion Clinic, National Hospital for Neurology and Neurosurgery, MRC Prion Unit and Department of Neurodegenerative Disease, UCL Institute of Neurology,Search for more papers by this authorS. Hampson, S. Hampson National Prion Clinic, National Hospital for Neurology and Neurosurgery,Search for more papers by this authorJ. D. F. Wadsworth, J. D. F. Wadsworth MRC Prion Unit and Department of Neurodegenerative Disease, UCL Institute of Neurology,Search for more papers by this authorI. Dalmau Mena, I. Dalmau Mena MRC Prion Unit and Department of Neurodegenerative Disease, UCL Institute of Neurology,Search for more papers by this authorC. O'Malley, C. O'Malley MRC Prion Unit and Department of Neurodegenerative Disease, UCL Institute of Neurology,Search for more papers by this authorS. Wroe, S. Wroe National Prion Clinic, National Hospital for Neurology and Neurosurgery, MRC Prion Unit and Department of Neurodegenerative Disease, UCL Institute of Neurology,Search for more papers by this authorA. Schapira, A. Schapira and University Department of Clinical Neurosciences, Royal Free & University College Medical School, London, UK.Search for more papers by this authorS. Brandner, S. Brandner MRC Prion Unit and Department of Neurodegenerative Disease, UCL Institute of Neurology,Search for more papers by this authorJ. Collinge, J. Collinge National Prion Clinic, National Hospital for Neurology and Neurosurgery, MRC Prion Unit and Department of Neurodegenerative Disease, UCL Institute of Neurology,Search for more papers by this author First published: 30 June 2009 https://doi.org/10.1111/j.1365-2990.2009.01012.xCitations: 10 Disclosure: J.C. is a Director, and J.C. and J.D.F.W. are shareholders and consultants of D-Gen Limited, an academic spin-out company working in the field of prion disease diagnosis, decontamination and therapeutics. D-Gen markets the ICSM18 antibody used in this study. 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The neuropsychology of variant CJD: a comparative study with inherited and sporadic forms of prion disease

Objective: To assess cognitive function in variant Creutzfeldt-Jakob disease (vCJD). We describe the neuropsychological profiles of 10 cases and compare these data with cross sectional data obtained from patients with...