Peter Rudge's research while affiliated with UCL Eastman Dental Institute and other places

Alzheimer’s disease (AD) is characterized pathologically by amyloid-beta (Aβ) deposition in brain parenchyma and blood vessels (as cerebral amyloid angiopathy (CAA)) and by neurofibrillary tangles of hyperphosphorylated tau. Compelling genetic and biomarker evidence supports Aβ as the root cause of AD. We previously reported human transmission of Aβ pathology and CAA in relatively young adults who had died of iatrogenic Creutzfeldt–Jakob disease (iCJD) after childhood treatment with cadaver-derived pituitary growth hormone (c-hGH) contaminated with both CJD prions and Aβ seeds. This raised the possibility that c-hGH recipients who did not die from iCJD may eventually develop AD. Here we describe recipients who developed dementia and biomarker changes within the phenotypic spectrum of AD, suggesting that AD, like CJD, has environmentally acquired (iatrogenic) forms as well as late-onset sporadic and early-onset inherited forms. Although iatrogenic AD may be rare, and there is no suggestion that Aβ can be transmitted between individuals in activities of daily life, its recognition emphasizes the need to review measures to prevent accidental transmissions via other medical and surgical procedures. As propagating Aβ assemblies may exhibit structural diversity akin to conventional prions, it is possible that therapeutic strategies targeting disease-related assemblies may lead to selection of minor components and development of resistance.

Human prion diseases are remarkable for long incubation times followed typically by rapid clinical decline. Seed amplification assays and neurodegeneration biofluid biomarkers are remarkably useful in the clinical phase, but their potential to predict clinical onset in healthy people remains unclear. This is relevant not only to the design of preventive strategies in those at-risk of prion diseases, but more broadly, because prion-like mechanisms are thought to underpin many neurodegenerative disorders. Here, we report the accrual of a longitudinal biofluid resource in patients, controls and healthy people at risk of prion diseases, to which ultrasensitive techniques such as real-time quaking-induced conversion (RT-QuIC) and single molecule array (Simoa) digital immunoassays were applied for preclinical biomarker discovery. We studied 648 CSF and plasma samples, including 16 people who had samples taken when healthy but later developed inherited prion disease (IPD) (‘converters’; range from 9.9 prior to, and 7.4 years after onset). Symptomatic IPD CSF samples were screened by RT-QuIC assay variations, before testing the entire collection of at-risk samples using the most sensitive assay. Glial fibrillary acidic protein (GFAP), neurofilament light (NfL), tau and UCH-L1 levels were measured in plasma and CSF. Second generation (IQ-CSF) RT-QuIC proved 100% sensitive and specific for sporadic Creutzfeldt-Jakob disease (CJD), iatrogenic and familial CJD phenotypes, and subsequently detected seeding activity in four presymptomatic CSF samples from three E200K carriers; one converted in under 2 months while two remain asymptomatic after at least 3 years’ follow-up. A bespoke HuPrP P102L RT-QuIC showed partial sensitivity for P102L disease. No compatible RT-QuIC assay was discovered for classical 6-OPRI, A117V and D178N, and these at-risk samples tested negative with bank vole RT-QuIC. Plasma GFAP and NfL, and CSF NfL levels emerged as proximity markers of neurodegeneration in the typically slow IPDs (e.g. P102L), with significant differences in mean values segregating healthy control from IPD carriers (within 2 years to onset) and symptomatic IPD cohorts; plasma GFAP appears to change before NfL, and before clinical conversion. In conclusion, we show distinct biomarker trajectories in fast and slow IPDs. Specifically, we identify several years of presymptomatic seeding positivity in E200K, a new proximity marker (plasma GFAP) and sequential neurodegenerative marker evolution (plasma GFAP followed by NfL) in slow IPDs. We suggest a new preclinical staging system featuring clinical, seeding and neurodegeneration aspects, for validation with larger prion at-risk cohorts, and with potential application to other neurodegenerative proteopathies.

Human prion diseases are remarkable for long incubation times followed by typically rapid clinical decline. Seed amplification assays and neurodegeneration biofluid biomarkers are remarkably useful in the clinical phase, but their potential to predict clinical onset in healthy people remains unclear. This is relevant not only to the design of preventive strategies in those at-risk of prion diseases, but more broadly, because prion-like mechanisms are thought to underpin many neurodegenerative disorders. Here we report the accrual of a longitudinal biofluid resource in patients, controls and healthy people at-risk of prion diseases, to which ultrasensitive techniques such as real-time quaking-induced conversion (RT-QuIC), and single molecule array (Simoa) digital immunoassays were applied for preclinical biomarker discovery. We studied a total of 648 CSF and plasma samples, including importantly, 16 people who had samples taken when healthy but later developed IPD (converters, range from 9.9 prior to, and 7.4 years after onset). A second generation (IQ-CSF) RT-QuIC assay was used to screen symptomatic IPD samples, followed by optimisation for other IPDs, before the entire collection of at-risk samples was screened using the most sensitive assay. Glial fibrillary acidic protein (GFAP), neurofilament light (NfL), tau and ubiquitin carboxy-terminal hydrolase L1 (UCH-L1) levels were measured in plasma and CSF. IQ-CSF RT-QuIC proved 100% sensitive and specific for sporadic CJD, iCJD and familial CJD phenotypes, and subsequently detected seeding activity in four CSF samples from three PRNP E200K carriers in the presymptomatic phase, one of whom converted shortly after but the other two remain asymptomatic after two and three years of follow up. A bespoke HuPrP P102L RT-QuIC showed partial sensitivity for P102L disease and was positive in a CSF sample from an individual at risk of P102L IPD. No compatible RT-QuIC assay iterations were discovered for classical 6-OPRI, A117V and D178N, and these at-risk samples tested negative with bank vole RT-QuIC. Plasma GFAP and NfL, and CSF NfL levels emerged as proximity markers of neurodegeneration in slowly progressive forms of IPDs, with highly statistically significant differences in mean values segregating normal control (together with IPD > 2 years to onset) from IPD < 2 years to onset and symptomatic IPD cohorts. The trajectories of biomarker change appeared to correspond to expected fast and slow clinical phenotypes of progression in IPD with plasma GFAP changes preceding NfL changes. We propose a staging system for prion diseases based on the presence of clinical, seeding and neurodegeneration features.

Inherited prion diseases (IPD) are caused by mutations in the prion protein gene ( PRNP ) leading to accu- mulation of misfolded prion protein (PrP). Here we describe three novel PRNP mutations. A patient with gradually progressive cognitive decline, peripheral neuropathy, diarrhoea and autonomic dysfunction, starting in the 6th decade, whose father suffered a similar illness with neuropathology showing PrP-cerebral amyloid angiopathy, PrP-amyloid plaques and abundant tau disease with co-localising TDP-43, had a truncation mutation at codon 157. A missense mutation at codon 107 of PRNP causing an amino acid change from threonine to isoleucine was observed in a patient with a 9-year illness starting with cognitive decline followed by gait disturbance. Neuropathology shows multi-centric PrP-amyloid plaques. Substitution of proline to serine at codon 105 has previously been reported in one patient, however our case exhibited a different phenotype: dysphasia in the absence of neurological signs, with subsequent rapid cognitive then motor decline with myoclonus. Neuropathology showed predominantly synaptic deposition of PrP and sparse cerebellar plaques. These cases highlight the remarkable heterogeneity which can be seen within IPD, and the importance of genetic screening of PRNP in cases where there is an unexplained phenotype, particularly when there is a family history.

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.

Background MRI is invaluable for the pre-mortem diagnosis of sporadic Creutzfeldt-Jakob disease (sCJD), demonstrating characteristic diffusion abnormalities. Previous work showed these changes were often not reported (low sensitivity), leading to eventual diagnosis at a more advanced state. Here, we reviewed the situation a decade later, on the presumption of improved access and awareness over time. Methods We reviewed initial MRI scans of 102 consecutive suspected sCJD patients recruited to the National Prion Monitoring Cohort study between 2015 and 2019, assessing for characteristic signal changes in the striatum, thalamus and cortical ribbon. We compared our findings to formal reports from referring centres. Requesting indications were studied to assess if they were suggestive of CJD. Patients were examined and their MRC Prion Disease Rating Scale scores recorded. Results We identified characteristic MRI abnormalities in 101 cases (99% sensitivity), whilst referring centres reported changes in 70 cases (69% sensitivity), which was a significant improvement in reporting sensitivity from 2012. Reporting sensitivity was associated with signal change in the cerebral cortex, and with the number of regions involved, but not significantly affected by clinical information on request forms, or referring centres being regional neuroscience/non-neuroscience centres. Similar to a previous study, patients with missed abnormalities on initial reporting possessed lower MRC Scale scores when referred to the NPC than those correctly identified. Conclusions Whilst local MRI reporting of sCJD has improved with time, characteristic abnormalities remain significantly under detected on initial scans. Sensitivity is better when the cerebral cortex and multiple regions are involved. We re-emphasize the utility of MRI and encourage further efforts to improve awareness and sensitivity in the assessment of patients with rapidly progressive dementia.

Background: Prion diseases cause a range of movement disorders involving the cortical, extrapyramidal, and cerebellar systems, and yet there are no large systematic studies of their prevalence, features, associations, and responses to commonly used treatments. Objectives: We sought to describe the natural history and pharmacological management of movement disorders in prion diseases. Methods: We studied the serial examination findings, investigation results, and symptomatic treatment recorded for 700 patients with prion diseases and 51 mimics who had been enrolled onto the prospective longitudinal National Prion Monitoring Cohort study between 2008 and 2020. We performed an analysis to identify whether there were patterns of movement disorders associated with disease aetiology, PRNP codon 129 polymorphism, disease severity rating scales, magnetic resonance imaging (MRI) and cerebrospinal fluid (CSF) findings. Results: Gait disturbances, myoclonus, and increased tone are the most frequently observed movement disorders in patients with prion diseases. The typical pattern of early motor dysfunction involves gait disturbance, limb ataxia, impaired smooth pursuit, myoclonus, tremor, and increased limb tone. Disturbances of gait, increased tone, and myoclonus become more prevalent and severe as the disease progresses. Chorea, alien limb phenomenon, and nystagmus were the least frequently observed movement disorders, with these symptoms showing spontaneous resolution in approximately half of symptomatic patients. Disease severity and PRNP codon 129 polymorphism were associated with different movement disorder phenotypes. Antiepileptics and benzodiazepines were found to be effective in treating myoclonus. Conclusions: We describe the prevalence, severity, evolution, treatment, and associated features of movement disorders in prion diseases based on a prospective cohort study. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

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.

Introduction MRI sensitivity of up to 96% for pre-mortem diagnosis of sporadic Creutzfeldt-Jakob disease (sCJD) has previously been reported. However, in 2012, Carswell et al. found that the initial neuroradio- logical report often failed to identify CJD-associated MRI changes (47% sensitivity). These patients were at a more advanced stage of disease when referred to specialist services. Here we assessed whether there has been a change over time. Methods We reviewed MRI scans of 106 patients (sCJD=102, IPD=4) referred to the NPC between 2015- 2019, and compared our findings with the formal reports from referring centres. We recorded the MRC Scale scores at initial patient assessment. Results We found characteristic MRI abnormalities in 101 out of 102 sCJD cases. A differential diagnosis of CJD was documented on the neuroradiological reports of 70 of these cases, giving a significantly improved sensitivity of 69% compared to 2012. There was no association between the location of signal change and reporting accuracy. Patients had less advanced disease compared to 2012. Conclusions MRI reporting of sCJD by referring centres has improved, but further improvement seems possible. We re-emphasize the importance of analysing scans thoroughly for characteristic MRI patterns of sCJD to enable earlier identification of these patients. Danielle sequeira@nhs.net|ABN Bursary 26

In the last 6 years, following the first pathological description of presumed amyloid-beta (Aβ) transmission in humans (in 2015) and subsequent experimental confirmation (in 2018), clinical cases of iatrogenic cerebral amyloid angiopathy (CAA)-attributed to the transmission of Aβ seeds-have been increasingly recognised and reported. This newly described form of CAA is associated with early disease onset (typically in the third to fifth decade), and often presents with intracerebral haemorrhage, but also seizures and cognitive impairment. Although assumed to be rare, it is important that clinicians remain vigilant for potential cases, particularly as the optimal management, prognosis, true incidence and public health implications remain unknown. This review summarises our current understanding of the clinical spectrum of iatrogenic CAA and provides a diagnostic framework for clinicians. We provide clinical details for three patients with pathological evidence of iatrogenic CAA and present a summary of the published cases to date (n=20), identified following a systematic review. Our aims are: (1) To describe the clinical features of iatrogenic CAA, highlighting important similarities and differences between iatrogenic and sporadic CAA; and (2) To discuss potential approaches for investigation and diagnosis, including suggested diagnostic criteria for iatrogenic CAA.