Population structure and migration in the Eastern Highlands of Papua New Guinea, a region impacted by the kuru epidemic.

Populations of the Eastern Highlands of Papua New Guinea (EHPNG, area 11,157 km2) lived in relative isolation from the rest of the world until the mid-20th century, and the region contains a wealth of linguistic and cultural diversity. Notably, several populations of EHPNG were devastated by an epidemic prion disease, kuru, which at its peak in the mid-twentieth century led to some villages being almost depleted of adult women. Until now, population genetic analyses to learn about genetic diversity, migration, admixture, and the impact of the kuru epidemic have been restricted to a small number of variants or samples. Here, we present a population genetic analysis of the region based on genome-wide genotype data of 943 individuals from 21 linguistic groups and 68 villages in EHPNG, including 34 villages in the South Fore linguistic group, the group most affected by kuru. We find a striking degree of genetic population structure in the relatively small region (average FST between linguistic groups 0.024). The genetic population structure correlates well with linguistic grouping, with some noticeable exceptions that reflect the clan system of community organization that has historically existed in EHPNG. We also detect the presence of migrant individuals within the EHPNG region and observe a significant excess of females among migrants compared to among non-migrants in areas of high kuru exposure (p = 0.0145, chi-squared test). This likely reflects the continued practice of patrilocality despite documented fears and strains placed on communities as a result of kuru and its associated skew in female incidence.

Creutzfeldt-Jakob disease and other prion diseases.

Prion diseases share common clinical and pathological characteristics such as spongiform neuronal degeneration and deposition of an abnormal form of a host-derived protein, termed prion protein. The characteristic features of prion diseases are long incubation times, short clinical courses, extreme resistance of the transmissible agent to degradation and lack of nucleic acid involvement. Sporadic and genetic forms of prion diseases occur worldwide, of which genetic forms are associated with mutations in PRNP. Human to human transmission of these diseases has occurred due to iatrogenic exposure, and zoonotic forms of prion diseases are linked to bovine disease. Significant progress has been made in the diagnosis of these disorders. Clinical tools for diagnosis comprise brain imaging and cerebrospinal fluid tests. Aggregation assays for detection of the abnormally folded prion protein have a clear potential to diagnose the disease in peripherally accessible biofluids. After decades of therapeutic nihilism, new treatment strategies and clinical trials are on the horizon. Although prion diseases are relatively rare disorders, understanding their pathogenesis and mechanisms of prion protein misfolding has significantly enhanced the field in research of neurodegenerative diseases.

Iatrogenic Alzheimer's disease in recipients of cadaveric pituitary-derived growth hormone.

Alzheimer's disease (AD) is characterized pathologically by amyloid-beta (Aß) 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 Aß as the root cause of AD. We previously reported human transmission of Aß 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 Aß 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 Aß 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 Aß 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.

Characterisation and prion transmission study in mice with genetic reduction of sporadic Creutzfeldt-Jakob disease risk gene Stx6.

Sporadic Creutzfeldt-Jakob disease (sCJD), the most common human prion disease, is thought to occur when the cellular prion protein (PrPC) spontaneously misfolds and assembles into prion fibrils, culminating in fatal neurodegeneration. In a genome-wide association study of sCJD, we recently identified risk variants in and around the gene STX6, with evidence to suggest a causal increase of STX6 expression in disease-relevant brain regions. STX6 encodes syntaxin-6, a SNARE protein primarily involved in early endosome to trans-Golgi network retrograde transport. Here we developed and characterised a mouse model with genetic depletion of Stx6 and investigated a causal role of Stx6 expression in mouse prion disease through a classical prion transmission study, assessing the impact of homozygous and heterozygous syntaxin-6 knockout on disease incubation periods and prion-related neuropathology. Following inoculation with RML prions, incubation periods in Stx6-/- and Stx6+/- mice differed by 12 days relative to wildtype. Similarly, in Stx6-/- mice, disease incubation periods following inoculation with ME7 prions also differed by 12 days. Histopathological analysis revealed a modest increase in astrogliosis in ME7-inoculated Stx6-/- animals and a variable effect of Stx6 expression on microglia activation, however no differences in neuronal loss, spongiform change or PrP deposition were observed at endpoint. Importantly, Stx6-/- mice are viable and fertile with no gross impairments on a range of neurological, biochemical, histological and skeletal structure tests. Our results provide some support for a pathological role of Stx6 expression in prion disease, which warrants further investigation in the context of prion disease but also other neurodegenerative diseases considering syntaxin-6 appears to have pleiotropic risk effects in progressive supranuclear palsy and Alzheimer's disease.

Clinical considerations in early-onset cerebral amyloid angiopathy.

Cerebral amyloid angiopathy (CAA) is an important cerebral small vessel disease associated with brain haemorrhage and cognitive change. The commonest form, sporadic amyloid-ß CAA, usually affects people in mid- to later life. However, early-onset forms, though uncommon, are increasingly recognized and may result from genetic or iatrogenic causes that warrant specific and focused investigation and management. In this review, we firstly describe the causes of early-onset CAA, including monogenic causes of amyloid-ß CAA (APP missense mutations and copy number variants; mutations of PSEN1 and PSEN2) and non-amyloid-ß CAA (associated with ITM2B, CST3, GSN, PRNP and TTR mutations), and other unusual sporadic and acquired causes including the newly-recognized iatrogenic subtype. We then provide a structured approach for investigating early-onset CAA, and highlight important management considerations. Improving awareness of these unusual forms of CAA amongst healthcare professionals is essential for facilitating their prompt diagnosis, and an understanding of their underlying pathophysiology may have implications for more common, late-onset, forms of the disease.

Seed amplification and neurodegeneration marker trajectories in individuals at risk of prion disease.

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.

Gene expression and epigenetic markers of prion diseases.

Epigenetics, meaning the variety of mechanisms underpinning gene regulation and chromatin states, plays a key role in normal development as well as in disease initiation and progression. Epigenetic mechanisms like alteration of DNA methylation, histone modifications, and non-coding RNAs, have been proposed as biomarkers for diagnosis, classification, or monitoring of responsiveness to treatment in many diseases. In prion diseases, the profound associations with human aging, the effects of cell type and differentiation on in vitro susceptibility, and recently identified human risk factors, all implicate causal epigenetic mechanisms. Here, we review the current state of the art of epigenetics in prion diseases and its interaction with genetic determinants. In particular, we will review recent advances made by several groups in the field profiling DNA methylation and microRNA expression in mammalian prion diseases and the potential for these discoveries to be exploited as biomarkers.

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.

Prevalence and Treatments of Movement Disorders in Prion Diseases: A Longitudinal Cohort Study.

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.

The Future of Seed Amplification Assays and Clinical Trials.

Prion-like seeded misfolding of host proteins is the leading hypothesised cause of neurodegenerative diseases. The exploitation of the mechanism in the protein misfolding cyclic amplification (PMCA) and real-time quaking-induced conversion (RT-QuIC) assays have transformed prion disease research and diagnosis and have steadily become more widely used for research into other neurodegenerative disorders. Clinical trials in adult neurodegenerative diseases have been expensive, slow, and disappointing in terms of clinical benefits. There are various possible factors contributing to the failure to identify disease-modifying treatments for adult neurodegenerative diseases, some of which include: limited accuracy of antemortem clinical diagnosis resulting in the inclusion of patients with the "incorrect" pathology for the therapeutic; the role of co-pathologies in neurodegeneration rendering treatments targeting one pathology alone ineffective; treatment of the primary neurodegenerative process too late, after irreversible secondary processes of neurodegeneration have become established or neuronal loss is already extensive; and preclinical models used to develop treatments not accurately representing human disease. The use of seed amplification assays in clinical trials offers an opportunity to tackle these problems by sensitively detecting in vivo the proteopathic seeds thought to be central to the biology of neurodegenerative diseases, enabling improved diagnostic accuracy of the main pathology and co-pathologies, and very early intervention, particularly in patients at risk of monogenic forms of neurodegeneration. The possibility of quantifying proteopathic seed load, and its reduction by treatments, is an attractive pharmacodynamic biomarker in the preclinical and early clinical stages of drug development. Here we review some potential applications of seed amplification assays in clinical trials.

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.

Iatrogenic cerebral amyloid angiopathy: an emerging clinical phenomenon.

In the last 6 years, following the first pathological description of presumed amyloid-beta (Aß) transmission in humans (in 2015) and subsequent experimental confirmation (in 2018), clinical cases of iatrogenic cerebral amyloid angiopathy (CAA)-attributed to the transmission of Aß 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.

Prion protein gene mutation detection using long-read Nanopore sequencing.

Prion diseases are fatal neurodegenerative conditions that affect humans and animals. Rapid and accurate sequencing of the prion gene PRNP is paramount to human prion disease diagnosis and for animal surveillance programmes. Current methods for PRNP genotyping involve sequencing of small fragments within the protein-coding region. The contribution of variants in the non-coding regions of PRNP including large structural changes is poorly understood. Here, we used long-range PCR and Nanopore sequencing to sequence the full length of PRNP, including its regulatory region, in 25 samples from blood and brain of individuals with inherited or sporadic prion diseases. Nanopore sequencing detected the same variants as identified by Sanger sequencing, including repeat expansions/deletions. Nanopore identified additional single-nucleotide variants in the non-coding regions of PRNP, but no novel structural variants were discovered. Finally, we explored somatic mosaicism of PRNP's octapeptide repeat region, which is a hypothetical cause of sporadic prion disease. While we found changes consistent with somatic mutations, we demonstrate that they may have been generated by the PCR. Our study illustrates the accuracy of Nanopore sequencing for rapid and field prion disease diagnosis and highlights the need for single-molecule sequencing methods for the detection of somatic mutations.

Assessing initial MRI reports for suspected CJD patients.

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.

Prion protein monoclonal antibody (PRN100) therapy for Creutzfeldt-Jakob disease: evaluation of a first-in-human treatment programme.

BACKGROUND: Human prion diseases, including Creutzfeldt-Jakob disease (CJD), are rapidly progressive, invariably fatal neurodegenerative conditions with no effective therapies. Their pathogenesis involves the obligate recruitment of cellular prion protein (PrPC) into self-propagating multimeric assemblies or prions. Preclinical studies have firmly validated the targeting of PrPC as a therapeutic strategy. We aimed to evaluate a first-in-human treatment programme using an anti-PrPC monoclonal antibody under a Specials Licence. METHODS: We generated a fully humanised anti-PrPC monoclonal antibody (an IgG4κ isotype; PRN100) for human use. We offered treatment with PRN100 to six patients with a clinical diagnosis of probable CJD who were not in the terminal disease stages at the point of first assessment and who were able to readily travel to the University College London Hospital (UCLH) Clinical Research Facility, London, UK, for treatment. After titration (1 mg/kg and 10 mg/kg at 48-h intervals), patients were treated with 80-120 mg/kg of intravenous PRN100 every 2 weeks until death or withdrawal from the programme, or until the supply of PRN100 was exhausted, and closely monitored for evidence of adverse effects. Disease progression was assessed by use of the Medical Research Council (MRC) Prion Disease Rating Scale, Motor Scale, and Cognitive Scale, and compared with that of untreated natural history controls (matched for disease severity, subtype, and PRNP codon 129 genotype) recruited between Oct 1, 2008, and July 31, 2018, from the National Prion Monitoring Cohort study. Autopsies were done in two patients and findings were compared with those from untreated natural history controls. FINDINGS: We treated six patients (two men; four women) with CJD for 7-260 days at UCLH between Oct 9, 2018, and July 31, 2019. Repeated intravenous dosing of PRN100 was well tolerated and reached the target CSF drug concentration (50 nM) in four patients after 22-70 days; no clinically significant adverse reactions were seen. All patients showed progressive neurological decline on serial assessments with the MRC Scales. Neuropathological examination was done in two patients (patients 2 and 3) and showed no evidence of cytotoxicity. Patient 2, who was treated for 140 days, had the longest clinical duration we have yet documented for iatrogenic CJD and showed patterns of disease-associated PrP that differed from untreated patients with CJD, consistent with drug effects. Patient 3, who had sporadic CJD and only received one therapeutic dose of 80 mg/kg, had weak PrP synaptic labelling in the periventricular regions, which was not a feature of untreated patients with sporadic CJD. Brain tissue-bound drug concentrations across multiple regions in patient 2 ranged from 9·9 µg per g of tissue (SD 0·3) in the thalamus to 27·4 µg per g of tissue (1·5) in the basal ganglia (equivalent to 66-182 nM). INTERPRETATION: Our academic-led programme delivered what is, to our knowledge, the first rationally designed experimental treatment for human prion disease to a small number of patients with CJD. The treatment appeared to be safe and reached encouraging CSF and brain tissue concentrations. These findings justify the need for formal efficacy trials in patients with CJD at the earliest possible clinical stages and as prophylaxis in those at risk of prion disease due to PRNP mutations or prion exposure. FUNDING: The Cure CJD Campaign, the National Institute for Health Research UCLH Biomedical Research Centre, the Jon Moulton Charitable Trust, and the UK MRC.

Development of novel clinical examination scales for the measurement of disease severity in Creutzfeldt-Jakob disease.

OBJECTIVE: To use a robust statistical methodology to develop and validate clinical rating scales quantifying longitudinal motor and cognitive dysfunction in sporadic Creutzfeldt-Jakob disease (sCJD) at the bedside. METHODS: Rasch analysis was used to iteratively construct interval scales measuring composite cognitive and motor dysfunction from pooled bedside neurocognitive examinations collected as part of the prospective National Prion Monitoring Cohort study, October 2008-December 2016.A longitudinal clinical examination dataset constructed from 528 patients with sCJD, comprising 1030 Motor Scale and 757 Cognitive Scale scores over 130 patient-years of study, was used to demonstrate scale utility. RESULTS: The Rasch-derived Motor Scale consists of 8 items, including assessments reliant on pyramidal, extrapyramidal and cerebellar systems. The Cognitive Scale comprises 6 items, and includes measures of executive function, language, visual perception and memory. Both scales are unidimensional, perform independently of age or gender and have excellent inter-rater reliability. They can be completed in minutes at the bedside, as part of a normal neurocognitive examination. A composite Examination Scale can be derived by averaging both scores. Several scale uses, in measuring longitudinal change, prognosis and phenotypic heterogeneity are illustrated. CONCLUSIONS: These two novel sCJD Motor and Cognitive Scales and the composite Examination Scale should prove useful to objectively measure phenotypic and clinical change in future clinical trials and for patient stratification. This statistical approach can help to overcome obstacles to assessing clinical change in rapidly progressive, multisystem conditions with limited longitudinal follow-up.

NT1-Tau Is Increased in CSF and Plasma of CJD Patients, and Correlates with Disease Progression.

This study investigates the diagnostic and prognostic potential of different forms of tau in biofluids from patients with Creutzfeldt-Jakob disease (CJD). Extracellular tau, which is molecularly heterogeneous, was measured using ultra-sensitive custom-made Simoa assays for N-terminal (NT1), mid-region, and full-length tau. We assessed cross-sectional CSF and plasma from healthy controls, patients with Alzheimer's disease (AD) and CJD patients. Then, we evaluated the correlation of the best-performing tau assay (NT1-tau) with clinical severity and functional decline (using the MRC Prion Disease Rating Scale) in a longitudinal CJD cohort (n = 145). In a cross-sectional study, tau measured in CSF with the NT1 and mid-region Simoa assays, separated CJD (n = 15) from AD (n = 18) and controls (n = 21) with a diagnostic accuracy (AUCs: 0.98-1.00) comparable to or better than neurofilament light chain (NfL; AUCs: 0.96-0.99). In plasma, NT1-measured tau was elevated in CJD (n = 5) versus AD (n = 15) and controls (n = 15). Moreover, in CJD plasma (n = 145) NT1-tau levels correlated with stage and rate of disease progression, and the effect on clinical progression was modified by the PRNP codon 129. Our findings suggest that plasma NT1-tau shows promise as a minimally invasive diagnostic and prognostic biomarker of CJD, and should be further investigated for its potential to monitor disease progression and response to therapies.