Isolation of a novel human prion strain from a PRNP codon 129 heterozygous vCJD patient.

The epizootic prion disease of cattle, bovine spongiform encephalopathy (BSE), caused variant Creutzfeldt-Jakob disease (vCJD) in humans following dietary exposure. Codon 129 polymorphism of the human prion protein gene (PRNP), encoding either methionine (M) or valine (V), dictates the propagation of distinct human prion strains and up to now all but one neuropathologically confirmed vCJD patients have had a 129MM genotype. Concordant with this genetic association, transgenic modelling has established that human PrP 129V is incompatible with the vCJD prion strain and that depending on codon 129 genotype, primary human infection with BSE prions may, in addition to vCJD, result in sporadic CJD-like or novel phenotypes.

Multiomic analyses direct hypotheses for Creutzfeldt-Jakob disease risk genes.

Prions are assemblies of misfolded prion protein that cause several fatal and transmissible neurodegenerative diseases, with the most common phenotype in humans being sporadic Creutzfeldt-Jakob disease (sCJD). Aside from variation of the prion protein itself, molecular risk factors are not well understood. Prion and prion-like mechanisms are thought to underpin common neurodegenerative disorders meaning that the elucidation of mechanisms could have broad relevance.

The novel T107I Inherited prion disease can present as a clinical and biomarker mimic of familial Alzheimer's disease.

Inherited prion diseases (IPD) secondary to mutations of the prion protein gene, exhibit diverse clinical phenotypes, capable of mimicking numerous primary neurodegenerative conditions. We describe the clinical phenotype and neuropathological findings in a family from County Limerick in Ireland presenting with Alzheimer's disease-like cognitive decline and motor symptoms caused by a novel missense mutation of This mutation occurs in the central lysine cluster (CLC; codon 101-110), resulting in substitution of threonine with isoleucine at codon 107 (T107I). This case series highlights that IPD can be hard to distinguish from overlapping clinical syndromes seen in other neurodegenerative diseases.

Huntington's disease phenocopy syndromes revisited: a clinical comparison and next-generation sequencing exploration.

Background: Genetic testing for Huntington's disease (HD) was initially usually positive but more recently the negative rate has increased: patients with negative HD tests are described as having HD phenocopy syndromes (HDPC). This study examines their clinical characteristics and investigates the genetic causes of HDPC.

Methods: Clinical data from neurogenetics clinics and HDPC gene-panel data were analysed.

Syntaxin-6 delays prion protein fibril formation and prolongs the presence of toxic aggregation intermediates.

Prions replicate via the autocatalytic conversion of cellular prion protein (PrP) into fibrillar assemblies of misfolded PrP. While this process has been extensively studied in vivo and in vitro, non-physiological reaction conditions of fibril formation in vitro have precluded the identification and mechanistic analysis of cellular proteins, which may alter PrP self-assembly and prion replication. Here, we have developed a fibril formation assay for recombinant murine and human PrP (23-231) under near-native conditions (NAA) to study the effect of cellular proteins, which may be risk factors or potential therapeutic targets in prion disease.

Deciphering Distinct Genetic Risk Factors for FTLD-TDP Pathological Subtypes via Whole-Genome Sequencing.

Frontotemporal lobar degeneration with neuronal inclusions of the TAR DNA-binding protein 43 (FTLD-TDP) is a fatal neurodegenerative disorder with only a limited number of risk loci identified. We report our comprehensive genome-wide association study as part of the International FTLD-TDP Whole-Genome Sequencing Consortium, including 985 cases and 3,153 controls, and meta-analysis with the Dementia-seq cohort, compiled from 26 institutions/brain banks in the United States, Europe and Australia. We confirm as the strongest overall FTLD-TDP risk factor and identify as a novel FTLD-TDP risk factor.

Academic neurology in the UK: a plea to turn away from the precipice.

Devine argue that recent changes to clinical neurology training in the UK have the potential to exacerbate an existing crisis in academic neurology, and discuss what might be done to remedy the situation.

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 km) lived in relative isolation from the rest of the world until the mid-20 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.

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.

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

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.

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 (PrP) 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.

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-β 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.

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.

Exome sequencing identifies rare damaging variants in ATP8B4 and ABCA1 as risk factors for Alzheimer's disease.

Alzheimer's disease (AD), the leading cause of dementia, has an estimated heritability of approximately 70%. The genetic component of AD has been mainly assessed using genome-wide association studies, which do not capture the risk contributed by rare variants. Here, we compared the gene-based burden of rare damaging variants in exome sequencing data from 32,558 individuals-16,036 AD cases and 16,522 controls.

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.

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.

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.

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.

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.

Iatrogenic cerebral amyloid angiopathy: an emerging clinical phenomenon.

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.