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View article: Domain mapping of disease mutations reveals pathogenic SORL1 variants in Alzheimer’s disease
Domain mapping of disease mutations reveals pathogenic SORL1 variants in Alzheimer’s disease Open
View article: A dividing cell model for stable propagation and curing of <i>bona fide</i> human sporadic Creutzfeldt-Jakob Disease prions
A dividing cell model for stable propagation and curing of <i>bona fide</i> human sporadic Creutzfeldt-Jakob Disease prions Open
Prions are assemblies of misfolded proteins that cause transmissible, progressive neurodegenerative disease in humans and other mammals. Human prion diseases have particular public health and biological significance, both due to their tran…
View article: Intracellular trafficking SNARE protein, syntaxin-6, modifies prion cellular phenotypes and risk of disease development in vivo
Intracellular trafficking SNARE protein, syntaxin-6, modifies prion cellular phenotypes and risk of disease development in vivo Open
View article: Estimating future variant Creutzfeldt-Jakob disease cases in the UK: a cohort-based probabilistic model
Estimating future variant Creutzfeldt-Jakob disease cases in the UK: a cohort-based probabilistic model Open
View article: Development of a user guide to support administration of the MRC Prion Disease Rating Scale in research and clinical settings for prion diseases
Development of a user guide to support administration of the MRC Prion Disease Rating Scale in research and clinical settings for prion diseases Open
The final User Guide was designed to accompany the MRC Scale and assist with rater decisions related to which response option most accurately describes a patient's health status. Conclusions: The User Guide is expected to be a valuable com…
View article: Inherited prion disease caused by a novel frameshift mutation of <i>PRNP</i> resulting in protein truncation at codon 157
Inherited prion disease caused by a novel frameshift mutation of <i>PRNP</i> resulting in protein truncation at codon 157 Open
Background PrP systemic amyloidosis is increasingly recognized as a novel inherited prion disease (IPD) syndrome caused by PRNP C-terminal truncating mutations. As well as systemic manifestations they cause gradually progressive cognitive …
View article: Decoding Huntington’s disease: a global survey on symptoms and genetic testing practices
Decoding Huntington’s disease: a global survey on symptoms and genetic testing practices Open
View article: Deciphering distinct genetic risk factors for FTLD-TDP pathological subtypes via whole-genome sequencing
Deciphering distinct genetic risk factors for FTLD-TDP pathological subtypes via whole-genome sequencing Open
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 assoc…
View article: PRNP E146G mutation inherited prion disease: distinctive clinical, pathological and fluid biomarker features
PRNP E146G mutation inherited prion disease: distinctive clinical, pathological and fluid biomarker features Open
Inherited prion diseases (IPDs) are phenotypically diverse neurodegenerative conditions caused by mutations in the prion protein gene ( PRNP ). We describe IPD due to a novel PRNP E146G mutation in a 50-year-old man presenting with slowly …
View article: Intracellular Trafficking SNARE Protein, Syntaxin-6, is a Modifier of Prion and Tau Pathogenesis <i>in vivo</i> and in Cellular Models
Intracellular Trafficking SNARE Protein, Syntaxin-6, is a Modifier of Prion and Tau Pathogenesis <i>in vivo</i> and in Cellular Models Open
Syntaxin-6, a SNARE protein involved in intracellular protein trafficking, is a proposed risk factor for sporadic prion disease, progressive supranuclear palsy and Alzheimer’s disease. However, no study has validated its functional role in…
View article: Isolation of a novel human prion strain from a PRNP codon 129 heterozygous vCJD patient
Isolation of a novel human prion strain from a PRNP codon 129 heterozygous vCJD patient Open
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 …
View article: Multiomic analyses direct hypotheses for Creutzfeldt-Jakob disease risk genes
Multiomic analyses direct hypotheses for Creutzfeldt-Jakob disease risk genes Open
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 p…
View article: The novel T107I Inherited prion disease can present as a clinical and biomarker mimic of familial Alzheimer’s disease
The novel T107I Inherited prion disease can present as a clinical and biomarker mimic of familial Alzheimer’s disease Open
Inherited prion diseases (IPD) secondary to mutations of the prion protein gene, PRNP, exhibit diverse clinical phenotypes, capable of mimicking numerous primary neurodegenerative conditions. We describe the clinical phenotype and n…
View article: Human Genetic Evidence for New Targets in Prion Diseases: Opportunities and Challenges
Human Genetic Evidence for New Targets in Prion Diseases: Opportunities and Challenges Open
Human genetics offers a powerful, causally grounded approach to therapeutic target identification in prion diseases. In this chapter, we examine strategies used to discover and evaluate gene candidates, emphasizing the complementary roles …
View article: Extremely rare CNVs contributing to Alzheimer disease risk: a case-control association analysis of exome sequencing data from 22,319 individuals
Extremely rare CNVs contributing to Alzheimer disease risk: a case-control association analysis of exome sequencing data from 22,319 individuals Open
Rare coding single nucleotide variants (SNV) and short insertions or deletions (indels) contribute to Alzheimer disease (AD) genetic risk, from pathogenic variants in autosomal dominant genes to risk factors with diverse effects. In contra…
View article: Huntington’s disease phenocopy syndromes revisited: a clinical comparison and next-generation sequencing exploration
Huntington’s disease phenocopy syndromes revisited: a clinical comparison and next-generation sequencing exploration Open
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 ex…
View article: Syntaxin-6 delays prion protein fibril formation and prolongs the presence of toxic aggregation intermediates
Syntaxin-6 delays prion protein fibril formation and prolongs the presence of toxic aggregation intermediates Open
Prions replicate via the autocatalytic conversion of cellular prion protein (PrP C ) into fibrillar assemblies of misfolded PrP. While this process has been extensively studied in vivo and in vitro, non-physiological reaction conditions of…
View article: Genome wide association study of clinical duration and age at onset of sporadic CJD
Genome wide association study of clinical duration and age at onset of sporadic CJD Open
Human prion diseases are rare, transmissible and often rapidly progressive dementias. The most common type, sporadic Creutzfeldt-Jakob disease (sCJD), is highly variable in clinical duration and age at onset. Genetic determinants of late o…
View article: Deciphering Distinct Genetic Risk Factors for FTLD-TDP Pathological Subtypes via Whole-Genome Sequencing
Deciphering Distinct Genetic Risk Factors for FTLD-TDP Pathological Subtypes via Whole-Genome Sequencing Open
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 assoc…
View article: Neuronal downregulation of PLCG2 impairs synaptic function and elicits Alzheimer disease hallmarks
Neuronal downregulation of PLCG2 impairs synaptic function and elicits Alzheimer disease hallmarks Open
We developed a high content screening to investigate how Alzheimer disease (AD) genetic risk factors may impair synaptic mechanisms in rat primary neuronal cultures. Out of the gene targets identified, we found that shRNA-mediated downregu…
View article: Academic neurology in the UK: a plea to turn away from the precipice
Academic neurology in the UK: a plea to turn away from the precipice Open
Devine et al. 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.
View article: Population structure and migration in the Eastern Highlands of Papua New Guinea, a region impacted by the kuru epidemic
Population structure and migration in the Eastern Highlands of Papua New Guinea, a region impacted by the kuru epidemic Open
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 c…
View article: Creutzfeldt–Jakob disease and other prion diseases
Creutzfeldt–Jakob disease and other prion diseases Open
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 disease…
View article: Iatrogenic Alzheimer’s disease in recipients of cadaveric pituitary-derived growth hormone
Iatrogenic Alzheimer’s disease in recipients of cadaveric pituitary-derived growth hormone Open
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 gen…
View article: Characterisation and prion transmission study in mice with genetic reduction of sporadic Creutzfeldt-Jakob disease risk gene Stx6
Characterisation and prion transmission study in mice with genetic reduction of sporadic Creutzfeldt-Jakob disease risk gene Stx6 Open
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 neurodegene…
View article: Genome wide association study of clinical duration and age at onset of sporadic CJD
Genome wide association study of clinical duration and age at onset of sporadic CJD Open
Human prion diseases are rare, transmissible and often rapidly progressive dementias. The most common type, sporadic Creutzfeldt-Jakob disease (sCJD), is highly variable in clinical duration and age at onset. Genetic determinants of late o…
View article: Survival and critical care use among people with dementia in a large English cohort
Survival and critical care use among people with dementia in a large English cohort Open
Background Admitting people with dementia to critical care units may not always lead to a clear survival benefit. Critical care admissions of people with dementia vary across countries. Little is known about the use and trends of critical …
View article: Domain mapping of disease mutations supports genetic testing of specific<i>SORL1</i>variants in familial Alzheimer’s Disease
Domain mapping of disease mutations supports genetic testing of specific<i>SORL1</i>variants in familial Alzheimer’s Disease Open
Background Protein truncating variants (PTVs) in SORL1 are observed almost exclusively in Alzheimer’s Disease (AD) cases, but the effect of rare SORL1 missense variants is unclear. Methods To identify high-priority missense variants (HPVs)…
View article: Clinical considerations in early-onset cerebral amyloid angiopathy
Clinical considerations in early-onset cerebral amyloid angiopathy Open
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, earl…
View article: Seed amplification and neurodegeneration marker trajectories in individuals at risk of prion disease
Seed amplification and neurodegeneration marker trajectories in individuals at risk of prion disease Open
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 potentia…