Simon Mead

Publications (66)710.67 Total impact

• Article: Genetic Analysis of Inherited Leukodystrophies: Genotype-Phenotype Correlations in the CSF1R Gene.

  Rita Guerreiro, Eleanna Kara, Isabelle Le Ber, Jose Bras, Jonathan D Rohrer, Ricardo Taipa, Tammaryn Lashley, Céline Dupuits, Nicole Gurunlian, Fanny Mochel, [......], Foucaud Du Boisguéheneuc, Lucia Schottlaender, Nick C Fox, Jonathan Beck, Simon Mead, Martin N Rossor, John Hardy, Tamas Revesz, Alexis Brice, Henry Houlden
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  ABSTRACT: IMPORTANCE The leukodystrophies comprise a clinically and genetically heterogeneous group of progressive hereditary neurological disorders mainly affecting the myelin in the central nervous system. Their onset is variable from childhood to adulthood and presentation can be with a variety of clinical features that include mainly for adult-onset cases cognitive decline, seizures, parkinsonism, muscle weakness, neuropathy, spastic paraplegia, personality/behavioral problems, and dystonia. Recently, Rademakers and colleagues identified mutations in the CSF1R gene as the cause of hereditary diffuse leukoencephalopathy with spheroids (HDLS), offering the possibility for an in-life diagnosis. The detection of mutations in this gene in cases diagnosed with different clinical entities further demonstrated the difficulties in the clinical diagnosis of HDLS. OBJECTIVE To better understand the genetic role of mutations in this gene, we sequenced a large cohort of adult-onset leukodystrophy cases. DESIGN Whole-exome sequencing and follow up-screening by Sanger sequencing. SETTING Collaborative study between the Institute of Neurology, University College London and the Inserm, Paris, France. PARTICIPANTS A total of 114 probands, mostly European patients, with a diagnosis of adult-onset leukodystrophy or atypical cases that could fit within a picture of leukodystrophy. These included 3 extended families within the spectrum of leukodystrophy phenotype. INTERVENTIONS Whole-exome sequencing in a family and Sanger sequencing of CSF1R. MAIN OUTCOMES AND MEASURES Mutations in CSF1R. RESULTS We identified 12 probands with mutations in CSF1R. The clinical diagnoses given to these patients included dementia with spastic paraplegia, corticobasal degeneration syndrome, and stroke disorders. Our study shows that CSF1R mutations are responsible for a significant proportion of clinically and pathologically proven HDLS. CONCLUSIONS AND RELEVANCE These results give an indication of the frequency of CSF1R mutations in a European leukodystrophy series and expand the phenotypic spectrum of disorders that should be screened for this gene.
  JAMA neurology. 05/2013;
• Article: The Presenilin 1 P264L Mutation Presenting as non-Fluent/Agrammatic Primary Progressive Aphasia.

  Colin J Mahoney, Laura E Downey, Jon Beck, Yuying Liang, Simon Mead, Richard J Perry, Jason D Warren
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  ABSTRACT: Primary progressive aphasia (PPA) represents a diverse group of language-led dementias most often due to frontotemporal lobar degeneration. We report clinical, neuropsychological, and neuroimaging data in the case of a 47-year-old woman presenting with non-fluent PPA due to a genetically confirmed pathogenic Presenilin 1 P264L mutation. This case highlights an unusual clinical presentation of familial Alzheimer's disease and a novel presentation of the P264L mutation. The case adds to accumulating evidence that particular mutations can promote specific brain network degeneration, with wider implications for understanding the sporadic forms of Alzheimer's disease and PPA.
  Journal of Alzheimer's disease: JAD 04/2013; · 3.74 Impact Factor
• Article: The Medical Research Council Prion Disease Rating Scale: a new outcome measure for prion disease therapeutic trials developed and validated using systematic observational studies.

  Andrew G B Thompson, Jessica Lowe, Zoe Fox, Ana Lukic, Marie-Claire Porter, Liz Ford, Michele Gorham, Gosala S Gopalakrishnan, Peter Rudge, A Sarah Walker, John Collinge, Simon Mead
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  ABSTRACT: Progress in therapeutics for rare disorders like prion disease is impeded by the lack of validated outcome measures and a paucity of natural history data derived from prospective observational studies. The first analysis of the UK National Prion Monitoring Cohort involved 1337 scheduled clinical assessments and 479 telephone assessments in 437 participants over 373 patient-years of follow-up. Scale development has included semi-quantitative and qualitative carer interviews, item response modelling (Rasch analysis), inter-rater reliability testing, construct analysis and correlation with several existing scales. The proposed 20-point Medical Research Council Prion Disease Rating Scale assesses domains of cognitive function, speech, mobility, personal care/feeding and continence, according to their relative importance documented by carer interviews. It is quick and simple to administer, and has been validated for use by doctors and nurses and for use over the telephone, allowing for frequent assessments that capture the rapid change typical of these diseases. The Medical Research Council Scale correlates highly with widely used cognitive and single item scales, but has substantial advantages over these including minimal floor effects. Three clear patterns of decline were observed using the scale: fast linear decline, slow linear decline (usually inherited prion disease) and in some patients, decline followed by a prolonged preterminal plateau at very low functional levels. Rates of decline and progress through milestones measured using the scale vary between sporadic, acquired and inherited prion diseases following clinical expectations. We have developed and validated a new functionally-oriented outcome measure and propose that future clinical trials in prion disease should collect data compatible with this scale, to allow for combined and comparative analyses. Such approaches may be advantageous in orphan conditions, where single studies of feasible duration will often struggle to achieve statistical power.
  Brain 04/2013; 136(Pt 4):1116-27. · 9.46 Impact Factor
• Article: Genetics of prion diseases.

  Sarah E Lloyd, Simon Mead, John Collinge
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  ABSTRACT: Prion diseases are transmissible, fatal neurodegenerative diseases that include scrapie and bovine spongiform encephalopathy (BSE) in animals and Creutzfeldt-Jakob disease (CJD) in human. The prion protein gene (PRNP) is the major genetic determinant of susceptibility, however, several studies now suggest that other genes are also important. Two recent genome wide association studies in human have identified four new loci of interest: ZBTB38-RASA2 in UK CJD cases and MTMR7 and NPAS2 in variant CJD. Complementary studies in mouse have used complex crosses to identify new modifiers such as Cpne8 and provided supporting evidence for previously implicated genes (Rarb and Stmn2). Expression profiling has identified new candidates, including Hspa13, which reduces incubation time in a transgenic model.
  Current opinion in genetics & development 03/2013; · 8.99 Impact Factor
• Article: Large C9orf72 Hexanucleotide Repeat Expansions Are Seen in Multiple Neurodegenerative Syndromes and Are More Frequent Than Expected in the UK Population.

  Jon Beck, Mark Poulter, Davina Hensman, Jonathan D Rohrer, Colin J Mahoney, Gary Adamson, Tracy Campbell, James Uphill, Aaron Borg, Pietro Fratta, [......], Henry Houlden, Jonathan M Schott, Nick C Fox, Martin N Rossor, Sarah J Tabrizi, Adrian M Isaacs, John Hardy, Jason D Warren, John Collinge, Simon Mead
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  ABSTRACT: Hexanucleotide repeat expansions in C9orf72 are a major cause of frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS). Understanding the disease mechanisms and a method for clinical diagnostic genotyping have been hindered because of the difficulty in estimating the expansion size. We found 96 repeat-primed PCR expansions: 85/2,974 in six neurodegenerative diseases cohorts (FTLD, ALS, Alzheimer disease, sporadic Creutzfeldt-Jakob disease, Huntington disease-like syndrome, and other nonspecific neurodegenerative disease syndromes) and 11/7,579 (0.15%) in UK 1958 birth cohort (58BC) controls. With the use of a modified Southern blot method, the estimated expansion range (smear maxima) in cases was 800-4,400. Similarly, large expansions were detected in the population controls. Differences in expansion size and morphology were detected between DNA samples from tissue and cell lines. Of those in whom repeat-primed PCR detected expansions, 68/69 were confirmed by blotting, which was specific for greater than 275 repeats. We found that morphology in the expansion smear varied among different individuals and among different brain regions in the same individual. Expansion size correlated with age at clinical onset but did not differ between diagnostic groups. Evidence of instability of repeat size in control families, as well as neighboring SNP and microsatellite analyses, support multiple expansion events on the same haplotype background. Our method of estimating the size of large expansions has potential clinical utility. C9orf72-related disease might mimic several neurodegenerative disorders and, with potentially 90,000 carriers in the United Kingdom, is more common than previously realized.
  The American Journal of Human Genetics 02/2013; · 10.60 Impact Factor
• Article: Genetic Influences on Atrophy Patterns in Familial Alzheimer's Disease: A Comparison of APP and PSEN1 Mutations.

  Rachael I Scahill, Gerard R Ridgway, Jonathan W Bartlett, Josephine Barnes, Natalie S Ryan, Simon Mead, Jonathan Beck, Matthew J Clarkson, Sebastian J Crutch, Jonathan M Schott, Sebastien Ourselin, Jason D Warren, John Hardy, Martin N Rossor, Nick C Fox
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  ABSTRACT: Mutations in the presenilin1 (PSEN1) and amyloid beta (A4) precursor protein (APP) genes account for the majority of cases of autosomal dominantly inherited Alzheimer's disease (AD). We wished to assess and compare the patterns of cerebral loss produced by these two groups of mutations. Volumetric magnetic resonance imaging and neuropsychological assessments were performed in individuals with clinical AD carrying mutations in the APP (n = 10) and PSEN1 (n = 18) genes and in healthy controls (n = 18). Voxel-based morphometry (VBM), cortical thickness, and region of interest analyses were performed. Mini-Mental State Examination scores were similar in the two disease groups suggesting similar levels of disease severity. There was evidence that APP subjects have smaller hippocampal volume compared with PSEN1 subjects (p = 0.007), and weak evidence that they have larger whole-brain and grey matter volumes (both p = 0.07). Although there was no evidence of statistically significant differences between APP and PSEN1 in VBM or cortical thickness analyses, effect maps were suggestive of APP subjects having more medial temporal lobe atrophy and conversely PSEN1 subjects showing more neocortical loss. Neuropsychological data were consistent with these regional differences and suggested greater memory deficits in the APP patients and greater impairment in non-memory domains in the PSEN1 group, although these differences were not statistically significant. We conclude that the mechanisms by which APP and PSEN1 mutations cause neuronal loss may differ which furthers our understanding of the neuropathology underlying AD and may inform future therapeutic strategies and trial designs.
  Journal of Alzheimer's disease: JAD 02/2013; · 3.74 Impact Factor
• Article: MRI findings are often missed in the diagnosis of Creutzfeldt-Jakob disease.

  Christopher Carswell, Andrew Thompson, Ana Lukic, John Stevens, Peter Rudge, Simon Mead, John Collinge, Harpreet Hyare
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  ABSTRACT: BACKGROUND: Establishing 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. METHODS: We 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. RESULTS: In 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). CONCLUSIONS: CJD-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.
  BMC Neurology 12/2012; 12(1):153. · 2.17 Impact Factor
• Source

  Available from: PubMed Central

  Article: Frontotemporal dementia with the C9ORF72 hexanucleotide repeat expansion: clinical, neuroanatomical and neuropathological features.

  Colin J Mahoney, Jon Beck, Jonathan D Rohrer, Tammaryn Lashley, Kin Mok, Tim Shakespeare, Tom Yeatman, Elizabeth K Warrington, Jonathan M Schott, Nick C Fox, Martin N Rossor, John Hardy, John Collinge, Tamas Revesz, Simon Mead, Jason D Warren
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  ABSTRACT: An expanded hexanucleotide repeat in the C9ORF72 gene has recently been identified as a major cause of familial frontotemporal lobar degeneration and motor neuron disease, including cases previously identified as linked to chromosome 9. Here we present a detailed retrospective clinical, neuroimaging and histopathological analysis of a C9ORF72 mutation case series in relation to other forms of genetically determined frontotemporal lobar degeneration ascertained at a specialist centre. Eighteen probands (19 cases in total) were identified, representing 35% of frontotemporal lobar degeneration cases with identified mutations, 36% of cases with clinical evidence of motor neuron disease and 7% of the entire cohort. Thirty-three per cent of these C9ORF72 cases had no identified relevant family history. Families showed wide variation in clinical onset (43-68 years) and duration (1.7-22 years). The most common presenting syndrome (comprising a half of cases) was behavioural variant frontotemporal dementia, however, there was substantial clinical heterogeneity across the C9ORF72 mutation cohort. Sixty per cent of cases developed clinical features consistent with motor neuron disease during the period of follow-up. Anxiety and agitation and memory impairment were prominent features (between a half to two-thirds of cases), and dominant parietal dysfunction was also frequent. Affected individuals showed variable magnetic resonance imaging findings; however, relative to healthy controls, the group as a whole showed extensive thinning of frontal, temporal and parietal cortices, subcortical grey matter atrophy including thalamus and cerebellum and involvement of long intrahemispheric, commissural and corticospinal tracts. The neuroimaging profile of the C9ORF72 expansion was significantly more symmetrical than progranulin mutations with significantly less temporal lobe involvement than microtubule-associated protein tau mutations. Neuropathological examination in six cases with C9ORF72 mutation from the frontotemporal lobar degeneration series identified histomorphological features consistent with either type A or B TAR DNA-binding protein-43 deposition; however, p62-positive (in excess of TAR DNA-binding protein-43 positive) neuronal cytoplasmic inclusions in hippocampus and cerebellum were a consistent feature of these cases, in contrast to the similar frequency of p62 and TAR DNA-binding protein-43 deposition in 53 control cases with frontotemporal lobar degeneration-TAR DNA-binding protein. These findings corroborate the clinical importance of the C9ORF72 mutation in frontotemporal lobar degeneration, delineate phenotypic and neuropathological features that could help to guide genetic testing, and suggest hypotheses for elucidating the neurobiology of a culprit subcortical network.
  Brain 03/2012; 135(Pt 3):736-50. · 9.46 Impact Factor
• Article: The role of variation at AβPP, PSEN1, PSEN2, and MAPT in late onset Alzheimer's disease.

  Amy Gerrish, Giancarlo Russo, Alexander Richards, Valentina Moskvina, Dobril Ivanov, Denise Harold, Rebecca Sims, Richard Abraham, Paul Hollingworth, Jade Chapman, [......], Norman Klopp, H-Erich Wichmann, Minerva M Carrasquillo, V Shane Pankratz, Steven G Younkin, Lesley Jones, Peter A Holmans, Michael C O'Donovan, Michael J Owen, Julie Williams
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  ABSTRACT: Rare mutations in AβPP, PSEN1, and PSEN2 cause uncommon early onset forms of Alzheimer's disease (AD), and common variants in MAPT are associated with risk of other neurodegenerative disorders. We sought to establish whether common genetic variation in these genes confer risk to the common form of AD which occurs later in life (>65 years). We therefore tested single-nucleotide polymorphisms at these loci for association with late-onset AD (LOAD) in a large case-control sample consisting of 3,940 cases and 13,373 controls. Single-marker analysis did not identify any variants that reached genome-wide significance, a result which is supported by other recent genome-wide association studies. However, we did observe a significant association at the MAPT locus using a gene-wide approach (p = 0.009). We also observed suggestive association between AD and the marker rs9468, which defines the H1 haplotype, an extended haplotype that spans the MAPT gene and has previously been implicated in other neurodegenerative disorders including Parkinson's disease, progressive supranuclear palsy, and corticobasal degeneration. In summary common variants at AβPP, PSEN1, and PSEN2 and MAPT are unlikely to make strong contributions to susceptibility for LOAD. However, the gene-wide effect observed at MAPT indicates a possible contribution to disease risk which requires further study.
  Journal of Alzheimer's disease: JAD 01/2012; 28(2):377-87. · 3.74 Impact Factor
• Source

  Available from: Michelle K Lupton

  Article: The Role of Variation at AβPP, PSEN1, PSEN2, and MAPT in Late Onset Alzheimer's Disease

  Amy Gerrish, Giancarlo Russo, Alexander Richards, Valentina Moskvina, Dobril Ivanov, Denise Harold, Rebecca Sims, Richard Abraham, Paul Hollingworth, Jade Chapman, [......], Norman Klopp, H-Erich Wichmann, Minerva M Carrasquillo, Shane Pankratz, Steven G Younkin, Lesley Jones, Peter A Holmans, Michael C O 'donovan, Michael J Owen, Julie Williams
  Journal of Alzheimer's disease: JAD 01/2012; 28:377-387. · 3.74 Impact Factor
• Article: Video Rating in Neurodegenerative Disease Clinical Trials: The Experience of PRION-1.

  Christopher Carswell, Michael Rañopa, Suvankar Pal, Rebecca Macfarlane, Durre Siddique, Dafydd Thomas, Tom Webb, Steve Wroe, Sarah Walker, Janet Darbyshire, John Collinge, Simon Mead, Peter Rudge
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  ABSTRACT: Large clinical trials including patients with uncommon diseases involve assessors in different geographical locations, resulting in considerable inter-rater variability in assessment scores. As video recordings of examinations, which can be individually rated, may eliminate such variability, we measured the agreement between a single video rater and multiple examining physicians in the context of PRION-1, a clinical trial of the antimalarial drug quinacrine in human prion diseases. We analysed a 43-component neurocognitive assessment battery, on 101 patients with Creutzfeldt-Jakob disease, focusing on the correlation and agreement between examining physicians and a single video rater. In total, 335 videos of examinations of 101 patients who were video-recorded over the 4-year trial period were assessed. For neurocognitive examination, inter-observer concordance was generally excellent. Highly visual neurological examination domains (e.g. finger-nose-finger assessment of ataxia) had good inter-rater correlation, whereas those dependent on non-visual clues (e.g. power or reflexes) correlated poorly. Some non-visual neurological domains were surprisingly concordant, such as limb muscle tone. Cognitive assessments and selected neurological domains can be practically and accurately recorded in a clinical trial using video rating. Video recording of examinations is a valuable addition to any trial provided appropriate selection of assessment instruments is used and rigorous training of assessors is undertaken.
  Dementia and geriatric cognitive disorders extra. 01/2012; 2(1):286-97.
• Article: Genome-wide association study in multiple human prion diseases suggests genetic risk factors additional to PRNP.

  Simon Mead, James Uphill, John Beck, Mark Poulter, Tracy Campbell, Jessica Lowe, Gary Adamson, Holger Hummerich, Norman Klopp, Ina-Maria Rückert, [......], Dhoyazan Azazi, Vincent Plagnol, Wandagi H Pako, Jerome Whitfield, Michael P Alpers, John Whittaker, David J Balding, Inga Zerr, Hans Kretzschmar, John Collinge
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  ABSTRACT: Prion diseases are fatal neurodegenerative diseases of humans and animals caused by the misfolding and aggregation of prion protein (PrP). Mammalian prion diseases are under strong genetic control but few risk factors are known aside from the PrP gene locus (PRNP). No genome-wide association study (GWAS) has been done aside from a small sample of variant Creutzfeldt-Jakob disease (CJD). We conducted GWAS of sporadic CJD (sCJD), variant CJD (vCJD), iatrogenic CJD, inherited prion disease, kuru and resistance to kuru despite attendance at mortuary feasts. After quality control, we analysed 2000 samples and 6015 control individuals (provided by the Wellcome Trust Case Control Consortium and KORA-gen) for 491032-511862 SNPs in the European study. Association studies were done in each geographical and aetiological group followed by several combined analyses. The PRNP locus was highly associated with risk in all geographical and aetiological groups. This association was driven by the known coding variation at rs1799990 (PRNP codon 129). No non-PRNP loci achieved genome-wide significance in the meta-analysis of all human prion disease. SNPs at the ZBTB38-RASA2 locus were associated with CJD in the UK (rs295301, P = 3.13 × 10(-8); OR, 0.70) but these SNPs showed no replication evidence of association in German sCJD or in Papua New Guinea-based tests. A SNP in the CHN2 gene was associated with vCJD [P = 1.5 × 10(-7); odds ratio (OR), 2.36], but not in UK sCJD (P = 0.049; OR, 1.24), in German sCJD or in PNG groups. In the overall meta-analysis of CJD, 14 SNPs were associated (P < 10(-5); two at PRNP, three at ZBTB38-RASA2, nine at nine other independent non-PRNP loci), more than would be expected by chance. None of the loci recently identified as genome-wide significant in studies of other neurodegenerative diseases showed any clear evidence of association in prion diseases. Concerning common genetic variation, it is likely that the PRNP locus contains the only strong risk factors that act universally across human prion diseases. Our data are most consistent with several other risk loci of modest overall effects which will require further genetic association studies to provide definitive evidence.
  Human Molecular Genetics 12/2011; 21(8):1897-906. · 7.64 Impact Factor
• Article: Prion protein gene M232R variation is probably an uncommon polymorphism rather than a pathogenic mutation.

  Jon Beck, John Collinge, Simon Mead
  Brain 11/2011; 135(Pt 2):e209; author reply e210. · 9.46 Impact Factor
• Source

  Available from: Claire Troakes

  Article: Clinical and neuroanatomical signatures of tissue pathology in frontotemporal lobar degeneration.

  Jonathan D Rohrer, Tammaryn Lashley, Jonathan M Schott, Jane E Warren, Simon Mead, Adrian M Isaacs, Jonathan Beck, John Hardy, Rohan de Silva, Elizabeth Warrington, [......], Safa Al-Sarraj, Andrew King, Barbara Borroni, Matthew J Clarkson, Sebastien Ourselin, Janice L Holton, Nick C Fox, Tamas Revesz, Martin N Rossor, Jason D Warren
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  ABSTRACT: Relating clinical symptoms to neuroanatomical profiles of brain damage and ultimately to tissue pathology is a key challenge in the field of neurodegenerative disease and particularly relevant to the heterogeneous disorders that comprise the frontotemporal lobar degeneration spectrum. Here we present a retrospective analysis of clinical, neuropsychological and neuroimaging (volumetric and voxel-based morphometric) features in a pathologically ascertained cohort of 95 cases of frontotemporal lobar degeneration classified according to contemporary neuropathological criteria. Forty-eight cases (51%) had TDP-43 pathology, 42 (44%) had tau pathology and five (5%) had fused-in-sarcoma pathology. Certain relatively specific clinicopathological associations were identified. Semantic dementia was predominantly associated with TDP-43 type C pathology; frontotemporal dementia and motoneuron disease with TDP-43 type B pathology; young-onset behavioural variant frontotemporal dementia with FUS pathology; and the progressive supranuclear palsy syndrome with progressive supranuclear palsy pathology. Progressive non-fluent aphasia was most commonly associated with tau pathology. However, the most common clinical syndrome (behavioural variant frontotemporal dementia) was pathologically heterogeneous; while pathologically proven Pick's disease and corticobasal degeneration were clinically heterogeneous, and TDP-43 type A pathology was associated with similar clinical features in cases with and without progranulin mutations. Volumetric magnetic resonance imaging, voxel-based morphometry and cluster analyses of the pathological groups here suggested a neuroanatomical framework underpinning this clinical and pathological diversity. Frontotemporal lobar degeneration-associated pathologies segregated based on their cerebral atrophy profiles, according to the following scheme: asymmetric, relatively localized (predominantly temporal lobe) atrophy (TDP-43 type C); relatively symmetric, relatively localized (predominantly temporal lobe) atrophy (microtubule-associated protein tau mutations); strongly asymmetric, distributed atrophy (Pick's disease); relatively symmetric, predominantly extratemporal atrophy (corticobasal degeneration, fused-in-sarcoma pathology). TDP-43 type A pathology was associated with substantial individual variation; however, within this group progranulin mutations were associated with strongly asymmetric, distributed hemispheric atrophy. We interpret the findings in terms of emerging network models of neurodegenerative disease: the neuroanatomical specificity of particular frontotemporal lobar degeneration pathologies may depend on an interaction of disease-specific and network-specific factors.
  Brain 09/2011; 134(Pt 9):2565-81. · 9.46 Impact Factor
• Article: No evidence that extended tracts of homozygosity are associated with Alzheimer's disease.

  Rebecca Sims, Sarah Dwyer, Denise Harold, Amy Gerrish, Paul Hollingworth, Jade Chapman, Nicola Jones, Richard Abraham, Dobril Ivanov, Jaspreet Singh Pahwa, [......], John Collinge, Gill Livingston, Nicholas J Bass, Hugh Gurling, Andrew McQuillin, Lesley Jones, Peter A Holmans, Michael O'Donovan, Michael J Owen, Julie Williams
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  ABSTRACT: We sought to investigate the contribution of extended runs of homozygosity in a genome-wide association dataset of 1,955 Alzheimer's disease cases and 955 elderly screened controls genotyped for 529,205 autosomal single nucleotide polymorphisms. Tracts of homozygosity may mark regions inherited from a common ancestor and could reflect disease loci if observed more frequently in cases than controls. We found no excess of homozygous tracts in Alzheimer's disease cases compared to controls and no individual run of homozygosity showed association to Alzheimer's disease.
  American Journal of Medical Genetics Part B Neuropsychiatric Genetics 08/2011; 156B(7):764-71. · 3.70 Impact Factor
• Article: Genome wide association studies and prion disease.

  Ana Lukic, Simon Mead
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  ABSTRACT: Over the last decade remarkable advances in genotyping and sequencing technology have resulted in hundreds of novel gene associations with disease. These have typically involved high frequency alleles in common diseases and with the advent of next generation sequencing, disease causing recessive mutations in rare inherited syndromes. Here we discuss the impact of these advances and other gene discovery methods in the prion diseases. Several quantitative trait loci in mouse have been mapped and their human counterparts analysed (HECTD2, CPNE8); other candidate genes regions have been chosen for functional reasons (SPRN, CTSD). Human genome wide association has been done in variant Creutzfeldt-Jakob disease (CJD) and are ongoing in larger collections of sporadic CJD with findings around, but not clearly beyond, the levels of statistical significance required in these studies (THRB-RARB, STMN2). Future work will include closer integration of animal and human genetic studies, larger and combined genome wide association, analysis of structural genetic variantion and next generation sequencing studies involving the entire coding exome or genome.
  Prion 07/2011; 5(3):154-60. · 2.85 Impact Factor
• Chapter: Prion Diseases

  Simon Mead, Peter Rudge
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  ABSTRACT: Prion diseases are a diverse group of neurodegenerative disorders of humans and animals. Generally these are recognized as rapidly progressive cognitive disorders with additional neurological signs such as myoclonus, ataxia, and pyramidal and extrapyramidal dysfunction. Inherited forms of prion disease may be highly atypical with clinical durations up to 20 years and can mimic any other neurodegenerative disease in the earlier stages. MRI, CSF, and genetic analyses are particularly helpful investigations, although tissue biopsy may be needed in some patients. Symptom management strategies, experimental therapeutics, and public health measures are discussed. KeywordsPrion-Creutzfeldt–Jakob disease (CJD)-Transmissible spongiform encephalopathy-Dementia- PRNP
  06/2011: pages 197-224;
• Article: Inherited prion disease with 4-octapeptide repeat insertion: disease requires the interaction of multiple genetic risk factors.

  Diego N Kaski, Catherine Pennington, Jon Beck, Mark Poulter, James Uphill, Matthew T Bishop, Jaqueline M Linehan, Catherine O'Malley, Jonathan D F Wadsworth, Susan Joiner, Richard S G Knight, James W Ironside, Sebastian Brandner, John Collinge, Simon Mead
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  ABSTRACT: Genetic factors are implicated in the aetiology of sporadic late-onset neurodegenerative diseases. Whether these genetic variants are predominantly common or rare, and how multiple genetic factors interact with each other to cause disease is poorly understood. Inherited prion diseases are highly heterogeneous and may be clinically mistaken for sporadic Creutzfeldt-Jakob disease because of a negative family history. Here we report our investigation of patients from the UK with four extra octapeptide repeats, which suggest that the risk of clinical disease is increased by a combination of the mutation and a susceptibility haplotype on the wild-type chromosome. The predominant clinical syndrome is a progressive cortical dementia with pyramidal signs, myoclonus and cerebellar abnormalities that closely resemble sporadic Creutzfeldt-Jakob disease. Autopsy shows perpendicular deposits of prion protein in the molecular layer of the cerebellum. Identity testing, PRNP microsatellite haplotyping and genealogical work confirm no cryptic close family relationships and suggests multiple progenitor disease haplotypes. All patients were homozygous for methionine at polymorphic codon 129. In addition, at a single nucleotide polymorphism upstream of PRNP thought to confer susceptibility to sporadic Creutzfeldt-Jakob disease (rs1029273), all patients were homozygous for the risk allele (combined P=5.9×10(-5)). The haplotype identified may also be a risk factor in other partially penetrant inherited prion diseases although it does not modify age of onset. Blood expression of PRNP in healthy individuals was modestly higher in carriers of the risk haplotype. These findings may provide a precedent for understanding apparently sporadic neurodegenerative diseases caused by rare high-risk mutations.
  Brain 06/2011; 134(Pt 6):1829-38. · 9.46 Impact Factor
• Article: Genetics of prion disease.

  Sarah Lloyd, Simon Mead, John Collinge
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  ABSTRACT: Prion diseases or transmissible spongiform encephalopathies (TSEs) are neurodegenerative disorders of humans and animals for which there are no effective treatments or cure. They include Creutzfeldt-Jakob disease (CJD) in humans and sheep scrapie, bovine spongiform encephalopathy (BSE) and chronic wasting disease (CWD) in cervids. The prion protein (PrP) is central to the disease process. An abnormal form of PrP is generally considered to be the sole or principal component of the infectious agent and a multimeric isomer (PrP(Sc)) is deposited in affected brains. Inherited prion diseases are caused by over 30 mutations in the prion protein gene (PRNP) and common polymorphisms can have a considerable affect on susceptibility and phenotype. Susceptibility and incubation time are also partly determined by other (non-PRNP) genetic modifiers. Understanding how these other genes modify prion diseases may lead to insights into biological mechanisms. Several approaches including human genome wide association studies (GWAS), mouse mapping and differential expression studies are now revealing some of these genes which include RARB (retinoic acid receptor beta), the E3 ubiquitin ligase HECTD2 and SPRN (Shadoo, shadow of prion protein gene).
  Topics in current chemistry 04/2011; 305:1-22. · 4.29 Impact Factor
• Article: 11C-PiB PET does not detect PrP-amyloid in prion disease patients including variant Creutzfeldt-Jakob disease.

  Harpreet Hyare, Anil Ramlackhansingh, Giorgio Gelosa, Paul Edison, Peter Rudge, Sebastian Brandner, David J Brooks, John Collinge, Simon Mead
  Journal of neurology, neurosurgery, and psychiatry 04/2011; 83(3):340-1. · 4.87 Impact Factor