Stuart Pickering-Brown

The University of Manchester, Manchester, England, United Kingdom

Are you Stuart Pickering-Brown?

Claim your profile

Publications (139)1155.67 Total impact

  • Journal of neurology, neurosurgery, and psychiatry 07/2015; DOI:10.1136/jnnp-2015-311311 · 5.58 Impact Factor
  • Stuart Pickering-Brown · John Hardy
    Brain 06/2015; DOI:10.1093/brain/awv173 · 10.23 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: GGGGCC repeat expansions of C9ORF72 represent the most common genetic variant of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia. We and others have proposed that RNA transcribed from the repeat sequence is toxic via sequestration of RNA-binding factors. Both GGGGCC-repeat (sense) and CCCCGG-repeat (antisense) molecules are detectable by fluorescence in situ hybridisation as RNA foci, but their relative expression pattern within the CNS and contribution to disease has not been determined. Blinded examination of CNS biosamples from ALS patients with a repeat expansion of C9ORF72 showed that antisense foci are present at a significantly higher frequency in cerebellar Purkinje neurons and motor neurons, whereas sense foci are present at a significantly higher frequency in cerebellar granule neurons. Consistent with this, inclusions containing sense or antisense derived dipeptide repeat proteins were present at significantly higher frequency in cerebellar granule neurons or motor neurons, respectively. Immunohistochemistry and UV-crosslinking studies showed that sense and antisense RNA molecules share similar interactions with SRSF2, hnRNP K, hnRNP A1, ALYREF, and hnRNP H/F. Together these data suggest that, although sense and antisense RNA molecules might be expected to be equally toxic via their shared protein binding partners, distinct patterns of expression in various CNS neuronal populations could lead to relative differences in their contribution to the pathogenesis of neuronal injury. Moreover in motor neurons, which are the primary target of pathology in ALS, the presence of antisense foci (χ 2, p
    Acta Neuropathologica 05/2015; DOI:10.1007/s00401-015-1429-9 · 10.76 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: We previously reported1 that expansions in the C9orf72 gene, identified by Southern blotting or using a repeat primed PCR assay,2 may go undetected using an alternative, standard PCR assay.3 We attributed this discrepancy to a 10 base pair deletion adjacent to the expansion which was presumed to interfere with genotyping.1 To determine the possible clinical and pathological relevance of the deletion, we compared patients in whom the C9orf72 expansion was detected using the Renton3 assay (C9 reference group) with those carrying an expansion not detected by this method (deletion group).
    Journal of neurology, neurosurgery, and psychiatry 04/2015; DOI:10.1136/jnnp-2015-310441 · 5.58 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Frontotemporal lobar degeneration is a highly familial disease and the most common known genetic cause is the repeat expansion mutation in the gene C9orf72. We have identified 2 brothers with an expansion mutation in C9orf72 using Southern blotting that is undetectable using repeat-primed polymerase chain reaction. Sequencing using high concentrations of DNA denaturants of a bacterial artificial chromosome clone obtained from one of the brothers identified a 10-base pair deletion adjacent to the expansion that presumably confers strong secondary structure that interferes with the genotyping. Using an alternative method, we have identified missed expansion carriers in our cohort, and this number has increased by approximately 25%. This observation has important implications for patients undergoing genetic testing for C9orf72. Copyright © 2015 Elsevier Inc. All rights reserved.
    Neurobiology of Aging 12/2014; 51(3). DOI:10.1016/j.neurobiolaging.2014.12.009 · 4.85 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Mutations in the gene p62/SQSTM1 have been reported as a relatively rare cause of frontotemporal lobar degeneration (FTLD). To establish whether this was the case for cases of FTLD from the United Kingdom, we sequenced the sequenced the entire open reading frame of this gene in a large cohort of patients. We identified 3 novel mutations in p62/SQSTM1 in 4 patients. One of these was a premature stop codon that removed the last 101 amino acids of the protein that presumably has a negative effect on protein function. Another mutation was also found in a case with a repeat expansion mutation in C9orf72 confirmed by Southern blot. These findings confirm a role of p62/SQSTM1 as a cause of FTLD. Copyright © 2014 Elsevier Inc. All rights reserved.
    Neurobiology of Aging 10/2014; 36(3). DOI:10.1016/j.neurobiolaging.2014.08.035 · 4.85 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: We have measured plasma progranulin and interleukin-6 in 230 patients with frontotemporal lobar degeneration (FTLD), 104 patients with Alzheimer's disease, and 161 control subjects. We have replicated previous findings of decreased levels of progranulin protein in FTLD because of mutations in GRN and show this is not observed in FTLD cases because of other causes. interleukin-6 levels were increased in FTLD overall, but these did not discriminate between clinical and genetic subtypes. Copyright © 2014 Elsevier Inc. All rights reserved.
    Neurobiology of Aging 10/2014; 36(3). DOI:10.1016/j.neurobiolaging.2014.10.023 · 4.85 Impact Factor
  • Source
    Alzheimer Disease and Associated Disorders 10/2014; DOI:10.1097/WAD.0000000000000064 · 2.69 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Important insights into the pathogenic mechanism of Alzheimer's disease (AD) have arisen from the identification of genetic risk factors. Recently, a variant in the TREM2 gene (rs75932628), causing a C-to-T base-pair change that results in the substitution of histidine for arginine at amino acid position 47 (R47H) in the TREM2 protein, has been associated with an increased risk of AD. We, therefore, genotyped samples from a cohort of 474 AD patients and 608 healthy controls, from the northwest region of the UK, using allelic discrimination assays, to replicate the results of the previous studies. We show a significant association of the T allele of the rs75932628 variant of TREM2 with AD (allelic odds ratio 11.08, 95% confidence interval 2.55-48.09, and Yates' corrected p value = 0.000146). TREM2 is an innate immune receptor that regulates microglial cytokine production and phagocytosis, implying that dysregulation of these processes may be involved in AD pathology, with implications for disease management.
    Neurobiology of Aging 08/2014; 36(1). DOI:10.1016/j.neurobiolaging.2014.08.001 · 4.85 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: An expanded GGGGCC repeat in C9orf72 is the most common genetic cause of frontotemporal dementia and amyotrophic lateral sclerosis. A fundamental question is whether toxicity is driven by the repeat RNA itself and/or by dipeptide repeat proteins generated by repeat-associated, non-ATG translation. To address this question, we developed in vitro and in vivo models to dissect repeat RNA and dipeptide repeat protein toxicity. Expression of pure repeats, but not stop codon–interrupted “RNA-only” repeats in Drosophila caused adult-onset neurodegeneration. Thus, expanded repeats promoted neurodegeneration through dipeptide repeat proteins. Expression of individual dipeptide repeat proteins with a non-GGGGCC RNA sequence revealed that both poly-(glycine-arginine) and poly-(proline-arginine) proteins caused neurodegeneration. These findings are consistent with a dual toxicity mechanism, whereby both arginine-rich proteins and repeat RNA contribute to C9orf72-mediated neurodegeneration.
    Science 08/2014; 345(6201). DOI:10.1126/science.1256800 · 31.48 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) are considered to be part of a disease spectrum. However, with the exception of C9orf72, genes that cause ALS are rarely found to cause FTD and vice versa. To investigate this further, we have sequenced the ALS gene UBQLN2 in our FTD cohort and have found a single putative mutation. This further supports the concept that ALS genes are a rare cause of FTD.
    Neurobiology of Aging 08/2014; 36(1). DOI:10.1016/j.neurobiolaging.2014.08.002 · 4.85 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: BACKGROUND: Frontotemporal dementia (FTD) is a complex disorder characterised by a broad range of clinical manifestations, differential pathological signatures, and genetic variability. Mutations in three genes-MAPT, GRN, and C9orf72-have been associated with FTD. We sought to identify novel genetic risk loci associated with the disorder. METHODS: We did a two-stage genome-wide association study on clinical FTD, analysing samples from 3526 patients with FTD and 9402 healthy controls. To reduce genetic heterogeneity, all participants were of European ancestry. In the discovery phase (samples from 2154 patients with FTD and 4308 controls), we did separate association analyses for each FTD subtype (behavioural variant FTD, semantic dementia, progressive non-fluent aphasia, and FTD overlapping with motor neuron disease [FTD-MND]), followed by a meta-analysis of the entire dataset. We carried forward replication of the novel suggestive loci in an independent sample series (samples from 1372 patients and 5094 controls) and then did joint phase and brain expression and methylation quantitative trait loci analyses for the associated (p<5 × 10(-8)) single-nucleotide polymorphisms. FINDINGS: We identified novel associations exceeding the genome-wide significance threshold (p<5 × 10(-8)). Combined (joint) analyses of discovery and replication phases showed genome-wide significant association at 6p21.3, HLA locus (immune system), for rs9268877 (p=1·05 × 10(-8); odds ratio=1·204 [95% CI 1·11-1·30]), rs9268856 (p=5·51 × 10(-9); 0·809 [0·76-0·86]) and rs1980493 (p value=1·57 × 10(-8), 0·775 [0·69-0·86]) in the entire cohort. We also identified a potential novel locus at 11q14, encompassing RAB38/CTSC (the transcripts of which are related to lysosomal biology), for the behavioural FTD subtype for which joint analyses showed suggestive association for rs302668 (p=2·44 × 10(-7); 0·814 [0·71-0·92]). Analysis of expression and methylation quantitative trait loci data suggested that these loci might affect expression and methylation in cis. INTERPRETATION: Our findings suggest that immune system processes (link to 6p21.3) and possibly lysosomal and autophagy pathways (link to 11q14) are potentially involved in FTD. Our findings need to be replicated to better define the association of the newly identified loci with disease and to shed light on the pathomechanisms contributing to FTD
    The Lancet Neurology 07/2014; 3(7):686-99. DOI:10.1016/S1474-4422(14)70065-1 · 21.82 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Clinical and neuropathological similarities between dementia with Lewy bodies (DLB), Parkinson's and Alzheimer's diseases (PD and AD, respectively) suggest that these disorders may share etiology. To test this hypothesis, we have performed an association study of 54 genomic regions, previously implicated in PD or AD, in a large cohort of DLB cases and controls. The cohort comprised 788 DLB cases and 2624 controls. To minimize the issue of potential misdiagnosis, we have also performed the analysis including only neuropathologically proven DLB cases (667 cases). The results show that the APOE is a strong genetic risk factor for DLB, confirming previous findings, and that the SNCA and SCARB2 loci are also associated after a study-wise Bonferroni correction, although these have a different association profile than the associations reported for the same loci in PD. We have previously shown that the p.N370S variant in GBA is associated with DLB, which, together with the findings at the SCARB2 locus, suggests a role for lysosomal dysfunction in this disease. These results indicate that DLB has a unique genetic risk profile when compared with the two most common neurodegenerative diseases and that the lysosome may play an important role in the etiology of this disorder. We make all these data available.
    Human Molecular Genetics 06/2014; 23(23). DOI:10.1093/hmg/ddu334 · 6.68 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: A hexanucleotide (GGGGCC) expansion in C9ORF72 gene is the most common genetic change seen in familial Frontotemporal Lobar Degeneration (FTLD) and familial Motor Neurone Disease (MND). Pathologically, expansion bearers show characteristic p62 positive, TDP-43 negative inclusion bodies within cerebellar and hippocampal neurons which also contain dipeptide repeat proteins (DPR) formed from sense and antisense RAN (repeat associated non ATG-initiated) translation of the expanded repeat region itself. 'Inappropriate' formation, and aggregation, of DPR might therefore confer neurotoxicity and influence clinical phenotype. Consequently, we compared the topographic brain distribution of DPR in 8 patients with Frontotemporal dementia (FTD), 6 with FTD + MND and 7 with MND alone (all 21 patients bearing expansions in C9ORF72) using a polyclonal antibody to poly-GA, and related this to the extent of TDP-43 pathology in key regions of cerebral cortex and hippocampus. There were no significant differences in either the pattern or severity of brain distribution of DPR between FTD, FTD + MND and MND groups, nor was there any relationship between the distribution of DPR and TDP-43 pathologies in expansion bearers. Likewise, there were no significant differences in the extent of TDP-43 pathology between FTLD patients bearing an expansion in C9ORF72 and non-bearers of the expansion. There were no association between the extent of DPR pathology and TMEM106B or APOE genotypes. However, there was a negative correlation between the extent of DPR pathology and age at onset. Present findings therefore suggest that although the presence and topographic distribution of DPR may be of diagnostic relevance in patients bearing expansion in C9ORF72 this has no bearing on the determination of clinical phenotype. Because TDP-43 pathologies are similar in bearers and non-bearers of the expansion, the expansion may act as a major genetic risk factor for FTLD and MND by rendering the brain highly vulnerable to those very same factors which generate FTLD and MND in sporadic disease.
    06/2014; 2(1):70. DOI:10.1186/2051-5960-2-70
  • Janis Bennion Callister · Stuart M Pickering-Brown
    [Show abstract] [Hide abstract]
    ABSTRACT: One of the most interesting findings in the field of neurodegeneration in recent years is tfche discovery of a genetic mutation in the C9orf72 gene, the most common mutation found to be causative of sporadic and familial frontotemporal lobar degeneration (FTLD), amyotrophic lateral sclerosis (ALS) and concomitant FTD-ALS (DeJesus-Hernandez et al., 2011b; Renton et al., 2011). While clinical and molecular data, such as the identification of TDP-43 being a common pathological protein (Neumann et al., 2006) have hinted at such a link for years, the identification of what was formally known as "the chromosome 9 FTLD-ALS gene" has provided a foundation for better understanding of the relationship between the two. Indeed, it is now recognized that ALS and FTLD-TDP represent a disease spectrum. In this review, we will discuss the current genetic and pathological features of the FTLD-ALS spectrum.
    Experimental Neurology 06/2014; 262. DOI:10.1016/j.expneurol.2014.06.001 · 4.62 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: AimsFrontotemporal lobar degeneration (FTLD) is clinically and pathologically heterogeneous. Although associated with variations in MAPT, GRN and C9ORF72, the pathogenesis of these, and of other nongenetic, forms of FTLD, remains unknown. Epigenetic factors such as histone regulation by histone deacetylases (HDAC) may play a role in the dysregulation of transcriptional activity, thought to underpin the neurodegenerative process.Methods The distribution and intensity of HDACs 4, 5 and 6 was assessed semi-quantitatively in immunostained sections of temporal cortex with hippocampus, and cerebellum, from 33 pathologically confirmed cases of FTLD and 27 controls.ResultsWe found a significantly greater intensity of cytoplasmic immunostaining for HDAC4 and HDAC6 in granule cells of the dentate gyrus in cases of FTLD overall compared with controls, and specifically in cases of FTLD tau-Picks compared with FTLD tau-MAPT and controls. No differences were noted between FTLD-TDP subtypes, or between the different genetic and nongenetic forms of FTLD. No changes were seen in HDAC5 in any FTLD or control cases.Conclusions Dysregulation of HDAC4 and/or HDAC6 could play a role in the pathogenesis of FTLD-tau associated with Pick bodies, although their lack of immunostaining implies that such changes do not contribute directly to the formation of Pick bodies.
    Neuropathology and Applied Neurobiology 05/2014; 41(2). DOI:10.1111/nan.12153 · 4.97 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Frontotemporal lobar degeneration (FTLD) is classified mainly into FTLD-tau and FTLD-TDP according to the protein present within inclusion bodies. While such a classification implies only a single type of protein should be present, recent studies have demonstrated dual tau and TDP-43 proteinopathy can occur, particularly in inherited FTLD. We therefore investigated 33 patients with FTLD-tau (including 9 with MAPT mutation) for TDP-43 pathological changes, and 45 patients with FTLD-TDP (including 12 with hexanucleotide expansion in C9ORF72 and 12 with GRN mutation), and 23 patients with motor neurone disease (3 with hexanucleotide expansion in C9ORF72), for tauopathy. TDP-43 pathological changes, of the kind seen in many elderly individuals with Alzheimer's disease, were seen in only two FTLD-tau cases – a 70-year-old male with exon 10 + 13 mutation in MAPT, and a 73-year-old female with corticobasal degeneration. Such changes were considered to be secondary and probably reflective of advanced age. Conversely, there was generally only scant tau pathology, usually only within hippocampus and/or entorhinal cortex, in most patients with FTLD-TDP or MND. The extent of tau pathology in FTLD-TDP and MND, as with amyloid β protein, may relate to increased age and possession of Apolipoprotein ε4 allele. We find no predilection or predisposition towards an accompanying TDP-43 pathology in patients with FTLD-tau, irrespective of presence or absence of MAPT mutation, or that genetic changes associated with FTLD-TDP predispose towards excessive tauopathy. Where the two processes coexist, this is limited and probably causatively independent of each other.
    Neuropathology and Applied Neurobiology 05/2014; 40(7). DOI:10.1111/nan.12155 · 4.97 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Dystonia is a common movement disorder. A number of monogenic causes have been identified. However, the majority of dystonia cases are not explained by single gene defects. Cervical dystonia is one of the commonest forms without genetic causes identified. This pilot study aimed to identify large effect-size risk loci in cervical dystonia. A genomewide association study (GWAS) was performed. British resident cervical dystonia patients of European descent were genotyped using the Illumina-610-Quad. Comparison was made with controls of European descent from the Wellcome Trust Case Control Consortium using logistic regression algorithm from PLINK. SNPs not genotyped by the array were imputed with 1000 Genomes Project data using the MaCH algorithm and minimac. Postimputation analysis was done with the mach2dat algorithm using a logistic regression model. After quality control measures, 212 cases were compared with 5173 controls. No single SNP passed the genomewide significant level of 5 × 10(-8) in the analysis of genotyped SNP in PLINK. Postimputation, there were 5 clusters of SNPs that had P value <5 × 10(-6) , and the best cluster of SNPs was found near exon 1 of NALCN, (sodium leak channel) with P = 9.76 × 10(-7) . Several potential regions were found in the GWAS and imputation analysis. The lowest P value was found in NALCN. Dysfunction of this ion channel is a plausible cause for dystonia. Further replication in another cohort is needed to confirm this finding. We make this data publicly available to encourage further analyses of this disorder. © 2013 International Parkinson and Movement Disorder Society.
    Movement Disorders 02/2014; 29(2). DOI:10.1002/mds.25732 · 5.68 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Pathological heterogeneity within patients with Frontotemporal lobar degeneration (FTLD) in general precludes the accurate assignment of diagnostic subtype in life. The aim of this study was to assess the extent of microglial cell activation in FTLD in order to determine whether it might be possible to employ this as a diagnostic marker in vivo using PET ligand [11C](R)-PK11195 in order to differentiate cases of FTLD according to histological subtype. The distribution and extent of microglial cell activation was assessed semi-quantitatively in cortical grey and subcortical white matter of CD68 immunostained sections of frontal and temporal cortex from 78 pathologically confirmed cases of FTLD, 13 of Alzheimer's disease (AD) and 13 controls. Significantly higher levels of microglial cell activation than controls occurred in all 4 regions in FTLD, and in 3 of the 4 regions in AD. Microglial activation was greater in frontal subcortical white matter in FTLD than AD, whereas it was higher in temporal cortical grey matter in AD than FTLD. Microglial cell activation was significantly higher in temporal subcortical white matter in FTLD-MAPT than in other genetic (GRN, C9ORF72) or non-genetic forms of FTLD. The present study suggests that high levels of microglial cell involvement in temporal lobe (subcortical white matter) might serve as a marker of inherited FTLD associated with intronic mutations in MAPT, with a relatively intense signal in this region in PET studies using [11C](R)-PK11195 as microglial cell marker could indicate the presence of MAPT mutation in vivo.
    Neuropathology and Applied Neurobiology 10/2013; 40(6). DOI:10.1111/nan.12092 · 4.97 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Background Cases of Frontotemporal Lobar Degeneration (FTLD) and Motor Neurone Disease (MND) associated with expansions in C9ORF72 gene are characterised pathologically by the presence of TDP-43 negative, but p62 positive, inclusions in granule cells of the cerebellum and in cells of dentate gyrus and area CA4 of the hippocampus. Results We screened 84 cases of pathologically confirmed FTLD and 23 cases of MND for the presence of p62 positive inclusions in these three brain regions, and identified 13 positive cases of FTLD and 3 of MND. All cases demonstrated expansions in C9ORF72 by Southern blotting where frozen tissues were available. The p62 positive inclusions in both cerebellum and hippocampus were immunostained by antibodies to dipeptide repeat proteins (DPR), poly Gly-Ala (poly-GA), poly Gly-Pro (poly-GP) and poly Gly-Arg (poly-GR), these arising from a putative non-ATG initiated (RAN) sense translation of the GGGGCC expansion. There was also some slight, but variable, immunostaining with poly-AP antibody implying some antisense translation might also occur, though the relative paucity of immunostaining could reflect poor antigen avidity on the part of the antisense antibodies. Of the FTLD cases with DPR, 6 showed TDP-43 type A and 6 had TDP-43 type B histology; one had FTLD-tau with the pathology of corticobasal degeneration. There were no qualitative or quantitative differences in the pattern of immunostaining with antibodies to DPR, or p62, proteins between TDP-43 type A and type B cases. Ratings for frequency of inclusions immunostained by these poly-GA, poly-GP and poly-GR antibodies broadly correlated with those for immunolabelled by p62 antibody in all three regions. Conclusion We conclude that DPR are a major component of p62 positive inclusions in FTLD and MND.
    10/2013; 1(1). DOI:10.1186/2051-5960-1-68

Publication Stats

9k Citations
1,155.67 Total Impact Points


  • 1994–2015
    • The University of Manchester
      • • Institute of Brain, Behaviour and Mental Health
      • • Mental Health and Neurodegeneration Research Group
      • • School of Community-Based Medicine
      • • Faculty of Medical and Human Sciences
      • • School of Translational Medicine
      • • Centre for Clinical and Cognitive Neurosciences
      • • Neuroscience Research Group
      • • Faculty of Life Sciences
      • • School of Psychological Sciences
      Manchester, England, United Kingdom
  • 2004
    • Institut Pasteur de Lille
      Lille, Nord-Pas-de-Calais, France
    • University College London
      Londinium, England, United Kingdom
  • 2003–2004
    • King's College London
      • Institute of Psychiatry
      London, ENG, United Kingdom