Imperial College London

Professor Steve Gentleman

Faculty of MedicineDepartment of Brain Sciences

Professor of Neuropathology
 
 
 
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Contact

 

+44 (0)20 7594 6586s.gentleman Website

 
 
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Location

 

E408Burlington DanesHammersmith Campus

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Summary

 

Publications

Publication Type
Year
to

276 results found

Majeed M, Gentleman S, Nicholas RS, 2020, Patient Reported Outcomes (PROs) predicting outcome in Parkinson's disease: a Systematic Review, 6th Congress of the European-Academy-of-Neurology (EAN), Publisher: WILEY, Pages: 903-903, ISSN: 1351-5101

Conference paper

Van der Perren A, Gelders G, Fenyi A, Bousset L, Brit F, Peelaerts W, Van den Haute C, Gentleman S, Melki R, Baekelandt Vet al., 2020, The structural differences between patient-derived alpha-synuclein strains dictate characteristics of Parkinson's disease, multiple system atrophy and dementia with Lewy bodies, Acta Neuropathologica, Vol: 139, Pages: 977-1000, ISSN: 0001-6322

Synucleinopathies, such as Parkinson’s disease (PD), multiple system atrophy (MSA), and dementia with Lewy bodies (DLB), are defined by the presence of α-synuclein (αSYN) aggregates throughout the nervous system but diverge from one another with regard to their clinical and pathological phenotype. The recent generation of pure fibrillar αSYN polymorphs with noticeable differences in structural and phenotypic traits has led to the hypothesis that different αSYN strains may be in part responsible for the heterogeneous nature of synucleinopathies. To further characterize distinct αSYN strains in the human brain, and establish a structure-pathology relationship, we pursued a detailed comparison of αSYN assemblies derived from well-stratified patients with distinct synucleinopathies. We exploited the capacity of αSYN aggregates found in the brain of patients suffering from PD, MSA or DLB to seed and template monomeric human αSYN in vitro via a protein misfolding cyclic amplification assay. A careful comparison of the properties of total brain homogenates and pure in vitro amplified αSYN fibrillar assemblies upon inoculation in cells and in the rat brain demonstrates that the intrinsic structure of αSYN fibrils dictates synucleinopathies characteristics. We report that MSA strains show several similarities with PD strains, but are significantly more potent in inducing motor deficits, nigrostriatal neurodegeneration, αSYN pathology, spreading, and inflammation, reflecting the aggressive nature of this disease. In contrast, DLB strains display no or only very modest neuropathological features under our experimental conditions. Collectively, our data demonstrate a specific signature for PD, MSA, and DLB-derived strains that differs from previously described recombinant strains, with MSA strains provoking the most aggressive phenotype and more similarities with PD compared to DLB strains.

Journal article

Patel S, Tilley B, Pearce RKB, Gentleman Set al., 2020, A clinicopathological investigation of brainstem nuclei in dementia with Lewy bodies and Parkinson's disease dementia, 121st Meeting of the British-Neuropathological-Society / Developmental Neuropathology Symposium, Publisher: WILEY, Pages: 19-20, ISSN: 0305-1846

Conference paper

Pitz V, Malek N, Tobias ES, Grosset KA, Gentleman S, Grosset DGet al., 2020, The levodopa response varies in pathologically confirmed Parkinson's Disease: a systematic review, Movement Disorders Clinical Practice, Vol: 7, Pages: 218-222, ISSN: 2330-1619

BackgroundA good response to levodopa is a key feature of Parkinson's disease (PD), and a poor response suggests an alternative diagnosis, but the extent of variation in the levodopa response in definite PD is not well defined.Literature ReviewA systematic review of articles reporting pathologically confirmed PD and levodopa responsiveness from 1971 to 2018 was performed using the medical subheadings “postmortem,” “Parkinson's disease,” "levodopa," and “l ‐dopa” in PubMed, Embase, and Latin American and Caribbean Health Sciences Literature (LILACS) databases.CasesA total of 12 articles described 445 PD cases: 61.7% male, age at disease onset 64.0 years (SD 9.6), age at death 77.1 years (SD 7.2). Levodopa responsiveness was reported in 399 cases (89.7%) either as a graded or a binary response. In the 280 cases (70.2%) describing a graded response, it was excellent in 37.5%, good in 45.7%, moderate in 12.1%, and poor in 4.6%. In the 119 cases describing a binary response (29.8%), 73.1% were levodopa responsive, and 26.9% were nonresponsive. Comorbid brain pathology was present in 137 of 235 cases assessed, being cerebrovascular in 46.0% and Alzheimer's disease in 37.2% of these, but its contribution to levodopa responsiveness was unclear.ConclusionsThe levodopa motor response varies in definite PD. Explanations other than diagnostic inaccuracy should be explored.

Journal article

Perez-Rodriguez D, Kalyva M, Leija-Salazar M, Lashley T, Tarabichi M, Chelban V, Gentleman S, Schottlaender L, Franklin H, Vasmatzis G, Houlden H, Schapira AHV, Warner TT, Holton JL, Jaunmuktane Z, Proukakis Cet al., 2019, Investigation of somatic CNVs in brains of synucleinopathy cases using targeted SNCA analysis and single cell sequencing, Acta Neuropathologica Communications, Vol: 7, ISSN: 2051-5960

Synucleinopathies are mostly sporadic neurodegenerative disorders of partly unexplained aetiology, and include Parkinson's disease (PD) and multiple system atrophy (MSA). We have further investigated our recent finding of somatic SNCA (α-synuclein) copy number variants (CNVs, specifically gains) in synucleinopathies, using Fluorescent in-situ Hybridisation for SNCA, and single-cell whole genome sequencing for the first time in a synucleinopathy. In the cingulate cortex, mosaicism levels for SNCA gains were higher in MSA and PD than controls in neurons (> 2% in both diseases), and for MSA also in non-neurons. In MSA substantia nigra (SN), we noted SNCA gains in > 3% of dopaminergic (DA) neurons (identified by neuromelanin) and neuromelanin-negative cells, including olig2-positive oligodendroglia. Cells with CNVs were more likely to have α-synuclein inclusions, in a pattern corresponding to cell categories mostly relevant to the disease: DA neurons in Lewy-body cases, and other cells in the striatonigral degeneration-dominant MSA variant (MSA-SND). Higher mosaicism levels in SN neuromelanin-negative cells may correlate with younger onset in typical MSA-SND, and in cingulate neurons with younger death in PD. Larger sample sizes will, however, be required to confirm these putative findings. We obtained genome-wide somatic CNV profiles from 169 cells from the substantia nigra of two MSA cases, and pons and putamen of one. These showed somatic CNVs in ~ 30% of cells, with clonality and origins in segmental duplications for some. CNVs had distinct profiles based on cell type, with neurons having a mix of gains and losses, and other cells having almost exclusively gains, although control data sets will be required to determine possible disease relevance. We propose that somatic SNCA CNVs may contribute to the aetiology and pathogenesis of synucleinopathies, and that genome-wide somatic CNVs in MSA brain merit further study.

Journal article

Tilley BS, Romozzi M, Hession CM, Shiwani T, Goldfinger MH, Gentleman SM, Nicholas Ret al., 2019, GAIT SYMPTOMS CORRELATE WITH COGNITIVE PROBLEMS IN PARKINSON'S, Annual Meeting of the Association-of-British-Neurologists (ABN), Publisher: BMJ PUBLISHING GROUP, Pages: E21-E21, ISSN: 0022-3050

Conference paper

Kaye S, Abbott J, Gentleman S, Oertel W, McClure M, Hawkes CHet al., 2019, VIRAL & BACTERIAL RNA TRANSCRIPTS OF SUBSTANTIA NIGRA AND OLFACTORY BULB IN PARKINSON DISEASE, Annual Meeting of the Association-of-British-Neurologists (ABN), Publisher: BMJ PUBLISHING GROUP, Pages: E43-E43, ISSN: 0022-3050

Conference paper

Liu AKL, Lim YM, Pearce RKB, Gentleman SMet al., 2019, DO ANTICHOLINERGIC DRUGS INCREASE ALZHEIMER'S PATHOLOGY IN PARKINSON'S PATIENTS? A RETROSPECTIVE POST-MORTEM INVESTIGATION, Annual Meeting of the Association-of-British-Neurologists (ABN), Publisher: BMJ PUBLISHING GROUP, Pages: E20-E20, ISSN: 0022-3050

Conference paper

Smith C, Malek N, Grosset K, Cullen B, Gentleman S, Grosset DGet al., 2019, Neuropathology of dementia in patients with Parkinson's disease: a systematic review of autopsy studies, Journal of Neurology, Neurosurgery and Psychiatry, Vol: 90, Pages: 1234-1243, ISSN: 0022-3050

BACKGROUND: Dementia is a common, debilitating feature of late Parkinson's disease (PD). PD dementia (PDD) is associated with α-synuclein propagation, but coexistent Alzheimer's disease (AD) pathology may coexist. Other pathologies (cerebrovascular, transactive response DNA-binding protein 43 (TDP-43)) may also influence cognition. We aimed to describe the neuropathology underlying dementia in PD. METHODS: Systematic review of autopsy studies published in English involving PD cases with dementia. Comparison groups included PD without dementia, AD, dementia with Lewy bodies (DLB) and healthy controls. RESULTS: 44 reports involving 2002 cases, 57.2% with dementia, met inclusion criteria. While limbic and neocortical α-synuclein pathology had the strongest association with dementia, between a fifth and a third of all PD cases in the largest studies had comorbid AD. In PD cases with dementia, tau pathology was moderate or severe in around a third, and amyloid-β pathology was moderate or severe in over half. Amyloid-β was associated with a more rapid cognitive decline and earlier mortality, and in the striatum, distinguished PDD from DLB. Positive correlations between multiple measures of α-synuclein, tau and amyloid-β were found. Cerebrovascular and TDP-43 pathologies did not generally contribute to dementia in PD. TDP-43 and amyloid angiopathy correlated with coexistent Alzheimer pathology. CONCLUSIONS: While significant α-synuclein pathology is the main substrate of dementia in PD, coexistent pathologies are common. In particular, tau and amyloid-β pathologies independently contribute to the development and pattern of cognitive decline in PD. Their presence should be assessed in future clinical trials where dementia is a key outcome measure. TRIAL REGISTRATION NUMBER: CRD42018088691.

Journal article

Martin-Bastida A, Tilley B, Alireza T, Gentleman S, Dexter D, Ward Ret al., 2019, The interaction between iron metabolism and inflammation in Parkinson's disease: an in vivo and post mortem study, International Congress of Parkinson's Disease and Movement Disorders, Publisher: WILEY, Pages: S730-S730, ISSN: 0885-3185

Conference paper

Alexandris AS, Walker L, Liu AKL, McAleese KE, Johnson M, Pearce RKB, Gentleman SM, Attems Jet al., 2019, Cholinergic deficits and galaninergic hyperinnervation of the nucleus basalis of Meynert in Alzheimer's disease and Lewy body disorders, NEUROPATHOLOGY AND APPLIED NEUROBIOLOGY, Vol: 46, Pages: 264-278, ISSN: 0305-1846

Journal article

Liu KL, Chau TW, Lim EJ, Ahmed I, Chang R, Kalaitzakis M, Graeber M, Gentleman S, Pearce Ret al., 2019, Hippocampal CA2 Lewy pathology is associated with cholinergic degeneration in Parkinson’s disease with cognitive decline, Acta Neuropathologica Communications, Vol: 7, ISSN: 2051-5960

Although the precise neuropathological substrates of cognitive decline in Parkinson’s disease (PD) remain elusive, it has long been regarded that pathology in the CA2 hippocampal subfield is characteristic of Lewy body dementias, including dementia in PD (PDD). Early non-human primate tracer studies demonstrated connections from the nucleus of the vertical limb of the diagonal band of Broca (nvlDBB, Ch2) to the hippocampus. However, the relationship between Lewy pathology of the CA2 subfield and cholinergic fibres has not been explored. Therefore, in this study, we investigated the burden of pathology in the CA2 subsector of PD cases with varying degrees of cognitive impairment and correlated this with the extent of septohippocampal cholinergic deficit. Hippocampal sections from 67 PD, 34 PD with mild cognitive impairment and 96 PDD cases were immunostained for tau and alpha-synuclein, and the respective pathology burden was assessed semi-quantitatively. In a subset of cases, the degree of CA2 cholinergic depletion was quantified using confocal microscopy and correlated with cholinergic neuronal loss in Ch2. We found that only cases with dementia have a significantly greater Lewy pathology, whereas cholinergic fibre depletion was evident in cases with mild cognitive impairment and this was significantly correlated with loss of cholinergic neurons in Ch2. In addition, multiple antigen immunofluorescence demonstrated colocalisation between cholinergic fibres and alpha-synuclein but not tau pathology. Such specific Lewy pathology targeting the cholinergic system within the CA2 subfield may contribute to the unique memory retrieval deficit seen in patients with Lewy body disorders, as distinct from the memory storage deficit seen in Alzheimer’s disease.

Journal article

Goldfinger M, Tilley B, Sastre M, Gentleman Set al., 2019, A tale of two tauopathies: a comparison of vasculature changes in ARTAG and chronic traumatic encephalopathy, 120th Meeting of the British-Neuropathological-Society (BNS) / Developmental Neuropathology Symposium, Publisher: WILEY, Pages: 13-13, ISSN: 0305-1846

Conference paper

Tilley B, Goldfinger M, Pearce R, Gentleman Set al., 2019, The role of tau and basal ganglia cholinergic pathology in the pathogenesis of Parkinson's disease motor subtypes, 120th Meeting of the British-Neuropathological-Society (BNS) / Developmental Neuropathology Symposium, Publisher: WILEY, Pages: 18-19, ISSN: 0305-1846

Conference paper

Sinclair L, Brenton J, Liu AKL, Gentleman S, Love Set al., 2019, Are visual hallucinations in Parkinson's disease a result of decreased perfusion of visual processing areas of the brain?, 120th Meeting of the British-Neuropathological-Society (BNS) / Developmental Neuropathology Symposium, Publisher: WILEY, Pages: 44-45, ISSN: 0305-1846

Conference paper

Liu AKL, Lim YM, Pearce R, Gentleman Set al., 2019, Do anti-cholinergic drugs increase Alzheimer-type pathology in Parkinson's patients? A retrospective postmortem investigation, 120th Meeting of the British-Neuropathological-Society (BNS) / Developmental Neuropathology Symposium, Publisher: WILEY, Pages: 45-45, ISSN: 0305-1846

Conference paper

Stewart W, Allinson K, Al-Sarraj S, Bachmeier C, Barlow K, Belli A, Burns MP, Carson A, Crawford F, Dams-O'Connor K, Diaz-Arrastia R, Dixon CE, Edlow BL, Ferguson S, Fischl B, Folkerth RD, Gentleman S, Giza CC, Grady MS, Helmy A, Herceg M, Holton JL, Howell D, Hutchinson PJ, Iacono D, Iglesias JE, Ikonomovic MD, Johnson VE, Keene CD, Kofler JK, Koliatsos VE, Lee EB, Levin H, Lifshitz J, Ling H, Loane DJ, Love S, Maas AIR, Marklund N, Master CL, McElvenny DM, Meaney DF, Menon DK, Montine TJ, Mouzon B, Mufson EJ, Ojo JO, Prins M, Revesz T, Ritchie CW, Smith C, Sylvester R, Tang CY, Trojanowski JQ, Urankar K, Vink R, Wellington C, Wilde EA, Wilson L, Yeates K, Smith DHet al., 2019, Primum non nocere: A call for balance when reporting on CTE, Lancet Neurology, Vol: 18, Pages: 231-233, ISSN: 1474-4422

Journal article

Woerman AL, Oehler A, Kazmi SA, Lee J, Halliday GM, Middleton LT, Gentleman SM, Mordes DA, Spina S, Grinberg LT, Olson SH, Prusiner SBet al., 2019, Multiple system atrophy prions retain strain specificity after serial propagation in two different Tg(SNCA*A53T) mouse lines, Acta Neuropathologica, Vol: 137, Pages: 437-454, ISSN: 1432-0533

Previously, we reported that intracranial inoculation of brain homogenate from multiple system atrophy (MSA) patient samples produces neurological disease in the transgenic (Tg) mouse model TgM83+/−, which uses the prion protein promoter to express human α-synuclein harboring the A53T mutation found in familial Parkinson’s disease (PD). In our studies, we inoculated MSA and control patient samples into Tg mice constructed using a P1 artificial chromosome to express wild-type (WT), A30P, and A53T human α-synuclein on a mouse α-synuclein knockout background [Tg(SNCA+/+)Nbm, Tg(SNCA*A30P+/+)Nbm, and Tg(SNCA*A53T+/+)Nbm]. In contrast to studies using TgM83+/− mice, motor deficits were not observed by 330–400 days in any of the Tg(SNCA)Nbm mice after inoculation with MSA brain homogenates. However, using a cell-based bioassay to measure α-synuclein prions, we found brain homogenates from Tg(SNCA*A53T+/+)Nbm mice inoculated with MSA patient samples contained α-synuclein prions, whereas control mice did not. Moreover, these α-synuclein aggregates retained the biological and biochemical characteristics of the α-synuclein prions in MSA patient samples. Intriguingly, Tg(SNCA*A53T+/+)Nbm mice developed α-synuclein pathology in neurons and astrocytes throughout the limbic system. This finding is in contrast to MSA-inoculated TgM83+/− mice, which develop exclusively neuronal α-synuclein aggregates in the hindbrain that cause motor deficits with advanced disease. In a crossover experiment, we inoculated TgM83+/− mice with brain homogenate from two MSA patient samples or one control sample first inoculated, or passaged, in Tg(SNCA*A53T+/+)Nbm animals. Additionally, we performed the reverse experiment by inoculating Tg(SNCA*A53T+/+)Nbm mice with brain homogenate from the same two MSA samples and one control sample first passaged in TgM83+/− animals. The TgM83+/− mice inoculated wit

Journal article

Goldfinger MH, Tilley B, Mediratta S, Sastre M, Gentleman Set al., 2019, Chronic traumatic encephalopathy: The role of gliovascular pathology, 19th International Congress of Neuropathology, Publisher: WILEY, Pages: 10-10, ISSN: 1015-6305

Conference paper

Tilley BS, Goldfinger MH, Pearce RKB, Gentleman SMet al., 2019, The neuropathology of motor subtypes of Parkinson's disease: from the brainstem to basal ganglia, 19th International Congress of Neuropathology, Publisher: WILEY, Pages: 132-132, ISSN: 1015-6305

Conference paper

Prokopenko I, Miyakawa G, Zheng B, Heikkinen J, Petrova Quayle D, Udeh-Momoh C, Claringbould A, Neumann J, Haytural H, Kaakinen MA, Loizidou E, Meissner E, Bertram L, BIOS consortium, Gveric DO, Gentleman SM, Attems J, Perneczky R, Arzberger T, Muglia P, Lill CM, Parkkinen L, Middleton LTet al., 2019, Alzheimer's disease pathology explains association between dementia with Lewy bodies and APOE-ε4/TOMM40 long poly-T repeat allele variants., Alzheimers & Dementia, Vol: 5, Pages: 814-824, ISSN: 1552-5260

Introduction: The role of TOMM40-APOE 19q13.3 region variants is well documented in Alzheimer's disease (AD) but remains contentious in dementia with Lewy bodies (DLB) and Parkinson's disease dementia (PDD). Methods: We dissected genetic profiles within the TOMM40-APOE region in 451 individuals from four European brain banks, including DLB and PDD cases with/without neuropathological evidence of AD-related pathology and healthy controls. Results: TOMM40-L/APOE-ε4 alleles were associated with DLB (OR TOMM40 -L = 3.61; P value = 3.23 × 10-9; OR APOE -ε4 = 3.75; P value = 4.90 × 10-10) and earlier age at onset of DLB (HR TOMM40 -L = 1.33, P value = .031; HR APOE -ε4 = 1.46, P value = .004), but not with PDD. The TOMM40-L/APOE-ε4 effect was most pronounced in DLB individuals with concomitant AD pathology (OR TOMM40 -L = 4.40, P value = 1.15 × 10-6; OR APOE -ε4 = 5.65, P value = 2.97 × 10-8) but was not significant in DLB without AD. Meta-analyses combining all APOE-ε4 data in DLB confirmed our findings (ORDLB = 2.93, P value = 3.78 × 10-99; ORDLB+AD = 5.36, P value = 1.56 × 10-47). Discussion: APOE-ε4/TOMM40-L alleles increase susceptibility and risk of earlier DLB onset, an effect explained by concomitant AD-related pathology. These findings have important implications in future drug discovery and development efforts in DLB.

Journal article

Liu AKL, Lim EJ, Ahmed I, Chang RC-C, Pearce RKB, Gentleman SMet al., 2018, Review: revisiting the human cholinergic nucleus of the diagonal band of Broca, Neuropathology and Applied Neurobiology, Vol: 44, Pages: 647-662, ISSN: 0305-1846

Although the nucleus of the vertical limb of the diagonal band of Broca (nvlDBB) is the second largest cholinergic nucleus in the basal forebrain, after the nucleus basalis of Meynert (nbM), it has not generally been a focus for studies of neurodegenerative disorders. However, the nvlDBB does have an important projection to the hippocampus and discrete lesions of the rostral basal forebrain have been shown to disrupt retrieval memory function, a major deficit seen in patients with Lewy body disorders. One reason for its neglect is that the anatomical boundaries of the nvlDBB are ill defined and this area of the brain is not part of routine diagnostic sampling protocols. We have reviewed the history and anatomy of the nvlDBB and now propose guidelines for distinguishing nvlDBB from other neighbouring cholinergic cell groups for standardising future clinicopathological work. Thorough review of the literature regarding neurodegenerative conditions reveals inconsistent results in terms of cholinergic neuronal loss within the nvlDBB. This is likely to be due to the use of variable neuronal inclusion criteria and omission of cholinergic immunohistochemical markers. Extrapolating from those studies showing significant nvlDBB neuronal loss in Lewy body dementia, we propose an anatomical and functional connection between the cholinergic component of the nvlDBB (Ch2) and the CA2 subfield in the hippocampus which may be especially vulnerable in Lewy body disorders. This article is protected by copyright. All rights reserved.

Journal article

Goldfinger MH, Ling H, Tilley BS, Liu AKL, Davey K, Holton JL, Revesz T, Gentleman SMet al., 2018, The aftermath of boxing revisited: identifying chronic traumatic encephalopathy pathology in the original Corsellis boxer series, Acta Neuropathologica, Vol: 136, Pages: 973-974, ISSN: 1432-0533

Journal article

Pihlstrøm L, Schottlaender L, Chelban V, Houlden H, Al-Sarraj S, Arzberger T, Bettencourt C, Bhatia K, Dickson DW, Federoff M, Gelpi E, Gentleman S, Hardy J, Holton J, Huitinga I, Levey A, Mann D, Meissner W, Morris H, Morris C, Pittman A, Rascol O, Riederer P, Rogaeva E, Ross O, Scholtz S, Singleton AB, Trojanowski J, Vandrovcova J, Warner T, Wood Net al., 2018, LRP10 in α-synucleinopathies, The Lancet Neurology, Vol: 17, Pages: 1033-1034, ISSN: 1474-4422

Journal article

Sastre M, Gentleman S, Van Leuven F, 2018, TauBI or not TauBI: what was the question?, Brain, Vol: 141, Pages: 2536-2539, ISSN: 1460-2156

Journal article

Arena JD, Johnson VE, Trojanowski JQ, Gentleman SM, Stewart W, Smith DHet al., 2018, TAU ASTROGLIOPATHY CONSISTENT WITH ARTAG IS A COMMON FEATURE OF REPETITIVE MILD AND LATE SINGLE SEVERE TBI IN HUMANS, 3rd Joint Symposium of the International-and-National-Neurotrauma-Societies-and-AANS/CNS-Section on Neurotrauma and Critical Care, Publisher: MARY ANN LIEBERT, INC, Pages: A140-A140, ISSN: 0897-7151

Conference paper

Mokretar K, Pease D, Taanman J-W, Soenmez A, Ejaz A, Lashley T, Ling H, Gentleman S, Houlden H, Holton JL, Schapira AHV, Nacheva E, Proukakis Cet al., 2018, Somatic copy number gains of α-synuclein (SNCA) in Parkinson's disease and multiple system atrophy brains, Brain, Vol: 141, Pages: 2419-2431, ISSN: 1460-2156

The α-synuclein protein, encoded by SNCA, has a key role in the pathogenesis of Parkinson's disease and other synucleinopathies. Although usually sporadic, Parkinson's disease can result from inherited copy number variants in SNCA and other genes. We have hypothesized a role of somatic SNCA mutations, leading to mosaicism, in sporadic synucleinopathies. The evidence for mosaicism in healthy and diseased brain is increasing rapidly, with somatic copy number gains of APP reported in Alzheimer's brain. Here we demonstrate somatic SNCA copy number gains in synucleinopathies (Parkinson's disease and multiple system atrophy), focusing on substantia nigra. We selected sporadic cases with relatively young onset or short disease duration, and first excluded high level copy number variant mosaicism by DNA analysis using digital PCR for SNCA, and/or customized array comparative genomic hybridization. To detect low level SNCA copy number variant mosaicism, we used fluorescent in situ hybridization with oligonucleotide custom-designed probes for SNCA, validated on brain and fibroblasts with known copy number variants. We determined SNCA copy number in nigral dopaminergic neurons and other cells in frozen nigra sections from 40 cases with Parkinson's disease and five with multiple system atrophy, and 25 controls, in a blinded fashion. Parkinson's disease cases were significantly more likely than controls to have any SNCA gains in dopaminergic neurons (P = 0.0036), and overall (P = 0.0052). The average proportion of dopaminergic neurons with gains in each nigra was significantly higher in Parkinson's disease than controls (0.78% versus 0.45%; P = 0.017). There was a negative correlation between the proportion of dopaminergic neurons with gains and onset age in Parkinson's disease (P = 0.013), but not with disease duration, or age of death in cases or controls. Cases with tremor at onset were less likely to have gains (P = 0.035). All multiple system atrophy cases had gains

Journal article

Jabbari E, Woodside J, Tan M, Shoai M, Pittman A, Ferrari R, Mok KY, Zhang D, Reynolds RH, de Silva R, Grimm MJ, Respondek G, Müller U, Al-Sarraj S, Gentleman SM, Lees AJ, Warner TT, Hardy J, Revesz T, Höglinger GU, Holton JL, Ryten M, Morris HRet al., 2018, Variation at the TRIM11 locus modifies Progressive Supranuclear Palsy phenotype, Annals of Neurology, Vol: 84, Pages: 485-496, ISSN: 0364-5134

OBJECTIVE: The basis for clinical variation related to underlying Progressive Supranuclear Palsy (PSP) pathology is unknown. We performed a genome wide association study (GWAS) to identify genetic determinants of PSP phenotype. METHODS: Two independent pathological and clinically diagnosed PSP cohorts were genotyped and phenotyped to create Richardson's syndrome (RS) and non-RS groups. We carried out separate logistic regression GWAS to compare RS and non-RS groups and then combined datasets to carry out a whole cohort analysis (RS=367, non-RS=130). We validated our findings in a third cohort by referring to data from 100 deeply phenotyped cases from a recent GWAS. We assessed the expression/co-expression patterns of our identified genes and used our data to carry out gene-based association testing. RESULTS: Our lead single nucleotide polymorphism (SNP), rs564309, showed an association signal in both cohorts, reaching genome wide significance in our whole cohort analysis - OR 5.5 (3.2-10.0), p-value 1.7x10-9 . rs564309 is an intronic variant of the tripartite motif-containing protein 11 (TRIM11) gene, a component of the ubiquitin proteasome system (UPS). In our third cohort, minor allele frequencies of surrogate SNPs in high linkage disequilibrium with rs564309 replicated our findings. Gene based association testing confirmed an association signal at TRIM11. We found that TRIM11 is predominantly expressed neuronally, in the cerebellum and basal ganglia. INTERPRETATION: Our study suggests that the TRIM11 locus is a genetic modifier of PSP phenotype and potentially adds further evidence for the UPS having a key role in tau pathology, therefore representing a target for disease modifying therapies. This article is protected by copyright. All rights reserved.

Journal article

Calsolaro V, Fan Z, Veronese M, Femminella G, Pasqualetti G, Trigg W, Buckley C, Turkheimer F, Gentleman S, Hinz R, Brooks D, Edison Pet al., 2018, Novel third generation microglial marker flutriciclamide ([18F]GE180) in Alzheimer’s disease and mild cognitive impairment, Alzheimer's and Dementia, Vol: 14, Pages: P506-P506, ISSN: 1552-5260

Journal article

Lai HM, Liu KL, Ng HHM, Goldfinger M, Chau TW, DeFelice J, Tilley B, Wong WM, Wu W, Gentleman SMet al., 2018, Next generation histology methods for three-dimensional imaging of fresh and archival human brain tissues, Nature Communications, Vol: 9, ISSN: 2041-1723

Modern clearing techniques for the three-dimensional (3D) visualization of neural tissue microstructure have been very effective when used on rodent brain but very few studies haveutilized them on human brain material, mainly due to the inherent difficulties in processing post26mortem tissue. Here, we develop a tissue clearing solution, OPTIClear, optimised for fresh and archival human brain tissue, including formalin-fixed paraffin-embedded material. In light ofpractical challenges with immunostaining in tissue clearing, we adapt the use of cresyl violet for visualization of neurons in cleared tissue, with the potential for 3D quantification in regions ofinterest. Furthermore, we use lipophilic tracers for tracing of neuronal processes in post-mortem tissue, enabling the study of the morphology of human dendritic spines in 3D. The development ofthese different strategies for human tissue clearing has wide applicability and, we hope, will provide a baseline for further technique development.

Journal article

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