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
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293 results found

Feleke R, Reynolds RH, Smith AM, Tilley B, Taliun SAG, Hardy J, Matthews PM, Gentleman S, Owen DR, Johnson MR, Srivastava PK, Ryten Met al., 2021, Cross-platform transcriptional profiling identifies common and distinct molecular pathologies in Lewy body diseases, Acta Neuropathologica, Vol: 142, Pages: 449-474, ISSN: 0001-6322

Parkinson's disease (PD), Parkinson's disease with dementia (PDD) and dementia with Lewy bodies (DLB) are three clinically, genetically and neuropathologically overlapping neurodegenerative diseases collectively known as the Lewy body diseases (LBDs). A variety of molecular mechanisms have been implicated in PD pathogenesis, but the mechanisms underlying PDD and DLB remain largely unknown, a knowledge gap that presents an impediment to the discovery of disease-modifying therapies. Transcriptomic profiling can contribute to addressing this gap, but remains limited in the LBDs. Here, we applied paired bulk-tissue and single-nucleus RNA-sequencing to anterior cingulate cortex samples derived from 28 individuals, including healthy controls, PD, PDD and DLB cases (n = 7 per group), to transcriptomically profile the LBDs. Using this approach, we (i) found transcriptional alterations in multiple cell types across the LBDs; (ii) discovered evidence for widespread dysregulation of RNA splicing, particularly in PDD and DLB; (iii) identified potential splicing factors, with links to other dementia-related neurodegenerative diseases, coordinating this dysregulation; and (iv) identified transcriptomic commonalities and distinctions between the LBDs that inform understanding of the relationships between these three clinical disorders. Together, these findings have important implications for the design of RNA-targeted therapies for these diseases and highlight a potential molecular "window" of therapeutic opportunity between the initial onset of PD and subsequent development of Lewy body dementia.

Journal article

Calsolaro V, Matthews PM, Donat CK, Livingston NR, Femminella GD, Guedes SS, Myers J, Fan Z, Tyacke RJ, Venkataraman AV, Perneczky R, Gunn R, Rabiner EA, Gentleman S, Parker CA, Murphy PS, Wren PB, Hinz R, Sastre M, Nutt DJ, Edison Pet al., 2021, Astrocyte reactivity with late onset cognitive impairment assessed in-vivo using 11C-BU99008 PET and its relationship with amyloid load, Molecular Psychiatry, ISSN: 1359-4184

11C-BU99008 is a novel positron emission tomography (PET) tracer that enables selective imaging of astrocyte reactivity in vivo. To explore astrocyte reactivity associated with Alzheimer’s disease, 11 older, cognitively impaired (CI) subjects and 9 age-matched healthy controls (HC) underwent 3T magnetic resonance imaging (MRI), 18F-florbetaben and 11C-BU99008 PET. The 8 amyloid (Aβ)-positive CI subjects had higher 11C-BU99008 uptake relative to HC across the whole brain, but particularly in frontal, temporal, medial temporal and occipital lobes. Biological parametric mapping demonstrated a positive voxel-wise neuroanatomical correlation between 11C-BU99008 and 18F-florbetaben. Autoradiography using 3H-BU99008 with post-mortem Alzheimer’s brains confirmed through visual assessment that increased 3H-BU99008 binding localised with the astrocyte protein glial fibrillary acid protein and was not displaced by PiB or florbetaben. This proof-of-concept study provides direct evidence that 11C-BU99008 can measure in vivo astrocyte reactivity in people with late-life cognitive impairment and Alzheimer’s disease. Our results confirm that increased astrocyte reactivity is found particularly in cortical regions with high Aβ load. Future studies now can explore how clinical expression of disease varies with astrocyte reactivity.

Journal article

de Pablo-Fernandez E, Courtney R, Rockliffe A, Gentleman S, Holton JL, Warner TTet al., 2021, Faster disease progression in Parkinson's disease with type 2 diabetes is not associated with increased alpha-synuclein, tau, amyloid-beta or vascular pathology, NEUROPATHOLOGY AND APPLIED NEUROBIOLOGY, ISSN: 0305-1846

Journal article

Ries M, Watts H, Mota B, Yanez Lopez M, Donat C, Baxan N, Pickering J, Chau TSZ, Semmler A, Gurung B, Aleksynas R, Abelleira Hervas L, Iqbal S, Romero-Molina C, Hernandez Mir G, d'Amati A, Reutelingsperger C, Goldfinger M, Gentleman S, Van Leuven F, Solito E, Sastre Met al., 2021, Annexin-A1 restores cerebrovascular integrity concomitant with reduced amyloid-β and tau pathology, Brain: a journal of neurology, Vol: 144, Pages: 1526-1541, ISSN: 0006-8950

Alzheimer’s disease (AD), characterized by brain deposits of amyloid-β(Aβ) plaques and neurofibrillary tangles, is also linked to neurovascular dysfunction and blood-brain barrier (BBB) breakdown, affecting the passage of substances into and out of the brain. We hypothesized that treatment of neurovascular alterations could be beneficial in AD. Annexin A1 (ANXA1) is a mediator of glucocorticoids anti-inflammatory action that can suppress microglial activation and reduce BBB leakage. We have reported recently that treatment with recombinant human ANXA1 (hrANXA1) 2reduced Aβ levels by increased degradation in neuroblastoma cells and phagocytosis by microglia. Here, we show the beneficial effects of hrANXA1 in vivo by restoring efficient BBB function and decreasing Aβ and tau pathology in 5xFAD mice and Tau-P301L mice. We demonstrate that young 5xFAD mice already suffer cerebrovascular damage, while acute pre-administration of hrANXA1 rescued the vascular defects. Interestingly, the ameliorated BBB permeability in young 5xFAD mice by hrANXA1 correlated with reduced brain A load, due to increased clearance and degradation of Aβ by the insulin degrading enzyme (IDE). The systemic anti-inflammatory properties of hrANXA1 were also observed in 5XFAD mice, increasing IL-10 and reducing TNF-α expression. Additionally, the prolonged treatment with hrANXA1 reduced the memory deficits and increased synaptic density in young 5xFAD mice. Similarly, in Tau-P301L mice, acute hrANXA1 administration restored vascular architecture integrity, affecting the distribution of tight junctions, and reduced tau phosphorylation. The combined data support the hypothesis that the BBB breakdown early in AD can be restored by hrANXA1 as a potential therapeutic approach.

Journal article

Chia R, Sabir MS, Bandres-Ciga S, Saez-Atienzar S, Reynolds RH, Gustavsson E, Walton RL, Ahmed S, Viollet C, Ding J, Makarious MB, Diez-Fairen M, Portley MK, Shah Z, Abramzon Y, Hernandez DG, Blauwendraat C, Stone DJ, Eicher J, Parkkinen L, Ansorge O, Clark L, Honig LS, Marder K, Lemstra A, St George-Hyslop P, Londos E, Morgan K, Lashley T, Warner TT, Jaunmuktane Z, Galasko D, Santana I, Tienari PJ, Myllykangas L, Oinas M, Cairns NJ, Morris JC, Halliday GM, Van Deerlin VM, Trojanowski JQ, Grassano M, Calvo A, Mora G, Canosa A, Floris G, Bohannan RC, Brett F, Gan-Or Z, Geiger JT, Moore A, May P, Kruger R, Goldstein DS, Lopez G, Tayebi N, Sidransky E, Norcliffe-Kaufmann L, Palma J-A, Kaufmann H, Shakkottai VG, Perkins M, Newell KL, Gasser T, Schulte C, Landi F, Salvi E, Cusi D, Masliah E, Kim RC, Caraway CA, Monuki ES, Brunetti M, Dawson TM, Rosenthal LS, Albert MS, Pletnikova O, Troncoso JC, Flanagan ME, Mao Q, Bigio EH, Rodriguez-Rodriguez E, Infante J, Lage C, Gonzalez-Aramburu I, Sanchez-Juan P, Ghetti B, Keith J, Black SE, Masellis M, Rogaeva E, Duyckaerts C, Brice A, Lesage S, Xiromerisiou G, Barrett MJ, Tilley BS, Gentleman S, Logroscino G, Serrano GE, Beach TG, McKeith IG, Thomas AJ, Attems J, Morris CM, Palmer L, Love S, Troakes C, Al-Sarraj S, Hodges AK, Aarsland D, Klein G, Kaiser SM, Woltjer R, Pastor P, Bekris LM, Leverenz JB, Besser LM, Kuzma A, Renton AE, Goate A, Bennett DA, Scherzer CR, Morris HR, Ferrari R, Albani D, Pickering-Brown S, Faber K, Kukull WA, Morenas-Rodriguez E, Lleo A, Fortea J, Alcolea D, Clarimon J, Nalls MA, Ferrucci L, Resnick SM, Tanaka T, Foroud TM, Graff-Radford NR, Wszolek ZK, Ferman T, Boeve BF, Hardy JA, Topol EJ, Torkamani A, Singleton AB, Ryten M, Dickson DW, Chio A, Ross OA, Gibbs JR, Dalgard CL, Traynor BJ, Scholz SWet al., 2021, Genome sequencing analysis identifies new loci associated with Lewy body dementia and provides insights into its genetic architecture, NATURE GENETICS, Vol: 53, Pages: 294-+, ISSN: 1061-4036

Journal article

Patel S, Gentleman S, Pearce R, 2021, A Clinicopathological Investigation of Brainstem Nuclei in Lewy Body Dementias (LBD), Publisher: WILEY, Pages: 12-12, ISSN: 0305-1846

Conference paper

Attems J, Toledo JB, Walker L, Gelpi E, Gentleman S, Halliday G, Hortobagyi T, Jellinger K, Kovacs GG, Lee EB, Love S, McAleese KE, Nelson PT, Neumann M, Parkkinen L, Polvikoski T, Sikorska B, Smith C, Grinberg LT, Thal DR, Trojanowski JQ, McKeith IGet al., 2021, Neuropathological consensus criteria for the evaluation of Lewy pathology in post-mortem brains: a multi-centre study, Acta Neuropathologica, Vol: 141, Pages: 159-172, ISSN: 0001-6322

Currently, the neuropathological diagnosis of Lewy body disease (LBD) may be stated according to several staging systems, which include the Braak Lewy body stages (Braak), the consensus criteria by McKeith and colleagues (McKeith), the modified McKeith system by Leverenz and colleagues (Leverenz), and the Unified Staging System by Beach and colleagues (Beach). All of these systems use semi-quantitative scoring (4- or 5-tier scales) of Lewy pathology (LP; i.e., Lewy bodies and Lewy neurites) in defined cortical and subcortical areas. While these systems are widely used, some suffer from low inter-rater reliability and/or an inability to unequivocally classify all cases with LP. To address these limitations, we devised a new system, the LP consensus criteria (LPC), which is based on the McKeith system, but applies a dichotomous approach for the scoring of LP (i.e., “absent” vs. “present”) and includes amygdala-predominant and olfactory-only stages. α-Synuclein-stained slides from brainstem, limbic system, neocortex, and olfactory bulb from a total of 34 cases with LP provided by the Newcastle Brain Tissue Resource (NBTR) and the University of Pennsylvania brain bank (UPBB) were scanned and assessed by 16 raters, who provided diagnostic categories for each case according to Braak, McKeith, Leverenz, Beach, and LPC systems. In addition, using LP scores available from neuropathological reports of LP cases from UPBB (n = 202) and NBTR (n = 134), JT (UPBB) and JA (NBTR) assigned categories according to all staging systems to these cases. McKeith, Leverenz, and LPC systems reached good (Krippendorff’s α ≈ 0.6), while both Braak and Beach systems had lower (Krippendorff’s α ≈ 0.4) inter-rater reliability, respectively. Using the LPC system, all cases could be unequivocally classified by the majority of raters, which was also seen for 97.1% when the Beach system was used. However, a

Journal article

Jabbari E, Koga S, Valentino RR, Reynolds RH, Ferrari R, Tan MMX, Rowe JB, Dalgard CL, Scholz SW, Dickson DW, Warner TT, Revesz T, Höglinger GU, Ross OA, Ryten M, Hardy J, Shoai M, Morris HR, PSP Genetics Groupet al., 2021, Genetic determinants of survival in progressive supranuclear palsy: a genome-wide association study, Lancet Neurology, Vol: 20, Pages: 107-116, ISSN: 1474-4422

BACKGROUND: The genetic basis of variation in the progression of primary tauopathies has not been determined. We aimed to identify genetic determinants of survival in progressive supranuclear palsy (PSP). METHODS: In stage one of this two stage genome-wide association study (GWAS), we included individuals with PSP, diagnosed according to pathological and clinical criteria, from two separate cohorts: the 2011 PSP GWAS cohort, from brain banks based at the Mayo Clinic (Jacksonville, FL, USA) and in Munich (Germany), and the University College London PSP cohort, from brain banks and the PROSPECT study, a UK-wide longitudinal study of patients with atypical parkinsonian syndromes. Individuals were included if they had clinical data available on sex, age at motor symptom onset, disease duration (from motor symptom onset to death or to the date of censoring, Dec 1, 2019, if individuals were alive), and PSP phenotype (with reference to the 2017 Movement Disorder Society criteria). Genotype data were used to do a survival GWAS using a Cox proportional hazards model. In stage two, data from additional individuals from the Mayo Clinic brain bank, which were obtained after the 2011 PSP GWAS, were used for a pooled analysis. We assessed the expression quantitative trait loci (eQTL) profile of variants that passed genome-wide significance in our GWAS using the Functional Mapping and Annotation of GWAS platform, and did colocalisation analyses using the eQTLGen and PsychENCODE datasets. FINDINGS: Data were collected and analysed between Aug 1, 2016, and Feb 1, 2020. Data were available for 1001 individuals of white European ancestry with PSP in stage one. We found a genome-wide significant association with survival at chromosome 12 (lead single nucleotide polymorphism rs2242367, p=7·5 × 10-10, hazard ratio 1·42 [95% CI 1·22-1·67]). rs2242367 was associated with survival in the individuals added in stage two (n=238; p=0·049, 1·22 [1&

Journal article

Dewan R, Chia R, Ding J, Hickman RA, Stein TD, Abramzon Y, Ahmed S, Sabir MS, Portley MK, Tucci A, Ibáñez K, Shankaracharya FNU, Keagle P, Rossi G, Caroppo P, Tagliavini F, Waldo ML, Johansson PM, Nilsson CF, Rowe JB, Benussi L, Binetti G, Ghidoni R, Jabbari E, Viollet C, Glass JD, Singleton AB, Silani V, Ross OA, Ryten M, Torkamani A, Tanaka T, Ferrucci L, Resnick SM, Pickering-Brown S, Brady CB, Kowal N, Hardy JA, Van Deerlin V, Vonsattel JP, Harms MB, Morris HR, Ferrari R, Landers JE, Chiò A, Gibbs JR, Dalgard CL, Scholz SW, Traynor BJ, Adeleye A, Alba C, Bacikova D, Hupalo DN, Martinez EM, Pollard HB, Sukumar G, Soltis AR, Tuck M, Zhang X, Wilkerson MD, Smith BN, Ticozzi N, Fallini C, Gkazi AS, Topp SD, Kost J, Scotter EL, Kenna KP, Miller JW, Tiloca C, Vance C, Danielson EW, Troakes C, Colombrita C, Al-Sarraj S, Lewis EA, King A, Calini D, Pensato V, Castellotti B, de Belleroche J, Baas F, ten Asbroek ALMA, Sapp PC, McKenna-Yasek D, McLaughlin RL, Polak M, Asress S, Esteban-Pérez J, Muñoz-Blanco JL, Stevic Z, DAlfonso S, Mazzini L, Comi GP, Del Bo R, Ceroni M, Gagliardi S, Querin G, Bertolin C, van Rheenen W, Diekstra FP, Rademakers R, van Blitterswijk M, Boylan KB, Lauria G, Duga S, Corti S, Cereda C, Corrado L, Sorarù G, Williams KL, Nicholson GA, Blair IP, Leblond-Manry C, Rouleau GA, Hardiman O, Morrison KE, Veldink JH, van den Berg LH, Al-Chalabi A, Pall H, Shaw PJ, Turner MR, Talbot K, Taroni F, García-Redondo A, Wu Z, Gellera C, Ratti A, Brown RH, Shaw CE, Ambrose JC, Arumugam P, Baple EL, Bleda M, Boardman-Pretty F, Boissiere JM, Boustred CR, Brittain H, Caulfield MJ, Chan GC, Craig CEH, Daugherty LC, de Burca A, Devereau A, Elgar G, Foulger RE, Fowler T, Furió-Tarí P, Hackett JM, Halai D, Hamblin A, Henderson S, Holman JE, Hubbard TJP, Jackson R, Jones LJ, Kasperaviciute D, Kayikci M, Lahnstein L, Lawson K, Leigh SEA, Leong IUS, Lopez JF, Maleady-Crowe F, Mason J, McDonagh EM, Moutsianas L, Mueller M, Murugaesu N, Need AC, Odhams CA, Patch C, Perez-Giet al., 2021, Pathogenic huntingtin repeat expansions in patients with frontotemporal dementia and amyotrophic lateral sclerosis, Neuron, Vol: 109, Pages: 448-460.e4, ISSN: 0896-6273

We examined the role of repeat expansions in the pathogenesis of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) by analyzing whole-genome sequence data from 2,442 FTD/ALS patients, 2,599 Lewy body dementia (LBD) patients, and 3,158 neurologically healthy subjects. Pathogenic expansions (range, 40–64 CAG repeats) in the huntingtin (HTT) gene were found in three (0.12%) patients diagnosed with pure FTD/ALS syndromes but were not present in the LBD or healthy cohorts. We replicated our findings in an independent collection of 3,674 FTD/ALS patients. Postmortem evaluations of two patients revealed the classical TDP-43 pathology of FTD/ALS, as well as huntingtin-positive, ubiquitin-positive aggregates in the frontal cortex. The neostriatal atrophy that pathologically defines Huntington’s disease was absent in both cases. Our findings reveal an etiological relationship between HTT repeat expansions and FTD/ALS syndromes and indicate that genetic screening of FTD/ALS patients for HTT repeat expansions should be considered.

Journal article

Donat C, Yanez Lopez M, Sastre M, Baxan N, Goldfinger M, Seeamber R, Mueller F, Davies P, Hellyer P, Siegkas P, Gentleman S, Sharp D, Ghajari Met al., 2021, From biomechanics to pathology: predicting axonal injury from patterns of strain after traumatic brain injury., Brain: a journal of neurology, Vol: 144, Pages: 70-91, ISSN: 0006-8950

The relationship between biomechanical forces and neuropathology is key to understanding traumatic brain injury. White matter tracts are damaged by high shear forces during impact, resulting in axonal injury, a key determinant of long-term clinical outcomes. However, the relationship between biomechanical forces and patterns of white matter injuries, associated with persistent diffusion MRI abnormalities, is poorly understood. This limits the ability to predict the severity of head injuries and the design of appropriate protection. Our previously developed human finite element model of head injury predicted the location of post-traumatic neurodegeneration. A similar rat model now allows us to experimentally test whether strain patterns calculated by the model predicts in vivo MRI and histology changes. Using a Controlled Cortical Impact, mild and moderate injuries(1 and 2 mm) were performed. Focal and axonal injuries were quantified withvolumetric and diffusion 9.4T MRI two weeks post injury. Detailed analysis of the corpus callosum was conducted using multi-shell diffusion MRI and histopathology. Microglia and astrocyte density, including process parameters,along with white matter structural integrity and neurofilament expression were determined by quantitative immunohistochemistry. Linear mixed effects regression analyses for strain and strain rate with the employed outcome measures were used to ascertain how well immediate biomechanics could explain MRI and histology changes.The spatial pattern of mechanical strain and strain rate in the injured cortex shows good agreement with the probability maps of focal lesions derived from volumetric MRI. Diffusion metrics showed abnormalities in segments of the corpus callosum predicted to have a high strain, indicating white matter changes. The same segments also exhibited a severity-dependent increase in glia cell density, white matter thinning

Journal article

Liu AKL, Gentleman SM, 2021, The diagonal band of Broca in health and disease., Pages: 175-187

The diagonal band of Broca (DBB) contains the second largest cholinergic cell group in the human brain, known as the nucleus of the vertical limb of the DBB (nvlDBB). It has major projections to the hippocampus, but it is often underinvestigated, partly due to its ill-defined anatomical boundaries and hence the difficulty of reliable sampling. In this chapter, we have reviewed the historical literature to reestablish the anatomy of the nvlDBB, distinguishing it from neighboring basal forebrain cholinergic nuclei. Although varying degrees of neuronal loss in the nvlDBB have been reported in a range of neurological disorders, and in the aged brain, the significant nvlDBB cholinergic neuronal loss reported in Lewy body dementias is of particular interest. Retrograde tracer study in rodents has demonstrated reciprocal connections between the DBB and the hippocampal CA2 subfield, an area particularly susceptible to Lewy pathologies. Previous functional studies have demonstrated that the nvlDBB is particularly involved in memory retrieval, a cognitive domain severely affected in Lewy body disorders. Based on these observations, we propose an anatomical and functional connection between the cholinergic component of the nvlDBB (Ch2) and the hippocampal CA2.

Book chapter

Edison P, Leng F, Hinz R, Dani M, Hampshire A, Gentleman S, Brooks DJet al., 2020, Influence of microglial activation on structural and functional connectivity in mild cognitive impairment subjects: Development of new models and analysis methods/neuroinflammation, Alzheimer's and Dementia, ISSN: 1552-5260

Journal article

Edison P, Calsolaro V, Hinz R, Femminella GD, Pasqualetti G, Buckley CJ, Gentleman S, Brooks DJet al., 2020, Microglial activation evaluated using flutriciclamide (11F-GE180) in subjects with cognitive impairment: Neuroimaging /Optimal neuroimaging measures for ..., Alzheimer's and Dementia, ISSN: 1552-5260

Journal article

Leng F, Hinz R, Dani M, Hampshire A, Gentleman S, Brooks D, Edison Pet al., 2020, Tau formation is associated with microglial activation in more widespread cortical areas than amyloid deposition: Multimodal neuroimaging comparison, Alzheimer's and Dementia, ISSN: 1552-5260

Journal article

Martin-Bastida A, Tilley BS, Bansal S, Gentleman SM, Dexter DT, Ward RJet al., 2020, Iron and inflammation: in vivo and post-mortem studies in Parkinson’s disease, Journal of Neural Transmission, ISSN: 0300-9564

Journal article

Edison P, Calsolaro V, Hinz R, Femminella GD, Pasqualetti G, Buckley CJ, Gentleman S, Brooks Det al., 2020, Microglial activation evaluated using Flutriciclamide (11F-GE180) in subjects with cognitive impairment, 2020 Alzheimer's Association International Conference

Journal article

Edison P, Leng F, Hinz R, Dani M, Hampshire A, Gentleman S, Brooks Det al., 2020, Tau formation is associated with microglial activation in more widespread cortical areas than amyloid deposition does, 2020 Alzheimer's Association International Conference

Journal article

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

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