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

266 results found

Alexandris AS, Walker L, Liu AKL, McAleese K, 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., Neuropathol Appl Neurobiol

AIMS: Galanin is a highly inducible neuroprotective neuropeptide and in Alzheimer's disease (AD), a network of galaninergic fibres has been reported to hypertrophy and hyperinnervate the surviving cholinergic neurons in the basal forebrain. We aimed to determine a) the extent of galanin hyperinnervation in patients with AD and Lewy body disease and b) whether galanin expression relates to the neuropathological burden and cholinergic losses. METHODS: Galanin immunohistochemistry was carried out in the anterior nucleus basalis of Meynert of 27 Parkinson's disease (PD) cases without cognitive impairment (MCI), 15 with PD with MCI, 42 with Parkinson's disease dementia (PDD), 12 with Dementia with Lewy bodies (DLB), 19 with AD, 12 mixed AD/DLB and 16 controls. Galaninergic innervation of cholinergic neurons was scored semi-quantitatively. For a subgroup of cases (n=60), cholinergic losses were determined from maximum densities of choline acetyltransferase positive (ChAT+ve) neurons and their projection fibres. Quantitative data for α-synuclein, amyloid beta and tau pathology were obtained from tissue microarrays covering cortical/subcortical regions. RESULTS: Significant losses of cholinergic neurons and their projection fibres were observed across all diseases. Galaninergic hyperinnervation was infrequent and particularly uncommon in established AD and DLB. We found that hyperinnervation frequencies are significantly higher in the transition between PD without MCI to PDD and that higher burdens of co-existent AD pathology, impair this galaninergic response. CONCLUSIONS: Our results suggest that galanin upregulation represents an intrinsic response early in Lewy body diseases but which fails with increasing burdens of AD related pathology. This article is protected by copyright. All rights reserved.

Journal article

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., J Neurol Neurosurg Psychiatry

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

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

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

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

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 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

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

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

Lai HM, Liu AKL, Ng HHM, Goldfinger MH, Chau TW, DeFelice J, Tilley BS, Wong WM, Wu W, Gentleman SMet al., 2018, Author correction: Next generation histology methods for three-dimensional imaging of fresh and archival human brain tissues, Nature Communications, Vol: 9, Pages: 2726-2726, ISSN: 2041-1723

In the original version of this Article, the concentration of boric acid buffer for the SDS clearing solution was given incorrectly as '1 M sodium borate' and should have read '0.2 M boric acid'. Also, the composition of PBST incorrectly read '1% Triton X-100 (vol/vol) and 0.1% sodium azide (wt/vol)' and should have read '0.1% Triton X-100 (vol/vol) and 0.01% sodium azide (wt/vol)'. Further, the pH of the OPTIClear solution was not stated, and should have read 'with a pH between 7 to 8 adjusted with hydrochloric acid'. These errors have been corrected in both the PDF and HTML versions of the Article.

Journal article

Fan Z, Dani M, Femminella GD, Wood M, Calsolaro V, Veronese M, Turkheimer F, Gentleman S, Brooks DJ, Hinz R, Edison Pet al., 2018, Parametric mapping using spectral analysis for11C-PBR28 PET reveals neuroinflammation in mild cognitive impairment subjects, European Journal of Nuclear Medicine and Molecular Imaging, Vol: 45, Pages: 1432-1441, ISSN: 1619-7070

PURPOSE: Neuroinflammation and microglial activation play an important role in amnestic mild cognitive impairment (MCI) and Alzheimer's disease. In this study, we investigated the spatial distribution of neuroinflammation in MCI subjects, using spectral analysis (SA) to generate parametric maps and quantify11C-PBR28 PET, and compared these with compartmental and other kinetic models of quantification. METHODS: Thirteen MCI and nine healthy controls were enrolled in this study. Subjects underwent11C-PBR28 PET scans with arterial cannulation. Spectral analysis with an arterial plasma input function was used to generate11C-PBR28 parametric maps. These maps were then compared with regional11C-PBR28 VT(volume of distribution) using a two-tissue compartment model and Logan graphic analysis. Amyloid load was also assessed with18F-Flutemetamol PET. RESULTS: With SA, three component peaks were identified in addition to blood volume. The11C-PBR28 impulse response function (IRF) at 90 min produced the lowest coefficient of variation. Single-subject analysis using this IRF demonstrated microglial activation in five out of seven amyloid-positive MCI subjects. IRF parametric maps of11C-PBR28 uptake revealed a group-wise significant increase in neuroinflammation in amyloid-positive MCI subjects versus HC in multiple cortical association areas, and particularly in the temporal lobe. Interestingly, compartmental analysis detected group-wise increase in11C-PBR28 binding in the thalamus of amyloid-positive MCI subjects, while Logan parametric maps did not perform well. CONCLUSIONS: This study demonstrates for the first time that spectral analysis can be used to generate parametric maps of11C-PBR28 uptake, and is able to detect microglial activation in amyloid-positive MCI subjects. IRF parametric maps of11C-PBR28 uptake allow voxel-wise single-subject analysis and could be used to evaluate microglial activation in individual subjects.

Journal article

Harrison CH, Buckland GR, Brooks SE, Johnston DA, Chatelet DS, Liu AKL, Gentleman SM, Boche D, Nicoll JARet al., 2018, A novel method to visualise the three-dimensional organisation of the human cerebral cortical vasculature, Journal of Anatomy, Vol: 232, Pages: 1025-1030, ISSN: 1469-7580

Current tissue-clearing protocols for imaging in three dimensions (3D) are typically applied to optimally fixed, small-volume rodent brain tissue - which is not representative of the tissue found in diagnostic neuropathology laboratories. We present a method to visualise the cerebral cortical vasculature in 3D in human post-mortem brain tissue which had been preserved in formalin for many years. Tissue blocks of cerebral cortex from two control cases, two Alzheimer's brains and two cases from Alzheimer's patients immunised against Aβ42 were stained with fluorescent Lycopersicon esculentum agglutinin (Tomato lectin), dehydrated and cleared using an adapted three-dimensional imaging of solvent cleared organs (3DISCO) protocol to visualise the vascular endothelium. Tissue was imaged using light sheet and confocal microscopy and reconstructed in 3D using amira software. The method permits visualisation of the arrangement of the parallel penetrating cortical vasculature in the human brain. The presence of four vascular features including anastomosis, U-shaped vessels, spiralling and loops were revealed. In summary, we present a low cost and simple method to visualise the human cerebral vasculature in 3D compatible with prolonged fixation times (years), allowing study of vascular involvement in a range of normative and pathological states.

Journal article

Tilley B, Goldfinger M, Pearce R, Gentleman Set al., 2018, Locus coeruleus pathology illustrates a continuum of lewy body dementia, 119th Meeting of the British-Neuropathological-Society (BNS) / Epilepsy Neuropathology Symposium, Publisher: WILEY, Pages: 14-15, ISSN: 0305-1846

Conference paper

Goldfinger M, Tilley B, Mediratta S, Sastre M, Gentleman Set al., 2018, Boxing and the brain: disruption of the neurovascular unit in chronic traumatic encephalopathy, 119th Meeting of the British-Neuropathological-Society (BNS) / Epilepsy Neuropathology Symposium, Publisher: WILEY, Pages: 29-29, ISSN: 0305-1846

Conference paper

Gentleman S, Liu AKL, 2018, Neuropathological Assessment as an Endpoint in Clinical Trial Design., Methods Mol Biol, Vol: 1750, Pages: 271-279

Different neurodegenerative conditions can have complex, overlapping clinical presentations that make accurate diagnosis during life very challenging. For this reason, confirmation of the clinical diagnosis still requires postmortem verification. This is particularly relevant for clinical trials of novel therapeutics where it is important to ascertain what disease and/or pathology modifying effects the therapeutics have had. Furthermore, it is important to confirm that patients in the trial actually had the correct clinical diagnosis as this will have a major bearing on the interpretation of trial results. Here we present a simple protocol for pathological assessment of neurodegenerative changes.

Journal article

Woerman AL, Kazmi SA, Patel S, Freyman Y, Oehler A, Aoyagi A, Mordes DA, Halliday GM, Middleton LT, Gentleman SM, Olson SH, Prusiner SBet al., 2017, MSA prions exhibit remarkable stability and resistance to inactivation., Acta Neuropathologica, Vol: 135, Pages: 49-63, ISSN: 1432-0533

In multiple system atrophy (MSA), progressive neurodegeneration results from the protein α-synuclein misfolding into a self-templating prion conformation that spreads throughout the brain. MSA prions are transmissible to transgenic (Tg) mice expressing mutated human α-synuclein (TgM83(+/-)), inducing neurological disease following intracranial inoculation with brain homogenate from deceased patient samples. Noting the similarities between α-synuclein prions and PrP scrapie (PrP(Sc)) prions responsible for Creutzfeldt-Jakob disease (CJD), we investigated MSA transmission under conditions known to result in PrP(Sc) transmission. When peripherally exposed to MSA via the peritoneal cavity, hind leg muscle, and tongue, TgM83(+/-) mice developed neurological signs accompanied by α-synuclein prions in the brain. Iatrogenic CJD, resulting from PrP(Sc) prion adherence to surgical steel instruments, has been investigated by incubating steel sutures in contaminated brain homogenate before implantation into mouse brain. Mice studied using this model for MSA developed disease, whereas wire incubated in control homogenate had no effect on the animals. Notably, formalin fixation did not inactivate α-synuclein prions. Formalin-fixed MSA patient samples also transmitted disease to TgM83(+/-) mice, even after incubating in fixative for 244 months. Finally, at least 10% sarkosyl was found to be the concentration necessary to partially inactivate MSA prions. These results demonstrate the robustness of α-synuclein prions to denaturation. Moreover, they establish the parallel characteristics between PrP(Sc) and α-synuclein prions, arguing that clinicians should exercise caution when working with materials that might contain α-synuclein prions to prevent disease.

Journal article

Fan Z, Dani M, Femminella G, Calsolaro V, Veronese M, Turkheimer F, Gentleman S, Hinz R, Edison Pet al., 2017, Regional kinetic modelling application for TSPO PET tracer [11C]PBR28, Alzheimer's and Dementia, Vol: 13, Pages: P289-P289, ISSN: 1552-5260

Journal article

Calsolaro V, Fan Z, Femminella G, Veronese M, Pasqualetti G, Trigg W, Turkheimer F, Gentleman S, Brooks D, Hinz R, Edison P, Buckley Cet al., 2017, Microglial activation in Alzheimer’s disease detected by novel third generation translocator protein tracer flutriciclamide ([18F]GE180), Alzheimer's and Dementia, Vol: 13, Pages: P922-P922, ISSN: 1552-5260

Journal article

Donat CK, Scott G, Gentleman S, Sastre Met al., 2017, Microglial activation in traumatic brain injury, Frontiers in Aging Neuroscience, Vol: 9, ISSN: 1663-4365

Microglia have a variety of functions in the brain, including synaptic pruning, CNS repair and mediating the immune response against peripheral infection. Microglia rapidly become activated in response to CNS damage. Depending on the nature of the stimulus, microglia can take a number of activation states, which correspond to altered microglia morphology, gene expression and function. It has been reported that early microglia activation following traumatic brain injury (TBI) may contribute to the restoration of homeostasis in the brain. On the other hand, if they remain chronically activated, such cells display a classically activated phenotype, releasing pro-inflammatory molecules, resulting in further tissue damage and contributing potentially to neurodegeneration. However, new evidence suggests that this classification is over-simplistic and the balance of activation states can vary at different points. In this article, we review the role of microglia in TBI, analyzing their distribution, morphology and functional phenotype over time in animal models and in humans. Animal studies have allowed genetic and pharmacological manipulations of microglia activation, in order to define their role. In addition, we describe investigations on the in vivo imaging of microglia using translocator protein (TSPO) PET and autoradiography, showing that microglial activation can occur in regions far remote from sites of focal injuries, in humans and animal models of TBI. Finally, we outline some novel potential therapeutic approaches that prime microglia/macrophages toward the beneficial restorative microglial phenotype after TBI.

Journal article

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