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

 

E407Burlington DanesHammersmith Campus

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Summary

 

Publications

Publication Type
Year
to

305 results found

Dobricic V, Schilling M, Farkas I, Gveric DO, Ohlei O, Schulz J, Middleton L, Gentleman SM, Parkkinen L, Bertram L, Lill CMet al., 2022, Common signatures of differential microRNA expression in Parkinson's and Alzheimer's disease brains, BRAIN COMMUNICATIONS, Vol: 4

Journal article

Toomey CE, Heywood WE, Evans JR, Lachica J, Pressey SN, Foti SC, Al Shahrani M, D'Sa K, Hargreaves IP, Heales S, Orford M, Troakes C, Attems J, Gelpi E, Palkovits M, Lashley T, Gentleman SM, Revesz T, Mills K, Gandhi Set al., 2022, Mitochondrial dysfunction is a key pathological driver of early stage Parkinson's, ACTA NEUROPATHOLOGICA COMMUNICATIONS, Vol: 10, ISSN: 2051-5960

Journal article

Giunchiglia V, Gentleman S, Nicholas R, 2022, An automated data cleaning approach to remove preparation artefacts from brain histology slide images, Publisher: WILEY, Pages: S113-S113, ISSN: 0885-3185

Conference paper

Kaivola K, Shah Z, Chia R, International LBD Genomics Consortium, Scholz SWet al., 2022, Genetic evaluation of dementia with Lewy bodies implicates distinct disease subgroups., Brain, Vol: 145, Pages: 1757-1762

The APOE locus is strongly associated with risk for developing Alzheimer's disease and dementia with Lewy bodies. In particular, the role of the APOE ε4 allele as a putative driver of α-synuclein pathology is a topic of intense debate. Here, we performed a comprehensive evaluation in 2466 dementia with Lewy bodies cases versus 2928 neurologically healthy, aged controls. Using an APOE-stratified genome-wide association study approach, we found that GBA is associated with risk for dementia with Lewy bodies in patients without APOE ε4 (P = 6.58 × 10-9, OR = 3.41, 95% CI = 2.25-5.17), but not with dementia with Lewy bodies with APOE ε4 (P = 0.034, OR = 1.87, 95%, 95% CI = 1.05-3.37). We then divided 495 neuropathologically examined dementia with Lewy bodies cases into three groups based on the extent of concomitant Alzheimer's disease co-pathology: pure dementia with Lewy bodies (n = 88), dementia with Lewy bodies with intermediate Alzheimer's disease co-pathology (n = 66) and dementia with Lewy bodies with high Alzheimer's disease co-pathology (n = 341). In each group, we tested the association of the APOE ε4 against the 2928 neurologically healthy controls. Our examination found that APOE ε4 was associated with dementia with Lewy bodies + Alzheimer's disease (P = 1.29 × 10-32, OR = 4.25, 95% CI = 3.35-5.39) and dementia with Lewy bodies + intermediate Alzheimer's disease (P = 0.0011, OR = 2.31, 95% CI = 1.40-3.83), but not with pure dementia with Lewy bodies (P = 0.31, OR = 0.75, 95% CI = 0.43-1.30). In conclusion, although deep clinical data were not available for these samples, our findings do not support the notion that APOE ε4 is an independent driver of α-synuclein pathology in pure dementia with Lewy bodies, but rather implicate GBA as the main risk gene for the pure dementia with Lewy bodies subgroup.

Journal article

Patel S, Pearce R, Gentleman S, 2022, Lewy body dementias-A limbic problem?, Publisher: WILEY, ISSN: 0305-1846

Conference paper

Gray-Rodriguez S, Jensen M, Otero-Jimenez M, Hanley B, Swann O, Ward P, Salguero F, Querido N, Farkas I, Velentza-Almpani E, Weir J, Barclay W, Carroll M, Jaunmuktane Z, Brandner S, Pohl U, Allinson K, Thom M, Troakes C, Al-Sarraj S, Sastre M, Gveric D, Gentleman S, Roufosse C, Osborn M, Alegre-Abarrategui Jet al., 2022, Detection of SARS-CoV-2 within enteric neurons and in brain, Publisher: WILEY, ISSN: 0305-1846

Conference paper

Sinclair L, Brenton J, Liu AKL, MacLachlan R, Gentleman SM, Love Set al., 2022, Possible Contribution of Altered Cholinergic Activity in the Visual Cortex in Visual Hallucinations in Parkinson's Disease, JOURNAL OF NEUROPSYCHIATRY AND CLINICAL NEUROSCIENCES, Vol: 34, Pages: 168-176, ISSN: 0895-0172

Journal article

Patel S, Tilley B, Pearce R, Gentleman Set al., 2022, A clinicopathological investigation of the locus coeruleus in Lewy body dementias, Publisher: WILEY, ISSN: 0305-1846

Conference paper

Livingston NR, Calsolaro V, Hinz R, Nowell J, Raza S, Gentleman S, Tyacke RJ, Myers J, Venkataraman AV, Perneczky R, Gunn RN, Rabiner EA, Parker CA, Murphy PS, Wren PB, Nutt DJ, Matthews PM, Edison Pet al., 2022, Relationship between astrocyte reactivity, using novel C-11-BU99008 PET, and glucose metabolism, grey matter volume and amyloid load in cognitively impaired individuals, MOLECULAR PSYCHIATRY, Vol: 27, Pages: 2019-2029, ISSN: 1359-4184

Journal article

Gray-Rodriguez S, Jensen MP, Otero-Jimenez M, Hanley B, Swann OC, Ward PA, Salguero FJ, Querido N, Farkas I, Velentza-Almpani E, Weir J, Barclay WS, Carroll MW, Jaunmuktane Z, Brandner S, Pohl U, Allinson K, Thom M, Troakes C, Al-Sarraj S, Sastre M, Gveric D, Gentleman S, Roufosse C, Osborn M, Alegre-Abarrategui Jet al., 2022, Multisystem screening reveals SARS-CoV-2 in neurons of the myenteric plexus and in megakaryocytes, Journal of Pathology, Vol: 257, ISSN: 0022-3417

SARS-CoV-2, the causative agent of COVID-19, typically manifests as a respiratory illness although extrapulmonary involvement, such as in the gastrointestinal tract and nervous system, as well as frequent thrombotic events, are increasingly recognised. How this maps onto SARS-CoV-2 organ tropism at the histological level, however, remains unclear. Here, we perform a comprehensive validation of a monoclonal antibody against the SARS-CoV-2 nucleocapsid protein (NP) followed by systematic multisystem organ immunohistochemistry analysis of the viral cellular tropism in tissue from 36 patients, 16 post-mortem cases and 16 biopsies with polymerase chain reaction (PCR)-confirmed SARS-CoV-2 status from the peaks of the pandemic in 2020 and four pre-COVID post-mortem controls. SARS-CoV-2 anti-NP staining in the post-mortem cases revealed broad multiorgan involvement of the respiratory, digestive, haematopoietic, genitourinary and nervous systems, with a typical pattern of staining characterised by punctate paranuclear and apical cytoplasmic labelling. The average time from symptom onset to time of death was shorter in positively versus negatively stained post-mortem cases (mean = 10.3 days versus mean = 20.3 days, p = 0.0416, with no cases showing definitive staining if the interval exceeded 15 days). One striking finding was the widespread presence of SARS-CoV-2 NP in neurons of the myenteric plexus, a site of high ACE-2 expression, the entry receptor for SARS-CoV-2, and one of the earliest affected cells in Parkinson's disease. In the bone marrow, we observed viral SARS-CoV-2 NP within megakaryocytes, key cells in platelet production and thrombus formation. In 15 tracheal biopsies performed in patients requiring ventilation, there was a near complete concordance between immunohistochemistry and PCR swab results. Going forward, our findings have relevance to correlating clinical symptoms to the organ tropism of

Journal article

Leng F, Hinz R, Gentleman S, Brooks DJ, Edison Pet al., 2021, Neuroinflammation, functional connectivity and structural network integrity in the Alzheimer's spectrum, Alzheimer's & dementia : the journal of the Alzheimer's Association, Vol: 17

BACKGROUND: To investigate whether neuroinflammation and β-amyloid (Aβ) deposition influence brain structural and functional connectivity in Alzheimer's spectrum, we conducted a cross-sectional multimodal imaging study and interrogated the associations between imaging biomarkers of neuroinflammation, Aβ deposition, brain connectivity and cognition. METHOD: 58 participants (25 MCI, 16 AD dementia and 17 healthy controls) were recruited and scanned with 11 C-PBR28 and 18 F-flutemetamol PET, T1-weighted, diffusion tensor and resting-state functional MRI. Brain structural and functional connectivity were assessed by global white matter integrity and functional topology metrics, while neuroinflammation and Aβ deposition were evaluated by 11 C-PBR28 and 18 F-flutemetamol uptake, respectively. Changes of the biomarkers were compared between diagnostic groups and robust regression analyses at both voxel and regional level were performed on Aβ positive patients, who were considered to be representative of Alzheimer's continuum. RESULT: Increased 11 C-PBR28 and 18 F-flutemetamol uptake, decreased FA values, impaired small-worldness and local efficiency of functional network were observed in the AD cohort. In Aβ-positive patients, cortical 11 C-PBR28 uptake correlated with decreased structural integrity and network local efficiency independent of 18 F-flutemetamol uptake and cortical thickness. Network structural integrity and cortical thickness correlated with functional metrics, including small-worldness and local efficiency, which were all associated with cognition. CONCLUSION: Our findings suggest that cortical neuroinflammation may lead to disruption of structural and functional brain network independent of amyloid deposition and cortical atrophy, which in turn can lead to cognitive impairment in AD.

Journal article

Smith AM, Davey K, Tsartsalis S, Khozoie C, Fancy N, Tang SS, Liaptsi E, Weinert M, McGarry A, Muirhead RCJ, Gentleman S, Owen DR, Matthews PMet al., 2021, Diverse human astrocyte and microglial transcriptional responses to Alzheimer's pathology, ACTA NEUROPATHOLOGICA, Vol: 143, Pages: 75-91, ISSN: 0001-6322

Journal article

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, Vol: 26, Pages: 5848-5855, 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, Vol: 47, Pages: 1080-1091, 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

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

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

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

Tilley BS, Patel SR, Goldfinger MH, Pearce RKB, Gentleman SMet al., 2021, Locus Coeruleus Pathology Indicates a Continuum of Lewy Body Dementia, 119th Meeting of the British-Neuropathological-Society (BNS) / Epilepsy Neuropathology Symposium, Publisher: IOS PRESS, Pages: 1641-1650, ISSN: 1877-7171

Conference paper

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

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