Publications
313 results found
Donat C, Yanez Lopez M, Sastre M, et 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
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.
Edison P, Leng F, Hinz R, et 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
Edison P, Calsolaro V, Hinz R, et 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
Leng F, Hinz R, Dani M, et 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
Martin-Bastida A, Tilley BS, Bansal S, et al., 2020, Iron and inflammation: in vivo and post-mortem studies in Parkinson’s disease, Journal of Neural Transmission, ISSN: 0300-9564
Edison P, Calsolaro V, Hinz R, et al., 2020, Microglial activation evaluated using Flutriciclamide (11F-GE180) in subjects with cognitive impairment, 2020 Alzheimer's Association International Conference
Edison P, Leng F, Hinz R, et al., 2020, Tau formation is associated with microglial activation in more widespread cortical areas than amyloid deposition does, 2020 Alzheimer's Association International Conference
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
Van der Perren A, Gelders G, Fenyi A, et 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.
Alexandris AS, Walker L, Liu AKL, et al., 2020, 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
- Author Web Link
- Cite
- Citations: 14
Patel S, Tilley B, Pearce RKB, et 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
Pitz V, Malek N, Tobias ES, et 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.
Perez-Rodriguez D, Kalyva M, Leija-Salazar M, et 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.
Liu AKL, Lim YM, Pearce RKB, et 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
Tilley BS, Romozzi M, Hession CM, et 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
Kaye S, Abbott J, Gentleman S, et 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
Smith C, Malek N, Grosset K, et 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.
Martin-Bastida A, Tilley B, Alireza T, et 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
Liu KL, Chau TW, Lim EJ, et 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.
Woerman AL, Oehler A, Kazmi SA, et 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
Stewart W, Allinson K, Al-Sarraj S, et al., 2019, Primum non nocere: A call for balance when reporting on CTE, Lancet Neurology, Vol: 18, Pages: 231-233, ISSN: 1474-4422
Goldfinger M, Tilley B, Sastre M, et 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
Tilley B, Goldfinger M, Pearce R, et 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
Sinclair L, Brenton J, Liu AKL, et 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
Liu AKL, Lim YM, Pearce R, et 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
Goldfinger MH, Tilley B, Mediratta S, et al., 2019, Chronic traumatic encephalopathy: The role of gliovascular pathology, 19th International Congress of Neuropathology, Publisher: WILEY, Pages: 10-10, ISSN: 1015-6305
Tilley BS, Goldfinger MH, Pearce RKB, et 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
Prokopenko I, Miyakawa G, Zheng B, et al., 2019, Alzheimer's disease pathology explains association between dementia with Lewy bodies and APOE-ε4/TOMM40 long poly-T repeat allele variants., Alzheimers & Dementia, Vol: 5, Pages: 814-824, ISSN: 1552-5260
Introduction: The role of TOMM40-APOE 19q13.3 region variants is well documented in Alzheimer's disease (AD) but remains contentious in dementia with Lewy bodies (DLB) and Parkinson's disease dementia (PDD). Methods: We dissected genetic profiles within the TOMM40-APOE region in 451 individuals from four European brain banks, including DLB and PDD cases with/without neuropathological evidence of AD-related pathology and healthy controls. Results: TOMM40-L/APOE-ε4 alleles were associated with DLB (OR TOMM40 -L = 3.61; P value = 3.23 × 10-9; OR APOE -ε4 = 3.75; P value = 4.90 × 10-10) and earlier age at onset of DLB (HR TOMM40 -L = 1.33, P value = .031; HR APOE -ε4 = 1.46, P value = .004), but not with PDD. The TOMM40-L/APOE-ε4 effect was most pronounced in DLB individuals with concomitant AD pathology (OR TOMM40 -L = 4.40, P value = 1.15 × 10-6; OR APOE -ε4 = 5.65, P value = 2.97 × 10-8) but was not significant in DLB without AD. Meta-analyses combining all APOE-ε4 data in DLB confirmed our findings (ORDLB = 2.93, P value = 3.78 × 10-99; ORDLB+AD = 5.36, P value = 1.56 × 10-47). Discussion: APOE-ε4/TOMM40-L alleles increase susceptibility and risk of earlier DLB onset, an effect explained by concomitant AD-related pathology. These findings have important implications in future drug discovery and development efforts in DLB.
Goldfinger MH, Ling H, Tilley BS, et 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
This data is extracted from the Web of Science and reproduced under a licence from Thomson Reuters. You may not copy or re-distribute this data in whole or in part without the written consent of the Science business of Thomson Reuters.