Publications
313 results found
Scott GPT, Ramlackhansingh A, Edison P, et al., 2016, Amyloid pathology and axonal injury after brain trauma, Neurology, Vol: 86, Pages: 821-828, ISSN: 0028-3878
Objective: To image amyloid-β (Aβ) plaque burden in long-term survivors of traumatic brain injury (TBI), test whether traumatic axonal injury and Aβ are correlated, and compare the spatial distribution of Aβ to Alzheimer’s disease.Methods: Patients 11 months to 17 years after moderate-severe TBI had 11C-Pittsburgh compound-B (PIB) PET, structural and diffusion MRI and neuropsychological examination. Healthy aged controls and AD patients had PET and structural MRI. Binding potential (BPND) images of 11C-PIB, which index Aβ plaque density, were computed using an automatic reference region extraction procedure. Voxelwise and regional differences in BPND were assessed. In TBI, a measure of white matter integrity, fractional anisotropy (FA), was estimated and correlated with 11C-PIB BPND.Results: 28 participants (9 TBI, 9 controls, 10 AD) were assessed. Increased 11C-PIB BPND was found in TBI versus controls in the posterior cingulate cortex (PCC) and cerebellum. Binding in the PCC increased with decreasing FA of associated white matter tracts, and increased with time since injury. Compared to AD, binding after TBI was lower in neocortical regions, but increased in the cerebellum. Conclusions: Increased Aβ burden was observed in TBI. The distribution overlaps with, but is distinct from, that of AD. This suggests a mechanistic link between TBI and the development of neuropathological features of dementia, which may relate to axonal damage produced by the injury.
Harrison CH, Buckland GR, Brooks SE, et al., 2016, Methods to demonstrate the three dimensional organization of the cerebral cortical vasculature-relevance to Alzheimer's disease, 117th Meeting of the British-Neuropathological-Society, Publisher: WILEY-BLACKWELL, Pages: 23-23, ISSN: 0305-1846
Questari HE, Liu AKL, Pearce RKB, et al., 2016, Chronic traumatic encephalopathy-like changes within the basal forebrain among cases in the Parkinson's UK Tissue Bank, 117th Meeting of the British-Neuropathological-Society, Publisher: WILEY-BLACKWELL, Pages: 39-39, ISSN: 0305-1846
Lim EJ, Liu AKL, Ahmed I, et al., 2016, Clinicopathological correlations of the nucleus of the diagonal band of Broca in Lewy body disorders, 117th Meeting of the British-Neuropathological-Society, Publisher: WILEY, Pages: 12-13, ISSN: 0305-1846
- Author Web Link
- Cite
- Citations: 1
Liu AKL, Lai HM, Hurry ME, et al., 2016, Three-dimensional visualisation of human post-mortem brain tissues: potential and challenges, 117th Meeting of the British-Neuropathological-Society, Publisher: WILEY-BLACKWELL, Pages: 31-32, ISSN: 0305-1846
Kovacs GG, Ferrer I, Grinberg LT, et al., 2015, Aging-related tau astrogliopathy (ARTAG): harmonized evaluation strategy, Acta Neuropathologica, Vol: 131, Pages: 87-102, ISSN: 0001-6322
Liu AKL, Hurry MED, Ng OTW, et al., 2015, Bringing CLARITY to the human brain: visualization of Lewy pathology in three dimensions, Neuropathology and Applied Neurobiology, Vol: 42, Pages: 573-587, ISSN: 1365-2990
Aims: CLARITY is a novel technique which enables three-dimensional visualisation of immunostained tissue for the study of circuitry and spatial interactions between cells and molecules in the brain. In this study we aimed to compare methodological differences in the application of CLARITY between rodent and large human post-mortem brain samples. In addition, we aimed to investigate if this technique could be used to visualise Lewy pathology in a post-mortem Parkinson’s brain. Methods: Rodent and human brain samples were clarified and immunostained using the passive version of the CLARITY technique. Samples were then immersed in different refractive index matching media before mounting and visualising under a confocal microscope. Results: We found that tissue clearing speed using passive CLARITY differs according to species (human vs rodents), brain region and degree of fixation (fresh vs formalin-fixed tissues). Furthermore, there were advantages to using specific refractive index matching media. We have applied this technique and have successfully visualised Lewy body inclusions in three dimensions within the nucleus basalis of Meynert, and the spatial relationship between monoaminergic fibres and Lewy pathologies among nigrostriatal fibres in the midbrain without the need for physical serial sectioning of brain tissue. Conclusions: The effective use of CLARITY on large samples of human tissue opens up many potential avenues for detailed pathological and morphological studies.
Alexandris A, Liu AKL, Chang RCC, et al., 2015, Differential expression of galanin in the cholinergic basal forebrain of patients with Lewy body disorders., Acta Neuropathologica Communications, Vol: 3, ISSN: 2051-5960
IntroductionDepletion of cholinergic neurons within the nucleus basalis of Meynert (nbM) is thought to contribute to the development of cognitive impairments in both Alzheimer’s disease (AD) and Lewy body disorders (LBD). It has been reported that, in late stage AD, a network of fibres that contain the neuropeptide galanin displays significant hypertrophy and ‘hyperinnervates’ the surviving cholinergic neurons. Galanin is considered as a highly inducible neuroprotective factor and in AD this is assumed to be part of a protective tissue response. The aim of this study was to determine if a similar galanin upregulation is present in the nbM in post-mortem tissue from patients with LBD. Gallatin immunohistochemistry was carried out on anterior nbM sections from 76 LBD cases (27 PD, 15 PD with mild cognitive impairment (MCI), 34 PD with dementia (PDD) and 4 aged-matched controls. Galaninergic innervation of cholinergic neurons was assessed on a semi-quantitative scale.ResultsThe LBD group had significantly higher galaninergic innervation scores (p = 0.016) compared to controls. However, this difference was due to increased innervation density only in a subgroup of LBD cases and this correlated positively with choline acetyltransferase–immunopositive neuron density.ConclusionGalanin upregulation within the basal forebrain cholinergic system in LBD, similar to that seen in AD, may represent an intrinsic adaptive response to neurodegeneration that is consistent with its proposed roles in neurogenesis and neuroprotection.
Ruffmann C, Calboli FC, Bravi I, et al., 2015, Cortical Lewy bodies and Aβ burden are associated with prevalence and timing of dementia in Lewy body diseases., Neuropathology and Applied Neurobiology, Vol: 42, Pages: 436-450, ISSN: 1365-2990
AIMS: Our main objective was to determine the neuropathological correlates of dementia in patients with Lewy body disease (LBD). Furthermore, we used data derived from clinical, neuropathological and genetic studies to investigate boundary issues between Dementia with Lewy bodies (DLB) and Parkinson's disease with (PDD) and without (PDND) dementia. METHODS: 121 cases with a neuropathological diagnosis of LBD and clinical information on dementia status were included in the analysis (55 PDD, 17 DLB and 49 PDND). We carried out topographical and semi-quantitative assessment of Lewy bodies (LB), Aβ plaques and tau-positive neuropil threads (NT). The APOE genotype and MAPT haplotype status were also determined. RESULTS: The cortical LB (CLB) burden was the only independent predictor of dementia (OR: 4.12, p<0.001). The total cortical Aβ plaque burden was an independent predictor of a shorter latency to dementia from onset of motor signs (p=0.001). DLB cases had a higher LB burden in the parietal and temporal cortex, compared to PDD. Carrying at least one APOE ϵ4 allele was associated with a higher cortical LB burden (p=0.02), particularly in the neocortical frontal, parietal, and temporal regions. CONCLUSIONS: High CLB burden is a key neuropathological substrate of dementia in LBD. Elevated cortical LB pathology and Aβ plaque deposition are both correlated with a faster progression to dementia. The higher CLB load in the temporal and parietal regions, which seems to be a distinguishing feature of DLB, may account for the shorter latency to dementia and could be mediated by the APOE ϵ4 allele. This article is protected by copyright. All rights reserved.
Howell OW, Schulz-Trieglaff EK, Carassiti D, et al., 2015, Extensive grey matter pathology in the cerebellum in multiple sclerosis is linked to inflammation in the subarachnoid space, NEUROPATHOLOGY AND APPLIED NEUROBIOLOGY, Vol: 41, Pages: 798-813, ISSN: 0305-1846
- Author Web Link
- Cite
- Citations: 68
Prusiner SB, Woerman AL, Mordes DA, et al., 2015, Evidence for alpha-synuclein prions causing multiple system atrophy in humans with parkinsonism, PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, Vol: 112, Pages: E5308-E5317, ISSN: 0027-8424
Prions are proteins that adopt alternative conformations that become self-propagating; the PrPSc prion causes the rare human disorder Creutzfeldt–Jakob disease (CJD). We report here that multiple system atrophy (MSA) is caused by a different human prion composed of the α-synuclein protein. MSA is a slowly evolving disorder characterized by progressive loss of autonomic nervous system function and often signs of parkinsonism; the neuropathological hallmark of MSA is glial cytoplasmic inclusions consisting of filaments of α-synuclein. To determine whether human α-synuclein forms prions, we examined 14 human brain homogenates for transmission to cultured human embryonic kidney (HEK) cells expressing full-length, mutant human α-synuclein fused to yellow fluorescent protein (α-syn140*A53T–YFP) and TgM83+/− mice expressing α-synuclein (A53T). The TgM83+/− mice that were hemizygous for the mutant transgene did not develop spontaneous illness; in contrast, the TgM83+/+ mice that were homozygous developed neurological dysfunction. Brain extracts from 14 MSA cases all transmitted neurodegeneration to TgM83+/− mice after incubation periods of ∼120 d, which was accompanied by deposition of α-synuclein within neuronal cell bodies and axons. All of the MSA extracts also induced aggregation of α-syn*A53T–YFP in cultured cells, whereas none of six Parkinson’s disease (PD) extracts or a control sample did so. Our findings argue that MSA is caused by a unique strain of α-synuclein prions, which is different from the putative prions causing PD and from those causing spontaneous neurodegeneration in TgM83+/+ mice. Remarkably, α-synuclein is the first new human prion to be identified, to our knowledge, since the discovery a half century ago that CJD was transmissible.
Woerman AL, Stoehr J, Aoyagi A, et al., 2015, Propagation of prions causing synucleinopathies in cultured cells, Proceedings of the National Academy of Sciences of the United States of America, Vol: 112, Pages: E4949-E4958, ISSN: 1091-6490
Increasingly, evidence argues that many neurodegenerative diseases,including progressive supranuclear palsy (PSP), are causedby prions, which are alternatively folded proteins undergoing selfpropagation.In earlier studies, PSP prions were detected byinfecting human embryonic kidney (HEK) cells expressing a taufragment [TauRD(LM)] fused to yellow fluorescent protein (YFP).Here, we report on an improved bioassay using selective precipitationof tau prions from human PSP brain homogenatesbefore infection of the HEK cells. Tau prions were measured bycounting the number of cells with TauRD(LM)–YFP aggregates usingconfocal fluorescence microscopy. In parallel studies, we fusedα-synuclein to YFP to bioassay α-synuclein prions in the brains ofpatients who died of multiple system atrophy (MSA). Previously,MSA prion detection required ∼120 d for transmission into transgenicmice, whereas our cultured cell assay needed only 4 d. Variationin MSA prion levels in four different brain regions fromthree patients provided evidence for three different MSA prionstrains. Attempts to demonstrate α-synuclein prions in brain homogenatesfrom Parkinson’s disease patients were unsuccessful,identifying an important biological difference between the twosynucleinopathies. Partial purification of tau and α-synucleinprions facilitated measuring the levels of these protein pathogensin human brains. Our studies should facilitate investigationsof the pathogenesis of both tau and α-synuclein prion disordersas well as help decipher the basic biology of those prions thatattack the CNS.
Hurley MJ, Durrenberger PF, Gentleman SM, et al., 2015, Altered Expression of Brain Proteinase-Activated Receptor-2, Trypsin-2 and Serpin Proteinase Inhibitors in Parkinson's Disease, Journal of Molecular Neuroscience, Vol: 57, Pages: 48-62, ISSN: 1559-1166
Neuroinflammation is thought to contribute to celldeath in neurodegenerative disorders, but the factors involvedin the inflammatory process are not completely understood.Proteinase-activated receptor-2 (PAR2) expression in brain isincreased in Alzheimer’s disease and multiple sclerosis, butthe status of PAR2 in Parkinson’s disease is unknown. Thisstudy examined expression of PAR2 and endogenous proteinaseactivators (trypsin-2, mast cell tryptase) and proteinaseinhibitors (serpin-A5, serpin-A13) in areas vulnerable and resistantto neurodegeneration in Parkinson’s disease at differentBraak α-synuclein stages of the disease in post-mortem brain.In normal aged brain, expression of PAR-2, trypsin-2, andserpin-A5 and serpin-A13 was found in neurons and microglia,and alterations in the amount of immunoreactivity for theseproteins were found in some brain regions. Namely, therewas a decrease in neurons positive for serpin-A5 in the dorsalmotor nucleus, and serpin-A13 expression was reduced in thelocus coeruleus and primary motor cortex, while expression ofPAR2, trypsin-2 and both serpins was reduced in neuronswithin the substantia nigra. There was an increased numberof microglia that expressed serpin-A5 in the dorsal motor nucleusof vagus and elevated numbers of microglia thatexpressed serpin-A13 in the substantia nigra of lateParkinson’s disease cases. The number of microglia thatexpressed trypsin-2 increased in primary motor cortex of incidentalLewy body disease cases. Analysis of Parkinson’sdisease cases alone indicated that serpin-A5 and serpin-A13,and trypsin-2 expression in midbrain and cerebral cortex wasdifferent in cases with a high incidence of L-DOPA-induceddyskinesia and psychosis compared to those with low levels ofthese treatment-induced side effects. This study showed thatthere was altered expression in brain of PAR2 and some proteinsthat can control its function in Parkinson’s disease. Giventhe role of PAR2 in neuroi
Liu AKL, Chang RC-C, Pearce RKB, et al., 2015, Nucleus basalis of Meynert revisited: anatomy, history and differential involvement in Alzheimer's and Parkinson's disease, ACTA NEUROPATHOLOGICA, Vol: 129, Pages: 527-540, ISSN: 0001-6322
- Author Web Link
- Open Access Link
- Cite
- Citations: 193
Hurley MJ, Gentleman SM, Dexter DT, 2015, Calcium CaV1 Channel Subtype mRNA Expression in Parkinson's Disease Examined by In Situ Hybridization, Journal of Molecular Neuroscience, Vol: 55, Pages: 715-724, ISSN: 0895-8696
The factors which make some neurons vulnerable to neurodegeneration in Parkinson's disease while others remain resistant are not fully understood. Studies in animal models of Parkinson's disease suggest that preferential use of CaV1.3 subtypes by neurons may contribute to the neurodegenerative process by increasing mitochondrial oxidant stress. This study quantified the level of mRNA for the CaV1 subtypes found in the brain by in situ hybridization using CaV1 subtype-specific [35S]-radiolabelled oligonucleotide probes. In normal brain, the greatest amount of messenger RNA (mRNA) for each CaV1 subtype was found in the midbrain (substantia nigra), with a moderate level in the pons (locus coeruleus) and lower quantities in cerebral cortex (cingulate and primary motor). In Parkinson's disease, the level of CaV1 subtype mRNA was maintained in the midbrain and pons, despite cell loss in these areas. In cingulate cortex, CaV1.2 and CaV1.3 mRNA increased in cases with late-stage Parkinson's disease. In primary motor cortex, the level of CaV1.2 mRNA increased in late-stage Parkinson's disease. The level of CaV1.3 mRNA increased in primary motor cortex of cases with early-stage Parkinson's disease and normalized to near the control level in cases from late-stage Parkinson's disease. The finding of elevated CaV1 subtype expression in cortical brain regions supports the view that disturbed calcium homeostasis is a feature of Parkinson's disease throughout brain and not only a compensatory consequence to the neurodegenerative process in areas of cell loss. © 2014 Springer Science+Business Media New York.
Liu AKL, Chang RCC, Pearce RKB, et al., 2015, Sub-regional nucleus basalis of Meynert pathology in Lewy body disorders, 116th Meeting of the British-Neuropathological-Society, Publisher: WILEY-BLACKWELL, Pages: 11-12, ISSN: 0305-1846
Liu AKL, Chang RCC, Pearce RKB, et al., 2015, Where is the human nucleus basalis of Meynert?, 116th Meeting of the British-Neuropathological-Society, Publisher: WILEY-BLACKWELL, Pages: 34-35, ISSN: 0305-1846
Alexandris A, Liu AKL, Pearce RKB, et al., 2015, Differential expression of galanin in the basal forebrain in Lewy body disorders, 116th Meeting of the British-Neuropathological-Society, Publisher: WILEY-BLACKWELL, Pages: 34-34, ISSN: 0305-1846
Murray CE, Pressey SN, Heywood WE, et al., 2015, Mitochondrial dysfunction in Parkinson's disease: Is it the earliest feature?, 116th Meeting of the British-Neuropathological-Society, Publisher: WILEY-BLACKWELL, Pages: 11-11, ISSN: 0305-1846
Hawkes CA, Gentleman SM, Nicoll JAR, et al., 2015, Prenatal high-fat diet alters the cerebrovasculature and clearance of β-amyloid in adult offspring, JOURNAL OF PATHOLOGY, Vol: 235, Pages: 619-631, ISSN: 0022-3417
- Author Web Link
- Cite
- Citations: 39
Zawada WM, Mrak RE, Biedermann J, et al., 2015, Loss of angiotensin II receptor expression in dopamine neurons in Parkinson’s disease correlates with pathological progression and is accompanied by increases in Nox4- and 8-OH guanosine-related nucleic acid oxidation and caspase-3 activation, Acta Neuropathologica Communications, Vol: 3, ISSN: 2051-5960
Pienaar IS, Lee CH, Elson JL, et al., 2015, Deep-brain stimulation associates with improved microvascular integrity in the subthalamic nucleus in Parkinson's disease, NEUROBIOLOGY OF DISEASE, Vol: 74, Pages: 392-405, ISSN: 0969-9961
- Author Web Link
- Open Access Link
- Cite
- Citations: 68
Heckman MG, Schottlaender L, Soto-Ortolaza AI, et al., 2014, <i>LRRK2</i> exonic variants and risk of multiple system atrophy, NEUROLOGY, Vol: 83, Pages: 2256-2261, ISSN: 0028-3878
- Author Web Link
- Cite
- Citations: 34
De Picker L, Dumont G, Morrens M, et al., 2014, Multi-immunostaining for microglial activation in schizophrenia, 27th ECNP Congress, Publisher: ELSEVIER SCIENCE BV, Pages: S188-S189, ISSN: 0924-977X
Alafuzoff I, Pikkarainen M, Neumann M, et al., 2014, Neuropathological assessments of the pathology in frontotemporal lobar degeneration with TDP43-positive inclusions: an inter-laboratory study by the BrainNet Europe consortium, Journal of Neural Transmission, Vol: 122, Pages: 957-972, ISSN: 1435-1463
The BrainNet Europe consortium assessed thereproducibility in the assignment of the type of frontotemporallobar degeneration (FTLD) with TAR DNA-bindingprotein (TDP) 43 following current recommendations. Theagreement rates were influenced by the immunohistochemical(IHC) method and by the classification strategy followed.p62-IHC staining yielded good uniform quality ofstains, but the most reliable results were obtained implementingspecific Abs directed against the hallmark proteinTDP43. Both assessment of the type and the extent of lesionswere influenced by the Abs and by the quality of stain.Assessment of the extent of the lesions yielded poor resultsrepeatedly; thus, the extent of pathology should not be usedin diagnostic consensus criteria. Whilst 31 neuropathologiststyped 30 FTLD-TDP cases, inter-rater agreement rangedfrom 19 to 100 per cent, being highest when applyingphosphorylated TDP43/IHC. The agreement was highestwhen designating Type C or Type A/B. In contrast, there wasa poor agreement when attempting to separate Type A or Type B FTLD-TDP. In conclusion, we can expect that neuropathologist,independent of his/her familiarity with FTLDTDPpathology, can identify a TDP43-positive FTLD case.The goal should be to state a Type (A, B, C, D) or a mixture ofTypes (A/B, A/C or B/C). Neuropathologists, other cliniciansand researchers should be aware of the pitfalls whilstdoing so. Agreement can be reached in an inter-laboratorysetting regarding Type C cases with thick and long neurites,whereas the differentiation between Types A and B may bemore troublesome.
Alafuzoff I, Pikkarainen M, Neumann M, et al., 2014, Neuropathological assessments of the pathology in frontotemporal lobar degeneration with TDP43-positive inclusions: an inter-laboratory study by the BrainNet Europe consortium, Journal of Neural Transmission, Vol: 122, Pages: 957-972, ISSN: 1435-1463
The BrainNet Europe consortium assessed the reproducibility in the assignment of the type of frontotemporal lobar degeneration (FTLD) with TAR DNA-binding protein (TDP) 43 following current recommendations. The agreement rates were influenced by the immunohistochemical (IHC) method and by the classification strategy followed. p62-IHC staining yielded good uniform quality of stains, but the most reliable results were obtained implementing specific Abs directed against the hallmark protein TDP43. Both assessment of the type and the extent of lesions were influenced by the Abs and by the quality of stain. Assessment of the extent of the lesions yielded poor results repeatedly; thus, the extent of pathology should not be used in diagnostic consensus criteria. Whilst 31 neuropathologists typed 30 FTLD-TDP cases, inter-rater agreement ranged from 19 to 100 per cent, being highest when applying phosphorylated TDP43/IHC. The agreement was highest when designating Type C or Type A/B. In contrast, there was a poor agreement when attempting to separate Type A or Type B FTLD-TDP. In conclusion, we can expect that neuropathologist, independent of his/her familiarity with FTLD-TDP pathology, can identify a TDP43-positive FTLD case. The goal should be to state a Type (A, B, C, D) or a mixture of Types (A/B, A/C or B/C). Neuropathologists, other clinicians and researchers should be aware of the pitfalls whilst doing so. Agreement can be reached in an inter-laboratory setting regarding Type C cases with thick and long neurites, whereas the differentiation between Types A and B may be more troublesome.
Gentleman S, Liu A, Cole P, et al., 2014, CTE in boxers: modern findings in classic cases, 18th International Congress of Neuropathology, Publisher: WILEY-BLACKWELL, Pages: 84-84, ISSN: 1015-6305
Gentleman S, Liu A, Pearce R, et al., 2014, Differential expression of galanin in the basal forebrain of patients with Lewy body disorders, 18th International Congress of Neuropathology, Publisher: WILEY-BLACKWELL, Pages: 70-71, ISSN: 1015-6305
Zhao Y, Zhao H, Lobo N, et al., 2014, Celastrol Enhances Cell Viability and Inhibits Amyloid-beta Production Induced by Lipopolysaccharide In Vitro, JOURNAL OF ALZHEIMERS DISEASE, Vol: 41, Pages: 835-844, ISSN: 1387-2877
Dexter DT, Gveric D, Gentleman S, et al., 2014, Parkinson's UK Tissue Bank: A unique tissue resource for fostering Parkinson's disease research, 18th International Congress of Parkinson's Disease and Movement Disorders, Publisher: WILEY-BLACKWELL, Pages: S8-S9, ISSN: 0885-3185
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.