40 results found
Altay MF, Liu AKL, Holton JL, et al., 2022, Prominent astrocytic alpha-synuclein pathology with unique post-translational modification signatures unveiled across Lewy body disorders
<jats:title>ABSTRACT</jats:title><jats:p>Alpha-synuclein (aSyn) is a pre-synaptic monomeric protein that can form aggregates in neurons in Parkinson’s disease (PD), Parkinson’s disease with dementia (PDD) and dementia with Lewy bodies (DLB), and in oligodendrocytes in multiple system atrophy (MSA). Although the accumulation of aSyn in astrocytes has previously been described in PD, PDD and DLB, the biochemical properties of aSyn in this type of pathology and its topographical distribution have not been studied in detail. Here, we present a systematic investigation of aSyn astrocytic pathology, using an expanded toolset of antibodies covering the entire sequence and known post-translational modifications (PTMs) of aSyn in Lewy body (LB) disorders, including sporadic PD, PDD, DLB, familial PD with <jats:italic>SNCA</jats:italic> G51D mutation and <jats:italic>SNCA</jats:italic> duplication, and in MSA. Astrocytic aSyn was mainly detected in the limbic cortical regions of LB disorders, but were absent in key pathological regions of MSA. These astrocytic aSyn accumulations were detected only with aSyn antibodies against the mid N-terminal and non-amyloid component (NAC) regions covering aSyn residues 34-99. The astroglial accumulations were negative to canonical aSyn aggregation markers, including p62, ubiquitin and aSyn pS129, but positive for phosphorylated and nitrated forms of aSyn at Tyrosine 39 (Y39), and mostly not resistant to proteinase K. Our findings suggest that astrocytic aSyn accumulations are a major part of aSyn pathology in LB disorders, and possess a distinct sequence and PTM signature that is characterized by both N- and C-terminal truncations and modifications at Y39. To the best of our knowledge, this is the first description of aSyn accumulation made solely from N- and C-terminally cleaved aSyn species and the first report demonstrating that astrocytic aSyn exists as a mixture of Y39 phosphoryla
Sinclair L, Brenton J, Liu AKL, et 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
Napier-Hemy TP, Liu AKL, Floyd MS, et al., 2021, Acute urinary retention in a 27-year-old male secondary to benign prostatic hyperplasia treated with Holmium Enucleation of the Prostate (HOLEP), UROLOGIA JOURNAL, ISSN: 0391-5603
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.
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
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: E17-E17, ISSN: 0022-3050
Alexandris AS, Walker L, Liu AKL, et al., 2019, Cholinergic deficits and galaninergic hyperinnervation of the nucleus basalis of Meynert in Alzheimer's disease and Lewy body disorders, NEUROPATHOLOGY AND APPLIED NEUROBIOLOGY, Vol: 46, Pages: 264-278, ISSN: 0305-1846
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.
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, 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
Liu AKL, Lim EJ, Ahmed I, et 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.
Lai HM, Liu AKL, Ng HHM, et 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.
Harrison CH, Buckland GR, Brooks SE, et 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.
Lai HM, Liu KL, Ng HHM, et 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.
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.
Perbellini F, Liu AK, Watson SA, et al., 2017, Free-of-acrylamide SDS-based Tissue Clearing (FASTClear) for Three Dimensional Imaging of Collagen Content and Vascular Organization in Adult Ventricular Tissue, Scientific Sessions of the American-Heart-Association / Resuscitation Science Symposium, Publisher: LIPPINCOTT WILLIAMS & WILKINS, ISSN: 0009-7322
Perbellini F, Liu AKL, Watson SA, et al., 2017, Free-of-acrylamide SDS-based tissue clearing (FASTClear) for three dimensional visualization of myocardial tissue, Scientific Reports, Vol: 7, ISSN: 2045-2322
Several pathologic conditions of the heart lead to cardiac structural remodelling. Given the high density and the opaque nature of the myocardium, deep three dimensional (3D) imaging is difficult to achieve and structural analysis of pathological myocardial structure is often limited to two dimensional images and of thin myocardial sections. Efficient methods to obtain optical clearing of the tissue for 3D visualisation are therefore needed. Here we describe a rapid, simple and versatile Free-of-Acrylamide SDS-based Tissue Clearing (FASTClear) protocol specifically designed for cardiac tissue. With this method 3D information regarding collagen content, collagen localization and distribution could be easily obtained across a whole 300 µm-thick myocardial slice. FASTClear does not induce structural or microstructural distortion and it can be combined with immunostaining to identify the micro- and macrovascular networks. In summary, we have obtained decolorized myocardial tissue suitable for high resolution 3D imaging, with implications for the study of complex cardiac tissue structure and its changes during pathology.
Liu K, Lai HM, Chang RCC, et al., 2017, Free-of-acrylamide SDS-based Tissue Clearing (FASTClear): A novel protocol of tissue clearing for three-dimensional visualisation of human brain tissues, Neuropathology and Applied Neurobiology, Vol: 43, Pages: 346-351, ISSN: 1365-2990
Liu KL, 2017, Clinicopathological investigations of the cholinergic basal forebrain in Lewy body disorders and ageing
Cholinergic dysfunction has long been associated with cognitive impairment in Alzheimer’s disease (AD). However, neuropathological and functional imaging studies have also found significant cortical cholinergic deficit in Lewy body disorders (LBD), but in a different pattern from that in AD. There is topographical cholinerigic innervation to the cortex and the hippocampus from the basal forebrain. In light of differences in cognitive deficits seen in LBD and AD, I hypothesised that cholinergic basal forebrain subregions are differentially affected in these disorders. In this thesis, novel tissue techniques have been developed for the visualisation of pathology in human post-mortem brain tissue in three-dimensions. Based on a thorough review of the literature and my personal observations, I have established a simplified subdivisional scheme of the nucleus basalis of Meynert (nbM) in the human brain. Using this scheme, a quantification of nbM cholinergic neurons and assessment of neuropathological burden were performed in a large cohort of LBD and AD cases. Severe neuronal depletion across the entire nbM was observed in LBD with cognitive impairment and relative sparing of the anterior nbM was found in AD, supporting findings from previous neuropathological and imaging studies. Further investigation was carried out in the more rostral, hippocampal-projecting cholinergic group in the vertical limb of the nucleus of the diagonal band of Broca. Significant neurodegeneration in this area was identified in LBD with cognitive impairment, but not AD, suggesting its possible role in retrieval memory function via projection to the hippocampal CA2 subfield. In the final section, it was demonstrated that lactacystin injection into the rat nbM can replicate certain pathological and clinical features of LBD with dementia and this may be a useful model for the disease. Results from these studies support my initial hypothesis regarding differential susceptibility of the basal
Lai HM, Liu AKL, Ng HHM, et al., 2017, Development of next generation histological methods for three-dimensional interrogation of the human brain, 118th Meeting of the British-Neuropathological-Society, Publisher: WILEY, Pages: 44-45, ISSN: 0305-1846
Alexandris A, Walker L, Liu AKL, et al., 2017, Differential expression of galanin in the cholinergic basal forebrain in Lewy body disorders and Alzheimer's disease, 118th Meeting of the British-Neuropathological-Society, Publisher: WILEY, Pages: 12-12, ISSN: 0305-1846
Liu AKL, Lai HM, Goldfinger MH, et al., 2017, Exploration of human brain anatomy in three-dimensions using the next generation histological pipeline, 118th Meeting of the British-Neuropathological-Society, Publisher: WILEY, Pages: 28-29, ISSN: 0305-1846
Chau TW, Liu AKL, Lim EJ, et al., 2017, Cognitive decline and hippocampal CA2 pathology in Lewy body disorders, 118th Meeting of the British-Neuropathological-Society, Publisher: WILEY, Pages: 11-12, ISSN: 0305-1846
Lai HM, Liu K, Ng WL, et al., 2016, Rationalisation and validation of an acrylamide-free procedure in three-dimensional histological imaging, PLOS One, Vol: 11, ISSN: 1932-6203
Three-dimensional visualization of intact tissues is now being achieved by turning tissues transparent. CLARITY is a unique tissue clearing technique, which features the use of detergents to remove lipids from fixed tissues to achieve optical transparency. To preserve tissue integrity, an acrylamide-based hydrogel has been proposed to embed the tissue. In this study, we examined the rationale behind the use of acrylamide in CLARITY, and presented evidence to suggest that the omission of acrylamide-hydrogel embedding in CLARITY does not alter the preservation of tissue morphology and molecular information in fixed tissues. We therefore propose a novel and simplified workflow for formaldehyde-fixed tissue clearing, which will facilitate the laboratory implementation of this technique. Furthermore, we have investigated the basic tissue clearing process in detail and have highlighted some areas for targeted improvement of technologies essential for the emerging subject of three-dimensional histology.
Liu K, Goldfinger MH, Questari HE, et al., 2016, ARTAG in the basal forebrain: Widening the constellation of astrocytic tau pathology, Acta Neuropathologica Communications, Vol: 4, ISSN: 2051-5960
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
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
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
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
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