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Article ; Online: Neuropathological Assessment as an Endpoint in Clinical Trial Design.

Gentleman, Steve M / Liu, Alan King Lun

Methods in molecular biology (Clifton, N.J.)

2024 Volume 2785, Page(s) 261–270

Abstract: 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 ...

Abstract	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 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.
MeSH term(s)	Humans ; Clinical Trials as Topic ; Neurodegenerative Diseases/pathology
Language	English
Publishing date	2024-03-01
Publishing country	United States
Document type	Clinical Trial Protocol ; Journal Article
ISSN	1940-6029
ISSN (online)	1940-6029
DOI	10.1007/978-1-0716-3774-6_15
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Article: The diagonal band of Broca in health and disease.

Liu, Alan King Lun / Gentleman, Steve M

Handbook of clinical neurology

2021 Volume 179, Page(s) 175–187

Abstract: 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 ... ...

Abstract	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.
MeSH term(s)	Aged ; Choline O-Acetyltransferase/metabolism ; Diagonal Band of Broca/metabolism ; Humans ; Lewy Body Disease
Chemical Substances	Choline O-Acetyltransferase (EC 2.3.1.6)
Language	English
Publishing date	2021-07-06
Publishing country	Netherlands
Document type	Journal Article ; Review
ISSN	0072-9752
ISSN	0072-9752
DOI	10.1016/B978-0-12-819975-6.00009-1
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Article ; Online: Neuropathological Assessment as an Endpoint in Clinical Trial Design.

Gentleman, Steve / Liu, Alan King Lun

Methods in molecular biology (Clifton, N.J.)

2018 Volume 1750, Page(s) 271–279

Abstract	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.
MeSH term(s)	Alzheimer Disease/diagnosis ; Brain/pathology ; Clinical Trials as Topic/standards ; Humans ; Research Design
Language	English
Publishing date	2018-03-06
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ISSN	1940-6029
ISSN (online)	1940-6029
DOI	10.1007/978-1-4939-7704-8_18
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Article ; Online: Prominent astrocytic alpha-synuclein pathology with unique post-translational modification signatures unveiled across Lewy body disorders.

Altay, Melek Firat / Liu, Alan King Lun / Holton, Janice L / Parkkinen, Laura / Lashuel, Hilal A

Acta neuropathologica communications

2022 Volume 10, Issue 1, Page(s) 163

Abstract: 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 ( ... ...

Abstract	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 aSyn in astrocytes has previously been described in PD, PDD and DLB, the biochemical properties and topographical distribution of astrocytic aSyn have not been studied in detail. Here, we present a systematic investigation of aSyn astrocytic pathology using an expanded antibody toolset covering the entire sequence and key post-translational modifications (PTMs) of aSyn in Lewy body disorders (LBDs) and in MSA. Astrocytic aSyn was detected in the limbic cortical regions of LBDs but were absent in main pathological regions of MSA. The astrocytic aSyn was revealed only with 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 not resistant to proteinase K. Our findings suggest that astrocytic aSyn accumulations represent a major part of aSyn pathology in LBDs and possess a distinct sequence and PTM signature that is characterized by both N- and C-terminal truncations and modifications at Y39. This is the first description that aSyn accumulations are made solely from N- and C-terminally cleaved aSyn species and the first report demonstrating that astrocytic aSyn is a mixture of Y39 phosphorylated and nitrated species. These observations underscore the importance of systematic characterization of aSyn accumulations in different cell types to capture the aSyn pathological diversity in the brain. Our findings combined with further studies on the role of astrocytic pathology in the progression of LBDs can pave the way towards identifying novel disease mechanisms and therapeutic targets.
MeSH term(s)	Humans ; alpha-Synuclein/metabolism ; Parkinson Disease/pathology ; Astrocytes/pathology ; Lewy Bodies/metabolism ; Synucleinopathies ; Multiple System Atrophy/pathology ; Protein Processing, Post-Translational ; Lewy Body Disease/pathology
Chemical Substances	alpha-Synuclein
Language	English
Publishing date	2022-11-12
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2715589-4
ISSN	2051-5960 ; 2051-5960
ISSN (online)	2051-5960
ISSN	2051-5960
DOI	10.1186/s40478-022-01468-8
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Article ; Online: Acute urinary retention in a 27-year-old male secondary to benign prostatic hyperplasia treated with Holmium Enucleation of the Prostate (HOLEP).

Napier-Hemy, Timothy P / Liu, Alan King Lun / Floyd, Michael S / McNulty, Sid / Omar, Ahmad M / Mistry, Rahul / Gana, Hosea By

Urologia

2021 Volume 90, Issue 2, Page(s) 426–429

Abstract: Introduction: Benign prostatic hyperplasia (BPH) is common in the ageing male. Clinical manifestations like retention impact on a patient's quality of life. Alterations in androgen activity at the androgen receptor complex level in the prostate ... ...

Abstract	Introduction: Benign prostatic hyperplasia (BPH) is common in the ageing male. Clinical manifestations like retention impact on a patient's quality of life. Alterations in androgen activity at the androgen receptor complex level in the prostate contribute to prostatic hyperplasia with the highest incidence occurring in males in their 70's. There remains a paucity of cases in young males who develop acute urinary retention secondary to BPH. We present a case of a 27-year-old male who developed acute urinary retention secondary to BPH who required a Holmium Laser Enucleation of his Prostate (HOLEP). Case description: A 27 year old man was admitted in acute urinary retention. BPH was diagnosed via way of radiological imaging and histological assessment. After pre-operative sperm banking and suprapubic catheterisation, the patient underwent a HOLEP. He had biochemically confirmed hypogonadotrophic hypogonadism which was at odds with his muscular, physical appearance. Total testosterone levels had fluctuated following admission suggesting an exogenous substance was interfering with the hypothalamic-pituitary-gonadal axis but he denied exogenous steroid use. Result: The patient successfully passed his voiding trial on the second post-operative day and remained catheter free. Post-operative uroflowmetry and sexual function remain unknown as patient disengaged with follow up. Conclusion: HOLEP prostatectomy is a safe and effective way of managing BPH in younger patients following sperm banking and assessment by endocrinology.
MeSH term(s)	Humans ; Male ; Adult ; Prostatic Hyperplasia/surgery ; Urinary Retention ; Prostate/pathology ; Holmium ; Transurethral Resection of Prostate/methods ; Quality of Life ; Treatment Outcome ; Laser Therapy/methods ; Semen ; Lasers, Solid-State/therapeutic use
Chemical Substances	Holmium (W1XX32SQN1)
Language	English
Publishing date	2021-05-19
Publishing country	United States
Document type	Case Reports ; Journal Article
ZDB-ID	204043-8
ISSN	1724-6075 ; 0376-0057 ; 0391-5603
ISSN (online)	1724-6075
ISSN	0376-0057 ; 0391-5603
DOI	10.1177/03915603211016613
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Article ; Online: Possible Contribution of Altered Cholinergic Activity in the Visual Cortex in Visual Hallucinations in Parkinson's Disease.

Sinclair, Lindsey / Brenton, Jake / Liu, Alan King Lun / MacLachlan, Rob / Gentleman, Steve M / Love, Seth

The Journal of neuropsychiatry and clinical neurosciences

2021 Volume 34, Issue 2, Page(s) 168–176

Abstract: Objective: Up to one-third of patients with Parkinson's disease (PD) experience visual hallucinations (VHs). Lewy bodies are sparse in the visual cortices and seem unlikely to explain the hallucinations. Some neuroimaging studies have found that ... ...

Abstract	Objective: Up to one-third of patients with Parkinson's disease (PD) experience visual hallucinations (VHs). Lewy bodies are sparse in the visual cortices and seem unlikely to explain the hallucinations. Some neuroimaging studies have found that perfusion is reduced in the occipital lobe in individuals with VHs. Recent work has suggested that decreased cholinergic input may directly lead to the decreased perfusion. The investigators hypothesized that individuals with PD and VHs would have biochemical evidence of reduced microvascular perfusion and reduced cholinergic activity in areas of the brain that process visual images. Methods: Tissue from Brodmann's area (BA) 18 and BA 19 was obtained from a well-characterized cohort matched for age, gender, and postmortem interval in 69 individuals (PD without VHs, N=11; PD without dementia plus VHs N=10, N=10; PD with dementia plus VHs, N=16; and control subjects, N=32). Von Willebrand factor, vascular endothelial growth factor A, and myelin-associated glycoprotein:proteolipid protein-1 (MAG:PLP1) ratio-a measure of tissue oxygenation relative to metabolic demand, acetylcholinesterase (AChE), butyrylcholinesterase (BChE), choline acetyltransferase, and α-synuclein-were quantified by enzyme-linked immunosorbent assay. The primary outcome was the MAG:PLP1 ratio. Results: There was no biochemical evidence of chronic hypoperfusion in PD, although microvessel density was decreased in ventral BA 18 and BA 19. There was no between-group difference in BChE in either dorsal BA 18 or BA 19. AChE concentration was reduced in individuals with PD compared with control subjects in dorsal and ventral BA 18 and dorsal BA 19, and it was increased in ventral BA 19. These changes were most marked in the PD plus VHs group. Conclusions: These results suggest that changes in cholinergic activity rather than chronic hypoperfusion may underlie VHs in PD.
MeSH term(s)	Acetylcholinesterase/metabolism ; Butyrylcholinesterase/metabolism ; Cholinergic Agents/metabolism ; Dementia ; Hallucinations/etiology ; Hallucinations/metabolism ; Humans ; Parkinson Disease/complications ; Parkinson Disease/metabolism ; Vascular Endothelial Growth Factor A/metabolism ; Visual Cortex/diagnostic imaging ; Visual Cortex/metabolism
Chemical Substances	Cholinergic Agents ; Vascular Endothelial Growth Factor A ; Acetylcholinesterase (EC 3.1.1.7) ; Butyrylcholinesterase (EC 3.1.1.8)
Language	English
Publishing date	2021-12-28
Publishing country	United States
Document type	Journal Article
ZDB-ID	1036340-3
ISSN	1545-7222 ; 0895-0172
ISSN (online)	1545-7222
ISSN	0895-0172
DOI	10.1176/appi.neuropsych.21040103
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Article ; Online: ARTAG in the basal forebrain: widening the constellation of astrocytic tau pathology.

Liu, Alan King Lun / Goldfinger, Marc H / Questari, Hayleigh E / Pearce, Ronald K B / Gentleman, Steve M

Acta neuropathologica communications

2016 Volume 4, Issue 1, Page(s) 59

MeSH term(s)	Basal Forebrain/metabolism ; Humans ; Tauopathies ; tau Proteins/metabolism
Chemical Substances	tau Proteins
Language	English
Publishing date	2016-06-13
Publishing country	England
Document type	Letter ; Comment
ZDB-ID	2715589-4
ISSN	2051-5960 ; 2051-5960
ISSN (online)	2051-5960
ISSN	2051-5960
DOI	10.1186/s40478-016-0330-7
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Article ; Online: Next generation histology methods for three-dimensional imaging of fresh and archival human brain tissues

Hei Ming Lai / Alan King Lun Liu / Harry Ho Man Ng / Marc H. Goldfinger / Tsz Wing Chau / John DeFelice / Bension S. Tilley / Wai Man Wong / Wutian Wu / Steve M. Gentleman

Nature Communications, Vol 9, Iss 1, Pp 1-

2018 Volume 12

Abstract: Current available tissue clearing techniques are mostly used for rodent tissues. Here, the authors develop OPTIClear solution for fresh and archival human brain tissue clearing and establish associated protocols for three-dimensional histological ... ...

Abstract	Current available tissue clearing techniques are mostly used for rodent tissues. Here, the authors develop OPTIClear solution for fresh and archival human brain tissue clearing and establish associated protocols for three-dimensional histological investigations.
Keywords	Science ; Q
Language	English
Publishing date	2018-03-01T00:00:00Z
Publisher	Nature Publishing Group
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Next generation histology methods for three-dimensional imaging of fresh and archival human brain tissues

Hei Ming Lai / Alan King Lun Liu / Harry Ho Man Ng / Marc H. Goldfinger / Tsz Wing Chau / John DeFelice / Bension S. Tilley / Wai Man Wong / Wutian Wu / Steve M. Gentleman

Nature Communications, Vol 9, Iss 1, Pp 1-

2018 Volume 12

Abstract	Current available tissue clearing techniques are mostly used for rodent tissues. Here, the authors develop OPTIClear solution for fresh and archival human brain tissue clearing and establish associated protocols for three-dimensional histological investigations.
Keywords	Science ; Q
Language	English
Publishing date	2018-03-01T00:00:00Z
Publisher	Nature Portfolio
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Differential expression of galanin in the cholinergic basal forebrain of patients with Lewy body disorders.

Alexandris, Athanasios / Liu, Alan King Lun / Chang, Raymond Chuen-Chung / Pearce, Ronald K B / Gentleman, Steve M

Acta neuropathologica communications

2015 Volume 3, Page(s) 77

Abstract: Introduction: Depletion 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 ...

Abstract	Introduction: Depletion 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. Results: The 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. Conclusion: Galanin 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.
MeSH term(s)	Aged ; Aged, 80 and over ; Cholinergic Agents/metabolism ; Cognitive Dysfunction/pathology ; Cohort Studies ; Female ; Galanin/metabolism ; Glial Fibrillary Acidic Protein/metabolism ; Humans ; Lewy Body Disease/pathology ; Male ; Microscopy, Confocal ; Prosencephalon/metabolism ; Statistics, Nonparametric
Chemical Substances	Cholinergic Agents ; Glial Fibrillary Acidic Protein ; Galanin (88813-36-9)
Language	English
Publishing date	2015-12-01
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2715589-4
ISSN	2051-5960 ; 2051-5960
ISSN (online)	2051-5960
ISSN	2051-5960
DOI	10.1186/s40478-015-0249-4
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