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Article: Heterogeneity in Regional Damage Detected by Neuroimaging and Neuropathological Studies in Older Adults With COVID-19: A Cognitive-Neuroscience Systematic Review to Inform the Long-Term Impact of the Virus on Neurocognitive Trajectories.

Manca, Riccardo / De Marco, Matteo / Ince, Paul G / Venneri, Annalena

2021 Volume 13, Page(s) 646908

Abstract: Background: ...

Abstract	Background:
Language	English
Publishing date	2021-06-03
Publishing country	Switzerland
Document type	Systematic Review
ZDB-ID	2558898-9
ISSN	1663-4365
ISSN	1663-4365
DOI	10.3389/fnagi.2021.646908
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Assessment of Alzheimer-related pathologies of dementia using machine learning feature selection.

Rajab, Mohammed D / Jammeh, Emmanuel / Taketa, Teruka / Brayne, Carol / Matthews, Fiona E / Su, Li / Ince, Paul G / Wharton, Stephen B / Wang, Dennis

Alzheimer's research & therapy

2023 Volume 15, Issue 1, Page(s) 47

Abstract: Although a variety of brain lesions may contribute to the pathological assessment of dementia, the relationship of these lesions to dementia, how they interact and how to quantify them remains uncertain. Systematically assessing neuropathological ... ...

Abstract	Although a variety of brain lesions may contribute to the pathological assessment of dementia, the relationship of these lesions to dementia, how they interact and how to quantify them remains uncertain. Systematically assessing neuropathological measures by their degree of association with dementia may lead to better diagnostic systems and treatment targets. This study aims to apply machine learning approaches to feature selection in order to identify critical features of Alzheimer-related pathologies associated with dementia. We applied machine learning techniques for feature ranking and classification to objectively compare neuropathological features and their relationship to dementia status during life using a cohort (n=186) from the Cognitive Function and Ageing Study (CFAS). We first tested Alzheimer's Disease and tau markers and then other neuropathologies associated with dementia. Seven feature ranking methods using different information criteria consistently ranked 22 out of the 34 neuropathology features for importance to dementia classification. Although highly correlated, Braak neurofibrillary tangle stage, beta-amyloid and cerebral amyloid angiopathy features were ranked the highest. The best-performing dementia classifier using the top eight neuropathological features achieved 79% sensitivity, 69% specificity and 75% precision. However, when assessing all seven classifiers and the 22 ranked features, a substantial proportion (40.4%) of dementia cases was consistently misclassified. These results highlight the benefits of using machine learning to identify critical indices of plaque, tangle and cerebral amyloid angiopathy burdens that may be useful for classifying dementia.
MeSH term(s)	Humans ; Alzheimer Disease/diagnosis ; Alzheimer Disease/pathology ; Amyloid beta-Peptides/metabolism ; Neurofibrillary Tangles/metabolism ; Cerebral Amyloid Angiopathy/pathology ; Machine Learning ; Brain/metabolism
Chemical Substances	Amyloid beta-Peptides
Language	English
Publishing date	2023-03-10
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2506521-X
ISSN	1758-9193 ; 1758-9193
ISSN (online)	1758-9193
ISSN	1758-9193
DOI	10.1186/s13195-023-01195-9
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Article ; Online: Insights into the pathological basis of dementia from population-based neuropathology studies.

Wharton, Stephen B / Simpson, Julie E / Ince, Paul G / Richardson, Connor D / Merrick, Richard / Matthews, Fiona E / Brayne, Carol

Neuropathology and applied neurobiology

2023 Volume 49, Issue 4, Page(s) e12923

Abstract: The epidemiological neuropathology perspective of population and community-based studies allows unbiased assessment of the prevalence of various pathologies and their relationships to late-life dementia. In addition, this approach provides complementary ... ...

Abstract	The epidemiological neuropathology perspective of population and community-based studies allows unbiased assessment of the prevalence of various pathologies and their relationships to late-life dementia. In addition, this approach provides complementary insights to conventional case-control studies, which tend to be more representative of a younger clinical cohort. The Cognitive Function and Ageing Study (CFAS) is a longitudinal study of cognitive impairment and frailty in the general United Kingdom population. In this review, we provide an overview of the major findings from CFAS, alongside other studies, which have demonstrated a high prevalence of pathology in the ageing brain, particularly Alzheimer's disease neuropathological change and vascular pathology. Increasing burdens of these pathologies are the major correlates of dementia, especially neurofibrillary tangles, but there is substantial overlap in pathology between those with and without dementia, particularly at intermediate burdens of pathology and also at the oldest ages. Furthermore, additional pathologies such as limbic-predominant age-related TDP-43 encephalopathy, ageing-related tau astrogliopathy and primary age-related tauopathies contribute to late-life dementia. Findings from ageing population-representative studies have implications for the understanding of dementia pathology in the community. The high prevalence of pathology and variable relationship to dementia status has implications for disease definition and indicate a role for modulating factors on cognitive outcome. The complexity of late-life dementia, with mixed pathologies, indicates a need for a better understanding of these processes across the life-course to direct the best research for reducing risk in later life of avoidable clinical dementia syndromes.
MeSH term(s)	Humans ; Longitudinal Studies ; Alzheimer Disease/epidemiology ; Alzheimer Disease/pathology ; Brain/pathology ; Tauopathies/pathology
Language	English
Publishing date	2023-08-02
Publishing country	England
Document type	Journal Article ; Review ; Research Support, Non-U.S. Gov't
ZDB-ID	80371-6
ISSN	1365-2990 ; 0305-1846
ISSN (online)	1365-2990
ISSN	0305-1846
DOI	10.1111/nan.12923
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Article: Alpha-synucleinopathy and neuropsychological symptoms in a population-based cohort of the elderly.

Zaccai, Julia / Brayne, Carol / Matthews, Fiona E / Ince, Paul G

Alzheimer's research & therapy

2015 Volume 7, Issue 1, Page(s) 19

Abstract: Introduction: Studies with strong selection biases propose that alpha-synucleinopathy (AS) spreads upwards and downwards in the neuraxis from the medulla, that amygdala-dominant AS is strongly associated with Alzheimer's disease (AD), and that a more ... ...

Abstract	Introduction: Studies with strong selection biases propose that alpha-synucleinopathy (AS) spreads upwards and downwards in the neuraxis from the medulla, that amygdala-dominant AS is strongly associated with Alzheimer's disease (AD), and that a more severe involvement of the cerebral cortex is correlated with increasing risk of dementia. This study examines the association of AS patterns and observed neuropsychological symptoms in brains of a population-representative donor cohort. Methods: Brains donated in 2 out of 6 cognitive function and ageing study cohorts (Cambridgeshire and Nottingham) were examined. Over 80% were >80 years old at death. The respondents were evaluated prospectively in life for cognitive decline and dementia. Immunocytochemistry for tau and alpha-synuclein (using LB509 by Zymed Laboratories) was carried out in 208 brains to establish Braak stage and the pattern and severity of AS following the dementia with Lewy bodies (DLB) consensus recommendations. Dementia, specific neuropsychological measures as measured using the Cambridge cognitive examination, the presence of hallucinations and Parkinson's disease were investigated. Results: Four patterns of AS were observed: no AS pathology (n = 92), AS pathology following the DLB consensus guidelines (n = 33, of which five were 'neocortical'), amygdala-predominant AS (n = 18), and other AS patterns (n = 33). Each group was subdivided according to high/low neurofibrillary tangles (NFT) Braak stage. Results showed no association between dementia and these patterns of AS, adjusting for the presence of NFT or not. The risk of visual hallucinations shows a weak association with AS in the substantia nigra (odds ratio (OR) = 3.2; 95% confidence interval (CI) 0.5 to 15.5; P = 0.09) and amygdala (OR = 3.0; 95% CI 0.7 to 12.3; P = 0.07). The analysis is similar for auditory hallucinations in subcortical regions. Conclusions: Among the whole population of older people, AS does not increase the risks for dementia, irrespective of Braak stage of NFT pathology. There was no evidence that the pattern of AS pathology in cortical areas was relevant to the risk of hallucination. In general, the hypothesis that AS as measured using these methods per se is a key determinant of cognitive clinical phenotypes is not supported.
Language	English
Publishing date	2015-04-13
Publishing country	England
Document type	Journal Article
ZDB-ID	2506521-X
ISSN	1758-9193
ISSN	1758-9193
DOI	10.1186/s13195-015-0101-x
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Article ; Online: Neutrophil-Derived Microvesicle Induced Dysfunction of Brain Microvascular Endothelial Cells In Vitro.

Ajikumar, Anjana / Long, Merete B / Heath, Paul R / Wharton, Stephen B / Ince, Paul G / Ridger, Victoria C / Simpson, Julie E

International journal of molecular sciences

2019 Volume 20, Issue 20

Abstract: The blood-brain barrier (BBB), composed of brain microvascular endothelial cells (BMEC) that are tightly linked by tight junction (TJ) proteins, restricts the movement of molecules between the periphery and the central nervous system. Elevated systemic ... ...

Abstract	The blood-brain barrier (BBB), composed of brain microvascular endothelial cells (BMEC) that are tightly linked by tight junction (TJ) proteins, restricts the movement of molecules between the periphery and the central nervous system. Elevated systemic levels of neutrophils have been detected in patients with altered BBB function, but the role of neutrophils in BMEC dysfunction is unknown. Neutrophils are key players of the immune response and, when activated, produce neutrophil-derived microvesicles (NMV). NMV have been shown to impact the integrity of endothelial cells throughout the body and we hypothesize that NMV released from circulating neutrophils interact with BMEC and induce endothelial cell dysfunction. Therefore, the current study investigated the interaction of NMV with human BMEC and determined whether they altered gene expression and function in vitro. Using flow cytometry and confocal imaging, NMV were shown to be internalized by the human cerebral microvascular endothelial cell line hCMEC/D3 via a variety of energy-dependent mechanisms, including endocytosis and macropinocytosis. The internalization of NMV significantly altered the transcriptomic profile of hCMEC/D3, specifically inducing the dysregulation of genes associated with TJ, ubiquitin-mediated proteolysis and vesicular transport. Functional studies confirmed NMV significantly increased permeability and decreased the transendothelial electrical resistance (TEER) of a confluent monolayer of hCMEC/D3. These findings indicate that NMV interact with and affect gene expression of BMEC as well as impacting their integrity. We conclude that NMV may play an important role in modulating the permeability of BBB during an infection.
MeSH term(s)	Blood-Brain Barrier/cytology ; Blood-Brain Barrier/metabolism ; Capillary Permeability ; Cells, Cultured ; Endocytosis ; Endothelial Cells/metabolism ; Endothelium, Vascular/cytology ; Endothelium, Vascular/metabolism ; Extracellular Vesicles/metabolism ; Humans ; Neutrophils/metabolism
Language	English
Publishing date	2019-10-22
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2019364-6
ISSN	1422-0067 ; 1422-0067 ; 1661-6596
ISSN (online)	1422-0067
ISSN	1422-0067 ; 1661-6596
DOI	10.3390/ijms20205227
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Article ; Online: Histological data of axons, astrocytes, and myelin in deep subcortical white matter populations.

Coelho, Santiago / Pozo, Jose M / Costantini, Marina / Highley, J Robin / Mozumder, Meghdoot / Simpson, Julie E / Ince, Paul G / Frangi, Alejandro F

Data in brief

2019 Volume 23, Page(s) 103762

Abstract: This immunohistochemistry dataset contains the main structures in deep subcortical white matter (axons, astrocytes, and myelinated axons) in a representative cohort of an ageing population. A set of samples from 90 subjects of the Cognitive Function and ... ...

Abstract	This immunohistochemistry dataset contains the main structures in deep subcortical white matter (axons, astrocytes, and myelinated axons) in a representative cohort of an ageing population. A set of samples from 90 subjects of the Cognitive Function and Ageing Study (CFAS) were analysed, stratified into three groups of 30 subjects each, in relation to the presence of age-associated deep subcortical lesions. High-resolution microscopy data enables the extraction of valuable information, such as volume fractions, for the construction and validation of diffusion MRI (dMRI) models. The dataset provided here was used in Coelho et al. [1].
Language	English
Publishing date	2019-03-06
Publishing country	Netherlands
Document type	Journal Article
ZDB-ID	2786545-9
ISSN	2352-3409 ; 2352-3409
ISSN (online)	2352-3409
ISSN	2352-3409
DOI	10.1016/j.dib.2019.103762
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Article ; Online: Dementia in the older population is associated with neocortex content of serum amyloid P component.

Ellmerich, Stephan / Taylor, Graham W / Richardson, Connor D / Minett, Thais / Schmidt, Amand Floriaan / Brayne, Carol / Matthews, Fiona E / Ince, Paul G / Wharton, Stephen B / Pepys, Mark B

Brain communications

2021 Volume 3, Issue 4, Page(s) fcab225

Abstract: Despite many reported associations, the direct cause of neurodegeneration responsible for cognitive loss in Alzheimer's disease and some other common dementias is not known. The normal human plasma protein, serum amyloid P component, a constituent of all ...

Abstract	Despite many reported associations, the direct cause of neurodegeneration responsible for cognitive loss in Alzheimer's disease and some other common dementias is not known. The normal human plasma protein, serum amyloid P component, a constituent of all human fibrillar amyloid deposits and present on most neurofibrillary tangles, is cytotoxic for cerebral neurones
Language	English
Publishing date	2021-10-09
Publishing country	England
Document type	Journal Article
ISSN	2632-1297
ISSN (online)	2632-1297
DOI	10.1093/braincomms/fcab225
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Article ; Online: Quantitative histomorphometry of capillary microstructure in deep white matter.

Mozumder, Meghdoot / Pozo, Jose M / Coelho, Santiago / Costantini, Marina / Simpson, Julie / Highley, J Robin / Ince, Paul G / Frangi, Alejandro F

NeuroImage. Clinical

2019 Volume 23, Page(s) 101839

Abstract: White matter lesions represent a major risk factor for dementia in elderly people. Magnetic Resonance Imaging (MRI) studies have demonstrated cerebral blood flow reduction in age-related white matter lesions, indicating that vascular alterations are ... ...

Abstract	White matter lesions represent a major risk factor for dementia in elderly people. Magnetic Resonance Imaging (MRI) studies have demonstrated cerebral blood flow reduction in age-related white matter lesions, indicating that vascular alterations are involved in developing white matter lesions. Hypoperfusion and changes in capillary morphology are generally linked to dementia. However, a quantitative study describing these microvascular alterations in white matter lesions is missing in the literature; most previous microvascular studies being on the cortex. The aim of this work is to identify and quantify capillary microstructural changes involved in the appearance of deep subcortical lesions (DSCL). We characterize the distribution of capillary diameter, thickness, and density in the deep white matter in a population of 75 elderly subjects, stratified into three equal groups according to DSCL: Control (subject without DSCL), Lesion (sample presenting DSCL), and Normal Appearing White Matter (NAWM, the subject presented DSCL but not at the sampled tissue location). Tissue samples were selected from the Cognitive Function and Aging Study (CFAS), a cohort representative of an aging population, from which immunohistochemically-labeled histological images were acquired. To accurately estimate capillary diameters and thicknesses from the 2D histological images, we also introduce a novel semi-automatic method robust to non-perpendicular incidence angle of capillaries into the imaging plane, and to non-circular deformations of capillary cross sections. Subjects with DSCL presented a significant increase in capillary wall thickness, a decrease in the diameter intra-subject variability (but not in the mean), and a decrease in capillary density. No significant difference was observed between controls and NAWM. Both capillary wall thickening and reduction in capillary density contribute to the reduction of cerebral blood flow previously reported for white matter lesions. The obtained distributions provide reliable statistics of capillary microstructure useful to inform the modeling of human cerebral blood flow, for instance to define microcirculation models for their estimation from MRI or to perform realistic cerebral blood flow simulations.
MeSH term(s)	Aged ; Aged, 80 and over ; Aging/pathology ; Aging/physiology ; Capillaries/diagnostic imaging ; Capillaries/pathology ; Capillaries/physiology ; Cerebrovascular Circulation/physiology ; Female ; Humans ; Magnetic Resonance Imaging/standards ; Magnetic Resonance Imaging/trends ; Male ; Single-Blind Method ; White Matter/diagnostic imaging ; White Matter/pathology ; White Matter/physiology
Language	English
Publishing date	2019-04-25
Publishing country	Netherlands
Document type	Journal Article ; Multicenter Study ; Research Support, Non-U.S. Gov't
ZDB-ID	2701571-3
ISSN	2213-1582 ; 2213-1582
ISSN (online)	2213-1582
ISSN	2213-1582
DOI	10.1016/j.nicl.2019.101839
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Article ; Online: Type 2 diabetes mellitus-associated transcriptome alterations in cortical neurones and associated neurovascular unit cells in the ageing brain.

Bury, Joanna J / Chambers, Annabelle / Heath, Paul R / Ince, Paul G / Shaw, Pamela J / Matthews, Fiona E / Brayne, Carol / Simpson, Julie E / Wharton, Stephen B

Acta neuropathologica communications

2021 Volume 9, Issue 1, Page(s) 5

Abstract: Type 2 diabetes mellitus (T2D), characterised by peripheral insulin resistance, is a risk factor for dementia. In addition to its contribution to small and large vessel disease, T2D may directly damage cells of the brain neurovascular unit. In this study, ...

Abstract	Type 2 diabetes mellitus (T2D), characterised by peripheral insulin resistance, is a risk factor for dementia. In addition to its contribution to small and large vessel disease, T2D may directly damage cells of the brain neurovascular unit. In this study, we investigated the transcriptomic changes in cortical neurones, and associated astrocytes and endothelial cells of the neurovascular unit, in the ageing brain. Neurone, astrocyte, and endothelial cell-enriched mRNA, obtained by immuno-laser capture microdissection of temporal cortex (Brodmann area 21/22) from 6 cases with self-reported T2D in the Cognitive Function and Ageing Study neuropathology cohort, and an equal number of age and sex-matched controls, was assessed by microarray analysis. Integrated Molecular Pathway Level Analysis was performed using the Kyoto Encyclopaedia of Genes and Genomes database on significantly differentially expressed genes, defined as P < 0.05 and fold-change ± 1.2. Hub genes identified from Weighted Gene Co-expression Network Analysis were validated in neurones using the NanoString nCounter platform. The expression and cellular localisation of proteins encoded by selected candidate genes were confirmed by immunohistochemistry. 912, 2202, and 1227 genes were significantly differentially expressed between cases with self-reported T2D and controls in neurones, astrocytes, and endothelial cells respectively. Changes in cortical neurones included alterations in insulin and other signalling pathways, cell cycle, cellular senescence, inflammatory mediators, and components of the mitochondrial respiratory electron transport chain. Impaired insulin signalling was shared by neurovascular unit cells with, additionally, apoptotic pathway changes in astrocytes and dysregulation of advanced glycation end-product signalling in endothelial cells. Transcriptomic analysis identified changes in key cellular pathways associated with T2D that may contribute to neuronal damage and dysfunction. These effects on brain cells potentially contribute to a diabetic dementia, and may provide novel approaches for therapeutic intervention.
MeSH term(s)	Aged ; Aged, 80 and over ; Aging/genetics ; Aging/metabolism ; Astrocytes/metabolism ; Brain/metabolism ; Diabetes Mellitus, Type 2/genetics ; Diabetes Mellitus, Type 2/metabolism ; Endothelial Cells/metabolism ; Female ; Humans ; Laser Capture Microdissection ; Male ; Neurons/metabolism ; RNA, Messenger/metabolism ; Temporal Lobe/cytology ; Temporal Lobe/metabolism ; Transcriptome
Chemical Substances	RNA, Messenger
Language	English
Publishing date	2021-01-06
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/s40478-020-01109-y
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Article: Histological data of axons, astrocytes, and myelin in deep subcortical white matter populations

Coelho, Santiago / Pozo, Jose M. / Costantini, Marina / Highley, J. Robin / Mozumder, Meghdoot / Simpson, Julie E. / Ince, Paul G. / Frangi, Alejandro F.

Data in Brief. 2019 Apr., v. 23

2019

Abstract	This immunohistochemistry dataset contains the main structures in deep subcortical white matter (axons, astrocytes, and myelinated axons) in a representative cohort of an ageing population. A set of samples from 90 subjects of the Cognitive Function and Ageing Study (CFAS) were analysed, stratified into three groups of 30 subjects each, in relation to the presence of age-associated deep subcortical lesions. High-resolution microscopy data enables the extraction of valuable information, such as volume fractions, for the construction and validation of diffusion MRI (dMRI) models. The dataset provided here was used in Coelho et al. [1].
Keywords	astrocytes ; cognition ; data collection ; immunohistochemistry ; microscopy ; myelin sheath
Language	English
Dates of publication	2019-04
Publishing place	Elsevier Inc.
Document type	Article
ZDB-ID	2786545-9
ISSN	2352-3409
ISSN	2352-3409
DOI	10.1016/j.dib.2019.103762
Database	NAL-Catalogue (AGRICOLA)

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