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Article ; Online: Soluble Biomarkers of Cerebrovascular Pathologies.

Foley, Kate E / Wilcock, Donna M

2024 Volume 55, Issue 4, Page(s) 801–811

Abstract: Vascular contributions to cognitive impairment and dementia (VCID) is an all-encompassing term that describes cognitive impairment due to cerebrovascular origins. With the advancement of imaging and pathological studies, we now understand that VCID is ... ...

Abstract	Vascular contributions to cognitive impairment and dementia (VCID) is an all-encompassing term that describes cognitive impairment due to cerebrovascular origins. With the advancement of imaging and pathological studies, we now understand that VCID is often comorbid with Alzheimer disease. While researchers in the Alzheimer disease field have been working for years to establish and test blood-based biomarkers for Alzheimer disease diagnosis, prognosis, clinical therapy discovery, and early detection, blood-based biomarkers for VCID are in their infancy and also face challenges. VCID is heterogeneous, comprising many different pathological entities (ischemic, or hemorrhagic), and spatial and temporal differences (acute or chronic). This review highlights pathways that are aiding the search for sensitive and specific blood-based cerebrovascular dysfunction markers, describes promising candidates, and explains ongoing initiatives to discover blood-based VCID biomarkers.
MeSH term(s)	Humans ; Alzheimer Disease/diagnosis ; Dementia, Vascular/diagnosis ; Cognitive Dysfunction ; Biomarkers/metabolism
Chemical Substances	Biomarkers
Language	English
Publishing date	2024-03-25
Publishing country	United States
Document type	Journal Article ; Review
ZDB-ID	80381-9
ISSN	1524-4628 ; 0039-2499 ; 0749-7954
ISSN (online)	1524-4628
ISSN	0039-2499 ; 0749-7954
DOI	10.1161/STROKEAHA.123.044172
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Article ; Online: Vascular Considerations for Amyloid Immunotherapy.

Foley, Kate E / Wilcock, Donna M

Current neurology and neuroscience reports

2022 Volume 22, Issue 11, Page(s) 709–719

Abstract: Purpose of review: Amyloid beta (Aβ) plaque accumulation is a hallmark pathology contributing to Alzheimer's disease (AD) and is widely hypothesized to lead to cognitive decline. Decades of research into anti-Aβ immunotherapies provide evidence for ... ...

Abstract	Purpose of review: Amyloid beta (Aβ) plaque accumulation is a hallmark pathology contributing to Alzheimer's disease (AD) and is widely hypothesized to lead to cognitive decline. Decades of research into anti-Aβ immunotherapies provide evidence for increased Aβ clearance from the brain; however, this is frequently accompanied by complicated vascular deficits. This article reviews the history of anti-Aβ immunotherapies and clinical findings and provides recommendations moving forward. Recent findings: In 20 years of both animal and human studies, anti-Aβ immunotherapies have been a prevalent avenue of reducing hallmark Aβ plaques. In both models and with different anti-Aβ antibody designs, amyloid-related imaging abnormalities (ARIA) indicating severe cerebrovascular compromise have been common and concerning occurrence. ARIA caused by anti-Aβ immunotherapy has been noted since the early 2000s, and the mechanisms driving it are still unknown. Recent approval of aducanumab comes with renewed urgency to consider vascular deficits caused by anti-Aβ immunotherapy.
MeSH term(s)	Animals ; Humans ; Amyloid beta-Peptides ; Plaque, Amyloid/drug therapy ; Plaque, Amyloid/pathology ; Alzheimer Disease/drug therapy ; Amyloidogenic Proteins ; Amyloid ; Immunotherapy/methods ; Immunologic Factors ; Disease Models, Animal
Chemical Substances	Amyloid beta-Peptides ; Amyloidogenic Proteins ; Amyloid ; Immunologic Factors
Language	English
Publishing date	2022-10-21
Publishing country	United States
Document type	Journal Article ; Review
ZDB-ID	2057363-7
ISSN	1534-6293 ; 1528-4042
ISSN (online)	1534-6293
ISSN	1528-4042
DOI	10.1007/s11910-022-01235-1
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Article ; Online: Mechanisms of ARIA: is it time to focus on the unique immune environment of the neurovascular unit?

Foley, Kate E / Weekman, Erica M / Wilcock, Donna M

Molecular neurodegeneration

2023 Volume 18, Issue 1, Page(s) 76

MeSH term(s)	Humans ; Brain ; Cerebral Amyloid Angiopathy ; Alzheimer Disease ; Blood-Brain Barrier
Language	English
Publishing date	2023-10-20
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2244557-2
ISSN	1750-1326 ; 1750-1326
ISSN (online)	1750-1326
ISSN	1750-1326
DOI	10.1186/s13024-023-00667-8
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Article: Assessment of Neurovascular Uncoupling:

Onos, Kristen / Lin, Peter B / Pandey, Ravi S / Persohn, Scott A / Burton, Charles P / Miner, Ethan W / Eldridge, Kierra / Kanyinda, Jonathan Nyandu / Foley, Kate E / Carter, Gregory W / Howell, Gareth R / Territo, Paul R

bioRxiv : the preprint server for biology

2024

Abstract: Background: Alzheimer's disease (AD) is the most common cause of dementia worldwide, with apolipoprotein ε4 (: Methods: PET imaging was used to assess metabolism-perfusion in both sexes of aging C57BL/6J, and h: Results: All h: Discussion: This ...

Abstract	Background: Alzheimer's disease (AD) is the most common cause of dementia worldwide, with apolipoprotein ε4 ( Methods: PET imaging was used to assess metabolism-perfusion in both sexes of aging C57BL/6J, and h Results: All h Discussion: This work highlights
Language	English
Publishing date	2024-03-13
Publishing country	United States
Document type	Preprint
DOI	10.1101/2023.12.13.571584
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Article ; Online: Assessment of neurovascular uncoupling: APOE status is a key driver of early metabolic and vascular dysfunction.

Onos, Kristen D / Lin, Peter B / Pandey, Ravi S / Persohn, Scott A / Burton, Charles P / Miner, Ethan W / Eldridge, Kierra / Kanyinda, Jonathan Nyandu / Foley, Kate E / Carter, Gregory W / Howell, Gareth R / Territo, Paul R

Alzheimer's & dementia : the journal of the Alzheimer's Association

2024

Abstract: Background: Alzheimer's disease (AD) is the most common cause of dementia worldwide, with apolipoprotein Eε4 (APOEε4) being the strongest genetic risk factor. Current clinical diagnostic imaging focuses on amyloid and tau; however, new methods are ... ...

Abstract	Background: Alzheimer's disease (AD) is the most common cause of dementia worldwide, with apolipoprotein Eε4 (APOEε4) being the strongest genetic risk factor. Current clinical diagnostic imaging focuses on amyloid and tau; however, new methods are needed for earlier detection. Methods: PET imaging was used to assess metabolism-perfusion in both sexes of aging C57BL/6J, and hAPOE mice, and were verified by transcriptomics, and immunopathology. Results: All hAPOE strains showed AD phenotype progression by 8 months, with females exhibiting the regional changes, which correlated with GO-term enrichments for glucose metabolism, perfusion, and immunity. Uncoupling analysis revealed APOEε4/ε4 exhibited significant Type-1 uncoupling (↓ glucose uptake, ↑ perfusion) at 8 and 12 months, while APOEε3/ε4 demonstrated Type-2 uncoupling (↑ glucose uptake, ↓ perfusion), while immunopathology confirmed cell specific contributions. Discussion: This work highlights APOEε4 status in AD progression manifests as neurovascular uncoupling driven by immunological activation, and may serve as an early diagnostic biomarker. Highlights: We developed a novel analytical method to analyze PET imaging of
Language	English
Publishing date	2024-05-07
Publishing country	United States
Document type	Journal Article
ZDB-ID	2211627-8
ISSN	1552-5279 ; 1552-5260
ISSN (online)	1552-5279
ISSN	1552-5260
DOI	10.1002/alz.13842
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Article ; Online: APOE

Foley, Kate E / Diemler, Cory A / Hewes, Amanda A / Garceau, Dylan T / Sasner, Michael / Howell, Gareth R

Alzheimer's & dementia (New York, N. Y.)

2022 Volume 8, Issue 1, Page(s) e12308

Abstract: Introduction: Apolipoprotein E (: Methods: To address this, male and female : Results: Data revealed chronic running decreased age-dependent weight gain, lean and fat mass, and serum low-density lipoprotein concentration dependent on : ... ...

Abstract	Introduction: Apolipoprotein E ( Methods: To address this, male and female Results: Data revealed chronic running decreased age-dependent weight gain, lean and fat mass, and serum low-density lipoprotein concentration dependent on Discussion: These data in humanized mouse models provide compelling evidence that
Language	English
Publishing date	2022-06-29
Publishing country	United States
Document type	Journal Article
ZDB-ID	2832891-7
ISSN	2352-8737 ; 2352-8737
ISSN (online)	2352-8737
ISSN	2352-8737
DOI	10.1002/trc2.12308
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Article: The

Foley, Kate E / Hewes, Amanda A / Garceau, Dylan T / Kotredes, Kevin P / Carter, Gregory W / Sasner, Michael / Howell, Gareth R

Frontiers in aging neuroscience

2022 Volume 14, Page(s) 838436

Abstract: Introduction: Restrictions on existing : Methods: As a part of MODEL-AD, we created and validated new versions of humanized : Results: Expression of human APOE isoforms were confirmed in : Discussion: ... ...

Abstract	Introduction: Restrictions on existing Methods: As a part of MODEL-AD, we created and validated new versions of humanized Results: Expression of human APOE isoforms were confirmed in Discussion: APOE
Language	English
Publishing date	2022-03-16
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2558898-9
ISSN	1663-4365
ISSN	1663-4365
DOI	10.3389/fnagi.2022.838436
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Article ; Online: Transcriptional profiling predicts running promotes cerebrovascular remodeling in young but not midlife mice.

Foley, Kate E / Yang, Hongtian Stanley / Graham, Leah C / Howell, Gareth R

BMC genomics

2019 Volume 20, Issue 1, Page(s) 860

Abstract: Background: The incidence of dementia and cognitive decline is increasing with no therapy or cure. One of the reasons treatment remains elusive is because there are various pathologies that contribute to age-related cognitive decline. Specifically, with ...

Abstract	Background: The incidence of dementia and cognitive decline is increasing with no therapy or cure. One of the reasons treatment remains elusive is because there are various pathologies that contribute to age-related cognitive decline. Specifically, with Alzheimer's disease, targeting to reduce amyloid beta plaques and phosphorylated tau aggregates in clinical trials has not yielded results to slow symptomology, suggesting a new approach is needed. Interestingly, exercise has been proposed as a potential therapeutic intervention to improve brain health and reduce the risk for dementia, however the benefits throughout aging are not well understood. Results: To better understand the effects of exercise, we preformed transcriptional profiling on young (1-2 months) and midlife (12 months) C57BL/6 J (B6) male mice after 12 weeks of voluntary running. Data was compared to age-matched sedentary controls. Interestingly, the midlife running group naturally broke into two cohorts based on distance ran - either running a lot and more intensely (high runners) or running less and less intensely (low runners). Midlife high runners had lower LDL cholesterol as well as lower adiposity (%fat) compared to sedentary, than midlife low runners compared to sedentary suggesting more intense running lowered systemic markers of risk for age-related diseases including dementias. Differential gene analysis of transcriptional profiles generated from the cortex and hippocampus showed thousands of differentially expressed (DE) genes when comparing young runners to sedentary controls. However, only a few hundred genes were DE comparing either midlife high runners or midlife low runners to midlife sedentary controls. This indicates that, in our study, the effects of running are reduced through aging. Gene set enrichment analyses identified enrichment of genes involved in extracellular matrix (ECM), vascular remodeling and angiogenesis in young runners but not midlife runners. These genes are known to be expressed in multiple vascular-related cell types including astrocytes, endothelial cells, pericytes and smooth muscle cells. Conclusions: Taken together these results suggest running may best serve as a preventative measure to reduce risk for cerebrovascular decline. Ultimately, this work shows that exercise may be more effective to prevent dementia if introduced at younger ages.
MeSH term(s)	Age Factors ; Animals ; Cerebral Cortex/blood supply ; Cerebral Cortex/metabolism ; Cerebrovascular Circulation ; Computational Biology/methods ; Extracellular Matrix/genetics ; Extracellular Matrix/metabolism ; Gene Expression Profiling ; Gene Expression Regulation ; Gene Ontology ; Male ; Mice ; Models, Biological ; Organ Specificity/genetics ; Running ; Transcriptome ; Vascular Remodeling/genetics
Language	English
Publishing date	2019-11-14
Publishing country	England
Document type	Journal Article
ISSN	1471-2164
ISSN (online)	1471-2164
DOI	10.1186/s12864-019-6230-z
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Article: Genetic basis of susceptibility to low‐dose paraquat and variation between the sexes in Drosophila melanogaster

Lovejoy, Pamela C / Foley, Kate E / Conti, Melissa M / Meadows, Samantha M / Bishop, Christopher / Fiumera, Anthony C

Molecular ecology. 2021 May, v. 30, no. 9

2021

Abstract: Toxicant resistance is a complex trait, affected both by genetics and the environment. Like most complex traits, it can exhibit sexual dimorphism, yet sex is often overlooked as a factor in studies of toxicant resistance. Paraquat, one such toxicant, is ... ...

Abstract	Toxicant resistance is a complex trait, affected both by genetics and the environment. Like most complex traits, it can exhibit sexual dimorphism, yet sex is often overlooked as a factor in studies of toxicant resistance. Paraquat, one such toxicant, is a commonly used herbicide and is known to produce mitochondrial oxidative stress, decrease dopaminergic neurons and dopamine (DA) levels, and decrease motor ability. While the main effects of paraquat are well‐characterized, less is known about the naturally occurring variation in paraquat susceptibility. The purpose of this study was to map the genes contributing to low‐dose paraquat susceptibility in Drosophila melanogaster, and to determine if susceptibility differs between the sexes. One hundred of the Drosophila Genetic Reference Panel (DGRP) lines were scored for susceptibility via climbing ability and used in a genome‐wide association study (GWAS). Variation in seventeen genes in females and thirty‐five genes in males associated with paraquat susceptibility. Only two candidate genes overlapped between the sexes despite a significant positive correlation between male and female susceptibilities. Many associated polymorphisms had significant interactions with sex, with most having conditionally neutral effects. Conditional neutrality between the sexes probably stems from sex‐biased expression which may result from partial resolution of sexual conflict. Candidate genes were verified with RNAi knockdowns, gene expression analyses, and DA quantification. Several of these genes are novel associations with paraquat susceptibility. This research highlights the importance of assessing both sexes when studying toxicant susceptibility.
Keywords	Drosophila melanogaster ; dopamine ; ecology ; females ; gene expression ; genome-wide association study ; males ; mitochondria ; oxidative stress ; paraquat ; sexual dimorphism
Language	English
Dates of publication	2021-05
Size	p. 2040-2053.
Publishing place	John Wiley & Sons, Ltd
Document type	Article
Note	NAL-AP-2-clean ; JOURNAL ARTICLE
ZDB-ID	1126687-9
ISSN	1365-294X ; 0962-1083
ISSN (online)	1365-294X
ISSN	0962-1083
DOI	10.1111/mec.15878
Database	NAL-Catalogue (AGRICOLA)

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Article ; Online: Alzheimer's disease and inflammatory biomarkers positively correlate in plasma in the UK-ADRC cohort.

Foley, Kate E / Winder, Zachary / Sudduth, Tiffany L / Martin, Barbara J / Nelson, Peter T / Jicha, Gregory A / Harp, Jordan P / Weekman, Erica M / Wilcock, Donna M

Alzheimer's & dementia : the journal of the Alzheimer's Association

2023 Volume 20, Issue 2, Page(s) 1374–1386

Abstract: Introduction: Protein-based plasma assays provide hope for improving accessibility and specificity of molecular diagnostics to diagnose dementia.: Methods: Plasma was obtained from participants (N = 837) in our community-based University of Kentucky ... ...

Abstract	Introduction: Protein-based plasma assays provide hope for improving accessibility and specificity of molecular diagnostics to diagnose dementia. Methods: Plasma was obtained from participants (N = 837) in our community-based University of Kentucky Alzheimer's Disease Research Center cohort. We evaluated six Alzheimer's disease (AD)- and neurodegeneration-related (Aβ40, Aβ42, Aβ42/40, p-tau181, total tau, and NfLight) and five inflammatory biomarkers (TNF, IL6, IL8, IL10, and GFAP) using the SIMOA-based protein assay platform. Statistics were performed to assess correlations. Results: Our large cohort reflects previous plasma biomarker findings. Relationships between biomarkers to understand AD-inflammatory biomarker correlations showed significant associations between AD and inflammatory biomarkers suggesting peripheral inflammatory interactions with increasing AD pathology. Biomarker associations parsed out by clinical diagnosis (normal, MCI, and dementia) reveal changes in strength of the correlations across the cognitive continuum. Discussion: Unique AD-inflammatory biomarker correlations in a community-based cohort reveal a new avenue for utilizing plasma-based biomarkers in the assessment of AD and related dementias. Highlights: Large community cohorts studying sex, age, and APOE genotype effects on biomarkers are few. It is unknown how biomarker-biomarker associations vary through aging and dementia. Six AD (Aβ40, Aβ42, Aβ42/40, p-tau181, total tau, and NfLight) and five inflammatory biomarkers (TNFα, IL6, IL8, IL10, and GFAP) were used to examine associations between biomarkers. Plasma biomarkers suggesting increasing cerebral AD pathology corresponded to increases in peripheral inflammatory markers, both pro-inflammatory and anti-inflammatory. Strength of correlations, between pairs of classic AD and inflammatory plasma biomarker, changes throughout cognitive progression to dementia.
MeSH term(s)	Humans ; Alzheimer Disease/pathology ; Amyloid beta-Peptides ; Interleukin-10 ; Interleukin-6 ; Interleukin-8 ; tau Proteins ; Biomarkers ; United Kingdom ; Cognitive Dysfunction
Chemical Substances	Amyloid beta-Peptides ; Interleukin-10 (130068-27-8) ; Interleukin-6 ; Interleukin-8 ; tau Proteins ; Biomarkers
Language	English
Publishing date	2023-11-27
Publishing country	United States
Document type	Journal Article
ZDB-ID	2211627-8
ISSN	1552-5279 ; 1552-5260
ISSN (online)	1552-5279
ISSN	1552-5260
DOI	10.1002/alz.13485
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