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Article: Genetic insights into the association between inflammatory bowel disease and Alzheimer's disease.

Zeng, Lu / White, Charles C / Bennett, David A / Klein, Hans-Ulrich / De Jager, Philip L

medRxiv : the preprint server for health sciences

2023

Abstract: Background: Myeloid cells, including monocytes, macrophages, microglia, dendritic cells and neutrophils are a part of innate immunity, playing a major role in orchestrating innate and adaptive immune responses. Microglia are the resident myeloid cells ... ...

Abstract	Background: Myeloid cells, including monocytes, macrophages, microglia, dendritic cells and neutrophils are a part of innate immunity, playing a major role in orchestrating innate and adaptive immune responses. Microglia are the resident myeloid cells of the central nervous system, and many Alzheimer's disease (AD) risk loci are found in or near genes that are highly or sometimes uniquely expressed in myeloid cells. Similarly, inflammatory bowel disease (IBD) loci are also enriched for genes expressed by myeloid cells. However, the extent to which there is overlap between the effects of AD and IBD susceptibility loci in myeloid cells remains poorly described, and the substantial IBD genetic maps may help to accelerate AD research. Methods: Here, we leveraged summary statistics from large-scale genome-wide association studies (GWAS) to investigate the causal effect of IBD (including ulcerative colitis and Crohn's disease) variants on AD and AD endophenotypes. Microglia and monocyte expression Quantitative Trait Locus (eQTLs) were used to examine the functional consequences of IBD and AD risk variants enrichment in two different myeloid cell subtypes. Results: Our results showed that, while Conclusion: To our knowledge, this is the first study to systematically contrast the genetic association between IBD and AD, our findings highlight a possible genetically protective effect of IBD on AD even if the majority of effects on myeloid cell gene expression by the two sets of disease variants are distinct. Thus, IBD myeloid studies may not help to accelerate AD functional studies, but our observation reinforces the role of myeloid cells in the accumulation of tau proteinopathy and provides a new avenue for discovering a protective factor.
Language	English
Publishing date	2023-04-17
Publishing country	United States
Document type	Preprint
DOI	10.1101/2023.04.17.23286845
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Article ; Online: Postoperative Infection and Revision Surgery Rates in Foot and Ankle Surgery Without Routine Prescription of Prophylactic Antibiotics.

Huang, Neal / Miles, Daniel T / Read, Connor R / White, Charles C / Murray, Richard D / Wilson, Andrew W / Doty, Jesse F

Journal of the American Academy of Orthopaedic Surgeons. Global research & reviews

2023 Volume 7, Issue 3

Abstract: Introduction: Surgical site infections (SSIs) are associated with patient morbidity and increased healthcare costs. Limited literature in foot and ankle surgery provides guidance about routine administration of postoperative antibiotic prophylaxis. The ... ...

Abstract	Introduction: Surgical site infections (SSIs) are associated with patient morbidity and increased healthcare costs. Limited literature in foot and ankle surgery provides guidance about routine administration of postoperative antibiotic prophylaxis. The purpose of this study was to examine the incidence and revision surgery rates of SSI in outpatient foot and ankle surgeries in patients not receiving oral postoperative antibiotic prophylaxis. Methods: A retrospective review of all outpatient surgeries (n = 1517) conducted by a single surgeon in a tertiary referral academic center was conducted through electronic medical records. Incidence of SSI, revision surgery rate, and associated risk factors were determined. The median follow-up was 6 months. Results: Postoperative infection occurred in 2.9% (n = 44) of the surgeries conducted, with 0.9% of patients (n = 14) requiring return to the operating room. Thirty patients (2.0%) were diagnosed with simple superficial infections, which resolved with local wound care and oral antibiotics. Diabetes (adjusted odds ratio, 2.09; 95% confidence interval, 1.00 to 4.38; P = 0.049) and increasing age (adjusted odds ratio, 1.02; 95% confidence interval, 1.00 to 1.04; P = 0.016) were significantly associated with postoperative infection. Discussion: This study demonstrated low postoperative infection and revision surgery rates without the routine prescription of prophylactic postoperative antibiotics. Increasing age and diabetes are signficant risk factors for developing a postoperative infection.
MeSH term(s)	Humans ; Ankle/surgery ; Reoperation ; Anti-Bacterial Agents/therapeutic use ; Antibiotic Prophylaxis/adverse effects ; Communicable Diseases/drug therapy ; Communicable Diseases/etiology ; Communicable Diseases/surgery ; Prescriptions
Chemical Substances	Anti-Bacterial Agents
Language	English
Publishing date	2023-03-08
Publishing country	United States
Document type	Journal Article
ZDB-ID	2898328-2
ISSN	2474-7661 ; 1067-151X
ISSN (online)	2474-7661
ISSN	1067-151X
DOI	10.5435/JAAOSGlobal-D-23-00015
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Article: Transversus Abdominis Plane Block as Part of a Multimodal Analgesic Regimen in Patients Undergoing Anterior Lumbar Interbody Fusion: A Retrospective Cohort Study.

Colón, Luis Felipe / White, Charles C / Miles, Daniel T / Wilson, Andrew W / Salazar, Oscar / Patel, Prayash / Miller, Joseph

International journal of spine surgery

2023 Volume 17, Issue 3, Page(s) 426–433

Language	English
Publishing date	2023-04-06
Publishing country	Netherlands
Document type	Journal Article
ISSN	2211-4599
ISSN	2211-4599
DOI	10.14444/8442
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Article ; Online: Sex-Specific Association of the X Chromosome With Cognitive Change and Tau Pathology in Aging and Alzheimer Disease.

Davis, Emily J / Solsberg, Caroline W / White, Charles C / Miñones-Moyano, Elena / Sirota, Marina / Chibnik, Lori / Bennett, David A / De Jager, Philip L / Yokoyama, Jennifer S / Dubal, Dena B

JAMA neurology

2024 Volume 78, Issue 10, Page(s) 1249–1254

Abstract: Importance: The X chromosome represents 5% of the human genome in women and men, and its influence on cognitive aging and Alzheimer disease (AD) is largely unknown.: Objective: To determine whether the X chromosome is associated with sex-specific ... ...

Abstract	Importance: The X chromosome represents 5% of the human genome in women and men, and its influence on cognitive aging and Alzheimer disease (AD) is largely unknown. Objective: To determine whether the X chromosome is associated with sex-specific cognitive change and tau pathology in aging and AD. Design, setting, participants: This study examined differential gene expression profiling of the X chromosome from an RNA sequencing data set of the dorsolateral prefrontal cortex obtained from autopsied, elderly individuals enrolled in the Religious Orders Study and Rush Memory and Aging Project joint cohorts. Samples were collected from the cohort study with enrollment from 1994 to 2017. Data were last analyzed in May 2021. Main outcomes and measures: The main analysis examined whether X chromosome gene expression measured by RNA sequencing of the dorsolateral prefrontal cortex was associated with cognitive change during aging and AD, independent of AD pathology and at the transcriptome-wide level in women and men. Whether X chromosome gene expression was associated with neurofibrillary tangle burden, a measure of tau pathology that influences cognition, in women and men was also explored. Results: Samples for RNA sequencing of the dorsolateral prefrontal cortex were obtained from 508 individuals (mean [SD] age at death, 88.4 [6.6] years; 315 [62.0%] were female; 197 [38.8%] had clinical diagnosis of AD at death; 293 [58.2%] had pathological diagnosis of AD at death) enrolled in the Religious Orders Study and Rush Memory and Aging Project joint cohorts and were followed up annually for a mean (SD) of 6.3 (3.9) years. X chromosome gene expression (29 genes), adjusted for age at death, education, and AD pathology, was significantly associated with cognitive change at the genome-wide level in women but not men. In the majority of identified X genes (19 genes), increased expression was associated with slower cognitive decline in women. In contrast with cognition, X chromosome gene expression (3 genes), adjusted for age at death and education, was associated with neuropathological tau burden at the genome-wide level in men but not women. Conclusions and relevance: In this study, the X chromosome was associated with cognitive trajectories and neuropathological tau burden in aging and AD in a sex-specific manner. This is important because specific X chromosome factors could contribute risk or resilience to biological pathways of aging and AD in women, men, or both.
MeSH term(s)	Aged ; Aged, 80 and over ; Aging/physiology ; Alzheimer Disease/genetics ; Alzheimer Disease/pathology ; Chromosomes, Human, X ; Cognition ; Cognitive Dysfunction ; Cohort Studies ; Dorsolateral Prefrontal Cortex ; Female ; Humans ; Male ; Middle Aged ; Neurofibrillary Tangles/pathology ; Sex Characteristics ; Transcriptome
Language	English
Publishing date	2024-02-21
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2702023-X
ISSN	2168-6157 ; 2168-6149
ISSN (online)	2168-6157
ISSN	2168-6149
DOI	10.1001/jamaneurol.2021.2806
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Article ; Online: Neuroticism alters the transcriptome of the frontal cortex to contribute to the cognitive decline and onset of Alzheimer's disease.

De Jager, Céline H / White, Charles C / Bennett, David A / Ma, Yiyi

Translational psychiatry

2021 Volume 11, Issue 1, Page(s) 139

Abstract: Accumulating evidence has suggested that the molecular transcriptional mechanism contributes to Alzheimer's disease (AD) and its endophenotypes of cognitive decline and neuropathological traits, β-amyloid (Aβ) and phosphorylated tangles (TAU). However, ... ...

Abstract	Accumulating evidence has suggested that the molecular transcriptional mechanism contributes to Alzheimer's disease (AD) and its endophenotypes of cognitive decline and neuropathological traits, β-amyloid (Aβ) and phosphorylated tangles (TAU). However, it is unknown what is the impact of the AD risk factors, personality characteristics assessed by the NEO Five-Factor Inventory, on the human brain's transcriptome. Using postmortem human brain samples from 466 subjects, we found that neuroticism has a significant overall impact on the brain transcriptome (omnibus P = 0.005) but not the other four personality characteristics. Focused on those cognitive decline related gene co-expressed modules, neuroticism has nominally significant associations (P < 0.05) with four neuronal modules, which are more related to PHFtau than Aβ across all eight brain regions. Furthermore, the effect of neuroticism on cognitive decline and AD might be mediated through the expression of module 7 and TAU pathology (P = 0.008). To conclude, neuroticism has a broad impact on the transcriptome of human brains, and its effect on cognitive decline and AD may be mediated through gene transcription programs related to TAU pathology.
MeSH term(s)	Alzheimer Disease/genetics ; Amyloid beta-Peptides/metabolism ; Brain/metabolism ; Cognitive Dysfunction/genetics ; Frontal Lobe/metabolism ; Humans ; Neuroticism ; Transcriptome ; tau Proteins/metabolism
Chemical Substances	Amyloid beta-Peptides ; tau Proteins
Language	English
Publishing date	2021-02-24
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	2609311-X
ISSN	2158-3188 ; 2158-3188
ISSN (online)	2158-3188
ISSN	2158-3188
DOI	10.1038/s41398-021-01253-6
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Article ; Online: Effects of the Obesity Epidemic on Total Hip and Knee Arthroplasty Demographics.

Johnson, Charles A / White, Charles C / Kunkle, Bryce F / Eichinger, Josef K / Friedman, Richard J

The Journal of arthroplasty

2021 Volume 36, Issue 9, Page(s) 3097–3100

Abstract: Background: Higher body mass index (BMI) is a well-known risk factor for the development of hip and knee osteoarthritis and predicts total hip arthroplasty (THA) and total knee arthroplasty (TKA) at an earlier age. The purpose of this study is to ... ...

Abstract	Background: Higher body mass index (BMI) is a well-known risk factor for the development of hip and knee osteoarthritis and predicts total hip arthroplasty (THA) and total knee arthroplasty (TKA) at an earlier age. The purpose of this study is to document the nationwide trends in age and obesity in primary THA and TKA throughout the obesity epidemic. Methods: A retrospective analysis of the National Inpatient Sample database was conducted on patients undergoing primary THA and TKA for primary OA between 2002 and 2017. Analysis of variance and chi-square tests were performed to examine changes in age and obesity percentage over time, respectively. Pearson correlations were used to assess the relationship between patient age, BMI, and year of surgery. Results: A total of 688,371 THA and 1,556,651 TKA were identified over the sixteen-year period. Between 2002 and 2017, the proportion of obese patients increased for both THA (7.0% to 22.7%, P < .001) and TKA (10.7% to 30.4%, P < .001). Mean age significantly decreased for both THA (66.7 to 65.9 years, P < .001) and TKA (67.6 to 66.8 years; P < .001). Over time, BMI significantly increased (THA: r = 0.221 vs. TKA: r = 0.272) and patient age decreased (THA: r = -0.031 vs. TKA: r = -0.137) for both procedures (P < .001 for all). Conclusion: THA and TKA patients have become younger and increasingly more obese throughout the obesity epidemic, as obesity rates have tripled over this time period. The current investigation is the first to demonstrate significant trends in both age and obesity in the THA and TKA populations on a national level. Level of evidence: III.
MeSH term(s)	Arthroplasty, Replacement, Hip ; Arthroplasty, Replacement, Knee ; Demography ; Epidemics ; Humans ; Obesity/epidemiology ; Osteoarthritis, Hip/epidemiology ; Osteoarthritis, Hip/surgery ; Osteoarthritis, Knee/epidemiology ; Osteoarthritis, Knee/etiology ; Osteoarthritis, Knee/surgery ; Retrospective Studies
Language	English
Publishing date	2021-04-22
Publishing country	United States
Document type	Journal Article
ZDB-ID	632770-9
ISSN	1532-8406 ; 0883-5403
ISSN (online)	1532-8406
ISSN	0883-5403
DOI	10.1016/j.arth.2021.04.017
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Zs.A 2134: Show issues

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Article: A single-nucleus transcriptome-wide association study implicates novel genes in depression pathogenesis.

Zeng, Lu / Fujita, Masashi / Gao, Zongmei / White, Charles C / Green, Gilad S / Habib, Naomi / Menon, Vilas / Bennett, David A / Boyle, Patricia A / Klein, Hans-Ulrich / De Jager, Philip L

medRxiv : the preprint server for health sciences

2023

Abstract: Background: Depression is a common psychiatric illness and global public health problem. However, our limited understanding of the biological basis of depression has hindered the development of novel treatments and interventions.: Methods: To ... ...

Abstract	Background: Depression is a common psychiatric illness and global public health problem. However, our limited understanding of the biological basis of depression has hindered the development of novel treatments and interventions. Methods: To identify new candidate genes for therapeutic development, we examined single-nucleus RNA sequencing (snucRNAseq) data from the dorsolateral prefrontal cortex (N=424) in relation to ante-mortem depressive symptoms. To complement these direct analyses, we also used genome-wide association study (GWAS) results for depression (N=500,199) along with genetic tools for inferring the expression of 22,159 genes in 7 cell types and 55 cell subtypes to perform transcriptome-wide association studies (TWAS) of depression followed by Mendelian randomization (MR). Results: Our single-nucleus TWAS analysis identified 71 causal genes in depression that have a role in specific neocortical cell subtypes; 59 of 71 genes were novel compared to previous studies. Depression TWAS genes showed a cell type specific pattern, with the greatest enrichment being in both excitatory and inhibitory neurons as well as astrocytes. Gene expression in different neuron subtypes have different directions of effect on depression risk. Compared to lower genetically correlated traits (e.g. body mass index) with depression, higher correlated traits (e.g., neuroticism) have more common TWAS genes with depression. In parallel, we performed differential gene expression analysis in relation to depression in 55 cortical cell subtypes, and we found that genes such as Conclusions: These two sets of analyses illustrate the utility of large snucRNAseq data to uncover both genes whose expression is altered in specific cell subtypes in the context of depression and to enhance the interpretation of well-powered GWAS so that we can prioritize specific susceptibility genes for further analysis and therapeutic development.
Language	English
Publishing date	2023-03-29
Publishing country	United States
Document type	Preprint
DOI	10.1101/2023.03.27.23286844
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Article ; Online: A Single-Nucleus Transcriptome-Wide Association Study Implicates Novel Genes in Depression Pathogenesis.

Zeng, Lu / Fujita, Masashi / Gao, Zongmei / White, Charles C / Green, Gilad S / Habib, Naomi / Menon, Vilas / Bennett, David A / Boyle, Patricia / Klein, Hans-Ulrich / De Jager, Philip L

Biological psychiatry

2023

Abstract: Background: Depression, a common psychiatric illness and global public health problem, remains poorly understood across different life stages, which hampers the development of novel treatments.: Methods: To identify new candidate genes for ... ...

Abstract	Background: Depression, a common psychiatric illness and global public health problem, remains poorly understood across different life stages, which hampers the development of novel treatments. Methods: To identify new candidate genes for therapeutic development, we performed differential gene expression analysis of single-nucleus RNA sequencing data from the dorsolateral prefrontal cortex of older adults (n = 424) in relation to antemortem depressive symptoms. Additionally, we integrated genome-wide association study results for depression (n = 500,199) along with genetic tools for inferring the expression of 14,048 unique genes in 7 cell types and 52 cell subtypes to perform a transcriptome-wide association study of depression followed by Mendelian randomization. Results: Our single-nucleus transcriptome-wide association study analysis identified 68 candidate genes for depression and showed the greatest number being in excitatory and inhibitory neurons. Of the 68 genes, 53 were novel compared to previous studies. Notably, gene expression in different neuronal subtypes had varying effects on depression risk. Traits with high genetic correlations with depression, such as neuroticism, shared more transcriptome-wide association study genes than traits that were not highly correlated with depression. Complementing these analyses, differential gene expression analysis across 52 neocortical cell subtypes showed that genes such as KCNN2, SCAI, WASF3, and SOCS6 were associated with late-life depressive symptoms in specific cell subtypes. Conclusions: These 2 sets of analyses illustrate the utility of large single-nucleus RNA sequencing data both to uncover genes whose expression is altered in specific cell subtypes in the context of depressive symptoms and to enhance the interpretation of well-powered genome-wide association studies so that we can prioritize specific susceptibility genes for further analysis and therapeutic development.
Language	English
Publishing date	2023-12-21
Publishing country	United States
Document type	Journal Article
ZDB-ID	209434-4
ISSN	1873-2402 ; 0006-3223
ISSN (online)	1873-2402
ISSN	0006-3223
DOI	10.1016/j.biopsych.2023.12.012
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Zs.A 720: Show issues

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Article ; Online: Multicellular communities are perturbed in the aging human brain and Alzheimer's disease.

Cain, Anael / Taga, Mariko / McCabe, Cristin / Green, Gilad S / Hekselman, Idan / White, Charles C / Lee, Dylan I / Gaur, Pallavi / Rozenblatt-Rosen, Orit / Zhang, Feng / Yeger-Lotem, Esti / Bennett, David A / Yang, Hyun-Sik / Regev, Aviv / Menon, Vilas / Habib, Naomi / De Jager, Philip L

Nature neuroscience

2023 Volume 26, Issue 7, Page(s) 1267–1280

Abstract: The role of different cell types and their interactions in Alzheimer's disease (AD) is a complex and open question. Here, we pursued this question by assembling a high-resolution cellular map of the aging frontal cortex using single-nucleus RNA ... ...

Abstract	The role of different cell types and their interactions in Alzheimer's disease (AD) is a complex and open question. Here, we pursued this question by assembling a high-resolution cellular map of the aging frontal cortex using single-nucleus RNA sequencing of 24 individuals with a range of clinicopathologic characteristics. We used this map to infer the neocortical cellular architecture of 638 individuals profiled by bulk RNA sequencing, providing the sample size necessary for identifying statistically robust associations. We uncovered diverse cell populations associated with AD, including a somatostatin inhibitory neuronal subtype and oligodendroglial states. We further identified a network of multicellular communities, each composed of coordinated subpopulations of neuronal, glial and endothelial cells, and we found that two of these communities are altered in AD. Finally, we used mediation analyses to prioritize cellular changes that might contribute to cognitive decline. Thus, our deconstruction of the aging neocortex provides a roadmap for evaluating the cellular microenvironments underlying AD and dementia.
MeSH term(s)	Humans ; Alzheimer Disease/metabolism ; Endothelial Cells/metabolism ; Brain/metabolism ; Aging/pathology ; Cognitive Dysfunction/pathology ; Neocortex/pathology
Language	English
Publishing date	2023-06-19
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	1420596-8
ISSN	1546-1726 ; 1097-6256
ISSN (online)	1546-1726
ISSN	1097-6256
DOI	10.1038/s41593-023-01356-x
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Zs.A 4891: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (2.OG) ab Jg. 2022: Lesesaal (EG)
Zs.MG 67: Show issues

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Article: Cellular dynamics across aged human brains uncover a multicellular cascade leading to Alzheimer's disease.

Green, Gilad Sahar / Fujita, Masashi / Yang, Hyun-Sik / Taga, Mariko / McCabe, Cristin / Cain, Anael / White, Charles C / Schmidtner, Anna K / Zeng, Lu / Wang, Yangling / Regev, Aviv / Menon, Vilas / Bennett, David A / Habib, Naomi / De Jager, Philip L

bioRxiv : the preprint server for biology

2023

Abstract: Alzheimer's Disease (AD) is a progressive neurodegenerative disease seen with advancing age. Recent studies have revealed diverse AD-associated cell states, yet when and how they impact the causal chain leading to AD remains unknown. To reconstruct the ... ...

Abstract	Alzheimer's Disease (AD) is a progressive neurodegenerative disease seen with advancing age. Recent studies have revealed diverse AD-associated cell states, yet when and how they impact the causal chain leading to AD remains unknown. To reconstruct the dynamics of the brain's cellular environment along the disease cascade and to distinguish between AD and aging effects, we built a comprehensive cell atlas of the aged prefrontal cortex from 1.64 million single-nucleus RNA-seq profiles. We associated glial, vascular and neuronal subpopulations with AD-related traits for 424 aging individuals, and aligned them along the disease cascade using causal modeling. We identified two distinct lipid-associated microglial subpopulations, one contributed to amyloid-β proteinopathy while the other mediated the effect of amyloid-β in accelerating tau proteinopathy, as well as an astrocyte subpopulation that mediated the effect of tau on cognitive decline. To model the coordinated dynamics of the entire cellular environment we devised the BEYOND methodology which uncovered two distinct trajectories of brain aging that are defined by distinct sequences of changes in cellular communities. Older individuals are engaged in one of two possible trajectories, each associated with progressive changes in specific cellular communities that end with: (1) AD dementia or (2) alternative brain aging. Thus, we provide a cellular foundation for a new perspective of AD pathophysiology that could inform the development of new therapeutic interventions targeting cellular communities, while designing a different clinical management for those individuals on the path to AD or to alternative brain aging.
Language	English
Publishing date	2023-03-09
Publishing country	United States
Document type	Preprint
DOI	10.1101/2023.03.07.531493
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