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Article ; Online: Age and sex differences in the genetic architecture of measures of subjective health: Relationships with physical health, depressive symptoms, and episodic memory.

Finkel, Deborah / Gatz, Margaret / Franz, Carol E / Catts, Vibeke S / Christensen, Kaare / Kremen, William / Nygaard, Marianne / Plassman, Brenda L / Sachdev, Perminder S / Whitfield, Keith / Pedersen, Nancy L

The journals of gerontology. Series B, Psychological sciences and social sciences

2024

Abstract: Objectives: Subjective health (SH) is not just an indicator of physical health, but also reflects active cognitive processing of information about one's own health and has been associated with emotional health measures, such as neuroticism and ... ...

Abstract	Objectives: Subjective health (SH) is not just an indicator of physical health, but also reflects active cognitive processing of information about one's own health and has been associated with emotional health measures, such as neuroticism and depression. Behavior genetic approaches investigate the genetic architecture of SH, i.e., genetic and environmental influences on individual differences in SH and associations with potential components such as physical, cognitive, and emotional health. Previous twin analyses have been limited by sex, sample size, age range, and focus on single covariates. Methods: The current analysis used data from 24,173 adults ranging in age from 40-90 years from the international Interplay of Genes and Environment Across Multiple Studies (IGEMS) consortium to investigate the genetic architecture of three measures of SH: self-rated health, health compared to others, and impact of health on activities. Independent pathways model of SH included physical health, depressive symptoms, and episodic memory, with age, sex, and country included as covariates. Results: Most or all of the genetic variance for SH measures was shared with physical health, depressive symptoms, and episodic memory. Genetic architecture of SH differed across measures, age groups (40-65, 66-90), and sexes. Age comparisons indicated stronger correlations with all 3 covariates in older adults, often resulting from greater shared genetic variance. Discussion: The predictive value of SH has been amply demonstrated. The higher genetic contributions to associations between SH and its components in older adults support the increasing conceptualization with age of SH as an intuitive summation of one's vital reserve.
Language	English
Publishing date	2024-04-17
Publishing country	United States
Document type	Journal Article
ZDB-ID	1223664-0
ISSN	1758-5368 ; 1079-5014
ISSN (online)	1758-5368
ISSN	1079-5014
DOI	10.1093/geronb/gbae062
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Article ; Online: Issues and recommendations for the residual approach to quantifying cognitive resilience and reserve.

Elman, Jeremy A / Vogel, Jacob W / Bocancea, Diana I / Ossenkoppele, Rik / van Loenhoud, Anna C / Tu, Xin M / Kremen, William S

Alzheimer's research & therapy

2022 Volume 14, Issue 1, Page(s) 102

Abstract: Background: Cognitive reserve and resilience are terms used to explain interindividual variability in maintenance of cognitive health in response to adverse factors, such as brain pathology in the context of aging or neurodegenerative disorders. There ... ...

Abstract	Background: Cognitive reserve and resilience are terms used to explain interindividual variability in maintenance of cognitive health in response to adverse factors, such as brain pathology in the context of aging or neurodegenerative disorders. There is substantial interest in identifying tractable substrates of resilience to potentially leverage this phenomenon into intervention strategies. One way of operationalizing cognitive resilience that has gained popularity is the residual method: regressing cognition on an adverse factor and using the residual as a measure of resilience. This method is attractive because it provides a statistical approach that is an intuitive match to the reserve/resilience conceptual framework. However, due to statistical properties of the regression equation, the residual approach has qualities that complicate its interpretation as an index of resilience and make it statistically inappropriate in certain circumstances. Methods and results: We describe statistical properties of the regression equation to illustrate why the residual is highly correlated with the cognitive score from which it was derived. Using both simulations and real data, we model common applications of the approach by creating a residual score (global cognition residualized for hippocampal volume) in individuals along the AD spectrum. We demonstrate that in most real-life scenarios, the residual measure of cognitive resilience is highly correlated with cognition, and the degree of this correlation depends on the initial relationship between the adverse factor and cognition. Subsequently, any association between this resilience metric and an external variable may actually be driven by cognition, rather than by an operationalized measure of resilience. We then assess several strategies proposed as potential solutions to this problem, such as including both the residual and original cognitive measure in a model. However, we conclude these solutions may be insufficient, and we instead recommend against "pre-regression" strategies altogether in favor of using statistical moderation (e.g., interactions) to quantify resilience. Conclusions: Caution should be taken in the use and interpretation of the residual-based method of cognitive resilience. Rather than identifying resilient individuals, we encourage building more complete models of cognition to better identify the specific adverse and protective factors that influence cognitive decline.
MeSH term(s)	Alzheimer Disease/pathology ; Brain/pathology ; Cognition/physiology ; Cognitive Dysfunction/pathology ; Cognitive Reserve/physiology ; Disease Progression ; Humans
Language	English
Publishing date	2022-07-25
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, U.S. Gov't, Non-P.H.S. ; 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/s13195-022-01049-w
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Article ; Online: Alzheimer's Disease Polygenic Scores Predict Changes in Episodic Memory and Executive Function Across 12 Years in Late Middle Age.

Gustavson, Daniel E / Reynolds, Chandra A / Hohman, Timothy J / Jefferson, Angela L / Elman, Jeremy A / Panizzon, Matthew S / Neale, Michael C / Logue, Mark W / Lyons, Michael J / Franz, Carol E / Kremen, William S

Journal of the International Neuropsychological Society : JINS

2022 Volume 29, Issue 2, Page(s) 136–147

Abstract: Objective: Alzheimer's disease (AD) is highly heritable, and AD polygenic risk scores (AD-PRSs) have been derived from genome-wide association studies. However, the nature of genetic influences very early in the disease process is still not well known. ... ...

Abstract	Objective: Alzheimer's disease (AD) is highly heritable, and AD polygenic risk scores (AD-PRSs) have been derived from genome-wide association studies. However, the nature of genetic influences very early in the disease process is still not well known. Here we tested the hypothesis that an AD-PRSs would be associated with changes in episodic memory and executive function across late midlife in men who were cognitively unimpaired at their baseline midlife assessment.. Method: We examined 1168 men in the Vietnam Era Twin Study of Aging (VETSA) who were cognitively normal (CN) at their first of up to three assessments across 12 years (mean ages 56, 62, and 68). Latent growth models of episodic memory and executive function were based on 6-7 tests/subtests. AD-PRSs were based on Kunkle et al. (Nature Genetics, 51, 414-430, 2019), Results: AD-PRSs were correlated with linear slopes of change for both cognitive abilities. Men with higher AD-PRSs had steeper declines in both memory ( Conclusions: Memory is most characteristically impaired in AD, but executive functions are one of the first cognitive abilities to decline in midlife in normal aging. This study is among the first to demonstrate that this early decline also relates to AD genetic influences, even in men CN at baseline.
MeSH term(s)	Humans ; Male ; Middle Aged ; Alzheimer Disease/complications ; Apolipoprotein E4/genetics ; Cognition ; Executive Function ; Genome-Wide Association Study ; Memory, Episodic ; Aged
Chemical Substances	Apolipoprotein E4
Language	English
Publishing date	2022-02-21
Publishing country	England
Document type	Journal Article
ZDB-ID	1230632-0
ISSN	1469-7661 ; 1355-6177
ISSN (online)	1469-7661
ISSN	1355-6177
DOI	10.1017/S1355617722000108
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Article: Practice Effects in Mild Cognitive Impairment Increase Reversion Rates and Delay Detection of New Impairments.

Sanderson-Cimino, Mark / Elman, Jeremy A / Tu, Xin M / Gross, Alden L / Panizzon, Matthew S / Gustavson, Daniel E / Bondi, Mark W / Edmonds, Emily C / Eppig, Joel S / Franz, Carol E / Jak, Amy J / Lyons, Michael J / Thomas, Kelsey R / Williams, McKenna E / Kremen, William S

Frontiers in aging neuroscience

2022 Volume 14, Page(s) 847315

Abstract: Objective: Cognitive practice effects (PEs) can delay detection of progression from cognitively unimpaired to mild cognitive impairment (MCI). They also reduce diagnostic accuracy as suggested by biomarker positivity data. Even among those who decline, ... ...

Abstract	Objective: Cognitive practice effects (PEs) can delay detection of progression from cognitively unimpaired to mild cognitive impairment (MCI). They also reduce diagnostic accuracy as suggested by biomarker positivity data. Even among those who decline, PEs can mask steeper declines by inflating cognitive scores. Within MCI samples, PEs may increase reversion rates and thus impede detection of further impairment. Within an MCI sample at baseline, we evaluated how PEs impact prevalence, reversion rates, and dementia progression after 1 year. Methods: We examined 329 baseline Alzheimer's Disease Neuroimaging Initiative MCI participants (mean age = 73.1; Results: Accounting for PEs increased MCI prevalence at follow-up by 9.2% (272 vs. 249 MCI), and reduced reversion to normal by 28.8% (57 vs. 80 reverters). PEs also increased stability of single-domain MCI by 12.0% (164 vs. 147). Compared to PE-unadjusted diagnoses, use of PE-adjusted follow-up diagnoses led to a twofold increase in hazard ratios for incident dementia. We classified individuals as false reverters if they reverted to cognitively unimpaired status based on PE-unadjusted scores, but remained classified as MCI cases after accounting for PEs. When amyloid and tau positivity were examined together, 72.2% of these false reverters were positive for at least one biomarker. Interpretation: Even when PEs are small, they can meaningfully change whether some individuals with MCI retain the diagnosis at a 1-year follow-up. Accounting for PEs resulted in increased MCI prevalence and altered stability/reversion rates. This improved diagnostic accuracy also increased the dementia-predicting ability of MCI diagnoses.
Language	English
Publishing date	2022-04-25
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2558898-9
ISSN	1663-4365
ISSN	1663-4365
DOI	10.3389/fnagi.2022.847315
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Article ; Online: Cognitive practice effects delay diagnosis of MCI: Implications for clinical trials.

Sanderson-Cimino, Mark / Elman, Jeremy A / Tu, Xin M / Gross, Alden L / Panizzon, Matthew S / Gustavson, Daniel E / Bondi, Mark W / Edmonds, Emily C / Eglit, Graham M L / Eppig, Joel S / Franz, Carol E / Jak, Amy J / Lyons, Michael J / Thomas, Kelsey R / Williams, McKenna E / Kremen, William S

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

2022 Volume 8, Issue 1, Page(s) e12228

Abstract: Introduction: Practice effects (PEs) on cognitive tests obscure decline, thereby delaying detection of mild cognitive impairment (MCI). Importantly, PEs may be present even when there are performance declines, if scores would have been even lower ... ...

Abstract	Introduction: Practice effects (PEs) on cognitive tests obscure decline, thereby delaying detection of mild cognitive impairment (MCI). Importantly, PEs may be present even when there are performance declines, if scores would have been even lower without prior test exposure. We assessed how accounting for PEs using a replacement-participants method impacts incident MCI diagnosis. Methods: Of 889 baseline cognitively normal (CN) Alzheimer's Disease Neuroimaging Initiative (ADNI) participants, 722 returned 1 year later (mean age = 74.9 ± 6.8 at baseline). The scores of test-naïve demographically matched "replacement" participants who took tests for the first time were compared to returnee scores at follow-up. PEs-calculated as the difference between returnee follow-up scores and replacement participants scores-were subtracted from follow-up scores of returnees. PE-adjusted cognitive scores were then used to determine if individuals were below the impairment threshold for MCI. Cerebrospinal fluid amyloid beta, phosphorylated tau, and total tau were used for criterion validation. In addition, based on screening and recruitment numbers from a clinical trial of amyloid-positive individuals, we estimated the effect of earlier detection of MCI by accounting for cognitive PEs on a hypothetical clinical trial in which the key outcome was progression to MCI. Results: In the ADNI sample, PE-adjusted scores increased MCI incidence by 19% ( Discussion: Detecting MCI as early as possible is of obvious importance. Accounting for cognitive PEs with the replacement-participants method leads to earlier detection of MCI, improved diagnostic accuracy, and can lead to multi-million-dollar cost reductions for clinical trials.
Language	English
Publishing date	2022-02-01
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/trc2.12228
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Article: Genomic Structural Equation Modeling Reveals Latent Phenotypes in the Human Cortex with Distinct Genetic Architecture.

Morey, Rajendra / Zheng, Yuanchao / Sun, Delin / Garrett, Melanie / Gasperi, Marianna / Maihofer, Adam / Baird, C Lexi / Grasby, Katrina / Huggins, Ashley / Haswell, Courtney / Thompson, Paul / Medland, Sarah / Gustavson, Daniel / Panizzon, Matthew / Kremen, William / Nievergelt, Caroline / Ashley-Koch, Allison / Logue, Logue

Research square

2023

Abstract: Genetic contributions to human cortical structure manifest pervasive pleiotropy. This pleiotropy may be harnessed to identify unique genetically-informed parcellations of the cortex that are neurobiologically distinct from functional, cytoarchitectural, ... ...

Abstract	Genetic contributions to human cortical structure manifest pervasive pleiotropy. This pleiotropy may be harnessed to identify unique genetically-informed parcellations of the cortex that are neurobiologically distinct from functional, cytoarchitectural, or other cortical parcellation schemes. We investigated genetic pleiotropy by applying genomic structural equation modeling (SEM) to map the genetic architecture of cortical surface area (SA) and cortical thickness (CT) for the 34 brain regions recently reported in the ENIGMA cortical GWAS. Genomic SEM uses the empirical genetic covariance estimated from GWAS summary statistics with LD score regression (LDSC) to discover factors underlying genetic covariance, which we are denoting
Language	English
Publishing date	2023-10-03
Publishing country	United States
Document type	Preprint
DOI	10.21203/rs.3.rs-3253035/v1
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Article ; Online: Recommendations to address key recruitment challenges of Alzheimer's disease clinical trials.

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

2022 Volume 19, Issue 2, Page(s) 696–707

Abstract: Clinical trials for Alzheimer's disease (AD) are slower to enroll study participants, take longer to complete, and are more expensive than trials in most other therapeutic areas. The recruitment and retention of a large number of qualified, diverse ... ...

Abstract	Clinical trials for Alzheimer's disease (AD) are slower to enroll study participants, take longer to complete, and are more expensive than trials in most other therapeutic areas. The recruitment and retention of a large number of qualified, diverse volunteers to participate in clinical research studies remain among the key barriers to the successful completion of AD clinical trials. An advisory panel of experts from academia, patient-advocacy organizations, philanthropy, non-profit, government, and industry convened in 2020 to assess the critical challenges facing recruitment in Alzheimer's clinical trials and develop a set of recommendations to overcome them. This paper briefly reviews existing challenges in AD clinical research and discusses the feasibility and implications of the panel's recommendations for actionable and inclusive solutions to accelerate the development of novel therapies for AD.
MeSH term(s)	Humans ; Alzheimer Disease/drug therapy ; Patient Selection
Language	English
Publishing date	2022-08-10
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	2211627-8
ISSN	1552-5279 ; 1552-5260
ISSN (online)	1552-5279
ISSN	1552-5260
DOI	10.1002/alz.12737
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Article: The Impact of Genes and Environment on Brain Ageing in Males Aged 51 to 72 Years.

Frontiers in aging neuroscience

2022 Volume 14, Page(s) 831002

Abstract: Magnetic resonance imaging data are being used in statistical models to predicted brain ageing (PBA) and as biomarkers for neurodegenerative diseases such as Alzheimer's Disease. Despite their increasing application, the genetic and environmental ... ...

Abstract	Magnetic resonance imaging data are being used in statistical models to predicted brain ageing (PBA) and as biomarkers for neurodegenerative diseases such as Alzheimer's Disease. Despite their increasing application, the genetic and environmental etiology of global PBA indices is unknown. Likewise, the degree to which genetic influences in PBA are longitudinally stable and how PBA changes over time are also unknown. We analyzed data from 734 men from the Vietnam Era Twin Study of Aging with repeated MRI assessments between the ages 51-72 years. Biometrical genetic analyses "twin models" revealed significant and highly correlated estimates of additive genetic heritability ranging from 59 to 75%. Multivariate longitudinal modeling revealed that covariation between PBA at different timepoints could be explained by a single latent factor with 73% heritability. Our results suggest that genetic influences on PBA are detectable in midlife or earlier, are longitudinally very stable, and are largely explained by common genetic influences.
Language	English
Publishing date	2022-04-15
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2558898-9
ISSN	1663-4365
ISSN	1663-4365
DOI	10.3389/fnagi.2022.831002
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Article: Shifts in species interactions and farming contexts mediate net effects of birds in agroecosystems.

Olimpi, E M / Garcia, K / Gonthier, D J / De Master, K T / Echeverri, A / Kremen, C / Sciligo, A R / Snyder, W E / Wilson-Rankin, E E / Karp, D S

Ecological applications : a publication of the Ecological Society of America

2020 Volume 30, Issue 5, Page(s) e02115

Abstract: Some birds are viewed as pests and vectors of foodborne pathogens in farmlands, yet birds also benefit growers by consuming pests. While many growers seek to prevent birds from accessing their farms, few studies have attempted to quantify the net effects ...

Abstract	Some birds are viewed as pests and vectors of foodborne pathogens in farmlands, yet birds also benefit growers by consuming pests. While many growers seek to prevent birds from accessing their farms, few studies have attempted to quantify the net effects of bird services and disservices, let alone how net effects shift across farm management strategies. We quantified the net effect of birds on crop production across 20 California strawberry (Fragaria × ananassa) farms that varied in local management practices and landscape context. We surveyed farms for berry damage and bird droppings (as potential sources of pathogens) and implemented a large-scale exclusion experiment to quantify the impact of birds on production. We found that birds had only a slightly negative overall impact on strawberry production, reducing economic value by 3.6%. Direct bird damage and intraguild predation contributed equally to this net effect, underscoring the importance of indirect trophic interactions that may be less apparent to growers. In simple landscapes (e.g., low proportions of surrounding seminatural habitat), birds provided pest control in the interiors of farm fields, and costs from bird damage to crops peaked at field edges. In complex landscapes (e.g., high proportions of seminatural habitat), birds were more likely to disrupt pest control by feeding as intraguild predators. Nonetheless, seminatural habitat dampened bird services and disservices, and our models predicted that removing habitat around farm fields would increase costs from bird damage to crops by up to 76%. Fecal contamination of crops was extremely rare (0.01%). However, both fecal contamination and bird damage did increase on farms with higher densities of fencing and wires, where birds often perch. Our results demonstrate that maintaining seminatural habitat around farms may enhance bird diversity and mitigate bird damage without increasing food safety risks. We also show that the net effects of birds depend on farming context and vary in complex ways in relation to locations within a farm, local farm attributes, and the surrounding landscape. This context-specific variation must be considered in order to optimize the management of wild birds in agroecosystems.
MeSH term(s)	Agriculture ; Animals ; Birds ; Crops, Agricultural ; Ecosystem ; Farms
Language	English
Publishing date	2020-04-15
Publishing country	United States
Document type	Journal Article ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	1074505-1
ISSN	1939-5582 ; 1051-0761
ISSN (online)	1939-5582
ISSN	1051-0761
DOI	10.1002/eap.2115
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Article ; Online: In Vivo Imaging of Exogenous Progenitor Cells in Tendon Regeneration via Superparamagnetic Iron Oxide Particles.

Kremen, Thomas J / Bez, Maxim / Sheyn, Dmitriy / Ben-David, Shiran / Da, Xiaoyu / Tawackoli, Wafa / Wagner, Shawn / Gazit, Dan / Pelled, Gadi

The American journal of sports medicine

2019 Volume 47, Issue 11, Page(s) 2737–2744

Abstract: Background: Although tendon injuries and repairs are common, treatment of these injuries has limitations. The application of mesenchymal progenitor cells (MPCs) is increasingly used to optimize the biological process of tendon repair healing. However, ... ...

Abstract	Background: Although tendon injuries and repairs are common, treatment of these injuries has limitations. The application of mesenchymal progenitor cells (MPCs) is increasingly used to optimize the biological process of tendon repair healing. However, clinically relevant technologies that effectively assess the localization of exogenous MPCs in vivo are lacking. Hypothesis: Exogenous MPCs labeled with superparamagnetic iron oxide (SPIO) particles would allow monitoring of the localization and retention of cells within the site of implantation via magnetic resonance imaging (MRI) without negatively affecting cell survival or differentiation. Study design: Descriptive laboratory study. Methods: Genetically modified C3H10T1/2 MPCs engineered to express luciferase (Luc+) reporter gene were implanted into surgically created Achilles tendon defects of 10 athymic nude rats (Hsd:RH-Foxn1 Results: Optical imaging demonstrated that the implanted cells not only survived but also proliferated in vivo, and these cells remained viable for at least 4 weeks after implantation. In addition, SPIO labeling did not appear to affect MPC survival or proliferation, as assessed by quantitative bioluminescence imaging ( Conclusion: MRI of exogenous MPCs labeled with SPIO particles allows for effective in vivo assessments of cell localization and retention in the setting of tendon regeneration for at least 4 weeks after implantation. This SPIO labeling does not appear to impair cell survival, transgene expression, or differentiation. Clinical relevance: SPIO labeling of MPCs appears to be safe for in vivo assessments of MPCs in tendon regeneration therapies and may be used for future clinical investigations of musculoskeletal regenerative medicine.
MeSH term(s)	Animals ; Cell Differentiation ; Cell Survival ; Ferric Compounds ; Magnetic Resonance Imaging/methods ; Magnetite Nanoparticles ; Mesenchymal Stem Cell Transplantation ; Mesenchymal Stem Cells/physiology ; Mice ; Optical Imaging ; Rats ; Rats, Nude ; Regeneration/physiology ; Tendon Injuries/diagnostic imaging ; Tendon Injuries/physiopathology ; Tendons/diagnostic imaging ; Tendons/physiology
Chemical Substances	Ferric Compounds ; Magnetite Nanoparticles ; ferric oxide (1K09F3G675)
Language	English
Publishing date	2019-07-23
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	197482-8
ISSN	1552-3365 ; 0363-5465
ISSN (online)	1552-3365
ISSN	0363-5465
DOI	10.1177/0363546519861080
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