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Article ; Online: When prion disease Isn't suspected: prion disease as the cause of terminal decline in chronic mixed dementia.

Krishnamurthy, Sudarshan / Harrison, William / Craft, Suzanne / Lockhart, Samuel N / Bateman, James R

2024 , Page(s) 1–6

Abstract: Alzheimer's Disease (AD) is the most common cause of dementia, although multiple pathologies are found in nearly half of the cases with clinically diagnosed AD. Prion diseases, such as Creutzfeldt-Jakob disease (CJD), are rare causes of dementia and ... ...

Abstract	Alzheimer's Disease (AD) is the most common cause of dementia, although multiple pathologies are found in nearly half of the cases with clinically diagnosed AD. Prion diseases, such as Creutzfeldt-Jakob disease (CJD), are rare causes of dementia and typically manifest as a rapidly progressive dementia, where symptom onset to dementia most often occurs over the course of months. In this brief report, we describe a patient's typically progressive dementia with a precipitous decline at the end of their life who, on neuropathological evaluation, was found to have multiple neurodegenerative proteinopathies as well as spongiform encephalopathy due to CJD. This case of unsuspected CJD highlights a rare, but epidemiologically important, cause of sudden decline in well-established neurodegenerative dementias.
Language	English
Publishing date	2024-04-30
Publishing country	England
Document type	Journal Article
ZDB-ID	1302651-3
ISSN	1465-3656 ; 1355-4794
ISSN (online)	1465-3656
ISSN	1355-4794
DOI	10.1080/13554794.2024.2346990
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Article ; Online: Parametric cerebral blood flow and arterial transit time mapping using a 3D convolutional neural network.

Kim, Donghoon / Lipford, Megan E / He, Hongjian / Ding, Qiuping / Ivanovic, Vladimir / Lockhart, Samuel N / Craft, Suzanne / Whitlow, Christopher T / Jung, Youngkyoo

Magnetic resonance in medicine

2023 Volume 90, Issue 2, Page(s) 583–595

Abstract: Purpose: To reduce the total scan time of multiple postlabeling delay (multi-PLD) pseudo-continuous arterial spin labeling (pCASL) by developing a hierarchically structured 3D convolutional neural network (H-CNN) that estimates the arterial transit time ...

Abstract	Purpose: To reduce the total scan time of multiple postlabeling delay (multi-PLD) pseudo-continuous arterial spin labeling (pCASL) by developing a hierarchically structured 3D convolutional neural network (H-CNN) that estimates the arterial transit time (ATT) and cerebral blow flow (CBF) maps from the reduced number of PLDs as well as averages. Methods: A total of 48 subjects (38 females and 10 males), aged 56-80 years, compromising a training group (n = 45) and a validation group (n = 3) underwent MRI including multi-PLD pCASL. We proposed an H-CNN to estimate the ATT and CBF maps using a reduced number of PLDs and a separately reduced number of averages. The proposed method was compared with a conventional nonlinear model fitting method using the mean absolute error (MAE). Results: The H-CNN provided the MAEs of 32.69 ms for ATT and 3.32 mL/100 g/min for CBF estimations using a full data set that contains six PLDs and six averages in the 3 test subjects. The H-CNN also showed that the smaller number of PLDs can be used to estimate both ATT and CBF without significant discrepancy from the reference (MAEs of 231.45 ms for ATT and 9.80 mL/100 g/min for CBF using three of six PLDs). Conclusion: The proposed machine learning-based ATT and CBF mapping offers substantially reduced scan time of multi-PLD pCASL.
MeSH term(s)	Male ; Female ; Humans ; Reproducibility of Results ; Arteries ; Magnetic Resonance Imaging/methods ; Neural Networks, Computer ; Cerebrovascular Circulation/physiology ; Spin Labels
Chemical Substances	Spin Labels
Language	English
Publishing date	2023-04-24
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	605774-3
ISSN	1522-2594 ; 0740-3194
ISSN (online)	1522-2594
ISSN	0740-3194
DOI	10.1002/mrm.29674
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Zs.A 1959: Show issues

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Article: Differential diagnosis of frontotemporal dementia subtypes with explainable deep learning on structural MRI.

Ma, Da / Stocks, Jane / Rosen, Howard / Kantarci, Kejal / Lockhart, Samuel N / Bateman, James R / Craft, Suzanne / Gurcan, Metin N / Popuri, Karteek / Beg, Mirza Faisal / Wang, Lei

Frontiers in neuroscience

2024 Volume 18, Page(s) 1331677

Abstract: Background: Frontotemporal dementia (FTD) represents a collection of neurobehavioral and neurocognitive syndromes that are associated with a significant degree of clinical, pathological, and genetic heterogeneity. Such heterogeneity hinders the ... ...

Abstract	Background: Frontotemporal dementia (FTD) represents a collection of neurobehavioral and neurocognitive syndromes that are associated with a significant degree of clinical, pathological, and genetic heterogeneity. Such heterogeneity hinders the identification of effective biomarkers, preventing effective targeted recruitment of participants in clinical trials for developing potential interventions and treatments. In the present study, we aim to automatically differentiate patients with three clinical phenotypes of FTD, behavioral-variant FTD (bvFTD), semantic variant PPA (svPPA), and nonfluent variant PPA (nfvPPA), based on their structural MRI by training a deep neural network (DNN). Methods: Data from 277 FTD patients (173 bvFTD, 63 nfvPPA, and 41 svPPA) recruited from two multi-site neuroimaging datasets: the Frontotemporal Lobar Degeneration Neuroimaging Initiative and the ARTFL-LEFFTDS Longitudinal Frontotemporal Lobar Degeneration databases. Raw T1-weighted MRI data were preprocessed and parcellated into patch-based ROIs, with cortical thickness and volume features extracted and harmonized to control the confounding effects of sex, age, total intracranial volume, cohort, and scanner difference. A multi-type parallel feature embedding framework was trained to classify three FTD subtypes with a weighted cross-entropy loss function used to account for unbalanced sample sizes. Feature visualization was achieved through post-hoc analysis using an integrated gradient approach. Results: The proposed differential diagnosis framework achieved a mean balanced accuracy of 0.80 for bvFTD, 0.82 for nfvPPA, 0.89 for svPPA, and an overall balanced accuracy of 0.84. Feature importance maps showed more localized differential patterns among different FTD subtypes compared to groupwise statistical mapping. Conclusion: In this study, we demonstrated the efficiency and effectiveness of using explainable deep-learning-based parallel feature embedding and visualization framework on MRI-derived multi-type structural patterns to differentiate three clinically defined subphenotypes of FTD: bvFTD, nfvPPA, and svPPA, which could help with the identification of at-risk populations for early and precise diagnosis for intervention planning.
Language	English
Publishing date	2024-02-07
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2411902-7
ISSN	1662-453X ; 1662-4548
ISSN (online)	1662-453X
ISSN	1662-4548
DOI	10.3389/fnins.2024.1331677
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Article ; Online: Examining a Preclinical Alzheimer's Cognitive Composite for Telehealth Administration for Reliability Between In-Person and Remote Cognitive Testing with Neuroimaging Biomarkers.

Duran, Tugce / Gaussoin, Sarah A / Latham, Lauren A / Rundle, Melissa M / Espeland, Mark A / Williams, Benjamin J / Hughes, Timothy M / Craft, Suzanne / Sachs, Bonnie C / Bateman, James R / Lockhart, Samuel N

Journal of Alzheimer's disease : JAD

2024

Abstract: Background: The preclinical Alzheimer's cognitive composite (PACC) was developed for in-person administration to capture subtle cognitive decline. At the outset of the COVID-19 pandemic, cognitive testing was increasingly performed remotely by telephone ...

Abstract	Background: The preclinical Alzheimer's cognitive composite (PACC) was developed for in-person administration to capture subtle cognitive decline. At the outset of the COVID-19 pandemic, cognitive testing was increasingly performed remotely by telephone or video administration. It is desirable to have a harmonized composite measurement derived from both in-person and remote assessments for identifying cognitive changes and to examine its relationship with common neuroimaging biomarkers. Objective: We defined a telehealth compatible PACC (tPACC) and examined its relationship with neuroimaging biomarkers related to neurodegeneration, brain function and perfusion, white matter integrity, and amyloid-β. Methods: We examined 648 participants' neuroimaging and in-person and remote cognitive testing data from the Wake Forest Alzheimer's Disease Research Center's Clinical Core cohort (observational study) to calculate a modified PACC (PACC5-RAVLT) score and tPACC scores (in-person and remote). We performed Spearman/intraclass correlation coefficient (ICC) analyses for reliability of tPACC scores and linear regression models to evaluate associations between tPACC and neuroimaging. Bland-Altman plots for agreement were constructed across cognitively normal and impaired (mild cognitive impairment and dementia) participants. Results: There was a significant positive relationship between tPACCin - person and PACC5-RAVLT (Overall group: r2 = 0.94, N = 648), and tPACCin - person and tPACCremote (validation subgroup: ICC = 0.82, n = 53). Overall, tPACC showed significant associations with brain thickness/volume, gray matter perfusion, white matter free water, and amyloid-β deposition. Conclusions: There is a good agreement between tPACCand PACC5-RAVLTfor cognitively normal and impaired individuals. The tPACC is associated with common neuroimaging markers of Alzheimer's disease.
Language	English
Publishing date	2024-04-26
Publishing country	Netherlands
Document type	Journal Article
ZDB-ID	1440127-7
ISSN	1875-8908 ; 1387-2877
ISSN (online)	1875-8908
ISSN	1387-2877
DOI	10.3233/JAD-231435
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Article ; Online: Age and beta amyloid deposition impact gait speed, stride length, and gait smoothness while transitioning from an even to an uneven walking surface in older adults.

Zukowski, Lisa A / Fino, Peter C / Levin, Ilana / Hsieh, Katherine L / Lockhart, Samuel N / Miller, Michael E / Laurienti, Paul J / Kritchevsky, Stephen B / Hugenschmidt, Christina E

Human movement science

2024 Volume 93, Page(s) 103175

Abstract: Background: Capturing a measure of movement quality during a complex walking task may indicate the earliest signs of detrimental changes to the brain due to beta amyloid (Aβ) deposition and be a potential differentiator of older adults at elevated and ... ...

Abstract	Background: Capturing a measure of movement quality during a complex walking task may indicate the earliest signs of detrimental changes to the brain due to beta amyloid (Aβ) deposition and be a potential differentiator of older adults at elevated and low risk of developing Alzheimer's disease. This study aimed to determine: 1) age-related differences in gait speed, stride length, and gait smoothness while transitioning from an even to an uneven walking surface, by comparing young adults (YA) and older adults (OA), and 2) if gait speed, stride length, and gait smoothness in OA while transitioning from an even to an uneven walking surface is influenced by the amount of Aβ deposition present in an OA's brain. Methods: Participants included 56 OA (>70 years of age) and 29 YA (25-35 years of age). In OA, Aβ deposition in the brain was quantified by PET imaging. All participants completed a series of cognitive assessments, a functional mobility assessment, and self-report questionnaires. Then participants performed two sets of walking trials on a custom-built walkway containing a mixture of even and uneven surface sections, including three trials with a grass uneven surface and three trials with a rocks uneven surface. Gait data were recorded using a wireless inertial measurement unit system. Stride length, gait speed, and gait smoothness (i.e., log dimensionless lumbar jerk) in the anteroposterior (AP), mediolateral (ML), and vertical (VT) directions were calculated for each stride. Outcomes were retained for five stride locations immediately surrounding the surface transition. Results: OA exhibited slower gait (Grass: p < 0.001; Rocks: p = 0.006), shorter strides (Grass: p < 0.001; Rocks: p = 0.008), and smoother gait (Grass AP: p < 0.001; Rocks AP: p = 0.002; Rocks ML: p = 0.02) than YA, but they also exhibited greater reductions in gait speed and stride length than YA while transitioning to the uneven grass and rocks surfaces. Within the OA group, those with greater Aβ deposition exhibited decreases in smoothness with age (Grass AP: p = 0.02; Rocks AP: p = 0.03; Grass ML: p = 0.04; Rocks ML: p = 0.03), while those with lower Aβ deposition exhibited increasing smoothness with age (Grass AP: p = 0.01; Rocks AP: p = 0.02; Grass ML: p = 0.08; Rocks ML: p = 0.07). Better functional mobility was associated with less smooth gait (Grass ML: p = 0.02; Rocks ML: p = 0.05) and with less variable gait smoothness (Grass and Rocks AP: both p = 0.04) in the OA group. Conclusion: These results suggest that, relative to YA, OA may be adopting more cautious, compensatory gait strategies to maintain smoothness when approaching surface transitions. However, OA with greater Aβ deposition may have limited ability to adopt compensatory gait strategies to increase the smoothness of their walking as they get older because of neuropathological changes altering the sensory integration process and causing worse dynamic balance (i.e., jerkier gait). Functional mobility, in addition to age and Aβ deposition, may be an important factor of whether or not an OA chooses to employ compensatory strategies to prioritize smoothness while walking and what type of compensatory strategy an OA chooses.
MeSH term(s)	Young Adult ; Humans ; Aged ; Adult ; Walking Speed ; Amyloid beta-Peptides ; Gait ; Walking ; Brain ; Movement Disorders
Chemical Substances	Amyloid beta-Peptides
Language	English
Publishing date	2024-01-09
Publishing country	Netherlands
Document type	Journal Article
ZDB-ID	601851-8
ISSN	1872-7646 ; 0167-9457
ISSN (online)	1872-7646
ISSN	0167-9457
DOI	10.1016/j.humov.2023.103175
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Article ; Online: Associations among plasma, MRI, and amyloid PET biomarkers of Alzheimer's disease and related dementias and the impact of health-related comorbidities in a community-dwelling cohort.

Rudolph, Marc D / Sutphen, Courtney L / Register, Thomas C / Whitlow, Christopher T / Solingapuram Sai, Kiran K / Hughes, Timothy M / Bateman, James R / Dage, Jeffrey L / Russ, Kristen A / Mielke, Michelle M / Craft, Suzanne / Lockhart, Samuel N

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

2024

Abstract: Introduction: We evaluated associations between plasma and neuroimaging-derived biomarkers of Alzheimer's disease and related dementias and the impact of health-related comorbidities.: Methods: We examined plasma biomarkers (neurofilament light chain, ...

Abstract	Introduction: We evaluated associations between plasma and neuroimaging-derived biomarkers of Alzheimer's disease and related dementias and the impact of health-related comorbidities. Methods: We examined plasma biomarkers (neurofilament light chain, glial fibrillary acidic protein, amyloid beta [Aβ] 42/40, phosphorylated tau 181) and neuroimaging measures of amyloid deposition (Aβ-positron emission tomography [PET]), total brain volume, white matter hyperintensity volume, diffusion-weighted fractional anisotropy, and neurite orientation dispersion and density imaging free water. Participants were adjudicated as cognitively unimpaired (CU; N = 299), mild cognitive impairment (MCI; N = 192), or dementia (DEM; N = 65). Biomarkers were compared across groups stratified by diagnosis, sex, race, and APOE ε4 carrier status. General linear models examined plasma-imaging associations before and after adjusting for demographics (age, sex, race, education), APOE ε4 status, medications, diagnosis, and other factors (estimated glomerular filtration rate [eGFR], body mass index [BMI]). Results: Plasma biomarkers differed across diagnostic groups (DEM > MCI > CU), were altered in Aβ-PET-positive individuals, and were associated with poorer brain health and kidney function. Discussion: eGFR and BMI did not substantially impact associations between plasma and neuroimaging biomarkers. Highlights: Plasma biomarkers differ across diagnostic groups (DEM > MCI > CU) and are altered in Aβ-PET-positive individuals. Altered plasma biomarker levels are associated with poorer brain health and kidney function. Plasma and neuroimaging biomarker associations are largely independent of comorbidities.
Language	English
Publishing date	2024-05-15
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.13835
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Article: Simultaneous Covariance Inference for Multimodal Integrative Analysis

Xia, Yin / Li, Lexin / Lockhart, Samuel N / Jagust, William J

Journal of the American Statistical Association. 2020 July 2, v. 115, no. 531

2020

Abstract: Multimodal integrative analysis fuses different types of data collected on the same set of experimental subjects. It is becoming a norm in many branches of scientific research, such as multi-omics and multimodal neuroimaging analysis. In this article, we ...

Abstract	Multimodal integrative analysis fuses different types of data collected on the same set of experimental subjects. It is becoming a norm in many branches of scientific research, such as multi-omics and multimodal neuroimaging analysis. In this article, we address the problem of simultaneous covariance inference of associations between multiple modalities, which is of a vital interest in multimodal integrative analysis. Recognizing that there are few readily available solutions in the literature for this type of problem, we develop a new simultaneous testing procedure. It provides an explicit quantification of statistical significance, a much improved detection power, as well as a rigid false discovery control. Our proposal makes novel and useful contributions from both the scientific perspective and the statistical methodological perspective. We demonstrate the efficacy of the new method through both simulations and a multimodal positron emission tomography study of associations between two hallmark pathological proteins of Alzheimer’s disease.
Keywords	covariance ; multiomics ; positron-emission tomography
Language	English
Dates of publication	2020-0702
Size	p. 1279-1291.
Publishing place	Taylor & Francis
Document type	Article
Note	NAL-AP-2-clean
ZDB-ID	2064981-2
ISSN	1537-274X ; 0003-1291 ; 0162-1459
ISSN (online)	1537-274X
ISSN	0003-1291 ; 0162-1459
DOI	10.1080/01621459.2019.1623040
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Article ; Online: Intranasal insulin modulates cerebrospinal fluid markers of neuroinflammation in mild cognitive impairment and Alzheimer's disease: a randomized trial.

Kellar, Derek / Register, Thomas / Lockhart, Samuel N / Aisen, Paul / Raman, Rema / Rissman, Robert A / Brewer, James / Craft, Suzanne

Scientific reports

2022 Volume 12, Issue 1, Page(s) 1346

Abstract: Intranasal insulin (INI) has shown promise as a treatment for Alzheimer's disease (AD) in pilot clinical trials. In a recent phase 2 trial, participants with mild cognitive impairment (MCI) or AD who were treated with INI with one of two delivery devices ...

Abstract	Intranasal insulin (INI) has shown promise as a treatment for Alzheimer's disease (AD) in pilot clinical trials. In a recent phase 2 trial, participants with mild cognitive impairment (MCI) or AD who were treated with INI with one of two delivery devices showed improved cerebral spinal fluid (CSF) biomarker profiles and slower symptom progression compared with placebo. In the cohort which showed benefit, we measured changes in CSF markers of inflammation, immune function and vascular integrity and assessed their relationship with changes in cognition, brain volume, and CSF amyloid and tau concentrations. The insulin-treated group had increased CSF interferon-γ (p = 0.032) and eotaxin (p = 0.049), and reduced interleukin-6 (p = 0.048) over the 12 month trial compared to placebo. Trends were observed for increased CSF macrophage-derived chemokine for the placebo group (p = 0.083), and increased interleukin-2 in the insulin-treated group (p = 0.093). Insulin-treated and placebo groups showed strikingly different patterns of associations between changes in CSF immune/inflammatory/vascular markers and changes in cognition, brain volume, and amyloid and tau concentrations. In summary, INI treatment altered the typical progression of markers of inflammation and immune function seen in AD, suggesting that INI may promote a compensatory immune response associated with therapeutic benefit.
MeSH term(s)	Administration, Intranasal ; Aged ; Alzheimer Disease/drug therapy ; Biomarkers/cerebrospinal fluid ; Cohort Studies ; Female ; Humans ; Inflammation/drug therapy ; Insulin/pharmacology ; Male ; Middle Aged
Chemical Substances	Biomarkers ; Insulin
Language	English
Publishing date	2022-01-25
Publishing country	England
Document type	Journal Article ; Randomized Controlled Trial ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2615211-3
ISSN	2045-2322 ; 2045-2322
ISSN (online)	2045-2322
ISSN	2045-2322
DOI	10.1038/s41598-022-05165-3
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Article: Simultaneous Covariance Inference for Multimodal Integrative Analysis.

Xia, Yin / Li, Lexin / Lockhart, Samuel N / Jagust, William J

Journal of the American Statistical Association

2019 Volume 115, Issue 531, Page(s) 1279–1291

Abstract	Multimodal integrative analysis fuses different types of data collected on the same set of experimental subjects. It is becoming a norm in many branches of scientific research, such as multi-omics and multimodal neuroimaging analysis. In this article, we address the problem of simultaneous covariance inference of associations between multiple modalities, which is of a vital interest in multimodal integrative analysis. Recognizing that there are few readily available solutions in the literature for this type of problem, we develop a new simultaneous testing procedure. It provides an explicit quantification of statistical significance, a much improved detection power, as well as a rigid false discovery control. Our proposal makes novel and useful contributions from both the scientific perspective and the statistical methodological perspective. We demonstrate the efficacy of the new method through both simulations and a multimodal positron emission tomography study of associations between two hallmark pathological proteins of Alzheimer's disease.
Language	English
Publishing date	2019-06-28
Publishing country	United States
Document type	Journal Article
ZDB-ID	2064981-2
ISSN	1537-274X ; 0162-1459 ; 0003-1291
ISSN (online)	1537-274X
ISSN	0162-1459 ; 0003-1291
DOI	10.1080/01621459.2019.1623040
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Article ; Online: Mediterranean diet protects against a neuroinflammatory cortical transcriptome: Associations with brain volumetrics, peripheral inflammation, social isolation, and anxiety in nonhuman primates (Macaca fascicularis).

Frye, Brett M / Negrey, Jacob D / Johnson, Corbin S C / Kim, Jeongchul / Barcus, Richard A / Lockhart, Samuel N / Whitlow, Christopher T / Chiou, Kenneth L / Snyder-Mackler, Noah / Montine, Thomas J / Craft, Suzanne / Shively, Carol A / Register, Thomas C

Brain, behavior, and immunity

2024 Volume 119, Page(s) 681–692

Abstract: Mediterranean diets may be neuroprotective and prevent cognitive decline relative to Western diets; however, the underlying biology is poorly understood. We assessed the effects of Western versus Mediterranean-like diets on RNAseq-generated ... ...

Abstract	Mediterranean diets may be neuroprotective and prevent cognitive decline relative to Western diets; however, the underlying biology is poorly understood. We assessed the effects of Western versus Mediterranean-like diets on RNAseq-generated transcriptional profiles in lateral temporal cortex and their relationships with longitudinal changes in neuroanatomy, circulating monocyte gene expression, and observations of social isolation and anxiety in 38 socially-housed, middle-aged female cynomolgus macaques (Macaca fascicularis). Diet resulted in differential expression of seven transcripts (FDR < 0.05). Cyclin dependent kinase 14 (CDK14), a proinflammatory regulator, was lower in the Mediterranean group. The remaining six transcripts [i.e., "lunatic fringe" (LFNG), mannose receptor C type 2 (MRC2), solute carrier family 3 member 2 (SLCA32), butyrophilin subfamily 2 member A1 (BTN2A1), katanin regulatory subunit B1 (KATNB1), and transmembrane protein 268 (TMEM268)] were higher in cortex of the Mediterranean group and generally associated with anti-inflammatory/neuroprotective pathways. KATNB1 encodes a subcomponent of katanin, important in maintaining microtubule homeostasis. BTN2A1 is involved in immunomodulation of γδ T-cells which have anti-neuroinflammatory and neuroprotective effects. CDK14, LFNG, MRC2, and SLCA32 are associated with inflammatory pathways. The latter four differentially expressed cortex transcripts were associated with peripheral monocyte transcript levels, neuroanatomical changes determined by MRI, and with social isolation and anxiety. These results provide important insights into the potential mechanistic processes linking diet, peripheral and central inflammation, and behavior. Collectively, our results provide evidence that, relative to Western diets, Mediterranean diets confer protection against peripheral and central inflammation which is reflected in preserved brain structure and socioemotional behavior. Ultimately, such protective effects may confer resilience to the development of neuropathology and associated disease.
Language	English
Publishing date	2024-04-16
Publishing country	Netherlands
Document type	Journal Article
ZDB-ID	639219-2
ISSN	1090-2139 ; 0889-1591
ISSN (online)	1090-2139
ISSN	0889-1591
DOI	10.1016/j.bbi.2024.04.016
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