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Article: Validation of the ND-PAE Diagnosis in Children with Heavy Prenatal Alcohol Exposure.

Veziris, Christina R / Hyland, Matthew T / Kable, Julie A / Wozniak, Jeffrey R / Coles, Claire D / May, Philip A / Kalberg, Wendy O / Sowell, Elizabeth R / Jones, Kenneth L / Riley, Edward P / Mattson, Sarah N

Research square

2024

Abstract: This study evaluated criteria for Neurobehavioral Disorder Associated with Prenatal Alcohol Exposure (ND-PAE). Kable et al. (2022) assessed the validity of this diagnosis in a sample with low exposure to alcohol. The current study expanded this ... ...

Abstract	This study evaluated criteria for Neurobehavioral Disorder Associated with Prenatal Alcohol Exposure (ND-PAE). Kable et al. (2022) assessed the validity of this diagnosis in a sample with low exposure to alcohol. The current study expanded this assessment to a sample with a wider age range and heavier alcohol exposure. Data were collected from participants (5-17y) with prenatal alcohol exposure (PAE) and typically developing controls at six Collaborative Initiative on Fetal Alcohol Spectrum Disorders sites using neuropsychological assessment and caregiver reports. Impairment was tested at 1SD, 1.5SD, and 2SD below the normative average and a modification of the adaptive functioning requirement was tested. Testing impairment at 1SD resulted in the highest endorsement rates in both groups. Our findings replicated the study by Kable et al. and show that current criteria captured a high rate of those with PAE and that requiring fewer adaptive functioning criteria resulted in higher sensitivity to PAE.
Language	English
Publishing date	2024-02-12
Publishing country	United States
Document type	Preprint
DOI	10.21203/rs.3.rs-3922436/v1
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Article ; Online: Learning Spectral Fractional Anisotropy and Mean Diffusivity Features as Neuroimaging Biomarkers for Tracking White Matter Integrity Changes in Myotonic Dystrophy Type 1 Patients using Deep Convolutional Neural Networks.

Kamali, Tahereh / Day, John W / Deutsch, Gayle K / Sampson, Jacinda B / Murad, Alejandro / Chaufty, Jeremy / Parker, Dana / Wozniak, Jeffrey R

Annual International Conference of the IEEE Engineering in Medicine and Biology Society. IEEE Engineering in Medicine and Biology Society. Annual International Conference

2023 Volume 2023, Page(s) 1–4

Abstract: Myotonic dystrophy type 1 (DM1) is a genetic neuromuscular progressive multisystem disease that results in a broad spectrum of clinical central nervous system (CNS) involvement, including problems with memory, attention, executive functioning, and social ...

Abstract	Myotonic dystrophy type 1 (DM1) is a genetic neuromuscular progressive multisystem disease that results in a broad spectrum of clinical central nervous system (CNS) involvement, including problems with memory, attention, executive functioning, and social cognition. Fractional anisotropy and mean diffusivity along-tract data calculated using diffusion tensor imaging techniques play a vital role in assessing white matter microstructural changes associated with neurodegeneration caused by DM1. In this work, a novel spectrogram-based deep learning method is proposed to characterize white matter network alterations in DM1 with the goal of building a deep learning model as neuroimaging biomarkers of DM1. The proposed method is evaluated on fractional anisotropies and mean diffusivities along-tract data calculated for 25 major white matter tracts of 46 DM1 patients and 96 unaffected controls. The evaluation data consists of a total of 7100 spectrogram images. The model achieved 91% accuracy in identifying DM1, a significant improvement compared to previous methods.Clinical relevance- Clinical care of DM1 is particularly challenging due to DM1 multisystem involvement and the disease variability. Patients with DM1 often experience neurological and psychological symptoms, such as excessive sleepiness and apathy, that greatly impact their quality of life. Some of DM1 CNS symptoms may be responsive to treatment. The goal of this research is to gain a deeper understanding of the impact of DM1 on the CNS and to develop a deep learning model that can serve as a biomarker for the disease, with the potential to be used in future clinical trials as an outcome measure.
MeSH term(s)	Humans ; White Matter/diagnostic imaging ; Myotonic Dystrophy/diagnostic imaging ; Myotonic Dystrophy/complications ; Myotonic Dystrophy/psychology ; Diffusion Tensor Imaging ; Anisotropy ; Quality of Life ; Neuroimaging
Language	English
Publishing date	2023-12-28
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ISSN	2694-0604
ISSN (online)	2694-0604
DOI	10.1109/EMBC40787.2023.10340468
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Article ; Online: Polymorphisms in SLC44A1 are associated with cognitive improvement in children diagnosed with fetal alcohol spectrum disorder: an exploratory study of oral choline supplementation.

Smith, Susan M / Virdee, Manjot S / Eckerle, Judith K / Sandness, Kristin E / Georgieff, Michael K / Boys, Christopher J / Zeisel, Steven H / Wozniak, Jeffrey R

The American journal of clinical nutrition

2023 Volume 114, Issue 2, Page(s) 617–627

Abstract: Background: The essential nutrient choline provides one-carbon units for metabolite synthesis and epigenetic regulation in tissues including brain. Dietary choline intake is often inadequate, and higher intakes are associated with improved cognitive ... ...

Abstract	Background: The essential nutrient choline provides one-carbon units for metabolite synthesis and epigenetic regulation in tissues including brain. Dietary choline intake is often inadequate, and higher intakes are associated with improved cognitive function. Objective: Choline supplements confer cognitive improvement for those diagnosed with fetal alcohol spectrum disorder (FASD), a common set of neurodevelopmental impairments; however, the effect sizes have been modest. In this retrospective analysis, we report that genetic polymorphisms affecting choline utilization are associated with cognitive improvement following choline intervention. Methods: Fifty-two children from the upper midwestern United States and diagnosed with FASD, ages 2-5 y, were randomly assigned to receive choline (500 mg/d; n = 26) or placebo (n = 26) for 9 mo, and were genotyped for 384 choline-related single nucleotide polymorphisms (SNPs). Memory and cognition were assessed at enrollment, study terminus, and at 4-y follow-up for a subset. Results: When stratified by intervention (choline vs. placebo), 14-16 SNPs within the cellular choline transporter gene solute carrier family 44 member 1 (SLC44A1) were significantly associated with performance in an elicited imitation sequential memory task, wherein the effect alleles were associated with the greatest pre-/postintervention improvement. Of these, rs3199966 is a structural variant (S644A) and rs2771040 is a single-nucleotide variant within the 3' untranslated region of the plasma membrane isoform. An additive genetic model best explained the genotype associations. Lesser associations were observed for cognitive outcome and polymorphisms in flavin monooxygenase-3 (FMO3), methylenetetrahydrofolate dehydrogenase-1 (MTHFD1), fatty acid desaturase-2 (FADS2), and adiponectin receptor 1 (ADIPOR1). Conclusions: These SLC44A1 variants were previously associated with greater vulnerability to choline deficiency. Our data potentially support the use of choline supplements to improve cognitive function in individuals diagnosed with FASD who carry these effect alleles. Although these findings require replication in both retrospective and prospective confirmatory trials, they emphasize the need to incorporate similar genetic analyses of choline-related polymorphisms in other FASD-choline trials, and to test for similar associations within the general FASD population. This trial was registered at www.clinicaltrials.gov as NCT01149538.
MeSH term(s)	Administration, Oral ; Antigens, CD/genetics ; Antigens, CD/metabolism ; Child, Preschool ; Choline/administration & dosage ; Choline/pharmacology ; Cognition ; Dietary Supplements ; Female ; Fetal Alcohol Spectrum Disorders/drug therapy ; Fetal Alcohol Spectrum Disorders/genetics ; Fetal Alcohol Spectrum Disorders/pathology ; Gene Expression Regulation/drug effects ; Genotype ; Humans ; Male ; Organic Cation Transport Proteins/genetics ; Organic Cation Transport Proteins/metabolism ; Polymorphism, Single Nucleotide ; Retrospective Studies
Chemical Substances	Antigens, CD ; Organic Cation Transport Proteins ; SLC44A1 protein, human ; Choline (N91BDP6H0X)
Language	English
Publishing date	2023-01-10
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	280048-2
ISSN	1938-3207 ; 0002-9165
ISSN (online)	1938-3207
ISSN	0002-9165
DOI	10.1093/ajcn/nqab081
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Article ; Online: Clinical presentation, diagnosis, and management of fetal alcohol spectrum disorder.

Wozniak, Jeffrey R / Riley, Edward P / Charness, Michael E

The Lancet. Neurology

2019 Volume 18, Issue 8, Page(s) 760–770

Abstract: Although prenatal alcohol exposure causes craniofacial anomalies, growth retardation, neurological abnormalities, cognitive impairment, and birth defects, fetal alcohol spectrum disorder is underdiagnosed. Global prevalence of fetal alcohol spectrum ... ...

Abstract	Although prenatal alcohol exposure causes craniofacial anomalies, growth retardation, neurological abnormalities, cognitive impairment, and birth defects, fetal alcohol spectrum disorder is underdiagnosed. Global prevalence of fetal alcohol spectrum disorder is 0·77%, with a higher prevalence of 2-5% in Europe and North America, highlighting the need for increased diagnosis and treatment. However, diagnosis remains challenging because of the poor reliability of self-reported maternal drinking histories, an absence of sensitive biomarkers, and the infrequency of diagnostic dysmorphic facial features among individuals with fetal alcohol spectrum disorder. Different diagnostic systems and disagreements over criteria have slowed progress in the diagnosis and management of the disorder. Neuroimaging shows abnormalities in brain structure, cortical development, white matter microstructure, and functional connectivity in individuals with fetal alcohol spectrum disorder. These abnormalities modify developmental trajectories and are associated with deficits in cognition, executive function, memory, vision, hearing, motor skills, behaviour, and social adaptation. Promising trials of nutritional interventions and cognitive rehabilitation therapies are underway, with the aim of treating cognitive deficits in fetal alcohol spectrum disorders.
MeSH term(s)	Cognitive Dysfunction/diagnosis ; Cognitive Dysfunction/epidemiology ; Cognitive Dysfunction/therapy ; Disease Management ; Female ; Fetal Alcohol Spectrum Disorders/diagnosis ; Fetal Alcohol Spectrum Disorders/epidemiology ; Fetal Alcohol Spectrum Disorders/therapy ; Humans ; Pregnancy ; Prevalence
Language	English
Publishing date	2019-05-31
Publishing country	England
Document type	Journal Article ; Review
ZDB-ID	2081241-3
ISSN	1474-4465 ; 1474-4422
ISSN (online)	1474-4465
ISSN	1474-4422
DOI	10.1016/S1474-4422(19)30150-4
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Article: Neurophysiological correlates of memory change in children with fetal alcohol spectrum disorders treated with choline.

Fuglestad, Anita J / Miller, Neely C / Fink, Birgit A / Boys, Christopher J / Eckerle, Judith K / Georgieff, Michael K / Wozniak, Jeffrey R

Frontiers in psychology

2022 Volume 13, Page(s) 936019

Abstract: Background: Prenatal and early postnatal choline supplementation reduces cognitive and behavioral deficits in animal models of Fetal Alcohol Spectrum Disorder (FASD). In a previously published 9-month clinical trial of choline supplementation in ... ...

Abstract	Background: Prenatal and early postnatal choline supplementation reduces cognitive and behavioral deficits in animal models of Fetal Alcohol Spectrum Disorder (FASD). In a previously published 9-month clinical trial of choline supplementation in children with FASD, we reported that postnatal choline was associated with improved performance on a hippocampal-dependent recognition memory task. The current paper describes the neurophysiological correlates of that memory performance for trial completers. Methods: Children with FASD ( Results: Delayed recall on EI was correlated with two ERP components commonly associated with recognition memory in young children: middle latency negative component (Nc amplitude; range: Conclusion: Although the small sample size limits the ability to draw clear conclusions about the treatment effect of choline on ERP, the results suggest a relationship between memory performance and underlying neurophysiological status in FASD. This trial was registered.
Language	English
Publishing date	2022-09-26
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2563826-9
ISSN	1664-1078
ISSN	1664-1078
DOI	10.3389/fpsyg.2022.936019
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Article ; Online: Toward Developing Robust Myotonic Dystrophy Brain Biomarkers using White Matter Tract Profiles Sub-Band Energy and A Framework of Ensemble Predictive Learning.

Kamali, Tahereh / Parker, Dana / Day, John W / Sampson, Jacinda / Deutsch, Gayle K / Wozniak, Jeffrey R

Annual International Conference of the IEEE Engineering in Medicine and Biology Society. IEEE Engineering in Medicine and Biology Society. Annual International Conference

2021 Volume 2021, Page(s) 3838–3841

Abstract: The myotonic dystrophies (DM1 and DM2) are dominantly inherited disorders that cause pathological changes throughout the body and the brain. DM patients have difficulties with memory, attention, executive functioning, social cognition, and visuospatial ... ...

Abstract	The myotonic dystrophies (DM1 and DM2) are dominantly inherited disorders that cause pathological changes throughout the body and the brain. DM patients have difficulties with memory, attention, executive functioning, social cognition, and visuospatial function. Quantifying and understanding diffusion measures along main brain white matter fiber tracts offer a unique opportunity to reveal new insights into DM development and characterization. In this work, a novel supervised system is proposed, which is based on Tract Profiles sub-band energy information. The proposed system utilizes a Bayesian stacked random forest to diagnose, characterize, and predict DM clinical outcomes. The evaluation data consists of fractional anisotropies calculated for twelve major white matter tracts of 96 healthy controls and 62 DM patients. The proposed system discriminates DM vs. control with 86% accuracy, which is significantly higher than previous works. Additionally, it discovered DM brain biomarkers that are accurate and robust and will be helpful in planning clinical trials and monitoring clinical performance.
MeSH term(s)	Bayes Theorem ; Biomarkers ; Brain/diagnostic imaging ; Humans ; Myotonic Dystrophy ; White Matter/diagnostic imaging
Chemical Substances	Biomarkers
Language	English
Publishing date	2021-12-05
Publishing country	United States
Document type	Journal Article
ISSN	2694-0604
ISSN (online)	2694-0604
DOI	10.1109/EMBC46164.2021.9630544
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Article ; Online: Cognitive Impairment Analysis of Myotonic Dystrophy via Weakly Supervised Classification of Neuropsychological Features.

Kamali, Tahereh / Deutsch, Gayle K / Hagerman, Katharine A / Parker, Dana / Day, John W / Sampson, Jacinda B / Wozniak, Jeffrey R

Annual International Conference of the IEEE Engineering in Medicine and Biology Society. IEEE Engineering in Medicine and Biology Society. Annual International Conference

2022 Volume 2022, Page(s) 4377–4382

Abstract: The myotonic dystrophies (DM1 and DM2) are dominantly inherited disorders that cause pathological changes throughout the body. Many individuals with DM experience cognitive, behavioral and other functional central nervous system effects that impact their ...

Abstract	The myotonic dystrophies (DM1 and DM2) are dominantly inherited disorders that cause pathological changes throughout the body. Many individuals with DM experience cognitive, behavioral and other functional central nervous system effects that impact their quality of life. The extent of psychological impairment that will develop in each patient is variable and unpredictable. Hence, it is difficult to get strong supervision information like fully ground truth labels for all cognitive involvement patterns. This study is to assess cognitive involvement among healthy controls and patients with DM. The DM cognitive impairment pattern observation is modeled in a weakly supervised setting and supervision information is used to transform the input feature space to a more discriminative representation suitable for pattern observation. This study incorporated results from 59 adults with DM and 92 control subjects. The developed system categorized the neuropsychological testing data into five cognitive clusters. The quality of the obtained clustering solution was assessed using an internal validity metric. The experimental results show that the proposed algorithm can discover interesting patterns and useful information from neuropsychological data, which will be be crucial in planning clinical trials and monitoring clinical performance. The proposed system resulted in an average classification accuracy of 88%, which is very promising considering the unique challenges present in this population.
MeSH term(s)	Adult ; Cluster Analysis ; Cognitive Dysfunction/diagnosis ; Humans ; Myotonic Dystrophy/diagnosis ; Myotonic Dystrophy/pathology ; Neuropsychological Tests ; Quality of Life
Language	English
Publishing date	2022-09-10
Publishing country	United States
Document type	Journal Article
ISSN	2694-0604
ISSN (online)	2694-0604
DOI	10.1109/EMBC48229.2022.9871626
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Article ; Online: Prenatal and Postnatal Choline Supplementation in Fetal Alcohol Spectrum Disorder.

Ernst, Abigail M / Gimbel, Blake A / de Water, Erik / Eckerle, Judith K / Radke, Joshua P / Georgieff, Michael K / Wozniak, Jeffrey R

Nutrients

2022 Volume 14, Issue 3

Abstract: Fetal alcohol spectrum disorder (FASD) is common and represents a significant public health burden, yet very few interventions have been tested in FASD. Cognitive deficits are core features of FASD, ranging from broad intellectual impairment to selective ...

Abstract	Fetal alcohol spectrum disorder (FASD) is common and represents a significant public health burden, yet very few interventions have been tested in FASD. Cognitive deficits are core features of FASD, ranging from broad intellectual impairment to selective problems in attention, executive functioning, memory, visual-perceptual/motor skills, social cognition, and academics. One potential intervention for the cognitive impairments associated with FASD is the essential nutrient choline, which is known to have numerous direct effects on brain and cognition in both typical and atypical development. We provide a summary of the literature supporting the use of choline as a neurodevelopmental intervention in those affected by prenatal alcohol. We first discuss how alcohol interferes with normal brain development. We then provide a comprehensive overview of the nutrient choline and discuss its role in typical brain development and its application in the optimization of brain development following early insult. Next, we review the preclinical literature that provides evidence of choline's potential as an intervention following alcohol exposure. Then, we review a handful of existing human studies of choline supplementation in FASD. Lastly, we conclude with a review of practical considerations in choline supplementation, including dose, formulation, and feasibility in children.
MeSH term(s)	Child ; Choline ; Dietary Supplements ; Ethanol/adverse effects ; Female ; Fetal Alcohol Spectrum Disorders/prevention & control ; Fetal Alcohol Spectrum Disorders/psychology ; Humans ; Pregnancy ; Vitamins
Chemical Substances	Vitamins ; Ethanol (3K9958V90M) ; Choline (N91BDP6H0X)
Language	English
Publishing date	2022-02-06
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2518386-2
ISSN	2072-6643 ; 2072-6643
ISSN (online)	2072-6643
ISSN	2072-6643
DOI	10.3390/nu14030688
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Article ; Online: Normative Magnetic Resonance Imaging Data Increase the Sensitivity to Brain Volume Abnormalities in the Classification of Fetal Alcohol Spectrum Disorder.

Gimbel, Blake A / Roediger, Donovan J / Ernst, Abigail M / Anthony, Mary E / Mueller, Bryon A / de Water, Erik / Rockhold, Madeline N / Wozniak, Jeffrey R

The Journal of pediatrics

2023 Volume 266, Page(s) 113868

Abstract: Objective: To evaluate the use of a large magnetic resonance imaging (MRI) normative dataset to quantify structural brain anomalies that may improve diagnostic sensitivity for atypical brain volume in youth with fetal alcohol spectrum disorder (FASD).!## ...

Abstract	Objective: To evaluate the use of a large magnetic resonance imaging (MRI) normative dataset to quantify structural brain anomalies that may improve diagnostic sensitivity for atypical brain volume in youth with fetal alcohol spectrum disorder (FASD). Study design: Participants included 48 children with prenatal alcohol exposure (PAE) and 43 controls, ages 8-17 years, from the longitudinal Collaborative Initiative on FASD s. Recently published lifespan brain charts were used to quantify participants' (per)centile for brain volumes (cortical and subcortical gray matter and cortical white matter), providing an index of (dis)similarity to typically developing individuals of the same age and sex. Results: Participants with PAE demonstrated lower mean centile scores compared with controls. Participants with PAE and scores ≤ 10 Conclusion: Age- and sex-adjusted brain volumes based on a large normative dataset may be useful predictors of functional outcomes and may identify a greater number of individuals with FASD than the currently used criterion of OFC.
MeSH term(s)	Pregnancy ; Child ; Adolescent ; Female ; Humans ; Fetal Alcohol Spectrum Disorders/diagnostic imaging ; Prenatal Exposure Delayed Effects ; Brain Diseases ; Brain/diagnostic imaging ; Magnetic Resonance Imaging
Language	English
Publishing date	2023-12-06
Publishing country	United States
Document type	Journal Article
ZDB-ID	3102-1
ISSN	1097-6833 ; 0022-3476
ISSN (online)	1097-6833
ISSN	0022-3476
DOI	10.1016/j.jpeds.2023.113868
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Article: Atypical developmental trajectories of white matter microstructure in prenatal alcohol exposure: Preliminary evidence from neurite orientation dispersion and density imaging.

Gimbel, Blake A / Roediger, Donovan J / Ernst, Abigail M / Anthony, Mary E / de Water, Erik / Rockhold, Madeline N / Mueller, Bryon A / Mattson, Sarah N / Jones, Kenneth L / Riley, Edward P / Lim, Kelvin O / Wozniak, Jeffrey R

Frontiers in neuroscience

2023 Volume 17, Page(s) 1172010

Abstract: Introduction: Fetal alcohol spectrum disorder (FASD), a life-long condition resulting from prenatal alcohol exposure (PAE), is associated with structural brain anomalies and neurobehavioral differences. Evidence from longitudinal neuroimaging suggest ... ...

Abstract	Introduction: Fetal alcohol spectrum disorder (FASD), a life-long condition resulting from prenatal alcohol exposure (PAE), is associated with structural brain anomalies and neurobehavioral differences. Evidence from longitudinal neuroimaging suggest trajectories of white matter microstructure maturation are atypical in PAE. We aimed to further characterize longitudinal trajectories of developmental white matter microstructure change in children and adolescents with PAE compared to typically-developing Controls using diffusion-weighted Neurite Orientation Dispersion and Density Imaging (NODDI). Materials and methods: Participants: Youth with PAE ( Results: While linear trajectories suggested similar overall microstructural integrity in PAE and Controls, analyses of symmetrized percent change (SPC) indicated group differences in the timing and magnitude of age-related increases in ODI (indexing the bending and fanning of axons) in the central region of the CC, with PAE participants demonstrating atypically steep increases in dispersion with age compared to Controls. Participants with PAE also demonstrated greater increases in ODI in the mid posterior CC (trend-level group difference). In addition, SPC in ODI and NDI was differentially correlated with executive function performance for PAE participants and Controls, suggesting an atypical relationship between white matter microstructure maturation and cognitive function in PAE. Discussion: Preliminary findings suggest subtle atypicality in the timing and magnitude of age-related white matter microstructure maturation in PAE compared to typically-developing Controls. These findings add to the existing literature on neurodevelopmental trajectories in PAE and suggest that advanced biophysical diffusion modeling (NODDI) may be sensitive to biologically-meaningful microstructural changes in the CC that are disrupted by PAE. Findings of atypical brain maturation-behavior relationships in PAE highlight the need for further study. Further longitudinal research aimed at characterizing white matter neurodevelopmental trajectories in PAE will be important.
Language	English
Publishing date	2023-04-24
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.2023.1172010
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