Social vulnerability and surgery outcomes: a cross-sectional analysis
(2024) BMC Public Health, 24 (1), art. no. 1907, .
Abdelhack, M.a c , Tripathi, S.a , Chen, Y.b , Avidan, M.S.a , King, C.R.a
a Department of Anesthesiology, Washington University School of Medicine, St. Louis, MO, United States
b Department of Computer Science, Washington University in St. Louis, St. Louis, MO, United States
c Krembil Centre for Neuroinformatics, Centre for Addiction and Mental Health, Toronto, ON, Canada
Abstract
Background: Post-operative complications present a challenge to the healthcare system due to the high unpredictability of their incidence. Socioeconomic conditions have been established as social determinants of health. However, their contribution relating to postoperative complications is still unclear as it can be heterogeneous based on community, type of surgical services, and sex and gender. Uncovering these relations can enable improved public health policy to reduce such complications. Methods: In this study, we conducted a large population cross-sectional analysis of social vulnerability and the odds of various post-surgical complications. We collected electronic health records data from over 50,000 surgeries that happened between 2012 and 2018 at a quaternary health center in St. Louis, Missouri, United States and the corresponding zip code of the patients. We built statistical logistic regression models of postsurgical complications with the social vulnerability index of the tract consisting of the zip codes of the patient as the independent variable along with sex and race interaction. Results: Our sample from the St. Louis area exhibited high variance in social vulnerability with notable rapid increase in vulnerability from the south west to the north of the Mississippi river indicating high levels of inequality. Our sample had more females than males, and females had slightly higher social vulnerability index. Postoperative complication incidence ranged from 0.75% to 41% with lower incidence rate among females. We found that social vulnerability was associated with abnormal heart rhythm with socioeconomic status and housing status being the main association factors. We also found associations of the interaction of social vulnerability and female sex with an increase in odds of heart attack and surgical wound infection. Those associations disappeared when controlling for general health and comorbidities. Conclusions: Our results indicate that social vulnerability measures such as socioeconomic status and housing conditions could affect postsurgical outcomes through preoperative health. This suggests that the domains of preventive medicine and public health should place social vulnerability as a priority to achieve better health outcomes of surgical interventions. © The Author(s) 2024.
Author Keywords
Housing status; Postsurgical complications; Sex interaction; Social vulnerability; Socioeconomic status
Document Type: Article
Publication Stage: Final
Source: Scopus
Papillary tumor of the pineal region: analysis of DNA methylation profiles and clinical outcomes in 76 cases
(2024) Acta Neuropathologica Communications, 12 (1), art. no. 117, .
Wu, Z.a , Dazelle, K.a , Abdullaev, Z.a , Chung, H.-J.a , Dahiya, S.b , Wood, M.c , Lee, H.d , Lucas, C.-H.G.e , Mao, Q.f , Robinson, L.f , Fernandes, I.g , McCord, M.h , Pytel, P.i , Conway, K.S.j , Yoda, R.k , Eschbacher, J.M.l , Maher, O.M.m , Hasselblatt, M.n , Mobley, B.C.o , Raisanen, J.p , Hatanpaa, K.J.p , Byers, J.q , Lehman, N.L.r , Cimino, P.J.s , Pratt, D.a , Quezado, M.a , Aldape, K.a
a Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, 10 Center Dr., Room 2S235, Bethesda, MD 20892, United States
b Division of Neuropathology, Washington University, St. Louis, MO, United States
c Department of Pathology and Laboratory Medicine, Oregon Health & amp; Science University, Portland, OR, United States
d Neuropathology Division, Department of Pathology, University of California Davis, Sacramento, CA, United States
e Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, United States
f Department of Pathology, Primary Children’s Hospital, Salt Lake City, UT, United States
g Laboratorio Bacchi, São Paulo, Brazil
h Department of Pathology, Northwestern Memorial Hospital, Chicago, IL, United States
i Department of Pathology, University of Chicago, Chicago, IL, United States
j Department of Pathology, University of Michigan Medical Center, Ann Arbor, MI, United States
k Department of Pathology, University of Washington, Seattle, WA, United States
l Department of Neuropathology, Barrow Neurological Institute, St. Joseph’s Hospital and Medical Center, Phoenix, AZ, United States
m Division of Pediatric Neuro -Oncology, Pediatric Hematology and Oncology, Kidz Medical Services, Nicklaus Children’s Hospital, Miami, FL, United States
n Institute of Neuropathology, University Hospital Münster, Münster, Germany
o Department of Pathology, Microbiology and Immunology, Vanderbilt University, Nashville, TN, United States
p Division of Neuropathology, University of Texas Southwestern Medical Center, Dallas, TX, United States
q Department of Laboratory Medicine, University of California-San Francisco, San Francisco, CA, United States
r Department of Pathology, Baylor College of Medicine, Baylor Scott & amp; White Medical Center, Temple, TX, United States
s Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, United States
Abstract
Papillary tumor of the pineal region (PTPR) is an uncommon tumor of the pineal region with distinctive histopathologic and molecular characteristics. Experience is limited with respect to its molecular heterogeneity and clinical characteristics. Here, we describe 39 new cases and combine these with 37 previously published cases for a cohort of 76 PTPR’s, all confirmed by methylation profiling. As previously reported, two main methylation groups were identified (PTPR-A and PTPR-B). In our analysis we extended the subtyping into three subtypes: PTPR-A, PTPR-B1 and PTPR-B2 supported by DNA methylation profile and genomic copy number variations. Frequent loss of chromosome 3 or 14 was found in PTPR-B1 tumors but not in PTPR-B2. Examination of clinical outcome showed that nearly half (14/30, 47%) of examined patients experienced tumor progression with significant difference among the subtypes (p value = 0.046). Our analysis extends the understanding of this uncommon but distinct neuroepithelial tumor by describing its molecular heterogeneity and clinical outcomes, including its tendency towards tumor recurrence. © This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply 2024.
Document Type: Article
Publication Stage: Final
Source: Scopus
Early depletion of gut microbiota shape oligodendrocyte response after traumatic brain injury
(2024) Journal of Neuroinflammation, 21 (1), art. no. 171, .
Shumilov, K.a , Ni, A.b , Garcia-Bonilla, M.a , Celorrio, M.b , Friess, S.H.b c
a Department of Neurosurgery, Virginia Commonwealth University, Richmond, VA, United States
b Department of Pediatrics, Washington University in St. Louis School of Medicine, St. Louis, MO, United States
c Division of Critical Care Medicine, Department of Pediatrics, Washington University in St. Louis School of Medicine and St. Louis Children’s Hospital, Campus Box 8028, 3rd Fl MPRB 660 S. Euclid Avenue, St. Louis, MO 63110, United States
Abstract
White matter injury (WMI) is thought to be a major contributor to long-term cognitive dysfunctions after traumatic brain injury (TBI). This damage occurs partly due to apoptotic death of oligodendrocyte lineage cells (OLCs) after the injury, triggered directly by the trauma or in response to degenerating axons. Recent research suggests that the gut microbiota modulates the inflammatory response through the regulation of peripheral immune cell infiltration after TBI. Additionally, T-cells directly impact OLCs differentiation and proliferation. Therefore, we hypothesized that the gut microbiota plays a critical role in regulating the OLC response to WMI influencing T-cells differentiation and activation. Gut microbial depletion early after TBI chronically reduced re-myelination, acutely decreased OLCs proliferation, and was associated with increased myelin debris accumulation. Surprisingly, the absence of T-cells in gut microbiota depleted mice restored OLC proliferation and remyelination after TBI. OLCs co-cultured with T-cells derived from gut microbiota depleted mice resulted in impaired proliferation and increased expression of MHC-II compared with T cells from control-injured mice. Furthermore, MHC-II expression in OLCs appears to be linked to impaired proliferation under gut microbiota depletion and TBI conditions. Collectively our data indicates that depletion of the gut microbiota after TBI impaired remyelination, reduced OLCs proliferation with concomitantly increased OLC MHCII expression, and required the presence of T cells. This data suggests that T cells are an important mechanistic link by which the gut microbiota modulate the oligodendrocyte response and white matter recovery after TBI. © The Author(s) 2024.
Author Keywords
Gut microbiota; Neuroinflammation; Oligodendrocytes; Remyelination; T cells; Traumatic brain injury; White matter injury
Document Type: Article
Publication Stage: Final
Source: Scopus
Mate selection and current trends in the prevalence of autism
(2024) Molecular Autism, 15 (1), art. no. 29, .
Forsen, E.a , Marrus, N.b , Joyce, J.c , Zhang, Y.b , Constantino, J.N.d
a Washington University in St. Louis, St. Louis, MO, United States
b Department of Psychiatry, Washington University in St. Louis, St. Louis, MO, United States
c Emory University, Atlanta, GA 30322, United States
d Department of Behavioral and Mental Health, Children’s Healthcare of Atlanta, Atlanta, GA 30322, United States
Abstract
Background: According to the most recent U.S. CDC surveillance data, the rise in prevalence of childhood autism spectrum disorder among minority children has begun to outpace that of non-Hispanic white children. Since prior research has identified possible differences in the extent of mate selection for autistic traits across families of different ethnicity, this study examined variation in autism related traits in contemporaneous, epidemiologically ascertained samples of spousal pairs representing Hispanic and non-Hispanic white populations. The purpose was to determine whether discrepancies by ethnicity could contribute to differential increases in prevalence in the current generation of young children. Methods: Birth records were used to identify all twin pairs born between 2011 and 2013 in California and Missouri. Families were selected at random from pools of English-speaking Hispanic families in California and Non-Hispanic White families in Missouri. Autistic trait data of parents was obtained using the Adult Report Form of the Social Responsiveness Scale (SRS-2). Results: We did not identify a statistically significant difference in the degree of mate selection for autism related traits between Hispanic and non-Hispanic white spousal pairs. However, the degree of spousal correlation observed in this recent cohort was pronounced (on the order of ICC 0.45) and exceeded that typically reported in prior research (on the order of 0.30), surpassing also widely reported estimates for sibling correlation (also on the order of 0.30). Limitations: The sample did not allow for a direct appraisal of change in the magnitude of spousal correlation over time and the ascertainments of trait burden were derived from spouse report. Conclusion: Across two epidemiologically ascertained samples of spousal pairs representing Hispanic and non-Hispanic white families across two U.S. states (respectively, California and Missouri), the extent of autism-related trait co-variation for parents of the current generation of young children is substantial and exceeds correlations typically observed for siblings. Given the heritability of these traits and their relation to autism risk, societal trends in the degree of mate selection for these traits should be considered as possible contributors to subtle increases in the incidence of autism over time and across generations. © The Author(s) 2024.
Author Keywords
Assortative mating; Autism; Autism prevalence; Mate selection; Racial and ethnic minorities
Document Type: Article
Publication Stage: Final
Source: Scopus
Genetic and multi-omic resources for Alzheimer disease and related dementia from the Knight Alzheimer Disease Research Center
(2024) Scientific Data, 11 (1), art. no. 768, .
Fernandez, M.V.a b c , Liu, M.a b , Beric, A.a b , Johnson, M.a b , Cetin, A.a b , Patel, M.a b , Budde, J.a b , Kohlfeld, P.a b , Bergmann, K.a b , Lowery, J.a b , Flynn, A.a b , Brock, W.a b , Sanchez Montejo, B.a b , Gentsch, J.a b , Sykora, N.a b , Norton, J.a b , Gentsch, J.a b , Valdez, O.a b , Gorijala, P.a b , Sanford, J.a b , Sun, Y.a b , Wang, C.a b , Western, D.a b , Timsina, J.a b , Mangetti Goncalves, T.d , Do, A.N.a b e , Sung, Y.J.a b , Zhao, G.d f g , Morris, J.C.f h , Moulder, K.f h , Holtzman, D.M.f h i , Bateman, R.J.f h i j , Karch, C.a h i j , Hassenstab, J.f h , Xiong, C.e f h j , Schindler, S.E.f h , Balls-Berry, J.f h , Benzinger, T.L.S.f h j k , Perrin, R.J.g h j , Denny, A.f h , Snider, B.J.f h i , Stark, S.L.h l , Ibanez, L.a b f j , Cruchaga, C.a b d f h i j
a Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, United States
b NeuroGenomics and Informatics Center, Washington University School of Medicine, St. Louis, MO 63110, United States
c Research Center and Memory Clinic, ACE Alzheimer Center, Barcelona, Spain
d Department of Genetics, Washington University School of Medicine, St. Louis, MO, United States
e Division of Biostatistics, Washington University School of Medicine, St. Louis, MO 63110, United States
f Department of Neurology, Washington University School of Medicine, St. Louis, MO 63110, United States
g Pathology and Immunology Department, Washington University School of Medicine, St. Louis, MO 63110, United States
h Knight Alzheimer Disease Research Center, Washington University School of Medicine, St. Louis, MO, United States
i Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO, United States
j Dominantly Inherited Alzheimer Disease Network (DIAN), St. Louis, United States
k Radiology Department, Washington University School of Medicine, St. Louis, MO 63110, United States
l Occupational Therapy, Neurology and Social Work, St. Louis, United States
Abstract
The Knight-Alzheimer Disease Research Center (Knight-ADRC) at Washington University in St. Louis has pioneered and led worldwide seminal studies that have expanded our clinical, social, pathological, and molecular understanding of Alzheimer Disease. Over more than 40 years, research volunteers have been recruited to participate in cognitive, neuropsychologic, imaging, fluid biomarkers, genomic and multi-omic studies. Tissue and longitudinal data collected to foster, facilitate, and support research on dementia and aging. The Genetics and high throughput -omics core (GHTO) have collected of more than 26,000 biological samples from 6,625 Knight-ADRC participants. Samples available include longitudinal DNA, RNA, non-fasted plasma, cerebrospinal fluid pellets, and peripheral blood mononuclear cells. The GHTO has performed deep molecular profiling (genomic, transcriptomic, epigenomic, proteomic, and metabolomic) from large number of brain (n = 2,117), CSF (n = 2,012) and blood/plasma (n = 8,265) samples with the goal of identifying novel risk and protective variants, identify novel molecular biomarkers and causal and druggable targets. Overall, the resources available at GHTO support the increase of our understanding of Alzheimer Disease. © The Author(s) 2024.
Document Type: Data Paper
Publication Stage: Final
Source: Scopus
Apparent Diffusion Coefficient (ADC) Differentiates Retinoblastoma from Coats Disease on MRI
(2024) American Journal of Ophthalmology, 267, pp. 8-12.
ZHANG, W.X.a b , SHIMONY, J.S.c , LUEDER, G.T.b , REYNOLDS, M.M.b
a University of Missouri School of Medicine (W.X.Z.), Columbia, MO, United States
b Department of Ophthalmology and Visual Sciences, Washington University School of Medicine (W.X.Z., G.T.L., M.M.R.), St. Louis, MO, United States
c Mallinckrodt Institute of Radiology, Washington University School of Medicine (J.S.S.), St. Louis, MO, United States
Abstract
PURPOSE: Coats’ disease can be difficult to differentiate from retinoblastoma. While MR imaging of retinoblastoma and Coats’ disease have been examined for differentiating features such as eye size, vitreous seeding, and shape of retinal detachment, there is a lack of data on apparent diffusion coefficient (ADC). ADC is a measure of the diffusion (of water molecules) within tissue, and is commonly clinically calculated using MRI. DESIGN: Retrospective cross-sectional study. METHODS: Patient or study population: Children < 18 diagnosed with Coats disease or Retinoblastoma between January 1, 2018 and January 8, 2022 who had MRI imaging that was reviewable. Main outcome measure: Apparent diffusion coefficient (ADC) of the intraocular lesion. Retrospective brain MRIs were obtained from records of 5 eyes of 5 Coats’ patients and 29 eyes of 23 patients with retinoblastoma. All MRIs were obtained prior to treatment. The eyedropper tool in Epic’s default viewer (Ambra DICOM) was used to measure the ADC of five to eight randomly sampled points within the eye lesions seen on MRI. Average ADC was calculated for each affected eye. Internal reliability was confirmed by re-measuring mean ADC for a random sample of patients masked to their diagnosis and prior measurements. T-test was used to determine if ADC values differ between groups. RESULTS: The mean ADC for retinoblastoma patients (442 +/- 210 mm2/s) differed significantly from the mean for Coats’ patients (1364 +/- 309 mm2/s), (P < .001). T-test between baseline and repeat measurements was not significantly different. Since ADC values can differ between different scanners and DW MRI pulse sequences, an ADC threshold may be difficult to generalize across institutes, in our data set a threshold of 900 mm2/s was useful in separating the two diagnoses with a high degree of accuracy. CONCLUSIONS: Clinical features of retinoblastoma and Coats’ disease often resemble each other and can lead to misdiagnosis. Since ADCs are derived from diffusion-weighted MRI as an objective parameter, it has the potential to aid in establishing or confirming the diagnosis when retinoblastoma and/or Coats’ disease are suspected. © 2024 Elsevier Inc.
Document Type: Article
Publication Stage: Final
Source: Scopus
Sex moderates the effect of anhedonia on parietal alpha asymmetry
(2024) Journal of Psychiatric Research, 177, pp. 97-101.
Gupta, R.S.a , Light, G.A.b c , Simmons, A.N.b d , Harlé, K.M.b d , Stout, D.M.b d
a Department of Psychological & Brain Sciences, Washington University in St. Louis, St. Louis, MO 63130, United States
b Department of Psychiatry, University of California San Diego, La JollaCA 92093, United States
c Desert Pacific Mental Illness Research Education and Clinical Center, La JollaCA, United States
d Center of Excellence for Stress and Mental Health, VA San Diego Healthcare System, San Diego, CA 92161, United States
Abstract
Anhedonia, a transdiagnostic symptom present in many neuropsychiatric disorders, differs in males and females. Parietal EEG alpha asymmetry is associated with reduced arousal and low positive emotionality, and is, therefore, a promising neurophysiologic biomarker of anhedonia. To date, however, no prior studies have determined whether this measure captures sex differences in anhedonic expression. This preliminary study (N = 36) investigated whether anhedonia severity is associated with EEG resting-state parietal alpha asymmetry in adults and whether sex moderates this relationship. Results showed that there was a significant moderating effect of sex such that, only for females, higher levels of anhedonia were associated with increased parietal alpha asymmetry. These findings suggest that parietal alpha asymmetry is a promising biomarker of anhedonia severity in female adults and reinforces the need to account for sex differences in future research. © 2024 Elsevier Ltd
Author Keywords
Anhedonia; EEG; Parietal alpha asymmetry; Sexual dimorphism
Document Type: Article
Publication Stage: Final
Source: Scopus
Structural Changes in Brain White Matter Tracts Associated With Overactive Bladder Revealed by Diffusion Tensor Magnetic Resonance Imaging: Findings From a Symptoms of Lower Urinary Tract Dysfunction Research Network Cross-Sectional Case-Control Study
(2024) The Journal of Urology, 212 (2), pp. 351-361.
Lai, H.H.a , Rutlin, J.b , Smith, A.R.c , Helmuth, M.E.c , Hokanson, J.A.d , Yang, C.C.e , Clemens, J.Q.f , Magnotta, V.A.g , Bretschneider, C.E.h , Kenton, K.i , DeLancey, J.O.L.j , John, K.h , Kirkali, Z.k , Shimony, J.S.b
a Division of Urologic Surgery, Departments of Surgery and Anesthesiology, Washington University School of Medicine, St Louis, MO, United States
b Departments of Radiology, Mallinckrodt Institute of Radiology, Washington University School of Medicine, St Louis, MO, United States
c Arbor Research Collaborative for Health, Ann Arbor, MI, United States
d Department of Biomedical Engineering, Medical College of Wisconsin, Milwaukee, WI, United States
e Department of Urology, University of Washington, Seattle, WA, United States
f Department of Urology, University of Michigan, Ann Arbor, MI, United States
g Department of Radiology, University of Iowa, Iowa City, IA, United States
h Department of Obstetrics and Gynecology, Northwestern University, Chicago, IL, United States
i Department of Obstetrics and Gynecology, University of Chicago, Chicago, IL, United States
j Department of Obstetrics and Gynecology, University of Michigan, Ann Arbor, MI, United States
k National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, Liberia
Abstract
PURPOSE: Our objective was to investigate structural changes in brain white matter tracts using diffusion tensor imaging (DTI) in patients with overactive bladder (OAB). MATERIALS AND METHODS: Treatment-seeking OAB patients and matched controls enrolled in the cross-sectional case-control LURN (Symptoms of Lower Urinary Tract Dysfunction Research Network) Neuroimaging Study received a brain DTI scan. Microstructural integrity of brain white matter was assessed using fractional anisotropy (FA) and mean diffusivity. OAB and urgency urinary incontinence (UUI) symptoms were assessed using the OAB Questionnaire Short-Form and International Consultation on Incontinence Questionnaire-Urinary Incontinence. The Lower Urinary Tract Symptoms Tool UUI questions and responses were correlated with FA values. RESULTS: Among 221 participants with evaluable DTI data, 146 had OAB (66 urinary urgency-only without UUI, 80 with UUI); 75 were controls. Compared with controls, participants with OAB showed decreased FA and increased mean diffusivity, representing greater microstructural abnormalities of brain white matter tracts among OAB participants. These abnormalities occurred in the corpus callosum, bilateral anterior thalamic radiation and superior longitudinal fasciculus tracts, and bilateral insula and parahippocampal region. Among participants with OAB, higher OAB Questionnaire Short-Form scores were associated with decreased FA in the left inferior fronto-occipital fasciculus, P < .0001. DTI differences between OAB and controls were driven by the urinary urgency-only (OAB-dry) but not the UUI (OAB-wet) subgroup. CONCLUSIONS: Abnormalities in microstructural integrity in specific brain white matter tracts were more frequent in OAB patients. More severe OAB symptoms were correlated with greater degree of microstructural abnormalities in brain white matter tracts in patients with OAB. TRIAL REGISTRATION: ClinicalTrials.gov: NCT02485808.
Author Keywords
brain MRI; diffusion tensor imaging; overactive bladder; urgency urinary incontinence
Document Type: Article
Publication Stage: Final
Source: Scopus
Plasma galectin-9 relates to cognitive performance and inflammation among adolescents with vertically acquired HIV
(2024) AIDS, 38 (10), pp. 1460-1467. Cited 1 time.
Moar, P.a , Linn, K.b , Premeaux, T.A.a , Bowler, S.a , Sardarni, U.K.c , Gopalan, B.P.d e , Shwe, E.E.f , San, T.f , Han, H.b , Clements, D.g , Hlaing, C.S.b , Kyu, E.H.b , Thair, C.b , Mar, Y.Y.b , Nway, N.b , Mannarino, J.h , Bolzenius, J.h , Mar, S.i , Aye, A.M.M.b , Tandon, R.j , Paul, R.h , Ndhlovu, L.C.a
a Division of Infectious Diseases, Department of Medicine, Weill Cornell Medicine, New York, United States
b Department of Pediatrics, Yangon Children’s Hospital, University of Medicine 1, Yangon, Myanmar
c Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, United States
d Division of infectious diseases, St. John’s Research Institute, Bengaluru, India
e Sickle Thrombosis and Vascular Biology Lab, Sickle Cell Branch, National Heart Lung and Blood Institute, National Institutes of Health, Bethesda, United States
f Department of Pathology, Yangon Children’s Hospital, University of Medicine 1, Yangon, Myanmar
g Department of Tropical Medicine, Medical Microbiology & Pharmacology, John A. Burns School of Medicine, University of Hawaii at Manoa, Honolulu, United States
h Missouri Institute of Mental Health, University of Missouri-St. Louis, Missouri, United States
i Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States
j Laboratory of AIDS Research and Immunology, School of Biotechnology, Jawaharlal Nehru University, New Delhi, India
Abstract
Objective: Adolescents with perinatally acquired HIV (AWH) are at an increased risk of poor cognitive development yet the underlying mechanisms remain unclear. Circulating galectin-9 (Gal-9) has been associated with increased inflammation and multimorbidity in adults with HIV despite antiretroviral therapy (ART); however, the relationship between Gal-9 in AWH and cognition remain unexplored. Design: A cross-sectional study of two independent age-matched cohorts from India [AWH on ART (n = 15), ART-naive (n = 15), and adolescents without HIV (AWOH; n = 10)] and Myanmar [AWH on ART (n = 54) and AWOH (n = 22)] were studied. Adolescents from Myanmar underwent standardized cognitive tests. Methods: Plasma Gal-9 and soluble mediators were measured by immunoassays and cellular immune markers by flow cytometry. We used Mann – Whitney U tests to determine group-wise differences, Spearman’s correlation for associations and machine learning to identify a classifier of cognitive status (impaired vs. unimpaired) built from clinical (age, sex, HIV status) and immunological markers. Results: Gal-9 levels were elevated in ART-treated AWH compared with AWOH in both cohorts (all P < 0.05). Higher Gal-9 in AWH correlated with increased levels of inflammatory mediators (sCD14, TNFa, MCP-1, IP-10, IL-10) and activated CD8+ T cells (all P < 0.05). Irrespective of HIV status, higher Gal-9 levels correlated with lower cognitive test scores in multiple domains [verbal learning, visuospatial learning, memory, motor skills (all P < 0.05)]. ML classification identified Gal-9, CTLA-4, HVEM, and TIM-3 as significant predictors of cognitive deficits in adolescents [mean area under the curve (AUC) = 0.837]. Conclusion: Our results highlight a potential role of Gal-9 as a biomarker of inflammation and cognitive health among adolescents with perinatally acquired HIV. Copyright © 2024 The Author(s).
Author Keywords
antiretroviral therapy; galectin-9; inflammation; neurocognition; perinatal HIV
Document Type: Article
Publication Stage: Final
Source: Scopus
Infection and chronic disease activate a systemic brain-muscle signaling axis
(2024) Science Immunology, 9 (97), p. eadm7908.
Yang, S.a b , Tian, M.c , Dai, Y.d e f , Wang, R.b , Yamada, S.a , Feng, S.d , Wang, Y.g , Chhangani, D.h , Ou, T.a , Li, W.i , Guo, X.j , McAdow, J.a , Rincon-Limas, D.E.h , Yin, X.f , Tai, W.e , Cheng, G.d e k l , Johnson, A.a
a Department of Developmental Biology, Washington University School of Medicine in St. Louis, St. Louis, MO 63110, United States
b Department of Genetics and Genetics Engineering, School of Life Science, Fudan UniversityShanghai 200438, China
c Genetics Branch, Oncogenomics Section, National Cancer Institute, NIH, Bethesda, MD 20892, United States
d New Cornerstone Science Laboratory, Tsinghua University-Peking University Joint Center for Life Sciences, School of Basic Medical Sciences, Tsinghua UniversityBeijing 100084, China
e Institute of Infectious Diseases, Shenzhen Bay Laboratory, Shenzhen, 518000, China
f State Key Laboratory for Animal Disease Control and Prevention, Harbin Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Harbin, 150069, China
g Department of Forensic Medicine, Tongji Medical College of Huazhong University of Science and Technology, Wuhan, Hubei 430074, China
h Department of Neurology and McKnight Brain Institute, Department of Neuroscience and Center for Translational Research in Neurodegenerative Disease, Genetics Institute, Norman Fixel Institute for Neurological Diseases, University of Florida College of Medicine, Gainesville, FL 32611, United States
i State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics & Center for Molecular Imaging and Translational Medicine, School of Public Health, Xiamen University, Xiamen, 361102, China
j Life Science Institute, Jinzhou Medical University, Jinzhou, 121001, China
k Shenzhen Center for Disease Control and Prevention, Shenzhen, 518055, China
l Southwest United Graduate School, Kunming, 650092, China
Abstract
Infections and neurodegenerative diseases induce neuroinflammation, but affected individuals often show nonneural symptoms including muscle pain and muscle fatigue. The molecular pathways by which neuroinflammation causes pathologies outside the central nervous system (CNS) are poorly understood. We developed multiple models to investigate the impact of CNS stressors on motor function and found that Escherichia coli infections and SARS-CoV-2 protein expression caused reactive oxygen species (ROS) to accumulate in the brain. ROS induced expression of the cytokine Unpaired 3 (Upd3) in Drosophila and its ortholog, IL-6, in mice. CNS-derived Upd3/IL-6 activated the JAK-STAT pathway in skeletal muscle, which caused muscle mitochondrial dysfunction and impaired motor function. We observed similar phenotypes after expressing toxic amyloid-β (Aβ42) in the CNS. Infection and chronic disease therefore activate a systemic brain-muscle signaling axis in which CNS-derived cytokines bypass the connectome and directly regulate muscle physiology, highlighting IL-6 as a therapeutic target to treat disease-associated muscle dysfunction.
Document Type: Article
Publication Stage: Final
Source: Scopus
DISPLACE study shows poor quality of transcranial doppler ultrasound for stroke risk screening in sickle cell anemia
(2024) Blood Advances, 8 (13), pp. 3444-3452.
Davidow, K.A.a , Miller, R.E.a , Phillips, S.M.b , Schlenz, A.M.c d , Mueller, M.b e , Hulbert, M.L.f , Hsu, L.L.g , Bhasin, N.h , Adams, R.J.i , Kanter, J.j
a Department of Pediatrics, Lisa Dean Moseley Foundation Institute for Cancer and Blood Disorders, Nemours Children’s Hospital, DE, Wilmington, DE, United States
b College of Nursing, India
c Department of Pediatrics, Medical University of South Carolina, Charleston, SC, United States
d Department of Pediatrics, University of Colorado School of Medicine, Aurora, CO, United States
e Department of Public Health Sciences, Medical University of South Carolina, Charleston, SC, United States
f Division of Hematology/Oncology, Department of Pediatrics, Washington University School of Medicine, St. Louis, MO, United States
g Division of Pediatric Hematology/Oncology, University of Illinois at Chicago, Chicago, IL, United States
h Division of Hematology, Department of Pediatrics, University of California, San Francisco, Oakland, CA, United States
i Department of Neurology, Medical University of South Carolina, Charleston, SC, United States
j Division of Hematology/Oncology, University of Alabama at Birmingham, Birmingham, AL, United States
Abstract
Children with sickle cell anemia (SCA) are at increased risk of stroke when compared with their age-based counterparts. The Stroke Prevention Trial in Sickle Cell Anemia (STOP) previously demonstrated that with the use of transcranial Doppler ultrasound (TCD; Sickle Stroke Screen) and chronic red cell transfusion, the risk of stroke is reduced by over 90%. The STOP criteria detailed the type and method of measurement required; the time–averaged mean maximum velocity (TAMMV). Unfortunately, it has been difficult to adhere to the appropriate TAMMV measurements. The objectives of this study were to assess the quality of TCD and transcranial Doppler imaging (TCDi) reports to determine the report quality and accuracy. This is a subanalysis of the DISPLACE (Dissemination and Implementation of Stroke Prevention Looking at the Care Environment) study. Over 12 000 TCD/TCDi reports were collected during this study from 28 institutions; 391 TCDs were reviewed for this subanalysis. There were significant variations in the vessels being assessed, the velocities used to define abnormal results, and who was interpreting the scans. In 52% of reports, it was impossible to identify whether the TAMMV was what was measured. Similarly, it was only clear in 42% of reports that the TAMMV was used to interpret the examination as normal/abnormal. Given this inconsistency, we strongly recommend standardization of TCD/TCDi reporting, specialized training for those performing and interpreting the scans in the use of TCD/TCDi in patients with SCA, internal quality assurance, and institutional quality improvement work to ensure appropriate use of this potentially lifesaving technology. © 2024 by The American Society of Hematology.
Document Type: Article
Publication Stage: Final
Source: Scopus
Increased intraindividual variability (IIV) in reaction time is the earliest indicator of cognitive change in MS: A two-year observational study
(2024) International Journal of Clinical and Health Psychology, 24 (3), art. no. 100486, .
Pilloni, G.a b , Casper, T.C.c , Mar, S.d , Ness, J.e , Schreiner, T.f , Waltz, M.c , Waubant, E.g , Weinstock-Guttman, B.h , Wheeler, Y.e , Krupp, L.a b , Charvet, L.a b
a Department of Neurology, NYU Grossman School of Medicine, New York, NY, United States
b Parekh Center for Interdisciplinary Neurology, NYU Grossman School of Medicine, New York, NY, United States
c University of Utah, Salt Lake City, UT, United States
d Washington University, St. Louis, MO, United States
e University of Alabama, Birmingham, AL, United States
f Children’s Hospital Colorado, Broomfield, CO, United States
g University of California – San Francisco, San Francisco, CA, United States
h University of Buffalo, Williamsville, NY, United States
Abstract
Background: Cognitive decline in multiple sclerosis (MS) is common, but unpredictable, and increases with disease duration. As such, early detection of cognitive decline may improve the effectiveness of interventions. To that end, the Symbol Digit Modalities Test (SDMT) is effective in detecting slow processing speed as it relates to cognitive impairment, and intraindividual variability (IIV) observed in trials assessing continuous reaction time (RT) may be a useful indicator of early cognitive changes. Here, we will assess cognitive IIV changes in adults with early MS. Methods: Adults with relapsing-remitting MS (RRMS), <11 years since diagnosis, were recruited nationally. Baseline and two-year follow-up assessments included Brief International Cognitive Assessment in MS (BICAMS) and Cogstate computerized tests. Intraindividual variability in RT was calculated from psychomotor tasks and data were age-normalized. Results: A total of 44 of the 66 participants completed follow-up (mean age, 34.0 ± 5.5 years; 66 % female; mean disease duration, 4.1 ± 2.9 years; median Expanded Disability Status Scale (EDSS) score, 1.5 [0 to 6.0]). Participants were grouped by SDMT z-score median split. Groups did not differ in demographics or clinical features. The higher baseline SDMT group was faster (p = 0.05) in RT and less variable (lower IIV, p = 0.001). At the two-year follow-up, the higher SDMT group showed increased variability (p = 0.05) compared to the lower SDMT group, with no significant RT or BICAMS changes. Conclusions: In early MS, higher SDMT performance at baseline is associated with less cognitive variability but may indicate susceptibility to increased variability over time, highlighting the importance of monitoring IIV for early cognitive changes. © 2024 The Authors
Author Keywords
Cognitive dysfunction; Computer-assisted testing; Intraindividual variability; Multiple sclerosis; Reaction time; Relapsing remitting
Document Type: Article
Publication Stage: Final
Source: Scopus
Integrating Multisector Molecular Characterization into Personalized Peptide Vaccine Design for Patients with Newly Diagnosed Glioblastoma
(2024) Clinical Cancer Research, 30 (13), pp. 2729-2742.
Johanns, T.M.a b c , Garfinkle, E.A.R.d , Miller, K.E.d , Livingstone, A.J.a , Roberts, K.F.e , Venkata, L.P.R.d , Dowling, J.L.c f , Chicoine, M.R.g , Dacey, R.G.f , Zipfel, G.J.c f , Kim, A.H.c f , Mardis, E.R.d h , Dunn, G.P.i j
a Division of Medical Oncology, Washington University, School of Medicine, St. Louis, MO, United States
b Andrew M. and Jane M. Bursky Center for Human Immunology and Immunotherapy Programs, Washington University, School of Medicine, St. Louis, MO, United States
c The Brain Tumor Center, Siteman Cancer Center, Washington University, School of Medicine, St. Louis, MO, United States
d The Steve and Cindy Rasmussen Institute for Genomic Medicine, Nationwide Children’s Hospital, Columbus, OH, United States
e Department of Pathology and Immunology, Washington University, School of Medicine, St. Louis, MO, United States
f Department of Neurological Surgery, Washington University, School of Medicine, St Louis, MO, United States
g Department of Neurosurgery, University of Missouri in Columbia, Columbia, MO, United States
h Department of Pediatrics, Ohio State University, College of Medicine, Columbus, OH, United States
i Department of Neurosurgery, Harvard Medical School, Massachusetts General Hospital, Boston, MA, United States
j Brain Tumor Immunology and Immunotherapy Program, Department of Neurosurgery, Harvard Medical School, Massachusetts General Hospital, Boston, MA, United States
Abstract
Purpose: Outcomes for patients with glioblastoma (GBM) remain poor despite multimodality treatment with surgery, radiation, and chemotherapy. There are few immunotherapy options due to the lack of tumor immunogenicity. Several clinical trials have reported promising results with cancer vaccines. To date, studies have used data from a single tumor site to identify targetable antigens, but this approach limits the antigen pool and is antithetical to the heterogeneity of GBM. We have implemented multisector sequencing to increase the pool of neoantigens across the GBM genomic landscape that can be incorporated into personalized peptide vaccines called NeoVax. Patients and Methods: In this study, we report the findings of four patients enrolled onto the NeoVax clinical trial (NCT0342209). Results: Immune reactivity to NeoVax neoantigens was assessed in peripheral blood mononuclear cells pre- and post- NeoVax for patients 1 to 3 using IFNγ-ELISPOT assay. A statistically significant increase in IFNγ producing T cells at the post-NeoVax time point for several neoantigens was observed. Furthermore, a post-NeoVax tumor biopsy was obtained from patient 3 and, upon evaluation, revealed evidence of infiltrating, clonally expanded T cells. Conclusions: Collectively, our findings suggest that NeoVax stimulated the expansion of neoantigen-specific effector T cells and provide encouraging results to aid in the development of future neoantigen vaccine-based clinical trials in patients with GBM. Herein, we demonstrate the feasibility of incorporating multisector sampling in cancer vaccine design and provide information on the clinical applicability of clonality, distribution, and immunogenicity of the neoantigen landscape in patients with GBM. © 2024 The Authors.
Document Type: Article
Publication Stage: Final
Source: Scopus
Physician Approaches to the Pharmacologic Treatment of Dystonia in Cerebral Palsy
(2024) Pediatrics, 154 (1), .
Lott, E.a , Fehlings, D.b , Gelineau-Morel, R.c , Kruer, M.d , Mink, J.W.e , Thomas, S.P.f , Wisniewski, S.g , Aravamuthan, B.a , Cerebral Palsy Research Networkh
a Division of Pediatric Neurology, Department of Neurology, Washington University School of Medicine, St Louis, MO, United States
b Division of Developmental Paediatrics, Department of Paediatrics, Holland Bloorview Kids Rehabilitation Hospital, University of Toronto, Toronto, ON, Canada
c Division of Neurology, Department of Pediatrics, University of Missouri-Kansas City School of Medicine, Children’s Mercy Kansas City, Kansas City, MO, United States
d Barrow Neurologic Institute, Phoenix Children’s Hospital, Departments of Child Health, Cellular and Molecular Medicine, Genetics, Neurology, University of Arizona College of Medicine-Phoenix, Phoenix, AZ, United States
e Pittsford, NY, United States
f H. Ben Taub Department of Physical Medicine and Rehabilitation and Departments of Neurosurgery and Pediatrics, Baylor College of Medicine, Houston, TX, United States
g Department of Epidemiology, Epidemiology Data Center, University of Pittsburgh, Pittsburgh, PA, United States
Document Type: Article
Publication Stage: Final
Source: Scopus
The effect of retrieval practice on vocabulary learning for DHH children
(2024) Journal of Deaf Studies and Deaf Education, 29 (3), pp. 377-387.
Reimer, C.K.a , Grantham, H.a b , Butler, A.C.c
a Department of Otolaryngology, Washington University in St. Louis, St. Louis, MO, United States
b CID – Central Institute for the Deaf, St. Louis, MO, United States
c Department of Education and Department of Psychology, Washington Universityin St. Louis, St. Louis, MO, United States
Abstract
On average, deaf and hard-of-hearing (DHH) children have difficulty developing expressive spoken vocabulary comparable to hearing peers. Yet, there are no evidence-based practices to guide classroom instruction for teachers of the deaf. Retrieval practice – a robust learning strategy – has been shown to improve children’s retention of vocabulary, but it has not been investigated with DHH children who use listening and spoken language. The present study examined whether DHH children benefit from using retrieval practice to learn new vocabulary. Sixteen DHH children (in the age range of 5.0-8.11 years) were taught a set of new vocabulary words using retrieval practice or repeated exposure. A recall test was administered two days later. Results showed that DHH children were twice as likely to recall a word taught through retrieval practice than exposure (OR = 2.01, p =. 02). Presence of an additional diagnosis and number of practice trials were also significant predicting factors of vocabulary learning. © 2024 The Author(s). Published by Oxford University Press. All rights reserved.
Funding details
U.S. Department of EducationED
Document Type: Article
Publication Stage: Final
Source: Scopus
Improvement in symptoms of Rett syndrome with trofinetide beyond clinical trial efficacy assessments: case reports
(2024) Future Rare Diseases, 4 (1), art. no. 2375191, .
Ryther, R.C.a , Palladino, C.b , Kothare, S.V.b
a Department of Neurology, Washington University School of Medicine, St. Louis, MO 63110, United States
b Northwell Health, Cohen Children’s Medical Center, Division of Pediatric Neurology, New Hyde Park, NY 11042, United States
Abstract
Trofinetide is the first approved treatment for Rett syndrome (RTT) in adults and pediatric patients aged ≥2 years. In LAVENDER and DAFFODIL, clinical studies of trofinetide in female participants with RTT, the efficacy of trofinetide was evaluated with the caregiver- and clinician-assessed questionnaires that measure RTT symptom improvement. These scales do not measure improvements in all symptoms of RTT. Here, we present three female patients with RTT treated with trofinetide that aim to describe improvements in symptoms of RTT not properly covered by clinical study efficacy end points. The first case is focused on improvements in verbal communication skills, the second case is focused on reduction in the incidence of seizures with improvement in sleep, and the third case focuses on improvements in motor skills. These anecdotal, real-world cases suggest that trofinetide could improve symptoms of RTT not covered in clinical trial outcomes. © 2024 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.
Author Keywords
DAFFODIL; LAVENDER; motor skills; Rett syndrome; seizures; sleep; trofinetide; verbal communication
Document Type: Article
Publication Stage: Final
Source: Scopus
A nonoscillatory, millisecond-scale embedding of brain state provides insight into behavior
(2024) Nature Neuroscience, .
Parks, D.F.a , Schneider, A.M.b , Xu, Y.b , Brunwasser, S.J.b , Funderburk, S.b , Thurber, D.c , Blanche, T.d , Dyer, E.L.e , Haussler, D.a , Hengen, K.B.b
a Department of Biomolecular Engineering, University of California, Santa Cruz, CA, United States
b Department of Biology, Washington University in Saint Louis, St. Louis, MO, United States
c Independent researcher, Exeter, NH, United States
d White Matter LLC, Seattle, WA, United States
e Department of Biomedical Engineering, Georgia Institute of Technology, Atlanta, GA, United States
Abstract
The most robust and reliable signatures of brain states are enriched in rhythms between 0.1 and 20 Hz. Here we address the possibility that the fundamental unit of brain state could be at the scale of milliseconds and micrometers. By analyzing high-resolution neural activity recorded in ten mouse brain regions over 24 h, we reveal that brain states are reliably identifiable (embedded) in fast, nonoscillatory activity. Sleep and wake states could be classified from 100 to 101 ms of neuronal activity sampled from 100 µm of brain tissue. In contrast to canonical rhythms, this embedding persists above 1,000 Hz. This high-frequency embedding is robust to substates, sharp-wave ripples and cortical on/off states. Individual regions intermittently switched states independently of the rest of the brain, and such brief state discontinuities coincided with brief behavioral discontinuities. Our results suggest that the fundamental unit of state in the brain is consistent with the spatial and temporal scale of neuronal computation. © The Author(s), under exclusive licence to Springer Nature America, Inc. 2024.
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
Pathogenic variants in KMT2C result in a neurodevelopmental disorder distinct from Kleefstra and Kabuki syndromes
(2024) American Journal of Human Genetics, . Cited 1 time.
Rots, D.a b c , Choufani, S.d , Faundes, V.e ch , Dingemans, A.J.M.a , Joss, S.f , Foulds, N.g , Jones, E.A.h i , Stewart, S.h , Vasudevan, P.j , Dabir, T.k , Park, S.-M.l , Jewell, R.m , Brown, N.n o , Pais, L.p q , Jacquemont, S.r , Jizi, K.s , Ravenswaaij-Arts, C.M.A.V.t , Kroes, H.Y.u , Stumpel, C.T.R.M.v w , Ockeloen, C.W.a , Diets, I.J.a , Nizon, M.x , Vincent, M.x , Cogné, B.x , Besnard, T.x , Kambouris, M.y , Anderson, E.z , Zackai, E.H.aa , McDougall, C.ab , Donoghue, S.ab , O’Donnell-Luria, A.p q , Valivullah, Z.p , O’Leary, M.p ac , Srivastava, S.ad , Byers, H.ae , Leslie, N.af , Mazzola, S.ag , Tiller, G.E.ah , Vera, M.ah , Shen, J.J.ai aj , Boles, R.ak , Jain, V.al , Brischoux-Boucher, E.am , Kinning, E.an , Simpson, B.N.ao , Giltay, J.C.u , Harris, J.ap aq , Keren, B.ar , Guimier, A.as , Marijon, P.at , Vries, B.B.A.D.a , Motter, C.S.au , Mendelsohn, B.A.av , Coffino, S.aw , Gerkes, E.H.ax , Afenjar, A.ay , Visconti, P.az , Bacchelli, E.ba , Maestrini, E.ba , Delahaye-Duriez, A.bb , Gooch, C.bc , Hendriks, Y.bd , Adams, H.a b , Thauvin-Robinet, C.be bf bg , Josephi-Taylor, S.bh bi , Bertoli, M.bj , Parker, M.J.bk , Rutten, J.W.bd , Caluseriu, O.bl , Vernon, H.J.bm , Kaziyev, J.q , Zhu, J.q , Kremen, J.bn , Frazier, Z.bo , Osika, H.bo , Breault, D.q , Nair, S.bp , Lewis, S.M.E.bq , Ceroni, F.ba br , Viggiano, M.ba , Posar, A.az bs , Brittain, H.bt , Giovanna, T.bu , Giulia, G.bv , Quteineh, L.bw , Ha-Vinh Leuchter, R.bx , Zonneveld-Huijssoon, E.ax , Mellado, C.by , Marey, I.bz , Coudert, A.bz , Aracena Alvarez, M.I.ca , Kennis, M.G.P.a , Bouman, A.a , Roifman, M.cb , Amorós Rodríguez, M.I.cc , Ortigoza-Escobar, J.D.cd , Vernimmen, V.v w , Sinnema, M.v , Pfundt, R.a , Brunner, H.G.a v , Vissers, L.E.L.M.a ce , Kleefstra, T.a b cf , Weksberg, R.d cg , Banka, S.h ch
a Department of Human Genetics, Radboud University Medical Center, Nijmegen, Netherlands
b Department of Clinical Genetics, Erasmus MC, Rotterdam, Netherlands
c Genetics Laboratory, Children’s Clinical University Hospital, Riga, Latvia
d Genetics and Genome Biology Program, Research Institute, the Hospital for Sick Children, Toronto, ON M5G 1X8, Canada
e Laboratorio de Genética y Enfermedades Metabólicas, Instituto de Nutrición y Tecnología de Los Alimentos (INTA), Universidad de Chile, Santiago, Chile
f West of Scotland Centre for Genomic Medicine, Queen Elizabeth University Hospital, Glasgow, United Kingdom
g Wessex Clinical Genetics Services, University Hospital Southampton NHS Foundation Trust, Southampton, SO16 5YA, United Kingdom
h Manchester Centre for Genomic Medicine, St Mary’s Hospital, Manchester University NHS Foundation Trust, Health Innovation Manchester, Manchester, United Kingdom
i Division of Evolution, Infection and Genomics, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, United Kingdom
j Department of Clinical Genetics, University Hospitals of Leicester, Leicester Royal Infirmary, Leicester, LE1 7RH, United Kingdom
k Northern Ireland Regional Genetics Centre, Belfast City Hospital, Belfast, United Kingdom
l Department of Clinical Genetics, Cambridge University Hospitals NHS Foundation Trust, Cambridge, United Kingdom
m Yorkshire Regional Genetics Service, Chapel Allerton Hospital, Leeds Teaching Hospitals NHS Trust, Leeds, United Kingdom
n Victorian Clinical Genetics Service, Murdoch Children’s Research Institute, Melbourne, VIC, Australia
o Department of Paediatrics, Royal Children’s Hospital, The University of Melbourne, Melbourne, VIC, Australia
p Center for Mendelian Genomics, Broad Institute of MIT and Harvard, Cambridge, MA, United States
q Division of Genetics and Genomics, Boston Children’s Hospital, Harvard Medical School, Boston, MA, United States
r Department of Pediatrics, University of Montreal, Montreal, QC, Canada
s Service de Génétique Médicale, CHU Ste-Justine, Montréal, QC, Canada
t University of Groningen, University Medical Centre Groningen, Department Genetics, Groningen, Netherlands
u Division Laboratories, Pharmacy and Biomedical Genetics, University Medical Center Utrecht, Utrecht, Netherlands
v Department of Clinical Genetics, Maastricht University Medical Center, Maastricht, Netherlands
w GROW-School for Oncology and Reproduction, Maastricht, Netherlands
x Service de Génétique Médicale, Centre Hospitalier Universitaire de Nantes, Nantes, France
y Division of Genetics, Department of Pathology and Laboratory Medicine Department, Sidra Medicine, Doha, Qatar
z Liverpool Centre for Genomic Medicine, Liverpool Women’s NHS Foundation Trust, Liverpool, United Kingdom
aa Division of Human Genetics, Children’s Hospital of Philadelphia, Philadelphia, PA, United States
ab Division of Human Genetics, Department of Pediatrics, The Children’s Hospital of Philadelphia, Philadelphia, PA, United States
ac Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA, United States
ad Department of Neurology, Boston Children’s Hospital, Boston, MA, United States
ae Department of Pediatrics, Stanford University, Stanford, CA, United States
af Division of Human Genetics, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, United States
ag Center for Personalized Genetic Healthcare, Cleveland Clinic, Cleveland, OH, United States
ah Department of Genetics, Kaiser Permanente, Los Angeles, CA, United States
ai Division of Genetics, Department of Pediatrics, UCSF Fresno, Fresno, CA, United States
aj Division of Genomic Medicine, Department of Pediatrics, University of California Davis, Sacramento, CA, United States
ak NeuraBilities Healthcare, Philadelphia, PA, United States
al All Wales Medical Genomics Service, Wales Genomic Health Centre, Cardiff Edge Business Park, Longwood Drive, Cardiff, Whitchurch, CF14 7YU, United Kingdom
am Centre de Génétique Humaine, CHU de Besançon, Université de Franche-Comté, Besançon, France
an Clinical Genetics, Birmingham Women’s and Children’s, Birmingham, United Kingdom
ao Division of Human Genetics, Cincinnati Children’s Hospital Medical Center, Department of Pediatrics, University of Cincinnati, Cincinnati, OH, United States
ap Kennedy Krieger Institute, Baltimore, MD, United States
aq Department of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, United States
ar Department of Genetics, APHP Sorbonne University, Paris, France
as Service de Médecine Genomique des Maladies Rares, CRMR Anomalies Du Développement, Hôpital Necker-Enfants Malades, Assistance Publique des Hôpitaux de Paris, Paris, France
at Laboratoire de Biologie Médicale Multisites Seqoia FMG2025, Paris, 75014, France
au Genetic Center, Akron Children’s Hospital, Akron, OH, United States
av Department of Medical Genetics, Kaiser Permanente, Oakland, CA, United States
aw Department of Pediatric Neurology, Kaiser Permanente, Oakland, CA, United States
ax Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, Netherlands
ay APHP Sorbonne Université, Centre de Référence Malformations et Maladies Congénitales Du Cervelet et Déficiences Intellectuelles de Causes Rares, Département de Génétique et Embryologie Médicale, Hôpital Trousseau, Paris, France
az IRCCS Istituto Delle Scienze Neurologiche di Bologna, UOSI Disturbi Dello Spettro Autistico, Bologna, Italy
ba Pharmacy and Biotechnology Department, University of Bologna, Bologna, Italy
bb Medical Genomics and Clinical Genetics Unit, AP-HP, Hôpital Jean Verdier, Bondy, France
bc Division of Genetics and Genomic Medicine, Department of Pediatrics, Washington University School of Medicine, St Louis, MO, United States
bd Department of Clinical Genetics, Leiden University Medical Center, Leiden, Netherlands
be Unité Fonctionnelle Innovation en, Diagnostic Génomique des Maladies Rares, Dijon, France
bf Inserm, UMR1231, Equipe GAD, Bâtiment B3, Université de Bourgogne Franche Comté, Dijon Cedex, France
bg Centre de Référence Déficiences Intellectuelles de Causes Rares, FHU-TRANSLAD, CHU Dijon Bourgogne, Dijon, France
bh Department of Clinical Genetics, The Children’s Hospital at Westmead, Sydney, NSW, Australia
bi Discipline of Genomic Medicine, Faculty of Medicine and Health, The University of Sydney, Sydney, NSW, Australia
bj Northern Genetics Service, Newcastle Upon Tyne NHS Foundation Trust, Newcastle Upon Tyne, United Kingdom
bk Department of Clinical Genetics, Sheffield Children’s Hospital, Sheffield, United Kingdom
bl Department of Medical Genetics, University of Alberta, Edmonton, Canada
bm Johns Hopkins University School of Medicine, Baltimore, MD, United States
bn Division of Endocrinology, Boston Children’s Hospital, Harvard Medical School, Boston, MA, United States
bo Rosamund Stone Zander Translational Neuroscience Center, Boston Children’s Hospital, Harvard Medical School, Boston, MA, United States
bp Department of Fetal Medicine, Lifeline Super Specialty Hospital, Kerala, India
bq Department of Medical Genetics, BC Children’s Hospital Research Institute, The University of British Columbia, Vancouver, BC, Canada
br Faculty of Health and Life Sciences, Oxford Brookes University, Oxford, United Kingdom
bs Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy
bt Department of Clinical Genetics, Birmingham Women’s & Children’s NHS Trust, Birmingham, United Kingdom
bu Medical Genetics Unit, Meyer Children’s Hospital IRCCS Florence, Florence, Italy
bv Medical Genetics Unit, Meyer Children’s Hospital IRCCS, Florence, Italy
bw Division of Genetic Medicine, Geneva University Hospitals, Geneva, 1205, Switzerland
bx Division of Development and Growth, Department of Pediatrics, University of Geneva, Geneva, Switzerland
by Sección de Genética y Errores Congénitos Del Metabolismo, División de Pediatría, Pontificia Universidad Católica de Chile, Santiago, Chile
bz CHU Grenoble Alpes, Grenoble, France
ca Unit of Genetics and Metabolic Diseases, Division of Pediatrics, School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile
cb The Prenatal Diagnosis and Medical Genetics Program, Division of Maternal Fetal Medicine, Department of Obstetrics and Gynaecology, University of Toronto, Toronto, Canada
cc Deparment of Pediatrics, Hospital Punta Europa Algeciras, Cadiz, Spain
cd Movement Disorders Unit, Institut de Recerca Sant Joan de Déu, CIBERER-ISCIII and European Reference Network for Rare Neurological Diseases (ERN-RND), Barcelona, Spain
ce Research Institute for Medical Innovation, Radboud University Medical Center, Nijmegen, Netherlands
cf Center of Excellence for Neuropsychiatry, Vincent van Gogh Institute for Psychiatry, Venray, Netherlands
cg Division of Clinical and Metabolic Genetics, Department of Pediatrics, the Hospital for Sick Children, University of Toronto, Toronto, ON M5G 1X8, Canada
ch Manchester Centre for Genomic Medicine, Division of Evolution and Genomic Sciences, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, United Kingdom
Abstract
Trithorax-related H3K4 methyltransferases, KMT2C and KMT2D, are critical epigenetic modifiers. Haploinsufficiency of KMT2C was only recently recognized as a cause of neurodevelopmental disorder (NDD), so the clinical and molecular spectrums of the KMT2C-related NDD (now designated as Kleefstra syndrome 2) are largely unknown. We ascertained 98 individuals with rare KMT2C variants, including 75 with protein-truncating variants (PTVs). Notably, ∼15% of KMT2C PTVs were inherited. Although the most highly expressed KMT2C transcript consists of only the last four exons, pathogenic PTVs were found in almost all the exons of this large gene. KMT2C variant interpretation can be challenging due to segmental duplications and clonal hematopoesis-induced artifacts. Using samples from 27 affected individuals, divided into discovery and validation cohorts, we generated a moderate strength disorder-specific KMT2C DNA methylation (DNAm) signature and demonstrate its utility in classifying non-truncating variants. Based on 81 individuals with pathogenic/likely pathogenic variants, we demonstrate that the KMT2C-related NDD is characterized by developmental delay, intellectual disability, behavioral and psychiatric problems, hypotonia, seizures, short stature, and other comorbidities. The facial module of PhenoScore, applied to photographs of 34 affected individuals, reveals that the KMT2C-related facial gestalt is significantly different from the general NDD population. Finally, using PhenoScore and DNAm signatures, we demonstrate that the KMT2C-related NDD is clinically and epigenetically distinct from Kleefstra and Kabuki syndromes. Overall, we define the clinical features, molecular spectrum, and DNAm signature of the KMT2C-related NDD and demonstrate they are distinct from Kleefstra and Kabuki syndromes highlighting the need to rename this condition. © 2024 American Society of Human Genetics
Author Keywords
DNA methylation; EHMT1; Kabuki syndrome; Kleefstra syndrome; KMT2C; KMT2D; neurodevelopmental disorder
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
Perceiving objects the brain does not represent
(2024) Phenomenology and the Cognitive Sciences, .
Barkasi, M.a b , Openshaw, J.b c
a Oviedo Lab, Department of Neuroscience, Washington University School of Medicine in St. Louis, St. Louis, United States
b Centre for Philosophy of Memory, Université Grenoble Alpes, Grenoble, France
c Nanyang Technological University, Singapore, Singapore
Abstract
It is often assumed that neural representation, with content that is in principle detachable from the flow of natural-factive information, is necessary to perceptually experience an object. In this paper we present and discuss two cases challenging this assumption. We take them to show that it is possible to experience an object with which you are interacting through your sensory systems without those systems constructing a representation of the object. The first example is viewing nearby medium-sized groups of objects. The second is hearing objects through misbound sounds. These cases bring out two different ways object representation can fail while object experience persists, suggesting that object experience requires only that the object be revealed through sensory information, not full-blown representation. Constructing object representations is one way sensory systems reveal objects, but it is not the only way. Object representation in neural sensory systems is relatively demanding, rare, and fragile; object experience is relatively easy, pervasive, and robust. We conclude that even minimal forms of neural phenomenal internalism are false. © The Author(s), under exclusive licence to Springer Nature B.V. 2024.
Author Keywords
Ensemble perception; Multimodal binding; Object representation; Perceptual experience; Phenomenal internalism; Representationalism
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
Mental health and body image among SGM youth engaged with a digital eating disorder intervention
(2024) Journal of LGBT Youth, .
Kasson, E.a , Szlyk, H.S.a , Li, X.a , Sirko, G.a , Rehg, I.a , Vázquez, M.M.a , Wilfley, D.E.b , Taylor, C.B.c d , Fitzsimmons-Craft, E.E.a
a Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, United States
b Department of Psychology, Washington University in St. Louis, St. Louis, MO, United States
c Department of Psychiatry and Behavioral Science, Stanford University School of Medicine, Stanford, CA, United States
d Center for m2Health, Palo Alto University, Palo Alto, CA, United States
Abstract
Sexual and gender minority (SGM) teens may experience body image concerns and eating disorders (EDs) at higher rates than their non-SGM peers. The current investigation examined differences in baseline survey responses by SGM and non-SGM youth who participated in a pilot randomized controlled trial of a digital intervention for EDs. Eligible teens (N = 147) aged 14–17 years old who screened positive or at high risk for an ED completed a baseline survey to assess current ED symptoms, mental health comorbidities, and ED treatment history. The majority of participants (mean age 16.021 years) screened positive for symptoms of a clinical/subclinical ED (n = 98, 66.7%), 123 endorsed severe anxiety (83.7%), and 81 endorsed severe depression (55.1%). A total of 72.1% (n = 106) identified as SGM and were more likely to report severe symptoms of depression (p = 0.01), any symptoms of anxiety (p = 0.03), social anxiety disorder (p = 0.02), and lifetime suicide attempts (p<.001), compared with non-SGM peers. Qualitative feedback on the intersection of SGM identities and body image concerns were also reported among SGM teens. Future eating disorder interventions provided to SGM youth should include content on comorbidities like depression and anxiety, which may be barriers to ED recovery among SGM teens. © 2024 Taylor & Francis Group, LLC.
Author Keywords
eating disorders; LGBTQ+; mHealth; SGM; social media; youth
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
Predictors of a relapsing course in myelin oligodendrocyte glycoprotein antibody-associated disease
(2024) Journal of Neurology, Neurosurgery and Psychiatry, art. no. jnnp-2024-333464, .
Virupakshaiah, A.a , Schoeps, V.A.a , Race, J.b , Waltz, M.b , Sharayah, S.c , Nasr, Z.a , Moseley, C.E.a , Zamvil, S.S.a d , Gaudioso, C.c , Schuette, A.b , Casper, T.C.b , Rose, J.b , Flanagan, E.P.e , Rodriguez, M.e , Tillema, J.-M.e , Chitnis, T.f , Gorman, M.P.g , Graves, J.S.h , Benson, L.A.g , Rensel, M.i , Abrams, A.i , Krupp, L.j , Lotze, T.E.k , Aaen, G.l , Wheeler, Y.m , Schreiner, T.n , Waldman, A.o , Chong, J.a , Mar, S.c , Waubant, E.a
a Neurology, UCSF Weill Institute for Neurosciences, San Francisco, CA, United States
b The University of Utah, Salt Lake City, UT, United States
c Department of Neurology, Washington University in St Louis, St Louis, MO, United States
d Program in Immunology, UCSF, San Francisco, CA, United States
e Neurology, Mayo Clinic Rochester, Rochester, MN, United States
f Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States
g Boston Children’s Hospital, Boston, MA, United States
h Department of Neurology, University of California San Diego, San Diego, CA, United States
i Cleveland Clinic, Cleveland, OH, United States
j Pediatric MS Center, NYU Langone Health, New York, NY, United States
k Texas Children’s Hospital, Houston, TX, United States
l Loma Linda University Medical Center, Loma Linda, CA, United States
m University of Alabama at Birmingham, Birmingham, AL, United States
n Children’s Hospital Colorado, Aurora, CO, United States
o The Children’s Hospital of Philadelphia, Philadelphia, PA, United States
Abstract
Background: Myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) is a recently described demyelinating disorder, and children represent about 50% of all cases. Almost half of the patients experience relapses, but very few studies have evaluated predictors of relapse risk, challenging clinical management. The study aimed to identify predictors at MOGAD onset that are associated with a relapsing course. Methods: Prospectively collected data from paediatric patients with MOGAD seen by the US Network of Paediatric MS Centres were leveraged. Univariable and adjusted multivariable models were used to predict recurrent disease. Results: We identified 326 MOGAD cases (mean age at first event 8.9 years [SD 4.3], 57% female, 77% white and 74% non-Hispanic) and 46% relapsed during a mean follow-up of 3.9 years (SD 4.1). In the adjusted multivariable model, female sex (HR 1.66, 95% CI 1.17 to 2.36, p=0.004) and Hispanic/Latino ethnicity (HR 1.77, 95% CI 1.19 to 2.64, p=0.005) were associated with a higher risk of relapsing MOGAD. Maintenance treatment initiated before a second event with rituximab (HR 0.25, 95% CI 0.07 to 0.92, p=0.037) or intravenous immunoglobulin (IVIG) (HR 0.35, 95% CI 0.14 to 0.88, p=0.026) was associated with lower risk of a second event in multivariable analyses. Conversely, maintenance steroids were associated with a higher estimated relapse risk (HR 1.76, 95% CI 0.90 to 3.45, p=0.097). Conclusion: Sex and ethnicity are associated with relapsing MOGAD. Use of rituximab or IVIG therapy shortly after onset is associated with a lower risk of the second event. Preventive treatment after a first event could be considered for those with a higher relapse risk. © Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.
Author Keywords
MULTIPLE SCLEROSIS; NEUROIMMUNOLOGY
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
Pharmacokinetic Modeling of the Effect of Tariquidar on Ondansetron Disposition into the Central Nervous System
(2024) Pharmaceutical Research, .
Chiang, M.a , Back, H.a , Lee, J.B.a , Oh, S.a , Guo, T.a , Girgis, S.a , Park, C.a , Haroutounian, S.b , Kagan, L.a c
a Department of Pharmaceutics, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, 160 Frelinghuysen Road, Piscataway, NJ 08854, United States
b Division of Clinical and Translational Research and Washington University Pain Center, Department of Anesthesiology, Washington University School of Medicine, St Louis, MO, United States
c Center of Excellence for Pharmaceutical Translational Research and Education, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ, United States
Abstract
Purpose: Serotonin (5-HT3) receptor antagonists are promising agents for treatment of neuropathic pain. However, insufficient drug exposure at the central nervous system (CNS) might result in lack of efficacy. The goal of this study was to evaluate the impact of administration of a Pgp inhibitor (tariquidar) on ondansetron exposure in the brain, spinal cord, and cerebrospinal fluid in a wild-type rat model. Methods: Ondansetron (10 mg/kg) and tariquidar (7.5 mg/kg) were administered intravenously, plasma and tissue samples were collected and analyzed by HPLC. A mathematical model with brain, spinal cord, cerebrospinal fluid and two systemic disposition compartments was developed to describe the data. Results: The results demonstrate that tariquidar at 7.5 mg/kg resulted in a complete inhibition of Pgp efflux of ondansetron in the brain and spinal cord. The compartmental model successfully captured pharmacokinetics of ondansetron in wild type and Pgp knockout (KO) animals receiving the drug alone or in wild type animals receiving the ondansetron and tariquidar combination. Conclusions: The study provided important quantitative information on enhancement of CNS exposure to ondansetron using co-administration of Pgp Inhibitor in a rat model, which will be further utilized in conducting a clinical study. Tariquidar co-administration resulted in ondansetron CNS exposure comparable to observed in Pgp KO rats. Results also highlighted the effect of tariquidar on plasma disposition of ondansetron, which may not be dependent on Pgp inhibition, and should be evaluated in future studies. © The Author(s) 2024.
Author Keywords
biodisposition; brain; neuropathic pain; P-glycoprotein
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
A maternal brain hormone that builds bone
(2024) Nature, .
Babey, M.E.a , Krause, W.C.b , Chen, K.c , Herber, C.B.b i , Torok, Z.b , Nikkanen, J.b j , Rodriguez, R.b k , Zhang, X.d , Castro-Navarro, F.b , Wang, Y.e , Wheeler, E.E.c f , Villeda, S.g , Leach, J.K.c f , Lane, N.E.h , Scheller, E.L.d , Chan, C.K.F.e , Ambrosi, T.H.c , Ingraham, H.A.b
a Department of Medicine, Division of Endocrinology and Metabolism, University of California, San Francisco, San Francisco, CA, United States
b Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA, United States
c Department of Orthopaedic Surgery, University of California, Davis, Sacramento, CA, United States
d Department of Medicine, Washington University, St Louis, MO, United States
e Institute for Stem Cell Biology and Regenerative Medicine and Department of Surgery, Stanford University School of Medicine, Stanford, CA, United States
f Department of Biomedical Engineering, University of California, Davis, Davis, CA, United States
g Department of Anatomy, University of California, San Francisco, San Francisco, CA, United States
h Department of Medicine, Division of Rheumatology, University of California, Davis, Sacramento, CA, United States
i Denali Therapeutics, South San Francisco, CA, United States
j Department of Integrative Biology, University of California, Berkeley, Berkeley, CA, United States
k Carmot Therapeutics, Berkeley, CA, United States
Abstract
In lactating mothers, the high calcium (Ca2+) demand for milk production triggers significant bone loss1. Although oestrogen normally counteracts excessive bone resorption by promoting bone formation, this sex steroid drops precipitously during this postpartum period. Here we report that brain-derived cellular communication network factor 3 (CCN3) secreted from KISS1 neurons of the arcuate nucleus (ARCKISS1) fills this void and functions as a potent osteoanabolic factor to build bone in lactating females. We began by showing that our previously reported female-specific, dense bone phenotype2 originates from a humoral factor that promotes bone mass and acts on skeletal stem cells to increase their frequency and osteochondrogenic potential. This circulatory factor was then identified as CCN3, a brain-derived hormone from ARCKISS1 neurons that is able to stimulate mouse and human skeletal stem cell activity, increase bone remodelling and accelerate fracture repair in young and old mice of both sexes. The role of CCN3 in normal female physiology was revealed after detecting a burst of CCN3 expression in ARCKISS1 neurons coincident with lactation. After reducing CCN3 in ARCKISS1 neurons, lactating mothers lost bone and failed to sustain their progeny when challenged with a low-calcium diet. Our findings establish CCN3 as a potentially new therapeutic osteoanabolic hormone for both sexes and define a new maternal brain hormone for ensuring species survival in mammals. © The Author(s) 2024.
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
Sense of purpose in life and extending the cognitive healthspan: evidence from multistate survival modeling
(2024) Aging, Neuropsychology, and Cognition, .
Lewis, N.A.a b , Hofer, S.M.a b , Bennett, D.A.c , Hill, P.L.d
a Department of Psychology, University of Victoria, Victoria, BC, Canada
b Institute on Aging and Lifelong Health, University of Victoria, Victoria, BC, Canada
c Rush Alzheimer’s Disease Center, Rush University Medical Center, Chicago, IL, United States
d Department of Psychological and Brain Sciences, Washington University in St. Louis, St. Louis, MO, United States
Abstract
Having a sense of purpose in life predicts better maintenance of cognitive function in older adulthood and reduced risk of mild cognitive impairment (MCI) and dementia. However, little research has examined its influence on the rate of cognitive decline and length of cognitive healthspan. This study evaluated the role of sense of purpose on the risk and timing of transitions between normal cognition, MCI, and dementia. Older adults from the Memory and Aging Project (MAP; n = 1821) and the Health and Retirement Study (HRS; n = 10,542) were followed annually for 19 years and biennially for 12 years, respectively. Multistate survival models assessed whether sense of purpose predicted transitions across normal cognition, MCI, dementia, and death. More purposeful older adults had lower risk of developing MCI (HR = 0.82 in MAP; HR = 0.93 in HRS), higher likelihood of cognitive improvement, and longer cognitively healthy life expectancies. Results suggest sense of purpose may extend the cognitive healthspan. © 2024 Informa UK Limited, trading as Taylor & Francis Group.
Author Keywords
Cognition; cognitive reserve; dementia; sense of purpose in life; well-being
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
Unexpected Low Rate of Amyloid-β Pathology in Multiple Sclerosis Patients
(2024) Annals of Neurology, .
Brier, M.R.a b , Schindler, S.E.a , Salter, A.c , Perantie, D.a , Shelley, N.a , Judge, B.a , Keefe, S.b , Kirmess, K.M.d , Verghese, P.B.d , Yarasheski, K.E.d , Venkatesh, V.d , Raji, C.A.b , Gordon, B.A.b , Bateman, R.J.a , Morris, J.C.a , Naismith, R.T.a , Holtzman, D.M.a , Benzinger, T.L.S.b , Cross, A.H.a
a Department of Neurology, Washington University in St. Louis, St. Louis, MO, United States
b Mallinckrodt Institute of Radiology, Washington University in St. Louis, St. Louis, MO, United States
c Department of Neurology, University of Texas Southwestern Medical Center, Dallas, TX, United States
d C2N Diagnostics, St. Louis, MO, United States
Abstract
The life expectancy of people with multiple sclerosis (MS) has increased, yet we have noted that development of a typical Alzheimer disease dementia syndrome is uncommon. We hypothesized that Alzheimer disease pathology is uncommon in MS patients. In 100 MS patients, the rate of amyloid-β plasma biomarker positivity was approximately half the rate in 300 non-MS controls matched on age, sex, apolipoprotein E proteotype, and cognitive status. Interestingly, most MS patients who did have amyloid-β pathology had features atypical for MS at diagnosis. These results support that MS is associated with reduced Alzheimer disease risk, and suggest new avenues of research. ANN NEUROL 2024. © 2024 American Neurological Association.
Funding details
National Institute on AgingNIAR01AG070941, K23AG053426, P01AG026276, CA2016636, P30AG066444, R44 AG059489, P01AG003991
National Institute on AgingNIA
K23NS128325
Alzheimer’s Drug Discovery FoundationADDFGC‐201711‐2013978
Alzheimer’s Drug Discovery FoundationADDF
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
Toddler hair cortisol levels are associated with maternal prenatal depression
(2024) American Journal of Human Biology, .
Thayer, Z.M.a , Nemeth, K.L.b , Beauregard, J.A.b , Gildner, T.E.b
a Department of Anthropology, Dartmouth College, Hanover, NH, United States
b Anthropology Department, Washington University at St. Louis, St. Louis, MO, United States
Abstract
Objectives: Cortisol is an important metabolic hormone that regulates multiple physiologic systems. Cortisol metabolism is sensitive to early life environments, including that experienced prenatally. Limited research has evaluated factors that predict variation in maternal and offspring toddler hair cortisol, which is important since hair cortisol represents different dynamics of hypothalamic pituitary adrenal (HPA)-axis function than more common salivary or serum measures. Methods: To address this gap, we longitudinally evaluated whether maternal depression measured in pregnancy and 1 month postnatal was associated with maternal and offspring hair cortisol levels approximately 15 months after birth (n = 46 mothers, 40 toddlers; mean 15.6 months postnatal, SD = 2.9 months). Results: Mean depression symptoms were highest during the prenatal period. Prenatal, but not postnatal, maternal depression was associated with offspring hair cortisol levels (B = 0.095, p =.01). Maternal hair cortisol was not associated with depression measured at either time point. Conclusions: These findings indicate that offspring hair cortisol more than a year after birth is associated with maternal prenatal depression, consistent with previous research in salivary cortisol, suggesting that long-term offspring stress physiology may be influenced by conditions experienced in utero. These findings highlight the potential for hair cortisol—a minimally invasive and easy-to-collect measure— to index toddler HPA-axis dynamics. © 2024 Wiley Periodicals LLC.
Document Type: Article
Publication Stage: Article in Press
Source: Scopus