Scopus list of publications for October 22, 2022
Dramatic impacts on brain pathology, anxiety, and cognitive function in the knock-in APPNL-G-F mouse model of Alzheimer disease following long-term voluntary exercise
(2022) Alzheimer’s Research and Therapy, 14 (1), art. no. 143, .
Mehla, J.a b , Deibel, S.H.a c , Karem, H.a , Hossain, S.a , Lacoursiere, S.G.a , Sutherland, R.J.a , Mohajerani, M.H.a , McDonald, R.J.a
a Canadian Centre for Behavioural Neuroscience, University of Lethbridge, 4401 University Dr W, Lethbridge, AB T1K 3M4, Canada
b Department of Neurological Surgery, Washington University School of Medicine, St. Louis, MO 63110, United States
c Present address: Department of Psychology, University of New Brunswick, POB 4400, Fredericton, NB E3B 3A1, Canada
Abstract
Background: An active lifestyle is associated with improved cognitive functions in aged people and may prevent or slow down the progression of various neurodegenerative diseases including Alzheimer’s disease (AD). To investigate these protective effects, male APPNL-G-F mice were exposed to long-term voluntary exercise. Methods: Three-month-old AD mice were housed in a cage supplemented with a running wheel for 9 months for long-term exercise. At the age of 12 months, behavioral tests were completed for all groups. After completing behavioral testing, their brains were assessed for amyloid pathology, microgliosis, and cholinergic cells. Results: The results showed that APPNL-G-F mice allowed to voluntarily exercise showed an improvement in cognitive functions. Furthermore, long-term exercise also improved anxiety in APPNL-G-F mice as assessed by measuring thigmotaxis in the Morris water task. We also found reductions in amyloid load and microgliosis, and a preservation of cholinergic cells in the brain of APPNL-G-F mice allowed to exercise in their home cages. These profound reductions in brain pathology associated with AD are likely responsible for the observed improvement of learning and memory functions following extensive and regular exercise. Conclusion: These findings suggest the potential of physical exercise to mitigate the cognitive deficits in AD. © 2022, The Author(s).
Author Keywords
Alzheimer disease; APPNL-G-F mice; Choline acetyltransferase; Cognitive dysfunction; Microgliosis; Physical exercise
Funding details
Natural Sciences and Engineering Research Council of CanadaNSERC03857, 06347, 40352
Document Type: Article
Publication Stage: Final
Source: Scopus
Parsing genetically influenced risk pathways: genetic loci impact problematic alcohol use via externalizing and specific risk
(2022) Translational Psychiatry, 12 (1), art. no. 420, .
Barr, P.B.a b , Mallard, T.T.c d , Sanchez-Roige, S.e f , Poore, H.E.g h , Linnér, R.K.i , Porjesz, B.o , Hesselbrock, V.p , Foroud, T.q , Agrawal, A.r , Dick, D.s t , Edenberg, H.J.q u , Nurrnberger, J., Jr.q v , Liu, Y.q , Kuperman, S.w , Kramer, J.w , Meyers, J.o , Kamarajan, C.o , Pandey, A.o , Bierut, L.x , Rice, J.x , Bucholz, K.x , Schuckit, M.y , Tischfield, J.z , Hart, R.aa , Salvatore, J.s , Almasy, L.ab , Goate, A.ac , Kapoor, M.ac , Slesinger, P.ad , Scott, D.ae af , Bauer, L.p , Wetherill, L.q , Xuei, X.ag , Lai, D.q , O’Connor, S.v , Plawecki, M.v , Acion, L.w , Chan, G.p ah , Chorlian, D.B.o , Zhang, J.o , Kinreich, S.o , Pandey, G.o , Chao, M.ac , Anokhin, A.x , McCutcheon, V.x , Saccone, S.x , Aliev, F.s , Chin, H.ai , Parsian, A.ai , Waldman, I.D.j k , Palmer, A.A.e l , Harden, K.P.m n , Dick, D.M.g h , COGA Collaboratorsaj
a Department of Psychiatry & Behavioral Sciences, SUNY Downstate Health Sciences University, Brooklyn, NY, United States
b VA New York Harbor Healthcare System, Brooklyn, NY, United States
c Psychiatric and Neurodevelopmental Genetics Unit, Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, United States
d Department of Psychiatry, Harvard Medical School, Boston, MA, United States
e Department of Psychiatry, University of California San Diego, La Jolla, CA, United States
f Division of Genetic Medicine, Vanderbilt University Medical Center, Nashville, TN, United States
g Department of Psychiatry, Robert Wood Johnson Medical School, Rutgers University, Piscataway, NJ, United States
h Rutgers Addiction Research Center, Rutgers University, Piscataway, NJ, United States
i Department of Economics, Leiden University, Leiden, Netherlands
j Department of Psychology, Emory University, Atlanta, GA, United States
k Center for Computational and Quantitative Genetics, Emory University, Atlanta, GA, United States
l Institute for Genomic Medicine, University of California San Diego, La Jolla, CA, United States
m Department of Psychology, University of Texas at Austin, Austin, TX, United States
n Population Research Center, University of Texas at Austin, Austin, TX, United States
o Henri Begleiter Neurodynamics Lab, Department of Psychiatry, State University of New York, Downstate Medical Center, Brooklyn, NY, United States
p Department of Psychiatry, University of Connecticut School of Medicine, Farmington, CT, United States
q Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, United States
r Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, United States
s Department of Psychiatry, Rutgers Robert Wood Johnson Medical School, Piscataway, NJ, United States
t Rutgers Addiction Research Center, Brain Health Institute, Rutgers Biomedical and Health Sciences, Newark, United States
u Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN, United States
v Department of Psychiatry, Indiana University School of Medicine, Indianapolis, IN, United States
w Department of Psychiatry, University of Iowa Carver College of Medicine, Iowa City, IA, United States
x Department of Psychiatry, Washington University in St. Louis, St. Louis, MO, United States
y University of California, San Diego, La Jolla, CA, United States
z Department of Genetics, Rutgers University, Piscataway, NJ, United States
aa Department of Cell Biology and Neuroscience, Rutgers University, Piscataway, NJ, United States
ab Department of Genetics, Perelman School of Medicine, and the Penn-CHOP Lifespan Brain Institute, University of Pennsylvania, Philadelphia, PA, United States
ac Department of Genetics and Genomic Sciences, Ronald M. Loeb Center for Alzheimer’s Disease Icahn School of Medicine at Mount Sinai, New York, NY, United States
ad Nash Family Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, United States
ae Department of Pediatrics, Howard University, Washington, DC, United States
af Department of Human Genetics, Howard University, Washington, DC, United States
ag Center of for Medical Genomics, Indiana University School of Medicine, Indianapolis, IN, United States
ah Department of Psychiatry, University of Iowa, Iowa City, IA, United States
ai NIAAA, Bethesda, United States
Abstract
Genome-wide association studies (GWAS) identify genetic variants associated with a trait, regardless of how those variants are associated with the outcome. Characterizing whether variants for psychiatric outcomes operate via specific versus general pathways provides more informative measures of genetic risk. In the current analysis, we used multivariate GWAS to tease apart variants associated with problematic alcohol use (ALCP-total) through either a shared risk for externalizing (EXT) or a problematic alcohol use-specific risk (ALCP-specific). SNPs associated with ALCP-specific were primarily related to alcohol metabolism. Genetic correlations showed ALCP-specific was predominantly associated with alcohol use and other forms of psychopathology, but not other forms of substance use. Polygenic scores for ALCP-total were associated with multiple forms of substance use, but polygenic scores for ALCP-specific were only associated with alcohol phenotypes. Polygenic scores for both ALCP-specific and EXT show different patterns of associations with alcohol misuse across development. Our results demonstrate that focusing on both shared and specific risk can better characterize pathways of risk for substance use disorders. Parsing risk pathways will become increasingly relevant as genetic information is incorporated into clinical practice. © 2022, The Author(s).
Funding details
National Institutes of HealthNIH
National Institute on Drug AbuseNIDADP1DA054394, K02AA018755, P50AA022537, R01DA050721, U10AA008401
National Institute on Alcohol Abuse and AlcoholismNIAAA
Indiana UniversityIU
State University of New YorkSUNY
Washington University in St. LouisWUSTL
Icahn School of Medicine at Mount SinaiISMMS
University of Connecticut
University of California, San DiegoUCSD
University of IowaUI
Virginia Commonwealth UniversityVCU
Rutgers, The State University of New JerseyRU
Howard University
Vanderbilt University Medical CenterVUMC
European Research CouncilERC647648 EdGe
Document Type: Article
Publication Stage: Final
Source: Scopus
Altered methylation pattern in EXOC4 is associated with stroke outcome: an epigenome-wide association study
(2022) Clinical Epigenetics, 14 (1), art. no. 124, .
Cullell, N.a b c , Soriano-Tárraga, C.d e f , Gallego-Fábrega, C.a , Cárcel-Márquez, J.a , Muiño, E.a , Llucià-Carol, L.a , Lledós, M.a , Esteller, M.g h i , de Moura, M.C.g , Montaner, J.j k , Rosell, A.j , Delgado, P.j , Martí-Fábregas, J.l , Krupinski, J.b m , Roquer, J.d , Jiménez-Conde, J.d , Fernández-Cadenas, I.a
a Stroke Pharmacogenomics and Genetics, IIB-Sant Pau, Institut de Recerca de Sant Pau, Hospital Sant Pau, C/Sant Antoni Mª Claret,167, Barcelona, 08025, Spain
b Neurology, Hospital Universitari MútuaTerrassa/Fundacio Docència i Recerca MutuaTerrassa, Terrassa, Spain
c Facultat de Medicina, Universitat de Barcelona, Barcelona, Spain
d Neurology, Hospital del Mar, Neurovascular Research Group, IMIM, Universitat Autònoma de Barcelona/DCEXS‐Universitat Pompeu Fabra, Barcelona, Spain
e Department of Psychiatry, Washington University School of Medicine, Saint Louis, Missouri, United States
f NeuroGenomics and Informatics, Washington University School of Medicine, Saint Louis, Missouri, United States
g Cancer Epigenetics & Biology Program (PEBC), L’Hospitalet, Spain
h Department of Physiological Sciences II, School of Medicine, Universitat de Barcelona, Barcelona, Spain
i Institució Catalana de Recerca I Estudis Avançats (ICREA), Barcelona, Spain
j Neurovascular Research Laboratory, Vall d’Hebron Institut de Recerca (VHIR), Barcelona, Spain
k Department of Neurology, Hospital Universitario Virgen Macarena Sevilla, Instituto de Biomedicina de Sevilla, IBiS/Hospital Universitario Virgen del Rocío/CSIC, Universidad de Sevilla, Sevilla, Spain
l Neurology, Hospital de La Santa Creu i Sant Pau, Barcelona, Spain
m Centre for Bioscience, School of HealthCare Science, Manchester Metropolitan University, Manchester, United Kingdom
Abstract
Background and purpose: The neurological course after stroke is highly variable and is determined by demographic, clinical and genetic factors. However, other heritable factors such as epigenetic DNA methylation could play a role in neurological changes after stroke. Methods: We performed a three-stage epigenome-wide association study to evaluate DNA methylation associated with the difference between the National Institutes of Health Stroke Scale (NIHSS) at baseline and at discharge (ΔNIHSS) in ischaemic stroke patients. DNA methylation data in the Discovery (n = 643) and Replication (n = 62) Cohorts were interrogated with the 450 K and EPIC BeadChip. Nominal CpG sites from the Discovery (p value < 10–06) were also evaluated in a meta-analysis of the Discovery and Replication cohorts, using a random-fixed effect model. Metabolic pathway enrichment was calculated with methylGSA. We integrated the methylation data with 1305 plasma protein expression levels measured by SOMAscan in 46 subjects and measured RNA expression with RT-PCR in a subgroup of 13 subjects. Specific cell-type methylation was assessed using EpiDISH. Results: The meta-analysis revealed an epigenome-wide significant association in EXOC4 (p value = 8.4 × 10–08) and in MERTK (p value = 1.56 × 10–07). Only the methylation in EXOC4 was also associated in the Discovery and in the Replication Cohorts (p value = 1.14 × 10–06 and p value = 1.3 × 10–02, respectively). EXOC4 methylation negatively correlated with the long-term outcome (coefficient = − 4.91) and showed a tendency towards a decrease in EXOC4 expression (rho = − 0.469, p value = 0.091). Pathway enrichment from the meta-analysis revealed significant associations related to the endocytosis and deubiquitination processes. Seventy-nine plasma proteins were differentially expressed in association with EXOC4 methylation. Pathway analysis of these proteins showed an enrichment in natural killer (NK) cell activation. The cell-type methylation analysis in blood also revealed a differential methylation in NK cells. Conclusions: DNA methylation of EXOC4 is associated with a worse neurological course after stroke. The results indicate a potential modulation of pathways involving endocytosis and NK cells regulation. © 2022, The Author(s).
Funding details
III Institute/FEDER—PI18/01338, PI20/00678
CM18/00198
CD20/00043, FI19/00309
2019_FI_B 00853
RD16/0019/0002, RD16/0019/0010, RD16/0019/0011, RD16/0019/0021
Agència de Gestió d’Ajuts Universitaris i de RecercaAGAUR
Instituto de Salud Carlos IIIISCIII
European Social FundESFCP12/03298
European Regional Development FundERDF2017SGR-1427, PI17/02089
Document Type: Article
Publication Stage: Final
Source: Scopus
Shared brain and genetic architectures between mental health and physical activity
(2022) Translational Psychiatry, 12 (1), art. no. 428, .
Zhang, W.a , Paul, S.E.b , Winkler, A.c , Bogdan, R.b , Bijsterbosch, J.D.a
a Radiology Department, Washington University School of Medicine, St. Louis, MO, United States
b Department of Psychological & Brain Sciences, Washington University in St. Louis, St. Louis, MO, United States
c National Institute of Mental Health/National Institutes of Health, Rockville, MD, United States
Abstract
Physical activity is correlated with, and effectively treats various forms of psychopathology. However, whether biological correlates of physical activity and psychopathology are shared remains unclear. Here, we examined the extent to which the neural and genetic architecture of physical activity and mental health are shared. Using data from the UK Biobank (N = 6389), we applied canonical correlation analysis to estimate associations between the amplitude and connectivity strength of subnetworks of three major neurocognitive networks (default mode, DMN; salience, SN; central executive networks, CEN) with accelerometer-derived measures of physical activity and self-reported mental health measures (primarily of depression, anxiety disorders, neuroticism, subjective well-being, and risk-taking behaviors). We estimated the genetic correlation between mental health and physical activity measures, as well as putative causal relationships by applying linkage disequilibrium score regression, genomic structural equational modeling, and latent causal variable analysis to genome-wide association summary statistics (GWAS N = 91,105–500,199). Physical activity and mental health were associated with connectivity strength and amplitude of the DMN, SN, and CEN (r’s ≥ 0.12, p’s < 0.048). These neural correlates exhibited highly similar loading patterns across mental health and physical activity models even when accounting for their shared variance. This suggests a largely shared brain network architecture between mental health and physical activity. Mental health and physical activity (including sleep) were also genetically correlated (|rg| = 0.085–0.121), but we found no evidence for causal relationships between them. Collectively, our findings provide empirical evidence that mental health and physical activity have shared brain and genetic architectures and suggest potential candidate subnetworks for future studies on brain mechanisms underlying beneficial effects of physical activity on mental health. © 2022, The Author(s).
Funding details
National Institutes of HealthNIH
National Institute of Mental HealthNIMHR01 MH128286
National Institute of Neurological Disorders and StrokeNINDSR34 NS118618
McDonnell Center for Systems Neuroscience1 F31 AA029934-01
Document Type: Article
Publication Stage: Final
Source: Scopus
Location-atypical lesions in non-ketotic hyperglycemic epilepsy: Expanding the clinico-radiographic phenotype [Location-atypical lesions in non-ketotic hyperglycemic epilepsy: expanding the clinico-radiographic phenotype]
(2022) Epileptic Disorders: International Epilepsy Journal with Videotape, 24 (6), pp. 1-8.
Amar, J.Y.a , Bhattacharya, A.K.b , Uzo-Okereke, A.M.a , Chou, C.A.c , Vo, K.D.d , Goyal, M.S.d , Bucelli, R.C.a
a Department of Neurology, Washington University School of Medicine, St. Louis, MO 63110, United States
b Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, MO, United States
c Department of Neurology, Oregon Health & Science University, Portland, OR, USA
d Division of Neuroradiology, Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, MO, United States
Abstract
Non-ketotic hyperglycemia (NKH) is associated with a spectrum of symptoms and radiographic findings due to poorly-controlled diabetes mellitus. These lesions, which predominantly affect the parieto-occipital cortex, are commonly missed by neurologists and neuroradiologists due to their subtle hypointense appearance on T2-based imaging. We report four atypical cases of this syndrome to highlight its subtle, protean presentation in order to aid timely diagnosis. Based on our institutional case series, we describe four cases of NKH with atypical presentation and lesion burden affecting the anterior cortex. We review the clinical presentations, laboratory abnormalities, neuroimaging, and corresponding electroencephalography. Four patients with atypical NKH were characterized in our series. Presenting symptoms ranged from rhythmic hand-tapping to generalized tonic-clonic status epilepticus. Laboratory values were notable for marked hyperglycemia (range: 447 – 627 mg/dL), mild pseudo-hyponatremia (range: 127 – 136 mmol/L), and elevated hemoglobin A1C levels (range: 10.9 – 16.1%). All patients were found to have the classically described pattern of T2-based hypointensity; three with atypical distributions involving the “anterior” cortex. These lesions corresponded to the electrographic nidus of seizure burden. During follow-up, both seizures and T2-based hypointensity resolved within weeks of serum glucose normalization. Our series of four NKH patients with atypical findings of T2-based signal abnormalities expands the clinico-radiographic phenotype revealing a more protean distribution than previously described. Knowledge of these atypical imaging features will aid both the neurologist and radiologist in timely diagnosis and care of these patients.
Author Keywords
epilepsy; hyperglycemia; hypointensity; NKH; non-ketotic; seizure
Document Type: Article
Publication Stage: Final
Source: Scopus
Blood–brain barrier opening in a large animal model using closed-loop microbubble cavitation-based feedback control of focused ultrasound sonication
(2022) Scientific Reports, 12 (1), art. no. 16147, .
Chien, C.-Y.a , Xu, L.a , Pacia, C.P.a , Yue, Y.a , Chen, H.a b
a Department of Biomedical Engineering, Washington University in St. Louis, Saint Louis, MO 63130, United States
b Department of Radiation Oncology, Washington University School of Medicine, 4511 Forest Park Ave., Saint Louis, MO 63108, United States
Abstract
Focused ultrasound (FUS) in combination with microbubbles has been established as a promising technique for noninvasive and localized Blood–brain barrier (BBB) opening. Real-time passive cavitation detection (PCD)-based feedback control of the FUS sonication is critical to ensure effective BBB opening without causing hemorrhage. This study evaluated the performance of a closed-loop feedback controller in a porcine model. Calibration of the baseline cavitation level was performed for each targeted brain location by a FUS sonication in the presence of intravenously injected microbubbles at a low acoustic pressure without inducing BBB opening. The target cavitation level (TCL) was defined for each target based on the baseline cavitation level. FUS treatment was then performed under real-time PCD-based feedback controller to maintain the cavitation level at the TCL. After FUS treatment, contrast-enhanced MRI and ex vivo histological staining were performed to evaluate the BBB permeability and safety. Safe and effective BBB opening was achieved with the BBB opening volume increased from 3.8 ± 0.7 to 53.6 ± 23.3 mm3 as the TCL was increased from 0.25 to 1 dB. This study validated that effective and safe FUS-induced BBB opening in a large animal model can be achieved with closed-loop feedback control of the FUS sonication. © 2022, The Author(s).
Funding details
National Institutes of HealthNIHR01EB027223, R01EB030102, R01MH116981
Document Type: Article
Publication Stage: Final
Source: Scopus
The effect of A1 and A2 reactive astrocyte expression on hydrocephalus shunt failure
(2022) Fluids and Barriers of the CNS, 19 (1), art. no. 78, .
Khodadadei, F.a , Arshad, R.b , Morales, D.M.c , Gluski, J.d , Marupudi, N.I.d , McAllister, J.P., IIc , Limbrick, D.D., Jr.c , Harris, C.A.a d e
a Department of Chemical Engineering and Materials Science, Wayne State University, Detroit, MI, United States
b School of Medicine, Wayne State University, Detroit, MI, United States
c Department of Neurosurgery, Washington University School of Medicine, St. Louis, MO, United States
d Department of Neurosurgery, Wayne State University School of Medicine, Detroit, MI, United States
e Department of Biomedical Engineering, Wayne State University, Detroit, MI, United States
Abstract
Background: The composition of tissue obstructing neuroprosthetic devices is largely composed of inflammatory cells with a significant astrocyte component. In a first-of-its-kind study, we profile the astrocyte phenotypes present on hydrocephalus shunts. Methods: qPCR and RNA in-situ hybridization were used to quantify pro-inflammatory (A1) and anti-inflammatory (A2) reactive astrocyte phenotypes by analyzing C3 and EMP1 genes, respectively. Additionally, CSF cytokine levels were quantified using ELISA. In an in vitro model of astrocyte growth on shunts, different cytokines were used to prevent the activation of resting astrocytes into the A1 and A2 phenotypes. Obstructed and non-obstructed shunts were characterized based on the degree of actual tissue blockage on the shunt surface instead of clinical diagnosis. Results: The results showed a heterogeneous population of A1 and A2 reactive astrocytes on the shunts with obstructed shunts having a significantly higher proportion of A2 astrocytes compared to non-obstructed shunts. In addition, the pro-A2 cytokine IL-6 inducing proliferation of astrocytes was found at higher concentrations among CSF from obstructed samples. Consequently, in the in vitro model of astrocyte growth on shunts, cytokine neutralizing antibodies were used to prevent activation of resting astrocytes into the A1 and A2 phenotypes which resulted in a significant reduction in both A1 and A2 growth. Conclusions: Therefore, targeting cytokines involved with astrocyte A1 and A2 activation is a promising intervention aimed to prevent shunt obstruction. © 2022, The Author(s).
Author Keywords
A1 and A2 reactive astrocyte phenotype; Glial Scar; Hydrocephalus; Neuroprosthetic device failure; Targeted drug delivery
Funding details
Wayne State UniversityWSU
Hydrocephalus AssociationHA
Document Type: Article
Publication Stage: Final
Source: Scopus
Association of Pretreatment Hippocampal Volume With Neurocognitive Function in Patients Treated With Hippocampal Avoidance Whole Brain Radiation Therapy for Brain Metastases: Secondary Analysis of NRG Oncology/RTOG 0933
(2022) Advances in Radiation Oncology, 7 (6), art. no. 100859, .
Abraham, C.D.a b , Pugh, S.L.c , Bovi, J.A.d , Gondi, V.e , Mehta, M.P.f , Benzinger, T.a , Owen, C.J.a , Lo, S.S.g , Kundapur, V.h , Brown, P.D.i , Sun, A.Y.j , Howard, S.P.k , DeNittis, A.S.l , Robinson, C.G.a , Kachnic, L.A.m
a Washington University School of Medicine, Saint Louis, Missouri
b Barnes-Jewish Hospital, Saint Louis, Missouri
c NRG Oncology Statistics and Data Management Center, Philadelphia, Pennsylvania
d Froedtert and the Medical College of Wisconsin, Milwaukee, WI, United States
e Northwestern Medicine Cancer, Warrenville, IL, United States
f Miami Cancer Institute, Miami, Florida
g University of Washington Medical Center, Seattle, WA, United States
h Saskatoon Cancer Centre, Saskatoon, SK, Canada
i Mayo Clinic, Rochester, Minnesota
j University Health Network–Princess Margaret Hospital, Toronto, ON, Canada
k University of Wisconsin Hospital and Clinics, Madison, WI, United States
l MainLine Health NCORP, WynnewoodPennsylvania
m Columbia University, New York, New York
Abstract
Purpose: Hippocampal volume (HV) is an established predicting factor for neurocognitive function (NCF) in neurodegenerative disease. Whether the same phenomenon exists with hippocampal-avoidant whole brain radiation therapy is not known; therefore, we assessed the association of baseline HV with NCF among patients enrolled on RTOG 0933. Methods and Materials: Hippocampal volume and total brain volume were calculated from the radiation therapy plan. Hippocampal volume was correlated with baseline and 4-month NCF scores (Hopkins Verbal Learning Test–Revised [HVLT-R] Total Recall [TR], Immediate Recognition, and Delayed Recall [DR]) using Pearson correlation. Deterioration in NCF was defined per the primary endpoint of RTOG 0933(mean 4-month relative decline in HVLT-R DR). Comparisons between patients with deteriorated and nondeteriorated NCF were made using the Wilcoxon test. Results: Forty-two patients were evaluable. The median age was 56.5 years (range, 28-83 years), and 81% had a class II recursive partitioning analysis. The median total, right, and left HVs were 5.4 cm3 (range, 1.9-7.4 cm3), 2.8 cm3 (range, 0.9-4.0 cm3), and 2.7 cm3 (range, 1.0-3.7 cm3), respectively. The median total brain volume was 1343 cm3 (range, 1120.5-1738.8 cm3). For all measures of corrected HV, increasing HV was associated with higher baseline HVLT-R TR and DR scores (ρ: range, 0.35-0.40; P-value range,. 009-.024) and 4-month TR and DR scores (ρ: range, 0.29-0.40; P-value range,. 009-.04), with the exception of right HV and 4-month DR scores (ρ: 0.29; P = .059). There was no significant association between HV and NCF change between baseline and 4 months. Fourteen patients (33.3%) developed NCF deterioration per the primary endpoint of RTOG 0933. There was no significant difference in HV between patients with deteriorated and nondeteriorated NCF, although in all instances, patients with deteriorated NCF had numerically lower HV. Conclusions: Larger HV was positively associated with improved performance on baseline and 4-month HVLT-R TR and DR scores in patients with brain metastases undergoing hippocampal-avoidant whole brain radiation therapy but was not associated with a change in NCF. © 2021 The Authors
Funding details
National Cancer InstituteNCI
Merck
Roche
Biogen
Elekta
Document Type: Article
Publication Stage: Final
Source: Scopus
A bioresorbable peripheral nerve stimulator for electronic pain block
(2022) Science Advances, 8 (40), p. eabp9169.
Lee, G.a b , Ray, E.c d , Yoon, H.-J.a , Genovese, S.d , Choi, Y.S.a , Lee, M.-K.a , Şahin, S.a e , Yan, Y.d , Ahn, H.-Y.a , Bandodkar, A.J.f g , Kim, J.a , Park, M.a , Ryu, H.h , Kwak, S.S.i , Jung, Y.H.j , Odabas, A.d k , Khandpur, U.d , Ray, W.Z.c d , MacEwan, M.R.c d , Rogers, J.A.a l m n o
a Northwestern University, Evanston, IL 60208, United States
b Precision Biology Research Center, Sungkyunkwan University, Suwon, 16419, South Korea
c Department of Biomedical Engineering, Washington University in St. Louis, St. Louis, MO 63130, United States
d Department of Neurological Surgery, Washington University School of Medicine in St. Louis, St. Louis, MO 63110, United States
e Department of Bioengineering, Bilecik Şeyh Edebali UniversityBilecik 11230, Turkey
f Department of Electrical and Computer Engineering, North Carolina State University, Raleigh, United States
g Center for Advanced Self-Powered Systems of Integrated Sensors and Technologies (ASSIST), North Carolina State University, Raleigh, United States
h Department of Advanced Materials Engineering, Chung-Ang University, Anseong, 17546, South Korea
i Center for Bionics, Biomedical Research Division, Korea Institute of Science and TechnologySeoul 02792, South Korea
j Department of Electronic Engineering, Hanyang UniversitySeoul 04763, South Korea
k Department of Internal Medicine, Stanford University Medical Center, Stanford, CA 94305, USA
l Department of Materials Science and Engineering, Northwestern University, Evanston, IL 60208, United States
m Department of Mechanical Engineering, Northwestern University, Evanston, IL 60208, United States
n Department of Biomedical Engineering, Northwestern University, Evanston, IL 60208, United States
o Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, United States
Abstract
Local electrical stimulation of peripheral nerves can block the propagation of action potentials, as an attractive alternative to pharmacological agents for the treatment of acute pain. Traditional hardware for such purposes, however, involves interfaces that can damage nerve tissue and, when used for temporary pain relief, that impose costs and risks due to requirements for surgical extraction after a period of need. Here, we introduce a bioresorbable nerve stimulator that enables electrical nerve block and associated pain mitigation without these drawbacks. This platform combines a collection of bioresorbable materials in architectures that support stable blocking with minimal adverse mechanical, electrical, or biochemical effects. Optimized designs ensure that the device disappears harmlessly in the body after a desired period of use. Studies in live animal models illustrate capabilities for complete nerve block and other key features of the technology. In certain clinically relevant scenarios, such approaches may reduce or eliminate the need for use of highly addictive drugs such as opioids.
Document Type: Article
Publication Stage: Final
Source: Scopus
Integrating transcriptomics, metabolomics, and GWAS helps reveal molecular mechanisms for metabolite levels and disease risk
(2022) American Journal of Human Genetics, 109 (10), pp. 1727-1741.
Yin, X.a , Bose, D.a , Kwon, A.a , Hanks, S.C.a , Jackson, A.U.a , Stringham, H.M.a , Welch, R.a , Oravilahti, A.b , Fernandes Silva, L.b , Locke, A.E.c , Fuchsberger, C.a d , Service, S.K.e , Erdos, M.R.f , Bonnycastle, L.L.f , Kuusisto, J.b g , Stitziel, N.O.c h i , Hall, I.M.j , Morrison, J.a , Ripatti, S.k l m , Palotie, A.k l n , Freimer, N.B.e , Collins, F.S.f , Mohlke, K.L.o , Scott, L.J.a , Fauman, E.B.p , Burant, C.q , Boehnke, M.a , Laakso, M.b , Wen, X.a , FinnGenr
a Department of Biostatistics and Center for Statistical Genetics, University of Michigan School of Public Health, Ann Arbor, MI 48109, United States
b Institute of Clinical Medicine, Internal Medicine, University of Eastern Finland and Kuopio University Hospital, Kuopio, 70210, Finland
c McDonnell Genome Institute, Washington University School of Medicine, St Louis, MO 63108, United States
d Institute for Biomedicine, Eurac Research, Bolzano, 39100, Italy
e Center for Neurobehavioral Genetics, Jane and Terry Semel Institute for Neuroscience and Human Behavior, University of California Los Angeles, Los Angeles, CA 90024, United States
f Molecular Genetics Section, Center for Precision Health Research, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, United States
g Center for Medicine and Clinical Research, Kuopio University Hospital, Kuopio, 70210, Finland
h Cardiovascular Division, Department of Medicine, Washington University School of Medicine, St Louis, MO 63110, United States
i Department of Genetics, Washington University School of Medicine, St Louis, MO 63110, United States
j Center for Genomic Health, Department of Genetics, Yale University, New Haven, CT 06510, United States
k Institute for Molecular Medicine Finland, FIMM, HiLIFE, University of Helsinki, Helsinki, 00290, Finland
l Department of Public Health, University of Helsinki, Helsinki, 00014, Finland
m Broad Institute of MIT and Harvard, Cambridge, MA 02142, United States
n Analytic and Translational Genetics Unit, Department of Medicine, Department of Neurology, Department of Psychiatry, Massachusetts General Hospital, Boston, MA 02114, United States
o Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, United States
p Internal Medicine Research Unit, Pfizer Worldwide Research, Development and Medical, Cambridge, MA 02139, United States
q Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, United States
Abstract
Transcriptomics data have been integrated with genome-wide association studies (GWASs) to help understand disease/trait molecular mechanisms. The utility of metabolomics, integrated with transcriptomics and disease GWASs, to understand molecular mechanisms for metabolite levels or diseases has not been thoroughly evaluated. We performed probabilistic transcriptome-wide association and locus-level colocalization analyses to integrate transcriptomics results for 49 tissues in 706 individuals from the GTEx project, metabolomics results for 1,391 plasma metabolites in 6,136 Finnish men from the METSIM study, and GWAS results for 2,861 disease traits in 260,405 Finnish individuals from the FinnGen study. We found that genetic variants that regulate metabolite levels were more likely to influence gene expression and disease risk compared to the ones that do not. Integrating transcriptomics with metabolomics results prioritized 397 genes for 521 metabolites, including 496 previously identified gene-metabolite pairs with strong functional connections and suggested 33.3% of such gene-metabolite pairs shared the same causal variants with genetic associations of gene expression. Integrating transcriptomics and metabolomics individually with FinnGen GWAS results identified 1,597 genes for 790 disease traits. Integrating transcriptomics and metabolomics jointly with FinnGen GWAS results helped pinpoint metabolic pathways from genes to diseases. We identified putative causal effects of UGT1A1/UGT1A4 expression on gallbladder disorders through regulating plasma (E,E)-bilirubin levels, of SLC22A5 expression on nasal polyps and plasma carnitine levels through distinct pathways, and of LIPC expression on age-related macular degeneration through glycerophospholipid metabolic pathways. Our study highlights the power of integrating multiple sets of molecular traits and GWAS results to deepen understanding of disease pathophysiology. © 2022 The Author(s)
Author Keywords
colocalizataion; genome-wide association study; metabolomics; transcriptome-wide association study; transcriptomics
Funding details
National Institutes of HealthNIHP01 HL151328, R01 DK093757, R01 DK119380, R01 HL131961, R35 GM138121, U01 DK062370, U01 DK105561, UM1 HG008853
American Diabetes AssociationADA1-19-PDF-061
National Human Genome Research InstituteNHGRIZIA HG000024
Pfizer
University of MichiganU-M
Helsingin YliopistoHY
Regeneron Pharmaceuticals
Academy of FinlandAKA321428
Sydäntutkimussäätiö
Sigrid Juséliuksen Säätiö312062, 312074, 336820, 336824
Horizon 2020101016775
Document Type: Article
Publication Stage: Final
Source: Scopus
GABBR1 monoallelic de novo variants linked to neurodevelopmental delay and epilepsy
(2022) American Journal of Human Genetics, 109 (10), pp. 1885-1893.
Cediel, M.L.a , Stawarski, M.b , Blanc, X.a , Nosková, L.c , Magner, M.c d , Platzer, K.e , Gburek-Augustat, J.f , Baldridge, D.g , Constantino, J.N.g , Ranza, E.a , Bettler, B.b , Antonarakis, S.E.a
a Medigenome, Swiss Institute of Genomic Medicine, Geneva, 1207, Switzerland
b Department of Biomedicine, Pharmazentrum, University of Basel, Klingelbergstrasse 50/70, Basel, 4056, Switzerland
c Department of Pediatrics and Inherited Metabolic Disorders, First Faculty of Medicine, Charles University and General University Hospital in Prague, Prague, Czech Republic
d Department of Pediatrics, First Faculty of Medicine, Charles University and University Thomayer Hospital in Prague, Prague, Czech Republic
e Institute of Human Genetics, University of Leipzig Medical Center, Leipzig, Germany
f Division of Neuropaediatrics, Hospital for Children and Adolescents, University Hospital Leipzig, Leipzig, Germany
g Washington University in St. Louis, St. Louis, MO, United States
Abstract
GABAB receptors are obligatory heterodimers responsible for prolonged neuronal inhibition in the central nervous system. The two receptor subunits are encoded by GABBR1 and GABBR2. Variants in GABBR2 have been associated with a Rett-like phenotype (MIM: 617903), epileptic encephalopathy (MIM: 617904), and milder forms of developmental delay with absence epilepsy. To date, however, no phenotypes associated with pathogenic variants of GABBR1 have been established. Through GeneMatcher, we have ascertained four individuals who each have a monoallelic GABBR1 de novo non-synonymous variant; these individuals exhibit motor and/or language delay, ranging from mild to severe, and in one case, epilepsy. Further phenotypic features include varying degrees of intellectual disability, learning difficulties, autism, ADHD, ODD, sleep disorders, and muscular hypotonia. We functionally characterized the four de novo GABBR1 variants, p.Glu368Asp, p.Ala397Val, p.Ala535Thr, and p.Gly673Asp, in transfected HEK293 cells. GABA fails to efficiently activate the variant receptors, most likely leading to an increase in the excitation/inhibition balance in the central nervous system. Variant p.Gly673Asp in transmembrane domain 3 (TMD3) renders the receptor completely inactive, consistent with failure of the receptor to reach the cell surface. p.Glu368Asp is located near the orthosteric binding site and reduces GABA potency and efficacy at the receptor. GABA exhibits normal potency but decreased efficacy at the p.Ala397Val and p.Ala535Thr variants. Functional characterization of GABBR1-related variants provides a rationale for understanding the severity of disease phenotypes and points to possible therapeutic strategies. © 2022 American Society of Human Genetics
Author Keywords
GABBR1; gene; mendelian disease
Funding details
LM2018132
NV19-07-00136
Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen ForschungSNF31003A-152970
Ministerstvo Zdravotnictví Ceské RepublikyMZCR
Document Type: Article
Publication Stage: Final
Source: Scopus
A non-canonical retina-ipRGCs-SCN-PVT visual pathway for mediating contagious itch behavior
(2022) Cell Reports, 41 (1), art. no. 111444, .
Gao, F.a b , Ma, J.a b , Yu, Y.-Q.a b c , Gao, X.-F.a b , Bai, Y.a d , Sun, Y.a d , Liu, J.a b , Liu, X.a b , Barry, D.M.a b , Wilhelm, S.a b , Piccinni-Ash, T.a b , Wang, N.a b , Liu, D.a b g , Ross, R.A.e , Hao, Y.a b , Huang, X.f , Jia, J.-J.a b , Yang, Q.a b , Zheng, H.f , van Nispen, J.a b , Chen, J.c , Li, H.d , Zhang, J.f , Li, Y.-Q.d , Chen, Z.-F.a b
a Center for the Study of Itch and Sensory Disorders, Washington University School of Medicine, St. Louis, MO 63110, United States
b Departments of Anesthesiology, Medicine, Psychiatry and, Developmental Biology, Washington University School of Medicine, St. Louis, MO 63110, United States
c Institute for Biomedical Sciences of Pain, Tangdu Hospital, Fourth Military Medical University, Xi’an, 710038, China
d Department of Anatomy, Histology and Embryology & K.K. Leung Brain Research Centre, Fourth Military Medical University, Xi’an, 710032, China
e Department of Neuroscience, Psychiatry and Medicine, Albert Einstein College of Medicine Rose F. Kennedy Center, Bronx, NY, United States
f Institutes of Brain Science, State Key Laboratory of Medical Neurobiology, MOE Frontiers Center for Brain Science and Institute for Medical and Engineering Innovation, Eye & ENT Hospital, Fudan University, Shanghai, 200031, China
g Department of Pain Management, the State Key Clinical Specialty in Pain Medicine, the Second Affiliated Hospital, Guangzhou Medical University, Guangzhou, 510260, China
Abstract
Contagious itch behavior informs conspecifics of adverse environment and is crucial for the survival of social animals. Gastrin-releasing peptide (GRP) and its receptor (GRPR) in the suprachiasmatic nucleus (SCN) of the hypothalamus mediates contagious itch behavior in mice. Here, we show that intrinsically photosensitive retina ganglion cells (ipRGCs) convey visual itch information, independently of melanopsin, from the retina to GRP neurons via PACAP-PAC1R signaling. Moreover, GRPR neurons relay itch information to the paraventricular nucleus of the thalamus (PVT). Surprisingly, neither the visual cortex nor superior colliculus is involved in contagious itch. In vivo calcium imaging and extracellular recordings reveal contagious itch-specific neural dynamics of GRPR neurons. Thus, we propose that the retina-ipRGC-SCN-PVT pathway constitutes a previously unknown visual pathway that probably evolved for motion vision that encodes salient environmental cues and enables animals to imitate behaviors of conspecifics as an anticipatory mechanism to cope with adverse conditions. © 2022 The Author(s)
Author Keywords
contagious itch behavior; CP: Neuroscience; GRP; GRPR; ipRGCs; itch stimuli; neural dynamics; PACAP; SCN; scratching motion; stress
Funding details
National Institutes of HealthNIH1R01AR056318–06, R01 DA037261-01A1, R01NS094344
Document Type: Article
Publication Stage: Final
Source: Scopus
DNA Methylation and Ischemic Stroke Risk: An Epigenome-Wide Association Study
(2022) Thrombosis and Haemostasis, 122 (10), pp. 1767-1778.
Cullell, N.a b c , Soriano-Tárraga, C.d e , Gallego-Fábrega, C.a , Cárcel-Márquez, J.a , Torres-Águila, N.P.a f , Muiño, E.a , Lledós, M.a , Llucià-Carol, L.a g , Esteller, M.h i j k , Castro De Moura, M.h , Montaner, J.l , Fernández-Sanlés, A.m n , Elosua, R.m o p , Delgado, P.q , Martí-Fábregas, J.r , Krupinski, J.b s , Roquer, J.d , Jiménez-Conde, J.d , Fernández-Cadenas, I.a b
a Institut d’Investigació Biomèdica Sant Pau (IIB Sant PAU), Sant Quintí, Barcelona, Spain
b Department of Neurology, Hospital Universitari MútuaTerrassa, Fundacio Docència i Recerca MútuaTerrassa, Barcelona, Spain
c Facultat de Medicina, Universitat de Barcelona, Barcelona, Spain
d Neurovascular Research Group, Department of Neurology, Hospital Del Mar, Imim, Universitat Autònoma de Barcelona, DCEXS-Universitat Pompeu Fabra, Barcelona, Spain
e Department of Psychiatry, NeuroGenomics and Informatics, Washington University School of Medicine, St. Louis, MO, United States
f Evolutionary Developmental Genomics Research Group, The Scottish Oceans Institute, University of St Andrews, St Andrews, United Kingdom
g Department of Brain Ischemia and Neurodegeneration, Institut d’Investigacions Biomèdiques de Barcelona, Consejo Superior de Investigaciones Científicas (CSIC), Barcelona, Spain
h Josep Carreras Leukaemia Research Institute, Barcelona, Spain
i Physiological Sciences Department, School of Medicine and Health Sciences, University of Barcelona, Barcelona, Spain
j Institució Catalana de Recerca i Estudis Avançats, Barcelona, Spain
k Centro de Investigación Biomédica en Red Cancer, Barcelona, Spain
l Department of Neurology, Hospital Universitario Virgen Macarena, Institute of Biomedicine of Seville, Hospital Universitario Virgen Del Rocío, Csic, University of Seville, Seville, Spain
m Cardiovascular Epidemiology and Genetics Research Group, Imim, Barcelona, Spain
n Medical Research Council Integrative Epidemiology Unit, University of Bristol, Bristol, United Kingdom
o Ciber Cardiovascular Diseases, Instituto Carlos Iii, Barcelona, Spain
p School of Medicine, University of Vic-Central University of Catalonia, Barcelona, Spain
q Neurovascular Research Laboratory, Vall d’Hebron Institute of Research, Barcelona, Spain
r Department of Neurology, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain
s Centre for Bioscience, School of HealthCare Science, Manchester Metropolitan University, Manchester, United Kingdom
Abstract
Background Ischemic stroke (IS) risk heritability is partly explained by genetics. Other heritable factors, such as epigenetics, could explain an unknown proportion of the IS risk. The objective of this study is to evaluate DNA methylation association with IS using epigenome-wide association studies (EWAS). Methods We performed a two-stage EWAS comprising 1,156 subjects. Differentially methylated positions (DMPs) and differentially methylated regions (DMRs) were assessed using the Infinium 450K and EPIC BeadChip in the discovery cohort (252 IS and 43 controls). Significant DMPs were replicated in an independent cohort (618 IS and 243 controls). Stroke subtype associations were also evaluated. Differentially methylated cell-type (DMCT) was analyzed in the replicated CpG sites using EpiDISH. We additionally performed pathway enrichment analysis and causality analysis with Mendelian randomization for the replicated CpG sites. Results A total of 957 CpG sites were epigenome-wide-significant (p ≤ 10 -7) in the discovery cohort, being CpG sites in the top signals (logFC = 0.058, p = 2.35 × 10 -22; logFC = 0.035, p = 3.22 × 10 -22, respectively). ZFHX3 and MAP3K1 were among the most significant DMRs. In addition, 697 CpG sites were replicated considering Bonferroni-corrected p -values (p < 5.22 × 10 -5). All the replicated DMPs were associated with risk of cardioembolic, atherothrombotic, and undetermined stroke. The DMCT analysis demonstrated that the significant associations were driven by natural killer cells. The pathway enrichment analysis showed overrepresentation of genes belonging to certain pathways including oxidative stress. ZFHX3 and MAP3K1 methylation was causally associated with specific stroke-subtype risk. Conclusion Specific DNA methylation pattern is causally associated with IS risk. These results could be useful for specifically predicting stroke occurrence and could potentially be evaluated as therapeutic targets. © 2022 Georg Thieme Verlag. All rights reserved.
Author Keywords
DNA methylation; epigenetics; epigenome-wide association studies; EWAS; stroke
Document Type: Article
Publication Stage: Final
Source: Scopus
Stroke Mimics Are Not Benign in Immunocompromised Children
(2022) Stroke, 53 (10), pp. E442-E443.
Mahdi, J.a , Bach, A.b , Smith, A.E.c , Tomko, S.R.c , Fields, M.E.d , Griffith, J.L.c , Morris, S.M.c , Guerriero, R.M.c , Noetzel, M.J.c , Guilliams, K.P.d e , Agner, S.C.c
a Department of Neurology, Stanford University, Palo Alto, CA, United States
b Department of Pediatrics, University of Missouri Health Care, Washington University, School of Medicine, St. Louis, MO, United States
c Department of Neurology, Washington University, School of Medicine, St. Louis, MO, United States
d Department of Pediatrics, Washington University, School of Medicine, St. Louis, MO, United States
e Mallinckrodt Institute of Radiology, Washington University, School of Medicine, St. Louis, MO, United States
Document Type: Article
Publication Stage: Final
Source: Scopus
Substance Use and Performance of Toxicology Screens in the Greater Cincinnati Northern Kentucky Stroke Study
(2022) Stroke, 53 (10), pp. 3082-3090.
Madsen, T.E.a b , Cummings, O.W.a , De Los Rios La Rosa, F.c d , Khoury, J.C.e f , Alwell, K.d , Woo, D.d g , Ferioli, S.d g , Martini, S.h , Adeoye, O.i , Khatri, P.d g , Flaherty, M.L.d g , Mackey, J.j , Mistry, E.A.d g , Demel, S.L.d g , Coleman, E.k , Jasne, A.S.l , Slavin, S.J.m , Walsh, K.d g , Star, M.n , Broderick, J.P.d g , Kissela, B.M.d g , Kleindorfer, D.O.d g
a Department of Emergency Medicine, Alpert Medical School, Brown University, Providence, RI, United States
b Department of Epidemiology, Brown University, School of Public Health, Providence, RI, United States
c Miami Neuroscience Institute, Baptist Health South Florida
d Department of Neurology and Rehabilitation Medicine, University of Cincinnati, College of MedicineOH, United States
e Department of Pediatrics, University of Cincinnati, College of MedicineOH, United States
f Division of Biostatistics and Epidemiology, Cincinnati Children’s Hospital, Medical CenterOH, United States
g UC Gardner Neuroscience Institute, Cincinnati, OH, United States
h Neurology Program, Veterans Health Administration and Department of Neurology, Baylor College of Medicine, Houston, TX, United States
i Department of Emergency Medicine, Washington University, St. Louis, MO, United States
j Department of Neurology, Indiana University, School of Medicine, Indianapolis, United States
k Department of Neurology, University of ChicagoIL, United States
l Department of Neurology, Yale School of Medicine, New Haven, CT, United States
m University of Kansas Medical Center, Beersheva, Israel
n Soroka Medical Center, Beersheva, Israel
Abstract
Background: Though stroke risk factors such as substance use may vary with age, less is known about trends in substance use over time or about performance of toxicology screens in young adults with stroke. Methods: Using the Greater Cincinnati Northern Kentucky Stroke Study, a population-based study in a 5-county region comprising 1.3 million people, we reported the frequency of documented substance use (cocaine/marijuana/opiates/other) obtained from electronic medical record review, overall and by race/gender subgroups among physician-adjudicated stroke events (ischemic and hemorrhagic) in adults 20 to 54 years of age. Secondary analyses included heavy alcohol use and cigarette smoking. Data were reported for 5 one-year periods spanning 22 years (1993/1994-2015), and trends over time were tested. For 2015, to evaluate factors associated with performance of toxicology screens, multiple logistic regression was performed. Results: Overall, 2152 strokes were included: 74.5% were ischemic, mean age was 45.7±7.6, 50.0% were women, and 35.9% were Black. Substance use was documented in 4.4%, 10.4%, 19.2%, 24.0%, and 28.8% of cases in 1993/1994, 1999, 2005, 2010, and 2015, respectively (Ptrend<0.001). Between 1993/1994 and 2015, documented substance use increased in all demographic subgroups. Adjusting for gender, comorbidities, and National Institutes of Health Stroke Scale, predictors of toxicology screens included Black race (adjusted odds ratio, 1.58 [95% CI, 1.02-2.45]), younger age (adjusted odds ratio, 0.70 [95% CI, 0.53-0.91], per 10 years), current smoking (adjusted odds ratio, 1.62 [95% CI, 1.06-2.46]), and treatment at an academic hospital (adjusted odds ratio, 1.80 [95% CI, 1.14-2.84]). After adding chart-reported substance use to the model, only chart-reported substance abuse and age were significant. Conclusions: In a population-based study of young adults with stroke, documented substance use increased over time, and documentation of substance use was higher among Black compared with White individuals. Further work is needed to confirm race-based disparities and trends in substance use given the potential for bias in screening and documentation. Findings suggest a need for more standardized toxicology screening. © 2022 Lippincott Williams and Wilkins. All rights reserved.
Author Keywords
documentation; racial groups; risk factors; stroke; substance-related disorders
Funding details
National Heart, Lung, and Blood InstituteNHLBIK23 HL140081
National Institute of Neurological Disorders and StrokeNINDSR01 NS 30678
American Heart AssociationAHA
Document Type: Article
Publication Stage: Final
Source: Scopus
Evaluating brain damage in multiple sclerosis with simultaneous multi-angular-relaxometry of tissue
(2022) Annals of Clinical and Translational Neurology, 9 (10), pp. 1514-1527.
Xiang, B.a , Wen, J.a , Schmidt, R.E.b , Sukstanskii, A.L.a , Mamah, D.c , Yablonskiy, D.A.a , Cross, A.H.d
a Department of Radiology, Washington University, St. Louis, MO 63110, United States
b Department of Pathology, Washington University, St. Louis, MO 63110, United States
c Department of Psychiatry, Washington University, St. Louis, MO 63110, United States
d Department of Neurology, Washington University, St. Louis, MO 63110, United States
Abstract
Objective: Multiple sclerosis (MS) is a common demyelinating central nervous system disease. MRI methods that can quantify myelin loss are needed for trials of putative remyelinating agents. Quantitative magnetization transfer MRI introduced the macromolecule proton fraction (MPF), which correlates with myelin concentration. We developed an alternative approach, Simultaneous-Multi-Angular-Relaxometry-of-Tissue (SMART) MRI, to generate MPF. Our objective was to test SMART-derived MPF metric as a potential imaging biomarker of demyelination. Methods: Twenty healthy control (HC), 11 relapsing–remitting MS (RRMS), 22 progressive MS (PMS), and one subject with a biopsied tumefactive demyelinating lesion were scanned at 3T using SMART MRI. SMART-derived MPF metric was determined in normal-appearing cortical gray matter (NAGM), normal-appearing subcortical white matter (NAWM), and demyelinating lesions. MPF metric was evaluated for correlations with physical and cognitive test scores. Comparisons were made between HC and MS and between MS subtypes. Furthermore, correlations were determined between MPF and neuropathology in the biopsied person. Results: SMART-derived MPF in NAGM and NAWM were lower in MS than HC (p < 0.001). MPF in NAGM, NAWM and lesions differentiated RRMS from PMS (p < 0.01, p < 0.001, p < 0.001, respectively), whereas lesion volumes did not. MPF in NAGM, NAWM and lesions correlated with the Expanded Disability Status Scale (p < 0.01, p < 0.001, p < 0.001, respectively) and nine-hole peg test (p < 0.001, p < 0.001, p < 0.01, respectively). MPF was lower in the histopathologically confirmed inflammatory demyelinating lesion than the contralateral NAWM and increased in the biopsied lesion over time, mirroring improved clinical performance. Interpretation: SMART-derived MPF metric holds potential as a quantitative imaging biomarker of demyelination and remyelination. © 2022 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.
Funding details
National Institutes of HealthNIHR01 AG054513
National Multiple Sclerosis SocietyNMSSFG-1908-34882
Conrad N. Hilton FoundationCNHF20140257
Bristol-Myers SquibbBMS
EMD Serono
Foundation for Barnes-Jewish HospitalFBJH
Horizon Pharma
Greenwich Biosciences
Document Type: Article
Publication Stage: Final
Source: Scopus
The effect on brain volume in HIV-negative and non-transplant cryptococcal meningitis
(2022) Medical Mycology, 60 (9), .
Qin, B.-E.a , Cheng, C.b , Luo, C.c , Liu, J.a , Xu, X.-F.a , Tong, J.d , Yuan, D.a , Chen, Y.d , Peng, F.-H.a , Jiang, Y.a
a Department of Neurology, Third Affiliated Hospital of Sun Yat-sen University, 600# Tianhe Road, Guangzhou, Guangdong 510630, China
b Department of Neurology, Affiliated Hospital of Hangzhou Normal University, Wenzhou Road 126, Hangzhou, Zhejiang 310015, China
c Division of Public Health Sciences, Washington University School of Medicine in St. Louis, St Louis, MO 63110, United States
d Department of Biostatistics, Epidemiology and Informatics, University of Pennsylvania, Philadelphia, PA 19104, United States
Abstract
To explore the brain volume (BV) changes of HIV-negative and non-transplant cryptococcal meningitis (CM) in 1 year after initial therapy. Case data were collected from 78 CM patients who underwent magnetic resonance imaging (MRI) scanning at least 3 times in 1-year interval after initial therapy. The assessment of BV was measured by a non-commercial software, uAI Research Portal. Linear mixed model was used to investigate the association between clinical characteristics and the changes in BV. Longitudinal study showed a decrease in total brain volume (-4.65 cm3, P = .005), regional brain volume including white matter (-2.86 cm3, P = .031) and basal ganglia (-0.25 cm3, P = .007), and increase in cerebrospinal fluid (CSF) volume (3.58 cm3, P = .013) in CM patients in 1 year after initial therapy. Ventricular volume in patients with ventriculoperitoneal shunts (VPS) was lower than that in patients without VPS (-7.5 cm3, P < .05). Ventricular volume in patients with post-infectious inflammatory response syndrome (PIIRS) was larger than that in patients without PIIRS (7.1 cm3, P < .01). In addition, temporal lobe atrophy was associated with corticosteroid therapy (-6.8 cm3, P < .01). The present study suggested that brain atrophy, especially regional BV decrease, could happen in HIV-negative and non-transplant CM patients over a 1-year interval. © The Author(s) 2022. Published by Oxford University Press on behalf of The International Society for Human and Animal Mycology.
We investigated the evolution of brain volume changes in different regions among HIV-negative and non-transplant cryptococcal meningitis (CM) patients within 1 year after initial therapy. To assess whether brain atrophy occurs among HIV-negative and non-transplant CM patients.
Author Keywords
brain volume; cryptococcal meningitis; HIV-negative; non-transplant; post-infectious inflammatory response syndrome; ventriculoperitoneal shunts
Document Type: Article
Publication Stage: Final
Source: Scopus
Sleep-promoting neurons remodel their response properties to calibrate sleep drive with environmental demands
(2022) PLoS Biology, 20 (9), p. e3001797.
Dissel, S.a , Klose, M.K.b , van Swinderen, B.c , Cao, L.d , Ford, M.d , Periandri, E.M.d , Jones, J.D.a , Li, Z.d , Shaw, P.J.d
a Division of Biological and Biomedical Systems, School of Science and Engineering, University of Missouri-Kansas City, Kansas City, MO, United States
b University of Pittsburgh School of Medicine, Department of Pharmacology & Chemical Biology, Pittsburgh, PA, United States
c Queensland Brain Institute, University of Queensland, St Lucia, Australia
d Department of Neuroscience, Washington University School of Medicine, St. Louis, MO, United States
Abstract
Falling asleep at the wrong time can place an individual at risk of immediate physical harm. However, not sleeping degrades cognition and adaptive behavior. To understand how animals match sleep need with environmental demands, we used live-brain imaging to examine the physiological response properties of the dorsal fan-shaped body (dFB) following interventions that modify sleep (sleep deprivation, starvation, time-restricted feeding, memory consolidation) in Drosophila. We report that dFB neurons change their physiological response-properties to dopamine (DA) and allatostatin-A (AstA) in response to different types of waking. That is, dFB neurons are not simply passive components of a hard-wired circuit. Rather, the dFB neurons intrinsically regulate their response to the activity from upstream circuits. Finally, we show that the dFB appears to contain a memory trace of prior exposure to metabolic challenges induced by starvation or time-restricted feeding. Together, these data highlight that the sleep homeostat is plastic and suggests an underlying mechanism.
Document Type: Article
Publication Stage: Final
Source: Scopus
Adult Attachment and Interpersonal Emotion Regulation Motives in Daily Life
(2022) Emotion, .
Springstein, T., Hamerling-Potts, K.K., Landa, I., English, T.
Department of Psychological and Brain Sciences, Washington University in St. Louis, United States
Abstract
Interpersonal goals and adult attachment have implications for how people interact with others as well as for emotion experience and regulation. Literature on intrapersonal emotional processes has typically not examined motivations underlying people’s engagement with others’ emotions and its connections to individual differences related to close relationships such as attachment. This study analyzed the relationships between interpersonal emotion regulation motives, perceived social interaction outcomes, and attachment. Undergraduates (N = 211) reported their trait attachment. Experience sampling was used to examine the reasons why they wanted to regulate others’ emotions during daily interactions and perceived changes in their own well-being and relationship quality with the target of regulation. Attachment anxiety was associated with more self-focused prohedonic motives and impression management motives, while attachment avoidance predicted less perceived increases in emotional and relational well-being after interactions. People who tended to report more (self and other-focused) prohedonic and less impression management motives in daily life perceived more positive changes in their emotional well-being and people who tended to report higher emotional similarity motives perceived more positive changes in their relational well-being after interactions People also perceived more positive emotional and relational interaction outcomes at times when they held more (self and other-focused) prohedonic, impression management, or relationship maintenance motives and less self-focused performance and relationship distancing motives. Overall, these findings suggest that attachment anxiety may guide why people engage with other people’s emotions and these extrinsic interpersonal emotion regulation motives may play a role in socioemotional outcomes of daily interactions. © 2022 American Psychological Association
Author Keywords
Attachment; Emotion; Emotion regulation; Experience sampling; Relationships
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
Herpes simplex virus and rates of cognitive decline or whole brain atrophy in the Dominantly Inherited Alzheimer Network
(2022) Annals of Clinical and Translational Neurology, .
Warren-Gash, C.a , Cadogan, S.L.a , Nicholas, J.M.b , Breuer, J.M.c d , Shah, D.d , Pearce, N.b , Shiekh, S.a , Smeeth, L.a , Farlow, M.R.e , Mori, H.f , Gordon, B.A.g , Nuebling, G.h i , McDade, E.j , Bateman, R.J.j , Schofield, P.R.k l , Lee, J.-H.m , Morris, J.C.j , Cash, D.M.n o , Fox, N.C.o p , Ridha, B.H.o p , Rossor, M.N.o p , for the Dominantly Inherited Alzheimer Networkq
a Department of Non-Communicable Disease Epidemiology, London School of Hygiene and Tropical Medicine, London, United Kingdom
b Department of Medical Statistics, London School of Hygiene and Tropical Medicine, London, United Kingdom
c Institute of Child Health, University College London, Gower Street, London, WC1E 6BT, United Kingdom
d Virology Department, Great Ormond Street Hospital, London, United Kingdom
e Indiana University School of Medicine, Indianapolis, IN, United States
f Department of Clinical Neuroscience, Osaka Metropolitan University Medical School, Sutoku University, Osaka, Japan
g Department of Radiology, Washington University School of Medicine in St LouisMO, United States
h German Center for Neurodegenerative Diseases, Site Munich, Germany
i Department of Neurology, Ludwig-Maximilians University, Munich, Germany
j Department of Neurology, Washington University School of Medicine, St. Louis, United States
k Neuroscience Research Australia, Sydney, NSW, Australia
l School of Medical Sciences, University of New South Wales, Sydney, NSW, Australia
m Department of Neurology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, South Korea
n UK Dementia Research Institute, University College London, London, United Kingdom
o Dementia Research Centre, Institute of Neurology, University College London, Queen Square, London, United Kingdom
p NIHR University College London Hospitals Biomedical Research Centre, London, United Kingdom
Abstract
Objective: To investigate whether herpes simplex virus type 1 (HSV-1) infection was associated with rates of cognitive decline or whole brain atrophy among individuals from the Dominantly Inherited Alzheimer Network (DIAN). Methods: Among two subsets of the DIAN cohort (age range 19.6–66.6 years; median follow-up 3.0 years) we examined (i) rate of cognitive decline (N = 164) using change in mini-mental state examination (MMSE) score, (ii) rate of whole brain atrophy (N = 149), derived from serial MR imaging, calculated using the boundary shift integral (BSI) method. HSV-1 antibodies were assayed in baseline sera collected from 2009–2015. Linear mixed-effects models were used to compare outcomes by HSV-1 seropositivity and high HSV-1 IgG titres/IgM status. Results: There was no association between baseline HSV-1 seropositivity and rates of cognitive decline or whole brain atrophy. Having high HSV-1 IgG titres/IgM was associated with a slightly greater decline in MMSE points per year (difference in slope − 0.365, 95% CI: −0.958 to −0.072), but not with rate of whole brain atrophy. Symptomatic mutation carriers declined fastest on both MMSE and BSI measures, however, this was not influenced by HSV-1. Among asymptomatic mutation carriers, rates of decline on MMSE and BSI were slightly greater among those who were HSV-1 seronegative. Among mutation-negative individuals, no differences were seen by HSV-1. Stratifying by APOE4 status yielded inconsistent results. Interpretation: We found no evidence for a major role of HSV-1, measured by serum antibodies, in cognitive decline or whole brain atrophy among individuals at high risk of early-onset AD. © 2022 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.
Funding details
NF‐SI‐0512‐10033
National Institutes of HealthNIH
National Institute on AgingNIA
Alzheimer’s AssociationAA
Queen Mary University of LondonQMUL
Fondation Brain Canada
Japan Agency for Medical Research and DevelopmentAMED17929884
Schizophrenia Research FundSRF
Wellcome TrustWT201440/Z/16/Z
Australasian Neuroscience SocietyANSP01AG003991, P01AG026276, P30 AG066444
Canadian Institutes of Health ResearchIRSC
Fonds de Recherche du Québec – SantéFRQS
Medical Research CouncilMRCMR/L023784/2, U19AG032438
National Institute for Health and Care ResearchNIHR
Alzheimer’s Society
Multiple Sclerosis SocietyMS Society
University of Warwick
Imperial College London
University of Bristol
Alzheimer’s Research UKARUK
Korea Health Industry Development InstituteKHIDI
Instituto de Salud Carlos IIIISCIII
Deutsches Zentrum für Neurodegenerative ErkrankungenDZNE
Strategic Research CouncilRSF
NSW Health
UCLH Biomedical Research CentreNIHR BRC
Fleni
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
Clinical, environmental, and genetic risk factors for substance use disorders: characterizing combined effects across multiple cohorts
(2022) Molecular Psychiatry, .
Barr, P.B.a b , Driver, M.N.c , Kuo, S.I.-C.d , Stephenson, M.e , Aliev, F.d f , Linnér, R.K.g , Marks, J.h , Anokhin, A.P.i , Bucholz, K.i , Chan, G.j k , Edenberg, H.J.l m , Edwards, A.C.e , Francis, M.W.i , Hancock, D.B.h , Harden, K.P.n o , Kamarajan, C.a , Kaprio, J.p , Kinreich, S.a , Kramer, J.R.k , Kuperman, S.k , Latvala, A.q , Meyers, J.L.a b , Palmer, A.A.r s , Plawecki, M.H.t , Porjesz, B.a , Rose, R.J.u , Schuckit, M.A.r , Salvatore, J.E.d , Dick, D.M.d f
a Department of Psychiatry and Behavioral Sciences, SUNY Downstate Health Sciences University, Brooklyn, NY, United States
b VA New York Harbor Healthcare System, Brooklyn, NY, United States
c Department of Human and Molecular Genetics, Virginia Commonwealth University, Richmond, VA, United States
d Department of Psychiatry, Robert Wood Johnson Medical School, Rutgers University, Piscataway, NJ, United States
e Virginia Institute for Psychiatric and Behavioral Genetics, Department of Psychiatry, Virginia Commonwealth University, Richmond, VA, United States
f Rutgers Addiction Research Center, Rutgers University, Piscataway, NJ, United States
g Department of Economics, Leiden University, Leiden, Netherlands
h Biostatistics and Epidemiology Division, RTI International, Research Triangle Park, Durham, NC, United States
i Department of Psychiatry, School of Medicine, Washington University in St. Louis, St Louis, MO, United States
j Department of Psychiatry, School of Medicine, University of Connecticut, Farmington, CT, United States
k Department of Psychiatry, Carver College of Medicine, University of Iowa, Iowa City, IA, United States
l Department of Medical and Molecular Genetics, School of Medicine, Indiana University, Indianapolis, IN, United States
m Department of Biochemistry and Molecular Biology, School of Medicine, Indiana University, Indianapolis, IN, United States
n Department of Psychology, University of Texas at Austin, Austin, TX, United States
o Population Research Center, University of Texas at Austin, Austin, TX, United States
p Institute for Molecular Medicine Finland, University of Helsinki, Helsinki, Finland
q Institute of Criminology and Legal Policy, University of Helsinki, Helsinki, Finland
r Department of Psychiatry, University of California San Diego, La JollaCA, United States
s Institute for Genomic Medicine, University of California San Diego, La JollaCA, United States
t Department of Psychiatry, School of Medicine, Indiana University, Indianapolis, IN, United States
u Department of Psychological and Brain Sciences, Indiana University, Bloomington, IN, United States
Abstract
Substance use disorders (SUDs) incur serious social and personal costs. The risk for SUDs is complex, with risk factors ranging from social conditions to individual genetic variation. We examined whether models that include a clinical/environmental risk index (CERI) and polygenic scores (PGS) are able to identify individuals at increased risk of SUD in young adulthood across four longitudinal cohorts for a combined sample of N = 15,134. Our analyses included participants of European (NEUR = 12,659) and African (NAFR = 2475) ancestries. SUD outcomes included: (1) alcohol dependence, (2) nicotine dependence; (3) drug dependence, and (4) any substance dependence. In the models containing the PGS and CERI, the CERI was associated with all three outcomes (ORs = 01.37–1.67). PGS for problematic alcohol use, externalizing, and smoking quantity were associated with alcohol dependence, drug dependence, and nicotine dependence, respectively (OR = 1.11–1.33). PGS for problematic alcohol use and externalizing were also associated with any substance dependence (ORs = 1.09–1.18). The full model explained 6–13% of the variance in SUDs. Those in the top 10% of CERI and PGS had relative risk ratios of 3.86–8.04 for each SUD relative to the bottom 90%. Overall, the combined measures of clinical, environmental, and genetic risk demonstrated modest ability to distinguish between affected and unaffected individuals in young adulthood. PGS were significant but added little in addition to the clinical/environmental risk index. Results from our analysis demonstrate there is still considerable work to be done before tools such as these are ready for clinical applications. © 2022, The Author(s), under exclusive licence to Springer Nature Limited.
Funding details
National Institutes of HealthNIHK02AA018755, R01AA015416, R01DA042090, R01DA050721
National Institute on Drug AbuseNIDAP50AA022537, U10AA008401
National Institute on Alcohol Abuse and AlcoholismNIAAA
National Institute on AgingNIAU01 AG071448, U01AG071450
University of North Carolina WilmingtonUNCWP01 HD31921
Eunice Kennedy Shriver National Institute of Child Health and Human DevelopmentNICHD
Wellcome TrustWT086684, 217065/Z/19/Z, 5R01AA018333–05
Medical Research CouncilMRC
European Research CouncilERC647648 EdGe
University of BristolG0800612/86812, MR/L022206/1, MR/M006727/1
Academy of FinlandAKA100499, 118555, 141054, 205585, 265240, 308248, 308698, 312073
Türkiye Bilimsel ve Teknolojik Araştırma KurumuTÜBİTAK114C117
Sigrid Juséliuksen Säätiö
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
A new look at cognitive functioning in pediatric MS
(2022) Multiple Sclerosis Journal, .
Krupp, L.B.a , Waubant, E.b , Waltz, M.c , Casper, T.C.c , Belman, A.a , Wheeler, Y.d , Ness, J.d , Graves, J.e , Gorman, M.f , Benson, L.f , Mar, S.g , Goyal, M.g , Schreiner, T.h , Weinstock-Guttman, B.i , Rodriguez, M.j , Tillema, J.-M.j , Lotze, T.k , Aaen, G.l , Rensel, M.m , Rose, J.c , Chitinis, T.n , George, A.a , Charvet, L.E.a , and the US Network of Pediatric MS Centerso
a Multiple Sclerosis Comprehensive Care Center, Department of Neurology, NYU Langone Health, New York, NY, United States
b Pediatric Multiple Sclerosis Center, University of California San Francisco, San Francisco, CA, United States
c Data Coordinating and Analysis Center, The University of Utah, Salt Lake City, UT, United States
d Center for Pediatric-Onset Demyelinating Disease, The University of Alabama at Birmingham, Birmingham, AL, United States
e Pediatric Multiple Sclerosis Center, University of California San Diego, San Diego, CA, United States
f Pediatric Multiple Sclerosis and Related Disorders Program at Boston Children’s Hospital, Boston, MA, United States
g Washington University in St. Louis, St. Louis, MO, United States
h Rocky Mountain Multiple Sclerosis Center, Children’s Hospital Colorado, University of Colorado Denver, Aurora, CO, United States
i Jacobs Pediatric Multiple Sclerosis Center, State University of New York at Buffalo, Buffalo, NY, United States
j Mayo Clinic Pediatric Multiple Sclerosis Center, Mayo Clinic, Rochester, MN, United States
k The Blue Bird Circle Clinic for Multiple Sclerosis, Texas Children’s Hospital, Baylor College of Medicine, Houston, TX, United States
l Pediatric Multiple Sclerosis Center, Loma Linda University Children’s Hospital, Loma Linda, CA, United States
m Cleveland Clinic Mellen Center for Multiple Sclerosis, Cleveland Clinic, Cleveland, OH, United States
n Partners Pediatric Multiple Sclerosis Center, Massachusetts General Hospital, Boston, MA, United States
Abstract
Objective: Cognitive involvement in pediatric multiple sclerosis (MS) relative to adult MS is less defined. This study advances our understanding by measuring cognitive performances in pediatric MS, adult MS, and pediatric healthy controls. Methods: Consecutive relapsing pediatric MS participants from the United States Network of Pediatric MS Centers were compared with pediatric healthy controls and adults with relapsing MS. Participants were compared on two screening batteries: the Brief International Cognitive Assessment for MS and the Cogstate Brief Battery. Results were transformed to age-normative z scores. Results: The pediatric groups (MS vs. Healthy Controls) did not differ on either battery’s composite mean score or individual test scores (ps > 0.32), nor in the proportions impaired on either battery, Brief International Cognitive Assessment for MS (26% vs. 24%, p = 0.83); Cogstate Brief Battery (26% vs. 32%, p = 0.41). The pediatric versus adult MS group even after controlling for differences in disease duration performed better on the Brief International Cognition Assessment for MS composite (p = 0.03), Symbol Digit Modalities Test (p = 0.02), Rey Auditory Verbal Learning Test (p = 0.01), and Cogstate choice reaction time (p < 0.001). Conclusion: Pediatric MS patients do not differ from healthy pediatric controls on cognitive screens but perform better than adults with MS. © The Author(s), 2022.
Author Keywords
adult MS; BICAMS; cognition; cognitive screening; Cogstate; Pediatric MS
Funding details
National Institutes of HealthNIH
U.S. Department of DefenseDOD
National Multiple Sclerosis SocietyNMSSHC-1509-06233, RG150705285
Pfizer
Novartis
Roche
Biogen
Patient-Centered Outcomes Research InstitutePCORI
Teva Pharmaceutical Industries
Biogen Idec
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
Cognitive Development in Lambdoid Craniosynostosis: A Systematic Review and Meta-Analysis
(2022) Cleft Palate-Craniofacial Journal, .
Chiang, S.N.a , Fotouhi, A.R.a , Doering, M.M.b , Skolnick, G.B.a , Naidoo, S.D.a , Strahle, J.M.c , McEvoy, S.D.c , Patel, K.B.a
a Department of Surgery, Division of Plastic and Reconstructive Surgery, Washington University School of Medicine, St. Louis, MO, United States
b Bernard Becker Medical Library, Washington University School of Medicine, St. Louis, MO, United States
c Department of Neurosurgery, Washington University School of Medicine, St. Louis, MO, United States
Abstract
Objective: Lambdoid craniosynostosis affects approximately 1 in 33 000 live births per year, and surgical correction is often sought in order to achieve normocephaly and allow for adequate brain growth. However, the effects of lambdoid synostosis and its treatment on cognitive development are unknown. Design: Systematic review and meta-analysis. Patients, Participants: A systematic review of Ovid Medline, Embase, Web of Science, Scopus, Cochrane Central Register of Controlled Trials, and Clinicaltrials.gov was conducted in January 2022. Included studies assessed cognitive development of patients with nonsyndromic unilateral lambdoid craniosynostosis. Main Outcome Measures: Results of developmental tests were compared to normative data or controls to generate Hedges’ g for meta-analysis. Results: Nine studies met the inclusion criteria. Meta-analysis of 3 studies describing general cognition showed that cases scored significantly lower than their peers, but within 1 standard deviation (g = 0.37, 95% CI [−0.64, −0.10], P =.01). Meta-analysis of verbal and psychomotor development showed no significant differences in children with lambdoid synostosis. Studies were of fair quality and had moderate-to-high heterogeneity. Conclusions: Patients with lambdoid craniosynostosis may score slightly below average on tests of general cognition in comparison to normal controls, but results in other domains are variable. Analyses were limited by small sample sizes. Multidisciplinary care and involvement of a child psychologist may be helpful in identifying areas of concern and providing adequate scholastic support. Further research recruiting larger cohorts will be necessary to confirm these findings and extend them to other developmental domains such as attention and executive function. © 2022, American Cleft Palate-Craniofacial Association.
Author Keywords
language development; mental development; psychomotor development; speech development
Funding details
Washington University School of Medicine in St. LouisWUSM
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
MOG and AQP4 Antibodies among Children with Multiple Sclerosis and Controls
(2022) Annals of Neurology, .
Gaudioso, C.M.a , Mar, S.a , Casper, T.C.b , Codden, R.b , Nguyen, A.c , Aaen, G.d , Benson, L.e , Chitnis, T.f , Francisco, C.g , Gorman, M.P.e , Goyal, M.S.a , Graves, J.h , Greenberg, B.M.i , Hart, J.g , Krupp, L.j , Lotze, T.k , Narula, S.l , Pittock, S.J.c , Rensel, M.m , Rodriguez, M.n , Rose, J.o , Schreiner, T.p , Tillema, J.-M.n , Waldman, A.l , Weinstock-Guttman, B.q , Wheeler, Y.r , Waubant, E.g , Flanagan, E.P.c , United States Network of Pediatric Multiple Sclerosis Centerss
a Department of Neurology, Washington University Pediatric MS and Other Demyelinating Disease Center, St. Louis, MO, United States
b Department of Pediatrics, University of Utah, Salt Lake City, UT, United States
c Department of Neurology and Laboratory Medicine and Pathology and the Center for MS and Autoimmune Neurology, Mayo Clinic, Rochester, MN, United States
d Department of Pediatrics, Pediatric Multiple Sclerosis Center at Loma Linda University Children’s Hospital, Loma Linda University, Loma Linda, CA, United States
e Department of Neurology, Pediatric Multiple Sclerosis and Related Disorders Program at Boston Children’s Hospital, Harvard Medical School, Boston, MA, United States
f Partners Pediatric MS Center, Massachusetts General Hospital, Boston, MA, United States
g Department of Neurology, UCSF Regional Pediatric MS Center, San Francisco, CA, United States
h Department of Neurology, University of California San Diego Health, Rady Children’s Hospital San Diego, San Diego, CA, United States
i Department of Neurology, University of Texas Southwestern and Children’s Health, Dallas, TX, United States
j Department of Neurology, New York University, Pediatric MS Center, Neurology, New York, NY, United States
k Texas Children’s Hospital, Baylor College of Medicine, Houston, TX, United States
l Department of Pediatrics, Children’s Hospital of Philadelphia, Philadelphia, PA, United States
m Mellen Center for Multiple Sclerosis, Cleveland Clinic, Cleveland, OH, United States
n Mayo Clinic Pediatric MS Center, Mayo Clinic, Rochester, MN, United States
o Department of Neurology, University of Utah, Salt Lake City, UT, United States
p Rocky Mountain MS Center, Children’s Hospital Colorado, University of Colorado, Aurora, CO, United States
q Department of Neurology, The Pediatric MS Center at the Jacobs Neurological Institute, State University of New York at Buffalo, Buffalo, NY, United States
r Center for Pediatric-Onset Demyelinating Disease at the Children’s of Alabama, University of Alabama, Birmingham, AL, United States
Abstract
Objective: The purpose of this study was to determine the frequency of myelin oligodendrocyte glycoprotein (MOG)-IgG and aquaporin-4 (AQP4)-IgG among patients with pediatric-onset multiple sclerosis (POMS) and healthy controls, to determine whether seropositive cases fulfilled their respective diagnostic criteria, to compare characteristics and outcomes in children with POMS versus MOG-IgG-associated disease (MOGAD), and identify clinical features associated with final diagnosis. Methods: Patients with POMS and healthy controls were enrolled at 14 US sites through a prospective case–control study on POMS risk factors. Serum AQP4-IgG and MOG-IgG were assessed using live cell-based assays. Results: AQP4-IgG was negative among all 1,196 participants, 493 with POMS and 703 healthy controls. MOG-IgG was positive in 30 of 493 cases (6%) and zero controls. Twenty-five of 30 patients positive with MOG-IgG (83%) had MOGAD, whereas 5 of 30 (17%) maintained a diagnosis of multiple sclerosis (MS) on re-review of records. MOGAD cases were more commonly in female patients (21/25 [84%] vs 301/468 [64%]; p = 0.044), younger age (mean = 8.2 ± 4.2 vs 14.7 ± 2.6 years; p < 0.001), more commonly had initial optic nerve symptoms (16/25 [64%] vs 129/391 [33%]; p = 0.002), or acute disseminated encephalomyelitis (ADEM; 8/25 [32%] vs 9/468 [2%]; p < 0.001), and less commonly had initial spinal cord symptoms (3/20 [15%] vs 194/381 [51%]; p = 0.002), serum Epstein–Barr virus (EBV) positivity (11/25 [44%] vs 445/468 [95%]; p < 0.001), or cerebrospinal fluid oligoclonal bands (5/25 [20%] vs 243/352 [69%]; p < 0.001). Interpretation: MOG-IgG and AQP4-IgG were not identified among healthy controls confirming their high specificity for pediatric central nervous system (CNS) demyelinating disease. Five percent of those with prior POMS diagnoses ultimately had MOGAD; and none had AQP4-IgG positivity. Clinical features associated with a final diagnosis of MOGAD in those with suspected MS included initial ADEM phenotype, younger age at disease onset, and lack of EBV exposure. ANN NEUROL 2022. © 2022 American Neurological Association.
Funding details
National Institute of Neurological Disorders and StrokeNINDS1R01NS071463, R01NS113828, S1‐1808‐32326
National Multiple Sclerosis SocietyNMSS
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
Exploring the Relationships Between Autozygosity, Educational Attainment, and Cognitive Ability in a Contemporary, Trans-Ancestral American Sample
(2022) Behavior Genetics, .
Colbert, S.M.a , Keller, M.C.b c , Agrawal, A.a , Johnson, E.C.a
a Department of Psychiatry, Washington University School of Medicine, Saint Louis, MO, United States
b Department of Psychology, University of Colorado Boulder, Boulder, CO, United States
c Institute for Behavioral Genetics, University of Colorado Boulder, Boulder, CO, United States
Abstract
Previous studies have found significant associations between estimated autozygosity – the proportion of an individual’s genome contained in homozygous segments due to distant inbreeding – and multiple traits, including educational attainment (EA) and cognitive ability. In one study, estimated autozygosity showed a stronger association with parental EA than the subject’s own EA. This was likely driven by parental EA’s association with mobility: more educated parents tended to migrate further from their hometown, and because of the strong correlation between ancestry and geography in the Netherlands, these individuals chose partners farther from their ancestry and therefore more different from them genetically. We examined the associations between estimated autozygosity, cognitive ability, and parental EA in a contemporary sub-sample of adolescents from the Adolescent Brain Cognitive Development Study℠ (ABCD Study®) (analytic N = 6,504). We found a negative association between autozygosity and child cognitive ability consistent with previous studies, while the associations between autozygosity and parental EA were in the expected direction of effect (with greater levels of autozygosity being associated with lower EA) but the effect sizes were significantly weaker than those estimated in previous work. We also found a lower mean level of autozygosity in the ABCD sample compared to previous autozygosity studies, which may reflect overall decreasing levels of autozygosity over generations. Variation in spousal similarities in ancestral background in the ABCD study compared to other studies may explain the pattern of associations between estimated autozygosity, EA, and cognitive ability in the current study. © 2022, The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.
Author Keywords
Assortative mating; Autozygosity; Cognitive ability; Educational attainment; Runs of homozygosity
Funding details
National Institutes of HealthNIHU01DA041022, U01DA041025, U01DA041028, U01DA041048, U01DA041089, U01DA041093, U01DA041106, U01DA041117, U01DA041120, U01DA041134, U01DA041148, U01DA041156, U01DA041174, U01DA050987, U01DA050988, U01DA050989, U01DA051016, U01DA051018, U01DA051037, U01DA051038, U01DA051039, U10AA008401, U24DA041123, U24DA041147
National Institute on Drug AbuseNIDA
National Institute on Alcohol Abuse and AlcoholismNIAAA
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
Racial and Ethnic Differences in Amyloid PET Positivity in Individuals with Mild Cognitive Impairment or Dementia: A Secondary Analysis of the Imaging Dementia-Evidence for Amyloid Scanning (IDEAS) Cohort Study
(2022) JAMA Neurology, .
Wilkins, C.H.a , Windon, C.C.b , Dilworth-Anderson, P.c , Romanoff, J.d , Gatsonis, C.d e , Hanna, L.d , Apgar, C.f , Gareen, I.F.d e , Hill, C.V.g , Hillner, B.E.h , March, A.i , Siegel, B.A.j , Whitmer, R.A.k l , Carrillo, M.C.g , Rabinovici, G.D.b m n
a Department of Medicine, Division of Geriatric Medicine, Vanderbilt University Medical Center, Nashville, TN, United States
b Department of Neurology, Memory and Aging Center, Weill Institute for Neurosciences, University of California, San Francisco, United States
c Health Policy and Management, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, United States
d Center for Statistical Sciences, Brown University, School of Public Health, Providence, RI, United States
e Department of Epidemiology, Brown University, School of Public Health, Providence, RI, United States
f Center for Research and Innovation, American College of Radiology, Reston, VA, United States
g Alzheimer’s Association, Chicago, IL, United States
h Department of Medicine, Virginia Commonwealth University, Richmond, United States
i Center for Research and Innovation, American College of Radiology, Philadelphia, PA, United States
j Edward Mallinckrodt Institute of Radiology, Washington University, School of Medicine, St Louis, MO, United States
k Division of Research, Kaiser Permanente, Oakland, CA, United States
l Department of Public Health Sciences, University of California, Davis, United States
m JAMA Neurology, United States
n Department of Radiology & Biomedical Imaging, University of California, San Francisco, United States
Abstract
Importance: Racial and ethnic groups with higher rates of clinical Alzheimer disease (AD) are underrepresented in studies of AD biomarkers, including amyloid positron emission tomography (PET). Objective: To compare amyloid PET positivity among a diverse cohort of individuals with mild cognitive impairment (MCI) or dementia. Design, Setting, and Participants: Secondary analysis of the Imaging Dementia-Evidence for Amyloid Scanning (IDEAS), a single-arm multisite cohort study of Medicare beneficiaries who met appropriate-use criteria for amyloid PET imaging between February 2016 and September 2017 with follow-up through January 2018. Data were analyzed between April 2020 and January 2022. This study used 2 approaches: the McNemar test to compare amyloid PET positivity proportions between matched racial and ethnic groups and multivariable logistic regression to assess the odds of having a positive amyloid PET scan. IDEAS enrolled participants at 595 US dementia specialist practices. A total of 21949 were enrolled and 4842 (22%) were excluded from the present analysis due to protocol violations, not receiving an amyloid PET scan, not having a positive or negative scan, or because of small numbers in some subgroups. Exposures: In the IDEAS study, participants underwent a single amyloid PET scan. Main Outcomes and Measures: The main outcomes were amyloid PET positivity proportions and odds. Results: Data from 17107 individuals (321 Asian, 635 Black, 829 Hispanic, and 15322 White) with MCI or dementia and amyloid PET were analyzed between April 2020 and January 2022. The median (range) age of participants was 75 (65-105) years; 8769 participants (51.3%) were female and 8338 (48.7%) were male. In the optimal 1:1 matching analysis (n = 3154), White participants had a greater proportion of positive amyloid PET scans compared with Asian participants (181 of 313; 57.8%; 95% CI, 52.3-63.2 vs 142 of 313; 45.4%; 95% CI, 39.9-50.9, respectively; P =.001) and Hispanic participants (482 of 780; 61.8%; 95% CI, 58.3-65.1 vs 425 of 780; 54.5%; 95% CI, 51.0-58.0, respectively; P =.003) but not Black participants (359 of 615; 58.4%; 95% CI, 54.4-62.2 vs 333 of 615; 54.1%; 95% CI, 50.2-58.0, respectively; P =.13). In the adjusted model, the odds of having a positive amyloid PET scan were lower for Asian participants (odds ratio [OR], 0.47; 95% CI, 0.37-0.59; P <.001), Black participants (OR, 0.71; 95% CI, 0.60-0.84; P <.001), and Hispanic participants (OR, 0.68; 95% CI, 0.59-0.79; P <.001) compared with White participants. Conclusions and Relevance: Racial and ethnic differences found in amyloid PET positivity among individuals with MCI and dementia in this study may indicate differences in underlying etiology of cognitive impairment and guide future treatment and prevention approaches.. © 2022 American Medical Association. All rights reserved.
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
Bespoke library docking for 5-HT2A receptor agonists with antidepressant activity
(2022) Nature, .
Kaplan, A.L.a , Confair, D.N.b , Kim, K.c d , Barros-Álvarez, X.e , Rodriguiz, R.M.f g , Yang, Y.a , Kweon, O.S.b , Che, T.h , McCorvy, J.D.i , Kamber, D.N.b , Phelan, J.P.b , Martins, L.C.a j , Pogorelov, V.M.f , DiBerto, J.F.c , Slocum, S.T.c , Huang, X.-P.k , Kumar, J.M.c , Robertson, M.J.e , Panova, O.e , Seven, A.B.e , Wetsel, A.Q.f , Wetsel, W.C.f g l m , Irwin, J.J.a , Skiniotis, G.e , Shoichet, B.K.a , Roth, B.L.c n , Ellman, J.A.b
a Department of Pharmaceutical Chemistry, University of California, San Francisco, CA, United States
b Department of Chemistry, Yale University, New Haven, CT, United States
c Department of Pharmacology, University of North Carolina, Chapel Hill School of Medicine, Chapel Hill, NC, United States
d Department of Pharmacy, Yonsei University, Incheon, South Korea
e Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA, United States
f Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, Durham, NC, United States
g Mouse Behavioral and Neuroendocrine Analysis Core Facility, Duke University Medical Center, Durham, NC, United States
h Center for Clinical Pharmacology, Department of Anesthesiology, Washington University School of Medicine, St Louis, MO, United States
i Department of Cell Biology, Neurobiology and Anatomy, Medical College of Wisconsin, Milwaukee, WI, United States
j Biochemistry Department, Institute for Biological Sciences, Federal University of Minas Gerais, Belo Horizonte, Brazil
k National Institute of Mental Health Psychoactive Drug Screening Program, University of North Carolina Chapel Hill School of Medicine, Chapel Hill, NC, United States
l Department of Cell Biology, Duke University Medical Center, Durham, NC, United States
m Department of Neurobiology, Duke University Medical Center, Durham, NC, United States
n Division of Chemical Biology and Medicinal Chemistry, Eshelman School of Pharmacy, University of North Carolina Chapel Hill, Chapel Hill, NC, United States
Abstract
There is considerable interest in screening ultralarge chemical libraries for ligand discovery, both empirically and computationally1–4. Efforts have focused on readily synthesizable molecules, inevitably leaving many chemotypes unexplored. Here we investigate structure-based docking of a bespoke virtual library of tetrahydropyridines—a scaffold that is poorly sampled by a general billion-molecule virtual library but is well suited to many aminergic G-protein-coupled receptors. Using three inputs, each with diverse available derivatives, a one pot C–H alkenylation, electrocyclization and reduction provides the tetrahydropyridine core with up to six sites of derivatization5–7. Docking a virtual library of 75 million tetrahydropyridines against a model of the serotonin 5-HT2A receptor (5-HT2AR) led to the synthesis and testing of 17 initial molecules. Four of these molecules had low-micromolar activities against either the 5-HT2A or the 5-HT2B receptors. Structure-based optimization led to the 5-HT2AR agonists (R)-69 and (R)-70, with half-maximal effective concentration values of 41 nM and 110 nM, respectively, and unusual signalling kinetics that differ from psychedelic 5-HT2AR agonists. Cryo-electron microscopy structural analysis confirmed the predicted binding mode to 5-HT2AR. The favourable physical properties of these new agonists conferred high brain permeability, enabling mouse behavioural assays. Notably, neither had psychedelic activity, in contrast to classic 5-HT2AR agonists, whereas both had potent antidepressant activity in mouse models and had the same efficacy as antidepressants such as fluoxetine at as low as 1/40th of the dose. Prospects for using bespoke virtual libraries to sample pharmacologically relevant chemical space will be considered. © 2022, The Author(s), under exclusive licence to Springer Nature Limited.
Funding details
National Institutes of HealthNIHGM71896, R01MH11205, R35GM122473, R35GM122481, R37DA045657
Defense Advanced Research Projects AgencyDARPAHR001119S0092
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
Thyroid hormone levels in Alzheimer disease: a systematic review and meta-analysis
(2022) Endocrine, .
Dolatshahi, M.a b , Salehipour, A.b c , Saghazadeh, A.d e , Sanjeari Moghaddam, H.e , Aghamollaii, V.e f , Fotouhi, A.g , Tafakhori, A.e f
a Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, 510 South Kingshighway Boulevard, Campus Box 8131, St. Louis, MO 63110, United States
b NeuroImaging Network (NIN), Universal Scientific Education and Research Network (USERN), Tehran, Iran
c Neurosurgery Research Group (NRG), Student Research Committee, Hamadan University of Medical Sciences, Hamadan, Iran
d Systematic Review and Meta Analysis Group (SRMEG), Universal Scientific Education and Research Network (USERN), Tehran, Iran
e Department of Neurology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
f Iranian Center of Neurological Research, Neuroscience Institute, Tehran University of Medical Sciences, Tehran, Iran
g Department of Epidemiology and Biostatistics, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran
Abstract
Background and objective: Thyroid hormone (TH) disturbances are perceived to contribute to cognitive impairment and dementia. However, there is no consensus on the association between TH levels and Alzheimer Disease (AD). In this study, we aimed to compare serum and cerebrospinal fluid (CSF) TH levels in AD patients to controls by performing a meta-analysis. Methods: We systematically searched online databases for papers comparing CSF or serum TH levels in AD patients to controls, and performed a meta-analysis on the extracted data. Results: Out of 1604 records identified, 32 studies were included. No significant difference in serum TSH (standardized mean difference (SMD): −0.03; 95% confidence interval (CI): −0.22–0.16), total T4 (SMD: 0.10; 95% CI: −0.29–0.49), and free T4 (SMD: 0.25; 95% CI: −0.16–0.69) levels were observed. However, there was significantly lower serum total T3 (SMD: −0.56; 95%CI: −0.97 to −0.15) and free T3 (SMD: −0.47; 95%CI: −0.89 to −0.05) levels in AD group compared to controls. Subgroup analyses on studies including only euthyroid patients did not show any significant difference in either of the thyroid hormone levels. Also, no significant difference in CSF total T4 and total T3/total T4 ratios but significantly lower CSF total T3 (SMD: −2.45; 95% CI: −4.89 to −0.02) in AD group were detected. Conclusion: Serum total and free T3 and CSF total T3 levels are significantly lower in AD patients compared to controls. The temporality of changes in thyroid hormone levels and AD development should be illustrated by further longitudinal studies. © 2022, The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.
Author Keywords
Alzheimer disease; Cerebrospinal fluid; Meta-analysis; Serum; Thyroid hormones
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
Comparison of plasma and CSF biomarkers in predicting cognitive decline
(2022) Annals of Clinical and Translational Neurology, .
Aschenbrenner, A.J.a b , Li, Y.b c , Henson, R.L.a b , Volluz, K.a b , Hassenstab, J.a b , Verghese, P.d , West, T.d , Meyer, M.R.d , Kirmess, K.M.d , Fagan, A.M.a b e , Xiong, C.b c , Holtzman, D.a b e , Morris, J.C.a b e , Bateman, R.J.a b e , Schindler, S.E.a b
a Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States
b Knight Alzheimer Disease Research Center, Washington University School of Medicine, St. Louis, MO, United States
c Division of Biostatistics, Washington University School of Medicine, St. Louis, MO, United States
d C2N Diagnostics, St. Louis, MO, United States
e Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO, United States
Abstract
Objectives: Concentrations of amyloid-β peptides (Aβ42/Aβ40) and neurofilament light (NfL) can be measured in plasma or cerebrospinal fluid (CSF) and are associated with Alzheimer’s disease brain pathology and cognitive impairment. This study directly compared plasma and CSF measures of Aβ42/Aβ40 and NfL as predictors of cognitive decline. Methods: Participants were 65 years or older and cognitively normal at baseline with at least one follow-up cognitive assessment. Analytes were measured with the following types of assays: plasma Aβ42/Aβ40, immunoprecipitation-mass spectrometry; plasma NfL, Simoa; CSF Aβ42/Aβ40, automated immunoassay; CSF NfL plate-based immunoassay. Mixed effects models evaluated the global cognitive composite score over a maximum of 6 years as predicted by the fluid biomarkers. Results: Analyses included 371 cognitively normal participants, aged 72.7 ± 5.2 years (mean ± standard deviation) with an average length of follow-up of 3.9 ± 1.6 years. Standardized concentrations of biomarkers were associated with annualized cognitive change: plasma Aβ42/Aβ40, 0.014 standard deviations (95% confidence intervals 0.002 to 0.026); CSF Aβ42/Aβ40, 0.020 (0.008 to 0.032); plasma Nfl, −0.018 (−0.030 to −0.005); and CSF NfL, −0.024 (−0.036 to −0.012). Power analyses estimated that 266 individuals in each treatment arm would be needed to detect a 50% slowing of decline if identified by abnormal plasma measures versus 229 for CSF measures. Interpretation: Both plasma and CSF measures of Aβ42/Aβ40 and NfL predicted cognitive decline. A clinical trial that enrolled individuals based on abnormal plasma Aβ42/Aβ40 and NfL levels would require only a marginally larger cohort than if CSF measures were used. © 2022 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.
Funding details
National Institute on AgingNIAP01AG003991, P01AG026276, P30AG066444, R01AG053550, R01AG070941
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
A flexible modeling approach for biomarker-based computation of absolute risk of Alzheimer’s disease dementia
(2022) Alzheimer’s and Dementia, .
Hartz, S.M.a , Mozersky, J.a , Schindler, S.E.a , Linnenbringer, E.a , Wang, J.a , Gordon, B.A.a , Raji, C.A.a , Moulder, K.L.a , West, T.b , Benzinger, T.L.S.a , Cruchaga, C.a , Hassenstab, J.J.a , Bierut, L.J.a , Xiong, C.a , Morris, J.C.a
a Washington University School of Medicine, St. Louis, MO, United States
b C2N Diagnostics, St. Louis, MO, United States
Abstract
Introduction: As Alzheimer’s disease (AD) biomarkers rapidly develop, tools are needed that accurately and effectively communicate risk of AD dementia. Methods: We analyzed longitudinal data from >10,000 cognitively unimpaired older adults. Five-year risk of AD dementia was modeled using survival analysis. Results: A demographic model was developed and validated on independent data with area under the receiver operating characteristic curve (AUC) for 5-year prediction of AD dementia of 0.79. Clinical and cognitive variables (AUC = 0.79), and apolipoprotein E genotype (AUC = 0.76) were added to the demographic model. We then incorporated the risk computed from the demographic model with hazard ratios computed from independent data for amyloid positron emission tomography status and magnetic resonance imaging hippocampal volume (AUC = 0.84), and for plasma amyloid beta (Aβ)42/Aβ40 (AUC = 0.82). Discussion: An adaptive tool was developed and validated to compute absolute risks of AD dementia. This approach allows for improved accuracy and communication of AD risk among cognitively unimpaired older adults. © 2022 the Alzheimer’s Association.
Author Keywords
return of research results; risk estimation; survival analysis
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
Non-sedative cortical EEG signatures of allopregnanolone and functional comparators
(2022) Neuropsychopharmacology, .
Lambert, P.M.a b , Ni, R.a , Benz, A.a , Rensing, N.R.c , Wong, M.c , Zorumski, C.F.a d , Mennerick, S.a d
a Department of Psychiatry, Washington University in St. Louis School of Medicine, 660S. Euclid Ave., MSC 8134-0181-0G, St. Louis, MO 63110, United States
b Medical Scientist Training Program, Washington University in St. Louis School of Medicine, 660S. Euclid Ave., MSC 8134-0181-0G, St. Louis, MO 63110, United States
c Department of Neurology, Washington University in St. Louis School of Medicine, 660S. Euclid Ave., MSC 8134-0181-0G, St. Louis, MO 63110, United States
d Taylor Family Institute for Innovative Psychiatric Research, Washington University in St. Louis School of Medicine, 660S. Euclid Ave., MSC 8134-0181-0G, St. Louis, MO 63110, United States
Abstract
Neurosteroids that positively modulate GABAA receptors are among a growing list of rapidly acting antidepressants, including ketamine and psychedelics. To develop increasingly specific treatments with fewer side effects, we explored the possibility of EEG signatures in mice, which could serve as a cross-species screening tool. There are few studies of the impact of non-sedative doses of rapid antidepressants on EEG in either rodents or humans. Here we hypothesize that EEG features may separate a rapid antidepressant neurosteroid, allopregnanolone, from other GABAA positive modulators, pentobarbital and diazepam. Further, we compared the actions GABA modulators with those of ketamine, an NMDA antagonist and prototype rapid antidepressant. We examined EEG spectra during active exploration at two cortical locations and examined cross-regional and cross-frequency interactions. We found that at comparable doses, the effects of allopregnanolone, despite purported selectivity for certain GABAAR subtypes, was indistinguishable from pentobarbital during active waking exploration. The actions of diazepam had recognizable common features with allopregnanolone and pentobarbital but was also distinct, consistent with subunit selectivity of benzodiazepines. Finally, ketamine exhibited no distinguishing overlap with allopregnanolone in the parameters examined. Our results suggest that rapid antidepressants with different molecular substrates may remain separated at the level of large-scale ensemble activity, but the studies leave open the possibility of commonalities in more discrete circuits and/or in the context of a dysfunctional brain. © 2022, The Author(s).
Funding details
National Institute of Mental HealthNIMHHD103525, MH122379, MH123748, MH126548
Taylor Family Institute for Innovative Psychiatric Research, Washington University School of Medicine in St. Louis
Document Type: Article
Publication Stage: Article in Press
Source: Scopus