Differences in the link between social trait judgment and socio-emotional experience in neurotypical and autistic individuals
(2024) Scientific Reports, 14 (1), art. no. 5400, .
Zhao, S.a , Cao, R.b , Lin, C.c , Wang, S.b , Yu, H.a
a Department of Psychological and Brain Sciences, University of California Santa Barbara, Santa Barbara, CA 93106, United States
b Department of Radiology, Washington University in St. Louis, St. Louis, MO 63110, United States
c Department of Psychology, University of California San Diego, San Diego, CA 92093, United States
Abstract
Neurotypical (NT) individuals and individuals with autism spectrum disorder (ASD) make different judgments of social traits from others’ faces; they also exhibit different social emotional responses in social interactions. A common hypothesis is that the differences in face perception in ASD compared with NT is related to distinct social behaviors. To test this hypothesis, we combined a face trait judgment task with a novel interpersonal transgression task that induces measures social emotions and behaviors. ASD and neurotypical participants viewed a large set of naturalistic facial stimuli while judging them on a comprehensive set of social traits (e.g., warm, charismatic, critical). They also completed an interpersonal transgression task where their responsibility in causing an unpleasant outcome to a social partner was manipulated. The purpose of the latter task was to measure participants’ emotional (e.g., guilt) and behavioral (e.g., compensation) responses to interpersonal transgression. We found that, compared with neurotypical participants, ASD participants’ self-reported guilt and compensation tendency was less sensitive to our responsibility manipulation. Importantly, ASD participants and neurotypical participants showed distinct associations between self-reported guilt and judgments of criticalness from others’ faces. These findings reveal a novel link between perception of social traits and social emotional responses in ASD. © The Author(s) 2024.
Author Keywords
Guilt; Interpersonal transgression; Responsibility; Social trait perception
Funding details
National Science FoundationNSFBCS-1945230, IIS-2114644
National Institutes of HealthNIHR01MH129426
Air Force Office of Scientific ResearchAFOSRFA9550-21-1-0088
Dana FoundationDF
Document Type: Article
Publication Stage: Final
Source: Scopus
Distributed feature representations of natural stimuli across parallel retinal pathways
(2024) Nature Communications, 15 (1), art. no. 1920, .
Hsiang, J.-C.a , Shen, N.a , Soto, F.a , Kerschensteiner, D.a b c
a Department of Ophthalmology and Visual Sciences, Washington University School of Medicine, St. Louis, MO 63110, United States
b Department of Neuroscience, Washington University School of Medicine, St. Louis, MO 63110, United States
c Department of Biomedical Engineering, Washington University School of Medicine, St. Louis, MO 63110, United States
Abstract
How sensory systems extract salient features from natural environments and organize them across neural pathways is unclear. Combining single-cell and population two-photon calcium imaging in mice, we discover that retinal ON bipolar cells (second-order neurons of the visual system) are divided into two blocks of four types. The two blocks distribute temporal and spatial information encoding, respectively. ON bipolar cell axons co-stratify within each block, but separate laminarly between them (upper block: diverse temporal, uniform spatial tuning; lower block: diverse spatial, uniform temporal tuning). ON bipolar cells extract temporal and spatial features similarly from artificial and naturalistic stimuli. In addition, they differ in sensitivity to coherent motion in naturalistic movies. Motion information is distributed across ON bipolar cells in the upper and the lower blocks, multiplexed with temporal and spatial contrast, independent features of natural scenes. Comparing the responses of different boutons within the same arbor, we find that axons of all ON bipolar cell types function as computational units. Thus, our results provide insights into the visual feature extraction from naturalistic stimuli and reveal how structural and functional organization cooperate to generate parallel ON pathways for temporal and spatial information in the mammalian retina. © The Author(s) 2024.
Funding details
National Institutes of HealthNIHEY026978, EY027411, EY034001
McDonnell Center for Systems Neuroscience
Document Type: Article
Publication Stage: Final
Source: Scopus
Quantitative T2 mapping-based longitudinal assessment of brain injury and therapeutic rescue in the rat following acute organophosphate intoxication
(2024) Neuropharmacology, 249, art. no. 109895, .
Almeida, A.J.D.a b , Hobson, B.A.c , Saito, N.d , Bruun, D.A.e , Porter, V.A.a b , Harvey, D.J.d , Garbow, J.R.f , Chaudhari, A.J.b c , Lein, P.J.e
a Department of Biomedical Engineering, University of California-Davis College of Engineering, Davis, CA 95616, United States
b Department of Radiology, University of California-Davis School of Medicine, Sacramento, CA 95817, United States
c Center for Molecular and Genomic Imaging, Department of Biomedical Engineering, University of California-Davis College of Engineering, Davis, CA 95616, United States
d Department of Public Health Sciences, University of California-Davis School of Medicine, Davis, CA 95616, United States
e Department of Molecular Biosciences, University of California-Davis School of Veterinary Medicine, Davis, CA 95616, United States
f Department of Radiology, Washington University School of Medicine, St Louis, MO 63110, United States
Abstract
Acute intoxication with organophosphate (OP) cholinesterase inhibitors poses a significant public health risk. While currently approved medical countermeasures can improve survival rates, they often fail to prevent chronic neurological damage. Therefore, there is need to develop effective therapies and quantitative metrics for assessing OP-induced brain injury and its rescue by these therapies. In this study we used a rat model of acute intoxication with the OP, diisopropylfluorophosphate (DFP), to test the hypothesis that T2 measures obtained from brain magnetic resonance imaging (MRI) scans provide quantitative metrics of brain injury and therapeutic efficacy. Adult male Sprague Dawley rats were imaged on a 7T MRI scanner at 3, 7 and 28 days post-exposure to DFP or vehicle (VEH) with or without treatment with the standard of care antiseizure drug, midazolam (MDZ); a novel antiseizure medication, allopregnanolone (ALLO); or combination therapy with MDZ and ALLO (DUO). Our results show that mean T2 values in DFP-exposed animals were: (1) higher than VEH in all volumes of interest (VOIs) at day 3; (2) decreased with time; and (3) decreased in the thalamus at day 28. Treatment with ALLO or DUO, but not MDZ alone, significantly decreased mean T2 values relative to untreated DFP animals in the piriform cortex at day 3. On day 28, the DUO group showed the most favorable T2 characteristics. This study supports the utility of T2 mapping for longitudinally monitoring brain injury and highlights the therapeutic potential of ALLO as an adjunct therapy to mitigate chronic morbidity associated with acute OP intoxication. © 2024 The Authors
Author Keywords
Allopregnanolone; Diisopropylfluorophosphate; Magnetic resonance imaging; Midazolam; Neurosteroid; T2 mapping
Funding details
National Institutes of HealthNIHR21 AG064599, U54 NS079202, U54 NS127758
National Center for Advancing Translational SciencesNCATSTL1 TR001861, UL1 TR001860
Document Type: Article
Publication Stage: Final
Source: Scopus
Explainable AI-based Deep-SHAP for mapping the multivariate relationships between regional neuroimaging biomarkers and cognition
(2024) European Journal of Radiology, 174, art. no. 111403, .
Bhattarai, P.a , Thakuri, D.S.a b , Nie, Y.a c , Chand, G.B.a d e f
a Department of Radiology, Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, MO, United States
b University of Missouri, School of Medicine, Columbia, MO, United States
c Institute for Informatics, Data Science and Biostatistics, Washington University School of Medicine, St. Louis, MO, United States
d Imaging Core, Knight Alzheimer Disease Research Center, Washington University School of Medicine, St. Louis, MO, United States
e Institute of Clinical and Translational Sciences, Washington University School of Medicine, St. Louis, MO, United States
f NeuroGenomics and Informatics Center, Washington University School of Medicine, St. Louis, MO, United States
Abstract
Background: Mild cognitive impairment (MCI)/Alzheimer’s disease (AD) is associated with cognitive decline beyond normal aging and linked to the alterations of brain volume quantified by magnetic resonance imaging (MRI) and amyloid-beta (Aβ) quantified by positron emission tomography (PET). Yet, the complex relationships between these regional imaging measures and cognition in MCI/AD remain unclear. Explainable artificial intelligence (AI) may uncover such relationships. Method: We integrate the AI-based deep learning neural network and Shapley additive explanations (SHAP) approaches and introduce the Deep-SHAP method to investigate the multivariate relationships between regional imaging measures and cognition. After validating this approach on simulated data, we apply it to real experimental data from MCI/AD patients. Results: Deep-SHAP significantly predicted cognition using simulated regional features and identified the ground-truth simulated regions as the most significant multivariate predictors. When applied to experimental MRI data, Deep-SHAP revealed that the insula, lateral occipital, medial frontal, temporal pole, and occipital fusiform gyrus are the primary contributors to global cognitive decline in MCI/AD. Furthermore, when applied to experimental amyloid Pittsburgh compound B (PiB)-PET data, Deep-SHAP identified the key brain regions for global cognitive decline in MCI/AD as the inferior temporal, parahippocampal, inferior frontal, supratemporal, and lateral frontal gray matter. Conclusion: Deep-SHAP method uncovered the multivariate relationships between regional brain features and cognition, offering insights into the most critical modality-specific brain regions involved in MCI/AD mechanisms. © 2024 Elsevier B.V.
Author Keywords
Amyloid-beta; Deep learning; Feature importance; Machine learning algorithms; Mild cognitive impairment; Shapley additive explanations
Funding details
National Institutes of HealthNIHK01AG083230
University of WashingtonUW
Institute of Clinical and Translational SciencesICTS
Mallinckrodt Institute of RadiologyMIR
Document Type: Article
Publication Stage: Final
Source: Scopus
A unified total synthesis route to 18-trideuterated and/or 19-trideuterated testosterone, androstenedione and progesterone
(2024) Steroids, 205, art. no. 109391, .
Qian, M.a , Covey, D.F.a b c d
a Department of Developmental Biology, Washington University in St. Louis, School of Medicine, 660 S. Euclid Ave., St. Louis, MO 63110, United States
b Department of Psychiatry, Washington University in St. Louis, School of Medicine, 660 S. Euclid Ave., St. Louis, MO 63110, United States
c Department of Anesthesiology, Washington University in St. Louis, School of Medicine, 660 S. Euclid Ave., St. Louis, MO 63110, United States
d The Taylor Family Institute for Innovative Psychiatric Research, Washington University in St. Louis, School of Medicine, 660 S. Euclid Ave., St. Louis, MO 63110, United States
Abstract
A unified total synthesis route has been used to prepare 18- and 19-trideuterated testosterone, androstenedione and progesterone. The 18-trideuterated steroid synthetic method starts with the synthesis of 2-(methyl-d3)-1,3-cyclopentanedione from CD3I and 1,3-cyclopentanedione and is subsequently converted into the Hajos-Parrish ketone for synthesis of these trideuterated steroids. The 19-trideuterated steroid synthesis proceeds through non-deuterated Hajos-Parrish ketone with incorporation of the 19-methyl-d3 group from CD3I at a later stage of the same synthetic route. Utilization of CD3I at both the initial and later stages of the synthesis provides a route to 18,19-hexadeuterated steroids. The deuterated steroids are useful for studies of steroid biosynthesis and metabolism. © 2024 Elsevier Inc.
Author Keywords
Deuterated androstenedione; Deuterated progesterone; Deuterated steroids; Deuterated testosterone
Funding details
8P41GM103422
National Institutes of HealthNIH1 P50 MH122379
Document Type: Article
Publication Stage: Final
Source: Scopus
Cholesterol 25-hydroxylase mediates neuroinflammation and neurodegeneration in a mouse model of tauopathy
(2024) The Journal of Experimental Medicine, 221 (4), .
Toral-Rios, D.a , Long, J.M.b c d , Ulrich, J.D.b c , Yu, J.e , Strickland, M.R.b , Han, X.f , Holtzman, D.M.b c d , Cashikar, A.G.a b c g , Paul, S.M.a b c g
a Department of Psychiatry, Washington University School of Medicine, St Louis, MO, United States
b Department of Neurology, Washington University School of Medicine, St Louis, MO, United States
c Hope Center for Neurological Disorders, Washington University School of Medicine, St Louis, MO, United States
d Knight Alzheimer Disease Research Center, Washington University School of Medicine, St Louis, MO, United States
e Department of Genetics, Genome Technology Access Center at the McDonnell Genome Institute, Washington University School of Medicine, St Louis, MO, United States
f Department of Medicine, Barshop Institute for Longevity and Aging Studies, University of Texas Health Science Center San Antonio, San Antonio, TX, United States
g Taylor Family Institute for Innovative Psychiatric Research, Washington University School of Medicine, St Louis, MO, United States
Abstract
Alzheimer’s disease (AD) is characterized by amyloid plaques and neurofibrillary tangles, in addition to neuroinflammation and changes in brain lipid metabolism. 25-Hydroxycholesterol (25-HC), a known modulator of both inflammation and lipid metabolism, is produced by cholesterol 25-hydroxylase encoded by Ch25h expressed as a “disease-associated microglia” signature gene. However, whether Ch25h influences tau-mediated neuroinflammation and neurodegeneration is unknown. Here, we show that in the absence of Ch25h and the resultant reduction in 25-HC, there is strikingly reduced age-dependent neurodegeneration and neuroinflammation in the hippocampus and entorhinal/piriform cortex of PS19 mice, which express the P301S mutant human tau transgene. Transcriptomic analyses of bulk hippocampal tissue and single nuclei revealed that Ch25h deficiency in PS19 mice strongly suppressed proinflammatory signaling in microglia. Our results suggest a key role for Ch25h/25-HC in potentiating proinflammatory signaling to promote tau-mediated neurodegeneration. Ch25h may represent a novel therapeutic target for primary tauopathies, AD, and other neuroinflammatory diseases. © 2024 Toral-Rios et al.
Document Type: Article
Publication Stage: Final
Source: Scopus
Threat experiences moderate the link between hippocampus volume and depression symptoms prospectively in adolescence
(2024) Developmental Cognitive Neuroscience, 66, art. no. 101359, .
Herzberg, M.P.a , DeJoseph, M.L.b , Luby, J.a , Barch, D.M.a c d
a Department of Psychiatry, Washington University in St. Louis, St. Louis, MO, United States
b Graduate School of Education, Stanford University, Stanford, CA, United States
c Department of Psychological & Brain Sciences, Washington University in St. Louis, St. Louis, MO, United States
d Department of Radiology, Washington University in St. Louis, St. Louis, MO, United States
Abstract
Identifying neuroimaging risk markers for depression has been an elusive goal in psychopathology research. Despite this, smaller hippocampal volume has emerged as a potential risk marker for depression, with recent research suggesting this association is moderated by family income. The current pre-registered study aimed to replicate and extend these findings by examining the moderating role of family income and three dimensions of environmental experience on the link between hippocampus volume and later depression. Data were drawn from the Adolescent Brain Cognitive Development (ABCD) study and were comprised of 6693 youth aged 9–10 years at baseline. Results indicated that psychosocial threat moderated the association between right hippocampus volume and depression symptoms two years later, such that a negative association was evident in low-threat environments (std. beta=0.15, 95% CI [0.05, 0.24]). This interaction remained significant when baseline depression symptoms were included as a covariate, though only in youth endorsing 1 or more depression symptoms at baseline (β = 0.13, 95% CI = [0.03, 0.22]). These results suggest that hippocampus volume may not be a consistent correlate of depression symptoms in high risk environments and emphasize the importance of including measures of environmental heterogeneity when seeking risk markers for depression. © 2024 The Authors
Author Keywords
Depression; Family income; Hippocampus; Longitudinal; Threat
Funding details
National Institutes of HealthNIHU01DA041022, U01DA041025, U01DA041028, U01DA041048, U01DA041089, U01DA041093, U01DA041106, U01DA041117, U01DA041120, U01DA041134, U01DA041148, U01DA041156, U01DA041174, U24DA041123, U24DA041147
National Institute of Mental HealthNIMHT32 MH100019
National Institute of Child Health and Human DevelopmentNICHD1F32HD112065-01
Document Type: Article
Publication Stage: Final
Source: Scopus
Germline knockout of Nr2e3 protects photoreceptors in three distinct mouse models of retinal degeneration
(2024) Proceedings of the National Academy of Sciences of the United States of America, 121 (11), pp. e2316118121.
Kolesnikov, A.V.a , Murphy, D.P.b , Corbo, J.C.b , Kefalov, V.J.a
a Department of Ophthalmology, Gavin Herbert Eye Institute, University of California, Irvine, CA 92697
b Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, United States
Abstract
Retinitis pigmentosa (RP) is a common form of retinal dystrophy that can be caused by mutations in any one of dozens of rod photoreceptor genes. The genetic heterogeneity of RP represents a significant challenge for the development of effective therapies. Here, we present evidence for a potential gene-independent therapeutic strategy based on targeting Nr2e3, a transcription factor required for the normal differentiation of rod photoreceptors. Nr2e3 knockout results in hybrid rod photoreceptors that express the full complement of rod genes, but also a subset of cone genes. We show that germline deletion of Nr2e3 potently protects rods in three mechanistically diverse mouse models of retinal degeneration caused by bright-light exposure (light damage), structural deficiency (rhodopsin-deficient Rho-/- mice), or abnormal phototransduction (phosphodiesterase-deficient rd10 mice). Nr2e3 knockout confers strong neuroprotective effects on rods without adverse effects on their gene expression, structure, or function. Furthermore, in all three degeneration models, prolongation of rod survival by Nr2e3 knockout leads to lasting preservation of cone morphology and function. These findings raise the possibility that upregulation of one or more cone genes in Nr2e3-deficient rods may be responsible for the neuroprotective effects we observe.
Author Keywords
photoreceptors; retina; retinitis pigmentosa
Document Type: Article
Publication Stage: Final
Source: Scopus
A Transdiagnostic Study of Effort-Cost Decision-Making in Psychotic and Mood Disorders
(2024) Schizophrenia Bulletin, 50 (2), pp. 339-348.
Culbreth, A.J.a , Moran, E.K.b , Mahaphanit, W.c , Erickson, M.A.d , Boudewyn, M.A.e , Frank, M.J.f , Barch, D.M.b g h , MacDonald III, A.W.i , Ragland, J.D.j , Luck, S.J.k , Silverstein, S.M.l , Carter, C.S.j , Gold, J.M.a
a Department of Psychiatry, Maryland Psychiatric Research Center, University of Maryland, School of Medicine, Baltimore, United States
b Department of Psychological and Brain Sciences, Washington University in St. Louis, Saint Louis, United States
c Department of Psychological and Brain Sciences, Dartmouth College, Hanover, United States
d Department of Psychiatry and Behavioral Neuroscience, University of Chicago, Chicago, United States
e Department of Psychology, University of California, Santa Cruz, United States
f Department of Cognitive Linguistics and Psychological Sciences, Brown University, Providence, United States
g Department of Psychiatry, Washington University, School of Medicine, St Louis, United States
h Department of Radiology, Mallinckrodt Institute of Radiology, Washington University, School of Medicine, St Louis, United States
i Department of Psychology, University of Minnesota, Minneapolis, United States
j Department of Psychiatry, University of California Davis, School of Medicine, Davis, United States
k Center for Mind and Brain, University of California Davis, Davis, United States
l Department of Psychiatry, University of Rochester Medical Center, Rochester, United States
Abstract
Background: Research suggests that effort-cost decision- making (ECDM), the estimation of work required to obtain reward, may be a relevant framework for understanding motivational impairment in psychotic and mood pathology. Specifically, research has suggested that people with psychotic and mood pathology experience effort as more costly than controls, and thus pursue effortful goals less frequently. This study examined ECDM across psychotic and mood pathology. Hypothesis: We hypothesized that patient groups would show reduced willingness to expend effort compared to controls. Study Design: People with schizophrenia (N = 33), schizoaffective disorder (N = 28), bipolar disorder (N = 39), major depressive disorder (N = 40), and controls (N = 70) completed a physical ECDM task. Participants decided between completing a low-effort or high-effort option for small or larger rewards, respectively. Reward magnitude, reward probability, and effort magnitude varied trial-by-trial. Data were analyzed using standard and hierarchical logistic regression analyses to assess the subject-specific contribution of various factors to choice. Negative symptoms were measured with a clinician-rated interview. Study Results: There was a significant effect of group, driven by reduced choice of high-effort options in schizophrenia. Hierarchical logistic regression revealed that reduced choice of high-effort options in schizophrenia was driven by weaker contributions of probability information. Use of reward information was inversely associated with motivational impairment in schizophrenia. Surprisingly, individuals with major depressive disorder and bipolar disorder did not differ from controls. Conclusions: Our results provide support for ECDM deficits in schizophrenia. Additionally, differences between groups in ECDM suggest a seemingly similar behavioral phenotype, reduced motivation, could arise from disparate mechanisms. © The Author(s) 2023.
Author Keywords
eff ort-cost decision-making; experimental psychopathology; motivation; reward processing; schizophrenia; transdiagnostic
Funding details
National Institute of Mental HealthNIMHR01 MH084821, K23 MH126986
Document Type: Article
Publication Stage: Final
Source: Scopus
Periodic and aperiodic changes to cortical EEG in response to pharmacological manipulation
(2024) Journal of Neurophysiology, 131 (3), pp. 529-540.
Salvatore, S.V.a , Lambert, P.M.a c , Benz, A.a , Rensing, N.R.b , Wong, M.b , Zorumski, C.F.a d , Mennerick, S.a d
a Department of Psychiatry, Washington University, St. Louis School of Medicine, St. Louis, MO, United States
b Department of Neurology, Washington University, St. Louis School of Medicine, St. Louis, MO, United States
c Medical Scientist Training Program, Washington University, St. Louis School of Medicine, St. Louis, MO, United States
d Taylor Family Institute for Innovative Psychiatric Research, Washington University, St. Louis School of Medicine, St. Louis, MO, United States
Abstract
Cortical electroencephalograms (EEGs) may help understanding of neuropsychiatric illness and new treatment mechanisms. The aperiodic component (1/f) of EEG power spectra is often treated as noise, but recent studies suggest that changes to the aperiodic exponent of power spectra may reflect changes in excitation/inhibition balance, a concept linked to antidepressant effects, epilepsy, autism, and other clinical conditions. One confound of previous studies is behavioral state, because factors associated with behavioral state other than excitation/inhibition ratio may alter EEG parameters. Thus, to test the robustness of the aperiodic exponent as a predictor of excitation/inhibition ratio, we analyzed video-EEG during active exploration in mice of both sexes during various pharmacological manipulations with the fitting oscillations and one over f (FOOOF) algorithm. We found that GABAA receptor (GABAAR)-positive allosteric modulators increased the aperiodic exponent, consistent with the hypothesis that an increased exponent signals enhanced cortical inhibition, but other drugs (ketamine and GABAAR antagonists at subconvulsive doses) did not follow the prediction. To tilt excitation/inhibition ratio more selectively toward excitation, we suppressed the activity of parvalbumin-positive interneurons with Designer Receptors Exclusively Activated by Designer Drugs (DREADDs). Contrary to our expectations, circuit disinhibition with the DREADD increased the aperiodic exponent. We conclude that the aperiodic exponent of EEG power spectra does not yield a universally reliable marker of cortical excitation/inhibition ratio. © 2024 the American Physiological Society.
Author Keywords
cortical; electroencephalogram; gamma aminobutyric acid; inhibition
Document Type: Article
Publication Stage: Final
Source: Scopus
Eye movements and event segmentation: Eye movements reveal age-related differences in event model updating
(2024) Psychology and Aging, 39 (2), pp. 180-187.
Smith, M.E.a , Loschky, L.C.b , Bailey, H.R.b
a Department of Psychological and Brain Sciences, Washington University in St. Louis
b Department of Psychological Sciences, Kansas State University
Abstract
People spontaneously segment continuous ongoing actions into sequences of events. Prior research found that gaze similarity and pupil dilation increase at event boundaries and that older adults segment more idiosyncratically than do young adults. We used eye tracking to explore age-related differences in gaze similarity (i.e., the extent to which individuals look at the same places at the same time as others) and pupil dilation at event boundaries. Older and young adults watched naturalistic videos of actors performing everyday activities while we tracked their eye movements. Afterward, they segmented the videos into subevents. Replicating prior work, we found that pupil size and gaze similarity increased at event boundaries. Thus, there were fewer individual differences in eye position at boundaries. We also found that young adults had higher gaze similarity than older adults throughout an entire video and at event boundaries. This study is the first to show that age-related differences in how people parse continuous everyday activities into events may be partially explained by individual differences in gaze patterns. Those who segment less normatively may do so because they fixate less normative regions. Results have implications for future interventions designed to improve encoding in older adults. (PsycInfo Database Record (c) 2024 APA, all rights reserved).
Document Type: Article
Publication Stage: Final
Source: Scopus
Reduction of cell surface attachment in experimental hydrocephalus using a novel ventricular catheter with modified tethered liquid perfluorocarbon
(2024) Journal of Neurosurgery, 140 (3), pp. 627-638.
Garcia-Bonilla, M.a , Harris, C.A.b , Bandyopadhyay, S.c , Moore, J.a , Horbatiuk, J.b , Limbrick, D.D.a , Swarup, R.a , Crouthamel, J.a , Jones, A.c , Khasawneh, A.b , Petroj, A.b , Hehar, S.b , Sierra, M.b , Anderson, J.c , Murray, R.c , Talcott, M.R.a d , McAllister, J.P.a
a Department of Neurosurgery, Washington University in St. Louis School of Medicine, St. Louis, MO, United States
b Department of Chemical Engineering and Materials Science, Wayne State University, Detroit, MI, United States
c 3FreeFlow Medical Devices LLC, Lancaster, Pennsylvania; and
d Chicago, IL, United States
Abstract
OBJECTIVE: Ventriculoperitoneal shunting, the most common treatment for the neurological disorder hydrocephalus, has a failure rate of up to 98% within 10 years of placement, mainly because of proximal obstruction of the ventricular catheter (VC). The authors developed a new VC design modified with tethered liquid perfluorocarbon (TLP) and tested it in a porcine model of hydrocephalus. In this study, they aimed to determine if their TLP VC design reduced cell surface attachment and consequent shunt obstruction in the pig model. METHODS: TLP VCs were designed to reduce drainage hole obstruction using modified TLP and slightly enlarged draining holes, but their number and placement remained very similar to standard VCs. First, the authors tested the device in nonhydrocephalic rats to assess biocompatibility. After confirming safety, they implanted the VCs in hydrocephalic pigs. Hydrocephalus was induced by intracisternal kaolin injections in 30-day-old domestic juvenile pigs. Surgical implantation of the ventriculoperitoneal shunt (clinical control or TLP) was performed 10-14 days postinduction and maintained up to 30 days posttreatment. MRI was performed to measure ventricular volume before treatment and 10 and 30 days after treatment. Histological and immunohistochemical analyses of brain tissue and explanted VCs, intracranial pressure measurement, and clinical scoring were performed when the animals were euthanized. RESULTS: TLP VCs showed a similar surgical feel, kink resistance, and stiffness to control VCs. In rats (biocompatibility assessment), TLP VCs did not show brain inflammatory reactions after 30 or 60 days of implantation. In pigs, TLP VCs demonstrated increased survival time, improved clinical outcome scores, and significantly reduced total attached cells on the VCs compared with standard clinical control VCs. TLP VCs exhibited similar, but not worse, results related to ventriculomegaly, intracranial pressure, and the local tissue response around the cortical shunt track in pigs. CONCLUSIONS: TLP VCs may be a strong candidate to reduce proximal VC obstruction and improve hydrocephalus treatment.
Author Keywords
hydrocephalus; modified tethered liquid perfluorocarbon; pig model; shunt obstruction; ventricular catheter
Document Type: Article
Publication Stage: Final
Source: Scopus
The brain’s “dark energy” puzzle: How strongly is glucose metabolism linked to resting-state brain activity?
(2024) Journal of Cerebral Blood Flow and Metabolism, .
Volpi, T.a b , Silvestri, E.c , Aiello, M.d , Lee, J.J.e , Vlassenko, A.G.e , Goyal, M.S.e , Corbetta, M.a f , Bertoldo, A.a c
a Padova Neuroscience Center, University of Padova, Padova, Italy
b Department of Radiology and Biomedical Imaging, Yale University School of Medicine, New Haven, CT, United States
c Department of Information Engineering, University of Padova, Padova, Italy
d IRCCS SDN, Naples, 80143, Italy
e Neuroimaging Laboratories, the Mallinckrodt Institute of Radiology, Washington University School of Medicine, St Louis, MO, United States
f Department of Neuroscience, University of Padova, Padova, Italy
Abstract
Brain glucose metabolism, which can be investigated at the macroscale level with [18F]FDG PET, displays significant regional variability for reasons that remain unclear. Some of the functional drivers behind this heterogeneity may be captured by resting-state functional magnetic resonance imaging (rs-fMRI). However, the full extent to which an fMRI-based description of the brain’s spontaneous activity can describe local metabolism is unknown. Here, using two multimodal datasets of healthy participants, we built a multivariable multilevel model of functional-metabolic associations, assessing multiple functional features, describing the 1) rs-fMRI signal, 2) hemodynamic response, 3) static and 4) time-varying functional connectivity, as predictors of the human brain’s metabolic architecture. The full model was trained on one dataset and tested on the other to assess its reproducibility. We found that functional-metabolic spatial coupling is nonlinear and heterogeneous across the brain, and that local measures of rs-fMRI activity and synchrony are more tightly coupled to local metabolism. In the testing dataset, the degree of functional-metabolic spatial coupling was also related to peripheral metabolism. Overall, although a significant proportion of regional metabolic variability can be described by measures of spontaneous activity, additional efforts are needed to explain the remaining variance in the brain’s ‘dark energy’. © The Author(s) 2024.
Author Keywords
Brain glucose metabolism; functional-metabolic model; multilevel modeling; spontaneous activity; [18F]FDG PET
Funding details
National Institutes of HealthNIH
McDonnell Center for Systems Neuroscience
National Institute on AgingNIAR01AG053503, R01AG057536
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
Test–Retest Repeatability of Patlak Slopes versus Standardized Uptake Values for Hypermetabolic Lesions and Normal Organs in an Oncologic PET/CT Population
(2024) Molecular Imaging and Biology, .
Ince, S.a , Laforest, R.a , Ashrafinia, S.b , Smith, A.M.b , Wahl, R.L.a c , Fraum, T.J.a
a Department of Radiology, Washington University School of Medicine, 510 S. Kingshighway Blvd, Campus Box 8131, St. Louis, MO 63110, United States
b Siemens Medical Solutions USA, Inc., 810 Innovation Drive, Knoxville, TN 37932, United States
c Department of Radiation Oncology, Washington University School of Medicine, St. Louis, MO, United States
Abstract
Purpose: We aimed to determine the test–retest repeatability of quantitative metrics based on the Patlak slope (PS) versus the standardized uptake value (SUV) among lesions and normal organs on oncologic [18F]FDG-PET/CT. Procedures: This prospective, single-center study enrolled adults undergoing standard-of-care oncologic [18F]FDG-PET/CTs. Early (35–50 min post-injection) and late (75–90 min post-injection) SUV and PS images were reconstructed from dynamic whole-body PET data. Repeat imaging occurred within 7 days. Relevant quantitative metrics were extracted from lesions and normal organs. Repeatability was assessed via mean test–retest percent changes [T-RT %Δ], within-subject coefficients of variation (wCVs), and intra-class correlation coefficients (ICCs). Results: Nine subjects (mean age, 61.7 ± 6.2 years; 6 females) completed the test–retest protocol. Four subjects collectively had 17 [18F]FDG-avid lesions. Lesion wCVs were higher (i.e., worse repeatability) for PS-early-max (16.2%) and PS-early-peak (15.6%) than for SUV-early-max (8.9%) and SUV-early-peak (8.1%), with similar early metric ICCs (0.95–0.98). Lesion wCVs were similar for PS-late-max (8.5%) and PS-late-peak (6.4%) relative to SUV-late-max (9.7%) and SUV-late-peak (7.2%), with similar late metric ICCs (0.93–0.98). There was a significant bias toward higher retest SUV and PS values in the lesion analysis (T-RT %Δ [95% CI]: SUV-late-max, 10.0% [2.6%, 17.0%]; PS-late-max, 20.4% [14.3%, 26.4%]) but not in the normal organ analysis. Conclusions: Among [18F]FDG-avid lesions, the repeatability of PS-based metrics is similar to equivalent SUV-based metrics at late post-injection time points, indicating that PS-based metrics may be suitable for tracking response to oncologic therapies. However, further validation is required in light of our study’s limitations, including small sample size and bias toward higher retest values for some metrics. © The Author(s), under exclusive licence to World Molecular Imaging Society 2024.
Author Keywords
FDG; Metabolic rate; Patlak; PET; Repeatability; Test-retest
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
Characterization of hyperpolarization-activated cyclic nucleotide-gated channels in oligodendrocytes
(2024) Frontiers in Cellular Neuroscience, 18, art. no. 1321682, .
Lyman, K.A.a , Han, Y.b , Robinson, A.P.c , Weinberg, S.E.d , Fisher, D.W.e , Heuermann, R.J.f , Lyman, R.E.g , Kim, D.K.h i j k , Ludwig, A.l , Chandel, N.S.d , Does, M.D.h i j k , Miller, S.D.c , Chetkovich, D.M.b
a Department of Neurology, Massachusetts General Hospital, Boston, MA, United States
b Department of Neurology, Vanderbilt University Medical Center, Nashville, TN, United States
c Department of Microbiology-Immunology and Interdepartmental Immunobiology Center, Northwestern University, Chicago, IL, United States
d Department of Medicine, Northwestern University, Chicago, IL, United States
e Department of Psychiatry, University of Washington, Seattle, WA, United States
f Department of Neurology, Washington University, St. Louis, MO, United States
g Heritage College of Osteopathic Medicine, Ohio University, Dublin, OH, United States
h Department of Biomedical Engineering, Vanderbilt University, Nashville, TN, United States
i Vanderbilt University Institute of Imaging Science, Vanderbilt University, Nashville, TN, United States
j Department of Radiology and Radiological Sciences, Vanderbilt University School of Medicine, Nashville, TN, United States
k Department of Electrical Engineering, Vanderbilt University, Nashville, TN, United States
l Institut fur Experimentelle und Klinische Pharmakologie und Toxikologie, Friedrich-Alexander-Universitat Erlangen-Nurnberg, Erlangen, Germany
Abstract
Mature oligodendrocytes (OLG) are the myelin-forming cells of the central nervous system. Recent work has shown a dynamic role for these cells in the plasticity of neural circuits, leading to a renewed interest in voltage-sensitive currents in OLG. Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels and their respective current (Ih) were recently identified in mature OLG and shown to play a role in regulating myelin length. Here we provide a biochemical and electrophysiological characterization of HCN channels in cells of the oligodendrocyte lineage. We observed that mice with a nonsense mutation in the Hcn2 gene (Hcn2ap/ap) have less white matter than their wild type counterparts with fewer OLG and fewer oligodendrocyte progenitor cells (OPCs). Hcn2ap/ap mice have severe motor impairments, although these deficits were not observed in mice with HCN2 conditionally eliminated only in oligodendrocytes (Cnpcre/+; Hcn2F/F). However, Cnpcre/+; Hcn2F/F mice develop motor impairments more rapidly in response to experimental autoimmune encephalomyelitis (EAE). We conclude that HCN2 channels in OLG may play a role in regulating metabolism. Copyright © 2024 Lyman, Han, Robinson, Weinberg, Fisher, Heuermann, Lyman, Kim, Ludwig, Chandel, Does, Miller and Chetkovich.
Author Keywords
EAE; HCN; Ih; mitochondria; multiple sclerosis; oligodendrocyte; oligodendrocyte progenitor cell; TRIP8b
Funding details
National Institutes of HealthNIHR21MH104471, R21MH113262, RO1-NS059934, RO1MH106511
Brain and Behavior Research FoundationBBRF
Vanderbilt Institute for Clinical and Translational ResearchVICTRVR52450, VR53895
National Alliance for Research on Schizophrenia and DepressionNARSAD25138
Document Type: Article
Publication Stage: Final
Source: Scopus
Promoting diverse perspectives: Addressing health disparities related to Alzheimer’s and all dementias
(2024) Alzheimer’s and Dementia, .
Maestre, G.a , Hill, C.b , Griffin, P.b , Hall, S.b , Hu, W.c , Flatt, J.d , Babulal, G.e , Thorpe, R.f , Henderson, J.N.g , Buchwald, D.h , Manson, S.i , Cicero, E.j , Gilmore-Bykovskyi, A.k , Gamaldo, A.l , Glover, C.m , Barnes, L.m , Kind, A.k , James, B.m , Zeki Al Hazzouri, A.n , Wharton, W.j , Caramelli, P.o , Szanton, S.p , Whitmer, R.q , Benn Torres, J.r , Deters, K.s , Okonkwo, O.t , Das, R.u , Martinez-Gonzalez, K.v , Carrillo, M.b
a School of Medicine, Alzheimer’s Disease Resource Center for Minority Aging Research, University of Texas Rio Grande Valley, Brownsville, TX, United States
b Medical & Scientific Relations, Alzheimer’s Association, Chicago, IL, United States
c Rutgers Robert Wood Johnson Medical School and Rutgers Institute for Health, Health Care Policy, and Aging Research, New Brunswick, NJ, United States
d Department of Social and Behavioral Health, School of Public Health, University of Nevada Las Vegas, Las Vegas, NV, United States
e Department of Neurology, School of Medicine, Washington University in St. Louis, St. Louis, MO, United States
f Center on Aging, Center on Health Disparities Solutions, Hopkins Population Center, Alzheimer’s Disease Resource Center for Minority Aging Research, Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD, United States
g University of Minnesota Medical School, Duluth, MN, United States
h Institute for Research and Education to Advance Community Health Elson S Floyd College of Medicine Washington State University, Seattle, WA, United States
i Centers for American Indian and Alaska Native Health, University of Colorado Anschutz Medical Campus, Aurora, CO, United States
j Nell Hodgson Woodruff School of Nursing, Emory University, Atlanta, GA, United States
k BerbeeWalsh Department of Emergency Medicine, University of Wisconsin-Madison School of Medicine and Public Health, Madison, WI, United States
l Pennsylvania State University, State College, PA, United States
m Rush University Medical Center, Chicago, IL, United States
n Mailman School of Public Health, Department of Epidemiology, Columbia University, New York, NY, United States
o Behavioral and Cognitive Neurology Unit, Faculdade de Medicina, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
p Johns Hopkins University School of Nursing, Baltimore, MD, United States
q Department of Public Health Sciences, Department of Neurology, University of California Davis, Davis, CA, United States
r Vanderbilt University, Nashville, TN, United States
s Department of Neurosciences, University of California San Diego School of Medicine, La Jolla, CA, United States
t Department of Medicine and the Wisconsin Alzheimer’s Disease Research Center, University of Wisconsin School of Medicine and Public Health, Madison, WI, United States
u National Institute on Minority Health and Health Disparities, Bethesda, MD, United States
v University of Puerto Rico, San Juan, Puerto Rico
Abstract
Dementia research lacks appropriate representation of diverse groups who often face substantial adversity and greater risk of dementia. Current research participants are primarily well-resourced, non-Hispanic White, cisgender adults who live close to academic medical centers where much of the research is based. Consequently, the field faces a knowledge gap about Alzheimer’s-related risk factors in those other groups. The Alzheimer’s Association hosted a virtual conference on June 14–16, 2021, supported in part by the National Institute on Aging (R13 AG072859-01), focused on health disparities. The conference was held entirely online and consisted of 2 days of core programming and a day of focused meetings centered on American Indian and Alaska Natives and on LGBTQIA+ populations. Over 1300 registrants attended discussions focused on the structural and systemic inequities experienced across diverse groups, as well as ways to investigate and address these inequities. © 2024 The Authors. Alzheimer’s & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer’s Association.
Author Keywords
disparities; diversity; LGBTQIA+; racial/ethnic minorities; sexual and gender minorities
Funding details
National Institute on AgingNIAR13 AG072859‐01
National Institute on AgingNIA
U.S. Department of Veterans AffairsVA
Roche
Emory UniversityEU
University of Health Sciences LahoreUHS
Conselho Nacional de Desenvolvimento Científico e TecnológicoCNPq
Conselho Nacional de Desenvolvimento Científico e TecnológicoCNPq
Universidade Federal de Minas GeraisUFMG
National Institutes of HealthNIH
Universidad de Puerto RicoUPRR25MD007607, R21MD013652
National Institute on AgingNIA
Washington State UniversityWSU
University of VirginiaUV
Kuni Foundation
School of Medicine and Public Health, University of Wisconsin-MadisonUWSMPH
Biogen
Harvard University
Medical University of South CarolinaMUSC
Alzheimer’s Disease Research Center, University of PittsburghADRCR01AG054029, 1P30AG072975‐01, 2R01AG022018‐12, P30AG064200, R01AG060376
Alzheimer’s AssociationAA
University of Wisconsin-MadisonUW
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
Redox-dependent Cd2+ inhibition of BK-type Ca2+-activated K+ channels
(2024) Biophysical Journal, .
Zhang, G.a , Yang, H.a b , Wang, Y.a , Liang, H.a , Shi, J.a , Cui, J.a
a Department of Biomedical Engineering, Washington University, St. Louis, Missouri, United States
b Department of Biochemistry, Duke University Medical Center, Durham, North Carolina, United States
Abstract
Large-conductance Ca2+-activated K+ channels (BK channels) are formed by Slo1 subunits as a homotetramer. Besides Ca2+, other divalent cations, such as Cd2+, also activate BK channels when applied intracellularly by shifting the conductance-voltage relation to more negative voltages. However, we found that if the inside-out patch containing BK channels was treated with solution containing reducing agents such as dithiothreitol (DTT), then subsequent Cd2+ application completely inhibited BK currents. The DTT-dependent Cd2+ inhibition could be reversed by treating the patch with solutions containing H2O2, suggesting that a redox reaction regulates the Cd2+ inhibition of BK channels. Similar DTT-dependent Cd2+ inhibition was also observed in a mutant BK channel, Core-MT, in which the cytosolic domain of the channel is deleted, and in the proton-activated Slo3 channels but not observed in the voltage-gated Shaker K+ channels. A possible mechanism for the DTT-dependent Cd2+ inhibition is that DTT treatment breaks one or more disulfide bonds between cysteine pairs in the BK channel protein and the freed thiol groups coordinate with Cd2+ to form an ion bridge that blocks the channel or locks the channel at the closed state. However, surprisingly, none of the mutations of all cysteine residues in Slo1 affect the DTT-dependent Cd2+ inhibition. These results are puzzling, with an apparent contradiction: on one hand, a redox reaction seems to regulate Cd2+ inhibition of the channel, but on the other hand, no cysteine residue in the Slo1 subunit seems to be involved in such inhibition. © 2024 Biophysical Society
Funding details
National Institutes of HealthNIHGM149998, RO1 GM114694
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
Study Partner Report of Apathy in Older Adults is Associated with AD Biomarkers: Findings from the Harvard Aging Brain Study
(2024) American Journal of Geriatric Psychiatry, .
Burling, J.E.a , Katz, Z.b , Yuan, Z.a , Munro, C.c d e , Mimmack, K.a , Ma, G.e f , Hanseeuw, B.J.e g h , Papp, K.V.a c e , Amariglio, R.E.a c e , Vannini, P.a c e , Rentz, D.M.a c e , Quiroz, Y.T.a d e , Johnson, K.A.a c e i , Sperling, R.A.a c e , Blacker, D.d e j , Marshall, G.A.a c e , Yang, H.-S.a c e , Gatchel, J.R.d e k l m n
a Department of Neurology (JEB, ZY, KM, KVP, REA, PV, DMR, YTQ, KAJ, RAS, GAM, H-SY), Massachusetts General Hospital, Boston, MA, United States
b Washington University School of Medicine in St. Louis (ZK), St. Louis, MO, United States
c Department of Neurology (CM, KVP, REA, PV, DMR, KAJ, RAS, GAM, H-SY), Brigham and Women’s Hospital, Boston, MA, United States
d Department of Psychiatry (CM, YTQ, DB, JRG), Massachusetts General Hospital, Boston, MA, United States
e Harvard Medical School (CM, GM, BJH, KVP, REA, PV, DMR, YTQ, KAJ, RAS, DB, GAM, H-SY, JRG), Boston, MA, United States
f Department of Psychiatry (GM), Brigham and Women’s Hospital, Boston, MA, United States
g Department of Radiology (BJH), Massachusetts General Research Institute, Boston, MA, United States
h Department of Neurology (BJH), Cliniques Universitaires Saint-Luc, Belgium, Brussels, Belgium
i Department of Radiology (KAJ), Massachusetts General Hospital, Boston, MA, United States
j Department of Epidemiology (DB), Harvard T. H. Chan School of Public Health, Boston, MA, United States
k Department of Psychiatry (JRG), Massachusetts General Hospital, Boston, MA, United States
l Department of Psychiatry (JRG), McLean Hospital, Belmont, MA, United States
m Department of Psychiatry (JRG), Baylor College of Medicine, Houston, TX, United States
n Michael E. DeBakey VA Medical Center (JRG), Houston, TX, United States
Abstract
Objectives: We examined relationships between apathy (self and study-partner-reported) and markers of Alzheimer’s disease (AD) in older adults. Design: The study utilized a well-characterized sample of participants from the Harvard Aging Brain Study (HABS), a longitudinal cohort study. Participants were cognitively unimpaired without clinically significant neuropsychiatric symptoms at HABS baseline. The dependent variables, apathy evaluation scale-self (AES-S) and informant (AES-I), were administered cross-sectionally between years 6–9 and compared to the independent variables, amyloid and tau PET neuroimaging, from the same year. Setting: Community-dwelling participants assessed at research visits in an academic medical center. Participants: Participants (n = 170) completed assessments within 1.5 years of their neuroimaging visit. At the time of apathy assessment, N = 156 were cognitively unimpaired and 14 had progressed to mild cognitive impairment (n = 8) or dementia (n = 6). Measurements: We utilized linear regression models to assess cross-sectional associations of AES-S and AES-I with AD PET imaging measures (beta-amyloid (Pittsburgh Compound B) and tau (Flortaucipir)), covarying for age, sex, education, and the time between PET scan-apathy assessment. Results: AES-I was significantly associated with beta-amyloid and temporal lobe tau, and the associations were retained after further adjusting for depressive symptoms. The associations between AES-S and AD biomarkers were not significant. In an exploratory subgroup analysis of cognitively unimpaired individuals with elevated Aβ, we observed an association between AES-I and inferior temporal tau. Conclusions: Study-partner-reported, but not self-reported, apathy in older adults is associated with AD pathology, and we observed this relationship starting from the preclinical stage. Our findings highlight the importance of collateral information in capturing AD-related apathy. © 2024
Author Keywords
Alzheimer’s disease; amyloid; Apathy; positron emission tomography; study-partner-report; tau
Funding details
P41EB015896
National Institutes of HealthNIHK23AG05880, K23AG062750, P01 AG036694, P50 AG005134, R01AG07819, S10RR021110, S10RR023043, S10RR023401
National Institute of Biomedical Imaging and BioengineeringNIBIB
Massachusetts General HospitalMGH
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
Highly accurate blood test for Alzheimer’s disease is similar or superior to clinical cerebrospinal fluid tests
(2024) Nature Medicine, .
Barthélemy, N.R.a b , Salvadó, G.c , Schindler, S.E.a d , He, Y.a b , Janelidze, S.c , Collij, L.E.c e f , Saef, B.a , Henson, R.L.a , Chen, C.D.g , Gordon, B.A.g , Li, Y.a h , La Joie, R.i , Benzinger, T.L.S.g , Morris, J.C.a d , Mattsson-Carlgren, N.c j k , Palmqvist, S.c l , Ossenkoppele, R.c f m , Rabinovici, G.D.i n , Stomrud, E.c l , Bateman, R.J.a b d , Hansson, O.c l
a Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States
b Tracy Family Stable Isotope Labeling Quantitation (SILQ) Center, Washington University School of Medicine, St. Louis, MO, United States
c Clinical Memory Research Unit, Department of Clinical Sciences Malmö, Faculty of Medicine, Lund University, Lund, Sweden
d Charles F. and Joanne Knight Alzheimer Disease Research Center (Knight ADRC), Washington University School of Medicine, St. Louis, MO, United States
e Department of Radiology and Nuclear Medicine, Amsterdam UMC, location VUmc, Amsterdam, Netherlands
f Amsterdam Neuroscience, Brain Imaging, Amsterdam, Netherlands
g Department of Radiology, Washington University School of Medicine, St. Louis, MO, United States
h Division of Biostatistics, Washington University in St. Louis, St. Louis, MO, United States
i Department of Neurology, Memory and Aging Center, Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA, United States
j Wallenberg Center for Molecular Medicine, Lund University, Lund, Sweden
k Department of Neurology, Skåne University Hospital, Lund University, Lund, Sweden
l Memory Clinic, Skåne University Hospital, Malmö, Sweden
m Alzheimer Center Amsterdam, Neurology, Vrije Universiteit Amsterdam, Amsterdam UMC, location VUmc, Amsterdam, Netherlands
n Department of Radiology and Biomedical Imaging, University of California, San Francisco, San Francisco, CA, United States
Abstract
With the emergence of Alzheimer’s disease (AD) disease-modifying therapies, identifying patients who could benefit from these treatments becomes critical. In this study, we evaluated whether a precise blood test could perform as well as established cerebrospinal fluid (CSF) tests in detecting amyloid-β (Aβ) plaques and tau tangles. Plasma %p-tau217 (ratio of phosporylated-tau217 to non-phosphorylated tau) was analyzed by mass spectrometry in the Swedish BioFINDER-2 cohort (n = 1,422) and the US Charles F. and Joanne Knight Alzheimer Disease Research Center (Knight ADRC) cohort (n = 337). Matched CSF samples were analyzed with clinically used and FDA-approved automated immunoassays for Aβ42/40 and p-tau181/Aβ42. The primary and secondary outcomes were detection of brain Aβ or tau pathology, respectively, using positron emission tomography (PET) imaging as the reference standard. Main analyses were focused on individuals with cognitive impairment (mild cognitive impairment and mild dementia), which is the target population for available disease-modifying treatments. Plasma %p-tau217 was clinically equivalent to FDA-approved CSF tests in classifying Aβ PET status, with an area under the curve (AUC) for both between 0.95 and 0.97. Plasma %p-tau217 was generally superior to CSF tests in classification of tau-PET with AUCs of 0.95–0.98. In cognitively impaired subcohorts (BioFINDER-2: n = 720; Knight ADRC: n = 50), plasma %p-tau217 had an accuracy, a positive predictive value and a negative predictive value of 89–90% for Aβ PET and 87–88% for tau PET status, which was clinically equivalent to CSF tests, further improving to 95% using a two-cutoffs approach. Blood plasma %p-tau217 demonstrated performance that was clinically equivalent or superior to clinically used FDA-approved CSF tests in the detection of AD pathology. Use of high-performance blood tests in clinical practice can improve access to accurate AD diagnosis and AD-specific treatments. © The Author(s) 2024.
Funding details
1412/22
2022-1259
2022-Projekt0080
National Institutes of HealthNIHR01AG070941
National Institute on AgingNIAR01AG083740
Alzheimer’s AssociationAASG-23-1061717, ZEN24-1069572
Siemens USA
GE Healthcare
Foundation for Barnes-Jewish HospitalFBJH
Cure Alzheimer’s FundCAF
American College of RadiologyACR
Horizon 2020 Framework ProgrammeH2020101061836, AARF-22-972612, AF-980942
Coins for Alzheimer’s Research TrustCART
GHR FoundationGHR
Rainwater Charitable FoundationRCF
Charles F. and Joanne Knight Alzheimer Disease Research Center, Washington University in St. LouisKGADP01AG003991, P01AG026276, P30-AG062422, P30AG066444, R35 AG072362, R56AG061900, RF1AG061900, U01 AG057195, ZEN-21-848216
European Research CouncilERCADG-101096455
Lunds UniversitetLU
HjärnfondenFO2021-0293
Knut och Alice Wallenbergs Stiftelse2022-0231
VetenskapsrådetVR2022-00775, ERAPERMED2021-184
Konung Gustaf V:s och Drottning Victorias Frimurarestiftelse
AlzheimerfondenAF-980907
University Hospital FoundationUHF2020-O000028
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
Eating disorder symptoms and comorbid mental health risk among teens recruited to a digital intervention research study via two online approaches
(2024) International Journal of Eating Disorders, .
Kasson, E.a , Szlyk, H.S.a , Li, X.a , Constantino-Pettit, A.a , Smith, A.C.b , Vázquez, M.M.a , Wilfley, D.E.c , Taylor, C.B.d e , Fitzsimmons-Craft, E.E.a , Cavazos-Rehg, P.a
a Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, United States
b Department of Medical Social Sciences, Feinberg School of Medicine, Northwestern University, Chicago, IL, United States
c Department of Psychology, Washington University in St. Louis, St. Louis, MO, United States
d Department of Psychiatry and Behavioral Science, Stanford University School of Medicine, Stanford, CA, United States
e Center for m2Health, Palo Alto University, Palo Alto, CA, United States
Abstract
Introduction: It is crucial to identify and evaluate feasible, proactive ways to reach teens with eating disorders (EDs) who may not otherwise have access to screening or treatment. This study aimed to explore the feasibility of recruiting teens with EDs to a digital intervention study via social media and a publicly available online ED screen, and to compare the characteristics of teens recruited by each approach in an exploratory fashion. Method: Teens aged 14–17 years old who screened positive for a clinical/subclinical ED or at risk for an ED and who were not currently in ED treatment completed a baseline survey to assess current ED symptoms, mental health comorbidities, and barriers to treatment. Bivariate analyses were conducted to examine differences between participants recruited via social media and those recruited after completion of a widely available online EDs screen (i.e., National Eating Disorders Association [NEDA] screen). Results: Recruitment of teens with EDs using the two online approaches was found to be feasible, with 934 screens completed and a total of 134 teens enrolled over 6 months: 77% (n = 103) via social media 23% (n = 31) via the NEDA screen. Mean age of participants (N = 134) was 16 years old, with 49% (n = 66) identifying as non-White, and 70% (n = 94) identifying as a gender and/or sexual minority. Teens from NEDA reported higher ED psychopathology scores (medium effect size) and more frequent self-induced vomiting and driven exercise (small effect sizes). Teens from NEDA also endorsed more barriers to treatment, including not feeling ready for treatment and not knowing where to find a counselor or other resources (small effect sizes). Discussion: Online recruitment approaches in this study reached a large number of teens with an interest in a digital intervention to support ED recovery, demonstrating the feasibility of these outreach methods. Both approaches reached teens with similar demographic characteristics; however, teens recruited from NEDA reported higher ED symptom severity and barriers to treatment. Findings suggest that proactive assessment and intervention methods should be developed and tailored to meet the needs of each of these groups. Public Significance: This study examined the feasibility of recruiting teens with EDs to a digital intervention research study via social media and NEDA’s online screen, and demonstrated differences in ED symptoms among participants by recruitment approach. © 2024 Wiley Periodicals LLC.
Author Keywords
barriers to treatment; eating disorders; mHealth; screening; social media; teens
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
Extracellular vesicles released by microglia and macrophages carry endocannabinoids which foster oligodendrocyte differentiation
(2024) Frontiers in Immunology, 15, art. no. 1331210, .
Lombardi, M.a b , Scaroni, F.a , Gabrielli, M.a b , Raffaele, S.c , Bonfanti, E.c , Filipello, F.d o , Giussani, P.e , Picciolini, S.f , de Rosbo, N.K.g h , Uccelli, A.g i , Golia, M.T.a b , D’Arrigo, G.a b , Rubino, T.j , Hooshmand, K.k , Legido-Quigley, C.k l , Fenoglio, C.m n , Gualerzi, A.f , Fumagalli, M.c , Verderio, C.a b
a Department of Biomedical Sciences, National Research Council (CNR) Institute of Neuroscience, Vedano al Lambro, Italy
b NeuroMI Milan Center for Neuroscience, University of Milano-Bicocca, Milan, Italy
c Department of Pharmacological and Biomolecular Sciences “Rodolfo Paoletti”, Università degli Studi di Milano, Milan, Italy
d Scientific Institute for Research, Hospitalization and Healthcare (IRCCS) Humanitas Research Hospital, Rozzano, Italy
e Department of Medical Biotechnology and Translational Medicine, Università degli Studi di Milano, Segrate, Italy
f Scientific Institute for Research, Hospitalization and Healthcare (IRCCS) Fondazione Don Carlo Gnocchi Onlus, Milan, Italy
g Scientific Institute for Research, Hospitalization and Healthcare (IRCCS) Ospedale Policlinico San Martino, Genoa, Italy
h TomaLab, Institute of Nanotechnology, CNR, Rome, Italy
i Department of Neurology, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (DINOGMI), University of Genoa, Genoa, Italy
j Department of Biotechnology and Life Sciences (DBSV) and Neuroscience Center, University of Insubria, Busto Arsizio, Italy
k System Medicine, Steno Diabetes Center Copenhagen, Copenhagen, Denmark
l Institute of Pharmaceutical Sciences, Faculty of Life Sciences and Medicine, King’s College London, London, United Kingdom
m Department of Biomedical, Surgical and Dental Sciences, Università degli Studi di Milano, Milan, Italy
n Fondazione Scientific Institute for Research, Hospitalization and Healthcare (IRCCS) Ca’ Granda, Ospedale Maggiore Policlinico, Milan, Italy
o Department of Psychiatry, Washington University in St Louis, St Louis, MO, United States
Abstract
Introduction: Microglia and macrophages can influence the evolution of myelin lesions through the production of extracellular vesicles (EVs). While microglial EVs promote in vitro differentiation of oligodendrocyte precursor cells (OPCs), whether EVs derived from macrophages aid or limit OPC maturation is unknown. Methods: Immunofluorescence analysis for the myelin protein MBP was employed to evaluate the impact of EVs from primary rat macrophages on cultured OPC differentiation. Raman spectroscopy and liquid chromatography-mass spectrometry was used to define the promyelinating lipid components of myelin EVs obtained in vitro and isolated from human plasma. Results and discussion: Here we show that macrophage-derived EVs do not promote OPC differentiation, and those released from macrophages polarized towards an inflammatory state inhibit OPC maturation. However, their lipid cargo promotes OPC maturation in a similar manner to microglial EVs. We identify the promyelinating endocannabinoids anandamide and 2-arachidonoylglycerol in EVs released by both macrophages and microglia in vitro and circulating in human plasma. Analysis of OPC differentiation in the presence of the endocannabinoid receptor antagonists SR141716A and AM630 reveals a key role of vesicular endocannabinoids in OPC maturation. From this study, EV-associated endocannabinoids emerge as important mediators in microglia/macrophage-oligodendrocyte crosstalk, which may be exploited to enhance myelin repair. Copyright © 2024 Lombardi, Scaroni, Gabrielli, Raffaele, Bonfanti, Filipello, Giussani, Picciolini, de Rosbo, Uccelli, Golia, D’Arrigo, Rubino, Hooshmand, Legido-Quigley, Fenoglio, Gualerzi, Fumagalli and Verderio.
Author Keywords
2-arachidonoylglycerol; anandamide; endocannabinoids; extracellular vesicles; macrophages; microglia; oligodendrocytes
Funding details
Fondazione Italiana Sclerosi MultiplaFISM12365333, 2018/R/22
Fondazione Cariplo2015-0910
Regione Lombardia2016/B/2, POR-FESR 2014-2020
Document Type: Article
Publication Stage: Final
Source: Scopus
Day-to-day bidirectional associations between sleep and emotion states in early childhood: Importance of end-of-day mood for sleep quality
(2024) Sleep Health, .
Hoyniak, C.P.a , Vogel, A.C.a , Puricelli, A.b , Luby, J.L.a , Whalen, D.J.a
a Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, United States
b Foster and Adoptive Care Coalition, St. Louis, MO, United States
Abstract
Objectives: Poor quality sleep can impact emotions and emotion regulation, resulting in a “sleep-mood” cycle where poor sleep affects mood and vice-versa. This relationship is poorly understood during early childhood, when sleep patterns and emotion displays are rapidly changing. This study aimed to understand the day-to-day effects of poor sleep on emotions in preschoolers by using objective (actigraphy) and subjective (ecological momentary assessment) measures to assess both between- and within-child effects. We hypothesized that disrupted sleep would lead to affect disruptions and vice versa. Methods: This study included 133 preschoolers and their caregivers recruited from the community. Children’s sleep was measured via actigraphy (ActiGraph GT3X+) across 1 week. Affect was collected concurrently via caregiver report during an ecological momentary assessment protocol. Caregivers reported on their child’s affect four times per day: morning, afternoon, early evening, and before bed. Results: Multilevel modeling analyses revealed that children with sleep disturbances displayed less positive affect overall, more negative affect in the evenings, and alterations in positive affect lability, and that daytime affect was associated with subsequent nighttime sleep. Within-child associations also showed fluctuations in positive affect correlated with shorter sleep durations and later bedtimes. Conclusions: This study identified both between- and within-child associations between sleep and affect in early childhood, revealing a dynamic and reciprocal relationship between the two. These findings highlight the importance of considering both sleep and affect in early childhood interventions, as promoting positive affect may enhance sleep quality and vice versa. © 2024 National Sleep Foundation
Author Keywords
Affect; Early childhood; Ecological momentary assessment; Sleep
Funding details
National Institutes of HealthNIHK23 MH118426, K23 MH127305, K23 MH131849, L30 MH108015
Brain and Behavior Research FoundationBBRF
National Alliance for Research on Schizophrenia and DepressionNARSAD
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
Associations between the resting EEG aperiodic slope and broad domains of cognitive ability
(2024) Psychophysiology, .
Euler, M.J.a , Vehar, J.V.a , Guevara, J.E.a , Geiger, A.R.a , Deboeck, P.R.a , Lohse, K.R.b
a Department of Psychology, University of Utah, Salt Lake City, UT, United States
b Physical Therapy and Neurology, Washington University School of Medicine in Saint Louis, Saint Louis, MO, United States
Abstract
Recent studies suggest that the EEG aperiodic exponent (often represented as a slope in log–log space) is sensitive to individual differences in momentary cognitive skills such as selective attention and information processing speed. However, findings are mixed, and most of the studies have focused on just a narrow range of cognitive domains. This study used an archival dataset to help clarify associations between resting aperiodic features and broad domains of cognitive ability, which vary in their demands on momentary processing. Undergraduates (N = 166) of age 18–52 years completed a resting EEG session as well as a standardized, individually administered assessment of cognitive ability that included measures of processing speed, working memory, and higher-order visuospatial and verbal skills. A subsample (n = 110) also completed a computerized reaction time task with three difficulty levels. Data reduction analyses revealed strong correlations between the aperiodic offset and slope across electrodes, and a single component accounted for ~60% of variance in slopes across the scalp, in both eyes-closed and eyes-open conditions. Structural equation models did not support relations between the slope and specific domains tapping momentary processes. However, secondary analyses indicated that the eyes-open slope was related to higher overall performance, as represented by a single general ability factor. A latent reaction time variable was significantly inversely related to both eyes-closed and eyes-open resting exponents, such that faster reaction times were associated with steeper slopes. These findings support and help clarify the relation of the resting EEG exponent to individual differences in cognitive skills. © 2024 The Authors. Psychophysiology published by Wiley Periodicals LLC on behalf of Society for Psychophysiological Research.
Author Keywords
intelligence; processing speed; psychometric g; reaction time; reasoning; spectral slope
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
Biobehavioral Predictors of Pain Intensity, Pain Interference, and Chronic Pain Episodes: A Prospective Cohort Study of African-American Adults
(2024) Journal of Pain, .
Morris, M.C.a b , Bruehl, S.a , Rao, U.c d , Goodin, B.R.e , Karlson, C.b f , Carter, C.g , Nag, S.a , Huber, F.A.e , Bendinskas, K.G.h , Hidoyatov, M.h , Kinney, K.i , Rochelle, A.b , Funches, G.b
a Department of Anesthesiology, Vanderbilt University Medical Center, Nashville, TN, United States
b Department of Psychiatry and Human Behavior, University of Mississippi Medical Center, Jackson, Mississippi, United States
c Department of Psychiatry & Human Behavior and Center for the Neurobiology of Learning and Memory, University of California, Irvine, Irvine, California, United States
d Psychiatry Division, Children’s Hospital of Orange County, Orange, California, United States
e Department of Anesthesiology, Washington University in St. Louis, St. Louis, Missouri, United States
f Department of Hematology and Oncology, University of Mississippi Medical Center, Jackson, Mississippi, United States
g School of Medicine, Meharry Medical College, Nashville, TN, United States
h Chemistry Department, State University of New York at Oswego, Oswego, NY, United States
i Department of Psychology, Vanderbilt University, Nashville, TN, United States
Abstract
Racial disparities in pain experiences are well-established, with African-American (AA) adults reporting higher rates of daily pain, increased pain severity, and greater pain-related interference compared to non-Hispanic Whites. However, the biobehavioral factors that predict the transition to chronic pain among AA adults are not well understood. This prospective cohort study provided a unique opportunity to evaluate predictors of chronic pain onset among 130 AA adults (81 women), ages 18 to 44, who did not report chronic pain at their baseline assessment and subsequently completed follow-up assessments at 6- and 12-months. Outcome measures included pain intensity, pain-related interference, and chronic pain status. Comprehensive assessments of sociodemographic and biobehavioral factors were used to evaluate demographics, socioeconomic status, stress exposure, psychosocial factors, prolonged hypothalamic-pituitary-adrenal secretion, and quantitative sensory testing responses. At baseline, 30 adults (23.1%) reported a history of prior chronic pain. Over the 12-month follow-up period, 13 adults (10.0%) developed a new chronic pain episode, and 18 adults (13.8%) developed a recurrent chronic pain episode. Whereas socioeconomic status measures (ie, annual income, education) predicted changes in pain intensity over the follow-up period, quantitative sensory testing measures (ie, pain threshold, temporal summation of pain) predicted changes in pain interference. A history of chronic pain and higher depressive symptoms at baseline independently predicted the onset of a new chronic pain episode. The present findings highlight distinct subsets of biobehavioral factors that are differentially associated with trajectories of pain intensity, pain-related interference, and onset of chronic pain episodes in AA adults. Perspective: This prospective study sought to advance understanding of biobehavioral factors that predicted pain outcomes over a 12-month follow-up period among AA adults without chronic pain at their initial assessment. Findings revealed distinct subsets of factors that were differentially associated with pain intensity, pain-related interference, and onset of chronic pain episodes. © 2024 The Authors
Author Keywords
African-American; biobehavioral; Chronic pain; prospective; socioeconomic
Funding details
National Institutes of HealthNIHR01DA040966, R01DA050334, R01HL164823, R01MD010757, R01MD016838, R01MD017565, R01MH108155, T32MH018921, U54MD007586, U54MD007593
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
Comparison of cerebral oxygen extraction fraction using ASE and TRUST methods in patients with sickle cell disease and healthy controls
(2024) Journal of Cerebral Blood Flow and Metabolism, .
Fellah, S.a , Ying, C.b , Wang, Y.a , Guilliams, K.P.a c , Fields, M.E.a c , Chen, Y.a , Lewis, J.a , Mirro, A.c , Cohen, R.a , Igwe, N.a , Eldeniz, C.b , Jiang, D.d , Lu, H.d , Powers, W.J.e , Lee, J.-M.a b , Ford, A.L.a b , An, H.a b
a Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States
b Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, MO, United States
c Department of Pediatrics, Washington University School of Medicine, St. Louis, MO, United States
d Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine, Baltimore, MD, United States
e Department of Neurology, Duke University School of Medicine, Durham, NC, United States
Abstract
Abnormal oxygen extraction fraction (OEF), a putative biomarker of cerebral metabolic stress, may indicate compromised oxygen delivery and ischemic vulnerability in patients with sickle cell disease (SCD). Elevated OEF was observed at the tissue level across the brain using an asymmetric spin echo (ASE) MR method, while variable global OEFs were found from the superior sagittal sinus (SSS) using a T2-relaxation-under-spin-tagging (TRUST) MRI method with different calibration models. In this study, we aimed to compare the average ASE-OEF in the SSS drainage territory and TRUST-OEF in the SSS from the same SCD patients and healthy controls. 74 participants (SCD: N = 49; controls: N = 25) underwent brain MRI. TRUST-OEF was quantified using the Lu-bovine, Bush-HbA and Li-Bush-HbS models. ASE-OEF and TRUST-OEF were significantly associated in healthy controls after controlling for hematocrit using the Lu-bovine or the Bush-HbA model. However, no association was found between ASE-OEF and TRUST-OEF in patients with SCD using either the Bush-HbA or the Li-Bush-HbS model. Plausible explanations include a discordance between spatially volume-averaged oxygenation brain tissue and flow-weighted volume-averaged oxygenation in SSS or sub-optimal calibration in SCD. Further work is needed to refine and validate non-invasive MR OEF measurements in SCD. © The Author(s) 2024.
Author Keywords
Asymmetric spin echo; magnetic resonance imaging; oxygen extraction fraction; sickle cell disease; T2-relaxation-under-spin-tagging
Funding details
National Institutes of HealthNIHR01HL129241, RF1NS116565
National Institute of Neurological Disorders and StrokeNINDSR01NS121065
National Center for Advancing Translational SciencesNCATSKL2TR002346, R01HL157188, R01NS082561, R21NS127425
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
Associations between Plasma, Imaging, and Cerebrospinal Fluid Biomarkers with Driving Behavior and Cognitive Tests: Implications for Biomarker Usefulness
(2023) Journal of Alzheimer’s Disease Reports, 7 (1), pp. 1095-1102.
Roe, C.M.a , Bayat, S.b c d , Babulal, G.M.e f g h
a Roe Research LLC, St. Louis, MO, United States
b Department of Biomedical Engineering, University of Calgary, Calgary, Canada
c Department of Geomatics Engineering, University of Calgary, Calgary, Canada
d Hotchkiss Brain Institute, University of Calgary, Calgary, Canada
e Department of Neurology, Washington University in St. Louis, St. Louis, MO, United States
f Institute of Public Health, Washington University in St. Louis, St. Louis, MO, United States
g Department of Psychology, Faculty of Humanities, University of Johannesburg, Johannesburg, South Africa
h Department of Clinical Research and Leadership, George Washington University School of Medicine and Health Sciences, Washington, DC, United States
Abstract
Background: Declines in instrumental activities of daily living like driving are hallmarks sequelae of Alzheimer’s disease (AD). Although driving has been shown to be associated with traditional imaging and cerebrospinal fluid (CSF) biomarkers, it is possible that some biomarkers have stronger associations with specific aspects of driving behavior. Furthermore, associations between newer plasma biomarkers and driving behaviors are unknown. Objective: This study assessed the extent to which individual plasma, imaging, and CSF biomarkers are related to specific driving behaviors and cognitive functions among cognitively normal older adults. Methods: We analyzed naturalistic driving behavior from cognitively healthy older drivers (N = 167, 47% female, mean age = 73.3 years). All participants had driving, clinical, and demographic data and completed biomarker testing, including imaging, CSF, and/or plasma, within two years of study commencement. Results: AD biomarkers were associated with different characteristics of driving and cognitive functioning within the same individuals. Elevated levels of plasma Aβ40 were associated with more speeding incidents, higher levels of CSF tau were related to shorter duration of trips, and higher CSF neurofilament light chain values were associated with traveling shorter distances, smaller radius of gyration, and fewer trips at night. We demonstrated that plasma, like CSF and imaging biomarkers, were helpful in predicting everyday driving behaviors. Conclusions: These findings suggest that different biomarkers offer complementary information with respect to driving behaviors. These distinct relationships may help in understanding how different biological changes that occur during the preclinical stage of AD can impact various sensorimotor and cognitive processes. © 2023 – The authors. Published by IOS Press.
Author Keywords
Alzheimer’s disease; biomarkers; cerebrospinal fluid; imaging; naturalistic driving
Funding details
National Institutes of HealthNIH
National Institute on AgingNIAR01AG056466, R01AG067428, R01AG068183
BrightFocus FoundationBFFA2021142 S.
Document Type: Article
Publication Stage: Final
Source: Scopus