Experimental Framework for Assessing Mouse Retinal Regeneration Through Single-Cell RNA-Sequencing
(2025) Methods in Molecular Biology (Clifton, N.J.), 2848, pp. 117-134.
Hernández-Núñez, I.a , Clark, B.S.a b
a John F Hardesty, MD Department of Ophthalmology and Visual Sciences, Washington University School of Medicine, St. Louis, MO, United States
b Department of Developmental Biology, Washington University School of Medicine, St. Louis, MO, United States
Abstract
Retinal degenerative diseases including age-related macular degeneration and glaucoma are estimated to currently affect more than 14 million people in the United States, with an increased prevalence of retinal degenerations in aged individuals. An expanding aged population who are living longer forecasts an increased prevalence and economic burden of visual impairments. Improvements to visual health and treatment paradigms for progressive retinal degenerations slow vision loss. However, current treatments fail to remedy the root cause of visual impairments caused by retinal degenerations-loss of retinal neurons. Stimulation of retinal regeneration from endogenous cellular sources presents an exciting treatment avenue for replacement of lost retinal cells. In multiple species including zebrafish and Xenopus, Müller glial cells maintain a highly efficient regenerative ability to reconstitute lost cells throughout the organism’s lifespan, highlighting potential therapeutic avenues for stimulation of retinal regeneration in humans. Here, we describe how the application of single-cell RNA-sequencing (scRNA-seq) has enhanced our understanding of Müller glial cell-derived retinal regeneration, including the characterization of gene regulatory networks that facilitate/inhibit regenerative responses. Additionally, we provide a validated experimental framework for cellular preparation of mouse retinal cells as input into scRNA-seq experiments, including insights into experimental design and analyses of resulting data. © 2025. The Author(s), under exclusive license to Springer Science+Business Media, LLC, part of Springer Nature.
Author Keywords
Müller glia; Regeneration; Retina; Retinal regeneration; scRNA-seq; Single-cell RNA-sequencing
Document Type: Article
Publication Stage: Final
Source: Scopus
Social and Quality-of-Life Impact of Refractive Surgery in Children With Developmental Disorders and Spectacle Nonadherence
(2025) American Journal of Ophthalmology, 269, pp. 20-29.
Strelnikov, J.a , Zdonczyk, A.a , Pruett, J.R., Jr.b , Culican, S.c , Tychsen, L.a , Gordon, M.a , Marrus, N.b , Todorov, A.b , Reynolds, M.a b
a From the Department of Ophthalmology & Visual Sciences (J.S., A.Z., L.T., M.G., M.R.), Washington University School of Medicine, St. Louis, MO, United States
b Department of Psychiatry (J.R.P., N.M., A.T.), Washington University School of Medicine, St. Louis, MO, United States
c Department of Ophthalmology and Visual Neurosciences (S.C.), University of Minnesota Medical School, Minneapolis, MN, United States
Abstract
PURPOSE: Children with autism spectrum disorder and intellectual disability often cannot tolerate wearing spectacles or contact lenses, which are the standard-of-care for treating ametropia.1,2 We aimed to assess the impact of refractive surgery on social functioning and vision-specific quality-of-life (VSQOL) in this population. DESIGN: Prospective, before-and-after case series. METHODS: Setting: Single, academic tertiary care center. Study population: 18 children with autism spectrum disorder and/or intellectual disability, ametropia, and spectacle nonadherence were included in the analysis. Procedure: Participants underwent refractive surgery with either intraocular lens implantation or keratectomy. Parents completed the Social Responsiveness Scale (SRS-2) and Pediatric Eye Questionnaire (PedEyeQ) at baseline and 1, 6, and 12 months postsurgery.3,4 Main outcome measures: Median change in SRS-2 T-scores and PedEyeQ scores 12 months after surgery, compared to baseline. The minimum clinically important difference was set at 5 points for the SRS-2 and 10 points for the PedEyeQ. RESULTS: At 12 months after surgery, statistically significant improvements were observed in the SRS-2 domains of Social Awareness (8 points, 95% CI 2-13, P = .03) and Social Motivation (7 points, 95% CI 2-15, P = .03). Total SRS-2 T-score improved in a clinically important manner for 56% (10/18) of patients, but the median change was not statistically significant (5 points, 95% CI –1 to 9, P = .10). VSQOL showed statistically significant improvements in the domains of Functional Vision (40 points, 95% CI 7-73, P = .02) and Bothered by Eyes/Vision (23 points, 95% CI 3-45, P = .02). CONCLUSIONS: Refractive surgery led to clinically and statistically significant improvements in domains of social functioning and VSQOL at 12 months after surgery. A narrow majority of patients demonstrated a clinically important improvement in overall social functioning, but these changes were not statistically significant. The results suggest that refractive surgery in children with neurodevelopmental disorders, ametropia, and spectacle nonadherence may provide developmental and quality-of-life benefits. Larger, controlled studies are required to validate these findings. © 2024 Elsevier Inc.
Funding details
National Center for Advancing Translational SciencesNCATS
Research to Prevent BlindnessRPB
National Institutes of HealthNIHTL1TR002344
National Institutes of HealthNIH
Doris Duke Charitable FoundationDDCF2020144
Doris Duke Charitable FoundationDDCF
Document Type: Article
Publication Stage: Final
Source: Scopus
Orthostatic Hypotension: a clinical marker for the body-first subtype of patients with Parkinson’s Disease
(2024) npj Parkinson’s Disease, 10 (1), art. no. 173, .
Mei, S.a b , Wang, X.a , Mao, W.a b , Liu, Y.c , Tian, Z.d , Han, C.e , Chan, P.a b e f
a Department of Neurology, Xuanwu Hospital Capital Medical University, Beijing, China
b Key Laboratory on Neurodegenerative Disorders of Ministry of Education, Key Laboratory on Parkinson’s Disease of Beijing, Beijing, China
c Department of Neurology, Boren Hospital, Beijing, China
d Washington University School of Medicine, St. Louis, MI, United States
e National Clinical Research Center for Geriatric Disorders, Xuanwu Hospital Capital Medical University, Beijing, China
f Parkinson’s Disease Center of Beijing Institute of Brain Disorders, Collaborative Innovation Center for Brain Disorders, Xuanwu Hospital Capital Medical University, Beijing, China
Abstract
Our study aimed to investigate the clinical characteristics of PD patients stratified by OH status before and after levodopa challenge to explore the hypothesis that OH might serve as a clinical marker for the body-first subtype of PD. Supine and standing blood pressure were measured in a large cross-sectional cohort of PD patients at the OFF status before and after levodopa challenge test (LCT). Based on OH status, patients were divided into three groups: spontaneous OH (SOH), only levodopa-induced OH (LOH) and non-OH (NOH). Clinical characteristics and associated factors were compared among the groups. A total of 928 patients with a mean age of 62.4 years and average disease duration of 7.9 years were included. There were 224 (24.1%) patients with SOH, 321 (34.6%) with LOH, and 383 (41.3%) with NOH. Compared to NOH, both SOH and LOH were associated with older age, motor fluctuations, and probable rapid eye movement sleep behavior disorder (pRBD). In addition, OH was more associated with cardiovascular and digestive dysfunction, disease severity and worse quality of life. Results of the current study suggest that PD patients developed OH which is more likely to comorbid with RBD, severe autonomic dysfunction and motor fluctuations, consistent with the body-first subtype of PD. © The Author(s) 2024.
Document Type: Article
Publication Stage: Final
Source: Scopus
Regional desynchronization of microglial activity is associated with cognitive decline in Alzheimer’s disease
(2024) Molecular Neurodegeneration, 19 (1), art. no. 64, .
Zatcepin, A.a b , Gnörich, J.a b , Rauchmann, B.-S.c d , Bartos, L.M.a , Wagner, S.a , Franzmeier, N.e f g , Malpetti, M.h , Xiang, X.i j , Shi, Y.b , Parhizkar, S.k , Grosch, M.l , Wind-Mark, K.a b , Kunte, S.T.a , Beyer, L.a , Meyer, C.b , Brösamle, D.m n o , Wendeln, A.-C.m n , Osei-Sarpong, C.p q , Heindl, S.e , Liesz, A.e g , Stoecklein, S.r , Biechele, G.a r , Finze, A.a , Eckenweber, F.a , Lindner, S.a , Rominger, A.s , Bartenstein, P.a , Willem, M.i , Tahirovic, S.b , Herms, J.b g t , Buerger, K.b e , Simons, M.b e g u , Haass, C.b g i , Rupprecht, R.v , Riemenschneider, M.J.w , Albert, N.L.a x y , Beyer, M.p q , Neher, J.J.g m n o , Paeger, L.b , Levin, J.b g z , Höglinger, G.U.b g z aa , Perneczky, R.b d g ab ac , Ziegler, S.I.a , Brendel, M.a b g
a Department of Nuclear Medicine, University Hospital, LMU Munich, Munich, Germany
b German Center for Neurodegenerative Diseases (DZNE), Munich, Germany
c Institute of Neuroradiology, University Hospital LMU, Munich, Germany
d Department of Psychiatry and Psychotherapy, University Hospital, LMU Munich, Munich, Germany
e Institute for Stroke and Dementia Research, University Hospital of Munich, LMU Munich, Munich, Germany
f Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
g Munich Cluster for Systems Neurology (SyNergy), Munich, Germany
h Department of Clinical Neurosciences, Cambridge University Hospitals NHS Trust, University of Cambridge, Cambridge, United Kingdom
i Biomedical Center (BMC), Division of Metabolic Biochemistry, Faculty of Medicine, LMU Munich, Munich, Germany
j CAS Key Laboratory of Brain Connectome and Manipulation, the Brain Cognition and Brain Disease Institute, Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen-Hong Kong Institute of Brain Science-Shenzhen Fundamental Research Institutions, Shenzhen Shenzhen, 518055, China
k Department of Neurology, Washington University in St. Louis, St. Louis, MO, United States
l German Center for Vertigo and Balance Disorders, University Hospital of Munich, LMU Munich, Munich, Germany
m German Center for Neurodegenerative Disease (DZNE), Neuroimmunology and Neurodegenerative Diseases, Göttingen, Germany
n Dept. of Cellular Neurology, Hertie Institute for Clinical Brain Research, Tübingen, Germany
o Metabolic Biochemistry, Faculty of Medicine, Biomedical Center Munich (BMC), LMU Munich, Munich, Germany
p Platform for Single Cell Genomics and Epigenomics (PRECISE), German Center for Neurodegenerative Diseasesand, University of Bonn and West German Genome Center, Bonn, Germany
q German Center for Neurodegenerative Diseases (DZNE), Immunogenomics & Neurodegeneration, Bonn, Germany
r Department of Radiology, University Hospital, LMU Munich, Munich, Germany
s Department of Nuclear Medicine, Inselpital, Bern University Hospital, University of Bern, Bern, Switzerland
t Center for Neuropathology and Prion Research, LMU Munich, Munich, Germany
u Institute of Neuronal Cell Biology, Technical University Munich, Munich, Germany
v Department of Psychiatry and Psychotherapy, University of Regensburg, Molecular Neurosciences, Regensburg, Germany
w Department of Neuropathology, Regensburg University Hospital, Regensburg, Germany
x German Cancer Research Center (DKFZ), German Cancer Consortium (DKTK), Partner Site Munich, Heidelberg, 69120, Germany
y Bavarian Cancer Research Center (BZKF), Erlangen, 91054, Germany
z Department of Neurology, University Hospital, LMU Munich, Munich, Germany
aa Department of Neurology, Hannover Medical School, Carl-Neuberg-Str. 1, Hannover, 30625, Germany
ab Ageing Epidemiology (AGE) Research Unit, School of Public Health, Imperial College London, London, W6 8RP, United Kingdom
ac Sheffield Institute for Translational Neuroscience (SITraN), University of Sheffield, Sheffield, S10 2HQ, United Kingdom
Abstract
Background: Microglial activation is one hallmark of Alzheimer disease (AD) neuropathology but the impact of the regional interplay of microglia cells in the brain is poorly understood. We hypothesized that microglial activation is regionally synchronized in the healthy brain but experiences regional desynchronization with ongoing neurodegenerative disease. We addressed the existence of a microglia connectome and investigated microglial desynchronization as an AD biomarker. Methods: To validate the concept, we performed microglia depletion in mice to test whether interregional correlation coefficients (ICCs) of 18 kDa translocator protein (TSPO)-PET change when microglia are cleared. Next, we evaluated the influence of dysfunctional microglia and AD pathophysiology on TSPO-PET ICCs in the mouse brain, followed by translation to a human AD-continuum dataset. We correlated a personalized microglia desynchronization index with cognitive performance. Finally, we performed single-cell radiotracing (scRadiotracing) in mice to ensure the microglial source of the measured desynchronization. Results: Microglia-depleted mice showed a strong ICC reduction in all brain compartments, indicating microglia-specific desynchronization. AD mouse models demonstrated significant reductions of microglial synchronicity, associated with increasing variability of cellular radiotracer uptake in pathologically altered brain regions. Humans within the AD-continuum indicated a stage-depended reduction of microglia synchronicity associated with cognitive decline. scRadiotracing in mice showed that the increased TSPO signal was attributed to microglia. Conclusion: Using TSPO-PET imaging of mice with depleted microglia and scRadiotracing in an amyloid model, we provide first evidence that a microglia connectome can be assessed in the mouse brain. Microglia synchronicity is closely associated with cognitive decline in AD and could serve as an independent personalized biomarker for disease progression. © The Author(s) 2024.
Author Keywords
Alzheimer’s disease; Brain connectivity; Dementia; Microglia; Microglia desynchronization; Microglia synchronicity; Neuroinflammation; PET; TSPO
Funding details
Eberhard Karls Universität Tübingen
Document Type: Article
Publication Stage: Final
Source: Scopus
A 2-stage model of heterogenous treatment effects for brain atrophy in multiple sclerosis utilizing the MS PATHS research network
(2024) Multiple Sclerosis and Related Disorders, 91, art. no. 105847, .
Hersh, C.M.a , Sun, Z.b , Conway, D.S.c , Sotirchos, E.S.d , Fitzgerald, K.C.d , Hua, L.H.a , Ziemssen, T.e , Naismith, R.T.f , Pellegrini, F.b , Grossman, C.b , Campbell, N.b
a Lou Ruvo Center for Brain Health, Cleveland Clinic, Las Vegas, NV, United States
b Biogen, Cambridge, MA, United States
c Mellen Center for MS Treatment and Research, Cleveland Clinic, Cleveland, OH, United States
d Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, United States
e Center of Clinical Neuroscience, Department of Neurology, University Clinic Carl-Gustav Carus, TU Dresden, Dresden, Germany
f Department of Neurology, Washington University, St. Louis, MO, United States
Abstract
Background: Two-stage models of heterogenous treatment effects (HTE) may advance personalized medicine in multiple sclerosis (MS). Brain atrophy is a relatively objective outcome measure that has strong relationships to MS prognosis and treatment effects and is enabled by standardized MRI. Objectives: To predict brain atrophy outcomes for patients initiating disease-modifying therapies (DMT) with different efficacies, considering the patients’ baseline brain atrophy risk measured via brain parenchymal fraction (BPF). Methods: Analyses included patients enrolled in the Multiple Sclerosis Partners Advancing Technology and Health Solutions (MS PATHS) network who started DMT and had complete baseline data and ≥ 6-month brain MRI follow-up. All brain MRIs were acquired using standardized acquisition sequences on Siemens 3T scanners. BPF change risk was derived by linear mixed effects models using baseline covariates. Model performance was assessed by predicted versus actual BPF change R2. Propensity score (PS) weighting was used to balance covariates between groups defined by DMT efficacy (high: natalizumab, alemtuzumab, ocrelizumab, and rituximab; moderate: dimethyl fumarate, fingolimod, and cladribine; low: teriflunomide, interferons, and glatiramer acetate). HTE models predicting 1 year change in BPF were built using a weighted linear mixed effects model with low-efficacy DMT as the reference. Results: Analyses included 581 high-, 183 moderate-, and 106 low-efficacy DMT-treated patients. The mean and median number of brain MRI observations per treatment period were 2.9 and 3.0, respectively. Risk model performance R2=0.55. After PS weighting, covariate standardized mean differences were <10 %, indicating excellent balance across measured variables. Changes in BPF between baseline and follow-up were found to be statistically significant (p < 0.001), suggesting a pathological change. Patients with low brain atrophy risk had a similar outcome regardless of DMT selection. In patients with high brain atrophy risk, high- and moderate-efficacy DMTs performed similarly, while a 2-fold worse BPF change was predicted for patients selecting low-efficacy DMTs (p < 0.001). Similar results were observed in a sensitivity analysis adjusting for pseudoatrophy effects in a sub-population of patients treated with natalizumab. Conclusions: The relative benefit of selecting higher efficacy treatments may vary depending on patients’ baseline brain atrophy risk. Poor outcomes are predicted in individuals with high baseline risk who are treated with low-efficacy DMTs. © 2024 The Authors
Author Keywords
Brain atrophy; Brain parenchymal fraction; Disease-modifying therapy; Heterogenous treatment effects; Multiple sclerosis; Personalized treatment; Precision-medicine; Real-world data
Funding details
Biogen
Document Type: Article
Publication Stage: Final
Source: Scopus
High frequency oscillations may improve somatosensory evoked potential detection of good outcomes in disorders of consciousness secondary to acute neurologic injury
(2024) Resuscitation, 203, art. no. 110377, .
Duarte, S.a , Ou, Z.b , Cao, M.c , Cho, S.-M.e , Thakor, N.V.c , Ritzl, E.K.d , Geocadin, R.G.e
a Department of Neurology – Division of Neurocritical Care, University of California, San Francisco, United States
b Medical Scientist Training Program, Washington University in St. Louis School of Medicine, St. Louis, MO 63110, United States
c Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, United States
d Department of Neurology, Mass General Brigham, Boston, MA, United States
e Departments of Neurology, Anesthesiology, Critical Care Medicine and Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, MD 21287, United States
Abstract
Background: Somatosensory evoked potentials (SEPs) are highly specific predictors of poor prognosis in hypoxic-ischemic coma when cortical responses (N20s) are absent. However, bilateral N20 presence is nonspecific for good outcomes. High-frequency oscillations (HFOs) in the SEP waveform predict neurologic recovery in animals, but clinical applications are poorly understood. We sought to develop a clinical measure of HFOs to potentially improve detection of good outcomes in coma. Materials and Methods: We collected SEP waveform data from all comatose inpatients (GCS<=8) who underwent neurologic prognostication from 2020 to 2022 at Johns Hopkins Hospital. We developed a novel measure − HFO evoked to spontaneous ratios (HFO-ESRs) – and applied this to those patients with bilaterally present N20s using both standard univariate classification and cubic kernal vector machine (SVM) models to predict the last documented in-hospital Glasgow Coma Scale (GCS) prior to discharge or death. Results: Of 58 total patients, 34 (58.6%) had bilaterally present N20s. Of these, 14 had final GCS>=9, and 20 had final GCS<=8. Mean age was 52 (+/− 17) years, 20.1% female. Etiologies of coma were primarily global hypoxic-ischemic brain injury (79.4%), intracranial hemorrhage (11.8%), and traumatic brain injury (2.9%). In univariate classification, the addition of averaged HFO-ESRs to bilaterally present N20s predicted final GCS>=9 with 68% specificity. The SVM model further improved specificity to 85%. Conclusions: In this pilot investigation, we developed a novel clinical measure of SEP HFOs. Incorporation of this measure may improve the specificity of the SEP to predict in-hospital GCS outcomes in coma, but requires further validation in specific neurologic injuries and with longitudinal outcomes. © 2024 The Authors
Author Keywords
Coma; Critical care; Evoked potentials; Neurophysiology; Prognostication
Document Type: Article
Publication Stage: Final
Source: Scopus
Novel cyclic homogeneous oscillation detection method for high accuracy and specific characterization of neural dynamics
(2024) eLife, 12, .
Cho, H.a b , Adamek, M.a b , Willie, J.T.a b , Brunner, P.a b
a Department of Neurosurgery, Washington University School of Medicine, St. Louis, United States
b National Center for Adaptive Neurotechnologies, St. Louis, United States
Abstract
Determining the presence and frequency of neural oscillations is essential to understanding dynamic brain function. Traditional methods that detect peaks over 1/f noise within the power spectrum fail to distinguish between the fundamental frequency and harmonics of often highly non-sinusoidal neural oscillations. To overcome this limitation, we define fundamental criteria that characterize neural oscillations and introduce the cyclic homogeneous oscillation (CHO) detection method. We implemented these criteria based on an autocorrelation approach to determine an oscillation’s fundamental frequency. We evaluated CHO by verifying its performance on simulated non-sinusoidal oscillatory bursts and validated its ability to determine the fundamental frequency of neural oscillations in electrocorticographic (ECoG), electroencephalographic (EEG), and stereoelectroencephalographic (SEEG) signals recorded from 27 human subjects. Our results demonstrate that CHO outperforms conventional techniques in accurately detecting oscillations. In summary, CHO demonstrates high precision and specificity in detecting neural oscillations in time and frequency domains. The method’s specificity enables the detailed study of non-sinusoidal characteristics of oscillations, such as the degree of asymmetry and waveform of an oscillation. Furthermore, CHO can be applied to identify how neural oscillations govern interactions throughout the brain and to determine oscillatory biomarkers that index abnormal brain function.
Author Keywords
brain rhythm; ECoG; EEG; human; neural oscillation; neuroscience; SEEG
Document Type: Article
Publication Stage: Final
Source: Scopus
Adjunctive Intravenous Argatroban or Eptifibatide for Ischemic Stroke
(2024) The New England Journal of Medicine, 391 (9), pp. 810-820.
Adeoye, O., Broderick, J., Derdeyn, C.P., Grotta, J.C., Barsan, W., Bentho, O., Berry, S., Concha, M., Davis, I., Demel, S., Elm, J., Gentile, N., Graves, T., Hoffman, M., Huang, J., Ingles, J., Janis, S., Jasne, A.S., Khatri, P., Levine, S.R., Majjhoo, A., Panagos, P., Pancioli, A., Pizzella, S., Ranasinghe, T., Sabagha, N., Sivakumar, S., Streib, C., Vagal, A., Wilson, A., Wintermark, M., Yoo, A.J., Barreto, A.D.
From the Department of Emergency Medicine, Washington University, St. Louis (O.A., P.P., S.P.); the Departments of Neurology and Rehabilitation Medicine (J.B., I.D., S.D., M.H., P.K.), Emergency Medicine (A.P.), and Radiology (A.V.), University of Cincinnati, and the Department of Pharmacy, University of Cincinnati Medical Center (N.S.) – both in Cincinnati; the Department of Radiology, University of Virginia, Charlottesville (C.P.D.); the Clinical Institute for Research and Innovation, Memorial Hermann Hospital (J.C.G.), the Department of Neuroradiology, University of Texas M.D. Anderson Cancer Center (M.W.), and the Department of Neurology, University of Texas Health Science Center (A.D.B.), Houston, Berry Consultants, Austin (S.B., T.G.), and the Texas Stroke Institute, Medical City Healthcare, Dallas (A.J.Y.) – all in Texas
Abstract
BACKGROUND: Intravenous thrombolysis is a standard treatment of acute ischemic stroke. The efficacy and safety of combining intravenous thrombolysis with argatroban (an anticoagulant agent) or eptifibatide (an antiplatelet agent) are unclear. METHODS: We conducted a phase 3, three-group, adaptive, single-blind, randomized, controlled clinical trial at 57 sites in the United States. Patients with acute ischemic stroke who had received intravenous thrombolysis within 3 hours after symptom onset were assigned to receive intravenous argatroban, eptifibatide, or placebo within 75 minutes after the initiation of thrombolysis. The primary efficacy outcome, the utility-weighted 90-day modified Rankin scale score (range, 0 to 10, with higher scores reflecting better outcomes), was assessed by means of centralized adjudication. The primary safety outcome was symptomatic intracranial hemorrhage within 36 hours after randomization. RESULTS: A total of 514 patients were assigned to receive argatroban (59 patients), eptifibatide (227 patients), or placebo (228 patients). All the patients received intravenous thrombolysis (70% received alteplase, and 30% received tenecteplase), and 225 patients (44%) underwent endovascular thrombectomy. At 90 days, the mean (±SD) utility-weighted modified Rankin scale scores were 5.2±3.7 with argatroban, 6.3±3.2 with eptifibatide, and 6.8±3.0 with placebo. The posterior probability that argatroban was better than placebo was 0.002 (posterior mean difference in utility-weighted modified Rankin scale score, -1.51±0.51) and that eptifibatide was better than placebo was 0.041 (posterior mean difference, -0.50±0.29). The incidence of symptomatic intracranial hemorrhage was similar in the three groups (4% with argatroban, 3% with eptifibatide, and 2% with placebo). Mortality at 90 days was higher in the argatroban group (24%) and the eptifibatide group (12%) than in the placebo group (8%). CONCLUSIONS: In patients with acute ischemic stroke treated with intravenous thrombolysis within 3 hours after symptom onset, adjunctive treatment with intravenous argatroban or eptifibatide did not reduce poststroke disability and was associated with increased mortality. (Funded by the National Institute of Neurological Disorders and Stroke; MOST ClinicalTrials.gov number, NCT03735979.). Copyright © 2024 Massachusetts Medical Society.
Document Type: Article
Publication Stage: Final
Source: Scopus
A genetic screen in Drosophila uncovers a role for senseless-2 in surface glia in the peripheral nervous system to regulate CNS morphology
(2024) G3 (Bethesda, Md.), 14 (9), .
Lacin, H.a , Zhu, Y.b , DiPaola, J.T.b , Wilson, B.A.b , Zhu, Y.b , Skeath, J.B.b
a Division of Biological and Biomedical Systems, University of Missouri-Kansas City, 5009 Rockhill Road, Kansas City, MO 64110, United States
b Department of Genetics, Washington University School of Medicine, 4523 Clayton Avenue, St. Louis, MO 63110, United States
Abstract
Despite increasing in mass approximately 100-fold during larval life, the Drosophila CNS maintains its characteristic form. Dynamic interactions between the overlying basement membrane and underlying surface glia are known to regulate CNS structure in Drosophila, but the genes and pathways that establish and maintain CNS morphology during development remain poorly characterized. To identify genes that regulate CNS shape in Drosophila, we conducted an EMS-based, forward genetic screen of the second chromosome, uncovered 50 mutations that disrupt CNS structure, and mapped these alleles to 17 genes. Analysis of whole genome sequencing data wedded to genetic studies uncovered the affected gene for all but 1 mutation. Identified genes include well-characterized regulators of tissue shape, like LanB1, viking, and Collagen type IV alpha1, and previously characterized genes, such as Toll-2 and Rme-8, with no known role in regulating CNS structure. We also uncovered that papilin and C1GalTA likely act in the same pathway to regulate CNS structure and found that the fly homolog of a glucuronosyltransferase, B4GAT1/LARGE1, that regulates Dystroglycan function in mammals is required to maintain CNS shape in Drosophila. Finally, we show that the senseless-2 transcription factor is expressed and functions specifically in surface glia found on peripheral nerves but not in the CNS to govern CNS structure, identifying a gene that functionally subdivides a glial subtype along the peripheral-central axis. Future work on these genes should clarify the genetic mechanisms that ensure the homeostasis of CNS form during development. © The Author(s) 2024. Published by Oxford University Press on behalf of The Genetics Society of America.
Author Keywords
Drosophila; papilin; senseless-2; basement membrane; CNS; glia
Document Type: Article
Publication Stage: Final
Source: Scopus
Exoskeletal-Assisted Walking in Veterans with Paralysis: A Randomized Clinical Trial
(2024) JAMA Network Open, 7 (9), p. e2431501.
Spungen, A.M.a b , Dematt, E.J.c , Biswas, K.c d , Jones, K.M.c , Mi, Z.c , Snodgrass, A.J.f g , Morin, K.a h , Asselin, P.K.a , Cirnigliaro, C.M.a i , Kirshblum, S.i j , Gorman, P.H.k , Goetz, L.L.l m , Stenson, K.n o , White, K.T.p q , Hon, A.r s , Sabharwal, S.t u , Kiratli, B.J.v , Ota, D.v w , Bennett, B.x y , Berman, J.E.z , Castillo, D.z aa , Lee, K.K.z aa , Eddy, B.W.ab , Henzel, M.K.ac ad , Trbovich, M.ae af , Holmes, S.A.ag ah , Skelton, F.ag ah , Priebe, M.c ai , Kornfeld, S.L.b aj , Huang, G.D.e , Bauman, W.A.b
a Spinal Cord Damage Research Center, James J. Peters Veterans Affairs (VA), Medical Center, Bronx, NY, United States
b Departments of Rehabilitation and Human Performance and Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, United States
c VA Cooperative Studies Program Coordinating Center, VA Maryland Health Care System, Perry Point, United States
d Department of Epidemiology and Public Health, Division of Biostatistics, School of Medicine, University of Maryland, Baltimore, United States
e VA Cooperative Studies Program Central Office, VA Office of Research and Development, Washington, DC, United States
f VA Cooperative Studies Program Clinical Research Pharmacy Coordinating Center, Albuquerque, NM, United States
g University of New Mexico, College of Pharmacy, Albuquerque, United States
h VA Providence Healthcare System, Providence, RI, United States
i Department of Physical Medicine and Rehabilitation, Rutgers New Jersey Medical School, Newark, United States
j Kessler Institute for Rehabilitation and the Kessler Foundation, West Orange, NJ, United States
k Department of Neurology, University of Maryland, School of Medicine, Baltimore, United States
l Richmond VA Medical Center, Richmond, VA, United States
m Department of Physical Medicine and Rehabilitation, Virginia Commonwealth University, School of Medicine, Richmond, United States
n VA St Louis Health Care System-Jefferson Barracks, St Louis, MO, United States
o Departments of Orthopaedics and Neurology, Division of Physical Medicine and Rehabilitation, Washington University, School of Medicine, St Louis, MO, United States
p James A. Haley Veterans’ Hospital, Tampa, FL, United States
q Department of Physical Medicine and Rehabilitation, University of South Florida, Tampa, United States
r VA Long Beach Health Care System, Long Beach, CA, United States
s Department of Physical Medicine and Rehabilitation, University of California Irvine, United States
t VA Boston Health Care System, Boston, MA, United States
u Department of Physical Medicine and Rehabilitation, Harvard Medical School, Boston, MA, United States
v VA Palo Alto Health Care System, Palo Alto, CA, United States
w Department of Orthopaedic Surgery, Stanford University, School of Medicine, Stanford, CA, United States
x VA North Texas Health Care System, Dallas, United States
y Department of Physical Medicine and Rehabilitation, The University of Texas, Southwestern Medical Center, Dallas, United States
z Clement J. Zablocki VA Medical Center, Milwaukee, WI, United States
aa Department of Physical Medicine and Rehabilitation, Medical College of Wisconsin, Milwaukee, United States
ab Minneapolis VA Health Care System, Minneapolis, MN, United States
ac Louis Stokes Cleveland VA Medical Center, Cleveland, OH, United States
ad Department of Physical Medicine & Rehabilitation, Case Western Reserve School of Medicine, Cleveland, OH, United States
ae South Texas Veterans Health Care System-Audie Murphy Division, San Antonio, United States
af Department of Rehabilitation Medicine, University of Texas, Health Science Center, San Antonio, United States
ag Michael E. DeBakey VA Medical Center, Houston, TX, United States
ah Department of Physical Medicine and Rehabilitation, Baylor College of Medicine, Houston, TX, United States
ai Charlie Norwood VA Medical Center, VA Augusta Health Care System, Augusta, GA, United States
aj Spinal Cord Injury/Disorders Service, James J. Peters VA Medical Center, Bronx, NY, United States
Abstract
Importance: Robotic exoskeletons leverage technology that assists people with spinal cord injury (SCI) to walk. The efficacy of home and community exoskeletal use has not been studied in a randomized clinical trial (RCT). Objective: To examine whether use of a wheelchair plus an exoskeleton compared with use of only a wheelchair led to clinically meaningful net improvements in patient-reported outcomes for mental and physical health. Design, Setting, and Participants: This RCT of veterans with SCI was conducted at 15 Veterans Affairs medical centers in the US from September 6, 2016, to September 27, 2021. Data analysis was performed from March 10, 2022, to June 20, 2024. Interventions: Participants were randomized (1:1) to standard of care (SOC) wheelchair use or SOC plus at-will use of a US Food and Drug Administration (FDA)-cleared exoskeletal-assisted walking (EAW) device for 4 months in the home and community. Main Outcomes and Measures: Two primary outcomes were studied: 4.0-point or greater improvement in the mental component summary score on the Veterans RAND 36-Item Health Survey (MCS/VR-36) and 10% improvement in the total T score of the Spinal Cord Injury-Quality of Life (SCI-QOL) physical and medical health domain and reported as the proportion who achieved clinically meaningful changes. The primary outcomes were measured at baseline, post randomization after advanced EAW training sessions, and at 2 months and 4 months (primary end point) in the intervention period. Device usage, reasons for not using, and adverse events were collected. Results: A total of 161 veterans with SCI were randomized to the EAW (n = 78) or SOC (n = 83) group; 151 (94%) were male, the median age was 47 (IQR, 35-56) years, and median time since SCI was 7.3 (IQR, 0.5 to 46.5) years. The difference in proportion of successes between the EAW and SOC groups on the MCS/VR-36 (12 of 78 [15.4%] vs 14 of 83 [16.9%]; relative risk, 0.91; 95% CI, 0.45-1.85) and SCI-QOL physical and medical health domain (10 of 78 [12.8%] vs 11 of 83 [13.3%]; relative risk, 0.97; 95% CI, 0.44-2.15) was not statistically different. Device use was lower than expected (mean [SD] distance, 1.53 [0.02] miles per month), primarily due to the FDA-mandated companion being unavailable 43.9% of the time (177 of 403 instances). Two EAW-related foot fractures and 9 unrelated fractures (mostly during wheelchair transfers) were reported. Conclusions and Relevance: In this RCT of veterans with SCI, the lack of improved outcomes with EAW device use may have been related to the relatively low device usage. Solutions for companion requirements and user-friendly technological adaptations should be considered for improved personal use of these devices. Trial Registration: ClinicalTrials.gov Identifier: NCT02658656. © 2024 Spungen AM et al. JAMA Network Open.
Document Type: Article
Publication Stage: Final
Source: Scopus
Exposure to Glycolysis-Enhancing Drugs and Risk of Parkinson’s Disease: A Meta-Analysis
(2024) Journal of Parkinson’s Disease, 14 (6), pp. 1237-1242.
Barros e Silva Ribeiro, G.a , Rodrigues, F.R.b , Pasqualotto, E.c , Dantas, J.M.d , Di Luca, D.G.e
a Department of Neurology, State University of Campinas (UNICAMP), SP, Campinas, Brazil
b Department of Medicine, Federal University of Vicosa (UFV), MG, Vicosa, Brazil
c Department of Medicine, Federal University of Santa Catarina (UFSC), SC, Florianopolis, Brazil
d Department of Medicine, Federal University of Rio Grande do Norte (UFRN), RN, Natal, Brazil
e Department of Neurology, Washington University, St. Louis, MO, United States
Abstract
Background: Impaired glucose and energy metabolism has been suggested as a pathogenic mechanism underlying Parkinson’s disease (PD). In recent cohorts, phosphoglycerate kinase 1 activators (PGK1a) have been associated with a lower incidence of PD when compared with other antiprostatic agents that do not activate PGK1. Objective: We aimed to perform a systematic review and meta-analysis comparing the incidence of PD in patients taking PGK1a versus tamsulosin. Methods: We searched PubMed, Embase, and Cochrane Library for studies comparing PGK1a vs. tamsulosin in adults and elderly. The primary outcome was the incidence of PD. We computed hazard ratios (HR) for binary endpoints, with 95% confidence intervals (CIs). Statistical analysis was performed using Review Manager 5.4 and R (version 4.3.1). Results: A total of 678,433 participants from four cohort studies were included, of whom 287,080 (42.3%) received PGK1a. Mean age ranged from 62 to 74.7 years and nearly all patients were male. Patients taking PGK1a had a lower incidence of PD (PGK1a 1.04% vs. tamsulosin 1.31%; HR 0.80; 95% CI 0.71–0.90; p < 0.01). This result remained consistent in a sensitivity analysis excluding patients of age 60 years old or younger (PGK1a 1.21% vs. tamsulosin 1.42%; HR 0.82; 95% CI 0.71–0.95; p < 0.01). Conclusions: Glycolysis-enhancing drugs are associated with a lower incidence of PD when compared with tamsulosin in adults and elderly individuals with prostatic disease in use of alpha-blockers. Our findings support the notion of glycolysis as a potential neuroprotective mechanism in PD. Future investigations with randomized controlled trials are needed. © 2024 – The authors. Published by IOS Press.
Author Keywords
Adrenergic alpha-1 receptor antagonists; meta-analysis; Parkinson’s disease; tamsulosin
Document Type: Article
Publication Stage: Final
Source: Scopus
Developing a scoring system for gene curation prioritization in lysosomal diseases
(2024) Molecular Genetics and Metabolism, 143 (1-2), art. no. 108572, .
Vernet Machado Bressan Wilke, M.a , Goldstein, J.b , Groopman, E.c , Mohan, S.b , Waddell, A.b , Fernandez, R.d , Chen, H.e , Bali, D.f , Baudet, H.b , Clarke, L.g , Hung, C.h , Mao, R.i j , Yuzyuk, T.i j , Craigen, W.J.k , Pinto e Vairo, F.l m
a Department of Pathology and Immunology, Washington University in St. LouisMO, United States
b University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
c Children’s National Hospital, Washington, DC, United States
d American College of Genetics and Genomics, Bethesda, MD, United States
e Prevention Genetics, part of Exact Sciences, Marshfield, WI, United States
f Duke University Health System, Durham, NC, United States
g University of British Columbia, Vancouver, Canada
h Invitae, San Francisco, CA, United States
i ARUP Laboratories, Salt Lake City, UT, United States
j University of Utah, Salt Lake City, UT, United States
k Baylor College of Medicine, Houston, TX, United States
l Center for Individualized Medicine, Mayo Clinic, Rochester, MN, United States
m Department of Clinical Genomics, Mayo Clinic, Rochester, MN, United States
Abstract
Introduction: Diseases caused by lysosomal dysfunction often exhibit multisystemic involvement, resulting in substantial morbidity and mortality. Ensuring accurate diagnoses for individuals with lysosomal diseases (LD) is of great importance, especially with the increasing prominence of genetic testing as a primary diagnostic method. As the list of genes associated with LD continues to expand due to the use of more comprehensive tests such as exome and genome sequencing, it is imperative to understand the clinical validity of the genes, as well as identify appropriate genes for inclusion in multi-gene testing and sequencing panels. The Clinical Genome Resource (ClinGen) works to determine the clinical importance of genes and variants to support precision medicine. As part of this work, ClinGen has developed a semi-quantitative framework to assess the strength of evidence for the role of a gene in a disease. Given the diversity in gene composition across LD panels offered by various laboratories and the evolving comprehension of genetic variants affecting secondary lysosomal functions, we developed a scoring system to define LD (Lysosomal Disease Scoring System – LDSS). This system sought to aid in the prioritization of genes for clinical validity curation and assess their suitability for LD-targeted sequencing panels. Methods: Through literature review encompassing terms associated with both classically designated LD and LFRD, we identified 14 criteria grouped into “Overall Definition,” “Phenotype,” and “Pathophysiology.” These criteria included concepts such as the “accumulation of undigested or partially digested macromolecules within the lysosome” and being “associated with a wide spectrum of clinical manifestations impacting multiple organs and systems.” The criteria, along with their respective weighted values, underwent refinement through expert panel evaluation differentiating them between “major” and “minor” criteria. Subsequently, the LDSS underwent validation on 12 widely acknowledged LD and was later tested by applying these criteria to the Lysosomal Disease Network’s (LDN) official Gene List. Results: The final LDSS comprised 4 major criteria and 10 minor criteria, with a cutoff of 2 major or 1 major and 3 minor criteria established to define LD. Interestingly, when applied to both the LDN list and a comprehensive gene list encompassing genes included in clinical panels and published as LFRD genes, we identified four genes (GRN, SLC29A3, CLN7 and VPS33A) absent from the LDN list, that were deemed associated with LD. Conversely, a subset of non-classic genes included in the LDN list, such as MTOR, OCRL, and SLC9A6, received lower LDSS scores for their associated disease entities. While these genes may not be suitable for inclusion in clinical LD multi-gene panels, they could be considered for inclusion on other, non-LD gene panels. Discussion: The LDSS offers a systematic approach to prioritize genes for clinical validity assessment. By identifying genes with high scores on the LDSS, this method enhanced the efficiency of gene curation by the ClinGen LD GCEP. Conclusion: The LDSS not only serves as a tool for gene prioritization prior to clinical validity curation, but also contributes to the ongoing discussion on the definition of LD. Moreover, the LDSS provides a flexible framework adaptable to future discoveries, ensuring its relevance in the ever-expanding landscape of LD research. © 2024 Elsevier Inc.
Author Keywords
ClinGen; Genetics; Lysosomal diseases; Lysosomal storage diseases
Document Type: Article
Publication Stage: Final
Source: Scopus
TREM2 on microglia cell surface binds to and forms functional binary complexes with heparan sulfate modified with 6-O-sulfation and iduronic acid
(2024) Journal of Biological Chemistry, 300 (9), art. no. 107691, .
McMillan, I.O.a , Liang, L.b c , Su, G.d , Song, X.a , Drago, K.a , Yang, H.a , Alvarez, C.a , Sood, A.e , Gibson, J.b c , Woods, R.J.e , Wang, C.b c , Liu, J.f , Zhang, F.b c , Brett, T.J.g , Wang, L.a
a Department of Molecular Pharmacology and Physiology, University of South Florida Morsani College of Medicine, Tampa, FL, United States
b Departments of Chemistry and Chemical Biology, Center for Biotechnology and Interdisciplinary Studies, Rensselaer Polytechnic Institute, Troy, NY, United States
c Department of Biological Sciences, Rensselaer Polytechnic Institute, Troy, NY, United States
d Glycan Therapeutics, Raleigh, NC, United States
e Complex Carbohydrate Research Center, University of Georgia, Athens, GA, United States
f Division of Chemical Biology and Medicinal Chemistry, University of North Carolina at Chapel Hill, Eshelman School of Pharmacy, Chapel Hill, NC, United States
g Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Washington University School of Medicine, St Louis, MO, United States
Abstract
The triggering receptor expressed on myeloid cells-2 (TREM2), a pivotal innate immune receptor, orchestrates functions such as inflammatory responses, phagocytosis, cell survival, and neuroprotection. TREM2 variants R47H and R62H have been associated with Alzheimer’s disease, yet the underlying mechanisms remain elusive. Our previous research established that TREM2 binds to heparan sulfate (HS) and variants R47H and R62H exhibit reduced affinity for HS. Building upon this groundwork, our current study delves into the interplay between TREM2 and HS and its impact on microglial function. We confirm TREM2’s binding to cell surface HS and demonstrate that TREM2 interacts with HS, forming HS-TREM2 binary complexes on microglia cell surfaces. Employing various biochemical techniques, including surface plasmon resonance, low molecular weight HS microarray screening, and serial HS mutant cell surface binding assays, we demonstrate TREM2’s robust affinity for HS, and the effective binding requires a minimum HS size of approximately 10 saccharide units. Notably, TREM2 selectively binds specific HS structures, with 6-O-sulfation and, to a lesser extent, the iduronic acid residue playing crucial roles. N-sulfation and 2-O-sulfation are dispensable for this interaction. Furthermore, we reveal that 6-O-sulfation is essential for HS-TREM2 ternary complex formation on the microglial cell surface, and HS and its 6-O-sulfation are necessary for TREM2-mediated ApoE3 uptake in microglia. By delineating the interaction between HS and TREM2 on the microglial cell surface and demonstrating its role in facilitating TREM2-mediated ApoE uptake by microglia, our findings provide valuable insights that can inform targeted interventions for modulating microglial functions in Alzheimer’s disease. © 2024 The Authors
Author Keywords
binary complex; heparan sulfate; microglia; structure-function; TREM2
Document Type: Article
Publication Stage: Final
Source: Scopus
Syllable processing is organized in discrete subregions of the human superior temporal gyrus
(2024) PLoS Biology, 22 (9), art. no. e3002774, .
Cleary, D.R.a b , Tchoe, Y.c , Bourhis, A.c , Dickey, C.W.d , Stedelin, B.b , Ganji, M.c , Lee, S.H.c , Lee, J.c , Siler, D.A.b , Brown, E.C.b , Rosen, B.Q.e , Kaestner, E.f , Yang, J.C.g h , Soper, D.J.g , Han, S.J.b , Paulk, A.C.g i , Cash, S.S.g i , Raslan, A.M.b , Dayeh, S.A.c j k , Halgren, E.l m
a Department of Neurosurgery, University of California San Diego, La JollaCA, United States
b Department of Neurological Surgery, Oregon Health & Science University, Portland, OR, United States
c Department of Electrical and Computer Engineering, University of California San Diego, La JollaCA, United States
d Neurosciences Graduate Program, University of California, San Diego, La JollaCA, United States
e Department of Neuroscience, Washington University School of Medicine, St. Louis, MO, United States
f Center for Multimodal Imaging and Genetics, University of California San Diego, La JollaCA, United States
g Department of Neurology, Massachusetts General Hospital, Boston, MA, United States
h Department of Neurosurgery, Massachusetts General Hospital, Boston, MA, United States
i Center for Neurotechnology and Neurorecovery, Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States
j Materials Science and Engineering Program, University of California San Diego, La JollaCA, United States
k Department of Bioengineering, University of California San Diego, La JollaCA, United States
l Department of Radiology, University of California San Diego, La JollaCA, United States
m Department of Neuroscience, University of California San Diego, La JollaCA, United States
Abstract
Modular organization at approximately 1 mm scale could be:fundamental to cortical processing, but its presence in human association cortex is unknown. Using custom-built, high-density electrode arrays placed on the cortical surface of 7 patients undergoing awake craniotomy for tumor excision, we investigated receptive speech processing in the left (dominant) human posterior superior temporal gyrus. Responses to consonant-vowel syllables and noise-vocoded controls recorded with 1,024 channel micro-grids at 200 μm pitch demonstrated roughly circular domains approximately 1.7 mm in diameter, with sharp boundaries observed in 128 channel linear arrays at 50 μm pitch, possibly consistent with a columnar organization. Peak latencies to syllables in different modules were bimodally distributed centered at 252 and 386 ms. Adjacent modules were sharply delineated from each other by their distinct time courses and stimulus selectivity. We suggest that receptive language cortex may be organized in discrete processing modules. Copyright: This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.
Funding details
Tiny Blue Dot FoundationTBDF
National Science FoundationNSF
National Institutes of HealthNIH
National Institute of Biomedical Imaging and BioengineeringNIBIB#DP2-EB029757, R01DA050159, UG3NS123723, 1728497, R01NS123655
National Institute of Mental HealthNIMH#K24-NS088568, R01 MH117155
Document Type: Article
Publication Stage: Final
Source: Scopus
Differential components of bradykinesia in Parkinson’s disease revealed by deep brain stimulation
(2024) Journal of Neurophysiology, 132 (3), pp. 870-878.
Mazzoni, P.a b , Ushe, M.b , Younce, J.R.b , Norris, S.A.b , Hershey, T.b , Karimi, M.b , Tabbal, S.D.b , Perlmutter, J.S.b
a Division of Movement Disorders, Department of Neurology, Ohio State University, Columbus, OH, United States
b Division of Movement Disorders, Department of Neurology, Washington University in St. Louis, St. Louis, MO, United States
Abstract
Bradykinesia is a term describing several manifestations of movement disruption caused by Parkinson’s disease (PD), including movement slowing, amplitude reduction, and gradual decrease of speed and amplitude over multiple repetitions of the same movement. Deep brain stimulation (DBS) of the subthalamic nucleus (STN) improves bradykinesia in patients with PD. We examined the effect of DBS on specific components of bradykinesia when applied at two locations within the STN, using signal processing techniques to identify the time course of amplitude and frequency of repeated hand pronation-supination movements performed by participants with and without PD. Stimulation at either location increased movement amplitude, increased frequency, and decreased variability, though not to the range observed in the control group. Amplitude and frequency showed decrement within trials, which was similar in PD and control groups and did not change with DBS. Decrement across trials, by contrast, differed between PD and control groups, and was reduced by stimulation. We conclude that DBS improves specific aspects of movement that are disrupted by PD, whereas it does not affect short-term decrement that could reflect muscular fatigue. NEW & NOTEWORTHY In this study, we examined different components of bradykinesia in patients with Parkinson’s disease (PD). We identified different components through signal processing techniques and their response to deep brain stimulation (DBS). We found that some components of bradykinesia respond to stimulation, whereas others do not. This knowledge advances our understanding of brain mechanisms that control movement speed and amplitude.
Author Keywords
DBS; kinematics; motor control; movement; wearable sensors
Document Type: Article
Publication Stage: Final
Source: Scopus
Discrimination training affects stimulus generalization in mice during Pavlovian eyeblink conditioning
(2024) Frontiers in Behavioral Neuroscience, 18, art. no. 1446991, .
Fiocchi, F.R.a b , van Dorp, N.E.S.a c , Dijkhuizen, S.a , van den Berg, M.a , Wong, A.a , De Zeeuw, C.I.a d , Boele, H.-J.a c
a Department of Neuroscience, Erasmus MC Rotterdam, Rotterdam, Netherlands
b Department of Psychiatry, Washington University in St. Louis, Saint Louis MO, United States
c Princeton Neuroscience Institute, Princeton University, Princeton, NJ, United States
d Royal Dutch Academy of Arts & Science (KNAW), Netherland Institute for Neuroscience, Amsterdam, Netherlands
Abstract
The delicate balance between discrimination and generalization of responses is crucial for survival in our ever-changing environment. In particular, it is important to understand how stimulus discrimination affects the level of stimulus generalization. For example, when we use non-differential training for Pavlovian eyeblink conditioning to investigate generalization of cerebellar-related eyelid motor responses, we find generalization effects on amount, amplitude and timing of the conditioned responses. However, it is unknown what the generalization effects are following differential training. We trained mice to close their eyelids to a 10 kHz tone with an air-puff as the reinforcing stimulus (CS+), while alternatingly exposing them to a tone frequency of either 4 kHz, 9 kHz or 9.5 kHz without the air-puff (CS−) during the training blocks. We tested the generalization effects during the expression of the responses after the training period with tones ranging from 2 kHz to 20 kHz. Our results show that the level of generalization tended to positively correlate with the difference between the CS+ and the CS− training stimuli. These effects of generalization were found for the probability, amplitude but not for the timing of the conditioned eyelid responses. These data indicate the specificity of the generalization effects following differential versus non-differential training, highlighting the relevance of discrimination learning for stimulus generalization. Copyright © 2024 Fiocchi, van Dorp, Dijkhuizen, van den Berg, Wong, De Zeeuw and Boele.
Author Keywords
cerebellum; classical conditioning; differential training; generalization; learning
Document Type: Article
Publication Stage: Final
Source: Scopus
Hypertension and cerebral blood flow in the development of Alzheimer’s disease
(2024) Alzheimer’s and Dementia, .
Bachmann, D.a b , Saake, A.a , Studer, S.a , Buchmann, A.a , Rauen, K.a c d , Gruber, E.a , Michels, L.e , Nitsch, R.M.a f , Hock, C.a f , Gietl, A.a c , Treyer, V.a g , Weiner, M.W.h , Trojanowski, J.Q.i , Shaw, L.i , Beckett, L.j , Aisen, P.k , Petersen, R.l , Morris, J.C.m , Perrin, R.J.l , Toga, A.W.k , Jack, C.l , Green, R.C.n , Jagust, W.o , Saykin, A.J.p , for the Alzheimer’s Disease Neuroimaging Initiativeq
a Institute for Regenerative Medicine, University of Zurich, Zurich, Switzerland
b Department of Health Sciences and Technology, ETH Zürich, Zurich, Switzerland
c Department of Geriatric Psychiatry, Psychiatric Hospital Zurich, Zurich, Switzerland
d Neuroscience Center Zurich, University of Zurich, Zurich, Switzerland
e Department of Neuroradiology, Clinical Neuroscience Center, University Hospital Zurich, Zurich, Switzerland
f Neurimmune, Zurich, Switzerland
g Department of Nuclear Medicine, University Hospital of Zurich, University of Zurich, Zurich, Switzerland
h University of California, San Francisco, United States
i University of PennsylvaniaPA, United States
j University of California, Davis, United States
k University of Southern CaliforniaCA, United States
l Mayo Clinic, Rochester, MN, United States
m Washington University, St. Louis, United States
n Brigham and Women’s Hospital/Harvard Medical SchoolMA, United States
o University of California, Berkeley, United States
p Indiana University, Indiana, United States
Abstract
INTRODUCTION: We investigated the interactive associations between amyloid and hypertension on the entorhinal cortex (EC) tau and atrophy and the role of cerebral blood flow (CBF) as a shared mechanism by which amyloid and hypertension contribute to EC tau and regional white matter hyperintensities (WMHs). METHODS: We analyzed data from older adults without dementia participating in the Add-Tau study (NCT02958670, n = 138) or Alzheimer’s Disease Neuroimaging Initiative (ADNI) (n = 523) who had available amyloid-positron emission tomography (PET), tau-PET, fluid-attenuated inversion recovery (FLAIR), and T1-weighted magnetic resonance imaging (MRI). A subsample in both cohorts had available arterial spin labeling (ASL) MRI (Add-Tau: n = 78; ADNI: n = 89). RESULTS: The detrimental effects of hypertension on AD pathology and EC thickness were more pronounced in the Add-Tau cohort. Increased amyloid burden was associated with decreased occipital gray matter CBF in the ADNI cohort. In both cohorts, lower regional gray matter CBF was associated with higher EC tau and posterior WMH burden. DISCUSSION: Reduced cerebral perfusion may be one common mechanism through which hypertension and amyloid are related to increased EC tau and WMH volume. Highlights: Hypertension is associated with increased entorhinal cortex (EC) tau, particularly in the presence of amyloid. Decreased cortical cerebral blood flow (CBF) is associated with higher regional white matter hyperintensity volume. Increasing amyloid burden is associated with decreasing CBF in the occipital lobe. MTL CBF and amyloid are synergistically associated with EC tau. © 2024 The Author(s). Alzheimer’s & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer’s Association.
Author Keywords
Alzheimer’s disease; amyloid pathology; arterial spin labeling; cerebral perfusion; regional white matter hyperintensities; small vessel disease; tau pathology
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
Physical Activity and Neurocognitive Symptoms in Older Adults During COVID-19 Pandemic
(2024) Journal of Applied Gerontology, .
Ortiz-Acosta, P.K.a b , Martínez, J.E.b c , Vila-Castelar, C.b , Fox-Fuller, J.T.b c , Pluim, C.b c , Babulal, G.M.d e , Ramírez-Gómez, L.f , Munera, D.b , Quiroz, Y.T.b f g , Guzmán-Vélez, E.b
a Department of Psychology, University of Puerto Rico, San Juan, Puerto Rico
b Department of Psychiatry, Harvard Medical School, Massachusetts General Hospital, Boston, MA, United States
c Department of Psychological and Brain Sciences, Boston University, Boston, MA, United States
d Department of Neurology, Washington University School of Medicine, St Louis, MO, United States
e Department of Psychology, Faculty of Humanities, University of Johannesburg, Johannesburg, South Africa
f Department of Neurology, Harvard Medical School, Massachusetts General Hospital, Boston, MA, United States
g Grupo de Neurociencias, Universidad de Antioquia, Medellín, Colombia
Abstract
Objectives: Examine whether physical activity (PA) changes during the COVID-19 pandemic were related to subjective cognitive decline (SCD), depression, and anxiety in older adults and whether these varied by sociodemographic variables. Methods: 301 older adults completed an online survey between May and October 2020 and 3 months later, including self-report questionnaires of SCD, depression, and anxiety. PA changes were determined with a question. Results: 60% of participants reported decreased PA. Those who reduced their PA were more likely to be from low to middle income and younger. PA increase was related to less SCD and depressive symptoms compared to those who decreased it. Participants who maintained their PA had fewer SCD concerns, depressive, and anxiety symptoms than those who decreased it. Discussion: Reducing PA was associated with worse neuropsychiatric and cognitive symptoms. Encouraging older adults to increase PA may help mitigate some of the pandemic’s adverse effects on psychological well-being. © The Author(s) 2024.
Author Keywords
anxiety; depression; exercise; SARS-CoV-2; subjective cognitive decline
Funding details
Israel National Road Safety AuthorityNRSA
F31AG06215801 A
BrightFocus FoundationBFFA2021142S
National Institutes of HealthNIH5T32HL007901-23
Alzheimer’s AssociationAAAACSFD-21-853089, 2019A00585
National Institute on AgingNIAK23AG 061276, R01 AG054671, R01 AG068183, K99AG073452, R01 AG074302, R01 AG080469, R01 AG067428, R01 AG056466
3P30AG062421-01S1, UCSF 2P30AG015272-21, R01AG066823-01A1, 5P30AG062421-03
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
Co-occurring autism, ADHD, and gender dysphoria in children, adolescents, and young adults with eating disorders: an examination of pre- vs. post-COVID pandemic outbreak trends with real-time electronic health record data
(2024) Frontiers in Psychiatry, 15, art. no. 1402312, .
Brown, T.R.a b , Jansen, M.O.a b , Zhou, A.N.c d , Moog, D.e , Xie, H.f , Liebesny, K.V.g , Xu, K.Y.h i , Lin, B.Y.d g , Deng, W.Y.j
a Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine at, University of California-Los Angeles (UCLA), Los Angeles, CA, United States
b Jane and Terry Semel Institute for Neuroscience and Human Behavior, University of California-Los Angeles (UCLA), Los Angeles, CA, United States
c San Francisco Department of Public Health, San Francisco, CA, United States
d Department of Psychiatry and Behavioral Sciences, University of California, San FranciscoCA, United States
e Washington University School of Medicine, St. LouisMO, United States
f Zilber School of Public Health, University of Wisconsin-Milwaukee, Milwaukee, WI, United States
g Department of Psychiatry and Behavioral Medicine, Carilion Clinic – Virginia Tech Carilion School of Medicine, Roanoke, VA, United States
h School of Medicine, Washington University in St. Louis, St. LouisMO, United States
i Department of Psychiatry, Division of Addiction Science, Prevention and Treatment, Washington University School of Medicine, St. LouisMO, United States
j Department of Psychology, Yale University, New Haven, CT, United States
Abstract
Background: Incidence rates of autism, attention-deficit/hyperactivity disorder (ADHD), and gender dysphoria (GD) are rising not only in the general population, but particularly among children, adolescents, and young adults with eating disorders (EDs). While ED rates have risen during the COVID pandemic, trends in co-occurring autism, ADHD, and GD have yet to be investigated in detail or at scale by way of large electronic medical record data. Objectives: To investigate trends in rates of co-occurring autism, ADHD, and GD among children, adolescents, and young adults with EDs in years prior to and during the COVID-19 pandemic. Methods: We utilized a de-identified multinational electronic health records database (TriNetX) with 48,558 individuals aged 5-26 diagnosed with eating disorders (EDs) at least twice between 2017 and 2022. The primary predictor variable differentiated between the years of each person’s index (first) ED diagnosis (2017-2019 vs. 2020-2022). The primary outcome variable was the rate of new co-occurring psychiatric diagnoses of autism, ADHD, and GD in the year following each patient’s first ED diagnosis. We applied propensity score-matched multivariable logistic regressions to compare primary outcomes between 2017-2019 and 2020-2022. Results: Our analysis included 17,445 individuals diagnosed with EDs in 2017-2019 (8% autism, 13.5% ADHD, 1.9% GD) and 31,113 diagnosed with EDs in 2020-2022 (8% autism, 14.6% ADHD, 3.2% GD). After 1:1 propensity score matching, 17,202 individuals from the 2017-2019 cohort were matched to peers mirroring the 2020-2022 cohort. Those diagnosed in 2020-2022 showed a 19% (aOR[95%CI]=1.19[1.07-1.33]), 25% (aOR=1.25[1.04-1.49]), and 36% (aOR=1.36[1.07-1.74]) increase in odds for autism, ADHD, and GD diagnoses, respectively, within the 365 days after the index EDs diagnosis, compared to the 2017-2019 cohort. Discussion: Rates of autism, ADHD, and GD are significantly higher in individuals with ED in the post-pandemic 2020-2022 cohort in comparison to the pre-pandemic 2017-2019 cohort, even after controlling for baseline levels of co-occurring psychiatric diagnoses. Such findings reveal a critical gap in our current understanding of the totality of ways in which COVID-19 may have impacted the onset and clinical course of EDs, autism, ADHD, and GD among children, adolescents, and young adults. Copyright © 2024 Brown, Jansen, Zhou, Moog, Xie, Liebesny, Xu, Lin and Deng.
Author Keywords
ADHD; adolescent and young adult; autism; children; eating disorder; gender dysphoria; real-world data
Funding details
American Academy of Child and Adolescent PsychiatryAACAP
American Psychiatric AssociationAPA
Document Type: Article
Publication Stage: Final
Source: Scopus
Naloxone Stigma among People Who Use Drugs: Characteristics and Associations with Stigma Toward Medication for Opioid Use Disorder
(2024) Journal of Addiction Medicine, art. no. 10.1097/ADM.0000000000001377, .
Banks, D.E.a , Li, X.a , Park, B.b , Winograd, R.P.b c , Cavazos-Rehg, P.a
a The Washington University School of Medicine, St Louis, MO, United States
b Department of Psychological Sciences, University of Missouri-St Louis, St Louis, MO, United States
c Missouri Institute of Mental Health, University of Missouri – St Louis, St Louis, MO, United States
Abstract
Objectives: Widespread naloxone distribution is key to mitigating opioid-relatedmorbidity, but stigma remains a barrier. Naloxone stigma among providers, emergency responders, and the public is welldocumented and associated with treatment and policy preferences, but little is known about naloxone stigma among people who use drugs (PWUD), who may be overdose first responders. This study examines naloxone stigma, its correlates, and its association with stigma toward medication for opioid use disorder (MOUD) among PWUD. Methods: We recruited 293 individuals with a history of substance misuse from facilities that provide substance use and/or health care services (retained n = 195, 54% women, 75% White). Participants completed self-report measures, including the 5-item Naloxone-Related Risk Compensation Beliefs scale. Results: One in 5 respondents agreed with beliefs that access to naloxone leads to more opioid use and less treatment seeking and is “enabling.”Those with nonopioid drug misuse, without prior overdose, and with fewer recovery attempts endorsed more naloxone stigma. Opioid misuse, prior overdose, and MOUD utilization were also inversely associated with MOUD stigma. There were no demographic differences in either stigma type. Naloxone stigma was positively associated with MOUD stigma in adjusted models. Conclusions: This is the first study to quantitatively examine naloxone stigma among PWUD. Findings emphasize the potential role of overdose education and naloxone distribution among those earlier in the substance use disorder course and who use nonopioid drugs. They support integrating MOUD stigma interventions into current overdose education and naloxone distribution targeted at PWUD to increase the acceptance and uptake of both medications. Copyright © 2024 American Society of Addiction Medicine.
Author Keywords
drug misuse; medication for opioid use disorder; naloxone; opioid-related disorders; social stigma
Funding details
Substance Abuse and Mental Health Services AdministrationSAMHSA1H79TI081697, 1H79TI080271
Substance Abuse and Mental Health Services AdministrationSAMHSA
National Institute on Drug AbuseNIDAK08 DA058080
National Institute on Drug AbuseNIDA
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
Constructing the “Family Personality”: Can Family Functioning Be Linked to Parent–Child Interpersonal Neural Synchronization?
(2024) Journal of Personality, .
Thompson, K.a , Schneider, C.a , Rocha-Hidalgo, J.b , Jeyaram, S.a , Mata-Centeno, B.a , Furtado, E.a , Vachhani, S.a , Pérez-Edgar, K.b , Perlman, S.a
a Department of Psychiatry, Washington University in St. Louis School of Medicine, St. Louis, MO, United States
b Department of Psychology, Pennsylvania State University, State College, University Park, PA, United States
Abstract
Introduction: Early child development occurs within an interactive environment, initially dominated by parents or caregivers, and is heavily influenced by the dynamics of this social context. The current study probed the neurobiology of “family personality”, or family functioning, in the context of parent–child dyadic interaction using a two-person neuroimaging modality. Methods: One hundred and five parent–child dyads (child mean age 5 years 4 months) were recruited. Functional near-infrared spectroscopy (fNIRS) hyperscanning was employed to measure neural synchrony while dyads completed a mildly stressful interactive task. Family functioning was measured through the Family Adaptability and Cohesion Scale IV (FACES-IV). Results: Synchrony during stress was significantly greater than synchrony during both baseline and recovery conditions for all dyads. A significant interaction between neural synchrony in each task condition and familial balanced flexibility was found, such that higher levels of balanced flexibility were associated with greater changes in frontal cortex neural synchrony as dyads progressed through the three task conditions. Discussion: Parent–child dyads from families who display heightened levels of balanced flexibility are also more flexible in their engagement of neural synchrony when shifting between social conditions. This is one of the first studies to utilize a two-person imaging modality to explore the links between family functioning and interbrain synchrony between parents and their children. © 2024 Wiley Periodicals LLC.
Author Keywords
dyadic processes; family; fNIRS; interpersonal functioning; personality; social
Funding details
National Institutes of HealthNIHR56 MH126349, R01 MH130007, R01 MH124266
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
The Relationship Between Neighborhood Disadvantage and Markers of Chronic Pain Risk: Findings From the Oklahoma Study of Native American Pain Risk (OK-SNAP)
(2024) Journal of Pain, art. no. 104659, .
Kell, P.A.a , Huber, F.A.a b , Lowe, T.S.c , Shadlow, J.O.a d , Rhudy, J.L.a e
a Department of Psychology, The University of Tulsa, Tulsa, Oklahoma, United States
b Department of Anesthesiology, Washington University, St. Louis, Missouri, United States
c Department of Sociology, The University of Tulsa, Tulsa, Oklahoma, United States
d Department of Psychology, Oklahoma State University, Tulsa, Oklahoma, United States
e Department of Health Promotions Sciences, University of Oklahoma Health Sciences Center, Tulsa, Oklahoma, United States
Abstract
Socioeconomic disadvantage contributes to health inequities, including chronic pain. Yet, research examining socioeconomic disadvantage and pain risk in Native Americans (NAs) is scant. This exploratory analysis assessed relationships between socioeconomic position (SEP), ethnicity, and neighborhood disadvantage on pronociceptive processes in 272 healthy, chronic pain-free NAs (n = 139) and non-Hispanic Whites (NHWs, n = 133) from the Oklahoma Study of Native American Pain Risk (OK-SNAP). Neighborhood disadvantage was quantified using the Area Deprivation Index (ADI). Regression models tested whether ADI predicted pain-promoting outcomes (ie, peripheral fiber functionality, pain sensitivity, pain and nociceptive amplification, and endogenous pain inhibition) above-and-beyond SEP and ethnicity. The Ethnicity × ADI interaction was also tested. Of the 11 outcomes tested, 9 were not statistically significant. Of the significant findings, neighborhood disadvantage predicted impaired inhibition of the nociceptive flexion reflex above-and-beyond SEP and ethnicity. Additionally, ethnicity moderated the relationship between ADI and warm detection threshold; disadvantage was associated with higher thresholds for NAs, but not for NHWs. Together, the results suggest neighborhood disadvantage is associated with reduced C-fiber function and impaired spinal inhibition, thus pointing to a role of neighborhood disadvantage in the relationship between the environment and pain inequities. Perspective: This study assessed neighborhood socioeconomic disadvantage and pronociceptive processes in chronic pain-free Native Americans (NAs) and non-Hispanic Whites (NHWs). Irrespective of ethnicity, greater neighborhood disadvantage predicted less descending inhibition of spinal nociception. Neighborhood disadvantage was associated with a marker of C-fiber impairment (higher warm detection threshold) in NAs only. © 2024 United States Association for the Study of Pain, Inc.
Author Keywords
chronic pain risk factors; Health disparities; Native American health; social determinants of health
Funding details
National Institute on Minority Health and Health DisparitiesNIMHD
National Institutes of HealthNIHR01MD007807
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
Improving Sleep in People with HIV and Chronic Pain: A Pilot Study of Brief Behavioral Treatment for Insomnia
(2024) Behavioral Sleep Medicine, .
Cody, S.L.a , Kusko, D.A.b , Gonzalez, C.E.c , Owens, M.A.d , Hobson, J.M.b , Gilstrap, S.R.b , Thomas, S.J.d , Goodin, B.R.c
a Capstone College of Nursing, University of Alabama, Tuscaloosa, AL, United States
b Department of Psychology, University of Alabama at Birmingham, Birmingham, AL, United States
c Department of Anesthesiology, Washington University Pain Center, Washington University, St. Louis, MO, United States
d Department of Psychiatry & Behavioral Neurobiology, University of Alabama at Birmingham, Birmingham, AL, United States
Abstract
Objectives: Insomnia and chronic pain are common symptoms in people with HIV. Poor sleep has been associated with chronic pain. While cognitive behavioral therapy for insomnia improves insomnia in clinical populations, there are barriers to people with HIV accessing treatment including the lack of trained providers and lengthy sessions. Only one study has examined the efficacy of brief behavioral treatment for insomnia (BBTI) in people with HIV. This study examined BBTI effects on sleep and pain in people with HIV. Methods: Ten adults with HIV and chronic pain completed a 4-week, telephone-delivered BBTI treatment. A control group (n = 10) completed a brief mindfulness training (BMT). The Insomnia Severity Index and Brief Pain Inventory were used to assess insomnia severity and pain outcomes, respectively. Results: There was a significant interaction between intervention and time on insomnia severity, F (2,14) = 5.7, p =.02, partial η2 = 0.45). The BBTI group demonstrated significant improvements in insomnia severity from pre- to post-intervention (p <.001) and from pre-intervention to one-month post-intervention (p =.001) compared to the BMT group. There was a significant interaction between intervention and time on pain interference, F (1,18) = 4.9, p =.02, partial η2 = 0.27). The BBTI group demonstrated a significant decrease in pain interference from pre- to post-intervention (p <.001) compared to the BMT group. Conclusions: This pilot study demonstrated that BBTI improved insomnia in people with HIV for up to one-month post-treatment. Novel preliminary evidence suggests that BBTI may also improve pain outcomes in people with HIV. © 2024 Taylor & Francis Group, LLC.
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
Missense and loss-of-function variants at GWAS loci in familial Alzheimer’s disease
(2024) Alzheimer’s and Dementia, .
Gunasekaran, T.I.a , Reyes-Dumeyer, D.a , Faber, K.M.b , Goate, A.c , Boeve, B.d , Cruchaga, C.e , Pericak-Vance, M.f , Haines, J.L.g , Rosenberg, R.h , Tsuang, D.i , Mejia, D.R.j k , Medrano, M.l , Lantigua, R.A.a m , Sweet, R.A.n , Bennett, D.A.o , Wilson, R.S.o , Alba, C.p , Dalgard, C.p , Foroud, T.b , Vardarajan, B.N.a , Mayeux, R.a
a Department of Neurology, Taub Institute for Research on Alzheimer’s Disease and the Aging Brain and the Gertrude H. Sergievsky Center, Columbia University, New York, NY, United States
b Department of Medical and Molecular Genetics, National Centralized Repository for Alzheimer’s Disease and Related Dementias (NCRAD), 410 W. 10th St., HS 4000. Indiana University School of Medicine, Indianapolis, IN, United States
c Department of Genetics & Genomic Sciences, Ronald M. Loeb Center for Alzheimer’s disease, Icahn School of Medicine at Mount Sinai, Icahn Bldg., One Gustave L. Levy Place, New York, NY, United States
d Department of Neurology, Mayo Clinic, Rochester, MN, United States
e Department of Psychiatry, Washington University in St. Louis, Rand Johnson Building, 600 S Euclid Ave., Wohl Hospital Building, St. Louis, MO, United States
f John P Hussman Institute for Human Genomics, Dr. John T Macdonald Foundation Department of Human Genetics, University of Miami Miller School of Medicine, Miami, FL, United States
g Department of Population & Quantitative Health Sciences and Cleveland Institute for Computational Biology. Case Western Reserve University, Cleveland, OH, United States
h Department of Neurology, University of Texas Southwestern Medical Center, Dallas, TX, United States
i Department of Psychiatry and Behavioral Sciences, University of Washington, GRECC VA Puget Sound, 1660 South Columbian Way, Seattle, WA, United States
j Los Centros de Diagnóstico y Medicina Avanzada y de Conferencias Médicas y Telemedicina, CEDIMAT, Arturo Logroño, Plaza de la Salud, Dr. Juan Manuel Taveras Rodríguez, C. Pepillo Salcedo esq, Santo Domingo, Dominican Republic
k Universidad Pedro Henríquez Urena, Av. John F. Kennedy Km. 7-1/2 Santo Domingo 1423, Santo Domingo, Dominican Republic
l Pontíficia Universidad Católica Madre y Maestra (PUCMM), Autopista Duarte Km 1 1/2, Santiago de los Caballeros, Dominican Republic
m Department of Medicine, Vagelos College of Physicians and Surgeons, Columbia University, and the New York Presbyterian Hospital, New York, NY, United States
n Departments of Psychiatry and Neurology, University of Pittsburgh, Pittsburgh, PA, United States
o Rush Alzheimer’s Disease Center, Rush University Medical Center, 1750, West Harrison St, Chicago, IL, United States
p Department of Anatomy, Physiology and Genetics, Uniformed Services University of the Health Sciences, Bethesda, MD, United States
Abstract
BACKGROUND: Few rare variants have been identified in genetic loci from genome-wide association studies (GWAS) of Alzheimer’s disease (AD), limiting understanding of mechanisms, risk assessment, and genetic counseling. METHODS: Using genome sequencing data from 197 families in the National Institute on Aging Alzheimer’s Disease Family Based Study and 214 Caribbean Hispanic families, we searched for rare coding variants within known GWAS loci from the largest published study. RESULTS: Eighty-six rare missense or loss-of-function (LoF) variants completely segregated in 17.5% of families, but in 91 (22.1%) families Apolipoprotein E (APOE)-Ԑ4 was the only variant segregating. However, in 60.3% of families, APOE Ԑ4, missense, and LoF variants were not found within the GWAS loci. DISCUSSION: Although APOE Ԑ4and several rare variants were found to segregate in both family datasets, many families had no variant accounting for their disease. This suggests that familial AD may be the result of unidentified rare variants. Highlights: Rare coding variants from GWAS loci segregate in familial Alzheimer’s disease. Missense or loss of function variants were found segregating in nearly 7% of families. APOE-Ԑ4 was the only segregating variant in 29.7% in familial Alzheimer’s disease. In Hispanic and non-Hispanic families, different variants were found in segregating genes. No coding variants were found segregating in many Hispanic and non-Hispanic families. © 2024 The Author(s). Alzheimer’s & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer’s Association.
Author Keywords
familial Alzheimer’s disease; gene loci; genetic segregation; genome wide association studies; rare variants
Funding details
Rainwater Charitable FoundationRCF
Lewy Body Dementia AssociationLBDA
M.B. and Edna Zale Foundation
American Academy of NeurologyAAN
American Brain FoundationABF
AG072547, AG074865, AG062677, AG070864
National Institutes of HealthNIHR01 AG067501, R56AG051876, U01AG066752, RF1AG015473
National Institute on AgingNIAU24AG056270, U24AG026395, U24AG021886
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
Better cardiovascular health is associated with slowed clinical progression in autosomal dominant frontotemporal lobar degeneration variant carriers
(2024) Alzheimer’s and Dementia, .
VandeBunte, A.M.a b , Lee, H.c , Paolillo, E.W.a , Hsiung, G.-Y.R.c , Staffaroni, A.M.a , Saloner, R.a , Tartaglia, C.d , Yaffe, K.a , Knopman, D.S.e , Ramos, E.M.f , Rascovsky, K.g , Bozoki, A.C.h , Wong, B.i , Domoto-Reilly, K.j , Snyder, A.k , Pressman, P.l , Mendez, M.F.m , Litvan, I.n , Fields, J.A.e , Galasko, D.R.n , Darby, R.o , Masdeu, J.C.p , Pasqual, M.B.p , Honig, L.S.q , Ghoshal, N.r , Appleby, B.S.s , Mackenzie, I.R.t , Heuer, H.W.a , Kramer, J.H.a , Boxer, A.L.a , Forsberg, L.K.e , Boeve, B.e , Rosen, H.J.a , Casaletto, K.B.a , the ALLFTD Consortiumu
a Department of Neurology, University of California, San Francisco, Memory and Aging Center, San Francisco, CA, United States
b Department of Psychology, Palo Alto University, Palo Alto, CA, United States
c Division of Neurology, UBC Hospital, University of British Columbia, Vancouver, BC, Canada
d Tanz Centre for Research in Neurodegenerative Diseases, Division of Neurology, Department of Medicine, University of Toronto, Toronto, ON, Canada
e Department of Neurology, Mayo Clinic, Rochester, MN, United States
f David Geffen School of Medicine at UCLA, UCLA Semel Institute for Neuroscience and Human Behavior, Los Angeles, CA, United States
g Department of Neurology, University of Pennsylvania, Philadelphia, PA, United States
h Department of Neurology, University of North Carolina, Chapel Hill, NC, United States
i Harvard Massachusetts General Hospital Frontotemporal Disorders Unit, Charlestown, MA, United States
j Department of Neurology, University of Washington, Seattle, WA, United States
k National Institute of Neurological Disorders and Stroke, Bethesda, MD, United States
l Department of Neurology, University of Colorado School of Medicine, Aurora, CO, United States
m David Geffen School of Medicine at UCLA, Reed Neurological Research Center, Los Angeles, CA, United States
n San Diego Department of Neurosciences, University of California, San Diego, La Jolla, CA, United States
o Department of Neurology, Vanderbilt University, Nashville, TN, United States
p Houston Methodist Neurological Institute, Houston, TX, United States
q Department of Neurology, Irving Medical Center, Columbia University, New York, NY, United States
r Department of Neurology, St. Louis School of Medicine, Washington University, St. Louis, MO, United States
s Department of Neurology, Case Western Reserve University, Cleveland, OH, United States
t Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC, Canada
Abstract
INTRODUCTION: Cardiovascular health is important for brain aging, yet its role in the clinical manifestation of autosomal dominant or atypical forms of dementia has not been fully elucidated. We examined relationships between Life’s Simple 7 (LS7) and clinical trajectories in individuals with autosomal dominant frontotemporal lobar degeneration (FTLD). METHODS: Two hundred forty-seven adults carrying FTLD pathogenic genetic variants (53% asymptomatic) and 189 non-carrier controls completed baseline LS7, and longitudinal neuroimaging and neuropsychological testing. RESULTS: Among variant carriers, higher baseline LS7 is associated with slower accumulation of frontal white matter hyperintensities (WMHs), as well as slower memory and language declines. Higher baseline LS7 associated with larger baseline frontotemporal volume, but not frontotemporal volume trajectories. DISCUSSION: Better baseline cardiovascular health related to slower cognitive decline and accumulation of frontal WMHs in autosomal dominant FTLD. Optimizing cardiovascular health may be an important modifiable approach to bolster cognitive health and brain integrity in FTLD. Highlights: Better cardiovascular health associates with slower cognitive decline in frontotemporal lobar degeneration (FTLD). Lifestyle relates to the accumulation of frontal white matter hyperintensities in FTLD. More optimal cardiovascular health associates with greater baseline frontotemporal lobe volume. Optimized cardiovascular health relates to more favorable outcomes in genetic dementia. © 2024 The Author(s). Alzheimer’s & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer’s Association.
Author Keywords
aging; cardiovascular health; frontotemporal dementia; genetic dementia; Life’s Simple 7; lifestyle behaviors; modifiable risk; neuropsychology
Funding details
National Institute on AgingNIA
U24 AG21886
R01AG072475, U19AG063911, R56AG082414, U01AG045390, K23AG058752, U54NS092089, P01AG019724
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
(2024) Nature
Engineered T cell therapy for central nervous system injury
(2024) Nature, .
Gao, W.a b , Kim, M.W.a b c d , Dykstra, T.a b , Du, S.a b c , Boskovic, P.a b , Lichti, C.F.b e , Ruiz-Cardozo, M.A.f , Gu, X.a b , Weizman Shapira, T.g , Rustenhoven, J.a b , Molina, C.f , Smirnov, I.a b , Merbl, Y.g , Ray, W.Z.f , Kipnis, J.a b c d
a Center for Brain Immunology and Glia (BIG), Washington University in St. Louis, School of Medicine, St. Louis, MO, United States
b Department of Pathology and Immunology, Washington University in St. Louis, School of Medicine, St. Louis, MO, United States
c Immunology Program, School of Medicine, Washington University in St. Louis, School of Medicine, St. Louis, MO, United States
d Medical Scientist Training Program, School of Medicine, Washington University in St. Louis, School of Medicine, St. Louis, MO, United States
e Bursky Center for Human Immunology and Immunotherapy Programs, Washington University in St. Louis, School of Medicine, St. Louis, MO, United States
f Department of Neurological Surgery, Washington University in St. Louis, School of Medicine, St. Louis, MO, United States
g Systems Immunology Department, The Weizmann Institute of Science, Rehovot, Israel
Abstract
Traumatic injuries to the central nervous system (CNS) afflict millions of individuals worldwide1, yet an effective treatment remains elusive. Following such injuries, the site is populated by a multitude of peripheral immune cells, including T cells, but a comprehensive understanding of the roles and antigen specificity of these endogenous T cells at the injury site has been lacking. This gap has impeded the development of immune-mediated cellular therapies for CNS injuries. Here, using single-cell RNA sequencing, we demonstrated the clonal expansion of mouse and human spinal cord injury-associated T cells and identified that CD4+ T cell clones in mice exhibit antigen specificity towards self-peptides of myelin and neuronal proteins. Leveraging mRNA-based T cell receptor (TCR) reconstitution, a strategy aimed to minimize potential adverse effects from prolonged activation of self-reactive T cells, we generated engineered transiently autoimmune T cells. These cells demonstrated notable neuroprotective efficacy in CNS injury models, in part by modulating myeloid cells via IFNγ. Our findings elucidate mechanistic insight underlying the neuroprotective function of injury-responsive T cells and pave the way for the future development of T cell therapies for CNS injuries. © The Author(s), under exclusive licence to Springer Nature Limited 2024.
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
Frontostriatal salience network expansion in individuals in depression
(2024) Nature, .
Lynch, C.J.a , Elbau, I.G.a , Ng, T.a , Ayaz, A.a , Zhu, S.a , Wolk, D.a , Manfredi, N.a , Johnson, M.a , Chang, M.a , Chou, J.a , Summerville, I.a , Ho, C.a , Lueckel, M.b c , Bukhari, H.a , Buchanan, D.d , Victoria, L.W.a , Solomonov, N.a , Goldwaser, E.a , Moia, S.e f g , Caballero-Gaudes, C.g , Downar, J.h , Vila-Rodriguez, F.i , Daskalakis, Z.J.j , Blumberger, D.M.h k l , Kay, K.m , Aloysi, A.n , Gordon, E.M.o , Bhati, M.T.d , Williams, N.d , Power, J.D.a , Zebley, B.a , Grosenick, L.a , Gunning, F.M.a , Liston, C.a
a Department of Psychiatry, Weill Cornell Medicine, New York, NY, United States
b Leibniz Institute for Resilience Research, Mainz, Germany
c Neuroimaging Center (NIC), Focus Program Translational Neurosciences (FTN), Johannes Gutenberg University Medical Center, Mainz, Germany
d Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA, United States
e Neuro-X Institute, École Polytechnique Fédérale de Lausanne, Geneva, Switzerland
f Department of Radiology and Medical Informatics, Faculty of Medicine, University of Geneva, Geneva, Switzerland
g Basque Center on Cognition, Brain and Language, Donostia, Spain
h Department of Psychiatry and Institute of Medical Science, University of Toronto, Toronto, ON, Canada
i Department of Psychiatry, University of British Columbia, Vancouver, BC, Canada
j Department of Psychiatry, University of California, San Diego, CA, United States
k Temerty Centre for Therapeutic Brain Intervention, Toronto, ON, Canada
l Centre for Addiction and Mental Health, Toronto, ON, Canada
m Center for Magnetic Resonance Research, University of Minnesota, Minneapolis, MN, United States
n Icahn School of Medicine at Mount Sinai, New York, NY, United States
o Department of Radiology, Washington University School of Medicine, St. Louis, MO, United States
Abstract
Decades of neuroimaging studies have shown modest differences in brain structure and connectivity in depression, hindering mechanistic insights or the identification of risk factors for disease onset1. Furthermore, whereas depression is episodic, few longitudinal neuroimaging studies exist, limiting understanding of mechanisms that drive mood-state transitions. The emerging field of precision functional mapping has used densely sampled longitudinal neuroimaging data to show behaviourally meaningful differences in brain network topography and connectivity between and in healthy individuals2–4, but this approach has not been applied in depression. Here, using precision functional mapping and several samples of deeply sampled individuals, we found that the frontostriatal salience network is expanded nearly twofold in the cortex of most individuals with depression. This effect was replicable in several samples and caused primarily by network border shifts, with three distinct modes of encroachment occurring in different individuals. Salience network expansion was stable over time, unaffected by mood state and detectable in children before the onset of depression later in adolescence. Longitudinal analyses of individuals scanned up to 62 times over 1.5 years identified connectivity changes in frontostriatal circuits that tracked fluctuations in specific symptoms and predicted future anhedonia symptoms. Together, these findings identify a trait-like brain network topology that may confer risk for depression and mood-state-dependent connectivity changes in frontostriatal circuits that predict the emergence and remission of depressive symptoms over time. © The Author(s) 2024.
Funding details
Wellcome Leap
Hope for Depression Research FoundationHDRF
Deutsche ForschungsgemeinschaftDFG
National Institute of Mental HealthNIMHF32MH120989, K23 MH123864
California Department of Fish and GameDFGCRC 1193
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
Alzheimer’s disease genetic risk and changes in brain atrophy and white matter hyperintensities in cognitively unimpaired adults
(2024) Brain Communications, 6 (5), art. no. fcae276, .
Soldan, A.a , Wang, J.b , Pettigrew, C.a , Davatzikos, C.c , Erus, G.c , Hohman, T.J.d , Dumitrescu, L.d , Bilgel, M.e , Resnick, S.M.e , Rivera-Rivera, L.A.f , Langhough, R.f , Johnson, S.C.f , Benzinger, T.g , Morris, J.C.g , Laws, S.M.h , Fripp, J.i , Masters, C.L.j , Albert, M.S.a
a Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, United States
b Department of Biostatistics, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21205, United States
c Centre for Biomedical Image Computing and Analytics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, United States
d Department of Neurology, Vanderbilt University Medical Center, Nashville, TN 37212, United States
e Laboratory of Behavioral Neuroscience, National Institute on Aging Intramural Research Program, Baltimore, MD 21224, United States
f Wisconsin Alzheimer’s Disease Research Center, University of Wisconsin-Madison, School of Medicine and Public Health, Madison, WI 53726, United States
g Knight Alzheimer Disease Research Center, Washington University, School of Medicine, St. Louis, MO 63110, United States
h Centre for Precision Health, Edith Cowan University, Joondalup, WA 6027, Australia
i Australian E-Health Research Centre, CSIRO Health and Biosecurity, Herston, QLD 4029, Australia
j The Florey Institute, University of Melbourne, Parkville, VIC 3052, Australia
Abstract
Reduced brain volumes and more prominent white matter hyperintensities on MRI scans are commonly observed among older adults without cognitive impairment. However, it remains unclear whether rates of change in these measures among cognitively normal adults differ as a function of genetic risk for late-onset Alzheimer’s disease, including APOE- ε4, APOE-ε2 and Alzheimer’s disease polygenic risk scores (AD-PRS), and whether these relationships are influenced by other variables. This longitudinal study examined the trajectories of regional brain volumes and white matter hyperintensities in relationship to APOE genotypes (N = 1541) and AD-PRS (N = 1093) in a harmonized dataset of middle-aged and older individuals with normal cognition at baseline (mean baseline age = 66 years, SD = 9.6) and an average of 5.3 years of MRI follow-up (max = 24 years). Atrophy on volumetric MRI scans was quantified in three ways: (i) a composite score of regions vulnerable to Alzheimer’s disease (SPARE-AD); (ii) hippocampal volume; and (iii) a composite score of regions indexing advanced non-Alzheimer’s disease-related brain aging (SPARE-BA). Global white matter hyperintensity volumes were derived from fluid attenuated inversion recovery (FLAIR) MRI. Using linear mixed effects models, there was an APOE-ε4 gene-dose effect on atrophy in the SPARE-AD composite and hippocampus, with greatest atrophy among ε4/ε4 carriers, followed by ε4 heterozygouts, and lowest among ε3 homozygouts and ε2/ε2 and ε2/ε3 carriers, who did not differ from one another. The negative associations of APOE-ε4 with atrophy were reduced among those with higher education (P < 0.04) and younger baseline ages (P < 0.03). Higher AD-PRS were also associated with greater atrophy in SPARE-AD (P = 0.035) and the hippocampus (P = 0.014), independent of APOE-ε4 status. APOE-ε2 status (ε2/ε2 and ε2/ε3 combined) was not related to baseline levels or atrophy in SPARE-AD, SPARE-BA or the hippocampus, but was related to greater increases in white matter hyperintensities (P = 0.014). Additionally, there was an APOE-ε4 × AD-PRS interaction in relation to white matter hyperintensities (P = 0.038), with greater increases in white matter hyperintensities among APOE-ε4 carriers with higher AD-PRS. APOE and AD-PRS associations with MRI measures did not differ by sex. These results suggest that APOE-ε4 and AD-PRS independently and additively influence longitudinal declines in brain volumes sensitive to Alzheimer’s disease and synergistically increase white matter hyperintensity accumulation among cognitively normal individuals. Conversely, APOE-ε2 primarily influences white matter hyperintensity accumulation, not brain atrophy. Results are consistent with the view that genetic factors for Alzheimer’s disease influence atrophy in a regionally specific manner, likely reflecting preclinical neurodegeneration, and that Alzheimer’s disease risk genes contribute to white matter hyperintensity formation. © 2024 The Author(s).
Author Keywords
Alzheimer’s disease (AD); APOE; magnetic resonance imaging (MRI); polygenic risk score (PRS); white matter hyperintensities
Funding details
Commonwealth Scientific and Industrial Research OrganisationCSIRO
National Institutes of HealthNIHRF1-AG027161, RF1-AG059869, U19-AG033655, P01-AG026276
National Institute on AgingNIAP30-AG062715, P01-AG003991, U19-AG024904, P30-AG066444, P20-AG068082, P30-AG066507, U19-AG032438
Document Type: Article
Publication Stage: Final
Source: Scopus
Electrocochleography-Based Tonotopic Map: I. Place Coding of the Human Cochlea With Hearing Loss
(2024) Ear and Hearing, art. no. 10.1097/AUD.0000000000001579, .
Walia, A., Ortmann, A.J., Lefler, S., Holden, T.A., Puram, S.V., Herzog, J.A., Buchman, C.A.
Department of Otolaryngology—Head and Neck Surgery, Washington University School of Medicine in St. Louis, St Louis, MO, United States
Abstract
Objectives: Due to the challenges of direct in vivo measurements in humans, previous studies of cochlear tonotopy primarily utilized human cadavers and animal models. This study uses cochlear implant electrodes as a tool for intracochlear recordings of acoustically evoked responses to achieve two primary goals: (1) to map the in vivo tonotopy of the human cochlea, and (2) to assess the impact of sound intensity and the creation of an artificial “third window” on this tonotopic map. Design: Fifty patients with hearing loss received cochlear implant electrode arrays. Postimplantation, pure-tone acoustic stimuli (0.25 to 4 kHz) were delivered, and electrophysiological responses were recorded from all 22 electrode contacts. The analysis included fast Fourier transformation to determine the amplitude of the first harmonic, indicative of predominantly outer hair cell activity, and tuning curves to identify the best frequency (BF) electrode. These measures, coupled with postoperative imaging for precise electrode localization, facilitated the construction of an in vivo frequency-position function. The study included a specific examination of 2 patients with auditory neuropathy spectrum disorder (ANSD), with preserved cochlear function as assessed by present distortion-product otoacoustic emissions, to determine the impact of sound intensity on the frequency-position map. In addition, the electrophysiological map was recorded in a patient undergoing a translabyrinthine craniotomy for vestibular schwannoma removal, before and after creating an artificial third window, to explore whether an experimental artifact conducted in cadaveric experiments, as was performed in von Békésy landmark experiments, would produce a shift in the frequency-position map. Results: A significant deviation from the Greenwood model was observed in the electrophysiological frequency-position function, particularly at high-intensity stimulations. In subjects with hearing loss, frequency tuning, and BF location remained consistent across sound intensities. In contrast, ANSD patients exhibited Greenwood-like place coding at low intensities (~40 dB SPL) and a basal shift in BF location at higher intensities (~70 dB SPL or greater). Notably, creating an artificial “third-window” did not alter the frequency-position map. Conclusions: This study successfully maps in vivo tonotopy of human cochleae with hearing loss, demonstrating a near-octave shift from traditional frequency-position maps. In patients with ANSD, representing more typical cochlear function, intermediate intensity levels (~70 to 80 dB SPL) produced results similar to high-intensity stimulation. These findings highlight the influence of stimulus intensity on the cochlear operational point in subjects with hearing loss. This knowledge could enhance cochlear implant programming and improve auditory rehabilitation by more accurately aligning electrode stimulation with natural cochlear responses. Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.
Author Keywords
Acoustics; Cochlea; Cochlear microphonics; Hearing; Intracochlear electrocochleography; Tonotopic organization
Funding details
National Institutes of HealthNIH
National Institute on Deafness and Other Communication DisordersNIDCDT32DC000022
American Neurotology SocietyANSR01DC020936
Document Type: Article
Publication Stage: Article in Press
Source: Scopus