Diagnostic accuracy of screening tools for depression and anxiety in cervical dystonia
(2025) Parkinsonism and Related Disorders, 136, art. no. 107891, .
Martino, D.a , Ramezani, M.a , Bellows, S.b , Berman, B.D.c , Chang, F.C.-F.d , Feuerstein, J.e f , Fung, V.g , Berkmen, G.K.h , Malaty, I.A.i , MacIver, C.j , Norris, S.A.k , Peall, K.J.l , Perlmutter, J.S.m , Richardson, S.P.n , Wright, L.J.o , Goodarzi, Z.p , Jinnah, H.A.q
a Department of Clinical Neuroscience, Cumming School of Medicine & Hotchkiss Brain Institute, University of Calgary, Calgary, AB, Canada
b Parkinson’s Disease Center and Movement Disorders Clinic, Baylor College of Medicine, Houston, TX, United States
c VCU Parkinson’s and Movement Disorders Center, Virginia Commonwealth University School of Medicine, Richmond, VA, United States
d Department of Neurology, Westmead Hospital, Sydney, NSW, Australia
e Department of Neurology, University of Colorado School of Medicine, Aurora, CO, United States
f Department of Neurology, Rocky Mountain Regional VA Medical Center, Aurora, CO, United States
g Sydney Medical School, Westmead Clinical School, Faculty of Medicine and Health, University of Sydney, Sydney, NSW, Australia
h Department of Neurology, Emory University School of Medicine, Atlanta, GA, United States
i Department of Neurology, University of Florida, Fixel Institute for Neurological Diseases, Gainesville, FL, United States
j Cardiff University Brain Research Imaging Centre (CUBRIC), Neuroscience and Mental Health Innovation Institute, Cardiff University, Cardiff, CF24 4HQ, United Kingdom
k Departments of Neurology and Radiology, Washington University School of Medicine, St. Louis, MO, United States
l Division of Psychological Medicine and Clinical Neurosciences, Neuroscience and Mental Health Innovation Institute, Cardiff University, Cardiff, CF24 4HQ, United Kingdom
m Departments of Neurology, Radiology, Neuroscience, Physical Therapy and Occupational Therapy, Washington University School of Medicine in St. Louis, St. Louis, MO, United States
n Department of Neurology, University of New Mexico Health Sciences Center and New Mexico VA Health Care System, Albuquerque, NM, United States
o Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States
p Division of Geriatric Medicine, Department of Medicine, Community Health Sciences and Clinical Neurosciences, Cumming School of Medicine, Hotchkiss Brain Institute and O’Brien Institute of Public Health, University of Calgary, Calgary, AB, Canada
q Department of Neurology, Human Genetics, and Pediatrics, Emory University School of Medicine, Atlanta, GA, United States
Abstract
Introduction: Despite their high prevalence and impact, depression and anxiety are not routinely screened for, and accuracy of screening procedures is unknown in adult-onset dystonia. We evaluated accuracy parameters of selected self-rated scales for depression and anxiety in patients with idiopathic cervical dystonia (CD). Methods: Two-hundred-and-ten patients with idiopathic CD were recruited from 10 movement disorders centers from the US, Canada, Australia, and UK. At the end of each botulinum toxin cycle, participants were administered the Adult Standard Mini-International Neuropsychiatric Interview (MINI) as reference standard for depression and anxiety. Participants completed 8 self-administered index instruments (2 for depression, 2 for anxiety, and 4 combining screening for both). Sensitivity, specificity, positive and negative predictive values, covariate-adjusted area under the receiver operating characteristic curve (AUC), and likelihood ratios were calculated for all instruments. Results: On the MINI, 8.6 % (100 % female) fulfilled criteria for current major depressive disorder and 10.5 % (91 % female) fulfilled criteria for any current disorder amongst panic, social anxiety or generalized anxiety disorders. For depression screening, all tools had an AUC higher than 0.80, with the two most accurate being the BDI-II (AUC 0.91, sensitivity 87.5 %) and the HADS-Depression (AUC 0.88, sensitivity 93.7 %). For anxiety screening, the only instrument showing clinical usefulness was the HADS-Anxiety (AUC 0.82, sensitivity 86.3 %). Conclusion: Current major depression can be screened in CD with high degree of accuracy using different self-administered scales, whereas existing screening tools for anxiety perform worse. Dystonia-specific instruments are less accurate than scales developed for the general population. © 2025
Author Keywords
Accuracy; Anxiety; Cervical dystonia; Depression; Rating scales; Screening
Funding details
National Institute of Neurological Disorders and StrokeNINCDS
Dystonia Medical Research FoundationDMRF
National Center for Advancing Translational SciencesNCATSNS065701, TR001456
National Center for Advancing Translational SciencesNCATS
National Institutes of HealthUSNIHNS116025
National Institutes of HealthUSNIH
Document Type: Article
Publication Stage: Final
Source: Scopus
Impact of Y chromosome loss on the risk of Parkinson’s disease and progression
(2025) eBioMedicine, 117, art. no. 105769, .
Wang, J.a b , Chen, X.a b , Du, W.a b , Lin, C.a b , Liao, Y.a b , Corvol, J.-C.c , Maple-Grødem, J.d e , Campbell, M.C.f , Elbaz, A.g , Lesage, S.c , Brice, A.c , Schwarzschild, M.A.h , Taba, P.i j , Kõks, S.k l , Alves, G.d e m , Tysnes, O.-B.n o , Perlmutter, J.S.f p q , Maiti, B.f , van Hilten, J.J.r , Barker, R.A.s t , Williams-Gray, C.H.s , Scherzer, C.R.u v w x , Liu, G.a b y , International Genetics of Parkinson Disease Progression (IGPP) Consortiumz
a Shenzhen Key Laboratory of Systems Medicine in Inflammatory Diseases, School of Medicine, Shenzhen Campus of Sun Yat-sen University, No. 66, Gongchang Road, Guangming District, Guangdong, Shenzhen, 518107, China
b Neurobiology Research Center, School of Medicine, Shenzhen Campus of Sun Yat-sen University, No. 66, Gongchang Road, Guangdong, Shenzhen, 518107, China
c Sorbonne Université, Institut du Cerveau – Paris Brain Institute – ICM, Institut National de la Santé et de la Recherche Médicale, Centre National de la Recherche Scientifique, Assistance Publique Hôpitaux de Paris, Département de Neurologie et de Génétique, Hôpital Pitié-Salpêtrière, Paris, F-75013, France
d The Centre for Movement Disorders, Centre for Brain Health, Stavanger University Hospital, Stavanger, 4011, Norway
e Department of Chemistry, Bioscience and Environmental Engineering, University of Stavanger, Stavanger, 4021, Norway
f Departments of Neurology and Radiology, Washington University School of Medicine, St. Louis, MO 63110, United States
g Université Paris-Saclay, UVSQ, Inserm, Gustave Roussy, CESP, Villejuif, 94805, France
h Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, United States
i Department of Neurology and Neurosurgery, Institute of Clinical Medicine, University of Tartu, Tartu, 50406, Estonia
j Neurology Clinic, Tartu University Hospital, Tartu, 50406, Estonia
k Centre for Molecular Medicine and Innovative Therapeutics, Murdoch University, Murdoch, Perth, WA 6150, Australia
l Perron Institute for Neurological and Translational Science, Nedlands, WA 6009, Australia
m Department of Neurology, Stavanger University Hospital, Stavanger, 4068, Norway
n Department of Neurology, Haukeland University Hospital, Bergen, 5020, Norway
o Department of Clinical Medicine, University of Bergen5020, Norway
p Departments of Radiology and Neuroscience, Washington University School of Medicine, St. Louis, MO 63110, United States
q Program of Physical Therapy and Program of Occupational Therapy, Washington University School of Medicine, St. Louis, MO 63110, United States
r Department of Neurology, Leiden University Medical Center, Albinusdreef 2, ZA, Leiden, 2333, Netherlands
s John Van Geest Centre for Brain Repair, Department of Clinical Neurosciences, University of Cambridge, Cambridge, CB2 0PY, United Kingdom
t Wellcome – MRC Cambridge Stem Cell Institute, University of Cambridge, Cambridge, CB2 0AW, United Kingdom
u Stephen & Denise Adams Center for Parkinson’s Disease Research of Yale School of Medicine, New Haven, CT 06510, United States
v APDA Center for Parkinson Precision Medicine, Yale, New Haven, CT 06510, United States
w Department of Neurology, Yale, New Haven, CT 06510, United States
x Department of Genetics, Yale, New Haven, CT 06510, United States
y Guangdong Provincial Key Laboratory of Brain Function and Disease, Guangzhou, 510080, China
Abstract
Background: Loss of Y chromosome (LOY), an age-related somatic mutation, is associated with various age-related diseases, but its role in the onset and progression of Parkinson’s disease (PD) remains unclear. This study investigated the relationship between blood LOY levels and the risk of PD onset and progression. Methods: We estimated the LOY level for each male participant based on genome-wide arrays or whole genome sequencing data. We performed Cox proportional hazards regression analysis among 222,598 male participants in the UK Biobank and linear mixed model analysis involving 2574 male individuals with PD across 14 cohorts, encompassing 19,562 visits. In the Parkinson’s Progression Markers Initiative (PPMI) cohort, we further compared brain structure using T1-weighted magnetic resonance imaging (MRI) scans, and carried out brain network functional connectivity analysis based on resting-state functional MRI (rs-fMRI) datasets. Additionally, we assessed the LOY status in single-nucleus RNA sequencing (snRNA-seq) data, which included 1,303,531 cells from 279 post-mortem samples across five brain regions, and performed temporal dynamic gene expression analysis. Findings: Male participants with LOY had a slightly higher risk of developing PD during follow-up (HR = 1·16, 95% CI = 1·01–1·34, P = 0·04). Among males affected by PD, LOY carriers experienced accelerated neurodegenerative progression, manifesting as more rapid motor impairment (P = 0·0072) and cognitive decline (P = 0·0005) compared to non-LOY carriers. Patients with PD carrying LOY also exhibited decreased network functional connectivity in certain brain regions. Notably, LOY cells were particularly enriched in microglia/immune and vascular/epithelial cells, and a subset of genes in LOY-Mic P2RY12 cells were associated with PD progression. Interpretation: This data-driven study highlights the potential association of LOY with the onset and progression of PD through the analysis of multi-scale data, including clinical phenotypes, brain neuroimaging maps, and molecular profiles from single-nucleus transcriptome across multi-brain regions. These findings suggest that LOY may be an accomplice to the onset and progression of PD. Funding: G.L.’s work is supported by the Shenzhen Fundamental Research Program (JCYJ20240813151132042), National Natural Science Foundation of China (32270701, 32470708), Young Talent Recruitment Project of Guangdong (2019QN01Y139), the Science and Technology Planning Project of Guangdong Province (2023B1212060018) and Shenzhen Key Laboratory for Systems Medicine in Inflammatory Diseases (ZDSYS20220606100803007). This study is supported by High-performance Computing Public Platform (Shenzhen Campus) of Sun Yat-sen University. C.R.S.’s work is supported by NIH grants NINDS/NIA R01NS115144, the U.S. Department of Defense, and the American Parkinson Disease Association Center for Advanced Parkinson Research. C.R.S.’s research work was funded in part by Aligning Science Across Parkinson’s 000301 through the Michael J. Fox Foundation for Parkinson’s Research (MJFF). The study was made possible in part by a philanthropic support for Illumina MEGA chip genotyping (to Brigham & Women’s Hospital and C.R.S.). CHWG received funding support from an RCUK/UKRI Research Innovation Fellowship awarded by the Medical Research Council (MR/R007446/1; MR/W029235/1) and from the NIHR Cambridge Biomedical Research Centre (NIHR203312). The views expressed are those of the author(s) and not necessarily those of the NIHR or the Department of Health and Social Care. For the purpose of open access, the author has applied a CC BY public copyright licence to all Author Accepted Manuscripts arising from this submission. © 2025 The Author(s)
Author Keywords
LOY; Onset; Parkinson’s disease; Progression
Funding details
American Parkinson Disease AssociationAPDA
National Institute on Handicapped ResearchNIHR
National Institute of Neurological Disorders and StrokeNINDS
National Institutes of HealthUSNIH
Sun Yat-sen UniversitySYSU
U.S. Department of DefenseUSDOD
Research Councils UKRCUK
UK Research and InnovationUKRI
2019QN01Y139
Shenzhen Municipal Fundamental Research ProgramJCYJ20240813151132042
Shenzhen Municipal Fundamental Research Program
National Institute on AgingNIAR01NS115144
National Institute on AgingNIA
Aligning Science Across Parkinson’sASAP000301
Aligning Science Across Parkinson’sASAP
Science and Technology Planning Project of Guangdong Province2023B1212060018
Science and Technology Planning Project of Guangdong Province
ZDSYS20220606100803007
National Natural Science Foundation of ChinaNNSF32470708, 32270701
National Natural Science Foundation of ChinaNNSF
Medical Research CouncilMRCMR/W029235/1, MR/R007446/1
Medical Research CouncilMRC
NIHR Cambridge Biomedical Research CentreNIHR203312
NIHR Cambridge Biomedical Research Centre
Document Type: Article
Publication Stage: Final
Source: Scopus
Tunable metastability of condensates reconciles their dual roles in amyloid fibril formation
(2025) Molecular Cell, 85 (11), pp. 2230-2245.e7.
Das, T.a , Zaidi, F.K.a , Farag, M.b , Ruff, K.M.b , Mahendran, T.S.c , Singh, A.c , Gui, X.a , Messing, J.d , Taylor, J.P.d , Banerjee, P.R.c , Pappu, R.V.b , Mittag, T.a
a Department of Structural Biology, St. Jude Children’s Research Hospital, Memphis, TN 38105, United States
b Department of Biomedical Engineering and Center for Biomolecular Condensates, Washington University in St. Louis, St. Louis, MO 63130, United States
c Department of Physics, the State University of New York at Buffalo, Buffalo, NY 14260, United States
d Department of Cell and Molecular Biology, St. Jude Children’s Research Hospital, Memphis, TN 38105, United States
Abstract
Stress granules form via co-condensation of RNA-binding proteins (RBPs) containing prion-like low-complexity domains (PLCDs) with RNA molecules. Homotypic interactions among PLCDs can drive amyloid fibril formation that is enhanced by amyotrophic lateral sclerosis (ALS)-associated mutations. We report that condensation- versus fibril-driving homotypic interactions are separable for A1-LCD, the PLCD of hnRNPA1. These separable interactions lead to thermodynamically metastable condensates and globally stable fibrils. Interiors of condensates suppress fibril formation, whereas interfaces have the opposite effect. ALS-associated mutations enhance the stability of fibrils and weaken condensate metastability, thus enhancing the rate of fibril formation. We designed mutations to enhance A1-LCD condensate metastability and discovered that stress granule disassembly in cells can be restored even when the designed variants carry ALS-causing mutations. Therefore, fibril formation can be suppressed by condensate interiors that function as sinks. Condensate sink potentials are influenced by their metastability, which is tunable through separable interactions even among minority components of stress granules. © 2025 The Authors
Author Keywords
amyotrophic lateral sclerosis; fibril formation; frontotemporal dementia; metastability; phase separation; prion-like domain; RNP granule; sink potential; stress granule; supersaturation
Funding details
American Lebanese Syrian Associated CharitiesALSAC
National Cancer InstituteNCIP30 CA021765
National Cancer InstituteNCI
National Institutes of HealthUSNIHR01NS121114, R35NS097974, R35GM138186
National Institutes of HealthUSNIH
Air Force Office of Scientific ResearchAFOSRFA9550-20-1-0241
Air Force Office of Scientific ResearchAFOSR
Document Type: Article
Publication Stage: Final
Source: Scopus
Auricular vagus nerve stimulation for mitigation of inflammation and vasospasm in subarachnoid hemorrhage: a single-institution randomized controlled trial
(2025) Journal of Neurosurgery, 142 (6), pp. 1720-1731.
Huguenard, A.L.a e , Tan, G.b e , Rivet, D.J.d , Gao, F.f , Johnson, G.W.a , Adamek, M.b , Coxon, A.T.a , Kummer, T.T.c , Osbun, J.W.a e , Vellimana, A.K.a , Limbrick, D.D., Jr.d , Zipfel, G.J.a , Brunner, P.a b e , Leuthardt, E.C.a b e
a Departments of Neurosurgery, Washington University in St. LouisMO, United States
b Departments of Biomedical Engineering, Washington University in St. LouisMO, United States
c Departments of Neurology, Washington University in St. LouisMO, United States
d Department of Neurosurgery, Virginia Commonwealth University, Richmond, VA, United States
e Division of Neurotechnology, Washington University in St. LouisMO, United States
f Department of Surgery, Division of Public Health Sciences, Washington University, St. Louis, MO, United States
Abstract
OBJECTIVE Inflammation contributes to morbidity following subarachnoid hemorrhage (SAH). The authors of this study evaluate how applying noninvasive transauricular vagus nerve stimulation (taVNS) can target this deleterious inflammatory response following SAH and reduce the rate of radiographic vasospasm. METHODS In this prospective, triple-blinded, randomized controlled trial, 27 patients were randomized to taVNS or sham stimulation. Serial blood and CSF samples were collected every 3 days to quantify inflammatory markers. Radiographic cerebral vasospasm severity and functional outcomes (modified Rankin Scale scores) were analyzed. RESULTS No adverse events occurred. Radiographic vasospasm was significantly reduced (p = 0.018), with serial vessel caliber measurements demonstrating a more rapid return to normal than in the sham-treated group (p < 0.001). In the taVNS group, tumor necrosis factor–α was significantly reduced in both plasma (days 7 and 10) and CSF (day 13); interleukin-6 was also significantly reduced in plasma (day 4) and CSF (day 13) (p < 0.05). Patients receiving taVNS had higher rates of favorable outcomes at discharge (38.4% vs 21.4%) and first follow-up (76.9% vs 57.1%). Patients treated with taVNS had significant improvement in modified Rankin Scale scores from admission to first follow-up (p = 0.014), unlike patients in the sham-treated group (p = 0.18). The taVNS group had a significantly lower rate of discharge to a skilled nursing facility or hospice (p = 0.04). CONCLUSIONS taVNS is a noninvasive method of neuro- and systemic immunomodulation. This trial supports the finding that taVNS following SAH can mitigate the inflammatory response, reduce radiographic vasospasm, and potentially improve functional and neurological outcomes. © 2025 The authors.
Author Keywords
aneurysm; inflammation; radiographic vasospasm; subarachnoid hemorrhage; vagus nerve stimulation; vascular disorders
Funding details
American Association of Neurological SurgeonsAANS
University of WashingtonUW
McDonnell Center for Systems Neuroscience
National Institute of Neurological Disorders and StrokeNINCDSR21-NS128307
National Institute of Neurological Disorders and StrokeNINCDS
National Institute of Biomedical Imaging and BioengineeringNIBIBP41-EB018783
National Institute of Biomedical Imaging and BioengineeringNIBIB
Document Type: Article
Publication Stage: Final
Source: Scopus
Racial disparities in hydrocephalus mortality and shunt revision: a study from the Hydrocephalus Clinical Research Network
(2025) Journal of Neurosurgery: Pediatrics, 35 (6), pp. 554-562.
Rocque, B.G.a , Jensen, H.b , Reeder, R.W.b , Rozzelle, C.J.a , Kulkarni, A.V.d , Pollack, I.F.e , McDowell, M.M.e , Naftel, R.P.f g , Jackson, E.M.h , Whitehead, W.E.i , Pindrik, J.A.j , Isaacs, A.M.j , Strahle, J.M.k , McDonald, P.J.l , Tamber, M.S.l , Hankinson, T.C.m , Browd, S.R.n , Hauptman, J.S.o , Krieger, M.D.p , Chu, J.q , Riva-Cambrin, J.r , Limbrick, D.D., Jr.s , Holubkov, R.b , Kestle, J.R.W.c , Wellons, J.C., IIIf g , Hydrocephalus Clinical Research Networkt
a Department of Neurosurgery, Children’s of Alabama, The University of Alabama, Birmingham, AL, United States
b Departments of Pediatrics, University of Utah, Salt Lake City, UT, United States
c Departments of Neurosurgery, University of Utah, Salt Lake City, UT, United States
d Division of Neurosurgery, Hospital for Sick Children, Toronto, ON, Canada
e Department of Neurosurgery, UPMC Children’s Hospital of Pittsburgh, University of PittsburghPA, United States
f Department of Neurosurgery, Vanderbilt University Medical Center, Nashville, TN, United States
g Surgical Outcomes Center for Kids, Monroe Carell Jr. Children’s Hospital at Vanderbilt University, Nashville, TN, United States
h Department of Neurosurgery, The Johns Hopkins Hospital, Johns Hopkins University, Baltimore, MD, United States
i Department of Neurosurgery, Baylor College of Medicine, Houston, TX, United States
j Department of Neurosurgery, The Ohio State University College of Medicine, Columbus, OH, United States
k Department of Neurosurgery, Washington University School of Medicine, St. Louis, MO, United States
l Division of Neurosurgery, British Columbia Children’s Hospital, The University of British Columbia, Vancouver, BC, Canada
m Department of Neurosurgery, Children’s Hospital Colorado, Aurora, CO, United States
n Department of Neurosurgery, Seattle Children’s Hospital, University of Washington, Seattle, WA, United States
o Department of Neurosurgery, Phoenix Children’s Hospital, Phoenix, AZ, United States
p Department of Neurosurgery, Children’s Hospital Los Angeles, University of Southern California, Los Angeles, CA, United States
q Department of Neurosurgery, Riley Children’s Hospital, Indiana University School of Medicine, Indianapolis, IN, United States
r Division of Neurosurgery, Alberta Children’s Hospital, University of CalgaryAB, Canada
s Department of Neurosurgery, Virginia Commonwealth University, Richmond, VA, United States
Abstract
OBJECTIVE Several studies of administrative data have noted higher mortality rates for Black/African American children with shunted hydrocephalus. A longitudinal study of children with hydrocephalus secondary to myelomeningocele showed lower lifetime rates of shunt revision in minority children compared to White children, indicating a possible disparity in hydrocephalus treatment. The goal of this study is to identify racial and ethnic disparities in mortality or in shunt revision rates by using the Hydrocephalus Clinical Research Network (HCRN) hydrocephalus registry sample. METHODS The HCRN registry was queried for patients with shunted hydrocephalus for whom data on all lifetime hydrocephalus procedures were available. Patients with a primary shunt placement prior to 2023 were included, with follow-up extending through March 19, 2024. A Cox proportional hazards model was created to determine the effect of race and ethnicity on mortality while controlling for age at initial shunt placement, sex, hydrocephalus etiology, gestational age at birth, and presence of complex chronic conditions. Similarly, a proportional means model was used to evaluate association with lifetime number of shunt revision surgeries. The authors’ hypothesis was that when controlling for other variables, minority children would have higher mortality and fewer shunt revision surgeries than White children. RESULTS A total of 5656 children were included in the analysis of mortality. There were 579 deaths. Race and ethnicity were independently associated with mortality, with Black (HR 1.32, 95% CI 1.05–1.65), other non-White (HR 1.39, 95% CI 1.03–1.86), and Hispanic (HR 1.50, 95% CI 1.22–1.84) children having a higher mortality rate than White children. In the analysis of 4081 children with shunts, Hispanic ethnicity was also independently associated with fewer total shunt revisions (HR 0.84, 95% CI 0.72–0.98). CONCLUSIONS In children with hydrocephalus, when controlling for other factors, there is a higher mortality rate among Hispanic, Black, and other non-White children, and fewer shunt revisions among Hispanic children. These findings highlight important potential disparities in hydrocephalus treatment. ©AANS 2025.
Author Keywords
healthcare disparities; hydrocephalus; mortality; ventriculoperitoneal shunt
Funding details
Hydrocephalus AssociationHA
National Institute of Neurological Disorders and StrokeNINDB1RC1NS 068943-01, 1U01NS107486-01A1 ESTHI
National Institute of Neurological Disorders and StrokeNINDB
Patient-Centered Outcomes Research InstitutePCORICER-1403-13857
Patient-Centered Outcomes Research InstitutePCORI
Document Type: Article
Publication Stage: Final
Source: Scopus
Mechanisms of photoreceptor protection upon targeting the Nrl–Nr2e3 pathway
(2025) Proceedings of the National Academy of Sciences of the United States of America, 122 (21), art. no. e2500446122, .
Murphy, D.P.a , Kolesnikov, A.V.b , Montana, C.L.a c , Khaja, Z.M.a d , Liu, Y.a , Kefalov, V.J.b e , Corbo, J.C.a
a Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, United States
b Gavin Herbert Eye Institute, Department of Ophthalmology, University of California, Irvine, CA 92617, United States
c Department of Ophthalmology, Washington University School of Medicine, St. Louis, MO 63110, United States
d Saint Louis University School of Medicine, St. Louis, MO 63104, United States
e Department of Physiology and Biophysics, University of California, Irvine, CA 92617, United States
Abstract
Acute knockout of the rod photoreceptor transcription factor Nrl delays retinal degeneration in multiple mouse models of blindness, but the downstream transcriptomic changes that mediate these therapeutic effects are unknown. Here, we show that acute Nrl knockout causes upregulation of a subset of cone genes in rods as well as downregulation of rod genes, including the rod-specific transcriptional repressor Nr2e3. We hypothesized that Nr2e3 downregulation might mediate some of the therapeutic effects of Nrl knockout. Indeed, acute knockout of Nr2e3 prevents photoreceptor degeneration and preserves visual function in mice with mutations in the catalytic subunit of the rod-specific phosphodiesterase (Pde6brd10/rd10). Upregulation of Pde6c, the cone-specific paralog of Pde6b, in Nr2e3-knockout rods is required to prevent degeneration in Pde6brd10/rd10 mice, suggesting that this therapeutic effect is mediated, at least in part, by a gene-replacement mechanism. In contrast, acute Nr2e3 knockout fails to prevent degeneration caused by loss- or gain-of-function mutations in Rhodopsin (Rho−/− and RhoP23H/P23H), whereas acute Nrl knockout delays degeneration in both models. Surprisingly, the therapeutic effect of acute Nrl knockout in Pde6brd10/rd10 mice does not depend on Pde6c upregulation. These results suggest that acute Nrl knockout may exert its therapeutic effects via a mechanism independent of Nr2e3 downregulation, perhaps by downregulating other rod genes. We conclude that acute NRL knockout may be a promising gene-independent strategy for preventing photoreceptor degeneration in human patients. Copyright © 2025 the Author(s).
Author Keywords
Nr2e3; Nrl; photoreceptor; retina; retinitis pigmentosa
Funding details
University of WashingtonUW
McDonnell Center for Systems Neuroscience
National Institutes of HealthUSNIHEY030075, EY033810
National Institutes of HealthUSNIH
Research to Prevent BlindnessRPBP30 EY034070
Research to Prevent BlindnessRPB
Document Type: Article
Publication Stage: Final
Source: Scopus
The generalizability of cortical area parcellations across early childhood
(2025) Cerebral Cortex, 35 (5), art. no. bhaf116, .
Tu, J.C.a , Myers, M.J.a , Li, W.b , Li, J.b c , Wang, X.a , Dierker, D.a , Day, T.K.M.d e f , Snyder, A.a , Latham, A.g , Kenley, J.K.g , Sobolewski, C.M.a h , Wang, Y.b , Labonte, A.K.i , Feczko, E.d , Kardan, O.j , Moore, L.A.d , Sylvester, C.M.a i k , Fair, D.A.d e , Elison, J.T.d e , Warner, B.B.l , Barch, D.M.a i m , Rogers, C.E.i , Luby, J.L.i , Smyser, C.D.a g i l , Gordon, E.M.a , Laumann, T.O.i , Eggebrecht, A.T.a , Wheelock, M.D.a
a Mallinckrodt Institute of Radiology, Washington University in St. Louis, 4525 Scott Ave, St. Louis, MO 63110, United States
b Department of Mathematics and Statistics, Washington University in St. Louis, One Brookings Drive, St. Louis, MO 63130, United States
c Department of Statistics, University of Chicago, 5747 S Ellis Ave, Chicago, IL 60637, United States
d Masonic Institute for the Developing Brain, University of Minnesota, 2025 E River Pkwy, Minneapolis, MN 55414, United States
e Institute of Child Development, University of Minnesota, Campbell Hall, 51 E River Rd, Minneapolis, MN 55455, United States
f Center for Brain Plasticity and Recovery, Georgetown University, Department of Neurology, Building D, Suite 145, 4000 Reservoir Road, N.W., Washington, DC 20007, United States
g Department of Neurology, Washington University in St. Louis, 660 South Euclid Avenue, St. Louis, MO 63110, United States
h Department of Psychology, Virginia Commonwealth University, White House 806 W. Franklin St. Box 842018, Richmond, VA 23284-2018, United States
i Department of Psychiatry, Washington University in St. Louis, 660 S. Euclid Ave., St. Louis, MO 63110-1010, United States
j Department of Psychiatry, University of Michigan, 250 Plymouth Road, Ann Arbor, 48109, United States
k The Taylor Family Institute for Innovative Psychiatric Research, Washington University in St. Louis, 4444 Forest Park Ave #2600, St. Louis, MO 63108, United States
l Department of Pediatrics, Washington University in St. Louis, 660 S Euclid Ave, St. Louis, MO 63110, United States
m Department of Psychological and Brain Sciences, Washington University in St. Louis, 1 Brookings Drive, St. Louis, MO 63130, United States
Abstract
The cerebral cortex consists of distinct areas that develop through intrinsic embryonic patterning and postnatal experiences. Accurate parcellation of these areas in neuroimaging studies improves statistical power and cross-study comparability. Given significant brain changes in volume, microstructure, and connectivity during early life, we hypothesized that cortical areas in 1- to 3-year-olds would differ markedly from neonates and increasingly resemble adult patterns as development progresses. Here, we parcellated the cerebral cortex into putative areas using local functional connectivity (FC) gradients in 92 toddlers at 2 years old. We demonstrate high reproducibility of these cortical areas across 1- to 3-year-olds in two independent datasets. The area boundaries in 1- to 3-year-olds were more similar to those in adults than those in neonates. While the age-specific group area parcellation better fits the underlying FC in individuals during the first 3 years, adult area parcellations still have utility in developmental studies, especially in children older than 6 years. Additionally, we provide connectivity-based community assignments of the area parcels, showing fragmented anterior and posterior components based on the strongest connectivity, yet alignment with adult systems when weaker connectivity was included. © The Author(s) 2025. Published by Oxford University Press. All rights reserved.
Author Keywords
area; development; FMRI; functional connectivity; lifespan; parcellation
Funding details
School of Medicine, Washington University in St. LouisWUSM
Canadian Nuclear Safety CommissionCCSN
National Institutes of HealthNIH
McDonnell Center for Systems Neuroscience
National Institute of Child Health and Human DevelopmentNICHDR01MH122389, R01 HD115540, R01MH134966
National Institute of Child Health and Human DevelopmentNICHD
National Institute of Biomedical Imaging and BioengineeringNIBIBK99/R00 EB029343
National Institute of Biomedical Imaging and BioengineeringNIBIB
National Institute of Mental HealthNIMHR01 MH113883, U01 MH110274, R01 MH104324
National Institute of Mental HealthNIMH
Document Type: Article
Publication Stage: Final
Source: Scopus
Ubiquitin–proteasome system in the different stages of dominantly inherited Alzheimer’s disease
(2025) Alzheimer’s and Dementia, 21 (5), art. no. e70243, .
Liu, H.a , Bui, Q.b , Hassenstab, J.a , Gordon, B.A.c , Benzinger, T.L.S.c , Timsina, J.d , Sung, Y.J.d , Karch, C.d , Renton, A.E.e , Daniels, A.a , Morris, J.C.a , Xiong, C.b , Ibanez, L.d , Perrin, R.J.a f , Llibre-Guerra, J.J.a , Day, G.S.g , Supnet-Bell, C.a , Xu, X.b , Berman, S.B.h , Chhatwal, J.P.i , Ikeuchi, T.j , Kasuga, K.j , Niimi, Y.k , Huey, E.D.l , Schofield, P.R.m n , Brooks, W.S.m n , Ryan, N.S.o p , Jucker, M.q r , Laske, C.q r , Levin, J.s t u , Vöglein, J.u v w , Roh, J.H.x , Lopera, F.y , Bateman, R.J.a , Cruchaga, C.d , McDade, E.M.a , For DIAN study teamz
a Department of Neurology, Washington University in St. Louis, St. Louis, MO, United States
b Department of Biostatistics, Washington University in St. Louis, St. Louis, MO, United States
c Department of Radiology, Washington University in St. Louis, St. Louis, MO, United States
d Department of Psychiatry, Washington University in St. Louis, St. Louis, MO, United States
e Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, United States
f Department of Pathology and Immunology, Washington University in St. Louis, St. Louis, MO, United States
g Department of Neurology, Mayo Clinic in Florida, Jacksonville, FL, United States
h Departments of Neurology and Clinical & Translational Science, University of Pittsburgh, Pittsburgh, PA, United States
i Brigham and Women’s Hospital, Massachusetts General Hospital, Harvard Medical School, Cambridge, MA, United States
j Brain Research Institute, Niigata University, Niigata, Japan
k Specially appointed lecturer, Unit for Early and Exploratory Clinical Development, The University of Tokyo, Tokyo, Japan
l Memory and Aging Program, Butler Hospital, Department of Psychiatry and Human Behavior, Alpert Medical School, Brown University, Providence, RI, United States
m Neuroscience Research Australia, Sydney, NSW, Australia
n Faculty of Medicine and Health, University of New South Wales, Sydney, NSW, Australia
o Dementia Research Centre, UCL Queen Square Institute of Neurology, London, United Kingdom
p UK Dementia Research Institute at UCL, London, United Kingdom
q German Center for Neurodegenerative Diseases (DZNE) Tübingen, Tübingen, Germany
r Section for Dementia Research, Hertie Institute for Clinical Brain Research, Department of Psychiatry and Psychotherapy, University of Tübingen, Tübingen, Germany
s German Center for Neurodegenerative Diseases, Munich, Site Munich, Germany
t Department of Neurology, Ludwig-Maximilians-Universität München, Munich, Germany
u Munich Cluster for Systems Neurology (SyNergy), Munich, Germany
v Department of Neurology, LMU University Hospital, Munich, LMU Munich, Germany
w German Center for Neurodegenerative Diseases (DZNE), Munich, Germany
x Departments of Neurology and Physiology, Korea University Anam Hospital, Korea University College of Medicine, Seoul, South Korea
y Grupo de Neurociencias de Antioquia (GNA), Facultad de Medicina, Universidad de Antioquia, Medellín, Colombia
Abstract
INTRODUCTION: This study investigated the role of the ubiquitin–proteasome system (UPS) in dominantly inherited Alzheimer’s disease (DIAD) by examining cerebrospinal fluid (CSF) levels of UPS proteins. METHOD: The SOMAscan assay was used to detect changes in UPS proteins in mutation carriers (MCs) relative to disease progression; imaging and CSF biomarkers of amyloid, tau, and neurodegeneration measures; and Clinical Dementia Rating scale. RESULTS: Subtle increases in specific ubiquitin enzymes were detected in MCs up to two decades before symptom onset, with more pronounced elevations in UPS-activating enzymes near symptom onset. Significant correlations were found between UPS proteins and Alzheimer’s disease (AD) biomarkers, especially between autophagy markers and late-stage tau biomarkers, microglia, and axonal degeneration. DISCUSSION: The rise in UPS proteins alongside tau-related markers suggests UPS involvement in tau neurofibrillary tangles. Elevated CSF UPS proteins in DIAD MCs may serve as indicators of disease progression, and may support the UPS as a therapeutic target in AD. Highlights: This study investigates the ubiquitin-proteasome system (UPS) in Dominantly Inherited Alzheimer’s Disease (DIAD), highlighting early molecular changes linked to disease progression. Using SOMAscan proteomics, we identified significant UPS protein alterations in cerebrospinal fluid of mutation carriers, notably up to 20 years before clinical symptom onset. Correlations between UPS protein levels and Alzheimer’s biomarkers, particularly tau and neurodegeneration markers, suggest a strong association between UPS dysregulation and tau pathology in DIAD. Dynamic UPS changes align with A/T biological staging: UPS proteins were shown to increase across Aβ/tau (A/T) groups, with largest increases in the A+/T+ group, reinforcing their role in late-stage tau pathology and disease progression. These findings underscore the potential of UPS proteins as early biomarkers for Alzheimer’s disease progression and as novel therapeutic targets, especially in tau-pathology-driven neurodegeneration. This work contributes to understanding AD pathogenesis, by emphasizing the importance of protein quality control systems and by offering avenues for future biomarker discovery and therapeutic development in Alzheimer’s disease. © 2025 The Author(s). Alzheimer’s & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer’s Association.
Author Keywords
amyloid beta; amyloid precursor protein; autophagy–lysosome pathway; biomarker discovery; dominantly inherited Alzheimer’s disease; genetic mutations; neurodegeneration; presenilin 1; presenilin 2; protein aggregation; protein degradation; proteomic analysis; proteostasis; tau pathology; ubiquitin–proteasome system
Funding details
School of Medicine, Washington University in St. LouisWUSM
Hope Center for Neurological Disorders, Washington University in St. Louis
Chan Zuckerberg InitiativeCZI
National Center for Advancing Translational SciencesNCATS
National Institutes of HealthUSNIHR01AG078964, R01AG064614, RF1AG058501
National Institutes of HealthUSNIH
HU21C0066
Alzheimer’s AssociationAAZEN‐22‐848604
Alzheimer’s AssociationAA
U19AG032438, K23AG064029, U01NS120901, U01AG057195
JP23dk0207066, JP23dk0207049
P30 AG066444, U19 AG024904, R01 AG067505, P01AG003991, R01 AG053550, P01AG026276
Institute of Clinical and Translational SciencesICTSUL1TR002345
Institute of Clinical and Translational SciencesICTS
Document Type: Article
Publication Stage: Final
Source: Scopus
Psychosocial behavioral phenotypes of racially/ethnically minoritized older adults enrolled in HABS-HD differ on neuroimaging measures of brain age gap, hippocampal volume, and cortical thickness
(2025) Alzheimer’s and Dementia: Translational Research and Clinical Interventions, 11 (2), art. no. e70109, .
Clark, A.L.a , McGill, M.B.a , Weigand, A.J.b , Wisch, J.K.c , Petersen, K.c , Ances, B.c , Braskie, M.N.d , O’Bryant, S.e f , Thomas, K.R.g h , HABS-HD Study Teami
a Department of Psychology, The University of Texas at Austin, Austin, TX, United States
b Department of Neurology, University of California San Francisco Medical School, San Francisco, CA, United States
c Department of Neurology, Washington University School of Medicine in St. Louis, St. Louis, MO, United States
d Stevens Neuroimaging and Informatics InstituteKeck School of Medicine, University of Southern California, Los Angeles, CA, United States
e Institute for Translational Research, University of North Texas Health Science Center, Fort Worth, TX, United States
f Department of Family Medicine, University of North Texas Health Science Center, Fort Worth, TX, United States
g Research Service, VA San Diego Healthcare System, San Diego, CA, United States
h Department of Psychiatry, University of California San Diego Medical School, La JollaCA, United States
Abstract
INTRODUCTION: This study examined whether previously identified psychosocial behavioral phenotypes differed on structural neuroimaging markers. METHODS: Latent profile analysis (LPA) employed in a sample of 1820 community-dwelling older adults (1118 Hispanic and 702 Black) replicated previous Low Resource/Low Distress, High Resource/Low Distress, and Low Resource/High Distress phenotype classifications. Analyses of covariance (ANCOVAs) adjusting for relevant factors examined phenotype differences on neuroimaging outcomes of predicted brain age gap (BAG) (DeepBrainNet Predicted Age – Chronological Age), hippocampal volume, and cortical thickness of a meta-temporal region of interest. RESULTS: The Low Resource/Low Distress and Low Resource/High Distress phenotypes had significantly higher predicted BAGs relative to the High Resource/Low Distress phenotype, and the Low Resource/High Distress group displayed significantly lower hippocampal volumes and meta-temporal cortical thickness relative to High Resource/Low Distress phenotype. DISCUSSION: Results highlight there are neurostructural variations across psychosocial behavioral phenotypes and indicate the Low Resource/High Distress group may be at risk for ADRD. Highlights: Brain age gap (BAG), hippocampal volumes, and cortical thickness differences were tested. The High Resource/Low Distress phenotype had the most favorable imaging outcomes. The Low Resource/High Distress phenotype demonstrated the poorest imaging outcomes. Risk for Alzheimer’s disease and related dementias (ADRD) may differ across psychosocial behavioral phenotypes. © 2025 The Author(s). Alzheimer’s & Dementia: Translational Research & Clinical Interventions published by Wiley Periodicals LLC on behalf of Alzheimer’s Association.
Author Keywords
brain age gap; health disparities; hippocampal volume; neurodegeneration; neuroimaging; phenotyping; psychosocial; risk and resilience to ADRD
Funding details
National Institute on AgingNIA
U.S. Department of Veterans AffairsVAP41EB015922, R03 AG070435, 1IK2CX001865
U.S. Department of Veterans AffairsVA
National Institutes of HealthNIHR01AG054073, R01AG058533
National Institutes of HealthNIH
U19AG078109, R03 AG085241
Alzheimer’s AssociationAAAARG‐22‐723000
Alzheimer’s AssociationAA
Document Type: Article
Publication Stage: Final
Source: Scopus
Tracking Daily Variations in Rest-Wake to Guide Personalized Timing of Temozolomide for High-Grade Glioma Patients
(2025) Journal of Biological Rhythms, art. no. 07487304251336826, .
Gonzalez-Aponte, M.F.a , Damato, A.R.a , Katumba, R.G.N.b , Talcott, G.R.b , Campian, J.L.c , Butt, O.H.b , Ruben, M.D.d , Rubin, J.B.e f , Herzog, E.D.a , Walch, O.J.g h
a Department of Biology, Division of Biology and Biomedical Sciences, Washington University in St. Louis, St. Louis, MO, United States
b Division of Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, MO, United States
c Department of Medical Oncology, Mayo Clinic, Rochester, MN, United States
d Divisions of Pulmonary Medicine and Biomedical Informatics, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, United States
e Department of Pediatrics, St. Louis Children’s Hospital, Washington University School of Medicine, St. Louis, MO, United States
f Department of Neuroscience, Washington University School of Medicine, St. Louis, MO, United States
g Arcascope Inc., Arlington, VA, United States
h Department of Neurology, University of Michigan, Ann Arbor, MI, United States
Abstract
High-grade gliomas, like glioblastoma multiforme (GBM), are the most common malignant brain tumors in adults and are treated with the chemotherapy drug temozolomide (TMZ). In humans, a retrospective analysis of patients’ overall survival suggests that morning dosing may confer a benefit over evening dosing. Circadian variation in O6-methylguanine-DNA methyltransferase (MGMT) gene expression and promoter methylation has been implicated in increased tumor cell sensitivity to TMZ in the morning. Although patient compliance with timed oral administration of TMZ was high in a prospective trial, it is not known whether differences in daily sleep patterns of patients impact the biological time of drug administration or overall survival. Using wrist actigraphy collected from 10 high-grade glioma patients, we quantified the moment of oral TMZ delivery in terms of wall clock time and internal biological time during the months after surgical tumor resection. We found that variation of daily rhythms within and between individuals caused dosing times to vary more in their internal biological time than wall clock time so that, for example, some doses taken by patients assigned for the evening (2000 h) were closer to the patient’s internal biological morning. We conclude that wrist actigraphy provides a reliable and non-invasive estimate of personal circadian time that could improve efficacy and precision of TMZ delivery. These findings may inform personalized circadian medicine and optimized times for TMZ delivery in the clinic. © 2025 The Author(s).
Author Keywords
actigraphy; biological time; chronotherapy; GBM; high-grade gliomas; personalized circadian medicine; TMZ
Funding details
Washington University in St. LouisWUSTL
Alvin J. Siteman Cancer CenterSCC
Children’s Discovery InstituteCDI
Foundation for Barnes-Jewish HospitalFBJH
University of WashingtonUW
National Cancer InstituteNCIF31CA250161, R01NS134885
National Cancer InstituteNCI
National Institute of Neurological Disorders and StrokeNINDBR21NS120003
National Institute of Neurological Disorders and StrokeNINDB
National Institutes of HealthNIHR25GM103757-10, T32NS121881-01
National Institutes of HealthNIH
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
Lemborexant ameliorates tau-mediated sleep loss and neurodegeneration in males in a mouse model of tauopathy
(2025) Nature Neuroscience, .
Parhizkar, S.a , Bao, X.a , Chen, W.a , Rensing, N.a , Chen, Y.a , Kipnis, M.a , Song, S.a , Gent, G.a , Tycksen, E.b , Manis, M.a , Lee, C.a , Serrano, J.R.a , Bosch, M.E.a , Franke, E.a , Yuede, C.M.a c d , Landsness, E.C.a , Wong, M.a , Holtzman, D.M.a
a Department of Neurology, Hope Center for Neurological Disorders, Knight Alzheimer’s Disease Research Center, Washington University School of Medicine, St. Louis, MO, United States
b Genome Technology Access Center, Washington University School of Medicine, St. Louis, MO, United States
c Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, United States
d Department of Neuroscience, Washington University School of Medicine, St. Louis, MO, United States
Abstract
Sleep disturbances are associated with the pathogenesis of neurodegenerative diseases such as Alzheimer’s disease and primary tauopathies. Here we demonstrate that administration of the dual orexin receptor antagonist lemborexant in the P301S/E4 mouse model of tauopathy improves tau-associated impairments in sleep–wake behavior. It also protects against chronic reactive microgliosis and brain atrophy in male P301S/E4 mice by preventing abnormal phosphorylation of tau. These neuroprotective effects in males were not observed after administration of the nonorexinergic drug zolpidem that similarly promoted nonrapid eye movement sleep. Furthermore, both genetic ablation of orexin receptor 2 and lemborexant treatment reduced wakefulness and decreased seeding and spreading of phosphorylated tau in the brain of wild-type mice. These findings raise the therapeutic potential of targeting sleep by orexin receptor antagonism to prevent abnormal tau phosphorylation and limit tau-induced damage. © The Author(s), under exclusive licence to Springer Nature America, Inc. 2025.
Funding details
Freedom Together Foundation
National Institutes of HealthNIHP01NS074969, RF1NS090934, RF1AG061776
National Institutes of HealthNIH
Alzheimer’s AssociationAAAARF-21-850865
Alzheimer’s AssociationAA
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
Protocol for a pilot clinical trial of the senolytic drug combination Dasatinib Plus Quercetin to mitigate age-related health and cognitive decline in mental disorders
(2025) F1000Research, 13, art. no. 1072, .
Schweiger, A.a b , Diniz, B.c , Nicol, G.b , Schweiger, J.b , Dasklakis-Perez, A.E.b , Lenze, E.J.b
a Social Work, Saint Louis University School of Social Work, St. Louis, MO 63103, United States
b Psychiatry, Washington University in St Louis School of Medicine, St. Louis, MO 63108, United States
c Psychiatry, University of Connecticut Department of Psychiatry, Farmington, CT 06030-1419, United States
Abstract
Background: Major depressive disorder (MDD) and schizophrenia are linked to accelerated aging leading to reduced lifespan, health span and cognitive decline. Cellular senescence, in which cells lose proliferative capacity and develop a senescence-associated secretory phenotype (SASP), plays a role in this process. Emerging research suggests that the senolytic regimen of dasatinib+quercetin (D+Q) reduces senescent cells, potentially mitigating age-related health and cognitive decline. This pilot study aims to assess the feasibility and safety of D+Q in older adults with schizophrenia, schizoaffective disorder, and treatment-resistant depression (TRD). Methods: This single-center study will recruit 30 participants total aged 50 years or older with schizophrenia/schizoaffective disorder or 60 years or older with TRD; the difference in age limits is because individuals with schizophrenia are biologically about 10 years older than general population owing to metabolic burden. Each participant will receive two consecutive days of 100 mg oral dasatinib plus 1250 mg oral quercetin at baseline and weeks one through three, (i.e., two days on, five days off) along with lifestyle risk management education. Questionnaires and assessments will measure health and cognitive function as well as psychiatric function at baseline, week 10, and one year. Magnetic Resonance Imaging (MRI) will measure structural and functional brain health at baseline and 10 weeks. Blood sampling for SASP testing will occur at seven time points: baseline, weeks one through four, week 10, and one year. Conclusion: This pilot aims to evaluate the safety and feasibility of the senolytic regimen and D+Q’s potential to counteract accelerated aging in adults with schizophrenia/schizoaffective disorder and TRD. Trial registration: Dasatinib Plus Quercetin for Accelerated Aging in Mental Disorders is registered on ClinicalTrials.gov: NCT05838560; posted May 1, 2023. Copyright: © 2025 Schweiger A et al.
Author Keywords
Aging; cellular senescence; cognitive decline; depressive disorder; geriatrics; major; schizophrenia
Funding details
Merck
Institute of Clinical and Translational SciencesWUICTS
Skoll Foundation
Boehringer Ingelheim
National Institute of Mental HealthNIMH
Health Resources and Services AdministrationHRSA
Mallinckrodt Institute of Radiology, School of Medicine, Washington University in St. LouisMIR
Foundation for Barnes-Jewish HospitalFBJH
Patient-Centered Outcomes Research InstitutePCORI
University of WashingtonUW
Taylor Family Institute for Innovative Psychiatric Research, School of Medicine, Washington University in St. Louis
McDonnell Center for Systems Neuroscience
Document Type: Article
Publication Stage: Final
Source: Scopus
Choroid plexus apocrine secretion shapes CSF proteome during mouse brain development
(2025) Nature Neuroscience, art. no. 134, .
Courtney, Y.a b , Head, J.P.a , Dani, N.a c , Chechneva, O.V.d , Shipley, F.B.a e , Zhang, Y.f , Holtzman, M.J.f , Sadegh, C.d , Libermann, T.A.g , Lehtinen, M.K.a b e
a Department of Pathology, Boston Children’s Hospital and Harvard Medical School, Boston, MA, United States
b Graduate Program in Neuroscience, Harvard Medical School, Boston, MA, United States
c Department of Cell and Developmental Biology, Vanderbilt University, Nashville, TN, United States
d Department of Neurosurgery, University of California, Davis, Sacramento, CA, United States
e Graduate Program in Biophysics, Harvard University, Cambridge, MA, United States
f Pulmonary and Critical Care Medicine, Department of Medicine, Washington University School of Medicine, St. Louis, MO, United States
g Proteomics, Bioinformatics and Systems Biology Center, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, United States
Abstract
The choroid plexus (ChP) regulates cerebrospinal fluid (CSF) composition, providing essential molecular cues for brain development; yet, embryonic ChP secretory mechanisms remain poorly defined. Here we identify apocrine secretion by embryonic ChP epithelial cells as a key regulator of the CSF proteome and neurodevelopment in male and female mice. We demonstrate that the activation of serotonergic 5-HT2C receptors (by WAY-161503) triggers sustained Ca2+ signaling, driving high-volume apocrine secretion in mouse and human ChP. This secretion alters the CSF proteome, stimulating neural progenitors lining the brain’s ventricles and shifting their developmental trajectory. Inducing ChP secretion in utero in mice disrupts neural progenitor dynamics, cerebral cortical architecture and offspring behavior. Additionally, illness or lysergic acid diethylamide exposure during pregnancy provokes coordinated ChP secretion in the mouse embryo. Our findings reveal a fundamental secretory pathway in the ChP that shapes brain development, highlighting how its disruption can have lasting consequences for brain health. © The Author(s) 2025.
Funding details
National Science FoundationNSF
BE-Basic Foundation
Harvard University
Howard Hughes Medical InstituteHHMI
Human Frontier Science ProgramHFSPORGP0063/2018
Human Frontier Science ProgramHFSPO
National Heart, Lung, and Blood InstituteNHLBIR35HL145242
National Heart, Lung, and Blood InstituteNHLBI
Simons FoundationSF610670
Simons FoundationSF
New York Stem Cell FoundationNYSCFR01NS088566, RF1DA048790, R01NS129823
New York Stem Cell FoundationNYSCF
National Institutes of HealthNIHP30CA006516
National Institutes of HealthNIH
Intellectual and Developmental Disabilities Research CenterIDDRC1U54HD090255, P50HD105351, S10OD016453
Intellectual and Developmental Disabilities Research CenterIDDRC
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
Physical Therapy and Deep Brain Stimulation in Parkinson Disease: Safety, Feasibility, and Preliminary Efficacy
(2025) Journal of Neurologic Physical Therapy, art. no. 10.1097/NPT.0000000000000519, .
Tueth, L.E.a , Rawson, K.S.a b , Van Dillen, L.R.a c , Earhart, G.M.a b d , Perlmutter, J.S.a b d e f , Duncan, R.P.a b
a Washington University, St. Louis School of Medicine, Program in Physical Therapy, St. Louis, MO, United States
b Washington University, St. Louis School of Medicine, Department of Neurology, St. Louis, MO, United States
c Washington University, St. Louis School of Medicine, Department of Orthopedic Surgery, St. Louis, MO, United States
d Washington University, St. Louis School of Medicine, Department of Neuroscience, St. Louis, MO, United States
e Washington University, St. Louis School of Medicine, Department of Radiology, St. Louis, MO, United States
f Washington University, St. Louis School of Medicine, Program in Occupational Therapy, St. Louis, MO, United States
Abstract
Background and Purpose: Subthalamic nucleus deep brain stimulation (STN-DBS) effectively treats some of the motor manifestations of Parkinson disease (PD). However, previous work suggests STN-DBS may lead to worsening of balance and gait in some people with PD. Physical therapy (PT) is often used to improve balance and gait in PD, but its safety, feasibility, and efficacy have not been tested in people with STN-DBS. The purpose of this study was to test the safety, feasibility, and preliminary efficacy of PT for improving gait and balance in persons with PD and STN-DBS. Methods: This randomized pilot study compared the effects of an 8-week PT intervention (n = 15) on balance and gait to a usual care control group (n = 14) among people with PD with STN-DBS. Individuals were evaluated in the on medication/on stimulation state as well as off medication/off stimulation state. Results: PT was safe as there were no serious adverse events during treatment. PT was feasible as the average percentage of session attendance was 93%. PT significantly improved balance as measured by the Balance Evaluation Systems Test (BESTest) in the on medication/on stimulation state but did not significantly improve gait. No significant differences between groups were found in the off medication/off stimulation state. Discussion and Conclusions: PT was safe, feasible, and may improve balance for individuals with PD with STN-DBS. Further work is needed to understand how modifying the frequency and intensity of PT interventions may impact balance and gait in individuals with STN-DBS. © 2025 Wolters Kluwer Health, Inc.
Author Keywords
balance; deep brain stimulation; gait; Parkinson disease; physical therapy
Funding details
American Parkinson Disease AssociationAPDA
National Institutes of HealthUSNIH
Foundation for Barnes-Jewish HospitalFBJH
St. Louis American Parkinson Disease Association
University of WashingtonUW
National Institute of Child Health and Human DevelopmentNICHDK12 HD055931
National Institute of Child Health and Human DevelopmentNICHD
Institute of Clinical and Translational SciencesWUICTSUL1TR00048
Institute of Clinical and Translational SciencesWUICTS
National Center for Advancing Translational SciencesNCATSR01 NS075321
National Center for Advancing Translational SciencesNCATS
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
BrainQCNet: A Deep Learning attention-based model for the automated detection of artifacts in brain structural MRI scans
(2024) Imaging Neuroscience, 2, pp. 1-16.
Garcia, M.a b , Dosenbach, N.c , Kelly, C.a b d
a Department of Psychiatry, School of Medicine, Trinity College Dublin, Dublin, Ireland
b Trinity College Institute of Neuroscience, Trinity College, Dublin, Ireland
c Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States
d School of Psychology, Trinity College Dublin, Dublin, Ireland
Abstract
Analyses of structural MRI (sMRI) data depend on robust upstream data quality control (QC). It is also crucial that researchers seek to retain maximal amounts of data to ensure reproducible, generalizable models and to avoid wasted effort, including that of participants. The time-consuming and difficult task of manual QC evaluation has prompted the development of tools for the automatic assessment of brain sMRI scans. Existing tools have proved particularly valuable in this age of Big Data; as datasets continue to grow, reducing execution time for QC evaluation will be of considerable benefit. The development of Deep Learning (DL) models for artifact detection in structural MRI scans offers a promising avenue toward fast, accurate QC evaluation. In this study, we trained an interpretable Deep Learning model, ProtoPNet, to classify minimally preprocessed 2D slices of scans that had been manually annotated with a refined quality assessment (ABIDE 1; n = 980 scans). To evaluate the best model, we applied it to 2141 ABCD T1-weighted MRI scans for which gold-standard manual QC annotations were available. We obtained excellent accuracy: 82.4% for good quality scans (Pass), 91.4% for medium to low quality scans (Fail). Further validation using 799 T1w MRI scans from ABIDE 2 and 750 T1w MRI scans from ADHD-200 confirmed the reliability of our model. Accuracy was comparable to or exceeded that of existing ML models, with fast processing and prediction time (1 minute per scan, GPU machine, CUDA-compatible). Our attention model also performs better than traditional DL (i.e., convolutional neural network models) in detecting poor quality scans. To facilitate faster and more accurate QC prediction for the neuroimaging community, we have shared the model that returned the most reliable global quality scores as a BIDS-app (https://github.com/garciaml/BrainQCNet). © 2024 The Authors. Published under a Creative Commons Attribution 4.0 International (CC BY 4.0) license.
Author Keywords
Deep Learning; interpretable; QC; quality control; structural MRI
Funding details
Trinity College DublinTCD
Irish Research CouncilGOIPG/2021/1508
Irish Research Council
Document Type: Article
Publication Stage: Final
Source: Scopus