Differential impact of lymphatic outflow pathways on cerebrospinal fluid homeostasis
(2025) The Journal of Experimental Medicine, 222 (2), .
Papadopoulos, Z.a b c , Smyth, L.C.D.a b , Smirnov, I.a b , Gibson, D.A.a b , Herz, J.a b , Kipnis, J.a b c
a Brain Immunology and Glia (BIG) Center, Washington University in St. Louis, St. Louis, MO, United States
b Department of Pathology and Immunology, School of Medicine, Washington University in St. Louis, St. Louis, MO, United States
c Neuroscience Graduate Program, School of Medicine, Washington University in St. Louis, St. Louis, MO, United States
Abstract
Dysfunctional lymphatic drainage from the central nervous system (CNS) has been linked to neuroinflammatory and neurodegenerative disorders, but our understanding of the lymphatic contribution to CNS fluid autoregulation remains limited. Here, we studied forces that drive the outflow of the cerebrospinal fluid (CSF) into the deep and superficial cervical lymph nodes (dcLN and scLN) and tested how the blockade of lymphatic networks affects CNS fluid homeostasis. Outflow to the dcLN occurred spontaneously in the absence of lymphatic pumping and was coupled to intracranial pressure (ICP), whereas scLN drainage was driven by pumping. Impaired dcLN drainage led to elevated CSF outflow resistance and delayed CSF-to-blood efflux despite the recruitment of the nasal-to-scLN pathway. Fluid regulation was better compensated after scLN obstruction. The dcLN pathway exhibited steady, consistent drainage across conditions, while the nasal-to-scLN pathway was dynamically activated to mitigate perturbances. These findings highlight the complex physiology of CSF homeostasis and lay the groundwork for future studies aimed at assessing and modulating CNS lymphatic function. © 2025 Papadopoulos et al.
Document Type: Article
Publication Stage: Final
Source: Scopus
Cerebrospinal fluid biomarkers as predictors of multiple sclerosis severity
(2025) Multiple Sclerosis and Related Disorders, 94, art. no. 106268, .
Tolentino, M.a , Pace, F.a , Perantie, D.C.a , Mikesell, R.a , Huecker, J.b , Chahin, S.a , Ghezzi, L.a , Piccio, L.a , Cross, A.H.a
a Department of Neurology, School of Medicine, Washington University in St. Louis, 660 South Euclid Avenue, St Louis, MO 63110, United States
b Center for Biostatistics and Data Science, School of Medicine, Washington University in St. Louis, 660 South Euclid Avenue, St Louis, MO 63110, United States
Abstract
Background: Prognostic biomarkers at multiple sclerosis (MS) onset to predict disease severity may help guide initial therapy selection for people with MS. Over 20 disease-modifying treatments (DMTs) of varying levels of risk and efficacy now exist. The ability to predict MS severity would help to identify those patients at higher risk where a highly effective, but potentially risky, therapy would be optimal. The goal of this project was to determine if cerebrospinal fluid (CSF) soluble markers obtained near time of diagnosis can predict disease severity in people with relapsing remitting MS (RRMS). Methods: We identified 42 RRMS subjects with 4 or more years of clinical follow-up at our center, 8 subjects with other inflammatory neurological diseases (OIND), and 4 subjects with non-inflammatory neurological diseases (NIND) who had donated CSF samples collected for disease diagnosis. This study evaluated soluble CSF biomarkers chosen to reflect neuroinflammation (chemokine ligand 13 – CXCL13), microglia activity (soluble triggering receptor expressed on myeloid cells 2 – sTREM2), demyelination (myelin basic protein –MBP), axon injury and loss (neurofilament light, heavy, and intermediate chains – NFL, NFH, internexin-alpha – INT-α) and neuronal loss (parvalbumin – PVALB) to determine whether any of these CSF factors might predict future MS disease severity. The main outcome measure was MS Severity Score (MSSS), which takes into account disability accumulation (expanded disability status scale – EDSS) and duration of disease. EDSS at last clinical visit was a secondary outcome measure. Univariate and multivariable regression models were used for analysis. Spearman correlations were performed to evaluate correlation between laboratory and clinical variables. Results: Forty-two RRMS patients with mean 9.4 years follow-up since lumbar puncture (LP) contributed data. Higher NFH, NFL, and sTREM2 each predicted worse MSSS using both univariate and multivariable regression models. Older age at the time of LP predicted worse MSSS both in the univariate and multivariable models. NFL correlated with NFH, and both were positively correlated with sTREM2 and CXCL13. In the combined OIND and NIND comparator group, NFH correlated with both NFL and CXCL13. Conclusion: These data support that CSF sTREM2, NFH, and NFL are predictors of MSSS, a measure of MS disease aggressiveness. This study adds to a growing literature implicating microglial activity and axonal injury in MS progression, starting from early stages of the disease. © 2025
Author Keywords
Biomarkers: cerebrospinal fluid; Neurofilament heavy chain; Neurofilament light chain; Soluble TREM2
Document Type: Article
Publication Stage: Final
Source: Scopus
Gene therapy ameliorates bowel dysmotility and enteric neuron degeneration and extends survival in lysosomal storage disorder mouse models
(2025) Science Translational Medicine, 17 (781), art. no. eadj1445, .
Ziółkowska, E.A.a , Jansen, M.J.a , Williams, L.L.a , Wang, S.H.a , Eultgen, E.M.a , Takahashi, K.a , Le, S.Q.a , Nelvagal, H.R.a , Sharma, J.a , Sardiello, M.a , DeBosch, B.J.a , Dickson, P.I.a b , Anderson, J.B.c , Sax, S.E.c , Wright, C.M.c , Bradley, R.P.c , Whiteman, I.T.d e , Makita, T.f , Grider, J.R.g h , Sands, M.S.b i , Heuckeroth, R.O.c , Cooper, J.D.a b j
a Department of Pediatrics, Washington University in St. Louis, School of Medicine, St. Louis, MO 63110, United States
b Department of Genetics, Washington University in St. Louis, School of Medicine, St. Louis, MO 63110, United States
c Children’s Hospital of Philadelphia Research Institute, Perelman School of Medicine, the University of Pennsylvania, Philadelphia, PA 19104, United States
d Batten Disease Support, Research and Advocacy Foundation (US), P.O. Box 30049, Gahanna, OH 43230, United States
e Batten Disease Support and Research Association (Australia), 74 McLachlan Avenue, Shelly BeachNSW 2261, Australia
f Department of Regenerative Medicine and Cell Biology, Medical University of South Carolina, Charleston, SC 29425, United States
g Department of Physiology and Biophysics, Division of Gastroenterology, VCU Program in Enteric Neuromuscular Sciences (VPENS), Virginia Commonwealth University, Richmond, VA 23298, United States
h Department of Medicine, Virginia Commonwealth University, Richmond, VA 23298, United States
i Department of Medicine, Washington University in St. Louis, School of Medicine, St. Louis, MO 63110, United States
j Department of Neurology, Washington University in St. Louis, School of Medicine, St. Louis, MO 63110, United States
Abstract
Children with neurodegenerative disease often have debilitating gastrointestinal symptoms. We hypothesized that this may be due at least in part to underappreciated degeneration of neurons in the enteric nervous system (ENS), the master regulator of bowel function. To test this hypothesis, we evaluated mouse models of neuronal ceroid lipofuscinosis type 1 and 2 (CLN1 and CLN2 disease, respectively), neurodegenerative lysosomal storage disorders caused by deficiencies in palmitoyl protein thioesterase-1 and tripeptidyl peptidase-1, respectively. Both mouse lines displayed slow bowel transit in vivo that worsened with age. Although the ENS appeared to develop normally in these mice, there was a progressive and profound loss of myenteric plexus neurons accompanied by changes in enteric glia in adult mice. Similar pathology was evident in colon autopsy material from a child with CLN1 disease. Neonatal administration of adeno-associated virus–mediated gene therapy prevented bowel transit defects, ameliorated loss of enteric neurons, and extended survival in mice. Treatment after weaning was less effective than treating neonatally but still extended the lifespan of CLN1 disease mice. These data provide proof-of-principle evidence of ENS degeneration in two lysosomal storage diseases and suggest that gene therapy can ameliorate ENS disease, also improving survival. Copyright © 2025 The Authors, some rights reserved.
Document Type: Article
Publication Stage: Final
Source: Scopus
Inhaled xenon modulates microglia and ameliorates disease in mouse models of amyloidosis and tauopathy
(2025) Science Translational Medicine, 17 (781), art. no. eadk3690, .
Brandao, W.a , Jain, N.b c d , Yin, Z.a e , Kleemann, K.L.a f , Carpenter, M.a , Bao, X.b c d , Serrano, J.R.b c d , Tycksen, E.g , Durao, A.a , Barry, J.-L.a , Baufeld, C.a , Guneykaya, D.a , Zhang, X.a , Litvinchuk, A.b c d , Jiang, H.b c d , Rosenzweig, N.a , Pitts, K.M.a e , Aronchik, M.a , Yahya, T.a , Cao, T.a , Takahashi, M.K.a h , Krishnan, R.a , Davtyan, H.i , Ulrich, J.D.b c d , Blurton-Jones, M.i , Ilin, I.j , Weiner, H.L.a k , Holtzman, D.M.b c d , Butovsky, O.a k
a department of neurology, Brigham and Women’s hospital, harvard Medical School, Boston, Ma, United States
b department of neurology, Washington University School of Medicine, Mo, St. louis, United States
c hope center for neurological disorders, Washington University School of Medicine, Mo, St. louis, United States
d Knight alzheimer’s disease research center, Washington University School of Medicine, Mo, St. louis, United States
e department of ophthalmology, Massachusetts eye and ear infirmary, harvard Medical School, Boston, Ma, United States
f institute for clinical chemistry and clinical Pharmacology, University hospital Bonn, Bonn, Germany
g Mcdonnell Genome institute, Genome Technology access center, Washington University School of Medicine, Mo, St. louis, United States
h Faculty of Medicine, University of São Paulo (USP), São Paulo, Brazil
i department of neurobiology and Behavior, University of california, Irvine, CA, United States
j General Biophysics llc, Boston, Ma, United States
k Gene lay institute of immunology and inflammation, Brigham and Women’s hospital, Mass General hospital, harvard Medical School, Boston, Ma, United States
Abstract
Alzheimer’s disease (AD) is the most prevalent neurodegenerative disorder. Antiamyloid antibody treatments modestly slow disease progression in mild dementia due to AD. Emerging evidence shows that homeostatic dysregulation of the brain immune system, especially that orchestrated by microglia, plays an important role in disease onset and progression. Thus, a major question is how to modulate the phenotype and function of microglia to treat AD. Xenon (Xe) gas is a noble gas used in human patients as an anesthetic and a neuroprotectant used for treating brain injuries. Xe penetrates the blood-brain barrier, which could make it an effective therapeutic. To assess the effect of Xe on microglia and AD pathology, we designed a custom Xe inhalation chamber and treated several mouse models of AD with Xe gas. Xe treatment induced mouse microglia to adopt an intermediate activation state that we have termed pre–neurodegenerative microglia (pre-MGnD). This microglial phenotypic transition was observed in mouse models of acute neurodegeneration and amyloidosis (APP/PS1 and 5xFAD mice) and tauopathy (P301S mice). This microglial state enhanced amyloid plaque compaction and reduced dystrophic neurites in the APP/PS1 and 5xFAD mouse models. Moreover, Xe inhalation reduced brain atrophy and neuroinflammation and improved nest-building behavior in P301S mice. Mechanistically, Xe inhalation induced homeostatic brain microglia toward a pre-MGnD state through IFN-γ signaling that maintained the microglial phagocytic response in APP/PS1 and 5xFAD mice while suppressing the microglial proinflammatory phenotype in P301S mice. These results support the translation of Xe inhalation as an approach for treating AD. copyright © 2025 The authors, some rights reserved;
Document Type: Article
Publication Stage: Final
Source: Scopus
Engaging dystonia networks with subthalamic stimulation
(2025) Proceedings of the National Academy of Sciences of the United States of America, 122 (2), art. no. e2417617122, .
Butenko, K.a , Neudorfer, C.a b , Dembek, T.A.c , Hollunder, B.d e f , Meyer, G.M.a , Li, N.d , Oxenford, S.d , Bahners, B.H.a g h , Al-Fatly, B.d , Lofredi, R.d , Gordon, E.M.i , Dosenbach, N.U.F.i j k , Ganos, C.l , Hallett, M.m , Jinnah, H.A.n , Starr, P.A.o , Ostrem, J.L.p , Wu, Y.q , Zhang, C.r , Fox, M.D.a , Horn, A.a b d e
a Center for Brain Circuit Therapeutics, Department of Neurology, Brigham & Women’s Hospital, Harvard Medical School, Boston, MA 02115, United States
b Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, United States
c Department of Neurology, Faculty of Medicine, University of Cologne, Cologne, 50937, Germany
d Movement Disorders and Neuromodulation Unit, Department of Neurology, Charité—Universitätsmedizin Berlin, Berlin, 10117, Germany
e Einstein Center for Neurosciences Berlin, Charité—Universitätsmedizin Berlin, Berlin, 10117, Germany
f Berlin School of Mind and Brain, Humboldt—Universität zu Berlin, Berlin, 10117, Germany
g Institute of Clinical Neuroscience and Medical Psychology, Medical Faculty University Hospital Düsseldorf, Heinrich Heine University, Düsseldorf, 40225, Germany
h Department of Neurology, Center for Movement Disorders and Neuromodulation, Medical Faculty University Hospital Düsseldorf, Heinrich Heine University, Düsseldorf, 40225, Germany
i Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, MO 63110, United States
j Department of Neurology, Washington University School of Medicine, St. Louis, MO 63108, United States
k Department of Biomedical Engineering, Washington University in St. Louis, St. Louis, MO 63130, United States
l Movement Disorder Clinic, Edmond J. Safra Program in Parkinson’s Disease, Division of Neurology, University of Toronto, Toronto Western Hospital, Toronto, ON M5T 2S6, Canada
m Human Motor Control Section, Medical Neurology Branch, National Institute of Neurological Disorders and Stroke, NIH, Bethesda, MD 20892, United States
n Department of Neurology, Emory University, Atlanta, GA 30322, United States
o Department of Neurological Surgery, University of California, San Francisco, CA 94143, United States
p Movement Disorders and Neuromodulation Centre, Department of Neurology, University of California, San Francisco, CA 94143, United States
q Department of Neurology &, Institute of Neurology, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, 200025, China
r Department of Neurosurgery, Rujin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, 200025, China
Abstract
Deep brain stimulation is an efficacious treatment for dystonia. While the internal pallidum serves as the primary target, recently, stimulation of the subthalamic nucleus (STN) has been investigated. However, optimal targeting within this structure and its surroundings have not been studied in depth. Indeed, historical targets that have been used for surgical treatment of dystonia are directly adjacent to the STN. Further, multiple types of dystonia exist, and outcomes are variable, suggesting that not all types would profit maximally from the same target. Therefore, a thorough investigation of neural substrates underlying stimulation effects on dystonia signs and symptoms is warranted. Here, we analyze a multicenter cohort of isolated dystonia patients with subthalamic implantations (N = 58) and relate their stimulation sites to improvements of appendicular and cervical symptoms as well as blepharospasm. Stimulation of the ventral oral posterior nucleus of thalamus and surrounding regions were associated with improvements in cervical dystonia, while stimulation of the dorsolateral STN was associated with improvements in limb dystonia and blepharospasm. This dissociation was matched by structural connectivity analysis, where the cerebellothalamic, corticospinal, and pallidosubthalamic tracts were associated with improvements of cervical dystonia, while hyperdirect and subthalamopallidal pathways with alleviation of limb dystonia and blepharospasm. On the level of functional networks, improvements of limb dystonia were associated with connectivity to the corresponding somatotopic regions in the primary motor cortex, while alleviation of cervical dystonia to the cingulo-opercular network. These findings shed light on the pathophysiology of dystonia and may guide DBS targeting and programming in the future. Copyright © 2025 the Author(s).
Author Keywords
cervical dystonia; deep brain stimulation; limb dystonia; structural connectivity; sweet-spot analysis
Document Type: Article
Publication Stage: Final
Source: Scopus
Control of neurovascular coupling by ATP-sensitive potassium channels
(2025) Journal of Cerebral Blood Flow and Metabolism, .
Bowen, R.M.a b , York, N.W.c d , Padawer-Curry, J.e f , Bauer, A.Q.b f , Lee, J.-M.a b , Nichols, C.G.c d
a Department of Neurology, Washington University in St. Louis, St. Louis, MO, United States
b Department of Biomedical Engineering, Washington University in St. Louis, St. Louis, MO, United States
c Department of Cell Biology and Physiology, Washington University in St. Louis, St. Louis, MO, United States
d Center for the Investigation of Membrane Excitability and Diseases, Washington University in St. Louis, St. Louis, MO, United States
e Imaging Sciences PhD Program, Washington University in St. Louis, St. Louis, MO, United States
f Department of Radiology, Washington University in St. Louis, St. Louis, MO, United States
Abstract
Regional blood flow within the brain is tightly coupled to regional neuronal activity, a process known as neurovascular coupling (NVC). In this study, we demonstrate the striking role of SUR2- and Kir6.1-dependent ATP-sensitive potassium (KATP) channels in control of NVC in the sensory cortex of conscious mice, in response to mechanical stimuli. We demonstrate that either globally increased (pinacidil-activated) or decreased (glibenclamide-inhibited) KATP activity markedly disrupts NVC; pinacidil-activation is capable of completely abolishing stimulus-evoked cortical hemodynamic responses, while glibenclamide slows and reduces the response. The response is similarly slowed and reduced in SUR2 KO animals, while animals expressing gain-of-function (GOF) mutations in Kir6.1, which underlie Cantú syndrome, exhibit baseline reduction of NVC as well as increased sensitivity to pinacidil. In revealing the dramatic effects of either increasing or decreasing SUR2/Kir6.1-dependent KATP activity on NVC, whether pharmacologically or genetically induced, the study has important implications both for monogenic KATP channel diseases and for more common brain pathologies. © The Author(s) 2025.
Author Keywords
ABCC9; Cantú syndrome; KCNJ8; Kir6.1; SUR2
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
Decoding brain structure to stage Alzheimer’s disease pathology in Down syndrome
(2025) Alzheimer’s and Dementia, .
Kennedy, J.T.a , Wisch, J.K.a , Dincer, A.b , Roman, J.a , Gordon, B.A.b c , Handen, B.d , Benzinger, T.L.S.b , Head, E.e f , Mapstone, M.g , Christian, B.T.h i , Tudorascu, D.L.d , Laymon, C.L.j , Hartley, S.L.h k , Lao, P.l m , Brickman, A.M.l m , Zaman, S.H.n , Ances, B.M.a , the ABC-DS and DIAN Consortiao
a Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States
b Department of Radiology, Washington University School of Medicine, St. Louis, MO, United States
c Department of Psychological & Brain Sciences, Washington University, St. Louis, MO, United States
d Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA, United States
e Department of Pathology and Laboratory Medicine, University of California, Medical Sciences D, Irvine, CA, United States
f Department of Neurobiology and Behavior, University of California, Irvine, CA, United States
g Department of Neurology, University of California, Irvine, CA, United States
h Waisman Laboratory for Brain Imaging and Behavior, University of Wisconsin-Madison, Madison, WI, United States
i Department of Medical Physics, University of Wisconsin-Madison, Madison, WI, United States
j Department of Radiology, University of Pittsburgh, Pittsburgh, PA, United States
k Department of Human Development & Family Studies, University of Wisconsin-Madison, Madison, WI, United States
l Department of Neurology, Columbia University, New York, NY, United States
m Gertrude H. Sergievsky Center and Taub Institute for Research on Alzheimer’s Disease and the Aging Brain, Columbia University, New York, NY, United States
n Cambridge Intellectual and Developmental Disabilities Research Group, University of Cambridge, Cambridge, United Kingdom
Abstract
INTRODUCTION: Alzheimer’s disease (AD) in Down syndrome (DS) is associated with changes in brain structure. It is unknown if thickness and volumetric changes can identify AD stages and if they are similar to other genetic forms of AD. METHODS: Magnetic resonance imaging scans were collected for 178 DS adults (106 nonclinical, 45 preclinical, and 27 symptomatic). Cortical thickness and subcortical volumes were compared between DS groups and evaluated as a staging metric using receiver operating characteristic analyses. Thickness patterns were compared to those previously reported in autosomal-dominant AD (ADAD). RESULTS: Decreased parietal and temporal lobe thickness differentiated amyloid positivity (area under the curve [AUC] = 0.83) and impairment (AUC = 0.81), and slightly outperformed subcortical volumes (AUC = 0.8/0.74). Thickness differences in DS were more widespread, severe, and had better discriminative ability than ADAD. DISCUSSION: Cortical thickness can stage AD pathology in DS. Identification of brain regions affected by AD may aid in tracking disease course and evaluating treatment effects. Highlights: DSAD is associated with reduced temporal and parietal cortical thickness. DSAD is associated with smaller hippocampal and striatal volumes. Thickness differences can stage DSAD better than other forms of AD. DSAD thickness differences are more extensive and severe than ADAD. © 2025 The Author(s). Alzheimer’s & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer’s Association.
Author Keywords
Alzheimer’s; amyloid; autosomal dominant Alzheimer’s disease; cognitive impairment; cortical thickness; dementia; Down syndrome; MRI; subcortical volume
Document Type: Article
Publication Stage: Article in Press
Source: Scopus