Synthesis and in vitro evaluation of novel compounds and discovery of a promising iodine-125 radioligand for purinergic P2X7 receptor (P2X7R)
(2025) Bioorganic and Medicinal Chemistry, 118, art. no. 118054, .
Qiu, L.a , Wang, J.a , Tewari, M.b , Rensing, D.T.a , Egan, T.M.b , Perlmutter, J.S.a c , Tu, Z.a
a Department of Radiology, Washington University School of Medicine, St. Louis, MO 63110, United States
b Department of Pharmacology and Physiology, Saint Louis University School of Medicine, St. Louis, MO 63104, United States
c Neurology, Neuroscience, Physical Therapy and Occupational Therapy, Washington University School of Medicine, St. Louis, MO 63110, United States
Abstract
The purinergic P2X ligand-gated ion channel 7 receptor (P2X7R) plays a critical role in various inflammatory processes and other diseases. Fast determination of compounds P2X7R binding potency and discovery of a promise PET radiotracer for imaging P2X7R require a P2X7R suitable radioligand for radioactive competitive binding assay. Herein, we designed and synthesized thirteen new P2X7R ligands and determined the in vitro binding potency. The fluorescence screening assay identified the iodide compound 1c with high potency and specificity toward P2X7R with an IC50 of 0.25 ± 0.05 nM. Therefore, 1c was 125I-labeled to afford [125I]1c with a good radiochemical yield (44 ± 12 %, n = 3) and high radiochemical purity (>95 %). Radioligand saturation binding assay showed that [125I]1c specifically bound to human P2X7R with high affinity (Kd = 1.68 nM and Bmax = 94 fmol/mg). A radioactive high throughput binding assay using [125I]1c for our new compounds demonstrated that the imidazole compounds 1b, 1c, and 1d exhibited high inhibition for >70 %, while the analogues of GSK314181A exhibited low inhibition for <35 %. In addition, our radioligand competitive binding assays using [125I]1c demonstrated that 1b, 1c, and 1d have high potency with IC50 values of 7.91 ± 0.22, 7.06 ± 1.68, and 7.16 ± 0.41 nM toward P2X7R, respectively.Together, compounds 1b, 1c, and 1d are highly potent for P2X7R, and [125I]1c has great potential to be a radioligand for screening P2X7R binding potency of the new compounds and investigating the P2X7R expression in animal models of human disease. © 2024 The Author(s)
Author Keywords
Fluorescence assay; I-125 radiotracer; Purinergic P2X7 receptor; Radioligand competitive binding assay; Radioligand saturation binding assay
Funding details
American Parkinson Disease AssociationAPDA
National Institute of Neurological Disorders and StrokeNINDS
National Institutes of HealthNIH
Foundation for Barnes-Jewish HospitalFBJH
National Institute of Biomedical Imaging and BioengineeringNIBIBEB025815, 1R01GM112188
National Institute on AgingNIANS075527, NS103988, NS061025, NS134586, NS107281
National Institute of Mental HealthNIMHMH092797
Document Type: Article
Publication Stage: Final
Source: Scopus
Factor analysis and clustering of motor and psychiatric dimensions in idiopathic blepharospasm
(2025) Parkinsonism and Related Disorders, 131, art. no. 107241, .
Gigante, A.F.a , Hallett, M.b , Jinnah, H.A.c , Berardelli, A.d e , Perlmutter, J.S.f , Berman, B.D.g , Jankovic, J.h , Bäumer, T.i , Comella, C.j , Ercoli, T.k , Belvisi, D.d , Fox, S.H.l , Kim, H.-J.m , Moukheiber, E.S.n , Richardson, S.P.o , Weissbach, A.p , Muroni, A.q , Defazio, G.e r
a Section of Neurology, San Paolo Hospital, Bari, Italy
b National Institute of Neurological Disorders and Stroke, NIH, Bethesda, United States
c Department of Neurology and Human Genetics, Emory University School of Medicine, Atlanta, GA, United States
d Department of Human Neurosciences, Sapienza University of Rome, Italy
e IRCCS NEUROMED, Pozzilli, Italy
f Department of Neurology, Radiology, Neuroscience, Physical Therapy and Occupational Therapy, Washington University School of Medicine, St Louis, MO, United States
g Department of Neurology, Virginia Commonwealth University, Richmond, VA, United States
h Parkinson’s Disease Center and Movement Disorders Clinic, Department of Neurology, Baylor College of Medicine, Houston, TX, United States
i Institute of Systems Motor Science, University of Lübeck, Germany
j Department of Neurological Sciences, Rush University Medical Center, Chicago, IL, United States
k Department of Medical Sciences and Public Health, University of Cagliari, Italy
l Movement Disorder Clinic, Krembil Brain Institute, University Health Network, Toronto, ON, Canada
m Department of Neurology and Movement Disorder Centre, Seoul National University Hospital, Seoul, South Korea
n Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, United States
o Department of Neurology, University of New Mexico/New Mexico VA Healthcare System, Albuquerque, NM, United States
p Institute of Systems Motor Science and Institute of Neurogenetics, University of Lübeck, Germany
q Neurology Unit, Azienda Ospedaliero-Universitaria of Cagliari, Italy
r Department of Translational Biomedicine and Neuroscience, Aldo Moro University of Bari, Italy
Abstract
Introduction: Idiopathic blepharospasm is a clinically heterogeneous form of focal dystonia, also associated with psychiatric symptoms. The identification of the most relevant sets of motor and psychiatric manifestations may help better understand the specific phenomenology of the condition and delineate blepharospasm subtypes more accurately. Methods: Patients with idiopathic blepharospasm were from the Dystonia Coalition project. Factor analysis of several motor and psychiatric scales was performed to identify the relevant determinants of blepharospasm severity. The selected items were then used in a data-driven cluster analysis to subtype blepharospasm individuals. Results: Factor analysis reduced the many variables in the motor and psychiatric scales to 13 variables distributed in four factors. When the four sets were used as clustering variables, three blepharospasm clusters were identified: cluster 1 was characterized by low levels of motor and psychiatric factors; cluster 2 showed high levels of both motor and psychiatric factors; and cluster 3 showed high levels of psychiatric factors (similar to cluster 2) but low level of motor factors (similar to that of cluster 1). Conclusions: Factor analysis enabled the identification of key motor and psychiatric determinants of blepharospasm severity. The derived factor sets provide a streamlined tool for predicting and measuring these dimensions. This approach also facilitated more precise cluster analysis and improved recognition of clinical subtypes. © 2024 Elsevier Ltd
Document Type: Article
Publication Stage: Final
Source: Scopus
Diffusion MRI Metrics Characterize Postoperative Clinical Outcomes After Surgery for Cervical Spondylotic Myelopathy
(2025) Neurosurgery, 96 (1), pp. 69-77.
Zhang, J.K.a b , Javeed, S.a , Greenberg, J.K.a , Yakdan, S.a , Kaleem, M.I.a , Botterbush, K.S.a , Benedict, B.a , Dibble, C.F.a , Sun, P.c , Sherrod, B.b , Dailey, A.T.b , Bisson, E.F.b , Mahan, M.b , Mazur, M.b , Song, S.-K.a , Ray, W.Z.a
a Department of Neurological Surgery, Washington University School of Medicine, Saint Louis , Missouri , USA
b Department of Neurological Surgery, University of Utah, Salt Lake City, UT, United States
c Department of Imaging Physics, UT MD Anderson Cancer Center, Houston, TX, United States
Abstract
BACKGROUND AND OBJECTIVES: Advanced diffusion-weighted MRI (DWI) modeling, such as diffusion tensor imaging (DTI) and diffusion basis spectrum imaging (DBSI), may help guide rehabilitation strategies after surgical decompression for cervical spondylotic myelopathy (CSM). Currently, however, postoperative DWI is difficult to interpret, owing to signal distortions from spinal instrumentation. Therefore, we examined the relationship between postoperative DTI/DBSI-extracted from the rostral C3 spinal level-and clinical outcome measures at 2-year follow-up after decompressive surgery for CSM. METHODS: Fifty patients with CSM underwent complete clinical and DWI evaluation-followed by DTI/DBSI analysis-at baseline and 2-year follow-up. Clinical outcomes included the modified Japanese Orthopedic Association score and comprehensive patient-reported outcomes. DTI metrics included apparent diffusion coefficient, fractional anisotropy, axial diffusivity, and radial diffusivity. DBSI metrics evaluated white matter tracts through fractional anisotropy, fiber fraction, axial diffusivity, and radial diffusivity as well as extra-axonal pathology through restricted and nonrestricted fraction. Cross-sectional Spearman’s correlations were used to compare postoperative DTI/DBSI metrics with clinical outcomes. RESULTS: Twenty-seven patients with CSM, including 15, 7, and 5 with mild, moderate, and severe disease, respectively, possessed complete baseline and postoperative DWI scans. At 2-year follow-up, there were 10 significant correlations among postoperative DBSI metrics and postoperative clinical outcomes compared with 3 among postoperative DTI metrics. Of the 13 significant correlations, 7 involved the neck disability index (NDI). The strongest relationships were between DBSI axial diffusivity and NDI (r = 0.60, P < .001), DBSI fiber fraction and NDI (r s = -0.58, P < .001), and DBSI restricted fraction and NDI (r s = 0.56, P < .001). The weakest correlation was between DTI apparent diffusion coefficient and NDI (r = 0.35, P = .02). CONCLUSION: Quantitative measures of spinal cord microstructure after surgery correlate with postoperative neurofunctional status, quality of life, and pain/disability at 2 years after decompressive surgery for CSM. In particular, DBSI metrics may serve as meaningful biomarkers for postoperative disease severity for patients with CSM. Copyright © Congress of Neurological Surgeons 2024. All rights reserved.
Document Type: Article
Publication Stage: Final
Source: Scopus
Longitudinal cognitive performance of participants with sporadic early onset Alzheimer’s disease from LEADS
(2024) Alzheimer’s and Dementia, .
Hammers, D.B.ab , Eloyan, A.a , Taurone, A.a , Thangarajah, M.a , Gao, S.b , Beckett, L.c , Polsinelli, A.J.ab , Kirby, K.ab , Dage, J.L.ab , Nudelman, K.d , Aisen, P.e , Reman, R.e , La Joie, R.f , Lagarde, J.f , Atri, A.g , Clark, D.ab , Day, G.S.h , Duara, R.i , Graff-Radford, N.R.h , Grant, I.j , Honig, L.S.k , Johnson, E.C.B.l , Jones, D.T.m , Masdeu, J.C.n , Mendez, M.F.o , Womack, K.p , Musiek, E.p , Onyike, C.U.q , Riddle, M.r , Rogalski, E.s , Salloway, S.r , Sha, S.J.t , Turner, R.S.u , Wingo, T.S.v , Wolk, D.A.w , Carrillo, M.C.x , Rabinovici, G.D.f y , Dickerson, B.C.z , Apostolova, L.G.d ab aa ab , the LEADS Consortiumab
a Department of Biostatistics, Center for Statistical Sciences, Brown University, Providence, RI, United States
b Department of Biostatistics, Indiana University School of Medicine, Indianapolis, IN, United States
c Department of Public Health Sciences, University of California – Davis, Davis, CA, United States
d Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, United States
e Alzheimer’s Therapeutic Research Institute, University of Southern California, San Diego, CA, United States
f Department of Neurology, University of California – San Francisco, San Francisco, CA, United States
g Banner Sun Health Research Institute, Sun City, AZ, United States
h Department of Neurology, Mayo Clinic, Jacksonville, FL, United States
i Wien Center for Alzheimer’s Disease and Memory Disorders, Mount Sinai Medical Center, Miami, FL, United States
j Department of Psychiatry and Behavioral Sciences, Mesulam Center for Cognitive Neurology and Alzheimer’s Disease, Feinberg School of Medicine, Northwestern University, Chicago, IL, United States
k Taub Institute and Department of Neurology, Columbia University Irving Medical Center, New York, NY, United States
l Department of Neurology and Human Genetics, Emory University School of Medicine, Atlanta, GA, United States
m Department of Neurology, Mayo Clinic, Rochester, MN, United States
n Nantz National Alzheimer Center, Houston Methodist and Weill Cornell Medicine, Houston, TX, United States
o Department of Neurology, David Geffen School of Medicine at UCLA, Los Angeles, CA, United States
p Department of Neurology, Washington University in St. Louis, St. Louis, MO, United States
q Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, United States
r Department of Neurology, Alpert Medical School, Brown University, Providence, RI, United States
s Healthy Aging & Alzheimer’s Research Care Center, Department of Neurology, University of Chicago, Chicago, IL, United States
t Department of Neurology & Neurological Sciences, Stanford University, Palo Alto, CA, United States
u Department of Neurology, Georgetown University, Washington, DC, United States
v Department of Neurology, UC Davis Alzheimer’s Disease Research Center, University of California – Davis, Davis, CA, United States
w Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States
x Medical & Scientific Relations Division, Alzheimer’s Association, Chicago, IL, United States
y Department of Radiology & Biomedical Imaging, University of California – San Francisco, San Francisco, CA, United States
z Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, United States
aa Department of Radiology and Imaging Sciences, Center for Neuroimaging, Indiana University School of Medicine Indianapolis, Indianapolis, IN, United States
ab Department of Neurology, Indiana University School of Medicine, Indianapolis, IN, United States
Abstract
INTRODUCTION: Early-onset Alzheimer’s disease (EOAD) manifests prior to the age of 65, and affects 4%–8% of patients with Alzheimer’s disease (AD). The current analyses sought to examine longitudinal cognitive trajectories of participants with early-onset dementia. METHODS: Data from 307 cognitively normal (CN) volunteer participants and those with amyloid-positive EOAD or amyloid-negative cognitive impairment (EOnonAD) were compared. Cognitive trajectories across a comprehensive cognitive battery spanning 42 months were examined using mixed-effects modeling. RESULTS: The EOAD group displayed worse cognition at baseline relative to EOnonAD and CN groups, and more aggressive declines in cognition over time. The largest effects were observed on measures of executive functioning domains, while memory declines were blunted in EOAD. DISCUSSION: EOAD declined 2–4× faster than EOnonAD, and EOAD pathology is not restricted to memory networks. Early identification of deficits is critical to ensure that individuals with sporadic EOAD can be considered for treatment using disease-modifying medications. Highlights: Represents the most comprehensive longitudinal characterization of sporadic EOAD to date. The trajectory of cognitive declines was steep for EOAD participants and worse than for other groups. Executive functioning measures exhibited the greatest declines over time in EOAD. © 2024 The Author(s). Alzheimer’s & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer’s Association.
Author Keywords
Alzheimer’s disease; amnestic; atypical variant; early-onset; longitudinal
Funding details
Fondation pour la Recherche sur Alzheimer
National Institute on AgingNIAU01 AG016976, P50 AG005146, P50 AG008702, P30 AG010124, P50 AG005681, P30 AG062422, U01AG6057195, P50AG047366, U24AG021886, P30 AG010133, P30AG066506, P50 AG025688, P30 AG062421, P30 AG013854, K23AG080071, R56 AG057195, P50 AG023501
National Institute on AgingNIA
Alzheimer’s AssociationAALDRFP‐21‐818464, AARG‐22‐926940
Alzheimer’s AssociationAA
Document Type: Article
Publication Stage: Article in Press
Source: Scopus