List of publications for the week of September 20, 2021
Is comprehensiveness critical? Comparing short and long format cognitive assessments in preclinical Alzheimer disease
(2021) Alzheimer’s Research and Therapy, 13 (1), art. no. 153, .
Hassenstab, J.a b , Nicosia, J.a , LaRose, M.a , Aschenbrenner, A.J.a , Gordon, B.A.b c , Benzinger, T.L.S.c , Xiong, C.a d , Morris, J.C.a
a Charles F. and Joanne Knight Alzheimer Disease Research Center, Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States
b Department of Psychological & Brain Sciences, Washington University in St. Louis, St. Louis, MO, United States
c Department of Radiology, Washington University School of Medicine, St. Louis, MO, United States
d Division of Biostatistics, Washington University School of Medicine, St. Louis, MO, United States
Abstract
Background: Comprehensive testing of cognitive functioning is standard practice in studies of Alzheimer disease (AD). Short-form tests like the Montreal Cognitive Assessment (MoCA) use a “sampling” of measures, administering key items in a shortened format to efficiently assess cognition while reducing time requirements, participant burden, and administrative costs. We compared the MoCA to a commonly used long-form cognitive battery in predicting AD symptom onset and sensitivity to AD neuroimaging biomarkers. Methods: Survival, area under the receiver operating characteristic (ROC) curve (AUC), and multiple regression analyses compared the MoCA and long-form measures in predicting time to symptom onset in cognitively normal older adults (n = 6230) from the National Alzheimer’s Coordinating Center (NACC) cohort who had, on average, 2.3 ± 1.2 annual assessments. Multiple regression models in a separate sample (n = 416) from the Charles F. and Joanne Knight Alzheimer Disease Research Center (Knight ADRC) compared the sensitivity of the MoCA and long-form measures to neuroimaging biomarkers including amyloid PET, tau PET, and cortical thickness. Results: Hazard ratios suggested that both the MoCA and the long-form measures are similarly and modestly efficacious in predicting symptomatic conversion, although model comparison analyses indicated that the long-form measures slightly outperformed the MoCA (HRs > 1.57). AUC analyses indicated no difference between the measures in predicting conversion (DeLong’s test, Z = 1.48, p = 0.13). Sensitivity to AD neuroimaging biomarkers was similar for the two measures though there were only modest associations with tau PET (rs = − 0.13, ps < 0.02) and cortical thickness in cognitively normal participants (rs = 0.15–0.16, ps < 0.007). Conclusions: Both test formats showed weak associations with symptom onset, AUC analyses indicated low diagnostic accuracy, and biomarker correlations were modest in cognitively normal participants. Alternative assessment approaches are needed to improve how clinicians and researchers monitor cognitive changes and disease progression prior to symptom onset. © 2021, The Author(s).
Author Keywords
Alzheimer disease; Cognitive assessment; Cognitive decline
Funding details
National Institutes of HealthNIHP30 AG008017, P30 AG008051, P30 AG010124, P30 AG010129, P30 AG010133, P30 AG010161, P30 AG012300, P30 AG013846, P30 AG013854, P30 AG019610, P30 AG028383, P30 AG035982, P30 AG049638, P30 AG053760, P50 AG005131, P50 AG005133, P50 AG005134, P50 AG005136, P50 AG005138, P50 AG005142, P50 AG005146, P50 AG008702, P50 AG016573, P50 AG016574, P50 AG023501, P50 AG025688, P50 AG033514, P50 AG047266, P50 AG047270, P50 AG047366, U24 AG072122
National Institute on AgingNIAK01AG053474, P01AG026276, P01AG03991, P30AG066444
Document Type: Article
Publication Stage: Final
Source: Scopus
Neuropathology of blepharospasm
(2021) Experimental Neurology, 346, art. no. 113855, .
Fagan, M.a , Scorr, L.a , Bernhardt, D.a , Hess, E.J.b , Perlmutter, J.S.c , Pardo, C.A.d , Jinnah, H.A.e
a Department of Neurology, Emory University, Atlanta, GA, United States
b Departments of Pharmacology and Neurology, Emory University, Atlanta, GA, United States
c Departments of Neurology, Radiology, Neuroscience, Physical Therapy and Occupational Therapy, Washington University in St. LouisMO, United States
d Departments of Neurology and Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, United States
e Departments of Neurology, Human Genetics and Pediatrics, Emory University, Atlanta, GA, United States
Abstract
Background: The dystonias are a group of disorders characterized by excessive muscle contractions leading to abnormal repetitive movements or postures. In blepharospasm, the face is affected, leading to excessive eye blinking and spasms of muscles around the eyes. The pathogenesis of blepharospasm is not well understood, but several imaging studies have implied subtle structural defects in several brain regions, including the cerebellum. Objective: To delineate cerebellar pathology in brains collected at autopsy from 7 human subjects with blepharospasm and 9 matched controls. Methods: Sections from 3 cerebellar regions were sampled and processed using Nissl and silver impregnation stains. Purkinje neurons were the focus of the evaluation, along with as several other subtle pathological features of cerebellar dysfunction such as Purkinje neuron axonal swellings (torpedo bodies), proliferation of basket cell processes around Purkinje neurons (hairy baskets), empty baskets (missing Purkinje neurons), and displacement of cell soma from their usual location (ectopic Purkinje neurons). Results: The results revealed a significant reduction in Purkinje neuron and torpedo body density, but no changes in any of the other measures. Conclusions: These findings demonstrate subtle neuropathological changes similar to those reported for subjects with cervical dystonia. These findings may underly some of the subtle imaging changes reported for blepharospasm. © 2021 Elsevier Inc.
Funding details
National Institutes of HealthNIH
National Institute on AgingNIANS075321
National Institute of Neurological Disorders and StrokeNINDSNS119831
National Center for Advancing Translational SciencesNCATS
American Parkinson Disease AssociationAPDA
Alzheimer’s Disease Research Center, Emory UniversityADRC
Washington University in St. LouisWUSTL
Foundation for Barnes-Jewish Hospital
Benign Essential Blepharospasm Research FoundationBEBRF
Dystonia CoalitionNS065701, NS116025, TR001456
Document Type: Article
Publication Stage: Final
Source: Scopus
Bcl6 controls meningeal Th17-B cell interaction in murine neuroinflammation
(2021) Proceedings of the National Academy of Sciences of the United States of America, 118 (36), art. no. e2023174118, .
Hartlehnert, M.a , Börsch, A.-L.a , Li, X.a , Burmeister, M.b c , Gerwien, H.b c , Schafflick, D.a , Heming, M.a , Lu, I.-N.a , Narayanan, V.a , Strecker, J.-K.a , Kolz, A.d , Peters, A.d e , Wu, G.F.f , Wiendl, H.a c , Sorokin, L.b c , zu Horste, G.M.a
a Department of Neurology, Institute of Translational Neurology, University Hospital Münster, Münster, 48149, Germany
b Institute of Physiological Chemistry and Pathobiochemistry, University of Münster, Münster, 48149, Germany
c Cells in Motion Interfaculty Centre, University of Münster, Münster, 48149, Germany
d Institute of Clinical Neuroimmunology, University Hospital, Ludwig-Maximilians University Munich, Munich, 81377, Germany
e Biomedical Center, Faculty of Medicine, Ludwig-Maximilians University Munich, Munich, 81377, Germany
f Department of Neurology, Washington University in St. Louis, St. Louis, MO 63108, United States
Abstract
Ectopic lymphoid tissue containing B cells forms in the meninges at late stages of human multiple sclerosis (MS) and when neuroinflammation is induced by interleukin (IL)-17 producing T helper (Th17) cells in rodents. B cell differentiation and the subsequent release of class-switched immunoglobulins have been speculated to occur in the meninges, but the exact cellular composition and underlying mechanisms of meningeal-dominated inflammation remain unknown. Here, we performed in-depth characterization of meningeal versus parenchymal Th17-induced rodent neuroinflammation. The most pronounced cellular and transcriptional differences between these compartments was the localization of B cells exhibiting a follicular phenotype exclusively to the meninges. Correspondingly, meningeal but not parenchymal Th17 cells acquired a B cell-supporting phenotype and resided in close contact with B cells. This preferential B cell tropism for the meninges and the formation of meningeal ectopic lymphoid tissue was partially dependent on the expression of the transcription factor Bcl6 in Th17 cells that is required in other T cell lineages to induce isotype class switching in B cells. A function of Bcl6 in Th17 cells was only detected in vivo and was reflected by the induction of B cell-supporting cytokines, the appearance of follicular B cells in the meninges, and of immunoglobulin class switching in the cerebrospinal fluid. We thus identify the induction of a B cell-supporting meningeal microenvironment by Bcl6 in Th17 cells as a mechanism controlling compartment specificity in neuroinflammation. © 2021 National Academy of Sciences. All rights reserved.
Author Keywords
Bcl6; CNS meninges; Ectopic lymphoid tissue; Single-cell RNA-seq; Th17
Funding details
MzH3/020/20, SEED/016/21
PE2681/1-1, RG-1802-30253
National Institutes of HealthNIHR01 NS106289
National Multiple Sclerosis Society
Deutsche ForschungsgemeinschaftDFGE-Rare-3, EXC1009, ME4050/12-1, ME4050/13-1, ME4050/4-1, ME4050/8-1, SFB1009 A02, TR128 B03
Ministerium für Innovation, Wissenschaft und Forschung des Landes Nordrhein-WestfalenMIWF-NRW
Document Type: Article
Publication Stage: Final
Source: Scopus
Lumbar Puncture for Diagnosis of Idiopathic Intracranial Hypertension in Typical Patients
(2021) Journal of Neuro-Ophthalmology: The Official Journal of the North American Neuro-Ophthalmology Society, 41 (3), pp. 375-378.
Margolis, M.S., DeBusk, A.A., Moster, M.L., Falardeau, J.M., Eggenberger, E.R., Sergott, R.C., Van Stavern, G.P.
Department of Ophthalmology and Visual Sciences (MSM), Illinois Eye and Ear Infirmary, University of Illinois at Chicago, Chicago, Illinois; Department of Ophthalmology and Visual Sciences (GVS), Washington University School of Medicine, St. Louis, Missouri; Department of Neuro-Ophthalmology (AD, MLM, RCS), Wills Eye Hospital; Department of Ophthalmology (JF), Oregon Health and Science University; and Department of Neurology (EE), Mayo Clinic, Jacksonville, Florida
Abstract
BACKGROUND: Patients with typical features of pseudotumor cerebri syndrome (PTCS) must undergo lumbar puncture (LP) to demonstrate elevated opening pressure and cerebrospinal fluid (CSF) analysis to rule out alternative diagnoses. As LP may be associated with significant morbidity, this study aims to determine its necessity in diagnosing typical PTCS. METHODS: Retrospective chart review at 3 university-based neuro-ophthalmology practices included women aged 18-45 years with body mass index >25, papilledema, negative neuroimaging, and who met criteria for PTCS or probable PTCS. RESULTS: One hundred fifty-six patients were enrolled. Seven (4.5%) had clinically insignificant CSF abnormalities. No diagnoses or management changed based on LP/CSF results. CONCLUSION: LP may not be routinely required in the initial evaluation of typical patients with PTCS evaluated by experienced clinicians We caution, however, that further prospective study is required to determine potential risks and benefits of LP as a tool in the diagnosis of IIH before recommending general practice changes. Copyright © 2021 by North American Neuro-Ophthalmology Society.
Document Type: Article
Publication Stage: Final
Source: Scopus
Pharmacophore-Based Design of Phenyl-[hydroxycyclohexyl] Cycloalkyl-Carboxamide Mitofusin Activators with Improved Neuronal Activity
(2021) Journal of Medicinal Chemistry, .
Dang, X.a b , Williams, S.B.c , Devanathan, S.c , Franco, A.b , Fu, L.d , Bernstein, P.R.e , Walters, D.f , Dorn, G.W.b c
a Department of Cardiology, The First Affiliated Hospital of xi’An Jiao Tong University, Shaanxi, Xi’an, 710061, China
b Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO 63110, United States
c Mitochondria in Motion, Inc., 4340 Duncan Avenue, Suite 216, St. Louis, MO 63110, United States
d WuXi AppTec Co., Ltd., 666 Gaoxin Road, East Lake High-tech Development Zone, Hubei, Wuhan, 430075, China
e PharmaB LLC, 50 S. 16th Street, Unit 5201, Philadelphia, PA 19102, United States
f Crystal Pharmatech Inc., 3000 Eastpark Blvd., Ste 500B, Cranbury, NJ 08512, United States
Abstract
Mitochondrial fragmentation from defective fusion or unopposed fission contributes to many neurodegenerative diseases. Small molecule mitofusin activators reverse mitochondrial fragmentation in vitro, promising a novel therapeutic approach. The first-in-class mitofusin activator, 2, has a short plasma t1/2 and limited neurological system bioavailability, conferring “burst activation”. Here, pharmacophore-based rational redesign generated analogues of 2 incorporating cycloalkyl linker groups. A cyclopropyl-containing linker, 5, improved plasma and brain t1/2, increased nervous system bioavailability, and prolonged neuron pharmacodynamic effects. Functional and single-crystal X-ray diffraction studies of stereoisomeric analogues of 5 containing sulfur as a “heavy atom”, 14A and 14B, showed that 5 biological activity resides in the trans-R/R configuration, 5B. Structural analysis revealed stereoselective interactions of 5 associated with its mimicry of MFN2 Val372, Met376, and His380 side chains. Modification of murine ALS phenotypes in vitro and in vivo supports advancement of 5B for neurological conditions that may benefit from sustained mitofusin activation. © 2021 American Chemical Society.
Funding details
National Institutes of HealthNIH628906, R35135736, R41NS113642, R41NS115184
Muscular Dystrophy AssociationMDA
China Scholarship CouncilCSC
Document Type: Article
Publication Stage: Article in Press
Source: Scopus