List of publications for week of May 9, 2022
Cardiac and pulmonary findings in dysferlinopathy: A 3-year, longitudinal study
(2022) Muscle & Nerve, 65 (5), pp. 531-540.
Moore, U.a , Fernandez-Torron, R.a b , Jacobs, M.c d , Gordish-Dressman, H.c d , Diaz-Manera, J.e f , James, M.K.a , Mayhew, A.G.a , Harris, E.a , Guglieri, M.a , Rufibach, L.E.g , Feng, J.c , Blamire, A.M.h , Carlier, P.G.i , Spuler, S.j , Day, J.W.k , Jones, K.J.l , Bharucha-Goebel, D.X.m n , Salort-Campana, E.o , Pestronk, A.p , Walter, M.C.q , Paradas, C.r , Stojkovic, T.s , Mori-Yoshimura, M.t , Bravver, E.u , Pegoraro, E.v , Lowes, L.P.w , Mendell, J.R.w , Bushby, K.a , Bourke, J.x , Straub, V.a , Jain COS Consortiumy
a John Walton Muscular Dystrophy Research Centre, Translational and Clinical Research Institute, Newcastle University and Newcastle Hospitals NHS Foundation Trust, Newcastle upon Tyne, United Kingdom
b Neurology Department, Biodonostia Health Research Institute, Neuromuscular Area, Hospital Donostia, Basque Health Service, Donostia-San Sebastian, Spain
c Center for Translational Science, Division of Biostatistics and Study Methodology, Children’s National Health System, Washington, District of Columbia, USA
d Pediatrics, Epidemiology and Biostatistics, George Washington University, Washington, District of Columbia, USA
e Centro de Investigación Biomédica en Red en Enfermedades Raras (CIBERER), Barcelona, Spain
f Neuromuscular Disorders Unit, Neurology Department, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain
g Jain Foundation, Seattle, WA, United States
h Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, United Kingdom
i University Paris-Saclay, CEA, DRF, Service Hospitalier Frederic Joliot, Orsay, France
j Charite Muscle Research Unit, Experimental and Clinical Research Center, joint cooperation of the Charité Medical Faculty and the Max Delbrück Center for Molecular MedicineBerlin, Germany
k Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, United States
l Children’s Hospital at Westmead, The University of Sydney, WestmeadNSW, Australia
m Department of Neurology Children’s National Health System, Washington, District of Columbia, USA
n National Institutes of Health (NINDS), Bethesda, MD, United States
o Service des maladies neuromusculaire et de la SLA, Hôpital de La Timone, Marseille, France
p Department of Neurology Washington University School of Medicine, St. Louis, MO, United States
q Friedrich-Baur-Institute, Department of Neurology, Ludwig-Maximilians-University of Munich, Munich, Germany
r Neuromuscular Unit, Department of Neurology, Hospital U. Virgen del Rocío/Instituto de Biomedicina de Sevilla, Seville, Spain
s Centre de référence des maladies neuromusculaires, Institut de Myologie, AP-HP, Sorbonne Université, Hôpital Pitié-Salpêtrière, Paris, France
t Department of Neurology, National Center Hospital, National Center of Neurology and PsychiatryTokyo, Japan
u Neuroscience Institute, Carolinas Neuromuscular/ALS-MDA Center, Carolinas HealthCare System, Charlotte, North Carolina, USA
v Department of Neuroscience, University of Padova, Padua, Italy
w Abigail Wexner Research Institute at Nationwide Children’s Hospital, Columbus, OH, United States
x Department of Cardiology, Freeman Hospital, NUTH NHS Hospitals Foundation Trust, Newcastle upon Tyne, United Kingdom
Abstract
INTRODUCTION/AIMS: There is debate about whether and to what extent either respiratory or cardiac dysfunction occurs in patients with dysferlinopathy. This study aimed to establish definitively whether dysfunction in either system is part of the dysferlinopathy phenotype. METHODS: As part of the Jain Foundation’s International Clinical Outcome Study (COS) for dysferlinopathy, objective measures of respiratory and cardiac function were collected twice, with a 3-y interval between tests, in 188 genetically confirmed patients aged 11-86 y (53% female). Measures included forced vital capacity (FVC), electrocardiogram (ECG), and echocardiogram (echo). RESULTS: Mean FVC was 90% predicted at baseline, decreasing to 88% at year 3. FVC was less than 80% predicted in 44 patients (24%) at baseline and 48 patients (30%) by year 3, including ambulant participants. ECGs showed P-wave abnormalities indicative of delayed trans-atrial conduction in 58% of patients at baseline, representing a risk for developing atrial flutter or fibrillation. The prevalence of impaired left ventricular function or hypertrophy was comparable to that in the general population. DISCUSSION: These results demonstrate clinically significant respiratory impairment and abnormal atrial conduction in some patients with dysferlinopathy. Therefore, we recommend that annual or biannual follow-up should include FVC measurement, enquiry about arrhythmia symptoms and peripheral pulse palpation to assess cardiac rhythm. However, periodic specialist cardiac review is probably not warranted unless prompted by symptoms or abnormal pulse findings. © 2022 The Authors. Muscle & Nerve published by Wiley Periodicals LLC.
Author Keywords
cardiac; dysferlin; limb girdle muscular dystrophy R2; Miyoshi myopathy; respiratory
Document Type: Article
Publication Stage: Final
Source: Scopus
Circadian pacemaker neurons display cophasic rhythms in basal calcium level and in fast calcium fluctuations
(2022) Proceedings of the National Academy of Sciences of the United States of America, 119 (17), pp. e2109969119.
Liang, X., Holy, T.E., Taghert, P.H.
Department of Neuroscience, Washington University in St. Louis, St. Louis, MO 63110
Abstract
SignificanceDaily rhythms in the molecular clock, in calcium, and in electrical activity all interact to support the functions of circadian pacemaker neurons. However, the regulatory mechanisms that unify these properties are not defined. Here, we utilize the cellular resolution of the Drosophila circadian neural circuit with technological improvements in light-sheet imaging. We report that individual Drosophila pacemakers display two cophasic rhythms of daily calcium fluctuations. We previously described the first: slow changes in intracellular calcium. The second involves high-frequency calcium fluctuations that depend on the function of the T-type calcium channel. We propose that the fast rhythms, emerging sequentially across the 24-h day, correspond to spontaneous electrical activity patterns displayed by different pacemaker groups.
Author Keywords
calcium; circadian rhythms; Drosophila; ITPR; T-type calcium channel
Document Type: Article
Publication Stage: Final
Source: Scopus
Inhibition of the enzyme autotaxin reduces cortical excitability and ameliorates the outcome in stroke
(2022) Science Translational Medicine, 14 (641), p. eabk0135.
Bitar, L.a , Uphaus, T.a , Thalman, C.a , Muthuraman, M.a , Gyr, L.b , Ji, H.a c , Domingues, M.a , Endle, H.a c , Groppa, S.a , Steffen, F.a , Koirala, N.a , Fan, W.d , Ibanez, L.e , Heitsch, L.f , Cruchaga, C.e , Lee, J.-M.g , Kloss, F.b , Bittner, S.a , Nitsch, R.h , Zipp, F.a , Vogt, J.a c
a Department of Neurology, Focus Program Translational Neuroscience (FTN) and Immunotherapy (FZI), Rhine Main Neuroscience Network (rmn2), University Medical Center of the Johannes Gutenberg University Mainz, Mainz, 55131, Germany
b Transfer Group Anti-Infectives, Leibniz Institute for Natural Product Research and Infection Biology, Hans Knoell Institute, Jena, 07745, Germany
c Department of Molecular and Translational Neuroscience, Cologne Excellence Cluster for Stress Responses in Aging-Associated Diseases (CECAD), Center for Molecular Medicine Cologne (CMMC), University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne, 50937, Germany
d Focus Program Translational Neuroscience (FTN), University Medical Center of the Johannes Gutenberg University Mainz, Mainz, 55131, Germany
e Department of Psychiatry, Department of Neurology, NeuroGenomics and Informatics Center, Washington University School of Medicine, St. Louis, MO 63110, USA
f Department of Emergency Medicine, Department of Neurology, Washington University School of Medicine, St. Louis, MO 63110, USA
g Department of Neurology, Radiology, and Biomedical Engineering, Washington University School of Medicine, St. Louis, MO 63110, USA
h Institute of Translational Neuroscience, Westfälische Wilhelms-Universität Münster48149 Münster, Germany
Abstract
Stroke penumbra injury caused by excess glutamate is an important factor in determining stroke outcome; however, several therapeutic approaches aiming to rescue the penumbra have failed, likely due to unspecific targeting and persistent excitotoxicity, which continued far beyond the primary stroke event. Synaptic lipid signaling can modulate glutamatergic transmission via presynaptic lysophosphatidic acid (LPA) 2 receptors modulated by the LPA-synthesizing molecule autotaxin (ATX) present in astrocytic perisynaptic processes. Here, we detected long-lasting increases in brain ATX concentrations after experimental stroke. In humans, cerebrospinal fluid ATX concentration was increased up to 14 days after stroke. Using astrocyte-specific deletion and pharmacological inhibition of ATX at different time points after experimental stroke, we showed that inhibition of LPA-related cortical excitability improved stroke outcome. In transgenic mice and in individuals expressing a single-nucleotide polymorphism that increased LPA-related glutamatergic transmission, we found dysregulated synaptic LPA signaling and subsequent negative stroke outcome. Moreover, ATX inhibition in the animal model ameliorated stroke outcome, suggesting that this approach might have translational potential for improving the outcome after stroke.
Document Type: Article
Publication Stage: Final
Source: Scopus
Plasma Neurofilament Light Chain Levels Are Elevated in Children and Young Adults With Wolfram Syndrome
(2022) Frontiers in Neuroscience, 16, art. no. 795317, .
Eisenstein, S.A.a b , Boodram, R.S.a k , Sutphen, C.L.c l , Lugar, H.M.a , Gordon, B.A.b d , Marshall, B.A.e f , Urano, F.g h i , Fagan, A.M.c d j , Hershey, T.a b c
a Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, United States
b Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, MO, United States
c Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States
d Alzheimer’s Disease Research Center, Washington University School of Medicine, St. Louis, MO, United States
e Department of Pediatrics, Washington University School of Medicine, St. Louis, MO, United States
f Department of Cell Biology, Washington University School of Medicine, St. Louis, MO, United States
g Department of Medicine, Washington University School of Medicine, St. Louis, MO, United States
h Division of Endocrinology, Metabolism and Lipid Research, Washington University School of Medicine, St. Louis, MO, United States
i Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, United States
j Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO, United States
k University of Missouri–Columbia, School of Medicine, Columbia, MO, United States
l Wake Forest School of Medicine, Winston-Salem, NC, United States
Abstract
Wolfram syndrome is a rare disease caused by pathogenic variants in the WFS1 gene with progressive neurodegeneration. As an easily accessible biomarker of progression of neurodegeneration has not yet been found, accurate tracking of the neurodegenerative process over time requires assessment by costly and time-consuming clinical measures and brain magnetic resonance imaging (MRI). A blood-based measure of neurodegeneration, neurofilament light chain (NfL), is relatively inexpensive and can be repeatedly measured at remote sites, standardized, and measured in individuals with MRI contraindications. To determine whether NfL levels may be of use in disease monitoring and reflect disease activity in Wolfram syndrome, plasma NfL levels were compared between children and young adults with Wolfram syndrome (n = 38) and controls composed of their siblings and parents (n = 35) and related to clinical severity and selected brain region volumes within the Wolfram group. NfL levels were higher in the Wolfram group [median (interquartile range) NfL = 11.3 (7.8–13.9) pg/mL] relative to controls [5.6 (4.5–7.4) pg/mL]. Within the Wolfram group, higher NfL levels related to worse visual acuity, color vision and smell identification, smaller brainstem and thalamic volumes, and faster annual rate of decrease in thalamic volume over time. Our findings suggest that plasma NfL levels can be a powerful tool to non-invasively assess underlying neurodegenerative processes in children, adolescents and young adults with Wolfram syndrome. Copyright © 2022 Eisenstein, Boodram, Sutphen, Lugar, Gordon, Marshall, Urano, Fagan and Hershey.
Author Keywords
axonal injury; neurodegeneration; neurofilament light chain; thalamus; WFS1 gene; Wolfram syndrome
Funding details
National Institutes of HealthNIHK01 AG053474, R01 DK112921, R01 HD070855, R21 DK113487, U54 HD087011, UH3 TR002065
American Diabetes AssociationADA
Alzheimer’s AssociationAA
University of WashingtonUWP30 DK020579, UL1 RR024992, UL1 TR000448
Institute of Clinical and Translational SciencesICTSUL1 TR002345
McDonnell Center for Systems Neuroscience
Document Type: Article
Publication Stage: Final
Source: Scopus
Assessment of a Plasma Amyloid Probability Score to Estimate Amyloid Positron Emission Tomography Findings Among Adults With Cognitive Impairment
(2022) JAMA Network Open, 5 (4), p. e228392.
Hu, Y.a , Kirmess, K.M.a , Meyer, M.R.a , Rabinovici, G.D.b , Gatsonis, C.c , Siegel, B.A.d , Whitmer, R.A.e , Apgar, C.f , Hanna, L.c , Kanekiyo, M.g , Kaplow, J.g , Koyama, A.g , Verbel, D.g , Holubasch, M.S.a , Knapik, S.S.a , Connor, J.h , Contois, J.H.a , Jackson, E.N.a , Harpstrite, S.E.a , Bateman, R.J.i , Holtzman, D.M.i , Verghese, P.B.a , Fogelman, I.a , Braunstein, J.B.a , Yarasheski, K.E.a , West, T.a
a 2 N Diagnostics, St Louis, MO, United States
b Departments of Neurology, Radiology & Biomedical Imaging, University of California, San Francisco, Mexico
c Center for Statistical Sciences, Brown University School of Public Health, Providence, RI, United States
d Mallinckrodt Institute of Radiology, Washington University School of Medicine, St Louis, MO, United States
e Department of Public Health Sciences, University of California, Davis, United States
f American College of Radiology, Reston, VA, United States
g Eisai, Woodcliff LakeNJ
h Miami, FL, United States
i Department of Neurology, Washington University School of Medicine, St Louis, MO, United States
Abstract
Importance: The diagnostic evaluation for Alzheimer disease may be improved by a blood-based diagnostic test identifying presence of brain amyloid plaque pathology. Objective: To determine the clinical performance associated with a diagnostic algorithm incorporating plasma amyloid-β (Aβ) 42:40 ratio, patient age, and apoE proteotype to identify brain amyloid status. Design, Setting, and Participants: This cohort study includes analysis from 2 independent cross-sectional cohort studies: the discovery cohort of the Plasma Test for Amyloidosis Risk Screening (PARIS) study, a prospective add-on to the Imaging Dementia-Evidence for Amyloid Scanning study, including 249 patients from 2018 to 2019, and MissionAD, a dataset of 437 biobanked patient samples obtained at screenings during 2016 to 2019. Data were analyzed from May to November 2020. Exposures: Amyloid detected in blood and by positron emission tomography (PET) imaging. Main Outcomes and Measures: The main outcome was the diagnostic performance of plasma Aβ42:40 ratio, together with apoE proteotype and age, for identifying amyloid PET status, assessed by accuracy, sensitivity, specificity, and area under the receiver operating characteristic curve (AUC). Results: All 686 participants (mean [SD] age 73.2 [6.3] years; 368 [53.6%] men; 378 participants [55.1%] with amyloid PET findings) had symptoms of mild cognitive impairment or mild dementia. The AUC of plasma Aβ42:40 ratio for PARIS was 0.79 (95% CI, 0.73-0.85) and 0.86 (95% CI, 0.82-0.89) for MissionAD. Ratio cutoffs for Aβ42:40 based on the Youden index were similar between cohorts (PARIS: 0.089; MissionAD: 0.092). A logistic regression model (LRM) incorporating Aβ42:40 ratio, apoE proteotype, and age improved diagnostic performance within each cohort (PARIS: AUC, 0.86 [95% CI, 0.81-0.91]; MissionAD: AUC, 0.89 [95% CI, 0.86-0.92]), and overall accuracy was 78% (95% CI, 72%-83%) for PARIS and 83% (95% CI, 79%-86%) for MissionAD. The model developed on the prospectively collected samples from PARIS performed well on the MissionAD samples (AUC, 0.88 [95% CI, 0.84-0.91]; accuracy, 78% [95% CI, 74%-82%]). Training the LRM on combined cohorts yielded an AUC of 0.88 (95% CI, 0.85-0.91) and accuracy of 81% (95% CI, 78%-84%). The output of this LRM is the Amyloid Probability Score (APS). For clinical use, 2 APS cutoff values were established yielding 3 categories, with low, intermediate, and high likelihood of brain amyloid plaque pathology. Conclusions and Relevance: These findings suggest that this blood biomarker test could allow for distinguishing individuals with brain amyloid-positive PET findings from individuals with amyloid-negative PET findings and serve as an aid for Alzheimer disease diagnosis.
Document Type: Article
Publication Stage: Final
Source: Scopus
Laser Interstitial Thermal Therapy in Grade 2/3 IDH1/2 Mutant Gliomas: A Preliminary Report and Literature Review
(2022) Current Oncology, 29 (4), pp. 2550-2563.
Johnson, G.W.a , Han, R.H.a , Smyth, M.D.b , Leuthardt, E.C.a c , Kim, A.H.a c
a Department of Neurosurgery, Washington University School of Medicine, St. Louis, MO 63110, United States
b Department of Neurosurgery, Johns Hopkins All Children’s Hospital, St. Petersburg, FL 33701, United States
c Brain Tumor Center, Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO 63110, United States
Abstract
Laser interstitial thermal therapy (LITT) has become an increasingly utilized alternative to surgical resection for the treatment of glioma in patients. However, treatment outcomes in isocitrate dehydrogenase 1 and 2 (IDH1/2) mutant glioma, specifically, have not been reported. The objective of this study was to characterize a single institution’s cohort of IDH1/2 mutant grade 2/3 glioma patients treated with LITT. We collected data on patient presentation, radiographic features, tumor molecular profile, complications, and outcomes. We calculated progression-free survival (PFS) and tested factors for significant association with longer PFS. Overall, 22.7% of our cohort experienced progression at a median follow up of 1.8 years. The three-and five-year estimates of PFS were 72.5% and 54.4%, respectively. This is the first study to characterize outcomes in patients with IDH1/2 mutant glioma after LITT. Our results suggest that LITT is an effective treatment option for IDH1/2 mutant glioma. © 2022 by the authors. Licensee MDPI, Basel, Switzerland.
Author Keywords
astrocytoma; glioma; IDH1 mutation; IDH2 mutation; laser interstitial thermal therapy; oligodendroglioma
Funding details
American Cancer SocietyACS
Document Type: Article
Publication Stage: Final
Source: Scopus
Usability and Acceptability of Clinical Decision Support Based on the KIIDS-TBI Tool for Children with Mild Traumatic Brain Injuries and Intracranial Injuries
(2022) Applied Clinical Informatics, 13 (2), pp. 456-467.
Greenberg, J.K.a , Otun, A.a , Kyaw, P.T.b , Carpenter, C.R.c , Brownson, R.C.d , Kuppermann, N.e , Limbrick, D.D., Jra , Foraker, R.E.f , Yen, P.-Y.f
a Department of Neurological Surgery, Washington University School of Medicine in St. Louis, St. Louis, MO, United States
b McKelvey School of Engineering, Washington University School of Medicine in St. Louis, St. Louis, MO, United States
c Department of Emergency Medicine, Washington University School of Medicine in St. Louis, St. Louis, MO, United States
d Brown School of Social Work, Washington University School of Medicine in St. Louis, St. Louis, MO, United States
e Department of Emergency Medicine, University of California Davis, Davis, CA, United States
f Institute for Informatics, Washington University School of Medicine in St. Louis, St. Louis, MO, United States
Abstract
BACKGROUND: The Kids Intracranial Injury Decision Support tool for Traumatic Brain Injury (KIIDS-TBI) tool is a validated risk prediction model for managing children with mild traumatic brain injuries (mTBI) and intracranial injuries. Electronic clinical decision support (CDS) may facilitate the clinical implementation of this evidence-based guidance. OBJECTIVE: Our objective was to evaluate the acceptability and usability of an electronic CDS tool for managing children with mTBI and intracranial injuries. METHODS: Emergency medicine and neurosurgery physicians (10 each) from 10 hospitals in the United States were recruited to participate in usability testing of a novel CDS prototype in a simulated electronic health record environment. Testing included a think-aloud protocol, an acceptability and usability survey, and a semi-structured interview. The prototype was updated twice during testing to reflect user feedback. Usability problems recorded in the videos were categorized using content analysis. Interview transcripts were analyzed using thematic analysis. RESULTS: Among the 20 participants, most worked at teaching hospitals (80%), freestanding children’s hospitals (95%), and level-1 trauma centers (75%). During the two prototype updates, problems with clarity of terminology and navigating through the CDS interface were identified and corrected. Corresponding to these changes, the number of usability problems decreased from 35 in phase 1 to 8 in phase 3 and the number of mistakes made decreased from 18 (phase 1) to 2 (phase 3). Through the survey, participants found the tool easy to use (90%), useful for determining a patient’s level of care (95%), and likely to improve resource use (90%) and patient safety (79%). Interview themes related to the CDS’s ability to support evidence-based decision-making and improve clinical workflow proposed implementation strategies and potential pitfalls. CONCLUSION: After iterative evaluation and refinement, the KIIDS-TBI CDS tool was found to be highly usable and useful for aiding the management of children with mTBI and intracranial injuries. Thieme. All rights reserved.
Document Type: Article
Publication Stage: Final
Source: Scopus
Investigating the combination of plasma amyloid-beta and geroscience biomarkers on the incidence of clinically meaningful cognitive decline in older adults
(2022) GeroScience, .
Lu, W.-H.a b , Giudici, K.V.a , Morley, J.E.c , Guyonnet, S.a b , Parini, A.d , Aggarwal, G.c e , Nguyen, A.D.c e , Li, Y.f g , Bateman, R.J.f , Vellas, B.a b , de Souto Barreto, P.a b , Carrié, I.h , Brigitte, L.h , Faisant, C.h , Lala, F.h , Delrieu, J.h , Villars, H.h , Combrouze, E.h , Badufle, C.h , Zueras, A.h , Andrieu, S.h , Cantet, C.h , Morin, C.h , Abellan Van Kan, G.h , Rolland, Y.h , Dupuy, C.h , Caillaud, C.h , Ousset, P.-J.h , Lala, F.h , Willis, S.h , Belleville, S.h , Gilbert, B.h , Fontaine, F.h , Dartigues, J.-F.h , Marcet, I.h , Delva, F.h , Foubert, A.h , Cerda, S.h , Cuffi, M.-N.h , Costes, C.h , Rouaud, O.h , Manckoundia, P.h , Quipourt, V.h , Marilier, S.h , Franon, E.h , Bories, L.h , Pader, M.-L.h , Basset, M.-F.h , Lapoujade, B.h , Faure, V.h , Tong, M.L.Y.h , Malick-Loiseau, C.h , Cazaban-Campistron, E.h , Desclaux, F.h , Blatge, C.h , Dantoine, T.h , Laubarie-Mouret, C.h , Saulnier, I.h , Clément, J.-P.h , Picat, M.-A.h , Bernard-Bourzeix, L.h , Willebois, S.h , Désormais, I.h , Cardinaud, N.h , Bonnefoy, M.h , Livet, P.h , Rebaudet, P.h , Gédéon, C.h , Burdet, C.h , Terracol, F.h , Pesce, A.h , Roth, S.h , Chaillou, S.h , Louchart, S.h , Sudres, K.h , Lebrun, N.h , Barro-Belaygues, N.h , Touchon, J.h , Bennys, K.h , Gabelle, A.h , Romano, A.h , Touati, L.h , Marelli, C.h , Pays, C.h , Robert, P.h , Le Duff, F.h , Gervais, C.h , Gonfrier, S.h , Gasnier, Y.h , Bordes, S.h , Begorre, D.h , Carpuat, C.h , Khales, K.h , Lefebvre, J.-F.h , Idrissi, S.M.E.h , Skolil, P.h , Salles, J.-P.h , Dufouil, C.h , Lehéricy, S.h , Chupin, M.h , Mangin, J.-F.h , Bouhayia, A.h , Allard, M.h , Ricolfi, F.h , Dubois, D.h , Martel, M.P.B.h , Cotton, F.h , Bonafé, A.h , Chanalet, S.h , Hugon, F.h , Bonneville, F.h , Cognard, C.h , Chollet, F.h , Payoux, P.h , Voisin, T.h , Delrieu, J.h , Peiffer, S.h , Hitzel, A.h , Allard, M.h , Zanca, M.h , Monteil, J.h , Darcourt, J.h , Molinier, L.h , Derumeaux, H.h , Costa, N.h , Perret, B.h , Vinel, C.h , Caspar-Bauguil, S.h , Olivier-Abbal, P.h , Coley, N.h , for the MAPT/DSA Grouph
a Gerontopole of Toulouse, Institute of Ageing, Toulouse University Hospital (CHU Toulouse), Toulouse, 31000, France
b Inserm CERPOP – UMR1295, University of Toulouse III, Toulouse, 31000, France
c Division of Geriatric Medicine, Saint Louis University School of Medicine, St. Louis, MO, United States
d Institute of Metabolic and Cardiovascular Diseases (I2MC), Inserm UMR 1048, University of Toulouse, Toulouse, 31400, France
e Henry and Amelia Nasrallah Center for Neuroscience, Saint Louis University, St. Louis, MO, United States
f Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States
g Division of Biostatistics, Washington University School of Medicine, St. Louis, MO, United States
Abstract
We investigated combining a core AD neuropathology measure (plasma amyloid-beta [Aβ] 42/40) with five plasma markers of inflammation, cellular stress, and neurodegeneration to predict cognitive decline. Among 401 participants free of dementia (median [IQR] age, 76 [73–80] years) from the Multidomain Alzheimer Preventive Trial (MAPT), 28 (7.0%) participants developed dementia, and 137 (34.2%) had worsening of clinical dementia rating (CDR) scale over 4 years. In the models utilizing plasma Aβ alone, a tenfold increased risk of incident dementia (nonsignificant) and a fivefold increased risk of worsening CDR were observed as each nature log unit increased in plasma Aβ levels. Models incorporating Aβ plus multiple plasma biomarkers performed similarly to models included Aβ alone in predicting dementia and CDR progression. However, improving Aβ model performance for composite cognitive score (CCS) decline, a proxy of dementia, was observed after including plasma monocyte chemoattractant protein 1 (MCP1) and growth differentiation factor 15 (GDF15) as covariates. Participants with abnormal Aβ, GDF15, and MCP1 presented higher CCS decline (worsening cognitive function) compared to their normal-biomarker counterparts (adjusted β [95% CI], − 0.21 [− 0.35 to − 0.06], p = 0.005). In conclusion, our study found limited added values of multi-biomarkers beyond the basic Aβ models for predicting clinically meaningful cognitive decline among non-demented older adults. However, a combined assessment of inflammatory and cellular stress status with Aβ pathology through measuring plasma biomarkers may improve the evaluation of cognitive performance. © 2022, The Author(s), under exclusive licence to American Aging Association.
Author Keywords
Aging; Alzheimer’s disease; Amyloid-beta; Cognitive decline; Inflammation; Neurodegeneration
Funding details
1901175
National Institutes of HealthNIHR56AG061900
National Institute on AgingNIA
Avid Radiopharmaceuticals
Ministère des Affaires Sociales et de la Santé
Centre Hospitalier Universitaire de Toulouse
European Regional Development FundERDFANR-18-EURE-0003, MP0022856
Document Type: Article
Publication Stage: Article in Press
Source: Scopus