List of publications for the week of January 24, 2022
Plasma MCP-1 and changes on cognitive function in community-dwelling older adults
(2022) Alzheimer’s Research and Therapy, 14 (1), art. no. 5, .
Sanchez-Sanchez, J.L.a b , Giudici, K.V.a , Guyonnet, S.a c , Delrieu, J.a c , Li, Y.d e , Bateman, R.J.d e f g , Parini, A.h , Vellas, B.a c , de Souto Barreto, P.a c , Vellas, B.i , Guyonnet, S.i , Carrié, I.i , Brigitte, L.i , Faisant, C.i , Lala, F.i , Delrieu, J.i , Villars, H.i , Combrouze, E.i , Badufle, C.i , Zueras, A.i , Andrieu, S.i , Cantet, C.i , Morin, C.i , Van Kan, G.A.i , Dupuy, C.i , Rolland, Y.i , Caillaud, C.i , Ousset, P.-J.i , Lala, F.i , Willis, S.i , Belleville, S.i , Gilbert, B.i , Fontaine, F.i , Dartigues, J.-F.i , Marcet, I.i , Delva, F.i , Foubert, A.i , Cerda, S.i , Marie-Noëlle-Cuffii , Costes, C.i , Rouaud, O.i , Manckoundia, P.i , Quipourt, V.i , Marilier, S.i , Franon, E.i , Bories, L.i , Pader, M.-L.i , Basset, M.-F.i , Lapoujade, B.i , Faure, V.i , Tong, M.L.Y.i , Malick-Loiseau, C.i , Cazaban-Campistron, E.i , Desclaux, F.i , Blatge, C.i , Dantoine, T.i , Laubarie-Mouret, C.i , Saulnier, I.i , Clément, J.-P.i , Picat, M.-A.i , Bernard-Bourzeix, L.i , Willebois, S.i , Désormais, I.i , Cardinaud, N.i , Bonnefoy, M.i , Livet, P.i , Rebaudet, P.i , Gédéon, C.i , Burdet, C.i , Terracol, F.i , Pesce, A.i , Roth, S.i , Chaillou, S.i , Louchart, S.i , Sudres, K.i , Lebrun, N.i , Barro-Belaygues, N.i , Touchon, J.i , Bennys, K.i , Gabelle, A.i , Romano, A.i , Touati, L.i , Marelli, C.i , Pays, C.i , Robert, P.i , Le Duff, F.i , Gervais, C.i , Gonfrier, S.i , Gasnier, Y.i , Bordes, S.i , Begorre, D.i , Carpuat, C.i , Khales, K.i , Lefebvre, J.-F.i , El Idrissi, S.M.i , Skolil, P.i , Salles, J.-P.i , Dufouil, C.i , Lehéricy, S.i , Chupin, M.i , Mangin, J.-F.i , Bouhayia, A.i , Allard, M.i , Ricolfi, F.i , Dubois, D.i , Martel, M.P.B.i , Cotton, F.i , Bonafé, A.i , Chanalet, S.i , Hugon, F.i , Bonneville, F.i , Cognard, C.i , Chollet, F.i , Payoux, P.i , Voisin, T.i , Peiffer, S.i , Hitzel, A.i , Zanca, M.i , Monteil, J.i , Darcourt, J.i , Molinier, L.i , Derumeaux, H.i , Costa, N.i , Perret, B.i , Vinel, C.i , Caspar-Bauguil, S.i , Olivier-Abbal, P.i , Coley, N.i , for the MAPT/DSA Groupi
a Gérontopôle de Toulouse, Institut du Vieillissement, Centre Hospitalier-Universitaire de Toulouse, 37 allées Jules Guesde, Toulouse, 31000, France
b Faculty of Sport Sciences, Universidad Europea de Madrid, Villaviciosa de Odón, Madrid, 28670, Spain
c CERPOP, Inserm 1295, Université de Toulouse, UPS, Toulouse, France
d Department of Neurology, Washington University in St. Louis, St. Louis, MO, United States
e Division of Biostatistics, Washington University in St. Louis, St. Louis, MO, United States
f Knight Alzheimer’s Disease Research Center, Washington University in St. Louis, St. Louis, MO, United States
g Hope Center for Neurological Disorders, Washington University in St. Louis, St. Louis, MO, United States
h Institut des Maladies Métaboliques et Cardiovasculaires, Inserm/Université Paul Sabatier UMR 1048 – I2MC 1, Toulouse, France
Abstract
Background: Monocyte Chemoattractant Protein-1 (MCP-1), a glial-derived chemokine, mediates neuroinflammation and may regulate memory outcomes among older adults. We aimed to explore the associations of plasma MCP-1 levels (alone and in combination with β-amyloid deposition—Aβ42/40) with overall and domain-specific cognitive evolution among older adults. Methods: Secondary analyses including 1097 subjects (mean age = 75.3 years ± 4.4; 63.8% women) from the Multidomain Alzheimer Preventive Trial (MAPT). MCP-1 (higher is worse) and Aβ42/40 (lower is worse) were measured in plasma collected at year 1. MCP-1 in continuous and as a dichotomy (values in the highest quartile (MCP-1+)) were used, as well as a dichotomy of Aβ42/40. Outcomes were measured annually over 4 years and included the following: cognitive composite z-score (CCS), the Mini-Mental State Examination (MMSE), and Clinical Dementia Rating (CDR) sum of boxes (overall cognitive function); composite executive function z-score, composite attention z-score, Free and Cued Selective Reminding Test (FCSRT – memory). Results: Plasma MCP-1 as a continuous variable was associated with the worsening of episodic memory over 4 years of follow-up, specifically in measures of free and cued delayed recall. MCP-1+ was associated with worse evolution in the CCS (4-year between-group difference: β = −0.14, 95%CI = −0.26, −0.02) and the CDR sum of boxes (2-year: β = 0.19, 95%CI = 0.06, 0.32). In domain-specific analyses, MCP-1+ was associated with declines in the FCSRT delayed recall sub-domains. In the presence of low Aβ42/40, MCP-1+ was not associated with greater declines in cognitive functions. The interaction with continuous biomarker values Aβ42/40× MCP-1 × time was significant in models with CDR sum of boxes and FCSRT DTR as dependent variables. Conclusions: Baseline plasma MCP-1 levels were associated with longitudinal declines in overall cognitive and episodic memory performance in older adults over a 4-year follow-up. How plasma MCP-1 interacts with Aβ42/40 to determine cognitive decline at different stages of cognitive decline/dementia should be clarified by further research. The MCP-1 association on cognitive decline was strongest in those with amyloid plaques, as measured by blood plasma Aβ42/40. © 2022, The Author(s).
Author Keywords
Alzheimer’s disease; Cognitive function; Episodic memory; MCP-1; Older adults
Funding details
1901175
Avid Radiopharmaceuticals
Ministère des Affaires Sociales et de la Santé
European Regional Development FundERDFMP0022856
Document Type: Article
Publication Stage: Final
Source: Scopus
(2022) The Journal of Cell Biology
Sarm1 activation produces cADPR to increase intra-axonal Ca++ and promote axon degeneration in PIPN
(2022) The Journal of Cell Biology, 221 (2), .
Li, Y.a b , Pazyra-Murphy, M.F.a b , Avizonis, D.c , de Sá Tavares Russo, M.c , Tang, S.b , Chen, C.-Y.d , Hsueh, Y.-P.d , Bergholz, J.S.b e f , Jiang, T.b , Zhao, J.J.b e f , Zhu, J.g , Ko, K.W.h , Milbrandt, J.g i , DiAntonio, A.h i , Segal, R.A.a b
a Department of Neurobiology, Harvard Medical School, MA, Boston
b Department of Cancer Biology, Dana-Farber Cancer Institute, MA, Boston
c Metabolomics Innovation Resource, Goodman Cancer Research Centre, McGill University, Montréal, QC, Canada
d Institute of Molecular Biology, Academia Sinica, Republic of ChinaTaipei, Taiwan
e Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, MA, Boston
f Broad Institute of Harvard and Massachusetts Institute of Technology, MA, Cambridge
g Department of Genetics, Washington University School of Medicine, St. Louis, MO
h Department of Developmental Biology, Washington University School of Medicine, St. Louis, MO
i Needleman Center for Neurometabolism and Axonal Therapeutics, Washington University School of Medicine, St. Louis, MO
Abstract
Cancer patients frequently develop chemotherapy-induced peripheral neuropathy (CIPN), a painful and long-lasting disorder with profound somatosensory deficits. There are no effective therapies to prevent or treat this disorder. Pathologically, CIPN is characterized by a “dying-back” axonopathy that begins at intra-epidermal nerve terminals of sensory neurons and progresses in a retrograde fashion. Calcium dysregulation constitutes a critical event in CIPN, but it is not known how chemotherapies such as paclitaxel alter intra-axonal calcium and cause degeneration. Here, we demonstrate that paclitaxel triggers Sarm1-dependent cADPR production in distal axons, promoting intra-axonal calcium flux from both intracellular and extracellular calcium stores. Genetic or pharmacologic antagonists of cADPR signaling prevent paclitaxel-induced axon degeneration and allodynia symptoms, without mitigating the anti-neoplastic efficacy of paclitaxel. Our data demonstrate that cADPR is a calcium-modulating factor that promotes paclitaxel-induced axon degeneration and suggest that targeting cADPR signaling provides a potential therapeutic approach for treating paclitaxel-induced peripheral neuropathy (PIPN). © 2021 Li et al.
Document Type: Article
Publication Stage: Final
Source: Scopus
Characterization of the Genomic and Immunologic Diversity of Malignant Brain Tumors through Multisector Analysis
(2022) Cancer Discovery, 12 (1), pp. 154-171.
Schaettler, M.O.a b , Richters, M.M.c d e , Wang, A.Z.a b , Skidmore, Z.L.c d e , Fisk, B.c d e , Miller, K.E.f , Vickery, T.L.g , Kim, A.H.a , Chicoine, M.R.a , Osbun, J.W.a , Leuthardt, E.C.a , Dowling, J.L.a , Zipfel, G.J.a , Dacey, R.G.a , Lu, H.-C.b , Johanns, T.M.c g , Griffith, O.L.c d e , Mardis, E.R.f h , Griffith, M.c d e , Dunn, G.P.a b g
a Department of Neurological Surgery, Washington University School of Medicine, St. Louis, MO, United States
b Department of Pathology & Immunology, Washington University School of Medicine, St. Louis, MO, United States
c Division of Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, MO, United States
d Department of Genetics, Washington University School of Medicine, St. Louis, MO, United States
e The McDonnell Genome Institute, Washington University in St. Louis, St. Louis, MO, United States
f The Steve and Cindy Rasmussen Institute for Genomic Medicine, Nationwide Children’s Hospital, Columbus, OH, United States
g Andrew M. and Jane M. Bursky Center for Human Immunology and Immunotherapy Programs, Washington University School of Medicine, St. Louis, MO, United States
h Department of Pediatrics, Ohio State University College of Medicine, Columbus, OH, United States
Abstract
Despite some success in secondary brain metastases, targeted or immune-based therapies have shown limited efficacy against primary brain malignancies such as glioblastoma (GBM). Although the intratumoral heterogeneity of GBM is implicated in treatment resistance, it remains unclear whether this diversity is observed within brain metastases and to what extent cancer cell–intrinsic heterogeneity sculpts the local immune microenvironment. Here, we profiled the immunogenomic state of 93 spatially distinct regions from 30 malignant brain tumors through wholeexome, RNA, and T-cell receptor sequencing. Our analyses identified differences between primary and secondary malignancies, with gliomas displaying more spatial heterogeneity at the genomic and neoantigen levels. In addition, this spatial diversity was recapitulated in the distribution of T-cell clones in which some gliomas harbored highly expanded but spatially restricted clonotypes. This study defines the immunogenomic landscape across a cohort of malignant brain tumors and contains implications for the design of targeted and immune-based therapies against intracranial malignancies. © 2021 The Authors; Published by the American Association for Cancer Research.
Funding details
National Institutes of HealthNIH2T32HG000045–21, R00HG007940, T32 AI007163, T32 GM 7200–43
National Human Genome Research InstituteNHGRI
National Cancer InstituteNCIU01CA248235
Damon Runyon Cancer Research FoundationDRCRF94-17
V Foundation for Cancer ResearchVFCRV2018–007
Document Type: Article
Publication Stage: Final
Source: Scopus
Sharper in the morning: Cognitive time of day effects revealed with high-frequency smartphone testing
(2022) Journal of Clinical and Experimental Neuropsychology, .
Wilks, H.a , Aschenbrenner, A.J.a b , Gordon, B.A.b c , Balota, D.A.b , Fagan, A.M.a , Musiek, E.a , Balls-Berry, J.a , Benzinger, T.L.S.c , Cruchaga, C.d , Morris, J.C.a , Hassenstab, J.a b
a Department of Neurology, Washington University in St. Louis 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 in St. Louis School of Medicine, St. Louis, MO, United States
d Department of Psychiatry, Washington University in St. Louis School of Medicine, St. Louis, MO, United States
Abstract
Decades of research has established a shift from an “eveningness” preference to a “morningness” preference with increasing age. Accordingly, older adults typically have better cognition in morning hours compared to evening hours. We present the first known attempt to capture circadian fluctuations in cognition in individuals at risk for Alzheimer disease (AD) using a remotely administered smartphone assessment that samples cognition rapidly and repeatedly over several days. Older adults (N = 169, aged 61–94 years; 93% cognitively normal) completed four brief smartphone-based testing sessions per day for 7 consecutive days at quasi-random time intervals, assessing associate memory, processing speed, and visual working memory. Scores completed during early hours were averaged for comparison with averaged scores completed during later hours. Mixed effects models evaluated time of day effects on cognition. Additional models included clinical status and cerebrospinal fluid (CSF) biomarkers for beta amyloid (Aβ42) and phosphorylated tau181 (pTau). Models with terms for age, gender, education, APOE ε4 status, and clinical status revealed significantly worse performance on associate memory in evening hours compared to morning hours. Contemporaneously reported mood and fatigue levels did not moderate relationships. Using CSF data to classify individuals with and without significant AD pathology, there were no group differences in performance in morning hours, but subtle impairment emerged in associate memory in evening hours in those with CSF-confirmed AD pathology. These findings indicate that memory is worse in evening hours in older adults, that this pattern is consistent across several days, and is independent of measures of mood and fatigue. Further, they provide preliminary evidence of a “cognitive sundowning” in the very earliest stages of AD. Time of day may be an important consideration for assessments in observational studies and clinical trials in AD populations. © 2022 Informa UK Limited, trading as Taylor & Francis Group.
Author Keywords
Aging; Alzheimer’s disease; circadian rhythms; neuropsychological tests; smartphone-based cognitive testing
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
The Role of the Human Brain Neuron–Glia–Synapse Composition in Forming Resting-State Functional Connectivity Networks
(2021) Brain Sciences, 11 (12), art. no. 1565, .
Kahali, S.a , Raichle, M.E.a b , Yablonskiy, D.A.a
a Department of Radiology, Washington University in Saint Louis, Saint Louis, MO 63110, United States
b Department of Neurology, Washington University in Saint Louis, Saint Louis, MO 63110, United States
Abstract
While significant progress has been achieved in studying resting-state functional networks in a healthy human brain and in a wide range of clinical conditions, many questions related to their relationship to the brain’s cellular constituents remain. Here, we use quantitative Gradient-Recalled Echo (qGRE) MRI for mapping the human brain cellular composition and BOLD (blood–oxygen level-dependent) MRI to explore how the brain cellular constituents relate to resting-state functional networks. Results show that the BOLD signal-defined synchrony of connections between cellular circuits in network-defined individual functional units is mainly associated with the regional neuronal density, while the between-functional units’ connectivity strength is also influenced by the glia and synaptic components of brain tissue cellular constituents. These mechanisms lead to a rather broad distribution of resting-state functional network properties. Visual networks with the highest neuronal density (but lowest density of glial cells and synapses) exhibit the strongest coherence of the BOLD signal as well as the strongest intra-network connectivity. The Default Mode Network (DMN) is positioned near the opposite part of the spectrum with relatively low coherence of the BOLD signal but with a remarkably balanced cellular contents, enabling DMN to have a prominent role in the overall organization of the brain and hierarchy of functional networks. © 2021 by the authors. Licensee MDPI, Basel, Switzerland.
Author Keywords
Brain cellular composition; Default mode network; Functional connectivity networks; MRI; QGRE; Quantitative Gradient-Recalled Echo
Funding details
R01 AG054513
1U54MH091657
National Institutes of HealthNIH
NIH Blueprint for Neuroscience Research
McDonnell Center for Systems Neuroscience
Document Type: Article
Publication Stage: Final
Source: Scopus
Limited Longitudinal Change in Self-reported Spatial Navigation Ability in Preclinical Alzheimer Disease
(2021) Alzheimer Disease and Associated Disorders, .
Levine, T.F.a , Roe, C.M.b c , Babulal, G.M.b c f , Fagan, A.M.b c d , Head, D.a b e
a Department of Psychological and Brain Sciences, Washington University, United States
b Charles F. and Joanne Knight Alzheimer Disease Research Center, United States
c Department of Neurology, United States
d Hope Center for Neurological Disorders, United States
e Department of Radiology, Washington University School of Medicine, St. Louis, MO, United States
f Department of Psychology, Faculty of Humanities, University of Johannesburg, Johannesburg, South Africa
Abstract
Subtle changes in objective spatial navigation ability have been observed in the preclinical stage of Alzheimer disease (AD) cross-sectionally and have been found to predict clinical progression. However, longitudinal change in self-reported spatial navigation ability in preclinical AD has yet to be examined. The current study examined whether AD biomarkers suggestive of preclinical AD at baseline spatial navigation assessment and APOE genotype predicted decline in self-reported spatial navigation ability and whether APOE genotype moderated the association of AD biomarkers with change in self-reported spatial navigation. Clinically normal (Clinical Dementia Rating Scale=0) adults aged 56 to 90 completed the Santa Barbara Sense of Direction Scale (SBSOD) annually for an average of 2.73 years. Biomarker data was collected within +/-2 years of baseline (ie, cerebrospinal fluid Aβ42, p-tau181, p-tau181/Aβ42ratio, positron emission tomography imaging with Florbetapir or Pittsburgh Compound-B, and hippocampal volume). APOE genotyping was obtained for all participants. SBSOD demonstrated a nonsignificant trend toward a decline over time (P=0.082). AD biomarkers did not predict change in self-reported spatial navigation (all Ps>0.163). APOE genotype did not moderate the relationship between AD biomarkers and self-reported spatial navigation in planned analyses (all Ps>0.222). Results suggest that self-reported spatial navigation ability, as estimated with the SBSOD, may be limited as a measure of subtle cognitive change in the preclinical stage of AD. © 2021 Lippincott Williams and Wilkins. All rights reserved.
Author Keywords
allocentric navigation; cognitive mapping; subjective cognitive complaints
Funding details
National Science FoundationNSFDGE-1745038
National Institutes of HealthNIHP01 AG026276, P01 AG03991, P30 AG066444, R01AG056466, R01AG067428, R01AG068183
BrightFocus FoundationBFFA2021142S
Document Type: Article
Publication Stage: Article in Press
Source: Scopus