Generation of a gene-corrected human isogenic iPSC line from an Alzheimer’s disease iPSC line carrying the PSEN1 H163R mutation
(2024) Stem Cell Research, 79, art. no. 103495, .
Hernández, D.a f , Morgan Schlicht, S.a , Elli Clarke, J.a , Daniszewski, M.a , Karch, C.M.b , Adams, S.e , Allegri, R.e , Araki, A.e , Barthelemy, N.e , Bateman, R.e , Bechara, J.e , Benzinger, T.e , Berman, S.e , Bodge, C.e , Brandon, S.e , (Bill) Brooks, W.e , Brosch, J.e , Buck, J.e , Buckles, V.e , Carter, K.e , Cash, L.e , Chen, C.e , Chhatwal, J.e , Chrem Mendez, P.e , Chua, J.e , Chui, H.e , Courtney, L.e , Cruchaga, C.e , Day, G.S.e , DeLaCruz, C.e , Denner, D.e , Diffenbacher, A.e , Dincer, A.e , Donahue, T.e , Douglas, J.e , Duong, D.e , Egido, N.e , Esposito, B.e , Fagan, A.e , Farlow, M.e , Feldman, B.e , Fitzpatrick, C.e , Flores, S.e , Fox, N.e , Franklin, E.e , Joseph-Mathurin, N.e , Fujii, H.e , Gardener, S.e , Ghetti, B.e , Goate, A.e , Goldberg, S.e , Goldman, J.e , Gonzalez, A.e , Gordon, B.e , Gr¨aber-Sultan, S.e , Graff-Radford, N.e , Graham, M.e , Gray, J.e , Gremminger, E.e , Grilo, M.e , Groves, A.e , Haass, C.e , H¨asler, L.e , Hassenstab, J.e , Hellm, C.e , Herries, E.e , Hoechst-Swisher, L.e , Hofmann, A.e , Holtzman, D.e , Hornbeck, R.e , Igor, Y.e , Ihara, R.e , Ikeuchi, T.e , Ikonomovic, S.e , Ishii, K.e , Jack, C.e , Jerome, G.e , Johnson, E.e , Jucker, M.e , Karch, C.e , K¨aser, S.e , Kasuga, K.e , Keefe, S.e , Klunk, W.e , Koeppe, R.e , Koudelis, D.e , Kuder-Buletta, E.e , Laske, C.e , Levey, A.e , Levin, J.e , Li, Y.e , Lopez, O.e , Marsh, J.e , Martins, R.e , Scott Mason, N.e , Masters, C.e , Mawuenyega, K.e , McCullough, A.e , McDade, E.e , Mejia, A.e , Morenas-Rodriguez, E.e , Morris, J.e , Mountz, J.e , Mummery, C.e , Nadkarni, N.e , Nagamatsu, A.e , Neimeyer, K.e , Niimi, Y.e , Noble, J.e , Norton, J.e , Nuscher, B.e , Obermüller, U.e , O’Connor, A.e , Patira, R.e , Perrin, R.e , Ping, L.e , Preische, O.e , Renton, A.e , Ringman, J.e , Salloway, S.e , Schofield, P.e , Senda, M.e , Seyfried, N.T.e , Shady, K.e , Shimada, H.e , Sigurdson, W.e , Smith, J.e , Smith, L.e , Snitz, B.e , Sohrabi, H.e , Stephens, S.e , Taddei, K.e , Thompson, S.e , V¨oglein, J.e , Wang, P.e , Wang, Q.e , Weamer, E.e , Xiong, C.e , Xu, J.e , Xu, X.e , Goate, A.M.c , Pébay, A.a d , Dominantly Inherited Alzheimer Network (DIAN)g
a Department of Anatomy and Physiology, the University of Melbourne, Parkville, VIC 3010, Australia
b Department of Psychiatry, Washington University School of Medicine, St. Louis, MO 63110, United States
c Department of Genetics and Genomic Sciences, Ronald M. Loeb Center for Alzheimer’s Disease, Icahn School of Medicine at Mount Sinai, 1425 Madison Avenue, New York, NY 10029, United States
d Department of Surgery, Royal Melbourne Hospital, the University of Melbourne, Parkville, VIC 3010, Australia
f The Institute for Mental and Physical Health and Clinical Translation, Deakin University, GeelongVIC 3220, Australia
Abstract
We report the generation of a gene-edited human induced pluripotent stem cell (iPSC) line from an Alzheimer’s disease patient-derived iPSC line harbouring the PSEN1 H163R mutation. This line demonstrates pluripotent stem cell morphology, expression of pluripotency markers, and maintains a normal karyotype. © 2024 The Author(s)
Funding details
Deutsches Zentrum für Neurodegenerative ErkrankungenDZNE
Fleni
Japan Agency for Medical Research and DevelopmentAMED
Korea Health Industry Development InstituteKHIDI
National Health and Medical Research CouncilNHMRC1154389
Document Type: Article
Publication Stage: Final
Source: Scopus
Cross-sectional and longitudinal changes in mind-wandering in older adulthood
(2024) Psychology and Aging, 39 (5), pp. 495-509.
Welhaf, M.S.a , Balota, D.A.a , Morris, J.C.b , Hassenstab, J.a , Aschenbrenner, A.J.b
a Department of Psychological and Brain Sciences, Washington University in St. Louis
b Department of Neurology, Washington University in St. Louis
Abstract
Age-related declines in the frequency of mind-wandering are well established. Theories of mind-wandering have attempted to explain why this decline occurs, but no one theory firmly predicts such changes. One problem with these theoretical views, and the studies that have grown out of them, is their reliance on cross-sectional methods, which do not account for within-person changes over time in mind-wandering, and it is well-documented that cross-sectional and longitudinal changes in some cognitive domains do not align. We present a novel analysis of longitudinal change in subjective and objective indicators of mind-wandering during a sustained attention task. Cognitively normal adults (N = 277, age range 42-94) completed a sustained attention task with thought probes to measure mind-wandering repeatedly over several years. Linear mixed effect models revealed baseline differences in subjective mind-wandering reports among middle-aged and older adults. However, longitudinally, middle-aged participants showed a significant increase in subjective mind-wandering, whereas older participants showed no change. Changes in mind-wandering could not be explained by attentional control ability or contemporaneous estimates of interest and perceived difficulty, but they were explained by baseline levels of conscientiousness. Objective measures of mind-wandering did not show these same patterns and were largely only associated with participants perceived difficulty. Our results build on previous cross-sectional research and suggest that incorporating longitudinal analyses into theories of ageing and mind-wandering and mind-wandering more broadly is important for refining these theories. (PsycInfo Database Record (c) 2024 APA, all rights reserved).
Document Type: Article
Publication Stage: Final
Source: Scopus
GABAA receptor subunit composition regulates circadian rhythms in rest-wake and synchrony among cells in the suprachiasmatic nucleus
(2024) Proceedings of the National Academy of Sciences of the United States of America, 121 (31), pp. e2400339121.
Granados-Fuentes, D.a , Lambert, P.b , Simon, T.a , Mennerick, S.b , Herzog, E.D.a
a Department of Biology, Washington University in St. Louis
b Department of Psychiatry, Washington University in St. Louis
Abstract
The mammalian circadian clock located in the suprachiasmatic nucleus (SCN) produces robust daily rhythms including rest-wake. SCN neurons synthesize and respond to γ-aminobutyric acid (GABA), but its role remains unresolved. We tested the hypothesis that γ2- and δ-subunits of the GABAA receptor in the SCN differ in their regulation of synchrony among circadian cells. We used two approaches: 1) shRNA to knock-down (KD) the expression of either γ2 or δ subunits in the SCN or 2) knock-in mice harboring a point mutation in the M2 domains of the endogenous GABAA γ2 or δ subunits. KD of either γ2 or δ subunits in the SCN increased daytime running and reduced nocturnal running by reducing their circadian amplitude by a third. Similarly, δ subunit knock-in mice showed decreased circadian amplitude, increased duration of daily activity, and decreased total daily activity. Reduction, or mutation of either γ2 or δ subunits halved the synchrony among, and amplitude of, circadian SCN cells as measured by firing rate or expression of the PERIOD2 protein, in vitro. Surprisingly, overexpression of the γ2 subunit rescued these phenotypes following KD or mutation of the δ subunit, and overexpression of the δ subunit rescued deficiencies due to γ2 subunit KD or mutation. We conclude that γ2 and δ GABAA receptor subunits play similar roles in maintaining circadian synchrony in the SCN and amplitude of daily rest-wake rhythms, but that modulation of their relative densities can change the duration and amplitude of daily activities.
Author Keywords
Gabrd; Gabrg2; SCN; γ2; δ
Document Type: Article
Publication Stage: Final
Source: Scopus
Using Multimodal Assessments to Reevaluate Depression Designations for Spine Surgery Candidates
(2024) Journal of Bone and Joint Surgery, .
Benedict, B.a , Frumkin, M.b , Botterbush, K.a , Javeed, S.a , Zhang, J.K.a c , Yakdan, S.a , Neuman, B.J.d , Steinmetz, M.P.e , Ghogawala, Z.f , Kelly, M.P.g , Goodin, B.R.h , Piccirillo, J.F.i , Ray, W.Z.a , Rodebaugh, T.L.j , Greenberg, J.K.a
a Department of Neurological Surgery, Washington University, St. Louis, MO, United States
b Department of Psychology and Brain Sciences, Washington University, St. Louis, MO, United States
c Department of Neurological Surgery, University of Utah, Salt Lake City, UT, United States
d Department of Orthopedic Surgery, Washington University, St. Louis, MO, United States
e Department of Neurosurgery, Cleveland Clinic Lerner College of Medicine, Cleveland, OH, United States
f Department of Neurosurgery, Lahey Hospital and Medical Center, Burlington, MA, United States
g Department of Orthopedic Surgery, Rady Children’s Hospital, San Diego, CA, United States
h Department of Anesthesiology, Washington University, St. Louis, MO, United States
i Department of Otolaryngology, Washington University, St. Louis, MO, United States
j Department of Psychology and Neuroscience, University of North Carolina, Chapel Hill, NC, United States
Abstract
Background: Depression is common in spine surgery candidates and may influence postoperative outcomes. Ecological momentary assessments (EMAs) can overcome limitations of existing depression screening methods (e.g., recall bias, inaccuracy of historical diagnoses) by longitudinally monitoring depression symptoms in daily life. In this study, we compared EMA-based depression assessment with retrospective self-report (a 9-item Patient Health Questionnaire [PHQ-9]) and chart-based depression diagnosis in lumbar spine surgery candidates. We further examined the associations of each depression assessment method with surgical outcomes. Methods: Adult patients undergoing lumbar spine surgery (n = 122) completed EMAs quantifying depressive symptoms up to 5 times daily for 3 weeks preoperatively. Correlations (rank-biserial or Spearman) among EMA means, a chart-based depression history, and 1-time preoperative depression surveys (PHQ-9 and Psychache Scale) were analyzed. Confirmatory factor analysis was used to categorize PHQ-9 questions as somatic or non-somatic; subscores were compared with a propensity score-matched general population cohort. The associations of each screening modality with 6-month surgical outcomes (pain, disability, physical function, pain interference) were analyzed with multivariable regression. Results: The association between EMA Depression scores and a depression history was weak (rrb = 0.34 [95% confidence interval (CI), 0.14 to 0.52]). Moderate correlations with EMA-measured depression symptoms were observed for the PHQ-9 (rs = 0.51 [95% CI, 0.37 to 0.63]) and the Psychache Scale (rs = 0.68 [95% CI, 0.57 to 0.76]). Compared with the matched general population cohort, spine surgery candidates endorsed similar non-somatic symptoms but significantly greater somatic symptoms on the PHQ-9. EMA Depression scores had a stronger association with 6-month surgical outcomes than the other depression screening modalities did. Conclusions: A history of depression in the medical record is not a reliable indication of preoperative depression symptom severity. Cross-sectional depression assessments such as PHQ-9 have stronger associations with daily depression symptoms but may conflate somatic depression symptoms with spine-related disability. As an alternative to these methods, mobile health technology and EMAs provide an opportunity to collect real-time, longitudinal data on depression symptom severity, potentially improving prognostic accuracy. Copyright © 2024 by The Journal of Bone and Joint Surgery.
Funding details
Scoliosis Research SocietySRS
Foundation for Barnes-Jewish HospitalFBJH
Cervical Spine Research SocietyCSRS
National Institute of Mental HealthNIMH1F31MH124291-01A
Document Type: Article
Publication Stage: Article in Press
Source: Scopus