Scopus list of publications for May 28, 2023
Resting-state MRI functional connectivity as a neural correlate of multidomain lifestyle adherence in older adults at risk for Alzheimer’s disease
(2023) Scientific Reports, 13 (1), art. no. 7487, .
Ai, M.a , Morris, T.P.b , Zhang, J.a , de la Colina, A.N.c , Tremblay-Mercier, J.d e , Villeneuve, S.d e f , Whitfield-Gabrieli, S.a , Kramer, A.F.a g , Geddes, M.R.c d h , Aisen, P.h i , Anthal, E.d e , Appleby, M.d e , Bellec, P.d h j , Benbouhoud, F.e , Bohbot, V.d e f , Brandt, J.k , Breitner, J.C.S.d e f , Brunelle, C.d e , Chakravarty, M.d e f , Cheewakriengkrai, L.d e l , Collins, L.d h m , Couture, D.e , Craft, S.n , Dadar, M.f h , Daoust, L.-A.d , Das, S.h o , Dauar-Tedeschi, M.d e l , Dea, D.d e , Desrochers, N.d e , Dubuc, S.e , Duclair, G.d e , Dufour, M.d e , Eisenberg, M.p , El-Khoury, R.d e , Etienne, P.d e f , Evans, A.d e m , Faubert, A.-M.e , Ferdinand, F.d e , Fonov, V.m o , Fontaine, D.d e , Francoeur, R.d e , Frenette, J.d e , Gagné, G.d e , Gauthier, S.c d e f l , Gervais, V.d e , Giles, R.d e , Gonneaud, J.d e , Gordon, R.d e , Greco, C.d e , Hoge, R.c d m , Hudon, L.d , Ituria-Medina, Y.c d m o , Kat, J.d e m , Kazazian, C.d e , Kligman, S.d e , Kostopoulos, P.m q , Labonté, A.d e , Lafaille-Magnan, M.-E.d e r , Lee, T.d e , Leoutsakos, J.-M.k , Leppert, I.d e h , Madjar, C.d e h , Mahar, L.d e , Maltais, J.-R.d e l , Mathieu, A.e , Mathotaarachchi, S.e l , Mayrand, G.d e , McSweeney, M.r , Meyer, P.-F.d e r , Michaud, D.e , Miron, J.d e r , Morris, J.C.s , Multhaup, G.t , Münter, L.-M.t , Nair, V.e f l , Near, J.e f , Newbold-Fox, H.e , Nilsson, N.d e r , Pagé, V.e , Pascoal, T.A.c d e l , Petkova, M.d e h , Picard, C.d e , Binette, A.P.d e , Pogossova, G.d e , Poirier, J.d e f , Rajah, N.d e q , Remz, J.e , Rioux, P.h , Rosa-Neto, P.d e f l , Sager, M.A.u , Saint-Fort, E.F.e , Savard, M.d e , Soucy, J.-P.h o , Sperling, R.A.v , Spreng, N.h , St-Onge, F.d e r , Tardif, C.d e , Théroux, L.d e , Thomas, R.G.w , Toussaint, P.-J.h o , Tuwaig, M.d e , Vachon-Presseau, E.e x , Vallée, I.d e , Venugopalan, V.d e , Wan, K.d e , Wang, S.e l r , for the PREVENT-AD Research Groupy
a Department of Psychology, Northeastern University, Boston, MA, United States
b Department of Physical Therapy, Movement and Rehabilitation Sciences, Northeastern University, Boston, MA, United States
c Department of Neurology and Neurosurgery, Faculty of Medicine, McGill University, Montreal, QC, Canada
d STOP-AD Centre, Centre for Studies on Prevention of Alzheimer’s Disease, Montreal, QC, Canada
e Douglas Mental Health University Institute Research Centre, Affiliated with, McGill University, Montreal, QC, Canada
f Department of Psychiatry, McGill University, Montreal, QC, Canada
g Beckman Institute for Advanced Science and Technology, University of Illinois at Urbana Champaign, Urbana-Champaign, IL, United States
h Montreal Neurological Institute, Montreal, QC, Canada
i Alzheimer’s Therapeutic Research Institute at University of Southern California, San Diego, CA, United States
j Université de Montréal, Montreal, QC, Canada
k John Hopkins University, Baltimore, MD, United States
l Research Centre for Studies in Aging, McGill University, Montreal, QC, Canada
m Department of Biomedical Engineering, McGill University, Montreal, QC, Canada
n Wake Forest School of Medicine, Winston-Salem, NC, United States
o McConnell Brain Imaging Center, McGill University, Montreal, QC, Canada
p School of Population and Global Health, McGill University, Montreal, QC, Canada
q Department of Psychology, McGill University, Montreal, QC, Canada
r Neuroscience Department, McGill University, Montreal, QC, Canada
s Washington University School of Medecine in St-Louis, St. Louis, MO, United States
t Department of Pharmacology, McGill University, Montreal, QC, Canada
u Wisconsin Alzheimer’s Institute, UW School of Medicine and Public Health, Milwaukee, WI, United States
v Center for Alzheimer’s Research and Treatment Harvard Medical School, Boston, MA, United States
w School of Medicine, University California, San Diego, La JollaCA, United States
x Northwestern University, Chicago, IL, United States
Abstract
Prior research has demonstrated the importance of a healthy lifestyle to protect brain health and diminish dementia risk in later life. While a multidomain lifestyle provides an ecological perspective to voluntary engagement, its association with brain health is still under-investigated. Therefore, understanding the neural mechanisms underlying multidomain lifestyle engagement, particularly in older adults at risk for Alzheimer’s disease (AD), gives valuable insights into providing lifestyle advice and intervention for those in need. The current study included 139 healthy older adults with familial risk for AD from the Prevent-AD longitudinal aging cohort. Self-reported exercise engagement, cognitive activity engagement, healthy diet adherence, and social activity engagement were included to examine potential phenotypes of an individual’s lifestyle adherence. Two adherence profiles were discovered using data-driven clustering methodology [i.e., Adherence to healthy lifestyle (AL) group and Non-adherence to healthy lifestyle group]. Resting-state functional connectivity matrices and grey matter brain features obtained from magnetic resonance imaging were used to classify the two groups using a support vector machine (SVM). The SVM classifier was 75% accurate in separating groups. The features that show consistently high importance to the classification model were functional connectivity mainly between nodes located in different prior-defined functional networks. Most nodes were located in the default mode network, dorsal attention network, and visual network. Our results provide preliminary evidence of neurobiological characteristics underlying multidomain healthy lifestyle choices. © 2023, The Author(s).
Funding details
NIG-17-08
Alzheimer’s AssociationAANIRG-397028
Canadian Institutes of Health ResearchIRSCPJT-148963
Natural Sciences and Engineering Research Council of CanadaNSERC
Alzheimer Society
Fonds de Recherche du Québec – SantéFRQS
Canada Research Chairs
Document Type: Article
Publication Stage: Final
Source: Scopus
Unsupervised high-frequency smartphone-based cognitive assessments are reliable, valid, and feasible in older adults at risk for Alzheimer’s disease
(2023) Journal of the International Neuropsychological Society: JINS, 29 (5), pp. 459-471. Cited 3 times.
Nicosia, J.a , Aschenbrenner, A.J.a , Balota, D.A.b , Sliwinski, M.J.c , Tahan, M.a , Adams, S.a , Stout, S.S.a , Wilks, H.a , Gordon, B.A.b d , Benzinger, T.L.S.d , Fagan, A.M.a , Xiong, C.a e , Bateman, R.J.a , Morris, J.C.a , Hassenstab, J.a b
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 Human Development and Family Studies, Pennsylvania State University, University ParkPA, United States
d Department of Radiology, Washington University, School of Medicine, St. Louis, MO, United States
e Division of Biostatistics, Washington University, School of Medicine, St. Louis, MO, United States
Abstract
OBJECTIVE: Smartphones have the potential for capturing subtle changes in cognition that characterize preclinical Alzheimer’s disease (AD) in older adults. The Ambulatory Research in Cognition (ARC) smartphone application is based on principles from ecological momentary assessment (EMA) and administers brief tests of associative memory, processing speed, and working memory up to 4 times per day over 7 consecutive days. ARC was designed to be administered unsupervised using participants’ personal devices in their everyday environments. METHODS: We evaluated the reliability and validity of ARC in a sample of 268 cognitively normal older adults (ages 65-97 years) and 22 individuals with very mild dementia (ages 61-88 years). Participants completed at least one 7-day cycle of ARC testing and conventional cognitive assessments; most also completed cerebrospinal fluid, amyloid and tau positron emission tomography, and structural magnetic resonance imaging studies. RESULTS: First, ARC tasks were reliable as between-person reliability across the 7-day cycle and test-retest reliabilities at 6-month and 1-year follow-ups all exceeded 0.85. Second, ARC demonstrated construct validity as evidenced by correlations with conventional cognitive measures (r = 0.53 between composite scores). Third, ARC measures correlated with AD biomarker burden at baseline to a similar degree as conventional cognitive measures. Finally, the intensive 7-day cycle indicated that ARC was feasible (86.50% approached chose to enroll), well tolerated (80.42% adherence, 4.83% dropout), and was rated favorably by older adult participants. CONCLUSIONS: Overall, the results suggest that ARC is reliable and valid and represents a feasible tool for assessing cognitive changes associated with the earliest stages of AD.
Author Keywords
digital biomarkers; ecological momentary assessment; mobile testing; preclinical Alzheimer’s disease
Document Type: Article
Publication Stage: Final
Source: Scopus
Resting-state cortical hubs in youth organize into four categories
(2023) Cell Reports, 42 (5), art. no. 112521, .
Demeter, D.V.a , Gordon, E.M.b , Nugiel, T.c , Garza, A.d , Larguinho, T.L.d , Church, J.A.d
a Department of Cognitive Science, University of California San Diego, La Jolla, CA 92093, United States
b Department of Radiology, Washington University School of Medicine, St. Louis, MO 63110, United States
c Carolina Institute for Developmental Disabilities, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, United States
d Department of Psychology, The University of Texas at Austin, Austin, TX 78712, United States
Abstract
During childhood, neural systems supporting high-level cognitive processes undergo periods of rapid growth and refinement, which rely on the successful coordination of activation across the brain. Some coordination occurs via cortical hubs—brain regions that coactivate with functional networks other than their own. Adult cortical hubs map into three distinct profiles, but less is known about hub categories during development, when critical improvement in cognition occurs. We identify four distinct hub categories in a large youth sample (n = 567, ages 8.5–17.2), each exhibiting more diverse connectivity profiles than adults. Youth hubs integrating control-sensory processing split into two distinct categories (visual control and auditory/motor control), whereas adult hubs unite under one. This split suggests a need for segregating sensory stimuli while functional networks are experiencing rapid development. Functional coactivation strength for youth control-processing hubs are associated with task performance, suggesting a specialized role in routing sensory information to and from the brain’s control system. © 2023 The Author(s)
Author Keywords
cortical hubs; CP: Neuroscience; executive functions; fMRI; functional connectivity; resting state
Funding details
20141031a
National Institutes of HealthNIHU01DA041022, U01DA041025, U01DA041028, U01DA041048, U01DA041089, U01DA041093, U01DA041106, U01DA041117, U01DA041120, U01DA041134, U01DA041148, U01DA041156, U01DA041174, U01DA050987, U01DA050988, U01DA050989, U01DA051016, U01DA051018, U01DA051037, U01DA051038, U01DA051039, U24DA041123, U24DA041147
National Institute of Mental HealthNIMH
Brain and Behavior Research FoundationBBRF
Eunice Kennedy Shriver National Institute of Child Health and Human DevelopmentNICHDR21 HD081437
Document Type: Article
Publication Stage: Final
Source: Scopus
Mechanically manipulating glymphatic transport by ultrasound combined with microbubbles
(2023) Proceedings of the National Academy of Sciences of the United States of America, 120 (21), pp. e2212933120.
Ye, D.a , Chen, S.a , Liu, Y.a , Weixel, C.a , Hu, Z.a , Yuan, J.a , Chen, H.a b c d
a Department of Biomedical Engineering, Washington University in St. Louis, St. Louis, MO 63130, United States
b Department of Radiation Oncology, Washington University School of Medicine, St. Louis, MO 63130, United States
c Department of Neurosurgery, Washington University School of Medicine, St. Louis, MO 63110, United States
d Department of Neurosurgery, Washington University School of Medicine, St. Louis, United States
Abstract
The glymphatic system is a perivascular fluid transport system for waste clearance. Glymphatic transport is believed to be driven by the perivascular pumping effect created by the pulsation of the arterial wall caused by the cardiac cycle. Ultrasound sonication of circulating microbubbles (MBs) in the cerebral vasculature induces volumetric expansion and contraction of MBs that push and pull on the vessel wall to generate a MB pumping effect. The objective of this study was to evaluate whether glymphatic transport can be mechanically manipulated by focused ultrasound (FUS) sonication of MBs. The glymphatic pathway in intact mouse brains was studied using intranasal administration of fluorescently labeled albumin as fluid tracers, followed by FUS sonication at a deep brain target (thalamus) in the presence of intravenously injected MBs. Intracisternal magna injection, the conventional technique used in studying glymphatic transport, was employed to provide a comparative reference. Three-dimensional confocal microscopy imaging of optically cleared brain tissue revealed that FUS sonication enhanced the transport of fluorescently labeled albumin tracer in the perivascular space (PVS) along microvessels, primarily the arterioles. We also obtained evidence of FUS-enhanced penetration of the albumin tracer from the PVS into the interstitial space. This study revealed that ultrasound combined with circulating MBs could mechanically enhance glymphatic transport in the brain.
Author Keywords
cerebral blood vessels; focused ultrasound; glymphatic; intranasal; mechanics
Document Type: Article
Publication Stage: Final
Source: Scopus
TREM2 inhibition triggers antitumor cell activity of myeloid cells in glioblastoma
(2023) Science Advances, 9 (19), p. eade3559.
Sun, R.a , Han, R.a , McCornack, C.a , Khan, S.a , Tabor, G.T.b , Chen, Y.b c , Hou, J.c , Jiang, H.d , Schoch, K.M.b e , Mao, D.D.a , Cleary, R.a , Yang, A.a , Liu, Q.d , Luo, J.f g , Petti, A.a h i , Miller, T.M.b e , Ulrich, J.D.b e , Holtzman, D.M.b e j , Kim, A.H.a b h i k
a Department of Neurological Surgery, Washington University School of MedicineMO, United States
b Department of Neurology, Washington University School of MedicineMO, United States
c Department of Pathology and Immunology, Washington University School of MedicineMO, United States
d Department of Anesthesiology, Washington University School of MedicineMO, United States
e Hope Center for Neurological Disorders, Washington University in St. LouisMO, United States
f Department of Surgery, Washington University School of MedicineMO, United States
g Division of Biostatistics, Washington University School of MedicineMO, United States
h Department of Genetics, Washington University School of MedicineMO, United States
i Brain Tumor Center, Siteman Cancer Center, Washington University School of MedicineMO, United States
j Center for Science and Engineering of Living Systems, Washington University in St. LouisMO, United States
k Department of Developmental Biology, Washington University School of MedicineMO, United States
Abstract
Triggering receptor expressed on myeloid cells 2 (TREM2) plays important roles in brain microglial function in neurodegenerative diseases, but the role of TREM2 in the GBM TME has not been examined. Here, we found that TREM2 is highly expressed in myeloid subsets, including macrophages and microglia in human and mouse GBM tumors and that high TREM2 expression correlates with poor prognosis in patients with GBM. TREM2 loss of function in human macrophages and mouse myeloid cells increased interferon-γ-induced immunoactivation, proinflammatory polarization, and tumoricidal capacity. In orthotopic mouse GBM models, mice with chronic and acute Trem2 loss of function exhibited decreased tumor growth and increased survival. Trem2 inhibition reprogrammed myeloid phenotypes and increased programmed cell death protein 1 (PD-1)+CD8+ T cells in the TME. Last, Trem2 deficiency enhanced the effectiveness of anti-PD-1 treatment, which may represent a therapeutic strategy for patients with GBM.
Document Type: Article
Publication Stage: Final
Source: Scopus
Two forms of asynchronous release with distinctive spatiotemporal dynamics in central synapses
(2023) eLife, 12, .
Malagon, G., Myeong, J., Klyachko, V.A.
Department of Cell Biology and Physiology, Washington University School of Medicine, St Louis, United States
Abstract
Asynchronous release is a ubiquitous form of neurotransmitter release that persists for tens to hundreds of milliseconds after an action potential. How asynchronous release is organized and regulated at the synaptic active zone (AZ) remains debatable. Using nanoscale-precision imaging of individual release events in rat hippocampal synapses, we observed two spatially distinct subpopulations of asynchronous events, ~75% of which occurred inside the AZ and with a bias towards the AZ center, while ~25% occurred outside of the functionally defined AZ, that is, ectopically. The two asynchronous event subpopulations also differed from each other in temporal properties, with ectopic events occurring at significantly longer time intervals from synchronous events than the asynchronous events inside the AZ. Both forms of asynchronous release did not, to a large extent, utilize the same release sites as synchronous events. The two asynchronous event subpopulations also differ from synchronous events in some aspects of exo-endocytosis coupling, particularly in the contribution from the fast calcium-dependent endocytosis. These results identify two subpopulations of asynchronous release events with distinctive organization and spatiotemporal dynamics. © 2023, Malagon, Myeong et al.
Author Keywords
active zone; asynchronous release; neuroscience; neurotransmitter release; presynaptic organization; rat; synaptic terminals
Document Type: Article
Publication Stage: Final
Source: Scopus
Mitigating the Associations of Kidney Dysfunction with Blood Biomarkers of Alzheimer Disease by Using Phosphorylated Tau to Total Tau Ratios
(2023) JAMA Neurology, 80 (5), pp. 516-522.
Janelidze, S.a , Barthélemy, N.R.b c , He, Y.b c , Bateman, R.J.b c , Hansson, O.a d
a Clinical Memory Research Unit, Department of Clinical Sciences Malmö, Lund University, Lund, Sweden
b Department of Neurology, Washington University, School of Medicine, St Louis, MO, United States
c The Tracy Family SILQ Center, St Louis, MO, United States
d Skåne University Hospital, Malmö, Sweden
Abstract
Importance: Chronic kidney disease (CKD) has been associated with increased plasma concentrations of phosphorylated tau (p-tau) 217 and p-tau181, which potentially decreases their usefulness in the diagnostic workup of Alzheimer disease (AD). Objective: To investigate associations of CKD with plasma ratios of p-tau217 and p-tau181 to the corresponding unphosphorylated peptides in AD. Design, Setting, and Participants: This cross-sectional study included patients with mild cognitive impairment (cohort 1; enrollment in 2000-2005) and replication in cohort 2 from the Swedish BioFINDER-2 study, including both cognitively unimpaired individuals and those with cognitive impairment (enrollment in 2017-2022). All participants were from 2 memory clinics in Sweden and had plasma tau assessments and CKD status established within 6 months of plasma collection. Exposures: P-tau217 and p-tau181, unphosphorylated peptides (Tau212-221 and Tau181-190), and the ratios (pT217/T217 and pT181/T181) as well as estimated glomerular filtration rate (eGFR) as an indicator of CKD. Main Outcomes and Measures: Associations between plasma-soluble p-tau and CKD. Results: A total of 141 participants from cohort 1 (mean [SD] age, 72.2 [7.7] years; 82 [58.2%] women) and 332 participants from cohort 2 (172 with cognitive impairment and 160 cognitively unimpaired individuals; mean [SD] age, 69.8 [9.4] years; 169 [50.9%] women) were included. Higher eGFR was associated with increased levels of plasma p-tau217, p-tau181, Tau212-221, and Tau181-190 in individuals with cognitive impairment (cohort 1: R range, -0.24 to -0.59; P <.004; cohort 2: R range, -0.18 to -0.53; P <.02) and cognitively unimpaired individuals (cohort 2: R range, -0.44 to -0.50; P <.001). However, eGFR did not correlate with the pT217/T217 ratio in patients with cognitive impairment (cohort 1: R, -0.11; P =.19; cohort 2: R, -0.02; P =.78), and the correlations with pT217/T217 ratio were significantly attenuated in cognitively unimpaired individuals (difference: R, -0.14 [95% CI, -0.22 to -0.007]; P =.001). For p-tau217 and pT217/T217, the mean fold increases in amyloid-β positive (Aβ+) compared with Aβ- groups ranged from 2.31 (95% CI, 1.86-2.77) to 4.61 (95% CI, 3.39-5.83) in participants with cognitive impairment and from 1.26 (95% CI, 0.98-1.55) to 1.27 (95% CI, 0.94-1.59) in cognitively unimpaired individuals and were clearly higher than the mean fold increases in those with CKD compared with those without CKD, ranging from 0.05 (95% CI, -0.28 to 0.38) to 0.72 (95% CI, 0.25-1.19) in participants with cognitive impairment and from 0.09 (95% CI, -0.08 to 0.26) to 0.36 (95% CI, 0.19-0.52) in cognitively unimpaired individuals. Conclusions and Relevance: In this study, CKD was associated with increased plasma levels of soluble tau, but for p-tau217 the associations were considerably lower than the association with Aβ positivity. Importantly, the ratios, and especially pT217/T217, were less associated with CKD than p-tau forms alone and therefore are likely to more accurately reflect AD-related pathological changes.. © 2023 American Medical Association. All rights reserved.
Document Type: Article
Publication Stage: Final
Source: Scopus
MYT1L is required for suppressing earlier neuronal development programs in the adult mouse brain
(2023) Genome Research, 33 (4), pp. 541-556.
Chen, J.a b , Fuhler, N.A.b c , Noguchi, K.K.b c , Dougherty, J.D.b c d
a Department of Genetics, Washington University School of Medicine, St. Louis, MO 63110, United States
b Department of Psychiatry, Washington University School of Medicine, St. Louis, MO 63110, United States
c Intellectual and Developmental Disabilities Research Center, Washington University School of Medicine, St. Louis, MO 63108, United States
d Department of Genetics, Washington University School of Medicine, St. Louis, Missouri 63110, USA;
Abstract
In vitro studies indicate the neurodevelopmental disorder gene myelin transcription factor 1-like (MYT1L) suppresses non-neuronal lineage genes during fibroblast-to-neuron direct differentiation. However, MYT1L’s molecular and cellular functions in the adult mammalian brain have not been fully characterized. Here, we found that MYT1L loss leads to up-regulated deep layer (DL) gene expression, corresponding to an increased ratio of DL/UL neurons in the adult mouse cortex. To define potential mechanisms, we conducted Cleavage Under Targets & Release Using Nuclease (CUT&RUN) to map MYT1L binding targets and epigenetic changes following MYT1L loss in mouse developing cortex and adult prefrontal cortex (PFC). We found MYT1L mainly binds to open chromatin, but with different transcription factor co-occupancies between promoters and enhancers. Likewise, multiomic data set integration revealed that, at promoters, MYT1L loss does not change chromatin accessibility but increases H3K4me3 and H3K27ac, activating both a subset of earlier neuronal development genes as well as Bcl11b, a key regulator for DL neuron development. Meanwhile, we discovered that MYT1L normally represses the activity of neurogenic enhancers associated with neuronal migration and neuronal projection development by closing chromatin structures and promoting removal of active histone marks. Further, we showed that MYT1L interacts with HDAC2 and transcriptional repressor SIN3B in vivo, providing potential mechanisms underlying repressive effects on histone acetylation and gene expression. Overall, our findings provide a comprehensive map of MYT1L binding in vivo and mechanistic insights into how MYT1L loss leads to aberrant activation of earlier neuronal development programs in the adult mouse brain. © 2023 Chen et al.; Published by Cold Spring Harbor Laboratory Press.
Document Type: Article
Publication Stage: Final
Source: Scopus
Design and feasibility of an Alzheimer’s disease blood test study in a diverse community-based population
(2023) Alzheimer’s and Dementia, .
Li, M.a b , Li, Y.a b , Schindler, S.E.a c d , Yen, D.a , Sutcliffe, S.e , Babulal, G.M.a , Benzinger, T.L.S.d f , Lenze, E.J.g , Bateman, R.J.a b c d
a Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States
b The Tracy Family Stable Isotope Labeling Quantitation Center for Neurodegenerative Biology, Washington University School of Medicine, St. Louis, MO, United States
c Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO, United States
d Knight Alzheimer Disease Research Center, Washington University School of Medicine, St. Louis, MO, United States
e Department of Surgery – Public Health Sciences, Washington University School of Medicine, St. Louis, MO, United States
f Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, MO, United States
g Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, United States
Abstract
INTRODUCTION: Alzheimer’s disease (AD) blood tests are likely to become increasingly important in clinical practice, but they need to be evaluated in diverse groups before use in the general population. METHODS: This study enrolled a community-based sample of older adults in the St. Louis, Missouri, USA area. Participants completed a blood draw, Eight-Item Informant Interview to Differentiate Aging and Dementia (AD8®), Montreal Cognitive Assessment (MoCA), and survey about their perceptions of the blood test. A subset of participants completed additional blood collection, amyloid positron emission tomography (PET), magnetic resonance imaging (MRI), and Clinical Dementia Rating (CDR®). RESULTS: Of the 859 participants enrolled in this ongoing study, 20.6% self-identified as Black or African American. The AD8 and MoCA correlated moderately with the CDR. The blood test was well accepted by the cohort, but it was perceived more positively by White and highly educated individuals. DISCUSSION: Studying an AD blood test in a diverse population is feasible and may accelerate accurate diagnosis and implementation of effective treatments. HIGHLIGHTS: A diverse group of older adults was recruited to evaluate a blood amyloid test. The enrollment rate was high and the blood test was well accepted by participants. Cognitive impairment screens have moderate performance in a diverse population. Alzheimer’s disease blood tests are likely to be feasible for use in real-world settings. © 2023 The Authors. Alzheimer’s & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer’s Association.
Author Keywords
Alzheimer’s disease; amyloid PET; blood test; blood-based biomarkers; clinical trial enrollment; cognitive impairment; dementia; recruitment
Funding details
National Institutes of HealthNIHR56AG061900
National Center for Advancing Translational SciencesNCATS
Foundation for Barnes-Jewish HospitalFBJH
Institute of Clinical and Translational SciencesICTSUL1TR002345
GHR FoundationGHR
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
Generation of iPSC-derived human forebrain organoids assembling bilateral eye primordia
(2023) Nature Protocols, .
Gabriel, E.a , Albanna, W.b c , Pasquini, G.d , Ramani, A.a , Josipovic, N.e f , Mariappan, A.a , Riparbelli, M.G.g , Callaini, G.g , Karch, C.M.h , Goureau, O.i , Papantonis, A.e f , Busskamp, V.d , Schneider, T.b , Gopalakrishnan, J.a
a Institute of Human Genetics, University Hospital, Heinrich-Heine-University, Düsseldorf, Germany
b Institute for Neurophysiology, University of Cologne, Cologne, Germany
c Department of Neurosurgery, RWTH Aachen University, Aachen, Germany
d Department of Ophthalmology, Medical Faculty, University of Bonn, Bonn, Germany
e Institute of Pathology, University Medicine Göttingen, Georg-August University Göttingen, Göttingen, Germany
f Center of Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany
g Department of Life Sciences and Medical Biotechnology University of Siena, Siena, Italy
h Department of Psychiatry, Washington University in St. Louis, St. Louis, MO, United States
i Institut de la Vision, Sorbonne Université, INSERM, CNRS, Paris, France
Abstract
Induced pluripotent stem cell-derived brain organoids enable the developmental complexities of the human brain to be deconstructed. During embryogenesis, optic vesicles (OVs), the eye primordium attached to the forebrain, develop from diencephalon. However, most 3D culturing methods generate either brain or retinal organoids individually. Here we describe a protocol to generate organoids with both forebrain entities, which we call OV-containing brain organoids (OVB organoids). In this protocol, we first induce neural differentiation (days 0–5) and collect neurospheres, which we culture in a neurosphere medium to initiate their patterning and further self-assembly (days 5–10). Then, upon transfer to spinner flasks containing OVB medium (days 10–30), neurospheres develop into forebrain organoids with one or two pigmented dots restricted to one pole, displaying forebrain entities of ventral and dorsal cortical progenitors and preoptic areas. Further long-term culture results in photosensitive OVB organoids constituting complementary cell types of OVs, including primitive corneal epithelial and lens-like cells, retinal pigment epithelia, retinal progenitor cells, axon-like projections and electrically active neuronal networks. OVB organoids provide a system to help dissect interorgan interactions between the OVs as sensory organs and the brain as a processing unit, and can help model early eye patterning defects, including congenital retinal dystrophy. To conduct the protocol, experience in sterile cell culture and maintenance of human induced pluripotent stem cells is essential; theoretical knowledge of brain development is advantageous. Furthermore, specialized expertise in 3D organoid culture and imaging for the analysis is needed. © 2023, Springer Nature Limited.
Funding details
Deutsche ForschungsgemeinschaftDFGEXC-2151-390873048-Cluster, SPP2127-BU 2974/4-1
Volkswagen FoundationA110720
Fritz Thyssen Stiftung
Rheinische Friedrich-Wilhelms-Universität BonnUni Bonn
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
Twelve Weeks of Intermittent Caloric Restriction Diet Mitigates Neuroinflammation in Midlife Individuals with Multiple Sclerosis: A Pilot Study with Implications for Prevention of Alzheimer’s Disease
(2023) Journal of Alzheimer’s Disease: JAD, 93 (1), pp. 263-273.
Rahmani, F.a , Ghezzi, L.b , Tosti, V.b , Liu, J.a c , Song, S.-K.d e , Wu, A.T.d e , Rajamanickam, J.a , Obert, K.A.b , Benzinger, T.L.S.a f , Mittendorfer, B.g , Piccio, L.b e h i , Raji, C.A.a f
a Mallinckrodt Institute of Radiology, Division of Neuroradiology, Washington University in St. Louis, St. Louis, MO, United States
b Department of Neurology, Washington University in St. Louis, St. Louis, MO, United States
c Department of Surgery, Division of Public Health Sciences, Washington University in St. Louis, St. Louis, MO, United States
d Department of Physics, Washington University in St. Louis, St. Louis, MO, United States
e Hope Center for Neurological Disorders, Washington University in St. Louis, St. Louis, MO, United States
f Charles F. and Joanne Knight Alzheimer Disease Research Center, Washington University in St Louis, St. Louis, MO, United States
g Department of Medicine, Division of Geriatrics and Nutritional Science, Washington University in St. Louis, St. Louis, MO, United States
h Brain and Mind Centre, School of Medical Sciences, University of Sydney, NSW, Australia
i Charles Perkin Centre, University of Sydney NSW, Australia
Abstract
BACKGROUND: Multiple sclerosis (MS) is a prototype neuroinflammatory disorder with increasingly recognized role for neurodegeneration. Most first-line treatments cannot prevent the progression of neurodegeneration and the resultant disability. Interventions can improve symptoms of MS and might provide insights into the underlying pathology. OBJECTIVE: To investigate the effect of intermittent caloric restriction on neuroimaging markers of MS. METHODS: We randomized ten participants with relapsing remitting MS to either a 12-week intermittent calorie restriction (iCR) diet (n = 5) or control (n = 5). Cortical thickness and volumes were measured through FreeSurfer, cortical perfusion was measured by arterial spin labeling and neuroinflammation through diffusion basis spectrum imaging. RESULTS: After 12 weeks of iCR, brain volume increased in the left superior and inferior parietal gyri (p: 0.050 and 0.049, respectively) and the banks of the superior temporal sulcus (p: 0.01). Similarly in the iCR group, cortical thickness improved in the bilateral medial orbitofrontal gyri (p: 0.04 and 0.05 in right and left, respectively), the left superior temporal gyrus (p: 0.03), and the frontal pole (p: 0.008) among others. Cerebral perfusion decreased in the bilateral fusiform gyri (p: 0.047 and 0.02 in right and left, respectively) and increased in the bilateral deep anterior white matter (p: 0.03 and 0.013 in right and left, respectively). Neuroinflammation, demonstrated through hindered and restricted water fractions (HF and RF), decreased in the left optic tract (HF p: 0.02), and the right extreme capsule (RF p: 0.007 and HF p: 0.003). CONCLUSION: These pilot data suggest therapeutic effects of iCR in improving cortical volume and thickness and mitigating neuroinflammation in midlife adults with MS.
Author Keywords
Alzheimer’s disease; arterial spin labeling; caloric restriction; diffusion basis spectrum imaging; multiple sclerosis; neuroinflammation; prevention; relative cerebral blood flow
Document Type: Article
Publication Stage: Final
Source: Scopus
CSF-Based Volumetric Imaging Biomarkers Highlight Incidence and Risk Factors for Cerebral Edema After Ischemic Stroke
(2023) Neurocritical Care, .
Bui, Q.a , Kumar, A.a , Chen, Y.a , Hamzehloo, A.a , Heitsch, L.b , Slowik, A.c , Strbian, D.d , Lee, J.-M.a , Dhar, R.a
a Department of Neurology, Washington University School of Medicine, 660 S Euclid Avenue, Campus Box 8111, St. Louis, MO, United States
b Department of Emergency Medicine, Washington University School of Medicine, St. Louis, MO, United States
c Department of Neurology, Jagiellonian University Medical College, Krakow, Poland
d Department of Neurology, Helsinki University Hospital, Helsinki, Finland
Abstract
Background: Cerebral edema has primarily been studied using midline shift or clinical deterioration as end points, which only captures the severe and delayed manifestations of a process affecting many patients with stroke. Quantitative imaging biomarkers that measure edema severity across the entire spectrum could improve its early detection, as well as identify relevant mediators of this important stroke complication. Methods: We applied an automated image analysis pipeline to measure the displacement of cerebrospinal fluid (ΔCSF) and the ratio of lesional versus contralateral hemispheric cerebrospinal fluid (CSF) volume (CSF ratio) in a cohort of 935 patients with hemispheric stroke with follow-up computed tomography scans taken a median of 26 h (interquartile range 24–31) after stroke onset. We determined diagnostic thresholds based on comparison to those without any visible edema. We modeled baseline clinical and radiographic variables against each edema biomarker and assessed how each biomarker was associated with stroke outcome (modified Rankin Scale at 90 days). Results: The displacement of CSF and CSF ratio were correlated with midline shift (r = 0.52 and − 0.74, p < 0.0001) but exhibited broader ranges. A ΔCSF of greater than 14% or a CSF ratio below 0.90 identified those with visible edema: more than half of the patients with stroke met these criteria, compared with only 14% who had midline shift at 24 h. Predictors of edema across all biomarkers included a higher National Institutes of Health Stroke Scale score, a lower Alberta Stroke Program Early CT score, and lower baseline CSF volume. A history of hypertension and diabetes (but not acute hyperglycemia) predicted greater ΔCSF but not midline shift. Both ΔCSF and a lower CSF ratio were associated with worse outcome, adjusting for age, National Institutes of Health Stroke Scale score, and Alberta Stroke Program Early CT score (odds ratio 1.7, 95% confidence interval 1.3–2.2 per 21% ΔCSF). Conclusions: Cerebral edema can be measured in a majority of patients with stroke on follow-up computed tomography using volumetric biomarkers evaluating CSF shifts, including in many without visible midline shift. Edema formation is influenced by clinical and radiographic stroke severity but also by chronic vascular risk factors and contributes to worse stroke outcomes. © 2023, Springer Science+Business Media, LLC, part of Springer Nature and Neurocritical Care Society.
Author Keywords
Biomarkers; Brain edema; Computed tomography; Imaging; Stroke
Funding details
National Institutes of HealthNIHK23NS099440, K23NS099487, R01NS085419, R01NS121218, U24NS107230
Biogen
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
Relationships Between Hourly Cognitive Variability and Risk of Alzheimer’s Disease Revealed With Mixed-Effects Location Scale Models
(2023) Neuropsychology, .
Aschenbrenner, A.J.a , Hassenstab, J.a b , Morris, J.C.a , Cruchaga, C.c , Jackson, J.J.b
a Department of Neurology, School of Medicine, Washington University, St. Louis, United States
b Department of Psychological and Brain Sciences, Washington University, St. Louis, United States
c Department of Psychiatry, School of Medicine, Washington University, St. Louis, United States
Abstract
Objective: Observational studies on aging and Alzheimer’s disease (AD) typically focus on mean-level changes in cognitive performance over relatively long periods of time (years or decades). Additionally, some studies have examined how trial-level fluctuations in speeded reaction time are related to both age and AD. The aim of the current project was to describe patterns of variability across repeated days of testing as a function of AD risk in cognitively normal older adults. Method: The current project examined the performance of the Ambulatory Research in Cognition (ARC) smartphone application, a highfrequency remote cognitive assessment paradigm, that administers brief tests of episodic memory, spatial working memory, and processing speed. Bayesian mixed-effects location scale models were used to explore differences in mean cognitive performance and intraindividual variability across 28 repeated sessions over a 1-week assessment interval as function of age and genetic risk of AD, specifically the presence of at least one apolipoprotein E (APOE) ε4 allele. Results: Mean performance on processing speed and working memory was negatively related to age and APOE status.More importantly, e4 carriers exhibited increased session-level variability on a test of processing speed compared to noncarriers. Age and education did not consistently relate to cognitive variability, contrary to expectations. Conclusion: Preclinical AD risk, defined as possessing at least one APOE ε4 allele, is not only associated with meanlevel performance differences, but also with increases in variability across repeated testing occasions particularly on a test of processing speed. Thus, cognitive variability may serve as an additional and important indicator of AD risk © 2023 American Psychological Association
Author Keywords
Alzheimer’s disease; apolipoprotein E; cognition; measurement burst; variability
Funding details
R01 AG057840
National Institute on AgingNIAK01 AG071847, P01-AG003991, P01-AG026276, P30 AG066444
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
Endogenous recapitulation of Alzheimer’s disease neuropathology through human 3D direct neuronal reprogramming
(2023) bioRxiv 2023.05.24.542155
Zhao Sun, Ji-Sun Kwon, Yudong Ren, Shawei Chen, Kitra Cates, Xinguo Lu, Courtney K. Walker, Hande Karahan, Sanja Sviben, James A J Fitzpatrick, Clarissa Valdez, Henry Houlden, Celeste M. Karch, Randall J. Bateman, Chihiro Sato, Steven J. Mennerick, Marc I. Diamond, Jungsu Kim, Rudolph E. Tanzi, David M. Holtzman, Andrew S. Yoo
Abstract
Alzheimer’s disease (AD) is a neurodegenerative disorder that primarily affects elderly individuals, and is characterized by hallmark neuronal pathologies including extracellular amyloid-β (Aβ) plaque deposition, intracellular tau tangles, and neuronal death. However, recapitulating these age-associated neuronal pathologies in patient-derived neurons has remained a significant challenge, especially for late-onset AD (LOAD), the most common form of the disorder. Here, we applied the high efficiency microRNA-mediated direct neuronal reprogramming of fibroblasts from AD patients to generate cortical neurons in three-dimensional (3D) Matrigel and self-assembled neuronal spheroids. Our findings indicate that neurons and spheroids reprogrammed from both autosomal dominant AD (ADAD) and LOAD patients exhibited AD-like phenotypes linked to neurons, including extracellular Aβ deposition, dystrophic neurites with hyperphosphorylated, K63-ubiquitin-positive, seed-competent tau, and spontaneous neuronal death in culture. Moreover, treatment with β- or γ-secretase inhibitors in LOAD patient-derived neurons and spheroids before Aβ deposit formation significantly lowered Aβ deposition, as well as tauopathy and neurodegeneration. However, the same treatment after the cells already formed Aβ deposits only had a mild effect. Additionally, inhibiting the synthesis of age-associated retrotransposable elements (RTEs) by treating LOAD neurons and spheroids with the reverse transcriptase inhibitor, lamivudine, alleviated AD neuropathology. Overall, our results demonstrate that direct neuronal reprogramming of AD patient fibroblasts in a 3D environment can capture age-related neuropathology and reflect the interplay between Aβ accumulation, tau dysregulation, and neuronal death. Moreover, miRNA-based 3D neuronal conversion provides a human-relevant AD model that can be used to identify compounds that can potentially ameliorate AD-associated pathologies and neurodegeneration.
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