Clinical and magnetic resonance imaging outcomes in pediatric-onset MS patients on fingolimod and ocrelizumab
(2024) Multiple Sclerosis and Related Disorders, 87, art. no. 105647, .
Nasr, Z.a , Casper, T.C.b , Waltz, M.b , Virupakshaiah, A.a , Lotze, T.c , Shukla, N.c , Chitnis, T.d , Gorman, M.e , Benson, L.A.e , Rodriguez, M.f , Tillema, J.M.f , Krupp, L.g , Schreiner, T.h , Mar, S.i , Rensel, M.j , Rose, J.k , Liu, C.l , Guye, S.l , Manlius, C.l , Waubant, E.a , U.S. Network of Pediatric Multiple Sclerosis Centersm
a UCSF, Weill Institute for Neurosciences, San Francisco, United States
b University of Utah, Department of Pediatrics, Salt Lake City, United States
c Baylor College of Medicine/Texas Children’s Hospital, Neurology and Developmental Neuroscience, Houston, United States
d Massachusetts General Hospital for Children, Mass General Brigham Pediatric MS Center, Boston, United States
e Boston Children’s Hospital, Pediatric Multiple Sclerosis and Related Disorders Program, Boston, United States
f Mayo Clinic, Pediatric MS Center, Rochester, United States
g New York University Langone Medical Center, Pediatric Multiple Sclerosis Center, New York, United States
h University of Colorado, Rocky Mountain MS Center, Aurora, United States
i Washington University, Pediatric MS and other Demyelinating Disease Center, St. Louis, United States
j Cleveland Clinic, Mellen Center for Multiple Sclerosis, Cleveland, United States
k University of Utah, Department of Neurology, Salt Lake City, United States
l F. Hoffmann-La Roche Ltd, Basel, Switzerland
Abstract
Background: Observational studies looking at clinical a++nd MRI outcomes of treatments in pediatric MS, could assess current treatment algorithms, and provide insights for designing future clinical trials. Objective: To describe baseline characteristics and clinical and MRI outcomes in MS patients initiating ocrelizumab and fingolimod under 18 years of age. Methods: MS patients seen at 12 centers of US Network of Pediatric MS were included in this study if they had clinical and MRI follow-up and started treatment with either ocrelizumab or fingolimod prior to the age of 18. Results: Eighty-seven patients initiating fingolimod and 52 initiating ocrelizumab met the inclusion criteria. Before starting fingolimod, mean annualized relapse rate was 0.43 (95 % CI: 0.29 – 0.65) and 78 % developed new T2 lesions while during treatment it was 0.12 (95 % CI: 0.08 – 1.9) and 47 % developed new T2 lesions. In the ocrelizumab group, the mean annualized relapse rate prior to initiation of treatment was 0.64 (95 % CI: 0.38–1.09) and a total of 83 % of patients developed new T2 lesions while during treatment it was 0.09 (95 % CI: 0.04–0.21) and none developed new T2 lesions. Conclusion: This study highlights the importance of evaluating current treatment methods and provides insights about the agents in the ongoing phase III trial comparing fingolimod and ocrelizumab. © 2024
Author Keywords
Fingolimod; MRI outcome; Multiple sclerosis; Ocrelizumab
Document Type: Article
Publication Stage: Final
Source: Scopus
Replication and reliability of Parkinson’s disease clinical subtypes
(2024) Parkinsonism and Related Disorders, 124, art. no. 107016, .
Cash, T.V.a , Lessov-Schlaggar, C.N.b , Foster, E.R.a b f , Myers, P.S.a , Jackson, J.J.c , Maiti, B.a d , Kotzbauer, P.T.a , Perlmutter, J.S.a d e f g , Campbell, M.C.a d
a Department of Neurology, Washington University School of Medicine, United States
b Department of Psychiatry, Washington University School of Medicine, United States
c Department of Psychological and Brain Sciences, Washington University in St. Louis, United States
d Department of Radiology, Washington University School of Medicine, United States
e Department of Neuroscience, Washington University School of Medicine, United States
f Program in Occupational Therapy, Washington University School of Medicine, United States
g Program in Physical Therapy, Washington University School of Medicine, United States
Abstract
Background: We recently identified three distinct Parkinson’s disease subtypes: “motor only” (predominant motor deficits with intact cognition and psychiatric function); “psychiatric & motor” (prominent psychiatric symptoms and moderate motor deficits); “cognitive & motor” (cognitive and motor deficits). Objective: We used an independent cohort to replicate and assess reliability of these Parkinson’s disease subtypes. Methods: We tested our original subtype classification with an independent cohort (N = 100) of Parkinson’s disease participants without dementia and the same comprehensive evaluations assessing motor, cognitive, and psychiatric function. Next, we combined the original (N = 162) and replication (N = 100) datasets to test the classification model with the full combined dataset (N = 262). We also generated 10 random split-half samples of the combined dataset to establish the reliability of the subtype classifications. Latent class analyses were applied to the replication, combined, and split-half samples to determine subtype classification. Results: First, LCA supported the three-class solution – Motor Only, Psychiatric & Motor, and Cognitive & Motor– in the replication sample. Next, using the larger, combined sample, LCA again supported the three subtype groups, with the emergence of a potential fourth group defined by more severe motor deficits. Finally, split-half analyses showed that the three-class model also had the best fit in 13/20 (65%) split-half samples; two-class and four-class solutions provided the best model fit in five (25%) and two (10%) split-half replications, respectively. Conclusions: These results support the reproducibility and reliability of the Parkinson’s disease behavioral subtypes of motor only, psychiatric & motor, and cognitive & motor groups. © 2024 The Authors
Author Keywords
Classification; Latent class analysis; Parkinson disease; Psychometrics
Funding details
Washington University in St. LouisWUSTL
Huntington’s Disease Society of AmericaHDSA
American Academy of NeurologyAAN
Mallinckrodt Institute of Radiology, School of Medicine, Washington University in St. LouisMIR
Foundation for Barnes-Jewish HospitalFBJH
Michael J. Fox Foundation for Parkinson’s ResearchMJFF
McDonnell Center for Systems Neuroscience
U.S. Department of DefenseDODW81XWH-217-1-0393
U.S. Department of DefenseDOD
National Institute of Neurological Disorders and StrokeNINDSK23 NS125107, TR 001456, NS097799, NS075321, NS097437
National Institute of Neurological Disorders and StrokeNINDS
UL1RR024992
BiogenU19 NS110456, NS092865, AG050263, NS109487, ES029524, NS075527, U54NS116025, AG-64937, NS107281, R61 AT010753, NS103957, U10NS077384
Biogen
National Institutes of HealthNIHKL2 TR002346, AT011015, NS124738
National Institutes of HealthNIH
National Institute on AgingNIAR21AG063974, R01AG065214
National Institute on AgingNIA
National Institute of Diabetes and Digestive and Kidney DiseasesNIDDKR01DK126826, R01DK064832
National Institute of Diabetes and Digestive and Kidney DiseasesNIDDK
AT010753, AT010753-S1, AG063974, NS124378
National Center for Advancing Translational SciencesNCATSNS118146
National Center for Advancing Translational SciencesNCATS
American Parkinson Disease AssociationAPDA971949
American Parkinson Disease AssociationAPDA
American Brain FoundationABFNS110436, NS110456, NS123860, AG071754
American Brain FoundationABF
CHDI FoundationCHDINS116025, NS065701
CHDI FoundationCHDI
Document Type: Article
Publication Stage: Final
Source: Scopus
Glutamatergic supramammillary nucleus neurons respond to threatening stressors and promote active coping
(2024) eLife, 12, .
Escobedo, A.a , Holloway, S.-A.a , Votoupal, M.b , Cone, A.L.a , Skelton, H.a , Legaria, A.A.c d , Ndiokho, I.e , Floyd, T.f , Kravitz, A.V.a c d , Bruchas, M.R.g h i j , Norris, A.J.a
a Department of Anesthesiology, Washington University in St. Louis, St. Louis, United States
b Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, United States
c Department of Neuroscience, Washington University in St. Louis, St. Louis, United States
d Department of Psychiatry, Washington University in St. Louis, St. Louis, United States
e Medical College of Wisconsin, Milwaukee, United States
f Department of Obstetrics and Gynecology, Washington University in St. Louis, St. Louis, United States
g Center for Neurobiology of Addiction, Pain, Emotion University of Washington, Seattle, United States
h Department of Anesthesiology and Pain Medicine University of Washington, Seattle, United States
i Department of Pharmacology University of Washington, Seattle, United States
j Department of Bioengineering University of Washington, Seattle, United States
Abstract
Threat-response neural circuits are conserved across species and play roles in normal behavior and psychiatric diseases. Maladaptive changes in these neural circuits contribute to stress, mood, and anxiety disorders. Active coping in response to stressors is a psychosocial factor associated with resilience against stress-induced mood and anxiety disorders. The neural circuitry underlying active coping is poorly understood, but the functioning of these circuits could be key for overcoming anxiety and related disorders. The supramammillary nucleus (SuM) has been suggested to be engaged by threat. SuM has many projections and a poorly understood diversity of neural populations. In studies using mice, we identified a unique population of glutamatergic SuM neurons (SuMVGLUT2+::POA) based on projection to the preoptic area of the hypothalamus (POA) and found SuMVGLUT2+::POA neurons have extensive arborizations. SuMVGLUT2+::POA neurons project to brain areas that mediate features of the stress and threat responses including the paraventricular nucleus thalamus (PVT), periaqueductal gray (PAG), and habenula (Hb). Thus, SuMVGLUT2+::POA neurons are positioned as a hub, connecting to areas implicated in regulating stress responses. Here we report SuMVGLUT2+::POA neurons are recruited by diverse threatening stressors, and recruitment correlated with active coping behaviors. We found that selective photoactivation of the SuMVGLUT2+::POA population drove aversion but not anxiety like behaviors. Activation of SuMVGLUT2+::POA neurons in the absence of acute stressors evoked active coping like behaviors and drove instrumental behavior. Also, activation of SuMVGLUT2+::POA neurons was sufficient to convert passive coping strategies to active behaviors during acute stress. In contrast, we found activation of GABAergic (VGAT+) SuM neurons (SuMVGAT+) neurons did not alter drive aversion or active coping, but termination of photostimulation was followed by increased mobility in the forced swim test. These findings establish a new node in stress response circuitry that has projections to many brain areas and evokes flexible active coping behaviors. © 2023, Escobedo et al.
Author Keywords
coping; mouse; neuroscience; optogenetics; stress; supramammillary nucleus; Threat
Document Type: Article
Publication Stage: Final
Source: Scopus
Alcohol and substance use in older adults with treatment-resistant depression
(2024) International Journal of Geriatric Psychiatry, 39 (6), art. no. e6105, .
Srifuengfung, M.a b , Lenze, E.J.a , Roose, S.P.c , Brown, P.J.c , Lavretsky, H.d , Karp, J.F.e , Reynolds, C.F., IIIf , Yingling, M.a , Sa-nguanpanich, N.b , Mulsant, B.H.g
a Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, United States
b Department of Psychiatry, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand
c Department of Psychiatry, Columbia University College of Physicians and Surgeons and the New York State Psychiatric Institute, New York, NY, United States
d Department of Psychiatry and Biobehavioral Sciences, University of California, Los Angeles, CA, United States
e Department of Psychiatry, College of Medicine-Tucson, University of Arizona, Tucson, AZ, United States
f Department of Psychiatry, School of Medicine, University of Pittsburgh, Pittsburgh, PA, United States
g Centre for Addiction and Mental Health and Department of Psychiatry, Temerty Faculty of Medicine, University of Toronto, Toronto, ON, Canada
Abstract
Introduction: Alcohol and substance use are increasing in older adults, many of whom have depression, and treatment in this context may be more hazardous. We assessed alcohol and other substance use patterns in older adults with treatment-resistant depression (TRD). We examined patient characteristics associated with higher alcohol consumption and examined the moderating effect of alcohol on the association between clinical variables and falls during antidepressant treatment. Methods: This secondary and exploratory analysis used baseline clinical data and data on falls during treatment from a large randomized antidepressant trial in older adults with TRD (the OPTIMUM trial). Multivariable ordinal logistic regression was used to identify variables associated with higher alcohol use. An interaction model was used to evaluate the moderating effect of alcohol on falls during treatment. Results: Of 687 participants, 51% acknowledged using alcohol: 10% were hazardous drinkers (AUDIT-10 score ≥5) and 41% were low-risk drinkers (score 1–4). Benzodiazepine use was seen in 24% of all participants and in 21% of drinkers. Use of other substances (mostly cannabis) was associated with alcohol consumption: it was seen in 5%, 9%, and 15% of abstainers, low-risk drinkers, and hazardous drinkers, respectively. Unexpectedly, use of other substances predicted increased risk of falls during antidepressant treatment only in abstainers. Conclusions: One-half of older adults with TRD in this study acknowledged using alcohol. Use of alcohol concurrent with benzodiazepine and other substances was common. Risks—such as falls—of using alcohol and other substances during antidepressant treatment needs further study. © 2024 The Author(s). International Journal of Geriatric Psychiatry published by John Wiley & Sons Ltd.
Author Keywords
aging; cannabis; depressive disorder; elderly; falls; major depressive disorder; marijuana; polysubstance; seniors; treatment-resistant depression
Funding details
Johnson & Johnson Innovative Medicine
Patient-Centered Outcomes Research InstitutePCORITRD‐1511‐33321
Patient-Centered Outcomes Research InstitutePCORI
Taylor Family Institute for Innovative Psychiatric Research, School of Medicine, Washington University in St. LouisUL1TR002345
Taylor Family Institute for Innovative Psychiatric Research, School of Medicine, Washington University in St. Louis
National Institutes of HealthNIHMH114981
National Institutes of HealthNIH
Document Type: Article
Publication Stage: Final
Source: Scopus
Neurobehavioral Mechanisms Influencing the Association Between Generativity, the Desire to Promote Well-Being of Younger Generations, and Purpose in Life in Older Adults at Risk for Alzheimer’s Disease
(2024) Journals of Gerontology – Series B Psychological Sciences and Social Sciences, 79 (6), art. no. gbae060, .
Walker, C.S.a , Li, L.b , Baracchini, G.a c , Tremblay-Mercier, J.c , Spreng, R.N.a c , Geddes, M.R.a c , Aisen, P.g h , Anthal, E.d e , Appleby, M.d e , Bellec, P.d g i , Benbouhoud, F.e , Bohbot, V.d e f , Brandt, J.j , Breitner, J.C.S.d e f , Brunelle, C.d e , Chakravarty, M.d e f , Cheewakriengkrai, L.d e k , Collins, L.d g l , Couture, D.e , Craft, S.m , Dadar, M.f g , Daoust, L.-A.d , Das, S.g n , Dauar-Tedeschi, M.d e k , Dea, D.d e , Desrochers, N.d e , Dubuc, S.e , Duclair, G.d e , Dufour, M.d e , Eisenberg, M.o , El-Khoury, R.d e , Etienne, P.d e f , Evans, A.d e l , Faubert, A.-M.e , Ferdinand, F.d e , Fonov, V.l n , Fontaine, D.d e , Francoeur, R.d e , Frenette, J.d e , Gagné, G.d e , Gauthier, S.c d e f k , Geddes, M.R.c d g , Gervais, V.d e , Giles, R.d e , Gonneaud, J.d e , Gordon, R.d e , Greco, C.d e , Hoge, R.c d l , Hudon, L.d , Ituria-Medina, Y.c d l n , Kat, J.d e l , Kazazian, C.d e , Kligman, S.d e , Kostopoulos, P.l p , Labonté, A.d e , Lafaille-Magnan, M.-E.d e q , Lee, T.d e , Leoutsakos, J.-M.j , Leppert, I.d e g , Madjar, C.d e g , Mahar, L.d e , Maltais, J.-R.d e k , Mathieu, A.e , Mathotaarachchi, S.e k , Mayrand, G.d e , McSweeney, M.q , Meyer, P.-F.d e q , Michaud, D.e , Miron, J.d e q , Morris, J.C.r , Multhaup, G.s , Münter, L.-M.s , Nair, V.e f k , Near, J.e f , Newbold-Fox, H.e , Nilsson, N.d e q , Pagé, V.e , Pascoal, T.A.c d e k , Petkova, M.d e g , Picard, C.d e , Binette, A.P.d e , Pogossova, G.d e , Poirier, J.d e f , Rajah, N.d e p , Remz, J.e , Rioux, P.g , Rosa-Neto, P.d e f k , Sager, M.A.t , Saint-Fort, E.F.e , Savard, M.d e , Soucy, J.-P.g n , Sperling, R.A.u , Spreng, N.g , St-Onge, F.d e q , Tardif, C.d e , Théroux, L.d e , Thomas, R.G.v , Toussaint, P.-J.h n , Tremblay-Mercier, J.d e , Tuwaig, M.d e , Vachon-Presseau, E.e w , Vallée, I.d e , Venugopalan, V.d e , Villeneuve, S.d e f , Ducharme, S.d e f , Wan, K.d e , Wang, S.e k q , The PREVENT-AD Research Groupx
a Faculty of Medicine, Department of Neurology and Neurosurgery, Montreal Neurological Institute (MNI), McGill University, Montreal, QC, Canada
b Department of Pharmacology and Therapeutics, McGill University, Montreal, QC, Canada
c Centre for Studies in the Prevention of Alzheimer’s Disease, Douglas Mental Health Institute, 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, McGill University, Montreal, QC, Canada
f Department of Psychiatry, McGill University, Montreal, QC, Canada
g Montreal Neurological Institute, Montreal, QC, Canada
h Alzheimer’s Therapeutic Research Institute, University of Southern California, San Diego, CA, United States
i Université de Montréal, Montreal, QC, Canada
j John Hopkins University, Baltimore, MD, United States
k Research Centre for Studies in Aging, McGill University, Montreal, QC, Canada
l Department of Biomedical Engineering, McGill University, Montreal, QC, Canada
m Wake Forest School of Medicine, Winston-Salem, NC, United States
n McConnell Brain Imaging Center, McGill University, Montreal, QC, Canada
o School of Population and Global Health, McGill University, Montreal, QC, Canada
p Department of Psychology, McGill University, Montreal, QC, Canada
q Neuroscience Department, McGill University, Montreal, QC, Canada
r Washington University School of Medecine in St-Louis, St. Louis, MO, United States
s Department of Pharmacology, McGill University, Montreal, QC, Canada
t Wisconsin Alzheimer’s Institute, UW School of Medicine and Public Health, Milwaukee, WI, United States
u Center for Alzheimer’s Research and Treatment Harvard Medical School, Boston, MA, United States
v School of Medicine, University California, San Diego, La Jolla, San Diego, CA, United States
w Northwestern University, Chicago, IL, United States
Abstract
Objectives: Generativity, the desire and action to improve the well-being of younger generations, is associated with purpose in life among older adults. However, the neurobehavioral factors supporting the relationship between generativity and purpose in life remain unknown. This study aims to identify the functional neuroanatomy of generativity and mechanisms linking generativity with purpose in life in at-risk older adults. Methods: Fifty-eight older adults (mean age = 70.8, SD = 5.03, 45 females) with a family history of Alzheimer’s disease (AD) were recruited from the PREVENT-AD cohort. Participants underwent brain imaging and completed questionnaires assessing generativity, social support, and purpose in life. Mediation models examined whether social support mediated the association between generativity and purpose in life. Seed-to-voxel analyses investigated the association between generativity and resting-state functional connectivity (rsFC) to the ventromedial prefrontal cortex (vmPFC) and ventral striatum (VS), and whether this rsFC moderated the relationship between generativity and purpose in life. Results: Affectionate social support mediated the association between generative desire and purpose in life. Generative desire was associated with rsFC between VS and precuneus, and, vmPFC and right dorsolateral prefrontal cortex (rdlPFC). The vmPFC–rdlPFC rsFC moderated the association between generative desire and purpose in life. Discussion: These findings provide insight into how the brain supports complex social behavior and, separately, purpose in life in at-risk aging. Affectionate social support may be a putative target process to enhance purpose in life in older adults. This knowledge contributes to future developments of personalized interventions that promote healthy aging. © The Author(s) 2024. Published by Oxford University Press on behalf of The Gerontological Society of America.
Author Keywords
Prosociality; Resting-state fMRI; Self-transcendence; Ventral striatum; Ventromedial prefrontal cortex
Funding details
Fonds de Recherche du Québec – SantéFRQS
National Institutes of HealthNIH
McGill UniversityMGU
Canada First Research Excellence FundCFREF
Natural Sciences and Engineering Research Council of CanadaNSERCDGECR-2022-00299, RGPIN-2022-04496
Natural Sciences and Engineering Research Council of CanadaNSERC
National Institute on AgingNIAP30 AG048785
National Institute on AgingNIA
Document Type: Article
Publication Stage: Final
Source: Scopus
A microbiota-directed complementary food intervention in 12–18-month-old Bangladeshi children improves linear growth
(2024) eBioMedicine, 104, art. no. 105166, .
Mostafa, I.a e , Hibberd, M.C.b c d , Hartman, S.J.b c d , Hafizur Rahman, M.H.a , Mahfuz, M.a e , Hasan, S.M.T.a , Ashorn, P.e , Barratt, M.J.b c d , Ahmed, T.a , Gordon, J.I.b c d
a International Centre for Diarrhoeal Disease Research, Bangladesh (icddr,b), Dhaka, 1212, Bangladesh
b Edison Family Center for Genome Sciences and Systems Biology, Washington University School of Medicine, St. Louis, MO 63110, United States
c The Newman Center for Gut Microbiome and Nutrition Research, Washington University School of Medicine, St. Louis, MO 63110, United States
d Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, United States
e Center for Child, Adolescent, and Maternal Health Research, Faculty of Medicine and Health Technology, Tampere University and Tampere University Hospital, Tampere, Finland
Abstract
Background: Globally, stunting affects ∼150 million children under five, while wasting affects nearly 50 million. Current interventions have had limited effectiveness in ameliorating long-term sequelae of undernutrition including stunting, cognitive deficits and immune dysfunction. Disrupted development of the gut microbiota has been linked to the pathogenesis of undernutrition, providing potentially new treatment approaches. Methods: 124 Bangladeshi children with moderate acute malnutrition (MAM) enrolled (at 12–18 months) in a previously reported 3-month RCT of a microbiota-directed complementary food (MDCF-2) were followed for two years. Weight and length were monitored by anthropometry, the abundances of bacterial strains were assessed by quantifying metagenome-assembled genomes (MAGs) in serially collected fecal samples and levels of growth-associated proteins were measured in plasma. Findings: Children who had received MDCF-2 were significantly less stunted during follow-up than those who received a standard ready-to-use supplementary food (RUSF) [linear mixed-effects model, βtreatment group x study week (95% CI) = 0.002 (0.001, 0.003); P = 0.004]. They also had elevated fecal abundances of Agathobacter faecis, Blautia massiliensis, Lachnospira and Dialister, plus increased levels of a group of 37 plasma proteins (linear model; FDR-adjusted P < 0.1), including IGF-1, neurotrophin receptor NTRK2 and multiple proteins linked to musculoskeletal and CNS development, that persisted for 6-months post-intervention. Interpretation: MDCF-2 treatment of Bangladeshi children with MAM, which produced significant improvements in wasting during intervention, also reduced stunting during follow-up. These results suggest that the effectiveness of supplementary foods for undernutrition may be improved by including ingredients that sponsor healthy microbiota-host co-development. Funding: This work was supported by the BMGF (Grants OPP1134649/INV-000247). © 2024 The Author(s)
Author Keywords
Childhood undernutrition; Human gut microbiome development and repair; Microbiome-directed therapeutic foods; Plasma protein mediators of growth/postnatal development; Post-treatment follow-up; Stunting and wasting
Funding details
Bill and Melinda Gates FoundationBMGFOPP1134649/INV-000247
Bill and Melinda Gates FoundationBMGF
Document Type: Article
Publication Stage: Final
Source: Scopus
Propofol enhancement of slow wave sleep to target the nexus of geriatric depression and cognitive dysfunction: Protocol for a phase i open label trial
(2024) BMJ Open, 14 (5), art. no. e087516, .
Rios, R.L.a , Green, M.a , Smith, S.K.a b , Kafashan, M.a b , Ching, S.c , Farber, N.B.d , Lin, N.e , Lucey, B.P.b f , Reynolds, C.F.g , Lenze, E.J.a d , Palanca, B.J.A.a b d h i
a Department of Anesthesiology, Washington University, School of Medicine in St. Louis, St Louis, MO, United States
b Center on Biological Rhythms and Sleep, Washington University, School of Medicine in St. Louis, St. Louis, MO, United States
c Department of Electrical & Systems Engineering, Washington University in St. Louis, St Louis, MO, United States
d Department of Psychiatry, Washington University, School of Medicine in St. Louis, St Louis, MO, United States
e Department of Biostatistics and Data Science, Washington University in St Louis, St Louis, MO, United States
f Department of Neurology, Washington University, School of Medicine in St. Louis, St. Louis, MO, United States
g Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA, United States
h Division of Biology and Biomedical Sciences, Washington University, School of Medicine in St. Louis, St. Louis, MO, United States
i Department of Biomedical Engineering, Washington University in St. Louis, St. Louis, MO, United States
Abstract
Introduction Late-life treatment-resistant depression (LL-TRD) is common and increases risk for accelerated ageing and cognitive decline. Impaired sleep is common in LL-TRD and is a risk factor for cognitive decline. Slow wave sleep (SWS) has been implicated in key processes including synaptic plasticity and memory. A deficiency in SWS may be a core component of depression pathophysiology. The anaesthetic propofol can induce electroencephalographic (EEG) slow waves that resemble SWS. Propofol may enhance SWS and oral antidepressant therapy, but relationships are unclear. We hypothesise that propofol infusions will enhance SWS and improve depression in older adults with LL-TRD. This hypothesis has been supported by a recent small case series. Methods and analysis SWIPED (Slow Wave Induction by Propofol to Eliminate Depression) phase I is an ongoing open-label, single-arm trial that assesses the safety and feasibility of using propofol to enhance SWS in older adults with LL-TRD. The study is enrolling 15 English-speaking adults over age 60 with LL-TRD. Participants will receive two propofol infusions 2-6 days apart. Propofol infusions are individually titrated to maximise the expression of EEG slow waves. Preinfusion and postinfusion sleep architecture are evaluated through at-home overnight EEG recordings acquired using a wireless headband equipped with dry electrodes. Sleep EEG recordings are scored manually. Key EEG measures include sleep slow wave activity, SWS duration and delta sleep ratio. Longitudinal changes in depression, suicidality and anhedonia are assessed. Assessments are performed prior to the first infusion and up to 10 weeks after the second infusion. Cognitive ability is assessed at enrolment and approximately 3 weeks after the second infusion. Ethics and dissemination The study was approved by the Washington University Human Research Protection Office. Recruitment began in November 2022. Dissemination plans include presentations at scientific conferences, peer-reviewed publications and mass media. Positive results will lead to a larger phase II randomised placebo-controlled trial. Trial registration number NCT04680910. © Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.
Author Keywords
Adult anaesthesia; Cognition; Depression & mood disorders; Electroencephalography; GERIATRIC MEDICINE; Sleep medicine
Funding details
National Institute of Mental HealthNIMH
P50MH122351
National Institutes of HealthNIHU01MH128483, K01MH128663, UL1TR002345
National Institutes of HealthNIH
Document Type: Article
Publication Stage: Final
Source: Scopus
Type 2 cannabinoid receptor expression on microglial cells regulates neuroinflammation during graft-versus-host disease
(2024) The Journal of Clinical Investigation, 134 (11), .
Moe, A.a , Rayasam, A.a , Sauber, G.b , Shah, R.K.a , Doherty, A.b , Yuan, C.-Y.a , Szabo, A.c , Moore, B.M., 2ndd , Colonna, M.e , Cui, W.f , Romero, J.g , Zamora, A.E.a , Hillard, C.J.b , Drobyski, W.R.a
a Department of Medicine
b Department of Pharmacology
c Division of Biostatistics, Institute of Health and Equity, Medical College of Wisconsin, Milwaukee, WI, United States
d College of Pharmacy, Department of Pharmaceutical Sciences, University of Tennessee Health Science Center, Memphis, TN, United States
e Department of Pathology and Immunology, Washington University, Saint Louis, Missouri, USA
f Department of Pathology, Northwestern University, Chicago, IL, United States
g Faculty of Experimental Sciences, Francisco de Vitoria UniversityMadrid, Spain
Abstract
Neuroinflammation is a recognized complication of immunotherapeutic approaches such as immune checkpoint inhibitor treatment, chimeric antigen receptor therapy, and graft versus host disease (GVHD) occurring after allogeneic hematopoietic stem cell transplantation. While T cells and inflammatory cytokines play a role in this process, the precise interplay between the adaptive and innate arms of the immune system that propagates inflammation in the central nervous system remains incompletely understood. Using a murine model of GVHD, we demonstrate that type 2 cannabinoid receptor (CB2R) signaling plays a critical role in the pathophysiology of neuroinflammation. In these studies, we identify that CB2R expression on microglial cells induces an activated inflammatory phenotype that potentiates the accumulation of donor-derived proinflammatory T cells, regulates chemokine gene regulatory networks, and promotes neuronal cell death. Pharmacological targeting of this receptor with a brain penetrant CB2R inverse agonist/antagonist selectively reduces neuroinflammation without deleteriously affecting systemic GVHD severity. Thus, these findings delineate a therapeutically targetable neuroinflammatory pathway and have implications for the attenuation of neurotoxicity after GVHD and potentially other T cell-based immunotherapeutic approaches.
Author Keywords
Bone marrow transplantation; Immunotherapy; Neuroscience; Transplantation
Document Type: Article
Publication Stage: Final
Source: Scopus
A bistable inhibitory optoGPCR for multiplexed optogenetic control of neural circuits
(2024) Nature Methods, .
Wietek, J.a b l , Nozownik, A.c s , Pulin, M.c t , Saraf-Sinik, I.a b , Matosevich, N.d , Gowrishankar, R.e f , Gat, A.a b , Malan, D.g , Brown, B.J.h , Dine, J.a b u , Imambocus, B.N.i , Levy, R.a b , Sauter, K.c , Litvin, A.a b , Regev, N.j , Subramaniam, S.a b , Abrera, K.e , Summarli, D.e , Goren, E.M.d v , Mizrachi, G.a b , Bitton, E.a b , Benjamin, A.a b , Copits, B.A.h , Sasse, P.g , Rost, B.R.k l , Schmitz, D.k l m n o , Bruchas, M.R.e f p , Soba, P.i q , Oren-Suissa, M.a b , Nir, Y.d j r , Wiegert, J.S.c w , Yizhar, O.a b
a Department of Brain Sciences, Weizmann Institute of Science, Rehovot, Israel
b Department of Molecular Neuroscience, Weizmann Institute of Science, Rehovot, Israel
c Center for Molecular Neurobiology, Hamburg, Germany
d Sagol School of Neuroscience, Tel Aviv University, Tel Aviv, Israel
e Department of Anesthesiology and Pain Medicine, University of Washington, Seattle, WA, United States
f Center for Excellence in the Neurobiology of Addiction, Pain and Emotion, University of Washington, Seattle, WA, United States
g Institut für Physiologie I, University of Bonn, Bonn, Germany
h Washington University Pain Center, Department of Anesthesiology, Washington University School of Medicine, St. Louis, MO, United States
i LIMES-Institute, University of Bonn, Bonn, Germany
j Department of Physiology and Pharmacology, Tel Aviv University, Tel Aviv, Israel
k German Center for Neurodegenerative Diseases (DZNE), Berlin, Germany
l Neuroscience Research Center, Charité – Universitätsmedizin Berlin, Berlin, Germany
m Bernstein Center for Computational Neuroscience, Berlin, Germany
n Einstein Center for Neurosciences, Berlin, Germany
o Max Delbrück Center for Molecular Medicine, Berlin, Germany
p Department of Pharmacology, University of Washington, Seattle, WA, United States
q Institute of Physiology and Pathophysiology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
r Department of Biomedical Engineering, Faculty of Engineering, Tel Aviv University, Tel Aviv, Israel
s Paris Brain Institute, Institut du Cerveau (ICM), CNRS UMR 7225, INSERM U1127, Sorbonne Université, Paris, France
t Laboratory of Sensory Processing, Brain Mind Institute, Faculty of Life Sciences, Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland
u Boehringer Ingelheim Pharma GmbH & amp; Co. KG; CNS Diseases, Biberach an der Riss, Germany
v University of Michigan, Ann Arbor, MI, United States
w MCTN, Medical Faculty Mannheim of the University of Heidelberg, Mannheim, Germany
Abstract
Information is transmitted between brain regions through the release of neurotransmitters from long-range projecting axons. Understanding how the activity of such long-range connections contributes to behavior requires efficient methods for reversibly manipulating their function. Chemogenetic and optogenetic tools, acting through endogenous G-protein-coupled receptor pathways, can be used to modulate synaptic transmission, but existing tools are limited in sensitivity, spatiotemporal precision or spectral multiplexing capabilities. Here we systematically evaluated multiple bistable opsins for optogenetic applications and found that the Platynereis dumerilii ciliary opsin (PdCO) is an efficient, versatile, light-activated bistable G-protein-coupled receptor that can suppress synaptic transmission in mammalian neurons with high temporal precision in vivo. PdCO has useful biophysical properties that enable spectral multiplexing with other optogenetic actuators and reporters. We demonstrate that PdCO can be used to conduct reversible loss-of-function experiments in long-range projections of behaving animals, thereby enabling detailed synapse-specific functional circuit mapping. © The Author(s) 2024.
Funding details
Azrieli Foundation
National Institutes of HealthNIH1U01NS128537-01
National Institutes of HealthNIH
European Research CouncilERCH2020-RIA DEEPER 101016787, 819496, 810580
European Research CouncilERC
Deutsche ForschungsgemeinschaftDFGSFB 1315, SPP 1665, SFB 958, SPP 1926, EXC-2049 – 390688087
Deutsche ForschungsgemeinschaftDFG
ERC-2019-STG 850784, 714762
European Molecular Biology OrganizationEMBOALTF 378-2019
European Molecular Biology OrganizationEMBO
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
Nf1 mutation disrupts activity-dependent oligodendroglial plasticity and motor learning in mice
(2024) Nature Neuroscience, .
Pan, Y.a b c , Hysinger, J.D.a , Yalçın, B.a , Lennon, J.J.a , Byun, Y.G.a d , Raghavan, P.a , Schindler, N.F.a , Anastasaki, C.e , Chatterjee, J.e , Ni, L.a , Xu, H.a , Malacon, K.a , Jahan, S.M.a , Ivec, A.E.a , Aghoghovwia, B.E.b , Mount, C.W.a , Nagaraja, S.a , Scheaffer, S.e , Attardi, L.D.f g , Gutmann, D.H.e , Monje, M.a d
a Department of Neurology and Neurological Sciences, Stanford University, Stanford, CA, United States
b Department of Symptom Research, University of Texas MD Anderson Cancer Center, Houston, TX, United States
c Department of Neuro-Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, United States
d Howard Hughes Medical Institute, Stanford University, Stanford, CA, United States
e Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States
f Department of Radiation Oncology, Stanford University, Stanford, CA, United States
g Department of Genetics, Stanford University, Stanford, CA, United States
Abstract
Neurogenetic disorders, such as neurofibromatosis type 1 (NF1), can cause cognitive and motor impairments, traditionally attributed to intrinsic neuronal defects such as disruption of synaptic function. Activity-regulated oligodendroglial plasticity also contributes to cognitive and motor functions by tuning neural circuit dynamics. However, the relevance of oligodendroglial plasticity to neurological dysfunction in NF1 is unclear. Here we explore the contribution of oligodendrocyte progenitor cells (OPCs) to pathological features of the NF1 syndrome in mice. Both male and female littermates (4–24 weeks of age) were used equally in this study. We demonstrate that mice with global or OPC-specific Nf1 heterozygosity exhibit defects in activity-dependent oligodendrogenesis and harbor focal OPC hyperdensities with disrupted homeostatic OPC territorial boundaries. These OPC hyperdensities develop in a cell-intrinsic Nf1 mutation-specific manner due to differential PI3K/AKT activation. OPC-specific Nf1 loss impairs oligodendroglial differentiation and abrogates the normal oligodendroglial response to neuronal activity, leading to impaired motor learning performance. Collectively, these findings show that Nf1 mutation delays oligodendroglial development and disrupts activity-dependent OPC function essential for normal motor learning in mice. © The Author(s) 2024.
Funding details
Gatsby Charitable Foundation
Gilbert Family FoundationGFF
Cancer Research UKCRUK
Robert J. Kleberg, Jr. and Helen C. Kleberg Foundation
McKenna Claire FoundationMCF
Commonwealth of Virginia
National Institutes of HealthNIHDP1NS111132
National Institutes of HealthNIH
U.S. Department of DefenseDODW81XWH-19-1-0260, HT9425-23-1-0239, HT9425-23-1-0270, W81XWH-15-1-0131
U.S. Department of DefenseDOD
Alex’s Lemonade Stand Foundation for Childhood CancerALSF19-16681
Alex’s Lemonade Stand Foundation for Childhood CancerALSF
National Cancer InstituteNCIR01CA258384, 1-R50-CA233164-01
National Cancer InstituteNCI
National Institute of Neurological Disorders and StrokeNINDSR35NS07211-01, R01NS092597
National Institute of Neurological Disorders and StrokeNINDS
CGCATF-2021/100012, OT2CA278688
Cancer Prevention and Research Institute of TexasCPRIT1S10OD021763, RR210085, S10OD025212
Cancer Prevention and Research Institute of TexasCPRIT
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
Post-GWAS multiomic functional investigation of the TNIP1 locus in Alzheimer’s disease highlights a potential role for GPX3
(2024) Alzheimer’s and Dementia, .
Panyard, D.J.a b , Reus, L.M.c d e , Ali, M.f g h , Liu, J.i j , Deming, Y.K.b k l , Lu, Q.i j , Kollmorgen, G.m , Carboni, M.n , Wild, N.m , Visser, P.J.c d o p , Bertram, L.q r , Zetterberg, H.s t u v w , Blennow, K.s t , Gobom, J.s t , Western, D.f g h , Sung, Y.J.f g h , Carlsson, C.M.k l x y , Johnson, S.C.k l x y , Asthana, S.k l y , Cruchaga, C.f g h , Tijms, B.M.c d , Engelman, C.D.b , Snyder, M.P.a
a Department of Genetics, Stanford University School of Medicine, Stanford University, Stanford, CA, United States
b Department of Population Health Sciences, University of Wisconsin-Madison, Madison, WI, United States
c Alzheimer Center Amsterdam, Neurology, Vrije Universiteit Amsterdam, Amsterdam UMC location VUmc, Amsterdam, Netherlands
d Amsterdam Neuroscience, Neurodegeneration, Amsterdam, Netherlands
e Center for Neurobehavioral Genetics, University of California, Los Angeles, CA, United States
f Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, United States
g NeuroGenomics and Informatics Center, Washington University School of Medicine, St. Louis, MO, United States
h Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO, United States
i Department of Biostatistics and Medical Informatics, University of Wisconsin-Madison, Madison, WI, United States
j Department of Statistics, University of Wisconsin-Madison, Madison, WI, United States
k Wisconsin Alzheimer’s Disease Research Center, University of Wisconsin-Madison, Madison, WI, United States
l Department of Medicine, University of Wisconsin-Madison, Madison, WI, United States
m Roche Diagnostics GmbH, Penzberg, Germany
n Roche Diagnostics International Ltd, Rotkreuz, Switzerland
o Department of Psychiatry, Maastricht University, Maastricht, Netherlands
p Department of Neurobiology, Care Sciences and Society, Division of Neurogeriatrics, Karolinska Institutet, Stockholm, Sweden
q Lübeck Interdisciplinary Platform for Genome Analytics, Institutes of Neurogenetics and Cardiogenetics, University of Lübeck, Lübeck, Germany
r Department of Psychology, University of Oslo, Oslo, Norway
s Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden
t Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden
u Department of Neurodegenerative Disease, UCL Institute of Neurology, London, United Kingdom
v UK Dementia Research Institute at UCL, London, United Kingdom
w Hong Kong Center for Neurodegenerative Diseases, Hong Kong
x Wisconsin Alzheimer’s Institute, University of Wisconsin-Madison, Madison, WI, United States
y William S. Middleton Memorial Veterans Hospital, Madison, WI, United States
Abstract
INTRODUCTION: Recent genome-wide association studies (GWAS) have reported a genetic association with Alzheimer’s disease (AD) at the TNIP1/GPX3 locus, but the mechanism is unclear. METHODS: We used cerebrospinal fluid (CSF) proteomics data to test (n = 137) and replicate (n = 446) the association of glutathione peroxidase 3 (GPX3) with CSF biomarkers (including amyloid and tau) and the GWAS-implicated variants (rs34294852 and rs871269). RESULTS: CSF GPX3 levels decreased with amyloid and tau positivity (analysis of variance P = 1.5 × 10−5) and higher CSF phosphorylated tau (p-tau) levels (P = 9.28 × 10−7). The rs34294852 minor allele was associated with decreased GPX3 (P = 0.041). The replication cohort found associations of GPX3 with amyloid and tau positivity (P = 2.56 × 10−6) and CSF p-tau levels (P = 4.38 × 10−9). DISCUSSION: These results suggest variants in the TNIP1 locus may affect the oxidative stress response in AD via altered GPX3 levels. Highlights: Cerebrospinal fluid (CSF) glutathione peroxidase 3 (GPX3) levels decreased with amyloid and tau positivity and higher CSF phosphorylated tau. The minor allele of rs34294852 was associated with lower CSF GPX3. levels when also controlling for amyloid and tau category. GPX3 transcript levels in the prefrontal cortex were lower in Alzheimer’s disease than controls. rs34294852 is an expression quantitative trait locus for GPX3 in blood, neutrophils, and microglia. © 2024 The Authors. Alzheimer’s & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer’s Association.
Author Keywords
Alzheimer’s disease; genome-wide association studies; genomics; glutathione peroxidase 3; proteomics
Funding details
Alzheimer’s AssociationAA
Stiftelsen för Gamla Tjänarinnor
Erling-Perssons Stiftelse
Hope Center for Neurological Disorders, Washington University in St. Louis
Wisconsin Alumni Research FoundationWARF
Cerveau Technologies
European CommissionEC
Office of the Vice Chancellor for Research and Graduate Education, University of Wisconsin-MadisonVCRGE, UW
Cosmetic Surgery FoundationCSF
Olav Thon Stiftelsen
73305095005
National Institute on AgingNIAT32AG000213
National Institute on AgingNIA
VetenskapsrådetVR2018‐02532
VetenskapsrådetVR
733050824
115372
Horizon 2020860197
Horizon 2020
ZonMw10510022110012
ZonMw
P01AG003991, R01AG064877, R01AG044546, P30AG066444, RF1AG058501, RF1AG053303, R01AG064614, U01AG058922, 1RF1AG074007
UK Dementia Research InstituteUK DRI2017‐00915
UK Dementia Research InstituteUK DRI
P30AG017266
University of Wisconsin-MadisonUWP2CHD047873
University of Wisconsin-MadisonUW
National Institutes of HealthNIHP41GM108538, R01AG054047, R01AG037639, R21AG067092, R01AG021155, R01AG27161
National Institutes of HealthNIH
Alzheimerfonden#ALZ2022‐0006, ‐930351, ‐939721, ‐968270
Alzheimerfonden
P50AG033514, P30AG062715
National Center for Advancing Translational SciencesNCATSUL1TR000427
National Center for Advancing Translational SciencesNCATS
Alzheimer’s Drug Discovery FoundationADDF201809‐2016862
Alzheimer’s Drug Discovery FoundationADDF
European Research CouncilERC101053962
European Research CouncilERC
Innovative Medicines InitiativeIMI101034344, 115952, 806999, 733050824736
Innovative Medicines InitiativeIMI
ZEN‐21‐848495, 715986, 965240, AF‐930934
720931
Document Type: Article
Publication Stage: Article in Press
Source: Scopus