WashU weekly Neuroscience publications: June 9, 2024

Quantifying the effects of sleep on sensor-derived variables from upper limb accelerometry in people with and without upper limb impairment
(2024) Journal of NeuroEngineering and Rehabilitation, 21 (1), art. no. 86, . 

Miller, A.E.^a , Lang, C.E.^a b c , Bland, M.D.^a b c , Lohse, K.R.^a c

^a Program in Physical Therapy, Washington University School of Medicine, 4444 Forest Park Avenue, MSC: 8502-66-1101, St. Louis, MO 63018, United States
^b Program in Occupational Therapy, Washington University School of Medicine, St. Louis, MO 63018, United States
^c Department of Neurology, Washington University School of Medicine, St. Louis, MO 63018, United States

Abstract
Background: Despite the promise of wearable sensors for both rehabilitation research and clinical care, these technologies pose significant burden on data collectors and analysts. Investigations of factors that may influence the wearable sensor data processing pipeline are needed to support continued use of these technologies in rehabilitation research and integration into clinical care settings. The purpose of this study was to investigate the effect of one such factor, sleep, on sensor-derived variables from upper limb accelerometry in people with and without upper limb impairment and across a two-day wearing period. Methods: This was a secondary analysis of data collected during a prospective, longitudinal cohort study (n = 127 individuals, 62 with upper limb impairment and 65 without). Participants wore a wearable sensor on each wrist for 48 h. Five upper limb sensor variables were calculated over the full wear period (sleep included) and with sleep time removed (sleep excluded): preferred time, non-preferred time, use ratio, non-preferred magnitude and its standard deviation. Linear mixed effects regression was used to quantify the effect of sleep on each sensor variable and determine if the effect differed between people with and without upper limb impairment and across a two-day wearing period. Results: There were significant differences between sleep included and excluded for the variables preferred time (p < 0.001), non-preferred time (p < 0.001), and non-preferred magnitude standard deviation (p = 0.001). The effect of sleep was significantly different between people with and without upper limb impairment for one variable, non-preferred magnitude (p = 0.02). The effect of sleep was not substantially different across wearing days for any of the variables. Conclusions: Overall, the effects of sleep on sensor-derived variables of upper limb accelerometry are small, similar between people with and without upper limb impairment and across a two-day wearing period, and can likely be ignored in most contexts. Ignoring the effect of sleep would simplify the data processing pipeline, facilitating the use of wearable sensors in both research and clinical practice. © The Author(s) 2024.

Author Keywords
Accelerometry;  Breast cancer;  Fracture;  Multiple sclerosis;  Sleep;  Stroke;  Wearable sensors

Funding details
National Institutes of HealthNIHR37 HD068290
National Institutes of HealthNIH

Document Type: Article
Publication Stage: Final
Source: Scopus

TCAF1 promotes TRPV2-mediated Ca2+ release in response to cytosolic DNA to protect stressed replication forks
(2024) Nature Communications, 15 (1), art. no. 4609, . 

Kong, L.^a , Cheng, C.^a , Cheruiyot, A.^a , Yuan, J.^a , Yang, Y.^a , Hwang, S.^a , Foust, D.^a , Tsao, N.^b , Wilkerson, E.^a , Mosammaparast, N.^b , Major, M.B.^a , Piston, D.W.^a , Li, S.^a c d , You, Z.^a

^a Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, MO 63110, United States
^b Department of Pathology and Immunology, Washington University in St. Louis School of Medicine, St. Louis, MO 63110, United States
^c Zhejiang Provincial Key Laboratory of Pancreatic Disease in the First Affiliated Hospital, Zhejiang University School of Medicine, Zhejiang, Hangzhou, 310029, China
^d Cancer Center, Zhejiang University, Zhejiang, Hangzhou, 310029, China

Abstract
The protection of the replication fork structure under stress conditions is essential for genome maintenance and cancer prevention. A key signaling pathway for fork protection involves TRPV2-mediated Ca2+ release from the ER, which is triggered after the generation of cytosolic DNA and the activation of cGAS/STING. This results in CaMKK2/AMPK activation and subsequent Exo1 phosphorylation, which prevent aberrant fork processing, thereby ensuring genome stability. However, it remains poorly understood how the TRPV2 channel is activated by the presence of cytosolic DNA. Here, through a genome-wide CRISPR-based screen, we identify TRPM8 channel-associated factor 1 (TCAF1) as a key factor promoting TRPV2-mediated Ca2+ release under replication stress or other conditions that activate cGAS/STING. Mechanistically, TCAF1 assists Ca2+ release by facilitating the dissociation of STING from TRPV2, thereby relieving TRPV2 repression. Consistent with this function, TCAF1 is required for fork protection, chromosomal stability, and cell survival after replication stress. © The Author(s) 2024.

Funding details
National Natural Science Foundation of ChinaNSFC82272984
National Natural Science Foundation of ChinaNSFC
University of WashingtonUW5124
University of WashingtonUW
National Institutes of HealthNIHR01GM098535, R01CA193318
National Institutes of HealthNIH
American Cancer SocietyACSRSG-13-212-01-DMC
American Cancer SocietyACS

Document Type: Article
Publication Stage: Final
Source: Scopus

Estimation of differential pathlength factor from NIRS measurement in skeletal muscle
(2024) Respiratory Physiology and Neurobiology, 326, art. no. 104283, . 

Koirala, B.^b i , Concas, A.^a , Cincotti, A.^a , Sun, Y.^e f , Hernández, A.^h , Goodwin, M.L.ⁱ , Gladden, L.B.^g , Lai, N.^a b c d

^a Department of Mechanical, Chemical and Materials Engineering, University of Cagliari, Italy
^b Department of Electrical and Computer Engineering, Old Dominion University, Norfolk, VA, United States
^c Biomedical Engineering Institute; Old Dominion University, Norfolk, VA, United States
^d Department of Biomedical Engineering, Case Western Reserve University, Cleveland, OH, United States
^e Key Laboratory of Adolescent Health Assessment and Exercise Intervention of Ministry of Education, East China Normal University, Shanghai, 200241, China
^f School of Physical Education & Health Care, East China Normal University, Shanghai, 200241, China
^g School of Kinesiology, Auburn University, Auburn, AL 36849, United States
^h Faculty Research Liaison School of Social Sciences, Humanities and Arts University of California, United States
ⁱ Department of Orthopedic Surgery, Washington University, St. Louis, MO, United States

Abstract
The utilization of continuous wave (CW) near-infrared spectroscopy (NIRS) device to measure non-invasively muscle oxygenation in healthy and disease states is limited by the uncertainties related to the differential path length factor (DPF). DPF value is required to quantify oxygenated and deoxygenated heme groups’ concentration changes from measurement of optical densities by NIRS. An integrated approach that combines animal and computational models of oxygen transport and utilization was used to estimate the DPF value in situ. The canine model of muscle oxidative metabolism allowed measurement of both venous oxygen content and tissue oxygenation by CW NIRS under different oxygen delivery conditions. The experimental data obtained from the animal model were integrated in a computational model of O2 transport and utilization and combined with Beer-Lambert law to estimate DPF value in contracting skeletal muscle. A 2.1 value was found for DPF by fitting the mathematical model to the experimental data obtained in contracting muscle (T3) (Med.Sci.Sports.Exerc.48(10):2013–2020,2016). With the estimated value of DPF, model simulations well predicted the optical density measured by NIRS on the same animal model but with different blood flow, arterial oxygen contents and contraction rate (J.Appl.Physiol.108:1169–1176, 2010 and 112:9–19,2013) and demonstrated the robustness of the approach proposed in estimating DPF value. The approach used can overcome the semi-quantitative nature of the NIRS and estimate non-invasively DPF to obtain an accurate concentration change of oxygenated and deoxygenated hemo groups by CW NIRS measurements in contracting skeletal muscle under different oxygen delivery and contraction rate. © 2024 The Authors

Author Keywords
Contraction;  Convection;  Diffusion;  Heme group;  Hyperoxia;  Modeling;  Transport

Funding details
National Institute of Arthritis and Musculoskeletal and Skin DiseasesNIAMSK25AR057206
National Institute of Arthritis and Musculoskeletal and Skin DiseasesNIAMS

Document Type: Article
Publication Stage: Final
Source: Scopus

Diet/photoperiod mediated changes in cerebellar clock genes causes locomotor shifts and imperative changes in BDNF-TrkB pathway
(2024) Neuroscience Letters, 835, art. no. 137843, . 

Karnik, R.^a b , Vohra, A.^a c , Khatri, M.^a , Dalvi, N.^a , Vyas, H.S.^a d , Shah, H.^a b , Gohil, S.^a , Kanojiya, S.^a b , Devkar, R.^a b

^a Division of Chronobiology and Metabolic Endocrinology, Department of Zoology, Faculty of Science, The Maharaja Sayajirao University of Baroda, India
^b Dr. Vikram Sarabhai Institute of Cell & Molecular Biology, Faculty of Science, The Maharaja Sayajirao University of Baroda, India
^c Department of Neurology, Washington University in St. Louis, Saint Louis, MO 63110, United States
^d Department of Internal Medicine, University of Michigan, Ann Arbor, MI, United States

Abstract
Neuropsychological studies report anxiety and depression like symptoms in patients suffering from lifestyle disorder but its impact on locomotor function lacks clarity. Our study investigates locomotor deficits resulting due to perturbations in cerebellum of high fat diet (HFD), chronodisruption (CD) or a combination (HCD) model of lifestyle disorder. Significant downregulation in levels of cerebellar clock genes (Bmal-1, Clock, Per 1 and Per 2) and Bdnf-Trkb pathway genes (Bdnf, TrkB and Syn1 levels) were recorded. Further, locomotor deficits were observed in all the three experimental groups as evidenced by actimeter test, pole test and wire hanging test. Nuclear pyknosis of Purkinje cells, their derangement and inflammation were the hallmark of cerebellar tissue of all the three experimental groups. Taken together, this study generates important links between cerebellar clock oscillations, locomotor function and Bdnf-TrkB signaling. © 2024 Elsevier B.V.

Author Keywords
Bdnf-Trkb pathway;  Chronodisruption;  High fat diet;  Lifestyle Disorder;  Locomotor deficits;  Neurobehavior

Funding details
Lady Tata Memorial TrustLTMT
Department of Science and Technology, Ministry of Science and Technology, IndiaDST
Department of Biotechnology, Ministry of Science and Technology, IndiaDBTBT/PR36169/MED/30/2197/2020
Department of Biotechnology, Ministry of Science and Technology, IndiaDBT

Document Type: Article
Publication Stage: Final
Source: Scopus

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 Centers^m

^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

Further unpacking individual differences in mind wandering: The role of emotional valence and awareness
(2024) Consciousness and Cognition, 122, art. no. 103697, . 

Welhaf, M.S.^a , Astacio, M.A.^b , Banks, J.B.^b

^a Department of Psychological & Brain Sciences, Washington University in St. Louis, United States
^b Department of Psychology & Neuroscience, Nova Southeastern University, United States

Abstract
Previous work has established a link between executive attention ability and mind wandering propensity, these studies typically collapse thought reports into a single category of task-unrelated thoughts (TUTs). We have shown that these TUTs can be differentiated by the emotional valence of their content. Awareness of TUTs might also be an important to consider, yet little work has been done on this front. The current study conceptually replicated and extended previous work by investigating the relationship between individual differences in executive attention, emotional valence and awareness of TUTs. Latent variable models indicated that Executive Attention was differentially correlated with emotional valence TUTs. However, only Attention Control was related to frequency of mind wandering with awareness. Intra-individual analyses indicated that negatively valenced TUTs and TUTs that occurred without awareness were associated with worse performance. Considering different dimensions of TUTs can provide a more complete picture of individual differences in mind wandering. © 2024 Elsevier Inc.

Author Keywords
Awareness;  Emotional valence;  Executive attention;  Mind wandering

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., III^f , 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

Inherited C-terminal TREX1 variants disrupt homology-directed repair to cause senescence and DNA damage phenotypes in Drosophila, mice, and humans
(2024) Nature Communications, 15 (1), p. 4696. 

Chauvin, S.D.^a b , Ando, S.^c , Holley, J.A.^a b , Sugie, A.^d , Zhao, F.R.^e , Poddar, S.^a b , Kato, R.^c , Miner, C.A.^a b , Nitta, Y.^d , Krishnamurthy, S.R.^f g , Saito, R.^h , Ning, Y.^a b , Hatano, Y.^c , Kitahara, S.^c , Koide, S.^c , Stinson, W.A.^e , Fu, J.^a b , Surve, N.^a b , Kumble, L.^a b , Qian, W.^e , Polishchuk, O.^a b , Andhey, P.S.ⁱ , Chiang, C.^j k , Liu, G.^j k , Colombeau, L.^l , Rodriguez, R.^l , Manel, N.^m , Kakita, A.^h , Artyomov, M.N.ⁱ , Schultz, D.C.ⁿ , Coates, P.T.^o p , Roberson, E.D.O.^e , Belkaid, Y.^f g q , Greenberg, R.A.^r , Cherry, S.^s t , Gack, M.U.^j k , Hardy, T.^u v , Onodera, O.^c w , Kato, T.^w , Miner, J.J.^{a b e s x y}

^a Division of Rheumatology, Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, United States
^b RVCL Research Center, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, United States
^c Department of Neurology, Clinical Neuroscience Branch, Brain Research Institute, Niigata UniversityNiigata, Japan
^d Department of Neuroscience of Disease, Brain Research Institute, Niigata UniversityNiigata, Japan
^e Department of Medicine, Washington University in Saint Louis, Saint Louis, MO, USA
^f Metaorganism Immunity Section, Laboratory of Immune System Biology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, United States
^g NIAID Microbiome Program, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, United States
^h Department of Pathology, Clinical Neuroscience Branch, Brain Research Institute, Niigata UniversityNiigata, Japan
ⁱ Department of Pathology and Immunology, Washington University in Saint Louis, Saint Louis, MO, USA
^j Department of Microbiology, University of Chicago, Chicago, IL, United States
^k Florida Research and Innovation Center, Cleveland Clinic, Port Saint Lucie, FL, United States
^l Equipe Labellisée Ligue Contre le Cancer, Institut Curie, CNRS, INSERM, PSL Research University, Paris, France
^m INSERM U932, Institut Curie, PSL Research University, Paris, France
ⁿ University of Pennsylvania, Philadelphia, PA, United States
^o Central and Northern Adelaide Renal and Transplantation Service (CNARTS), Royal Adelaide Hospital, Adelaide, SA, Australia
^p School of Medicine, Faculty of Health Sciences, University of Adelaide, Adelaide, SA, Australia
^q Institut Pasteur, Paris, France
^r Department of Cancer Biology, Penn Center for Genome Integrity, Basser Center for BRCA, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States
^s Institute for Immunology and Immune Health, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, United States
^t Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, United States
^u Genetics, Monash IVF, RepromedSA, Australia
^v Genetics and Molecular Pathology, SA Pathology, Adelaide, Australia
^w Department of Molecular Neuroscience, Brain Science Branch, Brain Research Institute, Niigata UniversityNiigata, Japan
^x Department of Microbiology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, United States
^y Penn Colton Center for Autoimmunity, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, United States

Abstract
Age-related microangiopathy, also known as small vessel disease (SVD), causes damage to the brain, retina, liver, and kidney. Based on the DNA damage theory of aging, we reasoned that genomic instability may underlie an SVD caused by dominant C-terminal variants in TREX1, the most abundant 3′-5′ DNA exonuclease in mammals. C-terminal TREX1 variants cause an adult-onset SVD known as retinal vasculopathy with cerebral leukoencephalopathy (RVCL or RVCL-S). In RVCL, an aberrant, C-terminally truncated TREX1 mislocalizes to the nucleus due to deletion of its ER-anchoring domain. Since RVCL pathology mimics that of radiation injury, we reasoned that nuclear TREX1 would cause DNA damage. Here, we show that RVCL-associated TREX1 variants trigger DNA damage in humans, mice, and Drosophila, and that cells expressing RVCL mutant TREX1 are more vulnerable to DNA damage induced by chemotherapy and cytokines that up-regulate TREX1, leading to depletion of TREX1-high cells in RVCL mice. RVCL-associated TREX1 mutants inhibit homology-directed repair (HDR), causing DNA deletions and vulnerablility to PARP inhibitors. In women with RVCL, we observe early-onset breast cancer, similar to patients with BRCA1/2 variants. Our results provide a mechanistic basis linking aberrant TREX1 activity to the DNA damage theory of aging, premature senescence, and microvascular disease. © 2024. The Author(s).

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 Group^x

^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 &lt; 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

Concurrent Collection of Fetal Murine Brain and Serum to Assess Effects of Maternal Diet on Nutrition and Neurodevelopment in Neurofibromatosis Type 1
(2024) Journal of Visualized Experiments, 2024 (207), art. no. e66226, . 

Martin, G.E., Chan, A., Brossier, N.M.

Department of Pediatrics, Washington University in St. Louis, United States

Abstract
Maternal diet-induced obesity has been demonstrated to alter neurodevelopment in offspring, which may lead to reduced cognitive capacity, hyperactivity, and impairments in social behavior. Patients with the clinically heterogeneous genetic disorder Neurofibromatosis Type 1 (NF1) may present with similar deficits, but it is currently unclear whether environmental factors such as maternal diet influence the development of these phenotypes, and if so, the mechanism by which such an effect would occur. To enable evaluation of how maternal obesogenic diet exposure affects systemic factors relevant to neurodevelopment in NF1, we have developed a method to simultaneously collect non-hemolyzed serum and whole or regionally micro-dissected brains from fetal offspring of murine dams fed a control diet versus a high-fat, high-sucrose diet. Brains were processed for cryosectioning or flash frozen to use for subsequent RNA or protein isolation; the quality of the collected tissue was verified by immunostaining. The quality of the serum was verified by analyzing macronutrient profiles. Using this technique, we have identified that maternal obesogenic diet increases fetal serum cholesterol similarly between WT and Nf1-heterozygous pups. © 2024 JoVE Journal of Visualized Experiments.

Funding details
Neurofibromatosis Therapy Acceleration ProgramNTAP
School of Medicine, Johns Hopkins UniversitySOM, JHU
CDI-CORE-2019-813, CDI-CORE-2015-505
St. Louis Children’s HospitalSLCHFDN-2022-1082
St. Louis Children’s HospitalSLCH
National Institutes of HealthNIHP30 DK020579
National Institutes of HealthNIH
Foundation for Barnes-Jewish HospitalFBJH4642, 3770
Foundation for Barnes-Jewish HospitalFBJH

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., 2nd^d , 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

Searching for Synthetic Opioid Rescue Agents: Identification of a Potent Opioid Agonist with Reduced Respiratory Depression
(2024) Journal of Medicinal Chemistry, . 

Vu, L.Y.^a , Luo, D.^a b , Johnson, K.^a , Denehy, E.D.^c , Songrady, J.C.^a , Martin, J.^c , Trivedi, R.^a , Alsum, A.R.^a , Shaykin, J.D.^c , Chaudhary, C.L.^a b , Woloshin, E.J.^a , Kornberger, L.^a , Bhuiyan, N.^a b , Parkin, S.^d , Jiang, Q.^e , Che, T.^e , Alilain, W.^f g , Turner, J.R.^a , Bardo, M.T.^c , Prisinzano, T.E.^a b

^a Department of Pharmaceutical Sciences, University of Kentucky, Lexington, KY 40506, United States
^b Center for Pharmaceutical Research and Innovation, College of Pharmacy, University of Kentucky, Lexington, KY 40506, United States
^c Department of Psychology, University of Kentucky, Lexington, KY 40536, United States
^d Department of Chemistry, University of Kentucky, Lexington, KY 40506, United States
^e Center for Clinical Pharmacology, University of Health Sciences and Pharmacy, Washington University School of Medicine, St. Louis, MO 63110, United States
^f Spinal Cord and Brain Injury Research Center (SCoBIRC), College of Medicine, University of Kentucky, Lexington, KY 40536, United States
^g Department of Neuroscience, University of Kentucky, Lexington, KY 40536, United States

Abstract
While in the process of designing more effective synthetic opioid rescue agents, we serendipitously identified a new chemotype of potent synthetic opioid. Here, we report that conformational constraint of a piperazine ring converts a mu opioid receptor (MOR) antagonist into a potent MOR agonist. The prototype of the series, which we have termed atoxifent (2), possesses potent in vitro agonist activity. In mice, atoxifent displayed long-lasting antinociception that was reversible with naltrexone. Repeated dosing of atoxifent produced antinociceptive tolerance and a level of withdrawal like that of fentanyl. In rats, while atoxifent produced complete loss of locomotor activity like fentanyl, it failed to produce deep respiratory depression associated with fentanyl-induced lethality. Assessment of brain biodistribution demonstrated ample distribution of atoxifent into the brain with a Tmax of approximately 0.25 h. These results indicate enhanced safety for atoxifent-like molecules compared to fentanyl. © 2024 American Chemical Society.

Funding details
National Institute on Drug AbuseNIDAU01 DA051377
National Institute on Drug AbuseNIDA
National Center for Advancing Translational SciencesNCATSUL1TR001998
National Center for Advancing Translational SciencesNCATS
National Institutes of HealthNIHS10 OD28690, P20 GM130456
National Institutes of HealthNIH

Document Type: Article
Publication Stage: Article in Press
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

Continuous Associations between Remote Self-Administered Cognitive Measures and Imaging Biomarkers of Alzheimer’s Disease
(2024) Journal of Prevention of Alzheimer’s Disease, . 

Boots, E.A.^a , Frank, R.D.^b , Fan, W.Z.^b , Christianson, T.J.^b , Kremers, W.K.^b , Stricker, J.L.^c , Machulda, M.M.^a , Fields, J.A.^a , Hassenstab, J.^d , Graff-Radford, J.^e , Vemuri, P.^f , Jack, C.R.^f , Knopman, D.S.^e , Petersen, R.C.^e , Stricker, N.H.^a g

^a Divison of Neurocognitive Disorders, Department of Psychiatry and Psychology, Mayo Clinic, Rochester, MN, United States
^b Division of Biomedical Statistics and Informatics, Department of Quantitative Health Sciences, Mayo Clinic, Rochester, MN, United States
^c Department of Information Technology, Mayo Clinic, Rochester, MN, United States
^d Department of Neurology and Psychological & amp; Brain Sciences, Washington University in St. Louis, St. Louis, MO, United States
^e Department of Neurology, Mayo Clinic, Rochester, MN, United States
^f Department of Radiology, Mayo Clinic, Rochester, MN, United States
^g ABPP-CN, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, United States

Abstract
Background: Easily accessible and self-administered cognitive assessments that can aid early detection for Alzheimer’s disease (AD) dementia risk are critical for timely intervention. Objectives/Design: This cross-sectional study investigated continuous associations between Mayo Test Drive (MTD)–a remote, self-administered, multi-device compatible, web-based cognitive assessment–and AD-related imaging biomarkers. Participants/Setting: 684 adults from the Mayo Clinic Study of Aging and Mayo Clinic Alzheimer’s Disease Research Center participated (age=70.4±11.2, 49.7% female). Participants were predominantly cognitively unimpaired (CU; 94.0%). Measurements: Participants completed (1) brain amyloid and tau PET scans and MRI scans for hippocampal volume (HV) and white matter hyperintensities (WMH); (2) MTD remotely, consisting of the Stricker Learning Span and Symbols Test which combine into an MTD composite; and (3) in-person neuropsychological assessment including measures to obtain Mayo Preclinical Alzheimer’s disease Cognitive Composite (Mayo-PACC) and Global-z. Multiple regressions adjusted for age, sex, and education queried associations between imaging biomarkers and scores from remote and in-person cognitive measures. Results: Lower performances on MTD were associated with greater amyloid, entorhinal tau, and global tau PET burden, lower HV, and higher WMH. Mayo-PACC and Global-z were associated with all imaging biomarkers except global tau PET burden. MCI/Dementia participants showed lower performance on all MTD measures compared to CU with large effect sizes (Hedge’s g’s=1.65–2.02), with similar findings for CU versus MCI only (Hedge’s g’s=1.46–1.83). Conclusion: MTD is associated with continuous measures of AD-related imaging biomarkers, demonstrating ability to detect subtle cognitive change using a brief, remote assessment in predominantly CU individuals and criterion validity for MTD. © The Authors 2024.

Author Keywords
amyloid;  Digital health;  Mayo Test Drive;  mild cognitive impairment;  Neuropsychological Tests

Funding details
Mayo Foundation for Medical Education and ResearchMFMER
Mayo Clinic
GHR FoundationGHR
National Institute on AgingNIA
National Institutes of HealthNIHR01 AG041851, R21 AG073967, P30 AG062677, RF1 AG069052, U01 AG006786, R37 AG011378, R01 AG081955
National Institutes of HealthNIH
R01 AG034676

Document Type: Article
Publication Stage: Article in Press
Source: Scopus

Sex Differences in Response Inhibition–Related Neural Predictors of Posttraumatic Stress Disorder in Civilians With Recent Trauma
(2024) Biological Psychiatry: Cognitive Neuroscience and Neuroimaging, . 

Borst, B.^a b , Jovanovic, T.^c , House, S.L.^d , Bruce, S.E.^e , Harnett, N.G.^f g , Roeckner, A.R.^a , Ely, T.D.^a , Lebois, L.A.M.^f g , Young, D.^h , Beaudoin, F.L.^i j , An, X.^k , Neylan, T.C.^l , Clifford, G.D.^m n , Linnstaedt, S.D.^k , Germine, L.T.^g o p , Bollen, K.A.^q , Rauch, S.L.^g o r , Haran, J.P.^s , Storrow, A.B.^t , Lewandowski, C.^u , Musey, P.I., Jr.^v , Hendry, P.L.^w , Sheikh, S.^w , Jones, C.W.^x , Punches, B.E.^y z , Hudak, L.A.^aa , Pascual, J.L.^ab ac , Seamon, M.J.^ac ad , Datner, E.M.^ae af , Pearson, C.^ag , Peak, D.A.^ah , Domeier, R.M.^ai , Rathlev, N.K.^aj , O’Neil, B.J.^ak , Sergot, P.^al , Sanchez, L.D.^am an , Harte, S.E.^ao ap , Koenen, K.C.^aq , Kessler, R.C.^ar , McLean, S.A.^as at , Ressler, K.J.^f g , Stevens, J.S.^a , van Rooij, S.J.H.^a

^a Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Georgia, Atlanta, Georgia
^b Faculty of Behavioural and Movement Sciences, Vrije Universiteit Amsterdam, Amsterdam, Netherlands
^c Department of Psychiatry and Behavioral Neurosciences, Wayne State University, Detroit, MI, United States
^d Department of Emergency Medicine, Washington University School of Medicine, St. Louis, Missouri, United States
^e Department of Psychological Sciences, University of Missouri St. Louis, St. Louis, Missouri, United States
^f Division of Depression and Anxiety, McLean Hospital, Belmont, Massachusetts, United States
^g Department of Psychiatry, Harvard Medical School, Boston, Massachusetts, United States
^h Department of Psychiatry and Behavioral Sciences, University of California San Francisco, San Francisco, California, United States
ⁱ Department of Epidemiology, Brown University, Rehabilitation International, Providence, Rhode Island, United States
^j Department of Emergency Medicine, Brown University, Providence, Rhode Island, United States
^k Institute for Trauma Recovery, Department of Anesthesiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
^l Departments of Psychiatry and Neurology, University of California San Francisco, San Francisco, California, United States
^m Department of Biomedical Informatics, Emory University School of Medicine, Georgia, Atlanta, Georgia
ⁿ Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Georgia, Atlanta, Georgia
^o Institute for Technology in Psychiatry, McLean Hospital, Belmont, Massachusetts, United States
^p Many Brains Project, Belmont, Massachusetts, United States
^q Department of Psychology and Neuroscience & Department of Sociology, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
^r Department of Psychiatry, McLean Hospital, Belmont, Massachusetts, United States
^s Department of Emergency Medicine, University of Massachusetts Chan Medical School, Worcester, Massachusetts, United States
^t Department of Emergency Medicine, Vanderbilt University Medical Center, Nashville, TN, United States
^u Department of Emergency Medicine, Henry Ford Health System, Detroit, MI, United States
^v Department of Emergency Medicine, Indiana University School of Medicine, Indianapolis, IN, United States
^w Department of Emergency Medicine, University of Florida College of Medicine, Jacksonville, Jacksonville, Florida, United States
^x Department of Emergency Medicine, Cooper Medical School of Rowan University, Camden, New Jersey, United States
^y Department of Emergency Medicine, Ohio State University College of Medicine, Columbus, OH, United States
^z Ohio State University College of Nursing, Columbus, OH, United States
^aa Department of Emergency Medicine, Emory University School of Medicine, Georgia, Atlanta, Georgia
^ab Department of Surgery, Department of Neurosurgery, University of Pennsylvania, Philadelphia, Pennsylvania, United States
^ac Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States
^ad Department of Surgery, Division of Traumatology, Surgical Critical Care and Emergency Surgery, University of Pennsylvania, Philadelphia, Pennsylvania, United States
^ae Department of Emergency Medicine, Jefferson Einstein Hospital, Jefferson Health, Philadelphia, Pennsylvania, United States
^af Department of Emergency Medicine, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania, United States
^ag Department of Emergency Medicine, Wayne State University, Ascension St. John Hospital, Detroit, MI, United States
^ah Department of Emergency Medicine, Massachusetts General Hospital, Boston, Massachusetts, United States
^ai Department of Emergency Medicine, Trinity Health, Ann Arbor, Ypsilanti, MI, United States
^aj Department of Emergency Medicine, University of Massachusetts Medical School-Baystate, Springfield, Massachusetts, United States
^ak Department of Emergency Medicine, Wayne State University, Detroit Receiving Hospital, Detroit, Michigan, United States
^al Department of Emergency Medicine, McGovern Medical School at UTHealth, Houston, Texas, United States
^am Department of Emergency Medicine, Brigham and Women’s Hospital, Boston, Massachusetts, United States
^an Department of Emergency Medicine, Harvard Medical School, Boston, Massachusetts, United States
^ao Department of Anesthesiology, University of Michigan Medical School, Ann Arbor, MI, United States
^ap Department of Internal Medicine-Rheumatology, University of Michigan Medical School, Ann Arbor, MI, United States
^aq Department of Epidemiology, Harvard T.H. Chan School of Public Health, Harvard University, Boston, Massachusetts, United States
^ar Department of Health Care Policy, Harvard Medical School, Boston, Massachusetts, United States
^as Department of Emergency Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
^at Institute for Trauma Recovery, Department of Psychiatry, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States

Abstract
Background: Females are more likely to develop posttraumatic stress disorder (PTSD) than males. Impaired inhibition has been identified as a mechanism for PTSD development, but studies on potential sex differences in this neurobiological mechanism and how it relates to PTSD severity and progression are relatively rare. Here, we examined sex differences in neural activation during response inhibition and PTSD following recent trauma. Methods: Participants (n = 205, 138 female sex assigned at birth) were recruited from emergency departments within 72 hours of a traumatic event. PTSD symptoms were assessed 2 weeks and 6 months posttrauma. A Go/NoGo task was performed 2 weeks posttrauma in a 3T magnetic resonance imaging scanner to measure neural activity during response inhibition in the ventromedial prefrontal cortex, right inferior frontal gyrus, and bilateral hippocampus. General linear models were used to examine the interaction effect of sex on the relationship between our regions of interest and the whole brain, PTSD symptoms at 6 months, and symptom progression between 2 weeks and 6 months. Results: Lower response inhibition–related ventromedial prefrontal cortex activation 2 weeks posttrauma predicted more PTSD symptoms at 6 months in females but not in males, while greater response inhibition–related right inferior frontal gyrus activation predicted lower PTSD symptom progression in males but not females. Whole-brain interaction effects were observed in the medial temporal gyrus and left precentral gyrus. Conclusions: There are sex differences in the relationship between inhibition-related brain activation and PTSD symptom severity and progression. These findings suggest that sex differences should be assessed in future PTSD studies and reveal potential targets for sex-specific interventions. © 2024 Society of Biological Psychiatry

Author Keywords
Functional magnetic resonance imaging (fMRI);  Posttraumatic stress disorder (PTSD);  Response inhibition;  Right inferior frontal gyrus (rIFG);  Sex differences;  Ventromedial prefrontal cortex (vmPFC)

Funding details
Broad InstituteBI
Brain Research FoundationBRF
Henry J. Kaiser Family FoundationKFF
Robert Wood Johnson FoundationRWJF
Boehringer Ingelheim
Blue Cross and Blue Shield of Florida Foundation
MAYDAY Fund
Harvard University
National Institutes of HealthNIH
Allergan Foundation
Cohen Veterans BioscienceCVB
R33AG05654
Substance Abuse and Mental Health Services AdministrationSAMHSA1H79TI083101-01
Substance Abuse and Mental Health Services AdministrationSAMHSA
National Institute of Mental HealthNIMHU01MH110925, K01MH121653
National Institute of Mental HealthNIMH

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

Osteopathia striata with cranial sclerosis as a cancer predisposition syndrome: The first report of neuroblastoma and review of all cancers in OSCS
(2024) American Journal of Medical Genetics, Part A, . 

Abu-El-Haija, A.^a b , Dillahunt, K.^c , Safina, N.^c d , Aldeeri, A.^a b e , Glavan, T.^f , Mihalek, I.^f , Shinawi, M.^g

^a Division of Medical Genetics and Genomics, Department of Pediatrics, Boston Children’s Hospital, Boston, United States
^b Harvard Medical School, Boston, United States
^c Division of Medical Genetics and Genomics, Department of Pediatrics, University of Iowa, Iowa City, United States
^d Department of Pediatrics, UI Stead Family Children’s Hospital, Iowa City, United States
^e Department of Internal Medicine, King Saud University, Riyadh, Saudi Arabia
^f Department of Molecular Medicine and Biotechnology, University of Rijeka, Rijeka, Croatia
^g Division of Genetics and Genomic Medicine, Department of Pediatrics, Washington University School of Medicine, St. Louis, United States

Abstract
Osteopathia Striata with Cranial Sclerosis (OSCS) is a rare genetic condition primarily characterized by metaphyseal striations of long bones, bone sclerosis, macrocephaly, and other congenital anomalies. It is caused by pathogenic variants in AMER1, a tumor suppressor and a WNT signaling repressor gene with key roles in tissue regeneration, neurodevelopment, tumorigenesis, and other developmental processes. While somatic AMER1 pathogenic variants have frequently been identified in several tumor types (e.g., Wilms tumor and colorectal cancer), whether OSCS (i.e., with AMER1 germline variants) is a tumor predisposition syndrome is not clear, with only nine cases reported with tumors. We here report the first case of neuroblastoma diagnosed in a male child with OSCS, review all previously reported tumors diagnosed in individuals with OSCS, and discuss potential tumorigenic mechanisms of AMER1. Our report adds to the accumulating evidence suggesting OSCS is a tumor predisposition condition, highlighting the importance of maintaining a high index of suspicion for the associated tumors when evaluating patients with OSCS. Importantly, Wilms tumor stands out as the most commonly observed tumor in OSCS patients, underscoring the need for regular surveillance. © 2024 Wiley Periodicals LLC.

Author Keywords
AMER1;  cancer predisposition;  neuroblastoma;  OSCS;  Wilms tumor

Document Type: Article
Publication Stage: Article in Press
Source: Scopus