Single-cell profiling of human dura and meningioma reveals cellular meningeal landscape and insights into meningioma immune response(2022) Genome Medicine, 14 (1), art. no. 49, .
Wang, A.Z.a b c d e , Bowman-Kirigin, J.A.a b c d , Desai, R.a d , Kang, L.-I.f , Patel, P.R.g , Patel, B.a d , Khan, S.M.a d , Bender, D.c , Marlin, M.C.h , Liu, J.i j , Osbun, J.W.a d , Leuthardt, E.C.a d , Chicoine, M.R.a d , Dacey, R.G., Jr.a d , Zipfel, G.J.a d , Kim, A.H.a d , DeNardo, D.G.k , Petti, A.A.a d i l , Dunn, G.P.e
AbstractBackground: Recent investigations of the meninges have highlighted the importance of the dura layer in central nervous system immune surveillance beyond a purely structural role. However, our understanding of the meninges largely stems from the use of pre-clinical models rather than human samples. Methods: Single-cell RNA sequencing of seven non-tumor-associated human dura samples and six primary meningioma tumor samples (4 matched and 2 non-matched) was performed. Cell type identities, gene expression profiles, and T cell receptor expression were analyzed. Copy number variant (CNV) analysis was performed to identify putative tumor cells and analyze intratumoral CNV heterogeneity. Immunohistochemistry and imaging mass cytometry was performed on selected samples to validate protein expression and reveal spatial localization of select protein markers. Results: In this study, we use single-cell RNA sequencing to perform the first characterization of both non-tumor-associated human dura and primary meningioma samples. First, we reveal a complex immune microenvironment in human dura that is transcriptionally distinct from that of meningioma. In addition, we characterize a functionally diverse and heterogenous landscape of non-immune cells including endothelial cells and fibroblasts. Through imaging mass cytometry, we highlight the spatial relationship among immune cell types and vasculature in non-tumor-associated dura. Utilizing T cell receptor sequencing, we show significant TCR overlap between matched dura and meningioma samples. Finally, we report copy number variant heterogeneity within our meningioma samples. Conclusions: Our comprehensive investigation of both the immune and non-immune cellular landscapes of human dura and meningioma at single-cell resolution builds upon previously published data in murine models and provides new insight into previously uncharacterized roles of human dura. © 2022, The Author(s).
Fluoxetine exposure throughout neurodevelopment differentially influences basilar dendritic morphology in the motor and prefrontal cortices(2022) Scientific Reports, 12 (1), art. no. 7605,
Maloney, S.E.a b , Tabachnick, D.R.a c , Jakes, C.a c , Avdagic, S.a c , Bauernfeind, A.L.d e , Dougherty, J.D.a b c
AbstractThe significance of serotonin (5HT) in mental health is underscored by the serotonergic action of many classes of psychiatric medication. 5HT is known to have a significant role in neurodevelopment, thus 5HT disruption during development may have a long term impact on brain structure and circuits. We previously generated a model of 5HT alteration throughout neurodevelopment by maternal administration of the selective serotonin reuptake inhibitor fluoxetine. We found resulting social behavior alterations in the offspring during both postnatal and adult ages. Previous work by others has indicated that early 5HT disruption influences neuronal morphology. Therefore, in the current study we sought to determine if dendritic morphological changes occur in areas involved in the social behavior deficits we previously observed, specifically the primary motor (M1) and medial prefrontal (mPFC) cortices. We quantified dendritic morphology of projection neurons in M1 and mPFC at postnatal day (P)10 and P79 in mice exposed to fluoxetine. Basilar dendritic complexity and spine density were persistently decreased in M1 fluoxetine-exposed neurons while in the mPFC, similar reductions were observed at P79 but were not present at P10. Our findings underscore that the developing brain, specifically the projection cortex, is vulnerable to 5HT system perturbation, which may be related to later behavioral disruptions. © 2022, The Author(s).
Millar, P.R.a , Luckett, P.H.a , Gordon, B.A.b , Benzinger, T.L.S.b , Schindler, S.E.a , Fagan, A.M.a , Cruchaga, C.c k , Bateman, R.J.a , Allegri, R.d k , Jucker, M.e f k , Lee, J.-H.g , Mori, H.h , Salloway, S.P.i , Yakushev, I.j , Morris, J.C.a , Ances, B.M.a b , … Xu, J.k , Xu, X.k , for the Dominantly Inherited Alzheimer Networkl
Predicting brain age from functional connectivity in symptomatic and preclinical Alzheimer disease(2022) NeuroImage, 256, art. no. 119228, .
Abstract“Brain-predicted age” quantifies apparent brain age compared to normative neuroimaging trajectories. Advanced brain-predicted age has been well established in symptomatic Alzheimer disease (AD), but is underexplored in preclinical AD. Prior brain-predicted age studies have typically used structural MRI, but resting-state functional connectivity (FC) remains underexplored. Our model predicted age from FC in 391 cognitively normal, amyloid-negative controls (ages 18–89). We applied the trained model to 145 amyloid-negative, 151 preclinical AD, and 156 symptomatic AD participants to test group differences. The model accurately predicted age in the training set. FC-predicted brain age gaps (FC-BAG) were significantly older in symptomatic AD and significantly younger in preclinical AD compared to controls. There was minimal correspondence between networks predictive of age and AD. Elevated FC-BAG may reflect network disruption during symptomatic AD. Reduced FC-BAG in preclinical AD was opposite to the expected direction, and may reflect a biphasic response to preclinical AD pathology or may be driven by inconsistency between age-related vs. AD-related networks. Overall, FC-predicted brain age may be a sensitive AD biomarker. © 2022
Shi, Y.a , Kerry, P.S.b , Nanson, J.D.c , Bosanac, T.d , Sasaki, Y.e , Krauss, R.d , Saikot, F.K.c , Adams, S.E.b , Mosaiab, T.a , Masic, V.a , Mao, X.e , Rose, F.a , Vasquez, E.a , Furrer, M.f , Cunnea, K.b , Brearley, A.b , Gu, W.c , Luo, Z.c , Brillault, L.g , Landsberg, M.J.c , DiAntonio, A.h , Kobe, B.c , Milbrandt, J.e , Hughes, R.O.d , Ve, T.aStructural basis of SARM1 activation, substrate recognition, and inhibition by small molecules(2022) Molecular Cell, 82 (9), pp. 1643-1659.e10.
AbstractThe NADase SARM1 (sterile alpha and TIR motif containing 1) is a key executioner of axon degeneration and a therapeutic target for several neurodegenerative conditions. We show that a potent SARM1 inhibitor undergoes base exchange with the nicotinamide moiety of nicotinamide adenine dinucleotide (NAD+) to produce the bona fide inhibitor 1AD. We report structures of SARM1 in complex with 1AD, NAD+ mimetics and the allosteric activator nicotinamide mononucleotide (NMN). NMN binding triggers reorientation of the armadillo repeat (ARM) domains, which disrupts ARM:TIR interactions and leads to formation of a two-stranded TIR domain assembly. The active site spans two molecules in these assemblies, explaining the requirement of TIR domain self-association for NADase activity and axon degeneration. Our results reveal the mechanisms of SARM1 activation and substrate binding, providing rational avenues for the design of new therapeutics targeting SARM1. © 2022 The Authors
Wang, L.ab , Covey, D.F.acd , Akk, G.ae , Evers, A.S.aceNeurosteroid Modulation of GABAA Receptor Function by Independent Action at Multiple Specific Binding Sites(2022) Current Neuropharmacology, 20 (5), pp. 886-890.
AbstractNeurosteroids are endogenous modulators of GABAA receptors that mediate anxiety, pain, mood and arousal. The 3-hydroxyl epimers, allopregnanolone (3α-OH) and epi-allopregnanolone (3β-OH) are both prevalent in the mammalian brain and produce opposite effects on GABAA receptor function, acting as positive and negative allosteric modulators, respectively. This Perspective provides a model to explain the actions of 3α-OH and 3β-OH neurosteroids. The model is based on evidence that the neurosteroid epimers bind to an overlapping subset of specific sites on GABAA receptors, with their net functional effect on channel gating being the sum of their independent effects at each site. © 2022 Bentham Science Publishers.
Randomized phase 2 study of ACE-083, a muscle-promoting agent, in facioscapulohumeral muscular dystrophy(2022) Muscle and Nerve, .
Statland, J.M.a , Campbell, C.b , Desai, U.c , Karam, C.d , Díaz-Manera, J.efg , Guptill, J.T.h , Korngut, L.i , Genge, A.j , Tawil, R.N.k , Elman, L.l , Joyce, N.C.m , Wagner, K.R.n , Manousakis, G.o , Amato, A.A.p , Butterfield, R.J.q , Shieh, P.B.r , Wicklund, M.s , Gamez, J.t , Bodkin, C.u , Pestronk, A.v , Weihl, C.C.v , Vilchez-Padilla, J.J.wx , Johnson, N.E.y , Mathews, K.D.z , Miller, B.aa , Leneus, A.aa , Fowler, M.aa , van de Rijn, M.aa , Attie, K.M.aa
AbstractIntroduction/Aims: Facioscapulohumeral muscular dystrophy (FSHD) is a slowly progressive muscular dystrophy without approved therapies. In this study we evaluated whether locally acting ACE-083 could safely increase muscle volume and improve functional outcomes in adults with FSHD. Methods: Participants were at least 18 years old and had FSHD1/FSHD2. Part 1 was open label, ascending dose, assessing safety and tolerability (primary objective). Part 2 was randomized, double-blind for 6 months, evaluating ACE-083240 mg/muscle vs placebo injected bilaterally every 3 weeks in the biceps brachii (BB) or tibialis anterior (TA) muscles, followed by 6 months of open label. Magnetic resonance imaging measures included total muscle volume (TMV; primary objective), fat fraction (FF), and contractile muscle volume (CMV). Functional measures included 6-minute walk test, 10-meter walk/run, and 4-stair climb (TA group), and performance of upper limb midlevel/elbow score (BB group). Strength, patient-reported outcomes (PROs), and safety were also evaluated. Results: Parts 1 and 2 enrolled 37 and 58 participants, respectively. Among 55 participants evaluable in Part 2, the least-squares mean (90% confidence interval, analysis of covariance) treatment difference for TMV was 16.4% (9.8%-23.0%) in the BB group (P <.0001) and 9.5% (3.2%-15.9%) in the TA group (P =.01). CMV increased significantly in the BB and TA groups and FF decreased in the TA group. There were no consistent improvements in functional or PRO measures in either group. The most common adverse events were mild or moderate injection-site reactions. Discussion: Significant increases in TMV with ACE-083 vs placebo did not result in consistent functional or PRO improvements with up to 12 months of treatment. © 2022 The Authors. Muscle & Nerve published by Wiley Periodicals LLC.
Chen, X.ah , Du, Y.b , Broussard, G.J.c , Kislin, M.c , Yuede, C.M.d , Zhang, S.b , Dietmann, S.ef , Gabel, H.a , Zhao, G.a , Wang, S.S.-H.c , Zhang, X.b , Bonni, A.ag
AbstractCellular diversification is critical for specialized functions of the brain including learning and memory1. Single-cell RNA sequencing facilitates transcriptomic profiling of distinct major types of neuron2–4, but the divergence of transcriptomic profiles within a neuronal population and their link to function remain poorly understood. Here we isolate nuclei tagged5 in specific cell types followed by single-nucleus RNA sequencing to profile Purkinje neurons and map their responses to motor activity and learning. We find that two major subpopulations of Purkinje neurons, identified by expression of the genes Aldoc and Plcb4, bear distinct transcriptomic features. Plcb4+, but not Aldoc+, Purkinje neurons exhibit robust plasticity of gene expression in mice subjected to sensorimotor and learning experience. In vivo calcium imaging and optogenetic perturbation reveal that Plcb4+ Purkinje neurons have a crucial role in associative learning. Integrating single-nucleus RNA sequencing datasets with weighted gene co-expression network analysis uncovers a learning gene module that includes components of FGFR2 signalling in Plcb4+ Purkinje neurons. Knockout of Fgfr2 in Plcb4+ Purkinje neurons in mice using CRISPR disrupts motor learning. Our findings define how diversification of Purkinje neurons is linked to their responses in motor learning and provide a foundation for understanding their differential vulnerability to neurological disorders. © 2022, The Author(s), under exclusive licence to Springer Nature Limited.
Comparison of sonication patterns and microbubble administration strategies for focused ultrasound-mediated large-volume drug delivery(2022) IEEE Transactions on Biomedical Engineering, .
Gong, Y.a , Ye, D.b , Chien, C.b , Yue, Y.b , Chen, H.c
AbstractObjective: Diffuse intrinsic pontine glioma (DIPG) is the most common and deadliest brainstem tumor in children. Focused ultrasound combined with microbubble-mediated BBB opening (FUS-BBBO) is a promising technique for overcoming the frequently intact blood-brain barrier (BBB) in DIPG to enhance therapeutic drug delivery to the brainstem. Since DIPG is highly diffusive, large-volume FUS-BBBO is needed to cover the entire tumor region. The objective of this study was to determine the optimal treatment strategy to achieve efficient and homogeneous large-volume BBBO at the brainstem for the delivery of an immune checkpoint inhibitor, anti-PD-L1 antibody (aPD-L1). Methods: Two critical parameters for large-volume FUS-BBBO, multi-point sonication pattern (interleaved vs. serial) and microbubble injection method (bolus vs. infusion), were evaluated by treating mice with four combinations of these two parameters. 2D Passive cavitation imaging (PCI) was performed for monitoring the large-volume sonication. Results: Interleaved sonication combined with bolus injection of microbubbles resulted in 1.29 to 2.06 folds higher efficiency than other strategies as evaluated by Evans blue extravasation. The average coefficient of variation of the Evans blue delivery was 0.66 for interleaved sonication with bolus injection, compared to 0.680.88 for all other strategies. Similar trend was also observed in the quantified total cavitation dose and coefficient of variance of the cavitation dose. This strategy was then applied to deliver fluorescently labeled aPD-L1 quantified using fluorescence imaging. A strong segmented linear correlation (R2=0.81) was found between the total cavitation dose and the total fluorescence intensity of aPD-L1 delivered at different sonication pressures (0.15 MPa, 0.30 MPa, and 0.45 MPa). Significance: Findings from this study suggest that efficient and homogeneous large-volume FUS-BBBO can be achieved by interleaved sonication combined with bolus injection of microbubbles, and the efficiency and homogeneity can be monitored by PCI. IEEE
Ecological Momentary Assessment of Real-World Functional Behaviors in Individuals With Stroke: A Longitudinal Observational Study(2022) Archives of Physical Medicine and Rehabilitation, .
Bui, Q.a , Kaufman, K.J.b , Pham, V.c , Lenze, E.J.c , Lee, J.-M.d , Mohr, D.C.e f , Fong, M.W.M.d g h , Metts, C.L.i , Tomazin, S.E.b , Wong, A.W.K.b g j
AbstractObjective: To validate and characterize real-world functional behaviors in individuals after stroke. Design: Longitudinal observational study using ecological momentary assessment (EMA) as a real-time assessment of functional behaviors in natural contexts. Wilcoxon rank-sum tests, Fisher exact tests, and Spearman correlations were used to analyze data. Setting: Community. Participants: Individuals with mild to moderate stroke (N=212). Interventions: Not applicable. Main Outcome Measures: Individuals were assessed 5 times daily for 14 days with EMA surveys to determine what, with whom, and where individuals were doing activities and appraise mental, somatic, and cognitive symptoms. Individuals also completed standardized assessments during laboratory visits, including Lawton Instrumental Activities of Daily Living Scale, Activity Card Sort, Patient-Reported Outcome Measurement Information System, and Quality of Life in Neurological Disorders. Results: Most individuals (median age, 60 years; 55% male) were ischemic stroke (90%) and had mild stroke severity (median National Institutes of Health Stroke Scale, 2). A total of 14,140 EMA surveys were analyzed. Individuals were home 78% of the time; primarily participated in passive, unproductive activities (27%), especially watching television and resting; and participated least in physical activities (4%). EMA was sensitive to indicators of poststroke disability; unemployed individuals reported fewer vocational activities but more activities of daily living (ADL) and passive activities than employed counterparts. Users of mobility devices and individuals with cognitive problems spent significantly less time on vocational activities and more on ADL than nonusers and those without cognitive problems. Our data supported the validity of EMA methods in stroke, with small to moderate correlations of EMA with in-laboratory measures of daily functioning (r=−0.30 to 0.35, P<.05) and very large correlations between EMA and in-laboratory measures of symptoms, especially those measuring same constructs (r=−0.64 to 0.79, P<.0001). Conclusions: Our findings reveal that EMA tracked poststroke functioning precisely. EMA may be beneficial in examining poststroke functional recovery, in monitoring patients for home-based interventions, and for longitudinal research. © 2022 American Congress of Rehabilitation Medicine