Hope Center member publications

Ketamine as a therapeutic agent for depression and pain: mechanisms and evidence
(2022) Journal of the Neurological Sciences, 434, art. no. 120152, . 

Subramanian, S.^a , Haroutounian, S.^b , Palanca, B.J.A.^a b c , Lenze, E.J.^a

^a Department of Psychiatry, Washington University in St. Louis School of Medicine, St. Louis, MO, United States
^b Department of Anesthesiology, Washington University in St. Louis School of Medicine, St. Louis, MO, United States
^c Department of Biomedical Engineering, Washington University in St. Louis, St. Louis, MO, United States

Abstract
Ketamine is an anesthetic drug which is now used to treat chronic pain conditions and psychiatric disorders, especially depression. It is an N-methyl-D-aspartate (NMDA) receptor antagonist with additional effects on α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors, hyperpolarization-activated cyclic nucleotide-gated (HCN) channels, opioid receptors, and monoaminergic receptors. This article focuses on ketamine’s role in treating depression and pain, two commonly comorbid challenging conditions with potentially shared neurobiologic circuitry. Many clinical trials have utilized intravenous or intranasal ketamine for treating depression and pain. Intravenous ketamine is more bioavailable than intranasal ketamine and both are effective for acute depressive episodes. Intravenous ketamine is advantageous for post-operative analgesia and is associated with a reduction in total opioid requirements. Few studies have treated chronic pain or concurrent depression and pain with ketamine. Larger, randomized control trials are needed to examine the safety and efficacy of intravenous vs. intranasal ketamine, ideal target populations, and optimal dosing to treat both depression and pain. © 2022 Elsevier B.V.

Author Keywords
Esketamine;  Interventional psychiatry;  Ketamine;  Major depressive disorder;  Pain

Funding details
National Institute of Mental HealthNIMHR25 MH112473
U.S. Food and Drug AdministrationFDA
National Institute on AgingNIA
Office of Behavioral and Social Sciences ResearchOBSSR
James S. McDonnell FoundationJSMF
American Foundation for Suicide PreventionAFSP
Sidney R. Baer, Jr. Foundation
Roche
Patient-Centered Outcomes Research InstitutePCORI
Foundation for Barnes-Jewish HospitalFBJH
National Center for Complementary and Integrative HealthNCCIH
Janssen Pharmaceuticals
McDonnell Center for Systems Neuroscience
Jazz Pharmaceuticals
H. Lundbeck A/S

Document Type: Article
Publication Stage: Final
Source: Scopus

Head tremor in cervical dystonia: Quantifying severity with computer vision
(2022) Journal of the Neurological Sciences, 434, art. no. 120154, . 

Vu, J.P.^a , Cisneros, E.^a , Lee, H.Y.^a , Le, L.^a , Chen, Q.^a , Guo, X.A.^a , Rouzbehani, R.^a , Jankovic, J.^b , Factor, S.^c , Goetz, C.G.^d , Barbano, R.L.^e , Perlmutter, J.S.^f g , Jinnah, H.A.^c h , Pirio Richardson, S.^i j , Stebbins, G.T.^d , Elble, R.^k , Comella, C.L.^d , Peterson, D.A.^a l

^a Institute for Neural Computation, University of California, San Diego, La Jolla, CA, United States
^b Parkinson’s Disease Center and Movement Disorders Clinic, Department of Neurology, Baylor College of Medicine, Houston, TX, United States
^c Department of Neurology, Emory University School of Medicine, Atlanta, GA, United States
^d Department of Neurological Sciences, Rush University Medical Center, Chicago, IL, United States
^e Department of Neurology, University of Rochester, Rochester, NY, United States
^f Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States
^g Departments of Radiology, Neuroscience, Physical Therapy, and Occupational Therapy, Washington University School of Medicine, St. Louis, MO, United States
^h Departments of Human Genetics, Emory University School of Medicine, Atlanta, GA, United States
ⁱ Department of Neurology, University of New Mexico Health Sciences Center, Albuquerque, NM, United States
^j Neurology Service, New Mexico Veterans Affairs Health Care System, Albuquerque, NM, United States
^k Department of Neurology, Southern Illinois University School of Medicine, Springfield, IL, United States
^l Computational Neurobiology Laboratory, Salk Institute for Biological Studies, La Jolla, CA, United States

Abstract
Background: Head tremor (HT) is a common feature of cervical dystonia (CD), usually quantified by subjective observation. Technological developments offer alternatives for measuring HT severity that are objective and amenable to automation. Objectives: Our objectives were to develop CMOR (Computational Motor Objective Rater; a computer vision-based software system) to quantify oscillatory and directional aspects of HT from video recordings during a clinical examination and to test its convergent validity with clinical rating scales. Methods: For 93 participants with isolated CD and HT enrolled by the Dystonia Coalition, we analyzed video recordings from an examination segment in which participants were instructed to let their head drift to its most comfortable dystonic position. We evaluated peak power, frequency, and directional dominance, and used Spearman’s correlation to measure the agreement between CMOR and clinical ratings. Results: Power averaged 0.90 (SD 1.80) deg2/Hz, and peak frequency 1.95 (SD 0.94) Hz. The dominant HT axis was pitch (antero/retrocollis) for 50%, roll (laterocollis) for 6%, and yaw (torticollis) for 44% of participants. One-sided t-tests showed substantial contributions from the secondary (t = 18.17, p < 0.0001) and tertiary (t = 12.89, p < 0.0001) HT axes. CMOR’s HT severity measure positively correlated with the HT item on the Toronto Western Spasmodic Torticollis Rating Scale-2 (Spearman’s rho = 0.54, p < 0.001). Conclusions: We demonstrate a new objective method to measure HT severity that requires only conventional video recordings, quantifies the complexities of HT in CD, and exhibits convergent validity with clinical severity ratings. © 2022 Elsevier B.V.

Author Keywords
Computer vision;  Head tremor;  Severity rating;  TWSTRS;  Video

Funding details
W81XWH-17-1-0393
National Institutes of HealthNIHAG-64937, AG050263, ES029524, NS075321, NS075527, NS092865, NS097437, NS097799, NS103957, NS107281, NS109487, P20 GM109899, R61 AT010753, U10 NS077366, U10NS077384, U19 NS110456
U.S. Department of DefenseDODW81XWH-19-CTRR-CTA, W81XWH-217-1-0393
National Institute on AgingNIAR01AG065214, RO1NS118146
National Institute of Neurological Disorders and StrokeNINDSNS065701, NS116025
Michael J. Fox Foundation for Parkinson’s ResearchMJFF
Huntington’s Disease Society of AmericaHDSA
Parkinson’s Disease FoundationPDF
Dystonia Medical Research FoundationDMRF
CHDI FoundationCHDI
National Center for Advancing Translational SciencesNCATSU54 TR001456
Teva Pharmaceutical Industries
American Parkinson Disease AssociationAPDA
AbbVie
Foundation for Barnes-Jewish HospitalFBJH
Allergan
Parkinsonfonden
International Essential Tremor FoundationIETF
Boston Scientific CorporationBSC
Benign Essential Blepharospasm Research FoundationBEBRF
National Spasmodic Dysphonia AssociationNSDA
ACADIA PharmaceuticalsACADIA
Dystonia Coalition
Government of South Australia
RevanceRVNC

Document Type: Article
Publication Stage: Final
Source: Scopus

Alterations of host-gut microbiome interactions in multiple sclerosis
(2022) eBioMedicine, 76, art. no. 103798, . 

Cantoni, C.^a , Lin, Q.^b , Dorsett, Y.^c , Ghezzi, L.^a d , Liu, Z.^e , Pan, Y.^e , Chen, K.^e , Han, Y.^f , Li, Z.^f , Xiao, H.^f , Gormley, M.^g , Liu, Y.^g , Bokoliya, S.^c , Panier, H.^c , Suther, C.^f , Evans, E.^a , Deng, L.^a h , Locca, A.^a , Mikesell, R.^a , Obert, K.^a , Newland, P.ⁱ , Wu, Y.^b , Salter, A.^j , Cross, A.H.^a k , Tarr, P.I.^l , Lovett-Racke, A.^g , Piccio, L.^a k m , Zhou, Y.^c

^a Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States
^b Department of Computer Science and Engineering, University of Connecticut, Storrs, CT, United States
^c Department of Medicine, UConn Health, Farmington, CT, United States
^d Dino Ferrari Center, University of Milan, Milan, Italy
^e Department of Statistics, University of Connecticut, Storrs, CT, United States
^f Department of Food Science, University of Massachusetts, Amherst, Massachusetts, United States
^g Department of Microbial Infection and Immunity, Ohio State University, Columbus, OH, United States
^h Department of Anesthesiology, First Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215006, China
ⁱ Barnes Jewish College, Goldfarb School of Nursing, St. Louis, MO, United States
^j Division of Biostatistics, School of Medicine, Washington University, St. Louis, MO, United States
^k Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO 63110, United States
^l Departments of Pediatrics and Molecular Microbiology, Washington University School of Medicine, St. Louis, MO, United States
^m Brain and Mind Centre, School of Medical Sciences, University of Sydney, Sydney, NSW 2050, Australia

Abstract
Background: Multiple sclerosis (MS) has a complex genetic, immune and metabolic pathophysiology. Recent studies implicated the gut microbiome in MS pathogenesis. However, interactions between the microbiome and host immune system, metabolism and diet have not been studied over time in this disorder. Methods: We performed a six-month longitudinal multi-omics study of 49 participants (24 untreated relapse remitting MS patients and 25 age, sex, race matched healthy control individuals. Gut microbiome composition and function were characterized using 16S and metagenomic shotgun sequencing. Flow cytometry was used to characterize blood immune cell populations and cytokine profiles. Circulating metabolites were profiled by untargeted UPLC-MS. A four-day food diary was recorded to capture the habitual dietary pattern of study participants. Findings: Together with changes in blood immune cells, metagenomic analysis identified a number of gut microbiota decreased in MS patients compared to healthy controls, and microbiota positively or negatively correlated with degree of disability in MS patients. MS patients demonstrated perturbations of their blood metabolome, such as linoleate metabolic pathway, fatty acid biosynthesis, chalcone, dihydrochalcone, 4-nitrocatechol and methionine. Global correlations between multi-omics demonstrated a disrupted immune-microbiome relationship and a positive blood metabolome-microbiome correlation in MS. Specific feature association analysis identified a potential correlation network linking meat servings with decreased gut microbe B. thetaiotaomicron, increased Th17 cell and greater abundance of meat-associated blood metabolites. The microbiome and metabolome profiles remained stable over six months in MS and control individuals. Interpretation: Our study identified multi-system alterations in gut microbiota, immune and blood metabolome of MS patients at global and individual feature level. Multi-OMICS data integration deciphered a potential important biological network that links meat intakes with increased meat-associated blood metabolite, decreased polysaccharides digesting bacteria, and increased circulating proinflammatory marker. Funding: This work was supported by the Washington University in St. Louis Institute of Clinical and Translational Sciences, funded, in part, by Grant Number # UL1 TR000448 from the National Institutes of Health, National Center for Advancing Translational Sciences, Clinical and Translational Sciences Award (Zhou Y, Piccio, L, Lovett-Racke A and Tarr PI); R01 NS10263304 (Zhou Y, Piccio L); the Leon and Harriet Felman Fund for Human MS Research (Piccio L and Cross AH). Cantoni C. was supported by the National MS Society Career Transition Fellowship (TA-180531003) and by donations from Whitelaw Terry, Jr. / Valerie Terry Fund. Ghezzi L. was supported by the Italian Multiple Sclerosis Society research fellowship (FISM 2018/B/1) and the National Multiple Sclerosis Society Post-Doctoral Fellowship (FG-190734474). Anne Cross was supported by The Manny & Rosalyn Rosenthal-Dr. John L. Trotter MS Center Chair in Neuroimmunology of the Barnes-Jewish Hospital Foundation. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. © 2022 The Authors

Author Keywords
Diet;  Microbiome;  Multi-omics;  Multiple sclerosis

Funding details
National Institutes of HealthNIH
National Multiple Sclerosis SocietyNMSSFG-1907–34474, TA-1805–31003
Biogen
National Center for Advancing Translational SciencesNCATSR01 NS102633–04
Foundation for Barnes-Jewish HospitalFBJH
Associazione Italiana Sclerosi MultiplaAISMFISM 2018/B/1
University of MassachusettsUMASS31003, 34474, FG-1907, PRJNA634779, R01 NS102633, TA-1805
Institute of Clinical and Translational SciencesICTSUL1 TR000448

Document Type: Article
Publication Stage: Final
Source: Scopus

Importance of CSF-based Aβ clearance with age in humans increases with declining efficacy of blood-brain barrier/proteolytic pathways
(2022) Communications Biology, 5 (1), p. 98. 

Elbert, D.L.^a , Patterson, B.W.^b , Lucey, B.P.^c d , Benzinger, T.L.S.^d e , Bateman, R.J.^c d

^a Department of Neurology, Dell Medical School, University of Texas at Austin, TX, Austin, United States
^b Department of Medicine, Washington University in St. Louis, St. Louis, MO, USA
^c Department of Neurology, Washington University School of Medicine, St. Louis, MO, USA
^d Hope Center for Neurological Disorders, Washington University School of Medicine, St Louis, MO, USA
^e Department of Radiology, Washington University School of Medicine, St. Louis, MO, USA

Abstract
The kinetics of amyloid beta turnover within human brain is still poorly understood. We previously found a dramatic decline in the turnover of Aβ peptides in normal aging. It was not known if brain interstitial fluid/cerebrospinal fluid (ISF/CSF) fluid exchange, CSF turnover, blood-brain barrier function or proteolysis were affected by aging or the presence of β amyloid plaques. Here, we describe a non-steady state physiological model developed to decouple CSF fluid transport from other processes. Kinetic parameters were estimated using: (1) MRI-derived brain volumes, (2) stable isotope labeling kinetics (SILK) of amyloid-β peptide (Aβ), and (3) lumbar CSF Aβ concentration during SILK. Here we show that changes in blood-brain barrier transport and/or proteolysis were largely responsible for the age-related decline in Aβ turnover rates. CSF-based clearance declined modestly in normal aging but became increasingly important due to the slowing of other processes. The magnitude of CSF-based clearance was also lower than that due to blood-brain barrier function plus proteolysis. These results suggest important roles for blood-brain barrier transport and proteolytic degradation of Aβ in the development Alzheimer’s Disease in humans. © 2022. The Author(s).

Document Type: Article
Publication Stage: Final
Source: Scopus

Association Between Time Spent Outdoors and Risk of Multiple Sclerosis
(2022) Neurology, 98 (3), pp. e267-e278. 

Sebastian, P., Cherbuin, N., Barcellos, L.F., Roalstad, S., Casper, C., Hart, J., Aaen, G.S., Krupp, L., Benson, L., Gorman, M., Candee, M., Chitnis, T., Goyal, M., Greenberg, B., Mar, S., Rodriguez, M., Rubin, J., Schreiner, T., Waldman, A., Weinstock-Guttman, B., Graves, J., Waubant, E., Lucas, R., US Network of Pediatric Multiple Sclerosis Centers

From the Australian National University Medical School (P.S.), Centre for Research on Ageing, Health and Wellbeing (N.C.), and National Centre for Epidemiology and Population Health (R.L.), Australian National University, Canberra; Division of Epidemiology (L.F.B.), University of California Berkeley; Department of Pediatrics (S.R., C.C.), University of Utah School of Medicine, Salt Lake City; Pediatric Multiple Sclerosis Center (J.H.) and Department of Neurology (E.W.), University of California San Francisco; Pediatric Multiple Sclerosis Center (G.S.A.), Loma Linda University Children’s Hospital, CA; MS Comprehensive Care Center (L.K.), New York University Langone, NY; Pediatric Multiple Sclerosis and Related Disorders Program (L.B., M. Gorman), Boston Children’s Hospital, MA; Division of Pediatric Neurology (M.C.), University of Utah Primary Children’s Hospital, Salt Lake City; Partners Pediatric Multiple Sclerosis Center (T.C.), Massachusetts General Hospital for Children, Boston; Department of Radiology (M. Goyal), Washington University St. Louis, MO; Department of Neurology (B.G.), University of Texas Southwestern, Dallas; Pediatric-Onset Demyelinating Diseases and Autoimmune Encephalitis Center (S.M.), St. Louis Children’s Hospital, Washington University School of Medicine, MO; Mayo Clinic Pediatric Multiple Sclerosis Center (M.R.), Mayo Clinic, Rochester, MN; Department of Pediatric Neurology (J.R.), Northwestern Feinberg School of Medicine, Chicago, IL; Children’s Hospital Colorado (T.S.), University of Colorado, Denver; Division of Neurology (A.W.), Children’s Hospital of Philadelphia, PA; Pediatric Multiple Sclerosis Center (B.W.-G.), Jacobs Neurological Institute, State University of New York Buffalo; and Department of Neurosciences (J.G.), University of California San Diego

Abstract
BACKGROUND AND OBJECTIVES: This study aims to determine the contributions of sun exposure and ultraviolet radiation (UVR) exposure to risk of pediatric-onset multiple sclerosis (MS). METHODS: Children with MS and controls recruited from multiple centers in the United States were matched on sex and age. Multivariable conditional logistic regression was used to investigate the association of time spent outdoors daily in summer, use of sun protection, and ambient summer UVR dose in the year before birth and the year before diagnosis with MS risk, with adjustment for sex, age, race, birth season, child’s skin color, mother’s education, tobacco smoke exposure, being overweight, and Epstein-Barr virus infection. RESULTS: Three hundred thirty-two children with MS (median disease duration 7.3 months) and 534 controls were included after matching on sex and age. In a fully adjusted model, compared to spending <30 minutes outdoors daily during the most recent summer, greater time spent outdoors was associated with a marked reduction in the odds of developing MS, with evidence of dose-response (30 minutes-1 hour: adjusted odds ratio [AOR] 0.48, 95% confidence interval [CI] 0.23-0.99, p = 0.05; 1-2 hours: AOR 0.19, 95% CI 0.09-0.40, p < 0.001). Higher summer ambient UVR dose was also protective for MS (AOR 0.76 per 1 kJ/m2, 95% CI 0.62-0.94, p = 0.01). DISCUSSION: If this is a causal association, spending more time in the sun during summer may be strongly protective against developing pediatric MS, as well as residing in a sunnier location. © 2021 American Academy of Neurology.

Document Type: Article
Publication Stage: Final
Source: Scopus

Perspective on the Relationship between GABAA Receptor Activity and the Apparent Potency of an Inhibitor
(2022) Current Neuropharmacology, 20 (1), pp. 90-93. 

Germann, A.L.^a , Pierce, S.R.^a , Evers, A.S.^a b , Steinbach, J.H.^a b , Akk, G.^a b

^a Department of Anesthesiology, Washington University School of Medicine, St. Louis, MO 63110, United States
^b The Taylor Family Institute for Innovative Psychiatric Research, Washington University School of Medicine, St. Louis, MO 63110, United States

Abstract
Background: In electrophysiological experiments, inhibition of a receptor-channel, such as the GABAA receptor, is measured by co-applying an agonist producing a predefined control response with an inhibitor to calculate the fraction of the control response remaining in the presence of the inhibitor. The properties of the inhibitor are determined by fitting the inhibition concentra-tion-response relationship to the Hill equation to estimate the midpoint (IC50) of the inhibition curve. Objective: We sought to estimate sensitivity of the fitted IC50 to the level of activity of the control response. Methods: The inhibition concentration-response relationships were calculated for models with distinct mechanisms of inhibition. In Model I, the inhibitor acts allosterically to stabilize the resting state of the receptor. In Model II, the inhibitor competes with the agonist for a shared binding site. In Model III, the inhibitor stabilizes the desensitized state. Results: The simulations indicate that the fitted IC50 of the inhibition curve is sensitive to the degree of activity of the control response. In Models I and II, the IC50 of inhibition was increased as the probability of being in the active state (PA) of the control response increased. In Model III, the IC50 of inhibition was reduced at higher PA. Conclusion: We infer that the apparent potency of an inhibitor depends on the PA of the control re-sponse. While the calculations were carried out using the activation and inhibition properties that are representative of the GABAA receptor, the principles and conclusions apply to a wide variety of re-ceptor-channels. © 2022 Bentham Science Publishers.

Author Keywords
Activation;  GABAA receptor;  IC50;  Inhibition;  Modeling

Funding details
National Institute of General Medical SciencesNIGMSR01GM108580, R01GM108799, R35GM140947
Taylor Family Institute for Innovative Psychiatric Research, Washington University School of Medicine in St. Louis

Document Type: Article
Publication Stage: Final
Source: Scopus

Intrinsic Mechanisms in the Gating of Resurgent Na+ Currents
(2022) eLife, 11, art. no. e70173, . 

Ransdell, J.L.^a , Moreno, J.D.^c , Bhagavan, D.^c , Silva, J.R.^c , Nerbonne, J.M.^a b

^a Department of Medicine, Cardiovascular Division, Washington University in St. Louis, St. Louis, MO 63110, United States
^b Department of Developmental Biology, Washington University in St. Louis, St. Louis, MO 63110, United States
^c Biomedical Engineering, Washington University in St. Louis, St. Louis, MO 63110, United States

Abstract
The resurgent component of the voltage-gated sodium current (INaR) is a depolarizing conductance, revealed on membrane hyperpolarizations following brief depolarizing voltage steps, which has been shown to contribute to regulating the firing properties of numerous neuronal cell types throughout the central and peripheral nervous systems. Although mediated by the same voltage-gated sodium (Nav) channels that underlie the transient and persistent Nav current components, the gating mechanisms that contribute to the generation of INaR remain unclear. Here, we characterized Nav currents in mouse cerebellar Purkinje neurons, and used tailored voltage-clamp protocols to define how the voltage and the duration of the initial membrane depolarization affect the amplitudes and kinetics of INaR. Using the acquired voltage-clamp data, we developed a novel Markov kinetic state model with parallel (fast and slow) inactivation pathways and, we show that this model reproduces the properties of the resurgent, as well as the transient and persistent, Nav currents recorded in (mouse) cerebellar Purkinje neurons. Based on the acquired experimental data and the simulations, we propose that resurgent Na+ influx occurs as a result of fast inactivating Nav channels transitioning into an open/conducting state on membrane hyperpolarization, and that the decay of INaR reflects the slow accumulation of recovered/opened Nav channels into a second, alternative and more slowly populated, inactivated state. Additional simulations reveal that extrinsic factors that affect the kinetics of fast or slow Nav channel inactivation and/or impact the relative distribution of Nav channels in the fast-and slow-inactivated states, such as the accessory Navβ4 channel subunit, can modulate the amplitude of INaR. © 2022, eLife Sciences Publications Ltd. All rights reserved.

Author Keywords
INaR;  Markov modelling;  Mouse cerebellar Purkinje neurons;  Nav channel gating

Funding details
National Institutes of HealthNIHF32 NS090765, R01 HL136553, R01 NS065761, T32 HL007081
Foundation for Barnes-Jewish HospitalFBJH

Document Type: Article
Publication Stage: Final
Source: Scopus

Risk Factors for Phenoconversion in Rapid Eye Movement Sleep Behavior Disorder
(2022) Annals of Neurology, . 

Zhang, H.^a b , Iranzo, A.^c , Högl, B.^d , Arnulf, I.^e , Ferini-Strambi, L.^f , Manni, R.^g , Miyamoto, T.^h , Oertel, W.H.ⁱ , Dauvilliers, Y.^j , Ju, Y.-E.^k , Puligheddu, M.^l , Sonka, K.^m , Pelletier, A.ⁿ , Montplaisir, J.Y.^n o , Stefani, A.^d , Ibrahim, A.^d , Frauscher, B.^d , Leu-Semenescu, S.^e , Zucconi, M.^f , Terzaghi, M.^g , Miyamoto, M.^p , Janzen, A.ⁱ , Figorilli, M.^l , Fantini, M.L.^l q , Postuma, R.B.^b n

^a Department of Neurology, Xuanwu Hospital Capital Medical University, Beijing, China
^b Department of Neurology, McGill University, Montreal General Hospital, Montreal, QC, Canada
^c Neurology Service, Hospital Clinic of Barcelona, August Pi i Sunyer Biomedical Research Institute, Center for Biomedical Research on Neurodegenerative Diseases, Barcelona, Spain
^d Department of Neurology, Innsbruck Medical University, Innsbruck, Austria
^e Paris Brain Institute and Sleep Disorder Unit, Pitié-Salpêtrière Hospital, Public Hospital Network of Paris, Sorbonne University, Paris, France
^f Sleep Disorders Center, Vita-Salute San Raffaele University, Milan, Italy
^g C. Mondino National Neurological Institute, Pavia, Italy
^h Department of Neurology, Dokkyo Medical University Saitama Medical Center, Saitama, Japan
ⁱ Department of Neurology, Philipps University, Marburg, Germany
^j Department of Neurology, Gui de Chauliac Hospital, Montpellier, National Institute of Health and Medical Research U1061, Montpellier, France
^k Department of Neurology, Washington University School of Medicine, St Louis, MO, United States
^l Sleep Center, Department of Cardiovascular and Neurological Sciences, University of Cagliari, Cagliari, Italy
^m Department of Neurology, First Faculty of Medicine, Charles University and General University Hospital, Prague, Czech Republic
ⁿ Center for Advanced Studies in Sleep Medicine, Montreal Sacred Heart Hospital, Montreal, QC, Canada
^o Department of Psychiatry, University of Montreal, Montreal, QC, Canada
^p Department of Neurology, Dokkyo Medical University School of Medicine, Tochigi, Japan
^q Department of Neurology, University of Auvergne, Clermont-Ferrand, France

Abstract
Objective: This study was undertaken to follow up predictive factors for α-synuclein–related neurodegenerative diseases in a multicenter cohort of idiopathic/isolated rapid eye movement sleep behavior disorder (iRBD). Methods: Patients with iRBD from 12 centers underwent a detailed assessment for potential environmental and lifestyle risk factors via a standardized questionnaire at baseline. Patients were then prospectively followed and received assessments for parkinsonism or dementia during follow-up. The cumulative incidence of parkinsonism or dementia was estimated with competing risk analysis. Cox regression analyses were used to evaluate the predictive value of environmental/lifestyle factors over a follow-up period of 11 years, adjusting for age, sex, and center. Results: Of 319 patients who were free of parkinsonism or dementia, 281 provided follow-up information. After a mean follow-up of 5.8 years, 130 (46.3%) patients developed neurodegenerative disease. The overall phenoconversion rate was 24.2% after 3 years, 44.8% after 6 years, and 67.5% after 10 years. Patients with older age (adjusted hazard ratio [aHR] = 1.05) and nitrate derivative use (aHR = 2.18) were more likely to phenoconvert, whereas prior pesticide exposure (aHR = 0.21–0.64), rural living (aHR = 0.53), lipid-lowering medication use (aHR = 0.59), and respiratory medication use (aHR = 0.36) were associated with lower phenoconversion risk. Risk factors for those converting to primary dementia and parkinsonism were generally similar, with dementia-first converters having lower coffee intake and beta-blocker intake, and higher occurrence of family history of dementia. Interpretation: Our findings elucidate the predictive values of environmental factors and comorbid conditions in identifying RBD patients at higher risk of phenoconversion. ANN NEUROL 2022. © 2022 American Neurological Association.

Funding details
Canadian Institutes of Health ResearchIRSC
Fonds de Recherche du Québec – SantéFRQS

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

Metabolic sensing in AgRP neurons integrates homeostatic state with dopamine signalling in the striatum
(2022) eLife, 11, art. no. e72668, . 

Reichenbach, A.^a , Clarke, R.E.^a , Stark, R.^a , Lockie, S.H.^a , Mequinion, M.^a , Dempsey, H.^a , Rawlinson, S.^a , Reed, F.^a , Sepehrizadeh, T.^b , Deveer, M.^b , Munder, A.C.^a c , Nunez-Iglesias, J.^d , Spanswick, D.C.^a e , Mynatt, R.^f , Kravitz, A.V.^g , Dayas, C.V.^h , Brown, R.^c i , Andrews, Z.B.^a

^a Monash Biomedicine Discovery Institute and Department of Physiology, Monash University, Clayton, Australia
^b Monash Biomedical Imaging Facility, Monash University, Clayton, Australia
^c Florey Institute of Neuroscience & Mental Health, Parkville, Australia
^d Monash Biomedicine Discovery Institute and Department of Anatomy and Developmental Biology, Monash University, Clayton, Australia
^e Warwick Medical School, University of Warwick, Coventry, United Kingdom
^f Gene Nutrient Interactions Laboratory, Pennington Biomedical Research Center, Louisiana State University System, Baton Rouge, United States
^g Departments of Psychiatry, Anesthesiology, and Neuroscience, Washington University in St Louis, St Louis, United States
^h School of Biomedical Sciences and Pharmacy, University of Newcastle, Newcastle, Australia
ⁱ Department of Biochemistry and Pharmacology, University of Melbourne, Parkville, Australia

Abstract
Agouti-related peptide (AgRP) neurons increase motivation for food, however, whether metabolic sensing of homeostatic state in AgRP neurons potentiates motivation by inter-acting with dopamine reward systems is unexplored. As a model of impaired metabolic-sensing, we used the AgRP-specific deletion of carnitine acetyltransferase (Crat) in mice. We hypothesised that metabolic sensing in AgRP neurons is required to increase motivation for food reward by modulating accumbal or striatal dopamine release. Studies confirmed that Crat deletion in AgRP neurons (KO) impaired ex vivo glucose-sensing, as well as in vivo responses to peripheral glucose injection or repeated palatable food presentation and consumption. Impaired metabolic-sensing in AgPP neurons reduced acute dopamine release (seconds) to palatable food consumption and during operant responding, as assessed by GRAB-DA photometry in the nucleus accumbens, but not the dorsal striatum. Impaired metabolic-sensing in AgRP neurons suppressed radiolabelled 18F-fDOPA accumulation after ~30 min in the dorsal striatum but not the nucleus accumbens. Impaired metabolic sensing in AgRP neurons suppressed motivated operant responding for sucrose rewards during fasting. Thus, metabolic-sensing in AgRP neurons is required for the appropriate temporal integration and transmission of homeostatic hunger-sensing to dopamine signalling in the striatum. © 2022, eLife Sciences Publications Ltd. All rights reserved.

Funding details
National Health and Medical Research CouncilNHMRCAPP1126724, APP1154974
Monash UniversityMU

Document Type: Article
Publication Stage: Final
Source: Scopus

Does ventricle size contribute to cognitive outcomes in posthemorrhagic hydrocephalus? Role of early definitive intervention
(2022) Journal of Neurosurgery. Pediatrics, 29 (1), pp. 10-20. 

Paturu, M.^a , Triplett, R.L.^b , Thukral, S.^a , Alexopoulos, D.^b , Smyser, C.D.^b c , Limbrick, D.D.^a , Strahle, J.M.^a d

^a Departments of Neurological Surgery
^b 2Neurology
^c 4Radiology, Washington University in St. LouisMO
^d 3Pediatrics

Abstract
OBJECTIVE: Posthemorrhagic hydrocephalus (PHH) is associated with significant morbidity, smaller hippocampal volumes, and impaired neurodevelopment in preterm infants. The timing of temporary CSF (tCSF) diversion has been studied; however, the optimal time for permanent CSF (pCSF) diversion is unknown. The objective of this study was to determine whether cumulative ventricle size or timing of pCSF diversion is associated with neurodevelopmental outcome and hippocampal size in preterm infants with PHH. METHODS: Twenty-five very preterm neonates (born at ≤ 32 weeks’ gestational age) with high-grade intraventricular hemorrhage (IVH), subsequent PHH, and pCSF diversion with a ventriculoperitoneal shunt (n = 20) or endoscopic third ventriculostomy (n = 5) were followed until 2 years of age. Infants underwent serial cranial ultrasounds from birth until 1 year after pCSF diversion, brain MRI at term-equivalent age, and assessment based on the Bayley Scales of Infant and Toddler Development, Third Edition, at 2 years of age. Frontooccipital horn ratio (FOHR) measurements were derived from cranial ultrasounds and term-equivalent brain MRI. Hippocampal volumes were segmented and calculated from term-equivalent brain MRI. Cumulative ventricle size until the time of pCSF diversion was estimated using FOHR measurements from each cranial ultrasound performed prior to permanent intervention. RESULTS: The average gestational ages at tCSF and pCSF diversion were 28.9 and 39.0 weeks, respectively. An earlier chronological age at the time of pCSF diversion was associated with larger right hippocampal volumes on term-equivalent MRI (Pearson’s r = -0.403, p = 0.046) and improved cognitive (r = -0.554, p = 0.047), motor (r = -0.487, p = 0.048), and language (r = -0.414, p = 0.021) outcomes at 2 years of age. Additionally, a smaller cumulative ventricle size from birth to pCSF diversion was associated with larger right hippocampal volumes (r = -0.483, p = 0.014) and improved cognitive (r = -0.711, p = 0.001), motor (r = -0.675, p = 0.003), and language (r = -0.618, p = 0.011) outcomes. There was no relationship between time to tCSF diversion or cumulative ventricle size prior to tCSF diversion and neurodevelopmental outcome or hippocampal size. Finally, a smaller cumulative ventricular size prior to either tCSF diversion or pCSF diversion was associated with a smaller ventricular size 1 year after pCSF diversion (r = 0.422, p = 0.040, R2 = 0.178 and r = 0.519, p = 0.009, R2 = 0.269, respectively). CONCLUSIONS: In infants with PHH, a smaller cumulative ventricular size and shorter time to pCSF diversion were associated with larger right hippocampal volumes, improved neurocognitive outcomes, and reduced long-term ventriculomegaly. Future prospective randomized studies are needed to confirm these findings.

Author Keywords
endoscopic third ventriculostomy;  ETV;  intraventricular hemorrhage;  posthemorrhagic hydrocephalus;  ventriculoperitoneal shunt

Document Type: Article
Publication Stage: Final
Source: Scopus

Modeling the Effects of HIV and Aging on Resting-State Networks Using Machine Learning
(2021) Journal of Acquired Immune Deficiency Syndromes (1999), 88 (4), pp. 414-419. 

Luckett, P.H.^a , Paul, R.H.^b , Hannon, K.^a , Lee, J.J.^c , Shimony, J.S.^c , Meeker, K.L.^a , Cooley, S.A.^a , Boerwinkle, A.H.^a , Ances, B.M.^a

^a Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States
^b Department of Psychological Sciences, University of Missouri Saint Louis, St. Louis, Missouri; and
^c Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, MO, United States

Abstract
BACKGROUND: The relationship between HIV infection, the functional organization of the brain, cognitive impairment, and aging remains poorly understood. Understanding disease progression over the life span is vital for the care of people living with HIV (PLWH). SETTING: Virologically suppressed PLWH (n = 297) on combination antiretroviral therapy and 1509 HIV-uninfected healthy controls were evaluated. PLWH were further classified as cognitively normal (CN) or cognitively impaired (CI) based on neuropsychological testing. METHODS: Feature selection identified resting-state networks (RSNs) that predicted HIV status and cognitive status within specific age bins (younger than 35 years, 35-55 years, and older than 55 years). Deep learning models generated voxelwise maps of RSNs to identify regional differences. RESULTS: Salience (SAL) and parietal memory networks (PMNs) differentiated individuals by HIV status. When comparing controls with PLWH CN, the PMN and SAL had the strongest predictive strength across all ages. When comparing controls with PLWH CI, the SAL, PMN, and frontal parietal network (FPN) were the best predictors. When comparing PLWH CN with PLWH CI, the SAL, FPN, basal ganglia, and ventral attention were the strongest predictors. Only minor variability in predictive strength was observed with aging. Anatomically, differences in RSN topology occurred primarily in the dorsal and rostral lateral prefrontal cortex, cingulate, and caudate. CONCLUSION: Machine learning identified RSNs that classified individuals by HIV status and cognitive status. The PMN and SAL were sensitive for discriminating HIV status, with involvement of FPN occurring with cognitive impairment. Minor differences in RSN predictive strength were observed by age. These results suggest that specific RSNs are affected by HIV, aging, and HIV-associated cognitive impairment. Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.

Document Type: Article
Publication Stage: Final
Source: Scopus