Weekly Publications

WashU weekly Neuroscience publications: March 26, 2023

Astrocytic APOE4 removal confers cerebrovascular protection despite increased cerebral amyloid angiopathy” (2023) Molecular Neurodegeneration

Astrocytic APOE4 removal confers cerebrovascular protection despite increased cerebral amyloid angiopathy
(2023) Molecular Neurodegeneration, 18 (1), art. no. 17, . 

Xiong, M.a b c , Wang, C.d , Gratuze, M.a e , Saadi, F.a , Bao, X.a , Bosch, M.E.a , Lee, C.a , Jiang, H.a , Serrano, J.R.a , Gonzales, E.R.a , Kipnis, M.a , Holtzman, D.M.a

a Department of Neurology, Hope Center for Neurological Disorders, Knight Alzheimer’s Disease Research Center, Washington University School of Medicine, St. Louis, MO 63110, United States
b Division of Biology and Biomedical Sciences (DBBS), Washington University School of Medicine, St. Louis, MO 63110, United States
c Present Address: Genentech, 1 DNA Way, South San Francisco, CA 94080, United States
d Institute for Brain Science and Disease, Chongqing Medical University, Chongqing, 400016, China
e Institute of Neurophysiopathology (INP UMR7051), CNRS, Aix-Marseille Université, Marseille, 13005, France

Abstract
Background: Alzheimer Disease (AD) and cerebral amyloid angiopathy (CAA) are both characterized by amyloid-β (Aβ) accumulation in the brain, although Aβ deposits mostly in the brain parenchyma in AD and in the cerebrovasculature in CAA. The presence of CAA can exacerbate clinical outcomes of AD patients by promoting spontaneous intracerebral hemorrhage and ischemia leading to CAA-associated cognitive decline. Genetically, AD and CAA share the ε4 allele of the apolipoprotein E (APOE) gene as the strongest genetic risk factor. Although tremendous efforts have focused on uncovering the role of APOE4 on parenchymal plaque pathogenesis in AD, mechanistic studies investigating the role of APOE4 on CAA are still lacking. Here, we addressed whether abolishing APOE4 generated by astrocytes, the major producers of APOE, is sufficient to ameliorate CAA and CAA-associated vessel damage. Methods: We generated transgenic mice that deposited both CAA and plaques in which APOE4 expression can be selectively suppressed in astrocytes. At 2-months-of-age, a timepoint preceding CAA and plaque formation, APOE4 was removed from astrocytes of 5XFAD APOE4 knock-in mice. Mice were assessed at 10-months-of-age for Aβ plaque and CAA pathology, gliosis, and vascular integrity. Results: Reducing the levels of APOE4 in astrocytes shifted the deposition of fibrillar Aβ from the brain parenchyma to the cerebrovasculature. However, despite increased CAA, astrocytic APOE4 removal reduced overall Aβ-mediated gliosis and also led to increased cerebrovascular integrity and function in vessels containing CAA. Conclusion: In a mouse model of CAA, the reduction of APOE4 derived specifically from astrocytes, despite increased fibrillar Aβ deposition in the vasculature, is sufficient to reduce Aβ-mediated gliosis and cerebrovascular dysfunction. © 2023, The Author(s).

Author Keywords
Amyloid-β;  APOE;  Astrocyte;  Cerebral amyloid angiopathy;  Cerebrovasculature

Funding details
A2020257F
National Institutes of HealthNIHAG062027, P01 AG078106, R01 NS034467, RF1AG047644, RF1NS090934
JPB FoundationJPBF
Cure Alzheimer’s FundCAF

Document Type: Article
Publication Stage: Final
Source: Scopus

Neurofibromatosis type 1-dependent alterations in mouse microglia function are not cell-intrinsic” (2023) Acta Neuropathologica Communications

Neurofibromatosis type 1-dependent alterations in mouse microglia function are not cell-intrinsic
(2023) Acta Neuropathologica Communications, 11 (1), art. no. 36, . 

Logiacco, F.a c , Grzegorzek, L.C.a c , Cordell, E.C.b , Popp, O.d , Mertins, P.d , Gutmann, D.H.b , Kettenmann, H.a e , Semtner, M.a

a Cellular Neurosciences, Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association, Berlin, 13125, Germany
b Department of Neurology, Washington University School of Medicine, St. Louis, MO 63110, United States
c Institute of Cell Biology and Neurobiology, Charité–Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität Berlin, and Berlin Institute of Health, Berlin, 10117, Germany
d Proteomics Platform, Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association, Berlin, 13125, Germany
e Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China

Abstract
We previously discovered a sex-by-genotype defect in microglia function using a heterozygous germline knockout mouse model of Neurofibromatosis type 1 (Nf1 ± mice), in which only microglia from male Nf1 ± mice exhibited defects in purinergic signaling. Herein, we leveraged an unbiased proteomic approach to demonstrate that male, but not female, heterozygous Nf1 ± microglia exhibit differences in protein expression, which largely reflect pathways involved in cytoskeletal organization. In keeping with these predicted defects in cytoskeletal function, only male Nf1 ± microglia had reduced process arborization and surveillance capacity. To determine whether these microglial defects were cell autonomous or reflected adaptive responses to Nf1 heterozygosity in other cells in the brain, we generated conditional microglia Nf1-mutant knockout mice by intercrossing Nf1flox/flox with Cx3cr1-CreER mice (Nf1flox/wt; Cx3cr1-CreER mice, Nf1MG ± mice). Surprisingly, neither male nor female Nf1MG ± mouse microglia had impaired process arborization or surveillance capacity. In contrast, when Nf1 heterozygosity was generated in neurons, astrocytes and oligodendrocytes by intercrossing Nf1flox/flox with hGFAP-Cre mice (Nf1flox/wt; hGFAP-Cre mice, Nf1GFAP ± mice), the microglia defects found in Nf1 ± mice were recapitulated. Collectively, these data reveal that Nf1 ± sexually dimorphic microglia abnormalities are likely not cell-intrinsic properties, but rather reflect a response to Nf1 heterozygosity in other brain cells. © 2023, The Author(s).

Author Keywords
Cortex;  Genetically engineered mice;  Microglia;  Neurofibromin;  NF1;  Purinergic signaling;  Sex differences

Funding details
National Institutes of HealthNIH
National Cancer InstituteNCI1-R01-CA214146-01
Berlin Institute of HealthBIH
NeuroCure Exzellenzcluster

Document Type: Article
Publication Stage: Final
Source: Scopus

Molecular mechanism of biased signaling at the kappa opioid receptor” (2023) Nature Communications

Molecular mechanism of biased signaling at the kappa opioid receptor
(2023) Nature Communications, 14 (1), art. no. 1338, . 

El Daibani, A.a b , Paggi, J.M.c , Kim, K.d j , Laloudakis, Y.D.c , Popov, P.e , Bernhard, S.M.a b , Krumm, B.E.d , Olsen, R.H.J.d , Diberto, J.d , Carroll, F.I.f , Katritch, V.g , Wünsch, B.h , Dror, R.O.c i , Che, T.a b

a Department of Anesthesiology, Washington University School of Medicine, Saint Louis, MO, United States
b Center for Clinical Pharmacology, University of Health Sciences & Pharmacy and Washington University School of Medicine, Saint Louis, MO, United States
c Department of Computer Science, Stanford University, Stanford, CA, United States
d Department of Pharmacology, University of North Carolina School of Medicine, Chapel Hill, NC, United States
e iMolecule, Skolkovo Institute of Science and Technology, Moscow, Russian Federation
f Research Triangle Institute, P.O. Box 12194, Research Triangle Park, NC 27709, United States
g Department of Biological Sciences, University of Southern California, Los Angeles, CA, United States
h Institut für Pharmazeutische und Medizinische Chemie, Universität Münster, Corrensstraße 48, Münster, 48149, Germany
i Departments of Molecular and Cellular Physiology and of Structural Biology, Stanford University School of Medicine, Stanford, CA, United States
j Department of Pharmacy, Yonsei University, Incheon, 21983, South Korea

Abstract
The κ-opioid receptor (KOR) has emerged as an attractive drug target for pain management without addiction, and biased signaling through particular pathways of KOR may be key to maintaining this benefit while minimizing side-effect liabilities. As for most G protein-coupled receptors (GPCRs), however, the molecular mechanisms of ligand-specific signaling at KOR have remained unclear. To better understand the molecular determinants of KOR signaling bias, we apply structure determination, atomic-level molecular dynamics (MD) simulations, and functional assays. We determine a crystal structure of KOR bound to the G protein-biased agonist nalfurafine, the first approved KOR-targeting drug. We also identify an arrestin-biased KOR agonist, WMS-X600. Using MD simulations of KOR bound to nalfurafine, WMS-X600, and a balanced agonist U50,488, we identify three active-state receptor conformations, including one that appears to favor arrestin signaling over G protein signaling and another that appears to favor G protein signaling over arrestin signaling. These results, combined with mutagenesis validation, provide a molecular explanation of how agonists achieve biased signaling at KOR. © 2023, The Author(s).

Funding details
National Institutes of HealthNIHF31-NS093917, R01GM127359, R35GM143061
U.S. Department of EnergyUSDOE
National Cancer InstituteNCIACB-12002
National Institute of General Medical SciencesNIGMSAGM-12006
Russell Sage FoundationRSF22-74-10098
Office of ScienceSCDE-AC05-00OR22725
Argonne National LaboratoryANLDE-AC02-06CH11357

Document Type: Article
Publication Stage: Final
Source: Scopus

Individualized precision targeting of dorsal attention and default mode networks with rTMS in traumatic brain injury-associated depression” (2023) Scientific Reports

Individualized precision targeting of dorsal attention and default mode networks with rTMS in traumatic brain injury-associated depression
(2023) Scientific Reports, 13 (1), art. no. 4052, . 

Siddiqi, S.H.a b c , Kandala, S.a , Hacker, C.D.d , Trapp, N.T.e , Leuthardt, E.C.d , Carter, A.R.f , Brody, D.L.c f

a Department of Psychiatry, Washington University School of Medicine, 660 S Euclid Ave, St. Louis, MO 63110, United States
b Center for Brain Circuit Therapeutics, Brigham & Women’s Hospital, 60 Fenwood Rd, Boston, MA 02115, United States
c Center for Neuroscience and Regenerative Medicine, Uniformed Services University of the Health Sciences, 4301 Jones Bridge Rd, Bethesda, MD 20814, United States
d Department of Neurosurgery, Washington University School of Medicine, 660 S Euclid Ave, St. Louis, MO 63110, United States
e Department of Psychiatry, University of Iowa Carver College of Medicine, 500 Newton Rd, Iowa City, IA 52246, United States
f Department of Neurology, Washington University School of Medicine, 660 S Euclid Ave, St. Louis, MO 63110, United States

Abstract
At the group level, antidepressant efficacy of rTMS targets is inversely related to their normative connectivity with subgenual anterior cingulate cortex (sgACC). Individualized connectivity may yield better targets, particularly in patients with neuropsychiatric disorders who may have aberrant connectivity. However, sgACC connectivity shows poor test–retest reliability at the individual level. Individualized resting-state network mapping (RSNM) can reliably map inter-individual variability in brain network organization. Thus, we sought to identify individualized RSNM-based rTMS targets that reliably target the sgACC connectivity profile. We used RSNM to identify network-based rTMS targets in 10 healthy controls and 13 individuals with traumatic brain injury-associated depression (TBI-D). These “RSNM targets” were compared with consensus structural targets and targets based on individualized anti-correlation with a group-mean-derived sgACC region (“sgACC-derived targets”). The TBI-D cohort was also randomized to receive active (n = 9) or sham (n = 4) rTMS to RSNM targets with 20 daily sessions of sequential high-frequency left-sided stimulation and low-frequency right-sided stimulation. We found that the group-mean sgACC connectivity profile was reliably estimated by individualized correlation with default mode network (DMN) and anti-correlation with dorsal attention network (DAN). Individualized RSNM targets were thus identified based on DAN anti-correlation and DMN correlation. These RSNM targets showed greater test–retest reliability than sgACC-derived targets. Counterintuitively, anti-correlation with the group-mean sgACC connectivity profile was also stronger and more reliable for RSNM-derived targets than for sgACC-derived targets. Improvement in depression after RSNM-targeted rTMS was predicted by target anti-correlation with the portions of sgACC. Active treatment also led to increased connectivity within and between the stimulation sites, the sgACC, and the DMN. Overall, these results suggest that RSNM may enable reliable individualized rTMS targeting, although further research is needed to determine whether this personalized approach can improve clinical outcomes. © 2023, The Author(s).

Funding details
Sidney R. Baer, Jr. Foundation
McDonnell Center for Systems Neuroscience

Document Type: Article
Publication Stage: Final
Source: Scopus

Flexible reuse of cortico-hippocampal representations during encoding and recall of naturalistic events” (2023) Nature Communications

Flexible reuse of cortico-hippocampal representations during encoding and recall of naturalistic events
(2023) Nature Communications, 14 (1), art. no. 1279, . 

Reagh, Z.M.a , Ranganath, C.b c

a Department of Psychological & Brain Sciences, Washington University in St. Louis, St. Louis, MO, United States
b UC Davis Center for Neuroscience, University of California, Davis, CA, United States
c Department of Psychology, University of California, Davis, CA, United States

Abstract
Although every life event is unique, there are considerable commonalities across events. However, little is known about whether or how the brain flexibly represents information about different event components at encoding and during remembering. Here, we show that different cortico-hippocampal networks systematically represent specific components of events depicted in videos, both during online experience and during episodic memory retrieval. Regions of an Anterior Temporal Network represented information about people, generalizing across contexts, whereas regions of a Posterior Medial Network represented context information, generalizing across people. Medial prefrontal cortex generalized across videos depicting the same event schema, whereas the hippocampus maintained event-specific representations. Similar effects were seen in real-time and recall, suggesting reuse of event components across overlapping episodic memories. These representational profiles together provide a computationally optimal strategy to scaffold memory for different high-level event components, allowing efficient reuse for event comprehension, recollection, and imagination. © 2023, The Author(s).

Funding details
Office of Naval ResearchONRN00014-15-1-0033
National Institute on AgingNIAT32AG050061

Document Type: Article
Publication Stage: Final
Source: Scopus

Prevalence of potentially traumatic events and symptoms of depression, anxiety, hazardous alcohol use, and post-traumatic stress disorder among people with HIV initiating HIV care in Cameroon” (2023) BMC Psychiatry

Prevalence of potentially traumatic events and symptoms of depression, anxiety, hazardous alcohol use, and post-traumatic stress disorder among people with HIV initiating HIV care in Cameroon
(2023) BMC Psychiatry, 23 (1), art. no. 150, . 

Parcesepe, A.M.a b , Filiatreau, L.M.c , Ebasone, P.V.d , Dzudie, A.d , Pence, B.W.c , Wainberg, M.e , Yotebieng, M.f , Anastos, K.g , Pefura-Yone, E.h , Nsame, D.i , Ajeh, R.d , Nash, D.j

a Gillings School of Global Public Health, Department of Maternal and Child Health, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
b University of North Carolina at Chapel Hill, Carolina Population Center, Chapel Hill, NC, United States
c Department of Psychiatry, School of Medicine, Washington University in St. Louis, St. Louis, MO, United States
d Clinical Research Education Networking and Consultancy, Yaounde, Cameroon
e Department of Psychiatry, Columbia University and New York State Psychiatric Institute, New York, NY, United States
f Albert Einstein College of Medicine, Department of Medicine, Bronx, NY, United States
g Albert Einstein College of Medicine, Departments of Medicine and Epidemiology & Population Health, Bronx, NY, United States
h Jamot Hospital, Yaounde, Cameroon
i Bamenda Regional Hospital, Bamenda, Cameroon
j Institute for Implementation Science in Population Health, City University of New York, New York, NY, United States

Abstract
Background: This study explored the relationship between specific types of potentially traumatic events (PTEs) and symptoms of mental health disorders among people with HIV (PWH) in Cameroon. Methods: We conducted a cross-sectional study with 426 PWH in Cameroon between 2019–2020. Multivariable log binominal regression was used to estimate the association between exposure (yes/no) to six distinct types of PTE and symptoms of depression (Patient Health Questionnaire-9 score > 9), PTSD (PTSD Checklist for DSM-5 score > 30), anxiety (Generalized Anxiety Disorder-7 scale score > 9), and hazardous alcohol use (Alcohol Use Disorders Identification Test score > 7 for men; > 6 for women). Results: A majority of study participants (96%) reported exposure to at least one PTE, with a median of 4 PTEs (interquartile range: 2–5). The most commonly reported PTEs were seeing someone seriously injured or killed (45%), family members hitting or harming one another as a child (43%), physical assault or abuse from an intimate partner (42%) and witnessing physical assault or abuse (41%). In multivariable analyses, the prevalence of PTSD symptoms was significantly higher among those who reported experiencing PTEs during childhood, violent PTEs during adulthood, and the death of a child. The prevalence of anxiety symptoms was significantly higher among those who reported experiencing both PTEs during childhood and violent PTEs during adulthood. No significant positive associations were observed between specific PTEs explored and symptoms of depression or hazardous alcohol use after adjustment. Conclusions: PTEs were common among this sample of PWH in Cameroon and associated with PTSD and anxiety symptoms. Research is needed to foster primary prevention of PTEs and to address the mental health sequelae of PTEs among PWH. © 2023, The Author(s).

Author Keywords
Cameroon;  HIV;  Mental health;  Trauma

Funding details
National Institute of Mental HealthNIMHK01 MH114721
National Institute of Allergy and Infectious DiseasesNIAIDU01AI096299
National Institute on Minority Health and Health DisparitiesNIMHDT37 MD014218
Eunice Kennedy Shriver National Institute of Child Health and Human DevelopmentNICHDP2C HD050924
Carolina Population Center, University of North Carolina at Chapel HillCPC

Document Type: Article
Publication Stage: Final
Source: Scopus

Cochlear implantation and audiological findings in a child with Zellweger spectrum disorder” (2023) Otolaryngology Case Reports

Cochlear implantation and audiological findings in a child with Zellweger spectrum disorder
(2023) Otolaryngology Case Reports, 27, art. no. 100513, . 

Walia, A.a , Birath, A.L.b , Buchman, C.A.a

a Department of Otolaryngology—Head and Neck Surgery, Washington University School of Medicine in St. Louis, St. Louis, MO, United States
b Moog Center for Deaf Education, St. Louis, MO, United States

Abstract
Peroxisome Biogenesis Disorders in the Zellweger Spectrum (PBD-ZSD) are autosomal recessive disorders characterized by defects in functional peroxisomes. Clinical manifestations can range in severity and age at presentation and often include retinitis pigmentosa, neuroregression, and peripheral neuropathy. Although hearing loss is often associated with PBD-ZSD, the site of lesion is poorly understood. This study reports our experience with a child with a moderate form of PBD-ZSD who underwent successful bilateral cochlear implantation for progressive severe-to-profound hearing loss and performs well with the device. The audiological profile was characterized by severe sensorineural hearing loss bilaterally on auditory brainstem responses, reduced cochlear microphonic potentials with absent compound action potential and summating potential on electrocochleography, and clear neural responses on cochlear implant-evoked, electrical compound action potential testing after implantation. These findings suggest a cochlear-neural site of lesion rather than a true auditory neuropathy. © 2023

Author Keywords
Cochlear implantation;  Electrocochleography;  Peroxisome biogenesis disorder;  Zellweger syndrome

Funding details
National Institutes of HealthNIH
National Institute on Deafness and Other Communication DisordersNIDCDT32DC000022
American Hearing Research FoundationAHRF

Document Type: Article
Publication Stage: Final
Source: Scopus

Blockade of TRPV channels by intracellular spermine” (2023) The Journal of General Physiology

Blockade of TRPV channels by intracellular spermine
(2023) The Journal of General Physiology, 155 (5), . 

Maksaev, G., Yuan, P., Nichols, C.G.

Department of Cell Biology and Physiology, Center for Investigation of Membrane Excitability Diseases, Washington University School of Medicine, St. Louis, MO, United States

Abstract
The Vanilloid thermoTRP (TRPV1-4) subfamily of TRP channels are involved in thermoregulation, osmoregulation, itch and pain perception, (neuro)inflammation and immune response, and tight control of channel activity is required for perception of noxious stimuli and pain. Here we report voltage-dependent modulation of each of human TRPV1, 3, and 4 by the endogenous intracellular polyamine spermine. As in inward rectifier K channels, currents are blocked in a strongly voltage-dependent manner, but, as in cyclic nucleotide-gated channels, the blockade is substantially reduced at more positive voltages, with maximal blockade in the vicinity of zero voltage. A kinetic model of inhibition suggests two independent spermine binding sites with different affinities as well as different degrees of polyamine permeability in TRPV1, 3, and 4. Given that block and relief occur over the physiological voltage range of action potentials, voltage-dependent polyamine block may be a potent modulator of TRPV-dependent excitability in multiple cell types. © 2023 Maksaev et al.

Document Type: Article
Publication Stage: Final
Source: Scopus

Incorporating Intraoperative Mechanomyography to Peripheral Nerve Decompression Surgery” (2023) Operative Neurosurgery (Hagerstown, Md.)

Incorporating Intraoperative Mechanomyography to Peripheral Nerve Decompression Surgery
(2023) Operative Neurosurgery (Hagerstown, Md.), 24 (4), pp. 445-450. 

Guerrero, J.R.a , Taghlabi, K.M.a , Bhenderu, L.S.a , Cruz-Garza, J.G.a , Javeed, S.b , Dibble, C.F.b , Ray, W.Z.b , Faraji, A.H.a

a Department of Neurological Surgery, Houston Methodist Hospital, Houston, TX, United States
b Department of Neurological Surgery, Washington University in St. Louis, St. Louis, MO, United States

Abstract
BACKGROUND: Mechanomyography (MMG) is a novel intraoperative tool to detect and quantify nerve activity with high sensitivity as compared with traditional electromyographic recordings. MMG reflects the mechanical vibrations of single motor units detected through accelerometer sensors after direct motor neuron stimulation. OBJECTIVE: To determine the feasibility of applying intraoperative MMG during peripheral nerve surgery. METHODS: A total of 20 consecutive patients undergoing surgical decompression of the ulnar nerve at the cubital tunnel or common peroneal nerve at the fibular head were included in this study. Intraoperatively, the common peroneal and ulnar nerves were directly stimulated through the MMG electrode probe starting at 0.1 mA threshold and increasing by 0.1 mA increments until target muscle activity was noted. The lowest threshold current required to elicit a muscle response was recorded before decompression and after proximal and distal nerve decompression. RESULTS: Of the patients, 80% (16/20) had MMG signals detected and recorded. Four patients were unable to have MMG signal detected despite direct nerve visualization and complete neurolysis. The mean predecompression stimulus threshold was 1.59 ± 0.19 mA. After surgical decompression, improvement in the mean MMG stimulus threshold was noted (0.47 ± 0.03 mA, P = .0002). Postoperatively, all patients endorsed symptomatic improvement with no complications. CONCLUSION: MMG may provide objective guidance for the intraoperative determination of the extent of nerve decompression. Lower stimulus thresholds may represent increased sparing of axonal tissue. Future work should focus on validating normative values of MMG stimulus thresholds in various nerves and establishing clinical associations with functional outcomes. Copyright © Congress of Neurological Surgeons 2023. All rights reserved.

Document Type: Article
Publication Stage: Final
Source: Scopus

Multidimensional poverty is associated with dementia among adults in Afghanistan” (2023) eClinicalMedicine

Multidimensional poverty is associated with dementia among adults in Afghanistan
(2023) eClinicalMedicine, 58, art. no. 101906, . 

Trani, J.-F.a b c , Zhu, Y.d , Park, S.a , Khuram, D.e , Azami, R.f , Fazal, M.R.e , Babulal, G.M.c g h i

a Brown School, Washington University, St. Louis, MO, United States
b National Conservatory of Arts and Crafts, Paris, France
c Department of Psychology, Faculty of Humanities, University of Johannesburg, South Africa
d Adelphi University, New York, United States
e Knowledge House, United Kingdom
f World Health Organization, Geneva, Switzerland
g Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States
h Institute of Public Health, Washington University in St. Louis, St. Louis, MO, United States
i Department of Clinical Research and Leadership, The George Washington University School of Medicine and Health Sciences, Washington, DC, United States

Abstract
Background: Multidimensional poverty is associated with dementia, but no evidence is available for countries in conflict. Methods: A cross-sectional study was conducted in two provinces of Afghanistan between February 15th 2022 and April 20th 2022 among adults age 50 and older. Multidimensional poverty included six dimensions of well-being and 16 indicators of deprivation. The Rowland Universal Dementia Assessment Scale measured dementia. Poverty between adults with and without dementia was examined, adjusting for sex. Associations between dementia and poverty were investigated using multivariate regression model. Findings: Of the 478 adults included, 89 (52.7%) had mild, and 25 (14.8%) had moderate to severe dementia. More women than men had mild (52.7% vs 33.3%) and moderate-to-severe dementia (14.8% vs 5.8%). Approximately 33.9% adults with mild and 51.2% adults with moderate-to-severe dementia were found to be deprived in four or more dimensions compared to 21.8% without dementia. The difference in four dimensions of multidimensional poverty between adults with mild and moderate-to-severe dementia and adults without dementia was respectively 59.5% and 152.88%. Education, employment, health, and living conditions were the main contributors to the adjusted poverty head count ratio. Multidimensional poverty in four or five dimensions was strongly associated with dementia among older adults particularly over 70 years old (odds ratio [OR], 17.38; 95% CI, 2.22–135.63), with greater odds for older women overall (OR, 2.69; 95% CI, 1.76–4.11). Interpretation: Our findings suggest that early improvement in social determinants of health through targeted structural policies may lower dementia risk later in life. Specifically, better access to free, quality education, healthcare, and basic living standard together with employment opportunities could reduce risk of dementia. Funding: The present study was funded by a grant from the Alzheimer Association (AARG-NTF-21-851241). © 2023

Author Keywords
Afghanistan;  Dementia;  Multidimensional poverty;  Rural areas;  Social and environmental determinants of health

Funding details
National Institutes of HealthNIH
National Institute on AgingNIAR01AG067428, R01AG068183, R01AG074302
Alzheimer’s AssociationAAAARG-NTF-21-851241
BrightFocus FoundationBFFA2021142S
National Arts Council – SingaporeNAC

Document Type: Article
Publication Stage: Final
Source: Scopus

Mirror movements and callosal dysgenesis in a family with a DCC mutation: Neuropsychological and neuroimaging outcomes” (2023) Cortex

Mirror movements and callosal dysgenesis in a family with a DCC mutation: Neuropsychological and neuroimaging outcomes
(2023) Cortex, 161, pp. 38-50. 

Knight, J.L.a , Barker, M.S.a b , Edwards, T.J.b c , Barnby, J.M.b d , Richards, L.J.b e , Robinson, G.A.a b

a Neuropsychology Research Unit, School of Psychology, The University of Queensland, St Lucia, Brisbane, QLD 4072, Australia
b Queensland Brain Institute, The University of Queensland, St Lucia, Brisbane, Australia
c Metro South Addiction and Mental Health Services, Brisbane, QLD 4102, Australia
d Social Computation and Cognitive Representation Lab, Department of Psychology, Royal Holloway, University of London, London, United Kingdom
e Department of Neuroscience, Washington University in St Louis School of Medicine, St LouisMO, United States

Abstract
Corpus callosum dysgenesis is a congenital abnormality whereby the corpus callosum fails to develop normally, and has been associated with a range of neuropsychological outcomes. One specific finding in some individuals with corpus callosum dysgenesis is “congenital mirror movement disorder”, which is the presence of involuntary movements on one side of the body that mimic voluntary movements of the other side. Mirror movements have also been associated with mutations in the deleted in colorectal carcinoma (DCC) gene. The current study aims to comprehensively document the neuropsychological outcomes and neuroanatomical mapping of a family (a mother, daughter and son) with known DCC mutations. All three family members experience mirror movements, and the son additionally has partial agenesis of the corpus callosum (pACC). All family members underwent extensive neuropsychological testing, spanning general intellectual functioning, memory, language, literacy, numeracy, psychomotor speed, visuospatial perception, praxis and motor functioning, executive functioning, attention, verbal/nonverbal fluency, and social cognition. The mother and daughter had impaired memory for faces, and reduced spontaneous speech, and the daughter demonstrated scattered impairments in attention and executive functioning, but their neuropsychological abilities were largely within normal limits. By contrast, the son showed areas of significant impairment across multiple domains including reduced psychomotor speed, fine motor dexterity and general intellectual functioning, and he was profoundly impaired across areas of executive functioning and attention. Reductions in his verbal/non-verbal fluency, with relatively intact core language, resembled dynamic frontal aphasia. His relative strengths included aspects of memory and he demonstrated largely sound theory of mind. Neuroimaging revealed an asymmetric sigmoid bundle in the son, connecting, via the callosal remnant, the left frontal cortex with contralateral parieto-occipital cortex. Overall, this study documents a range of neuropsychological and neuroanatomical outcomes within one family with DCC mutations and mirror movements, including one with more severe consequences and pACC. © 2023 The Author(s)

Author Keywords
Corpus callosum dysgenesis;  DCC genetic Mutation;  Mirror movements;  Neuropsychological outcomes;  Partial ACC

Funding details
Australian Research CouncilARCDP210101712
National Health and Medical Research CouncilNHMRCAPP1120615, APP1135769

Document Type: Article
Publication Stage: Final
Source: Scopus

Single substitution in H3.3G34 alters DNMT3A recruitment to cause progressive neurodegeneration” (2023) Cell

Single substitution in H3.3G34 alters DNMT3A recruitment to cause progressive neurodegeneration
(2023) Cell, 186 (6), pp. 1162-1178.e20. 

Khazaei, S.a , Chen, C.C.L.a , Andrade, A.F.a , Kabir, N.a , Azarafshar, P.a , Morcos, S.M.b c , França, J.A.d , Lopes, M.e , Lund, P.J.e , Danieau, G.f g , Worme, S.h , Adnani, L.i , Nzirorera, N.a , Chen, X.j k l , Yogarajah, G.i m , Russo, C.n , Zeinieh, M.a , Wong, C.J.o , Bryant, L.p , Hébert, S.a h , Tong, B.q , Sihota, T.S.a , Faury, D.i , Puligandla, E.a i , Jawhar, W.f r s , Sandy, V.i , Cowan, M.t , Nakada, E.M.i , Jerome-Majewska, L.A.a n u , Ellezam, B.v , Gomes, C.C.d , Denecke, J.w , Lessel, D.x y , McDonald, M.T.z , Pizoli, C.E.aa , Taylor, K.z , Cocanougher, B.T.ab , Bhoj, E.J.ac , Gingras, A.-C.c o , Garcia, B.A.e , Lu, C.j k , Campos, E.I.b c , Kleinman, C.L.a h , Garzia, L.f g , Jabado, N.a i n s

a Department of Human Genetics, McGill University, Montreal, QC H3A 0C7, Canada
b Genetics & Genome Biology Program, The Hospital for Sick Children, Toronto, ON, Canada
c Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada
d Department of Pathology, Biological Sciences Institute, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
e Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, St. Louis, MO, United States
f Cancer Research Program, The Research Institute of the McGill University Health Centre, Montreal, QC H4A 3J1, Canada
g Division of Orthopedic Surgery, Faculty of Surgery, McGill University, Montreal, QC H3G 1A4, Canada
h Lady Davis Research Institute, Jewish General Hospital, Montreal, QC H3T 1E2, Canada
i Research Institute of the McGill University Health Centre, Montreal, QC H4A 3J1, Canada
j Department of Genetics and Development, Columbia University Irving Medical Center, New York, NY, United States
k Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, New York, NY, United States
l Marine College, Shandong University, Weihai, 264209, China
m Department of Biochemistry and Molecular Medicine, Université de Montreal, Research Center of the CHU Sainte-Justine, Montreal, QC H3T 1C5, Canada
n Department of Pediatrics, McGill University, The Research Institute of the McGill University Health Centre, Montreal, QC H4A 3J1, Canada
o Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Sinai Health System, Toronto, ON, Canada
p Center for Applied Genomics, Children’s Hospital of Philadelphia, Philadelphia, PA 19104, United States
q Department of Chemistry and Chemical Biology, McMaster University, Hamilton, Canada
r Child Health and Human Development, The Research Institute of the McGill University Health Centre, Montreal, QC H4A 3J1, Canada
s Division of Experimental Medicine, Department of Medicine, McGill University, Montreal, QC H4A 3J1, Canada
t McGill Integrated Core for Animal Modeling (MICAM), McGill University, Montreal, QC, Canada
u Department of Anatomy and Cell Biology, McGill University, Montreal, QC, Canada
v Department of Pathology, Centre Hospitalier Universitaire Sainte-Justine, Université de Montréal, Montréal, QC H3T 1C5, Canada
w Department of Pediatrics, University Medical Center Eppendorf, Hamburg, Germany
x Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
y Institute of Human Genetics, University Hospital of the Paracelsus Medical University Salzburg, Salzburg, Austria
z Division of Medical Genetics, Duke University Hospital, Durham, NC, United States
aa Division of Pediatric Neurology, Duke University Hospital, Durham, NC, United States
ab Department of Pediatrics, Duke University Hospital, Durham, NC, United States
ac Children’s Hospital of Philadelphia, Philadelphia, PA, United States

Abstract
Germline histone H3.3 amino acid substitutions, including H3.3G34R/V, cause severe neurodevelopmental syndromes. To understand how these mutations impact brain development, we generated H3.3G34R/V/W knock-in mice and identified strikingly distinct developmental defects for each mutation. H3.3G34R-mutants exhibited progressive microcephaly and neurodegeneration, with abnormal accumulation of disease-associated microglia and concurrent neuronal depletion. G34R severely decreased H3K36me2 on the mutant H3.3 tail, impairing recruitment of DNA methyltransferase DNMT3A and its redistribution on chromatin. These changes were concurrent with sustained expression of complement and other innate immune genes possibly through loss of non-CG (CH) methylation and silencing of neuronal gene promoters through aberrant CG methylation. Complement expression in G34R brains may lead to neuroinflammation possibly accounting for progressive neurodegeneration. Our study reveals that H3.3G34-substitutions have differential impact on the epigenome, which underlie the diverse phenotypes observed, and uncovers potential roles for H3K36me2 and DNMT3A-dependent CH-methylation in modulating synaptic pruning and neuroinflammation in post-natal brains. © 2023 Elsevier Inc.

Author Keywords
CH methylation;  complement;  DNA methylation;  DNMT3A;  H3.3 G34R/V/W;  H3K36me2;  neurodegeneration;  neuroinflammation;  oncohistones;  synaptic pruning

Funding details
MJD-574-AC, WST-164-AB
PJT-159683
AI118891
National Institutes of HealthNIHCA196539, R01- R01CA255369, R01-CA266978, R35-GM138181
Genome CanadaGC
Cancer Research SocietyCRS
Crohn’s and Colitis FoundationCCFRFA 598467, T32CA009140
Ontario Research FoundationORF
Government of Ontario25056, OGI-139
Canadian Institutes of Health ResearchIRSCFDN-154307, MOP-286756, PJT-156086
Natural Sciences and Engineering Research Council of CanadaNSERCRGPIN-2016-05559
Fonds de Recherche du Québec – SantéFRQS33902, RGPIN-2016-04911
Canada Foundation for InnovationCFICFI 33474
Canadian Cancer Society705182, 705799
Canada Research Chairs
Coordenação de Aperfeiçoamento de Pessoal de Nível SuperiorCAPESPDSE 88881.187783/2018-01
University of TorontoU of T
Conselho Nacional de Desenvolvimento Científico e TecnológicoCNPq
Fondation Charles-Bruneau
Garron Family Cancer CentreGFCC

Document Type: Article
Publication Stage: Final
Source: Scopus

Multi-mode fiber-based speckle contrast optical spectroscopy: analysis of speckle statistics” (2023) Optics Letters

Multi-mode fiber-based speckle contrast optical spectroscopy: analysis of speckle statistics
(2023) Optics Letters, 48 (6), pp. 1427-1430. 

Lin, C.H.P.a b , Orukari, I.b , Tracy, C.b , Frisk, L.K.c , Verma, M.c , Chetia, S.c , Durduran, T.c d , Trobaugh, J.W.e , Culver, J.P.a b

a Department of Physics, Washington University in St. Louis, St. Louis, MO 63130, United States
b Department of Radiology, Washington University School of Medicine, St. Louis, MO 63110, United States
c ICFO-Institut de Ciéncies Fotóniques, The Barcelona Institute of Science and Technology, Castelldefels, Barcelona, Spain
d Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain
e Department of Electrical and Systems Engineering, Washington University in St. Louis, St. Louis, MO 63130, United States

Abstract
Speckle contrast optical spectroscopy/tomography (SCOS/T) provides a real-time, non-invasive, and cost-efficient optical imaging approach to mapping of cerebral blood flow. By measuring many speckles (n>>10), SCOS/T has an increased signal-to-noise ratio relative to diffuse correlation spectroscopy, which measures one or a few speckles. However, the current free-space SCOS/T designs are not ideal for large field-of-view imaging in humans because the curved head contour cannot be readily imaged with a single flat sensor and hair obstructs optical access. Herein, we evaluate the feasibility of using cost-efficient multi-mode fiber (MMF) bundles for use in SCOS/T systems. One challenge with speckle contrast measurements is the potential for confounding noise sources (e.g., shot noise, readout noise) which contribute to the standard deviation measure and corrupt the speckle contrast measure that is central to the SCOS/T systems. However, for true speckle measurements, the histogram of pixel intensities from light interference follows a non-Gaussian distribution, specifically a gamma distribution with non-zero skew, whereas most noise sources have pixel intensity distributions that are Gaussian. By evaluating speckle data from static and dynamic targets imaged through an MMF, we use histograms and statistical analysis of pixel histograms to evaluate whether the statistical properties of the speckles are retained. We show that flow-based speckle can be distinguished from static speckle and from sources of system noise through measures of skew in the pixel intensity histograms. Finally, we illustrate in humans that MMF bundles relay blood flow information. © 2023 Optica Publishing Group.

Funding details
National Institute of Neurological Disorders and StrokeNINDSNS090874
Albert Ellis InstituteAEIDTS22/00023, PRE2018
Ministerio de Ciencia e InnovaciónMICINN

Document Type: Article
Publication Stage: Final
Source: Scopus

Spontaneous Activity Patterns in Human Attention Networks Code for Hand Movements” (2023) The Journal of Neuroscience: The Official Journal of the Society for Neuroscience

Spontaneous Activity Patterns in Human Attention Networks Code for Hand Movements
(2023) The Journal of Neuroscience: The Official Journal of the Society for Neuroscience, 43 (11), pp. 1976-1986. 

Zhang, L.a , Pini, L.a , Kim, D.b , Shulman, G.L.b , Corbetta, M.a b c d

a Padova Neuroscience Center, University of Padova, Padova, 35131, Italy
b Departments of Neurology and Radiology, Washington University-St Louis, St Louis, MO 63110, United States
c Department of Neuroscience, University of Padova, Padova, 35131, Italy
d Venetian Institute of Molecular Medicine, Padova, 35129, Italy

Abstract
Recent evidence suggests that, in the absence of any task, spontaneous brain activity patterns and connectivity in the visual and motor cortex code for natural stimuli and actions, respectively. These “resting-state” activity patterns may underlie the maintenance and consolidation (replay) of information states coding for ecological stimuli and behaviors. In this study, we examine whether replay patterns occur in resting-state activity in association cortex grouped into high-order cognitive networks not directly processing sensory inputs or motor outputs. Fifteen participants (7 females) performed four hand movements during an fMRI study. Three movements were ecological. The fourth movement as control was less ecological. Before and after the task scans, we acquired resting-state fMRI scans. The analysis examined whether multivertex task activation patterns for the four movements computed at the cortical surface in different brain networks resembled spontaneous activity patterns measured at rest. For each movement, we computed a vector of r values indicating the strength of the similarity between the mean task activation pattern and frame-by-frame resting-state patterns. We computed a cumulative distribution function of r2 values and used the 90th percentile cutoff value for comparison. In the dorsal attention network, resting-state patterns were more likely to match task patterns for the ecological movements than the control movement. In contrast, rest-task pattern correlation was more likely for less ecological movement in the ventral attention network. These findings show that spontaneous activity patterns in human attention networks code for hand movements.SIGNIFICANCE STATEMENT fMRI indirectly measures neural activity noninvasively. Resting-state (spontaneous) fMRI signals measured in the absence of any task resemble signals evoked by task performance both in topography and inter-regional (functional) connectivity. However, the function of spontaneous brain activity is unknown. We recently showed that spatial activity patterns evoked by visual and motor tasks in visual and motor cortex, respectively, occur at rest in the absence of any stimulus or response. Here we show that activity patterns related to hand movements replay at rest in frontoparietal regions of the human attention system. These findings show that spontaneous activity in the human cortex may mediate the maintenance and consolidation of information states coding for ecological stimuli and behaviors. Copyright © 2023 the authors.

Author Keywords
attention networks;  hand movements;  representation;  resting-state fMRI;  spontaneous brain activity;  task fMRI

Document Type: Article
Publication Stage: Final
Source: Scopus

Mood and Anxiety Disorders and Suicidality in Patients with Newly Diagnosed Focal Epilepsy: An Analysis of a Complex Comorbidity” (2023) Neurology

Mood and Anxiety Disorders and Suicidality in Patients with Newly Diagnosed Focal Epilepsy: An Analysis of a Complex Comorbidity
(2023) Neurology, 100 (11), pp. E1123-E1134. Cited 2 times.

Kanner, A.M.a , Saporta, A.S.a , Kim, D.H.a , Barry, J.J.b , Altalib, H.c , Omotola, H.c , Jette, N.n , O’Brien, T.J.d , Nadkarni, S.f , Winawer, M.R.g , Sperling, M.h , French, J.A.i , Abou-Khalil, B.i , Alldredge, B.j , Bebin, M.k , Cascino, G.D.h , Cole, A.J.m , Cook, M.J.e , Detyniecki, K.f , Devinsky, O.g , Dlugos, D.o , Faught, E.p , Ficker, D.q , Fields, M.l , Gidal, B.r , Gelfand, M.i , Glynn, S.s , Halford, J.J.t , Haut, S.u , Hegde, M.m , Holmes, M.G.n , Kalviainen, R.v , Kang, J.o , Klein, P.a , Knowlton, R.C.a , Krishnamurthy, K.a , Kuzniecky, R.f , Kwan, P.a , Lowenstein, D.H.a , Marcuse, L.ad , Meador, K.J.w , Mintzer, S.c , Pardoe, H.R.v , Park, K.x , Penovich, P.y , Singh, R.K.z , Somerville, E.aa , Szabo, C.A.ab , Szaflarski, J.P.ac , Lin Thio, K.L.c , Trinka, E.ae , Burneo, J.G.e af

a The University of Miami, Miller School of Medicine, United States
b Stanford University, School of Medicine, United States
c Yale University, School of Medicine, United States
d University of Texas in Houston, School of Medicine Icahan School of Medicine at Mount Sinai, United States
e Monash University School of Medicine, Australia
f New York University, Grossman School of Medicine, United States
g Columbia University, College of Physicians and Surgeons, United States
h Thomas Jefferson University, Sidney Kimmel Medical College, United States
i Vanderbilt University, School of Medicine, United States
j University of California San Francisco, School of Medicine, United States
k University of Alabama in Birmingham, School of Medicine, United States
l Mayo Clinic, School of Medicine, United States
m Harvard Medical School, United States
n University of Melbourne, School of Medicine, Australia
o University of Pennsylvania, Pearlman School of Medicine, United States
p Emory University, School of Medicine, United States
q University of Cincinnati, School of Medicine, United States
r University of Wisconsin, School of Medicine, United States
s University of Michigan, School of Medicine, United States
t Medical University of South Carolina, United States
u Albert Einstein School of Medicine, United States
v University of Eastern Finland, School of Medicine, Finland
w Johns Hopkins School of Medicine, United States
x Mid-Atlantic Epilepsy and Sleep Center, United States
y University of Colorado, School of Medicine, United States
z Minnesota Epilepsy Group, United States
aa Carolinas Pediatric Neurology Care, United States
ab New South Wales Hospital, Australia
ac University of Texas in San Antonio, School of Medicine, United States
ad Washington University in Saint Louis, School of Medicine, United States
ae Paracelsus Medical University, Austria
af University of Western Ontario, School of Medicine, Canada

Abstract
Background and ObjectivesMood, anxiety disorders, and suicidality are more frequent in people with epilepsy than in the general population. Yet, their prevalence and the types of mood and anxiety disorders associated with suicidality at the time of the epilepsy diagnosis are not established. We sought to answer these questions in patients with newly diagnosed focal epilepsy and to assess their association with suicidal ideation and attempts.MethodsThe data were derived from the Human Epilepsy Project study. A total of 347 consecutive adults aged 18-60 years with newly diagnosed focal epilepsy were enrolled within 4 months of starting treatment. The types of mood and anxiety disorders were identified with the Mini International Neuropsychiatric Interview, whereas suicidal ideation (lifetime, current, active, and passive) and suicidal attempts (lifetime and current) were established with the Columbia Suicidality Severity Rating Scale (CSSRS). Statistical analyses included the t test, χ2 statistics, and logistic regression analyses.ResultsA total of 151 (43.5%) patients had a psychiatric diagnosis; 134 (38.6%) met the criteria for a mood and/or anxiety disorder, and 75 (21.6%) reported suicidal ideation with or without attempts. Mood (23.6%) and anxiety (27.4%) disorders had comparable prevalence rates, whereas both disorders occurred together in 43 patients (12.4%). Major depressive disorders (MDDs) had a slightly higher prevalence than bipolar disorders (BPDs) (9.5% vs 6.9%, respectively). Explanatory variables of suicidality included MDD, BPD, panic disorders, and agoraphobia, with BPD and panic disorders being the strongest variables, particularly for active suicidal ideation and suicidal attempts.DiscussionIn patients with newly diagnosed focal epilepsy, the prevalence of mood, anxiety disorders, and suicidality is higher than in the general population and comparable to those of patients with established epilepsy. Their recognition at the time of the initial epilepsy evaluation is of the essence. © American Academy of Neurology.

Document Type: Article
Publication Stage: Final
Source: Scopus

A carotid body-brainstem neural circuit mediates sighing in hypoxia” (2023) Current Biology

A carotid body-brainstem neural circuit mediates sighing in hypoxia
(2023) Current Biology, 33 (5), pp. 827-837.e4. 

Yao, Y.a b , Chen, J.a , Li, X.a , Chen, Z.-F.c , Li, P.a d e

a Life Sciences Institute, University of Michigan, Ann Arbor, MI 48109, United States
b Department of Neurosurgery, Shengjing Hospital of China Medical University, Shenyang, 110004, China
c Department of Anesthesiology, Center for the Study of Itch and Sensory Disorders, Washington University School of Medicine, St. Louis, MO 63110, United States
d Department of Biologic and Materials Sciences, School of Dentistry, University of Michigan, Ann Arbor, MI 48109, United States
e Department of Molecular and Integrative Physiology, School of Medicine, University of Michigan, Ann Arbor, MI 48109, United States

Abstract
Increased ventilation is a critical process that occurs when the body responds to a hypoxic environment. Sighs are long, deep breaths that prevent alveolar collapse, and their frequency is significantly increased by hypoxia. In this study, we first show that sighing is induced by hypoxia as a function of increased hypoxic severity and that hypoxia-induced sighing is capable of increasing the oxygen saturation in a mouse model. We next found that the gastrin-releasing peptide (Grp) expressing neurons in the nucleus of the solitary tract (NTS) are important in mediating hypoxia-induced sighing. Retrograde tracing from these Grp neurons reveals their direct afferent input from the petrosal ganglion neurons that innervate the carotid body, the major peripheral chemoreceptor that senses blood oxygen. Acute hypoxia preferentially activates these Grp neurons in the NTS. Photoactivation of these neurons through their projections in the inspiratory rhythm generator in the ventral medulla induces sighing, whereas genetic ablation or chemogenetic silencing of these neurons specifically diminishes the sighs, but not other respiratory responses, induced by hypoxia. Finally, the mice with reduced sighing in hypoxia exhibit an elevated heart-rate increase, which may compensate for maintaining the blood oxygen level. Therefore, we identified a neural circuit that connects the carotid body to the breathing control center in the ventral medulla with a specific function for hypoxia-induced sighing, which restores the oxygen level. © 2023 Elsevier Inc.

Author Keywords
blood oxygen;  breathing;  carotid body;  gastrin-releasing peptide;  hypoxia;  hypoxic ventilatory response;  neural circuit;  sighing;  the nucleus of the solitary tract

Funding details
National Institutes of HealthNIHAT011652, HL156989
American Thoracic SocietyATS

Document Type: Article
Publication Stage: Final
Source: Scopus

Masked features of task states found in individual brain networks” (2023) Cerebral Cortex (New York, N.Y. : 1991)

Masked features of task states found in individual brain networks
(2023) Cerebral Cortex (New York, N.Y. : 1991), 33 (6), pp. 2879-2900. 

Porter, A.a , Nielsen, A.b , Dorn, M.a , Dworetsky, A.a , Edmonds, D.a , Gratton, C.a c

a Department of Psychology, Northwestern University, 633 Clark St, Evanston, IL 60208, United States
b Department of Neurology, Washington University in St. Louis, 1 Brookings Dr, St. Louis, MO 63130, United States
c Department of Neurology, Northwestern University, 633 Clark St, Evanston, IL 60208, United States

Abstract
Completing complex tasks requires that we flexibly integrate information across brain areas. While studies have shown how functional networks are altered during different tasks, this work has generally focused on a cross-subject approach, emphasizing features that are common across people. Here we used extended sampling “precision” fMRI data to test the extent to which task states generalize across people or are individually specific. We trained classifiers to decode state using functional network data in single-person datasets across 5 diverse task states. Classifiers were then tested on either independent data from the same person or new individuals. Individualized classifiers were able to generalize to new participants. However, classification performance was significantly higher within a person, a pattern consistent across model types, people, tasks, feature subsets, and even for decoding very similar task conditions. Notably, these findings also replicated in a new independent dataset. These results suggest that individual-focused approaches can uncover robust features of brain states, including features obscured in cross-subject analyses. Individual-focused approaches have the potential to deepen our understanding of brain interactions during complex cognition. © The Author(s) 2022. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Author Keywords
BOLD fMRI;  functional connectivity;  individual differences;  machine learning;  task states

Document Type: Article
Publication Stage: Final
Source: Scopus

Familial and syndromic forms of arachnoid cyst implicate genetic factors in disease pathogenesis” (2023) Cerebral Cortex (New York, N.Y. : 1991)

Familial and syndromic forms of arachnoid cyst implicate genetic factors in disease pathogenesis
(2023) Cerebral Cortex (New York, N.Y. : 1991), 33 (6), pp. 3012-3025. Cited 3 times.

Qureshi, H.M.a , Mekbib, K.Y.a b , Allington, G.b c , Elsamadicy, A.A.a , Duy, P.Q.a , Kundishora, A.J.a , Jin, S.C.d , Kahle, K.T.a b e f g h

a Department of Neurosurgery, Yale University School of Medicine, CT 06510, New Haven, United States
b Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, United States
c Department of Pathology, Yale University School of Medicine, CT 06510, New Haven, United States
d Department of Genetics, Washington University School of Medicine, St. Louis, MO 63110, United States
e Division of Genetics and Genomics, Boston Children’s Hospital, Boston, MA 02115, United States
f Department of Pediatrics, Harvard Medical School, Boston, MA 02115, United States
g Department of Neurology, Harvard Medical School, Boston, MA 02115, United States
h Broad Institute of MIT and Harvard, Cambridge, MA 02142, United States

Abstract
Arachnoid cysts (ACs) are the most common space-occupying lesions in the human brain and present significant challenges for clinical management. While most cases of ACs are sporadic, nearly 40 familial forms have been reported. Moreover, ACs are seen with increased frequency in multiple Mendelian syndromes, including Chudley-McCullough syndrome, acrocallosal syndrome, and autosomal recessive primary ciliary dyskinesia. These findings suggest that genetic factors contribute to AC pathogenesis. However, traditional linkage and segregation approaches have been limited in their ability to identify causative genes for ACs because the disease is genetically heterogeneous and often presents asymptomatically and sporadically. Here, we comprehensively review theories of AC pathogenesis, the genetic evidence for AC formation, and discuss a different approach to AC genomics that could help elucidate this perplexing lesion and shed light on the associated neurodevelopmental phenotypes seen in a significant subset of these patients. © The Author(s) 2022. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Author Keywords
arachnoid cyst;  genomics;  multiomics;  neurodevelopmental disorders;  whole-exome sequencing

Document Type: Article
Publication Stage: Final
Source: Scopus

Mechanism of KMT5B haploinsufficiency in neurodevelopment in humans and mice” (2023) Science Advances

Mechanism of KMT5B haploinsufficiency in neurodevelopment in humans and mice
(2023) Science Advances, 9 (10), art. no. eade1463, . 

Sheppard, S.E.a b , Bryant, L.a , Wickramasekara, R.N.c d , Vaccaro, C.a , Robertson, B.c , Hallgren, J.c , Hulen, J.c , Watson, C.J.c , Faundes, V.e f , Duffourd, Y.g , Lee, P.h , Celeste Simon, M.h , de la Cruz, X.i j , Padilla, N.i , Flores-Mendez, M.k , Akizu, N.k l , Smiler, J.a m , Da Silva, R.P.a , Li, D.a , March, M.a , Diaz-Rosado, A.a , de Barcelos, I.P.a , Choa, Z.X.n o , Lim, C.Y.n o , Dubourg, C.p , Journel, H.q , Demurger, F.r , Mulhern, M.s t , Akman, C.t , Lippa, N.u , Andrews, M.v , Baldridge, D.v , Constantino, J.w , van Haeringen, A.x , Snoeck-Streef, I.y , Chow, P.z , Hing, A.z , Graham, J.M.aa , Au, M.aa , Faivre, L.ab ac , Shen, W.ad ae , Mao, R.ad , Palumbos, J.ad , Viskochil, D.ad , Gahl, W.af , Tifft, C.af , Macnamara, E.af , Hauser, N.ag , Miller, R.ag , Maffeo, J.ag , Afenjar, A.ah , Doummar, D.ah , Keren, B.ai , Arn, P.aj , Macklin-Mantia, S.ak , Meerschaut, I.al , Callewaert, B.al am , Reis, A.an , Zweier, C.an ao , Brewer, C.ap , Saggar, A.aq , Smeland, M.F.ar as , Kumar, A.at , Elmslie, F.au , Deshpande, C.av , Nizon, M.aw , Cogne, B.aw ax , van Ierland, Y.ay , Wilke, M.ay , van Slegtenhorst, M.ay , Koudijs, S.az , Chen, J.Y.ba , Dredge, D.bb , Pier, D.ba , Wortmann, S.bb bc , Kamsteeg, E.-J.bb , Koch, J.bb , Haynes, D.bd , Pollack, L.bd , Titheradge, H.be , Ranguin, K.bf , Denommé-Pichon, A.-S.g ab , Weber, S.bf , de la Fuente, R.P.bg , del Pozo, J.S.bg , Rosales, J.M.L.bg , Joset, P.bh , Steindl, K.bh , Rauch, A.bh bi bj bk bl , Mei, D.bm , Mari, F.bm , Guerrini, R.bm , Lespinasse, J.bn , Mau-Them, F.T.g ab , Philippe, C.g ab , Dauriat, B.bo , Raymond, L.bp , Moutton, S.bp , Cueto-González, A.M.bq br , Tan, T.Y.bs bt , Mignot, C.bu , Grotto, S.bu , Renaldo, F.bv , Drivas, T.G.bw bx , Hennessy, L.bx , Raper, A.bx , Parenti, I.by , Kaiser, F.J.by bz , Kuechler, A.by , Busk, Ø.L.ca , Islam, L.be , Siedlik, J.A.cb , Henderson, L.B.cc , Juusola, J.cc , Person, R.cc , Schnur, R.E.cc cd , Vitobello, A.g ab , Banka, S.e , Bhoj, E.J.a , Stessman, H.A.F.c

a Center for Applied Genomics, Children’s Hospital of Philadelphia, Philadelphia, PA, United States
b Unit on Vascular Malformations, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, MD, United States
c Stessman Laboratory, Department of Pharmacology and Neuroscience, Creighton University Medical School, Omaha, NE, United States
d Molecular Diagnostic Laboratory, Boys Town National Research Hospital, Omaha, NE, United States
e Division of Evolution and Genomic Sciences, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, United Kingdom
f Laboratorio de Genética y Enfermedades Metabólicas, Instituto de Nutrición y Tecnología de los Alimentos (INTA), Universidad de Chile, Santiago, Chile
g Unité Fonctionnelle d’Innovation diagnostique des maladies rares, FHU-TRANSLAD, CHU Dijon Bourgogne, Dijon, France
h Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States
i Vall d’Hebron Institute of Research (VHIR), Universitat Autònoma de Barcelona, Barcelona, Spain
j Institució Catalana de Recerca I Estudis Avançats (ICREA), Barcelona, Spain
k Raymond G. Perelman Center for Cellular and Molecular Therapeutics, Children’s Hospital of Philadelphia, Philadelphia, PA, United States
l Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA, United States
m 10x Genomics, Pleasanton, CA, United States
n Epithelial Epigenetics and Development Laboratory, A*STAR Skin Research Labs, Singapore, Singapore
o Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
p Laboratoire de Génétique Moléculaire et Génomique, Centre Hospitalier Universitaire de Rennes, Rennes, 35033, France
q Service de Génétique Médicale, Hopital Chubert, Vannes, Bretagne, France
r Department of Clinical Genetics, Service de Génétique Clinique, Centre de Référence Maladies Rares Centre Labellisé Anomalies du Développement-Ouest, Centre Hospitalier Universitaire de Rennes, Rennes, 35033, France
s Department of Pathology, Columbia University Irving Medical Center, New York, NY, United States
t Department of Neurology, Columbia University Irving Medical Center, New York, NY, United States
u Institute for Genomic Medicine, Columbia University Irving Medical Center, New York, NY, United States
v Division of Genetics and Genomic Medicine, Department of Pediatrics, Washington University School of Medicine, St. Louis, MO, United States
w Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, United States
x Department of Clinical Genetics, Leiden University Medical Center, Leiden, Netherlands
y Department of Child Neurology, University Medical Center Utrecht, Utrecht, Netherlands
z Department of Pediatrics, Division of Craniofacial Medicine, University of Washington, Seattle, WA, United States
aa Medical Genetics, Department of Pediatrics, Cedars-Sinai Medical Center, UCLA School of Medicine, Los Angeles, CA, United States
ab UFR Des Sciences de Santé, INSERM, Université de Bourgogne UMR1231 GAD “Génétique des Anomalies du Développement, ” FHU-TRANSLAD, Dijon, France
ac Centre de Référence Anomalies du Développement et Syndromes Malformatifs, CHU Dijon, Bourgogne, France
ad University of Utah, Salt Lake City, UT, United States
ae Mayo Clinic, Rochester, MN, United States
af NIH Undiagnosed Diseases Program, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, United States
ag Medical Genetics, Inova Fairfax Hospital, Falls Church, VA, United States
ah AP-HP, Sorbonne Université, Département de neuropediatrie, Hospital Armand Trousseau, Paris, France
ai Genetic Department, Pitié-Salpêtrière Hospital, AP-HP, Sorbonne Université, Paris, France
aj Department of Pediatrics, Nemours Children’s Specialty Care, Jacksonville, FL, United States
ak Department of Clinical Genomics, Mayo Clinic Florida, Jacksonville, FL, United States
al Center for Medical Genetics, Ghent University Hospital, Ghent, Belgium
am Department of Biomolecular Medicine, Ghent University, Ghent, Belgium
an Institute of Human Genetics, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, 91054, Germany
ao Department of Human Genetics, Inselspital, Bern University Hospital, University of Bern, Bern, 3010, Switzerland
ap Clinical Genetics Department, Royal Devon and Exeter Hospital (Heavitree), Exeter, EX1 2ED, United Kingdom
aq Clinical Genetics Department, St George’s Hospital, St George’s Healthcare NHS Trust, London, SW17 0QT, United Kingdom
ar Department of Medical Genetics, University Hospital of North Norway, Tromsø, Norway
as Department of Pediatric Rehabilitation, University Hospital of North Norway, Norway
at Northeast Thames Regional Genetics Service, Great Ormond Street Hospital, London, WC1N 3JH, United Kingdom
au South West Thames Centre for Genomics, St George’s University Hospitals NHS Foundation Trust, London, SW17 0QT, United Kingdom
av Department of Medical Genetics, Guy’s Hospital, London, SE1 9RT, United Kingdom
aw CHU Nantes, Service de Génétique Médicale, 9 quai Moncousu, Nantes, CEDEX 144093, France
ax Nantes Université, CNRS, INSERM, L’institut du thorax, Nantes, F-44000, France
ay Department of Clinical Genetics, Erasmus University Medical Center, P.O. Box 2040, Rotterdam, 3000 CA, Netherlands
az Department of Neurology, Erasmus University Medical Center, Sophia Children’s Hospital, P.O. Box 2040, Rotterdam, 3000 CA, Netherlands
ba Neurology Department, Massachusetts General Hospital, Boston, MA, United States
bb University Children’s Hospital Salzburg, Paracelsus Medical University (PMU), Salzburg, Austria
bc Amalia Children’s Hospital, RadboudUMC Nijmegen, Nijmegen, Netherlands
bd Division of Genetics, Arnold Palmer Hospital for Children–Orlando Health, Orlando, FL, United States
be West Midlands Regional Genetics Service and Birmingham Health Partners, Birmingham Women’s and Children’s NHS Trust, Birmingham, B15 2TG, United Kingdom
bf Department of Genetics, Reference Centre for Rare Diseases and Developmental Anomalies, Caen Hospital, Caen, France
bg UDISGEN (Unidad de Dismorfología y Genética), de Octubre University Hospital, Madrid, Spain
bh University of Zurich, Institute of Medical Genetics, Schlieren, Zurich, 8952, Switzerland
bi University of Zurich, University Children’s Hospital Zurich, Zurich, 8032, Switzerland
bj University of Zurich, URPP Adaptive Brain Circuits in Development and Learning (AdaBD), Zurich, Switzerland
bk University of Zurich Research Priority Program (URPP) AdaBD: Adaptive Brain Circuits in Development and Learning, Zurich, 8006, Switzerland
bl University of Zurich Research Priority Program (URPP) ITINERARE: Innovative Therapies in Rare Diseases, Zurich, 8006, Switzerland
bm Pediatric Neurology, Neurogenetics and Neurobiology Unit and Laboratories, Meyer Children’s Hospital, Member of ERN Epicare, University of Florence, Florence, Italy
bn UF de Génétique Chromosomique, Centre Hospitalier de Chambéry, Hôtel-Dieu, France
bo Service de cytogénétique et génétique médicale, Centre Hospitalier Universitaire de Limoges, France
bp Service de génétique, Laboratoire Eurofins Biomnis, Lyon, France
bq Hospital Vall d’Hebron, Barcelona, Spain
br Department of Clinical and Molecular Genetics, Vall d’Hebron Barcelona Hospital Campus, Passeig Vall d’Hebron 119-129, Barcelona, 08035, Spain
bs Victorian Clinical Genetics Services, Murdoch Children’s Research Institute, Melbourne, VIC, Australia
bt Department of Paediatrics, University of Melbourne, Melbourne, VIC, Australia
bu AP-HP, Sorbonne Université, Département de Génétique, Paris, France
bv AP-HP, Sorbonne Université, Département de neuropediatrie, Centre de référence neurogénétique, Hôpital Armand Trousseau, Paris, France
bw Department of Genetics, Perelman School of Medicine, the University of Pennsylvania, Philadelphia, PA, United States
bx Division of Translational Medicine and Human Genetics, Department of Medicine, Perelman School of Medicine, the University of Pennsylvania, Philadelphia, PA, United States
by Institut für Humangenetik, Universitätsklinikum Essen, Universität Duisburg-Essen, Essen, Germany
bz Essener Zentrum für Seltene Erkrankungen (EZSE), Universitätsklinikum Essen, Essen, Germany
ca Department of Medical Genetics, Telemark Hospital Trust, Skien, 3710, Norway
cb Department of Exercise Science and Pre-Health Professions, Creighton University, Omaha, NE, United States
cc GeneDx, Gaithersburg, MD, United States
cd Department of Pediatrics, Division of Genetics Cooper Medical School of Rowan University Cooper University Health Care 3, Cooper Plaza, Camden, NJ, United States

Abstract
Pathogenic variants in KMT5B, a lysine methyltransferase, are associated with global developmental delay, macrocephaly, autism, and congenital anomalies (OMIM# 617788). Given the relatively recent discovery of this disorder, it has not been fully characterized. Deep phenotyping of the largest (n = 43) patient cohort to date identified that hypotonia and congenital heart defects are prominent features that were previously not associated with this syndrome. Both missense variants and putative loss-of-function variants resulted in slow growth in patient-derived cell lines. KMT5B homozygous knockout mice were smaller in size than their wild-type littermates but did not have significantly smaller brains, suggesting relative macrocephaly, also noted as a prominent clinical feature. RNA sequencing of patient lymphoblasts and Kmt5b haploinsufficient mouse brains identified differentially expressed pathways associated with nervous system development and function including axon guidance signaling. Overall, we identified additional pathogenic variants and clinical features in KMT5Brelated neurodevelopmental disorder and provide insights into the molecular mechanisms of the disorder using multiple model systems. © 2023 American Association for the Advancement of Science. All rights reserved.

Document Type: Article
Publication Stage: Final
Source: Scopus

The role of PIEZO ion channels in the musculoskeletal system” (2023) American Journal of Physiology. Cell Physiology

The role of PIEZO ion channels in the musculoskeletal system
(2023) American Journal of Physiology. Cell Physiology, 324 (3), pp. C728-C740. 

Savadipour, A.a b c d , Palmer, D.a b c e , Ely, E.V.a b c e , Collins, K.H.a b c , Garcia-Castorena, J.M.a b c f , Harissa, Z.a b c e , Kim, Y.S.a b c , Oestrich, A.a b c , Qu, F.a b c , Rashidi, N.a b c d , Guilak, F.a b c d e

a Department of Orthopaedic Surgery, Washington University School of Medicine, St. Louis, MO, United States
b Shriners Hospitals for Children – St. Louis, St. Louis, MO, United States
c Center of Regenerative Medicine, Washington University School of Medicine, St. Louis, MO, United States
d Department of Mechanical Engineering and Materials Science, Washington University, St. Louis, MO, United States
e Department of Biomedical Engineering, Washington University, St. Louis, MO, United States
f Division of Biology and Biomedical Sciences, Washington University School of Medicine, St. Louis, MO, United States

Abstract
PIEZO1 and PIEZO2 are mechanosensitive cation channels that are highly expressed in numerous tissues throughout the body and exhibit diverse, cell-specific functions in multiple organ systems. Within the musculoskeletal system, PIEZO1 functions to maintain muscle and bone mass, sense tendon stretch, and regulate senescence and apoptosis in response to mechanical stimuli within cartilage and the intervertebral disc. PIEZO2 is essential for transducing pain and touch sensations as well as proprioception in the nervous system, which can affect musculoskeletal health. PIEZO1 and PIEZO2 have been shown to act both independently as well as synergistically in different cell types. Conditions that alter PIEZO channel mechanosensitivity, such as inflammation or genetic mutations, can have drastic effects on these functions. For this reason, therapeutic approaches for PIEZO-related disease focus on altering PIEZO1 and/or PIEZO2 activity in a controlled manner, either through inhibition with small molecules, or through dietary control and supplementation to maintain a healthy cell membrane composition. Although many opportunities to better understand PIEZO1 and PIEZO2 remain, the studies summarized in this review highlight how crucial PIEZO channels are to musculoskeletal health and point to promising possible avenues for their modulation as a therapeutic target.

Author Keywords
mechanobiology;  mechanosensitive ion channels;  mechanotransduction;  PIEZO1;  PIEZO2

Document Type: Review
Publication Stage: Final
Source: Scopus

Cnih3 Deletion Dysregulates Dorsal Hippocampal Transcription across the Estrous Cycle” (2023) eNeuro

Cnih3 Deletion Dysregulates Dorsal Hippocampal Transcription across the Estrous Cycle
(2023) eNeuro, 10 (3), art. no. ENEURO.0153-22.2023, . 

Mulvey, B.a b , Frye, H.E.c , Lintz, T.c , Fass, S.a b , Tycksen, E.a d , Nelson, E.C.b , Morón, J.A.c , Dougherty, J.D.a b

a Department of Genetics, Washington University School of Medicine, St. Louis, MO 63110, United States
b Department of Psychiatry, Washington University School of Medicine, St. Louis, MO 63110, United States
c Department of Anesthesiology, Washington University School of Medicine, St. Louis, MO 63110, United States
d McDonnell Genome Institute, Washington University School of Medicine, St. Louis, MO 63110, United States

Abstract
In females, the hippocampus, a critical brain region for coordination of learning, memory, and behavior, displays altered physiology and behavioral output across the estrous or menstrual cycle. However, the molecular effectors and cell types underlying these observed cyclic changes have only been partially characterized to date. Recently, profiling of mice null for the AMPA receptor trafficking gene Cnih3 have demonstrated estrous-dependent phenotypes in dorsal hippocampal synaptic plasticity, composition, and learning/memory. We therefore profiled dorsal hippocampal transcriptomes from female mice in each estrous cycle stage, and contrasted it with that of males, across wild-type (WT) and Cnih3 mutants. In wild types, we identified only subtle differences in gene expression between the sexes, while comparing estrous stages to one another revealed up to .1000 differentially expressed genes (DEGs). These estrous-responsive genes are especially enriched in gene markers of oligodendrocytes and the dentate gyrus, and in functional gene sets relating to estrogen response, potassium channels, and synaptic gene splicing. Surprisingly, Cnih3 knock-outs (KOs) showed far broader transcriptomic differences between estrous cycle stages and males. Moreover, Cnih3 knock-out drove subtle but extensive expression changes accentuating sex differential expression at diestrus and estrus. Altogether, our profiling highlights cell types and molecular systems potentially impacted by estrous-specific gene expression patterns in the adult dorsal hippocampus, enabling mechanistic hypothesis genera-tion for future studies of sex-differential neuropsychiatric function and dysfunction. Moreover, these findings suggest an unrecognized role of Cnih3 in buffering against transcriptional effects of estrous, providing a candidate molecular mechanism to explain estrous-dependent phenotypes observed with Cnih3 loss. © 2023 Mulvey et al.

Author Keywords
candidate gene;  gene expression;  opioid use disorder;  sex differences;  sex hormones

Funding details
National Institutes of HealthNIHR01DA042499, R33DA041883
Simons FoundationSF734069

Document Type: Article
Publication Stage: Final
Source: Scopus

Validity Assessment of an Automated Brain Morphometry Tool for Patients with De Novo Memory Symptoms” (2023) AJNR. American Journal of Neuroradiology

Validity Assessment of an Automated Brain Morphometry Tool for Patients with De Novo Memory Symptoms
(2023) AJNR. American Journal of Neuroradiology, 44 (3), pp. 261-267. 

Rahmani, F.a b , Jindal, S.a b , Raji, C.A.a b , Wang, W.a b , Nazeri, A.a b , Perez-Carrillo, G.G.a , Miller-Thomas, M.M.a , Graner, P.c d e f g , Marechal, B.c d e f g , Shah, A.f , Zimmermann, M.c d e f g , Chen, C.D.a b , Keefe, S.a , LaMontagne, P.a , Benzinger, T.L.S.a b

a From the Mallinckrodt Institute of Radiology, C.A.R., C.D.C., P.L.S.K
b Charles F. and Joanne Knight Alzheimer Disease Research Center (F.R., C.A.R., C.D.C., Washington University in St. Louis, St. LousMO, United States
c Malvern, PA, United States
d Advanced Clinical Imaging Technology (P.G., Siemens Healthcare, Lausanne, Switzerland
e Department of Radiology (P.G., Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland
f LTS5, École Polytechnique Fédérale de Lausanne (P.G., B.M., A.S., M.Z.), Lausanne, Switzerland
g Siemens Healthcare (P.G., Erlangen, Germany

Abstract
BACKGROUND AND PURPOSE: Automated volumetric analysis of structural MR imaging allows quantitative assessment of brain atrophy in neurodegenerative disorders. We compared the brain segmentation performance of the AI-Rad Companion brain MR imaging software against an in-house FreeSurfer 7.1.1/Individual Longitudinal Participant pipeline. MATERIALS AND METHODS: T1-weighted images of 45 participants with de novo memory symptoms were selected from the OASIS-4 database and analyzed through the AI-Rad Companion brain MR imaging tool and the FreeSurfer 7.1.1/Individual Longitudinal Participant pipeline. Correlation, agreement, and consistency between the 2 tools were compared among the absolute, normalized, and standardized volumes. Final reports generated by each tool were used to compare the rates of detection of abnormality and the compatibility of radiologic impressions made using each tool, compared with the clinical diagnoses. RESULTS: We observed strong correlation, moderate consistency, and poor agreement between absolute volumes of the main cortical lobes and subcortical structures measured by the AI-Rad Companion brain MR imaging tool compared with FreeSurfer. The strength of the correlations increased after normalizing the measurements to the total intracranial volume. Standardized measurements differed significantly between the 2 tools, likely owing to differences in the normative data sets used to calibrate each tool. When considering the FreeSurfer 7.1.1/Individual Longitudinal Participant pipeline as a reference standard, the AI-Rad Companion brain MR imaging tool had a specificity of 90.6%-100% and a sensitivity of 64.3%-100% in detecting volumetric abnormalities. There was no difference between the rate of compatibility of radiologic and clinical impressions when using the 2 tools. CONCLUSIONS: The AI-Rad Companion brain MR imaging tool reliably detects atrophy in cortical and subcortical regions implicated in the differential diagnosis of dementia. © 2023 by American Journal of Neuroradiology.

Document Type: Article
Publication Stage: Final
Source: Scopus

Allopregnanolone Effects on Inhibition in Hippocampal Parvalbumin Interneurons” (2023) eNeuro

Allopregnanolone Effects on Inhibition in Hippocampal Parvalbumin Interneurons
(2023) eNeuro, 10 (3), art. no. ENEURO.0392-22.2023, . 

Lu, X.a , Lambert, P.a , Benz, A.a , Zorumski, C.F.a b c , Mennerick, S.J.a b c

a Department of Psychiatry, Washington University in St. Louis, St. Louis, MO 63110, United States
b Department of Neuroscience, Washington University in St. Louis, St. Louis, MO 63110, United States
c Taylor Family Institute for Innovative Psychiatric Research, Washington University in St. Louis, St. Louis, MO 63110, United States

Abstract
Allopregnanolone (AlloP) is a neurosteroid that potentiates ionotropic GABAergic (GABAA) inhibition and is ap-proved for treating postpartum depression in women. Although the antidepressant mechanism of AlloP is largely unknown, it could involve selective action at GABAA receptors containing the d subunit. Despite previ-ous evidence for selective effects of AlloP on a4/d-containing receptors of hippocampal dentate granule cells (DGCs), other recent results failed to demonstrate selectivity at these receptors (Lu et al., 2020). In contrast to DGCs, hippocampal fast-spiking parvalbumin (PV) interneurons express an unusual variant partnership of d subunits with a1 subunits. Here, we hypothesized that native a1/d receptors in hippocampal fast-spiking inter-neurons may provide a preferred substrate for AlloP. Contrary to the hypothesis, electrophysiology from genet-ically tagged PV interneurons in hippocampal slices from male mice showed that 100 nM AlloP promoted phasic inhibition by increasing the sIPSC decay, but tonic inhibition was not detectably altered. Co-application of AlloP with 5 mM GABA did augment tonic current, which was not primarily through d-containing receptors. Furthermore, AlloP decreased the membrane resistance and the number of action potentials of DGCs, but the impact on PV interneurons was weaker than on DGCs. Thus, our results indicate that hippocampal PV inter-neurons possess low sensitivity to AlloP and suggest they are unlikely contributors to mood-altering effects of neurosteroids through GABA effects. © 2023 Lu et al.

Author Keywords
antidepressant;  inhibition;  interneuron;  neurosteroid

Funding details
National Institutes of HealthNIHF30MH126548, P50MH122379, R01MH123748

Document Type: Article
Publication Stage: Final
Source: Scopus

Transcriptomic Analyses of Brains of RBM8A Conditional Knockout Mice at Different Developmental Stages Reveal Conserved Signaling Pathways Contributing to Neurodevelopmental Diseases” (2023) International Journal of Molecular Sciences

Transcriptomic Analyses of Brains of RBM8A Conditional Knockout Mice at Different Developmental Stages Reveal Conserved Signaling Pathways Contributing to Neurodevelopmental Diseases
(2023) International Journal of Molecular Sciences, 24 (5), art. no. 4600, . 

McSweeney, C.a , Chen, M.a , Dong, F.a b , Sebastian, A.c , Reynolds, D.J.d , Mott, J.a , Pei, Z.a , Zou, J.e , Shi, Y.d , Mao, Y.a

a Department of Biology, Pennsylvania State University, University Park, PA 16802, United States
b Department of Genetics, Washington University School of Medicine, St. Louis, MO 63110, United States
c Department of Biochemistry and Molecular Biology, Pennsylvania State University, University Park, PA 16802, United States
d Department of Microbiology & Molecular Genetics, School of Medicine, University of California, Irvine, CA 92697, United States
e Systems Biology Center, National Heart, Lung, and Blood Institute, NIH, Bethesda, Rockville, MD 20892, United States

Abstract
RNA-binding motif 8A (RBM8A) is a core component of the exon junction complex (EJC) that binds pre-mRNAs and regulates their splicing, transport, translation, and nonsense-mediated decay (NMD). Dysfunction in the core proteins has been linked to several detriments in brain development and neuropsychiatric diseases. To understand the functional role of Rbm8a in brain development, we have generated brain-specific Rbm8a knockout mice and used next-generation RNA-sequencing to identify differentially expressed genes (DEGs) in mice with heterozygous, conditional knockout (cKO) of Rbm8a in the brain at postnatal day 17 (P17) and at embryonic day 12. Additionally, we analyzed enriched gene clusters and signaling pathways within the DEGs. At the P17 time point, between the control and cKO mice, about 251 significant DEGs were identified. At E12, only 25 DEGs were identified in the hindbrain samples. Bioinformatics analyses have revealed many signaling pathways related to the central nervous system (CNS). When E12 and P17 results were compared, three DEGs, Spp1, Gpnmb, and Top2a, appeared to peak at different developmental time points in the Rbm8a cKO mice. Enrichment analyses suggested altered activity in pathways affecting cellular proliferation, differentiation, and survival. The results support the hypothesis that loss of Rbm8a causes decreased cellular proliferation, increased apoptosis, and early differentiation of neuronal subtypes, which may lead ultimately to an altered neuronal subtype composition in the brain. © 2023 by the authors.

Author Keywords
autism;  exon junction complex;  nonsense-mediated decay;  RBM8A;  RNAseq;  schizophrenia

Funding details
National Institutes of HealthNIHR01MH122556
National Institute of Mental HealthNIMH
National Center for Advancing Translational SciencesNCATSUL1TR002014

Document Type: Article
Publication Stage: Final
Source: Scopus

Caffeine and the Risk of Diabetic Retinopathy in Type 2 Diabetes Mellitus: Findings from Clinical and Experimental Studies” (2023) Nutrients

Caffeine and the Risk of Diabetic Retinopathy in Type 2 Diabetes Mellitus: Findings from Clinical and Experimental Studies
(2023) Nutrients, 15 (5), art. no. 1169, . 

Alcubierre, N.a , Granado-Casas, M.b c d e , Bogdanov, P.d f , Hernández, C.d f , Ramos, H.d f , Castelblanco, E.e g , Real, J.d e , Rubinat-Arnaldo, E.b c d , Traveset, A.c h , Hernández, M.c i , Jurjo, C.c h , Vioque, J.j k , Navarrete-Muñoz, E.M.l m , Simó, R.d f , Mauricio, D.d e n o

a Avantmedic Center, Lleida, 25008, Spain
b Department of Nursing and Physiotherapy, Health Sciences Faculty, University of Lleida, Lleida, 25198, Spain
c Institute of Biomedical Research in Lleida (IRBLleida), Lleida, 25198, Spain
d Center for Biomedical Research on Diabetes and Associated Metabolic Diseases (CIBERDEM), Instituto de Salud Carlos III, Barcelona, 08907, Spain
e DAP-Cat Group, Unitat de Suport a la Recerca Barcelona, Institut Universitari d’Investigació en Atenció Primària Jordi Gol (IDIAP Jordi Gol), Barcelona, 08041, Spain
f Diabetes and Metabolism Research Unit, Vall d’Hebron Research Institute (VHIR) and Autonomous University of Barcelona (UAB), Barcelona, 08035, Spain
g Endocrinology, Metabolism and Lipid Research Division, Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO 63110, United States
h Department of Ophthalmology, University Hospital Arnau de Vilanova, Lleida, 25198, Spain
i Department of Endocrinology & Nutrition, University Hospital Arnau de Vilanova, Lleida, 25198, Spain
j Nutritional Epidemiology Unit, Instituto de Investigación Sanitaria y Biomédica de Alicante (ISABIAL), Miguel Hernández University, Alicante, 46020, Spain
k CIBER Epidemiología y Salud Pública (CIBERESP), Instituto de Salud Carlos III (ISCIII), Madrid, 28029, Spain
l Grupo de Investigación en Terapia Ocupacional (InTeO), Department of Surgery and Pathology, Miguel Hernández University, Alicante, 03550, Spain
m Alicante Institute for Health and Biomedical Research (ISABIAL-FISABIO Foundation), Alicante, 03010, Spain
n Department of Endocrinology and Nutrition, Hospital de la Santa Creu i Sant Pau, Institut d’Investigació Biomèdica Sant Pau (IIB Sant Pau), Barcelona, 08041, Spain
o Faculty of Medicine, University of Vic (UVIC/UCC), Vic, 08500, Spain

Abstract
The aim of this study was to assess the potential benefits of caffeine intake in protecting against the development of diabetic retinopathy (DR) in subjects with type 2 diabetes (T2D). Furthermore, we tested the effect of topical administration of caffeine on the early stages of DR in an experimental model of DR. In the cross-sectional study, a total of 144 subjects with DR and 147 individuals without DR were assessed. DR was assessed by an experienced ophthalmologist. A validated food frequency questionnaire (FFQ) was administered. In the experimental model, a total of 20 mice were included. One drop (5 μL) of caffeine (5 mg/mL) (n = 10) or vehicle (5 μL PBS, pH 7.4) (n = 10) was randomly administered directly onto the superior corneal surface twice daily for two weeks in each eye. Glial activation and retinal vascular permeability were assessed using standard methods. In the cross-sectional study in humans, the adjusted-multivariable model showed that a moderate and high (Q2 and Q4) caffeine intake had a protective effect of DR (odds ratio (95% confidence interval) = 0.35 (0.16–0.78); p = 0.011 and 0.35 (0.16–0.77); p = 0.010, respectively). In the experimental model, the administration of caffeine did not improve either reactive gliosis or retinal vascular permeability. Our results suggest a dose-dependent protective effect of caffeine in the development of DR, while the potential benefits of antioxidants in coffee and tea should also be considered. Further research is needed to establish the benefits and mechanisms of caffeinated beverages in the development of DR. © 2023 by the authors.

Author Keywords
caffeine intake;  coffee consumption;  diabetic retinopathy;  retinal ganglion cell layer;  tea consumption;  type 2 diabetes

Funding details
Ministerio de Educación, Cultura y DeporteMECDCB15/00071, FPU15/03005
Instituto de Salud Carlos IIIISCIIIFI11/0008
European Regional Development FundERDF

Document Type: Article
Publication Stage: Final
Source: Scopus

Health disparities in the treatment of bipolar disorder” (2023) Personalized Medicine in Psychiatry

Health disparities in the treatment of bipolar disorder
(2023) Personalized Medicine in Psychiatry, 37-38, art. no. 100101, . 

Tchikrizov, V.a , Ladner, M.E.a , Caples, F.V.b , Morris, M.c , Spillers, H.c , Jordan, C.D.c , Balls-Berry, J.E.d , Taylor-Desir, M.J.e , Frye, M.A.e , Vallender, E.J.a

a Department of Psychiatry and Human Behavior, University of Mississippi Medical Center, Jackson, MS 39216
b Department of Behavioral and Environmental Health, Jackson State University, Jackson, MS 39217
c Department of Medicine, All of Us Research Program, University of Mississippi Medical Center, Jackson, MS 39216
d Department of Neurology, Washington University, St. Louis, MO 63108
e Department of Psychiatry and Psychology, Mayo Clinic, Rochester, MN 55905

Abstract
Background: Therapeutic options for bipolar disorder vary based on individual presentation and phase of illness. In addition to well documented disparities in diagnosis, racial and gender differences in treatment complicate efforts to provide effective individualized treatment to patients with bipolar disorder. The present work was undertaken to identify the persistence of racial and gender disparities across diverse community and national populations and to compare treatment disparities in bipolar disorder with those observed for schizophrenia. Methods: Commonly prescribed treatments for bipolar disorder and schizophrenia were quantified using information gathered from the All of Us Research Program and de-identified electronic health records at the University of Mississippi Medical Center. Results: Black patients with bipolar disorder, in comparison to white patients, had significantly less utilization of lithium, lamotrigine, and antidepressants, but greater utilization of haloperidol and other first-generation antipsychotics. Disparities in antipsychotic use were reduced in patients with schizophrenia compared to those with a bipolar diagnosis. Conclusions: The disparities enumerated here have real world clinical implications. Black patients with bipolar disorder have less utilization of lithium, the gold standard mood stabilization treatment. Further community-guided research to better understand the origins of these disparities and clinical trials to evaluate non-antipsychotic mood stabilization treatment for bipolar disorder across populations is warranted. © 2023 The Authors

Author Keywords
Antipsychotics;  Bipolar disorder;  Gender disparities;  Lithium;  Mood stabilizers;  Racial disparities

Document Type: Article
Publication Stage: Final
Source: Scopus

Association of parental divorce, discord, and polygenic risk with children’s alcohol initiation and lifetime risk for alcohol use disorder” (2023) Alcoholism: Clinical and Experimental Research

Association of parental divorce, discord, and polygenic risk with children’s alcohol initiation and lifetime risk for alcohol use disorder
(2023) Alcoholism: Clinical and Experimental Research, . 

Kuo, S.I.-C.a , Thomas, N.S.b , Aliev, F.a , Bucholz, K.K.c , Dick, D.M.a , McCutcheon, V.V.c , Meyers, J.L.d , Chan, G.e , Kamarajan, C.d , Kramer, J.R.f , Hesselbrock, V.e , Plawecki, M.H.g , Porjesz, B.d , Tischfield, J.h , Salvatore, J.E.a

a Department of Psychiatry, Robert Wood Johnson Medical School, Rutgers University, Piscataway, NJ, United States
b Department of Psychology, Virginia Commonwealth University, Richmond, VA, United States
c Department of Psychiatry, School of Medicine, Washington University in St. Louis, St. Louis, MO, United States
d Department of Psychiatry and Behavioral Sciences, SUNY Downstate Health Sciences University, Brooklyn, NY, United States
e Department of Psychiatry, University of Connecticut School of Medicine, Farmington, CT, United States
f Department of Psychiatry, University of Iowa, Iowa City, IA, United States
g Department of Psychiatry, Indiana University, Indianapolis, IN, United States
h Department of Genetics, Rutgers University, Piscataway, NJ, United States

Abstract
Background: Parental divorce and discord are associated with poorer alcohol-related outcomes for offspring. However, not all children exposed to these stressors develop alcohol problems. Our objective was to test gene-by-environment interaction effects whereby children’s genetic risk for alcohol problems modifies the effects of parental divorce and discord to predict alcohol outcomes. Methods: The sample included European (EA; N = 5608, 47% male, Mage ~ 36 years) and African (AA; N = 1714, 46% female, Mage ~ 33 years) ancestry participants from the Collaborative Study on the Genetics of Alcoholism. Outcomes included age at initiation of regular drinking and lifetime DSM-5 alcohol use disorder (AUD). Predictors included parental divorce, parental relationship discord, and offspring alcohol problems polygenic risk scores (PRSALC). Mixed effects Cox proportional hazard models were used to examine alcohol initiation and generalized linear mixed effects models were used to examine lifetime AUD. Tests of PRS moderation of the effects of parental divorce/relationship discord on alcohol outcomes were examined on multiplicative and additive scales. Results: Among EA participants, parental divorce, parental discord, and higher PRSALC were associated with earlier alcohol initiation and greater lifetime AUD risk. Among AA participants, parental divorce was associated with earlier alcohol initiation and discord was associated with earlier initiation and AUD. PRSALC was not associated with either. Parental divorce/discord and PRSALC interacted on an additive scale in the EA sample, but no interactions were found in AA participants. Conclusions: Children’s genetic risk for alcohol problems modifies the impact of parental divorce/discord, consistent with an additive model of diathesis–stress interaction, with some differences across ancestry. © 2023 The Authors. Alcohol: Clinical and Experimental Research published by Wiley Periodicals LLC on behalf of Research Society on Alcohol.

Author Keywords
alcohol use disorder;  divorce;  gene–environment;  parental conflict;  polygenic scores

Funding details
U10 AA008401
National Institutes of HealthNIHK01 AA024152, R01 AA028064, U10AA008401
National Institute on Drug AbuseNIDA
National Institute on Alcohol Abuse and AlcoholismNIAAA

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

Sleep Disturbances Following Total Knee Arthroplasty” (2023) Journal of Arthroplasty

Sleep Disturbances Following Total Knee Arthroplasty
(2023) Journal of Arthroplasty, . 

Gibian, J.T.a , Bartosiak, K.A.a , Lucey, B.P.b , Riegler, V.a , King, J.a , Barrack, R.L.a

a Washington University School of Medicine Department of Orthopaedics, St. Louis, MO, United States
b Washington University School of Medicine Department of Neurology, St. Louis, MO, United States

Abstract
Background: Sleep disturbances are common after total knee arthroplasty (TKA), yet literature examining sleep and postoperative pain remains sparse. With the use of wearable devices, convenient objective remote sleep monitoring is now possible. We aimed to measure patient sleep following TKA using validated questionnaires and wearable devices to compare sleep patterns to pain scores 90 days postoperatively. Methods: Adult patients with body mass index < 45 undergoing unilateral primary TKA were enrolled. Patients wore a monitor, which tracked sleep duration and disturbances (getting up at least once during the night). They completed weekly Pittsburgh Sleep Quality Index (PSQI) questionnaires and visual analog scale (VAS) pain scores. Sleep patterns were compared with pain scores and sleep duration was compared with PSQI responses. Results: There were 110 patients included with 54.5% women; average age was 64 years (range, 43-80). VAS scores decreased postoperatively. PSQI overall sleep scores, sleep quantity, and sleep quality worsened for the first 30 days then improved past baseline levels by 90 days. Recorded sleep duration did not change, and recordings did not correlate at any point with VAS scores. PSQI overall score and sleep quantity did not correlate with VAS. At 30 days postoperatively, patients reporting “very bad” sleep had significantly worse VAS scores than those reporting “bad” sleep. Conclusion: Patient-reported sleep quality (very bad sleep) correlated well with VAS pain score at 30 days, while sleep duration (monitored or patient-reported) did not correlate with any clinical measure and does not seem to be a useful metric in assessing TKA outcome. © 2023 Elsevier Inc.

Author Keywords
outcome monitoring;  patient reported outcomes;  sleep disturbance;  total knee arthroplasty;  wearable devices

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

Internal capsule microstructure mediates the relationship between childhood maltreatment and PTSD following adulthood trauma exposure” (2023) Molecular Psychiatry

Internal capsule microstructure mediates the relationship between childhood maltreatment and PTSD following adulthood trauma exposure
(2023) Molecular Psychiatry, . 

Wong, S.A.a , Lebois, L.A.M.a b , Ely, T.D.c , van Rooij, S.J.H.c , Bruce, S.E.d , Murty, V.P.e , Jovanovic, T.f , House, S.L.g , Beaudoin, F.L.h i , An, X.j , Zeng, D.k , Neylan, T.C.l , Clifford, G.D.m n , Linnstaedt, S.D.j , Germine, L.T.b o p , Bollen, K.A.q , Rauch, S.L.b 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 , Kurz, M.C.aa ab ac , Swor, R.A.ad , Hudak, L.A.ae , Pascual, J.L.af ag , Seamon, M.J.ag ah , Pearson, C.ai , Peak, D.A.aj , Merchant, R.C.ak , Domeier, R.M.al , Rathlev, N.K.am , O’Neil, B.J.an , Sergot, P.ao , Sanchez, L.D.ak ap , Miller, M.W.aq ar , Pietrzak, R.H.as at , Joormann, J.au , Barch, D.M.av , Pizzagalli, D.A.a b , Harte, S.E.aw ax , Elliott, J.M.ay az ba , Kessler, R.C.bb , Koenen, K.C.bc , McLean, S.A.bd be , Ressler, K.J.a b , Stevens, J.S.c , Harnett, N.G.a b

a Division of Depression and Anxiety, McLean Hospital, Belmont, MA, United States
b Department of Psychiatry, Harvard Medical School, Boston, MA, United States
c Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, GA, United States
d Department of Psychological Sciences, University of Missouri—St. Louis, St. Louis, MO, United States
e Department of Psychology, Temple University, Philadelphia, PA, United States
f Department of Psychiatry and Behavioral Neurosciences, Wayne State University, Detroit, MI, United States
g Department of Emergency Medicine, Washington University School of Medicine, St. Louis, MO, United States
h Department of Epidemiology, Brown University, Providence, RI, United States
i Department of Emergency Medicine, Brown University, Providence, RI, United States
j Institute for Trauma Recovery, Department of Anesthesiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
k Department of Biostatistics, Gillings School of Global Public Health, University of North Carolina, Chapel Hill, NC, United States
l Departments of Psychiatry and Neurology, University of California San Francisco, San Francisco, CA, United States
m Department of Biomedical Informatics, Emory University School of Medicine, Atlanta, GA, United States
n Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, GA, United States
o Institute for Technology in Psychiatry, McLean Hospital, Belmont, MA, United States
p The Many Brains Project, Belmont, MA, 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, MA, United States
s Department of Emergency Medicine, University of Massachusetts Chan Medical School, Worcester, MA, 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, FL, United States
x Department of Emergency Medicine, Cooper Medical School of Rowan University, Camden, NJ, 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, University of Alabama School of Medicine, Birmingham, AL, United States
ab Department of Surgery, Division of Acute Care Surgery, University of Alabama School of Medicine, Birmingham, AL, United States
ac Center for Injury Science, University of Alabama at Birmingham, Birmingham, AL, United States
ad Department of Emergency Medicine, Oakland University William Beaumont School of Medicine, Rochester, MI, United States
ae Department of Emergency Medicine, Emory University School of Medicine, Atlanta, GA, United States
af Department of Surgery, Department of Neurosurgery, University of Pennsylvania, Philadelphia, PA, United States
ag Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States
ah Department of Surgery, Division of Traumatology, Surgical Critical Care and Emergency Surgery, University of Pennsylvania, Philadelphia, PA, United States
ai Department of Emergency Medicine, Wayne State University, Ascension St. John Hospital, Detroit, MI, United States
aj Department of Emergency Medicine, Massachusetts General Hospital, Boston, MA, United States
ak Department of Emergency Medicine, Brigham and Women’s Hospital, Boston, MA, United States
al Department of Emergency Medicine, Saint Joseph Mercy Hospital, Ypsilanti, MI, United States
am Department of Emergency Medicine, University of Massachusetts Medical School-Baystate, Springfield, MA, United States
an Department of Emergency Medicine, Wayne State University, Detroit Receiving Hospital, Detroit, MI, United States
ao Department of Emergency Medicine, McGovern Medical School at UTHealth, Houston, TX, United States
ap Department of Emergency Medicine, Harvard Medical School, Boston, MA, United States
aq National Center for PTSD, Behavioral Science Division, VA Boston Healthcare System, Boston, MA, United States
ar Department of Psychiatry, Boston University School of Medicine, Boston, MA, United States
as National Center for PTSD, Clinical Neurosciences Division, VA Connecticut Healthcare System, West Haven, CT, United States
at Department of Psychiatry, Yale School of Medicine, New Haven, CT, United States
au Department of Psychology, Yale University, New Haven, CT, United States
av Department of Psychological & Brain Sciences, Washington University in St. Louis, St. Louis, MO, United States
aw Department of Anesthesiology, University of Michigan Medical School, Ann Arbor, MI, United States
ax Department of Internal Medicine-Rheumatology, University of Michigan Medical School, Ann Arbor, MI, United States
ay Kolling Institute, University of Sydney, St Leonards, NSW, Australia
az Faculty of Medicine and Health, University of Sydney, Northern Sydney Local Health District, Camperdown, NSW, Australia
ba Physical Therapy & Human Movement Sciences, Feinberg School of Medicine, Northwestern University, Chicago, IL, United States
bb Department of Health Care Policy, Harvard Medical School, Boston, MA, United States
bc Department of Epidemiology, Harvard T.H. Chan School of Public Health, Harvard University, Boston, MA, United States
bd Department of Emergency Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
be Institute for Trauma Recovery, Department of Psychiatry, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States

Abstract
Childhood trauma is a known risk factor for trauma and stress-related disorders in adulthood. However, limited research has investigated the impact of childhood trauma on brain structure linked to later posttraumatic dysfunction. We investigated the effect of childhood trauma on white matter microstructure after recent trauma and its relationship with future posttraumatic dysfunction among trauma-exposed adult participants (n = 202) recruited from emergency departments as part of the AURORA Study. Participants completed self-report scales assessing prior childhood maltreatment within 2-weeks in addition to assessments of PTSD, depression, anxiety, and dissociation symptoms within 6-months of their traumatic event. Fractional anisotropy (FA) obtained from diffusion tensor imaging (DTI) collected at 2-weeks and 6-months was used to index white matter microstructure. Childhood maltreatment load predicted 6-month PTSD symptoms (b = 1.75, SE = 0.78, 95% CI = [0.20, 3.29]) and inversely varied with FA in the bilateral internal capsule (IC) at 2-weeks (p = 0.0294, FDR corrected) and 6-months (p = 0.0238, FDR corrected). We observed a significant indirect effect of childhood maltreatment load on 6-month PTSD symptoms through 2-week IC microstructure (b = 0.37, Boot SE = 0.18, 95% CI = [0.05, 0.76]) that fully mediated the effect of childhood maltreatment load on PCL-5 scores (b = 1.37, SE = 0.79, 95% CI = [−0.18, 2.93]). IC microstructure did not mediate relationships between childhood maltreatment and depressive, anxiety, or dissociative symptomatology. Our findings suggest a unique role for IC microstructure as a stable neural pathway between childhood trauma and future PTSD symptoms following recent trauma. Notably, our work did not support roles of white matter tracts previously found to vary with PTSD symptoms and childhood trauma exposure, including the cingulum bundle, uncinate fasciculus, and corpus callosum. Given the IC contains sensory fibers linked to perception and motor control, childhood maltreatment might impact the neural circuits that relay and process threat-related inputs and responses to trauma. © 2023, The Author(s).

Funding details
National Institute of Mental HealthNIMHK00MH119603, U01MH110925
MAYDAY Fund

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

Neuroinflammation and amyloid deposition in the progression of mixed Alzheimer and vascular dementia” (2023) NeuroImage: Clinical

Neuroinflammation and amyloid deposition in the progression of mixed Alzheimer and vascular dementia
(2023) NeuroImage: Clinical, 38, art. no. 103373, . 

Ying, C.a c , Kang, P.b , Binkley, M.M.b , Ford, A.L.b c , Chen, Y.b , Hassenstab, J.b d , Wang, Q.c d , Strain, J.b , Morris, J.C.d , Lee, J.-M.a b c , Benzinger, T.L.S.c d e , An, H.a b c

a Department of Biomedical Engineering, Washington University in St. Louis, United States
b Department of Neurology, Washington University School of Medicine, United States
c Mallinckrodt Institute of Radiology, Washington University School of Medicine, United States
d Knight Alzheimer Disease Research Center, Washington University School of Medicine, United States
e Department of Neurosurgery, Washington University School of Medicine, United States

Abstract
Background: Alzheimer’s disease (AD) and vascular contributions to cognitive impairment and dementia (VCID) pathologies coexist in patients with cognitive impairment. Abnormal amyloid beta (Aβ) deposition is the hallmark pathologic biomarker for AD. Neuroinflammation may be a pathophysiological mechanism in both AD and VCID. In this study, we aimed to understand the role of neuroinflammation and Aβ deposition in white matter hyperintensities (WMH) progression and cognitive decline over a decade in patients with mixed AD and VCID pathologies. Methods: Twenty-four elderly participants (median [interquartile range] age 78 [64.8, 83] years old, 14 female) were recruited from the Knight Alzheimer Disease Research Center. 11C-PK11195 standard uptake value ratio (SUVR) and 11C-PiB mean cortical binding potential (MCBP) were used to evaluate neuroinflammation and Aβ deposition in-vivo, respectively. Fluid-attenuated inversion recovery MR images were acquired to obtain baseline WMH volume and its progression over 11.5 years. Composite cognitive scores (global, processing speed and memory) were computed at baseline and follow-up over 7.5 years. Multiple linear regression models evaluated the association between PET biomarkers (11C-PK11195 SUVR and 11C-PiB MCBP) and baseline WMH volume and cognitive function. Moreover, linear mixed-effects models evaluated whether PET biomarkers predicted greater WMH progression or cognitive decline over a decade. Results: Fifteen participants (62.5%) had mixed AD (positive PiB) and VCID (at least one vascular risk factor) pathologies. Elevated 11C-PK11195 SUVR, but not 11C-PiB MCBP, was associated with greater baseline WMH volume and predicted greater WMH progression. Elevated 11C-PiB MCBP was associated with baseline memory and global cognition. Elevated 11C-PK11195 SUVR and elevated 11C-PiB MCBP independently predicted greater global cognition and processing speed declines. No association was found between 11C-PK11195 SUVR and 11C-PiB MCBP. Conclusions: Neuroinflammation and Aβ deposition may represent two distinct pathophysiological pathways, and both independently contributed to the progression of cognitive impairment in mixed AD and VCID pathologies. Neuroinflammation, but not Aβ deposition, contributed to WMH volume and progression. © 2023

Author Keywords
Alzheimer’s disease;  Amyloid beta peptides;  Neuroinflammation;  Vascular contributions to cognitive impairment and dementia;  White matter hyperintensities

Funding details
National Institutes of HealthNIH1P30NS098577, 1R01AG054567, 1R01NS082561, KL2TR002346, P01AG003991, P01AG026276, P30AG066444, R01AG074909, R01HL129241, R01NS085419, R03AG072375, R21NS127425, RF1NS116565, U24NS107230

Document Type: Article
Publication Stage: Final
Source: Scopus

Effects of stress-dependent growth on evolution of sulcal direction and curvature in models of cortical folding” (2023) Brain Multiphysics

Effects of stress-dependent growth on evolution of sulcal direction and curvature in models of cortical folding
(2023) Brain Multiphysics, 4, art. no. 100065, . 

Balouchzadeh, R.a , Bayly, P.V.a , Garcia, K.E.a b

a Mechanical Engineering and Materials Science, Washington University in St. LouisMO, United States
b Radiology and Imaging Sciences, Indiana University School of MedicineIN, United States

Abstract
The majority of human brain folding occurs during the third trimester of gestation. Although many studies have investigated the physical mechanisms of brain folding, a comprehensive understanding of this complex process has not yet been achieved. In mechanical terms, the “differential growth hypothesis” suggests that the formation of folds results from a difference in expansion rates between cortical and subcortical layers, which eventually leads to mechanical instability akin to buckling. It has also been observed that axons, a substantial component of subcortical tissue, can elongate or shrink under tensile or compressive stress, respectively. Previous work has proposed that this cell-scale behavior in aggregate can produce stress-dependent growth in the subcortical layers. The current study investigates the potential role of stress-dependent growth on cortical surface morphology, in particular the variations in folding direction and curvature over the course of development. Evolution of sulcal direction and mid-cortical surface curvature were calculated from finite element simulations of three-dimensional folding in four different initial geometries: (i) sphere; (ii) axisymmetric oblate spheroid; (iii) axisymmetric prolate spheroid; and (iv) triaxial spheroid. The results were compared to mid-cortical surface reconstructions from four preterm human infants, imaged and analyzed at four time points during the period of brain folding. Results indicate that models incorporating subcortical stress-dependent growth predict folding patterns that more closely resemble those in the developing human brain. Statement of Significance: Cortical folding is a critical process in human brain development. Aberrant folding is associated with disorders such as autism and schizophrenia, yet our understanding of the physical mechanism of folding remains limited. Ultimately mechanical forces must shape the brain. An important question is whether mechanical forces simply deform tissue elastically, or whether stresses in the tissue modulate growth. Evidence from this paper, consisting of quantitative comparisons between patterns of folding in the developing human brain and corresponding patterns in simulations, supports a key role for stress-dependent growth in cortical folding. © 2023 The Authors

Author Keywords
Brain development;  Cortical folding;  Growth;  Hyperelasticity;  Modeling;  Viscoelasticity

Funding details
National Institutes of HealthNIH
National Institute of Neurological Disorders and StrokeNINDSR01 NS111948

Document Type: Article
Publication Stage: Final
Source: Scopus

Determinants of physical activity engagement in older adults” (2023) Journal of Behavioral Medicine

Determinants of physical activity engagement in older adults
(2023) Journal of Behavioral Medicine, . 

Stojanovic, M.a , Babulal, G.M.b c d e , Head, D.a f g

a Department of Psychological & Brain Sciences, Washington University in St. Louis, One Brookings Drive, Box 1125, St. Louis, MO, United States
b Department of Psychology, Faculty of Humanities, University of Johannesburg, Johannesburg, South Africa
c Department of Clinical Research and Leadership, The George Washington University School of Medicine and Health Sciences, Washington, DC, United States
d Institute of Public Health, Washington University in St. Louis, St. Louis, MO, United States
e Department of Neurology, Washington University in St. Louis, St. Louis, MO, United States
f Charles F. and Joanne Knight Alzheimer Disease Research Center, Washington University in St. Louis, St. Louis, MO, United States
g Department of Radiology, Washington University in St. Louis, St. Louis, MO, United States

Abstract
In order to increase engagement in physical activity, it is important to determine which factors contribute to physical activity engagement in older adults. The current study examined the relative predictive ability of several potential determinants, in terms of both the concurrent level as well as longitudinal trajectories. Clinically normal adults aged 61–92 completed the Physical Activity Scale for the Elderly (n = 189 for cross-sectional models; n = 214 for longitudinal models). Potential determinants included age, gender, education, physical health, sensory health, mood, cardiovascular health, cognitive status, and biomarkers of Alzheimer disease (AD). We observed a novel finding that both concurrent physical health (p < 0.001) and change in physical health (p < 0.001) were significant predictors above and beyond other determinants. Concurrent mood predicted levels of physical activity (p = 0.035), particularly in females. These findings suggest that poor physical health and low mood might be important to consider as potential barriers to physical activity engagement in older adults. © 2023, The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.

Author Keywords
Amyloid and exercise;  Dementia and physical activity;  Physical activity determinants

Funding details
National Institutes of HealthNIHP01 AG026276, P01 AG03991, P30 AG066444, R01 AG067428, R01AG056466, R01AG068183
BrightFocus FoundationBFFA2021142S

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

A Cre-deleter specific for embryo-derived brain macrophages reveals distinct features of microglia and border macrophages” (2023) Immunity

A Cre-deleter specific for embryo-derived brain macrophages reveals distinct features of microglia and border macrophages
(2023) Immunity, . 

Brioschi, S.a , Belk, J.A.b c , Peng, V.a , Molgora, M.a , Rodrigues, P.F.a , Nguyen, K.M.a , Wang, S.a , Du, S.a , Wang, W.-L.a , Grajales-Reyes, G.E.a , Ponce, J.M.d , Yuede, C.M.e , Li, Q.f g , Baer, J.M.h , DeNardo, D.G.a h i , Gilfillan, S.a , Cella, M.a , Satpathy, A.T.c j k l , Colonna, M.a

a Department of Pathology and Immunology, Washington University School of Medicine in Saint Louis, Saint Louis, MO, United States
b Department of Computer Science, Stanford University, Stanford, CA, United States
c Gladstone-UCSF Institute of Genomic Immunology, San Francisco, CA, United States
d McDonnell Genome Institute, Washington University School of Medicine in Saint Louis, Saint Louis, MO, United States
e Department of Psychiatry, Washington University School of Medicine in Saint Louis, Saint Louis, MO, United States
f Department of Neuroscience, Washington University School of Medicine in Saint Louis, Saint Louis, MO, United States
g Department of Genetics, Washington University School of Medicine in Saint Louis, Saint Louis, MO, United States
h Department of Medicine, Washington University School of Medicine in Saint Louis, Saint Louis, MO, United States
i Siteman Cancer Center, Washington University School of Medicine in Saint Louis, Saint Louis, MO, United States
j Department of Pathology, Stanford University, Stanford, CA, United States
k Stanford Cancer Institute, Stanford University, Stanford, CA, United States
l Parker Institute for Cancer Immunotherapy, Stanford University, Stanford, CA, United States

Abstract
Genetic tools to target microglia specifically and efficiently from the early stages of embryonic development are lacking. We generated a constitutive Cre line controlled by the microglia signature gene Crybb1 that produced nearly complete recombination in embryonic brain macrophages (microglia and border-associated macrophages [BAMs]) by the perinatal period, with limited recombination in peripheral myeloid cells. Using this tool in combination with Flt3-Cre lineage tracer, single-cell RNA-sequencing analysis, and confocal imaging, we resolved embryonic-derived versus monocyte-derived BAMs in the mouse cortex. Deletion of the transcription factor SMAD4 in microglia and embryonic-derived BAMs using Crybb1-Cre caused a developmental arrest of microglia, which instead acquired a BAM specification signature. By contrast, the development of genuine BAMs remained unaffected. Our results reveal that SMAD4 drives a transcriptional and epigenetic program that is indispensable for the commitment of brain macrophages to the microglia fate and highlight Crybb1-Cre as a tool for targeting embryonic brain macrophages. © 2023 Elsevier Inc.

Author Keywords
BAMs;  fate-mapping;  macrophages ontogeny;  microglia;  SMAD4

Funding details
R01AI158579, R21AG059176, RF1AG05148501, RF1AG059082
National Science FoundationNSFDGE-1656518
National Institutes of HealthNIH
National Institute of Arthritis and Musculoskeletal and Skin DiseasesNIAMSP30AR073752
Burroughs Wellcome FundBWF
Merck
Stanford UniversitySU
Washington University in St. LouisWUSTL
Cure Alzheimer’s FundCAF
University of California, IrvineUCI
Rheumatic Diseases Research Resource-Based Center, Washington University School of Medicine in St. LouisWU-RDRRC
University of QueenslandUQ

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

CSF tau phosphorylation occupancies at T217 and T205 represent improved biomarkers of amyloid and tau pathology in Alzheimer’s disease” (2023) Nature Aging

CSF tau phosphorylation occupancies at T217 and T205 represent improved biomarkers of amyloid and tau pathology in Alzheimer’s disease
(2023) Nature Aging, . 

Barthélemy, N.R.a b , Saef, B.a , Li, Y.a , Gordon, B.A.c , He, Y.a b , Horie, K.a b , Stomrud, E.d e , Salvadó, G.d , Janelidze, S.d , Sato, C.a b , Ovod, V.a b , Henson, R.L.a , Fagan, A.M.a f , Benzinger, T.L.S.c f , Xiong, C.f g , Morris, J.C.a f , Hansson, O.d e , Bateman, R.J.a b f , Schindler, S.E.a f

a Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States
b Tracy Family SILQ Center for Neurodegenerative Biology, St. Louis, MO, United States
c Department of Radiology, Washington University School of Medicine, St. Louis, MO, United States
d Clinical Memory Research Unit, Department of Clinical Sciences Malmö, Lund University, Lund, Sweden
e Memory Clinic, Skåne University Hospital, Malmö, Sweden
f Knight Alzheimer Disease Research Center, Washington University School of Medicine, St. Louis, MO, United States
g Division of Biostatistics, Washington University School of Medicine, St. Louis, MO, United States

Abstract
Cerebrospinal fluid (CSF) amyloid-β peptide (Aβ)42/Aβ40 and the concentration of tau phosphorylated at site 181 (p-tau181) are well-established biomarkers of Alzheimer’s disease (AD). The present study used mass spectrometry to measure concentrations of nine phosphorylated and five nonphosphorylated tau species and phosphorylation occupancies (percentage phosphorylated/nonphosphorylated) at ten sites. In the present study we show that, in 750 individuals with a median age of 71.2 years, CSF pT217/T217 predicted the presence of brain amyloid by positron emission tomography (PET) slightly better than Aβ42/Aβ40 (P = 0.02). Furthermore, for individuals with positive brain amyloid by PET (n = 263), CSF pT217/T217 was more strongly correlated with the amount of amyloid (Spearman’s ρ = 0.69) than Aβ42/Aβ40 (ρ = −0.42, P < 0.0001). In two independent cohorts of participants with symptoms of AD dementia (n = 55 and n = 90), CSF pT217/T217 and pT205/T205 were better correlated with tau PET measures than CSF p-tau181 concentration. These findings suggest that CSF pT217/T217 and pT205/T205 represent improved CSF biomarkers of amyloid and tau pathology in AD. © 2023, The Author(s).

Funding details
1280/20
2020-0314
2018-Projekt0279
National Institutes of HealthNIHR01AG070941
Alzheimer’s AssociationAA
Roche
Biogen
Alzheimer’s Disease Research Center, Emory UniversityADRCP01AG003991, P01AG026276, P30AG066444, R56AG061900, RF1AG061900, U19AG024904, U19AG032438
GE Healthcare
Foundation for Barnes-Jewish HospitalFBJH
Cure Alzheimer’s FundCAF
H2020 Marie Skłodowska-Curie ActionsMSCA101061836
European CommissionEC
Lunds Universitet
HjärnfondenFO2021-0293
Knut och Alice Wallenbergs Stiftelse2017-0383
VetenskapsrådetVR2016-00906
Siemens
Konung Gustaf V:s och Drottning Victorias Frimurarestiftelse
Horizon 2020
AlzheimerfondenAF-939932
Marcus och Amalia Wallenbergs minnesfondMAW2015-0125
University Hospital FoundationUHF2020-O000028

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

A call for clinical trial globalization in Alzheimer’s disease and related dementia” (2023) Alzheimer’s and Dementia

A call for clinical trial globalization in Alzheimer’s disease and related dementia
(2023) Alzheimer’s and Dementia, . 

Llibre-Guerra, J.J.a b c , Heavener, A.d , Brucki, S.M.D.e , Marante, J.P.D.f , Pintado-Caipa, M.g , Chen, Y.h , Behrens, M.I.i , Hardi, A.j , Admirall-Sanchez, A.k , Akinyemi, R.l , Alladi, S.m , Dorsman, K.A.n , Rodriguez-Salgado, A.M.o , Solorzano, J.p , Babulal, G.M.a c q r , for the Diversity and Disparity Professional Interest Area Increasing Sustained Diversity in Clinical Trials Working Groups

a Department of Neurology, Washington University, School of Medicine, St. Louis, MO, United States
b Dominantly Inherited Alzheimer’s Network Trial Unit, St. Louis, MO, United States
c Institute of Public Health, Washington University, St. Louis, MO, United States
d Department of Global Health and Social Medicine, Harvard Medical School, St. Louis, MO, United States
e Cognitive and Behavioral Neurology Unit, Department of Neurology, University of Sao Paulo, São Paulo, Brazil
f Department of Primary Care, Espirutu Santo, Brazil
g Instituto Peruano de Neurociencias, Lima, Peru
h Department of Geriatrics, Lille Neurosciences & Cognition, University of Lille, Lille, France
i Departamento de Neurología y Neurocirugía, Hospital Clínico Universidad de Chile, Independencia, Santiago, Chile
j Becker Medical Library, Washington University School of Medicine, St. Louis, MO, United States
k Centre of Public Health, Trinity College Dublin, Dublin, Ireland
l Centre for Genomic and Precision Medicine, College of Medicine, University of Ibadan, Ibadan, Nigeria
m National Institute of Mental Health and Neuroscience, Bangalore, India
n University of Texas Southwestern Medical Center, Dallas, TX, United States
o Global Brain Health Institute, San Francisco, CA, United States
p Department of Medicine, Hospital Antonio Luaces Iralola, Ciego de Avila, Cuba
q Department of Clinical Research and Leadership, The George Washington University School of Medicine and Health Sciences, Washington, DC, United States
r Department of Psychology, University of Johannesburg, Johannesburg, South Africa

Abstract
Background: The burden of Alzheimer’s disease and related dementia (ADRD) is projected to disproportionally impact low-middle-income countries (LMICs). However, there is a systematic under-representation of LMICs in ADRD clinical trial platforms. Methods: We aimed to determine the global distribution of ADRD clinical trials and identify existing barriers for conducting clinical trials in LMICs. Primary data sources to identify trial distribution in LMICs included ClinicalTrials.gov and the International Trials Registry Platform. An additional systematic review and expert consensus interviews were conducted to identify barriers for conducting clinical trials in LMICs. Findings: Among 1237 disease-modifying therapies tested in ADRD clinical trials, only 11.6% have been or are conducted in emerging economies (upper-middle income [9.6%] and low-middle income [2.0%]). We identified several limitations for trial implementation including a lack of financial resources, low industry presence, regulatory obstacles, and operational barriers. Interpretation: Although LMICs bear the greatest burden of ADRD globally, substantial development of clinical trial platforms to address this inequity and health disparity is lacking. © 2023 The Authors. Alzheimer’s & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer’s Association.

Funding details
K01AG073526
National Institutes of HealthNIHR01AG056466, R01AG067428, R01AG068183, R01AG074302
National Institute on AgingNIA
Michael J. Fox Foundation for Parkinson’s ResearchMJFFMJFF‐020770
Alzheimer’s AssociationAAAARFD‐21‐851415, SG‐20‐690363
BrightFocus FoundationBFFA2021142S
Foundation for Barnes-Jewish HospitalFBJH

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

Effects of clinical, comorbid, and social determinants of health on brain ageing in people with and without HIV: a retrospective case-control study” (2023) The Lancet HIV

Effects of clinical, comorbid, and social determinants of health on brain ageing in people with and without HIV: a retrospective case-control study
(2023) The Lancet HIV, . Cited 1 time.

Petersen, K.J.a , Lu, T.a , Wisch, J.a , Roman, J.a , Metcalf, N.a , Cooley, S.A.a , Babulal, G.M.a , Paul, R.c , Sotiras, A.b , Vaida, F.d , Ances, B.M.a

a Department of Neurology, Washington University School of Medicine, St Louis, MO, United States
b Department of Radiology, Washington University School of Medicine, St Louis, MO, United States
c Missouri Institute of Mental Health, University of Missouri, St Louis, MO, United States
d Department of Family Medicine, The University of California, San Diego, CA, United States

Abstract
Background: Neuroimaging reveals structural brain changes linked with HIV infection and related neurocognitive disorders; however, group-level comparisons between people with HIV and people without HIV do not account for within-group heterogeneity. The aim of this study was to quantify the effects of comorbidities such as cardiovascular disease and adverse social determinants of health on brain ageing in people with HIV and people without HIV. Methods: In this retrospective case-control study, people with HIV from Washington University in St Louis, MO, USA, and people without HIV identified through community organisations or the Research Participant Registry were clinically characterised and underwent 3-Tesla T1-weighted MRI between Dec 3, 2008, and Oct 4, 2022. Exclusion criteria were established by a combination of self-reports and medical records. DeepBrainNet, a publicly available machine learning algorithm, was applied to estimate brain-predicted age from MRI for people with HIV and people without HIV. The brain-age gap, defined as the difference between brain-predicted age and true chronological age, was modelled as a function of clinical, comorbid, and social factors by use of linear regression. Variables were first examined singly for associations with brain-age gap, then combined into multivariate models with best-subsets variable selection. Findings: In people with HIV (mean age 44·8 years [SD 15·5]; 78% [296 of 379] male; 69% [260] Black; 78% [295] undetectable viral load), brain-age gap was associated with Framingham cardiovascular risk score (p=0·0034), detectable viral load (&gt;50 copies per mL; p=0·0023), and hepatitis C co-infection (p=0·0065). After variable selection, the final model for people with HIV retained Framingham score, hepatitis C, and added unemployment (p=0·0015). Educational achievement assayed by reading proficiency was linked with reduced brain-age gap (p=0·016) for people without HIV but not for people with HIV, indicating a potential resilience factor. When people with HIV and people without HIV were modelled jointly, selection resulted in a model containing cardiovascular risk (p=0·0039), hepatitis C (p=0·037), Area Deprivation Index (p=0·033), and unemployment (p=0·00010). Male sex (p=0·078) and alcohol use history (p=0·090) were also included in the model but were not individually significant. Interpretation: Our findings indicate that comorbid and social determinants of health are associated with brain ageing in people with HIV, alongside traditional HIV metrics such as viral load and CD4 cell count, suggesting the need for a broadened clinical perspective on healthy ageing with HIV, with additional focus on comorbidities, lifestyle changes, and social factors. Funding: National Institute of Mental Health, National Institute of Nursing Research, and National Institute of Drug Abuse. © 2023 Elsevier Ltd

Funding details
National Institutes of HealthNIHF32MH129151, R01MH118031
National Institute of Mental HealthNIMH
National Institute on Drug AbuseNIDAR01DA123446
National Institute of Nursing ResearchNINRR01NR012657, R01NR012907, R01NR014449, R01NR015738

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

Pronator Quadratus: A Preferable Recipient for Targeted Muscle Reinnervation of Neuromas in the Hand” (2022) Plastic and Reconstructive Surgery – Global Ope

Pronator Quadratus: A Preferable Recipient for Targeted Muscle Reinnervation of Neuromas in the Hand
(2022) Plastic and Reconstructive Surgery – Global Open, 10 (11), art. no. 4640, . 

Felder, J.M., Saoud, K.

Division of Plastic and Reconstructive Surgery, Department of Surgery, Washington University in St. Louis School of Medicine, St. Louis, MO, United States

Abstract
Summary: Targeted muscle reinnervation (TMR) has emerged as a useful solution to the problem of painful neuromas and is increasingly being applied in many clinical circumstances. Relatively little has been written about TMR for painful neuromas of the hand, and what has been written describes use of the intrinsic muscles as recipients for the nerve transfer. Except in cases of amputation, intrinsic muscle sacrifice carries morbidity. Furthermore, TMR to intrinsic muscles will place the nerve coaptation in areas subject to pressure with loading of the palm. For these reasons, the pronator quadratus may be a preferable target muscle when performing TMR for painful neuromas of the hand. In this report, we describe the rationale for its use and demonstrate the surgical technique and outcomes with case examples. © 2022 Lippincott Williams and Wilkins. All rights reserved.

Document Type: Article
Publication Stage: Final
Source: Scopus

Genetic Addiction Risk Severity Assessment Identifies Polymorphic Reward Genes as Antecedents to Reward Deficiency Syndrome (RDS) Hypodopaminergia’s Effect on Addictive and Non-Addictive Behaviors in a Nuclear Family” (2022) Journal of Personalized Medicine

Genetic Addiction Risk Severity Assessment Identifies Polymorphic Reward Genes as Antecedents to Reward Deficiency Syndrome (RDS) Hypodopaminergia’s Effect on Addictive and Non-Addictive Behaviors in a Nuclear Family
(2022) Journal of Personalized Medicine, 12 (11), art. no. 1864, . 

Dennen, C.A.a , Blum, K.b c d e f g , Bowirrat, A.h , Thanos, P.K.i , Elman, I.j , Ceccanti, M.k , Badgaiyan, R.D.l , McLaughlin, T.m , Gupta, A.n , Bajaj, A.o , Baron, D.b , Downs, B.W.b , Bagchi, D.p , Gold, M.S.q

a Department of Family Medicine, Jefferson Health Northeast, Philadelphia, PA 08033, United States
b Division of Addiction Research & Education, Center for Sports and Mental Health, Western University of Health Sciences, Pomona, CA 91766, United States
c Division of Nutrigenomics, The Kenneth Blum Behavioral & Neurogenetic Institute, Austin, TX 78701, United States
d Institute of Psychology, ELTE Eötvös Loránd University, Egyetem tér 1–3, Budapest, 1053, Hungary
e Department of Psychiatry, School of Medicine, University of Vermont, Burlington, VT 05405, United States
f Department of Psychiatry, Wright State University, Boonshoft School of Medicine and Dayton VA Medical Centre, Dayton, OH 45324, United States
g Center for Genomics and Applied Gene Technology, Institute of Integrative Omics and Applied Biotechnology (IIOAB), Nonakuri, Purba Medinipur, West Bengal721172, India
h Department of Molecular Biology and Adelson School of Medicine, Ariel University, Ariel, 40700, Israel
i Behavioral Neuropharmacology and Neuroimaging Laboratory, Clinical Research Institute on Addictions, Department of Pharmacology and Toxicology, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, NY 14203, United States
j Center for Pain and the Brain (P.A.I.N Group), Department of Anesthesiology, Critical Care & Pain Medicine, Boston Children’s Hospital, Boston, MA 02115, United States
k Società Italiana per il Trattamento dell’Alcolismo e le sue Complicanze (SITAC), ASL Roma, Sapienza University of Rome, Rome, 00185, Italy
l Department of Psychiatry, South Texas Veteran Health Care System, Audie L. Murphy Memorial VA Hospital, Long School of Medicine, University of Texas Medical Center, San Antonio, TX 78229, United States
m Reward Deficiency Clinics of America, Austin, TX 78701, United States
n Future Biologics, Lawrenceville, GA 30043, United States
o Bajaj Chiropractic Clinic, New York, NY 10010, United States
p Department of Pharmaceutical Sciences, Southern University College of Pharmacy, Houston, TX 77004, United States
q Department of Psychiatry, Washington University School of Medicine, St. Louis, MO 63110, United States

Abstract
This case series presents the novel genetic addiction risk score (GARS), which shows a high prevalence of polymorphic risk alleles of reward genes in a nuclear family with multiple reward deficiency syndrome (RDS) behavioral issues expressing a hypodopaminergic antecedent. The family consists of a mother, father, son, and daughter. The mother experienced issues with focus, memory, anger, and amotivational syndrome. The father experienced weight issues and depression. The son experienced heavy drinking, along with some drug abuse and anxiety. The daughter experienced depression, lethargy, brain fog, focus issues, and anxiety, among others. A major clinical outcome of the results presented to the family members helped reduce personal guilt and augment potential hope for future healing. Our laboratory’s prior research established that carriers of four or more alleles measured by GARS (DRD1-DRD4, DAT1, MOR, GABABR3, COMT, MAOAA, and 5HTLPR) are predictive of the addiction severity index (ASI) for drug abuse, and carriers of seven or more alleles are predictive of severe alcoholism. This generational case series shows the impact that genetic information has on reducing stigma and guilt in a nuclear family struggling with RDS behaviors. The futuristic plan is to introduce an appropriate DNA-guided “pro-dopamine regulator” into the recovery and enhancement of life. © 2022 by the authors.

Author Keywords
genetic addiction risk severity (GARS);  hypodopaminergia;  polymorphisms;  reward circuitry;  reward deficiency syndrome (RDS);  single nucleotide polymorphisms (SNPs)

Funding details
National Institutes of HealthNIHR01NS073884
Howard University

Document Type: Article
Publication Stage: Final
Source: Scopus

Discovery of a Promising Fluorine-18 Positron Emission Tomography Radiotracer for Imaging Sphingosine-1-Phosphate Receptor 1 in the Brain” (2022) Journal of Medicinal Chemistry

Discovery of a Promising Fluorine-18 Positron Emission Tomography Radiotracer for Imaging Sphingosine-1-Phosphate Receptor 1 in the Brain
(2022) Journal of Medicinal Chemistry, . 

Qiu, L.a , Jiang, H.a , Zhou, C.a , Wang, J.a , Yu, Y.a , Zhao, H.a , Huang, T.a , Gropler, R.a , Perlmutter, J.S.b , Benzinger, T.L.S.a , Tu, Z.a

a Department of Radiology, Washington University School of Medicine, Saint Louis, MO 63110, United States
b Department of Neurology, Radiology, Neuroscience, Physical Therapy and Occupational Therapy, Washington University School of Medicine, Saint Louis, MO 63110, United States

Abstract
Sphingosine-1-phosphate receptor 1 (S1PR1) is recognized as a novel therapeutic and diagnostic target in neurological disorders. We recently transferred the S1PR1 radioligand [11C]CS1P1 into clinical investigation for multiple sclerosis. Herein, we reported the design, synthesis and evaluation of novel F-18 S1PR1 radioligands. We combined the structural advantages of our two lead S1PR1 radioligands and synthesized 14 new S1PR1 compounds, then performed F-18 radiochemistry on the most promising compounds. Compound 6h is potent (IC50 = 8.7 nM) and selective for S1PR1. [18F]6h exhibited a high uptake in macaque brain (SUV &gt; 3.0) and favorable brain washout pharmacokinetics in positron emission tomography (PET) study. PET blocking and displacement studies confirmed the specificity of [18F]6h in vivo. Radiometabolite analysis confirmed no radiometabolite of [18F]6h entered into the brain to confound the PET measurement. In summary, [18F]6h is a promising radioligand to image S1PR1 and worth translational clinical investigation for humans with brain disorders. © 2023 American Chemical Society.

Funding details
National Institutes of HealthNIH
National Institute of Neurological Disorders and StrokeNINDSNS0103957, NS103988, NS75527
National Institute of Biomedical Imaging and BioengineeringNIBIBEB025815

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

Metabolomic and lipidomic signatures in autosomal dominant and late-onset Alzheimer’s disease brains” (2022) Alzheimer’s and Dementia

Metabolomic and lipidomic signatures in autosomal dominant and late-onset Alzheimer’s disease brains
(2022) Alzheimer’s and Dementia, . 

Novotny, B.C.a b c , Fernandez, M.V.a b c , Wang, C.a b c d , Budde, J.P.a b c , Bergmann, K.a b c , Eteleeb, A.M.a b c , Bradley, J.d , Webster, C.a b c , Ebl, C.a b c , Norton, J.a b c , Gentsch, J.a b c , Dube, U.a , Wang, F.a b c , Morris, J.C.b e f , Bateman, R.J.b e f , Perrin, R.J.b e f g , McDade, E.f , Xiong, C.e , Chhatwal, J.h , Goate, A.i , Farlow, M.j , Schofield, P.k , Chui, H.l , Karch, C.M.a b c , Cruchaga, C.a b c e , Benitez, B.A.m , Harari, O.a b c e , for the Dominantly Inherited Alzheimer Network (DIAN) Study Groupn , the Alzheimer’s Disease Neuroimaging Initiativen , and the Alzheimer’s Disease Metabolomics Consortium (ADMC)n

a Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, United States
b Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO, United States
c NeuroGenomics and Informatics Center, Washington University School of Medicine, St. Louis, MO, United States
d Division of Biology & Biomedical Sciences, Washington University in St. Louis, St. Louis, MO, United States
e The Charles F. and Joanne Knight Alzheimer Disease Research Center, Washington University School of Medicine, St. Louis, MO, United States
f Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States
g Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, United States
h Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States
i Icahn School of Medicine at Mount Sinai, New York, NY, United States
j Department of Neurology, Indiana University School of Medicine, Indianapolis, IN, United States
k Neuroscience Research Australia, Randwick, Sydney, NSW, Australia
l Neurology, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States
m Department of Neurology, Harvard Medical School and Beth Israel Deaconess Medical Center, Boston, MA, United States

Abstract
Introduction: The identification of multiple genetic risk factors for Alzheimer’s disease (AD) suggests that many pathways contribute to AD onset and progression. However, the metabolomic and lipidomic profiles in carriers of distinct genetic risk factors are not fully understood. The metabolome can provide a direct image of dysregulated pathways in the brain. Methods: We interrogated metabolomic signatures in the AD brain, including carriers of pathogenic variants in APP, PSEN1, and PSEN2 (autosomal dominant AD; ADAD), APOE ɛ4, and TREM2 risk variant carriers, and sporadic AD (sAD). Results: We identified 133 unique and shared metabolites associated with ADAD, TREM2, and sAD. We identified a signature of 16 metabolites significantly altered between groups and associated with AD duration. Discussion: AD genetic variants show distinct metabolic perturbations. Investigation of these metabolites may provide greater insight into the etiology of AD and its impact on clinical presentation. HIGHLIGHTS: APP/PSEN1/PSEN2 and TREM2 variant carriers show distinct metabolic changes. A total of 133 metabolites were differentially abundant in AD genetic groups. β-citrylglutamate is differentially abundant in autosomal dominant, TREM2, and sporadic AD. A 16-metabolite profile shows differences between Alzheimer’s disease (AD) genetic groups. The identified metabolic profile is associated with duration of disease. © 2022 The Authors. Alzheimer’s & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer’s Association.

Author Keywords
APOE;  APP;  autosomal dominant Alzheimer’s disease;  lipidomics;  metabolomics;  PSEN1;  PSEN2;  TREM2;  β-citrylglutamate

Funding details
R01AG36836, R01AG48015, RC2AG036547, RF1AG57473, U01AG32984, U01AG46152, U01AG46161, U01AG61356
National Institutes of HealthNIH
U.S. Department of DefenseDODW81XWH‐12‐2‐0012
Foundation for the National Institutes of HealthFNIH
National Institute on AgingNIAK99AG061281, P01AGO26276, P30AG066444, P30AG10161, R01AG046171, R01AG057777, R01AG059093, R01AG15819, R01AG17917, R01AG30146, R01AG36042, RF1AG051550, RF1AG057452, RF1AG058942, U01 AG024904, U01AG061359, U19AG063744
National Institute of Neurological Disorders and StrokeNINDSP01AG003991, R01AG044546, R01NS118146, RF1AG053303, RF1AG058501, U01AG058922
National Institute of Biomedical Imaging and BioengineeringNIBIB
Alzheimer’s AssociationAA
Alzheimer’s Drug Discovery FoundationADDF
Illinois Department of Public HealthIDPH
Biogen
AbbVie
Alzheimer’s Disease Neuroimaging InitiativeADNI
BioClinica
Fondation Brain Canada
Japan Agency for Medical Research and DevelopmentAMED
Translational Genomics Research InstituteTGEN3R01AG046171‐02S2
Alzheimer’s Disease Research Center, University of PittsburghADRC
Canadian Institutes of Health ResearchIRSC
Fonds de Recherche du Québec – SantéFRQS
Korea Health Industry Development InstituteKHIDI
Instituto de Salud Carlos IIIISCIII
Deutsches Zentrum für Neurodegenerative ErkrankungenDZNE
Fleni

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