Hope Center Member Publications

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, 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

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.), 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

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, 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

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

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, 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, 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

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

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, 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

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, . 

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

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

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