Publications

Hope Center Member Publications

Scopus list of publications for December 12, 2022

Macrophage depletion blocks congenital SARM1-dependent neuropathy” (2022) The Journal of Clinical Investigation

Macrophage depletion blocks congenital SARM1-dependent neuropathy
(2022) The Journal of Clinical Investigation, 132 (23), . 

Dingwall, C.B.a , Strickland, A.a , Yum, S.W.b , Yim, A.K.a , Zhu, J.a , Wang, P.L.a c , Yamada, Y.a , Schmidt, R.E.c , Sasaki, Y.a , Bloom, A.J.a d , DiAntonio, A.d e , Milbrandt, J.a d

a Department of Genetics, Washington University School of Medicine, St. Louis, MO, United States
b Division of Neurology, Children’s Hospital of Philadelphia, Department of Neurology, Perelman School of Medicine, Philadelphia, PA, United States
c Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, United States
d Needleman Center for Neurometabolism and Axonal Therapeutics, St. Louis, MO, United States
e Department of Developmental Biology, Washington University School of Medicine, St. Louis, MO, United States

Abstract
Axon loss contributes to many common neurodegenerative disorders. In healthy axons, the axon survival factor NMNAT2 inhibits SARM1, the central executioner of programmed axon degeneration. We identified 2 rare NMNAT2 missense variants in 2 brothers afflicted with a progressive neuropathy syndrome. The polymorphisms resulted in amino acid substitutions V98M and R232Q, which reduced NMNAT2 NAD+-synthetase activity. We generated a mouse model to mirror the human syndrome and found that Nmnat2V98M/R232Q compound-heterozygous CRISPR mice survived to adulthood but developed progressive motor dysfunction, peripheral axon loss, and macrophage infiltration. These disease phenotypes were all SARM1-dependent. Remarkably, macrophage depletion therapy blocked and reversed neuropathic phenotypes in Nmnat2V98M/R232Q mice, identifying a SARM1-dependent neuroimmune mechanism as a key driver of disease pathogenesis. These findings demonstrate that SARM1 induced inflammatory neuropathy and highlight the potential of immune therapy as a treatment for this rare syndrome and other neurodegenerative conditions associated with NMNAT2 loss and SARM1 activation.

Author Keywords
Macrophages;  Mouse models;  Neurodegeneration;  Neuroscience

Document Type: Article
Publication Stage: Final
Source: Scopus

A SARM1-mitochondrial feedback loop drives neuropathogenesis in a Charcot-Marie-Tooth disease type 2A rat model” (2022) The Journal of Clinical Investigation

A SARM1-mitochondrial feedback loop drives neuropathogenesis in a Charcot-Marie-Tooth disease type 2A rat model
(2022) The Journal of Clinical Investigation, 132 (23), . 

Sato-Yamada, Y.a b , Strickland, A.a , Sasaki, Y.a , Bloom, J.a c , DiAntonio, A.c d , Milbrandt, J.a c e

a Department of Genetics, Washington University School of Medicine, St. Louis, MO, United States
b Center for Advanced Oral Science, Niigata University Graduate School of Medical and Dental Science, Niigata City, Japan
c Needleman Center for Neurometabolism and Axonal Therapeutics, St. Louis, MO, United States
d Department of Developmental Biology and
e McDonnell Genome Institute, Washington University School of Medicine, St. Louis, MO, United States

Abstract
Charcot-Marie-Tooth disease type 2A (CMT2A) is an axonal neuropathy caused by mutations in the mitofusin 2 (MFN2) gene. MFN2 mutations result in profound mitochondrial abnormalities, but the mechanism underlying the axonal pathology is unknown. Sterile α and Toll/IL-1 receptor motif-containing 1 (SARM1), the central executioner of axon degeneration, can induce neuropathy and is activated by dysfunctional mitochondria. We tested the role of SARM1 in a rat model carrying a dominant CMT2A mutation (Mfn2H361Y) that exhibits progressive dying-back axonal degeneration, neuromuscular junction (NMJ) abnormalities, muscle atrophy, and mitochondrial abnormalities – all hallmarks of the human disease. We generated Sarm1-KO (Sarm1-/-) and Mfn2H361Y Sarm1 double-mutant rats and found that deletion of Sarm1 rescued axonal, synaptic, muscle, and functional phenotypes, demonstrating that SARM1 was responsible for much of the neuropathology in this model. Despite the presence of mutant MFN2 protein in these double-mutant rats, loss of SARM1 also dramatically suppressed many mitochondrial defects, including the number, size, and cristae density defects of synaptic mitochondria. This surprising finding indicates that dysfunctional mitochondria activated SARM1 and that activated SARM1 fed back on mitochondria to exacerbate the mitochondrial pathology. As such, this work identifies SARM1 inhibition as a therapeutic candidate for the treatment of CMT2A and other neurodegenerative diseases with prominent mitochondrial pathology.

Author Keywords
Neurodegeneration;  Neurological disorders;  Neuromuscular disease;  Neuroscience

Document Type: Article
Publication Stage: Final
Source: Scopus

A single-cell analysis framework allows for characterization of CSF leukocytes and their tissue of origin in multiple sclerosis” (2022) Science Translational Medicine

A single-cell analysis framework allows for characterization of CSF leukocytes and their tissue of origin in multiple sclerosis
(2022) Science Translational Medicine, 14 (673), p. eadc9778. 

Ostkamp, P.a , Deffner, M.a , Schulte-Mecklenbeck, A.a , Wünsch, C.a , Lu, I.-N.a , Wu, G.F.b c , Goelz, S.d , De Jager, P.L.e , Kuhlmann, T.f , Gross, C.C.a , Klotz, L.a , Meyer Zu Hörste, G.a , Wiendl, H.a , Schneider-Hohendorf, T.a , Schwab, N.a

a Department of Neurology with Institute of Translational Neurology, University Hospital MünsterMünster 48149, Germany
b Department of Pathology and Immunology, Washington University School of MedicineMO 63110, United States
c Department of Neurology, Washington University School of MedicineMO 63110, United States
d Oregon Health and Science UniversityPortland OR 97239, United States
e Center for Translational and Computational Neuroimmunology and Multiple Sclerosis Center, Department of Neurology, Columbia University Irving Medical Center, NY, 10032, United States
f Institute of Neuropathology, University Hospital MünsterMünster 48149, Germany

Abstract
Peripheral central nervous system (CNS)-infiltrating lymphocytes are a hallmark of relapsing-remitting multiple sclerosis. Tissue-resident memory T cells (TRM) not only populate the healthy CNS parenchyma but also are suspected to contribute to multiple sclerosis pathology. Because cerebrospinal fluid (CSF), unlike CNS parenchyma, is accessible for diagnostics, we evaluated whether human CSF, apart from infiltrating cells, also contains TRM cells and CNS-resident myeloid cells draining from the parenchyma or border tissues. Using deep generative models, we integrated 41 CSF and 14 CNS parenchyma single-cell RNA sequencing (scRNAseq) samples from eight independent studies, encompassing 120,629 cells. By comparing CSF immune cells collected during multiple sclerosis relapse with cells collected during therapeutic very late antigen-4 blockade, we could identify immune subsets with tissue provenance across multiple lineages, including CNS border-associated macrophages, CD8 and CD4 TRM cells, and tissue-resident natural killer cells. All lymphocytic CNS-resident cells shared expression of CXCR6 but showed differential ITGAE expression (encoding CD103). A common signature defined CD4 and CD8 TRM cells by expression of ZFP36L2, DUSP1, and ID2. We further developed a user interface-driven application based on this analysis framework for atlas-level cell identity transfer onto new CSF scRNAseq data. Together, these results define CNS-resident immune cells involved in multiple sclerosis pathology that can be detected and monitored in CSF. Targeting these cell populations might be promising to modulate immunopathology in progressive multiple sclerosis and other neuroinflammatory diseases.

Document Type: Article
Publication Stage: Final
Source: Scopus

A new mouse model of Charcot-Marie-Tooth 2J neuropathy replicates human axonopathy and suggest alteration in axo-glia communication” (2022) PLoS Genetics

A new mouse model of Charcot-Marie-Tooth 2J neuropathy replicates human axonopathy and suggest alteration in axo-glia communication
(2022) PLoS Genetics, 18 (11), art. no. e1010477, . 

Shackleford, G.G.a b c , Marziali, L.N.a b , Sasaki, Y.d , Claessens, A.c , Ferri, C.c , Weinstock, N.I.a b , Rossor, A.M.e , Silvestri, N.J.a b , Wilson, E.R.a b , Hurley, E.a b , Kidd, G.J.f , Manohar, S.g , Ding, D.g , Salvi, R.J.g , Laura Feltri, M.a b , D’Antonio, M.c , Wrabetz, L.a b

a Department of Neurology, Institute for Myelin and Glia Exploration, Jacobs School of Medicine and Biomedical Sciences, State University of New York at Buffalo, Buffalo, NY, United States
b Department of Biochemistry, Institute for Myelin and Glia Exploration, Department Biochemistry and Neurology, Jacobs School of Medicine and Biomedical Sciences, State University of New York, Buffalo, NY, United States
c Biology of Myelin Unit, Division of Genetics and Cell Biology, San Raffaele Scientific Institute, Milan, Italy
d Needleman Center for Neurometabolism and Axonal Therapeutics, Department of Genetics, Washington University School of Medicine in Saint Louis, St. Louis, MO, United States
e Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, London, United Kingdom
f Department of Neurosciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, United States
g Center for Hearing and Deafness, State University of New York at Buffalo, Buffalo, NY, United States

Abstract
Myelin is essential for rapid nerve impulse propagation and axon protection. Accordingly, defects in myelination or myelin maintenance lead to secondary axonal damage and subsequent degeneration. Studies utilizing genetic (CNPase-, MAG-, and PLP-null mice) and naturally occurring neuropathy models suggest that myelinating glia also support axons independently from myelin. Myelin protein zero (MPZ or P0), which is expressed only by Schwann cells, is critical for myelin formation and maintenance in the peripheral nervous system. Many mutations in MPZ are associated with demyelinating neuropathies (Charcot-Marie-Tooth disease type 1B [CMT1B]). Surprisingly, the substitution of threonine by methionine at position 124 of P0 (P0T124M) causes axonal neuropathy (CMT2J) with little to no myelin damage. This disease provides an excellent paradigm to understand how myelinating glia support axons independently from myelin. To study this, we generated targeted knock-in MpzT124M mutant mice, a genetically authentic model of T124M-CMT2J neuropathy. Similar to patients, these mice develop axonopathy between 2 and 12 months of age, characterized by impaired motor performance, normal nerve conduction velocities but reduced compound motor action potential amplitudes, and axonal damage with only minor compact myelin modifications. Mechanistically, we detected metabolic changes that could lead to axonal degeneration, and prominent alterations in non-compact myelin domains such as paranodes, Schmidt-Lanterman incisures, and gap junctions, implicated in Schwann cell-axon communication and axonal metabolic support. Finally, we document perturbed mitochondrial size and distribution along MpzT124M axons suggesting altered axonal transport. Our data suggest that Schwann cells in P0T124M mutant mice cannot provide axons with sufficient trophic support, leading to reduced ATP biosynthesis and axonopathy. In conclusion, the MpzT124M mouse model faithfully reproduces the human neuropathy and represents a unique tool for identifying the molecular basis for glial support of axons. Copyright: © 2022 Shackleford et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Document Type: Article
Publication Stage: Final
Source: Scopus

Upper Limb Nerve Transfer Surgery in Patients With Tetraplegia” (2022) JAMA Network Open

Upper Limb Nerve Transfer Surgery in Patients With Tetraplegia
(2022) JAMA Network Open, 5 (11), p. e2243890. 

Javeed, S.a , Dibble, C.F.a , Greenberg, J.K.a , Zhang, J.K.a , Khalifeh, J.M.b , Park, Y.c , Wilson, T.J.d , Zager, E.L.e , Faraji, A.H.f , Mahan, M.A.g , Yang, L.J.h , Midha, R.i , Juknis, N.j , Ray, W.Z.a

a Department of Neurological Surgery, Washington University, St Louis, MO, United States
b Department of Neurological Surgery, Johns Hopkins University, Baltimore, MD, Liberia
c Division of Public Health Sciences, Department of Surgery, Washington University School of Medicine, St Louis, MO, United States
d Department of Neurosurgery, Stanford University, Stanford, CA, United States
e Department of Neurosurgery, Hospital of the University of Pennsylvania, Philadelphia, United States
f Department of Neurological Surgery, Houston Methodist Hospital, Houston, TX, United States
g Department of Neurosurgery, Clinical Neurosciences Center, University of Utah, Salt Lake City, United States
h Department of Neurological Surgery, University of Michigan School of Medicine, Ann Arbor, United States
i Department of Clinical Neurosciences, University of Calgary, Calgary, AB, Canada
j Physical Medicine and Rehabilitation, Washington University, St Louis, MO, United States

Abstract
Importance: Cervical spinal cord injury (SCI) causes devastating loss of upper extremity function and independence. Nerve transfers are a promising approach to reanimate upper limbs; however, there remains a paucity of high-quality evidence supporting a clinical benefit for patients with tetraplegia. Objective: To evaluate the clinical utility of nerve transfers for reanimation of upper limb function in tetraplegia. Design, Setting, and Participants: In this prospective case series, adults with cervical SCI and upper extremity paralysis whose recovery plateaued were enrolled between September 1, 2015, and January 31, 2019. Data analysis was performed from August 2021 to February 2022. Interventions: Nerve transfers to reanimate upper extremity motor function with target reinnervation of elbow extension and hand grasp, pinch, and/or release. Main Outcomes and Measures: The primary outcome was motor strength measured by Medical Research Council (MRC) grades 0 to 5. Secondary outcomes included Sollerman Hand Function Test (SHFT); Michigan Hand Outcome Questionnaire (MHQ); Disabilities of Arm, Shoulder, and Hand (DASH); and 36-Item Short Form Health Survey (SF-36) physical component summary (PCS) and mental component summary (MCS) scores. Outcomes were assessed up to 48 months postoperatively. Results: Twenty-two patients with tetraplegia (median age, 36 years [range, 18-76 years]; 21 male [95%]) underwent 60 nerve transfers on 35 upper limbs at a median time of 21 months (range, 6-142 months) after SCI. At final follow-up, upper limb motor strength improved significantly: median MRC grades were 3 (IQR, 2.5-4; P = .01) for triceps, with 70% of upper limbs gaining an MRC grade of 3 or higher for elbow extension; 4 (IQR, 2-4; P < .001) for finger extensors, with 79% of hands gaining an MRC grade of 3 or higher for finger extension; and 2 (IQR, 1-3; P < .001) for finger flexors, with 52% of hands gaining an MRC grade of 3 or higher for finger flexion. The secondary outcomes of SHFT, MHQ, DASH, and SF36-PCS scores improved beyond the established minimal clinically important difference. Both early (<12 months) and delayed (≥12 months) nerve transfers after SCI achieved comparable motor outcomes. Continual improvement in motor strength was observed in the finger flexors and extensors across the entire duration of follow-up. Conclusions and Relevance: In this prospective case series, nerve transfer surgery was associated with improvement of upper limb motor strength and functional independence in patients with tetraplegia. Nerve transfer is a promising intervention feasible in both subacute and chronic SCI.

Document Type: Article
Publication Stage: Final
Source: Scopus

Normalization of cerebral hemodynamics after hematopoietic stem cell transplant in children with sickle cell disease” (2022) Blood

Normalization of cerebral hemodynamics after hematopoietic stem cell transplant in children with sickle cell disease
(2022) Blood, . 

Hulbert, M.L.a , Fields, M.E.a b , Guilliams, K.P.a b c , Bijlani, P.d , Shenoy, S.a , Fellah, S.c , Towerman, A.S.a , Binkley, M.M.e , McKinstry, R.C.c , Shimony, J.S.c , Chen, Y.c , Eldeniz, C.c , Ragan, D.K.f , Vo, K.c , An, H.c , Lee, J.-M.b c , Ford, A.L.b c

a Department, of Pediatrics, Washington University in St. Louis, St. Louis, MO
b Department of Neurology, Washington University in St. Louis, St. Louis, MO
c Mallinckrodt Institute of Radiology, Washington University in St. Louis, St. Louis, MO
d Department of Internal Medicine, University of California San Diego, San Diego, CA
e CNS Consultants, LLC, St. Louis, MO
f Department of Radiology, Medical College of Wisconsin, Milwaukee, WI, United States

Abstract
Children with sickle cell disease (SCD) demonstrate cerebral hemodynamic stress and are at high risk of strokes. We hypothesized that curative hematopoietic stem cell transplant (HSCT) normalizes cerebral hemodynamics in children with SCD compared with pre-transplant baseline. Whole-brain cerebral blood flow (CBF) and oxygen extraction fraction (OEF) were measured by magnetic resonance imaging 1 to 3 months before and 12 to 24 months after HSCT in 10 children with SCD. Three children had prior overt strokes, 5 children had prior silent strokes, and 1 child had abnormal transcranial Doppler ultrasound velocities. CBF and OEF of HSCT recipients were compared with non-SCD control participants and with SCD participants receiving chronic red blood cell transfusion therapy (CRTT) before and after a scheduled transfusion. Seven participants received matched sibling donor HSCT, and 3 participants received 8 out of 8 matched unrelated donor HSCT. All received reduced-intensity preparation and maintained engraftment, free of hemolytic anemia and SCD symptoms. Pre-transplant, CBF (93.5 mL/100 g/min) and OEF (36.8%) were elevated compared with non-SCD control participants, declining significantly 1 to 2 years after HSCT (CBF, 72.7 mL/100 g per minute; P = .004; OEF, 27.0%; P = .002), with post-HSCT CBF and OEF similar to non-SCD control participants. Furthermore, HSCT recipients demonstrated greater reduction in CBF (−19.4 mL/100 g/min) and OEF (−8.1%) after HSCT than children with SCD receiving CRTT after a scheduled transfusion (CBF, −0.9 mL/100 g/min; P = .024; OEF, −3.3%; P = .001). Curative HSCT normalizes whole-brain hemodynamics in children with SCD. This restoration of cerebral oxygen reserve may explain stroke protection after HSCT in this high-risk patient population. © 2022 The American Society of Hematology

Funding details
National Institutes of HealthNIHK23HL136904, K23NS099472, R01HL129241, R01HL157188
Washington University School of Medicine in St. LouisWUSM

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

Differential roles of Aβ42/40, p-tau231 and p-tau217 for Alzheimer’s trial selection and disease monitoring” (2022) Nature Medicine

Differential roles of Aβ42/40, p-tau231 and p-tau217 for Alzheimer’s trial selection and disease monitoring
(2022) Nature Medicine, . 

Ashton, N.J.a b c d , Janelidze, S.e , Mattsson-Carlgren, N.e f g , Binette, A.P.e , Strandberg, O.e , Brum, W.S.a h , Karikari, T.K.a i , González-Ortiz, F.a , Di Molfetta, G.a , Meda, F.J.a , Jonaitis, E.M.j k , Koscik, R.L.j k , Cody, K.j k , Betthauser, T.J.j k , Li, Y.l m , Vanmechelen, E.n , Palmqvist, S.e o , Stomrud, E.e o , Bateman, R.J.l m , Zetterberg, H.a p q r s , Johnson, S.C.j k , Blennow, K.a n , Hansson, O.e o

a Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, the Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden
b King’s College London, Institute of Psychiatry, Psychology and Neuroscience, Maurice Wohl Institute Clinical Neuroscience Institute, London, United Kingdom
c NIHR Biomedical Research Centre for Mental Health and Biomedical Research Unit for Dementia at South London and Maudsley NHS Foundation, London, United Kingdom
d Centre for Age-Related Medicine, Stavanger University Hospital, Stavanger, Norway
e Clinical Memory Research Unit, Faculty of Medicine, Lund University, Lund, Sweden
f Department of Neurology, Skåne University Hospital, Lund University, Lund, Sweden
g Wallenberg Center for Molecular Medicine, Lund University, Lund, Sweden
h Graduate Program in Biological Sciences: Biochemistry, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, Brazil
i Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA, United States
j Wisconsin Alzheimer’s Institute, School of Medicine and Public Health, University of Wisconsin, Madison, WI, United States
k Wisconsin Alzheimer’s Disease Research Center, School of Medicine and Public Health, University of Wisconsin, Madison, WI, United States
l Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States
m SILQ Center, Washington University School of Medicine, St. Louis, MO, United States
n ADx NeuroSciences, Technologiepark 94, Ghent, Belgium
o Memory Clinic, Skåne University Hospital, Malmö, Sweden
p Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden
q Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen Square, London, United Kingdom
r UK Dementia Research Institute at UCL, London, United Kingdom
s Hong Kong Center for Neurodegenerative Diseases, Hong Kong

Abstract
Blood biomarkers indicative of Alzheimer’s disease (AD) pathology are altered in both preclinical and symptomatic stages of the disease. Distinctive biomarkers may be optimal for the identification of AD pathology or monitoring of disease progression. Blood biomarkers that correlate with changes in cognition and atrophy during the course of the disease could be used in clinical trials to identify successful interventions and thereby accelerate the development of efficient therapies. When disease-modifying treatments become approved for use, efficient blood-based biomarkers might also inform on treatment implementation and management in clinical practice. In the BioFINDER-1 cohort, plasma phosphorylated (p)-tau231 and amyloid-β42/40 ratio were more changed at lower thresholds of amyloid pathology. Longitudinally, however, only p-tau217 demonstrated marked amyloid-dependent changes over 4–6 years in both preclinical and symptomatic stages of the disease, with no such changes observed in p-tau231, p-tau181, amyloid-β42/40, glial acidic fibrillary protein or neurofilament light. Only longitudinal increases of p-tau217 were also associated with clinical deterioration and brain atrophy in preclinical AD. The selective longitudinal increase of p-tau217 and its associations with cognitive decline and atrophy was confirmed in an independent cohort (Wisconsin Registry for Alzheimer’s Prevention). These findings support the differential association of plasma biomarkers with disease development and strongly highlight p-tau217 as a surrogate marker of disease progression in preclinical and prodromal AD, with impact for the development of new disease-modifying treatments. © 2022, The Author(s).

Funding details
ALFGBG-715986, ALFGBG-965240
JPND2019-466-236
1280/20
2020-0314
ALFGBG-720931
2018-Projekt0054, 2018-Projekt0279, AG021155, AG027161
2019
National Institutes of HealthNIH2016-00906, 2021-02219
Alzheimer’s AssociationAAADSF-21-831376-C, ADSF-21-831377-C, ADSF-21-831381-C, ZEN-21-848495
Alzheimer’s Drug Discovery FoundationADDF1R01AG068398-01, 201809-2016862, RDAPB-201809-2016615
Familjen Erling-Perssons Stiftelse
Horizon 2020 Framework ProgrammeH2020
H2020 Marie Skłodowska-Curie ActionsMSCA860197
Stiftelsen för Gamla Tjänarinnor2019-00845, ALZ2022-0006, FO2017-0243, FO2019-0228
European Research CouncilERC681712
Brain FoundationFO2020-0271
Lunds UniversitetAF-930655, AF-939932, AF-968453
HjärnfondenFO2019-0029, FO2020-0275, FO2021-0293
Knut och Alice Wallenbergs Stiftelse2017-0383
VetenskapsrådetVR2017-00915, 2018-02052, 2018-02532
Konung Gustaf V:s och Drottning Victorias Frimurarestiftelse
AlzheimerfondenAF-930351, AF-939721, AF-940046, AF-968270
Region Skåne
Marcus och Amalia Wallenbergs minnesfondMAW2015.0125
UK Dementia Research InstituteUK DRI
University Hospital FoundationUHF2020-O000028
Olav Thon Stiftelsen
Stiftelsen Bundy Academy

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

Characterization of the Targeting Accuracy of a Neuronavigation-guided Transcranial FUS system in vitro, in vivo, and in silico” (2022) IEEE Transactions on Biomedical Engineering

Characterization of the Targeting Accuracy of a Neuronavigation-guided Transcranial FUS system in vitro, in vivo, and in silico
(2022) IEEE Transactions on Biomedical Engineering, pp. 1-11. 

Xu, L.a , Pacia, C.P.a , Gong, Y.a , Hu, Z.a , Chien, C.a , Yang, L.a , Gach, H.M.b , Hao, Y.c , Comron, H.c , Huang, J.c , Leuthardt, E.C.d , Chen, H.e

a Department of Biomedical Engineering, Washington University in St. Louis, St. Louis, MO, USA
b Department of Radiation Oncology, Department of Radiology, and the Department of Biomedical Engineering, Washington University in St. Louis, MO, USA
c Department of Radiation Oncology, Washington University School of Medicine, St. Louis, MO, USA
d Department of Neurosurgery, Department of Biomedical Engineering, Department of Neuroscience, Center for Innovation in Neuroscience and Technology, Washington University in St. Louis, MO, USA
e Department of Biomedical Engineering and the Department of Radiation Oncology, Washington University in St. Louis, MO, USA

Abstract
Focused ultrasound (FUS)-enabled liquid biopsy (sonobiopsy) is an emerging technique for the noninvasive and spatiotemporally controlled diagnosis of brain cancer by inducing blood-brain barrier (BBB) disruption to release brain tumor-specific biomarkers into the blood circulation. The feasibility, safety, and efficacy of sonobiopsy were demonstrated in both small and large animal models using magnetic resonance-guided FUS devices. However, the high cost and complex operation of magnetic resonance-guided FUS devices limit the future broad application of sonobiopsy in the clinic. In this study, a neuronavigation-guided sonobiopsy device is developed and its targeting accuracy is characterized <italic>in vitro</italic>, <italic>in vivo</italic>, and <italic>in silico</italic>. The sonobiopsy device integrated a commercially available neuronavigation system (BrainSight) with a nimble, lightweight FUS transducer. Its targeting accuracy was characterized <italic>in vitro</italic> in a water tank using a hydrophone. The performance of the device in BBB disruption was verified <italic>in vivo</italic> using a pig model, and the targeting accuracy was quantified by measuring the offset between the target and the actual locations of BBB opening. The feasibility of the FUS device in targeting glioblastoma (GBM) tumors was evaluated <italic>in silico</italic> using numerical simulation by the k-Wave toolbox in glioblastoma patients. It was found that the targeting accuracy of the neuronavigation-guided sonobiopsy device was 1.7 &#x00B1; 0.8 mm as measured in the water tank. The neuronavigation-guided FUS device successfully induced BBB disruption in pigs with a targeting accuracy of 3.3 &#x00B1; 1.4 mm. The targeting accuracy of the FUS transducer at the GBM tumor was 5.5 &#x00B1; 4.9 mm. Age, sex, and incident locations were found to be not correlated with the targeting accuracy in glioblastoma patients. This study demonstrated that the developed neuronavigation-guided FUS device could target the brain with a high spatial targeting accuracy, paving the foundation for its application in the clinic. IEEE

Author Keywords
Biomarkers;  blood-brain barrier;  Computed tomography;  Focused ultrasound;  glioblastoma;  Magnetic resonance imaging;  neuronavigation;  Storage tanks;  Target tracking;  targeting accuracy;  Transducers;  Tumors

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