Publications

Hope Center member publications

List of publications for the week of January 17, 2022

Constitutively active SARM1 variants that induce neuropathy are enriched in ALS patients” (2022) Molecular Neurodegeneration

Constitutively active SARM1 variants that induce neuropathy are enriched in ALS patients
(2022) Molecular Neurodegeneration, 17 (1), art. no. 1, . 

Bloom, A.J.a , Mao, X.a , Strickland, A.a , Sasaki, Y.a , Milbrandt, J.a , DiAntonio, A.b

a Needleman Center for Neurometabolism and Axonal Therapeutics and Department of Genetics, Washington University School of Medicine in Saint Louis, St. Louis, MO, United States
b Needleman Center for Neurometabolism and Axonal Therapeutics and Department of Developmental Biology, Washington University School of Medicine in Saint Louis, St. Louis, MO, United States

Abstract
Background: In response to injury, neurons activate a program of organized axon self-destruction initiated by the NAD+ hydrolase, SARM1. In healthy neurons SARM1 is autoinhibited, but single amino acid changes can abolish autoinhibition leading to constitutively active SARM1 enzymes that promote degeneration when expressed in cultured neurons. Methods: To investigate whether naturally occurring human variants might disrupt SARM1 autoinhibition and potentially contribute to risk for neurodegenerative disease, we assayed the enzymatic activity of all 42 rare SARM1 alleles identified among 8507 amyotrophic lateral sclerosis (ALS) patients and 9671 controls. We then intrathecally injected mice with virus expressing SARM1 constructs to test the capacity of an ALS-associated constitutively active SARM1 variant to promote neurodegeneration in vivo. Results: Twelve out of 42 SARM1 missense variants or small in-frame deletions assayed exhibit constitutive NADase activity, including more than half of those that are unique to the ALS patients or that occur in multiple patients. There is a > 5-fold enrichment of constitutively active variants among patients compared to controls. Expression of constitutively active ALS-associated SARM1 alleles in cultured dorsal root ganglion (DRG) neurons is pro-degenerative and cytotoxic. Intrathecal injection of an AAV expressing the common SARM1 reference allele is innocuous to mice, but a construct harboring SARM1V184G, the constitutively active variant found most frequently among the ALS patients, causes axon loss, motor dysfunction, and sustained neuroinflammation. Conclusions: These results implicate rare hypermorphic SARM1 alleles as candidate genetic risk factors for ALS and other neurodegenerative conditions. © 2022, The Author(s).

Author Keywords
ALS;  Axon;  Human genetics;  NAD;  Neurodegeneration;  Neuropathy;  SARM1

Funding details
National Institutes of HealthNIHR01NS087632, R01NS119812, R37NS065053, RF1AG013730

Document Type: Article
Publication Stage: Final
Source: Scopus

From karyotypes to precision genomics in 9p deletion and duplication syndromes” (2022) Human Genetics and Genomics Advances, 3 (1), art. no. 100081, . 

From karyotypes to precision genomics in 9p deletion and duplication syndromes
(2022) Human Genetics and Genomics Advances, 3 (1), art. no. 100081, . 

Sams, E.I.a , Ng, J.K.a , Tate, V.b , Claire Hou, Y.-C.c , Cao, Y.c , Antonacci-Fulton, L.d , Belhassan, K.c , Neidich, J.b c , Mitra, R.D.a d , Cole, F.S.b , Dickson, P.a b , Milbrandt, J.a d e , Turner, T.N.a

a Department of Genetics, Washington University School of Medicine, St. Louis, MO 63110, United States
b Edward Mallinckrodt Department of Pediatrics, Washington University School of Medicine, St. Louis, MO 63110, United States
c Department of Pathology & Immunology, 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
e Needleman Center for Neurometabolism and Axonal Therapeutics, St. Louis, MO, United States

Abstract
While 9p deletion and duplication syndromes have been studied for several years, small sample sizes and minimal high-resolution data have limited a comprehensive delineation of genotypic and phenotypic characteristics. In this study, we examined genetic data from 719 individuals in the worldwide 9p Network Cohort: a cohort seven to nine times larger than any previous study of 9p. Most breakpoints occur in bands 9p22 and 9p24, accounting for 35% and 38% of all breakpoints, respectively. Bands 9p11 and 9p12 have the fewest breakpoints, with each accounting for 0.6% of all breakpoints. The most common phenotype in 9p deletion and duplication syndromes is developmental delay, and we identified eight known neurodevelopmental disorder genes in 9p22 and 9p24. Since it has been previously reported that some individuals have a secondary structural variant related to the 9p variant, we examined our cohort for these variants and found 97 events. The top secondary variant involved 9q in 14 individuals (1.9%), including ring chromosomes and inversions. We identified a gender bias with significant enrichment for females (p = 0.0006) that may arise from a sex reversal in some individuals with 9p deletions. Genes on 9p were characterized regarding function, constraint metrics, and protein-protein interactions, resulting in a prioritized set of genes for further study. Finally, we achieved precision genomics in one child with a complex 9p structural variation using modern genomic technologies, demonstrating that long-read sequencing will be integral for some cases. Our study is the largest ever on 9p-related syndromes and provides key insights into genetic factors involved in these syndromes. © 2021 The Author(s)

Author Keywords
9p;  CNV;  deletion;  developmental;  duplication;  neurodevelopmental;  phenotype;  syndrome

Funding details
National Institutes of HealthNIH201102181, 201706062, P50HD103525, R00MH117165

Document Type: Article
Publication Stage: Final
Source: Scopus

Diffusion Tensor MRI Structural Connectivity and PET Amyloid Burden in Preclinical Autosomal Dominant Alzheimer Disease: The DIAN Cohort” (2022) Radiology, 302 (1), pp. 143-150. Cited 1 time.

Diffusion Tensor MRI Structural Connectivity and PET Amyloid Burden in Preclinical Autosomal Dominant Alzheimer Disease: The DIAN Cohort
(2022) Radiology, 302 (1), pp. 143-150. Cited 1 time.

Prescott, J.W.a b , Doraiswamy, P.M.c , Gamberger, D.d , Benzinger, T.e , Petrella, J.R.b , the Dominantly Inherited Alzheimer Networkf

a The Department of Radiology, The MetroHealth System, 2500 MetroHealth Dr, Cleveland, OH 44109, United States
b Department of Radiology, Duke University Medical Center, Durham, NC, United States
c Department of Psychiatry, Duke University Medical Center, Durham, NC, United States
d Ruder Boškovic Institute, Zagreb, Croatia
e Mallinckrodt Institute of Radiology, Washington University School of Medicine, St Louis, MO, United States

Abstract
Background: Pathologic evidence of Alzheimer disease (AD) is detectable years before onset of clinical symptoms. Imaging-based identification of structural changes of the brain in people at genetic risk for early-onset AD may provide insights into how genes influence the pathologic cascade that leads to dementia. Purpose: To assess structural connectivity differences in cortical networks between cognitively normal autosomal dominant Alzheimer disease (ADAD) mutation carriers versus noncarriers and to determine the cross-sectional relationship of structural connectivity and cortical amyloid burden with estimated years to symptom onset (EYO) of dementia in carriers. Materials and Methods: In this exploratory analysis of a prospective trial, all participants enrolled in the Dominantly Inherited Alzheimer Network between January 2009 and July 2014 who had normal cognition at baseline, T1-weighted MRI scans, and diffusion tensor imaging (DTI) were analyzed. Amyloid PET imaging using Pittsburgh compound B was also analyzed for mutation carriers. Areas of the cerebral cortex were parcellated into three cortical networks: the default mode network, frontoparietal control network, and ventral attention network. The structural connectivity of the three networks was calculated from DTI. General linear models were used to examine differences in structural connectivity between mutation carriers and noncarriers and the relationship between structural connectivity, amyloid burden, and EYO in mutation carriers. Correlation network analysis was performed to identify clusters of related clinical and imaging markers. Results: There were 30 mutation carriers (mean age ± standard deviation, 34 years ± 10; 17 women) and 38 noncarriers (mean age, 37 years ± 10; 20 women). There was lower structural connectivity in the frontoparietal control network in mutation carriers compared with noncarriers (estimated effect of mutation-positive status, 20.0266; P = .04). Among mutation carriers, there was a correlation between EYO and white matter structural connectivity in the frontoparietal control network (estimated effect of EYO, 20.0015, P = .01). There was no significant relationship between cortical global amyloid burden and EYO among mutation carriers (P > .05). Conclusion: White matter structural connectivity was lower in autosomal dominant Alzheimer disease mutation carriers compared with noncarriers and correlated with estimated years to symptom onset. © RSNA, 2021.

Funding details
National Institute on AgingNIA
Japan Agency for Medical Research and DevelopmentAMED
Korea Health Industry Development InstituteKHIDI

Document Type: Article
Publication Stage: Final
Source: Scopus

Cognitive Phenotypes of HIV Defined Using a Novel Data-driven Approach” (2022) Journal of Neuroimmune Pharmacology, . 

Cognitive Phenotypes of HIV Defined Using a Novel Data-driven Approach
(2022) Journal of Neuroimmune Pharmacology, . 

Paul, R.H.a b , Cho, K.b , Belden, A.b , Carrico, A.W.c , Martin, E.d , Bolzenius, J.b , Luckett, P.e , Cooley, S.A.e , Mannarino, J.b , Gilman, J.M.f , Miano, M.g , Ances, B.M.e

a Department of Psychological Sciences, University of Missouri Saint Louis, Saint Louis, MO, United States
b Missouri Institute of Mental Health, University of Missouri Saint Louis, Saint Louis, MO, United States
c Department of Public Health, University of Miami School of Medicine, Coral Gables, FL, United States
d Department of Psychiatry, Rush University School of Medicine, Chicago, IL, United States
e Department of Neurology, Washington University, Saint Louis, MO, United States
f Center for Addiction Medicine, Harvard Medical School/Massachusetts General Hospital, Boston, MA, United States
g Department of Communication Sciences and Disorders, Northern Arizona University, Flagstaff, AZ, United States

Abstract
The current study applied data-driven methods to identify and explain novel cognitive phenotypes of HIV. Methods: 388 people with HIV (PWH) with an average age of 46 (15.8) and median plasma CD4+ T-cell count of 555 copies/mL (79% virally suppressed) underwent cognitive testing and 3T neuroimaging. Demographics, HIV disease variables, and health comorbidities were recorded within three months of cognitive testing/neuroimaging. Hierarchical clustering was employed to identify cognitive phenotypes followed by ensemble machine learning to delineate the features that determined membership in the cognitive phenotypes. Hierarchical clustering identified five cognitive phenotypes. Cluster 1 (n=97) was comprised of individuals with normative performance on all cognitive tests. The remaining clusters were defined by impairment on action fluency (Cluster 2; n=46); verbal learning/memory (Cluster 3; n=73); action fluency and verbal learning/memory (Cluster 4; n=56); and action fluency, verbal learning/memory, and tests of executive function (Cluster 5; n=114). HIV detectability was most common in Cluster 5. Machine learning revealed that polysubstance use, race, educational attainment, and volumes of the precuneus, cingulate, nucleus accumbens, and thalamus differentiated membership in the normal vs. impaired clusters. The determinants of persistent cognitive impairment among PWH receiving suppressive treatment are multifactorial nature. Viral replication after ART plays a role in the causal pathway, but psychosocial factors (race inequities, substance use) merit increased attention as critical determinants of cognitive impairment in the context of ART. Results underscore the need for comprehensive person-centered interventions that go beyond adherence to patient care to achieve optimal cognitive health among PWH. Graphic Abstract: [Figure not available: see fulltext.] © 2022, The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.

Author Keywords
Cognition;  HIV;  Machine learning;  Substance use

Funding details
National Institute of Mental HealthNIMHK23MH08175, R01MH118031
National Institute on Drug AbuseNIDAR01DA054009, R01MH113560
National Institute of Nursing ResearchNINRR01NR012657, R01NR012907, R01NR014449, R01NR015738

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

Hyperexcitability of Sensory Neurons in Fragile X Mouse Model” (2021) Frontiers in Molecular Neuroscience, 14, art. no. 796053, . 

Hyperexcitability of Sensory Neurons in Fragile X Mouse Model
(2021) Frontiers in Molecular Neuroscience, 14, art. no. 796053, . 

Deng, P.-Y.a , Avraham, O.b , Cavalli, V.b c d , Klyachko, V.A.a c

a Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, MO, United States
b Department of Neuroscience, Washington University School of Medicine, St. Louis, MO, United States
c Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO, United States
d Center of Regenerative Medicine, Washington University School of Medicine, St. Louis, MO, United States

Abstract
Sensory hypersensitivity and somatosensory deficits represent the core symptoms of Fragile X syndrome (FXS). These alterations are believed to arise from changes in cortical sensory processing, while potential deficits in the function of peripheral sensory neurons residing in dorsal root ganglia remain unexplored. We found that peripheral sensory neurons exhibit pronounced hyperexcitability in Fmr1 KO mice, manifested by markedly increased action potential (AP) firing rate and decreased threshold. Unlike excitability changes found in many central neurons, no significant changes were observed in AP rising and falling time, peak potential, amplitude, or duration. Sensory neuron hyperexcitability was caused primarily by increased input resistance, without changes in cell capacitance or resting membrane potential. Analyses of the underlying mechanisms revealed reduced activity of HCN channels and reduced expression of HCN1 and HCN4 in Fmr1 KO compared to WT. A selective HCN channel blocker abolished differences in all measures of sensory neuron excitability between WT and Fmr1 KO neurons. These results reveal a hyperexcitable state of peripheral sensory neurons in Fmr1 KO mice caused by dysfunction of HCN channels. In addition to the intrinsic neuronal dysfunction, the accompanying paper examines deficits in sensory neuron association/communication with their enveloping satellite glial cells, suggesting contributions from both neuronal intrinsic and extrinsic mechanisms to sensory dysfunction in the FXS mouse model. Copyright © 2021 Deng, Avraham, Cavalli and Klyachko.

Author Keywords
action potential;  Fragile X syndrome;  HCN channel;  hyperexcitability;  sensory neuron

Funding details
National Institutes of HealthNIHR01 NS111719, R35 NS111596, R35 NS122260

Document Type: Article
Publication Stage: Final
Source: Scopus

A Proinflammatory Stimulus Disrupts Hippocampal Plasticity and Learning via Microglial Activation and 25-Hydroxycholesterol” (2021) The Journal of Neuroscience: The Official Journal of the Society for Neuroscience

A Proinflammatory Stimulus Disrupts Hippocampal Plasticity and Learning via Microglial Activation and 25-Hydroxycholesterol
(2021) The Journal of Neuroscience: The Official Journal of the Society for Neuroscience, 41 (49), pp. 10054-10064. 

Izumi, Y.a , Cashikar, A.G.a b , Krishnan, K.c , Paul, S.M.a b , Covey, D.F.a b c , Mennerick, S.J.a b , Zorumski, C.F.a d

a Taylor Family Institute for Innovative Psychiatric Research, Washington University School of Medicine in St. Louis, St. Louis, Missouri 63110-1093, United States
b Department of Psychiatry, Washington University School of Medicine in St. Louis, St. Louis, Missouri 63110-1010, United States
c Department of Developmental Biology, Washington University School of Medicine in St. Louis, St. Louis, MO 63110, United States
d Department of Psychiatry, Washington University School of Medicine in St. Louis, St. Louis, Missouri 63110-1010, United States

Abstract
Inflammatory cells, including macrophages and microglia, synthesize and release the oxysterol 25-hydroxycholesterol (25HC), which has antiviral and immunomodulatory properties. Here, we examined the effects of lipopolysaccharide (LPS), an activator of innate immunity, on 25HC production in microglia, and the effects of LPS and 25HC on CA1 hippocampal synaptic plasticity and learning. In primary microglia, LPS markedly increases the expression of cholesterol 25-hydroxylase (Ch25h), the key enzyme involved in 25HC synthesis, and increases the levels of secreted 25HC. Wild-type microglia produced higher levels of 25HC than Ch25h knock-out (KO) microglia with or without LPS. LPS treatment also disrupts long-term potentiation (LTP) in hippocampal slices via induction of a form of NMDA receptor-dependent metaplasticity. The inhibitory effects of LPS on LTP were mimicked by exogenous 25HC, and were not observed in slices from Ch25h KO mice. In vivo, LPS treatment also disrupts LTP and inhibits one-trial learning in wild-type mice, but not Ch25h KO mice. These results demonstrate that the oxysterol 25HC is a key modulator of synaptic plasticity and memory under proinflammatory stimuli.SIGNIFICANCE STATEMENT Neuroinflammation is thought to contribute to cognitive impairment in multiple neuropsychiatric illnesses. In this study, we found that a proinflammatory stimulus, LPS, disrupts hippocampal LTP via a metaplastic mechanism. The effects of LPS on LTP are mimicked by the oxysterol 25-hydroxycholesterol (25HC), an immune mediator synthesized in brain microglia. Effects of LPS on both synaptic plasticity and one-trial inhibitory avoidance learning are eliminated in mice deficient in Ch25h (cholesterol 25-hydroxylase), the primary enzyme responsible for endogenous 25HC synthesis. Thus, these results indicate that 25HC is a key mediator of the effects of an inflammatory stimulus on hippocampal function and open new potential avenues to overcome the effects of neuroinflammation on brain function. Copyright © 2021 the authors.

Author Keywords
lipopolysaccharide;  long-term potentiation;  memory;  metaplasticity;  neurosteroids;  oxysterols

Document Type: Article
Publication Stage: Final
Source: Scopus

A deep learning framework identifies dimensional representations of Alzheimer’s Disease from brain structure” (2021) Nature Communications

A deep learning framework identifies dimensional representations of Alzheimer’s Disease from brain structure
(2021) Nature Communications, 12 (1), p. 7065. 

Yang, Z.a b , Nasrallah, I.M.a c , Shou, H.a d , Wen, J.a c , Doshi, J.a c , Habes, M.a e , Erus, G.a c , Abdulkadir, A.a c , Resnick, S.M.f , Albert, M.S.g , Maruff, P.h , Fripp, J.i , Morris, J.C.j , Wolk, D.A.a k l , Davatzikos, C.a c , iSTAGING Consortiumm , Baltimore Longitudinal Study of Aging (BLSA)n , Alzheimer’s Disease Neuroimaging Initiative (ADNI)o

a Center for Biomedical Image Computing and Analytics, University of Pennsylvania, PA, Philadelphia, United States
b Graduate Group in Applied Mathematics and Computational Science, University of Pennsylvania, PA, Philadelphia, United States
c Department of Radiology, University of Pennsylvania, PA, Philadelphia, United States
d Department of Biostatistics, Epidemiology and Informatics, University of Pennsylvania, PA, Philadelphia, United States
e Neuroimage Analytics Laboratory (NAL) and the Biggs Institute Neuroimaging Core (BINC), Glenn Biggs Institute for Alzheimer’s & Neurodegenerative Diseases, University of Texas Health Science Center San Antonio (UTHSCSA), TX, San Antonio, United States
f Laboratory of Behavioral Neuroscience, National Institute on Aging, MD, Baltimore, United States
g Department of Neurology, Johns Hopkins University School of Medicine, MD, Baltimore, United States
h Florey Institute of Neuroscience and Mental Health, University of Melbourne, Melbourne, VIC, Australia
i CSIRO Health and Biosecurity, Australian e-Health Research Centre CSIRO, Brisbane, QLD, Australia
j Knight Alzheimer Disease Research Center, Washington University in St. Louis, St. Louis, MO, USA
k Alzheimer’s Disease Research Center, University of Pennsylvania, PA, Philadelphia, United States
l Department of Neurology, University of Pennsylvania, PA, Philadelphia, United States

Abstract
Heterogeneity of brain diseases is a challenge for precision diagnosis/prognosis. We describe and validate Smile-GAN (SeMI-supervised cLustEring-Generative Adversarial Network), a semi-supervised deep-clustering method, which examines neuroanatomical heterogeneity contrasted against normal brain structure, to identify disease subtypes through neuroimaging signatures. When applied to regional volumes derived from T1-weighted MRI (two studies; 2,832 participants; 8,146 scans) including cognitively normal individuals and those with cognitive impairment and dementia, Smile-GAN identified four patterns or axes of neurodegeneration. Applying this framework to longitudinal data revealed two distinct progression pathways. Measures of expression of these patterns predicted the pathway and rate of future neurodegeneration. Pattern expression offered complementary performance to amyloid/tau in predicting clinical progression. These deep-learning derived biomarkers offer potential for precision diagnostics and targeted clinical trial recruitment. © 2021. The Author(s).

Document Type: Article
Publication Stage: Final
Source: Scopus

BNP facilitates NMB-encoded histaminergic itch via NPRC-NMBR crosstalk” (2021) eLife

BNP facilitates NMB-encoded histaminergic itch via NPRC-NMBR crosstalk
(2021) eLife, 10, art. no. e70151, . 

Meng, Q.-T.a g , Liu, X.-Y.a b , Liu, X.-T.a e , Liu, J.a b , Munanairi, A.a b , Barry, D.M.a b , Liu, B.a b , Jin, H.a b h , Sun, Y.a i , Yang, Q.a b , Gao, F.a b , Wan, L.a f , Peng, J.a b , Jin, J.-H.a j , Shen, K.-F.a k , Kim, R.a l , Yin, J.a b , Tao, A.a e , Chen, Z.-F.a b c d e

a Center for the Study of Itch and Sensory Disorders, Washington University School of Medicine, St. Louis, MO 63110, United States
b Department of Anesthesiology, Washington University School of Medicine, St. Louis, MO 63110, United States
c Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, United States
d Department of Psychiatry, Washington University School of Medicine, St. Louis, MO 63110, United States
e Department of Developmental Biology The Second Affiliated Hospital The State Key Laboratory of Respiratory Disease, Guangdong Provincial Key Laboratory of Allergy and Clinical Immunology, Guangzhou Medical University, Guangzhou, China
f Department of Pain, Guangzhou Medical University, Guangzhou-Guangdong, 510260, China
g Department of Anesthesiology, Renmin Hospital of Wuhan University, Wuhan-Hubei, 430060, China
h The First Hospital of Yunnan Province, Kunming-Yunnan, 650031, China
i Department of Anesthesiology, Shanghai Ninth People’s Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, 200011, China
j Department of Anesthesiology, Chinese Academy of Medical Sciences Plastic Surgery Hospital, Beijing, 100144, China
k Department of Neurosurgery, Xinqiao Hospital, Third Military Medical University, Chongqing, 400037, China
l Department of Genetics, Yale University School of Medicine, New Haven, CT 06511, United States

Abstract
Histamine-dependent and independent itch is conveyed by parallel peripheral neural pathways that express gastrin-releasing peptide (GRP) and neuromedin B (NMB), respectively, to the spinal cord of mice. B-type natriuretic peptide (BNP) has been proposed to transmit both types of itch via its receptor NPRA encoded by Npr1However, BNP also binds to its cognate receptor, NPRC encoded by Npr3 with equal potency. Moreover, natriuretic peptides (NP) signal through the Gi-couped inhibitory cGMP pathway that is supposed to inhibit neuronal activity, raising the question of how BNP may transmit itch information. Here we report that Npr3 expression in laminae I-II of the dorsal horn partially overlaps with NMB receptor (NMBR) that transmits histaminergic itch via Gq-couped PLCβ-Ca2+signaling pathway. Functional studies indicate that NPRC is required for itch evoked by histamine but not chloroquine (CQ), a nonhistaminergic pruritogen. Importantly, BNP significantly facilitates scratching behaviors mediated by NMB, but not GRP. Consistently, BNP evoked Ca2+responses in NMBR/NPRC HEK 293 cells and NMBR/NPRC dorsal horn neurons. These results reveal a previously unknown mechanism by which BNP facilitates NMB-encoded itch through a novel NPRC-NMBR cross-signaling in mice. Our studies uncover distinct modes of action for neuropeptides in transmission and modulation of itch in mice. © 2021, eLife Sciences Publications Ltd. All rights reserved.

Author Keywords
BNP;  Chloroquine;  GRP;  Histamine;  Itch;  NMB;  NPRA;  NPRC;  Spinal cord

Funding details
National Institutes of HealthNIHR01, R01 DA037261-01A1, R01NS094344, R01NS113938-01A1
National Natural Science Foundation of ChinaNSFC82171764
Guangzhou Municipal Science and Technology Project202102010104

Document Type: Article
Publication Stage: Final
Source: Scopus

C-X-C Chemokine Receptor Type 4-Targeted Imaging in Glioblastoma Multiforme Using 64Cu-Radiolabeled Ultrasmall Gold Nanoclusters” (2021) ACS Applied Bio Materials

C-X-C Chemokine Receptor Type 4-Targeted Imaging in Glioblastoma Multiforme Using 64Cu-Radiolabeled Ultrasmall Gold Nanoclusters
(2021) ACS Applied Bio Materials, . 

Zhang, X.a , Detering, L.a , Sultan, D.a , Heo, G.S.a , Luehmann, H.a , Taylor, S.b c , Choksi, A.d , Rubin, J.B.b c , Liu, Y.a

a Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, MO 63110, United States
b Department of Pediatrics, Washington University School of Medicine, St. Louis, MO 63110, United States
c Department of Neuroscience, Washington University School of Medicine, St. Louis, MO 63110, United States
d School of Medicine, University of Maryland, Baltimore, MD 21201, United States

Abstract
Glioblastoma multiforme (GBM) is the most prevalent and aggressive primary malignant brain cancer in adults, and it carries a poor prognosis. Despite the current multimodality treatment, including surgery, radiation, and chemotherapy, the overall survival is still poor. Neurooncological imaging plays an important role in the initial diagnosis and prediction of the treatment response of GBM. Positron emission tomography (PET) imaging using radiotracers that target disease-specific hallmarks, which are both noninvasive and specific, has drawn much attention. C-X-C chemokine receptor 4 (CXCR4) plays an important role in neoangiogenesis and vasculogenesis, and, moreover, it is reported to be overexpressed in GBM, which is associated with poor patient survival; thus, CXCR4 can be an ideal candidate for PET imaging of GBM. Nanomaterials, which possess multifunctional capabilities, effective drug delivery, and favorable pharmacokinetics, are now being applied to improve the diagnosis and therapy of the most difficult-to-treat cancers. Herein, we engineered an ultrasmall, renal-clearable gold nanoclusters intrinsically radiolabeled with 64Cu (64Cu-AuNCs-FC131) for targeted PET imaging of CXCR4 in a U87 intracranial GBM mouse model. These targeted nanoclusters demonstrated specific binding to U87 cells with minimal cytotoxicity. The in vivo biodistribution showed favorable pharmacokinetics and efficient renal clearance. PET/computed tomography imaging of the U87 model revealed the effective delivery of 64Cu-AuNCs-FC131 into the tumors. In vivo toxicity studies demonstrated insignificant safety concerns at various dosages, indicating its potential as a useful platform for GBM imaging and drug delivery. © 2021 American Chemical Society.

Author Keywords
C-X-C chemokine receptor type4;  FC131 peptide;  glioblastoma multiforme;  nanoclusters;  positron emission tomography

Funding details
MC-II-2017-661

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