Solutes unmask differences in clustering versus phase separation of FET proteins
(2024) Nature Communications, 15 (1), art. no. 4408, .
Kar, M.a , Vogel, L.T.b , Chauhan, G.c , Felekyan, S.b , Ausserwöger, H.d , Welsh, T.J.d , Dar, F.c , Kamath, A.R.a , Knowles, T.P.J.d , Hyman, A.A.a , Seidel, C.A.M.b , Pappu, R.V.c
a Max Planck Institute of Cell Biology and Genetics, Dresden, 01307, Germany
b Department of Molecular Physical Chemistry, Heinrich Heine University, Düsseldorf, 40225, Germany
c Department of Biomedical Engineering and Center for Biomolecular Condensates, Washington University in St. Louis, St. Louis, MO 63130, United States
d Centre for Misfolding Diseases, Yusuf Hamied Department of Chemistry, University of Cambridge, Cambridge, CB2 1EW, United Kingdom
Abstract
Phase separation and percolation contribute to phase transitions of multivalent macromolecules. Contributions of percolation are evident through the viscoelasticity of condensates and through the formation of heterogeneous distributions of nano- and mesoscale pre-percolation clusters in sub-saturated solutions. Here, we show that clusters formed in sub-saturated solutions of FET (FUS-EWSR1-TAF15) proteins are affected differently by glutamate versus chloride. These differences on the nanoscale, gleaned using a suite of methods deployed across a wide range of protein concentrations, are prevalent and can be unmasked even though the driving forces for phase separation remain unchanged in glutamate versus chloride. Strikingly, differences in anion-mediated interactions that drive clustering saturate on the micron-scale. Beyond this length scale the system separates into coexisting phases. Overall, we find that sequence-encoded interactions, mediated by solution components, make synergistic and distinct contributions to the formation of pre-percolation clusters in sub-saturated solutions, and to the driving forces for phase separation. © The Author(s) 2024.
Funding details
Max-Planck-GesellschaftMPG
St. Jude Children’s Research Hospital
Technische Universität DresdenTUD
NOMIS Stiftung
Deutsche ForschungsgemeinschaftDFGEXC-2068—390729961
National Science FoundationNSFMCB-2227268
National Institutes of HealthNIHR01NS121114
Wellcome TrustWT209194/Z/17/Z, SPP2191
European Research CouncilERC337969
Document Type: Article
Publication Stage: Final
Source: Scopus
Use of computed tomography to identify muscle quality subgroups, spatial mapping, and preliminary relationships to function in those with diabetic peripheral neuropathy
(2024) Gait and Posture, 112, pp. 159-166.
Kaszyk, E.M.a , Commean, P.K.b , Meyer, G.A.a c d e f , Smith, G.a , Jeong, H.-J.a g h , York, A.a , Chen, L.i , Mueller, M.J.a , Zellers, J.A.a c , Hastings, M.K.a c
a Program in Physical Therapy, Washington University School of Medicine, St. Louis, MO, United States
b Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, MO, United States
c Department of Orthopaedic Surgery, Washington University in St. LouisMO, United States
d Center of Regenerative Medicine, Washington University in St. LouisMO, United States
e Department of Biomedical Engineering, Washington University in St. LouisMO, United States
f Department of Neurology, Washington University in St. Louis, St LouisMO, United States
g Orthopaedic and Rehabilitation Engineering Center, Marquette University, MilwaukeeWI, United States
h Department of Rehabilitation Sciences & Technology, University of Wisconsin-Milwaukee, Milwaukee, WI, United States
i Division of Biostatistics, Washington University School of Medicine, St. Louis, MO, United States
Abstract
Background: Decreased muscle volume and increased muscle-associated adipose tissue (MAAT, sum of intra and inter-muscular adipose tissue) of the foot intrinsic muscle compartment are associated with deformity, decreased function, and increased risk of ulceration and amputation in those with diabetic peripheral neuropathy (DPN). Research question: What is the muscle quality (normal, abnormal muscle, and adipose volumes) of the DPN foot intrinsic compartment, how does it change over time, and is muscle quality related to gait and foot function? Methods: Computed tomography was performed on the intrinsic foot muscle compartment of 45 subjects with DPN (mean age: 67.2 ± 6.4 years) at baseline and 3.6 years. Images were processed to obtain volumes of MAAT, highly abnormal, mildly abnormal, and normal muscle. For each category, annual rates of change were calculated. Paired t-tests compared baseline and follow-up. Foot function during gait was assessed using 3D motion analysis and the Foot and Ankle Ability Measure. Correlations between muscle compartment and foot function during gait were analyzed using Pearson’s correlations. Results: Total muscle volume decreased, driven by a loss of normal muscle and mildly abnormal muscle (p<0.05). MAAT and the adipose-muscle ratio increased. At baseline, 51.5% of the compartment was abnormal muscle or MAAT, increasing to 55.0% at follow-up. Decreased total muscle volume correlated with greater midfoot collapse during gait (r = −0.40, p = 0.02). Greater volumes of highly abnormal muscle correlated with a lower FAAM score (r = −0.33, p = 0.03). Significance: Muscle volume loss may progress in parallel with MAAT accumulation, impacting contractile performance in individuals with DPN. Only 48.5% of the DPN intrinsic foot muscle compartment consists of normal muscle and greater abnormal muscle is associated with worse foot function. These changes identify an important target for rehabilitative intervention to slow or prevent muscle deterioration and poor foot outcomes. © 2024 Elsevier B.V.
Author Keywords
Computed tomography; Diabetes; Muscle deterioration; Muscle quality; Peripheral neuropathy
Funding details
National Center for Advancing Translational SciencesNCATSUL1TR002345
National Center for Advancing Translational SciencesNCATS
National Institute of Arthritis and Musculoskeletal and Skin DiseasesNIAMSAR075773
National Institute of Arthritis and Musculoskeletal and Skin DiseasesNIAMS
National Institute on Disability, Independent Living, and Rehabilitation ResearchNIDILRR90ARHF0006
National Institute on Disability, Independent Living, and Rehabilitation ResearchNIDILRR
National Institute of Diabetes and Digestive and Kidney DiseasesNIDDKF32 DK1916, F32 DK123916
National Institute of Diabetes and Digestive and Kidney DiseasesNIDDK
National Institutes of HealthNIHR01-DK107809
National Institutes of HealthNIH
Document Type: Article
Publication Stage: Final
Source: Scopus
Disentangling factors contributing to individual differences and health disparities in chronic pain and whole person health with measures of allostatic load
(2024) Brain, Behavior, and Immunity – Health, 38, art. no. 100794, .
Mickle, A.M.a , Tanner, J.J.b , Antoine, L.H.c , Garvan, C.d , Lai, S.e , Przkora, R.d , Edberg, J.C.f , Staud, R.g , Redden, D.h , Goodin, B.R.i , Price, C.C.b , Fillingim, R.B.j , Sibille, K.T.a d
a Department of Physical Medicine & Rehabilitation, University of Florida, 101 Newell Dr, Gainesville, FL 32603, United States
b Department of Clinical and Health Psychology, University of Florida, 1225 Center Dr, Gainesville, FL 32603, United States
c Department of Psychology, University of Alabama at Birmingham, Campbell Hall 415, 1300 University Blvd, Birmingham, AL 35223, United States
d Department of Anesthesiology, Division of Pain Medicine, University of Florida, 1600 SW Archer Road, Gainesville, FL 32610, United States
e Department of Radiation Oncology & CTSI Human Imaging Core, University of Florida, 2004 Mowry Rd Gainesville, FL, Gainesville, FL 32610, United States
f Department of Immunology and Rheumatology, University of Alabama at Birmingham, 1720 2nd Ave South, Birmingham, AL 35294, United States
g Department of Medicine, University of Florida, PO Box 100277, Gainesville, FL, United States
h Department of Biostatistics, The University of Alabama at Birmingham, University Boulevard, Birmingham, AL 1665, United States
i Department of Anesthesiology, Washington University, St. Louis, MO, 660 S. Euclid Avenue, St. Louis, MO 63110, United States
j Department of Community of Dentistry, University of Florida, 1329 SW 16th St, Room 5180, Gainesville, FL 32610, United States
Funding details
University of AlabamaUA
National Institutes of HealthNIH
University of FloridaUF
National Institute on AgingNIAR37AG033906, R01AG054370
National Institute on AgingNIA
Diabetes Research CenterDRCP30DK079626
Diabetes Research CenterDRC
UL1TR001427, UL1TR000064, UL1TR001417
Center for Clinical and Translational Science, University of Alabama at BirminghamCCTSU54TR002731
Center for Clinical and Translational Science, University of Alabama at BirminghamCCTS
Document Type: Article
Publication Stage: Final
Source: Scopus
Predicting Driving Cessation Among Cognitively Normal Older Drivers: The Role of Alzheimer Disease Biomarkers and Clinical Assessments
(2024) Neurology, 102 (12), p. e209426.
Babulal, G.M., Chen, L., Murphy, S.A., Carr, D.B., Morris, J.C.
From the Department of Neurology (G.M.B., S.A.M., Division of Biostatistics (L.C.), Department of Medicine (D.B.C.), Washington University School of Medicine, St. Louis, MO, United States
Abstract
BACKGROUND AND OBJECTIVES: With the aging US population and increasing incidence of Alzheimer disease (AD), understanding factors contributing to driving cessation among older adults is crucial for clinicians. Driving is integral for maintaining independence and functional mobility, but the risk factors for driving cessation, particularly in the context of normal aging and preclinical AD, are not well understood. We studied a well-characterized community cohort to examine factors associated with driving cessation. METHODS: This prospective, longitudinal observation study enrolled participants from the Knight Alzheimer Disease Research Center and The DRIVES Project. Participants were enrolled if they were aged 65 years or older, drove weekly, and were cognitively normal (Clinical Dementia Rating [CDR] = 0) at baseline. Participants underwent annual clinical, neurologic, and neuropsychological assessments, including β-amyloid PET imaging and CSF (Aβ42, total tau [t-Tau], and phosphorylated tau [p-Tau]) collection every 2-3 years. The primary outcome was time from baseline visit to driving cessation, accounting for death as a competing risk. The cumulative incidence function of driving cessation was estimated for each biomarker. The Fine and Gray subdistribution hazard model was used to examine the association between time to driving cessation and biomarkers adjusting for clinical and demographic covariates. RESULTS: Among the 283 participants included in this study, there was a mean follow-up of 5.62 years. Driving cessation (8%) was associated with older age, female sex, progression to symptomatic AD (CDR ≥0.5), and poorer performance on a preclinical Alzheimer cognitive composite (PACC) score. Aβ PET imaging did not independently predict driving cessation, whereas CSF biomarkers, specifically t-Tau/Aβ42 (hazard ratio [HR] 2.82, 95% CI 1.23-6.44, p = 0.014) and p-Tau/Aβ42 (HR 2.91, 95% CI 1.28-6.59, p = 0.012) ratios, were independent predictors in the simple model adjusting for age, education, and sex. However, in the full model, progression to cognitive impairment based on the CDR and PACC score across each model was associated with a higher risk of driving cessation, whereas AD biomarkers were not statistically significant. DISCUSSION: Female sex, CDR progression, and neuropsychological measures of cognitive functioning obtained in the clinic were strongly associated with future driving cessation. The results emphasize the need for early planning and conversations about driving retirement in the context of cognitive decline and the immense value of clinical measures in determining functional outcomes.
Document Type: Article
Publication Stage: Final
Source: Scopus
Defining cis-regulatory elements and transcription factors that control human cortical interneuron development
(2024) iScience, 27 (6), art. no. 109967, .
Chapman, G., Determan, J., Jetter, H., Kaushik, K., Prakasam, R., Kroll, K.L.
Department of Developmental Biology, Washington University School of Medicine, St. Louis, MO 63110, United States
Abstract
Although human cortical interneurons (cINs) are a minority population in the cerebral cortex, disruption of interneuron development is a frequent contributor to neurodevelopmental disorders. Here, we utilized a model for deriving cINs from human embryonic stem cells to profile chromatin state changes and generate an atlas of cis-regulatory elements (CREs) controlling human cIN development. We used these data to define candidate transcription factors (TFs) that may bind these CREs to regulate interneuron progenitor specification. Among these were RFX3 and RFX4, risk genes for autism spectrum disorder (ASD) with uncharacterized roles in human neuronal development. Using RFX3 and RFX4 knockdown models, we demonstrated new requirements for both genes in interneuron progenitor specification, with RFX3 deficiency causing precocious neuronal differentiation while RFX4 deficiency instead resulted in cessation of progenitor cell proliferation. Together, this work both defined central features of cis-regulatory control and identified new TF requirements for human interneuron development. © 2024 The Author(s)
Author Keywords
Biological sciences; Developmental neuroscience; Epigenetics; Neuroscience
Funding details
West Virginia Clinical and Translational Science InstituteWVCTSI
Intellectual and Developmental Disabilities Research Center, School of Medicine, Washington University in St. LouisIDDRC
Children’s Discovery InstituteCDI
Simons FoundationSF
National Institutes of HealthNIHR01NS114551, R01MH124808, R01HD110556, P50HD103525
National Institutes of HealthNIH
Document Type: Article
Publication Stage: Final
Source: Scopus
Detecting recollection: Human evaluators can successfully assess the veracity of others’ memories
(2024) Proceedings of the National Academy of Sciences of the United States of America, 121 (22), art. no. e2310979121, .
Gamoran, A.a , Lieberman, L.b c , Gilead, M.d e , Dobbins, I.G.f , Sadeh, T.a b c
a Department of Psychology, Ben-Gurion University of the Negev, Beer Sheva, 8410501, Israel
b Department of Cognitive and Brain Sciences, Ben-Gurion University of the Negev, Beer Sheva, 8410501, Israel
c Zelman School of Brain Sciences and Cognition, Ben-Gurion University of the Negev, Beer Sheva, 8410501, Israel
d School of Psychological Sciences, Tel Aviv University, Tel Aviv, 6997801, Israel
e Sagol School of Neuroscience, Tel Aviv University, Tel Aviv, 6997801, Israel
f Department of Psychological and Brain Sciences, Washington University in Saint Louis, St. Louis, MO 63130, United States
Abstract
Humans have the highly adaptive ability to learn from others’ memories. However, because memories are prone to errors, in order for others’ memories to be a valuable source of information, we need to assess their veracity. Previous studies have shown that linguistic information conveyed in self-reported justifications can be used to train a machine-learner to distinguish true from false memories. But can humans also perform this task, and if so, do they do so in the same way the machine-learner does? Participants were presented with justifications corresponding to Hits and False Alarms and were asked to directly assess whether the witness’s recognition was correct or incorrect. In addition, participants assessed justifications’ recollective qualities: their vividness, specificity, and the degree of confidence they conveyed. Results show that human evaluators can discriminate Hits from False Alarms above chance levels, based on the justifications provided per item. Their performance was on par with the machine learner. Furthermore, through assessment of the perceived recollective qualities of justifications, participants were able to glean more information from the justifications than they used in their own direct decisions and than the machine learner did. Copyright © 2024 the Author(s). Published by PNAS.
Author Keywords
language; machine learning; memory justifications; recognition memory
Document Type: Article
Publication Stage: Final
Source: Scopus
Biobank-wide association scan identifies risk factors for late-onset Alzheimer’s disease and endophenotypes
(2024) eLife, 12, .
Yan, D.a , Hu, B.b , Darst, B.F.c , Mukherjee, S.d , Kunkle, B.W.e , Deming, Y.c , Dumitrescu, L.f , Wang, Y.a , Naj, A.g , Kuzma, A.g , Zhao, Y.g , Kang, H.b , Johnson, S.C.h i j , Carlos, C.k , Hohman, T.J.f , Crane, P.K.d , Engelman, C.D.c h j , Lu, Q.b l , Alzheimer’s Disease Genetics Consortium (ADGC)m
a University of Wisconsin-Madison, Madison, United States
b Department of Statistics, University of Wisconsin-Madison, Madison, United States
c Department of Population Health Sciences, University of Wisconsin-Madison, Madison, United States
d Division of General Internal Medicine, Department of Medicine, University of Washington, Seattle, United States
e University of Miami Miller School of Medicine, Miami, United States
f Vanderbilt Memory and Alzheimer’s Center, Vanderbilt University Medical Center, Vanderbilt University School of Medicine, Nashville, United States
g School of Medicine, University of Pennsylvania, Philadelphia, United States
h Wisconsin Alzheimer’s Institute, University of Wisconsin School of Medicine and Public Health, Madison, United States
i Geriatric Research Education and Clinical Center, Wm. S. Middleton Memorial VA Hospital, Madison, United States
j Alzheimer’s Disease Research Center, University of Wisconsin School of Medicine and Public Health, Madison, United States
k Department of Psychiatry, Washington University in St. Louis, St. Louis, United States
l Department of Biostatistics and Medical Informatics, University of Wisconsin-Madison, Madison, United States
Abstract
Rich data from large biobanks, coupled with increasingly accessible association statistics from genome-wide association studies (GWAS), provide great opportunities to dissect the complex relationships among human traits and diseases. We introduce BADGERS, a powerful method to perform polygenic score-based biobank-wide association scans. Compared to traditional approaches, BADGERS uses GWAS summary statistics as input and does not require multiple traits to be measured in the same cohort. We applied BADGERS to two independent datasets for late-onset Alzheimer’s disease (AD; n=61,212). Among 1738 traits in the UK biobank, we identified 48 significant associations for AD. Family history, high cholesterol, and numerous traits related to intelligence and education showed strong and independent associations with AD. Furthermore, we identified 41 significant associations for a variety of AD endophenotypes. While family history and high cholesterol were strongly associated with AD subgroups and pathologies, only intelligence and education-related traits predicted pre-clinical cognitive phenotypes. These results provide novel insights into the distinct biological processes underlying various risk factors for AD. © 2023, Yan, Hu et al.
Author Keywords
Alzheimer’s disease; genetics; genomics; GWAS; human; neuroscience; UK-biobank
Document Type: Article
Publication Stage: Final
Source: Scopus
Identification of 1,3,8-Triazaspiro[4.5]Decane-2,4-Dione Derivatives as a Novel δ Opioid Receptor-Selective Agonist Chemotype
(2024) The Journal of Pharmacology and Experimental Therapeutics, 389 (3), pp. 301-309.
Meqbil, Y.J.a , Aguilar, J.b , Blaine, A.T.b , Chen, L.b , Cassell, R.J.b , Pradhan, A.A.b , van Rijn, R.M.a
a Borch Department of Medicinal Chemistry and Molecular Pharmacology (Y.J.M., A.T.B., R.J.C., R.M.v.R.), Computational Interdisciplinary Graduate Programs, Computational Life Sciences (Y.J.M.), and Interdisciplinary Life Science-PULSe (A.T.B.), Purdue University, West Lafayette, Indiana; Purdue Institute for Integrative Neuroscience, West Lafayette, Indiana (R.M.v.R.); Purdue Institute for Drug Discovery, West Lafayette, Indiana (L.C., R.M.v.R.); Septerna Inc., South San Francisco, California (R.M.v.R.); and Center for Clinical Pharmacology, Department of Anesthesiology, Washington University School of Medicine, St. Louis, Missouri (J.A., A.A.P.) rvanrijn@septerna.com yazancompchem@gmail.com
b Borch Department of Medicinal Chemistry and Molecular Pharmacology (Y.J.M., A.T.B., R.J.C., R.M.v.R.), Computational Interdisciplinary Graduate Programs, Computational Life Sciences (Y.J.M.), and Interdisciplinary Life Science-PULSe (A.T.B.), Purdue University, West Lafayette, Indiana; Purdue Institute for Integrative Neuroscience, West Lafayette, Indiana (R.M.v.R.); Purdue Institute for Drug Discovery, West Lafayette, Indiana (L.C., R.M.v.R.); Septerna Inc., South San Francisco, California (R.M.v.R.); and Center for Clinical Pharmacology, Department of Anesthesiology, Washington University School of Medicine, St. Louis, Missouri (J.A., A.A.P.)
Abstract
δ opioid receptors (DORs) hold potential as a target for neurologic and psychiatric disorders, yet no DOR agonist has proven efficacious in critical phase II clinical trials. The exact reasons for the failure to produce quality drug candidates for the DOR are unclear. However, it is known that certain DOR agonists can induce seizures and exhibit tachyphylaxis. Several studies have suggested that those adverse effects are more prevalent in delta agonists that share the (+)-4-[(αR)-α-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-methoxybenzyl]-N,N-diethylbenzamide (SNC80)/4-[(αR*)-α-((2S*,5R*)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl]-N,N-diethylbenzamide chemotype. There is a need to find novel lead candidates for drug development that have improved pharmacological properties to differentiate them from the current failed delta agonists. Our objective in this study was to identify novel DOR agonists. We used a β-arrestin assay to screen a small G-protein coupled receptors (GPCR)-focused chemical library. We identified a novel chemotype of DOR agonists that appears to bind to the orthosteric site based of docking and molecular dynamic simulation. The most potent agonist hit compound is selective for the DOR over a panel of 167 other GPCRs, is slightly biased toward G-protein signaling and has anti-allodynic efficacy in a complete Freund’s adjuvant model of inflammatory pain in C57BL/6 male and female mice. The newly discovered chemotype contrasts with molecules like SNC80 that are highly efficacious β-arrestin recruiters and may suggest this novel class of DOR agonists could be expanded on to develop a clinical candidate drug. SIGNIFICANCE STATEMENT: δ opioid receptors are a clinical target for various neurological disorders, including migraine and chronic pain. Many of the clinically tested delta opioid agonists share a single chemotype, which carries risks during drug development. Through a small-scale high-throughput screening assay, this study identified a novel δ opioid receptor agonist chemotype, which may serve as alternative for the current analgesic clinical candidates. Copyright © 2024 by The American Society for Pharmacology and Experimental Therapeutics.
Document Type: Article
Publication Stage: Final
Source: Scopus
Exercise Influences the Brain’s Metabolic Response to Chronic Cocaine Exposure in Male Rats
(2024) Journal of Personalized Medicine, 14 (5), art. no. 500, .
Powell, A.a , Hanna, C.a , Sajjad, M.b , Yao, R.b , Blum, K.c d , Gold, M.S.e , Quattrin, T.f , Thanos, P.K.a d
a Behavioral Neuropharmacology and Neuroimaging Laboratory on Addictions, Department of Pharmacology and Toxicology, Clinical Research Institute on Addictions, Jacobs School of Medicine and Biomedical Science, State University of New York at Buffalo, Buffalo, NY 14203, United States
b Department of Nuclear Medicine, University at Buffalo, Buffalo, NY 14214, United States
c Center for Sports, Exercise, and Mental Health, Western University of Health Sciences, Pomona, CA 91766, United States
d Department of Molecular Biology, Adelson School of Medicine, Ariel University, Ariel, 40700, Israel
e Department of Psychiatry, Washington University School of Medicine, St. Louis, MO 63110, United States
f UBMD Pediatrics, JR Oishei Children’s Hospital, University at Buffalo, Buffalo, NY 14203, United States
Abstract
Cocaine use is associated with negative health outcomes: cocaine use disorders, speedballing, and overdose deaths. Currently, treatments for cocaine use disorders and overdose are non-existent when compared to opioid use disorders, and current standard cocaine use disorder treatments have high dropout and recidivism rates. Physical exercise has been shown to attenuate addiction behavior as well as modulate brain activity. This study examined the differential effects of chronic cocaine use between exercised and sedentary rats. The effects of exercise on brain glucose metabolism (BGluM) following chronic cocaine exposure were assessed using Positron Emission Tomography (PET) and [18F]-Fluorodeoxyglucose (FDG). Compared to sedentary animals, exercise decreased metabolism in the SIBF primary somatosensory cortex. Activation occurred in the amygdalopiriform and piriform cortex, trigeminothalamic tract, rhinal and perirhinal cortex, and visual cortex. BGluM changes may help ameliorate various aspects of cocaine abuse and reinstatement. Further investigation is needed into the underlying neuronal circuits involved in BGluM changes and their association with addiction behaviors. © 2024 by the authors.
Author Keywords
18F-FDG fluorodeoxyglucose; aerobic exercise; cocaine; glucose metabolism; positron emission tomography; statistical parametric mapping
Funding details
RIAQ0940
Document Type: Article
Publication Stage: Final
Source: Scopus
Presence of Epstein-Barr virus in cerebrospinal fluid is associated with increased mortality in HIV-negative cryptococcal meningitis
(2024) Medical Mycology, 62 (5), art. no. myae052, .
Lu, Y.a b , Li, S.c , Su, Z.a , Luo, C.d , Gu, M.a , Yuan, D.a , Qin, B.-E.a , Dai, K.e , Xia, H.f , Chen, Y.a , Peng, F.a , Jiang, Y.a
a Department of Neurology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
b Department of Neurology, The Eighth Affiliated Hospital of Sun Yat-sen University, Shenzhen, Guangdong, China
c Department of Statistics, The Pennsylvania State University, State College, PA, United States
d Division of Public Health Sciences, Washington University School of Medicine in St. Louis, St Louis, MO, United States
e Department of Scientific Affairs, Hugobiotech Co, Beijing, China
f Department of Biostatistics, Epidemiology, and Informatics, University of Pennsylvania, Philadelphia, PA, United States
Abstract
Cryptococcus neoformans is the most common cause of fungal meningitis and is associated with a high mortality. The clinical significance of concurrent Epstein-Barr virus (EBV) in the cerebrospinal fluid (CSF) of human immunodeficiency virus (HIV)-negative patients with cryptococcal meningitis (CM) remains unclear. A retrospective cohort study was performed by analyzing CSF samples from 79 HIV-negative Chinese Han patients with confirmed CM. We identified CSF viral DNA in these patients by metagenomic next-generation sequencing (mNGS) and compared 10-week survival rates among those with and without EBV DNA in CSF. Of the 79 CSF samples tested, 44.3% (35/79) had detectable viral DNA in CSF, while 55.7% (44/79) were virus-negative. The most frequent viral pathogen was EBV, which was detected in 22.8% (18/79) patients. The median number of CSF-EBV DNA reads was 4 reads with a range from 1 to 149 reads. The 10-week mortality rates were 22.2% (4/18) in those with positive CSF-EBV and 2.3% (1/44) in those with negative CSF-virus (hazard ratio 8.20, 95% confidence interval [CI] 1.52-81.80; P = 0.014), which remained significant after a multivariate adjustment for the known risk factors of mortality (adjusted hazard ratio 8.15, 95% CI 1.14-92.87; P = 0.037). mNGS can identify viruses that coexist in CSF of HIV-negative patients with CM. EBV DNA is most commonly found together with C. neoformans in CSF and its presence is associated with increased mortality in HIV-negative CM patients. © 2024 The Author(s).
Author Keywords
cryptococcal meningitis; Epstein-Barr virus; HIV-negative; metagenomic next-generation sequencing; mortality
Funding details
National Natural Science Foundation of ChinaNSFC81671182
National Natural Science Foundation of ChinaNSFC
Natural Science Foundation of Guangdong Province2016A030313228
Natural Science Foundation of Guangdong Province
Document Type: Article
Publication Stage: Final
Source: Scopus
Genetic Complexities of Cerebral Small Vessel Disease, Blood Pressure, and Dementia
(2024) JAMA Network Open, 7 (5), p. e2412824.
Sargurupremraj, M.a b , Soumaré, A.a , Bis, J.C.c , Surakka, I.d , Jürgenson, T.e , Joly, P.a , Knol, M.J.f , Wang, R.g h , Yang, Q.g h , Satizabal, C.L.b g h , Gudjonsson, A.i , Mishra, A.a , Bouteloup, V.a , Phuah, C.-L.j k , van Duijn, C.M.l , Cruchaga, C.k m n , Dufouil, C.a , Chêne, G.a o , Lopez, O.L.p q , Psaty, B.M.c r s , Tzourio, C.a o , Amouyel, P.t u , Adams, H.H.v w , Jacqmin-Gadda, H.a , Ikram, M.A.f , Gudnason, V.i x , Milani, L.e , Winsvold, B.S.y z aa , Hveem, K.z ab , Matthews, P.M.ac ad ae , Longstreth, W.T.r af , Seshadri, S.b g h , Launer, L.J.ag , Debette, S.a g ah
a Bordeaux Population Health Research Center, University of Bordeaux, Inserm, Bordeaux, France
b Glenn Biggs Institute for Alzheimer’s & Neurodegenerative Diseases, University of Texas Health Sciences Center, San Antonio, Mexico
c Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, United States
d Department of Internal Medicine, University of Michigan, Ann Arbor, United States
e Estonian Genome Centre, Institute of Genomics, University of TartuTartu, Estonia
f Department of Epidemiology, Erasmus MC University Medical Center, Rotterdam, Netherlands
g School of Public Health, Boston University and the National Heart, Lung, Blood Institute Framingham Heart Study, Boston, MA, United States
h Department of Neurology, Boston University School of Medicine, Boston, MA, United States
i Icelandic Heart Association, Kopavogur, Iceland
j Department of Neurology, Washington University School of Medicine & Barnes-Jewish Hospital, St Louis, MO, United States
k NeuroGenomics and Informatics Center, Washington University in St Louis, St Louis, MO, United States
l Nuffield Department of Population Health, University of Oxford, Oxford, United Kingdom
m Department of Psychiatry, Washington University School of Medicine, St Louis, MO, United States
n Charles F. and Joanne Knight Alzheimer Disease Research Center, Washington University School of Medicine, St Louis, MO, United States
o Department of Public Health, CHU de Bordeaux, Bordeaux, France
p Department of Neurology, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States
q Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States
r Department of Epidemiology, University of Washington, Seattle, United States
s Department of Health Systems and Population Health, University of Washington, Seattle, United States
t INSERM U1167, University of Lille, Institut Pasteur de Lille, Lille, France
u Department of Epidemiology and Public Health, CHRU de Lille, Lille, France
v Department of Human Genetics, Radboud University Medical Center, Nijmegen, Netherlands
w Latin American Brain Health (BrainLat), Universidad Adolfo IbáñezSantiago, Chile
x Faculty of Medicine, University of Iceland, Reykjavik, Iceland
y Division of Clinical Neuroscience, Department of Research and Innovation, Oslo University HospitalOslo, Norway
z K. G. Jebsen Center for Genetic Epidemiology, Department of Public Health and Nursing, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology (NTNU), Trondheim, Norway
aa Department of Neurology, Oslo University HospitalOslo, Norway
ab HUNT Research Centre, Department of Public Health and Nursing, Norwegian University of Science and Technology, Levanger, Norway
ac Department of Brain Sciences, Imperial College London, London, United Kingdom
ad UK Dementia Research Institute, Imperial College London, London, United Kingdom
ae Data Science Institute, Imperial College London, London, United Kingdom
af Department of Neurology, University of Washington, Seattle, United States
ag Laboratory of Epidemiology and Population Sciences, Intramural Research Program, National Institute on Aging, Bethesda, MD, Liberia
ah Institute for Neurodegenerative Diseases, Department of Neurology, Bordeaux University Hospital, Bordeaux, France
Abstract
Importance: Vascular disease is a treatable contributor to dementia risk, but the role of specific markers remains unclear, making prevention strategies uncertain. Objective: To investigate the causal association between white matter hyperintensity (WMH) burden, clinical stroke, blood pressure (BP), and dementia risk, while accounting for potential epidemiologic biases. Design, Setting, and Participants: This study first examined the association of genetically determined WMH burden, stroke, and BP levels with Alzheimer disease (AD) in a 2-sample mendelian randomization (2SMR) framework. Second, using population-based studies (1979-2018) with prospective dementia surveillance, the genetic association of WMH, stroke, and BP with incident all-cause dementia was examined. Data analysis was performed from July 26, 2020, through July 24, 2022. Exposures: Genetically determined WMH burden and BP levels, as well as genetic liability to stroke derived from genome-wide association studies (GWASs) in European ancestry populations. Main Outcomes and Measures: The association of genetic instruments for WMH, stroke, and BP with dementia was studied using GWASs of AD (defined clinically and additionally meta-analyzed including both clinically diagnosed AD and AD defined based on parental history [AD-meta]) for 2SMR and incident all-cause dementia for longitudinal analyses. Results: In 2SMR (summary statistics-based) analyses using AD GWASs with up to 75 024 AD cases (mean [SD] age at AD onset, 75.5 [4.4] years; 56.9% women), larger WMH burden showed evidence for a causal association with increased risk of AD (odds ratio [OR], 1.43; 95% CI, 1.10-1.86; P = .007, per unit increase in WMH risk alleles) and AD-meta (OR, 1.19; 95% CI, 1.06-1.34; P = .008), after accounting for pulse pressure for the former. Blood pressure traits showed evidence for a protective association with AD, with evidence for confounding by shared genetic instruments. In the longitudinal (individual-level data) analyses involving 10 699 incident all-cause dementia cases (mean [SD] age at dementia diagnosis, 74.4 [9.1] years; 55.4% women), no significant association was observed between larger WMH burden and incident all-cause dementia (hazard ratio [HR], 1.02; 95% CI, 1.00-1.04; P = .07). Although all exposures were associated with mortality, with the strongest association observed for systolic BP (HR, 1.04; 95% CI, 1.03-1.06; P = 1.9 × 10-14), there was no evidence for selective survival bias during follow-up using illness-death models. In secondary analyses using polygenic scores, the association of genetic liability to stroke, but not genetically determined WMH, with dementia outcomes was attenuated after adjusting for interim stroke. Conclusions: These findings suggest that WMH is a primary vascular factor associated with dementia risk, emphasizing its significance in preventive strategies for dementia. Future studies are warranted to examine whether this finding can be generalized to non-European populations.
Document Type: Article
Publication Stage: Final
Source: Scopus
Intermuscular coherence as an early biomarker for amyotrophic lateral sclerosis: The protocol for a prospective, multicenter study
(2024) PLoS ONE, 19 (5), art. no. e0303053, .
Issa, N.P.a , Aydin, S.a , Polley, E.a , Carberry, N.b , Garret, M.A.c , Smith, S.d , Habib, A.A.e , Baumgartner, N.W.f , Soliven, B.a , Rezania, K.a
a University of Chicago Medical Center, Chicago, IL, United States
b University of Miami, Coral Gables, FL, United States
c Massachusetts General Hospital, Boston, MA, United States
d Washington University, St. Louis, MO, United States
e University of California, Irvine, Irvine, CA, United States
f Rush University Medical Center, Chicago, IL, United States
Abstract
Objective To describe the protocol of a prospective study to test the validity of intermuscular coherence (IMC) as a diagnostic tool and biomarker of upper motor neuron degeneration in amyotrophic lateral sclerosis (ALS). Methods This is a multicenter, prospective study. IMC of muscle pairs in the upper and lower limbs is gathered in *650 subjects across three groups using surface electrodes and conventional electromyography (EMG) machines. The following subjects will be tested: 1) neurotypical controls; 2) patients with symptomatology suggestive for early ALS but not meeting probable or definite ALS by Awaji Criteria; 3) patients with a known ALS mimic. The recruitment period is between 3/31/2021 and 12/31/2025. Written consent will be sought from the subject or the subject’s legally authorized representative during enrollment. Results The endpoints of this study include: 1) whether adding IMC to the Awaji ALS criteria improve its sensitivity in early ALS and can allow for diagnosis earlier; 2) constructing a database of IMC across different ages, genders, and ethnicities. Significance This study may validate a new inexpensive, painless, and widely available tool for the diagnosis of ALS. © 2024 Issa 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
Predicting post-surgical functional status in high-grade glioma with resting state fMRI and machine learning
(2024) Journal of Neuro-Oncology, .
Luckett, P.H.a , Olufawo, M.O.a , Park, K.Y.a , Lamichhane, B.a b , Dierker, D.c , Verastegui, G.T.a , Lee, J.J.c , Yang, P.a , Kim, A.a , Butt, O.H.d , Chheda, M.G.d , Snyder, A.Z.c d , Shimony, J.S.c , Leuthardt, E.C.a e f g h i j
a Department of Neurological Surgery, Washington University School of Medicine, St. Louis, MO, United States
b Center for Health Sciences, Oklahoma State University, Tulsa, OK, United States
c Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, MO, United States
d Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States
e Department of Biomedical Engineering, Washington University in Saint Louis, St. Louis, MO, United States
f Department of Neuroscience, Washington University School of Medicine, St. Louis, MO, United States
g Department of Mechanical Engineering and Materials Science, Washington University in Saint Louis, St. Louis, MO, United States
h Center for Innovation in Neuroscience and Technology, Washington University School of Medicine, St. Louis, MO, United States
i Brain Laser Center, Washington University School of Medicine, St. Louis, MO, United States
j National Center for Adaptive Neurotechnologies, Albany, NY, United States
Abstract
Purpose: High-grade glioma (HGG) is the most common and deadly malignant glioma of the central nervous system. The current standard of care includes surgical resection of the tumor, which can lead to functional and cognitive deficits. The aim of this study is to develop models capable of predicting functional outcomes in HGG patients before surgery, facilitating improved disease management and informed patient care. Methods: Adult HGG patients (N = 102) from the neurosurgery brain tumor service at Washington University Medical Center were retrospectively recruited. All patients completed structural neuroimaging and resting state functional MRI prior to surgery. Demographics, measures of resting state network connectivity (FC), tumor location, and tumor volume were used to train a random forest classifier to predict functional outcomes based on Karnofsky Performance Status (KPS < 70, KPS ≥ 70). Results: The models achieved a nested cross-validation accuracy of 94.1% and an AUC of 0.97 in classifying KPS. The strongest predictors identified by the model included FC between somatomotor, visual, auditory, and reward networks. Based on location, the relation of the tumor to dorsal attention, cingulo-opercular, and basal ganglia networks were strong predictors of KPS. Age was also a strong predictor. However, tumor volume was only a moderate predictor. Conclusion: The current work demonstrates the ability of machine learning to classify postoperative functional outcomes in HGG patients prior to surgery accurately. Our results suggest that both FC and the tumor’s location in relation to specific networks can serve as reliable predictors of functional outcomes, leading to personalized therapeutic approaches tailored to individual patients. © The Author(s) 2024.
Author Keywords
Brain tumor; Functional MRI; High-grade glioma; Machine learning
Funding details
University of WashingtonUW
National Cancer InstituteNCIR01CA203861
National Cancer InstituteNCI
National Institute of Neurological Disorders and StrokeNINDSU24NS109103
National Institute of Neurological Disorders and StrokeNINDS
National Institute of Biomedical Imaging and BioengineeringNIBIBP41EB018783, R01EB026439
National Institute of Biomedical Imaging and BioengineeringNIBIB
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
Molecular neuroimaging in dominantly inherited versus sporadic early-onset Alzheimer’s disease
(2024) Brain Communications, 6 (3), art. no. fcae159, .
Iaccarino, L.a , Llibre-Guerra, J.J.b c , Mcdade, E.b c , Edwards, L.a , Gordon, B.d , Benzinger, T.d , Hassenstab, J.b c , Kramer, J.H.a , Li, Y.e , Miller, B.L.a , Miller, Z.a , Morris, J.C.b c , Mundada, N.a , Perrin, R.J.f , Rosen, H.J.a , Soleimani-Meigooni, D.a , Strom, A.a , Tsoy, E.a , Wang, G.e , Xiong, C.e , Allegri, R.g , Chrem, P.g , Vazquez, S.g , Berman, S.B.h , Chhatwal, J.i , Masters, C.L.j , Farlow, M.R.k , Jucker, M.l , Levin, J.m n o , Salloway, S.p , Fox, N.C.q , Day, G.S.r , Gorno-Tempini, M.L.a , Boxer, A.L.a , La Joie, R.a , Bateman, R.b c , Rabinovici, G.D.a s
a Department of Neurology, Weill Institute for Neurosciences, University of California San Francisco, Memory and Aging Center, San Francisco, CA 94158, United States
b Dominantly Inherited Alzheimer Network (DIAN), St Louis, MO 63108, United States
c Department of Neurology, Washington University in St Louis, St Louis, MO 63108, United States
d Department of Radiology, Washington University in St Louis, St Louis, MO 63110, United States
e Department of Biostatistics, Washington University in St Louis, St Louis, MO 63110, United States
f Department of Pathology and Immunology, Washington University in St Louis, St Louis, MO 63110, United States
g Institute for Neurological Research Fleni, Department of Cognitive Neurology, Buenos Aires, 1428, Argentina
h Department of Neurology, University of Pittsburgh, Pittsburgh, PA 15213, United States
i Harvard Medical School, Massachusetts General Hospital, Boston, MA 02114, United States
j Department of Neuroscience, Florey Institute, University of Melbourne, Melbourne, 3052, Australia
k Neuroscience Center, Indiana University School of Medicine, Indianapolis, IN 46202, United States
l DZNE-German Center for Neurodegenerative Diseases, Tübingen, 72076, Germany
m Department of Neurology, Ludwig-Maximilians-University, Munich, 80539, Germany
n German Center for Neurodegenerative Diseases, Munich, 81377, Germany
o Munich Cluster for Systems Neurology (SyNergy),, Munich, 81377, Germany
p Memory and Aging Program, Butler Hospital, Brown University, Providence, RI 02906, United States
q Dementia Research Centre, Department of Neurodegenerative Disease, University College London Institute of Neurology, London, WC1N 3BG, United Kingdom
r Department of Neurology, Mayo Clinic Florida, Jacksonville, FL 33224, United States
s Department of Radiology and Biomedical Imaging, University of California, San Francisco, CA 94143, United States
Abstract
Approximately 5% of Alzheimer’s disease patients develop symptoms before age 65 (early-onset Alzheimer’s disease), with either sporadic (sporadic early-onset Alzheimer’s disease) or dominantly inherited (dominantly inherited Alzheimer’s disease) presentations. Both sporadic early-onset Alzheimer’s disease and dominantly inherited Alzheimer’s disease are characterized by brain amyloid-β accumulation, tau tangles, hypometabolism and neurodegeneration, but differences in topography and magnitude of these pathological changes are not fully elucidated. In this study, we directly compared patterns of amyloid-β plaque deposition and glucose hypometabolism in sporadic early-onset Alzheimer’s disease and dominantly inherited Alzheimer’s disease individuals. Our analysis included 134 symptomatic sporadic early-onset Alzheimer’s disease amyloid-Positron Emission Tomography (PET)-positive cases from the University of California, San Francisco, Alzheimer’s Disease Research Center (mean ± SD age 59.7 ± 5.6 years), 89 symptomatic dominantly inherited Alzheimer’s disease cases (age 45.8 ± 9.3 years) and 102 cognitively unimpaired non-mutation carriers from the Dominantly Inherited Alzheimer Network study (age 44.9 ± 9.2). Each group underwent clinical and cognitive examinations, 11C-labelled Pittsburgh Compound B-PET and structural MRI. 18F-Fluorodeoxyglucose-PET was also available for most participants. Positron Emission Tomography scans from both studies were uniformly processed to obtain a standardized uptake value ratio (PIB50-70 cerebellar grey reference and FDG30-60 pons reference) images. Statistical analyses included pairwise global and voxelwise group comparisons and group-independent component analyses. Analyses were performed also adjusting for covariates including age, sex, Mini-Mental State Examination, apolipoprotein ϵ4 status and average composite cortical of standardized uptake value ratio. Compared with dominantly inherited Alzheimer’s disease, sporadic early-onset Alzheimer’s disease participants were older at age of onset (mean ± SD, 54.8 ± 8.2 versus 41.9 ± 8.2, Cohen’s d = 1.91), with more years of education (16.4 ± 2.8 versus 13.5 ± 3.2, d = 1) and more likely to be apolipoprotein ϵ4 carriers (54.6% ϵ4 versus 28.1%, Cramer’s V = 0.26), but similar Mini-Mental State Examination (20.6 ± 6.1 versus 21.2 ± 7.4, d = 0.08). Sporadic early-onset Alzheimer’s disease had higher global cortical Pittsburgh Compound B-PET binding (mean ± SD standardized uptake value ratio, 1.92 ± 0.29 versus 1.58 ± 0.44, d = 0.96) and greater global cortical 18F-fluorodeoxyglucose-PET hypometabolism (mean ± SD standardized uptake value ratio, 1.32 ± 0.1 versus 1.39 ± 0.19, d = 0.48) compared with dominantly inherited Alzheimer’s disease. Fully adjusted comparisons demonstrated relatively higher Pittsburgh Compound B-PET standardized uptake value ratio in the medial occipital, thalami, basal ganglia and medial/dorsal frontal regions in dominantly inherited Alzheimer’s disease versus sporadic early-onset Alzheimer’s disease. Sporadic early-onset Alzheimer’s disease showed relatively greater 18F-fluorodeoxyglucose-PET hypometabolism in Alzheimer’s disease signature temporoparietal regions and caudate nuclei, whereas dominantly inherited Alzheimer’s disease showed relatively greater hypometabolism in frontal white matter and pericentral regions. Independent component analyses largely replicated these findings by highlighting common and unique Pittsburgh Compound B-PET and 18F-fluorodeoxyglucose-PET binding patterns. In summary, our findings suggest both common and distinct patterns of amyloid and glucose hypometabolism in sporadic and dominantly inherited early-onset Alzheimer’s disease. © The Author(s) 2024.
Author Keywords
Alzheimer’s disease; amyloid-PET; brain glucose metabolism; FDG-PET
Funding details
Deutsches Zentrum für Neurodegenerative ErkrankungenDZNE
Instituto de Salud Carlos IIIISCIII
Fleni
Fonds de Recherche du Québec – SantéFRQS
Fondation Brain Canada
Japan Agency for Medical Research and DevelopmentAMED
Canadian Institutes of Health ResearchCIHR
Korea Health Industry Development InstituteKHIDI
Alzheimer’s AssociationAASG-20-690363, ZEN-21-848216, SG-20-690363-DIAN
Alzheimer’s AssociationAA
University of CaliforniaUCP30 AG062422, R35-AG072362, P01-AG019724, K99AG065501, R01-AG045611
University of CaliforniaUC
National Institute of Neurological Disorders and StrokeNINDSR01-NS050915
National Institute of Neurological Disorders and StrokeNINDS
National Institute on AgingNIAU19AG032438
National Institute on AgingNIA
Document Type: Article
Publication Stage: Final
Source: Scopus
A Pilot Study of Simulation-Free Hippocampal-Avoidance Whole Brain Radiation Therapy Using Diagnostic MRI-Based and Online Adaptive Planning
(2024) International Journal of Radiation Oncology Biology Physics, .
Kang, K.H.a , Price, A.T.b , Reynoso, F.J.a , Laugeman, E.a , Morris, E.D.a , Samson, P.P.a , Huang, J.a , Badiyan, S.N.c , Kim, H.a , Brenneman, R.J.d , Abraham, C.D.a , Knutson, N.C.a , Henke, L.E.b
a Washington University School of Medicine in St Louis, Department of Radiation Oncology, St Louis, Missouri, United States
b University Hospitals, Department of Radiation Oncology, Case Western Reserve University, Cleveland, Ohio, United States
c University of Texas Southwestern Medical Center, Department of Radiation Oncology, Dallas, Texas, United States
d Banner MD Anderson Cancer Center at Banner North Colorado Medical Center, Greeley, CO, United States
Abstract
Purpose: We aimed to demonstrate the clinical feasibility and safety of simulation-free hippocampal avoidance whole brain radiation therapy (HA-WBRT) in a pilot study (National Clinical Trial 05096286). Methods and Materials: Ten HA-WBRT candidates were enrolled for treatment on a commercially available computed tomography (CT)-guided linear accelerator with online adaptive capabilities. Planning structures were contoured on patient-specific diagnostic magnetic resonance imaging (MRI), which were registered to a CT of similar head shape, obtained from an atlas-based database (AB-CT). These patient-specific diagnostic MRI and AB-CT data sets were used for preplan calculation, using NRG-CC001 constraints. At first fraction, AB-CTs were used as primary data sets and deformed to patient-specific cone beam CTs (CBCT) to give patient-matched density information. Brain, ventricle, and brain stem contours were matched through rigid translation and rotation to the corresponding anatomy on CBCT. Lens, optic nerve, and brain contours were manually edited based on CBCT visualization. Preplans were then reoptimized through online adaptation to create final, simulation-free plans, which were used if they met all objectives. Workflow tasks were timed. In addition, patients underwent CT-simulation to create immobilization devices and for prospective dosimetric comparison of simulation-free and simulation-based plans. Results: Median time from MRI importation to completion of “preplan” was 1 weekday (range, 1-4). Median on-table workflow duration was 41 minutes (range, 34-70). NRG-CC001 constraints were achieved by 90% of the simulation-free plans. One patient’s simulation-free plan failed a planning target volume coverage objective (89% instead of 90% coverage); this was deemed acceptable for first-fraction delivery, with an offline replan used for subsequent fractions. Both simulation-free and simulation CT-based plans otherwise met constraints, without clinically meaningful differences. Conclusions: Simulation-free HA-WBRT using online adaptive radiation therapy is feasible, safe, and results in dosimetrically comparable treatment plans to simulation CT-based workflows while providing convenience and time savings for patients. © 2024
Funding details
Varian Medical Systems
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
Salvage Stereotactic Radiosurgery for Recurrent WHO Grade 2 and 3 Meningiomas: A Multicenter Study (STORM)
(2024) International Journal of Radiation Oncology Biology Physics, .
Gallitto, M.a , Sedor, G.a , Lee, A.a , Pasetsky, J.a , Kinslow, C.J.a , Santos, G.D.L.a , Obiri-Yeboah, D.b , Kshettry, V.R.b , Helis, C.A.c , Chan, M.D.d , Beckham, T.H.e , McGovern, S.L.e , Matsui, J.f , Palmer, J.D.f , Bell, J.B.g , Mellon, E.A.g , Lakomy, D.h , Huang, J.h , Boor, I.i , Rusthoven, C.G.i , Sisti, M.B.j , Wang, T.J.C.a
a Department of Radiation Oncology, Columbia University Vagelos College of Physicians and Surgeons and New York-Presbyterian, New York, New York, United States
b Department of Neurological Surgery and Rose Ella Burkhardt Brain Tumor and Neuro-Oncology Center, Cleveland Clinic, Cleveland, Ohio, United States
c Department of Radiation Oncology, Alexander T. Augusta Military Medical Center, Fort Belvoir, Virginia, United States
d Department of Radiation Oncology, Wake Forest University School of Medicine, Winston-Salem, NC, United States
e Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States
f The James Comprehensive Cancer Center at The Ohio State University Wexner Medical Center, Columbus, OH, United States
g Department of Radiation Oncology, Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, Florida, United States
h Department of Radiation Oncology, Siteman Cancer Center, Washington University School of Medicine in St Louis, St Louis, Missouri, United States
i University of Colorado School of Medicine, Department of Radiation Oncology, Aurora, Colorado, United States
j Department of Neurological Surgery, Columbia University Medical Center, New York, New York, United States
Abstract
Purpose: The role of stereotactic radiosurgery (SRS) in the management of grade 2 and 3 meningiomas is not well elucidated. Unfortunately, local recurrence rates are high, and guidelines for management of recurrent disease are lacking. To address this knowledge gap, we conducted STORM (Salvage Stereotactic Radiosurgery for Recurrent WHO Grade 2 and 3 Meningiomas), a multicenter retrospective cohort study of patients treated with primary SRS for recurrent grade 2 and 3 meningiomas. Methods and Materials: Data on patients with recurrent grade 2 and 3 meningioma treated with SRS at first recurrence were retrospectively collected from 8 academic centers in the United States. Patients with multiple lesions at the time of initial diagnosis or more than 2 lesions at the time of first recurrence were excluded from this analysis. Patient demographics and treatment parameters were extracted at time of diagnosis, first recurrence, and second recurrence. Oncologic outcomes, including progression-free survival (PFS) and overall survival, as well as toxicity outcomes, were reported at the patient level. Results: From 2000 to 2022, 108 patients were identified (94% grade 2, 6.0% grade 3). A total of 106 patients (98%) had upfront surgical resection (60% gross-total resection) with 18% receiving adjuvant radiation therapy (RT). Median time to first progression was 2.5 years (IQR, 1.34-4.30). At first recurrence, patients were treated with single or fractionated SRS to a median marginal dose of 16 Gy to a maximum of 2 lesions (87% received single-fraction SRS). The median follow-up time after SRS was 2.6 years. The 1-, 2-, and 3-year PFS was 90%, 75%, and 57%, respectively, after treatment with SRS. The 1-, 2-, and 3-year overall survival was 97%, 94%, and 92%, respectively. In the multivariable analysis, grade 3 disease (HR, 6.80; 95% CI, 1.61-28.6), male gender (HR, 3.48; 95% CI, 1.47-8.26), and receipt of prior RT (HR, 2.69; 95% CI, 1.23-5.86) were associated with worse PFS. SRS dose and tumor volume were not correlated with progression. Treatment was well tolerated, with a 3.0% incidence of grade 2+ radiation necrosis. Conclusions: This is the largest multicenter study to evaluate salvage SRS in recurrent grade 2 and 3 meningiomas. In this select cohort of patients with primarily grade 2 meningioma with a potentially more favorable natural history of delayed, localized first recurrence amenable to salvage SRS, local control rates and toxicity profiles were favorable, warranting further prospective validation. © 2024 Elsevier Inc.
Funding details
Merck
Genentech
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
Plasticity-Induced Effects of Theta Burst Transcranial Ultrasound Stimulation in Parkinson’s Disease
(2024) Movement Disorders, .
Grippe, T.a b c d , Shamli-Oghli, Y.e , Darmani, G.c , Nankoo, J.-F.c , Raies, N.c , Sarica, C.c e , Arora, T.c f , Gunraj, C.c , Ding, M.Y.R.c e , Rinchon, C.c e , DiLuca, D.G.a c d g , Pichardo, S.h , Cardoso, F.b , Lozano, A.M.c i , Chen, R.a c d e
a Department of Neurology, Edmond J. Safra Program in Parkinson’s Disease, Morton and Gloria Shulman Movement Disorders Clinic, Toronto Western Hospital, UHN, Toronto, Canada
b Neuroscience Graduate Program, Federal University of Minas Gerais, Belo Horizonte, Brazil
c University Health Network, Toronto, Canada
d Division of Neurology, Department of Medicine, University of Toronto, Toronto, Canada
e Institute of Medical Science, University of Toronto, Toronto, Canada
f Division of Clinical Neuroscience, Department of Neurology, Oslo University Hospital, Oslo, Norway
g Department of Neurology, Washington University in St. Louis, St. Louis, MO, United States
h Cumming School of Medicine, Department of Radiology and Clinical Neurosciences, University of Calgary, Calgary, Canada
i Division of Neurosurgery, Department of Surgery, University of Toronto, Toronto, Canada
Abstract
Background: Low-intensity transcranial ultrasound stimulation (TUS) is a noninvasive brain stimulation (NIBS) technique with high spatial specificity. Previous studies showed that TUS delivered in a theta burst pattern (tbTUS) increased motor cortex (MI) excitability up to 30 minutes due to long-term potentiation (LTP)–like plasticity. Studies using other forms of NIBS suggested that cortical plasticity may be impaired in patients with Parkinson’s disease (PD). Objective: The aim was to investigate the neurophysiological effects of tbTUS in PD patients off and on dopaminergic medications compared to healthy controls. Methods: We studied 20 moderately affected PD patients in on and off dopaminergic medication states (7 with and 13 without dyskinesia) and 17 age-matched healthy controls in a case-controlled study. tbTUS was applied for 80 seconds to the MI. Motor-evoked potentials (MEP), short-interval intracortical inhibition (SICI), and short-interval intracortical facilitation (SICF) were recorded at baseline, and at 5 minutes (T5), T30, and T60 after tbTUS. Motor Unified Parkinson’s Disease Rating Scale (mUPDRS) was measured at baseline and T60. Results: tbTUS significantly increased MEP amplitude at T30 compared to baseline in controls and in PD patients on but not in PD patients off medications. SICI was reduced in PD off medications compared to controls. tbTUS did not change in SICI or SICF. The bradykinesia subscore of mUPDRS was reduced at T60 compared to baseline in PD on but not in the off medication state. The presence of dyskinesia did not affect tbTUS-induced plasticity. Conclusions: tbTUS-induced LTP plasticity is impaired in PD patients off medications and is restored by dopaminergic medications. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
Author Keywords
Parkinson’s disease; plasticity; transcranial ultrasound stimulation
Funding details
Merz Therapeutics
Ipsen
AbbVie Canada
Dystonia Medical Research Foundation CanadaDMRFC
Canadian Institutes of Health ResearchCIHR
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
Kenya Psychosis-Risk Outcomes Study (KePROS): Development of an Accelerated Medicine Partnership Schizophrenia-Aligned Project in Africa
(2024) Schizophrenia Bulletin Open, 5 (1), art. no. sgae009, .
Mamah, D.a , Mutiso, V.b , Musyimi, C.b , Harms, M.P.a , Anokhin, A.P.a , Chen, S.a , Torous, J.c , Muyela, L.b , Nashed, J.a , Al-Hosni, Y.a , Odera, A.b , Yarber, A.a , Golosheykin, S.a , Faghankhani, M.a , Sneed, M.a , Ndetei, D.M.b d
a Department of Psychiatry, Washington University Medical School, St. Louis, MO, United States
b African Mental Health Research and Training Foundation, Nairobi, Kenya
c Department of Psychiatry, Beth Israel Deaconess Medical Center at Harvard Medical School, Boston, MA, United States
d Department of Psychiatry, University of Nairobi, Nairobi, Kenya
Abstract
Background and Hypothesis: The Accelerating Medicines Partnership Schizophrenia (AMP SCZ) funds a longitudinal study of 43 research sites across 5 continents to develop tools to stratify developmental trajectories of youth at clinical high risk for psychosis (CHR) and identify homogenous targets for future clinical trials. However, there are no sites in Africa, leaving a critical gap in our knowledge of clinical and biological outcomes among CHR individuals. Study Design: We describe the development of the Kenya Psychosis-Risk Outcomes Study (KePROS), a 5-year NIH-funded project in Kenya designed to harmonize with AMP SCZ. The study will recruit over 100 CHR and 50 healthy participants and conduct multiple clinical and biomarker assessments over 2 years. Capacity building is a key component of the study, including the construction of an electroencephalography (EEG) laboratory and the upgrading of a local 3 T magnetic resonance imaging (MRI) machine. We detail community recruitment, study methodologies and protocols, and unique challenges with this pioneering research in Africa. Study Results: This paper is descriptive only. Planned future analyses will investigate possible predictors of clinical outcomes and will be compared to results from other global populations. Conclusions: KePROS will provide the research community with a rich longitudinal clinical and biomarker dataset from an African country in the developing Global South, which can be used alongside AMP SCZ data to delineate CHR outcome groups for future treatment development. Training in mental health assessment and investment in cutting-edge biomarker assessment and other technologies is needed to facilitate the inclusion of African countries in large-scale research consortia. © 2024 The Author(s). Published by Oxford University Press on behalf of the University of Maryland’s school of medicine, Maryland Psychiatric Research Center.
Author Keywords
AMP SCZ; CHR; clinical high risk; EEG; Kenya; KePROS; MRI; psychosis; schizophrenia
Document Type: Article
Publication Stage: Final
Source: Scopus
Sex Differences in Dystonia
(2024) Movement Disorders Clinical Practice, .
Kilic-Berkmen, G.a , Scorr, L.M.a , McKay, L.a b c , Thayani, M.a , Donsante, Y.d , Perlmutter, J.S.e , Norris, S.A.f , Wright, L.g , Klein, C.h , Feuerstein, J.S.i , Mahajan, A.j , Wagle-Shukla, A.k , Malaty, I.k , LeDoux, M.S.l m , Pirio-Richardson, S.n , Pantelyat, A.o , Moukheiber, E.o , Frank, S.p , Ondo, W.q , Saunders-Pullman, R.r , Lohman, K.h , Hess, E.J.a d , Jinnah, H.A.a s
a Department of Neurology, Emory University School of Medicine, Atlanta, GA, United States
b Department of Biomedical Informatics, Emory University School of Medicine, Atlanta, GA, United States
c Department of Biomedical Engineering, Emory University and Georgia Tech, Atlanta, GA, United States
d Department of Pharmacology and Chemical Biology, Emory University School of Medicine, Atlanta, GA, United States
e Department of Neurology, Radiology, Neuroscience, Physical Therapy and Occupational Therapy, Washington University School of Medicine, St Louis, MO, United States
f Department of Neurology and Radiology, Washington University School of Medicine, St Louis, MO, United States
g Department of Neurology, Washington University School of Medicine, St Louis, MO, United States
h Institute of Neurogenetics, University of Lübeck, Lübeck, Germany
i Department of Neurology, University of Colorado, Aurora, CO, United States
j Department of Neurological Sciences, Rush Parkinson’s Disease and Movement Disorders Program, Chicago, IL, United States
k Fixel Institute for Neurological Disease, University of Florida Department of Neurology, University of Florida, Gainesville, FL, United States
l Department of Psychology, University of Memphis, Memphis, TN, United States
m Veracity Neuroscience LLC, Memphis, TN, United States
n Department of Neurology, University of New Mexico/New Mexico VA Healthcare System, Albuquerque, NM, United States
o Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, United States
p Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, United States
q Movement Disorders Clinic, Methodist Neurological Institute, Houston, TX, United States
r Department of Neurology, Icahn School of Medicine at Mount Sinai, and Mount Sinai Beth Israel, New York, NY, United States
s Department of Human Genetics, Emory University School of Medicine, Atlanta, GA, United States
Abstract
Background: Prior studies have indicated that female individuals outnumber male individuals for certain types of dystonia. Few studies have addressed factors impacting these sex differences or their potential biological mechanisms. Objectives: To evaluate factors underlying sex differences in the dystonias and explore potential mechanisms for these differences. Methods: Data from individuals with various types of dystonia were analyzed in relation to sex. Data came from two different sources. One source was the Dystonia Coalition database, which contains predominantly idiopathic adult-onset focal and segmental dystonias. The second source was the MDSGene database, which contains predominantly early-onset monogenic dystonias. Results: The 3222 individuals from the Dystonia Coalition included 71% female participants and 29% male participants for an overall female-to-male ratio (F:M) of 2.4. This ratio varied according to body region affected and whether dystonia was task-specific. The female predominance was age-dependent. Sex did not have a significant impact on co-existing tremor, geste antagoniste, depression or anxiety. In the 1377 individuals from the MDSGene database, female participants outnumbered male participants for some genes (GNAL, GCH1, and ANO3) but not for other genes (THAP1, TH, and TOR1A). Conclusions: These results are in keeping with prior studies that have indicated female individuals outnumber male individuals for both adult-onset idiopathic and early onset monogenic dystonias. These results extend prior observations by revealing that sex ratios depend on the type of dystonia, age, and underlying genetics. © 2024 International Parkinson and Movement Disorder Society.
Author Keywords
blepharospasm; dystonia; sex differences; spasmodic dysphonia; writer’s cramp
Funding details
Rare Diseases Clinical Research NetworkRDCRN
National Institute of Neurological Disorders and StrokeNINDS
National Institutes of HealthNIHNS124764
National Institutes of HealthNIH
Dystonia CoalitionDCU54 NS065701, U54 TR001456, U54 NS116025
Dystonia CoalitionDC
Document Type: Article
Publication Stage: Article in Press
Source: Scopus