Mapping human tissues with highly multiplexed RNA in situ hybridization
(2024) Nature Communications, 15 (1), art. no. 2511, .
Kalhor, K.a , Chen, C.-J.a b , Lee, H.S.a c , Cai, M.a , Nafisi, M.a , Que, R.a , Palmer, C.R.d e , Yuan, Y.a , Zhang, Y.f , Li, X.g , Song, J.a , Knoten, A.h , Lake, B.B.a g , Gaut, J.P.i , Keene, C.D.j , Lein, E.k , Kharchenko, P.V.f g , Chun, J.d , Jain, S.h i , Fan, J.-B.l , Zhang, K.a g
a Department of Bioengineering, University of California San Diego, La JollaCA, United States
b Program in Bioinformatics and Systems Biology, University of California San Diego, La JollaCA, United States
c Department of Electrical Engineering, University of California San Diego, La JollaCA, United States
d Sanford Burnham Prebys Medical Discovery Institute, La JollaCA, United States
e Program in Biomedical Sciences, University of California San Diego, La JollaCA, United States
f Department of Biomedical Informatics, Harvard Medical School, Boston, MA, United States
g Altos Labs, San Diego, CA, United States
h Department of Medicine, Washington University School of Medicine, St. Louis, MO, United States
i Department of Pathology and Immunology, Washington University School of Medicine, St.Louis, MO, United States
j Department of Laboratory Medicine and Pathology, University of Washington School of Medicine, Seattle, WA, United States
k Allen Institute for Brain Science, Seattle, WA 98103, United States
l Illumina, San Diego, CA, United States
Abstract
In situ transcriptomic techniques promise a holistic view of tissue organization and cell-cell interactions. There has been a surge of multiplexed RNA in situ mapping techniques but their application to human tissues has been limited due to their large size, general lower tissue quality and high autofluorescence. Here we report DART-FISH, a padlock probe-based technology capable of profiling hundreds to thousands of genes in centimeter-sized human tissue sections. We introduce an omni-cell type cytoplasmic stain that substantially improves the segmentation of cell bodies. Our enzyme-free isothermal decoding procedure allows us to image 121 genes in large sections from the human neocortex in <10 h. We successfully recapitulated the cytoarchitecture of 20 neuronal and non-neuronal subclasses. We further performed in situ mapping of 300 genes on a diseased human kidney, profiled >20 healthy and pathological cell states, and identified diseased niches enriched in transcriptionally altered epithelial cells and myofibroblasts. © The Author(s) 2024.
Document Type: Article
Publication Stage: Final
Source: Scopus
Isoflurane preconditioning induced genomic changes in mouse cortex
(2024) BJA Open, 10, art. no. 100268, .
Athiraman, U.a b , Giri, T.a
a Department of Anesthesiology, Washington University, St. Louis, MO, United States
b Department of Neurological Surgery, Washington University, St. Louis, MO, United States
Abstract
Background: Altered patterns of genetic expression induced by isoflurane preconditioning in mouse brain have not yet been investigated. The aim of our pilot study is to examine the temporal sequence of changes in the transcriptome of mouse brain cortex produced by isoflurane preconditioning. Methods: Twelve-wk-old wild-type (C57BL/6J) male mice were randomly assigned for the experiments. Mice were exposed to isoflurane 2% in air for 1 h and brains were harvested at the following time points—immediately (0 h), and at 6, 12, 24, 36, 48, and 72 h after isoflurane exposure. A separate cohort of mice were exposed to three doses of isoflurane on days 1, 2, and 3 and brains were harvested after the third exposure. The NanoString mouse neuropathology panel was used to analyse isoflurane-induced gene expression in the cortex. The neuropathology panel included 760 genes covering pathways involved in neurodegeneration and other nervous system diseases, and 10 internal reference genes for data normalisation. Results: Genes involving several pathways were upregulated and downregulated by isoflurane preconditioning. Interestingly, a biphasic response was noted, meaning, an early expression of genes (until 6 h), followed by a transient pause (until 24 h), and a second wave of genomic response beginning at 36 h of isoflurane exposure was noted. Conclusions: Isoflurane preconditioning induces significant alterations in the genes involved in neurodegeneration and other nervous system disorders in a temporal sequence. These data could aid in the identification of molecular mechanisms behind isoflurane preconditioning-induced neuroprotection in various central nervous system diseases. © 2024 The Authors
Author Keywords
genomics; isoflurane preconditioning; mouse cortex; nervous system disorders; neurodegeneration
Document Type: Article
Publication Stage: Final
Source: Scopus
Genetic and Congenital Anomalies in Infants With Hypoxic-Ischemic Encephalopathy
(2024) Pediatric Neurology, 154, pp. 44-50.
Morell, A.S.a , Monsell, S.E.b , Cornet, M.-C.c , Wisnowski, J.L.d e , McKinstry, R.C.f , Mathur, A.M.g , Li, Y.h , Glass, H.C.a c i , Gonzalez, F.F.c , Mayock, D.E.j , Benninger, K.L.k , Van Meurs, K.P.l , Lampland, A.L.m , Wu, T.-W.d n , Riley, D.o p q , Mietzsch, U.j r , Chalak, L.s , Flibotte, J.t u , Weitkamp, J.-H.v , Ahmad, K.A.w x y , Yanowitz, T.D.z aa ab , Baserga, M.ac , Merhar, S.ad ae , Rao, R.af , Sokol, G.M.r , Comstock, B.A.b , Heagerty, P.J.b , Juul, S.E.j , Wu, Y.W.a c
a Department of Neurology, University of California San Francisco, San Francisco, California, United States
b Department of Biostatistics, University of Washington, Seattle, WA, United States
c Department of Pediatrics, University of California San Francisco, San Francisco, California, United States
d Department of Pediatrics, Children’s Hospital Los Angeles, Los Angeles, California, United States
e Department of Radiology, Children’s Hospital Los Angeles, Los Angeles, California, United States
f Department of Radiology, Washington University School of Medicine, St. Louis, Missouri, United States
g Department of Pediatrics, Saint Louis University School of Medicine, St. Louis, Missouri, United States
h Department of Radiology and Biomedical Imaging, University of California San Francisco, San Francisco, California, United States
i Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, California, United States
j Department of Pediatrics, University of Washington School of Medicine, Seattle, WA, United States
k Department of Pediatrics, Nationwide Children’s Hospital, Columbus, OH, United States
l Department of Pediatrics, Stanford University School of Medicine, Stanford, California, United States
m Department of Neonatology, Children’s Minnesota, St. Paul, Minnesota, United States
n Department of Pediatrics, University of Southern California Keck School of Medicine, Los Angeles, California, United States
o Department of Pediatrics, Cook Children’s Medical Center, Ft. Worth, Texas, United States
p Department of Pediatrics, Texas Christian University, Ft. Worth, Texas, United States
q Department of Pediatrics, University of North Texas Health Science Center, Ft. Worth, Texas, United States
r Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN, United States
s Department of Pediatrics, The University of Texas Southwestern Medical Center, Dallas, Texas, United States
t Department of Pediatrics, The Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, United States
u Department of Pediatrics, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, United States
v Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN, United States
w Pediatrix Medical Group of San Antonio, San Antonio, Texas, United States
x Department of Pediatrics, Children’s Hospital of San Antonio, San Antonio, Texas, United States
y Department of Pediatrics, Methodist Children’s Hospital, San Antonio, Texas, United States
z Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States
aa Department of Pediatrics, Children’s Hospital of Pittsburgh of UPMC, Pittsburgh, PA, United States
ab Department of Pediatrics, Magee Women’s Hospital of UPMC, Pittsburgh, PA, United States
ac Department of Pediatrics, University of Utah, Salt Lake City, Utah, United States
ad Department of Pediatrics, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio, United States
ae Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio, United States
af Department of Pediatrics, Washington University School of Medicine, St. Louis, Missouri, United States
Abstract
Background: Infants with hypoxic ischemic encephalopathy (HIE) may have underlying conditions predisposing them to hypoxic-ischemic injury during labor and delivery. It is unclear how genetic and congenital anomalies impact outcomes of HIE. Methods: Infants with HIE enrolled in a phase III trial underwent genetic testing when clinically indicated. Infants with known genetic or congenital anomalies were excluded. The primary outcome, i.e., death or neurodevelopmental impairment (NDI), was determined at age two years by a standardized neurological examination, Bayley Scales of Infant Development, Third Edition (BSID-III), and the Gross Motor Function Classification Scales. Secondary outcomes included cerebral palsy and BSID-III motor, cognitive, and language scores at age two years. Results: Of 500 infants with HIE, 24 (5%, 95% confidence interval 3% to 7%) were diagnosed with a genetic (n = 15) or congenital (n = 14) anomaly. Infants with and without genetic or congenital anomalies had similar rates of severe encephalopathy and findings on brain magnetic resonance imaging. However, infants with genetic or congenital anomalies were more likely to have death or NDI (75% vs 50%, P = 0.02). Among survivors, those with a genetic or congenital anomaly were more likely to be diagnosed with cerebral palsy (32% vs 13%, P = 0.02), and had lower BSID-III scores in all three domains than HIE survivors without such anomalies. Conclusions: Among infants with HIE, 5% were diagnosed with a genetic or congenital anomaly. Despite similar clinical markers of HIE severity, infants with HIE and a genetic or congenital anomaly had worse neurodevelopmental outcomes than infants with HIE alone. © 2024
Author Keywords
Congenital anomaly; Genetic anomaly; Hypoxic-ischemic encephalopathy; Neonatal
Document Type: Article
Publication Stage: Final
Source: Scopus
Cannabis oil extracts for chronic pain: what else can be learned from another structured prospective cohort?
(2024) Pain Reports, 9 (2), art. no. e1143, .
Pud, D.a , Aamar, S.b , Schiff-Keren, B.c , Sheinfeld, R.d , Brill, S.e , Robinson, D.f , Fogelman, Y.g h , Habib, G.i , Sharon, H.j k , Amital, H.d , Boltyansky, B.a , Haroutounian, S.l , Eisenberg, E.h
a Faculty of Social Welfare and Health Sciences, University of Haifa, Haifa, Israel
b Hadassah-Hebrew University Medical Center, Jerusalem, Israel
c Schiff-Keren Pain Clinic, Tel-Aviv, Israel
d Institute for Pain Medicine, Chaim Sheba Medical Center, Tel Hashomer, Israel
e Pain Center, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel
f Orthopedic Research Unit, Hasharon Hospital, Rabin Medical Center, Petah Tikwa, Israel
g Leumit Health Services, Tel Aviv, Israel
h The Ruth & Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel
i Reumatology Unit, Laniado Hospital, Netanya, Israel
j Sagol Brain Institute, The Institute of Pain Medicine, Tel Aviv Medical Center, Tel Aviv, Israel
k Sackler Faculty of Medicine, Sagol School of Neuroscience, Tel Aviv, Israel
l Department of Anesthesiology, Washington University School of Medicine, St. Louis, MO, United States
Abstract
Introduction: The use of medicinal cannabis for managing pain expands, although its efficacy and safety have not been fully established through randomized controlled trials. Objectives: This structured, prospective questionnaire-based cohort was aimed to assess long-term effectiveness and safety of cannabis oil extracts in patients with chronic pain. Methods: Adult Israeli patients licensed to use cannabis oil extracts for chronic pain were followed prospectively for 6 months. The primary outcome measure was change from baseline in average weekly pain intensity, and secondary outcomes were changes in related symptoms and quality of life, recorded before treatment initiation and 1, 3, and 6 months thereafter. Generalized linear mixed model was used to analyze changes over time. In addition, “responders” ($30% reduction in weekly pain at any time point) were identified. Results: The study included 218 patients at baseline, and 188, 154, and 131 at 1, 3, and 6 months, respectively. At 6 months, the mean daily doses of cannabidiol and D9-tetrahydrocannabinol were 22.4 6 24.0 mg and 20.8 6 30.1 mg, respectively. Pain decreased from 7.9 6 1.7 at baseline to 6.6 6 2.2 at 6 months (F(3,450) 5 26.22, P, 0.0001). Most secondary parameters also significantly improved. Of the 218 participants, 24% were “responders” but could not be identified by baseline parameters. “Responders” exhibited higher improvement in secondary outcomes. Adverse events were common but mostly nonserious. Conclusion: This prospective cohort demonstrated a modest overall long-term improvement in chronic pain and related symptoms and a reasonable safety profile with the use of relatively low doses of individually titrated D9-tetrahydrocannabinol and cannabidiol. © 2024 The Author(s).
Author Keywords
Chronic pain; Medical cannabis; Oil extract; Related symptoms
Funding details
Pfizer
Document Type: Article
Publication Stage: Final
Source: Scopus
Final report of the phase II NEXT/CNS-GCT-4 trial: GemPOx followed by marrow-ablative chemotherapy for recurrent intracranial germ cell tumors
(2024) Neuro-Oncology Practice, 11 (2), pp. 188-198.
Shatara, M.a , Blue, M.b , Stanek, J.b , Liu, Y.A.c , Prevedello, D.M.d , Giglio, P.e , Puduvalli, V.K.f , Gardner, S.L.g , Allen, J.C.g , Wong, K.K.h i , Nelson, M.D.j , Gilles, F.H.k , Adams, R.H.l , Pauly, J.m , O’Halloran, K.h , Margol, A.S.h , Dhall, G.n , Finlay, J.L.b
a Division of Hematology and Oncology, St. Louis Children’s Hospital, Washington University School of Medicine, St. Louis, MO, United States
b Division of Hematology, Oncology, Blood and Marrow Transplant, Nationwide Children’s Hospital, Ohio State University College of Medicine, Columbus, OH, United States
c Department of Ophthalmology, Neurology, and Neurosurgery, University of California, Davis, Sacramento, CA, United States
d Department of Neurological Surgery, Ohio State University Wexner Medical Center, Columbus, OH, United States
e Division of Neuro-Oncology, Ohio State University Wexner Medical Center, James Cancer Center, Columbus, OH, United States
f Department of Neuro-oncology, MD Anderson Cancer Center, Houston, TX, United States
g Department of Pediatrics, New York University Grossman School of Medicine, New York, NY, United States
h Division of Hematology and Oncology, Cancer and Blood Disease Institute, Children’s Hospital Los Angeles, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States
i Department of Radiation Oncology, University of Southern California, Los Angeles, CA, United States
j Department of Radiology, Children’s Hospital of Los Angeles, Los Angeles, CA, United States
k Department of Pathology, Children’s Hospital of Los Angeles, Los Angeles, CA, United States
l Phoenix Children’s Center for Cancer & Blood Disorders, University of Arizona School of Medicine-Phoenix, Mayo ClinicAZ, United States
m Division of Hematology and Oncology, Cancer and Blood Disease Institute, Children’s Hospital, Los Angeles, CA, United States
n Division of Pediatric Hematology/Oncology, Children’s Hospital of Alabama, The University of Alabama at Birmingham, Birmingham, AL, United States
Abstract
Background. Patients with relapsed intracranial germinoma can achieve durable remission with standard chemotherapy regimens and/or reirradiation; however, innovative therapies are required for patients with relapsed and/or refractory intracranial nongerminomatous germ cell tumors (NGGCTs) due to their poor prognosis. Improved outcomes have been reported using reinduction chemotherapy to achieve minimal residual disease, followed by marrow-ablative chemotherapy (HDCx) with autologous hematopoietic progenitor cell rescue (AuHPCR). We conducted a phase II trial evaluating the response and toxicity of a 3-drug combination developed for recurrent intracranial germ cell tumors consisting of gemcitabine, paclitaxel, and oxaliplatin (GemPOx). Methods. A total of 9 patients with confirmed relapsed or refractory intracranial GCT were enrolled after signing informed consent, and received at least 2 cycles of GemPOx, of which all but 1 had relapsed or refractory NGGCTs. One patient with progressive disease was found to have pathologically confirmed malignant transformation to pure embryonal rhabdomyosarcoma (without GCT elements), hence was ineligible and not included in the analysis. Patients who experienced sufficient responses proceeded to receive HDCx with AuHPCR.Treatment response was determined based on radiographic tumor assessments and tumor markers. Results. A total of 7 patients achieved sufficient response and proceeded with HDCx and AuHPCR, and 5 subsequently received additional radiotherapy. A total of 2 patients developed progressive disease while receiving GemPOx. Myelosuppression and transaminitis were the most common treatment-related adverse events. With a mean follow-up of 44 months, 4 patients (3 NGGCTs, 1 germinoma) are alive without evidence of disease. Conclusions. GemPOx demonstrates efficacy in facilitating stem cell mobilization, thus facilitating the feasibility of both HDCx and radiotherapy. © The Author(s) 2023. Published by Oxford University Press on behalf of the Society for Neuro-Oncology and the European.
Author Keywords
GemPOx; long-term survival; objective response rate; outcomes; relapsed intracranial GCTs
Document Type: Article
Publication Stage: Final
Source: Scopus
High Clinical Exome Sequencing Diagnostic Rates and Novel Phenotypic Expansions for Nonisolated Microphthalmia, Anophthalmia, and Coloboma
(2024) Investigative Ophthalmology & Visual Science, 65 (3), p. 25.
Kunisetty, B.a , Martin-Giacalone, B.A.b c , Zhao, X.a d , Luna, P.N.a , Brooks, B.P.e , Hufnagel, R.B.e , Shaw, C.A.a , Rosenfeld, J.A.a , Agopian, A.J.f , Lupo, P.J.c , Scott, D.A.a g
a Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, United States
b Division of Public Health Sciences, Department of Surgery, Washington University School of Medicine, St. Louis, MO, United States
c Section of Hematology-Oncology, Department of Pediatrics, Baylor College of Medicine, Houston, TX, United States
d Baylor Genetics, Houston, TX, United States
e Ophthalmic Genetics & Visual Function Branch, National Eye Institute, NIH, Bethesda, MD, United States
f Department of Epidemiology, Human Genetics & Environmental Sciences, UTHealth School of Public Health, Houston, TX, United States
g Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, TX, United States
Abstract
Purpose: A molecular diagnosis is only made in a subset of individuals with nonisolated microphthalmia, anophthalmia, and coloboma (MAC). This may be due to underutilization of clinical (whole) exome sequencing (cES) and an incomplete understanding of the genes that cause MAC. The purpose of this study is to determine the efficacy of cES in cases of nonisolated MAC and to identify new MAC phenotypic expansions. Methods: We determined the efficacy of cES in 189 individuals with nonisolated MAC. We then used cES data, a validated machine learning algorithm, and previously published expression data, case reports, and animal models to determine which candidate genes were most likely to contribute to the development of MAC. Results: We found the efficacy of cES in nonisolated MAC to be between 32.3% (61/189) and 48.1% (91/189). Most genes affected in our cohort were not among genes currently screened in clinically available ophthalmologic gene panels. A subset of the genes implicated in our cohort had not been clearly associated with MAC. Our analyses revealed sufficient evidence to support low-penetrance MAC phenotypic expansions involving nine of these human disease genes. Conclusions: We conclude that cES is an effective means of identifying a molecular diagnosis in individuals with nonisolated MAC and may identify putatively damaging variants that would be missed if only a clinically available ophthalmologic gene panel was obtained. Our data also suggest that deleterious variants in BRCA2, BRIP1, KAT6A, KAT6B, NSF, RAC1, SMARCA4, SMC1A, and TUBA1A can contribute to the development of MAC.
Document Type: Article
Publication Stage: Final
Source: Scopus
Longitudinal analysis of CSF HIV RNA in untreated people with HIV: Identification of CSF controllers
(2024) Journal of Medical Virology, 96 (3), art. no. e29550, .
Trunfio, M.a b , Tang, B.a , Okwuegbuna, O.a , Iudicello, J.E.a , Bharti, A.c , Moore, D.J.a , Gelman, B.B.d , Morgello, S.e , Patel, P.B.f , Rubin, L.H.g h , Ances, B.M.i , Gianella, S.c , Heaton, R.K.a , Ellis, R.J.a , Letendre, S.L.a
a HIV Neurobehavioral Research Program, Departments of Neurosciences and Psychiatry, University of California San Diego, San Diego, CA, United States
b Department of Medical Sciences, University of Turin, Turin, Italy
c Division of Infectious Diseases and Global Health, University of California San Diego, San Diego, CA, United States
d Department of Pathology, University of Texas Medical Branch, Galveston, TX, United States
e Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY, United States
f Department of Neurology, University of Washington, Seattle, WA, United States
g Department of Neurology, Psychiatry and Behavioral Sciences, Molecular and Cellular Pathobiology, Johns Hopkins University School of Medicine, Baltimore, MD, United States
h Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, United States
i Department of Neurology, Washington University, St Louis, MO, United States
Abstract
Interindividual variation of human immunodeficiency virus (HIV) RNA setpoint in cerebrospinal fluid (CSF) and its determinants are poorly understood, but relevant for HIV neuropathology, brain reservoirs, viral escape, and reseeding after antiretroviral interruptions. Longitudinal multicentric study on demographic, clinical, and laboratory correlates of CSF HIV RNA in 2000 follow-up visits from 597 people with HIV (PWH) off antiretroviral therapy (ART) and with plasma HIV RNA > the lower limit of quantification (LLQ). Factors associated with CSF control (CSFC; CSF HIV RNA < LLQ while plasma HIV RNA > LLQ) and with CSF/plasma discordance (CSF > plasma HIV RNA > LLQ) were also assessed through mixed-effects models. Posthoc and sensitivity analyses were performed for persistent CSFC and ART-naïve participants, respectively. Over a median follow-up of 2.1 years, CSF HIV RNA was associated with CD4+ and CD8+ T cells, CSF leukocytes, blood–brain barrier (BBB) integrity, biomarkers of iron and lipid metabolism, serum globulins, past exposure to lamivudine, and plasma HIV RNA (model p < 0.0001). CSFC (persistent in 7.7% over 3 years) and CSF/plasma discordance (persistent in <0.01% over 1 year) were variably associated with the same parameters (model p < 0.001). Sensitivity analyses confirmed most of the previous associations in participants never exposed to ART. Persistent CSFC was associated with higher CD4+ T-cell count nadir (p < 0.001), lower serum globulins (p = 0.003), and lower CSF leukocytes (p < 0.001). Without ART, one in 13 PWH had persistently undetectable CSF HIV RNA, while persistent CSF/plasma discordance was extremely rare over years. Immune responses, inflammation, BBB permeability, and iron and lipid metabolism were all associated with HIV replication in CSF. © 2024 Wiley Periodicals LLC.
Author Keywords
antiretroviral naïve; blood–brain barrier; central nervous system; CSF control; CSF/plasma discordance; HIV viral load
Document Type: Article
Publication Stage: Final
Source: Scopus
Migraine is a risk factor for pseudophakic positive dysphotopsia following monofocal lens implantation
(2024) Canadian Journal of Ophthalmology, .
Xing, M.J.a , Moulin, T.A.a , Suresh, T.a , Gira, J.P.b , Sheybani, A.a , Van Stavern, G.P.a
a Department of Ophthalmology and Visual Sciences, Washington University School of Medicine, St. Louis, MO, United States
b Ophthalmology Consultants, St. Louis, MO, United States
Abstract
Objective: To identify neuroadaptation-related risk factors for persistent positive dysphotopsia (>6 months) following monofocal lens implantation. Design: Retrospective cohort study. Participants: Patients of an academic institution and a private practice in Saint Louis, Missouri. Inclusion criteria were adults with cataract extraction between January 2010 and April 2021 with monofocal intraocular lens implantation. Exclusion criteria included dementia, <20/40 acuity, visual pathway damage, visual field loss, and significant pathology causing photopsia. Methods: Participants were surveyed via telephone. Results: There were 385 participants (385 eyes), of whom 66 had persistent dysphotopsia (58 positive), 298 had none, and 21 had nonpersistent dysphotopsia. Among the 58 who had positive persistent dysphotopsia, mean Pseudophakic Dysphotopsia Questionnaire 6 (PDQ-6) score was 14.11 (SD, 8.46). There were no significant differences in sex or race. Migraine prevalence was greater among those with dysphotopsia (21.2%) than among those without (11.4%; p = 0.054). History of migraine was associated with an increase in PDQ-6 score of 2.76 points (p = 0.006). Six people in each group had Visual Aura Rating Scale (VARS) scores greater than zero. Mean VARS score was 0.48 for those with dysphotopsia and 0.14 for those without (p = 0.03). History of migraine or increased VARS score, younger age, and female sex were associated with lower satisfaction. Conclusion: History of migraine was associated with increased dysphotopsia severity and decreased patient satisfaction. Although further study with a larger sample size is warranted, these preliminary results highlight the potential of simple questions to individualize lens choice, reduce the risk of dysphotopsia, and improve patient satisfaction. © 2024
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
Structural MRI measures are associated with fatigue severity and persistence in a large, real-world cohort of people with multiple sclerosis
(2024) Multiple Sclerosis Journal, .
Simpson, A.C.a , Hu, C.a , Mowry, E.M.a c , Naismith, R.T.b , Fitzgerald, K.C.a c , Nourbakhsh, B.a
a Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, United States
b Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States
c Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, United States
Abstract
Background: Results of research on radiological hallmarks of multiple sclerosis (MS) fatigue have been conflicting. Objective: To investigate the associations of lesion and brain compartment volumes with fatigue severity and persistence in people with multiple sclerosis (PwMS). Methods: The Multiple Sclerosis Partners Advancing Technology and Health Solutions (MS PATHS) network collects standardized data during routine care of PwMS from 10 healthcare institutions. Magnetic resonance imaging (MRI) predictors included baseline brain parenchymal (BPF) and gray matter fractions (GMF) and T2 lesion volume (T2LV). The Quality of Life in Neurological Disorders (Neuro-QOL) fatigue subscore was analyzed linearly and categorically using T-score cutpoints, with a period of elevated symptoms defined as T-score ⩾ mean + 0.5 SD over follow-up. Results: At baseline, of 4012 participants (average age: 45.6 ± 11.8 years; 73% female; 31% progressive MS), 2058 (51%) had no fatigue, 629 (16%) had mild fatigue, and 1325 (33%) had moderate-to-severe fatigue. One SD greater baseline BPF and GMF were associated with 0.83 (p < 0.001) and 0.38 (p = 0.02) lower values in the baseline Neuro-QOL fatigue T-score. A 1 SD lower log of total T2LV was associated with a 0.49 (p < 0.001) lower baseline fatigue T-score. Higher BPF and lower T2LV at baseline were associated with lower odds of subsequent periods of elevated fatigue. Conclusion: Baseline lesion burden and lower generalized whole-brain volumes were associated with MS fatigue in cross-sectional and longitudinal analyses in a large, real-world cohort of PwMS. © The Author(s), 2024.
Author Keywords
epidemiology; Fatigue; multiple sclerosis; quantitative MRI; T2 lesions
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
Clinical validation of the PrecivityAD2 blood test: A mass spectrometry-based test with algorithm combining %p-tau217 and Aβ42/40 ratio to identify presence of brain amyloid
(2024) Alzheimer’s and Dementia, .
Meyer, M.R.a , Kirmess, K.M.a , Eastwood, S.a , Wente-Roth, T.L.a , Irvin, F.a , Holubasch, M.S.a , Venkatesh, V.a , Fogelman, I.a , Monane, M.a , Hanna, L.b , Rabinovici, G.D.c , Siegel, B.A.d , Whitmer, R.A.e , Apgar, C.f , Bateman, R.J.d , Holtzman, D.M.d , Irizarry, M.g , Verbel, D.g , Sachdev, P.g , Ito, S.h , Contois, J.a , Yarasheski, K.E.a , Braunstein, J.B.a , Verghese, P.B.a , West, T.a
a C2N Diagnostics, St. Louis, MO, United States
b Center for Statistical Sciences, Brown University School of Public Health, Providence, RI, United States
c UCSF, San Francisco, CA, United States
d School of Medicine, Washington University, St. Louis, MO, United States
e UC Davis, Sacramento, CA, United States
f American College of Radiology, Philadelphia, PA, United States
g Eisai Inc., Nutley, NJ, United States
h Eisai Co., Ltd., Tokyo, Japan
Abstract
BACKGROUND: With the availability of disease-modifying therapies for Alzheimer’s disease (AD), it is important for clinicians to have tests to aid in AD diagnosis, especially when the presence of amyloid pathology is a criterion for receiving treatment. METHODS: High-throughput, mass spectrometry-based assays were used to measure %p-tau217 and amyloid beta (Aβ)42/40 ratio in blood samples from 583 individuals with suspected AD (53% positron emission tomography [PET] positive by Centiloid > 25). An algorithm (PrecivityAD2 test) was developed using these plasma biomarkers to identify brain amyloidosis by PET. RESULTS: The area under the receiver operating characteristic curve (AUC-ROC) for %p-tau217 (0.94) was statistically significantly higher than that for p-tau217 concentration (0.91). The AUC-ROC for the PrecivityAD2 test output, the Amyloid Probability Score 2, was 0.94, yielding 88% agreement with amyloid PET. Diagnostic performance of the APS2 was similar by ethnicity, sex, age, and apoE4 status. DISCUSSION: The PrecivityAD2 blood test showed strong clinical validity, with excellent agreement with brain amyloidosis by PET. © 2024 C2N Diagnostics LLC. Alzheimer’s & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer’s Association.
Author Keywords
Alzheimer’s; amyloid beta; blood biomarker; clinical validity; diagnostic; p-tau217
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
Comparison of cerebrospinal fluid, plasma and neuroimaging biomarker utility in Alzheimer’s disease
(2024) Brain Communications, 6 (2), .
Meeker, K.L.a , Luckett, P.H.b , Barthélemy, N.R.a , Hobbs, D.A.c , Chen, C.c , Bollinger, J.a , Ovod, V.a , Flores, S.c , Keefe, S.c , Henson, R.L.a , Herries, E.M.a , McDade, E.a , Hassenstab, J.J.a d , Xiong, C.d e , Cruchaga, C.d f , Benzinger, T.L.S.c d , Holtzman, D.M.a d , Schindler, S.E.a d , Bateman, R.J.a , Morris, J.C.a d , Gordon, B.A.c d , Ances, B.M.a c d
a Department of Neurology, Washington University in St Louis, St Louis, MO 63110, United States
b Department of Neurosurgery, Washington University in St Louis, St Louis, MO 63110, United States
c Department of Radiology, Washington University in St Louis, St Louis, MO 63110, United States
d Knight Alzheimer Disease Research Center, Washington University School of Medicine, St Louis, MO 63110, United States
e Division of Biostatistics, Washington University in St Louis, St Louis, MO 63110, United States
f Department of Psychiatry, Washington University School of Medicine, St Louis, MO 63110, United States
Abstract
Alzheimer’s disease biomarkers are crucial to understanding disease pathophysiology, aiding accurate diagnosis and identifying target treatments. Although the number of biomarkers continues to grow, the relative utility and uniqueness of each is poorly understood as prior work has typically calculated serial pairwise relationships on only a handful of markers at a time. The present study assessed the cross-sectional relationships among 27 Alzheimer’s disease biomarkers simultaneously and determined their ability to predict meaningful clinical outcomes using machine learning. Data were obtained from 527 community-dwelling volunteers enrolled in studies at the Charles F. and Joanne Knight Alzheimer Disease Research Center at Washington University in St Louis. We used hierarchical clustering to group 27 imaging, CSF and plasma measures of amyloid beta, tau [phosphorylated tau (p-tau), total tau t-tau)], neuronal injury and inflammation drawn from MRI, PET, mass-spectrometry assays and immunoassays. Neuropsychological and genetic measures were also included. Random forest-based feature selection identified the strongest predictors of amyloid PET positivity across the entire cohort. Models also predicted cognitive impairment across the entire cohort and in amyloid PET-positive individuals. Four clusters emerged reflecting: core Alzheimer’s disease pathology (amyloid and tau), neurodegeneration, AT8 antibody-associated phosphorylated tau sites and neuronal dysfunction. In the entire cohort, CSF p-tau181/Aβ40lumi and Aβ42/Aβ40lumi and mass spectrometry measurements for CSF pT217/T217, pT111/T111, pT231/T231 were the strongest predictors of amyloid PET status. Given their ability to denote individuals on an Alzheimer’s disease pathological trajectory, these same markers (CSF pT217/T217, pT111/T111, p-tau/Aβ40lumi and t-tau/Aβ40lumi) were largely the best predictors of worse cognition in the entire cohort. When restricting analyses to amyloid-positive individuals, the strongest predictors of impaired cognition were tau PET, CSF t-tau/Aβ40lumi, p-tau181/Aβ40lumi, CSF pT217/217 and pT205/T205. Non-specific CSF measures of neuronal dysfunction and inflammation were poor predictors of amyloid PET and cognitive status. The current work utilized machine learning to understand the interrelationship structure and utility of a large number of biomarkers. The results demonstrate that, although the number of biomarkers has rapidly expanded, many are interrelated and few strongly predict clinical outcomes. Examining the entire corpus of available biomarkers simultaneously provides a meaningful framework to understand Alzheimer’s disease pathobiological change as well as insight into which biomarkers may be most useful in Alzheimer’s disease clinical practice and trials. © The Author(s) 2024.
Author Keywords
Alzheimer’s disease; biomarkers; machine learning
Document Type: Article
Publication Stage: Final
Source: Scopus
Mental Health Mediators for Subjective, Not Objective, Cognition, and Community Participation Poststroke
(2024) OTJR: Occupational Therapy Journal of Research, .
Lee, Y.a , Nicholas, M.L.b , Connor, L.T.a
a Washington University School of Medicine, St. Louis, MO, United States
b MGH Institute of Health Professions, Boston, MA, United States
Abstract
Previous studies have stated that both objective and subjective cognitive abilities and mental health symptoms are associated with community participation poststroke. However, there is a need to understand the direct and indirect associations among these variables in persons with stroke. The objective of this study was to investigate whether mental health symptoms mediate the associations of subjective and objective cognitive abilities with community participation poststroke. We built regression-based mediation models with 74 participants with mild to moderate stroke. Independent variables were objective and subjective cognitive abilities. The dependent variable was community participation. Mediators were mental health symptoms including depression, apathy, and anxiety. The results indicated that depression (b =.093), apathy (b =.134), and anxiety (b =.116) fully mediated the association between subjective cognitive ability (p <.05), but not objective cognitive ability (p >.05), and community participation poststroke. Our findings suggest that poor subjective cognitive ability combined with mental health symptoms should be addressed together to promote community participation poststroke. © The Author(s) 2024.
Author Keywords
community participation; mental health symptoms; objective cognitive ability; stroke; subjective cognitive ability
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
Discrimination and sense of purpose: Taking an intergenerational lens
(2024) International Journal of Behavioral Development, .
Wolk, M.W., Bogdan, R., Oltmanns, T.F., Hill, P.L.
Washington University, St. Louis, United States
Abstract
Given the developmental benefits associated with higher sense of purpose, past work has aimed to understand how experiences of adversity relate to sense of purpose. With a specific focus on experiences of adversity that may impact individuals from marginalized groups, past work has found that discrimination is related to lower sense of purpose in life, but that these effects are weaker for Black adults relative to White adults. The current research aims to extend past work by examining how and for whom discrimination is related to sense of purpose in life. Moreover, the current work also aimed to understand the extent to which sense of purpose spans across generations and whether there are generational differences in the relationship between discrimination and sense of purpose. Using data from the St. Louis Personality and Aging Network study, 822 parents (G1 participants) and 654 children (G2 participants) completed measures for sense of purpose, major experiences of discrimination, and personality traits. Results found mixed evidence for a relationship between discrimination and sense of purpose, with little evidence for consistent moderators. In addition, while the current work found no evidence of intergenerational associations for sense of purpose, results showed that discrimination was positively associated across generations, suggesting a potential for an intergenerational cycle of marginalization. © The Author(s) 2024.
Author Keywords
Discrimination; intergenerational; sense of purpose
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
Disease staging of Alzheimer’s disease using a CSF-based biomarker model
(2024) Nature Aging, .
Salvadó, G.a , Horie, K.b c d , Barthélemy, N.R.b c , Vogel, J.W.a e , Pichet Binette, A.a , Chen, C.D.f , Aschenbrenner, A.J.c g , Gordon, B.A.f , Benzinger, T.L.S.f g , Holtzman, D.M.c g , Morris, J.C.c g , Palmqvist, S.a h , Stomrud, E.a h , Janelidze, S.a , Ossenkoppele, R.a i j , Schindler, S.E.c g , Bateman, R.J.b c g , Hansson, O.a h
a Clinical Memory Research Unit, Department of Clinical Sciences Malmö, Lund University, Lund, Sweden
b Tracy Family Stable Isotope Labeling Quantitation (SILQ) Center, Washington University School of Medicine, St. Louis, MO, United States
c Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States
d Eisai, Inc., Nutley, NJ, United States
e Department of Clinical Science, Malmö, SciLifeLab, Lund University, Lund, Sweden
f Department of Radiology, Washington University School of Medicine, St. Louis, MO, United States
g Charles F. and Joanne Knight Alzheimer Disease Research Center, Washington University School of Medicine, St. Louis, MO, United States
h Memory Clinic, Skåne University Hospital, Malmö, Sweden
i Alzheimer Center Amsterdam, Neurology, Vrije Universiteit Amsterdam, Amsterdam UMC location VUmc, Amsterdam, Netherlands
j Amsterdam Neuroscience, Neurodegeneration, Amsterdam, Netherlands
Abstract
Biological staging of individuals with Alzheimer’s disease (AD) may improve diagnostic and prognostic workup of dementia in clinical practice and the design of clinical trials. In this study, we used the Subtype and Stage Inference (SuStaIn) algorithm to establish a robust biological staging model for AD using cerebrospinal fluid (CSF) biomarkers. Our analysis involved 426 participants from BioFINDER-2 and was validated in 222 participants from the Knight Alzheimer Disease Research Center cohort. SuStaIn identified a singular biomarker sequence and revealed that five CSF biomarkers effectively constituted a reliable staging model (ordered: Aβ42/40, pT217/T217, pT205/T205, MTBR-tau243 and non-phosphorylated mid-region tau). The CSF stages (0–5) demonstrated a correlation with increased abnormalities in other AD-related biomarkers, such as Aβ-PET and tau-PET, and aligned with longitudinal biomarker changes reflective of AD progression. Higher CSF stages at baseline were associated with an elevated hazard ratio of clinical decline. This study highlights a common molecular pathway underlying AD pathophysiology across all patients, suggesting that a single CSF collection can accurately indicate the presence of AD pathologies and characterize the stage of disease progression. The proposed staging model has implications for enhancing diagnostic and prognostic assessments in both clinical practice and the design of clinical trials. © The Author(s) 2024.
Document Type: Article
Publication Stage: Article in Press
Source: Scopus