Hope Center member publications

Severe acute neurotoxicity reflects absolute intra-carotid 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine dose in non-human primates
(2022) Journal of Neuroscience Methods, 366, art. no. 109406, . 

Norris, S.A.^a b , White, H.C.B.^a , Tanenbaum, A.^a , Williams, E.L.^a , Cruchaga, C.^c , Tian, L.^a , Schmidt, R.E.^d , Perlmutter, J.S.^{a b e f g}

^a Departments of Neurology, Washington University School of Medicine, 660 S. Euclid Ave, St. Louis, MO 63110, United States
^b Departments of Radiology, Washington University School of Medicine, 660 S. Euclid Ave, St. Louis, MO 63110, United States
^c Departments of Psychiatry, Washington University School of Medicine, 660 S. Euclid Ave, St. Louis, MO 63110, United States
^d Departments of Pathology, Washington University School of Medicine, 660 S. Euclid Ave, St. Louis, MO 63110, United States
^e Departments of Neuroscience, Washington University School of Medicine, 660 S. Euclid Ave, St. Louis, MO 63110, United States
^f Departments of Physical, Washington University School of Medicine, 660 S. Euclid Ave, St. Louis, MO 63110, United States
^g Departments of Occupational Therapy, Washington University School of Medicine, 660 S. Euclid Ave, St. Louis, MO 63110, United States

Author Keywords
Basal ganglia;  Monkey;  MPTP;  Neurotoxicity;  Striatum

Funding details
National Institute on AgingNIANS039913, NS050425, NS058714, NS075321, NS075527, NS103957, NS107281
National Institute of Neurological Disorders and StrokeNINDS
American Parkinson Disease AssociationAPDA
Washington University in St. LouisWUSTL
Foundation for Barnes-Jewish Hospital
McDonnell Center for Systems Neuroscience

Document Type: Article
Publication Stage: Final
Source: Scopus

The phenotypic spectrum of PCDH12 associated disorders – Five new cases and review of the literature
(2022) European Journal of Paediatric Neurology, 36, pp. 7-13.

Fazeli, W.^a b c , Bamborschke, D.^a d , Moawia, A.^a d , Bakhtiari, S.^e f , Tafakhori, A.^g , Giersdorf, M.^a , Hahn, A.^h , Weik, A.ⁱ , Kolzter, K.^j , Shafiee, S.^k , Jin, S.C.^l , Körber, F.^m , Lee-Kirsch, M.A.ⁿ , Darvish, H.^o , Cirak, S.^a d , Kruer, M.C.^e f , Koy, A.^a 

^a Department of Pediatrics, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany
^b Institute for Molecular and Behavioral Neuroscience, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany
^c Department of Neuropediatrics, University Hospital Bonn, Bonn, Germany
^d Center for Molecular Medicine Cologne (CMMC), Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany
^e Pediatric Movement Disorders Program, Barrow Neurological Institute, Phoenix Children’s Hospital, Phoenix, AZ, United States
^f Departments of Child Health, Cellular & Molecular Medicine, and Neurology and Program in Genetics, University of Arizona College of Medicine Phoenix, Phoenix, AZ, United States
^g Iranian Center of Neurological Research, Neuroscience Institute, Tehran University of Medical Sciences, Tehran, Iran
^h Department of Child Neurology, Justus-Liebig-University Giessen, Giessen, Germany
ⁱ CeGAT GmbH and Praxis für Humangenetik Tübingen, Tübingen, Germany
^j Children’s Hospital Amsterdamer Straße, Kliniken der Stadt Köln, Cologne, Germany
^k Neurological Surgery Department, Mazandaran University of Medical Sciences, Sari, Iran
^l Department of Genetics, Washington University School of Medicine, St. Louis, MO, United States
^m Department of Radiology, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany
ⁿ Department of Pediatrics, Medical Faculty Carl Gustav Carus, Technical University Dresden, Dresden, Germany
^o Neuroscience Research Center, Faculty of Medicine, Golestan University of Medical Sciences, Gorgan, Iran

Abstract
PCDH12 is a member of the non-clustered protocadherin family of calcium-dependent cell adhesion proteins, which are involved in the regulation of brain development and endothelial adhesion. To date, only 15 families have been reported with PCDH12 associated disease. The main features previously associated with PCDH12 deficiency are developmental delay, movement disorder, epilepsy, microcephaly, visual impairment, midbrain malformations, and intracranial calcifications. Here, we report novel clinical features such as onset of epilepsy after infancy, episodes of transient developmental regression, and dysplasia of the medulla oblongata associated with three different novel truncating PCDH12 mutations in five cases (three children, two adults) from three unrelated families. Interestingly, our data suggests a clinical overlap with interferonopathies, and we show an elevated interferon score in two pediatric patients. This case series expands the genetic and phenotypic spectrum of PCDH12 associated diseases and highlights the broad clinical variability. © 2021 European Paediatric Neurology Society

Author Keywords
Brain malformation;  Epilepsy;  Interferonopathy;  Intracranial calcification;  Movement disorder;  PCDH12

Funding details
Cerebral Palsy Alliance Research FoundationCPARF01318
Deutsche ForschungsgemeinschaftDFGCRC237 369799452/B21, Cl 218/1-1
Universität zu KölnUoC

Document Type: Article
Publication Stage: Final
Source: Scopus

A novel model of acquired hydrocephalus for evaluation of neurosurgical treatments
(2021) Fluids and Barriers of the CNS, 18 (1), art. no. 49, . 

McAllister, J.P., II^a i , Talcott, M.R.^a b , Isaacs, A.M.^c , Zwick, S.H.^a , Garcia-Bonilla, M.^a , Castaneyra-Ruiz, L.^a , Hartman, A.L.^a , Dilger, R.N.^d e , Fleming, S.A.^d e , Golden, R.K.^d , Morales, D.M.^a , Harris, C.A.^f g , Limbrick, D.D., Jr^a h

^a Department of Neurosurgery, Washington University in St. Louis School of Medicine, St. Louis, MO 63110, United States
^b Division of Comparative Medicine, Washington University in St. Louis School of Medicine, St. Louis, MO 63110, United States
^c Department of Surgery, Division of Neurosurgery, University of Calgary School of Medicine, Calgary, AB T2N 2T9, Canada
^d Department of Animal Sciences, Division of Nutritional Sciences, Neuroscience Program, University of Illinois, Champagne-Urbana, Illinois, 61801, United States
^e Traverse Science, Champaign, IL 61801, United States
^f Department of Chemical Engineering and Materials Science, Wayne State University, Detroit, MI 48202, United States
^g Department of Neurosurgery, Wayne State University School of Medicine, Detroit, MI 48202, United States
^h Department of Pediatrics, St. Louis Children’s Hospital, St. Louis, MO 63110, United States
ⁱ Department of Neurosurgery, BJC Institute of Health, 425 S. Euclid, Campus, Box 8057, St. Louis, MO 63143, United States

Abstract
Background: Many animal models have been used to study the pathophysiology of hydrocephalus; most of these have been rodent models whose lissencephalic cerebral cortex may not respond to ventriculomegaly in the same way as gyrencephalic species and whose size is not amenable to evaluation of clinically relevant neurosurgical treatments. Fewer models of hydrocephalus in gyrencephalic species have been used; thus, we have expanded upon a porcine model of hydrocephalus in juvenile pigs and used it to explore surgical treatment methods. Methods: Acquired hydrocephalus was induced in 33–41-day old pigs by percutaneous intracisternal injections of kaolin (n = 17). Controls consisted of sham saline-injected (n = 6) and intact (n = 4) animals. Magnetic resonance imaging (MRI) was employed to evaluate ventriculomegaly at 11–42 days post-kaolin and to plan the surgical implantation of ventriculoperitoneal shunts at 14–38-days post-kaolin. Behavioral and neurological status were assessed. Results: Bilateral ventriculomegaly occurred post-induction in all regions of the cerebral ventricles, with prominent CSF flow voids in the third ventricle, foramina of Monro, and cerebral aqueduct. Kaolin deposits formed a solid cast in the basal cisterns but the cisterna magna was patent. In 17 untreated hydrocephalic animals. Mean total ventricular volume was 8898 ± 5917 SD mm3 at 11–43 days of age, which was significantly larger than the baseline values of 2251 ± 194 SD mm3 for 6 sham controls aged 45–55 days, (p < 0.001). Past the post-induction recovery period, untreated pigs were asymptomatic despite exhibiting mild-moderate ventriculomegaly. Three out of 4 shunted animals showed a reduction in ventricular volume after 20–30 days of treatment, however some developed ataxia and lethargy, from putative shunt malfunction. Conclusions: Kaolin induction of acquired hydrocephalus in juvenile pigs produced an in vivo model that is highly translational, allowing systematic studies of the pathophysiology and clinical treatment of hydrocephalus. © 2021, The Author(s).

Author Keywords
Acquired hydrocephalus;  Animal models;  Cognition;  Hydrocephalus;  Kaolin;  Shunt;  Ventriculomegaly

Funding details
National Institutes of HealthNIH5R21NS111249-02
Washington University School of Medicine in St. LouisWUSM

Document Type: Article
Publication Stage: Final
Source: Scopus

GABAergic neuronal IL-4R mediates T cell effect on memory
(2021) Neuron, 109 (22), pp. 3609-3618.e9. 

Herz, J.^a b , Fu, Z.^a b , Kim, K.^a b , Dykstra, T.^a b , Wall, M.^f , Li, H.^c , Salvador, A.F.^a b g , Zou, B.^e , Yan, N.^e , Blackburn, S.M.^a b , Andrews, P.H.^f , Goldman, D.H.^a b g , Papadopoulos, Z.^a b d , Smirnov, I.^a b , Xie, X.S.^e , Kipnis, J.^a b d

^a Center for Brain Immunology and Glia (BIG), Washington University in St. Louis, St. Louis, MO, United States
^b Department of Pathology and Immunology, Washington University in St. Louis, St. Louis, MO, United States
^c Department of Child Health Care, Children’s Hospital of Fudan University, Shanghai, China
^d Neuroscience Graduate Program, School of Medicine, Washington University in St. Louis, St. Louis, MO 63110, United States
^e AfaSci Research Laboratories, 522 Second Avenue, Redwood City, CA, United States
^f Department of Neuroscience, University of Virginia School of Medicine, Charlottesville, VA, United States
^g Neuroscience Graduate Program, University of Virginia, Charlottesville, VA, United States

Abstract
Mechanisms governing how immune cells and their derived molecules impact homeostatic brain function are still poorly understood. Here, we elucidate neuronal mechanisms underlying T cell effects on synaptic function and episodic memory. Depletion of CD4 T cells led to memory deficits and impaired long-term potentiation. Severe combined immune-deficient mice exhibited amnesia, which was reversible by repopulation with T cells from wild-type but not from IL-4-knockout mice. Behaviors impacted by T cells were mediated via IL-4 receptors expressed on neurons. Exploration of snRNA-seq of neurons participating in memory processing provided insights into synaptic organization and plasticity-associated pathways regulated by immune cells. IL-4Rα knockout in inhibitory (but not in excitatory) neurons was sufficient to impair contextual fear memory, and snRNA-seq from these mice pointed to IL-4-driven regulation of synaptic function in promoting memory. These findings provide new insights into complex neuroimmune interactions at the transcriptional and functional levels in neurons under physiological conditions. © 2021 Elsevier Inc.

Author Keywords
IL-4;  learning and memory;  meninges;  neuroimmunology;  T cells

Funding details
National Institutes of HealthNIHAG034113, AG057496, AT010416, NS096967

Document Type: Article
Publication Stage: Final
Source: Scopus

MR imaging differences in the circle of willis between healthy children and adults
(2021) American Journal of Neuroradiology, 42 (11), . 

Guilliams, K.P.^a b c , Gupta, N.^c , Srinivasan, S.^c , Binkley, M.M.^a , Ying, C.^c , Couture, L.^c , Gross, J.^f , Wallace, A.^g , McKinstry, R.C.^b c , Vo, K.^c , Lee, J.-M.^a c d , An, H.^c , Goyal, M.S.^a c e

^a Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States
^b Department of Pediatrics, Washington University School of Medicine, St. Louis, MO, United States
^c Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, MO, United States
^d Department of Biomedical Engineering, Washington University School of Medicine, St. Louis, MO, United States
^e Department of Neuroscience, Washington University School of Medicine, St. Louis, MO, United States
^f Division of Neuroradiology, Midwest Radiology, St. Paul, MN, United States
^g Department of Neurointerventional Surgery, Ascension Columbia St. Mary’s Hospital, Milwaukee, WI, United States

Abstract
BACKGROUND AND PURPOSE: Asymmetries in the circle of Willis have been associated with several conditions, including migraines and stroke, but they may also be age-dependent. This study examined the impact of age and age-dependent changes in cerebral perfusion on circle of Willis anatomy in healthy children and adults. MATERIALS AND METHODS: We performed an observational, cross-sectional study of bright and black-blood imaging of the proximal cerebral vasculature using TOF-MRA and T2 sampling perfection with application-optimized contrasts by using different flip angle evolution (T2-SPACE) imaging at the level of the circle of Willis in 23 healthy children and 43 healthy adults (4–74 years of age). We compared arterial diameters measured manually and cerebral perfusion via pseudocontinuous arterial spin-labeling between children and adults. RESULTS: We found that the summed cross-sectional area of the circle of Willis is larger in children than in adults, though the effect size was smaller with T2-SPACE-based measurements than with TOF-MRA. The circle of Willis is also more symmetric in children, and nonvisualized segments occur more frequently in adults than in children. Moreover, the size and symmetry of the circle of Willis correlate with cerebral perfusion. CONCLUSIONS: Our results demonstrate that the circle of Willis is different in size and symmetry in healthy children compared with adults, likely associated with developmental changes in cerebral perfusion. Further work is needed to understand why asymmetric vasculature develops in some but not all adults. Copyright 2021 by American Society of Neuroradiology.

Funding details
National Institutes of HealthNIHK23NS099472, R01AG057536
McDonnell Center for Systems Neuroscience

Document Type: Article
Publication Stage: Final
Source: Scopus

Unbiased high-content screening reveals Aβ- And tau-independent synaptotoxic activities in human brain homogenates from Alzheimer’s patients and high-pathology controls
(2021) PLoS ONE, 16 (11 November), art. no. e0259335, . 

Jiang, H.^a , Esparza, T.J.^a b c , Kummer, T.T.^a , Brody, D.L.^a c d

^a Department of Neurology, Washington University, School of Medicine, St Louis, MO, United States
^b HenryM Jackson Foundation for the Advancement of Military Medicine, Bethesda, MD, United States
^c National Institute of Neurological Disorders and Stroke, Bethesda, MD, United States
^d Department of Neurology, Uniformed Services University of the Health Sciences, Bethesda, MD, United States

Abstract
Alzheimer’s disease (AD) is tightly correlated with synapse loss in vulnerable brain regions. It is assumed that specific molecular entities such as Aβ and tau cause synapse loss in AD, yet unbiased screens for synaptotoxic activities have not been performed. Here, we performed size exclusion chromatography on soluble human brain homogenates from AD cases, high pathology non-demented controls, and low pathology age-matched controls using our novel high content primary cultured neuron-based screening assay. Both presynaptic and postsynaptic toxicities were elevated in homogenates from AD cases and high pathology non-demented controls to a similar extent, with more modest synaptotoxic activities in homogenates from low pathology normal controls. Surprisingly, synaptotoxic activities were found in size fractions peaking between the 17-44 kDa size standards that did not match well with Aβ and tau immunoreactive species in these homogenates. The fractions containing previously identified high molecular weight soluble amyloid beta aggregates/ “oligomers”were non-toxic in this assay. Furthermore, immunodepletion of Aβ and tau did not reduce synaptotoxic activity. This result contrasts with previous findings involving the same methods applied to 3xTg-AD mouse brain extracts. The nature of the synaptotoxic species has not been identified. Overall, our data indicates one or more potential Aβ and tau independent synaptotoxic activities in human AD brain homogenates. This result aligns well with the key role of synaptic loss in the early cognitive decline and may provide new insight into AD pathophysiology. © 2021 This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.

Document Type: Article
Publication Stage: Final
Source: Scopus

Estradiol protects against noise-induced hearing loss and modulates auditory physiology in female mice
(2021) International Journal of Molecular Sciences, 22 (22), art. no. 12208, . 

Shuster, B.^a , Casserly, R.^a , Lipford, E.^a , Olszewski, R.^b , Milon, B.^a , Viechweg, S.^c , Davidson, K.^c , Enoch, J.^c , McMurray, M.^a , Rutherford, M.A.^d , Ohlemiller, K.K.^d , Hoa, M.^b , Depireux, D.A.^e , Mong, J.A.^c , Hertzano, R.^a f g

^a Department of Otorhinolaryngology—Head and Neck Surgery, University of Maryland School of Medicine, Baltimore, MD 21201, United States
^b Auditory Development and Restoration Program, National Institute on Deafness and Other Communication Disorders, NIH, Bethesda, MD 20892, United States
^c Department of Pharmacology, University of Maryland School of Medicine, Baltimore, MD 21201, United States
^d Department of Otolaryngology, Washington University School of Medicine, St. Louis, MO 63110, United States
^e Otolith Labs, Washington, DC 20036, United States
^f Department of Anatomy and Neurobiology, University of Maryland School of Medicine, Baltimore, MD 21201, United States
^g Institute for Genome Sciences, University of Maryland School of Medicine, Baltimore, MD 21201, United States

Abstract
Recent studies have identified sex-differences in auditory physiology and in the susceptibility to noise-induced hearing loss (NIHL). We hypothesize that 17β-estradiol (E2 ), a known modulator of auditory physiology, may underpin sex-differences in the response to noise trauma. Here, we gonadectomized B6CBAF1/J mice and used a combination of electrophysiological and histological techniques to study the effects of estrogen replacement on peripheral auditory physiology in the absence of noise exposure and on protection from NIHL. Functional analysis of auditory physiology in gonadectomized female mice revealed that E2-treatment modulated the peripheral response to sound in the absence of changes to the endocochlear potential compared to vehicle-treatment. E2-replacement in gonadectomized female mice protected against hearing loss following permanent threshold shift (PTS)-and temporary threshold shift (TTS)-inducing noise exposures. Histological analysis of the cochlear tissue revealed that E2-replacement mitigated outer hair cell loss and cochlear synaptopathy following noise exposure compared to vehicle-treatment. Lastly, using fluorescent in situ hybridization, we demonstrate co-localization of estrogen receptor-2 with type-1C, high threshold spiral ganglion neurons, suggesting that the observed protection from cochlear synaptopathy may occur through E2-mediated preservation of these neurons. Taken together, these data indicate the estrogen signaling pathways may be harnessed for the prevention and treatment of NIHL. © 2021 by the authors. Licensee MDPI, Basel, Switzerland.

Author Keywords
Auditory physiology;  Cochlear synaptopa-thy;  Estrogen;  Inner ear;  Mouse model;  Noise-induced hearing loss;  Sex-differences

Funding details
National Institutes of HealthNIHR01DC013817
U.S. Department of DefenseDODMR130240, W81XWH2110578
National Institute on Deafness and Other Communication DisordersNIDCDR01DC014712, Z01DC000088
School of Medicine, University of MarylandSOM, UMD

Document Type: Article
Publication Stage: Final
Source: Scopus

Specific RNA interactions promote TDP-43 multivalent phase separation and maintain liquid properties
(2021) EMBO Reports, . 

Grese, Z.R.^a , Bastos, A.C.S.^a , Mamede, L.D.^a , French, R.L.^a , Miller, T.M.^b , Ayala, Y.M.^a

^a Edward Doisy Department of Biochemistry and Molecular Biology, Saint Louis University, St. Louis, MO, United States
^b Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States

Abstract
TDP-43 is an RNA-binding protein that forms ribonucleoprotein condensates via liquid-liquid phase separation (LLPS) and regulates gene expression through specific RNA interactions. Loss of TDP-43 protein homeostasis and dysfunction are tied to neurodegenerative disorders, mainly amyotrophic lateral sclerosis (ALS) and frontotemporal dementia. Alterations of TDP-43 LLPS properties may be linked to protein aggregation. However, the mechanisms regulating TDP-43 LLPS are ill-defined, particularly how TDP-43 association with specific RNA targets regulates TDP-43 condensation remains unclear. We show that RNA binding strongly promotes TDP-43 LLPS through sequence-specific interactions. RNA-driven condensation increases with the number of adjacent TDP-43-binding sites and is also mediated by multivalent interactions involving the amino and carboxy-terminal TDP-43 domains. The physiological relevance of RNA-driven TDP-43 condensation is supported by similar observations in mammalian cellular lysate. Importantly, we find that TDP-43-RNA association maintains liquid-like properties of the condensates, which are disrupted in the presence of ALS-linked TDP-43 mutations. Altogether, RNA binding plays a central role in modulating TDP-43 condensation while maintaining protein solubility, and defects in this RNA-mediated activity may underpin TDP-43-associated pathogenesis. © 2021 The Authors

Author Keywords
amyotrophic lateral sclerosis;  liquid-liquid phase separation;  ribonucleoprotein (RNP) granules;  RNA-binding protein;  TDP-43

Funding details
R01 NS078398, W81XWH‐20‐1‐0241
R01 NS114289, R56 NS105806
National Institutes of HealthNIH
U.S. Department of DefenseDOD
National Institute of Neurological Disorders and StrokeNINDS

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

Evaluation of 2D FLAIR hyperintensity of the optic nerve and optic nerve head and visual parameters in idiopathic intracranial hypertension
(2021) Journal of Neuroradiology, . 

Orlowski, H.^a , Sharma, A.^a , Alvi, F.^b , Arora, J.^c , Parsons, M.S.^a , Van Stavern, G.P.^d

^a Mallinckrodt Institute of Radiology, Washington University School of Medicine, 510 S. Kingshighway Blvd. St. LouisMO, United States
^b Washington University School of Medicine, 660 S. Euclid Ave. St. LouisMO, United States
^c Division of Biostatistics, Washington University School of Medicine, 660 S. Euclid Ave, CB, St. Louis, MO 8067, United States
^d Department of Ophthalmology and Visual Sciences, Washington University School of Medicine, 517 S. Euclid Ave, St. Louis, MO, United States

Abstract
Background and purpose: T2/FLAIR hyperintensity of the optic nerve/optic nerve head has been described as a sensitive finding in idiopathic intracranial hypertension using post-contrast 3D-T2/FLAIR imaging. The purpose of this study is to assess whether hyperintensity on non-enhanced 2D-T2/FLAIR imaging occurs more likely in diseased patients than controls and to evaluate the relationship between FLAIR signal and visual parameters Materials and methods: A retrospective case-control study was performed of patients with idiopathic intracranial hypertension and controls who underwent orbital MRI. Three neuroradiologists reviewed the FLAIR images, subjectively evaluating for hyperintense signal within the optic nerves/optic nerve heads using a 5-point Likert Scale. Quantitative assessment of optic nerve signal using regions of interests was performed. Clinical parameters were extracted. The diagnostic performance was evaluated, and Spearman correlation calculated to assess the relationship between FLAIR signal and visual outcomes. Results: The sensitivity of abnormal FLAIR signal within the optic nerves and optic nerve heads in patients with idiopathic intracranial hypertension ranged from 25–54% and 4–29%, respectively, with specificities ranging from 67–92% and 83–100%. Quantitative assessment revealed a significant difference in CNR between cases and controls in the left posterior optic nerve (p=.002). A positive linear relationship existed between abnormal optic nerve head signal and papilledema grade (OD: p=.02, OS: p=.008) but not with other visual parameters. Conclusion: T2/FLAIR hyperintensity in the optic nerve/optic nerve head may support the diagnosis of idiopathic intracranial hypertension but its absence should not dissuade it. If present, abnormal signal in the optic nerve head correlates with papilledema. © 2021 Elsevier Masson SAS

Author Keywords
FLAIR imaging;  Idiopathic intracranial hypertension;  Magnetic resonance imaging;  Orbits;  Papilledema

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

Solvent exposed occupations and risk of Parkinson disease in Finland
(2021) Clinical Parkinsonism and Related Disorders, 4, art. no. 100092, . 

Nielsen, S.S.^a , Warden, M.N.^a , Sallmén, M.^b , Sainio, M.^b , Uuksulainen, S.^b , Checkoway, H.^c d , Hublin, C.^b , Racette, B.A.^a e

^a Washington University School of Medicine in St. Louis, Department of Neurology, 660 S. Euclid Avenue, St. Louis, MO 63110, United States
^b Finnish Institute of Occupational Health, PO Box 18, FI-00032 Tyoterveyslaitos, Arinatie 3 A, Helsinki, 00370, Finland
^c University of California, San Diego, Herbert Wertheim School of Public Health, 9500 Gilman Drive, La Jolla, CA 92093, United States
^d University of California, San Diego, Department of Neurosciences, 9500 Gilman Drive, La Jolla, CA 92093, United States
^e University of the Witwatersrand, School of Public Health, Faculty of Health Sciences, 27 St. Andrews Road, Parktown, Johannesburg 2193, South Africa

Abstract
Introduction: Epidemiologic and toxicology studies suggest that exposure to various solvents, especially chlorinated hydrocarbon solvents, might increase Parkinson disease (PD) risk. Methods: In a population-based case-control study in Finland, we examined whether occupations with potential for solvent exposures were associated with PD. We identified newly diagnosed cases age 45–84 from a nationwide medication reimbursement register in 1995–2014. From the population register, we randomly selected non-PD controls matched on sex, along with birth and diagnosis years (age). We included 11,757 cases and 23,236 controls with an occupation in the 1990 census, corresponding to age 40–60. We focused on 28 occupations with ≥ 5% probability of solvent exposure according to the Finnish Job Exposure Matrix. We estimated odds ratios (ORs) and 95% confidence intervals (CIs) by logistic regression modeling, adjusting for age, sex, socioeconomic status, and smoking probability. Results: Similar proportions of cases (5.5%) and controls (5.6%) had an occupation with potential exposure to any solvents. However, all occupations with a point estimate above one, and all significantly or marginally significantly associated with PD (electronic/telecommunications worker [OR = 1.63, 95% CI 1.05–2.50], laboratory assistant [OR = 1.40, 95% CI 0.98–1.99], and machine/engine mechanic [OR = 1.23, 95% CI 0.99–1.52]) entailed potential for exposure to chlorinated hydrocarbon solvents, specifically. Secondary analyses indicated exposure to polycyclic aromatic hydrocarbons and some metals might contribute to the association for mechanics. Conclusion: PD risk might be slightly increased in occupations with potential exposure to chlorinated hydrocarbon solvents. Confirmation is required in additional studies that adjust for other occupational exposures and smoking. © 2021 The Author(s)

Author Keywords
1,1,1-trichloroethane;  Methylene chloride;  Parkinson disease;  Solvents;  Trichloroethylene

Document Type: Article
Publication Stage: Final
Source: Scopus

Independently validated sex-specific nomograms for predicting survival in patients with newly diagnosed glioblastoma: NRG Oncology RTOG 0525 and 0825
(2021) Journal of Neuro-Oncology, . 

Patil, N.^a , Somasundaram, E.^b , Waite, K.A.^c , Lathia, J.D.^d e , Machtay, M.^f , Gilbert, M.R.^g , Connor, J.R.^f , Rubin, J.B.^h , Berens, M.E.ⁱ , Buerki, R.A.^a , Choi, S.^a , Sloan, A.E.^a b e , Penas-Prado, M.^j , Ashby, L.S.^k , Blumenthal, D.T.^l , Werner-Wasik, M.^m , Hunter, G.K.ⁿ , Flickinger, J.C.^o , Wendland, M.M.^p , Panet-Raymond, V.^q , Robins, H.I.^r , Pugh, S.L.^s , Mehta, M.P.^t , Barnholtz-Sloan, J.S.^a b c u

^a University Hospitals, Cleveland, OH, United States
^b Case Western Reserve University School of Medicine, Cleveland, OH, United States
^c Division of Cancer Epidemiology and Genetics (DCEG), Trans-Divisional Research Program (TDRP) National Cancer Institute (NCI) National Institutes of Health (NIH), Shady Grove, MD, United States
^d Cleveland Clinic Foundation, Cleveland, OH, United States
^e Case Comprehensive Cancer Center, Cleveland, OH, United States
^f Penn State Milton S Hershey Medical Center, Hershey, PA, United States
^g National Cancer Institute, Neuro-Oncology Branch, Bethesda, MD, United States
^h Washington University of St Louis, St. Louis, MO, United States
ⁱ TGen, Translational Genomics Research Institute, an Affiliate of City of Hope, Phoenix, AZ, United States
^j National Cancer Institute, Neuro-Oncology Branch; Accruals for University of Texas-MD Anderson Cancer Center (Houston, TX, USA), Bethesda, MD, United States
^k Barrow Neurology Clinics Accruals for Arizona Oncology Services Foundation, Phoenix, AZ, United States
^l Tel-Aviv Medical Center, Tel-Aviv University, Tel Aviv-Yafo, Israel
^m Thomas Jefferson University Hospital, Philadelphia, PA, United States
ⁿ Intermountain Medical Center, Salt Lake City, UT, United States
^o UPMC-Shadyside Hospital, Pittsburgh, PA, United States
^p USON- Willamette Valley Cancer Center, Eugene, OR, United States
^q McGill University Health Center, Montreal, QC, Canada
^r University of Wisconsin School of Medicine and Public Health, Madison, WI, United States
^s NRG Oncology Statistics and Data Management Center, American College of Radiology, Philadelphia, PA, United States
^t Miami Cancer Institute, Miami, FL, United States
^u Center for Biomedical Informatics and Information Technology (CBITT), National Cancer Institute (NCI)/National Institutes of Health (NIH), Shady Grove, MD, United States

Abstract
Background/purpose: Glioblastoma (GBM) is the most common primary malignant brain tumor. Sex has been shown to be an important prognostic factor for GBM. The purpose of this study was to develop and independently validate sex-specific nomograms for estimation of individualized GBM survival probabilities using data from 2 independent NRG Oncology clinical trials. Methods: This analysis included information on 752 (NRG/RTOG 0525) and 599 (NRG/RTOG 0825) patients with newly diagnosed GBM. The Cox proportional hazard models by sex were developed using NRG/RTOG 0525 and significant variables were identified using a backward selection procedure. The final selected models by sex were then independently validated using NRG/RTOG 0825. Results: Final nomograms were built by sex. Age at diagnosis, KPS, MGMT promoter methylation and location of tumor were common significant predictors of survival for both sexes. For both sexes, tumors in the frontal lobes had significantly better survival than tumors of multiple sites. Extent of resection, and use of corticosteroids were significant predictors of survival for males. Conclusions: A sex specific nomogram that assesses individualized survival probabilities (6-, 12- and 24-months) for patients with GBM could be more useful than estimation of overall survival as there are factors that differ between males and females. A user friendly online application can be found here—https://npatilshinyappcalculator.shinyapps.io/SexDifferencesInGBM/. © 2021, This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply.

Author Keywords
Glioblastoma;  Nomogram;  Sex differences;  Survival

Funding details
National Cancer InstituteNCI
Genentech5P30CA043703-30S1
Merck

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