“Autosomal dominantly inherited alzheimer disease: Analysis of genetic subgroups by machine learning” (2020) Information Fusion
Autosomal dominantly inherited alzheimer disease: Analysis of genetic subgroups by machine learning
(2020) Information Fusion, 58, pp. 153-167.
Castillo-Barnes, D.a , Su, L.b , Ramírez, J.a , Salas-Gonzalez, D.a , Martinez-Murcia, F.J.c , Illan, I.A.a , Segovia, F.a , Ortiz, A.c , Cruchaga, C.d , Farlow, M.R.e , Xiong, C.f , Graff-Radford, N.R.g , Schofield, P.R.h , Masters, C.L.i , Salloway, S.j , Jucker, M.k , Mori, H.l , Levin, J.m , Gorriz, J.M.a b , (DIAN), D.I.A.N.n
a Department of Signal Theory, Telematics and Communications, University of Granada, Granada, Spain
b Department of Psychiatry, University of Cambridge, Cambridge, United Kingdom
c Department of Communications Engineering, University of Malaga, Malaga, Spain
d Department of Psychiatry and Neurology, Washington University School of Medicine, St. Louis, Missouri, United States
e Department of Neurology, Indiana University School of Medicine, Indianapolis, IN, United States
f Division of Biostatistics, Washington University School of Medicine, St. Louis, Missouri, United States
g Department of Neurology, Mayo Clinic, Jacksonville, FL, United States
h Neuroscience Research Australia and School of Medical Sciences, University of New South Wales, Sydney, Australia
i Florey Institute and University of Melbourne, Victoria, Australia
j Butler Hospital, Rhode Island, United States
k German Center for Neurodegenerative Diseases (DZNE) and Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany
l Department of Clinical Neuroscience, Osaka City University Medical school, Osaka, Japan
m Department of Neurology, Ludwig-Maximilians-University of Munich, German Center of Neurodegenerative Diseases (DZNE) and Munich Cluster of Systems Neurology (SyNergy), Munich, Germany
Abstract
Despite subjects with Dominantly-Inherited Alzheimer’s Disease (DIAD) represent less than 1% of all Alzheimer’s Disease (AD) cases, the Dominantly Inherited Alzheimer Network (DIAN) initiative constitutes a strong impact in the understanding of AD disease course with special emphasis on the presyptomatic disease phase. Until now, the 3 genes involved in DIAD pathogenesis (PSEN1, PSEN2 and APP) have been commonly merged into one group (Mutation Carriers, MC) and studied using conventional statistical analysis. Comparisons between groups using null-hypothesis testing or longitudinal regression procedures, such as the linear-mixed-effects models, have been assessed in the extant literature. Within this context, the work presented here performs a comparison between different groups of subjects by considering the 3 genes, either jointly or separately, and using tools based on Machine Learning (ML). This involves a feature selection step which makes use of ANOVA followed by Principal Component Analysis (PCA) to determine which features would be realiable for further comparison purposes. Then, the selected predictors are classified using a Support-Vector-Machine (SVM) in a nested k-Fold cross-validation resulting in maximum classification rates of 72–74% using PiB PET features, specially when comparing asymptomatic Non-Carriers (NC) subjects with asymptomatic PSEN1 Mutation-Carriers (PSEN1-MC). Results obtained from these experiments led to the idea that PSEN1-MC might be considered as a mixture of two different subgroups including: a first group whose patterns were very close to NC subjects, and a second group much more different in terms of imaging patterns. Thus, using a k-Means clustering algorithm it was determined both subgroups and a new classification scenario was conducted to validate this process. The comparison between each subgroup vs. NC subjects resulted in classification rates around 80% underscoring the importance of considering DIAN as an heterogeneous entity. © 2020 Elsevier B.V.
Author Keywords
Alzheimer’s disease (AD); DIAN; Dominantly-inherited Alzheimer’s disease (DIAD); Machine learning; Neuroimaging
Document Type: Article
Publication Stage: Final
Source: Scopus
“Toddlers imitate prosocial demonstrations in bystander but not transgressor contexts” (2020) Journal of Experimental Child Psychology
Toddlers imitate prosocial demonstrations in bystander but not transgressor contexts
(2020) Journal of Experimental Child Psychology, 192, art. no. 104776, .
Donohue, M.R.a b , Williamson, R.A.a , Tully, E.C.a
a Department of Psychology, Georgia State University, Atlanta, GA 30303, United States
b Department of Psychiatry, Washington University School of Medicine, St. Louis, MO 63110, United States
Abstract
Although prosocial abilities are associated with a wide range of healthy outcomes, few studies have experimentally examined socialization practices that may cause increased prosocial responding. The purpose of this study was to investigate conditions under which 2- and 3-year-old children can acquire prosocial behaviors through imitation. In Study 1 (N = 53), toddlers in the experimental condition watched a video of an adult comfort a woman in distress by performing a novel prosocial action without depicting how the woman was hurt. Parents then pretended they hurt their own finger and feigned distress. Children in the experimental condition were more likely to imitate the novel action relative to two control groups: (a) children who did not watch the video but witnessed a distressed parent, and (b) children who watched the video but witnessed parents engage in a neutral interaction. Thus, in a bystander context where children witnessed parent distress, toddlers imitated a general demonstration of how to respond prosocially to distress and applied this information to a specific distress scenario. In Study 2 (N = 54), the procedures were identical to those in the first study except that children were led to believe that they had transgressed to cause parent distress. In a transgressor context, children in the experimental condition were not more likely to imitate the prosocial behavior relative to children in either control group. These studies demonstrate that whether or not children have caused a victim’s distress greatly affects their ability to apply a socially learned prosocial behavior, possibly due to self-conscious emotions such as guilt and shame. © 2019 Elsevier Inc.
Author Keywords
Guilt; Imitation; Prosocial behavior; Reparative behavior; Self-conscious emotion; Transgression
Document Type: Article
Publication Stage: Final
Source: Scopus
“Diversity of neurogenic smooth muscle electrical rhythmicity in mouse proximal colon” (2020) American Journal of Physiology. Gastrointestinal and Liver Physiology
Diversity of neurogenic smooth muscle electrical rhythmicity in mouse proximal colon
(2020) American Journal of Physiology. Gastrointestinal and Liver Physiology, 318 (2), pp. G244-G253.
Spencer, N.J.a , Travis, L.a , Wiklendt, L.b , Hibberd, T.J.a , Costa, M.a , Dinning, P.b , Hu, H.c
a Visceral Neurophysiology Laboratory, College of Medicine and Public Health, Centre for Neuroscience, Flinders University, Bedford ParkSA, Australia
b Department of Gastroenterology, Flinders Medical Center, Bedford ParkSA, Australia
c Department of Anesthesiology, Center for the Study of Itch, Washington University, St. Louis, MO, United States
Abstract
The mechanisms underlying electrical rhythmicity in smooth muscle of the proximal colon are incompletely understood. Our aim was to identify patterns of electrical rhythmicity in smooth muscle of the proximal region of isolated whole mouse colon and characterize their mechanisms of origin. Two independent extracellular recording electrodes were used to record the patterns of electrical activity in smooth muscle of the proximal region of whole isolated mouse colon. Cross-correlation analysis was used to quantify spatial coordination of these electrical activities over increasing electrode separation distances. Four distinct neurogenic patterns of electrical rhythmicity were identified in smooth muscle of the proximal colon, three of which have not been identified and consisted of bursts of rhythmic action potentials at 1-2 Hz that were abolished by hexamethonium. These neurogenic patterns of electrical rhythmicity in smooth muscle were spatially and temporally synchronized over large separation distances (≥2 mm rosto-caudal axis). Myogenic slow waves could be recorded from the same preparations, but they showed poor spatial and temporal coordination over even short distances (≤1 mm rostro-caudal axis). It is not commonly thought that electrical rhythmicity in gastrointestinal smooth muscle is dependent upon the enteric nervous system. Here, we identified neurogenic patterns of electrical rhythmicity in smooth muscle of the proximal region of isolated mouse colon, which are dependent on synaptic transmission in the enteric nervous system. If the whole colon is studied in vitro, recordings can preserve novel neurogenic patterns of electrical rhythmicity in smooth muscle.NEW & NOTEWORTHY Previously, it has not often been thought that electrical rhythmicity in smooth muscle of the gastrointestinal tract is dependent upon the enteric nervous system. We identified patterns of electrical rhythmicity in smooth muscle of the mouse proximal colon that were abolished by hexamethonium and involved the temporal synchronization of smooth muscle membrane potential over large spatial fields. We reveal different patterns of electrical rhythmicity in colonic smooth muscle that are dependent on the ENS.
Author Keywords
autonomic; colon; enteric nervous system; peristalsis; smooth muscle
Document Type: Article
Publication Stage: Final
Source: Scopus
“Current opinion neurology: visual pathway biomarkers in Alzheimer’s disease” (2020) Current Opinion in Neurology
Current opinion neurology: visual pathway biomarkers in Alzheimer’s disease
(2020) Current Opinion in Neurology, 33 (1), pp. 79-86.
Van Stavern, G.P.
Department of Ophthalmology and Visual Sciences, Washington University in St. Louis School of Medicine, St. Louis, MO, United States
Abstract
PURPOSE OF REVIEW: The incidence of Alzheimer’s disease is increasing. Premortem diagnosis of Alzheimer’s disease is now possible but require invasive and expensive testing such as PET amyloid beta binding and/or spinal fluid amyloid beta levels. There is a great need for minimally invasive and inexpensive biomarkers to allow for early diagnosis and intervention. RECENT FINDINGS: There has been a large volume of literature assessing ocular biomarkers for Alzheimer’s disease. Much of the research to date has significant limitations, including sample size, variable diagnostic criteria for Alzheimer’s disease, lack of biomarker assessment, and focus on patients with well established dementia. Work that is more recent has included individuals with early and preclinical Alzheimer’s disease with biomarkers included in the design. These studies have shown consistent features of visual pathway involvement in Alzheimer’s disease, even in the earliest and preclinical stages. SUMMARY: It is possible that in the future, ocular biomarkers (particularly retinal imaging techniques) may be part of a multimodality alogorithm screening for preclinical Alzheimer’s disease, perhaps combined with other methods, such as blood-based biomarkers.
Document Type: Article
Publication Stage: Final
Source: Scopus
“Opioid-induced Miosis Is Unaltered by Obstructive Sleep Apnea: Reply” (2020) Anesthesiology
Opioid-induced Miosis Is Unaltered by Obstructive Sleep Apnea: Reply
(2020) Anesthesiology, 132 (2), pp. 400-401.
Montana, M.C.
Washington University in St. Louis, School of Medicine, St. Louis, MO, United States
Document Type: Article
Publication Stage: Final
Source: Scopus
“The functionally relevant site for paxilline inhibition of BK channels” (2020) Proceedings of the National Academy of Sciences of the United States of America
The functionally relevant site for paxilline inhibition of BK channels
(2020) Proceedings of the National Academy of Sciences of the United States of America, 117 (2), pp. 1021-1026.
Zhou, Y.a , Xia, X.-M.b , Lingle, C.J.c
a Department of Anesthesiology, Washington University School of Medicine, St. Louis, MO 63110 clingle@morpheus.wustl.edu
b Department of Anesthesiology, Washington University School of Medicine, St. Louis, MO 63110
c Department of Anesthesiology, Washington University School of Medicine, St. Louis, MO 63110 zhouy@wustl.edu clingle@morpheus.wustl.edu
Abstract
The tremorgenic fungal alkaloid paxilline (PAX) is a commonly used specific inhibitor of the large-conductance, voltage- and Ca2+-dependent BK-type K+ channel. PAX inhibits BK channels by selective interaction with closed states. BK inhibition by PAX is best characterized by the idea that PAX gains access to the channel through the central cavity of the BK channel, and that only a single PAX molecule can interact with the BK channel at a time. The notion that PAX reaches its binding site via the central cavity and involves only a single PAX molecule would be consistent with binding on the axis of the permeation pathway, similar to classical open channel block and inconsistent with the observation that PAX selectively inhibits closed channels. To explore the potential sites of interaction of PAX with the BK channel, we undertook a computational analysis of the interaction of PAX with the BK channel pore gate domain guided by recently available liganded (open) and metal-free (closed) Aplysia BK channel structures. The analysis unambiguously identified a preferred position of PAX occupancy that accounts for all previously described features of PAX inhibition, including state dependence, G311 sensitivity, stoichiometry, and central cavity accessibility. This PAX-binding pose in closed BK channels is supported by additional functional results.
Author Keywords
BK channels; Ca2+- and voltage-gated K+ channels; K+ channels; mSlo1 channels; paxilline
Document Type: Article
Publication Stage: Final
Source: Scopus
“Mutations in the J domain of DNAJB6 cause dominant distal myopathy” (2020) Neuromuscular Disorders
Mutations in the J domain of DNAJB6 cause dominant distal myopathy
(2020) Neuromuscular Disorders, .
Palmio, J.a , Jonson, P.H.b , Inoue, M.c , Sarparanta, J.b , Bengoechea, R.d , Savarese, M.b , Vihola, A.a b , Jokela, M.a e , Nakagawa, M.f , Noguchi, S.c , Olivé, M.g , Masingue, M.h , Kerty, E.i , Hackman, P.b , Weihl, C.C.d , Nishino, I.c , Udd, B.a b
a Neuromuscular Research Center, Tampere University Hospital and Tampere University, P.O. box 100, Tampere, FIN-33014, Finland
b Folkhälsan Research Center, Helsinki, Finland and University of Helsinki, Medicum, Helsinki, Finland
c National Center of Neurology and Psychiatry (NCNP), Department of Neuromuscular Research, National Institute of Neuroscience, Tokyo, Japan
d Department of Neurology, Washington University in St. Louis, St. Louis, MO, United States
e Division of Clinical Neurosciences, Turku University Hospital and University of Turku, Turku, Finland
f North Medical Center, Kyoto Prefectural University of Medicine, Kyoto, Japan
g Department of Pathology and Neuromuscular Unit, IDIBELL-Hospital de Bellvitge, Barcelona, Spain
h University Hospital of Salpêtrière, UPMC, Institute of Myology, National Reference Center for Neuromuscular Disorders, Paris, France
i Department of Neurology, Oslo University Hospital, Rikshospitalet, University of Oslo, Oslo, Norway
Abstract
Eight patients from five families with undiagnosed dominant distal myopathy underwent clinical, neurophysiological and muscle biopsy examinations. Molecular genetic studies were performed using targeted sequencing of all known myopathy genes followed by segregation of the identified mutations in the affected families using Sanger sequencing. Two novel mutations in DNAJB6 J domain, c.149C>T (p.A50V) and c.161A>C (p.E54A), were identified as the cause of disease. The muscle involvement with p.A50V was distal calf-predominant, and the p.E54A was more proximo-distal. Histological findings were similar to those previously reported in DNAJB6 myopathy. In line with reported pathogenic mutations in the glycine/phenylalanine (G/F) domain of DNAJB6, both the novel mutations showed reduced anti-aggregation capacity by filter trap assay and TDP-43 disaggregation assays. Modeling of the protein showed close proximity of the mutated residues with the G/F domain. Myopathy-causing mutations in DNAJB6 are not only located in the G/F domain, but also in the J domain. The identified mutations in the J domain cause dominant distal and proximo-distal myopathy, confirming that mutations in DNAJB6 should be considered in distal myopathy cases. © 2019 Elsevier B.V.
Author Keywords
Chaperonopathy; DNAJB6 gene; Limb-girdle muscular dystrophy
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
“Overcoming Neurophobia with the Help of Peruvian Talking Bears” (2020) JAMA Neurology
Overcoming Neurophobia with the Help of Peruvian Talking Bears
(2020) JAMA Neurology, .
Dewar, B.a , Day, G.S.b , Shamy, M.C.F.a c
a Ottawa Hospital Research Institute, Ottawa, ON, Canada
b Department of Neurology, Washington University in St Louis, St Louis, MO, United States
c Department of Medicine (Neurology), University of Ottawa, Ottawa, ON, Canada
Document Type: Note
Publication Stage: Article in Press
Source: Scopus
“Leveraging social media to explore the barriers to treatment among individuals with depressive symptoms” (2020) Depression and Anxiety
Leveraging social media to explore the barriers to treatment among individuals with depressive symptoms
(2020) Depression and Anxiety, .
Szlyk, H.b , Deng, J.a b b , Xu, C.a b b , Krauss, M.J.b , Cavazos-Rehg, P.A.a
a Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, United States
b George Warren Brown School, Washington University in St. Louis, St. Louis, MO, United States
Abstract
Background: Individuals with depression may not seek treatment for their symptoms due to several types of barriers to treatment. In support of the growing research on mental health care access and the role of social media, this study aimed to increase knowledge of these barriers among social media users. Methods: Participants were recruited from several social media platforms, including Instagram, Facebook, Twitter, Reddit, Tumblr, and online depression forums. Eligible participants had endorsed having posted about feeling sad or depressed on social media, or followed social media groups that post about depression-related topics. Participants completed an online survey about their depression symptoms, interest in treatment, and potential barriers to accessing treatment. Results: Of the participants reaching criteria for depression, those with major depression were more likely to seek out treatment, to report an unmet need for treatment, and have a higher risk of suicide. For participants with major depression, barriers to treatment were more likely to be attitudinal, while participants with mild depression experienced more structural barriers. Conclusions: This study demonstrates several barriers to treatment that occur for individuals struggling with depression, and that online platforms are effective mediums to recruit individuals with depression symptoms who seek mental health support. © 2019 Wiley Periodicals, Inc.
Author Keywords
barriers; depression; mental health; social media
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
“Publisher Correction: Dietary salt promotes cognitive impairment through tau phosphorylation (Nature, (2019), 574, 7780, (686-690), 10.1038/s41586-019-1688-z)” (2020) Nature
Faraco, G.a , Hochrainer, K.a , Segarra, S.G.a , Schaeffer, S.a , Santisteban, M.M.a , Menon, A.a , Jiang, H.b , Holtzman, D.M.b , Anrather, J.a , Iadecola, C.a
a Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY, United States
b Department of Neurology, Hope Center for Neurological Disorders, Knight Alzheimer’s Disease Research Center, Washington University, St. Louis, MO, United States
Abstract
In Fig. 1d of this Article, owing to an error in the production process, an asterisk on the bracket for the 12-weeks (12w) time-point is missing. In addition, Fig. 3 contains errors present at submission. In Fig. 3f in the calpain activity panel, the two data points at 0.00 × 103 relative fluorescence units (RFU) per mg for the normal diet (ND) group should not be there. In the two rightmost panels of Fig. 3h, both of the first two bars should be blue (indicating the wild type (WT)) and both of the second two bars should be red (indicating eNOS−/− or nNOS−/−, respectively). These errors have been corrected online. © 2020, The Author(s), under exclusive licence to Springer Nature Limited.
Document Type: Erratum
Publication Stage: Article in Press
Source: Scopus
Access Type: Open Access
“A step toward the future of seamless measurement with wearable sensors in pediatric populations with neuromuscular diseases” (2019) Muscle and Nerve
A step toward the future of seamless measurement with wearable sensors in pediatric populations with neuromuscular diseases
(2019) Muscle and Nerve, .
Lang, C.E., Cade, W.T.
Program in Physical Therapy, Washington University School of Medicine, St Louis, MO, United States
Document Type: Editorial
Publication Stage: Article in Press
Source: Scopus
“Chronic activation of anti-oxidant pathways and iron accumulation in epileptogenic malformations” (2019) Neuropathology and Applied Neurobiology
Chronic activation of anti-oxidant pathways and iron accumulation in epileptogenic malformations
(2019) Neuropathology and Applied Neurobiology, .
Zimmer, T.S.a , Ciriminna, G.a , Arena, A.a b , Anink, J.J.a , Korotkov, A.a , Jansen, F.E.c , van Hecke, W.d , Spliet, W.G.d , van Rijen, P.C.e , Baayen, J.C.f , Idema, S.f , Rensing, N.R.g , Wong, M.g , Mills, J.D.a , van Vliet, E.A.a h , Aronica, E.a i
a Department of (Neuro)Pathology, Amsterdam UMC, University of Amsterdam, Amsterdam Neuroscience, Amsterdam, Netherlands
b Department of Biochemical Sciences, Sapienza University of Rome, Rome, Italy
c Department of Paediatric Neurology, University Medical Center Utrecht, Netherlands
d Department of Pathology, University Medical Center Utrecht, Netherlands
e Department of Neurosurgery, Brain Centre, Rudolf Magnus Institute for Neuroscience, University Medical Center Utrecht, Utrecht, Netherlands
f Department of Neurosurgery, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam Neuroscience, Amsterdam, Netherlands
g Department of Neurology, Washington University, Saint Louis, MO, United States
h Center for Neuroscience, Swammerdam Institute for Life Sciences, University of Amsterdam, Amsterdam, Netherlands
i Stichting Epilepsie Instellingen Nederland (SEIN), Heemstede, Netherlands
Abstract
Aims: Oxidative stress is evident in resected epileptogenic brain tissue of patients with developmental brain malformations related to mammalian target of rapamycin activation: tuberous sclerosis complex (TSC) and focal cortical dysplasia type IIb (FCD IIb). Whether chronic activation of anti-oxidant pathways is beneficial or contributes to pathology is not clear. Methods: We investigated oxidative stress markers, including haem oxygenase 1, ferritin and the inflammation associated microRNA-155 in surgically resected epileptogenic brain tissue of TSC (n = 10) and FCD IIb (n = 8) patients and in a TSC model (Tsc1GFAP−/− mice) using immunohistochemistry, in situ hybridization, real-time quantitative PCR and immunoblotting. Using human foetal astrocytes we performed an in vitro characterization of the anti-oxidant response to acute and chronic oxidative stress and evaluated overexpression of the disease-relevant pro-inflammatory microRNA-155. Results: Resected TSC or FCD IIb tissue displayed higher expression of oxidative stress markers and microRNA-155. Tsc1GFAP−/− mice expressed more microRNA-155 and haem oxygenase 1 in the brain compared to wild-type, preceding the typical development of spontaneous seizures in these animals. In vitro, chronic microRNA-155 overexpression induced haem oxygenase 1, iron regulatory elements and increased susceptibility to oxidative stress. Overexpression of iron regulatory genes was also detected in patients with TSC, FCD IIb and Tsc1GFAP−/− mice. Conclusion: Our results demonstrate that early and sustained activation of anti-oxidant signalling and dysregulation of iron metabolism are a pathological hallmark of FCD IIb and TSC. Our findings suggest novel therapeutic strategies aimed at controlling the pathological link between both processes. © 2019 The Authors. Neuropathology and Applied Neurobiology published by John Wiley & Sons Ltd on behalf of British Neuropathological Society
Author Keywords
epilepsy; focal cortical dysplasia; haem oxygenase 1; iron metabolism; oxidative stress; tuberous sclerosis complex
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
Access Type: Open Access