Study of the Association Between Menarche and Disease Course in Pediatric Multiple Sclerosis
(2025) Neurology, 104 (4), art. no. e210213, .
Krysko, K.M.a b c , Waltz, M.d , Chitnis, T.e , Weinstock-Guttman, B.f , Aaen, G.S.g , Belman, A.h , Benson, L.A.i , Gorman, M.P.i , Lotze, T.E.j , Mar, S.S.k , Moodley, M.l , Ness, J.M.m , Rensel, M.n , Rodriguez, M.o , Rose, J.W.p , Edwards, A.R.q , Schreiner, T.L.r , Wheeler, Y.S.s , Barney, B.J.d , Waubant, E.q , Casper, T.C.d , Graves, J.S.t
a Division of Neurology, Department of Medicine, BARLO MS Centre, St. Michael’s Hospital, Toronto, Canada
b Division of Neurology, Department of Medicine, University of Toronto, Canada
c Li Ka Shing Knowledge Institute, Toronto, Canada
d Department of Pediatrics, University of Utah, Salt Lake City, United States
e Department of Pediatric Neurology, Massachusetts General Hospital, Boston, United States
f Department of Neurology, State University of New York, Buffalo, United States
g Department of Pediatrics, Loma Linda University, San Bernardino, CA, United States
h Department of Neurology, New York University Langone Medical CenterNY, United States
i Department of Neurology, Boston Children’s HospitalMA, United States
j Department of Neurology, Texas Children’s Hospital, Houston, United States
k Department of Neurology, Washington University, Saint Louis, MO, United States
l Department of Pediatrics and Neurology, Dell Children’s Hospital, University of Texas, Austin, United States
m Department of Pediatrics, University of Alabama at Birmingham, United States
n Department of Neurology, Cleveland ClinicOH, United States
o Department of Neurology, Mayo Clinic, Rochester, NY, United States
p Department of Neurology, University of Utah, Salt Lake City, United States
q Department of Neurology, UCSF Weill Institute for Neurosciences, University of California San Francisco, United States
r Departments of Neurology and Pediatrics, University of Colorado, Aurora, United States
s UAB School of Nursing, University of Alabama, Birmingham, United States
t Department of Neurology, University of California San Diego, San diego, United States
Abstract
Background and Objectives Sex steroid hormones have been demonstrated to affect the immune system in multiple sclerosis (MS), and puberty may trigger MS activity. We aimed to evaluate the association between menarche and disease course in pediatric MS through comparison of relapse rates across premenarche, perimenarche, and postmenarche periods. Methods This is a retrospective analysis of a prospectively followed female cohort with pediatric-onset MS in the US Network of Pediatric MS Centers database. Perimenarche was considered the period from 1 year before to 1 year after the estimated menarche date based on menarche integer age. Relapses were collected prospectively. Negative binomial and repeated-measures Cox regression models were used to assess the association of pubertal development stage with relapse rate, adjusted for race, body mass index, and disease-modifying therapy (DMT). Results Of 736 participants (all female; mean onset age 14.4 ± 2.8 years; mean menarche age 11.6 ± 1.4 years), onset was in premenarche in 73, perimenarche in 112 (± 1 year of menarche), and postmenarche in 551. The median time of MS onset was 2.8 years after menarche. Most (86%) were exposed to DMT in follow-up. In adjusted negative binomial analysis, the annualized relapse rate during premenarche was 0.43, perimenarche was 0.65, and postmenarche was 0.43 (premenarche rate ratio [RR] 1.00 (95% CI 0.70-1.43) and perimenarche RR 1.52 (95% CI 1.16-1.99), compared with reference of postmenarche, p = 0.0049. In adjusted repeated-events Cox regression analysis, there was increased hazard to relapse in perimenarche and postmenarche compared with premenarche (perimenarche hazard ratio [HR] 1.78 [95% CI 1.17-2.70] and postmenarche HR 1.67 [95% CI 1.12-2.50], compared with reference of premenarche, p = 0.025). In this analysis, use of oral and infusion DMTs significantly lowered the relapse hazard compared with periods of no DMT use (injectable HR 0.98 [95% CI 0.83-1.15], oral HR 0.48 [95% CI 0.37-0.61], and infusion HR 0.24 [95% CI 0.18-0.31], compared with no DMT, p < 0.001). Discussion Onset of puberty may be a time of increase in disease activity and may require consideration of a change in therapeutic approach. Menarche age was used as a surrogate for puberty, and future studies measuring sex steroid hormones may be informative. © 2025 American Academy of Neurology.
Funding details
National Multiple Sclerosis SocietyNMSSHC-1509-06233, FP-1605-08753
National Multiple Sclerosis SocietyNMSS
Document Type: Article
Publication Stage: Final
Source: Scopus
Robust Cluster Prediction Across Data Types Validates Association of Sex and Therapy Response in GBM
(2025) Cancers, 17 (3), art. no. 445, .
Gibbs, D.L.a , Cioffi, G.b , Aguilar, B.a , Waite, K.A.b , Pan, E.c , Mandel, J.d , Umemura, Y.e , Luo, J.f g , Rubin, J.B.h i , Pot, D.j , Barnholtz-Sloan, J.b k
a Thorsson-Shmulevich Lab, Institute of Systems Biology, Seattle, WA 98109, United States
b Trans Divisional Research Program, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD 20892, United States
c Global Oncology Research & Development, Daiichi-Sankyo, Inc., Basking Ridge, NJ 07920, United States
d Department of Neurology and Neurosurgery, Baylor College of Medicine, Houston, TX 77030, United States
e IVY Brain Tumor Center, Barrow Neurological Institute, Phoenix, AZ 85013, United States
f Department of Surgery, Division of Public Health Sciences, Washington University School of Medicine, St. Louis, MO 63110, United States
g Siteman Cancer Center Biostatistics and Qualitative Research Shared Resource, Washington University School of Medicine, St. Louis, MO 63110, United States
h Department of Pediatrics, Washington University School of Medicine, St. Louis, MO 63110, United States
i Department of Neuroscience, Washington University School of Medicine, St. Louis, MO 63110, United States
j General Dynamics Information Technology, Falls Church, VA 22042, United States
k Center for Biomedical Informatics and Information Technology, National Cancer Institute, Bethesda, MD 20892, United States
Abstract
Background: Previous studies have described sex-specific patient subtyping in glioblastoma. The cluster labels associated with these “legacy data” were used to train a predictive model capable of recapitulating this clustering in contemporary contexts. Methods: We used robust ensemble machine learning to train a model using gene microarray data to perform multi-platform predictions including RNA-seq and potentially scRNA-seq. Results: The engineered feature set was composed of many previously reported genes that are associated with patient prognosis. Interestingly, these well-known genes formed a predictive signature only for female patients, and the application of the predictive signature to male patients produced unexpected results. Conclusions: This work demonstrates how annotated “legacy data” can be used to build robust predictive models capable of multi-target predictions across multiple platforms. © 2025 by the authors.
Author Keywords
clustering; disease subtyping; feature engineering; female; GBM; gene expression signatures; glioblastoma multiforme; machine learning
Funding details
National Cancer InstituteNCI
Division of Cancer Epidemiology and GeneticsDCEG
National Institutes of HealthNIH
U.S. Department of Health and Human ServicesHHSHHSN261201400008C, 17X146, HHSN261201500003I
U.S. Department of Health and Human ServicesHHS
Document Type: Article
Publication Stage: Final
Source: Scopus
Depressive Symptoms and Amyloid Pathology
(2025) JAMA Psychiatry, .
Wiels, W.A.a b , Oomens, J.E.c , Engelborghs, S.d e f , Baeken, C.d e g h , Von Arnim, C.A.F.i j , Boada, M.k l , Didic, M.m n , Dubois, B.o , Fladby, T.p , Van Der Flier, W.M.q r , Frisoni, G.B.s , Fröhlich, L.t , Gill, K.D.u , Grimmer, T.v , Hildebrandt, H.w , Hort, J.x , Itoh, Y.y , Iwatsubo, T.z , Klimkowicz-Mrowiec, A.aa , Lee, D.Y.ab , Lleó, A.l ac , Martinez-Lage, P.ad , De Mendonça, A.ae , Meyer, P.T.af , Kapaki, E.N.ag , Parchi, P.ah ai , Pardini, M.aj , Parnetti, L.ak , Popp, J.al am , Rami, L.an , Reiman, E.M.ao , Rinne, J.O.ap , Rodrigue, K.M.aq , Sánchez-Juan, P.l ar , Santana, I.as at au , Sarazin, M.av aw , Scarmeas, N.ax ay , Skoog, I.az , Snyder, P.J.ba , Sperling, R.A.bb bc , Villeneuve, S.bd be bf , Wallin, A.bg , Wiltfang, J.bh bi , Zetterberg, H.bj bk bl bm bn bo , Ossenkoppele, R.s bp , Verhey, F.R.J.c , Vos, S.J.B.c , Visser, P.J.c p bq , Jansen, W.J.c ao , Alcolea, D.l ac , Altomare, D.br , Baiardi, S.ai , Baldeiras, I.as at au , Bateman, R.J.bs , Blennow, K.bk , Bottlaender, M.aw bt , Den Braber, A.q , Van Buchem, M.A.bu , Byun, M.S.ab , Cerman, J.x , Chen, K.ao , Chipi, E.ak , Day, G.S.bv , Drzezga, A.bw bx by , Eckerström, M.bz , Ekblad, L.L.ap ca , Epelbaum, S.o , Förster, S.cb cc , Fortea, J.l ac , Freund-Levi, Y.cd ce cf , Frings, L.af , Guedj, E.cg , Hausner, L.t , Hellwig, S.ch , Huey, E.D.ci , Jiménez-Bonilla, J.F.cj , Johnson, K.A.ck , Juaristi, A.I.ad , Kandimalla, R.cl cm cn , Paraskevas, G.ag , Kern, S.bj co , Kirsebom, B.-E.S.cp cq , Kornhuber, J.cr , Lagarde, J.av aw , Landau, S.M.cs , Legdeur, N.q , Llibre Guerra, J.J.bs , Maserejian, N.N.ct , Marquié, M.k l , Minatani, S.y , Morbelli, S.D.cu cv , Mroczko, B.cw cx , Ntanasi, E.cy , De Oliveira, C.R.at , Olivieri, P.aw , Orellana, A.k l , Perrin, R.J.cz , Peters, O.da , Prabhakar, S.db , Ramakers, I.H.a , Rodríguez-Rodriguez, E.dc , Ruiz, A.k l , Rüther, E.dd , Selnes, P.p , Silva, D.ae , Soininen, H.df dg , Spiru, L.dh di , Takeda, A.y , Teichmann, M.o , Tijms, B.M.q , Teunissen, C.E.dj , Thompson, L.I.ci , Vogelgsangs, J.dl , Vöglein, J.dm dn do , Waldemar, G.dp dq , Wallin, Å.K.dk , Yannakoulia, M.cy , Yi, D.de , Zettergren, A.bj , The Amyloid Biomarker Study group; for the Alzheimer’s Disease Neuroimaging Initiative (ADNI), the A4 Study group, Dominantly Inherited Alzheimer Network (DIAN), European Prevention of Alzheimer’s Dementia (EPAD) consortium, Fundacio ACE Healthy Brain Initiative (FACEHBI), Harvard Aging Brain Study (HABS), Japanese ADNI, Korean Brain Aging Study for the Early Diagnosis and Prediction of Alzheimer’s disease (KBASE), Presymptomatic Evaluation of Experimental or Novel Treatments for Alzheimer’s Disease (PREVENT-AD) research groupdr
a Faculty of Medicine and Pharmacy, Vrije Universiteit Brussel, Brussels, Belgium
b Department of Neurology, Onze-Lieve-Vrouw Hospital, Aalst, Belgium
c Department of Psychiatry & Neuropsychology, Alzheimer Center Limburg, School for Mental Health and Neuroscience, Maastricht University, Maastricht, Netherlands
d Vrije Universiteit Brussel, Center for Neurosciences, Neuroprotection & Neuromodulation Research Group, Brussels, Belgium
e Departments of Neurology and Psychiatry and Bru-BRAIN, Universitair Ziekenhuis Brussel, Brussels, Belgium
f Department of Biomedical Sciences, University of Antwerp, Antwerp, Belgium
g Department of Head and Skin, Ghent Experimental Psychiatry Lab, Faculty of Medicine and Health Sciences, Ghent University, Ghent, Belgium
h Department of Electrical Engineering, Eindhoven University of Technology, Eindhoven, Netherlands
i Department of Geriatrics, University of Goettingen Medical School, Goettingen, Germany
j Clinic for Neurogeriatrics and Neurological Rehabilitation, University and Rehabilitation Hospital Ulm, Ulm, Germany
k Ace Alzheimer Center Barcelona, Universitat Internacional de Catalunya, Barcelona, Spain
l Centre for Biomedical Research Network on Neurodegenerative Diseases, Network Center for Biomedical Research in Neurodegenerative Diseases, National Institute of Health Carlos III, Madrid, Spain
m Assitance Publique des Hopitaux de Marseille, Timone, Service de Neurologie et Neuropsychologie, Hôpital Timone Adultes, Marseille, France
n Aix Marseille University, National Institute of Health and Medical Research, Neurosciences des Systèmes, Marseille, France
o Department of Neurology, Institut de la Mémoire et de la Maladie d’Alzheimer, Centre de Référence Démences Rares, Hôpital de la Pitié-Salpêtrière, Assistance Publique- Hôpitaux de Paris, Paris, France
p Department of Neurology, Akershus University Hospital, Lorenskog, Norway
q Department of Neurology, Alzheimer Centre Amsterdam, Amsterdam Neuroscience, Amsterdam University Medical Centers, Vrije Universiteit Medical Center, Amsterdam, Amsterdam, Netherlands
r Epidemiology and Data Science, Vrije Universiteit Amsterdam, Amsterdam University Medical Centers, Vrije Universiteit Medical Center, Amsterdam, Netherlands
s Memory Clinic, University Hospitals and University of Geneva, Geneva, Switzerland
t Department of Geriatric Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany
u Department of Biochemistry, Postgraduate Institute of Medical Education and Research, Chandigarh, India
v Department of Psychiatry and Psychotherapy, Klinikum rechts der Isar, Technical University of Munich, School of Medicine and Health, Munich, Germany
w Klinikum Bremen-Ost, University of Oldenburg, Institute of Psychology, Oldenburg, Germany
x Department of Neurology, Second Faculty of Medicine, Charles University and Motol University Hospital, Prague, Czech Republic
y Department of Neurology, Osaka Metropolitan University, Graduate School of Medicine, Osaka, Japan
z Graduate School of Medicine, Faculty of Medicine, The University of Tokyo, Tokyo, Japan
aa Department of Internal Medicine and Gerontology, Faculty of Medicine, Jagiellonian University Medical College, Krakow, Poland
ab Department of Psychiatry, Seoul National University College of Medicine, Seoul, South Korea
ac Memory Unit, Neurology Department, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain
ad Center for Research and Advanced Therapies, Cita-Alzheimer Foundation, Donostia-San Sebastian, Spain
ae Faculty of Medicine, University of Lisbon, Lisboa, Portugal
af Department of Nuclear Medicine, Medical Center – University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
ag National and Kapodistrian University of Athens, School of Medicine, Department of Neurology, Eginition Hospital, Athens, Greece
ah Istituto delle Scienze Neurologiche di Bologna, Scientific Institute for Research, Hospitalization and Healthcare, Bologna, Italy
ai Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy
aj Department of Neurosciences, Rehabilitation, Ophthalmology and Maternal-Fetal Medicine, University of Genoa, Genoa, Italy
ak Centro Disturbi della Memoria, Laboratorio di Neurochimica Clinica, Clinica Neurologica, Università di Perugia, Perugia, Italy
al Department of Geriatric Psychiatry, University Hospital of Psychiatry Zürich, University of Zürich, Zürich, Switzerland
am Old Age Psychiatry, Department of Psychiatry, University Hospital of Lausanne, University of Lausanne, Lausanne, Switzerland
an Alzheimer’s Disease and Other Cognitive Disorders Unit, Neurology Service, Hospital Clínic of Barcelona, August Pi i Sunyer Biomedical Research Institute, Barcelona, Spain
ao Banner Alzheimer’s Institute, Phoenix, AZ, United States
ap Turku Positron Emission Tomography Centre, University of Turku, Turku, Finland
aq Center for Vital Longevity, School of Behavioral and Brain Sciences, The University of Texas at Dallas, Richardson, United States
ar Alzheimer’s Centre Reina Sofia, Fundación Centro de Investigación de Enfermedades Neurológicas, Carlos III Institute of Health, Madrid, Spain
as Faculty of Medicine, University of Coimbra, Coimbra, Portugal
at Center for Neuroscience and Cell Biology, Centre for Innovative Biomedicine and Biotechnology, University of Coimbra, Coimbra, Portugal
au Neurology Department, Laboratory of Neurochemistry, Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal
av Department of Neurology of Memory and Language, Groupe Hospitalier Universitaire Paris Psychiatry and Neurosciences, Hôpital Sainte Anne, Paris, France
aw Paris-Saclay University, BioMaps, Inserm, Commissariat à l’énergie atomique et aux énergies alternatives, Service Hospitalier Frederic Joliot, Orsay, France
ax Department of Neurology, Aiginition Hospital, National and Kapodistrian University of Athens, Medical School, Athens, Greece
ay Department of Neurology, Columbia University, New York City, NY, United States
az Neuropsychiatric Epidemiology Unit, Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, Sahlgrenska Academy, The University of Gothenburg, Gothenburg, Sweden
ba Department of Biomedical and Pharmaceutical Sciences, College of Pharmacy, The University of Rhode Island, Kingston, United States
bb Center for Alzheimer Research and Treatment, Department of Neurology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, United States
bc Harvard Aging Brain Study, Department of Neurology, Harvard Medical School, Boston, MA, United States
bd McConnell Brain Imaging Centre, Montreal Neurological Institute, Montreal, QC, Canada
be Department of Psychiatry, Faculty of Medicine, McGill University, Montreal, QC, Canada
bf Douglas Mental Health University Institute, Montreal, QC, Canada
bg Cognitive Medicine Unit, Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, Sahlgrenska Academy, The University of Gothenburg, Gothenburg, Sweden
bh Department of Psychiatry and Psychotherapy, University Medical Center Göttingen, Göttingen, Germany
bi Center of Neurology, Department of Neurodegeneration and Hertie, Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany
bj Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, Sahlgrenska Academy, The University of Gothenburg, Mölndal, Sweden
bk Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden
bl Department of Neurodegenerative Disease, University College London, Queen Square Institute of Neurology, London, United Kingdom
bm United Kingdom Dementia Research Institute, London, United Kingdom
bn Hong Kong Center for Neurodegenerative Diseases, Hong Kong
bo Wisconsin Alzheimer’s Disease Research Center, University of Wisconsin School of Medicine and Public Health, University of Wisconsin-Madison, Madison, United States
bp Clinical Memory Research Unit, Department of Clinical Sciences, Lund University, Lund, Sweden
bq Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Stockholm, Sweden
br Neurology Unit, Department of Clinical and Experimental Sciences, University of Brescia, Brescia, Italy
bs Department of Neurology, The Alzheimer’s Disease Research Center, Washington University School of Medicine, St Louis, MO, United States
bt Paris-Saclay University, Research Unit in Clinical and Translational Applicative NeuroImaging, Neurospin, Commissariat à l’énergie atomique et aux énergies alternatives, Gif-sur-Yvette, France
bu Department of Radiology, University Medical Center Leiden, Leiden, Netherlands
bv Department of Neurology, Mayo Clinic in Florida, Jacksonville, United States
bw Department of Nuclear Medicine, Faculty of Medicine, University Hospital Cologne, University of Cologne, Germany
bx German Center for Neurodegenerative Diseases, Cologne, Bonn, Germany
by Institute of Neuroscience and Medicine, Molecular Organization of the Brain, Forschungszentrum Jülich, Jülich, Germany
bz Department of Psychology, University of Gothenburg, Gothenburg, Sweden
ca Department of Geriatrics, Turku University Hospital, Wellbeing Services County of Southwestern Finland, Turku, Finland
cb Department of Nuclear Medicine, Klinikum Rechts der Isar, Technical University of Munich, Munich, Germany
cc Department of Nuclear Medicine, Klinikum Bayreuth, Bayreuth, Germany
cd School of Medical Sciences, Örebro University, Örebro, Sweden
ce Department of Neurobiology, Care Sciences and Society, Division of Clinical Geriatrics, Karolinska Institutet Center for Alzheimer Research, Stockholm, Sweden
cf Department of Old Age Psychiatry, Psychology and Neuroscience, King’s College, London, United Kingdom
cg Aix Marseille University, L’Assistance publique-Hôpitaux de Marseille, Centre National de la Recherche Scientifique, Centrale Marseille, Institut Fresnel, Timone Hospital, Centre Européen de Recherche en Imagerie Médicale, Nuclear Medicine Department, Marseille, France
ch Department of Psychiatry and Psychotherapy Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany
ci Department of Psychiatry and Human Behavior, Alpert Medical School of Brown University, Providence, RI, United States
cj Department of Nuclear Medicine, Marqués de Valdecilla University Hospital, Instituto de Investigación Marqués de Valdecilla, Santander, Spain
ck Department of Radiology, Massachusetts General Hospital, Boston, United States
cl Department of Radiation Oncology, Emory University, Atlanta, GA, United States
cm Applied Biology, Council of Scientific and Industrial Research, Indian Institute of Chemical Technology, Telangana State, Hyderabad, India
cn Department of Biochemistry, Kakatiya Medical College, Mahatma Gandhi Memorial Hospital, Telangana State, Warangal, India
co Department of Psychiatry, Cognition and Old Age Psychiatry, Sahlgrenska University Hospital, Västra Götalandsregion, Sweden
cp Department of Neurology, University Hospital of North Norway, Tromsø, Norway
cq Department of Psychology, The Arctic University of Norway, Tromsø, Norway
cr Department of Psychiatry and Psychotherapy, University Hospital, Friedrich-Alexander-University Erlangen-Nuremberg, Erlangen, Germany
cs Helen Wills Neuroscience Institute, University of California, Berkeley, United States
ct Department of Epidemiology, Biogen, Cambridge, MA, United States
cu Department of Health Sciences, University of Genoa, Genoa, Italy
cv Ospedale Policlinico San Martino, Scientific Institute for Research, Hospitalization and Healthcare, Genoa, Italy
cw Department of Neurodegeneration Diagnostics, Medical University of Białystok, Białystok, Poland
cx Department of Biochemical Diagnostics, University Hospital of Białystok, Białystok, Poland
cy Department of Nutrition and Diatetics, Harokopio University, Kallithea, Athens, Greece
cz Department of Pathology and Immunology, Department of Neurology, Washington University School of Medicine, Saint Louis, MO, United States
da Charité Universitätsmedizin Berlin, Campus Benjamin Franklin, Berlin, Germany
db Department of Neurology, Nehru Hospital, Postgraduate Institute of Medical Education and Research, Chandigarh, India
dc Neurology Department, Hospital Universitario Marqués de Valdecilla, Instituto de Investigación Sanitaria Valdecilla, University of Cantabria, Santander, Biomedical Research Networking Center on Neurodegenerative Diseases, Santander, Madrid, Spain
dd Department of Psychiatry and Psychotherapy, University Medical Center, Georg-August University, Göttingen, Germany
de Institute of Human Behavioral Medicine, Medical Research Center Seoul National University, Seoul, South Korea
df Department of Neurology, Institute of Clinical Medicine, University of Eastern Finland, Kuopio, Finland
dg Neurocenter, Department of Neurology, Kuopio University Hospital, Kuopio, Finland
dh Geriatrics, Gerontology and Old Age Psychiatry Clinical Department, Carol Davila University of Medicine and Pharmacy-Elias, Emergency Clinical Hospital, Bucharest, Romania
di Excellence Center for Memory Diseases, Brain Health and Longevity Medicine, Ana Aslan International Foundation, Bucharest, Romania
dj Neurochemistry Lab, Department of Laboratory Medicine, Amsterdam Neuroscience, Amsterdam University Medical Centers, Vrije Universiteit Medical Center, Amsterdam, Netherlands
dk Cognitive Disorder Research Unit, Department of Clinical Sciences, Malmö, Sweden
dl Translational Neuroscience Laboratory, McLean Hospital, Harvard Medical School, Belmont, MA, United States
dm Department of Neurology, University Hospital of Munich, Munich, Germany
dn German Center for Neurodegenerative Diseases, Munich, Germany
do Munich Cluster for Systems Neurology, Munich, Germany
dp Danish Dementia Research Center, Department of Neurology, Copenhagen University Hospital-Rigshospitalet, Copenhagen, Denmark
dq Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark
Abstract
Importance: Depressive symptoms are associated with cognitive decline in older individuals. Uncertainty about underlying mechanisms hampers diagnostic and therapeutic efforts. This large-scale study aimed to elucidate the association between depressive symptoms and amyloid pathology. Objective: To examine the association between depressive symptoms and amyloid pathology and its dependency on age, sex, education, and APOE genotype in older individuals without dementia. Design, Setting, and Participants: Cross-sectional analyses were performed using data from the Amyloid Biomarker Study data pooling initiative. Data from 49 research, population-based, and memory clinic studies were pooled and harmonized. The Amyloid Biomarker Study has been collecting data since 2012 and data collection is ongoing. At the time of analysis, 95 centers were included in the Amyloid Biomarker Study. The study included 9746 individuals with normal cognition (NC) and 3023 participants with mild cognitive impairment (MCI) aged between 34 and 100 years for whom data on amyloid biomarkers, presence of depressive symptoms, and age were available. Data were analyzed from December 2022 to February 2024. Main Outcomes and Measures: Amyloid-β1-42 levels in cerebrospinal fluid or amyloid positron emission tomography scans were used to determine presence or absence of amyloid pathology. Presence of depressive symptoms was determined on the basis of validated depression rating scale scores, evidence of a current clinical diagnosis of depression, or self-reported depressive symptoms. Results: In individuals with NC (mean [SD] age, 68.6 [8.9] years; 5664 [58.2%] female; 3002 [34.0%] APOE ϵ4 carriers; 937 [9.6%] had depressive symptoms; 2648 [27.2%] had amyloid pathology), the presence of depressive symptoms was not associated with amyloid pathology (odds ratio [OR], 1.13; 95% CI, 0.90-1.40; P =.29). In individuals with MCI (mean [SD] age, 70.2 [8.7] years; 1481 [49.0%] female; 1046 [44.8%] APOE ϵ4 carriers; 824 [27.3%] had depressive symptoms; 1668 [55.8%] had amyloid pathology), the presence of depressive symptoms was associated with a lower likelihood of amyloid pathology (OR, 0.73; 95% CI 0.61-0.89; P =.001). When considering subgroup effects, in individuals with NC, the presence of depressive symptoms was associated with a higher frequency of amyloid pathology in APOE ϵ4 noncarriers (mean difference, 5.0%; 95% CI 1.0-9.0; P =.02) but not in APOE ϵ4 carriers. This was not the case in individuals with MCI. Conclusions and Relevance: Depressive symptoms were not consistently associated with a higher frequency of amyloid pathology in participants with NC and were associated with a lower likelihood of amyloid pathology in participants with MCI. These findings were not influenced by age, sex, or education level. Mechanisms other than amyloid accumulation may commonly underlie depressive symptoms in late life. Copyright © 2025 American Medical Association. All rights reserved, including those for text and data mining, AI training, and similar technologies.
Funding details
Universität zu KölnUoC
Mayo Clinic
University of California BerkeleyUCB
Universitetet i TromsøUiT
Gentofte Hospital
Università di BolognaUNIBO
Alzheimer’s Disease Research Center, University of WashingtonADRC, UW
School of Medicine, Washington University in St. LouisWUSM
Universität Heidelberg
McLean Hospital
Deutsches Zentrum für Neurodegenerative ErkrankungenDZNE
Department of Radiology, Weill Cornell Medicine
King’s College LondonKCL
Université Paris-Saclay
Kuopion Yliopistollinen SairaalaKYS
Sahlgrenska UniversitetssjukhusetSU
Västra GötalandsregionenVGR
Institut National de la Santé et de la Recherche MédicaleInserm
Turun Yliopistollinen KeskussairaalaAUCS
UNC Department of Radiation Oncology
Biogen
Department of Psychiatry
Helen Wills Neuroscience Institute, University of California BerkeleyHWNI
Department of Neurology, College of Medicine, Medical University of South Carolina
Utah State Psychology Department
Commissariat à l’Énergie Atomique et aux Énergies AlternativesCEA
Aix-Marseille UniversitéAMU
Friedrich-Alexander-Universität Erlangen-NürnbergFAU
Massachusetts General HospitalMGH
Università degli Studi di BresciaUNIBS
Centro de Investigación Biomédica en Red sobre Enfermedades NeurodegenerativasCIBERNED
Charité – Universitätsmedizin Berlin
Postgraduate Institute of Medical Education and Research, ChandigarhPGIMER
Harokopio University
Università degli Studi di Genova
Ospedale Policlinico San Martino, Istituto di Ricovero e Cura a Carattere Scientifico
Örebro Universitet
Akershus UniversitetssykehusAhus
Medizinische Fakultät der Albert-Ludwigs-Universität Freiburg
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
Three-Dimensional Curvature of the Cervical Carotid Artery Predicts Long-Term Neurovascular Risk in Loeys-Dietz Syndrome
(2025) Stroke, 56 (3), pp. 667-677.
Lee, J.V.a c , Huguenard, A.L.a , Braverman, A.C.b , Dacey, R.G.a , Osbun, J.W.a
a Department of Neurological Surgery, Washington University School of Medicine, St. Louis, MO, United States
b Cardiovascular Division, Department of Medicine, Washington University School of Medicine, St. Louis, MO, United States
c Department of Biomedical Engineering, Washington University, St. Louis, MO, United States
Abstract
BACKGROUND: Although the relationship between cervical carotid tortuosity and cardiovascular risk in patients with Loeys-Dietz syndrome has been studied, it is unclear whether cervical carotid tortuosity influences the risk of neurovascular events. METHODS: This is a single-institution retrospective cohort study. Cervical carotid tortuosity and morphology were assessed in patients with Loeys-Dietz syndrome who underwent baseline computed tomography/magnetic resonance imaging of the cervical and cerebral arteries from 2010 to 2022. The primary end point was a composite of adverse neurovascular events (multiple vessel cervical artery dissection, ischemic stroke, intracerebral hemorrhage, and any neurovascular intervention) at 5- and 10-year follow-ups. Independent risk factors were identified using univariate and multivariate logistic regression analyses. Single-variable predictors of 5- and 10-year outcomes were analyzed via receiver operating curve analyses. Cutoff values were determined per the Youden J index. Stratification analyses were performed for ages <60 and ≥60 years. RESULTS: Of 105 eligible participants, 63 were included (mean age, 40±17 years; 52% female). During a mean follow-up of 8.7±4.1 years, 23 (37%) developed an adverse neurovascular event. Five-year follow-up was achieved in 86% and 10-year follow-up in 48%. Carotid total absolute curvature (TAC; P=0.008), coiling morphology (P=0.012), and TGFBR1/2 genetic variant (P=0.037) were independently associated with 5-year events. Stratification analyses revealed that the age group <60 years was more vulnerable to high TAC (unadjusted odds ratio, 7.2 [95% CI, 2.0-25.4]; P=0.002). Baseline TAC was the only independent predictor of adverse events at 5 years (area under the curve, 0.84; P<0.001) and 10 years (area under the curve, 0.75; P=0.007) in this age group. An optimal threshold for predicting neurovascular events was TAC ≥16.5. None were predictive in the age group ≥60 years. CONCLUSIONS: Cervical carotid tortuosity is associated with a long-term increased risk of neurovascular events in Loeys-Dietz syndrome. Angiographic findings of high-risk features such as increased TAC and coiling morphology may help to identify neurovascular vulnerability noninvasively at an early stage. © 2025 American Heart Association, Inc.
Author Keywords
arterial dissection; carotid arteries; Loeys-Dietz syndrome; magnetic resonance imaging; stroke; tomography
Document Type: Article
Publication Stage: Final
Source: Scopus
Assessing Dynamic Cognitive Function in the Daily Lives of Youths With and Without Type 1 Diabetes: Usability Study
(2025) JMIR Formative Research, 9, art. no. e60275, .
Ray, M.K.a b , Fleming, J.a , Aschenbrenner, A.c , Hassenstab, J.c , Redwine, B.a , Burns, C.a , Arbelaez, A.M.d , Vajravelu, M.E.e , Hershey, T.a b
a Department of Psychiatry, Washington University in St. Louis, St. Louis, MO, United States
b Department of Radiology, Washington University in St. Louis, St. Louis, MO, United States
c Department of Neurology, Washington University in St. Louis, St. Louis, MO, United States
d Department of Pediatrics, Washington University in St. Louis, St. Louis, MO, United States
e Division of Pediatric Endocrinology Diabetes and Metabolism, UPMC Children’s Hospital of Pittsburgh, University of Pittsburgh, School of Medicine, Pittsburgh, PA, United States
Abstract
Background: Studies have shown a relationship between worse glycemic control and lower cognitive scores in youths with type 1 diabetes (T1D). However, most studies assess long-term glucose control (eg, years-decades) and cognition at a single time point. Understanding this relationship at a higher temporal resolution (eg, minutes-hours) and in naturalistic settings has potential clinical implications. Newer technology (eg, continuous glucose monitoring [CGM] and ecological momentary assessment) provides a unique opportunity to explore the glucose dynamics that influence dynamic cognition; that is, cognitive functions that fluctuate short-term and are influenced by environmental factors. Objective: Before we can assess this relationship, we need to determine the feasibility of measuring cognition in youths in daily life and determine the plausibility of obtaining glucose variation with CGM to be integrated with real-time cognition measures. This study’s purpose was to assess the acceptability of measuring dynamic cognition using a smartphone app and adherence to cognitive testing in daily life in youths with and without T1D. Further, we assessed CGM-derived glucose measures at temporally related timeframes to cognitive testing in naturalistic settings. Methods: Data were obtained from 3 studies including one in-laboratory study and 2 remote studies. For all studies, youths were asked to complete cognitive tests on the Ambulatory Research in Cognition (ARC) smartphone app that measured processing speed, associative memory, and working memory. For the in-laboratory study, youths completed testing 4 times during 1 session. For the remote studies, youths were asked to complete cognitive tests 5 times per day for either 10 or 14 consecutive days in daily life. Youths were asked to rate their impressions of the app. Youths with T1D wore a CGM. Results: 74 youths (n=53 control; n=21 T1D) aged 4-16 years participated. Youths generally reported liking or understanding the ARC app tasks in a laboratory and remote setting. Youths had high testing adherence in daily life (2350/3080 to 721/900, 76.3%-80.2%) and none dropped out. The percentage of measurements within each glycemic range taken immediately before the app’s cognitive testing was 3% (28/942) low glucose, 51% (484/942) euglycemia, 23% (221/942) high glucose, and 22% (210/942) very high glucose. In the 2-hour window before each cognitive task, mean glucose was 182.5 (SD 76.2) mg/dL, SD in glucose was 27.1 mg/dL (SD 18.7), and the mean maximum difference between the highest and lowest glucose was 85.5 (SD 53.7) mg/dL. Conclusions: The results suggest that using the ARC smartphone app to assess dynamic cognitive functions in youths with and without T1D is feasible. Further, we showed CGM-derived glycemic variability at temporally associated timeframes of dynamic cognitive assessments. The next steps include using ecological momentary assessment in a fully powered study to determine the relationship between short-term glycemic control and cognition in youths with T1D. © 2025 JMIR Publications Inc.. All rights reserved.
Author Keywords
acceptability; ambulatory; app; application; assessment; CGM; cognitive test; continuous glucose monitoring; daily lives; diabetes; ecological momentary assessment; EMA; environmental factor; feasibility study; glycemic control; mobile phone; phone; pilot study; smartphone; type 1 diabetes; young; youth
Funding details
Diabetes Research ConnectionDRC
National Center for Advancing Translational SciencesNCATS
National Institute of Diabetes and Digestive and Kidney DiseasesNIDDKT32HL130357, T32DA007261, 1K01DK131339
National Institute of Diabetes and Digestive and Kidney DiseasesNIDDK
National Institutes of HealthNIHKL2TR002346
National Institutes of HealthNIH
P30DK092950
National Institute on AgingNIAK01AG071847, K23DK125719
National Institute on AgingNIA
Washington University in St. LouisWUSTLP30DK020579
Washington University in St. LouisWUSTL
Document Type: Article
Publication Stage: Final
Source: Scopus
Longitudinal analysis of a dominantly inherited Alzheimer disease mutation carrier protected from dementia
(2025) Nature Medicine, art. no. 1711.e15, .
Llibre-Guerra, J.J.a , Fernandez, M.V.b , Joseph-Mathurin, N.a , Bian, S.c , Carter, K.c , Li, Y.a , Aschenbrenner, A.J.a , Pottier, C.a , Sigurdson, W.a , McDade, E.a , Gordon, B.A.a , Renton, A.E.d , Benzinger, T.L.S.a , Ibañez, L.a , Barthelemy, N.a , Johnson, M.a , Hassenstab, J.a , Wang, G.a , Goate, A.M.d , Western, D.a , Wang, C.a , Hobbs, D.a , Daniels, A.a , Karch, C.a , Morris, J.C.a , Cruchaga, C.a , Johnson, E.C.B.d , Bateman, R.J.a , Ziegemeier, E.a , Ziegemeier, A.a , Xu, J.a , Xu, X.a , Xiong, C.a , Wang, Y.a , Wang, Q.a , Vöglein, J.r , Vlassenko, A.a , Vazquez, S.f , Timofejavaite, R.m , Surace, E.f , Supnet-Bell, C.a , Stout, S.a , Stauber, J.a , Smith, J.a , Skrbec, K.a , Simmons, A.a , Seyfried, N.T.n , Serna, L.e , Senda, M.aa , Scott, J.a , Schofield, P.R.g , Sanchez-Valle, R.z , Salloway, S.n , Sabaredzovic, E.a , Ryan, N.S.i , Rosa-Neto, P.y , Roh, J.H.q , Rödenbeck, Y.r , Rizzo, J.a , Ringman, J.x , Reischl, G.m , Ramirez, L.e , Pulizos, C.a , Picarello, D.M.d , Perrin, R.J.a , Obermueller, U.m , Noble, J.M.w , Niimi, Y.v , Nie, Y.a , Nicklaus, J.a , Mori, H.u , Minton, M.a , McKay, N.a , McCullough, A.a , Masters, C.t , Massoumzadeh, P.a , Martins, R.s , Martin, M.a , Marsh, J.a , Maa, C.j , Lu, R.a , Lopera, F.e , Leon, Y.M.e , Levin, J.r , Levey, A.I.n , Lee, J.-H.q , Laske, C.m , la Fougère, C.m , Kuder-Buletta, E.m , Koudelis, D.a , Keefe, S.a , Kasuga, K.o , Karch, C.M.a , Jucker, M.m , Jerome, G.a , Jackson, K.a , Ishii, K.p , Ishiguro, T.o , Ikonomovic, S.h , Ikeuchi, T.o , Ibanez, L.a , Huey, E.D.n , Hornbeck, R.a , Holtzman, D.M.a , Hellm, C.a , Gremminger, E.a , Graff-Radford, N.R.k , Graber-Sultan, S.m , Goyal, M.a , Fulton-Howard, B.d , Franklin, E.a , Fox, N.C.i , Flores, S.a , Farlow, M.l , Fagan, A.M.a , Devenney, E.g , Day, G.S.k , Daniels, A.J.a , Courtney, L.a , Mendez, P.C.f , Chhatwal, J.P.j , Chen, C.a , Chen, A.a , Cash, D.M.i , Brooks, W.S.g , Bocanegra, Y.e , Berman, S.B.h , Bechara, J.A.g , Bateman, R.a , Bartzel, J.a , Barthélemy, N.R.a , Banks, J.a , Baker, B.a , Baena, A.e , Allegri, R.F.f , Aguillon, D.e , on behalf of the Dominantly Inherited Alzheimer Networkab
a Washington University in St Louis, St Louis, MO, United States
b Research Center and Memory Clinic, Fundació ACE Institut Català de Neurociències Aplicades – Universitat Internacional de Catalunya (UIC), Barcelona, Spain
c Emory University School of Medicine, Atlanta, GA, United States
d Ronald M. Loeb Center for Alzheimer’s Disease, Dept of Genetics and Genomic Sciences, and Nash Family Dept of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, United States
e Grupo de Neurociencias de Antioquia (GNA), Facultad de Medicina, Universidad de Antioquia, Medellín, Colombia
f Institute for Neurological Research Fleni, Buenos Aires, Argentina
g Neuroscience Research Australia, Sydney, NSW, Australia
h University of Pittsburgh, Pittsburgh, PA, United States
i Dementia Research Centre, UCL Queen Square Institute of Neurology, London, United Kingdom
j Massachusetts General Hospital, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, United States
k Mayo Clinic in Florida, Jacksonville, FL, United States
l Indiana University, School of Medicine, Bloomington, IN, United States
m German Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany
n Goizueta Alzheimer’s Disease Research Center, Emory University, Atlanta, GA, United States
o Brain Research Institute, Niigata University, Niigata, Japan
p Tokyo Metropolitan Institute of Gerontology, Tokyo, Japan
q Korea University College of Medicine, Seoul, South Korea
r German Center for Neurodegenerative Diseases, Munich, Munich, Germany
s Edith Cowan University, Perth, WA, Australia
t Florey Institute, The University of Melbourne, Melbourne, VIC, Australia
u Osaka Metropolitan University, Osaka, Japan
v The University of Tokyo Hospital, Tokyo, Japan
w Taub Institute for Research on Alzheimer’s Disease and the Aging Brain, Columbia University Irving Medical Center, New York, NY, United States
x Department of Neurology, Keck School of Medicine of USC, University of Southern California, Los Angeles, CA, United States
y McGill University, Montreal, QC, Canada
z University of Barcelona, Barcelona, Spain
aa Kobe City Medical Center General Hospital, Kobe, Japan
Abstract
We conducted an in-depth longitudinal study on an individual carrying the presenilin 2 p.Asn141Ile mutation, traditionally associated with dominantly inherited Alzheimer’s disease (AD), who has remarkably remained asymptomatic past the expected age of clinical onset. This study combines genetic, neuroimaging and biomarker analyses to explore the underpinnings of this resilience. Unlike typical progression in dominantly inherited AD, tau pathology in this case was confined to the occipital region without evidence of spread, potentially explaining the preservation of cognitive functions. Genetic analysis revealed several variants that, although not previously associated with protection against AD, suggest new avenues for understanding disease resistance. Notably, environmental factors such as significant heat exposure and a unique proteomic profile rich in heat shock proteins might indicate adaptive mechanisms contributing to the observed phenotype. This case underscores the complexity of Alzheimer’s pathology and suggests that blocking tau deposition could be a promising target for therapeutic intervention. The study highlights the need for further research to identify and validate the mechanisms that could inhibit or localize tau pathology as a strategy to mitigate or delay the onset of Alzheimer’s dementia. © The Author(s), under exclusive licence to Springer Nature America, Inc. 2025.
Funding details
Deutsches Zentrum für Neurodegenerative ErkrankungenDZNE
Instituto de Salud Carlos IIIISCIII
Fleni
SantéFRQS
Fondation Brain Canada
Canadian Institutes of Health ResearchCIHR
National Institute on AgingNIA
Korea Health Industry Development InstituteKHIDI
U19AG032438
Alzheimer’s AssociationAASG-20-690363-DIAN
Alzheimer’s AssociationAA
Japan Agency for Medical Research and DevelopmentAMEDJP22dk0207049
Japan Agency for Medical Research and DevelopmentAMED
Document Type: Article
Publication Stage: Article in Press
Source: Scopus