Scopus list of publications for March 24, 2024
New insights into astrocyte diversity from the lens of transcriptional regulation and their implications for neurodegenerative disease treatments
(2024) Neural Regeneration Research, 19 (11), pp. 2335-2336.
Saliu, I.O.a , Zhao, G.a b
a Department of Genetics, Washington University School of Medicine, St. Louis, MO, United States
b Department of Neurology, Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, United States
Document Type: Article
Publication Stage: Final
Source: Scopus
Comprehensive proteomics of CSF, plasma, and urine identify DDC and other biomarkers of early Parkinson’s disease
(2024) Acta Neuropathologica, 147 (1), art. no. 52, .
Rutledge, J.a b , Lehallier, B.b , Zarifkar, P.b e , Losada, P.M.b f , Shahid-Besanti, M.b , Western, D.c d , Gorijala, P.c d , Ryman, S.b g , Yutsis, M.b , Deutsch, G.K.b , Mormino, E.b , Trelle, A.h , Wagner, A.D.f h , Kerchner, G.A.b i , Tian, L.j , Cruchaga, C.c d , Henderson, V.W.b k , Montine, T.J.l , Borghammer, P.m , Wyss-Coray, T.b f n , Poston, K.L.b f n o
a Department of Genetics, Stanford University School of Medicine, Stanford University, Stanford, CA, United States
b Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford University, Stanford, CA, United States
c Department of Psychiatry, Washington University in St Louis, St Louis, MO, United States
d NeuroGenomics and Informatics Center, Washington University School of Medicine, St. Louis, MO, United States
e Department of Clinical Epidemiology, Aarhus University, Aarhus, Denmark
f Wu Tsai Neurosciences Institute, Stanford University School of Medicine, Stanford, CA, United States
g Translational Neuroscience, Mind Research Network, Albuquerque, NM, United States
h Department of Psychology, Stanford University School of Medicine, Stanford University, Stanford, CA, United States
i Roche Medical, Basel, Switzerland
j Department of Biomedical Data Science, Stanford University School of Humanities and Sciences, Stanford University, Stanford, CA, United States
k Department of Epidemiology and Population Health, Stanford University, Stanford, CA, United States
l Department of Pathology, Stanford University School of Medicine, Stanford University, Stanford, CA, United States
m Department of Nuclear Medicine and PET, Aarhus University Hospital, Aarhus, Denmark
n The Knight Initiative for Brain Resilience, Stanford University, Stanford, CA, United States
o Department of Neurosurgery, Stanford University School of Medicine, Stanford University, Stanford, CA, United States
Abstract
Parkinson’s disease (PD) starts at the molecular and cellular level long before motor symptoms appear, yet there are no early-stage molecular biomarkers for diagnosis, prognosis prediction, or monitoring therapeutic response. This lack of biomarkers greatly impedes patient care and translational research—l-DOPA remains the standard of care more than 50 years after its introduction. Here, we performed a large-scale, multi-tissue, and multi-platform proteomics study to identify new biomarkers for early diagnosis and disease monitoring in PD. We analyzed 4877 cerebrospinal fluid, blood plasma, and urine samples from participants across seven cohorts using three orthogonal proteomics methods: Olink proximity extension assay, SomaScan aptamer precipitation assay, and liquid chromatography–mass spectrometry proteomics. We discovered that hundreds of proteins were upregulated in the CSF, blood, or urine of PD patients, prodromal PD patients with DAT deficit and REM sleep behavior disorder or anosmia, and non-manifesting genetic carriers of LRRK2 and GBA mutations. We nominate multiple novel hits across our analyses as promising markers of early PD, including DOPA decarboxylase (DDC), also known as l-aromatic acid decarboxylase (AADC), sulfatase-modifying factor 1 (SUMF1), dipeptidyl peptidase 2/7 (DPP7), glutamyl aminopeptidase (ENPEP), WAP four-disulfide core domain 2 (WFDC2), and others. DDC, which catalyzes the final step in dopamine synthesis, particularly stands out as a novel hit with a compelling mechanistic link to PD pathogenesis. DDC is consistently upregulated in the CSF and urine of treatment-naïve PD, prodromal PD, and GBA or LRRK2 carrier participants by all three proteomics methods. We show that CSF DDC levels correlate with clinical symptom severity in treatment-naïve PD patients and can be used to accurately diagnose PD and prodromal PD. This suggests that urine and CSF DDC could be a promising diagnostic and prognostic marker with utility in both clinical care and translational research. © The Author(s) 2024.
Funding details
Texas Workforce CommissionTWCNS062684
McKnight Foundation
National Institutes of HealthNIHP50 AG047366, P30 AG066515, NS075097, NS115114, AG048076
Alzheimer’s AssociationAA
Document Type: Article
Publication Stage: Final
Source: Scopus
Fatness but Not Fitness Linked to BrainAge: Longitudinal Changes in Brain Aging during an Exercise Intervention
(2024) Medicine and Science in Sports and Exercise, 56 (4), pp. 655-662.
Wing, D.a b , Eyler, L.T.e g , Lenze, E.J.c , Wetherell, J.L.d e , Nichols, J.F.a b , Meeusen, R.f k , Godino, J.G.a b , Shimony, J.S.j , Snyder, A.Z.j , Nishino, T.c , Nicol, G.E.c , Nagels, G.h i , Roelands, B.f k
a Herbert Wertheim School of Public Health, University of California, San Diego, CA, United States
b Exercise and Physical Activity Resource Center (EPARC), University of California, San Diego, CA, United States
c Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, United States
d Mental Health Service, VA San Diego Healthcare System, San Diego, CA, United States
e Department of Psychiatry, University of California, San Diego, CA, United States
f Human Physiology and Sports Physiotherapy Research Group, Faculty of Physical Education and Physiotherapy, Vrije Universiteit Brussel, Brussels, Belgium
g Desert-Pacific Mental Illness Research, Education, Clinical Center, San Diego Veterans Administration Healthcare System, San Diego, CA, United States
h Department of Neurology, UZ Brussel, Brussel, Belgium
i Center for Neurosciences (C4N) Vrije Universiteit Brussel (VUB), Brussels, Belgium
j Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, MO, United States
k Brubotics, Vrije Universiteit Brussel, Brussels, Belgium
Abstract
WING, D., L. T. EYLER, E. J. LENZE, J. L. WETHERELL, J. F. NICHOLS, R. MEEUSEN, J. G. GODINO, J. S. SHIMONY, A. Z. SNYDER, T. NISHINO, G. E. NICOL, G. NAGELS, and B. ROELANDS. Fatness but Not Fitness Linked to BrainAge: Longitudinal Changes in Brain Aging during an Exercise Intervention. Med. Sci. Sports Exerc., Vol. 56, No. 4, pp. 655- 662, 2024. Purpose: Fitness, physical activity, body composition, and sleep have all been proposed to explain differences in brain health. We hypothesized that an exercise intervention would result in improved fitness and body composition and would be associated with improved structural brain health. Methods: In a randomized controlled trial, we studied 485 older adults who engaged in an exercise intervention (n = 225) or a nonexercise comparison condition (n = 260). Using magnetic resonance imaging, we estimated the physiological age of the brain (BrainAge) and derived a predicted age difference compared with chronological age (brain-predicted age difference (BrainPAD)). Aerobic capacity, physical activity, sleep, and body composition were assessed and their impact on BrainPAD explored. Results: There were no significant differences between experimental groups for any variable at any time point. The intervention group gained fitness, improved body composition, and increased total sleep time but did not have significant changes in BrainPAD. Analyses of changes in BrainPAD independent of group assignment indicated significant associations with changes in body fat percentage (r(479) = 0.154, P = 0.001), and visceral adipose tissue (VAT) (r(478) = 0.141, P = 0.002), but not fitness (r(406) = −0.075, P = 0.129), sleep (r(467) range, −0.017 to 0.063; P range, 0.171 to 0.710), or physical activity (r (471) = −0.035, P = 0.444). With linear regression, changes in body fat percentage and VAT significantly predicted changes in BrainPAD (β = 0.948, P = 0.003) with 1-kg change in VAT predicting 0.948 yr of change in BrainPAD. Conclusions: In cognitively normal older adults, exercise did not appear to impact BrainPAD, although it was effective in improving fitness and body composition. Changes in body composition, but not fitness, physical activity, or sleep impacted BrainPAD. These findings suggest that focus on weight control, particularly reduction of central obesity, could be an interventional target to promote healthier brains. © 2024 Lippincott Williams and Wilkins. All rights reserved.
Author Keywords
BRAIN HEALTH; EXERCISE INTERVENTION; MAXIMAL CARDIOVASCULAR FITNESS; SUCCESSFUL AGING; VISCERAL ADIPOSE TISSUE
Document Type: Article
Publication Stage: Final
Source: Scopus
Predation without direction selectivity
(2024) Proceedings of the National Academy of Sciences of the United States of America, 121 (12), pp. e2317218121.
Krizan, J.a b , Song, X.a c , Fitzpatrick, M.J.a b , Shen, N.a , Soto, F.a , Kerschensteiner, D.a d e
a Department of Ophthalmology and Visual Sciences, Washington University School of Medicine, St. Louis, MO 63110, United States
b Graduate program in Neuroscience, Roy and Diana Vagelos Division of Biology and Biomedical Sciences, Washington University School of Medicine, St. Louis, MO 63110, United States
c Graduate program in Biomedical Engineering, Department of Biomedical Engineering, Washington University in St. Louis, St. Louis, MO 63130, United States
d Department of Neuroscience, Washington University School of Medicine, St. Louis, MO 63110, United States
e Department of Biomedical Engineering, Washington University in St. Louis, St. Louis, MO 63130, United States
Abstract
Across the animal kingdom, visual predation relies on motion-sensing neurons in the superior colliculus (SC) and its orthologs. These neurons exhibit complex stimulus preferences, including direction selectivity, which is thought to be critical for tracking the unpredictable escape routes of prey. The source of direction selectivity in the SC is contested, and its contributions to predation have not been tested experimentally. Here, we use type-specific cell removal to show that narrow-field (NF) neurons in the mouse SC guide predation. In vivo recordings demonstrate that direction-selective responses of NF cells are independent of recently reported stimulus-edge effects. Monosynaptic retrograde tracing reveals that NF cells receive synaptic input from direction-selective ganglion cells. When we eliminate direction selectivity in the retina of adult mice, direction-selective responses in the SC, including in NF cells, are lost. However, eliminating retinal direction selectivity does not affect the hunting success or strategies of mice, even when direction selectivity is removed after mice have learned to hunt, and despite abolishing the gaze-stabilizing optokinetic reflex. Thus, our results identify the retinal source of direction selectivity in the SC. They show that NF cells in the SC guide predation, an essential spatial orienting task, independent of their direction selectivity, revealing behavioral multiplexing of complex neural feature preferences and highlighting the importance of feature-selective manipulations for neuroethology.
Author Keywords
direction-selective; ganglion cells; narrow-field cells; retina; superior colliculus
Document Type: Article
Publication Stage: Final
Source: Scopus
Circadian Biology and the Neurovascular Unit
(2024) Circulation Research, 134 (6), pp. 748-769.
Li, W.a b , Tiedt, S.b c , Lawrence, J.H.b d , Harrington, M.E.b e , Musiek, E.S.b d , Lo, E.H.a b
a Neuroprotection Research Laboratories, Departments of Radiology and Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, United States
b Consortium International pour la Recherche Circadienne sur l’AVC, Munich, Germany
c Institute for Stroke and Dementia Research, University Hospital, Ludwig-Maximilians-Universität München, Munich, Germany
d Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States
e Neuroscience Program, Smith College, Northampton, MA, United States
Abstract
Mammalian physiology and cellular function are subject to significant oscillations over the course of every 24-hour day. It is likely that these daily rhythms will affect function as well as mechanisms of disease in the central nervous system. In this review, we attempt to survey and synthesize emerging studies that investigate how circadian biology may influence the neurovascular unit. We examine how circadian clocks may operate in neural, glial, and vascular compartments, review how circadian mechanisms regulate cell-cell signaling, assess interactions with aging and vascular comorbidities, and finally ask whether and how circadian effects and disruptions in rhythms may influence the risk and progression of pathophysiology in cerebrovascular disease. Overcoming identified challenges and leveraging opportunities for future research might support the development of novel circadian-based treatments for stroke. © 2024 Lippincott Williams and Wilkins. All rights reserved.
Author Keywords
aging; central nervous system; cerebrovascular disorders; circadian clocks; stroke
Funding details
Corona-Stiftung
Ludwig-Maximilians-Universität MünchenLMU
National Institutes of HealthNIHR01AG081841
Document Type: Article
Publication Stage: Final
Source: Scopus
Mindfulness-Based Stress Reduction for Symptom Management in Older Individuals with HIV-Associated Neurocognitive Disorder
(2024) AIDS and Behavior, .
Moskowitz, J.T.a b l , Sharma, B.c d , Javandel, S.c , Moran, P.j , Paul, R.e , De Gruttola, V.f , Tomov, D.g , Azmy, H.g , Sandoval, R.c , Hillis, M.c , Chen, K.P.c , Tsuei, T.c , Addington, E.L.a b , Cummings, P.D.a b , Hellmuth, J.c , Allen, I.E.h , Ances, B.M.g , Valcour, V.c i , Milanini, B.k
a Department of Medical Social Sciences, Northwestern University Feinberg School of Medicine, Chicago, IL, United States
b Osher Center for Integrative Health, Northwestern University, Chicago, IL, United States
c Department of Neurology, Memory and Aging Center, University of California San Francisco, San Francisco, CA, United States
d College of Osteopathic Medicine of the Pacific, Western University of Health Sciences, Pomona, CA, United States
e Missouri Institute of Mental Health, University of Missouri-St. Louis, St. Louis, MO, United States
f Division of Biostatistics, Herbert Wertheim School of Public Health, University of California San Diego, San Diego, CA, United States
g Department of Neurology, School of Medicine, Washington University in St. Louis, St. Louis, MO, United States
h Department of Epidemiology & amp; Biostatistics, University of California, San Francisco, CA, United States
i Global Brain Health Institute, University of California, San Francisco, CA, United States
j Osher Center for Integrative Health, University of California, San Francisco, CA, United States
k Inovigate GmbH, Basel, Switzerland
l Northwestern University Feinberg School of Medicine, 625 N. Michigan Ave, Suite 2700, Chicago, IL 60611, United States
Abstract
The growing number of people aging with HIV represents a group vulnerable to the symptom burdens of HIV-associated neurocognitive disorder (HAND). Among younger groups, Mindfulness-Based Stress Reduction (MBSR) has been shown to help people living with HIV manage HIV-related and other life stress, and although there is some theoretical and empirical evidence that it may be effective among those with cognitive deficits, the approach has not been studied in older populations with HAND. Participants (n = 180) 55 years or older with HIV and cognitive impairment were randomly assigned to either an 8-week MBSR arm or a waitlist control. We assessed the impact of MBSR compared to a waitlist control on psychological outcomes [stress, anxiety, depression, and quality of life (QOL)] and cognitive metrics (e.g., speed of information processing, working memory, attention, impulsivity) measured at baseline, immediately post intervention (8 weeks) and one month later (16 weeks). Intent to treat analyses showed significant improvement in the MBSR group compared to control on symptoms of depression from baseline to 8 weeks, however, the difference was not sustained at 16 weeks. The MBSR group also showed improvement in perceived QOL from baseline to 16 weeks compared to the waitlist control group. Cognitive performance did not differ between the two treatment arms. MBSR shows promise as a tool to help alleviate the symptom burden of depression and low QOL in older individuals living with HAND and future work should address methods to better sustain the beneficial impact on depression and QOL. © The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature 2024.
Author Keywords
Aging; Cognition; HIV; HIV-associated neurocognitive disorder; Mindfulness Based Stress Reduction
Funding details
National Institutes of HealthNIHR01NR015223, K24MH098759
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
Emerging Cerebrospinal Fluid Biomarkers of Disease Activity and Progression in Multiple Sclerosis
(2024) JAMA Neurology, .
Cross, A.H.b , Gelfand, J.M.c , Thebault, S.d , Bennett, J.L.e , Christian von Büdingen, H.f , Cameron, B.g , Carruthers, R.i , Edwards, K.j , Fallis, R.k , Gerstein, R.l , Giacomini, P.S.m , Greenberg, B.n , Hafler, D.A.o , Ionete, C.l , Kaunzner, U.W.p q , Kodama, L.g , Lock, C.s , Longbrake, E.E.o , Musch, B.g , Pardo, G.r t , Piehl, F.u , Weber, M.S.x , Yuen, S.x , Ziemssen, T.v , Bose, G.w , Freedman, M.S.w , Anania, V.G.x , Ramesh, A.x , Winger, R.C.x , Jia, X.x , Herman, A.x , Harp, C.h , Bar-Or, A.a d
a Department of Neurology, Perelman School of Medicine, University of Pennsylvania, 3400 Spruce St, 3 Gates Building, Philadelphia, PA 19104, United States
b Washington University School of Medicine, St Louis, MO, United States
c University of California, San Francisco, United States
d Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States
e University of Colorado Anschutz Medical Campus, Aurora, United States
f F. Hoffmann-La Roche, Basel, Switzerland
g Genentech, South San Francisco, CA, United States
h Yuen, Anania, Ramesh, Herman Winger, Jia, China
i University of British Columbia, Vancouver, BC, Canada
j MS Center of Northeastern, Latham, New York, United States
k Ohio State University Wexner Medical Center, Columbus, United States
l University of Massachusetts Medical School, Worcester, United States
m McGill University, Montreal, QC, Canada
n The University of Texas Southwestern Medical Center, Dallas, United States
o Yale School of Medicine, New Haven, CT, United States
p Weill Cornell Medicine, New York, NY, United States
q Stanford University, Stanford, CA, United States
r Oklahoma Medical Research Foundation, Oklahoma City, United States
s Karolinska Institutet, Solna, Sweden
t Institute of Neuropathology, Department of Neurology, University Medical Center, Göttingen, Germany
u Fraunhofer Institute for Translational Medicine and Pharmacology, Göttingen, Germany
v Center of Clinical Neuroscience, Carl Gustav Carus University Clinic, Dresden, Germany
w Department of Medicine in Neurology, University of Ottawa, Ottawa Hospital Research Institute, Ottawa, ON, Canada
Abstract
IMPORTANCE Biomarkers distinguishing nonrelapsing progressive disease biology from relapsing biology in multiple sclerosis (MS) are lacking. Cerebrospinal fluid (CSF) is an accessible fluid that most closely reflects central nervous system biology. OBJECTIVE To identify CSF biological measures associated with progressive MS pathobiology. DESIGN, SETTING, AND PARTICIPANTS This cohort study assessed data from 2 prospective MS cohorts: a test cohort provided serial CSF, clinical, and imaging assessments in a multicenter study of patients with relapsing MS (RMS) or primary progressive MS (PPMS) who were initiating anti-CD20 treatment (recruitment: 2016-2018; analysis: 2020-2023). A single-site confirmation cohort was used to assess CSF at baseline and long-term (>10 year) clinical follow-up (analysis: 2022-2023). EXPOSURES Test-cohort participants initiated standard-of-care ocrelizumab treatment. Confirmation-cohort participants were untreated or received standard-of-care disease-modifying MS therapies. MAIN OUTCOMES AND MEASURES Twenty-five CSF markers, including neurofilament light chain, neurofilament heavy chain, and glial fibrillary acid protein (GFAP); 24-week confirmed disability progression (CDP24); and brain magnetic resonance imaging measures reflecting focal injury, tissue loss, and progressive biology (slowly expanding lesions [SELs]). RESULTS The test cohort (n = 131) included 100 patients with RMS (mean [SD] age, 36.6 [10.4] years; 68 [68%] female and 32 [32%] male; Expanded Disability Status Scale [EDSS] score, 0-5.5), and 31 patients with PPMS (mean [SD] age, 44.9 [7.4] years; 15 [48%] female and 16 [52%] male; EDSS score, 3.0-6.5). The confirmation cohort (n = 68) included 41 patients with RMS and 27 with PPMS enrolled at diagnosis (age, 40 years [range, 20-61 years]; 47 [69%] female and 21 [31%] male). In the test cohort, GFAP was correlated with SEL count (r = 0.33), greater proportion of T2 lesion volume from SELs (r = 0.24), and lower T1-weighted intensity within SELs (r = –0.33) but not with acute inflammatory measures. Neurofilament heavy chain was correlated with SEL count (r = 0.25) and lower T1-weighted intensity within SELs (r = –0.28). Immune markers correlated with measures of acute inflammation and, unlike GFAP, were impacted by anti-CD20. In the confirmation cohort, higher baseline CSF GFAP levels were associated with long-term CDP24 (hazard ratio, 2.1; 95% CI, 1.3-3.4; P = .002). CONCLUSIONS AND RELEVANCE In this study, activated glial markers (in particular GFAP) and neurofilament heavy chain were associated specifically with nonrelapsing progressive disease outcomes (independent of acute inflammatory activity). Elevated CSF GFAP was associated with long-term MS disease progression. © 2024 Cross AH et al. JAMA Neurology.
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
Dominantly Inherited Alzheimer Network Trials Unit (DIAN-TU): Trial Satisfaction and Attitudes towards Future Clinical Trials
(2024) Journal of Prevention of Alzheimer’s Disease, .
Liu, H.a , Li, J.b , Ziegemeier, E.a , Adams, S.a , McDade, E.a , Clifford, D.B.a , Cao, Y.c , Wang, G.c , Li, Y.a c , Mills, S.L.a , Santacruz, A.M.b , Belyew, S.a , Grill, J.D.d , Snider, B.J.a , Mummery, C.J.e , Surti, G.f , Hannequin, D.g , Wallon, D.g , Berman, S.B.h , Jimenez-Velazquez, I.Z.i , Roberson, E.D.j , van Dyck, C.H.k , Honig, L.S.l , Sanchez-Valle, R.m , Brooks, W.S.n , Gauthier, S.o , Galasko, D.p , Masters, C.L.q , Brosch, J.r , Hsiung, G.Y.R.s , Jayadev, S.t , Formaglio, M.u , Masellis, M.v , Clarnette, R.w , Pariente, J.x , Dubois, B.y , Pasquier, F.z , Bateman, R.J.a , Llibre-Guerra, J.J.a
a Department of Neurology, Washington University School of Medicine, 4488 Forest Park 00328, St Louis, MO 63108, United States
b Department of Medicine, University of Missouri, Columbia, MO, United States
c Division of Biostatistics, Washington University in St Louis, St Louis, MO, United States
d Departments of Psychiatry & amp; Human Behavior and Neurobiology & amp; Behavior at the University of California, Irvine, United States
e University College of London, London, United Kingdom
f Brown University, Providence, RI, United States
g Centre Hospitalier Universitaire de Rouen, Rouen, France
h University of Pittsburgh, Pittsburgh, PA, United States
i University of Puerto Rico School of Medicine, San Juan, PR, United States
j University of Alabama at Birmingham, Birmingham, AL, United States
k Yale University School of Medicine, New Haven, CT, United States
l Columbia University Irving Medical Center, New York, NY, United States
m Hospital Clínic i Provincial de Barcelona, IDIBAPS-Universitat de Barcelona, Barcelona, Spain
n Neuroscience Research Australia and University of New South Wales Medicine, Kensington, NSW, Australia
o McGill University Research Center for Studies in Aging, Montreal, Canada
p University of California, San Diego, CA, United States
q The Florey Institute, University of Melbourne, Melbourne, Australia
r Indiana University School of Medicine, Indianapolis, IN, United States
s University of British Columbia, Vancouver, Canada
t University of Washington School of Medicine, Seattle, WA, United States
u Neurological Hospital, Centre Hospitalier Universitaire de Lyon, Bron, France
v Sunnybrook Research Institute, Toronto, Canada
w Australian Alzheimer’s Research Foundation, University of Western Australia, Perth, Australia
x Centre Hospitalier Universitaire de Toulouse, Toulouse, France
y Neurological Institute of the Salpetriere, University Hospital, Paris, France
z Centre Hospitalier Régional Universitaire de Lille, Lille, France
Abstract
Background: Clinical trial satisfaction is increasingly important for future trial designs and is associated with treatment adherence and willingness to enroll in future research studies or to recommend trial participation. In this post-trial survey, we examined participant satisfaction and attitudes toward future clinical trials in the Dominantly Inherited Alzheimer Network Trials Unit (DIAN-TU). Methods: We developed an anonymous, participant satisfaction survey tailored to participants enrolled in the DIAN-TU-001 double-blind clinical trial of solanezumab or gantenerumab and requested that all study sites share the survey with their trial participants. A total of 194 participants enrolled in the trial at 24 study sites. We utilized regression analysis to explore the link between participants’ clinical trial experiences, their satisfaction, and their willingness to participate in upcoming trials. Results: Survey responses were received over a sixteen-month window during 2020–2021 from 58 participants representing 15 study sites. Notably, 96.5% of the survey respondents expressed high levels of satisfaction with the trial, 91.4% would recommend trial participation, and 96.5% were willing to enroll again. Age, gender, and education did not influence satisfaction levels. Participants reported enhanced medical care (70.7%) and pride in contributing to the DIAN-TU trial (84.5%). Satisfaction with personnel and procedures was high (98.3%). Respondents had a mean age of 48.7 years, with most being from North America and Western Europe, matching the trial’s demographic distribution. Participants’ decisions to learn their genetic status increased during the trial, and most participants endorsed considering future trial participation regardless of the DIAN-TU-001 trial outcome. Conclusion: Results suggest that DIAN-TU-001 participants who responded to the survey exhibited high motivation to participate in research, overall satisfaction with the clinical trial, and willingness to participate in research in the future, despite a long trial duration of 4–7 years with detailed annual clinical, cognitive, PET, MRI, and lumbar puncture assessments. Implementation of features that alleviate barriers and challenges to trial participation is like to have a high impact on trial satisfaction and reduce participant burden. © Serdi 2024.
Author Keywords
Alzheimer’s Disease (AD); Clinical trial satisfaction; Dominantly Inherited Alzheimer Network-Trial Unit (DIAN-TU); Dominantly Inherited Alzheimer’s Disease (DIAD); Home Health Nursing (HHN)
Funding details
Alzheimer’s AssociationAA
Deutsches Zentrum für Neurodegenerative ErkrankungenDZNE
Fleni
Eli Lilly and Company
Japan Agency for Medical Research and DevelopmentAMED
GHR FoundationGHR
Korea Health Industry Development InstituteKHIDI
National Institute on AgingNIAU19AG032438
National Institutes of HealthNIHU01AG042791
Foundation for the National Institutes of HealthFNIHR01AG046179, R01AG053267-S1
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
Pneumococcal Meningitis Induces Hearing Loss and Cochlear Ossification Modulated by Chemokine Receptors CX3CR1 and CCR2
(2024) JARO – Journal of the Association for Research in Otolaryngology, .
Hirose, K.a , Li, S.Z.a , Gill, R.a b , Hartsock, J.a c
a Department of Otolaryngology-Head and Neck Surgery, Washington University School of Medicine, 660 S. Euclid Avenue, St. Louis, MO 63110, United States
b Department of Obstetric and Gynecology, Washington University, St. Louis, MO, United States
c Turner Scientific, Jacksonville, IL, United States
Abstract
Purpose: Pneumococcal meningitis is a major cause of hearing loss and permanent neurological impairment despite widely available antimicrobial therapies to control infection. Methods to improve hearing outcomes for those who survive bacterial meningitis remains elusive. We used a mouse model of pneumococcal meningitis to evaluate the impact of mononuclear phagocytes on hearing outcomes and cochlear ossification by altering the expression of CX3CR1 and CCR2 in these infected mice. Methods: We induced pneumococcal meningitis in approximately 500 C57Bl6 adult mice using live Streptococcus pneumoniae (serotype 3, 1 × 105 colony forming units (cfu) in 10 µl) injected directly into the cisterna magna of anesthetized mice and treated these mice with ceftriaxone daily until recovered. We evaluated hearing thresholds over time, characterized the cochlear inflammatory response, and quantified the amount of new bone formation during meningitis recovery. We used microcomputed tomography (microCT) scans to quantify cochlear volume loss caused by neo-ossification. We also performed perilymph sampling in live mice to assess the integrity of the blood-perilymph barrier during various time intervals after meningitis. We then evaluated the effect of CX3CR1 or CCR2 deletion in meningitis symptoms, hearing loss, macrophage/monocyte recruitment, neo-ossification, and blood labyrinth barrier function. Results: Sixty percent of mice with pneumococcal meningitis developed hearing loss. Cochlear fibrosis could be detected within 4 days of infection, and neo-ossification by 14 days. Loss of spiral ganglion neurons was common, and inner ear anatomy was distorted by scarring caused by new soft tissue and bone deposited within the scalae. The blood-perilymph barrier was disrupted at 3 days post infection (DPI) and was restored by seven DPI. Both CCR2 and CX3CR1 monocytes and macrophages were present in the cochlea in large numbers after infection. Neither chemokine receptor was necessary for the induction of hearing loss, cochlear fibrosis, ossification, or disruption of the blood-perilymph barrier. CCR2 knockout (KO) mice suffered the most severe hearing loss. CX3CR1 KO mice demonstrated an intermediate phenotype with greater susceptibility to hearing loss compared to control mice. Elimination of CX3CR1 mononuclear phagocytes during the first 2 weeks after meningitis in CX3CR1-DTR transgenic mice did not protect mice from any of the systemic or hearing sequelae of pneumococcal meningitis. Conclusions: Pneumococcal meningitis can have devastating effects on cochlear structure and function, although not all mice experienced hearing loss or cochlear damage. Meningitis can result in rapid progression of hearing loss with fibrosis starting at four DPI and ossification within 2 weeks of infection detectable by light microscopy. The inflammatory response to bacterial meningitis is robust and can affect all three scalae. Our results suggest that CCR2 may assist in controlling infection and maintaining cochlear patency, as CCR2 knockout mice experienced more severe disease, more rapid hearing loss, and more advanced cochlear ossification after pneumococcal meningitis. CX3CR1 also may play an important role in the maintenance of cochlear patency. © The Author(s) under exclusive licence to Association for Research in Otolaryngology 2024.
Author Keywords
Cochlea; Inflammation; Labyrinthitis ossificans; Meningitis
Funding details
National Institute on Deafness and Other Communication DisordersNIDCDDC011315
Document Type: Article
Publication Stage: Article in Press
Source: Scopus