WashU weekly Neuroscience publications: May 12, 2024

Association between retinal microvascular abnormalities and late-life brain amyloid-β deposition: the ARIC-PET study
(2024) Alzheimer’s Research and Therapy, 16 (1), art. no. 100, . 

Egle, M.^a , Deal, J.A.^b , Walker, K.A.^c , Wong, D.F.^d , Sharrett, A.R.^b , Gottesman, R.F.^a

^a National Institute of Neurological Disorders and Stroke Intramural Research Program, National Institutes of Health, Bethesda, MD 20814, United States
^b Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21231, United States
^c Laboratory of Behavioral Neuroscience, National Institute on Aging, Intramural Research Program, Baltimore, MD 21224, United States
^d Mallinckrodt Institute of Radiology, Washington University School of Medicine in St. Louis, St. Louis, MO 63110, United States

Abstract
Background: Retinal microvascular signs are accessible measures of early alterations in microvascular dysregulation and have been associated with dementia; it is unclear if they are associated with AD (Alzheimer’s disease) pathogenesis as a potential mechanistic link. This study aimed to test the association of retinal microvascular abnormalities in mid and late life and late life cerebral amyloid. Methods: Participants from the ARIC‐PET (Atherosclerosis Risk in Communities‐Positron Emission Tomography) study with a valid retinal measure (N = 285) were included. The associations of mid- and late-life retinal signs with late-life amyloid-β (Aβ) by florbetapir PET were tested. Two different measures of Aβ burden were included: (1) elevated amyloid (SUVR > 1.2) and (2) continuous amyloid SUVR. The retinal measures’ association with Aβ burden was assessed using logistic and robust linear regression models. A newly created retinal score, incorporating multiple markers of retinal abnormalities, was also evaluated in association with greater Aβ burden. Results: Retinopathy in midlife (OR (95% CI) = 0.36 (0.08, 1.40)) was not significantly associated with elevated amyloid burden. In late life, retinopathy was associated with increased continuous amyloid standardized value uptake ratio (SUVR) (β (95%CI) = 0.16 (0.02, 0.32)) but not elevated amyloid burden (OR (95%CI) = 2.37 (0.66, 9.88)) when accounting for demographic, genetic and clinical risk factors. A high retinal score in late life, indicating a higher burden of retinal abnormalities, was also significantly associated with increased continuous amyloid SUVR (β (95% CI) = 0.16 (0.04, 0.32)) independent of vascular risk factors. Conclusions: Retinopathy in late life may be an easily obtainable marker to help evaluate the mechanistic vascular pathway between retinal measures and dementia, perhaps acting via AD pathogenesis. Well-powered future studies with a greater number of retinal features and other microvascular signs are needed to test these findings. © This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply 2024.

Author Keywords
Alzheimer’s disease;  Amyloid burden;  Aβ burden;  Biomarkers;  Fundus retinal photography;  Microvasculature;  Positron emission tomography;  Retinal markers;  Vascular burden

Funding details
National Institute of Neurological Disorders and StrokeNINDS
National Institutes of HealthNIH
National Heart, Lung, and Blood InstituteNHLBIU01HL096917, 75N92022D00002, 75N92022D00001, U01HL096812, U01HL096814, 75N92022D00004, 75N92022D00005, U01HL096902, U01HL096899, 75N92022D00003
National Heart, Lung, and Blood InstituteNHLBI
National Institute on Deafness and Other Communication DisordersNIDCDR01AG040282
National Institute on Deafness and Other Communication DisordersNIDCD
National Institute on AgingNIAK01AG054693
National Institute on AgingNIA

Document Type: Article
Publication Stage: Final
Source: Scopus

SDPR expression in human trabecular meshwork and its potential role in racial disparities of glaucoma
(2024) Scientific Reports, 14 (1), art. no. 10258, . 

Shui, Y.-B., Liu, Y., Huang, A.J.W., Siegfried, C.J.

Department of Ophthalmology and Visual Sciences, Washington University School of Medicine, St. Louis, MO 63110, United States

Abstract
In order to identify how differential gene expression in the trabecular meshwork (TM) contributes to racial disparities of caveolar protein expression, TM dysfunction and development of primary open angle glaucoma (POAG), RNA sequencing was performed to compare TM tissue obtained from White and Black POAG surgical (trabeculectomy) specimens. Healthy donor TM tissue from White and Black donors was analyzed by PCR, qPCR, immunohistochemistry staining, and Western blot to evaluate SDPR (serum deprivation protein response; Cavin 2) and CAV1/CAV2 (Caveolin 1/Caveolin 2). Standard transmission electron microscopy (TEM) and immunogold labeled studies were performed. RNA sequencing demonstrated reduced SDPR expression in TM from Black vs White POAG patients’ surgical specimens, with no significant expression differences in other caveolae-associated genes, confirmed by qPCR analysis. No racial differences in SDPR gene expression were noted in healthy donor tissue by PCR analysis, but there was greater expression as compared to specimens from patients with glaucoma. Analysis of SDPR protein expression confirmed specific expression in the TM regions, but not in adjacent tissues. TEM studies of TM specimens from healthy donors did not demonstrate any racial differences in caveolar morphology, but a significant reduction of caveolae with normal morphology and immuno-gold staining of SDPR were noted in glaucomatous TM as compared to TM from healthy donors. Linkage of SDPR expression levels in TM, POAG development, and caveolar ultrastructural morphology may provide the basis for a novel pathway of exploration of the pathologic mechanisms of glaucoma. Differential gene expression of SDPR in TM from Black vs White subjects with glaucoma may further our understanding of the important public health implications of the racial disparities of this blinding disease. © The Author(s) 2024.

Funding details
Research to Prevent BlindnessRPB

Document Type: Article
Publication Stage: Final
Source: Scopus

A personalized semi-automatic sleep spindle detection (PSASD) framework
(2024) Journal of Neuroscience Methods, 407, art. no. 110064, . 

Kafashan, M.^a b , Gupte, G.^a , Kang, P.^a , Hyche, O.^a , Luong, A.H.^a , Prateek, G.V.^d , Ju, Y.-E.S.^b e , Palanca, B.J.A.^{a b c f g}

^a Department of Anesthesiology, Washington University School of Medicine in St. Louis, St. Louis, MO, United States
^b Center on Biological Rhythms and Sleep, Washington University in St. Louis, St. Louis, MO, United States
^c Department of Biomedical Engineering, Washington University in St. Louis, St. Louis, MO, United States
^d Calico Life Sciences LLC, South San Francisco, CA, United States
^e Department of Neurology, Division of Sleep Medicine, Washington University School of Medicine in St. Louis, St. Louis, MO, United States
^f Department of Psychiatry, Washington University School of Medicine in St. Louis, St. Louis, MO, United States
^g Division of Biology and Biomedical Sciences, Washington University School of Medicine in St. Louis, St. Louis, MO, United States

Abstract
Background: Sleep spindles are distinct electroencephalogram (EEG) patterns of brain activity that have been posited to play a critical role in development, learning, and neurological disorders. Manual scoring for sleep spindles is labor-intensive and tedious but could supplement automated algorithms to resolve challenges posed with either approaches alone. New methods: A Personalized Semi-Automatic Sleep Spindle Detection (PSASD) framework was developed to combine the strength of automated detection algorithms and visual expertise of human scorers. The underlying model in the PSASD framework assumes a generative model for EEG sleep spindles as oscillatory components, optimized to EEG amplitude, with remaining signals distributed into transient and low-frequency components. Results: A single graphical user interface (GUI) allows both manual scoring of sleep spindles (model training data) and verification of automatically detected spindles. A grid search approach allows optimization of parameters to balance tradeoffs between precision and recall measures. Comparison with existing methods: PSASD outperformed DETOKS in F1-score by 19% and 4% on the DREAMS and P-DROWS-E datasets, respectively. It also outperformed YASA in F1-score by 25% in the P-DROWS-E dataset. Further benchmarking analysis showed that PSASD outperformed four additional widely used sleep spindle detectors in F1-score in the P-DROWS-E dataset. Titration analysis revealed that four 30-second epochs are sufficient to fine-tune the model parameters of PSASD. Associations of frequency, duration, and amplitude of detected sleep spindles matched those previously reported with automated approaches. Conclusions: Overall, PSASD improves detection of sleep spindles in EEG data acquired from both younger healthy and older adult patient populations. © 2024

Author Keywords
Automated pattern recognition;  Electroencephalogram (EEG);  Non-rapid eye movement sleep;  Polysomnography;  Signal processing;  Sleep;  Sleep spindle;  Wireless EEG devices

Funding details
National Institute on AgingNIA
McDonnell Center for Systems Neuroscience
R01AG057901
National Institute of Mental HealthNIMHK01 MH128663
National Institute of Mental HealthNIMH
National Institute of Neurological Disorders and StrokeNINDSK23NS089922
National Institute of Neurological Disorders and StrokeNINDS

Document Type: Article
Publication Stage: Final
Source: Scopus

Relationships between plasma neurofilament light chain protein, cognition, and brain aging in people with HIV
(2024) AIDS (London, England), 38 (7), pp. 955-962. 

Cooley, S.A.^a , Petersen, K.J.^a , Tice, C.^b , Langford, D.^b , Burdo, T.H.^c , Roman, J.^a , Ances, B.M.^a

^a Department of Neurology, Washington University in St. Louis, St. Louis, MO, United States
^b Department of Neural Sciences
^c Department of Microbiology, Immunology, Inflammation, Center for Neurovirology and Gene Editing, Lewis Katz School of Medicine, Temple University, Philadelphia, PA, United States

Abstract
OBJECTIVE: Neurofilament light chain protein (NfL) is a marker of neuronal injury and neurodegeneration. Typically assessed in cerebrospinal fluid, recent advances have allowed this biomarker to be more easily measured in plasma. This study assesses plasma NfL in people with HIV (PWH) compared with people without HIV (PWoH), and its relationship with cognitive impairment, cardiovascular risk, and a neuroimaging metric of brain aging [brain-age gap (BAG)]. DESIGN: One hundred and four PWH (HIV RNA <50 copies/ml) and 42 PWoH provided blood samples and completed a cardiovascular risk score calculator, neuroimaging, and cognitive testing. METHOD: Plasma NfL was compared between PWoH and PWH and assessed for relationships with age, HIV clinical markers, cardiovascular disease risk, cognition, and BAG (difference between a brain-predicted age and chronological age). RESULTS: Plasma NfL was not significantly different between PWoH and PWH. Higher NfL related to increasing age in both groups. Plasma NfL was not associated with typical HIV disease variables. Within PWH, NfL was higher with higher cardiovascular risk, cognitive impairment and a greater BAG. CONCLUSION: Virally suppressed PWH who are cognitively normal likely do not have significant ongoing neurodegeneration, as evidenced by similar plasma NfL compared with PWoH. However, NfL may represent a biomarker of cognitive impairment and brain aging in PWH. Further research examining NfL with longitudinal cognitive decline is needed to understand this relationship more fully. Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.

Document Type: Article
Publication Stage: Final
Source: Scopus

Novel loss-of-function variants expand ABCC9-related intellectual disability and myopathy syndrome
(2024) Brain: A Journal of Neurology, 147 (5), pp. 1822-1836. 

Efthymiou, S.^a , Scala, M.^a b c , Nagaraj, V.^d , Ochenkowska, K.^e , Komdeur, F.L.^f , Liang, R.A.^g , Abdel-Hamid, M.S.^h , Sultan, T.ⁱ , Barøy, T.^j , Van Ghelue, M.^g , Vona, B.^k , Maroofian, R.^a , Zafar, F.^l , Alkuraya, F.S.^m , Zaki, M.S.ⁿ , Severino, M.^o , Duru, K.C.^d , Tryon, R.C.^p , Brauteset, L.V.^q , Ansari, M.^r , Hamilton, M.^s , van Haelst, M.M.^f , van Haaften, G.^t , Zara, F.^c , Houlden, H.^a , Samarut, É.^e , Nichols, C.G.^p , Smeland, M.F.^u v , McClenaghan, C.^d

^a Department of Neuromuscular Disorders, University College London, UCL Queen Square Institute of Neurology, London, WC1N 3BG, United Kingdom
^b Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genoa, Genoa, 16147, Italy
^c U.O.C. Genetica Medica, IRCCS Istituto Giannina Gaslini, Genoa, 16147, Italy
^d Center for Advanced Biotechnology and Medicine, Departments of Pharmacology and Medicine, Robert Wood Johnson Medical School, Rutgers the State University of New JerseyNJ 08854, United States
^e Centre de Recherche du Centre Hospitalier de l’Université de Montréal (CRCHUM), Department of Neuroscience, Université de Montréal, Montreal, QC H2X 0A9, Canada
^f Section Clinical Genetics, Department of Human Genetics and Amsterdam Reproduction and Development, Amsterdam University Medical Centers, Amsterdam, 1105 AZ, Netherlands
^g Department of Medical Genetics, Division of Child and Adolescent Health, University Hospital of North Norway, Norway
^h Medical Molecular Genetics Department, Human Genetics and Genome Research Institute, National Research CentreCairo 12622, Egypt
ⁱ Department of Pediatric Neurology, Children Hospital, University of Child Health Sciences, Lahore, Punjab 54000, Pakistan
^j Department of Medical Genetics, Oslo University HospitalOslo 0450, Norway
^k Institute of Human Genetics and Institute for Auditory Neuroscience and InnerEarLab, University Medical Center Göttingen, 37073 Göttingen, Germany
^l Department of Paediatric Neurology, Children’s Hospital and Institute of Child Health, Multan, Punjab 60000, Pakistan
^m Department of Translational Genomics, Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center, Riyadh, 12713, Saudi Arabia
ⁿ Clinical Genetics Department, Human Genetics and Genome Research Institute, National Research CentreCairo 12622, Egypt
^o Neuroradiology Unit, IRCCS Istituto Giannina Gaslini, Genova, 16147, Italy
^p Department of Cell Biology and Physiology, Center for the Investigation of Membrane Excitability Diseases (CIMED), Washington University, St Louis, MO 63110, United States
^q Innlandet Hospital Sanderud, Hamar, 2312, Norway
^r Western General Hospital, South East Scotland Genetic Service, Edinburgh, EH4 2XU, United Kingdom
^s West of Scotland Clinical Genetics Service, Queen Elizabeth University Hospital, Glasgow, G51 4TF, United Kingdom
^t Department of Genetics, University Medical CenterUtrecht 3584 CX, Netherlands
^u Department of Pediatric Rehabilitation, University Hospital of North Norway, Norway
^v Institute of Clinical Medicine, UiT The Arctic University of Norway, Tromsø9019, Norway

Abstract
Loss-of-function mutation of ABCC9, the gene encoding the SUR2 subunit of ATP sensitive-potassium (KATP) channels, was recently associated with autosomal recessive ABCC9-related intellectual disability and myopathy syndrome (AIMS). Here we identify nine additional subjects, from seven unrelated families, harbouring different homozygous loss-of-function variants in ABCC9 and presenting with a conserved range of clinical features. All variants are predicted to result in severe truncations or in-frame deletions within SUR2, leading to the generation of non-functional SUR2-dependent KATP channels. Affected individuals show psychomotor delay and intellectual disability of variable severity, microcephaly, corpus callosum and white matter abnormalities, seizures, spasticity, short stature, muscle fatigability and weakness. Heterozygous parents do not show any conserved clinical pathology but report multiple incidences of intra-uterine fetal death, which were also observed in an eighth family included in this study. In vivo studies of abcc9 loss-of-function in zebrafish revealed an exacerbated motor response to pentylenetetrazole, a pro-convulsive drug, consistent with impaired neurodevelopment associated with an increased seizure susceptibility. Our findings define an ABCC9 loss-of-function-related phenotype, expanding the genotypic and phenotypic spectrum of AIMS and reveal novel human pathologies arising from KATP channel dysfunction. © The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain.

Author Keywords
ABCC9;  KATP channels;  neurodevelopmental disorder;  SUR2

Document Type: Article
Publication Stage: Final
Source: Scopus

Atypical functional connectivity between the amygdala and visual, salience regions in infants with genetic liability for autism
(2024) Cerebral Cortex (New York, N.Y. : 1991), 34 (13), pp. 30-39. 

Liu, J.^a b c , Girault, J.B.^d e , Nishino, T.^f , Shen, M.D.^d e , Kim, S.H.^d , Burrows, C.A.^f , Elison, J.T.^f , Marrus, N.^g , Wolff, J.J.^h , Botteron, K.N.^g , Estes, A.M.ⁱ , Dager, S.R.^j , Hazlett, H.C.^d e , McKinstry, R.C.^k , Schultz, R.T.^l , Snyder, A.Z.^k , Styner, M.^d , Zwaigenbaum, L.^m , Pruett, J.R., Jr^g , Piven, J.^d e , Gao, W.^a b c

^a Department of Biomedical Sciences and Imaging, Cedars-Sinai Medical Center, 8700 Beverly Blvd., Los Angeles, CA 90048, USA
^b Biomedical Imaging Research Institute, Cedars-Sinai Medical Center, 116 N. Robertson Bldv., Los Angeles, CA 90048, USA
^c Department of Medicine, David Geffen School of Medicine, UCLA, 10833 Le Conte Ave., Los Angeles, CA 90095, USA
^d Department of Psychiatry, UNC Chapel Hill, 333 S. Columbia Street ,Chapel HillNC 27514, United States
^e Carolina Institute for Developmental Disabilities, UNC Chapel Hill, 101 Renee Lynne Court, Carrboro, United States
^f Institute for Child Development, University of Minnesota, 51 East River Rd., Minneapolis, United States
^g Department of Psychiatry, Washington University School of Medicine, 660 S Euclid Ave., St. Louis, MO 63110, United States
^h Department of Educational Psychology, University of Minnesota, 56 E River Rd., Minneapolis, United States
ⁱ Department of Speech and Hearing Science, University of Washington, 1417 NE 42nd St., Seattle, WA 98105, USA
^j Department of Radiology, University of Washington, 1959 NE Pacific St., Seattle, WA 98195, USA
^k Department of Radiology, Washington University School of Medicine, 660 S Euclid Ave., St. Louis, MO 63110, United States
^l Center for Autism Research, Children’s Hospital of Philadelphia, 2716 South St., Philadelphia, PA 19104, United States
^m Department of Pediatrics, University of Alberta, 116 St. and 85 Ave, Edmonton, Alberta, T6G 2R3, CA

Abstract
The amygdala undergoes a period of overgrowth in the first year of life, resulting in enlarged volume by 12 months in infants later diagnosed with ASD. The overgrowth of the amygdala may have functional consequences during infancy. We investigated whether amygdala connectivity differs in 12-month-olds at high likelihood (HL) for ASD (defined by having an older sibling with autism), compared to those at low likelihood (LL). We examined seed-based connectivity of left and right amygdalae, hypothesizing that the HL and LL groups would differ in amygdala connectivity, especially with the visual cortex, based on our prior reports demonstrating that components of visual circuitry develop atypically and are linked to genetic liability for autism. We found that HL infants exhibited weaker connectivity between the right amygdala and the left visual cortex, as well as between the left amygdala and the right anterior cingulate, with evidence that these patterns occur in distinct subgroups of the HL sample. Amygdala connectivity strength with the visual cortex was related to motor and communication abilities among HL infants. Findings indicate that aberrant functional connectivity between the amygdala and visual regions is apparent in infants with genetic liability for ASD and may have implications for early differences in adaptive behaviors. © The Author(s) 2024. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Natural history and growth rate of intracranial aneurysms in Loeys-Dietz syndrome: implications for treatment
(2024) Journal of Neurosurgery, 140 (5), pp. 1381-1388. 

Huguenard, A.L.^a , Johnson, G.W.^a , Osbun, J.W.^a , Dacey, R.G.^a , Braverman, A.C.^b

^a 1Department of Neurosurgery, Washington University in St. Louis, Missouri; and
^b Department of Medicine, Cardiovascular Division, Washington University in St. Louis MO, United States

Abstract
OBJECTIVE: Loeys-Dietz syndrome (LDS) is a heritable aortopathy associated with craniofacial abnormalities and dilatation and dissection of the aorta and its branches, as well as increased risk for intracranial aneurysms (ICAs). Given the rarity of the disease, the authors aimed to better define the natural history and role for the treatment for ICAs in these patients. METHODS: The medical records of 83 patients with LDS were retrospectively reviewed to obtain clinical and genetic history and vascular imaging of the aorta, aortic branches, and intracranial vessels. Serial radiology reports and cervical and intracranial vascular images were reviewed to determine presence, location, and size of ICAs. RESULTS: In total, 55 patients (66.3%) had at least two screening intracranial vascular examinations, and 19 (22.9%) had at least 1 ICA detected. Aneurysms were typically small (mean ± SD 3.2 ± 1.8 mm). ICAs were most often located in the cavernous carotid, followed by the ophthalmic and anterior cerebral artery vessels. The rate of ICA growth was 0.43 ± 0.53 mm/year, similar to that of the general population. Three patients underwent intervention for an ICA, with 1 procedure complicated by stroke and resulting in transient hemiparesis. Several illustrative cases detail the authors’ experience with ICA growth, de novo aneurysm formation, and ICA intervention in this rare patient population. CONCLUSIONS: ICAs in patients with LDS are common, are frequently small, and have a growth rate similar to that of unruptured ICAs in the general population. More aggressive or earlier intervention for asymptomatic ICAs identified in LDS patients compared with the general population is likely unwarranted based on the authors’ experience at their institution.

Author Keywords
endovascular;  endovascular neurosurgery;  growth rate;  intracranial aneurysm;  Loeys-Dietz syndrome;  serial screening;  subarachnoid hemorrhage;  vascular disorders

Document Type: Article
Publication Stage: Final
Source: Scopus

Mapping brain function in adults and young children during naturalistic viewing with high-density diffuse optical tomography
(2024) Human Brain Mapping, 45 (7), art. no. e26684, . 

Tripathy, K.^a b c , Fogarty, M.^b d , Svoboda, A.M.^b , Schroeder, M.L.^b , Rafferty, S.M.^b , Richter, E.J.^e , Tracy, C.^b , Mansfield, P.K.^b , Booth, M.^b , Fishell, A.K.^b , Sherafati, A.^b f , Markow, Z.E.^b g , Wheelock, M.D.^b , Arbeláez, A.M.^h , Schlaggar, B.L.^i j k , Smyser, C.D.^b h l , Eggebrecht, A.T.^{a b d e f g} , Culver, J.P.^b d f g

^a Division of Biological and Biomedical Sciences, Washington University in St. Louis, St. Louis, MO, United States
^b Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, MO, United States
^c Western Psychiatric Hospital, University of Pittsburgh Medical Center, Pittsburgh, PA, United States
^d Imaging Science Program, Washington University in St. Louis, St. Louis, MO, United States
^e Department of Electrical and Systems Engineering, Washington University in St. Louis, St. Louis, MO, United States
^f Department of Physics, Washington University in St. Louis, St. Louis, MO, United States
^g Department of Biomedical Engineering, Washington University in St. Louis, St. Louis, MO, United States
^h Department of Pediatrics, Washington University School of Medicine, St. Louis, MO, United States
ⁱ Kennedy Krieger Institute, Baltimore, MD, United States
^j Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, United States
^k Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD, United States
^l Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States

Abstract
Human studies of early brain development have been limited by extant neuroimaging methods. MRI scanners present logistical challenges for imaging young children, while alternative modalities like functional near-infrared spectroscopy have traditionally been limited by image quality due to sparse sampling. In addition, conventional tasks for brain mapping elicit low task engagement, high head motion, and considerable participant attrition in pediatric populations. As a result, typical and atypical developmental trajectories of processes such as language acquisition remain understudied during sensitive periods over the first years of life. We evaluate high-density diffuse optical tomography (HD-DOT) imaging combined with movie stimuli for high resolution optical neuroimaging in awake children ranging from 1 to 7 years of age. We built an HD-DOT system with design features geared towards enhancing both image quality and child comfort. Furthermore, we characterized a library of animated movie clips as a stimulus set for brain mapping and we optimized associated data analysis pipelines. Together, these tools could map cortical responses to movies and contained features such as speech in both adults and awake young children. This study lays the groundwork for future research to investigate response variability in larger pediatric samples and atypical trajectories of early brain development in clinical populations. © 2024 The Authors. Human Brain Mapping published by Wiley Periodicals LLC.

Author Keywords
brain development;  feature regressor analysis;  functional near-infrared spectroscopy;  movie viewing;  optical neuroimaging

Funding details
James S. McDonnell FoundationJSMF
Bill and Melinda Gates FoundationBMGFOPP1184813
Bill and Melinda Gates FoundationBMGF
National Institutes of HealthNIHU01EB027005, R01NS090874, R01MH122751
National Institutes of HealthNIH

Document Type: Article
Publication Stage: Final
Source: Scopus

Unrecognized Focal Nonmotor Seizures in Adolescents Presenting to Emergency Departments
(2024) Neurology, 102 (10), p. e209389. 

Jandhyala, N., Ferrer, M., Pellinen, J., Greenwood, H.T., Dlugos, D.J., Park, K.L., Thio, L.L., French, J., for Human Epilepsy Project Investigators

From the Department of Neurology (N.J.), NYU Langone Health, New York; Departments of Pediatrics and Neurology (M.F.) and Neurology (H.T.G., J.F.), NYU Grossman School of Medicine, New York, NY; Departments of Neurology (J.P.) and Pediatrics and Neurology (K.L.P.), University of Colorado School of Medicine, Aurora; Department of Neurology (D.J.D.), Children’s’ Hospital of Philadelphia, PA; and Department of Neurology (L.L.T.), Washington University in St. Louis, MO

Abstract
BACKGROUND AND OBJECTIVES: Many adolescents with undiagnosed focal epilepsy seek evaluation in emergency departments (EDs). Accurate history-taking is essential to prompt diagnosis and treatment. In this study, we investigated ED recognition of motor vs nonmotor seizures and its effect on management and treatment of focal epilepsy in adolescents. METHODS: This was a retrospective analysis of enrollment data from the Human Epilepsy Project (HEP), an international multi-institutional study that collected data from 34 sites between 2012 and 2017. Participants were 12 years or older, neurotypical, and within 4 months of treatment initiation for focal epilepsy. We used HEP enrollment medical records to review participants’ initial diagnosis and management. RESULTS: A total of 83 adolescents were enrolled between 12 and 18 years. Fifty-eight (70%) presented to an ED before diagnosis of epilepsy. Although most ED presentations were for motor seizures (n = 52; 90%), many patients had a history of nonmotor seizures (20/52 or 38%). Adolescents with initial nonmotor seizures were less likely to present to EDs (26/44 or 59% vs 32/39 or 82%, p = 0.02), and nonmotor seizures were less likely to be correctly identified (2/6 or 33% vs 42/52 or 81%, p = 0.008). A history of initial nonmotor seizures was not recognized in any adolescent who presented for a first-lifetime motor seizure. As a result, initiation of treatment and admission from the ED was not more likely for these adolescents who met the definition of epilepsy compared with those with no seizure history. This lack of nonmotor seizure history recognition in the ED was greater than that observed in the adult group (0% vs 23%, p = 0.03) and occurred in both pediatric and nonpediatric ED settings. DISCUSSION: Our study supports growing evidence that nonmotor seizures are often undiagnosed, with many individuals coming to attention only after conversion to motor seizures. We found this treatment gap is exacerbated in the adolescent population. Our study highlights a critical need for physicians to inquire about the symptoms of nonmotor seizures, even when the presenting seizure is motor. Future interventions should focus on improving nonmotor seizure recognition for this population in EDs.

Document Type: Article
Publication Stage: Final
Source: Scopus

Long-Term Neurobehavioral and Functional Outcomes of Pediatric Extracorporeal Membrane Oxygenation Survivors
(2024) ASAIO Journal (American Society for Artificial Internal Organs: 1992), 70 (5), pp. 409-416. 

Turner, A.D.^a , Streb, M.M.^b , Ouyang, A.^b , Leonard, S.S.^c , Hall, T.A.^c , Bosworth, C.C.^d , Williams, C.N.^e , Guerriero, R.M.^b , Hartman, M.E.^a , Said, A.S.^a , Guilliams, K.P.^a b f

^a From the Division of Pediatric Critical Care, Department of Pediatrics, Washington University in St. Louis, St. Louis, MO, United States
^b Division of Pediatric Neurology, Department of Neurology, Washington University in St. Louis, St. Louis, MO, United States
^c Division of Pediatric Psychology, Department of Pediatrics, Oregon Health & Science University, Portland, Oregon
^d Department of Psychology, St. Louis Children’s Hospital, St. Louis, MO, United States
^e Division of Pediatric Critical Care, Department of Pediatrics, Oregon Health & Science University, Portland, Oregon
^f Division of Neuroradiology, Mallinckrodt Institute of Radiology, Washington University in St. Louis, St. Louis, MO, United States

Abstract
There are limited reports of neurobehavioral outcomes of children supported on extracorporeal membrane oxygenation (ECMO). This observational study aims to characterize the long-term (≥1 year) neurobehavioral outcomes, identify risk factors associated with neurobehavioral impairment, and evaluate the trajectory of functional status in pediatric ECMO survivors. Pediatric ECMO survivors ≥1-year postdecannulation and ≥3 years of age at follow-up were prospectively enrolled and completed assessments of adaptive behavior (Vineland Adaptive Behavior Scales, Third Edition [Vineland-3]) and functional status (Functional Status Scale [FSS]). Patient characteristics were retrospectively collected. Forty-one ECMO survivors cannulated at 0.0-19.8 years (median: 2.4 [IQR: 0.0, 13.1]) were enrolled at 1.3-12.8 years (median: 5.5 [IQR: 3.3, 6.5]) postdecannulation. ECMO survivors scored significantly lower than the normative population in the Vineland-3 Adaptive Behavior Composite (85 [IQR: 70, 99], P < 0.001) and all domains (Communication, Daily Living, Socialization, Motor). Independent risk factors for lower Vineland-3 composite scores included extracorporeal cardiopulmonary resuscitation, electrographic seizures during ECMO, congenital heart disease, and premorbid developmental delay. Of the 21 patients with impaired function at discharge (FSS ≥8), 86% reported an improved FSS at follow-up. Pediatric ECMO survivors have, on average, mild neurobehavioral impairment related to adaptive functioning years after decannulation. Continued functional recovery after hospital discharge is likely. Copyright © ASAIO 2024.

Document Type: Article
Publication Stage: Final
Source: Scopus

Distribution of Silent Cerebral Infarcts in Adults With Sickle Cell Disease
(2024) Neurology, 102 (10), p. e209247. 

Jones, R.S., Ford, A.L., Donahue, M.J., Fellah, S., Davis, L.T., Pruthi, S., Balamurugan, C., Cohen, R., Davis, S., Debaun, M.R., Kassim, A.A., Rodeghier, M., Jordan, L.C.

From the Departments of Pediatrics (R.S.J., C.B., S.D.), Vanderbilt University Medical Center, Nashville, TN; Neurology (A.L.F., S.F., R.C.), Washington University, St. Louis, MO; Neurology (M.J.D.); Radiology (L.T.D., S.P.); Vanderbilt-Meharry Center of Excellence in Sickle Cell Disease (M.R.D.); Medicine (A.A.K.), Vanderbilt University Medical Center, Nashville, TN; Rodeghier Consulting (M.R.), Chicago, IL; Pediatrics, Neurology and Radiology (L.C.J.), Vanderbilt University Medical Center, Nashville, TN

Abstract
BACKGROUND AND OBJECTIVES: Previously we demonstrated that 90% of infarcts in children with sickle cell anemia occur in the border zone regions of cerebral blood flow (CBF). We tested the hypothesis that adults with sickle cell disease (SCD) have silent cerebral infarcts (SCIs) in the border zone regions, with a secondary hypothesis that older age and traditional stroke risk factors would be associated with infarct occurrence in regions outside the border zones. METHODS: Adults with SCD 18-50 years of age were enrolled in a cross-sectional study at 2 centers and completed a 3T brain MRI. Participants with a history of overt stroke were excluded. Infarct masks were manually delineated on T2-fluid-attenuated inversion-recovery MRI and registered to the Montreal Neurological Institute 152 brain atlas to generate an infarct heatmap. Border zone regions between anterior, middle, and posterior cerebral arteries (ACA, MCA, and PCA) were quantified using the Digital 3D Brain MRI Arterial Territories Atlas, and logistic regression was applied to identify relationships between infarct distribution, demographics, and stroke risk factors. RESULTS: Of 113 participants with SCD (median age 26.1 years, interquartile range [IQR] 21.6-31.4 years, 51% male), 56 (49.6%) had SCIs. Participants had a median of 5.5 infarcts (IQR 3.2-13.8). Analysis of infarct distribution showed that 350 of 644 infarcts (54.3%) were in 4 border zones of CBF and 294 (45.6%) were in non-border zone territories. More than 90% of infarcts were in 3 regions: the non-border zone ACA and MCA territories and the ACA-MCA border zone. Logistic regression showed that older participants have an increased chance of infarcts in the MCA territory (odds ratio [OR] 1.08; 95% CI 1.03-1.13; p = 0.001) and a decreased chance of infarcts in the ACA-MCA border zone (OR 0.94; 95% CI 0.90-0.97; p < 0.001). The presence of at least 1 stroke risk factor did not predict SCI location in any model. DISCUSSION: When compared with children with SCD, in adults with SCD, older age is associated with expanded zones of tissue infarction that stretch beyond the traditional border zones of CBF, with more than 45% of infarcts in non-border zone regions.

Document Type: Article
Publication Stage: Final
Source: Scopus

Brexanolone Treatment in a Real-World Patient Population: A Case Series and Pilot Feasibility Study of Precision Neuroimaging
(2024) Journal of Clinical Psychopharmacology, 44 (3), pp. 240-249. 

Guard, M.^e , Labonte, A.K.^a , Mendoza, M.^a , Myers, M.J.^a , Duncan, M.^a , Drysdale, A.T.^b , Mukherji, E.^a , Rahman, T.^a , Tandon, M.^a , Kelly, J.C.^c , Cooke, E.^d , Rogers, C.E.^f , Lenze, S.^a , Sylvester, C.M.^g

^a From the Department of Psychiatry, Washington University in St Louis, St Louis, MO, United States
^b New York State Psychiatric Institute and the Department of Psychiatry, Columbia University Irving Medical Center, New York, NY
^c Department of Obstetrics and Gynecology, Washington University in St Louis, St Louis, MO, United States
^d Department of Pharmacy, Barnes-Jewish Hospital, St Louis, MO, United States

Abstract
PURPOSE/BACKGROUND: Brexanolone is approved for postpartum depression (PPD) by the United States Food and Drug Administration. Brexanolone has outperformed placebo in clinical trials, but less is known about the efficacy in real-world patients with complex social and medical histories. Furthermore, the impact of brexanolone on large-scale brain systems such as changes in functional connectivity (FC) is unknown. METHODS/PROCEDURES: We tracked changes in depressive symptoms across a diverse group of patients who received brexanolone at a large medical center. Edinburgh Postnatal Depression Scale (EPDS) scores were collected through chart review for 17 patients immediately prior to infusion through approximately 1 year postinfusion. In 2 participants, we performed precision functional neuroimaging (pfMRI), including before and after treatment in 1 patient. pfMRI collects many hours of data in individuals for precision medicine applications and was performed to assess the feasibility of investigating changes in FC with brexanolone. FINDINGS/RESULTS: The mean EPDS score immediately postinfusion was significantly lower than the mean preinfusion score (mean change [95% CI]: 10.76 [7.11-14.40], t (15) = 6.29, P < 0.0001). The mean EPDS score stayed significantly lower at 1 week (mean difference [95% CI]: 9.50 [5.23-13.76], t (11) = 4.90, P = 0.0005) and 3 months (mean difference [95% CI]: 9.99 [4.71-15.27], t (6) = 4.63, P = 0.0036) postinfusion. Widespread changes in FC followed infusion, which correlated with EPDS scores. IMPLICATIONS/CONCLUSIONS: Brexanolone is a successful treatment for PPD in the clinical setting. In conjunction with routine clinical care, brexanolone was linked to a reduction in symptoms lasting at least 3 months. pfMRI is feasible in postpartum patients receiving brexanolone and has the potential to elucidate individual-specific mechanisms of action. Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.

Document Type: Article
Publication Stage: Final
Source: Scopus

Loneliness in the Daily Lives of People With Mood and Psychotic Disorders
(2024) Schizophrenia Bulletin, 50 (3), pp. 557-566. 

Moran, E.K.^a , Shapiro, M.^a , Culbreth, A.J.^b , Nepal, S.^c , Ben-Zeev, D.^d , Campbell, A.^c , Barch, D.M.^a e f

^a Department of Psychological & Brain Sciences, Washington University in St. Louis, St. Louis, MO, United States
^b Department of Psychiatry, Maryland Psychiatric Research Center, University of Maryland, Baltimore, MD, United States
^c Department of Computer Science, Dartmouth College, Hanover, NH, USA
^d Department of Psychiatry, BRiTE Center, University of Washington, Seattle, WA, United States
^e Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, United States
^f Department of Radiology, Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, MO, United States

Abstract
BACKGROUND AND HYPOTHESIS: Loneliness, the subjective experience of feeling alone, is associated with physical and psychological impairments. While there is an extensive literature linking loneliness to psychopathology, limited work has examined loneliness in daily life in those with serious mental illness. We hypothesized that trait and momentary loneliness would be transdiagnostic and relate to symptoms and measures of daily functioning. STUDY DESIGN: The current study utilized ecological momentary assessment and passive sensing to examine loneliness in those with schizophrenia (N = 59), bipolar disorder (N = 61), unipolar depression (N = 60), remitted unipolar depression (N = 51), and nonclinical comparisons (N = 82) to examine relationships of both trait and momentary loneliness to symptoms and social functioning in daily life. STUDY RESULTS: Findings suggest that both trait and momentary loneliness are higher in those with psychopathology (F(4,284) = 28.00, P < .001, ηp2 = 0.27), and that loneliness significantly relates to social functioning beyond negative symptoms and depression (β = -0.44, t = 6.40, P < .001). Furthermore, passive sensing measures showed that greater movement (β = -0.56, t = -3.29, P = .02) and phone calls (β = -0.22, t = 12.79, P = .04), but not text messaging, were specifically related to decreased loneliness in daily life. Individuals higher in trait loneliness show stronger relationships between momentary loneliness and social context and emotions in everyday life. CONCLUSIONS: These findings provide further evidence pointing to the importance of loneliness transdiagnostically and its strong relation to social functioning. Furthermore, we show that passive sensing technology can be used to measure behaviors related to loneliness in daily life that may point to potential treatment implications or early detection markers of loneliness. © The Author(s) 2024. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please c

Author Keywords
bipolar disorder;  depression;  ecological momentary assessment;  loneliness;  mobile sensing;  schizophrenia;  social functioning

Document Type: Article
Publication Stage: Final
Source: Scopus

Proliferative Diabetic Retinopathy in Pregnancy
(2024) Ophthalmic Surgery Lasers and Imaging Retina, 55 (4), pp. 194-196. 

Wang, W.X.^a c , Fine, H.F.^b c c , Apte, R.S.^a c b c

^a Department of Ophthalmology and Visual Sciences, Washington University, School of Medicine, St. Louis, MO, United States
^b Rutgers University, Robert Wood Johnson Medical School, New Brunswick, NJ, United States
^c Department of Medicine, Washington University, St. Louis, MO, United States

Funding details
Research to Prevent BlindnessRPB
Denardo Education and Research Foundation

Document Type: Article
Publication Stage: Final
Source: Scopus

Brain high-throughput multi-omics data reveal molecular heterogeneity in Alzheimer’s disease
(2024) PLoS Biology, 22 (4 April), art. no. e3002607, . 

Eteleeb, A.M.^a b , Novotny, B.C.^a , Tarraga, C.S.^a , Sohn, C.^a , Dhungel, E.^c , Brase, L.^a , Nallapu, A.^a , Buss, J.^a , Farias, F.^a d , Bergmann, K.^a d , Bradley, J.^a d , Norton, J.^a d , Gentsch, J.^a d , Wang, F.^a d , Davis, A.A.^e f , Morris, J.C.^b e f , Karch, C.M.^a b d f , Perrin, R.J.^b e f g , Benitez, B.A.^h , Harari, O.^a b f

^a Department of Psychiatry, Washington University, Saint Louis, St. Louis, MO, United States
^b The Charles F. and Joanne Knight Alzheimer Disease Research Center, Washington University, St. Louis, MO, United States
^c Department of Bioinformatics and Genomics, University of North Carolina at Charlotte, Charlotte, NC, United States
^d NeuroGenomics and Informatics Center, Washington University, St. Louis, MO, United States
^e Department of Neurology, Washington University, St. Louis, MO, United States
^f Hope Center for Neurological Disorders, Washington University, St. Louis, MO, United States
^g Department of Pathology and Immunology, Washington University, St. Louis, MO, United States
^h Department of Neurology and Neuroscience, Harvard Medical School, Beth Israel Deaconess Medical Center, Boston, MA, United States

Abstract
Unbiased data-driven omic approaches are revealing the molecular : heterogeneity of Alzheimer disease. Here, we used machine learning approaches to integrate high-throughput transcriptomic, proteomic, metabolomic, and lipidomic profiles with clinical and neuropathological data from multiple human AD cohorts. We discovered 4 unique multimodal molecular profiles, one of them showing signs of poor cognitive function, a faster pace of disease progression, shorter survival with the disease, severe neurodegeneration and astrogliosis, and reduced levels of metabolomic profiles. We found this molecular profile to be present in multiple affected cortical regions associated with higher Braak tau scores and significant dysregulation of synapse-related genes, endocytosis, phagosome, and mTOR signaling pathways altered in AD early and late stages. AD cross-omics data integration with transcriptomic data from an SNCA mouse model revealed an overlapping signature. Furthermore, we leveraged single-nuclei RNA-seq data to identify distinct cell-types that most likely mediate molecular profiles. Lastly, we identified that the multimodal clusters uncovered cerebrospinal fluid biomarkers poised to monitor AD progression and possibly cognition. Our cross-omics analyses provide novel critical molecular insights into AD. © 2024 Eteleeb et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Funding details
Hope Center for Neurological Disorders, Washington University in St. Louis
National Institute on AgingNIAP30 AG066444
National Institute on AgingNIA
National Institutes of HealthNIHR21NS127211, R01AG074012, K01AG046374, R01NS118146, K25AG083057, R56AG067764, U01AG072464, R01AG057777
National Institutes of HealthNIH
P01AG003991
American Cancer SocietyACSP01AG026276
American Cancer SocietyACS

Document Type: Article
Publication Stage: Final
Source: Scopus

Longitudinal MRI of the developing ferret brain reveals regional variations in timing and rate of growth
(2024) Cerebral Cortex, 34 (4), art. no. bhae172, . 

Garcia, K.E.^a b , Wang, X.^c , Santiago, S.E.^d , Bakshi, S.^c , Barnes, A.P.^d , Kroenke, C.D.^c e

^a Department of Radiology and Imaging Sciences, Indiana University School of Medicine, Evansville, IN 47715, United States
^b Department of Mechanical Engineering and Materials Science, Washington University in St. Louis, St. Louis, MO 63130, United States
^c Division of Neuroscience, Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, OR 97006, United States
^d Knight Cardiovascular Institute, Oregon Health & Science University, Portland, OR 97239, United States
^e Oregon Health and Science Advanced Imaging Research Center, Portland, OR 97239, United States

Abstract
Normative ferret brain development was characterized using magnetic resonance imaging. Brain growth was longitudinally monitored in 10 ferrets (equal numbers of males and females) from postnatal day 8 (P8) through P38 in 6-d increments. Template T2-weighted images were constructed at each age, and these were manually segmented into 12 to 14 brain regions. A logistic growth model was used to fit data from whole brain volumes and 8 of the individual regions in both males and females. More protracted growth was found in males, which results in larger brains; however, sex differences were not apparent when results were corrected for body weight. Additionally, surface models of the developing cortical plate were registered to one another using the anatomically-constrained Multimodal Surface Matching algorithm. This, in turn, enabled local logistic growth parameters to be mapped across the cortical surface. A close similarity was observed between surface area expansion timing and previous reports of the transverse neurogenic gradient in ferrets. Regional variation in the extent of surface area expansion and the maximum expansion rate was also revealed. This characterization of normative brain growth over the period of cerebral cortex folding may serve as a reference for ferret studies of brain development. © 2024 The Author(s). Published by Oxford University Press. All rights reserved.

Author Keywords
cortical plate;  logistic growth;  longitudinal design;  magnetic resonance imaging

Funding details
National Institutes of HealthNIHR01 NS111948
National Institutes of HealthNIH

Document Type: Article
Publication Stage: Final
Source: Scopus

Assessment of neurovascular uncoupling: APOE status is a key driver of early metabolic and vascular dysfunction
(2024) Alzheimer’s and Dementia, . 

Onos, K.D.^a , Lin, P.B.^b c , Pandey, R.S.^d , Persohn, S.A.^b , Burton, C.P.^b , Miner, E.W.^b , Eldridge, K.^b , Kanyinda, J.N.^a , Foley, K.E.^a b , Carter, G.W.^a d , Howell, G.R.^a , Territo, P.R.^b e

^a The Jackson Laboratory, Bar Harbor, ME, United States
^b Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, IN, United States
^c Department of Neurology, Washington University in St. Louis, St. Louis, MO, United States
^d The Jackson Laboratory for Genomic Medicine, Farmington, CT, United States
^e Department of Medicine, Division of Clinical Pharmacology, Indiana University School of Medicine, Indianapolis, IN, United States

Abstract
BACKGROUND: Alzheimer’s disease (AD) is the most common cause of dementia worldwide, with apolipoprotein Eε4 (APOEε4) being the strongest genetic risk factor. Current clinical diagnostic imaging focuses on amyloid and tau; however, new methods are needed for earlier detection. METHODS: PET imaging was used to assess metabolism-perfusion in both sexes of aging C57BL/6J, and hAPOE mice, and were verified by transcriptomics, and immunopathology. RESULTS: All hAPOE strains showed AD phenotype progression by 8 months, with females exhibiting the regional changes, which correlated with GO-term enrichments for glucose metabolism, perfusion, and immunity. Uncoupling analysis revealed APOEε4/ε4 exhibited significant Type-1 uncoupling (↓ glucose uptake, ↑ perfusion) at 8 and 12 months, while APOEε3/ε4 demonstrated Type-2 uncoupling (↑ glucose uptake, ↓ perfusion), while immunopathology confirmed cell specific contributions. DISCUSSION: This work highlights APOEε4 status in AD progression manifests as neurovascular uncoupling driven by immunological activation, and may serve as an early diagnostic biomarker. Highlights: We developed a novel analytical method to analyze PET imaging of 18F-FDG and 64Cu-PTSM data in both sexes of aging C57BL/6J, and hAPOEε3/ε3, hAPOEε4/ε4, and hAPOEε3/ε4 mice to assess metabolism-perfusion profiles termed neurovascular uncoupling. This analysis revealed APOEε4/ε4 exhibited significant Type-1 uncoupling (decreased glucose uptake, increased perfusion) at 8 and 12 months, while APOEε3/ε4 demonstrated significant Type-2 uncoupling (increased glucose uptake, decreased perfusion) by 8 months which aligns with immunopathology and transcriptomic signatures. This work highlights that there may be different mechanisms underlying age related changes in APOEε4/ε4 compared with APOEε3/ε4. We predict that these changes may be driven by immunological activation and response, and may serve as an early diagnostic biomarker. © 2024 The Authors. Alzheimer’s & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer’s Association.

Author Keywords
Alzheimer’s disease;  APOE;  metabolism;  perfusion;  uncoupling

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

Do We Become More Lonely With Age? A Coordinated Data Analysis of Nine Longitudinal Studies
(2024) Psychological Science, . 

Graham, E.K.^a , Beck, E.D.^b , Jackson, K.^a , Yoneda, T.^b , McGhee, C.^c , Pieramici, L.^d , Atherton, O.E.^e , Luo, J.^a , Willroth, E.C.^f , Steptoe, A.^g , Mroczek, D.K.^a d , Ong, A.D.^h

^a Department of Medical Social Sciences, Northwestern University, United States
^b Department of Psychology, University of California, Davis, United States
^c Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, United States
^d Department of Psychology, Northwestern University, United States
^e Department of Psychology, University of Houston, United States
^f Department of Psychology, Washington University in Saint Louis, United States
^g Department of Behavioural Science and Health, University College London, United Kingdom
^h Department of Psychology, Cornell University, Canada

Abstract
Loneliness is a pervasive experience with adverse impacts on health and well-being. Despite its significance, notable gaps impede a full understanding of how loneliness changes across the adult life span and what factors influence these changes. To address this, we conducted a coordinated data analysis of nine longitudinal studies encompassing 128,118 participants ages 13 to 103 from over 20 countries. Using harmonized variables and models, we examined loneliness trajectories and predictors. Analyses revealed that loneliness follows a U-shaped curve, decreasing from young adulthood to midlife and increasing in older adulthood. These patterns were consistent across studies. Several baseline factors (i.e., sex, marital status, physical function, education) were linked to loneliness levels, but few moderated the loneliness trajectories. These findings highlight the dynamic nature of loneliness and underscore the need for targeted interventions to reduce social disparities throughout adulthood. © The Author(s) 2024.

Author Keywords
coordinated analysis;  lifespan development;  loneliness

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

Preadolescent Suicidal Thoughts and Behaviors: An Intensive Longitudinal Study of Risk Factors
(2024) Journal of the American Academy of Child and Adolescent Psychiatry, . 

Thompson, R.J., Whalen, D.J., Gilbert, K., Tillman, R., Hennefield, L., Donohue, M.R., Hoyniak, C.P., Barch, D.M., Luby, J.L.

Washington University in St. Louis, St. Louis, Missouri, United States

Abstract
Objective: Dramatic increases in rates of suicidal thoughts and behaviors (STBs) among youth highlight the need to pinpoint early risk factors. This study used intensive longitudinal sampling to assess what the concurrent associations were between risk factors and STB status, how proximal changes in risk factors were related to STB status, and how risk factors prospectively predicted changes in STB status in a preadolescent sample enriched for early childhood psychopathology. Method: A total of 192 participants were included from the Parent-Child Interaction Therapy-Emotional Development (PCIT-ED) Study, a longitudinal study of children with and without preschool depression. Participants 7 to 12 years of age completed a diagnostic interview, followed by 12 months of intensive longitudinal sampling, assessing experiences of suicidal ideation and 11 psychosocial variables with known links to STBs in adolescents and adults. Preadolescents with STB history (high-risk) received surveys weekly, and those without STB history (lower-risk) received surveys monthly. Results: Female sex, elevated depressive symptoms, greater use of expressive suppression and rumination, emotional clarity, and perceived burdensomeness were uniquely concurrently associated with the likelihood of STB endorsement. Within the high-risk group, (1) increases in depression, expressive suppression, rumination, and perceived burdensomeness, and decreases in positive affect from weekt to weekt+1 were associated with a higher likelihood of a positive STB status at weekt+1; and (2) higher expressive suppression, perceived burdensomeness, and caregiver criticism and conflict at weekt compared to participants’ mean levels prospectively predicted increases in the likelihood of a positive STB report from weekt to weekt+1. Conclusion: Psychosocial factors influencing STBs in adolescents and adults also affect preadolescents in day-to-day life. Expressive suppression and perceived burdensomeness consistently emerged as novel risk indicators and potential targets for treatment. In addition, increases in depression, rumination, and caregiver criticism and conflict, as well as decreases in positive affect, might prompt heightened STB screening and assessments for preadolescents with a history of STBs. © 2024 American Academy of Child and Adolescent Psychiatry

Author Keywords
children;  depression;  intensive longitudinal methods;  suicidal thoughts;  suicide behavior

Funding details
National Institute of Mental HealthNIMHK23MH118426, R01MH090786, K01MH127412, R01MH117436

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

A systematic review/meta-analysis of prevalence and incidence rates illustrates systemic underrepresentation of individuals racialized as Asian and/or Asian-American in ADRD research
(2024) Alzheimer’s and Dementia, . 

Zhu, Y.^a , Park, S.^b , Kolady, R.^c , Zha, W.^d , Ma, Y.^e , Dias, A.^a , McGuire, K.^a , Hardi, A.^f , Lin, S.^g , Ismail, Z.^h i , Adkins-Jackson, P.B.^j , Trani, J.-F.^b k l m , Babulal, G.M.^d k m n

^a School of Social Work, Adelphi University, Garden City, NY, United States
^b Brown School, Washington University in St. Louis, St. Louis, MO, United States
^c University of Rochester, Rochester, NY, United States
^d Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States
^e University of Houston, 56B M.D. Anderson Library HoustonTX, United States
^f Bernard Becker Medical Library, Washington University School of Medicine, St. Louis, MO, United States
^g Division of General Medical Sciences, Department of Medicine, Washington University School of Medicine, St. Louis, MO, United States
^h Departments of Psychiatry, Clinical Neurosciences, and Community Health Sciences, Hotchkiss Brain Institute, University of Calgary, Calgary, AB, Canada
ⁱ Department of Clinical and Biomedical Sciences, Faculty of Health and Life Sciences, University of Exeter, Devon, United Kingdom
^j Departments of Epidemiology and Sociomedical Sciences, Mailman School of Public Health, Columbia University, New York, NY, United States
^k Institute of Public Health, Washington University, St. Louis, MO, United States
^l Centre for Social Development in Africa, Faculty of Humanities, University of Johannesburg, Cnr Kingsway & University Roads, Johannesburg, South Africa
^m National Conservatory of Arts and Crafts, Paris, France
ⁿ Department of Clinical Research and Leadership, The George Washington University School of Medicine and Health Sciences, Washington, DC, United States

Abstract
We investigate Alzheimer’s disease and related dementia (ADRD) prevalence, incidence rate, and risk factors in individuals racialized as Asian and/or Asian-American and assess sample representation. Prevalence, incidence rate, risk factors, and heterogeneity of samples were assessed. Random-effects meta-analysis was conducted, generating pooled estimates. Of 920 records across 14 databases, 45 studies were included. Individuals racialized as Asian and/or Asian-American were mainly from Eastern and Southern Asia, had higher education, and constituted a smaller sample relative to non-Hispanic white cohorts. The average prevalence was 10.9%, ranging from 0.4% to 46%. The average incidence rate was 20.03 (12.01-33.8) per 1000 person-years with a range of 75.19–13.59 (12.89-14.33). Risk factors included physiological, genetic, psychological, behavioral, and social factors. This review underscores the systemic underrepresentation of individuals racialized as Asian and/or Asian-American in ADRD research and the need for inclusive approaches accounting for culture, language, and immigration status. Highlights: There is considerable heterogeneity in the prevalence of ADRD among studies of Asian-Americans. There is limited data on group-specific risk factors for ADRD among Asian–Americans. The average prevalence of (ADRD) among Asian–Americans was found to be 7.4%, with a wide range from 0.5% to 46%. © 2024 The Authors. Alzheimer’s & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer’s Association.

Author Keywords
Alzheimer’s disease and related dementia;  asian;  asian-american;  disparity;  incidence;  prevalence

Funding details
National Institutes of HealthNIH
National Institute on AgingNIAR01AG068183, R01AG056466, R01AG067428

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

Management of Select Adverse Events Following Delandistrogene Moxeparvovec Gene Therapy for Patients With Duchenne Muscular Dystrophy
(2024) Journal of Neuromuscular Diseases, 11 (3), pp. 687-699. 

Zaidman, C.M.^a , Goedeker, N.L.^a , Aqul, A.A.^b , Butterfield, R.J.^c , Connolly, A.M.^d , Crystal, R.G.^e , Godwin, K.E.^f , Hor, K.N.^g , Mathews, K.D.^h , Proud, C.M.ⁱ , Kula Smyth, E.^f , Veerapandiyan, A.^j , Watkins, P.B.^k , Mendell, J.R.^d

^a Washington University School of Medicine and St. Louis Children’s Hospital, St Louis, MO, United States
^b University of Texas Southwestern Medical Center, Dallas, TX, United States
^c University of Utah School of Medicine, Salt Lake City, UT, United States
^d Center for Gene Therapy, The Abigail Wexner Research Institute, Nationwide Children’s Hospital, Columbus, OH, USA; The Ohio State University, Columbus, OH, USA
^e Weill Cornell Medical College, New York, NY, USA
^f Sarepta Therapeutics, Cambridge, MA, United States
^g The Heart Center, Nationwide Children’s Hospital, Columbus, OH, USA; The Ohio State University, Columbus, OH, USA
^h University of Iowa Carver College of Medicine, Iowa City, IA, United States
ⁱ Children’s Hospital of the King’s Daughters, Norfolk, VA, United States
^j University of Arkansas for Medical Sciences, Arkansas Children’s Hospital, Little RockAR, United States
^k Eshelman School of Pharmacy, University of North Carolina Institute for Drug Safety Sciences ,Chapel HillNC, United States

Abstract
BACKGROUND: Duchenne muscular dystrophy (DMD) is a rare, degenerative, recessive X-linked neuromuscular disease. Mutations in the gene encoding dystrophin lead to the absence of functional dystrophin protein. Individuals living with DMD exhibit progressive muscle weakness resulting in loss of ambulation and limb function, respiratory insufficiency, and cardiomyopathy, with multiorgan involvement. Adeno-associated virus vector-mediated gene therapy designed to enable production of functional dystrophin protein is a new therapeutic strategy. Delandistrogene moxeparvovec (Sarepta Therapeutics, Cambridge, MA) is indicated for treatment of ambulatory pediatric patients aged 4 through 5 years with DMD who have an indicated mutation in the DMD gene. OBJECTIVE: Evidence-based considerations for management of potential adverse events following gene therapy treatment for DMD are lacking in clinical literature. Our goal was to provide interdisciplinary consensus considerations for selected treatment-related adverse events (TRAEs) (vomiting, acute liver injury, myocarditis, and immune-mediated myositis) that may arise following gene therapy dosing with delandistrogene moxeparvovec. METHODS: An interdisciplinary panel of 12 specialists utilized a modified Delphi process to develop consensus considerations for the evaluation and management of TRAEs reported in delandistrogene moxeparvovec clinical studies. Panelists completed 2 Questionnaires prior to gathering for an in-person discussion. Consensus was defined as a majority (≥58% ; 7/12) of panelists either agreeing or disagreeing. RESULTS: Panelists agreed that the choice of baseline assessments should be informed by individual clinical indications, the treating provider’s judgment, and prescribing information. Corticosteroid dosing for treatment of TRAEs should be optimized by considering individual risk versus benefit for each indication. In all cases involving patients with a confirmed TRAE, consultations with appropriate specialists were suggested. CONCLUSIONS: The Delphi Panel established consensus considerations for the evaluation and management of potential TRAEs for patients receiving delandistrogene moxeparvovec, including vomiting, acute liver injury, myocarditis, and immune-mediated myositis.

Author Keywords
Duchenne muscular dystrophy;  dystrophin;  gene therapy;  liver injury;  myocarditis;  myositis;  vomiting

Document Type: Article
Publication Stage: Final
Source: Scopus

Two common and distinct forms of variation in human functional brain networks
(2024) Nature Neuroscience, . 

Dworetsky, A.^a b c , Seitzman, B.A.^d , Adeyemo, B.^e , Nielsen, A.N.^e , Hatoum, A.S.^f , Smith, D.M.^c g , Nichols, T.E.^h i , Neta, M.^j k , Petersen, S.E.^{a e f l m} , Gratton, C.^{b c n o p}

^a Department of Radiology, Washington University School of Medicine, St. Louis, MO, United States
^b Department of Psychology, Florida State University, Tallahassee, FL, United States
^c Department of Psychology, Northwestern University, Evanston, IL, United States
^d Department of Radiation Oncology, Washington University School of Medicine, St. Louis, MO, United States
^e Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States
^f Department of Psychological and Brain Sciences, Washington University School of Medicine, St. Louis, MO, United States
^g Department of Neurology, Division of Cognitive Neurology/Neuropsychology, The Johns Hopkins University School of Medicine, Baltimore, MD, United States
^h Big Data Institute, Li Ka Shing Centre for Health Information and Discovery, Nuffield Department of Population Health, University of Oxford, Oxford, United Kingdom
ⁱ Wellcome Centre for Integrative Neuroimaging, FMRIB, Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, United Kingdom
^j Department of Psychology, University of Nebraska-Lincoln, Lincoln, NE, United States
^k Center for Brain, Biology, and Behavior, University of Nebraska-Lincoln, Lincoln, NE, United States
^l Department of Neuroscience, Washington University School of Medicine, St. Louis, MO, United States
^m Department of Biomedical Engineering, Washington University School of Medicine, St. Louis, MO, United States
ⁿ Neuroscience Program, Florida State University, Tallahassee, FL, United States
^o Department of Neurology, Northwestern University, Evanston, IL, United States
^p Interdepartmental Neuroscience Program, Northwestern University, Evanston, IL, United States

Abstract
The cortex has a characteristic layout with specialized functional areas forming distributed large-scale networks. However, substantial work shows striking variation in this organization across people, which relates to differences in behavior. While most previous work treats individual differences as linked to boundary shifts between the borders of regions, here we show that cortical ‘variants’ also occur at a distance from their typical position, forming ectopic intrusions. Both ‘border’ and ‘ectopic’ variants are common across individuals, but differ in their location, network associations, properties of subgroups of individuals, activations during tasks, and prediction of behavioral phenotypes. Border variants also track significantly more with shared genetics than ectopic variants, suggesting a closer link between ectopic variants and environmental influences. This work argues that these two dissociable forms of variation—border shifts and ectopic intrusions—must be separately accounted for in the analysis of individual differences in cortical systems across people. © The Author(s), under exclusive licence to Springer Nature America, Inc. 2024.

Funding details
National Institutes of HealthNIHR01MH118370
James S. McDonnell FoundationJSMFR01MH111640, T32MH100019, K01AA030083

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

LXR/CD38 activation drives cholesterol-induced macrophage senescence and neurodegeneration via NAD+ depletion
(2024) Cell Reports, art. no. 114102, . 

Terao, R.^a b , Lee, T.J.^a , Colasanti, J.^a , Pfeifer, C.W.^a , Lin, J.B.^a , Santeford, A.^a , Hase, K.^a c , Yamaguchi, S.^a , Du, D.^a , Sohn, B.S.^a , Sasaki, Y.^d , Yoshida, M.^a e , Apte, R.S.^a f g

^a John F. Hardesty, MD Department of Ophthalmology & Visual Sciences, Washington University School of Medicine, St. Louis, MO, United States
^b Department of Ophthalmology, Graduate School of Medicine, the University of Tokyo, Tokyo, Japan
^c Department of Ophthalmology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Hokkaido, Japan
^d Department of Genetics, Washington University School of Medicine, St. Louis, MO, United States
^e Department of Anesthesiology, Washington University School of Medicine, St. Louis, MO, United States
^f Department of Medicine, Washington University School of Medicine, St. Louis, MO, United States
^g Department of Developmental Biology, Washington University School of Medicine, St. Louis, MO, United States

Abstract
Although dysregulated cholesterol metabolism predisposes aging tissues to inflammation and a plethora of diseases, the underlying molecular mechanism remains poorly defined. Here, we show that metabolic and genotoxic stresses, convergently acting through liver X nuclear receptor, upregulate CD38 to promote lysosomal cholesterol efflux, leading to nicotinamide adenine dinucleotide (NAD+) depletion in macrophages. Cholesterol-mediated NAD+ depletion induces macrophage senescence, promoting key features of age-related macular degeneration (AMD), including subretinal lipid deposition and neurodegeneration. NAD+ augmentation reverses cellular senescence and macrophage dysfunction, preventing the development of AMD phenotype. Genetic and pharmacological senolysis protect against the development of AMD and neurodegeneration. Subretinal administration of healthy macrophages promotes the clearance of senescent macrophages, reversing the AMD disease burden. Thus, NAD+ deficit induced by excess intracellular cholesterol is the converging mechanism of macrophage senescence and a causal process underlying age-related neurodegeneration. © 2024 The Author(s)

Author Keywords
age-related macular degeneration;  CD38;  cellular senescence;  cholesterol efflux;  CP: Immunology;  CP: Metabolism;  NAD+;  neurodegeneration;  nicotinamide adenine dinucleotide;  nicotinamide mononucleotide;  NMN

Funding details
Research to Prevent BlindnessRPB
School of Medicine, Washington University in St. LouisWUSM
Alvin J. Siteman Cancer CenterSCC
International Retinal Research FoundationIRRF
National Center for Research ResourcesNCRR
University of CaliforniaUC
Carl Marshall and Mildred Almen Reeves Foundation
Japan Society for the Promotion of ScienceJSPS1T32GM1397740-1
Japan Society for the Promotion of ScienceJSPS
Genome Technology Access CenterGTAC#P30 CA91842
Genome Technology Access CenterGTAC
Washington University in St. LouisWUSTLT32GM07200, RF1 AG013730
Washington University in St. LouisWUSTL
VitreoRetinal Surgery FoundationVRSFVGR0023118
VitreoRetinal Surgery FoundationVRSF
National Cancer InstituteNCI#P30 CA91842
National Cancer InstituteNCI
National Institutes of HealthNIHR01 EY019287, EY02687
National Institutes of HealthNIH
McDonnell Center for Cellular and Molecular Neurobiology, Washington University in St. LouisGF0011083, F30DK130282
McDonnell Center for Cellular and Molecular Neurobiology, Washington University in St. Louis
Diabetes Research Center, University of WashingtonDRC, UW5 P30 DK020579
Diabetes Research Center, University of WashingtonDRC, UW
T32 EY013360

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

Downstream Biomarker Effects of Gantenerumab or Solanezumab in Dominantly Inherited Alzheimer Disease The DIAN-TU-001 Randomized Clinical Trial
(2024) JAMA Neurology, . Cited 1 time.

Wagemann, O.^a b , Liu, H.^a , Wang, G.^c , Shi, X.^c , Bittner, T.^d , Scelsi, M.A.^e , Farlow, M.R.^f , Clifford, D.B.^a , Supnet-Bell, C.^a , Santacruz, A.M.^a , Aschenbrenner, A.J.^a , Hassenstab, J.J.^a , Benzinger, T.L.S.^g , Gordon, B.A.^g , Coalier, K.A.^h , Cruchaga, C.ⁱ , Ibanez, L.^a i , Perrin, R.J.^a j , Xiong, C.^c , Li, Y.^a , Morris, J.C.^a , Lah, J.J.^k , Berman, S.B.^l , Roberson, E.D.^m , van Dyck, C.H.ⁿ , Galasko, D.^o , Gauthier, S.^p , Hsiung, G.-Y.R.^q , Brooks, W.S.^r s , Pariente, J.^t , Mummery, C.J.^u , Day, G.S.^v , Ringman, J.M.^w , Mendez, P.C.^x , St. George-Hyslop, P.^y , Fox, N.C.^u , Suzuki, K.^z , Okhravi, H.R.^aa , Chhatwal, J.^ab , Levin, J.^b ac ad , Jucker, M.^ae af , Sims, J.R.^ag , Holdridge, K.C.^ag , Proctor, N.K.^ag , Yaari, R.^ag , Andersen, S.W.^ag , Mancini, M.^ag , Llibre-Guerra, J.^a , Bateman, R.J.^a , McDade, E.^a , Dominantly Inherited Alzheimer Network-Trials Unit^ah

^a Department of Neurology, Washington University School of Medicine, St Louis, MO, United States
^b Department of Neurology, Ludwig-Maximilians-Universität München, Munich, Germany
^c Department of Biostatistics, Washington University in St Louis, St Louis, MO, United States
^d F. Hoffmann-La Roche Ltd, Basel, Switzerland
^e F. Hoffmann-La Roche Products Ltd, Welwyn Garden City, United Kingdom
^f Department of Neurology, Indiana University School of Medicine, Indianapolis, United States
^g Department of Radiology, Washington University in St Louis, St Louis, MO, United States
^h IQVIA, Durham, NC, United States
ⁱ Department of Psychiatry, Washington University in St Louis, St Louis, MO, United States
^j Department of Pathology and Immunology, Washington University in St Louis, St Louis, MO, United States
^k Department of Neurology, School of Medicine Emory University, Atlanta, GA, United States
^l Department of Neurology, University of Pittsburgh, Pittsburgh, PA, United States
^m Department of Neurology, University of Alabama at Birmingham, Birmingham, United States
ⁿ Alzheimer’s Disease Research Unit, Yale School of Medicine, New Haven, CT, United States
^o Department of Neurology, University of California, San Diego, United States
^p Department of Neurology and Psychiatry, McGill University, Montréal, QC, Canada
^q Department of Neurology, University of British Columbia, Vancouver, BC, Canada
^r Neuroscience Research Australia, Sydney, NSW, Australia
^s School of Clinical Medicine, University of New South Wales, Randwick, NSW, Australia
^t Department of Neurology, Centre Hospitalier Universitaire de Toulouse, Toulouse, France
^u Dementia Research Centre, Institute of Neurology, University College London, London, United Kingdom
^v Department of Neurology, Mayo Clinic Florida, Jacksonville, United States
^w Department of Neurology, University of Southern California, Los Angeles, United States
^x Fundación Para la Lucha Contra las Enfermedades Neurológicas de la Infancia (FLENI), Buenos Aires, Argentina
^y Department of Neurology, Columbia University, New York, NY, United States
^z National Defense Medical College, Saitama, Japan
^aa Department of Geriatrics, Eastern Virginia Medical School, Norfolk, United States
^ab Department of Neurology, Massachusetts General and Brigham and Women’s Hospitals, Harvard Medical School, Boston, United States
^ac German Center for Neurodegenerative Diseases (DZNE), Munich, Germany
^ad Munich Cluster for Systems Neurology (SyNergy), Munich, Germany
^ae German Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany
^af Department of Cellular Neurology, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany
^ag Eli Lilly and Company, Indianapolis, IN, United States

Abstract
IMPORTANCE Effects of antiamyloid agents, targeting either fibrillar or soluble monomeric amyloid peptides, on downstream biomarkers in cerebrospinal fluid (CSF) and plasma are largely unknown in dominantly inherited Alzheimer disease (DIAD). OBJECTIVE To investigate longitudinal biomarker changes of synaptic dysfunction, neuroinflammation, and neurodegeneration in individuals with DIAD who are receiving antiamyloid treatment. DESIGN, SETTING, AND PARTICIPANTS From 2012 to 2019, the Dominantly Inherited Alzheimer Network Trial Unit (DIAN-TU-001) study, a double-blind, placebo-controlled, randomized clinical trial, investigated gantenerumab and solanezumab in DIAD. Carriers of gene variants were assigned 3:1 to either drug or placebo. The present analysis was conducted from April to June 2023. DIAN-TU-001 spans 25 study sites in 7 countries. Biofluids and neuroimaging from carriers of DIAD gene variants in the gantenerumab, solanezumab, and placebo groups were analyzed. INTERVENTIONS In 2016, initial dosing of gantenerumab, 225 mg (subcutaneously every 4 weeks) was increased every 8 weeks up to 1200 mg. In 2017, initial dosing of solanezumab, 400 mg (intravenously every 4 weeks) was increased up to 1600 mg every 4 weeks. MAIN OUTCOMES AND MEASURES Longitudinal changes in CSF levels of neurogranin, soluble triggering receptor expressed on myeloid cells 2 (sTREM2), chitinase 3–like 1 protein (YKL-40), glial fibrillary acidic protein (GFAP), neurofilament light protein (NfL), and plasma levels of GFAP and NfL. RESULTS Of 236 eligible participants screened, 43 were excluded. A total of 142 participants (mean [SD] age, 44 [10] years; 72 female [51%]) were included in the study (gantenerumab, 52 [37%]; solanezumab, 50 [35%]; placebo, 40 [28%]). Relative to placebo, gantenerumab significantly reduced CSF neurogranin level at year 4 (mean [SD] β = −242.43 [48.04] pg/mL; P < .001); reduced plasma GFAP level at year 1 (mean [SD] β = −0.02 [0.01] ng/mL; P = .02), year 2 (mean [SD] β = −0.03 [0.01] ng/mL; P = .002), and year 4 (mean [SD] β = −0.06 [0.02] ng/mL; P < .001); and increased CSF sTREM2 level at year 2 (mean [SD] β = 1.12 [0.43] ng/mL; P = .01) and year 4 (mean [SD] β = 1.06 [0.52] ng/mL; P = .04). Solanezumab significantly increased CSF NfL (log) at year 4 (mean [SD] β = 0.14 [0.06]; P = .02). Correlation analysis for rates of change found stronger correlations between CSF markers and fluid markers with Pittsburgh compound B positron emission tomography for solanezumab and placebo. CONCLUSIONS AND RELEVANCE This randomized clinical trial supports the importance of fibrillar amyloid reduction in multiple AD-related processes of neuroinflammation and neurodegeneration in CSF and plasma in DIAD. Additional studies of antiaggregated amyloid therapies in sporadic AD and DIAD are needed to determine the utility of nonamyloid biomarkers in determining disease modification. © 2024 Wagemann O et al.

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

Data-driven decomposition and staging of flortaucipir uptake in Alzheimer’s disease
(2024) Alzheimer’s and Dementia, . 

Earnest, T.^a , Bani, A.^a , Ha, S.M.^a , Hobbs, D.A.^a , Kothapalli, D.^a , Yang, B.^a , Lee, J.J.^a , Benzinger, T.L.S.^a , Gordon, B.A.^a , Sotiras, A.^a b , for the Alzheimer’s Disease Neuroimaging Initiative^c

^a Mallinckrodt Institute of Radiology, Washington University School of Medicine in St Louis, Saint Louis, MO, United States
^b Institute for Informatics, Data Science & Biostatistics, Washington University School of Medicine in St Louis, Saint Louis, MO, United States

Abstract
INTRODUCTION: Previous approaches pursuing in vivo staging of tau pathology in Alzheimer’s disease (AD) have typically relied on neuropathologically defined criteria. In using predefined systems, these studies may miss spatial deposition patterns which are informative of disease progression. METHODS: We selected discovery (n = 418) and replication (n = 132) cohorts with flortaucipir imaging. Non-negative matrix factorization (NMF) was applied to learn tau covariance patterns and develop a tau staging system. Flortaucipir components were also validated by comparison with amyloid burden, gray matter loss, and the expression of AD-related genes. RESULTS: We found eight flortaucipir covariance patterns which were reproducible and overlapped with relevant gene expression maps. Tau stages were associated with AD severity as indexed by dementia status and neuropsychological performance. Comparisons of flortaucipir uptake with amyloid and atrophy also supported our model of tau progression. DISCUSSION: Data-driven decomposition of flortaucipir uptake provides a novel framework for tau staging which complements existing systems. Highlights: NMF reveals patterns of tau deposition in AD. Data-driven staging of flortaucipir tracks AD severity. Learned flortaucipir patterns overlap with AD-related gene expression. © 2024 The Authors. Alzheimer’s & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer’s Association.

Author Keywords
Alzheimer’s disease;  AV-1451;  Braak;  data-driven;  disease staging;  flortaucipir;  machine learning;  NMF;  non-negative matrix factorization;  tau;  tau staging

Funding details
Alzheimer’s AssociationAA
BioClinica
National Institute of Biomedical Imaging and BioengineeringNIBIB
AbbVie
National Institute on AgingNIA
Alzheimer’s Drug Discovery FoundationADDF
U.S. Department of DefenseDODW81XWH‐12‐2‐0012
U.S. Department of DefenseDOD
National Institutes of HealthNIH1S10RR022984‐01A1, S10OD025200, R01‐AG067103, 1S10OD018091‐01
National Institutes of HealthNIH
BiogenP01 AG003991, UL1 TR000448, P01 AG026276, P30 NS09857781, P30 AG066444, R01 AG043434, P50 AG00561, R01 EB009352
Biogen
Alzheimer’s Disease Neuroimaging InitiativeADNIU01 AG024904
Alzheimer’s Disease Neuroimaging InitiativeADNI

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