Hope Center Member Publications: November 24, 2024

Epidemiology and Impact of Social Hardships in Children With Multiple Sclerosis in the United States
(2024) Neurology, 103 (11), p. e209991. 

Wilson, E., Meeks, H.D., Barney, B.J., Waltz, M., Canenguez, K., Casper, T.C., Rose, J.W., Rodriguez, M., Tillema, J.-M., Chitnis, T., Gorman, M.P., Rensel, M., Abrams, A.W., Krupp, L.B., Lotze, T.E., Fisher, K.S., Shukla, N.M., Schreiner, T.L., Mar, S.S., Waubant, E., Virupakshaiah, A., Wheeler, Y.S., Ness, J.M., Benson, L.A., as the United States Network of Pediatric Multiple Sclerosis Centers

From the Department of Neurology (E. Wilson), Cincinnati Children’s Hospital, OH; Department of Neurology (E. Wilson, M.P.G., L.A.B.), Boston Children’s Hospital, MA; Department of Pediatric Neurology (E. Wilson, K.C., T.C.), Massachusetts General Hospital, Boston; Department of Pediatrics (H.D.M., B.J.B., M.W., T.C.C., J.W.R.), University of Utah, Salt Lake City; Department of Neurology (M. Rodriguez, J.-M.T.), Mayo Clinic, Rochester, MN; Department of Neurology (M. Rensel, A.W.A.), Cleveland Clinic, OH; Department of Neurology (L.B.K.), New York University Medical Center, NY; Department of Neurology (T.E.L., K.S.F., N.M.S.), Texas Children’s Hospital, Houston; Department of Neurology (T.L.S.), Children’s Hospital Colorado, Aurora; Department of Neurology (S.S.M.), Washington University in St. Louis, MO; Department of Neurology (E. Waubant, A.V.), UCSF Weill Institute for Neurosciences, University of California San Francisco; and Department of Neurology (Y.S.W., J.M.N.), University of Alabama at Birmingham

Abstract
BACKGROUND AND OBJECTIVES: Social determinants of health (SDOH) affect patient health outcomes, but the impact on patients with pediatric-onset multiple sclerosis (POMS) has not been well studied. Study objectives were to (1) describe the frequency of adverse SDOH, (2) evaluate social hardships as a potential barrier to the initiation of disease-modifying therapy (DMT), and (3) explore the association between adverse SDOH and disease outcomes in POMS, as well as study attrition. METHODS: This was a retrospective multicenter observational study conducted through the United States Network of Pediatric MS Centers database. Participants were patients diagnosed with POMS (excluding primary progressive MS). The primary outcome was time to initiation of DMT. Secondary outcomes included most recent Expanded Disability Status Scale (EDSS) score, steroid treatment for the first event, time to second event, and study attrition. Demographic variables and clinical outcomes were compared between patients with and without hardships (maternal education of high school or less, public insurance/no insurance, or single/no-income household). Multivariable regression models were used to assess the impact of social hardship on study outcomes. RESULTS: There were 996 total participants (69% female, mean age at symptom onset and EDSS score [±SD] were 14.2 ± 3 and 1.2 ± 1.1, respectively). Of 768 patients with complete demographic information, 66% reported a hardship. Hardship was associated with younger age at symptom onset and diagnosis. While there was no difference in time to DMT initiation, patients with hardship were more likely to receive steroids for the first event (odds ratio [OR] 1.66, 95% CI 1.21-2.26, p = 0.002). Lack of private insurance was associated with increased risk of study attrition (OR 1.85, 95% CI 1.14-3.00, p = 0.012) and higher EDSS score (β = 0.15, 95% CI 0.01, 0.28). Living in a no-income household (vs dual-income) was associated with a shorter time to second event (hazard ratio 1.33, 95% CI 1.02-1.74, p = 0.034). DISCUSSION: The experience of hardships is common and associated with younger age at symptom onset and diagnosis, as well as shorter time to second event. Lack of private insurance is associated with study attrition and a higher EDSS score despite no difference in time to initiating DMT. There may be differences in early disease pathophysiology related to social hardship, and future studies are needed to better understand this complex relationship.

Document Type: Article
Publication Stage: Final
Source: Scopus

Timeline to symptomatic Alzheimer’s disease in people with Down syndrome as assessed by amyloid-PET and tau-PET: a longitudinal cohort study
(2024) The Lancet Neurology, 23 (12), pp. 1214-1224. Cited 1 time.

Schworer, E.K.^a , Zammit, M.D.^a , Wang, J.^e , Handen, B.L.^f , Betthauser, T.^b d , Laymon, C.M.^g h , Tudorascu, D.L.^e f , Cohen, A.D.^f , Zaman, S.H.ⁱ , Ances, B.M.^j , Mapstone, M.^k m , Head, E.^l m , Christian, B.T.^a b , Hartley, S.L.^a c , Aizenstein, H.^m , Ances, B.^m , Andrews, H.^m , Bell, K.^m , Birn, R.^m , Brickman, A.^m , Bulova, P.^m , Cheema, A.^m , Chen, K.^m , Christian, B.^m , Clare, I.^m , Clark, L.^m , Cohen, A.^m , Constantino, J.^m , Doran, E.^m , Fagan, A.^m , Feingold, E.^m , Foroud, T.^m , Handen, B.^m , Harp, J.^m , Hartley, S.^m , Henson, R.^m , Hom, C.^m , Honig, L.^m , Ikonomovic, M.^m , Johnson, S.^m , Jordan, C.^m , Kamboh, M.I.^m , Keator, D.^m , Klunk, W.^m , Kofler, J.^m , Kreisl, W.^m , Krinsky-McHale, S.^m , Lai, F.^m , Lao, P.^m , Laymon, C.^m , Lee, J.^m , Lott, I.^m , Lupson, V.^m , Mathis, C.^m , Minhas, D.^m , Nadkarni, N.^m , O’Bryant, S.^m , Parisi, M.^m , Pang, D.^m , Petersen, M.^m , Price, J.^m , Pulsifer, M.^m , Rafii, M.^m , Reiman, E.^m , Rizvi, B.^m , Rosas, D.^m , Ryan, L.^m , Schmitt, F.^m , Schupf, N.^m , Silverman, W.^m , Tudorascu, D.^m , Tumuluru, R.^m , Tycko, B.^m , Varadarajan, B.^m , White, D.^m , Yassa, M.^m , Zaman, S.^m , Zhang, F.^m , Alzheimer’s Biomarker Consortium-Down Syndrome (ABC-DS)ⁿ

^a Waisman Center, University of Wisconsin-Madison, Madison, WI, United States
^b Alzheimer’s Disease Research Center, University of Wisconsin-Madison, Madison, WI, United States
^c School of Human Ecology, University of Wisconsin-Madison, Madison, WI, United States
^d Department of Medicine, University of Wisconsin-Madison, Madison, WI, United States
^e Department of Biostatistics, School of Public Health, University of Pittsburgh, Pittsburgh, PA, United States
^f Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA, United States
^g Department of Radiology, University of Pittsburgh, Pittsburgh, PA, United States
^h Department of Bioengineering, University of Pittsburgh, Pittsburgh, PA, United States
ⁱ Cambridge Intellectual Disability Research Group, University of Cambridge, Cambridge, United Kingdom
^j Department of Neurology, Washington University in St Louis, St Louis, MO, United States
^k Department of Neurology, University of California, Irvine School of Medicine, Irvine, CA, United States
^l Department of Pathology and Laboratory Medicine, University of California, Irvine School of Medicine, Irvine, CA, United States

Abstract
Background: Adults with Down syndrome are at risk for Alzheimer’s disease. Natural history cohort studies have characterised the progression of Alzheimer’s disease biomarkers in people with Down syndrome, with a focus on amyloid β-PET and tau-PET. In this study, we aimed to leverage these well characterised imaging biomarkers in a large cohort of individuals with Down syndrome, to examine the timeline to symptomatic Alzheimer’s disease based on estimated years since the detection on PET of amyloid β-positivity, referred to here as amyloid age, and in relation to tau burden as assessed by PET. Methods: In this prospective, longitudinal, observational cohort study, data were collected at four university research sites in the UK and USA as part of the Alzheimer’s Biomarker Consortium–Down Syndrome (ABC–DS) study. Eligible participants were aged 25 years or older with Down syndrome, had a mental age of at least 3 years (based on a standardised intelligence quotient test), and had trisomy 21 (full, mosaic, or translocation) confirmed through karyotyping. Participants were assessed twice between 2017 and 2022, with approximately 32 months between visits. Participants had amyloid-PET and tau-PET scans, and underwent cognitive assessment with the modified Cued Recall Test (mCRT) and the Down Syndrome Mental Status Examination (DSMSE) to assess cognitive functioning. Study partners completed the National Task Group-Early Detection Screen for Dementia (NTG-EDSD). Generalised linear models were used to assess the association between amyloid age (whereby 0 years equated to 18 centiloids) and mCRT, DSMSE, NTG-EDSD, and tau PET at baseline and the 32-month follow-up. Broken stick regression was used to identify the amyloid age that corresponded to decreases in cognitive performance and increases in tau PET after the onset of amyloid β positivity. Findings: 167 adults with Down syndrome, of whom 92 had longitudinal data, were included in our analyses. Generalised linear regressions showed significant quadratic associations between amyloid age and cognitive performance and cubic associations between amyloid age and tau, both at baseline and at the 32-month follow-up. Using broken stick regression models, differences in mCRT total scores were detected beginning 2·7 years (95% credible interval [CrI] 0·2 to 5·4; equating to 29·8 centiloids) after the onset of amyloid β positivity in cross-sectional models. Based on cross-sectional data, increases in tau deposition started a mean of 2·7–6·1 years (equating to 29·8–47·9 centiloids) after the onset of amyloid β positivity. Mild cognitive impairment was observed at a mean amyloid age of 7·4 years (SD 6·6; equating to 56·8 centiloids) and dementia was observed at a mean amyloid age of 12·7 years (5·6; equating to 97·4 centiloids). Interpretation: There is a short timeline to initial cognitive decline and dementia from onset of amyloid β positivity and tau deposition in people with Down syndrome. This newly established timeline based on amyloid age (or equivalent centiloid values) is important for clinical practice and informing the design of Alzheimer’s disease clinical trials, and it avoids the limitations of timelines based on chronological age. Funding: National Institute on Aging and the National Institute for Child Health and Human Development. © 2024 Elsevier Ltd

Funding details
National Institute for Health and Care ResearchNIHR
National Institutes of HealthNIH
University of Pittsburgh
NIHR Cambridge Biomedical Research Centre
R01AG080766
P50 HD105353, U54 HD090256, U54 HD087011
National Center for Advancing Translational SciencesNCATSUL1 TR001414, UL1 TR002373, UL1 TR001857, UL1 TR002345, UL1 TR001873
National Center for Advancing Translational SciencesNCATS
National Institute on AgingNIAK99AG084738
National Institute on AgingNIA
AV-1451
National Institute of Child Health and Human DevelopmentNICHDU01 AG051406, P50 AG005681, U19 AG068054, P30 AG062421, P50 AG008702, U01 AG051412, P50 AG005133, P50 AG16537, P30 AG062715, P30 AG066519
National Institute of Child Health and Human DevelopmentNICHD
U24 AG21886
Eunice Kennedy Shriver National Institute of Child Health and Human DevelopmentNICHDT32 HD007489
Eunice Kennedy Shriver National Institute of Child Health and Human DevelopmentNICHD

Document Type: Article
Publication Stage: Final
Source: Scopus

Samd7 represses short-wavelength cone genes to preserve long-wavelength cone and rod photoreceptor identity
(2024) Proceedings of the National Academy of Sciences of the United States of America, 121 (47), pp. e2402121121. 

Volkov, L.I.^a , Ogawa, Y.^a , Somjee, R.^a , Vedder, H.E.^a , Powell, H.E.^a , Poria, D.^b , Meiselman, S.^a , Kefalov, V.J.^b , Corbo, J.C.^a

^a Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, United States
^b Department of Ophthalmology, University of California Irvine, Irvine, CA 92697

Abstract
The role of transcription factors in photoreceptor gene regulation is fairly well understood, but knowledge of the cell-type-specific function of transcriptional cofactors remains incomplete. Here, we show that the transcriptional corepressor samd7 promotes rod differentiation and represses short-wavelength cone genes in long-wavelength cones in zebrafish. In samd7-/- retinas, red cones are transformed into hybrid red/ultraviolet (UV) cones, green cones are absent, the number of blue cones is approximately doubled, and the number of rods is greatly reduced. We also find that mouse Samd7 represses S-opsin expression in dorsal M-cones-analogous to its role in repressing UV cone genes in zebrafish red cones. Thus, samd7 plays a key role in ensuring appropriate patterns of gene expression in rods and cone subtypes of both zebrafish and mice.

Author Keywords
development;  photoreceptor;  retina

Document Type: Article
Publication Stage: Final
Source: Scopus

Synthesis and evaluation of photoaffinity labeling reagents for identifying binding sites of sulfated neurosteroids on NMDA and GABAA receptors
(2024) RSC Advances, 14 (49), pp. 36352-36369. 

Qian, M.^a , Xu, Y.^a , Shu, H.-J.^b , Chen, Z.-W.^c d , Wang, L.^c e f , Zorumski, C.F.^b d , Evers, A.S.^a c d , Mennerick, S.^b d , Covey, D.F.^a b c d

^a Department of Developmental Biology, Washington University in St. Louis, 660 S. Euclid Ave., St. Louis, MO 63110, United States
^b Department of Psychiatry, Washington University in St. Louis, 660 S. Euclid Ave., St. Louis, MO 63110, United States
^c Department of Anesthesiology, Washington University in St. Louis, 660 S. Euclid Ave., St. Louis, MO 63110, United States
^d Taylor Family Institute for Innovative Psychiatric Research, Washington University in St. Louis, 660 S. Euclid Ave., St. Louis, MO 63110, United States
^e Department of Anesthesiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
^f Key Laboratory of Anesthesiology and Resuscitation (Huazhong University of Science and Technology), Ministry of Education, China

Abstract
The endogenous neurosteroids dehydroepiandrosterone sulfate (DHEAS) and pregnenolone sulfate (PS) are allosteric modulators of γ-aminobutyric acid type A (GABAA) and N-methyl-d-aspartate (NMDA) type glutamate receptors. Analogues of these endogenous steroid sulfates can be either positive or negative allosteric modulators (PAMs or NAMs, respectively) of these receptors, but there is limited information about the steroid-protein binding interactions that mediate these effects and photoaffinity labeling reagents (PALs) of sulfated steroids have not been reported previously. The synthesis of a panel of ten sulfated steroid analogues containing a diazirine group, five of which also contain an alkyne group for click chemistry reactions, for use in photoaffinity labeling studies to identify binding sites for steroid sulfates that are either positive or negative allosteric modulators is reported. Electrophysiological measurements on cultured rat hippocampal neurons were made to determine the modes of allosteric modulation in comparison to those of PS on both receptors. PALs with the activity profile of PS (NMDA PAM, GABAA NAM) were identified. Unexpectedly, PALs with PAM activity at both receptors were also found. Photolabeling of both receptors by two of the PALs was performed to demonstrate their utility, and by inference those of the other PALs, for future studies to identify binding sites for endogenous steroid sulfates on both receptors. © 2024 The Royal Society of Chemistry.

Document Type: Article
Publication Stage: Final
Source: Scopus

Regulatory T cells require peripheral CCL2-CCR2 signaling to facilitate the resolution of medication overuse headache-related behavioral sensitization
(2024) The Journal of Headache and Pain, 25 (1), p. 197. 

Ryu, S.^a b , Zhang, J.^a b , Simoes, R.^a b , Liu, X.^a b , Guo, Z.^a b , Feng, L.^a b , Unsinger, J.^a , Hotchkiss, R.S.^a c d , Cao, Y.-Q.^a b

^a Department of Anesthesiology, Washington University in St. Louis School of Medicine, St. Louis, MO 63110, United States
^b Washington University Pain Center, Washington University in St. Louis School of Medicine, St. Louis, MO 63110, United States
^c Department of Medicine, Washington University in St. Louis School of Medicine, St. Louis, MO 63110, United States
^d Department of Surgery, Washington University in St. Louis School of Medicine, St. Louis, MO 63110, United States

Abstract
BACKGROUND: Medication overuse headache (MOH) is the most common secondary headache disorder, resulting from chronic and excessive use of medication to treat headaches, for example, sumatriptan. In a recent study, we have shown that the peripheral C-C motif ligand 2 (CCL2), C-C motif chemokine receptor 2 (CCR2) and calcitonin-gene-related peptide (CGRP) signaling pathways interact with each other and play critical roles in the development of chronic migraine-related behavioral and cellular sensitization. In the present study, we investigated whether CCL2-CCR2 and CGRP signaling pathways play a role in the development of sumatriptan overuse-induced sensitization, and whether they are involved in its resolution by the low-dose interleukin-2 (LD-IL-2) treatment. METHODS: Mice received daily sumatriptan administration for 12 days. MOH-related behavioral sensitization was assessed by measuring changes of periorbital mechanical thresholds for 3 weeks. CCL2-CCR2 and CGRP signaling pathways were inhibited by targeted gene deletion or with an anti-CCL2 antibody. Ca2+-imaging was used to examine whether repetitive sumatriptan treatment enhances CGRP and pituitary adenylate cyclase-activating polypeptide (PACAP) signaling in trigeminal ganglion (TG) neurons. LD-IL-2 treatment was initiated after the establishment of sumatriptan-induced sensitization. Immunohistochemistry and flow cytometry analyses were used to examine whether CCL2-CCR2 signaling controls regulatory T (Treg) cell proliferation and/or trafficking. RESULTS: CCL2, CCR2 and CGRPα global KO mice exhibited robust sumatriptan-induced behavioral sensitization comparable to wild-type controls. Antibody neutralization of peripheral CCL2 did not affect sumatriptan-induced behaviors either. Repeated sumatriptan administration did not enhance the strength of CGRP or PACAP signaling in TG neurons. Nevertheless, LD-IL-2 treatment, which facilitated the resolution of sumatriptan-induced sensitization in wild-type and CGRPα KO mice, was completely ineffective in mice with compromised CCL2-CCR2 signaling. In CCL2 KO mice, we observed normal LD-IL-2-induced Treg expansion in peripheral blood, but the increase of Treg cells in dura and TG tissues was significantly reduced in LD-IL-2-treated CCL2 KO mice relative to wild-type controls. CONCLUSIONS: These results indicate that the endogenous CCL2-CCR2 and CGRP signaling pathways are not involved in sumatriptan-induced behavioral sensitization, suggesting that distinct molecular mechanisms underlie chronic migraine and MOH. On the other hand, peripheral CCL2-CCR2 signaling is required for LD-IL-2 to reverse chronic headache-related sensitization. © 2024. The Author(s).

Author Keywords
C-C motif chemokine receptor 2 (CCR2);  C-C motif ligand 2 (CCL2);  Calcitonin gene-related peptide (CGRP);  Facial mechanical hypersensitivity;  Low-dose interleukin-2 (LD-IL-2);  Medication overuse headache;  Regulatory T (Treg) cell

Document Type: Article
Publication Stage: Final
Source: Scopus

Microglia drive diurnal variation in susceptibility to inflammatory blood-brain barrier breakdown
(2024) JCI Insight, 9 (21), art. no. e180081, . 

Lawrence, J.H.^a , Patel, A.^a , King, M.W.^a , Nadarajah, C.J.^a , Daneman, R.^b , Musiek, E.S.^a c

^a Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States
^b Department of Pharmacology, UCSD, San Diego, CA, United States
^c Center On Biological Rhythms And Sleep (COBRAS), Washington University School of Medicine, St. Louis, MO, United States

Abstract
The blood-brain barrier (BBB) is critical for maintaining brain homeostasis but is susceptible to inflammatory dysfunction. While transporter-dependent efflux of some lipophilic substrates across the BBB shows circadian variation due to rhythmic transporter expression, basal transporter–independent permeability and leakage is nonrhythmic. Whether daily timing influences BBB permeability in response to inflammation is unknown. Here, we induced systemic inflammation through repeated LPS injections either in the morning (ZT1) or evening (ZT13) under standard lighting conditions; we then examined BBB permeability to a polar molecule that is not a transporter substrate, sodium fluorescein. We observed clear diurnal variation in inflammatory BBB permeability, with a striking increase in paracellular leak across the BBB specifically following evening LPS injection. Evening LPS led to persisting glia activation as well as inflammation in the brain that was not observed in the periphery. The exaggerated evening neuroinflammation and BBB disruption were suppressed by microglial depletion or through keeping mice in constant darkness. Our data show that diurnal rhythms in microglial inflammatory responses to LPS drive daily variability in BBB breakdown and reveal time of day as a key regulator of inflammatory BBB disruption. Copyright: © 2024, Lawrence et al. This is an open access article published under the terms of the Creative Commons Attribution 4.0 International License.

Funding details
Washington University in St. LouisWUSTL
Center for Cellular Imaging, Washington UniversityWUCCI
Institute of Clinical and Translational SciencesICTS
Université Paris-Saclay
National Institutes of HealthNIH
Genome Technology Access CenterGTAC
National Center for Research ResourcesNCRR
College of Natural Resources and Sciences, Humboldt State UniversityCNRS
Foundation for Barnes-Jewish HospitalFBJH4642, 3770
Foundation for Barnes-Jewish HospitalFBJH
National Institute on AgingNIAR01AG054517
National Institute on AgingNIA
National Cancer InstituteNCIP30 CA91842
National Cancer InstituteNCI
Georgia Clinical and Translational Science AllianceGaCTSAUL1TR002345
Georgia Clinical and Translational Science AllianceGaCTSA
St. Louis Children’s HospitalSLCHCDI-CORE-2019-813, CDI-CORE-2015-505
St. Louis Children’s HospitalSLCH
National Science FoundationNSFDGE-2139839, DGE-1745038
National Science FoundationNSF

Document Type: Article
Publication Stage: Final
Source: Scopus

Examining heterogeneity in dementia using data-driven unsupervised clustering of cognitive profiles
(2024) PLoS ONE, 19 (11 November), art. no. e0313425, . 

Kumar, S.^a b , Oh, I.Y.^b , Schindler, S.E.^c , Ghoshal, N.^c d , Abrams, Z.^b , Payne, P.R.O.^a b

^a Department of Computer Science and Engineering, McKelvey School of Engineering, Washington University in St Louis, St. Louis, MO, United States
^b Institute for Informatics, Data Science and Biostatistics (I2DB), Washington University School of Medicine, St. Louis, MO, United States
^c Division of Neurology, Washington University School of Medicine, St Louis, MO, United States
^d Department of Psychiatry, Washington University School of Medicine, St Louis, MO, United States

Abstract
Dementia is characterized by a decline in memory and thinking that is significant enough to impair function in activities of daily living. Patients seen in dementia specialty clinics are highly heterogenous with a variety of different symptoms that progress at different rates. Recent research has focused on finding data-driven subtypes for revealing new insights into dementia’s underlying heterogeneity, rather than assuming that the cohort is homogenous. However, current studies on dementia subtyping have the following limitations: (i) focusing on AD-related dementia only and not examining heterogeneity within dementia as a whole, (ii) using only cross-sectional baseline visit information for clustering and (iii) predominantly relying on expensive imaging biomarkers as features for clustering. In this study, we seek to overcome such limitations, using a data-driven unsupervised clustering algorithm named SillyPutty, in combination with hierarchical clustering on cognitive assessment scores to estimate subtypes within a real-world clinical dementia cohort. We use a longitudinal patient data set for our clustering analysis, instead of relying only on baseline visits, allowing us to explore the ongoing temporal relationship between subtypes and disease progression over time. Results showed that subtypes with very mild or mild dementia were more heterogenous in their cognitive profiles and risk of disease progression. Copyright: © 2024 Kumar 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
Centene CorporationP19-00559
Centene Corporation

Document Type: Article
Publication Stage: Final
Source: Scopus

Evaluation of ComBat Harmonization for Reducing Across-Tracer Differences in Regional Amyloid PET Analyses
(2024) Human Brain Mapping, 45 (16), art. no. e70068, . 

Yang, B.^a , Earnest, T.^a , Kumar, S.^a , Kothapalli, D.^a , Benzinger, T.^a , Gordon, B.^a , Sotiras, A.^a b

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

Abstract
Differences in amyloid positron emission tomography (PET) radiotracer pharmacokinetics and binding properties lead to discrepancies in amyloid-β uptake estimates. Harmonization of tracer-specific biases is crucial for optimal performance of downstream tasks. Here, we investigated the efficacy of ComBat, a data-driven harmonization model, for reducing tracer-specific biases in regional amyloid PET measurements from [18F]-florbetapir (FBP) and [11C]-Pittsburgh compound-B (PiB). One hundred thirteen head-to-head FBP-PiB scan pairs, scanned from the same subject within 90 days, were selected from the Open Access Series of Imaging Studies 3 (OASIS-3) dataset. The Centiloid scale, ComBat with no covariates, ComBat with biological covariates, and GAM-ComBat with biological covariates were used to harmonize both global and regional amyloid standardized uptake value ratios (SUVR). Variants of ComBat, including longitudinal ComBat and PEACE, were also tested. Intraclass correlation coefficient (ICC) and mean absolute error (MAE) were computed to measure the absolute agreement between tracers. Additionally, longitudinal amyloid SUVRs from an anti-amyloid drug trial were simulated using linear mixed effects modeling. Differences in rates-of-change between simulated treatment and placebo groups were tested, and change in statistical power/Type-I error after harmonization was quantified. In the head-to-head tracer comparison, ComBat with no covariates was the best at increasing ICC and decreasing MAE of both global summary and regional amyloid PET SUVRs between scan pairs of the same group of subjects. In the clinical trial simulation, harmonization with both Centiloid and ComBat increased statistical power of detecting true rate-of-change differences between groups and decreased false discovery rate in the absence of a treatment effect. The greatest benefit of harmonization was observed when groups exhibited differing FBP-to-PiB proportions. ComBat outperformed the Centiloid scale in harmonizing both global and regional amyloid estimates. Additionally, ComBat improved the detection of rate-of-change differences between clinical trial groups. Our findings suggest that ComBat is a viable alternative to Centiloid for harmonizing regional amyloid PET analyses. © 2024 The Author(s). Human Brain Mapping published by Wiley Periodicals LLC.

Author Keywords
amyloid-β;  Centiloid;  ComBat;  harmonization;  positron emission tomography

Funding details
National Institutes of HealthNIHP01 AG003991, R01 EB009352, P30 NS09857781, R01 AG043434, P50 AG00561, P01 AG026276, UL1 TR000448, 1S10RR022984‐01A1, S10OD025200, R01 AG067103, 1S10OD018091‐01
National Institutes of HealthNIH
BrightFocus FoundationBFFADR A2021042S
BrightFocus FoundationBFF
T32 EB014855
McDonnell Center for Systems NeuroscienceP01 AG003991, UL1 TR000448, R01 EB009352, R01 AG043434, P50 AG00561, P01 AG026276, P30 NS09857781
McDonnell Center for Systems Neuroscience

Document Type: Article
Publication Stage: Final
Source: Scopus

The mediating role of plasma glial fibrillary acidic protein in amyloid and tau pathology in Down’s syndrome
(2024) Alzheimer’s and Dementia, . 

Boerwinkle, A.H.^a , Wisch, J.K.^b , Handen, B.L.^c , Head, E.^d , Mapstone, M.^e , Rafii, M.S.^f , O’Bryant, S.E.^g , Krinsky-McHale, S.J.^h , Lai, F.ⁱ , Rosas, H.D.^j , Zaman, S.^k , Lott, I.T.^l , Tudorascu, D.^c , Zammit, M.^m , Brickman, A.M.ⁿ , Lee, J.H.^n o , Ances, B.M.^b , the Alzheimer’s Biomarker Consortium-Down Syndrome^p

^a McGovern Medical School, University of Texas in Houston, Houston, TX, United States
^b Department of Neurology, Washington University in St. Louis, St. Louis, MO, United States
^c Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA, United States
^d Department of Pathology, Gillespie Neuroscience Research Facility, University of California – Irvine, Irvine, CA, United States
^e Department of Neurology, University of California Irvine School of Medicine, Orange, CA, United States
^f Alzheimer’s Therapeutic Research Institute, Keck School of Medicine of USC, Los Angeles, CA, United States
^g Institute for Translational Research Department of Pharmacology and Neuroscience, University of North Texas Health Science Center, Fort Worth, TX, United States
^h Department of Psychology, New York State Institute for Basic Research in Developmental Disabilities, Staten Island, NY, United States
ⁱ Department of Radiology, Harvard Medical School, Massachusetts General Hospital, Boston, MA, United States
^j Department of Neurology, Harvard Medical School, Massachusetts General Hospital, Boston, MA, United States
^k Cambridge Intellectual and Developmental Disabilities Research Group, University of Cambridge, Cambridge, United Kingdom
^l Department of Pediatrics, University of California Irvine School of Medicine, Orange, CA, United States
^m Department of Medical Physics and Psychiatry, University of Wisconsin Madison, Madison, WI, United States
ⁿ Department of Neurology, Columbia University Irving Medical Center, New York, NY, United States
^o Department of Epidemiology, Columbia University Irving Medical Center, New York, NY, United States

Abstract
INTRODUCTION: Development of Alzheimer’s disease (AD) pathology in Down’s syndrome (DS) occurs within a compressed timeline compared to sporadic or other genetic forms of AD. METHODS: Plasma glial fibrillary acidic protein (GFAP) and plasma pTau-217 levels were compared by AD pathophysiology (amyloid (A+) and tau (T+) positron emission tomography [PET]) in persons with DS (N = 348) and sibling controls (N = 42). Plasma GFAP, plasma pTau-217, amyloid-PET, and tau-PET levels were compared with regard to estimated years to onset of clinical symptoms (52.5 years old). We evaluated if plasma GFAP mediated the relationship between amyloid PET and plasma pTau-217 or tau PET. RESULTS: Plasma GFAP, a measure of astrogliosis, was elevated in A+/T- and A+/T+ individuals with DS. Plasma pTau-217 was elevated in A+/T+ individuals with DS. GFAP partially mediated the relationship between amyloid-PET and tau-PET (15.3%) and amyloid-PET and plasma pTau-217 (42.1%). DISCUSSION: Astrogliosis is a key component in the advancement of preclinical AD pathophysiology in DS. Highlights: Amyloid may be a necessary precursor for stimulating astrocytes. Astrogliosis may play a key role in modifications to tau phosphorylation. Targeting neuroinflammation may only aid amyloid positive individuals. Alzheimer’s disease timecourse is compressed in individuals with Down’s syndrome. © 2024 The Author(s). Alzheimer’s & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer’s Association.

Author Keywords
Alzheimer’s disease;  biomarkers;  Down’s syndrome;  plasma

Funding details
Hereditary Disease FoundationHDF
Hope Center for Neurological Disorders, Washington University in St. Louis
Eunice Kennedy Shriver National Institute of Child Health and Human DevelopmentNICHD
National Institutes of HealthNIH
Roche
Mallinckrodt Institute of Radiology, School of Medicine, Washington University in St. LouisMIR
Foundation for Barnes-Jewish HospitalFBJH
Autism SpeaksAS
BrightFocus FoundationBFF
National Institute on AgingNIA
U01AG051406, U01AG051412, U19 AG068054‐04

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

TYK2 regulates tau levels, phosphorylation and aggregation in a tauopathy mouse model
(2024) Nature Neuroscience, . 

Kim, J.^a b , Tadros, B.^a b , Liang, Y.H.^a b , Kim, Y.^a b , Lasagna-Reeves, C.^c , Sonn, J.Y.^a b , Chung, D.-E.C.^a b , Hyman, B.^d , Holtzman, D.M.^e , Zoghbi, H.Y.^a b f g

^a Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, United States
^b Jan and Dan Duncan Neurological Research Institute at Texas Children’s Hospital, Houston, TX, United States
^c Stark Neurosciences Research Institute and Department of Anatomy, Cell Biology & amp; Physiology, Indiana University School of Medicine, Indianapolis, IN, United States
^d Neurology at Harvard Medical School and Massachusetts General Hospital, Boston, MA, United States
^e Department of Neurology, Hope Center for Neurological Disorders, Knight Alzheimers’ Disease Research Center, Washington University in St. Louis, St. Louis, MO, United States
^f Departments of Neuroscience, Pediatrics, and Neurology, Baylor College of Medicine, Houston, TX, United States
^g Howard Hughes Medical Institute, Chevy Chase, MD, United States

Abstract
Alzheimer’s disease is one of at least 26 diseases characterized by tau-positive accumulation in neurons, glia or both. However, it is still unclear what modifications cause soluble tau to transform into insoluble aggregates. We previously performed genetic screens that identified tyrosine kinase 2 (TYK2) as a candidate regulator of tau levels. Here we verified this finding and found that TYK2 phosphorylates tau at tyrosine 29 (Tyr29) leading to its stabilization and promoting its aggregation in human cells. We discovered that TYK2-mediated Tyr29 phosphorylation interferes with autophagic clearance of tau. We also show that TYK2-mediated phosphorylation of Tyr29 facilitates pathological tau accumulation in P301S tau-transgenic mice. Furthermore, knockdown of Tyk2 reduced total tau and pathogenic tau levels and rescued gliosis in a tauopathy mouse model. Collectively, these data suggest that partial inhibition of TYK2 could thus be a strategy to reduce tau levels and toxicity. © The Author(s) 2024.

Funding details
Eunice Kennedy Shriver National Institute of Child Health and Human DevelopmentNICHD
AbbVie
JPB FoundationJPBF
Cure Alzheimer’s FundCAF
Howard Hughes Medical InstituteHHMI
Tau Consortium
National Institute of Neurological Disorders and StrokeNINDSR01NS119280
National Institute of Neurological Disorders and StrokeNINDS
Alzheimer’s Disease Research Center, University of PittsburghADRCP30AG066507, U19AG033655
Alzheimer’s Disease Research Center, University of PittsburghADRC
National Institutes of HealthNIHP50HD103555
National Institutes of HealthNIH
National Institute on AgingNIAP30AG062421-01
National Institute on AgingNIA
P50NS38377

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

Genetic architecture of cerebrospinal fluid and brain metabolite levels and the genetic colocalization of metabolites with human traits
(2024) Nature Genetics, . 

Wang, C.^a b c , Yang, C.^a b , Western, D.^a b c , Ali, M.^a b , Wang, Y.^a b , Phuah, C.-L.^b d , Budde, J.^a b , Wang, L.^a b , Gorijala, P.^a b , Timsina, J.^a b , Ruiz, A.^e f g , Pastor, P.^h i , Fernandez, M.V.^a b , Perrin, R.^q r s , Panyard, D.J.^j , Engelman, C.D.^k , Deming, Y.^l , Boada, M.^e f , Cano, A.^e f , Garcia-Gonzalez, P.^e , Graff-Radford, N.R.^m , Mori, H.^n o , Lee, J.-H.^p , Perrin, R.J.^q r s , Ibanez, L.^a b r , Sung, Y.J.^a b t , Cruchaga, C.^a b q , Dominantly Inherited Alzheimer Network (DIAN)^u , The Alzheimer’s Disease Neuroimaging Initiative (ADNI)^u

^a Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, United States
^b NeuroGenomics and Informatics Center, Washington University School of Medicine, St. Louis, MO, United States
^c Division of Biology and Biomedical Sciences, Washington University School of Medicine, St. Louis, MO, United States
^d Division of Neurocritical Care, Department of Neurology, Barrow Neurological Institute, Phoenix, AZ, United States
^e Research Center and Memory Clinic, ACE Alzheimer Center Barcelona, Universitat Internacional de Catalunya, Barcelona, Spain
^f CIBERNED, Network Center for Biomedical Research in Neurodegenerative Diseases, Instituto de Salud Carlos III, Madrid, Spain
^g Glenn Biggs Institute for Alzheimer’s & amp; Neurodegenerative Diseases, University of Texas Health Science Center, San Antonio, TX, United States
^h Unit of Neurodegenerative Diseases, Department of Neurology, University Hospital Germans Trias i Pujol, Badalona, Spain
ⁱ The Germans Trias i Pujol Research Institute (IGTP), Barcelona, Spain
^j Department of Genetics, Stanford University School of Medicine, Stanford University, Stanford, CA, United States
^k Department of Population Health Sciences, School of Medicine and Public Health, University of Wisconsin—Madison, Madison, WI, United States
^l Wisconsin Alzheimer’s Disease Research Center, University of Wisconsin—Madison, Madison, WI, United States
^m Department of Neurology, Mayo Clinic, Jacksonville, FL, United States
ⁿ Department of Clinical Neuroscience, Faculty of Medicine, Osaka Metropolitan University, Osaka, Japan
^o Nagaoka Sutoku University, Niigata, Japan
^p University of Ulsan College of Medicine, Asan Medical Center, Seoul, South Korea
^q Hope Center for Neurologic Disorders, Washington University, St. Louis, MO, United States
^r Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States
^s Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, United States
^t Division of Biostatistics, Washington University School of Medicine, St. Louis, MO, United States

Abstract
Brain metabolism perturbation can contribute to traits and diseases. We conducted a genome-wide association study for cerebrospinal fluid (CSF) and brain metabolite levels, identifying 205 independent associations (47.3% new signals, containing 11 new loci) for 139 CSF metabolites, and 32 independent associations (43.8% new signals, containing 4 new loci) for 31 brain metabolites. Of these, 96.9% (CSF) and 71.4% (brain) of the new signals belonged to previously analyzed metabolites in blood or urine. We integrated the metabolite quantitative trait loci (MQTLs) with 23 neurological, psychiatric and common human traits and diseases through colocalization to identify metabolites and biological processes implicated in these phenotypes. Combining CSF and brain, we identified 71 metabolite–trait associations, such as glycerophosphocholines with Alzheimer’s disease, O-sulfo-l-tyrosine with Parkinson’s disease, glycine, xanthine with waist-to-hip ratio and ergothioneine with inflammatory bowel disease. Our study expanded the knowledge of MQTLs in the central nervous system, providing insights into human traits. © The Author(s), under exclusive licence to Springer Nature America, Inc. 2024.

Funding details
Hope Center for Neurological Disorders, Washington University in St. Louis
Chan Zuckerberg InitiativeCZI
Michael J. Fox Foundation for Parkinson’s ResearchMJFF
National Institutes of HealthNIHRF1AG074007, RF1AG053303, R01AG044546, RF1AG058501, P01AG003991, U01AG058922
National Institutes of HealthNIH
Instituto de Salud Carlos IIIISCIIIPID2021-122473OA-I00, CD22/00125
Instituto de Salud Carlos IIIISCIII
National Institute on AgingNIAU19AG032438, SG-20-690363-DIAN
National Institute on AgingNIA
Alzheimer’s Disease Neuroimaging InitiativeADNIU01 AG024904
Alzheimer’s Disease Neuroimaging InitiativeADNI
R01/RF1AG054047
Alzheimer’s AssociationAAP30AG066444, P01AG03991, P01AG026276, ZEN-22-848604
Alzheimer’s AssociationAA
U.S. Department of DefenseDODLI-W81XWH2010849
U.S. Department of DefenseDOD
W81XWH-12-2-0012
Ministerio de Ciencia, Innovación y UniversidadesMCIUFJC2018-036012-I
Ministerio de Ciencia, Innovación y UniversidadesMCIU

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

Proteogenomic analysis of human cerebrospinal fluid identifies neurologically relevant regulation and implicates causal proteins for Alzheimer’s disease
(2024) Nature Genetics, . Cited 1 time.

Western, D.^a b c , Timsina, J.^a b , Wang, L.^a b , Wang, C.^a b c , Yang, C.^a b , Phillips, B.^a b c , Wang, Y.^a b , Liu, M.^a b , Ali, M.^a b , Beric, A.^a b , Gorijala, P.^a b , Kohlfeld, P.^a b , Budde, J.^a b , Levey, A.I.^d , Morris, J.C.^e , Perrin, R.J.^e f g , Ruiz, A.^h i j , Marquié, M.^h i , Boada, M.^h i , de Rojas, I.^h i , Rutledge, J.^k , Oh, H.^k , Wilson, E.N.^k l , Le Guen, Y.^l m , Reus, L.M.^n o , Tijms, B.^n o , Visser, P.J.^n o p , van der Lee, S.J.^n o q , Pijnenburg, Y.A.L.^n o , Teunissen, C.E.^r , del Campo Milan, M.^s t , Alvarez, I.^u , Aguilar, M.^u , Greicius, M.D.^k l , Pastor, P.^u v , Pulford, D.J.^w , Ibanez, L.^a b e , Wyss-Coray, T.^k , Sung, Y.J.^a b x , Cruchaga, C.^a b g y , Dominantly Inherited Alzheimer Network (DIAN)^z , the Alzheimer’s Disease Neuroimaging Initiative (ADNI)^z

^a Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, United States
^b NeuroGenomics and Informatics Center, Washington University School of Medicine, St. Louis, MO, United States
^c Division of Biology and Biomedical Sciences, Washington University School of Medicine, St. Louis, MO, United States
^d Department of Neurology, Emory University School of Medicine, Atlanta, GA, United States
^e Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States
^f Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, United States
^g Hope Center for Neurological Disorders, Washington University, St. Louis, MO, United States
^h ACE Alzheimer Center Barcelona, Universitat Internacional de Catalunya, Barcelona, Spain
ⁱ Networking Research Center on Neurodegenerative Diseases (CIBERNED), Instituto de Salud Carlos III, Madrid, Spain
^j Glenn Biggs Institute for Alzheimer’s and Neurodegenerative Diseases, University of Texas Health Science Center, San Antonio, TX, United States
^k Wu Tsai Neurosciences Institute, Stanford University, Stanford, CA, United States
^l Department of Neurology and Neurological Sciences, Stanford University, Stanford, CA, United States
^m Quantitative Sciences Unit, Department of Medicine, Stanford University, Stanford, CA, United States
ⁿ Alzheimer Center Amsterdam, Neurology, Vrije Universiteit Amsterdam, Amsterdam UMC location VUmc, Amsterdam, Netherlands
^o Amsterdam Neuroscience, Neurodegeneration, Vrije Universiteit Amsterdam, Amsterdam UMC location VUmc, Amsterdam, Netherlands
^p Department of Psychiatry, Maastricht University, Maastricht, Netherlands
^q Genomics of Neurodegenerative Diseases and Aging, Department of Human Genetics, Vrije Universiteit Amsterdam, Amsterdam UMC, Amsterdam, Netherlands
^r Neurochemistry Laboratory, Department of Clinical Chemistry, Amsterdam Neuroscience, Amsterdam University Medical Centers, Location VUmc, Amsterdam, Netherlands
^s Departamento de Ciencias Farmacéuticas y de la Salud, Facultad de Farmacia, Universidad San Pablo CEU, CEU Universities, Madrid, Spain
^t Barcelonaβeta Brain Research Center, Pasqual Maragall Foundation, Barcelona, Spain
^u Memory Disorders Unit, Department of Neurology, University Hospital Mutua Terrassa, Terrassa, Spain
^v Unit of Neurodegenerative Diseases, Department of Neurology, University Hospital Germans Trias i Pujol and the Germans Trias i Pujol Research Institute (IGTP) Badalona, Barcelona, Spain
^w Medicines R & amp;D, GlaxoSmithKline, Stevenage, United Kingdom
^x Division of Biostatistics, Washington University School of Medicine, St. Louis, MO, United States
^y Department of Genetics, Washington University School of Medicine, St. Louis, MO, United States

Abstract
The integration of quantitative trait loci (QTLs) with disease genome-wide association studies (GWASs) has proven successful in prioritizing candidate genes at disease-associated loci. QTL mapping has been focused on multi-tissue expression QTLs or plasma protein QTLs (pQTLs). We generated a cerebrospinal fluid (CSF) pQTL atlas by measuring 6,361 proteins in 3,506 samples. We identified 3,885 associations for 1,883 proteins, including 2,885 new pQTLs, demonstrating unique genetic regulation in CSF. We identified CSF-enriched pleiotropic regions on chromosome (chr)3q28 near OSTN and chr19q13.32 near APOE that were enriched for neuron specificity and neurological development. We integrated our associations with Alzheimer’s disease (AD) through proteome-wide association study (PWAS), colocalization and Mendelian randomization and identified 38 putative causal proteins, 15 of which have drugs available. Finally, we developed a proteomics-based AD prediction model that outperforms genetics-based models. These findings will be instrumental to further understand the biology and identify causal and druggable proteins for brain and neurological traits. © The Author(s), under exclusive licence to Springer Nature America, Inc. 2024.

Funding details
Hope Center for Neurological Disorders, Washington University in St. Louis
Chan Zuckerberg InitiativeCZI
Eli Lilly and Company
Roche
Michael J. Fox Foundation for Parkinson’s ResearchMJFF
Alzheimer’s AssociationAAZEN-22-848604
Alzheimer’s AssociationAA
National Institute on AgingNIASG-20-690363-DIAN
National Institute on AgingNIA
National Institutes of HealthNIHP01AG003991, RF1AG058501, RF1AG074007, R00AG062723, P30 AG066515, U01AG058922, R01AG044546, RF1AG053303, P30AG066444, P01AG026276
National Institutes of HealthNIH
Selfridges Group FoundationNR170065
Selfridges Group Foundation
Alzheimer’s Disease Neuroimaging InitiativeADNIU01 AG024904
Alzheimer’s Disease Neuroimaging InitiativeADNI
U.S. Department of DefenseDODW81XWH2010849
U.S. Department of DefenseDOD
W81XWH-12-2-0012, WE.03-2018-05
U19AG032438
BrightFocus FoundationBFFA2021033S
BrightFocus FoundationBFF
ZonMw10510022110012
ZonMw

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