Scopus list of publications for December 26, 2022
Diffusion Basis Spectrum Imaging Provides Insights Into Cervical Spondylotic Myelopathy Pathology
(2023) Neurosurgery, 92 (1), pp. 102-109.
Zhang, J.K.a , Jayasekera, D.b , Song, C.c , Greenberg, J.K.a , Javeed, S.a , Dibble, C.F.a , Blum, J.c , Sun, P.c , Song, S.-K.c , Ray, W.Z.a
a Department of Neurological Surgery, Washington University School of Medicine, Saint Louis, Missouri, USA
b Department of Biomedical Engineering, Washington University in St. Louis McKelvey School of Engineering, Saint Louis, Missouri, USA
c Department of Radiology, Washington University School of Medicine, St. Louis, MO, United States
Abstract
BACKGROUND: Diffusion basis spectrum imaging (DBSI) is a noninvasive quantitative imaging modality that may improve understanding of cervical spondylotic myelopathy (CSM) pathology through detailed evaluations of spinal cord microstructural compartments. OBJECTIVE: To determine the utility of DBSI as a biomarker of CSM disease severity. METHODS: A single-center prospective cohort study enrolled 50 patients with CSM and 20 controls from 2018 to 2020. All patients underwent clinical evaluation and diffusion-weighted MRI, followed by diffusion tensor imaging and DBSI analyses. Diffusion-weighted MRI metrics assessed white matter integrity by fractional anisotropy, axial diffusivity, radial diffusivity, and fiber fraction. In addition, DBSI further evaluates extra-axonal changes by isotropic restricted and nonrestricted fraction. Including an intra-axonal diffusion compartment, DBSI improves estimations of axonal injury through intra-axonal axial diffusivity. Patients were categorized into mild, moderate, and severe CSM using modified Japanese Orthopedic Association classifications. Imaging parameters were compared among patient groups using independent samples t tests and ANOVA. RESULTS: Twenty controls, 27 mild (modified Japanese Orthopedic Association 15-17), 12 moderate (12-14), and 11 severe (0-11) patients with CSM were enrolled. Diffusion tensor imaging and DBSI fractional anisotropy, axial diffusivity, and radial diffusivity were significantly different between control and patients with CSM ( P < .05). DBSI fiber fraction, restricted fraction, and nonrestricted fraction were significantly different between groups ( P < .01). DBSI intra-axonal axial diffusivity was lower in mild compared with moderate (mean difference [95% CI]: 1.1 [0.3-2.1], P < .01) and severe (1.9 [1.3-2.4], P < .001) CSM. CONCLUSION: DBSI offers granular data on white matter tract integrity in CSM that provide novel insights into disease pathology, supporting its potential utility as a biomarker of CSM disease progression. Copyright © Congress of Neurological Surgeons 2022. All rights reserved.
Document Type: Article
Publication Stage: Final
Source: Scopus
Association Between Neighborhood-Level Socioeconomic Disadvantage and Patient-Reported Outcomes in Lumbar Spine Surgery
(2023) Neurosurgery, 92 (1), pp. 92-101.
Zhang, J.K.a , Greenberg, J.K.a , Javeed, S.a , Khalifeh, J.M.a , Dibble, C.F.a , Park, Y.b , Jain, D.c , Buchowski, J.M.c , Dorward, I.a , Santiago, P.a , Molina, C.a , Pennicooke, B.H.a , Ray, W.Z.a
a Department of Neurological Surgery, Washington University School of MedicineSaint Louis, Seychelles
b Division of Public Health Sciences, Department of Surgery, Washington University School of Medicine, Saint Louis, Missouri, USA
c Department of Orthopedic Surgery, Washington University School of Medicine, Saint Louis, Missouri, USA
Abstract
BACKGROUND: Despite an increased understanding of the impact of socioeconomic status on neurosurgical outcomes, the impact of neighborhood-level social determinants on lumbar spine surgery patient-reported outcomes remains unknown. OBJECTIVE: To evaluate the impact of geographic social deprivation on physical and mental health of lumbar surgery patients. METHODS: A single-center retrospective cohort study analyzing patients undergoing lumbar surgery for degenerative disease from 2015 to 2018 was performed. Surgeries were categorized as decompression only or decompression with fusion. The area deprivation index was used to define social deprivation. Study outcomes included preoperative and change in Patient-Reported Outcomes Measurement (PROMIS) physical function (PF), pain interference (PI), depression, and anxiety (mean follow-up: 43.3 weeks). Multivariable imputation was performed for missing data. One-way analysis of variance and multivariable linear regression were used to evaluate the association between area deprivation index and PROMIS scores. RESULTS: In our cohort of 2010 patients, those with the greatest social deprivation had significantly worse mean preoperative PROMIS scores compared with the least-deprived cohort (mean difference [95% CI]-PF: -2.5 [-3.7 to -1.4]; PI: 3.0 [2.0-4.1]; depression: 5.5 [3.4-7.5]; anxiety: 6.0 [3.8-8.2], all P < .001), without significant differences in change in these domains at latest follow-up (PF: +0.5 [-1.2 to 2.2]; PI: -0.2 [-1.7 to 2.1]; depression: -2 [-4.0 to 0.1]; anxiety: -2.6 [-4.9 to 0.4], all P > .05). CONCLUSION: Lumbar spine surgery patients with greater social deprivation present with worse preoperative physical and mental health but experience comparable benefit from surgery than patients with less deprivation, emphasizing the need to further understand social and health factors that may affect both disease severity and access to care. Copyright © Congress of Neurological Surgeons 2022. All rights reserved.
Document Type: Article
Publication Stage: Final
Source: Scopus
A pilot randomized sham controlled trial of bilateral iTBS for depression and executive function in older adults
(2023) International Journal of Geriatric Psychiatry, 38 (1), p. e5851.
Cristancho, P.a , Arora, J.b , Nishino, T.c , Berger, J.a , Carter, A.d , Blumberger, D.e , Miller, P.b , Snyder, A.c d f , Barch, D.g , Lenze, E.J.a
a Department of Psychiatry, Healthy Mind Lab, School of Medicine, Washington University in St. Louis, St. Louis, MO, United States
b Division of Biostatistics, School of Medicine, Washington University in St. Louis, St. Louis, MO, United States
c Neuroimaging Laboratories, Washington University in St. Louis, St. Louis, MO, United States
d Department of Neurology, School of Medicine, Washington University in St. Louis, St. Louis, MO, United States
e Department of Psychiatry, Centre for Addiction and Mental Health, University of Toronto, Toronto, ON, Canada
f Department of Radiology, School of Medicine, Washington University in St. Louis, St. Louis, MO, United States
g Department of Psychological and Brain Sciences, Washington University, St. Louis, MO, United States
Abstract
INTRODUCTION: Executive function deficits (EFD) in late life depression (LLD) are associated with poor outcomes. Dysfunction of the cognitive control network (CCN) has been posited in the pathophysiology of LLD with EFD. METHODS: Seventeen older adults with depression and EFD were randomized to iTBS or sham for 6 weeks. Intervention was delivered bilaterally using a recognized connectivity target. RESULTS: A total of 89% (17/19) participants completed all study procedures. No serious adverse events occurred. Pre to post-intervention change in mean Montgomery-Asberg-depression scores was not different between iTBS or sham, p = 0.33. No significant group-by-time interaction for Montgomery-Asberg Depression rating scale scores (F 3, 44 = 0.51; p = 0.67) was found. No significant differences were seen in the effects of time between the two groups on executive measures: Flanker scores (F 1, 14 = 0.02, p = 0.88), Dimensional-change-card-sort scores F 1, 14 = 0.25, p = 0.63, and working memory scores (F 1, 14 = 0.98, p = 0.34). The Group-by-time interaction effect for functional connectivity (FC) within the Fronto-parietal-network was not significant (F 1, 14 = 0.36, p = 0.56). No significant difference in the effect-of-time between the two groups was found on FC within the Cingulo-opercular-network (F 1, 14 = 0, p = 0.98). CONCLUSION: Bilateral iTBS is feasible in LLD. Preliminary results are unsupportive of efficacy on depression, executive function or target engagement of the CCN. A future Randomized clinical trial requires a larger sample size with stratification of cognitive and executive variables and refinement in the target engagement. © 2022 John Wiley & Sons Ltd.
Author Keywords
Cingulo opercular network; depression; executive dysfunction; Fronto parietal network; intermittent theta burst stimulation; late life depression; neuromodulation; older adults; resting state functional connectivity; transcranial magnetic stimulation
Document Type: Article
Publication Stage: Final
Source: Scopus
Comparison of amyloid burden in individuals with Down syndrome versus autosomal dominant Alzheimer’s disease: a cross-sectional study
(2023) The Lancet Neurology, 22 (1), pp. 55-65. Cited 1 time.
Boerwinkle, A.H.a , Gordon, B.A.b c , Wisch, J.a , Flores, S.c , Henson, R.L.a , Butt, O.H.a , McKay, N.c , Chen, C.D.c , Benzinger, T.L.S.b c , Fagan, A.M.a b , Handen, B.L.g , Christian, B.T.h , Head, E.i , Mapstone, M.j , Rafii, M.S.l , O’Bryant, S.m , Lai, F.n , Rosas, H.D.n , Lee, J.H.o p , Silverman, W.k , Brickman, A.M.o q r , Chhatwal, J.P.n , Cruchaga, C.b d , Perrin, R.J.a b e , Xiong, C.f , Hassenstab, J.a , McDade, E.a , Bateman, R.J.a b , Ances, B.M.a b c , Aizenstein, H.J.s , Andrews, H.F.s , Bell, K.s , Birn, R.M.s , Bulova, P.s , Cheema, A.s , Chen, K.s , Clare, I.s , Clark, L.s , Cohen, A.D.s , Constantino, J.N.s , Doran, E.W.s , Feingold, E.s , Foroud, T.M.s , Hartley, S.L.s , Hom, C.s , Honig, L.s , Ikonomovic, M.D.s , Johnson, S.C.s , Jordan, C.s , Kamboh, M.I.s , Keator, D.s , Klunk MD, W.E.s , Kofler, J.K.s , Kreisl, W.C.s , Krinsky- McHale, S.J.s , Lao, P.s , Laymon, C.s , Lott, I.T.s , Lupson, V.s , Mathis, C.A.s , Minhas, D.S.s , Nadkarni, N.s t , Pang, D.s , Petersen, M.s , Price, J.C.s , Pulsifer, M.s , Reiman, E.s , Rizvi, B.s , Sabbagh, M.N.s , Schupf, N.s , Tudorascu, D.L.s , Tumuluru, R.s , Tycko, B.s , Varadarajan, B.s , White, D.A.s , Yassa, M.A.s , Zaman, S.s , Zhang, F.s , Adams, S.t , Allegri, R.t , Araki, A.t , Barthelemy, N.t , Bechara, J.t , Berman, S.t , Bodge, C.t , Brandon, S.t , Brooks, W.t , Brosch, J.t , Buck, J.t , Buckles, V.t , Carter, K.t , Cash, L.t , Mendez, P.C.t , Chua, J.t , Chui, H.t , Courtney, L.t , Day, G.t , DeLaCruz, C.t , Denner, D.t , Diffenbacher, A.t , Dincer, A.t , Donahue, T.t , Douglas, J.t , Duong, D.t , Egido, N.t , Esposito, B.t , Farlow, M.t , Feldman, B.t , Fitzpatrick, C.t , Fox, N.t , Franklin, E.t , Joseph-Mathurin, N.t , Fujii, H.t , Gardener, S.t , Ghetti, B.t , Goate, A.t , Goldberg, S.t , Goldman, J.t , Gonzalez, A.t , Gräber-Sultan, S.t , Graff-Radford, N.t , Graham, M.t , Gray, J.t , Gremminger, E.t , Grilo, M.t , Groves, A.t , Haass, C.t , Häslerc, L.t , Hellm, C.t , Herries, E.t , Hoechst-Swisher, L.t , Hofmann, A.t , Holtzman, D.t , Hornbeck, R.t , Igor, Y.t , Ihara, R.t , Ikeuchi, T.t , Ikonomovic, S.t , Ishii, K.t , Jack, C.t , Jerome, G.t , Johnson, E.t , Jucker, M.t , Karch, C.t , Käser, S.t , Kasuga, K.t , Keefe, S.t , Klunk, W.t , Koeppe, R.t , Koudelis, D.t , Kuder-Buletta, E.t , Laske, C.t , Levey, A.t , Levin, J.t , Li, Y.t , Lopez, O.t , Marsh, J.t , Martins, R.t , Mason, N.S.t , Masters, C.t , Mawuenyega, K.t , McCullough, A.t , Mejia, A.t , Morenas-Rodriguez, E.t , Morris, J.C.t , Mountz, J.t , Mummery, C.t , Nagamatsu, A.t , Neimeyer, K.t , Niimi, Y.t , Noble, J.t , Norton, J.t , Nuscher, B.t , Obermüller, U.t , O’Connor, A.t , Patira, R.t , Ping, L.t , Preische, O.t , Renton, A.t , Ringman, J.t , Salloway, S.t , Schofield, P.t , Senda, M.t , Seyfried, N.T.t , Shady, K.t , Shimada, H.t , Sigurdson, W.t , Smith, J.t , Smith, L.t , Snitz, B.t , Sohrabi, H.t , Stephens, S.t , Taddei, K.t , Thompson, S.t , Vöglein, J.t , Wang, P.t , Wang, Q.t , Weamer, E.t , Xu, J.t , Xu, X.t , Alzheimer’s Biomarker Consortium-Down Syndromeu v , Dominantly Inherited Alzheimer Networku v
a Department of Neurology, Washington University in St Louis, St Louis, MO, United States
b Hope Center for Neurological Disorders, Washington University in St Louis, St Louis, MO, United States
c Department of Radiology, Washington University in St Louis, St Louis, MO, United States
d Department of Psychiatry, Washington University in St Louis, St Louis, MO, United States
e Department of Pathology and Immunology, Washington University in St Louis, St Louis, MO, United States
f Division of Biostatistics, Washington University School of Medicine, Washington University in St Louis, St Louis, MO, United States
g Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA, United States
h Department of Medical Physics and Psychiatry, University of Wisconsin–Madison, Madison, WI, United States
i Department of Pathology and Laboratory Medicine, University of California Irvine School of Medicine, University of California, Irvine, CA, United States
j Department of Neurology, University of California Irvine School of Medicine, University of California, Irvine, CA, United States
k Department of Pediatrics, University of California Irvine School of Medicine, University of California, Irvine, CA, United States
l Alzheimer’s Therapeutic Research Institute, Keck School of Medicine of USC, Los Angeles, CA, United States
m Institute for Translational Research, University of North Texas Health Science Center, Fort Worth, TX, United States
n Department of Neurology, Harvard Medical School, Massachusetts General Hospital and Brigham and Women’s Hospital, Boston, MA, United States
o Department of Neurology, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, United States
p Department of Epidemiology, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, United States
q Taub Institute for Research on Alzheimer’s Disease and the Aging Brain, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, United States
r G H Sergievsky Center, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, United States
Abstract
Background: Important insights into the early pathogenesis of Alzheimer’s disease can be provided by studies of autosomal dominant Alzheimer’s disease and Down syndrome. However, it is unclear whether the timing and spatial distribution of amyloid accumulation differs between people with autosomal dominant Alzheimer’s disease and those with Down syndrome. We aimed to directly compare amyloid changes between these two groups of people. Methods: In this cross-sectional study, we included participants (aged ≥25 years) with Down syndrome and sibling controls who had MRI and amyloid PET scans in the first data release (January, 2020) of the Alzheimer’s Biomarker Consortium-Down Syndrome (ABC-DS) study. We also included carriers of autosomal dominant Alzheimer’s disease genetic mutations and non-carrier familial controls who were within a similar age range to ABC-DS participants (25–73 years) and had MRI and amyloid PET scans at the time of a data freeze (December, 2020) of the Dominantly Inherited Alzheimer Network (DIAN) study. Controls from the two studies were combined into a single group. All DIAN study participants had genetic testing to determine PSEN1, PSEN2, or APP mutation status. APOE genotype was determined from blood samples. CSF samples were collected in a subset of ABC-DS and DIAN participants and the ratio of amyloid β42 (Aβ42) to Aβ40 (Aβ42/40) was measured to evaluate its Spearman’s correlation with amyloid PET. Global PET amyloid burden was compared with regards to cognitive status, APOE ɛ4 status, sex, age, and estimated years to symptom onset. We further analysed amyloid PET deposition by autosomal dominant mutation type. We also assessed regional patterns of amyloid accumulation by estimated number of years to symptom onset. Within a subset of participants the relationship between amyloid PET and CSF Aβ42/40 was evaluated. Findings: 192 individuals with Down syndrome and 33 sibling controls from the ABC-DS study and 265 carriers of autosomal dominant Alzheimer’s disease mutations and 169 non-carrier familial controls from the DIAN study were included in our analyses. PET amyloid centiloid and CSF Aβ42/40 were negatively correlated in carriers of autosomal dominant Alzheimer’s disease mutations (n=216; r=–0·565; p<0·0001) and in people with Down syndrome (n=32; r=–0·801; p<0·0001). There was no difference in global PET amyloid burden between asymptomatic people with Down syndrome (mean 18·80 centiloids [SD 28·33]) versus asymptomatic mutation carriers (24·61 centiloids [30·27]; p=0·11) and between symptomatic people with Down syndrome (77·25 centiloids [41·76]) versus symptomatic mutation carriers (69·15 centiloids [51·10]; p=0·34). APOE ɛ4 status and sex had no effect on global amyloid PET deposition. Amyloid deposition was elevated significantly earlier in mutation carriers than in participants with Down syndrome (estimated years to symptom onset –23·0 vs –17·5; p=0·0002). PSEN1 mutations primarily drove this difference. Early amyloid accumulation occurred in striatal and cortical regions for both mutation carriers (n=265) and people with Down syndrome (n=128). Although mutation carriers had widespread amyloid accumulation in all cortical regions, the medial occipital regions were spared in people with Down syndrome. Interpretation: Despite minor differences, amyloid PET changes were similar between people with autosomal dominant Alzheimer’s disease versus Down syndrome and strongly supported early amyloid dysregulation in individuals with Down syndrome. Individuals with Down syndrome aged at least 35 years might benefit from early intervention and warrant future inclusion in clinical trials, particularly given the relatively high incidence of Down syndrome. Funding: The National Institute on Aging, Riney and Brennan Funds, the Eunice Kennedy Shriver National Institute of Child Health and Human Development, the German Center for Neurodegenerative Diseases, and the Japan Agency for Medical Research and Development. © 2023 Elsevier Ltd
Funding details
U01AG051406, U01AG051412
National Institute on AgingNIA
Alzheimer’s AssociationAASG-20-690363-DIAN
Foundation for Barnes-Jewish HospitalFBJH
Fondation Brain Canada
Japan Agency for Medical Research and DevelopmentAMED
Eunice Kennedy Shriver National Institute of Child Health and Human DevelopmentNICHDU19AG032438
Hope Center for Neurological Disorders
Canadian Institutes of Health ResearchIRSC
Fonds de Recherche du Québec – SantéFRQS
Korea Health Industry Development InstituteKHIDI
Instituto de Salud Carlos IIIISCIII
Deutsches Zentrum für Neurodegenerative ErkrankungenDZNE
Fleni
NIHR Cambridge Biomedical Research CentreBRC-1215-20014*
Document Type: Article
Publication Stage: Final
Source: Scopus
Transferability of Alzheimer Disease Polygenic Risk Score Across Populations and Its Association With Alzheimer Disease-Related Phenotypes
(2022) JAMA Network Open, 5 (12), p. e2247162.
Jung, S.-H.a b , Kim, H.-R.c , Chun, M.Y.d e , Jang, H.d e , Cho, M.b , Kim, B.b , Kim, S.b , Jeong, J.H.f , Yoon, S.J.g , Park, K.W.h , Kim, E.-J.i , Yoon, B.j , Jang, J.-W.k , Kim, Y.k , Hong, J.Y.l , Choi, S.H.m , Noh, Y.n , Kim, K.W.o , Kim, S.E.p , Lee, J.S.q , Jung, N.-Y.r , Lee, J.s , Lee, A.Y.s , Kim, B.C.t , Cho, S.H.t , Cho, H.u , Kim, J.H.v , Jung, Y.H.w , Lee, D.Y.x , Lee, J.-H.y , Lee, E.-S.z , Kim, S.J.aa , Moon, S.Y.ab , Son, S.J.ac , Hong, C.H.ac , Bae, J.-S.ad , Lee, S.ad , Na, D.L.d e ae , Seo, S.W.b d e ae af , Cruchaga, C.ag ah ai , Kim, H.J.b d e ae , Won, H.-H.b ae aj
a Department of Biostatistics, Epidemiology and Informatics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States
b Department of Digital Health, Samsung Advanced Institute for Health Sciences & Technology, Sungkyunkwan University, Samsung Medical CenterSeoul, South Korea
c Department of Neurology, Dongguk University Ilsan Hospital, Dongguk University College of Medicine, Goyang, South Korea
d Department of Neurology, Samsung Medical Center, Sungkyunkwan University School of MedicineSeoul, South Korea
e Alzheimer’s Disease Convergence Research Center, Samsung Medical CenterSeoul, South Korea
f Department of Neurology, Ewha Womans University Seoul Hospital, Ewha Womans University School of MedicineSeoul, South Korea
g Department of Neurology, Eulji University Hospital, Eulji University School of MedicineDaejeon, South Korea
h Department of Neurology, Dong-A University College of Medicine, Department of Translational Biomedical Sciences, Graduate School of Dong-A UniversityBusan, South Korea
i Department of Neurology, Pusan National University Hospital, Pusan National University School of Medicine and Medical Research InstituteBusan, South Korea
j Department of Neurology, Konyang University College of MedicineDaejeon, South Korea
k Department of Neurology, Kangwon National University Hospital, Kangwon National University College of Medicine, Chuncheon, South Korea
l Department of Neurology, Yonsei University Wonju College of Medicine, Wonju, South Korea
m Department of Neurology, Inha University School of MedicineIncheon, South Korea
n Department of Neurology, Gachon University College of Medicine, Gil Medical CenterIncheon, South Korea
o Department of Neurology, School of Medicine, Jeonbuk National University Hospital, Jeonju, South Korea
p Department of Neurology, Inje University College of Medicine, Haeundae Paik HospitalBusan, South Korea
q Department of Neurology, Kyung Hee University College of Medicine, Kyung Hee University HospitalSeoul, South Korea
r Department of Neurology, Pusan National University Yangsan Hospital, Pusan National University School of Medicine and Medical Research InstituteBusan, South Korea
s Department of Neurology, Chungnam National University HospitalDaejeon, South Korea
t Departmet of Neurology, Chonnam National University School of MedicineGwangju, South Korea
u Department of Neurology, Gangnam Severance Hospital, Yonsei University College of MedicineSeoul, South Korea
v Department of Neurology, National Health Insurance Service Ilsan Hospital, Goyang, South Korea
w Department of Neurology, Myongji Hospital, Hanyang University, Goyang, South Korea
x Department of Psychiatry, Seoul National University HospitalSeoul, South Korea
y Department of Neurology, University of Ulsan College of Medicine, Asan Medical CenterSeoul, South Korea
z Department of Neurology, Soonchunhyang University Bucheon Hospital, Bucheon, South Korea
aa Department of Neurology, Gyeongsang National University School of Medicine and Gyeongsang National University Changwon Hospital, Changwon, South Korea
ab Department of Neurology, Ajou University School of Medicine, Suwon, South Korea
ac Department of Psychiatry, Ajou University School of Medicine, Suwon, South Korea
ad Eone-Diagnomics Genome Center (EDGC)Incheon, South Korea
ae Department of Health Sciences and Technology, SAIHST, Sungkyunkwan UniversitySeoul, South Korea
af Department of Intelligent Precision Healthcare Convergence, Sungkyunkwan UniversitySeoul, South Korea
ag Department of Psychiatry, Washington University School of Medicine, St Louis, MO, United States
ah NeuroGenomics and Informatics Center, Washington University School of Medicine, St Louis, MO, United States
ai Charles F. and Joanne Knight Alzheimer Disease Research Center, Washington University School of Medicine, St Louis, MO, United States
aj Samsung Genome Institute, Samsung Medical CenterSeoul, South Korea
Abstract
Importance: Polygenic risk scores (PRSs), which aggregate the genetic effects of single-nucleotide variants identified in genome-wide association studies (GWASs), can help distinguish individuals at a high genetic risk for Alzheimer disease (AD). However, genetic studies have predominantly focused on populations of European ancestry. Objective: To evaluate the transferability of a PRS for AD in the Korean population using summary statistics from a prior GWAS of European populations. Design, Setting, and Participants: This cohort study developed a PRS based on the summary statistics of a large-scale GWAS of a European population (the International Genomics of Alzheimer Project; 21 982 AD cases and 41 944 controls). This PRS was tested for an association with AD dementia and its related phenotypes in 1634 Korean individuals, who were recruited from 2013 to 2019. The association of a PRS based on a GWAS of a Japanese population (the National Center for Geriatrics and Gerontology; 3962 AD cases and 4074 controls) and a transancestry meta-analysis of European and Japanese GWASs was also evaluated. Data were analyzed from December 2020 to June 2021. Main Outcomes and Measures: Risk of AD dementia, amnestic mild cognitive impairment (aMCI), earlier symptom onset, and amyloid β deposition (Aβ). Results: A total of 1634 Korean patients (969 women [59.3%]), including 716 individuals (43.6%) with AD dementia, 222 (13.6%) with aMCI, and 699 (42.8%) cognitively unimpaired controls, were analyzed in this study. The mean (SD) age of the participants was 71.6 (9.0) years. Higher PRS was associated with a higher risk of AD dementia independent of APOE ɛ4 status in the Korean population (OR, 1.95; 95% CI, 1.40-2.72; P < .001). Furthermore, PRS was associated with aMCI, earlier symptom onset, and Aβ deposition independent of APOE ɛ4 status. The PRS based on a transancestry meta-analysis of data sets comprising 2 distinct ancestries showed a slightly improved accuracy. Conclusions and Relevance: In this cohort study, a PRS derived from a European GWAS identified individuals at a high risk for AD dementia in the Korean population. These findings emphasize the transancestry transferability and clinical value of PRSs and suggest the importance of enriching diversity in genetic studies of AD.
Document Type: Article
Publication Stage: Final
Source: Scopus
Defective proteostasis in induced pluripotent stem cell models of frontotemporal lobar degeneration
(2022) Translational Psychiatry, 12 (1), art. no. 508, .
Mahali, S.a , Martinez, R.a , King, M.b , Verbeck, A.a , Harari, O.a c , Benitez, B.A.a c , Horie, K.b , Sato, C.b , Temple, S.d , Karch, C.M.a c
a Department of Psychiatry, Washington University in St Louis, St Louis, MO, United States
b Department of Neurology, Washington University in St Louis, St Louis, MO, United States
c Hope Center for Neurological Disorders, Washington University in St Louis, St Louis, MO, United States
d Neural Stem Cell Institute, Rensselaer, NY, United States
Abstract
Impaired proteostasis is associated with normal aging and is accelerated in neurodegeneration. This impairment may lead to the accumulation of protein, which can be toxic to cells and tissue. In a subset of frontotemporal lobar degeneration with tau pathology (FTLD-tau) cases, pathogenic mutations in the microtubule-associated protein tau (MAPT) gene are sufficient to cause tau accumulation and neurodegeneration. However, the pathogenic events triggered by the expression of the mutant tau protein remain poorly understood. Here, we show that molecular networks associated with lysosomal biogenesis and autophagic function are disrupted in brains from FTLD-tau patients carrying a MAPT p.R406W mutation. We then used human induced pluripotent stem cell (iPSC)-derived neurons and 3D cerebral organoids from patients carrying the MAPT p.R406W mutation and CRISPR/Cas9, corrected controls to evaluate proteostasis. MAPT p.R406W was sufficient to induce morphological and functional deficits in the lysosomal pathway in iPSC-neurons. These phenotypes were reversed upon correction of the mutant allele with CRISPR/Cas9. Treatment with mTOR inhibitors led to tau degradation specifically in MAPT p.R406W neurons. Together, our findings suggest that MAPT p.R406W is sufficient to cause impaired lysosomal function, which may contribute to disease pathogenesis and serve as a cellular phenotype for drug screening. © 2022, The Author(s).
Funding details
National Institutes of HealthNIHAG005681, AG053303, AG056293, AG066444, NS110890, OD021629
Hope Center for Neurological Disorders
Office of Research Infrastructure Programs, National Institutes of HealthORIP, NIH
Document Type: Article
Publication Stage: Final
Source: Scopus
Mendelian randomization and genetic colocalization infer the effects of the multi-tissue proteome on 211 complex disease-related phenotypes
(2022) Genome Medicine, 14 (1), art. no. 140, .
Yang, C.a b c , Fagan, A.M.c d e , Perrin, R.J.c d e f , Rhinn, H.g , Harari, O.a b c e , Cruchaga, C.a b c e
a Department of Psychiatry, Washington University School of Medicine, 4444 Forest Park Ave., Box 8134, St. Louis, MO 63108, United States
b NeuroGenomics and Informatics Center, Washington University School of Medicine, St Louis, MO, United States
c Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO, United States
d Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States
e The Charles F. and Joanne Knight Alzheimer’s Disease Research Center, 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 Department of Bioinformatics, Alector, Inc., 151 Oyster Point Blvd. #300, South San Francisco, CA, United States
Abstract
Background: Human proteins are widely used as drug targets. Integration of large-scale protein-level genome-wide association studies (GWAS) and disease-related GWAS has thus connected genetic variation to disease mechanisms via protein. Previous proteome-by-phenome-wide Mendelian randomization (MR) studies have been mainly focused on plasma proteomes. Previous MR studies using the brain proteome only reported protein effects on a set of pre-selected tissue-specific diseases. No studies, however, have used high-throughput proteomics from multiple tissues to perform MR on hundreds of phenotypes. Methods: Here, we performed MR and colocalization analysis using multi-tissue (cerebrospinal fluid (CSF), plasma, and brain from pre- and post-meta-analysis of several disease-focus cohorts including Alzheimer disease (AD)) protein quantitative trait loci (pQTLs) as instrumental variables to infer protein effects on 211 phenotypes, covering seven broad categories: biological traits, blood traits, cancer types, neurological diseases, other diseases, personality traits, and other risk factors. We first implemented these analyses with cis pQTLs, as cis pQTLs are known for being less prone to horizontal pleiotropy. Next, we included both cis and trans conditionally independent pQTLs that passed the genome-wide significance threshold keeping only variants associated with fewer than five proteins to minimize pleiotropic effects. We compared the tissue-specific protein effects on phenotypes across different categories. Finally, we integrated the MR-prioritized proteins with the druggable genome to identify new potential targets. Results: In the MR and colocalization analysis including study-wide significant cis pQTLs as instrumental variables, we identified 33 CSF, 13 plasma, and five brain proteins to be putative causal for 37, 18, and eight phenotypes, respectively. After expanding the instrumental variables by including genome-wide significant cis and trans pQTLs, we identified a total of 58 CSF, 32 plasma, and nine brain proteins associated with 58, 44, and 16 phenotypes, respectively. For those protein-phenotype associations that were found in more than one tissue, the directions of the associations for 13 (87%) pairs were consistent across tissues. As we were unable to use methods correcting for horizontal pleiotropy given most of the proteins were only associated with one valid instrumental variable after clumping, we found that the observations of protein-phenotype associations were consistent with a causal role or horizontal pleiotropy. Between 66.7 and 86.3% of the disease-causing proteins overlapped with the druggable genome. Finally, between one and three proteins, depending on the tissue, were connected with at least one drug compound for one phenotype from both DrugBank and ChEMBL databases. Conclusions: Integrating multi-tissue pQTLs with MR and the druggable genome may open doors to pinpoint novel interventions for complex traits with no effective treatments, such as ovarian and lung cancers. © 2022, The Author(s).
Author Keywords
Complex human phenotypes; Genetic colocalization; Mendelian randomization; Multi-tissue proteomics; Protein quantitative trait loci
Funding details
National Institutes of HealthNIHP01AG026276, P01AG03991, P30AG066444, R01AG044546, RF1AG053303, RF1AG058501, U01AG058922
Alzheimer’s AssociationAAZEN-22-848604
Hope Center for Neurological Disorders
Document Type: Article
Publication Stage: Final
Source: Scopus
Distinctive chaperonopathy in skeletal muscle associated with the dominant variant in DNAJB4
(2022) Acta Neuropathologica, .
Inoue, M.a b c , Noguchi, S.a b , Inoue, Y.U.d , Iida, A.b , Ogawa, M.a , Bengoechea, R.c , Pittman, S.K.c , Hayashi, S.a b , Watanabe, K.e , Hosoi, Y.e , Sano, T.f , Takao, M.f , Oya, Y.g , Takahashi, Y.g , Miyajima, H.e , Weihl, C.C.c , Inoue, T.d , Nishino, I.a b
a Department of Neuromuscular Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, 4-1-1 Ogawahigashi, Tokyo, Kodaira, 187–8502, Japan
b Medical Genome Center, National Center of Neurology and Psychiatry, Tokyo, Japan
c Department of Neurology, Washington University School of Medicine, Saint Louis, United States
d Department of Biochemistry and Cellular Biology, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo, Japan
e First Department of Medicine/Department of Neurology, Hamamatsu University School of Medicine, Hamamatsu, Japan
f Department of Laboratory Medicine, National Center Hospital, National Center of Neurology and Psychiatry, Tokyo, Japan
g Department of Neurology, National Center Hospital, National Center of Neurology and Psychiatry, Tokyo, Japan
Abstract
DnaJ homolog, subfamily B, member 4, a member of the heat shock protein 40 chaperones encoded by DNAJB4, is highly expressed in myofibers. We identified a heterozygous c.270 T > A (p.F90L) variant in DNAJB4 in a family with a dominantly inherited distal myopathy, in which affected members have specific features on muscle pathology represented by the presence of cytoplasmic inclusions and the accumulation of desmin, p62, HSP70, and DNAJB4 predominantly in type 1 fibers. Both Dnajb4F90L knockin and knockout mice developed muscle weakness and recapitulated the patient muscle pathology in the soleus muscle, where DNAJB4 has the highest expression. These data indicate that the identified variant is causative, resulting in defective chaperone function and selective muscle degeneration in specific muscle fibers. This study demonstrates the importance of DNAJB4 in skeletal muscle proteostasis by identifying the associated chaperonopathy. © 2022, The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.
Funding details
National Institutes of HealthNIHK24AR073317, R01AR068797
Japan Agency for Medical Research and DevelopmentAMED22ek0109490h0003
Japan Society for the Promotion of ScienceKAKEN
National Center of Neurology and PsychiatryNCNP19K17021
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
Nucleus Accumbens D1 Receptor–Expressing Spiny Projection Neurons Control Food Motivation and Obesity
(2022) Biological Psychiatry, .
Matikainen-Ankney, B.A.a , Legaria, A.A.a c , Pan, Y.a , Vachez, Y.M.b , Murphy, C.A.b , Schaefer, R.F.a b , McGrath, Q.J.a , Wang, J.G.a c , Bluitt, M.N.a , Ankney, K.C.d , Norris, A.J.b , Creed, M.C.a b c , Kravitz, A.V.a b c
a Department of Psychiatry, Washington University in St. Louis, St. Louis, Missouri, United States
b Department of Anesthesiology, Washington University in St. Louis, St. Louis, Missouri, United States
c Department of Neuroscience, Washington University in St. Louis, St. Louis, Missouri, United States
d Department of Economics, Georgetown University, Washington, DC, United States
Abstract
Background: Obesity is a chronic relapsing disorder that is caused by an excess of caloric intake relative to energy expenditure. There is growing recognition that food motivation is altered in people with obesity. However, it remains unclear how brain circuits that control food motivation are altered in obese animals. Methods: Using a novel behavioral assay that quantifies work during food seeking, in vivo and ex vivo cell-specific recordings, and a synaptic blocking technique, we tested the hypothesis that activity of circuits promoting appetitive behavior in the core of the nucleus accumbens (NAc) is enhanced in the obese state, particularly during food seeking. Results: We first confirmed that mice made obese with ad libitum exposure to a high fat diet work harder than lean mice to obtain food, consistent with an increase in food motivation in obese mice. We observed greater activation of D1 receptor–expressing NAc spiny projection neurons (NAc D1SPNs) during food seeking in obese mice relative to lean mice. This enhanced activity was not observed in D2 receptor–expressing neurons (D2SPNs). Consistent with these in vivo findings, both intrinsic excitability and excitatory drive onto D1SPNs were enhanced in obese mice relative to lean mice, and these measures were selective for D1SPNs. Finally, blocking synaptic transmission from D1SPNs, but not D2SPNs, in the NAc core decreased physical work during food seeking and, critically, attenuated high fat diet–induced weight gain. Conclusions: These experiments demonstrate the necessity of NAc core D1SPNs in food motivation and the development of diet-induced obesity, establishing these neurons as a potential therapeutic target for preventing obesity. © 2022 Society of Biological Psychiatry
Author Keywords
Accumbens; Direct-pathway; Electrophysiology; Food seeking; Motivation; Obesity
Funding details
Howard Hughes Medical InstituteHHMI
National Institute on Drug AbuseNIDAR01-DA049924, R21-DA047127
National Institute of General Medical SciencesNIGMST32-GM108539
National Institute of Diabetes and Digestive and Kidney DiseasesNIDDKDK126355
Brain and Behavior Research FoundationBBRF27197, 27461
American Heart AssociationAHA
Diabetes Research Center, University of WashingtonDRC, UWDK020579
American AirlinesAA
Nutrition Obesity Research Center, University of North CarolinaNORCDK056341
Washington University School of Medicine in St. LouisWUSM
Document Type: Article
Publication Stage: Article in Press
Source: Scopus