WashU weekly Neuroscience publications: 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 Syndrome^u v , Dominantly Inherited Alzheimer Network^u 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

Multi-omics insights into the biological mechanisms underlying statistical gene-by-lifestyle interactions with smoking and alcohol consumption
(2022) Frontiers in Genetics, 13, art. no. 954713, . 

Majarian, T.D.^a , Bentley, A.R.^b , Laville, V.^c , Brown, M.R.^d , Chasman, D.I.^e , de Vries, P.S.^d , Feitosa, M.F.^f , Franceschini, N.^g , Gauderman, W.J.^h , Marchek, C.^a i , Levy, D.^j , Morrison, A.C.^d , Province, M.^f , Rao, D.C.^k , Schwander, K.^f k , Sung, Y.J.^k , Rotimi, C.N.^b , Aschard, H.^c l , Gu, C.C.^k , Manning, A.K.^a i m , on behalf of the CHARGE Gene-Lifestyle Interactions Working Groupⁿ

^a Program in Metabolism, Broad Institute of MIT and Harvard, Cambridge, MA, United States
^b Center for Research on Genomics and Global Health, National Human Genome Research Institute, US National Institutes of Health, BethesdaMD, United States
^c Department of Computational Biology, Institut Pasteur, Université Paris Cité, Paris, France
^d Human Genetics Center, Department of Epidemiology, Human Genetics, and Environmental Sciences, School of Public Health, The University of Texas Health Science Center at Houston, Houston, TX, United States
^e Division of Preventive Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, United States
^f Division of Statistical Genomics, Department of Genetics, Washington University School of Medicine, St. Louis, MO, United States
^g Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
^h Biostatistics, Department of Preventive Medicine, University of Southern California, Los Angeles, CA, United States
ⁱ Clinical and Translational Epidemiology Unit, Massachusetts General Hospital, Boston, MA, United States
^j The Population Sciences Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MA, United States
^k Division of Biostatistics, Washington University School of Medicine, St. Louis, MO, United States
^l Program in Genetic Epidemiology and Statistical Genetics, Harvard T.H. Chan School of Public Health, Boston, MA, United States
^m Department of Medicine and Harvard Medical School, Boston, MA, United States

Abstract
Though both genetic and lifestyle factors are known to influence cardiometabolic outcomes, less attention has been given to whether lifestyle exposures can alter the association between a genetic variant and these outcomes. The Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium’s Gene-Lifestyle Interactions Working Group has recently published investigations of genome-wide gene-environment interactions in large multi-ancestry meta-analyses with a focus on cigarette smoking and alcohol consumption as lifestyle factors and blood pressure and serum lipids as outcomes. Further description of the biological mechanisms underlying these statistical interactions would represent a significant advance in our understanding of gene-environment interactions, yet accessing and harmonizing individual-level genetic and ‘omics data is challenging. Here, we demonstrate the coordinated use of summary-level data for gene-lifestyle interaction associations on up to 600,000 individuals, differential methylation data, and gene expression data for the characterization and prioritization of loci for future follow-up analyses. Using this approach, we identify 48 genes for which there are multiple sources of functional support for the identified gene-lifestyle interaction. We also identified five genes for which differential expression was observed by the same lifestyle factor for which a gene-lifestyle interaction was found. For instance, in gene-lifestyle interaction analysis, the T allele of rs6490056 (ALDH2) was associated with higher systolic blood pressure, and a larger effect was observed in smokers compared to non-smokers. In gene expression studies, this allele is associated with decreased expression of ALDH2, which is part of a major oxidative pathway. Other results show increased expression of ALDH2 among smokers. Oxidative stress is known to contribute to worsening blood pressure. Together these data support the hypothesis that rs6490056 reduces expression of ALDH2, which raises oxidative stress, leading to an increase in blood pressure, with a stronger effect among smokers, in whom the burden of oxidative stress is greater. Other genes for which the aggregation of data types suggest a potential mechanism include: GCNT4×current smoking (HDL), PTPRZ1×ever-smoking (HDL), SYN2×current smoking (pulse pressure), and TMEM116×ever-smoking (mean arterial pressure). This work demonstrates the utility of careful curation of summary-level data from a variety of sources to prioritize gene-lifestyle interaction loci for follow-up analyses. Copyright © 2022 Majarian, Bentley, Laville, Brown, Chasman, de Vries, Feitosa, Franceschini, Gauderman, Marchek, Levy, Morrison, Province, Rao, Schwander, Sung, Rotimi, Aschard, Gu and Manning.

Author Keywords
alcohol;  blood pressure;  gene-lifestyle interactions;  multi-omics;  serum lipids;  smoking;  summary data

Funding details
National Institutes of HealthNIH
National Heart, Lung, and Blood InstituteNHLBI
National Human Genome Research InstituteNHGRI
National Institute of Diabetes and Digestive and Kidney DiseasesNIDDK
Center for Information TechnologyCIT
Office of the DirectorODZ01HG200362

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

Improving Early Recognition of Creutzfeldt-Jakob Disease Mimics
(2022) Neurology: Clinical Practice, 12 (6), pp. 406-413. 

Lazar, E.B.^a , Porter, A.L.^a , Prusinski, C.C.^a , Dunham, S.R.^b , Lopez-Chiriboga, A.S.^a , Hammami, M.B.^c , Dubey, D.^c , Day, G.S.^a

^a Department of Neurology, Mayo Clinic in Florida, Jacksonville, FL, United States
^b Department of Neurology, Washington University School of Medicine, Saint Louis, MO, United States
^c Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, United States

Abstract
Background and ObjectivesDiagnostic criteria emphasize the use of sensitive and disease-specific tests to distinguish patients with rapidly progressive dementia (RPD) due to Creutzfeldt-Jakob disease (CJD) vs other causes (mimics). These tests are often performed in specialized centers, with results taking days to return. There is a need to leverage clinical features and rapidly reporting tests to distinguish patients with RPD due to CJD from those due to other causes (mimics) early in the symptomatic course.MethodsIn this case-control series, clinical features and the results of diagnostic tests were compared between mimics (n = 11) and patients with definite (pathologically proven, n = 33) or probable CJD (with positive real-Time quaking-induced conversion [RT-QuIC], n = 60). Patients were assessed at Mayo Clinic Enterprise or Washington University from January 2014 to February 2021. Mimics were enrolled in prospective studies of RPD; mimics met the diagnostic criteria for probable CJD but did not have CJD.ResultsMimics were ultimately diagnosed with autoimmune encephalitis (n = 6), neurosarcoidosis, frontotemporal lobar degeneration with motor neuron disease, dural arteriovenous fistula, cerebral amyloid angiopathy with related inflammation, and systemic lupus erythematous with polypharmacy. Age at symptom onset, sex, presenting features, and MRI and EEG findings were similar in CJD cases and mimics. Focal motor abnormalities (49/93, 11/11), CSF leukocytosis (4/92, 5/11), and protein >45 mg/dL (39/92, 10/11) were more common in mimics (p < 0.01). Positive RT-QuIC (77/80, 0/9) and total tau >1149 pg/mL (74/82, 2/10) were more common in CJD cases (all p < 0.01). Protein 14-3-3 was elevated in 64/89 CJD cases and 4/10 mimics (p = 0.067). Neural-specific autoantibodies associated with autoimmune encephalitis were detected within the serum (5/9) and CSF (5/10) of mimics; nonspecific antibodies were detected within the serum of 9/71 CJD cases.DiscussionImmune-mediated, vascular, granulomatous, and neurodegenerative diseases may mimic CJD at presentation and should be considered in patients with early motor dysfunction and abnormal CSF studies. The detection of atypical features-particularly elevations in CSF leukocytes and protein-should prompt evaluation for mimics and consideration of empiric treatment while waiting for the results of more specific tests. © American Academy of Neurology.

Funding details
National Institutes of HealthNIH
National Institute on AgingNIAK23AG064029

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

Clinical and molecular characteristics of a novel rare de novo variant in PPP2CA in a patient with a developmental disorder, autism, and epilepsy
(2022) Frontiers in Cell and Developmental Biology, 10, art. no. 1059938, . 

Verbinnen, I.^a b , Procknow, S.S.^c , Lenaerts, L.^a , Reynhout, S.^a b , Mehregan, A.^d , Ulens, C.^d , Janssens, V.^a b , King, K.A.^c

^a Laboratory of Protein Phosphorylation and Proteomics, Department of Cellular and Molecular Medicine, University of Leuven (KU Leuven), Leuven, Belgium
^b KU Leuven Brain Institute (LBI), Leuven, Belgium
^c Division of Genetics and Genomic Medicine, Department of Pediatrics, Washington University in St. Louis, St. Louis, MO, United States
^d Laboratory of Structural Neurobiology, Department of Cellular and Molecular Medicine, University of Leuven (KU Leuven), Leuven, Belgium

Abstract
PP2A-related (neuro) developmental disorders are a family of genetic diseases caused by a heterozygous alteration in one of several genes encoding a subunit of type 2A protein phosphatases. Reported affected genes, so far, are PPP2R5D, encoding the PP2A regulatory B56δ subunit; PPP2R1A, encoding the scaffolding Aα subunit; and PPP2CA, encoding the catalytic Cα subunit—in that order of frequency. Patients with a pathogenic de novo mutation in one of these genes, in part, present with overlapping features, such as generalized hypotonia, intellectual and developmental delay, facial dysmorphologies, seizures, and autistic features, and, in part, with opposite features, e.g., smaller versus larger head sizes or normal versus absent corpus callosum. Molecular variant characterization has been consistent so far with loss-of-function or dominant-negative disease mechanisms for all three affected genes. Here, we present a case report of another PPP2CA-affected individual with a novel de novo missense variant, resulting in a one-amino acid substitution in the Cα subunit: p.Cys196Arg. Biochemical characterization of the variant revealed its pathogenicity, as it appeared severely catalytically impaired, showed mildly affected A subunit binding, and moderately decreased binding to B/B55, B”/PR72, and all B56 subunits, except B56γ1. Carboxy-terminal methylation appeared unaffected, as was binding to B”’/STRN3—all being consistent with a partial loss of function. Clinically, the girl presented with mild-to-moderate developmental delay, a full-scale IQ of 83, mild dysmorphic facial features, tonic–clonic seizures, and autistic behaviors. Brain MRI appeared normal. We conclude that this individual falls within the milder end of the clinical and molecular spectrum of previously reported PPP2CA cases. Copyright © 2022 Verbinnen, Procknow, Lenaerts, Reynhout, Mehregan, Ulens, Janssens and King.

Author Keywords
autism (ASD);  case report;  de novo mutation;  developmental delay;  epilepsy;  PP2A-related neurodevelopmental disorders;  PPP2CA

Funding details
National Institutes of HealthNIHT32 HL125241
Fonds Wetenschappelijk OnderzoekFWO
Vlaamse regering

Document Type: Article
Publication Stage: Final
Source: Scopus

Investigating Individual Variation Using Dynamic Structural Equation Modeling: A Tutorial With Tinnitus
(2022) Clinical Psychological Science, . 

Rodebaugh, T.L.^a , Piccirillo, M.L.^a , Frumkin, M.R.^a , Kallogjeri, D.^b , Gerull, K.M.^b , Piccirillo, J.F.^b

^a Department of Psychological and Brain Sciences, Washington University in St. Louis, United States
^b Department of Otolaryngology, Washington University School of Medicine in St. Louis, United States

Abstract
A growing body of research suggests that standard group-based models might provide little insight regarding individuals. In the current study, we sought to compare group-based and individual predictors of bothersome tinnitus, illustrating how researchers can use dynamic structural equation modeling (DSEM) for intensive longitudinal data to examine whether findings from analyses of the group apply to individuals. A total of 43 subjects with bothersome tinnitus responded to up to 200 surveys each. In multilevel DSEM, survey items loaded on three factors (tinnitus bother, cognitive symptoms, and anxiety), and results indicated a reciprocal relationship between tinnitus bother and anxiety. In fully idiographic models, the three-factor model fit poorly for two individuals, and the multilevel model did not generalize to most individuals, possibly because of limited power. Research examining heterogeneous conditions, such as tinnitus bother, may benefit from methods such as DSEM that allow researchers to model dynamic relationships. © The Author(s) 2022.

Author Keywords
idiographic models;  intensive longitudinal data;  multilevel analyses;  tinnitus

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

Dopamine D2/3 Receptor Availabilities in Striatal and Extrastriatal Regions of the Adult Human Brain: Comparison of Four Methods of Analysis
(2022) Neurochemical Research, . 

Khodaii, J.^a b , Nomura, Y.^c , Chang, N.H.S.^d , Wong, D.F.^e , Møller, A.^f g , Gjedde, A.^{d h i j k}

^a Department of Mechanical Engineering, Amirkabir University of Technology, Tehran, Iran
^b Aging Research Institute, Tabriz University of Medical Sciences, Tabriz, Iran
^c Department of Radiology, Faculty of Medicine, Mie University, 2-174 Edobashi, Mie, Tsu, 514-8507, Japan
^d Department of Clinical Research, University of Southern Denmark, Odense M, 5000, Denmark
^e Radiology, Psychiatry, Neurology and Neurosciences Washington University, St Louis, United States
^f Department of Nuclear Medicine and PET Center, Aarhus University Hospital, Aarhus, 8000, Denmark
^g Center of Functionally Integrative Neuroscience, Aarhus University, Aarhus, 8000, Denmark
^h Translational Neuropsychiatry Unit, Department of Clinical Medicine, Aarhus University, Aarhus C, 8000, Denmark
ⁱ Department of Neuroscience, Panum Institute, University of Copenhagen, 3 Blegdamsvej, Copenhagen N, DK-2200, Denmark
^j Department of Neurology and Neurosurgery, McGill University, Montreal, QC H3A 2B4, Canada
^k Neuroscience Center, Tabriz University of Medical Sciences, Tabriz, 5166/15731, Iran

Abstract
Values of binding potentials (BPND) of dopamine D2/3 receptors differ in different regions of the brain, but we do not know with certainty how much of this difference is due either to different receptor numbers, or to different affinities of tracers to the receptors, or to both. We tested the claim that both striatal and extrastriatal dopamine D2/3 receptor availabilities vary with age in vivo in humans by determining the values of BPND of the specific radioligand [11C]raclopride. We determined values of BPND in striatal and extrastriatal volumes-of-interest (VOI) with the same specific receptor radioligand. We estimated values of BPND in individual voxels of brains of healthy volunteers in vivo, and we obtained regional averages of VOI by dynamic positron emission tomography (PET). We calculated average values of BPND in caudate nucleus and putamen of striatum, and in frontal, occipital, parietal, and temporal cortices of the forebrain, by means of four methods, including the ERLiBiRD (Estimation of Reversible Ligand Binding and Receptor Density) method, the tissue reference methods of Logan and Logan-Ichise, respectively, and the SRTM (Simplified Reference Tissue Method). Voxelwise generation of parametric maps of values of BPND used the multi-linear regression version of SRTM. Age-dependent changes of the binding potential presented with an inverted U-shape with peak binding potentials reached between the ages of 20 and 30. The estimates of BPND declined significantly with age after the peak in both striatal and extrastriatal regions, as determined by all four methods, with the greatest decline observed in posterior (occipital and parietal) cortices (14% per decade) and the lowest decline in caudate nucleus (3% per decade). The sites of the greatest declines are of particular interest because of the clinical implications. © 2022, The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.

Author Keywords
Aging brain;  Dopamine;  Dopamine receptor density;  Dopaminergic neurotransmission;  Neuroreceptor;  Non-linear inverted-U regression;  Positron emission tomography;  Raclopride

Funding details
Danmarks Frie ForskningsfondDFF

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

Children’s Sleep and Externalizing Problems: A Day-to-day Multilevel Modeling Approach
(2022) Behavioral Sleep Medicine, . 

McQuillan, M.E.^a , Bates, J.E.^b , Hoyniak, C.P.^c , Staples, A.D.^d , Honaker, S.M.^a

^a Department of Pediatrics, Indiana University School of Medicine, United States
^b Department of Psychological and Brain Sciences, Indiana University, United States
^c Department of Psychiatry, Washington University in St. Louis School of Medicine, United States
^d Department of Psychology, Eastern Michigan University, Ypsilanti, MI, United States

Abstract
Background: Sleep problems and externalizing problems tend to be positively associated, but the direction of this association is unclear. Method: Day-to-day associations between sleep and behavior were examined in children (N = 22) ages 3–8 with clinical levels of externalizing problems. These children were enrolled in Parent Management Training and behavioral sleep intervention. During assessments before and after treatment, children wore actigraphs for seven days and parents concurrently completed sleep diaries and daily tallies of noncompliance, aggression, and tantrums. Multilevel modeling was used to account for the nested structure of the data, at the day-to-day level (level 1), within assessment points (level 2), and within children (level 3). Results: Late sleep timing and fragmentation were predictive of next-day noncompliance and tantrums, respectively. There were fewer associations for a given day’s behavior predicting that night’s sleep, although children who showed more aggression and noncompliance at baseline tended to have later bedtimes and sleep onset times compared to other children. © 2022 Taylor & Francis Group, LLC.

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

Dimethyl Fumarate Delays Multiple Sclerosis in Radiologically Isolated Syndrome
(2022) Annals of Neurology, . 

Okuda, D.T.^a , Kantarci, O.^b , Lebrun-Frénay, C.^c , Sormani, M.P.^d e , Azevedo, C.J.^f , Bovis, F.^d , Hua, L.H.^g , Amezcua, L.^f , Mowry, E.M.^h , Hotermans, C.ⁱ , Mendoza, J.^j , Walsh, J.S.^k , von Hehn, C.^l , Vargas, W.S.^m , Donlon, S.ⁿ , Naismith, R.T.^o , Okai, A.^p , Pardo, G.^q , Repovic, P.^r , Stüve, O.^a s , Siva, A.^t , Pelletier, D.^f

^a Department of Neurology, Neuroinnovation Program, Multiple Sclerosis & Neuroimmunology Imaging Program, The University of Texas Southwestern Medical Center, Dallas, TX, United States
^b Department of Neurology, Mayo Clinic, Rochester, MN, United States
^c Department of Neurology, Universitaire de Nice, Nice, France
^d Department of Health Sciences, University of Genoa, Genoa, Italy
^e Department of Health Sciences, IRCCS Ospedale Policlinico San Martino, Genoa, Italy
^f Department of Neurology, University of Southern California, Los Angeles, CA, United States
^g Department of Neurology, Cleveland Clinic Lou Ruvo Center for Brain Health, Las Vegas, NV, United States
^h Department of Neurology-Neuroimmunology and Neurological Infections, Johns Hopkins University, Baltimore, MD, United States
ⁱ Alexion, Astra Zeneca Rare Disease, Boston, MA, United States
^j Biogen Inc., Cambridge, MA, United States
^k Thirteen Consulting Group, Inc., Berlin, MA, United States
^l Takeda Pharmaceutical Company, Tokyo, Japan
^m Department of Neurology, Columbia University Medical Center, New York, NY, United States
ⁿ Department of Neuroimmunology, Multicare Auburn Medical Center, Tacoma, WA, United States
^o Department of Neurology, Washington University, St. Louis, MO, United States
^p Department of Neurology, Baylor University Medical Center, Dallas, TX, United States
^q Oklahoma Medical Research Foundation, Oklahoma City, OK, United States
^r Department of Neurology, Swedish Medical Center, Seattle, WA, United States
^s Neurology Section, Dallas Veterans Affairs Medical Center, Dallas, TX, United States
^t Department of Neurology, Cerrahpasa School of Medicine, Istanbul, Turkey

Abstract
Objective: The radiologically isolated syndrome (RIS) represents the earliest detectable pre-clinical phase of multiple sclerosis (MS). This study evaluated the impact of therapeutic intervention in preventing first symptom manifestation at this stage in the disease spectrum. Methods: We conducted a multi-center, randomized, double-blinded, placebo-controlled study involving people with RIS. Individuals without clinical symptoms typical of MS but with incidental brain MRI anomalies consistent with central nervous system (CNS) demyelination were included. Within 12 MS centers in the United States, participants were randomly assigned 1:1 to oral dimethyl fumarate (DMF) 240 mg twice daily or placebo. The primary endpoint was the time to onset of clinical symptoms attributable to a CNS demyelinating event within a follow-up period of 96 weeks. An intention-to-treat analysis was applied to all participating individuals in the primary and safety investigations. The study is registered at ClinicalTrials.gov, NCT02739542 (ARISE). Results: Participants from 12 centers were recruited from March 9, 2016, to October 31, 2019, with 44 people randomized to dimethyl fumarate and 43 to placebo. Following DMF treatment, the risk of a first clinical demyelinating event during the 96-week study period was highly reduced in the unadjusted Cox proportional-hazards regression model (hazard ratio [HR] = 0.18, 95% confidence interval [CI] = 0.05–0.63, p = 0.007). More moderate adverse reactions were present in the DMF (34 [32%]) than placebo groups (19 [21%]) but severe events were similar (DMF, 3 [5%]; placebo, 4 [9%]). Interpretation: This is the first randomized clinical trial demonstrating the benefit of a disease-modifying therapy in preventing a first acute clinical event in people with RIS. ANN NEUROL 2022. © 2022 American Neurological Association.

Funding details
Biogen

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

LATE-NC staging in routine neuropathologic diagnosis: an update
(2022) Acta Neuropathologica, . 

Nelson, P.T.^a , Lee, E.B.^b , Cykowski, M.D.^c , Alafuzoff, I.^d , Arfanakis, K.^e f , Attems, J.^g , Brayne, C.^h , Corrada, M.M.ⁱ , Dugger, B.N.^j , Flanagan, M.E.^k , Ghetti, B.^l , Grinberg, L.T.^m , Grossman, M.^b , Grothe, M.J.ⁿ , Halliday, G.M.^o , Hasegawa, M.^p , Hokkanen, S.R.K.^h , Hunter, S.^h , Jellinger, K.^q , Kawas, C.H.ⁱ , Keene, C.D.^r , Kouri, N.^s , Kovacs, G.G.^t u v w , Leverenz, J.B.^x , Latimer, C.S.^r , Mackenzie, I.R.^y , Mao, Q.^z , McAleese, K.E.^g , Merrick, R.^h , Montine, T.J.^aa , Murray, M.E.^s , Myllykangas, L.^ab , Nag, S.^e , Neltner, J.H.^a , Newell, K.L.^l , Rissman, R.A.^ac , Saito, Y.^ad , Sajjadi, S.A.ⁱ , Schwetye, K.E.^ae , Teich, A.F.^af , Thal, D.R.^ag ah , Tomé, S.O.^ag , Troncoso, J.C.^ai , Wang, S.-H.J.^aj , White, C.L., III^ak , Wisniewski, T.^al , Yang, H.-S.^am , Schneider, J.A.^e , Dickson, D.W.^s , Neumann, M.^an

^a University of Kentucky, Rm 575 Todd Building, Lexington, KY, United States
^b University of Pennsylvania, Philadelphia, PA, United States
^c Houston Methodist Hospital, Houston, TX, United States
^d Uppsala University, Uppsala, Sweden
^e Rush University Medical Center, Chicago, IL, United States
^f Illinois Institute of Technology, Chicago, IL, United States
^g Newcastle University, Newcastle Upon Tyne, United Kingdom
^h University of Cambridge, Cambridge, United Kingdom
ⁱ University of California, Irvine, CA, United States
^j University of California, Davis, CA, United States
^k Northwestern University Medical Center, Chicago, IL, United States
^l Indiana University, Indianapolis, IN, United States
^m University of California, San Francisco, CA, United States
ⁿ Unidad de Trastornos del Movimiento, Servicio de Neurología Y Neurofisiología Clínica, Instituto de Biomedicina de Sevilla, Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, Seville, Spain
^o University of Sydney, Sydney, NSW, Australia
^p Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan
^q Institute of Clinical Neurobiology, Vienna, Austria
^r University of Washington, Seattle, WA, United States
^s Mayo Clinic, Jacksonville, FL, United States
^t Tanz Centre for Research in Neurodegenerative Disease, University of Toronto, Toronto, Canada
^u Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Canada
^v Laboratory Medicine Program, University Health Network, Toronto, Canada
^w Institute of Neurology, Medical University of Vienna, Vienna, Austria
^x The Cleveland Clinic, Cleveland, OH, United States
^y The University of British Columbia, Vancouver, BC, Canada
^z University of Utah, Salt Lake City, UT, United States
^aa Stanford University, Stanford, CA, United States
^ab University of Helsinki and Helsinki University Hospital, Helsinki, Finland
^ac University of California San Diego, San Diego, CA, United States
^ad Tokyo Metropolitan Geriatric Hospital & Institute of Gerontology, Tokyo, Japan
^ae Washington University, St. Louis, MO, United States
^af Columbia University, New York, NY, United States
^ag Laboratory for Neuropathology, Department of Imaging and Pathoogy, and Leuven Brain Institute, KU Leuven, Leuven, Belgium
^ah Department of Pathology, University Hospital Leuven, Leuven, Belgium
^ai Johns Hopkins University, Baltimore, MD, United States
^aj Duke University, Durham, NC, United States
^ak University of Texas Southwestern Medical Center, Dallas, TX, United States
^al New York University Grossman School of Medicine, New York, NY, United States
^am Department of Neurology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MAMA, United States
^an University of Tübingen and DZNE Tübingen, Tübingen, Germany

Abstract
An international consensus report in 2019 recommended a classification system for limbic-predominant age-related TDP-43 encephalopathy neuropathologic changes (LATE-NC). The suggested neuropathologic staging system and nomenclature have proven useful for autopsy practice and dementia research. However, some issues remain unresolved, such as cases with unusual features that do not fit with current diagnostic categories. The goal of this report is to update the neuropathologic criteria for the diagnosis and staging of LATE-NC, based primarily on published data. We provide practical suggestions about how to integrate available genetic information and comorbid pathologies [e.g., Alzheimer’s disease neuropathologic changes (ADNC) and Lewy body disease]. We also describe recent research findings that have enabled more precise guidance on how to differentiate LATE-NC from other subtypes of TDP-43 pathology [e.g., frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS)], and how to render diagnoses in unusual situations in which TDP-43 pathology does not follow the staging scheme proposed in 2019. Specific recommendations are also made on when not to apply this diagnostic term based on current knowledge. Neuroanatomical regions of interest in LATE-NC are described in detail and the implications for TDP-43 immunohistochemical results are specified more precisely. We also highlight questions that remain unresolved and areas needing additional study. In summary, the current work lays out a number of recommendations to improve the precision of LATE-NC staging based on published reports and diagnostic experience. © 2022, The Author(s).

Author Keywords
Aging;  Dementia;  FTD;  Hippocampal sclerosis;  NCI;  Neuroanatomy;  Processes;  Stages;  TDP-43

Funding details
AS-JF-18-01, JP22wm0425019
2020/017
California Department of Public HealthCDPH19-10611, K23 AG062750
BrightFocus FoundationBFFA2022019F, CP19/00031, PI20/00613
Alzheimer’s Disease Research Center, Emory UniversityADRCK24 AG053435, P01 AG066597, P30 AG 066507, P30 AG010161/P30 AG072975, P30 AG072946, P30 AG072959, P30 AG072972, P30 AG072979, R01 AG022018, R01 AG052132, R01 AG054449, R01 AG056519, R01 AG057187, R01 AG061111, R01 AG062517, R01 AG062706, R01 AG064233, R01 AG067482, R01 AG075802, RF1 AG069052, RF1 NS118584, U01 AG061357, U19 AG033655, U19 AG062418, U19 AG069701
Nancy and Buster Alvord Endowment
Alzheimer Forschung InitiativeAFI13803, 21004
Medical Research CouncilMRC900108, G0900582, MRC/G9901400, U.1052.00.0013
Alzheimer’s SocietyAS-PG-2019b-024
Academy of FinlandAKA341007, TYH2020231, TYH2022316
Fonds Wetenschappelijk OnderzoekFWOG065721N, G0F8516N
Edmond J. Safra Philanthropic Foundation
KU LeuvenC14/17/107, C14/22/132, C3/20/057, PDMT2/21/069
NOMIS Stiftung
NIHR Cambridge Biomedical Research CentreUK ARUK-PhD2014-19
Rossy FoundationRF

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

Family income buffers the relationship between childhood adverse experiences and putamen volume
(2022) Developmental Neurobiology, . 

Herzberg, M.P.^a , Hennefield, L.^a , Luking, K.R.^b , Sanders, A.F.P.^a , Vogel, A.C.^a , Kandala, S.^a , Tillman, R.^a , Luby, J.^a , Barch, D.M.^a b c

^a Department of Psychiatry, Washington University in St. Louis, St. Louis, MO, United States
^b Department of Psychological & Brain Sciences, Washington University in St. Louis, St. Louis, MO, United States
^c Department of Radiology, Washington University in St. Louis, St. Louis, MO, United States

Abstract
Adverse experiences and family income in childhood have been associated with altered brain development. While there is a large body of research examining these associations, it has primarily used cross-sectional data sources and studied adverse experiences and family income in isolation. However, it is possible that low family income and adverse experiences represent dissociable and potentially interacting profiles of risk. To address this gap in the literature, we examined brain structure as a function of adverse experiences in childhood and family income in 158 youths with up to five waves of MRI data. Specifically, we assessed the interactive effect of these two risk factors on six regions of interest: hippocampus, putamen, amygdala, nucleus accumbens, caudate, and thalamus. Adverse experiences and family income interacted to predict putamen volume (B = 0.086, p = 0.011) but only in participants with family income one standard deviation below the mean (slope estimate = −0.11, p = 0.03). These results suggest that adverse experiences in childhood result in distinct patterns of brain development across the socioeconomic gradient. Given previous findings implicating the role of the putamen in psychopathology-related behaviors, these results emphasize the importance of considering life events and socioeconomic context when evaluating markers of risk. Future research should include interactive effects of environmental exposures and family income to better characterize risk for psychopathology in diverse samples. © 2022 Wiley Periodicals LLC.

Author Keywords
adverse experiences;  brain structure;  early childhood;  poverty;  psychopathology

Funding details
National Institute of Mental HealthNIMHR01 MH064769, R01 MH090786, T32 MH100019

Document Type: Article
Publication Stage: Article in Press
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

An ECM-Mimicking, Injectable, Viscoelastic Hydrogel for Treatment of Brain Lesions
(2022) Advanced Healthcare Materials, . 

Hu, Y.^a b , Jia, Y.^a b , Wang, S.^c , Ma, Y.^a b , Huang, G.^d , Ding, T.^e , Feng, D.^f , Genin, G.M.^{a b f g h i} , Wei, Z.^a b , Xu, F.^a b

^a The Key Laboratory of Biomedical Information Engineering of Ministry of Education, Xi’an Jiaotong University, Xi’an, 710049, China
^b Bioinspired Engineering and Biomechanics Center (BEBC), Xi’an Jiaotong University, Xi’an, 710049, China
^c School of Safety Science and Engineering, Xi’an University of Science and Technology, Xi’an, 710054, China
^d Department of Engineering Mechanics, School of Civil Engineering, Wuhan University, Wuhan, 430072, China
^e Xijing Orthopaedics Hospital, Fourth Military Medical University, Xi’an, 710032, China
^f Department of Neurosurgery, Tangdu Hospital, The Fourth Military Medical University, Xi’an, 710038, China
^g Department of Mechanical Engineering & Materials Science, Washington University in St. Louis, St. Louis, MO 63130, United States
^h NSF Science and Technology Center for Engineering Mechanobiology, Washington University in St. Louis, St. Louis, MO 63130, United States
ⁱ Department of Neurological Surgery, Washington University School of Medicine, St. Louis, MO 63130, United States

Abstract
Brain lesions can arise from traumatic brain injury, infection, and craniotomy. Although injectable hydrogels show promise for promoting healing of lesions and health of surrounding tissue, enabling cellular ingrowth and restoring neural tissue continue to be challenging. It is hypothesized that these challenges arise in part from the mismatch of composition, stiffness, and viscoelasticity between the hydrogel and the brain parenchyma, and this hypothesis is tested by developing and evaluating a self-healing hydrogel that not only mimics the composition, but also the stiffness and viscoelasticity of native brain parenchyma. The hydrogel is crosslinked by dynamic boronate ester bonds between phenylboronic acid grafted hyaluronic acid (HA-PBA) and dopamine grafted gelatin (Gel-Dopa). This HA-PBA/Gel-Dopa hydrogel could be injected into a lesion cavity in a shear-thinning manner with rapid hemostasis, high tissue adhesion, and efficient self-healing. In an in vivo mouse model of brain lesions, the multi-functional injectable hydrogel is found to support neural cell infiltration, decrease astrogliosis and glial scars, and close the lesions. The results suggest a role for extracellular matrix-mimicking viscoelasticity in brain lesion healing, and motivate additional experimentation in larger animals as the technology progresses toward potential application in humans. © 2022 Wiley-VCH GmbH.

Author Keywords
injectable hydrogels;  mechanical microenvironments;  neural regeneration;  viscoelasticity

Funding details
2020LHM‐KFKT005
National Natural Science Foundation of ChinaNSFC11972280, 12002263
Xi’an Jiaotong UniversityXJTU
Fundamental Research Funds for the Central Universitiesxzd012021037, xzy012020079

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

Sport-related Structural Brain Injury in High School and College American Football Athletes, 2002-2020: Effect of Lystedt Law
(2022) Sports Health, . 

Boden, B.P.^a , Brown, I.D.J.^b , Huckleby, J.M.^c , Ahmed, A.E.^d , Anderson, S.A.^e

^a The Orthopedic Center, a division of CAO, Rockville, MD, United States
^b The University of Chicago Pritzer School of Medicine, Chicago, IL, United States
^c Department of Orthopedic Surgery, Washington University in St. Louis, St. Louis, MO, United States
^d Henry M. Jackson Foundation for the Advancement of Military Medicine, Bethesda, MD, United States
^e Department of Intercollegiate Athletics, University of Oklahoma, Norman, OK, Canada

Abstract
Background: A previous report revealed an average of 7.2 (0.67 per 100,000 participants) sport-related structural brain injuries (SRSBIs) with macroscopic lesions per year in high school (HS) and college football players. The Lystedt law and other rule changes have been implemented with intent to reduce the risk of brain injury in football. Hypothesis: To update the profile of SRSBIs in HS and college football players and evaluate the efficacy of legislation intended to reduce brain injuries. Study Design: Descriptive epidemiology study. Level of Evidence: Level 4. Methods: We retrospectively reviewed 18 academic years (July 2002 through June 2020) of SRSBIs catalogued by the National Registry of Catastrophic Sports Injuries. The incidence of SRSBIs was assessed at the HS level during the pre (July 2002 through June 2009), transitional (July 2009 through June 2014), and post (July 2014 through June 2020) universal adoption time periods of the Lystedt law. In addition, the incidence of SRSBIs during the second half of the study (2011-2012 through 2019-2020) was compared with the first half of the study (2002-2003 through 2010-2011). Results: During the study period, there was a total of 228 SRSBIs (12.7 per year, 1.01 per 100,000 participants): 212 (93%, 11.8 per year, 1.00 per 100,000) in HS athletes and 16 (7%, 0.89 per year, 1.17 per 100,000) in college athletes. There were 52 fatalities (2.9 per year, 0.22 per 100,000 participants) with 46 (2.56 per year, 0.22 per 100,000) in HS athletes and 6 (0.33 per year, 0.43/100,000) in college athletes. There was no significant difference in risk of HS total SRSBIs or fatalities during the 3 Lystedt periods. The risk of combined SRSBI cases [relative risk (RR) = 1.22, P = 0.13] and fatalities (RR = 1.20, P = 0.52) was similar in the second half of the study compared with the first half of the study. Conclusion: Despite implementation of rule changes intended to reduce head injury, in particular the Lystedt law, the incidence of SRSBIs has remained unchanged. Further research is necessary to develop effective prevention programs for SRSBIs. Clinical Relevance: SRSBIs remain a persistent problem in HS and college American football. The recent head injury rule changes have not been effective at reducing SRSBIs. © 2022 The Author(s).

Author Keywords
fatalities;  football;  subdural hematoma;  traumatic brain injury

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

Recombinant Human Perlecan DV and Its LG3 Subdomain Are Neuroprotective and Acutely Functionally Restorative in Severe Experimental Ischemic Stroke
(2022) Translational Stroke Research, . 

Biose, I.J.^a , Rutkai, I.^a b , Clossen, B.^c , Gage, G.^c , Schechtman, K.^d , Adkisson, H.D., IV^c , Bix, G.J.^a b e

^a Department of Neurosurgery, Clinical Neuroscience Research Center, Tulane University School of Medicine, New Orleans, LA 70112, United States
^b Tulane Brain Institute, Tulane University, New Orleans, LA 70112, United States
^c Stream Biomedical, Inc., 2450 Holcombe, Suite J, Houston, TX 77021, United States
^d Division of Biostatistics, Washington University School of Medicine, St. Louis, MO 63110, United States
^e Department of Neurology, Tulane University School of Medicine, New Orleans, LA 70112, United States

Abstract
Despite recent therapeutic advancements, ischemic stroke remains a major cause of death and disability. It has been previously demonstrated that ~ 85-kDa recombinant human perlecan domain V (rhPDV) binds to upregulated integrin receptors (α2β1 and α5β1) associated with neuroprotective and functional improvements in various animal models of acute ischemic stroke. Recombinant human perlecan laminin-like globular domain 3 (rhPDVLG3), a 21-kDa C-terminal subdomain of rhPDV, has been demonstrated to more avidly bind to the α2β1 integrin receptor than its parent molecule and consequently was postulated to evoke significant neuroprotective and functional effects. To test this hypothesis, fifty male C57Bl/6 J mice studied in a t-MCAO model were randomly allocated to either rhPDV treatment, rhPDVLG3, or equivalent volume of PBS at the time of reperfusion in a study where all procedures and analyses were conducted blind to treatment. On post-MCAO day 7, 2,3,5-triphenyltetrazolium chloride staining of brain slices was used to quantify infarct volume. We observed that treatment with rhPDVLG3 reduced infarct volume by 65.6% (p = 0.0001), improved weight loss (p &lt; 0.05), and improved functional outcome measures (p &lt; 0.05) when compared to PBS controls, improvements which were generally greater in magnitude than those observed for 2 mg/kg of rhPDV. In addition, treatment with 6 mg/kg of rhPDVLG3 was observed to significantly reduce mortality due to stroke in one model, an outcome not previously observed for rhPDV. Our initial findings suggest that treatment with rhPDVLG3 provides significant improvement in neuroprotective and functional outcomes in experimental stroke models and that further investigation of rhPDVLG3 as a novel neuroprotective therapy for patients with stroke is warranted. © 2022, The Author(s).

Author Keywords
Basement membrane;  LG3;  Neuroprotection and acute ischemic stroke;  Perlecan;  Perlecan domain V

Funding details
R44 NS107152-02

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