List of publications for the week of June 28, 2021
GPS driving: a digital biomarker for preclinical Alzheimer disease
(2021) Alzheimer’s Research and Therapy, 13 (1), art. no. 115, .
Bayat, S.a b , Babulal, G.M.c d e , Schindler, S.E.c d , Fagan, A.M.c d f , Morris, J.C.c d f g h i , Mihailidis, A.a b j , Roe, C.M.c d
a Institute of Biomedical Engineering, University of Toronto, 550 University Avenue, Toronto, ON M5G 1X5, Canada
b KITE Research Institute, Toronto Rehabilitation Institute, Toronto, ON, Canada
c Charles F. and Joanne Knight Alzheimer Disease Research Center, 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 Department of Psychology, University of Johannesburg, Johannesburg, South Africa
f Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO, United States
g Department of Pathology & Immunology, Washington University School of Medicine, St. Louis, MO, United States
h Department of Physical Therapy, Washington University School of Medicine, St. Louis, MO, United States
i Department of Occupational Science & Occupational Therapy, Washington University School of Medicine, St. Louis, MO, United States
j Department of Occupational Science and Occupational Therapy, University of Toronto, Toronto, ON, Canada
Abstract
Background: Alzheimer disease (AD) is the most common cause of dementia. Preclinical AD is the period during which early AD brain changes are present but cognitive symptoms have not yet manifest. The presence of AD brain changes can be ascertained by molecular biomarkers obtained via imaging and lumbar puncture. However, the use of these methods is limited by cost, acceptability, and availability. The preclinical stage of AD may have a subtle functional signature, which can impact complex behaviours such as driving. The objective of the present study was to evaluate the ability of in-vehicle GPS data loggers to distinguish cognitively normal older drivers with preclinical AD from those without preclinical AD using machine learning methods. Methods: We followed naturalistic driving in cognitively normal older drivers for 1 year with a commercial in-vehicle GPS data logger. The cohort included n = 64 individuals with and n = 75 without preclinical AD, as determined by cerebrospinal fluid biomarkers. Four Random Forest (RF) models were trained to detect preclinical AD. RF Gini index was used to identify the strongest predictors of preclinical AD. Results: The F1 score of the RF models for identifying preclinical AD was 0.85 using APOE ε4 status and age only, 0.82 using GPS-based driving indicators only, 0.88 using age and driving indicators, and 0.91 using age, APOE ε4 status, and driving. The area under the receiver operating curve for the final model was 0.96. Conclusion: The findings suggest that GPS driving may serve as an effective and accurate digital biomarker for identifying preclinical AD among older adults. © 2021, The Author(s).
Author Keywords
Global positioning system; Machine learning; Naturalistic driving; Preclinical Alzheimer disease
Funding details
National Institutes of HealthNIHP01AG003991, P01AG026276, P30AG066444, U19AG024904, U19AG032438
National Institute on AgingNIAAG056466, R01AG067428, R01AG068183
Biogen
BrightFocus FoundationBFFA2021142S
Document Type: Article
Publication Stage: Final
Source: Scopus
Activated microglia mitigate Aβ-associated tau seeding and spreading
(2021) The Journal of Experimental Medicine, 218 (8), .
Gratuze, M.a b c , Chen, Y.a b c d , Parhizkar, S.a b c , Jain, N.a b c , Strickland, M.R.a b c , Serrano, J.R.a b c , Colonna, M.b c d , Ulrich, J.D.a b c , Holtzman, D.M.a b c
a Department of Neurology, Washington University School of Medicine, St. Louis, MO
b Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO
c Knight Alzheimer’s Disease Research Center, Washington University School of Medicine, St. Louis, MO
d Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO
Abstract
In Alzheimer’s disease (AD) models, AD risk variants in the microglial-expressed TREM2 gene decrease Aβ plaque-associated microgliosis and increase neuritic dystrophy as well as plaque-associated seeding and spreading of tau aggregates. Whether this Aβ-enhanced tau seeding/spreading is due to loss of microglial function or a toxic gain of function in TREM2-deficient microglia is unclear. Depletion of microglia in mice with established brain amyloid has no effect on amyloid but results in less spine and neuronal loss. Microglial repopulation in aged mice improved cognitive and neuronal deficits. In the context of AD pathology, we asked whether microglial removal and repopulation decreased Aβ-driven tau seeding and spreading. We show that both TREM2KO and microglial ablation dramatically enhance tau seeding and spreading around plaques. Interestingly, although repopulated microglia clustered around plaques, they had a reduction in disease-associated microglia (DAM) gene expression and elevated tau seeding/spreading. Together, these data suggest that TREM2-dependent activation of the DAM phenotype is essential in delaying Aβ-induced pathological tau propagation. © 2021 Gratuze et al.
Document Type: Article
Publication Stage: Final
Source: Scopus
Executive Function Moderates Functional Outcomes of Engagement Strategies During Rehabilitation in Older Adults
(2021) American Journal of Physical Medicine & Rehabilitation, 100 (7), pp. 635-642.
Ercal, B., Rodebaugh, T.L., Bland, M.D., Barco, P., Lenard, E., Lang, C.E., Miller, J.P., Yingling, M., Lenze, E.J.
From the Healthy Mind Lab, Department of Psychiatry, Washington University School of Medicine in St. Louis (BE, EL, MY, EJL); Department of Psychological and Brain Sciences, Washington University in St. Louis (TLR); and Program in Physical Therapy (MDB, CEL), Program in Occupational Therapy (PB), and Division of Biostatistics (JPM), Washington University School of Medicine in St. Louis, Missouri
Abstract
OBJECTIVE: This study examined cognitive, affective, and medical impairments and their impact on rehabilitation approaches for improving functional outcome after hospitalization in older adults. DESIGN: A secondary analysis of a randomized clinical trial in 229 adults 65 yrs or older admitted to two skilled nursing facilities undergoing rehabilitation services was conducted. Patients were randomized to receive physical and occupational therapy by therapists trained in systematic approaches to engage patients, called Enhanced Medical Rehabilitation, or standard of care. The outcome of interest was functional improvement, defined as Barthel Index at discharge (controlling for Barthel Index upon admission). This study analyzed the relationship of measures of cognition, depression, and medical comorbidities as predictors of functional outcome and as moderators interacting with treatment group. RESULTS: Clock drawing score moderated treatment effect size; the functional improvement of Enhanced Medical Rehabilitation over standard of care therapy reduced with increasing executive impairment. In contrast, general cognitive abilities, depression, medical comorbidities, and readiness for rehabilitation were neither predictors nor moderators of functional improvement. CONCLUSIONS: For older adults undergoing rehabilitation, greater functional improvement with the motivational techniques of Enhanced Medical Rehabilitation was contingent on patients having intact executive function. Given that executive function impairments are common in rehabilitation populations, new strategies are needed to improve treatment outcomes in physical/occupational therapy. TO CLAIM CME CREDITS: Complete the self-assessment activity and evaluation online at http://www.physiatry.org/JournalCME. CME OBJECTIVES: Upon completion of this article, the reader should be able to (1) Discuss the role of baseline affective, cognitive, and medical impairments in impacting functional outcomes of older adults undergoing rehabilitation; (2) Describe the behavioral change and motivational approaches that are core features of the novel intervention known as Enhanced Medical Rehabilitation (E-MR); and (3) Determine the role of baseline executive function in moderating the effect of rehabilitation intervention on functional outcomes in older adults.Advanced. ACCREDITATION: The Association of Academic Physiatrists is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.The Association of Academic Physiatrists designates this Journal-based CME activity for a maximum of 1.0 AMA PRA Category 1 Credit(s)™. Physicians should only claim credit commensurate with the extent of their participation in the activity. Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.
Document Type: Article
Publication Stage: Final
Source: Scopus
Relationships Between Viral Load, Neuroimaging, and NP in Persons Living With HIV
(2021) Journal of Acquired Immune Deficiency Syndromes (1999), 87 (3), pp. 985-992.
Cooley, S.A.a , Navid, J.a , Wisch, J.K.a , Boerwinkle, A.a , Doyle, J.a , Paul, R.H.b , Ances, B.M.a c d
a Department of Neurology, Washington University in Saint Louis, MO, Saint Louis, Seychelles
b Department of Psychology, University of Missouri, MO, Saint Louis, Seychelles
c Department of Radiology, Washington University in Saint Louis, Saint Louis, MO; and
d Hope Center for Neurological Disorders, Washington University in Saint Louis, MO, Saint Louis, Seychelles
Abstract
BACKGROUND: This study examined whether recommended viral load (VL) classifications by the Department of Health and Human Services map onto changes in brain integrity observed in people living with HIV (PLWH). METHODS: Three hundred forty-nine PLWH on combination antiretroviral therapy meeting criteria for virologic suppression (VS) (VL ≤ 20 copies/mL; n = 206), “low-level viremia” (20-200 copies/mL; n = 63), or virologic failure (VF) (>200 copies/mL; n = 80) and 195 demographically similar HIV-negative controls were compared for cognition and brain volumes from 10 regions of interest that are sensitive to HIV. Changes in cognition and brain volumes were examined in a subset of PLWH (n = 132) who completed a follow-up evaluation (mean interval = 28 months) and had no change in treatment regimen. RESULTS: Significant differences in cognition and brain volumes were observed between the HIV-negative control and VS groups compared with those in the VF groups, with few differences observed between the 3 PLWH subgroups. Longitudinally, PLWH who continued to have VF exhibited a greater decline in cognition and brain volumes compared with PLWH who remained with VS. Observed longitudinal changes in cognition correlated with brain volume changes. CONCLUSION: PLWH with continued VF (consecutive VL measurements of >200 copies/mL) represent a cause for clinical concern and may benefit from change in treatment in addition to consideration of other potential etiologies of VF to reduce loss of brain integrity. Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.
Document Type: Article
Publication Stage: Final
Source: Scopus
Depression and anxiety in a manganese-exposed community
(2021) NeuroToxicology, 85, pp. 222-233.
Racette, B.A.a b , Nelson, G.b , Dlamini, W.W.a , Hershey, T.c , Prathibha, P.d , Turner, J.R.d , Checkoway, H.e , Sheppard, L.f , Searles Nielsen, S.a
a Department of Neurology, Washington University School of Medicine, 660 South Euclid Avenue, Campus Box 8111, St. Louis, MO 63110, United States
b School of Public Health, Faculty of Health Sciences, University of the Witwatersrand, 7 York Road, Parktown, 2193, South Africa
c Departments of Psychiatry and Radiology, Washington University School of Medicine, 660 South Euclid Avenue, Campus Box 8225, St. Louis, MO 63110, United States
d Department of Energy, Environmental, and Chemical Engineering, Washington University, Campus Box 1180, One Brookings Drive, St. Louis, MO 63130, United States
e Herbert Wertheim School of Public Health, University of California, San Diego, 9500 Gilman Drive, #0725, La Jolla, CA 92093, United States
f Departments of Biostatistics and Environmental and Occupational Health Sciences, University of Washington, Box 357232, Seattle, WA 98195, United States
Abstract
Objective: To characterize the association between residential environmental manganese (Mn) exposure and depression and anxiety, given prior associations among occupationally-exposed workers. Methods: We administered the Beck Depression Inventory (BDI) and the State-Trait Anxiety Inventory (STAI) to 697 study participants in their preferred languages. These participants represented a population-based sample of residents aged ≥40 from two predominantly Black African communities in Gauteng province, South Africa: 605 in Meyerton, adjacent to a large Mn smelter, and 92 in Ethembalethu, a comparable non-exposed community. We investigated the associations between community (Meyerton vs. Ethembalethu) and severity of depression and anxiety, using linear regression, adjusting for age and sex. To document community-level differences in Mn exposure, we measured airborne PM2.5-Mn. Results: Meyerton residents had BDI scores 5.63 points (95 % CI 3.07, 8.20) higher than Ethembalethu residents, with all questions contributing to this significant difference. STAI-state scores were marginally higher in Meyerton than Ethembalethu residents [2.12 (95 % CI -0.17, 4.41)], whereas STAI-trait scores were more similar between the communities [1.26 (95 % CI -0.82, 3.35)]. Mean PM2.5-Mn concentration was 203 ng/m3 at a long-term fixed site in Meyerton and 10 ng/m3 in Ethembalethu. Conclusion: Residence near Mn emission sources may be associated with greater depression symptomatology, and possibly current, but not lifetime, anxiety. © 2021 Elsevier B.V.
Author Keywords
Beck depression inventory; Manganese; PM2.5-Mn; South Africa; State-trait anxiety inventory
Funding details
National Institutes of HealthNIHDK064832, HD070855, NS098577, NS109487, P42ES023716, R01ES029846, R01HD098255
U.S. Department of DefenseDODPD190057
National Institute on AgingNIAP01AG055367, R01ES026187
National Institute of Environmental Health SciencesNIEHSK01ES028295, R01ES025991-02S1, R01ES026246, R01ES026891, R01ES027696, R01ES029509, R01ES029524, R01ES030937-S1, R25ES025503
National Institute for Occupational Safety and HealthNIOSHR01OH011661
U.S. Department of TransportationDOTDTFH6117C00036
Health Effects InstituteHEI
Federal Highway AdministrationFHWA
UNICEFGLA/2880/2019/002-PCA
Harvard University
University of MichiganU-M
Cure Alzheimer’s FundCAF
Hope Center for Neurological Disorders
National Institute of Occupational Safety and Health, JapanJNIOSH
Document Type: Article
Publication Stage: Final
Source: Scopus
Re-evaluating Biopsy for Recurrent Glioblastoma: A Position Statement by the Christopher Davidson Forum Investigators
(2021) Neurosurgery, 89 (1), pp. 129-132.
Nduom, E.K.a , Gephart, M.H.b , Chheda, M.G.c , Suva, M.L.d , Amankulor, N.e , Battiste, J.D.f , Campian, J.L.g , Dacey, R.G.h , Das, S.i , Fecci, P.E.j , Hadjipanayis, C.G.k , Hoang, K.B.a , Jalali, A.l , Orringer, D.m , Patel, A.J.l , Placantonakis, D.m , Rodriguez, A.n , Yang, I.o , Yu, J.S.p , Zipfel, G.J.h , Dunn, G.P.h , Leuthardt, E.C.h , Kim, A.H.h
a Department of Neurological Surgery, Emory University School of Medicine, Atlanta, GA, United States
b Department of Neurological Surgery, Stanford University School of Medicine, Palo Alto, CA, United States
c Departments of Medicine and Neurology, Washington University School of Medicine, St Louis, MO, United States
d Department of Pathology, Harvard Medical School, Boston, MA, United States
e Department of Neurological Surgery, University of Pittsburgh Medical Center, Pittsburgh, PA, United States
f Department of Neurology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, United States
g Department of Medicine, Washington University School of Medicine, St Louis, MO, United States
h Department of Neurological Surgery, Washington University School of Medicine, St Louis, MO, United States
i Division of Neurosurgery, University of Toronto, Toronto, Canada
j Department of Neurosurgery, Duke University Medical Center, Durham, NC, United States
k Department of Neurosurgery, Icahn School of Medicine at Mount SinaiNY, United States
l Department of Neurosurgery, Baylor College of Medicine, Houston, TX, United States
m Department of Neurosurgery, NYU Grossman School of MedicineNY, United States
n Department of Neurosurgery, University of Arkansas for Medical Sciences, Little RockAR, United States
o Department of Neurosurgery, David Geffen School of Medicine at UCLA, Los Angeles, CA, United States
p Department of Radiation Oncology and Cancer Biology, Cleveland Clinic, Cleveland, OH, United States
Abstract
Patients with glioblastoma (GBM) need bold new approaches to their treatment, yet progress has been hindered by a relative inability to dynamically track treatment response, mechanisms of resistance, evolution of targetable mutations, and changes in mutational burden. We are writing on behalf of a multidisciplinary group of academic neuro-oncology professionals who met at the collaborative Christopher Davidson Forum at Washington University in St Louis in the fall of 2019. We propose a dramatic but necessary change to the routine management of patients with GBM to advance the field: to routinely biopsy recurrent GBM at the time of presumed recurrence. Data derived from these samples will identify true recurrence vs treatment effect, avoid treatments with little chance of success, enable clinical trial access, and aid in the scientific advancement of our understanding of GBM. © Congress of Neurological Surgeons 2021.
Author Keywords
Clinical trials; Glioblastoma; Personalized medicine; Pseudoprogression; Recurrent glioblastoma; Stereotactic biopsy
Document Type: Article
Publication Stage: Final
Source: Scopus
Role of anesthetics and their adjuvants in neurovascular protection in secondary brain injury after aneurysmal subarachnoid hemorrhage
(2021) International Journal of Molecular Sciences, 22 (12), art. no. 6550, .
Athiraman, U.a , Zipfel, G.J.b
a Department of Anesthesiology, Washington University, Saint Louis, MO 63110, United States
b Department of Neurological Surgery, Washington University, Saint Louis, MO 63110, United States
Abstract
Aneurysmal rupture accounts for the majority of subarachnoid hemorrhage and is responsible for most cerebrovascular deaths with high mortality and morbidity. Initial hemorrhage severity and secondary brain injury due to early brain injury and delayed cerebral ischemia are the major determinants of outcomes after aneurysmal subarachnoid hemorrhage. Several therapies have been explored to prevent these secondary brain injury processes after aneurysmal subarachnoid hemorrhage with limited clinical success. Experimental and clinical studies have shown a neuropro-tective role of certain anesthetics in cerebrovascular disorders including aneurysmal subarachnoid hemorrhage. The vast majority of aneurysmal subarachnoid hemorrhage patients require general anesthesia for surgical or endovascular repair of their aneurysm. Given the potential impact certain anesthetics have on secondary brain injury after SAH, appropriate selection of anesthetics may prove impactful on overall outcome of these patients. This narrative review focuses on the available evidence of anesthetics and their adjuvants in neurovascular protection in aneurysmal subarachnoid hemorrhage and discusses current impact on clinical care and future investigative directions. © 2021 by the authors. Licensee MDPI, Basel, Switzerland.
Author Keywords
Anesthetic adjuvants; Anesthetics; Aneurysmal subarachnoid hemorrhage; Delayed cerebral ischemia; Early brain injury; Neurological outcomes; Neurovascular protection
Funding details
National Institutes of HealthNIHR01 NS091603
Document Type: Review
Publication Stage: Final
Source: Scopus
CROI 2021: Neurologic Complications of HIV-1 Infection or COVID-19
(2021) Topics in Antiviral Medicine, 29 (2), pp. 334-343.
Ances, B.M.a , Anderson, A.M.b , Letendre, S.L.c
a Washington University, St Louis, MO, USA
b Emory University, Atlanta, United States
c University of California San Diego, San Diego, CA, USA
Abstract
The 2021 Conference on Retroviruses and Opportunistic Infections (CROI) featured a timely review of the neurologic complications of COVID-19 as well as new research findings on mechanisms by which SARS-CoV-2 may affect the brain. CROI included new and important findings about the neurologic complications of HIV-1, human polyomavirus 2 (also known as JC Virus), and cryptococcus. New long-term analyses of cognition in people with HIV-1 identified that cognitive decline over time is associated with multimorbidity, particularly diabetes, chronic lung disease, and vascular disease risk conditions. These conditions are associated with aging, and the question of whether people with HIV are at risk for premature aging was addressed by several reports. New findings from large analyses of resting state networks also provided valuable information on the structural and functional networks that are affected by HIV-1 infection and cognitive impairment. Several reports addressed changes after initiating or switching antiretroviral therapy (ART). Findings that will improve understanding of the biologic mechanisms of brain injury in people with HIV were also presented and included evidence that host (eg, myeloid activation, inflammation, and endothelial activation) and viral (eg, transcriptional activity and compartmentalization) factors adversely affect brain health. Other research focused on adjunctive therapies to treat HIV-1 and its complications in the central nervous system. This summary will review these and other findings in greater detail and identify key gaps and opportunities for researchers and clinicians.
Document Type: Article
Publication Stage: Final
Source: Scopus
DIAPH1 Variants in Non–East Asian Patients with Sporadic Moyamoya Disease
(2021) JAMA Neurology, .
Kundishora, A.J.a , Peters, S.T.b , Pinard, A.a , Duran, D.b , Panchagnula, S.c , Barak, T.c d e f , Miyagishima, D.F.c d e f , Dong, W.d g , Smith, H.a , Ocken, J.a , Dunbar, A.c , Nelson-Williams, C.d , Haider, S.h , Walker, R.L.i , Li, B.j , Zhao, H.j , Thumkeo, D.k , Marlier, A.c , Duy, P.Q.a , Diab, N.S.c d , Reeves, B.C.a , Robert, S.M.c , Sujijantarat, N.c , Stratman, A.N.l , Chen, Y.-H.m , Zhao, S.m , Roszko, I.n , Lu, Q.o , Zhang, B.n , Mane, S.p , Castaldi, C.p , López-Giráldez, F.p , Knight, J.R.p , Bamshad, M.J.q , Nickerson, D.A.q , Geschwind, D.H.r , Chen, S.-S.L.s , Storm, P.B.s , Diluna, M.L.c , Matouk, C.C.c , Orbach, D.B.t , Alper, S.L.u , Smith, E.R.t , Lifton, R.P.d g , Gunel, M.c d , Milewicz, D.M.a , Jin, S.C.m , Kahle, K.T.c v w
a Department of Internal Medicine, McGovern Medical School, University of Texas Health Science Center, Houston, United States
b Department of Neurosurgery, University of Mississippi Medical Center, Jackson, United States
c Department of Neurosurgery, Yale School of Medicine, New Haven, CT, United States
d Department of Genetics, Yale School of Medicine, New Haven, CT, United States
e Department of Neuroscience, Yale School of Medicine, New Haven, CT, United States
f Yale Program on Neurogenetics, Yale School of Medicine, New Haven, CT, United States
g Laboratory of Human Genetics and Genomics, The Rockefeller University, New York, NY, United States
h Department of Pharmaceutical and Biological Chemistry, University College London School of Pharmacy, London, United Kingdom
i Department of Neurology, Center for Autism Research and Treatment, Semel Institute, David Geffen School of Medicine, University of California, Los Angeles, United States
j Department of Biostatistics, Yale School of Public Health, New Haven, CT, United States
k Department of Drug Discovery Medicine, Kyoto University, Graduate School of Medicine, Yoshida-Konoe-cho, Sakyo-ku, Kyoto, Japan
l Department of Cell Biology and Physiology, Washington University School of Medicine, St Louis, MO, United States
m Department of Genetics, Washington University School of Medicine, St Louis, MO, United States
n Department of Developmental Biology, Center of Regenerative Medicine, Washington University School of Medicine, St Louis, MO, United States
o Department of Biostatistics and Medical Informatics, University of Wisconsin, Madison, United States
p Yale Center for Genome Analysis, West Haven, CT, United States
q Genome Sciences, University of Washington School of Medicine, Seattle, United States
r Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, United States
s Division of Neurosurgery, Children’s Hospital of Philadelphia, Department of Neurosurgery, University of Pennsylvania Perelman School of Medicine, Philadelphia, United States
t Department of Neurosurgery, Boston Children’s Hospital, Harvard Medical School, Boston, MA, United States
u Division of Nephrology, Center for Vascular Biology Research, Beth Israel Deaconess Medical Center, Department of Medicine, Harvard Medical School, Boston, MA, United States
v Department of Pediatrics, Yale School of Medicine, New Haven, CT, United States
w Department of Cellular and Molecular Physiology, Yale School of Medicine, New Haven, CT, United States
Abstract
Importance: Moyamoya disease (MMD), a progressive vasculopathy leading to narrowing and ultimate occlusion of the intracranial internal carotid arteries, is a cause of childhood stroke. The cause of MMD is poorly understood, but genetic factors play a role. Several familial forms of MMD have been identified, but the cause of most cases remains elusive, especially among non-East Asian individuals. Objective: To assess whether ultrarare de novo and rare, damaging transmitted variants with large effect sizes are associated with MMD risk. Design, Setting, and Participants: A genetic association study was conducted using whole-exome sequencing case-parent MMD trios in a small discovery cohort collected over 3.5 years (2016-2019); data were analyzed in 2020. Medical records from US hospitals spanning a range of 1 month to 1.5 years were reviewed for phenotyping. Exomes from a larger validation cohort were analyzed to identify additional rare, large-effect variants in the top candidate gene. Participants included patients with MMD and, when available, their parents. All participants who met criteria and were presented with the option to join the study agreed to do so; none were excluded. Twenty-four probands (22 trios and 2 singletons) composed the discovery cohort, and 84 probands (29 trios and 55 singletons) composed the validation cohort. Main Outcomes and Measures: Gene variants were identified and filtered using stringent criteria. Enrichment and case-control tests assessed gene-level variant burden. In silico modeling estimated the probability of variant association with protein structure. Integrative genomics assessed expression patterns of MMD risk genes derived from single-cell RNA sequencing data of human and mouse brain tissue. Results: Of the 24 patients in the discovery cohort, 14 (58.3%) were men and 18 (75.0%) were of European ancestry. Three of 24 discovery cohort probands contained 2 do novo (1-tailed Poisson P = 1.1 × 10-6) and 1 rare, transmitted damaging variant (12.5% of cases) in DIAPH1 (mammalian diaphanous-1), a key regulator of actin remodeling in vascular cells and platelets. Four additional ultrarare damaging heterozygous DIAPH1 variants (3 unphased) were identified in 3 other patients in an 84-proband validation cohort (73.8% female, 77.4% European). All 6 patients were non-East Asian. Compound heterozygous variants were identified in ena/vasodilator-stimulated phosphoproteinlike protein EVL, a mammalian diaphanous-1 interactor that regulates actin polymerization. DIAPH1 and EVL mutant probands had severe, bilateral MMD associated with transfusion-dependent thrombocytopenia. DIAPH1 and other MMD risk genes are enriched in mural cells of midgestational human brain. The DIAPH1 coexpression network converges in vascular cell actin cytoskeleton regulatory pathways. Conclusions and Relevance: These findings provide the largest collection to date of non-East Asian individuals with sporadic MMD harboring pathogenic variants in the same gene. The results suggest that DIAPH1 is a novel MMD risk gene and impaired vascular cell actin remodeling in MMD pathogenesis, with diagnostic and therapeutic ramifications.. © 2021 American Medical Association. All rights reserved.
Document Type: Article
Publication Stage: Article in Press
Source: Scopus