Arts & Sciences Brown School McKelvey School of Engineering School of Law School of Medicine Weekly Publications

WashU weekly Neuroscience publications

“Constitutive activation of canonical Wnt signaling disrupts choroid plexus epithelial fate” (2022) Nature Communications

Constitutive activation of canonical Wnt signaling disrupts choroid plexus epithelial fate(2022) Nature Communications, 13 (1), art. no. 633, . 

Parichha, A.a , Suresh, V.a , Chatterjee, M.a g , Kshirsagar, A.b , Ben-Reuven, L.b , Olender, T.b , Taketo, M.M.c , Radosevic, V.d e , Bobic-Rasonja, M.d e , Trnski, S.d , Holtzman, M.J.f , Jovanov-Milosevic, N.d e , Reiner, O.b , Tole, S.a

a Department of Biological Sciences, Tata Institute of Fundamental Research, Mumbai, 400005, Indiab Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israelc Division of Experimental Therapeutics Graduate School of Medicine, Kyoto University (Yoshida-Konoé-Cho, Sakyo), Kyoto, 606-8501, Japand Croatian Institute for Brain Research, Department of Medical Biology, School of Medicine University of Zagreb, Šalata 12, Zagreb, Croatiae University Hospital Centre Zagreb, Department of Gynecology and Department of Pathology and Cytology, Petrova 13, Zagreb, Croatiaf Pulmonary and Critical Care Medicine, Washington University, St. Louis, MO 63110, United Statesg Amity Institute of Neuropsychology and Neurosciences, Amity University, Noida, India

AbstractThe choroid plexus secretes cerebrospinal fluid and is critical for the development and function of the brain. In the telencephalon, the choroid plexus epithelium arises from the Wnt- expressing cortical hem. Canonical Wnt signaling pathway molecules such as nuclear β-CATENIN are expressed in the mouse and human embryonic choroid plexus epithelium indicating that this pathway is active. Point mutations in human β-CATENIN are known to result in the constitutive activation of canonical Wnt signaling. In a mouse model that recapitulates this perturbation, we report a loss of choroid plexus epithelial identity and an apparent transformation of this tissue to a neuronal identity. Aspects of this phenomenon are recapitulated in human embryonic stem cell derived organoids. The choroid plexus is also disrupted when β-Catenin is conditionally inactivated. Together, our results indicate that canonical Wnt signaling is required in a precise and regulated manner for normal choroid plexus development in the mammalian brain. © 2022, The Author(s).

Funding detailsIA-E-12-1-500765Canadian Institutes of Health ResearchCIHRInternational Development Research CentreIDRCTata Institute of Fundamental ResearchTIFRIsrael Science FoundationISFAzrieli Foundation108875

Document Type: ArticlePublication Stage: FinalSource: Scopus

“Astrocytes deficient in circadian clock gene Bmal1 show enhanced activation responses to amyloid-beta pathology without changing plaque burden” (2022) Scientific Reports

Astrocytes deficient in circadian clock gene Bmal1 show enhanced activation responses to amyloid-beta pathology without changing plaque burden(2022) Scientific Reports, 12 (1), art. no. 1796, . 

McKee, C.A.a , Lee, J.a , Cai, Y.a d , Saito, T.b , Saido, T.c , Musiek, E.S.a

a Department of Neurology and Center On Biological Rhythms And Sleep, Washington University in St. Louis School of Medicine, St. Louis, MO, United Statesb Department of Neurocognitive Science, Institute of Brain Science, Nagoya City University Graduate School of Medical Sciences, Aichi, Nagoya, Japanc Laboratory for Proteolytic Neuroscience, RIKEN Center for Brain Science, Wako-shi, Saitama, Japand Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, United States

AbstractAn emerging link between circadian clock function and neurodegeneration has indicated a critical role for the molecular clock in brain health. We previously reported that deletion of the core circadian clock gene Bmal1 abrogates clock function and induces cell-autonomous astrocyte activation. Regulation of astrocyte activation has important implications for protein aggregation, inflammation, and neuronal survival in neurodegenerative conditions such as Alzheimer’s disease (AD). Here, we investigated how astrocyte activation induced by Bmal1 deletion regulates astrocyte gene expression, amyloid-beta (Aβ) plaque-associated activation, and plaque deposition. To address these questions, we crossed astrocyte-specific Bmal1 knockout mice (Aldh1l1-CreERT2;Bmal1fl/fl, termed BMAL1 aKO), to the APP/PS1-21 and the APPNL-G-F models of Aβ accumulation. Transcriptomic profiling showed that BMAL1 aKO induced a unique transcriptional profile affecting genes involved in both the generation and elimination of Aβ. BMAL1 aKO mice showed exacerbated astrocyte activation around Aβ plaques and altered gene expression. However, this astrogliosis did not affect plaque accumulation or neuronal dystrophy in either model. Our results demonstrate that the striking astrocyte activation induced by Bmal1 knockout does not influence Aβ deposition, which indicates that the effect of astrocyte activation on plaque pathology in general is highly dependent on the molecular mechanism of activation. © 2022, The Author(s).

Document Type: ArticlePublication Stage: FinalSource: Scopus

“Selective reduction of astrocyte apoE3 and apoE4 strongly reduces Aβ accumulation and plaque-related pathology in a mouse model of amyloidosis” (2022) Molecular Neurodegeneration

Selective reduction of astrocyte apoE3 and apoE4 strongly reduces Aβ accumulation and plaque-related pathology in a mouse model of amyloidosis(2022) Molecular Neurodegeneration, 17 (1), art. no. 13, . 

Mahan, T.E., Wang, C., Bao, X., Choudhury, A., Ulrich, J.D., Holtzman, D.M.

Department of Neurology, Hope Center for Neurological Disorders, Knight Alzheimer’s Disease Research Center, Washington University School of Medicine, 660 S. Euclid Ave, St. Louis, MO 63110, United States

AbstractBackground: One of the key pathological hallmarks of Alzheimer disease (AD) is the accumulation of the amyloid-β (Aβ) peptide into amyloid plaques. The apolipoprotein E (APOE) gene is the strongest genetic risk factor for late-onset AD and has been shown to influence the accumulation of Aβ in the brain in an isoform-dependent manner. ApoE can be produced by different cell types in the brain, with astrocytes being the largest producer of apoE, although reactive microglia also express high levels of apoE. While studies have shown that altering apoE levels in the brain can influence the development of Aβ plaque pathology, it is not fully known how apoE produced by specific cell types, such as astrocytes, contributes to amyloid pathology. Methods: We utilized APOE knock-in mice capable of having APOE selectively removed from astrocytes in a tamoxifen-inducible manner and crossed them with the APP/PS1-21 mouse model of amyloidosis. We analyzed the changes to Aβ plaque levels and assessed the impact on cellular responses to Aβ plaques when astrocytic APOE is removed. Results: Tamoxifen administration was capable of strongly reducing apoE levels in the brain by markedly reducing astrocyte apoE, while microglial apoE expression remained. Reduction of astrocytic apoE3 and apoE4 led to a large decrease in Aβ plaque deposition and less compact plaques. While overall Iba1+ microglia were unchanged in the cortex after reducing astrocyte apoE, the expression of the disease-associated microglial markers Clec7a and apoE were lower around amyloid plaques, indicating decreased microglial activation. Additionally, astrocyte GFAP levels are unchanged around amyloid plaques, but overall GFAP levels are reduced in the cortex of female apoE4 mice after a reduction in astrocytic apoE. Finally, while the amount of neuritic dystrophy around remaining individual plaques was increased with the removal of astrocytic apoE, the overall amount of cortical amyloid-associated neuritic dystrophy was significantly decreased. Conclusion: This study reveals an important role of astrocytic apoE3 and apoE4 on the deposition and accumulation of Aβ plaques as well as on certain Aβ-associated downstream effects. © 2022, The Author(s).

Author KeywordsAldh1l1-Cre;  Alzheimer disease;  Amyloid;  apoE;  Apolipoprotein E;  Astrocyte;  Aβ

Document Type: ArticlePublication Stage: FinalSource: Scopus

“Acute minocycline administration reduces brain injury and improves long-term functional outcomes after delayed hypoxemia following traumatic brain injury” (2022) Acta Neuropathologica Communications

Acute minocycline administration reduces brain injury and improves long-term functional outcomes after delayed hypoxemia following traumatic brain injury(2022) Acta Neuropathologica Communications, 10 (1), art. no. 10, . 

Celorrio, M., Shumilov, K., Payne, C., Vadivelu, S., Friess, S.H.

Division of Critical Care Medicine, Department of Pediatrics, Washington University in St. Louis School of Medicine, 660 South Euclid Avenue, St. Louis, MO 63110, United States

AbstractClinical trials of therapeutics for traumatic brain injury (TBI) demonstrating preclinical efficacy for TBI have failed to replicate these results in humans, in part due to the absence of clinically feasible therapeutic windows for administration. Minocycline, an inhibitor of microglial activation, has been shown to be neuroprotective when administered early after experimental TBI but detrimental when administered chronically to human TBI survivors. Rather than focusing on the rescue of primary injury with early administration of therapeutics which may not be clinically feasible, we hypothesized that minocycline administered at a clinically feasible time point (24 h after injury) would be neuroprotective in a model of TBI plus delayed hypoxemia. We first explored several different regimens of minocycline dosing with the initial dose 24 h after injury and 2 h prior to hypoxemia, utilizing short-term neuropathology to select the most promising candidate. We found that a short course of minocycline reduced acute microglial activation, monocyte infiltration and hippocampal neuronal loss at 1 week post injury. We then conducted a preclinical trial to assess the long-term efficacy of a short course of minocycline finding reductions in hippocampal neurodegeneration and synapse loss, preservation of white matter myelination, and improvements in fear memory performance at 6 months after injury. Timing in relation to injury and duration of minocycline treatment and its impact on neuroinflammatory response may be responsible for extensive neuroprotection observed in our studies. © 2022, The Author(s).

Author KeywordsHypoxemia;  Minocycline;  Neuroprotection;  Pre-clinical trial;  Secondary injury;  Traumatic brain injury

Funding detailsCDI-CORE-2015-505, CDI-CORE-2019-813National Institutes of HealthNIHOD021629, R01NS097721Foundation for Barnes-Jewish HospitalFBJH3770, 4642Washington University School of Medicine in St. LouisWUSMOffice of Research Infrastructure Programs, National Institutes of HealthORIP, NIH

Document Type: ArticlePublication Stage: FinalSource: Scopus

“The brain as a structure: A model of how fluid–structure interactions stiffen brain tissue after injury” (2022) Engineering Structures

The brain as a structure: A model of how fluid–structure interactions stiffen brain tissue after injury(2022) Engineering Structures, 256, art. no. 113960, . 

Feng, Y.a , Chen, Y.a , Yao, Y.b , Li, X.a , Zhang, A.a , Genin, G.M.c

a School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, 200230, Chinab Engineering Research Center of Digital Medicine and Clinical Translation, Ministry of Education, School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, 200230, Chinac NSF Science and Technology Center for Engineering Mechanobiology, Washington University in St. Louis, St. Louis, MO 63130, United States

AbstractThe brain contains a tree of vasculature that contributes not only oxygen and nutrients but also structural integrity to the brain parenchyma. The structure formed by this vasculature affects the mechanical response of brain tissue both before and after injury, and maybe a determinant of an individual’s injury susceptibility. To investigate structural changes of brain tissue after injury, we constructed an idealized representative volume element model of fluid–structure interactions within brain parenchyma and applied it to study how vessel size, cerebral spinal fluid (CSF) flow velocity, and CSF flow networks relate to previous experimental observations of healthy and injured brain tissue. We hypothesized that injury-associated structural changes to the neurovasculature may alter the mechanical responses of brain tissue and predispose an individual to subsequent injury. Parameters representing the mechanics of uninjured and injured brain tissue were verified against experimental characterizations of these tissue in uniaxial compression and shear. Results supported our hypothesis, and highlight the importance of considering cerebral vasculature as a structure in predicting and analyzing the brain’s response to mechanical loading. © 2022 Elsevier Ltd

Author KeywordsBrain injury;  Fluid–structure interactions;  Tissue mechanics

Funding detailsUniversity of WashingtonUW31870941National Natural Science Foundation of ChinaNSFC19441907700Science and Technology Commission of Shanghai MunicipalitySTCSM

Document Type: ArticlePublication Stage: FinalSource: Scopus

“Depression interventions for individuals with coronary artery disease – Cost-effectiveness calculations from an Irish perspective” (2022) Journal of Psychosomatic Research

Depression interventions for individuals with coronary artery disease – Cost-effectiveness calculations from an Irish perspective(2022) Journal of Psychosomatic Research, 155, art. no. 110747, . 

Jabakhanji, S.B.a , Sorensen, J.a , Carney, R.M.b , Dickens, C.c , Dempster, M.d , Gallagher, J.e , Caramlau, I.f , Doyle, F.g

a Healthcare Outcomes Research Centre, RCSI University of Medicine and Health Sciences, Dublin, Irelandb Department of Psychiatry, Washington University School of Medicine, St Louis, MO, United Statesc College of Medicine and Health, University of Exeter, Exeter, United Kingdomd School of Psychology, Queen’s University BelfastNorthern Ireland, United Kingdome Department of Cardiology, Beaumont Hospital, Dublin, Irelandf Department of Psychology, Beaumont Hospital, Dublin, Irelandg Department of Health Psychology, RCSI University of Medicine and Health Sciences, Dublin, Ireland

AbstractBackground: A substantial proportion of individuals with coronary artery disease experience moderate or severe acute depression that requires treatment. We assessed the cost-effectiveness of four interventions for depression in individuals with coronary artery disease. Methods: We assessed effectiveness of pharmacotherapy, psychotherapy, collaborative care and exercise as remission rate after 8 and 26 weeks using estimates from a recent network meta-analysis. The cost assessment included standard doses of antidepressants, contact frequency, and staff time per contact. Unit costs were calculated as health services’ purchase price for pharmaceuticals and mid-point staff salaries obtained from the Irish Health Service Executive and validated by clinical staff. Incremental cost-effectiveness ratios were calculated as the incremental costs over incremental remissions compared to usual care. High- and low-cost scenarios and sensitivity analysis were performed with changed contact frequencies, and assuming individual vs. group psychotherapy or exercise. Results: After 8 weeks, the estimated incremental cost-effectiveness ratio was lowest for group exercise (€526 per remission), followed by pharmacotherapy (€589), individual psychotherapy (€3117) and collaborative care (€4964). After 26 weeks, pharmacotherapy was more cost-effective (€591) than collaborative care (€7203) and individual psychotherapy (€9387); no 26-week assessment for exercise was possible. Sensitivity analysis showed that group psychotherapy could be most cost-effective after 8 weeks (€519) and cost-effective after 26 weeks (€1565); however no group psychotherapy trials were available investigating its effectiveness. Discussion: Large variation in incremental cost-effectiveness ratios was seen. With the current assumptions, the most cost-effective depression intervention for individuals with coronary artery disease after 8 weeks was group exercise. © 2022

Author KeywordsCoronary artery disease;  Cost-effectiveness;  Depression;  Exercise therapy;  Ireland;  Psychosocial intervention

Document Type: ArticlePublication Stage: FinalSource: Scopus

“Age-related changes and longitudinal stability of individual differences in ABCD Neurocognition measures” (2022) Developmental Cognitive Neuroscience

Age-related changes and longitudinal stability of individual differences in ABCD Neurocognition measures(2022) Developmental Cognitive Neuroscience, 54, art. no. 101078, . 

Anokhin, A.P.a , Luciana, M.b , Banich, M.c , Barch, D.a , Bjork, J.M.d , Gonzalez, M.R.e , Gonzalez, R.f , Haist, F.e , Jacobus, J.e , Lisdahl, K.g , McGlade, E.h , McCandliss, B.i , Nagel, B.j , Nixon, S.J.k , Tapert, S.e , Kennedy, J.T.a , Thompson, W.e

a Washington University in St. Louis, United Statesb University of Minnesota, United Statesc University of Colorado Boulder, United Statesd Virginia Commonwealth University, United Statese University of California San Diego, United Statesf Florida International University, United Statesg University of Wisconsin-Milwaukee, United Statesh The University of Utah, United Statesi Stanford University, United Statesj Oregon Health & Science University, United Statesk University of Florida, United States

AbstractTemporal stability of individual differences is an important prerequisite for accurate tracking of prospective relationships between neurocognition and real-world behavioral outcomes such as substance abuse and psychopathology. Here we report age-related changes and longitudinal test-retest stability (TRS) for the Neurocognition battery of the Adolescent Brain and Cognitive Development (ABCD) study, which included the NIH Toolbox (TB) Cognitive Domain and additional memory and visuospatial processing tests administered at baseline (ages 9–11) and two-year follow-up. As expected, performance improved significantly with age, but the effect size varied broadly, with Pattern Comparison and the Crystallized Cognition Composite showing the largest age-related gain (Cohen’s d:.99 and.97, respectively). TRS ranged from fair (Flanker test: r = 0.44) to excellent (Crystallized Cognition Composite: r = 0.82). A comparison of longitudinal changes and cross-sectional age-related differences within baseline and follow-up assessments suggested that, for some measures, longitudinal changes may be confounded by practice effects and differences in task stimuli or procedure between baseline and follow-up. In conclusion, a subset of measures showed good stability of individual differences despite significant age-related changes, warranting their use as prospective predictors. However, caution is needed in the interpretation of observed longitudinal changes as indicators of neurocognitive development. © 2022

Author KeywordsDevelopment;  Longitudinal;  Neurocognition;  Test-retest reliability

Funding detailsNational Institutes of HealthNIHNational Institute on Drug AbuseNIDAR01HD083614Eunice Kennedy Shriver National Institute of Child Health and Human DevelopmentNICHD

Document Type: ArticlePublication Stage: FinalSource: Scopus

“Revesal of unilateral hand movement dysfunction by high definition transcranial direct current stimulation in a patient with chronic traumatic brain injury” (2022) Brain Stimulation

Revesal of unilateral hand movement dysfunction by high definition transcranial direct current stimulation in a patient with chronic traumatic brain injury(2022) Brain Stimulation, 15 (2), pp. 283-285. 

Chiang, H.-S.a b c , Shakal, S.d , Strain, J.F.e , Womack, K.f , Kraut, M.g , Vanneste, S.h , Hart, J., Jr.i j

a Department of Neurology, The University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard DallasTexas 75390, United Statesb The University of Texas Southwestern Medical Center, Dallas, TX, United Statesc The University of Texas at Dallas, Richardson, TX, United Statesd The University of North Texas Health Science Center, 3500 Camp Bowie Blvd, Fort Worth, TX 76107, United Statese Department of Neurology, Washington University in St. Louis, 660 S Euclid Ave, St. Louis, MO 63108, United Statesf Department of Neurology, Washington University in St. Louis, Campus Box 8111, 4488 Forest Park, Suite 200, St. Louis, MO 63108, United Statesg Department of Radiology, The Johns Hopkins University School of Medicine, 601 N Caroline St, Baltimore, MD 21205, United Statesh Trinity College Dublin, The University of Dublin, College Green Dublin 2, Irelandi School of Behavioral and Brain Sciences, The University of Texas at Dallas, 800 W Campbell Rd, Richardson, TX 75080, United Statesj Department of Neurology and Psychiatry, The University of Texas Southwestern Medical Center, United States

Funding detailsNational Institute of Neurological Disorders and StrokeNINDSNS09898702

Document Type: LetterPublication Stage: FinalSource: Scopus

“Radiosynthesis and evaluation of a fluorine-18 radiotracer (18F)FS1P1 for imaging sphingosine-1-phosphate receptor 1” (2022) Organic and Biomolecular Chemistry

Radiosynthesis and evaluation of a fluorine-18 radiotracer [18F]FS1P1 for imaging sphingosine-1-phosphate receptor 1(2022) Organic and Biomolecular Chemistry, 20 (5), pp. 1041-1052. 

Qiu, L.a , Jiang, H.a , Yu, Y.a , Gu, J.a , Wang, J.a , Zhao, H.a , Huang, T.a , Gropler, R.J.a , Klein, R.S.b c d , Perlmutter, J.S.c e f , Tu, Z.a

a Department of Radiology, Washington University School of Medicine, Saint Louis, MO 63110, United Statesb Department of Medicine, Washington University School of Medicine, Saint Louis, MO 63110, United Statesc Departments of Neuroscience, Washington University School of Medicine, Saint Louis, MO 63110, United Statesd Department of Pathology and Immunology, Washington University School of Medicine, Saint Louis, MO 63110, United Statese Department of Neurology, Washington University School of Medicine, Saint Louis, MO 63110, United Statesf Physical Therapy and Occupational Therapy, Washington University School of Medicine, Saint Louis, MO 63110, United States

AbstractAssessment of sphingosine-1-phosphate receptor 1 (S1PR1) expression could be a unique tool to determine the neuroinflammatory status for central nervous system (CNS) disorders. Our preclinical results indicate that PET imaging with [11C]CS1P1 radiotracer can quantitatively measure S1PR1 expression changes in different animal models of inflammatory diseases. Here we developed a multiple step F-18 labeling strategy to synthesize the radiotracer [18F]FS1P1, sharing the same structure with [11C]CS1P1. We explored a wide range of reaction conditions for the nucleophilic radiofluorination starting with the key ortho-nitrobenzaldehyde precursor 10. The tertiary amine additive TMEDA proved crucial to achieve high radiochemical yield of ortho-[18F]fluorobenzaldehyde [18F]12 starting with a small amount of precursor. Based on [18F]12, a further four-step modification was applied in one-pot to generate the target radiotracer [18F]FS1P1 with 30–50% radiochemical yield, >95% chemical and radiochemical purity, and a high molar activity (37–166.5 GBq μmol−1, decay corrected to end of synthesis, EOS). Subsequently, tissue distribution of [18F]FS1P1 in rats showed a high brain uptake (ID% g−1) of 0.48 ± 0.06 at 5 min, and bone uptake of 0.27 ± 0.03, 0.11 ± 0.02 at 5, and 120 min respectively, suggesting no in vivo defluorination. MicroPET studies showed [18F]FS1P1 has high macaque brain uptake with a standard uptake value (SUV) of 2.3 at 120 min. Radiometabolite analysis of macaque plasma samples indicated that [18F]FS1P1 has good metabolic stability, and no major radiometabolite confounded PET measurements of S1PR1 in nonhuman primate brain. Overall, [18F]FS1P1 is a promising F-18 S1PR1 radiotracer worthy of further clinical investigation for human use. This journal is © The Royal Society of Chemistry

Funding detailsNational Institutes of HealthNIHNational Institute of Neurological Disorders and StrokeNINDSNS0103957, NS103988, NS75527National Institute of Biomedical Imaging and BioengineeringNIBIBEB025815

Document Type: ArticlePublication Stage: FinalSource: Scopus

“Using Smartphones to Reduce Research Burden in a Neurodegenerative Population and Assessing Participant Adherence: A Randomized Clinical Trial and Two Observational Studies” (2022) JMIR mHealth and uHealth

Using Smartphones to Reduce Research Burden in a Neurodegenerative Population and Assessing Participant Adherence: A Randomized Clinical Trial and Two Observational Studies(2022) JMIR mHealth and uHealth, 10 (2), art. no. e31877, . 

Beukenhorst, A.L.a b , Burke, K.M.c , Scheier, Z.c , Miller, T.M.d , Paganoni, S.c e , Keegan, M.c , Collins, E.c , Connaghan, K.P.f , Tay, A.d , Chan, J.g , Berry, J.D.c , Onnela, J.-P.a

a Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA, United Statesb Centre for Epidemiology Versus Arthritis, Manchester Academic Health Science Centre, University of Manchester, Manchester, United Kingdomc Neurological Clinical Research Institute and Sean M. Healey & AMG Center for ALS, Massachusetts General Hospital, Boston, MA, United Statesd Department of Neurology, Washington University, Saint Louis, MO, United Statese Department of Physical Medicine and Rehabilitation, Spaulding Rehabilitation Hospital, Harvard Medical School, Boston, MA, United Statesf MGH Institute of Health Professions, Charlestown, MA, United Statesg Biostatistics Center, Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States

AbstractBackground: Smartphone studies provide an opportunity to collect frequent data at a low burden on participants. Therefore, smartphones may enable data collection from people with progressive neurodegenerative diseases such as amyotrophic lateral sclerosis at high frequencies for a long duration. However, the progressive decline in patients’ cognitive and functional abilities could also hamper the feasibility of collecting patient-reported outcomes, audio recordings, and location data in the long term. Objective: The aim of this study is to investigate the completeness of survey data, audio recordings, and passively collected location data from 3 smartphone-based studies of people with amyotrophic lateral sclerosis. Methods: We analyzed data completeness in three studies: 2 observational cohort studies (study 1: N=22; duration=12 weeks and study 2: N=49; duration=52 weeks) and 1 clinical trial (study 3: N=49; duration=20 weeks). In these studies, participants were asked to complete weekly surveys; weekly audio recordings; and in the background, the app collected sensor data, including location data. For each of the three studies and each of the three data streams, we estimated time-to-discontinuation using the Kaplan–Meier method. We identified predictors of app discontinuation using Cox proportional hazards regression analysis. We quantified data completeness for both early dropouts and participants who remained engaged for longer. Results: Time-to-discontinuation was shortest in the year-long observational study and longest in the clinical trial. After 3 months in the study, most participants still completed surveys and audio recordings: 77% (17/22) in study 1, 59% (29/49) in study 2, and 96% (22/23) in study 3. After 3 months, passively collected location data were collected for 95% (21/22), 86% (42/49), and 100% (23/23) of the participants. The Cox regression did not provide evidence that demographic characteristics or disease severity at baseline were associated with attrition, although it was somewhat underpowered. The mean data completeness was the highest for passively collected location data. For most participants, data completeness declined over time; mean data completeness was typically lower in the month before participants dropped out. Moreover, data completeness was lower for people who dropped out in the first study month (very few data points) compared with participants who adhered long term (data completeness fluctuating around 75%). Conclusions: These three studies successfully collected smartphone data longitudinally from a neurodegenerative population. Despite patients’ progressive physical and cognitive decline, time-to-discontinuation was higher than in typical smartphone studies. Our study provides an important benchmark for participant engagement in a neurodegenerative population. To increase data completeness, collecting passive data (such as location data) and identifying participants who are likely to adhere during the initial phase of a study can be useful. © 2022 JMIR Publications. All rights reserved.

Author KeywordsAttrition;  Digital phenotyping;  Mobile health;  Mobile phone;  Smartphones;  Trial

Document Type: ArticlePublication Stage: FinalSource: Scopus

“Transfusion-Associated Delirium in Children: No Difference Between Short Storage Versus Standard Issue RBCs” (2022) Critical Care Medicine

Transfusion-Associated Delirium in Children: No Difference Between Short Storage Versus Standard Issue RBCs(2022) Critical Care Medicine, 50 (2), pp. 173-182. 

Traube, C.a , Tucci, M.b , Nellis, M.E.a , Avery, K.L.c , McQuillen, P.S.d , Fitzgerald, J.C.e , Muszynski, J.A.f , Cholette, J.M.g , Schwarz, A.J.h , Stalets, E.L.i j , Quaid, M.A.k , Hanson, S.J.l , Lacroix, J.m , Reeder, R.W.n , Spinella, P.C.o , Transfusion-Associated Delirium ABC-PICU Study Groupp

a Division of Critical Care Medicine, Department of Pediatrics, Weill Cornell Medical College, New York, NY, United Statesb Department of Pediatrics, CHU Sainte-Justine, University of Montreal, Montreal, QC, Canadac Department of Pediatrics, University of Florida College of Medicine, Gainesville, FL, United Statesd Department of Pediatrics, University of California San Francisco, San Francisco, CA, United Statese Department of Anesthesiology and Critical Care, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, United Statesf Division of Critical Care Medicine, Department of Pediatrics, Nationwide Children’s Hospital, Columbus, OH, United Statesg Department of Pediatrics, University of Rochester, Golisano Children’s Hospital, Rochester, NY, United Statesh Critical Care, CHOC Children’s Hospital, Orange, CA, United Statesi Division of Critical Care Medicine, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, United Statesj Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, United Statesk Department of Pediatrics, Advocate Children’s Hospital, Park Ridge, IL, United Statesl Department of Pediatrics and Children’s Wisconsin, Critical Care Section, Medical College of Wisconsin, Milwaukee, WI, United Statesm Division of Pediatric Critical Care, Department of Pediatrics, CHU Sainte-Justine, Université de Montréal, Montréal, QC, Canadan Department of Pediatrics, University of Utah, Salt Lake City, UT, United Stateso Division of Critical Care Medicine, Department of Pediatrics, Washington University School of Medicine, St. Louis, MO, United States

AbstractOBJECTIVES: Primary objective is to determine if transfusion of short storage RBCs compared with standard issue RBCs reduced risk of delirium/coma in critically ill children. Secondary objective is to assess if RBC transfusion was independently associated with delirium/coma. DESIGN: This study was performed in two stages. First, we compared patients receiving either short storage or standard RBCs in a multi-institutional prospective randomized controlled trial. Then, we compared all transfused patients in the randomized controlled trial with a single-center cohort of nontransfused patients matched for confounders of delirium/coma. SETTING: Twenty academic PICUs who participated in the Age of Transfused Blood in Critically Ill Children trial. PATIENTS: Children 3 days to 16 years old who were transfused RBCs within the first 7 days of admission. INTERVENTIONS: Subjects were randomized to either short storage RBC study arm (defined as RBCs stored for up to seven days) or standard issue RBC study arm. In addition, subjects were screened for delirium prior to transfusion and every 12 hours after transfusion for up to 3 days. MEASUREMENTS AND MAIN RESULTS: Primary outcome measure was development of delirium/coma within 3 days of initial transfusion. Additional outcome measures were dose-response relationship between volume of RBCs transfused and delirium/coma, and comparison of delirium/coma rates between transfused patients and individually matched nontransfused patients. We included 146 subjects in the stage I analysis; 69 were randomized to short storage RBCs and 77 to standard issue. There was no significant difference in delirium/coma development between study arms (79.5% vs 70.1%; p = 0.184). In the stage II analysis, adjusted odds for delirium in the transfused cohort was more than eight-fold higher than in the nontransfused matched cohort, even after controlling for hemoglobin (adjusted odds ratio, 8.9; CI, 2.8–28.4; p < 0.001). CONCLUSIONS: RBC transfusions (and not anemia) are independently associated with increased odds of subsequent delirium/coma. However, storage age of RBCs does not affect delirium risk. Copyright © 2022 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

Author KeywordsAge of blood;  Cornell assessment of pediatric delirium;  Delirium;  Pediatric critical care;  Red blood cell transfusions

Funding detailsNational Institutes of HealthNIHNational Heart, Lung, and Blood InstituteNHLBINational Institute of Diabetes and Digestive and Kidney DiseasesNIDDKNational Institute of Child Health and Human DevelopmentNICHDWashington University in St. LouisWUSTLWeill Cornell Medical CollegeCanadian Institutes of Health ResearchCIHRMinistère des Affaires Sociales et de la SantéEtablissement Français du SangEFS

Document Type: ArticlePublication Stage: FinalSource: Scopus

“A callosal biomarker of behavioral intervention outcomes for autism spectrum disorder? A case-control feasibility study with diffusion tensor imaging” (2022) PLoS ONE

A callosal biomarker of behavioral intervention outcomes for autism spectrum disorder? A case-control feasibility study with diffusion tensor imaging(2022) PLoS ONE, 17 (2 February), art. no. e0262563, . 

Virues-Ortega, J.a b , McKay, N.S.c , McCormack, J.C.d , Lopez, N.e , Liu, R.a , Kirk, I.a

a School of Psychology, The University of Auckland, Auckland, New Zealandb Facultad de Psychology, Universidad Autónoma de Madrid, Madrid, Spainc Department of Neurology, Washington University, St Louis, MO, United Statesd National Institute for Health Innovation, School of Population Health, University of Auckland, Auckland, New Zealande Facultad de Psicologia, Universidad Nacional de Educación a Distancia, Madrid, Spain

AbstractTentative results from feasibility analyses are critical for planning future randomized control trials (RCTs) in the emerging field of neural biomarkers of behavioral interventions. The current feasibility study used MRI-derived diffusion imaging data to investigate whether it would be possible to identify neural biomarkers of a behavioral intervention among people diagnosed with autism spectrum disorder (ASD). The corpus callosum has been linked to cognitive processing and callosal abnormalities have been previously found in people diagnosed with ASD. We used a case-control design to evaluate the association between the type of intervention people diagnosed with ASD had previously received and their current white matter integrity in the corpus callosum. Twenty-six children and adolescents with ASD, with and without a history of parent-managed behavioral intervention, underwent an MRI scan with a diffusion data acquisition sequence. We conducted tract-based spatial statistics and a region of interest analysis. The fractional anisotropy values (believed to indicate white matter integrity) in the posterior corpus callosum was significantly different across cases (exposed to parent-managed behavioral intervention) and controls (not exposed to parentmanaged behavioral intervention). The effect was modulated by the intensity of the behavioral intervention according to a dose-response relationship. The current feasibility casecontrol study provides the basis for estimating the statistical power required for future RCTs in this field. In addition, the study demonstrated the effectiveness of purposely-developed motion control protocols and helped to identify regions of interest candidates. Potential clinical applications of diffusion tensor imaging in the evaluation of treatment outcomes in ASD are discussed. © 2022 Virues-Ortega et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Document Type: ArticlePublication Stage: FinalSource: Scopus

“Supporting robust research on adult emotional development by considering context” (2022) Psychology and Aging

Supporting robust research on adult emotional development by considering context(2022) Psychology and Aging, 37 (1), pp. 97-110. 

Springstein, T., Growney, C.M., English, T.

Department of Psychological and Brain Sciences, Washington University in St. Louis

AbstractA criterion for high quality science is to produce findings that are robust and replicable across studies. A potential hinderance to successful replication however is context dependency. To formally address issues of context dependency, context has to be defined and integrated into research and replication practices. Emotion research and particularly research on adult emotional development have long emphasized the importance of context. Drawing on established theories of adult development and existing frameworks of context, we define context as it relates to emotional development in adulthood, highlighting specific aspects of immediate surroundings (familiarity, cognitive demands, and social aspects) as well as sociocultural and socioeconomic context, situated within ontogenetic development and historical time. In order to improve the robustness of research on adult emotional development, we encourage researchers to consider these contextual aspects in formulating and testing research questions as well as when interpreting failed replications. We discuss how to adapt study designs to facilitate more context sensitive adult emotional development research. Considering context not only enables new discoveries in aging research, but also can help clarify significant long-standing research questions and further enhance the robustness of research on adult development in emotion. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Document Type: ArticlePublication Stage: FinalSource: Scopus

“Risks and Benefits of Cannabis and Cannabinoids in Psychiatry” (2022) The American Journal of Psychiatry

Risks and Benefits of Cannabis and Cannabinoids in Psychiatry(2022) The American Journal of Psychiatry, 179 (2), pp. 98-109. 

Hill, K.P., Gold, M.S., Nemeroff, C.B., McDonald, W., Grzenda, A., Widge, A.S., Rodriguez, C., Kraguljac, N.V., Krystal, J.H., Carpenter, L.L.

Department of Psychiatry, Harvard Medical School, Boston, andBeth Israel Deaconess Medical Center, Boston (Hill);Department of Psychiatry, School of Medicine, Washington University in St. Louis (Gold);Department of Psychiatry, Dell Medical School, University of Texas at Austin (Nemeroff);Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta (McDonald);Department of Psychiatry, David Geffen School of Medicine, University of California, Los Angeles (Grzenda);Department of Psychiatry, University of Minnesota, Minneapolis (Widge);Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, Calif., andVeterans Affairs Palo Alto Health Care System, Palo Alto, Calif. (Rodriguez);Department of Psychiatry and Behavioral Neurobiology, University of Alabama at Birmingham (Kraguljac);Department of Psychiatry, Yale University School of Medicine, New Haven, Conn. (Krystal);Department of Psychiatry and Human Behavior, Alpert Medical School of Brown University, andButler Hospital, Providence, R.I. (Carpenter)

AbstractOBJECTIVE: The United States is in the midst of rapidly changing laws regarding cannabis. The increasing availability of cannabis for recreational and medical use requires that mental health clinicians be knowledgeable about evidence to be considered when counseling both patients and colleagues. In this review, the authors outline the evidence from randomized double-blind placebo-controlled trials for therapeutic use of cannabinoids for specific medical conditions and the potential side effects associated with acute and chronic cannabis use. METHODS: Searches of PubMed and PsycInfo were conducted for articles published through July 2021 reporting on “cannabis” or “cannabinoids” or “medicinal cannabis.” Additional articles were identified from the reference lists of published reviews. Articles that did not contain the terms “clinical trial” or “therapy” in the title or abstract were not reviewed. A total of 4,431 articles were screened, and 841 articles that met criteria for inclusion were reviewed by two or more authors. RESULTS: There are currently no psychiatric indications approved by the U.S. Food and Drug Administration (FDA) for cannabinoids, and there is limited evidence supporting the therapeutic use of cannabinoids for treatment of psychiatric disorders. To date, evidence supporting cannabinoid prescription beyond the FDA indications is strongest for the management of pain and spasticity. CONCLUSIONS: As cannabinoids become more available, the need for an evidence base adequately evaluating their safety and efficacy is increasingly important. There is considerable evidence that cannabinoids have a potential for harm in vulnerable populations such as adolescents and those with psychotic disorders. The current evidence base is insufficient to support the prescription of cannabinoids for the treatment of psychiatric disorders.

Author KeywordsCannabinoids;  Cannabis;  Substance-Related and Addictive Disorders

Document Type: ArticlePublication Stage: FinalSource: Scopus

“Supporting COVID-19 School Safety for Children With Disabilities and Medical Complexity” (2022) Pediatrics

Supporting COVID-19 School Safety for Children With Disabilities and Medical Complexity(2022) Pediatrics, 149, art. no. e2021054268H, . Cited 1 time.

Sherby, M.R.a , Kalb, L.G.b , Coller, R.J.c , DeMuri, G.P.c , Butteris, S.c , Foxe, J.J.d , Zand, M.S.d , Freedman, E.G.d , Dewhurst, S.d , Newland, J.G.a , Gurnett, C.A.a

a Washington University in St Louis, St Louis, MO, United Statesb Kennedy Krieger Institute, Johns Hopkins Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD, United Statesc University of Wisconsin-Madison, Madison, WI, United Statesd School of Medicine and Dentistry, University of Rochester, Rochester, NY, United States

AbstractChildren with intellectual and developmental disabilities (IDDs) and children with medical complexity (CMC) have been disproportionally impacted by the coronavirus disease 2019 pandemic, including school closures. Children with IDDs and CMC rely on schools for a vast array of educational, therapeutic, medical, and social needs. However, maintaining safe schools for children with IDDs and CMC during the coronavirus disease 2019 pandemic may be difficult because of the unique challenges of implementing prevention strategies, such as masking, social distancing, and hand hygiene in this high-risk environment. Furthermore, children with IDDs and CMC are at a higher risk of infectious complications and mortality, underscoring the need for effective mitigation strategies. The goal of this report is to describe the implementation of several screening testing models for severe acute respiratory syndrome coronavirus 2 in this high-risk population. By describing these models, we hope to identify generalizable and scalable approaches to facilitate safe school operations for children with IDDs and CMC during the current and future pandemics. Copyright © 2022 by the American Academy of Pediatrics

Funding detailsUL1 TR0020011R34HL153570-01A1National Institutes of HealthNIH1 OT2 HD107543-01, 1 OT2 HD107544-01, 1 OT2 HD107553-01, 1 OT2 HD107555-01, 1 OT2 HD107556-01, 1 OT2 HD107557-01, 1 OT2 HD107558-01, 1 OT2 HD107559-01U.S. Department of Health and Human ServicesHHSUA6MC31101National Heart, Lung, and Blood InstituteNHLBINational Institute of Arthritis and Musculoskeletal and Skin DiseasesNIAMSNational Institute of Child Health and Human DevelopmentNICHDHHSN275201000003IHealth Resources and Services AdministrationHRSAAgency for Healthcare Research and QualityAHRQMerckUL1TR002345National Center for Advancing Translational SciencesNCATSUL1TR000427U.S. Public Health ServiceUSPHSP50 HD103536, U01DA050988Eunice Kennedy Shriver National Institute of Child Health and Human DevelopmentNICHDP50HD103525, R03HD104065

Document Type: ArticlePublication Stage: FinalSource: Scopus

“Validation of actigraphy for sleep measurement in children with cerebral palsy” (2022) Sleep Medicine

Validation of actigraphy for sleep measurement in children with cerebral palsy(2022) Sleep Medicine, 90, pp. 65-73. 

Xue, B.a , Licis, A.b c , Boyd, J.b , Hoyt, C.R.b d , Ju, Y.-E.S.b c e

a School of Engineering, Washington University, Saint Louis, MO, United Statesb Department of Neurology, Washington University School of Medicine, Saint Louis, MO, United Statesc Center on Biological Rhythms and Sleep (COBRAS), Washington University, Saint Louis, MO, United Statesd Department of Pediatrics, Washington University School of Medicine, Saint Louis, MO, United Statese Hope Center for Neurological Disorders, Saint Louis, MO, United States

AbstractObjectives: Sleep issues are common in children with cerebral palsy (CP), although there are challenges in obtaining objective data about their sleep patterns. Actigraphs measure movement to quantify sleep but their accuracy in children with CP is unknown. Our goals were to validate actigraphy for sleep assessment in children with CP and to study their sleep patterns in a cross-sectional cohort study. Methods: We recruited children with (N = 13) and without (N = 13) CP aged 2–17 years (mean age 9 y 11mo [SD 4 y 10mo] range 4–17 y; 17 males, 9 females; 54% spastic quadriplegic, 23% spastic diplegic, 15% spastic hemiplegic, 8% unclassified CP). We obtained wrist and forehead actigraphy with concurrent polysomnography for one night, and home wrist actigraphy for one week. We developed actigraphy algorithms and evaluated their accuracy (agreement with polysomnography-determined sleep versus wake staging), sensitivity (sleep detection), and specificity (wake detection). Results: Our actigraphy algorithms had median 72–80% accuracy, 87–91% sensitivity, and 60–71% specificity in children with CP and 86–89% accuracy, 88–92% sensitivity, and 70–75% specificity in children without CP, with similar accuracies in wrist and forehead locations. Our algorithms had increased specificity and accuracy compared to existing algorithms, facilitating detection of sleep disruption. Children with CP showed lower sleep efficiency and duration than children without CP. Conclusions: Actigraphy is a valid tool for sleep assessment in children with CP. Children with CP have worse sleep efficiency and duration. © 2022 The Authors

Author KeywordsActigraphy;  Cerebral palsy;  Children;  Polysomnography;  Validation

Funding detailsNational Institutes of HealthNIHK23-NS089922, KL2-TR000450, R01-AG059507, UL1RR024992, UL1TR000448, UL1TR002345National Center for Advancing Translational SciencesNCATSInstitute of Clinical and Translational SciencesICTSCTSA 604

Document Type: ArticlePublication Stage: FinalSource: Scopus

“Phase 2 Trial of Rituximab in Acetylcholine Receptor Antibody-Positive Generalized Myasthenia Gravis: The BeatMG Study” (2022) Neurology

Phase 2 Trial of Rituximab in Acetylcholine Receptor Antibody-Positive Generalized Myasthenia Gravis: The BeatMG Study(2022) Neurology, 98 (4), pp. E376-E389. 

Nowak, R.J.a , Coffey, C.S.b , Goldstein, J.M.d , Dimachkie, M.M.e , Benatar, M.f , Kissel, J.T.g , Wolfe, G.I.h , Burns, T.M.i , Freimer, M.L.g , Nations, S.j , Granit, V.f k , Smith, A.G.l , Richman, D.P.m , Ciafaloni, E.n , Al-Lozi, M.T.o , Sams, L.A.p , Quan, D.q , Ubogu, E.r , Pearson, B.b , Sharma, A.a c , Yankey, J.W.b , Uribe, L.b , Shy, M.s , Amato, A.A.t , Conwit, R.u , O’Connor, K.C.a , Hafler, D.A.a , Cudkowicz, M.E.v , Barohn, R.J.e w , the NeuroNEXT NN103 BeatMG Study Teamx

a The Department of Neurology, Yale University, School of Medicine, New Haven, CT, United Statesb Clinical Trials Statistical and Data Management Center, University of Iowa, Iowa City, United Statesc Department of Neurology, University of Iowa, Iowa City, United Statesd Department of Neurology, Hospital for Special Surgery, New York, NY, United Statese Department of Neurology, Kansas University, School of Medicine, Kansas City, United Statesf Department of Neurology, University of Miami Miller, School of MedicineFL, United Statesg Department of Neurology, The Ohio State University Wexner Medical Center, Columbus, United Statesh Department of Neurology, University at Buffalo, Jacobs School of Medicine and Biomedical Sciences, Buffalo, NY, United Statesi Department of Neurology, University of Virginia, School of Medicine, Charlottesville, United Statesj Department of Neurology, University of Texas Southwestern Medical School, Dallas, United Statesk Department of Neurology, Albert Einstein College of Medicine, Bronx, NY, United Statesl Department of Neurology, University of Utah, School of Medicine, Salt Lake City, United Statesm Department of Neurology, University of California, Davis School of Medicine, Sacramento, United Statesn Department of Neurology, University of Rochester, School of Medicine and DentistryNY, United Stateso Department of Neurology, Washington University, School of Medicine, St. Louis, MO, United Statesp Department of Neurology, University of Cincinnati College of MedicineOH, United Statesq Department of Neurology, University of Colorado, School of Medicine, Aurora, United Statesr Department of Neurology, The University of Alabama at Birmingham, School of Medicine, United Statess Department of Neurology, Carver College of Medicine, University of Iowa, Iowa City, United Statest Department of Neurology, Brigham and Women’s Hospital, Boston, MA, United Statesu Division of Clinical Research, National Institute of Neurological Disorders and Stroke, Rockville, MD, United Statesv Department of Neurology, Massachusetts General Hospital, Boston, United Statesw Department of Neurology, University of Missouri, Columbia, United States

AbstractBackground and Objective To determine whether rituximab is safe and potentially beneficial, warranting further investigation in an efficacy trial for acetylcholine receptor antibody-positive generalized myasthenia gravis (AChR-Ab+ gMG). Methods The B-Cell Targeted Treatment in MG (BeatMG) study was a randomized, double-blind, placebo-controlled, multicenter phase 2 trial that utilized a futility design. Individuals 21-90 years of age, with AChR-Ab+ gMG (MG Foundation of America Class II-IV) and receiving prednisone ≥15 mg/d were eligible. The primary outcome was a measure of steroid-sparing effect, defined as the proportion achieving ≥75% reduction in mean daily prednisone dose in the 4-weeks prior to week 52 and with clinical improvement or no significant worsening as compared to the 4-week period prior to randomization. The coprimary outcome was safety. Secondary outcomes included MG-specific clinical assessments. Fifty-two individuals were randomized (1:1) to a 2-cycle rituximab/placebo regimen, with follow-up through 52 weeks. Results Of the 52 participants included, mean ± SD age at enrollment was 55.1 ± 17.1 years; 23 (44.2%) were women and 31 (59.6%) were Myasthenia Gravis Foundation of America Class II. The mean ± SD baseline prednisone dose was 22.1 ± 9.7 mg/d. The primary steroid-sparing outcome was achieved in 60% of those on rituximab vs 56% on placebo. The study reached its futility endpoint (p = 0.03), suggesting that the predefined clinically meaningful improvement of 30% due to rituximab over placebo was unlikely to be achieved in a subsequent, larger trial. No safety issues were identified. Copyright © 2021 American Academy of Neurology

Funding detailsUL1 TR002556UL1 TR001860UL3 TR002535UL1 TR000457-06National Institutes of HealthNIHU01NS077179, U01NS077352, U01NS084495Centers for Disease Control and PreventionCDCU.S. Food and Drug AdministrationFDANational Institute of Neurological Disorders and StrokeNINDS1R21NS104516Michael J. Fox Foundation for Parkinson’s ResearchMJFFBristol-Myers SquibbBMSCharcot-Marie-Tooth AssociationCMTAMyasthenia Gravis Foundation of AmericaMGFAAmylin PharmaceuticalsGenentechNovartisMuscular Dystrophy AssociationMDABrigham and Women’s HospitalBWH1UL1TR001102BiogenParent Project Muscular DystrophyPPMDPatient-Centered Outcomes Research InstitutePCORINational Center for Advancing Translational SciencesNCATSAlexion PharmaceuticalsUniversity of PennsylvaniaPennOhio State UniversityOSUUL1 TR001070Yale School of MedicineYSMUL1 TR001863State University of New YorkSUNYUL1TR001412Washington University in St. LouisWUSTLUL1 TR002345University of UtahUL1 TR001067University of KansasKUUL1 TR002366University of RochesterURUL1 TR002001University of CincinnatiUC5UL1TR001425-03University at BuffaloUBCSL BehringPTC TherapeuticsPTCSarepta TherapeuticsSRPT

Document Type: ArticlePublication Stage: FinalSource: Scopus

“Microstructural Periventricular White Matter Injury in Post-hemorrhagic Ventricular Dilatation” (2022) Neurology

Microstructural Periventricular White Matter Injury in Post-hemorrhagic Ventricular Dilatation(2022) Neurology, 98 (4), pp. E364-E375. 

Isaacs, A.M.a b , Neil, J.J.c , McAllister, J.P.d , Dahiya, S.e , Castaneyra-Ruiz, L.d , Merisaari, H.h , Botteron, H.E.d , Alexopoulos, D.c , George, A.h , Sun, P.h , Morales, D.M.d , Shimony, J.S.i , Strahle, J.h , Yan, Y.f , Song, S.-K.h , Limbrick, D.D.d , Smyser, C.D.c g h

a The Department of Neuroscience, Washington University, St. Louis, MO, United Statesb Department of Clinical Neurosciences, University of Calgary, Canadac Department of Neurology, Washington University School of Medicine, St. Louis, MO, United Statesd Department of Neurosurgery, Washington University School of Medicine, St. Louis, MO, United Statese Department of Pathology, Washington University School of Medicine, St. Louis, MO, United Statesf Public Health Sciences, Washington University School of Medicine, St. Louis, MO, United Statesg Department of Pediatrics, Washington University School of Medicine, St. Louis, MO, United Statesh Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, MO, United States

AbstractBackground and Objectives The neurologic deficits of neonatal post-hemorrhagic hydrocephalus (PHH) have been linked to periventricular white matter injury. To improve understanding of PHH-related injury, diffusion basis spectrum imaging (DBSI) was applied in neonates, modeling axonal and myelin integrity, fiber density, and extrafiber pathologies. Objectives included characterizing DBSI measures in periventricular tracts, associating measures with ventricular size, and examining MRI findings in the context of postmortem white matter histology from similar cases. Methods A prospective cohort of infants born very preterm underwent term equivalent MRI, including infants with PHH, high-grade intraventricular hemorrhage without hydrocephalus (IVH), and controls (very preterm [VPT]). DBSI metrics extracted from the corpus callosum, corticospinal tracts, and optic radiations included fiber axial diffusivity, fiber radial diffusivity, fiber fractional anisotropy, fiber fraction (fiber density), restricted fractions (cellular infiltration), and nonrestricted fractions (vasogenic edema). Measures were compared across groups and correlated with ventricular size. Corpus callosum postmortem immunohistochemistry in infants with and without PHH assessed intra- and extrafiber pathologies. Results Ninety-five infants born very preterm were assessed (68 VPT, 15 IVH, 12 PHH). Infants with PHH had the most severe white matter abnormalities and there were no consistent differences in measures between IVH and VPT groups. Key tract-specific white matter injury patterns in PHH included reduced fiber fraction in the setting of axonal or myelin injury, increased cellular infiltration, vasogenic edema, and inflammation. Specifically, measures of axonal injury were highest in the corpus callosum; both axonal and myelin injury were observed in the corticospinal tracts; and axonal and myelin integrity were preserved in the setting of increased extrafiber cellular infiltration and edema in the optic radiations. Increasing ventricular size correlated with worse DBSI metrics across groups. On histology, infants with PHH had high cellularity, variable cytoplasmic vacuolation, and low synaptophysin marker intensity. Discussion PHH was associated with diffuse white matter injury, including tract-specific patterns of axonal and myelin injury, fiber loss, cellular infiltration, and inflammation. Larger ventricular size was associated with greater disruption. Postmortem immunohistochemistry confirmed MRI findings. These results demonstrate DBSI provides an innovative approach extending beyond conventional diffusion MRI for investigating neuropathologic effects of PHH on neonatal brain development. Copyright © 2021 American Academy of Neurology

Funding details396212National Institutes of HealthNIHK02 NS089852, K23 MH105179, K23 NS075151, P30 NS098577, R01 HD057098, R01 HD061619, R01 MH113570, R01 NS047592, TR002344, U01 EY025500Doris Duke Charitable FoundationDDCFDana FoundationCerebral Palsy International Research FoundationCPIRFChild Neurology FoundationCNFEunice Kennedy Shriver National Institute of Child Health and Human DevelopmentNICHDP50 HD103525

Document Type: ArticlePublication Stage: FinalSource: Scopus

“Associations Between Diabetic Retinopathy and Parkinson’s Disease: Results From the Catalonian Primary Care Cohort Study” (2022) Frontiers in Medicine

Associations Between Diabetic Retinopathy and Parkinson’s Disease: Results From the Catalonian Primary Care Cohort Study(2022) Frontiers in Medicine, 8, art. no. 800973, . 

Mauricio, D.a b c d , Vlacho, B.a , Barrot de la Puente, J.a e , Mundet-Tudurí, X.a f , Real, J.a d , Kulisevsky, J.g , Ortega, E.a h i , Castelblanco, E.a j , Julve, J.k , Franch-Nadal, J.a d l

a DAP-Cat Group, Unitat de Suport a la Recerca Barcelona, Fundació Institut Universitari per a la recerca a l’Atenció Primària de Salut Jordi Gol i Gurina, Barcelona, Spainb Departament of Medicine, University of Vic-Central University of Catalonia, Catalonia, Spainc Department of Endocrinology and Nutrition, Hospital de la Santa Creu i Sant Pau, Barcelona, Spaind CIBER of Diabetes and Associated Metabolic Diseases, Instituto de Salud Carlos III, Madrid, Spaine Primary Health Care Center Dr, Jordi Nadal i Fàbregas (Salt), Gerència d’Atenció Primaria, Institut Català de la Salut, Girona, Spainf Faculty of Medicine, Department of Medicine, Autonomous University of Barcelona, Barcelona, Spaing Movement Disorders Unit, Neurology Department, Hospital de la Santa Creu i Sant Pau, Barcelona, Spainh Department of Endocrinology and Nutrition, Institut d’Investigacions Biomèdiques August Pi i Suñer, Hospital Clinic, Barcelona, Spaini CIBER of Physiopathology of Obesity and Nutrition, Instituto de Salud Carlos III, Madrid, Spainj Division of Endocrinology, Metabolism and Lipid Research, Washington University School of Medicine in St. Louis, St. Louis, MO, United Statesk Institut de Recerca de l’Hospital de la Santa Creu i Sant Pau, Barcelona, Spainl Primary Health Care Center Raval Sud, Gerència d’Atenció Primaria, Institut Català de la Salut, Barcelona, Spain

AbstractThe purpose of this study was to assess the risk of occurrence of Parkinson’s disease (PD) among subjects with type 2 diabetes and diabetic retinopathy (DR) in our large primary health care database from Catalonia (Spain). A retrospective cohort study with pseudo-anonymized routinely collected health data from SIDIAP was conducted from 2008 to 2016. We calculated the number of events, time to event, cumulative incidence, and incidence rates of PD for subjects with and without DR and for different stages of DR. The proportional hazards regression analysis was done to assess the probability of occurrence between DR and PD. In total, 26,453 type 2 diabetic subjects with DR were identified in the database, and 216,250 subjects without DR at inclusion. During the follow-up period, 1,748 PD events occurred. PD incidence rate and cumulative incidence were higher among subjects with DR (16.95 per 10,000 person-years and 0.83%, respectively). In the unadjusted analysis, subjects with DR were at 1.25 times higher risk (hazard ratio: 1.22, 95% confidence interval: 1.06; 1.41) of developing PD during the study period. However, we did not find any statistically significant HR for DR in any models after adjusting for different risk factors (age, sex, duration of diabetes, smoking, body mass index, glycosylated hemoglobin, comorbidities). In conclusion, in our primary health care population database, DR was not associated with an increased risk of PD after adjusting for different risk factors. In our retrospective cohort study, age, male sex, and diabetes duration were independent risk factors for developing PD. Copyright © 2022 Mauricio, Vlacho, Barrot de la Puente, Mundet-Tudurí, Real, Kulisevsky, Ortega, Castelblanco, Julve and Franch-Nadal.

Author Keywordsage;  diabetes type 2;  diabetic retinopathy;  Parkinson’s disease;  primary care;  real world data (RWD)

Document Type: ArticlePublication Stage: FinalSource: Scopus

“Association of BDNF Val66Met with Tau Hyperphosphorylation and Cognition in Dominantly Inherited Alzheimer Disease” (2022) JAMA Neurology

Association of BDNF Val66Met with Tau Hyperphosphorylation and Cognition in Dominantly Inherited Alzheimer Disease(2022) JAMA Neurology, . 

Lim, Y.Y.a , Maruff, P.a b , Barthélemy, N.R.c , Goate, A.d , Hassenstab, J.c , Sato, C.c , Fagan, A.M.c , Benzinger, T.L.S.e , Xiong, C.f , Cruchaga, C.g , Levin, J.h i j , Farlow, M.R.k , Graff-Radford, N.R.l , Laske, C.i m , Masters, C.L.n , Salloway, S.o p , Schofield, P.R.q r , Morris, J.C.c , Bateman, R.J.c , McDade, E.c

a Turner Institute for Brain and Mental Health, School of Psychological Sciences, Monash University, Clayton, VIC, Australiab Cogstate Ltd, Melbourne, VIC, Australiac Department of Neurology, Washington University, School of Medicine in St Louis, St Louis, MO, United Statesd Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, United Statese Department of Radiology, Washington University, School of Medicine in St Louis, St Louis, MO, United Statesf Division of Biostatistics, Washington University, School of Medicine in St Louis, St Louis, MO, United Statesg Department of Psychiatry, Washington University, School of Medicine in St Louis, St Louis, MO, United Statesh Department of Neurology, Ludwig-Maximilians-Universität München, Munich, Germanyi German Center for Neurodegenerative Diseases, Munich, Germanyj Munich Cluster for Systems Neurology (SyNergy), Munich, Germanyk Department of Neurology, Indiana University, Indianapolis, United Statesl Department of Neurology, Mayo Clinic Jacksonville, Jacksonville, FL, United Statesm Section for Dementia Research, Department of Cellular Neurology, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germanyn Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville, VIC, Australiao Butler Hospital, Providence, RI, United Statesp Warren Alpert Medical School, Brown University, Providence, RI, United Statesq Neuroscience Research Australia, Sydney, NSW, Australiar School of Medical Sciences, University of New South Wales, Sydney, NSW, Australia

AbstractImportance: Allelic variation in the brain-derived neurotrophic factor (BDNF) Val66Met polymorphism moderates increases in cerebrospinal fluid (CSF) levels of tau and phosphorylated tau 181 (p-tau181), measured using immunoassay, and cognitive decline in presymptomatic dominantly inherited Alzheimer disease (DIAD). Advances in mass spectrometry show that CSF tau phosphorylation occupancy at threonine 181 and 217 (p-tau181/tau181, p-tau217/tau217) increases with initial β-amyloid (Aβ) aggregation, while phosphorylation occupancy at threonine 205 (p-tau205/tau205) and level of total tau increase when brain atrophy and clinical symptoms become evident. Objective: To determine whether site-specific tau phosphorylation occupancy (ratio of phosphorylated to unphosphorylated tau) is associated with BDNF Val66Met in presymptomatic and symptomatic DIAD. Design, Setting, and Participants: This cross-sectional cohort study included participants from the Dominantly Inherited Alzheimer Network (DIAN) and Aβ-positive cognitively normal older adults in the Alzheimer’s Disease Neuroimaging Initiative (ADNI). Data were collected from 2009 through 2018 at multicenter clinical sites in the United States, United Kingdom, and Australia, with no follow-up. DIAN participants provided a CSF sample and completed clinical and cognitive assessments. Data analysis was conducted between March 2020 and March 2021. Main Outcomes and Measures: Mass spectrometry analysis was used to determine site-specific tau phosphorylation level; tau levels were also measured using immunoassay. Episodic memory and global cognitive composites were computed. Results: Of 374 study participants, 144 were mutation noncarriers, 156 were presymptomatic mutation carriers, and 74 were symptomatic carriers. Of the 527 participants in the network, 153 were excluded because their CSF sample, BDNF status, or both were unavailable. Also included were 125 Aβ-positive cognitively normal older adults in the ADNI. The mean (SD) age of DIAD participants was 38.7 (10.9) years; 43% were women. The mean (SD) age of participants with preclinical sporadic AD was 74.8 (5.6) years; 52% were women. In presymptomatic mutation carriers, compared with Val66 homozygotes, Met66 carriers showed significantly poorer episodic memory (d = 0.62; 95% CI, 0.28-0.95), lower hippocampal volume (d = 0.40; 95% CI, 0.09-0.71), and higher p-tau217/tau217 (d = 0.64; 95% CI, 0.30-0.97), p-tau181/tau181 (d = 0.65; 95% CI, 0.32-0.99), and mass spectrometry total tau (d = 0.43; 95% CI, 0.10-0.76). In symptomatic mutation carriers, Met66 carriers showed significantly poorer global cognition (d = 1.17; 95% CI, 0.65-1.66) and higher p-tau217/tau217 (d = 0.53; 95% CI, 0.05-1.01), mass spectrometry total tau (d = 0.78; 95% CI, 0.28-1.25), and p-tau205/tau205 (d = 0.97; 95% CI, 0.46-1.45), when compared with Val66 homozygotes. In preclinical sporadic AD, Met66 carriers showed poorer episodic memory (d = 0.39; 95% CI, 0.00-0.77) and higher total tau (d = 0.45; 95% CI, 0.07-0.84) and p-tau181 (d = 0.46; 95% CI, 0.07-0.85). Conclusions and Relevance: In DIAD, clinical disease stage and BDNF Met66 were associated with cognitive impairment and levels of site-specific tau phosphorylation. This suggests that pharmacological strategies designed to increase neurotrophic support in the presymptomatic stages of AD may be beneficial. © 2022 American Medical Association. All rights reserved.

Document Type: ArticlePublication Stage: Article in PressSource: Scopus

“Prevalence Estimates of Amyloid Abnormality Across the Alzheimer Disease Clinical Spectrum” (2022) JAMA Neurology

Prevalence Estimates of Amyloid Abnormality Across the Alzheimer Disease Clinical Spectrum(2022) JAMA Neurology, . Cited 1 time.

Jansen, W.J.a b , Janssen, O.a , Tijms, B.M.c , Vos, S.J.B.a , Ossenkoppele, R.c d , Visser, P.J.a c e , Aarsland, D.f g , Alcolea, D.h i , Altomare, D.j k , Von Arnim, C.l m , Baiardi, S.n , Baldeiras, I.o p q , Barthel, H.r , Bateman, R.J.s , Van Berckel, B.t , Binette, A.P.u v , Blennow, K.w , Boada, M.x y , Boecker, H.z , Bottlaender, M.aa , Den Braber, A.ab , Brooks, D.J.ac ad ae , Van Buchem, M.A.af , Camus, V.ag , Carill, J.M.ah , Cerman, J.ai , Chen, K.aj , Chételat, G.ak , Chipi, E.al , Cohen, A.D.am , Daniels, A.an , Delarue, M.ak , Didic, M.ao ap , Drzezga, A.z aq , Dubois, B.ar , Eckerström, M.as , Ekblad, L.L.at , Engelborghs, S.au av , Epelbaum, S.ar , Fagan, A.M.aw , Fan, Y.ax , Fladby, T.ay , Fleisher, A.S.az , Van Der Flier, W.M.ab , Förster, S.ba bb , Fortea, J.h i , Frederiksen, K.S.bc , Freund-Levi, Y.bd be bf , Frings, L.bg , Frisoni, G.B.bh , Fröhlich, L.bi , Gabryelewicz, T.bj , Gertz, H.-J.bk , Gill, K.D.bl , Gkatzima, O.bm , Gómez-Tortosa, E.bn , Grimmer, T.bo , Guedj, E.bp , Habeck, C.G.bq , Hampel, H.br , Handels, R.bs , Hansson, O.bt , Hausner, L.bu , Hellwig, S.bv , Heneka, M.T.bw bx , Herukka, S.-K.by bz , Hildebrandt, H.ca , Hodges, J.cb , Hort, J.ai , Huang, C.-C.cc , Iriondo, A.J.cd , Itoh, Y.ce , Ivanoiu, A.cf , Jagust, W.J.cg ch , Jessen, F.ci cj ck , Johannsen, P.cl , Johnson, K.A.cm , Kandimalla, R.bl cn co cp , Kapaki, E.N.cq , Kern, S.cr , Kilander, L.cs , Klimkowicz-Mrowiec, A.ct , Klunk, W.E.cu cv , Koglin, N.cw , Kornhuber, J.cx , Kramberger, M.G.cy , Kuo, H.-C.cz , Van Laere, K.da db , Landau, S.M.dc , Landeau, B.ak , Lee, D.Y.dd , De Leon, M.de , Leyton, C.E.df , Lin, K.-J.dg dh , Lleó, A.h i , Löwenmark, M.di , Madsen, K.dj , Maier, W.dk , Marcusson, J.dl , Marquié, M.x y , Martinez-Lage, P.dm , Maserejian, N.dn , Mattsson, N.bt , De Mendonça, A.do , Meyer, P.T.bg , Miller, B.L.dp , Minatani, S.ce , Mintun, M.A.dq , Mok, V.C.T.dr ds dt , Molinuevo, J.L.du , Morbelli, S.D.dv dw , Morris, J.C.aw , Mroczko, B.dx dy , Na, D.L.dz ea , Newberg, A.eb , Nobili, F.ec ed , Nordberg, A.a , Olde Rikkert, M.G.M.ee , De Oliveira, C.R.o , Olivieri, P.ef fd , Orellana, A.x y , Paraskevas, G.eg , Parchi, P.eh ei , Pardini, M.ej , Parnetti, L.al , Peters, O.ek , Poirier, J.el , Popp, J.em en , Prabhakar, S.eo , Rabinovici, G.D.ep , Ramakers, I.H.bs , Rami, L.eq , Reiman, E.M.aj , Rinne, J.O.er , Rodrigue, K.M.es , Rodríguez-Rodriguez, E.et , Roe, C.M.aw , Rosa-Neto, P.el , Rosen, H.J.eu , Rot, U.ev , Rowe, C.C.ew ex , Rüther, E.ey , Ruiz, A.x y , Sabri, O.r , Sakhardande, J.ez , Sánchez-Juan, P.fa , Sando, S.B.fb fc , Santana, I.o p q , Sarazin, M.ef fd , Scheltens, P.ab , Schröder, J.fe , Selnes, P.ay , Seo, S.W.ff , Silva, D.fg , Skoog, I.cr , Snyder, P.J.fh , Soininen, H.fi fj , Sollberger, M.fk fl , Sperling, R.A.fm fn , Spiru, L.fo fp , Stern, Y.ez , Stomrud, E.bt , Takeda, A.ce , Teichmann, M.ar fq , Teunissen, C.E.ab , Thompson, L.I.fr , Tomassen, J.ab , Tsolaki, M.fs , Vandenberghe, R.ft fu , Verbeek, M.M.fv , Verhey, F.R.J.bs , Villemagne, V.ew fw , Villeneuve, S.u v fx , Vogelgsang, J.fy , Waldemar, G.bc fz , Wallin, A.cr , Wallin, Å.K.bt , Wiltfang, J.ga gb , Wolk, D.A.gc , Yen, T.-C.gd ge , Zboch, M.gf , Zetterberg, H.cr gg gh gi gj

a Alzheimer Centre Limburg, Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience, Maastricht University, PO Box 616, Maastricht, 6200 MD, Netherlandsb Banner Alzheimer’s Institute, Phoenix, AZ, United Statesc Alzheimer Center Amsterdam, Department of Neurology, Amsterdam Neuroscience, Vrije Universiteit Amsterdam, Amsterdam University Medical Center (UMC), Amsterdam, Netherlandsd Clinical Memory Research Unit, Department of Clinical Sciences, Malmö, Lund University, Lund, Swedene Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Stockholm, Swedenf Department of Neurobiology, Care Sciences and Society, Center for Alzheimer Research, Division for Neurogeriatrics, Karolinska Institutet, Huddinge, Swedeng Centre for Age-Related Medicine, Stavanger University Hospital, Stavanger, Norwayh Centro de Investigación Biomédica en Red Sobre Enfermedades Neurodegenerativas, Madrid, Spaini Memory Unit, Neurology Department, Hospital de la Santa Creu i Sant Pau, Barcelona, Spainj Laboratory Alzheimer’s Neuroimaging and Epidemiology, Istituto di Ricovero e Cura A Carattere Scientifico (IRCCS) Fatebenefratelli, Brescia, Italyk Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italyl Division of Geriatrics, University of Goettingen Medical School, Goettingen, Germanym Clinic for Neurogeriatrics and Neurological Rehabilitation, University and Rehabilitation Hospital Ulm, Ulm, Germanyn Department of Experimental Diagnostic and Specialty Medicine (DIMES), University of Bologna, Bologna, Spaino Center for Neuroscience and Cell Biology (CIBB), University of Coimbra, Coimbra, Portugalp Neurology Department and Laboratory of Neurochemistry, Centro Hospitalar e Universitário de Coimbra, Praceta Professor Mota Pinto, Coimbra, Portugalq Faculty of Medicine, University of Coimbra, Azinhaga de Santa Comba, Coimbra, Portugalr Department of Nuclear Medicine, University Hospital of Leipzig, Leipzig, Germanys Department of Neurology and the Alzheimer’s Disease Research Center, Washington University, School of Medicine in St Louis, St Louis, MO, United Statest Department of Radiology and Nuclear Medicine, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, Netherlandsu Department of Psychiatry, Faculty of Medicine, McGill University, Montreal, QC, Canadav Douglas Mental Health University Institute, Montreal, QC, Canadaw Clinical Neurochemistry Laboratory, Department of Neuroscience and Physiology, Sahlgren’s University Hospital, Mölndal, Swedenx Research Center and Memory Clinic of Fundació, Alzheimer Centre Educacional, Institut Català de Neurociències Aplicades, Universitat Internacional de Catalunya, Barcelona, Spainy CIBERNED, Network Center for Biomedical Research in Neurodegenerative Diseases, National Institute of Health Carlos III, Madrid, Spainz Deutsches Zentrum für Neurodegenerative Erkrankungen E.V. (DZNE), Bonn, Germanyaa Université Paris-Saclay, Service Hospitalier Frédéric Joliot (CEA), French National Centre for Scientific Research (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM), BioMaps, Service Hospitalier Frederic Joliot, Orsay, Franceab Department of Neurology, Alzheimer Centre Amsterdam, Amsterdam Neuroscience, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, Netherlandsac Translational and Clinical Research Institute, University of Newcastle Upon Tyne, United Kingdomad Department of Nuclear Medicine, Positron Emission Tomography Centre, Aarhus University, Aarhus, Denmarkae Department of Brain Sciences, Imperial College London, London, United Kingdomaf Department of Neurology, University Hospital Leiden, Leiden, Netherlandsag Unite Mixte de Recherche, INSERM U930, French National Centre for Scientific Research (CNRS), ERL, Tours, Franceah Nuclear Medicine Department, University Hospital Marqués de Valdecilla, Molecular Imaging, Instituto de Investigación Sanitaria Valdecilla (IDIVAL), University of Cantabria, Santander, Spainai Department of Neurology, Second Faculty of Medicine, Charles University, Motol University Hospital, Prague, Czech Republicaj Banner Alzheimer’s Institute, Phoenix, AZ, United Statesak Normandie University, University of Caen Normandie (UNICAEN), INSERM, U1237, Physiopathology and Imaging of Neurological Disorders (PhIND), Institut Blood and Brain at Caen-Normandie, Cyceron, Caen, Franceal Centro Disturbi della Memoria, Laboratorio di Neurochimica Clinica, Clinica Neurologica, Università di Perugia, Perugia, Italyam Department of Psychiatry, University of Pittsburgh, School of Medicine, Pittsburgh, PA, United Statesan Department of Neurology, Washington University, School of Medicine in St Louis, St Louis, MO, United Statesao Assistance Publique Hôpitaux de Marseille (AP-HM), Timone, Service de Neurologie et Neuropsychologie, Hôpital Timone Adultes, Marseille, Franceap Aix Marseille Univ, INSERM, Institut de Neurosciences des Systèmes (INS), Marseille, Franceaq Department of Nuclear Medicine, University Hospital of Cologne, Cologne, Germanyar Department of Neurology, Institut de la Mémoire et de la Maladie d’Alzheimer, Centre de Reference Demences Rares, Hopital de la Pitie-Salpetriere, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, Franceas Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Mölndal, Swedenat Turku PET Centre, University of Turku, Turku, Finlandau Reference Center for Biological Markers of Dementia (BIODEM), University of Antwerp, Antwerp, Belgiumav Center for Neurosciences, Vrije Universiteit Brussel, Brussels, Belgiumaw Department of Neurology, The Alzheimer’s Disease Research Center, Washington University, School of Medicine in St Louis, St Louis, MO, United Statesax Department of Radiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United Statesay Department of Neurology, Akershus University Hospital, Lorenskog, Norwayaz Eli Lilly and Company, Indianapolis, IN, United Statesba Department of Nuclear Medicine, Klinikum Rechts der Isar, Technische Universität München, Munich, Germanybb Department of Nuclear Medicine, Klinikum Bayreuth, Bayreuth, Germanybc Danish Dementia Research Center, Department of Neurology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmarkbd School of Medical Sciences, Örebro University, Örebro, Swedenbe Department of Neurobiology, Care Sciences and Society, Division of Clinical Geriatrics, Karolinska Institutet, Center for Alzheimer Research, Stockholm, Swedenbf Department of Old Age Psychiatry, Psychology and Neuroscience, King’s College London, London, United Kingdombg Department of Nuclear Medicine, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germanybh Memory Clinic, University Hospitals, University of Geneva, Geneva, Switzerlandbi Department of Geriatric Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Heidelberg, Germanybj Department of Neurodegenerative Disorders, Mossakowski Medical Research Centre, Polish Academy of Sciences, Warsaw, Polandbk Klinik und Poliklinik für Psychiatrie und Psychotherapie, Universitätsklinikum Leipzig, Leipzig, Germanybl Department of Biochemistry, Postgraduate Institute of Medical Education and Research, Chandigarh, Indiabm Greek Association of Alzheimer’s Disease and Related Disorders, Thessaloniki, Greecebn Department of Neurology, Fundación Jiménez Díaz, Madrid, Spainbo Department of Psychiatry and Psychotherapy, Klinikum Rechts der Isar, Technical University of Munich, School of Medicine, Munich, Germanybp Aix Marseille University, AP-HM, CNRS, Centrale Marseille, Institut Fresnel, Timone Hospital, Centre Européen de Recherche en Imagerie Médicale (CERIMED), Nuclear Medicine Department, Marseille, Francebq Department of Neurology, Taub Institute for Research on Alzheimer’s Disease and the Aging Brain, Columbia University, Irving Medical Center, New York, NY, United Statesbr Sorbonne University, Clinical Research Group No. 21, Alzheimer Precision Medicine, AP-HP, Pitié-Salpêtrière Hospital, Paris, Francebs Alzheimer Centre Limburg, Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience, Maastricht University, Maastricht, Netherlandsbt Clinical Memory Research Unit, Department of Clinical Sciences, Malmö, Lund University, Lund, Swedenbu Universität Heidelberg, Abteilung Gerontopsychiatrie, Zentralinstitut für Seelische Gesundheit Mannheim, Mannheim, Germanybv Department of Psychiatry, Psychotherapy Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germanybw Department of Neurodegenerative Diseases and Geriatric Psychiatry, University Hospital of Bonn, Bonn, Germanybx Division of Infectious Diseases and Immunology, University of Massachusetts Medical School, Worcester, United Statesby Institute of Clinical Medicine-Neurology, University of Eastern Finland, Kuopio, Finlandbz Neurocenter, Neurology, Kuopio University Hospital, Kuopio, Finlandca Klinikum Bremen-Ost, University of Oldenburg, Institute of Psychology, Oldenburg, Germanycb Brain and Mind Centre, Faculty of Medicine and Health, The University of Sydney, Sydney, NSW, Australiacc Chang Gung Memorial Foundation-Linkou, Taoyuan, Taiwancd Center for Research and Advanced Therapies, Centro de Investigación y Ciencias Avanzadas-Alzheimer Foundation, Donostia-San Sebastian, Spaince Department of Neurology, Osaka City University, Graduate School of Medicine, Osaka, Japancf Department of Neurology, Cliniques Universitaires Saint-Luc, Brussels, Belgiumcg Helen Wills Neuroscience Institute, University of California, Berkeley, Berkeley, United Statesch Division of Molecular Biophysics and Integrated Bioimaging, Lawrence Berkeley National Laboratory, Berkeley, CA, United Statesci Department of Psychiatry, Medical Faculty, University of Cologne, Cologne, Germanycj Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germanyck DZNE, Bonn, Germanycl Memory Disorder Unit, Copenhagen University Hospital, Copenhagen, Denmarkcm Department of Radiology, Massachusetts General Hospital, Boston, United Statescn Department of Radiation Oncology, Emory University, Atlanta, GA, United Statesco Applied Biology, Council of Scientific and Industrial Research (CSIR)-Indian Institute of Chemical Technology, Uppal Road, Tarnaka, Telangana State, Hyderabad, Indiacp Department of Biochemistry, Kakatiya Medical College, Mahatma Gandhi Memorial Hospital, Telangana State, Warangal, Indiacq National and Kapodistrian University of Athens, School of Medicine, 1st Department of Neurology, Eginition Hospital, Athens, Greececr Neuropsychiatric Epidemiology Unit, Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, Sahlgrenska Academy, The University of Gothenburg, Gothenburg, Swedencs Department of Public Health and Caring Sciences/Geriatrics, Uppsala University, Uppsala, Swedenct Department of Internal Medicine and Gerontology, Faculty of Medicine, Jagiellonian University Medical College, Krakow, Polandcu Department of Psychiatry, Massachusetts General Hospital, Boston, United Statescv Department of Neurology, University of Pittsburgh, Pittsburgh, PA, United Statescw Life Molecular Imaging GmbH, Berlin, Germanycx Department of Psychiatry and Psychotherapy, University Hospital, Friedrich-Alexander-University Erlangen-Nuremberg, Erlangen, Germanycy Department of Neurology, University Medical Centre Ljubljana, Ljubljana, Sloveniacz Department of Neurology, Chang Gung Memorial Hospital, Linkou Medical Center, Chang Gung University, College of Medicine, Taoyuan, Taiwanda Division of Nuclear Medicine and Molecular Imaging, University Hospitals Leuven, Leuven, Belgiumdb Department of Imaging and Pathology, Katholieke Universiteit Leuven, Leuven, Belgiumdc Helen Wills Neuroscience Institute, University of California, Berkeley, Berkeley, United Statesdd Department of Neuropsychiatry, Seoul National University Hospital, Seoul, South Koreade Brain Health Imaging Institute, Department of Radiology, Weill Cornell Medicine, New York, NY, United Statesdf School of Psychology, Faculty of Science, The University of Sydney, Sydney, NSW, Australiadg Healthy Aging Research Center, Department of Medical Imaging and Radiological Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwandh Department of Nuclear Medicine, Molecular Imaging Center, Linkou Chang Gung Memorial Hospital, Guishan, Taoyuan, Taiwandi Memory Clinic, Department of Geriatrics, Uppsala University Hospital, Uppsala, Swedendj Neurobiology Research Unit, Copenhagen University Hospital, Copenhagen, Denmarkdk Department of Neurodegenerative Diseases and Geriatric Psychiatry, University of Bonn, Bonn, Germanydl Acute Internal Medicine and Geriatrics, Department of Health, Medicine and Caring Sciences, Linköping University, Linköping, Swedendm Center for Research and Advanced Therapies, CITA-Alzheimer Foundation, Donostia-San Sebastian, Spaindn Biogen, Cambridge, MA, United Statesdo Faculty of Medicine, University of Lisboa, Lisboa, Portugaldp Memory and Aging Center, Department of Neurology, University of California, San Francisco, San Francisco, United Statesdq Avid Radiopharmaceuticals, Philadelphia, PA, United Statesdr Division of Neurology, Department of Medicine and Therapeutics, Prince of Wales Hospital, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, Hong Kongds Margaret K.L. Cheung Research Centre for Management of Parkinsonism, Gerald Choa Neuroscience Centre, Lui Che Woo Institute of Innovative Medicine, The Chinese University of Hong Kong, Hong Kong, Hong Kongdt BrainNow Research Institute, Guangdong Province, Shenzhen, Chinadu Alzheimer’s Disease and Other Cognitive Disorders Unit, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Clinic University Hospital, Barcelona, Spaindv Department of Health Sciences (DISSAL), University of Genoa, Genoa, Italydw Ospedale Policlinico San Martino, IRCCS, Genoa, Italydx Department of Neurodegeneration Diagnostics, Medical University of Białystok, Białystok, Polanddy Department of Biochemical Diagnostics, University Hospital of Białystok, Białystok, Polanddz Department of Neurology, Samsung Medical Center, Sungkyunkwan University, School of Medicine, Seoul, South Koreaea Neuroscience Center, Samsung Medical Center, Seoul, South Koreaeb Myrna Brind Center of Integrative Medicine, Thomas Jefferson University and Hospital, Philadelphia, PA, United Statesec Dipartimento di Neuroscienze, Riabilitazione, Oftalmologia, Genetica e Scienze Materno-Infantili, University of Genoa, Genoa, Italyed Ospedale Policlinico San Martino, IRCCS, Genoa, Italyee Radboudumc Alzheimer Centre, Radboud University Medical Center, Nijmegen, Netherlandsef Department of Neurology of Memory and Language, Groupe Hospitalier Universitaire Paris Psychiatry and Neurosciences, Hôpital Sainte Anne, Paris, F-75014, Franceeg National and Kapodistrian University of Athens, School of Medicine, 1st Department of Neurology, Eginition Hospital, Athens, Greeceeh Istituto Delle Scienze Neurologiche di Bologna, IRCCS, Bologna, Italyei DIMES, University of Bologna, Bologna, Italyej DINOGMI, University of Genoa, Genoa, Italyek Klinik für Psychiatrie und Psychotherapie, Charité Universitätsmedizin Berlin-CBF, Berlin, Germanyel Studies on Prevention of Alzheimer’s Disease (StOP-AD) Centre, Montreal, QC, Canadaem Department of Geriatric Psychiatry, University Hospital of Psychiatry Zürich, University of Zürich, Zürich, Switzerlanden Old Age Psychiatry, Department of Psychiatry, University Hospital of Lausanne, University of Lausanne, Lausanne, Switzerlandeo Department of Neurology, Nehru Hospital, Postgraduate Institute of Medical Education and Research, Chandigarh, Indiaep Memory and Aging Center, Department of Neurology, University of California, San Francisco, San Francisco, United Stateseq Alzheimer’s Disease and Other Cognitive Disorders Unit, Neurology Service, Hospital Clínic of Barcelona, IDIBAPS, Barcelona, Spainer Turku PET Centre, Turku, Finlandes Center for Vital Longevity, School of Behavioral and Brain Sciences, The University of Texas at Dallas, Dallas, United Stateset Neurology Department, Hospital Universitario Marqués de Valdecilla, IDIVAL, Santander, Spaineu Memory and Aging Center, Department of Neurology, University of California, San Francisco, San Francisco, United Statesev Department of Neurology, Medical Center, Zaloska 7, Ljubljana, Sloveniaew Department of Molecular Imaging, Austin Health, Melbourne, VIC, Australiaex Florey Department of Neuroscience, University of Melbourne, Melbourne, VIC, Australiaey Department of Psychiatry and Psychotherapy, University Medical Center, Georg-August University, Göttingen, Germany, Germanyez Cognitive Neuroscience Division, Department of Neurology, The Taub Institute, Columbia University, New York, NY, United Statesfa Service of Neurology, University Hospital Marqués de Valdecilla-IDIVAL, CIBERNED, Santander, Spainfb Department of Neuroscience, Faculty of Medicine, Norwegian University of Science and Technology, Trondheim, Norwayfc Department of Neurology, University Hospital of Trondheim, Trondheim, Norwayfd Université de Paris, Paris, Université Paris-Saclay, BioMaps, CEA, CNRS, INSERM, Orsay, Francefe Section for Geriatric Psychiatry, University of Heidelberg, Heidelberg, Germanyff Department of Neurology, Sungkyunkwan University, School of Medicine, Samsung Medical Center, Seoul, South Koreafg Faculty of Medicine, University of Lisboa, Lisboa, Portugalfh Department of Biomedical and Pharmaceutical Sciences, College of Pharmacy, The University of Rhode Island, Kingston, United Statesfi Department of Neurology, Institute of Clinical Medicine, University of Eastern Finland, Kuopio, Finland, Finlandfj Neurocenter, Department of Neurology, Kuopio University Hospital, Kuopio, Finlandfk Memory Clinic, University Department of Geriatric Medicine, Felix Platter-Hospital, Basel, Switzerlandfl Department of Neurology, University Hospital Basel, Basel, Switzerlandfm Center for Alzheimer Research and Treatment, Department of Neurology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, United Statesfn Harvard Aging Brain Study, Department of Neurology, Harvard Medical School, Boston, Massachusetts, United Statesfo Geriatrics, Gerontology and Old Age Psychiatry Clinical Department, Carol Davila University of Medicine and Pharmacy-Elias, Emergency Clinical Hospital, Bucharest, Romaniafp Memory Clinic and Longevity Medicine, Ana Aslan International Foundation, Bucharest, Romaniafq Centre de Référence Démences Rares, Pitié-Salpêtrière University Hospital, AP-HP, Paris, Francefr Department of Psychiatry and Human Behavior, Alpert Medical School, Brown University, Providence, RI, United Statesfs Aristotle University of Thessaloniki, Memory and Dementia Center, 3rd Department of Neurology, George Papanicolau General Hospital of Thessaloniki, Thessaloniki, Greeceft Laboratory for Cognitive Neurology, Department of Neurosciences, University of Leuven, Leuven, Belgiumfu Neurology Department, University Hospitals Leuven, Leuven, Belgium, Belgiumfv Departments of Neurology and Laboratory Medicine, Radboud University Medical Center, Donders Institute for Brain, Cognition and Behaviour, Radboud Alzheimer Centre, Nijmegen, Netherlandsfw Molecular Biomarkers in Psychiatry, University of Pittsburgh, Pittsburgh, PA, United Statesfx McConnell Brain Imaging Centre, Montreal Neurological Institute, Montreal, QC, Canadafy Translational Neuroscience Laboratory, McLean Hospital, Harvard Medical School, Belmont, MA, United Statesfz Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmarkga Department of Psychiatry and Psychotherapy, University Medical Center Göttingen, Göttingen, Germanygb Center of Neurology, Department of Neurodegeneration, Hertie-Institute for Clinical Brain Research, University of Tuebingen, Tuebingen, Germanygc Department of Neurology, University of Pennsylvania, Philadelphia, United Statesgd Department of Nuclear Medicine, Molecular Imaging Center, Linkou Chang Gung Memorial Hospital, Guishan, Taoyuan, Taiwange Healthy Aging Research Center, Department of Medical Imaging and Radiological Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwangf Research-Scientific-Didactic Centre of Dementia-Related Diseases in Scinawa, Medical University of Wroclaw, Wroclaw, Polandgg Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Swedengh Department of Neurodegenerative Disease, University College London (UCL), Queen Square Institute of Neurology, Queen Square, London, United Kingdomgi UK Dementia Research Institute, London, United Kingdomgj Hong Kong Center for Neurodegenerative Diseases, Hong Kong, China, Hong Kong

AbstractImportance: One characteristic histopathological event in Alzheimer disease (AD) is cerebral amyloid aggregation, which can be detected by biomarkers in cerebrospinal fluid (CSF) and on positron emission tomography (PET) scans. Prevalence estimates of amyloid pathology are important for health care planning and clinical trial design. Objective: To estimate the prevalence of amyloid abnormality in persons with normal cognition, subjective cognitive decline, mild cognitive impairment, or clinical AD dementia and to examine the potential implications of cutoff methods, biomarker modality (CSF or PET), age, sex, APOE genotype, educational level, geographical region, and dementia severity for these estimates. Design, Setting, and Participants: This cross-sectional, individual-participant pooled study included participants from 85 Amyloid Biomarker Study cohorts. Data collection was performed from January 1, 2013, to December 31, 2020. Participants had normal cognition, subjective cognitive decline, mild cognitive impairment, or clinical AD dementia. Normal cognition and subjective cognitive decline were defined by normal scores on cognitive tests, with the presence of cognitive complaints defining subjective cognitive decline. Mild cognitive impairment and clinical AD dementia were diagnosed according to published criteria. Exposures: Alzheimer disease biomarkers detected on PET or in CSF. Main Outcomes and Measures: Amyloid measurements were dichotomized as normal or abnormal using cohort-provided cutoffs for CSF or PET or by visual reading for PET. Adjusted data-driven cutoffs for abnormal amyloid were calculated using gaussian mixture modeling. Prevalence of amyloid abnormality was estimated according to age, sex, cognitive status, biomarker modality, APOE carrier status, educational level, geographical location, and dementia severity using generalized estimating equations. Results: Among the 19097 participants (mean [SD] age, 69.1 [9.8] years; 10148 women [53.1%]) included, 10139 (53.1%) underwent an amyloid PET scan and 8958 (46.9%) had an amyloid CSF measurement. Using cohort-provided cutoffs, amyloid abnormality prevalences were similar to 2015 estimates for individuals without dementia and were similar across PET- and CSF-based estimates (24%; 95% CI, 21%-28%) in participants with normal cognition, 27% (95% CI, 21%-33%) in participants with subjective cognitive decline, and 51% (95% CI, 46%-56%) in participants with mild cognitive impairment, whereas for clinical AD dementia the estimates were higher for PET than CSF (87% vs 79%; mean difference, 8%; 95% CI, 0%-16%; P =.04). Gaussian mixture modeling-based cutoffs for amyloid measures on PET scans were similar to cohort-provided cutoffs and were not adjusted. Adjusted CSF cutoffs resulted in a 10% higher amyloid abnormality prevalence than PET-based estimates in persons with normal cognition (mean difference, 9%; 95% CI, 3%-15%; P =.004), subjective cognitive decline (9%; 95% CI, 3%-15%; P =.005), and mild cognitive impairment (10%; 95% CI, 3%-17%; P =.004), whereas the estimates were comparable in persons with clinical AD dementia (mean difference, 4%; 95% CI, -2% to 9%; P =.18). Conclusions and Relevance: This study found that CSF-based estimates using adjusted data-driven cutoffs were up to 10% higher than PET-based estimates in people without dementia, whereas the results were similar among people with dementia. This finding suggests that preclinical and prodromal AD may be more prevalent than previously estimated, which has important implications for clinical trial recruitment strategies and health care planning policies. © 2022 American Medical Association. All rights reserved.

Document Type: ArticlePublication Stage: Article in PressSource: Scopus

“Depressive symptoms improve over 2 years of type 2 diabetes treatment via a digital continuous remote care intervention focused on carbohydrate restriction” (2022) Journal of Behavioral Medicine

Depressive symptoms improve over 2 years of type 2 diabetes treatment via a digital continuous remote care intervention focused on carbohydrate restriction(2022) Journal of Behavioral Medicine, . 

Adams, R.N.a , Athinarayanan, S.J.a , McKenzie, A.L.a , Hallberg, S.J.a b , McCarter, J.P.c d , Phinney, S.D.a , Gonzalez, J.S.e f

a Virta Health Corp, 501 Folsom Street, San Francisco, CA 94105, United Statesb Indiana University Health Arnett, Lafayette, IN, United Statesc Abbott Diabetes Care, Alameda, CA, United Statesd Department of Genetics, Washington University School of Medicine, St. Louis, MO, United Statese Ferkauf Graduate School of Psychology, Yeshiva University, Bronx, NY, United Statesf Departments of Medicine (Endocrinology) and Epidemiology & Population Health, Albert Einstein College of Medicine, Bronx, NY, United States

AbstractDepressive symptoms are prevalent among people with type 2 diabetes (T2D) and, even at low severity levels, are associated with worse diabetes outcomes. Carbohydrate restriction is an effective treatment for T2D but its long-term impacts on depressive symptoms are unclear. In the current study we explored changes in depressive symptoms over 2 years among 262 primarily non-depressed T2D patients participating in a continuous remote care intervention emphasizing carbohydrate restriction. Subclinical depressive symptoms decreased over the first 10 weeks and reductions were maintained out to 2 years. Increased frequency of blood ketone levels indicative of adherence to low carbohydrate eating predicted decreases in depressive symptoms. Concerns have been raised with recommending restrictive diets due to potential negative impacts on quality-of-life factors such as mood; however, results of the current study support positive rather than negative long-term impacts of closely monitored carbohydrate restriction on depressive symptoms. © 2022, The Author(s).

Author KeywordsDepression;  Lifestyle intervention;  Nutrition;  Nutritional ketosis;  Type 2 diabetes

Document Type: ArticlePublication Stage: Article in PressSource: Scopus

“Two Cases of Wolfram Syndrome Who Were Initially Diagnosed With Type 1 Diabetes” (2022) AACE Clinical Case Reports

Two Cases of Wolfram Syndrome Who Were Initially Diagnosed With Type 1 Diabetes(2022) AACE Clinical Case Reports, . 

Silvestri, F.a , Tromba, V.a , Costantino, F.a , Palaniappan, N.b c , Urano, F.b d

a Department of Pediatric Diabetology, “Sapienza” University of Rome, Italyb Department of Medicine, Division of Endocrinology, Metabolism, and Lipid Research, Washington University School of Medicine, St. Louis, Missouric University of Missouri-Kansas City School of Medicine, Kansas City, Missourid Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri

AbstractObjective: Early diagnosis of syndromic monogenic diabetes allows for proper management and can lead to improved quality of life in the long term. This report aimed to describe 2 genetically confirmed cases of Wolfram syndrome, a rare endoplasmic reticulum disorder characterized by insulin-dependent diabetes mellitus, optic nerve atrophy, and progressive neurodegeneration. Case Report: A 16-year-old Caucasian male patient and a 25-year-old Caucasian female patient with a history of diabetes mellitus and optic nerve atrophy presented at our medical center. Both patients were initially diagnosed with type 1 diabetes but negative for islet autoantibodies. Their body mass indexes were under 25 at the diagnosis. Their history and presentation were highly suspicious for Wolfram syndrome. Discussion: The genetic tests revealed a known Wolfram syndrome 1 (WFS1) pathogenic variant (homozygous) in the 16-year-old male patient and 2 known WFS1 pathogenic variants (compound heterozygous) in the 25-year-old female patient with diabetes mellitus and optic nerve atrophy, confirming the diagnosis of Wolfram syndrome. The first patient had a moderate form, and the second patient had a milder form of Wolfram syndrome. Conclusion: Providers should consider monogenic diabetes genetic testing, including WFS1 gene, for patients with early-onset diabetes who are negative for islet autoantibodies and lean. Two patients described in this article could have been diagnosed with Wolfram syndrome before they developed optic nerve atrophy. Genetic testing is a valuable tool for the early detection of Wolfram syndrome, which leads to proper management and improved quality of life in patients with this rare medical condition. © 2022 AACE

Author Keywordsdiabetes mellitus;  endoplasmic reticulum stress;  monogenic diabetes genetic testing;  optic nerve atrophy;  Wolfram syndrome

Funding detailsEli Lilly and CompanyUS 10,695,324, US 9,891,231

Document Type: ArticlePublication Stage: Article in PressSource: Scopus

“BNP facilitates NMB-encoded histaminergic itch via NPRC-NMBR crosstalk” (2021) eLife

BNP facilitates NMB-encoded histaminergic itch via NPRC-NMBR crosstalk(2021) eLife, 10, . 

Meng, Q.-T.a , Liu, X.-Y.a b , Liu, X.-T.a c d , Liu, J.a b , Munanairi, A.a b , Barry, D.M.a b , Liu, B.a b , Jin, H.a b , Sun, Y.a , Yang, Q.a b , Gao, F.a b , Wan, L.a e , Peng, J.a b , Jin, J.-H.a , Shen, K.-F.a , Kim, R.a , Yin, J.a b , Tao, A.d , Chen, Z.-F.a b c d f g

a Center for the Study of Itch and Sensory Disorders, Washington University School of Medicine, St Louis, United Statesb Departments of Anesthesiology, Washington University School of Medicine, St Louis, United Statesc Developmental Biology, Washington University School of Medicine, St. Louis, United Statesd Second Affiliated Hospital, State Key Laboratory of Respiratory Disease, Guangdong Provincial Key Laboratory of Allergy & Clinical Immunology, Guangzhou Medical University, Guangzhou, Chinae Department of Pain, Guangzhou Medical University, Guangzhou, Chinaf Departments of Medicine, Washington University School of Medicine, St. Louis, United Statesg Departments of Psychiatry, Washington University School of Medicine, St. Louis, United States

AbstractHistamine-dependent and -independent itch is conveyed by parallel peripheral neural pathways that express gastrin-releasing peptide (GRP) and neuromedin B (NMB), respectively, to the spinal cord of mice. B-type natriuretic peptide (BNP) has been proposed to transmit both types of itch via its receptor NPRA encoded by Npr1. However, BNP also binds to its cognate receptor, NPRC encoded by Npr3 with equal potency. Moreover, natriuretic peptides (NP) signal through the Gi-couped inhibitory cGMP pathway that is supposed to inhibit neuronal activity, raising the question of how BNP may transmit itch information. Here, we report that Npr3 expression in laminae I-II of the dorsal horn partially overlaps with NMB receptor (NMBR) that transmits histaminergic itch via Gq-couped PLCβ-Ca2+ signaling pathway. Functional studies indicate that NPRC is required for itch evoked by histamine but not chloroquine (CQ), a nonhistaminergic pruritogen. Importantly, BNP significantly facilitates scratching behaviors mediated by NMB, but not GRP. Consistently, BNP evoked Ca2+ responses in NMBR/NPRC HEK 293 cells and NMBR/NPRC dorsal horn neurons. These results reveal a previously unknown mechanism by which BNP facilitates NMB-encoded itch through a novel NPRC-NMBR cross-signaling in mice. Our studies uncover distinct modes of action for neuropeptides in transmission and modulation of itch in mice. © 2021, Meng et al.An itch is a common sensation that makes us want to scratch. Most short-term itches are caused by histamine, a chemical that is released by immune cells following an infection or in response to an allergic reaction. Chronic itching, on the other hand, is not usually triggered by histamine, and is typically the result of neurological or skin disorders, such as atopic dermatitis. The sensation of itching is generated by signals that travel from the skin to nerve cells in the spinal cord. Studies in mice have shown that the neuropeptides responsible for delivering these signals differ depending on whether or not the itch involves histamine: GRPs (short for gastrin-releasing proteins) convey histamine-independent itches, while NMBs (short for neuromedin B) convey histamine-dependent itches. It has been proposed that another neuropeptide called BNP (short for B-type natriuretic peptide) is able to transmit both types of itch signals to the spinal cord. But it remains unclear how this signaling molecule is able to do this. To investigate, Meng, Liu, Liu, Liu et al. carried out a combination of behavioral, molecular and pharmacological experiments in mice and nerve cells cultured in a laboratory. The experiments showed that BNP alone cannot transmit the sensation of itching, but it can boost itching signals that are triggered by histamine. It is widely believed that BNP activates a receptor protein called NPRA. However, Meng et al. found that the BNP actually binds to another protein which alters the function of the receptor activated by NMBs. These findings suggest that BNP modulates rather than initiates histamine-dependent itching by enhancing the interaction between NMBs and their receptor. Understanding how itch signals travel from the skin to neurons in the spinal cord is crucial for designing new treatments for chronic itching. The work by Meng et al. suggests that treatments targeting NPRA, which was thought to be a key itch receptor, may not be effective against chronic itching, and that other drug targets need to be explored.

Author KeywordsBNP;  GRP;  itch;  mouse;  neuroscience;  NPRA;  NPRC;  spinal cord

Document Type: ArticlePublication Stage: FinalSource: Scopus

“The Caribbean-American Dementia and Aging Study (CADAS): A multinational initiative to address dementia in Caribbean populations” (2021) Alzheimer’s & Dementia: The Journal of the Alzheimer’s Association

The Caribbean-American Dementia and Aging Study (CADAS): A multinational initiative to address dementia in Caribbean populations(2021) Alzheimer’s & Dementia: The Journal of the Alzheimer’s Association, 17, p. e053789. 

Llibre-Guerra, J.J.a , Li, J.b , Harrati, A.c , Jiménez-Velazquez, I.d , Acosta, D.M.e , Llibre-Rodriguez, J.J.f , Liu, M.-M.g , Dow, W.H.g

a Washington University in St Louis, St Louis, MO, USAb Cornell University, NY, NY, United Statesc Stanford University, Stanford, CA, USAd University of Puerto Rico, School of MedicineSan Juan, Puerto Ricoe Universidad Nacional Pedro Henriquez UreñaSanto Domingo, Dominican Republicf Medical University of HavanaHavana, Cubag University of California, Berkeley, Berkeley, CA, USA

AbstractBACKGROUND: Latinos represent the fastest growing proportion of dementia cases among different ethnic groups. Most of the studies in Alzheimer’s Disease (AD) include Latino populations within the same group, failing to sufficiently account for the real richness of linguistic, ethnic, ancestry, cultural, and socioeconomic diversity represented across Latino communities (e.g., Caribbean-Hispanic vs Non Caribbean-Hispanics), yet there is substantial AD disparities and disease heterogeneity among Hispanic groups. METHODS: The Caribbean-American Dementia and Aging Study (CADAS) is a multinational initiative aimed to answer key questions regarding dementia determinants and consequences in Caribbean-origin populations in origin communities as well as among emigrant populations in the United States. By building a collaborative team of leading Caribbean and U.S-based dementia researches, CADAS will analyze differences in dementia prevalence and risk factor profiles between Caribbean-Hispanics living in the main Hispanic Caribbean Islands and extend comparisons to Hispanic immigrant groups in the US as well as non-Hispanic whites, exploiting the considerable difference in life course risk exposures across these populations. RESULTS: Preliminary findings from the CADAS study indicate that prevalence of dementia in the older Caribbean population is high, both in the main islands and in U.S. compared to non-Hispanic-whites. We found overall weaker associations between education and dementia probability in the three main Caribbean islands. By contrast, a stronger association between education and dementia probability was found in the US among non-Hispanic whites, Mexican Hispanics, and non-Mexican Hispanics; these persist even after controlling for income and wealth. CONCLUSIONS: There are differential associations between SES risk factors, education, and dementia probability between Caribbean islands and the U.S., which may be attributed to differences across societies in risk factors correlated with education. The CADAS study will fill a critical gap in AD knowledge, exploiting rich variation in life-course exposures to better disentangle genetic versus environmental determinants of dementia levels and disparities. Future studies within this populations will focus on early-life socioeconomic status, gene by environment interactions and societal cost. © 2021 the Alzheimer’s Association.

Document Type: ArticlePublication Stage: FinalSource: Scopus

“Genome-wide scan of Alzheimer disease cohort identifies genetic loci associated with human brain metabolite levels” (2021) Alzheimer’s & Dementia: The Journal of the Alzheimer’s Association

Genome-wide scan of Alzheimer disease cohort identifies genetic loci associated with human brain metabolite levels(2021) Alzheimer’s & Dementia: The Journal of the Alzheimer’s Association, 17, p. e051756.

Wang, C.a , Farias, F.H.G.a b , Novotny, B.C.c , Yang, C.b c , Wang, F.b c , Fernandez, V.b c , Harari, O.b c d , Cruchaga, C.b e f 

a Washington University in St. Louis, St. Louis, MO, USAb Hope Center for Neurological Disorders, St. Louis, MO, USAc Washington University School of Medicine, St. Louis, MO, USAd Washington University, MO, Saint Louis, United Statese Washington University, St. Louis, MO, USAf Knight Alzheimer Disease Research Center, MO, Saint Louis, United States

AbstractBACKGROUND: Although metabolome-wide association study (MWAS) has been performed in a wide range of tissue types, such as serum, plasma, urine, saliva, and cerebrospinal fluid (CSF), it has not been conducted on any brain tissue. Here we seek to expand our knowledge on the genetic influence of brain metabolism and on the contribution of metabolism abnormality to AD with the metabolomics approach. We aim to identify metabolite quantitative trait loci (metabQTLs) with the largest AD brain cohort available. METHOD: We performed the first brain MWAS with 460 parietal cortex brains from the Knight-ADRC. 880 metabolites were measured by the powerful non-targeted Metabolon platform (HD4). European individuals were selected, and the analyses were adjusted for age at death, sex, genotype array methods, and genetic components. RESULT: We identified 31 locus-metabolite associations in 30 metabolites with genome-wide significance. 7 associations were significant after study-wide Bonferroni correction. We are performing functional characterization and replication leveraging datasets from ROSMAP brain cohort, WADRC CSF cohort, and other tissues’ cohorts. The strongest locus-metabolite association (p=5.2e-104), found in N6-methyllysine in the discovery phase, was first identified in CSF MWAS (Panyard et al., biorxiv, 2020). CONCLUSION: The first brain metabolome-wide association study discovered the importance of genetic influence on brain metabolite levels. Following expectation, brain metabQTLs can be replicated in the CSF study, implicating that brain and CSF share genetic features in modulating metabolism. © 2021 the Alzheimer’s Association.

Document Type: ArticlePublication Stage: FinalSource: Scopus

“Presence of co-pathology in sporadic early-onset Alzheimer disease versus dominantly inherited Alzheimer disease” (2021) Alzheimer’s & Dementia: The Journal of the Alzheimer’s Association

Presence of co-pathology in sporadic early-onset Alzheimer disease versus dominantly inherited Alzheimer disease(2021) Alzheimer’s & Dementia: The Journal of the Alzheimer’s Association, 17, p. e055045. 

Llibre-Guerra, J.J.a , Li, Y.a , Franklin, E.E.a , Miller, C.A.b , Teich, A.F.c , Kofler, J.d , Dickson, D.W.e , Ghetti, B.F.f , Frosch, M.P.g , Halliday, G.M.h , McLean, C.i , Lashley, T.j , Gordon, B.A.a , Schindler, S.E.k , Chen, C.D.a , Fagan, A.M.a , Benzinger, T.L.S.a , Wang, G.a , Hassenstab, J.a , Morris, J.C.a , Bateman, R.J.a , Perrin, R.J.l , McDade, E.a

a Washington University in St. Louis, St. Louis, MO, USAb Keck School of Medicine, University of Southern California, Los Angeles, CA, USAc Columbia University Medical Center, NY, NY, United Statesd University of Pittsburgh School of Medicine, PA, Pittsburgh, United Statese Mayo Clinic, FL, Jacksonville, United Statesf Indiana University School of Medicine, ININ, United Statesg Massachusetts General Hospital, Harvard Medical School, MA, Boston, United Statesh Neuroscience Research Australia, Randwick, Australiai Victorian Brain Bank Network (VBBN), Melbourne, Australiaj University College London, Queen Square Institute of Neurology, London, United Kingdomk Washington University School of Medicine, MO, Saint Louis, United Statesl Washington University in St. Louis School of Medicine, St. Louis, MO, USA

AbstractBACKGROUND: A small proportion of Alzheimer disease (AD), known as early onset AD (EOAD), has symptomatic age at onset (AAO) before age 65. About 5-10% of EOAD is dominantly inherited (DIAD); the rest is termed to be sporadic (sEOAD). Although DIAD and sEOAD share the hallmark plaques and tangles that define AD neuropathologic change (ADNC), the relative burdens of these lesions and the frequencies of non-AD co-pathologies in sEOAD relative to DIAD remain unknown. METHODS: We compared the neuropathological burden of AD and the frequency of AD and non-AD pathologies in 363 sEOAD cases from the National Alzheimer’s Coordinating Center (NACC) and in 62 DIAD cases (45 from the Dominantly Inherited Alzheimer Network (DIAN); 17 from NACC). Operational criteria for the classification of AD and other co-pathologies followed accepted NACC guidelines. Only cases with AAO under 65 and a primary pathological diagnosis of ‘high ADNC’ were included. RESULTS: DIAD participants [mean AAO = 42.9 ± 8.1 years] had higher CERAD scores than sEOAD cases [mean AAO = 57.1 ±7.2 years] [p=0.03]. Braak stages were similar for both cohorts. The frequency and severity of cerebral amyloid angiopathy (CAA) was higher in DIAD versus sEOAD [CAA: 100% vs 83.7%, p=0.001; severe CAA: 40.3% versus 20.1%, p<0.001, respectively]. The frequency of at least one non-AD/non-CAA pathology was similar between DIAD and sEOAD [63.9% vs 59.7%, p=0.61], but the frequency of multiple pathologies (two or more) was lower in DIAD [3.2%] than in sEOAD [21.0%, p<0.001]. Lewy body disease (LBD) was the most prevalent non-AD/non-CAA pathology in both cohorts [58.1% in DIAD, 51.2% in sEOAD; p=0.39]. Hippocampal sclerosis [14.5%] and argyrophilic grain disease [2.5%], were observed in sEOAD, but were absent from DIAD. CONCLUSIONS: DIAD cases show greater neuritic plaque density and more severe CAA than sEOAD cases, but comparable Braak NFT stages. The similar frequencies of LBD in both cohorts may be linked to severe AD neuropathological change, rather than co-incident age-related pathologies. Future studies should include methodologically uniform assessments of both cohorts to explore age-related and non-age-related mechanisms that may account for differences in the burdens of ADNC lesions and non-AD co-pathologies. © 2021 the Alzheimer’s Association.

Document Type: ArticlePublication Stage: FinalSource: Scopus

“Gearing up for the future: Exploring facilitators and barriers to inform clinical trial design in frontotemporal lobar degeneration” (2021) Alzheimer’s & Dementia: The Journal of the Alzheimer’s Association

Gearing up for the future: Exploring facilitators and barriers to inform clinical trial design in frontotemporal lobar degeneration(2021) Alzheimer’s & Dementia: The Journal of the Alzheimer’s Association, 17, p. e052495. 

Banga, Y.B.a b , Lai, Y.a b , Kim, P.a b , Boeve, B.F.c , Boxer, A.L.d , Rosen, H.J.d , Forsberg, L.K.c , Heuer, H.W.d , Brushaber, D.c , Appleby, B.e , Biernacka, J.M.c , Bordelon, Y.M.f , Botha, H.c , Bozoki, A.C.g , Brannelly, P.h , Dickerson, B.C.i , Dickinson, S.j , Dickson, D.W.k , Domoto-Reilly, K.l , Faber, K.m , Fagan, A.M.n , Fields, J.A.c , Fishman, A.o , Foroud, T.M.p , Galasko, D.R.q , Gavrilova, R.H.c , Gendron, T.F.k , Geschwind, D.H.r , Ghoshal, N.s , Goldman, J.t , Graff-Radford, J.c , Graff-Radford, N.R.k , Grant, I.u , Grossman, M.v , Hsiung, G.-Y.R.w , Huang, E.J.x , Huey, E.D.y , Irwin, D.J.v , Jones, D.T.c , Kantarci, K.c , Karydas, A.M.d , Kaufer, D.z , Knopman, D.S.c , Kramer, J.H.d , Kremers, W.K.c , Kornak, J.d , Kukull, W.A.aa , Lagone, E.p , Leger, G.C.ab , Litvan, I.ab , Ljubenkov, P.A.d , Lucente, D.E.i , Mackenzie, I.R.ac , Manoochehri, M.y , Masdeu, J.C.ad , McGinnis, S.ae , Mendez, M.F.af , Miller, B.L.ag , Miyagawa, T.c , Nelson, K.M.c , Onyike, C.U.ah , Pantelyat, A.ah , Pascual, B.ad , Pearlman, R.ai , Petrucelli, L.k , Pottier, C.P.k , Rademakers, R.k , Ramos, E.M.aj , Rankin, K.P.ak , Rascovsky, K.al , Rexach, J.E.r , Ritter, A.am , Roberson, E.D.an , Rojas, J.C.d , Sabbagh, M.N.am , Salmon, D.P.ao , Savica, R.c , Seeley, W.W.ak , Staffaroni, A.M.d , Syrjanen, J.A.c , Tartaglia, M.C.ap , Tatton, N.aq , Taylor, J.C.d , Toga, A.W.ar , Weintraub, S.as , Wheaton, D.at , Wong, B.au , Wszolek, Z.k , ALLFTD Consortiumav

a Heritage University, Toppenish, WA, USAb Pacific Northwest University of Health Sciences, Yakima, WA, USAc Mayo Clinic, MN, Rochester, United Statesd University of California, San Francisco, San Francisco, CA, USAe Case Western Reserve University, Cleveland, OH, USAf University of California Los Angeles, Los Angeles, CA, USAg Michigan State University, MI, East Lansing, United Statesh Rainwater Charitable Foundation, TX, Fort Worth, United Statesi Massachusetts General Hospital, MA, Boston, United Statesj AFTD, PA, King of Prussia, United Statesk Mayo Clinic, FL, Jacksonville, United Statesl University of Washington, Seattle, WA, USAm Indiana University School of Medicine, IN, Indianapolis, United Statesn Washington University School of Medicine, MO, Saint Louis, United Stateso Johns Hopkins University, MD, Baltimore, United Statesp Indiana University, IN, Indianapolis, United Statesq University of California, San Diego, La Jolla, CA, USAr University of California, Los Angeles School of Medicine, Los Angeles, CA, USAs Washington University, St. Louis, MO, USAt Columbia University, NY, NY, United Statesu Northwestern University, Chicago, United Statesv Perelman School of Medicine, University of Pennsylvania, PA, Philadelphia, United Statesw Djavad Mowafaghian Centre for Brain Health, University of British Colombia, Vancouver, Canadax Department of Pathology, University of California, San Francisco, San Francisco, CA, USAy Gertrude H. Sergievsky Center at Columbia University, NY, NY, United Statesz University of North Carolina, Chapel Hill, United Statesaa National Alzheimer’s Coordinating Center, University of Washington, Seattle, WA, USAab University of California, San Diego, San Diego, CA, USAac University of British Columbia, Vancouver, Canadaad Houston Methodist Neurological Institute, TX, Houston, United Statesae Harvard Medical School, MA, Boston, United Statesaf David Geffen School of Medicine at UCLA, Los Angeles, CA, USAag University of California, San Francisco (UCSF), San Francisco, CA, USAah Johns Hopkins University School of Medicine, MD, Baltimore, United Statesai The Bluefield Project to Cure FTD, San Francisco, CA, USAaj University of California, Los Angeles, Los Angeles, CA, USAak Memory and Aging Center, UCSF Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA, USAal Penn FTD Center, Perelman School of Medicine, University of Pennsylvania, PA, Philadelphia, United Statesam Cleveland Clinic Lou Ruvo Center for Brain Health, NV, Las Vegas, United Statesan University of Alabama at Birmingham, Birmingham, AL, USAao Shiley-Marcos Alzheimer’s Disease Research Center, La Jolla, CA, United Statesap Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, ON, Toronto, Canadaaq AFTD, PA, Radnor, United Statesar Laboratory of Neuro Imaging, Stevens Neuroimaging and Informatics Institute, Keck School of Medicine, University of Southern California, Los Angeles, CA, USAas Northwestern University Feinberg School of Medicine, Chicago, United Statesat FTD Disorders Registry, San Francisco, CA, USAau National Neuroscience Institute, Tan Tock Seng Hospital, Singapore

AbstractBACKGROUND: Frontotemporal lobar degeneration (FTLD) refers to a group of neurodegenerative conditions, affecting the frontal and/or temporal lobes. Ongoing research has provided insight into developing clinical trials for FTLD and key clinical measures such as structural MRI. To inform clinical trial design and optimize participation, it is imperative to explore facilitators and barriers for potential candidates. OBJECTIVE: The objective of this study is to explore facilitators and barriers to participating in future clinical trials for FTLD. METHODS: Advancing Research and Treatment for Frontotemporal Lobar Degeneration (ARTFL) and Longitudinal Evaluation of Familial Frontotemporal Dementia Subjects (LEFFTDS) are observational studies focused on characterizing FTLD syndromes in preparation for clinical trials. The 584 participants enrolled across 18 research sites in the United States and Canada completed a survey assessing interest in clinical trial participation. RESULTS: 29% of respondents self-reported as patients (63±10 years), 26% self-reported as caregivers answering on behalf of patients (65±10 years), and 45% self-reported as healthy but at risk for FTLD (48±14 years). Travel reimbursement was the most common factor reported to positively influence participation (66%), with the healthy but at risk group showing the strongest endorsement (83%). Cost and time involved in travel were possible barriers for about half of the patients (48%) and healthy but at risk respondents (53%). The respondents value receiving feedback on the study findings (80%) and being informed of their individual disease progression (75%). Particularly, keeping participation confidential was very important for the healthy but at risk group (62%). In regard to research assessments, most participants demonstrated a high interest in physical and neurological exams at a research center (87%) whereas only half were interested in doing more invasive procedures such as the lumbar puncture (52%). Overall, respondents showed a positive attitude and support for research participation (77%) and trusted that their health information would remain confidential in a clinical trial (53%). CONCLUSIONS: Favorable attitudes and interest towards medical research exist among participants. To optimize participation, clinical trials should allocate funding for travel and involve participants in feedback about study results and their disease progression. Alternatives to invasive assessments may increase participation. © 2021 the Alzheimer’s Association.

Document Type: ArticlePublication Stage: FinalSource: Scopus

“The impacts of menopause on a mouse model of co-morbid metabolic syndrome and Alzheimer’s disease” (2021) Alzheimer’s & Dementia: The Journal of the Alzheimer’s Association

The impacts of menopause on a mouse model of co-morbid metabolic syndrome and Alzheimer’s disease(2021) Alzheimer’s & Dementia: The Journal of the Alzheimer’s Association, 17, p. e051172. 

Abi-Ghanem, C.a , Salinero, A.E.a , Gannon, O.J.a , Riccio, D.a , Mansour, F.a , Kelly, R.D.a , Kordit, D.a , Wang, M.a , Kyaw, N.-R.a , Cirrito, J.R.b , Zuloaga, K.L.a

a Albany Medical College, Albany, NY, USAb Washington University School of Medicine, MO, Saint Louis, United States

AbstractBACKGROUND: Alzheimer’s disease (AD) is the leading cause of disability and 5th cause of death in people over 65 years of age. Approximately 2/3 of AD patients are women, most of whom are postmenopausal. Menopause is linked with cognitive changes in women: younger age at menopause is associated with worse cognitive outcomes. Moreover, menopause accelerates mid-life risk factors for dementia, by increasing risk for cardiovascular and cerebrovascular disease and metabolic disease which is by itself a risk factor for dementia. We have previously shown that female 3xTg-AD mice are more greatly impacted cognitively and metabolically by a high fat diet when compared to males. We therefore hypothesized that menopause would exacerbate both metabolic and cognitive impairment and pathology in a mouse model of AD. METHOD: Female App NL-F mice were placed on either low fat (LF; 10% fat) or high fat (HF; 60% fat; metabolic disease model) diet for 7 months. An accelerated ovarian failure model of menopause (4-vinylcyclohexene diepoxide) was used at diet onset and female estrus cycles were monitored to determine menopause onset. Metabolic status was assessed by tracking weight gain and assessing glucose tolerance. Mice were then subjected to a battery of behavioral tests before being euthanized and brains and serum were collected. RESULT: Menopausal mice tended to be more metabolically impaired (worse glucose tolerance) regardless of diet. Cognitive impairment differences between groups were investigated using several behavioral tests. Neither menopause nor HF diet affected anxiety-like behavior (open field testing), however HF diet decreased general activity levels. Novel object recognition testing demonstrated that menopause, regardless of diet, impaired episodic-like memory. Additionally, HF diet, regardless of menopause, impaired spatial learning (assessed via Barnes maze testing). We are currently evaluating the underlying pathology in the brain that could mediate these cognitive deficits (i.e. Amyloid pathology, white matter damage and neuroinflammation). CONCLUSION: We hope that this work will highlight the need to model endocrine aging in animal models of dementia and will contribute to further understanding of the interaction between metabolic disease and menopause in the scope of AD. © 2021 the Alzheimer’s Association.

Document Type: ArticlePublication Stage: FinalSource: Scopus

“25-Hydroxycholesterol modulates tau-mediated neurodegeneration and microglial chemotaxis and phagocytosis” (2021) Alzheimer’s & Dementia: The Journal of the Alzheimer’s Association

25-Hydroxycholesterol modulates tau-mediated neurodegeneration and microglial chemotaxis and phagocytosis(2021) Alzheimer’s & Dementia: The Journal of the Alzheimer’s Association, 17, p. e056404.

Long, J.M.a b c , Tran, A.a , Serrano, J.R.d , Bao, X.d , Wang, C.a , Reznikov, J.a , Cashikar, A.G.a b , Paul, S.M.a b e , Holtzman, D.M.a b f 

a Washington University in St. Louis, School of Medicine, St. Louis, MO, USAb Hope Center for Neurological Disorders, St. Louis, MO, USAc Knight Alzheimer Disease Research Center, St. Louis, MO, USAd Washington University in St. Louis, St. Louis, MO, USAe MA, Boston, United Statesf Knight Alzheimer Disease Research Center, MO, Saint Louis, United States

AbstractBACKGROUND: Immune activation is an important component of Alzheimer disease (AD) pathology, with microglia playing a critical role in driving ApoE-dependent tau-mediated neurodegeneration. The oxysterol 25-hydroxycholesterol (25-HC) is an established potent regulator of peripheral innate immune response, though less is known regarding its role in CNS neuroimmune pathobiology. The enzyme that synthesizes 25-HC, cholesterol 25-hydroxylase (CH25H), is exclusively expressed by microglia in the CNS and is significantly upregulated in human AD brain and in transgenic AD mouse models. We have recently reported pro-inflammatory effects of 25-HC in ApoE4-expressing mouse microglia, including increased microglial IL-1β secretion and inflammasome activation. In this study we explored the role of 25-HC in ApoE-dependent tau-mediated neurodegeneration. METHOD: PS19 tauopathy mice previously crossed with ApoE targeted replacement (TR) mice were subsequently crossed with CH25H KO mice. Hippocampal (HC), entorhinal and pyriform cortical (EC/PC) and ventricular volumes were measured at 9 months of age. In vitro primary cell cultures containing neurons, mixed glia or microglia were utilized to evaluate effects of 25-HC or 7α,25-dihydroxycholesterol (7α,25-diHC), on neurotoxicity, microglial cytokine secretion, chemotaxis and phagocytic activity. RESULT: We found that in female tau mice expressing human ApoE4, genetic deletion of CH25H was protective (increased EC/PC volumes and reduced ventricular volumes). Similar trends were observed in male mice though these were not statistically significant. In a neuronal-glial co-culture model of ApoE4-mediated neurotoxicity, 25-HC protected against neurite loss and neuronal death at low concentrations but was potently neurotoxic at higher concentrations. In primary microglial cultures, 25-HC modulated secretion of a number of chemokines and provoked a potent microglial chemotaxic response that was most robust in microglia derived from CH25H KO, ApoE4-TR or ApoE4-TR-CH25H KO mice. 7α,25-diHC also stimulated chemotaxis but less robustly than 25-HC. Assays testing the effect of 25-HC and 7α,25-diHC on phagocytosis in microglia were also performed, and these data will be presented. CONCLUSION: 25-HC appears to modulate tau-mediated neurodegeneration in an ApoE-dependent manner, especially in female mice, possibly through effects on critical microglial cellular functions. CH25H and 25-HC may be viable therapeutic targets for AD-related neuroimmune activation. © 2021 the Alzheimer’s Association.

Document Type: ArticlePublication Stage: FinalSource: Scopus

“Defining the role of PLD3 in Alzheimer disease pathology” (2021) Alzheimer’s & Dementia: The Journal of the Alzheimer’s Association

Defining the role of PLD3 in Alzheimer disease pathology(2021) Alzheimer’s & Dementia: The Journal of the Alzheimer’s Association, 17, p. e054611.

Rosene, M.J.a , Hsu, S.b , Martinez, R.c , Norton, J.a b d e , Yan, P.a , Cirrito, J.R.f , Lee, J.-M.a , Cuervo, A.M.g , Goate, A.M.h i , Cruchaga, C.d j k l m , Karch, C.M.c d j k 

a Washington University School of Medicine, St. Louis, MO, USAb Washington University in St. Louis, St. Louis, MO, USAc Washington University, MO, Saint Louis, United Statesd Hope Center for Neurological Disorders, St. Louis, MO, USAe Knight Alzheimer Disease Research Center, St. Louis, MO, USAf Washington University School of Medicine, MO, Saint Louis, United Statesg Albert Einstein College of Medicine, NY, NY, United Statesh Ronald M. Loeb Center for Alzheimer’s Disease, NY, NY, United Statesi Icahn School of Medicine at Mount Sinai, NY, NY, United Statesj Washington University in St. Louis School of Medicine, St. Louis, MO, USAk NeuroGenomics and Informatics Center, St. Louis, MO, USAl Washington University, St. Louis, MO, USAm Knight Alzheimer Disease Research Center, MO, Saint Louis, United States

AbstractBACKGROUND: Alzheimer’s disease (AD) is characterized by the accumulation of amyloid-β (Aβ) in the brain. We recently identified coding variants in the phospholipase D3 (PLD3) gene that double the risk for late onset AD. METHOD: We examined the impact of PLD3 risk variants on PLD3 and Aβ metabolism using CRISPR/Cas9 in induced pluripotent stem cells (iPSC). We then modeled the PLD3 expression patterns observed in AD brains in immortalized cell and AD mouse models. Lysosomal function was assessed in human brain tissue. RESULT: PLD3 A442A disrupts a splicing enhancer binding site and reduces PLD3 splicing in human brains. Differentiation of PLD3 A442A and isogenic control iPSCs into cortical neurons produced cells that were morphologically similar. At the molecular level, PLD3 A442A neurons displayed a similar defect in PLD3 splicing as was observed in human brains and a significant increase in Aβ42/Aβ40 compared with isogenic control lines. Thus, PLD3 A442A is sufficient to alter PLD3 splicing and Aβ metabolism. PLD3 expression was significantly lower in AD brains compared with controls, and PLD3 expression was highly correlated with expression of lysosomal genes. Thus, we sought to determine whether PLD3 contributes to Aβ accumulation in AD via disrupted Aβ metabolism. We found that overexpression of PLD3 in immortalized cells decreased Aβ levels while shRNA silencing of PLD3 increased Aβ levels. In an AD mouse model, overexpression of PLD3 in hippocampal neurons produced decreased interstitial fluid (ISF) Aβ levels and accelerated Aβ turnover. Conversely, knocking out PLD3 increased ISF Aβ, reduced Aβ turnover, and increased APP protein levels. Thus, reduced turnover of ISF Aβ along with increase APP substrate may lead to Aβ accumulation. To begin to determine whether PLD3 influences Aβ turnover via the lysosome, we isolated lysosomal fractions from human AD and control brains. PLD3 was enriched in lysosomal subfractions and PLD3 distribution in these subfractions was altered in AD. Furthermore, PLD3 stability in the lysosomal fractions was disrupted in AD brains. CONCLUSION: Together, our findings demonstrate that PLD3 promotes Aβ clearance through pathways involving lysosomal degradation. © 2021 the Alzheimer’s Association.

Document Type: ArticlePublication Stage: FinalSource: Scopus

“Functional exploration of AGFG2, a novel player in the pathology of Alzheimer disease” (2021) Alzheimer’s & Dementia: The Journal of the Alzheimer’s Association

Functional exploration of AGFG2, a novel player in the pathology of Alzheimer disease(2021) Alzheimer’s & Dementia: The Journal of the Alzheimer’s Association, 17, p. e054240. 

Fernandez, M.V.a b , Budde, J.P.c d , Eteleeb, A.b , Wang, F.c d , Martinez, R.e , Norton, J.c d , Gentsch, J.c d , Morris, J.C.a f g , Bateman, R.J.c d h , McDade, E.c h , Perrin, R.J.d h i , Harari, O.c d h j , Benitez, B.A.c d j , Karch, C.M.d e , Cruchaga, C.d j k

a Hope Center for Neurological Disorders, MO, Saint Louis, United Statesb Washington University School of Medicine, MO, Saint Louis, United Statesc Washington University School of Medicine, St. Louis, MO, USAd Hope Center for Neurological Disorders, St. Louis, MO, USAe Washington University, MO, Saint Louis, United Statesf Knight Alzheimer Disease Research Center, MO, Saint Louis, United Statesg Washington University in St. Louis, MO, Saint Louis, United Statesh Knight Alzheimer Disease Research Center, St. Louis, MO, USAi Washington University in St. Louis School of Medicine, St. Louis, MO, USAj NeuroGenomics and Informatics Center, St. Louis, MO, USAk Washington University, St. Louis, MO, USA

AbstractBACKGROUND: There are three main clinical presentations in Alzheimer disease (AD) with diversity in phenotype, onset and progression of clinical symptoms: autosomal dominant (ADAD), early onset (EOAD) and late onset (LOAD). Ultimately, AD is characterized by the deposition of Aβ and ptau protein aggregates in the brain. This work aims to identify and characterize common disrupted pathways across AD etiologies. METHOD: We examined bulk transcriptomic data from brain donors to the DIAN (ADAD, N=19) and Knight-ADRC (EOAD, N=13; LOAD, N=55; controls, N=16). We performed differential gene expression (DGE) analyses using DSeq2 and cross-checked significant signals with known GWAs loci. We replicated our findings in three AMP-AD independent studies. RESULT: DGE analysis identified 57 significantly differentiated genes across ADAD, EOAD or LOAD vs controls. Among those, AGFG2 (p=7×10-4 ) had a higher expression in cases and falls under the AD GWAs signal for NYAP1 (rs1476679). This effect replicated in all independent datasets: Mount Sinai (p=8.63×10-3 ), Mayo (p=5.88×10-12 ), ROSMAP (p=3.96×10-05 ). AGFG2 is expressed primarily in astrocytes and is a member of the HIV-1 Rev binding protein family that mediates the nucleocytoplasmic transfer of proteins and RNAs. AGFG2 has been implicated in APP metabolism, leading to the hypothesis that higher expression of AGFG2 could promote more release of APP to the media. CONCLUSION: Our results suggest that AGFG2 may be a novel player in the etiology of AD. We are currently modifying AGFG2 expression on iPSC-derived astrocytes using CRIPR-Cas9 technology to evaluate AGFG2 role in APP and Tau metabolism. We will present these results at the conference. © 2021 the Alzheimer’s Association.

Document Type: ArticlePublication Stage: FinalSource: Scopus

“LMNA-mediated nucleoskeleton dysregulation in Alzheimer disease” (2021) Alzheimer’s & Dementia: The Journal of the Alzheimer’s Association

LMNA-mediated nucleoskeleton dysregulation in Alzheimer disease(2021) Alzheimer’s & Dementia: The Journal of the Alzheimer’s Association, 17, p. e054396. 

Rosene, M.J.a , Wen, N.b , Li, Z.a , Brase, L.b , Hsu, S.b , Cruchaga, C.c d e f g , Temple, S.h , Harari, O.a d e i j , Karch, C.M.c d e i

a Washington University School of Medicine, St. Louis, MO, USAb Washington University in St. Louis, St. Louis, MO, USAc Washington University in St. Louis School of Medicine, St. Louis, MO, USAd Hope Center for Neurological Disorders, St. Louis, MO, USAe NeuroGenomics and Informatics Center, St. Louis, MO, USAf Washington University, St. Louis, MO, USAg Knight Alzheimer Disease Research Center, MO, Saint Louis, United Statesh Neural Stem Cell Institute, Albany, NY, USAi Washington University, MO, Saint Louis, United Statesj Knight Alzheimer Disease Research Center, St. Louis, MO, USA

AbstractBACKGROUND: Nucleoskeleton dysfunction has been implicated in Alzheimer disease (AD). Tubular invaginations of the nuclear envelope observed in AD brains are consistent with the accumulation of farnesylated prelamin A (encoded by the LMNA gene) that occurs in Hutchinson-Gilford Progeria Syndrome, a premature aging disorder caused by LMNA mutations. Proper function of the nuclear membrane is required for neuronal survival and for maintenance of genetic architecture. METHOD: To determine whether dysregulated LMNA expression and prelamin A processing are responsible for nucleoskeleton dysfunction in AD, we performed differential gene expression and network analyses in human AD and age-matched control brains. Lamin A protein levels were evaluated in AD and control brains using mass spectrometry. Gene network analyses were carried out using induced pluripotent stem cell-derived neurons transduced with progerin or GFP controls in order to identify molecular pathways influenced by altered LMNA processing. RESULT: In AD brains, we observed a significant increase in LMNA and a significant decrease in ZMPSTE24, resulting in a significant increase Lamin A protein levels, which we observe through mass spectrometry. We replicated these findings in laser capture microdissected neurons from AD brains, suggesting that the effect is neuronally driven. Thus, high levels of LMNA paired with low levels of ZMPSTE24 could result in the accumulation of farnesylated prelamin A and tubular invaginations in the nuclear membrane. LMNA-associated networks were also differentially expressed in AD brains. Genes within the dysregulated LMNA network were enriched in lysosomal and chromatin remodeling pathways. CONCLUSION: Our findings suggest that β-amyloid and tau accumulation disrupts prelamin A processing and downstream changes in the nuclear membrane. Alterations in the nucleoskeleton induce genomic instability, loss of proteostasis, and cellular senescence, which may accelerate AD pathogenesis. © 2021 the Alzheimer’s Association.

Document Type: ArticlePublication Stage: FinalSource: Scopus

“COVID-19 and preclinical Alzheimer disease: Driving, mobility, activity and experiences of older adults in the United States” (2021) Alzheimer’s & Dementia: The Journal of the Alzheimer’s Association

COVID-19 and preclinical Alzheimer disease: Driving, mobility, activity and experiences of older adults in the United States(2021) Alzheimer’s & Dementia: The Journal of the Alzheimer’s Association, 17, p. e057692.

Bayat, S.a b , Babulal, G.M.c d , Widener, M.b , Schindler, S.E.c e , Morris, J.C.c d e , Mihailidis, A.a b , Roe, C.M.c d 

a KITE – Toronto Rehabilitation Institute, ON, University Health Network, Toronto, Canadab University of Toronto, ON, Toronto, Canadac Washington University School of Medicine, St. Louis, MO, USAd Knight Alzheimer Disease Research Center, St. Louis, MO, USAe Hope Center for Neurological Disorders, St. Louis, MO, USA

AbstractBACKGROUND: As the world grapples with the COVID-19 pandemic, there have been widespread disruptions to everyday life due to social distancing. Older adults with Alzheimer disease (AD) are at increased risk of morbidity and mortality from COVID-19. It is unknown how COVID-19 affects the mobility patterns of older adults with preclinical AD. Since before the pandemic, we have been monitoring the driving behaviors of older adults, enabling us to evaluate the impact of the pandemic on individuals with and without preclinical AD. METHOD: We used in-vehicle Global Positioning System (GPS) devices to study driving behaviors of 115 older adults enrolled in the DRIVES study (aged 65+) from 1/1/2019 to 31/12/2020. The cohort included 62 individuals with preclinical AD (PreAD) and 53 without preclinical AD (CTL), as determined by cerebrospinal fluid biomarkers. All participants completed an online survey about their overall experiences during the pandemic. Using the GPS data, we determined the average monthly distance travelled, and the number of visitations to destinations categorized as food shopping, place of worship, restaurant, leisure, or health. All measures were computed monthly. RESULT: oth groups experienced an approximate 40% decline in average monthly distance travelled overall after the start of the pandemic (PreAD: 1287.92 to 783.38 km vs. CTL: 1751.26 to 1053.29 km). Visits to places of worship, restaurants, leisure and health places declined by 70%, 46%, 23%, and 23% for the PreAD group, and by 48%, 31%, 48%, and 22% for the CTL group, respectively. However, the pandemic did not result in a significant decline in Food Shopping among either of the groups. Overall, compared to the CTL group, the PreAD group experienced a higher level of stress in response to the recommendations for socially distancing (p<0.01), more uncertainty about their risk of COVID-19 (p<0.05), more decline in trips for worship (p<0.05) and less decline in trips for leisure (p<0.01). CONCLUSION: Our findings indicate decreased mobility in all older adults during the pandemic, with the preclinical AD group exhibiting more decline in trips to places of worship, less decline in leisure activities, and increased stress and uncertainty in response to COVID-19. © 2021 the Alzheimer’s Association.

Document Type: ArticlePublication Stage: FinalSource: Scopus

“Demographic and psychosocial factors associated with the decision to learn mutation status in familial frontotemporal dementia and the impact of disclosure on mood” (2021) Alzheimer’s & Dementia: The Journal of the Alzheimer’s Association

Demographic and psychosocial factors associated with the decision to learn mutation status in familial frontotemporal dementia and the impact of disclosure on mood(2021) Alzheimer’s & Dementia: The Journal of the Alzheimer’s Association, 17, p. e050692. 

Bajorek, L.P.a , Kiekhofer, R.a , Hall, M.a , Taylor, J.a , Lucente, D.E.b , Brushaber, D.c , Appleby, B.d , Coppolla, G.e , Bordelon, Y.M.f , Botha, H.c , Dickerson, B.C.b , Dickson, D.W.g , Domoto-Reilly, K.h , Fagan, A.M.i , Fields, J.A.c , Fong, J.C.j , Foroud, T.M.k , Forsberg, L.K.c , Galasko, D.R.l , Gavrilova, R.H.c , Geschwind, D.H.m , Ghoshal, N.n , Goldman, J.o , Graff-Radford, N.R.g , Graff-Radford, J.c , Grant, I.p , Grossman, M.q , Heuer, H.W.a , Hsiung, G.-Y.R.r , Huang, E.J.s , Huey, E.D.t , Irwin, D.J.u , Jones, D.T.c , Kantarci, K.c , Kornak, J.a , Kremers, W.K.c , Lapid, M.I.c , Leger, G.C.v , Litvan, I.v , Ljubenkov, P.A.a , Mackenzie, I.R.r , Masdeu, J.C.w , McMillan, C.q , Mendez, M.m , Miller, B.L.x , Miyagawa, T.c , Onyike, C.U.y , Pascual, B.w , Pedraza, O.g , Petrucelli, L.g , Rademakers, R.g , Ramos, E.M.m , Rankin, K.P.a , Rascovsky, K.q , Rexach, J.E.m , Ritter, A.z , Roberson, E.D.aa , Savica, R.c , Rojas, J.C.a , Seeley, W.W.ab , Tartaglia, M.C.ac , Toga, A.W.ad , Weintraub, S.ae , Wong, B.af , Wszolek, Z.g , Vandevrede, L.a , Boeve, B.F.c , Boxer, A.L.a , Rosen, H.J.a , Staffaroni, A.M.a , ALLFTD Consortiumag

a University of California, San Francisco, San Francisco, CA, USAb Massachusetts General Hospital, MA, Boston, United Statesc Mayo Clinic, MN, Rochester, United Statesd Case Western Reserve University, Cleveland, OH, USAe University of California, Los Angeles School of Medicine, Los Angeles, CA, USAf University of California Los Angeles, Los Angeles, CA, USAg Mayo Clinic, FL, Jacksonville, United Statesh University of Washington, Seattle, WA, USAi Washington University in St. Louis, St. Louis, MO, USAj Baylor College of Medicine, TX, Houston, United Statesk National Centralized Repository for Alzheimer’s Disease and Related Dementias (NCRAD), IN, Indianapolis, United Statesl University of California, San Diego, La Jolla, CA, USAm University of California, Los Angeles, Los Angeles, CA, USAn Washington University School of Medicine, St. Louis, MO, USAo Columbia University Medical Center, NY, NY, United Statesp Northwestern University, Chicago, United Statesq University of Pennsylvania, PA, Philadelphia, United Statesr University of British Columbia, Vancouver, Canadas Department of Pathology, University of California, San Francisco, San Francisco, CA, USAt Columbia University, NY, NY, United Statesu Perelman School of Medicine, University of Pennsylvania, PA, Philadelphia, United Statesv University of California, San Diego, San Diego, CA, USAw Houston Methodist Neurological Institute, TX, Houston, United Statesx University of California, San Francisco (UCSF), San Francisco, CA, USAy Johns Hopkins University School of Medicine, MD, Baltimore, United Statesz Cleveland Clinic Lou Ruvo Center for Brain Health, NV, Las Vegas, United Statesaa University of Alabama at Birmingham, Birmingham, AL, USAab Weill Institute for Neurosciences and Memory and Aging Center, Department of Neurology, University of California, San Francisco, CA, USAac University of Toronto, ON, Toronto, Canadaad University of Southern California, Los Angeles, CA, USAae Northwestern University Feinberg School of Medicine, Chicago, United Statesaf Massachusetts General Hospital/Harvard Medical School, MA, Boston, United States

AbstractBACKGROUND: Up to 30% of frontotemporal dementia (FTD) cases are due to known pathogenic mutations (f-FTD). Little is known about the factors that predict who will choose to learn their results. Upcoming clinical trials in f-FTD may require disclosure prior to enrollment, even before symptom onset, and thus characterizing this sample is important. Furthermore, understanding the mood impacts of genetic disclosure may guide genetic counseling practice. METHOD: F-FTD participants (n=568) from families with a known pathogenic mutation (MAPT, C9orf72, GRN) were enrolled through the ARTFL/LEFFTDS Longitudinal FTD Study (ALLFTD) and provided the opportunity for disclosure. Independent-sample t-tests compared demographic and psychosocial factors between participants who did and did not receive their results. In participants who were asymptomatic at baseline and follow up (n=199,177 with follow-up), linear mixed effects modeling was used to investigate pre- to post-disclosure changes in the 15-item Geriatric Depression Scale (GDS). RESULT: Of participants from families with a known pathogenic genetic mutation, 47% received genetic disclosure. Of the asymptomatic subset (n=386), 36% know their mutation status. Of these asymptomatic learners, 46% received disclosure through the study, and the remainder learned their genetic status prior to study enrollment. None of the analyzed demographic or psychosocial factors (i.e., sex, age, education, having children) differed between learners and non-learners (p’s > 0.05). In the longitudinal analysis of asymptomatic participants, learners showed a pre- to post-increase of 0.31 GDS points/year (95%CI: -0.08, 0.69, p = 0.12), whereas non-learners showed a slight decline (-0.15 points/year, 95%CI: -0.36, 0.06, p = 0.16). This difference between slopes was statistically significant (0.46, 95%CI: 0.02, 0.89, p=0.04) but represents a small clinical effect. In asymptomatic learners, slopes did not differ based on mutation status (0.28, 95%CI: -0.66, 1.20, p=0.55). Conclusions were based on the estimates and full range of confidence intervals. CONCLUSION: The majority of asymptomatic research participants do not know their genetic status, which will be a consideration for clinical trials that require disclosure. No considered demographic factors were strongly associated with the decision to receive disclosure. The findings suggest that disclosure in asymptomatic participants has minimal impact on depressive symptoms regardless of genetic results. © 2021 the Alzheimer’s Association.

Document Type: ArticlePublication Stage: FinalSource: Scopus

“Identification of genetic modifiers for Alzheimer disease: The Familial Alzheimer Sequencing (FASe) project” (2021) Alzheimer’s & Dementia: The Journal of the Alzheimer’s Association

Identification of genetic modifiers for Alzheimer disease: The Familial Alzheimer Sequencing (FASe) project(2021) Alzheimer’s & Dementia: The Journal of the Alzheimer’s Association, 17, p. e054224. 

Neupane, A.a b , Budde, J.P.a b , Bergmann, K.a b , Norton, J.a b , Gentsch, J.a b , Wang, F.a b , Del-Aguila, J.L.a b , Ibanez, L.a b , Morris, J.C.c d , Goate, A.M.e f , Renton, A.E.e , Fernandez, V.a b , Cruchaga, C.b g

a Washington University School of Medicine, St. Louis, MO, USAb Hope Center for Neurological Disorders, St. Louis, MO, USAc Knight Alzheimer Disease Research Center, MO, Saint Louis, United Statesd Washington University in St. Louis, MO, Saint Louis, United Statese Ronald M. Loeb Center for Alzheimer’s disease, NY, NY, United Statesf Icahn School of Medicine at Mount Sinai, NY, NY, United Statesg Washington University, St. Louis, MO, USA

AbstractBACKGROUND: The Familial Alzheimer Sequencing (FASe) project aims to identify rare and high penetrant variants that have strong effect in the etiology of Alzheimer Disease (AD) by using sequencing data from families densely affected by late onset AD (fLOAD). METHOD: We have generated whole genome sequence (WGS) data for 952 samples (758 cases, 194 controls) from the Knight-ADRC at Washington University (WASHU), the NIALOAD and NCRAD repositories. These samples are being added to our current dataset of whole exome (WES) and WGS from 1,235 non-Hispanic white participants (824 cases, 411 controls) across 285 fLOAD families. These samples have no or minimum overlap with the families sequenced by the ADSP consortia which will also be incorporated to our dataset; a total of 440 families and 3,187 samples (average of 5 cases and 2 controls per family) will be analyzed. We are processing all the data using the same bioinformatics pipeline. Briefly, sequence reads are aligned against reference build GRCh38 using BWA; variant calling is restricted to exonic regions following GATK v4.1.2 best practices. Data analysis includes single variant association, segregation, gene-based and pathway analysis. RESULT: We have detected a genetic cross-over between AD, Frontotemporal Dementia and Parkinson disease, and we also identified rare variants in novel candidate genes for AD (PLD3, UNC5C, CPAMD8) highlighting the power of our dataset and the feasibility of our approach. CONCLUSION: We hope to identify novel variants and pathways implicated on AD, which will be followed-up in the case-control ADSP. © 2021 the Alzheimer’s Association.

Document Type: ArticlePublication Stage: FinalSource: Scopus

“Polygenic risk scores for Alzheimer’s disease predict MMSE decline in APOE4 carriers and noncarriers and the impact of sample overlap with GWAS summary statistics” (2021) Alzheimer’s & Dementia: The Journal of the Alzheimer’s Association

Polygenic risk scores for Alzheimer’s disease predict MMSE decline in APOE4 carriers and noncarriers and the impact of sample overlap with GWAS summary statistics(2021) Alzheimer’s & Dementia: The Journal of the Alzheimer’s Association, 17, p. e054622.

Cara, J.a , Collens, J.a , Zhang, H.a , Cruchaga, C.b c d , Hohman, T.J.e 

a Vivid Genomics, San Diego, CA, USAb Washington University in St. Louis School of Medicine, St. Louis, MO, USAc Washington University, St. Louis, MO, USAd Knight Alzheimer Disease Research Center, MO, Saint Louis, United Statese Vanderbilt Genetics Institute, Vanderbilt University Medical Center, TN, Nashville, United States

AbstractBACKGROUND: Heterogeneity in the progression of cognitive impairment, which is common in sporadic Alzheimer’s disease (AD) trials, is especially challenging to predict in pre-symptomatic populations, and has a negative impact on clinical trial power. Heritability of AD extends beyond the APOE genotype, with multiple common genetic variants identified in large genome wide association studies (GWAS). Incorporating APOE and additional genetic variants into models has the potential to improve the prediction of disease progression. The limited volume of genetic cohorts in AD and the sample overlap in GWAS summary statistics poses some concern for polygenic risk score (PRS) overfitting. METHOD: A PRS was calculated using genome-wide association study (GWAS) summary statistics for clinical AD diagnosis. PRS derived from this GWAS study was computed for participants drawn from two aging studies. Logistic regression models assessed the association between PRS and Mini Mental State Exam (MMSE) decline covarying for age, sex, education, APOE-ε4, and baseline MMSE score. Age and sex interactions with PRS were also assessed. Samples assumed to be used in the GWAS calculations were then removed from the test set and the impact to performance was analyzed. RESULT: Participants in the training and test set showed similar baseline ages, years of education and baseline MMSE scores in the whole sample and after stratification by APOE4 carrier status. The PRS model was a significant predictor of MMSE decline, as well as in APOE4 carriers and noncarriers. Model performance was compared to the test set excluding the GWAS overlap samples and no significant difference was observed. CONCLUSION: The proposed model including PRS explains heterogeneity in cognitive decline above and beyond the APOE4 allele. Testing the model in a dataset excluding GWAS overlap samples did not result in a significant difference in performance and potential overfitting does not appear to be an impact. Utilization of demographic and genomic factors beyond APOE in PRS models could enhance clinical trial recruitment and stratification strategies for trial analyses, such that APOE4 carriers are selected for probable cognitive decline, in addition to APOE3 carriers that are high on polygenic risk. © 2021 the Alzheimer’s Association.

Document Type: ArticlePublication Stage: FinalSource: Scopus

“Impact of MAPT mutations on transcriptomic signatures of FTLD brains and patient-derived pluripotent cell models” (2021) Alzheimer’s & Dementia: The Journal of the Alzheimer’s Association

Impact of MAPT mutations on transcriptomic signatures of FTLD brains and patient-derived pluripotent cell models(2021) Alzheimer’s & Dementia: The Journal of the Alzheimer’s Association, 17, p. e054570. 

Minaya, M.a , Martinez, R.a , Seeley, W.W.b , Eteleeb, A.M.a , Cruchaga, C.c , Harari, O.a , Karch, C.M.a

a Washington University, MO, Saint Louis, United Statesb Weill Institute for Neurosciences and Memory and Aging Center, Department of Neurology, University of California, San Francisco, San Francisco, CA, USAc Washington University, St. Louis, MO, USA

AbstractBACKGROUND: Mutations in the microtubule-associated protein tau (MAPT) cause heterogeneous forms of frontotemporal lobar dementia with tau inclusions (FTLD-tau). Yet, the pathogenic events linked to disease remain poorly understood. This study was aimed at identifying genes and pathways that drive to FTLD-tau. METHOD: To identify the earliest genes and pathways that are dysregulated in FTLD-tau, we detected differentially expressed genes in RNA-seq data generated from induced pluripotent stem cell (iPSC)-derived cortical neurons carrying MAPT R406W, MAPT P301L, and MAPT IVS10+16 and isogenic, controls and 26 brain tissue samples (3 R406W carriers, 7 IVS10+16, 3 P301L, and 13 unrelated controls). We then identified pathological pathways and drug targets that were enriched among the differentially expressed genes. RESULT: We identified 61 genes that were differentially expressed in iPSC-derived cortical neurons from MAPT R406W carriers compared with isogenic, control neurons and replicated a subset of these genes in brain tissue from MAPT R406W carriers. We identified 15 genes that were differentially expressed in iPSC-derived cortical neurons from MAPT IVS10+16 carriers compared with isogenic, control neurons and replicated a subset of these genes in brain tissue from MAPT IVS10+16 carriers. We identified 37 genes that were differentially expressed in iPSC-derived cortical neurons from MAPT P301L carriers compared with isogenic, control neurons and replicated a subset of these genes in brain tissue from MAPT P301L carriers. Interestingly, there is little overlap among genes differentially expressed for MAPT R406W, MAPT P301L, and MAPT IVS10+16, which suggests that these mutations may lead to tau aggregation and neurodegeneration by different mechanisms. CONCLUSION: The results from this study demonstrate that iPSC-derived neurons capture molecular processes that occur in human brains and can be used to model disease. © 2021 the Alzheimer’s Association.

Document Type: ArticlePublication Stage: FinalSource: Scopus

“Single nuclei RNA-sequencing of GWAS loci variant carriers elucidates cell-types and transcriptional profile alterations associated with Alzheimer disease” (2021) Alzheimer’s & Dementia: The Journal of the Alzheimer’s Association

Single nuclei RNA-sequencing of GWAS loci variant carriers elucidates cell-types and transcriptional profile alterations associated with Alzheimer disease(2021) Alzheimer’s & Dementia: The Journal of the Alzheimer’s Association, 17, p. e054402.

Brase, L.a , Del-Aguila, J.L.b , You, S.-F.c , Soriano-Tarraga, C.a d , Farias, F.H.G.e f , Benitez, B.A.b d f g , Karch, C.M.d f h , Cruchaga, C.i j k , Harari, O.b d f g , Dominantly Inherited Alzheimer Networkl 

a Washington University in St. Louis, St. Louis, MO, USAb Washington University School of Medicine, St. Louis, MO, USAc Washington University, St. Louis, MO, USAd NeuroGenomics and Informatics Center, St. Louis, MO, USAe Washington University in St. Louis, School of Medicine, St. Louis, MO, USAf Hope Center for Neurological Disorders, St. Louis, MO, USAg Knight Alzheimer Disease Research Center, St. Louis, MO, USAh Washington University, MO, Saint Louis, United Statesi Hope Center for Neurological Disorders, MO, Saint Louis, United Statesj Washington University in St. Louis School of Medicine, St. Louis, MO, USAk Knight Alzheimer Disease Center, MO, Saint Louis, United States

AbstractBACKGROUND: AD has a substantial genetic, molecular and cellular heterogeneity associated with its etiology. We sought to investigate the glial and neuronal pathways affected by AD at a cell specific resolution. To do so, we generated single-nuclei RNA-seq (snRNA-seq) from the parietal cortex of Mendelian mutation carriers, sporadic AD and neuropath-free donors from the Knight-ADRC and Dominantly Inherited Alzheimer Network banks. METHOD: We generated snRNAseq (10X chemistry v3) for 18 APP and PSEN1 mutation carriers, 36 sporadic AD and 9 controls. After data cleaning and quality control, 336,892 nuclei remained for clustering and downstream analyses (Figure 1). Our analytical approach is based on the identification of cellular states (subclusters), their characterization and identification of genes associated with AD genetic strata. RESULT: We identified a myriad of transcriptional states for the most representative brain cell-types (Figure 1) with distinguishing expression profiles (mean of 600 genes overexpressed; FDR<0.05). We identified that neuronal and glial cells have specific transcriptional states enriched in nuclei from brains with APP and PSEN1 mutations. For example, an astrocyte cell state specific for these brains shows overexpression of genes identified in the Disease Associated Astrocytes (DAA) expression signature. We also noted a microglia cell state enriched for a subset of TREM2 variant carriers showing overexpression of genes related to cell migration and lamellipodium assembly. CONCLUSION: We developed a unique molecular atlas to study the pathways dysregulated in AD. Our analyses indicate that in the backdrop of neuropath free and even sporadic AD brains, ADAD samples have distinctive cell states and altered pathways in neurons and glia. © 2021 the Alzheimer’s Association.

Document Type: ArticlePublication Stage: FinalSource: Scopus

“Heritability analyses show partial genetic overlap between (non-Mendelian) early and late onset Alzheimer disease due to an intriguing APOE effect” (2021) Alzheimer’s & Dementia: The Journal of the Alzheimer’s Association

Heritability analyses show partial genetic overlap between (non-Mendelian) early and late onset Alzheimer disease due to an intriguing APOE effect(2021) Alzheimer’s & Dementia: The Journal of the Alzheimer’s Association, 17, p. e056143. 

da Fonseca, E.L.a , Jean-Francois, M.N.a , Kurup, J.T.b , Slifer, S.H.a , Martin, E.R.a , Kunkle, B.W.a , Schellenberg, G.D.c , Pericak-Vance, M.A.a , Fernandez, V.d , Cruchaga, C.e , Reitz, C.b , Beecham, G.W.a

a University of Miami, Miller School of Medicine, John P. Hussman Institute for Human Genomics, FL, Miami, United Statesb Columbia University, Departments of Neurology and Epidemiology, NY, NY, United Statesc University of Pennsylvania Perelman School of Medicine, Path & Lab Med, PA, Philadelphia, United Statesd Washington University School of Medicine, St. Louis, MO, USAe Washington University in St. Louis School of Medicine, St. Louis, MO, USA

AbstractBACKGROUND: Alzheimer disease (AD) is a degenerative brain disease, being the most common cause of progressive dementia and listed as the sixth leading cause of mortality in the USA. It is often described as either early onset (EOAD, age at onset, [AAO] <= 65) or late onset (LOAD, [AAO]>65). Non-Mendelian EOAD (not monogenic; nmEOAD) has irregular inheritance patterns and fluctuating AAO, characteristics also present in LOAD cases. There is still a lack of evidence in the literature depicting the similarities (if any) between nmEOAD and LOAD forms, being unclear how much genetic etiology is shared by the two forms of AD. To shed light to this question, a genome-wide association study (GWAS) and heritability analyses of nmEOAD and LOAD were performed. METHOD: Genetic data on 21,622 individuals from the Alzheimer Disease Genetics Consortium (ADGC) were used: (1,476 nmEOAD, 9,695 LOAD and 10,451 control). Single-variant association analyses were performed using logistic regression under two models: (1) ancestry plus SNP, and (2) ancestry, sex, APOE dosage, and SNP. nmEOAD and LOAD were considered separately. LD score regression was used to estimate the SNP heritability (h2 ) and genetic correlation (rg), considering two additional models: (3) ancestry, sex, and SNP and (4) ancestry, APOE dosage and SNP. RESULT: Several known candidate genes confirmed for LOAD along with novel regions associated with immune and cell-signaling pathways in nmEOAD models. Gene based tests showed significant association for APOE gene (Chr19): nmEOAD (p=3.89×10-16 and p=4.29×10-12 ) and LOAD (p=1.07×10-65 and p=1.12×10-14 ), models (1) and (2) respectively. Heritability analyses showed higher h2 values for EOAD (h2 =0.24, 0.23, 0.25 and 0.24) than LOAD (h2 =0.18, 0.14, 0.18, and 0.14) for models (1) to (4) respectively. Genetic correlation showed moderate genetic overlap between EOAD and LOAD only for models: (2) rg=0.35 (p=0.0283) and (4) rg=0.34 (p=0.0261). CONCLUSION: GWAS and heritability analysis suggest that the genetic etiology of EOAD has a noncomplete genetic overlap with LOAD, with a moderate overlap when APOE dosage is modeled and a minimal overlap otherwise (APOE effect). The results also suggest a stronger polygenic effect in EOAD than LOAD, confirming the need for additional genomics efforts in nmEOAD. © 2021 the Alzheimer’s Association.

Document Type: ArticlePublication Stage: FinalSource: Scopus

“Body mass index predicts lower connectivity in associational fibers of the temporal lobe in older men” (2021) Alzheimer’s & Dementia: The Journal of the Alzheimer’s Association

Body mass index predicts lower connectivity in associational fibers of the temporal lobe in older men(2021) Alzheimer’s & Dementia: The Journal of the Alzheimer’s Association, 17, p. e052902. 

Rahmani, F.a , Raji, C.A.b , Benzinger, T.L.S.a c d

a Mallinckrodt Institute of Radiology, MO, Saint Louis, United Statesb Mallinckrodt Institute of Radiology, Washington University, St. Louis, MO, USAc Washington University in St. Louis School of Medicine, St. Louis, MO, USAd Knight Alzheimer Disease Research Center, MO, Saint Louis, United States

AbstractBACKGROUND: Increased body mass index (BMI) is related to changes in white matter (WM) connectivity1 . We investigated whether WM connectivity patterns as a function of BMI varies across sex differences. METHOD: We enrolled 289 individuals (58 CDR=0 & 231 CDR=0.5) from the Knight Alzheimer Disease Research Center (ADRC) (Table 1). Participants were included if they had a physical evaluation within 12 months of a diffusion MRI scan and excluded if they had clinical dementia. Connectome analyses were performed using the DSI Studio software (http://dsi-studio.labsolver.org/). Diffusion data were reconstructed in the MNI space using q-space diffeomorphic reconstruction (QSDR)2 . The quantitative anisotropy was extracted as the local connectome fingerprint. A multi-regression model were used to derive the correlation and a false discovery rate threshold of 0.05 was adopted to select tracts using a deterministic fiber tracking algorithm. RESULT: A positive association between connectivity in the left arcuate fasciculus (AF) and the left middle cerebellar peduncle in men did not survive regression for age (Figure 1-A). Men also showed a statistically significant negative association between connectivity in the bilateral inferior longitudinal fasciculi (ILF), right inferior fronto-occipital fasciculus (IFOF), the frontoparietal and parahippocampal parts of the right cingulum, the tapetum part of the corpus callosum (CC), right fornix and right corticospinal, corticostriatal, and corticopontine tracts. All of these relationships persisted when co-varying for age (Figure 1-B). Results in women revealed a significant positive correlation between connectivity of the right IFOF, right superior longitudinal fasciculus (SLF), right corticopontine, corticospinal tracts, bilateral reticulospinal tracts, and left arcuate fasciculus (AF) (Figure 2-A) even when controlling for age. Connectivity in the bilateral ILF, right IFOF and the tapetum part of the CC showed an inverse correlation with BMI in women (Figure 2-B). CONCLUSION: Increased BMI is related to lower structural connectivity in important associational WM fibers of the temporal lobe, particularly in older men. References: (1) Gupta A, Mayer EA, Sanmiguel CP, et al. Patterns of brain structural connectivity differentiate normal weight from overweight subjects. NeuroImage Clin. 2015;7:506-517. (2) Yeh F-C, Wedeen VJ, Tseng W-YI. Estimation of fiber orientation and spin density distribution by diffusion deconvolution. Neuroimage. 2011;55(3):1054-1062. © 2021 the Alzheimer’s Association.

Document Type: ArticlePublication Stage: FinalSource: Scopus

“Stem cell models of primary tauopathies reveal defects in synaptic function” (2021) Alzheimer’s & Dementia: The Journal of the Alzheimer’s Association

Stem cell models of primary tauopathies reveal defects in synaptic function(2021) Alzheimer’s & Dementia: The Journal of the Alzheimer’s Association, 17, p. e054566. 

Martinez, R.a , Jiang, S.b , Marsh, J.c , Harari, O.d , Cruchaga, C.e , Goate, A.M.f , Temple, S.g , Karch, C.M.a , Tau Consortium Stem Cell Grouph

a Washington University, Saint Louis, St. Louis, MO, USAb Washington University School of Medicine, MO, Saint Louis, United Statesc Washington University in St. Louis, St. Louis, MO, USAd Washington University School of Medicine, St. Louis, MO, USAe Washington University, St. Louis, St. Louis, MO, USAf Icahn School of Medicine at Mount Sinai, NY, NY, United Statesg Neural Stem Cell Institute, Albany, NY, USA

AbstractBACKGROUND: Primary tauopathies are characterized neuropathologically by inclusions containing abnormal forms of the microtubule-associated protein tau (MAPT) and clinically by diverse neuropsychiatric, cognitive, and motor impairments. Autosomal dominant mutations in the MAPT gene cause heterogeneous forms of frontotemporal lobar degeneration with tauopathy (FTLD-Tau). Common and rare variants in the MAPT gene increase the risk for sporadic FTLD-Tau, including progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD). METHOD: We generated a collection of fibroblasts from 140 MAPT mutation/risk variant carriers, PSP, CBD, and cognitively normal controls; 31 induced pluripotent stem cell (iPSC) lines from MAPT mutation carriers, non-carrier family members, and autopsy-confirmed PSP patients; 33 genome engineered iPSCs that were corrected or mutagenized; and forebrain neural progenitor cells (NPCs). RESULT: To begin to identify the genes and pathways that are dysregulated in primary tauopathies, we performed transcriptomic analyses in induced pluripotent stem cell (iPSC)-derived neurons carrying MAPT p.R406W and CRISPR/Cas9-corrected isogenic controls. We found that the expression of the MAPT p.R406W mutation was sufficient to create a significantly different transcriptomic profile compared with that of the isogeneic controls and to cause the differential expression of 328 genes. Sixty-one of these genes were also differentially expressed between MAPT p.R406W carriers and control brains. Twelve of these genes are also differentially expressed between PSP and control brains. Together, these genes are enriched for pathways involved in GABA-mediated signaling and synaptic function, which may contribute to the pathogenesis of FTLD-tau and other primary tauopathies. CONCLUSION: Here, we present a resource of fibroblasts, iPSCs, and NPCs with comprehensive clinical histories that can be accessed by the scientific community for disease modeling and development of novel therapeutics for tauopathies. © 2021 the Alzheimer’s Association.

Document Type: ArticlePublication Stage: FinalSource: Scopus

“Exome sequencing identifies rare damaging variants in the ATB8B4 and ABCA1 genes as novel risk factors for Alzheimer’s disease” (2021) Alzheimer’s & Dementia: The Journal of the Alzheimer’s Association

Exome sequencing identifies rare damaging variants in the ATB8B4 and ABCA1 genes as novel risk factors for Alzheimer’s disease(2021) Alzheimer’s & Dementia: The Journal of the Alzheimer’s Association, 17, p. e055982. 

Holstege, H.a , Hulsman, M.a , Charbonnier, C.b , Grenier-Boley, B.c , Quenez, O.d , Grozeva, D.e , van Rooij, J.G.J.f , Sims, R.e , Ahmad, S.f , Amin, N.g , Norsworthy, P.h , Dols-Icardo, O.i , Hummerich, H.h , Kawalia, A.j , Amouyel, P.c , Beecham, G.W.k , Berr, C.l , Bis, J.C.m , Boland, A.n , Bossù, P.o , Bouwman, F.H.p , Bras, J.q , Campion, D.b , Cochran, J.N.r , Daniele, A.s , Dartigues, J.-F.t , Debette, S.t , Deleuze, J.-F.n , Denning, N.e , Destefano, A.L.u , Farrer, L.A.u , Fernandez, V.v , Fox, N.C.h , Galimberti, D.w , Génin, E.x , Gille, H.a , Guen, Y.L.y , Guerreiro, R.q , Haines, J.L.z , Holmes, C.aa , Ikram, M.A.f , Ikram, M.K.f , Jansen, I.E.a , Kraaij, R.f , Lathrop, M.ab , Lemstra, A.W.a , Lleó, A.ac , Luckcuck, L.e , Marshall, R.e , Martin, E.R.ad , Masullo, C.ae , Mayeux, R.af , Mecocci, P.ag , Meggy, A.e , Mol, M.O.f , Morgan, K.ah , Myers, R.M.r , Nacmias, B.ai , Naj, A.C.aj , Napolioni, V.y , Pastor, P.ak , Pericak-Vance, M.A.k , Raybould, R.e , Redon, R.al , Reinders, M.J.am , Richard, A.-C.b , Riedel-Heller, S.G.an , Rivadeneira, F.f , Rousseau, S.b , Ryan, N.S.h , Saad, S.e , Sanchez-Juan, P.ao , Schellenberg, G.D.aj , Scheltens, P.a , Schott, J.M.h , Seripa, D.ap , Sie, D.a , Sistermans, E.a , Sorbi, S.ai , van Spaendonk, R.M.L.a , Spalletta, G.o , Tesi, N.a , Tijms, B.M.a , Van Der Lee, S.J.a , Uitterlinden, A.G.f , Visser, P.J.a , Wagner, M.aq , Wallon, D.d , Wang, L.-S.aj , Zarea, A.d , Clarimón, J.ac , van Swieten, J.C.f , Hardy, J.h , Greicius, M.D.y , Ramirez, A.j , Mead, S.h , Yokoyama, J.S.ar , van der Flier, W.M.a , Cruchaga, C.v , Van Duijn, C.M.g , Williams, J.e , Nicolas, G.d , Bellenguez, C.c , Lambert, J.-C.c

a Amsterdam, Netherlandsb Inserm U1079 / Rouen University, Rouen, Francec Inserm, Institut Pasteur de Lille, Lille, Franced Inserm U1245 / Rouen University Hospital, Rouen, Francee Cardiff University, Cardiff, United Kingdomf Erasmus MC, Rotterdam, Netherlandsg University of Oxford, Oxford, United Kingdomh University College London, London, United Kingdomi Universitat Autònoma de Barcelona, Barcelona, Spainj University of Bonn, Bonn, Germanyk University of Miami, FL, Miami, United Statesl University of Montpellier, Montpellier, Francem University of Washington, Seattle, WA, USAn Centre National de Génotypage, Institut de Génomique / CEA, Evry, Franceo IRCCS Santa Lucia Foundation, Rome, Italyp Alzheimer Center Amsterdam, Amsterdam, Netherlandsq Van Andel Institute, Grand Rapids, MI, United Statesr HudsonAlpha Institute for Biotechnology, Huntsville, AL, USAs Università Cattolica del Sacro Cuore, Rome, Italyt Bordeaux University Hospital, Bordeaux, Franceu Boston University, MA, Boston, United Statesv Washington University, St. Louis, MO, USAw University of Milan, Milan, Italyx Université Bretagne OccidentaleBrest, Francey Stanford University, Stanford, CA, USAz Case Western Reserve University School of Medicine, Cleveland, OH, USAaa University of SouthamptonSouthampton, United Kingdomab McGill University and Génome Québec Innovation Centre, QC, Montréal, Canadaac Hospital de la Santa Creu i Sant Pau, Barcelona, Spainad University of Miami Miller School of Medicine, FL, Miami, United Statesae Universitario A. Gemelli, Rome, Italyaf Columbia University, NY, NY, United Statesag University of Perugia, Perugia, Italyah University of Nottingham, Nottingham, United Kingdomai University of Florence, Florence, Italyaj University of Pennsylvania, PA, Philadelphia, United Statesak Universidad de Navarra, Pamplona, Spainal CNRS UMR 6291 / Université de Nantes, Nantes, Franceam Delft University of Technology, Delft, Netherlandsan University of Leipzig, Leipzig, Germanyao CIBERNEDMadrid, Spainap IRCCS Ospedale Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italyaq University Hospital Bonn, Bonn, Germanyar University of California, San Francisco, San Francisco, CA, USA

AbstractBACKGROUND: Damaging rare variants in the TREM2, SORL1 and ABCA7 genes have been associated with an increased risk of developing Alzheimer’s Disease (AD) with odds ratios that were not observed since the identification of the main AD genetic risk factor, the APOE-ε4 allele. Here, we aimed to identify additional AD-associated genes by investigating the burden of rare damaging variants in the exomes of AD cases and controls. METHOD: On a single server, we analyzed in two stages, the data from 52,270 exome sequences from several independent datasets from Europe and the United States. After comprehensive QC, Stage-1 and Stage-2 datasets comprised in total 16,396 AD cases (5,672 EOAD) and 18,107 controls with European ancestry. All detected non-synonymous and loss-of-function rare variants were prioritized by REVEL and LOFTEE, and analyzed in a per-gene burden analysis. After a Stage-1 discovery analysis, we replicated findings in an independent dataset (Stage-2). We combined the Stage-1 and Stage-2 datasets and determined, for each gene, the features of the variants that drive the burden-associations. RESULTS: We confirmed the AD-association of rare damaging variants SORL1, TREM2, ABCA7, and newly identified a significant AD-association of rare damaging variants in the ATP8B4 and ABCA1 genes. In addition, we find a strong indication for the AD-association of ADAM10 and SRC genes (Stage-2 p<0.05). For most genes, we observed a larger effect size for LOF variants compared to missense variants (Figure-A). High-impact variants in these genes are mostly extremely rare and enriched in AD patients with early ages at onset (Figure-B). CONCLUSION: We identified, for the first time, the AD-association of rare damaging variants in two genes: (i) microglial ATP8B4 which is involved in phospholipid transport, and (ii) ABCA1 which plays a critical role in lipidation of apoE thereby supporting Aβ processing. Further, we found strong evidence for the AD-association of damaging variants in ADAM10 and SRC genes. ADAM10 is involved in the proteolytic processing of APP, while SRC is a Non-Receptor Tyrosine Kinase which binds PTK2B/Pyk2, a known AD risk factor. Together, our study provides further evidence for the role of Aβ and microglia in AD pathophysiology. © 2021 the Alzheimer’s Association.

Document Type: ArticlePublication Stage: FinalSource: Scopus

“Profiling the metabolic landscape of AD” (2021) Alzheimer’s & Dementia: The Journal of the Alzheimer’s Association

Profiling the metabolic landscape of AD(2021) Alzheimer’s & Dementia: The Journal of the Alzheimer’s Association, 17, p. e050086. 

Novotny, B.C.a , Fernandez, V.a b , Budde, J.P.a b , Bergmann, K.a b , Morris, J.C.c d e , Bateman, R.J.a b f , Karch, C.M.b g , Benitez, B.A.a b , Cruchaga, C.b e h , Harari, O.a b , Dominantly Inherited Alzheimer Networki

a Washington University School of Medicine, St. Louis, MO, USAb Hope Center for Neurological Disorders, St. Louis, MO, USAc Washington University in St. Louis, St. Louis, MO, USAd Hope Center for Neurological Disorders, MO, Saint Louis, United Statese Knight Alzheimer Disease Research Center, MO, Saint Louis, United Statesf Knight Alzheimer Disease Research Center, St. Louis, MO, USAg Washington University, MO, Saint Louis, United Statesh Washington University, St. Louis, MO, USA

AbstractBACKGROUND: Metabolic dysfunction, including perturbations in lipid, neurotransmitter, and polyamine metabolism, is an early indicator of cognitive impairment and Alzheimer disease (AD) risk. Further investigation is needed to elucidate the role of genetic heterogeneity in these metabolic disturbances. Here, we interrogate metabolomic signatures in the brains of carriers of pathological mutations in APP, PSEN1, and PSEN2 (Autosomal Dominant AD; ADAD), risk variants in TREM2, non-carrier sporadic AD cases (sAD), individuals with neuropathology but without clinical symptoms (Presymptomatic), and neuropathology-free controls (CO). METHOD: Metabolomic data from parietal brain tissue of donors to the Knight Alzheimer Disease Research Center and the Dominantly Inherited Alzheimer Network (ADAD, n=25; TREM2, n=21; sAD, n=305; Presymptomatic, n=15; CO, n=27) were generated using the Metabolon global metabolomics platform. A total of 627 metabolites passed our QC process. Differential abundance between AD strata and controls was tested using linear regression corrected for sex, age, and post-mortem interval. Age was excluded from ADAD models. Benjamini-Hochberg multiple testing correction was applied, and pathway analysis was performed with MetaboAnalyst and IMPaLA. RESULT: In total, we identified 138 metabolites associated with distinct genetic strata (FDR q-value<0.05). For sAD, these included tryptophan betaine (β=-0.55) and N-acetylputrescine (β=-0.14). Metabolites associated with both sAD and ADAD were ergothioneine (β=-0.22 and -0.26 respectively) and serotonin (β=-0.34 and -0.57). TREM2 and ADAD showed association with α-tocopherol (β=-0.12 and -0.12). β-citrylglutamate abundance decreased in sAD, ADAD, and TREM2 versus controls (β=-0.14; -0.22; and -0.29). Pathways identified included glutamate, vitamin, and antioxidant metabolism. A 16-metabolite subset showed consistent direction of effect among the genetic strata with the magnitude of effect of ADAD greater than that of TREM2, in turn greater than sAD. A representation of these (eigengene) is associated with disease duration in sAD (p=5.65×10-03 ), possibly driven by tau accumulation. Hierarchical clustering identified 41 “early stage” sAD individuals with Braak tau stage similar to Presymptomatic (p=0.35), but lower than other sAD individuals (β=-0.56, p=3.09×10-04 ) (Figure 1). CONCLUSION: Our findings suggest distinct and characteristic metabolic perturbations in ADAD and TREM2 brains. Investigation of these differentially abundant metabolites may lead to greater insight into the metabolic etiology of AD and its impact on clinical presentation. © 2021 the Alzheimer’s Association.

Document Type: ArticlePublication Stage: FinalSource: Scopus

“TREM2-independent neuroprotection is mediated by monocyte-derived macrophages in a mouse model of Alzheimer’s disease” (2021) Alzheimer’s & Dementia: The Journal of the Alzheimer’s Association

TREM2-independent neuroprotection is mediated by monocyte-derived macrophages in a mouse model of Alzheimer’s disease(2021) Alzheimer’s & Dementia: The Journal of the Alzheimer’s Association, 17, p. e052775. 

Dvir-Szternfeld, R.a , Castellani, G.a , Arad, M.a , Cahalon, L.a , Colaiuta, S.P.a , Keren-Shaul, H.a , Croese, T.a , Ulland, T.K.b , Colonna, M.b , Weiner, A.a , Amit, I.a , Schwartz, M.a

a Weizmann Institute of Science, Rehovot, Israelb Washington University in St. Louis, St. Louis, MO, USA

AbstractBACKGROUND: The relative contributions of microglia and infiltrating monocyte-derived macrophages (MDMs) to containing Alzheimer’s disease (AD) are not fully understood. In the 5xFAD animal model of amyloidosis, disease-associated microglia (DAM) expressing the Triggering receptor expressed on myeloid cells 2 (TREM2), are found in close proximity to amyloid beta (Aβ) plaques. Deletion of TREM2 results in the absence of DAM and in an increased Aβ-plaque load. However, the necessity of TREM2 and DAM for resolving AD pathology is still debatable. METHOD: Here, we activated systemic immunity by blocking the programmed cell death protein 1 / ligand (PD-1/PD-L1) pathway in TREM2-/- and TREM2+/+ 5xFAD mice, to decipher the roles of the different myeloid populations in mitigating AD pathology. RESULT: We found that anti-PD-L1 treatment resulted in cognitive improvement in TREM2-/- and TREM2+/+ 5xFAD mice. In addition, in both TREM2-/- 5xFAD and TREM2+/+ 5xFAD, the treatment resulted in a reduction in water soluble-Aβ, while reduction of insoluble-Aβ was observed only in TREM2+/+ 5xFAD mice. Eliminating monocytes using anti-CCR2 antibody fully abrogated the observed effects of anti-PD-L1 treatment in TREM-/- 5xFAD mice, and partially eliminated the effects in the TREM2+/+ 5xFAD. Single-cell RNA-seq of myeloid cells isolated from TREM2-/- 5xFAD brains revealed that MDMs express unique scavenger receptors, previously linked to soluble-Aβ removal, such as Macrophage scavenger receptor 1 (MSR1). CONCLUSION: Overall, our findings highlight a novel TREM2-independent pathway by which cognitive improvement and removal of soluble-Aβ are achieved in an amyloidosis model. Thus, our results support the potential of MDM-harnessing immunotherapy in treating AD patients, irrespective of whether they carry a TREM2 mutation. © 2021 the Alzheimer’s Association.

Document Type: ArticlePublication Stage: FinalSource: Scopus

“A large-scale, whole genome sequencing study of unexplained early-onset Alzheimer disease” (2021) Alzheimer’s & Dementia: The Journal of the Alzheimer’s Association

A large-scale, whole genome sequencing study of unexplained early-onset Alzheimer disease(2021) Alzheimer’s & Dementia: The Journal of the Alzheimer’s Association, 17, p. e056664. 

Beecham, G.W.a , Fonseca, E.L.b , Kurup, J.T.c , Pericak-Vance, M.A.a d , Martin, E.R.d , Schellenberg, G.D.e , Fernandez, V.f , Cruchaga, C.f , Reitz, C.g

a Dr. John T. Macdonald Foundation Department of Human Genetics, University of Miami Miller School of Medicine, FL, Miami, United Statesb University of Miami, Miller School of Medicine, John P. Hussman Institute for Human Genomics, FL, Miami, United Statesc Columbia University, Departments of Neurology and Epidemiology, NY, NY, United Statesd John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, FL, Miami, United Statese University of Pennsylvania Perelman School of Medicine, PA, Philadelphia, United Statesf Washington University, St. Louis, MO, USAg Columbia University Medical Center, NY, NY, United States

AbstractBACKGROUND: Genomic studies of Alzheimer disease (AD) have primarily focused on non-Hispanic White (NHW) participants affected by the late-onset form (LOAD; onset age: >65), or the study of early onset AD (EOAD; onset age <=65) cases showing Mendelian inheritance patterns associated with mutations in the APP, PSEN1 and PSEN2 genes. However, mutations in these three genes explain 10% of EOAD cases. There are no large-scale efforts to collect and study EOAD cases not explained by these genes, despite this unexplained category accounting for 90% of EOAD cases. METHOD: To address this, we aim to identify additional EOAD-associated variants, genes and pathways through a large-scale whole-genome sequencing (WGS) study of unexplained EOAD. We will include cases from several AD cohorts, including the Resource for Early-onset Alzheimer Disease Research (READR), the Knight-ADRC at Washington University, the Alzheimer’s Disease Genetics Consortium (ADGC), and others. Generating and harmonizing a dataset of 200 non-Hispanic White (NHW) and Caribbean Hispanic (CH) multiplex EOAD families, over 5,400 EOAD singletons and over 13,000 unrelated, cognitive controls, all with WGS, this project will yield the largest EOAD genomics dataset to-date, improving statistical power for variant identification and allowing us to assess the impact of specific factors such as APOE genotype, vascular risk factors, and neuropsychiatric comorbidities. The inclusion of a large set of Hispanic families and singletons allows the examination of EOAD risk in a significantly understudied population. Analyses will comprise both linkage and association-based approaches, analyses of polygenic and ancestry effects, and a thorough examination of neurocognitive, neuropsychiatric and cardiovascular endophenotypes. RESULT: When completed this study will point to novel genetic contributors to EOAD, shed light on the mechanisms of AD and facilitate the development of novel prediction models and therapeutics. CONCLUSION: Sampling, phenotyping and sequencing analysis protocols will be complementary to and compatible with the existing LOAD genomics resources, such as the Alzheimer Disease Sequencing Project (ADSP) and related studies. This phenotypic and genomic consistency, together with the use of existing AD infrastructure (NIAGADS), allows for immediate integration with the leading efforts on LOAD, enabling rapid large-scale investigation of a variety of additional critical AD genomics hypotheses. © 2021 the Alzheimer’s Association.

Document Type: ArticlePublication Stage: FinalSource: Scopus

“Defective proteostasis in patient-derived iPSC astrocytes and neurons carrying a MAPT IVS10+16 mutation” (2021) Alzheimer’s & Dementia: The Journal of the Alzheimer’s Association

Defective proteostasis in patient-derived iPSC astrocytes and neurons carrying a MAPT IVS10+16 mutation(2021) Alzheimer’s & Dementia: The Journal of the Alzheimer’s Association, 17, p. e054448. 

Mahali, S.a , Martinez, R.b , Hu, M.a , Marsh, J.a , Temple, S.c , Karch, C.M.a d

a Washington University in St. Louis, St. Louis, MO, USAb Washington University, Saint Louis, St. Louis, MO, USAc Neural Stem Cell Institute, Albany, NY, USAd Hope Center for Neurological Disorders, St. Louis, MO, USA

AbstractBACKGROUND: Impaired proteostasis is associated with normal aging and is accelerated in neurodegeneration. This impairment may lead to the toxic accumulation of protein. In a subset of frontotemporal dementia (FTD) cases, mutations in the microtubule-associated protein tau (MAPT) that alter the relative levels of tau isoforms are sufficient to cause tau inclusions in neurons and astroglia and neurodegeneration without the presence of mutated protein (e.g. MAPTIVS10+16). However, the pathogenic events triggered by the expression of the alternatively spliced tau remain poorly understood. METHOD: To determine whether altered tau splicing induced from MAPT IVS10+16 mutations is sufficient to alter proteostasis in neurons and glia, we used human induced pluripotent stem cell (iPSC)-derived neurons and astrocytes from patients carrying the MAPT IVS10+16 mutation and CRISPR/Cas9, isogenic corrected controls. RESULT: We found that neurons from MAPT IVS10+16 carriers exhibited significantly higher levels of tau containing 4 microtubule binding repeats (4R tau), deficits in lysosomal trafficking, and acidity relative to isogenic-control neurons. Conversely, astrocytes from MAPT IVS10+16 carriers exhibited morphologically an increase in acidic lysosomes compared to isogenic-control astrocytes. Astrocytes from MAPT IVS10+16 carriers were also larger in size, consistent with cellular hypertrophy observed in brains from FTD-tau patients. CONCLUSION: Our findings suggest that altered tau splicing induced by the MAPT IVS10+16 mutation is sufficient to cause impaired lysosomal function and altered proteostasis in a cell-type specific manner. © 2021 the Alzheimer’s Association.

Document Type: ArticlePublication Stage: FinalSource: Scopus

“DNAJC5 affects the endo-lysosomal pathway, APP processing, and AD pathology in vitro and in vivo” (2021) Alzheimer’s & Dementia: The Journal of the Alzheimer’s Association

DNAJC5 affects the endo-lysosomal pathway, APP processing, and AD pathology in vitro and in vivo(2021) Alzheimer’s & Dementia: The Journal of the Alzheimer’s Association, 17, p. e054177.

Nykanen, N.a , Wang, Z.a b , Davis, T.A.c , Nunez, M.d , O’Dell, K.d , Cirrito, J.R.c , Sands, M.d , Benitez, B.A.e f g h i 

a NeuroGenomics and Informatic Center, MO, Saint Louis, United Statesb Washington University in Saint Louis, MO, Saint Louis, United Statesc Washington University School of Medicine, MO, Saint Louis, United Statesd Washington University in Saint Louis, St. Louis, MO, USAe Hope Center for Neurological Disorders, St. Louis, MO, USAf Washington University School of Medicine, St. Louis, MO, USAg Washington University in St. Louis, St. Louis, MO, USAh NeuroGenomics and Informatics Center, St. Louis, MO, USAi Knight Alzheimer Disease Research Center, St. Louis, MO, USA

AbstractBACKGROUND: The DnaJ heat shock protein family member C5 (DNAJC5) gene encodes Cysteine String Protein-alpha (CSPα). CSPα is a key endo-lysosomal element of the misfolding-associated protein secretion (MAPS) machinery. MAPS eliminates misfolded cytosolic proteins, including alpha-synuclein, tau, TDP-43, huntingtin. Mutations in the DNAJC5 gene cause rare early-onset dementia called adult-onset Neuronal ceroid lipofuscinosis (ANCL). Data from CSPα-deficient mice and flies suggest that CSPα is critical for preventing age-dependent neurodegeneration. The endo-lysosome plays an essential role in normal and abnormal Amyloid-beta precursor protein (APP) processing and subsequent β-amyloidogenesis in Alzheimer’s disease (AD). However, the role of CSPα in APP processing, trafficking, and amyloidogenesis is not well understood. METHODS: We used histological staining and whole transcriptome data from ANCL, AD patients, and age-matched pathology-free controls. Differential expression (DE) analysis was performed using DESeq2 software. We performed histological analysis of 5XFAD mouse models crossed with DNAJC5 mice. We used mouse neuroblastoma (N2A) cells stably expressing wild-type human APP695 (N2A695) and human wild-type (WT) and mutant DNAJC5. We used ELISA to quantify Aβ40 and Aβ42 in cell culture media and human brain lysates. RESULTS: CSPα co-localizes with endo-lysosomal and synaptic markers in N2A695 cells. CSPα overexpression affects lysosomal function and SNAP29-mediated exocytosis. Overexpression and knockdown of hCSPα-WT in N2A695 cells significantly affect extracellular Aβ40, Aβ42, full-length APP, and APP C-terminal fragments (CTF). N2A-APP cells expressing a gain-of-function DNAJC5 mutant displayed a significant increase in lysosomal and autophagy (LC3-II and p62) proteins, lysosomal exocytosis, and secreted levels of Aβ40 and Aβ42. ANCL brains showed considerable neuronal Aβ accumulation. ANCL brains exhibit a significant reduction of soluble and insoluble Aβ4 and Aβ42. Transcriptome analysis from ANCL brains shows changes in the mTOR pathway. DNAJC5 transcript levels are significantly reduced in AD cases compared to controls. A mouse AD model exhibits an inverse correlation between DNAJC5 transcript levels and Aβ plaques. 5XFAD mice haploinsufficient for DNAJC5 gene significantly increased the Aβ plaque burden and decreased Aβ plaque latency. CONCLUSIONS: Our results provide evidence of the novel and unexpected role of CSPα in endo-lysosomal function, lysosomal exocytosis, β-amyloidogenesis both in vitro and in vivo. © 2021 the Alzheimer’s Association.

Document Type: ArticlePublication Stage: FinalSource: Scopus

“Genome-wide DNA methylation analysis of autosomal dominantly inherited and sporadic Alzheimer disease brains” (2021) Alzheimer’s & Dementia: The Journal of the Alzheimer’s Association

Genome-wide DNA methylation analysis of autosomal dominantly inherited and sporadic Alzheimer disease brains(2021) Alzheimer’s & Dementia: The Journal of the Alzheimer’s Association, 17, p. e053502. 

Soriano-Tarraga, C.a b , Farias, F.H.G.a c , Budde, J.P.c d , Ebl, C.a , Norton, J.a c , Gentsch, J.c d e , Morris, J.C.a f g , Bateman, R.J.c h i j , Swisher, L.h , McDade, E.a e , Perrin, R.J.c e h , Cruchaga, C.b c g h , Harari, O.b c e i

a Washington University in St. Louis, St. Louis, MO, USAb NeuroGenomics and Informatics Center, St. Louis, MO, USAc Hope Center for Neurological Disorders, St. Louis, MO, USAd Washington University School of Medicine, St. Louis, MO, USAe Knight Alzheimer Disease Research Center, St. Louis, MO, USAf Hope Center for Neurological Disorders, MO, Saint Louis, United Statesg Knight Alzheimer Disease Research Center, MO, Saint Louis, United Statesh Washington University in St. Louis School of Medicine, St. Louis, MO, USAi Washington University, MO, Saint Louis, United Statesj Knight Alzheimer’s Disease Research Center, St. Louis, MO, USA

AbstractBACKGROUND: Alzheimer’s disease (AD) is a multifactorial neurodegenerative disorder with many biological processes, and molecular changes. The etiology of AD is complex and not specific to a single genetic factor. Epigenetic changes could help explain the missing heritability not capture in GWAS chips and determine functional variants in genome-wide significant loci. METHOD: Our discovery cohort includes 460 post-mortem brains, 452 AD and 25 controls from Knight-ADRC and Dominantly Inherited Alzheimer Network cohorts. Our study included late-onset (LOAD), but also subjects with Mendelian mutations in APP, PSEN1 and PSEN2 genes (Autosomal Dominant AD; ADAD) and controls. We performed a genome-wide methylation study using DNA from parietal cortex. We used Infinium MethylationEPIC Beadchip arrays (Illumina) to measure DNA methylation. All statistical analyses were adjusted for sex, age at death and neuron proportion. RESULT: Completion of this project will provide an enhanced characterization of the epigenetic factors associated with AD etiology. This study will enhance the understanding of the molecular dynamics underlying the pathophysiology of AD, and may lead to novel clues for its early detection, prevention and treatment. CONCLUSION: Epigenetics of AD brains have been previously studied, but this is the first study to analyze both LOAD and ADAD. These results will be presented in the conference. © 2021 the Alzheimer’s Association.

Document Type: ArticlePublication Stage: FinalSource: Scopus

“Evidence that the gut microbiota regulates progression of neurodegeneration in a mouse model of tauopathy, in a sex- and ApoE isoform-dependent manner” (2021) Alzheimer’s & Dementia: The Journal of the Alzheimer’s Association

Evidence that the gut microbiota regulates progression of neurodegeneration in a mouse model of tauopathy, in a sex- and ApoE isoform-dependent manner(2021) Alzheimer’s & Dementia: The Journal of the Alzheimer’s Association, 17, p. e049741. 

Seo, D.-O.a , Stanley, J.G.a , Shi, Y.a , Wang, C.b , Serrano, J.R.a , Bao, X.a , O’Donnell, D.a , Lelwala-Guruge, J.a , Griffin, N.a , Meier, M.a , Dodiya, H.B.c , Sisodia, S.S.c , Gordon, J.I.a , Holtzman, D.M.a

a Washington University in St. Louis, St. Louis, MO, USAb Washington University in St. Louis, School of Medicine, St. Louis, MO, USAc University of Chicago, Chicago, United States

AbstractBACKGROUND: Alzheimer’s disease (AD) is a fatal progressive neurodegenerative disease. Mounting evidence supports that an unbalanced gut microbiota (GM) is linked to amyloid-β deposition potentially by disrupting neuroinflammation and metabolic homeostasis. However, the contribution of the GM to tau-mediated neurodegeneration is poorly characterized. Furthermore, recent studies have reported that the configuration of the GM is also affected by ApoE isoforms, which is the strongest genetic risk factor for late-onset AD. Here, we explore the hypothesis that the GM regulates tau-mediated neurodegeneration in a sex- and ApoE isoform- dependent manner, using a mouse model of tauopathy. METHOD: Male and female P301S tau transgenic mice were crossed with human ApoE knock-in mice (ApoE3 or ApoE4) or ApoE knockout mice (EKO) to generate P301S::ApoE3/E3, ApoE4/E4, or P301S/EKO mice, termed TE3F, TE4F, and TEKO, respectively. The GM in each group was perturbed by gastric gavage of a combination of antibiotics (ABX) from post-natal day 16-22; controls were gavaged with water (H2O). Mice were housed in a specific pathogen-free facility and fed a standard mouse chow diet ad libitum until they were euthanized at 9 months of age. In addition, a separate group of male and female TE4F mice were housed under germ-free conditions. Collected brains were sectioned, stained with 0.1% Sudan black and used to measure volumes of regions of interest. RESULT: In males, TE3F and TE4F mice treated with H2O showed significant hippocampal atrophy compared to P301S mice lacking a functional ApoE gene (TEKO). However, TE3F mice treated with a short-term ABX showed significantly milder hippocampal atrophy compared to the water-treated group (p < 0.001, t-test). ABX treatment of TE4F animals was also associated with milder atrophy, although the effect did not reach statistical significance (p = 0.09, t-test). There were no effects in TEKO mice treated with ABX. Remarkably, these phenotypic effects of ABX treatment were not observed in females. Moreover, germ-free TE4F mice showed a marked decrease in brain atrophy compared to conventionally-raised animals; this was true for both sexes. CONCLUSION: Our results indicate that tau-mediated neurodegeneration occurs in a ApoE- dependent manner and is influenced by the gut microbiota and gender. © 2021 the Alzheimer’s Association.

Document Type: ArticlePublication Stage: FinalSource: Scopus

“Multi-omics approaches reveal a link between the MS4A gene loci, TREM2, and microglia function” (2021) Alzheimer’s & Dementia: The Journal of the Alzheimer’s Association

Multi-omics approaches reveal a link between the MS4A gene loci, TREM2, and microglia function(2021) Alzheimer’s & Dementia: The Journal of the Alzheimer’s Association, 17, p. e054553.

You, S.-F.a , Brase, L.b , Filipello, F.c , Del-Aguila, J.L.d , Mihindukulasuriya, K.A.e , Benitez, B.A.d , Cruchaga, C.a , Harari, O.d , Karch, C.M.f 

a Washington University, St. Louis, MO, USAb Washington University in St. Louis, St. Louis, MO, USAc Washington University School of Medicine, MO, Saint Louis, United Statesd Washington University School of Medicine, St. Louis, MO, USAe Washington University in St. Louis, School of Medicine, St. Louis, MO, USAf Washington University, MO, Saint Louis, United States

AbstractBACKGROUND: Soluble triggering receptor expressed on myeloid cells 2 (sTREM2) in cerebrospinal fluid (CSF) has been associated with Alzheimer’s disease (AD). TREM2 plays a critical role in microglial activation, survival, and phagocytosis; however, the pathophysiological role of sTREM2 in AD is not well understood. Understanding the role of sTREM2 in AD may reveal new pathological mechanisms and lead to the identification of therapeutic targets. We recently identified common variants in the membrane-spanning 4-domains subfamily A (MS4A) gene region that were associated with CSF sTREM2 concentrations. One variant (rs1582763) was associated with increased CSF sTREM2 and reduced AD risk, while a second variant (rs6591561) was associated with reduced CSF sTREM2 and increased AD risk. Using human induced pluripotent stem cell-derived microglia, we found that MS4A4A and TREM2 colocalize on lipid rafts at the plasma membrane. Here, we sought to define the molecular mechanism by which variants in the MS4A gene region impact sTREM2, microglia function and AD risk. METHOD: To define the functional effects of MS4A variants, we used genotype and bulk RNAseq data from 579 human brain samples. We then evaluated microglia specific effects using single nuclei RNAseq data obtained from 64 human brains. RESULT: Leveraging genotypic and transcriptomic data in human brain tissue, we found that rs1582763 and rs6591561 alter distinct molecular pathways. Rs1582763, which confers AD resilience, impacts pathways associated with cholesterol metabolism, while rs6591561, which confers AD risk, impacts pathways associated with chemokine regulation. Using single nuclei RNAseq data in human brain tissue, we found that these variants are associated with MS4A4A expression within microglia. Additionally, these variants modify cellular proportions of a functionally distinct microglia population. CONCLUSION: Together, these findings begin to provide a mechanistic explanation for the original GWAS signal in the MS4A locus for AD risk and indicate that TREM2 may be involved in AD pathogenesis not only in TREM2 risk-variant carriers but also in those with sporadic disease. © 2021 the Alzheimer’s Association.

Document Type: ArticlePublication Stage: FinalSource: Scopus

“Multi-omics data integration reveals clinically meaningful molecular profiles of Alzheimer disease” (2021) Alzheimer’s & Dementia: The Journal of the Alzheimer’s Association

Multi-omics data integration reveals clinically meaningful molecular profiles of Alzheimer disease(2021) Alzheimer’s & Dementia: The Journal of the Alzheimer’s Association, 17, p. e052942. 

Eteleeb, A.M.a b , Novotny, B.C.b c , Morris, J.C.c d e , Bateman, R.J.c f g , Perrin, R.J.f g h , Karch, C.M.b f h , Cruchaga, C.b e f h , Benitez, B.A.b c f g , Harari, O.a b f g

a Washington University, MO, Saint Louis, United Statesb NeuroGenomics and Informatics Center, St. Louis, MO, USAc Washington University in St. Louis, St. Louis, MO, USAd Hope Center for Neurological Disorders, MO, Saint Louis, United Statese Knight Alzheimer Disease Research Center, MO, Saint Louis, United Statesf Hope Center for Neurological Disorders, St. Louis, MO, USAg Knight Alzheimer Disease Research Center, St. Louis, MO, USAh Washington University in St. Louis School of Medicine, St. Louis, MO, USA

AbstractBACKGROUND: Alzheimer disease (AD) is a complex polygenic disease in which multiple molecular pathways and biological processes are affected in distinct cell-types of the brain. Increasingly, novel machine learning approaches have been applied in other areas of similarly high complexity (e.g., cancer) to integrate different modalities of “-omics” data and provide novel insights. We sought to apply high-throughput “multi-omics” and machine learning approaches to a large assembly of clinically and neuropathologically well-characterized brain samples to identify genes and biological pathways that may lead to new biomarkers and therapies for AD. METHOD: We analyzed high-throughput transcriptomics, proteomics, metabolomics and lipidomics profiles of postmortem parietal cortex samples from the Knight ADRC (n=328) and the DIAN (n =21) participants including APP, PSEN1 and PSEN2 autosomal dominant AD mutation carriers (ADAD, n=28), sporadic AD (sAD, n=282), presymptomatic AD (preAD, n=14), and controls with minimal neuropathologic changes (n=25). We applied a Bayesian integrative clustering method (iClusterBayes), designed to identify disease subtypes, to cluster sAD samples on the basis of 2,676 transcripts, 1,067 proteins, 350 metabolites, and 277 lipids. RESULT: Our analyses identified four different molecular signatures among sAD cases (Figure 1A). Cluster 4 was associated with higher Clinical Dementia Rating (CDR; p=2.2 x10-20) scores and shorter life span (p=5.6 x10-3, HR=1.6; Figure 1B). In particular, alpha-synuclein (SNCA) transcriptomic and proteomic levels were differentially expressed between samples in cluster 4 and others representing sAD, ADAD, preAD, and controls (Figure 1C) suggesting a unique role for SNCA in sAD cases with unfavorable outcomes. The lower levels of soluble SNCA protein in AD samples may be associated with insoluble aggregated SNCA (Lewy bodies) reported in 50-60% of sAD. CONCLUSION: By applying machine learning approaches to sAD samples with high-throughput multi-omic profiles, we identified novel molecular signatures missed by single layer analyses. These signatures are associated with clinical phenotypes and offer new insights into which molecules may wax or wane as cognition declines. The association of SNCA with poor outcomes suggests that concomitant Lewy bodies may be a negative prognostic factor in sAD. Currently, we are extending these analyses to incorporate replication cohorts and to perform downstream pathway and enrichment analyses. © 2021 the Alzheimer’s Association.

Document Type: ArticlePublication Stage: FinalSource: Scopus