A personalized semi-automatic sleep spindle detection (PSASD) framework
(2024) Journal of Neuroscience Methods, 407, art. no. 110064, .
Kafashan, M.a b , Gupte, G.a , Kang, P.a , Hyche, O.a , Luong, A.H.a , Prateek, G.V.d , Ju, Y.-E.S.b e , Palanca, B.J.A.a b c f g
a Department of Anesthesiology, Washington University School of Medicine in St. Louis, St. Louis, MO, United States
b Center on Biological Rhythms and Sleep, Washington University in St. Louis, St. Louis, MO, United States
c Department of Biomedical Engineering, Washington University in St. Louis, St. Louis, MO, United States
d Calico Life Sciences LLC, South San Francisco, CA, United States
e Department of Neurology, Division of Sleep Medicine, Washington University School of Medicine in St. Louis, St. Louis, MO, United States
f Department of Psychiatry, Washington University School of Medicine in St. Louis, St. Louis, MO, United States
g Division of Biology and Biomedical Sciences, Washington University School of Medicine in St. Louis, St. Louis, MO, United States
Abstract
Background: Sleep spindles are distinct electroencephalogram (EEG) patterns of brain activity that have been posited to play a critical role in development, learning, and neurological disorders. Manual scoring for sleep spindles is labor-intensive and tedious but could supplement automated algorithms to resolve challenges posed with either approaches alone. New methods: A Personalized Semi-Automatic Sleep Spindle Detection (PSASD) framework was developed to combine the strength of automated detection algorithms and visual expertise of human scorers. The underlying model in the PSASD framework assumes a generative model for EEG sleep spindles as oscillatory components, optimized to EEG amplitude, with remaining signals distributed into transient and low-frequency components. Results: A single graphical user interface (GUI) allows both manual scoring of sleep spindles (model training data) and verification of automatically detected spindles. A grid search approach allows optimization of parameters to balance tradeoffs between precision and recall measures. Comparison with existing methods: PSASD outperformed DETOKS in F1-score by 19% and 4% on the DREAMS and P-DROWS-E datasets, respectively. It also outperformed YASA in F1-score by 25% in the P-DROWS-E dataset. Further benchmarking analysis showed that PSASD outperformed four additional widely used sleep spindle detectors in F1-score in the P-DROWS-E dataset. Titration analysis revealed that four 30-second epochs are sufficient to fine-tune the model parameters of PSASD. Associations of frequency, duration, and amplitude of detected sleep spindles matched those previously reported with automated approaches. Conclusions: Overall, PSASD improves detection of sleep spindles in EEG data acquired from both younger healthy and older adult patient populations. © 2024
Author Keywords
Automated pattern recognition; Electroencephalogram (EEG); Non-rapid eye movement sleep; Polysomnography; Signal processing; Sleep; Sleep spindle; Wireless EEG devices
Funding details
National Institute on AgingNIA
McDonnell Center for Systems Neuroscience
R01AG057901
National Institute of Mental HealthNIMHK01 MH128663
National Institute of Mental HealthNIMH
National Institute of Neurological Disorders and StrokeNINDSK23NS089922
National Institute of Neurological Disorders and StrokeNINDS
Document Type: Article
Publication Stage: Final
Source: Scopus
Relationships between plasma neurofilament light chain protein, cognition, and brain aging in people with HIV
(2024) AIDS (London, England), 38 (7), pp. 955-962.
Cooley, S.A.a , Petersen, K.J.a , Tice, C.b , Langford, D.b , Burdo, T.H.c , Roman, J.a , Ances, B.M.a
a Department of Neurology, Washington University in St. Louis, St. Louis, MO, United States
b Department of Neural Sciences
c Department of Microbiology, Immunology, Inflammation, Center for Neurovirology and Gene Editing, Lewis Katz School of Medicine, Temple University, Philadelphia, PA, United States
Abstract
OBJECTIVE: Neurofilament light chain protein (NfL) is a marker of neuronal injury and neurodegeneration. Typically assessed in cerebrospinal fluid, recent advances have allowed this biomarker to be more easily measured in plasma. This study assesses plasma NfL in people with HIV (PWH) compared with people without HIV (PWoH), and its relationship with cognitive impairment, cardiovascular risk, and a neuroimaging metric of brain aging [brain-age gap (BAG)]. DESIGN: One hundred and four PWH (HIV RNA <50 copies/ml) and 42 PWoH provided blood samples and completed a cardiovascular risk score calculator, neuroimaging, and cognitive testing. METHOD: Plasma NfL was compared between PWoH and PWH and assessed for relationships with age, HIV clinical markers, cardiovascular disease risk, cognition, and BAG (difference between a brain-predicted age and chronological age). RESULTS: Plasma NfL was not significantly different between PWoH and PWH. Higher NfL related to increasing age in both groups. Plasma NfL was not associated with typical HIV disease variables. Within PWH, NfL was higher with higher cardiovascular risk, cognitive impairment and a greater BAG. CONCLUSION: Virally suppressed PWH who are cognitively normal likely do not have significant ongoing neurodegeneration, as evidenced by similar plasma NfL compared with PWoH. However, NfL may represent a biomarker of cognitive impairment and brain aging in PWH. Further research examining NfL with longitudinal cognitive decline is needed to understand this relationship more fully. Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.
Document Type: Article
Publication Stage: Final
Source: Scopus
Novel loss-of-function variants expand ABCC9-related intellectual disability and myopathy syndrome
(2024) Brain: A Journal of Neurology, 147 (5), pp. 1822-1836.
Efthymiou, S.a , Scala, M.a b c , Nagaraj, V.d , Ochenkowska, K.e , Komdeur, F.L.f , Liang, R.A.g , Abdel-Hamid, M.S.h , Sultan, T.i , Barøy, T.j , Van Ghelue, M.g , Vona, B.k , Maroofian, R.a , Zafar, F.l , Alkuraya, F.S.m , Zaki, M.S.n , Severino, M.o , Duru, K.C.d , Tryon, R.C.p , Brauteset, L.V.q , Ansari, M.r , Hamilton, M.s , van Haelst, M.M.f , van Haaften, G.t , Zara, F.c , Houlden, H.a , Samarut, É.e , Nichols, C.G.p , Smeland, M.F.u v , McClenaghan, C.d
a Department of Neuromuscular Disorders, University College London, UCL Queen Square Institute of Neurology, London, WC1N 3BG, United Kingdom
b Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genoa, Genoa, 16147, Italy
c U.O.C. Genetica Medica, IRCCS Istituto Giannina Gaslini, Genoa, 16147, Italy
d Center for Advanced Biotechnology and Medicine, Departments of Pharmacology and Medicine, Robert Wood Johnson Medical School, Rutgers the State University of New JerseyNJ 08854, United States
e Centre de Recherche du Centre Hospitalier de l’Université de Montréal (CRCHUM), Department of Neuroscience, Université de Montréal, Montreal, QC H2X 0A9, Canada
f Section Clinical Genetics, Department of Human Genetics and Amsterdam Reproduction and Development, Amsterdam University Medical Centers, Amsterdam, 1105 AZ, Netherlands
g Department of Medical Genetics, Division of Child and Adolescent Health, University Hospital of North Norway, Norway
h Medical Molecular Genetics Department, Human Genetics and Genome Research Institute, National Research CentreCairo 12622, Egypt
i Department of Pediatric Neurology, Children Hospital, University of Child Health Sciences, Lahore, Punjab 54000, Pakistan
j Department of Medical Genetics, Oslo University HospitalOslo 0450, Norway
k Institute of Human Genetics and Institute for Auditory Neuroscience and InnerEarLab, University Medical Center Göttingen, 37073 Göttingen, Germany
l Department of Paediatric Neurology, Children’s Hospital and Institute of Child Health, Multan, Punjab 60000, Pakistan
m Department of Translational Genomics, Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center, Riyadh, 12713, Saudi Arabia
n Clinical Genetics Department, Human Genetics and Genome Research Institute, National Research CentreCairo 12622, Egypt
o Neuroradiology Unit, IRCCS Istituto Giannina Gaslini, Genova, 16147, Italy
p Department of Cell Biology and Physiology, Center for the Investigation of Membrane Excitability Diseases (CIMED), Washington University, St Louis, MO 63110, United States
q Innlandet Hospital Sanderud, Hamar, 2312, Norway
r Western General Hospital, South East Scotland Genetic Service, Edinburgh, EH4 2XU, United Kingdom
s West of Scotland Clinical Genetics Service, Queen Elizabeth University Hospital, Glasgow, G51 4TF, United Kingdom
t Department of Genetics, University Medical CenterUtrecht 3584 CX, Netherlands
u Department of Pediatric Rehabilitation, University Hospital of North Norway, Norway
v Institute of Clinical Medicine, UiT The Arctic University of Norway, Tromsø9019, Norway
Abstract
Loss-of-function mutation of ABCC9, the gene encoding the SUR2 subunit of ATP sensitive-potassium (KATP) channels, was recently associated with autosomal recessive ABCC9-related intellectual disability and myopathy syndrome (AIMS). Here we identify nine additional subjects, from seven unrelated families, harbouring different homozygous loss-of-function variants in ABCC9 and presenting with a conserved range of clinical features. All variants are predicted to result in severe truncations or in-frame deletions within SUR2, leading to the generation of non-functional SUR2-dependent KATP channels. Affected individuals show psychomotor delay and intellectual disability of variable severity, microcephaly, corpus callosum and white matter abnormalities, seizures, spasticity, short stature, muscle fatigability and weakness. Heterozygous parents do not show any conserved clinical pathology but report multiple incidences of intra-uterine fetal death, which were also observed in an eighth family included in this study. In vivo studies of abcc9 loss-of-function in zebrafish revealed an exacerbated motor response to pentylenetetrazole, a pro-convulsive drug, consistent with impaired neurodevelopment associated with an increased seizure susceptibility. Our findings define an ABCC9 loss-of-function-related phenotype, expanding the genotypic and phenotypic spectrum of AIMS and reveal novel human pathologies arising from KATP channel dysfunction. © The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain.
Author Keywords
ABCC9; KATP channels; neurodevelopmental disorder; SUR2
Document Type: Article
Publication Stage: Final
Source: Scopus
Unrecognized Focal Nonmotor Seizures in Adolescents Presenting to Emergency Departments
(2024) Neurology, 102 (10), p. e209389.
Jandhyala, N., Ferrer, M., Pellinen, J., Greenwood, H.T., Dlugos, D.J., Park, K.L., Thio, L.L., French, J., for Human Epilepsy Project Investigators
From the Department of Neurology (N.J.), NYU Langone Health, New York; Departments of Pediatrics and Neurology (M.F.) and Neurology (H.T.G., J.F.), NYU Grossman School of Medicine, New York, NY; Departments of Neurology (J.P.) and Pediatrics and Neurology (K.L.P.), University of Colorado School of Medicine, Aurora; Department of Neurology (D.J.D.), Children’s’ Hospital of Philadelphia, PA; and Department of Neurology (L.L.T.), Washington University in St. Louis, MO
Abstract
BACKGROUND AND OBJECTIVES: Many adolescents with undiagnosed focal epilepsy seek evaluation in emergency departments (EDs). Accurate history-taking is essential to prompt diagnosis and treatment. In this study, we investigated ED recognition of motor vs nonmotor seizures and its effect on management and treatment of focal epilepsy in adolescents. METHODS: This was a retrospective analysis of enrollment data from the Human Epilepsy Project (HEP), an international multi-institutional study that collected data from 34 sites between 2012 and 2017. Participants were 12 years or older, neurotypical, and within 4 months of treatment initiation for focal epilepsy. We used HEP enrollment medical records to review participants’ initial diagnosis and management. RESULTS: A total of 83 adolescents were enrolled between 12 and 18 years. Fifty-eight (70%) presented to an ED before diagnosis of epilepsy. Although most ED presentations were for motor seizures (n = 52; 90%), many patients had a history of nonmotor seizures (20/52 or 38%). Adolescents with initial nonmotor seizures were less likely to present to EDs (26/44 or 59% vs 32/39 or 82%, p = 0.02), and nonmotor seizures were less likely to be correctly identified (2/6 or 33% vs 42/52 or 81%, p = 0.008). A history of initial nonmotor seizures was not recognized in any adolescent who presented for a first-lifetime motor seizure. As a result, initiation of treatment and admission from the ED was not more likely for these adolescents who met the definition of epilepsy compared with those with no seizure history. This lack of nonmotor seizure history recognition in the ED was greater than that observed in the adult group (0% vs 23%, p = 0.03) and occurred in both pediatric and nonpediatric ED settings. DISCUSSION: Our study supports growing evidence that nonmotor seizures are often undiagnosed, with many individuals coming to attention only after conversion to motor seizures. We found this treatment gap is exacerbated in the adolescent population. Our study highlights a critical need for physicians to inquire about the symptoms of nonmotor seizures, even when the presenting seizure is motor. Future interventions should focus on improving nonmotor seizure recognition for this population in EDs.
Document Type: Article
Publication Stage: Final
Source: Scopus
Brain high-throughput multi-omics data reveal molecular heterogeneity in Alzheimer’s disease
(2024) PLoS Biology, 22 (4 April), art. no. e3002607, .
Eteleeb, A.M.a b , Novotny, B.C.a , Tarraga, C.S.a , Sohn, C.a , Dhungel, E.c , Brase, L.a , Nallapu, A.a , Buss, J.a , Farias, F.a d , Bergmann, K.a d , Bradley, J.a d , Norton, J.a d , Gentsch, J.a d , Wang, F.a d , Davis, A.A.e f , Morris, J.C.b e f , Karch, C.M.a b d f , Perrin, R.J.b e f g , Benitez, B.A.h , Harari, O.a b f
a Department of Psychiatry, Washington University, Saint Louis, St. Louis, MO, United States
b The Charles F. and Joanne Knight Alzheimer Disease Research Center, Washington University, St. Louis, MO, United States
c Department of Bioinformatics and Genomics, University of North Carolina at Charlotte, Charlotte, NC, United States
d NeuroGenomics and Informatics Center, Washington University, St. Louis, MO, United States
e Department of Neurology, Washington University, St. Louis, MO, United States
f Hope Center for Neurological Disorders, Washington University, St. Louis, MO, United States
g Department of Pathology and Immunology, Washington University, St. Louis, MO, United States
h Department of Neurology and Neuroscience, Harvard Medical School, Beth Israel Deaconess Medical Center, Boston, MA, United States
Abstract
Unbiased data-driven omic approaches are revealing the molecular : heterogeneity of Alzheimer disease. Here, we used machine learning approaches to integrate high-throughput transcriptomic, proteomic, metabolomic, and lipidomic profiles with clinical and neuropathological data from multiple human AD cohorts. We discovered 4 unique multimodal molecular profiles, one of them showing signs of poor cognitive function, a faster pace of disease progression, shorter survival with the disease, severe neurodegeneration and astrogliosis, and reduced levels of metabolomic profiles. We found this molecular profile to be present in multiple affected cortical regions associated with higher Braak tau scores and significant dysregulation of synapse-related genes, endocytosis, phagosome, and mTOR signaling pathways altered in AD early and late stages. AD cross-omics data integration with transcriptomic data from an SNCA mouse model revealed an overlapping signature. Furthermore, we leveraged single-nuclei RNA-seq data to identify distinct cell-types that most likely mediate molecular profiles. Lastly, we identified that the multimodal clusters uncovered cerebrospinal fluid biomarkers poised to monitor AD progression and possibly cognition. Our cross-omics analyses provide novel critical molecular insights into AD. © 2024 Eteleeb et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Funding details
Hope Center for Neurological Disorders, Washington University in St. Louis
National Institute on AgingNIAP30 AG066444
National Institute on AgingNIA
National Institutes of HealthNIHR21NS127211, R01AG074012, K01AG046374, R01NS118146, K25AG083057, R56AG067764, U01AG072464, R01AG057777
National Institutes of HealthNIH
P01AG003991
American Cancer SocietyACSP01AG026276
American Cancer SocietyACS
Document Type: Article
Publication Stage: Final
Source: Scopus
Downstream Biomarker Effects of Gantenerumab or Solanezumab in Dominantly Inherited Alzheimer Disease The DIAN-TU-001 Randomized Clinical Trial
(2024) JAMA Neurology, . Cited 1 time.
Wagemann, O.a b , Liu, H.a , Wang, G.c , Shi, X.c , Bittner, T.d , Scelsi, M.A.e , Farlow, M.R.f , Clifford, D.B.a , Supnet-Bell, C.a , Santacruz, A.M.a , Aschenbrenner, A.J.a , Hassenstab, J.J.a , Benzinger, T.L.S.g , Gordon, B.A.g , Coalier, K.A.h , Cruchaga, C.i , Ibanez, L.a i , Perrin, R.J.a j , Xiong, C.c , Li, Y.a , Morris, J.C.a , Lah, J.J.k , Berman, S.B.l , Roberson, E.D.m , van Dyck, C.H.n , Galasko, D.o , Gauthier, S.p , Hsiung, G.-Y.R.q , Brooks, W.S.r s , Pariente, J.t , Mummery, C.J.u , Day, G.S.v , Ringman, J.M.w , Mendez, P.C.x , St. George-Hyslop, P.y , Fox, N.C.u , Suzuki, K.z , Okhravi, H.R.aa , Chhatwal, J.ab , Levin, J.b ac ad , Jucker, M.ae af , Sims, J.R.ag , Holdridge, K.C.ag , Proctor, N.K.ag , Yaari, R.ag , Andersen, S.W.ag , Mancini, M.ag , Llibre-Guerra, J.a , Bateman, R.J.a , McDade, E.a , Dominantly Inherited Alzheimer Network-Trials Unitah
a Department of Neurology, Washington University School of Medicine, St Louis, MO, United States
b Department of Neurology, Ludwig-Maximilians-Universität München, Munich, Germany
c Department of Biostatistics, Washington University in St Louis, St Louis, MO, United States
d F. Hoffmann-La Roche Ltd, Basel, Switzerland
e F. Hoffmann-La Roche Products Ltd, Welwyn Garden City, United Kingdom
f Department of Neurology, Indiana University School of Medicine, Indianapolis, United States
g Department of Radiology, Washington University in St Louis, St Louis, MO, United States
h IQVIA, Durham, NC, United States
i Department of Psychiatry, Washington University in St Louis, St Louis, MO, United States
j Department of Pathology and Immunology, Washington University in St Louis, St Louis, MO, United States
k Department of Neurology, School of Medicine Emory University, Atlanta, GA, United States
l Department of Neurology, University of Pittsburgh, Pittsburgh, PA, United States
m Department of Neurology, University of Alabama at Birmingham, Birmingham, United States
n Alzheimer’s Disease Research Unit, Yale School of Medicine, New Haven, CT, United States
o Department of Neurology, University of California, San Diego, United States
p Department of Neurology and Psychiatry, McGill University, Montréal, QC, Canada
q Department of Neurology, University of British Columbia, Vancouver, BC, Canada
r Neuroscience Research Australia, Sydney, NSW, Australia
s School of Clinical Medicine, University of New South Wales, Randwick, NSW, Australia
t Department of Neurology, Centre Hospitalier Universitaire de Toulouse, Toulouse, France
u Dementia Research Centre, Institute of Neurology, University College London, London, United Kingdom
v Department of Neurology, Mayo Clinic Florida, Jacksonville, United States
w Department of Neurology, University of Southern California, Los Angeles, United States
x Fundación Para la Lucha Contra las Enfermedades Neurológicas de la Infancia (FLENI), Buenos Aires, Argentina
y Department of Neurology, Columbia University, New York, NY, United States
z National Defense Medical College, Saitama, Japan
aa Department of Geriatrics, Eastern Virginia Medical School, Norfolk, United States
ab Department of Neurology, Massachusetts General and Brigham and Women’s Hospitals, Harvard Medical School, Boston, United States
ac German Center for Neurodegenerative Diseases (DZNE), Munich, Germany
ad Munich Cluster for Systems Neurology (SyNergy), Munich, Germany
ae German Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany
af Department of Cellular Neurology, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany
ag Eli Lilly and Company, Indianapolis, IN, United States
Abstract
IMPORTANCE Effects of antiamyloid agents, targeting either fibrillar or soluble monomeric amyloid peptides, on downstream biomarkers in cerebrospinal fluid (CSF) and plasma are largely unknown in dominantly inherited Alzheimer disease (DIAD). OBJECTIVE To investigate longitudinal biomarker changes of synaptic dysfunction, neuroinflammation, and neurodegeneration in individuals with DIAD who are receiving antiamyloid treatment. DESIGN, SETTING, AND PARTICIPANTS From 2012 to 2019, the Dominantly Inherited Alzheimer Network Trial Unit (DIAN-TU-001) study, a double-blind, placebo-controlled, randomized clinical trial, investigated gantenerumab and solanezumab in DIAD. Carriers of gene variants were assigned 3:1 to either drug or placebo. The present analysis was conducted from April to June 2023. DIAN-TU-001 spans 25 study sites in 7 countries. Biofluids and neuroimaging from carriers of DIAD gene variants in the gantenerumab, solanezumab, and placebo groups were analyzed. INTERVENTIONS In 2016, initial dosing of gantenerumab, 225 mg (subcutaneously every 4 weeks) was increased every 8 weeks up to 1200 mg. In 2017, initial dosing of solanezumab, 400 mg (intravenously every 4 weeks) was increased up to 1600 mg every 4 weeks. MAIN OUTCOMES AND MEASURES Longitudinal changes in CSF levels of neurogranin, soluble triggering receptor expressed on myeloid cells 2 (sTREM2), chitinase 3–like 1 protein (YKL-40), glial fibrillary acidic protein (GFAP), neurofilament light protein (NfL), and plasma levels of GFAP and NfL. RESULTS Of 236 eligible participants screened, 43 were excluded. A total of 142 participants (mean [SD] age, 44 [10] years; 72 female [51%]) were included in the study (gantenerumab, 52 [37%]; solanezumab, 50 [35%]; placebo, 40 [28%]). Relative to placebo, gantenerumab significantly reduced CSF neurogranin level at year 4 (mean [SD] β = −242.43 [48.04] pg/mL; P < .001); reduced plasma GFAP level at year 1 (mean [SD] β = −0.02 [0.01] ng/mL; P = .02), year 2 (mean [SD] β = −0.03 [0.01] ng/mL; P = .002), and year 4 (mean [SD] β = −0.06 [0.02] ng/mL; P < .001); and increased CSF sTREM2 level at year 2 (mean [SD] β = 1.12 [0.43] ng/mL; P = .01) and year 4 (mean [SD] β = 1.06 [0.52] ng/mL; P = .04). Solanezumab significantly increased CSF NfL (log) at year 4 (mean [SD] β = 0.14 [0.06]; P = .02). Correlation analysis for rates of change found stronger correlations between CSF markers and fluid markers with Pittsburgh compound B positron emission tomography for solanezumab and placebo. CONCLUSIONS AND RELEVANCE This randomized clinical trial supports the importance of fibrillar amyloid reduction in multiple AD-related processes of neuroinflammation and neurodegeneration in CSF and plasma in DIAD. Additional studies of antiaggregated amyloid therapies in sporadic AD and DIAD are needed to determine the utility of nonamyloid biomarkers in determining disease modification. © 2024 Wagemann O et al.
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
Data-driven decomposition and staging of flortaucipir uptake in Alzheimer’s disease
(2024) Alzheimer’s and Dementia, .
Earnest, T.a , Bani, A.a , Ha, S.M.a , Hobbs, D.A.a , Kothapalli, D.a , Yang, B.a , Lee, J.J.a , Benzinger, T.L.S.a , Gordon, B.A.a , Sotiras, A.a b , for the Alzheimer’s Disease Neuroimaging Initiativec
a Mallinckrodt Institute of Radiology, Washington University School of Medicine in St Louis, Saint Louis, MO, United States
b Institute for Informatics, Data Science & Biostatistics, Washington University School of Medicine in St Louis, Saint Louis, MO, United States
Abstract
INTRODUCTION: Previous approaches pursuing in vivo staging of tau pathology in Alzheimer’s disease (AD) have typically relied on neuropathologically defined criteria. In using predefined systems, these studies may miss spatial deposition patterns which are informative of disease progression. METHODS: We selected discovery (n = 418) and replication (n = 132) cohorts with flortaucipir imaging. Non-negative matrix factorization (NMF) was applied to learn tau covariance patterns and develop a tau staging system. Flortaucipir components were also validated by comparison with amyloid burden, gray matter loss, and the expression of AD-related genes. RESULTS: We found eight flortaucipir covariance patterns which were reproducible and overlapped with relevant gene expression maps. Tau stages were associated with AD severity as indexed by dementia status and neuropsychological performance. Comparisons of flortaucipir uptake with amyloid and atrophy also supported our model of tau progression. DISCUSSION: Data-driven decomposition of flortaucipir uptake provides a novel framework for tau staging which complements existing systems. Highlights: NMF reveals patterns of tau deposition in AD. Data-driven staging of flortaucipir tracks AD severity. Learned flortaucipir patterns overlap with AD-related gene expression. © 2024 The Authors. Alzheimer’s & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer’s Association.
Author Keywords
Alzheimer’s disease; AV-1451; Braak; data-driven; disease staging; flortaucipir; machine learning; NMF; non-negative matrix factorization; tau; tau staging
Funding details
Alzheimer’s AssociationAA
BioClinica
National Institute of Biomedical Imaging and BioengineeringNIBIB
AbbVie
National Institute on AgingNIA
Alzheimer’s Drug Discovery FoundationADDF
U.S. Department of DefenseDODW81XWH‐12‐2‐0012
U.S. Department of DefenseDOD
National Institutes of HealthNIH1S10RR022984‐01A1, S10OD025200, R01‐AG067103, 1S10OD018091‐01
National Institutes of HealthNIH
BiogenP01 AG003991, UL1 TR000448, P01 AG026276, P30 NS09857781, P30 AG066444, R01 AG043434, P50 AG00561, R01 EB009352
Biogen
Alzheimer’s Disease Neuroimaging InitiativeADNIU01 AG024904
Alzheimer’s Disease Neuroimaging InitiativeADNI
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
Biochemical, Biomarker, and Behavioral Characterization of the GrnR493X Mouse Model of Frontotemporal Dementia
(2024) Molecular Neurobiology, Cited 0 times. DOI: 10.1007/s12035-024-04190-9
Smith D.M., Aggarwal G., Niehoff M.L., Jones S.A., Banerjee S., Farr S.A., Nguyen A.D.
Division of Geriatric Medicine, Department of Internal Medicine, Saint Louis University School of Medicine, St. Louis, United States; Department of Pharmacology and Physiology, Saint Louis University School of Medicine, St. Louis, United States; Institute for Translational Neuroscience, Saint Louis University, St. Louis, United States; Veterans Affairs Medical Center, St. Louis, United States
Abstract
Heterozygous loss-of-function mutations in the progranulin gene (GRN) are a major cause of frontotemporal dementia due to progranulin haploinsufficiency; complete deficiency of progranulin causes neuronal ceroid lipofuscinosis. Several progranulin-deficient mouse models have been generated, including both knockout mice and knockin mice harboring a common patient mutation (R493X). However, the GrnR493X mouse model has not been characterized completely. Additionally, while homozygous GrnR493X and Grn knockout mice have been extensively studied, data from heterozygous mice is still limited. Here, we performed more in-depth characterization of heterozygous and homozygous GrnR493X knockin mice, which includes biochemical assessments, behavioral studies, and analysis of fluid biomarkers. In the brains of homozygous GrnR493X mice, we found increased phosphorylated TDP-43 along with increased expression of lysosomal genes, markers of microgliosis and astrogliosis, pro-inflammatory cytokines, and complement factors. Heterozygous GrnR493X mice did not have increased TDP-43 phosphorylation but did exhibit limited increases in lysosomal and inflammatory gene expression. Behavioral studies found social and emotional deficits in GrnR493X mice that mirror those observed in Grn knockout mouse models, as well as impairment in memory and executive function. Overall, the GrnR493X knockin mouse model closely phenocopies Grn knockout models. Lastly, in contrast to homozygous knockin mice, heterozygous GrnR493X mice do not have elevated levels of fluid biomarkers previously identified in humans, including neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP) in both plasma and CSF. These results may help to inform pre-clinical studies that use this Grn knockin mouse model and other Grn knockout models. © The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature 2024.
Author keywords
Biomarkers; Frontotemporal dementia; Mouse model; Neuronal ceroid lipofuscinosis; Progranulin
Funding details
National Center for Advancing Translational Sciences, NCATS
National Institutes of Health, NIH, AG047339, AG064069
National Institutes of Health, NIH
Institute of Clinical and Translational Sciences, ICTS, UL1TR002345
Institute of Clinical and Translational Sciences, ICTS
This work was supported by grants from the National Institutes of Health (AG047339 and AG064069) and the Bluefield Project to Cure FTD to ADN. Research reported in this publication was also supported by the Washington University Institute of Clinical and Translational Sciences grant UL1TR002345 from the National Center for Advancing Translational Sciences (NCATS) of the National Institutes of Health.
Document title: Article
Publication stage: Article in press
Source: Scopus