Multi-omic analysis of Huntington’s disease reveals a compensatory astrocyte state
(2024) Nature Communications, 15 (1), art. no. 6742, .
Paryani, F.a , Kwon, J.-S.b , Ng, C.W.c , Jakubiak, K.d , Madden, N.d , Ofori, K.d , Tang, A.d , Lu, H.d , Xia, S.d , Li, J.d , Mahajan, A.d , Davidson, S.M.e , Basile, A.O.f , McHugh, C.f , Vonsattel, J.P.d , Hickman, R.d , Zody, M.C.f , Housman, D.E.c , Goldman, J.E.d g , Yoo, A.S.b , Menon, V.a g , Al-Dalahmah, O.d g
a Department of Neurology, Columbia University Irving Medical Center, New York, NY, United States
b Department of Developmental Biology Washington University School of Medicine in St. Louis, St. Louis, MO, United States
c Massachusetts Institute of Technology, Department of Biological Engineering, Cambridge, MA, United States
d Department of Pathology and Cell Biology, Columbia University Irving Medical Center, New York, NY, United States
e Northwestern Feinberg School of Medicine, Northwestern University, Evanston, IL, United States
f New York Genome Center, New York, NY, United States
g Taub Institute for Research on Alzheimer’s Disease and the Aging Brain, New York, NY, United States
Abstract
The mechanisms underlying the selective regional vulnerability to neurodegeneration in Huntington’s disease (HD) have not been fully defined. To explore the role of astrocytes in this phenomenon, we used single-nucleus and bulk RNAseq, lipidomics, HTT gene CAG repeat-length measurements, and multiplexed immunofluorescence on HD and control post-mortem brains. We identified genes that correlated with CAG repeat length, which were enriched in astrocyte genes, and lipidomic signatures that implicated poly-unsaturated fatty acids in sensitizing neurons to cell death. Because astrocytes play essential roles in lipid metabolism, we explored the heterogeneity of astrocytic states in both protoplasmic and fibrous-like (CD44+) astrocytes. Significantly, one protoplasmic astrocyte state showed high levels of metallothioneins and was correlated with the selective vulnerability of distinct striatal neuronal populations. When modeled in vitro, this state improved the viability of HD-patient-derived spiny projection neurons. Our findings uncover key roles of astrocytic states in protecting against neurodegeneration in HD. © The Author(s) 2024.
Funding details
Hereditary Disease FoundationHDF
American Brain Tumor AssociationABTA
Huntington’s Disease Society of AmericaHDSA
Niagara UniversityNUP30AG066462
Niagara UniversityNU
Nihon Kohden AmericaR21 AG075754
Nihon Kohden America
Document Type: Article
Publication Stage: Final
Source: Scopus
Drug-Resistant Epilepsy in Tuberous Sclerosis Complex Is Associated With TSC2 Genotype: More Findings From the Preventing Epilepsy Using Vigatrin (PREVeNT) Trial
(2024) Pediatric Neurology, 159, pp. 62-71.
Farach, L.S., MDa , Richard, M.A., PhDb , Wulsin, A.C., MD, PhDc , Bebin, E.M., MDd , Krueger, D.A., MD, PhDc , Sahin, M.e f s s , Porter, B.E., MD, PhDg , McPherson, T.O., PhDh , Peters, J.M.e f s s , O’Kelley, S.i s s , O’Kelley, S.j , Rajaraman, R.k s , Rajaraman, R.l , McClintock, W.M.m s , Koenig, M.K., MDa , McClintock, W.M.n , Werner, K.o s , Nolan, D.A., MDp , Wong, M.q s , Cutter, G.r s , Northrup, H.a s , Au, K.S., PhDa , Bebin, E.M.s , Krueger, D.s , Flamini, R.s , Sergott, R.C.s , McPherson, T.s , Peri, K.s , Krefting, J.s , Porter, B.s , Taub, K.s , Litt, B.s , Wu, J.s , Lagory, D.s , Korf, B.s , Messiaen, L.s , Biasini, F.s , Byars, A.s , Roberds, S.L.s , Rushing, G.s , Griffith, M.s , Davis, P.s , Hansen, E.s , Arcasoy, E.s , Phillips, J.s , Solidum, R.s , Gulsrud, A.s , Solis, N.s , Randle, S.s , Patrick, K.s , Lee-Eng, J.s , Frost, M.D.s , Branson, J.s , Ellis, S.s , White, D.s , Novak, O.s , Fasciola, A.s , Lorenzi, J.s , Layer, M.s , Thomas, A.s , Chanbers, E.s , Berl, M.s , Elling, N.s , Kassoff, B.s , Hardie, K.s , Nolan, D.s , DeBastos, A.s , Batchelder, C.s , Koening, M.K.s , Au, K.S.s , Pearson, D.s , Mansour, R.s , Farach, L.s , Salazar, E.s , PREVeNT Study Groupt
a Department of Pediatrics, McGovern Medical School at the University of Texas Health Science Center at Houston (UTHealth Houston) and Children’s Memorial Hermann Hospital, Houston, Texas, United States
b Division of Hematology-Oncology, Department of Pediatrics, Baylor College of Medicine, Houston, Texas, United States
c Division of Neurology, Department of Pediatrics, Cincinnati Children’s Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, Ohio, United States
d Department of Neurology, University of Alabama at Birmingham, Birmingham, Alabama, United States
e Rosamund Stone Zander Translational Neuroscience Center, Boston Children’s Hospital, Boston, Massachusetts, United States
f Department of Neurology, Boston Children’s Hospital, Harvard Medical School, Boston, Massachusetts, United States
g Department of Neurology, Stanford University, Stanford, California, United States
h Department of Biostatistics and Bioinformatics, Emory University, Georgia, Atlanta, Georgia
i Department of Psychology, University of Alabama at Birmingham, Birmingham, Alabama, United States
j Department of Pediatrics, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, United States
k Department of Pediatrics and Psychiatry and Biobehavioral Sciences, University of California, Los Angeles, Los Angeles, California, United States
l Division Pediatric Neurology and Epilepsy, Department of Neurology, Seattle Children’s Hospital, Seattle, WA, United States
m Division of Neurology, Department of Pediatrics, Children’s National Medical Center, Washington, District of Columbia, United States
n Minnesota Epilepsy Group, P.A., Roseville, Minnesota, United States
o Department of Pediatrics, Duke University, Durham, North Carolina, United States
p Beaumont Florence and Richard McBrien Pediatric Neuroscience Center, Beaumont Hospital, Royal Oak, MI, United States
q Department of Neurology, Washington University in Saint Louis, Saint Louis, Missouri, United States
r Department of Biostatistics, University of Alabama at BirminghamAlabama, United States
Abstract
Background: Children with tuberous sclerosis complex (TSC) are at high risk for drug-resistant epilepsy (DRE). The ability to stratify those at highest risk for DRE is important for counseling and prompt, aggressive management, necessary to optimize neurocognitive outcomes. Using the extensively phenotyped PREVeNT cohort, we aimed to characterize whether the TSC genotype was associated with DRE. Methods: The study group (N = 70) comprised participants with TSC enrolled at age less than or equal to six months with detailed epilepsy and other phenotypic and genotypic data, prospectively collected as part of the PREVeNT trial. Genotype-phenotype correlations of DRE, time to first abnormal electroencephalography, and time to epilepsy onset were compared using Fisher exact test and regression models. Results: Presence of a TSC2 pathogenic variant was significantly associated with DRE, compared with TSC1 and participants with no pathogenic mutation identified. In fact, all participants with DRE had a TSC2 pathogenic variant. Furthermore, TSC2 variants expected to result in no protein product were associated with higher risk for DRE. Finally, TSC1 pathogenic variants were associated with later-onset epilepsy, on average 21.2 months later than those with other genotypes. Conclusions: Using a comprehensively phenotyped cohort followed from infancy, this study is the first to delineate genotype-phenotype correlations for epilepsy severity and onset in children with TSC. Patients with TSC2 pathogenic variants, especially TSC2 pathogenic variants predicted to result in lack of TSC2 protein, are at highest risk for DRE, and are likely to have earlier epilepsy onset than those with TSC1. Clinically, these insights can inform counseling, surveillance, and management. © 2024 Elsevier Inc.
Author Keywords
Drug-resistant epilepsy; Epilepsy; Genotype; Phenotype; Tuberous sclerosis complex (TSC); Vigabatrin
Document Type: Article
Publication Stage: Final
Source: Scopus
Evaluating the interaction between hemorrhagic transformation and cerebral edema on functional outcome after ischemic stroke
(2024) Journal of Stroke and Cerebrovascular Diseases, 33 (10), art. no. 107913, .
Avula, A.a , Bui, Q.a , Kumar, A.a , Chen, Y.a , Hamzehloo, A.a , Cifarelli, J.a , Heitsch, L.a b , Slowik, A.c , Strbian, D.d , Lee, J.-M.a , Dhar, R.a
a Department of Neurology, Washington University School of Medicine, Campus Box 8111, 660 S Euclid Avenue, St. Louis, MO, United States
b Department of Emergency Medicine, Washington University School of Medicine, St. Louis, MO, United States
c Department of Neurology, Jagiellonian University Medical College, Krakow, Poland
d Department of Neurology, Helsinki University Hospital, Helsinki, Finland
Abstract
Background: Hemorrhagic transformation (HT) and cerebral edema (CED) are both major complications following ischemic stroke, but few studies have evaluated their overlap. We evaluated the frequency and predictors of CED/HT overlap and whether their co-occurrence impacts functional outcome more than each in isolation. Methods: 892 stroke patients enrolled in a prospective study had follow-up CT imaging evaluated for HT and CED; the latter was quantified using the ratio of hemispheric CSF volumes (with hemispheric CSF ratio < 0.90 used as the CED threshold). The interaction between HT and CED on functional outcome (using modified Rankin Scale at 3 months) was compared to that for each condition separately. Results: Among the 275 (31%) who developed HT, 233 (85%) manifested hemispheric CSF ratio < 0.9 (CED/HT), with this overlap group representing half of the 475 with measurable CED. Higher baseline NIHSS scores and larger infarct volumes were observed in the CED/HT group compared with those with CED or HT alone. Functional outcome was worse in those with CED/HT [median mRS 3 (IQR 2-5)] than those with CED [median 2 (IQR 1-4)] or HT alone [median 1 (IQR 0-2), p < 0.0001]. Overlap of CED/HT independently predicted worse outcome [OR 1.89 (95% CI: 1.12-3.18), p = 0.02] while HT did not; however, CED/HT was no longer associated with worse outcome after adjusting for severity of CED [adjusted OR 0.35 (95% CI: 0.23, 0.51) per 0.21 lower hemispheric CSF ratio, p < 0.001]. Conclusions: Most stroke patients with HT also have measurable CED. The co-occurrence of CED and HT occurs in larger and more severe strokes and is associated with worse functional outcome, although this is driven by greater severity of stroke-related edema in those with HT. © 2024
Author Keywords
Cerebral edema; Functional outcome; Hemorrhagic transformation; Overlap of HT and CED
Funding details
National Institutes of HealthNIHR01NS085419, R01NS121218, K23NS099440, K23NS099487, U24NS107230
National Institutes of HealthNIH
Document Type: Article
Publication Stage: Final
Source: Scopus
Brief Report: Veterans Aging Cohort Study Index 2.0 Shows Improved Discrimination of Neurocognitive Impairment and Frailty in People with HIV
(2024) Journal of Acquired Immune Deficiency Syndromes, 97 (1), pp. 63-67.
Yan, C.Y.a , Cooley, S.A.a , Ances, B.M.a b c
a Department of Neurology, Washington University in Saint Louis, St. Louis, MO, United States
b Department of Radiology, Washington University in Saint Louis, St. Louis, MO, United States
c Department of Biomedical Engineering, Washington University in Saint Louis, St. Louis, MO, United States
Abstract
Objective:To examine whether the revised Veterans Aging Cohort Study (VACS2.0) index [including serum albumin, body mass index, and white blood cell count] had stronger correlations with cognitive function, brain volume, and frailty in persons with HIV (PWHs) ≥50 years compared with the VACS1.0.Design and methods:Neuropsychological performance (NP) Z-scores (learning, retention, executive functioning, psychomotor function/processing speed, language, and global cognition), and neuroimaging measures (brain volumetrics) were analyzed in PWHs (n = 162). A subset of the sample (n = 159) was defined as either frail (n = 18) or nonfrail (n = 141) according to the Fried phenotype criteria. Brain volumes, NP scores, and frailty subgroups were analyzed with VACS scores, albumin, body mass index, and white blood cell count using Pearson significance tests and independent T tests.Results:Higher VACS scores significantly correlated with lower brain volumes. Higher VACS2.0 scores were associated with lower NP in the executive functioning and psychomotor function/processing speed domains and were primarily driven by albumin. VACS1.0 scores did not correlate with cognition Z-scores. There was no relationship between frailty status and VACS1.0. PWHs who were frail had significantly greater VACS2.0 scores than nonfrail PWHs.Conclusions:The addition of albumin to the VACS index improved its correlations with NP and frailty in PWHs. While low albumin levels may contribute to cognitive decline or frailty, the reverse causality should also be considered. These findings suggest that the VACS2.0 index (especially albumin) is a valuable measure for clinicians to improve outcomes in PWHs. © 2024 Wolters Kluwer Health, Inc.
Author Keywords
albumin; frailty; HIV; neuropsychology; VACS
Document Type: Article
Publication Stage: Final
Source: Scopus
γ-Secretase activity, clinical features, and biomarkers of autosomal dominant Alzheimer’s disease: cross-sectional and longitudinal analysis of the Dominantly Inherited Alzheimer Network observational study (DIAN-OBS)
(2024) The Lancet Neurology, 23 (9), pp. 913-924. Cited 1 time.
Schultz, S.A.a b , Liu, L.c d , Schultz, A.P.a b , Fitzpatrick, C.D.a b , Levin, R.a b , Bellier, J.-P.c d , Shirzadi, Z.a b c , Joseph-Mathurin, N.e , Chen, C.D.e , Benzinger, T.L.S.e , Day, G.S.k , Farlow, M.R.l , Gordon, B.A.e , Hassenstab, J.J.f , Jack, C.R., Jrm , Jucker, M.n , Karch, C.M.g , Lee, J.-H.o , Levin, J.p q r , Perrin, R.J.g h , Schofield, P.R.s t , Xiong, C.i , Johnson, K.A.a b , McDade, E.j , Bateman, R.J.j , Sperling, R.A.a b c , Selkoe, D.J.b c d , Chhatwal, J.P.a b c d , Aguillon, D.u , Allegri, R.F.u , Aschenbrenner, A.J.u , Baker, B.u , Barthelemy, N.u , Bechara, J.A.u , Berman, S.B.u , Brooks, W.S.u , Cash, D.M.u , Chen, A.u , Chrem Mendez, P.u , Courtney, L.u , Cruchaga, C.u , Daniels, A.J.u , Fagan, A.M.u , Flores, S.u , Fox, N.C.u , Franklin, E.u , Goate, A.M.u , Graber-Sultan, S.u , Graff-Radford, N.R.u , Gremminger, E.u , Herries, E.u , Hofmann, A.u , Holtzman, D.M.u , Hornbeck, R.u , Huey, E.D.u , Ibanez, L.u , Ikeuchi, T.u , Ikonomovic, S.u , Jackson, K.u , Jarman, S.u , Jerome, G.u , Johnson, E.C.B.u , Kasuga, K.u , Keefe, S.u , Koudelis, D.u , Kuder-Buletta, E.u , Laske, C.u , Leon, Y.M.u , Levey, A.I.u , Li, Y.u , Llibre-Guerra, J.J.u , Lopera, F.u , Lu, R.u , Marsh, J.u , Martins, R.u , Massoumzadeh, P.u , Masters, C.u , McCullough, A.u , McKay, N.u , Minton, M.u , Mori, H.u , Morris, J.C.u , Nadkarni, N.K.u , Nicklaus, J.u , Niimi, Y.u , Noble, J.M.u , Obermueller, U.u , Picarello, D.M.u , Pulizos, C.u , Ramirez, L.u , Renton, A.E.u , Ringman, J.u , Rizzo, J.u , Roedenbeck, Y.u , Roh, J.H.u , Rosa-Neto, P.u , Ryan, N.S.u , Sabaredzovic, E.u , Salloway, S.u , Sanchez-Valle, R.u , Scott, J.u , Seyfried, N.T.u , Simmons, A.u , Smith, J.u , Smith, H.u , Stauber, J.u , Stout, S.u , Supnet-Bell, C.u , Surace, E.u , Vazquez, S.u , Vöglein, J.u , Wang, G.u , Wang, Q.u , Xu, X.u , Xu, J.u , Dominantly Inherited Alzheimer Networkv
a Department of Neurology, Massachusetts General Hospital, Boston, MA, United States
b Department of Neurology, Medical School, Harvard University, Boston, MA, United States
c Department of Neurology, Brigham and Women’s Hospital, Boston, MA, United States
d Ann Romney Center for Neurologic Diseases, Boston, MA, United States
e Mallinckrodt Institute of Radiology, Washington University, St Louis, MO, United States
f Department of Psychology, Washington University, St Louis, MO, United States
g Department of Psychiatry, Washington University, St Louis, MO, United States
h Department of Pathology and Immunology, Washington University, St Louis, MO, United States
i Division of Biostatistics, Washington University, St Louis, MO, United States
j Department of Neurology, Washington University, St Louis, MO, United States
k Department of Neurology, Mayo Clinic, Jacksonville, FL, United States
l Indiana Alzheimer’s Disease Research Center, Indianapolis, IN, United States
m Department of Neurology, Mayo Clinic, Rochester, MN, United States
n German Center for Neurodegenerative Diseases, Tübingen, Germany
o Department of Neurology, Asan Medical Center, College of Medicine, University of Ulsan, Seoul, South Korea
p German Center for Neurodegenerative Diseases, Munich, Germany
q Department of Neurology, Ludwig Maximilian University of Munich, Munich, Germany
r Munich Cluster for Systems Neurology, Munich, Germany
s Neuroscience Research Australia, Randwick, NSW, Australia
t School of Biomedical Sciences, University of New South Wales, Sydney, NSW, Australia
Abstract
Background: Genetic variants that cause autosomal dominant Alzheimer’s disease are highly penetrant but vary substantially regarding age at symptom onset (AAO), rates of cognitive decline, and biomarker changes. Most pathogenic variants that cause autosomal dominant Alzheimer’s disease are in presenilin 1 (PSEN1), which encodes the catalytic core of γ-secretase, an enzyme complex that is crucial in production of amyloid β. We aimed to investigate whether the heterogeneity in AAO and biomarker trajectories in carriers of PSEN1 pathogenic variants could be predicted on the basis of the effects of individual PSEN1 variants on γ-secretase activity and amyloid β production. Methods: For this cross-sectional and longitudinal analysis, we used data from participants enrolled in the Dominantly Inherited Alzheimer Network observational study (DIAN-OBS) via the DIAN-OBS data freeze version 15 (data collected between Feb 29, 2008, and June 30, 2020). The data freeze included data from 20 study sites in research institutions, universities, hospitals, and clinics across Europe, North and South America, Asia, and Oceania. We included individuals with PSEN1 pathogenic variants for whom relevant genetic, clinical, imaging, and CSF data were available. PSEN1 pathogenic variants were characterised via genetically modified PSEN1 and PSEN2 double-knockout human embryonic kidney 293T cells and immunoassays for Aβ37, Aβ38, Aβ40, Aβ42, and Aβ43. A summary measure of γ-secretase activity (γ-secretase composite [GSC]) was calculated for each variant and compared with clinical history-derived AAO using correlation analyses. We used linear mixed-effect models to assess associations between GSC scores and multimodal-biomarker and clinical data from DIAN-OBS. We used separate models to assess associations with Clinical Dementia Rating Sum of Boxes (CDR-SB), Mini-Mental State Examination (MMSE), and Wechsler Memory Scale-Revised (WMS-R) Logical Memory Delayed Recall, [11C]Pittsburgh compound B (PiB)–PET and brain glucose metabolism using [18F] fluorodeoxyglucose (FDG)–PET, CSF Aβ42-to-Aβ40 ratio (Aβ42/40), CSF log10 (phosphorylated tau 181), CSF log10 (phosphorylated tau 217), and MRI-based hippocampal volume. Findings: Data were included from 190 people carrying PSEN1 pathogenic variants, among whom median age was 39·0 years (IQR 32·0 to 48·0) and AAO was 44·5 years (40·6 to 51·4). 109 (57%) of 190 carriers were female and 81 (43%) were male. Lower GSC values (ie, lower γ-secretase activity than wild-type PSEN1) were associated with earlier AAO (r=0·58; p<0·0001). GSC was associated with MMSE (β=0·08, SE 0·03; p=0·0043), CDR-SB (–0·05, 0·02; p=0·0027), and WMS-R Logical Memory Delayed Recall scores (0·09, 0·02; p=0·0006). Lower GSC values were associated with faster increase in PiB–PET signal (p=0·0054), more rapid decreases in hippocampal volume (4·19, 0·77; p<0·0001), MMSE (0·02, 0·01; p=0·0020), and WMS-R Logical Memory Delayed Recall (0·004, 0·001; p=0·0003). Interpretation: Our findings suggest that clinical heterogeneity in people with autosomal dominant Alzheimer’s disease can be at least partly explained by different effects of PSEN1 variants on γ-secretase activity and amyloid β production. They support targeting γ-secretase as a therapeutic approach and suggest that cell-based models could be used to improve prediction of symptom onset. Funding: US National Institute on Aging, Alzheimer’s Association, German Center for Neurodegenerative Diseases, Raul Carrea Institute for Neurological Research, Japan Agency for Medical Research and Development, Korea Health Industry Development Institute, South Korean Ministry of Health and Welfare, South Korean Ministry of Science and ICT, and Spanish Institute of Health Carlos III. © 2024 Elsevier Ltd
Funding details
National Institute of Child Health and Human DevelopmentNICHD
Barrow Neurological InstituteBNI
Instituto de Salud Carlos IIIISCIII
Korea Research Institute of Chemical TechnologyKRICT
Center for Performance ResearchCPR
German Network for Motor Neuron DiseasesMND-NET
Ministry of Health and WelfareMOHW
National Institute on AgingNIA
Japan Agency for Medical Research and DevelopmentAMEDJP23dk0207066, JP22dk0207049
Japan Agency for Medical Research and DevelopmentAMED
Ministry of Science and ICT, South KoreaMSITHI21C0066
Ministry of Science and ICT, South KoreaMSIT
Alzheimer’s AssociationAASG-20–690363-DIAN
Alzheimer’s AssociationAA
Document Type: Article
Publication Stage: Final
Source: Scopus
Parvalbumin expression does not account for discrete electrophysiological profiles of glutamatergic ventral pallidal subpopulations
(2024) Addiction Neuroscience, 12, art. no. 100170, .
Graham, R.D.a , Fang, L.Z.a , Tooley, J.R.a b , Kalyanaraman, V.a , Stander, M.C.a , Sapkota, D.e f , Lynch, M.R.a d , Dougherty, J.D.b c f , Copits, B.A.a b , Creed, M.C.a b
a Department of Anesthesiology, Washington University in St. Louis, United States
b Graduate program in neuroscience, Division of Biological and Biomedical Sciences, United States
c Department of Psychiatry, Washington University in St. Louis, United States
d NINDS Neuroscience Postbaccalaureate Program, Washington University School of Medicine, St. Louis, MO, United States
e Department of Biological Sciences, University of Texas at Dallas, United States
f Department of Genetics, Washington University in St. Louis, United States
Abstract
The ventral pallidum (VP) has emerged as a critical node in the mesolimbic reward system. Modulating the VP can impact the subjective valuation of rewards, reward motivation, and reward seeking under conflict, making it an attractive target for clinical neuromodulation therapies that manage substance use disorders. To understand how to rationally modulate the VP, we need a better understanding of the electrophysiological properties of VP neurons and the molecular and biophysical determinants of these properties. Here, we used patch-clamp electrophysiology to characterize the intrinsic properties of glutamatergic VP (VPGlu) neurons and observed two distinct electrophysiological profiles: VPGlu neurons that undergo depolarization block in response to progressively increasing current injection amplitudes and those that were resistant to depolarization block. To explore the mechanisms that could contribute to these distinct profiles, we used targeted ribosome affinity purification to identify ion channel subunits and regulatory proteins by isolating actively transcribed mRNA selectively from VPGlu neurons. We then used this transcriptomic information to implement a Markov Chain Monte Carlo method to parameterize a large population of biophysically distinct multicompartment models of VPGlu neurons conforming to either subpopulation. Based on prior literature suggesting parvalbumin (PV) is expressed in a subset of VPGlu neurons, and that PV expression governs the firing properties of those neurons, we tested the hypothesis that PV expression accounted for differences in subgroups, by increasing the maximal firing frequency and conferring resistance to depolarization block. In contrast, our model determined that PV expression at physiological levels had no effect on maximum firing rate. However, supraphysiological expression levels of PV appeared to induce a depolarization block in previously depolarization block-resistant neuron models, suggesting that other intracellular calcium-binding proteins could play a role in determining the firing phenotype of VPGlu neurons. We corroborated this result with single-cell patch-clamp RT-PCR, which confirmed that PV expression did not distinguish the two electrophysiologically distinct subpopulations. Together, these findings establish that VPGlu neurons are composed of biophysically distinct subpopulations that have not been appreciated in prior studies interrogating the function of this population. With the advent of novel tools for cell-type specific pharmacology and targeted neurostimulation, this understanding will be critical for developing strategies to rationally modulate VPGlu cells to treat disorders characterized by maladaptive reward seeking. © 2024 The Author(s)
Author Keywords
Electrophysiology; Ion channels; Markov chain Monte-Carlo; Neuron modeling; Translating ribosome affinity purification
Funding details
Joint Genome InstituteJGI
National Institutes of HealthNIH
Genome Technology Access CenterGTAC
National Center for Research ResourcesNCRR
Institute for Diabetes, Obesity and Metabolism, Perelman School of Medicine, University of PennsylvaniaIDOM
Foundation for Barnes-Jewish HospitalFBJH4642, 3770
#P30 CA91842
National Institute on Drug AbuseNIDAR01DA058755, R01DA049924, R01DA056829
R25NS130965
St. Louis Children’s HospitalSLCHCDI-CORE-2019-813, CDI-CORE-2015-505
University of WashingtonUWT32DA007261, P30DK020579
Document Type: Article
Publication Stage: Final
Source: Scopus
A Protocol for the Inclusion of Minoritized Persons in Alzheimer Disease Research From the ADNI3 Diversity Taskforce
(2024) JAMA Network Open, 7 (8), p. e2427073.
Okonkwo, O.C.a , Rivera Mindt, M.b c , Ashford, M.T.d e , Conti, C.d e , Strong, J.a , Raman, R.f , Donohue, M.C.f , Nosheny, R.L.e g , Flenniken, D.d e , Miller, M.J.d e , Diaz, A.d e , Soto, A.M.c , Ances, B.M.h , Beigi, M.R.i , Doraiswamy, P.M.j , Duara, R.k l m , Farlow, M.R.n , Grossman, H.T.o , Mintzer, J.E.p , Reist, C.q r s , Rogalski, E.J.t , Sabbagh, M.N.u , Salloway, S.v , Schneider, L.S.w , Shah, R.C.x , Petersen, R.C.y , Aisen, P.S.f , Weiner, M.W.d e g z aa ab , Alzheimer’s Disease Neuroimaging Initiativeac
a Department of Medicine and Wisconsin Alzheimer’s Disease Research Center, University of Wisconsin School of Medicine and Public Health, Madison, United States
b Department of Psychology, Latin American Latinx Studies Institute, African and African American Studies, Fordham University, Bronx, NY, United States
c Department of Neurology, Icahn School of Medicine at Mount SinaiNY, United States
d Northern California Institute for Research and Education, Department of Veterans Affairs Medical Center, San Francisco, Mexico
e VA Advanced Imaging Research Center, San Francisco Veteran’s Administration Medical Center, San Francisco, CA, United States
f Alzheimer’s Therapeutic Research Institute, University of Southern California, San Diego, Mexico
g Department of Psychiatry and Behavioral Sciences, University of California, San Francisco, Mexico
h Department of Neurology, Washington University in Saint Louis, Saint Louis, Missouri
i Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, Mexico
j Departments of Psychiatry and Medicine, Duke University School of Medicine, Durham, NC, United States
k Wein Center for Alzheimer’s Disease and Memory Disorders, Mount Sinai Medical Center, Miami BeachFL, Puerto Rico
l Herbert Wertheim College of Medicine, Florida International University, Miami, United States
m Alzheimer’s Disease Research Center, University of Florida College of Medicine, Gainesville, United States
n Department of Neurology, Indiana University Health, Indianapolis, United States
o Alzheimer Disease Research Center, Mount Sinai School of MedicineNY, United States
p Medical University of South Carolina, Ralph H. Johnson VA Healthcare Center, Charleston, United States
q MindX Sciences Inc, Indianapolis, IN, United States
r Science 37 Inc, Durham, NC, United States
s Department of Psychiatry, University of California Irvine, Long Beach
t Department of Neurology, University of Chicago, Chicago, IL, United States
u Alzheimer’s and Memory Disorders Division, Department of Neurology, Barrow Neurological Institute, Phoenix, AZ, United States
v Memory and Aging Program, Butler Hospital, Alpert Medical School, Brown University, Providence, RI, United States
w Department of Psychiatry and Behavioral Sciences, Department of Neurology, Alzheimer’s Disease Research Center, Keck School of Medicine of USC, Los Angeles, CA, United States
x Department of Family and Preventive Medicine and the Rush Alzheimer’s Disease Center, Rush University Medical Center, Chicago, IL, United States
y Alzheimer’s Disease Research Center, Mayo Clinic College of Medicine, Rochester, MN, United States
z Department of Radiology and Biomedical Imaging, University of California, San Francisco, Mexico
aa Department of Medicine, University of California, San Francisco, Mexico
ab Department of Neurology, University of California, San Francisco, Mexico
Abstract
Importance: Black or African American (hereinafter, Black) and Hispanic or Latino/a/x (hereinafter, Latinx) adults are disproportionally affected by Alzheimer disease, but most research studies do not enroll adequate numbers of both of these populations. The Alzheimer’s Disease Neuroimaging Initiative-3 (ADNI3) launched a diversity taskforce to pilot a multipronged effort to increase the study inclusion of Black and Latinx older adults. Objective: To describe and evaluate the culturally informed and community-engaged inclusion efforts to increase the screening and enrollment of Black and Latinx older adults in ADNI3. Design, Setting, and Participants: This cross-sectional study used baseline data from a longitudinal, multisite, observational study conducted from January 15, 2021, to July 12, 2022, with no follow-up. The study was conducted at 13 ADNI3 sites in the US. Participants included individuals aged 55 to 90 years without cognitive impairment and those with mild cognitive impairment or Alzheimer disease. Exposures: Efforts included (1) launch of an external advisory board, (2) changes to the study protocol, (3) updates to the digital prescreener, (4) selection and deployment of 13 community-engaged research study sites, (5) development and deployment of local and centralized outreach efforts, and (6) development of a community-science partnership board. Main Outcomes and Measures: Screening and enrollment numbers from centralized and local outreach efforts, digital advertisement metrics, and digital prescreener completion. Results: A total of 91 participants enrolled in the trial via centralized and local outreach efforts, of which 22 (24.2%) identified as Latinx and 55 (60.4%) identified as Black (median [IQR] age, 65.6 [IQR, 61.5-72.5] years; 62 women [68.1%]). This represented a 267.6% increase in the monthly rate of enrollment (before: 1.11 per month; during: 4.08 per month) of underrepresented populations. For the centralized effort, social media advertisements were run between June 1, 2021, and July 31, 2022, which resulted in 2079 completed digital prescreeners, of which 1289 met criteria for subsequent site-level screening. Local efforts were run between June 1, 2021, to July 31, 2022. A total of 151 participants underwent site-level screening (100 from local efforts, 41 from centralized efforts, 10 from other sources). Conclusions and Relevance: In this cross-sectional study of pilot inclusion efforts, a culturally informed, community-engaged approach increased the inclusion of Black and Latinx participants in an Alzheimer disease cohort study.
Document Type: Article
Publication Stage: Final
Source: Scopus
NF1 mutation-driven neuronal hyperexcitability sets a threshold for tumorigenesis and therapeutic targeting of murine optic glioma
(2024) Neuro-Oncology, 26 (8), pp. 1496-1508.
Anastasaki, C.a , Chatterjee, J.a , Koleske, J.P.a , Gao, Y.a , Bozeman, S.L.a , Kernan, C.M.a , Marco Y Marquez, L.I.a , Chen, J.-K.a , Kelly, C.E.b , Blair, C.J.b , Dietzen, D.J.b , Kesterson, R.A.c , Gutmann, D.H.a
a Departments of Neurology, Washington University, School of Medicine, St. Louis, MO, United States
b Department of Pathology & Immunology, Washington University, School of Medicine, St. Louis, MO, United States
c Pennington Biomedical Research Center, Louisiana State University, Baton Rouge, LA, United States
Abstract
Background: With the recognition that noncancerous cells function as critical regulators of brain tumor growth, we recently demonstrated that neurons drive low-grade glioma initiation and progression. Using mouse models of neurofibromatosis type 1 (NF1)-associated optic pathway glioma (OPG), we showed that Nf1 mutation induces neuronal hyperexcitability and midkine expression, which activates an immune axis to support tumor growth, such that high-dose lamotrigine treatment reduces Nf1-OPG proliferation. Herein, we execute a series of complementary experiments to address several key knowledge gaps relevant to future clinical translation. Methods: We leverage a collection of Nf1-mutant mice that spontaneously develop OPGs to alter both germline and retinal neuron-specific midkine expression. Nf1-mutant mice harboring several different NF1 patient-derived germline mutations were employed to evaluate neuronal excitability and midkine expression. Two distinct Nf1-OPG preclinical mouse models were used to assess lamotrigine effects on tumor progression and growth in vivo. Results: We establish that neuronal midkine is both necessary and sufficient for Nf1-OPG growth, demonstrating an obligate relationship between germline Nf1 mutation, neuronal excitability, midkine production, and Nf1-OPG proliferation. We show anti-epileptic drug (lamotrigine) specificity in suppressing neuronal midkine production. Relevant to clinical translation, lamotrigine prevents Nf1-OPG progression and suppresses the growth of existing tumors for months following drug cessation. Importantly, lamotrigine abrogates tumor growth in two Nf1-OPG strains using pediatric epilepsy clinical dosing. Conclusions: Together, these findings establish midkine and neuronal hyperexcitability as targetable drivers of Nf1-OPG growth and support the use of lamotrigine as a potential chemoprevention or chemotherapy agent for children with NF1-OPG. © 2024 The Author(s). Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved.
Author Keywords
lamotrigine; midkine; neuronal excitability; NF1; optic glioma
Funding details
WITH Foundation
Gilbert Family FoundationGFF
Molecular Engineering Materials Center, University of WashingtonMEM-C
Erasmus MC Vriendenfonds
National Institutes of HealthNIHR35NS097211, R50CA233164
National Institutes of HealthNIH
P30-CA091842
National Eye InstituteNEIP30EY002687
National Eye InstituteNEI
National Cancer InstituteNCI1R01CA261939
National Cancer InstituteNCI
Document Type: Article
Publication Stage: Final
Source: Scopus
Plasma Phosphorylated Tau 217 and Aβ42/40 to Predict Early Brain Aβ Accumulation in People Without Cognitive Impairment
(2024) JAMA Neurology, pp. E1-E11.
Janelidze, S.a , Barthélemy, N.R.b c , Salvadó, G.a , Schindler, S.E.b c d , Palmqvist, S.a e , Mattsson-Carlgren, N.a f g , Braunstein, J.B.h , Ovod, V.b c , Bollinger, J.G.b c , He, Y.b c , Li, Y.b c , Raji, C.A.i , Morris, J.C.b , Holtzman, D.M.j , Ashton, N.J.k l m n , Blennow, K.k o p , Stomrud, E.a e , Bateman, R.J.b c , Hansson, O.a e
a Clinical Memory Research Unit, Department of Clinical Sciences Malmö, Lund University, Lund, Sweden
b Department of Neurology, Washington University School of Medicine in St Louis, St Louis, MO, United States
c The Tracy Family SILQ Center, St Louis, MO, United States
d The Knight ADRC, Washington University School of Medicine, St Louis, MO, United States
e Memory Clinic, Skåne University Hospital, Malmö, Sweden
f Department of Neurology, Skåne University Hospital, Lund University, Lund, Sweden
g Wallenberg Center for Molecular Medicine, Lund University, Lund, Sweden
h C2N Diagnostics, St Louis, MO, United States
i Department of Radiology and Neurology, Washington University in St Louis, St Louis, MO, United States
j Department of Neurology, Hope Center for Neurological Disorders, Knight ADRC, Washington University in St Louis, St Louis, MO, United States
k Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg, Mölndal, Sweden
l Wallenberg Centre for Molecular Medicine, University of Gothenburg, Gothenburg, Sweden
m King’s College London, Institute of Psychiatry, Psychology and Neuroscience, Maurice Wohl Institute, Clinical Neuroscience Institute, London, United Kingdom
n NIHR Biomedical Research Centre for Mental Health, Biomedical Research Unit for Dementia, South London and Maudsley NHS Foundation, London, United Kingdom
o Paris Brain Institute, ICM, Pitié-Salpêtrière Hospital, Sorbonne University, Paris, France
p Clinical Neurochemistry Lab, Sahlgrenska University Hospital, Mölndal, Sweden
Abstract
Importance: Phase 3 trials of successful antiamyloid therapies in Alzheimer disease (AD) have demonstrated improved clinical efficacy in people with less severe disease. Plasma biomarkers will be essential for efficient screening of participants in future primary prevention clinical trials testing antiamyloid therapies in cognitively unimpaired (CU) individuals with initially low brain β-amyloid (Aβ) levels who are at high risk of accumulating Aβ. Objective: To investigate if combining plasma biomarkers could be useful in predicting subsequent development of Aβ pathology in CU individuals with subthreshold brain Aβ levels (defined as Aβ levels <40 Centiloids) at baseline. Design, Setting, and Participants: This was a longitudinal study including Swedish BioFINDER-2 (enrollment 2017-2022) and replication in 2 independent cohorts, the Knight Alzheimer Disease Research Center (Knight ADRC; enrollment 1988 and 2019) and Swedish BioFINDER-1 (enrollment 2009-2015). Included for analysis was a convenience sample of CU individuals with baseline plasma phosphorylated tau 217 (p-tau217) and Aβ42/40 assessments and Aβ assessments with positron emission tomography (Aβ-PET) or cerebrospinal fluid (CSF) Aβ42/40. Data were analyzed between April 2023 and May 2024. Exposures: Baseline plasma levels of Aβ42/40, p-tau217, the ratio of p-tau217 to nonphosphorylated tau (%p-tau217), p-tau231, and glial fibrillary acidic protein (GFAP). Main Outcomes and Measures: Cross-sectional and longitudinal PET and CSF measures of brain Aβ pathology. Results: This study included 495 (BioFINDER-2), 283 (Knight ADRC), and 205 (BioFINDER-1) CU participants. In BioFINDER-2, the mean (SD) age was 65.7 (14.4) with 261 females (52.7%). When detecting abnormal CSF Aβ-status, a combination of plasma %p-tau217 and Aβ42/40 showed better performance (area under the curve =0.949; 95% CI, 0.929-0.970; P <.02) than individual biomarkers. In CU participants with subthreshold baseline Aβ-PET, baseline plasma %p-tau217 and Aβ42/40 levels were significantly associated with baseline Aβ-PET (n = 384) and increases in Aβ-PET over time (n = 224). Associations of plasma %p-tau217 and Aβ42/40 and their interaction with baseline Aβ-PET (%p-tau217: β = 2.77; 95% CI, 1.84-3.70; Aβ42/40: β = -1.64; 95% CI, -2.53 to -0.75; %p-tau217 × Aβ42/40: β = -2.14; 95% CI, -2.79 to -1.49; P <.001) and longitudinal Aβ-PET (%p-tau217: β = 0.67; 95% CI, 0.48-0.87; Aβ42/40: β = -0.33; 95% CI, -0.51 to -0.15; %p-tau217 × Aβ42/40: β = -0.31; 95% CI, -0.44 to -0.18; P <.001) were also significant in the models combining the 2 baseline biomarkers as predictors. Similarly, baseline plasma p-tau217 and Aβ42/40 were independently associated with longitudinal Aβ-PET in Knight ADRC (%p-tau217: β = 0.71; 95% CI, 0.26-1.16; P =.002; Aβ42/40: β = -0.74; 95% CI, -1.26 to -0.22; P =.006) and longitudinal CSF Aβ42/40 in BioFINDER-1 (p-tau217: β = -0.0003; 95% CI, -0.0004 to -0.0001; P =.01; Aβ42/40: β = 0.0004; 95% CI, 0.0002-0.0006; P <.001) in CU participants with subthreshold Aβ levels at baseline. Plasma p-tau231 and GFAP did not provide any clear independent value. Conclusions and Relevance: Results of this cohort study suggest that combining plasma p-tau217and Aβ42/40 levels could be useful for predicting development of Aβ pathology in people with early stages of subthreshold Aβ accumulation. These biomarkers might thus facilitate screening of participants for future primary prevention trials. © 2024 American Medical Association. All rights reserved.
Funding details
GE Healthcare
Henrietta B. and Frederick H. Bugher Foundation
Horizon 2020 Framework ProgrammeH2020
Harald och Greta Jeanssons Stiftelse
FLÄK Research School, Lunds UniversityFLÄK
GHR FoundationGHR
Sahlgrenska University Hospitals Research Foundations2020-O000028
Sahlgrenska University Hospitals Research Foundations
Alzheimer’s SocietyZEN24-1069572, SG-23-1061717
Alzheimer’s Society
Banner Alzheimer’s FoundationFRS-0003
Banner Alzheimer’s Foundation
European Research CouncilERCADG-101096455
European Research CouncilERC
EU Joint Programme – Neurodegenerative Disease ResearchJPND2019-03401
EU Joint Programme – Neurodegenerative Disease ResearchJPND
Helse Vest Regionalt Helseføretak2022-1259
Helse Vest Regionalt Helseføretak
Marie-Claire Cronstedts Stiftelse101061836, -22-972612
Marie-Claire Cronstedts Stiftelse
Swedish Cancer FoundationFO2023-0163, FO2021-0293, AF-994229, AF-980907, AF-980942
Swedish Cancer Foundation
National Institute on AgingNIAR01AG083740, R01AG070941, P30 AG066444, P01AG003991, P01AG026276
National Institute on AgingNIA
Alzheimer’s Drug Discovery FoundationADDFGC-201711-2013978
Alzheimer’s Drug Discovery FoundationADDF
WASP/DDLS22-066
Sweden-Japan FoundationSJF1412/22
Sweden-Japan FoundationSJF
Nihon SuperiorCA2016636, R44 AG059489
Nihon Superior
Knut och Alice Wallenbergs Stiftelse2022-0231
Knut och Alice Wallenbergs Stiftelse
Swedish Foundation for MS Research2022-00775, 2018-02052, ERAPERMED2021-184, 2021-02219
Swedish Foundation for MS Research
Swedish Brain PowerSBP2022-Projekt0080, 2022-Projekt0107
Swedish Brain PowerSBP
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
Blood Biomarkers to Detect Alzheimer Disease in Primary Care and Secondary Care
(2024) JAMA, . Cited 2 times.
Palmqvist, S.a b , Tideman, P.a b , Mattsson-Carlgren, N.a c d , Schindler, S.E.e , Smith, R.a b , Ossenkoppele, R.a f g , Calling, S.h i , West, T.j , Monane, M.j , Verghese, P.B.j , Braunstein, J.B.j , Blennow, K.k l m , Janelidze, S.a , Stomrud, E.a b , Salvadó, G.a , Hansson, O.a b
a Clinical Memory Research Unit, Department of Clinical Sciences Malmö, Faculty of Medicine, Lund University, Lund, Sweden
b Memory Clinic, Skåne University Hospital, Malmö, Sweden
c Neurology Clinic, Skåne University Hospital, Lund, Sweden
d Wallenberg Center for Molecular Medicine, Lund University, Lund, Sweden
e Department of Neurology, Washington University School of Medicine, St Louis, MO, United States
f Alzheimer Center Amsterdam, Neurology, Vrije Universiteit Amsterdam, Amsterdam UMC, Amsterdam, Netherlands
g Amsterdam Neuroscience, Neurodegeneration, Amsterdam, Netherlands
h Center for Primary Health Care Research, Department of Clinical Sciences, Lund University, Malmö, Sweden
i University Clinic Primary Care, Skåne, Sweden
j C2N Diagnostics LLC, St Louis, MO, United States
k Paris Brain Institute, Pitié-Salpêtrière Hospital, Sorbonne University, Paris, France
l Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Mölndal, Sweden
m Clinical Neurochemistry Lab, Sahlgrenska University Hospital, Mölndal, Sweden
Abstract
Importance: An accurate blood test for Alzheimer disease (AD) could streamline the diagnostic workup and treatment of AD. Objective: To prospectively evaluate a clinically available AD blood test in primary care and secondary care using predefined biomarker cutoff values. Design, Setting, and Participants: There were 1213 patients undergoing clinical evaluation due to cognitive symptoms who were examined between February 2020 and January 2024 in Sweden. The biomarker cutoff values had been established in an independent cohort and were applied to a primary care cohort (n = 307) and a secondary care cohort (n = 300); 1 plasma sample per patient was analyzed as part of a single batch for each cohort. The blood test was then evaluated prospectively in the primary care cohort (n = 208) and in the secondary care cohort (n = 398); 1 plasma sample per patient was sent for analysis within 2 weeks of collection. Exposure: Blood tests based on plasma analyses by mass spectrometry to determine the ratio of plasma phosphorylated tau 217 (p-tau217) to non-p-tau217 (expressed as percentage of p-tau217) alone and when combined with the amyloid-β 42 and amyloid-β 40 (Aβ42:Aβ40) plasma ratio (the amyloid probability score 2 [APS2]). Main Outcomes and Measures: The primary outcome was AD pathology (determined by abnormal cerebrospinal fluid Aβ42:Aβ40 ratio and p-tau217). The secondary outcome was clinical AD. The positive predictive value (PPV), negative predictive value (NPV), diagnostic accuracy, and area under the curve (AUC) values were calculated. Results: The mean age was 74.2 years (SD, 8.3 years), 48% were women, 23% had subjective cognitive decline, 44% had mild cognitive impairment, and 33% had dementia. In both the primary care and secondary care assessments, 50% of patients had AD pathology. When the plasma samples were analyzed in a single batch in the primary care cohort, the AUC was 0.97 (95% CI, 0.95-0.99) when the APS2 was used, the PPV was 91% (95% CI, 87%-96%), and the NPV was 92% (95% CI, 87%-96%); in the secondary care cohort, the AUC was 0.96 (95% CI, 0.94-0.98) when the APS2 was used, the PPV was 88% (95% CI, 83%-93%), and the NPV was 87% (95% CI, 82%-93%). When the plasma samples were analyzed prospectively (biweekly) in the primary care cohort, the AUC was 0.96 (95% CI, 0.94-0.98) when the APS2 was used, the PPV was 88% (95% CI, 81%-94%), and the NPV was 90% (95% CI, 84%-96%); in the secondary care cohort, the AUC was 0.97 (95% CI, 0.95-0.98) when the APS2 was used, the PPV was 91% (95% CI, 87%-95%), and the NPV was 91% (95% CI, 87%-95%). The diagnostic accuracy was high in the 4 cohorts (range, 88%-92%). Primary care physicians had a diagnostic accuracy of 61% (95% CI, 53%-69%) for identifying clinical AD after clinical examination, cognitive testing, and a computed tomographic scan vs 91% (95% CI, 86%-96%) using the APS2. Dementia specialists had a diagnostic accuracy of 73% (95% CI, 68%-79%) vs 91% (95% CI, 88%-95%) using the APS2. In the overall population, the diagnostic accuracy using the APS2 (90% [95% CI, 88%-92%]) was not different from the diagnostic accuracy using the percentage of p-tau217 alone (90% [95% CI, 88%-91%]). Conclusions and Relevance: The APS2 and percentage of p-tau217 alone had high diagnostic accuracy for identifying AD among individuals with cognitive symptoms in primary and secondary care using predefined cutoff values. Future studies should evaluate how the use of blood tests for these biomarkers influences clinical care. © 2024 American Medical Association. All rights reserved.
Funding details
GE Healthcare
Alzheimer’s Society
Knut och Alice Wallenbergs Stiftelse
Sweden-Japan FoundationSJF
Cure Alzheimer’s FundCAF
Swedish Brain PowerSBP101061836
Swedish Brain PowerSBP
GHR FoundationGHRADG-101096455
GHR FoundationGHR
Swedish Cancer FoundationFO2023-0163, FO2021-0293, FO2022-0204, 1412/22, FRS-0003, FRS-0004
Swedish Cancer Foundation
EU Joint Programme – Neurodegenerative Disease ResearchJPND2022-1259, 2022-Projekt0080, 2022-Projekt0107, 22-066
EU Joint Programme – Neurodegenerative Disease ResearchJPND
European Research CouncilERC2022-00775, 2021-02219, 2018-02052
European Research CouncilERC
National Institute on AgingNIASG-23-1061717, ZEN24-1069572
National Institute on AgingNIA
FLÄK Research School, Lunds UniversityFLÄKAF-981132, AF-994229, AF-980907, AF-980942
FLÄK Research School, Lunds UniversityFLÄK
Stiftelsen Konung Gustaf V:s Jubileumsfond2020-O000028
Stiftelsen Konung Gustaf V:s Jubileumsfond
Horizon 2020 Framework ProgrammeH2020AARF-22-972612
Horizon 2020 Framework ProgrammeH2020
Swedish Foundation for MS Research2021-184, 2022-0231
Swedish Foundation for MS Research
Sahlgrenska University Hospitals Research Foundations2019-03401
Sahlgrenska University Hospitals Research Foundations
Document Type: Article
Publication Stage: Article in Press
Source: Scopus