Hope Center Member Publications

Standardized immunoprecipitation protocol for efficient isolation of native apolipoprotein E particles utilizing HJ15.4 monoclonal antibody
(2023) STAR Protocols, 4 (2), art. no. 102271, .

O’Leary, J.^a , Raulin, A.-C.^a , Li, Z.^a , Martens, Y.^a , Inoue, Y.^a , Strickland, M.R.^b , Han, X.^c d , Holtzman, D.M.^b , Bu, G.^a , Zhao, N.^a

^a Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, United States
^b Department of Neurology, Hope Center for Neurological Disorders, Knight Alzheimer’s Disease Research Center, Washington University in St. Louis, St. Louis, MO 63110, United States
^c Department of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, United States
^d Barshop Institute for Longevity and Aging Studies, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, United States

Abstract
The apolipoprotein E protein (apoE) confers differential risk for Alzheimer’s disease depending on which isoforms are expressed. Here, we present a 2-day immunoprecipitation protocol using the HJ15.4 monoclonal apoE antibody for the pull-down of native apoE particles. We describe major steps for apoE production via immortalized astrocyte culture and HJ15.4 antibody bead coupling for apoE particle pull-down, elution, and characterization. This protocol could be used to isolate native apoE particles from multiple model systems or human biospecimens. © 2023 The Author(s)

Author Keywords
Cell Biology;  Molecular Biology;  Neuroscience

Funding details
National Institutes of HealthNIHRF1AG046205, RF1AG061872, U19AG069701
BrightFocus FoundationBFF

Document Type: Article
Publication Stage: Final
Source: Scopus

Profiling baseline performance on the Longitudinal Early-Onset Alzheimer’s Disease Study (LEADS) cohort near the midpoint of data collection
(2023) Alzheimer’s and Dementia, . 

Hammers, D.B.^a , Eloyan, A.^b , Taurone, A.^b , Thangarajah, M.^b , Beckett, L.^c , Gao, S.^d , Kirby, K.^a , Aisen, P.^e , Dage, J.L.^a , Foroud, T.^f , Griffin, P.^g , Grinberg, L.T.^h i , Jack, C.R., Jr.^j , Kramer, J.ⁱ , Koeppe, R.^k , Kukull, W.A.^l , Mundada, N.S.ⁱ , La Joie, R.ⁱ , Soleimani-Meigooni, D.N.ⁱ , Iaccarino, L.ⁱ , Murray, M.E.^m , Nudelman, K.^f , Polsinelli, A.J.^a , Rumbaugh, M.^f , Toga, A.ⁿ , Touroutoglou, A.^o , Vemuri, P.^j , Atri, A.^p , Day, G.S.^q , Duara, R.^r , Graff-Radford, N.R.^q , Honig, L.S.^s , Jones, D.T.^j t , Masdeu, J.^u , Mendez, M.F.^v , Womack, K.^w , Musiek, E.^w , Onyike, C.U.^x , Riddle, M.^y , Rogalski, E.^z , Salloway, S.^y , Sha, S.J.^aa , Turner, R.S.^ab , Wingo, T.S.^ac , Wolk, D.A.^ad , Carrillo, M.C.^g , Dickerson, B.C.^o , Rabinovici, G.D.ⁱ , Apostolova, L.G.^a f ae , the LEADS Consortium^af

^a Department of Neurology, Indiana University School of Medicine, Indianapolis, IN, United States
^b Department of Biostatistics, Center for Statistical Sciences, Brown University, Providence, RI, United States
^c Department of Public Health Sciences, University of California – Davis, Davis, CA, United States
^d Department of Biostatistics, Indiana University School of Medicine, Indianapolis, IN, United States
^e Alzheimer’s Therapeutic Research Institute, University of Southern California, San Diego, CA, United States
^f Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, United States
^g Medical & Scientific Relations Division, Alzheimer’s Association, Chicago, IL, United States
^h Department of Pathology, University of California – San Francisco, San Francisco, CA, United States
ⁱ Department of Neurology, University of California – San Francisco, San Francisco, CA, United States
^j Department of Radiology, Mayo Clinic, Rochester, MN, United States
^k Department of Radiology, University of Michigan, Ann Arbor, MI, United States
^l Department of Epidemiology, University of Washington, Seattle, WA, United States
^m Department of Neuroscience, Mayo Clinic, Jacksonville, FL, United States
ⁿ Laboratory of Neuro Imaging, USC Stevens Neuroimaging and Informatics Institute, Keck School of Medicine of USC, Los Angeles, CA, United States
^o Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, United States
^p Banner Sun Health Research Institute, Sun City, AZ, United States
^q Department of Neurology, Mayo Clinic, Jacksonville, FL, United States
^r Wien Center for Alzheimer’s Disease and Memory Disorders, Mount Sinai Medical Center, Miami, FL, United States
^s Taub Institute and Department of Neurology, Columbia University Irving Medical Center, New York, NY, United States
^t Department of Neurology, Mayo Clinic, Rochester, MN, United States
^u Nantz National Alzheimer Center, Houston Methodist and Weill Cornell Medicine, Houston, TX, United States
^v Department of Neurology, David Geffen School of Medicine at UCLA, Los Angeles, CA, United States
^w Department of Neurology, Washington University in St. Louis, St. Louis, MO, United States
^x Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, United States
^y Department of Neurology, Alpert Medical School, Brown University, Providence, RI, United States
^z Department of Psychiatry and Behavioral Sciences, Mesulam Center for Cognitive Neurology and Alzheimer’s Disease, Feinberg School of Medicine, Northwestern University, Chicago, IL, United States
^aa Department of Neurology & Neurological Sciences, Stanford University, Palo Alto, CA, United States
^ab Department of Neurology, Georgetown University, Washington, DC, United States
^ac Department of Neurology and Human Genetics, Emory University School of Medicine, Atlanta, GA, United States
^ad Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States
^ae Department of Radiology and Imaging Sciences, Center for Neuroimaging, Indiana University School of Medicine Indianapolis, Indianapolis, IN, United States

Abstract
Objective: The Longitudinal Early-Onset Alzheimer’s Disease Study (LEADS) seeks to provide comprehensive understanding of early-onset Alzheimer’s disease (EOAD; onset <65 years), with the current study profiling baseline clinical, cognitive, biomarker, and genetic characteristics of the cohort nearing the data-collection mid-point. Methods: Data from 371 LEADS participants were compared based on diagnostic group classification (cognitively normal [n = 89], amyloid-positive EOAD [n = 212], and amyloid-negative early-onset non-Alzheimer’s disease [EOnonAD; n = 70]). Results: Cognitive performance was worse for EOAD than other groups, and EOAD participants were apolipoprotein E (APOE) ε4 homozygotes at higher rates. An amnestic presentation was common among impaired participants (81%), with several clinical phenotypes present. LEADS participants generally consented at high rates to optional trial procedures. Conclusions: We present the most comprehensive baseline characterization of sporadic EOAD in the United States to date. EOAD presents with widespread cognitive impairment within and across clinical phenotypes, with differences in APOE ε4 allele carrier status appearing to be relevant. HIGHLIGHTS: Findings represent the most comprehensive baseline characterization of sporadic early-onset Alzheimer’s disease (EOAD) to date. Cognitive impairment was widespread for EOAD participants and more severe than other groups. EOAD participants were homozygous apolipoprotein E (APOE) ε4 carriers at higher rates than the EOnonAD group. Amnestic presentation predominated in EOAD and EOnonAD participants, but other clinical phenotypes were present. © 2023 the Alzheimer’s Association.

Author Keywords
Alzheimer’s disease;  amnestic;  atypical variant;  early-onset;  memory

Funding details
National Institute on AgingNIAR56 AG057195, U01AG6057195, U24AG021886
Alzheimer’s AssociationAALEADS GENETICS‐19‐639372, P30 AG010124, P30 AG010133, P30 AG013854, P30 AG062421, P30 AG062422, P30AG066506, P50 AG005146, P50 AG005681, P50 AG008702, P50 AG023501, P50 AG025688, P50AG047366, U01 AG016976

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

COURAGE-ALS: a randomized, double-blind phase 3 study designed to improve participant experience and increase the probability of success
(2023) Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration, . 

Shefner, J.M.^a , Al-Chalabi, A.^b , Andrews, J.A.^c , Chio, A.^d , De Carvalho, M.^e , Cockroft, B.M.^f , Corcia, P.^g , Couratier, P.^h , Cudkowicz, M.E.ⁱ , Genge, A.^j , Hardiman, O.^k , Heiman-Patterson, T.^l , Henderson, R.D.^m , Ingre, C.ⁿ , Jackson, C.E.^o , Johnston, W.^p , Lechtzin, N.^q , Ludolph, A.^r , Maragakis, N.J.^s , Miller, T.M.^t , Mora Pardina, J.S.^u , Petri, S.^v , Simmons, Z.^w , Van Den Berg, L.H.^x , Zinman, L.^y , Kupfer, S.^z , Malik, F.I.^z , Meng, L.^z , Simkins, T.J.^z , Wei, J.^z , Wolff, A.A.^z , Rudnicki, S.A.^z

^a Barrow Neurological Institute, University of Arizona, and Creighton University, Phoenix, AZ, United States
^b King’s College London, London, United Kingdom
^c The Neurological Institute of New York, Columbia University Irving Medical Center, New York, NY, United States
^d Rita Levi Montalcini’ Department of Neuroscience, University of Turin, Turin, Italy
^e Department of Neurosciences of Centro Hospitalar Universitário Lisboa-Norte, Faculty of Medicine, Centro de Estudos Egas Moniz, Institute of Molecular Medicine, Universidade de Lisboa, Lisbon, Portugal
^f Sangamo Therapeutics, Inc, Brisbane, CA, United States
^g Centre de Réference SLA, CHU Bretonneau, Tours, France
^h Neurology Department, LS Centre CHU Dupuytren, Limoges, France
ⁱ Neurological Clinical Research Institute, Massachusetts General Hospital, Boston, MA, United States
^j Montreal Neurological Institute, Montreal, QC, Canada
^k Academic Unit of Neurology, Trinity Biomedical Sciences Institute, Trinity College, Dublin, Ireland
^l Neurology Lewis Katz School of Medicine at Temple University, Philadelphia, PA, United States
^m UQ Centre for Clinical Research, The University of Queensland, Brisbane, Australia
ⁿ Department of Clinical Neuroscience, Karolinska Institute, Stockholm, Sweden
^o University of Texas Health Science Center at San Antonio, San Antonio, TX, United States
^p University of Alberta, Edmonton, AB, Canada
^q Johns Hopkins University School of Medicine, Baltimore, MD, United States
^r UULM Clinic of Neurology, Ulm University, Ulm, Germany
^s Johns Hopkins ALS Clinical Trials Unit, Johns Hopkins University, Baltimore, MD, United States
^t Washington University School of Medicine, St. Louis, MO, United States
^u ALS Unit, Hospital Universitario San Rafael, Madrid, Spain
^v Department of Neurology, Hannover Medical School, Hannover, Germany
^w Penn State Health Milton S Hershey Medical Center, Hershey, PA, United States
^x Department of Neurology, UMC Utrecht Brain Center, Netherlands ALS Centre, University Medical Center Utrecht, Utrecht, Netherlands
^y Sunnybrook Health Sciences Centre, Toronto, ON, Canada
^z Cytokinetics, Incorporated, South San Francisco, CA, United States

Abstract
Objective: To determine the target population and optimize the study design of the phase 3 clinical trial evaluating reldesemtiv in participants with amyotrophic lateral sclerosis (ALS). Methods: We evaluated the phase 2 study of reldesemtiv, FORTITUDE-ALS, to inform eligibility criteria and design features that would increase trial efficiency and reduce participant burden of the phase 3 trial. Results: In FORTITUDE-ALS, the effect of reldesemtiv was particularly evident among participants in the intermediate- and fast-progressing tertiles for pre-study disease progression. These participants most often had symptom onset ≤24 months and an ALS Functional Rating Scale-Revised (ALSFRS-R) total score ≤44 at baseline. Compared with the overall FORTITUDE-ALS population, the subgroup meeting these criteria declined by fewer ALSFRS-R points at 12 weeks (difference of least-squares mean [SE] versus placebo 1.84 [0.49] and 0.87 [0.35] for the overall population). These inclusion criteria will be used for the phase 3 clinical trial, COURAGE-ALS, in which the primary outcome is the change in ALSFRS-R total score at week 24. We also measure durable medical equipment use and evaluate strength in muscles expected to change rapidly. To reduce participant burden, study visits are often remote, and strength evaluation is simplified to reduce time and effort. Conclusions: In COURAGE-ALS, the phase 3 clinical trial to evaluate reldesemtiv, the sensitivity of detecting a potential treatment effect may be increased by defining eligibility criteria that limit the proportion of participants who have slower disease progression. Implementing remote visits and simplifying strength measurements will reduce both site and participant burden. ClinicalTrials.gov identifiers: NCT03160898 (FORTITUDE-ALS) and NCT04944784 (COURAGE-ALS). © 2023 World Federation of Neurology on behalf of the Research Group on Motor Neuron Diseases.

Author Keywords
ALSFRS-R;  Amyotrophic lateral sclerosis;  randomized clinical trial;  reldesemtiv

Funding details
CytokineticsCYTK

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