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Browsing by Author "Schindler, Suzanne E."
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Item Blood-based biomarkers for Alzheimer's disease: Current state and future use in a transformed global healthcare landscape(Elsevier, 2023) Hampel, Harald; Hu, Yan; Cummings, Jeffrey; Mattke, Soeren; Iwatsubo, Takeshi; Nakamura, Akinori; Vellas, Bruno; O’Bryant, Sid; Shaw, Leslie M.; Cho, Min; Batrla, Richard; Vergallo, Andrea; Blennow, Kaj; Dage, Jeffrey; Schindler, Suzanne E.; Neurology, School of MedicineTimely detection of the pathophysiological changes and cognitive impairment caused by Alzheimer's disease (AD) is increasingly pressing because of the advent of biomarker-guided targeted therapies that may be most effective when provided early in the disease. Currently, diagnosis and management of early AD are largely guided by clinical symptoms. FDA-approved neuroimaging and cerebrospinal fluid biomarkers can aid detection and diagnosis, but the clinical implementation of these testing modalities is limited because of availability, cost, and perceived invasiveness. Blood-based biomarkers (BBBMs) may enable earlier and faster diagnoses as well as aid in risk assessment, early detection, prognosis, and management. Herein, we review data on BBBMs that are closest to clinical implementation, particularly those based on measures of amyloid-β peptides and phosphorylated tau species. We discuss key parameters and considerations for the development and potential deployment of these BBBMs under different contexts of use and highlight challenges at the methodological, clinical, and regulatory levels.Item Cerebrospinal fluid biomarkers in the Longitudinal Early-onset Alzheimer's Disease Study(Wiley, 2023) Dage, Jeffrey L.; Eloyan, Ani; Thangarajah, Maryanne; Hammers, Dustin B.; Fagan, Anne M.; Gray, Julia D.; Schindler, Suzanne E.; Snoddy, Casey; Nudelman, Kelly N. H.; Faber, Kelley M.; Foroud, Tatiana; Aisen, Paul; Griffin, Percy; Grinberg, Lea T.; Iaccarino, Leonardo; Kirby, Kala; Kramer, Joel; Koeppe, Robert; Kukull, Walter A.; La Joie, Renaud; Mundada, Nidhi S.; Murray, Melissa E.; Rumbaugh, Malia; Soleimani-Meigooni, David N.; Toga, Arthur W.; Touroutoglou, Alexandra; Vemuri, Prashanthi; Atri, Alireza; Beckett, Laurel A.; Day, Gregory S.; Graff-Radford, Neill R.; Duara, Ranjan; Honig, Lawrence S.; Jones, David T.; Masdeu, Joseph C.; Mendez, Mario F.; Musiek, Erik; Onyike, Chiadi U.; Riddle, Meghan; Rogalski, Emily; Salloway, Stephen; Sha, Sharon J.; Turner, Raymond S.; Wingo, Thomas S.; Wolk, David A.; Womack, Kyle B.; Carrillo, Maria C.; Dickerson, Bradford C.; Rabinovici, Gil D.; Apostolova, Liana G.; LEADS Consortium; Neurology, School of MedicineIntroduction: One goal of the Longitudinal Early Onset Alzheimer's Disease Study (LEADS) is to define the fluid biomarker characteristics of early-onset Alzheimer's disease (EOAD). Methods: Cerebrospinal fluid (CSF) concentrations of Aβ1-40, Aβ1-42, total tau (tTau), pTau181, VILIP-1, SNAP-25, neurogranin (Ng), neurofilament light chain (NfL), and YKL-40 were measured by immunoassay in 165 LEADS participants. The associations of biomarker concentrations with diagnostic group and standard cognitive tests were evaluated. Results: Biomarkers were correlated with one another. Levels of CSF Aβ42/40, pTau181, tTau, SNAP-25, and Ng in EOAD differed significantly from cognitively normal and early-onset non-AD dementia; NfL, YKL-40, and VILIP-1 did not. Across groups, all biomarkers except SNAP-25 were correlated with cognition. Within the EOAD group, Aβ42/40, NfL, Ng, and SNAP-25 were correlated with at least one cognitive measure. Discussion: This study provides a comprehensive analysis of CSF biomarkers in sporadic EOAD that can inform EOAD clinical trial design.Item Comparative Analysis of Alzheimer's Disease Cerebrospinal Fluid Biomarkers Measurement by Multiplex SOMAscan Platform and Immunoassay-Based Approach(IOS Press, 2022) Timsina, Jigyasha; Gomez-Fonseca, Duber; Wang, Lihua; Do, Anh; Western, Dan; Alvarez, Ignacio; Aguilar, Miquel; Pastor, Pau; Henson, Rachel L.; Herries, Elizabeth; Xiong, Chengjie; Schindler, Suzanne E.; Fagan, Anne M.; Bateman, Randall J.; Farlow, Martin; Morris, John C.; Perrin, Richard J.; Moulder, Krista; Hassenstab, Jason; Vöglein, Jonathan; Chhatwal, Jasmeer; Mori, Hiroshi; Alzheimer’s Disease Neuroimaging Initiative; Dominantly Inherited Alzheimer Network Consortia; Sung, Yun Ju; Cruchaga, Carlos; Neurology, School of MedicineBackground: The SOMAscan assay has an advantage over immunoassay-based methods because it measures a large number of proteins in a cost-effective manner. However, the performance of this technology compared to the routinely used immunoassay techniques needs to be evaluated. Objective: We performed comparative analyses of SOMAscan and immunoassay-based protein measurements for five cerebrospinal fluid (CSF) proteins associated with Alzheimer's disease (AD) and neurodegeneration: NfL, Neurogranin, sTREM2, VILIP-1, and SNAP-25. Methods: We compared biomarkers measured in ADNI (N = 689), Knight-ADRC (N = 870), DIAN (N = 115), and Barcelona-1 (N = 92) cohorts. Raw protein values were transformed using z-score in order to combine measures from the different studies. sTREM2 and VILIP-1 had more than one analyte in SOMAscan; all available analytes were evaluated. Pearson's correlation coefficients between SOMAscan and immunoassays were calculated. Receiver operating characteristic curve and area under the curve were used to compare prediction accuracy of these biomarkers between the two platforms. Results: Neurogranin, VILIP-1, and NfL showed high correlation between SOMAscan and immunoassay measures (r > 0.9). sTREM2 had a fair correlation (r > 0.6), whereas SNAP-25 showed weak correlation (r = 0.06). Measures in both platforms provided similar predicted performance for all biomarkers except SNAP-25 and one of the sTREM2 analytes. sTREM2 showed higher AUC for SOMAscan based measures. Conclusion: Our data indicate that SOMAscan performs as well as immunoassay approaches for NfL, Neurogranin, VILIP-1, and sTREM2. Our study shows promise for using SOMAscan as an alternative to traditional immunoassay-based measures. Follow-up investigation will be required for SNAP-25 and additional established biomarkers.Item Considerations for widespread implementation of blood-based biomarkers of Alzheimer's disease(Wiley, 2024) Mielke, Michelle M.; Anderson, Matthew; Ashford, J. Wesson; Jeromin, Andreas; Lin, Pei-Jung; Rosen, Allyson; Tyrone, Jamie; VandeVrede, Lawren; Willis, Deanna; Hansson, Oskar; Khachaturian, Ara S.; Schindler, Suzanne E.; Weiss, Joan; Batrla, Richard; Bozeat, Sasha; Dwyer, John R.; Holzapfel, Drew; Jones, Daryl Rhys; Murray, James F.; Partrick, Katherine A.; Scholler, Emily; Vradenburg, George; Young, Dylan; Braunstein, Joel B.; Burnham, Samantha C.; de Oliveira, Fabricio Ferreira; Hu, Yan Helen; Mattke, Soeren; Merali, Zul; Monane, Mark; Sabbagh, Marwan Noel; Shobin, Eli; Weiner, Michael W.; Udeh-Momoh , Chinedu T.; Medicine, School of MedicineDiagnosing Alzheimer's disease (AD) poses significant challenges to health care, often resulting in delayed or inadequate patient care. The clinical integration of blood-based biomarkers (BBMs) for AD holds promise in enabling early detection of pathology and timely intervention. However, several critical considerations, such as the lack of consistent guidelines for assessing cognition, limited understanding of BBM test characteristics, insufficient evidence on BBM performance across diverse populations, and the ethical management of test results, must be addressed for widespread clinical implementation of BBMs in the United States. The Global CEO Initiative on Alzheimer's Disease BBM Workgroup convened to address these challenges and provide recommendations that underscore the importance of evidence-based guidelines, improved training for health-care professionals, patient empowerment through informed decision making, and the necessity of community-based studies to understand BBM performance in real-world populations. Multi-stakeholder engagement is essential to implement these recommendations and ensure credible guidance and education are accessible to all stakeholders.Item Head-to-head comparison of leading blood tests for Alzheimer's disease pathology(Wiley, 2024) Schindler, Suzanne E.; Petersen, Kellen K.; Saef, Benjamin; Tosun, Duygu; Shaw, Leslie M.; Zetterberg, Henrik; Dage, Jeffrey L.; Ferber, Kyle; Triana-Baltzer, Gallen; Du-Cuny, Lei; Li, Yan; Coomaraswamy, Janaky; Baratta, Michael; Mordashova, Yulia; Saad, Ziad S.; Raunig, David L.; Ashton, Nicholas J.; Meyers, Emily A.; Rubel, Carrie E.; Rosenbaugh, Erin G.; Bannon, Anthony W.; Potter, William Z.; Neurology, School of MedicineIntroduction: Blood tests have the potential to improve the accuracy of Alzheimer's disease (AD) clinical diagnosis, which will enable greater access to AD-specific treatments. This study compared leading commercial blood tests for amyloid pathology and other AD-related outcomes. Methods: Plasma samples from the Alzheimer's Disease Neuroimaging Initiative were assayed with AD blood tests from C2N Diagnostics, Fujirebio Diagnostics, ALZPath, Janssen, Roche Diagnostics, and Quanterix. Outcomes measures were amyloid positron emission tomography (PET), tau PET, cortical thickness, and dementia severity. Logistic regression models assessed the classification accuracies of individual or combined plasma biomarkers for binarized outcomes, and Spearman correlations evaluated continuous relationships between individual plasma biomarkers and continuous outcomes. Results: Measures of plasma p-tau217, either individually or in combination with other plasma biomarkers, had the strongest relationships with all AD outcomes. Discussion: This study identified the plasma biomarker analytes and assays that most accurately classified amyloid pathology and other AD-related outcomes. Highlights: Plasma p-tau217 measures most accurately classified amyloid and tau status. Plasma Aβ42/Aβ40 had relatively low accuracy in classification of amyloid status. Plasma p-tau217 measures had higher correlations with cortical thickness than NfL. Correlations of plasma biomarkers with dementia symptoms were relatively low.Item Longitudinal clinical, cognitive and biomarker profiles in dominantly inherited versus sporadic early-onset Alzheimer's disease(Oxford University Press, 2023-10-18) Llibre-Guerra, Jorge J.; Iaccarino, Leonardo; Coble, Dean; Edwards, Lauren; Li, Yan; McDade, Eric; Strom, Amelia; Gordon, Brian; Mundada, Nidhi; Schindler, Suzanne E.; Tsoy, Elena; Ma, Yinjiao; Lu, Ruijin; Fagan, Anne M.; Benzinger, Tammie L. S.; Soleimani-Meigooni, David; Aschenbrenner, Andrew J.; Miller, Zachary; Wang, Guoqiao; Kramer, Joel H.; Hassenstab, Jason; Rosen, Howard J.; Morris, John C.; Miller, Bruce L.; Xiong, Chengjie; Perrin, Richard J.; Allegri, Ricardo; Chrem, Patricio; Surace, Ezequiel; Berman, Sarah B.; Chhatwal, Jasmeer; Masters, Colin L.; Farlow, Martin R.; Jucker, Mathias; Levin, Johannes; Fox, Nick C.; Day, Gregory; Gorno-Tempini, Maria Luisa; Boxer, Adam L.; La Joie, Renaud; Rabinovici, Gil D.; Bateman, Randall; Neurology, School of MedicineApproximately 5% of Alzheimer's disease cases have an early age at onset (<65 years), with 5-10% of these cases attributed to dominantly inherited mutations and the remainder considered as sporadic. The extent to which dominantly inherited and sporadic early-onset Alzheimer's disease overlap is unknown. In this study, we explored the clinical, cognitive and biomarker profiles of early-onset Alzheimer's disease, focusing on commonalities and distinctions between dominantly inherited and sporadic cases. Our analysis included 117 participants with dominantly inherited Alzheimer's disease enrolled in the Dominantly Inherited Alzheimer Network and 118 individuals with sporadic early-onset Alzheimer's disease enrolled at the University of California San Francisco Alzheimer's Disease Research Center. Baseline differences in clinical and biomarker profiles between both groups were compared using t-tests. Differences in the rates of decline were compared using linear mixed-effects models. Individuals with dominantly inherited Alzheimer's disease exhibited an earlier age-at-symptom onset compared with the sporadic group [43.4 (SD ± 8.5) years versus 54.8 (SD ± 5.0) years, respectively, P < 0.001]. Sporadic cases showed a higher frequency of atypical clinical presentations relative to dominantly inherited (56.8% versus 8.5%, respectively) and a higher frequency of APOE-ε4 (50.0% versus 28.2%, P = 0.001). Compared with sporadic early onset, motor manifestations were higher in the dominantly inherited cohort [32.5% versus 16.9% at baseline (P = 0.006) and 46.1% versus 25.4% at last visit (P = 0.001)]. At baseline, the sporadic early-onset group performed worse on category fluency (P < 0.001), Trail Making Test Part B (P < 0.001) and digit span (P < 0.001). Longitudinally, both groups demonstrated similar rates of cognitive and functional decline in the early stages. After 10 years from symptom onset, dominantly inherited participants experienced a greater decline as measured by Clinical Dementia Rating Sum of Boxes [3.63 versus 1.82 points (P = 0.035)]. CSF amyloid beta-42 levels were comparable [244 (SD ± 39.3) pg/ml dominantly inherited versus 296 (SD ± 24.8) pg/ml sporadic early onset, P = 0.06]. CSF phosphorylated tau at threonine 181 levels were higher in the dominantly inherited Alzheimer's disease cohort (87.3 versus 59.7 pg/ml, P = 0.005), but no significant differences were found for t-tau levels (P = 0.35). In summary, sporadic and inherited Alzheimer's disease differed in baseline profiles; sporadic early onset is best distinguished from dominantly inherited by later age at onset, high frequency of atypical clinical presentations and worse executive performance at baseline. Despite these differences, shared pathways in longitudinal clinical decline and CSF biomarkers suggest potential common therapeutic targets for both populations, offering valuable insights for future research and clinical trial design.Item Multimodal brain age estimates relate to Alzheimer disease biomarkers and cognition in early stages: a cross-sectional observational study(eLife Sciences, 2023-01-06) Millar, Peter R.; Gordon, Brian A.; Luckett, Patrick H.; Benzinger, Tammie L. S.; Cruchaga, Carlos; Fagan, Anne M.; Hassenstab, Jason J.; Perrin, Richard J.; Schindler, Suzanne E.; Allegri, Ricardo F.; Day, Gregory S.; Farlow, Martin R.; Mori, Hiroshi; Nübling, Georg; The Dominantly Inherited Alzheimer Network; Bateman, Randall J.; Morris, John C.; Ances, Beau M.; Neurology, School of MedicineBackground: Estimates of 'brain-predicted age' quantify apparent brain age compared to normative trajectories of neuroimaging features. The brain age gap (BAG) between predicted and chronological age is elevated in symptomatic Alzheimer disease (AD) but has not been well explored in presymptomatic AD. Prior studies have typically modeled BAG with structural MRI, but more recently other modalities, including functional connectivity (FC) and multimodal MRI, have been explored. Methods: We trained three models to predict age from FC, structural (S), or multimodal MRI (S+FC) in 390 amyloid-negative cognitively normal (CN/A-) participants (18-89 years old). In independent samples of 144 CN/A-, 154 CN/A+, and 154 cognitively impaired (CI; CDR > 0) participants, we tested relationships between BAG and AD biomarkers of amyloid and tau, as well as a global cognitive composite. Results: All models predicted age in the control training set, with the multimodal model outperforming the unimodal models. All three BAG estimates were significantly elevated in CI compared to controls. FC-BAG was significantly reduced in CN/A+ participants compared to CN/A-. In CI participants only, elevated S-BAG and S+FC BAG were associated with more advanced AD pathology and lower cognitive performance. Conclusions: Both FC-BAG and S-BAG are elevated in CI participants. However, FC and structural MRI also capture complementary signals. Specifically, FC-BAG may capture a unique biphasic response to presymptomatic AD pathology, while S-BAG may capture pathological progression and cognitive decline in the symptomatic stage. A multimodal age-prediction model improves sensitivity to healthy age differences.Item Novel avenues of tau research(Wiley, 2024) Sexton, Claire E.; Bitan, Gal; Bowles, Kathryn R.; Brys, Miroslaw; Buée, Luc; Bukar Maina, Mahmoud; Clelland, Claire D.; Cohen, Ann D.; Crary, John F.; Dage, Jeffrey L.; Diaz, Kristophe; Frost, Bess; Gan, Li; Goate, Alison M.; Golbe, Lawrence I.; Hansson, Oskar; Karch, Celeste M.; Kolb, Hartmuth C.; La Joie, Renaud; Lee, Suzee E.; Matallana, Diana; Miller, Bruce L.; Onyike, Chiadi U.; Quiroz, Yakeel T.; Rexach, Jessica E.; Rohrer, Jonathan D.; Rommel, Amy; Sadri-Vakili, Ghazaleh; Schindler, Suzanne E.; Schneider, Julie A.; Sperling, Reisa A.; Teunissen, Charlotte E.; Weninger, Stacie C.; Worley, Susan L.; Zheng, Hui; Carrillo, Maria C.; Neurology, School of MedicineIntroduction: The pace of innovation has accelerated in virtually every area of tau research in just the past few years. Methods: In February 2022, leading international tau experts convened to share selected highlights of this work during Tau 2022, the second international tau conference co-organized and co-sponsored by the Alzheimer's Association, CurePSP, and the Rainwater Charitable Foundation. Results: Representing academia, industry, and the philanthropic sector, presenters joined more than 1700 registered attendees from 59 countries, spanning six continents, to share recent advances and exciting new directions in tau research. Discussion: The virtual meeting provided an opportunity to foster cross-sector collaboration and partnerships as well as a forum for updating colleagues on research-advancing tools and programs that are steadily moving the field forward.Item Proteomics of brain, CSF, and plasma identifies molecular signatures for distinguishing sporadic and genetic Alzheimer's disease(American Association for the Advancement of Science, 2023) Sung, Yun Ju; Yang, Chengran; Norton, Joanne; Johnson, Matt; Fagan, Anne; Bateman, Randall J.; Perrin, Richard J.; Morris, John C.; Farlow, Martin R.; Chhatwal, Jasmeer P.; Schofield, Peter R.; Chui, Helena; Wang, Fengxian; Novotny, Brenna; Eteleeb, Abdallah; Karch, Celeste; Schindler, Suzanne E.; Rhinn, Herve; Johnson, Erik C. B.; Oh, Hamilton Se-Hwee; Rutledge, Jarod Evert; Dammer, Eric B.; Seyfried, Nicholas T.; Wyss-Coray, Tony; Harari, Oscar; Cruchaga, Carlos; Neurology, School of MedicineProteomic studies for Alzheimer's disease (AD) are instrumental in identifying AD pathways but often focus on single tissues and sporadic AD cases. Here, we present a proteomic study analyzing 1305 proteins in brain tissue, cerebrospinal fluid (CSF), and plasma from patients with sporadic AD, TREM2 risk variant carriers, patients with autosomal dominant AD (ADAD), and healthy individuals. We identified 8 brain, 40 CSF, and 9 plasma proteins that were altered in individuals with sporadic AD, and we replicated these findings in several external datasets. We identified a proteomic signature that differentiated TREM2 variant carriers from both individuals with sporadic AD and healthy individuals. The proteins associated with sporadic AD were also altered in patients with ADAD, but with a greater effect size. Brain-derived proteins associated with ADAD were also replicated in additional CSF samples. Enrichment analyses highlighted several pathways, including those implicated in AD (calcineurin and Apo E), Parkinson's disease (α-synuclein and LRRK2), and innate immune responses (SHC1, ERK-1, and SPP1). Our findings suggest that combined proteomics across brain tissue, CSF, and plasma can be used to identify markers for sporadic and genetically defined AD.Item Recommendations for clinical implementation of blood-based biomarkers for Alzheimer's disease(Wiley, 2024) Mielke, Michelle M.; Anderson, Matthew; Ashford, J. Wesson; Jeromin, Andreas; Lin, Pei-Jung; Rosen, Allyson; Tyrone, Jamie; Vandevrede, Lawren; Willis, Deanna R.; Hansson, Oskar; Khachaturian, Ara S.; Schindler, Suzanne E.; Weiss, Joan; Batrla, Richard; Bozeat, Sasha; Dwyer, John R.; Holzapfel, Drew; Jones, Daryl Rhys; Murray, James F.; Partrick, Katherine A.; Scholler, Emily; Vradenburg, George; Young, Dylan; Braunstein, Joel B.; Burnham, Samantha C.; de Oliveira, Fabricio Ferreira; Hu, Yan Helen; Mattke, Soeren; Merali, Zul; Monane, Mark; Sabbagh, Marwan Noel; Shobin, Eli; Weiner, Michael; Udeh-Momoh, Chinedu T.; Medicine, School of MedicineBlood-based biomarkers (BBM) for Alzheimer's disease (AD) are being increasingly used in clinical practice to support an AD diagnosis. In contrast to traditional diagnostic modalities, such as amyloid positron emission tomography and cerebrospinal fluid biomarkers, BBMs offer a more accessible and lower cost alternative for AD biomarker testing. Their unique scalability addresses the anticipated surge in demand for biomarker testing with the emergence of disease-modifying treatments (DMTs) that require confirmation of amyloid pathology. To facilitate the uptake of BBMs in clinical practice, The Global CEO Initiative on Alzheimer's Disease convened a BBM Workgroup to provide recommendations for two clinical implementational pathways for BBMs: one for current use for triaging and another for future use to confirm amyloid pathology. These pathways provide a standardized diagnostic approach with guidance on interpreting BBM test results. Integrating BBMs into clinical practice will simplify the diagnostic process and facilitate timely access to DMTs for eligible patients.