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Browsing by Subject "Amyloid beta-peptides"
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Item Amyloid-Related Imaging Abnormalities in the DIAN-TU-001 Trial of Gantenerumab and Solanezumab: Lessons from a Trial in Dominantly Inherited Alzheimer Disease(Wiley, 2022) Joseph-Mathurin, Nelly; Llibre-Guerra, Jorge J.; Li, Yan; McCullough, Austin A.; Hofmann, Carsten; Wojtowicz, Jakub; Park, Ethan; Wang, Guoqiao; Preboske, Gregory M.; Wang, Qing; Gordon, Brian A.; Chen, Charles D.; Flores, Shaney; Aggarwal, Neelum T.; Berman, Sarah B.; Bird, Thomas D.; Black, Sandra E.; Borowski, Bret; Brooks, William S.; Chhatwal, Jasmeer P.; Clarnette, Roger; Cruchaga, Carlos; Fagan, Anne M.; Farlow, Martin; Fox, Nick C.; Gauthier, Serge; Hassenstab, Jason; Hobbs, Diana A.; Holdridge, Karen C.; Honig, Lawrence S.; Hornbeck, Russ C.; Hsiung, Ging-Yuek R.; Jack, Clifford R., Jr.; Jimenez-Velazquez, Ivonne Z.; Jucker, Mathias; Klein, Gregory; Levin, Johannes; Mancini, Michele; Masellis, Mario; McKay, Nicole S.; Mummery, Catherine J.; Ringman, John M.; Shimada, Hiroyuki; Snider, B. Joy; Suzuki, Kazushi; Wallon, David; Xiong, Chengjie; Yaari, Roy; McDade, Eric; Perrin, Richard J.; Bateman, Randall J.; Salloway, Stephen P.; Benzinger, Tammie L. S.; Clifford, David B.; Dominantly Inherited Alzheimer Network Trials Unit; Neurology, School of MedicineObjective: To determine the characteristics of participants with amyloid-related imaging abnormalities (ARIA) in a trial of gantenerumab or solanezumab in dominantly inherited Alzheimer disease (DIAD). Methods: 142 DIAD mutation carriers received either gantenerumab SC (n = 52), solanezumab IV (n = 50), or placebo (n = 40). Participants underwent assessments with the Clinical Dementia Rating® (CDR®), neuropsychological testing, CSF biomarkers, β-amyloid positron emission tomography (PET), and magnetic resonance imaging (MRI) to monitor ARIA. Cross-sectional and longitudinal analyses evaluated potential ARIA-related risk factors. Results: Eleven participants developed ARIA-E, including 3 with mild symptoms. No ARIA-E was reported under solanezumab while gantenerumab was associated with ARIA-E compared to placebo (odds ratio [OR] = 9.1, confidence interval [CI][1.2, 412.3]; p = 0.021). Under gantenerumab, APOE-ɛ4 carriers were more likely to develop ARIA-E (OR = 5.0, CI[1.0, 30.4]; p = 0.055), as were individuals with microhemorrhage at baseline (OR = 13.7, CI[1.2, 163.2]; p = 0.039). No ARIA-E was observed at the initial 225 mg/month gantenerumab dose, and most cases were observed at doses >675 mg. At first ARIA-E occurrence, all ARIA-E participants were amyloid-PET+, 60% were CDR >0, 60% were past their estimated year to symptom onset, and 60% had also incident ARIA-H. Most ARIA-E radiologically resolved after dose adjustment and developing ARIA-E did not significantly increase odds of trial discontinuation. ARIA-E was more frequently observed in the occipital lobe (90%). ARIA-E severity was associated with age at time of ARIA-E. Interpretation: In DIAD, solanezumab was not associated with ARIA. Gantenerumab dose over 225 mg increased ARIA-E risk, with additional risk for individuals APOE-ɛ4(+) or with microhemorrhage. ARIA-E was reversible on MRI in most cases, generally asymptomatic, without additional risk for trial discontinuation.Item Blood biomarkers for Alzheimer’s disease in clinical practice and trials(Springer Nature, 2023) Hansson, Oskar; Blennow, Kaj; Zetterberg, Henrik; Dage, Jeffrey; Neurology, School of MedicineBlood-based biomarkers hold great promise to revolutionize the diagnostic and prognostic work-up of Alzheimer's disease (AD) in clinical practice. This is very timely, considering the recent development of anti-amyloid-β (Aβ) immunotherapies. Several assays for measuring phosphorylated tau (p-tau) in plasma exhibit high diagnostic accuracy in distinguishing AD from all other neurodegenerative diseases in patients with cognitive impairment. Prognostic models based on plasma p-tau levels can also predict future development of AD dementia in patients with mild cognitive complaints. The use of such high-performing plasma p-tau assays in the clinical practice of specialist memory clinics would reduce the need for more costly investigations involving cerebrospinal fluid samples or positron emission tomography. Indeed, blood-based biomarkers already facilitate identification of individuals with pre-symptomatic AD in the context of clinical trials. Longitudinal measurements of such biomarkers will also improve the detection of relevant disease-modifying effects of new drugs or lifestyle interventions.Item Cryo-EM structures of amyloid-β 42 filaments from human brains(American Association for the Advancement of Science, 2022) Yang, Yang; Arseni, Diana; Zhang, Wenjuan; Huang, Melissa; Lövestam, Sofia; Schweighauser, Manuel; Kotecha, Abhay; Murzin, Alexey G.; Peak-Chew, Sew Y.; Macdonald, Jennifer; Lavenir, Isabelle; Garringer, Holly J.; Gelpi, Ellen; Newell, Kathy L.; Kovacs, Gabor G.; Vidal, Ruben; Ghetti, Bernardino; Falcon, Benjamin; Scheres, Sjors H.W.; Goedert, Michel; Pathology and Laboratory Medicine, School of MedicineFilament assembly of amyloid-β peptides ending at residue 42 (Aβ42) is a central event in Alzheimer’s disease. Here, we report the cryo–electron microscopy (cryo-EM) structures of Aβ42 filaments from human brains. Two structurally related S-shaped protofilament folds give rise to two types of filaments. Type I filaments were found mostly in the brains of individuals with sporadic Alzheimer’s disease, and type II filaments were found in individuals with familial Alzheimer’s disease and other conditions. The structures of Aβ42 filaments from the brain differ from those of filaments assembled in vitro. By contrast, in AppNL-F knock-in mice, Aβ42 deposits were made of type II filaments. Knowledge of Aβ42 filament structures from human brains may lead to the development of inhibitors of assembly and improved imaging agents.Item Plasma p-tau231 and p-tau217 as state markers of amyloid-β pathology in preclinical Alzheimer's disease(Springer Nature, 2022) Milà-Alomà, Marta; Ashton, Nicholas J.; Shekari, Mahnaz; Salvadó, Gemma; Ortiz-Romero, Paula; Montoliu-Gaya, Laia; Benedet, Andrea L.; Karikari, Thomas K.; Lantero-Rodriguez, Juan; Vanmechelen, Eugeen; Day, Theresa A.; González-Escalante, Armand; Sánchez-Benavides, Gonzalo; Minguillon, Carolina; Fauria, Karine; Molinuevo, José Luis; Dage, Jeffrey L.; Zetterberg, Henrik; Gispert, Juan Domingo; Suárez-Calvet, Marc; Blennow, Kaj; Neurology, School of MedicineBlood biomarkers indicating elevated amyloid-β (Aβ) pathology in preclinical Alzheimer's disease are needed to facilitate the initial screening process of participants in disease-modifying trials. Previous biofluid data suggest that phosphorylated tau231 (p-tau231) could indicate incipient Aβ pathology, but a comprehensive comparison with other putative blood biomarkers is lacking. In the ALFA+ cohort, all tested plasma biomarkers (p-tau181, p-tau217, p-tau231, GFAP, NfL and Aβ42/40) were significantly changed in preclinical Alzheimer's disease. However, plasma p-tau231 reached abnormal levels with the lowest Aβ burden. Plasma p-tau231 and p-tau217 had the strongest association with Aβ positron emission tomography (PET) retention in early accumulating regions and associated with longitudinal increases in Aβ PET uptake in individuals without overt Aβ pathology at baseline. In summary, plasma p-tau231 and p-tau217 better capture the earliest cerebral Aβ changes, before overt Aβ plaque pathology is present, and are promising blood biomarkers to enrich a preclinical population for Alzheimer's disease clinical trials.Item Publisher Correction: Plasma p-tau231 and p-tau217 as state markers of amyloid-β pathology in preclinical Alzheimer's disease(Springer Nature, 2022) Milà-Alomà, Marta; Ashton, Nicholas J.; Shekari, Mahnaz; Salvadó, Gemma; Ortiz-Romero, Paula; Montoliu-Gaya, Laia; Benedet, Andrea L.; Karikari, Thomas K.; Lantero-Rodriguez, Juan; Vanmechelen, Eugeen; Day, Theresa A.; González-Escalante, Armand; Sánchez-Benavides, Gonzalo; Minguillon, Carolina; Fauria, Karine; Molinuevo, José Luis; Dage, Jeffrey L.; Zetterberg, Henrik; Gispert, Juan Domingo; Suárez-Calvet, Marc; Blennow, Kaj; Neurology, School of MedicineThis corrects the article "Plasma p-tau231 and p-tau217 as state markers of amyloid-β pathology in preclinical Alzheimer’s disease" in Nat Med, volume 28 on page 1797.Item Signatures for Viral Infection and Inflammation in the Proximal Olfactory System in Familial Alzheimer’s Disease(Elsevier, 2023) Bubak, Andrew N.; Merle, Laetitia; Niemeyer, Christy S.; Baxter, B. Dnate’; Gentile Polese, Arianna; Ramakrishnan, Vijay; Gomez, Johana; Madrigal, Lucia; Villegas-Lanau, Andres; Lopera, Francisco; Macklin, Wendy; Frietze, Seth; Nagel, Maria A.; Restrepo, Diego; Otolaryngology -- Head and Neck Surgery, School of MedicineAlzheimer's disease (AD) is characterized by deficits in olfaction and olfactory pathology preceding diagnosis of dementia. Here we analyzed differential gene and protein expression in the olfactory bulb (OB) and tract (OT) of familial AD (FAD) individuals carrying the autosomal dominant presenilin 1 E280A mutation. Compared to control, FAD OT had increased immunostaining for β-amyloid (Aβ) and CD68 in high and low myelinated regions, as well as increased immunostaining for Iba1 in the high myelinated region. In FAD samples, RNA sequencing showed: (1) viral infection in the OB; (2) inflammation in the OT that carries information via entorhinal cortex from the OB to hippocampus, a brain region essential for learning and memory; and (3) decreased oligodendrocyte deconvolved transcripts. Interestingly, spatial proteomic analysis confirmed altered myelination in the OT of FAD individuals, implying dysfunction of communication between the OB and hippocampus. These findings raise the possibility that viral infection and associated inflammation and dysregulation of myelination of the olfactory system may disrupt hippocampal function, contributing to acceleration of FAD progression.Item The human connectome in Alzheimer disease - relationship to biomarkers and genetics(Springer Nature, 2021) Yu, Meichen; Sporns, Olaf; Saykin, Andrew J.; Radiology and Imaging Sciences, School of MedicineThe pathology of Alzheimer disease (AD) damages structural and functional brain networks, resulting in cognitive impairment. The results of recent connectomics studies have now linked changes in structural and functional network organization in AD to the patterns of amyloid-β and tau accumulation and spread, providing insights into the neurobiological mechanisms of the disease. In addition, the detection of gene-related connectome changes might aid in the early diagnosis of AD and facilitate the development of personalized therapeutic strategies that are effective at earlier stages of the disease spectrum. In this article, we review studies of the associations between connectome changes and amyloid-β and tau pathologies as well as molecular genetics in different subtypes and stages of AD. We also highlight the utility of connectome-derived computational models for replicating empirical findings and for tracking and predicting the progression of biomarker-indicated AD pathophysiology.Item Thiophene‐Based Optical Ligands That Selectively Detect Aβ Pathology in Alzheimer's Disease(Wiley, 2021-08-03) Klingstedt, Therése; Shirani, Hamid; Ghetti, Bernardino; Nilsson, K. Peter R.; Pathology and Laboratory Medicine, School of MedicineIn several neurodegenerative diseases, the presence of aggregates of specific proteins in the brain is a significant pathological hallmark; thus, developing ligands able to bind to the aggregated proteins is essential for any effort related to imaging and therapeutics. Here we report the synthesis of thiophene‐based ligands containing nitrogen heterocycles. The ligands selectively recognized amyloid‐β (Aβ) aggregates in brain tissue from individuals diagnosed neuropathologically as having Alzheimer's disease (AD). The selectivity for Aβ was dependent on the position of nitrogen in the heterocyclic compounds, and the ability to bind Aβ was shown to be reduced when introducing anionic substituents on the thiophene backbone. Our findings provide the structural and functional basis for the development of ligands that can differentiate between aggregated proteinaceous species comprised of distinct proteins. These ligands might also be powerful tools for studying the pathogenesis of Aβ aggregation and for designing molecules for imaging of Aβ pathology.