73 results on '"Salvadó G"'
Search Results
2. DHA intake relates to better cerebrovascular and neurodegeneration neuroimaging phenotypes in middle-aged adults at increased genetic risk of Alzheimer disease
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Sala-Vila, A. Arenaza-Urquijo, E.M. Sánchez-Benavides, G. Suárez-Calvet, M. Milà-Alomà, M. Grau-Rivera, O. González-De-Echávarri, J.M. Crous-Bou, M. Minguillón, C. Fauria, K. Operto, G. Falcón, C. Salvadó, G. Cacciaglia, R. Ingala, S. Barkhof, F. Schröder, H. Scarmeas, N. Gispert, J.-D. Molinuevo, J.L. ALFA study
- Abstract
Background: The number of APOE-ϵ4 alleles is a major nonmodifiable risk factor for sporadic Alzheimer disease (AD). There is increasing evidence on the benefits of dietary DHA (22:6n-3) before the onset of AD symptoms, particularly in APOE-ϵ4 carriers. Brain alterations in the preclinical stage can be detected by structural MRI. Objectives: We aimed, in middle-aged cognitively unimpaired individuals at increased risk of AD, to cross-sectionally investigate whether dietary DHA intake relates to cognitive performance and to MRI-based markers of cerebral small vessel disease and AD-related neurodegeneration, exploring the effect modification by APOE-ϵ4 status. Methods: In 340 participants of the ALFA (ALzheimer and FAmilies) study, which is enriched for APOE-ϵ4 carriership (n = 122, noncarriers; n = 157, 1 allele; n = 61, 2 alleles), we assessed self-reported DHA intake through an FFQ. We measured cognitive performance by administering episodic memory and executive function tests. We performed high-resolution structural MRI to assess cerebral small vessel disease [white matter hyperintensities (WMHs) and cerebral microbleeds (CMBs)] and AD-related brain atrophy (cortical thickness in an AD signature). We constructed regression models adjusted for potential confounders, exploring the interaction DHA × APOE-ϵ4. Results: We observed no significant associations between DHA and cognitive performance or WMH burden. We observed a nonsignificant inverse association between DHA and prevalence of lobar CMBs (OR: 0.446; 95% CI: 0.195, 1.018; P = 0.055). DHA was found to be significantly related to greater cortical thickness in the AD signature in homozygotes but not in nonhomozygotes (P-interaction = 0.045). The association strengthened when analyzing homozygotes and nonhomozygotes matched for risk factors. Conclusions: In cognitively unimpaired APOE-ϵ4 homozygotes, dietary DHA intake related to structural patterns that may result in greater resilience to AD pathology. This is consistent with the current hypothesis that those subjects at highest risk would obtain the largest benefits from DHA supplementation in the preclinical stage. This trial was registered at clinicaltrials.gov as NCT01835717. © 2021 The Author(s). Published by Oxford University Press on behalf of the American Society for Nutrition.
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- 2021
3. Multi-tracer model for staging cortical amyloid deposition using PET imaging
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Collij, L. E., Markiewicz, P., Golla, S. S. V., Wottschel, V., Wink, A. M., Visser, P. J., Teunissen, C. E., Lammertsma, A. A., Scheltens, P., van der Flier, W. M., Boellaard, R., Heeman, F., van Berckel, B. N. M., Molinuevo, J. L., Gispert, J. D., Schmidt, M. E., Bsarkhof, F., Alves, I. L., ALFA Study for the Alzheimer’s Disease Neuroimaging Initiative, Salvadó, G., Ingala, S., Altomare, D., Wilde, A., Konijnenberg, E., van Buchem, M., and Yaqub, M.
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mental disorders - Abstract
OBJECTIVE: To develop and evaluate a model for staging cortical amyloid deposition using PET with high generalizability. METHODS: 3027 subjects (1763 Cognitively Unimpaired (CU), 658 Impaired, 467 Alzheimer's disease (AD) dementia, 111 non-AD dementia, and 28 with missing diagnosis) from six cohorts (EMIF-AD, ALFA, ABIDE, ADC, OASIS-3, ADNI) who underwent amyloid PET were retrospectively included; 1049 subjects had follow-up scans. Applying dataset-specific cut-offs to global Standard Uptake Value ratio (SUVr) values from 27 regions, single-tracer and pooled multi-tracer regional rankings were constructed from the frequency of abnormality across 400 CU subjects (100 per tracer). The pooled multi-tracer ranking was used to create a staging model consisting of four clusters of regions as it displayed a high and consistent correlation with each single-tracer ranking. Relationships between amyloid stage, clinical variables and longitudinal cognitive decline were investigated. RESULTS: SUVr abnormality was most frequently observed in cingulate, followed by orbitofrontal, precuneal, and insular cortices, then the associative, temporal and occipital regions. Abnormal amyloid levels based on binary global SUVr classification were observed in 1.0%, 5.5%, 17.9%, 90.0%, and 100.0% of stage 0-4 subjects, respectively. Baseline stage predicted decline in MMSE (ADNI: N=867, F=67.37, p3000 subjects across cohorts and radiotracers, and detects pre-global amyloid burden and distinct risk profiles of cognitive decline within globally amyloid-positive subjects.
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- 2020
4. Amyloid beta, tau, synaptic, neurodegeneration, and glial biomarkers in the preclinical stage of the Alzheimer's continuum
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Milà-Alomà, M. (Marta), Salvadó, G. (Gemma), Gispert, J.D. (Juan Domingo), Vilor-Tejedor, N. (Natàlia), Grau-Rivera, O. (Oriol), Sala-Vila, A. (Aleix), Sánchez-Benavides, G. (Gonzalo), Arenaza-Urquijo, E.M. (Eider M.), Crous-Bou, M. (Marta), González-de-Echávarri, J.M. (José Maria), Minguillon, C. (Carolina), Fauria, K. (Karine), Simon, M. (Maryline), Kollmorgen, G. (Gwendlyn), Zetterberg, H. (Henrik), Blennow, K. (Kaj), Suárez-Calvet, M. (Marc), Molinuevo, J.L. (José Luis), Milà-Alomà, M. (Marta), Salvadó, G. (Gemma), Gispert, J.D. (Juan Domingo), Vilor-Tejedor, N. (Natàlia), Grau-Rivera, O. (Oriol), Sala-Vila, A. (Aleix), Sánchez-Benavides, G. (Gonzalo), Arenaza-Urquijo, E.M. (Eider M.), Crous-Bou, M. (Marta), González-de-Echávarri, J.M. (José Maria), Minguillon, C. (Carolina), Fauria, K. (Karine), Simon, M. (Maryline), Kollmorgen, G. (Gwendlyn), Zetterberg, H. (Henrik), Blennow, K. (Kaj), Suárez-Calvet, M. (Marc), and Molinuevo, J.L. (José Luis)
- Abstract
INTRODUCTION: The biological pathways involved in the preclinical stage of the Alzheimer's continuum are not well understood. METHODS: We used NeuroToolKit and Elecsys® immunoassays to measure cerebrospinal fluid (
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- 2020
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5. Comparative Analysis of Different Definitions of Amyloid-β Positivity to Detect Early Downstream Pathophysiological Alterations in Preclinical Alzheimer
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Milà-Alomà, M., primary, Salvadó, G., additional, Shekari, M., additional, Grau-Rivera, O., additional, Sala-Vila, A., additional, Sánchez-Benavides, G., additional, Arenaza-Urquijo, E.M., additional, González-de-Echávarri, J.M., additional, Simon, M., additional, Kollmorgen, G., additional, Zetterberg, H., additional, Blennow, K., additional, and Gispert, J.D., additional
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- 2020
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6. Factor estimulante de colonias granulocíticas en prevención de sepsis nosocomial del prematuro: estudio doble ciego randomizado, controlado
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Lina Sánchez G., Marianela García S., Pamela Ramolfo B., Irene Rojas E., Jimena Núñez C., Marisol Escobar M., Antonio Salvadó G., Jane Standen H., and Inés Aguayo T.
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medicine.medical_specialty ,Pediatrics ,business.industry ,infección nosocomial ,Neutropenia ,medicine.disease ,rH-GCSF ,Neutrophilia ,law.invention ,Sepsis ,premature neonate ,prematuros ,Randomized controlled trial ,Infectious disease (medical specialty) ,law ,nosocomial infection ,Pediatrics, Perinatology and Child Health ,Hospital-acquired infection ,medicine ,Neonatology ,medicine.symptom ,business ,Prospective cohort study - Abstract
Resumen El recién nacido presenta con frecuencia infecciones bacterianas severas que pueden o no acompañarse de neutropenia, las que se ven favorecidas por una insuficiencia cualitativa y cuantitativa del sistema fagocítico neutrófilo en esta etapa de la vida. Lo anterior se acentúa aún más en el prematuro, lo que contribuye a altas tasas de morbimortalidad por infección. Publicaciones recientes sugieren la utilidad del factor estimulante de colonias granulocíticas (rH-GCF). El objetivo de nuestro estudio fue la evaluación prospectiva del uso precoz de rH-GCSF en prevención de sepsis nosocomial. Pacientes y Métodos: Se estudiaron 68 recién nacidos pretérmino de menos de 32 semanas de edad gestacional y peso inferior a 1 500 g, libres de infección clínica. 34 de ellos fueron asignados a tratamiento diario por un período de 15 días con rH-GCSF desde antes de las 72 horas de vida; la asignación se realizó en forma ciega y randomizada por tablas de números al azar. Resultados: la morbilidad infecciosa tanto sospechada como confirmada no mostró diferencias entre ambos grupos, a pesar de lograr una neutrofilia significativa. Conclusión: En este estudio, rH-GCF no demostró ser útil en la prevención de sepsis de origen intrahospitalario Neonates often develop severe bacterial infections, at this age there is a failure in the quantity and quality of the phagocytic system, often associated with a neutropenia. This is usually more severe in the premature contributing to the higher mortality seen in this group. Recent publications favour the use of GCSF for the prevention of nosocomial infections. This was a prospective study to evaluate the early use of GCSF in the prevention of hospital acquired infection in preterm neonates. 34 preterms were randomized to treatment with GCSF and 34 to the placebo group. In this double blind trial there was no reduction in infections in this group of patients inspite of achieving a significant neutrophilia. Conclusions: In this trial GCSF was not useful in the prevention of nosocomial infections in premature neonates
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- 2002
7. Uso precoz de la eritropoyetina en la prevención de la anemia del prematuro
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Lina Sánchez G., Jane Standen H., Antonio Salvadó G, Alejandra Núñez C, Angela Cabello M, Marisol Escobar M., Inés Aguayo T, and Pamela Ramolfo B.
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Gynecology ,Pediatrics ,medicine.medical_specialty ,Anemia ,business.industry ,Infant, low birth weight ,General Medicine ,medicine.disease ,Placebo ,Anemia neonatal ,law.invention ,Low birth weight ,medicine.anatomical_structure ,Reticulocyte ,Randomized controlled trial ,Reticulocyte count ,Erythropoietin ,law ,hemic and lymphatic diseases ,medicine ,Active treatment ,medicine.symptom ,business ,medicine.drug - Abstract
Background: Anemia is common among very low birth weight newborns and requires frequent blood tranfusions. Erythropoietin was been reported to be useful in the prevention of this anemia. Aim: To asses the benefits of early (before the third week of life) Human recombinant Erythropoietin (r-EPO) administration to reduce the requirement of blood tranfusions in very low birth weight newborns. Patients and methods: sixty newborns under 1500g of birthweight were randomly assigned to recive r-EPO (n=29) or placebo (n=31) three times per week, during four weeks. Packed red cell volume and reticulocyte counts were measured weekly. Serum erythropoietin was measured prior to eigth dose. Transfusion requirements were recorded. Results: r-EPO reduced transfusions from 1.41 ± 1.1 to 0.69 ± 1 transfusions/newborns (p
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- 2000
8. Uso precoz de la eritropoyetina en la prevención de la anemia del prematuro
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Salvadó G, Antonio, Ramolfo B, Pamela, Escobar M, Marisol, Núñez C, Alejandra, Aguayo T, Inés, Standen H, Jane, Sánchez G, Lina, and Cabello M, Angela
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hemic and lymphatic diseases ,Infant, low birth weight ,Anemia neonatal ,Erythropoietin - Abstract
Background: Anemia is common among very low birth weight newborns and requires frequent blood tranfusions. Erythropoietin was been reported to be useful in the prevention of this anemia. Aim: To asses the benefits of early (before the third week of life) Human recombinant Erythropoietin (r-EPO) administration to reduce the requirement of blood tranfusions in very low birth weight newborns. Patients and methods: sixty newborns under 1500g of birthweight were randomly assigned to recive r-EPO (n=29) or placebo (n=31) three times per week, during four weeks. Packed red cell volume and reticulocyte counts were measured weekly. Serum erythropoietin was measured prior to eigth dose. Transfusion requirements were recorded. Results: r-EPO reduced transfusions from 1.41 ± 1.1 to 0.69 ± 1 transfusions/newborns (p
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- 2000
9. Factor estimulante de colonias granulocíticas en prevención de sepsis nosocomial del prematuro: estudio doble ciego randomizado, controlado
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Salvadó G., Antonio, primary, Ramolfo B., Pamela, additional, Escobar M., Marisol, additional, Núñez C., Jimena, additional, Aguayo T., Inés, additional, Sánchez G., Lina, additional, Standen H., Jane, additional, García S., Marianela, additional, and Rojas E., Irene, additional
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- 2002
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10. Uso precoz de la eritropoyetina en la prevención de la anemia del prematuro
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Salvadó G, Antonio, primary, Ramolfo B, Pamela, additional, Escobar M, Marisol, additional, Núñez C, Alejandra, additional, Aguayo T, Inés, additional, Standen H, Jane, additional, Sánchez G, Lina, additional, and Cabello M, Angela, additional
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- 2000
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11. Vitamin D receptor gene polymorphism and bone mass in primary biliary cirrhosis
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Parés, A., primary, Guañabens, N., additional, Martínez de Osaba, MJ., additional, Oriola, J., additional, Pons, F., additional, Monegal, A., additional, Salvadó, G., additional, Peris, P., additional, Rivera, F., additional, and Rodés, J., additional
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- 1998
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12. Retrospective study: 8 years of obstrutive sleep apnea analysis
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Araújo, C., Pimentel, C., and Salvado, G.
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- 2013
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13. Efecto del Clenbuterol en el Asma Inducido por Ejercicio en Niños
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Manuel Yanez Z, Antonio Salvadó G., and Beatriz Robles U
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Exercise-induced asthma ,Inhalation ,business.industry ,Pharmacology ,medicine.disease ,clenbuterol ,asma ,Asthmatic children ,Clenbuterol ,Pediatrics, Perinatology and Child Health ,Medicine ,ejercicio ,business ,Asthma ,medicine.drug - Abstract
Clenbuterol, a Beta-2 Sympathomimetic was administered by inhalation to fourteen asthmatic children asprofilaxis for Exercise Induced Asthma (EIA). Our results sugest that Clenbuterol is a valuable drug whenadministered five minutes before exercise. New studies are on their way in order to see if it offers some advantageover other drugs of the same chemical group, which are already known to be useful in the pro filaxis of KIA.(Key words: Clenbuterol. Asthma. Kxercise).
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- 1985
14. The statuary condition in contemporary Portuguese cinema,La condición estatuaria en el cine Portugués contemporáneo
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Salvadó, G. and Fran Benavente
15. Blood Biomarkers to Detect Alzheimer Disease in Primary Care and Secondary Care.
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Palmqvist S, Tideman P, Mattsson-Carlgren N, Schindler SE, Smith R, Ossenkoppele R, Calling S, West T, Monane M, Verghese PB, Braunstein JB, Blennow K, Janelidze S, Stomrud E, Salvadó G, and Hansson O
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- Aged, Aged, 80 and over, Female, Humans, Male, Middle Aged, Cognitive Dysfunction diagnosis, Cognitive Dysfunction blood, Phosphorylation, Prospective Studies, Sensitivity and Specificity, Sweden, Alzheimer Disease diagnosis, Alzheimer Disease blood, Amyloid beta-Peptides blood, Biomarkers blood, Peptide Fragments blood, Primary Health Care, Secondary Care, tau Proteins blood
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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.
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- 2024
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16. Proteomic changes in Alzheimer's disease associated with progressive Aβ plaque and tau tangle pathologies.
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Pichet Binette A, Gaiteri C, Wennström M, Kumar A, Hristovska I, Spotorno N, Salvadó G, Strandberg O, Mathys H, Tsai LH, Palmqvist S, Mattsson-Carlgren N, Janelidze S, Stomrud E, Vogel JW, and Hansson O
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- Humans, Female, Aged, Male, Aged, 80 and over, Proteome metabolism, Brain metabolism, Brain pathology, Biomarkers metabolism, Alzheimer Disease metabolism, Alzheimer Disease pathology, tau Proteins metabolism, Plaque, Amyloid pathology, Plaque, Amyloid metabolism, Proteomics methods, Amyloid beta-Peptides metabolism, Neurofibrillary Tangles pathology, Neurofibrillary Tangles metabolism
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Proteomics can shed light on the dynamic and multifaceted alterations in neurodegenerative disorders like Alzheimer's disease (AD). Combining radioligands measuring β-amyloid (Aβ) plaques and tau tangles with cerebrospinal fluid proteomics, we uncover molecular events mirroring different stages of AD pathology in living humans. We found 127 differentially abundant proteins (DAPs) across the AD spectrum. The strongest Aβ-related proteins were mainly expressed in glial cells and included SMOC1 and ITGAM. A dozen proteins linked to ATP metabolism and preferentially expressed in neurons were independently associated with tau tangle load and tau accumulation. Only 20% of the DAPs were also altered in other neurodegenerative diseases, underscoring AD's distinct proteome. Two co-expression modules related, respectively, to protein metabolism and microglial immune response encompassed most DAPs, with opposing, staggered trajectories along the AD continuum. We unveil protein signatures associated with Aβ and tau proteinopathy in vivo, offering insights into complex neural responses and potential biomarkers and therapeutics targeting different disease stages., (© 2024. The Author(s).)
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- 2024
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17. Plasma Phosphorylated Tau 217 and Aβ42/40 to Predict Early Brain Aβ Accumulation in People Without Cognitive Impairment.
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Janelidze S, Barthélemy NR, Salvadó G, Schindler SE, Palmqvist S, Mattsson-Carlgren N, Braunstein JB, Ovod V, Bollinger JG, He Y, Li Y, Raji CA, Morris JC, Holtzman DM, Ashton NJ, Blennow K, Stomrud E, Bateman RJ, and Hansson O
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- Humans, Female, Male, Aged, Longitudinal Studies, Middle Aged, Phosphorylation, Aged, 80 and over, Cognitive Dysfunction blood, Amyloid beta-Peptides blood, Amyloid beta-Peptides metabolism, tau Proteins blood, Biomarkers blood, Peptide Fragments blood, Peptide Fragments cerebrospinal fluid, Brain diagnostic imaging, Brain metabolism, Positron-Emission Tomography
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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.
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- 2024
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18. Continuous β-Amyloid CSF/PET Imbalance Model to Capture Alzheimer Disease Heterogeneity.
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Mastenbroek SE, Sala A, Vállez García D, Shekari M, Salvadó G, Lorenzini L, Pieperhoff L, Wink AM, Lopes Alves I, Wolz R, Ritchie C, Boada M, Visser PJ, Bucci M, Farrar G, Hansson O, Nordberg AK, Ossenkoppele R, Barkhof F, Gispert JD, Rodriguez-Vieitez E, and Collij LE
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- Humans, Female, Male, Aged, Peptide Fragments cerebrospinal fluid, Aged, 80 and over, Cognitive Dysfunction cerebrospinal fluid, Cognitive Dysfunction diagnostic imaging, Middle Aged, Alzheimer Disease cerebrospinal fluid, Alzheimer Disease diagnostic imaging, Amyloid beta-Peptides cerebrospinal fluid, Positron-Emission Tomography, Biomarkers cerebrospinal fluid
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Background and Objectives: Discordance between CSF and PET biomarkers of β-amyloid (Aβ) might reflect an imbalance between soluble and aggregated species, possibly reflecting disease heterogeneity. Previous studies generally used binary cutoffs to assess discrepancies in CSF/PET biomarkers, resulting in a loss of information on the extent of discordance. In this study, we (1) jointly modeled Aβ-CSF/PET data to derive a continuous measure of the imbalance between soluble and fibrillar pools of Aβ, (2) investigated factors contributing to this imbalance, and (3) examined associations with cognitive trajectories., Methods: Across 822 cognitively unimpaired (n = 261) and cognitively impaired (n = 561) Alzheimer's Disease Neuroimaging Initiative individuals (384 [46.7%] females, mean age 73.0 ± 7.4 years), we fitted baseline CSF-Aβ
42 and global Aβ-PET to a hyperbolic regression model, deriving a participant-specific Aβ-aggregation score (standardized residuals); negative values represent more soluble relative to aggregated Aβ and positive values more aggregated relative to soluble Aβ. Using linear models, we investigated whether methodological factors, demographics, CSF biomarkers, and vascular burden contributed to Aβ-aggregation scores. With linear mixed models, we assessed whether Aβ-aggregation scores were predictive of cognitive functioning. Analyses were repeated in an early independent validation cohort of 383 Amyloid Imaging to Prevent Alzheimer's Disease Prognostic and Natural History Study individuals (224 [58.5%] females, mean age 65.2 ± 6.9 years)., Results: The imbalance model could be fit (pseudo- R2 = 0.94) in both cohorts, across CSF kits and PET tracers. Although no associations were observed with the main methodological factors, lower Aβ-aggregation scores were associated with larger ventricular volume (β = 0.13, p < 0.001), male sex (β = -0.18, p = 0.019), and homozygous APOE -ε4 carriership (β = -0.56, p < 0.001), whereas higher scores were associated with increased uncorrected CSF p-tau (β = 0.17, p < 0.001) and t-tau (β = 0.16, p < 0.001), better baseline executive functioning (β = 0.12, p < 0.001), and slower global cognitive decline (β = 0.14, p = 0.006). In the validation cohort, we replicated the associations with APOE -ε4, CSF t-tau, and, although modestly, with cognition., Discussion: We propose a novel continuous model of Aβ CSF/PET biomarker imbalance, accurately describing heterogeneity in soluble vs aggregated Aβ pools in 2 independent cohorts across the full Aβ continuum. Aβ-aggregation scores were consistently associated with genetic and AD-associated CSF biomarkers, possibly reflecting disease heterogeneity beyond methodological influences.- Published
- 2024
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19. A Comprehensive Head-to-Head Comparison of Key Plasma Phosphorylated Tau 217 Biomarker Tests.
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Warmenhoven N, Salvadó G, Janelidze S, Mattsson-Carlgren N, Bali D, Dolado AO, Kolb H, Triana-Baltzer G, Barthélemy NR, Schindler SE, Aschenbrenner AJ, Raji CA, Benzinger TLS, Morris JC, Ibanez L, Timsina J, Cruchaga C, Bateman RJ, Ashton N, Arslan B, Zetterberg H, Blennow K, Pichet Binette A, and Hansson O
- Abstract
Plasma phosphorylated-tau 217 (p-tau217) is currently the most promising biomarkers for reliable detection of Alzheimer's disease (AD) pathology. Various p-tau217 assays have been developed, but their relative performance is unclear. We compared key plasma p-tau217 tests using cross-sectional and longitudinal measures of amyloid-β (Aβ)-PET, tau-PET, and cognition as outcomes, and benchmarked them against cerebrospinal fluid (CSF) biomarker tests. Samples from 998 individuals (mean[range] age 68.5[20.0-92.5], 53% female) from the Swedish BioFINDER-2 cohort were analyzed. Plasma p-tau217 was measured with mass spectrometry (MS) assays (the ratio between phosphorylated and non-phosphorylated [%p-tau217
WashU ]and ptau217WashU ) as well as with immunoassays (p-tau217Lilly , p-tau217Janssen , p-tau217ALZpath ). CSF biomarkers included p-tau217Lilly , and the FDA-approved p-tau181/Aβ42Elecsys and p-tau181Elecsys . All plasma p-tau217 tests exhibited high ability to detect abnormal Aβ-PET (AUC range: 0.91-0.96) and tau-PET (AUC range: 0.94-0.97). Plasma %p-tau217WashU had the highest performance, with significantly higher AUCs than all the immunoassays ( Pdiff <0.007). For detecting Aβ-PET status, %p-tau217WashU had an accuracy of 0.93 (immunoassays: 0.83-0.88), sensitivity of 91% (immunoassays: 84-87%), and a specificity of 94% (immunoassays: 85-89%). Among immunoassays, p-tau217Lilly and plasma p-tau217ALZpath had higher AUCs than plasma p-tau217Janssen for Aβ-PET status ( Pdiff <0.006), and p-tau217Lilly outperformed plasma p-tau217ALZpath for tau-PET status ( Pdiff =0.025). Plasma %p-tau217WashU exhibited higher associations with all PET load outcomes compared to immunoassays; baseline Aβ-PET load (R2 : 0.72; immunoassays: 0.47-0.58; Pdiff <0.001), baseline tau-PET load (R2 : 0.51; immunoassays: 0.38-0.45; Pdiff <0.001), longitudinal Aβ-PET load (R2 : 0.53; immunoassays: 0.31-0.38; Pdiff <0.001) and longitudinal tau-PET load (R2 : 0.50; immunoassays: 0.35-0.43; Pdiff <0.014). Among immunoassays, plasma p-tau217Lilly was more strongly associated with Aβ-PET load than plasma p-tau217Janssen ( Pdiff <0.020) and with tau-PET load than both plasma p-tau217Janssen and plasma p-tau217ALZpath (all Pdiff <0.010). Plasma %p-tau217 also correlated more strongly with baseline cognition (Mini-Mental State Examination[MMSE]) than all immunoassays (R2 %p-tau217WashU : 0.33; immunoassays: 0.27-0.30; Pdiff <0.024). The main results were replicated in an external cohort from Washington University in St Louis ( n =219). Finally, p-tau217Nulisa showed similar performance to other immunoassays in subsets of both cohorts. In summary, both MS- and immunoassay-based p-tau217 tests generally perform well in identifying Aβ-PET, tau-PET, and cognitive abnormalities, but %p-tau217WashU performed significantly better than all the examined immunoassays. Plasma %p-tau217 may be considered as a stand-alone confirmatory test for AD pathology, while some immunoassays might be better suited as triage tests where positive results are confirmed with a second test., Competing Interests: N.W, G.S, S.J, N.M.C, D.B, A.O.D, H.K, A.A, C.A.R, T.L.S.B, J.C.M, L.I, J.T, N.J.A., B.A, K.B, and A.P.B report no competing interests. N.R.B is co-inventor on a US patent application “Methods to detect novel tau species in CSF and use thereof to track tau neuropathology in Alzheimer’s disease and other tauopathies,” and “CSF phosphorylated tau and Amyloid beta profiles as biomarkers of tauopathies.” N.R.B is co-inventors on a non-provisional patent application “Methods of Diagnosing and Treating Based on Site-Specific Tau Phosphorylation.” NRB receives royalty income based on technology (blood plasma assay and methods of diagnosing AD with phosphorylation changes) licensed by Washington University to C2N Diagnostics. N.R.B. and R.J.B. are co-inventors on US patent applications: ‘Methods to detect novel tau species in CSF and use thereof to track tau neuropathology in Alzheimer’s disease and other tauopathies’ and ‘CSF phosphorylated tau and amyloid beta profiles as biomarkers of tauopathies’. G.T.B is an employee of Johnson and Johnson Innovative Medicine. S.E.S has received consultancy/speaker fees from Eisai, Eli Lilly, and Novo Nordisk. C.C has received research support from: GSK and EISAI. C.C is a member of the scientific advisory board of Circular Genomics and owns stocks. C.C is a member of the scientific advisory board of Admit. H.Z. has served at scientific advisory boards and/or as a consultant for Abbvie, Acumen, Alector, Alzinova, ALZPath, Amylyx, Annexon, Apellis, Artery Therapeutics, AZTherapies, Cognito Therapeutics, CogRx, Denali, Eisai, LabCorp, Merry Life, Nervgen, Novo Nordisk, Optoceutics, Passage Bio, Pinteon Therapeutics, Prothena, Red Abbey Labs, reMYND, Roche, Samumed, Siemens Healthineers, Triplet Therapeutics, and Wave, has given lectures in symposia sponsored by Alzecure, Biogen, Cellectricon, Fujirebio, Lilly, Novo Nordisk, and Roche, and is a cofounder of Brain Biomarker Solutions in Gothenburg AB (BBS), which is a part of the GU Ventures Incubator Program (outside submitted work). N.R.B. and R.J.B. are co-inventors on a non-provisional patent application: ‘Methods of diagnosing and treating based on site-specific tau phosphorylation’. R.J.B. co-founded C2N Diagnostics. Washington University and R.J.B. have equity ownership interest in C2N Diagnostics and receive royalty income based on technology (stable isotope labeling kinetics, blood plasma assay and methods of diagnosing Alzheimer’s disease with phosphorylation changes) that is licensed by Washington University to C2N Diagnostics. R.J.B. receives income from C2N Diagnostics for serving on the scientific advisory board. R.J.B. has received research funding from Avid Radiopharmaceuticals, Janssen, Roche/Genentech, Eli Lilly, Eisai, Biogen, AbbVie, Bristol Myers Squibb and Novartis. O.H. has acquired research support (for the institution) from AVID Radiopharmaceuticals, Biogen, C2N Diagnostics, Eli Lilly, Eisai, Fujirebio, GE Healthcare, and Roche. In the past 2 years, he has received consultancy/speaker fees from Alzpath, BioArctic, Biogen, Bristol Meyer Squibb, Eisai, Eli Lilly, Fujirebio, Merck, Novartis, Novo Nordisk, Roche, Sanofi and Siemens.- Published
- 2024
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20. Prediction of future cognitive decline among cognitively unimpaired individuals using measures of soluble phosphorylated tau or tau tangle pathology.
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Ossenkoppele R, Salvadó G, Janelidze S, Binette AP, Bali D, Karlsson L, Palmqvist S, Mattsson-Carlgren N, Stomrud E, Therriault J, Rahmouni N, Rosa-Neto P, Coomans EM, van de Giessen E, van der Flier WM, Teunissen CE, Jonaitis EM, Johnson SC, Villeneuve S, Benzinger TLS, Schindler SE, Bateman RJ, Doecke JD, Doré V, Feizpour A, Masters CL, Rowe C, Wiste HJ, Petersen RC, Jack CR Jr, and Hansson O
- Abstract
Plasma p-tau217 and Tau-PET are strong prognostic biomarkers in Alzheimer's disease (AD), but their relative performance in predicting future cognitive decline among cognitively unimpaired (CU) individuals is unclear. In this head-to-head comparison study including 9 cohorts and 1534 individuals, we found that plasma p-tau217 and medial temporal lobe Tau-PET signal showed similar associations with cognitive decline on a global cognitive composite test (R
2 PET =0.32 vs R2 PLASMA =0.32, pdifference =0.812) and with progression to mild cognitive impairment (Hazard ratio[HR]PET =1.56[1.43-1.70] vs HRPLASMA =1.63[1.50-1.77], pdifference =0.627). Combined plasma and PET models were superior to the single biomarker models (R2 =0.36, p<0.01). Furthermore, sequential selection using plasma p-tau217 and then Tau-PET reduced the number of participants required for a clinical trial by 94%, compared to a 75% reduction when using plasma p-tau217 alone. We conclude that plasma p-tau217 and Tau-PET showed similar performance for predicting future cognitive decline in CU individuals, and their sequential use (i.e., plasma p-tau217 followed by Tau-PET in a subset with high plasma p-tau217) is useful for screening in clinical trials in preclinical AD., Competing Interests: DECLARATION OF INTERESTS R.O. has received research support from Avid Radiopharmaceuticals, Janssen Research & Development, Roche, Quanterix and Optina Diagnostics. He has given lectures in symposia sponsored by GE Healthcare and serves on advisory boards for Asceneuron and Bristol Myers Squibb. SP has acquired research support (for the institution) from ki elements / ADDF and Avid. In the past 2 years, he has received consultancy/speaker fees from Bioartic, Biogen, Esai, Lilly, and Roche. Research programs of WF have been funded by ZonMW, NWO, EU-JPND, EU-IHI, Alzheimer Nederland, Hersenstichting CardioVascular Onderzoek Nederland, Health~Holland, Topsector Life Sciences & Health, stichting Dioraphte, Gieskes-Strijbis fonds, stichting Equilibrio, Edwin Bouw fonds, Pasman stichting, stichting Alzheimer & Neuropsychiatrie Foundation, Philips, Biogen MA Inc, Novartis-NL, Life-MI, AVID, Roche BV, Fujifilm, Eisai, Combinostics. WF holds the Pasman chair. WF is recipient of ABOARD, which is a public-private partnership receiving funding from ZonMW (#73305095007) and Health~Holland, Topsector Life Sciences & Health (PPP-allowance; #LSHM20106). WF is recipient of TAP-dementia (www.tap-dementia.nl), receiving funding from ZonMw (#10510032120003) in the context of Onderzoeksprogramma Dementie, part of the Dutch National Dementia Strategy. TAP-dementia receives co-financing from Avid Radiopharmaceuticals and Amprion. Gieskes-Strijbis fonds also contributes to TAP-dementia. WF has been an invited speaker at Biogen MA Inc, Danone, Eisai, WebMD Neurology (Medscape), NovoNordisk, Springer Healthcare, European Brain Council. WF is consultant to Oxford Health Policy Forum CIC, Roche, Biogen MA Inc, and Eisai. WF participated in advisory boards of Biogen MA Inc, Roche, and Eli Lilly. WF is member of the steering committee of EVOKE/EVOKE+ (NovoNordisk). All funding is paid to her institution. WF is member of the steering committee of PAVE, and Think Brain Health. WF was associate editor of Alzheimer, Research & Therapy in 2020/2021. WF is associate editor at Brain. EvdG has performed contract research for Heuron Inc. and Roche. EvdG has a consultancy agreement with IXICO and Life Molecular Imaging for reading PET scans. CET has research contracts with Acumen, ADx Neurosciences, AC-Immune, Alamar, Aribio, Axon Neurosciences, Beckman-Coulter, BioConnect, Bioorchestra, Brainstorm Therapeutics, Celgene, Cognition Therapeutics, EIP Pharma, Eisai, Eli Lilly, Fujirebio, Instant Nano Biosensors, Novo Nordisk, Olink, PeopleBio, Quanterix, Roche, Toyama, Vivoryon. She is editor in chief of Alzheimer Research and Therapy, and serves on editorial boards of Medidact Neurologie/Springer, and Neurology: Neuroimmunology & Neuroinflammation. She had consultancy/speaker contracts for Eli Lilly, Merck, Novo Nordisk, Olink and Roche. SES has served as a consultant to Eisai and Novo Nordisk and has received speaker fees from Eli Lilly and Medscape. She has analyzed biomarker data provided by C2N Diagnostics. JT has served as a consultant for the Neurotorium educational platform and for Alzheon. PR-N has served at scientific advisory boards and/or as a consultant for Roche, Novo Nordisk, Eisai, and Cerveau radiopharmaceuticals. CCR has received research grants from NHMRC, Enigma Australia, Biogen, Eisai and Abbvie. He is on the scientific advisory board for Enigma/Mellieur Technologies and has consulted for Prothena, Eisai, Roche, and Biogen Australia. RJB laboratory research funding from the National Institutes of Health, Alzheimer’s Association, BrightFocus Foundation, Rainwater Foundation, Association for Frontotemporal Degeneration FTD Biomarkers Initiative, Avid Radiopharmaceuticals, Janssen, Tau Consortium, Novartis, Centene Corporation, Association for Frontotemporal Degeneration, the Cure Alzheimer’s Fund, Coins for Alzheimer’s Research Trust Fund, The Foundation for Barnes-Jewish Hospital, Good Ventures Foundation, DIAN-TU Pharma Consortium, Tau SILK Consortium (AbbVie, Biogen, Eli Lilly, and an anonymous organization), the NfL Consortium (AbbVie, Biogen, Bristol Meyers Squibb, Hoffman La Roche), and the Tracy Family SILQ Center; having equity ownership interest in C2N Diagnostics and receiving income based on technology licensed by Washington University to C2N Diagnostics; and receiving income from C2N Diagnostics for serving on the scientific advisory board. OH has acquired research support (for the institution) from AVID Radiopharmaceuticals, Biogen, C2N Diagnostics, Eli Lilly, Eisai, Fujirebio, GE Healthcare, and Roche. In the past 2 years, he has received consultancy/speaker fees from AC Immune, Alzpath, BioArctic, Biogen, Bristol Meyer Squibb, Cerveau, Eisai, Eli Lilly, Fujirebio, Merck, Novartis, Novo Nordisk, Roche, Sanofi and Siemens. SCJ has served in the past two years on advisory boards for Enigma Biomedical and ALZPath. The other authors report no competing interests.- Published
- 2024
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21. Disease staging of Alzheimer's disease using a CSF-based biomarker model.
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Salvadó G, Horie K, Barthélemy NR, Vogel JW, Pichet Binette A, Chen CD, Aschenbrenner AJ, Gordon BA, Benzinger TLS, Holtzman DM, Morris JC, Palmqvist S, Stomrud E, Janelidze S, Ossenkoppele R, Schindler SE, Bateman RJ, and Hansson O
- Subjects
- Humans, Female, Male, Aged, Disease Progression, Peptide Fragments cerebrospinal fluid, Algorithms, Middle Aged, Positron-Emission Tomography, Alzheimer Disease cerebrospinal fluid, Alzheimer Disease pathology, Alzheimer Disease diagnosis, Biomarkers cerebrospinal fluid, tau Proteins cerebrospinal fluid, Amyloid beta-Peptides cerebrospinal fluid
- Abstract
Biological staging of individuals with Alzheimer's disease (AD) may improve diagnostic and prognostic workup of dementia in clinical practice and the design of clinical trials. In this study, we used the Subtype and Stage Inference (SuStaIn) algorithm to establish a robust biological staging model for AD using cerebrospinal fluid (CSF) biomarkers. Our analysis involved 426 participants from BioFINDER-2 and was validated in 222 participants from the Knight Alzheimer Disease Research Center cohort. SuStaIn identified a singular biomarker sequence and revealed that five CSF biomarkers effectively constituted a reliable staging model (ordered: Aβ42/40, pT217/T217, pT205/T205, MTBR-tau243 and non-phosphorylated mid-region tau). The CSF stages (0-5) demonstrated a correlation with increased abnormalities in other AD-related biomarkers, such as Aβ-PET and tau-PET, and aligned with longitudinal biomarker changes reflective of AD progression. Higher CSF stages at baseline were associated with an elevated hazard ratio of clinical decline. This study highlights a common molecular pathway underlying AD pathophysiology across all patients, suggesting that a single CSF collection can accurately indicate the presence of AD pathologies and characterize the stage of disease progression. The proposed staging model has implications for enhancing diagnostic and prognostic assessments in both clinical practice and the design of clinical trials., (© 2024. The Author(s).)
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- 2024
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22. Biomarker-based staging of Alzheimer disease: rationale and clinical applications.
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Therriault J, Schindler SE, Salvadó G, Pascoal TA, Benedet AL, Ashton NJ, Karikari TK, Apostolova L, Murray ME, Verberk I, Vogel JW, La Joie R, Gauthier S, Teunissen C, Rabinovici GD, Zetterberg H, Bateman RJ, Scheltens P, Blennow K, Sperling R, Hansson O, Jack CR Jr, and Rosa-Neto P
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- Humans, Amyloid beta-Peptides, Positron-Emission Tomography, Biomarkers cerebrospinal fluid, Alzheimer Disease diagnostic imaging
- Abstract
Disease staging, whereby the spatial extent and load of brain pathology are used to estimate the severity of Alzheimer disease (AD), is pivotal to the gold-standard neuropathological diagnosis of AD. Current in vivo diagnostic frameworks for AD are based on abnormal concentrations of amyloid-β and tau in the cerebrospinal fluid or on PET scans, and breakthroughs in molecular imaging have opened up the possibility of in vivo staging of AD. Focusing on the key principles of disease staging shared across several areas of medicine, this Review highlights the potential for in vivo staging of AD to transform our understanding of preclinical AD, refine enrolment criteria for trials of disease-modifying therapies and aid clinical decision-making in the era of anti-amyloid therapeutics. We provide a state-of-the-art review of recent biomarker-based AD staging systems and highlight their contributions to the understanding of the natural history of AD. Furthermore, we outline hypothetical frameworks to stage AD severity using more accessible fluid biomarkers. In addition, by applying amyloid PET-based staging to recently published anti-amyloid therapeutic trials, we highlight how biomarker-based disease staging frameworks could illustrate the numerous pathological changes that have already taken place in individuals with mildly symptomatic AD. Finally, we discuss challenges related to the validation and standardization of disease staging and provide a forward-looking perspective on potential clinical applications., (© 2024. Springer Nature Limited.)
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- 2024
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23. Highly accurate blood test for Alzheimer's disease is similar or superior to clinical cerebrospinal fluid tests.
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Barthélemy NR, Salvadó G, Schindler SE, He Y, Janelidze S, Collij LE, Saef B, Henson RL, Chen CD, Gordon BA, Li Y, La Joie R, Benzinger TLS, Morris JC, Mattsson-Carlgren N, Palmqvist S, Ossenkoppele R, Rabinovici GD, Stomrud E, Bateman RJ, and Hansson O
- Subjects
- Humans, tau Proteins, Biomarkers, Amyloid beta-Peptides cerebrospinal fluid, Hematologic Tests, Positron-Emission Tomography, Alzheimer Disease, Cognitive Dysfunction diagnosis, Cognitive Dysfunction cerebrospinal fluid
- Abstract
With the emergence of Alzheimer's disease (AD) disease-modifying therapies, identifying patients who could benefit from these treatments becomes critical. In this study, we evaluated whether a precise blood test could perform as well as established cerebrospinal fluid (CSF) tests in detecting amyloid-β (Aβ) plaques and tau tangles. Plasma %p-tau217 (ratio of phosporylated-tau217 to non-phosphorylated tau) was analyzed by mass spectrometry in the Swedish BioFINDER-2 cohort (n = 1,422) and the US Charles F. and Joanne Knight Alzheimer Disease Research Center (Knight ADRC) cohort (n = 337). Matched CSF samples were analyzed with clinically used and FDA-approved automated immunoassays for Aβ42/40 and p-tau181/Aβ42. The primary and secondary outcomes were detection of brain Aβ or tau pathology, respectively, using positron emission tomography (PET) imaging as the reference standard. Main analyses were focused on individuals with cognitive impairment (mild cognitive impairment and mild dementia), which is the target population for available disease-modifying treatments. Plasma %p-tau217 was clinically equivalent to FDA-approved CSF tests in classifying Aβ PET status, with an area under the curve (AUC) for both between 0.95 and 0.97. Plasma %p-tau217 was generally superior to CSF tests in classification of tau-PET with AUCs of 0.95-0.98. In cognitively impaired subcohorts (BioFINDER-2: n = 720; Knight ADRC: n = 50), plasma %p-tau217 had an accuracy, a positive predictive value and a negative predictive value of 89-90% for Aβ PET and 87-88% for tau PET status, which was clinically equivalent to CSF tests, further improving to 95% using a two-cutoffs approach. Blood plasma %p-tau217 demonstrated performance that was clinically equivalent or superior to clinically used FDA-approved CSF tests in the detection of AD pathology. Use of high-performance blood tests in clinical practice can improve access to accurate AD diagnosis and AD-specific treatments., (© 2024. The Author(s).)
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- 2024
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24. Plasma N-terminal containing tau fragments (NTA-tau): a biomarker of tau deposition in Alzheimer's Disease.
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Lantero-Rodriguez J, Salvadó G, Snellman A, Montoliu-Gaya L, Brum WS, Benedet AL, Mattsson-Carlgren N, Tideman P, Janelidze S, Palmqvist S, Stomrud E, Ashton NJ, Zetterberg H, Blennow K, and Hansson O
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- Humans, tau Proteins, Amyloid beta-Peptides, Atrophy, Biomarkers, Disease Progression, Positron-Emission Tomography, Alzheimer Disease, Cognitive Dysfunction
- Abstract
Background: Novel phosphorylated-tau (p-tau) blood biomarkers (e.g., p-tau181, p-tau217 or p-tau231), are highly specific for Alzheimer's disease (AD), and can track amyloid-β (Aβ) and tau pathology. However, because these biomarkers are strongly associated with the emergence of Aβ pathology, it is difficult to determine the contribution of insoluble tau aggregates to the plasma p-tau signal in blood. Therefore, there remains a need for a biomarker capable of specifically tracking insoluble tau accumulation in brain., Methods: NTA is a novel ultrasensitive assay targeting N-terminal containing tau fragments (NTA-tau) in cerebrospinal fluid (CSF) and plasma, which is elevated in AD. Using two well-characterized research cohorts (BioFINDER-2, n = 1,294, and BioFINDER-1, n = 932), we investigated the association between plasma NTA-tau levels and disease progression in AD, including tau accumulation, brain atrophy and cognitive decline., Results: We demonstrate that plasma NTA-tau increases across the AD continuum¸ especially during late stages, and displays a moderate-to-strong association with tau-PET (β = 0.54, p < 0.001) in Aβ-positive participants, while weak with Aβ-PET (β = 0.28, p < 0.001). Unlike plasma p-tau181, GFAP, NfL and t-tau, tau pathology determined with tau-PET is the most prominent contributor to NTA-tau variance (52.5% of total R
2 ), while having very low contribution from Aβ pathology measured with CSF Aβ42/40 (4.3%). High baseline NTA-tau levels are predictive of tau-PET accumulation (R2 = 0.27), steeper atrophy (R2 ≥ 0.18) and steeper cognitive decline (R2 ≥ 0.27) in participants within the AD continuum. Plasma NTA-tau levels significantly increase over time in Aβ positive cognitively unimpaired (βstd = 0.16) and impaired (βstd = 0.18) at baseline compared to their Aβ negative counterparts. Finally, longitudinal increases in plasma NTA-tau levels were associated with steeper longitudinal decreases in cortical thickness (R2 = 0.21) and cognition (R2 = 0.20)., Conclusion: Our results indicate that plasma NTA-tau levels increase across the AD continuum, especially during mid-to-late AD stages, and it is closely associated with in vivo tau tangle deposition in AD and its downstream effects. Moreover, this novel biomarker has potential as a cost-effective and easily accessible tool for monitoring disease progression and cognitive decline in clinical settings, and as an outcome measure in clinical trials which also need to assess the downstream effects of successful Aβ removal., (© 2024. The Author(s).)- Published
- 2024
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25. Comparison of immunoassay- with mass spectrometry-derived p-tau quantification for the detection of Alzheimer's disease pathology.
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Therriault J, Woo MS, Salvadó G, Gobom J, Karikari TK, Janelidze S, Servaes S, Rahmouni N, Tissot C, Ashton NJ, Benedet AL, Montoliu-Gaya L, Macedo AC, Lussier FZ, Stevenson J, Vitali P, Friese MA, Massarweh G, Soucy JP, Pascoal TA, Stomrud E, Palmqvist S, Mattsson-Carlgren N, Gauthier S, Zetterberg H, Hansson O, Blennow K, and Rosa-Neto P
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- Humans, Amyloidogenic Proteins, Immunoassay, Mass Spectrometry, Biomarkers, Alzheimer Disease diagnosis
- Abstract
Background: Antibody-based immunoassays have enabled quantification of very low concentrations of phosphorylated tau (p-tau) protein forms in cerebrospinal fluid (CSF), aiding in the diagnosis of AD. Mass spectrometry enables absolute quantification of multiple p-tau variants within a single run. The goal of this study was to compare the performance of mass spectrometry assessments of p-tau
181 , p-tau217 and p-tau231 with established immunoassay techniques., Methods: We measured p-tau181 , p-tau217 and p-tau231 concentrations in CSF from 173 participants from the TRIAD cohort and 394 participants from the BioFINDER-2 cohort using both mass spectrometry and immunoassay methods. All subjects were clinically evaluated by dementia specialists and had amyloid-PET and tau-PET assessments. Bland-Altman analyses evaluated the agreement between immunoassay and mass spectrometry p-tau181 , p-tau217 and p-tau231 . P-tau associations with amyloid-PET and tau-PET uptake were also compared. Receiver Operating Characteristic (ROC) analyses compared the performance of mass spectrometry and immunoassays p-tau concentrations to identify amyloid-PET positivity., Results: Mass spectrometry and immunoassays of p-tau217 were highly comparable in terms of diagnostic performance, between-group effect sizes and associations with PET biomarkers. In contrast, p-tau181 and p-tau231 concentrations measured using antibody-free mass spectrometry had lower performance compared with immunoassays., Conclusions: Our results suggest that while similar overall, immunoassay-based p-tau biomarkers are slightly superior to antibody-free mass spectrometry-based p-tau biomarkers. Future work is needed to determine whether the potential to evaluate multiple biomarkers within a single run offsets the slightly lower performance of antibody-free mass spectrometry-based p-tau quantification., (© 2023. The Author(s).)- Published
- 2024
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26. CSF MTBR-tau243 is a specific biomarker of tau tangle pathology in Alzheimer's disease.
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Horie K, Salvadó G, Barthélemy NR, Janelidze S, Li Y, He Y, Saef B, Chen CD, Jiang H, Strandberg O, Pichet Binette A, Palmqvist S, Sato C, Sachdev P, Koyama A, Gordon BA, Benzinger TLS, Holtzman DM, Morris JC, Mattsson-Carlgren N, Stomrud E, Ossenkoppele R, Schindler SE, Hansson O, and Bateman RJ
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- Humans, tau Proteins cerebrospinal fluid, Amyloid beta-Peptides cerebrospinal fluid, Positron-Emission Tomography, Biomarkers cerebrospinal fluid, Alzheimer Disease pathology, Cognitive Dysfunction
- Abstract
Aggregated insoluble tau is one of two defining features of Alzheimer's disease. Because clinical symptoms are strongly correlated with tau aggregates, drug development and clinical diagnosis need cost-effective and accessible specific fluid biomarkers of tau aggregates; however, recent studies suggest that the fluid biomarkers currently available cannot specifically track tau aggregates. We show that the microtubule-binding region (MTBR) of tau containing the residue 243 (MTBR-tau243) is a new cerebrospinal fluid (CSF) biomarker specific for insoluble tau aggregates and compared it to multiple other phosphorylated tau measures (p-tau181, p-tau205, p-tau217 and p-tau231) in two independent cohorts (BioFINDER-2, n = 448; and Knight Alzheimer Disease Research Center, n = 219). MTBR-tau243 was most strongly associated with tau-positron emission tomography (PET) and cognition, whereas showing the lowest association with amyloid-PET. In combination with p-tau205, MTBR-tau243 explained most of the total variance in tau-PET burden (0.58 ≤ R
2 ≤ 0.75) and the performance in predicting cognitive measures (0.34 ≤ R2 ≤ 0.48) approached that of tau-PET (0.44 ≤ R2 ≤ 0.52). MTBR-tau243 levels longitudinally increased with insoluble tau aggregates, unlike CSF p-tau species. CSF MTBR-tau243 is a specific biomarker of tau aggregate pathology, which may be utilized in interventional trials and in the diagnosis of patients. Based on these findings, we propose to revise the A/T/(N) criteria to include MTBR-tau243 as representing insoluble tau aggregates ('T')., (© 2023. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)- Published
- 2023
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27. Novel CSF tau biomarkers can be used for disease staging of sporadic Alzheimer's disease.
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Salvadó G, Horie K, Barthélemy NR, Vogel JW, Binette AP, Chen CD, Aschenbrenner AJ, Gordon BA, Benzinger TLS, Holtzman DM, Morris JC, Palmqvist S, Stomrud E, Janelidze S, Ossenkoppele R, Schindler SE, Bateman RJ, and Hansson O
- Abstract
Biological staging of individuals with Alzheimer's disease (AD) may improve diagnostic and prognostic work-up of dementia in clinical practice and the design of clinical trials. Here, we created a staging model using the Subtype and Stage Inference (SuStaIn) algorithm by evaluating cerebrospinal fluid (CSF) amyloid-β (Aβ) and tau biomarkers in 426 participants from BioFINDER-2, that represent the entire spectrum of AD. The model composition and main analyses were replicated in 222 participants from the Knight ADRC cohort. SuStaIn revealed in the two cohorts that the data was best explained by a single biomarker sequence (one subtype), and that five CSF biomarkers (ordered: Aβ42/40, tau phosphorylation occupancies at the residues 217 and 205 [pT217/T217 and pT205/T205], microtubule-binding region of tau containing the residue 243 [MTBR-tau243], and total tau) were sufficient to create an accurate disease staging model. Increasing CSF stages (0-5) were associated with increased abnormality in other AD-related biomarkers, such as Aβ- and tau-PET, and aligned with different phases of longitudinal biomarker changes consistent with current models of AD progression. Higher CSF stages at baseline were associated with higher hazard ratio of clinical decline. Our findings indicate that a common pathophysiologic molecular pathway develops across all AD patients, and that a single CSF collection is sufficient to reliably indicate the presence of both AD pathologies and the degree and stage of disease progression.
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- 2023
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28. Optimal combinations of CSF biomarkers for predicting cognitive decline and clinical conversion in cognitively unimpaired participants and mild cognitive impairment patients: A multi-cohort study.
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Salvadó G, Larsson V, Cody KA, Cullen NC, Jonaitis EM, Stomrud E, Kollmorgen G, Wild N, Palmqvist S, Janelidze S, Mattsson-Carlgren N, Zetterberg H, Blennow K, Johnson SC, Ossenkoppele R, and Hansson O
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- Humans, Cohort Studies, tau Proteins cerebrospinal fluid, Biomarkers cerebrospinal fluid, Amyloid beta-Peptides metabolism, Alzheimer Disease diagnosis, Alzheimer Disease cerebrospinal fluid, Cognitive Dysfunction diagnosis, Cognitive Dysfunction cerebrospinal fluid
- Abstract
Introduction: Our objective was determining the optimal combinations of cerebrospinal fluid (CSF) biomarkers for predicting disease progression in Alzheimer's disease (AD) and other neurodegenerative diseases., Methods: We included 1,983 participants from three different cohorts with longitudinal cognitive and clinical data, and baseline CSF levels of Aβ42, Aβ40, phosphorylated tau at threonine-181 (p-tau), neurofilament light (NfL), neurogranin, α-synuclein, soluble triggering receptor expressed on myeloid cells 2 (sTREM2), glial fibrillary acidic protein (GFAP), YKL-40, S100b, and interleukin 6 (IL-6) (Elecsys NeuroToolKit)., Results: Change of modified Preclinical Alzheimer's Cognitive Composite (mPACC) in cognitively unimpaired (CU) was best predicted by p-tau/Aβ42 alone (R
2 ≥ 0.31) or together with NfL (R2 = 0.25), while p-tau/Aβ42 (R2 ≥ 0.19) was sufficient to accurately predict change of the Mini-Mental State Examination (MMSE) in mild cognitive impairment (MCI) patients. P-tau/Aβ42 (AUC ≥ 0.87) and p-tau/Aβ42 together with NfL (AUC ≥ 0.75) were the best predictors of conversion to AD and all-cause dementia, respectively., Discussion: P-tau/Aβ42 is sufficient for predicting progression in AD, with very high accuracy. Adding NfL improves the prediction of all-cause dementia conversion and cognitive decline., (© 2023 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)- Published
- 2023
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29. Quantification of [ 18 F]florbetaben amyloid-PET imaging in a mixed memory clinic population: The ABIDE project.
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Collij LE, Salvadó G, de Wilde A, Altomare D, Shekari M, Gispert JD, Bullich S, Stephens A, Barkhof F, Scheltens P, Bouwman F, and van der Flier WM
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- Humans, Positron-Emission Tomography methods, Aniline Compounds, Amyloid, Amyloidogenic Proteins, Amyloid beta-Peptides, Alzheimer Disease diagnostic imaging
- Abstract
Introduction: We investigated amyloid-burden quantification in a mixed memory clinic population., Methods: [
18 F]Florbetaben amyloid-PET (positron emission tomography) scans of 348 patients were visually read and quantified using the Centiloid (CL) method. General linear models were used to assess CL differences across syndromic and etiological diagnosis. Linear mixed models were fitted to assess the predictive value of visual read (VR) and CL on longitudinal Mini-Mental Status Examination (MMSE)., Results: CL was associated with syndromic (F = 4.42, p = 0.014) and etiological diagnosis (F = -12.66, p < 0.001), with Alzheimer's disease (AD) patients showing the highest amyloid burden (62.9 ± 27.5), followed by dementia with Lewy bodies (DLB) (25.3 ± 35.5) and cardiovascular disease (CVD) (16.7 ± 24.5), and finally frontotemporal lobe degeneration (FTLD) (5.0 ± 17.22, t = -12.66, p < 0.001). CL remained predictive of etiological diagnosis (t = -2.41, p = 0.017) within the VR+ population (N = 157). VR was not a significant predictor of MMSE (t = -1.53, p = 0.13) for the SCD population (N = 90), whereas CL was (t = -3.30, p = 0.001)., Discussion: The extent of amyloid pathology through quantification holds clinical value, potentially in the context of differential diagnosis as well as prognosis., (© 2022 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)- Published
- 2023
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30. Specific associations between plasma biomarkers and postmortem amyloid plaque and tau tangle loads.
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Salvadó G, Ossenkoppele R, Ashton NJ, Beach TG, Serrano GE, Reiman EM, Zetterberg H, Mattsson-Carlgren N, Janelidze S, Blennow K, and Hansson O
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- Humans, Autopsy, Neuropathology, Biomarkers, tau Proteins, Amyloid beta-Peptides, Plaque, Amyloid, Alzheimer Disease diagnosis
- Abstract
Several promising plasma biomarkers for Alzheimer's disease have been recently developed, but their neuropathological correlates have not yet been fully determined. To investigate and compare independent associations between multiple plasma biomarkers (p-tau181, p-tau217, p-tau231, Aβ42/40, GFAP, and NfL) and neuropathologic measures of amyloid and tau, we included 105 participants from the Arizona Study of Aging and Neurodegenerative Disorders (AZSAND) with antemortem plasma samples and a postmortem neuropathological exam, 48 of whom had longitudinal p-tau217 and p-tau181. When simultaneously including plaque and tangle loads, the Aβ42/40 ratio and p-tau231 were only associated with plaques (ρ
Aβ42/40 [95%CI] = -0.53[-0.65, -0.35], ρp-tau231 [95%CI] = 0.28[0.10, 0.43]), GFAP was only associated with tangles (ρGFAP [95%CI] = 0.39[0.17, 0.57]), and p-tau217 and p-tau181 were associated with both plaques (ρp-tau217 [95%CI] = 0.40[0.21, 0.56], ρp-tau181 [95%CI] = 0.36[0.15, 0.50]) and tangles (ρp-tau217 [95%CI] = 0.52[0.34, 0.66]; ρp-tau181 [95%CI] = 0.36[0.17, 0.52]). A model combining p-tau217 and the Aβ42/40 ratio showed the highest accuracy for predicting the presence of Alzheimer's disease neuropathological change (ADNC, AUC[95%CI] = 0.89[0.82, 0.96]) and plaque load (R2 = 0.55), while p-tau217 alone was optimal for predicting tangle load (R2 = 0.45). Our results suggest that high-performing assays of plasma p-tau217 and Aβ42/40 might be an optimal combination to assess Alzheimer's-related pathology in vivo., (© 2023 The Authors. Published under the terms of the CC BY 4.0 license.)- Published
- 2023
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31. Prediction of Longitudinal Cognitive Decline in Preclinical Alzheimer Disease Using Plasma Biomarkers.
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Mattsson-Carlgren N, Salvadó G, Ashton NJ, Tideman P, Stomrud E, Zetterberg H, Ossenkoppele R, Betthauser TJ, Cody KA, Jonaitis EM, Langhough R, Palmqvist S, Blennow K, Janelidze S, Johnson SC, and Hansson O
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- Humans, Female, Aged, Middle Aged, Male, Longitudinal Studies, Prospective Studies, Amyloid beta-Peptides metabolism, Positron-Emission Tomography, Biomarkers, tau Proteins cerebrospinal fluid, Alzheimer Disease cerebrospinal fluid, Cognitive Dysfunction
- Abstract
Importance: Alzheimer disease (AD) pathology starts with a prolonged phase of β-amyloid (Aβ) accumulation without symptoms. The duration of this phase differs greatly among individuals. While this disease phase has high relevance for clinical trial designs, it is currently unclear how to best predict the onset of clinical progression., Objective: To evaluate combinations of different plasma biomarkers for predicting cognitive decline in Aβ-positive cognitively unimpaired (CU) individuals., Design, Setting, and Participants: This prospective population-based prognostic study evaluated data from 2 prospective longitudinal cohort studies (the Swedish BioFINDER-1 and the Wisconsin Registry for Alzheimer Prevention [WRAP]), with data collected from February 8, 2010, to October 21, 2020, for the BioFINDER-1 cohort and from August 11, 2011, to June 27, 2021, for the WRAP cohort. Participants were CU individuals recruited from memory clinics who had brain Aβ pathology defined by cerebrospinal fluid (CSF) Aβ42/40 in the BioFINDER-1 study and by Pittsburgh Compound B (PiB) positron emission tomography (PET) in the WRAP study. A total of 564 eligible Aβ-positive and Aβ-negative CU participants with available relevant data from the BioFINDER-1 and WRAP cohorts were included in the study; of those, 171 Aβ-positive participants were included in the main analyses., Exposures: Baseline P-tau181, P-tau217, P-tau231, glial fibrillary filament protein, and neurofilament light measured in plasma; CSF biomarkers in the BioFINDER-1 cohort, and PiB PET uptake in the WRAP cohort., Main Outcomes and Measures: The primary outcome was longitudinal measures of cognition (using the Mini-Mental State Examination [MMSE] and the modified Preclinical Alzheimer Cognitive Composite [mPACC]) over a median of 6 years (range, 2-10 years). The secondary outcome was conversion to AD dementia. Baseline biomarkers were used in linear regression models to predict rates of longitudinal cognitive change (calculated separately). Models were adjusted for age, sex, years of education, apolipoprotein E ε4 allele status, and baseline cognition. Multivariable models were compared based on model R2 coefficients and corrected Akaike information criterion., Results: Among 171 Aβ-positive CU participants included in the main analyses, 119 (mean [SD] age, 73.0 [5.4] years; 60.5% female) were from the BioFINDER-1 study, and 52 (mean [SD] age, 64.4 [4.6] years; 65.4% female) were from the WRAP study. In the BioFINDER-1 cohort, plasma P-tau217 was the best marker to predict cognitive decline in the mPACC (model R2 = 0.41) and the MMSE (model R2 = 0.34) and was superior to the covariates-only models (mPACC: R2 = 0.23; MMSE: R2 = 0.04; P < .001 for both comparisons). Results were validated in the WRAP cohort; for example, plasma P-tau217 was associated with mPACC slopes (R2 = 0.13 vs 0.01 in the covariates-only model; P = .01) and MMSE slopes (R2 = 0.29 vs 0.24 in the covariates-only model; P = .046). Sparse models were identified with plasma P-tau217 as a predictor of cognitive decline. Power calculations for enrichment in hypothetical clinical trials revealed large relative reductions in sample sizes when using plasma P-tau217 to enrich for CU individuals likely to experience cognitive decline over time., Conclusions and Relevance: In this study, plasma P-tau217 predicted cognitive decline in patients with preclinical AD. These findings suggest that plasma P-tau217 may be used as a complement to CSF or PET for participant selection in clinical trials of novel disease-modifying treatments.
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- 2023
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32. CSF tau phosphorylation occupancies at T217 and T205 represent improved biomarkers of amyloid and tau pathology in Alzheimer's disease.
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Barthélemy NR, Saef B, Li Y, Gordon BA, He Y, Horie K, Stomrud E, Salvadó G, Janelidze S, Sato C, Ovod V, Henson RL, Fagan AM, Benzinger TLS, Xiong C, Morris JC, Hansson O, Bateman RJ, and Schindler SE
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- Humans, Aged, tau Proteins cerebrospinal fluid, Phosphorylation, Peptide Fragments cerebrospinal fluid, Amyloid, Biomarkers cerebrospinal fluid, Alzheimer Disease diagnosis
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Cerebrospinal fluid (CSF) amyloid-β peptide (Aβ)42/Aβ40 and the concentration of tau phosphorylated at site 181 (p-tau181) are well-established biomarkers of Alzheimer's disease (AD). The present study used mass spectrometry to measure concentrations of nine phosphorylated and five nonphosphorylated tau species and phosphorylation occupancies (percentage phosphorylated/nonphosphorylated) at ten sites. In the present study we show that, in 750 individuals with a median age of 71.2 years, CSF pT217/T217 predicted the presence of brain amyloid by positron emission tomography (PET) slightly better than Aβ42/Aβ40 (P = 0.02). Furthermore, for individuals with positive brain amyloid by PET (n = 263), CSF pT217/T217 was more strongly correlated with the amount of amyloid (Spearman's ρ = 0.69) than Aβ42/Aβ40 (ρ = -0.42, P < 0.0001). In two independent cohorts of participants with symptoms of AD dementia (n = 55 and n = 90), CSF pT217/T217 and pT205/T205 were better correlated with tau PET measures than CSF p-tau181 concentration. These findings suggest that CSF pT217/T217 and pT205/T205 represent improved CSF biomarkers of amyloid and tau pathology in AD., (© 2023. The Author(s).)
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- 2023
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33. APOE-ε4 modulates the association between regional amyloid deposition and cognitive performance in cognitively unimpaired middle-aged individuals.
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Brugulat-Serrat A, Sánchez-Benavides G, Cacciaglia R, Salvadó G, Shekari M, Collij LE, Buckley C, van Berckel BNM, Perissinotti A, Niñerola-Baizán A, Milà-Alomà M, Vilor-Tejedor N, Operto G, Falcon C, Grau-Rivera O, Arenaza-Urquijo EM, Minguillón C, Fauria K, Molinuevo JL, Suárez-Calvet M, and Gispert JD
- Abstract
Purpose: To determine whether the APOE-ε4 allele modulates the relationship between regional β-amyloid (Aβ) accumulation and cognitive change in middle-aged cognitively unimpaired (CU) participants., Methods: The 352 CU participants (mean aged 61.1 [4.7] years) included completed two cognitive assessments (average interval 3.34 years), underwent [
18 F]flutemetamol Aβ positron emission tomography (PET), T1w magnetic resonance imaging (MRI), as well as APOE genotyping. Global and regional Aβ PET positivity was assessed across five regions-of-interest by visual reading (VR) and regional Centiloids. Linear regression models were developed to examine the interaction between regional and global Aβ PET positivity and APOE-ε4 status on longitudinal cognitive change assessed with the Preclinical Alzheimer's Cognitive Composite (PACC), episodic memory, and executive function, after controlling for age, sex, education, cognitive baseline scores, and hippocampal volume., Results: In total, 57 participants (16.2%) were VR+ of whom 41 (71.9%) were APOE-ε4 carriers. No significant APOE-ε4*global Aβ PET interactions were associated with cognitive change for any cognitive test. However, APOE-ε4 carriers who were VR+ in temporal areas (n = 19 [9.81%], p = 0.04) and in the striatum (n = 8 [4.14%], p = 0.01) exhibited a higher decline in the PACC. The temporal areas findings were replicated when regional PET positivity was determined with Centiloid values. Regionally, VR+ in the striatum was associated with higher memory decline. As for executive function, interactions between APOE-ε4 and regional VR+ were found in temporal and parietal regions, and in the striatum., Conclusion: CU APOE-ε4 carriers with a positive Aβ PET VR in regions known to accumulate amyloid at later stages of the Alzheimer's disease (AD) continuum exhibited a steeper cognitive decline. This work supports the contention that regional VR of Aβ PET might convey prognostic information about future cognitive decline in individuals at higher risk of developing AD., Clinicaltrials: gov Identifier: NCT02485730. Registered 20 June 2015 https://clinicaltrials.gov/ct2/show/NCT02485730 and ClinicalTrials.gov Identifier:NCT02685969. Registered 19 February 2016 https://clinicaltrials.gov/ct2/show/NCT02685969 ., (© 2023. The Author(s).)- Published
- 2023
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34. Reactive astrogliosis is associated with higher cerebral glucose consumption in the early Alzheimer's continuum.
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Salvadó G, Milà-Alomà M, Shekari M, Ashton NJ, Operto G, Falcon C, Cacciaglia R, Minguillon C, Fauria K, Niñerola-Baizán A, Perissinotti A, Benedet AL, Kollmorgen G, Suridjan I, Wild N, Molinuevo JL, Zetterberg H, Blennow K, Suárez-Calvet M, and Gispert JD
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- Humans, Gliosis diagnostic imaging, Gliosis pathology, Glial Fibrillary Acidic Protein metabolism, Fluorodeoxyglucose F18 metabolism, tau Proteins metabolism, Amyloid beta-Peptides metabolism, Biomarkers metabolism, Inflammation, Glucose metabolism, Alzheimer Disease metabolism
- Abstract
Purpose: Glial activation is one of the earliest mechanisms to be altered in Alzheimer's disease (AD). Glial fibrillary acidic protein (GFAP) relates to reactive astrogliosis and can be measured in both cerebrospinal fluid (CSF) and blood. Plasma GFAP has been suggested to become altered earlier in AD than its CSF counterpart. Although astrocytes consume approximately half of the glucose-derived energy in the brain, the relationship between reactive astrogliosis and cerebral glucose metabolism is poorly understood. Here, we aimed to investigate the association between fluorodeoxyglucose ([
18 F]FDG) uptake and reactive astrogliosis, by means of GFAP quantified in both plasma and CSF for the same participants., Methods: We included 314 cognitively unimpaired participants from the ALFA + cohort, 112 of whom were amyloid-β (Aβ) positive. Associations between GFAP markers and [18 F]FDG uptake were studied. We also investigated whether these associations were modified by Aβ and tau status (AT stages)., Results: Plasma GFAP was positively associated with glucose consumption in the whole brain, while CSF GFAP associations with [18 F]FDG uptake were only observed in specific smaller areas like temporal pole and superior temporal lobe. These associations persisted when accounting for biomarkers of Aβ pathology but became negative in Aβ-positive and tau-positive participants (A + T +) in similar areas of AD-related hypometabolism., Conclusions: Higher astrocytic reactivity, probably in response to early AD pathological changes, is related to higher glucose consumption. With the onset of tau pathology, the observed uncoupling between astrocytic biomarkers and glucose consumption might be indicative of a failure to sustain the higher energetic demands required by reactive astrocytes., (© 2022. The Author(s).)- Published
- 2022
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35. Subjective cognitive decline and anxious/depressive symptoms during the COVID-19 pandemic: what is the role of stress perception, stress resilience, and β-amyloid?
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Akinci M, Sánchez-Benavides G, Brugulat-Serrat A, Peña-Gómez C, Palpatzis E, Shekari M, Deulofeu C, Fuentes-Julian S, Salvadó G, González-de-Echávarri JM, Suárez-Calvet M, Minguillón C, Fauria K, Molinuevo JL, Gispert JD, Grau-Rivera O, and Arenaza-Urquijo EM
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- Amyloid beta-Peptides, Anxiety diagnosis, Anxiety epidemiology, Depression diagnosis, Depression epidemiology, Humans, Pandemics, Perception, COVID-19, Cognitive Dysfunction diagnostic imaging, Cognitive Dysfunction epidemiology
- Abstract
Background: The COVID-19 pandemic may worsen the mental health of people reporting subjective cognitive decline (SCD) and therefore their clinical prognosis. We aimed to investigate the association between the intensity of SCD and anxious/depressive symptoms during confinement and the underlying mechanisms., Methods: Two hundred fifty cognitively unimpaired participants completed the Hospital Anxiety and Depression Scale (HADS) and SCD-Questionnaire (SCD-Q) and underwent amyloid-β positron emission tomography imaging with [
18 F] flutemetamol (N = 205) on average 2.4 (± 0.8) years before the COVID-19 confinement. During the confinement, participants completed the HADS, Perceived Stress Scale (PSS), Brief Resilience Scale (BRS), and an ad hoc questionnaire on worries (access to primary products, self-protection materials, economic situation) and lifestyle changes (sleep duration, sleep quality, eating habits). We investigated stress-related measurements, worries, and lifestyle changes in relation to SCD. We then conducted an analysis of covariance to investigate the association of SCD-Q with HADS scores during the confinement while controlling for pre-confinement anxiety/depression scores and demographics. Furthermore, we introduced amyloid-β positivity, PSS, and BRS in the models and performed mediation analyses to explore the mechanisms explaining the association between SCD and anxiety/depression., Results: In the whole sample, the average SCD-Q score was 4.1 (± 4.4); 70 (28%) participants were classified as SCD, and 26 (12.7%) were amyloid-β-positive. During the confinement, participants reporting SCD showed higher PSS (p = 0.035) but not BRS scores (p = 0.65) than those that did not report SCD. No differences in worries or lifestyle changes were observed. Higher SCD-Q scores showed an association with greater anxiety/depression scores irrespective of pre-confinement anxiety/depression levels (p = 0.002). This association was not significant after introducing amyloid-β positivity and stress-related variables in the model (p = 0.069). Amyloid-β positivity and PSS were associated with greater HADS irrespective of pre-confinement anxiety/depression scores (p = 0.023; p < 0.001). The association of SCD-Q with HADS was mediated by PSS (p = 0.01)., Conclusions: Higher intensity of SCD, amyloid-β positivity, and stress perception showed independent associations with anxious/depressive symptoms during the COVID-19 confinement irrespective of pre-confinement anxiety/depression levels. The association of SCD intensity with anxiety/depression was mediated by stress perception, suggesting stress regulation as a potential intervention to reduce affective symptomatology in the SCD population in the face of stressors., (© 2022. The Author(s).)- Published
- 2022
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36. Publisher Correction: Plasma p-tau231 and p-tau217 as state markers of amyloid-β pathology in preclinical Alzheimer's disease.
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Milà-Alomà M, Ashton NJ, Shekari M, Salvadó G, Ortiz-Romero P, Montoliu-Gaya L, Benedet AL, Karikari TK, Lantero-Rodriguez J, Vanmechelen E, Day TA, González-Escalante A, Sánchez-Benavides G, Minguillon C, Fauria K, Molinuevo JL, Dage JL, Zetterberg H, Gispert JD, Suárez-Calvet M, and Blennow K
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- 2022
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37. Plasma p-tau231 and p-tau217 as state markers of amyloid-β pathology in preclinical Alzheimer's disease.
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Milà-Alomà M, Ashton NJ, Shekari M, Salvadó G, Ortiz-Romero P, Montoliu-Gaya L, Benedet AL, Karikari TK, Lantero-Rodriguez J, Vanmechelen E, Day TA, González-Escalante A, Sánchez-Benavides G, Minguillon C, Fauria K, Molinuevo JL, Dage JL, Zetterberg H, Gispert JD, Suárez-Calvet M, and Blennow K
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- Amyloid beta-Peptides, Biomarkers, Humans, Plaque, Amyloid, Positron-Emission Tomography, tau Proteins, Alzheimer Disease diagnostic imaging
- Abstract
Blood 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., (© 2022. The Author(s).)
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- 2022
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38. Quantification of amyloid PET for future clinical use: a state-of-the-art review.
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Pemberton HG, Collij LE, Heeman F, Bollack A, Shekari M, Salvadó G, Alves IL, Garcia DV, Battle M, Buckley C, Stephens AW, Bullich S, Garibotto V, Barkhof F, Gispert JD, and Farrar G
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- Amyloid metabolism, Amyloid beta-Peptides metabolism, Brain metabolism, Humans, Positron-Emission Tomography methods, Alzheimer Disease complications, Alzheimer Disease diagnostic imaging, Amyloidosis, Cognitive Dysfunction complications
- Abstract
Amyloid-β (Aβ) pathology is one of the earliest detectable brain changes in Alzheimer's disease (AD) pathogenesis. The overall load and spatial distribution of brain Aβ can be determined in vivo using positron emission tomography (PET), for which three fluorine-18 labelled radiotracers have been approved for clinical use. In clinical practice, trained readers will categorise scans as either Aβ positive or negative, based on visual inspection. Diagnostic decisions are often based on these reads and patient selection for clinical trials is increasingly guided by amyloid status. However, tracer deposition in the grey matter as a function of amyloid load is an inherently continuous process, which is not sufficiently appreciated through binary cut-offs alone. State-of-the-art methods for amyloid PET quantification can generate tracer-independent measures of Aβ burden. Recent research has shown the ability of these quantitative measures to highlight pathological changes at the earliest stages of the AD continuum and generate more sensitive thresholds, as well as improving diagnostic confidence around established binary cut-offs. With the recent FDA approval of aducanumab and more candidate drugs on the horizon, early identification of amyloid burden using quantitative measures is critical for enrolling appropriate subjects to help establish the optimal window for therapeutic intervention and secondary prevention. In addition, quantitative amyloid measurements are used for treatment response monitoring in clinical trials. In clinical settings, large multi-centre studies have shown that amyloid PET results change both diagnosis and patient management and that quantification can accurately predict rates of cognitive decline. Whether these changes in management reflect an improvement in clinical outcomes is yet to be determined and further validation work is required to establish the utility of quantification for supporting treatment endpoint decisions. In this state-of-the-art review, several tools and measures available for amyloid PET quantification are summarised and discussed. Use of these methods is growing both clinically and in the research domain. Concurrently, there is a duty of care to the wider dementia community to increase visibility and understanding of these methods., (© 2022. The Author(s).)
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- 2022
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39. The protective gene dose effect of the APOE ε2 allele on gray matter volume in cognitively unimpaired individuals.
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Salvadó G, Ferreira D, Operto G, Cumplido-Mayoral I, Arenaza-Urquijo EM, Cacciaglia R, Falcon C, Vilor-Tejedor N, Minguillon C, Groot C, van der Flier WM, Barkhof F, Scheltens P, Ossenkoppele R, Kern S, Zettergren A, Skoog I, Hort J, Stomrud E, van Westen D, Hansson O, Molinuevo JL, Wahlund LO, Westman E, and Gispert JD
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- Alleles, Genotype, Gray Matter pathology, Humans, Alzheimer Disease genetics, Alzheimer Disease pathology, Apolipoprotein E2 genetics, Cognitive Dysfunction genetics, Gene Dosage
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Introduction: Harboring two copies of the apolipoprotein E (APOE) ε2 allele strongly protects against Alzheimer's disease (AD). However, the effect of this genotype on gray matter (GM) volume in cognitively unimpaired individuals has not yet been described., Methods: Multicenter brain magnetic resonance images (MRIs) from cognitively unimpaired ε2 homozygotes were matched (1:1) against all other APOE genotypes for relevant confounders (n = 223). GM volumes of ε2 genotypic groups were compared to each other and to the reference group (APOE ε3/ε3)., Results: Carrying at least one ε2 allele was associated with larger GM volumes in brain areas typically affected by AD and also in areas associated with cognitive resilience. APOE ε2 homozygotes, but not APOE ε2 heterozygotes, showed larger GM volumes in areas related to successful aging., Discussion: In addition to the known resistance against amyloid-β deposition, the larger GM volumes in key brain regions may confer APOE ε2 homozygotes additional protection against AD-related cognitive decline., (© 2021 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)
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- 2022
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40. Regional associations of white matter hyperintensities and early cortical amyloid pathology.
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Lorenzini L, Ansems LT, Lopes Alves I, Ingala S, Vállez García D, Tomassen J, Sudre C, Salvadó G, Shekari M, Operto G, Brugulat-Serrat A, Sánchez-Benavides G, Ten Kate M, Tijms B, Wink AM, Mutsaerts HJMM, den Braber A, Visser PJ, van Berckel BNM, Gispert JD, Barkhof F, and Collij LE
- Abstract
White matter hyperintensities (WMHs) have a heterogeneous aetiology, associated with both vascular risk factors and amyloidosis due to Alzheimer's disease. While spatial distribution of both amyloid and WM lesions carry important information for the underlying pathogenic mechanisms, the regional relationship between these two pathologies and their joint contribution to early cognitive deterioration remains largely unexplored. We included 662 non-demented participants from three Amyloid Imaging to Prevent Alzheimer's disease (AMYPAD)-affiliated cohorts: EPAD-LCS (N = 176), ALFA+ (N = 310), and EMIF-AD PreclinAD Twin60++ (N = 176). Using PET imaging, cortical amyloid burden was assessed regionally within early accumulating regions (medial orbitofrontal, precuneus, and cuneus) and globally, using the Centiloid method. Regional WMH volume was computed using Bayesian Model Selection. Global associations between WMH, amyloid, and cardiovascular risk scores (Framingham and CAIDE) were assessed using linear models. Partial least square (PLS) regression was used to identify regional associations. Models were adjusted for age, sex, and APOE-e4 status. Individual PLS scores were then related to cognitive performance in 4 domains (attention, memory, executive functioning, and language). While no significant global association was found, the PLS model yielded two components of interest. In the first PLS component, a fronto-parietal WMH pattern was associated with medial orbitofrontal-precuneal amyloid, vascular risk, and age. Component 2 showed a posterior WMH pattern associated with precuneus-cuneus amyloid, less related to age or vascular risk. Component 1 was associated with lower performance in all cognitive domains, while component 2 only with worse memory. In a large pre-dementia population, we observed two distinct patterns of regional associations between WMH and amyloid burden, and demonstrated their joint influence on cognitive processes. These two components could reflect the existence of vascular-dependent and -independent manifestations of WMH-amyloid regional association that might be related to distinct primary pathophysiology., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Guarantors of Brain.)
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- 2022
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41. Brain alterations in the early Alzheimer's continuum with amyloid-β, tau, glial and neurodegeneration CSF markers.
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Salvadó G, Shekari M, Falcon C, Operto G, Milà-Alomà M, Sánchez-Benavides G, Cacciaglia R, Arenaza-Urquijo E, Niñerola-Baizán A, Perissinotti A, Minguillon C, Fauria K, Kollmorgen G, Suridjan I, Molinuevo JL, Zetterberg H, Blennow K, Suárez-Calvet M, and Gispert JD
- Abstract
Higher grey matter volumes/cortical thickness and fluorodeoxyglucose uptake have been consistently found in cognitively unimpaired individuals with abnormal Alzheimer's disease biomarkers compared with those with normal biomarkers. It has been hypothesized that such transient increases may be associated with neuroinflammatory mechanisms triggered in response to early Alzheimer's pathology. Here, we evaluated, in the earliest stages of the Alzheimer's continuum , associations between grey matter volume and fluorodeoxyglucose uptake with CSF biomarkers of several pathophysiological mechanisms known to be altered in preclinical Alzheimer's disease stages. We included 319 cognitively unimpaired participants from the ALFA+ cohort with available structural MRI, fluorodeoxyglucose PET and CSF biomarkers of amyloid-β and tau pathology (phosphorylated tau and total tau), synaptic dysfunction (neurogranin), neuronal and axonal injury (neurofilament light), glial activation (soluble triggering receptor on myeloid cells 2, YKL40, GFAP, interleukin-6 and S100b) and α-synuclein using the Roche NeuroToolKit. We first used the amyloid-β/tau framework to investigate differences in the neuroimaging biomarkers between preclinical Alzheimer's disease stages. Then, we looked for associations between the neuroimaging markers and all the CSF markers. Given the non-negative nature of the concentrations of CSF biomarkers and their high collinearity, we clustered them using non-negative matrix factorization approach (components) and sought associations with the imaging markers. By groups, higher grey matter volumes were found in the amyloid-β-positive tau-negative participants with respect to the reference amyloid-β-negative tau-negative group. Both amyloid-β and tau-positive participants showed higher fluorodeoxyglucose uptake than tau-negative individuals. Using the obtained components, we observed that tau pathology accompanied by YKL-40 (astrocytic marker) was associated with higher grey matter volumes and fluorodeoxyglucose uptake in extensive brain areas. Higher grey matter volumes in key Alzheimer-related regions were also found in association with two other components characterized by a higher expression of amyloid-β in combination with different glial markers: one with higher GFAP and S100b levels (astrocytic markers) and the other one with interleukin-6 (pro-inflammatory). Notably, these components' expression had different behaviours across amyloid-β/tau stages. Taken together, our results show that CSF amyloid-β and phosphorylated tau, in combination with different aspects of glial response, have distinctive associations with higher grey matter volumes and increased glucose metabolism in key Alzheimer-related regions. These mechanisms combine to produce transient higher grey matter volumes and fluorodeoxyglucose uptake at the earliest stages of the Alzheimer's continuum , which may revert later on the course of the disease when neurodegeneration drives structural and metabolic cerebral changes., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Guarantors of Brain.)
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- 2022
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42. Spatial-Temporal Patterns of β-Amyloid Accumulation: A Subtype and Stage Inference Model Analysis.
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Collij LE, Salvadó G, Wottschel V, Mastenbroek SE, Schoenmakers P, Heeman F, Aksman L, Wink AM, Berckel BNM, van de Flier WM, Scheltens P, Visser PJ, Barkhof F, Haller S, Gispert JD, and Lopes Alves I
- Subjects
- Aged, Amyloid, Amyloid beta-Peptides, Apolipoprotein E4 genetics, Female, Humans, Magnetic Resonance Imaging, Male, Positron-Emission Tomography, Alzheimer Disease diagnostic imaging, Alzheimer Disease genetics, Amyloidosis
- Abstract
Background and Objectives: β-amyloid (Aβ) staging models assume a single spatial-temporal progression of amyloid accumulation. We assessed evidence for Aβ accumulation subtypes by applying the data-driven Subtype and Stage Inference (SuStaIn) model to amyloid-PET data., Methods: Amyloid-PET data of 3,010 participants were pooled from 6 cohorts (ALFA+, EMIF-AD, ABIDE, OASIS, and ADNI). Standardized uptake value ratios were calculated for 17 regions. We applied the SuStaIn algorithm to identify consistent subtypes in the pooled dataset based on the cross-validation information criterion and the most probable subtype/stage classification per scan. The effects of demographics and risk factors on subtype assignment were assessed using multinomial logistic regression., Results: Participants were mostly cognitively unimpaired (n = 1890 [62.8%]), had a mean age of 68.72 (SD 9.1) years, 42.1% were APOE ε4 carriers, and 51.8% were female. A 1-subtype model recovered the traditional amyloid accumulation trajectory, but SuStaIn identified 3 optimal subtypes, referred to as frontal, parietal, and occipital based on the first regions to show abnormality. Of the 788 (26.2%) with strong subtype assignment (>50% probability), the majority was assigned to frontal (n = 415 [52.5%]), followed by parietal (n = 199 [25.3%]) and occipital subtypes (n = 175 [22.2%]). Significant differences across subtypes included distinct proportions of APOE ε4 carriers (frontal 61.8%, parietal 57.1%, occipital 49.4%), participants with dementia (frontal 19.7%, parietal 19.1%, occipital 31.0%), and lower age for the parietal subtype (frontal/occipital 72.1 years, parietal 69.3 years). Higher amyloid (Centiloid) and CSF p-tau burden was observed for the frontal subtype; parietal and occipital subtypes did not differ. At follow-up, most participants (81.1%) maintained baseline subtype assignment and 25.6% progressed to a later stage., Discussion: Whereas a 1-trajectory model recovers the established pattern of amyloid accumulation, SuStaIn determined that 3 subtypes were optimal, showing distinct associations with Alzheimer disease risk factors. Further analyses to determine clinical utility are warranted., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)
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- 2022
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43. Age, sex and APOE-ε4 modify the balance between soluble and fibrillar β-amyloid in non-demented individuals: topographical patterns across two independent cohorts.
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Cacciaglia R, Salvadó G, Molinuevo JL, Shekari M, Falcon C, Operto G, Suárez-Calvet M, Milà-Alomà M, Sala A, Rodriguez-Vieitez E, Kollmorgen G, Suridjan I, Blennow K, Zetterberg H, and Gispert JD
- Subjects
- Apolipoprotein E4 genetics, Biomarkers metabolism, Brain metabolism, Female, Humans, Male, Positron-Emission Tomography methods, tau Proteins metabolism, Alzheimer Disease genetics, Alzheimer Disease metabolism, Amyloid beta-Peptides metabolism, Apolipoproteins E metabolism
- Abstract
Amyloid (Aβ) pathology is the earliest detectable pathophysiological event along the Alzheimer's continuum, which can be measured both in the cerebrospinal fluid (CSF) and by Positron Emission Tomography (PET). Yet, these biomarkers identify two distinct Aβ pools, reflecting the clearance of soluble Aβ as opposed to the presence of Aβ fibrils in the brain. An open question is whether risk factors known to increase Alzheimer's' disease (AD) prevalence may promote an imbalance between soluble and deposited Aβ. Unveiling such interactions shall aid our understanding of the biological pathways underlying Aβ deposition and foster the design of effective prevention strategies. We assessed the impact of three major AD risk factors, such as age, APOE-ε4 and female sex, on the association between CSF and PET Aβ, in two independent samples of non-demented individuals (ALFA: n = 320, ADNI: n = 682). We tested our hypotheses both in candidate regions of interest and in the whole brain using voxel-wise non-parametric permutations. All of the assessed risk factors induced a higher Aβ deposition for any given level of CSF Aβ42/40, although in distinct cerebral topologies. While age and sex mapped onto neocortical areas, the effect of APOE-ε4 was prominent in the medial temporal lobe, which represents a target of early tau deposition. Further, we found that the effects of age and APOE-ε4 was stronger in women than in men. Our data indicate that specific AD risk factors affect the spatial patterns of cerebral Aβ aggregation, with APOE-ε4 possibly facilitating a co-localization between Aβ and tau along the disease continuum., (© 2022. The Author(s).)
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- 2022
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44. P-tau235: a novel biomarker for staging preclinical Alzheimer's disease.
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Lantero-Rodriguez J, Snellman A, Benedet AL, Milà-Alomà M, Camporesi E, Montoliu-Gaya L, Ashton NJ, Vrillon A, Karikari TK, Gispert JD, Salvadó G, Shekari M, Toomey CE, Lashley TL, Zetterberg H, Suárez-Calvet M, Brinkmalm G, Rosa Neto P, and Blennow K
- Subjects
- Amyloid beta-Peptides, Biomarkers cerebrospinal fluid, Disease Progression, Humans, Phosphorylation, tau Proteins cerebrospinal fluid, Alzheimer Disease pathology
- Abstract
Alzheimer's disease (AD) is characterised by a long preclinical phase. Although phosphorylated tau (p-tau) species such as p-tau217 and p-tau231 provide accurate detection of early pathological changes, other biomarkers capable of staging disease progression during preclinical AD are still needed. Combining exploratory and targeted mass spectrometry methods in neuropathologically confirmed brain tissue, we observed that p-tau235 is a prominent feature of AD pathology. In addition, p-tau235 seemed to be preceded by p-tau231, in what appeared to be a sequential phosphorylation event. To exploit its biomarker potential in cerebrospinal fluid (CSF), we developed and validated a new p-tau235 Simoa assay. Using three clinical cohorts, we demonstrated that (i) CSF p-235 increases early in AD continuum, and (ii) changes in CSF p-tau235 and p-tau231 levels during preclinical AD are consistent with the sequential phosphorylation evidence in AD brain. In conclusion, CSF p-tau235 appears to be not only a highly specific biomarker of AD but also a promising staging biomarker for the preclinical phase. Thus, it could prove useful tracking disease progression and help enriching clinical trial recruitment., (© 2021 The Authors. Published under the terms of the CC BY 4.0 license.)
- Published
- 2021
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45. Differences Between Plasma and Cerebrospinal Fluid Glial Fibrillary Acidic Protein Levels Across the Alzheimer Disease Continuum.
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Benedet AL, Milà-Alomà M, Vrillon A, Ashton NJ, Pascoal TA, Lussier F, Karikari TK, Hourregue C, Cognat E, Dumurgier J, Stevenson J, Rahmouni N, Pallen V, Poltronetti NM, Salvadó G, Shekari M, Operto G, Gispert JD, Minguillon C, Fauria K, Kollmorgen G, Suridjan I, Zimmer ER, Zetterberg H, Molinuevo JL, Paquet C, Rosa-Neto P, Blennow K, and Suárez-Calvet M
- Subjects
- Aged, Aged, 80 and over, Cohort Studies, Cross-Sectional Studies, Humans, Middle Aged, Alzheimer Disease blood, Alzheimer Disease cerebrospinal fluid, Biomarkers blood, Biomarkers cerebrospinal fluid, Glial Fibrillary Acidic Protein blood, Glial Fibrillary Acidic Protein cerebrospinal fluid
- Abstract
Importance: Glial fibrillary acidic protein (GFAP) is a marker of reactive astrogliosis that increases in the cerebrospinal fluid (CSF) and blood of individuals with Alzheimer disease (AD). However, it is not known whether there are differences in blood GFAP levels across the entire AD continuum and whether its performance is similar to that of CSF GFAP., Objective: To evaluate plasma GFAP levels throughout the entire AD continuum, from preclinical AD to AD dementia, compared with CSF GFAP., Design, Setting, and Participants: This observational, cross-sectional study collected data from July 29, 2014, to January 31, 2020, from 3 centers. The Translational Biomarkers in Aging and Dementia (TRIAD) cohort (Montreal, Canada) included individuals in the entire AD continuum. Results were confirmed in the Alzheimer's and Families (ALFA+) study (Barcelona, Spain), which included individuals with preclinical AD, and the BioCogBank Paris Lariboisière cohort (Paris, France), which included individuals with symptomatic AD., Main Outcomes and Measures: Plasma and CSF GFAP levels measured with a Simoa assay were the main outcome. Other measurements included levels of CSF amyloid-β 42/40 (Aβ42/40), phosphorylated tau181 (p-tau181), neurofilament light (NfL), Chitinase-3-like protein 1 (YKL40), and soluble triggering receptor expressed on myeloid cells 2 (sTREM2) and levels of plasma p-tau181 and NfL. Results of amyloid positron emission tomography (PET) were available in TRIAD and ALFA+, and results of tau PET were available in TRIAD., Results: A total of 300 TRIAD participants (177 women [59.0%]; mean [SD] age, 64.6 [17.6] years), 384 ALFA+ participants (234 women [60.9%]; mean [SD] age, 61.1 [4.7] years), and 187 BioCogBank Paris Lariboisière participants (116 women [62.0%]; mean [SD] age, 69.9 [9.2] years) were included. Plasma GFAP levels were significantly higher in individuals with preclinical AD in comparison with cognitively unimpaired (CU) Aβ-negative individuals (TRIAD: Aβ-negative mean [SD], 185.1 [93.5] pg/mL, Aβ-positive mean [SD], 285.0 [142.6] pg/mL; ALFA+: Aβ-negative mean [SD], 121.9 [42.4] pg/mL, Aβ-positive mean [SD], 169.9 [78.5] pg/mL). Plasma GFAP levels were also higher among individuals in symptomatic stages of the AD continuum (TRIAD: CU Aβ-positive mean [SD], 285.0 [142.6] pg/mL, mild cognitive impairment [MCI] Aβ-positive mean [SD], 332.5 [153.6] pg/mL; AD mean [SD], 388.1 [152.8] pg/mL vs CU Aβ-negative mean [SD], 185.1 [93.5] pg/mL; Paris: MCI Aβ-positive, mean [SD], 368.6 [158.5] pg/mL; AD dementia, mean [SD], 376.4 [179.6] pg/mL vs CU Aβ-negative mean [SD], 161.2 [67.1] pg/mL). Plasma GFAP magnitude changes were consistently higher than those of CSF GFAP. Plasma GFAP more accurately discriminated Aβ-positive from Aβ-negative individuals than CSF GFAP (area under the curve for plasma GFAP, 0.69-0.86; area under the curve for CSF GFAP, 0.59-0.76). Moreover, plasma GFAP levels were positively associated with tau pathology only among individuals with concomitant Aβ pathology., Conclusions and Relevance: This study suggests that plasma GFAP is a sensitive biomarker for detecting and tracking reactive astrogliosis and Aβ pathology even among individuals in the early stages of AD.
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- 2021
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46. Associations between air pollution and biomarkers of Alzheimer's disease in cognitively unimpaired individuals.
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Alemany S, Crous-Bou M, Vilor-Tejedor N, Milà-Alomà M, Suárez-Calvet M, Salvadó G, Cirach M, Arenaza-Urquijo EM, Sanchez-Benavides G, Grau-Rivera O, Minguillon C, Fauria K, Kollmorgen G, Domingo Gispert J, Gascón M, Nieuwenhuijsen M, Zetterberg H, Blennow K, Sunyer J, and Luis Molinuevo J
- Subjects
- Adult, Amyloid beta-Peptides, Biomarkers, Humans, tau Proteins, Air Pollution adverse effects, Alzheimer Disease
- Abstract
Background: Air quality contributes to incidence of Alzheimer's disease (AD) although the underlying neurobiological mechanisms are unclear. This study was aimed to examine the association between air pollution and concentrations of cerebrospinal fluid (CSF) AD biomarkers and amyloid-β (Aβ) deposition. Participants and methods The sample included 156 cognitively unimpaired adults aged 57 years (61 at biomarkers assessment) with increased risk of AD from the ALFA + Study. We examined CSF levels of Aβ42, Aβ40, p-Tau, t-Tau, neurofilament light (NfL) and cerebral amyloid load (Centiloid). A Land Use Regression model from 2009 was used to estimate residential exposure to air pollutants including nitrogen dioxide (NO
2 ,) and particulate matter (PM2.5 , PM2.5 abs , PM10 ). This model was considered a surrogate of long-term exposure until time of data collection in 2013-2014. Participants have resided in the same residence for at least the previous 3 years. Multiple linear regression models were used to estimate associations between air pollutants and biomarkers. The effect modification by CSF Aβ status and APOE-ε4 carriership was also assessed., Results: A consistent pattern of results indicated that greater exposure to NO2 and PM2.5 absorbance was associated with higher levels of brain Aβ deposition, while greater exposure to PM10 and PM2.5 was associated with higher levels of CSF NfL. Most associations were driven by individuals that were Aβ-positive. Although APOE-ε4 status did not significantly modify these associations, the effect of air pollutants exposure on CSF NfL levels was stronger in APOE-ε4 carriers., Conclusion: In a population of cognitively unimpaired adults with increased risk of AD, long-term exposure to air pollution was associated with higher levels in biomarkers of AD pathology. While further research is granted to elucidate the mechanisms involved in such associations, our results reinforce the role of air pollution as an environmental risk factor for AD., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)- Published
- 2021
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47. CSF Synaptic Biomarkers in the Preclinical Stage of Alzheimer Disease and Their Association With MRI and PET: A Cross-sectional Study.
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Milà-Alomà M, Brinkmalm A, Ashton NJ, Kvartsberg H, Shekari M, Operto G, Salvadó G, Falcon C, Gispert JD, Vilor-Tejedor N, Arenaza-Urquijo EM, Grau-Rivera O, Sala-Vila A, Sanchez-Benavides G, González-de-Echávarri JM, Minguillon C, Fauria K, Niñerola-Baizán A, Perissinotti A, Kollmorgen G, Suridjan I, Zetterberg H, Molinuevo JL, Blennow K, and Suárez-Calvet M
- Subjects
- Amyloid beta-Peptides, Biomarkers, Cross-Sectional Studies, Female, Humans, Magnetic Resonance Imaging, Middle Aged, Positron-Emission Tomography, tau Proteins, Alzheimer Disease diagnostic imaging
- Abstract
Background and Objectives: To determine whether CSF synaptic biomarkers are altered in the early preclinical stage of the Alzheimer continuum and associated with Alzheimer disease (AD) risk factors, primary pathology, and neurodegeneration markers., Methods: This cross-sectional study was performed in the Alzheimer's and Families (ALFA+) cohort, comprising middle-aged cognitively unimpaired participants. CSF neurogranin and growth-associated protein-43 (GAP-43) were measured with immunoassays, and synaptosomal-associated protein-25 (SNAP-25) and synaptotagmin-1 were measured with immunoprecipitation mass spectrometry. AD CSF biomarkers β-amyloid (Aβ)
42/40 , phosphorylated tau (p-tau), and total tau and the neurodegeneration biomarker neurofilament light chain (NfL) were also measured. Participants underwent structural MRI and fluorodeoxyglucose and Aβ PET imaging. General linear modeling was used to test the associations between CSF synaptic biomarkers and risk factors, Aβ pathology, tau pathology, and neurodegeneration markers., Results: All CSF synaptic biomarkers increased with age. CSF neurogranin was higher in females, while CSF SNAP-25 was higher in APOE ε4 carriers. All CSF synaptic biomarkers increased with higher Aβ load (as measured by CSF Aβ42/40 and Aβ PET Centiloid values), and it is important to note that the synaptic biomarkers were increased even in individuals in the earliest stages of Aβ deposition. Higher CSF synaptic biomarkers were also associated with higher CSF p-tau and NfL. Higher CSF neurogranin and GAP-43 were significantly associated with higher brain metabolism but lower cortical thickness in AD-related brain regions., Discussion: CSF synaptic biomarkers increase in the early preclinical stages of the Alzheimer continuum even when a low burden of Aβ pathology is present, and they differ in their association with age, sex, APOE ε4 , and markers of neurodegeneration., Trial Registration Information: ClinicalTrials.gov Identifier NCT02485730., (Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)- Published
- 2021
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48. Regional amyloid accumulation predicts memory decline in initially cognitively unimpaired individuals.
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Collij LE, Mastenbroek SE, Salvadó G, Wink AM, Visser PJ, Barkhof F, van Berckel BNM, and Lopes Alves I
- Abstract
Introduction: The value of quantitative longitudinal and regional amyloid beta (Aβ) measurements in predicting cognitive decline in initially cognitively unimpaired (CU) individuals remains to be determined., Methods: We selected 133 CU individuals with two or more [
11 C]Pittsburgh compound B ([11 C]PiB) scans and neuropsychological data from Open Access Series of Imaging Studies (OASIS-3). Baseline and annualized distribution volume ratios were computed for a global composite and four regional clusters. The predictive value of Aβ measurements (baseline, slope, and interaction) on longitudinal cognitive performance was examined., Results: Global performance could only be predicted by Aβ burden in an early cluster (precuneus, lateral orbitofrontal, and insula) and the precuneus region of interest (ROI) by itself significantly improved the model. Precuneal Aβ burden was also predictive of immediate and delayed episodic memory performance. In Aβ subjects at baseline ( N = 93), lateral orbitofrontal Aβ burden predicted working and semantic memory performance., Discussion: Quantifying longitudinal and regional changes in Aβ can improve the prediction of cognitive functioning in initially CU individuals., Competing Interests: Lyduine E. Collij, Sophie E. Mastenbroek, Gemma Salvadó, Alle Meije Wink, and Isadora Lopes Alves report no disclosures relevant to this manuscript. Pieter Jelle Visser has served as member of the advisory board of Roche Diagnostics. Dr Visser received non‐financial support from GE Healthcare; research support from Biogen; and grants from Bristol‐Myers Squibb, EU/EFPIA Innovative Medicines Initiative Joint Undertaking, EU Joint Programme–Neurodegenerative Disease Research (JPND and ZonMw). Frederik Barkhof received payment and honoraria from Bayer Genzyme, Biogen‐Idec, TEVA, Merck, Novartis, Roche, IXICO Ltd, GeNeuro, and Apitope Ltd for consulting; payment from the IXICOLtd, and MedScape for educational presentations; and research support via grants from EU/EFPIA Innovative Medicines Initiative Joint Undertaking (AMYPAD consortium), EuroPOND (H2020), UK MS Society, Dutch MS Society, PICTURE (IMDI‐NWO), NIHR UCLH Biomedical Research Centre (BRC), and ECTRIMS‐MAGNIMS. Bart N.M. van Berckel received research support from ZON‐MW, AVID radiopharmaceuticals, CTMM, and Janssen Pharmaceuticals. BvB is a trainer for Piramal and GE; he receives no personal honoraria., (© 2021 The Authors. Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring published by Wiley Periodicals, LLC on behalf of Alzheimer's Association.)- Published
- 2021
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49. Cognitively unimpaired individuals with a low burden of Aβ pathology have a distinct CSF biomarker profile.
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Milà-Alomà M, Shekari M, Salvadó G, Gispert JD, Arenaza-Urquijo EM, Operto G, Falcon C, Vilor-Tejedor N, Grau-Rivera O, Sala-Vila A, Sánchez-Benavides G, González-de-Echávarri JM, Minguillon C, Fauria K, Niñerola-Baizán A, Perissinotti A, Simon M, Kollmorgen G, Zetterberg H, Blennow K, Suárez-Calvet M, and Molinuevo JL
- Subjects
- Amyloid beta-Peptides, Biomarkers, Cross-Sectional Studies, Humans, Middle Aged, Positron-Emission Tomography, tau Proteins, Alzheimer Disease
- Abstract
Background: Understanding the changes that occur in the transitional stage between absent and overt amyloid-β (Aβ) pathology within the Alzheimer's continuum is crucial to develop therapeutic and preventive strategies. The objective of this study is to test whether cognitively unimpaired individuals with a low burden of Aβ pathology have a distinct CSF, structural, and functional neuroimaging biomarker profile., Methods: Cross-sectional study of 318 middle-aged, cognitively unimpaired individuals from the ALFA+ cohort. We measured CSF Aβ42/40, phosphorylated tau (p-tau), total tau (t-tau), neurofilament light (NfL), neurogranin, sTREM2, YKL40, GFAP, IL6, S100B, and α-synuclein. Participants also underwent cognitive assessments, APOE genotyping, structural MRI, [
18 F]-FDG, and [18 F]-flutemetamol PET. To ensure the robustness of our results, we used three definitions of low burden of Aβ pathology: (1) positive CSF Aβ42/40 and < 30 Centiloids in Aβ PET, (2) positive CSF Aβ42/40 and negative Aβ PET visual read, and (3) 20-40 Centiloid range in Aβ PET. We tested CSF and neuroimaging biomarker differences between the low burden group and the corresponding Aβ-negative group, adjusted by age and sex., Results: The prevalence and demographic characteristics of the low burden group differed between the three definitions. CSF p-tau and t-tau were increased in the low burden group compared to the Aβ-negative in all definitions. CSF neurogranin was increased in the low burden group definitions 1 and 3, while CSF NfL was only increased in the low burden group definition 1. None of the defined low burden groups showed signs of atrophy or glucose hypometabolism. Instead, we found slight increases in cortical thickness and metabolism in definition 2., Conclusions: There are biologically meaningful Aβ-downstream effects in individuals with a low burden of Aβ pathology, while structural and functional changes are still subtle or absent. These findings support considering individuals with a low burden of Aβ pathology for clinical trials., Trial Registration: NCT02485730., (© 2021. The Author(s).)- Published
- 2021
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50. A multisite analysis of the concordance between visual image interpretation and quantitative analysis of [ 18 F]flutemetamol amyloid PET images.
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Bucci M, Savitcheva I, Farrar G, Salvadó G, Collij L, Doré V, Gispert JD, Gunn R, Hanseeuw B, Hansson O, Shekari M, Lhommel R, Molinuevo JL, Rowe C, Sur C, Whittington A, Buckley C, and Nordberg A
- Subjects
- Amyloid metabolism, Amyloid beta-Peptides metabolism, Aniline Compounds, Benzothiazoles, Brain diagnostic imaging, Brain metabolism, Humans, Alzheimer Disease diagnostic imaging, Positron-Emission Tomography
- Abstract
Background: [
18 F]flutemetamol PET scanning provides information on brain amyloid load and has been approved for routine clinical use based upon visual interpretation as either negative (equating to none or sparse amyloid plaques) or amyloid positive (equating to moderate or frequent plaques). Quantitation is however fundamental to the practice of nuclear medicine and hence can be used to supplement amyloid reading methodology especially in unclear cases., Methods: A total of 2770 [18 F]flutemetamol images were collected from 3 clinical studies and 6 research cohorts with available visual reading of [18 F]flutemetamol and quantitative analysis of images. These were assessed further to examine both the discordance and concordance between visual and quantitative imaging primarily using thresholds robustly established using pathology as the standard of truth. Scans covered a wide range of cases (i.e. from cognitively unimpaired subjects to patients attending the memory clinics). Methods of quantifying amyloid ranged from using CE/510K cleared marked software (e.g. CortexID, Brass), to other research-based methods (e.g. PMOD, CapAIBL). Additionally, the clinical follow-up of two types of discordance between visual and quantitation (V+Q- and V-Q+) was examined with competing risk regression analysis to assess possible differences in prediction for progression to Alzheimer's disease (AD) and other diagnoses (OD)., Results: Weighted mean concordance between visual and quantitation using the autopsy-derived threshold was 94% using pons as the reference region. Concordance from a sensitivity analysis which assessed the maximum agreement for each cohort using a range of cut-off values was also estimated at approximately 96% (weighted mean). Agreement was generally higher in clinical cases compared to research cases. V-Q+ discordant cases were 11% more likely to progress to AD than V+Q- for the SUVr with pons as reference region., Conclusions: Quantitation of amyloid PET shows a high agreement vs binary visual reading and also allows for a continuous measure that, in conjunction with possible discordant analysis, could be used in the future to identify possible earlier pathological deposition as well as monitor disease progression and treatment effectiveness.- Published
- 2021
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