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1. Personalized whole-brain neural mass models reveal combined Aβ and tau hyperexcitable influences in Alzheimer’s disease

Author

Sanchez-Rodriguez, Lazaro M, Bezgin, Gleb, Carbonell, Felix, Therriault, Joseph, Fernandez-Arias, Jaime, Servaes, Stijn, Rahmouni, Nesrine, Tissot, Cécile, Stevenson, Jenna, Karikari, Thomas K, Ashton, Nicholas J, Benedet, Andréa L, Zetterberg, Henrik, Blennow, Kaj, Triana-Baltzer, Gallen, Kolb, Hartmuth C, Rosa-Neto, Pedro, and Iturria-Medina, Yasser

Subjects
Biochemistry and Cell Biology, Biological Sciences, Clinical Research, Acquired Cognitive Impairment, Aging, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Brain Disorders, Neurosciences, Biomedical Imaging, Alzheimer's Disease, Neurodegenerative, Dementia, Aetiology, 2.1 Biological and endogenous factors, Neurological, Alzheimer Disease, Humans, tau Proteins, Amyloid beta-Peptides, Brain, Male, Female, Aged, Magnetic Resonance Imaging, Middle Aged, Positron-Emission Tomography, Models, Neurological, Biomarkers, Aged, 80 and over, Electroencephalography, Neurons, Biological sciences, Biomedical and clinical sciences
Abstract

Neuronal dysfunction and cognitive deterioration in Alzheimer's disease (AD) are likely caused by multiple pathophysiological factors. However, mechanistic evidence in humans remains scarce, requiring improved non-invasive techniques and integrative models. We introduce personalized AD computational models built on whole-brain Wilson-Cowan oscillators and incorporating resting-state functional MRI, amyloid-β (Aβ) and tau-PET from 132 individuals in the AD spectrum to evaluate the direct impact of toxic protein deposition on neuronal activity. This subject-specific approach uncovers key patho-mechanistic interactions, including synergistic Aβ and tau effects on cognitive impairment and neuronal excitability increases with disease progression. The data-derived neuronal excitability values strongly predict clinically relevant AD plasma biomarker concentrations (p-tau217, p-tau231, p-tau181, GFAP) and grey matter atrophy obtained through voxel-based morphometry. Furthermore, reconstructed EEG proxy quantities show the hallmark AD electrophysiological alterations (theta band activity enhancement and alpha reductions) which occur with Aβ-positivity and after limbic tau involvement. Microglial activation influences on neuronal activity are less definitive, potentially due to neuroimaging limitations in mapping neuroprotective vs detrimental activation phenotypes. Mechanistic brain activity models can further clarify intricate neurodegenerative processes and accelerate preventive/treatment interventions.

Published
2024

3. Biomarker-based staging of Alzheimer disease: rationale and clinical applications

Author

Therriault, Joseph, Schindler, Suzanne E., Salvadó, Gemma, Pascoal, Tharick A., Benedet, Andréa Lessa, Ashton, Nicholas J., Karikari, Thomas K., Apostolova, Liana, Murray, Melissa E., Verberk, Inge, Vogel, Jacob W., La Joie, Renaud, Gauthier, Serge, Teunissen, Charlotte, Rabinovici, Gil D., Zetterberg, Henrik, Bateman, Randall J., Scheltens, Philip, Blennow, Kaj, Sperling, Reisa, Hansson, Oskar, Jack, Jr, Clifford R., and Rosa-Neto, Pedro

Published
2024
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6. Neuropsychiatric Symptoms and Microglial Activation in Patients with Alzheimer Disease

Author

Aguzzoli, Cristiano Schaffer, Ferreira, Pâmela CL, Povala, Guilherme, Ferrari-Souza, João Pedro, Bellaver, Bruna, Katz, Carolina Soares, Zalzale, Hussein, Lussier, Firoza Z, Rohden, Francieli, Abbas, Sarah, Leffa, Douglas T, Medeiros, Marina Scop, Therriault, Joseph, Benedet, Andréa L, Tissot, Cécile, Servaes, Stijn, Rahmouni, Nesrine, Macedo, Arthur Cassa, Bezgin, Gleb, Kang, Min Su, Stevenson, Jenna, Pallen, Vanessa, Cohen, Ann, Lopez, Oscar L, Tudorascu, Dana L, Klunk, William E, Villemagne, Victor L, Soucy, Jean Paul, Zimmer, Eduardo R, Schilling, Lucas P, Karikari, Thomas K, Ashton, Nicholas J, Zetterberg, Henrik, Blennow, Kaj, Gauthier, Serge, Valcour, Victor, Miller, Bruce L, Rosa-Neto, Pedro, and Pascoal, Tharick A

Subjects
Health Services and Systems, Health Sciences, Aging, Alzheimer's Disease, Brain Disorders, Acquired Cognitive Impairment, Dementia, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Neurosciences, Biomedical Imaging, Neurodegenerative, Clinical Research, 4.2 Evaluation of markers and technologies, Detection, screening and diagnosis, 4.1 Discovery and preclinical testing of markers and technologies, Neurological, Male, Humans, Female, Aged, Alzheimer Disease, Microglia, tau Proteins, Cross-Sectional Studies, Amyloid beta-Peptides, Biomarkers, Biomedical and clinical sciences, Health sciences
Abstract

ImportanceNeuropsychiatric symptoms are commonly encountered and are highly debilitating in patients with Alzheimer disease. Understanding their underpinnings has implications for identifying biomarkers and treatment for these symptoms.ObjectiveTo evaluate whether glial markers are associated with neuropsychiatric symptoms in individuals across the Alzheimer disease continuum.Design, setting, and participantsThis cross-sectional study was conducted from January to June 2023, leveraging data from the Translational Biomarkers in Aging and Dementia cohort at McGill University, Canada. Recruitment was based on referrals of individuals from the community or from outpatient clinics. Exclusion criteria included active substance abuse, major surgery, recent head trauma, safety contraindications for positron emission tomography (PET) or magnetic resonance imaging, being currently enrolled in other studies, and having inadequately treated systemic conditions.Main outcomes and measuresAll individuals underwent assessment for neuropsychiatric symptoms (Neuropsychiatry Inventory Questionnaire [NPI-Q]), and imaging for microglial activation ([11C]PBR28 PET), amyloid-β ([18F]AZD4694 PET), and tau tangles ([18F]MK6240 PET).ResultsOf the 109 participants, 72 (66%) were women and 37 (34%) were men; the median age was 71.8 years (range, 38.0-86.5 years). Overall, 70 had no cognitive impairment and 39 had cognitive impairment (25 mild; 14 Alzheimer disease dementia). Amyloid-β PET positivity was present in 21 cognitively unimpaired individuals (30%) and in 31 cognitively impaired individuals (79%). The NPI-Q severity score was associated with microglial activation in the frontal, temporal, and parietal cortices (β = 7.37; 95% CI, 1.34-13.41; P = .01). A leave-one-out approach revealed that irritability was the NPI-Q domain most closely associated with the presence of brain microglial activation (β = 6.86; 95% CI, 1.77-11.95; P = .008). Furthermore, we found that microglia-associated irritability was associated with study partner burden measured by NPI-Q distress score (β = 5.72; 95% CI, 0.33-11.10; P = .03).Conclusions and relevanceIn this cross-sectional study of 109 individuals across the AD continuum, microglial activation was associated with and a potential biomarker of neuropsychiatric symptoms in Alzheimer disease. Moreover, our findings suggest that the combination of amyloid-β- and microglia-targeted therapies could have an impact on relieving these symptoms.

Published
2023

7. Hormone therapy is associated with lower Alzheimer’s disease tau biomarkers in post-menopausal females -evidence from two independent cohorts

Author

Wang, Yi-Ting, Therriault, Joseph, Tissot, Cécile, Servaes, Stijn, Rahmouni, Nesrine, Macedo, Arthur Cassa, Fernandez-Arias, Jaime, Mathotaarachchi, Sulantha S., Stevenson, Jenna, Lussier, Firoza Z., Benedet, Andréa L., Pascoal, Tharick A., Ashton, Nicholas J., Zetterberg, Henrik, Blennow, Kaj, Gauthier, Serge, and Rosa-Neto, Pedro

Published
2024
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14. Plasma p-tau212 antemortem diagnostic performance and prediction of autopsy verification of Alzheimer’s disease neuropathology

Author

Kac, Przemysław R., González-Ortiz, Fernando, Emeršič, Andreja, Dulewicz, Maciej, Koutarapu, Srinivas, Turton, Michael, An, Yang, Smirnov, Denis, Kulczyńska-Przybik, Agnieszka, Varma, Vijay R., Ashton, Nicholas J., Montoliu-Gaya, Laia, Camporesi, Elena, Winkel, Izabela, Paradowski, Bogusław, Moghekar, Abhay, Troncoso, Juan C., Lashley, Tammaryn, Brinkmalm, Gunnar, Resnick, Susan M., Mroczko, Barbara, Kvartsberg, Hlin, Gregorič Kramberger, Milica, Hanrieder, Jörg, Čučnik, Saša, Harrison, Peter, Zetterberg, Henrik, Lewczuk, Piotr, Thambisetty, Madhav, Rot, Uroš, Galasko, Douglas, Blennow, Kaj, and Karikari, Thomas K.

Published
2024
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17. Inflammatory biomarkers for neurobehavioral dysregulation in former American football players: findings from the DIAGNOSE CTE Research Project

Author

van Amerongen, Suzan, Pulukuri, Surya V., Tuz-Zahra, Fatima, Tripodis, Yorghos, Cherry, Jonathan D., Bernick, Charles, Geda, Yonas E., Wethe, Jennifer V., Katz, Douglas I., Alosco, Michael L., Adler, Charles H., Balcer, Laura J., Ashton, Nicholas J., Blennow, Kaj, Zetterberg, Henrik, Daneshvar, Daniel H., Colasurdo, Elizabeth A., Iliff, Jeffrey J., Li, Gail, Peskind, Elaine R., Shenton, Martha E., Reiman, Eric M., Cummings, Jeffrey L., and Stern, Robert A.

Published
2024
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18. Comparison of immunoassay- with mass spectrometry-derived p-tau quantification for the detection of Alzheimer’s disease pathology

Author

Therriault, Joseph, Woo, Marcel S., Salvadó, Gemma, Gobom, Johan, Karikari, Thomas K., Janelidze, Shorena, Servaes, Stijn, Rahmouni, Nesrine, Tissot, Cécile, Ashton, Nicholas J., Benedet, Andréa Lessa, Montoliu-Gaya, Laia, Macedo, Arthur C., Lussier, Firoza Z., Stevenson, Jenna, Vitali, Paolo, Friese, Manuel A., Massarweh, Gassan, Soucy, Jean-Paul, Pascoal, Tharick A., Stomrud, Erik, Palmqvist, Sebastian, Mattsson-Carlgren, Niklas, Gauthier, Serge, Zetterberg, Henrik, Hansson, Oskar, Blennow, Kaj, and Rosa-Neto, Pedro

Published
2024
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20. CSF p-tau205: a biomarker of tau pathology in Alzheimer’s disease

Author

Lantero-Rodriguez, Juan, Montoliu-Gaya, Laia, Benedet, Andrea L., Vrillon, Agathe, Dumurgier, Julien, Cognat, Emmanuel, Brum, Wagner S., Rahmouni, Nesrine, Stevenson, Jenna, Servaes, Stijn, Therriault, Joseph, Becker, Bruno, Brinkmalm, Gunnar, Snellman, Anniina, Huber, Hanna, Kvartsberg, Hlin, Ashton, Nicholas J., Zetterberg, Henrik, Paquet, Claire, Rosa-Neto, Pedro, and Blennow, Kaj

Published
2024
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21. Optimal blood tau species for the detection of Alzheimer’s disease neuropathology: an immunoprecipitation mass spectrometry and autopsy study

Author

Montoliu-Gaya, Laia, Alosco, Michael L., Yhang, Eukyung, Tripodis, Yorghos, Sconzo, Daniel, Ally, Madeline, Grötschel, Lana, Ashton, Nicholas J., Lantero-Rodriguez, Juan, Sauer, Mathias, Gomes, Bárbara, Nilsson, Johanna, Brinkmalm, Gunnar, Sugarman, Michael A., Aparicio, Hugo J., Martin, Brett, Palmisano, Joseph N., Steinberg, Eric G., Simkin, Irene, Turk, Katherine W., Budson, Andrew E., Au, Rhoda, Farrer, Lindsay, Jun, Gyungah R., Kowall, Neil W., Stern, Robert A., Goldstein, Lee E., Qiu, Wei Qiao, Mez, Jesse, Huber, Bertrand Russell, Alvarez, Victor E., McKee, Ann C., Zetterberg, Henrik, Gobom, Johan, Stein, Thor D., and Blennow, Kaj

Published
2024
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22. Association of CSF GAP-43 With the Rate of Cognitive Decline and Progression to Dementia in Amyloid-Positive Individuals

Author

Öhrfelt, Annika, Benedet, Andréa L, Ashton, Nicholas J, Kvartsberg, Hlin, Vandijck, Manu, Weiner, Michael W, Trojanowski, John Q, Shaw, Leslie M, Zetterberg, Henrik, Blennow, Kaj, and Initiative, for the Alzheimer's Disease Neuroimaging

Subjects
Biomedical and Clinical Sciences, Neurosciences, Clinical Sciences, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Acquired Cognitive Impairment, Clinical Research, Dementia, Neurodegenerative, Brain Disorders, Alzheimer's Disease, Aging, 4.1 Discovery and preclinical testing of markers and technologies, Detection, screening and diagnosis, Neurological, Humans, Alzheimer Disease, Amyloid beta-Peptides, GAP-43 Protein, Retrospective Studies, tau Proteins, Cognitive Dysfunction, Biomarkers, Amyloidogenic Proteins, Atrophy, Positron-Emission Tomography, Disease Progression, Alzheimer's Disease Neuroimaging Initiative, Cognitive Sciences, Neurology & Neurosurgery, Clinical sciences
Abstract

Background and objectivesTo test the associations between the presynaptic growth-associated protein 43 (GAP-43), quantified in CSF, and biomarkers of Alzheimer disease (AD) pathophysiology, cross-sectionally and longitudinally.MethodsIn this retrospective study, GAP-43 was measured in participants from the AD Neuroimaging Initiative (ADNI) cohort using an in-house ELISA method, and levels were compared between groups, both cross-sectionally and longitudinally. Linear regression models tested the associations between biomarkers of AD (amyloid beta [Aβ] and tau pathologies, neurodegeneration, and cognition) adjusted by age, sex, and diagnosis. Linear mixed-effect models evaluated how baseline GAP-43 predicts brain hypometabolism, atrophy, and cognitive decline over time. Cox proportional hazard regression models tested how GAP-43 levels and Aβ status, at baseline, increased the risk of progression to AD dementia over time.ResultsThis study included 786 participants from the ADNI cohort, which were further classified in cognitively unimpaired (CU) Aβ-negative (nCU- = 197); CU Aβ-positive (nCU+ = 55), mild cognitively impaired (MCI) Aβ-negative (nMCI- = 228), MCI Aβ-positive (nMCI+ = 193), and AD dementia Aβ-positive (nAD = 113). CSF GAP-43 levels were increased in Aβ-positive compared with Aβ-negative participants, independent of the cognitive status. In Aβ-positive participants, high baseline GAP-43 levels led to worse brain metabolic decline (p = 0.01), worse brain atrophy (p = 8.8 × 10-27), and worse MMSE scores (p = 0.03) over time, as compared with those with low GAP-43 levels. Similarly, Aβ-positive participants with high baseline GAP-43 had the highest risk to convert to AD dementia (hazard ratio [HR = 8.56, 95% CI 4.94-14.80, p = 1.5 × 10-14]). Despite the significant association with Aβ pathology (η2 Aβ PET = 0.09, P Aβ PET < 0.001), CSF total tau (tTau) and phosphorylated tau (pTau) had a larger effect size on GAP43 than Aβ PET (η2 pTau-181 = 0.53, P pTau-181 < 0.001; η2 tTau = 0.59, P tTau < 0.001).DiscussionHigh baseline levels of CSF GAP-43 are associated with progression in Aβ-positive individuals, with a more aggressive neurodegenerative process, faster rate of cognitive decline, and increased risk of converting to dementia.

Published
2023

23. APOEε4 potentiates amyloid β effects on longitudinal tau pathology

Author

Ferrari-Souza, João Pedro, Bellaver, Bruna, Ferreira, Pâmela C. L., Benedet, Andréa L., Povala, Guilherme, Lussier, Firoza Z., Leffa, Douglas T., Therriault, Joseph, Tissot, Cécile, Soares, Carolina, Wang, Yi-Ting, Chamoun, Mira, Servaes, Stijn, Macedo, Arthur C., Vermeiren, Marie, Bezgin, Gleb, Kang, Min Su, Stevenson, Jenna, Rahmouni, Nesrine, Pallen, Vanessa, Poltronetti, Nina Margherita, Cohen, Ann, Lopez, Oscar L., Klunk, William E., Soucy, Jean-Paul, Gauthier, Serge, Souza, Diogo O., Triana-Baltzer, Gallen, Saad, Ziad S., Kolb, Hartmuth C., Karikari, Thomas K., Villemagne, Victor L., Tudorascu, Dana L., Ashton, Nicholas J., Zetterberg, Henrik, Blennow, Kaj, Zimmer, Eduardo R., Rosa-Neto, Pedro, and Pascoal, Tharick A.

Published
2023
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24. Proteome-wide analysis identifies plasma immune regulators of amyloid-beta progression

Author

Duggan, Michael R., Gomez, Gabriela T., Joynes, Cassandra M., Bilgel, Murat, Chen, Jingsha, Fattorelli, Nicola, Hohman, Timothy J., Mancuso, Renzo, Cordon, Jenifer, Castellano, Tonnar, Koran, Mary Ellen I., Candia, Julián, Lewis, Alexandria, Moghekar, Abhay, Ashton, Nicholas J., Kac, Przemysław R., Karikari, Thomas K., Blennow, Kaj, Zetterberg, Henrik, Martinez-Muriana, Anna, De Strooper, Bart, Thambisetty, Madhav, Ferrucci, Luigi, Gottesman, Rebecca F., Coresh, Josef, Resnick, Susan M., and Walker, Keenan A.

Published
2024
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25. A two-step workflow based on plasma p-tau217 to screen for amyloid β positivity with further confirmatory testing only in uncertain cases

Author

Brum, Wagner S., Cullen, Nicholas C., Janelidze, Shorena, Ashton, Nicholas J., Zimmer, Eduardo R., Therriault, Joseph, Benedet, Andrea L., Rahmouni, Nesrine, Tissot, Cécile, Stevenson, Jenna, Servaes, Stijn, Triana-Baltzer, Gallen, Kolb, Hartmuth C., Palmqvist, Sebastian, Stomrud, Erik, Rosa-Neto, Pedro, Blennow, Kaj, and Hansson, Oskar

Published
2023
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26. Astrocyte reactivity influences amyloid-β effects on tau pathology in preclinical Alzheimer’s disease

Author

Bellaver, Bruna, Povala, Guilherme, Ferreira, Pamela C. L., Ferrari-Souza, João Pedro, Leffa, Douglas T., Lussier, Firoza Z., Benedet, Andréa L., Ashton, Nicholas J., Triana-Baltzer, Gallen, Kolb, Hartmuth C., Tissot, Cécile, Therriault, Joseph, Servaes, Stijn, Stevenson, Jenna, Rahmouni, Nesrine, Lopez, Oscar L., Tudorascu, Dana L., Villemagne, Victor L., Ikonomovic, Milos D., Gauthier, Serge, Zimmer, Eduardo R., Zetterberg, Henrik, Blennow, Kaj, Aizenstein, Howard J., Klunk, William E., Snitz, Beth E., Maki, Pauline, Thurston, Rebecca C., Cohen, Ann D., Ganguli, Mary, Karikari, Thomas K., Rosa-Neto, Pedro, and Pascoal, Tharick A.

Published
2023
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29. Plasma biomarkers for Alzheimer’s Disease in relation to neuropathology and cognitive change

Author

Smirnov, Denis S, Ashton, Nicholas J, Blennow, Kaj, Zetterberg, Henrik, Simrén, Joel, Lantero-Rodriguez, Juan, Karikari, Thomas K, Hiniker, Annie, Rissman, Robert A, Salmon, David P, and Galasko, Douglas

Subjects
Neurosciences, Neurodegenerative, Acquired Cognitive Impairment, Alzheimer's Disease, Dementia, Brain Disorders, Aging, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Aetiology, Detection, screening and diagnosis, 4.1 Discovery and preclinical testing of markers and technologies, 4.2 Evaluation of markers and technologies, 2.1 Biological and endogenous factors, Neurological, Alzheimer Disease, Amyloid beta-Peptides, Biomarkers, Cognition, Cognitive Dysfunction, Humans, Lewy Body Disease, tau Proteins, Biomarker, Neuropathology, Plasma, Alzheimer’s Disease, Clinical Sciences, Neurology & Neurosurgery
Abstract

Plasma biomarkers related to amyloid, tau, and neurodegeneration (ATN) show great promise for identifying these pathological features of Alzheimer's Disease (AD) as shown by recent clinical studies and selected autopsy studies. We have evaluated ATN plasma biomarkers in a series of 312 well-characterized longitudinally followed research subjects with plasma available within 5 years or less before autopsy and examined these biomarkers in relation to a spectrum of AD and related pathologies. Plasma Aβ42, Aβ40, total Tau, P-tau181, P-tau231 and neurofilament light (NfL) were measured using Single molecule array (Simoa) assays. Neuropathological findings were assessed using standard research protocols. Comparing plasma biomarkers with pathology diagnoses and ratings, we found that P-tau181 (AUC = 0.856) and P-tau231 (AUC = 0.773) showed the strongest overall sensitivity and specificity for AD neuropathological change (ADNC). Plasma P-tau231 showed increases at earlier ADNC stages than other biomarkers. Plasma Aβ42/40 was decreased in relation to amyloid and AD pathology, with modest diagnostic accuracy (AUC = 0.601). NfL was increased in non-AD cases and in a subset of those with ADNC. Plasma biomarkers did not show changes in Lewy body disease (LBD), hippocampal sclerosis of aging (HS) or limbic-predominant age-related TDP-43 encephalopathy (LATE) unless ADNC was present. Higher levels of P-tau181, 231 and NfL predicted faster cognitive decline, as early as 10 years prior to autopsy, even among people with normal cognition or mild cognitive impairment. These results support plasma P-tau181 and 231 as diagnostic biomarkers related to ADNC that also can help to predict future cognitive decline, even in predementia stages. Although NfL was not consistently increased in plasma in AD and shows increases in several neurological disorders, it had utility to predict cognitive decline. Plasma Aβ42/40 as measured in this study was a relatively weak predictor of amyloid pathology, and different assay methods may be needed to improve on this. Additional plasma biomarkers are needed to detect the presence and impact of LBD and LATE pathology.

Published
2022

30. Vascular risk burden is a key player in the early progression of Alzheimer’s disease

Author

Ferrari-Souza, João Pedro, Brum, Wagner S., Hauschild, Lucas A., Da Ros, Lucas U., Ferreira, Pâmela C.L., Bellaver, Bruna, Leffa, Douglas T., Bieger, Andrei, Tissot, Cécile, Lussier, Firoza Z., De Bastiani, Marco Antônio, Povala, Guilherme, Benedet, Andréa L., Therriault, Joseph, Wang, Yi-Ting, Ashton, Nicholas J., Zetterberg, Henrik, Blennow, Kaj, Martins, Sheila O., Souza, Diogo O., Rosa-Neto, Pedro, Karikari, Thomas K., Pascoal, Tharick A., and Zimmer, Eduardo R.

Published
2024
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31. 14-3-3 ζ/δ-reported early synaptic injury in Alzheimer’s disease is independently mediated by sTREM2

Author

Woo, Marcel S., Nilsson, Johanna, Therriault, Joseph, Rahmouni, Nesrine, Brinkmalm, Ann, Benedet, Andrea L., Ashton, Nicholas J., Macedo, Arthur C., Servaes, Stijn, Wang, Yi-Ting, Tissot, Cécile, Arias, Jaime Fernandez, Hosseini, Seyyed Ali, Chamoun, Mira, Lussier, Firoza Z., Karikari, Thomas K., Stevenson, Jenna, Mayer, Christina, Ferrari-Souza, João Pedro, Kobayashi, Eliane, Massarweh, Gassan, Friese, Manuel A., Pascoal, Tharick A., Gauthier, Serge, Zetterberg, Henrik, Blennow, Kaj, and Rosa-Neto, Pedro

Published
2023
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35. Clinical performance and head-to-head comparison of CSF p-tau235 with p-tau181, p-tau217 and p-tau231 in two memory clinic cohorts

Author

Lantero-Rodriguez, Juan, Vrillon, Agathe, Fernández-Lebrero, Aida, Ortiz-Romero, Paula, Snellman, Anniina, Montoliu-Gaya, Laia, Brum, Wagner S., Cognat, Emmanuel, Dumurgier, Julien, Puig-Pijoan, Albert, Navalpotro-Gómez, Irene, García-Escobar, Greta, Karikari, Thomas K., Vanmechelen, Eugeen, Ashton, Nicholas J., Zetterberg, Henrik, Suárez-Calvet, Marc, Paquet, Claire, and Blennow, Kaj

Published
2023
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39. The strategic biomarker roadmap for the validation of Alzheimer’s diagnostic biomarkers: methodological update

Author

Boccardi, Marina, Dodich, Alessandra, Albanese, Emiliano, Gayet-Ageron, Angèle, Festari, Cristina, Ashton, Nicholas J, Bischof, Gérard N, Chiotis, Konstantinos, Leuzy, Antoine, Wolters, Emma E, Walter, Martin A, Rabinovici, Gil D, Carrillo, Maria, Drzezga, Alexander, Hansson, Oskar, Nordberg, Agneta, Ossenkoppele, Rik, Villemagne, Victor L, Winblad, Bengt, Frisoni, Giovanni B, and Garibotto, Valentina

Subjects
Biomedical and Clinical Sciences, Clinical Sciences, Acquired Cognitive Impairment, Neurosciences, Aging, Neurodegenerative, Alzheimer's Disease, Brain Disorders, Dementia, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Detection, screening and diagnosis, 4.1 Discovery and preclinical testing of markers and technologies, 4.2 Evaluation of markers and technologies, Alzheimer Disease, Amyloid beta-Peptides, Biomarkers, Cognitive Dysfunction, Cross-Sectional Studies, Disease Progression, Humans, Reference Standards, tau Proteins, Biomarker, Alzheimer&#8217, s disease, MCI, Mild cognitive impairment, Validation methodology, Alzheimer’s disease, Other Physical Sciences, Nuclear Medicine & Medical Imaging, Clinical sciences
Abstract

BackgroundThe 2017 Alzheimer's disease (AD) Strategic Biomarker Roadmap (SBR) structured the validation of AD diagnostic biomarkers into 5 phases, systematically assessing analytical validity (Phases 1-2), clinical validity (Phases 3-4), and clinical utility (Phase 5) through primary and secondary Aims. This framework allows to map knowledge gaps and research priorities, accelerating the route towards clinical implementation. Within an initiative aimed to assess the development of biomarkers of tau pathology, we revised this methodology consistently with progress in AD research.MethodsWe critically appraised the adequacy of the 2017 Biomarker Roadmap within current diagnostic frameworks, discussed updates at a workshop convening the Alzheimer's Association and 8 leading AD biomarker research groups, and detailed the methods to allow consistent assessment of aims achievement for tau and other AD diagnostic biomarkers.ResultsThe 2020 update applies to all AD diagnostic biomarkers. In Phases 2-3, we admitted a greater variety of study designs (e.g., cross-sectional in addition to longitudinal) and reference standards (e.g., biomarker confirmation in addition to clinical progression) based on construct (in addition to criterion) validity. We structured a systematic data extraction to enable transparent and formal evidence assessment procedures. Finally, we have clarified issues that need to be addressed to generate data eligible to evidence-to-decision procedures.DiscussionThis revision allows for more versatile and precise assessment of existing evidence, keeps up with theoretical developments, and helps clinical researchers in producing evidence suitable for evidence-to-decision procedures. Compliance with this methodology is essential to implement AD biomarkers efficiently in clinical research and diagnostics.

Published
2021

40. A multicentre validation study of the diagnostic value of plasma neurofilament light.

Author

Ashton, Nicholas J, Janelidze, Shorena, Al Khleifat, Ahmad, Leuzy, Antoine, van der Ende, Emma L, Karikari, Thomas K, Benedet, Andrea L, Pascoal, Tharick A, Lleó, Alberto, Parnetti, Lucilla, Galimberti, Daniela, Bonanni, Laura, Pilotto, Andrea, Padovani, Alessandro, Lycke, Jan, Novakova, Lenka, Axelsson, Markus, Velayudhan, Latha, Rabinovici, Gil D, Miller, Bruce, Pariante, Carmine, Nikkheslat, Naghmeh, Resnick, Susan M, Thambisetty, Madhav, Schöll, Michael, Fernández-Eulate, Gorka, Gil-Bea, Francisco J, López de Munain, Adolfo, Al-Chalabi, Ammar, Rosa-Neto, Pedro, Strydom, Andre, Svenningsson, Per, Stomrud, Erik, Santillo, Alexander, Aarsland, Dag, van Swieten, John C, Palmqvist, Sebastian, Zetterberg, Henrik, Blennow, Kaj, Hye, Abdul, and Hansson, Oskar

Subjects
Humans, Neurodegenerative Diseases, Down Syndrome, Neurofilament Proteins, False Positive Reactions, Cohort Studies, Predictive Value of Tests, Depression, Age Factors, Sex Factors, Reference Values, Aged, Middle Aged, Female, Male, Biomarkers, Cognitive Dysfunction
Abstract

Increased cerebrospinal fluid neurofilament light (NfL) is a recognized biomarker for neurodegeneration that can also be assessed in blood. Here, we investigate plasma NfL as a marker of neurodegeneration in 13 neurodegenerative disorders, Down syndrome, depression and cognitively unimpaired controls from two multicenter cohorts: King's College London (n = 805) and the Swedish BioFINDER study (n = 1,464). Plasma NfL was significantly increased in all cortical neurodegenerative disorders, amyotrophic lateral sclerosis and atypical parkinsonian disorders. We demonstrate that plasma NfL is clinically useful in identifying atypical parkinsonian disorders in patients with parkinsonism, dementia in individuals with Down syndrome, dementia among psychiatric disorders, and frontotemporal dementia in patients with cognitive impairment. Data-driven cut-offs highlighted the fundamental importance of age-related clinical cut-offs for disorders with a younger age of onset. Finally, plasma NfL performs best when applied to indicate no underlying neurodegeneration, with low false positives, in all age-related cut-offs.

Published
2021

42. Relevance of biomarkers across different neurodegenerative diseases

Author

Ehrenberg, Alexander J, Khatun, Ayesha, Coomans, Emma, Betts, Matthew J, Capraro, Federica, Thijssen, Elisabeth H, Senkevich, Konstantin, Bharucha, Tehmina, Jafarpour, Mehrsa, Young, Peter NE, Jagust, William, Carter, Stephen F, Lashley, Tammaryn, Grinberg, Lea T, Pereira, Joana B, Mattsson-Carlgren, Niklas, Ashton, Nicholas J, Hanrieder, Jörg, Zetterberg, Henrik, Schöll, Michael, and Paterson, Ross W

Subjects
Health Services and Systems, Health Sciences, Neurodegenerative, Acquired Cognitive Impairment, Dementia, Brain Disorders, Aging, Alzheimer's Disease, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Neurosciences, 4.5 Resources and infrastructure (detection), Detection, screening and diagnosis, Neurological, Good Health and Well Being, Alzheimer Disease, Amyloid beta-Peptides, Biomarkers, Disease Progression, Humans, Neurodegenerative Diseases, tau Proteins, Neurodegenerative diseases, Alzheimer's disease, Tau, Amyloid, Neurofilament light chain, Magnetic resonance imaging, Positron emission tomography, Cerebrospinal fluid, Plasma biomarkers, Alzheimer’s disease, Medical and Health Sciences, Biomedical and clinical sciences, Health sciences
Abstract

BackgroundThe panel of fluid- and imaging-based biomarkers available for neurodegenerative disease research is growing and has the potential to close important gaps in research and the clinic. With this growth and increasing use, appropriate implementation and interpretation are paramount. Various biomarkers feature nuanced differences in strengths, limitations, and biases that must be considered when investigating disease etiology and clinical utility. For example, neuropathological investigations of Alzheimer's disease pathogenesis can fall in disagreement with conclusions reached by biomarker-based investigations. Considering the varied strengths, limitations, and biases of different research methodologies and approaches may help harmonize disciplines within the neurodegenerative disease field.Purpose of reviewAlong with separate review articles covering fluid and imaging biomarkers in this issue of Alzheimer's Research and Therapy, we present the result of a discussion from the 2019 Biomarkers in Neurodegenerative Diseases course at the University College London. Here, we discuss themes of biomarker use in neurodegenerative disease research, commenting on appropriate use, interpretation, and considerations for implementation across different neurodegenerative diseases. We also draw attention to areas where biomarker use can be combined with other disciplines to understand issues of pathophysiology and etiology underlying dementia. Lastly, we highlight novel modalities that have been proposed in the landscape of neurodegenerative disease research and care.

Published
2020

43. Correction to: Relevance of biomarkers across different neurodegenerative diseases

Author

Ehrenberg, Alexander J, Khatun, Ayesha, Coomans, Emma, Betts, Matthew J, Capraro, Federica, Thijssen, Elisabeth H, Senkevich, Konstantin, Bharucha, Tehmina, Jafarpour, Mehrsa, Young, Peter NE, Jagust, William, Carter, Stephen F, Lashley, Tammaryn, Grinberg, Lea T, Pereira, Joana B, Mattsson-Carlgren, Niklas, Ashton, Nicholas J, Hanrieder, Jörg, Zetterberg, Henrik, Schöll, Michael, and Paterson, Ross W

Subjects
Biomedical and Clinical Sciences, Health Sciences, Medical and Health Sciences, Biomedical and clinical sciences, Health sciences
Abstract

An amendment to this paper has been published and can be accessed via the original article.

Published
2020

44. Differential roles of Aβ42/40, p-tau231 and p-tau217 for Alzheimer’s trial selection and disease monitoring

Author

Ashton, Nicholas J., Janelidze, Shorena, Mattsson-Carlgren, Niklas, Binette, Alexa Pichet, Strandberg, Olof, Brum, Wagner S., Karikari, Thomas K., González-Ortiz, Fernándo, Di Molfetta, Guglielmo, Meda, Francisco J., Jonaitis, Erin M., Koscik, Rebecca Langhough, Cody, Karly, Betthauser, Tobey J., Li, Yan, Vanmechelen, Eugeen, Palmqvist, Sebastian, Stomrud, Erik, Bateman, Randall J., Zetterberg, Henrik, Johnson, Sterling C., Blennow, Kaj, and Hansson, Oskar

Published
2022
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45. Astrocyte biomarker signatures of amyloid-β and tau pathologies in Alzheimer’s disease

Author

Ferrari-Souza, João Pedro, Ferreira, Pâmela C. L., Bellaver, Bruna, Tissot, Cécile, Wang, Yi-Ting, Leffa, Douglas T., Brum, Wagner S., Benedet, Andréa L., Ashton, Nicholas J., De Bastiani, Marco Antônio, Rocha, Andréia, Therriault, Joseph, Lussier, Firoza Z., Chamoun, Mira, Servaes, Stijn, Bezgin, Gleb, Kang, Min Su, Stevenson, Jenna, Rahmouni, Nesrine, Pallen, Vanessa, Poltronetti, Nina Margherita, Klunk, William E., Tudorascu, Dana L., Cohen, Ann D., Villemagne, Victor L., Gauthier, Serge, Blennow, Kaj, Zetterberg, Henrik, Souza, Diogo O., Karikari, Thomas K., Zimmer, Eduardo R., Rosa-Neto, Pedro, and Pascoal, Tharick A.

Published
2022
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46. Reactive astrogliosis is associated with higher cerebral glucose consumption in the early Alzheimer’s continuum

Author

Salvadó, Gemma, Milà-Alomà, Marta, Shekari, Mahnaz, Ashton, Nicholas J., Operto, Grégory, Falcon, Carles, Cacciaglia, Raffaele, Minguillon, Carolina, Fauria, Karine, Niñerola-Baizán, Aida, Perissinotti, Andrés, Benedet, Andréa L., Kollmorgen, Gwendlyn, Suridjan, Ivonne, Wild, Norbert, Molinuevo, José Luis, Zetterberg, Henrik, Blennow, Kaj, Suárez-Calvet, Marc, and Gispert, Juan Domingo

Published
2022
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49. Neurochemical evidence of astrocytic and neuronal injury commonly found in COVID-19

Author

Kanberg, Nelly, Ashton, Nicholas J, Andersson, Lars-Magnus, Yilmaz, Aylin, Lindh, Magnus, Nilsson, Staffan, Price, Richard W, Blennow, Kaj, Zetterberg, Henrik, and Gisslén, Magnus

Subjects
Neurodegenerative, Neurosciences, Clinical Research, Neurological, Good Health and Well Being, Adult, Age Factors, Aged, Astrocytes, Betacoronavirus, Biomarkers, COVID-19, Case-Control Studies, Coronavirus Infections, Female, Follow-Up Studies, Glial Fibrillary Acidic Protein, Humans, Male, Middle Aged, Neurofilament Proteins, Neurons, Pandemics, Pneumonia, Viral, SARS-CoV-2, Severity of Illness Index, Single Molecule Imaging, Clinical Sciences, Cognitive Sciences, Neurology & Neurosurgery
Abstract

ObjectiveTo test the hypothesis that coronavirus disease 2019 (COVID-19) has an impact on the CNS by measuring plasma biomarkers of CNS injury.MethodsWe recruited 47 patients with mild (n = 20), moderate (n = 9), or severe (n = 18) COVID-19 and measured 2 plasma biomarkers of CNS injury by single molecule array, neurofilament light chain protein (NfL; a marker of intra-axonal neuronal injury) and glial fibrillary acidic protein (GFAp; a marker of astrocytic activation/injury), in samples collected at presentation and again in a subset after a mean of 11.4 days. Cross-sectional results were compared with results from 33 age-matched controls derived from an independent cohort.ResultsThe patients with severe COVID-19 had higher plasma concentrations of GFAp (p = 0.001) and NfL (p < 0.001) than controls, while GFAp was also increased in patients with moderate disease (p = 0.03). In patients with severe disease, an early peak in plasma GFAp decreased on follow-up (p < 0.01), while NfL showed a sustained increase from first to last follow-up (p < 0.01), perhaps reflecting a sequence of early astrocytic response and more delayed axonal injury.ConclusionWe show neurochemical evidence of neuronal injury and glial activation in patients with moderate and severe COVID-19. Further studies are needed to clarify the frequency and nature of COVID-19-related CNS damage and its relation to both clinically defined CNS events such as hypoxic and ischemic events and mechanisms more closely linked to systemic severe acute respiratory syndrome coronavirus 2 infection and consequent immune activation, as well as to evaluate the clinical utility of monitoring plasma NfL and GFAp in the management of this group of patients.

Published
2020

50. Comparative analysis of obesity-related cardiometabolic and renal biomarkers in human plasma and serum.

Author

Rajan, Meenu Rohini, Sotak, Matus, Barrenäs, Fredrik, Shen, Tong, Borkowski, Kamil, Ashton, Nicholas J, Biörserud, Christina, Lindahl, Tomas L, Ramström, Sofia, Schöll, Michael, Lindahl, Per, Fiehn, Oliver, Newman, John W, Perkins, Rosie, Wallenius, Ville, Lange, Stephan, and Börgeson, Emma

Subjects
Humans, Kidney Diseases, Obesity, Plasminogen Activator Inhibitor 1, Adult, Middle Aged, Female, Male, Biomarkers, Proprotein Convertase 9, Metabolic Syndrome
Abstract

The search for biomarkers associated with obesity-related diseases is ongoing, but it is not clear whether plasma and serum can be used interchangeably in this process. Here we used high-throughput screening to analyze 358 proteins and 76 lipids, selected because of their relevance to obesity-associated diseases, in plasma and serum from age- and sex-matched lean and obese humans. Most of the proteins/lipids had similar concentrations in plasma and serum, but a subset showed significant differences. Notably, a key marker of cardiovascular disease PAI-1 showed a difference in concentration between the obese and lean groups only in plasma. Furthermore, some biomarkers showed poor correlations between plasma and serum, including PCSK9, an important regulator of cholesterol homeostasis. Collectively, our results show that the choice of biofluid may impact study outcome when screening for obesity-related biomarkers and we identify several markers where this will be the case.

Published
2019

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