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1. 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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2. 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

3. 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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4. Tau follows principal axes of functional and structural brain organization in Alzheimer’s disease

Author

Ottoy, Julie, Kang, Min Su, Tan, Jazlynn Xiu Min, Boone, Lyndon, Vos de Wael, Reinder, Park, Bo-yong, Bezgin, Gleb, Lussier, Firoza Z., Pascoal, Tharick A., Rahmouni, Nesrine, Stevenson, Jenna, Fernandez Arias, Jaime, Therriault, Joseph, Hong, Seok-Jun, Stefanovic, Bojana, McLaurin, JoAnne, Soucy, Jean-Paul, Gauthier, Serge, Bernhardt, Boris C., Black, Sandra E., Rosa-Neto, Pedro, and Goubran, Maged

Published
2024
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6. Alzheimer blood biomarkers: practical guidelines for study design, sample collection, processing, biobanking, measurement and result reporting

Author

Zeng, Xuemei, Chen, Yijun, Sehrawat, Anuradha, Lee, Jihui, Lafferty, Tara K., Kofler, Julia, Berman, Sarah B., Sweet, Robert A., Tudorascu, Dana L., Klunk, William E., Ikonomovic, Milos D., Pfister, Anna, Zetterberg, Henrik, Snitz, Beth E., Cohen, Anne D., Villemagne, Victor L., Pascoal, Tharick A., Kamboh, M. llyas, Lopez, Oscar I., Blennow, Kaj, and Karikari, Thomas K.

Published
2024
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7. 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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9. 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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10. The neurophysiological brain-fingerprint of Parkinson’s disease

Author

Breitner, John, Poirier, Judes, Baillet, Sylvain, Bellec, Pierre, Bohbot, Véronique, Chakravarty, Mallar, Collins, Louis, Etienne, Pierre, Evans, Alan, Gauthier, Serge, Hoge, Rick, Ituria-Medina, Yasser, Multhaup, Gerhard, Münter, Lisa-Marie, Rajah, Natasha, Rosa-Neto, Pedro, Soucy, Jean-Paul, Vachon-Presseau, Etienne, Villeneuve, Sylvia, Amouyel, Philippe, Appleby, Melissa, Ashton, Nicholas, Auld, Daniel, Ayranci, Gülebru, Bedetti, Christophe, Beland, Marie-Lise, Blennow, Kaj, Westman, Ann Brinkmalm, Cuello, Claudio, Dadar, Mahsa, Daoust, Leslie-Ann, Das, Samir, Dauar-Tedeschi, Marina, De Beaumont, Louis, Dea, Doris, Descoteaux, Maxime, Dufour, Marianne, Farzin, Sarah, Ferdinand, Fabiola, Fonov, Vladimir, Gonneaud, Julie, Kat, Justin, Kazazian, Christina, Labonté, Anne, Lafaille-Magnan, Marie-Elyse, Lalancette, Marc, Lambert, Jean-Charles, Leoutsakos, Jeannie-Marie, Mahar, Laura, Mathieu, Axel, McSweeney, Melissa, Meyer, Pierre-François, Miron, Justin, Near, Jamie, NewboldFox, Holly, Nilsson, Nathalie, Orban, Pierre, Picard, Cynthia, Binette, Alexa Pichet, Poline, Jean-Baptiste, Rabipour, Sheida, Salaciak, Alyssa, Settimi, Matthew, Subramaniapillai, Sivaniya, Tam, Angela, Tardif, Christine, Théroux, Louise, Tremblay-Mercier, Jennifer, Tullo, Stephanie, Ulku, Irem, Vallée, Isabelle, Zetterberg, Henrik, Nair, Vasavan, Pruessner, Jens, Aisen, Paul, Anthal, Elena, Barkun, Alan, Beaudry, Thomas, Benbouhoud, Fatiha, Brandt, Jason, Carmo, Leopoldina, Carrier, Charles Edouard, Cheewakriengkrai, Laksanun, Courcot, Blandine, Couture, Doris, Craft, Suzanne, Dansereau, Christian, Debacker, Clément, Desautels, René, Dubuc, Sylvie, Duclair, Guerda, Eisenberg, Mark, El-Khoury, Rana, Faubert, Anne-Marie, Fontaine, David, Frappier, Josée, Frenette, Joanne, Gagné, Guylaine, Gervais, Valérie, Giles, Renuka, Gordon, Renee, Jack, Clifford, Jutras, Benoit, Khachaturian, Zaven, Knopman, David, Kostopoulos, Penelope, Lapalme, Félix, Lee, Tanya, Lepage, Claude, Leppert, Illana, Madjar, Cécile, Maillet, David, Maltais, Jean-Robert, Mathotaarachchi, Sulantha, Mayrand, Ginette, Michaud, Diane, Montine, Thomas, Morris, John, Pagé, Véronique, Pascoal, Tharick, Peillieux, Sandra, Petkova, Mirela, Pogossova, Galina, Rioux, Pierre, Sager, Mark, Saint-Fort, Eunice Farah, Savard, Mélissa, Sperling, Reisa, Tabrizi, Shirin, Tariot, Pierre, Teigner, Eduard, Thomas, Ronald, Toussaint, Paule-Joanne, Tuwaig, Miranda, Venugopalan, Vinod, Verfaillie, Sander, Vogel, Jacob, Wan, Karen, Wang, Seqian, Yu, Elsa, Beaulieu-Boire, Isabelle, Blanchet, Pierre, Bogard, Sarah, Bouchard, Manon, Chouinard, Sylvain, Cicchetti, Francesca, Cloutier, Martin, Dagher, Alain, Degroot, Clotilde, Desautels, Alex, Dion, Marie Hélène, Drouin-Ouellet, Janelle, Dufresne, Anne-Marie, Dupré, Nicolas, Duquette, Antoine, Durcan, Thomas, Fellows, Lesley K., Fon, Edward, Gagnon, Jean-François, Gan-Or, Ziv, Genge, Angela, Jodoin, Nicolas, Karamchandani, Jason, Lafontaine, Anne-Louise, Langlois, Mélanie, Leveille, Etienne, Lévesque, Martin, Melmed, Calvin, Monchi, Oury, Montplaisir, Jacques, Panisset, Michel, Parent, Martin, Pham-An, Minh-Thy, Postuma, Ronald, Pourcher, Emmanuelle, Rao, Trisha, Rivest, Jean, Rouleau, Guy, Sharp, Madeleine, Soland, Valérie, Sidel, Michael, Wing Sun, Sonia Lai, Thiel, Alexander, Vitali, Paolo, da Silva Castanheira, Jason, Wiesman, Alex I., Hansen, Justine Y., and Misic, Bratislav

Published
2024
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11. 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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12. Comparison of two plasma p-tau217 assays to detect and monitor Alzheimer’s pathology

Author

Therriault, Joseph, Ashton, Nicholas James, Pola, Ilaria, Triana-Baltzer, Gallen, Brum, Wagner Scheeren, Di Molfetta, Guglielmo, Arslan, Burak, Rahmouni, Nesrine, Tissot, Cecile, Servaes, Stijn, Stevenson, Jenna, Macedo, Arthur Cassa, Pascoal, Tharick Ali, Kolb, Hartmuth Christian, Jeromin, Andreas, Blennow, Kaj, Zetterberg, Henrik, Rosa-Neto, Pedro, and Benedet, Andrea Lessa

Published
2024
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13. 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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14. 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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16. A multicenter comparison of [18F]flortaucipir, [18F]RO948, and [18F]MK6240 tau PET tracers to detect a common target ROI for differential diagnosis

Author

Leuzy, Antoine, Pascoal, Tharick A, Strandberg, Olof, Insel, Philip, Smith, Ruben, Mattsson-Carlgren, Niklas, Benedet, Andréa L, Cho, Hannah, Lyoo, Chul H, La Joie, Renaud, Rabinovici, Gil D, Ossenkoppele, Rik, Rosa-Neto, Pedro, and Hansson, Oskar

Subjects
Biomedical and Clinical Sciences, Clinical Sciences, Alzheimer's Disease, Biomedical Imaging, Aging, Acquired Cognitive Impairment, Clinical Research, Neurodegenerative, Neurosciences, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Brain Disorders, Dementia, Neurological, Good Health and Well Being, Alzheimer Disease, Carbolines, Cognitive Dysfunction, Diagnosis, Differential, Humans, Positron-Emission Tomography, tau Proteins, Tau, PET, [F-18]Flortaucipir, [F-18]RO948, [F-18]MK6240, [18F]Flortaucipir, [18F]MK6240, [18F]RO948, Other Physical Sciences, Nuclear Medicine & Medical Imaging, Clinical sciences
Abstract

PurposeThis study aims to determine whether comparable target regions of interest (ROIs) and cut-offs can be used across [18F]flortaucipir, [18F]RO948, and [18F]MK6240 tau positron emission tomography (PET) tracers for differential diagnosis of Alzheimer's disease (AD) dementia vs either cognitively unimpaired (CU) individuals or non-AD neurodegenerative diseases.MethodsA total of 1755 participants underwent tau PET using either [18F]flortaucipir (n = 975), [18F]RO948 (n = 493), or [18F]MK6240 (n = 287). SUVR values were calculated across four theory-driven ROIs and several tracer-specific data-driven (hierarchical clustering) regions of interest (ROIs). Diagnostic performance and cut-offs for ROIs were determined using receiver operating characteristic analyses and the Youden index, respectively.ResultsComparable diagnostic performance (area under the receiver operating characteristic curve [AUC]) was observed between theory- and data-driven ROIs. The theory-defined temporal meta-ROI generally performed very well for all three tracers (AUCs: 0.926-0.996). An SUVR value of approximately 1.35 was a common threshold when using this ROI.ConclusionThe temporal meta-ROI can be used for differential diagnosis of dementia patients with [18F]flortaucipir, [18F]RO948, and [18F]MK6240 tau PET with high accuracy, and that using very similar cut-offs of around 1.35 SUVR. This ROI/SUVR cut-off can also be applied across tracers to define tau positivity.

Published
2021

17. Genetic risk for attention-deficit/hyperactivity disorder predicts cognitive decline and development of Alzheimer’s disease pathophysiology in cognitively unimpaired older adults

Author

Leffa, Douglas T., Ferrari-Souza, João Pedro, Bellaver, Bruna, Tissot, Cécile, Ferreira, Pamela C. L., Brum, Wagner S., Caye, Arthur, Lord, Jodie, Proitsi, Petroula, Martins-Silva, Thais, Tovo-Rodrigues, Luciana, Tudorascu, Dana L., Villemagne, Victor L., Cohen, Ann D., Lopez, Oscar L., Klunk, William E., Karikari, Thomas K., Rosa-Neto, Pedro, Zimmer, Eduardo R., Molina, Brooke S. G., Rohde, Luis Augusto, and Pascoal, Tharick A.

Published
2023
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18. 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

19. 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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22. Impact of cardiometabolic factors and blood beta-amyloid on the volume of white matter hyperintensities in dementia-free subjects with cognitive complaints

Author

Riquelme-Contreras, Patricio, primary, Hornberger, Michael, additional, Khondoker, Mizanur, additional, Henriquez, Fernando, additional, Gonzalez-Campo, Cecilia, additional, Altschuler, Florencia, additional, Fraile-Vazquez, Matias, additional, Lukasewicz Ferreira, Pamela, additional, Bellaver, Bruna, additional, Pascoal, Tharick, additional, Muniz-Terrera, Graciela, additional, Okuma, Cecilia, additional, Gonzalez-Billault, Christian, additional, Court, Felipe, additional, Cerda, Mauricio, additional, Lillo, Patricia, additional, and Slachevsky, Andrea, additional

Published
2024
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23. Reduction in Constitutively Activated Auditory Brainstem Microglia in Aging and Alzheimer’s Disease

Author

Butler, Tracy, primary, Wang, Xiuyuan, additional, Chiang, Gloria, additional, Xi, Ke, additional, Niogi, Sumit, additional, Glodzik, Lidia, additional, Li, Yi, additional, Razlighi, Qolamreza Ray, additional, Zhou, Liangdong, additional, Hojjati, Seyed Hani, additional, Ozsahin, Ilker, additional, Mao, Xiangling, additional, Maloney, Thomas, additional, Tanzi, Emily, additional, Rahmouni, Nesrine, additional, Tissot, Cécile, additional, Lussier, Firoza, additional, Shah, Sudhin, additional, Shungu, Dikoma, additional, Gupta, Ajay, additional, De Leon, Mony, additional, Mozley, P. David, additional, Pascoal, Tharick, additional, and Rosa-Neto, Pedro, additional

Published
2024
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25. Biomarker modeling of Alzheimer’s disease using PET-based Braak staging

Author

Therriault, Joseph, Pascoal, Tharick A., Lussier, Firoza Z., Tissot, Cécile, Chamoun, Mira, Bezgin, Gleb, Servaes, Stijn, Benedet, Andrea L., Ashton, Nicholas J., Karikari, Thomas K., Lantero-Rodriguez, Juan, Kunach, Peter, Wang, Yi-Ting, Fernandez-Arias, Jaime, Massarweh, Gassan, Vitali, Paolo, Soucy, Jean-Paul, Saha-Chaudhuri, Paramita, Blennow, Kaj, Zetterberg, Henrik, Gauthier, Serge, and Rosa-Neto, Pedro

Published
2022
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29. Author Correction: [11C]Martinostat PET analysis reveals reduced HDAC I availability in Alzheimer’s disease

Author

Pascoal, Tharick A., Chamoun, Mira, Lax, Elad, Wey, Hsiao-Ying, Shin, Monica, Ng, Kok Pin, Kang, Min Su, Mathotaarachchi, Sulantha, Benedet, Andrea L., Therriault, Joseph, Lussier, Firoza Z., Schroeder, Frederick A., DuBois, Jonathan M., Hightower, Baileigh G., Gilbert, Tonya M., Zürcher, Nicole R., Wang, Changning, Hopewell, Robert, Chakravarty, Mallar, Savard, Melissa, Thomas, Emilie, Mohaddes, Sara, Farzin, Sarah, Salaciak, Alyssa, Tullo, Stephanie, Cuello, A. Claudio, Soucy, Jean-Paul, Massarweh, Gassan, Hwang, Heungsun, Kobayashi, Eliane, Hyman, Bradley T., Dickerson, Bradford C., Guiot, Marie-Christine, Szyf, Moshe, Gauthier, Serge, Hooker, Jacob M., and Rosa-Neto, Pedro

Published
2022
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30. [11C]Martinostat PET analysis reveals reduced HDAC I availability in Alzheimer’s disease

Author

Pascoal, Tharick A., Chamoun, Mira, Lax, Elad, Wey, Hsiao-Ying, Shin, Monica, Ng, Kok Pin, Kang, Min Su, Mathotaarachchi, Sulantha, Benedet, Andrea L., Therriault, Joseph, Lussier, Firoza Z., Schroeder, Frederick A., DuBois, Jonathan M., Hightower, Baileigh G., Gilbert, Tonya M., Zürcher, Nicole R., Wang, Changning, Hopewell, Robert, Chakravarty, Mallar, Savard, Melissa, Thomas, Emilie, Mohaddes, Sara, Farzin, Sarah, Salaciak, Alyssa, Tullo, Stephanie, Cuello, A. Claudio, Soucy, Jean-Paul, Massarweh, Gassan, Hwang, Heungsun, Kobayashi, Eliane, Hyman, Bradley T., Dickerson, Bradford C., Guiot, Marie-Christine, Szyf, Moshe, Gauthier, Serge, Hooker, Jacob M., and Rosa-Neto, Pedro

Published
2022
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31. CSF tau368/total-tau ratio reflects cognitive performance and neocortical tau better compared to p-tau181 and p-tau217 in cognitively impaired individuals

Author

Simrén, Joel, Brum, Wagner S., Ashton, Nicholas J., Benedet, Andrea L., Karikari, Thomas K., Kvartsberg, Hlin, Sjons, Emma, Lussier, Firoza Z., Chamoun, Mira, Stevenson, Jenna, Hopewell, Robert, Pallen, Vanessa, Ye, Keqiang, Pascoal, Tharick A., Zetterberg, Henrik, Rosa-Neto, Pedro, and Blennow, Kaj

Published
2022
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33. Amyloid-beta modulates the association between neurofilament light chain and brain atrophy in Alzheimer’s disease

Author

Kang, Min Su, Aliaga, Arturo Aliaga, Shin, Monica, Mathotaarachchi, Sulantha, Benedet, Andrea L., Pascoal, Tharick A., Therriault, Joseph, Chamoun, Mira, Savard, Melissa, Devenyi, Gabriel A., Mathieu, Axel, Chakravarty, M. Mallar, Sandelius, Åsa, Blennow, Kaj, Zetterberg, Henrik, Soucy, Jean-Paul, Cuello, A. Claudio, Massarweh, Gassan, Gauthier, Serge, and Rosa-Neto, Pedro

Published
2021
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35. Anosognosia predicts default mode network hypometabolism and clinical progression to dementia

Author

Therriault, Joseph, Ng, Kok Pin, Pascoal, Tharick A, Mathotaarachchi, Sulantha, Kang, Min Su, Struyfs, Hanne, Shin, Monica, Benedet, Andrea L, Walpola, Ishan C, Nair, Vasavan, Gauthier, Serge, Rosa-Neto, Pedro, Initiative, For the Alzheimer's Disease Neuroimaging, Initiative, Alzheimer's Disease Neuroimaging, Weiner, Michael W, Aisen, Paul, Petersen, Ronald, Jack, Clifford, Jagust, William, Morris, John C, Saykin, Andrew J, Trojanowski, John Q, Toga, Arthur W, and Beckett, Laurel

Subjects
Biomedical and Clinical Sciences, Neurosciences, Clinical Sciences, Neurodegenerative, Dementia, Acquired Cognitive Impairment, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Aging, Clinical Research, Brain Disorders, Mental Health, Alzheimer's Disease, Neurological, Aged, Agnosia, Amyloid, Aniline Compounds, Apolipoprotein E4, Biomarkers, Brain, Cognitive Dysfunction, Disease Progression, Ethylene Glycols, Female, Fluorodeoxyglucose F18, Follow-Up Studies, Humans, Male, Prognosis, Radiopharmaceuticals, Alzheimer's Disease Neuroimaging Initiative, Cognitive Sciences, Neurology & Neurosurgery, Clinical sciences
Abstract

ObjectiveTo identify the pathophysiologic mechanisms and clinical significance of anosognosia for cognitive decline in mild cognitive impairment.MethodsWe stratified 468 patients with amnestic mild cognitive impairment into intact and impaired awareness groups, determined by the discrepancy between the patient and the informant score on the Everyday Cognition questionnaire. Voxel-based linear regression models evaluated the associations between self-awareness status and baseline β-amyloid load, measured by [18F]florbetapir, and the relationships between awareness status and regional brain glucose metabolism measured by [18F]fluorodeoxyglucose at baseline and at 24-month follow-up. Multivariate logistic regression tested the association of awareness status with conversion from amnestic mild cognitive impairment to dementia.ResultsWe found that participants with impaired awareness had lower [18F]fluorodeoxyglucose uptake and increased [18F]florbetapir uptake in the posterior cingulate cortex at baseline. In addition, impaired awareness in mild cognitive impairment predicted [18F]fluorodeoxyglucose hypometabolism in the posterior cingulate cortex, left basal forebrain, bilateral medial temporal lobes, and right lateral temporal lobe over 24 months. Furthermore, participants with impaired awareness had a nearly 3-fold increase in likelihood of conversion to dementia within a 2-year time frame.ConclusionsOur results suggest that anosognosia is linked to Alzheimer disease pathophysiology in vulnerable structures, and predicts subsequent hypometabolism in the default mode network, accompanied by an increased risk of progression to dementia. This highlights the importance of assessing awareness of cognitive decline in the clinical evaluation and management of individuals with amnestic mild cognitive impairment.

Published
2018

36. CYP2C19 variant mitigates Alzheimer disease pathophysiology in vivo and postmortem

Author

Benedet, Andréa L, Yu, Lei, Labbe, Aurélie, Mathotaarachchi, Sulantha, Pascoal, Tharick A, Shin, Monica, Kang, Min-Su, Gauthier, Serge, Rouleau, Guy A, Poirier, Judes, Bennett, David A, Rosa-Neto, Pedro, Weiner, Michael W, Aisen, Paul, Petersen, Ronald, Jack, Clifford, Jagust, William, Morris, John C, Saykin, Andrew J, Trojanowski, John Q, Toga, Arthur W, and Beckett, Laurel

Subjects
Pharmacology and Pharmaceutical Sciences, Biological Sciences, Biomedical and Clinical Sciences, Neurodegenerative, Dementia, Acquired Cognitive Impairment, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Aging, Neurosciences, Brain Disorders, Genetics, Alzheimer's Disease, 2.1 Biological and endogenous factors, Aetiology, Neurological, Alzheimer's Disease Neuroimaging Initiative, Clinical sciences
Abstract

ObjectiveTo verify whether CYP polymorphisms are associated with amyloid-β (Aβ) pathology across the spectrum of clinical Alzheimer disease using in vivo and postmortem data from 2 independent cohorts.MethodsA candidate-gene approach tested the association between 5 genes (28 single nucleotide polymorphisms) and Aβ load measured in vivo by the global [18F]florbetapir PET standardized uptake value ratio (SUVR) in 338 Alzheimer's Disease Neuroimaging Initiative participants. Significant results were then tested using plasma Aβ and CSF Aβ and Aβ/phosphorylated tau (Aβ/p-tau) ratio in the same cohort. The significant association was also generalized to postmortem Aβ load measurement in the Rush Religious Orders Study/Memory and Aging Project cohorts. In addition, global cognition was used as a phenotype in the analysis in both cohorts.ResultsAnalysis of Aβ PET identified a variant in the CYP2C19 gene (rs4388808; p = 0.0006), in which carriers of the minor allele (MA) had a lower global SUVR. A voxel-wise analysis revealed that the variant is associated with a lower Aβ load in the frontal, inferior temporal, and posterior cingulate cortices. MA carriers also had higher CSF Aβ (p = 0.003) and Aβ/p-tau ratio (p = 0.02) but had no association with Aβ plasma levels. In postmortem brains, MA carriers had a lower Aβ load (p = 0.03). Global cognition was higher in MA carriers, which was found to be mediated by Aβ.ConclusionsTogether, these findings point to an association between CYP2C19 polymorphism and Aβ pathology, suggesting a protective effect of the MA of rs4388808. Despite the several possibilities in which CYP2C19 affects brain Aβ, the biological mechanism by which this genetic variation may act as a protective factor merits further investigation.

Published
2018

37. Effect of blood collection tube containing protease inhibitors on the pre-analytical stability of Alzheimer’s disease plasma biomarkers

Author

Chen, Yijun, primary, Zeng, Xuemei, additional, Lee, Jihui, additional, Sehrawat, Anuradha, additional, Lafferty, Tara K., additional, Boslett, James J., additional, Klunk, William E., additional, Pascoal, Tharick A., additional, Villemagne, Victor L., additional, Cohen, Annie D., additional, Lopez, Oscar, additional, Yates, Nathan A., additional, and Karikari, Thomas K., additional

Published
2024
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38. Diagnostic Accuracy of a Plasma Phosphorylated Tau 217 Immunoassay for Alzheimer Disease Pathology

Author

Ashton, Nicholas J., primary, Brum, Wagner S., additional, Di Molfetta, Guglielmo, additional, Benedet, Andrea L., additional, Arslan, Burak, additional, Jonaitis, Erin, additional, Langhough, Rebecca E., additional, Cody, Karly, additional, Wilson, Rachael, additional, Carlsson, Cynthia M., additional, Vanmechelen, Eugeen, additional, Montoliu-Gaya, Laia, additional, Lantero-Rodriguez, Juan, additional, Rahmouni, Nesrine, additional, Tissot, Cecile, additional, Stevenson, Jenna, additional, Servaes, Stijn, additional, Therriault, Joseph, additional, Pascoal, Tharick, additional, Lleó, Alberto, additional, Alcolea, Daniel, additional, Fortea, Juan, additional, Rosa-Neto, Pedro, additional, Johnson, Sterling, additional, Jeromin, Andreas, additional, Blennow, Kaj, additional, and Zetterberg, Henrik, additional

Published
2024
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39. Predicting functional decline in aging and Alzheimer’s disease with PET-based Braak staging

Author

Macedo, Arthur C, primary, Therriault, Joseph, additional, Tissot, Cécile, additional, Fernandez Arias, Jaime, additional, Ferreira, Pamela C L, additional, Vitali, Paolo, additional, Servaes, Stijn, additional, Rahmouni, Nesrine, additional, Vermeiren, Marie, additional, Bezgin, Gleb, additional, Lussier, Firoza Z, additional, Stevenson, Jenna, additional, Wang, Yi-Ting, additional, Socualaya, Kely Quispialaya, additional, Kunach, Peter, additional, Nazneen, Tahnia, additional, Hosseini, Seyyed Ali, additional, Pallen, Vanessa, additional, Stevenson, Alyssa, additional, Ferrari-Souza, João Pedro, additional, Bellaver, Bruna, additional, Leffa, Douglas Teixeira, additional, Ng, Kok Pin, additional, Zimmer, Eduardo R, additional, Pascoal, Tharick A, additional, Gauthier, Serge, additional, and Rosa-Neto, Pedro, additional

Published
2024
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40. The glutamatergic system in Alzheimer’s disease: a systematic review with meta-analysis

Author

Soares, Carolina, primary, Da Ros, Lucas Uglione, additional, Machado, Luiza Santos, additional, Rocha, Andreia, additional, Lazzarotto, Gabriela, additional, Carello-Collar, Giovanna, additional, De Bastiani, Marco A., additional, Ferrari-Souza, João Pedro, additional, Lussier, Firoza Z., additional, Souza, Diogo O., additional, Rosa-Neto, Pedro, additional, Pascoal, Tharick A., additional, Bellaver, Bruna, additional, and Zimmer, Eduardo R., additional

Published
2024
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41. Association Between β-Amyloid Accumulation and Incident Dementia in Individuals 80 Years or Older Without Dementia

Author

Lopez, Oscar L., primary, Villemagne, Victor L., additional, Chang, Yue-Fang, additional, Cohen, Ann D., additional, Klunk, William E., additional, Mathis, Chester A., additional, Pascoal, Tharick, additional, Ikonomovic, Milos D., additional, Rowe, Christopher, additional, Dore, Vincent, additional, Snitz, Beth E., additional, Lopresti, Brian J., additional, Kamboh, M. Ilyas, additional, Aizenstein, Howard J., additional, and Kuller, Lewis H., additional

Published
2024
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42. The relation of synaptic biomarkers with Aβ, tau, glial activation, and neurodegeneration in Alzheimer’s disease.

Author

Wang, Yi-Ting, primary, Ashton, Nicholas J., additional, Servaes, Stijn, additional, Nilsson, Johanna, additional, Woo, Marcel S., additional, Pascoal, Tharick A., additional, Tissot, Cecile, additional, Rahmouni, Nesrine, additional, Therriault, Joseph, additional, Lussier, Firoza, additional, Chamoun, Mira, additional, Gauthier, Serge, additional, Brinkmalm, Ann, additional, Zetterberg, Henrik, additional, Blennow, Kaj, additional, Rosa-Neto, Pedro, additional, and Benedet, Andrea L., additional

Published
2024
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43. Microglial activation and tau propagate jointly across Braak stages

Author

Pascoal, Tharick A., Benedet, Andrea L., Ashton, Nicholas J., Kang, Min Su, Therriault, Joseph, Chamoun, Mira, and Savard, Melissa

Subjects
Tau proteins -- Health aspects -- Physiological aspects, Alzheimer's disease -- Diagnosis -- Development and progression, Biological sciences, Health
Abstract

Compelling experimental evidence suggests that microglial activation is involved in the spread of tau tangles over the neocortex in Alzheimer's disease (AD). We tested the hypothesis that the spatial propagation of microglial activation and tau accumulation colocalize in a Braak-like pattern in the living human brain. We studied 130 individuals across the aging and AD clinical spectrum with positron emission tomography brain imaging for microglial activation ([.sup.11C]PBR28), amyloid-[beta] (A[beta]) ([.sup.18F]AZD4694) and tau ([.sup.18F]MK-6240) pathologies. We further assessed microglial triggering receptor expressed on myeloid cells 2 (TREM2) cerebrospinal fluid (CSF) concentrations and brain gene expression patterns. We found that [.sup.11C]PBR28 correlated with CSF soluble TREM2 and showed regional distribution resembling TREM2 gene expression. Network analysis revealed that microglial activation and tau correlated hierarchically with each other following Braak-like stages. Regression analysis revealed that the longitudinal tau propagation pathways depended on the baseline microglia network rather than the tau network circuits. The co-occurrence of A[beta], tau and microglia abnormalities was the strongest predictor of cognitive impairment in our study population. Our findings support a model where an interaction between A[beta] and activated microglia sets the pace for tau spread across Braak stages. Microglial activation and tau accumulation propagate together in patients with Alzheimer's disease, suggesting an interaction that determines disease progression., Author(s): Tharick A. Pascoal [sup.1] [sup.2] [sup.3] [sup.4] , Andrea L. Benedet [sup.3] , Nicholas J. Ashton [sup.5] [sup.6] [sup.7] , Min Su Kang [sup.3] [sup.4] , Joseph Therriault [sup.3] [...]

Published
2021
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44. Neuropsychiatric symptoms predict hypometabolism in preclinical Alzheimer disease

Author

Ng, Kok Pin, Pascoal, Tharick A, Mathotaarachchi, Sulantha, Chung, Chang-Oh, Benedet, Andréa L, Shin, Monica, Kang, Min Su, Li, Xiaofeng, Ba, Maowen, Kandiah, Nagaendran, Rosa-Neto, Pedro, Gauthier, Serge, Weiner, Michael W, Aisen, Paul, Petersen, Ronald, Jack, Clifford, Jagust, William, Morris, John C, Saykin, Andrew J, Trojanowski, John Q, Toga, Arthur W, and Beckett, Laurel

Subjects
Brain Disorders, Aging, Neurodegenerative, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Dementia, Acquired Cognitive Impairment, Alzheimer's Disease, Mental Health, Neurosciences, Aetiology, 2.1 Biological and endogenous factors, Neurological, Aged, Alzheimer Disease, Aniline Compounds, Apolipoprotein E4, Biomarkers, Brain, Brain Mapping, Ethylene Glycols, Female, Fluorodeoxyglucose F18, Follow-Up Studies, Humans, Irritable Mood, Magnetic Resonance Imaging, Male, Neuropsychological Tests, Positron-Emission Tomography, Prodromal Symptoms, Prognosis, Radiopharmaceuticals, Sleep, tau Proteins, Alzheimer's Disease Neuroimaging Initiative, Clinical Sciences, Cognitive Sciences, Neurology & Neurosurgery
Abstract

ObjectiveTo identify regional brain metabolic dysfunctions associated with neuropsychiatric symptoms (NPS) in preclinical Alzheimer disease (AD).MethodsWe stratified 115 cognitively normal individuals into preclinical AD (both amyloid and tau pathologies present), asymptomatic at risk for AD (either amyloid or tau pathology present), or healthy controls (no amyloid or tau pathology present) using [18F]florbetapir PET and CSF phosphorylated tau biomarkers. Regression and voxel-based regression models evaluated the relationships between baseline NPS measured by the Neuropsychiatric Inventory (NPI) and baseline and 2-year change in metabolism measured by [18F]fluorodeoxyglucose (FDG) PET.ResultsIndividuals with preclinical AD with higher NPI scores had higher [18F]FDG uptake in the posterior cingulate cortex (PCC), ventromedial prefrontal cortex, and right anterior insula at baseline. High NPI scores predicted subsequent hypometabolism in the PCC over 2 years only in individuals with preclinical AD. Sleep/nighttime behavior disorders and irritability and lability were the components of the NPI that drove this metabolic dysfunction.ConclusionsThe magnitude of NPS in preclinical cases, driven by sleep behavior and irritability domains, is linked to transitory metabolic dysfunctions within limbic networks vulnerable to the AD process and predicts subsequent PCC hypometabolism. These findings support an emerging conceptual framework in which NPS constitute an early clinical manifestation of AD pathophysiology.

Published
2017

46. Association of plasma biomarkers of Alzheimer's disease and related disorders with cognition and cognitive decline: The MYHAT population‐based study.

Author

Zhang, Yingjin, Ferreira, Pamela C. L., Jacobsen, Erin, Bellaver, Bruna, Pascoal, Tharick A., Snitz, Beth E., Chang, Chung‐Chou H., Villemagne, Victor L., Ganguli, Mary, and Karikari, Thomas K.

Abstract

INTRODUCTION: Plasma biomarkers of Alzheimer's disease and related dementias predict global cognitive performance and decline over time; it remains unclear how they associate with changes in different dementia syndromes affecting distinct cognitive domains. METHODS: In a prospective study with repeated assessments of a randomly selected population‐based cohort (n = 787, median age 73), we evaluated performance and decline in different cognitive domains over up to 8 years in relation to plasma concentrations of amyloid beta 42/40 (Aβ42/40) ratio, phosphorylated tau181 (p‐tau181), neurofilament light chain (NfL), and glial fibrillary acidic protein (GFAP). RESULTS: Cross‐sectionally, memory showed the strongest associations with p‐tau181, and attention, executive, and visuospatial functions with NfL. Longitudinally, memory decline was distinguishable with all biomarker profiles dichotomized according to data‐driven cutoffs, most efficiently with Aβ42/40. GFAP and Aβ42/40 were the best discriminators of decline patterns in language and visuospatial functions, respectively. DISCUSSION: These relatively non‐invasive tests may be beneficial for clinical screening after replication in other populations and validation through neuroimaging or cerebrospinal fluid analysis. Highlights: We performed a prospective study with up to 8 years of repeated domain‐specific cognitive assessments and baseline plasma Alzheimer's disease and related dementias biomarker measurements in a randomly selected population‐based cohort.We considered distinct growth curves of trajectories of different cognitive domains and survival bias induced by missing data by adding quadratic time and applying joint modeling technique.Cross‐sectionally, memory showed the strongest associations with plasma phosphorylated tau181, while attention, executive, and visuospatial functions were most strongly associated with neurofilament light chain.Longitudinally, memory and visuospatial declines were most efficiently distinguished by dichotomized amyloid beta 42/40 profile among all plasma biomarkers, while language was by dichotomized glial fibrillary acidic protein.These relatively non‐invasive tests may be beneficial for clinical screening; however, they will need replication in other populations and validation through neuroimaging and/or cerebrospinal fluid assessments. [ABSTRACT FROM AUTHOR]

Published
2024
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47. Sex-specific modulation of amyloid-β on tau phosphorylation underlies faster tangle accumulation in females.

Author

Wang, Yi-Ting, Therriault, Joseph, Servaes, Stijn, Tissot, Cécile, Rahmouni, Nesrine, Macedo, Arthur Cassa, Fernandez-Arias, Jaime, Mathotaarachchi, Sulantha S, Benedet, Andréa L, Stevenson, Jenna, Ashton, Nicholas J, Lussier, Firoza Z, Pascoal, Tharick A, Zetterberg, Henrik, Rajah, Maria Natasha, Blennow, Kaj, Gauthier, Serge, Rosa-Neto, Pedro, and Initiative, for the Alzheimer's Disease Neuroimaging

Subjects
NEUROFIBRILLARY tangles, TAU proteins, SEX (Biology), ALZHEIMER'S disease, PHOSPHORYLATION
Abstract

Females are disproportionately affected by dementia due to Alzheimer's disease. Despite a similar amyloid-β (Aβ) load, a higher load of neurofibrillary tangles (NFTs) is seen in females than males. Previous literature has proposed that Aβ and phosphorylated-tau (p-tau) synergism accelerates tau tangle formation, yet the effect of biological sex in this process has been overlooked. In this observational study, we examined longitudinal neuroimaging data from the TRIAD and ADNI cohorts from Canada and USA, respectively. We assessed 457 participants across the clinical spectrum of Alzheimer's disease. All participants underwent baseline multimodal imaging assessment, including MRI and PET, with radioligands targeting Aβ plaques and tau tangles, respectively. CSF data were also collected. Follow-up imaging assessments were conducted at 1- and 2-year intervals for the TRIAD cohort and 1-, 2- and 4-year intervals for the ADNI cohort. The upstream pathological events contributing to faster tau progression in females were investigated—specifically, whether the contribution of Aβ and p-tau synergism to accelerated tau tangle formation is modulated by biological sex. We hypothesized that cortical Aβ predisposes tau phosphorylation and tangle accumulation in a sex-specific manner. Findings revealed that Aβ-positive females presented higher CSF p-tau181 concentrations compared with Aβ-positive males in both the TRIAD (P = 0.04, Cohen's d = 0.51) and ADNI (P = 0.027, Cohen's d = 0.41) cohorts. In addition, Aβ-positive females presented faster NFT accumulation compared with their male counterparts (TRIAD: P = 0.026, Cohen's d = 0.52; ADNI: P = 0.049, Cohen's d = 1.14). Finally, the triple interaction between female sex, Aβ and CSF p-tau181 was revealed as a significant predictor of accelerated tau accumulation at the 2-year follow-up visit (Braak I: P = 0.0067, t = 2.81; Braak III: P = 0.017, t = 2.45; Braak IV: P = 0.002, t = 3.17; Braak V: P = 0.006, t = 2.88; Braak VI: P = 0.0049, t = 2.93). Overall, we report sex-specific modulation of cortical Aβ in tau phosphorylation, consequently facilitating faster NFT progression in female individuals over time. This presents important clinical implications and suggests that early intervention that targets Aβ plaques and tau phosphorylation may be a promising therapeutic strategy in females to prevent the further accumulation and spread of tau aggregates. [ABSTRACT FROM AUTHOR]

Published
2024
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48. Blood phosphorylated tau 181 as a biomarker for Alzheimer's disease: a diagnostic performance and prediction modelling study using data from four prospective cohorts

Author

Karikari, Thomas K, Pascoal, Tharick A, Ashton, Nicholas J, Janelidze, Shorena, Benedet, Andréa Lessa, Rodriguez, Juan Lantero, Chamoun, Mira, Savard, Melissa, Kang, Min Su, Therriault, Joseph, Schöll, Michael, Massarweh, Gassan, Soucy, Jean-Paul, Höglund, Kina, Brinkmalm, Gunnar, Mattsson, Niklas, Palmqvist, Sebastian, Gauthier, Serge, Stomrud, Erik, Zetterberg, Henrik, Hansson, Oskar, Rosa-Neto, Pedro, and Blennow, Kaj

Published
2020
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49. Cholinergic dysfunction in the dorsal striatum promotes habit formation and maladaptive eating

Author

Favier, Mathieu, Janickova, Helena, Justo, Damian, Kljakic, Ornela, Runtz, Leonie, Natsheh, Joman Y., Pascoal, Tharick A., Germann, Jurgen, Gallino, Daniel, Kang, Jun-Il, Meng, Xiang Qi, Antinora, Christina, Raulic, Sanda, Jacobsen, Jacob P.R., Moquin, Luc, Vigneault, Erika, Gratton, Alain, Caron, Marc G., Duriez, Philibert, Brandon, Mark P., Neto, Pedro Rosa, Chakravarty, M. Mallar, Herzallah, Mohammad M., Gorwood, Philip, Prado, Marco A.M., Prado, Vania F., and El Mestikawy, Salah

Subjects
Cholinergic mechanisms -- Health aspects, Anorexia nervosa -- Development and progression -- Care and treatment, Health behavior -- Observations, Health care industry
Abstract

Dysregulation of habit formation has been recently proposed as pivotal to eating disorders. Here, we report that a subset of patients suffering from restrictive anorexia nervosa have enhanced habit formation compared with healthy controls. Habit formation is modulated by striatal cholinergic interneurons. These interneurons express vesicular transporters for acetylcholine (VAChT) and glutamate (VGLUT3) and use acetylcholine/glutamate cotransmission to regulate striatal functions. Using mice with genetically silenced VAChT (VAChT conditional KO, VAChTcKO) or VGLUT3 (VGLUT3cKO), we investigated the roles that acetylcholine and glutamate released by cholinergic interneurons play in habit formation and maladaptive eating. Silencing glutamate favored goal-directed behaviors and had no impact on eating behavior. In contrast, VAChTcKO mice were more prone to habits and maladaptive eating. Specific deletion of VAChT in the dorsomedial striatum of adult mice was sufficient to phenocopy maladaptive eating behaviors of VAChTcKO mice. Interestingly, VAChTcKO mice had reduced dopamine release in the dorsomedial striatum but not in the dorsolateral striatum. The dysfunctional eating behavior of VAChTcKO mice was alleviated by donepezil and by l-DOPA, confirming an acetylcholine/dopamine deficit. Our study reveals that loss of acetylcholine leads to a dopamine imbalance in striatal compartments, thereby promoting habits and vulnerability to maladaptive eating in mice., Introduction Eating disorders such as anorexia nervosa, bulimia nervosa, and binge eating disorder are severe psychiatric illnesses that are difficult to treat (1). Anorexia nervosa, in particular, has the highest [...]

Published
2020
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50. Sex modulates the role of astrocyte reactivity in preclinical Alzheimer’s disease

Author

Bellaver, Bruna, primary, Povala, Guilherme, additional, Ferreira, Pamela C.L., additional, Leffa, Douglas Teixeira, additional, Ferrari‐Souza, João Pedro, additional, Lussier, Firoza Z, additional, Zalzale, Hussein, additional, Soares, Carolina, additional, Aguzzoli, Cristiano Schaffer, additional, Rohden, Francieli, additional, Abbas, Sarah, additional, Benedet, Andrea Lessa, additional, Ashton, Nicholas J., additional, Tissot, Cécile, additional, Therriault, Joseph, additional, Servaes, Stijn, additional, Stevenson, Jenna, additional, Rahmouni, Nesrine, additional, Lopez, Oscar L., additional, Tudorascu, Dana, additional, Villemagne, Victor L, additional, Klunk, William E, additional, Cohen, Ann D., additional, Gauthier, Serge, additional, Zimmer, Eduardo R, additional, Zetterberg, Henrik, additional, Blennow, Kaj, additional, Karikari, Thomas K, additional, Rosa‐Neto, Pedro, additional, and Pascoal, Tharick Ali, additional

Published
2023
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