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7. Blood-based systems biology biomarkers for next-generation clinical trials in Alzheimer's disease
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Author

Hampel, Harald, Vergallo, Andrea, Afshar, Mohammad, Akman-Anderson, Leyla, Arenas, Joaquín, Benda, Norbert, Batrla, Richard, Broich, Karl, Caraci, Filippo, Cuello, A Claudio, Emanuele, Enzo, Haberkamp, Marion, Kiddle, Steven J, Lucía, Alejandro, Mapstone, Mark, Verdooner, Steven R, Woodcock, Janet, and Lista, Simone

Subjects
Humans, Alzheimer Disease, Early Diagnosis, Eligibility Determination, Clinical Trials as Topic, Biomarkers, Precision Medicine, Drug Development, Alzheimer’s disease, biomarker-drug codevelopment, blood-based biomarker, clinical trial, context of use, pathophysiology, precision medicine, predictive biomarker, systems biology, Alzheimer's disease, Clinical Research, Clinical Trials and Supportive Activities, Aging, Acquired Cognitive Impairment, Brain Disorders, Alzheimer's Disease, Prevention, Alzheimer's Disease including Alzheimer's Disease Related Dementias, Neurodegenerative, Dementia, Neurosciences, 4.1 Discovery and preclinical testing of markers and technologies, 5.1 Pharmaceuticals, Other Medical and Health Sciences, Psychiatry
Abstract

Alzheimer's disease (AD)-a complex disease showing multiple pathomechanistic alterations-is triggered by nonlinear dynamic interactions of genetic/epigenetic and environmental risk factors, which, ultimately, converge into a biologically heterogeneous disease. To tackle the burden of AD during early preclinical stages, accessible blood-based biomarkers are currently being developed. Specifically, next-generation clinical trials are expected to integrate positive and negative predictive blood-based biomarkers into study designs to evaluate, at the individual level, target druggability and potential drug resistance mechanisms. In this scenario, systems biology holds promise to accelerate validation and qualification for clinical trial contexts of use-including proof-of-mechanism, patient selection, assessment of treatment efficacy and safety rates, and prognostic evaluation. Albeit in their infancy, systems biology-based approaches are poised to identify relevant AD "signatures" through multifactorial and interindividual variability, allowing us to decipher disease pathophysiology and etiology. Hopefully, innovative biomarker-drug codevelopment strategies will be the road ahead towards effective disease-modifying drugs.
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Published
2019

9. 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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10. [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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12. Precision pharmacology for Alzheimer’s disease

Author

Hampel, Harald, Vergallo, Andrea, Aguilar, Lisi Flores, Benda, Norbert, Broich, Karl, Cuello, A Claudio, Cummings, Jeffrey, Dubois, Bruno, Federoff, Howard J, Fiandaca, Massimo, Genthon, Remy, Haberkamp, Marion, Karran, Eric, Mapstone, Mark, Perry, George, Schneider, Lon S, Welikovitch, Lindsay A, Woodcock, Janet, Baldacci, Filippo, Lista, Simone, and Initiative, for the Alzheimer Precision Medicine

Subjects
Pharmacology and Pharmaceutical Sciences, Biomedical and Clinical Sciences, Neurosciences, Dementia, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Alzheimer's Disease, Acquired Cognitive Impairment, Neurodegenerative, Brain Disorders, Aging, 2.1 Biological and endogenous factors, Aetiology, Neurological, Good Health and Well Being, Alzheimer Disease, Amyloid beta-Peptides, Animals, Biomarkers, Drug Discovery, Humans, Precision Medicine, tau Proteins, Alzheimer's disease, Precision pharmacology, Precision medicine, Pathway-based therapy, Pathophysiology, Clinical trials, Alzheimer Precision Medicine Initiative, Alzheimer’s disease, Pharmacology & Pharmacy, Pharmacology and pharmaceutical sciences
Abstract

The complex multifactorial nature of polygenic Alzheimer's disease (AD) presents significant challenges for drug development. AD pathophysiology is progressing in a non-linear dynamic fashion across multiple systems levels - from molecules to organ systems - and through adaptation, to compensation, and decompensation to systems failure. Adaptation and compensation maintain homeostasis: a dynamic equilibrium resulting from the dynamic non-linear interaction between genome, epigenome, and environment. An individual vulnerability to stressors exists on the basis of individual triggers, drivers, and thresholds accounting for the initiation and failure of adaptive and compensatory responses. Consequently, the distinct pattern of AD pathophysiology in space and time must be investigated on the basis of the individual biological makeup. This requires the implementation of systems biology and neurophysiology to facilitate Precision Medicine (PM) and Precision Pharmacology (PP). The regulation of several processes at multiple levels of complexity from gene expression to cellular cycle to tissue repair and system-wide network activation has different time delays (temporal scale) according to the affected systems (spatial scale). The initial failure might originate and occur at every level potentially affecting the whole dynamic interrelated systems within an organism. Unraveling the spatial and temporal dynamics of non-linear pathophysiological mechanisms across the continuum of hierarchical self-organized systems levels and from systems homeostasis to systems failure is key to understand AD. Measuring and, possibly, controlling space- and time-scaled adaptive and compensatory responses occurring during AD will represent a crucial step to achieve the capacity to substantially modify the disease course and progression at the best suitable timepoints, thus counteracting disrupting critical pathophysiological inputs. This approach will provide the conceptual basis for effective disease-modifying pathway-based targeted therapies. PP is based on an exploratory and integrative strategy to complex diseases such as brain proteinopathies including AD, aimed at identifying simultaneous aberrant molecular pathways and predicting their temporal impact on the systems levels. The depiction of pathway-based molecular signatures of complex diseases contributes to the accurate and mechanistic stratification of distinct subcohorts of individuals at the earliest compensatory stage when treatment intervention may reverse, stop, or delay the disease. In addition, individualized drug selection may optimize treatment safety by decreasing risk and amplitude of side effects and adverse reactions. From a methodological point of view, comprehensive "omics"-based biomarkers will guide the exploration of spatio-temporal systems-wide morpho-functional shifts along the continuum of AD pathophysiology, from adaptation to irreversible failure. The Alzheimer Precision Medicine Initiative (APMI) and the APMI cohort program (APMI-CP) have commenced to facilitate a paradigm shift towards effective drug discovery and development in AD.

Published
2018

13. Basal Forebrain Volume, but Not Hippocampal Volume, Is a Predictor of Global Cognitive Decline in Patients With Alzheimer's Disease Treated With Cholinesterase Inhibitors

Author

Teipel, Stefan J, Cavedo, Enrica, Hampel, Harald, Grothe, Michel J, Initiative, Alzheimer's Disease Neuroimaging, Initiative, Alzheimer Precision Medicine, Aguilar, Lisi Flores, Babiloni, Claudio, Baldacci, Filippo, Benda, Norbert, Black, Keith L, Bokde, Arun LW, Bonuccelli, Ubaldo, Broich, Karl, Bun, René S, Cacciola, Francesco, Castrillo, Juan, Ceravolo, Roberto, chiesa, Patrizia A, Colliot, Olivier, Coman, Cristina-Maria, Corvol, Jean-Christophe, Cuello, Augusto Claudio, Cummings, Jeffrey L, Depypere, Herman, Dubois, Bruno, Duggento, Andrea, Durrleman, Stanley, Escott-price, Valentina, Federoff, Howard, Ferretti, Maria Teresa, Fiandaca, Massimo, Frank, Richard A, Garaci, Francesco, Genthon, Remy, George, Nathalie, Giorgi, Filippo S, Graziani, Manuela, Haberkamp, Marion, Habert, Marie-Odile, Herholz, Karl, Karran, Eric, Seung, H KIM, Koronyo, Yosef, Koronyo-Hamaoui, Maya, Lamari, Foudil, Langevin, Todd, Lehéricy, Stéphane, Lista, Simone, Lorenceau, Jean, Mapstone, Mark, Neri, Christian, Nisticò, Robert, Nyasse-Messene, Francis, O'Bryant, Sid E, Perry, George, Ritchie, Craig, Rojkova, Katrine, Rossi, Simone, Saidi, Amira, Santarnecchi, Emiliano, Schneider, Lon S, Sporns, Olaf, Toschi, Nicola, Verdooner, Steven R, Vergallo, Andrea, Villain, Nicolas, Welikovitch, Lindsay A, Woodcock, Janet, and Younesi, Erfan

Subjects
Biological Psychology, Psychology, Neurosciences, Brain Disorders, Dementia, Neurodegenerative, Clinical Research, Acquired Cognitive Impairment, Behavioral and Social Science, Alzheimer's Disease, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Aging, Neurological, Alzheimer's Disease Neuroimaging Initiative, Alzheimer Precision Medicine Initiative, MRI, basal forebrain, cholinergic treatment, executive function, hippocampus, memory, prediction, Clinical Sciences, Clinical sciences, Biological psychology
Abstract

Background: Predicting the progression of cognitive decline in Alzheimer's disease (AD) is important for treatment selection and patient counseling. Structural MRI markers such as hippocampus or basal forebrain volumes might represent useful instruments for the prediction of cognitive decline. The primary objective was to determine the predictive value of hippocampus and basal forebrain volumes for global and domain specific cognitive decline in AD dementia during cholinergic treatment. Methods: We used MRI and cognitive data from 124 patients with the clinical diagnosis of AD dementia, derived from the ADNI-1 cohort, who were on standard of care cholinesterase inhibitor treatment during a follow-up period between 0.4 and 3.1 years. We used linear mixed effects models with cognitive function as outcome to assess the main effects as well as two-way interactions between baseline volumes and time controlling for age, sex, and total intracranial volume. This model accounts for individual variation in follow-up times. Results: Basal forebrain volume, but not hippocampus volume, was a significant predictor of rates of global cognitive decline. Larger volumes were associated with smaller rates of cognitive decline. Left hippocampus volume had a modest association with rates of episodic memory decline. Baseline performance in global cognition and memory was significantly associated with hippocampus and basal forebrain volumes; in addition, basal forebrain volume was associated with baseline performance in executive function. Conclusions: Our findings indicate that in AD dementia patients, basal forebrain volume may be a useful marker to predict subsequent cognitive decline during cholinergic treatment.

Published
2018

16. 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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18. Association of plasma YKL-40 with brain amyloid-β levels, memory performance, and sex in subjective memory complainers

Author

Bakardjian, Hovagim, Benali, Habib, Bertin, Hugo, Bonheur, Joel, Boukadida, Laurie, Boukerrou, Nadia, Cavedo, Enrica, Chiesa, Patrizia, Colliot, Olivier, Dubois, Bruno, Dubois, Marion, Epelbaum, Stéphane, Gagliardi, Geoffroy, Genthon, Remy, Habert, Marie-Odile, Hampel, Harald, Houot, Marion, Kas, Aurélie, Lamari, Foudil, Levy, Marcel, Lista, Simone, Metzinger, Christiane, Mochel, Fanny, Nyasse, Francis, Poisson, Catherine, Potier, Marie-Claude, Revillon, Marie, Santos, Antonio, Andrade, Katia Santos, Sole, Marine, Surtee, Mohmed, de Schotten, Michel Thiebaut, Vergallo, Andrea, Younsi, Nadjia, Afshar, Mohammad, Aguilar, Lisi Flores, Akman-Anderson, Leyla, Arenas, Joaquín, Ávila, Jesús, Babiloni, Claudio, Baldacci, Filippo, Batrla, Richard, Benda, Norbert, Black, Keith L., Bokde, Arun L.W., Bonuccelli, Ubaldo, Broich, Karl, Cacciola, Francesco, Caraci, Filippo, Caruso, Giuseppe, Castrillo†, Juan, Ceravolo, Roberto, Chiesa, Patrizia A., Corbo, Massimo, Corvol, Jean-Christophe, Cuello, Augusto Claudio, Cummings, Jeffrey L., Depypere, Herman, Duggento, Andrea, Emanuele, Enzo, Escott-Price, Valentina, Federoff, Howard, Ferretti, Maria Teresa, Fiandaca, Massimo, Frank, Richard A., Garaci, Francesco, Geerts, Hugo, Giacobini, Ezio, Giorgi, Filippo S., Goetzl, Edward J., Graziani, Manuela, Haberkamp, Marion, Hänisch, Britta, Herholz, Karl, Hernandez, Felix, Imbimbo, Bruno P., Kapogiannis, Dimitrios, Karran, Eric, Kiddle, Steven J., Kim, Seung H., Koronyo, Yosef, Koronyo-Hamaoui, Maya, Langevin, Todd, Lehéricy, Stéphane, Lemercier, Pablo, Llavero, Francisco, Lorenceau, Jean, Lucía, Alejandro, Mango, Dalila, Mapstone, Mark, Neri, Christian, Nisticò, Robert, O’bryant, Sid E., Palermo, Giovanni, Perry, George, Ritchie, Craig, Rossi, Simone, Saidi, Amira, Santarnecchi, Emiliano, Schneider, Lon S., Sporns, Olaf, Toschi, Nicola, Valenzuela, Pedro L., Vellas, Bruno, Verdooner, Steven R., Villain, Nicolas, Giudici, Kelly Virecoulon, Watling, Mark, Welikovitch, Lindsay A., Woodcock, Janet, Younesi, Erfan, Zugaza, José L., Zetterberg, Henrik, and Blennow, Kaj

Published
2020
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20. eIF2α controls memory consolidation via excitatory and somatostatin neurons

Author

Sharma, Vijendra, Sood, Rapita, Khlaifia, Abdessattar, Eslamizade, Mohammad Javad, Hung, Tzu-Yu, Lou, Danning, Asgarihafshejani, Azam, Lalzar, Maya, Kiniry, Stephen J., Stokes, Matthew P., Cohen, Noah, Nelson, Alissa J., Abell, Kathryn, Possemato, Anthony P., Gal-Ben-Ari, Shunit, Truong, Vinh T., Wang, Peng, Yiannakas, Adonis, Saffarzadeh, Fatemeh, Cuello, A. Claudio, Nader, Karim, Kaufman, Randal J., Costa-Mattioli, Mauro, Baranov, Pavel V., Quintana, Albert, Sanz, Elisenda, Khoutorsky, Arkady, Lacaille, Jean-Claude, Rosenblum, Kobi, and Sonenberg, Nahum

Published
2020
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22. Differential default mode network trajectories in asymptomatic individuals at risk for Alzheimer's disease

Author

Bakardjian, Hovagim, Benali, Habib, Bertin, Hugo, Bonheur, Joel, Boukadida, Laurie, Boukerrou, Nadia, Cavedo, Enrica, Chiesa, Patrizia, Colliot, Olivier, Dubois, Bruno, Dubois, Marion, Epelbaum, Stéphane, Gagliardi, Geoffroy, Genthon, Remy, Habert, Marie-Odile, Hampel, Harald, Houot, Marion, Kas, Aurélie, Lamari, Foudil, Levy, Marcel, Lista, Simone, Metzinger, Christiane, Mochel, Fanny, Nyasse, Francis, Poisson, Catherine, Potier, Marie-Claude, Revillon, Marie, Santos, Antonio, Andrade, Katia Santos, Sole, Marine, Surtee, Mohmed, de Schotten, Michel Thiebaud, Vergallo, Andrea, Younsi, Nadjia, Afshar, Mohammad, Aguilar, Lisi Flores, Akman-Anderson, Leyla, Arenas, Joaquín, Avila, Jesus, Babiloni, Claudio, Baldacci, Filippo, Batrla, Richard, Benda, Norbert, Black, Keith L., Bokde, Arun L.W., Bonuccelli, Ubaldo, Broich, Karl, Cacciola, Francesco, Caraci, Filippo, Castrillo, Juan, Ceravolo, Roberto, Chiesa, Patrizia A., Corvol, Jean-Christophe, Cuello, Augusto Claudio, Cummings, Jeffrey L., Depypere, Herman, Duggento, Andrea, Emanuele, Enzo, Escott-Price, Valentina, Federoff, Howard, Ferretti, Maria Teresa, Fiandaca, Massimo, Frank, Richard A., Garaci, Francesco, Geerts, Hugo, Giorgi, Filippo S., Goetzl, Edward J., Graziani, Manuela, Haberkamp, Marion, Herholz, Karl, Hernandez, Felix, Kapogiannis, Dimitrios, Karran, Eric, Kiddle, Steven J., Kim, Seung H., Koronyo, Yosef, Koronyo-Hamaoui, Maya, Langevin, Todd, Lehéricy, Stéphane, Lucía, Alejandro, Lorenceau, Jean, Mango, Dalila, Mapstone, Mark, Neri, Christian, Nisticó, Robert, O’Bryant, Sid E., Palermo, Giovanni, Perry, George, Ritchie, Craig, Rossi, Simone, Saidi, Amira, Santarnecchi, Emiliano, Schneider, Lon S., Sporns, Olaf, Toschi, Nicola, Verdooner, Steven R., Villain, Nicolas, Welikovitch, Lindsay A., Woodcock, Janet, Younesi, Erfan, and Thiebaut de Schotten, Michel

Published
2019
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23. Plasma amyloid β 40/42 ratio predicts cerebral amyloidosis in cognitively normal individuals at risk for Alzheimer's disease

Author

Bakardjian, H., Benali, H., Bertin, H., Bonheur, J., Boukadida, L., Boukerrou, N., Cavedo, E., Chiesa, P., Colliot, O., Dubois, B., Dubois, M., Epelbaum, S., Gagliardi, G., Genthon, R., Habert, M.O., Hampel, H., Houot, M., Kas, A., Lamari, F., Levy, M., Lista, S., Metzinger, C., Mochel, F., Nyasse, F., Poisson, C., Potier, M.C., Revillon, M., Santos, A., Andrade, K.S., Sole, M., Surtee, M., de Schotten M, Thiebaud, Vergallo, A., Younsi, N., Aguilar, Lisi Flores, Babiloni, Claudio, Baldacci, Filippo, Benda, Norbert, Black, Keith L., Bokde, Arun L.W., Bonuccelli, Ubaldo, Broich, Karl, Cacciola, Francesco, Castrillo, Juan, Cavedo, Enrica, Ceravolo, Roberto, Chiesa, Patrizia A., Corvol, Jean-Christophe, Cuello, Augusto Claudio, Cummings, Jeffrey L., Depypere, Herman, Dubois, Bruno, Duggento, Andrea, Escott-Price, Valentina, Federoff, Howard, Ferretti, Maria Teresa, Fiandaca, Massimo, Frank, Richard A., Garaci, Francesco, Geerts, Hugo, Giorgi, Filippo S., Graziani, Manuela, Haberkamp, Marion, Habert, Marie-Odile, Hampel, Harald, Herholz, Karl, Karran, Eric, Kim, Seung H., Koronyo, Yosef, Koronyo-Hamaoui, Maya, Lamari, Foudil, Langevin, Todd, Lehéricy, Stéphane, Lista, Simone, Lorenceau, Jean, Mango, Dalila, Mapstone, Mark, Neri, Christian, Nisticò, Robert, O'Bryant, Sid E., Perry, George, Ritchie, Craig, Rossi, Simone, Saidi, Amira, Santarnecchi, Emiliano, Schneider, Lon S., Sporns, Olaf, Toschi, Nicola, Verdooner, Steven R., Vergallo, Andrea, Villain, Nicolas, Welikovitch, Lindsay A., Woodcock, Janet, Younesi, Erfan, Mégret, Lucile, Zetterberg, Henrik, Blennow, Kaj, Vanmechelen, Eugeen, De Vos, Ann, and Potier, Marie-Claude

Published
2019
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25. mTORC2 mediates structural plasticity in distal nociceptive endings that contributes to pain hypersensitivity following inflammation

Author

Wong, Calvin, Barkai, Omer, Wang, Feng, Perez, Carolina Thorn, Lev, Shaya, Cai, Weihua, Tansley, Shannon, Yousefpour, Noosha, Hooshmandi, Mehdi, Lister, Kevin C., Latif, Mariam, Cuello, A. Claudio, Prager-Khoutorsky, Masha, Mogil, Jeffrey S., Seguela, Philippe, De Koninck, Yves, Ribeiro-da-Silva, Alfredo, Binshtok, Alexander M., and Khoutorsky, Arkady

Subjects
Nociceptors -- Physiological aspects, Inflammation -- Development and progression -- Complications and side effects, Protein kinases -- Physiological aspects -- Health aspects, Neuroplasticity -- Health aspects, Pain -- Development and progression -- Causes of, Health care industry
Abstract

The encoding of noxious stimuli into action potential firing is largely mediated by nociceptive free nerve endings. Tissue inflammation, by changing the intrinsic properties of the nociceptive endings, leads to nociceptive hyperexcitability and thus to the development of inflammatory pain. Here, we showed that tissue inflammation-induced activation of the mammalian target of rapamycin complex 2 (mTORC2) triggers changes in the architecture of nociceptive terminals and leads to inflammatory pain. Pharmacological activation of mTORC2 induced elongation and branching of nociceptor peripheral endings and caused long- lasting pain hypersensitivity. Conversely, nociceptor-specific deletion of the mTORC2 regulatory protein rapamycin-insensitive companion of mTOR (Rictor) prevented inflammation-induced elongation and branching of cutaneous nociceptive fibers and attenuated inflammatory pain hypersensitivity. Computational modeling demonstrated that mTORC2-mediated structural changes in the nociceptive terminal tree are sufficient to increase the excitability of nociceptors. Targeting mTORC2 using a single injection of antisense oligonucleotide against Rictor provided long-lasting alleviation of inflammatory pain hypersensitivity. Collectively, we showed that tissue inflammation-induced activation of mTORC2 causes structural plasticity of nociceptive free nerve endings in the epidermis and inflammatory hyperalgesia, representing a therapeutic target for inflammatory pain., Introduction Chronic pain is a common (~20% of the world population) debilitating condition that can persist for years, severely affecting the quality of life of affected individuals and their families [...]

Published
2022
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26. Nerve growth factor metabolic dysfunction in Down’s syndrome brains

Author

Iulita, M Florencia, Do Carmo, Sonia, Ower, Alison K, Fortress, Ashley M, Aguilar, Lisi Flores, Hanna, Michael, Wisniewski, Thomas, Granholm, Ann-Charlotte, Buhusi, Mona, Busciglio, Jorge, and Cuello, A Claudio

Subjects
Biomedical and Clinical Sciences, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Acquired Cognitive Impairment, Dementia, Alzheimer's Disease, Brain Disorders, Aging, Neurodegenerative, Neurosciences, 2.1 Biological and endogenous factors, Aetiology, Neurological, Adult, Aged, Animals, Case-Control Studies, Disease Models, Animal, Down Syndrome, Fetus, Gestational Age, Humans, Matrix Metalloproteinase 9, Mice, Mice, Transgenic, Middle Aged, Nerve Growth Factor, Prosencephalon, Protein Precursors, Down's syndrome, Alzheimer's disease, basal forebrain cholinergic neurons, proNGF, matrix metallo-protease 9, Alzheimer’s disease, Down’s syndrome, Medical and Health Sciences, Psychology and Cognitive Sciences, Neurology & Neurosurgery, Biomedical and clinical sciences, Health sciences, Psychology
Abstract

Basal forebrain cholinergic neurons play a key role in cognition. This neuronal system is highly dependent on NGF for its synaptic integrity and the phenotypic maintenance of its cell bodies. Basal forebrain cholinergic neurons progressively degenerate in Alzheimer's disease and Down's syndrome, and their atrophy contributes to the manifestation of dementia. Paradoxically, in Alzheimer's disease brains, the synthesis of NGF is not affected and there is abundance of the NGF precursor, proNGF. We have shown that this phenomenon is the result of a deficit in NGF's extracellular metabolism that compromises proNGF maturation and exacerbates its subsequent degradation. We hypothesized that a similar imbalance should be present in Down's syndrome. Using a combination of quantitative reverse transcription-polymerase chain reaction, enzyme-linked immunosorbent assay, western blotting and zymography, we investigated signs of NGF metabolic dysfunction in post-mortem brains from the temporal (n = 14), frontal (n = 34) and parietal (n = 20) cortex obtained from subjects with Down's syndrome and age-matched controls (age range 31-68 years). We further examined primary cultures of human foetal Down's syndrome cortex (17-21 gestational age weeks) and brains from Ts65Dn mice (12-22 months), a widely used animal model of Down's syndrome. We report a significant increase in proNGF levels in human and mouse Down's syndrome brains, with a concomitant reduction in the levels of plasminogen and tissue plasminogen activator messenger RNA as well as an increment in neuroserpin expression; enzymes that partake in proNGF maturation. Human Down's syndrome brains also exhibited elevated zymogenic activity of MMP9, the major NGF-degrading protease. Our results indicate a failure in NGF precursor maturation in Down's syndrome brains and a likely enhanced proteolytic degradation of NGF, changes which can compromise the trophic support of basal forebrain cholinergic neurons. The alterations in proNGF and MMP9 were also present in cultures of Down's syndrome foetal cortex; suggesting that this trophic compromise may be amenable to rescue, before frank dementia onset. Our study thus provides a novel paradigm for cholinergic neuroprotection in Alzheimer's disease and Down's syndrome.

Published
2014

27. Low TGF-β1 plasma levels are associated with cognitive decline in Down syndrome.

Author

Grasso, Margherita, Fidilio, Annamaria, L'Episcopo, Francesca, Recupero, Marilena, Barone, Concetta, Bacalini, Maria Giulia, Benatti, Cristina, Giambirtone, Maria Concetta, Caruso, Giuseppe, Greco, Donatella, Di Nuovo, Santo, Romano, Corrado, Ferri, Raffaele, Buono, Serafino, Cuello, A. Claudio, Blom, Johanna M. C., Tascedda, Fabio, Piazza, Pier Vincenzo, De La Torre, Rafael, and Caraci, Filippo

Subjects
COGNITION disorders, MONONUCLEAR leukocytes, DOWN syndrome, SEROTONIN uptake inhibitors, ALZHEIMER'S disease, NEUROFIBRILLARY tangles, APOLIPOPROTEIN E4, CLINICAL neuropsychology
Abstract

Almost all individuals with Down's syndrome (DS) show the characteristic neuropathological features of Alzheimer's disease (AD) by the age of 40, yet not every individual with DS experiences symptoms of AD later in life. Similar to neurotypical developing subjects, AD in people with DS lasts for a long preclinical phase in which biomarkers follow a predictable order of changes. Hence, a prolonged asymptomatic period precedes the onset of dementia, underscoring the importance of identifying new biomarkers for the early detection and monitoring of cognitive decline in individuals with DS. Blood-based biomarkers may offer an alternative non-invasive strategy for the detection of peripheral biological alterations paralleling nervous system pathology in an early phase of the AD continuum. In the last few years, a strong neurobiological link has been demonstrated between the deficit of transforming growth factor-β1 (TGF-β1) levels, an anti-inflammatory cytokine endowed with neuroprotective activity, and early pro-inflammatory processes in the AD brain. In this clinical prospective observational study, we found significant lower plasma TGF-β1 concentrations at the first neuropsychological evaluation (baseline = T0) both in young adult DS individuals (19-35 years) and older DS subjects without AD (35-60 years) compared to age- and sex-matched healthy controls. Interestingly, we found that the lower TGF-β1 plasma concentrations at T0 were strongly correlated with the following cognitive decline at 12 months. In addition, in young individuals with DS, we found, for the first time, a negative correlation between low TGF-β1 concentrations and high TNF-α plasma concentrations, a pro-inflammatory cytokine that is known to be associated with cognitive impairment in DS individuals with AD. Finally, adopting an ex vivo approach, we found that TGF-β1 concentrations were reduced in parallel both in the plasma and in the peripheral blood mononuclear cells (PBMCs) of DS subjects, and interestingly, therapeutic concentrations of fluoxetine (FLX) applied to cultured PBMCs (1 µM for 24 h) were able to rescue TGF-β1 concentrations in the culture media from DS PBMCs, suggesting that FLX, a selective serotonin reuptake inhibitor (SSRI) endowed with neuroprotective activity, might rescue TGF-β1 concentrations in DS subjects at higher risk to develop cognitive decline. [ABSTRACT FROM AUTHOR]

Published
2024
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29. Corrigendum to “Progressive human-like tauopathy with downstream neurodegeneration and neurovascular compromise in a transgenic rat model” [Neurobiol of Disease 184 (2023),106227 / YNBDI_106227]

Author

Emmerson, Joshua T., primary, Do Carmo, Sonia, additional, Liu, Yingying, additional, Shalhoub, Ali, additional, Liu, Ai, additional, Bonomo, Quentin, additional, Malcolm, Janice C., additional, Breuillaud, Lionel, additional, Martinez-Trujillo, Julio C., additional, and Cuello, A. Claudio, additional

Published
2023
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30. Sex differences in functional and molecular neuroimaging biomarkers of Alzheimer's disease in cognitively normal older adults with subjective memory complaints

Author

Bakardjian, Hovagim, Benali, Habib, Bertin, Hugo, Bonheur, Joel, Boukadida, Laurie, Boukerrou, Nadia, Cavedo, Enrica, Chiesa, Patrizia, Colliot, Olivier, Dubois, Bruno, Dubois, Marion, Epelbaum, Stéphane, Gagliardi, Geoffroy, Genthon, Remy, Habert, Marie-Odile, Hampel, Harald, Houot, Marion, Kas, Aurélie, Lamari, Foudil, Levy, Marcel, Lista, Simone, Metzinger, Christiane, Mochel, Fanny, Nyasse, Francis, Poisson, Catherine, Potier, Marie-Claude, Revillon, Marie, Santos, Antonio, Andrade, Katia Santos, Sole, Marine, Surtee, Mohmed, de Schotten, Michel Thiebaud, Vergallo, Andrea, Younsi, Nadjia, Aguilar, Lisi Flores, Babiloni, Claudio, Baldacci, Filippo, Benda, Norbert, Black, Keith L., Bokde, Arun L.W., Bonuccelli, Ubaldo, Broich, Karl, Bun, René S., Cacciola, Francesco, Castrillo, Juan, Ceravolo, Roberto, Chiesa, Patrizia A., Coman, Cristina-Maria, Corvol, Jean-Christophe, Cuello, Augusto Claudio, Cummings, Jeffrey L., Depypere, Herman, Duggento, Andrea, Durrleman, Stanley, Escott-Price, Valentina, Federoff, Howard, Ferretti, Maria Teresa, Fiandaca, Massimo, Frank, Richard A., Garaci, Francesco, George, Nathalie, Giorgi, Filippo S., Graziani, Manuela, Haberkamp, Marion, Herholz, Karl, Karran, Eric, Kim, Seung H., Koronyo, Yosef, Koronyo-Hamaoui, Maya, Langevin, Todd, Lehéricy, Stéphane, Lorenceau, Jean, Mapstone, Mark, Neri, Christian, Nisticò, Robert, Nyasse-Messene, Francis, O'bryant, Sid E., Perry, George, Ritchie, Craig, Rojkova, Katrine, Rossi, Simone, Saidi, Amira, Santarnecchi, Emiliano, Schneider, Lon S., Sporns, Olaf, Toschi, Nicola, Verdooner, Steven R., Villain, Nicolas, Welikovitch, Lindsay A., Woodcock, Janet, Younesi, Erfan, Grothe, Michel J., and Teipel, Stefan J.

Published
2018
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35. The Effect of Fat Intake with Increased Omega-6-to-Omega-3 Polyunsaturated Fatty Acid Ratio in Animal Models of Early and Late Alzheimer's Disease-like Pathogenesis.

Author

Galeano, Pablo, de Ceglia, Marialuisa, Mastrogiovanni, Mauricio, Campanelli, Lorenzo, Medina-Vera, Dina, Campolo, Nicolás, Novack, Gisela V., Rosell-Valle, Cristina, Suárez, Juan, Aicardo, Adrián, Campuzano, Karen, Castaño, Eduardo M., Do Carmo, Sonia, Cuello, A. Claudio, Bartesaghi, Silvina, Radi, Rafael, Rodríguez de Fonseca, Fernando, and Morelli, Laura

Subjects
ALZHEIMER'S disease, ANIMAL models in research, CORN oil, AMYLOID beta-protein, PRESENILINS, HIGH-fat diet, BASE oils, UNSATURATED fatty acids
Abstract

This work aims to clarify the effect of dietary polyunsaturated fatty acid (PUFA) intake on the adult brain affected by amyloid pathology. McGill-R-Thy1-APP transgenic (Tg) rat and 5xFAD Tg mouse models that represent earlier or later disease stages were employed. The animals were exposed to a control diet (CD) or an HFD based on corn oil, from young (rats) or adult (mice) ages for 24 or 10 weeks, respectively. In rats and mice, the HFD impaired reference memory in wild-type (WT) animals but did not worsen it in Tg, did not cause obesity, and did not increase triglycerides or glucose levels. Conversely, the HFD promoted stronger microglial activation in Tg vs. WT rats but had no effect on cerebral amyloid deposition. IFN-γ, IL-1β, and IL-6 plasma levels were increased in Tg rats, regardless of diet, while CXCL1 chemokine levels were increased in HFD-fed mice, regardless of genotype. Hippocampal 3-nitrotyrosine levels tended to increase in HFD-fed Tg rats but not in mice. Overall, an HFD with an elevated omega-6-to-omega-3 ratio as compared to the CD (25:1 vs. 8.4:1) did not aggravate the outcome of AD regardless of the stage of amyloid pathology, suggesting that many neurobiological processes relevant to AD are not directly dependent on PUFA intake. [ABSTRACT FROM AUTHOR]

Published
2023
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38. Chronic Hippocampal Expression of Notch Intracellular Domain Induces Vascular Thickening, Reduces Glucose Availability, and Exacerbates Spatial Memory Deficits in a Rat Model of Early Alzheimer

Author

Galeano, Pablo, Leal, María C., Ferrari, Carina C., Dalmasso, María C., Martino Adami, Pamela V., Farías, María I., Casabona, Juan C., Puntel, Mariana, Do Carmo, Sonia, Smal, Clara, Arán, Martín, Castaño, Eduardo M., Pitossi, Fernando J., Cuello, A. Claudio, and Morelli, Laura

Published
2018
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41. Basal forebrain atrophy along the Alzheimer's disease continuum in adults with Down syndrome

Author

Rozalem Aranha, Mateus, primary, Iulita, Maria Florencia, additional, Montal, Victor, additional, Pegueroles, Jordi, additional, Bejanin, Alexandre, additional, Vaqué‐Alcázar, Lídia, additional, Grothe, Michel J., additional, Carmona‐Iragui, Maria, additional, Videla, Laura, additional, Benejam, Bessy, additional, Arranz, Javier, additional, Padilla, Concepción, additional, Valldeneu, Sílvia, additional, Barroeta, Isabel, additional, Altuna, Miren, additional, Fernández, Susana, additional, Ribas, Laia, additional, Valle‐Tamayo, Natalia, additional, Alcolea, Daniel, additional, González‐Ortiz, Sofía, additional, Bargalló, Núria, additional, Zetterberg, Henrik, additional, Blennow, Kaj, additional, Blesa, Rafael, additional, Wisniewski, Thomas, additional, Busciglio, Jorge, additional, Cuello, A. Claudio, additional, Lleó, Alberto, additional, and Fortea, Juan, additional

Published
2023
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42. Basal forebrain atrophy along the Alzheimer's disease continuum in adults with Down syndrome

Author

Instituto de Salud Carlos III, Centro Investigación Biomédica en Red Enfermedades Neurodegenerativas (España), National Institutes of Health (US), Generalitat de Catalunya, Fundación Tatiana Pérez de Guzmán el Bueno, European Commission, Alzheimer's Association, Societat Catalana de Neurologia, Swedish Research Council, European Research Council, Alzheimer Drug Discovery Foundation, Olav Thon Foundation, The Erling-Persson Family Foundation, Gamla Tjänarinnor Foundation, Dementia Research Institute (UK), Hjärnfonden, Government of Sweden, Aranha, Mateus Rozalem, Iulita, Maria Florencia, Montal, Victor, Pegueroles, Jordi, Bejanin, Alexandre, Vaqué-Alcázar, Lídia, Grothe, Michel J., Carmona-Iragui, Maria, Videla, Laura, Benejam, Bessy, Arranz, Javier, Padilla, Concepción, Valldeneu, Sílvia, Barroeta, Isabel, Altuna, Miren, Fernández, Susana, Ribas, Laia, Valle-Tamayo, Natalia, Alcolea, Daniel, González-Ortiz, Sofía, Bargalló, Núria, Zetterberg, Henrik, Blennow, Kaj, Blesa, Rafael, Wisniewski, Thomas, Busciglio, Jorge, Cuello, A. Claudio, Lleó, Alberto, Fortea, Juan, Instituto de Salud Carlos III, Centro Investigación Biomédica en Red Enfermedades Neurodegenerativas (España), National Institutes of Health (US), Generalitat de Catalunya, Fundación Tatiana Pérez de Guzmán el Bueno, European Commission, Alzheimer's Association, Societat Catalana de Neurologia, Swedish Research Council, European Research Council, Alzheimer Drug Discovery Foundation, Olav Thon Foundation, The Erling-Persson Family Foundation, Gamla Tjänarinnor Foundation, Dementia Research Institute (UK), Hjärnfonden, Government of Sweden, Aranha, Mateus Rozalem, Iulita, Maria Florencia, Montal, Victor, Pegueroles, Jordi, Bejanin, Alexandre, Vaqué-Alcázar, Lídia, Grothe, Michel J., Carmona-Iragui, Maria, Videla, Laura, Benejam, Bessy, Arranz, Javier, Padilla, Concepción, Valldeneu, Sílvia, Barroeta, Isabel, Altuna, Miren, Fernández, Susana, Ribas, Laia, Valle-Tamayo, Natalia, Alcolea, Daniel, González-Ortiz, Sofía, Bargalló, Núria, Zetterberg, Henrik, Blennow, Kaj, Blesa, Rafael, Wisniewski, Thomas, Busciglio, Jorge, Cuello, A. Claudio, Lleó, Alberto, and Fortea, Juan

Abstract

[Background] Basal forebrain (BF) degeneration occurs in Down syndrome (DS)-associated Alzheimer's disease (AD). However, the dynamics of BF atrophy with age and disease progression, its impact on cognition, and its relationship with AD biomarkers have not been studied in DS., [Methods] We included 234 adults with DS (150 asymptomatic, 38 prodromal AD, and 46 AD dementia) and 147 euploid controls. BF volumes were extracted from T-weighted magnetic resonance images using a stereotactic atlas in SPM12. We assessed BF volume changes with age and along the clinical AD continuum and their relationship to cognitive performance, cerebrospinal fluid (CSF) and plasma amyloid/tau/neurodegeneration biomarkers, and hippocampal volume., [Results] In DS, BF volumes decreased with age and along the clinical AD continuum and significantly correlated with amyloid, tau, and neurofilament light chain changes in CSF and plasma, hippocampal volume, and cognitive performance., [Discussion] BF atrophy is a potentially valuable neuroimaging biomarker of AD-related cholinergic neurodegeneration in DS.

Published
2023

45. Nicotinamide as potential biomarker for Alzheimer’s disease: A translational study based on metabolomics

Author

Dalmasso, María C., primary, Arán, Martín, additional, Galeano, Pablo, additional, Perin, Silvina, additional, Giavalisco, Patrick, additional, Martino Adami, Pamela V., additional, Novack, Gisela V., additional, Castaño, Eduardo M., additional, Cuello, A. Claudio, additional, Scherer, Martin, additional, Maier, Wolfgang, additional, Wagner, Michael, additional, Riedel-Heller, Steffi, additional, Ramirez, Alfredo, additional, and Morelli, Laura, additional

Published
2023
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47. Correction: Applicability of in vivo staging of regional amyloid burden in a cognitively normal cohort with subjective memory complaints: the INSIGHT-preAD study

Author

Sakr, Fatemah A, Grothe, Michel J, Teipel, Stefan, Perry, George, Ritchie, Craig, Rojkova, Katrine, Rossi, Simone, Saidi, Amira, Santarnecchi, Emiliano, Schneider, Lon S, Sporns, Olaf, Toschi, Nicola, Verdooner, Steven R, Dubois, Bruno, Vergallo, Andrea, Villain, Nicolas, Welikovitch, Lindsay A, Woodcock, Janet, Younesi, Erfan, Hampel, Harald, group, INSIGHT-preAD study, Initiative, Alzheimer Precision Medicine, Bakardjian, Hovagim, Benali, Habib, Bertin, Hugo, Bonheur, Joel, Boukadida, Laurie, Cavedo, Enrica, Boukerrou, Nadia, Chiesa, Patrizia, Colliot, Olivier, Dubois, Marion, Epelbaum, Stéphane, Gagliardi, Geoffroy, Genthon, Remy, Habert, Marie-Odile, Jelistratova, Irina, Houot, Marion, Kas, Aurélie, Lamari, Foudil, Levy, Marcel, Lista, Simone, Metzinger, Christiane, Mochel, Fanny, Nyasse, Francis, Poisson, Catherine, Potier, Marie-Claude, Revillon, Marie, Santos, Antonio, Andrade, Katia Santos, Sole, Marine, Surtee, Mohmed, de Schotten, Michel Thiebaud, Younsi, Nadjia, Aguilar, Lisi Flores, Dyrba, Martin, Babiloni, Claudio, Baldacci, Filippo, Benda, Norbert, Black, Keith L, Bokde, Arun L W, Bonuccelli, Ubaldo, Broich, Karl, Bun, René S, Cacciola, Francesco, Castrillo, Juan, Gonzalez-Escamilla, Gabriel, Ceravolo, Roberto, Chiesa, Patrizia A, Coman, Cristina-Maria, Corvol, Jean-Christophe, Cuello, Augusto Claudio, Cummings, Jeffrey L, Depypere, Herman, Duggento, Andrea, Durrleman, Stanley, Escott-Price, Valentina, Federoff, Howard, Ferretti, Maria Teresa, Fiandaca, Massimo, Frank, Richard A, Garaci, Francesco, George, Nathalie, Locatelli, Maxime, Giorgi, Filippo S, Graziani, Manuela, Haberkamp, Marion, Herholz, Karl, Karran, Eric, Kim, Seung H, Koronyo, Yosef, Koronyo-Hamaoui, Maya, Lehericy, Stephane, Langevin, Todd, Lehéricy, Stéphane, Lorenceau, Jean, Mapstone, Mark, Neri, Christian, Nisticò, Robert, Nyasse-Messene, Francis, and O'bryant, Sid E

Subjects
Neurology, Cognitive Neuroscience, ddc:610, Neurology (clinical)
Published
2022

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