Browsing by Author "Villeneuve, Sylvia"

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    Accelerated functional brain aging in pre-clinical familial Alzheimer’s disease
    (Springer Nature, 2021-09-09) Gonneaud, Julie; Baria, Alex T.; Binette, Alexa Pichet; Gordon, Brian A.; Chhatwal, Jasmeer P.; Cruchaga, Carlos; Jucker, Mathias; Levin, Johannes; Salloway, Stephen; Farlow, Martin; Gauthier, Serge; Benzinger, Tammie L.S.; Morris, John C.; Bateman, Randall J.; Breitner, John C.S.; Poirier, Judes; Vachon-Presseau, Etienne; Villeneuve, Sylvia; Neurology, School of Medicine
    Resting state functional connectivity (rs-fMRI) is impaired early in persons who subsequently develop Alzheimer’s disease (AD) dementia. This impairment may be leveraged to aid investigation of the pre-clinical phase of AD. We developed a model that predicts brain age from resting state (rs)-fMRI data, and assessed whether genetic determinants of AD, as well as beta-amyloid (Aβ) pathology, can accelerate brain aging. Using data from 1340 cognitively unimpaired participants between 18–94 years of age from multiple sites, we showed that topological properties of graphs constructed from rs-fMRI can predict chronological age across the lifespan. Application of our predictive model to the context of pre-clinical AD revealed that the pre-symptomatic phase of autosomal dominant AD includes acceleration of functional brain aging. This association was stronger in individuals having significant Aβ pathology.
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    Amyloid and Tau Pathology Associations With Personality Traits, Neuropsychiatric Symptoms, and Cognitive Lifestyle in the Preclinical Phases of Sporadic and Autosomal Dominant Alzheimer’s Disease
    (Elsevier, 2021) Pichet Binette, Alexa; Vachon-Presseau, Étienne; Morris, John; Bateman, Randall; Benzinger, Tammie; Collins, D. Louis; Poirier, Judes; Breitner, John C. S.; Villeneuve, Sylvia; Dominantly Inherited Alzheimer Network (DIAN); PREVENT-AD Research Group; Psychiatry, School of Medicine
    Background: Major prevention trials for Alzheimer's disease (AD) are now focusing on multidomain lifestyle interventions. However, the exact combination of behavioral factors related to AD pathology remains unclear. In 2 cohorts of cognitively unimpaired individuals at risk of AD, we examined which combinations of personality traits, neuropsychiatric symptoms, and cognitive lifestyle (years of education or lifetime cognitive activity) related to the pathological hallmarks of AD, amyloid-β, and tau deposits. Methods: A total of 115 older adults with a parental or multiple-sibling family history of sporadic AD (PREVENT-AD [PRe-symptomatic EValuation of Experimental or Novel Treatments for AD] cohort) underwent amyloid and tau positron emission tomography and answered several questionnaires related to behavioral attributes. Separately, we studied 117 mutation carriers from the DIAN (Dominant Inherited Alzheimer Network) study group cohort with amyloid positron emission tomography and behavioral data. Using partial least squares analysis, we identified latent variables relating amyloid or tau pathology with combinations of personality traits, neuropsychiatric symptoms, and cognitive lifestyle. Results: In PREVENT-AD, lower neuroticism, neuropsychiatric burden, and higher education were associated with less amyloid deposition (p = .014). Lower neuroticism and neuropsychiatric features, along with higher measures of openness and extraversion, were related to less tau deposition (p = .006). In DIAN, lower neuropsychiatric burden and higher education were also associated with less amyloid (p = .005). The combination of these factors accounted for up to 14% of AD pathology. Conclusions: In the preclinical phase of both sporadic and autosomal dominant AD, multiple behavioral features were associated with AD pathology. These results may suggest potential pathways by which multidomain interventions might help delay AD onset or progression.
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    Genetic and clinical correlates of two neuroanatomical AI dimensions in the Alzheimer's disease continuum
    (Springer Nature, 2024-10-05) Wen, Junhao; Yang, Zhijian; Nasrallah, Ilya M.; Cui, Yuhan; Erus, Guray; Srinivasan, Dhivya; Abdulkadir, Ahmed; Mamourian, Elizabeth; Hwang, Gyujoon; Singh, Ashish; Bergman, Mark; Bao, Jingxuan; Varol, Erdem; Zhou, Zhen; Boquet-Pujadas, Aleix; Chen, Jiong; Toga, Arthur W.; Saykin, Andrew J.; Hohman, Timothy J.; Thompson, Paul M.; Villeneuve, Sylvia; Gollub, Randy; Sotiras, Aristeidis; Wittfeld, Katharina; Grabe, Hans J.; Tosun, Duygu; Bilgel, Murat; An, Yang; Marcus, Daniel S.; LaMontagne, Pamela; Benzinger, Tammie L.; Heckbert, Susan R.; Austin, Thomas R.; Launer, Lenore J.; Espeland, Mark; Masters, Colin L.; Maruff, Paul; Fripp, Jurgen; Johnson, Sterling C.; Morris, John C.; Albert, Marilyn S.; Bryan, R. Nick; Resnick, Susan M.; Ferrucci, Luigi; Fan, Yong; Habes, Mohamad; Wolk, David; Shen, Li; Shou, Haochang; Davatzikos, Christos; Radiology and Imaging Sciences, School of Medicine
    Alzheimer's disease (AD) is associated with heterogeneous atrophy patterns. We employed a semi-supervised representation learning technique known as Surreal-GAN, through which we identified two latent dimensional representations of brain atrophy in symptomatic mild cognitive impairment (MCI) and AD patients: the "diffuse-AD" (R1) dimension shows widespread brain atrophy, and the "MTL-AD" (R2) dimension displays focal medial temporal lobe (MTL) atrophy. Critically, only R2 was associated with widely known sporadic AD genetic risk factors (e.g., APOE ε4) in MCI and AD patients at baseline. We then independently detected the presence of the two dimensions in the early stages by deploying the trained model in the general population and two cognitively unimpaired cohorts of asymptomatic participants. In the general population, genome-wide association studies found 77 genes unrelated to APOE differentially associated with R1 and R2. Functional analyses revealed that these genes were overrepresented in differentially expressed gene sets in organs beyond the brain (R1 and R2), including the heart (R1) and the pituitary gland, muscle, and kidney (R2). These genes were enriched in biological pathways implicated in dendritic cells (R2), macrophage functions (R1), and cancer (R1 and R2). Several of them were "druggable genes" for cancer (R1), inflammation (R1), cardiovascular diseases (R1), and diseases of the nervous system (R2). The longitudinal progression showed that APOE ε4, amyloid, and tau were associated with R2 at early asymptomatic stages, but this longitudinal association occurs only at late symptomatic stages in R1. Our findings deepen our understanding of the multifaceted pathogenesis of AD beyond the brain. In early asymptomatic stages, the two dimensions are associated with diverse pathological mechanisms, including cardiovascular diseases, inflammation, and hormonal dysfunction-driven by genes different from APOE-which may collectively contribute to the early pathogenesis of AD. All results are publicly available at https://labs-laboratory.com/medicine/ .
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    The prevalence of tau‐PET positivity in aging and dementia
    (Wiley, 2025-01-09) Coomans, Emma M.; Groot, Colin; Rowe, Christopher C.; Dore, Vincent; Villemagne, Victor L.; van de Giessen, Elsmarieke; van der Flier, Wiesje M.; Pijnenburg, Yolande A. L.; Visser, Pieter Jelle; den Braber, Anouk; Pontecorvo, Michael; Shcherbinin, Sergey; Kennedy, Ian A.; Jagust, William J.; Baker, Suzanne L.; Harrison, Theresa M.; Gispert, Juan Domingo; Shekari, Mahnaz; Minguillon, Carolina; Smith, Ruben; Mattsson-Carlgren, Niklas; Palmqvist, Sebastian; Strandberg, Olof; Stomrud, Erik; Malpetti, Maura; O'Brien, John T.; Rowe, James B.; Jäger, Elena; Bischof, Gérard N.; Drzezga, Alexander; Garibotto, Valentina; Frisoni, Giovanni; Peretti, Débora Elisa; Schöll, Michael; Skoog, Ingmar; Kern, Silke; Sperling, Reisa A.; Johnson, Keith A.; Risacher, Shannon L.; Saykin, Andrew J.; Carrillo, Maria C.; Dickerson, Brad C.; Apostolova, Liana G.; Barthel, Henryk; Rullmann, Michael; Messerschmidt, Konstantin; Vandenberghe, Rik; Van Laere, Koen; Spruyt, Laure; Franzmeier, Nicolai; Brendel, Matthias; Gnörich, Johannes; Benzinger, Tammie L. S.; Lagarde, Julien; Sarazin, Marie; Bottlaender, Michel; Villeneuve, Sylvia; Poirier, Judes; Seo, Sang Won; Gu, Yuna; Kim, Jun Pyo; Mormino, Elizabeth; Young, Christina B.; Vossler, Hillary; Rosa-Neto, Pedro; Therriault, Joseph; Rahmouni, Nesrine; Coath, William; Cash, David M.; Schott, Jonathan M.; Rabinovici, Gil D.; La Joie, Renaud; Rosen, Howard J.; Johnson, Sterling C.; Christian, Bradley T.; Betthauser, Tobey J.; Hansson, Oskar; Ossenkoppele, Rik; Radiology and Imaging Sciences, School of Medicine
    Background Tau‐PET imaging allows in‐vivo detection of neurofibrillary tangles. One tau‐PET tracer (i.e., [18F]flortaucipir) has received FDA‐approval for clinical use, and multiple other tau‐PET tracers have been implemented into clinical trials for participant selection and/or as a primary or secondary outcome measure. To optimize future use of tau‐PET, it is essential to understand how demographic, clinical and genetic factors affect tau‐PET‐positivity rates. Method This large‐scale multi‐center study includes 9713 participants from 35 cohorts worldwide who underwent tau‐PET with [18F]flortaucipir (n = 6420), [18F]RO948 (n = 1999), [18F]MK6240 (n = 878) or [18F]PI2620 (n = 416) (Table‐1). We analyzed individual‐level tau‐PET SUVR data using a cerebellar reference region that were processed either centrally (n = 3855) or by each cohort (n = 5858). We computed cohort‐specific SUVR thresholds based on the mean + 2 standard deviations in a temporal meta‐region of amyloid‐negative cognitively normal (CN) individuals aged >50. Logistic generalized estimating equations were used to estimate tau‐PET‐positivity probabilities, using an exchangeable correlation structure to account for within‐cohort correlations. Analyses were performed with (interactions between) age, amyloid‐status, and APOE‐e4 carriership as independent variables, stratified for syndrome diagnosis. Result The study included 5962 CN participants (7.5% tau‐PET‐positive), 1683 participants with mild cognitive impairment (MCI, 33.8% tau‐PET‐positive) and 2068 participants with a clinical diagnosis of dementia (62.1% tau‐PET‐positive) (Figure‐1). From age 60 to 80 years, the estimated prevalence of tau‐PET‐positivity increased from 1.2% [95% CI: 0.9%‐1.5%] to 3.7% [2.3%‐5.1%] among CN amyloid‐negative participants; and from 16.4% [10.8%‐22.1%] to 20.5% [18.8%‐22.2%] among CN amyloid‐positive participants. Among amyloid‐negative participants with MCI and dementia, from age 60 to 80 years, the estimated prevalence of tau‐PET‐positivity increased from 3.5% [1.6%‐5.3%] to 11.8% [7.1%‐16.5%] and from 12.6% [4.5%‐20.7%] to 15.9% [6.7%‐25.1%] respectively. In contrast, among amyloid‐positive participants with MCI and dementia, from age 60 to 80 years, the estimated prevalence of tau‐PET‐positivity decreased from 66.5% [57.0%‐76.0%] to 48.3% [42.9%‐53.8%] and from 92.3% [88.7%‐95.9%] to 73.4% [67.5%‐79.3%] respectively. APOE‐e4 status primarily modulated the association of age with tau‐PET‐positivity estimates among CN and MCI amyloid‐positive participants (Figure‐2). Conclusion This large‐scale multi‐cohort study provides robust prevalence estimates of tau‐PET‐positivity, which can aid the interpretation of tau‐PET in the clinic and inform clinical trial designs.