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Browsing by Author "Benzinger, Tammie"
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Item 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 MedicineBackground: 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.Item CYP1B1-RMDN2 Alzheimer's disease endophenotype locus identified for cerebral tau PET(Springer Nature, 2024-09-20) Nho, Kwangsik; Risacher, Shannon L.; Apostolova, Liana G.; Bice, Paula J.; Brosch, Jared R.; Deardorff, Rachael; Faber, Kelley; Farlow, Martin R.; Foroud, Tatiana; Gao, Sujuan; Rosewood, Thea; Kim, Jun Pyo; Nudelman, Kelly; Yu, Meichen; Aisen, Paul; Sperling, Reisa; Hooli, Basavaraj; Shcherbinin, Sergey; Svaldi, Diana; Jack, Clifford R., Jr.; Jagust, William J.; Landau, Susan; Vasanthakumar, Aparna; Waring, Jeffrey F.; Doré, Vincent; Laws, Simon M.; Masters, Colin L.; Porter, Tenielle; Rowe, Christopher C.; Villemagne, Victor L.; Dumitrescu, Logan; Hohman, Timothy J.; Libby, Julia B.; Mormino, Elizabeth; Buckley, Rachel F.; Johnson, Keith; Yang, Hyun-Sik; Petersen, Ronald C.; Ramanan, Vijay K.; Ertekin-Taner, Nilüfer; Vemuri, Prashanthi; Cohen, Ann D.; Fan, Kang-Hsien; Kamboh, M. Ilyas; Lopez, Oscar L.; Bennett, David A.; Ali, Muhammad; Benzinger, Tammie; Cruchaga, Carlos; Hobbs, Diana; De Jager, Philip L.; Fujita, Masashi; Jadhav, Vaishnavi; Lamb, Bruce T.; Tsai, Andy P.; Castanho, Isabel; Mill, Jonathan; Weiner, Michael W.; Alzheimer’s Disease Neuroimaging Initiative (ADNI); Department of Defense Alzheimer’s Disease Neuroimaging Initiative (DoD-ADNI); Anti-Amyloid Treatment in Asymptomatic Alzheimer’s Study (A4 Study) and Longitudinal Evaluation of Amyloid Risk and Neurodegeneration (LEARN); Australian Imaging, Biomarker & Lifestyle Study (AIBL); Saykin, Andrew J.; Radiology and Imaging Sciences, School of MedicineDetermining the genetic architecture of Alzheimer's disease pathologies can enhance mechanistic understanding and inform precision medicine strategies. Here, we perform a genome-wide association study of cortical tau quantified by positron emission tomography in 3046 participants from 12 independent studies. The CYP1B1-RMDN2 locus is associated with tau deposition. The most significant signal is at rs2113389, explaining 4.3% of the variation in cortical tau, while APOE4 rs429358 accounts for 3.6%. rs2113389 is associated with higher tau and faster cognitive decline. Additive effects, but no interactions, are observed between rs2113389 and diagnosis, APOE4, and amyloid beta positivity. CYP1B1 expression is upregulated in AD. rs2113389 is associated with higher CYP1B1 expression and methylation levels. Mouse model studies provide additional functional evidence for a relationship between CYP1B1 and tau deposition but not amyloid beta. These results provide insight into the genetic basis of cerebral tau deposition and support novel pathways for therapeutic development in AD.Item Decreased body mass index in the preclinical stage of autosomal dominant Alzheimer's disease(SpringerNature, 2017-04-27) Müller, Stephan; Preische, Oliver; Sohrabi, Hamid R.; Gräber, Susanne; Jucker, Mathias; Dietzsch, Janko; Ringman, Ralph N.; Martins, Ralph N.; McDade, Eric; Schofield, Peter R.; Ghetti, Bernardino; Rossor, Martin; Graff-Radford, Neill R.; Levin, Johannes; Galasko, Douglas; Quaid, Kimberly A.; Salloway, Stephen; Xiong, Chengjie; Benzinger, Tammie; Buckles, Virginia; Masters, Colin L.; Sperling, Reisa; Bateman, Randall J.; Morris, John C.; Laske, Christoph; Department of Pathology and Laboratory Medicine, School of MedicineThe relationship between body-mass index (BMI) and Alzheimer´s disease (AD) has been extensively investigated. However, BMI alterations in preclinical individuals with autosomal dominant AD (ADAD) have not yet been investigated. We analyzed cross-sectional data from 230 asymptomatic members of families with ADAD participating in the Dominantly Inherited Alzheimer Network (DIAN) study including 120 preclinical mutation carriers (MCs) and 110 asymptomatic non-carriers (NCs). Differences in BMI and their relation with cerebral amyloid load and episodic memory as a function of estimated years to symptom onset (EYO) were analyzed. Preclinical MCs showed significantly lower BMIs compared to NCs, starting 11.2 years before expected symptom onset. However, the BMI curves begun to diverge already at 17.8 years before expected symptom onset. Lower BMI in preclinical MCs was significantly associated with less years before estimated symptom onset, higher global Aβ brain burden, and with lower delayed total recall scores in the logical memory test. The study provides cross-sectional evidence that weight loss starts one to two decades before expected symptom onset of ADAD. Our findings point toward a link between the pathophysiology of ADAD and disturbance of weight control mechanisms. Longitudinal follow-up studies are warranted to investigate BMI changes over time.Item First presentation with neuropsychiatric symptoms in autosomal dominant Alzheimer's disease: the Dominantly Inherited Alzheimer's Network Study(BMJ, 2023) O'Connor, Antoinette; Rice, Helen; Barnes, Josephine; Ryan, Natalie S.; Liu, Kathy Y.; Allegri, Ricardo Francisco; Berman, Sarah; Ringman, John M.; Cruchaga, Carlos; Farlow, Martin R.; Hassenstab, Jason; Lee, Jae-Hong; Perrin, Richard J.; Xiong, Chengjie; Gordon, Brian; Levey, Allan I.; Goate, Alison; Graff-Radford, Neil; Levin, Johannes; Jucker, Mathias; Benzinger, Tammie; McDade, Eric; Mori, Hiroshi; Noble, James M.; Schofield, Peter R.; Martins, Ralph N.; Salloway, Stephen; Chhatwal, Jasmeer; Morris, John C.; Bateman, Randall; Howard, Rob; Reeves, Suzanne; Fox, Nick C.; Dominantly Inherited Alzheimer Network; Neurology, School of MedicineItem Molecular neuroimaging in dominantly inherited versus sporadic early-onset Alzheimer's disease(Oxford University Press, 2024-05-03) Iaccarino, Leonardo; Llibre-Guerra, Jorge J.; McDade, Eric; Edwards, Lauren; Gordon, Brian; Benzinger, Tammie; Hassenstab, Jason; Kramer, Joel H.; Li, Yan; Miller, Bruce L.; Miller, Zachary; Morris, John C.; Mundada, Nidhi; Perrin, Richard J.; Rosen, Howard J.; Soleimani-Meigooni, David; Strom, Amelia; Tsoy, Elena; Wang, Guoqiao; Xiong, Chengjie; Allegri, Ricardo; Chrem, Patricio; Vazquez, Silvia; Berman, Sarah B.; Chhatwal, Jasmeer; Masters, Colin L.; Farlow, Martin R.; Jucker, Mathias; Levin, Johannes; Salloway, Stephen; Fox, Nick C.; Day, Gregory S.; Gorno-Tempini, Maria Luisa; Boxer, Adam L.; La Joie, Renaud; Bateman, Randall; Rabinovici, Gil D.; Neurology, School of MedicineApproximately 5% of Alzheimer's disease patients develop symptoms before age 65 (early-onset Alzheimer's disease), with either sporadic (sporadic early-onset Alzheimer's disease) or dominantly inherited (dominantly inherited Alzheimer's disease) presentations. Both sporadic early-onset Alzheimer's disease and dominantly inherited Alzheimer's disease are characterized by brain amyloid-β accumulation, tau tangles, hypometabolism and neurodegeneration, but differences in topography and magnitude of these pathological changes are not fully elucidated. In this study, we directly compared patterns of amyloid-β plaque deposition and glucose hypometabolism in sporadic early-onset Alzheimer's disease and dominantly inherited Alzheimer's disease individuals. Our analysis included 134 symptomatic sporadic early-onset Alzheimer's disease amyloid-Positron Emission Tomography (PET)-positive cases from the University of California, San Francisco, Alzheimer's Disease Research Center (mean ± SD age 59.7 ± 5.6 years), 89 symptomatic dominantly inherited Alzheimer's disease cases (age 45.8 ± 9.3 years) and 102 cognitively unimpaired non-mutation carriers from the Dominantly Inherited Alzheimer Network study (age 44.9 ± 9.2). Each group underwent clinical and cognitive examinations, 11C-labelled Pittsburgh Compound B-PET and structural MRI. 18F-Fluorodeoxyglucose-PET was also available for most participants. Positron Emission Tomography scans from both studies were uniformly processed to obtain a standardized uptake value ratio (PIB50-70 cerebellar grey reference and FDG30-60 pons reference) images. Statistical analyses included pairwise global and voxelwise group comparisons and group-independent component analyses. Analyses were performed also adjusting for covariates including age, sex, Mini-Mental State Examination, apolipoprotein ε4 status and average composite cortical of standardized uptake value ratio. Compared with dominantly inherited Alzheimer's disease, sporadic early-onset Alzheimer's disease participants were older at age of onset (mean ± SD, 54.8 ± 8.2 versus 41.9 ± 8.2, Cohen's d = 1.91), with more years of education (16.4 ± 2.8 versus 13.5 ± 3.2, d = 1) and more likely to be apolipoprotein ε4 carriers (54.6% ε4 versus 28.1%, Cramer's V = 0.26), but similar Mini-Mental State Examination (20.6 ± 6.1 versus 21.2 ± 7.4, d = 0.08). Sporadic early-onset Alzheimer's disease had higher global cortical Pittsburgh Compound B-PET binding (mean ± SD standardized uptake value ratio, 1.92 ± 0.29 versus 1.58 ± 0.44, d = 0.96) and greater global cortical 18F-fluorodeoxyglucose-PET hypometabolism (mean ± SD standardized uptake value ratio, 1.32 ± 0.1 versus 1.39 ± 0.19, d = 0.48) compared with dominantly inherited Alzheimer's disease. Fully adjusted comparisons demonstrated relatively higher Pittsburgh Compound B-PET standardized uptake value ratio in the medial occipital, thalami, basal ganglia and medial/dorsal frontal regions in dominantly inherited Alzheimer's disease versus sporadic early-onset Alzheimer's disease. Sporadic early-onset Alzheimer's disease showed relatively greater 18F-fluorodeoxyglucose-PET hypometabolism in Alzheimer's disease signature temporoparietal regions and caudate nuclei, whereas dominantly inherited Alzheimer's disease showed relatively greater hypometabolism in frontal white matter and pericentral regions. Independent component analyses largely replicated these findings by highlighting common and unique Pittsburgh Compound B-PET and 18F-fluorodeoxyglucose-PET binding patterns. In summary, our findings suggest both common and distinct patterns of amyloid and glucose hypometabolism in sporadic and dominantly inherited early-onset Alzheimer's disease.Item Neuropathologic assessment of participants in two multi-center longitudinal observational studies: the Alzheimer Disease Neuroimaging Initiative (ADNI) and the Dominantly Inherited Alzheimer Network (DIAN)(Wiley, 2015-08) Cairns, Nigel J.; Perrin, Richard J.; Franklin, Erin E.; Carter, Deborah; Vincent, Benjamin; Xie, Mingqiang; Bateman, Randall J.; Benzinger, Tammie; Friedrichsen, Karl; Brooks, William S.; Halliday, Glenda M.; McLean, Catriona; Ghetti, Bernardino; Morris, John C.; Alzheimer Disease Neuroimaging Initiative; Dominantly Inherited Alzheimer Network; Department of Pathology & Laboratory Medicine, IU School of MedicineIt has been hypothesized that the relatively rare autosomal dominant Alzheimer disease (ADAD) may be a useful model of the more frequent, sporadic, late-onset AD (LOAD). Individuals with ADAD have a predictable age at onset and the biomarker profile of ADAD participants in the preclinical stage may be used to predict disease progression and clinical onset. However, the extent to which the pathogenesis and neuropathology of ADAD overlaps with that of LOAD is equivocal. To address this uncertainty, two multicenter longitudinal observational studies, the Alzheimer Disease Neuroimaging Initiative (ADNI) and the Dominantly Inherited Alzheimer Network (DIAN), leveraged the expertise and resources of the existing Knight Alzheimer Disease Research Center (ADRC) at Washington University School of Medicine, St. Louis, Missouri, USA, to establish a Neuropathology Core (NPC). The ADNI/DIAN-NPC is systematically examining the brains of all participants who come to autopsy at the 59 ADNI sites in the USA and Canada and the 14 DIAN sites in the USA (8), Australia (3), UK (1), and Germany (2). By 2014, 41 ADNI and 24 DIAN autopsies (involving 9 participants and 15 family members) had been performed. The autopsy rate in the ADNI cohort in the most recent year was 93% (total since NPC inception: 70%). In summary, the ADNI/DIAN NPC has implemented a standard protocol for all sites to solicit permission for brain autopsy and to send brain tissue to the NPC for a standardized, uniform, and state-of-the-art neuropathologic assessment. The benefit to ADNI and DIAN of the implementation of the NPC is very clear. The NPC provides final ‘gold standard’ neuropathological diagnoses and data against which the antecedent observations and measurements of ADNI and DIAN can be compared.Item Serum neurofilament dynamics predicts neurodegeneration and clinical progression in presymptomatic Alzheimer's disease(Nature Research, 2019-02) Preische, Oliver; Schultz, Stephanie A.; Apel, Anja; Kuhle, Jens; Kaeser, Stephan A.; Barro, Christian; Gräber, Susanne; Kuder-Buletta, Elke; LaFougere, Christian; Laske, Christoph; Vöglein, Jonathan; Levin, Johannes; Masters, Colin L.; Martins, Ralph; Schofield, Peter R.; Rossor, Martin N.; Graff-Radford, Neill R.; Salloway, Stephen; Ghetti, Bernardino; Ringman, John M.; Noble, James M.; Chhatwal, Jasmeer; Goate, Alison M.; Benzinger, Tammie L. S.; Morris, John C.; Bateman, Randall J.; Wang, Guoqiao; Fagan, Anne M.; McDade, Eric M.; Gordon, Brian A.; Jucker, Mathias; Alzheimer Network; Allegri, Ricardo; Amtashar, Fatima; Bateman, Randall; Benzinger, Tammie; Berman, Sarah; Bodge, Courtney; Brandon, Susan; Brooks, William; Buck, Jill; Buckles, Virginia; Chea, Sochenda; Chhatwal, Jasmeer; Chrem, Patricio; Chui, Helena; Cinco, Jake; Clifford, Jack; Cruchaga, Carlos; D’Mello, Mirelle; Donahue, Tamara; Douglas, Jane; Edigo, Noelia; Erekin-Taner, Nilufer; Fagan, Anne; Farlow, Marty; Farrar, Angela; Feldman, Howard; Flynn, Gigi; Fox, Nick; Franklin, Erin; Fujii, Hisako; Gant, Cortaiga; Gardener, Samantha; Ghetti, Bernardino; Goate, Alison; Goldman, Jill; Gordon, Brian; Graff-Radford, Neill; Gray, Julia; Gurney, Jenny; Hassenstab, Jason; Hirohara, Mie; Holtzman, David; Hornbeck, Russ; DiBari, Siri Houeland; Ikeuchi, Takeshi; Ikonomovic, Snezana; Jerome, Gina; Jucker, Mathias; Karch, Celeste; Kasuga, Kensaku; Kawarabayashi, Takeshi; Klunk, William; Koeppe, Robert; Kuder-Buletta, Elke; Laske, Christoph; Lee, Jae-Hong; Levin, Johannes; Marcus, Daniel; Martins, Ralph; Mason, Neal Scott; Masters, Colin; Maue-Dreyfus, Denise; McDade, Eric; Montoya, Lucy; Mori, Hiroshi; Morris, John; Nagamatsu, Akem; Neimeyer, Katie; Noble, James; Norton, Joanne; Perrin, Richard; Raichle, Marc; Ringman, John; Roh, Jee Hoon; Salloway, Stephen; Schofield, Peter; Shimada, Hiroyuki; Shiroto, Tomoyo; Shoji, Mikio; Sigurdson, Wendy; Sohrabi, Hamid; Sparks, Paige; Suzuki, Kazushi; Swisher, Laura; Taddei, Kevin; Wang, Jen; Wang, Peter; Weiner, Mike; Wolfsberger, Mary; Xiong, Chengjie; Xu, Xiong; Pathology and Laboratory Medicine, School of MedicineNeurofilament light chain (NfL) is a promising fluid biomarker of disease progression for various cerebral proteopathies. Here we leverage the unique characteristics of the Dominantly Inherited Alzheimer Network and ultrasensitive immunoassay technology to demonstrate that NfL levels in the cerebrospinal fluid (n = 187) and serum (n = 405) are correlated with one another and are elevated at the presymptomatic stages of familial Alzheimer's disease. Longitudinal, within-person analysis of serum NfL dynamics (n = 196) confirmed this elevation and further revealed that the rate of change of serum NfL could discriminate mutation carriers from non-mutation carriers almost a decade earlier than cross-sectional absolute NfL levels (that is, 16.2 versus 6.8 years before the estimated symptom onset). Serum NfL rate of change peaked in participants converting from the presymptomatic to the symptomatic stage and was associated with cortical thinning assessed by magnetic resonance imaging, but less so with amyloid-β deposition or glucose metabolism (assessed by positron emission tomography). Serum NfL was predictive for both the rate of cortical thinning and cognitive changes assessed by the Mini-Mental State Examination and Logical Memory test. Thus, NfL dynamics in serum predict disease progression and brain neurodegeneration at the early presymptomatic stages of familial Alzheimer's disease, which supports its potential utility as a clinically useful biomarker.Item Widespread white matter and conduction defects in PSEN1-related spastic paraparesis(Elsevier, 2016-11) Soosman, Steffan K.; Joseph-Mathurin, Nelly; Braskie, Meredith N.; Bordelon, Yvette M.; Wharton, David; Casado, Maria; Coppola, Giovanni; McCallum, Holly; Nuwer, Marc; Coutin-Churchman, Pedro; Apostolova, Liana G.; Benzinger, Tammie; Ringman, John M.; Neurology, School of MedicineThe mechanisms underlying PSEN1 mutation-associated spastic paraparesis (SP) are not clear. We compared diffusion and volumetric magnetic resonance measures between 3 persons with SP associated with the A431E mutation and 7 symptomatic persons with PSEN1 mutations without SP matched for symptom duration. We performed amyloid imaging and central motor and somatosensory conduction studies in one subject with SP. We found decreases in fractional anisotropy and increases in mean diffusivity in widespread white matter areas including the corpus callosum, occipital, parietal, and frontal lobes in PSEN1 mutation carriers with SP. Volumetric measures were not different and amyloid imaging showed low signal in sensorimotor cortex and other areas in a single subject with SP. Electrophysiological studies demonstrated both slowed motor and sensory conduction in the lower extremities in this same subject. Our results suggest that SP in carriers of the A431E PSEN1 mutation is a manifestation of widespread white matter abnormalities not confined to the corticospinal tract that is at most indirectly related to the mutation’s effect on APP processing and amyloid deposition.