Browsing by Author "Chrem, Patricio"
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Item 15 Years of Longitudinal Genetic, Clinical, Cognitive, Imaging, and Biochemical Measures in DIAN(medRxiv, 2024-08-09) Daniels, Alisha J.; McDade, Eric; Llibre-Guerra, Jorge J.; Xiong, Chengjie; Perrin, Richard J.; Ibanez, Laura; Supnet-Bell, Charlene; Cruchaga, Carlos; Goate, Alison; Renton, Alan E.; Benzinger, Tammie L. S.; Gordon, Brian A.; Hassenstab, Jason; Karch, Celeste; Popp, Brent; Levey, Allan; Morris, John; Buckles, Virginia; Allegri, Ricardo F.; Chrem, Patricio; Berman, Sarah B.; Chhatwal, Jasmeer P.; Farlow, Martin R.; Fox, Nick C.; Day, Gregory S.; Ikeuchi, Takeshi; Jucker, Mathias; Lee, Jae-Hong; Levin, Johannes; Lopera, Francisco; Takada, Leonel; Sosa, Ana Luisa; Martins, Ralph; Mori, Hiroshi; Noble, James M.; Salloway, Stephen; Huey, Edward; Rosa-Neto, Pedro; Sánchez-Valle, Raquel; Schofield, Peter R.; Roh, Jee Hoon; Bateman, Randall J.; Dominantly Inherited Alzheimer Network; Neurology, School of MedicineThis manuscript describes and summarizes the Dominantly Inherited Alzheimer Network Observational Study (DIAN Obs), highlighting the wealth of longitudinal data, samples, and results from this human cohort study of brain aging and a rare monogenic form of Alzheimer's disease (AD). DIAN Obs is an international collaborative longitudinal study initiated in 2008 with support from the National Institute on Aging (NIA), designed to obtain comprehensive and uniform data on brain biology and function in individuals at risk for autosomal dominant AD (ADAD). ADAD gene mutations in the amyloid protein precursor (APP), presenilin 1 (PSEN1), or presenilin 2 (PSEN2) genes are deterministic causes of ADAD, with virtually full penetrance, and a predictable age at symptomatic onset. Data and specimens collected are derived from full clinical assessments, including neurologic and physical examinations, extensive cognitive batteries, structural and functional neuro-imaging, amyloid and tau pathological measures using positron emission tomography (PET), flurordeoxyglucose (FDG) PET, cerebrospinal fluid and blood collection (plasma, serum, and whole blood), extensive genetic and multi-omic analyses, and brain donation upon death. This comprehensive evaluation of the human nervous system is performed longitudinally in both mutation carriers and family non-carriers, providing one of the deepest and broadest evaluations of the human brain across decades and through AD progression. These extensive data sets and samples are available for researchers to address scientific questions on the human brain, aging, and AD.Item Longitudinal clinical, cognitive and biomarker profiles in dominantly inherited versus sporadic early-onset Alzheimer's disease(Oxford University Press, 2023-10-18) Llibre-Guerra, Jorge J.; Iaccarino, Leonardo; Coble, Dean; Edwards, Lauren; Li, Yan; McDade, Eric; Strom, Amelia; Gordon, Brian; Mundada, Nidhi; Schindler, Suzanne E.; Tsoy, Elena; Ma, Yinjiao; Lu, Ruijin; Fagan, Anne M.; Benzinger, Tammie L. S.; Soleimani-Meigooni, David; Aschenbrenner, Andrew J.; Miller, Zachary; Wang, Guoqiao; Kramer, Joel H.; Hassenstab, Jason; Rosen, Howard J.; Morris, John C.; Miller, Bruce L.; Xiong, Chengjie; Perrin, Richard J.; Allegri, Ricardo; Chrem, Patricio; Surace, Ezequiel; Berman, Sarah B.; Chhatwal, Jasmeer; Masters, Colin L.; Farlow, Martin R.; Jucker, Mathias; Levin, Johannes; Fox, Nick C.; Day, Gregory; Gorno-Tempini, Maria Luisa; Boxer, Adam L.; La Joie, Renaud; Rabinovici, Gil D.; Bateman, Randall; Neurology, School of MedicineApproximately 5% of Alzheimer's disease cases have an early age at onset (<65 years), with 5-10% of these cases attributed to dominantly inherited mutations and the remainder considered as sporadic. The extent to which dominantly inherited and sporadic early-onset Alzheimer's disease overlap is unknown. In this study, we explored the clinical, cognitive and biomarker profiles of early-onset Alzheimer's disease, focusing on commonalities and distinctions between dominantly inherited and sporadic cases. Our analysis included 117 participants with dominantly inherited Alzheimer's disease enrolled in the Dominantly Inherited Alzheimer Network and 118 individuals with sporadic early-onset Alzheimer's disease enrolled at the University of California San Francisco Alzheimer's Disease Research Center. Baseline differences in clinical and biomarker profiles between both groups were compared using t-tests. Differences in the rates of decline were compared using linear mixed-effects models. Individuals with dominantly inherited Alzheimer's disease exhibited an earlier age-at-symptom onset compared with the sporadic group [43.4 (SD ± 8.5) years versus 54.8 (SD ± 5.0) years, respectively, P < 0.001]. Sporadic cases showed a higher frequency of atypical clinical presentations relative to dominantly inherited (56.8% versus 8.5%, respectively) and a higher frequency of APOE-ε4 (50.0% versus 28.2%, P = 0.001). Compared with sporadic early onset, motor manifestations were higher in the dominantly inherited cohort [32.5% versus 16.9% at baseline (P = 0.006) and 46.1% versus 25.4% at last visit (P = 0.001)]. At baseline, the sporadic early-onset group performed worse on category fluency (P < 0.001), Trail Making Test Part B (P < 0.001) and digit span (P < 0.001). Longitudinally, both groups demonstrated similar rates of cognitive and functional decline in the early stages. After 10 years from symptom onset, dominantly inherited participants experienced a greater decline as measured by Clinical Dementia Rating Sum of Boxes [3.63 versus 1.82 points (P = 0.035)]. CSF amyloid beta-42 levels were comparable [244 (SD ± 39.3) pg/ml dominantly inherited versus 296 (SD ± 24.8) pg/ml sporadic early onset, P = 0.06]. CSF phosphorylated tau at threonine 181 levels were higher in the dominantly inherited Alzheimer's disease cohort (87.3 versus 59.7 pg/ml, P = 0.005), but no significant differences were found for t-tau levels (P = 0.35). In summary, sporadic and inherited Alzheimer's disease differed in baseline profiles; sporadic early onset is best distinguished from dominantly inherited by later age at onset, high frequency of atypical clinical presentations and worse executive performance at baseline. Despite these differences, shared pathways in longitudinal clinical decline and CSF biomarkers suggest potential common therapeutic targets for both populations, offering valuable insights for future research and clinical trial design.Item 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 Pattern and degree of individual brain atrophy predicts dementia onset in dominantly inherited Alzheimer's disease(Wiley, 2021-07-05) Keret, Ophir; Staffaroni, Adam M.; Ringman, John M.; Cobigo, Yann; Goh, Sheng-Yang M.; Wolf, Amy; Allen, Isabel Elaine; Salloway, Stephen; Chhatwal, Jasmeer; Brickman, Adam M.; Reyes-Dumeyer, Dolly; Bateman, Randal J.; Benzinger, Tammie L.S.; Morris, John C.; Ances, Beau M.; Joseph-Mathurin, Nelly; Perrin, Richard J.; Gordon, Brian A.; Levin, Johannes; Vöglein, Jonathan; Jucker, Mathias; la Fougère, Christian; Martins, Ralph N.; Sohrabi, Hamid R.; Taddei, Kevin; Villemagne, Victor L.; Schofield, Peter R.; Brooks, William S.; Fulham, Michael; Masters, Colin L.; Ghetti, Bernardino; Saykin, Andrew J.; Jack, Clifford R.; Graff-Radford, Neill R.; Weiner, Michael; Cash, David M.; Allegri, Ricardo F.; Chrem, Patricio; Yi, Su; Miller, Bruce L.; Rabinovici, Gil D.; Rosen, Howard J.; Pathology and Laboratory Medicine, School of MedicineIntroduction: Asymptomatic and mildly symptomatic dominantly inherited Alzheimer's disease mutation carriers (DIAD-MC) are ideal candidates for preventative treatment trials aimed at delaying or preventing dementia onset. Brain atrophy is an early feature of DIAD-MC and could help predict risk for dementia during trial enrollment. Methods: We created a dementia risk score by entering standardized gray-matter volumes from 231 DIAD-MC into a logistic regression to classify participants with and without dementia. The score's predictive utility was assessed using Cox models and receiver operating curves on a separate group of 65 DIAD-MC followed longitudinally. Results: Our risk score separated asymptomatic versus demented DIAD-MC with 96.4% (standard error = 0.02) and predicted conversion to dementia at next visit (hazard ratio = 1.32, 95% confidence interval [CI: 1.15, 1.49]) and within 2 years (area under the curve = 90.3%, 95% CI [82.3%-98.2%]) and improved prediction beyond established methods based on familial age of onset. Discussion: Individualized risk scores based on brain atrophy could be useful for establishing enrollment criteria and stratifying DIAD-MC participants for prevention trials.Item Pattern and implications of neurological examination findings in autosomal dominant Alzheimer disease(Wiley, 2023) Vöglein, Jonathan; Franzmeier, Nicolai; Morris, John C.; Dieterich, Marianne; McDade, Eric; Simons, Mikael; Preische, Oliver; Hofmann, Anna; Hassenstab, Jason; Benzinger, Tammie L.; Fagan, Anne; Noble, James M.; Berman, Sarah B.; Graff-Radford, Neill R.; Ghetti, Bernardino; Farlow, Martin R.; Chhatwal, Jasmeer P.; Salloway, Stephen; Xiong, Chengjie; Karch, Celeste M.; Cairns, Nigel; Perrin, Richard J.; Day, Gregory; Martins, Ralph; Sanchez-Valle, Raquel; Mori, Hiroshi; Shimada, Hiroyuki; Ikeuchi, Takeshi; Suzuki, Kazushi; Schofield, Peter R.; Masters, Colin L.; Goate, Alison; Buckles, Virginia; Fox, Nick C.; Chrem, Patricio; Allegri, Ricardo; Ringman, John M.; Yakushev, Igor; Laske, Christoph; Jucker, Mathias; Höglinger, Günter; Bateman, Randall J.; Danek, Adrian; Levin, Johannes; Dominantly Inherited Alzheimer Network; Pathology and Laboratory Medicine, School of MedicineIntroduction: As knowledge about neurological examination findings in autosomal dominant Alzheimer disease (ADAD) is incomplete, we aimed to determine the frequency and significance of neurological examination findings in ADAD. Methods: Frequencies of neurological examination findings were compared between symptomatic mutation carriers and non mutation carriers from the Dominantly Inherited Alzheimer Network (DIAN) to define AD neurological examination findings. AD neurological examination findings were analyzed regarding frequency, association with and predictive value regarding cognitive decline, and association with brain atrophy in symptomatic mutation carriers. Results: AD neurological examination findings included abnormal deep tendon reflexes, gait disturbance, pathological cranial nerve examination findings, tremor, abnormal finger to nose and heel to shin testing, and compromised motor strength. The frequency of AD neurological examination findings was 65.1%. Cross-sectionally, mutation carriers with AD neurological examination findings showed a more than two-fold faster cognitive decline and had greater parieto-temporal atrophy, including hippocampal atrophy. Longitudinally, AD neurological examination findings predicted a significantly greater decline over time. Discussion: ADAD features a distinct pattern of neurological examination findings that is useful to estimate prognosis and may inform clinical care and therapeutic trial designs.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.