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Browsing by Author "Suzuki, Kazushi"
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Item Amyloid-Related Imaging Abnormalities in the DIAN-TU-001 Trial of Gantenerumab and Solanezumab: Lessons from a Trial in Dominantly Inherited Alzheimer Disease(Wiley, 2022) Joseph-Mathurin, Nelly; Llibre-Guerra, Jorge J.; Li, Yan; McCullough, Austin A.; Hofmann, Carsten; Wojtowicz, Jakub; Park, Ethan; Wang, Guoqiao; Preboske, Gregory M.; Wang, Qing; Gordon, Brian A.; Chen, Charles D.; Flores, Shaney; Aggarwal, Neelum T.; Berman, Sarah B.; Bird, Thomas D.; Black, Sandra E.; Borowski, Bret; Brooks, William S.; Chhatwal, Jasmeer P.; Clarnette, Roger; Cruchaga, Carlos; Fagan, Anne M.; Farlow, Martin; Fox, Nick C.; Gauthier, Serge; Hassenstab, Jason; Hobbs, Diana A.; Holdridge, Karen C.; Honig, Lawrence S.; Hornbeck, Russ C.; Hsiung, Ging-Yuek R.; Jack, Clifford R., Jr.; Jimenez-Velazquez, Ivonne Z.; Jucker, Mathias; Klein, Gregory; Levin, Johannes; Mancini, Michele; Masellis, Mario; McKay, Nicole S.; Mummery, Catherine J.; Ringman, John M.; Shimada, Hiroyuki; Snider, B. Joy; Suzuki, Kazushi; Wallon, David; Xiong, Chengjie; Yaari, Roy; McDade, Eric; Perrin, Richard J.; Bateman, Randall J.; Salloway, Stephen P.; Benzinger, Tammie L. S.; Clifford, David B.; Dominantly Inherited Alzheimer Network Trials Unit; Neurology, School of MedicineObjective: To determine the characteristics of participants with amyloid-related imaging abnormalities (ARIA) in a trial of gantenerumab or solanezumab in dominantly inherited Alzheimer disease (DIAD). Methods: 142 DIAD mutation carriers received either gantenerumab SC (n = 52), solanezumab IV (n = 50), or placebo (n = 40). Participants underwent assessments with the Clinical Dementia Rating® (CDR®), neuropsychological testing, CSF biomarkers, β-amyloid positron emission tomography (PET), and magnetic resonance imaging (MRI) to monitor ARIA. Cross-sectional and longitudinal analyses evaluated potential ARIA-related risk factors. Results: Eleven participants developed ARIA-E, including 3 with mild symptoms. No ARIA-E was reported under solanezumab while gantenerumab was associated with ARIA-E compared to placebo (odds ratio [OR] = 9.1, confidence interval [CI][1.2, 412.3]; p = 0.021). Under gantenerumab, APOE-ɛ4 carriers were more likely to develop ARIA-E (OR = 5.0, CI[1.0, 30.4]; p = 0.055), as were individuals with microhemorrhage at baseline (OR = 13.7, CI[1.2, 163.2]; p = 0.039). No ARIA-E was observed at the initial 225 mg/month gantenerumab dose, and most cases were observed at doses >675 mg. At first ARIA-E occurrence, all ARIA-E participants were amyloid-PET+, 60% were CDR >0, 60% were past their estimated year to symptom onset, and 60% had also incident ARIA-H. Most ARIA-E radiologically resolved after dose adjustment and developing ARIA-E did not significantly increase odds of trial discontinuation. ARIA-E was more frequently observed in the occipital lobe (90%). ARIA-E severity was associated with age at time of ARIA-E. Interpretation: In DIAD, solanezumab was not associated with ARIA. Gantenerumab dose over 225 mg increased ARIA-E risk, with additional risk for individuals APOE-ɛ4(+) or with microhemorrhage. ARIA-E was reversible on MRI in most cases, generally asymptomatic, without additional risk for trial discontinuation.Item Longitudinal Accumulation of Cerebral Microhemorrhages in Dominantly Inherited Alzheimer Disease(American Academy of Neurology, 2021-03-23) Joseph-Mathurin, Nelly; Wang, Guoqiao; Kantarci, Kejal; Jack, Clifford R., Jr.; McDade, Eric; Hassenstab, Jason; Blazey, Tyler M.; Gordon, Brian A.; Su, Yi; Chen, Gengsheng; Massoumzadeh, Parinaz; Hornbeck, Russ C.; Allegri, Ricardo F.; Ances, Beau M.; Berman, Sarah B.; Brickman, Adam M.; Brooks, William S.; Cash, David M.; Chhatwal, Jasmeer P.; Chui, Helena C.; Correia, Stephen; Cruchaga, Carlos; Farlow, Martin R.; Fox, Nick C.; Fulham, Michael; Ghetti, Bernardino; Graff-Radford, Neill R.; Johnson, Keith A.; Karch, Celeste M.; Laske, Christoph; Lee, Athene K.W.; Levin, Johannes; Masters, Colin L.; Noble, James M.; O’Connor, Antoinette; Perrin, Richard J.; Preboske, Gregory M.; Ringman, John M.; Rowe, Christopher C.; Salloway, Stephen; Saykin, Andrew J.; Schofield, Peter R.; Shimada, Hiroyuki; Shoji, Mikio; Suzuki, Kazushi; Villemagne, Victor L.; Xiong, Chengjie; Yakushev, Igor; Morris, John C.; Bateman, Randall J.; Benzinger, Tammie L.S.; Pathology and Laboratory Medicine, School of MedicineObjective: To investigate the inherent clinical risks associated with the presence of cerebral microhemorrhages (CMHs) or cerebral microbleeds and characterize individuals at high risk for developing hemorrhagic amyloid-related imaging abnormality (ARIA-H), we longitudinally evaluated families with dominantly inherited Alzheimer disease (DIAD). Methods: Mutation carriers (n = 310) and noncarriers (n = 201) underwent neuroimaging, including gradient echo MRI sequences to detect CMHs, and neuropsychological and clinical assessments. Cross-sectional and longitudinal analyses evaluated relationships between CMHs and neuroimaging and clinical markers of disease. Results: Three percent of noncarriers and 8% of carriers developed CMHs primarily located in lobar areas. Carriers with CMHs were older, had higher diastolic blood pressure and Hachinski ischemic scores, and more clinical, cognitive, and motor impairments than those without CMHs. APOE ε4 status was not associated with the prevalence or incidence of CMHs. Prevalent or incident CMHs predicted faster change in Clinical Dementia Rating although not composite cognitive measure, cortical thickness, hippocampal volume, or white matter lesions. Critically, the presence of 2 or more CMHs was associated with a significant risk for development of additional CMHs over time (8.95 ± 10.04 per year). Conclusion: Our study highlights factors associated with the development of CMHs in individuals with DIAD. CMHs are a part of the underlying disease process in DIAD and are significantly associated with dementia. This highlights that in participants in treatment trials exposed to drugs, which carry the risk of ARIA-H as a complication, it may be challenging to separate natural incidence of CMHs from drug-related CMHs.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.