Browsing by Author "Iwatsubo, Takeshi"

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    Blood-based biomarkers for Alzheimer's disease: Current state and future use in a transformed global healthcare landscape
    (Elsevier, 2023) Hampel, Harald; Hu, Yan; Cummings, Jeffrey; Mattke, Soeren; Iwatsubo, Takeshi; Nakamura, Akinori; Vellas, Bruno; O’Bryant, Sid; Shaw, Leslie M.; Cho, Min; Batrla, Richard; Vergallo, Andrea; Blennow, Kaj; Dage, Jeffrey; Schindler, Suzanne E.; Neurology, School of Medicine
    Timely detection of the pathophysiological changes and cognitive impairment caused by Alzheimer's disease (AD) is increasingly pressing because of the advent of biomarker-guided targeted therapies that may be most effective when provided early in the disease. Currently, diagnosis and management of early AD are largely guided by clinical symptoms. FDA-approved neuroimaging and cerebrospinal fluid biomarkers can aid detection and diagnosis, but the clinical implementation of these testing modalities is limited because of availability, cost, and perceived invasiveness. Blood-based biomarkers (BBBMs) may enable earlier and faster diagnoses as well as aid in risk assessment, early detection, prognosis, and management. Herein, we review data on BBBMs that are closest to clinical implementation, particularly those based on measures of amyloid-β peptides and phosphorylated tau species. We discuss key parameters and considerations for the development and potential deployment of these BBBMs under different contexts of use and highlight challenges at the methodological, clinical, and regulatory levels.
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    Chronic neuropsychiatric sequelae of SARS-CoV-2: Protocol and methods from the Alzheimer's Association Global Consortium
    (Alzheimer’s Association, 2022-09-22) de Erausquin, Gabriel A.; Snyder, Heather; Brugha, Traolach S.; Seshadri, Sudha; Carrillo, Maria; Sagar, Rajesh; Huang, Yueqin; Newton, Charles; Tartaglia, Carmela; Teunissen, Charlotte; Håkanson, Krister; Akinyemi, Rufus; Prasad, Kameshwar; D'Avossa, Giovanni; Gonzalez-Aleman, Gabriela; Hosseini, Akram; Vavougios, George D.; Sachdev, Perminder; Bankart, John; Ole Mors, Niels Peter; Lipton, Richard; Katz, Mindy; Fox, Peter T.; Katshu, Mohammad Zia; Iyengar, M. Sriram; Weinstein, Galit; Sohrabi, Hamid R.; Jenkins, Rachel; Stein, Dan J.; Hugon, Jacques; Mavreas, Venetsanos; Blangero, John; Cruchaga, Carlos; Krishna, Murali; Wadoo, Ovais; Becerra, Rodrigo; Zwir, Igor; Longstreth, William T.; Kroenenberg, Golo; Edison, Paul; Mukaetova-Ladinska, Elizabeta; Staufenberg, Ekkehart; Figueredo-Aguiar, Mariana; Yécora, Agustín; Vaca, Fabiana; Zamponi, Hernan P.; Lo Re, Vincenzina; Majid, Abdul; Sundarakumar, Jonas; Gonzalez, Hector M.; Geerlings, Mirjam I.; Skoog, Ingmar; Salmoiraghi, Alberto; Boneschi, Filippo Martinelli; Patel, Vibuthi N.; Santos, Juan M.; Arroyo, Guillermo Rivera; Moreno, Antonio Caballero; Felix, Pascal; Gallo, Carla; Arai, Hidenori; Yamada, Masahito; Iwatsubo, Takeshi; Sharma, Malveeka; Chakraborty, Nandini; Ferreccio, Catterina; Akena, Dickens; Brayne, Carol; Maestre, Gladys; Williams Blangero, Sarah; Brusco, Luis I.; Siddarth, Prabha; Hughes, Timothy M.; Ramírez Zuñiga, Alfredo; Kambeitz, Joseph; Laza, Agustin Ruiz; Allen, Norrina; Panos, Stella; Merrill, David; Ibáñez, Agustín; Tsuang, Debby; Valishvili, Nino; Shrestha, Srishti; Wang, Sophia; Padma, Vasantha; Anstey, Kaarin J.; Ravindrdanath, Vijayalakshmi; Blennow, Kaj; Mullins, Paul; Łojek, Emilia; Pria, Anand; Mosley, Thomas H.; Gowland, Penny; Girard, Timothy D.; Bowtell, Richard; Vahidy, Farhaan S.; Psychiatry, School of Medicine
    Introduction: Coronavirus disease 2019 (COVID-19) has caused >3.5 million deaths worldwide and affected >160 million people. At least twice as many have been infected but remained asymptomatic or minimally symptomatic. COVID-19 includes central nervous system manifestations mediated by inflammation and cerebrovascular, anoxic, and/or viral neurotoxicity mechanisms. More than one third of patients with COVID-19 develop neurologic problems during the acute phase of the illness, including loss of sense of smell or taste, seizures, and stroke. Damage or functional changes to the brain may result in chronic sequelae. The risk of incident cognitive and neuropsychiatric complications appears independent from the severity of the original pulmonary illness. It behooves the scientific and medical community to attempt to understand the molecular and/or systemic factors linking COVID-19 to neurologic illness, both short and long term. Methods: This article describes what is known so far in terms of links among COVID-19, the brain, neurological symptoms, and Alzheimer's disease (AD) and related dementias. We focus on risk factors and possible molecular, inflammatory, and viral mechanisms underlying neurological injury. We also provide a comprehensive description of the Alzheimer's Association Consortium on Chronic Neuropsychiatric Sequelae of SARS-CoV-2 infection (CNS SC2) harmonized methodology to address these questions using a worldwide network of researchers and institutions. Results: Successful harmonization of designs and methods was achieved through a consensus process initially fragmented by specific interest groups (epidemiology, clinical assessments, cognitive evaluation, biomarkers, and neuroimaging). Conclusions from subcommittees were presented to the whole group and discussed extensively. Presently data collection is ongoing at 19 sites in 12 countries representing Asia, Africa, the Americas, and Europe. Discussion: The Alzheimer's Association Global Consortium harmonized methodology is proposed as a model to study long-term neurocognitive sequelae of SARS-CoV-2 infection. Key points: The following review describes what is known so far in terms of molecular and epidemiological links among COVID-19, the brain, neurological symptoms, and AD and related dementias (ADRD)The primary objective of this large-scale collaboration is to clarify the pathogenesis of ADRD and to advance our understanding of the impact of a neurotropic virus on the long-term risk of cognitive decline and other CNS sequelae. No available evidence supports the notion that cognitive impairment after SARS-CoV-2 infection is a form of dementia (ADRD or otherwise). The longitudinal methodologies espoused by the consortium are intended to provide data to answer this question as clearly as possible controlling for possible confounders. Our specific hypothesis is that SARS-CoV-2 triggers ADRD-like pathology following the extended olfactory cortical network (EOCN) in older individuals with specific genetic susceptibility. The proposed harmonization strategies and flexible study designs offer the possibility to include large samples of under-represented racial and ethnic groups, creating a rich set of harmonized cohorts for future studies of the pathophysiology, determinants, long-term consequences, and trends in cognitive aging, ADRD, and vascular disease. We provide a framework for current and future studies to be carried out within the Consortium. and offers a "green paper" to the research community with a very broad, global base of support, on tools suitable for low- and middle-income countries aimed to compare and combine future longitudinal data on the topic. The Consortium proposes a combination of design and statistical methods as a means of approaching causal inference of the COVID-19 neuropsychiatric sequelae. We expect that deep phenotyping of neuropsychiatric sequelae may provide a series of candidate syndromes with phenomenological and biological characterization that can be further explored. By generating high-quality harmonized data across sites we aim to capture both descriptive and, where possible, causal associations.
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    Peripheral and central effects of γ-secretase inhibition by semagacestat in Alzheimer's disease
    (BioMed Central, 2015-06-10) Doody, Rachelle S.; Raman, Rema; Sperling, Reisa A.; Seimers, Eric; Sethuraman, Gopalan; Mohs, Richard; Farlow, Martin R.; Iwatsubo, Takeshi; Vellas, Bruno; Sun, Xiaoying; Ernstrom, Karin; Thomas, Ronald G.; Aisen, Paul S.; Department of Neurology, IU School of Medicine
    INTRODUCTION: The negative efficacy study examining the γ-secretase inhibitor semagacestat in mild to moderate Alzheimer's disease (AD) included a number of biomarkers of the disease as well as safety outcomes. We analyzed these data to explore relationships between drug exposure and pharmacodynamic effects and to examine the correlations among outcome measures. METHODS: The study was a multicenter, randomized, placebo-controlled trial of two dose regimens of semagacestat and a placebo administered for 18 months to individuals with mild to moderate AD. Changes in measures of central and peripheral drug activity were compared between the three treatment groups using one-way analysis of variance. The relationship between changes in each of the outcome measures and measures of drug exposure and peripheral pharmacodynamic effect were assessed using Spearman's correlation coefficient. RESULTS: Assignment to the active treatment arms was associated with reduction in plasma amyloid-β (Aβ) peptides, increase in ventricular volume, decrease in cerebrospinal fluid phosphorylated tau (p-tau) and several other laboratory measures and adverse event categories. Within the active arms, exposure to drug, as indicated by area under the concentration curve (AUC) of blood concentration, was associated with reduction in plasma Aβ peptides and a subset of laboratory changes and adverse event rates. Ventricular volume increase, right hippocampal volume loss and gastrointestinal symptoms were related to change in plasma Aβ peptide but not AUC, supporting a link to inhibition of γ-secretase cleavage of the amyloid precursor protein. Cognitive decline correlated with ventricular expansion and reduction in p-tau. CONCLUSION: These findings may inform future studies of drugs targeting secretases involved in Aβ generation.
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    The Worldwide Alzheimer's Disease Neuroimaging Initiative: ADNI‐3 updates and global perspectives
    (Alzheimer’s Association, 2021-12-31) Weber, Christopher J.; Carrillo, Maria C.; Jagust, William; Jack, Clifford R., Jr.; Shaw, Leslie M.; Trojanowski, John Q.; Saykin, Andrew J.; Beckett, Laurel A.; Sur, Cyrille; Rao, Naren P.; Mendez, Patricio Chrem; Black, Sandra E.; Li, Kuncheng; Iwatsubo, Takeshi; Chang, Chiung-Chih; Sosa, Ana Luisa; Rowe, Christopher C.; Perrin, Richard J.; Morris, John C.; Healan, Amanda M.B.; Hall, Stephen E.; Weiner, Michael W.; Radiology and Imaging Sciences, School of Medicine
    The Worldwide Alzheimer's Disease Neuroimaging Initiative (WW‐ADNI) is a collaborative effort to investigate imaging and biofluid markers that can inform Alzheimer's disease treatment trials. It is a public‐private partnership that spans North America, Argentina, Australia, Canada, China, Japan, Korea, Mexico, and Taiwan. In 2004, ADNI researchers began a naturalistic, longitudinal study that continues today around the globe. Through several successive phases (ADNI‐1, ADNI‐GO, ADNI‐2, and ADNI‐3), the study has fueled amyloid and tau phenotyping and refined neuroimaging methodologies. WW‐ADNI researchers have successfully standardized analyses and openly share data without embargo, providing a rich data set for other investigators. On August 26, 2020, the Alzheimer's Association convened WW‐ADNI researchers who shared updates from ADNI‐3 and their vision for ADNI‐4.