Dominantly Inherited Alzheimer Network (DIAN)
Study Details
Study Description
Brief Summary
The purpose of this study is to identify potential biomarkers that may predict the development of Alzheimer's disease in people who carry an Alzheimer's mutation.
Condition or Disease | Intervention/Treatment | Phase |
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Detailed Description
Dominantly inherited Alzheimer's disease (AD) represents less than 1% of all cases of AD and is an important model for study because the responsible mutations have known biochemical consequences that are believed to underlie the pathological basis of the disorder. Three major hypotheses will be tested:
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First, that there is a period of preclinical (presymptomatic) AD in individuals who are destined to develop early-onset dementia (gene carriers) that can be detected by changes in biological fluids and in neuroimaging correlates in comparison with individuals who will not develop early-onset dementia (non-carriers).
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Second, because all identified causative mutations for AD affect the normal processing of amyloid precursor protein (APP) and increase brain levels of amyloid-beta 42 (Aβ42), the sequence of preclinical changes initially will involve Aβ42 (production and clearance; reduced levels in cerebrospinal fluid [CSF]), followed by evidence for cerebral deposition of Aβ42 (amyloid imaging), followed by cerebral metabolic activity (functional imaging), and finally by regional atrophy (structural imaging).
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Finally, that the phenotype of symptomatic early-onset familial AD, including its clinical course, is similar to that of late-onset "sporadic" AD.
The following specific aims will be used to test these hypotheses:
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Maintain the established international DIAN registry of individuals (MCs and non-carriers (NC), symptomatic and asymptomatic) who are biological adult children of an affected parent with an APP, PSEN1, or PSEN2 mutation causing AD and assess participants every 2 years with the uniform DIAN protocol.
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Recruit to the registry 50 new asymptomatic participants, both MCs and NCs, in Year 1 of the next budget period to maintain the total DIAN cohort at ~250 individuals. These new participants will include those who are more than 15 years younger than the estimated age of symptomatic onset (EAO) to explore the earliest observable biomarker changes of preclinical AD.
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Maintain the integrated DIAN database and biospecimen repository to disseminate data and tissue to qualified investigators (within and outside of DIAN) in a user-friendly manner and to permit analyses within, between, and among the various data domains that will include:
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In asymptomatic MCs (using NCs as controls), determine the temporal ordering and rate of intraindividual change in clinical, cognitive, imaging, and fluid biomarkers of AD prior to EAO
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In symptomatic MCs, compare the clinical and neuropathological phenotypes of ADAD to those of LOAD, using datasets such as ADNI.
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Utilize the DIAN cohort and its database and biospecimen repository to support new scientific studies, including use of exome chip technology to examine potential modifiers of age at symptomatic onset. Pursue other new scientific initiatives that are funded independently of the DIAN grant but are conducted within the DIAN infrastructure at no cost to DIAN including: Dermal fibroblasts and induced pluripotent stem cells (iPSCs), examine biomarker surrogates for neurogeneration in CSF including Visinin-like protein-1 (VILIP-1), Tau seeding assay, Stable Isotope Leucine Kinetics (SILK) in DIAN participants, determine the exact Abeta species that underlie AD pathology using Mass spectrometry, exome sequencing on all DIAN participants to search for both positive and negative modifiers of EYO, and amyloid imaging crossover to [18F]florbetapir.
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Provide genetic counseling to any and all DIAN participants who wish to learn their mutation status and, for those who decide to learn their status after counseling, provide genetic testing by Clinical Laboratory Improvement Amendments (CLIA)-approved laboratories (i.e., outside of DIAN).
Study Design
Arms and Interventions
Arm | Intervention/Treatment |
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1 Mutation Positive |
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2 Mutation Negative |
Outcome Measures
Primary Outcome Measures
- Positive predictive power of a biomarker or group of biomarkers [Variable follow-up assessment based on age in relation to age at onset of affected parent.]
- Biomarkers obtained by blood draw, lumbar puncture, MRI, FDG PET, PET amyloid imaging [Variable follow-up assessment based on age in relation to age at onset of affected parent]
- Clinical markers also examined from clinical interview and cognitive testing [Variable follow-up assessment based on age in relation to age at onset of affected parent]
Eligibility Criteria
Criteria
Inclusion Criteria:
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Written informed consent obtained from participant and collateral source prior to any study-related procedures.
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Aged 18 (inclusive) or older and the child of an affected individual (clinically or by testing) in a pedigree with a known mutation for ADAD.
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Cognitively normal. Primary enrollment will focus on recruitment of asymptomatic adult children who are more than 15 years younger than the estimated age of symptom onset. Enrollment of new participants with very mild, mild, or moderate cognitive impairment is allowed with the prior approval of the DIAN Coordinating Center.
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Has two persons who are not their full-blooded siblings who can serve as collateral sources for the study.
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Fluent in a language approved by the DIAN Coordinating Center at about the 6th grade level (international equivalent) or above.
Exclusion Criteria:
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Under age 18
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Medical or psychiatric illness that would interfere in completing initial and follow-up visits
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Requires nursing home level care
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Has no one who can serve as a study informant
Contacts and Locations
Locations
Site | City | State | Country | Postal Code | |
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1 | Mayo Clinic Jacksonville | Jacksonville | Florida | United States | 32224 |
2 | Indiana University-Indiana Alzheimer Disease Center | Indianapolis | Indiana | United States | 46202 |
3 | Brigham and Women's Hospital | Boston | Massachusetts | United States | 02115 |
4 | Washington University School of Medicine | Saint Louis | Missouri | United States | 63108 |
5 | Columbia University | New York | New York | United States | 10032 |
6 | University of Pittsburgh | Pittsburgh | Pennsylvania | United States | 15260 |
7 | Butler Hospital | Providence | Rhode Island | United States | 02906 |
8 | Fundación para la Lucha contra las Enfermedades Neurológicas de la Infancia" (FLENI) Instituto de Investigaciones Neurológicas Raúl Correa | Buenos Aires | Argentina | ||
9 | Neuroscience Research Australia | Sydney | New South Wales | Australia | 2031 |
10 | Mental Health Research Institute, University of Melbourne | Melbourne | Victoria | Australia | 3130 |
11 | Sir James McCusker Alzheimer's Disease Research Unit, Edith Cowan University | Perth | Western Australia | Australia | 6009 |
12 | Hospital das Clinicas da Faculdade de Medicina da Universidade de São Paulo | São Paulo | Brazil | 05403-900 | |
13 | McGill University Research Centre for Studies in Aging | Verdun | Quebec | Canada | H4H 1R3 |
14 | Grupo Neurociencias de Antioquia | Medellín | Colombia | ||
15 | German Center for Neurodegenerative Diseases (DZNE) Munich, and University Hospital Ludwig-Maximilians-Universitat (LMU) Munich | Munich | Germany | D-81377 | |
16 | German Center for Neurodegenerative Diseases (DZNE) Tübingen and Hertie-Institute for Clinical Brain Research, University of Tübingen | Tübingen | Germany | D-72076 | |
17 | Niigata University | Niigata | Japan | ||
18 | Osaka City University | Osaka City | Japan | ||
19 | Tokyo University | Tokyo | Japan | ||
20 | Asan Medical Center | Seoul | Songpa-Gu | Korea, Republic of | 05505 |
21 | Instituto Nacional de Neurología y Neurocirugía "Manuel Velasco Suarez" | Mexico City | Mexico | 14269 | |
22 | Hospital Clinic Barcelona | Barcelona | Catalunya | Spain | 08036 |
23 | Institute of Neurology, Queen Square | London | United Kingdom | WC1N 3BG |
Sponsors and Collaborators
- Washington University School of Medicine
- National Institute on Aging (NIA)
Investigators
- Principal Investigator: Randall J. Bateman, MD, Washington University School of Medicine
- Study Director: Alisha Daniels, MD,MHA, (314) 273-9057
Study Documents (Full-Text)
None provided.More Information
Additional Information:
Publications
- Fagan AM, Roe CM, Xiong C, Mintun MA, Morris JC, Holtzman DM. Cerebrospinal fluid tau/beta-amyloid(42) ratio as a prediction of cognitive decline in nondemented older adults. Arch Neurol. 2007 Mar;64(3):343-9. Epub 2007 Jan 8.
- Galvin JE, Powlishta KK, Wilkins K, McKeel DW Jr, Xiong C, Grant E, Storandt M, Morris JC. Predictors of preclinical Alzheimer disease and dementia: a clinicopathologic study. Arch Neurol. 2005 May;62(5):758-65.
- Godbolt AK, Cipolotti L, Anderson VM, Archer H, Janssen JC, Price S, Rossor MN, Fox NC. A decade of pre-diagnostic assessment in a case of familial Alzheimer's disease: tracking progression from asymptomatic to MCI and dementia. Neurocase. 2005 Feb;11(1):56-64.
- Mintun MA, Larossa GN, Sheline YI, Dence CS, Lee SY, Mach RH, Klunk WE, Mathis CA, DeKosky ST, Morris JC. [11C]PIB in a nondemented population: potential antecedent marker of Alzheimer disease. Neurology. 2006 Aug 8;67(3):446-52.
- Morris JC, McKeel DW Jr, Storandt M, Rubin EH, Price JL, Grant EA, Ball MJ, Berg L. Very mild Alzheimer's disease: informant-based clinical, psychometric, and pathologic distinction from normal aging. Neurology. 1991 Apr;41(4):469-78.
- IA0147
- U19AG032438
- UF1AG032438