Developing an international network for Alzheimer research: The Dominantly Inherited Alzheimer Network
the Centre of Excellence for Alzheimer's Disease Research and Care, Edith Cowan University, Joondalup, WA (RM), the Mental Health Research Institute, University of Melbourne, Melbourne, VIC (CM), and Neuroscience Research Australia and the School of Medical Sciences, University of New South Wales, Sydney (PS) - all in Australia
10/2012; 2(10):975-984. DOI: 10.4155/cli.12.93
The Dominantly Inherited Alzheimer Network (DIAN) is a collaborative effort of international Alzheimer disease (AD) centers that are conducting a multifaceted prospective biomarker study in individuals at-risk for autosomal dominant AD (ADAD). DIAN collects comprehensive information and tissue in accordance with standard protocols from asymptomatic and symptomatic ADAD mutation carriers and their non-carrier family members to determine the pathochronology of clinical, cognitive, neuroimaging, and fluid biomarkers of AD. This article describes the structure, implementation, and underlying principles of DIAN, as well as the demographic features of the initial DIAN cohort.
Available from: Hamid R Sohrabi
- "All demographical (age, gender, education, and estimated years to onset [EYO]), clinical (Geriatric Depression Scale [GDS]), and cognitive measurements (e.g., CDR global scores and sum of boxes  , logical memory subtest of The Wechsler Memory Test) were performed as recently described  . "
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We examined the diagnostic value of subjective memory complaints (SMCs) assessed with a single item in a large cross-sectional cohort consisting of families with autosomal dominant Alzheimer's disease (ADAD) participating in the Dominantly Inherited Alzheimer Network (DIAN).
The baseline sample of 183 mutation carriers (MCs) and 117 noncarriers (NCs) was divided according to Clinical Dementia Rating (CDR) scale into preclinical (CDR 0; MCs: n = 107; NCs: n = 109), early symptomatic (CDR 0.5; MCs: n = 48; NCs: n = 8), and dementia stage (CDR ≥ 1; MCs: n = 28; NCs: n = 0). These groups were subdivided by the presence or absence of SMCs.
At CDR 0, SMCs were present in 12.1% of MCs and 9.2% of NCs (P = 0.6). At CDR 0.5, SMCs were present in 66.7% of MCs and 62.5% of NCs (P = 1.0). At CDR ≥ 1, SMCs were present in 96.4% of MCs. SMCs in MCs were significantly associated with CDR, logical memory scores, Geriatric Depression Scale, education, and estimated years to onset.
The present study shows that SMCs assessed by a single-item scale have no diagnostic value to identify preclinical ADAD in asymptomatic individuals. These results demonstrate the need of further improvement of SMC measures that should be examined in large clinical trials.
Available from: PubMed Central
- "Follow-up assessments are scheduled according to the participant’s age relative to his or her parental AAO, with assessments every 3 years for asymptomatic individuals until they are within 3 years of the parental AAO, when assessments are done annually; all symptomatic individuals are seen annually. For a more detailed description of the DIAN assessment protocol and infrastructure, please see . "
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ABSTRACT: The Dominantly Inherited Alzheimer Network (DIAN) is an international registry of individuals at risk for developing autosomal dominant Alzheimer's disease (AD). Its primary aims are to investigate the temporal ordering of AD pathophysiological changes that occur in asymptomatic mutation carriers and to identify those markers that herald the transition from cognitive normality to symptomatic AD. DIAN participants undergo longitudinal evaluations, including clinical and cognitive assessments and measurements of molecular and imaging AD biomarkers. This review details the unique attributes of DIAN as a model AD biomarker study and how it provides the infrastructure for innovative research projects, including clinical trials. The recent design and launch of the first anti-amyloid-beta secondary prevention trial in AD, led by the related DIAN Trials Unit, also are discussed.
Available from: Michael Malek-Ahmadi
- "The Alzheimer's Prevention Initiative will utilize a large Colombian cohort with a significant number of individuals carrying the PSEN1 E280A paisa mutation and offers an unparalleled opportunity to test the effects of prophylactic immunotherapeutic in a presymptomatic single PSEN mutation carrier kindred . The DIAN prophylactic immunotherapy project will be implemented in patients harboring several PSEN-FAD mutations . In addi- tion, the Anti-Amyloid Treatment in Asymptomatic Alzheimer's Disease (A4) prevention clinical trial represents a complementary strategy in which putative dementia-prophylactic Aβ immunotherapy will be provided to asymptomatic individuals recognized by imaging technologies to possess substantial amyloid deposit burdens and hypothesized to be at imminent risk for SAD development . "
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ABSTRACT: Alzheimer's disease (AD) dementia impacts all facets of higher order cognitive function and is characterized by the presence of distinctive pathological lesions in the gray matter (GM). The profound alterations in GM structure and function have fostered the view that AD impacts are primarily a consequence of GM damage. However, the white matter (WM) represents about 50% of the cerebrum and this area of the brain is substantially atrophied and profoundly abnormal in both sporadic AD (SAD) and familial AD (FAD). We examined the WM biochemistry by ELISA and Western blot analyses of key proteins in 10 FAD cases harboring mutations in the presenilin genes PSEN1 and PSEN2 as well as in 4 non-demented control (NDC) individuals and 4 subjects with SAD. The molecules examined were direct substrates of PSEN1 such as Notch-1 and amyloid precursor protein (APP). In addition, apolipoproteins, axonal transport molecules, cytoskeletal and structural proteins, neurotrophic factors and synaptic proteins were examined. PSEN-FAD subjects had, on average, higher amounts of WM amyloid-beta (Aβ) peptides compared to SAD, which may play a role in the devastating dysfunction of the brain. However, the PSEN-FAD mutations we examined did not produce uniform increases in the relative proportions of Aβ42 and exhibited substantial variability in total Aβ levels. These observations suggest that neurodegeneration and dementia do not depend solely on enhanced Aβ42 levels. Our data revealed additional complexities in PSEN-FAD individuals. Some direct substrates of γ-secretase, such as Notch, N-cadherin, Erb-B4 and APP, deviated substantially from the NDC group baseline for some, but not all, mutation types. Proteins that were not direct γ-secretase substrates, but play key structural and functional roles in the WM, likewise exhibited varied concentrations in the distinct PSEN mutation backgrounds. Detailing the diverse biochemical pathology spectrum of PSEN mutations may offer valuable insights into dementia progression and the design of effective therapeutic interventions for both SAD and FAD.
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