Increased CNV-Region deletions in mild cognitive impairment (MCI) and Alzheimer's disease (AD) subjects in the ADNI sample

Guffanti, Guia; Torri, Federica; Rasmussen, Jerod; Clark, Andrew P.; Lakatos, Anita; Turner, Jessica A.; Fallon, James H.; Saykin, Andrew J.; Weiner, Michael W.; Vawter, Marquis P.; Knowles, James A.; Potkin, Steven G.; Macciardi, Fabìo

doi:10.1016/j.ygeno.2013.04.004

Cited by 24 publications

(22 citation statements)

References 63 publications

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“…Further refinements to GWAS have included pathway and network analyses [32][33][34], the use of proteomics [35], and whole exome data [36], and copy number variant analysis. The latter refinement, in particular, has identified novel candidate AD susceptibility loci [37][38][39]. Overall, these novel bioinformatic strategies reflect an increasing understanding of the biochemistry of AD and have helped narrow the search for AD risk alleles.…”

Section: North American Adnimentioning

confidence: 98%

The Worldwide Alzheimer's Disease Neuroimaging Initiative: An update

Hendrix

Finger²,

Weiner

et al. 2015

Alzheimer's & Dementia

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The Alzheimer's Disease Neuroimaging Initiative (ADNI), launched in 2004, has worked to accelerate drug development by validating imaging and blood/cerebrospinal fluid biomarkers for Alzheimer's disease clinical treatment trials. ADNI is a naturalistic (nontreatment) multisite longitudinal study. A true public-private partnership, the initiative has set a new standard for data sharing without embargo and for the use of biomarkers in dementia research. The ADNI effort in North America is not the only such effort in the world. The Alzheimer's Association recognized these global efforts and formed Worldwide ADNI (WW-ADNI). By creating a platform for international collaboration and cooperation, WW-ADNI's goals are to harmonize projects and results across geographical regions and to facilitate data management and availability to investigators around the world. WW-ADNI projects include those based in North America, Europe, Japan, Australia, Korea, and Argentina.

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Section: North American Adnimentioning

confidence: 98%

The Worldwide Alzheimer's Disease Neuroimaging Initiative: An update

Hendrix

Finger²,

Weiner

et al. 2015

Alzheimer's & Dementia

View full text Add to dashboard Cite

show abstract

“…Guffanti et al [540] used intensity variation in SNP microarrays to study differences in CNVs between control and AD/MCI patients and identified a number of CNV regions that included heterozygous deletions over-represented in MCI and AD patients. Genome resequencing identified genes putatively affected by these deletions, and functional pathway analysis revealed that these genes were involved in processes such as cell-cell adhesion, axon guidance, differentiation, and neuronal morphogenesis.…”

Section: Identification Of Genetic Risk Factors For Admentioning

confidence: 99%

2014 Update of the Alzheimer's Disease Neuroimaging Initiative: A review of papers published since its inception

Weiner

Veitch

Aisen

et al. 2015

Alzheimer's & Dementia

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282

224

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The Alzheimer’s Disease Neuroimaging Initiative (ADNI) is an ongoing, longitudinal, multicenter study designed to develop clinical, imaging, genetic, and biochemical biomarkers for the early detection and tracking of Alzheimer’s disease (AD). The initial study, ADNI-1, enrolled 400 subjects with early mild cognitive impairment (MCI), 200 with early AD, and 200 cognitively normal elderly controls. ADNI-1 was extended by a 2-year Grand Opportunities grant in 2009 and by a competitive renewal, ADNI-2, which enrolled an additional 550 participants and will run until 2015. This article reviews all papers published since the inception of the initiative and summarizes the results to the end of 2013. The major accomplishments of ADNI have been as follows: (1) the development of standardized methods for clinical tests, magnetic resonance imaging (MRI), positron emission tomography (PET), and cerebrospinal fluid (CSF) biomarkers in a multicenter setting; (2) elucidation of the patterns and rates of change of imaging and CSF biomarker measurements in control subjects, MCI patients, and AD patients. CSF biomarkers are largely consistent with disease trajectories predicted by β-amyloid cascade (Hardy, J Alzheimer’s Dis 2006;9(Suppl 3):151–3) and tau-mediated neurodegeneration hypotheses for AD, whereas brain atrophy and hypometabolism levels show predicted patterns but exhibit differing rates of change depending on region and disease severity; (3) the assessment of alternative methods of diagnostic categorization. Currently, the best classifiers select and combine optimum features from multiple modalities, including MRI, [18F]-fluorodeoxyglucose-PET, amyloid PET, CSF biomarkers, and clinical tests; (4) the development of blood biomarkers for AD as potentially noninvasive and low-cost alternatives to CSF biomarkers for AD diagnosis and the assessment of α-syn as an additional biomarker; (5) the development of methods for the early detection of AD. CSF biomarkers, β-amyloid 42 and tau, as well as amyloid PET may reflect the earliest steps in AD pathology in mildly symptomatic or even nonsymptomatic subjects and are leading candidates for the detection of AD in its preclinical stages; (6) the improvement of clinical trial efficiency through the identification of subjects most likely to undergo imminent future clinical decline and the use of more sensitive outcome measures to reduce sample sizes. Multimodal methods incorporating APOE status and longitudinal MRI proved most highly predictive of future decline. Refinements of clinical tests used as outcome measures such as clinical dementia rating-sum of boxes further reduced sample sizes; (7) the pioneering of genome-wide association studies that leverage quantitative imaging and biomarker phenotypes, including longitudinal data, to confirm recently identified loci, CR1, CLU, and PICALM and to identify novel AD risk loci; (8) worldwide impact through the establishment of ADNI-like programs in Japan, Australia, Argentina, Taiwan, China, Korea, Europe, and Italy; (9) understanding ...

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“…This holds true also for the brainwhere as many as 41% of neurons have been found exhibiting at least one megabase of de novo CNVs (McConnell et al, 2013) with studies suggesting that some CNVs may be shared by multiple neurons in both normal and pathological conditions (Cai et al, 2014). CNVs have been implicated in the pathogenesis of Neurodegenerative Diseases (NDs) with alterations being linked to Parkinson's Disease (PD) (Polymeropoulos et al, 1996), Alzheimer's Disease (AD) (Goate et al, 1991), Mental Retardation (MR), Autism, and Schizophrenia (Shi et al, 2009; Guffanti et al, 2013; Toft and Ross, 2010; Vittori et al, 2014) (Table 1). …”

Section: Gin-cin Complexity: a Two Sided Coinmentioning

confidence: 99%

Mechanisms and consequences of aneuploidy and chromosome instability in the aging brain

Andriani

Vijg

Montagna

2017

Mechanisms of Ageing and Development

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Aneuploidy and polyploidy are a form of Genomic Instability (GIN) known as Chromosomal Instability (CIN) characterized by sporadic abnormalities in chromosome copy numbers. Aneuploidy is commonly linked to pathological states. It is a hallmark of spontaneous abortions and birth defects and it is observed virtually in every human tumor, therefore being generally regarded as detrimental for the development or the maturation of tissues under physiological conditions. Polyploidy however, occurs as part of normal physiological processes during maturation and differentiation of some mammalian cell types. Surprisingly, high levels of aneuploidy are present in the brain, and their frequency increases with age suggesting that the brain is able to maintain its functionality in the presence of high levels of mosaic aneuploidy. Because somatic aneuploidy with age can reach exceptionally high levels, it is likely to have long-term adverse effects in this organ. We describe the mechanisms accountable for an abnormal DNA content with a particular emphasis on the CNS where cell division is limited. Next, we briefly summarize the types of GIN known to date and discuss how they interconnect with CIN. Lastly we highlight how several forms of CIN may contribute to genetic variation, tissue degeneration and disease in the CNS.

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Increased CNV-Region deletions in mild cognitive impairment (MCI) and Alzheimer's disease (AD) subjects in the ADNI sample

Cited by 24 publications

References 63 publications

The Worldwide Alzheimer's Disease Neuroimaging Initiative: An update

The Worldwide Alzheimer's Disease Neuroimaging Initiative: An update

2014 Update of the Alzheimer's Disease Neuroimaging Initiative: A review of papers published since its inception

Mechanisms and consequences of aneuploidy and chromosome instability in the aging brain

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