Browsing by Subject "Alzheimer's Disease Neuroimaging Initiative (ADNI)"

Now showing 1 - 2 of 2
  • Thumbnail Image
    Item
    MRI Measures of Neurodegeneration as Biomarkers of Alzheimer's Disease
    (2012-03-19) Risacher, Shannon Leigh; Shen, Li; Farlow, Martin R.; Gao, Sujuan; McDonald, Brenna C.; Saykin, Andrew J.; Yoder, Karmen K.
    Alzheimer’s disease (AD) is the most common age-related neurodegenerative disease. Many researchers believe that an effective AD treatment will prevent the development of disease rather than treat the disease after a diagnosis. Therefore, the development of tools to detect AD-related pathology in early stages is an important goal. In this report, MRI-based markers of neurodegeneration are explored as biomarkers of AD. In the first chapter, the sensitivity of cross-sectional MRI biomarkers to neurodegenerative changes is evaluated in AD patients and in patients with a diagnosis of mild cognitive impairment (MCI), a prodromal stage of AD. The results in Chapter 1 suggest that cross-sectional MRI biomarkers effectively measure neurodegeneration in AD and MCI patients and are sensitive to atrophic changes in patients who convert from MCI to AD up to 1 year before clinical conversion. Chapter 2 investigates longitudinal MRI-based measures of neurodegeneration as biomarkers of AD. In Chapter 2a, measures of brain atrophy rate in a cohort of AD and MCI patients are evaluated; whereas in Chapter 2b, these measures are assessed in a pre-MCI stage, namely older adults with cognitive complaints (CC) but no significant deficits. The results from Chapter 2 suggest that dynamic MRI-based measures of neurodegeneration are sensitive biomarkers for measuring progressive atrophy associated with the development of AD. In the final chapter, a novel biomarker for AD, visual contrast sensitivity, was evaluated. The results demonstrated contrast sensitivity impairments in AD and MCI patients, as well as slightly in CC participants. Impaired contrast sensitivity was also shown to be significantly associated with known markers of AD, including cognitive impairments and temporal lobe atrophy on MRI-based measures. The results of Chapter 3 support contrast sensitivity as a potential novel biomarker for AD and suggest that future studies are warranted. Overall, the results of this report support MRI-based measures of neurodegeneration as effective biomarkers for AD, even in early clinical and preclinical disease stages. Future therapeutic trials may consider utilizing these measures to evaluate potential treatment efficacy and mechanism of action, as well as for sample enrichment with patients most likely to rapidly progress towards AD.
  • Thumbnail Image
    Item
    Targeted neurogenesis pathway-based gene analysis identifies ADORA2A associated with hippocampal volume in mild cognitive impairment and Alzheimer's disease
    (Office of the Vice Chancellor for Research, 2016-04-08) Horgusluoglu, Emrin; Nho, Kwangsik; Risacher, Shannon L.; Saykin, Andrew J.
    Background: New neurons are generated throughout adulthood in the olfactory bulb and dentate gyrus of the hippocampus, and are incorporated into hippocampal networks during maintenance of neural circuits and in turn contribute to learning and memory. Numerous intrinsic and extrinsic factors such as growth factors, transcription factors, and cell cycle regulators control neural stem cells proliferation, differentiation, and maintenance into mature neurons. However, the genetic mechanisms controlling adult hippocampal neurogenesis remain unclear. We performed a gene-based association analysis of neurogenesis pathway-related candidate genes using data from the Alzheimer's Disease Neuroimaging Initiative (ADNI). Methods: Neurogenesis-related genes were curated from existing databases (Qiagen RT2 Profiler PCR Arrays, GoGene and MANGO). The gene list was filtered by AD susceptibility genes from the Alzgene database (http://www.alzgene.org/) and large-scale GWAS (Lambert,et al. 2013, Nature). Caucasian non-Hispanic individuals (N=1,525) with AD or mild cognitive impairment (MCI) and cognitively normal older adults from the ADNI cohort with MRI and genotyping data were included. Gene-based association analysis of neurogenesis pathway-related candidate genes was performed. Baseline bilateral hippocampus and hippocampal subfield (CA regions and dentate gyrus) volumes were extracted from MRI and served as phenotypes. Gender, age, intracranial volume, MRI field strength, and diagnosis at scanning were entered as covariates. The empirical p value from permutation testing for each gene was adjusted for the number of significant SNPs in each gene. Results: ADORA2A was significantly associated with total hippocampal volume and hippocampal subfield volumes (p<0.001). For the most significant SNP (rs9608282) in ADORA2A, dosage of the minor allele (T) increased hippocampal volume. rs9608282 was also associated with composite memory score (p= 0.0076). Conclusion: ADORA2A-mediated control of neuroinflammation modulates adult neurogenesis and the inhibition of ADORA2A prevents Aβ-induced neurotoxicity. Targeted pathway-based genetic analysis combined with brain imaging endophenotypes appears promising to help elucidate disease pathophysiology and identify potential therapeutic targets. **Data used in preparation of this article were obtained from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database (adni.loni.usc.edu). As such, the investigators within the ADNI contributed to the design and implementation of ADNI and/or provided data but did not participate in analysis or writing of this report. A complete listing of ADNI investigators can be found at: http://adni.loni.usc.edu/wpcontent/ uploads/how_to_apply/ADNI_Acknowledgement_List.pdf