Browsing by Subject "CSF biomarkers"

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    Altered bile acid profile in mild cognitive impairment and Alzheimer's disease: Relationship to neuroimaging and CSF biomarkers
    (Elsevier, 2019-02) Nho, Kwangsik; Kueider-Paisley, Alexandra; MahmoudianDehkordi, Siamak; Arnold, Matthias; Risacher, Shannon L.; Louie, Gregory; Blach, Colette; Baillie, Rebecca; Han, Xianlin; Kastenmüller, Gabi; Jia, Wei; Xie, Guoxiang; Ahmad, Shahzad; Hankemeier, Thomas; van Duijn, Cornelia M.; Trojanowski, John Q.; Shaw, Leslie M.; Weiner, Michael W.; Doraiswamy, P. Murali; Saykin, Andrew J.; Kaddurah-Daouk, Rima; Radiology and Imaging Sciences, School of Medicine
    INTRODUCTION: Bile acids (BAs) are the end products of cholesterol metabolism produced by human and gut microbiome co-metabolism. Recent evidence suggests gut microbiota influence pathological features of Alzheimer's disease (AD) including neuroinflammation and amyloid-β deposition. METHOD: Serum levels of 20 primary and secondary BA metabolites from the AD Neuroimaging Initiative (n = 1562) were measured using targeted metabolomic profiling. We assessed the association of BAs with the "A/T/N" (amyloid, tau, and neurodegeneration) biomarkers for AD: cerebrospinal fluid (CSF) biomarkers, atrophy (magnetic resonance imaging), and brain glucose metabolism ([18F]FDG PET). RESULTS: Of 23 BAs and relevant calculated ratios after quality control procedures, three BA signatures were associated with CSF Aβ1-42 ("A") and three with CSF p-tau181 ("T") (corrected P < .05). Furthermore, three, twelve, and fourteen BA signatures were associated with CSF t-tau, glucose metabolism, and atrophy ("N"), respectively (corrected P < .05). DISCUSSION: This is the first study to show serum-based BA metabolites are associated with "A/T/N" AD biomarkers, providing further support for a role of BA pathways in AD pathophysiology. Prospective clinical observations and validation in model systems are needed to assess causality and specific mechanisms underlying this association.
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    Shared Genetic Background Between Cerebrospinal Fluid Biomarkers and Risk for Alzheimer’s Disease: A Two-Sample Mendelian Randomization Study
    (IOS, 2021) Kim, Soyeon; Kim, Kiwon; Nho, Kwangsik; Myung, Woojae; Won, Hong-Hee; Radiology and Imaging Sciences, School of Medicine
    Background: Whether the epidemiological association of amyloid beta (Aβ) and tau pathology with Alzheimer’s disease (AD) is causal remains unclear. Recent failures to demonstrate the efficacy of several Aβ-modifying drugs may indicate a possibility that the observed association is not causal, which led to efforts to develop tau-directed treatments whose efficacy remains tentative. Methods: Herein, we conducted a two-sample Mendelian randomisation analysis to investigate shared genetic background between cerebrospinal fluid (CSF) biomarkers for amyloid and tau pathology and risk for AD, and to find genetic evidence for causal association between these CSF biomarkers and risk for AD. We used summary statistics of genome-wide association study (GWAS) for CSF biomarkers (Aβ 1-42 , phosphorylated tau 181 [p-tau], and total tau [t-tau]) in 3,146 individuals and for late-onset AD (LOAD) in 21,982 LOAD cases and 41,944 cognitively-normal controls. We tested association between changes in the genetically-predicted CSF biomarkers and LOAD risk. Results: We found a decrease in the LOAD risk per one-standard deviation (SD) increase in the genetically-predicted CSF Aβ (odds ratio [OR], 2.87×10 -3 for AD; 95% confidence interval [CI], 1.54×10 -4 –0.05; p = 8.91×10 -5 ). Conversely, we observed an increase in the LOAD risk per one-SD increase in the genetically-predicted CSF p-tau (OR, 19.46; 95% CI, 1.50–2.52×10 2 ; p = 0.02) and t-tau (OR, 33.80; 95% CI, 1.57–7.29×10 2 ; p = 0.02). Conclusions: Our findings suggest a shared genetic background between the CSF biomarkers and LOAD risk. Although it requires validation by future studies including more genetic variants identified in large-scale GWASs for CSF biomarkers, our results suggest a causal association between CSF biomarkers and risk for LOAD.
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    Telomere length associations with cognition depend on Alzheimer's disease biomarkers
    (Elsevier, 2019-01-01) Mahoney, Emily R.; Dumitrescu, Logan; Seto, Mabel; Nudelman, Kelly N.H.; Buckley, Rachel F.; Gifford, Katie A.; Saykin, Andrew J.; Jefferson, Angela J.; Hohman, Timothy J.; Medical and Molecular Genetics, School of Medicine
    Introduction While telomere shortening, a marker of cellular aging, may impact the progression of age‐related neurodegenerative diseases, its association with cognition is unclear, particularly in the context of Alzheimer's disease (AD) pathology. Methods Telomere, cognitive, and CSF data from 482 participants in the AD Neuroimaging Initiative (148 cognitively normal, 283 mild cognitive impairment, 51 AD) was leveraged to assess telomere length associations with cognition (measured by memory and executive function) and interactions with CSF amyloid‐β, tau, and APOE‐ε4. Secondary analyses assessed brain volume and thickness outcomes. Results Longer telomeres at baseline were associated with faster executive function decline. Amyloid‐β and tau interacted with telomere length on cognition, with longer telomeres related to faster decline among biomarker‐positive individuals. Discussion Telomere associations with cognition shift with AD progression, with longer telomeres related to worse outcomes as pathology increases, highlighting the need for further investigation of telomere length along the AD neuropathological cascade.
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    Utility of CSF biomarkers in assessing neurodegeneration in Early‐Onset Alzheimer’s disease
    (Wiley, 2025-01-09) Eldaief, Mark C.; Touroutoglou, Alexandra; Brickhouse, Michael; Katsumi, Yuta; Eloyan, Ani; Nudelman, Kelly N.; Foroud, Tatiana M.; Carrillo, Maria C.; Rabinovici, Gil D.; Apostolova, Liana G.; Schindler, Suzanne E.; Herries, Elizabeth M.; Henson, Rachel L.; Dage, Jeffrey L.; Dickerson, Bradford C.; Medical and Molecular Genetics, School of Medicine
    Background: There is a significant need for biomarkers of neurodegenerative burden in Early‐onset Alzheimer’s disease (EOAD). Evidence suggests that levels of specific CSF biomarkers (e.g., Neurofilament light (NfL), Synaptosomal‐Associated Protein (SNAP‐25), neurogranin, Visinin‐like protein 1 (VILIP‐1), Aß 42/40, phospho‐tau and total tau) index the extent of neurodegeneration in dementing illnesses. However, it remains unclear whether these biomarkers correlate to cortical atrophy patterns in EOAD. Based on prior work demonstrating correlations between NfL, SNAP‐25, neurogranin and Aß 42/40 CSF levels and cognitive impairment in EOAD (Dage et al. 2023), we hypothesized that these biomarkers (and not VILIP‐1, phospho‐tau or total tau) would variably predict cortical atrophy within our recently described EOAD signature (Touroutoglou et al. 2023). Method: We recruited 92 EOAD patients. In each patient, atrophy within the EOAD cortical signature were calculated as W‐scores (i.e., Z‐scores adjusted for age and sex relative to a sample of healthy controls). We first ran a simple regression analysis of each of the 7 CSF biomarkers and W‐scores in the EOAD signature across EOAD patients. We then entered the biomarkers with significant correlations to the EOAD signature into a stepwise regression analysis with backward elimination to ascertain the most parsimonious model predicting atrophy in the EOAD signature. As a control region not expected to be related to these biomarkers, we assessed correlations to calcarine fissure cortical atrophy. Result: As predicted, we observed a significant correlation between CSF levels of NfL, SNAP‐25, neurogranin and Aß 42/40 and atrophy within the EOAD signature. After entering these four biomarkers into the stepwise regression analysis, the most parsimonious model identified complementary contributions of NfL, SNAP‐25, and Aß 42/40, in predicting atrophy in the EOAD signature. There were no correlations between any biomarker and calcarine atrophy. Conclusion: Selected CSF biomarkers in EOAD patients predict the degree of atrophy within the EOAD cortical signature. Ongoing work includes correlating these biomarkers with topographical atrophy patterns on the whole‐brain voxel‐wise level. Our results suggest that certain CSF biomarkers could assess neurodegenerative burden within EOAD individuals. This would provide valuable information regarding disease progression for clinical care and clinical trials involving disease‐modifying therapies.