%0 Journal Article %J J Alzheimers Dis %D 2022 %T Proteomic Profiles of Neurodegeneration Among Mexican Americans and Non-Hispanic Whites in the HABS-HD Study. %A O'Bryant, Sid E %A Zhang, Fan %A Petersen, Melissa %A Hall, James R %A Johnson, Leigh A %A Yaffe, Kristine %A Braskie, Meredith %A Vig, Rocky %A Toga, Arthur W %A Rissman, Robert A %X

BACKGROUND: Hispanics are expected to experience the largest increase in Alzheimer's disease (AD) and AD related dementias over the next several decades. However, few studies have examined biomarkers of AD among Mexican Americans, the largest segment of the U.S. Hispanic population.

OBJECTIVE: We sought to examine proteomic profiles of an MRI-based marker of neurodegeneration from the AT(N) framework among a multi-ethnic, community-dwelling cohort.

METHODS: Community-dwelling Mexican Americans and non-Hispanic white adults and elders were recruited. All participants underwent comprehensive assessments including an interview, functional exam, clinical labs, informant interview, neuropsychological testing, and 3T MRI of the brain. A neurodegeneration MRI meta-ROI biomarker for the AT(N) framework was calculated.

RESULTS: Data was examined from n = 1,291 participants. Proteomic profiles were highly accurate for detecting neurodegeneration (i.e., N+) among both Mexican Americans (AUC = 1.0) and non-Hispanic whites (AUC = 0.98). The proteomic profile of N + was different between ethnic groups. Further analyses revealed that the proteomic profiles of N + varied by diagnostic status (control, MCI, dementia) and ethnicity (Mexican American versus non-Hispanic whites) though diagnostic accuracy was high for all classifications.

CONCLUSION: A proteomic profile of neurodegeneration has tremendous value and point towards novel diagnostic and intervention opportunities. The current findings demonstrate that the underlying biological factors associated with neurodegeneration are different between Mexican Americans versus non-Hispanic whites as well as at different levels of disease progression.

%B J Alzheimers Dis %V 86 %P 1243-1254 %8 2022 Apr 05 %G eng %N 3 %R 10.3233/JAD-210543 %0 Journal Article %J J Alzheimers Dis %D 2021 %T Plasma Total-Tau and Neurofilament Light Chain as Diagnostic Biomarkers of Alzheimer's Disease Dementia and Mild Cognitive Impairment in Adults with Down Syndrome. %A Petersen, Melissa E %A Rafii, Michael S %A Zhang, Fan %A Hall, James %A Julovich, David %A Ances, Beau M %A Schupf, Nicole %A Krinsky-McHale, Sharon J %A Mapstone, Mark %A Silverman, Wayne %A Lott, Ira %A Klunk, William %A Head, Elizabeth %A Christian, Brad %A Foroud, Tatiana %A Lai, Florence %A Diana Rosas, H %A Zaman, Shahid %A Wang, Mei-Cheng %A Tycko, Benjamin %A Lee, Joseph %A Handen, Benjamin %A Hartley, Sigan %A Fortea, Juan %A O'Bryant, Sid %X

BACKGROUND: The need for diagnostic biomarkers of cognitive decline is particularly important among aging adults with Down syndrome (DS). Growing empirical support has identified the utility of plasma derived biomarkers among neurotypical adults with mild cognitive impairment (MCI) and Alzheimer's disease (AD); however, the application of such biomarkers has been limited among the DS population.

OBJECTIVE: This study aimed to investigate the cross-sectional diagnostic performance of plasma neurofilament light chain (Nf-L) and total-tau, individually and in combination among a cohort of DS adults.

METHODS: Plasma samples were analyzed from n = 305 (n = 225 cognitively stable (CS); n = 44 MCI-DS; n = 36 DS-AD) participants enrolled in the Alzheimer's Biomarker Consortium -Down Syndrome.

RESULTS: In distinguishing DS-AD participants from CS, Nf-L alone produced an AUC of 90%, total-tau alone reached 74%, and combined reached an AUC of 86%. When age and gender were included, AUC increased to 93%. Higher values of Nf-L, total-tau, and age were all shown to be associated with increased risk for DS-AD. When distinguishing MCI-DS participants from CS, Nf-L alone produced an AUC of 65%, while total-tau alone reached 56%. A combined model with Nf-L, total-tau, age, and gender produced an AUC of 87%. Both higher values in age and total-tau were found to increase risk for MCI-DS; Nf-L levels were not associated with increased risk for MCI-DS.

CONCLUSION: Advanced assay techniques make total-tau and particularly Nf-L useful biomarkers of both AD pathology and clinical status in DS and have the potential to serve as outcome measures in clinical trials for future disease-modifying drugs.

%B J Alzheimers Dis %V 79 %P 671-681 %8 2021 Jan 19 %G eng %N 2 %& 671 %R 10.3233/JAD-201167 %0 Journal Article %J J Alzheimers Dis %D 2018 %T A Precision Medicine Model for Targeted NSAID Therapy in Alzheimer's Disease. %A O'Bryant, Sid E %A Zhang, Fan %A Johnson, Leigh A %A Hall, James %A Edwards, Melissa %A Grammas, Paula %A Oh, Esther %A Lyketsos, Constantine G %A Rissman, Robert A %X

BACKGROUND: To date, the therapeutic paradigm for Alzheimer's disease (AD) has focused on a single intervention for all patients. However, a large literature in oncology supports the therapeutic benefits of a precision medicine approach to therapy. Here we test a precision-medicine approach to AD therapy.

OBJECTIVE: To determine if a baseline, blood-based proteomic companion diagnostic predicts response to NSAID therapy.

METHODS: Proteomic assays of plasma from a multicenter, randomized, double-blind, placebo-controlled, parallel group trial, with 1-year exposure to rofecoxib (25 mg once daily), naproxen (220 mg twice-daily) or placebo.

RESULTS: 474 participants with mild-to-moderate AD were screened with 351 enrolled into the trial. Using support vector machine (SVM) analyses, 89% of the subjects randomized to either NSAID treatment arms were correctly classified using a general NSAID companion diagnostic. Drug-specific companion diagnostics yielded 98% theragnostic accuracy in the rofecoxib arm and 97% accuracy in the naproxen arm.

CONCLUSION: Inflammatory-based companion diagnostics have significant potential to identify select patients with AD who have a high likelihood of responding to NSAID therapy. This work provides empirical support for a precision medicine model approach to treating AD.

%B J Alzheimers Dis %V 66 %P 97-104 %8 2018 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/30198872?dopt=Abstract %R 10.3233/JAD-180619