Endpoints and outcomes: the challenge of biomarker choice for VCI trials. (20th December 2022)

• Record Type: Journal Article
• Authors: Winder, Zachary; Sudduth, Tiffany L; Patel, Ela; Anderson, Sonya; Neltner, Janna; Bahrani, Ahmed Ali; Abner, Erin L; Nelson, Peter T; Jicha, Gregory A; Wilcock, Donna M
• Is Part Of: Alzheimer's & dementia. Volume 18(2022)Supplement 6
• Page Start: n/a
• Page End: n/a
• Publication Date: 2022-12-20
• Subjects: Alzheimer's disease -- Periodicals; Alzheimer Disease -- Periodicals; Dementia -- Periodicals; Démence; Maladie d'Alzheimer; Périodique électronique (Descripteur de forme); Ressource Internet (Descripteur de forme); 616.83
• DOI: 10.1002/alz.060534
• Languages: English
• ISSNs: 1552-5260

Abstract

Abstract: Background: Clinical trials for Alzheimer's disease (AD) have been significantly enhanced by the development of a suite of biomarkers ranging from PET and MRI modalities to CSF and now, plasma. Such biomarkers have refined trials by enabling the specific inclusion of participants with the targeted pathology. Clinical trials for vascular cognitive impairment and dementia (VCID) will require similar development and validation of biomarkers to be used for inclusion, stratification, target engagement, and efficacy in trials. Methods: We have explored fluid biomarkers for VCID using two longitudinal cohorts: UK‐ADRC and MarkVCID. Using the Quanterix Simoa assays, we have examined) neurodegenerative (NfL), inflammatory (GFAP, IL1b, TNFa, IL6, IL10), and angiogenic (PlGF, VEGF‐A, MMP9) biomarkers in plasma. We examined associations of these plasma biomarkers with disease phenotypes: white matter hyperintensities (WMH) and cerebrovascular reactivity (CVR) on MRI, learning and memory assessments, and neuropathologic hallmarks including amyloid plaques, tangles, amyloid angiopathy (CAA), brain arteriolosclerosis and microinfarcts. Results: In association with WMH, a presumed neuroimaging indicator of small vessel disease, we found that PlGF and WMH were positively correlated. Further, higher plasma GFAP was significantly associated with decreased CVR. For cognition, PlGF was associated with decreased attention and processing speed as assessed by Trail Making Test‐A; anti‐inflammatory cytokine IL10 was positively correlated with performance on verbal memory and verbal fluency. As has been shown previously, we observed that plasma NfL was negatively associated verbal fluency. Finally, when examining cerebrovascular pathologies, we found PlGF was positively associated with CAA, while GFAP was positively associated with chronic small vessel pathology like microinfarcts; IL8, an endothelial‐derived cytokine, was positively associated with more severe brain arteriolosclerosis. Conclusion: A number of candidate plasma biomarkers have been identified for potential use in clinical trials for VCID and these warrant further validation and characterization. While angiogenic markers like PlGF were associated with WMH, small vessel pathology may be more strongly associated with inflammation as indicated by GFAP and IL8. Verbal memory and fluency may be negatively affected by inflammation, and NfL remains a robust biomarker for cognitive test performance.