Blood-Based Biomarkers of Systemic Inflammation, Metabolic Function, and Vascular Injury Distinguish Patients with Rapid and Typical Progressive Neurodegenerative Diseases
Gregory Day1, Lindsey Kuchenbecker2, Philip Tipton1, Matthew Brier3, Nihal Satyadev1, Yoav Piura1, Steven Dunham3, Sid O'Bryant4, Neill Graff-Radford1
1Neurology, 2Neuroscience, Mayo Clinic in Florida, 3Neurology, Washington University, 4Institute for Translational Research, University of North Texas Health Science Center at Fort Worth
Objective:
Evaluate the ability of blood-based biomarkers of systemic inflammation, metabolic function, and vascular injury to distinguish patients with rapid and typical progressive Alzheimer disease and related dementias (AD/ADRD).
Background:
Selected CSF biomarkers of neuronal injury (NfL, VILIP-1), AD neuropathology (p-tau181), and neuroinflammation (GFAP, MCP-1, sTREM2) measured at presentation associate with etiologic diagnoses and reliably differentiate patients with treatment-responsive causes of rapid progressive dementia. However, these same biomarkers do not differentiate between patients with rapid and typical progressive forms of AD/ADRD, leaving unanswered key questions concerning the mechanisms that drive rpAD/ADRD. Blood-based biomarkers may inform the systemic factors that contribute to rpAD/ADRD, including the systemic inflammation, metabolic function, and vascular injury.
Design/Methods:
Biomarkers of systemic inflammation, metabolic function, and vascular injury were measured using Meso Scale Discovery multiplexed assays in plasma obtained at presentation from patients with rpAD/ADRD (n=29), and age- and sex- similar participants with typical progressive AD/ADRD (n=39) enrolled in parallel studies of memory and aging. Biomarker concentrations were compared between groups using univariate analyses. Potential predictors (p<0.05) were further evaluated via stepwise multivariate logistic regression.
Results:
Markers of vascular injury (SAA, CRP, sICAM-1), metabolic function (I-309, TPO), and systemic inflammation (Eotaxin-3, TARC, TNF-α) were increased in patients with rapid versus typical progressive AD/ADRD (p<0.05). Eotaxin-3, I-309, and SAA were independently associated with rpAD/ADRD, after controlling for age and sex. The overall multivariate model correctly characterized 87% of patients, with an area under the curve of 0.90 (95%CI: 0.83-0.98; p<0.001).
Conclusions:
Blood-based biomarkers of systemic inflammation, metabolic function, and vascular injury were elevated at presentation in patients with rapid vs typical AD/ADRD. These findings may provide additional insights into the mechanisms that drive rpAD/ADRD. Longitudinal measures from larger cohorts are needed to decipher the relationship between candidate biomarkers and rpAD/ADRD.
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