Lower White Matter Volume and Worse Executive Functioning Reflected in Higher Levels of Plasma GFAP among Older Adults with and Without Cognitive Impairment

Abstract

Objective: There are minimal data directly comparing plasma neurofilament light (NfL) and glial fibrillary acidic protein (GFAP) in aging and neurodegenerative disease research. We evaluated associations of plasma NfL and plasma GFAP with brain volume and cognition in two independent cohorts of older adults diagnosed as clinically normal (CN), mild cognitive impairment (MCI), or Alzheimer’s dementia. Methods: We studied 121 total participants (Cohort 1: n = 50, age 71.6 ± 6.9 years, 78% CN, 22% MCI; Cohort 2: n = 71, age 72.2 ± 9.2 years, 45% CN, 25% MCI, 30% dementia). Gray and white matter volumes were obtained for total brain and broad subregions of interest (ROIs). Neuropsychological testing evaluated memory, executive functioning, language, and visuospatial abilities. Plasma samples were analyzed in duplicate for NfL and GFAP using single molecule array assays (Quanterix Simoa). Linear regression models with structural MRI and cognitive outcomes included plasma NfL and GFAP simultaneously along with relevant covariates. Results: Higher plasma GFAP was associated with lower white matter volume in both cohorts for temporal (Cohort 1: β = −0.33, p = .002; Cohort 2: β = −0.36, p = .03) and parietal ROIs (Cohort 1: β = −0.31, p = .01; Cohort 2: β = −0.35, p = .04). No consistent findings emerged for gray matter volumes. Higher plasma GFAP was associated with lower executive function scores (Cohort 1: β = −0.38, p = .01; Cohort 2: β = −0.36, p = .007). Plasma NfL was not associated with gray or white matter volumes, or cognition after adjusting for plasma GFAP. Conclusions: Plasma GFAP may be more sensitive to white matter and cognitive changes than plasma NfL. Biomarkers reflecting astroglial pathophysiology may capture complex dynamics of aging and neurodegenerative disease.

Association of plasma glial fibrillary acidic protein (GFAP) with neuroimaging of Alzheimer's disease and vascular pathology

“…Higher plasma GFAP levels have also been associated with lower brain volume, specifically in parietal and temporal subregions 12 . Similarly, we observed a trend between plasma GFAP and lower cortical thickness in a temporal region.…”

“…Higher plasma GFAP levels have also been associated with lower brain volume, specifically in parietal and temporal subregions. 12 Similarly, we observed a trend between plasma GFAP and lower cortical thickness in a temporal region. Again, after stratifying by amyloid PET status, the association only remained among those with elevated amyloid PET, further suggesting specificity to amyloid pathology.…”

“…Fewer studies have examined associations between GFAP and other imaging markers of neurodegeneration such as cortical thickness. One study reported an association between increased plasma GFAP levels and lower parietal and temporal cortical thickness 12 …”

Alzheimer’s Disease Biomarkers Revisited From the Amyloid Cascade Hypothesis Standpoint

“…Similar to CSF GFAP, elevated plasma GFAP concentrations have been observed in a variety of neurodegenerative and non-neurodegenerative neurological conditions, including AD ( Mayer et al, 2013 ; Elahi et al, 2020 ; Heller et al, 2020 ; van Ballegoij et al, 2020 ). However, further investigations have revealed that plasma GFAP concentrations correlate strongly with cerebral Aβ pathology, as measured by PET ( Verberk et al, 2020 ), as well as with decreasing white matter volume and worsening cognitive function ( Oeckl et al, 2019 ; Rajan et al, 2020 ; Verberk et al, 2020 ; Asken et al, 2021 ), and hence it is relatively Aβ-specific. In fact, simultaneous comparisons in two independent cohorts between plasma GFAP and NfL, a sensitive biomarker of neuronal injury independent of Aβ pathology, revealed that plasma GFAP may be more sensitive to cortical and cognitive changes than plasma NfL ( Asken et al, 2021 ).…”

“…However, further investigations have revealed that plasma GFAP concentrations correlate strongly with cerebral Aβ pathology, as measured by PET ( Verberk et al, 2020 ), as well as with decreasing white matter volume and worsening cognitive function ( Oeckl et al, 2019 ; Rajan et al, 2020 ; Verberk et al, 2020 ; Asken et al, 2021 ), and hence it is relatively Aβ-specific. In fact, simultaneous comparisons in two independent cohorts between plasma GFAP and NfL, a sensitive biomarker of neuronal injury independent of Aβ pathology, revealed that plasma GFAP may be more sensitive to cortical and cognitive changes than plasma NfL ( Asken et al, 2021 ). Plasma GFAP is higher in Aβ-positive cognitively unimpaired individuals at risk of developing AD ( Chatterjee et al, 2021 ), and longitudinal investigations have observed that plasma GFAP can predict subsequent conversion of mild cognitive impairment (MCI) patients to AD with an area under the receiver operating characteristic curve of 0.84 (95% CI 0.77–0.91) ( Cicognola et al, 2021 ).…”