A study of the longitudinal changes in multiple cerebrospinal fluid and volumetric magnetic resonance imaging biomarkers on converter and non-converter Alzheimer's disease subjects with consideration for their amyloid beta status.

Abstract

Introduction: This study aims to determine whether newly introduced biomarkers Visinin-like protein-1 (VILIP-1), chitinase-3-like protein 1 (YKL-40), synaptosomal-associated protein 25 (SNAP-25), and neurogranin (NG) in cerebrospinal fluid are useful in evaluating the asymptomatic and early symptomatic stages of Alzheimer's disease (AD). It further aims to shed new insight into the differences between stable subjects and those who progress to AD by associating cerebrospinal fluid (CSF) biomarkers and specific magnetic resonance imaging (MRI) regions with disease progression, more deeply exploring how such biomarkers relate to AD pathology.

Methods: We examined baseline and longitudinal changes over a 7-year span and the longitudinal interactions between CSF and MRI biomarkers for subjects from the Alzheimer's Disease Neuroimaging Initiative (ADNI). We stratified all CSF (140) and MRI (525) cohort participants into five diagnostic groups (including converters) further dichotomized by CSF amyloid beta (Aβ) status. Linear mixed models were used to compare within-person rates of change across diagnostic groups and to evaluate the association of CSF biomarkers as predictors of magnetic resonance imaging (MRI) biomarkers. CSF biomarkers and disease-prone MRI regions are assessed for CSF proteins levels and brain structural changes.

Results: VILIP-1 and SNAP-25 displayed within-person increments in early symptomatic, amyloid-positive groups. CSF amyloid-positive (Aβ+) subjects showed elevated baseline levels of total tau (tTau), phospho-tau181 (pTau), VILIP-1, and NG. YKL-40, SNAP-25, and NG are positively intercorrelated. Aβ+ subjects showed negative MRI biomarker changes. YKL-40, tTau, pTau, and VILIP-1 are longitudinally associated with MRI biomarkers atrophy.

Discussion: Converters (CNc, MCIc) highlight the evolution of biomarkers during the disease progression. Results show that underlying amyloid pathology is associated with accelerated cognitive impairment. CSF levels of Aβ42, pTau, tTau, VILIP-1, and SNAP-25 show utility to discriminate between mild cognitive impairment (MCI) converter and control subjects (CN). Higher levels of YKL-40 in the Aβ+ group were longitudinally associated with declines in temporal pole and entorhinal thickness. Increased levels of tTau, pTau, and VILIP-1 in the Aβ+ groups were longitudinally associated with declines in hippocampal volume. These CSF biomarkers should be used in assessing the characterization of the AD progression.