CSF VILIP-1 predicts rates of cognitive decline in early Alzheimer disease

Abstract

Objective: Measures of neuronal damage/dysfunction are likely good surrogates for disease progression in Alzheimer disease (AD). CSF markers of neuronal injury may offer utility in predicting disease progression and guiding prognostic and outcome assessments in therapeutic trials. Visinin-like protein-1 (VILIP-1) has demonstrated potential utility as a marker of neuronal injury. We here investigate the utility of VILIP-1 and VILIP-1/A␤42 in predicting rates of cognitive decline in early AD.Methods: Individuals with a clinical diagnosis of very mild or mild AD (n ϭ 60) and baseline CSF measures of VILIP-1, tau, p-tau181, and A␤42 were followed longitudinally for an average of 2.6 years. Annual assessments included the Clinical Dementia Rating (CDR), CDR-sum of boxes (CDR-SB), and global composite scores. Mixed linear models assessed the ability of CSF biomarker measures to predict rates of cognitive decline over time.Results: Baseline CSF VILIP-1 and VILIP-1/A␤42 levels predicted rates of future decline in CDR-SB and global composite scores over the follow-up period. Individuals with CSF VILIP-1 Ն560 pg/mL (corresponding to the upper tercile) progressed much more rapidly in CDR-SB (1.61 boxes/year; p ϭ 0.0077) and global scores (Ϫ0.53 points/year; p ϭ 0.0002) than individuals with lower values (0.85 boxes/year and Ϫ0.15 points/year, respectively) over the follow-up period. CSF tau, p-tau181, tau/A␤42, and p-tau181/A␤42 also predicted more rapid cognitive decline in CDR-SB and global scores over time. Conclusion:These findings suggest that CSF VILIP-1 and VILIP-1/A␤42 predict rates of global cognitive decline similarly to tau and tau/A␤42, and may be useful CSF surrogates for neurodegeneration in early AD. Neurology The aggregation and deposition of amyloid-␤ and tau, the 2 key proteins involved in Alzheimer disease (AD) pathogenesis, are estimated to begin years prior to the onset of cognitive impairment.1,2 However, it is only after a threshold of neuronal loss is reached in vulnerable brain regions that the first signs of cognitive impairment appear. Several lines of evidence suggest that neuronal and synaptic loss is the best surrogate for disease progression and cognitive decline in AD.2,4 While CSF tau and amyloid-beta 1-42 (A␤42) each predominantly reflect a specific AD pathology, neuronal injury/neurodegeneration likely represents the cumulative outcome of different pathologic substrates. Therefore, CSF markers of neuronal injury, along with CSF tau and A␤42, may offer utility in predicting disease progression and future cognitive decline in the early stages of disease.

Predictive Value of Cerebrospinal Fluid Visinin-Like Protein-1 Levels for Alzheimer’s Disease Early Detection and Differential Diagnosis in Patients with Mild Cognitive Impairment

“…AD risk groups within the MCI groups of patients were defined by the levels of five CSF AD biomarkers (Aβ 1-42 , t-tau, p-tau 181 ,p-tau 199 , and ptau 231 ). We tested VILIP-1 effectiveness in early detection of AD in MCI patients, and confirmed previous observations that VILIP-1 is a useful biomarker in early AD diagnosis [12,17,[27][28][29][30]]. Additionally, we tested VILIP-1 potential in differentiating AD from other primary causes of dementia, and its ability in predicting disease progression.…”

“…Also, recent genome-wide association studies (GWAS) showed an association of polymorphisms in VILIP-1 and VILIP-3 genes with the occurrence of AD [25,26]. Altogether, these factors may contribute to neuronal cell death and to the increase of VILIP-1 in CSF of AD patients [12,17,[27][28][29][30]. VILIP-1 levels were also increased in plasma of AD patients [27].…”

“…VILIP-1 levels were also increased in plasma of AD patients [27]. Recent studies reported the diagnostic potential of VILIP-1 in AD detection at early stages and in monitoring of disease progression [17,28]. However, whether VILIP-1 levels could discriminate MCI patients with higher risk of developing AD has not been investigated.…”

P1–206: Quantitative label‐free proteomics for discovery of biomarkers in cerebrospinal fluid: Assessment of technical and inter‐individual variation

“…Pittsburgh compound B, or PIB) and positron emission tomography, or indirectly, by measuring low CSF beta-amyloid42 (Ab42) concentrations that correlate with amyloid deposition [3,[10][11][12][13][14]. Imaging and fluid biomarker studies have also shown potential to predict cognitive decline by measuring amyloid deposition [5], regional volumetric and metabolic changes in the brain [15][16][17], or specific changes in the CSF proteome (including concentrations of tau, YKL-40, VILIP-1, and calbindin, each in association with Ab42) [2,3,18,19]. CSF analysis may even allow classification of disease stage [20] and monitoring of acute changes in response to disease modifying therapies, as illustrated recently with gamma-secretase inhibitors [21].…”

Cerebrospinal fluid biomarkers of Alzheimer’s disease

“…The ratio of YKL-40 to Aβ42 predicts cognitive impairment as well as the best CSF biomarkers (Aβ42, t-tau, and p-tau) [83] , suggesting potential as a biomarker for preclinical AD. dementias, and that CSF VILIP-1/Aβ42 predicts cognitive impairment as well as tau/Aβ42 and p-tau181/Aβ42 [84,85] . …”