Neuropsychiatric symptoms in cognitive decline and Alzheimer's disease: biomarker discovery using plasma proteomics

Abstract

Background and objectives: Neuropsychiatric symptoms (NPS) are common in older people with cognitive impairment and Alzheimer's disease (AD). No biomarkers to detect the related pathology or predict the clinical evolution of NPS are available yet. This study aimed to identify plasma proteins that may serve as biomarkers for NPS and NPS-related clinical disease progression.

Methods: A panel of 190 plasma proteins was quantified using Luminex xMAP in the Alzheimer's Disease Neuroimaging Initiative cohort. NPS and cognitive performance were assessed at baseline and after 1 and 2 years. Logistic regression, receiver operating characteristic analysis and cross-validation were used to address the relations of interest.

Results: A total of 507 participants with mild cognitive impairment (n=396) or mild AD dementia (n=111) were considered. Selected plasma proteins improved the prediction of NPS (area under the curve (AUC) from 0.61 to 0.76, p<0.001) and future NPS (AUC from 0.63 to 0.80, p<0.001) when added to a reference model. Distinct protein panels were identified for single symptoms. Among the selected proteins, ANGT, CCL1 and IL3 were associated with NPS at all three time points while CCL1, serum glutamic oxaloacetic transaminase and complement factor H were also associated with cognitive decline. The associations were independent of the presence of cerebral AD pathology as assessed using cerebrospinal fluid biomarkers.

Conclusions: Plasma proteins are associated with NPS and improve prediction of future NPS.

Keywords: ALZHEIMER'S DISEASE; APATHY; BEHAVIOURAL DISORDER; DEPRESSION; MOLECULAR BIOLOGY.

Figure 1. (A) Grouping of the study cohort (n=507) into participants with NPS (NPIQ>1) and without NPS (NPI-Q<2). (B) Frequency of the single items (symptoms) of the NPI-Q in the whole cohort. (C) Raincloud plot showing the distribution of NPI-Q total severity scores in the whole cohort at baseline (0), at 1-year follow-up (1) and 2-year follow-up (2). (D) Raincloud plot showing the distribution of NPS severity change (∆NPI-Q from baseline to 1 or 2-year follow-up. Higher values show an increasing (ie, worsening) NPI-Q score. (E) Spearman’s rank correlation of plasma proteins with all symptoms measured by the NPI-Q. P values of significant correlations are highlighted with colours according to the legend on the right. n, number; NPI-Q, Neuropsychiatric Inventory Questionnaire; NPS, neuropsychiatric symptoms.

Figure 2. Prediction of overall NPS at baseline (A) and follow-up visits after 1 year (B) and after 2 years (C). On the left side ROC curves indicating the AUC of the three different predictive models are shown. In brackets, the number of included proteins is shown. On the right side, the correlation dot plot is shown including all cross-validated proteins from the parsimonious model with their beta coefficients. The size of each dot corresponds to the B coefficient of the single protein. **p<0.01, ***p<0.001. AUC, area under the curve; NPS, neuropsychiatric symptoms; ROC, receiver operating characteristics.

Figure 3. (A) Venn diagram with the number of patients having 1–5 of the most common symptoms (irritability, depression, anxiety, agitation, apathy) at baseline. (B) Venn diagram with the number of associated and shared proteins between single symptoms. NPS, neuropsychiatric symptoms.

Figure 4. Data for the five most common single symptoms of NPS are displayed. On the left side, ROC curves indicating the AUC of the two different predictive models are shown. The x-axis corresponds to 1−specificity and the y-axis to sensitivity. In brackets, the number of included proteins is shown. On the right side, the correlation dot plot is shown including all proteins from the full model with their beta coefficients. The size of each dot corresponds to the B coefficient of the single protein. **p<0.01, ***p<0.001. AUC, area under the curve; NPS, neuropsychiatric symptoms; ROC, receiver operating characteristics.

Figure 5. Proteins commonly associated with neuropsychiatric symptoms at baseline, 1 and 2 years follow-up visits.