Cerebrospinal Fluid Proteome Alterations Associated with Neuropsychiatric Symptoms in Cognitive Decline and Alzheimer's Disease

Abstract

Although neuropsychiatric symptoms (NPS) are common and severely affect older people with cognitive decline, little is known about their underlying molecular mechanisms and relationships with Alzheimer’s disease (AD). The aim of this study was to identify and characterize cerebrospinal fluid (CSF) proteome alterations related to NPS. In a longitudinally followed-up cohort of subjects with normal cognition and patients with cognitive impairment (MCI and mild dementia) from a memory clinic setting, we quantified a panel of 790 proteins in CSF using an untargeted shotgun proteomic workflow. Regression models and pathway enrichment analysis were used to investigate protein alterations related to NPS, and to explore relationships with AD pathology and cognitive decline at follow-up visits. Regression analysis selected 27 CSF proteins associated with NPS. These associations were independent of the presence of cerebral AD pathology (defined as CSF p-tau181/Aβ1−42 > 0.0779, center cutoff). Gene ontology enrichment showed abundance alterations of proteins related to cell adhesion, immune response, and lipid metabolism, among others, in relation to NPS. Out of the selected proteins, three were associated with accelerated cognitive decline at follow-up visits after controlling for possible confounders. Specific CSF proteome alterations underlying NPS may both represent pathophysiological processes independent from AD and accelerate clinical disease progression.

Keywords: Alzheimer’s disease; cognitive decline; proteome.

Figure 1

EN variable selection and protein scores for total NPI positive individuals.Proteins sorted by absolute value of EN regression score (x-axis); IDS-Iduronate 2-sulfatase; CBLN3- Cerebellin-3; FBLN7-Fibulin-7; T132A-Transmembrane protein 132A; F9-Coagulation factor IX; CTSF-Cathepsin F; ATP1A2-Sodium/potassium-transporting ATPase subunit alpha-2; MANBA-Beta-mannosidase; SH3L3-SH3 domain-binding glutamic acid-rich-like protein 3; RELN-reelin; ATPB-ATP synthase subunit beta, mitochondrial; SYUG-Gamma-synuclein; K22E-Keratin, type II cytoskeletal 2 epidermal; GLU2B-Glucosidase 2 subunit beta; APOA4-Apolipoprotein A-IV; TSP1-Thrombospondin-1; KCRU-Creatine kinase U-type, mitochondrial; FHR1-Complement factor H-related protein 1; CD44-CD44 antigen; PRDX6-Peroxiredoxin-6; SPTB2-Spectrin beta chain, non-erythrocytic 1; ATPA; ATP synthase subunit alpha, mitochondrial; SLPI-Antileukoproteinase; AUGUN-Augurin; AP2B1-AP-2 complex subunit beta; PGS1-CDP-diacylglycerol-glycerol-3-phosphate 3-phosphatidyltransferase, mitochondrial; and MIME-Mimecan.

Figure 2

Venn diagram of analytes associated with total NPS, depression, or apathy, obtained by EN regression models.

Figure 3

Comparison of enriched pathways between total NPS, depression, and apathy. Above is the pathway enrichment analysis of identified proteins for total NPS, apathy, or depression. The number of over-represented categories within each symptom (expressed as a percentage) is illustrated.

Figure 4

ROC curve comparison for the reference and selected diagnostic models. (A) ROC curves and AUCs for the reference models (sex + age + MMSE score) with (green) or without considering cerebral AD (blue) and the final diagnostic models of the occurrence of NPS obtained after addition of three proteins (IDS + RELN + SH3L3) without AD (red) and three proteins (MIME + IDS + K22E) with AD (magenta). (B) ROC curves and AUCs for the reference model (age + sex+ baseline MMSE score + time to follow-up + cerebral AD status (blue)) and the final diagnostic model of decline in global cognition (MMSE change at last follow-up <−2) after addition of three proteins (IDS + PGS1 + AP2B1).