Systemic and central nervous system neuroinflammatory signatures of neuropsychiatric symptoms and related cognitive decline in older people

Abstract

Background: Neuroinflammation may contribute to psychiatric symptoms in older people, in particular in the context of Alzheimer's disease (AD). We sought to identify systemic and central nervous system (CNS) inflammatory alterations associated with neuropsychiatric symptoms (NPS); and to investigate their relationships with AD pathology and clinical disease progression.

Methods: We quantified a panel of 38 neuroinflammation and vascular injury markers in paired serum and cerebrospinal fluid (CSF) samples in a cohort of cognitively normal and impaired older subjects. We performed neuropsychiatric and cognitive evaluations and measured CSF biomarkers of AD pathology. Multivariate analysis determined serum and CSF neuroinflammatory alterations associated with NPS, considering cognitive status, AD pathology, and cognitive decline at follow-up visits.

Results: NPS were associated with distinct inflammatory profiles in serum, involving eotaxin-3, interleukin (IL)-6 and C-reactive protein (CRP); and in CSF, including soluble intracellular cell adhesion molecule-1 (sICAM-1), IL-8, 10-kDa interferon-γ-induced protein, and CRP. AD pathology interacted with CSF sICAM-1 in association with NPS. Presenting NPS was associated with subsequent cognitive decline which was mediated by CSF sICAM-1.

Conclusions: Distinct systemic and CNS inflammatory processes are involved in the pathophysiology of NPS in older people. Neuroinflammation may explain the link between NPS and more rapid clinical disease progression.

Keywords: Alzheimer’s disease, biomarkers; Cerebrospinal fluid; Cognitive decline; Neuroinflammation; Neuropsychiatric symptoms; Serum.

Fig. 1

Binary logistic regression models revealing associations between neuroinflammatory molecules and neuropsychiatric symptoms (NPS). Associations of CSF (left) and serum (right) neuroinflammatory marker concentrations with the occurrence of NPS. Individual β-coefficients for each significantly associated neuroinflammatory molecule are shown. *P value < 0.05; **P value < 0.01; ***P value < 0.001. CRP C-reactive protein, IP-10 10-kDa IFN-γ induced protein, sICAM-1 soluble intracellular adhesion molecule-1, IL-8 Interleukin-8, IL-6 Interleukin-6

Fig. 2

Associations of CSF (left) and serum (right) neuroinflammatory markers with anxiety, depression and apathy. Standardized β-coefficients obtained by regression models are shown. *P value < 0.05; **P value < 0.01; ***P value < 0.001. CRP C-reactive protein, IP-10 10-kDa IFN-γ induced protein, sICAM-1 soluble intracellular adhesion molecule-1, IL-8 Interleukin-8, MIP-1β macrophage inflammatory protein 1β, TARC thymus and activation-regulated chemokine, VEGF-D, vascular endothelial growth factor (D precursor)

Fig. 3

Associations of neuroinflammatory markers with progression of disease severity. A Correlations between NPI-Q total score at baseline and disease severity progression as measured by change in CDR-SoB (ΔCDR-SoB) over time. B Associations between neuroinflammatory markers and cognitive status at baseline and changes of disease severity in the whole cohort measured by change in CDR-SoB (ΔCDR-SoB) at 18 and 36 months. Standardized β-coefficients and obtained by linear regression models are shown. C Moderation model evaluating the contribution of NPI-Q score, CSF sICAM-1 at baseline and their interaction to disease severity progression at 18 and 36 months (ΔCDR-SoB). β-Coefficients obtained by binary logistic regression models are shown. CDR-SoB, Clinical Dementia Rating Sum of Boxes; CRP, C-reactive protein; sICAM-1, soluble intracellular adhesion molecule-1; IP-10, 10-kDa IFN-γ induced protein; NPI-Q, Neuropsychiatric Inventory Questionnaire score; Inter., Interaction Between NPI-Q score and sICAM-1 concentration (NPI-Q score × sICAM-1 levels)

Fig. 4

Graphical representation of the role of CNS neuroinflammation, in NPS, functional cognitive decline and regional brain atrophy. Significant associations or interactions are represented by arrows with standardized coefficients indicated alongside. The dashed arrow represents the interaction of sICAM-1 on the association between AD pathology and NPS. The dotted line represents an association demonstrated in a previous study [19]. Associations between neuroinflammation and NPS are described in detail in Fig. 1 and are independent of BBB function and cognitive status. *P value < 0.05; **P value < 0.01; ***P value < 0.001; C-reactive protein; IP-10, 10-kDa IFN-γ induced protein; sICAM-1, soluble intracellular adhesion molecule-1; A, correlation coefficient