Multiplex array analysis of serum cytokines offers minimal predictive value for cognitive function in the subacute phase after stroke

And WHY THE HELL  are you predicting cognitive function rather than doing the research to repair cognitive problems post stroke? 

Laziness? Incompetence? Or just don't care? No leadership? No strategy? Not my job?

Multiplex array analysis of serum cytokines offers minimal predictive value for cognitive function in the subacute phase after stroke

Yuling Zhang^1,2, Haixin Song^1,3, Jun Wang⁴, Xiao Xi^1,5, Philip Cefalo⁶, Lisa J. Wood⁷, Xun Luo^4,8* and Qing Mei Wang^1,6*

• ¹Stroke Biological Recovery Laboratory, Spaulding Rehabilitation Hospital, The Teaching Affiliate of Harvard Medical School, Charlestown, MA, United States
• ²School of Health Science and Engineering, University of Shanghai for Science and Technology, Shanghai, China
• ³Rehabilitation Department, Sir Run Run Show Hospital, Hangzhou, China
• ⁴School of Medicine, Shenzhen University, Shenzhen, China
• ⁵Department of Rehabilitation Medicine, Xijing Hospital, The Fourth Military Medical University, Xi'an, China
• ⁶Department of Physical Medicine and Rehabilitation, Spaulding Rehabilitation Hospital, The Teaching Affiliate of Harvard Medical School, Charlestown, MA, United States
• ⁷William F. Connell School of Nursing at Boston College, Boston, MA, United States
• ⁸Kerry Rehabilitation Medicine Research Institute, Shenzhen, China

Objective: The effects of inflammation on post-stroke cognitive function are still unclear. This study investigated the correlation between the Th17-related cytokines in peripheral blood and post-stroke cognitive function after ischemic stroke in the subacute phase.

Design: A retrospective cohort study.

Setting: Academic acute inpatient rehabilitation facility.

Participants: One hundred and fourteen patients with first ischemic stroke were categorized as the poor cognitive recovery group (n = 58) or good cognitive recovery group (n = 56) based on their cognitive MRFS efficiency.

Interventions: All subjects received routine physical, occupational, and speech-language pathology therapy.

Main outcome measures: Serum cytokines/chemokine (IL-1 β, IL-2, IL-4, IL-5, IL-6, IL-9, IL-10, IL-12p70, IL-13, IL-15, IL-17A, IL-17E, IL-17F, IL-21, IL-22, IL-23, IL-27, IL-28A, IL-31, IL-33, GM-CSF, IFN-γ, MIP-3 α, TNF-α, and TNF-β) levels were measured in duplicate using Human Th17 magnetic bead panel and multiplex array analysis (Luminex-200 system). The primary functional outcome was a gain in functional independence measure (FIM) cognitive subscore at discharge. The secondary outcome measures were FIM total score at discharge, length of stay in the hospital, and discharge destination. Cognitive Montebello Rehabilitation Factor Score (MRFS) and cognitive MRFS efficiency were calculated. Demographic and clinical characteristics were obtained from the medical record.

Results: The good cognitive recovery group had an interesting trend of higher IL-13 than the poor cognitive recovery group (good cognitive recovery group 257.82 ± 268.76 vs. poor cognitive recovery group 191.67 ± 201.82, p = 0.049, unit: pg/ml). However, Pearson's correlation analysis showed no significant correlation between cytokine levels and gain of cognition, cognitive MRFS, or cognitive MRFS efficiency. Receiver operating characteristic (ROC) analysis of cytokines also suggested a low accuracy of prediction as a predictor for post-stroke cognitive recovery improvement.

Conclusion: Our preliminary findings suggested that the level of serum cytokines had minimal predictive value for the recovery of cognitive function during the subacute inpatient rehabilitation after stroke.

Introduction

Stroke is the global leading cause of long-term disability (1), resulting not only in physical disability but also in significant cognitive impairment (2, 3). While cognitive impairment and cerebrovascular disease shared some pathophysiologic mechanisms, post-stroke cognitive impairment (PSCI) become one of the common post-stroke complications (4, 5). Post-stroke vascular dementia affects 30% of survivors, and the incidence of new-onset dementia after stroke increases from 7 to 48% in 25 years (6). PSCI can cause direct effects on the quality of life, often resulting in poor functional recovery through poor compliance with treatment guidelines (7). Cognitive function is a prerequisite for functional rehabilitation and played a critical role in patient functional recovery (8). Therefore, for the early prevention of PSCI via comprehensive monitoring and interventions, it is urgent to explore precise and reliable biomarkers to effectively predict the risk of PSCI after stroke.

Inflammation is a key component of stroke-related brain injury and has been implicated as an important mechanism underlying cognitive impairment (9). The development of inflammation in stroke is also affected by many factors. Inflammatory cytokines play a crucial role in information transmission, activation and regulation of immune cells, mediating the activation, multiplication, and differentiation of T and B cells and in the inflammatory caspase reaction (10). There is a close relationship between cytokines (such as IL, TNF, and interferons) and the neuroinflammation of ischemic stroke (11–14). However, few data are available regarding their involvement in vascular cognitive impairment (15).

Cytokines are a large group of small signaling proteins which are involved in the whole processing of neuroinflammation (16). To date, the relationship between PSCI and inflammatory cytokines is still controversial. There is a trend of increasing levels of both pro-inflammatory (TNF- α, IL-1β, and IL-6) and anti-inflammatory cytokines (IL-1ra and IL-10) in the plasma of patients with AD (17). Several serum cytokine markers could possibly take part in mediating the inflammatory processes after acute stroke onset. TNF- α, IL-1 β, IL-6, IL-8, IL-12, and IL-10 have been hypothesized to be involved in stoke prognosis (18). This implies that inflammatory cytokines may also serve as a key mediator in the development of PSCI. Few studies have examined the result of the inflammation on cognitive function in a post-stroke setting (18). However, there are limited data linking cytokine levels and PSCI (19).

In many immune-inflammatory diseases, Th17 cell plays a key role in the induction of tissue inflammation and destruction (20). Th17 cells can promote neuroinflammation directly by releasing pro-inflammatory cytokines (IL-17, IL-21, IL22, IL-23, IFN-γ, and GM-CSF) and by inducing neuronal apoptosis through direct cell-cell contact (21). Th17 can penetrate the blood-brain-barrier to become involved in inflammatory response of nervous tissue after ischemic (22). Cytokines from Th17 may be correlated with a gain of cognitive recovery after stroke.

Therefore, this study aimed to explore a potential association between Th17-related cytokines and poststroke cognitive function. We measured the levels of 25 cytokines/chemokines [IL-1 β, IL-2, IL-4, IL-5, IL-6, IL-9, IL-10, IL-12p70, IL-13, IL-15, IL-17A, IL-17E, IL-17F, IL-21, IL-22, IL-23, IL-27, IL-28A, IL-31, IL-33, granulocyte macrophage colony-stimulating factor (GM-CSF), interferon (IFN)-γ, macrophage inflammatory protein (MIP)-3α TNF-α, TNF-β] in serum from patients using Human Th17 magnetic bead panel and multiplex array analysis. In addition, the study also looked into the association between inflammatory markers and post-stroke cognitive outcomes in the subacute phase.

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