Lupine publishers|Association of IL-6 & C-Reactive Protein with Cognitive Decline in Dementia
Association of IL-6 & C-Reactive Protein with Cognitive Decline in Dementia
Abstract
Inflammatory markers Interleukin-6 (IL-6) and C-Reactive Protein (CRP) associated are with high rates of cognitive decline. Inverse relation between IL-6 levels and Hindi Mental Status Examination (HMSE) scores has been studied. IL-6 is a multifunctional cytokine is a key regulator of CRP. A cross sectional study was performed to examine the association between inflammatory markers (including IL-6, CRP and albumin) and cognition in subjects attending Neurobehavior clinic. 66 Dementia patients with average age of 69 ± 0.06 years were included in the study (44 Alzheimer’s Disease & 22 Vascular Dementia). AD cases
were diagnosed according to ICD-10 and National Institute of Neurological Disorders and Stroke-Alzheimer Disease and Related
Disorders Criteria (NINCDS-ADRDS) for probable AD and Vascular dementia cases were diagnosed with NINDS-AIREN criteria. All dementia cases were assessed using Hindi Mental Status Examination (HMSE) for cognitive function and Clinical Dementia Rating Scale (CDR) was applied for staging severity of dementia. Out of three inflammatory biomarkers (IL-6, CRP and albumin), IL-6 showed strong positive correlation with duration of illness in dementia cases, whereas CRP had weak positive correlation
with duration of illness. Albumin showed no such relationship in dementia cases. On elimination of confounding variables, age and
duration of illness, strength of relationship between HMSE and IL-6 was moderately negative but significant. Such relationship was nonexistent between HMSE and CRP as well as albumin.
Introduction
Cognitive decline in dementia is associated with cytokine
dysregulation. Neuroinflammation acts as independent pathological
factor in early preclinical stages of Alzheimer’s disease, along with other risk factors like systematic infections [1,2], decreased
physical activity [3,4] which also have an inflammatory component.
Furthermore, some epidemiological studies demonstrate that
non-steroidal anti-inflammatory drugs (NSAIDs) can prevent
or retard AD cognitive decline [5], although other studies have found little improvement [6]. This slowing of cognitive decline
may be attributed to decreased inflammation since NSAID therapy
substantially reduces the number of activated microglia associated with plaques [7].
Interleukin-6 (IL-6) and C-reactive protein (CRP) have been most widely studied in population, showing IL-6 and CRP associated with high rates of cognitive decline. The health ABC
study reported subjects with CRP and/or IL-6 levels in the upper
tertile were at higher risk of cognitive decline compared to those in the lowest [8]. Rotterdam study also established associated risk of developing dementia including Alzheimer’s disease with raised
IL-6 and CRP levels. However, elevated CRP levels had stronger
association with vascular dementia [9]. Another longitudinal follow up study performed on population based samples of non disabled
elderly people reported that subjects with higher IL-6 level were at
a higher risk of developing future cognitive decline [10]. Another
multi ethnic cohort study observed inverse relation between IL-6
levels and MMSE scores [11].
IL-6 is a multifunctional cytokine with dual role, predominantly pro-inflammatory [12] with some anti-inflammatory property.
It is also a key regulator of CRP. Microglia and astrocytes are the two main cell components of the CNS that play a pivotal role in
the neuroinflammatory process responsible for neuro-biological homeostasis. During aging, there is pro-inflammatory shift in
CNS leading to proliferation of activated microglia and astrocytes
resulting in continuous secretion of IL-6 [13].The production of cytokines like IL-6 in brain of patients with AD not only increases
the amyloid deposition in cortical areas, but also leads to blood brain barrier dysfunction. This increased permeability of blood brain barrier may cause peripheral spill over of these cytokines produced in the brain. As they enter the plasma, they stimulate the
production of peripheral inflammatory mediators like IL-6 and CRP. This activation of peripheral inflammation leads to further amyloid deposition which further stimulates production of IL-6 [13,14].
These findings suggest that peripheral inflammation is not only
the result also a causative agent in pathogenesis of AD. Bettcher et al, [15] has also reported modest associations between plasma
and CSF levels for IL-6 (r=0.16, p=0.05). Similarly CRP, a marker of inflammation, lead to low grade chronic inflammation which
may lead to cognitive impairment and predispose elderly for the development of dementia and act as risk factor for the development
of AD and Vascular dementia [16]. Our study group earlier evaluated IL-6, CRP and albumin levels
from the patients with AD and vascular dementia as compared with
age and sex matched nondemented subjects to elucidate their role in the pathogenesis of dementia and found significantly high levels of IL-6 in AD as compared to controls (Paper under publication). In the current study, we performed a cross sectional study to examine the association between inflammatory markers (including IL-6, CRP and albumin) and cognition in subjects attending outpatient
services after adjusting for age and duration of illness.
Material and Methods
Subjects
In the present cross sectional study, subjects were enrolled from outpatient services of Psychiatry and Neurology departments,
Institute of Human Behavior & Allied Sciences (IHBAS), New Delhi, India. Sixty six Dementia patients (42 males and 24 females) were included in the study after applying inclusion and exclusion criteria.
The study was approved by the ethical committee of IHBAS. Written consent was obtained from all the patients and controls.
Socio-Demographic Profile
A designed to collect personal information like religion, marital status, education level, occupation, smoking habit, alcohol use, family history of dementia along with clinical history including
chronic illness (like dyslipidemia, DM etc), treatment history,
history of substance use.
Clinical Assessment
AD cases were diagnosed according to ICD-10 and National Institute of Neurological Disorders and Stroke-Alzheimer Disease
and Related Disorders Criteria (NINCDS-ADRDS) [17] for probable AD. Vascular dementia was diagnosed with NINDS-AIREN criteria
[18]. All dementia cases were assessed using Hindi Mental Status
Examination (HMSE) for cognitive function [19] and Everyday Abilities Scale for India (EASI) for activities of daily living [20]. Clinical Dementia Rating Scale (CDR) was applied for staging
severity of dementia [21].
Laboratory Analysis
All subjects underwent estimation of Interleukin-6 (IL-6), C-Reactive Protein (CRP) and albumin along with routine laboratory
tests in serum. At baseline non fasting serum samples were obtained from patients taking all the standard precautions. The specimen was centrifuged within 30 min of sample collection to separate
the serum and examined for routine biochemistry. Serum samples for evaluation of IL-6 and CRP were stored at −20°C until analysis.
Serum IL-6 was measured on by Electrochemiluminescence
immunoassay Analyzer, Cobas e 611 (M/s Roche Diagnostics Asia Pacific Pvt. Ltd, Singapore) using sandwich immunoassay
technique. CRP was measured using Random Access Discrete Auto
Analyser, Pictus 700 from Spectrum Pvt. Ltd. using commercially
available kits. The Coefficient of Variation (CV%) for IL-6 and CRP was less than 10%.
Statistical Analysis
Frequency, percentage and descriptive statistics (Mean, Standard deviation, Median and Inter quartile range) were calculated. Pearson’s correlation coefficients and their 95% confidence intervals were calculated to explore the linear
relationship between two continuous variables. As Pearson’s
correlation coefficient cannot eliminate the effect of confounding variables, so the partial correlation coefficients were calculated to find out absolute strength of relationship after adjusting the effect of confounding variables. The 95% confidence intervals for partial correlation coefficients were also calculated by bootstrapping method. All the analysis was carried out by SPSS 25.0 software (IBM SPSS Statistics for Windows, 2018).
Results
Table 1 shows the details of socio demographic profile of the study subjects. The average age (SD) of the study subjects was 69.03 (7.63) years and majority of subjects were males and were residing in rural area (74.20%). 80% subjects were married, whereas 45% were educated upto matric level. 74.20% subjects were nonsmokers and 86.40% were non alcoholic. The mean (SD) of duration of illness (years), body mass index, HMSE score, and CDR score were 3.80(2.19), 23.05(3.09), 13.76(3.95) and 5.69(3.74) respectively. 90.90% subjects had family history of dementia. Only 24.20% subjects had dyslipidemia and DM. Table 2 shows the result
of biochemical variables measured in all study subjects. As it was anticipated that age of subjects and duration of illness may have the relationship with HMSE score and level of
inflammatory markers (IL-6, CRP & albumin), so the strength of relationship between age versus IL-6, age versus CRP, age versus albumin had explored by Pearson’s correlation coefficient along with 95% confidence interval. Similarly, the strength of relationship was explored between duration of illness with HMSE, IL6, CRP
and serum albumin separately. It was also suspected that gender
may have the significant contribution in strength of relationship,
so the same analysis were conducted for male and female subjects separately apart from total study subjects. Table 3 shows that for
total subject, age had significant but weak negative correlation (r = -0.21, 95% CI: -0.39, -0.05) with HMSE score. It was slightly more in male subjects (r = -0.27, 95% CI: -0.49, -0.05) as compared to total subjects and in female subjects (r = -0.12, 95% CI: -0.57, 0.21), it was much lower and statistically not significant. The IL 6, CRP and serum albumin levels had almost non-existent strength of
relationship with age for total subjects as well as among male & female separately. The duration of illness was strongly but inversely related with
HMSE for all subjects (r = 0.69, 95% CI: -0.81, -0.53) and for both
genders too separately whereas it was much stronger among
females (r = -0.66, 95% CI: -0.78, -0.53) as compared to males (r = -0.72, 95% CI: -0.89, -0.40). The duration of illness had strong, positive and statistically significant relationship with IL 6 for total subjects (r = 0.76, 95% CI: 0.67, 0.91) as well as for male (r = 0.82, 95% CI: 0.68, 0.92) and female (r = 0.82, 95% CI: 0.67, 0.95)
subjects separately. The CRP is moderately but positively correlated with duration
of illness among total subjects (r = 0.37, 95% CI: 0.14, 0.56) and
similar strength & type of relationship were observed among males
(r = 0.41, 95% CI: 0.07, 0.62) and female (r = 0.36, 95% CI: -0.05, 0.79) separately between these two variables. The correlation
between duration of illness and serum albumin was very weak and
statistically not significant. As
per objective of the present study,
relationship between HMSE score, a measure of cognitive decline,
and level of inflammatory markers (IL-6, CRP and albumin) had been explored separately. As it is well known that two variable age and duration of illness were also correlated with HMSE, IL-6, CRP and albumin, so these two variables (age & duration of illness) may confound the strength of relationship between HMSE & IL-
6, HMSE & CRP and HMSE & albumin. To eliminate the effect of age and duration of illness, partial correlation method was used
for examining the strength of relationship between HMSE & IL-
6, HMSE and CRP and HMSE and albumin. Table 4 shows that the
partial correlation coefficient (strength of relationship) between HMSE and IL-6 was moderately negative but statistically significant among total subjects (r = -0.39, 95% CI: -0.68, -0.21) whereas it was slightly higher among males (r = -0.57, 95% CI; -0.73, -0.40) as compared to females (r = -0.51, 95% CI: -0.84, -0.31). The strength of relationship was observed almost non-existent between HMSE
versus CRP and HMSE versus albumin.
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