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. 2023 Dec 9;13(1):382.
doi: 10.1038/s41398-023-02683-0.

Peripheral immunity and risk of incident brain disorders: a prospective cohort study of 161,968 participants

Xiaoling Zhong #  1   2 , Yixuan Qiang #  3 , Ling Wang  2 , Yaru Zhang  3 , Jieqiong Li  4 , Jianfeng Feng  5 , Wei Cheng  5 , Lan Tan  6 , Jintai Yu  7
Affiliations

Peripheral immunity and risk of incident brain disorders: a prospective cohort study of 161,968 participants

Xiaoling Zhong et al. Transl Psychiatry. .

Abstract

Whether peripheral immunity prospectively influences brain health remains controversial. This study aims to investigate the longitudinal associations between peripheral immunity markers with incident brain disorders. A total of 161,968 eligible participants from the UK Biobank were included. We investigated the linear and non-linear effects of peripheral immunity markers including differential leukocytes counts, their derived ratios and C-reactive protein (CRP) on the risk of dementia, Parkinson's disease (PD), stroke, schizophrenia, bipolar affective disorder (BPAD), major depressive disorder (MDD) and anxiety, using Cox proportional hazard models and restricted cubic spline models. Linear regression models were used to explore potential mechanisms driven by brain structures. During a median follow-up of 9.66 years, 16,241 participants developed brain disorders. Individuals with elevated innate immunity markers including neutrophils, monocytes, platelets, neutrophil-to-lymphocyte ratio (NLR), and systemic immune-inflammation index (SII) had an increased risk of brain disorders. Among these markers, neutrophils exhibited the most significant correlation with risk of dementia (hazard ratio 1.08, 95% confidence interval 1.04-1.12), stroke (HR 1.06, 95% CI 1.03-1.09), MDD (HR 1.13, 95% CI 1.10-1.16) and anxiety (HR 1.07, 95% CI 1.04-1.10). Subgroup analysis revealed age-specific and sex-specific associations between innate immunity markers with risk of dementia and MDD. Neuroimaging analysis highlighted the associations between peripheral immunity markers and alterations in multiple cortical, subcortical regions and white matter tracts, typically implicated in dementia and psychiatric disorders. These findings support the hypothesis that neuroinflammation is important to the etiology of various brain disorders, offering new insights into their potential therapeutic approaches.

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Conflict of interest statement

The authors declare no competing interests.

Figures

Fig. 1
Fig. 1. Flow chart of study design.
Five hundred and two thousand four hundred and ninety-three participants aged 37–73 years were included for initial assessment, after excluding participants with baseline diagnoses of the seven brain disorders, with a follow-up duration of less than five years or below 55 years, with conditions that could impact peripheral immunity markers. Finally, 161,968 participants were included in the primary analysis.
Fig. 2
Fig. 2. Linear associations between peripheral immunity markers and incident brain disorders.
The model was adjusted for age at baseline, sex, ethnicity, education, SBP and DBP. Exposures were log-transformed and standardized to Z score so that the HR represents the predicted effect of a one SD increment. Statistical significance at FDR-adjusted P (labeled as Q values) < 0.05. FDR, false discovery rate; HR hazard ratio, SD standard deviation, SBP systolic blood pressure, DBP diastolic blood pressure, PD Parkinson’s disease, MDD major depressive disorder, BPAD bipolar affective disorder.
Fig. 3
Fig. 3. Non-linear associations between peripheral immunity markers and incident brain disorder.
Restricted cubic spline models fitted for Cox proportional hazards models was utilized, and 11 significant non-linear associations were identified. Two dashed vertical lines indicate 25% and 75% values of each exposure. Results were adjusted for age at baseline, sex, ethnicity, education, SBP and DBP. The colors blue, green, red, and purple represent each brain disorder fitting into PD, stroke, dementia, and MDD categories. HR hazard ratio, PD Parkinson’s disease, MDD major depressive disorder.
Fig. 4
Fig. 4. Associations between peripheral immunity markers and brain structure.
Neutrophil (A), SII (B), platelet (C), NLR (D) are negatively associated with volume of cortical and subcortical structures (Bonferroni-corrected, P < 0.05). Models are adjusted for age at baseline, sex, ethnicity, education, SBP and DBP. T-value represents the correlation coefficient of the linear regression. SBP systolic blood pressure, DBP diastolic blood pressure, NLR neutrophils/lymphocytes ratio, SII systemic immune-inflammation index (neutrophils×platelets/lymphocytes).
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