A preliminary study about neurofilament light chain and tau protein levels in psoriasis: Correlation with disease severity

Abstract Background Studies investigating cognitive dysfunction in psoriatic patients remain inconclusive. Objective To investigate the risk of cognitive decline in plaque‐type psoriasis patients. Methods Serum neurofilament light chain (NFL) and tau protein concentrations in 45 patients with plaque‐type psoriasis and forty‐five healthy controls were measured by enzyme‐linked immunosorbent assay (ELISA). Results Mean homeostasis model assessment (HOMA‐IR) values (6.82 vs 3.25) and serum levels of insulin (28.19 vs 15.71), NFL (5.74 vs 1.98), and tau (348.17 vs 207.30) in patients with psoriasis were found to be significantly higher than those of in healthy controls. There was a significant positive correlation between NFL and tau (r = .257, P = .015). There was significant correlation between NFL, tau and PASI (r = .310, P = .040) and (r = .383, P = .010), respectively. Significant correlations between NFL and insulin, TC, HDL‐C, TG, VLDL‐C, and BMI were found. NFL (9.38 vs 3.08) and tau (439.28 vs 281.58) concentrations and PASI values (23.94 vs 14.18) in patients with disease onset before 40 years were significantly higher than that of the patients with disease onset after 40 years. C‐reactive protein (CRP) was significantly correlated with BMI (r = .449, P < .001), LDL‐C (r = .240, P = .026), TG (r = .244, P = .024), and VLDL‐C (r = .241, P = .025) in patients with psoriasis. Conclusions Increased serum NFL and tau protein levels and the presence of positive correlations between NFL, tau protein and PASI score show cognitive decline risk may be higher in moderate‐to‐severe psoriasis.


| INTRODUC TI ON
Psoriasis is a chronic skin disease, characterized by epidermal hyperplasia, inflammation, angiogenesis, and vascular remodeling. 1 It is caused by systemic inflammatory processes. Inflammatory myeloid dendritic cells release interleukin IL-23 and IL-12 that activate IL-17 producing T cells, Th1 cells, and Th22 cells. These cells further stimulate the production of the cytokines such as IL-1, IL-6, and tumor necrosis factor α (TNF-α) which have also been associated with cognitive impairment. Some studies have reported that patients with psoriasis have impaired cognitive function, 2 an increased risk for dementia, 3 or a genetic overlap with dementia. 4 However, it is unclear if the association between cognitive dysfunction and psoriasis can be attributed to cardiometabolic comorbidities of psoriasis or to psoriasis per se. 5 Neurofilaments are specifically expressed in neurons and are major cytoskeleton proteins. 6 Their gene expression 7 and protein phosphorylation levels 8 directly affect axonal diameter, myelination, and conduction velocity. 9 Upon neuronal damage, neurofilaments that are discharged into the interstitial fluid subsequently diffuse into the cerebrospinal fluid (CSF) and then the blood. 10 Elevated levels of neurofilaments are general indicators of axonal damage in many neurological conditions, including multiple sclerosis, 11 HIV-associated encephalopathy, 12 neurodegenerative disorders, 13 aging, 14 stroke, 15 and traumatic brain injury. 16 Increased levels of NFL are evident well before the clinical onset of cognitive impairments. Despite lacking diagnostic specificity, neurofilament blood levels are potentially valuable to monitor and to predict disease progression and to evaluate treatment efficacy.
Tau is microtubule-associated protein essentially located in the axons of neurons. It is also present in glial cells to a lesser extent. It plays a fundamental role in maintaining the stability and integrity of neurons by regulating microtubule polymerization, stabilization, and suppression of microtubule dynamics. 17 Dysregulation of the taumicrotubule complex impairs the maintenance of cellular polarity and viability.
Neurofilaments levels and tau protein are, therefore, used as surrogate markers of axonal damage. To our knowledge, this study is the first to investigate the levels of NFL and tau protein in patients with plaque-type psoriasis, their correlation to disease severity and their relationship with other clinical and biochemical characteristics of psoriasis.

| MATERIAL S AND ME THODS
Forty-five patients with psoriasis were included in this study.
Because this is the preliminary study, only plaque-type psoriasis patients participated who were not previously diagnosed with psoriatic arthritis. The study lasted from February 1, 2019, to August 30, 2019. The diagnosis of psoriasis was based on clinical data. 18 To evaluate the severity of the cutaneous manifestations of psoriasis, we used the Psoriasis Area Severity Index (PASI), 19 which assesses erythema, infiltration, desquamation, and the percentage of the affected body surface. The PASI score ranges from 0 to 72. Higher score denotes greater severity of psoriasis. All patients were clinically assessed using PASI by the same dermatologist to ensure the same standards in establishing disease severity. Clinical and anthropometric characteristics of the patients with psoriasis are given in Table 1. The control group (collected among the    E446Hu) were assayed using commercially available enzyme-linked immunosorbent assay (ELISA) kits (Bioassay Technology Laboratory). The sensitivity of this ELISA kit was 12.31 ng/L for tau protein and 0.054 ng/mL for NFL. The intra-assay and inter-assay coefficients of variation for the two parameters were <8% and <10%, respectively.

| RE SULTS
NFL and tau were analyzed in 45 patients with psoriasis (14 women and 31 men) and in 45 age-matched healthy controls (16 women and 29 men). The mean age (range) and BMI (range) of the controls were 33.3 (17-56) years and 26.9 (18-37) kg/m 2 , respectively. The values of the systolic and diastolic blood pressure (BP) (mean ± SD) of the controls were 111.2 ± 11.5 mmHg and 75.7 ± 7.5 mmHg, respectively. Eight controls (17.8%) smoked. Lipid profile and insulin resistance parameters recorded in controls and patients with psoriasis are given in Table 2. There were no significant differences between the groups in terms of age, gender, BMI, systolic-diastolic BP values, and lipid profile parameters. Mean insulin levels and HOMA-IR values were significantly increased in patients compared with those in controls (P = .001 and P < .001 respectively). In addition, serum NFL and tau levels in the patients with psoriasis were increased (P < .001 and P = .011, respectively) compared with those in healthy controls (Table 2).
We further performed analysis of covariance to investigate the influence of factors such as age, gender, BMI, and smoking status on NFL, tau, HOMA-IR, and insulin. The levels of NFL, tau, and insulin and the HOMA-IR values remained significantly increased in the patients with psoriasis compared to those in controls upon stratification by age, gender, BMI, and smoking status (Table 3).
There was a significant positive correlation between NFL and tau (r = .257, P = .015). Also, significant correlations between NFL, tau and PASI (r = .310, P = .040) and (r = .383, P = .010), respectively, were found. In addition, NFL was significantly correlated with insulin, TC, HDL-C, TG, and VLDL-C levels and BMI (Table 4). Additionally, CRP correlated significantly with LDL-C, TG and VLDL-C levels, and BMI (Table 4). As we expected, there were strong correlations between parameters of insulin resistance and lipid profile (data not shown).
In addition, we evaluated the effect of age of disease onset of psoriasis on NFL, tau, and PASI (

| D ISCUSS I ON
In this study, we investigated the correlation of the levels of serum there were significant correlations between CRP and LDL-C, TG and VLDL-C, and BMI; (f) NFL and tau concentrations and PASI score in patients with disease onset before 40 years were significantly higher than those observed in patients with disease onset after 40 years.
These findings suggest that the risk of mild cognitive impairment may be higher in moderate-to-severe psoriasis.
The pathogenesis of dementia remains elusive. However, the presence of amyloid deposition, vascular injury, and inflammation have been implicated to contribute to the pathogenesis of dementia. 22 Mild cognitive impairment (MCI)-wherein objective cognitive impairment does not affect daily living activities-is considered a transitional stage between normal aging and dementia. In some cases, MCI does not worsen and the affected individuals may even revert back to cognitive normality. Morphological abnormalities in the brain that characterize dementia may appear in people diagnosed with MCI 20 or more years before signs of the disease develop. 23 Therefore, most studies are prone to underestimated the risk for dementia because of  and tau may accumulate in susceptible regions earlier than amyloid, we measured NFL and tau proteins in the blood. 26 Several studies have shown increased plasma tau in individuals with Alzheimer's disease (AD) compared with that in healthy individuals. In a study of normal elderly people without cognitive impairment, elevated levels of NFL in CSF were observed in those who developed cognitive decline during follow-up. 27 The measurement of NFL in blood could be useful for preventative screening of preclinical stages of AD. Framingham Dementia Study indicated that higher plasma tau concentrations were associated with a higher risk of AD, suggesting that plasma tau might help predict dementia even in individuals who are cognitively unimpaired. 28 In a similar report from Mayo Clinic Study of Aging, a significant reduction in global cognition, memory, attention, and visuospatial ability was predicted by high plasma tau concentrations in individuals with MCI and no cognitive impairment. 29 Psoriasis has been found to be associated with an increased risk of cognitive impairment and dementia in most studies. 30 Marek- Studies in older adults rather than middle aged adults suggest that a higher BMI may be associated with a lower risk of cognitive decline, dementia, and AD. 36,37 Obesity may influence long-term risk of AD but the early or preclinical stages of AD may be associated with weight loss. In our study, it may explain higher NFL and tau concentrations and PASI score in patients with disease onset before 40 years than that of patients with disease onset after 40 years.
Our study has some limitations. First, we had a small number of participants. A larger population is needed to support the generalization of these results. Second, the current study did not perform amlyloid-beta positron emission tomography or provide neuropathological confirmation of dementia. Therefore, further studies with a larger number of patients and long enough follow-up periods will help us better understand the relationship between psoriasis and impaired cognition.

| CON CLUS IONS
Psoriasis is multisystem inflammatory disease associated with nu- More research will be necessary to refine and further elaborate our findings.

CONFLICT OF INTEREST
The authors declare no conflicts of interest. TA B L E 5 Serum neurofilament light chain (NFL), total tau protein (tau) concentrations, and psoriasis area and severity index (PASI) in patients with psoriasis with disease onset before 40 y, and after 40 y (mean, range)