This research is a continuation of our previous study attempting to establish the possible relations between NDSs and psoriasis in order to evaluate whether psoriatics are at greater risk of cognitive impairment. Similar to our other paper, this one also seems to suggest that there could actually be a susceptibility to NDs among psoriatics, basing on their blood biomarkers. We managed to find statistical significance in evaluated NDs biomarkers serum concentrations between psoriatics and subjects without psoriasis, moreover in all cases – also significant difference in their concentrations after the antipsoriatic treatment. It surely gives a new insight for the interplay between psoriasis and NDs and indicates the need for exploring this issue.
MAPT aberrations have been observed in different neurological conditions . As for the usefulness of blood as a biological fluid for concentration measurement, it has been established that MATP is elevated in the blood of patients with AD and in some cases also in PD . In PD it was discovered to positively correlate with cognitive performance and hippocampal atrophy [14, 15]. Previous research also suggested that the increased blood level of total MAPT was associated with faster progression of dementia . In our study, MAPT concentration was significantly higher in patients than in controls – same observation that has been made also in some of NDs. In the only paper in which MAPT had been studied in psoriatics before, the same results were obtained . Such observations may indicate that the probability of dementia and NDs occurrence in psoriatics may be increased and surely requires more in-depth research to be elucidated.
Psoriasis severity expressed by PASI, as well as BMI and duration of psoriasis do not seem to affect MAPT concentration and therefore the risk of NDs. There was no direct correlation between PASI and MAPT concentration, as well as after division into subgroups according to psoriasis severity nor BMI. These observations were also made in our previous paper regarding three other ND biomarkers, which even more confirms our hypothesis. Apparently, the psoriasis severity or duration do not influence MAPT concentrations and thus do not directly indicate increased risk of NDs. Different outcome was presented in the paper by Okan et al. who reported that serum MAPT concentration may be correlated with PASI in patients with psoriasis and that the age of psoriasis onset before 40 years old affects higher MAPT concentrations , although this study was performed on relatively smaller group than ours. Therefore, we conclude that PASI and psoriasis duration cannot be perceived as prognostic factors of NDs development possibility at this moment. It has to be verified in further studies.
We did not find any correlations between MAPT concentration and basic laboratory parameters in relation to the group of patients as a whole. However, we observed a negative correlation between MAPT and glucose, WBC and cholesterol levels in patients with mild psoriasis, therefore we might suspect that it could indicate its protective influence against the metaflammation in such individuals.
The extent of tau pathology depends on the dose, hence the idea for tau-lowering therapy. Another way is inhibition of tau aggregation and tau phosphorylation . In our study, after the antipsoriatic treatment MAPT concentration significantly decreased. After division into two subgroups according to the administered systemic agent, it was methotrexate which caused the significant drop in tau protein concentration. Therefore, basing on this observation, we could conclude that methotrexate could be considered as the drug of choice in patients with elevated MAPT serum concentration. Further, presumably methotrexate might exert protective effect via downregulation of tau protein on cognitive impairment in psoriatic patients. However, of note, literature data are conflicting. One study by Judge et al. mentions that methotrexate may exert a protective role on cognitive function in patients with rheumatic diseases , which is consistent with our results. On the other hand, the paper by Elens et al. seems to state the opposite: they indicate that methotrexate may contribute to the increased MAPT hyperphosphorylation. Methotrexate is among others administered to children with leukemia in order to provide CNS prophylaxis and apparently this agent, which is the dihydrofolate reductase inhibitor, alters the distribution of intracellular folates, decreases the CSF folates and increases MAPT concentrations . In paper on mice model by Elens et al. they observed that changes in 5- methyltetrahydrofolate serum concentrations and in CSF are associated with increased MAPT concentrations in CSF, which leads to decreased cell proliferation in hippocampus . This observation seems to be age-dependent though, and cited study was performed on mice. Obviously, this issue requires further treatment, but basing on available data and our study methotrexate seems to exert a protective effect on cognitive impairment. As for the possible influence of acitretin on MAPT, unfortunately we did not find any information. Similar, we did not manage to find any report on the potential influence of tau phosphorylation inhibitors, used in AD treatment, on psoriasis. Definitely the interrelations between both methotrexate and acitretin should be further explored.
NrCAM is a marker of ADAM10 activity and in case of its decreased activity, which may be monitored by decreased concentration of NrCAM, APP is less degraded and therefore more beta-amyloid accumulates, which is an important link in AD pathogenesis . In our study, concentration of NrCAM was significantly lower in patients before the treatment than in controls – exactly as in patients with AD, which may be another potential proof for their association. Similar to MAPT, NrCAM concentration was not associated with psoriasis severity or duration. Although there was no direct correlation between NrCAM and BMI, the highest concentrations were noted in obese patients which might point to links with adipose tissue or perhaps chronic metaflammation increasing within the weight observed in psoriasis.
We did not find any correlations between NrCAM concentration and basic laboratory parameters in relation to the group of patients as a whole, except for the negative correlation with ALT activity. Apparently, NrCAM might be associated with liver dysfunction in psoriatic patients, which needs to be further elucidated.
After the treatment NrCAM concentration increased significantly. Both systemic antipsoriatic drugs caused significant increase in NrCAM concentration. Acitretin has been described to enhance the activity of ADAM10 and have some kind of sparing effect towards NrCAM, thus our results remain in accordance with the literature data stating that this drug should increase NrCAM concentration . This is why acitretin, which is widely used for systemic antipsoriatic therapy could be also used in AD therapy. As for methotrexate, it caused significant elevation of NrCAM, but we did not find any information on its possible influence on the protein in available medical literature so the discussion at this point is inconclusive.
Under the natural circumstances in healthy persons amyloid formation and clearance are balanced, therefore there is no unfavorable accumulation observed . The problems occurs when formation excesses the clearance and that could be associated with decreased activity of enzymes involved, of which the most important is NEP . In our study NEP concentration was significantly lower in patients than in controls – such observation has been made also in NDs – hence again another cognitive impairment biomarker tends to be off normal limits in psoriatic patients.
Psoriasis severity probably does not have important impact on serum NEP concentration. However, we also found that in overweight patients PASI was negatively correlated with NEP, which could mean that patients with elevated body weight and more severe psoriasis are more prone to cognitive impairment. Hence, we believe it could suggest that psoriasis severity does not directly affect the risk of neurodegeneration but it may be important in patients with severe cases of psoriasis associated with obesity – perhaps such subjects are more susceptible to NDs development. This is what we managed to observe in our previous research and it is consistent with the data indicating greater psoriasis severity in patients with higher body mass.
We did not find any correlations between NEP concentration and basic laboratory parameters in relation to the group of patients as a whole. However, we would like to point out that in obese psoriatics, NEP negatively correlated with TG. This observation reflects literature data indicating the relationship of dementia with metabolic disorders, including obesity and dyslipidemia, which may exacerbate cognitive impairment .
NEP has been suggested not only as a marker of cognitive impairment but also a possible tool for its monitoring and treatment efficacy assessment . In our study, NEP concentration significantly increased after the antipsoriatic treatment, so we may assume that such therapy may have a beneficial influence on the cognitive function and decrease the risk of such complications. When analyzing particular antipsoriatic agents, we noticed that both of them caused the elevation in NEP concentration but methotrexate significantly. Therefore, we may suspect that this drug could be the therapy of choice in patients with decreased NEP concentrations but also perhaps of protective effect on NDs development. As for literature data on possible influence of methotrexate and acitretin on NEP, we did not manage to find any information. As NEP inhibitors are approved as drugs used in heart failure therapy, it could raise a question whether they could cause cognitive impairment. Apparently, there is no evidence to state that, but definitely further, longer observations are needed [19, 26]. At this moment we would like to remind the tight association between psoriasis and cardiometabolic syndrome , which makes even more possible that psoriatic would be prescribed such drugs, so the observation of such patients towards ND complications may turn out to be necessary. There were also preclinical studies in which NEP gene was transferred to mice overexpressing human amyloid precursor protein and successfully lead to decreased amyloid accumulation . This is a promising idea, nevertheless there are no such drugs available so far.
Our study is one of the first of its kind, which surely brings some novelty into the field of psoriasis but on the other hand, the obtained results may be difficult to analyze since we do not have other studies on psoriatics to compare with. As for pointing out the limitation of our study, patients and controls came from the same single department. They were all from the same geographical location and Caucasian ethnicity. We investigated only blood serum biomarkers without measurement in CSF or tissue samples. In the future we plan to expand our study group and methods in cooperation with neurologists or psychiatrists. We are aware that as for now our results should be treated as preliminary but still encouraging to develop this issue.