| Alcohol dependence is a global public health problem,which is very common in both developed and developing countries.Long-term high level alcohol intake is associated with increased morbidity and mortality of multiple system diseases.Studies have shown that alcoholism can cause serious adverse effects on cardiovascular system,gastrointestinal system and immune system,leading to the occurrence of coronary heart disease,stroke,cirrhosis and tumors.Heavy drinking has also been linked to a range of mental and psychological illnesses,including anxiety,depression,insomnia,suicide and other substance abuse.Alcohol dependence not only induces physical and mental impairment,but also may lead to unintentional injuries,exacerbating additional medical costs and placing a heavy financial and psychological burden on individuals,families and society.As a result,alcohol dependence has become a major public health and socio-economic problem,which need to raise public concern.Previous studies have shown that excessive alcohol consumption can lead to structural and functional damage in the brain.The brain structural changes induced by alcohol dependence include white matter lesions(WML),corpus callosum degeneration,gray matter atrophy and sulcal widening.Alcohol dependence patients present complex and varied clinical manifestations,the majority of whom are likely to have formal work and families,live a normal life,and present with general complaints existing in contemporary society,such as tension,anxiety,depression and sadness,making most persons with alcohol dependence hard to identify.And only about a quarter of the patients with alcohol dependence tend to seek for help.Therefore,it is very important to find biomarkers for the diagnosis and evaluation of alcohol dependence.Clinicians can diagnose patients with alcohol dependence more quickly and accurately through clinical consultation,questionnaire scoring and biomarker detection,so as to develop further treatment plans.In this study,we divided it into three parts.In the first part,the patients with alcohol dependence and the control group were evaluated in aspects of cognition,psychology and sleep.Voxel-based morphometry(VBM),Fazekas scores,cholinergic pathways hyperintensities scale(CHIPS)were employed to assess the white matter structure,severity of WMLs and WMLs in cholinergic pathway respectively.The characteristics of cognitive,psychological,sleep and imaging changes and the correlation between alcohol consumption,age,WMLs and cognitive function were analyzed in patients with alcohol dependence.In the second part,we detected NOD like receptor protein 3(NLRP3)in serum of patients with alcohol dependence and chronic alcohol intake rat models respectively.The correlation between NLRP3,alcohol consumption,cognitive and psychological function,white matter volume and degree of white matter lesions were analyzed.We explored the possibility of NLRP3 as a diagnostic biomarker in patients with alcohol dependence.In the third part,we explored the possibility of neurofilament light(NfL)protein as a biomarker for patients with alcohol dependence.The correlations between NfL,alcohol consumption,cognitive and psychological function,white matter volume and degree of white matter lesions were analyzed.The results of this study will provide new potential biomarkers for the diagnosis and evaluation of alcohol dependence,and lay a theoretical foundation for subsequent translational medicine research.Part 1:Evaluation of imaging changes and cognitive function and analysis of influencing factors in patients with alcohol dependenceObjectiveTo evaluate the changes of cognitive function,mental state,sleep and brain imaging,and to explore the correlation between alcohol consumption,age,white matter lesions and cognitive function in patients with alcohol dependence.MethodsFifty patients with alcohol dependence and fifty control subjects with no history of alcohol use were enrolled through social recruitment.Neuropsychological assessments,including Montreal cognitive assessment(MoCA),Pittsburgh sleep quality index(PSQI),generalized anxiety disorder(GAD-7),and patient health questionnaire-9(PHQ-9),were conducted to evaluate cognitive function,psychological states and sleep condition.All of participants received magnetic resonance imaging(MRI)examination.White matter structure was quantified by voxel-based morphometry(VBM)method.The degree of white matter lesions(WMLs)was rated by the Fazekas scale.Cholinergic pathways hyperintensities scale(CHIPS)was used to evaluate the degree of WMLs in cholinergic pathways.The differences in cognitive function,psychological state,sleep condition,white matter volume,severity of WMLs and WMLs of cholinergic pathway between patients with alcohol dependence and control group were analyzed,and the correlation between alcohol consumption,age,white matter lesions and cognitive function in patients with alcohol dependence were assessed.ResultsThe MoCA scores and white matter volume in alcohol dependence group were lower than those in control group,while the Fazekas,PSQI,GAD-7,PHQ-9 scores were higher in the alcohol dependence group than those in control group(P<0.05).The MoCA scores of heavy drinkers were lower than those of mild drinkers in the group with age≥49 years,while the MoCA scores of heavy drinkers were not significantly different from those of mild drinkers in the group with age<49 years.In heavy drinkers,the MoCA scores of age≥49 years group were lower than those of age<49 years group,while in mild drinkers,the MoCA scores of age≥ 49 years group were not statistically different from those of age<49 years group.Spearman correlation analysis indicated that Fazekas scores were negatively correlated with MoCA scores(r=-0.292,P=0.0397).There was no significant difference in Fazekas scores between heavy drinkers and mild drinkers,and there was no significant correlation between alcohol consumption and Fazekas scores(r=0.0085,P=0.953).CHIPS scoer was positively correlated with Fazekas scores(r=0.793,P<0.01).In alcohol dependence group,CHIPS score was higher in patients with cognitive dysfunction than patients with normal cognition(P<0.05),but not correlated with MoCA scores(r=-0.258,P=0.0710).ConclusionCompared with non-drinkers,patients with alcohol dependence tend more likely to have anxiety,depression,sleep disorders,and cognitive function decline.The older drinkers are more vulnerable to heavy drinking and tend to have more obvious cognitive decline.The degree of white matter lesions in patients with alcohol dependence is related with cognitive function.Part 2:The potential diagnostic value of serum NLRP3 as a biomarker in alcohol dependenceObjectiveAlcohol stimulates caspase-1 activation,induces the production of pro-inflammatory cytokines such as IL-1β and IL-18,and activates the NLRP3 inflammasome complex.We explored the possibility of NLRP3 as a diagnostic biomarker in alcohol dependence.MethodsFifty patients with alcohol dependence and fifty control subjects with no history of alcohol use were enrolled through social recruitment.Enzyme-linked immunosorbent assay(ELISA)was employed to detect the expression of serum NLRP3.The alcohol consumption was measured by standard drinks.The correlation between NLRP3 levels and alcohol consumption,MoCA,PSQI,GAD-7,PHQ-9,white matter volume,Fazekas scores and CHIPS scores were analyzed by Spearman analysis in alcohol dependence patients.Receiver operator characteristic curve(ROC)was used to evaluated the diagnostic effect of NLRP3 in alcohol dependence.Besides,chronic alcohol intake rats model was constructed and the expression change of NLRP3 in rats was detected.ResultsSerum NLRP3 levels were higher in the alcohol dependence group than those in control group.The NLRP3 levels were irrelevant to monthly alcohol assumption,MoCA,PSQI,GAD-7,PHQ-9,white matter volume,Fazekas scale scores and CHIPS scores.The area under the ROC curve was 0.8536 for NLPR3.At an NLRP3 cut-off value of 364.6pg/ml,the sensitivity for predicting alcohol dependence was 84%,and the specificity was 88%.ConclusionThe study support the potential diagnostic value of serum NLRP3 as a biomarker in alcohol dependence.Part 3:The potential value of serum NfL as a biomarker in alcohol dependenceObjectiveNfL is a biomarker of neuron and axon damage.We examined the expression levels of NfL in serum of patients with alcohol dependence,in order to explore the potential value of NfL as a potential biomarker in alcohol dependence.MethodsFifty patients with alcohol dependence and fifty control subjects with no history of alcohol use were enrolled through social recruitment.Single-Molecule Array(Simoa)assay was used to detect the expression of serum NfL.The correlation between NfL levels and alcohol consumption,MoCA,PSQI,GAD-7,PHQ-9,white matter volume,Fazekas scores and CHIPS scores were analyzed by Spearman analysis in alcohol dependence patients.ROC was used to evaluated the diagnostic effect of NfL in alcohol dependence.ResultsSerum NfL levels were higher in the alcohol dependence group than those in control group.The serum NfL expression levels between different genders were similar in patients with alcohol dependence and control group(P>0.05),but there was a positive correlation between NfL expression levels and age in patients with alcohol dependence and control group(P<0.05).In alcohol dependence group,NfL levels were positively correlated with PSQI scores(r=0.461,P=0.001)and PHQ-9 scores(r=0.423,P=0.002),and negatively correlated with MoCA scores(r=-0.94,P<0.01).However,NfL levels were not associated with monthly alcohol assumption and GAD-7 scores(P>0.05).The NfL levels were positively correlated with the Fazekas scale scores(r=0.930,P=0.000)and CHIPS scores(r=0.789,P<0.01),and negatively correlated with WMV(r=-0.343,P=0.015).The area under the ROC curve was 0.9234 for NfL.At an NfL cut-off value of 16.65 pg/ml,the sensitivity for predicting alcohol dependence was 84%,and the specificity was 94%.ConclusionThe study support the potential value of serum NfL as a biomarker in alcohol dependence.The association between NfL levels and neuropsychological dysfunction and the degree of WMLs has implications to use NfL as a promising biomarker to assess the severity of brain damage,progression and prognosis of alcohol dependence. |
PDF Full Text Request