Significance Of Determination Of Thyroid Hormone Levels And Structural Parameters Of Thyroid Homeostasis In Parkinson's Disease

Introduction:Parkinson's disease(PD)is a neurodegenerative disease characterized by the abnormal motor functions(including the bradykinesia,tremors and muscle stiffness),as well as the death of dopaminergic(DA)neurons in substantia nigra compacta.According to the National Parkinson Foundation,there are approximately one million patients currently suffering from PD,and 50,000-60,000 cases would be newly diagnosed as PD each year.However,the pathogenesis of PD has still been not completely understood.In addition to the factors of aging and sex,the environmental and genetic actors have been thought to play roles in the etiology of PD.Besides,oxidative stress has also been linked to the pathogenesis and development of PD.Thyroid disease refers to the endocrine dysfunction,which is most frequently associated with PD.In PD patients,the hypothyroid symptoms may be ambiguous,because the parkinsonism and hypothyroidism share some common clinical features,such as bradykinesia and hypomimia.Considering this coexistence,the uncommon phenomenon should be expected:the estimated prevalences of both the disorders tend to increase with advancing ages,Prevalence of hypothyroidism among adults varies between 2.3%and 18%,while the prevalence of PD ranges from 0.1%to 1.4%.In contrast,hyperthyroidism would worsen the parkinsonian tremor and cloud the levodopa responses in newly diagnosed PD patients.Occurrence of hyperthyroidism in elderly PD patients may be overlooked due to subtle symptoms and signs.Overall thyroid function has also been determined in patients with PD,though not any conclusive answer has been driven in regard to what role,if any,the thyroid function plays in the pathogenesis of PD.Several studies have shown that there is no significant relationship between the thyroid function and PD pathogenesis,while others have demonstrated association between them.Compared with normal subjects,subclinical hyperthyroidism is more prevalent in the PD patients,and the free thyroxine(FT4)levels are elevated in the de novo,medication-free PD patients.It has been shown that thyroid hormone(TH)level is closely associated with the motor symptoms in PD patients.However,in euthyroid patients with PD,whether the thyroid function is associated with the motor subtype and disease severity has not been reported.In this study,whether altered thyroid function within normal range was related to the motor subtype in patients with de novo PD was investigated.Moreover,the association between the TH level and the disease severity was analyzed.There is a recent debate that whether universal reference ranges for thyroid-stimulating hormone(TSH)and peripheral TH are appropriate.Improved diagnostic efficiency has also been observed using multivariate analysis rather than the conventional univariate approach.In order to identify and distinguish influences by the pituitary,the thyroid and deiodinases,we also calculated thyroid's secretory capacity(SPINA-GT),the total deiodinase activity(SPINA-GD)and,for pituitary function,Jostel's TSH index and the thyrotroph thyroid hormone sensitivity index(TTSI).We further compared these parameters among different groups.Part 1:Thyroid hormone levels and structural parameters of thyroid homeostasis are correlated with motor subtype and disease severity in euthyroid patients with Parkinson's diseasePurpose:We investigated the levels of the thyroid hormone and the parameters of thyroid homeostasis between groups to find the most relevant variables for motor subtypes and disease severity in patients with Parkinson's disease.Methods:Totally 77 patients with newly diagnosed PD were enrolled in this study.Healthy volunteers(n=27;age-matched)were also included for control.The subjects did not have a medical history of diagnosis of thyroid diseases,or receiving the TH replacement therapy or anti-thyroid drugs.The patients did not receive levodopa or other anti-PD drugs before.Exclusion criteria also included:the abnormal serum levels of total FT3,FT4 or TSH;cerebrovascular accident;head injury;other neurological and/or psychiatric disorders;clinical systemic disease;and current medications that could influence the parkinsonism and TH levels.77 PD patients were divided into tremor-dominant-type(TDT),akinetic-rigid-type(ART)and mixed-type(MXT)subgroups.Parkinsonism severity and stage was assessed by modified H-Y stage.Thyroid-stimulating hormone(TSH),FT3 and FT4 levels were detected to analyze thyroid function.Parameters of thyroid homeostasis,including thyroid' s secretory capacity(SPINA-GT),the total deiodinase activity(SPINA-GD)and Jostel' s TSH index and the thyrotroph thyroid hormone sensitivity index(TTSI),were calculated and compared.Results:Thyroid hormone levels in PD patients were lower than normal controls.Patients with TDT/MXT had significantly higher fT4 level than those with ART.TSH levels were 1.73±0.93 and 2.06±1.04 ulU/ml for patients with TDT/MXT and ART,respectively.The patients in the TDT/MXT group had significantly lower SPINA-GD while significantly higher SPINA-GT than ART group.The FT3 level was significantly higher in early group than advanced group.TSH index in the early group was significantly higher than the advanced group.The FT4 level was negatively correlated with UPDRS motor score.Univariate and multivariable logistic regression analysis indicated that FT4 was positively correlated with PD motor subtype,which disappeared after adjusting for confounding factors.The FT3 level was negatively correlated with PD disease severity,even after adjusting for confounding factors.In female PD patients,FT4 level in TDT/MXT group was significantly higher than ART group.Male PD patients had higher FT4 levels in early patients than advanced patients.Percentage of patients exhibiting ART was decreased significantly in higher FT4 level subgroups.With the increase of TSH index and TTSI,the proportion of advanced PD patients gradually decreased.The proportion of PD patients with TDT/MXT motor subtype gradually increased with the quartiles of SPINA-GT.Conclusion:FT4 and SPINA-GT is closely related to the motor subtypes of Parkinson's disease.With the increase of FT4 and SPINA-GT,the PD patients are more likely to be TDT/MXT.The analysis of the disease severity suggested that TSHI may be a potential biomarker.Part 2:The relationship between thyroid hormones and non-motor symptoms in Parkinson's diseasePurpose:To study the prevalence of different non-motor symptoms in Parkinson's disease;to analyze the correlation between different non-motor symptoms and motor subtypes and disease severity of Parkinson's disease;to investigate the relationship between non-motor symptoms and thyroid hormones and structural parameters of thyroid homeostasis.Methods:The analysis of non-motor symptoms mainly included cognitive function,orthostatic blood pressure,bladder residual urine,peripheral nerve damage,anxiety,depression and neuropsychiatric assessment.All patients completed the measurement of MMSE scale,SAS,SDS,NPI,electromyography of extremities and blood pressure in recumbent position.Results:The occurrence rate of non-motor symptoms in 77 patients with PD was high,among which neuropsychiatric disorders were the most serious.The incidence of peripheral nerve damage in TDT/MXT group was higher than that in ART group,and the incidence of postural hypotension in ART group was higher than that in early group.The incidence of bladder residual urine,postural hypotension and cognitive impairment in late group was higher than that in early group.After adjusting for sex,age,motor classification and H-Y disease severity,there was no correlation between thyroid hormone and non-motor symptom score of Parkinson's disease.The TSH level of PD patients with cognitive impairment is low,the TSH level of patients with depression is higher,and the TSH level of patients with anxiety symptoms is lower.Conclusion:The occurrence rate of non-motor symptoms in patients with Parkinson's disease is higher,among which neuropsychiatric abnormality is the most serious.The incidence of non-motor symptoms related to different motor subtypes and severity of Parkinson's disease is different.The changes of TSH within the normal reference range have effects on cognitive function,anxiety and depression symptoms.Serum thyroid function,structural parameters of thyroid homeostasis have certain effects on motor and non-motor symptoms of Parkinson's disease.The detection and calculation of them can provide reference for clinical diagnosis and treatment of Parkinson's disease.It may become a biochemical marker for the diagnosis of Parkinson's disease.