| Parkinson’s disease(PD)is a common neurodegenerative disease in middle-aged and elderly people.In recent years,the incidence of PD has been increasing rapidly with the global acceleration of population aging,increasing life expectancy,and the potential influence of environmental factors.However,the current diagnosis of PD is significantly lagging behind,mainly based on typical clinical symptoms,such as resting tremor,myotonia,bradykinesia,and postural balance disorders,which have already reached stage Ⅲ in Braak’s staging and are poorly treated.However,if we intervene and treat PD at an early stage,we may be able to achieve good treatment results.Therefore,how to diagnose PD at an early stage and improve the accuracy of diagnosis is a difficult and hot issue to be solved.The main pathological basis of PD is the apoptotic necrosis of dopaminergic neurons in the substantia nigra pars compacta(SNpc),which leads to a decrease in striatal dopamine function and the corresponding clinical symptoms.Two important substances in the oxidative pathway of dopamine are neuromelanin,a downstream product of dopamine metabolism,and iron ions in the environment.The amount of neuromelanin,a dopamine metabolite,indirectly reflects the amount of dopamine neurons in the dense nigrostriatal region.As a damage factor in the cellular environment,iron ions not only participate in the oxidation of dopamine,but also can be captured by neuromelanin to form autophagosomes.However,once the autophagosomes are overloaded with iron ions,the neuromelanin-iron complex will be cleaved and released back into the environment,causing neuronal damage.With the development of magnetic resonance imaging,Neuromelanin-sensitive magnetic resonance imaging(NM-MRI)can indirectly reflect the level of dopaminergic neurons in the substantia nigra by detecting the neuromelanin signal in the substantia nigra.Quantitative susceptibility mapping(QSM)can quantify the iron content in tissues and is widely used in the study of iron quantification in the substantia nigra(SN)of neurodegenerative diseases.Currently,MRI studies of neuromelanin and iron deposition changes can assist in the clinical diagnosis of PD to a certain extent,however,there is still a lack of neurobiological markers for the definitive diagnosis of early PD,so it is clinically important to find more reliable neuroimaging markers for the early diagnosis of PD.It is known from previous literature that the cells in the substantia nigra are not uniformly distributed,and the substantia nigra is anatomically and functionally divided into two parts:the SNpc region,which is rich in dopaminergic neurons and neuromelanin,and the substantia nigra pars reticulata(SNpr),which is rich in γaminobutyric acid(GABA)neurons and has a high iron content.The neurons in the SNpc are deeply distributed in the SNpr in the form of clustered cellular set islands.Therefore,this study suggests that the intersection region of the two is rich in both neuromelanin and high in iron.This region is defined as the overlap region,which appears in the MRI images as the intersection of the neuromelanin hyperintense region shown by NM-MRI and the iron deposition region shown by QSM.Given that the overlap region is rich in both neuromelanin and iron,and that the bidirectional effect of neuromelanin on cells(neuroprotection or neurodamage)depends to some extent on the altered iron content,it is hypothesized that the overlap region may provide more sensitive information on the onset and progression of substantia nigra degeneration.In addition to PD,the common parkinsonisms such as progressive supranuclear palsy(PSP),multiple system atrophy(MSA)and other neurodegenerative diseases have a high rate of disability and death.The common features with PD are insidious onset,progressive development,difficulty in early clinical diagnosis,and poor prognosis,as well as the fact that the substantia nigra is the main pathological damage structure in PSP and MSA.Although there are some reports that the differential diagnosis can be aided by the selective regional differences in neuromelanin and iron deposition changes in the substantia nigra of parkinsonisms syndrome,it is still very difficult to achieve a clear distinction in the early stage of the disease.In addition,neuromelanin and iron content in the substantia nigra vary with age over the life span of a normal population,and individual aging is accompanied by neurodegenerative changes,so a comprehensive understanding of neuromelanin and iron deposition changes in subregions of the substantia nigra associated with aging in healthy individuals is important for the study of neurodegenerative diseases.Therefore,this study will focus on the distribution of neuromelanin and iron deposition in the substantia nigra,delineate the subregions of the substantia nigra based on the distribution of neuromelanin and iron deposition,and focus on the overlap region to investigate aging,early PD and early parkinsonisms in normal population.In recent years,the emerging technology of 3 dimensional multi-echo magnetization transfer contrast neuromelanin-sensitive sequence(3D ME-MTC-NM)combines the multiecho technique with the magnetization transfer technique,which can combine the first ultrashort echo time(TE)echo in a short scan to obtain neuromelanin images and quantitative susceptibility mapping at the same time,which can solve the problem of intolerance of long scan time in patients with movement disorders,and avoid the errors caused by spatial alignment in multi-series studies.The neuromelanin signal can indirectly reflect the content of dopaminergic neurons in the SNpc to understand its physiological changes and the degree of pathological apoptosis;the quantitative susceptibility mapping can quantitatively detect the iron content in the substantia nigra.Therefore,this study is divided into three parts to investigate(1)the regional age-related changes of neuromelanin and iron in the substantia nigra in normal population,(2)the regional changes of neuromelanin and iron in the substantia nigra of early Parkinson’s disease and(3)the differences of neuromelanin and iron deposition changes in the substantia nigra subregions among early parkinsonisms by 3D MEMTC-NM sequence,respectively.Part 1 Regional age-related changes of neuromelanin and iron in the substantia nigra based on neuromelanin accumulation and iron deposition in normal populationBackground and purpose:To investigate age-related neuromelanin signal variation and iron content changes in the subregions of substantia nigra(SN)using magnetization transfer contrast neuromelanin-sensitive multi-echo sequence in a normal population.Methods:In this prospective study,115 healthy volunteers between 20 and 86 years of age were recruited and scanned using 3.0-T MRI.We manually delineated neuromelanin accumulation and iron deposition regions in neuromelanin image and quantitative susceptibility mapping,respectively.We calculated the overlap region using the two measurements mentioned above.Partial correlation analysis was used to evaluate the correlations between volume,contrast ratio(CR),susceptibility of three subregions of SN,and age.Curve estimation models were used to find the best regression model.Results:CR increased with age(r=0.379,P<0.001;r=0.371,P<0.001),while volume showed an age-related decline(r=-0.559,P<0.001;r=-0.410,P<0.001)in the neuromelanin accumulation and overlap regions.Cubic polynomial regression analysis found a small increase in neuromelanin accumulation volume with age until 34,followed by a significant decrease until the 80 s(R2=0.358,P<0.001).No significant correlations were found between susceptibility and age in any subregion.No correlation was found between CR and susceptibility in the overlap region.Conclusions:Our results indicated that CR increased with age,while volume showed an age-related decline in the overlap region.We further found that the neuromelanin accumulation region volume increased until the 30 s and decreased into the 80 s.This study may provide a reference for future neurodegenerative elucidations of substantia nigra.Part 2 Regional changes of neuromelanin and iron in the substantia nigra of early Parkinson’s diseaseObjective:To investigate the changes of neuromelanin and iron in the substantia nigra subregion of early Parkinson’s disease(PD).Materials and Methods:In this prospective study,3D ME-MTC-NM sequence was performed in 30 patients with early PD(patient group)and age-sex matched 70 healthy volunteers(control group).Manual outlining and arithmetic methods were used to obtain neuromelanin accumulation,iron deposition and overlap regions.Using analysis of covariance,age was used as a covariate to compare the differences in volume,contrast ratio(CR)and/or susceptibility of the three sub-regions(neuromelanin accumulation iron deposition and overlap regions)in early PD and healthy controls,and the receivee operating characteristic curve(ROC curve)was used to evaluate the diagnostic efficacy of each measured parameter.The diagnostic efficacy of each measurement parameter was evaluated using the receiver operating characteristic curve(ROC curve),and the area under curve(AUC)was compared to determine the measurement index with optimal diagnostic efficacy.Results:There was no significant difference in age(62.133±10.338 years,59.914±9.226 years,P=0.29)and sex distribution(P=0.664)between early PD group and healthy control group.The volume(271.613±61.854mm3,303.980±47.229 mm3,P=0.023)and contrast ratio(0.060±0.034,0.123±0.038,P<0.001)of neuromelanin accumulation regions in early PD patients were significantly lower than those in healthy controls;the susceptibility in iron deposition regions was higher than that in healthy controls(0.090±0.019,0.081±0.016,P=0.023).The volume and contrast ratio of overlap regions were significantly lower in early PD patients than in normal controls(155.881±47.039 mm3,176.671±3 7.367 mm3,P=0.047;0.063±0.034,0.1331±0.040,P<0.001),while susceptibility was higher than in normal controls(0.100±0.020,0.091±0.017,P=0.029).The volume(P=0.042),contrast ratio(P<0.001)of neuromelanin accumulation regions and contrast ratio(P<0.001)of overlap regions could diagnosed early PD from control group,with area under the curve AUCs of 0.650,0.898,and 0.920,respectively.Of these,the area under the curve for the contrast ratio in the overlap regions was significantly higher than the area under the curve for the contrast ratio in the neuromelanin accumulation regions(0.920,0.898,P=0.018).Conclusion:The volume and contrast ratio in the neuromelanin accumulation regions in early PD were reduced,and the of the iron deposition regions was increased.The volume and contrast ratio of the overlap regions were reduced and the susceptibility was increased.In addition,the contrast ratio of the overlap region showed higher diagnostic efficacy in the diagnosis of early PD,suggesting that the reduced contrast ratio of the overlap regions may be a sign of early nigrostriatal degeneration in PD.Part 3.A preliminary study on the differences in regional changes of neuromelanin and iron in substantia nigra among early parkinsonismsObjective:To investigate the difference of neuromelanin and iron changes in the substantia nigra subregion of early atypical parkinsonism by magnetization transfer multi-echo sequence.Materials and Methods:This prospective study included 30 patients with early Parkinson ’s disease,18 patients with progressive supranuclear palsy,and 17 patients with multiple system atrophy who underwent 3-dimensional multi-echo magnetization transfer contrast neuromelanin-sensitive sequence data collection from June 2020 to December 2022.Manual outlining and arithmetic methods were used to obtain neuromelanin accumulation,iron deposition and overlap regions.Covariance analysis was used to compare the differences in volume,contrast ratio,and/or susceptibility among the three regions of interest in early Parkinson ’s disease,progressive supranuclear palsy,and multiple system atrophy.According to the dyskinesia side,the subregions were divided into contralateral side and ipsilateral side.Covariance analysis was used to compare the differences of neuromelanin and iron changes in the three subregions of the contralateral side and ipsilateral side in the three groups of early parkinsonism,and pairwise comparison was performed between the three groups.Results:After multi-comparison correction by false discovery rate(FDR),there was difference in the susceptibility of the overlap regions between the early PD,PSP and MSA groups(P=0.035).In the pairwise comparison between groups,the susceptibility of the overlap regions in the early PSP group was significantly higher than that in the early PD group(0.104±0.0220 ppm,0.100±0.020 ppm,P=0.016)and the early MSA group(0.104±0.0220ppm,0.098±0.019ppm,P=0.022).Comparison of the affected contralateral subregion revealed that the susceptibility in the overlap regions differed between the three groups(P=0.038).Comparison of the affected ipsilateral subregion revealed a trend in the difference in volume of the neuromelanin accumulation regions and the susceptibility of the overlap regions between the three groups,while the difference was not statistically significant after FDR correction.Conclusion:The susceptibility of the overlap regions was elevated in early PSP compared with early PD and MSA,while no significant difference was seen between PD and MSA.The alteration of the overlap regions may be helpful to identify characteristic changes in parkinsonisms and needs to be further validated in future studies with large samples. |
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