A Multimodal MR Imaging Study Of Early-onset And Late-onse Parkinson's Disease

BackgroundParkinson's disease(PD)is a chronic neurodegenerative disorder with onset usually between 50 and 75 years of age,with an average age of 60 years.However,there is a subgroup of PD,early-onset Parkinson's disease(EOPD),in which patients present with a parkinsonian syndrome before the age of 50 years.The clinical evolution and characteristics of EOPD are somewhat different from those of late-onset Parkinson's disease(LOPD).For example,compared with LOPD,EOPD patients tend to have a slower disease progression(particularly with regard to falls,freezing and gait disturbances)and later development of cognitive impairment,but often have greater incidences of motor complications(such as dyskinesias,dystonia and motor fluctuations).Moreo-ver,despite the slower disease progression,EOPD patients often suffer from a poorer quality of life,with significantly higher depression scores than those of LOPD patients with similar disease severity.In recent years,neuroimaging technology has been increasingly used in EOPD and LOPD patients.The results of dopaminergic tracing on the synaptic layer of the nigra-striatal areas in EOPD and LOPD patients were contradictory,but they still provided brain clues for the clinical heterogeneity of these two types of patients.However,these radionuclide imaging studies were mostly confined to the substantia nigra or striatal nucleus imaging,ignoring the other parts of the brain structural and functional changes in the impact of the disease.Magnetic resonance imaging(MRI)can provide the information of the whole brain,and there have been already some of the literature on the use of this technique to EOPD and LOPD patients.These studies found that the EOPD and LOPD patients may have different changes of brain gray matter volume and functional connectivity,and different patterns of iron deposition.The results suggest possible different structural,functional and metabolic differences in this two types of patients,which may not only exist in the midbrain and basal ganglia,but also be widely present in the cortical tissues.Additionally,MRI is an efficient technique to detected these differences.Cerebellum is thought to be related with the motor and non-motor symptoms in PD patients and the hyperactivity of cerebellum may be compensated for the dopaminergic dysfunction in the basal ganglia.The probable pathological and compensatory effects of the cerebellum make it an important target for studying PD patients.In our study,the brain iron deposition,structure,especially the cerebellar structure,as well as resting state functional connectivity will be detected in EOPD and LOPD patients,using multimodal magnetic resonance imaging,to explore the brain iron metabolism,structural and functional differences and their clinical relevance in this two types of patients.Material and MethodsExperiment 1.Thirty-five EOPD patients and 24 matched young controls,33 LOPD patients and 22 matched older controls were recruited in the study.The iron content in the deep grey matter nuclei in the basal ganglia and midbrain(including bilateral globus pallidus,head of caudate nucleus,putamen,substantia nigra pars compacta and substantia nigra pars reticulata,red nucleus)were measured,using quantitative susceptibility mapping technique.Then the iron content was compared between patients and their corresponding controls.The correlations of regional iron content and clinical features were explored in patient groups.Experiment 2.We recruited two groups of patients(28 EOPD patients and 37 LOPD patients),and two age-and sex-matched control groups(23 controls in each group).The voxel-based morphometry(VBM)technique was used to examine changes in gray matter(GM)density of the whole brain,between patients and their corresponding controls.The correlations of regional GM density changes and their clinical revelance were explored in patient groups.Experiment 3.Thirty-one EOPD patients and 37 LOPD patients,and two age-and sex-matched control groups(23 controls in each group)were recruited in the study.The T1 image was isolated using the SUIT toolbox in SPM8 and segmentation maps were generated.GM images were normalized to the SUIT template,and then re-sliced the segmentation map into the SUIT atlas space.Finally,the GM probability images were smoothed with an 6-mm full-width half maximum(FWHM)Gaussian kernel.Global cerebellum measures were also estimated.The inter-group differences was detected using a two-sample t test.Age,sex and global cerebellum volume were used as the covariates.The correlations of regional cerebellar GM volume changes and their clinical revelance were explored in patient groups.Experiment 4.Twenty-nine EOPD patients and 22 matched young controls,33 LOPD patients and 23 matched older controls were recruited in the study.The clinical evaluations and MRI scans for the patients were performed in the OFF-state.The preprocessing of functional image was conducted by using Data Processing Assistant for Resting-State fMRI.Preprocessed images were analyzed with Group ICA/IVA of fMRI Toolbox using a temporal-concatenation spatial independent component analysis approach.In this step,temporally and spatially coherent patterns of signal variation were extracted from functional images with a predetermined dimensionality of 24.The Dorsal attention network and Default mode network were extracted from the 24 components as Smith et al.reported.To detect the inter-group differences of functional connectivity,two-sample t tests were performed between patients and their respective controls,adjusted for age and sex.The correlations of functional connectivity changes and their clinical revelance were explored in patient groups.ResultsExperiment 1.Both LOPD and EOPD patients showed increased iron content in the substantia nigra pars compacta(EOPD P =0.004;LOPD P =0.002)and substantia nigra pars reticulata(EOPD P =0.009;LOPD P =0.032).Increased iron content in the putamen(P=0.020)was only observed in LOPD patients.The relationship between theincreased iron content and disease severity(H&Y stages,UPDRS ? scores and UPDRS III scores)was observed in LOPD patients,but not in EOPD patients.Experiment 2.Compared with controls,EOPD patients had lower GM density in the left putamen,inferior frontal gyrus insula and brainstem,and higher GM density in the right occipital lobe and bilateral cerebellum posterior lobes.LOPD patients had lower GM density in the left cerebellum posterior lobe,occipital lobe,brainstem,and right supplementary motor area(SMA),and higher GM density in the left middle temporal gyrus.Correlation analyses showed that GM density values in the right cerebellum posterior lobe negatively correlated with the GM density in the brainstem in EOPD patients(P=0.029,r=-0.428).Experiment 3.At the threshold of PFDR<0.05,no region with significantly different cerebellar GM volume was found between the LOPD and their respective controls.Compared with the young controls,the EOPD patients showed reduced cerebellar GM volume in bilateral dental nucleus,and increased cerebellar GM volume in bilateral hemisphere ?b,?a,and Crus?.Moreover,the increased GM volume in the right hemisphere ?b,?a were positively correlated with duration,UPDRS scores and HAMD scores.Experiment 4.Compared with the corresponding controls,EOPD showed decreased functional connectivity in the left parietal region,and LOPD showed decreased functional connectivity in right frontal lobe and left posterior cerebellum,in DAN network.In DMN network,EOPD patients showed decreased functional connectivity in bilateral precuneus/posterior cingulate cortex,LOPD patients showed decreased functional connectivity in inbilateral dorsal medial prefrontal cortex.There was no statistically significant correlation between DAN and DMN dysfunction and the clinical scores.However,the region with decreased functional connectivity in DAN was positively correlated with the region with decreased functional connectivity in DMN in EOPD patients.ConclusionIn summary,our study suggested that:1.The iron deposition and brain structure pattern were greatly influenced by the onset-age of PD.2.The role of the cerebellum in EOPD and LOPD patients may be different:not only played a role in pathological process in both types of patients,but also may play an important role in the compensatory effect in EOPD patients,which may meanwhile contribute to the motor complications in EOPD patients.3.EOPD and LOPD patients both had nodes with reduced functional connectivity in DMN and DAN.But the nodes found in EOPD patients were the key nodes of the networks,suggesting that the function of the DAN and DMN may be impaired more severe in EOPD than LOPD patients.At the same time,in patients with EOPD,the reduced functional connectivities in DAN and DMN key nodes were positively correlated,and we speculated that this may reflect the overall brain functional level decrease in the resting state in this type of patients,but the speculation needed further confirmation.All in all,our findings in this study may increase the understanding of the different pathological underpinnings of EOPD and LOPD patients.