Neuromelanin-sensitive Magnetic Resonance Imaging For Diagnosis Of Parkinson’s Disease And Differentiation Of Motor Subtypes

BackgroundParkinson’s disease(PD)is a common progressive neurodegenerative disease.Its incidence is second only to Alzheimer’s disease(AD)and has a rising trend year by year.It is estimated that the prevalence of PD is 1%over the age of 60.Along with the growth of the age,the prevalence of both men and women increased.Motor symptoms of PD are mainly manifested as bradykinesia,rigidity,tremor and postural instability.Symptoms often start from one side of the limbs,gradually involving the contralateral limb.Besides motor symptoms,there are a range of different non motor symptoms(NMS),such as hyposmia,constipation,rapid eye movement sleep behaviour disorder(RBD),depression,cognitive impairment.These NMS can occur before motor symptoms,existing in different stages of PD.The exact etiology of PD is unclear.It is considered as a multifactorial disease,resulting from the effect of genetic susceptibility,environmental factors,aging and life-style and so on.The pathologic changes of PD are characterized by the marked loss of dopamine(DA)neurons in the substantia nigra pars com pacta(SNc)which contains neuromelanin(NM),the formation of Lewy bodies in neurons and severe shortage of DA in caudate nucleus,putamen,globus pallidus,nucleus accumbens and subthalamic nucleus.In the late course of PD,non-dopaminergic changes may also occur in the brain.PD is a heterogeneous neurodegenerative disorder.This heterogeneity is consistent with the existence of motor subtypes,empirically divided into tremor dominant(TD)and non-tremor dominant(NTD,either postural instability gait difficulty or akinetic-rigid)subtypes,and these subtypes are associated with different prognosis.This subtype classification method has got the most extensive research.Rajput and coworkers found that PIGD onset was present in 16%,and TD onset in 49%of all patients autopsied.Some studies have concentrated on the two subtypes of major motor signs,disease duration and patterns of cognitive function,founding that the two subtypes have different rates of disease progression and neuropathological characteristics.Compared to the NTD subtype,TD patients exhibit a more favorable disease course,fewer non-motor symptoms and less cognitive decline.Although the pathological changes observed in the TD patients differ from those observed in the NTD patients,the neural mechanism underlying these disparate presentations is still uncertain.Postmortem autopsy studies have shown that TD patients have milder cell loss in the ventrolateral part of the substantia nigra pars compacta and the locus coeruleus and lower Lewy body deposition in the cortex compared to the NTD subtype.A functional neuroimaging study showed a significant reduction of striatal dopamine and glucose metabolism in the ventral striatum,mainly in the caudate and anterior putamen in NTD patients as disease progressed,while TD patients remained relatively stable.Although the biological function of NM is not very clear,the selective vulnerability of NM neurons in patients with PD suggests the role of NM in neurodegeneration.NM is a dark colored polymeric pigment produced in specific populations of catecholaminergic neurons in the brain.There are three major regions in the brain that contain NM-producing cells:the substantia nigra(SN)of the midbrain,the LC within the pons and the ventrolateral reticular formation and nucleus of the solitary tract in the medulla oblongata.Among them,SNc and LC contain a large number of clusters of pigmented neurons,which in the naked eye under the performance of black and in the pathological section is also easy to identify.However,we can not detect neuronal loss by conventional magnetic resonance imaging(MRI),mainly because MRI can not directly visualize the normal or abnormal SNc and LC.With NM-MRI technology,Sasaki and coworkers performed the first study in which the normal and abnormal LC and SNc have been successfully visualized in 2006.NM has the general characteristics of paramagnetic T1-shortening effects and T1-weighted imaging of the high signal.The signals of LC and SNc are very obvious in healthy controls,while in PD patients are reduced,which is consistent with postmortem neuropathological findings.With NM-MRI,a significant decrease in the signal intensity,area,and volume of the SNc in PD has been detected,with a high diagnostic sensitivity and specificity.However,the loss of NM in SN in patients with PIGD and TD subtypes is not clear.Hitherto,there is no report evaluating the differences between the PD motor subtypes by NM-MRI.Objective:The purpose of the present study is to compare differences in signal attenuation between PD patients and control subjects,and differences between PD motor subtypes with NM-MRI,and to elucidate whether differences between PD patients with two different motor subtypes can be characterized by the underlying SN degeneration based on NM-MRI.Method:Patients with idiopathic PD were prospectively recruited in the Movement Disorder Clinic,having been assessed by a neurologist experienced in the movement disorders according to the UK PD Brain Bank criteria.The Modified Hoehn and Yahr staging scale(H-Y)and the motor part(part III)of the Unified Parkinson’s disease rating scale(UPDRS)were used to assess the severity of illness during an "off" phase(at least 12 h off medicine).PD patients were classified into PIGD(n = 14)and TD groups(n = 9);20 age and sex matched controls were recruited.All images were acquired using a 3.0-T MRI scanner.NM-MRI,Axial T1 and T2-weighted MRI,fluid attenuated inversion recovery MRI,and diffusion weighted images of the whole brain were obtained in all subjects.For quantitative evaluation of the signal intensity of the SNc on the NM-MRI,the regions of interest(ROIs)were measured on a liquid crystal display using round cursors at the following locations:bilateral SNc and the decussation of the superior cerebellar peduncle(SCP)at the section through the inferior edge of the inferior colliculus.The high-signal area of the bilateral SNc was divided into lateral and medial parts.One of the authors performed manual measurements three times using round cursors and the obtained signal intensity values were averaged.Contrast ratio(CR)of the SNc was calculated using the following equations:CR =(SSNC-SSCP)/SSCN wherein SSNC stood for the averaged values of the signal intensity of the bilateral SNc(including lateral and medial parts),and the Sscp represented that of the decussation of SCP.Statistical analysis was performed to determine differences in the CR,age and sex among PIGD,TD,and controls using ANOVA and Bonferroni tests.We used Student’s t-test to compare the CR,disease duration,H-Y stage,and UPDRS between PIGD and TD.To determine the sensitivity and specificity of the NM-MRI for discriminating differences between PIGD and TD,receiver operating characteristic(ROC)analyses were performed;wherein the cut-off values were determined using the Youden index when the area under the ROC curve(AUC)was>0.7.The alpha level for all analyses was 0.05.Results:1.There were 14 patients in the PIGD group,including 8 women(57.1%),6 men(42.9%)with a mean age of(59.8 ± 8.4)years and a duration of disease(3.3 ± 1.7)years,H-Y stage(2.2 ± 0.3),UPDRS(Part III)Score:(30.2 ± 7.7)points;The TD group consisted of 9 patients,including 6 females(66.7%),3 males(33.3%),with a mean age of(58.8 ± 7.7)years,disease duration(3.8±3.4)years,H-Y stage(2.1 ± 0.4),UPDRS(Part III)score:(32.1 ± 9.9)points;The control group consisted of 20 cases,of which 11 cases of women(55.0%),9 cases of men(45.0%).No significant differences were observed in sex and age among the three groups(P = 0.847,0.123,respectively).Moreover,significant differences were also not observed between PIGD and TD patients in disease durations,H-Y stage,and UPDRS(part III)scores(P=0.528,0.206,0.614,respectively).2.Compared to the control group,the signal intensity of both contralateral and ipsilateral SNc to the most clinically affected side on NM-MRI was obviously reduced in PD,especially in the lateral parts.Moreover,the measured CRs of both contralateral and ipsilateral SNc to the most clinically affected side were significantly reduced in the PD group when compared with the controls.However,the CRs of the SNc in PD only showed a trend for greater reduction in the SNc contralateral to the clinically predominantly affected side when compared with the ipsilateral part but not statistically significant(lateral:P = 0.71;medial:P = 0.75).3.A more significant decline was observed in the CRs of the medial part of SNc high signal area of PIGD patients,compared to those of the TD,especially the ipsilateral SNc to the most clinically affected side,while the CRs of the lateral part showed no significant differences between the two subtypes.4.The area under the ROC curve(AUC)of the medial part of ipsilateral SNc and contralateral SNc for differentiating between PIGD and TD were 81%(sensitivity 71.4%,specificity 77.8%)and 77%(sensitivity 78.6%,specificity 66.7%),respectively.ROC analysis indicated that there were no significant differences between contralateral and ipsilateral SNc for differentiating between PIGD and TD(P=0.72).Conclusions:We were able to detect more severe signal attenuation in the medial part of SNc in PIGD patients in comparison with that in the TD group.Also,the medial part of SNc,ipsilateral to the most clinically affected side,showed the highest power to discriminate the PD motor subtypes(AUC,81%;sensitivity,71.4%;specificity,77.8%).Our results indicated a potential diagnostic value of NM-MRI to discriminate the PD motor subtypes,providing new evidence for the neuropathology-based differences between the two subtypes.