The Effects Of Striatal Silent Infarction On The Substantia Nigra And Motor Impairments In Patients With Parkinson’s Disease

Parkinson’s disease (PD) is a neurodegenerative disease and commonly occurs in aged people.There is a selective loss of dopaminergic neurons in the substantia nigra (SN) at the point of clinical expression of PD, which results in impaired motor function, and mainly includes static tremor, muscle rigidity, bradykinesia, and loss of balance. These symptoms gradually progress with time and eventually become irreversible, which seriously affects the quality of life in patients with PD. In recent years, the incidence of PD has been on the rise. Most patients are not diagnosed in the early stage, thus the optimal time to treat is lost. PD not only seriously affects the quality of life, but also brings the family pain and a significant economic burden as the disease progresses. For the purpose of effective control of PD, it is important to diagnose and evaluate the severity of PD as soon as possible. A study has shown that the loss of dopaminergic neurons in the SN is more apparent with the aggravation of symptoms in PD patients.Although PD is a degenerative disease, many researchers believe that vascular factors play an important role in its progression. As most PD patients are older than 50 years and have one or more risk factors for cerebrovascular disease, they are prone to asymptomatic intracranial small vessel occlusion, namely silent lacunar infarction (SLI), of which striatal silent lacunar infarction (SSLI), located in the basal ganglia, is most common.There is a close connection between the striatum and the SN, which constitute the striato-nigral loop to coordinate movement of the human body. It is speculated that once lesions occur in the striatum, the connection is destroyed resulting in abnormal function of the SN. In view of this hypothesis, many studies have shown that striatal symptomatic infarctions can be secondary to damage to the SN in animals and humans. However, it is unclear if SSLI is associated with changes to the SN, and whether such changes are involved in the progression of PD. Researchers from the University of Manchester established a mild cerebral infarction model in mice similar to SSLI in humans. Based on this model, they found that SSLI could be secondary to neurodegeneration of the SN, which may further promote the progression of PD.But research into the effect of SSLI on structural change to the SN and progression of motor impairmentsin PD patients is still lacking until now.To detect structural changes to the SN in humans, it is necessary to find a safe and sensitive imaging method. Diffusion tensor imaging (DTI) is a non-invasive magnetic resonance imaging (MRI) technique that can accurately and quantitatively detect the structural integrity of intracranial nerve nuclei and fiber bundles. Fractional aninostropy (FA) is one of the important indices of DTI. In recent years, a number of studies have shown that FA in the SN of early-stage PD patients is decreased. Diffusion kurtosis imaging (DKI) is an improved DTI technique, and is more capable of detecting microstructural changes of tissues compared with DTI technique. Mean kurtosis (MK) is a major parameter of DKI. MK values are closely related to gray matter structure. When gray matter structures are more complex, MK values generated from DKI are higher. Studies involving DTI and DKI for PD diagnosis in Taiwan have shown that the MK index has higher diagnostic efficiency than the FA index, indicating that MK values can sensitively reflect structural changes to the SN and meet the requirement of this study.Furthermore, it has been reported that PD-related cell loss occurs mainly in the ventrolateral and caudal segment of the SN. To further clarify which section of the SN in DTI has the most notable lesions with the progression of PD, investigators divided the SN into three sections (rostral, middle, and caudal SN), then analyzed the sections. Some studies have shown that the rostral SN has the most notable lesions, while the other studies showed that caudal SN changes most significantly. It still remains unclear which section should be the focus during an imaging study of the SN. A number of studies involving magnetic resonance diffusion imaging in the SN of PD patients selected the average values of the index in these three sections to analyze. Therefore, the mean values of MK and FA in the rostral, middle, and caudal SN were used as the corrected values for analysis to reduce the errors caused by selection of ROIs in the current study.Therefore, this study was divided to three part. The objective of part Ⅰ were to evaluate the application of FA generated from DTI and MK generated from DKI for the diagnosis and evaluation of PD, and to develop a non-invasive method for detecting structural changes of the SN in human brains with more sensitivity. The purpose of part Ⅱ was to investigate the relationship between SSLI and MK values of SN in early-stage PD patients, to reveal whether SSLI is associated with structural changes to the SN. In part Ⅲ, a 1-year follow-up study was conducted to investigate the effects of SSLI on the SN and progression of motor impairments in patients with PD.Part Ⅰ:Diffusion kurtosis imaging of substantia nigra is a sensitive method for early diagnosis and disease evaluation in Parkinson’s diseaseObjective:To diagnose Parkinson disease (PD) in an early stage and accurately evaluate severity, it is important to develop a sensitive method for detecting structural changes in the substantia nigra (SN).Methods:Seventy-two untreated patients with early PD and 72 healthy controls underwent diffusion tensor and diffusion kurtosis imaging. Regions of interest were drawn in the rostral, middle and caudal SN by two blinded and independent raters. Mean kurtosis (MK) and fractional anisotropy in the SN were compared between the groups. Receiver operating characteristic (ROC) and Spearman correlation analyses were used to compare the diagnostic accuracy and correlate imaging findings with Hoehn-Yahr (H-Y) staging and part Ⅲ of the Unified Parkinson’s Disease Rating Scale (UPDRS Ⅲ).Results:1. There was no significant difference between patients and healthy controls with respect to age [t=0.734, P=0.464] or gender [χ2=0.119, P=0.731].2. Compared with healthy volunteers, FA in the SN was significantly decreased [0.339±0.029 vs. 0.410±0.033,t=13.787, P<0.001] and the MK in the SN was significantly increased [1.065±0.055 vs.0.941±0.041, t=15.400, P<0.001] in the PD group. Unpaired t-tests were performed between two raters for FA and MK in the SN; both t-test results were non-significant. In the assessment of inter-rater reliability between rater 1 and 2, there was strong agreement for FA and MK in the SN. The intra-class correlation coefficient of FA and MK in the SN was 0.780 and 0.838, respectively.3. The AUC was 0.948 for FA in the SN (mean cut-off,0.3805; sensitivity,0.861; specificity, 0.917). The AUC was 0.976 for MK in the SN (mean cut-off,1.0000; sensitivity, 0.944; specificity,0.917). Table 2 and Figure 2 show the sensitivity and specificity of FA and MK for the ROC analysis of the bilateral SN.4. The FA for the SN had no significant correlation with H-Y staging and UPDRS Ⅲ scores (r=0.011,P=0.925 and r=0.035, P=0.774, respectively). In contrast, the MK for the SN had a positive correlation with H-Y staging and UPDRS Ⅲ scores (r=0.585, P<0.001 and r=0.700, P<0.001, respectively).Conclusion:Diffusion kurtosis imaging is a sensitive method for PD diagnosis and severity evaluation. MK in the SN is a potential biomarker for imaging studies of early PD that can be widely used in clinic.Part Ⅱ:Striatal silent lacunar infarction is associated with changes to the substantia nigra in patients with Parkinson’s disease:a diffusion kurtosis imaging studyObjective:A recent study has shown that striatal silent infarction may occur secondary to the degeneration of dopaminergic neurons in the substantia nigra (SN) of mice. However, it is uncertain whether this phenomenon occurs in patients with early-stage Parkinson’s disease (PD) and can be detected by diffuse kurtosis imaging (DKI).Methods:A total of 72 untreated patients with early-stage PD underwent conventional magnetic resonance imaging and DKI. Participants were divided into control and striatal silent lacunar infarction (SSLI) groups. The differences in mean kurtosis (MK) values of the SN, Hoehn-Yahr (H-Y) staging, and Unified Parkinson’s Disease Rating Scale (UPDRS) Ⅲ score between groups were analyzed. Linear regression analysis was used to correlate age, SSLI count, silent lacunar infarction count in other brain areas and age-related white matter change score with MK values of the SN. Spearman correlation coefficient analysis was used to correlate MK values of the SN and SSLI count with H-Y staging and UPDRS Ⅲ score.Results:1. The 72 PD patient cases were divided into two groups:control group, comprising 38 cases (52.78%) and SSLI group, comprising 34 cases (47.22%). MK values of the SN for the SSLI group was significantly higher than that of the control group (t=4.851, P<0.001), with no significant differences in age (t=0.430, P=0.669), gender (χ2=0.019, P=0.891), disease duration (t=0.106, P=0.916), H-Y staging (t=0.883, P=0.380) and UPDRS Ⅲ score (t=0.483, P=0.631) between the two groups.2. SSLI count in the SSLI group was 2.29±0.91. SLI count for other brain areas in the SSLI group (2.71±2.36) was higher than that in the control group (0.79±1.30) (t=4.207, P<0.001). ARWMC score in the SSLI group (5.35±2.74) was higher than that in the control group (3.32±1.65;t=3.769, P<0.001).3. Linear regression analysis (enter method) showed that of the four potentially influential factors of SSLI, SLI count in other brain areas, ARWMC and age, only SSLI (P=0.001) was related to changes in MK values of the SN. The other three factors were independent of change to MK values of the SN (Table 4). A linear regression equation was obtained from further analysis of the effect of SSLI count on MK values of the SN. The results showed that SSLI count (P=0.018) was related to MK values in the SN.4. MK valuesin the SN positively correlated with H-Y staging and UPDRS Ⅲ score (r=0.585, P<0.001 and r=0.700, P<0.001, respectively). In contrast, SSLI count had no significant correlation with H-Y staging and UPDRS Ⅲ score (r=0.140, P=0.240 and r=0.156, P=0.192, respectively).Conclusion:SSLI is associated with structural changes to the SN in patients with early-stage PD, detectable by diffuse kurtosis imaging, and may aggravate their motor impairments.Part Ⅲ:The effects of striatal silent lacunar infarction on the substantia nigra and progression of motor impairments in patients with Parkinson’s disease:a follow-up studyObjective:Our previous study has shown that striatal silent lacunar infarction (SSLI) is associated with structural changes to the substantia nigra (SN), detectable by diffuse kurtosis imaging (DKI). In this study, we conducted a follow-up study to investigate the effects of striatal silent lacunar infarction on the SN and progression of motor impairments in patients with Parkinson’s disease (PD).Methods:A total of 60 untreated patients with early-stage PD were enrolled in this study. The basic data, including age, gender, disease duration and common risk factors of ischemic cerebrovascular disease, were obtained from participants and recorded. At baseline and at 1-year visit, all participants underwent conventional magnetic resonance imaging and DKI twice, and SSLI count, mean kurtosis (MK) value in the SN, Hoehn-Yahr (H-Y) staging, Unified Parkinson’s Disease Rating Scale (UPDRS) Ⅲ score of each subject were also recorded twice. Participants were divided into control and striatal silent lacunar infarction (SSLI) groups. The differences in basic data, MK values of the SN, H-Y staging, UPDRS Ⅲ score and daily dosage of levedopa between groups were analyzed at baseline and at 1-year visit. The differences in variation of these indexes from baseline to 1-year visit betweengroups were also analyzed. Spearman correlation coefficient analysis was used to correlate the variation in MK values of the SN with the variation in H-Y staging and UPDRS Ⅲ score. Logistic regression analysis was used to find the major risk factors for SSLI in patients with PD.Results:1. There was no significant difference in basic data and the severity of disease between two groups at baseline; SSLI count of SSLI group at 1-year visit was not significant different from that at baseline. However, the differences in H-Y staging, UPDRS Ⅲ score, daily dosage of levedopa and MK values of the SN at 1-year visit were significant.2. The variation in MK values of the SN, H-Y staging and UPDRS Ⅲ score were also significant different between groups.3. Moreover, the variation in MK values of the SN had positive correlation with the variation in H-Y staging and in UPDRS Ⅲ score.4. In addition, the results of logistic regression analysis showed that hypertension and hyperhomocysteinemia were independent factors for SSLI in patients with PD.Conclusion:As the progression of disease, motor impairments in patients with PD become more serious with an increase in structural changes to the SN. However, this phenomenon is more prominent in early-stage PD patients with SSLI. Furthermore, PD patients with hypertension and hyperhomocysteinemia are more likely to have SSLI.