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Gray and white matter alterations in different predominant side and type of motor symptom in Parkinson's disease

Abstract Background Parkinson's disease (PD) is highly heterogeneous reflected by different affected side of body and type of motor symptom. We aim to explore clinical characteristics and underlying brain structure alterations in PD with different predominant sides and motor types. Methods We recruited 161 PD patients and 50 healthy controls (HC). Patients were classified into four subtypes according to their predominant side and motor type: left akinetic/rigid‐dominant (LAR), left tremor‐dominant (LTD), right akinetic/rigid‐dominant (RAR), and right tremor‐dominant (RTD). All participants assessed motor and cognitive performances, then underwent T1‐weighted and diffusion tensor imaging scanning. A general linear model was used to compare neuroimaging parameters among five groups. Results Among four PD subtypes, patients of LAR subtype experienced the worst motor impairment, and only this subtype showed worse cognitive performance compared with HC. Compared with HC and other subtypes, LAR subtype showed a significant reduction in cortical thickness of the right caudal‐anterior‐cingulate gyrus and fractional anisotropy of the right cingulum bundle. Conclusions We demonstrated that LAR subtype had the worst clinical performance, which the severer damage in the right cingulate region might be the underlying mechanism. This study underscores the importance of classifying PD subtypes based on both the side and type of motor symptom for clinical intervention and research to optimize behavioral outcomes in the future.


| INTRODUC TI ON
Parkinson's disease (PD) is the second most prevalent neurodegenerative disorder, which is characterized by progressive loss of dopaminergic neurons in the nigrostriatal system and results in motor disturbances, including bradykinesia, rigidity, and resting tremor. [1][2][3] Researches have demonstrated that different types of motor symptoms (generally, akinesia/rigidity-dominant [AR], and tremor-dominant [TD] type) lead to diverse clinical prognoses. [4][5][6][7][8][9] Additionally, PD is often presented as asymmetric motor involvement in the initial course and may last throughout the whole period. 10,11 PD patients with predominant left-side or right-side motor symptoms reflect a degenerative process asymmetrically affecting the two hemispheres may indicate different prognoses either. [12][13][14][15] Preliminary studies suggest that there is an intricate relationship between laterality and type of motor symptoms and the combination of these factors may influence motor progression and cognitive deterioration. [16][17][18][19] Further exploration is worthwhile to discover the complex brain alterations that underlie these differences, which can deepen our perception of the underlying mechanisms corresponding to clinical prognosis.
Numerous studies suggested that patients presenting with TD have a slower motor progression than those with AR type. 4,7,20 As for the non-motor symptoms, the AR type is concerned with a faster rate of cognitive decline and a higher incidence of dementia. 7,21 In addition, the influence of predominant side of motor symptoms also has been reported. Results suggested that PD patients served milder motor impairment on their dominant side. 10,22 Other research reported that patients who favored the right hand but had served motor impairment at the left side were associated with faster symptom progression and worse outcomes in multiple clinical domains. [23][24][25] Interestingly, when concerned about the laterality and type of symptoms concurrently, most studies agreed that PD patients with the right-side tremor showed intact cognition compared with the right-side AR and left-side TD/AR subtypes, 16,19,24 while the left-side AR subtype may have a worse prognosis. 15 Thus, a complex relationship exists between these two factors and may influence the disease progression in turn. Nevertheless, the mechanism behind this remains unclear.
Structural magnetic resonance imaging (MRI) such as T1weighted imaging and diffusion tensor imaging (DTI) have been used to investigate neurodegeneration disease extensively, which provide us with changes in gray and white matters that can help reveal the mechanisms behind different clinical manifestations and outcomes. 26 Various structural MRI modals have applied for exploring potential differences in PD subtypes 27 ; for instance, researches based on T1 imaging showed smaller gray matter particularly in areas involving motor, cognitive, limbic, and associative functions in patients with AR type. 28 Similarly, a few DTI studies have revealed that AR type patients had greater diffusivities and greater reduction in white matter integrity in basal ganglia and out of nigrostriatal tracts. 29,30 On the other hand, studies with regard to laterality of PD suggest that patients with predominant the left-side or right-side motor symptoms may be associated with lateralized gray matter atrophy and white matter damage in the contralateral hemisphere. 31 Nonetheless, scarcely any MRI studies have examined the influence of side and type of motor symptom on the presence of motor and non-motor symptoms in PD so far. Investigations using combined brain imaging modalities may shed light on the alterations of brain structure in PD with different predominant sides and motor types and provide potential avenues for prognosis and intervention of the corresponding PD.

| SUBJEC TS AND ME THODS
This study was in accordance with the approval of the Medical Ethic Committee of Second Affiliated Hospital of Zhejiang University School of Medicine and all patients were informed consent forms.

| Subjects
We recruited 262 right-handed PD patients and 50 right-handed healthy controls (HCs). Subjects in the PD and HC groups were  36,37 Furthermore, patients were grouped into the TD type if the ratio was >1.0 and into the AR type if the ratio was <0.8 based on the ratio of tremor score to akinetic/rigid score. The patients who did not meet the criteria were excluded for they had no laterality and symptom preference (n = 87). Finally, a total of 161 PD patients (including 38 LAR, 32 LTD, 43 RAR, and 48 RTD) and 50 HC were enrolled in this study ( Figure 1).

| MRI data acquisition and processing
All subjects were scanned in a 3.0 Tesla MRI machine (GE Discovery 750) equipped with an 8-channel head coil. During MRI scanning, the heads of subjects were stabilized with restraining foam pads, and the subjects were told to stay still with their eyes closed.

| Structural imaging
Three dimensions T1-weighted images were acquired using a Fast- The T1-weighted images were pre-processed using the default command "recon-all" provided in the FreeSurfer (v6) pipeline (http:// surfer.nmr.mgh.harva rd.edu/). The "recon-all" procedure was used to perform its full reconstruction pipeline, which provided subcortical segmentation and volume measurement, in addition to cortical reconstruction, and measurement of cortical thickness. The preprocessing pipeline involved non-uniform intensity normalization, Talairach transform computation, intensity normalization, skull stripping, subcortical segmentation, intensity normalization (input was the brain volume without the skull), white matter segmentation, tessellation (of the gray and white matter boundary), automatic topology correction, creation of final surfaces (pial and white matter), and parcellation (creation and measurement). 38,39 Finally, the cortical thickness and subcortical volume features

| Statistics analysis
Demographic and clinical variables were analyzed by applying Statistical Product and Service Solutions (version 26.0). The Kolmogorov-Smirnov test was used to determine whether the quantitative variables were normally distributed. Accordingly, quantitative variables with normal distribution were presented as means ± standard deviations (SD) and compared by analysis of variance (ANOVA).
And quantitative variables with nonnormal distribution were presented as medians with ranges and compared by the Kruskal-Wallis test. All qualitative variables were analyzed by using the χ 2 -test. Post hoc analysis was also performed for multiple comparisons.
Statistical analyses for cortical thickness, subcortical volume (divided by total intracranial volume), and diffusion variables (FA and MD) were conducted using MATLAB (R2019a). A general linear model (GLM) with age, gender, and education as covariates was used to compare structural neuroimaging differences among the five groups. In ROI analyses, the false discovery rate (FDR) correction with a threshold at p < 0.05 was used for comparisons across multiple ROIs.

| RE SULTS
Demographic and clinical data for each of the four PD subtypes and HC were presented in Table 1. No significant differences were found in age (p = 0.834) and gender (p = 0.149) among five groups.
And four PD subtypes did not show significantly different disease duration (p = 0.458) and total levodopa equivalent daily dose (LEDD) (p = 0.904). Significant differences were found in UPDRS-total scores (p = 0.004), UPDRS-III scores (p = 0.003) and Hoehn and Yahr stages (p = 0.002) among four PD subtypes, the post hoc analyses showed the scores were higher in the LAR subtype than other PD subtypes.
Significant differences were also found in HAMD (p < 0.001) and HAMA (p = 0.008) scales. The post hoc analyses showed higher scores in four PD subtypes compared with HC, but there were no differences among four PD subtypes. The education was significantly different in five groups (p = 0.043), which post hoc analyses showed the education years were slightly lower in LAR and LTD than RAR subtype. The difference in MMSE was not statistically significant (p = 0.079), although post hoc analyses revealed the LAR subtype performed worse than HC and RAR subtype. Since education was strongly correlated with performance on cognitive measures and was therefore selected as a covariate together with age and gender for the neuroimaging analyses.

| DISCUSS ION
In this study, we found that PD patients characterized by different combinations of predominant-side and predominant-motor type (i.e., LAR, LTD, RAR, and RTD) served diverse severity of both motor and non-motor symptoms. Among all four PD subtypes, patients in LAR subtype had the worst motor manifestations, and only this subtype showed worsened cognitive performance compared with HC. Further brain structure comparison detected this subtype had significantly worse damage in gray and white matter of the right cingulate region, providing structure evidence of their worst symptoms.
Consistent with Riederer and his colleagues' findings summarizing that the LAR subtype had a poorer prognosis, 15 our results demonstrated that patients in this subtype had worst motor impairments relative to other patients, and only them showed decreased cognitive performance relative to HC. The influence of laterality of motor symptoms has been confirmed in previous studies. Primarily, the healthy brain appears to have an asymmetric dopamine distribution, with higher dopamine contents in the left than the right striatum. 42 This neurochemical asymmetry renders the right striatum relatively more vulnerable to the effects of dopaminergic denervation in PD and leads to disorders in the left-side body. 43 Furthermore, they suggested that dominant side had a protective effect due to enhanced exercise which in turn caused better synaptic plasticity in the dominant hemisphere. 31,44 As all patients enrolled in our study were right-handed subjects, which reflected their left hemisphere dominance, they might had better synaptic plasticity in the left hemisphere to overcome the pathological alternation in PD with the right-side motor symptoms. Moreover, more distribution of striatal dopamine in left hemisphere enhanced connections to the cortex to make it more robust in face of damage and therefore followed positive consequences in terms of symptoms. 24 Therefore, we speculated that right-handed patients predominating with the right-side motor symptoms (damage in the left hemisphere) performed milder severity compared with those predominating with left-side (damage in the right hemisphere), just as shown in previous research. 44 In   Effect of motor types should also be noted. Previous studies had confirmed that AR type was related to a more dopaminergic deficiency in nigrostriatal projection pathway compared with TD type. 45,46 Except for it, PD patients with predominant AR symptom have been reported undergoing degenerating across more brain regions. 5,8,47 Both two factors played an important role in worsening performance of PD with predominant AR symptom.
While a few studies did not find significant differences in motor manifestations among PD characterized by different side and type of motor symptoms. [16][17][18][19]48 These might be caused by two factors. First, most of these studies aimed at non-motor features of four PD subtypes, so motor severity across subtypes was con-  In addition, damage in cingulum bundle was a biomarker of mild cognitive impairment in Alzheimer's disease, 58 given the pathologic association of total tau, the LAR subtype might be at risk for developing cognitive impairment. Therefore, early awareness of LAR subtype is critical for prognosis and allows those patients for closer monitoring and management.

| CON CLUS IONS
In summary, our findings suggested that different combinations of laterality and motor types had diverse clinical characteristics; thereinto, LAR subtype had the worst motor and cognitive performance and the severer damage in the right cingulate region might be the underlying basis. This study underscores the importance of classifying PD subtypes based on both the side and type of motor symptom for clinical intervention and research to optimize behavioral outcomes in the future.

CO N FLI C T O F I NTE R E S T
The authors declare no competing interests.

DATA AVA I L A B I L I T Y S TAT E M E N T
The data supporting the findings of this study are available from the corresponding author upon reasonable request. They are not publicly available due to ethical restrictions.