Two clinical subtypes can be distinguished based on the characteristics of PD motor symptoms: the PD-AR dominate and PD-TD dominate. In general, PD-AR patients have an older age of onset and faster disease progression, have a poorer response to dopaminergic medications, are more prone to motor complications, and are at higher risk of cognitive dysfunction than PD-TD patients. In the current study, there is a lot of evidence that there are different patterns of intracranial dopaminergic nerve damage differs in PD patients with different clinical subtypes. Most researchers believe that the motor symptoms of PD patients are closely related to the pathological basis of the degeneration of dopaminergic neurons in the substantia nigra, which leads to the loss of a large number of neurons in the compact part of substantia nigra, and the presence of abnormal iron deposition within the substantia nigra16. At the same time, another theory says that the mutation or aggregation of α-synuclein in neurons to form Lewy bodies is also related to abnormal iron deposition. Rajput et al. 17found that PD patients with different subtypes have different pathophysiological basis. By examining the extent and pattern of dopaminergic neuron loss in the pallidum and striatum in the AR and TD dominates, they found that dopaminergic neurons were significantly lost in the ventral portion of the medial part of the pallidum of the AR type, but dopaminergic neurons in TD dominate was close to normal levels.
At An early stage, Hedi An et al. 18 found that Parkinson’s disease was correlated with iron deposition in the brain, especially in the compact part of substantia nigra7. As the disease progressed to the advanced stage, iron deposition expanded to the substantia nigra pars reticulata. However, after grouping PD into groups, Hedi An found that there were no significant differences in the scores of non-motor symptoms and iron deposition in each region of interest among the three subgroups, which was consistent with Li Jin19,20. However, several studies have shown that iron deposition in the substantia nigra region of PD-AR is higher than that of PD-TD. Fu Xiaodi et al. 21found that iron deposition in substantia nigra, red nucleus and putamen in PD-AR was significantly higher than that in the control group, and the significance level was higher than that in the tremor group. One study used traditional magnetic resonance techniques to measure the R2* values of the transverse relaxation rate of gray matter nuclei in the basal ganglia of patients with different exercise subtypes of PD, and to compare the iron deposition in the substantia nigra, caudate nucleus, putamen and thalamus in patients with different subtypes of PD. It is found that in PD-TD patients, except the substantia nigra region, the R2* value in other regions increases significantly compared with that in the PD-AR region, and more iron deposition in the basal ganglia region, suggesting that differences in iron deposition in these areas may serve as imaging markers to distinguish the two subtypes20. By comparing the differences in the magnetic susceptibility values of various brain regions of interest between the PD group and the control group, we found that the magnetic values of the left compact part of substantia nigra, putamen, caudate nucleus and frontal cortex in the PD group were significantly higher than those in the control group, with statistical significance, and the diagnostic efficacy of the putamen and frontal cortex was higher. Further comparing the magnetic susceptibility values of each area of interest in patients with different subtypes, it was found that the mean magnetic susceptibility values of QSM in PD-AR patients were higher than those of PD-TD. At the same time, the magnetic susceptibility of the substantia had statistical significant, and the specificity of the left substantia nigra pars reticulata was the best.
A study using SWI to evaluate iron content in brain regions showed that22, by detecting abnormal intracranial iron deposition in SNr/SNc of PD-TD and PD-AR patients and iron deposition characteristics of globus pallidus in the brain of PD-AR patients, it could be found that the iron content in GP of PD-AR patients was higher than that of PD-TD patients. Abnormal iron deposition in GP was associated with dyskinesia and stiffness. By constructing a multifactorial prediction model, we found that the compact part of substantia nigra is an independent prognostic factor affecting the stiffness of PD symptoms. In addition, the magnetic susceptibility value of the globus pallidus has good sensitivity and specificity, which indicates that the model has good prediction performance, and can effectively distinguish the rigid dominate from the tremor dominate. We further subdivided the globus pallidus into the medial part of the globus pallidus, the lateral part of the globus pallidus and the dorsal part of the globus pallidus, and finally found that the magnetic values of the medial and dorsal part of the left globus pallidus were significant and could be used for the diagnosis and analysis of different clinical subtypes. As the main target of PD treatment, the medial part of the globus pallidus can greatly improve clinical symptoms through electrode stimulation or pallidotomy23, but its relationship with PD subtypes is not yet well defined.
When the typical symptoms such as static tremor, myotonia, reduced movement and postural reflex disorder appear clinically, they are pathologically in the fourth stage of the Braak scale (middle and late stage). In fact, when Braak grading reaches the third stage, patients first exhibit typical motor symptoms, and pathological changes begin to generate and accumulate in the midbrain, especially causing damage to the compact part of substantia nigra 13. In the fourth stage, while continuously depositing in the substantia nigra region, AS will continue to spread upward along the substantia nigra-striatal pathway as it continues to be deposited in the substantia nigra, appearing in many structures of the basal ganglia and limbic system13. Our study found a significant increase in iron deposition in the left side of compact part of substantia nigra, the nucleus accumbens, and the caudate nucleus compared to controls, which is consistent with the areas of microstructural involvement in the brain at grades 3 and 4 in the Braak classification when typical symptoms are present. As the disease worsens, the lesions can accumulate in the cortex, which is consistent with the increase of iron deposition in the frontal cortex region we measured, and the frontal cortex has a high diagnostic efficacy. Visualization of the impact of variables on the risk of PD onset can be seen that the left frontal cortex has a a huge impact on the prediction of PD onset, even exceeding the globus globus pallidusand substantia nigra.
There are also some shortcomings in this study: the sample size included is not large enough, and the final result is biased to some extent; Due to the limited resolution of the QSM image, there are difficulties in delineating tiny nuclei accurately, which will affect the accuracy of the results to some extent. This study researched QSM technology separately, and failed to analyze it in comparison with the SWI and R2* techniques.
QSM can accurately quantify the changes in iron content in the brain regions of interest in PD patients. Among them, the change of iron content in substantia nigra not only confirms the abnormal distribution of iron in the brain during autopsy, but also are valuable for the monitoring of clinical typing and pathophysiologic studies of different subtypes of PD to a certain extent.