Synopsis

Keywords: Blood vessels, Brain

Increasing evidence showed that vascular changes might be involved in Parkinson's disease. However, the altered markers of neurovascular unit and cerebral vessels that serve as blood flow adaptors, remain unclear in early stage of de novo PD. In this study, we aimed to investigate regional cerebral blood flow (CBF), cerebrovascular reactivity (CVR) and artery morphological changes in de novo PD patients including cognitive impairment (PD-MCI) and normal cognition (PD-NC). Our data revealed that in the patient group, CVR was significantly reduced in left superior occipital gyrus, whose feeding arteries were dilated, but there was no significant change in CBF.

Introduction

Parkinson’s disease (PD) is a common progressive neurodegenerative disease. There is a growing appreciation that vascular alterations can contribute to disease onset and aggravate the neurodegenerative process¹. Although cerebral blood flow (CBF) alternation has been reported in patients with PD, these results remain controversial. The discrepancy may be partly due to individual differences in recruited subjects, with varied disease duration and medication. In addition to CBF, other vascular related parameters including cerebrovascular reactivity (CVR) which is partly representative of neurovascular unit (NVU) integrity, and cerebrovascular morphologies are also important in reflecting vascular functions, however are rarely studied in the early stage of PD. Thus, the aim of this study is to investigate the patterns of CVR, CBF and cerebral arteries alterations in the early drug-naïve PD patients with different cognitive status using multimodal MRI.

Materials and methods

Subjects
We recruited 46 de novo PD patients and 49 age and gender matched healthy control subjects (HCs). PD-MCI (n=12) was diagnosed according to the level 2 criteria recommended by the MDS Task Force². PD patients who did not meet the criteria for PD-MCI were classified as PD-NC (n=34).

Image acquisition
All MR data were acquired using a 3-Tesla MR unit (Discovery™ MR750, GE Healthcare, Milwaukee, WI). Resting-state BOLD images were acquired as follows: TR=2000ms,TE=30ms,flip angle=90°, FOV=24cm,matrix=64×64,number of slices=34,slice thickness=4.0mm,number of dynamic scans=210. ASL images were acquired using a 3D pCASL sequence: TR=4830ms;TE=10.5ms;labeling-duration=1500ms;post-labeling delay=2025ms;NEX=3;flip angle=155°. A 3D multi-echo GRE sequence was used to acquire QSM: TR=51.5ms;number of echoes=16;first-TE=2.9ms;TE-spacing=3ms;flip angle=12°; FOV=22cm;matrix = 220×220;acceleration factor=2.

Image processing
As shown in Figure-1A, the CBF maps were directly calculated according to PCASL one-compartment model³. The CVR and FC maps were generated from resting-state BOLD images. For CVR measures, after motion correction, smoothing, and linear detrending, the BOLD data were temporally filtered with a band-pass filter of 0.01 to 0.1Hz. And then the voxel-wise regression analysis was performed to generate a CVR index map, in which the whole brain signal was treated as an independent variable in this general linear model⁴. For FC analysis, the cluster results of one-way ANOVA in CVR, left superior occipital gyrus, were selected as the seed, and the FC was measured by a Pearson correlation between the seed and each voxel time courses.

Arterial morphology
The QSM magnitude images were used to measure arterial morphology. As shown in Figure-1B, vessel segmentation was performed on the first-echo magnitude image using self-developed routines based on a specialized software MeVisLab (Mevis, Germany). All segmentation results were visually checked and corrected manually by two neurologists who have over 5 years’ experience with neuroimaging interpretation. Finally, vessel centerlines and morphological parameters (Table-1), were extracted using Mimics Medical 21.0 software (Materialize NV, Leuven, Belgium).

Results

As shown in Figure-2A, one-way ANOVA revealed that the CVR of the left superior occipital gyrus (SOG) was significant different among three groups. The CVR in the same region of PD-MCI and PD-NC group were significantly lower than those in controls (Figure-2B), while no significant differences were found between PD-MCI and PD-NC group. Importantly, PD patients either with MCI or normal cognition showed no significant CBF differences than that of HCs. Even more, significant difference of functional connectivity between left SOG and cerebellum, right precuneus, right temporal inferior, right midcingulate, left inferior parietal and left precentral gyrus was showed among PD-MCI, PD-NC and HCs (Figure-3).
As shown in Figure-4 and Table-1, the radius of RMCA-M1, LMCA-M1 and LPCA-P2 were significantly different among three groups, and there was a significant dilation in the patient groups. In addition, the arterial territory template was used to divide the territories of LPCA into three parts: proximal, middle and distal. The significant CVR differences were only identified in the territories of distal-LPCA, with a tendency to decrease in the PD-MCI and PD-NC group.

Discussion and Conclusion

In this study, we revealed that the CVR of left SOG in PD-MCI and PD-NC patients were significantly lower than that of the HCs, while no significant CBF changes were observed among these three groups, suggesting that microvascular dysfunction rather than perfusion defect might be involved in the early PD. The CVR alteration occurred prior to CBF changes, which can be served as an early biomarker of PD. In addition, FC changes between the left SOG and widespread brain regions were observed among the three groups. This finding implies that NVU disfunction may be partly induced by weakened neural circuits in PD. Furthermore, some arteries were dilated in PD-MCI and PD-NC compared to HCs, indicating an adaptive process to compensate for impaired microvascular function. Also of note, significant CVR differences were identified in the territories of distal-LPCA, which further confirmed the structure-function relationship. Finally, we pointed out that there were no significant changes in CBF, CVR and arterial radius between PD-MCI and PD-NC group. The disease, rather than cognitive status might be correlated with vascular changes in early PD. However, our results might be bias by the relatively small sample size. In the future, larger multicenter studies may help confirm the current findings. In conclusion, our results contribute to a better understanding of the relationship between NVU integrity, cerebral artery morphology and arterial territory perfusion in de novo early PD.

Acknowledgements

This work was supported by the National Natural Science Foundation of China (No. 81971583), National Key R&D Program of China (No. 2018YFC1312900), Shanghai Natural Science Foundation (No. 20ZR1406400), Shanghai Municipal Science and Technology Major Project (No.2017SHZDZX01, No.2018SHZDZX01) and ZJLab, Young and Middle-aged Health Talents Training Project of Fujian Province (No. 2020GGB059).

References

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