We interrogated a DWI dataset with DTI and HARDI techniques to test whether brain midline microstructure is associated with cognitive function in patients with PD. Our primary findings were, 1) increased FA in the precuneus and the anterior cingulate in the PD-nonMCI participants compared with HV, which was not observed in PD-MCI participants; 2) precuneus FA was associated with executive and memory function, respectively, in PD and HV; 3) midline structure FA was negatively correlated with age in PD, but not in HV; and 4) the AFD index of the posterior cingulate-precuneus bundles were differentially associated with cognitive scores in HV and PD.
To our knowledge, this is the first study showing increased FA in the midline structure (the cingulate gyrus) in PD-nonMCI patients, compared with HV. FA in DTI is the most robust metric for quantifying diffusion anisotropy 50,51. Increased FA can reflect diminished axonal branching, increased axonal myelination 52, or axonal sprouting 53. Functional neuroimaging studies have repeatedly shown increased activity in the midline structure in PD patients vs. controls. This over-activation has been reported in the medial prefrontal cortex 18,19 and precuneus 21,25 while performing motor and cognitive tasks. During cognitive tasks, reduced deactivation in the default mode network, including the anterior and posterior midline structure, has also been reported in PD patients 54–56. This might include a dopamine component, and upregulation of dopaminergic projections in the anterior cingulate cortex are associated with PD motor dysfunction 14. These features appear to change as the disease progresses, and a longitudinal study showed greater activation in the midline structure at the second time compared to the first time in PD with and without mild cognitive impairment (Nagano-Saito et al, 2016). Increased hub function in PD-nonMCI has also been observed in the posterior part of the midline structure 27. Our present findings regarding the FA change, together with these previous studies, possibly reflects increased axonal packing or sprouting, rather than diminished axonal branching, in the midline structure of the PD-nonMCI patients.
Mean diffusivity (MD) represents the average diffusivity of the component and provides a generalized measure of diffusivity in the area, and is nonspecific with respect to the directionality of the diffusion process 57. Increased MD has been reported in disease-related neurodegeneration 58,59, and is thought to reflect decreases in membrane density due to cell degeneration 60. We observed increased precuneus MD but not decreased precuneus FA, in the PD-MCI, compared with PD-nonMCI (Fig. 4). In addition to dysfunction of the cognitive cortico-basal ganglia-thalamocortical circuit in PD patients 7–10, the cognitive deficits in PD patients are also originating from cortical Lewy Body/alpha-synuclein deposits that can occur in posterior regions of the brain 61. We speculate that the possible increased axonal packing or sprouting speculated in PD-nonMCI is not preserved in PD-MCI because of the increased neurodegeneration occurring in the latter group.
Correlation analyses with the cognitive Z-scores yielded statistically significant associations only in the precuneus FA. In the HV group, RAVLT Z-scores was positively correlated with the FA, whereas in the PD group, Brixton Z-scores was positively correlated with FA (Tables 1, Fig. 3). This would indicate that the precuneus cognitive contribution has a bigger effect on memory in HV, and a bigger effect on executive function in PD. Supporting this interpretation, there is evidence that the precuneus is involved in memory retrieval in HV 62. This observation may indicate that the possible increased axonal packing or sprouting in midline regions in PD-nonMCI patients compensates for executive dysfunction resulting from the impairment of the cortico-basal ganglia-thalamocortical circuits in PD, as we have previously proposed based on resting state fMRI data 27.
Although FA and MD are robust metrics for quantifying diffusion anisotropy, they do not provide information about streamlines passing the ROIs. They are voxel averages. This is why the AFD 47,48 were calculated. AFD indicates relative white matter fibre density per unit volume of tissue and we computed total AFD of associated streamlines belonging to specific bundles, normalized by the mean streamline length 47,63,64. Based on the results of group comparisons of FA and MD, we were most interested in the bundle of the PCG-Precuneus and Precuneus-PHG, which included the precuneus ROI in Fig. 1-a. While significant differences in AFD index were not observed in PD-nonMCI compared with HV in those bundles (Fig. 4), significant correlation of the Precuneus-FA was only observed with the PCG-Precuneus AFD index (r = 0.64, p = 0.0070, in HV; r = 0.39, p = 0.015 in PD, respectively), and not with other bundles AFD index (Supplementary Table 3).
There were significant differences of correlation patterns between the HV and PD, for PCG-Precuneus AFD index and age, and AFD index and RAVLT Z-scores (Fig. 5). In the HV, significant positive correlation with age, marginally negative correlation with the Brixton Z-scores, and marginal positive correlation with the RAVLT Z-scores with AFD index were observed, whereas in PD patients, negative correlation with the RAVLT Z-scores occurred. We propose that the PCG-Precuneus bundle, which are important for HV to support memory, is used for supporting executive function in PD, but that reorganization of other bundles also could support cognitive function, resulting in the positive correlation between Precuneus FA and Brixton scores in PD.
We have previously shown that the dopamine in the postmedial cortex including the precuneus has an important role for network regulation 65. The location of the PCG-Precuneus bundle seems to follow the D2/3 dopamine receptors distribution in the midline of our previous positron emission tomography study 65. Therefore, we compared the location of the six bundles of our present study to the D2/3 receptor distribution from our previous study, and the PCG-Precuneus bundle overlapped significantly with the D2/D3 distribution (Supplementary Fig. 1). Although all of the neurotransmitters associated with this possible compensation are unknown, we propose that dopamine in the postmedial cortex might at least partially contribute to this.
In HV, marginally positive correlations between the Precuneus FA and age, and significantly positive correlation between PCG-Precuneus AFD index and age, were observed (Table 1). To our knowledge, significant positive correlation between the posterior part of the midline microstructure and age in HV has not been reported. FA decreases in most part of the brain with age; however, in some specific regions, FA increases with age 66. The microstructure in the cingulum shows relative preservation with age 67. Thus, microstructure measurements for specific regions and their corresponding bundles may show positive correlations with age. More studies are required to investigate this finding further. Contrary to the HV group, we observed a strong negative correlation between the FA in the midline structure and age in PD patients (Table 1). With AFD, the Precuneus-Cross bundle, connecting the left and right hemisphere via corpus callosum, showed a significantly negative correlation with age in PD patients (Table 1, Fig. 5). Moreover, the positive correlation observed between the PCG-Precuneus bundle and age in HV disappeared in PD patients, and when the correlation rate in HV and in PD was compared, a significant difference was observed (p = 0.015). We hypothesize that the midline structure upregulates its hub function for cognition in PD patients 27, as long as the compensation potential is preserved.
This compensation process would start during the prodromal phase, which occurs at least a few years beforehand 3,5, accompanied by axonal packing or sprouting. A previous study indicated that early-stage PD patients (Hoehn and Yahr 1) showed increased white matter density of the corpus callosum, compared with HV and compared with more advanced stage PD patients (Hoehn and Yahr 2) 38, in accordance with our present results. At the time of disease onset, the compensation could occur in a limited fashion, resulting in the negative correlation between precuneus FA and age.
The proposed compensation mechanism in the prodromal phase, possibly associated with motor dysfunction, would be supported by reorganization in the posterior part of the brain prevalently, through the midline structure. This may explain why FA in the precuneus, but not the AFD index of PCG-Precuneus bundle, reached statistical significance when comparing HV and PD-nonMCI. Finally, although the present observations support and extend previous findings, DWI acquisition b-values were relatively low and the sample sizes were modest, underscoring the need for replication.
Using DWI data with DTI and HARDI techniques in HV and PD patients, we observed increased FA in the precuneus in PD-nonMCI but not in PD-MCI compared with HV, and change of association between AFD of the posterior midline structure and cognition. In accordance with our previous studies (Nagano-Saito et al., 2016, 2019), we propose that the posterior medial structure is overrecruited, plausibly reorganizing parts of the memory-related diffusion microstructures into executive function-related ones, in PD-nonMCI patients, to possibly compensate for damaged basal ganglia function.