Neurocognitive and psychiatric disorders-related axonal degeneration in Parkinson's disease

Abstract

Neurocognitive and psychiatric disorders have significant consequences for quality of life in patients with Parkinson's disease (PD). In the current study, we evaluated microstructural white matter (WM) alterations associated with neurocognitive and psychiatric disorders in PD using neurite orientation dispersion and density imaging (NODDI) and linked independent component analysis (LICA). The indices of NODDI were compared between 20 and 19 patients with PD with and without neurocognitive and psychiatric disorders, respectively, and 25 healthy controls using tract-based spatial statistics and tract-of-interest analyses. LICA was applied to model inter-subject variability across measures. A widespread reduction in axonal density (indexed by intracellular volume fraction [ICVF]) was demonstrated in PD patients with and without neurocognitive and psychiatric disorders, as compared with healthy controls. Compared with patients without neurocognitive and psychiatric disorders, patients with neurocognitive and psychiatric disorders exhibited more extensive (posterior predominant) decreases in axonal density. Using LICA, ICVF demonstrated the highest contribution (59% weight) to the main effects of diagnosis that reflected widespread decreases in axonal density. These findings suggest that axonal loss is a major factor underlying WM pathology related to neurocognitive and psychiatric disorders in PD, whereas patients with neurocognitive and psychiatric disorders had broader axonal pathology, as compared with those without. LICA suggested that the ICVF can be used as a useful biomarker of microstructural changes in the WM related to neurocognitive and psychiatric disorders in PD.

Keywords: Parkinson's disease; axons; biomarkers; diffusion tensor imaging; linked independent component analysis; neurite orientation dispersion and density imaging.

Figure 1

Comparison of DTI (FA, MD, AD, and RD) and NODDI (ICVF) measures among the healthy control, PD‐woNCPs and PD‐wNCPs groups. Using TBSS analysis, significantly lower FA and ICVF (blue–light blue) and significantly higher MD and RD (red–yellow) values were observed in the PD‐woNCPs group compared with the healthy controls. Compared with the healthy controls, the PD‐wNCPs group had significantly lower FA and ICVF and higher MD, RD, and AD values. Compared with the PD‐woNCPs group, the PD‐wNCPs group had significantly lower ICVF and higher MD, RD, and AD values. There were no significant differences in ODI values between the groups. The FA skeleton with FA > 0.2 is shown in green. To aid visualization, results are thickened using the fill script implemented in FMRIB Software Library. Abbreviations: DTI, diffusion tensor imaging; FA, fractional anisotropy; HC, healthy control; ICVF, intracellular volume fraction; MD, mean diffusivity; NODDI, neurite orientation dispersion and imaging; ODI, orientation dispersion index; PD‐woNCPs, Parkinson's disease without neurocognitive–psychiatric symptoms; PD‐wNCPs, Parkinson's disease with neurocognitive and psychiatric symptoms; RD, radial diffusivity [Color figure can be viewed at https://wileyonlinelibrary.com]

Figure 2

Significant tracts from tract‐of‐interest analysis comparing diagnostic groups. (a) Mean of each measure in the PD‐woNCPs and PD‐wNCPs groups (represented as the percentage difference from the healthy controls). Significant tracts (*p < .05, **p < .01, ***p < .001) are displayed in color, whereas non‐significant tracts are shown in gray. ^★Tracts with significant differences between the PD‐woNCPs and PD‐wNCPs groups. (b) Tracts obtained using the ICBM‐DTI‐81 white matter tractography atlas. Abbreviations: ATR, anterior thalamic radiation; FA, fractional anisotropy; HC, healthy control; ICVF, intracellular volume fraction; IFOF, inferior fronto‐occipital fasciculus; ILF, inferior longitudinal fasciculus; MD, mean diffusivity; PD‐woNCPs, Parkinson's disease without neurocognitive and psychiatric symptoms; PD‐wNCPs, Parkinson's disease with neurocognitive and psychiatric symptoms; RD, radial diffusivity; SLF, superior longitudinal fasciculus; UF, uncinate fasciculus [Color figure can be viewed at https://wileyonlinelibrary.com]

Figure 3

Upper panel: Spatial maps of independent component #1. The spatial maps represent the thresholded z‐scores (3 < |z| < 10). In the spatial maps, the weights (in percentage) indicate the relative contribution of each measure to the component at the group level. Lower panel: Boxplot of subject loadings for the three different groups. The bottom and top of the box are first and third quartiles, and the thick band inside the box is the median. Whiskers represent maximum and minimum values of all data. Abbreviations: DTI, diffusion tensor imaging; FA, fractional anisotropy; HC, healthy control; ICVF, intracellular volume fraction; MD, mean diffusivity; NODDI, neurite orientation dispersion and imaging; ODI, orientation dispersion index; PD‐woNCPs, Parkinson's disease without neurocognitive and psychiatric symptoms; PD‐wNCPs, Parkinson's disease with neurocognitive and psychiatric symptoms; RD, radial diffusivity; VBM, voxel‐based morphometry; WM vol, WM volume [Color figure can be viewed at https://wileyonlinelibrary.com]