Diffusion along perivascular spaces reveals evidence supportive of glymphatic function impairment in Parkinson disease

Abstract

Background: Reduced diffusion along perivascular spaces in adults with Alzheimer's-disease-related-dementias has been reported and attributed to reduced glymphatic function.

Objectives: To apply quantitative measures of diffusion along, and orthogonal to, perivascular spaces in a cohort of older adults with and without clinical symptoms of alpha-synuclein related neurodegeneration.

Methods: 181 adults with Parkinson disease (PD) or essential tremor (ET) additionally sub-classified by the presence of cognitive impairment underwent 3 T MRI. Diffusion-tensor-imaging (spatial resolution = 2x2x2 mm; b-value = 1000 s/mm²; directions = 33) measures of diffusion (mm²/s) parallel and orthogonal to perivascular spaces at the level of the medullary veins, and the ratio of these measures (ALPS-index), were calculated. Regions were identified by a board-certified neuroradiologist from T₁-weighted and T₂-weighted MRI. Evaluations of motor impairment and mild cognitive impairment (MCI) were interpreted by a board-certified neurologist and neuropsychologist, respectively. Multiple regression with false discovery rate correction was applied to understand how diffusion metrics related to (i) disease category (PD vs. ET), (ii) cognition (MCI status), and (iii) white matter disease severity from the Fazekas score.

Results: The ALPS-index was reduced in PD compared to ET participants (p = 0.037). No association between the ALPS-index and MCI status, but an inverse association between the ALPS-index and Fazekas score (p = 0.002), was observed. The ALPS-index was inversely associated with age (p = 0.007).

Conclusion: Diffusion aberrations near perivascular spaces are evident in patients with alpha-synuclein related neurodegenerative disorders, and are related to age and white matter disease severity.

Keywords: DTI-ALPS; Dementia; Diffusion; Essential tremor; Glymphatic; Parkinson disease.

Figure 1.

Diffusion tensor imaging along perivascular spaces (DTI-ALPS). Figure 1A shows a minimum intensity projection of a susceptibility-weighted-image (SWI), demonstrating that the lateral projections of the medullary veins course in the right-left direction (x) at the level of the lateral ventricles. A map of fiber tracts at this location (Figure 1B) shows that where the medullary veins course in the right-left (x) direction, the principal fiber tract runs orthogonally, in the craniocaudal direction (z) in the projection region and in the anterior-posterior direction (y) in the association region. In Figure 1C-D subsequent magnifications of the projection and association regions along the medullary veins with the diffusion tensors represented as ellipsoids. Figure 1E shows a schematic of the principal fiber tract orientation in these two projection and association regions demonstrating that the perivascular space runs parallel to the medullary vein and therefore orthogonal to the principal fiber tract orientations. In Figure 1F, the orientations of the diffusion components that course orthogonal to the principal fiber tracts within these voxels can be represented as a diffusion component orthogonal to both the perivascular space and principal fiber tract (yellow) and parallel to the perivascular fluid motion (gray). The ALPS-index score is a measure of the ratio of the diffusion parallel to the perivascular space and the diffusion orthogonal to the perivascular space (yellow), without incorporating the diffusion information from the primary fiber tracts. The x-component of the diffusion direction (D_xx; arrow) in the projection region may have perivascular fluid motion relevance, given the expected direction of perivascular fluid motion is along medullary veins while the projection and association fibers run orthogonal to the medullary veins at this location.

Figure 2.

Relationships between ALPS-index and age. Trend lines depict linear regression with 95% confidence intervals (shaded).

Figure 3.

Boxplots showing the distribution of the ALPS-index values for the matched participants with essential tremor (ET) and Parkinson disease (PD). The p-value was obtained from the general linear model (GLM) analysis.