Ghezzi, L. | Search bioRxiv

bioRxiv2025

DTI-ALPS PRIMARILY REFLECTS WHITE MATTER DIFFUSION DISPERSION AND MICROSTRUCTURAL HETEROGENEITY IN NEURODEGENERATION: INSIGHTS FROM MULTI-MODAL MRI

1.1.1 BackgroundThe glymphatic system facilitates clearance of metabolic waste and pathological proteins from the brain, and its dysfunction has been implicated in neurodegenerative disease. The diffusion tensor imaging-analysis along the perivascular space (DTI-ALPS) has been proposed as a non-invasive MRI marker of glymphatic flow, although its biological specificity remains uncertain. This study aimed to identify the determinants of DTI-ALPS and evaluate whether it primarily reflects white-matter (WM) microstructure rather than glymphatic flow in the context of neurodegeneration. 1.2 MethodsWe examined 100 individuals referred to the Memory Clinic of the Policlinico Hospital in Milan for suspected dementia. All participants underwent a 3T-MRI protocol including 3D-T1-weighted and 3D-FLAIR imaging, double-shell diffusion-weighted imaging (b=1000/2000 s/mm{superscript 2}), and multi-echo gradient-echo sequences for quantitative susceptibility mapping. Within standard DTI-ALPS ROIs, we extracted DTI-ALPS values together with fractional anisotropy (FA), mean diffusivity (MD), and mode of anisotropy (MA) at both b-values, as well as neurite orientation and density imaging (NODDI) metrics, particularly the orientation dispersion index (ODI). WM microstructure was further characterized using the T1/FLAIR ratio and diamagnetic component of susceptibility (DCS). 1.3 Results and conclusionsDTI-ALPS correlated inversely with MA (r = -0.84 at b = 1000; r = -0.86 at b = 2000) and positively with ODI (r = 0.73). Moderate correlations with the T1/FLAIR ratio and DCS supported sensitivity to WM alterations. Factor analysis indicated that DTI-ALPS clustered with MA and ODI rather than forming a distinct factor, suggesting that DTI-ALPS primarily reflects WM diffusion dispersion and heterogeneity rather than glymphatic flow in the context of neurodegeneration. KeypointsO_LIDTI-ALPS links strongly with mode of anisotropy at high b-values and orientation dispersion, indicating crossing-fibers loss C_LIO_LIDTI-ALPS is moderately associated to T1/FLAIR ratio and diamagnetic susceptibility values, reflecting microstructural WM changes C_LIO_LIDTI-ALPS reflects primarily WM features and may lack specificity for glymphatic flow in the context of neurodegeneration. C_LI

neuroscience↗

bioRxiv2024

Parkinson's disease-associated Pink1 loss disrupts vesicle trafficking in ensheathing glia causing dopaminergic neuron synapse loss

Parkinsons disease (PD) is commonly associated with the loss of dopaminergic neurons in the substantia nigra, but many other cell types are affected even before neuron loss occurs. Recent studies have linked oligodendrocytes to early stages of PD, though their precise role is still unclear. PINK1 is mutated in familial PD, and through unbiased single-cell sequencing of the entire brain of Drosophila Pink1 models, we observed significant gene deregulation in ensheathing glia (EG); cells that share functional similarities with oligodendrocytes. We found that the loss of Pink1 leads to abnormalities in EG, similar to the reactive response of EG seen upon nerve injury. Using cell-type-specific transcriptomics, we identified deregulated genes in EG as potential functional modifiers. Specifically downregulating two trafficking factors in EG, Vps35 and Vps13, also mutated in PD, was sufficient to rescue neuronal function and protect against dopaminergic synapse loss. Our findings demonstrate that Pink1 loss in neurons triggers an injury-like response in EG, and that Pink1 loss in EG in turn disrupts neuronal function. Vesicle trafficking components, which may regulate membrane interactions between organelles in EG, seem to play a role in maintaining neuronal health and ultimately preventing dopaminergic synapse loss. Our work highlights the essential role of glial support cells in the pathogenesis of PD and identifies vesicle trafficking within these cells in disease progression.

neuroscience↗