Aberrant White Matter Microstructure as a Potential Diagnostic Marker in Alzheimer’s Disease by Automated Fiber Quantification

Background: Alzheimer’s disease (AD) has been primarily considered a progressive neurodegenerative disorder of gray matter. Neuroimaging evidence has suggested white matter microstructure are also heavily affected in AD. However, whether white matter dysfunction are localized at the specific regions of fiber tracts and whether they would be a potential biomarker for AD remain unclear.Methods：By automated fiber quantification (AFQ), we applied diffusion tensor images from 25 healthy controls (HC), 24 amnestic mild cognitive impairment (aMCI) patients and 18 AD patients to create tract profiles along 16 major white matter fibers. We compared diffusion metrics [Fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (DA) and radial diffusivity (DR)] at the global and local level of fiber tracts between groups. Partial correlation analyses were used to explore the associations between white matter changes and cognitive performance. To assess the diagnostic value, we enrolled the significantly altered diffusion metrics into a random forest (RF) classifier, a type of machine learning method.Results: In the global tract level, we found that aMCI and AD patients showed higher MD, DA and DR values in some fiber tracts mostly in the left hemisphere compared to HC. In the point-wise level, widespread disruption were distributed on specific locations of different tracts. The point-wise MD measurements presented the best classification performance with respect to differentiating AD from HC. The two most important variables were localized in the prefrontal potion of left uncinate fasciculus and anterior thalamic radiation. In addition, the point-wise DA in the posterior component of the left cingulum cingulate displayed the most robust discriminative ability to identify AD from aMCI. Conclusion：Our findings provide evidence that the left-sided microstructural integrity was vulnerable in white matter fiber tracts in AD. Furthermore, the frontal lobe portion of left uncinate fasciculus and anterior thalamic radiation and the posterior component of the left cingulum cingulate played the important role in the diagnosis and surveillance of AD. These results demonstrated the potential of white matter abnormalities as a diagnostic biomarker in AD.