CSF T-Tau/Aβ42 predicts white matter microstructure in healthy adults at risk for Alzheimer's disease

Abstract

Cerebrospinal fluid (CSF) biomarkers T-Tau and Aβ(42) are linked with Alzheimer's disease (AD), yet little is known about the relationship between CSF biomarkers and structural brain alteration in healthy adults. In this study we examined the extent to which AD biomarkers measured in CSF predict brain microstructure indexed by diffusion tensor imaging (DTI) and volume indexed by T1-weighted imaging. Forty-three middle-aged adults with parental family history of AD received baseline lumbar puncture and MRI approximately 3.5 years later. Voxel-wise image analysis methods were used to test whether baseline CSF Aβ(42), total tau (T-Tau), phosphorylated tau (P-Tau) and neurofilament light protein predicted brain microstructure as indexed by DTI and gray matter volume indexed by T1-weighted imaging. T-Tau and T-Tau/Aβ(42) were widely correlated with indices of brain microstructure (mean, axial, and radial diffusivity), notably in white matter regions adjacent to gray matter structures affected in the earliest stages of AD. None of the CSF biomarkers were related to gray matter volume. Elevated P-Tau and P-Tau/Aβ(42) levels were associated with lower recognition performance on the Rey Auditory Verbal Learning Test. Overall, the results suggest that CSF biomarkers are related to brain microstructure in healthy adults with elevated risk of developing AD. Furthermore, the results clearly suggest that early pathological changes in AD can be detected with DTI and occur not only in cortex, but also in white matter.

Figure 1. CSF T-Tau/Aβ42 and mean diffusivity.

Higher T-Tau/Aβ42 at baseline was associated with increased mean diffusivity in follow-up scanning in several brain regions, encompassing both gray and white matter. As shown above, this relationship was especially prominent in temporal lobe white matter adjacent to hippocampus, but also encompassing gray and white matter in frontal and parietal lobes, portions of occipital white matter, and small clusters in cerebellum. Results are FDR corrected for multiple comparisons (p<.05) and displayed here with a cluster size threshold of 20 or more voxels. Sections are shown in sagittal view beginning from the left side of the brain to right. Variations in the color map reflect the size of the T-statistic (indexed by the color bar at bottom).

Figure 2. T-Tau/Aβ42 Plotted against mean, radial, and axial diffusivity.

Shown here are the results of the voxel-wise analysis, where regions with color overlay are those where higher T-Tau/Aβ42 was associated with higher diffusivity (mean, radial, and axial). In order to illustrate the relationship between T-Tau/Aβ42 and the diffusivity maps, we extracted diffusion values from representative regions of significant correlation in the voxel-wise analysis and plotted them against T-Tau/Aβ42. Shown on the top row are diffusion values extracted from the left temporal lobe (x = −42, y = −34, z = −16) plotted against T-Tau/Aβ42. In the middle row are diffusion values extracted from right posterior cingulum bundle (x = 8, y = −46, z = 16) plotted against T-Tau/Aβ42. In the bottom row are diffusion values extracted from left inferior frontal white matter (x = −22, y = 43, z = −12) plotted against T-Tau/Aβ42. Blue crosshairs overlaid on the brain sections indicate the location of the extracted values. Each point in the scatter represents diffusion values from one participant (n = 43). T-Tau/Aβ42 values were log-transformed and mean, radial, and axial diffusivity values were adjusted for age at time of scan, sex, and treatment (CSF data were collected at baseline in a Simvastatin treatment trial, data from the prevention trial are not shown here).