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 Aβ42 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 Aβ42, 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/Aβ42 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/Aβ42 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.

Increased Left Ventricular Mass Index Is Associated With Compromised White Matter Microstructure Among Older Adults

“…One explanation is that a higher degree of white matter microstructural damage, as seen in MCI,24 may be necessary before LV mass index relates to DTI measurements. MCI participants are more likely to have amyloid and tau pathology,25 which have been associated with white matter damage 26. It is possible that in the presence of pathology and more susceptible white matter, as seen in MCI, small changes in LV structure lead to greater changes in white matter microstructure.…”

Measuring Cortical Connectivity in Alzheimer’s Disease as a Brain Neural Network Pathology: Toward Clinical Applications

“…Other recent studies examined white matter changes in asymptomatic individuals showing biomarker evidence of amyloid or tau pathology (Bendlin et al, 2012;Chao et al, 2013;Gold et al, 2014;Kantarci et al, 2014;Molinuevo et al, 2014;Racine et al, 2014;Stenset et al, 2011). These cross-sectional studies of at-risk populations are now increasingly being complemented by longitudinal follow-up studies that allow relating the detected imaging abnormalities to future clinical outcomes Fletcher et al, 2013;Mielke et al, 2012;Zhuang et al, 2012).…”

Cerebrospinal Fluid Markers of Alzheimer’s Disease Pathology and Microglial Activation are Associated with Altered White Matter Microstructure in Asymptomatic Adults at Risk for Alzheimer’s Disease

“…CSF Aβ 42 and P-Tau 181 are markers of amyloid plaque and neurofibrillary tangle pathology respectively, with lower Aβ 42 indicating greater amyloid deposition and higher P-Tau 181 indicating greater tangle pathology. High P-Tau 181 and low Aβ 42 in CSF have been associated with atrophy, cortical thinning, and altered white matter microstructure in preclinical AD [41–45], but the extent to which neuroinflammation may moderate these effects is unknown. Given the potential negative effects of inflammation on neural health, we hypothesized that the negative effects of β-amyloid and neurofibrillary tangle pathology on tissue microstructure would be greater among individuals with higher inflammation.…”