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

Bendlin BB, Carlsson CM, Johnson SC, Zetterberg H, Blennow K, Willette AA, Okonkwo OC, Sodhi A, Ries ML, Birdsill AC, Alexander AL, Rowley HA, Puglielli L, Asthana S, Sager MA - PLoS ONE (2012)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Geriatric Research, Education and Clinical Center (GRECC), William S. Middleton Memorial Veteran's Hospital, Madison, Wisconsin, United States of America. bbb@medicine.wisc.edu

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.

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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).
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pone-0037720-g002: 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).

Mentions: Voxel-wise regression analysis indicated that both T-Tau and T-Tau/Aβ42 showed robust and widespread positive relationships with several of the DTI measures, specifically MD, axial and radial diffusion. These relationships were extensive in white matter and were prevalent in temporal, parietal and frontal lobes. The locations of peak T-value for MD and FA clusters obtained in the voxel-wise analysis are tabulated in Table 2 (axial and radial diffusivity results are tabulated in Table S1). The brain regions where CSF T-Tau/Aβ42 predicted MD values in the voxel-wise regression analysis are shown in Figure 1; the positive relationship between T-Tau/Aβ42 and MD is shown in Figure 2 in scatter plots from a subset of the significant clusters found in the voxel-wise regression analysis. The regional overlap between T-Tau and T-Tau/Aβ42 SPM result maps (MD, axial and radial diffusivity) was extensive, and is summarized in terms of percent overlap in Table 3.


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

Bendlin BB, Carlsson CM, Johnson SC, Zetterberg H, Blennow K, Willette AA, Okonkwo OC, Sodhi A, Ries ML, Birdsill AC, Alexander AL, Rowley HA, Puglielli L, Asthana S, Sager MA - PLoS ONE (2012)

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).
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pone-0037720-g002: 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).
Mentions: Voxel-wise regression analysis indicated that both T-Tau and T-Tau/Aβ42 showed robust and widespread positive relationships with several of the DTI measures, specifically MD, axial and radial diffusion. These relationships were extensive in white matter and were prevalent in temporal, parietal and frontal lobes. The locations of peak T-value for MD and FA clusters obtained in the voxel-wise analysis are tabulated in Table 2 (axial and radial diffusivity results are tabulated in Table S1). The brain regions where CSF T-Tau/Aβ42 predicted MD values in the voxel-wise regression analysis are shown in Figure 1; the positive relationship between T-Tau/Aβ42 and MD is shown in Figure 2 in scatter plots from a subset of the significant clusters found in the voxel-wise regression analysis. The regional overlap between T-Tau and T-Tau/Aβ42 SPM result maps (MD, axial and radial diffusivity) was extensive, and is summarized in terms of percent overlap in Table 3.

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Geriatric Research, Education and Clinical Center (GRECC), William S. Middleton Memorial Veteran's Hospital, Madison, Wisconsin, United States of America. bbb@medicine.wisc.edu

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.

Show MeSH
Related in: MedlinePlus