1. Neuroscience

Bundle-specific associations between white matter microstructure and Aβ and tau pathology in preclinical Alzheimer’s disease

  1. Alexa Pichet Binette  Is a corresponding author
  2. Guillaume Theaud
  3. François Rheault
  4. Maggie Roy
  5. D Louis Collins
  6. Johannes Levin
  7. Hiroshi Mori
  8. Jae Hong Lee
  9. Martin Rhys Farlow
  10. Peter Schofield
  11. Jasmeer P Chhatwal
  12. Colin L Masters
  13. Tammie Benzinger
  14. John Morris
  15. Randall Bateman
  16. John CS Breitner
  17. Judes Poirier
  18. Julie Gonneaud
  19. Maxime Descoteaux
  20. Sylvia Villeneuve  Is a corresponding author
  21. DIAN Study Group
  22. PREVENT-AD Research Group
  1. Department of Psychiatry, Faculty of Medicine, McGill University, Canada
  2. Douglas Mental Health University Institute, Canada
  3. Sherbrooke Connectivity Imaging Laboratory (SCIL), Université de Sherbrooke, Canada
  4. Electrical Engineering, Vanderbilt University, United States
  5. McConnell Brain Imaging Centre, Montreal Neurological Institute, Canada
  6. Department of Neurology, Ludwig-Maximilians-Universität München, Germany
  7. German Center for Neurodegenerative Diseases (DZNE), Germany
  8. Department of Clinical Neuroscience, Osaka City University Medical School, Japan
  9. Department of Neurology, Asan Medical Center, University of Ulsan College of Medicine, Republic of Korea
  10. Department of Neurology, Indiana University, United States
  11. Neuroscience Research Australia, Australia
  12. School of Medical Sciences, UNSW Sydney, Australia
  13. Harvard Medical School, Massachusetts General Hospital, United States
  14. The Florey Institute of Neuroscience and Mental Health, University of Melbourne, Australia
  15. Knight Alzheimer Disease Research Center, Washington University School of Medicine, United States
  16. Department of Neurology, Washington University School of Medicine, United States
  17. Normandie Univ, UNICAEN, INSERM, U1237, Institut Blood and Brain @ Caen-Normandie, Cyceron, France
https://doi.org/10.7554/eLife.62929
Share this article
Cite this article
  1. Alexa Pichet Binette
  2. Guillaume Theaud
  3. François Rheault
  4. Maggie Roy
  5. D Louis Collins
  6. Johannes Levin
  7. Hiroshi Mori
  8. Jae Hong Lee
  9. Martin Rhys Farlow
  10. Peter Schofield
  11. Jasmeer P Chhatwal
  12. Colin L Masters
  13. Tammie Benzinger
  14. John Morris
  15. Randall Bateman
  16. John CS Breitner
  17. Judes Poirier
  18. Julie Gonneaud
  19. Maxime Descoteaux
  20. Sylvia Villeneuve
  21. DIAN Study Group
  22. PREVENT-AD Research Group
(2021)
Bundle-specific associations between white matter microstructure and Aβ and tau pathology in preclinical Alzheimer’s disease
eLife 10:e62929.
https://doi.org/10.7554/eLife.62929
  2. Download BibTeX
  3. Download .RIS
4 figures, 3 tables and 1 additional file

Figures

Figure 1
Download asset Open asset
Overview of the processing steps.

PREVENT-AD and DIAN participants were processed following the same pipeline. Whole-brain tractogram was reconstructed using the TractoFlow Atlas-Based Segmentation pipeline, and automated bundle extraction tools were used to extract the bundles of interest in each hemisphere. Free-water-corrected tensor measures were calculated for each bundle. Associations between white matter microstructure and global Aβ and entorhinal tau PET were then investigated. Aβ: beta-amyloid; PET: positron emission tomography; SUVR: standardized uptake value ratio.

Figure 2
Download asset Open asset
Associations between diffusion measures and Aβ burden in Aβ-positive PREVENT-AD participants.

(A–C) Bivariate associations between FAT and global cortical Aβ in each bundle in the left hemisphere to show examples of raw values in PREVENT-AD. Data are represented for the full sample, with Aβ-positive in orange (our group of interest) and Aβ-negative in gray. (D–F) Partial correlations between diffusion measures (average diffusion measure in the bundle) and global cortical Aβ-PET controlling for age, sex, and bundle volume (divided by total intracranial volume) were performed in PREVENT Aβ-positive participants. Partial correlation coefficient for each diffusion measure in the right and left bundles is reported as bar graphs. Black asterisks highlight that associations are significant in both hemispheres, otherwise the color of the symbol matches the hemisphere where the association is significant. *p=0.05; ** 0.05 > p > 0.001; +p=0.06. See also Figure 2—source data 1. Aβ: beta-amyloid; FAT: tissue fractional anisotropy; MDT: tissue mean diffusivity; ADT: tissue axial diffusivity; RDT: tissue radial diffusivity; FW: free-water index; PET: positron emission tomography.

Figure 2—source data 1

Associations between microstructure and beta-amyloid–positron emission tomography (Aβ-PET) in PREVENT-AD.

https://cdn.elifesciences.org/articles/62929/elife-62929-fig2-data1-v2.docx
Figure 3
Download asset Open asset
Associations between diffusion measures and entorhinal tau burden in tau-positive PREVENT-AD participants.

(A–C) Bivariate associations between FAT and entorhinal tau in each bundle in the left hemisphere to show examples of raw values in PREVENT-AD. Data are represented for the full sample, with tau-positive in blue (our group of interest) and tau-negative in gray. (D–F) Partial correlations between diffusion measures (average diffusion measure in the bundle) and entorhinal tau-PET controlling for age, sex, and bundle volume (divided by total intracranial volume) were performed in PREVENT tau-positive participants. Partial correlation coefficient for each diffusion measure in the right and left bundles is reported as bar graphs. The color of the symbol on the bar graphs matches the hemisphere where the association is significant. *p=0.05; ** 0.05 > p > 0.001; +p=0.06. See also Figure 3—source data 1. FAT: tissue fractional anisotropy; MDT: tissue mean diffusivity; ADT: tissue axial diffusivity; RDT: tissue radial diffusivity; FW: free-water index; PET: positron emission tomography.

Figure 3—source data 1

Associations between microstructure and tau-positron emission tomography (tau-PET) in PREVENT-AD.

https://cdn.elifesciences.org/articles/62929/elife-62929-fig3-data1-v2.docx
Figure 4
Download asset Open asset
Associations between diffusion measures and Aβ burden in Aβ-positive DIAN mutation carriers.

(A–C) Bivariate associations between FAT and global cortical Aβ in each bundle in the left hemisphere to show examples of raw values in DIAN. Data are represented for the full sample, with Aβ-positive in red (our group of interest) and Aβ-negative in gray. (D–F) Partial correlations between diffusion measures (average diffusion measure in the bundle) and global cortical Aβ-PET controlling for age, sex, and bundle volume (divided by total intracranial volume) were performed in DIAN Aβ-positive participants. Partial correlation coefficient for each diffusion measure in the right and left bundles is reported as bar graphs. Black asterisks highlight that associations are significant in both hemispheres, otherwise the color of the symbol matches the hemisphere where the association is significant *p=0.05; ** 0.05 > p > 0.001. See also Figure 4—source data 1. Aβ: beta-amyloid; FAT: tissue fractional anisotropy; MDT: tissue mean diffusivity; ADT: tissue axial diffusivity; RDT: tissue radial diffusivity; FW: free-water index; PET: positron emission tomography.

Figure 4—source data 1

Associations between microstructure and beta-amyloid–positron emission tomography (Aβ-PET) in DIAN.

https://cdn.elifesciences.org/articles/62929/elife-62929-fig4-data1-v2.docx

Tables

Table 1
Demographics.
PREVENT-AD
(n = 126)		DIAN mutation carriers (n = 81)DIAN mutation non-carriers (n = 96)
Age (years)67.3 ± 4.8 (68–83)34.5 ± 9.9 (18–61)39.3 ± 11.7 (19–69)
Sex F:M (%F)94:32 (75%)42:39 (52%)56:40 (58%)
APOE4 carriers (%)50 (40%)24 (30%)26 (27%)
Education (years)15.2 ± 3.3 (7–24)15.2 ± 3.0 (10–24)15.1 ± 2.7 (10–26)
Handedness (n, % right-handed)114 (90%)69 (85%)82 (85%)
Systolic blood pressure129.0 ± 13.8 (100–164)122.5 ± 10.2 (95–155)123.5 ± 17.1 (90–190)
Diastolic blood pressure74.0 ± 8.1 (60–96)75.2 ± 8.8 (55–104)77.1 ± 10.1 (60–110)
Global Aβ SUVR*1.3 ± 0.3 (1.0–2.8)1.6 ± 0.7 (0.8–3.7)1.0 ± 0.1 (0.9–1.3)
Aβ-positive (%)24 (19%)35 (43%)0 (0%)
Entorhinal tau SUVR1.1 ± 0.1 (0.7–1.6)NANA
Mini-Mental State Examination28.8 ± 1.2 (24–30)29.0 ± 1.3 (24–30)29.2 ± 1.2 (25–30)
Estimated years to symptom onset†−5.7 ± 7.6 (−20.8 to 16.8)−13.6 ± 8.3 (−31.5 to 11.8)−7.4 ± 12.5 (−28.8 to 21.4)

  1. Values represent Mean ± SD (range). Participants with at least one ε4 allele were considered APOE4 positive. The Mini-Mental State Evaluation was administered at the same time as PET.

    * Note that NAV4694 was used in PREVENT-AD and PIB was used in DIAN.

  2. † Estimated years to symptom onset was calculated as the parent’s age at dementia onset minus the age of the participant; four missing values in PREVENT-AD.

    Aβ: beta-amyloid; APOE: apolipoprotein E; SUVR: standardized uptake value ratio; PET: positron emission tomography.

Table 2
Associations between gray matter volume and Aβ- and tau-PET in PREVENT-AD and DIAN.
PREVENT-AD
Aβ-positive		PREVENT-AD
Tau-positive		DIAN
Aβ-positive
Rpartialp-valueRpartialp-valueRpartialp-value
Left hemisphere
Anterior cingulate−0.2390.2710.0320.891−0.2070.248
Posterior cingulate−0.1160.598−0.1560.5−0.2520.156
Precuneus−0.2650.221−0.4390.047−0.3070.082
Parahippocampal gyrus0.1140.605−0.0730.7530.0790.661
Medial orbitofrontal cortex−0.4680.024−0.1970.392−0.1740.334
Right hemisphere
Anterior cingulate−0.3350.118−0.0850.713−0.1330.461
Posterior cingulate−0.3420.111−0.5460.01−0.3520.045
Precuneus−0.4680.024−0.4910.024−0.2870.105
Parahippocampal gyrus0.0140.948−0.2130.3550.160.373
Medial orbitofrontal cortex−0.3580.093−0.2370.3010.0140.94

  1. Rpartial and p-values from regression models investigating associations between gray matter volume (divided by total intracranial volume; independent variable) and pathology (dependent variable) in Aβ-positive or tau-positive participants in PREVENT-AD and DIAN. Models included age and sex as covariates.

    Aβ: beta-amyloid; PET: positron emission tomography.

Table 3
Associations between typical tensor measures and Aβ- and tau-PET in PREVENT-AD and DIAN.
PREVENT-AD
Aβ-positive
Anterior cingulumPosterior cingulumUncinate fasciculus
Rpartialp-valueRpartialp-valueRpartialp-value
Left hemisphere
FA−0.1280.571−0.4290.046−0.5260.012
MD0.0220.9230.180.4240.320.147
AD−0.1060.637−0.3150.153−0.3050.168
RD0.0810.7210.3050.1680.4480.037
Right hemisphere
FA−0.0210.927−0.30.175−0.5660.006
MD−0.0480.8310.1310.560.0780.729
AD−0.0670.766−0.1020.651−0.3810.08
RD−0.0190.9310.2210.3220.3440.116
Tau-positive
Anterior cingulumPosterior cingulumUncinate fasciculus
Rpartialp-valueRpartialp-valueRpartialp-value
Left hemisphere
FA−0.4650.039−0.5230.0180.1080.65
MD0.5110.0210.3960.0840.0540.821
AD0.1120.6390.0820.7310.2060.384
RD0.5460.0130.4650.039−0.0140.953
Right hemisphere
FA−0.4610.041−0.4870.029−0.3990.081
MD0.4160.0680.3720.1060.2110.372
AD0.0120.9590.1570.508−0.0110.965
RD0.4950.0270.4440.050.3110.182
DIAN
Aβ-positive
Anterior cingulumPosterior cingulumUncinate fasciculus
Rpartialp-valueRpartialp-valueRpartialp-value
Left hemisphere
FA−0.3730.035−0.1920.293−0.0310.868
MD0.150.413−0.0510.783−0.0150.935
AD−0.1960.283−0.2260.213−0.0670.716
RD0.3180.0760.0490.790.0210.91
Right hemisphere
FA−0.4520.009−0.40.023−0.350.049
MD0.1220.505−0.0020.9910.1080.558
AD−0.2390.188−0.2190.229−0.0980.595
RD0.3350.0610.1460.4260.2090.251

  1. Rpartial and p-values from regression models investigating associations between each tensor measure (average diffusion measure in the bundle; independent variable) and pathology (dependent variable) in PREVENT-AD Aβ-positive or tau-positive participants and DIAN Aβ-positive participants. Models included age, sex, bundle volume (divided by total intracranial volume) as covariates. 

    Aβ: beta-amyloid; FA: fractional anisotropy; MD: mean diffusivity; AD: axial diffusivity; RD: radial diffusivity; PET: positron emission tomography.

Additional files

Transparent reporting form
https://cdn.elifesciences.org/articles/62929/elife-62929-transrepform-v2.docx

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  1. Alexa Pichet Binette
  2. Guillaume Theaud
  3. François Rheault
  4. Maggie Roy
  5. D Louis Collins
  6. Johannes Levin
  7. Hiroshi Mori
  8. Jae Hong Lee
  9. Martin Rhys Farlow
  10. Peter Schofield
  11. Jasmeer P Chhatwal
  12. Colin L Masters
  13. Tammie Benzinger
  14. John Morris
  15. Randall Bateman
  16. John CS Breitner
  17. Judes Poirier
  18. Julie Gonneaud
  19. Maxime Descoteaux
  20. Sylvia Villeneuve
  21. DIAN Study Group
  22. PREVENT-AD Research Group
(2021)
Bundle-specific associations between white matter microstructure and Aβ and tau pathology in preclinical Alzheimer’s disease
eLife 10:e62929.
https://doi.org/10.7554/eLife.62929