Keith johnson

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webinar presented on AlzForum January 5, 2012.

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  • Least squares fit (solid curve) of thickness-PiB functional relationship assuming identical sigmoid time courses we calculated how far apart in time these midpoints would have to be in order to achieve the best fit to our data. the time lag = 0.35 times the amyloid saturation time (the time to go from zero to maximum amyloid). For example, if a 10-year amyloid saturation time were hypothesized, the time lag between the rapid phases of PiB increase and cortical thinning would be 3.5 years.
  • Keith johnson

    1. 1. Amyloid-β Associated Cortical Thinning In Clinically Normal Elderly K.A.Johnson, T.Hedden, R.L.Buckner, R.A.Sperling, J.A.Becker Massachusetts General Hospital Brigham and Women ’s Hospital Harvard Medical School
    2. 2. Background : β-amyloidosis is common in normal older individuals and may represent incipient Alzheimer ’s disease Hypothesis : β-amyloidosis of normal aging is associated with an AD-like pattern of brain volume loss.
    3. 4. Methods Volume : MP-RAGE MR Freesurfer: - cortical thickness at vertices (Fischl et al., 2004) - cortical ROI and hippocampal volume (Desikan et al., 2006) A-β deposition: Pittsburgh Compound-B; 60-min. PET acquisition: DVR(cerebellum reference) (Klunk et al., 2004) Partial volume correction (Meltzer et al.,1996)
    4. 5. PiB retention and thickness in cortex pial surface <ul><li>Coregistered PET data mapped to cortical surface by sampling within cortical ribbon </li></ul><ul><li>PiB-DVR computed in precuneus ROI in cortical ribbon (Desikan 2006) </li></ul><ul><li>Vertex PET data smoothed, 15mm in-surface prior to further analysis </li></ul>gray/white surface
    5. 6. 10 -1.3 10 -1.3 Age dependence of A-β deposition 10 -4 CN AD 10 -4 p p CN AD
    6. 7. Increased cortical PiB uptake in AD DVR at each surface vertex in AD compared to CN, age covaried vs. 10 -10 10 -24 p
    7. 8. Reduced cortical thickness in AD thickness at each surface vertex in AD compared to CN, age adjusted vs. 10 -3 10 -10 p
    8. 9. Aβ-associated reduction in cortical thickness Reduced thickness at each surface vertex per unit PiB DVR (post. cing./precuneus), age covaried
    9. 10. Aβ-associated reduction in cortical thickness Reduced thickness at each surface vertex per unit PiB DVR (post. cing./precuneus), age covaried CN
    10. 11. Aβ-associated reduction in cortical thickness: clinically normal (CN) subjects only, adjusted for age *Monte Carlo simulation
    11. 12. Aβ-associated reduction in cortical thickness/volume, by region Thickness change (mm) per unit PiB DVR
    12. 13. The pattern of amyloid-associated atrophy in CN is similar to that seen in AD. When adjusted for age, the association is more evident in cortical than in hippocampal regions. Part 1 Summary:
    13. 14. Effect Size Aβ-associated reduction in cortical thickness Reduced thickness at each surface vertex per unit PiB DVR (post. cing./precuneus), age covaried Significance regression coefficients (extent>3000 vertices)
    14. 15. Effect Size Aβ-associated reduction in cortical thickness Reduced thickness at each surface vertex per unit PiB DVR (post. cing./precuneus), age covaried Significance regression coefficients (extent>3000 vertices)
    15. 16. Thickness-Aβ sigmoid modeling amyloid acumulation loss of cortex
    16. 17. Thickness-Aβ sigmoid modeling amyloid acumulation What is the time lag between maximum A-β accumulation and maximal reduction in thickness? loss of cortex
    17. 18. Least squares fit (solid curve) of thickness-PiB functional relationship assuming identical sigmoid time courses we calculated how far apart in time these midpoints would have to be in order to achieve the best fit to our data. r-sq = 0.48; p<10^-4 the time lag = 0.35 times the amyloid saturation time (the time to go from zero to maximum amyloid). For example, if a 10-year amyloid saturation time were hypothesized, the time lag between the rapid phases of PiB increase and cortical thinning would be 3.5 years. Thickness-Aβ sigmoid modeling Model prediction: For a 10-year A-β saturation time, the time lag between rapid phase of A-β accumulation and rapid phase of cortical thinning is 3.5 years.
    18. 19. Conclusions : 1. In CN, A-β associated cortical thinning occurs in a pattern similar to AD, supporting the possibility that amyloidosis in CN represents preclinical AD 2. At stage of AD dementia, even steeper association between A-β and cortical thinning; inverse relationship with age 3. Relatively less A-β associated hippocampal volume loss in both CN and AD 4. Dynamic modeling of these data supports a definable temporal lag between maximal amyloid accumulation and maximal cortical thinning (Jack et al. Lancet Neurology 2010). -

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