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WHITE MATTER INTEGRITY REFLECTS TAU ACCUMULATION IN AD-DEFINED REGIONS

      Background

      Axonal loss and demyelination are pathological changes that co-occur in Alzheimer disease (AD). Diffusion tensor imaging (DTI) is sensitive at detecting white matter degeneration in AD with changes more pronounced at later stages of the disease. Deposition of tau in gray matter (GM) is associated with atrophy and cognitive impairment. However, the relationship between tau accumulation and white matter integrity has not been well characterized. We sought to correlate β-amyloid and tau deposition in predefined regions of interest (ROIs) with corresponding white matter (WM) projections from these ROIs.

      Methods

      Sixty-nine participants underwent DTI, β-amyloid (florbetapir) and tau ([18F]AV-1451 (T807, flortaucipir)) positron emission tomography imaging. Twenty-one were β-amyloid positive, including 8 persons who were CDR>0. DTI metrics were processed in FMRIB software library, and GM regions were obtained with Freesurfer 5.3. Two sets of four AD-defined regions were evaluated based on either β-amyloid (Table 1) or tau (Table 2) accumulation. Probabilistic tractography projections were created for these predefined ROIs using ten cognitively normal individuals from the Human Connectome Project (Figure 1). The projections were applied to each participant’s diffusion maps and average values calculated. Values were adjusted by age for partial correlations with either regional tau or β-amyloid. Correction for multiple comparisons was performed with false discovery rate correction (FDR).

      Results

      Within β-amyloid defied regions, no association was seen between β-amyloid and diffusion metrics after FDR correction. With tau defined ROIs, Diffusion values within the occipital and temporal projections were associated with tau in β-amyloid positive individuals (Table 1). For the tau defined regions, β-amyloid did not associate with any diffusion metric. Significant associations were seen in all tau-defined regions for tau and absolute diffusion metrics in β-amyloid positive individuals (Table 2). No relationship was present between tau and diffusion metrics in the β-amyloid negative subjects.

      Conclusions

      Tau and not β-amyloid accumulation was associated with changes in WM integrity. Observed changes were primarily seen in occipital and temporal projections. These results suggest that tau mediated changes primarily occur within posterior or temporal regions of the brain and are mediated by the presence of β-amyloid.
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      Table 1
      B-amyloid RegionsMean DiffusivityAxial DiffusivityRadial DiffusivityFractional Anisotropy
      Gyrus Rectus

      (R-value)

      (P-Value)
      0.06690.03780.0803-0.1245
      0.58770.75980.51500.3118
      Occipital0.40290.43690.3773-0.1574
      0.0014**0.0004**0.003**0.2
      Prefrontal0.08920.05820.1011-0.1113
      0.46920.63710.41190.3663
      Temporal0.45260.53560.3972-0.0366
      0.0004**0.00008**0.003**0.7672
      * p<0.05.
      ** p<0.01.
      The association for the β-amyloid regions between regional tau and DTI metrics in the β-amyloid positive subjects.
      Table 2
      Tau RegionsMean DiffusivityAxial DiffusivityRadial DiffusivityFractional Anisotropy
      Amygdala

      (R-value)

      (P-Value)
      0.64970.59910.6681-0.6476
      0.0026**0.0067**0.0018**0.0027**
      Entorhinal0.53450.51010.5456-0.6747
      0.0184*0.0256*0.0157*0.0054**
      Inferior Temporal0.78780.78060.7716-0.5229
      0.0004**0.0004**0.0004**0.0288*
      Lateral Occipital0.6600.59950.6583-0.3163
      0.0019**0.0067**0.0022**0.1871
      * p<0.05
      ** p<0.01
      The association for the tau regions between regional tau and DTI metrics in the β-amyloid positive subjects.