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PATTERNS OF [C-11]PIB AMYLOID BURDEN THAT ARE ASSOCIATED WITH CEREBROSPINAL FLUID AD BIOMARKERS IN PEOPLE AT RISK FOR ALZHEIMER'S DISEASE: FINDINGS FROM THE WRAP STUDY

      Background

      Further research is needed on the full spectrum of cerebrospinal fluid (CSF) markers and their relationships to amyloid imaging in all stages of Alzheimer's disease (AD). This study examines a wide range of CSF markers in a relatively young, preclinical cohort enriched with risk factors (APOE4 and AD parental history) for AD in conjunction with [C-11]Pittsburgh Compound B (PiB) positron emission tomography (PET).

      Methods

      N=106 Participants (mean age 60.43, SD 5.66) enriched with genetic and familial risk for AD from the Wisconsin Registry for Alzheimer's Prevention (WRAP) underwent PET-PiB imaging and lumbar puncture and were grouped as amyloid-positive (PiB+), amyloid-indeterminate (PiBi), or amyloid-negative (PiB-) based on the amount and pattern of amyloid deposition. ANOVAs were conducted on CSF Aß, tau, and CSF markers of inflammation (MCP-1, YKL-40) and axonal injury (NFL). Regional voxel-wise regression analyses of PiB scans were performed to examine the spatial relationship between CSF measures and amyloid load.

      Results

      ANOVA indicated a pattern of lower Aß42 in PiB+ compared to PiBi or PiB- while the ratios of Aß40, p-tau, t-tau, MCP-1, YKL40, and NFL to Aß42 were all higher in PiB+ compared to PiBi or PiB-. Correlations with extracted PiB distribution volume ratio from precuneus, and voxel-wise regressions, p(FWE)<0.05, showed a negative relationship between Aß42 and PiB while the ratios to ABß42 all showed a positive relationship to PiB. A common voxel-wise pattern was observed for all CSF, but most notably in p-tau/Aß42 and t-tau/Aß42 in regions previously implicated in symptomatic AD.

      Conclusions

      Group comparisons and voxel-based tests demonstrated that CSF ratios to Aß42 accounted for more variance than any single CSF measure alone. The positive relationship with PET-PiB likely reflects simultaneous amyloid deposition and early neurodegenerative processes. Voxel-based results are consistent with previous findings that the regions commonly labeled as the default mode network are functionally and anatomically affected in AD, even before symptom onset. An overlay of voxel-based results of Aß42, 1/Aß42 and p-tau/Aß42 indicate that Aß42 is likely driving the overall pattern, while tau provides additional sensitivity. This study shows that, together, CSF and PET-PiB provide critical and striking information about this important preclinical disease stage.
      TableCSF Statistical Contrasts by Amyloid Grouping
      CSF markerANOVAGroup ContrastPost-hoc T-test (Tukey-corrected)
      Aß42P=0.014PiBi > PiB+P=0.040
      PiB- > PiB+P=0.013
      Aß40/42P=0.000PiB+ > PiB-P=0.000
      PiB+ >PiBiP=0.000
      t-tau/Aß42P=0.000PiB+ > PiB-P=0.000
      PiB+ >PiBiP=0.000
      p-tau/Aß42P=0.000PiB+ > PiB-P=0.000
      PiB+ >PiBiP=0.000
      MCP-1/Aß42P=0.003PiB+ > PiB-P=0.002
      PiB+ >PiBiP=0.045
      YKL40/Aß42P=0.000PiB+ > PiB-P=0.000
      PiB+ >PiBiP=0.000
      NFL/Aß42P=0.000PiB+ > PiB-P=0.000
      PiB+ >PiBiP=0.001
      1/Aß42P=0.000PiB+ > PiB-P=0.000
      PiB+ >PiBiP=0.004
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