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Does Regional Amyloid Burden Impact Domain-Specific Cognitive Impairment?

Tiffini Voss, MD1; Ying Zhang, PhD1; Cyrille Sur, PhD1; James Kost, PhD1; Yi Mo, PhD1; Joyce Suhy, PhD2; Gregory Klein, PhD2; Jerome Barakos, MD3; Teresia Möller, PhD4; Benjamin Newton, PhD5; Lyn Harper Mozley, PhD1; Julie Chandler, PhD1; Yuki Mukai, MD1; Christopher Randolph, PhD, ABPP-CN6; and Michael Egan, MD1
1Merck & Co., Inc., Kenilworth, NJ, USA; 2Bioclinica, Inc., Newark, CA, USA; 3California Pacific Medical Center, San Francisco, CA, USA; 4GE Healthcare, Boston, MA, USA; 5GE Healthcare, Little Chalfont, United Kingdom; 6Loyola University Medical Center, Chicago, IL, USA

BACKGROUND

  • The presence of amyloid is required for a diagnosis of Alzheimer's disease
  • However, in prior work, amyloid burden does not always correlate with the severity of cognitive impairment, especially in more advanced disease (clinical dementia)
  • We analyzed screening data from the APECS trial (MK8931-019, NCT#01953601) to evaluate, in amnestic mild cognitive impairment (MCI), whether regional amyloid positivity is associated with lower cognitive performance in cognitive domains relevant to that anatomic region

OBJECTIVES

  1. To investigate gender differences age related changes of muscle and adipose tissue volume in the thigh.
  2. Propose a robust and automatic algorithm for the quantitative assessment of volume of thigh muscle, inter- and intra-muscular fat; Overcome the time-consuming and operator-dependent problems in traditional manual analysis, especially towards 3D datasets.

METHODS

  • Amyloid PET data and baseline cognitive performance were analyzed from the ongoing MK-8931-019 (APECS) trial of verubecestat
  • Trial participants were screened using the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) Delayed Memory Index (DMI) ≤85 to define memory impairment; only those with memory impairment underwent PET
  • PET positivity was determined by visual read in accordance with approved labelling. Six regions were examined in this exploratory analysis: frontal, parietal, temporal, cingulate, striatal, and precuneus
  • Cognitive performance was assessed using five RBANS index scores: immediate memory, delayed memory, language, attention, and visuospatial/constructional
  • For each anatomical region, the mean RBANS scores for PET negative vs positive were compared
  • The impact of number of additional PET-positive regions on RBANS score was also assessed

RESULTS

  • Of the 765 individuals analyzed, 556 (73%) were PET positive
  • Baseline age, education, MMSE, and ADCS-ADL were similar between PET-positive and PET-negative individuals
  • Within PET-positive individuals, 69% were positive for all six regions; 20% for 3–5 regions; 11% for 1 or 2 only. The frontal region was most often positive (94%), while temporal and striatal were least frequently positive (77%)
  • Regardless of anatomic region studied, PET-positive individuals had worse performance on the immediate memory index (IMI) and DMI as compared to PET-negative individuals: eg, for frontal region, mean DMI difference 9.1, 95%CI (7.01–11.2); IMI difference 9.25, 95%CI (6.95–11.56)
  • There were no nominal differences in attention, language, or visuospatial performance between PET-positive and PET-negative individuals, regardless of anatomic region
  • For both immediate and delayed memory, scores tended to decline as the number of positive PET regions increased; this pattern was not observed for the other cognitive domains

 

 

 

 

 

 

 

 

 

 

CONCLUSION

  • Immediate and delayed memory performance were lower among PET-positive individuals for all regions, with performance on these indices also declining as the number of amyloid-positive regions increased
  • Otherwise, there was no clear relationship between domain-specific cognitive performance and regional amyloid burden

DISCLOSURE STATEMENT:

  • This study was funded by Merck & Co., Inc.
  • Tiffini Voss, Ying Zhang, Cyrille Sur, James Kost, Lyn Harper Mozley, Yuki Mukai, and Michael Egan are employees of Merck & Co., Inc., and own stock/stock options in Merck & Co., Inc.
  • Yi Mo and Julie Chandler were previously employees of Merck and Co., Inc at the time the data were analyzed.

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