Florbetapir F 18 amyloid PET and 36-month cognitive decline: a prospective multicenter study

Abstract

This study was designed to evaluate whether subjects with amyloid beta (Aβ) pathology, detected using florbetapir positron emission tomorgraphy (PET), demonstrated greater cognitive decline than subjects without Aβ pathology. Sixty-nine cognitively normal (CN) controls, 52 with recently diagnosed mild cognitive impairment (MCI) and 31 with probable Alzheimer's disease (AD) dementia were included in the study. PET images obtained in these subjects were visually rated as positive (Aβ+) or negative (Aβ-), blind to diagnosis. Fourteen percent (10/69) of CN, 37% (19/52) of MCI and 68% (21/31) of AD were Aβ+. The primary outcome was change in ADAS-Cog score in MCI subjects after 36 months; however, additional outcomes included change on measures of cognition, function and diagnostic status. Aβ+ MCI subjects demonstrated greater worsening compared with Aβ- subjects on the ADAS-Cog over 36 months (5.66 ± 1.47 vs -0.71 ± 1.09, P = 0.0014) as well as on the mini-mental state exam (MMSE), digit symbol substitution (DSS) test, and a verbal fluency test (P < 0.05). Similar to MCI subjects, Aβ+ CN subjects showed greater decline on the ADAS-Cog, digit-symbol-substitution test and verbal fluency (P<0.05), whereas Aβ+ AD patients showed greater declines in verbal fluency and the MMSE (P < 0.05). Aβ+ subjects in all diagnostic groups also showed greater decline on the CDR-SB (P<0.04), a global clinical assessment. Aβ+ subjects did not show significantly greater declines on the ADCS-ADL or Wechsler Memory Scale. Overall, these findings suggest that in CN, MCI and AD subjects, florbetapir PET Aβ+ subjects show greater cognitive and global deterioration over a 3-year follow-up than Aβ- subjects do.

Figure 1

Example images of Aβ− and Aβ+ subjects clinically classified as CN, MCI and AD. Normalized SUVR images (color) and gray scale images (used for visual interpretation of Aβ− vs Aβ+ status) from representative subjects. Note the absence of gray matter uptake and the difference in average cortical SUVR in the Aβ− vs Aβ+ classified scans. The color images are shown for illustrative purposes.

Figure 2

Baseline test score and change in score per month (estimated slopes) for the ADAS-Cog, CDR-SB and MMSE in Aβ+ and Aβ− subjects classified as CN, MCI and AD. Baseline scores and slopes estimated from MMRM model adjusted for baseline age. See text for details.

Figure 3

(a) Percentage of Aβ+ and Aβ− MCI subjects progressing to dementia or reverting to cognitive normal (CN) status over 36 months. The bars depict the 36-month endpoint diagnostic status of subjects originally classified as MCI at baseline. The red and blue bars titled CN depict the percentage of MCI subjects who reverted to CN by amyloid status. The red and blue bars titled MCI depict the percentage of MCI subjects who continued to be classified as MCI at endpoint (that is, cognitive change was not sufficient to trigger conversion). The red and blue bars titled AD depict the percentage of MCI subjects who progressed to dementia by amyloid status. Conversion to dementia from MCI was almost three times higher in Aβ+ subjects while reversion to CN was almost three times lower than Aβ− subjects. The arrows depict conversion and reversion. Please see text for details. (b) Concomitant and initiation of AD medication use in MCI subjects over 36 months by baseline florbetapir PET status. The proportion of MCI subjects who started the study taking AD medications was greater among Aβ+ vs Aβ− subjects (35.3% vs 3.3% P=0.006). By study end, 70.6% of Aβ+ MCI subjects were taking AD medications vs 23.3% Aβ− MCI (P=0.002) because of the greater percentage who initiated AD medications in Aβ+MCI vs Aβ−MCI (54.5% vs 20.7%). Please see text for details.