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. Introduction The prognostic evaluation of people at risk for AD, such as normal elderly or those with mild cognitive impairment (MCI) is challenging due to considerable variability in progression rates and underlying pathologic heterogeneity. A reliable biomarker that could accurately identify subjects at greatest risk for progressive cognitive decline could enhance the clinical evaluation of at-risk subjects and accelerate the testing of preventive strategies.1,2,3 Accumulation of amyloid-β (Aβ) fibrils in the form of amyloid plaques is a neuropathological requirement for definitive diagnosis of dementia due to Alzheimer’s disease (AD).4 Insights gained from pathologic and biomarker studies suggest that Aβ changes in the brain begin years, and possibly decades, before cognitive symptoms emerge. Two recent cross-sectional studies of carriers at-risk for familial AD estimated that Aβ changes may occur 15 years prior to expected symptom onset.5,6 Likewise, biomarker studies of older asymptomatic and MCI subjects have reported an increased rate of AD pathologic changes. Such findings have led to the concept of preclinical7 and MCI stages of AD;2 however, the predictive value of available biomarkers at both the individual patient level and group level is not yet fully elucidated. Among the various biomarkers in development to assess Aβ, position emission tomorgraphy (PET) tracers offer the potential of directly imaging changes in cortical Aβ. 11C-labeled Pittsburgh compound B (PiB) was the first PET tracer to image cortical Aβ plaques8,9, and prior PiB studies have shown that PiB-positive normal and MCI subjects are more likely to show faster cognitive deterioration than PiB-negative subjects.10, 11, 12, 13, 14, 15, 16, 17, 18, 19 The short half-life of 11C (20 min) limits its viability for routine clinical use. Florbetapir F 18 is a PET ligand with high affinity and specificity to Aβ,20,21 and a multicenter clinical histopathologic study has shown a significant correlation between visual ratings of florbetapir PET in living subjects and autopsy measured Aβ pathology.22 It was recently approved by FDA to detect neuritic plaques in the evaluation of patients with progressive cognitive decline. Other F 18 amyloid PET tracers are also being developed.23,24 A limitation of current F 18 amyloid PET tracers has been the relative lack of longitudinal data. The current study was designed to test whether florbetapir PET can predict subsequent cognitive decline in older at-risk subjects. Materials and Methods This prospective, observational study (AV45-A11 (NCT00857506)) was sponsored by Avid Radiopharmaceuticals (a subsidiary of Eli Lilly & Co.) and conducted at 21 US clinical sites. It was a longitudinal extension of a cross-sectional Phase 2 florbetapir PET study (AV45-A05; NCT00702143). Baseline cross-sectional results25,26 and 18-month interim findings27 have been reported separately. Subjects Participants in the longitudinal study included 69 cognitively normal (CN) healthy controls, 52 MCI and 31 clinically diagnosed AD dementia patients. All previously received a florbetapir PET scan in the cross-sectional study. AD patients met NINCDS-ADRDA28 criteria for probable AD with mini-mental state examination (MMSE) scores between 10 and 24. MCI subjects were recently diagnosed (either at the screening visit or within the past year) on the basis of a global clinical dementia rating (CDR) score of 0.5 with an MMSE>24. All had memory complaint or cognitive impairment corroborated by an informant, but no episodic memory threshold was imposed. CN subjects were assessed clinically as cognitively normal, with a Global CDR of 0.0 and an MMSE of 29–30. CN subjects were all ≥50 years of age, recruited approximately equal distribution across age deciles (50–59, 60–69, 70–79 and ≥80 years of age). At the screening visit, subjects underwent a medical history, clinical interview, physical and neurologic examinations and laboratory evaluations. MRI was obtained at screening or within 6 months prior to enrollment to rule out significant central nervious system lesions. Subjects who had other neuropsychiatric diseases, contraindications to PET, received anti-amyloid investigational drugs, or were unable to complete psychometric testing were excluded. Baseline assessments Baseline measures included a clinical diagnostic interview and a cognitive/functional battery comprised of the Alzheimer’s Disease Assessment Scale (ADAS-cog; 11-item version), MMSE, CDR Global (CDR Global) and Sum of Boxes (CDR-SB), Alzheimer’s Disease Cooperative Study Activities of Daily Living Scale (ADCS-ADL), Digit-Symbol Substitution (DSS), Category Verbal Fluency (animals and vegetables) and Wechsler Logical Memory (immediate and delayed recall). Florbetapir PET Scan Site PET scanners were qualified with a Hoffman brain phantom. PET amyloid imaging was performed as part of study AV45-A05.25 Fifty minutes after intravenous injection of 10 mCi (370 MBq) of florbetapir F 18, a 10-min emission scan (acquired in 2 × 5 min frames) was obtained. PET scanners included Discovery LS PET/CT (GE, Fairfield, CT, USA), Advance PET (GE), ECAT HR+ (Siemens, Washington DC, USA) and Biograph PET/CT (Siemens) models. Image reconstruction utilized an ite (...truncated)