Florbetapir PET analysis of amyloid-β deposition in the presenilin 1 E280A autosomal dominant Alzheimer's disease kindred: a cross-sectional study

Abstract

Background: Fibrillar amyloid-β (Aβ) is thought to begin accumulating in the brain many years before the onset of clinical impairment in patients with Alzheimer's disease. By assessing the accumulation of Aβ in people at risk of genetic forms of Alzheimer's disease, we can identify how early preclinical changes start in individuals certain to develop dementia later in life. We sought to characterise the age-related accumulation of Aβ deposition in presenilin 1 (PSEN1) E280A mutation carriers across the spectrum of preclinical disease.

Methods: Between Aug 1 and Dec 6, 2011, members of the familial Alzheimer's disease Colombian kindred aged 18-60 years were recruited from the Alzheimer's Prevention Initiative's registry at the University of Antioquia, Medellín, Colombia. Cross-sectional assessment using florbetapir PET was done in symptomatic mutation carriers with mild cognitive impairment or mild dementia, asymptomatic carriers, and asymptomatic non-carriers. These assessments were done at the Banner Alzheimer's Institute in Phoenix, AZ, USA. A cortical grey matter mask consisting of six predefined regions.was used to measure mean cortical florbetapir PET binding. Cortical-to-pontine standard-uptake value ratios were used to characterise the cross-sectional accumulation of fibrillar Aβ deposition in carriers and non-carriers with regression analysis and to estimate the trajectories of fibrillar Aβ deposition.

Findings: We enrolled a cohort of 11 symptomatic individuals, 19 presymptomatic mutation carriers, and 20 asymptomatic non-carriers, ranging in age from 20 to 56 years. There was greater florbetapir binding in asymptomatic PSEN1 E280A mutation carriers than in age matched non-carriers. Fibrillar Aβ began to accumulate in PSEN 1E280A mutation carriers at a mean age of 28·2 years (95% CI 27·3-33·4), about 16 years and 21 years before the predicted median ages at mild cognitive impairment and dementia onset, respectively. (18)F florbetapir binding rose steeply over the next 9·4 years and plateaued at a mean age of 37·6 years (95% CI 35·3-40·2), about 6 and 11 years before the expected respective median ages at mild cognitive impairment and dementia onset. Prominent florbetapir binding was seen in the anterior and posterior cingulate, precuneus, and parietotemporal and frontal grey matter, as well as in the basal ganglia. Binding in the basal ganglia was not seen earlier or more prominently than in other regions.

Interpretation: These findings contribute to the understanding of preclinical familial Alzheimer's disease and help set the stage for assessment of amyloid-modifying treatments in the prevention of familial Alzheimer's disease.

Funding: Avid Radiopharmaceuticals, Banner Alzheimer's Foundation, Nomis Foundation, Anonymous Foundation, Forget Me Not Initiative, Colciencias, National Institute on Aging, and the State of Arizona.

Figure 1. Florbetapir (¹⁸F) binding in members of the Colombian kindred by age group and clinical diagnosis

Sagittal and axial standard uptake value ratio maps are presented in standardised atlas space. Cortical amyloid-β is evident in all patients with mild cognitive impairment and dementia and in all PSEN1 E280A mutation carriers aged 30 years or older. There is variability of visible tracer binding within each age subdivision and within the mild cognitive impairment and dementia groups. Typical patterns of non-specific white matter binding occurred in carriers under age 30 years and in all non-carriers. Participants’ data are displayed in age groupings to help protect individual anonymity.

Figure 2. Comparison of florbetapir (¹⁸F) levels in asymptomatic participants and non-carriers

Statistical map showing significantly greater cortical-to-pontine florbetapir standard uptake value ratios in 19 asymptomatic mutation carriers compared with 20 non-carriers. The pattern of cortical amyloid-β deposition is similar to that reported in patients with late-onset Alzheimer’s disease. See Online for appendix

Figure 3. Mean cortical standard uptake value ratios at different ages

The individual values of non-carriers are shown as artificially clustered at 5-year intervals to help preserve anonymity of carriers versus non-carriers related to specific ages. All datapoints over age 40 years are clustered at 42·5 years on the x axis because of limited non-carrier datapoints above age 40 years. SUVR=standard uptake value ratio.

Figure 4. Regional standard uptake value ratio differences according to participants’ age

Sigmoidal regression curves relating regional florbetapir PET SUVRs to age in PSEN1 E280A mutation carriers compared with non-carriers. Lines represent the differences between mutation carrier and non-carrier regression lines, accounting for variability in non-specific florbetapir binding between different regions. The greatest maximal plateau differences between carriers and non-carriers occurred in the anterior cingulate and precuneus regions (p=0·0008). SUVR=standard uptake value ratio.