ArticlesFlorbetapir PET analysis of amyloid-β deposition in the presenilin 1 E280A autosomal dominant Alzheimer's disease kindred: a cross-sectional study
Introduction
Fibrillar amyloid-β (Aβ) deposition is a cardinal neuropathological feature of Alzheimer's disease.1 Findings from histopathological, PET, and CSF studies show that fibrillar Aβ is present in a substantial number of cognitively normal old adults and suggest that it might reach neuropathologically diagnostic concentrations at least 10 years before the onset of dementia.2, 3, 4, 5, 6 These findings have led investigators to propose biomarker models to characterise the preclinical stages of Alzheimer's disease.7
Longitudinal studies using amyloid PET imaging may enable researchers to identify the extent to which cortical fibrillar Aβ deposition in asymptomatic individuals predicts subsequent clinical decline. Recent failures of anti-amyloid therapies in patients with Alzheimer's disease have highlighted the need for disease-modifying treatments to be used before the onset of clinical symptoms, when the neuropathological features of Alzheimer's disease are already extensive.8 Research is ongoing to assess biomarkers of brain function and pathological abnormalities in cognitively normal people at genetic risk to characterise the changes associated with their predisposition to Alzheimer's disease. These studies include the comparison of people with and without the apolipoprotein E (APOE) ɛ4 allele,4, 9, 10, 11 a major susceptibility gene for late-onset Alzheimer's disease, and the comparison of carriers and non-carriers of uncommon mutations that cause autosomal dominant early-onset Alzheimer's disease.2, 12, 13, 14
As recently shown by the Dominantly Inherited Alzheimer's Network (DIAN),2 in a study of a heterogeneous cohort of presymptomatic mutation carriers of various autosomal dominant Alzheimer's disease mutations, the investigation of genetically driven forms of Alzheimer's disease can provide insights into presymptomatic biomarker features associated with predictable future clinical outcomes. Cross-sectional studies of autosomal dominant Alzheimer's disease can be undertaken to analyse an individual's biomarker profile in comparison with clinical outcomes in affected family members, such as their age at onset of clinical symptoms, and enable a better understanding of the predictive characteristics of the biomarker under study, that could hypothetically emulate longitudinal outcomes.
Because different autosomal dominant mutations in the presenilin 1 (PSEN1), PSEN2, and amyloid precursor protein (APP) genes vary in clinical presentation and pathological features,15, 16 assessing presymptomatic biomarkers in a single-mutation kindred would be useful to reduce this heterogeneity. The PSEN1 E280A (Glu280Ala) mutation kindred comprises an extended family living in the region of Antioquia, Colombia, with about 5000 members, of whom about 1500 carry this mutation, which causes Alzheimer's disease.17 Findings from 15 years of observational studies from 1995 to 2010 in 449 PSEN1 E280A mutation carriers showed a predictable clinical course with a median age of 44 years (95% CI 43–45) at onset of mild cognitive impairment (MCI) and 49 years (49–50) at onset of dementia.12
In a previous study,18 our group assessed young PSEN1 E280A mutation carriers and non-carriers, and found significantly higher CSF and plasma Aβ1–42 concentrations in mutation carriers, consistent with Aβ1–42 overproduction, as well as functional and structural MRI abnormalities comparable to those reported in patients with sporadic late-onset Alzheimer's disease. We subsequently sought to characterise the accumulation of cortical Aβ deposition in mutation carriers across a broad age range, that is, across the spectrum of stages of preclinical disease. We undertook florbetapir (18F) amyloid PET analyses in presymptomatic PSEN1 E280A mutation carriers, non-carriers, and symptomatic patients from this single-mutation autosomal dominant Alzheimer's disease cohort.
Section snippets
Study design and participants
Between Aug 1 and Dec 6, 2011, members of the PSEN1 E280A mutation Colombian kindred were recruited from the Alzheimer's Prevention Initiative (API) registry. The API registry was developed in 2010 to establish a database of all living family members who were known through ongoing observational studies since 1995,12 in preparation for planned biomarker and preclinical treatment trials. This registry was searched for individuals potentially meeting the enrolment criteria for the present study,
Results
Our study cohort consisted of 11 symptomatic individuals, 19 presymptomatic mutation carriers, and 20 asymptomatic non-carriers, ranging in age from 20 to 56 years. Table 1 lists participants' characteristics. The symptomatic group was older than the presymptomatic carriers and non-carriers, and scored worse on all cognitive test measures. Symptomatic participants scored worse on all neuropsychological tests (p≤0·00011; table 1). There were no differences between non-carriers and presymptomatic
Discussion
In this study, we characterised the pattern of fibrillar amyloid deposition and estimated its temporal relation with clinical onset in PSEN1 E280A mutation carriers and non-carriers from the largest known kindred with autosomal dominant Alzheimer's disease. The cerebral pattern of fibrillar Aβ accumulation in the late preclinical and clinical stages of Alzheimer's disease was similar to that reported in individuals with late-onset Alzheimer's disease,5 including striatal uptake that was not out
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