Spatial patterns of neuroimaging biomarker change in individuals from families with autosomal dominant Alzheimer's disease: a longitudinal study

Abstract

BackgroundModels of Alzheimer disease propose a sequence of amyloid-β (Aβ) accumulation, hypometabolism, and structural declines that precede the onset of clinical dementia. These pathological features evolve both temporally and spatially in the brain. This study aimed to characterize where in the brain and when in the course of the disease neuroimaging biomarkers become abnormal.MethodsWe analyzed data from mutation non-carriers, asymptomatic carriers, and symptomatic carriers collected between January 1st 2009 and December 31st 2015 from families carrying PSEN1, PSEN2, or APP mutations enrolled in the Dominantly Inherited Alzheimer’s Network. We analyzed [11C]Pittsburgh Compound B positron emission tomography (PiB PET), [18F]Fluorodeoxyglucose (FDG PET), and structural magnetic resonance imaging (MRI) data using regions of interest to assess change throughout the brain. We estimated rates of biomarker change as a function of estimated years from symptom onset at baseline using linear mixed-effects models and determined the earliest point at which biomarker trajectories differed between mutation carriers and non-carriers.FindingsPiB PET was available for 346 individuals, with 162 having longitudinal imaging; FDG PET was available for 352 (175 longitudinal); and MRI data was available for 377 (201 longitudinal). We found a sequence to pathological changes, with rates of Aβ deposition in mutation carriers being significantly different from non-carriers first (on average across regions that showed a significant difference at −18·9 (sd 3·3) years before expected onset), followed by hypometabolism (−14·1 years, sd 5·1) and lastly structural declines (−4·7 years, sd 4·2). This biomarker ordering was preserved in most, but not all, regions. The temporal emergence within a biomarker varied across the brain, with the precuneus being the first cortical region in each modality to show divergence between groups (−22·2 years before expected onset for Aβ accumulation, −18·8 years for hypometabolism, and −13·0 years for cortical thinning).InterpretationMutation carriers had elevations in Aβ deposition, reduced glucose metabolism, and cortical thinning which preceded the expected onset of dementia. Accrual of these pathologies varied throughout the brain, suggesting differential regional and temporal vulnerabilities to Aβ, metabolic decline, and structural atrophy, which should be taken into account when using biomarkers in a clinical setting as well as designing and evaluating clinical trials.