The pattern of amyloid accumulation in the brains of adults with Down syndrome

Abstract

Introduction: Adults with Down syndrome (DS) invariably develop Alzheimer's disease (AD) neuropathology. Understanding amyloid deposition in DS can yield crucial information about disease pathogenesis.

Methods: Forty-nine adults with DS aged 25-65 underwent positron emission tomography with Pittsburgh compound-B (PIB). Regional PIB binding was assessed with respect to age, clinical, and cognitive status.

Results: Abnormal PIB binding became evident from 39 years, first in striatum followed by rostral prefrontal-cingulo-parietal regions, then caudal frontal, rostral temporal, primary sensorimotor and occipital, and finally parahippocampal cortex, thalamus, and amygdala. PIB binding was related to age, diagnostic status, and cognitive function.

Discussion: PIB binding in DS, first appearing in striatum, began around age 40 and was strongly associated with dementia and cognitive decline. The absence of a substantial time lag between amyloid accumulation and cognitive decline contrasts to sporadic/familial AD and suggests this population's suitability for an amyloid primary prevention trial.

Keywords: Alzheimer's disease; Amyloid; Dementia; Down syndrome; PET; PIB; Preclinical; Striatum.

Fig. 1

A scatter-plot representation of striatal non–displaceable binding potential for all participants, demonstrating the presence of two distinguishable populations. Classification of the two groups—PIB-positive and PIB-negative—was based on visual inspection of the data presented in this figure. Abbreviations: PIB, Pittsburgh compound–B; BP_ND, non–displaceable binding potential.

Fig. 2

Age has a strong nonlinear relationship with (A) the number of total regions with abnormal BP_ND (R² = 0.735) and (B) mean cortical BP_ND (R² = 0.728) in adults with DS. The youngest participant with abnormal PIB binding was 39 years old, and all individuals in this study aged >49 years displayed both abnormal subcortical and cortical PIB binding irrespective of their dementia status. The majority in the cognitively stable group (26 of the 33) had normal PIB binding; the other seven participants showed various levels of PIB binding. The majority (five of six) in the cognitive decline group had increased binding in 16 or more regions, whereas one participant in the cognitive decline and two in the dementia group had no evidence of increased PIB binding. Regions with abnormal/increased binding are defined as those with a BP_ND value that exceeds two standard deviations of the mean BP_ND for that given region in the PIB-negative group. (B) also includes BP_ND data of ten age-matched (mean = 36.4; range, 24–52 years), non–DS controls that act as “true control” of negative PIB binding, demonstrating that the PIB binding observed in the PIB-negative DS group is no different to what is considered negative in the typically developing population. Please note that some data points in (A) are overlapped if two or more participants of the same age had the same number of abnormal PIB-binding regions. Abbreviations: BP_ND, non–displaceable binding potential; DS, Down syndrome; PIB, Pittsburgh compound–B.

Fig. 3

A schematic brain map of numbered Brodmann areas and subcortical regions of interest colored according to the PIB staging model, where shade 1 denotes the area affected first (i.e. the striatum) and shade 9 the area affected latest (the amygdala). Abbreviations: thal, thalamus; amy, amygdala; PIB, Pittsburgh compound–B.