Neuropathological correlates of amyloid PET imaging in Down syndrome

Abstract

Down syndrome (DS) results in an overproduction of amyloid‐β (Aβ) peptide associated with early onset of Alzheimer's disease (AD). DS cases have Aβ deposits detectable histologically as young as 12–30 years of age, primarily in the form of diffuse plaques, the type of early amyloid pathology also seen at pre‐clinical (i.e., pathological aging) and prodromal stages of sporadic late onset AD. In DS subjects aged >40 years, levels of cortical Aβ deposition are similar to those observed in late onset AD and in addition to diffuse plaques involve cored plaques associated with dystrophic neurites (neuritic plaques), which are of neuropathological diagnostic significance in AD. The purpose of this review is to summarize and discuss findings from amyloid PET imaging studies of DS in reference to postmortem amyloid‐based neuropathology. PET neuroimaging applied to subjects with DS has the potential to (a) track the natural progression of brain pathology, including the earliest stages of amyloid accumulation, and (b) determine whether amyloid PET biomarkers predict the onset of dementia. In addition, the question that is still incompletely understood and relevant to both applications is the ability of amyloid PET to detect Aβ deposits in their earliest form.

Phosphorylated Aβ peptides in human Down syndrome brain and different Alzheimer’s-like mouse models

“…Previous studies showed that amyloid deposits of AD and DS brains are heterogeneous, and could contain post-translationally modified and truncated Aβ variants [ 16 , 18 – 23 , 29 , 31 , 35 , 36 , 39 , 42 , 54 , 61 , 76 ]. Some of these modified Aβ species are also observed in the brains of transgenic mice.…”

“…People with DS also have an increased risk of developing early onset AD [29][30][31]. Interestingly the gene encoding APP is localized within a region of chromosome 21 that is critical for DS, and the triplication of the APP gene results in elevated levels of Aβ peptides that form amyloid plaques at least two decades prior to the onset of the clinical AD-like symptoms [31][32][33]. DS brains demonstrate Aβ plaques already at 12-30 year of age, principally in the form of diffuse Aβ plaques, the type of early Aβ pathology also seen at preclinical (i.e., pathological aging) and prodromal stages of sporadic AD [30,[34][35][36].…”

“…Down syndrome is a genetic disorder caused by an extra copy of chromosome 21, and characterized by specific facial and neurological features. People with DS also have an increased risk of developing early onset AD [ 29 – 31 ]. Interestingly the gene encoding APP is localized within a region of chromosome 21 that is critical for DS, and the triplication of the APP gene results in elevated levels of Aβ peptides that form amyloid plaques at least two decades prior to the onset of the clinical AD-like symptoms [ 31 – 33 ].…”

“…DS brains demonstrate Aβ plaques already at 12–30 year of age, principally in the form of diffuse Aβ plaques, the type of early Aβ pathology also seen at pre-clinical (i.e., pathological aging) and prodromal stages of sporadic AD [ 30 , 34 – 36 ]. In DS subjects, aged > 40 years, levels of cortical Aβ deposition are similar to those observed in sporadic, late onset AD and demonstrate cored neuritic plaques, which are of neuropathological diagnostic significance in AD [ 29 – 31 ].Notably, autopsy studies of DS brain show the occurrence of isomerized, racemized, truncated, pyroglutamate and oxidized Aβ, indicating the accumulation of post-translationally modified Aβ variants as reviewed previously [ 30 ].…”

Alzheimer's disease in aging Down syndrome

“…Additional reviews explore neuroimaging of AD pathology in DS, including tau imaging (Rafii, ), imaging of cerebrovascular pathology (Carmona‐Iragui et al, ), and postmortem correlations of AD pathology to amyloid PET imaging (Abrahamson et al, ). Biomarkers are also a central theme of the reviews by Petersen and O'Bryant (2019) who explored the current state on the literature of blood‐based biomarkers found in individuals with DS, particularly those with AD or prodromal AD and by Alhajraf, Ness, Hye, & Strydom () who conducted meta‐analyses of studies comparing plasma amyloid beta (Aβ) levels between DS individuals and controls, and between DS individuals with and without dementia.…”