Delineating the topography of amyloid-associated cortical atrophy in Down syndrome

Abstract

Older adults with Down Syndrome (DS) often have Alzheimer's disease (AD) neuropathologies. While PET imaging studies of amyloid deposition (Aβ) have been associated with worse clinical prognosis and cognitive impairment, their relationships with cortical thickness remain unclear in people with DS. METHODS: In a sample of 44 DS adults who underwent cognitive assessments, [ 11 C]-PiB PET and T1-MPRAGE, we used mixed effect models to evaluate the spatial relationships between Aβ binding with patterns of cortical thickness. Partial Spearman correlations were used to delineate the topography of local Aβ-associated cortical thinning. RESULTS: [ 11 C]-PiB BP ND was negatively associated with decreased cortical thickness. Locally, regional [ 11 C]-PiB retention was negatively correlated with cortical thickness in widespread cortices, predominantly in temporo-parietal regions. CONCLUSION: Contrary to the prevailing evidence in established AD, we propose that our findings implicate Aβ in spatial patterns of atrophy that recapitulated the "cortical signature" of neurodegeneration in AD, conferring support to recent recommendations for earlier diseaseinterventions.

Targeting increased levels of APP in Down syndrome: Posiphen‐mediated reductions in APP and its products reverse endosomal phenotypes in the Ts65Dn mouse model

“…10,25,27 Although studies of genetic risk variants for AD in DS has received little attention, the APOE ɛ4 allele is associated with increased accumulation of Aβ 28 and increased risk of earlier onset of dementia. 29 In summary, the remarkable correspondence between the general and DS populations in clinical manifestations, biomarkers, [30][31][32][33] and neuropathological features [34][35][36] justifies the designation of AD in DS (AD-DS). 23 It is notable that the necessary role played by increased APP gene dose in AD-DS motivates, and may simplify, approaches for exploring AD pathogenesis and treatment of AD-DS.…”

Neuropathological correlates of amyloid PET imaging in Down syndrome

“…Understanding structural properties, biochemical constituents, and evolution of morphologically diverse Aβ plaques and other AD‐related pathology within and between brain regions in relation to age and development of dementia is needed to guide interpretation of amyloid PET imaging of subjects with DS (Head, Helman, Powell, & Schmitt, ; Neale, Padilla, Fonseca, Holland, & Zaman, ). Compared to the extensive number of amyloid PET studies performed in AD (Cohen et al, ), there are relatively few amyloid PET studies of DS (Annus et al, , ; Cohen et al, ; Cole et al, ; Handen et al, ; Hartley et al, ; Jennings et al, ; Landt et al, ; Lao et al, , ; Mak et al, ; Matthews et al, ; Rafii et al, ; Sabbagh et al, ), even fewer longitudinal studies (Hartley et al, ; Lao et al, ; Tudorascu et al, ), and only one imaging‐to‐autopsy analysis (Sabbagh et al, ). Building upon the understanding that AD and DS brains/pathology are not the same, the purpose of this article is to summarize amyloid PET imaging studies of people with DS in the context of neuropathology defined at autopsy, to guide interpretation of future investigations in larger numbers of subjects with DS over longer periods of time.…”

Multi-Modal Imaging in Down's Syndrome: Maximizing Utility Through Innovative Neuroimaging Approaches

“…In addition, several reports have highlighted the striatum as a possible nidus of amyloid accumulation, as it is commonly associated with the earliest and most prominent signal retention (8,10), similar to that observed in a [ 11 C]-PiB PET study of presenilin-1 (PS1) mutation carriers (11). The clinical relevance of Aβ in DS has been highlighted through its associations with brain atrophy (12) and mild cognitive impairment in DS (13). While longitudinal data is scarce, Aβ accumulation in DS rates are similar to that observed in late-onset AD (14), despite an earlier onset by ∼15-20 years (8,10).…”

“…The cortical signature of DS has been a subject of extensive investigations using T 1 -weighted MRI (9,12,19,25). A common finding in the literature points is that of Aβassociated atrophy in temporo-parietal cortices and subcortical atrophy, hallmarks of atrophy patterns in sporadic AD (26).…”