Distinct cerebral amyloid angiopathy patterns in adult Down syndrome

Cerebral amyloid angiopathy (CAA) is an important component of the neuropathology of adult Down syndrome (DS); however, there is a paucity of its systematic in-depth analysis.

Eleven adult DS cases were analyzed for the presence, type, severity (Vonsattel grade), extension (Love grade), and advancement (Thal stage) of CAA using amyloid-beta immunohistochemistry. Hemorrhagic and iron pathologies were assessed by Perls staining, with double-stainings for co-localization. Descriptive/associative analyses were performed.

10/11 cases had CAA (DS-CAA), all reaching stage 3. 10/10 demonstrated severe/extensive leptomeningeal-predominant neocortical CAA. 7/10 had neocortical capillary involvement (Type 1), accompanying more extensive CAA. Cerebellar CAA was ubiquitous and severe, with lowering frequencies/grades in other stage 2-3 regions. Hemorrhagic alterations were found only in 5/10 patients, without gross hematomas. One patient had extreme cerebellar glial iron pathology, with scattered iron-containing glia being common in the cerebellum and neocortex of all DS-CAA cases, likely reflecting hypoperfusion.

In this study unique in its depth and scale of analysis, CAA was found to be frequent, severe, and extensive in adult DS. Distinguishing features include the remarkable involvement of the cerebellum, the deep regions, and capillaries. The paucity of hemorrhages implies a complex mechanism for hemorrhage formation in CAA beyond vasculopathic severity. The observed iron pathology suggests the relevance of chronic hypoperfusion in DS-CAA.