Citations

AbstractBackgroundGiven the triplication of chromosome 21 and the location of the amyloid precursor protein gene on chromosome 21, almost all adults with Down syndrome (DS) develop Alzheimer disease (AD)‐like pathology and dementia during their lifetime. Comparing amyloid accumulation in DS to autosomal dominant AD (ADAD), another genetic form of AD, may improve our understanding of early AD pathology development.MethodWe assessed amyloid positron emission tomography (PET) imaging in 192 participants with DS and 33 sibling controls from the Alzheimer’s Biomarker Consortium‐Down Syndrome (ABC‐DS) and 265 mutation‐carriers (MC) and 169 familial controls from the Dominantly Inherited Alzheimer Network (DIAN) (Table 1). We calculated regional standard uptake value ratios (SUVR) using a cerebellar cortex reference region and converted global amyloid burden SUVR to centiloids. We compared amyloid PET by cognitive status and estimated‐years‐to‐symptom‐onset (EYO). EYO was calculated for DIAN participants by subtracting their age from parental age of symptom onset and for ABC‐DS participants by subtracting their age from 50.2 years, a published average age of symptom onset in a large sample of individuals with DS (Fortea et al., 2020). In a subset of participants, we assessed the relationship between amyloid PET and CSF Aβ42/40.ResultThe relationship between CSF Aβ42/40 and amyloid PET was similar in DS and MC participants (Figure 1). We did not observe significant differences between MC and DS grouped by cognitive status (Figure 2). However, when assessed over EYO, global amyloid burden was significantly elevated in MC at EYO ≥ ‐23 but was not elevated in DS until EYO ≥ ‐15 (Figure 3). We observed early cortical and subcortical amyloid PET increases in both groups, but we also measured some regional differences in amyloid PET changes between MC and DS, specifically in the medial occipital region (Figure 4 and 5).ConclusionThese results demonstrate similarities in the relationship between amyloid biomarkers and the levels of amyloid accumulation in ADAD and DS. However, we also observed a 5‐10 year delay and some regional differences in amyloid accumulation in DS. This is important for future clinical trials to consider when recruiting participants and determining treatment efficacy.

Abstract Eosinophils (Eos) are found at increased numbers within necrotic areas of tumors. We show that necrotic material from cell lysates containing damage-associated molecular pattern molecules induce eosinophil degranulation (release of major basic protein and eosinophil peroxidase) and enhance their oxidative burst while the stimulatory capacity of cell lysates is significantly diminished following oxidation. High mobility group box 1 (HMGB1), a prototypic damage-associated molecular pattern molecule, released following necrosis but not apoptosis, induced a similar effect on Eos. Additionally, we demonstrate that HMGB1 enhances eosinophil survival and acts as a chemoattractant. Consistently, we show that Eos express an HMGB1 receptor, the receptor for advanced glycation end product, and that anti-receptor for advanced glycation end product could diminish the HMGB1-mediated effects. Of all tested biologic activities, Eos respond most sensitively to the presence of necrotic material including HMGB1 with generation of peroxide. We postulate that Eos “sense” necrotic cell death, migrating to and responding to areas of tissue injury/necrosis. Oxidation of cell lysates reduces their biologic activity when compared with native lysates. We postulate that eosinophil-associated modulation of immunity within tumor and other damaged tissues may be primarily by promoting oxidative degradation of necrotic material. Novel therapeutic strategies may be considered by advancing oxidative denaturation of released necrotic material using Eos or other aerobic strategies.