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Amyloid accumulation in Down syndrome measured with amyloid load.

ABSTRACT: Introduction:Individuals with Down syndrome (DS) show enhanced amyloid beta (A?) deposition in the brain. A new positron emission tomography (PET) index of amyloid load (A?L ) was recently developed as an alternative to standardized uptake value ratios (SUVrs) to quantify A? burden with high sensitivity for detecting and tracking A? change.1. Methods:A?L was calculated in a DS cohort (N = 169, mean age ± SD = 39.6 ± 8.7 years) using [C-11]Pittsburgh compound B (PiB) PET imaging. DS-specific PiB templates were created for A? carrying capacity (K) and non-specific binding (NS). Results:The highest values of A? carrying capacity were found in the striatum and precuneus. Longitudinal changes in A?L displayed less variability when compared to SUVrs. Discussion:These results highlight the utility of A?L for characterizing A? deposition in DS. Rates of A? accumulation in DS were found to be similar to that observed in late-onset Alzheimer's disease (AD; ?3% to 4% per year), suggesting that AD progression in DS is of earlier onset but not accelerated.

SUBMITTER: Zammit MD

PROVIDER: S-EPMC7233422 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Amyloid accumulation in Down syndrome measured with amyloid load.

Zammit Matthew D MD Laymon Charles M CM Betthauser Tobey J TJ Cody Karly A KA Tudorascu Dana L DL Minhas Davneet S DS Sabbagh Marwan N MN Johnson Sterling C SC Zaman Shahid H SH Mathis Chester A CA Klunk William E WE Handen Benjamin L BL Cohen Ann D AD Christian Bradley T BT

Alzheimer's & dementia (Amsterdam, Netherlands) 20200416 1

<h4>Introduction</h4>Individuals with Down syndrome (DS) show enhanced amyloid beta (Aβ) deposition in the brain. A new positron emission tomography (PET) index of amyloid load (<i>Aβ<sub>L</sub></i> ) was recently developed as an alternative to standardized uptake value ratios (SUVrs) to quantify Aβ burden with high sensitivity for detecting and tracking Aβ change.<sup>1</sup>.<h4>Methods</h4><i>Aβ<sub>L</sub></i> was calculated in a DS cohort (N = 169, mean age ± SD = 39.6 ± 8.7 years) using [ ...[more]

PMID: 32435686

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Project description:Down syndrome (DS, trisomy 21) is the most common chromosomal disorder and the leading genetic cause of intellectual disability in humans. In DS, triplication of chromosome 21 invariably includes the APP gene (21q21) encoding the Alzheimer's disease (AD) amyloid precursor protein (APP). Triplication of the APP gene accelerates APP expression leading to cerebral accumulation of APP-derived amyloid-beta peptides (Abeta), early-onset AD neuropathology, and age-dependent cognitive sequelae. The DS phenotype complex also includes distinctive early-onset cerulean cataracts of unknown etiology. Previously, we reported increased Abeta accumulation, co-localizing amyloid pathology, and disease-linked supranuclear cataracts in the ocular lenses of subjects with AD. Here, we investigate the hypothesis that related AD-linked Abeta pathology underlies the distinctive lens phenotype associated with DS. Ophthalmological examinations of DS subjects were correlated with phenotypic, histochemical, and biochemical analyses of lenses obtained from DS, AD, and normal control subjects. Evaluation of DS lenses revealed a characteristic pattern of supranuclear opacification accompanied by accelerated supranuclear Abeta accumulation, co-localizing amyloid pathology, and fiber cell cytoplasmic Abeta aggregates (approximately 5 to 50 nm) identical to the lens pathology identified in AD. Peptide sequencing, immunoblot analysis, and ELISA confirmed the identity and increased accumulation of Abeta in DS lenses. Incubation of synthetic Abeta with human lens protein promoted protein aggregation, amyloid formation, and light scattering that recapitulated the molecular pathology and clinical features observed in DS lenses. These results establish the genetic etiology of the distinctive lens phenotype in DS and identify the molecular origin and pathogenic mechanism by which lens pathology is expressed in this common chromosomal disorder. Moreover, these findings confirm increased Abeta accumulation as a key pathogenic determinant linking lens and brain pathology in both DS and AD.

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Amyloid accumulation in Down syndrome measured with amyloid load.

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Amyloid accumulation in Down syndrome measured with amyloid load.

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