Dataset Information

The Down syndrome brain in the presence and absence of fibrillar β-amyloidosis.

ABSTRACT: People with Down syndrome (DS) have a neurodevelopmentally distinct brain and invariably developed amyloid neuropathology by age 50. This cross-sectional study aimed to provide a detailed account of DS brain morphology and the changes occuring with amyloid neuropathology. Forty-six adults with DS underwent structural and amyloid imaging-the latter using Pittsburgh compound B (PIB) to stratify the cohort into PIB-positive (n = 19) and PIB-negative (n = 27). Age-matched controls (n = 30) underwent structural imaging. Group differences in deep gray matter volumetry and cortical thickness were studied. PIB-negative people with DS have neurodevelopmentally atypical brain, characterized by disproportionately thicker frontal and occipitoparietal cortex and thinner motor cortex and temporal pole with larger putamina and smaller hippocampi than controls. In the presence of amyloid neuropathology, the DS brains demonstrated a strikingly similar pattern of posterior dominant cortical thinning and subcortical atrophy in the hippocampus, thalamus, and striatum, to that observed in non-DS Alzheimer's disease. Care must be taken to avoid underestimating amyloid-associated morphologic changes in DS due to disproportionate size of some subcortical structures and thickness of the cortex.

SUBMITTER: Annus T

PROVIDER: S-EPMC5391869 | biostudies-literature | 2017 May

REPOSITORIES: biostudies-literature

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The Down syndrome brain in the presence and absence of fibrillar β-amyloidosis.

Annus Tiina T Wilson Liam R LR Acosta-Cabronero Julio J Cardenas-Blanco Arturo A Hong Young T YT Fryer Tim D TD Coles Jonathan P JP Menon David K DK Zaman Shahid H SH Holland Anthony J AJ Nestor Peter J PJ

Neurobiology of aging 20170117

People with Down syndrome (DS) have a neurodevelopmentally distinct brain and invariably developed amyloid neuropathology by age 50. This cross-sectional study aimed to provide a detailed account of DS brain morphology and the changes occuring with amyloid neuropathology. Forty-six adults with DS underwent structural and amyloid imaging-the latter using Pittsburgh compound B (PIB) to stratify the cohort into PIB-positive (n = 19) and PIB-negative (n = 27). Age-matched controls (n = 30) underwent ...[more]

PMID: 28192686

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Project description:BackgroundDown syndrome appears to be associated with a virtually certain risk of fibrillar amyloid-β (Aβ) pathology by the age of 40 and a very high risk of dementia at older ages. The positron emission tomography (PET) ligand florbetapir F18 has been shown to characterize fibrillar Aβ in the living human brain and to provide a close correlation with subsequent Aβ neuropathology in individuals proximate to and after the end of life. The extent to which the most frequently used PET ligands can be used to detect fibrillar Aβ in patients with Down syndrome remains to be determined.ObjectivesTo characterize PET estimates of fibrillar Aβ burden in a Down syndrome patient very close to the end of life and to compare them with neuropathologic assessment made after his death. Design/MethodsWith the family's informed consent, florbetapir PET was used to study a 55-year-old Down syndrome patient with Alzheimer disease near the end of life; his brain was donated for neuropathologic assessment when he died 14 days later. Visual ratings of cerebral florbetapir uptake were performed by trained readers who were masked to the patient's diagnosis as part of a larger study, and an automated algorithm was used to characterize regional-to-cerebellar standard uptake value ratios in 6 cerebral regions of interest. Neuropathologic assessments were performed masked to the patient's diagnosis or PET measurements.ResultsVisual ratings and automated analyses of the PET image revealed a heavy fibrillar Aβ burden in cortical, striatal, and thalamic regions, similar to that reported for patients with late-onset Alzheimer disease. This matched neuropathologic findings of frequent neuritic and diffuse plaques, as well as frequent amyloid angiopathy, except for neuropathologically demonstrated frequent cerebellar diffuse plaques and amyloid angiopathy that were not detected by the PET scan.ConclusionsFlorbetapir PET can be used to detect increased cerebral-to-cerebellar fibrillar Aβ burden in a Down syndrome patient with Alzheimer disease, even in the presence of frequent amyloid angiopathy and diffuse plaques in the cerebellum. Additional studies are needed to determine the extent to which PET could be used to detect and to track fibrillar Aβ and to evaluate investigational Aβ-modifying treatments in the presymptomatic and symptomatic stages of Alzheimer disease.

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.

Project description:Objectives: In recent years several 18F-labeled amyloid PET (Aβ-PET) tracers have been developed and have obtained clinical approval. There is evidence that Aβ-PET perfusion can provide surrogate information about neuronal injury in neurodegenerative diseases when compared to conventional blood flow and glucose metabolism assessment. However, this paradigm has not yet been tested in neurodegenerative disorders with cortical and subcortical affection. Therefore, we investigated the performance of early acquisition 18F-flutemetamol Aβ-PET in comparison to 18F-fluorodeoxyglucose (FDG)-PET in corticobasal syndrome (CBS). Methods: Subjects with clinically possible or probable CBS were recruited within the prospective Activity of Cerebral Networks, Amyloid and Microglia in Aging and Alzheimer's Disease (ActiGliA) observational study and all CBS cases with an available FDG-PET prior to Aβ-PET were selected. Aβ-PET was acquired 0-10 min p.i. (early-phase) and 90-110 min p.i. (late-phase) whereas FDG-PET was recorded statically from 30 to 50 min p.i. Semiquantitative regional values and asymmetry indices (AI) were compared between early-phase Aβ-PET and FDG-PET. Visual assessments of hypoperfusion and hypometabolism were compared between both methods. Late-phase Aβ-PET was evaluated visually for assessment of Aβ-positivity. Results: Among 20 evaluated patients with CBS, 5 were Aβ-positive. Early-phase Aβ-PET and FDG-PET SUVr correlated highly in cortical (mean R = 0.86, range 0.77-0.92) and subcortical brain regions (mean R = 0.84, range 0.79-0.90). Strong asymmetry was observed in FDG-PET for the motor cortex (mean |AI| = 2.9%), the parietal cortex (mean |AI| = 2.9%), and the thalamus (mean |AI| = 5.5%), correlating well with AI of early-phase Aβ-PET (mean R = 0.87, range 0.62-0.98). Visual assessments of hypoperfusion and hypometabolism were highly congruent. Conclusion: Early-phase Aβ-PET facilitates assessment of neuronal injury in CBS for cortical and subcortical areas. Known asymmetries in CBS are captured by this method, enabling assessment of Aβ-status and neuronal injury with a single radiation exposure at a single visit.

Dataset Information

The Down syndrome brain in the presence and absence of fibrillar β-amyloidosis.

Publications

The Down syndrome brain in the presence and absence of fibrillar β-amyloidosis.

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