Postmortem Neocortical 3H-PiB Binding and Levels of Unmodified and Pyroglutamate Aβ in Down Syndrome and Sporadic Alzheimer’s Disease
Individuals with Down syndrome (DS) have a genetic predisposition for amyloid-β (Aβ) overproduction and earlier onset of Aβ deposits compared to patients with sporadic late-onset Alzheimer’s disease (AD). Positron emission tomography (PET) with Pittsburgh Compound-B (PiB) detects fibrillar Aβ pathol...
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Frontiers Media S.A.
2021-08-01
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Series: | Frontiers in Aging Neuroscience |
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Online Access: | https://www.frontiersin.org/articles/10.3389/fnagi.2021.728739/full |
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record_format |
Article |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Violetta N. Pivtoraiko Violetta N. Pivtoraiko Tamara Racic Eric E. Abrahamson Eric E. Abrahamson Victor L. Villemagne Benjamin L. Handen Ira T. Lott Elizabeth Head Milos D. Ikonomovic Milos D. Ikonomovic Milos D. Ikonomovic |
spellingShingle |
Violetta N. Pivtoraiko Violetta N. Pivtoraiko Tamara Racic Eric E. Abrahamson Eric E. Abrahamson Victor L. Villemagne Benjamin L. Handen Ira T. Lott Elizabeth Head Milos D. Ikonomovic Milos D. Ikonomovic Milos D. Ikonomovic Postmortem Neocortical 3H-PiB Binding and Levels of Unmodified and Pyroglutamate Aβ in Down Syndrome and Sporadic Alzheimer’s Disease Frontiers in Aging Neuroscience Alzheimer’s disease amyloid cerebral amyloid angiopathy default mode network Down syndrome Pittsburgh Compound-B |
author_facet |
Violetta N. Pivtoraiko Violetta N. Pivtoraiko Tamara Racic Eric E. Abrahamson Eric E. Abrahamson Victor L. Villemagne Benjamin L. Handen Ira T. Lott Elizabeth Head Milos D. Ikonomovic Milos D. Ikonomovic Milos D. Ikonomovic |
author_sort |
Violetta N. Pivtoraiko |
title |
Postmortem Neocortical 3H-PiB Binding and Levels of Unmodified and Pyroglutamate Aβ in Down Syndrome and Sporadic Alzheimer’s Disease |
title_short |
Postmortem Neocortical 3H-PiB Binding and Levels of Unmodified and Pyroglutamate Aβ in Down Syndrome and Sporadic Alzheimer’s Disease |
title_full |
Postmortem Neocortical 3H-PiB Binding and Levels of Unmodified and Pyroglutamate Aβ in Down Syndrome and Sporadic Alzheimer’s Disease |
title_fullStr |
Postmortem Neocortical 3H-PiB Binding and Levels of Unmodified and Pyroglutamate Aβ in Down Syndrome and Sporadic Alzheimer’s Disease |
title_full_unstemmed |
Postmortem Neocortical 3H-PiB Binding and Levels of Unmodified and Pyroglutamate Aβ in Down Syndrome and Sporadic Alzheimer’s Disease |
title_sort |
postmortem neocortical 3h-pib binding and levels of unmodified and pyroglutamate aβ in down syndrome and sporadic alzheimer’s disease |
publisher |
Frontiers Media S.A. |
series |
Frontiers in Aging Neuroscience |
issn |
1663-4365 |
publishDate |
2021-08-01 |
description |
Individuals with Down syndrome (DS) have a genetic predisposition for amyloid-β (Aβ) overproduction and earlier onset of Aβ deposits compared to patients with sporadic late-onset Alzheimer’s disease (AD). Positron emission tomography (PET) with Pittsburgh Compound-B (PiB) detects fibrillar Aβ pathology in living people with DS and AD, but its relationship with heterogeneous Aβ forms aggregated within amyloid deposits is not well understood. We performed quantitative in vitro3H-PiB binding assays and enzyme-linked immunosorbent assays of fibrillar (insoluble) unmodified Aβ40 and Aβ42 forms and N-terminus truncated and pyroglutamate-modified AβNpE3-40 and AβNpE3-42 forms in postmortem frontal cortex and precuneus samples from 18 DS cases aged 43–63 years and 17 late-onset AD cases aged 62–99 years. Both diagnostic groups had frequent neocortical neuritic plaques, while the DS group had more severe vascular amyloid pathology (cerebral amyloid angiopathy, CAA). Compared to the AD group, the DS group had higher levels of Aβ40 and AβNpE3-40, while the two groups did not differ by Aβ42 and AβNpE3-42 levels. This resulted in lower ratios of Aβ42/Aβ40 and AβNpE3-42/AβNpE3-40 in the DS group compared to the AD group. Correlations of Aβ42/Aβ40 and AβNpE3-42/AβNpE3-40 ratios with CAA severity were strong in DS cases and weak in AD cases. Pyroglutamate-modified Aβ levels were lower than unmodified Aβ levels in both diagnostic groups, but within group proportions of both pyroglutamate-modified Aβ forms relative to both unmodified Aβ forms were lower in the DS group but not in the AD group. The two diagnostic groups did not differ by 3H-PiB binding levels. These results demonstrate that compared to late-onset AD cases, adult DS individuals with similar severity of neocortical neuritic plaques and greater CAA pathology have a preponderance of both pyroglutamate-modified AβNpE3-40 and unmodified Aβ40 forms. Despite the distinct molecular profile of Aβ forms and greater vascular amyloidosis in DS cases, cortical 3H-PiB binding does not distinguish between diagnostic groups that are at an advanced level of amyloid plaque pathology. This underscores the need for the development of CAA-selective PET radiopharmaceuticals to detect and track the progression of cerebral vascular amyloid deposits in relation to Aβ plaques in individuals with DS. |
topic |
Alzheimer’s disease amyloid cerebral amyloid angiopathy default mode network Down syndrome Pittsburgh Compound-B |
url |
https://www.frontiersin.org/articles/10.3389/fnagi.2021.728739/full |
work_keys_str_mv |
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doaj-dd692ebe3f2b459687b02f367a106ae72021-08-18T12:13:57ZengFrontiers Media S.A.Frontiers in Aging Neuroscience1663-43652021-08-011310.3389/fnagi.2021.728739728739Postmortem Neocortical 3H-PiB Binding and Levels of Unmodified and Pyroglutamate Aβ in Down Syndrome and Sporadic Alzheimer’s DiseaseVioletta N. Pivtoraiko0Violetta N. Pivtoraiko1Tamara Racic2Eric E. Abrahamson3Eric E. Abrahamson4Victor L. Villemagne5Benjamin L. Handen6Ira T. Lott7Elizabeth Head8Milos D. Ikonomovic9Milos D. Ikonomovic10Milos D. Ikonomovic11Geriatric Research Education and Clinical Center, VA Pittsburgh Healthcare System, Pittsburgh, PA, United StatesDepartment of Neurology, University of Pittsburgh School of Medicine, Pittsburgh, PA, United StatesDepartment of Neurology, University of Pittsburgh School of Medicine, Pittsburgh, PA, United StatesGeriatric Research Education and Clinical Center, VA Pittsburgh Healthcare System, Pittsburgh, PA, United StatesDepartment of Neurology, University of Pittsburgh School of Medicine, Pittsburgh, PA, United StatesDepartment of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, PA, United StatesDepartment of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, PA, United StatesDepartment of Neurology, UC Irvine School of Medicine, Orange, CA, United StatesDepartment of Pathology and Laboratory Medicine, UC Irvine School of Medicine, Orange, CA, United StatesGeriatric Research Education and Clinical Center, VA Pittsburgh Healthcare System, Pittsburgh, PA, United StatesDepartment of Neurology, University of Pittsburgh School of Medicine, Pittsburgh, PA, United StatesDepartment of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, PA, United StatesIndividuals with Down syndrome (DS) have a genetic predisposition for amyloid-β (Aβ) overproduction and earlier onset of Aβ deposits compared to patients with sporadic late-onset Alzheimer’s disease (AD). Positron emission tomography (PET) with Pittsburgh Compound-B (PiB) detects fibrillar Aβ pathology in living people with DS and AD, but its relationship with heterogeneous Aβ forms aggregated within amyloid deposits is not well understood. We performed quantitative in vitro3H-PiB binding assays and enzyme-linked immunosorbent assays of fibrillar (insoluble) unmodified Aβ40 and Aβ42 forms and N-terminus truncated and pyroglutamate-modified AβNpE3-40 and AβNpE3-42 forms in postmortem frontal cortex and precuneus samples from 18 DS cases aged 43–63 years and 17 late-onset AD cases aged 62–99 years. Both diagnostic groups had frequent neocortical neuritic plaques, while the DS group had more severe vascular amyloid pathology (cerebral amyloid angiopathy, CAA). Compared to the AD group, the DS group had higher levels of Aβ40 and AβNpE3-40, while the two groups did not differ by Aβ42 and AβNpE3-42 levels. This resulted in lower ratios of Aβ42/Aβ40 and AβNpE3-42/AβNpE3-40 in the DS group compared to the AD group. Correlations of Aβ42/Aβ40 and AβNpE3-42/AβNpE3-40 ratios with CAA severity were strong in DS cases and weak in AD cases. Pyroglutamate-modified Aβ levels were lower than unmodified Aβ levels in both diagnostic groups, but within group proportions of both pyroglutamate-modified Aβ forms relative to both unmodified Aβ forms were lower in the DS group but not in the AD group. The two diagnostic groups did not differ by 3H-PiB binding levels. These results demonstrate that compared to late-onset AD cases, adult DS individuals with similar severity of neocortical neuritic plaques and greater CAA pathology have a preponderance of both pyroglutamate-modified AβNpE3-40 and unmodified Aβ40 forms. Despite the distinct molecular profile of Aβ forms and greater vascular amyloidosis in DS cases, cortical 3H-PiB binding does not distinguish between diagnostic groups that are at an advanced level of amyloid plaque pathology. This underscores the need for the development of CAA-selective PET radiopharmaceuticals to detect and track the progression of cerebral vascular amyloid deposits in relation to Aβ plaques in individuals with DS.https://www.frontiersin.org/articles/10.3389/fnagi.2021.728739/fullAlzheimer’s diseaseamyloidcerebral amyloid angiopathydefault mode networkDown syndromePittsburgh Compound-B |