Presenilin-1 mutation position influences amyloidosis, small vessel disease, and dementia with disease stage
© 2024 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association..
INTRODUCTION: Amyloidosis, including cerebral amyloid angiopathy, and markers of small vessel disease (SVD) vary across dominantly inherited Alzheimer's disease (DIAD) presenilin-1 (PSEN1) mutation carriers. We investigated how mutation position relative to codon 200 (pre-/postcodon 200) influences these pathologic features and dementia at different stages.
METHODS: Individuals from families with known PSEN1 mutations (n = 393) underwent neuroimaging and clinical assessments. We cross-sectionally evaluated regional Pittsburgh compound B-positron emission tomography uptake, magnetic resonance imaging markers of SVD (diffusion tensor imaging-based white matter injury, white matter hyperintensity volumes, and microhemorrhages), and cognition.
RESULTS: Postcodon 200 carriers had lower amyloid burden in all regions but worse markers of SVD and worse Clinical Dementia Rating® scores compared to precodon 200 carriers as a function of estimated years to symptom onset. Markers of SVD partially mediated the mutation position effects on clinical measures.
DISCUSSION: We demonstrated the genotypic variability behind spatiotemporal amyloidosis, SVD, and clinical presentation in DIAD, which may inform patient prognosis and clinical trials.
HIGHLIGHTS: Mutation position influences Aβ burden, SVD, and dementia. PSEN1 pre-200 group had stronger associations between Aβ burden and disease stage. PSEN1 post-200 group had stronger associations between SVD markers and disease stage. PSEN1 post-200 group had worse dementia score than pre-200 in late disease stage. Diffusion tensor imaging-based SVD markers mediated mutation position effects on dementia in the late stage.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2024 |
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| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:20 |
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| Enthalten in: |
Alzheimer's & dementia : the journal of the Alzheimer's Association - 20(2024), 4 vom: 26. Apr., Seite 2680-2697 |
| Sprache: |
Englisch |
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| Links: |
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| Anmerkungen: |
Date Completed 22.04.2024 Date Revised 26.04.2024 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1002/alz.13729 |
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| 100 | 1 | |a Joseph-Mathurin, Nelly |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Presenilin-1 mutation position influences amyloidosis, small vessel disease, and dementia with disease stage |
| 264 | 1 | |c 2024 | |
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| 500 | |a Date Completed 22.04.2024 | ||
| 500 | |a Date Revised 26.04.2024 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a © 2024 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association. | ||
| 520 | |a INTRODUCTION: Amyloidosis, including cerebral amyloid angiopathy, and markers of small vessel disease (SVD) vary across dominantly inherited Alzheimer's disease (DIAD) presenilin-1 (PSEN1) mutation carriers. We investigated how mutation position relative to codon 200 (pre-/postcodon 200) influences these pathologic features and dementia at different stages | ||
| 520 | |a METHODS: Individuals from families with known PSEN1 mutations (n = 393) underwent neuroimaging and clinical assessments. We cross-sectionally evaluated regional Pittsburgh compound B-positron emission tomography uptake, magnetic resonance imaging markers of SVD (diffusion tensor imaging-based white matter injury, white matter hyperintensity volumes, and microhemorrhages), and cognition | ||
| 520 | |a RESULTS: Postcodon 200 carriers had lower amyloid burden in all regions but worse markers of SVD and worse Clinical Dementia Rating® scores compared to precodon 200 carriers as a function of estimated years to symptom onset. Markers of SVD partially mediated the mutation position effects on clinical measures | ||
| 520 | |a DISCUSSION: We demonstrated the genotypic variability behind spatiotemporal amyloidosis, SVD, and clinical presentation in DIAD, which may inform patient prognosis and clinical trials | ||
| 520 | |a HIGHLIGHTS: Mutation position influences Aβ burden, SVD, and dementia. PSEN1 pre-200 group had stronger associations between Aβ burden and disease stage. PSEN1 post-200 group had stronger associations between SVD markers and disease stage. PSEN1 post-200 group had worse dementia score than pre-200 in late disease stage. Diffusion tensor imaging-based SVD markers mediated mutation position effects on dementia in the late stage | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a PSEN1 | |
| 650 | 4 | |a PiB‐PET | |
| 650 | 4 | |a autosomal dominant Alzheimer's disease (ADAD) | |
| 650 | 4 | |a cerebral amyloid angiopathy (CAA) | |
| 650 | 4 | |a codon 200 | |
| 650 | 4 | |a dominantly inherited Alzheimer's disease (DIAD) | |
| 650 | 4 | |a microbleeds | |
| 650 | 4 | |a microhemorrhages | |
| 650 | 4 | |a peak width of skeletonized mean diffusivity (PSMD) | |
| 650 | 4 | |a presenilin‐1 | |
| 650 | 4 | |a small vessel disease (SVD) | |
| 650 | 4 | |a white matter hyperintensity (WMH) | |
| 650 | 7 | |a Presenilin-1 |2 NLM | |
| 700 | 1 | |a Feldman, Rebecca L |e verfasserin |4 aut | |
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