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Evidence of beta amyloid independent small vessel disease in familial Alzheimer's disease

Lookup NU author(s): Dr Yoshiki HaseORCiD, Professor Raj KalariaORCiD

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This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (CC BY-NC-ND).


Abstract

© 2022 The Authors. Brain Pathology published by John Wiley & Sons Ltd on behalf of International Society of Neuropathology. We studied small vessel disease (SVD) pathology in Familial Alzheimer's disease (FAD) subjects carrying the presenilin 1 (PSEN1) p.Glu280Ala mutation in comparison to those with sporadic Alzheimer's disease (SAD) as a positive control for Alzheimer's pathology and Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL) bearing different NOTCH3 mutations, as positive controls for SVD pathology. Upon magnetic resonance imaging (MRI) in life, some FAD showed mild white matter hyperintensities and no further radiologic evidence of SVD. In post-mortem studies, total SVD pathology in cortical areas and basal ganglia was similar in PSEN1 FAD and CADASIL subjects, except for the feature of arteriosclerosis which was higher in CADASIL subjects than in PSEN1 FAD subjects. Further only a few SAD subjects showed a similar degree of SVD pathology as observed in CADASIL. Furthermore, we found significantly enlarged perivascular spaces in vessels devoid of cerebral amyloid angiopathy in FAD compared with SAD and CADASIL subjects. As expected, there was greater fibrinogen-positive perivascular reactivity in CADASIL but similar reactivity in PSEN1 FAD and SAD groups. Fibrinogen immunoreactivity correlated with onset age in the PSEN1 FAD cases, suggesting increased vascular permeability may contribute to cognitive decline. Additionally, we found reduced perivascular expression of PDGFRβ AQP4 in microvessels with enlarged PVS in PSEN1 FAD cases. We demonstrate that there is Aβ-independent SVD pathology in PSEN1 FAD, that was marginally lower than that in CADASIL subjects although not evident by MRI. These observations suggest presence of covert SVD even in PSEN1, contributing to disease progression. As is the case in SAD, these consequences may be preventable by early recognition and actively controlling vascular disease risk, even in familial forms of dementia.


Publication metadata

Author(s): Littau JL, Velilla L, Hase Y, Villalba-Moreno ND, Hagel C, Drexler D, Osorio Restrepo S, Villegas A, Lopera F, Vargas S, Glatzel M, Krasemann S, Quiroz YT, Arboleda-Velasquez JF, Kalaria R, Sepulveda-Falla D

Publication type: Article

Publication status: Published

Journal: Brain Pathology

Year: 2022

Volume: 32

Issue: 6

Print publication date: 01/11/2022

Online publication date: 13/06/2022

Acceptance date: 24/05/2022

Date deposited: 04/03/2024

ISSN (print): 1015-6305

ISSN (electronic): 1750-3639

Publisher: John Wiley and Sons Inc.

URL: https://doi.org/10.1111/bpa.13097

DOI: 10.1111/bpa.13097

Data Access Statement: Additional data supporting the findings of the study are available on request from the corresponding author. The data are not publicly available due to privacy of the patients and ethical restrictions.

PubMed id: 35695802


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Funding

Funder referenceFunder name
Bundesministerium für Bildung und Forschung
National Institute of Neurological Disorders and Stroke
RF1NS110048

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