Evidence of beta amyloid independent small vessel disease in familial Alzheimer's disease
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Evidence of beta amyloid independent small vessel disease in familial Alzheimer's disease. / Littau, Jessica Lisa; Velilla, Lina; Hase, Yoshiki; Villalba-Moreno, Nelson David; Hagel, Christian; Drexler, Dagmar; Osorio Restrepo, Santiago; Villegas, Andres; Lopera, Francisco; Vargas, Sergio; Glatzel, Markus; Krasemann, Susanne; Quiroz, Yakeel T; Arboleda-Velasquez, Joseph F; Kalaria, Rajesh; Sepulveda-Falla, Diego.
In: BRAIN PATHOL, Vol. 32, No. 6, 11.2022, p. e13097.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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TY - JOUR
T1 - Evidence of beta amyloid independent small vessel disease in familial Alzheimer's disease
AU - Littau, Jessica Lisa
AU - Velilla, Lina
AU - Hase, Yoshiki
AU - Villalba-Moreno, Nelson David
AU - Hagel, Christian
AU - Drexler, Dagmar
AU - Osorio Restrepo, Santiago
AU - Villegas, Andres
AU - Lopera, Francisco
AU - Vargas, Sergio
AU - Glatzel, Markus
AU - Krasemann, Susanne
AU - Quiroz, Yakeel T
AU - Arboleda-Velasquez, Joseph F
AU - Kalaria, Rajesh
AU - Sepulveda-Falla, Diego
N1 - © 2022 The Authors. Brain Pathology published by John Wiley & Sons Ltd on behalf of International Society of Neuropathology.
PY - 2022/11
Y1 - 2022/11
N2 - 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.
AB - 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.
U2 - 10.1111/bpa.13097
DO - 10.1111/bpa.13097
M3 - SCORING: Journal article
C2 - 35695802
VL - 32
SP - e13097
JO - BRAIN PATHOL
JF - BRAIN PATHOL
SN - 1015-6305
IS - 6
ER -
