Elevated complement mediator levels in endothelial-derived plasma exosomes implicate endothelial innate inflammation in diminished brain function of aging humans

AbstractWe test the hypothesis that endothelial cells adopt an inflammatory phenotype in functionally intact aged human subjects with radiographic evidence of white matter hyperintensity (WMH) suggestive of small cerebrovascular disease. Components of all three complement effector pathways and regulatory proteins were quantified in extracts of plasma endothelial-derived exosomes (EDE) of 11 subjects (age 70–82) with and 15 without evidence of WMH on MRI. Group differences and associations with plasma markers of immune activation (IL6, ICAM1), cognition and neuroimaging were calculated via regression modelling. EDE complement factors within the alternative and classical pathways were found to be higher and regulatory proteins lower in subjects with WMH. EDE levels of some complement components demonstrated significant associations with cognitive slowing and elevated systolic blood pressure. The inhibitor of the membrane attack complex, CD46, showed a significant positive association with cerebral grey matter volume. Plasma inflammatory markers, IL6 and ICAM1, were positively associated with EDE levels of several complement components. These findings provide the first in vivo evidence of the association of endothelial cell inflammation with white matter disease, age-associated cognitive changes, and brain degeneration in functionally normal older individuals. Future endothelial biomarker development may permit recognition of early or preclinical stages of vascular contributions to cognitive impairment and dementia.

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Endothelial-derived exosomes demonstrate a link between endothelial innate inflammation and brain dysfunction and injury in aging

10.1101/670083 ◽

2019 ◽

Cited By ~ 1

Author(s):

F.M. Elahi ◽

D. Harvey ◽

M. Altendahl ◽

K.B. Casaletto ◽

N. Fernandes ◽

...

Keyword(s):

White Matter ◽

Human Subjects ◽

Positive Association ◽

Regulatory Proteins ◽

White Matter Injury ◽

White Matter Hyperintensity ◽

Grey Matter Volume ◽

Older Individuals ◽

Significant Positive Association

ABSTRACTWe test the hypothesis that endothelial cells take on an inflammatory phenotype in functionally intact human subjects with radiographic evidence of white matter injury. Markers within all three complement effector pathways and regulatory proteins were quantified from endothelial-derived exosomes (EDE) of subjects (age 70-82) with (n=11) and without (n=16) evidence of white matter hyperintensity on MRI. Group differences and associations with systemic markers of immune activation (IL6, ICAM1), cognition and neuroimaging were calculated via regression modelling.EDE complement factors within the alternative and classical pathways were found to be higher and regulatory proteins lower in subjects with WMH. EDE levels of several factors demonstrated significant associations with cognitive slowing and systolic blood pressure. The inhibitor of the membrane attack complex, CD46, showed a significant positive association with cerebral grey matter volume. Systemic inflammatory markers, IL6 and ICAM1, were positively associated with EDE levels of several factors.These findings provide the first in vivo evidence of the association of endothelial cell inflammation with white matter injury, cognition, and brain degeneration in functionally normal older individuals, and form the basis for future biomarker development in early or preclinical stages of vascular cognitive impairment and dementia.

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[P2-420]: A COMPARISON OF BRAIN WHITE MATTER HYPERINTENSITY BURDEN ASSESSED IN VIVO AND EX VIVO

Alzheimer s & Dementia ◽

10.1016/j.jalz.2017.06.1076 ◽

2017 ◽

Vol 13 (7S_Part_16) ◽

pp. P794-P795

Author(s):

Arman P. Kulkarni ◽

Arnold M. Evia ◽

Julie A. Schneider ◽

David A. Bennett ◽

Konstantinos Arfanakis

Keyword(s):

White Matter ◽

Ex Vivo ◽

White Matter Hyperintensity ◽

Brain White Matter

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Abstract TP439: Temporary Cognitive Impairment in Transient Ischemic Attack and Minor Stroke Patients is Predicted by Chronic White Matter Hyperintensity Volume

Stroke ◽

10.1161/str.44.suppl_1.atp439 ◽

2013 ◽

Vol 44 (suppl_1) ◽

Author(s):

Leka Sivakumar ◽

Thomas Jeerakathil ◽

Negar Asdaghi ◽

Richard Camicioli ◽

Christian Beaulieu ◽

...

Keyword(s):

Cognitive Impairment ◽

White Matter ◽

White Matter Hyperintensity ◽

Minor Stroke ◽

Lesion Volume ◽

Cognitive Changes ◽

Mini Mental Status Examination ◽

History Of ◽

Ischemic Attack ◽

Patients Experience

Background: Cognitive changes have been described in subacute TIA/minor stroke (TIA/MIS), but the temporal profile is unknown. We tested the hypothesis that TIA/MIS patients experience transient cognitive impairment, and that this can be predicted by Diffusion-Weighted Imaging (DWI) lesion volume. Methods: Acute TIA/MIS stroke (NIH stroke scale score ≤3) patients with no history of cognitive impairment were prospectively recruited within 72 h of onset. Patients underwent Montreal Cognitive Assessment (MoCA), Mini-Mental Status Examination (MMSE) and MRI, including DWI and Fluid-Attenuated Inverse Recovery (FLAIR) sequences, at baseline, days 7 and 30. DWI lesion and FLAIR chronic white matter hyperintensity (WMH) volumes were measured planimetrically. Results: Fifty patients (mean age 68 ±15.1 years) were imaged at a median (IQR) of 26.5 (28.5) h after onset. Cognitive impairment (scores ≤26) was detected more frequently with MoCA (31/50, 62%) than MMSE (13/50, 26%, p=0.009). Acute ischemic lesions (DWI) were present in 33 (66%) patients. Mean DWI volume at baseline was 4.5 ± 11.1ml. Patients with DWI lesions (22/33, 67%) had similar impairment rates as those without (9/17, 53%; p=0.34). Linear regression indicated no relationship between acute DWI lesion volume (log transformed) and baseline MoCA scores (β=0.028, 95% CI [-2.09, 2.44]). Impaired patients had larger WMH volumes (13.6 ± 21.9 ml) than unaffected patients (2.6 ± 3.2 ml, p=0.01). Log transformed WMH volumes were inversely predictive of baseline MoCA scores (β=-0.54, 95% CI [-7.84, -2.28]). Median MoCA scores improved over time (27(5) at day 7 and 28(5) at day 30). Patients with baseline impairment and an increase of ≥2 points on MoCA by day 30 were defined as reverters (N=20). DWI lesion frequency was similar in reverters and those with persisting impairment (75% vs 64%, p= 0.50), as was DWI (6.9 ±14.3 ml vs 1.2 ±1.9 ml; p= 0.113) and WMH lesion volume (17.0 ± 26.2 ml vs 8.1 ± 8.1 ml; p= 0.18). Conclusions: Most TIA/MIS patients have evidence of temporary acute cognitive impairment when assessed with MoCA. Deficits are correlated with chronic WMH, suggesting an unmasking of subclinical cognitive impairment. Temporary cognitive deficits should be considered in the management of TIA/MIS patients.

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Threshold of white matter hyperintensity volume determines negative and positive associations between grey matter volume and hypertension

Alzheimer s & Dementia ◽

10.1002/alz.039298 ◽

2020 ◽

Vol 16 (S5) ◽

Author(s):

Ashwati Vipin ◽

Benjamin Wong ◽

Dilip Kumar ◽

Audrey Low ◽

Kok Pin Ng ◽

...

Keyword(s):

White Matter ◽

Grey Matter ◽

White Matter Hyperintensity ◽

Grey Matter Volume ◽

Matter Volume

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White Matter Hyperintensity Volume and Cerebral Perfusion in Older Individuals with Hypertension Using Arterial Spin-Labeling

American Journal of Neuroradiology ◽

10.3174/ajnr.a4828 ◽

2016 ◽

Vol 37 (10) ◽

pp. 1824-1830 ◽

Cited By ~ 26

Author(s):

J.W. van Dalen ◽

H.J.M.M. Mutsaerts ◽

A.J. Nederveen ◽

H. Vrenken ◽

M.D. Steenwijk ◽

...

Keyword(s):

White Matter ◽

Arterial Spin Labeling ◽

Cerebral Perfusion ◽

Spin Labeling ◽

White Matter Hyperintensity ◽

Older Individuals

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White Matter Hyperintensity Load Drives Differential Grey Matter Changes in Mild Cognitive Impairment

10.21203/rs.3.rs-131979/v1 ◽

2020 ◽

Author(s):

Ashwati Vipin ◽

Benjamin Yi Xin Wong ◽

Dilip Kumar ◽

Audrey Low ◽

Kok Pin Ng ◽

...

Keyword(s):

Cognitive Impairment ◽

Mild Cognitive Impairment ◽

White Matter ◽

Executive Control ◽

Grey Matter ◽

White Matter Hyperintensities ◽

White Matter Hyperintensity ◽

Grey Matter Volume ◽

Executive Control Network ◽

Matter Volume

Abstract Background: Small-vessel cerebrovascular disease often represented as white matter hyperintensities on magnetic resonance imaging, is considered an important risk factor for progression to dementia. Grey matter volume alterations in Alzheimer’s disease-specific regions comprising the default mode network and executive control network are also key features of early Alzheimer’s disease. However, the relationship between increasing white matter hyperintensity load and grey matter volume needs further examination in the cognitively normal and mild cognitive impairment. Here, we examined the load-dependent influence of white matter hyperintensities on grey matter volume and cognition in the cognitively normal and mild cognitive impairment stages.Methods: Magnetic resonance imaging data from 93 mild cognitive impairment and 90 cognitively normal subjects were studied and white matter hyperintensity load was categorized into low, medium and high terciles. We examined how differing loads of white matter hyperintensities related to whole-brain voxel-wise and regional grey matter volume in the default mode network and executive control network. We further investigated how regional grey matter volume moderated the relationship between white matter hyperintensities and cognition at differing white matter hyperintensity loads.Results: We found differential load-dependent effects of white matter hyperintensity burden on voxel-wise and regional grey matter atrophy in only mild cognitive impairment subjects. At low load, white matter hyperintensity load was positively related to grey matter volume in the executive control network but at high load, white matter hyperintensity load was negatively related to grey matter volume across both the executive control and default mode networks and no relationship was observed at medium white matter hyperintensity load. Additionally, negative associations between white matter hyperintensities and domains of memory and executive function were moderated by regional grey matter volume. Conclusions: Our results demonstrate dynamic relationships between white matter hyperintensity load, grey matter volume and cognition in the mild cognitive impairment stage. Interventions to slow the progression of white matter hyperintensities, instituted when white matter hyperintensity load is low could potentially prevent further cognitive decline.

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