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Effect of vascular amyloid on white matter disease is mediated by vascular dysfunction in cerebral amyloid angiopathy
Elif Gokcal1, Mitchell J Horn1, J Alex Becker2
1Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
Abstract:
We postulated that vascular dysfunction mediates the relationship between amyloid load and white matter hyperintensities (WMH) in cerebral amyloid angiopathy (CAA). Thirty-eight cognitively healthy patients with CAA (mean age 70 ± 7.1) were evaluated. WMH was quantified and expressed as percent of total intracranial volume (pWMH) using structural MRI. Mean global cortical Distribution Volume Ratio representing Pittsburgh Compound B (PiB) uptake (PiB-DVR) was calculated from PET scans. Time-to-peak [TTP] of blood oxygen level-dependent response to visual stimulation was used as an fMRI measure of vascular dysfunction. Higher PiB-DVR correlated with prolonged TTP (r = 0.373, p = 0.021) and higher pWMH (r = 0.337, p = 0.039). Prolonged TTP also correlated with higher pWMH (r = 0.485, p = 0.002). In a multivariate linear regression model, TTP remained independently associated with pWMH (p = 0.006) while PiB-DVR did not (p = 0.225). In a bootstrapping model, TTP had a significant indirect effect (ab = 0.97, 95% CI: 0.137-2.461), supporting that the association between PiB-DVR and pWMH is mediated by TTP response. There was no longer a direct effect independent of the hypothesized pathway. Our study suggests that the effect of vascular amyloid load on white matter disease is mediated by vascular dysfunction in CAA. Amyloid lowering strategies might prevent pathophysiological processes leading to vascular dysfunction, therefore limiting ischemic brain injury.
Insights
Vascular dysfunction mediates the link between amyloid in cerebral amyloid angiopathy (CAA) and white matter hyperintensities (WMH). Amyloid lowering therapies may prevent brain injury by targeting this vascular dysfunction.
Area of Science:
- Neurology
- Neuroimaging
- Vascular Biology
Background:
- Cerebral amyloid angiopathy (CAA) is associated with amyloid-beta deposition in cerebral vasculature.
- White matter hyperintensities (WMH) are common in CAA and may result from vascular damage.
- The relationship between amyloid load and WMH in CAA, and the role of vascular dysfunction, requires further elucidation.
Purpose of the Study:
- To investigate whether vascular dysfunction mediates the association between amyloid load and WMH in cognitively healthy individuals with CAA.
- To explore the role of amyloid burden (measured by PiB-PET) and vascular function (measured by fMRI) in the development of WMH.
Main Methods:
- Structural MRI was used to quantify white matter hyperintensities (WMH) as percent of total intracranial volume (pWMH).
- Positron Emission Tomography (PET) with Pittsburgh Compound B (PiB) measured global cortical amyloid load (PiB-DVR).
- Functional MRI (fMRI) assessed vascular dysfunction using time-to-peak (TTP) of the blood oxygen-level-dependent response to visual stimulation.
Main Results:
- Higher PiB-DVR (amyloid load) correlated with prolonged TTP (vascular dysfunction) and higher pWMH.
- Prolonged TTP was independently associated with higher pWMH in multivariate regression.
- Mediation analysis confirmed that TTP significantly mediated the relationship between PiB-DVR and pWMH.
Conclusions:
- Vascular dysfunction, as indicated by prolonged TTP, plays a crucial role in mediating the association between amyloid load and white matter hyperintensities in CAA.
- Amyloid-lowering strategies may prevent ischemic brain injury by improving vascular function and reducing WMH progression.
- These findings highlight vascular dysfunction as a key therapeutic target in managing CAA-related brain pathology.
