Increased cerebral blood volume in small arterial vessels is a correlate of amyloid-β–related cognitive decline

Jun Hua,Seungwook Lee,Nicholas I.S Blair,Michael Wyss,Jiri M.G Van Bergen,Simon J Schreiner,Sonja M Kagerer,Sandra E Leh,Anton F Gietl,Valerie Treyer,Alfred Buck,Roger M Nitsch,Klaas P Pruessmann,Hanzhang Lu,Peter C.M Van Zijl,Marilyn Albert,Christoph Hock,Paul G Unschuld

doi:10.1016/j.neurobiolaging.2019.01.001

Abstract

The protracted accumulation of amyloid-β (Aβ) is a major pathologic hallmark of Alzheimer's disease and may trigger secondary pathological processes that include neurovascular damage. This study was aimed at investigating long-term effects of Aβ burden on cerebral blood volume of arterioles and pial arteries (CBVa), possibly present before manifestation of dementia. Aβ burden was assessed by 11C Pittsburgh compound-B positron emission tomography in 22 controls and 18 persons with mild cognitive impairment (MCI), [ages: 75(±6) years]. After 2 years, inflow-based vascular space occupancy at ultra-high field strength of 7-Tesla was administered for measuring CBVa, and neuropsychological testing for cognitive decline. Crushing gradients were incorporated during MR-imaging to suppress signals from fast-flowing blood in large arteries, and thereby sensitize inflow-based vascular space occupancy to CBVa in pial arteries and arterioles. CBVa was significantly elevated in MCI compared to cognitively normal controls and regional CBVa related to local Aβ deposition. For both MCI and controls, Aβ burden and follow-up CBVa in several brain regions synergistically predicted cognitive decline over 2 years. Orbitofrontal CBVa was positively associated with apolipoprotein E e4 carrier status. Increased CBVa may reflect long-term effects of region-specific pathology associated with Aβ deposition. Additional studies are needed to clarify the role of the arteriolar system and the potential of CBVa as a biomarker for Aβ-related vascular downstream pathology.

Highlights

Late-onset Alzheimer’s disease (AD) is characterized by a decade-long preclinical phase and eventually leads to mild cognitive impairment (MCI) as its first clinical manifestation (Albert et al, 2011)
positron emission tomography (PET) studies were performed at study inclusion; the 7 Tesla MR sequences were administered during the follow-up visit, resulting in an average delay of 803 Æ 203 days between PET and 7T magnetic resonance imaging (MRI) measures
None of the participants progressed to AD dementia from TP1 to TP2

Summary

Introduction

Late-onset Alzheimer’s disease (AD) is characterized by a decade-long preclinical phase and eventually leads to mild cognitive impairment (MCI) as its first clinical manifestation (Albert et al, 2011). Neuropathological changes in AD are complex and include cerebrovascular disease, neuroinflammation, and aggregation of pathological tau and other proteins (Elahi and Miller, 2017; Serrano-Pozo et al, 2011), Ab-burden is considered to represent earliest brain pathology in AD and possibly trigger a multitude of pathologic downstream processes (Jack et al, 2010; Ossenkoppele et al, 2015; Rabinovici et al, 2017; Villemagne et al, 2018).

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