Developing new biomarkers for the pathogenesis and early diagnosis of Alzheimer’s disease

Roxana CarareMD, PhD  Prof of Clinical Neuroanatomy

Introduction

Alzheimer’s Disease (AD) is a devastating dementia affecting more than 32 million people worldwide. Early diagnosis of AD is difficult and current therapies have little effect in delaying cognitive decline. Pathological studies suggest that failure of elimination of amyloid-β (Aβ) with age is a major factor in the pathogenesis of AD and a target for therapy [1]. Fluid and solutes including Aβ are eliminated from the brain along 100-150nm wide basement membranes in the walls of cerebral arteries as Intramural Periarterial Drainage (IPAD) [2]. However, such perivascular elimination of Aβ fails with age and this is reflected in the accumulation of Aβ in brain tissue and in the walls of cerebrovascular arteries as cerebral amyloid angiopathy (CAA) in AD [3]. Attempts to remove Aβ from the brain in AD by immunotherapy have resulted in elimination of Aβ plaques from the brain but have been accompanied by an increase in CAA [4, 5]. The major questions that remain unanswered are: why does the elimination of Aβ fail with ageing? Why is the deposition of Aβ as CAA prevalent in some areas of the brain compared to others? We hypothesise that, in the normal healthy brain, the geometry of the arterial tree in the posterior cerebral circulation, displaying the highest incidence of CAA, differs from that in the anterior cerebral circulation.

Accumulation of amyloid in the brain has a pro-angiogenic effect and the consequent increase of the vascular bed in the brain may become a possible structural biomarker of early amyloid deposition and dementia [6]

Aims

We aim to design the methodologies and technological platform to be applied in the detection of the cerebral vasculature and its changes in AD. This project will define how the geometry and pattern of branching of the cerebral vasculature affects the efficiency of perivascular drainage and will translate this information into early detection of AD.

Project plan and objectives

Impaired perivascular drainage of Aβ is associated with morphological regional differences in the cerebral vasculature in humans. Through collaborative work with Computer Science within the University of Southampton (Prof Mark Nixon) , we aim to create a multiscale, personalised model of the arterial tree, measuring the symmetry, angle, length and density of the branches of the arterial tree. The analysis will be achieved automatically using established and new computer vision techniques applied to radiological images of the cerebral arterial tree from angiograms. Cerebrovascular branching patterns as measured by non-invasive imaging tools may become a reliable biomarker for early detection of AD.

In summary, we propose to create the electronic software tools for detecting different patterns of branching of the cerebral vasculature for early radiological detection of AD based on the pattern of arterial branching.

References

1. Mawuenyega, K.G., et al., Decreased clearance of CNS beta-amyloid in Alzheimer’s disease. Science, 2010. 330(6012): p. 1774.
2. Carare, R.O., et al., Solutes, but not cells, drain from the brain parenchyma along basement membranes of capillaries and arteries: significance for cerebral amyloid angiopathy and neuroimmunology. Neuropathol Appl Neurobiol, 2008. 34(2): p. 131-44.
3. Weller, R.O., et al., Perivascular Drainage of Amyloid-beta Peptides from the Brain and Its Failure in Cerebral Amyloid Angiopathy and Alzheimer’s Disease. Brain Pathol., 2008. 18(2): p. 253-266.
4. Boche, D., et al., Consequence of Abeta immunization on the vasculature of human Alzheimer’s disease brain. Brain, 2008. 131(Pt 12): p. 3299-310.
5. Nicoll, J.A., et al., Abeta species removal after abeta42 immunization. J.Neuropathol.Exp.Neurol., 2006. 65(11): p. 1040-1048.
6. Biron, K.E., et al., Amyloid triggers extensive cerebral angiogenesis causing blood brain barrier permeability and hypervascularity in Alzheimer’s disease. PLoS One, 2011. 6(8): p. e23789.
7. Larsen, J.O., H.J. Gundersen, and J. Nielsen, Global spatial sampling with isotropic virtual planes: estimators of length density and total length in thick, arbitrarily orientated sections. J Microsc, 1998. 191(3): p. 238-248.
8. Muhlfeld, C., J.R. Nyengaard, and T.M. Mayhew, A review of state-of-the-art stereology for better quantitative 3D morphology in cardiac research. Cardiovasc Pathol, 2010. 19(2): p. 65-82.