Fornix degeneration in risk factors of Alzheimer's disease, possible trigger of cognitive decline

Abstract

Risk factors of late-onset Alzheimer's disease (AD) such as aging, type 2 diabetes, obesity, heart failure, and traumatic brain injury can facilitate the appearance of cognitive decline and dementia by triggering cerebrovascular pathology and neuroinflammation. White matter (WM) microstructure and function are especially vulnerable to these conditions. Microstructural WM changes, assessed with diffusion weighted magnetic resonance imaging, can already be detected at preclinical stages of AD, and in the presence of the aforementioned risk factors. Particularly, the limbic system and cortico-cortical association WM tracts, which myelinate late during brain development, degenerate at the earliest stages. The fornix, a C-shaped WM tract that originates from the hippocampus, is one of the limbic tracts that shows early microstructural changes. Fornix integrity is necessary for ensuring an intact executive function and memory performance. Thus, a better understanding of the mechanisms that cause fornix degeneration is critical in the development of therapeutic strategies aiming to prevent cognitive decline in populations at risk. In this literature review, i) we deepen the idea that partial loss of forniceal integrity is an early event in AD, ii) we describe the role that common risk factors of AD can play in the degeneration of the fornix, and iii) we discuss some potential cellular and physiological mechanisms of WM degeneration in the scenario of cerebrovascular disease and inflammation.

Keywords: Blood-brain barrier; CVRFs, cardiovascular risk factors; Cerebrovascular pathology; DTI, difussion tensor imaging; Diffusion tensor imaging; Galectin-3; NODDI, neurite orientation dispersion and density imaging; Neuroinflammation; TBI, traumatic brain injury; WM, white matter; White matter.

Fig. 1

Three-dimensional representation of the fornix of a healthy adult subject. Coronal (left), axial (center) and sagittal (right) views, overlapped on a T1-weighted magnetic resonance image. DSI studio software was used for visualization (dsi-studio.labsolver.org).

Fig. 2

Schematic representation of a hypothetical model of fornix degeneration due to risk factors of Alzheimer's disease. A) Blood-brain barrier permeability induces inflammation of the white matter. The readjustment of endothelial tight junctions in response to a compromised blood microcirculation facilitates the extravasation of fibrinogen, capable of activating microglia. Reactive microglia can maintain and extend inflammation by releasing Gal-3 acting through TLR4. Reactive microglia phagocyte degenerated myeline and releases pro-NGF and TNFα that may impact oligodendrocytes viability and reduce retrograde axonal transport, thus, neuronal survival. B) Phagocytic phenotype in microglia is sustained by Gal-3 expression. Fibrinogen promotes microglia activation through binding the MAC-1 surface receptor. Gal-3 acts as a molecular switch that up-regulates and prolongs PI3K activity maintaining a phagocytic phenotype in microglia. Gal-3; galectin-3, TLR4; toll-like receptor 4, TNFα; tumor necrosis factor alpha; I3K; phosphatidylinositol 3-kinase; NGF, nerve growth factor; GTP, guanosine triphosphate; GDP, guanosine diphosphate; GEFs, guanine nucleotide exchange factors; GAPs, GTPase-activating proteins.