Fig. 2.

Biomarker studies to understand the cerebrovascular link between TBI and AD.

Multimodal biomarker studies can be used to better understand the complex interplay between TBI and the development of AD-like pathology. TBI induces early and subacute cerebrovascular function impairment that can be monitored by neuroimaging techniques. This includes blood flow impairment, hypoperfusion and ischemia, changes in brain metabolism and also an impairment of brain clearance systems. If these phenomena are not isolated but sustained because of repeated TBI events or severe TBI, secondary cerebrovascular damage can occur, including vascular damage, BBB abnormal permeability and microbleeds that can be also detected by neuroimaging techniques. Cerebrovascular function impairment and damage induce perivascular and parenchymal accumulation of tau and Aβ in the brain. All these processes act in a feed-forward loop, as an increase in perivascular accumulation of tau and Aβ induce vascular damage, limits vascular function and therefore impairment in blood flow and brain perfusion. These events induce changes in CSF, peripheral blood and biofluids molecules like tau, P-Tau, Aβ monomers/oligomers, metalloproteases and miRNAs, among others.