Dysfunction of the Blood-Brain Barrier: The Cause of Parkinson's Disease

The causes of Parkinson's disease are still unclear. Genetic vulnerability and exposure to environmental neurotoxins are assumed to be contributors to nerve cell loss (neurodegeneration) in certain locations in the midbrain of PD patients. Individual susceptibility to substances which are toxic for brain nerve cells is hypothesized to be a risk factor in PD. Toxic substances could enter the brain if the blood-brain barrier (BBB) would let these substances pass. The BBB is constructed in such a way that it normally keeps unwanted and potentially toxic substances out of the brain, whereas useful substances can enter and waste products can leave.

Loss of BBB function could until recently not directly be studied in humans during life. In a pilot study we recently studied for the first time the function of the BBB P-glycoprotein (P-gp) transporter in five patients with Parkinson's disease and five healthy control subjects. P-gp is a protein at the BBB which has as only function to remove many lipid soluble substances from the lining cells of the blood capillaries before these substances can enter nerve cell tissue. This P-gp is normally present at the BBB in very high concentrations. Using the radiotracer substance [11C]-verapamil and PET scans the activity of the P-gp protein in the brains of humans can be measured.

In our first preliminary study brain penetration of radiolabeled verapamil was elevated by 18 % in the midbrain of the PD patients relative to the controls. This suggests that BBB P-gp dysfunction plays a role in the aetiology of PD. Confirmation of the alteration of BBB P-gp expression in PD will be important to determine whether this is a general feature in PD. If so, further studies need to be carried out to assess whether this feature is primary or secondary and to assess its role in the pathogenesis and progression of PD and perhaps associated brain degenerative diseases. Since modulators of the P-gp transport system are available, these findings may potentially lead to a new strategy in prevention of progression of PD.