Decreased blood-brain barrier P-glycoprotein function in the progression of Parkinson's disease, PSP and MSA

Abstract

Decreased blood-brain barrier (BBB) efflux function of the P-glycoprotein (P-gp) transport system could facilitate the accumulation of toxic compounds in the brain, increasing the risk of neurodegenerative pathology such as Parkinson's disease (PD). This study investigated in vivo BBB P-gp function in patients with parkinsonian neurodegenerative syndromes, using [11C]-verapamil PET in PD, PSP and MSA patients. Regional differences in distribution volume were studied using SPM with higher uptake interpreted as reduced P-gp function. Advanced PD patients and PSP patients had increased [11C]-verapamil uptake in frontal white matter regions compared to controls; while de novo PD patients showed lower uptake in midbrain and frontal regions. PSP and MSA patients had increased uptake in the basal ganglia. Decreased BBB P-gp function seems a late event in neurodegenerative disorders, and could enhance continuous neurodegeneration. Lower [11C]-verapamil uptake in midbrain and frontal regions of de novo PD patients could indicate a regional up-regulation of P-gp function.

Fig. 1

a SPM t test on MRI overlay showing P < 0.001. Increased [¹¹C]-verapamil uptake in the frontal lobe in advanced PD patients compared to healthy controls; SPM coordinates 34, 30, 26 and −16, 48, 12 (Brodmann areas 9 and 10) with P corrected at cluster level 0.000. b Plot of the frontal effect (PD patients scan number 1–10 and controls 11–20) shows little overlap

Fig. 2

a de novo PD patients showed lower brainstem [¹¹C]-verapamil uptake in the brainstem compared to controls, P < 0.001; SPM coordinates 2, −26, −26 with P corrected at cluster level 0.000. b Plot of the brainstem effect shows more variation in PD de novo values (scan number 1–10) with some overlap with the control group (scan number 11–20)

Fig. 3

a PSP patients showed higher [11C]-verapamil uptake in lentiform nucleus and putamen compared to controls, P < 0.001; SPM coordinates 26, −10, 6 with P corrected at cluster level 0.06. b Plot of the basal ganglia effect shows higher values in four of the five PSP patients (scan number 1–5). PSP patient number 5 had shortest disease duration (<1 year)