Blood-brain barrier P-glycoprotein function decreases in specific brain regions with aging: a possible role in progressive neurodegeneration.
Cerebrovascular P-glycoprotein (P-gp) acts at the blood-brain barrier (BBB) as an active cell membrane efflux pump for several endogenous and exogenous compounds. Age-associated decline in P-gp function could facilitate the accumulation of toxic substances in the brain, thus increasing the risk of neurodegenerative pathology with aging. We hypothesised a regionally reduced BBB P-gp function in older healthy subjects. We studied cerebrovascular P-gp function using [(11)C]-verapamil positron emission tomography (PET) in seventeen healthy volunteers with age 18-86. Logan analysis was used to calculate the distribution volume (DV) of [(11)C]-verapamil in the brain. Statistical Parametric Mapping was used to study specific regional differences between the older compared with the younger adults. Older subjects showed significantly decreased P-gp function in internal capsule and corona radiata white matter and in orbitofrontal regions. Decreased BBB P-gp function in those regions could thus explain part of the vulnerability of the aging brain to white matter degeneration. Moreover, decreased BBB P-gp function with aging could be a mechanism by which age acts as the main risk factor for the development of neurodegenerative disease.
Bartels
Anna L
AL
Department of Neurology, University Medical Centre Groningen, University of Groningen, Hanzeplein 1, 9700 RB Groningen, The Netherlands. a.l.bartels@neuro.umcg.nl
Kortekaas
Rudie
R
Bart
Joost
J
Willemsen
Antoon T M
AT
de Klerk
Onno L
OL
de Vries
Jeroen J
JJ
van Oostrom
Joost C H
JC
Leenders
Klaus L
KL
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics / Q000378:metabolism*; D000293:Adolescent; D000328:Adult; D000367:Age Factors; D000368:Aged; D000369:Aged, 80 and over; D000375:Aging / Q000502:physiology*; D001812:Blood-Brain Barrier / Q000378:metabolism*; D001921:Brain / Q000000981:diagnostic imaging / Q000378:metabolism* / Q000473:pathology; D001931:Brain Mapping; D002247:Carbon Isotopes / Q000378:metabolism; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D011110:Polymorphism, Genetic / Q000235:genetics; D011877:Radionuclide Imaging; D014700:Verapamil / Q000378:metabolism; D055815:Young Adult
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D002247:Carbon Isotopes; D014700:Verapamil