Abstract
ObjectiveInterpretation of diffusion MRI in the living brain requires validation against gold standard histological measures. We compared diffusion values of the nigrostriatal tract to PET and histological results in non-human primates (NHPs) with varying degrees of unilateral nigrostriatal injury induced by MPTP, a toxin selective for dopaminergic neurons.MethodsSixteen NHPs had MRI and PET scans of three different presynaptic radioligands and blinded video-based motor ratings before and after unilateral carotid artery infusion of variable doses of MPTP. Diffusion measures of connections between midbrain and striatum were calculated. Then animals were euthanized to quantify striatal dopamine concentration, stereologic measures of striatal tyrosine hydroxylase (TH) immunostained fiber density and unbiased stereologic counts of TH stained nigral cells.ResultsDiffusion measures correlated with MPTP dose, nigral TH-positive cell bodies and striatal TH-positive fiber density but did not correlate with in vitro nigrostriatal terminal field measures or in vivo PET measures of striatal uptake of presynaptic markers. Once nigral TH cell count loss exceeded 50% the stereologic terminal field measures reached a near zero floor effect but the diffusion measures continued to correlate with nigral cell counts.ConclusionDiffusion measures in the nigrostriatal tract correlate with nigral dopamine neurons and striatal fiber density, but have the same relationship to terminal field measures as a previous report of striatal PET measures of presynaptic neurons. These diffusion measures have the potential to act as non-invasive index of the severity of nigrostriatal injury. Diffusion imaging of the nigrostriatal tract could potentially have diagnostic value in humans with Parkinson disease or related disorders.
Highlights
Diffusion tensor imaging (DTI) and diffusion tensor tractography (DTT) have been established as sensitive and valuable methods for probing microscopic changes in brain tissue in health and disease states
Diffusion measures correlated with MPTP dose, nigral tyrosine hydroxylase (TH)-positive cell bodies and striatal TH-positive fiber density but did not correlate with in vitro nigrostriatal terminal field measures or in vivo PET measures of striatal uptake of presynaptic markers
Monkeys with nigral cell body loss of less than 50% are represented with crosses, and monkeys with greater than 50% cell loss with circles
Summary
Diffusion tensor imaging (DTI) and diffusion tensor tractography (DTT) have been established as sensitive and valuable methods for probing microscopic changes in brain tissue in health and disease states. Molecular imaging methods have focused on measurements of striatal uptake of various radioligands targeting presynaptic function such as [18F]-6-fluorodopa (FD) (which primarily reflects presynaptic decarboxylase activity and subsequent storage), [11C]dihydrotetrabenazine (DTBZ) (which has specificity for vesicular monamine transporter type 2 [VMAT2]) and a variety of membranous presynaptic dopamine transporter (DAT) radioligands including [11C]carbomethoxy-3beta-(4-flurophenyl)tropane (CFT) [3, 4] Striatal uptake of these various radioligands reflects severity of nigrostriatal injury but only when less than 50% of nigral DA neuronal cells bodies are lost; At that point, these terminal field biomarkers have reached a nadir and no longer reflect increasing nigrostriatal injury, whereas nigral cell body injury fully reflects the subsequent severity of parkinsonism[3,4,5]. A measure of nigrostriatal fiber integrity could provide an alternative measure of this dopaminergic system
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
