Increased DAT binding in the early stage of the dopaminergic lesion: A longitudinal [11C]PE2I binding study in the MPTP-monkey

Abstract

The delayed appearance of motor symptoms in PD poses a crucial challenge for early detection of the disease. We measured the binding potential of the selective dopamine active transporter (DAT) radiotracer [(11)C]PE2I in MPTP-treated macaque monkeys, thus establishing a detailed profile of the nigrostriatal DA status following MPTP intoxication and its relation to induced motor and non-motor symptoms. Clinical score and cognitive performance were followed throughout the study. We measured longitudinally in vivo the non-displaceable binding potential to DAT in premotor, motor-recovered (i.e. both non-symptomatic) and symptomatic MPTP-treated monkeys. Results show an unexpected and pronounced dissociation between clinical scores and [(11)C]PE2I-BP(ND) during the premotor phase i.e. DAT binding in the striatum of premotor animals was increased around 20%. Importantly, this broad increase of DAT binding in the caudate, ventral striatum and anterior putamen was accompanied by i) deteriorated cognitive performance, showing a likely causal role of the observed hyperdopaminergic state (Cools, 2011; Cools and D'Esposito, 2011) and ii) an asymmetric decrease of DAT binding at a focal point of the posterior putamen, suggesting that increased DAT is one of the earliest, intrinsic compensatory mechanisms. Following spontaneous recovery from motor deficits, DAT binding was greatly reduced as recently shown in-vivo with other radiotracers (Blesa et al., 2010, 2012). Finally, high clinical scores were correlated to considerably low levels of DAT only after the induction of a stable parkinsonian state. We additionally show that the only striatal region which was significantly correlated to the degree of motor impairments is the ventral striatum. Further research on this period should allow better understanding of DA compensation at premature stages of PD and potentially identify new diagnosis and therapeutic index.

Prefrontal Markers and Cognitive Performance Are Dissociated during Progressive Dopamine Lesion

“…Monkeys showing full motor symptoms following MPTP treatment already have significant loss of nigral dopaminergic cells [52], and monkeys brought to a motor symptomatic state who subsequently recover nevertheless show reduced tyrosine hydroxylase (TH) cell labeling in the mesencephalon [51]. Previous work in our laboratory has measured the binding potential of the selective dopamine active transporter (DAT) radiotracer [ 11 C]PE2I in monkeys in a progressive MPTP protocol [53]. The use of this tracer is also established in patients with Parkinson’s disease [54].…”

“…We showed that DAT binding is increased in the early phases of a progressive MPTP lesion, returning to baseline levels around the onset of symptoms and then dropping as motor symptoms become persistent. The final strong motor symptomatic phase is associated with significant striatal TH depletion after immunohistochemical analyses [53]. On the basis of this previous work, we consider that at the onset of significant motor symptoms, the monkeys in the current protocol have received a significant lesion to the nigrostriatal dopamine system.…”

Individual and Familial Susceptibility to MPTP in a Common Marmoset Model for Parkinson's Disease

“…In nonhuman primates it is not uncommon to have a relatively high variation in the response to the same dose of MPTP [12,13,14]. The unique response of each individual animal might hold a key to solving the issue of susceptibility to MPTP, which in turn might lead to novel insights into the pathogenesis of PD and explain why some individuals are more prone to develop the disease than others.…”

“…Consequently, MPTP causes behavioral and neurochemical as well as pathological features related to PD [6,7,8,9,10]. Whereas many researchers aim for a phenotypically homogeneous group of animals in their experiments, and thus prefer to work with inbred mice or rats, outbred animals are known to respond dissimilarly to an equal dose of MPTP [11,12,13,14] and thus offer the advantage to study individual differences in MPTP susceptibility. Here we investigated how individual and/or familial differences determine susceptibility to Parkinson-related disease manifestation after MPTP administration in marmoset monkeys.…”

How Relevant Are Imaging Findings in Animal Models of Movement Disorders to Human Disease?

“…However, compensatory mechanisms may be investigated using animals models of parkinsonism and novel unlicensed tracers [46,66,71]. A typical example is the assessment of interactions between serotonergic and dopaminergic transmission in the disabling treatment-related complication of PD, levodopa (L-DOPA)-induced dyskinesias.…”