The catechol-O-methyltransferase Val(158)Met polymorphism modulates fronto-cortical dopamine turnover in early Parkinson's disease: a PET study.

Cognitive deficits occur in up to 30% of patients with early Parkinson's disease, some of which are thought to result from dysfunction within the fronto-striatal dopaminergic network. Recently, it has been shown that a common functional polymorphism (Val(158)Met) in the catechol-O-methyltransferase (COMT) gene is associated with changes in executive performance in tasks that have a fronto-striatal basis. This is thought to relate to changes in cortical dopamine levels as catechol-O-methyltransferase is the main mode of inactivation for dopamine in frontal areas. However to date, no study has investigated dopamine turnover as a function of this genetic polymorphism in Parkinson's disease. We, therefore, set out to investigate in vivo changes in presynaptic dopamine storage in patients with idiopathic Parkinson's disease as a function of the catechol-O-methyltransferase Val(158)Met polymorphism using (18)F-DOPA positron emission tomography. Twenty patients with Parkinson's disease (10 homozygous for Val/Val and 10 for Met/Met catechol-O-methyltransferase polymorphisms) underwent (18)F-DOPA positron emission tomography using a prolonged imaging protocol. The first dynamic scan was acquired from 0 to 90 min (early), and the second scan (late) from 150 to 210 min post-intravenous radioligand administration. Patients were matched for age, sex, verbal IQ, disease duration and severity of motor features. (18)F-DOPA influx constants (Ki) were calculated and compared for frontal and striatal regions. Late scan mean frontal and striatal Ki values were significantly reduced in both Parkinson's disease groups relative to early scan Ki values. Met/Met patients had significantly higher late scan Ki values compared with their Val/Val counterparts in anterior cingulate, superior frontal and mid-frontal regions but early frontal Ki values were not different between the two groups. As late Ki values reflect rates of dopamine metabolism to 3,4-dihydroxyphenylacetic acid and homovanillic acid, our results indicate that Met homozygotes have higher presynaptic dopamine levels in frontal regions than Val homozygotes, which may help to explain how this genotypic variation may influence the fronto-striatal cognitive deficits of Parkinson's disease.

Dopamine stimulates epidermal growth factor release from adult neural precursor cells derived from the subventricular zone by a disintegrin and metalloprotease.

Dopamine plays a key role in the regulation of stem cell turnover and neurogenesis in the subventricular zone. This effect is mediated by dopamine-induced release of epidermal growth factor (EGF), to promote stem cell proliferation in this area. We, therefore, sought to investigate whether a disintegrin and metalloprotease (ADAMs) are implicated in this process, as they have previously been shown to play a role in transactivation of the EGF receptor after stimulation of G protein-coupled receptors. We found that dopamine stimulation of stem cells caused the release of EGF, in agreement with our previous findings. However, the inhibition of ADAMs reversed this effect. Our results support a role for ADAMs in dopamine-induced release of EGF from stem cells in the subventricular zone.

Biomarkers in Huntington's and Parkinson's Disease.

Parkinson's (PD) and Huntington's disease (HD) are chronic neurodegenerative conditions of the brain with a variety of clinical presentations including a disorder of movement and a range of nonmotor deficits. HD is genetic in origin and the causative gene and protein known, namely mutant Huntingtin, which leads to widespread early neuronal dysfunction and death throughout the brain. In contrast, the etiology of sporadic PD is unknown, and the pathology targets the nigrostriatal dopaminergic neurons with the formation of alpha-synuclein positive Lewy bodies. In both diseases, the ability to accurately diagnose the disease in the early stages and monitor progression over time remains a major challenge given the majority of the pathology is sited deep within the CNS. This challenge has gained extra significance as the development of disease-modifying drugs starts to emerge into the clinic. To this end, there is a need to find biomarkers that will help in the accurate diagnosis of the disease and/or prediction of its clinical onset as well as biomarkers that are able to faithfully track disease progression independent of any symptomatic effects of any therapies. In addition, these same markers may also help stratify each of these heterogeneous disorders into specific subtypes that share particular clinical and pathological characteristics.

Dopaminergic modulation of neurogenesis in the subventricular zone of the adult brain.

Dopaminergic receptors are expressed on neural precursor cells (NPCs) in the subventricular zone (SVZ) and are known to regulate NPC proliferation and differentiation fate in this region. We now report that this optimally requires the simultaneous activation of both D1-like and D2-like dopaminergic receptors with the agonists Bromocriptine, SKF-38393 and 7-OH-pipat maleate (BSP) in vitro. This is consistent with our previous findings that dopamine stimulates NPC proliferation through an EGF paracrine mechanism within the SVZ. Furthermore this combined dopamine agonist therapy rescues NPC proliferation in the SVZ in the 6-OHDA animal model of PD and importantly significantly increases neuronal differentiation in the olfactory bulb to a greater extent than we showed previously with levodopa. This result has implications for the use of dopaminergic therapies in PD and in the development of such therapies focusing on upregulating SVZ neurogenesis.

Dopamine-induced proliferation of adult neural precursor cells in the mammalian subventricular zone is mediated through EGF.

A reduction in dopaminergic innervation of the subventricular zone (SVZ) is responsible for the impaired proliferation of its resident precursor cells in this region in Parkinson's disease (PD). Here, we show that this effect involves EGF, but not FGF2. In particular, we demonstrate that dopamine increases the proliferation of SVZ-derived cells by releasing EGF in a PKC-dependent manner in vitro and that activation of the EGF receptor (EGFR) is required for this effect. We also show that dopamine selectively expands the GFAP(+) multipotent stem cell population in vitro by promoting their self-renewal. Furthermore, in vivo dopamine depletion leads to a decrease in precursor cell proliferation in the SVZ concomitant with a reduction in local EGF production, which is reversed through the administration of the dopamine precursor levodopa (L-DOPA). Finally, we show that EGFR(+) cells are depleted in the SVZ of human PD patients compared with age-matched controls. We have therefore demonstrated a unique role for EGF as a mediator of dopamine-induced precursor cell proliferation in the SVZ, which has potential implications for future therapies in PD.