An [F-18]dopa-PET and clinical study of the rate of progression in Parkinson’s disease. Brain 119: 585-591

MRC Cyclotron Unit, Hammersmith Hospital, London, UK.
Brain (Impact Factor: 9.2). 05/1996; 119 ( Pt 2)(2):585-91.
Source: PubMed


We have studied disease progression in a group of 10 patients with recent onset idiopathic Parkinson's disease [mean age 53.7 +/- 12.6 years, mean duration 18.3 +/- 6.5 months, mean unified Parkinson's disease rating scale (UPDRS) 19.0 +/- 9.5], and a group of seven patients with established Parkinson's disease (mean age 60.1 +/- 15.1 years, mean duration 70.8 +/- 35.5 months, mean UPDRS 47.9 +/- 18.1), using both clinical assessment and [18F]dopa-PET. Results were compared with those of a group of 10 normal subjects (age 66 +/- 16 years). Mean putamen [18F]dopa influx constant (Ki) was a reliable measurement (R = 0.82) and the most sensitive marker of disease progression (r = -0.85, P < 0.0001). The mean annual rate of reduction in mean putamen Ki in the Parkinson's disease patients was 12.5% per annum, whereas the control group showed no significant change in Ki over a mean of 32 months follow up. The rate of progression was more rapid in the recent onset compared with the established disease group but this did not reach statistical significance. Assuming a linear progression for the entire group we estimate symptom onset at a mean putamen Ki 79% of normal with a mean preclinical period of 3.1 years.

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Available from: David J Brooks, Aug 15, 2014
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    • "Therefore, it is possible that defects in Parkin-mediated degradation of ARTS may also lead to increased but non-lethal levels of caspase activity that causes neurite degeneration. This may be particularly relevant during the early stage of PD, prior to the onset of widespread cell death [91]–[93]. Collectively, we show that ARTS is a novel substrate of Parkin. Furthermore, our work provides a new explanation for the neuroprotective activity of Parkin and reveals a potentially direct link between Parkin, apoptosis and PD. "
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    ABSTRACT: Parkinson's disease (PD) is associated with excessive cell death causing selective loss of dopaminergic neurons. Dysfunction of the Ubiquitin Proteasome System (UPS) is associated with the pathophysiology of PD. Mutations in Parkin which impair its E3-ligase activity play a major role in the pathogenesis of inherited PD. ARTS (Sept4_i2) is a mitochondrial protein, which initiates caspase activation upstream of cytochrome c release in the mitochondrial apoptotic pathway. Here we show that Parkin serves as an E3-ubiquitin ligase to restrict the levels of ARTS through UPS-mediated degradation. Though Parkin binds equally to ARTS and Sept4_i1 (H5/PNUTL2), the non-apoptotic splice variant of Sept4, Parkin ubiquitinates and degrades only ARTS. Thus, the effect of Parkin on ARTS is specific and probably related to its pro-apoptotic function. High levels of ARTS are sufficient to promote apoptosis in cultured neuronal cells, and rat brains treated with 6-OHDA reveal high levels of ARTS. However, over-expression of Parkin can protect cells from ARTS-induced apoptosis. Furthermore, Parkin loss-of-function experiments reveal that reduction of Parkin causes increased levels of ARTS and apoptosis. We propose that in brain cells in which the E3-ligase activity of Parkin is compromised, ARTS levels increase and facilitate apoptosis. Thus, ARTS is a novel substrate of Parkin. These observations link Parkin directly to a pro-apoptotic protein and reveal a novel connection between Parkin, apoptosis, and PD.
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    • "At present, there is no biomarker that is sufficiently well accepted to serve as a primary endpoint in a clinical trial of PD cell or gene therapy. The most relevant technologies available are the dopaminergic imaging modalities, including measuring presynaptic AADC activity using PET (18F-dopa) and the labelling of the dopamine transporter (DAT) using SPECT [69, 70]. Such neuroimaging endpoints have some advantages over clinical markers, being more objective, more sensitive, particularly in presymptomatic/early stages, however, may themselves be affected by drugs' symptomatic effects. "
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    ABSTRACT: Neural cell transplantation and gene therapy have attracted considerable interest as promising therapeutic alternatives for patients with Parkinson's disease (PD). Preclinical and open-label studies have suggested that grafted fetal neural tissue or viral vector gene transfer can achieve considerable biochemical and clinical improvements, whereas subsequent double-blind, placebo-controlled protocols have produced rather more modest and variable results. Detailed evaluation of these discordant findings has highlighted several crucial issues such as patient selection criteria, details surrounding transplantation or gene therapy methodologies, as well as the study designs themselves that ought to be carefully considered in the planning phases of future clinical trials. Beyond the provision of symptomatic efficacy and safety data, it also remains to be identified whether the possibilities offered by stem cell and gene therapy technological advances might translate to meaningful neuroprotection and/or disease-modifying effects or alleviate the nonmotor aspects of PD and thus offer additional benefits beyond those achieved through conventional pharmacotherapy or deep brain stimulation (DBS).
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    • "The dopaminergic nigrostriatal pathway is the primary focus of neurodegeneration in IPD (Brooks et al., 1990; Morrish et al., 1995, 1996). In IPD, dopamine uptake is reduced in the striatum, particularly the posterior putamen. "

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