Chronic pramipexole treatment increases tolerance for sucrose in normal and ventral tegmental lesioned rats.

The loss of dopamine neurons observed in Parkinson's disease (PD) elicits severe motor control deficits which are reduced by the use of dopamine agonists. However, recent works have indicated that D3-preferential agonists such as pramipexole can induce impulse control disorders (ICDs) such as food craving or compulsive eating. In the present study, we performed an intermittent daily feeding experiment to assess the effect of chronic treatment by pramipexole and VTA bilateral lesion on tolerance for sucrose solution. The impact of such chronic treatment on spontaneous locomotion and spatial memory was also examined. Changes in sucrose tolerance could indicate the potential development of a change in food compulsion or addiction related to the action of pramipexole. Neither the bilateral lesion of the VTA nor chronic treatment with pramipexole altered the spontaneous locomotion or spatial memory in rats. Rats without pramipexole treatment quickly developed a stable intake of sucrose solution in the 12 h access phase. On the contrary, when under daily pramipexole treatment, rats developed a stronger and ongoing escalation of their sucrose solution intakes. In addition, we noted that the change in sucrose consumption was sustained by an increase of the expression of the Dopamine D3 receptor in the core and the shell regions of the nucleus accumbens. The present results may suggest that long-term stimulation of the Dopamine D3 receptor in animals induces a strong increase in sucrose consumption, indicating an effect of this receptor on certain pathological aspects of food eating.journal article20142015 01 06importe

PTPA variants and impaired PP2A activity in early-onset parkinsonism with intellectual disability

The protein phosphatase 2A complex (PP2A), the major Ser/Thr phosphatase in the brain, is involved in a number of signalling pathways and functions, including the regulation of crucial proteins for neurodegeneration, such as alpha-synuclein, tau and LRRK2. Here, we report the identification of variants in the PTPA/PPP2R4 gene, encoding a major PP2A activator, in two families with early-onset parkinsonism and intellectual disability. We carried out clinical studies and genetic analyses, including genome-wide linkage analysis, whole-exome sequencing, and Sanger sequencing of candidate variants. We next performed functional studies on the disease-associated variants in cultured cells and knock-down of ptpa in Drosophila melanogaster. We first identified a homozygous PTPA variant, c.893T&gt;G (p.Met298Arg), in patients from a South African family with early-onset parkinsonism and intellectual disability. Screening of a large series of additional families yielded a second homozygous variant, c.512C&gt;A (p.Ala171Asp), in a Libyan family with a similar phenotype. Both variants co-segregate with disease in the respective families. The affected subjects display juvenile-onset parkinsonism and intellectual disability. The motor symptoms were responsive to treatment with levodopa and deep brain stimulation of the subthalamic nucleus. In overexpression studies, both the PTPA p.Ala171Asp and p.Met298Arg variants were associated with decreased PTPA RNA stability and decreased PTPA protein levels; the p.Ala171Asp variant additionally displayed decreased PTPA protein stability. Crucially, expression of both variants was associated with decreased PP2A complex levels and impaired PP2A phosphatase activation. PTPA orthologue knock-down in Drosophila neurons induced a significant impairment of locomotion in the climbing test. This defect was age-dependent and fully reversed by L-DOPA treatment. We conclude that bi-allelic missense PTPA variants associated with impaired activation of the PP2A phosphatase cause autosomal recessive early-onset parkinsonism with intellectual disability. Our findings might also provide new insights for understanding the role of the PP2A complex in the pathogenesis of more common forms of neurodegeneration.</p

Psycho-sensory modalities of visual hallucinations and illusions in Parkinson's disease

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Is RBD a risk factor for impulse control disorder in Parkinson's disease?

International audienceObjective: To assess the association between REM sleep behavior disorder (RBD) and other determinants and incident impulse control disorder behaviors (ICBs) in patients with early Parkinson's disease (PD) using longitudinal data from the Parkinson's Progression Markers Initiative (PPMI)

MRI anatomical mapping and direct stereotactic targeting in the subthalamic region: functional and anatomical correspondence in Parkinson's disease

International audienceObject Relationships between clinical effects, anatomy, and electrophysiology are not fully understood in DBS of the subthalamic region in Parkinson's disease. We proposed an anatomic study based on direct image-guided stereotactic surgery with a multiple source data analysis.Materials and Methods A manual anatomic mapping was realized on coronal 1.5-Tesla MRI of 15 patients. Biological data were collected under local anesthesia: the spontaneous neu-ron activities and the clinical efficiency and the appearance of adverse effects. They were related to relevant current values (mA), the benefit threshold (bt, minimal current leading an clear efficiency), the adverse effect threshold (at, minimal current leading an adverse effect) and the stimulation margin (sm = at − bt); they were matched with anatomy.Results We found consistent relationships between anatomy and biological data. The optimal stimulation parameters (low bt + high sm) were noted in the dorsolateral STN. The highest spontaneous neuron activity was found in the ventromedial STN. Dorsolateral (sensorimotor) STN seems the main DBS effector. The highest spontaneous neuron activity seems related to the anterior (rostral) ventromedial (limbic) STN.Conclusion 1.5 Tesla images provide sufficiently detailed sub-thalamic anatomy for image-guided stereotactic surgery and may aid in understanding DBS mechanisms