Apathy is considered to be a core feature of Parkinson’s disease (PD) and has been associated with a variety of states and symptoms of the disease, such as increased severity of motor symptoms, impaired cognition, executive dysfunction and dementia. Apart from the high prevalence of apathy in PD, which is estimated to be about 40%, the underlying pathophysiology remains poorly understood and current treatment approaches are unspecific and proved to be only partially effective. In animal models, apathy has been sub-optimally modeled, mostly by means of pharmacological and stress-induced methods, whereby concomitant depressive-like symptoms could not be ruled out. In the context of PD only a few studies on toxin-based models (i.e., 6-hydroxydopamine (6-OHDA) or 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)) claimed to have determined apathetic symptoms in animals. The assessment of apathetic symptoms in more elaborated and multifaceted genetic animal models of PD could help to understand the pathophysiological development of apathy in PD and eventually advance specific treatments for afflicted patients. Here we report the presence of behavioral signs of apathy in 12 months old mice that express only ~5% of the vesicular monoamine transporter 2 (VMAT2). Apathetic-like behavior in VMAT2 deficient (LO) mice was evidenced by impaired burrowing and nest building skills, and a reduced preference for sweet solution in the saccharin preference test, while the performance in the forced swimming test was normal. Our preliminary results suggest that VMAT2 deficient mice show an apathetic-like phenotype that might be independent of depressive-like symptoms. Therefore VMAT2 LO mice could be a useful tool to study the pathophysiological substrates of apathy and to test novel treatment strategies for apathy in the context of PD.

Parkinson disease is typically treated with L-3,4-dihydroxyphenylalanine (or levodopa) coprescribed with concentration stabilizers to prevent undesired motor fluctuations. However, the beneficial role of the chronic combined therapy on disease progression has not been thoroughly explored. We hypothesized that tolcapone, a catechol-O-methyl-transferase inhibitor, co-administered with levodopa may offer beneficial long-term disease-modifying effects through its dopamine stabilization actions. Here, we followed vesicular monoamine transporter 2-deficient and wild-type mice treated twice daily per os with vehicle, levodopa (20 mg/kg), tolcapone (15 mg/kg) or levodopa (12.5 mg/kg) + tolcapone (15 mg/kg) for 17 weeks. We assessed open field, bar test and rotarod performances at baseline and every 4th week thereafter, corresponding to OFF-medication weeks. Finally, we collected coronal sections from the frontal caudate-putamen and determined the reactivity level of dopamine transporter. Vesicular monoamine transporter 2-deficient mice responded positively to chronic levodopa + tolcapone intervention in the bar test during OFF-periods. Neither levodopa nor tolcapone interventions offered significant improvements on their own. Similarly, chronic levodopa + tolcapone intervention was associated with partially rescued dopamine transporter levels, whereas animals treated solely with levodopa or tolcapone did not present this effect. Interestingly, 4-month progression of bar test scores correlated significantly with dopamine-transporter-label density. Overall, we observed a moderate functional and histopathological improvement effect by chronic dopamine replacement when combined with tolcapone in vesicular monoamine transporter 2-deficient mice. Altogether, chronic stabilization of dopamine levels by catechol-O-methyl-transferase inhibition, besides its intended immediate actions, arises as a potential long-term beneficial approach during the progression of Parkinson disease.

A. Basic Sleep ScienceVII. Aging and Neurodegeneration p=0.014), and orbitofrontal (0.021, 95% CI: 0.009-0.034, p=0.001) areas. A post-hoc analysis showed similar trends throughout the brain. Conclusion: Baseline EDS was associated with a longitudinal increase in FDG-PET signal. This hypermetabolism may represent a compensatory mechanism in response to efficiency loss in the setting of overloaded synaptic activity. This hypothesis is consistent with previous findings suggesting increased blood flow at the end of the waking day when compared to blood flow after a night of sleep. However, the increase predicted by EDS does not imply an overall increase in brain metabolism, because the magnitude of the reduction predicted by baseline age is higher than the increase in FDG-PET signal predicted by EDS in all regions. Introduction: Light, particularly blue light, increases alertness, performance and cognitive brain responses, but age-related decrease in the effects of light has been reported. The extent to which these age-related modifications are caused by changes at the level of the eye (because of senile miosis and lens yellowing) or the brain is unclear. Methods: We conducted a neuroimaging protocol including 14 younger (20-30y), 12 older (60-80y) and 12 matched older healthy individuals with intraocular lens replacement after cataract surgery (IOL subjects), i.e. they differed from the healthy older group only in terms lens light absorption. Subjects completed two functional magnetic resonance imaging (fMRI) acquisitions while performing a working memory 2-back task (2b) and a simple letter detection "0-back" task (0b), once under blue monochromatic light (B) (480nm, 3x1013ph/cm2/s) and once under orange monochromatic light (O) (620nm, 3x1013ph/cm2/s). Each fMRI session was conterbalned and also included blocks of n-back task in darkness, as well as blocks of light alone (B, O). Results: First, all blue blocks were contrast against blocks completed in darkness [(2bB+0bB+B)-(2bD+0bD)]. Results revealed common group effects with greater brain activations in lateral geniculate nucleus, lingual, calcarine sulcus and median occipital gyrus under blue light exposure (P corrected < 0.05). As a second step, in order to estimate non-visual impact of light, we computed the effect of blue versus orange light on cognitive brain responses [(2bB-0bB)-(2bO-0bO)]. Results revealed a main effect of group (P corrected < 0.05) with group differences in various regions including the cingulate cortex, median prefrontal cortex and hippocampus. Young subjects showed greater brain sensitivity to light as compared to IOL and older individuals. No significant differences were found between IOL and older with their natural endogenous lens. Conclusion: Our results confirm that the aging brain is still sensitive to blue light. However, both older groups showed reduced non-visual effects of light on cognitive brain responses as compared to the young. These results suggest that cerebral modifications, not the lens, underlie age-related reduced...