[Automobile driving among patients with dementia. Survey in the Poitou-Charentes region]. / Conduite automobile des patients déments. Enquête en Poitou-Charentes.

OBJECTIVES: To determine the characteristics of drivers with dementia and analyze their driving habits. METHODS: The study was conducted among neurologists and geriatricians in the Poitou-Charentes region. We asked 75 physicians to question (according to a structured questionnaire) the patients they saw in January 2004 who were known to suffer from dementia, defined by a Folstein Mini-Mental State (MMS) score pound 25. We compared the epidemiologic characteristics of drivers and nondrivers and described their driving habits. RESULTS: Of the 75 practitioners asked to participate, 27 (36%) accepted and interviewed 146 patients, 74 women and 72 men. Their mean MMS score was 17.6 +/- 5.6 [0-25]. In all, 52 were still driving at the time of the interview, and 48 had stopped, 9 because of motor vehicle accidents. Logistic regression analysis revealed 3 significant variables that differed between the drivers and the nondrivers: drivers were mainly male (p=0.0002), younger (p=0.001) and more recently diagnosed (p=0.003). Half those still driving drove only occasionally (< or =3 times a week), usually during daylight and for short distances. One driver was involved in an accident the year before. DISCUSSION: Patients appeared to be aware of the dangers of driving and avoided taking risks. The MMS score predicted driving status. It is essential to develop simple tests to assess driving ability as objectively as possible.

mTOR/p70S6k signalling alteration by Abeta exposure as well as in APP-PS1 transgenic models and in patients with Alzheimer's disease.

In Alzheimer's disease, neuropathological hallmarks include the accumulation of beta-amyloid peptides (Abeta) in senile plaques, phosphorylated tau in neurofibrillary tangles and neuronal death. Abeta is the major aetiological agent according to the amyloid cascade hypothesis. Translational control includes phosphorylation of the kinases mammalian target of rapamycin (mTOR) and p70S6k which modulate cell growth, proliferation and autophagy. It is mainly part of an anti-apoptotic cellular signalling. In this study, we analysed modifications of mTOR/p70S6k signalling in cellular and transgenic models of Alzheimer's disease, as well as in lymphocytes of patients and control individuals. Abeta 1-42 produced a rapid and persistent down-regulation of mTOR/p70S6k phosphorylation in murine neuroblastoma cells associated with caspase 3 activation. Using western blottings, we found that phosphorylated forms of mTOR and p70S6k are decreased in the cortex but not in the cerebellum (devoid of plaques) of double APP/PS1 transgenic mice compared with control mice. These results were confirmed by immunohistochemical methods. Finally, the expression of phosphorylated p70S6k was significantly reduced in lymphocytes of Alzheimer's patients, and levels of phosphorylated p70S6k were statistically correlated with Mini Mental Status Examination (MMSE) scores. Taken together, these findings demonstrate that the mainly anti-apoptotic mTOR/p70S6k signalling is altered in cellular and transgenic models of Alzheimer's disease and in peripheral cells of patients, and could contribute to the pathogenesis of the disease.

The up-regulation of the striatal dopamine transporter's activity by cAMP is PKA-, CaMK II- and phosphatase-dependent.

The neuronal dopamine transporter (DAT) is a presynaptic plasma membrane protein mediating the re-uptake of dopamine released from synaptic cleft into the nerve terminals. While the regulation of its activity by protein kinase C signalling is well-characterized, there is controversial debate about its regulation by protein kinase A (PKA) signalling. In rat striatal synaptosomes, we showed that a cell-permeable cyclic adenosine 3',5'-monophosphate analogue up-regulated the DAT capacity without modification of its efficiency. This acute effect was PKA-, calcium calmodulin dependent kinase II- and phosphatase-dependent. Together, these results suggest that the activity of DAT may depend on a state of the transporter with both specific phosphorylated and dephosphorylated sites.

Lactic acidosis progressively impairs dopamine uptake in rat striatal synaptosomes by a mechanism partially independent of the Na+/K+-ATPase dysfunction.

Previous experiments reported that incubation of rat striatal synaptosomes with lactic acid (pH 5.5) resulted in an inhibition of dopamine (DA) uptake partially mediated by free radical damage. Since the DA uptake process is highly dependent on the functionality of Na+/K+-ATPase, the present study investigated whether this inhibition of DA uptake could be related to an alteration of the Na+/K+-ATPase activity. Striatal lactic acidosis was performed by direct addition of lactic acid in the incubation medium to obtain a pH as close as possible to that observed in ischemia. Acidosis (pH 5.5) induced a progressive decline in the specific DA uptake and a decrease of Na+/K+-ATPase activity in striatal synaptosomes. However, whereas loss of Na+/K+-ATPase activity was totally prevented by Trolox, a powerful antioxidant, DA uptake remained partially inhibited. Taken together, these data suggest that acidosis, in a degree encountered during ischemia, alters the high-affinity DA uptake in part by a mechanism that does not involve a Na+/K+ pump deficiency.