Review: experimental manipulations of microglia in mouse models of Alzheimer's pathology: activation reduces amyloid but hastens tau pathology.

The inflammation hypothesis of Alzheimer's pathogenesis has directed much scientific effort towards ameliorating this disease. The development of mouse models of amyloid deposition permitted direct tests of the proposal that amyloid-activated microglia could cause neurodegeneration in vivo. Many approaches to manipulating microglial activation have been applied to these mouse models, and are the subject of this review. In general, these results do not support a direct neuricidal action of microglia in mouse amyloid models under any activation state. Some of the manipulations cause both a reduction in pathology and a reduction in microglial activation. However, at least for agents like ibuprofen, this outcome may result from a direct action on amyloid production, and a reduction in the microglial-provoking amyloid deposits, rather than from reduced microglial activation leading to a decline in amyloid deposition. Instead, a surprising number of the experimental manipulations which increase microglial activation lead to enhanced clearance of the amyloid deposits. Both the literature and new data presented here suggest that either classical or alternative activation of microglia can lead to enhanced amyloid clearance. However, a limited number of studies comparing the same treatments in amyloid-depositing vs. tau-depositing mice find the opposite effects. Treatments that benefit amyloid pathology accelerate tau pathology. This observation argues strongly that potential treatments be tested for impact on both amyloid and tau pathology before consideration of testing in humans.

Disobedience and driving in patients with epilepsy.

OBJECTIVE: Motor vehicle accidents direct legislators to ensure pubic safety. We attempted to characterize and quantify driving risk in patients with seizures (PWS). METHODS: We delivered 12-question surveys to 287 consecutive PWS at an epilepsy clinic in Florida. Illegal and disobedient driving practices were analyzed. RESULTS: Eighty-three of 236 (35.2%) PWS were eligible to drive and 62.3% were ineligible with a seizure in <6 months (P<0.001, 95% CI: 0.57-0.70). Among the ineligible responders, 23.8% (35/147) of ineligible responders were illegally driving (14.83% of cohort); 11.86% (28/236) of PWS were disobedient refusing to obey the law, and 8.9% (21/236) of PWS were defiant and knew the law. Sadness (75/236, 31.8%) was the most common reaction to restriction, but disobedient PWS were angry (10/28, 35.7%). CONCLUSION: Overall, a small number of PWS are disobedient and illegally driving. A targeted approach to high-risk drivers with repeated verbal and supplemental driving information may help avoid unnecessary universal physician reporting for PWS.