Amisulpride as a potential disease-modifying drug in the treatment of tauopathies.

INTRODUCTION: Hyperphosphorylation and aggregation of the microtubule-associated protein tau cause the development of tauopathies, such as Alzheimer's disease and frontotemporal dementia (FTD). We recently uncovered a causal link between constitutive serotonin receptor 7 (5-HT7R) activity and pathological tau aggregation. Here, we evaluated 5-HT7R inverse agonists as novel drugs in the treatment of tauopathies. METHODS: Based on structural homology, we screened multiple approved drugs for their inverse agonism toward 5-HT7R. Therapeutic potential was validated using biochemical, pharmacological, microscopic, and behavioral approaches in different cellular models including tau aggregation cell line HEK293 tau bimolecular fluorescence complementation, primary mouse neurons, and human induced pluripotent stem cell-derived neurons carrying an FTD-associated tau mutation as well as in two mouse models of tauopathy. RESULTS: Antipsychotic drug amisulpride is a potent 5-HT7R inverse agonist. Amisulpride ameliorated tau hyperphosphorylation and aggregation in vitro. It further reduced tau pathology and abrogated memory impairment in mice. DISCUSSION: Amisulpride may be a disease-modifying drug for tauopathies.

Trends, patterns, and determinants of regional mortality in Belarus, 1990-2007.

We report analyses of regional trends in overall and cause-specific mortality in Belarus for the period 1990-2007. We explore the respective spatial patterns and attempt to determine the factors responsible for the regional mortality variation. The results show that inter-regional mortality differentials tend to rise, mainly because of the growing advantage of the capital over other regions. The increasing variation is associated with diverging trends in mortality from external causes of death. Mortality tends to be higher in the eastern part of the country. Regional data show that changes in mortality are largely explained by alcohol and socio-economic conditions, as measured by unemployment and poverty rates. Cardiovascular and external-cause mortality are strongly associated with alcohol and unemployment, while poverty is an important predictor of suicide and homicide mortality. Clusters of elevated mortality from certain cancers located in the contaminated zone point to the possible impact of the Chernobyl accident.

Projected numbers of people with movement disorders in the years 2030 and 2050.

BACKGROUND: Movement disorders are chronic diseases with an increasing prevalence in old age. Because these disorders pose a major challenge to patients, families, and health care systems, there is a need for reliable data about the future number of affected people. PATIENTS AND METHODS: We searched the literature to identify epidemiological studies to obtain age-specific prevalence data of movement disorders. We combined the age-specific prevalence data with population projections for Europe, the United States, and Canada. RESULTS: Movement disorders will increase considerably between 2010 and 2050. The highest increase will be for dementia with Lewy bodies. In several countries, we project a near doubling of patients with PD. CONCLUSIONS: There will be a strong increase in the number of people affected by most movement disorders between 2010 and 2050. This increase will mostly depend on the future aging of populations in terms of their age structure and future life expectancy.

Being born under adverse economic conditions leads to a higher cardiovascular mortality rate later in life: evidence based on individuals born at different stages of the business cycle.

We connect the recent medical and economic literatures on the long-run effects of early-life conditions by analyzing the effects of economic conditions on the individual cardiovascular (CV) mortality rate later in life, using individual data records from the Danish Twin Registry covering births since the 1870s and including the cause of death. To capture exogenous variation of conditions early in life, we use the state of the business cycle around birth. We find significant negative effects of economic conditions around birth on the individual CV mortality rate at higher ages. There is no effect on the cancer-specific mortality rate. From variation within and between monozygotic and dizygotic twin pairs born under different conditions, we conclude that the fate of an individual is more strongly determined by genetic and household-environmental factors if early-life conditions are poor. Individual-specific qualities come more to fruition if the starting position in life is better.

Health care consequences of demographic changes in Mecklenburg-West Pomerania: projected case numbers for age-related diseases up to the year 2020, based on the Study of Health in Pomerania (SHIP).

BACKGROUND: The population in the German federal state of Mecklenburg-West Pomerania is growing older. A resulting rise in age-related diseases will likely lead to a greater need for medical care, even though the population as a whole is declining. The predicted number of patients affected by these diseases varies from one district to another because of local differences in demographic trends. METHODS: Case numbers were forecasted on the basis of representative data on the morbidity from chronic diseases, which were derived from the Study of Health in Pomerania (SHIP), the conjoint cancer registry of the East German federal states (GKR), and a study on dementia morbidity. These data were combined with demographic prognoses for Mecklenburg-West Pomerania and its rural and urban districts up to the year 2020. RESULTS: The largest increases in case numbers are predicted for dementia (+91.1%), myocardial infarction (+28.3%), diabetes mellitus (+21.4%), and incident colon carcinoma (+31.0%; all figures are expressed in relation to the year 2005 as a baseline). The predicted changes in case numbers vary widely from one district to another. CONCLUSION: All of the German federal states located in the former East Germany are likely to experience similar developments to those predicted for Mecklenburg-West Pomerania, as will many rural areas of the former West Germany, in which a demographic transition is already evident. Because of the predicted rise in the number of patients, new health care concepts will have to be rapidly developed, implemented, and evaluated in order to ensure that comprehensive medical care will be delivered where it is needed.