Search

Summary Alzheimer's disease (AD) is a devastating neurodegenerative disorder that impairs memory and causes cognitive and psychiatric deficits. New evidences indicate that AD is conceptualized as a disease of synaptic failure, although the molecular and cellular mechanisms underlying these defects remain to be elucidated. Determining the timing and nature of the early synaptic deficits is critical for understanding the progression of the disease and for identifying effective targets for therapeutic intervention. Using single‐synapse functional and morphological analyses, we find that AMPA signaling, which mediates fast glutamatergic synaptic transmission in the central nervous system (CNS), is compromised early in the disease course in an AD mouse model. The decline in AMPA signaling is associated with changes in actin cytoskeleton integrity, which alters the number and the structure of dendritic spines. AMPA dysfunction and spine alteration correlate with the presence of soluble but not insoluble Aβ and tau species. In particular, we demonstrate that these synaptic impairments can be mitigated by Aβ immunotherapy. Together, our data suggest that alterations in AMPA signaling and cytoskeletal processes occur early in AD. Most important, these deficits are prevented by Aβ immunotherapy, suggesting that existing therapies, if administered earlier, could confer functional benefits.

Alzheimer's disease (AD), a progressive neurodegenerative disease characterized by the accumulation of amyloid-beta protein and neuronal loss, is the leading cause of age-related dementia in the world today. The disease is also associated with neuroinflammation, robust activation of astrocytes and microglia, and evidence of activation of the complement system, localized with both fibrillar amyloid-beta (fAbeta) plaques and tangles. The observations are consistent with a complement-dependent component of AD progression. We have previously shown that inhibition of the major complement receptor for C5a (CD88) with the antagonist PMX205 results in a significant reduction in pathology in two mouse models of AD. To further characterize the role of complement in AD-related neuroinflammation, we examined the age- and disease-associated expression of CD88 in brain of transgenic mouse models of AD and the influence of PMX205 on the presence of various complement activation products using flow cytometry, western blot, and immunohistochemistry. CD88 was found to be up-regulated in microglia, in the immediate vicinity of amyloid plaques. While thioflavine plaque load and glial recruitment is significantly reduced after treatment with PMX205, C1q remains co-localized with fAbeta plaques and C3 is still expressed by the recruited astrocytes. Thus, with PMX205, potentially beneficial activities of these early complement components may remain intact, while detrimental activities resulting from C5a-CD88 interaction are inhibited. This further supports the targeted inhibition of specific complement mediated activities as an approach for AD therapy.

Aims. This is the second of a set of three papers evaluating drinking status and mortality risk. Analysis of eight general population surveys of men evaluated all-cause mortality rates by drinking pattern. Design and participants. Raw data from three studies of youth and five studies of adults were evaluated. Logistic regression models controlled for confounding characteristics. Meta-analysis combined study results. Measurements. Drinking pattern was alternatively defined by quantity, frequency and volume of drinking. Final models included drinking pattern (as well as abstinence in the youth models and long-term abstainers and former drinkers in adult models), age and other confounding variables. Models also evaluated interactions of age and, respectively, long-term abstinence and former drinking. Findings. No evidence was found for the hypothesis that abstinence is associated with greater mortality risk than light drinking. In the youth samples, abstainers had a lower risk of dying than those drinking less than 15 times per month. One study of the adult samples showed a significant age by former drinker interaction; this did not alter the lack of association of former drinking with mortality risk or the homogeneity of results across studies for this finding. The most consistent finding was the association of heavy drinking with mortality among youth. Among adults, drinking 43 or more drinks per month and drinking 21 or more times per month were associated with increased mortality risk. Quantity per occasion was not significantly associated with mortality risk among adults. Conclusions. That frequent drinking was related to mortality risk, whereas heavier quantity was unrelated, is inconsistent with the belief that daily consumption of a few glasses of wine has salutary effects. Empirically, however, this pattern tends to be unusual. Findings were homogeneous across studies lending generalizability to results.

Aims. This is the first of a set of three papers evaluating drinking status and mortality risk. Analyses of multiple studies describe associations of drinking patterns with characteristics hypothesized to confound the relationships between drinking status and mortality. Characteristics which both significantly differentiate drinking groups and are consistent across studies would suggest that mortality studies not controlling for them may be compromised. Design and participants. Associations are evaluated from the raw data of 10 general population studies which contained mortality data. Long-term abstainers are compared to former drinkers, long-term abstainers and former drinkers are compared to light drinkers (by quantity, frequency and volume in separate analyses) and moderate to heavy drinkers are compared to light drinkers. Tetrachoric correlation coefficients assess statistical significance; meta-analysis determines if associations are homogeneous across studies. Measurements. Measures of alcohol consumption are quantity, frequency and volume; long-term abstainers are differentiated from former drinkers. Multiple measures of health, social position, social integration and mental health characteristics are evaluated. Findings. Across studies, adult male former drinkers are consistently more likely to be heavier smokers, depressed, unemployed, lower SES and to have used marijuana than long-term abstainers. Adult female former drinkers are consistently more likely to be heavier smokers, in poorer health, not religious, and unmarried than long-term abstainers. Both types of abstainers tend to be of lower SES than light drinkers and report poorer health (not consistent). Female abstainers are more likely to be of normal or overweight than light drinkers. Conclusions. Characteristics of two groups of abstainers, other than their non-use of alcohol, may confound the associations found between drinking and mortality risk.

AIMS: This is the third of a set of three papers evaluating drinking status and mortality risk. Analysis of three general population surveys of women evaluated all-cause mortality rates by drinking pattern. DESIGN AND PARTICIPANTS: Raw data from three studies of adult women were evaluated. Logistic regression models controlled for confounding characteristics. Meta-analysis combined study results. MEASUREMENTS: Drinking pattern was alternatively defined by quantity, frequency and volume of drinking. Final models included drinking pattern (including long-term abstainers and former drinkers) as well as age and other confounding variables. Models also evaluated interactions of age and, respectively, long-term abstinence and former drinking. FINDINGS: In models in which age was controlled, odds of death for long-term abstainers and former drinkers (defined by volume or quantity) were greater than those for light drinkers; odds of death for moderate and heavy drinkers (defined by quantity) were greater than those for light drinkers. When other psychosocial attributes were controlled, odds of death were similar for abstainers and light drinkers. When other psychosocial attributes were controlled, odds of death for heavy drinkers (defined by volume and quantity) were greater than those for light drinkers. When interactions of age and the two forms of abstinence were introduced, one study showed a significant effect of age and former drinking. CONCLUSIONS: Results were consistent with the hypothesis that characteristics of abstainers other than their non-use of alcohol may account for their higher mortality risk. With the exception of former drinkers compared to light drinkers, when interactions were introduced into models (for measures of quantity and frequency) findings were homogeneous across studies, lending generalizability to results. Language: en

The kinetics of imidazopyrimidines selected for development were investigated in the rat, dog, and cynomolgus monkey using high pressure liquid chromatography (HPLC) measurements of levels. These data were compared with levels estimated by benzodiazepine radioreceptor binding assays and with the in vivo binding of the compounds to these receptors in the brain. RU 32698, RU 33203, and RU 33543 were found in relatively high peak levels in the plasma of rats (1–6 μg/ml at 10 min-1 hr after 10–100 mg/kg orally [p.o.]), dogs (4–12 μg/ml at 2 hr after 20 mg/kg p.o.), and monkeys (0.4–10 μg/ml after 150–500 mg/kg p.o.). HPLC analysis showed one further prominent peak for either RU 33203 or RU 33543 which had similar characteristics in all three species and may represent a common route of metabolism. In the rat these putative metabolites were at low levels in the brain when compared with parent levels. Nuclear magnetic resonance (NMR) and mass spectra of these isolated metabolites identified them as the hydroxymethyl derivatives on the oxadiazole ring. The synthesised metabolites showed two to six times less affinity for 3H-flunitrazepam-labelled benzodiazepine receptors, and the RU 33203 metabolite, RU 34149, did not displace in vivo benzodiazepine receptor binding after administration to mice, despite high plasma levels. This, coupled with little activity in several in vivo pharmacological models, suggests that this metabolite only poorly crosses the blood brain barrier. A pharmacological effect in the stress-induced ultrasounds model is consistent with this view as the rat pups used have a poor blood brain barrier. Daily dosing of low, pharmacologically effective doses of all three compounds (25 or 30 mg/kg p.o.) in rats showed little change in the plasma levels of parents after the 14th dose. There were slight increases in the levels of the metabolites of RU 33203 and RU 33543. Higher doses showed some decrease of parent levels on day 14 but a clear increase in the metabolite levels, particularly with RU 33543, suggesting enhanced metabolism on repeated dosing. No marked differences in overall plasma level time courses of parent or metabolites were observed when comparing the first or last (28–30 days) daily dose in monkeys (150–500 mg/kg p.o.).

The synthesis and CNS activity of a noval class of annelated 1,4-benzodiazepines, the aminomethylene-2,4-dihydro-1H-imidazo[1,2-a][1,4]benzodiazepines, are described. An investigation of the structure--activity relationships in the series derived from 8-chloro-2,4-dihydro-2-dimethylaminomethylene-6-phenyl-1H-imidazo[1,2-a][1,4]-benzodiazepin-1-one (10) led to the synthesis of a group of compounds with potent minor tranquillizer activity.

A number of derivatives of 2-methyl-3-(o-tolyl)-4(3H)-quinazolone bearing new substituents on the 2-methyl group have been synthesized. It was established that most substitutions at this position reduce or remove the CNS depressant activity of methaqualone. From the series prepared only the 2-fluoromethyl derivative or certain isothiouronium salts, which could be hydrolyzed in vivo to the 2-mercaptomethyl derivative, showed activity of the same magnitude as methaqualone.