The Effects of Amygdalar Size Normalization on Group Analysis in Late-Life Depression

Structural MRI has been utilized in numerous ways to measure morphologic characteristics of subcortical brain regions. Volumetric analysis is frequently used to quantify the size of brain structures to ultimately compare size differences between individuals. In order to make such comparisons, inter-subject variability in brain and/or head size must be taken into consideration. A heterogeneous set of methods are commonly used to normalize regional volume by brain and/or head size yielding inconsistent findings making it diffcult to interpret and compare results from published volumetric studies. This study investigated the effect that various volume normalization methodologies might have on group analysis. Specifically, the amygdalae were the regions of interest in elderly, healthy and depressed individuals. Normalization methods investigated included spatial transformations, brain and head volume, and tissue volume techniques. Group analyses were conducted with independent t-tests by dividing amygdalar volumes by various volume measures, as well as with univariate analysis of covariance (ANCOVA) analyses by using amygdalar volumes as dependent variables and various volume measures as covariates. Repeated measures ANOVA was performed to assess the effect of each normalization procedure. Results indicate that volumetric differences between groups varied based on the normalization method utilized, which may explain, in part, the discrepancy found in amygdalar volumetric studies. We believe the findings of this study are extensible to other brain regions and demographics, and thus, investigators should carefully consider the normalization methods utilized in volumetric studies to properly interpret the results and conclusions

MRI Parameters Of Alzheimer's Disease in an Arab Population of Wadi Ara, Israel

Magnetic resonance imaging (MRI) findings are reported from 15 individuals in an Arab–Israeli community who were diagnosed with Alzheimer's disease (AD). The quantitative parameters that were used for MRI analyses included gradings (0–3) and linear measurements of different brain structures. Generalized tissue loss was assessed by combined measurements of the ventricles (ventricular score, VS) and sulcal grading and width (SG, SW, respectively). Loss of brain tissue in specific regions of interest, eg, temporal lobes, basal ganglia, and midbrain, was evaluated by precise measurements. We observed abnormal tissue characteristics, expressed as high intensity foci in white matter on T2W sequences, as well as tissue loss, both generalized and focal. Most notable were changes involving the head of the caudate nuclei, the midbrain, and to a lesser degree, medial temporal structures.National Institute of Aging (UO1-AG17173); National Institute on Alcohol Abuse and Alcoholism (R37-AA07112, K05-AA00219); US Department of Veterans Affair

Habituation of exploratory activity in aged rats: effects of pyritinol

A acetilcolina é um neurotransmissor que desempenha considerável papel crítico nos processos subjacentes ao comportamento, aprendizagem e memória. Piritinol (piritioxina, Encefabolâ, PRT) é um fármaco nootrópico que aumenta a transmissão colinérgica no sistema nervoso central. Habituação comportamental seguida de múltipla exposição no campo aberto é um paradigma experimental freqüentemente usado na avaliação das ações cognitivas de fármacos. Neste paradigma, a diminuição da atividade exploratória em função da exposição repetida ao mesmo ambiente é considerada como índice de memória. No presente estudo, os efeitos do piritinol (PRT) na forma de pó adicionado a dieta (200 mg/kg/dia, p.o., durante 14 dias) sobre a habituação em ratos idosos foram avaliados no campo aberto. Um total de 18 ratos idosos foram randomizados e divididos em dois grupos: controle (tratado com veículo, n=8) e experimental (tratado com PRT, n=10). Na avaliação da tarefa exploratória, o tratamento com PRT diminuiu significantemente os números totais de área cruzada e do levantar quando comparados com o grupo controle, indicando habituação. O tratamento com PRT aumentou a retenção no número total de cruzamentos e levantar quando comparado com o grupo controle. A análise dos dados em conjunto, sugere que o sistema muscarínico colinérgico pode estar envolvido com os efeitos da PRT sobre a habituação da atividade exploratória em ratos idosos.Acetylcholine (Ach) is a neurotransmitter considered to play a critical role in processes underlying behavior, learning, and memory. Pyritinol (pyrithioxine, Encephabolâ, PRT) is a nootropic drug that increases cholinergic transmission in the central nervous system. Behavioral habituation following multiple exposures to an open field is an experimental paradigm frequently used to assess the cognitive actions of drugs. In this paradigm the decrease of exploratory activity as a function of repeated exposure to the same environment is taken as an index memory. In the present study, effects PRT administrated to aged rats in powder form added to the diet (200 mg /kg / day, p.o., for 14 days) were evaluated in the habituation to an open field. A total of 18 aged rats were randomly assigned to one of two groups control (vehicle-treated rats, n = 8) and experimental group (PRT-treated rats, n = 10) and were used in the following procedure. In the exploratory task, the post-training treatment with PRT significantly decreased the number of total area crossings and rears when compared to the control group, indicating habituation. PRT treatment enhanced retention in the total number of area crossings and rears when compared with control animals. Taken together, the data of present study suggest that muscarinic cholinergic systems could be involved in the effect of PRT in habituation of exploratory activity to an open field in aged rats

Targeted polypharmacology: discovery of dual inhibitors of tyrosine and phosphoinositide kinases.

The clinical success of multitargeted kinase inhibitors has stimulated efforts to identify promiscuous drugs with optimal selectivity profiles. It remains unclear to what extent such drugs can be rationally designed, particularly for combinations of targets that are structurally divergent. Here we report the systematic discovery of molecules that potently inhibit both tyrosine kinases and phosphatidylinositol-3-OH kinases, two protein families that are among the most intensely pursued cancer drug targets. Through iterative chemical synthesis, X-ray crystallography and kinome-level biochemical profiling, we identified compounds that inhibit a spectrum of new target combinations in these two families. Crystal structures revealed that the dual selectivity of these molecules is controlled by a hydrophobic pocket conserved in both enzyme classes and accessible through a rotatable bond in the drug skeleton. We show that one compound, PP121, blocks the proliferation of tumor cells by direct inhibition of oncogenic tyrosine kinases and phosphatidylinositol-3-OH kinases. These molecules demonstrate the feasibility of accessing a chemical space that intersects two families of oncogenes

Repeated exposure of adolescent rats to oral methylphenidate does not induce behavioral sensitization or cross-sensitization to nicotine

Several lines of evidence indicate that the use of stimulant drugs, including methylphenidate (MPD), increases tobacco smoking. This has raised concerns that MPD use during adolescence could facilitate nicotine abuse. Preclinical studies have shown that repeated treatment with an addictive drug produces sensitization to that drug and usually cross-sensitization to other drugs. Behavioral sensitization has been implicated in the development of drug addiction. We examined whether repeated oral MPD administration during adolescence could induce behavioral sensitization to MPD and long-lasting cross-sensitization to nicotine. Adolescent male Wistar rats were treated orally with 10 mg/kg MPD or saline (SAL) from postnatal day (PND) 27 to 33. To evaluate behavioral sensitization to MPD in adolescent rats (PND 39), the SAL pretreated group was subdivided into two groups that received intragastric SAL (1.0 mL/kg) or MPD (10 mg/kg); MPD pretreated rats received MPD (10 mg/kg). Cross-sensitization was evaluated on PND 39 or PND 70 (adulthood). To this end, SAL- and MPD-pretreated groups received subcutaneous injections of SAL (1.0 mL/kg) or nicotine (0.4 mg/kg). All groups had 8 animals. Immediately after injections, locomotor activity was determined. The locomotor response to MPD challenge of MPD-pretreated rats was not significantly different from that of the SAL-pretreated group. Moreover, the locomotor response of MPD-pretreated rats to nicotine challenge was not significantly different from that of the SAL-pretreated group. This lack of sensitization and cross-sensitization suggests that MPD treatment during adolescence does not induce short- or long-term neuroadaptation in rats that could increase sensitivity to MPD or nicotine

A Homeostatic Model of Subjective Cognitive Decline

Subjective Cognitive Decline (SCD) is possibly one of the earliest detectable signs of dementia, but we do not know which mental processes lead to elevated concern. In this narrative review, we will summarize the previous literature on the biomarkers and functional neuroanatomy of SCD. In order to extend upon the prevailing theory of SCD, compensatory hyperactivation, we will introduce a new model: the breakdown of homeostasis in the prediction error minimization system. A cognitive prediction error is a discrepancy between an implicit cognitive prediction and the corresponding outcome. Experiencing frequent prediction errors may be a primary source of elevated subjective concern. Our homeostasis breakdown model provides an explanation for the progression from both normal cognition to SCD and from SCD to advanced dementia stages