Point mutant mice with hypersensitive α4 nicotinic receptors show dopaminergic deficits and increased anxiety

Knock-in mice were generated that harbored a leucine-to-serine mutation in the α4 nicotinic receptor near the gate in the channel pore. Mice with intact expression of this hypersensitive receptor display dominant neonatal lethality. These mice have a severe deficit of dopaminergic neurons in the substantia nigra, possibly because the hypersensitive receptors are continuously activated by normal extracellular choline concentrations. A strain that retains the neo selection cassette in an intron has reduced expression of the hypersensitive receptor and is viable and fertile. The viable mice display increased anxiety, poor motor learning, excessive ambulation that is eliminated by very low levels of nicotine, and a reduction of nigrostriatal dopaminergic function upon aging. These knock-in mice provide useful insights into the pathophysiology of sustained nicotinic receptor activation and may provide a model for Parkinson's disease.

Galanin transgenic mice display cognitive and neurochemical deficits characteristic of Alzheimer's disease

Galanin is a neuropeptide with multiple inhibitory actions on neurotransmission and memory. In Alzheimer's disease (AD), increased galanin-containing fibers hyperinnervate cholinergic neurons within the basal forebrain in association with a decline in cognition. We generated transgenic mice (GAL-tg) that overexpress galanin under the control of the dopamine β-hydroxylase promoter to study the neurochemical and behavioral sequelae of a mouse model of galanin overexpression in AD. Overexpression of galanin was associated with a reduction in the number of identifiable neurons producing acetylcholine in the horizontal limb of the diagonal band. Behavioral phenotyping indicated that GAL-tgs displayed normal general health and sensory and motor abilities; however, GAL-tg mice showed selective performance deficits on the Morris spatial navigational task and the social transmission of food preference olfactory memory test. These results suggest that elevated expression of galanin contributes to the neurochemical and cognitive impairments characteristic of AD.

Preserved neuron number in the hippocampus of aged rats with spatial learning deficits.

Hippocampal neuron loss is widely viewed as a hallmark of normal aging. Moreover, neuronal degeneration is thought to contribute directly to age-related deficits in learning and memory supported by the hippocampus. By taking advantage of improved methods for quantifying neuron number, the present study reports evidence challenging these long-standing concepts. The status of hippocampal-dependent spatial learning was evaluated in young and aged Long-Evans rats using the Morris water maze, and the total number of neurons in the principal cell layers of the dentate gyrus and hippocampus was quantified according to the optical fractionator technique. For each of the hippocampal fields, neuron number was preserved in the aged subjects as a group and in aged individuals with documented learning and memory deficits indicative of hippocampal dysfunction. The findings demonstrate that hippocampal neuronal degeneration is not an inevitable consequence of normal aging and that a loss of principal neurons in the hippocampus fails to account for age-related learning and memory impairment. The observed preservation of neuron number represents an essential foundation for identifying the neurobiological effects of hippocampal aging that account for cognitive decline.

Deficits in memory and hippocampal long-term potentiation in mice with reduced calbindin D28K expression.

The influx of calcium into the postsynaptic neuron is likely to be an important event in memory formation. Among the mechanisms that nerve cells may use to alter the time course or size of a spike of intracellular calcium are cytosolic calcium binding or "buffering" proteins. To consider the role in memory formation of one of these proteins, calbindin D28K, which is abundant in many neurons, including the CA1 pyramidal cells of the hippocampus, transgenic mice deficient in calbindin D28K have been created. These mice show selective impairments in spatial learning paradigms and fail to maintain long-term potentiation. These results suggest a role for calbindin D28K protein in temporally extending a neuronal calcium signal, allowing the activation of calcium-dependent intracellular signaling pathways underlying memory function.

Calpain inhibitor AK295 attenuates motor and cognitive deficits following experimental brain injury in the rat.

Marked increases in intracellular calcium may play a role in mediating cellular dysfunction and death following central nervous system trauma, in part through the activation of the calcium-dependent neutral protease calpain. In this study, we evaluated the effect of the calpain inhibitor AK295 [Z-Leu-aminobutyric acid-CONH(CH2)3-morpholine] on cognitive and motor deficits following lateral fluid percussion brain injury in rats. Before injury, male Sprague-Dawley rats (350-425 g) were trained to perform a beam-walking task and to learn a cognitive test using a Morris water maze paradigm. Animals were subjected to fluid percussion injury (2.2-2.4 atm; 1 atm = 101.3 kPa) and, beginning at 15 min postinjury, received a continuous intraarterial infusion of AK295 (120-140 mg/kg, n = 15) or vehicle (n= 16) for 48 hr. Sham (uninjured) animals received either drug (n = 5) or vehicle (n = 10). Animals were evaluated for neurobehavioral motor function at 48 hr and 7 days postinjury and were tested in the Morris water maze to evaluate memory retention at 7 days postinjury. At 48 hr, both vehicle- and AK295-treated injured animals showed significant neuromotor deficits (P< 0.005). At 7 days, injured animals that received vehicle continued to exhibit significant motor dysfunction (P< 0.01). However, brain-injured, AK295-treated animals showed markedly improved motor scores (P<0.02), which were not significantly different from sham (uninjured) animals. Vehicle-treated, injured animals demonstrated a profound cognitive deficit (P< 0.001), which was significantly attenuated by AK295 treatment (P< 0.05). To our knowledge, this study is the first to use a calpain inhibitor following brain trauma and suggests that calpain plays a role in the posttraumatic events underlying memory and neuromotor dysfunction.

Apolipoprotein E4 allele as a predictor of cholinergic deficits and treatment outcome in Alzheimer disease.

Apolipoprotein E (apoE) is critical in the modulation of cholesterol and phospholipid transport between cells of different types. Human apoE is a polymorphic protein with three common alleles, APO epsilon 2, APO epsilon 3, and APO epsilon 4. ApoE4 is associated with sporadic and late-onset familial Alzheimer disease (AD). Gene dose was shown to have an effect on risk of developing AD, age of onset, accumulation of senile plaques in the brain, and reduction of choline acetyltransferase (ChAT) activity in the hippocampus of AD subjects. To characterize the possible impact of the apoE4 allele on cholinergic markers in AD, we examined the effect of apoE4 allele copy number on pre- and postsynaptic markers of cholinergic activity. ApoE4 allele copy number showed an inverse relationship with residual brain ChAT activity and nicotinic receptor binding sites in both the hippocampal formation and the temporal cortex of AD subjects. AD cases lacking the apoE4 allele showed ChAT activities close or within age-matched normal control values. The effect of the apoE4 allele on cholinomimetic drug responsiveness was assessed next in a group (n = 40) of AD patients who completed a double-blind, 30-week clinical trial of the cholinesterase inhibitor tacrine. Results showed that > 80% of apoE4-negative AD patients showed marked improvement after 30 weeks as measured by the AD assessment scale (ADAS), whereas 60% of apoE4 carriers had ADAS scores that were worse compared to baseline. These results strongly support the concept that apoE4 plays a crucial role in the cholinergic dysfunction associated with AD and may be a prognostic indicator of poor response to therapy with acetylcholinesterase inhibitors in AD patients.

Age-related learning deficits in transgenic mice expressing the 751-amino acid isoform of human beta-amyloid precursor protein.

The beta-amyloid precursor protein (beta-APP), from which the beta-A4 peptide is derived, is considered to be central to the pathogenesis of Alzheimer disease (AD). Transgenic mice expressing the 751-amino acid isoform of human beta-APP (beta-APP751) have been shown to develop early AD-like histopathology with diffuse deposits of beta-A4 and aberrant tau protein expression in the brain, particularly in the hippocampus, cortex, and amygdala. We now report that beta-APP751 transgenic mice exhibit age-dependent deficits in spatial learning in a water-maze task and in spontaneous alternation in a Y maze. These deficits were mild or absent in 6-month-old transgenic mice but were severe in 12-month-old transgenic mice compared to age-matched wild-type control mice. No other behavioral abnormalities were observed. These mice therefore model the progressive learning and memory impairment that is a cardinal feature of AD. These results provide evidence for a relationship between abnormal expression of beta-APP and cognitive impairments.

Estudo de associação entre déficits de reconhecimento de emoções em faces, flexibilidade mental e adequação social, em pacientes com transtorno bipolar do tipo I eutímicos, comparados com controles normais

Introdução: O objetivo do estudo foi investigar se há associação entre déficits na capacidade de reconhecimento de emoções faciais e déficits na flexibilidade mental e na adequação social em pacientes com Transtorno Bipolar do tipo I eutímicos quando comparados a sujeitos controles sem transtorno mental. Métodos: 65 pacientes com Transtorno Bipolar do tipo I eutímicos e 95 controles sem transtorno mental, foram avaliados no reconhecimento de emoções faciais, na flexibilidade mental e na adequação social através de avaliações clínicas e neuropsicológicas. Os sintomas afetivos foram avaliados através da Escala de Depressão de Hamilton e da Escala de Mania de Young, o reconhecimento de emoções faciais através da Facial Expressions of Emotion: Stimuli and Tests, a flexibilidade mental avaliada através do Wisconsin Card Sorting Test e a adequação social através da Escala de Auto- Avaliação de Adequação Social. Resultados: Pacientes com Transtorno Bipolar do tipo I eutímicos apresentam uma associação de maior intensidade comparativamente aos controles entre o reconhecimento de emoções faciais e a flexibilidade mental, indicando que quanto mais preservada a flexibilidade mental, melhor será a habilidade para reconhecer emoções faciais Neste grupo às correlações de todas as emoções são positivas com o total de acertos e as categorias e são negativas com as respostas perseverativas, total de erros, erros perseverativos e erros não perseverativos. Não houve uma correlação entre o reconhecimento de emoções faciais e a adequação social, apesar dos pacientes com Transtorno Bipolar do tipo I eutímicos apresentar uma pior adequação social, sinalizando que a pior adequação social não parece ser devida a uma dificuldade em reconhecer e interpretar adequadamente as expressões faciais. Os pacientes com Transtorno Bipolar do tipo I eutímicos não apresentam diferenças significativas no reconhecimento de emoções faciais em relação aos controles, entretanto no subteste surpresa (p=0,080) as diferenças estão no limite da significância estatística, indicando que portadores de transtorno bipolar do tipo I eutímicos tendem a apresentar um pior desempenho no reconhecimento da emoção surpresa em relação aos controles. Conclusão: Nossos resultados reforçam a hipótese de que existe uma associação entre o reconhecimento de emoções faciais e a preservação do funcionamento executivo, mais precisamente a flexibilidade mental, indicando que quanto maior a flexibilidade mental, melhor será a habilidade para reconhecer emoções faciais e melhorar o desempenho funcional do paciente. Pacientes bipolares do tipo I eutímicos apresentam uma pior adequação social quando comparados aos controles, o que pode ser uma consequência do Transtorno Bipolar que ratifica a necessidade de uma intervenção terapêutica rápida e eficaz nestes pacientes

Habilidades do desenvolvimento infantil e linguagem de crianças com fissura labiopalatina

A Fissura Labiopalatina (FLP) é uma das malformações mais comuns da infância, apontada por alguns estudos como um risco para o desenvolvimento global, de fala e linguagem. O objetivo desse estudo foi caracterizar as habilidades do desenvolvimento infantil, enfocando a linguagem de crianças de 3 ano a 3 anos e 11 meses com fissura labiopalatina. A amostra foi dividida em grupo amostral (GA) com 30 crianças entre 3 anos a 3 anos e 11 meses com FLP e o grupo comparativo (GC) com 30 crianças sem FLP de 3 anos a 3 anos e 11 meses provenientes de um Banco de dados. Os grupos foram submetidos a avaliação de três instrumentos: Teste de Triagem de Desenvolvimento de Denver II; Escala ELM - Early language Milestone Scale e o Inventário MacArthur de Desenvolvimento Comunicativo (CDI´s). Houve relação entre a alteração no DNPM e nas habilidades de linguagem e a presença da FLP. Alteração nas habilidades Motor Grosso e de Linguagem, nas áreas Auditivo Expressivo (AE) e Auditivo Receptivo (AR), com prejuízo maior na AE, e no vocabulário expressivo, ambos relacionados a linguagem expressiva. Observou-se desempenho abaixo do esperado, com indicadores de risco para o desenvolvimento das habilidades comunicativas e globais, considerando a amostra estudada.

The Use of the Rey 15-Item Test and Recognition Trial to Evaluate Suboptimal Effort in Neuropsychological Assessment with a Pediatric Mild TBI Sample

The utilization of symptom validity tests (SVTs) in pediatric assessment is receiving increasing empirical support. The Rey 15-Item Test (FIT) is an SVT commonly used in adult assessment, with limited research in pediatric populations. Given that FIT classification statistics across studies to date have been quite variable, Boone, Salazar, Lu, Warner-Chacon, and Razani (2002) developed a recognition trial to use with the original measure to enhance accuracy. The current study aims to assess the utility of the FIT and recognition trial in a pediatric mild traumatic brain injury (TBI) sample (N = 112; M = 14.6 years), in which a suboptimal effort base rate of 17% has been previously established (Kirkwood & Kirk, 2010). All participants were administered the FIT as part of an abbreviated neuropsychological evaluation; failure on the Medical Symptom Validity Test (MSVT) was used as the criterion for suspect effort. The traditional adult cut-off score of(99%), but poor sensitivity (6%). When the recognition trial was also utilized, a combination score of(sensitivity = 64%, specificity = 93%). Results indicate that the FIT with recognition trial may be useful in the assessment of pediatric suboptimal effort, at least among relatively high functioning children following mild TBI.

Making and Keeping Friends: A social skills game that promotes parental involvement to more effectively address social deficits in children with ADHD

The social deficits of children with attention-deficit/hyperactivity disorder (ADHD) have great impact on overall functioning and life satisfaction; however, ways of addressing these deficits to promote positive interpersonal functioning have been limited. The following paper explores the literature that highlights these social deficits, identifies skills that are proposed to target these impairments, discusses child and parent factors that are relevant to positive therapeutic change, and describes the development of a therapeutic game that incorporates variables important to treatment success of these interpersonal difficulties.

Reducing visual deficits caused by refractive errors in school and preschool children: results of a pilot school program in the Andean region of Apurimac, Peru

Background: Refractive error is defined as the inability of the eye to bring parallel rays of light into focus on the retina, resulting in nearsightedness (myopia), farsightedness (Hyperopia) or astigmatism. Uncorrected refractive error in children is associated with increased morbidity and reduced educational opportunities. Vision screening (VS) is a method for identifying children with visual impairment or eye conditions likely to lead to visual impairment. Objective: To analyze the utility of vision screening conducted by teachers and to contribute to a better estimation of the prevalence of childhood refractive errors in Apurimac, Peru. Design: A pilot vision screening program in preschool (Group I) and elementary school children (Group II) was conducted with the participation of 26 trained teachers. Children whose visual acuity was<6/9 [20/30] (Group I) and≤6/9 (Group II) in one or both eyes, measured with the Snellen Tumbling E chart at 6 m, were referred for a comprehensive eye exam. Specificity and positive predictive value to detect refractive error were calculated against clinical examination. Program assessment with participants was conducted to evaluate outcomes and procedures. Results: A total sample of 364 children aged 3–11 were screened; 45 children were examined at Centro Oftalmológico Monseñor Enrique Pelach (COMEP) Eye Hospital. Prevalence of refractive error was 6.2% (Group I) and 6.9% (Group II); specificity of teacher vision screening was 95.8% and 93.0%, while positive predictive value was 59.1% and 47.8% for each group, respectively. Aspects highlighted to improve the program included extending training, increasing parental involvement, and helping referred children to attend the hospital. Conclusion: Prevalence of refractive error in children is significant in the region. Vision screening performed by trained teachers is a valid intervention for early detection of refractive error, including screening of preschool children. Program sustainability and improvements in education and quality of life resulting from childhood vision screening require further research.

Effets de la stimulation magnétique transcrânienne dans la maladie de Parkinson avec déficits cognitifs légers

Beaucoup de patients atteints de la maladie de Parkinson (MP) peuvent souffrir de troubles cognitifs dès les étapes initiales de la maladie et jusqu’à 80% d’entre eux vont développer une démence. Des altérations fonctionnelles au niveau du cortex préfrontal dorsolatéral (CPFDL), possiblement en relation avec le noyau caudé, seraient à l’origine de certains de ces déficits cognitifs. Des résultats antérieurs de notre groupe ont montré une augmentation de l’activité et de la connectivité dans la boucle cortico-striatale cognitive suite à la stimulation magnétique transcrânienne (SMT) utilisant des paramètres « theta burst » intermittent (iTBS) sur le CPFDL gauche. Pour cette étude, 24 patients atteints de la MP avec des troubles cognitifs ont été séparées en 2 groupes : le groupe iTBS active (N=15) et le groupe sham (stimulation simulée, N=9). Une batterie neuropsychologique détaillée évaluant cinq domaines cognitifs (attention, fonctions exécutives, langage, mémoire et habiletés visuo-spatiales) a été administrée lors des jours 1, 8, 17 et 37. Le protocole iTBS a été appliqué sur le CPFDL gauche durant les jours 2, 4 et 7. Les scores z ont été calculés pour chaque domaine cognitif et pour la cognition globale. Les résultats ont montré une augmentation significative de la cognition globale jusqu’à 10 jours suivant l’iTBS active, particulièrement au niveau de l’attention, des fonctions exécutives et des habiletés visuo-spatiales. Cet effet sur la cognition globale n’est pas répliqué dans le groupe sham. Ces résultats suggèrent donc que l’iTBS peut moduler la performance cognitive chez les patients atteints de MP avec des déficits cognitifs.

The causes of rising transit operating deficits. Final report.

Urban Mass Transportation Administration, Washington, D.C.

USSR : sharply higher budget deficits threaten perestroyka : a research paper.

"SOV 88-10043U, September 1988."