Age-related deficits in context discrimination learning in Ts65Dn mice that model Down syndrome and Alzheimer's disease.

All individuals with Down syndrome (DS) eventually develop the neuropathology of Alzheimer's disease (AD), which is characterized by a premature loss of basal forebrain cholinergic neurons. Similarly, between 4 and 6 months of age, Ts65Dn mice, which model DS, lose cholinergic markers in their medial septal neurons. It is not known whether Ts65Dn mice have age-related learning deficits as well. Control and Ts65Dn mice were tested at several ages in context discrimination. Controls at all ages showed no deficits in learning this task. Ts65Dn mice younger than 3 months demonstrated impaired learning, suggesting a possible developmental delay in Ts65Dn mice. Four-month-old Ts65Dn mice showed no deficits, whereas Ts65Dn mice older than 5 months were impaired in learning the task. Therefore, Ts65Dn mice have an age-related learning impairment that coincides with their age-related neuroanatomical abnormalities and, consequently, may be a useful model of AD. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Impaired Sustained Attention and Error-Induced Stereotypy in the Aged Ts65Dn Mouse: A Mouse Model of Down Syndrome and Alzheimer's Disease.

This study compared performance of 15- to 17-month-old Ts65Dn mice to that of littermate controls on an automated sustained attention task in which the location, onset time, and duration of brief visual cues varied unpredictably. Ts65Dn mice committed more omission errors than controls, particularly on trials with the briefest cues. Videotape data revealed that the trisomic mice attended less than controls during the period before cue presentation and engaged in stereotypic jumping and grooming immediately after making an error. These findings reveal that Ts65Dn mice are impaired in sustaining attention and exhibit heightened reactivity to committing an error, and support the validity of this mouse model for studying Down syndrome and Alzheimer's disease. The attention task, coupled with the videotape analyses of task performance, provides a useful paradigm for studying attention and reactivity to errors in mice. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Characterization of carbohydrates using a combination of derivatization, high-performance liquid chromatography and mass spectrometry

Mice trisomic for the distal portion of MMU 16 (Ts65Dn) were examined for differences in jejunal function and plasma amino acids as compared to diploid controls. Eighteen control and 19 Ts65Dn mice were compared for whole-body and intestinal O2 consumption, jejunal glucose uptake, and plasma amino acid concentrations. Ts65Dn mice consumed less (P < 0.02) O2 per gram of fasted body weight. No significant differences were found in either active or passive glucose uptake. Oxygen consumption by jejunal tissue was not different between Ts65Dn and control mice. The apparent energetic efficiency of jejunal active glucose uptake (eta mol ATP expended/eta mol glucose uptake) was significantly higher (115.6 vs. 80.8; P < 0.05) in Ts65Dn mice. Histomorphometric analysis of jejunal mucosa showed that Ts65Dn mice had shorter villus height (P < 0.04) and decreased planar villus circumference (P = 0.05). No differences were found in total jejunal protein (microgram/g) or DNA (mg/g) concentrations. Significantly higher concentrations of plasma tyrosine, phenylalanine, valine, leucine, isoleucine, and citrulline (P < 0.05) were found in Ts65Dn mice. Lower plasma concentrations of hydroxyproline were detected in Ts65Dn mice (P < 0.05). These data suggest that Ts65Dn mice have anomalies in digestive function and amino acid metabolism as compared to normal, diploid controls.     

Cholinergic, serotonergic and catecholaminergic neurons are not affected in Ts65Dn mice

Ts65DN mice were developed as a model of Down syndrome (DS); they are trisomic for the distal segment of chromosome 16 (MMU16), which contains genes syntenic with some of the genes located on the critical region of human chromosome 21 (HSA21). Since behavioral and neurochemical disturbances have been observed in this animal model, it seemed interesting to perform an immunohistochemical characterization of the main cholinergic, catecholaminergic and serotonergic nuclei. However, when the brains of Ts65Dn mice were compared with those of control littermates, no differences were found either in the morphology of the neurons of the three systems or in the number of immunoreactive cells. The results indicate that these systems are not affected by the triplication of some of the genes present on chromosome 16.     

Nerve growth factor: structure, function and therapeutic implications for Alzheimer's disease

Over the past decade, neurotrophic factors have generated much excitement for their potential as therapy for neurological disorders. In this regard, nerve growth factor (NGF), the founding member of the neurotrophin family, has generated great interest as a potential target for the treatment of Alzheimer's disease (AD). This interest is based on the observation that cholinergic basal forebrain (CBF) neurons which provide the major source of cholinergic innervation to the cerebral cortex and hippocampus undergo selective and severe degeneration in advanced AD and that these neurons are dependent upon NGF and its receptors for their survival. In fact, NGF transduces its effects by binding two classes of cell surface receptors, TrkA and p75(NTR), both of which are produced by CBF neurons. This review focuses on NGF/receptor binding, signal transduction, regulation of specific cellular endpoints, and the potential use of NGF in AD. Alterations in NGF ligand and receptor expression at different stages of AD are summarized. Recent results suggest that cognitive deficits in early AD and mild cognitive impairment (MCI) are not associated with a cholinergic deficit. Thus, the earliest cognitive deficits in AD may involve brain changes other than simply cholinergic system dysfunction. Recent findings indicate an early defect in NGF receptor expression in CBF neurons; therefore treatments aimed at facilitating NGF actions may prove highly beneficial in counteracting the cholinergic dysfunction found in end-stage AD and attenuating the rate of degeneration of these cholinergic neurons.     

Treatment of functional decline in adults with Down syndrome using selective serotonin-reuptake inhibitor drugs

Alzheimer's disease (AD) is a common cause of functional decline in Down syndrome (DS) adults. Acquired cognitive deficits may be difficult to evaluate in the context of baseline impairments. Behavioral symptoms are also common and may represent the effects of depression, AD, or both. Therefore, the objective of this study was to report a clinical case series of selected adults with DS and behavioral change who responded to treatment with selective serotonin-reuptake inhibitor (SSRI) medication. Six patients, aged 23 to 63 years, 5 women and 1 man, with the clinical diagnosis of DS presented for diagnosis and treatment of functional decline in adult life. Noncognitive symptoms were prominent and included aggression, social withdrawal, and compulsive behaviors. Memory dysfunction was reported in varying degrees. Treatment with SSRI antidepressants was instituted for depressive, apathetic, and compulsive behaviors. Treated patients showed improvement in behaviors as reported by caregivers, and on objective measures, such as workplace productivity. Noncognitive symptoms are a cardinal feature of functional decline in adults with DS and may represent either depression or AD. In some patients, the symptoms respond well to SSRI agents with concomitant improvement in daily function. Treatment trials with SSRIs may, therefore, be warranted in such cases.     

Offspring of normal and diabetic rats fed saturated fat in pregnancy demonstrate vascular dysfunction

BACKGROUND: Disturbances of the in utero environment may "program" for disease in later life. In this study, we determined whether dietary fat supplementation and/or diabetes in pregnancy can adversely affect vascular function in the offspring. METHODS AND RESULTS: Female Sprague-Dawley rats were fed a breeding diet or a diet high in saturated fat (30% wt/wt) for 10 days before mating, throughout pregnancy, and postpartum. Endothelium-dependent relaxation to acetylcholine was blunted in isolated femoral arteries of 15-day-old weanling pups from dams fed the 30%-fat diet. Endothelial dysfunction and enhanced constrictor responses to norepinephrine were also observed in an additional study of 60-day-old offspring of dams fed 20% saturated fat. Rats with streptozotocin-induced diabetes were also fed saturated fat during pregnancy. Femoral arteries from their 15-day-old offspring showed impairment of endothelium-dependent dilation and enhanced constrictor responses to norepinephrine and the thromboxane mimetic U46619 compared with young offspring of high-fat-fed normal dams. The 30%-fat diet was also deleterious to vascular function in the maternal diabetic animals when assessed in mesenteric arteries 16 days postpartum. CONCLUSIONS: A high-fat diet in pregnancy led to vascular dysfunction in rat weanlings and young adult offspring. Vascular function further deteriorated in weanlings if the maternal rat was diabetic.     

Reduced cognitive ability in alcohol dependence: Examining the role of covarying externalizing psychopathology.

Reduced executive cognitive ability is associated with alcohol dependence (AD) and other comorbid externalizing disorders. Working memory capacity, short-term memory, conditional associative learning, and intelligence were assessed in a sample (N = 477) with variation in lifetime histories of externalizing problems (conduct disorder, adult antisocial behavior, substance problems); this included a subsample (n = 285) with a Diagnostic and Statistical Manual of Mental Disorders (4th ed.; American Psychiatric Association, 1994) diagnosis of AD. Individuals with both AD and a history of childhood conduct disorder (CCD) scored lower on cognitive measures compared to those with AD and no history of CCD. Structural equation models showed that reduced ability in all cognitive domains was predicted by a latent externalizing factor reflecting covariation among lifetime problems with alcohol, drugs, childhood conduct, and adult antisocial behavior and was not uniquely related to any one problem. Further, for those with AD, the externalizing factor was associated with reductions in all the domains of cognitive ability. The results suggest that the reduced executive cognitive ability observed in AD individuals is partly accounted for by a general latent externalizing factor rather than alcohol-related problems per se. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Working memory and control of attention in persons with Alzheimer's disease and mild cognitive impairment.

The goal of the present study was to assess 3 attentional control processes--divided attention, manipulation capacities, and inhibition--in persons with mild cognitive impairment (MCI) and with mild Alzheimer's disease (AD). Manipulation capacities were tested by comparing immediate serial recall with alphabetical-order recall of words. Divided attention was tested with the Brown-Peterson procedure, in which participants divide their attention between simple addition tasks and consonant trigrams over delays. Inhibition was tested with the Hayling procedure, in which participants complete sentences with words irrelevant to their context. Persons with AD showed severe impairment on the 3 attentional control components. Persons with MCI exhibited impaired performance on the Brown-Peterson procedure but normal performance on the other 2 tasks. With AD and MCI participants, there was a negative correlation between general cognitive deficits and impairment on attentional control tasks, indicating that attentional control deficits increase in the MCI/AD continuum. When separating MCI with and without significant subsequent decline, those with subsequent decline showed impaired performance on both the Brown-Peterson procedure and manipulation task. These data suggest that control of attention tasks can track AD at a preclinical stage and that impairment increases gradually during the preclinical phase of AD. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Divided attention in youth-onset psychosis and attention deficit/hyperactivity disorder.

The authors used pupillary dilations to test whether divided attention deficits in youth-onset psychosis and attention deficit/hyperactivity disorder (ADHD) were because of limitations in recruitment of cognitive resources or abnormalities in attention allocation. Eight- to 19-year-olds with youth-onset psychosis or ADHD were administered a divided attention test consisting of an auditory digit span (DS) task and a simple visual response time (RT) task. In 4 conditions, participants performed neither (no task), 1 (DS or RT only), or both tasks (dual). Dependent variables were DS accuracy, RT, and pupillary dilation to digits as an estimate of recruitment of cognitive resources. The authors found no evidence for an abnormal attention strategy in either disorder. Instead, results were consistent with the hypothesis that both clinical groups have limitations in resource recruitment. These limitations were more severe in psychosis than in ADHD. Findings indicate that both clinical groups had difficulties in regulating physiological arousal on a moment-to-moment basis in accordance with task demands. Findings also demonstrate the importance of taking into account difficulties that constrain performance on simple tasks before interpreting impairments on complex tasks. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Selective Attention Impairments in Alzheimer's Disease: Evidence for Dissociable Components.

Tasks emphasizing 3 different aspects of selective attention-inhibition, visuospatial selective attention, and decision making-were administered to subjects with mild Alzheimer's disease (AD) and to healthy elderly control (HEC) subjects to determine which components of selective attention were impaired in AD subjects and whether selective attention could be dissociated into different components. The tasks were administered with easy versus hard levels of difficulty to assess proportional slowing as the key variable across tasks. The results indicated that the inhibitory and visual search tasks showed greater proportional slowing in subjects with AD than in HEC subjects, and that the task involving inhibition was significantly more affected in subjects with AD. Furthermore, there were no significant intertask correlations, and the results cannot be explained simply in terms of generalized cognitive slowing. These results provide evidence that inhibition is the most strikingly affected aspect of selective attention that is observed to be impaired in early stages of AD. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Losses in gross brain volume and cerebral blood flow account for age-related differences in speed but not in fluid intelligence.

Age-related gross head size; adjusted age-related change in brain volume and carotid and basilar blood flow; as well as scores on 3 tests of fluid intelligence (gf), 2 tests of information-processing speed, 2 memory tests, and 3 tests of executive function were obtained from 69 volunteers aged from 62 to 84 years. Brain volume negatively predicted scores on all 10 cognitive tasks, accounting for up to 78% of age-related variance in scores on the speed tasks and on 1 executive task. Cerebral blood flow (CBF) negatively predicted scores on 8 cognitive tasks, accounting for up to 36% of age-related variance in speed scores. However, neither brain volume nor CBF accounted for significant age-related variance between individuals on any of 3 gf tests. We conclude that speed, but not gf, is an exceptionally sensitive behavioral index of the progress of gross brain changes that affect cognition in old age and that speed and gf do not reflect integrity of the same functional systems. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Attention and brain function in Alzheimer's disease: A review.

Cognitive and neuroscience studies point to a selective impairment of attentional functions in Alzheimer's disease (AD). Prominent deficits occur in the shifting and division of attention, whereas phasic arousal and focused attention to stimulus features are only minimally affected in the early stages of AD. Macroscopic processing interpretations of these results—global cognitive impairment, generalized cognitive slowing, processing resource deficit, and failure of central executive control ("dysexecutive" syndrome)—are discussed. An alternative approach is based on the identification of component attentional operations and their mediation by corticocortical and subcortical networks. This analysis suggests that attention represents the first cognitive indicator of neocortical dysfunction in early AD. Disconnection between frontal and posterior parietal areas may mediate the selective disruption of attentional functions in AD. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Prenatal cocaine exposure impairs selective attention: Evidence from serial reversal and extradimensional shift tasks.

This study assessed the effects of prenatal cocaine exposure on cognitive functioning, using an intravenous (IV) rodent model that closely mimics the pharmacokinetics seen in humans after smoking or IV injection and that avoids maternal stress and undernutrition. Cocaine-exposed males were significantly impaired on a 3-choice, but not 2-choice, olfactory serial reversal learning task. Both male and female cocaine-exposed rats were significantly impaired on extradimensional shift tasks that required shifting from olfactory to spatial cues; however, they showed no impairment when required to shift from spatial to olfactory cues. In-depth analyses of discrete learning phases implicated deficient selective attention as the basis of impairment in both tasks. These data provide clear evidence that prenatal cocaine exposure produces long-lasting cognitive dysfunction, but they also underscore the specificity of the impairment. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Videogames and young people with developmental disorders.

Young people with developmental disorders experience difficulties with many cognitive and perceptual tasks, and often suffer social impairments. Yet, like typical youth, many appear to enjoy playing videogames. This review considers the appeal of videogames to individuals with autism spectrum disorders, attention deficit hyperactivity disorder, and specific language impairment. It examines how they respond to the various challenges that play entails with particular reference to sensory, cognitive, and social dimensions. It is argued that research into how these young people engage voluntarily with this dynamic and challenging medium offers great potential to extend our empirical and theoretical understanding of the disorders. Many gaps in our current knowledge are identified and several additional themes for possible future research are proposed. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Attentional control in normal aging and Alzheimer's disease.

Objective: Attentional control, the ability to maintain goal-directedness in the face of distraction, has been shown to decline in normal aging (NA) and Alzheimer's disease (AD), yet the nature and extent of deficits is under debate. This study investigated attentional control in NA and AD compared to healthy young adults in several tasks such as setting, suppressing, switching, and preparing attention. Method: Fifty-two participants (17 AD, 17 NA, and 18 young participants) underwent the Tower of London, the Zoo map test, the Stroop test, letter verbal fluency, a computerized version of the Rule shift cards tests, the Trail making test, the Plus-minus test, and a reaction time task with variable preparatory intervals. Results: Analyses of variance showed that NA as compared to young participants were impaired in the Tower of London, the Stroop test, and the Rule shift cards tests. AD as compared to NA participants were impaired in all tests except the Stroop test. Principal component analysis in young adults confirmed the modularity of attentional tasks, which was reduced in NA and AD participants. Principal component analysis in all populations showed a decline of attentional control with NA and AD regardless of the tasks, with an increase in between-participants variability only between young and NA participants. Conclusions: Attentional control dysfunction is different in NA and AD: NA affects suppressing attention, switching attention for unpredictable but not predictable events, and preparing attention for unpredictable events, whereas AD affects setting, suppressing, switching, and preparing attention with less specificity. (PsycINFO Database Record (c) 2011 APA, all rights reserved)     

Training to criterion in eyeblink classical conditioning in Alzheimer's disease, Down's syndrome with Alzheimer's disease, and healthy elderly.

The cholinergic antagonist scopolamine delays acquisition of eyeblink classical conditioning (EBCC) in rabbits and humans, but scopolamine-treated organisms eventually acquire conditioned responses (CRs). Patients with probable Alzheimer's disease (AD) and older adults with Down's syndrome (DS/AD) have disrupted cholinergic systems and perform EBCC very poorly. It was hypothesized that patients with probable AD and DS/AD, like scopolamine-injected organisms, would acquire CRs if given sufficient training. Twelve probable AD patients, 12 DS/AD patients, and 6 healthy elderly control individuals participated in 5 daily 90-trial sessions of EBCC. Fifty-eight percent of the probable AD, 92% of the DS-AD, and 100% of the control participants achieved learning criterion. Probable AD, DS/AD, and control participants had statistically significant increases in the percentage of CRs produced over 5 EBCC sessions. The neural substrate for EBCC was not eliminated in probable AD or DS/AD patients, although the learning mechanism was disrupted. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

The influence of apolipoprotein e genotype on visuospatial attention dissipates after age 80.

Although it is established that apolipoprotein E (APOE) e4 allele increases the risk of Alzheimer's disease (AD), epidemiological studies indicate that genetic risk decreases late in life. This raises the question of whether the effects of APOE on cognition that are seen in midlife arise from a cognitive phenotype of APOE or from the presence of early AD in some APOE-e4 carriers. The authors addressed this question by comparing the cognitive consequences of variation in the APOE gene between individuals over the age of 80 (old-old) and middle-aged and young-old individuals. A spatially cued discrimination paradigm--previously shown to be sensitive to AD and to APOE genotype--required a speeded categorization of a target letter following cues that were valid, invalid, or neutral in predicting target location. Results revealed greater costs of invalid cues in the APOE-e4 carriers of middle-aged and young-old, but not old-old, groups. The dissipation of the APOE effect in old-old individuals at lower risk of AD suggests that visuospatial attention impairments seen as early as midlife in APOE-e4 carriers may be a preclinical marker of AD. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Choline supplementation following third-trimester-equivalent alcohol exposure attenuates behavioral alterations in rats.

Despite the known adverse consequences of prenatal alcohol exposure, some pregnant women continue to drink alcohol, making it imperative to identify treatments for children with fetal alcohol spectrum disorders. The authors recently reported that perinatal choline supplementation can reduce some fetal alcohol effects (J. D. Thomas, M. Garrison, & T. M. O'Neill, 2004), and the present study examined whether choline supplementation is effective when administered after third-trimester-equivalent ethanol treatment. Rat pups were exposed to 6.0 g/kg/day ethanol during the neonatal brain growth spurt (Postnatal Days [PD] 4-9) and treated with choline chloride (0, 10, 50, or 100 mg/kg) from PD 10-30. Behavioral testing occurred after choline treatment had ceased. Female subjects exposed to ethanol were overactive and exhibited spatial learning deficits, effects that were attenuated with all doses of choline supplementation. These data indicate that choline supplementation can alter brain development following a developmental insult. Moreover, the data suggest that early dietary interventions may reduce the severity of some fetal alcohol effects, even when administered after birth. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Personality and risk of cancer in men with coronary heart disease

BACKGROUND: Virtually all individuals with Down syndrome (DS) have neuropathologic changes characteristic of Alzheimer's disease (AD) beginning at 40 years of age. Few studies have examined factors that influence age at onset of AD in DS. We investigated whether sex differences in age at onset and risk of AD among adults with DS are similar to those observed in the general population and whether the effect of sex on risk of AD is modified by apolipoprotein E (APOE) genotype. METHODS: A community-based sample of 111 adults with cytogenetically confirmed DS (34 to 71 years of age) was ascertained through the New York State Developmental Disabilities system. A semistructured interview with caregivers and review of medical records was used to ascertain the presence or absence of AD. APOE genotyping was carried out without knowledge of the subject's medical history or clinical diagnosis. RESULTS AND CONCLUSIONS: Both male gender and the presence of an APOE epsilon4 allele were associated with an earlier onset of AD. Compared with women, men with DS were three times as likely to develop AD. Compared with those with the APOE 3/3 genotype, adults with DS with the 3/4 or 4/4 genotypes were four times as likely to develop AD. No individual with an APOE epsilon2 allele developed AD. No evidence of interaction of sex and APOE genotype was found in risk of AD. The higher risk of AD in men may be related to differences in hormonal function between men and women with DS that are distinct from those in the general population.