Effects of chronic prenatal ethanol exposure on cGMP content and glutamate release in the hippocampus of the neonatal guinea pig.

The glutamate-N-methyl-D-aspartate (NMDA) receptor-nitric oxide synthase (NOS)-cGMP signal transduction system plays key neurotrophic and intercellular communication roles in the hippocampus. In the guinea pig, chronic prenatal ethanol exposure (CPEE), via maternal ethanol administration, suppresses the hippocampal glutamate-NMDA receptor-NOS pathway in the near-term fetus and decreases stimulated glutamate release in the hippocampus of young postnatal offspring, with no effect on NMDA receptor number or NOS activity. At present, the effect of CPEE on cGMP, a key second messenger of the glutamate signal transduction system, in the hippocampus is not known. The objective of this study was to test the hypothesis that CPEE suppresses the hippocampal glutamate signal transduction system in the neonatal guinea pig at the levels of cGMP content and glutamate release. Timed pregnant guinea pigs received chronic oral administration of 4 g ethanol/kg maternal body weight/day, isocaloric-sucrose/pair-feeding, or water treatment throughout gestation. CPEE decreased brain and hippocampal weights at postnatal day (PD) 1 and PD 5 (P<.05). CPEE did not affect basal, NMDA (1, 10, or 100 microM)-stimulated, or K(+) (15 or 30 mM)-stimulated cGMP content in transverse hippocampal slices at PD 1 or 5. At 60 mM K(+), however, CPEE decreased stimulated hippocampal cGMP content at PD 1 (P<.05) and increased stimulated cGMP content at PD 5 (P<.05). In transverse hippocampal slices, CPEE did not affect basal or K(+) (40 or 45 mM)-stimulated glutamate release at PD 1 or 5, or NMDA (50 microM)-stimulated glutamate release at PD 1, but did decrease NMDA (50 microM)-stimulated glutamate release at PD 5 (P<.05). The data demonstrate that the effects of CPEE on stimulated cGMP content and glutamate release in the hippocampus of the neonatal guinea pig are stimulating agent- and age-dependent.

In vitro ethanol exposure decreases potassium-stimulated, but not veratridine-stimulated, glutamate release in the guinea pig hippocampus.

In this study we determined the effect of in vitro ethanol exposure on stimulated glutamate release in transverse hippocampal slices (400-microm thickness) of the young postnatal guinea pig (PD 12) by using two chemical stimuli with different mechanisms of action. Ethanol (50 mM) decreased K+ (45 mM)-, but not veratridine (10 microM)-, stimulated glutamate release. The study findings demonstrate that in vitro ethanol exposure produces differential inhibition of stimulated glutamate release in the hippocampus, dependent on the stimulating agent.

Generation of a high-density rat EST map.

We have developed a high-density EST map of the rat, consisting of >11,000 ESTs. These ESTs were placed on a radiation hybrid framework map of genetic markers spanning all 20 rat autosomes, plus the X chromosome. The framework maps have a total size of approximately 12,400 cR, giving an average correspondence of 240 kb/cR. The frameworks are all LOD 3 chromosomal maps consisting of 775 radiation-hybrid-mapped genetic markers and ESTs. To date, we have generated radiation-hybrid-mapping data for >14,000 novel ESTs identified by our Rat Gene Discovery and Mapping Project (http://ratEST.uiowa.edu), from which we have placed >11,000 on our framework maps. To minimize mapping errors, ESTs were mapped in duplicate and consensus RH vectors produced for use in the placement procedure. This EST map was then used to construct high-density comparative maps between rat and human and rat and mouse. These maps will be a useful resource for positional cloning of genes for rat models of human diseases and in the creation and verification of a tiling set of map order for the upcoming rat-genome sequencing.

Effects of chronic prenatal ethanol exposure on hippocampal glutamate release in the postnatal guinea pig.

This study was designed to test the hypothesis that chronic prenatal ethanol exposure decreases basal and stimulated L-glutamate release in the hippocampus of young, postnatal guinea pigs. Timed, pregnant guinea pigs were randomly assigned to one of the following three chronic treatment groups: 4 g ethanol/kg maternal body weight/day, isocaloric-sucrose and pair-feeding to the ethanol group, and water. Each oral treatment was given daily throughout gestation. Spontaneous locomotor activity was increased on postnatal day (PD) 10, and brain and hippocampal weights were decreased on PD 12 in the offspring of the ethanol group compared with the isocaloric-sucrose/pair-fed and water groups. On PD 12, the 45 mM K(+)- and 10 microM veratridine-stimulated release of glutamate in transverse hippocampal slices was decreased in the ethanol group compared with the two control groups. This alteration in glutamate release produced by chronic prenatal ethanol exposure may decrease the efficiency of excitatory synaptic transmission in the hippocampus during postnatal life.

Effects of chronic prenatal ethanol exposure on locomotor activity, and hippocampal weight, neurons, and nitric oxide synthase activity of the young postnatal guinea pig.

Decreased nitric oxide synthase (NOS)-catalyzed formation of NO from L-arginine may be involved in ethanol teratogenesis involving the hippocampus. This hypothesis was tested by determining the effects of chronic prenatal ethanol exposure on locomotor activity and on hippocampal weight, number of CA1 and CA3 pyramidal cells and dentate gyrus granule cells, and NOS activity of the postnatal guinea pig. Timed, pregnant guinea pigs received one of the following chronic oral regimens throughout gestation: 4 g ethanol/kg maternal body weight/day, isocaloric-sucrose/pair-feeding, or water. At postnatal day (PD) 10, spontaneous locomotor activity was measured. At PD 12, histological analysis was performed on the hippocampal formation, in which hippocampal CA1 and CA3 pyramidal cells and dentate gyrus granule cells were counted; body, brain, and hippocampal weights were measured; and hippocampal NOS enzymatic activity was determined using a radiometric assay. Chronic prenatal ethanol exposure produced hyperactivity, decreased the brain and hippocampal weights with no change in body weight, decreased the number of hippocampal CA1 pyramidal cells by 25-30%, and had no effect on hippocampal NOS activity compared with the two control groups. These data, together with our previous findings in the fetal guinea pig, demonstrate that chronic prenatal ethanol exposure decreases hippocampal NOS activity in near-term fetal life that temporally precedes the selective loss of hippocampal CA1 pyramidal cells in postnatal life.

The deterioration of semantic memory in Alzheimer's disease.

Semantic memory impairment is a common feature of dementia of the Alzheimer type (DAT). Recent research has shown that patients with DAT are more impaired (relative to non-demented controls) in generating exemplars from a particular semantic category (e.g., animals) than words beginning with a particular letter, exhibit an altered temporal dynamic during the production of category exemplars, are impaired on confrontation naming tasks and make predominantly superordinate or semantically related errors, consistently misidentify the same objects across a variety of semantic tasks, and have alterations in multi-dimensional scaling models of their semantic network that are indicative of a loss of concepts and associations. These results are consistent with the view that Alzheimer's disease results in a breakdown in the organization and structure of semantic knowledge as neurodegeneration spreads to the association cortices that presumably store semantic representations.

Is there a "subcortical" profile of attentional dysfunction? A comparison of patients with Huntington's and Parkinson's diseases on a global-local focused attention task.

This study investigated focused attention in two subcortical degenerative disorders by examining the performance of patients with Huntington's disease (HD) and Parkinson's disease (PD) on a task utilizing global-local stimuli. Participants were presented with global-local figures and were instructed to focus their attention on either the global or local level. Stimuli were either "consistent", with the same form at the global and local levels, or "inconsistent", with different forms at the global and local levels. It was found that response times (RTs) of patients with PD were comparable to those of similarly-aged controls regardless of stimulus consistency. In contrast, patients with HD demonstrated disproportionately longer RTs to inconsistent stimuli relative to their age-matched control group. Difference scores between RTs for inconsistent versus consistent stimuli were not correlated with overall level of dementia or disease severity for either the HD or PD group. These results provide further evidence for the heterogeneity of attentional dysfunction among subcortical degenerative illnesses.

A population-based analysis of qualitative features of the neuropsychological test performance of individuals with dementia of the Alzheimer type: implications for individuals with questionable dementia.

Qualitative features of the neuropsychological test performance of individuals with dementia of the Alzheimer type (DAT) were examined in a population-based study. Qualitative error scores were derived from measures of verbal and figural memory, verbal fluency and confrontation naming for 38 patients with clinically diagnosed DAT, 236 normal elderly (NE) individuals, and 72 others who were questionably demented and at risk (AR) for DAT. Persons with DAT made a greater proportion of intrusion and perseverative errors, and more lexical and semantic naming errors, than the NE participants. These measures provided fair specificity but poor sensitivity for the diagnosis of DAT, and a logistic model based on these measures correctly classified 98% of the NE participants, but only 29% of the DAT participants. The AR participants demonstrated a pattern of errors that was highly similar to that of the DAT patients, and when their scores were subjected to the logistic model, 90% were classified as NE and 10% as DAT. These results indicate that specific error types that have been associated with DAT in self-referred or clinic-based samples also occur in the general population to a greater degree in individuals with DAT or questionable dementia than in NE individuals. Furthermore, these qualitative features may have some diagnostic usefulness in that their presence provides reasonable specificity for DAT or questionable dementia.

Memory for verbal information in individuals with HIV-associated dementia complex. HNRC Group.

Patterns of memory performance were examined for 9 participants with HIV-associated dementia (HAD), 15 HIV-seropositive participants without dementia, and 15 HIV-seronegative controls. Episodic and semantic memory were assessed using the California Verbal Learning Test, the Boston Naming Test, and Verbal Fluency tests. The HAD group showed deficits in episodic memory, with relative sparing of semantic memory. In addition, results suggest a retrieval deficit in HAD rather than a deficit in retention of information. This pattern is consistent with the presence of a subcortical dementing process and supports findings from previous neuropathological, neuroimaging, and neuropsychological studies suggesting that subcortical brain dysfunction is frequently associated with HIV disease (e.g., Navia, Jordan, & Price, 1986).

The deterioration of semantic networks in patients with Alzheimer's disease: a cross-sectional study.

Previous studies showed that the semantic networks of Alzheimer's disease (AD) patients are disrupted in the early stages of the disease. The present study examined the semantic networks of 33 AD patients in different stages of disease severity to compare the quantitative and qualitative changes in their networks as the disease progresses. The properties of the semantic networks (e.g. the dimensionality and strength of the connections) were examined with multidimensional scaling and Pathfinder analyses. The results showed that, as AD patients became more demented, they focused less on abstract attributes in categorizing concepts, and have an alteration in the relative strength of associations between concepts. These findings indicate that the structure of semantic knowledge deteriorates in a systematic manner throughout the course of AD.

Longitudinal examination of American National Adult Reading Test (AMNART) performance in dementia of the Alzheimer type (DAT): validation and correction based on degree of cognitive decline.

The American National Adult Reading Test (AMNART) was constructed to provide a valid and stable estimate of premorbid verbal IQ (VIQ) in dementing individuals. However, recent studies have brought into question its validity in patients with dementia of the Alzheimer type (DAT). The present study was designed to longitudinally assess the validity of the AMNART in 40 DAT patients and 40 demographically matched normal control (NC) subjects. The results showed that VIQ estimates for patients with DAT were significantly lower than those of NC subjects and declined significantly over time with increasing dementia severity as measured by the Mini-Mental State Examination (MMSE) and the Dementia Rating Scale (DRS). An MMSE-based correction factor was derived for the DAT group which allows for the effective estimation of premorbid VIQ in these patients.

Electrophysiological insights into the nature of the semantic deficit in Alzheimer's disease.

Event-related brain potential (ERP) and reaction-time measures were used to determine if the specificity of a category prime differentially affects the amount of semantic priming seen in patients with dementia of the Alzheimer type (DAT) compared with normal elderly and young controls. Subjects were primed with an auditory category name followed by the visually presented name of an imageable object and indicated whether the object was a category member; the category was either superordinate to, at, or subordinate to the basic level. All groups showed similar priming effects in response to the category manipulation, as evidenced in both reaction time and the amplitude of the N400 component of the ERP. Overall, DAT subjects showed the smallest ERP priming effects and young controls the largest. The present study did not provide evidence for a strong version of a strictly "bottom-up" breakdown of the semantic networks in subjects with DAT, suggesting a role for factors such as task difficulty and memory search strategies in online categorization tasks of this type.

Neuropsychological deficits associated with diffuse Lewy body disease.

Diffuse Lewy body disease (DLBD), in its pure form, is a neuropathologic condition in demented patients that is characterized by subcortical and diffusely distributed neocortical Lewy bodies with little or no concomitant Alzheimer's disease (AD) pathology. Clinically, DLBD patients initially present with dementia of insidious onset and subsequently develop mild extrapyramidal motor dysfunction. The present study retrospectively examined the neuropsychological test performance of five patients with DLBD and compared their performance to that of equally demented patients with neuropathologically confirmed "pure" AD. The results showed that the DLBD patients were globally demented with deficits in memory, attention, language, psychomotor performance, and "executive" functions, and a strikingly severe deficit in visuospatial and visuoconstructive abilities. The visuoconstructive and psychomotor impairments of the DLBD patients were significantly worse than those of the AD patients, whereas the memory performance of the AD patients was worse than that of the DLBD patients. These results indicate that DLBD without concomitant AD pathology can produce a global dementia with aspects of both cortical and subcortical dysfunction and suggests that Lewy body pathology contributes importantly to the clinical manifestation of the Lewy body variant of AD.

Longitudinal analysis of clock drawing in Alzheimer's disease patients.

Longitudinal changes in the role of conceptual, spatial, and graphic processes in the drawing deficits of patients with Alzheimer's disease (AD) were assessed over a 2-year period. Both the drawing-to-command and copy conditions of the Clock Drawing Test were administered to 33 AD patients as part of three consecutive annual examinations. The drawings from each administration were evaluated for overall accuracy and the types of errors manifested. Although the patients showed a gradual decline in overall accuracy on both command and copy conditions over the three test sessions, they performed more poorly and evidenced a steeper decline on the command condition. Conceptual errors in the command condition were noted in the early stages of AD and increased over the three administrations. Stimulus-bound errors were usually associated with conceptual errors in the same or in a contiguous year. When the patients' performances on the first test session were correlated with their yearly scores on Mattis' Dementia Rating Scale, the presence of conceptual errors was associated with a steep decline on this measure of mental status. These results suggest that drawing deficiencies in AD often reflect impairments in conceptualization and semantic knowledge and that such losses may prove useful in predicting the disease's rate of progression.

Neuropsychological assessment of severely demeted elderly: the severe cognitive impairment profile.

BACKGROUND: Although the assessment of cognitive functioning in the late stages of Alzheimer's Disease (AD) is important for identifying abilities that may improve communication and interactions with severely impaired patients in clinical and institutional settings and for assessing the efficacy of pharmacologic agents and behavioral interventions for the treatment of AD, few adequate instruments exist for measuring the cognitive capacities of these severely demented individuals. OBJECTIVES: To evaluate the reliability and validity of the Severe Cognitive Impairment Profile (SCIP), a measure of neuropsychological functioning in severely demented patients, and compare it with other available instruments. DESIGN AND METHODS: We administered the Mattis Dementia Rating Scale (DRS), Mini-Mental State Examination (MMSE), SCIP, and Severe Impairment Battery (SIB) to 41 severely demented patients with AD participating in an AD research center. We used (1) Spearman rank correlation coefficients to assess interrater and test-retest reliability and construct validity of the SCIP; (2) one-way analysis of variance with post hoc comparisons to examine performance on the SCIP and the SIB at different levels of dementia severity; and (3) descriptive statistics to establish the sensitivity of the SCIP to cognitive functioning in a subgroup of very severely demented patients. RESULTS: Interrater and test-retest reliability correlation coefficients were highly significant for total SCIP score (r=0.99 and r=0.96, respectively) as well as for all SCIP subscales. High correlations were also found between SCIP scores and two widely used tests of global cognitive functioning, the DRS (r=0.91) and the MMSE (r=0.84), suggesting good construct validity. The SCIP was able to significantly differentiate between four groups of severely impaired patients divided by level of dementia severity, while the SIB was unable to differentiate between the less severely demented groups. A subgroup of 16 very severely demented patients (DRS score, <50 points) obtained an average of 45% of total possible points on the SCIP, compared with an average of 1% and 21% of total possible points on the MMSE and DRS, respectively. After approximately 1 year of decline, 12 severely demented patients with AD were able to correctly answer an average of more than 58% of the items on the SCIP, compared with only 30% on the DRS and 20% on the MMSE. CONCLUSIONS: The SCIP is a reliable, valid measure of neuropsychological functioning in severely demented patients with AD with the ability to avoid both floor and ceiling effects and to evaluate a wider range of cognitive abilities than other tests used with severely impaired individuals.

Random number generation in dementia of the Alzheimer type: a test of frontal executive functions.

The quality of attempts at generating a random sequence of the numbers 1-6 was studied in 30 patients with dementia of the Alzheimer type (DAT) and 30 elderly normal control (NC) subjects. Three main findings emerged: (1) DAT patients' subjective random sequences were more streotyped (contained fewer digit combinations) than those of NC subjects. (2) This difference in response stereotypy was due to patients' enhanced tendency to arrange consecutive numbers in an ascending series ('counting bias'). (3) In the patient group, degree of sequential nonrandomness was positively correlated with overall severity of dementia and with the extent to which performance on neuropsychological tests specifically assessing executive functions (fluency, naming, error monitoring) was impaired. These results illustrate a loss of behavioral complexity in the course of dementia and are interpreted as reflecting a frontal dysexecutive syndrome in DAT.

Screening for dementia of the alzheimer type in the community: the utility of the Clock Drawing Test.

This study reports the sensitivity and specificity of the Clock Drawing Test (CDT) for detecting dementia of the Alzheimer type in a community-dwelling sample of elderly subjects. Forty-two patients with clinically diagnosed Alzheimer's disease and 237 cognitively intact subjects were administered the CDT as part of an epidemiological study of aging and dementia. Three individual measures of clock drawing performance (quantitative score, qualitative score, and combined quantitative and qualitative score) were determined for each participant. When qualitative elements such as errors and strategies were incorporated into the CDT score, the sensitivity was 84% and the specificity was 72%. The findings suggest that a CDT score which evaluates qualitative and quantitative features provides reasonably good discrimination between normal elderly individuals and DAT patients. However, the CDT appears to have limited utility as a single screening instrument in the community. Instruments such as the Dementia Rating Scale (Mattis, 1976) provide better discrimination of DAT, indicating that functions such as memory and verbal fluency need to be assessed during screening.

Episodic memory changes are associated with the APOE-epsilon 4 allele in nondemented older adults.

OBJECTIVE: To compare the memory performances of nondemented older adults with and without the epsilon 4 allele of the apolipoprotein E (APOE-epsilon 4). BACKGROUND: Few studies have examined the cognitive status of subjects at high risk for the development of dementia of the Alzheimer type (DAT). A newly reported risk factor for DAT allows for an examination of the cognitive performances of nondemented subjects who are at risk by virtue of being either heterozygous or homozygous for the APOE-epsilon 4 allele. METHODS: The California Verbal Learning Test (CVLT) was administered to 52 nondemented older adults. Subjects were divided into two groups on the basis of the presence (n = 17) or absence (n = 35) of one or two APOE-epsilon 4 alleles. RESULTS: APOE- epsilon 4 and non-epsilon 4 groups did not significantly differ in demographic, mental status, and functional characteristics. APOE-epsilon 4 subjects demonstrated significantly poorer mean performances than non-epsilon 4 subjects on nine CVLT variables. Seven group differences remained significant, and three approached significance (0.05 < p < 0.10), after the effects of age and gender were taken into account. Six of the 14 APOE-epsilon 4 subjects who completed annual follow-up evaluations developed either DAT or questionable DAT, whereas none of the 26 non-epsilon 4 subjects who received follow-up demonstrated any cognitive decline. CONCLUSIONS: Results suggest that episodic memory changes in older adults are associated with APOE-epsilon 4 allele; sensitive cognitive markers such as those of the CVLT may precede the subsequent development of DAT.

Decline in working memory associated with HIV infection. HNRC Group.

HIV infection has been associated with decline in a number of cognitive functions that are components of 'working memory'. Thus, tests of working memory that require the interaction of these components may be particularly sensitive to cognitive dysfunction that arises from HIV infection. To assess this possibility, working memory was examined in 147 HIV-seropositive (HIV+) and 38 HIV-seronegative (HIV-) males using the Reading Span Test and the Digit Span subtest from the Wechsler Memory Scale-Revised (WMS-R). Speed of information processing, a component of some working memory tasks, was assessed with a version of the Sternberg Memory Scanning task. Results indicated that symptomatic HIV+ subjects were impaired relative to HIV- control subjects on the Reading Span and Digit Span tests. Asymptomatic and mildly symptomatic HIV+ groups exhibited a trend toward impairment on these tests, and on the whole, a greater proportion of HIV+ subjects than HIV- subjects were impaired. The groups did not differ significantly in information processing speed. These results indicate that deficits in working memory are apparent in at least a subset of HIV-infected individuals. These deficits are most apparent in symptomatic HIV+ individuals, but the decline may begin during the asymptomatic phase of infection.