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PubMed1985

A new generation of phosphodiesterase inhibitors: multiple molecular forms of phosphodiesterase and the potential for drug selectivity.

With several notable exceptions, interest in the area of multiple molecular forms of phosphodiesterase remained relatively dormant during the decade following Thompson's discovery of more than one phosphodiesterase in brain in 1971. Within the last several years, however, over 20 novel agents have been identified that exert selective inhibitory effects on the various molecular forms of phosphodiesterase present within different cells. In addition, several studies have documented that such agents can produce discrete changes in cyclic AMP and cyclic GMP, an action that is not shared by "first generation" phosphodiesterase inhibitors such as theophylline. The purpose of this Perspective is to provide some clarity to this rapidly evolving area of selective phosphodiesterase inhibitors. Thus, we have attempted to characterize the different forms of phosphodiesterase present in various tissues and cells according to their kinetic properties, substrate specificity, etc. and also to characterize those major classes of agents that have been shown to inhibit phosphodiesterase activity, whether selectively or nonselectively. In addition, we have described several therapeutic areas wherein selective phosphodiesterase inhibitors might prove efficacious, paying particular attention to those areas in which selective phosphodiesterase inhibitors have already been shown to exert beneficial effects, namely, stimulation of myocardial contractility, inhibition of mediator release, and inhibition of platelet aggregation. Although focusing on these three areas, it is obvious that the potential therapeutic utility of selective phosphodiesterase inhibitors could conceivably extend to several other areas in which modulation of cyclic nucleotides can have desirable effects, including cancer chemotherapy, analgesia, the treatment of depression, Parkinson's disease, and learning and memory disorders. For example, the selective type III phosphodiesterase inhibitor rolipram has been shown to antagonize reserpine-induced hypothermia and also to potentiate yohimbine lethality, two tests that are indicative of antidepressant activity. In addition, microinjection of the selective PDE III inhibitor Ro 20-1724 into the rat brain stem has been shown to produce analgesia.(ABSTRACT TRUNCATED AT 400 WORDS)

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMedDate not supplied

Memory impairment in Parkinson's disease.

A total of 52 patients with Parkinson's disease (PD), 11 with presumptive Alzheimer's disease (AD), and 20 healthy subjects were studied; subjects were aged 55-74 years. Neurological symptoms were assessed quantitatively, and the state of higher mental processes were evaluated using the Luriya method. A number of memory tests were also used. These studies showed that PD was almost always accompanied by memory impairment exceeding the age norm. The major mechanism for memory impairment in PD without dementia was inadequate independent organization of memory-related activity at the memorizing and retrieval stages. In PD with dementia, there was also a primary impairment. Differences in memory impairments were found in PD with dementia (deeper derangements of involuntary memory and of information processing during memorizing). Impairments of consolidation of traces were more dependent on the age at onset of PD, while inadequacy of independent organization of memory-related activity was more dependent on disease duration. Most memory parameters in PD correlated with the severity of disturbances in gait and postural reflexes. It is suggested that memory impairment in PD is a manifestation of the major pathological process, which shows a number of differences from other neurogeriatric diseases.

Adult↗
PubMed2003

Amnestic behavior in dementia: symptoms to assist in early detection and diagnosis.

OBJECTIVES: This study evaluated two amnestic behavior changes (repetitive questioning and repetitive actions) to determine their utility in screening for early dementia. DESIGN: Patient data were collected through a retrospective chart review. Comparison data from nondemented older people were collected prospectively from acquaintances of clinic patients. SETTING: The setting was a hospital-based outpatient memory disorder clinic. PARTICIPANTS: Participants were older individuals with no cognitive impairment (n = 25), undetermined dementia (n = 50), and definite dementia (n = 25). The undetermined cases were followed for at least 1 year to assess for conversion to dementia. MEASUREMENTS: Amnestic behaviors were assessed using informant-report for all participants. The behaviors were examined for their ability to distinguish between definite dementia cases and noncases. They were further evaluated for the ability to differentiate undetermined cases that eventually converted to definite dementia from cases that did not convert. RESULTS: Results indicated that repetitive behaviors were common in early and more-severe dementia cases. Repetitive behaviors were relatively uncommon in cognitively intact older participants. In analyses of the full study sample, engagement in repetitive behaviors had high sensitivity (0.97) in identifying dementia cases. CONCLUSIONS: Assessing repetitive behaviors in patients may be a useful means for family members and primary care physicians to screen for early cognitive impairment. The assessment can help to identify individuals that should be evaluated further for dementia.

Aged↗
PubMed1998

Reversible inactivation of the medial septum or nucleus basalis impairs working memory in rats: a dissociation of memory and performance.

Lidocaine-induced inactivation of the medial septum immediately after training or prior to testing in a delay radial-arm maze task produced deficits in spatial working memory that reflected impaired acquisition of the task. Injection of lidocaine into the nucleus basalis magnocellularis produced a profile of behavioral changes that indicated that temporary inactivation of this structure impaired the behavioral expression of information already stored in working memory. This appears to reflect an impairment in processes that are required for performance (i.e., attention, motivation, sensorimotor function) of the task but not for retrieval of stored information. Site-specific inactivation of the basal forebrain should help to reveal the involvement of its component structures in different aspects of cognitive function.

Analysis of Variance↗
PubMed1999

MRI morphometry of mamillary bodies, caudate nuclei, and prefrontal cortices after chemotherapy for childhood leukemia: multivariate models of early and late developing memory subsystems.

Neurotoxic intrathecal chemotherapy for childhood acute lymphoblastic leukemia (ALL) affects developing structures and functions of memory and learning subsystems selectively. Results show significant reductions in magnetic resonance imaging morphometry of mamillary bodies, components of the corticolimbic-diencephalic subsystem subserving functionally later developing, single-trial memory, nonsignificant changes in bilateral heads of the caudate nuclei, components of the corticostriatal subsystem subserving functionally earlier developing, multitrial learning, significant reductions in prefrontal cortical volume, visual and verbal single-trial memory deficits, and visuospatial, but not verbal, multitrial learning deficits. Multiple regression models provide evidence for partial dissociation and connectivity between the subsystems, and suggest that greater involvement of caudate may compensate for inefficient corticolimbic-diencephalic components.

Adolescent↗
PubMed1997

False recollection induced by photographs: a comparison of older and younger adults.

Looking at photographs constitutes an important everyday memory activity for older adults. The authors found that reviewing photographs of events seen earlier in a videotape increases the likelihood that both older and younger adults remember specific details from the reviewed event (W. Koutstaal, D. L. Schacter, M. K. Johnson, K. E. Angell, & M. S. Gross, 1977). In the present study, the authors report 2 experiments demonstrating that photo review can also produce false recollection in elderly adults: After reviewing photos of events that had not been shown earlier in a videotape, older but not younger adults were later more likely to "remember" that those events had been shown in the videotape. False recollection induced by photo review appears to reflect an age-related deficit in source-monitoring abilities.

Adolescent↗
PubMed2003

Converging evidence that stereotype threat reduces working memory capacity.

Although research has shown that priming negative stereotypes leads to lower performance among stigmatized individuals, little is understood about the cognitive mechanism that accounts for these effects. Three experiments tested the hypothesis that stereotype threat interferes with test performance because it reduces individuals' working memory capacity. Results show that priming self-relevant negative stereotypes reduces women's (Experiment 1) and Latinos' (Experiment 2) working memory capacity. The final study revealed that a reduction in working memory capacity mediates the effect of stereotype threat on women's math performance (Experiment 3). Implications for future research on stereotype threat and working memory are discussed.

Adult↗
PubMed2003

Olfactory learning and memory impairments following lesions to the hippocampus and perirhinal-entorhinal cortex.

The role of the hippocampus and perirhinal-entorhinal cortex was examined in an olfactory discrimination paradigm. Small neurotoxic lesions of the hippocampus (21% tissue damage) yielded relatively unimpaired olfactory retention across brief (30 s), intermediate (approximately 5 min), and 24-hr delays, whereas impairments were noted at 5-day retention intervals. Larger hippocampal lesions (63% tissue damage) spared memory at intermediate delays, with no impact at 8-day retention intervals. Aspiration lesions directed at the perirhinal-entorhinal cortex produced a variable performance pattern, with impairments noted at intermediate, 24-hr, and 5-day delays. Results suggest the hippocampus is not specifically involved in retaining olfactory information, with additional consideration given to the relationship between lesion size and memory impairment.

Animals↗
PubMed2005

Impairment in long-term retention but not short-term performance on a water maze reversal task following hippocampal or mediodorsal striatal N-methyl-D-aspartate receptor blockade.

Male Long-Evans rats were injected with 32 ng/mul of the N-methyl-D-aspartate (NMDA) receptor antagonist 3-(2-carboxypiperazin-4-yl) propyl-1-phosphonic acid (CPP) or vehicle and trained to locate a hidden platform in a different location (reversal training) than used on the initial 4 days of training. Rats treated with vehicle or CPP into the dorsal hippocampus, basolateral amygdala, or mediodorsal striatum had similar latencies to locate the platform on the reversal day. Rats infused with CPP into the dorsal hippocampus or mediodorsal striatum failed to search preferentially in the novel location during a 24-hr, drug-free retention test, whereas all other groups searched preferentially in this location. Therefore, blocking dorsal hippocampal or mediodorsal striatal NMDA receptors selectively blocked long-term spatial retention without producing short-term performance deficits.

Analysis of Variance↗
PubMed2006

Effective cue utilization reduces memory errors in older adults.

When compared with younger adults, older adults typically manifest poorer episodic memory. One hypothesis for the episodic memory deficit is that older adults may not encode contextual information as well as younger adults. Alternatively, older adults may use contextual information at retrieval less effectively when compared with younger adults. If older adults encode context less well than younger adults, then manipulations that affect context should have little effect on memory performance. To evaluate these 2 hypotheses, the authors used manipulations that promoted effective contextual cue utilization at retrieval. Retention interval and instructions at retrieval were manipulated within the imagination inflation paradigm. Results suggest that older adults encode contextual cues useful in improving memory performance but have difficulty accessing and using those cues.

Aged↗
PubMed2003

On the use of scaling and clustering in the study of semantic deficits.

In the past decade, several studies have used scaling and clustering techniques to document semantic storage deficits in patients with Alzheimer's disease and in schizophrenia. In this article the authors argued that many of the conclusions drawn from these studies are unjustified by the data. They reviewed the methodology used in these studies and presented data from simulation studies to further investigate the validity of their conclusions. The authors elaborate on the criteria needed to exclude alternative accounts of the data and present empirical data from patients with Alzheimer's disease and normal control participants to demonstrate that analyses of the patients' proximity data do not provide unambiguous evidence for a generalized semantic storage deficit.

Aged↗
PubMed2003

Things aren't as bad as they seem: a comment on Storms et al. (2003).

G. Storms, T. Dirikx, J. Saerens, S. Verstraeten, and P. P. De Deyn (2003) criticized the use of scaling techniques, in proposing "semantic storage deficits" in Alzheimer's disease and schizophrenic patients in some studies, arguing that most reported multidimensionalscaling (MDS) models for patients were not adequately fit and did not differ from models generated by random data. The studies cited by G. Storms et al. were reexamined and all available data relevant to their claim were compared. A more complete review revealed somewhat different conclusions; it showed that many of the MDS models seem to meet the criteria of adequate fit, and it does not seem to support the notion that patients' performance is close to random. Suggestions are made to improve the validity of scaling analysis in neuropsychological studies.

Alzheimer Disease↗
PubMed2003

Structure versus processing deficits in Alzheimer's disease, a matter of degree: a comment on Storms et al. (2003).

G. Storms, T. Dirikx, J. Saerens, S. Verstraeten, and P. P. De Deyn (2003) argued that multidimensional scaling studies are ill-suited for investigating semantic deficits in individuals diagnosed with dementia of the Alzheimer type (DAT) because such individuals show great inter- and intraindividual variability in their proximity judgments. Discussed in this commentary are (a) the possible role of attentional set in producing inconsistent performance across trials, (b) the implications of attentional factors on the structure versus process debate, and (c) the inevitable semantic degradation following severe progression of the disease. A framework is presented for considering nonlinear performance differences as a function of attentional demands of the task, vulnerability of the semantic representation, and progression of the disease.

Alzheimer Disease↗
PubMed2003

Taking the thumbs off the multidimensional scales in the debate on semantic memory and Alzheimer's disease: a comment on Storms et al. (2003).

G. Storms, T. Dirikx, J. Saerens, S. Verstraeten, and P. P. De Deyn (2003) bring into focus at least 3 important issues. First, the performance of even simple tasks may be affected by several basic cognitive processes. Second, the statistical variance that these processes contribute to task performance may be different for a group of participants with neuropsychological deficits than for normal control particpants. Third, claims regarding the nature of semantic memory in Alzheimer's disease (AD) reflect indeterminacy about the nature and assessment of semantic memory itself. Critically, their analysis suggests that the T. Shallice and E. K. Warrington (1979) criteria widely used to operationalize the semantic memory deficit in AD be carefully scrutinized and reevaluated.

Alzheimer Disease↗
PubMed2005

Failing to get the gist: reduced false recognition of semantic associates in semantic dementia.

In 2 experiments involving patients with semantic dementia, the authors investigated the impact of semantic memory loss on both true and false recognition. Experiment 1 involved recognition memory for categories of everyday objects that shared a predominantly semantic relationship. The patients showed preserved item-specific recollection for the pictorial stimuli but, compared with control participants, exhibited significantly reduced utilization of gist information regarding the categories of objects. The latter result is consistent with the patients' degraded semantic knowledge. Experiment 2 involved categories of abstract objects that were related to one another perceptually rather than semantically. Patients with semantic dementia obtained item-specific recollection and gist memory scores that were indistinguishable from those of control participants. These results suggest that the reduction in gist memory in semantic dementia is largely specific to semantic representations and cannot be attributed to general difficulty with abstracting and/or utilizing gistlike commonalities between stimuli.

Aged↗
PubMed2001

A requirement for the immediate early gene Zif268 in the expression of late LTP and long-term memories.

The induction of long-term potentiation (LTP) in the dentate gyrus of the hippocampus is associated with a rapid and robust transcription of the immediate early gene Zif268. We used a mutant mouse with a targeted disruption of Zif268 to ask whether this gene, which encodes a zinc finger transcription factor, is required for the maintenance of late LTP and for the expression of long-term memory. We show that whereas mutant mice exhibit early LTP in the dentate gyrus, late LTP is absent when measured 24 and 48 hours after tetanus in the freely moving animal. In both spatial and non-spatial learning tasks, short-term memory remained intact, whereas performance was impaired in tests requiring long-term memory. Thus, Zif268 is essential for the transition from short- to long-term synaptic plasticity and for the expression of long-term memories.

Anesthetics↗
PubMed2005

Restoration of spatial working memory by genetic rescue of GluR-A-deficient mice.

Gene-targeted mice lacking the AMPA receptor subunit GluR-A (also called GluR1 encoded by the gene Gria1,) have deficits in hippocampal CA3-CA1 long-term potentiation (LTP) and have profoundly impaired hippocampus-dependent spatial working memory (SWM) tasks, although their spatial reference memory remains normal. Here we show that forebrain-localized expression of GFP-tagged GluR-A subunits in GluR-A-deficient mice rescues SWM, paralleling its rescue of CA3-CA1 LTP. This provides powerful new evidence linking hippocampal GluR-A-dependent synaptic plasticity to rapid, flexible memory processing.

Analysis of Variance↗