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PubMed2005

Hippocampal infusions of pyruvate reverse the memory-impairing effects of septal muscimol infusions.

Hippocampal infusions of glucose reverse memory deficits in spontaneous alternation and in a continuous multiple trial inhibitory avoidance task. The current experiments tested whether glucose metabolism may participate in these effects of glucose. Specifically, these experiments determined whether the glycolytic metabolite pyruvate would mimic these effects of glucose. Male Sprague-Dawley rats were given septal infusions of vehicle or the gamma-aminobutyric acid (GABA) receptor agonist muscimol (0.15 nmol for spontaneous alternation or 5 nmol for continuous multiple trial inhibitory avoidance) combined with hippocampal infusions of vehicle or pyruvate (200 nmol) 15 min prior to assessing spontaneous alternation or training in a continuous multiple trial inhibitory avoidance task. The infusions of muscimol decreased percent alternation scores and continuous multiple trial inhibitory avoidance retention latencies tested 48 h after training. More importantly, hippocampal infusions of pyruvate reversed the deficits produced by septal infusions of muscimol on both tasks. These findings show for the first time that hippocampal infusions of pyruvate influence memory and suggest that glucose may affect memory via glycolytic metabolism.

Animals↗

PubMed2005

Reversal of age-related deficits in object recognition memory in rats with l-deprenyl.

The monoamine-oxidase-B (MAO-B) inhibitor l-deprenyl (selegiline) is effective in treating Parkinson's disease and possibly cognitive deficits associated with aging, Alzheimer's disease and HIV dementia. The aim of the present study was to investigate the effects of l-deprenyl on short- and long-term recognition memory in aged rats. Young adult and aged male Wistar rats were trained in a novel object recognition task. Retention test trials were carried out at 1.5 or 24 h after training. Aged rats showed impaired recognition memory retention 24 h after training when compared to young animals. Treatment with a daily systemic injection of l-deprenyl (1.0 mg/kg) for 21 days reversed the memory impairment. A control experiment indicated that l-deprenyl did not affect sensorimotor functions. The results suggest that l-deprenyl reverses age-related deficits in long-term recognition memory.

Aging↗

PubMed2006

Sensitivity and specificity of the Clock Drawing Test, incorporating Rouleau scoring system, as a screening instrument for questionable and mild dementia: scale development.

OBJECTIVE: The objective of this study was to validate the Rouleau scoring system for the Clock Drawing Test (CDT) in northern Taiwan, a non-English speaking area, to increase its generalization by detecting subjects with questionable dementia (QD) from normal controls (NC) and subjects with mild dementia (AD). The system consists of two parts: a 10-point scoring and error types. A cross-sectional design was used. One hundred and sixteen subjects were recruited from a memory disorder clinic (n=40 NC; n=34 QD; n=42 AD). Reliability and validity were estimated, the predictive accuracy was calculated using the receiver operating characteristic (ROC) curve analysis, and the error types were counted. RESULTS: The results indicated that most of the error types committed were conceptual deficiencies and graphic difficulties; more errors were found in the command condition (CDT-command) than in the copy condition (CDT-copy); 15% of the subjects drew smaller clock circles in CDT-command, which did not relate to any other errors. No small clock was found in CDT-copy because a pre-dawn circle was provided. The inter-rater reliability of the Rouleau scoring system was .87 and .83 for the CDT-command and -copy, respectively, while the discriminate accuracy of the scoring system was relatively low in detecting QD vs. NC, QD vs. AD, but somewhat better in distinguishing AD vs. NC groups for the areas under the ROC curves was equal to .72 for the CDT-command, and .73 for the CDT-copy. Visuospatial construction and executive functioning explained the largest score variance of the CDT in both conditions, while depressive symptoms were not significantly associated with the CDT performance. CONCLUSION: The CDT using the Rouleau scoring system has been validated in mild AD subjects in Taiwan; however, to screen for QD sufferers, alternative scoring systems emphasizing hands or combining CDT with different neuropsychological tests such as the Clinical Abilities Screening Instrument are recommended.

Aged↗

PubMed2005

A quantitative and qualitative assessment of verbal short-term memory and phonological processing in 8-year-olds with a history of repetitive otitis media.

UNLABELLED: Language outcome in children experiencing fluctuant hearing loss due to otitis media (OME) remains highly equivocal. In the current study, we assessed performance on highly sensitive verbal short-term memory (STM), new word learning and phonological processing tasks in 8-year-old children who had suffered from recurrent OME before the age of 3. Relative to a control group with no history of OME, we observed strictly normal performance for different STM and new word learning tasks. Performance on these tasks was also normally influenced by phonotactic, lexical and semantic variables. However, at the level of phonological processing, a small but significant decrease of performance was found in a speeded nonword identification task and a rhyme judgment task. The results of this study suggest that outcome of OME is characterized by subtle impairments at the level of perceptual-phonological analysis, but there is no significant impact on verbal STM and new word learning abilities. LEARNING OUTCOMES: As a result of this activity, the participant will be able to (1) explain the outcome of recurrent OME before age 3 on later language and verbal STM development, (2) be aware of the complex relationships that link language development and verbal STM, (3) explain how fluctuant hearing loss during infancy and early childhood could affect verbal STM development and learning capacity for new phonological information, (4) describe different verbal STM measures that distinguish retention capacities for phonological and lexico-semantic information, and (5) explain the influence of phonotactic frequency on nonword processing in language and verbal STM tasks.

Child↗

PubMed2005

Impaired verbal short-term memory in Down syndrome reflects a capacity limitation rather than atypically rapid forgetting.

Individuals with Down syndrome suffer from relatively poor verbal short-term memory. Recent work has indicated that this deficit is not caused by problems of audition, speech, or articulatory rehearsal within the phonological loop component of Baddeley and Hitch's working memory model. Given this, two experiments were conducted to investigate whether abnormally rapid decay underlies the deficit. In a first experiment, we attempted to vary the time available for decay using a modified serial recall procedure that had both verbal and visuospatial conditions. No evidence was found to suggest that forgetting is abnormally rapid in phonological memory in Down syndrome, but a selective phonological memory deficit was indicated. A second experiment further investigated possible problems of decay in phonological memory, restricted to item information. The results indicated that individuals with Down syndrome do not show atypically rapid item forgetting from phonological memory but may have a limited-capacity verbal short-term memory system.

Adult↗

PubMed2006

Working memory deficit in children with mathematical difficulties: a general or specific deficit?

This study examined whether children with mathematical difficulties (MDs) or comorbid mathematical and reading difficulties have a working memory deficit and whether the hypothesized working memory deficit includes the whole working memory system or only specific components. In the study, 31 10-year-olds with MDs and 37 10-year-olds with both mathematical and reading difficulties were compared with 47 age-matched and 50 younger controls (9-year-olds) on a number of working memory tasks. Compared with the age-matched controls, both groups of children with MDs performed worse on tasks tapping the central executive (e.g., visual matrix span) and the phonological loop (e.g., word span). More important, the MD group performed worse than the younger controls on the counting span task, whereas the group with comorbid mathematical and reading difficulties performed worse on the counting span task and the visual matrix span task. These findings provide support for the assumption that children with MDs have a working memory deficit. More specifically, children with MDs have a central executive deficit connected to concurrent processing and storage of numerical and visual information.

Child↗

PubMed2006

Absence of the apolipoprotein E epsilon4 allele is associated with working memory impairment in Parkinson's disease.

The apolipoprotein E (APOE) epsilon4 allele has been associated with an increased risk of Alzheimer's disease (AD) and weaker episodic memory among elderly. Although this APOE allele has been linked to earlier onset of Parkinson's disease (PD), an association with dementia in PD has been only inconsistently demonstrated. Given the heterogeneity of cognitive impairment patterns in PD, this study sought to determine whether an association exists between APOE genotype and specific cognitive deficits in PD. The neuropsychological test performance of 42 PD patients without an epsilon4 allele (PD-Non4) and of 20 with at least one epsilon4 allele (PD-epsilon4) was compared to that of 146 elderly control subjects (NC). The PD groups were comparable in overall severity of cognitive impairment and disease duration, but the PD-epsilon4 group was younger, had an earlier disease onset, and contained a higher proportion of persons with dementia. Both PD groups showed wide-ranging cognitive impairments relative to NC. Once age differences between groups were controlled for, the PD groups generally did not differ from each other in cognitive performance. However, only the PD-Non4 group demonstrated working memory/attention impairments (digit span, visual span, Trailmaking test) relative to the NC group. Results suggest that the APOE genotype may influence the cognitive phenotype of PD, and specifically that absence of the epsilon4 allele is associated with working memory impairment. Additionally, results are consistent with prior findings showing an association between the epsilon4 allele and earlier onset of PD and presence of dementia.

Aged↗

PubMed2004

What is the risk of distress in palliative care survey research?

To determine whether caregivers believe that interviews about end-of-life care are distressing and to identify patient and respondent characteristics associated with an increased risk of distress, distress was assessed in four studies that used family interviews. The setting was four Medicare certified hospice organizations, the University of Pennsylvania Memory Disorders Clinic, and two nursing homes, and participants included 296 family members of seriously ill or recently deceased patients. For three of the studies, respondents described their distress on a 5-point scale. Distress was reported as either present or absent in the fourth study. Sixty-four respondents (22%) reported experiencing distress. Intensity of distress was higher for younger respondents (Spearman rho -0.16; P=0.013), younger patients (Spearman rho -0.28; P < 0.001), and family members of patients with cancer (mean 0.55 vs. 0.24; Rank sum test P < 0.001). In a multivariable model, after adjusting for study population, younger patient age and cancer diagnosis were independently associated with the severity of distress. Sensitive questions about death and dying are unlikely to cause distress for family members. Although the likelihood of distress is low overall, investigators recruiting from these populations may improve the research by incorporating methods to assess and manage distress.

Aged↗

PubMed2005

High-cholesterol diets impair short-term retention of memory in alloxan-induced diabetic mice, but not acquisition of memory nor retention of memory in prediabetic mice.

Whether high-cholesterol diets (HCD) induce a high incidence of memory deficits in diabetes requires to be established; if so, whether they induce impairments of memory acquired in the pre-diabetic stage as well as in the diabetic stage also needs to be elucidated, and part of the related mechanisms involved in this dysfunction should be determined. The mice were grouped into: normal mice fed normal diets (NN), diabetic mice fed normal diets (DN), normal mice fed HCD (NH), and diabetic mice fed HCD (DH). Animals were subjected to Morris water maze testing: 1) Learning in the pre-diabetic stage and memory retrieval in the diabetic stage; 2) Learning and memory retrieval in the diabetic stage. Following water maze testing, biochemical parameters were estimated in the animals. The results showed that significant impairments of memory retrieval, acquired in the diabetic stage, were observed only in DH group, neither in DN nor NH group in a short term compared with NN group. Biochemical parameters including fasting blood glucose, lipid peroxidation productions and acetylcholinesterase activities in frontal cortex and hippocampus increased more rapidly in DH group than those in the rest. These results indicate that HCD impair the diabetic retention of memory, but neither the diabetic acquisition of memory nor the pre-diabetic retention of memory in diabetic mice in a short term. Controlled HCD may be a strategy to prevent the loss of memory in diabetic individuals after they have acquired new information.

Acetylcholinesterase↗

PubMed2004

Nitrous oxide impairs selective stages of working memory in rats.

Working memory impairment under narcosis has never been investigated. Furthermore, mechanisms by which narcosis disturbs working memory processes remain relatively unknown. The present work was aimed at answering to these two questions using a well-known normobaric narcotic gas, nitrous oxide (N2O), and a classical working memory task (a two-trial recognition memory task). Ten Long-Evans rats were tested in this behavioral task under nitrous oxide exposure. The results showed (i) a dose-related impairment of working memory, (ii) a selective effect of N2O on two out of three mnemonic processes: acquisition, and retention, and (iii) a compensatory effect of increasing the acquisition phase duration on these impairments. These results, as previously suggested for long-term memory, agree with the fact that nitrous oxide disrupts in a dose-related manner working memory by notably slowing down acquisition processes.

Analgesics, Non-Narcotic↗

PubMed2005

Chronic intracerebroventricular NGF administration improves working memory in young adult memory deficient rats.

Although the beneficial effects of nerve growth factor (NGF) in age-related memory deficits are well documented, the therapeutic role of this neurotrophin in memory deficits occurring in young subjects remains unclear. In the present study, the effect of chronic NGF administration on spatial working memory was investigated in young adult memory deficient Wistar rats. Memory deficient rats were selected on the basis of their preoperative performance in delayed matching-to-position task (DMTP) carried out in the eight-arm radial maze. The delay between sample and test choices was prolonged stepwise from 10s, to 1, 5, and eventually 15 min. Rats that performance at the longest 15-min delay was at least 3 S.E.M. above the group mean were classified as "poor learners". They were randomly assigned to either Control or NGF group, and treated with either vehicle solution (artificial cerebrospinal fluid) or NGF at the total dose of 40 microg/rat. Intracerebroventricular (icv) drug infusion was made continuously over 28 days at the rate of 0.25 microl/h using Alzet 2004 osmotic mini-pump. The postoperative training included the same stages as the preoperative one. No significant between-group difference in the postoperative performance was noted at the shortest delay of 10s that could be bridged by the immediate memory. Conversely, at all three longer delays, postoperative performance in the NGF group was significantly better compared to control rats. The present study thus shows that NGF may have beneficial effects in memory-deficient young adults.

Animals↗

PubMed2005

The cyclooxygenase 2 -765 C promoter allele is a protective factor for Alzheimer's disease.

The cyclooxygenase-2 enzyme (COX-2) is of particular importance in the inflammatory response and recent findings have demonstrated a considerable role in Alzheimer's disease (AD) pathogenesis. In order to assess the possible putative role of a COX-2 polymorphism (765G/C) in AD, we examined its distribution in 161 community-based controls and 168 AD clinic-based cases previously recruited from memory disorder clinics in Tampa and Miami, Florida. There were no significant differences between the two groups in age/age of onset or gender. A significant difference was observed in the distribution of the COX-2 -765 alleles between AD cases and controls (chi(2) = 6.565, p = .010; OR = .596; CI = [.401-.888], p = .011), with the frequency of the C allele being higher in controls. In addition, a significant difference was observed for this polymorphism by genotype (chi(2) = 6.561, p = .038) and by presence or absence of C+ genotypes (chi(2) = 6.207, p = .013; OR = .464, CI = [.351-.885], p = .013). In this sample, the C allele of COX-2 -765 promoter polymorphism is associated with decreased risk of Alzheimer's disease, a finding which further supports the involvement of COX-2 in AD etiology.

Age of Onset↗

PubMed2006

APP23 mice display working memory impairment in the plus-shaped water maze.

Alzheimer's disease (AD) patients typically present short-term memory deficits, before long-term memory capacity declines with disease progression. Several studies have described learning and memory deficits in the APP23 mouse model. Our group reported a decline of learning and memory capacities from the age of 3 months onwards using a hidden-platform Morris water maze (MWM). The aim of the present study was to evaluate working and reference memory in APP23 mice in the same plus-shaped water maze. The transgenic mice had slower learning curves; however, consolidation of the learned information appeared intact in this learning paradigm. This report demonstrates impairment of working memory in this transgenic Alzheimer model.

Amyloid beta-Protein Precursor↗

PubMed2006

Analysis of sensitivity to MK-801 treatment in a novel active allothetic place avoidance task and in the working memory version of the Morris water maze reveals differences between Long-Evans and Wistar rats.

The aims of the present study were to compare the effect of subchronic administration of MK-801 on performance in the active allothetic place avoidance (AAPA) task and in the working version of Morris water maze (MWM) in Long-Evans and Wistar rats. Animals were trained for four daily sessions either in the AAPA or in the working memory version of the MWM. Wistar rats treated by MK-801 (0.1 mg/kg) showed a cognitive deficit in the AAPA task without a significant hyperlocomotion, whereas they were not impaired in the working memory version of the MWM compared to controls. Long-Evans rats treated by MK-801 (0.1 mg/kg) were not impaired either in the AAPA task or in the MWM task. Higher doses of MK-801 (0.2 and 0.3 mg/kg) produced hyperlocomotion in both strains which corresponded to an inability to solve both spatial tasks. Long-Evans rats were superior in the MWM to the Wistar rats in the groups treated with the low dose of MK-801. In conclusion, intact Wistar rats can efficiently solve both spatial tasks; however, they are more sensitive to MK-801-induced behavioural deficit. This has relevance for modeling of the schizophrenia-related deficits and for screening substances for their therapeutic potential.

Animals↗

PubMed2004

Within-subject memory decline in middle-aged rats: effects of intraseptal tacrine.

A longitudinal design was used to examine spatial working memory performance in aging Long-Evans rats on a 12-arm, delayed-non-match-to-sample radial maze task. Compared to performance at 12-13 months of age, the same rats exhibited a significant performance deficit at 15-16 months of age across all retention intervals (1.5-10h). All rats exhibited some degree of decline, and no rat performed as well as they had 3 months earlier. This early onset deficit may relate to the degree of difficulty required to perform accurately in a task that maximizes both spatial information processing and flexible working memory representations. Following our observation, rats were implanted with a chronic cannula aimed at the medial septal nucleus. Acute intraseptal tacrine treatments (0.0-25 micrograms/0.5 microl) did not significantly affect any index of performance. Rats exhibited further memory decline over the course of testing (up to 20 months of age). Detection of early onset dysfunction could allow for experimental analysis of underlying mechanisms and therapeutic strategies early in the course of age-related changes.

Acetylcholine↗

PubMed2006

GRK5 deficiency leads to early Alzheimer-like pathology and working memory impairment.

G-protein coupled receptor kinase-5 (GRK5) deficiency has been linked to early Alzheimer's disease in humans and mouse models of the disease. To determine potential roles of GRK5 in the disease pathogenesis, the GRK5 knockout mouse was evaluated at pathological and behavioral levels. We found that these mice displayed an age-dependent increase in hippocampal axonal defects characterized by clusters of axonal swellings that accumulated abnormal amounts of molecular motor proteins, microtubule-associated proteins, intracellular beta-amyloid, and subcellular organelles. In severe cases, extracellular beta-amyloid fibrillar deposits were occasionally observed, along with degenerating axonal components, and were tightly surrounded by reactive astrocytes. Moreover, significant loss of synaptic proteins and early signs of cholinoceptive neurodegeneration were evident in the hippocampus as well. Consistent with the moderate level of pathologic change, aged GRK5 knockout mice displayed selective working memory impairment, with other cognitive domains unaffected. Taken together, these findings not only strongly support an important role of GRK5 deficiency in early Alzheimer's pathogenesis, but also promote the GRK5 knockout mouse as an additional model for early Alzheimer-related studies.

Alzheimer Disease↗

PubMed2003

Cerebral localization, then and now.

We review some of the progress made in understanding the nature of functional specialization in the human brain, beginning with the anatomical claim that all mental faculties have their own distinct material substrate in different regions of the brain and the psychological claim that each mental faculty is characterized by the content domain with which it deals. This conceptual framework led behavioral neurologists to show how discrete brain lesions provoked different types of language, praxic, gnostic, spatial, and memory disorders. The simplest way of interpreting these anatomoclinical associations was to conjecture that the normal function (now impaired by brain damage) was localized within that lesioned region. It was also realized that cognitive impairments could arise from lesions that spared the functional centers themselves but disconnected them from other centers. Nonetheless, many neuroscientists remained skeptical of the entire paradigm. Accordingly, in the late 19th century functional localization began to be studied in the intact human brain by such techniques as measuring the temperature of different brain regions when different cognitive tasks were performed. During the 20th century these crude techniques gave way to positron emission tomography, functional magnetic resonance imaging, and magnetoencephalography. The relatively precise spatial and temporal resolution of modern methods now raises a crucial question: Do the functional localizations obtained by the anatomoclinical method converge with those implied by the functional neuroimaging of cognition in healthy volunteers? We then conclude with some recent suggestions that functional specialization is not such a fixed property of brain regions as previously supposed.

Brain↗

PubMed2004

Verbal episodic memory impairment in Alzheimer's disease: a combined structural and functional MRI study.

Anatomical and functional MRI images were acquired in a group of healthy elderly subjects (n = 11) and a group of patients diagnosed with probable Alzheimer's disease, from mild to moderate severity (n = 8). During functional sessions, verbal episodic Encoding and Recognition tasks were presented to subjects. Both groups were compared in terms of gray matter volume and cerebral activation. Furthermore, in the AD group, correlations between hippocampal gray matter volume and whole-brain activations were examined. When compared to healthy controls, AD patients presented significant gray matter atrophy as well as reduced activations during Encoding and Recognition in the medial temporal lobes and inferior parietal/superior temporal associative areas. In the same regions, the fMRI activity elicited by the Recognition task was positively correlated with hippocampal gray matter volume. Moreover, an increase of left prefrontal activity during Encoding and Recognition was observed in AD patients relative to controls and was correlated with memory performance. This additional activity elicited by episodic memory processes was not found to correlate with the degree of medial temporal atrophy in our group of patients. Our study shows that function in brain regions critical to episodic memory is altered in AD. During episodic Recognition, these functional changes may closely correlate with the progressive structural changes observed in the hippocampal region.

Aged↗